How water moves through leaves, and where the phase change from liquid to vapour occurs within leaves, remain largely mysterious. Some time ago we suggested that the stable isotope composition of leaf water may contain information on transport pathways beyond the xylem, through differences in the development of gradients in enrichment within the various pathways. Subsequent testing of this suggestion provided ambiguous results, and even questioned the existence of gradients in enrichment within the mesophyll. In this review we bring together recent theoretical developments in understanding leaf water transport pathways and stable isotope theory to map a path for future work into understanding pathways of water transport and leaf water stable isotope composition. We emphasize the need for a spatially, anatomically and isotopically explicit model of leaf water transport.
Aquaporins are channel proteins that function to increase the permeability of biological membranes. In plants, aquaporins are encoded by multigene families that have undergone substantial diversification in land plants. The plasma membrane intrinsic proteins (PIPs) subfamily of aquaporins is of particular interest given their potential to improve plant water relations and photosynthesis. Flowering plants have between 7 and 28 PIP genes. Their expression varies with tissue and cell type, through development and in response to a variety of factors, contributing to the dynamic and tissue specific control of permeability. There are a growing number of PIPs shown to act as water channels, but those altering membrane permeability to CO2 are more limited. The structural basis for selective substrate specificities has not yet been resolved, although a few key amino acid positions have been identified. Several regions important for dimerization, gating and trafficking are also known. PIP aquaporins assemble as tetramers and their properties depend on the monomeric composition. PIPs control water flux into and out of veins and stomatal guard cells and also increase membrane permeability to CO2 in mesophyll and stomatal guard cells. The latter increases the effectiveness of Rubisco and can potentially influence transpiration efficiency.
We propose a novel developmentally informed framework to push research beyond a focus on comorbidity between discrete diagnostic categories and to move toward research based on the well-validated dimensional and hierarchical structure of psychopathology. For example, a large body of research speaks to the validity and utility of the internalizing and externalizing spectra as organizing constructs for research on common forms of psychopathology. The internalizing and externalizing spectra act as powerful explanatory variables that channel the psychopathological effects of genetic and environmental risk factors, predict adaptive functioning, and account for the likelihood of disorder-level manifestations of psychopathology. As such, our proposed theoretical framework uses the internalizing and externalizing spectra as central constructs to guide future psychopathology research across the life span. The framework is particularly flexible, because any of the facets or factors from the dimensional and hierarchical structure of psychopathology can form the focus of research. We describe the utility and strengths of this framework for developmental psychopathology in particular and explore avenues for future research.
Individuals exposed to natural disasters are at risk for negative physical and psychological outcomes. Older adults may be particularly vulnerable; however, social support can act as a resource to help individuals respond to severe stressors. This study explored the challenges older people faced before, during, and after Hurricane Sandy in October 2012 and the people they turned to for support.
Semi-structured interviews were conducted with 20 older adults in New Jersey drawn from the ORANJ BOWL (Ongoing Research on Aging in New Jersey - Bettering Opportunities for Wellness in Life) research panel, who experienced high levels of primary home damage during Hurricane Sandy. Content analysis of interview transcripts classified older adults' perceptions on how they "made it" through-the challenges they faced and the support they received.
The findings suggested that older adults experienced emotional, instrumental, social, and financial challenges before, during, and after the storm. However, by relying on family and friends, as well as neighbors and community networks, older people were able to respond to stressors.
Our findings carry implications for ensuring that older adults are connected to social networks before, during, and after disasters. The role of neighbors is particularly important when disasters strike. (Disaster Med Public Health Preparedness. 2016;page 1 of 9).
A comprehensive investigation of the complementary H-bonding-mediated self-assembly between dipyrrolo[2,3-b:3',2'-e]pyridine (P2P) electron donors and naphthalenediimide/perylenediimide (NDI/PDI) acceptors is reported. The synthesis of parent P2P and several aryl-substituted derivatives is described, along with their optical, redox, and single-crystal packing characteristics. The dual functionality of heteroatoms in the P2P/NDI(PDI) assembly, which act as proton donors/acceptors and also contribute to π-conjugation, leads to H-bonding-induced perturbation of electronic levels. Concentration-dependent NMR and UV/Vis spectroscopic studies revealed a cooperative effect of H-bonding and π-π stacking interactions. This H-bonding-mediated co-assembly of donor (D) and acceptor (A) components leads to a new charge-transfer (CT) absorption that can be controlled throughout the visible range. The electronic interactions between D and A were further investigated by time-dependent DFT, which provided insights into the nature of the CT transition. Electropolymerization of difuryl-P2P afforded the first conjugated polymer incorporating H-bonding recognition units in its main chain.
Artificial photosynthesis-reduction of CO2 into chemicals and fuels with water oxidation in the presence of sunlight as the energy source-mimics natural photosynthesis in green plants, and is considered to have a significant part to play in future energy supply and protection of our environment. The high quantum efficiency and easy manipulation of heterogeneous molecular photosystems based on metal complexes enables them to act as promising platforms to achieve efficient conversion of solar energy. This Review describes recent developments in the heterogenization of such photocatalysts. The latest state-of-the-art approaches to overcome the drawbacks of low durability and inconvenient practical application in homogeneous molecular systems are presented. The coupling of photocatalytic CO2 reduction with water oxidation through molecular devices to mimic natural photosynthesis is also discussed.
Wide-angle X-ray scattering experiments and all-atomistic molecular dynamics calculations were performed to elucidate the detailed structure of bilayer vesicles constructed by self-assembly of an amphiphilic palladium NCN-pincer complex. We found an excellent agreement between the experimental and calculated X-ray spectra and between the membrane thickness determined from a TEM image and that calculated from an electron-density profile, indicating that the calculated structure was highly reliable. The analysis of the simulated bilayer structure showed that the membrane was softer than other phospholipid bilayer membranes in general. In this bilayer assemblage, the degree of alignment of complex molecules in the bilayer membrane was quite low. An analysis of the electron-density profile showed that the bilayer assemblage contains a space through which organic molecules can exit. Furthermore, the catalytically active center is near the space that is easily accessible by organic molecules, permitting the bilayer membrane to act as a nanoreactor. The free energy of permeation of water through the bilayer membrane of the amphiphilic complex was 12 kJ/mol, which is much lower than that for phospholipid bilayer membranes in general. Organic molecules are expected to pass though the bilayer membrane. The self-assembled vesicles were shown to be catalytically active in a Miyayra-Michael reaction in water.
An ongoing dispute in the nutrition field is whether dietary cholesterol contributes significantly to elevated serum cholesterol and to atherosclerotic disease. Carefully controlled metabolic studies have shown that high-cholesterol intakes cause moderate increases in serum cholesterol levels. It is been difficult to verify this in population studies because of confounding factors. Nonetheless, meta-analysis of controlled studies documents a cholesterol-raising action of dietary cholesterol. Most of this effect occurs in low-density lipoproteins (LDLs), but the cholesterol content of other lipoproteins can be increased as well. Moreover, population studies strongly suggest that dietary cholesterol is atherogenic beyond any rise in LDL concentrations. It must be emphasized that dietary cholesterol is only one of several dietary factors influencing serum cholesterol levels. Others include saturated fatty acids, trans fatty acids, soluble fiber, and total caloric intake. To achieve substantial serum cholesterol lowering, favorable changes in all of these factors must be combined. To maximize cardiovascular risk reduction, a lifetime of a healthy diet is needed. Reduced cholesterol intake is only one of several factors required to achieve such a diet. In addition, reduction of cholesterol absorption can enhance serum cholesterol lowering. This can be attained by the addition of plant sterols or plant stanols to the diet or by use of ezetimibe, a cholesterol absorption blocker. By combining dietary cholesterol
 reduction with other cholesterol-lowering modalities, it should be possible to substantially reduce atherosclerosis throughout life short of using cholesterol-lowering drugs that act systemically.
Monocytes of patients with ankylosing spondylitis (AS) have toll-like receptor 4 (TLR4) overexpression on their monocytes. Myeloid-related protein (MRP) 8/14 protein complexes are calcium-binding proteins, which act as endogenous ligands to TLR4. Thus, we studied the levels of MRP8/14 in adult AS patients. MRP8/14 levels were assessed in 99 adult AS patients satisfying Assessments in Ankylosing Spondylitis International Society 2010 criteria and 71 healthy controls by ELISA. Patient disease parameters like patient and physician global assessment, Bath Ankylosing Spondylitis Disease Activity Index (BASDAI), swollen and tender joint count, entheseal count by Maastricht enthesitis index, erythrocyte sedimentation rate (ESR), and C-reactive protein (CRP) were also recorded. Levels were reassessed in 23 patients after 2-5 months of treatment with NSAIDs. All values are in median (IQR). The serum MRP8/14 levels in patients [34.1 (17.94-264.58) μg/ml] were significantly higher than in healthy controls [4.94 (IQR 3.01-8.32) μg/ml (p < 0.0001)]. Patients with peripheral arthritis (n = 50) had higher levels than those with pure axial disease (n = 49) [40.63 (IQR 28.41-73.15) μg/ml vs. 23.72 (11.04-61.55) μg/ml; p = 0.012]. Levels of MRP8/14 correlated with AS Disease Activity Score (DAS)-CRP (r = 0.23, 95%CI = 0.038-0.422, p = 0.02) and CRP (r = 0.28, 95%CI = 0.081-0.45, p = 0.01), and the correlation was better in early disease [≤5 years disease duration; r = 0.40, p = 0.007 and r = 0.57, p = <0.0001, respectively]. Baseline levels were higher in treatment responders than in non-responders [51.17 vs. 32.22 μg/ml; p = 0.02]. Change in MRP8/14 levels correlated with change in BASDAI and ASDAS-CRP (r = 0.489, p = 0.018 and r = 0·498, p = 0.016, respectively). MRP8/14 levels may be used as a biomarker for activity, peripheral arthritis, and response to therapy.
The aim of the present study is to analyse complications after a floating elbow injury, attempting to establish which of them act as a poor prognosis factor regarding clinical and functional results.
Twenty-three patients who suffered a floating elbow injury, treated at our institution from 2004 to 2013, were retrospectively reviewed. Patients were divided into four groups depending on the type of injury. An analysis of demographic data, associated injuries, treatment options and complications was carried out. Clinical evaluation was made by a conventional goniometer, testing flexo-extension and prono-supination ranges. For functional evaluation, the Mayo Elbow Performance Score was employed. Association between radioulnar synostosis, articular surface disruption, nerve injury and clinical and functional results was analysed.
Patients with radioulnar synostosis had worse results in functional evaluation than patients without it (56.6 vs. 75); this difference was statistically significant (p = 0.05). Regarding intra-articular extension, we found statistical association with worse results in functional evaluation (p = 0.018); however, nerve palsy does not seem to influence functional results.
Radioulnar synostosis and intra-articular extension of the injury are poor prognosis factor in floating elbow.
Transient receptor potential family channels (TRPs) have been identified as relevant targets in many pharmacological as well as toxicological studies. TRP channels are ubiquitously expressed in different tissues and act among others as sensors for different external stimuli, such as mechanical stress or noxious impacts. Recent studies suggest that one member of this family, the transient receptor potential ankyrin 1 cation channel (TRPA1), is involved in pain, itch, and various diseases, suggesting TRPA1 as a potential therapeutic target. As a nociceptor, TRPA1 is mainly activated by noxious or electrophilic compounds, including alkylating substances. Previous studies already revealed an impact of 2-chloroethyl-ethyl sulfide on the ion channel TRPA1. In this study, we demonstrate that sulfur mustard (bis-(2-chloroethyl) sulfide, SM) activates the human TRPA1 (hTRPA1) in a dose-dependent manner measured by the increase in intracellular Ca(2+) concentration ([Ca(2+)]i). Besides that, SM-induced toxicity was attenuated by antioxidants. However, very little is known about the underlying mechanisms. Here, we demonstrate that N-acetyl-L-cysteine (NAC) prevents SM-induced hTRPA1-activation. HEK293-A1-E cells, overexpressing hTRPA1, show a distinct increase in [Ca(2+)]i immediately after SM exposure, whereas this increase is reduced in cells pretreated with NAC in a dose-dependent manner. Interestingly, glutathione, although being highly related to NAC, did not show an effect on hTRPA1 channel activity. Taken together, our results provide evidence that SM-dependent activation of hTRPA1 can be diminished by NAC treatment, suggesting a direct interaction of NAC and the hTRPA1 cation channel. Our previous studies already showed a correlation of hTRPA1-activation with cell damage after exposure to alkylating agents. Therefore, NAC might be a feasible approach mitigating hTRPA1-related dysregulations after exposure to SM.
Exertional heatstroke (EHS) is a life-threatening disease characterized clinically by central nervous system dysfunction and severe hyperthermia. It frequently occurs among athletes, soldiers, and laborers. While cardiopulmonary symptoms are common in patients undergoing EHS, irreversible acute liver failure is a rarely described phenomenon. When managing cases of EHS complicated by acute liver failure, it is crucial to act promptly with aggressive total body cooling in order to prevent progression of the clinical syndrome. However, an urgent liver transplantation can be a therapeutic strategy when patients fail to improve with supportive measures.
Molecular epidemiological research suggests that mouse double minute 4 (MDM4) polymorphisms may be associated with cancer susceptibility, but results remain controversial. To derive a more precise evaluation, we performed a PRISMA compliant meta-analysis focused on five single nucleotide polymorphisms (rs11801299, rs1380576, rs10900598, rs1563828, and rs4245739) of MDM4. Overall, 23 studies involving 22,218 cases and 55,033 controls were analyzed. The results showed that rs4245739 was significantly associated with a decreased cancer risk in the allelic (C vs. A: odds ratio [OR] = 0.848, 95% confidence interval [CI] = 0.765-0.941, P = 0.002 ), heterozygous (AC vs. AA: OR = 0.831, 95% CI = 0.735-0.939, P = 0.003), and dominant (AC+CC vs. A: OR = 0.823, 95% CI = 0.727-0.932, P = 0.002) models. The association was more prominent in Asians. No significant association was found using any genetic model for the rs11801299, rs1380576, rs10900598, and rs1563828 SNPs. These results indicate that the rs4245739 polymorphism may contribute to a decreased cancer susceptibility and support the hypothesis that genetic variants in the MDM4 genes act as important modifiers of cancer risk.
Immigrants have a negative health trajectory due to interactions between immigration policies and the totality of the immigration experience. Despite the enactment of the Patient Protection and Affordable Care Act in 2010, an association with the sociopolitical environment and its influence on chronic disease prevalence remains. The purpose of this review was to provide evidence for existing health disparities among immigrants based on ethnicity, immigration status, country of origin, duration in the United States. The sociopolitical environment affecting immigrant health and opportunities to change the course toward ameliorating health disparities is discussed.
Using PRISMA guidelines, the literature focused on immigrants, disease prevalence, health care access, and policy. Twenty-nine articles were selected for this review.
Chronic disease prevalence is associated with the restrictive immigration and health care policies among all immigrant groups.
Recent evidence and the current immigration debate signify an opportunity to explore strategies to improve health outcomes among immigrants.
Analysis of the effect of mental fatigue on a cognitive task and determination of the right start time for rest breaks in work environments.
Mental fatigue has been recognized as one of the most important factors influencing individual performance. Subjective and physiological measures are popular methods for analyzing fatigue, but they are restricted to physical experiments. Computational cognitive models are useful for predicting operator performance and can be used for analyzing fatigue in the design phase, particularly in industrial operations and inspections where cognitive tasks are frequent and the effects of mental fatigue are crucial.
A cyclic mental task is modeled by the ACT-R architecture, and the effect of mental fatigue on response time and error rate is studied. The task includes visual inspections in a production line or control workstation where an operator has to check products' conformity to specifications. Initially, simulated and experimental results are compared using correlation coefficients and paired t test statistics. After validation of the model, the effects are studied by human and simulated results, which are obtained by running 50-minute tests.
It is revealed that during the last 20 minutes of the tests, the response time increased by 20%, and during the last 12.5 minutes, the error rate increased by 7% on average.
The proper start time for the rest period can be identified by setting a limit on the error rate or response time.
The proposed model can be applied early in production planning to decrease the negative effects of mental fatigue by predicting
 the operator performance. It can also be used for determining the rest breaks in the design phase without an operator in the loop.
Mycoplasma gallisepticum causes coughing, ocular and nasal discharge, reduction in feed intake, lower and uneven growth, decline in egg production and quality, and increase in mortality. Among the attenuated vaccination strains, MGF can reduce clinical signs and lesions in layer hens, stimulate immune responses of cellular and humoral basis, act as an instrument of competitive exclusion in relation to field strains, and reduce the use of antimicrobials. This study aimed to investigate the effects of attenuated MG F-strain vaccination on egg quality in 3 groups of 30 hens each, being one control and 2 vaccinated. Vaccination was applied by ocular route at 8 and 12 wk of age. Comparisons were made among unvaccinated hens; vaccinated at 8 wk of age; and vaccinated at 8 and 12 wk of age. There were no statistical differences in eggshell thickness and weight among groups. Eggs from twice vaccinated birds yielded a Haugh unit significantly lower than the other groups without affecting egg classification. There was no significant difference in ELISA results between the vaccinated groups.
Mobile genetic elements in bacteria, such as plasmids, act as important vectors for the transfer of antibiotic resistance, virulence, and metal resistance genes. Here, we report the genome sequence of a new plasmid pLM-C-273, identified in a Listeria monocytogenes strain isolated from a clinical sample in Ontario, Canada.
There is evidence that elder abuse is a significant public health problem that is destined to grow as population age. Countries are considering how best to act and this requires an understanding of the complex causal mechanisms contributing to its occurrence and the identification of effective interventions which can potentially make a difference. Previously, a high quality synthesis of evidence for policy and practice has been missing. In this paper, we describe a new Cochrane review of interventions to prevent the occurrence or reoccurrence of elder abuse. Overall, the quality of the evidence available for decision making is very low and there is little to guide practice. Amongst the interventions, there is some evidence that teaching coping skills to family carers of persons with dementia might make the situation better. We argue that poor quality and wasteful research needs to be avoided, and front-line agencies be supported in undertaking comparative evaluation of their services.
This essay provides an ethical and conceptual argument for the use of informed consent prior to the diagnosis of brain death. It is meant to enable the family to make critical end-of-life decisions, particularly withdrawal of life support system and organ donation, before brain death is diagnosed, as opposed to the current practice of making such decisions after the diagnosis of death. The recent tragic case of a 13-year-old brain-dead patient in California who was maintained on a ventilator for over 2 years illustrates how such a consent would have made a crucial difference.
Conceptual, philosophical, and ethical analysis.
I first consider a conceptual justification for the use of consent for certain non-beneficial and unwanted medical diagnoses. I suggest that the diagnosis of brain death falls into this category for some patients. Because the diagnostic process of brain death lacks the transparency of traditional death determination, has a unique epistemic structure and a complex risk-benefit profile which differs markedly from case to case, and presents conflicts of interest for physicians and society, I argue that pre-diagnostic counseling and informed consent should be part of the diagnostic process. This approach can be termed as "allow cardiac death", whose parallel logic with "allow natural death" is discussed. I also discuss potential negative impacts on organ donation and health care cost from this proposal and offer possible mitigation. I show that the pre-diagnostic counseling can improve the possibility for well-thought-out decisions regarding organ donation and terminating life-support system in cases of hopeless prognosis. This approach differs conceptually from the pluralism of the definition of death, such as those in New Jersey and Japan, and it upholds the Uniform Determination of Death Act.
My intention is not to provide an instant panacea for the ongoing impasse of the brain death debate, but to point to a novel conceptual ground for a more pragmatic, and more patient- and family-centered approach. By enabling the family to consent to or decline the diagnostic process of brain death, but not to choose the definition of death, it upholds the current legal definition of death.
Activation of oncogenes downstream the EGFR gene contributes to colorectal tumorigenesis and determines the sensitivity to anti-EGFR treatments. The aim of this study was to evaluate the prognostic value of KRAS, BRAF, NRAS and PIK3CA mutations in a large collection of CRC patients from genetically-homogeneous Sardinian population.
A total of 1284 Sardinian patients with histologically-proven diagnosis of colorectal carcinoma (CRC) and presenting with metastatic disease were included into the study. Genomic DNA was isolated from formalin-fixed, paraffin-embedded primary tumour tissue samples of CRC patients and screened for mutations in RAS and BRAF genes, using pyrosequencing assays, and in PIK3CA gene, using automated DNA sequencing assays.
Overall, mutation rates were 35.6 % for KRAS, 4.1 % for NRAS, and 2.1 % for BRAF. Among available DNA samples, 114/796 (14.3 %) primary CRCs were found to carry a mutation in the PIK3CA gene. In this subset of patients analysed in all four genes, a pathogenetic mutation of at least one gene was discovered in about half (378/796; 47.5 %) of CRC cases. A mutated BRAF gene was found to steadily act as a negative prognostic factor for either time to progression as metastatic disease (from detection of primary CRC to diagnosis of first distant metastasis; p = 0.009) or partial survival (from diagnosis of advanced disease to the time of death or last control; p = 0.006) or overall survival (p < 0.001). No significant impact on prognosis was observed for mutated KRAS, NRAS, and PIK3CA genes or combined RAS mutations (all RAS).
Our study defines both prevalence and prognostic role of main activated oncogenes in a population-based large collection of CRC patients.
Anti-malarial drug resistance continues to be a leading threat to malaria control efforts and calls for continued monitoring of waning efficacy of artemisinin-based combination therapy (ACT). Artesunate + sulfadoxine/pyrimethamine (AS + SP) is used for the treatment of uncomplicated Plasmodium falciparum malaria in India. However, resistance against AS + SP is emerged in northeastern states. Therefore, artemether-lumefantrine (AL) is the recommended first line treatment for falciparum malaria in north eastern states. This study investigates the therapeutic efficacy and safety of AL for the treatment of uncomplicated falciparum malaria in three malaria-endemic states in India. The data generated through this study will benefit the immediate implementation of second-line ACT as and when required.
This was a one-arm prospective evaluation of clinical and parasitological responses for uncomplicated falciparum malaria using WHO protocol. Patients diagnosed with uncomplicated mono P. falciparum infection were administered six-dose regimen of AL over 3 days and subsequent follow-up was carried out up to 28 days. Molecular markers msp-1 and msp-2 were used to differentiate recrudescence and re-infection and K13 propeller gene was amplified and sequenced covering the codon 450-680.
A total of 402 eligible patients were enrolled in the study from all four sites. Overall, adequate clinical and parasitological response (ACPR) was 98 % without PCR correction and 99 % with PCR correction. At three study sites, ACPR rates were 100 %, while at Bastar, cure rate was 92.5 % on day 28. No early treatment failure was found. The PCR-corrected endpoint finding confirmed that one late clinical failure (LCF) and two late parasitological failures (LPF) were recrudescences. The PCR corrected cure rate was 96.5 %. The mean fever clearance time was 27.2 h ± 8.2 (24-48 h) and the mean parasite clearance time was 30.1 h ± 11.0 (24-72 h). Additionally, no adverse event was recorded. Analysis of total 186 samples revealed a mutation in the k13 gene along with non-synonymous mutation at codon M579T in three (1.6 %) samples.
AL is an efficacious drug for the treatment of uncomplicated falciparum malaria. However, regular monitoring of AL is required in view of malaria elimination initiatives, which will be largely dependent on therapeutic interventions, regular surveillance and targeted vector control.
Propofol is a widely used intravenous anesthetic that is well-known for its protective effect in various human and animal disease models. However, the effects of propofol on neurogenesis, especially on the development of neural stem cells (NSCs), remains unknown. Related microRNAs may act as important regulators in this process.
Published Gene Expression Omnibus (GEO) DataSets related to propofol were selected and re-analyzed to screen neural development-related genes and predict microRNA (miRNA) expression using bioinformatic methods. Screening of the genes and miRNAs was then validated by qRT-PCR analysis of propofol-treated primary embryonic NSCs.
Four differentially expressed mRNAs were identified in the screen and 19 miRNAs were predicted based on a published GEO DataSet. Two of four mRNAs and four of 19 predicted miRNAs were validated by qRT-PCR analysis of propofol-treated NSCs. Rno-miR-19a (Rno, Rattus Norvegicus) and rno-miR-137, and their target gene EGR2,
 as well as rno-miR-19b-2 and rno-miR-214 and their target gene ARC were found to be closely related to neural developmental processes, including proliferation, differentiation, and maturation of NSCs.
Propofol influences miRNA expression; however, further studies are required to elucidate the mechanism underlying the effects of propofol on the four miRNAs and their target genes identified in this study. In particular, the influence of propofol on the entire development process of NSCs remains to be clarified.
Research by economists suggests that recent Mexican migrants are better educated and have higher socioeconomic status (SES) than previous migrants. Because factors associated with higher SES and improved education can lead to positive secular changes in overall body form, secular changes in the craniofacial complex were analyzed within a recent migrant group from Mexico. The Mexican group represents individuals in the act of migration, not yet influenced by the American environment, and thus can serve as a starting point for future studies of secular change in this population group. The excavation of a historic Hispanic cemetery in Tucson, Arizona, also allows for a comparison between historic Hispanics and recent migrants to explore craniofacial trends over a broad time period, as both groups originate from Mexico. The present research addresses two main questions: (1) Are cranial secular changes evident in recent Mexican migrants? (2) Are historic Hispanics and recent Mexican migrants similar? By studying secular changes within a migrant population group, secular trends may be detected, which will be important for understanding the biological variation of the migrants themselves and will serve as a preliminary investigation of secular change within Mexican migrants. The comparison of a sample of recent Mexican migrants with a historic Hispanic sample, predominantly of Mexican origin, allows us to explore morphological similarities and differences between early and recent Mexicans within the United States. Vault and face size and a total of 82 craniofacial interlandmark distances were used to explore secular changes within the recent Mexican migrants (females, n = 38; males, n = 178) and to explore the morphological similarities between historic Hispanics (females, n = 54; males, n = 58) and recent migrants. Sexes were separated, and multivariate adaptive regression splines and basis splines (quadratic with one knot) were used to assess the direction and magnitude of secular trends for the recent Mexican migrants. Because dates of birth were unavailable for the historic sample, partial least squares discriminant analysis (PLS-DA) was used to evaluate morphological differences between historic and recent Mexican migrant samples. The data were separated into a training data set and a testing data set to ensure realistic results. Males had eight variables (four positive and four negative) and females had six variables (two positive and four negative) that demonstrated significant differences over time. In the PLS-DA, three components were identified as important in model creation and resulted in a classification accuracy of 87% when applied to a testing sample. The high classification accuracy demonstrates significant morphological differences between the two groups, with the historic Hispanic sample displaying overall larger craniofacial dimensions. While differences in cranial morphology are evident between historic Hispanics and recent Mexican migrants, relatively few positive and negative secular trends were detected within the recent migrant sample.
Members of the calcitonin peptide family-calcitonin gene-related peptide (CGRP), adrenomedullin (AM), and adrenomedullin2/intermedin (IMD)-exert modulatory effects upon monocytes and macrophages of various extrapulmonary origins. Utilizing the rat alveolar macrophage (AMφ) cell line NR8383, we here set out to determine to which extent these three peptides and their receptors are differentially regulated in AMφ and what specific effects they have on AMφ key functions. LPS treatment differentially up-regulated expression of the peptides and receptors. Among the three peptides, IMD mRNA content was lowest both in primary rat AMφ and NR8383 cells, whereas IMD peptide dominated in basal and LPS-stimulated secretion from NR8383 cells. Fcγ receptor-mediated phagocytosis and TNF-α production were inhibited by AM, IMD, and CGRP, whereas pro-IL-1β mRNA was slightly down-regulated exclusively by CGRP. Neither of these peptides affected IL-6 or IL-10 production. None increased intracellular calcium concentration, but AM significantly inhibited store-operated calcium entry. In conclusion, the rat AMφ cell line NR8383 is both a source and a target of the calcitonin peptide family members AM, IMD, and CGRP. Despite sharing proteins of the receptor complexes, AM, IMD, and CGRP each showed a characteristic pattern of effects and regulation, suggesting that these closely related peptides are not just redundant members of one common signaling pathway but act in concert by addressing parallel signaling cascades. Since peptide and receptor expression are up-regulated by LPS, these signaling pathways might act as inhibitory feedback mechanisms in pulmonary bacterial infection.
Conscientious objection to abortion, clinicians' refusal to perform legal abortions because of their religious or moral beliefs, has been the subject of increasing debate among bioethicists, policymakers, and public health advocates in recent years. Conscientious objection policies are intended to balance reproductive rights and clinicians' beliefs. However, in practice, clinician objection can act as a barrier to abortion access-impinging on reproductive rights, and increasing unsafe abortion and related morbidity and mortality. There is little information about conscientious objection from a medical or public health perspective. A quantitative instrument is needed to assess prevalence of conscientious objection and to provide insight on its practice. This paper describes the development of a survey instrument to measure conscientious objection to abortion provision.
A literature review, and in-depth formative interviews with stakeholders in Colombia were used to develop a conceptual model of conscientious objection. This model led to the development of a survey, which was piloted, and then administered, in Ghana.
The model posits three domains of conscientious objection that form the basis for the survey instrument: 1) beliefs about abortion and conscientious objection; 2) actions related to conscientious objection and abortion; and 3) self-identification as a conscientious objector.
The instrument is intended to be used to assess prevalence among clinicians trained to provide abortions, and to gain insight on how conscientious objection is practiced in a variety of settings. Its results can inform more effective and appropriate strategies to regulate conscientious objection.
Glutathionyl-hydroquinone reductases (GHRs) belong to the recently characterized Xi-class of glutathione transferases (GSTXs) according to unique structural properties and are present in all but animal kingdoms. The GHR ScECM4 from the yeast Saccharomyces cerevisiae has been studied since 1997 when it was found to be potentially involved in cell-wall biosynthesis. Up to now and in spite of biological studies made on this enzyme, its physiological role remains challenging. The work here reports its crystallographic study. In addition to exhibiting the general GSTX structural features, ScECM4 shows extensions including a huge loop which contributes to the quaternary assembly. These structural extensions are probably specific to Saccharomycetaceae. Soaking of ScECM4 crystals with GS-menadione results in a structure where glutathione forms a mixed disulfide bond with the cysteine 46. Solution studies confirm that ScECM4 has reductase activity for GS-menadione in presence of glutathione. Moreover, the high resolution structures allowed us to propose new roles of conserved residues of the active site to assist the cysteine 46 during the catalytic act.
19F-MRI and 19F-MRS can identify specific cell types after in-vitro or in-vivo 19F-labeling. Knowledge on the potential to track in-vitro 19F-labeled immune cells in tumor models by 19F-MRI/MRS is scarce.
To study 19F-based MR techniques for in-vivo tracking of adoptively transferred immune cells after in-vitro 19F-labeling, i.e. to detect and monitor their migration non-invasively in melanoma-bearing mice.
Splenocytes (SP) were labeled in-vitro with a perfluorocarbon (PFC) and IV-injected into non-tumor bearing mice. In-vitro PFC-labeled ovalbumin (OVA)-specific T cells from the T cell receptor-transgenic line OT-1, activated with anti-CD3 and anti-CD28 antibodies (Tact) or OVA-peptide pulsed antigen presenting cells (TOVA-act), were injected into B16 OVA melanoma-bearing mice. The distribution of the 19F-labelled donor cells was determined in-vivo by 19F-MRI/MRS. In-vivo 19F-MRI/MRS results were confirmed by ex-vivo 19F-NMR and flow cytometry.
SP, Tact, and TOVA-act were successfully PFC-labeled in-vitro yielding 3x1011-1.4x1012 19F-atoms/cell in the 3 groups. Adoptively transferred 19F-labeled SP, TOVA-act, and Tact were detected by coil-localized 19F-MRS in the chest, abdomen, and left flank in most animals (corresponding to lungs, livers, and spleens, respectively, with highest signal-to-noise for SP vs TOVA-act and Tact, p<0.009 for both). SP and Tact were successfully imaged by 19F-MRI (n = 3; liver). These in-vivo data were confirmed by ex-vivo high-resolution 19F-NMR-spectroscopy. By flow cytometric analysis, however, TOVA-act tended to be more abundant versus SP and Tact (liver: p = 0.1313; lungs: p = 0.1073; spleen: p = 0.109). Unlike 19F-MRI/MRS, flow cytometry also identified transferred
 immune cells (SP, Tact, and TOVA-act) in the tumors.
SP, Tact, and TOVA-act were successfully PFC-labeled in-vitro and detected in-vivo by non-invasive 19F-MRS/MRI in liver, lung, and spleen. The portion of 19F-labeled T cells in the adoptively transferred cell populations was insufficient for 19F-MRS/MRI detection in the tumor. While OVA-peptide-activated T cells (TOVA-act) showed highest infiltration into all organs, SP were detected more reliably by 19F-MRS/MRI, most likely explained by cell division of TOVA-act after injection, which dilutes the 19F content in the T cell-infiltrated organs. Non-dividing 19F-labeled cell species appear most promising to be tracked by 19F-MRS/MRI.
Novel families of short interspersed nuclear element (SINE) sequences in the human pathogenic fungus Aspergillus fumigatus, clinical isolate Af293, were identified and categorised into tRNA-related and 5S rRNA-related SINEs. Eight predicted tRNA-related SINE families originating from different tRNAs, and nominated as AfuSINE2 sequences, contained target site duplications of short direct repeat sequences (4-14 bp) flanking the elements, an extended tRNA-unrelated region and typical features of RNA polymerase III promoter sequences. The elements ranged in size from 140-493 bp and were present in low copy number in the genome and five out of eight were actively transcribed. One putative tRNAArg-derived sequence, AfuSINE2-1a possessed a unique feature of repeated trinucleotide ACT residues at its 3'-terminus. This element was similar in sequence to the I-4_AO element found in A. oryzae and an I-1_AF long nuclear interspersed element-like sequence identified in A. fumigatus Af293. Families of 5S rRNA-related SINE sequences, nominated as AfuSINE3, were also identified and their 5'-5S rRNA-related regions show 50-65% and 60-75% similarity to respectively A. fumigatus 5S rRNAs and SINE3-1_AO found in A. oryzae. A. fumigatus Af293 contains five copies of AfuSINE3 sequences ranging in size from 259-343 bp and two out of five AfuSINE3 sequences were actively transcribed. Investigations on AfuSINE distribution in the fungal genome revealed that the elements are enriched in pericentromeric and subtelomeric regions and inserted within gene-rich regions. We also demonstrated that some, but not all, AfuSINE sequences are targeted by host RNA silencing mechanisms. Finally, we demonstrated that infection of the fungus with mycoviruses had no apparent effects on SINE activity.
Sup35 is a prion-like protein from yeast and shares the ability to transmit its aberrant fold and to aggregate into amyloid fibrils. (7)GNNQQNY(13) from the prion-determining domain of Sup35 was reported to form an amyloid. We first investigated the self-aggregation transition behavior of GNNQQNY to the β-sheet amyloid state under various conditions. Mechanical stirring using a magnetic bar resulted in accelerated aggregation of the GNNQQNY. The aggregation rate of GNNQQNY was also dependent on its concentration; the higher the GNNQQNY concentration, the faster the aggregation. Circular dichroism and Fourier transform-infrared spectral data indicated the formation of the β-sheet structure in the GNNQQNY aggregates. The fluorescence experiments using an amyloid-specific thioflavin T also demonstrated that the GNNQQNY aggregates formed the amyloid structures. The amyloid structure of the GNNQQNY aggregates served as seeds for the elongation of the monomeric GNNQQNY in the solution state. We further studied the ability of the GNNQQNY amyloid fibrils to act as seeds for the elongation of the amyloid-forming monomeric proteins (albumin, lysozyme and insulin). The cross-seeding experiments suggested that the GNNQQNY aggregate could possibly promote the amyloid fibril formation of heterogeneous insulin. The inverse monomeric GNNQQNY would have a binding capacity for the heterogeneous already-formed amyloid-β fibrils on a mice brain section. These basic data could be informative for elucidating the pathogenic and/or propagation mechanisms of prion agents and developing effective therapeutics and/or diagnosis for prion diseases.
Interrupted time series with and without controls was used to evaluate whether the federal Mental Health Parity and Addiction Equity Act (MHPAEA) and its Interim Final Rule increased the probability of specialty behavioral health treatment and levels of utilization and expenditures among patients receiving treatment. Linked insurance claims, eligibility, plan and employer data from 2008 to 2013 were used to estimate segmented regression analyses, allowing for level and slope changes during the transition (2010) and post-MHPAEA (2011-2013) periods. The sample included 1,812,541 individuals ages 27-64 (49,968,367 person-months) in 10,010 Optum "carve-out" plans. Two-part regression models with Generalized Estimating Equations were used to estimate expenditures by payer and outpatient, intermediate and inpatient service use. We found little evidence that MHPAEA increased utilization significantly, but somewhat more robust evidence that costs shifted from patients to plans. Thus the primary impact of MHPAEA among carve-out enrollees may have been a reduction in patient financial burden.
Buprenorphine, a semisynthetic thebaine derivative, is a unique opioid, as it has activity at multiple receptors, including mu (partial agonist), kappa (antagonist), OLR-1 (agonist), and delta (antagonist). Because buprenorphine's pharmacology is relatively complex, misconceptions about its actions are common. Most other opioids act solely or predominately as full mu receptor agonists. Common practice at many institutions calls for the cessation of regular buprenorphine use 48-72 hours prior to surgery. This practice is based on three foundational theories that have come from scant data about the properties of buprenorphine: (1) that buprenorphine is only a partial mu agonist and therefore is not a potent analgesic; (2) because buprenorphine has a ceiling effect on respiratory depression, it also has a ceiling effect on analgesia; and (3) that buprenorphine acts as a "blockade" to the analgesic effects of other opiates when coadministered due to its strong binding affinity. However, several recent studies have called this practice into question. At our institution, we continue buprenorphine perioperatively, whenever possible, in order to provide superior pain control, discourage potentially problematic use and the more dangerous side effects of full mu agonist opiates, and avoid putting recovery at risk for those with opiate dependency issues. We present a unique case comparing two different outcomes for the same surgical course performed at two different times on the same chronic pain patient. These differences may be attributable to the variable of buprenorphine being present for one perioperative course and not the other. Pain control was easier to achieve, and functional recovery was greater when buprenorphine was maintained throughout the perioperative period when compared with using a full mu agonist opioid for chronic pain preoperatively. This is an outcome that much of the literature heretofore suggests would be unlikely. We review some aspects of buprenorphine's unique pharmacology that may explain why remaining on buprenorphine perioperatively may be preferable, which contradicts many practice guidelines.
Iron is an essential nutrient, acting as a catalyst for metabolic reactions that are fundamental to cell survival and proliferation. Iron complexed to transferrin is delivered to the metabolism after endocytosis via the CD71 surface receptor. We found that transformed cells from a murine PTEN-deficient T-cell lymphoma model and from T-cell acute lymphoblastic leukemia/lymphoma (T-ALL/T-LL) cell lines overexpress CD71. As a consequence, the cells developed an addiction toward iron whose chelation by deferoxamine (DFO) dramatically affected their survival to induce apoptosis. Interestingly, DFO displayed synergistic activity with three ALL-specific drugs: dexamethasone, doxorubicin, and L-asparaginase. DFO appeared to act through a reactive oxygen species-dependent DNA damage response and potentiated the action of an inhibitor of the PARP pathway of DNA repair. Our results demonstrate that targeting iron metabolism could be an interesting adjuvant therapy for acute lymphoblastic leukemia.
This investigation sought to determine the effect of training at 2100 metres natural altitude on running speed (RS) during training sessions over a range of intensities relevant to middle-distance running performance.
In an observational study, 19 elite middle-distance runners (mean ± SD; Age, 25 ± 5 years; VO2 max, 71 ± 5 ml.kg.min-1) completed either 4-6 weeks of sea-level training (CON, n = 7), or a 4-5 week natural altitude training camp living at 2100 m and training at 1400-2700 m (ALT, n = 12) following a period of sea-level training. Each training session was recorded on a GPS watch, and athletes also provided a session rating of perceived exertion (sRPE) score. Training sessions were grouped according to duration and intensity. Running speed (km.h-1) and sRPE from matched training sessions completed at sea-level and 2100 m were compared within ALT, with sessions completed at sea-level in CON describing normal variation.
In ALT, RS was reduced at altitude compared to sea-level, with the greatest decrements observed during threshold and VO2 max intensity sessions (5.8 and 3.6 % respectively). Velocity of low-intensity, and race pace sessions completed at a lower altitude (1400 m) and/or with additional recovery were maintained in ALT, though at a significantly greater sRPE (p = 0.04 and 0.05 respectively). There was no change in velocity or sRPE at any intensity within CON.
Running speed in elite middle-distance athletes is adversely affected at 2100 m natural altitude, with levels of
 impairment dependent on the intensity of training. Maintenance of RS at certain intensities whilst training at altitude can result in a higher perceived exertion.
To compile substate-level data on US school-age children's vaccination rates.
For states that did not have suitable data online, in 2015 we submitted information requests to the state health department and followed up with the state's Freedom of Information Act when necessary.
The accessibility, scale, and types of vaccination data varied considerably. Whereas 26 states provided data online, 14 released data only after a Freedom of Information Act request. School or school-district data were available for 24 states, 19 at the county level, 2 at the health department level, and 6 provided no substate-level data.
Effective vaccination policy requires a robust understanding of vaccination behavior. Some states make it difficult to access data or provide low-resolution data of limited value for identifying vaccination behavior.
Over the past couple of decades, coordination-driven self-assembly has evolved as a broad multidisciplinary domain that not only covers the syntheses of aesthetically pleasing supramolecular architectures but also emerges as a method to form new optical materials, chemical sensors, theranostic agents, and compounds with light-harvesting and emissive properties. The majority of these applications depend upon investigations that reveal the photophysical nature and electronic structure of supramolecular coordination complexes (SCCs), including two-dimensional (2D) metallacycles and three-dimensional (3D) metallacages. As such, well-defined absorption and emission spectra are important for a given SCC to be used for sensing, bioimaging, and other applications with molecular fluorescence being an important component. In this Account, we summarize the photophysical properties of some bis(phosphine)organoplatinum(II) compounds and their discrete SCCs. The platinum(II) based organometallic precursors typically display spectral red-shifts and have low fluorescence quantum yields and short fluorescence lifetimes compared to their organic counterparts because the introduction of metal centers enhances both intersystem crossing (ISC) and intramolecular charge transfer (ICT) processes, which can compete with the fluorescence emissions. Likewise ligands with conjugation can also increase the ICT process; hence the corresponding organoplatinum(II) compounds undergo a further decrease in fluorescence lifetimes. The use of endohedral amine functionalized 120°-bispyridyl ligands can dramatically enhance the emission properties of the resultant organoplatinum(II) based SCCs. As such these SCCs display emissions in the visible region (ca. 400-500 nm) and are significantly red-shifted (ca. 80-100 nm) compared to the ligands. This key feature makes them suitable as supramolecular theranostic agents wherein these unique emission properties provide diagnostic spectroscopic handles and the organoplatinum(II) centers act as potential anticancer agents. Using steady state and time-resolved-spectroscopic techniques and quantum computations in concert, we have determined that the emissive properties stem from the ligand-centered transitions involving π-type molecular orbitals with modest contributions from the metal-based orbitals. The self-assembly and the photophysics of organoplatinum(II) ← 3-substituted pyridyl based SCCs are highly diverse. Subtle changes in the ligands' structures can form molecular congener systems with distinct conformational and photophysical properties. Furthermore, the heterometallic SCCs described herein possess rich photophysical properties and can be used for sensing based applications. Tetraphenylethylene (TPE) based SCCs display emissions in the aggregated state as well as in dilute solutions. This is a unique phenomenon that bridges the aggregation caused quenching (ACQ) and aggregation induced emission (AIE) effects. Moreover, a TPE based metallacage exhibits solvatoluminescence, including white light emission in THF solvent, and can act as a fluorescence-sensor for structurally similar ester compounds.
For children with problematic severe asthma, achieving adequate control of asthma is difficult. The aim of this prospective observational study was to evaluate the effects of intensive multidisciplinary inpatient treatment on multiple outcome variables in children with problematic severe asthma.
Participants were 89 children with problematic severe asthma (mean age 13.6 ± 2.5 years) treated in tertiary care clinics at high altitude (Switzerland) or sea level (Netherlands) and their parents (85 mothers, 55 fathers). The primary outcome variable was the Childhood Asthma Control Test (C-ACT). Other outcome variables were forced expiratory volume in 1 sec (FEV1 ), fractional concentration of exhaled nitric oxide (FeNO), quality of life [PAQLQ(S)], children's coping (UCL-A), parents' report of behavioral problems (CBCL), and parenting stress (PSI/NOSI). Evaluations were taken pre-treatment, post-treatment, and 3-6 months follow-up. Median [P25;P75] treatment duration 74 [56;80] days; Median follow-up interval 131 [103;177] days.
The percentages of children showing controlled asthma (C-ACT) were 18% (pre-treatment), 69% (post-treatment), and 44% (follow-up). The vast majority of the children (80%) showed an improvement on C-ACT with 4% showing a deterioration. On C-ACT, FeNO, quality of life, and behavioral problems, improvements at post-treatment were highly significant. Improvements generally remained at a functional level at follow-up. Children's coping and parenting stress in parents did not change.
The improvement in asthma control and other outcome variables suggests that multidisciplinary inpatient treatment is an effective approach for a heterogeneous group of children with asthma that remained uncontrolled in secondary care. Pediatr Pulmonol. 2016; 9999:XX-XX. © 2016 Wiley Periodicals, Inc.
TRPA1 is a ligand-activated cation channel found in the intestine and other tissues. Components of food that stimulate TRPA1 receptors (phytonutrients) include allyl isothiocyanate, cinnamaldehyde and linalool, but these may also act at other receptors. Cells lining the intestinal mucosa are immunoreactive for TRPA1 and Trpa1 mRNA occurs in mucosal extracts, suggesting that the TRPA1 receptor is the target for these agonists. However, in situ hybridisation reveals Trpa1 expression in 5-HT containing enteroendocrine cells, not enterocytes. TRPA1 agonists evoke mucosal secretion, which may be indirect (through release of 5-HT) or direct by activation of enterocytes. We investigated effects of the phytonutrients on transmucosal ion currents in mouse duodenum and colon, and the specificity of the phytonutrients in cells transfected with Trpa1, and in Trpa1-deficient mice. The phytonutrients increased currents in the duodenum with the relative potencies: allyl isothiocyanate (AITC) > cinnamaldehyde > linalool (0.1 to 300 μM). The rank order was similar in the colon, but linalool was ineffective. Responses to AITC were reduced by the TRPA1 antagonist HC-030031 (100 μM), and were greatly diminished in Trpa1-/- duodenum and colon. Responses were not reduced by tetrodotoxin, 5-HT receptor antagonists, or atropine, but inhibition of prostaglandin synthesis reduced responses. Thus, functional TRPA1 channels are expressed by enterocytes of the duodenum and colon. Activation of enterocyte TRPA1 by food components has the potential to facilitate nutrient absorption.
Doxorubicin (DOXO) is widely used to treat solid tumors. However, its clinical use is limited by side effects including serious cardiotoxicity due to cardiomyocyte damage. Resident cardiac progenitor cells (hCPCs) act as key regulators of homeostasis in myocardial cells. However, little is known about the function of hCPCs in DOXO-induced cardiotoxicity. In this study, we found that DOXO-mediated hCPC toxicity is closely related to calcium-related autophagy signaling and was significantly attenuated by blocking mTOR signaling in human hCPCs. DOXO induced hCPC apoptosis with reduction of SMP30 (regucalcin) and autophagosome marker LC3, as well as remarkable induction of the autophagy-related markers, Beclin-1, APG7, and P62/SQSTM1 and induction of calcium-related molecules, CaM (Calmodulin) and CaMKII (Calmodulin kinase II). The results of an LC3 puncta assay further indicated that DOXO reduced autophagosome formation via accumulation of cytosolic Ca(2+). Additionally, DOXO significantly induced mTOR expression in hCPCs, and inhibition of mTOR signaling by rapamycin, a specific inhibitor, rescued DOXO-mediated autophagosome depletion in hCPCs with significant reduction of DOXO-mediated cytosolic Ca(2+) accumulation in hCPCs, and restored SMP30 and mTOR expression. Thus, DOXO-mediated hCPC toxicity is linked to Ca(2+)-related autophagy signaling, and inhibition of mTOR signaling may provide a cardio-protective effect against DOXO-mediated hCPC toxicity.
Photo-initiated supramolecular polymerization of a naphthalenediimide (NDI-1) derivative containing an ortho-nitrobenzyl (ONB)-protected amide group is demonstrated. In a hydrocarbon solvent (methylcyclohexane), it remains as monomer. Upon photo-irradiation, deprotection of the ONB group produces NDI-2 with a free amide group, which drives supramolecular polymerization by self-complementary H-bonding between the amide groups, leading to gelation. The polymerization rate can be controlled by tuning the energy of the light source. During photopolymerization, a gradual increase in hydrodynamic radius and viscosity is noticed. More interestingly, the morphology of the supramolecular polymer of NDI-2, produced by photo-irradiation, was a spherulite, which is in sharp contrast with the fibrillar morphology of NDI-2 polymer, when assembled spontaneously
 without a phototrigger. This is ascribed to the ability of the ONB-caged pro-monomer (NDI-1) to act as a chain-stopper by forming a H-bonded complex with the active monomer during the growth of the supramolecular polymer under photo-irradiation.
MicroRNAs (miRNAs) act as key regulators of diverse cellular activities by regulating the expression of protein-coding genes. Osteoblast differentiation, a fundamental step in skeletal development, involves the activation of several signaling pathways, including transforming growth factor β (TGF-β), bone morphogenetic protein (BMP), and Wnt signaling pathways.
miRNA expression was measured using TaqManRT-PCR. Western blot was used to detect the protein expression of Smad1. Luciferase reporter assay was used to measure the luciferase activity.
In this study, we found that miR-100 was expressed in mesenchymal progenitor cell lines; furthermore, its expression was reduced during osteoblast differentiation. Retroviral overexpression of miR-100 decreased Smad1 protein levels, whereas miR-100 inhibition had the opposite effect, suggesting that miR-100 acts as an endogenous attenuator of Smad1 in osteoblast differentiation.
Together, our data demonstrate that miR-100 acts as an important endogenous negative regulator of BMP-induced osteoblast differentiation.
A double-negative feedback loop formed by the morning genes CIRCADIAN CLOCK ASSOCIATED1 (CCA1)/LATE ELONGATED HYPOCOTYL (LHY) and the evening gene TIMING OF CAB EXPRESSION1 (TOC1) contributes to regulation of the circadian clock in Arabidopsis. A 24-h circadian cycle starts with the peak expression of CCA1 at dawn. Although CCA1 is targeted by multiple transcriptional repressors, including PSEUDO-RESPONSE REGULATOR9 (PRR9), PRR7, PRR5 and CCA1 HIKING EXPEDITION (CHE), activators of CCA1 remain elusive. Here we use mathematical modelling to infer a co-activator role for LIGHT-REGULATED WD1 (LWD1) in CCA1 expression. We show that the TEOSINTE BRANCHED 1-CYCLOIDEA-PCF20 (TCP20) and TCP22 proteins act as LWD-interacting transcriptional activators. The concomitant binding of LWD1 and TCP20/TCP22 to the TCP-binding site in the CCA1 promoter activates CCA1. Our study reveals activators of the morning gene CCA1 and provides an action mechanism that ensures elevated expression of CCA1 at dawn to sustain a robust clock.
Peptide analogues derived from bioactive hormones such as somatostatin or certain growth factors have great potential as angiogenesis inhibitors for cancer applications. In an attempt to combat emerging drug resistance many FDA-approved anti-angiogenesis therapies are co-administered with cytotoxic drugs as a combination therapy to target multiple signaling pathways of cancers. However, cancer therapies often encounter limiting factors such as high toxicities and side effects. Here, we combined two anti-angiogenic epitopes that act on different pathways of angiogenesis into a single non-toxic cyclic peptide framework, namely MCoTI-II (Momordica cochinchinensis trypsin inhibitor-II), and subsequently assessed the anti-angiogenic activity of the novel compound. We hypothesized that the combination of these two epitopes would elicit a synergistic effect by targeting different angiogenesis pathways and result in improved potency, compared to that of a single epitope. This novel approach has resulted in the development of a potent, non-toxic, stable and cyclic analogue with nanomolar potency inhibition in in vitro endothelial cell migration and in vivo chorioallantoic membrane angiogenesis assays. This is the first report to use the MCoTI-II framework to develop a 2-in-1 anti-angiogenic peptide, which has the potential to be used as a form of combination therapy for targeting a wide range of cancers.
Angiotensin I-converting enzyme (ACE) hydrolyzes numerous peptides and is a critical participant in blood pressure regulation and vascular remodeling. Elevated tissue ACE levels are associated with increased risk for cardiovascular and respiratory disorders. Blood ACE concentrations are determined by proteolytic cleavage of ACE from the endothelial cell surface, a process that remains incompletely understood. In this study, we identified a novel ACE gene mutation (Arg532Trp substitution in the N domain of somatic ACE) that increases blood ACE activity 7-fold and interrogated the mechanism by which this mutation significantly increases blood ACE levels. We hypothesized that this ACE mutation disrupts the binding site for blood components which may stabilize ACE conformation and diminish ACE shedding. We identified the ACE-binding protein in the blood as lysozyme and also a Low Molecular Weight (LMW) ACE effector, bilirubin, which act in concert to regulate ACE conformation and thereby influence ACE shedding. These results provide mechanistic insight into the elevated blood level of ACE observed in patients on ACE inhibitor therapy and elevated blood lysozyme and ACE levels in sarcoidosis patients.
Recently, there has been an increase in the consumption of designer drugs, substances aimed at producing psychoactive, energizing, euphoric or anesthetic effects. Designer drugs are substitutes of actual narcotics, whose possession is banned under Polish law according to the Act of 29 July 2005. The latest reports suggest that the number of synthetic psychoactive substances is increasing. In the span of 2012, a total of 28 new synthetic cannabinoids were discovered in member states of the European Union. Synthetic psychoactive substances appear in different forms on the market: tablets (often very colourful and interestingly-shaped), seeds, dried product (sprayed with synthetic substance and redried), crystals or powder. The way of application is greatly diverse, and depends on the form in which a drug is produced and dispensed. The methods of intoxication include smoke inhalation (oftentimes blends are smoked), intranasal or oral application, placing crystals on the eye, or injection. Said methods correspond, with varying degrees, to invoking different psychotic effects, such as agitation, panic attacks, paranoia, hallucinations, overall irritation, and aggression. Various cardiovascular effects, such as tachycardia or increase in blood pressure, may follow as well. However, the primary influence is on the nervous system, inhibiting the reuptake of neurotransmitters such as serotonin, noradrenalin and dopamine, and leading to their increased concentration at the presynaptic cleft, which in turn causes feelings of agitation and pleasure. The knowledge regarding the strength, toxicity, and metabolism of designer drugs is yet sparse. The same pertains to the knowledge regarding the handling of overdose cases.
People with severe mental illness (SMI) do not receive adequate attention in research or clinical practice. They are considered hard to reach and difficult to engage. Information is needed to help provide support for this vulnerable population. This paper aims to investigate the well-being of adults diagnosed with SMI and receiving Assertive Community Treatment (ACT) by applying the occupational well-being framework to the everyday activities of this vulnerable group of people.
Eleven adults diagnosed with an SMI, living in the community, participated in semi-structured interviews over a 12-month period. A longitudinal design was used to collect data through using field notes and audio recordings. For this paper, secondary analysis was conducted by coding the data deductively thereby investigating the participants' experiences in relation to the seven Occupational Well-being framework descriptors (accomplishment, affirmation, agency, coherence, companionship, pleasure and renewal).
Participants' everyday activities and occupational well-being appeared severely restricted and largely determined by the type of care they received. There was minimal evidence of the well-being descriptors, though all the participants reported experiencing some form of pleasure, even though some of the pleasurable experiences negatively impacted their health.
The episodic nature of SMI means that people living with an SMI require continuity in key relationships and support to achieve Occupational Well-being. Occupational therapists working with mental health consumers need to facilitate the types of activities that foster well-being through accomplishment, affirmation, agency and companionship, and that derive pleasure in healthy and positive ways.
Interface design between current collector and electroactive materials plays a key role in the electrochemical process for lithium-ion batteries. Here, a thin graphene film has been successfully synthesized on the surface of Cu current collector by a large-scale low-pressure chemical vapor deposition (LPCVD) process. The modified Cu foil was used as a current collector to support spinel Li4Ti5O12 anode directly. Electrochemical test results demonstrated that graphene coating Cu foil could effectively improve overall Li storage performance of Li4Ti5O12 anode. Especially under high current rate (e.g., 10 C), the Li4Ti5O12 electrode using modified current collector maintained a favorable capacity, which is 32% higher than that electrode using bare current collector. In addition, cycling performance has been improved using the new type current collector. The enhanced performance can be attributed to the reduced internal resistance and improved charge transfer kinetics of graphene film by increasing electron collection and decreasing lithium ion interfacial diffusion. Furthermore, the graphene film adhered on the Cu foil surface could act as an effective protective film to avoid oxidization, which can effectively improve chemical stability of Cu current collector.
Prior randomised studies of immunoglobulin replacement therapy have studied mixed populations with or without a history of infections. Immunoglobulin therapy
 is expensive and in limited supply suggesting that optimising patient selection is of value. In this retrospective study, infection history identified high-risk groups benefiting from treatment. A group of patients without any infection history had a low risk of infection without immunoglobulin.
A facile light-mediated preparation of small palladium nanoparticles (PdNPs) with a diameter of 1.3 nm and low dispersity by using low-priced and readily prepared photoactive polymers is presented. These polymers act as reagents for the photochemical reduction of Pd ions and they are also stabilizers for the PdNPs generated in situ. The PdNP-polymer hybrid materials prepared by this reliable approach are efficient hydrogenation catalysts that show high activity and Z-selectivity in the semi-hydrogenation of alkynes. These PdNP-catalyst hybrid materials can be readily recycled and reused up to five times.
Research on theory of mind (ToM) abilities in patients with bipolar disorder has yielded conflicting results. Meta-analyses point to a stable moderate impairment in remitted patients, but factors such as subsyndromal symptoms, illness severity, and deficits in basic neurocognitive functions might act as confounders. Also, differences in deficits depending on task area (cognitive or affective) or task modality (visual or verbal) have been observed. This study aimed to test the hypothesis that euthymic bipolar patients would perform more poorly than healthy subjects on visual cognitive and visual affective ToM tasks. Furthermore, we aimed to explore the relationship between ToM performance and basic neurocognitive functions, subsyndromal symptom severity, and illness burden. Twenty-nine clinically stable outpatients with bipolar disorder and 29 healthy comparison subjects completed a measure of visual cognitive ToM (Mental State Attribution Task, MSAT), a measure of visual affective ToM (Reading the Mind in the Eyes Test, RMET), and a battery of tests assessing neurocognitive functioning (attention, verbal memory, executive functions, and intelligence).
Patients did not differ significantly from healthy controls for the ToM tasks or any of the neurocognitive measures, suggesting a high level of neurocognitive functioning in the bipolar group. On average, patients were slower than controls to complete the ToM tasks. Within the bipolar group, ToM performance was moderately correlated with attention, verbal memory and reasoning abilities. Performance on the RMET was positively correlated with clinician-rated depressive symptoms with a small effect. Number of years of illness was weakly and negatively correlated with performance on the MSAT. Overall, no moderate or strong correlations were found between ToM performance, subsyndromal depressive or manic symptoms, illness duration, and number of depressive or (hypo)manic episodes. Moderate correlations between ToM performance and age were found for patients but nor for controls.
Our findings suggest preserved visual cognitive and affective ToM abilities in euthymic bipolar patients characterized by a high level of neurocognitive functioning.
Liver fibrosis occurs during chronic injury and represents, in large part, an exaggerated matrigenic output by hepatic stellate cells (HSCs) which become activated as a result of injury-induced signaling pathways in parenchymal and inflammatory cells (hepatocytes, macrophages, etc.). The molecular components in these pathways (e.g., CCN proteins) are modulated by transcription factors as well as by factors such as microRNAs (miRs) that act posttranscriptionally. MiRs are small (~23 nt) noncoding RNAs that regulate gene expression by specifically interacting with the 3' untranslated region (UTR) of target gene mRNA to repress translation or enhance mRNA cleavage. As well as acting in their cells of production, miRs (and other cellular constituents such as mRNAs and proteins) can be liberated from their cells of origin in nanovesicular membrane exosomes, which traverse the intercellular spaces, and can be delivered to neighboring cells into which they release their molecular payload, causing alterations in gene expression in the target cells. Here we summarize some of the experimental approaches for studying miR action and exosomal trafficking between hepatic cells. Insights into the mechanisms involved will yield new information about how hepatic fibrosis is regulated and, further, may identify new points of therapeutic intervention.
Evidence from in vitro and in vivo studies shows that Ski may act as both a tumor proliferation-promoting factor and a metastatic suppressor in human pancreatic cancer and also may be a therapeutic target of integrative therapies. At present, pancreatic cancer stem cells (CSCs) are responsible for tumor recurrence accompanied by resistance to conventional therapies. Sonic hedgehog (Shh) signaling pathway is found to be aberrantly activated in CSCs. The objectives of this study were to investigate the role of Ski in modulating pancreatic CSCs and to examine the molecular mechanisms involved in pancreatic cancer treatment both in vivo and in vitro. In in vitro study, the results showed that enhanced Ski expression could increase the expression of pluripotency maintaining markers, such as CD24, CD44, Sox-2, and Oct-4, and also components of Shh signaling pathway, such as Shh, Ptch-1, Smo, Gli-1, and Gli-2, whereas depletion of Ski to the contrary. Then, we investigated the underlying mechanism and found that inhibiting Gli-2 expression by short interfering RNA (siRNA) can decrease the effects of Ski on the maintenance of pancreatic CSCs, indicating that Ski mediates the pluripotency of pancreatic CSCs mainly through Shh pathway. The conclusion is that Ski may be an important factor in maintaining the stemness of pancreatic CSCs through modulating Shh pathway.
The objective of the study was to explore the impact of implementation of the Public Health Amendment (Vaccination of Children Attending Child Care Facilities) Act 2013 on child-care centres in the Northern Rivers region of New South Wales (NSW), from the perspective of child-care centre directors. Importance of study: Immunisation is an effective public health intervention, but more than 75 000 Australian children are not fully vaccinated. A recent amendment to the NSW Public Health Act 2010 asks child-care facilities to collect evidence of complete vaccination or approved exemption before allowing enrolment.
Ten child-care centre directors participated in a semiscripted interview. Interviews were recorded, transcribed and analysed.
Common themes included misinterpretation of the amendment before implementation, the importance of adequate notice for implementation, lack of understanding of assessment of compliance, increased administrative requirements, the importance of other public health efforts, and limited change in vaccination rates. Child-care centres differed in their experience of the resources provided by the government, interactions with Medicare, and ease of integration with existing record-keeping methods.
Participants felt that the amendment was successfully implemented. The amendment was felt to have fulfilled its aim of prompting parents who had forgotten to vaccinate, but failed to significantly affect conscientious objectors. Overall, the amendment was perceived to be a positive step in improving vaccination rates, but its impact was largely complementary to other components of the multifaceted vaccination policy.
The New South Wales (NSW) Public Health Act 2010 requires water suppliers to implement a drinking water quality assurance program that addresses the 'Framework for management of drinking water quality' in the Australian drinking water guidelines. NSW Health has recognised the importance of a staged implementation of this requirement and the need to support regional water utilities. To date, NSW Health has assisted 74 regional utilities to develop and implement their management systems. The Public Health Act 2010 has increased awareness of drinking water risk management, and offers a systematic process to identify and control risks. This has benefited large utilities, smaller suppliers, and remote and Aboriginal communities. Work is continuing to ensure implementation of the process by private suppliers and water carters.
Fishing is an occupation associated with uneven diet, strain, drunkenness, tobacco use, and deleterious habits. The physical state of laborers on a large scale will also be influenced by conditions at their work site. Oral mucosal lesions can occur as a result of infections, local shock or infuriation, systemic diseases, and uncontrolled usage of tobacco, betel quid, and alcohol. The aim of the present study is to assess the prevalence of deleterious oral habits and oral mucosal lesions among fishermen population of Mahe, South India.
The study population consists of 362 fishermen aged between 15 and 54. The questionnaire consisted of questions on personal data, and information related to the subjects' oral habits were collected by the interview. The World Health Organization (WHO) Oral Health Assessment Form was designed for the assessment of oral mucosal lesions.
Among the 362 fishermen, 266 (73.48%) were males and 96 (26.52%) were females. The overall prevalence of smoking, alcohol consumption, and gutka chewing was found to be 24.3, 48.85, and 32.4% respectively. Smokeless tobacco (32.4%) was the most prevalent habit followed by smoking tobacco (24.3%). The prevalence of oral mucosal lesions was 14.9%. There is a statistically significant association between age groups and habits considered.
Findings of the present study suggest that oral health condition of the fisherfolk community was relatively poor, with high habit prevalence and oral mucosal lesions. This epi-demiological study has provided baseline data to
 plan further research in this area.
Low socioeconomic status, strenuous working hours, inadequate diet and nutrition intake, stress, and use of tobacco and alcohol act as contributing factors for ill health and oral diseases. It is a challenging population to the clinician to identify and treat them.
The cytokine receptor activator of NFκB ligand (RANKL) produced by osteocytes is essential for osteoclast formation in cancellous bone under physiological conditions, and RANKL production by B lymphocytes is required for the bone loss caused by estrogen deficiency. Here, we examined whether RANKL produced by osteocytes is also required for the bone loss caused by estrogen deficiency. Mice lacking RANKL in osteocytes were protected from the increase in osteoclast number and the bone loss caused by ovariectomy. Moreover, these mice did not exhibit the increase in bone marrow B lymphocytes caused by ovariectomy that occurred in control littermates. Deletion of estrogen receptor α from B cells did not alter B cell number or bone mass and did not alter the response to ovariectomy. In addition, lineage-tracing studies demonstrated that B cells do not act as osteoclast progenitors in estrogen-replete or estrogen-deficient mice. Taken together, these results demonstrate that RANKL expressed by osteocytes is required for the bone loss as well as the increase in B cell number caused by estrogen deficiency. Moreover, they suggest that estrogen control of B cell number is indirect via osteocytes and that the increase in bone marrow B cells may be a necessary component of the cascade of events that lead to cancellous bone loss during estrogen deficiency. However, the role of B cells is not to act as osteoclast progenitors but may be to act as osteoclast support cells.
γ oscillations, which can be identified by rhythmic electrical signals ∼30-100 Hz, consist of interactions between excitatory and inhibitory neurons that result in rhythmic inhibition capable of entraining firing within local cortical circuits. Many possible mechanisms have been described through which γ oscillations could act on cortical circuits to modulate their responses to input, alter their patterns of activity, and/or enhance the efficacy of their outputs onto downstream targets. Recently, several studies have observed changes in behavior after optogenetically manipulating neocortical γ oscillations. Now, future studies should determine whether these manipulations elicit physiological correlates associated with specific mechanisms through which γ oscillations are hypothesized to modulate cortical circuit function. There are numerous such mechanisms, so identifying which ones are actually engaged by optogenetic manipulations known to affect behavior would help flesh out exactly how γ oscillations contribute to cortical circuit function under normal and/or pathological conditions.
Klotho is an aging-modulating protein expressed mainly in the kidneys, which can be cleaved and shed to act as a circulating hormone. Several lines of evidence suggest a tight interaction between klotho and the GH-IGF-I axis. We showed previously that klotho levels are decreased in pediatric patients with growth hormone deficiency (GHD). Our aim now is to investigate the effect of GH therapy on klotho levels in these patients and to elucidate the role of IGF-1 in mediating secretion of klotho.
Klotho levels were measured in 29 GHD pediatric patients (males=15, aged 12.2±3.3years), treated with GH for 2.5±2.8years; nineteen patients had samples obtained both before and during treatment. The effect of IGF-I and its downstream effectors on secretion of klotho to media was studied in COS-7 cells overexpressing klotho.
Klotho levels increased under GH treatment (from 1321±691pg/ml to 3380±2120pg/ml, p<0.001), and were higher compared to controls (1645±778pg/ml, p<0.001), resulting in supraphysiological levels. Fold-increase in klotho correlated with fold-increase in IGF-I (r=0.63, p=0.004). Studies in COS-7 cells overexpressing klotho revealed mTOR-dependent induction of klotho shedding by IGF-I.
Klotho levels increased during GH treatment of pediatric GHD patients. This increase was associated with an increase in IGF-I levels. Furthermore, we showed, for the first time, a direct role of IGF-I in the regulation of klotho's shedding which depends on activation of the AKT-mTOR pathway. Our findings add further support for the close association between klotho and the GH/IGF-I axis.
Zinc and ring finger 3 (ZNRF3), which belongs to the E3 ubiquitin ligase family is involved in the progression and development of cancer. However, the expression and function of ZNRF3 in human nasopharyngeal carcinoma (NPC) remains unclear. Thus, the aim of this paper was to investigate the role of ZNRF3 in human nasopharyngeal carcinoma. Our results showed that ZNRF3 was downregulated in nasopharyngeal carcinoma cell lines. Restoration of ZNRF3 significantly inhibited the proliferation of NPC cells and tumor xenograft growth in vivo. In addition, overexpression of ZNRF3 suppressed migration and invasion, as well as attenuated the epithelial-mesenchymal transition (EMT) process in NPC cells. Furthermore, restoration of ZNRF3 obviously downregulated the expression levels of β-catenin, cyclin D1 and c-Myc in NPC cells. In conclusion, these data suggest that ZNRF3 inhibited the metastasis and tumorigenesis via suppressing the Wnt/β-catenin signaling pathway in NPC cells. Thus, ZNRF3 may act as a novel molecular target for the treatment of NPC.
Herein we report the quantification of purine lesions arising from gamma-radiation sourced hydroxyl radicals (HO(•)) on tertiary dsDNA helical forms of supercoiled (SC), open circular (OC), and linear (L) conformation, along with single-stranded folded and non-folded sequences of guanine-rich DNA in selected G-quadruplex structures. We identify that DNA helical topology and folding plays major, and unexpected, roles in the formation of 8-oxo-7,8-dihydro-2'-deoxyguanosine (8-oxo-dG) and 8-oxo-7,8-dihydro-2'-deoxyadenosine (8-oxo-dA), along with tandem-type purine lesions 5',8-cyclo-2'-deoxyguanosine (5',8-cdG) and 5',8-cyclo-2'-deoxyadenosine (5',8-cdA). SC, OC, and L dsDNA conformers together with folded and non-folded G-quadruplexes d[TGGGGT]4 (TG4T), d[AGGG(TTAGGG)3] (Tel22), and the mutated tel24 d[TTGGG(TTAGGG)3A] (mutTel24) were exposed to HO(•) radicals and purine lesions were then quantified via stable isotope dilution LC-MS/MS analysis. Purine oxidation in dsDNA follows L > OC ≫ SC indicating greater damage towards the extended B-DNA topology. Conversely, G-quadruplex sequences were significantly more resistant toward purine oxidation in their unfolded states as compared with G-tetrad folded topologies; this effect is confirmed upon comparative analysis of Tel22 (∼50% solution folded) and mutTel24 (∼90% solution folded). In an effort to identify the accessibly of hydroxyl radicals to quadruplex purine nucleobases, G-quadruplex solvent cavities were then modeled at 1.33 Å with evidence suggesting that folded G-tetrads may act as potential oxidant traps to protect against chromosomal DNA damage.
H2S is a novel vasoactivator. To verify the hypothesis that H2S may act as an endothelium-derived hyperpolarizing factor (EDHF) in the rat cerebrovasculature, the role of H2S in endothelium-derived relaxing factor (EDRF)-mediated responses was investigated.
Cystathionine-γ-lyase (CSE) was knocked down with an siRNA technique. Artery diameter, hyperpolarization and Ca2+-activated K+ (KCa) current were measured.
CSE knockdown was indicated by a decrease in protein and mRNA expression in the rat middle cerebral artery (MCA) and cerebral basilar artery (CBA). Acetylcholine (ACh) induced significant hyperpolarization and vasodilation in endothelium-intact MCA and CBA. Removal of the endothelium abolished these responses. The nitric oxide (NO) synthase inhibitor L-NAME, but not the PGI2 production inhibitor indomethacin, significantly inhibited ACh-induced hyperpolarization and vasodilation in the CBA. In the presence of L-NAME and indomethacin, ACh-induced hyperpolarization and vasodilation in the MCA and CBA were attenuated. The non-NO/PGI2-mediated responses were abolished by the KCa channel blockers charybdotoxin and apamin. In the cerebral arteries from the CSE knockdown rat, non-NO/PGI2-mediated responses were significantly attenuated, and the remaining responses were abolished by charybdotoxin and apamin or the CSE inhibitor propargylglycine. CSE knockdown did not affect L-NAME-sensitive responses in the CBA. Sodium hydrosulfide (NaHS) augmented the KCa current in CBA vascular smooth muscle cells.
EDHF-mediated responses in rat cerebral arteries were due to H2S activating the KCa channel.
The cytoplasmic tyrosine kinase ABL exerts positive or negative effects in solid tumours according to the cellular context, thus functioning as a "switch modulator". The therapeutic effects of drugs targeting a set of signals encompassing ABL have been explored in several solid tumours. However, the net contribution of ABL inhibition by these agents remains elusive as these drugs also act on other signalling components. Here, using glioblastoma (GBM) as a cellular paradigm, we report that ABL inhibition exacerbates mesenchymal features as highlighted by down-regulation of epithelial markers and up-regulation of mesenchymal markers. Cells with permanent ABL inhibition exhibit enhanced motility and invasive capabilities, while proliferation and tumorigenic properties are reduced. Intriguingly, permanent ABL inhibition also interferes with GBM neurosphere formation and with expression of stemness markers in sphere-cultured GBM cells. Furthermore, we show that the molecular and biological characteristics of GBM cells with impaired ABL are reversible by restoring ABL levels, thus uncovering a remarkable
 plasticity of GBM cells to ABL threshold. A phospho-signalling screen revealed that loss of tumorigenic and self-renewal properties in GBM cells under permanent ABL inhibition coincide with drastic changes in the expression and/or phosphorylation levels of multiple signalling components. Our findings identify ABL as a crucial player for migration, invasion, proliferation, tumorigenic, and stem-cell like properties of GBM cells. Taken together, this work supports the notion that the oncogenic role of ABL in GBM cells is associated with its capability to coordinate a signalling setting that determines tumorigenic and stem-cell like properties.
Autophagy is a recycling program which allows cells to adapt to metabolic needs and to stress. Defects in autophagy can affect metabolism, aging, proteostasis and inflammation. Autophagy pathway genes, including autophagy related 7 (Atg7), have been associated with the regulation of skin pigmentation, and autophagy defects disturb the biogenesis and transport of melanosomes in melanocytes as well as transfer and processing of melanin into keratinocytes. We have previously shown that mice whose melanocytes or keratinocytes lack Atg7 (and thus autophagy) as a result of specific gene knockout still retained functioning melanosome synthesis and transfer, and displayed only moderate reduction of pigmentation. In cell culture the Atg7 deficient melanocytes were prone to premature senescence and dysregulation of nuclear factor (erythroid-derived 2)-like 2 (Nrf2) signaling. To elucidate the biochemical basis of this phenotype, we performed a study on global gene expression, protein secretion and phospholipid composition in Atg7 deficient versus Atg7 expressing melanocytes. In cell culture Atg7 deficient melanocytes showed a pro-inflammatory gene expression signature and secreted higher levels of C-X-C motif chemokine ligand -1,-2,-10 and -12 (Cxcl1, Cxcl2, Cxcl10, Cxcl12), which are implicated in the pathogenesis of pigmentary disorders and expressed higher amounts of matrix metalloproteinases -3 and -13 (Mmp3, Mmp13). The analysis of membrane phospholipid composition identified an increase in the arachidonic- to linoleic acid ratio in the autophagy deficient cells, as well as an increase in oxidized phospholipid species that act as danger associated molecular patterns (DAMPs). The secretion of inflammation related factors suggests that autophagy deficient melanocytes display a senescence associated secretory phenotype (SASP), and we propose oxidized lipid mediators as novel components of this SASP.
Learning a new language requires the identification of word units from continuous speech (the speech segmentation problem) and mapping them onto conceptual representation (the word to world mapping problem). Recent behavioral studies have revealed that the statistical properties found within and across modalities can serve as cues for both processes. However, segmentation and mapping have been largely studied separately, and thus it remains unclear whether both processes can be accomplished at the same time and if they share common neurophysiological features. To address this question, we recorded EEG of 20 adult participants during both an audio alone speech segmentation task and an audiovisual word-to-picture association task. The participants were tested for both the implicit detection of online mismatches (structural auditory and visual semantic violations) as well as for the explicit recognition of words and word-to-picture associations. The ERP results from the learning phase revealed a delayed learning-related fronto-central negativity (FN400) in the audiovisual condition compared to the audio alone condition. Interestingly, while online structural auditory violations elicited clear MMN/N200 components in the audio alone condition, visual-semantic violations induced meaning-related N400 modulations in the audiovisual condition. The present results support the idea that speech segmentation and meaning mapping can take place in parallel and act in synergy to enhance novel word learning.
In recent years, the potential for anabolic steroid abuse in equine sports has increased due to the growing availability of designer steroids. These compounds are readily accessible online in 'dietary' or 'nutritional' supplements and contain steroidal compounds which have never been tested or approved as veterinary agents. They typically have unusual structures or substitution and as a result may pass undetected through current anti-doping screening protocols, making them a significant concern for the integrity of the industry. Despite considerable focus in human sports, until recently there has been limited investigation into these compounds in equine systems. To effectively respond to the threat of designer steroids, a detailed understanding of their metabolism is needed to identify markers and metabolites arising from their misuse. A summary of the literature detailing the metabolism of these compounds in equine systems is presented with an aim to identify metabolites suitable for incorporation into screening protocols by anti-doping laboratories. The future of equine anti-doping research is likely to be guided by the incorporation of alternate testing matrices into routine screening, the improvement of in vitro technologies that can mimic in vivo equine metabolism, and the improvement of instrumentation or analytical methods that allow for the development of untargeted screening, and metabolomics approaches for use in anti-doping screening protocols. Copyright © 2016 John Wiley & Sons, Ltd.
Salmonella is a key cause of foodborne gastroenteritis in Australia and case numbers are increasing. We used negative binomial regression to analyze national surveillance data for 2000-2013, for Salmonella Typhimurium and non-Typhimurium Salmonella serovars. We estimated incidence rate ratios adjusted for sex and age to show trends over time. Almost all states and territories had significantly increasing trends of reported infection for S. Typhimurium, with states and territories reporting annual increases as high as 12% (95% confidence interval 10-14%) for S. Typhimurium in the Australian Capital Territory and 6% (95% CI 5-7%) for non-Typhimurium Salmonella in Victoria. S. Typhimurium notification rates were higher than non-Typhimurium Salmonella rates in most age groups in the south eastern states of Australia, while non-Typhimurium rates were higher in most age groups elsewhere. The S. Typhimurium notification rate peaked at 12-23 months of age and the non-Typhimurium Salmonella notification rate peaked at 0-11 months of age. The age-specific pattern of S. Typhimurium cases suggests a foodborne origin, while the age and geographic pattern for non-Typhimurium may indicate that other transmission routes play a key role for these serovars.
Children are heavy users of the Internet and prior studies have shown that many of them lack a good understanding of the risks of doing so and how to avoid them. This study examined if the cross-age teaching zone (CATZ) intervention could help children acquire important knowledge of online risks and safety. It allowed older students to act as CATZ tutors to design and deliver a lesson to younger schoolmates (tutees), using content material about online risks and safety provided by adults. Students in Year 6 (mean age = 11.5 years) were randomly assigned to act as either CATZ tutors (n = 100) or age-matched controls (n = 46) and students in Year 4 (mean age = 9.5 years) acted as either CATZ tutees (n = 117) or age-matched controls (n = 28) (total N = 291). CATZ tutors, but not matched controls scored significantly higher on objective measures of knowledge of both online risks and safety, and CATZ tutees, but not matched controls did so for online safety. Effect sizes were moderate or large. CATZ was highly acceptable to participants. The results suggest that CATZ is a viable way to help school students learn about online dangers and how to avoid them.
Impact-generated lithologies have recently been identified as viable and important microbial habitats, especially within cold and arid regions such as the polar deserts on Earth. These unique habitats provide protection from environmental stressors, such as freeze-thaw events, desiccation, and UV radiation, and act to trap aerially deposited detritus within the fissures and pore spaces, providing necessary nutrients for endoliths. This study provides the first culture-independent analysis of the microbial community structure within impact-generated lithologies in a Mars analog environment, involving the analysis of 44,534 16S rRNA sequences from an assemblage of 21 rock samples that comprises three shock metamorphism categories. We find that species diversity increases (H = 2.4-4.6) with exposure to higher shock pressures, which leads to the development of three distinct populations. In each population, Actinobacteria were the most abundant (41%, 65%, and 59%), and the dominant phototrophic taxa came from the Chloroflexi. Calculated porosity (a function of shock metamorphism) for these samples correlates (R(2) = 0.62) with inverse Simpson indices, accounting for overlap in populations in the higher shock levels. The results of our study show that microbial diversity is tied to the amount of porosity in the target substrate (as a function of shock metamorphism), resulting in the formation of distinct microbial populations. Key Words: Microbial diversity-Endoliths-Impact melt-rocks-Mars-Astrobiology. Astrobiology 16, 775-786.
Regulatory peptides produced in islet and gut endocrine cells, including glucagon, glucagon-like peptide-1 (GLP-1), GLP-2, and glucose-dependent insulinotropic polypeptide, exert actions with considerable metabolic importance and translational relevance. Although the clinical development of GLP-1 receptor agonists
 and dipeptidyl peptidase-4 inhibitors has fostered research into how these hormones act on the normal and diseased heart, less is known about the actions of these peptides on blood vessels. Here we review the effects of these peptide hormones on normal blood vessels and highlight their vascular actions in the setting of experimental and clinical vascular injury. The cellular localization and signal transduction properties of the receptors for glucagon, GLP-1, GLP-2, and glucose-dependent insulinotropic polypeptide are discussed, with emphasis on endothelial cells and vascular smooth muscle cells. The actions of these peptides on the control of blood flow, blood pressure, angiogenesis, atherosclerosis, and vascular inflammation are reviewed with a focus on elucidating direct and indirect mechanisms of action. How these peptides traverse the blood-brain barrier is highlighted, with relevance to the use of GLP-1 receptor agonists to treat obesity and neurodegenerative disorders. Wherever possible, we compare actions identified in cell lines and primary cell culture with data from preclinical studies and, when available, results of human investigation, including studies in subjects with diabetes, obesity, and cardiovascular disease. Throughout the review, we discuss pitfalls, limitations, and challenges of the existing literature and highlight areas of controversy and uncertainty. The increasing use of peptide-based therapies for the treatment of diabetes and obesity underscores the importance of understanding the vascular biology of peptide hormone action.
The Food and Drug Administration (FDA or Agency) is amending its regulations on the definition of a custom device so as to include new enumerated statutory requirements for custom devices under the Federal Food, Drug, and Cosmetic Act (the FD&C Act) as amended by the Food and Drug Administration Safety and Innovation Act (FDASIA). This new provision, under FDASIA, amends the existing custom device exemption and introduces new concepts and procedures applicable to custom devices. This action is being taken to align the regulations with the FD&C Act.
The Food and Drug Administration (FDA or the Agency) is amending its regulations to revise the list of drug products that have been withdrawn or removed from the market because the drug products or components of such drug products have been found to be unsafe or not effective. Drugs appearing on this list may not be compounded under the exemptions provided by sections 503A and 503B of the Federal Food, Drug, and Cosmetic Act (the FD&C Act). Specifically, the rule adds 24 entries to this list of drug products, modifies the description of one entry on this list, and revises the list's title and introductory language. These revisions are necessary because information has come to the Agency's attention since March 8, 1999, when FDA published the original list as a final rule.
The Food and Drug Administration (FDA, the Agency, or we) is issuing a final rule to implement Title XI of the Medicare Prescription Drug, Improvement, and Modernization Act of 2003 (MMA), which amended provisions of the Federal Food, Drug, and Cosmetic Act (the FD&C Act) that govern the approval of 505(b)(2) applications and abbreviated new drug applications (ANDAs). This final rule implements portions of Title XI of the MMA that pertain to provision of notice to each patent owner and the new drug application (NDA) holder of certain patent certifications made by applicants submitting 505(b)(2) applications or ANDAs; the availability of 30-month stays of approval on 505(b)(2) applications and ANDAs that are otherwise ready to be approved; submission of amendments and supplements to 505(b)(2) applications and ANDAs; and the types of bioavailability and bioequivalence data that can be used to support these applications. This final rule also amends certain regulations regarding 505(b)(2) applications and ANDAs to facilitate compliance with and efficient enforcement of the FD&C Act.
Current evidence suggests that pollen is both chemically and structurally protected. Despite increasing interest in studying bee-flower networks, the constraints for bee development related to pollen nutritional content, toxicity and digestibility as well as their role in the shaping of bee-flower interactions have been poorly studied. In this study we combined bioassays of the generalist bee Bombus terrestris on pollen of Cirsium, Trifolium, Salix and Cistus genera with an assessment of nutritional content, toxicity and digestibility of pollen. Micro-colonies showed significant differences in their development, non-host pollen of Cirsium being the most unfavourable. This pollen was characterized by the presence of quite rare δ7-sterols and a low digestibility. Cirsium consumption seemed increase syrup collection, which is probably related to a detoxification mixing behaviour. These results strongly suggest that pollen traits may act as drivers of plant selection by bees and partly explain why Asteraceae pollen is rare in bee generalist diet. This article is protected by copyright. All rights reserved.
This paper introduces a biopsychosocial model for use as a tool by medical social workers and other rehabilitation professionals for the descriptive analysis of the case history and follow-up of patients needing rehabilitative support. The model is based on action theory and emphasizes the demands on evidence-based clarification of the interplay between a subject's contextual life situation, their ability to act in order to realize their goals, and their emotional adaptation. Using clinical experience and literature searches, a standard operations procedure to adequately document the case history in clinical practice is suggested, thus providing strategies through which the work of medical social workers can be based on evidence. Some specific areas of concern for the medical social worker within the rehabilitation of disabled people are highlighted.
The Personal Data Protection Act (PDPA) of Singapore was first passed in 2012, with subsequent enforcement regulations effective in 2014. Although medical education via digital platforms is not often used in medical schools in Singapore as of yet, many current means of communication at all levels in the medical community from medical schools to clinics to hospitals are unsecure and noncompliant with the PDPA.
This pilot study will assess the effectiveness of MyDoc, a secure, mobile telehealth application and messaging platform, as an educational tool, secure communications tool, and a tool to raise awareness of the PDPA.
By replacing current methods of communication with MyDoc and using weekly clinical case discussions in the form of unidentifiable clinical photos and questions and answers, we raised awareness the PDPA among medical students and gained feedback and determined user satisfaction with this innovative system via questionnaires handed to 240 medical students who experienced using MyDoc over a 6-week period.
All 240 questionnaires were answered with very positive and promising results, including all 100 students who were not familiar with the PDPA prior to the study attributing their awareness of it to MyDoc.
Potential uses of MyDoc in a medical school setting include PDPA-compliant student-to-student and student-to-doctor communication and clinical group case discussions with the sharing of patient-sensitive data, including clinical images and/or videos of hospital patients that students may benefit from viewing from an educational perspective. With our pilot study having excellent results in terms of acceptance and satisfaction from medical students and raising awareness of the PDPA, the integration of a secure, mobile digital health application and messaging platform is something all medical schools should consider, because our students of today are our doctors of tomorrow.
Present investigation concern with combination of two drugs for the treatment of gout. One of these drug (naproxen sodium) is pain killer which is sustain their action within the body for 12 hours and the other drug (colchicine) is anti-gout, which release as conventional dosage. After oral administration naproxen will act as sustain release dosage and increase patient compliance about six batches of tablet were developed and evaluate .For the sustain release action polymers Methocel K4M and HPMCK15were used. These polymers were used in combination used with other inactive ingredients. Two methods were used for proration of final tablets. In 1st method only naproxen sodium granules were prepared which are sustained released. In second method these granules were mixed with colchicines powder and other all inactive ingredients. This method is easy and cost effective characterization of pallets and final tablets were performed. Final tablets were evaluated for all tests like appearance, friability, dissolution, hardness, assay, weight variation and in-vitro release study performed. The results obtained were satisfactory and complies with USP specification. Formulation containing combination of Methocel K4M and HPMC K15 showed good sustain release profile for 12 hours.
The unregulated use of chemical weapons has aroused researchers to develop sensors for chemical warfare agents (CWA) and likewise to abolish their harmful effects, the degradation through catalysis has great advantage. Chemically, the CWAs are versatile; however, mostly they contain organophosphates that act on inhibition of acetyl cholinesterase. In this work, we have designed and synthesized some novel benzimidazolium based fluorescent cations and their fluorescent aggregates were fabricated using anionic surfactants (SDS and SDBS) in aqueous medium. The prepared fluorescent aggregates have shown aggregation induced emission enhancement, which was further used as detection of chemical
 warfare agent in aqueous medium. The aggregates (Benz-2/SDBS and Benz-3/SDBS) have shown significant changes in emission profile upon interaction with diethylchlorophosphate. Contrarily, the pure dipodal receptor Benz-4 has not shown any response in emission after interaction with organophosphate, and consequently, it was concluded that benzimidazolium cation plays a decisive role in sensing. The mechanism of sensing was fully validated using (31)P NMR spectroscopy as well as GC-MS, which highlights the transformation of diethylchlorophosphate into diethylhydrogen phosphate. The aggregates selectively interact with diethylchlorophosphate over other biological important phosphates.
The Food and Drug Administration (FDA) is publishing an order denying a petition requesting exemption from the premarket notification requirements for method, metallic reduction, glucose (urinary, nonquantitative) devices that are in a reagent tablet format and are classified as class II devices as urinary glucose (nonquantitative) test system (hereinafter referred to as "copper reduction tablet test"). Urinary glucose (nonquantitative) measurements are used in the diagnosis and treatment of carbohydrate metabolism disorders including diabetes mellitus, hypoglycemia, and hyperglycemia. FDA is publishing this order in accordance with procedures established by the Food and Drug Administration Modernization Act of 1997 (FDAMA).
The Food and Drug Administration (FDA) is publishing an order denying a petition requesting exemption from the premarket notification requirements for "method, metallic reduction, glucose (urinary, nonquantitative)'' devices that are in a reagent tablet format and are classified as class II devices as urinary glucose (nonquantitative) test system (hereinafter referred to as copper reduction tablet test"). Urinary glucose (nonquantitative) measurements are used in the diagnosis and treatment of carbohydrate metabolism disorders including diabetes mellitus, hypoglycemia, and hyperglycemia. FDA is publishing this order in accordance with procedures established by the Food and Drug Administration Modernization Act of 1997 (FDAMA).
None of the existing treatments in the management of painful end-neuromas of the superficial branch of the radial nerve (SBRN) has been proven superior due to high levels of pain relapse. Fat grafts enriched with the stromal vascular fraction (SVF) could act as a mechanic barrier with biological effects decreasing the resorption rate and boosting the graft's regenerative potential. This study describes the novel surgical treatment technique of SVF-enriched fat grafting.
In this clinical study, five consecutive patients treated for painful end-neuromas of the SBRN between 2012 and 2013 were analyzed retrospectively. Microsurgical resection of end-neuromas followed by SVF-enriched fat grafting around the nerve stump was performed in all patients. Five different pain modalities and various predictors were compared pre- and up to 36 months postoperatively.
Pain reduction observed at 2 months after surgery was constant over time, though not statistically significant compared to preoperative levels. Spontaneous pain could be reduced from 1.6 ± 0.55 to 1.2 ± 1.1 (p = 0.414), spikes from 2.2 ± 1.3 to 1.4 ± 1.34 (p = 0.180), hyperaesthesia from 1.6 ± 1.14 to 1.2 ± 1.64 (p = 0.713), tap pain from 2.8 ± 0.45 to 1.8 ± 1.3 (p = 0.197) and motion pain from 2.8 ± 0.45 to 1.4 ± 1.34 (p = 0.066). An improvement in overall pain reduction could be observed from 2.2 ± 0.97 to 1.4 ± 1.26 3 years after the surgery (p = 0.104).
SVF-enriched fat grafting represents another alternative to numerous available treatments of painful end-neuromas of the SBRN. Our preliminary results could not show any significant difference in pain reduction following SVF-enriched fat grafting. Further larger trials are required in order to evaluate the therapeutic potential of SVF-enriched fat grafting.
Protein-protein interactions that have large, flat and featureless binding sites are difficult drug targets. In the development of their modulators conventional drug discovery strategies are often unsuccessful. Gaining a detailed understanding of the binding mode of protein-protein interaction inhibitors is therefore of vast importance for their future pharmaceutical use. The MDM2/p53 protein pair is a highly promising target for cancer treatment. Disruption of the protein complex using p53 α-helix mimetics has been shown to be a successful strategy to control p53 activity. To gain further insight into the binding of inhibitors to MDM2, the flexibility of four cyclic β-hairpins that act as α-helical mimetics and potential MDM2/p53 interaction inhibitors was investigated in relation to their inhibitory activity. MDM2-binding of the mimetics was determined using fluorescence polarization and surface plasmon resonance assays, whereas their conformation and dynamics in solution was described by the combined experimental and computational NAMFIS analysis. Molecular flexibility was shown to be important for the activity of the cyclic β-hairpin based MDM2 inhibitors.
Graphene is an active element used in the design of nano-electro-mechanical systems (NEMS) owing to its excellent in-plane physical properties on mechanical, electric and thermal aspects. Considering a component requiring negative Poisson's ratio in NEMS, a graphene kirigami (GK) containing periodic re-entrant honeycombs is a natural option. This study demonstrates that a GK with specific auxetic property can be obtained by adjusting the sizes of its honeycombs. Using molecular dynamics experiments, the size effects on the auxetic behaviour of GK are investigated. In some cases, the auxetic difference between the hydrogenated GK and continuum kirigami (CK) is negligible, in which the results from macro CK can be used to predict auxetic behaviour of nano kirigami. Surface effect of GK is demonstrated from two aspects. One is to identify the difference of mechanical responses between the pure carbon GK and the hydrogenated GK at same geometry and loading condition. Another is from the difference of mechanical responses between the GK model and the CK model under same loading condition and geometric configuration. Generally, surface energy makes the GK possess higher variation of auxetic behaviour. It also results in higher modulus for the GK as comparing with that of the CK.
Leucine rich repeat kinase 2 is a complex enzyme with both kinase and GTPase activities, closely linked to the pathogenesis of several human disorders including Parkinson's disease, Crohn's disease, leprosy and cancer. LRRK2 has been implicated in numerous cellular processes; however its physiological function remains unclear. Recent reports suggest that LRRK2 can act to regulate the cellular catabolic process of macroautophagy, although the precise mechanism whereby this occurs has not been identified. To investigate the signalling events through which LRRK2 acts to influence macroautophagy, the mammalian target of rapamycin (mTOR)/Unc-51-like kinase 1 (ULK1) and Beclin-1/phosphatidylinositol 3-kinase (PI3K) pathways were evaluated in astrocytic cell models in the presence and absence of LRRK2 kinase inhibitors. Chemical inhibition of LRRK2 kinase activity resulted in the stimulation of macroautophagy in a non-canonical fashion, independent of mTOR and ULK1, but dependent upon the activation of Beclin 1-containing class III PI3-kinase.
Some cyanobacteria exhibit compaction of DNA in synchrony with their circadian rhythms accompanying cell division. Since the structure is transient, it has not yet been described in detail. Here, we successfully visualize the ultrastructure of compacted DNA in the cyanobacterium Synechococcus elongatus PCC 7942 under rigorous synchronized cultivation by means of high-voltage cryo-electron tomography. In 3D reconstructions of rapidly frozen cells, the compacted DNA appears as an undulating rod resembling a eukaryotic condensed chromosome. The compacted DNA also includes many small and paired polyphosphate bodies (PPBs), some of which seem to maintain contact with DNA that appears to twist away from them, indicating that they may act as interactive suppliers and regulators of phosphate for DNA synthesis. These observations throw light on the duplication and segregation mechanisms of cyanobacterial DNA and point to an important role for PPBs.
Physicians and Internists in India have tended to brush under the carpet legal issues affecting their profession. Of concern to all Physicians is the judgment in a recent case where the NCDRC has stated that if MD Medicine Physicians write Physician & Cardiologist on their letterhead it is Quackery. What is MD Medicine degree holder in India qualified and trained to treat ? These are issues which need debate and that can only be initiated once we recognize that there is a problem. Either an MD Medicine is a cardiologist or he is not. If he is then it is the bounded duty of the Association of Physicians of India to challenge this judgment in a higher court of law and seek clear guidelines from MCI as well as Supreme Court on the issue. Editors of Specialty journals have a responsibility of selecting the best articles from those which are submitted to them to be published. Ultimately space in these journals is limited and hence the responsibility to select is enormous and simultaneously reason for rejection of an academic paper also has to be substantial. The question is "do issues which are not core to the specialty concerned deserve space in these?" Physicians and Internists in India have tended to brush under the carpet legal issues effecting their profession. Surgical specialties specially obstetricians and their associations have to some extent recognized the problem and taken steps to address the issue specially as regard PCPNDT Act.1 Physicians
 are more complacent and regard the Consumer Protection Act (CPA) 19862 and problems associated with it to primarily concern the surgical specialties. What is forgotten is that the maximum penalty of 6.08 crore plus interest of 5.5 cr has been awarded in case involving a patient treated primarily by a physician and on whom no surgical procedure was performed.3 It has also to be realized that there is no limit on the amount of compensation which can be asked for under CPA.2 Compensations have been awarded by National Consumer Dispute Redressal Commission (NCDRC) in a case where patient had fever with low platelet count for not doing LFT and ultrasound as patient later died of fulminant hepatic failure. Decisions have been given in complicated medical cases like GI Bleed in which the issue has been what modality should be chosen (balloon tamponade vs sclerotherapy),4 whether peritoneal lavage should have been done for acute pancreatitis. Trials in Consumer Fora being inherently Summary in nature and are meant to provide speedy redressal of greiviance of a consumer. These quasi judicial bodies are not exactly the place where complicated medical issues can be debated satisfactorily. Of concern to all Physicians is the judgment in a recent case where the NCDRC has stated that if MD Medicine Physicians write Physician & Cardiologist on their letterhead it is Quackery and also a clear case of negligence if he treats Rheumatic Valvular Heart Disease.5 The Honorable Supreme Court has already in 2009 decided that "if representation is made by a doctor that he is a specialist and ultimately turns out that he is not, deficiency in medical services would be presumed.6 An advisory has been issued by NCDRC in 2013 "to Medical Council of India and Health Ministry to initiate steps to strike down such practices of medical professionals who are posing as a specialist or misrepresenting as a superspecialist without any approved qualification by statute or controlling authority. In other words it is quackery, that is treating the patients in absence of a valid degree. Our questions are simple; 1) What is MD Medicine degree holder in India qualified and trained to treat ? 2) Is MD Medicine degree holder a qualified specialist and if so what is he specialist of ? Resolving this issue is extremely important in a country where quack AYUSH (BAMS, GAMS, BUMS, BHMS), MBBS doctor and even Physiotherapists are all qualified "Physicians". Given the substantial patient population which is uneducated and / or non-discerning, those with specialized training (MD Medicine) use terminologies like Heart Specialist, Cardiologist, Gastroenterologist, Endocrinologist, Specialist in Diabetes, Neurologist in addition to the Consultant Physician on their letterheads and nameplates. In absence of adequate number of qualified DM, DNB superspecialists in the country, it is MD Medicine doctors who work in various super-specialties in which they are trained and competent. Despite this well known fact no Association or Organization deemed it fit to challenge a judgment which discredits this practice and is logically out of sync with reality in a country like India. There is also the issue of differential liability for doctors while working in Government Hospitals and those working in private hospitals. If MD Medicine doing echocardiography is outright negligence in private sector it would also be so in Government Sector. In absence of DM Cardiologists most district hospitals and civil hospitals have MD Medicine doctors who are the official cardiologists doing echocardiography and other non-invasive investigations, reporting them and treating cardiology patients. The Goyal Hospital judgment had also stated that among "rampant unethical medical practices in India it is most common that nursing homes and hospitals provide facilities like diagnostic laboratory, radiology or sonology units without a specialist like Radiologist and Pathologist". Even under PCPNDT Act the requisite qualification to do ultrasonography is not only "MD Radiology". An MBBS doctor with required training or even a gynecologist is competent to do ultrasonography under the Act.1,2 No Government civil hospital or even General Hospitals in any state / UT has Radiologists or Pathologists, Anesthetists, Neurologists, Psychiatrists and more. If an MBBS degree along with training in required discipline is adequate qualification in a Government Hospital how can it not be in a Private Hospital. If however an MD Medicine doing echocardiography is negligence in a private hospital then it also has to also be so in a Government one. Most Government Hospitals including ESI hospitals7,8 are today covered under Consumer Protection Act hence differential liability is unacceptable. Training program and study curriculum of MD Medicine includes cardiology and the residents are posted in cardiology wards and ICCUs in all teaching institutions despite being only MBBS at the time. Though some institutions do not encourage active involvement in clinical care to be done by residents (who are as yet only MBBS) but most hospitals use the resident doctors as cheap workforce in various departments including cardiology. If in an institution the MD student is qualified to treat a cardiology patient under nominal supervision if at all, then a MD (Medicine) degree holder specially if has received further training should be able to perform routine functions of a cardiologist like doing an echocardiogram. Either way these are issues which need debate and that can only be initiated once we recognize that there is a problem. An ostrich-like attitude will not solve any conflict. Each conference of Association of Physicians of India has workshops on echocardiography, live demonstrations of difficult percutaneous interventions and talks on newer techniques in treatment of heart failure. If MD Medicine doctors are not specialists capable of treating cardiology patients, why burden them with knowledge they do not need. Their Association should focus on providing them knowledge and updates in their field of work of which they are specialists. Either an MD Medicine is a cardiologist or he is not. If he is then it is the bounded duty of the Association of Physicians of India to challenge this judgment in a higher court of law and seek clear guidelines from MCI as well as Supreme Court on the issue. Whether this challenge is done or not is also secondary to the question, whether these are issues important enough to be raised in speciality journals, to stimulate discussion and generate consensus.
IgA nephropathy (IgAN) is a common complex disease with a strong genetic involvement. We aimed to identify novel, rare, highly penetrant risk variants combining family-based linkage analysis with whole-exome sequencing (WES).
Linkage analysis of 16 kindreds of South Italian ancestry was performed using an 'affected-only' strategy. Eight most informative trios composed of two familial cases and an intrafamilial control were selected for WES. High-priority variants in linked regions were identified and validated using Sanger sequencing. Custom TaqMan assays were designed and carried out in the 16 kindreds and an independent cohort of 240 IgAN patients and 113 control subjects.
We found suggestive linkage signals in 12 loci. After sequential filtering and validation of WES data, we identified 24 private or extremely rare (MAF <0.0003) linked variants segregating with IgAN status. These were present within coding or regulatory regions of 23 genes that merged into a common functional network. The genes were interconnected by AKT, CTNNB1, NFKB, MYC and UBC, key modulators of WNT/β-catenin and PI3K/Akt pathways, which are implicated in IgAN pathogenesis. Overlaying publicly available expression data, genes/proteins with expression notably altered in IgAN were included in this immune-related network. In particular, the network included the glucocorticoid receptor gene, NR3C1, which is the target of corticosteroid therapy routinely used in the treatment of IgAN.
Our findings suggest that disease susceptibility could be influenced by multiple rare variants acting in a common network that could provide the starting point for the identification of potential drug targets for personalized therapy.
With insulin-resistance or type 2 diabetes mellitus, mismatches between mitochondrial fatty acid fuel delivery and oxidative phosphorylation/tricarboxylic acid cycle activity may contribute to inordinate accumulation of short- or medium-chain acylcarnitine fatty acid derivatives (markers of incomplete long-chain fatty acid oxidation [FAO]). We reasoned that incomplete FAO in muscle would be ameliorated concurrent with improved insulin sensitivity and fitness following a ∼14 wk training and weight loss intervention in obese, sedentary, insulin-resistant women. Contrary to this hypothesis, overnight-fasted and exercise-induced plasma C4-C14 acylcarnitines did not differ between pre-intervention and post-intervention phases. These metabolites all increased robustly with exercise (∼45% of pre-intervention VO2peak ) and decreased during a 20 min cool-down. This supports the idea that, regardless of insulin sensitivity and fitness, intramitochondrial muscle β-oxidation and attendant incomplete FAO are closely tethered to absolute ATP turnover rate. Acute exercise also led to branched-chain amino acid (BCAA) acylcarnitine derivative patterns suggestive of rapid diminution of BCAA flux through mitochondrial branched-chain ketoacid dehydrogenase complex. We confirmed our prior novel observation that weight loss/fitness intervention alters plasma xenometabolites (i.e., cis-3,4-methylene-heptanoylcarnitine and γ-butyrobetaine [a co-metabolite possibly derived in part from gut bacteria]), suggesting that host metabolic health regulated gut microbe metabolism. Finally, we considered
 if acylcarnitine metabolites signal to muscle-innervating afferents: palmitoylcarnitine at concentrations as low as 1-10 μm activated a sub-set (∼2.5-5%) of these neurons ex vivo. This supports the hypothesis that in addition to tracking exercise-associated shifts in fuel metabolism, muscle acylcarnitines act as exertion signals to short-loop somatosensory-motor circuits or to the brain. This article is protected by copyright. All rights reserved.
The main objectives of these two phase I studies were to investigate safety and tolerability as well as the pharmacokinetic/pharmacodynamic profile of the novel potent and selective formyl peptide receptor type 2 (FPR2)/Lipoxin A4 receptor (ALX) agonist ACT-389949. A challenge model was used to assess the drug's anti-inflammatory potential, with the aim of selecting a dosing regimen for future patient studies.
Two double-blind, randomized phase I studies investigated the safety, tolerability, pharmacokinetics and pharmacodynamics of ACT-389949 at different doses and dosing regimens. Drug exposure was correlated with target engagement markers such as receptor internalization and cytokine measurements. The effect of FPR2/ALX agonism on neutrophil migration was studied in a lipopolysaccharide (LPS) inhalation model.
ACT-389949 was well tolerated. Maximum concentrations were reached around 2 h after dosing, with a mean terminal half-life of 29.3 h [95% confidence interval (CI) 25.5, 33.7]. After multiple-dose administration, exposure increased by 111% (95% CI 89, 136), indicating drug accumulation. Administration of ACT-389949 resulted in a dose-dependent, long-lasting internalization of FPR2/ALX into leukocytes. Pro- and anti-inflammatory cytokines were dose-dependently but transiently upregulated only after the first dose. No pharmacological effect on neutrophil count was observed in the LPS challenge test performed at steady state.
FPR2/ALX agonism with ACT-389949 was shown to be safe and well tolerated in healthy subjects. Receptor internalization and downstream mediators pointed towards a desensitization of the system, which may explain the lack of effect on neutrophil recruitment in the LPS challenge model.
Sustainable exploitation of fisheries populations is challenging to achieve when the size of the population prior to exploitation and the actual numbers removed over time and across fishing zones are not clearly known. Quantitative fisheries' modeling is able to address this problem, but accurate and reliable model outcomes depend on high quality input data. Much of this information is obtained through the operation of the fishery under consideration, but while this seems appropriate, biases may occur. For example, poorly quantified changes in fishing methods that increase catch rates can erroneously suggest that the overall population size is increasing. Hence, the incorporation of estimates of abundance derived from independent data sources is preferable. We review and evaluate a fisheries-independent method of indexing population size; inferring adult abundance from estimates of the genetic effective size of a population (Ne ). Recent studies of elasmobranch species have shown correspondence between Ne and ecologically determined estimates of the population size (N). Simulation studies have flagged the possibility that the range of Ne /N ratios across species may be more restricted than previously thought, and also show that declines in Ne track declines in the abundance of model fisheries species. These key developments bring this new technology closer to implementation in fisheries science, particularly for data-poor fisheries or species of conservation interest.
Translation of mitochondrial encoded mRNAs by mitochondrial ribosomes is thought to play a major role in regulating the expression of mitochondrial proteins. However, the structure and function of plant mitochondrial ribosomes remains poorly understood. To study mitochondrial ribosomes, it is necessary to separate them from plastidic and cytosolic ribosomes that are generally present at much higher concentrations. Here, a straight forward protocol for the preparation of fractions highly enriched in mitochondrial ribosomes from plant cells is described. The method begins with purification of mitochondria followed by mitochondrial lysis and ultracentrifugation of released ribosomes through sucrose cushions and gradients. Dark-grown Arabidopsis cells were used in this example because of the ease with which good yields of pure mitochondria can be obtained from them. However, the steps for isolation of ribosomes from mitochondria could be applied to mitochondria obtained from other sources. Proteomic analyses of resulting fractions have confirmed strong enrichment of mitochondrial ribosomal proteins.
A solubility diagram was employed to understand growth promotion of Arthrospira (Spirulina) platensis by steelmaking slag (SMS). The growth promotion effect of 112 % of freshwater microalga A. platensis was obtained using 5 g/L SMS. However, metabolites, such as pigments, and protein content of A. platensis were not significantly affected. Several metals dissolved in Spirulina-Ogawa-Terui medium were detected by inductively coupled plasma atomic emission spectrometry just after the addition of SMS. The solubility diagram provides information on the chemical speciation of metal elements based on pH and concentration. It is a useful tool to understand the effect of metals on microalgal growth. The metal elements used to control microalgal growth are essential minerals but also act as a source of oxidative stress. Regarding the affecting mechanism of SMS, iron may be the primary element regulating microalgal growth via pathway involving reactive oxygen species, as revealed by superoxide dismutase assay.
In 1999-2003, SIIM (then SCAR) sponsored the creation of several special topic Primers, one of which was concerned with computer security. About the same time, a multi-society collaboration authored an ACR Guideline with a similar plot; the latter has recently been updated. The motivation for these efforts was the launch of Health Information Portability and Accountability Act (HIPAA). That legislation directed care providers to enable the portability of patient medical records across authorized medical centers, while simultaneously protecting patient confidentiality among unauthorized agents. These policy requirements resulted in the creation of numerous technical solutions which the above documents described. While the mathematical concepts and algorithms in those papers are as valid today as they were then, recent increases in the complexity of computer criminal applications (and defensive countermeasures) and the pervasiveness of Internet connected devices have raised the bar. This work examines how a medical center can adapt to these evolving threats.
This study examined differences in self-regulation among college-age expert, moderately expert, and non-expert video game players in playing video games for fun. Winne's model of self-regulation (Winne, 2001) guided the study. The main assumption of this study was that expert video game players used more processes of self-regulation than the less-expert players. We surveyed 143 college students about their game playing frequency, habits, and use of self-regulation. Data analysis indicated that while playing recreational video games, expert gamers self-regulated more than moderately expert and non-expert players and moderately expert players used more processes of self-regulation than non-experts. Semi-structured interviews also were conducted with selected participants at each of the expertise levels. Qualitative follow-up analyses revealed five themes: (1) characteristics of expert video gamers, (2) conditions for playing a video game, (3) figuring out a game, (4) how gamers act and, (5) game context. Overall, findings indicated that playing a video game is a highly self-regulated activity and that becoming an expert video game player mobilizes multiple sets of self-regulation related skills and processes. These findings are seen as promising for educators desiring to encourage student self-regulation, because they indicate the possibility of supporting students via recreational video games by recognizing that their play includes processes of self-regulation.
Specific profile of microRNAs (miRNAs, miR) expressed in psoriasis has been identified in the past few years, while the studies on roles and molecular mechanisms of these miRNAs are still on the way. In our previous study, four specific miRNAs (miR-31, miR-203, hsa-miR-99a and miR-125b) were found to be specifically altered in psoriatic lesions.We therefore conducted a systematic literature review in this study to reveal the role of these miRNAs in the pathogenesis of psoriasis in order to inform future research.
The related articles indexed in PubMed (MEDLINE) database were searched and analyzed. We identified eligible studies related to the mechanism research of miR-31, miR-203, hsa-miR-99a and miR-125b in psoriasis or psoriatic lesional skin from inception up to July 2016. The experts in the field of miRNAs and Psoriasis were involved in analysis process.
Both miR-31 and miR-203 are dramatically upregulated in psoriatic lesions. The former plays the pro-proliferative, pro-differentiative and pro-inflammatory roles and the latter holds the potentials for anti-proliferation, pro-inflammation and pro-differentiation in psoriatic keratinocytes. Conversely, both hsa-miR-99a and miR-125b are significantly downregulated in psoriatic skin. These two miRNAs are able to inhibit proliferation while promote differentiation of psoriatic keratinocytes, and miR-125b can also suppress inflammation in psoriatic lesions. By analyzing the contexts related to these miRNAs, we found that each of them does not act alone but
 rather work in concert with other miRNAs. The imbalance between miR-31/miR-203and hsa-miR-99a/miR-125b may contribute to the intense proliferation and abnormal differentiation of psoriatic keratinocytes, which is a characteristic of pathogenesis of psoriasis.
An imbalanced miRNAs axis was for the first time outlined. Apparently, upregulation of miR-31/miR-203 and downregulation of hsa-miR-99a/miR-125b work together in concert to facilitate the development of psoriasis pathogenesis. Further work in this field holds the potentials to open a new way to study psoriasis.
Phytoene synthase (PSY) catalyzes the highly regulated, frequently rate-limiting synthesis of the first biosynthetically formed carotene. While PSY constitutes a small gene family in most plant taxa, the Brassicaceae, including Arabidopsis (Arabidopsis thaliana), predominantly possess a single PSY gene. This monogenic situation is compensated by the differential expression of two alternative splice variants (ASV), which differ in length and in the exon/intron retention of their 5'UTRs. ASV1 contains a long 5'UTR (untranslated region) and is involved in developmentally regulated carotenoid formation, such as during deetiolation. ASV2 contains a short 5'UTR and is preferentially induced when an immediate increase in the carotenoid pathway flux is required, such as under salt stress or upon sudden light intensity changes. We show that the long 5'UTR of ASV1 is capable of attenuating the translational activity in response to high carotenoid pathway fluxes. This function resides in a defined 5'UTR stretch with two predicted interconvertible RNA conformations, as known from riboswitches, which might act as a flux sensor. The translation-inhibitory structure is absent from the short 5'UTR of ASV2 allowing to bypass translational inhibition under conditions requiring rapidly increased pathway fluxes. The mechanism is not found in the rice (Oryza sativa) PSY1 5'UTR, consistent with the prevalence of transcriptional control mechanisms in taxa with multiple PSY genes. The translational control mechanism identified is interpreted in terms of flux adjustments needed in response to retrograde signals stemming from intermediates of the plastid-localized carotenoid biosynthesis pathway.
Public opinion about the Affordable Care Act (ACA) has been polarized since the law's passage. Past research suggests these conditions would make any media influence on the public limited at best. However, during the early phase of implementation, locally broadcast ACA-related media messages-in the form of paid health insurance and political advertisements and news media stories-abounded as advocates, insurance marketers, and politicians sought to shape the public's perceptions of the law. To what extent did message exposure affect ACA perceptions during the first open enrollment period? We merge data on volumes of messaging at the media market level with nationally representative survey data to examine the relationship between estimated exposure to media messaging and the public's perceptions of how informed they were about and favorable toward the ACA in October 2013. We find that higher volumes of insurance advertising and local news coverage are associated with participants' perceptions of being informed about the law. Volumes of insurance advertising and of local news coverage are also associated with participants' favorability toward the law, but the relationship varies with partisanship, supporting the growing body of research describing partisan perceptual bias of media.
In most animals, female meiosis completes only after fertilization. Sperm entry has been implicated in providing a signal for the initiation of the final meiotic processes; however, a maternal component required for this process has not been previously identified. We report the characterization of a novel family of three highly similar paralogs (memi-1, memi-2, memi-3) that encode oocyte-specific proteins. A hyper-morphic mutation memi-1(sb41) results in failure to exit female meiosis II properly; however, loss of all three paralogs results in a "skipped meiosis II" phenotype. Mutations that prevent fertilization, such as fer-1(hc1), also cause a skipped meiosis II phenotype, suggesting that the MEMI proteins represent a maternal component of a postfertilization signal that specifies the meiosis II program. MEMI proteins are degraded before mitosis and sensitive to ZYG-11, a substrate-specific adapter for cullin-based ubiquitin ligase activity, and the memi-1(sb41) mutation results in inappropriate persistence of the MEMI-1 protein into mitosis. Using an RNAi screen for suppressors of memi-1(sb41), we identified a sperm-specific PP1 phosphatase, GSP-3/4, as a putative sperm component of the MEMI pathway. We also found that MEMI and GSP-3/4 proteins can physically interact via co-immunoprecipitation. These results suggest that sperm-specific PP1 and maternal MEMI proteins act in the same pathway after fertilization to facilitate proper meiosis II and the transition into embryonic mitosis.
Nicotinic α-7 acetylcholine receptor (nAChRα7) is a critical regulator of cholinergic anti-inflammatory actions in several diseases, including acute respiratory distress syndrome (ARDS). Given the potential importance of α7nAChR as a therapeutic target, we evaluated whether PNU-282987, an α7nAChR agonist, is effective in protecting the lung against inflammation. We performed intratracheal instillation of LPS to generate acute lung injury (ALI) in C57BL/6 mice. PNU-282987 treatment, either before or after ALI induction, reduced neutrophil recruitment and IL-1β, TNF-α, IL-6, keratinocyte chemoattractant (KC), and IL-10 cytokine levels in the bronchoalveolar lavage fluid (P < 0.05). In addition, lung NF-κB phosphorylation decreased, along with collagen fiber deposition and the number of matrix metalloproteinase-9(+) and -2(+) cells, whereas the number of tissue inhibitor of metalloproteinase-1(+) cells increased (P < 0.05). PNU-282987 treatment also reduced lung mRNA levels and the frequency of M1 macrophages, whereas cells expressing the M2-related markers CD206 and IL-10 increased, suggesting changes in the macrophage profile. Finally, PNU-282987 improved lung function in LPS-treated animals. The collective results suggest that PNU-282987, an agonist of α7nAChR, reduces LPS-induced experimental ALI, thus supporting the notion that drugs that act on α7nAChRs should be explored for ARDS treatment in humans.-Pinheiro, N. M., Santana, F. P. R., Almeida, R. R., Guerreiro, M., Martins, M. A., Caperuto, L. C., Câmara, N. O. S., Wensing, L. A., Prado, V. F., Tibério, I. F. L. C., Prado, M. A. M., Prado, C. M. Acute lung injury is reduced by the α7nAChR agonist PNU-282987 through changes in the macrophage profile.
RNA binding proteins (RBPs) control the fate and expression of a transcriptome. Despite this fundamental importance, our understanding of plant RBPs is rudimentary, being mainly derived via bioinformatic extrapolation from other kingdoms. Here, we adapted the mRNA-protein interactome capture method to investigate the RNA binding proteome in planta. From Arabidopsis thaliana etiolated seedlings, we captured more than 700 proteins, including 300 with high confidence that we have defined as the At-RBP set. Approximately 75% of these At-RBPs are bioinformatically linked with RNA biology, containing a diversity of canonical RNA binding domains (RBDs). As no prior experimental RNA binding evidence exists for the majority of these proteins, their capture now authenticates them as RBPs. Moreover, we identified protein families harboring emerging and potentially novel RBDs, including WHIRLY, LIM, ALBA, DUF1296, and YTH domain-containing proteins, the latter being homologous to animal RNA methylation readers. Other At-RBP set proteins include major signaling proteins, cytoskeleton-associated proteins, membrane transporters, and enzymes, suggesting the scope and function of RNA-protein interactions within a plant cell is much broader than previously appreciated. Therefore, our foundation data set has provided an unbiased insight into the RNA binding proteome of plants, on which future investigations into plant RBPs can be based.
Biological tissues at articulating surfaces, such as articular cartilage, typically have remarkable low-friction properties that limit tissue shear during movement. However, these frictional properties change with trauma, aging, and disease, resulting in an altered mechanical state within the tissues. Yet, it remains unclear how these surface changes affect the behaviour of embedded cells when the tissue is mechanically loaded. Here, we developed a cytocompatible, bilayered hydrogel system that permits control of surface frictional properties without affecting other bulk physicochemical characteristics such as compressive modulus, mass swelling ratio, and water content. This hydrogel system was applied to investigate the effect of variations in surface friction on the biological response of human articular chondrocytes to shear loading. Shear strain in these hydrogels during dynamic shear loading was significantly higher in high-friction hydrogels than in low-friction hydrogels. Chondrogenesis was promoted following dynamic shear stimulation in chondrocyte-encapsulated low-friction hydrogel constructs, whereas matrix synthesis was impaired in high-friction constructs, which instead exhibited increased catabolism. Our findings demonstrate that the surface friction of tissue-engineered cartilage may act as a potent regulator of cellular homeostasis by governing the magnitude of shear deformation during mechanical loading, suggesting a similar relationship may also exist for native articular cartilage.
Excessive mechanical loading is believed to be a major risk factor inducing pathogenesis of articular cartilage and
 other load-bearing tissues. Yet, the mechanisms leading to increased transmission of mechanical stimuli to cells embedded in the tissue remain largely unexplored. Here, we demonstrate that the tribological properties of loadbearing tissues regulate cellular behaviour by governing the magnitude of mechanical deformation arising from physiological tissue function. Based on these findings, we propose that changes to articular surface friction as they occur with trauma, aging, or disease, may initiate tissue pathology by increasing the magnitude of mechanical stress on embedded cells beyond a physiological level.
Valosin-containing protein (VCP) or p97, a member of AAA-ATPase protein family, has been associated with various cellular functions including endoplasmic reticulum-associated degradation (ERAD), Golgi membrane reassembly, autophagy, DNA repair, and cell division. Recent studies identified VCP and ubiquitin proteasome system (UPS) as synthetic lethal targets in ovarian cancer. Here, we describe the preclinical activity of VCP inhibitors in ovarian cancer. Results from our studies suggest that quinazoline-based VCP inhibitors initiate G1 cell cycle arrest, attenuate cap-dependent translation and induce programmed cell death via the intrinsic and the extrinsic modes of apoptosis. Mechanistic studies point to the unresolved unfolded protein response (UPR) as a mechanism by which VCP inhibitors contribute to cytotoxicity. These results support an emerging concept that UPR and endoplasmic reticulum (ER) stress pathways may be targeted in ovarian cancer as a source of vulnerability. Since prolonged ER stress may result in CHOP-mediated cell death, we tested the hypothesis that VCP inhibitors act synergistically with compounds that enhance CHOP expression. Here, we show that VCP inhibitors act synergistically with Salubrinal, an inhibitor of eIF2α dephosphorylation, by enhancing CHOP expression in ovarian cancer cell lines. Our results provide a proof-of-concept that VCP inhibitors can be used as a single agent and can be synergized with compounds that enhance CHOP expression to induce cell death in ovarian cancer cells.
The quality and efficiency of newborn hearing screening programs (NHS) rely heavily on appropriate follow-up. The Joint Committee on Infant Hearing recommends a follow-up rate of more than 95% of infants who fail the initial hearing screening. However, a 70% benchmark is considered to be more feasible. This high loss to follow-up (LTF) rate acts as a threat to the overall success of NHS programs. The objective of the study was to identify and examine the reported rates of LTF, attributed reasons for LTF and strategies undertaken to reduce LTF.
Using a systematic search, articles published between 2005 to December 2015 were identified from PubMed/Medline, Cumulative Index to Nursing and Allied Health Literature (CINAHL), Educational Resources Information Center (ERIC), Scopus, Ovid, ProQuest, and Cochrane Library. To be included in the review, the study should be exploring the loss to follow-up or drop-out rate in newborn hearing screening programs and be published in an indexed peer-reviewed journal in the English language. The main outcome measures were overall rate of LTF, factors leading to LTF and measures adopted to overcome LTF.
53 articles were short-listed for data extraction. Out of these, 27 were single-centre studies, 19 were multi-centre, 3 compared multiple databases, and 4 used survey-based methods. Overall LTF rates of 20% in single-centre and 21% in multiple-centre studies were observed. Educational disparity and lack of adequate knowledge among parents were associated with LTF. The most commonly used strategy to overcome LTF suggested by studies was the use of an adequate data management system.
This review is a novel attempt to explore the LTF among NHS studies, reasons for LTF and strategies to reduce LTF. This review can act as a basis for planning and execution of effective NHS programs.
Acts of targeted violence - including active shooter incidents - are typically over within 15 minutes, often before the first law enforcement personnel can respond to the scene. More than a third of active shooter incidents in the USA, for example, last less than five minutes. While this stark fact is often used, with unimpeachable validity, as the cornerstone of employee security awareness training and the need for each employee to make a quick decision on whether to run, hide or fight, it also underscores the importance of another critical priority: prevention. This paper focuses on several of the most effective strategies and tactics - increasingly used across the USA, but applicable all over the world - in preventing an act of targeted violence or active shooter event. It starts with a brief discussion of the common roadblocks to prevention within enterprises today as well as the warning signs that can reveal an individual's path toward an act of violence. Next, it defines targeted violence and summarises patterns that research has helped uncover with respect to attackers' backgrounds, motives and target selection. This paper also outlines the crucial role played by protective intelligence and threat assessment protocols and provides several case studies to illustrate key concepts in real-world applications. Finally, this discussion points to several emerging trends in the USA and Europe, among other regions - such as radicalisation within the workforce - that are likely to continue to mature in 2016 and the years ahead.
Graft-versus-host disease (GVHD) after liver and kidney transplantation has high mortality and causes diagnostic challenges. This study aims to describe the cytokine and human leukocyte antigen (HLA) profile in the GVHD after liver and kidney transplantation.
A high-throughput detection kit was applied and altogether 18 different cytokines were tested simultaneously. GVHD patients included 23 post-liver transplantation patients; 22 post-renal transplantation patients; The control patients include 22 hepatocellular carcinoma (HCC) patients without transplantation and 20 healthy controls. Their HLA characters were compared.
The full spectrum of cytokines was present. The inflammatory markers were activated significantly in liver transplantation. The level of inflammatory markers in liver transplantation was higher than that in renal transplantation, HCC or healthy controls. GVHD was associated with the HLA characters; HLA characters are involved in liver GVHD occurrence and act as risk factors.
Our findings confirmed that the inflammatory cytokines play a pathogenic role in GVHD and can be used as early diagnostic markers. The HLA mismatch acts as a risk factor in liver transplantation to predict GVHD occurrence.
Socioeconomic inequalities in cancer survival can in part be explained by long patient intervals among people from deprived groups; however, the reasons for this are unclear. This qualitative study explores the actual and anticipated barriers to cancer symptom presentation in the context of socioeconomic deprivation.
Thirty participants were recruited through the International Cancer Benchmarking Partnership Welsh database (n = 20), snowball sampling (n = 8) and community partners (n = 2). Semi-structured qualitative interviews were conducted with symptomatic and asymptomatic adults over the age of 50 years, who were identified as being from a low socioeconomic group based on multiple individual and group level indicators. Transcripts were analysed using a Framework approach based on the COM-B model (Capability, Opportunity, Motivation-Behaviour).
There was evidence of poor awareness of non-specific cancer symptoms (Capability), fearful and fatalistic beliefs about cancer (Motivation), and various barriers to accessing an appointment with the family physician (Opportunity) and full disclosure of symptoms (Capability). These in combination were associated with a lengthened patient interval among participants. Social networks (Opportunity) were influential on the formation of knowledge and beliefs about cancer. Participants' behavioural and normative beliefs were usually formed and reinforced by people they knew with cancer, and such beliefs were considered to lengthen the patient interval. Discussing symptoms with a family member or friend before a visit to the family physician was the norm, and could act as a barrier or facilitator depending on the quality of advice given (Opportunity). Economic hardship meant fulfilling basic day-to-day needs such as finding money for food were prioritised over medical help seeking (Opportunity).
The complex interaction between individual characteristics and socio-environmental factors is important for understanding cancer symptom presentation behaviour, especially in the context of socioeconomic deprivation. Interventions targeted at deprived communities should take into account the wider social influences on symptom presentation behaviour.
No study has assessed the association between patients' and doctors' gender and patient satisfaction with organizational aspects of health care in primary care. However, just like satisfaction regarding communication styles or technical skills, satisfaction towards organization of the general practitioner (GP) practice could also depend on doctors' and/or patients' gender. Different expectations between female and male patients regarding the organization of the practice or different ways of organizing care delivery between female and male GPs could act on this satisfaction. We aimed to compare female and male patients' satisfaction towards their GP overall, and according to GPs' gender.
In a cross-sectional study in Geneva, 23 randomly selected GPs (participation rate: 31 %) were asked to recruit up to 100 consecutive patients coming to the practice for a scheduled medical consultation. The patients
 completed an anonymous questionnaire about their satisfaction with their GP. Patient satisfaction was assessed using the six questions from the Europep questionnaire regarding organizational aspects of health care in terms of accessibility and availability, and presented in two different ways: % of patients very satisfied and mean score (SD). Multivariate analyses adjusting for patient and GP characteristics were conducted to compare outcomes between genders.
One thousand six hundred thirty-seven patients agreed to participate (participation rate: 97 %, women: 63 %, mean age: 54 years). The majority of patients were very satisfied (women 96.2 %, men 95.3 %, p = 0.38). Mean satisfaction scores were slightly higher in women (for overall satisfaction: women 4.7/5 (SD 0.6), men 4.6/5 (SD 0.6), p = 0.02) and in women visiting male GPs (women 4.6 (SD 0.6), men 4.5 (SD 0.6), p = 0.01), and the gender differences showed consistency across satisfaction items. These differences were small and no longer statistically significant in multivariate analyses.
These findings suggest that patients are highly satisfied with the organization of their GP's practice, regardless of patients' and GPs' gender. As patients' and GPs' gender are known to influence patient satisfaction towards primary care delivery and as the current study is the first to explore this aspect in relation to organizational aspects of GP practice, further studies are needed in various primary care settings to confirm our results.
Hypothalamic lipid metabolism plays a major role in the physiological regulation of energy balance. Modulation of several enzymatic activities that control lipid biosynthesis, such as fatty acid synthase (FAS) and AMP-activated protein kinase (AMPK), impacts both feeding and energy expenditure. However, lipids can also cause pathological alterations in the hypothalamus. Lipotoxicity is promoted by excess lipids in tissues non suitable for their storage. A large amount of evidence has demonstrated that lipotoxicity is a pathophysiological mechanism leading to metabolic diseases, such as insulin resistance, cardiomyopathy, atherosclerosis and steatohepatitis. Current data have reported that, similar to what is observed in peripheral tissues, complex lipids, such as ceramides and sphingolipids, act as lipotoxic species at hypothalamic level to impact metabolism. Here, we will review what it is currently known about hypothalamic lipid metabolism and the modulation of energy homeostasis.
The assimilation of the nearly water insoluble substrates hydrocarbons and lipids by bacteria entails specific adaptations such as the formation of oleolytic biofilms. The present article reports that the extracellular matrix of an oleolytic biofilm formed by Marinobacter hydrocarbonoclasticus at n-hexadecane-water interfaces is largely composed of proteins typically cytoplasmic such as translation factors and chaperones, and a lesser amount of proteins of unknown function that are predicted extra-cytoplasmic. Matrix proteins appear to form a structured film on hydrophobic interfaces and were found mandatory for the development of biofilms on lipids, alkanes and polystyrene. Exo-proteins secreted through the type-2 secretion system (T2SS) were shown to be essential for the formation of oleolytic biofilms on both alkanes and triglycerides. The T2SS effector involved in biofilm formation on triglycerides was identified as a lipase. In the case of biofilm formation on n-hexadecane, the T2SS effector is likely involved in the mass transfer, capture or transport of alkanes. We propose that M. hydrocarbonoclasticus uses cytoplasmic proteins released by cell lysis to form a proteinaceous matrix and dedicated proteins secreted through the T2SS to act specifically in the assimilation pathways of hydrophobic substrates.
The cinchona alkaloid dimer (DHQD)2 PHAL has been shown to be a broadly applicable catalyst for asymmetric halogenations. However, this catalyst does not have to be dimeric and a class of monomeric quinidine and quinine-derived catalysts was prepared, often showing superior selectivity in bromolactonisations of terminal alkynoic acids. Mechanistic investigations show that these organocatalysts act as host molecules that can bind carboxylic acid-based substrates as guests with substantial binding constants. Based on these findings, it is proposed that this class of catalysts is bifunctional in nature activating the halogenating agent as well as the nucleophile in electrophilic halogenation reactions.
The Affordable Care Act expanded Medicaid eligibility for millions of low-income adults. The choice for states to expand Medicaid could affect the financial health of hospitals by decreasing the proportion of patient volume and unreimbursed expenses attributable to uninsured patients while increasing revenue from newly covered patients.
To estimate the association between the Medicaid expansion in 2014 and hospital finances by assessing differences between hospitals in states that expanded Medicaid and in those states that did not expand Medicaid.
Observational study with analysis of data for nonfederal general medical or surgical hospitals in fiscal years 2011 through 2014, using data from the American Hospital Association Annual Survey and the Health Care Cost Report Information System from the US Centers for Medicare & Medicaid Services. Multivariable difference-in-difference regression analyses were used to compare states with Medicaid expansion with states without Medicaid expansion. Hospitals in states that expanded Medicaid eligibility before January 2014 were excluded.
Medicaid expansion in 2014, accounting for variation in fiscal year start dates.
Hospital-reported information on uncompensated care, uncompensated care as a percentage of total hospital expenses, Medicaid revenue, Medicaid as a percentage of total revenue, operating margins, and excess margins.
The sample included between 1200 and 1400 hospitals per fiscal year in 19 states with Medicaid expansion and between 2200 and 2400 hospitals per fiscal year in 25 states without Medicaid expansion (with sample size varying depending on the outcome measured). Expansion of Medicaid was associated with a decline of $2.8 million (95% CI, -$4.1 to -$1.6 million; P < .001) in mean annual uncompensated care costs per hospital. Hospitals in states with Medicaid expansion experienced a $3.2 million increase (95% CI, $0.9 to $5.6 million; P = .008) in mean annual Medicaid revenue per hospital, relative to hospitals in states without Medicaid expansion. Medicaid expansion was also significantly associated with improved excess margins (1.1 percentage points [95% CI, 0.1 to 2.0 percentage points]; P = .04), but not improved operating margins (1.1 percentage points [95% CI, -0.1 to 2.3 percentage points]; P = .06).
The hospitals located in the 19 states that implemented the Medicaid expansion had significantly increased Medicaid revenue, decreased uncompensated care costs, and improvements in profit margins compared with hospitals located in the 25 states that did not expand Medicaid. Further study is needed to assess longer-term implications of this policy change on hospitals' overall finances.
The integrative genomic island SGI1 and its variants confer multidrug resistance in numerous Salmonella enterica serovariants and several Proteus mirabilis and Acinetobacter strains. SGI1 is mobilized by the IncA/C family plasmids. The island exploits not only the conjugation apparatus of the plasmid, but also utilizes the plasmid-encoded master regulator AcaCD to induce the excision and formation of its transfer-competent form, which is a key step in the horizontal transfer of SGI1. Triggering of SGI1 excision occurs via the AcaCD-dependent activation of xis gene expression. AcaCD binds in Pxis to an unusually long recognition sequence. Beside the Pxis promoter, upstream regions of four additional SGI1 genes, S004, S005, S012 and S018, also contain putative AcaCD-binding sites. Furthermore, SGI1 also encodes an AcaCD-related activator, FlhDCSGI1, which has no known function. Here, we have analysed the functionality of the putative AcaCD-dependent promoter regions and proved their activation by either AcaCD or FlhDCSGI1. Moreover, we provide evidence that both activators act on the same binding site in Pxis and that FlhDCSGI1 is able to complement the acaCD deletion of the IncA/C family plasmid R16a. We determined the transcription start sites for the AcaCD-responsive promoters and showed that orf S004 is expressed probably from a different start codon than predicted earlier. Additionally, expression of S003 from promoter PS004 was ruled out. Pxis and the four SGI1 promoters examined here also lack obvious -35 promoter box and their promoter profile is consistent with the class II-type activation pathway. Although the role of the four additionally analysed AcaCD/FlhDCSGI1-controlled genes in transfer and/or maintenance of SGI1 is not yet clear, the conservation of the whole region suggests the existence of some selection for their functionality.
The rhizosphere microbiome is regulated by plant genotype, root exudates and environment. There is substantial interest in breeding and managing crops that host root microbial communities that increase productivity. The eudicot model species Arabidopsis has been used to investigate these processes, however a model for monocotyledons is also required. We characterized the rhizosphere microbiome and root exudates of Brachypodium distachyon, to develop it as a rhizosphere model for cereal species like wheat. The Brachypodium rhizosphere microbial community was dominated by Burkholderiales. However, these communities were also dependent on how tightly they were bound to roots, the root type they were associated with (nodal or seminal roots), and their location along the roots.
 Moreover, the functional gene categories detected in microorganisms isolated from around root tips differed from those isolated from bases of roots. The Brachypodium rhizosphere microbiota and root exudate profiles were similar to those reported for wheat rhizospheres, and different to Arabidopsis. The differences in root system development and cell wall chemistry between monocotyledons and eudicots may also influence the microorganism composition of these major plant types. Brachypodium is a promising model for investigating the microbiome of wheat.
The problem regarding the influence that industry may exert on physicians through various types of payments is not of exclusively ethical nature, but has also important practical implications. Using money, industry may distort prescribing habits in favor of their own products, generally more costly, but not always more effective or better tolerated. Moreover, industry is interested in increasing the number of people to whom their products could be prescribed, thus widening the market. If physicians do not oppose these enticements, the patients and the citizens' tax funded National Health Service will pay the bill. In fact, any largesse from the Sales & Marketing divisions of pharmaceutical industries is paid, indirectly and via major financial returns related to an increase in prescriptions, by citizens. In USA this is now demonstrated with the analysis of the first data on transfers of money from industry to physicians made publicly available after the implementation of the Physician Payment Sunshine Act.
The purpose of this study was to examine sociodemographic and health care-related characteristics of young adults covered through the Affordable Care Act (ACA)-dependent coverage expansion.
Our sample consisted of 36,802 young adults aged 19-25 years from 2011 to 2014 National Health Interview Survey. Sociodemographic differences among young adults with the four insurance types were described: privately insured under parents, privately insured under self/spouse, publicly insured, and uninsured. Multivariable logistic models were fitted to compare those covered under parent with those covered through other traditional insurance types, in terms of the following outcomes: health status, health behaviors, insurance history and experience, access to care, care utilization, and receipt of preventive service, controlling for sociodemographic factors.
Young adults who were covered under their parents' insurance were most likely to be college students and non-Hispanic whites. These young adults also had more stable insurance, better access to care, better care utilization patterns, and reported better health status, compared to their peers.
The beneficiaries of the ACA-dependent coverage expansion were more likely to be college students from families with high socioeconomic status. Coverage under parents was associated with improved access to care and health outcomes among young adults. The enrollees through the ACA represent the healthiest subgroup of young adults and those with the best care utilization patterns, suggesting that the added cost relative to premium for insurers from this population will likely be minimal.
Insulin-like growth factor-I (IGF-I) is a metabolic and anabolic biomarker that has been proposed to reflect physiological adaptations resulting from multistressor environments. The bioactivity of IGF-I is regulated by seven different insulin-like growth factor binding proteins (IGFBPs) which act not only as carriers of IGF-1, but also function as a modulator of IGF-I availability and activity. Supplementing with β-hydroxy-β-methylbutyrate (HMB) has been shown to enhance physiological outcomes associated with intense training, and has been reported to augment the IGF-1 response. The purpose of this study was to examine the effect of 23days of HMB supplementation on circulating levels of IGF-I and IGFBPs in combat soldiers during highly intense military training.
Thirteen male soldiers from an elite infantry unit volunteered to participate in this double-blind, parallel design study. Soldiers were provided 3g·day(-1) of either HMB (n=6) or placebo (PL; n=7). During the study soldiers performed advanced military training with periods of restricted sleep and severe environmental stressors. Blood samples were obtained prior to (PRE) and approximately 18h following the final supplement consumption (POST).
No significant differences were observed for circulating IGF-1 concentrations between HMB and PL (p=0.568). In addition, no differences were seen between the groups for IGFBP-1 (p=1.000), IGFBP-2 (p=0.855), IGFBP-3 (p=0.520), IGFBP-4 (p=0.103), IGFBP-5 (p=0.886), or IGFBP-6 (p=0.775). A significant difference was noted between HMB (169.9±23.0ng·ml(-1)) and PL (207.2±28.0ng·ml(-1)) for IGFBP-7 at POST (p=0.042).
Although the results of this study do not support the influence of HMB supplementation on circulating concentrations of IGF-1 or IGFBPs1-6 during high intensity military training, it does present initial evidence that it may lower circulating IGFBP-7 concentrations. This may provide some indication of a reduced stress response, but further investigation on the physiological role of IGFBP-7 and military training is needed.
NOD-like receptor (NLR) proteins, as much as Toll-like receptor proteins, play a major role in modulating myeloid cells in their immune functions. There is still, however, limited knowledge on the expression and function of several of the mammalian NLR proteins in myeloid lineages. Still, the function of pyrin domain-containing NLR proteins and NLRC4/NAIP as inflammasome components that drive interleukin-1β (IL-1β) and IL-18 maturation and secretion upon pathogen stimulation is well established. NOD1, NOD2, NLRP3, and NLRC4/NAIP act as bona fide pattern recognition receptors (PRRs) that sense microbe-associated molecular patterns (MAMPs) but also react to endogenous danger-associated molecular patterns (DAMPs). Ultimately, activation of these receptors achieves macrophage activation and maturation of dendritic cells to drive antigen-specific adaptive immune responses. Upon infection, sensing of invading pathogens and likely of DAMPs that are released in response to tissue injury is a process that involves multiple PRRs in both myeloid and epithelial cells, and these act in concert to design tailored, pathogen-adapted immune responses by induction of different cytokine profiles, giving rise to appropriate lymphocyte polarization.
Plant science is an important, rapidly developing area of study. Within plant science, one area of study that has grown tremendously with recent technological advances, such as mass spectrometry, is the field of plant-omics; however, plant peptidomics is relatively underdeveloped in comparison with proteomics and metabolomics. Endogenous plant peptides can act as signaling molecules and have been shown to affect cell division, development, nodulation, reproduction, symbiotic associations, and defense reactions. There is a growing need to uncover the role of endogenous peptides on a molecular level. Mass spectrometric imaging (MSI) is a valuable tool for biological analyses as it allows for the detection of thousands of analytes in a single experiment and also displays spatial information for the detected analytes. Despite the prediction of a large number of plant peptides, their detection and imaging with spatial localization and chemical specificity is currently lacking. Here we analyzed the endogenous peptides and proteins in Medicago truncatula using matrix-assisted laser desorption/ionization (MALDI)-MSI. Hundreds of endogenous peptides and protein fragments were imaged, with interesting peptide spatial distribution changes observed between plants in different developmental stages.
A strategy for the synthesis of 6,9-dihydropyrido[1,2-a]indoles through a cascade iodocyclization of 4-(3-methyl-1H-indol-1-yl)-1,1-diphenylbut-2-yn-1-ol derivatives is presented. This reaction was conducted under very mild conditions and in a short time. The reactions are metal-free, are environmentally friendly and give up to 94% yield. Moreover, the obtained halides allow functional group diversification by palladium-catalyzed coupling reactions, which could act as potential intermediates for the synthesis of valuable compounds.
This final rule makes regulatory changes to the Child Care and Development Fund (CCDF) based on the Child Care and Development Block Grant Act of 2014. These changes strengthen requirements to protect the health and safety of children in child care; help parents make informed consumer choices and access information to support child development; provide equal access to stable, high-quality child care for low-income children; and enhance the quality of child care and the early childhood workforce.
With the issuance of this final rule, the Administrator of the Drug Enforcement Administration places three synthetic phenethylamines: 2-(4-iodo-2,5-dimethoxyphenyl)-N-(2-methoxybenzyl)ethanamine (25I-NBOMe; 2C-I-NBOMe; 25I; Cimbi-5), 2-(4-chloro-2,5-dimethoxyphenyl)-N- (2-methoxybenzyl)ethanamine (25C-NBOMe; 2C-C-NBOMe; 25C; Cimbi-82), and 2-(4-bromo-2,5-dimethoxyphenyl)-N-(2-methoxybenzyl)ethanamine (25B- NBOMe; 2C-B-NBOMe; 25B; Cimbi-36), including their optical, positional, and geometric isomers, salts and salts of isomers, whenever the existence of such salts, isomers, and salts of isomers is possible, into schedule I of the Controlled Substances Act. This scheduling action is pursuant to the Controlled Substances Act which requires that such actions be made on the record after opportunity for a hearing through formal rulemaking. This action continues the application of the regulatory controls and administrative, civil, and criminal sanctions applicable to schedule I controlled substances on persons who
 handle (manufacture, distribute, reverse distribute, import, export, engage in research, conduct instructional activities or chemical analysis, or possess), or propose to handle 25I-NBOMe, 25C-NBOMe, or 25B-NBOMe.
Light gradients within tree canopies play a major role in the distribution of plant resources that define the photosynthetic capacity of sun and shade leaves. However, the biochemical and diffusional constraints on gas exchange in sun and shade leaves in response to light remain poorly quantified, but critical for predicting canopy carbon and water exchange. To investigate the CO2 diffusion pathway of sun and shade leaves, leaf gas exchange was coupled with concurrent measurements of carbon isotope discrimination to measure net leaf photosynthesis (An ), stomatal conductance (gs ) and mesophyll conductance (gm ) in Eucalyptus tereticornis trees grown in climate controlled whole-tree chambers. Compared to sun leaves, shade leaves had lower An , gm , leaf nitrogen and photosynthetic capacity (Amax ) but gs was similar. When light intensity was temporarily increased for shade leaves to match that of sun leaves, both gs and gm increased, and An increased to values greater than sun leaves. We show that dynamic physiological responses of shade leaves to altered light environments have implications for up-scaling leaf level measurements and predicting whole canopy carbon gain. Despite exhibiting reduced photosynthetic capacity, the rapid up-regulation of gm with increased light enables shade leaves to respond quickly to sunflecks.
The Havers-Halberg Oscillation (HHO) hypothesis links evidence for the timing of a biorhythm retained in permanent tooth enamel (Retzius periodicity) to adult body mass and life history traits across mammals. Potentially, these links provide a way to access life history of fossil species from teeth. Recently we assessed intra-specific predictions of the HHO on human children. We reported Retzius periodicity (RP) corresponded with enamel thickness, and cusp formation time, when calculated from isolated deciduous teeth. We proposed the biorhythm might not remain constant within an individual. Here, we test our findings. RP is compared between deciduous second and permanent first molars within the maxillae of four human children. Following this, we report the first RPs for deciduous teeth from modern great apes (n = 4), and compare these with new data for permanent teeth (n = 18) from these species, as well as with previously published values. We also explore RP in teeth that retain hypoplastic defects. Results show RP changed within the maxilla of each child, from thinner to thicker enameled molars, and from one side of a hypoplastic defect to the other. When considered alongside correlations between RP and cusp formation time, these observations provide further evidence that RP is associated with enamel growth processes and does not always remain constant within an individual. RP of 5 days for great ape deciduous teeth lay below the lowermost range of those from permanent teeth of modern orangutan and gorilla, and within the lowermost range of RPs from chimpanzee permanent teeth. Our data suggest associations between RP and enamel growth processes of humans might extend to great apes. These findings provide a new framework from which to develop the HHO hypothesis, which can incorporate enamel growth along with other physiological systems. Applications of the HHO to fossil teeth should avoid transferring RP between deciduous and permanent enamel, or including hypoplastic teeth.
Chronic unexplained nausea and vomiting (CUNV) refers to a symptom complex defined by nausea and/or vomiting with normal diagnostic testing, including anatomic assessments (including upper endoscopy) and measures of upper gut function (e.g., gastric emptying testing). Nausea and vomiting in this condition are postulated to result from aberrant peripheral or central neurohumoral activity. A substantial subset of patients satisfies this diagnosis as more than half of individuals referred for scintigraphic testing exhibit normal gastric emptying rates. No randomized, placebo-controlled trials of any medication treatment have been performed in CUNV. However, agents with potential therapeutic benefits in CUNV include antiemetic drugs, neuromodulatory treatments which are proposed to act by reducing gastric sensitivity, and medications with prokinetic action to stimulate upper gut propulsion. Recently approved drugs with antiemetic capability include serotonin antagonists with novel modes of delivery and neurokinin antagonists with or without additional serotonergic blocking capabilities. Existing neuroleptics and pain-modifying neuromodulatory therapies with fortuitous antiemetic benefits are being considered for their benefits in this disorder. Furthermore, current investigations will define potential therapeutic actions of agents that stimulate gastric emptying via action on gastroduodenal serotonin, motilin, and ghrelin receptors. This current research may broaden the treatment options for refractory cases of unexplained nausea and vomiting.
The evolutionary separated Gram-negative Chlamydiales show a biphasic life cycle and replicate exclusively within eukaryotic host cells. Members of the genus Chlamydia are responsible for many acute and chronic diseases in humans, and Chlamydia-related bacteria are emerging pathogens. We revisit past efforts to detect cell wall material in Chlamydia and Chlamydia-related bacteria in the context of recent breakthroughs in elucidating the underlying cellular and molecular mechanisms of the chlamydial cell wall biosynthesis. In this review, we also discuss the role of cell wall biosynthesis in chlamydial FtsZ-independent cell division and immune modulation. In the past, penicillin susceptibility of an invisible wall was referred to as the "chlamydial anomaly." In light of new mechanistic insights, chlamydiae may now emerge as model systems to understand how a minimal and modified cell wall biosynthetic machine supports bacterial cell division and how cell wall-targeting beta-lactam antibiotics can also act bacteriostatically rather than bactericidal. On the heels of these discussions, we also delve into the effects of other cell wall antibiotics in individual chlamydial lineages.
Influenza vaccination for health care personnel (HCP) is recommended particularly because it indirectly protects patients from contracting the disease. Vaccinating can therefore be interpreted as a prosocial act. However, HCP vaccination rates are often far too low to prevent nosocomial infections. Effective interventions are needed to increase HCP's influenza vaccine uptake. Here we devise a novel tool to experimentally test interventions that aim at increasing prosocially motivated vaccine uptake under controlled conditions. We conducted a large-scale and cross-cultural experiment with participants from countries with either a collectivistic (South Korea) or an individualistic (USA) cultural background. Results showed that prosocially motivated vaccination was more likely in South Korea compared to the US, mediated by a greater perception of vaccination as a social act. However, changing the default of vaccination, such that participants had to opt out rather than to opt in, increased vaccine uptake in the US and therefore compensated for the lower level of prosocial vaccination. In sum, the present study provides both a novel method to investigate HCP influenza vaccination behavior and interventions to increase their vaccine uptake.
X-box binding protein 1 (XBP1) was found to be overexpressed in glioma and breast cancers, suggesting that XBP1 might act as a potent oncogenic protein. However, the clinical significance and biological role of XBP1 in esophageal squamous cell carcinoma (ESCC) remain unknown. In this study, we report that XBP1 is markedly overexpressed in ESCC cell lines and clinical samples. XBP1 overexpression was significantly correlated with ESCC tumor stage, lymph node metastasis and poor outcome. A functional study demonstrated that XBP1 promoted cell growth and cell invasion both in vitro and in vivo. Further study found that the XBP1-mediated invasion and proliferation of cancer cells requires the up-regulation of matrix metalloproteinase-9 (MMP-9). Importantly, a significant correlation between XBP1 and MMP-9 levels was observed in ESCC clinical samples. Our findings demonstrate that XBP1 is an oncogene that plays an important role in the development of ESCC by activating MMP-9 expression.
Exosomes containing microRNA-155 act as molecule carriers during immune cell-cell communication and play an important role in the inflammatory response of H. pylori infection macrophages. Previous reports have found that miR-155 was over-expressed in H. pylori infection macrophages, but the significance of which is still unknown. In this study, we analyzed the impact of miR-155 loaded in exosomes derived from macrophages to the inflammatory response of H. pylori infection macrophages and possible mechanisms. We found that miR-155 promoted the expression of inflammatory cytokines including TNF-a, IL-6, IL-23, but also increased the expression of CD40, CD63, CD81, and MCH-I. Meanwhile, inflammatory signal pathways proteins, such as MyD88, NF-κB in H. pylori infection macrophages were down-regulated due to the over-expression of miR-155. Experiments in vitro or in vivo revealed that miR-155 promoted macrophages to inhibit or kill H. pylori by regulating the inflammatory response of cells to prevent the gastritis caused by H. pylori infection. These findings contribute to the understanding of miR-155 contained in exosomes in inflammatory responses of H. pylori infection macrophages.
There is little known about factors that contribute to the comorbidity of cigarette smoking and obesity. The current
 study sought to test whether exercise self-efficacy moderated the relation between anxiety sensitivity (fear of internal sensations) and BMI and exercise tolerance among cigarette smokers. Smokers (n = 72; 50% female; Mcpd = 19.3, SD = 10.65) were recruited to participate in a smoking cessation treatment trial. During medical screen, we measured weight, height, and exercise tolerance (functional capacity) employing a standardized maximal exercise testing protocol. After adjusting for participant sex and cigarettes per day, exercise self-efficacy moderated the association between anxiety sensitivity and BMI, such that the positive association between anxiety sensitivity and BMI was significantly stronger when exercise self-efficacy was low. The same pattern of results emerged for exercise tolerance. Exercise self-efficacy moderated the association between anxiety sensitivity and exercise tolerance, such that the negative association between anxiety sensitivity and exercise tolerance was significantly stronger when exercise self-efficacy was low. Among smokers, anxiety sensitivity may be a risk variable that, directly and indirectly in the context of low self-efficacy for exercise, causes or maintains higher body weight and lower exercise tolerance.
Vascular endothelial dysfunction can be induced by homocysteine (Hcy) through promoted oxidative stress. Huang Qi decoction (HQD) is a traditional Chinese medical formula and its components possess antioxidant effect. The study herein was therefore designed to investigate the effects of HQD at different dosage on endothelial dysfunction induced by Hcy. Tempol and apocynin were used to investigate whether antioxidant mechanisms were involved. Endothelium-dependent relaxation of rat aortas was investigated by isometric tension recordings. Reactive oxygen species (ROS) in human umbilical vein endothelial cells (HUVECs) was determined by DHE staining. The assessment related to oxidative stress and NO bioavailability was performed by assay kits and western blot. In isometric tension experiment, HQD at the dose of 30 or 100 μg/mL, tempol, or apocynin prevented impaired endothelium-dependent relaxation in isolated aortas elicited by Hcy. In cellular experiments, substantial enhancement in NADPH oxidase and ROS generation and reduction in NO bioavailability triggered by Hcy were reversed by pretreatment of HQD at the dose of 100 μg/mL, tempol, or apocynin. The results proved that HQD at an appropriate dosage presented favorable effects on endothelial dysfunction initiated by Hcy through antioxidant mechanisms. HQD can act as a potent prescription for the treatment of endothelium related vascular complications.
Preclinical, early phase clinical trials and epidemiological evidence support the potential role of insulin-sensitizers in cancer prevention and treatment. Insulin-sensitizers improve the metabolic and hormonal profile in PCOS patients and may also act as anticancer agents, especially in cancers associated with hyperinsulinemia and oestrogen dependent cancers. Several lines of evidence support the protection against cancer exerted by dietary inositol, in particular inositol hexaphosphate. Metformin, thiazolidinediones, and myoinositol postreceptor signaling may exhibit direct inhibitory effects on cancer cell growth. AMPK, the main molecular target of metformin, is emerging as a target for cancer prevention and treatment. PCOS may be correlated to an increased risk for developing ovarian and endometrial cancer (up to threefold). Several studies have demonstrated an increase in mortality rate from ovarian cancer among overweight/obese PCOS women compared with normal weight women. Long-term use of metformin has been associated with lower rates of ovarian cancer. Considering the evidence supporting a higher risk of gynaecological cancer in PCOS women, we discuss the potential use of insulin-sensitizers as a potential tool for chemoprevention, hypothesizing a possible rationale through which insulin-sensitizers may inhibit tumourigenesis.
There are now several examples of plant species engineered to synthesize and accumulate nutritionally important polyunsaturated fatty acids in their seed triacylglycerols (TAG). The utilization of TAG in germinating seeds of such transgenic plants was unknown. In this study, we examined the TAG utilization efficiency during seed germination in transgenic Arabidopsis seeds containing several examples of these fatty acids. Seed TAG species with native fatty acids had higher utilization rate than the TAG species containing transgenically produced polyunsaturated fatty acids. Conversely, quantification of the fatty acid components remaining in the total TAG after early stages of seed germination revealed that the undigested TAGs tended to contain elevated levels of the engineered polyunsaturated fatty acids (PUFA). LC-MS analysis further revealed asymmetrical mobilization rates for the individual TAG species. TAGs which contained multiple PUFA fatty acids were mobilized slower than the species containing single PUFA. The mobilized engineered fatty acids were used in de novo membrane lipid synthesis during seedling development.
Bacterial protein-tyrosine kinases (BY-kinases) are known to regulate different aspects of bacterial physiology, by phosphorylating cellular protein substrates. Physiological cues that trigger BY-kinases activity are largely unexplored. In Proteobacteria, BY-kinases contain a cytosol-exposed catalytic domain and a transmembrane activator domain in a single polypeptide chain. In Firmicutes, the BY-kinase catalytic domain and the transmembrane activator domain exist as separate polypeptides. We have previously speculated that this architecture might enable the Firmicutes BY-kinases to interact with alternative activators, and thus account for the observed ability of these kinases to phosphorylate several distinct classes of protein substrates. Here, we present experimental evidence that supports this hypothesis. We focus on the model Firmicute-type BY-kinase PtkA from Bacillus subtilis, known to phosphorylate several different protein substrates. We demonstrate that the transcriptional regulator SalA, hitherto known as a substrate of PtkA, can also act as a PtkA activator. In doing so, SalA competes with the canonical PtkA activator, TkmA. Our results suggest that the respective interactions of SalA and TkmA with PtkA favor phosphorylation of different protein substrates in vivo and in vitro. This observation may contribute to explaining how specificity is established in the seemingly promiscuous interactions of BY-kinases with their cellular substrates.
We are revising the criteria in the Listing of Impairments (listings) that we use to evaluate claims involving mental disorders in adults and children under titles II and XVI of the Social Security Act (Act). The revisions reflect our program experience, advances in medical knowledge, recommendations from a commissioned report, and public comments we received in response to a Notice of Proposed Rulemaking (NPRM).
Tyrosinases are responsible for melanin formation in all life domains. Tyrosinase inhibitors are used for the prevention of severe skin diseases, in skin-whitening creams and to avoid fruit browning, however continued use of many such inhibitors is considered unsafe. In this study we provide conclusive evidence of the inhibition mechanism of two well studied tyrosinase inhibitors, KA (kojic acid) and HQ (hydroquinone), which are extensively used in hyperpigmentation treatment. KA is reported in the literature with contradicting inhibition mechanisms, while HQ is described as both a tyrosinase inhibitor and a substrate. By visualization of KA and HQ in the active site of TyrBm crystals, together with molecular modeling, binding constant analysis and kinetic experiments, we have elucidated their mechanisms of inhibition, which was ambiguous for both inhibitors. We confirm that while KA acts as a mixed inhibitor, HQ can act both as a TyrBm substrate and as an inhibitor.
In this document, the Federal Communications Commission (Commission) adopts rules to convert the National Deaf-Blind Equipment Distribution Program (NDBEDP) from a pilot program to a permanent program. The NDBEDP supports the distribution of communications devices to low-income individuals who are deaf-blind.
In accordance with section 812 of the Bipartisan Budget Act of 2015 (BBA section 812), these rules explain how we will address evidence furnished by medical sources that meet one of BBA section 812's exclusionary categories (excluded medical sources of evidence) as described below. Under these new rules, we will not consider evidence furnished by an excluded medical source of evidence unless we find good cause to do so. We identify five circumstances in which we may find good cause. In these rules, we also require excluded medical sources of evidence to notify us of their excluded status under section 223(d)(5)(C)(i) of the Social Security Act (Act), as amended, in writing each time they furnish evidence to us that relates to a claim for initial or continuing benefits under titles II or XVI of the Act. These rules will allow us to fulfill obligations that we have under BBA section 812.
There is extensive evidence that social identities can shape people's attitudes and behavior, but what about sensory judgments? We examined the possibility that social identity concerns may also shape the judgment of non-social properties-namely, olfactory judgment. In two experiments, we presented Swiss and non-Swiss participants with the odor of chocolate, for which Switzerland is world-famous, and a control odor (popcorn). Swiss participants primed with Swiss identity reported the odor of chocolate (but not popcorn) as more intense than non-Swiss participants (Experiments 1 and 2) and than Swiss participants primed
 with individual identity or not primed (Experiment 2). The self-reported intensity of chocolate smell tended to increase as identity accessibility increased-but only among Swiss participants (Experiment 1). These results suggest that identity priming can counter-act classic sensory habituation effects, allowing identity-relevant smells to maintain their intensity after repeated presentations. This suggests that social identity dynamically influences sensory judgment. We discuss the potential implications for models of social identity and chemosensory perception.
The dynamin family of proteins play important regulatory roles in membrane remodelling and endocytosis, especially within brain and neuronal tissues. In the context of reproduction, dynamin 1 (DNM1) and dynamin 2 (DNM2) have recently been shown to act as key mediators of sperm acrosome formation and function. However, little is known about the roles that these proteins play in the developing testicular germ cells. In this study, we employed a DNM2 germ cell-specific knockout model to investigate the role of DNM2 in spermatogenesis. We demonstrate that ablation of DNM2 in early spermatogenesis results in germ cell arrest during prophase I of meiosis, subsequent loss of all post-meiotic germ cells and concomitant sterility. These effects become exacerbated with age, and ultimately result in the demise of the spermatogonial stem cells and a Sertoli cell only phenotype. We also demonstrate that DNM2 activity may be temporally regulated by phosphorylation of DNM2 via the kinase CDK1 in spermatogonia, and dephosphorylation by phosphatase PPP3CA during meiotic and post-meiotic spermatogenesis.
Recently, SIRT1 was found to play an important role in a variety of solid and hematologic malignancies. The expression and function of SIRT1 may differ completely depending on cell type and gene subtype, and it can act as a tumor suppressor or oncogene. We describe how SIRT1 mRNA and protein levels are overexpressed in t(8;21) AML cells. AML1-ETO triggers the activation of SIRT1 by binding at AML1 binding sites on the SIRT1 promoter. Pharmacologic targeting or RNAi-mediated inhibition of SIRT1 induces G1 arrest, apoptosis, and proliferation inhibition that is more sensitive in AML1-ETO-positive than AML1-ETO-negative cell lines. Our data suggest that targeting SIRT1 may be an attractive therapeutic strategy in t(8;21) AML.
Emerging evidence suggests that changes in quality of life (QoL) predicts later changes in eating disorder (ED) symptoms. The objective of this study was to explore individual sufferers' perspectives on the influence of QoL on the onset, maintenance, and/or remission of ED symptoms.
19 women from the community with a history of eating disorders (n = 13 currently symptomatic; n = 6 recovered) were interviewed about their observations on the relationship between QoL and ED symptoms over time in their own lives. Interviews were audio-taped and transcribed, and then thematically analysed.
Thematic analysis uncovered two major themes: 1. QoL as a Vulnerability Factor, and 2. QoL as a Recovery Factor. In relation to the first theme, onset of ED symptoms was discussed by women in this study as having been triggered by impairment in QoL, including a general sense of lacking control in life, stress, abusive intimate relationships, poor role modelling from family, physical impairment related to obesity, peer pressure, and weight-related teasing. On the other hand, and in relation to the second theme, subsequent improvement in QoL was nominated as central to symptom improvement and recovery. QoL improvement was described by participants differently, but included increased general satisfaction in life, emotional maturation, prioritising and improving physical health, the development of a supportive intimate relationship and social relationships, and having children.
Impairment in QoL may act as a trigger for the onset and maintenance of ED symptoms, whereas improvement in QoL may be central to eating disorder improvement and eventual recovery. Treatment should involve consideration of a core focus on QoL improvement as a potential 'backdoor' approach to improving ED symptoms.
Piroplasmids are tick-borne protozoan parasites that infect blood cells (erythrocytes, lymphocytes or other leukocytes) or endothelial cells of numerous wild and domestic vertebrates worldwide. They cause severe disease in livestock, dogs, cats, wild mammals and, occasionally, in humans. Piroplasmid infections are prevalent in wild carnivores worldwide although there is limited information about their clinical and epidemiological importance. There are currently nine recognized species of Babesia, two of Theileria, two of Cytauxzoon and one of Rangelia infecting captive and wild carnivores, including members of Canidae, Felidae, Mustelidae, Procyonidae, Ursidae, Viverridae, Hyaenidae and Herpestidae in the Americas, Eurasia and Africa. However, the number of piroplasmid species is likely higher than currently accepted due to the reported existence of DNA sequences that may correspond to new species and the lack of studies on many host species and biogeographical areas. Indeed, many species have been recognized in the last few years with the advancement of molecular analyses. Disease and mortality have been documented in some wild carnivores, whereas other species appear to act as natural, subclinical reservoirs. Various factors (e.g. unnatural hosts, stress due to captivity, habitat degradation, climate fluctuation or immunosuppression) have been associated with disease susceptibility to piroplasmid infections in some species in captivity. We aimed to review the current knowledge on the epidemiology of piroplasmid infections in wild carnivores and associated tick vectors. Emphasis is given to the role of wild carnivores as reservoirs of clinical piroplasmosis for domestic dogs and cats, and to the importance of piroplasmids as disease agents for endangered carnivores.
Promoting physical activity and healthy eating is important to combat the unprecedented rise in NCDs in many developing countries. Using modern information-and communication technologies to deliver physical activity and diet interventions is particularly promising considering the increased proliferation of such technologies in many developing countries. The objective of this systematic review is to investigate the effectiveness of e-& mHealth interventions to promote physical activity and healthy diets in developing countries.
Major databases and grey literature sources were searched to retrieve studies that quantitatively examined the effectiveness of e-& mHealth interventions on physical activity and diet outcomes in developing countries. Additional studies were retrieved through citation alerts and scientific social media allowing study inclusion until August 2016. The CONSORT checklist was used to assess the risk of bias of the included studies.
A total of 15 studies conducted in 13 developing countries in Europe, Africa, Latin-and South America and Asia were included in the review. The majority of studies enrolled adults who were healthy or at risk of diabetes or hypertension. The average intervention length was 6.4 months, and text messages and the Internet were the most frequently used intervention delivery channels. Risk of bias across the studies was moderate (55.7 % of the criteria fulfilled). Eleven studies reported significant positive effects of an e-& mHealth intervention on physical activity and/or diet behaviour. Respectively, 50 % and 70 % of the interventions were effective in promoting physical activity and healthy diets.
The majority of studies demonstrated that e-& mHealth interventions were effective in promoting physical activity and healthy diets in developing countries. Future interventions should use more rigorous study designs, investigate the cost-effectiveness and reach of interventions, and focus on emerging technologies, such as smart phone apps and wearable activity trackers.
The review protocol can be retrieved from the PROSPERO database (Registration ID: CRD42015029240 ).
High morphological diversity can occur in closely related animals when selection favors morphologies that are subject to intrinsic biological constraints. A good example is subterranean rodents of the genus Thomomys, one of the most taxonomically and morphologically diverse mammalian genera. Highly procumbent, tooth-digging rodent skull shapes are often geometric consequences of increased body size. Indeed, larger-bodied Thomomys species tend to inhabit harder soils. We used geometric morphometric analyses to investigate the interplay between soil hardness (the main extrinsic selection pressure on fossorial mammals) and allometry (i.e. shape change due to size change; generally considered the main intrinsic factor) on crania and humeri in this fast-evolving mammalian clade.
Larger Thomomys species/subspecies tend to have more procumbent cranial shapes with some exceptions, including a small-bodied species inhabiting hard soils. Counter to earlier suggestions, cranial shape within Thomomys does not follow a genus-wide allometric pattern as even regional subpopulations differ in allometric slopes. In contrast, humeral shape varies less with body size and with soil hardness. Soft-soil taxa have larger humeral muscle attachment sites but retain an orthodont (non-procumbent) cranial morphology. In intermediate soils, two pairs of sister taxa diverge through differential modifications on either the humerus or the cranium. In the hardest soils, both humeral and cranial morphology are derived through large muscle attachment sites and a high degree of procumbency.
Our results show that conflict between morphological function and intrinsic allometric patterning can quickly and differentially alter the rodent skeleton, especially the skull.
 In addition, we found a new case of convergent evolution of incisor procumbency among large-, medium-, and small-sized species inhabiting hard soils. This occurs through different combinations of allometric and non-allometric changes, contributing to shape diversity within the genus. The strong influence of allometry on cranial shape appears to confirm suggestions that developmental change underlies mammalian cranial shape divergences, but this requires confirmation from ontogenetic studies. Our findings illustrate how a variety of intrinsic processes, resulting in species-level convergence, could sustain a genus-level range across a variety of extrinsic environments. This might represent a mechanism for observations of genus-level niche conservation despite species extinctions in mammals.
Polymorphonuclear neutrophil granulocytes are the first responders of the immune system to threats by invading microorganisms. In the traditional view, they combat the intruders by phagocytosis and externalisation of granules containing lytic and microbicidal factors. A dozen years ago, this concept was expanded by the observation that neutrophils may react to bacteria by extruding their nuclear chromosomal DNA with attached nuclear and cytoplasmic constituents to form extracellular reticular structures. Since they trapped and immobilised the microbes, they were designated neutrophil extracellular traps (NETs), and their ensuing cell death NETosis. Subsequently, the NETs were shown to act against different types of pathogens, including viruses, and an intricate interplay between the NETs and countermeasures of the pathogens became apparent. The NETs were also found to induce inflammatory responses in the host that contributed to the pathophysiology of autoinflammatory and even autoimmune diseases. Of special interest is the direct link that NETs provide to infections that may initiate and maintain inflammation without the participation of adaptive immunity. In contrast, neutrophils seem capable of activating B cells to produce antibodies relevant to autoimmunity independently of T cell help. Further results imply NETs in the occurrence of thrombosis of the veins and recently also in the generation of arterial plaque. Data from the studies on the defence against pathogens and the pathophysiology of inflammation and thrombosis have started to drive applications to modulate NET formation and its effects and may provide opportunities to optimise current diagnostic and therapeutic concepts.
Several methods predict activity changes of transcription factors (TFs) from a given regulatory network and measured expression data. But available gene regulatory networks are incomplete and contain many condition-dependent regulations that are not relevant for the specific expression measurement. It is not known which combination of active TFs is needed to cause a change in the expression of a target gene. A method to systematically evaluate the inferred activity changes is missing. We present such an evaluation strategy that indicates for how many target genes the observed expression changes can be explained by a given set of active TFs. To overcome the problem that the exact combination of active TFs needed to activate a gene is typically not known, we assume a gene to be explained if there exists any combination for which the predicted active TFs can possibly explain the observed change of the gene. We introduce the i-score (inconsistency score), which quantifies how many genes could not be explained by the set of activity changes of TFs. We observe that, even for these minimal requirements, published methods yield many unexplained target genes, i.e. large i-scores. This holds for all methods and all expression datasets we evaluated. We provide new optimization methods to calculate the best possible (minimal) i-score given the network and measured expression data. The evaluation of this optimized i-score on a large data compendium yields many unexplained target genes for almost every case. This indicates that currently available regulatory networks are still far from being complete. Both the presented Act-SAT and Act-A* methods produce optimal sets of TF activity changes, which can be used to investigate the difficult interplay of expression and network data. A web server and a command line tool to calculate our i-score and to find the active TFs associated with the minimal i-score is available from https://services.bio.ifi.lmu.de/i-score.
This study uses a best-worst scaling experiment to test whether general practitioners (GPs) act as perfect agents for the patients in the consultation; and if not, whether this is due to asymmetric information and/or other motivations than user orientation. Survey data were collected from 775 GPs and 1379 Danish citizens eliciting preferences for a consultation. Sequential models allowing for within-person preference heterogeneity and heteroskedasticity between best and worst choices were estimated. We show that GPs do not always act as perfect agents and that this non-alignment stems from GPs being both unable and unwilling to do so. Unable since GPs have imperfect information about patients' preferences, and unwilling since they are also motivated by other factors than user orientation. Our findings highlight the need for multi-pronged strategies targeting different motivational factors to ensure that GPs act in correspondence with patients' preferences in areas where alignment is warranted.
In this study, a carbon nanotubes composite coated with N-isopropylacrylamide hydrogel (NIPAM-CNTs) has been synthesized. Mixed matrix membranes (MMMs) were fabricated by incorporating NIPAM-CNTs composite filler into poly(ether-block-amide) (Pebax® MH 1657) matrix for efficient CO2 separation. The as-prepared NIPAM-CNTs composite filler mainly plays two roles: i) The extraordinary smooth one-dimensional nanochannels of CNTs act as the highways to accelerate CO2 transport through membranes, increasing CO2 permeability; ii) The NIPAM hydrogel layer coated on the outer walls of CNTs acts as the super water absorbent to increase water content of membranes, appealing both CO2 permeability and CO2/gas selectivity. MMM containing 5 wt% NIPAM-CNTs exhibited the highest CO2 permeability of 567 Barrer, CO2/CH4 selectivity of 35 and CO2/N2 selectivity of 70, transcending 2008 Robeson upper bound line. The improved CO2 separation performance of MMMs is mainly attributed to the construction of the efficient CO2 transport pathways by NIPAM-CNTs. Thus, MMMs incorporated with NIPAM-CNTs composite filler can be used as an excellent membrane material for efficient CO2 separation.
Polyketide metabolites produced by modular type I polyketide synthases (PKS) acquire their chemical diversity through the variety of catalytic domains within modules of the pathway. Methyltransferases are among the least characterized of the catalytic domains common to PKS systems. We determined the domain boundaries and characterized the activity of a PKS C-methyltransferase (C-MT) from the curacin A biosynthetic pathway. The C-MT catalyzes S-adenosylmethionine-dependent methyl transfer to the α-position of β-ketoacyl substrates linked to acyl carrier protein (ACP) or a small-molecule analog, but does not act on β-hydroxyacyl substrates or malonyl-ACP. Key catalytic residues conserved in both bacterial and fungal PKS C-MTs were identified in a 2-Å crystal structure and validated biochemically. Analysis of the structure and the sequences bordering the C-MT provides insight into the positioning of this domain within complete PKS modules.
Nrf1 and Nrf2 (NF-E2-related factors 1 and 2, respectively) are transcription factors that belong to the Cap'n'collar (CNC) family and play critical roles in various tissues, including the liver. Liver-specific Nrf1 knockout mice show hepatic steatosis, accompanied by dysregulation of various metabolic genes. Nrf2 knockout mice show impairment in the induction of antioxidant and xenobiotic-metabolizing enzyme genes. Although it has been shown that small Maf (sMaf) proteins act as obligatory partners of CNC proteins, their precise contributions to the function of CNC proteins remain unclear especially in the context of adult liver functions. To address this issue, we generated mice that conditionally lack expression of all sMaf proteins in the liver. The liver-specific sMaf-deficient mice develop hepatic steatosis and dysregulation of genes involved in lipid and amino acid metabolism and proteasomal subunit expression. Importantly, the gene expression profiles in the sMaf-deficient livers share a strong similarity with those in Nrf1-deficient livers. In addition, the basal expression levels of a number of Nrf2 target genes were diminished in the sMaf-deficient livers. These results provide the first genetic evidence that sMaf proteins are indispensable for liver functions as heterodimeric partners for Nrf1 and Nrf2.
Herbivores emit plant-associated volatile organic compounds (VOCs) after feeding on plants. These plant-associated VOCs can be used by parasitoids to locate their hosts. It is hypothesized that certain compounds play key roles in the attractiveness of host-associated odor blends. The larval parasitoid, Microplitis croceipes (Hymenoptera: Braconidae) and its herbivore host, Heliothis virescens (Lepidoptera: Noctuidae), a major pest of cotton plant were used as model species to identify key compounds mediating attraction of parasitoids to hosts. Comparative GC/MS analyses of cotton-fed vs. artificial diet-fed hosts indicated that 12 of 17 compounds in the headspace of H. virescens larvae were exclusive to plant-fed hosts, and thus considered to be plant-associated. In order to identify key attractive compounds, a full blend of 15 commercially available synthetic compounds was modified by removing each of the 10 plant-associated
 compounds emitted by host larvae. In Y-tube olfactometer bioassays testing parasitoid responses to modified blends, 1-octen-3-ol, decanal, (E)-β-caryophyllene, α-humulene, α-farnesene, and β-pinene were identified as key compounds contributing to attractiveness of the natural blend of VOCs emitted by cotton-fed hosts. The results showed that while various host-associated compounds act in concert to serve as useful host location cues, only a fraction of the natural blend mediates attraction in parasitoids. Furthermore, the role of a compound is better assessed in the context of other compounds, and odor blends are better perceived as a whole rather than as individual components.
Social insects are known for their reproductive division of labor between queens and workers, whereby queens lay the majority of the colony's eggs, and workers engage mostly in non-reproductive tasks. Queens produce pheromones that signal their presence and fertility to workers, which in turn generally remain sterile. Recently, it has been discovered that specific queen-characteristic cuticular hydrocarbons (CHCs) function as queen pheromones across multiple lineages of social insects. In the common wasp, Vespula vulgaris, several long-chain linear alkanes and 3-methylalkanes were shown to act as queen signals. Here, we describe similar bioassays with a related species of highly eusocial vespine wasp, the Saxon wasp, Dolichovespula saxonica. We show that a blend of queen-characteristic hydrocarbons that are structurally related to those of the common wasp inhibit worker reproduction, suggesting conservation of queen pheromones across social wasps. Overall, our results highlight the central importance of CHCs in chemical communication among social insects in general, and as conserved queen pheromones in these social wasps in particular.
Three metal-organic frameworks (MOFs) {[Co4(OH)2(adc)6(H2O)5][Co2(OH)(btrb)]2·8H2O}n (1), {[Co4(OH)2(btrb)(nip)3(H2O)3]·4H2O}n (2·4H2O) and {[Co4(OH)2(btrb)(btc)2(H2O)2]·9H2O}n (3·9H2O) (btrb = 1,4-bis(1,2,4-triazol-4-ylmethyl)benzene, H2adc = 1,3-adamantanedicarboxylic acid, H2nip = 5-nitroisophthalic acid and H3btc = 1,3,5-benzenetricarboxylic acid) were synthesized by a hydrothermal method. 1 shows an unusual (3,4)-connected 2D network with a point symbol of (4·6(2))2(4(2)·6(2)·8(2)) based on [Co4(μ3-OH)2] and [Co2(μ3-OH)] units. 2 is a 6-connected pcu topology based on the [Co4(μ3-OH)2] unit. 3 is a rare (3,8)-connected 3D framework with a rare point symbol of (4·5·6)2(4(2)·5(6)·6(16)·7(2)·8(2)) based on the [Co4(μ3-OH)2] unit. The magnetic measurements reveal that 1-3 exhibit antiferromagnetic interactions between the adjacent cobalt(ii) centers. 1-3 are good photocatalysts for the degradation of methylene blue (MB). The 1,2-position nitrogen atoms of the 4-substituted 1,2,4-triazole ligand act as strong σ-donators to form a quite stable coordination quadrangle with two metal ions. The btrb ligand containing two 4-substituted 1,2,4-triazole rings is favorable to form tetranuclear metal units. By the regulation of the multicarboxylate ligands, the connection number of [Co4(μ3-OH)2] clusters increases from 4 in 1 to 6 in 2 and then 8 in 3. This work presents a novel but effective method to design and regulate the connection number (4, 6 and 8 connected in this work) of MOFs with 4-substituted 1,2,4-triazole and rigid multicarboxylate ligands.
Two-dimensional (2D) materials are characterised by their strong intraplanar bonding but weak interplanar interaction. Interfaces between neighboring 2D layers or between 2D overlayers and substrate surfaces provide intriguing confined spaces for chemical processes, which have stimulated a new area of "chemistry under 2D cover". In particular, well-defined 2D material overlayers such as graphene, hexagonal boron nitride, and transition metal dichalcogenides have been deposited on solid surfaces, which can be used as model systems to understand the new chemistry. In the present review, we first show that many atoms and molecules can intercalate ultrathin 2D materials supported on solid surfaces and the space under the 2D overlayers has been regarded as a 2D nanocontainer. Moreover, chemical reactions such as catalytic reactions, surface adlayer growth, chemical vapor deposition, and electrochemical reactions occur in the 2D confined spaces, which further act as 2D nanoreactors. It has been demonstrated that surface chemistry and catalysis are strongly modulated by the 2D covers, resulting in weakened molecule adsorption and enhanced surface reactions. Finally, we conclude that the confinement effect of the 2D cover leads to new chemistry in a small space, such as "catalysis under cover" and "electrochemistry under cover". These new concepts enable us to design advanced nanocatalysts encapsulated with 2D material shells which may present improved performance in many important processes of heterogeneous catalysis, electrochemistry, and energy conversion.
Payments to practitioners from drug and device manufacturers or group purchasing organizations are reported in the Centers for Medicare and Medicaid Services (CMS) databases as a part of the Sunshine Act. Characterizing these payments is a necessary step to identifying conflicts of interest and the influence of payments on practice patterns, if any. Payments have never been analyzed in detail amongst Urologists.
We reviewed the most recent CMS Open Payments database for the full year 2014, released on June 30, 2015. Urology practitioners were extracted and the database was analyzed for number of total payments, total dollar value of payments, mean, median, number of physicians, number of manufacturers, and number of drugs/biologicals. Data were further categorized according to provider specialty, form of payment, nature of payment, practitioner ownership, and dispute status.
Payments totaled $32,450,382. Practitioner payments were unevenly distributed, with a median payment of $15. The majority of payments were in the form of food and beverage. Female pelvic medicine practitioners received the highest payments out of the provider specialties. The largest categorical difference from the median was in the form of stock, options, and other ownership interests ($24,050). Ownership status and disputed payments were associated with payment values above median values ($400 and $61, respectively).
There are major disparities in industry payments to urology practitioners. Whether or not this influences practice patterns remains to be seen, though identifying categorical differences in payments is an important first step in the process.
Hepatocellular carcinoma (HCC) represents an increasing health burden worldwide and a challenging disease both in terms of diagnosis and treatment.
The literature available on PubMed for the period of 1990-2016 was reviewed with reference to liver allocation, HCC, liver transplantation (LT), and prediction, and the allocation rules of the German Transplant Act were reviewed.
Due to etiological and geographical diversity, HCC is not a homogeneous disease. In the vast majority of patients, HCC develops as a complication of chronic liver disease and cirrhosis. While most patients present with advanced HCC for which palliative strategies are the only available option, LT is the best treatment approach as it not only eliminates the diseased liver and the underlying hepatocarcinogenic mechanisms but also the cancer. The decision for LT is not an easy one to make, because outcome prediction, staging, bridging therapy, and recurrence prevention are difficult and are estimated against the background of the scarce resource of donor organs which are also competitively sought after by patients suffering from non-neoplastic terminal liver diseases, raising the issue of equality of chances in a rationed therapeutic modality. Currently, the Milan criteria are the best evaluated decision tool for LT, but many issues such as down-staging, favorable biological behavior during treatment, expansion of the morphological classification, molecular predictors, and individualized approaches are not yet satisfactorily addressed.
In order to provide a fair and effective approach to LT in HCC, the employed allocation rules require continuous development and scientific evaluation. Recently, the allocation rules for standard exception priority according to the German Transplant Act have been revised to improve patient selection for LT in HCC.
Esophageal cancer (EC) occurs commonly, especially in Asia, and is the sixth leading cause of cancer deaths worldwide. Recently, great progress has been made in research on the etiology and prevention of EC.
The major risk factors for esophageal squamous cell carcinoma (ESCC) are tobacco smoking and alcohol drinking, which act synergistically. Dietary parameters, including dietary carcinogens and insufficiency of micronutrients, could also be important risk factors in certain areas. A common etiological factor for both EC and some other cancers are low levels of intake of fruits and vegetables. With improvements in diet and drinking water in developing countries, the incidence of ESCC decreased. However, in economically well-developed countries, the incidence of esophageal adenocarcinoma (EAC) has markedly increased in the past 40 years. The major etiological factor for EAC is gastroesophageal reflux, which is also an etiological factor for gastric cardia adenocarcinoma (GCA). In certain areas of China, the occurrence of GCA is closely related to ESCC. Susceptibility genes for EC are starting to be discovered, and this may help to identify high-risk groups that have more need for preventive measures. Mitigation of the risk factors, early detection and treatment of precancerous lesions are effective approaches for prevention. Smoking cessation, avoidance of excessive alcohol, meat and caloric
 consumption, increasing physical activity and frequent consumption of vegetables and fruits are prudent lifestyle modifications for the prevention of EC as well as other diseases.
The etiology of EC includes tobacco smoking, alcohol drinking, low levels of intake of fruits and vegetables as well as gastroesophageal reflux and susceptibility genes.
A healthy lifestyle including smoking cessation, increasing physical activity, consumption of vegetables as well as reduction of alcohol intake and caloric consumption are major approaches to the prevention of EC.
Communication related to health not only substantially affects perceptions and behaviors related to health but is also positively associated with the extent of health-information seeking and the practice of preventive behavior. Despite the fact that the number of cancer survivors has increased dramatically, there are few studies of the lack of health information, factors which act as barriers, and the difficulties in follow-up care experienced by cancer survivors. Therefore, we reviewed media utilization and the types of media used by cancer survivors with regard to risk communication and suggested appropriate strategies for cancer communication. According to the results, health communication contributed to health promotion by providing health-related information, consolidating social support factors such as social solidarity and trust, and reducing anxiety. In particular, participatory health communication may establish preventive programs which reflect the needs of communities, expand accessibility to better quality healthcare, and intensify healthy living by reducing health inequalities. Therefore, when people do not have an intention to obtain cancer screening, we need to intervene to change their behavior, norms, and degrees of self-efficacy. The findings of this study may help those involved in building partnerships by assisting in their efforts to understand and communicate with the public.
Olanzapine is a well established treatment for schizophrenia. The olanzapine pamoate depot (long-acting injectable) formulation improves compliance and clinical trials have shown it to be effective. However, there are no previously published reports evaluating olanzapine depot in violent patients with schizophrenia in the community. We evaluated the clinical efficacy of olanzapine depot, its effect on violence, hospitalization and incarceration in community patients with schizophrenia and prior history of serious violence.
This was a retrospective service evaluation in a community forensic psychiatry service where patients had schizophrenia spectrum disorder and a significant history of violence. Treatment resistance, substance use disorders and antisocial personality disorder were common. Nine deidentified patient records were audited for 12 months pre and 12 months post olanzapine depot initiation to identify any clinical changes, breaches of (legislated) psychiatric treatment orders, hospital admission days, days incarcerated and emergency presentations.
Community forensic psychiatric patients treated with olanzapine depot showed an improvement in psychotic symptoms (p = 0.008) with overall decreases in violence, supported by reductions in hospitalization days (p = 0.018) and days incarcerated (p = 0.043). Several patients had reduced psychiatric treatment order breaches and emergency presentations.
Community forensic psychiatric patients with schizophrenia responded to olanzapine depot with decreased violence and reduced hostility. A depot antipsychotic medication that reduces violence and improves engagement has significant implications for greater effective community management of forensic patients with schizophrenia.
Miseq sequencing and data analysis for the actin gene and v9 region of 18S rDNA of 7 simulated samples consisting of different mixture of dinoflagellates and diatoms were carried out. Not all the species were detectable in all the 18S v9 samples, and sequence percent in all the v9 samples were not consistent with the corresponding cell percent which may suggest that 18S rDNA copy number in different cells of these species differed greatly which result in the large deviation of the amplification. And 18S rDNA amplification of the microalgae was prone to be contaminated by fungus. The amplification of actin gene all was from the dinoflagellates because of its targeted degenerate primers. All the actin sequences of dinoflagellates were detected in the act samples except act4, and sequence percentage of the dinoflagellates in the act samples was not completely consistent with the dinoflagellates percentage of cell samples, but with certain amplification deviations. Indexes of alpha diversity of actin gene sequencing may be better reflection of community structure, and beta diversity analysis could cluster the dinoflagellates samples with identical or similar composition together and was distinguishable with blooming simulating samples at the generic level. Hence, actin gene was more proper than rDNA as the molecular marker for the community analysis of the dinoflagellates.
The necessity of using granulocyte-colony stimulating factor (G-CSF) during dose-dense (DD) paclitaxel (T) after doxorubicin and cyclophosphamide (AC) is unclear.
This was a retrospective cohort study including patients with stage I-III breast cancer treated at Dana-Farber Cancer Institute with adjuvant DD-ACT between January 2011 and December 2013. Descriptive analyses evaluating patterns of G-CSF utilization during T were performed.
Overall, 156 patients were treated with DD-ACT by 26 providers. The majority of patients (135, 87%) received at least one dose of G-CSF during T (group 1), 17% of these patients received it in only one cycle and 48% received it in all four cycles. Reasons for omitting G-CSF included high baseline absolute neutrophil count and pain. Twenty-one (13%) patients did not receive any G-CSF during T (group 2). Respectively, 94% and 90% of patients completed the treatment in groups 1 and 2. There were no cases of treatment cessation due to neutropenia. Six percent of patients in group 1 had at least one treatment delay. There were no treatment delays reported in group 2. Variation in the use of G-CSF by provider and by patient was found, with 11 providers choosing not to use G-CSF in at least one patient.
We identified substantial variation in the use of G-CSF within the practice. However, omission of G-CSF was not associated with treatment delays or adverse events. Prospective studies are warranted to formally test whether routine G-CSF is necessary during dose-dense T therapy.
The complexity of Alzheimer's disease (AD) calls for search of multifunctional compounds as potential candidates for effective therapy. A series of phthalimide and saccharin derivatives linked by different alicyclic fragments (piperazine, hexahydropyrimidine, 3-aminopyrrolidine or 3-aminopiperidine) with phenylalkyl moieties attached have been designed, synthesized, and evaluated as multifunctional anti-AD agents with cholinesterase, β-secretase and β-amyloid inhibitory activities. In vitro studies showed that the majority of saccharin derivatives with piperazine moiety and one phthalimide derivative with 3-aminopiperidine fragment exhibited inhibitory potency toward acetylcholinesterase (AChE) with EeAChE IC50 values ranging from 0.83 μM to 19.18 μM. The target compounds displayed inhibition of human β-secretase-1 (hBACE1) ranging from 26.71% to 61.42% at 50 μM concentration. Among these compounds, two multifunctional agents (26, [2-(2-(4-benzylpiperazin-1-yl)ethyl)benzo[d]isothiazol-3(2H)-one 1,1-dioxide] and 52, 2-(2-(3-(3,5-difluorobenzylamino)piperidin-1-yl)ethyl)isoindoline-1,3-dione) have been identified. Compound 26 exhibited the highest inhibitory potency against EeAChE (IC50 = 0.83 μM) and inhibitory activity against hBACE1 (33.61% at 50 μM). Compound 52 is a selective AChE inhibitor (IC50 AChE = 6.47 μM) with BACE1 inhibitory activity (26.3% at 50 μM) and it displays the most significant Aβ anti-aggregating properties among all the obtained compounds (39% at 10 μM). Kinetic and molecular modeling studies indicate that 26 may act as non-competitive AChE inhibitor able to interact with both catalytic and peripheral active site of the enzyme.
Acceptance and Commitment Therapy (ACT) can be effective in treating anxiety disorders, yet there has been no study on Internet-delivered ACT for social anxiety disorder (SAD) and panic disorder (PD), nor any study investigating whether therapist guidance is superior to unguided self-help when supplemented with a smartphone application. In the current trial, n=152 participants diagnosed with SAD and/or PD were randomized to therapist-guided or unguided treatment, or a waiting-list control group. Both treatment groups used an Internet-delivered ACT-based treatment program and a smartphone application. Outcome measures were self-rated general and social anxiety and panic symptoms. Treatment groups saw reduced general (d=0.39) and social anxiety (d=0.70), but not panic symptoms (d=0.05) compared to the waiting-list group, yet no differences in outcomes were observed between guided and unguided interventions. We conclude that Internet-delivered ACT is appropriate for treating SAD and potentially PD. Smartphone applications may partially compensate for lack of therapist support.
F4 fimbriae are protein filaments found in enterotoxigenic Escherichia coli cells and are implicated in the process of bacterial infection due to their function as bacterial adhesins. These filaments are comprised from several proteins, but the bacterial adhesin FaeG, which is a lactose-binding protein, is the major subunit comprising F4 fimbriae. Crystal structures for three variants of the FaeG protein were recently solved, including the ad variant of FaeG that was crystallized
 in complex with lactose. However, the dynamics of the FaeG protein bound to lactose have not been explored previously using molecular dynamics simulations. Therefore, in order to study the dynamical interactions between the FaeG ad variant and lactose, we have carried out the first all-atom molecular dynamics simulations of this system. We have also probed the role of crystallographic water molecules on the stability of lactose in the FaeG binding site, and have simulated seven FaeG mutants to probe the influence of amino acid substitutions on the ability of FaeG to bind lactose effectively. Our simulations agree well with experimental results for the influence of mutations on lactose binding, provide dynamical insights into the interactions of FaeG with lactose, and also suggest the possibility of additional regions of the FaeG protein that may act as secondary lactose binding sites.
Cardiac myofilaments act as the central contractile apparatus of heart muscle cells. Covalent modification of constituent proteins through phosphorylation is a rapid and powerful mechanism to control myofilament function, and is increasingly seen as a mechanism of disease. While the relationship between protein kinases and cardiac myofilaments has been widely examined, the impact of protein dephosphorylation by protein phosphatases is poorly understood. This review outlines the mechanisms by which the mostly widely expressed protein phosphatases in cardiac myocytes regulate myofilament function, and the emerging role of myofilament-associated protein phosphatases in heart failure. The importance of regulatory subunits and subcellular compartmentalization in determining the functional impact of protein phosphatases on myofilament and myocardial function is also discussed, as are discrepancies about the roles of protein phosphatases in regulating myofilament function. The potential for targeting these molecular messengers in the treatment of heart failure is discussed as a key future direction.
Sleep difficulties are commonly reported by patients with asthma. However, the prevalence of insomnia and its association with disease burden and well-being is unknown.
We aimed to determine the prevalance of insomnia, defined as combined sleep-specific complaints with associated daytime symptoms, among a large sample of adults with asthma, and to compare well-being, asthma control, and asthma-related healthcare utilization in individuals with asthma and insomnia and those without insomnia.
Baseline data from adults with physician-confirmed asthma enrolled in the Severe Asthma Research Program (SARP) III was used for the analyses (n = 714). Participants completed the Insomnia Severity Index (ISI), Asthma Control Test (ACT), Asthma Quality of Life Questionnaire (AQLQ), and Hospital Anxiety and Depression Scale (HADS).
Insomnia (ISI ≥ 10) was identified in 263 participants (37%). Presence of insomnia was associated with higher levels of depression and anxiety symptoms and poorer quality of life. Those with insomnia had a 2.4-fold increased risk for having not well-controlled asthma and a 1.5-fold increased risk for asthma-related healthcare utilization in the past year compared to those without insomnia.
Insomnia is highly prevalent in asthma and is associated with adverse outcomes. Further studies are needed to gain a better understanding of the interaction between insomnia and asthma control.
During development of the inner ear, secreted morphogens act coordinately to establish otocyst dorsoventral polarity. Among these, Sonic hedgehog (SHH) plays a critical role in determining ventral polarity. However, how this extracellular signal is transduced intracellularly to establish ventral polarity is unknown. In this study, we show that cAMP dependent protein kinase A (PKA) is a key intracellular factor mediating SHH signaling through regulation of GLI3 processing. Gain-of-function experiments using targeted gene transfection by sonoporation or electroporation revealed that SHH signaling inactivates PKA, maintaining a basal level of PKA activity in the ventral otocyst. This, in turn, suppresses partial proteolytic processing of GLI3FL, resulting in a low GLI3R/GLI3FL ratio in the ventral otocyst and the expression of ventral-specific genes required for ventral otocyst morphogenesis. Thus, we identify a molecular mechanism that links extracellular and intracellular signaling, determines early ventral polarity of the inner ear, and has implications for understanding the integration of polarity signals in multiple organ rudiments regulated by gradients of signaling molecules.
The purpose of this study was to characterize anterolateral bowing of the femur using X-rays and muscular atrophy in the mid-thigh using computed tomography (CT) in patients with atypical femoral fractures (AFFs). We then compared the results with those of an intertrochanteric fracture to understand whether these measures act as causative factors of AFFs.
From January 2009 to December 2015, 37 patients with complete AFF and 12 patients with incomplete AFF were enrolled in this study. Lateral femoral bowing, anterior femoral bowing, cross-sectional area (CSA), and attenuation coefficient of thigh muscles in the AFF group are measured and compare with those in the intertrochanteric fracture group.
Lateral and anterior femoral bowing in the AFF group were significantly higher than those in the intertrochanteric fracture group. The level of fracture was found to be significantly associated with lateral and anterior femoral bowing (r = 0.569, r(2) = 0.324, p < 0.001; r = -0.530, r(2) = 0.281, p < 0.001, respectively). Total CSA and CSA of anterior and medial compartments were significantly lower in the AFF group (p < 0.05). The attenuation coefficient of the total thigh muscle and all three compartments in the AFF group were significantly lower than those in the intertrochanteric fracture group (p < 0.05).
This study demonstrated that anterolateral femoral bowing and loss of thigh muscle were highly associated with the occurrence of AFFs.
The current study examined the effect of publicity about Canada's recent Not Criminally Responsible (NCR) Reform Act - legislation surrounding accused in insanity cases that purportedly aims to enhance public safety - on juror decision-making. In line with agenda-setting theory, we expected that NCR Reform Act publicity might reinforce certain fears about the insanity defence, dependent on whether it had either a positive or negative evaluative slant. Contrary to previous work on the insanity defence, participants in this study generally favoured a NCR verdict. The evaluative slant of the NCR publicity had no effect on verdict decisions or insanity defence attitudes, but there was a significant difference in participants' evaluations of the fairness of the Reform Act, such that those exposed to a positive or control article viewed the act as fairer than those exposed to a negative article. This study may aid future researchers in evaluating potential unintended consequences of the NCR Reform Act.
There is an urgent need for methods that can rapidly and accurately assess therapeutic responses in patients with active tuberculosis (TB) in order to predict treatment outcomes. Exposure to bacterial pathogens can rapidly activate the plasma contact system, triggering the release of bradykinin (BK) and its metabolite desArg(9)-bradykinin (DABK) to induce inflammation and innate immune responses. We hypothesized that serum BK and DABK levels might act as sensitive immune response signatures for changes in Mycobacterium tuberculosis (Mtb) burden, and therefore examined how serum levels of these markers corresponded with anti-TB therapy in a small cohort of active TB cases.
Nanotrap Mass-Spectrometry (MS) was used to analyze serial blood specimens from 13 HIV-negative adults with microbiologically confirmed active TB who were treated with first-line anti-TB chemotherapy. MS signal for BK (m/z 1060.5) and DABK (m/z 904.5) serum peptides were evaluated at multiple time-points (before, during, and after treatment) to evaluate how BK and DABK levels corresponded with disease status.
Serum BK levels declined from pretreatment baseline levels during the early stage anti-TB therapy (induction phase) and tended to remain below baseline levels during extended treatment (consolidation phase) and after therapy completion. BK levels were consistent with induction phase sputum culture conversions indicative of decreased Mtb burden reflecting good treatment responses. Serum DABK levels tended to increase during the induction phase and decrease at consolidation and post-therapy time points, which may indicate a shift from active disease to chronic inflammation to a disease free state. Elevated BK and DABK levels after treatment completion in one patient may be related to the subsequent recurrent TB disease.
Our pilot data suggests that changes in the circulating BK and DABK levels in adult TB patients can be used as potential surrogate markers of the host response both early and late in anti-TB treatment for both pulmonary and extrapulmonary TB patients. We will further exploit these host-response signatures in the future as biomarkers in combination with other clinical and microbiologic tools which may improve treatment efficacy and facilitate the development of host-directed therapy.
Failure to identify and respond to clinical deterioration is an important measure of patient safety, hospital performance and quality of care. Although studies have identified the role of patient, system and human factors in failure to rescue events, the role of 'inattentional blindness' as a possible contributing factor has been overlooked.
To explore the nature and possible patient safety implications of inattentional blindness in critical care, emergency and perioperative nursing contexts.
Analysis
 of four case scenarios drawn from a naturalistic inquiry investigating how nurses identify and manage gaps (discontinuities) in care. Data were collected via in-depth interviews from a purposeful sample of 71 nurses, of which 20 were critical care nurses, 19 were emergency nurses and 16 were perioperative nurses. Case scenarios were identified, selected and analysed using inattentional blindness as an interpretive frame.
The four case scenarios presented here suggest that failures to recognise and act upon patient observations suggestive of clinical deterioration could be explained by inattentional blindness. In all but one of the cases reported, vital signs were measured and recorded on a regular basis. However, teams of nurses and doctors failed to 'see' the early signs of clinical deterioration. The high-stress, high-complexity nature of the clinical settings in which these cases occurred coupled with high cognitive workload, noise and frequent interruptions create the conditions for inattentional blindness.
The case scenarios considered in this report raise the possibility that inattentional blindness is a salient but overlooked human factor in failure to rescue events across the critical care spectrum. Further comparative cross-disciplinary research is warranted to enable a better understanding of the nature and possible patient safety implications of inattentional blindness in critical care nursing contexts.
The objective of this study was to determine the relative importance and contribution of several physiological factors as predictors of pregnancy risk in an Ovsynch (GnRH-1 - 7d - PGF2α - 56h - GnRH-2 - 16h - artificial insemination) timed artificial insemination program: (1) age of the corpus luteum (CL; original CL, new CL, or both in response to GnRH-1) and resulting progesterone concentrations as they affected luteolysis, ovulation after GnRH-2, and pregnancy risk; (2) progesterone concentration before GnRH-1 and GnRH-2 on subsequent ovulatory response to GnRH-1 and GnRH-2 as well as pregnancy risk; and (3) a combination of these factors in a multivariable logistic regression model to predict pregnancy risk. Original data from 7 published studies were combined including ovulatory responses to both GnRH injections, blood progesterone concentrations before GnRH-1, before PGF2α, and at 48h after PGF2α, pregnancy per artificial insemination at d 32 and 60 after artificial insemination, and intervening pregnancy loss. Ovulation outcomes were greater at lesser progesterone concentrations after both GnRH injections despite the fact that pregnancy outcomes were greatest when progesterone exceeded 3ng/mL before GnRH-1 and PGF2α, suggesting that greater progesterone concentration before GnRH-1 and incidence of ovulation act via different mechanisms to improve subsequent fertility. Ovulation after GnRH-2 and subsequent pregnancy outcome were positively related to lesser concentrations of progesterone at 48h after PGF2α; however, for maximal pregnancy outcome, progesterone should be <0.5ng/mL. Cows with a CL that also formed a new CL after GnRH-1 had the greatest pregnancy outcome, whereas cows with only a new CL (i.e., anovulatory cows and those at or near estrus without a CL at GnRH-1) had the poorest pregnancy outcome. Pregnancy loss was not affected by CL status during the timed artificial insemination program. Receiver operator curves produced cut points of progesterone concentration that predicted ovulation and pregnancy risk. Selected cut points of progesterone concentration 48h after PGF2α produced true positive risks greater than 90% and false positive risks less than 25%, thus demonstrating the high predictability of ovulation after GnRH-2 and subsequent pregnancy outcome based on progesterone concentration. We conclude that progesterone concentration is highly predictive of ovulation and pregnancy risk in addition to body condition, size of ovulatory follicle, and parity.
Adult beetles (Coleoptera) are covered primarily by a hard exoskeleton or cuticle. For example, the beetle elytron is a cuticle-rich highly modified forewing structure that shields the underlying hindwing and dorsal body surface from a variety of harmful environmental factors by acting as an armor plate. The elytron comes in a variety of colors and shapes depending on the coleopteran species. As in many other insect species, the cuticular tanning pathway begins with tyrosine and is responsible for production of a variety of melanin-like and other types of pigments. Tanning metabolism involves quinones and quinone methides, which also act as protein cross-linking agents for cuticle sclerotization. Electron microscopic analyses of rigid cuticles of the red flour beetle, Tribolium castaneum, have revealed not only numerous horizontal chitin-protein laminae but also vertically oriented columnar structures called pore canal fibers. This structural architecture together with tyrosine metabolism for cuticle tanning is likely to contribute to the rigidity and coloration of the beetle exoskeleton.
With more people having access to health care in the United States as a result of the Affordable Care Act, there is a greater need for nurses now than ever before. Generalist nurses will need to be educated, not just to care for people in hospitals, but also to promote health and help manage chronic conditions in a wide variety of health care settings. More advanced-practice nurses will be needed to provide primary care. Although the need for nurses educated at both the undergraduate and graduate levels in emerging health care systems is increasing, the number of nursing educators is decreasing. Nursing educators in the future will need to be nimble in addressing emerging health care needs while ensuring succession planning.
Our study examines the contribution of genetic and environmental factors (both shared and unique) to frailty, measured using the Rockwood Frailty Index (FI) in a sample of twins from the St Thomas' UK Adult Twin Registry. The FI was based on 39 items of potential health deficit. Study participants were 3,375 volunteer adult twins (840 monozygotic and 802 dizygotic twin-pairs) 40.0-84.5 years old. First, we used structural equation modeling to estimate the relative contribution of genetics and of the shared and unique environment to variance in FI adjusted for age. In a second analysis, multiple linear regression was used to examine variance in FI as a function of father's occupational class (a component of shared environment and a measure of childhood socioeconomic status [SES]), adjusting for age, birth weight, marital status, and health behaviors (smoking, alcohol consumption, and physical activity). Statistical analyses were conducted using IBM SPSS® Version 22 software and Mx open source software. Findings showed that 45% (95% confidence intervals [CIs] 30-53%) of the inter-individual variation in FI was heritable and 52% (95% CIs 47-57%) was due to the individual's unique environment. Multiple linear regression also showed a small but statistically significant inverse association between father's occupational class and FI, mediated by one's own educational attainment and birth weight. Our results indicate that frailty is both genetically and environmentally determined. Thus, its prevention and management call for a multifaceted approach that includes addressing deleterious environmental factors, some of which, like childhood SES, may act across the life course.
Deletion of phenylalanine 508 is the most frequent mutation causing cystic fibrosis. It causes multiple defects: 1) misfolding of the protein causing retention at the ER (processing defect); 2) reduced channel activity (gating defect); 3) reduced plasma membrane residency time due to increased internalization rate and defective recycling.
Druggability of F508del-CFTR was demonstrated by several studies. Correctors are molecules able to improve maturation and trafficking to the membrane of F508del-CFTR. Correctors could act as pharmacological chaperones or as proteostasis regulators. Pharmacological chaperones act directly on mutant CFTR, while proteostasis regulators modify the proteostasis environment leading to beneficial effects on CFTR maturation.
The use of a single compound is not sufficient to promote a therapeutically relevant F508del-CFTR rescue. Drug therapy for CF will require combinations of correctors exploiting different mechanisms of action, i.e. pharmacological chaperones combined together or with a proteostasis regulator.
Development of more effective CF drugs could therefore rely on a better understanding of the molecular events underlying CFTR processing/degradation. This review will focus on most promising pathways and related targets for the development of novel CF pharmacotherapies.
The field of bile acid research has become tremendously active. Bile acids have been shown to act as signaling molecules that are involved in many metabolic processes, but their role in carcinogenesis is also emerging.
The aim of this review was to summarize the present knowledge in the innovative field of bile acids pharmacology, to reveal the novel mechanisms of their action, particularly focusing on clinically relevant aspects, and to evaluate the role of both genetic and epigenetic variation in genes encoding bile acid-activated receptors in determining the therapy outcome.
Most effects of bile acids are mediated by both nuclear and G protein-coupled receptors. Three natural bile acids have already been registered for the use in humans, but various semi-synthetic bile acid analogues with improved pharmacokinetic and pharmacodynamic properties have been developed, which opens up new avenues in pharmacotherapy. Many efforts have been made to evaluate the impact of nuclear receptors on inter-individual variation in responses to drugs, since nuclear receptors are
 significant mediators between environmental stimuli and pharmacokinetics. Genetic variation of bile acid-activated receptors is associated with both benign and malignant diseases, in terms of disease risk and severity, but also with pharmacokinetics and therapy outcome. Furthermore, the activity of these receptors may be masked or amplified by epigenetic modifications.
Both genetic and epigenetic factors may alter complex and intricate network of bile acid signaling pathways, contributing to the development of several metabolic and non-metabolic diseases and altered activities of drug-metabolizing enzymes and transporters. These polymorphisms and epigenetic modifications may also impact the effectiveness and pharmacokinetics of bile acid analogues, which must be taken into account during the development of these compounds as novel therapeutic agents.
Medicinal plants continue to act as a repository for novel drug leads with novel mechanisms of action. Podophyllum hexandrum Royale (Berberideceae) treats diverse conditions in folk medicine.
The antimutagenic potential of P. hexandrum was evaluated against endosulfan-induced clastogenicity in a piscine model by cytogenetic endpoints.
Podophyllum hexandrum rhizomes were subjected to successive solvent extraction. Fish were exposed to hexane, chloroform, ethyl acetate, methanol and aqueous extracts (15 mg/L each) of plant and endosulfan (0.05 mg/L) alone followed by their combination for antimutagenicity estimates. Chromosomal aberrations (CA) were made from kidney cells and micronuclei (MN) slides from peripheral blood erythrocytes at 48, 72 and 96 h. Antioxidant activity was analyzed by the DPPH assay. Phytochemical analyses were carried out using chromatographic and spectroscopic techniques.
Endosulfan induced significant (p < .05) MN, authenticated by scanning electron microscopy, and CA in a time-dependent manner. However, methanol and ethyl acetate extracts revealed ameliorating effects. The column eluted methanolic fraction-2 (ME-F2) showed highest reduction profile of 83 and 84% in CA and MN, followed in its extent (73 and 72%) by ethyl acetate fraction-4 (EE-F4). ME-F2 and EE-F4 showed three and six major peaks when analyzed by GC-MS. To explore possible mechanism of action, ME-F2 showed potent antioxidant potential and strong correlation (R(2 )=( ).900) with antimutagenic activity, whereas EE-F4 seemed to act through a different mechanism.
This study confirms the antimutagenic potential of the subject plant with the identification of some novel compounds, justifying their use in folk medicine, and their corresponding benefit to mankind.
In recent years, a number of pharmacological approaches for treating neuropsychiatric conditions at older age have proven to be inadequate. The resulting increased prevalence of therapeutic failures (TF) and a worsening of clinical symptoms often linked to adverse reactions (ADRs), are perhaps among the major causes of the increasing rate of hospitalizations and institutionalizations observed in these patients. Areas covered: This review underlines the importance of pharmacogenetic data to fingerprint the pharmacological treatment of neuropsychiatric late-life conditions throughout the analysis of metabolizing enzymes and transporters of psychotropic drugs, mainly those of the cytochrome P450 (CYP) family. Pharmacodynamic response measures as treatment effects mediated through targets (i.e., receptors in the brain) may also contribute to this image. Expert opinion: CYP genetics is the basis of a continuum on which environmental and physiological factors act, modeling the phenotype observed in clinical practice with advancing age. Furthermore, other specific polymorphic genes influence drug response through differential effects of their functional genetic variants. The known genotypes associated with an altered metabolizer status and drug transporters may help clinical decision-making to avoid concomitant treatments, reduce therapeutic attempts and increase drug safety in neuropsychiatric conditions in older age, after controlling for other clinical variables.
Education of nurses in the Republic of Croatia is being developed as a result of compliance with education in the European Union and the implementation of nursing research that leads to the growth of the whole profession. However, prejudice against the nursing profession is still present and therefore it is necessary to explore the attitudes of the general population and the population of nurses in the nursing profession in order to discover the causes of such prejudices and act on them. Therefore, the aim of this paper was to present transcultural adaptation and validation of the Nursing Image Questionnaire, which was created by Toth and associates (1998). The questionnaire, which includes 30 items and measures how an individual looks at the roles, values, and professional activities of nurses, was conducted as part of a preliminary study and was culturally adapted. The final study included 905 students who in 2011 and 2012 enrolled in the first year of full-time and part-time nursing study; the questionnaire was completed by 725 students. Toth and associates assumed that the attitude toward nursing is expressed as the sum of the responses of all the items, which would mean a factor structure with high item intercorrelation, but they also split the questionnaire into five thematic units. Results showed that, contrary to expectations, intercorrelations of items were extremely low and that following the completion of factor analysis, no satisfactory construct validity was established. From the obtained results, it can be concluded that it is not justified to create a latent dimension as established by research of Toth and associates, and the items, although there is a correlation between some of them, should be interpreted and analysed as independent constructs.
Large magnitude (>10‰) carbon-isotope (δ(13) C) excursions recorded in carbonate-bearing sediments are increasingly used to monitor environmental change and constrain the chronology of the critical interval in the Neoproterozoic stratigraphic record that is timed with the first appearance and radiation of metazoan life. The ~10‰ Bitter Springs Anomaly preserved in Tonian-aged (1000-720 Ma) carbonate rocks in the Amadeus Basin of central Australia has been offered as one of the best preserved examples of a primary marine δ(13) C excursion because it is regionally reproducible and δ(13) C values covary in organic and carbonate carbon arguing against diagenetic exchange. However, here we show that δ(13) C values defining the excursion coincide with abrupt lithofacies changes between regularly cyclic grainstone and microbial carbonates, and desiccated red bed mudstones with interbedded evaporite and dolomite deposits, recording local environmental shifts from restricted marine conditions to alkaline lacustrine and playa settings that preserve negative (-4‰) and positive (+6‰) δ(13) C values, respectively. The stratigraphic δ(13) C pattern in both organic and carbonate carbon recurs within the basin in a similar way to associated sedimentary facies, reflecting the linkage of local paleoenvironmental conditions and δ(13) C values. These local excursions may be time transgressive or record a relative sea-level influence manifest through exposure of sub-basins isolated by sea-level fall below shallow sills, but are independent of secular seawater variation. As the shallow intracratonic setting of the Bitter Springs Formation is typical of other Neoproterozoic carbonate successions used to construct the present δ(13) C seawater record, it identifies the potential for local influences on δ(13) C excursions that are neither diagenetic nor representative of the global exogenic cycle.
A wide range of studies have shown that liposomes can act as suitable adjuvants for a range of vaccine antigens. Properties such as their amphiphilic character and biphasic nature allow them to incorporate antigens within the lipid bilayer, on the surface, or encapsulated within the inner core. However, appropriate methods for the manufacture of liposomes are limited and this has resulted in issues with cost, supply, and wider scale application of these systems. Within this chapter we explore manufacturing processes that can be used for the production of liposomal adjuvants, and we outline new manufacturing methods can that offer fast, scalable, and cost-effective production of liposomal adjuvants.
The peripheral auditory system of lizards has been extensively studied, because of its remarkable directionality. In this paper, we review the research that has been performed on this system using a biorobotic approach. The various robotic implementations developed to date, both wheeled and legged, of the auditory model exhibit strong phonotactic performance for two types of steering mechanisms-a simple threshold decision model and Braitenberg sensorimotor cross-couplings. The Braitenberg approach removed the need for a decision model, but produced relatively inefficient robot trajectories. Introducing various asymmetries in the auditory model reduced the efficiency of the robot trajectories, but successful phonotaxis was maintained. Relatively loud noise distractors degraded the trajectory efficiency and above-threshold noise resulted in unsuccessful phonotaxis. Machine learning techniques were applied to successfully compensate for asymmetries as well as noise distractors. Such techniques were also successfully used to construct a representation of auditory space, which is crucial for sound localisation while remaining stationary as opposed to phonotaxis-based localisation. The peripheral auditory model was furthermore found to adhere to an auditory scaling law governing the variation in frequency response with respect to physical ear separation. Overall,
 the research to date paves the way towards investigating the more fundamental topic of auditory metres versus auditory maps, and the existing robotic implementations can act as tools to compare the two approaches.
Sponge-associated bacteria play a critical role in sponge biology, metabolism and ecology, but how they interact with their host sponges and the role of these interactions are poorly understood. This study investigated the role of the interaction between the sponge Aplysilla rosea and its associated actinobacterium, Streptomyces ACT-52A, in modifying sponge microbial diversity, metabolite profile and bioactivity. A recently developed experimental approach that exposes sponges to bacteria of interest in a controlled aquarium system was improved by including the capture and analysis of secreted metabolites by the addition of an absorbent resin in the seawater. In a series of controlled aquaria, A. rosea was exposed to Streptomyces ACT-52A at 10(6) cfu/ml and monitored for up to 360 h. Shifts in microbial communities associated with the sponges occurred within 24 to 48 h after bacterial exposure and continued until 360 h, as revealed by TRFLP. The metabolite profiles of sponge tissues also changed substantially as the microbial community shifted. Control sponges (without added bacteria) and Streptomyces ACT-52A-exposed sponges released different metabolites into the seawater that was captured by the resin. The antibacterial activity of compounds collected from the seawater increased at 96 and 360 h of exposure for the treated sponges compared to the control group due to new compounds being produced and released. Increased antibacterial activity of metabolites from treated sponge tissue was observed only at 360 h, whereas that of control sponge tissue remained unchanged. The results demonstrate that the interaction between sponges and their associated bacteria plays an important role in regulating secondary metabolite production.
Reactive oxygen species (ROS) mediate vascular cell dysfunction and lead to atherosclerosis and other chronic cardiovascular diseases. The root of Pueraria lobata (Willd.) Ohwi, also known as kudzu or Gegen (Chinese name), is one of the most important herbs in traditional Chinese medicine and has been widely used in the treatment of cardiovascular diseases, diabetes, osteonecrosis and neurodegradation diseases. In this study, an ethanol extract from kudzu root was prepared and the in vitro protective effect of the kudzu root extract (KUD) on human umbilical vein endothelial cells (HUVECs) was investigated.
An ethanol extract of dried kudzu root was purified with an AB-8 resin column, and the concentrations of puerarin, daidzin and daidzein in the KUD were determined using UV spectroscopy. HUVECs were pretreated with various concentrations of the KUD with or without rotenone and the viability was assessed by AlamarBlue cell viability assay. Next, HUVECs were pretreated with the KUD and then treated with rotenone, and the levels of ROS generation, apoptosis, and changes of the mitochondrial membrane potential (ΔΨm) in HUVECs were measured using fluorescent staining assay and high-content analysis.
The contents of three major isoflavonoids (puerarin, daidzin and daidzein) were enriched by 7.75-27.51 fold in the extract. The KUD enhanced the proliferation of HUVECs, and protected HUVECs against rotenone-induced oxidative stress and apoptosis. Additionally, the KUD prevented the loss of ΔΨm in HUVECs stimulated by oxidative stress.
We demonstrated that an isoflavonoid-rich extract prepared from kudzu root has the potential to act as a protector for vascular endothelial cells against intracellular ROS mediated apoptosis and mitochondrial damage.
Evidence-based treatment and management for patients with bronchiectasis remain challenging. There is a need for regional disease measurements as focal distribution of disease is common. Our objective was to evaluate the ability of magnetic resonance imaging (MRI) to detect regional ventilation impairment and response to airway clearance therapy (ACT) in patients with noncystic fibrosis (CF) bronchiectasis, providing a new way to objectively and regionally evaluate response to therapy.
Fifteen participants with non-CF bronchiectasis and 15 age-matched healthy volunteers provided written informed consent to an ethics board-approved Health Insurance Portability and Accountability Act-compliant protocol and underwent spirometry, plethysmography, computed tomography (CT), and hyperpolarized (3)He MRI. Bronchiectasis patients also completed a Six-Minute Walk Test, the St. George's Respiratory questionnaire, and Patient Evaluation Questionnaire (PEQ), and returned for a follow-up visit after 3 weeks of daily oscillatory positive expiratory pressure use. CT evidence of bronchiectasis was qualitatively reported by lobe, and MRI ventilation defect percent (VDP) was measured for the entire lung and individual lobes.
CT evidence of bronchiectasis and abnormal VDP (14 ± 7%) was observed for all bronchiectasis patients and no healthy volunteers. There was CT evidence of bronchiectasis in all lobes for 3 patients and in 3 ± 1 lobes (range = 1-4) for 12 patients. VDP in lobes with CT evidence of bronchiectasis (19 ± 12%) was significantly higher than in lobes without CT evidence of bronchiectasis (8 ± 5%, P = .001). For patients, VDP in lung lobes with (P < .0001) and without CT evidence of bronchiectasis (P = .006) was higher than in healthy volunteers (3 ± 1%). For all patients, mean PEQ-ease-bringing-up-sputum (P = .048) and PEQ-patient-global-assessment (P = .01) were significantly improved post-oscillatory positive expiratory pressure. An improvement in regional VDP greater than the minimum clinical important difference was observed for 8 of the 14 patients evaluated.
There was CT and MRI evidence of structure-function abnormalities in patients with bronchiectasis; in approximately half, there was evidence of ventilation improvements after airway clearance therapy.
Crosstalk between metabolic and immune pathways has recently become appreciated to be key to the regulation of host defence. The hypoxia-inducible factor (HIF) is a transcription factor which was initially described as a ubiquitous master regulator of the transcriptional response to hypoxia. In this role, HIF regulates genes promoting adaptation to hypoxia including a number which influence the cellular metabolic strategy of a cell. It has more recently been appreciated that the regulation of HIF is not restricted to oxygen-dependent pathways, and is now known to be mediated by a number of additional metabolic and immune cues including metabolites and cytokines respectively. Furthermore, our understanding of the functional role of HIF has expanded to it now being appreciated as a major regulator of host immunity. This places HIF in an ideal position to act as a regulatory hub which links metabolic activity with immunity. In this review we synthesise recent data which identifies HIF as both a target and effector for metabolic and immune processes. Developing our understanding of the role of HIF in this context will uncover new therapeutic targets for inflammatory and infectious disease.
Q-type C2H2 zinc finger proteins (ZFPs) are plant-specific DNA-binding proteins containing a conserved QALGGH motif. This study investigated the function of abiotic stress-inducible and predominantly root-expressed Triticum aestivum ZFPs (TaZFP22, TaZFP34 and TaZFP46) with a focus on TaZFP34. Expression of TaZFP34 in roots was upregulated by high salinity, dehydration, oxidative and cold stresses. Overexpression of TaZFP34 in wheat roots resulted in an increased root-to-shoot ratio, a phenomenon observed during plant adaptation to drying soil. Expression of a number of genes which are potentially involved in modulating root growth was significantly altered in the roots of TaZFP34 overexpressing lines. In particular, the transcript levels of TaRR12B, TaRR12D and TaSHY2 that are homologues of known negative regulators of root growth were significantly reduced. Expression of shoot growth-related genes, such as GA3-ox and expansins, was downregulated in the transgenic shoots. TaZFP34 bound to (C/G)AGT(G/A)-like elements in the promoters of TaZFP34 down-regulated TaRR12D and TaSHY2 and transrepressed the reporter gene expression driven by TaRR12D and TaSHY2 promoters. Expression of the above reporter genes was also repressed by TaZFP46 and TaZFP22. These data suggest that TaZFP34 is a transcriptional repressor and is involved in modulating the root-to-shoot ratio.
Reactive oxygen species (ROS) produced in chloroplasts have been proposed to act as signaling molecules for plant immunity through pathogen-associated molecular patterns (PAMPs), such as flg22. To elucidate this process, we herein conducted genetic screening of flg22-sensitive mutants from T-DNA insertion lines lacking chloroplastic H2O2-responsive genes. The results obtained showed that knockout mutants lacking a clade IV TGA transcription factor, TGA10, were more sensitive to the flg22 treatment than wild-type plants. Furthermore, although no flg22-sensitive phenotype was detected in the knockout mutant of another clade IV TGA9, double knockout tga9 tga10 mutants showed more sensitivity to flg22 than single knockout mutants. Transcripts of TGA10 and TGA9 were strongly induced by flg22 in leaves, and this was facilitated by the double knockout of stromal and thylakoid-bound ascorbate peroxidases (APX), which are major H2O2 scavengers in chloroplasts. The flg22-induced H2O2 accumulation was maintained at high level in these APXs mutants, indicating the clade IV TGAs may be induced by the ROS. Furthermore, TGA10 was required for the complete activation of the expression of several flg22-responsive genes in plants treated with this PAMP. These have provided a
 new insight into the relationship between the TGA transcription factors and ROS-mediated signaling in PAMPs responses.
During apoptosis or activation, cells can release a subcellular structure, called a membrane microvesicle (also known as microparticle) into the extracellular environment. Microvesicles bud-off as a portion of cell membrane with its associated proteins and lipids surrounding a cytosolic core that contains intracellular proteins, lipids, and nucleic acids (DNA, RNA, siRNA, microRNA, lncRNA). Biologically active molecules on the microvesicle surface and encapsulated within can act on recipient cells as a novel mode of intercellular communication. Apoptosis has long been known to be involved in the development of diseases of autoimmunity. Abnormally persistent microvesicles, particularly apoptotic microvesicles, can accelerate autoimmune responses locally in specific organs and tissues as well as systemically. In this review, we focus on studies implicating microvesicles in the pathogenesis of autoimmune diseases and their complications.
The implementation of school nutrition policies, which govern the provision of food in schools, is recommended as a public health strategy to support the development of healthy dietary behaviours in school-aged children. Despite this, research internationally and in Australia indicates that few schools implement such policies. This study aims to examine whether a theoretically designed, multi-strategy intervention was effective in increasing the implementation of a healthy canteen policy in Australian primary schools.
A parallel group randomised controlled trial was conducted with all government and Catholic primary schools within one region in New South Wales, Australia who had an operational canteen that provided food to primary school aged children (5-12 years) and were not currently receiving an intervention to change their canteen practices. Schools randomised to the intervention arm received a 9-month multicomponent intervention including ongoing support, provision of resources, performance monitoring and feedback, executive support and recognition. The primary outcomes were the proportion of the schools with a canteen menu that: i) did not include 'red' or 'banned' items according to the healthy canteen policy; and ii) had more than 50 % 'green' items. The primary outcome was assessed via menu audit at baseline and follow up by dietitians blinded to group allocation.
Fifty-three eligible schools were randomised to either the intervention or control group (28 intervention; 25 control). Analyses with 51 schools who returned school menus found that intervention schools were significantly more likely relative to control schools to have a menu without 'red' or 'banned' items (RR = 5.78 (1.45-23.05); p = 0.002) and have at least 50 % of menu items classified as green (RR = 2.03 (1.01-4.08); p = 0.03).
This study found that a multi-component intervention was effective in improving primary schools' compliance with a healthy canteen policy. Given the lack of evidence regarding how best to support schools with implementing evidence-based policies to improve child diet, this trial for the first time provides high quality evidence to practitioners and policy makers seeking to improve nutrition policy implementation in schools.
This trial was prospectively registered with the Australian New Zealand Clinical Trials Registry ( ACTRN12614001148662 ) 30th October 2014.
Medical tourism has attracted considerable interest within the Latin American and Caribbean (LAC) region. Governments in the region tout the economic potential of treating foreign patients while several new private hospitals primarily target international patients. This analysis explores the perspectives of a range of medical tourism sector stakeholders in two LAC countries, Guatemala and Barbados, which are beginning to develop their medical tourism sectors. These perspectives provide insights into how beliefs about international patients are shaping the expanding regional interest in medical tourism.
Structured around the comparative case study methodology, semi-structured interviews were conducted with 50 medical tourism stakeholders in each of Guatemala and Barbados (n = 100). To capture a comprehensive range of perspectives, stakeholders were recruited to represent civil society (n = 5/country), health human resources (n = 15/country), public health care and tourism sectors (n = 15/country), and private health care and tourism sectors (n = 15/country). Interviews were transcribed verbatim, coded using a collaborative process of scheme development, and analyzed thematically following an iterative process of data review.
Many Guatemalan stakeholders identified the Guatemalan-American diaspora as a significant source of existing international patients. Similarly, Barbadian participants identified their large recreational tourism sector as creating a ready source of foreign patients with existing ties to the country. While both Barbadian and Guatemalan medical tourism proponents share a common understanding that intra-regional patients are an existing supply of international patients that should be further developed, the dominant perception driving interest in medical tourism is the proximity of the American health care market. In the short term, this supplies a vision of a large number of Americans lacking adequate health insurance willing to travel for care, while in the long term, the Affordable Care Act is seen to be an enormous potential driver of future medical tourism as it is believed that private insurers will seek to control costs by outsourcing care to providers abroad.
Each country has some comparative advantage in medical tourism. Assumptions about a large North American patient base, however, are not supported by reliable evidence. Pursuing this market could incur costs borne by patients in their public health systems.
With technological developments and modernised sedentary lifestyles has come an increase in diseases associated with inactivity such as obesity and other non-communicable diseases. Emerging evidence suggests that time spent sedentary may also interact with mental health. This systematic review examined the associations between sedentary behaviour and mental health problems among adolescents.
This systematic review followed Preferred Reporting Items for Systematic Reviews and Meta-Analyses, and applied a quality assessment tool for quantitative studies to identity best available evidence. Following stringent search strategy of the databases; Cumulative Index to Nursing and Allied Health Literature, Global Health, Health Source: Nursing and Academic Edition, MEDLINE, PsychARTICLES and PsycINFO, we identified 32 articles eligible for review.
All studies reported leisure screen time among adolescents, and two thirds of identified studies examined depressive symptomatology. Other mental health measures were; anxiety symptoms, self-esteem, suicide ideation, loneliness, stress, and psychological distress. Strong consistent evidence was found for the relationship between both depressive symptomatology and psychological distress, and time spent using screens for leisure. Moderate evidence supported the relationship between low self-esteem and screen use. Poorer mental health status was found among adolescents using screen time more than 2-3 h per day, and gender differences exist. Essential information was missing for quality of evidence including heterogeneity in mental health and screen time-based measures, and self-report data collection methods.
The findings are of particular significance given the global public health concern of lifestyle-attributed diseases and the possibility for novel approaches to mental health. Future research should examine the psychological impact of reducing time spent using screens for leisure among adolescents, whilst accounting for possible confounding factors such as physical activity and dietary behaviours. It is critical that the reciprocal relationship between lifestyle behaviours and mental health is represented in both the psychiatric and public health forum.
Several species of β-amyloid peptides (Aβ) exist as a result of differential cleavage from amyloid precursor protein (APP) to yield various C-terminal Aβ peptides. Several N-terminal modified Aβ peptides have also been identified in Alzheimer's disease (AD) brains, the most common of which is pyroglutamate-modified Aβ (AβpE3-42). AβpE3-42 peptide has an increased propensity to aggregate, appears to accumulate in the brain before the appearance of clinical symptoms of AD, and precedes Aβ1-42 deposition. Moreover, in vitro studies have shown that AβpE3-42 can act as a seed for full length Aβ1-42. In this study, we characterized the Drosophila model of AβpE3-42 toxicity by expressing the peptide in specific sets of neurons using the GAL4-UAS system, and measuring different phenotypic outcomes. We found that AβpE3-42 peptide had an increased propensity to aggregate. Expression of AβpE3-42 in the neurons of adult flies led to behavioural dysfunction and shortened lifespan. Expression of AβpE3-42 constitutively in the eyes led to disorganised ommatidia, and activation of the c-Jun N-terminal kinase (JNK) signaling pathway. The eye disruption was almost completely rescued by co-expressing a candidate Aβ degrading enzyme, neprilysin2. Furthermore, we found that neprilysin2 was capable of degrading AβpE3-42. Also, we tested the seeding hypothesis for AβpE3-42 in vivo, and measured its effect on Aβ1-42 levels. We found that Aβ1-42 levels were significantly increased when Aβ1-42 and AβpE3-42 peptides were co-expressed. Furthermore, we found that AβpE3-42 enhanced Aβ1-42 toxicity in vivo. Our findings implicate AβpE3-42 as an important source of toxicity in AD, and suggest that its specific degradation could
 be therapeutic.
Evidence regarding the association of the built environment with physical activity is influencing policy recommendations that advocate changing the built environment to increase population-level physical activity. However, to date there has been no rigorous appraisal of the quality of the evidence on the effects of changing the built environment. The aim of this review was to conduct a thorough quantitative appraisal of the risk of bias present in those natural experiments with the strongest experimental designs for assessing the causal effects of the built environment on physical activity.
Eligible studies had to evaluate the effects of changing the built environment on physical activity, include at least one measurement before and one measurement of physical activity after changes in the environment, and have at least one intervention site and non-intervention comparison site. Given the large number of systematic reviews in this area, studies were identified from three exemplar systematic reviews; these were published in the past five years and were selected to provide a range of different built environment interventions. The risk of bias in these studies was analysed using the Cochrane Risk of Bias Assessment Tool: for Non-Randomized Studies of Interventions (ACROBAT-NRSI).
Twelve eligible natural experiments were identified. Risk of bias assessments were conducted for each physical activity outcome from all studies, resulting in a total of fifteen outcomes being analysed. Intervention sites included parks, urban greenways/trails, bicycle lanes, paths, vacant lots, and a senior citizen's centre. All outcomes had an overall critical (n = 12) or serious (n = 3) risk of bias. Domains with the highest risk of bias were confounding (due to inadequate control sites and poor control of confounding variables), measurement of outcomes, and selection of the reported result.
The present review focused on the strongest natural experiments conducted to date. Given this, the failure of existing studies to adequately control for potential sources of bias highlights the need for more rigorous research to underpin policy recommendations for changing the built environment to increase physical activity. Suggestions are proposed for how future natural experiments in this area can be improved.
Horizontal transfer (HT) of genetic materials is increasingly being found in both animals and plants and mainly concerns transposable elements (TEs). Many crustaceans have big genome sizes and are thus likely to harbor high TE contents. Their habitat might offer them ample opportunities to exchange genetic materials with organisms that are ecologically close but taxonomically distant to them.
In this study, we analyzed the transcriptome of Pacific white shrimp (Litopenaeus vannamei), an important economic crustacean, to explore traces of HT events. From a collection of newly assembled transcripts, we identified 395 high reliable TE transcripts, most of which were retrotransposon transcripts. One hundred fifty-seven of those transcripts showed highest similarity to sequences from non-arthropod organisms, including ray-finned fishes, mollusks and putative parasites. In total, 16 already known L. vannamei TE families are likely to be involved in horizontal transfer events. Phylogenetic analyses of 10 L. vannamei TE families and their homologues (protein sequences) revealed that L. vannamei TE families were generally more close to sequences from aquatic species. Furthermore, TEs from other aquatic species also tend to group together, although they are often distantly related in taxonomy. Sequences from parasites and microorganisms were also widely present, indicating their possible important roles in HT events. Expression profile analyses of transcripts in two NCBI BioProjects revealed that transcripts involved in HT events are likely to play important roles in antiviral immunity. More specifically, those transcripts might act as inhibitors of antiviral immunity.
Close ecological relationship, especially predation, might greatly facilitate HT events among aquatic species. This could be achieved through exchange of parasites and microorganisms, or through direct DNA flow. The occurrence of HT events may be largely incidental, but the effects could be beneficial for recipients.
The combination of photothermal therapy (PTT) with gene therapy (GT) to improve PTT efficiency and thus eliminate cancer cells under mild hyperthermia is highly needed. Herein, multifunctional WS2 @poly(ethylene imine) (WS2 @PEI) nanoplatform has been designed and constructed for gene-photothermal synergistic therapy of tumors at mild condition. After a surface modification of WS2 with a positively charged PEI, the as-prepared WS2 @PEI nanoplatform can not only act as an efficient survivin-siRNA carrier for GT but also exhibit remarkable near-infrared (NIR) photothermal effects for PTT. On the one hand, the photothermal effects induced by WS2 @PEI upon NIR irradiation can enhance the cellular uptake owing to the increase of the cell membrane permeability, which leads to the remarkable enhancement of silencing efficiency of survivin. On the other hand, the silencing of survivin can increase the apoptosis as well as reduce the heat resistance of cancer cells by downregulating the heat shock protein 70 expressions, which greatly enhance the sensitivity of cancer cells to PTT. As a result, compared to PTT or GT treatment alone, WS2 @PEI mediated synergistic GT/PTT therapy remarkably enhances in vitro cancer cell damage and in vivo tumor elimination.
Mass spectrometry (MS) based quantitative proteomics and phosphoproteomics applied to monitor the alteration of nuclear proteins during the early stages (4 hours) of preadipocyte differentiation. A total of 4072 proteins including 2434 phosphorylated proteins identified, a majority of which were assigned as regulators of gene expression. Among 288 identified transcriptional regulators, 49 were regulated within four hours of adipogenic stimulation including several known and many novel potential adipogenic regulators. A kinase-substrate database for 3T3-L1 preadipocytes established. New insights into phosphorylation-dependent signaling networks that impact on nuclear proteins and controls adipocyte differentiation and cell fate. Adipocytes (fat cells) are important endocrine and metabolic cells critical for systemic insulin sensitivity. Both adipose excess and insufficiency are associated with adverse metabolic function. Adipogenesis is the process whereby preadipocyte precursor cells differentiate into lipid laden mature adipocytes. This process is driven by a network of transcriptional regulators (TRs). We hypothesized that protein post-translational modifications (PTMs), in particular phosphorylation, play a major role in activating and propagating signals within TR networks upon induction of adipogenesis by extracellular stimulus. We applied mass spectrometry (MS) based quantitative proteomics and phosphoproteomics to monitor the alteration of nuclear proteins during the early stages (4 hours) of preadipocyte differentiation. We identified a total of 4072 proteins including 2434 phosphorylated proteins, a majority of which were assigned as regulators of gene expression. Our results demonstrate that adipogenic stimuli increase the nuclear abundance and/or the phosphorylation levels of proteins involved in gene expression, cell organization, and oxidation-reduction pathways. Furthermore, proteins acting as negative modulators involved in negative regulation of gene expression, insulin stimulated glucose uptake, and cytoskeletal organization showed a decrease in their nuclear abundance and/or phosphorylation levels during the first 4 hours of adipogenesis. Among 288 identified transcriptional regulators, 49 were regulated within four hours of adipogenic stimulation including several known and many novel potential adipogenic regulators. We created a kinase-substrate database for 3T3-L1 preadipocytes by investigating the relationship between protein kinases and protein phosphorylation sites identified in our dataset. A majority of the putative protein kinases belong to the cyclin-dependent kinase (CDK) family and the mitogen activated protein kinase (MAPK) family including P38 and c-Jun N-terminal kinases (JNKs), suggesting that these kinases act as orchestrators of early adipogenesis. This article is protected by copyright. All rights reserved.
A simple and green method is developed for the preparation of nanostructured TiO2 supported on nitrogen-doped carbon foams (NCFs) as a free-standing and flexible electrode for lithium-ion batteries (LIBs), in which the TiO2 with 2.5-4 times higher loading than the conventional TiO2 -based flexible electrodes acts as the active material. In addition, the NCFs act as a flexible substrate and efficient conductive networks. The nanocrystalline TiO2 with a uniform size of ≈10 nm form a mesoporous layer covering the wall of the carbon foam. When used directly as a flexible electrode in a LIB, a capacity of 188 mA h g(-1) is achieved at a current density of 200 mA g(-1) for a potential window of 1.0-3.0 V, and a specific capacity of 149 mA h g(-1) after 100 cycles at a current density of 1000 mA g(-1) is maintained. The highly conductive NCF and flexible network, the mesoporous structure and nanocrystalline size of the TiO2 phase, the firm adhesion of TiO2 over the wall of the NCFs, the small volume change in the TiO2 during the charge/discharge processes, and the high cut-off potential contribute to the excellent capacity, rate capability, and cycling stability of the TiO2 /NCFs flexible electrode.
Early childhood high-frequency use (HFU) of the emergency department (ED) has been endorsed as a marker for increased risk of child maltreatment. In a prior analysis of pediatric ED (PED)
 visits by 16,664 children, 0-36 months old, we defined early childhood HFU (the 90th percentile) as five or more visits. The purpose of this study was to follow HFU patients to determine if they had a higher likelihood of reported maltreatment.
This is a single-center, cross-sectional, observational study of the association between PED use in early life and subsequent intervention by child protective services (CPS). CPS data were obtained from a Department of Social Services database for subjects meeting criteria for PED HFU as well as sex, race, and ethnicity-matched controls. Multivariable analyses were performed to assess if HFU was independently associated with child maltreatment.
While CPS involvement was more highly represented in the group with PED HFU, so were many confounding variables such as African American race, history of hospital admissions, and social work consultations in the PED for any reason. HFU, by itself, is not a risk factor for a major intervention by CPS.
In efforts to identify children at risk for maltreatment, objective assessments such as PED utilization are potential markers to utilize to aid in recognition. Unfortunately, there are many risk factors for increased PED utilization that act as confounders for this marker. Future work is necessary to identify children at risk for maltreatment in the ED.
It might be possible to treat genetic skin diseases by correcting defective RNA. In this issue of Experimental Dermatology, Bornert et al review the latest developments in this area. Progress is rapid and impressive. Clinical use of RNA correction looks set to soon become reality. The future looks bright indeed. But, as always, we have to think before we act. In my comment, I provide a much-needed reality check. This article is protected by copyright. All rights reserved.
RASSF enzymes act as key apoptosis activators and tumor suppressors, being downregulated in many human cancers, although their exact regulatory roles remain unknown. A key downstream event in the RASSF pathway is the regulation of MST kinases, which are main effectors of RASSF-induced apoptosis. The regulation of MST1/2 includes both homo- and heterodimerization, mediated by helical SARAH domains, though the underlying molecular interaction mechanism is unclear. Here, we study the interactions between RASSF1A, RASSF5, and MST2 SARAH domains by using both atomistic molecular simulation techniques and experiments. We construct and study models of MST2 homodimers and MST2-RASSF SARAH heterodimers, and we identify the factors that control their high molecular stability. In addition, we also analyze both computationally and experimentally the interactions of MST2 SARAH domains with a series of synthetic peptides particularly designed to bind to it, and hope that our approach can be used to address some of the challenging problems in designing new anti-cancer drugs.
Colorectal cancer (CRC) is the second most common cause of cancer-related death, encouraging the search for novel therapeutic targets affecting tumor cell proliferation and migration. These cellular processes are under tight control of two opposing groups of enzymes; kinases and phosphatases. Aberrant activity of kinases is observed in many forms of cancer and as phosphatases counteract such "oncogenic" kinases, it is generally assumed that phosphatases function as tumor suppressors. However, emerging evidence suggests that the lipid phosphatase SH2-domain-containing 5 inositol phosphatase (SHIP2), encoded by the INPPL1 gene, may act as an oncogene. Just like the well-known tumor suppressor gene Phosphatase and Tensin Homolog (PTEN) it hydrolyses phosphatidylinositol (3,4,5) triphosphate (PI(3,4,5)P3). However, unlike PTEN, the reaction product is PI(3,4)P2, which is required for full activation of the downstream protein kinase B (PKB/Akt), suggesting that SHIP2, in contrast to PTEN, could have a tumor initiating role through PKB activation. In this work, we investigated the role of SHIP2 in colorectal cancer. We found that SHIP2 and INPPL1 expression is increased in colorectal cancer tissue in comparison to adjacent normal tissue, and this is correlated with decreased patient survival. Moreover, SHIP2 is more active in colorectal cancer tissue, suggesting that SHIP2 can induce oncogenesis in colonic epithelial cells. Furthermore, in vitro experiments performed on colorectal cancer cell lines shows an oncogenic role for SHIP2, by enhancing chemoresistance, cell migration, and cell invasion. Together, these data indicate that SHIP2 expression contributes to the malignant potential of colorectal cancer, providing a possible target in the fight against this devastating disease.
Tertiapin (TPN), a short peptide isolated from the venom of the honey bee, is a potent and selective blocker of the inward rectifier K(+) (Kir) channel Kir3.2. Here we examine in atomic detail the binding mode of TPN to Kir3.2 using molecular dynamics, and deduce the key residue in Kir3.2 responsible for TPN selectivity. The binding of TPN to Kir3.2 is stable when the side chain of either Lys16 (TPN(K16)-Kir3.2) or Lys17 (TPN(K17)-Kir3.2) of the toxin protrudes into the channel pore. However, the binding affinity calculated from only TPN(K17)-Kir3.2 and not TPN(K16)-Kir3.2 is consistent with experiment, suggesting that Lys17 is the most plausible pore-blocking residue. The alanine mutation of Kir3.2-Glu127, which is not present in TPN-resistant channels, reduces the inhibitory ability of TPN by over 50 fold in TPN(K17)-Kir3.2, indicating that Kir3.2-Glu127 is important for the selectivity of TPN.
Approximately half of new invasive breast cancer cases diagnosed each year in the United States occur among women aged 65 years and older. The increasing life expectancy coupled with the attendant rise in breast cancer incidence and elimination of out-of-pocket expenses for screening mammography as a result of the Affordable Care Act could lead to higher utilization rates of screening mammography. Although research indicates that life expectancy should be a strong consideration when making screening decisions among older women, the extent to which screening mammography utilization is tailored to comorbidity and life expectancy is not well established.
To identify relevant studies, a systematic search of the literature will be conducted using PubMed and EMBASE between January 1, 1991, and March 1, 2016. Additional studies will be found through citation review or by contacting experts in the field. The inclusion criteria will be any study design comprised of women aged 65 and older, assessing women's comorbidity, functional impairments, and/or health status, and reporting outcome measures that addressed mammography utilization within the last 1-5 years. For each study, two authors will independently abstract data regarding study eligibility and outcomes to determine relevance. Quantitative results will be extracted from text and tables, choosing preferably those adjusted for important confounders.
The review will provide evidence on the impact of comorbidity, functional limitations, and health status on screening mammography utilization in older women and inform decision aids in this area.
PROSPERO CRD42016032661.
Isolated generalized dystonia is a central motor network disorder characterized by twisted movements or postures. The most frequent genetic cause is a GAG deletion in the Tor1a (DYT1) gene encoding torsinA with a reduced penetrance of 30-40 % suggesting additional genetic or environmental modifiers. Development of dystonia-like movements after a standardized peripheral nerve crush lesion in wild type (wt) and Tor1a+/- mice, that express 50 % torsinA only, was assessed by scoring of hindlimb movements during tail suspension, by rotarod testing and by computer-assisted gait analysis. Western blot analysis was performed for dopamine transporter (DAT), D1 and D2 receptors from striatal and quantitative RT-PCR analysis for DAT from midbrain dissections. Autoradiography was used to assess the functional DAT binding in striatum. Striatal dopamine and its metabolites were analyzed by high performance liquid chromatography. After nerve crush injury, we found abnormal posturing in the lesioned hindlimb of both mutant and wt mice indicating the profound influence of the nerve lesion (15x vs. 12x relative to control) resembling human peripheral pseudodystonia. In mutant mice the phenotypic abnormalities were increased by about 40 % (p < 0.05). This was accompanied by complex alterations of striatal dopamine homeostasis. Pharmacological blockade of dopamine synthesis reduced severity of dystonia-like movements, whereas treatment with L-Dopa aggravated these but only in mutant mice suggesting a DYT1 related central component relevant to the development of abnormal involuntary movements. Our findings suggest that upon peripheral nerve injury reduced torsinA concentration and environmental stressors may act in concert in causing the central motor network dysfunction of DYT1 dystonia.
Networks of clinical experts are increasingly being implemented as a strategy to improve health care processes and outcomes and achieve change in the health system. Few are ever formally evaluated and, when this is done, not all networks are equally successful in their efforts. There is a need to formatively assess the strategic and operational management and leadership of networks to identify where functioning could be improved to maximise impact. This paper outlines the development and psychometric evaluation of an Internet survey to measure features of clinical networks and provides descriptive results from a sample of members of 19 diverse clinical networks responsible for evidence-based quality improvement across a large geographical region.
Instrument development was based on: a review of published and grey literature; a
 qualitative study of clinical network members; a program logic framework; and consultation with stakeholders. The resulting domain structure was validated for a sample of 592 clinical network members using confirmatory factor analysis. Scale reliability was assessed using Cronbach's alpha. A summary score was calculated for each domain and aggregate level means and ranges are reported.
The instrument was shown to have good construct validity across seven domains as demonstrated by a high level of internal consistency, and all Cronbach's α coefficients were equal to or above 0.75. In the survey sample of network members there was strong reported commitment and belief in network-led quality improvement initiatives, which were perceived to have improved quality of care (72.8 %) and patient outcomes (63.2 %). Network managers were perceived to be effective leaders and clinical co-chairs were perceived as champions for change. Perceived external support had the lowest summary score across the seven domains.
This survey, which has good construct validity and internal reliability, provides a valid instrument to use in future research related to clinical networks. The survey will be of use to health service managers to identify strengths and areas where networks can be improved to increase effectiveness and impact on quality of care and patient outcomes. Equally, the survey could be adapted for use in the assessment of other types of networks.
Pharmaceutical nanotechnology has generated breakthrough developments in improving health care and human life from its emergence. The biomaterials employed mainly aim at improving drug delivery systems, imaging and diagnostic technologies while the nanoscale materials are in widespread use in other industries such as electronics and optics. Such advancement may revolutionize the drug development and therapy with new and more efficient treatments. Although, nanotechnology assists humankind in improving its well being, it has certain limitations that entail thorough investigation by the regulatory and scientific authorities. To address concerns regarding the safety and toxicity profile of the nanopharmaceuticals, we have reviewed the challenges and solutions of nanopharmaceuticals use in human health and the related health risks. In this regard, regulatory and scientific bodies such as countries' Food and Drug Administration (FDA), Organization for Economic Co-operation and Development (OECD), European Medicine Agency (EMA), Environmental Protection Agency (EPA), National Institute for Occupational Safety and Health (NIOSH), and World Health Organization (WHO) can participate in developing and reinforcing safety measures and regulatory frameworks to insure the public health. The regulatory authorities may enforce the nanopharmaceutical industries to conduct comprehensive toxicity tests and monitor the adverse drug reaction reports in close collaboration with the scientific community to act accordingly and inform the public as the implementation of the strategy. Nanopharmaceuticals have tremendous potential for human use as therapeutic or diagnostic agents. But their toxicity profile should be well addressed and the respective regulatory framework developed and reinforced by the authorities.
Adolescence is a period of accelerated development and increases in body composition. Physical activity (PA) practice has been associated with the development of major components of body composition (bone, muscle and fat). However, the longitudinal effects of PA of different intensities during adolescence are still not well understood. Thus, the main goal this study has investigate the association between practice of moderate- and vigorous-intensity physical activity throughout adolescence and body composition, specifically lean mass (LM) and fat mass (FM), at age 18.
In this cohort study, physical activity was measured at 11, 15 and 18 years, using questionnaires. Thresholds of 300, 150 and 75 min per week, were used for MVPA, moderate- and vigorous-intensity physical activity, respectively. Consistent physical activity was defined as reaching the thresholds at the three follow-ups. FM and LM at age 18 were assessed by DXA and expressed as fat mass (FMI) and lean mass (LMI) indexes. To verify the association between the trajectories of MVPA, moderate- and vigorous-intensity physical activity in adolescence and FM and LM at 18, multivariate analyses were performed through multiple linear regressions adjusted for co-variables.
A total of 3,176 adolescents were evaluated. The consistent practice of moderate- and vigorous-intensity physical activity according to thresholds during adolescence were directly related to the LMI in boys (moderate-intensity - β = 0.40 and CI95 % 0.13; 0.68 and vigorous-intensity - β = 0.95 and CI95 % 0.69; 1.21) and girls (Moderate-intensity - β = 0.23 and CI95 % 0.02; 0.45 and vigorous-intensity - β = 0.80 and CI95 % 0.29; 1.32). Practice of vigorous-intensity physical activity alone showed to be inversely associated with the FMI in boys (β = -0.53 and CI95 % -0.96;-0.10).
Consistent physical activity practice during adolescence was associated with greater lean mass in both sexes. In boys, vigorous-intensity physical activity was associated with less fat mass.
A large group of small Rab GTPases which mediate secretory and endosomal membrane transport, as well as autophagosome biogenesis, are essential components of vesicle trafficking machinery. Specific Rab protein together with the cognate effectors coordinates the dynamics of trafficking pathway and determines the cargo proteins destination. Functional impairments of Rab proteins by mutations or post-translational modifications disrupting the regulatory network of vesicle trafficking have been implicated in tumorigenesis. Therefore, the vesicle transport regulators play essential roles in the mediation of cancer cell biology, including uncontrolled cell growth, invasion and metastasis. The context-dependent role of the same Rab to act as either an oncoprotein or tumor suppressor in different cancers is found. Such discrepancies may be due in part to the interaction of specific Rab protein with different effectors or cargos in various tumors. Here, we review recent advances in the roles of Rab GTPases in communicating with other effectors in tumor progression. In this review, we also emphasize dysregulation of Rab-mediated membrane delivery shifting normal cell behaviors toward malignancy. Thus, recovery of the dysregulated vesicle trafficking systems in cancer cells may provide future directions for potential strategy to restrain tumor progression.
Glioma is one of the most common primary malignancies in the brain or spine. The transcription factor (TF) CCAAT/enhancer binding protein beta (CEBPB) is important for maintaining the tumor initiating capacity and invasion ability. To investigate the regulation mechanism of CEBPB in glioma, microarray data GSE47352 was analyzed.
GSE47352 was downloaded from Gene Expression Omnibus, including three samples of SNB19 human glioma cells transduced with non-target control small hairpin RNA (shRNA) lentiviral vectors for 72 h (normal glioma cells) and three samples of SNB19 human glioma cells transduced with CEBPB shRNA lentiviral vectors for 72 h (CEBPB-silenced glioma cells). The differentially expressed genes (DEGs) were screened using limma package and then annotated. Afterwards, the Database for Annotation, Visualization, and Integrated Discovery (DAVID) software was applied to perform enrichment analysis for the DEGs. Furthermore, the protein-protein interaction (PPI) network and transcriptional regulatory network were constructed using Cytoscape software.
Total 529 DEGs were identified in the normal glioma cells compared with the CEBPB-silenced glioma cells, including 336 up-regulated and 193 down-regulated genes. The significantly enriched pathways included chemokine signaling pathway (which involved CCL2), focal adhesion (which involved THBS1 and THBS2), TGF-beta signaling pathway (which involved THBS1, THBS2, SMAD5, and SMAD6) and chronic myeloid leukemia (which involved TGFBR2 and CCND1). In the PPI network, CCND1 (degree = 29) and CCL2 (degree = 12) were hub nodes. Additionally, CEBPB and TCF12 might function in glioma through targeting others (CEBPB → TCF12, CEBPB → TGFBR2, and TCF12 → TGFBR2).
CEBPB might act in glioma by regulating CCL2, CCND1, THBS1, THBS2, SMAD5, SMAD6, TGFBR2, and TCF12.
Several countries have launched public reporting systems based on quality indicators (QIs) to increase transparency and improve quality in health care organizations (HCOs). However, a prerequisite to quality improvement is successful local QI implementation. The aim of this study was to explore the pathway through which a mandatory QI of the French national public reporting system, namely the quality of the anesthesia file (QAF), was put into practice.
Seven ethnographic case studies in French HCOs combining in situ observations and 37 semi-structured interviews.
A significant proportion of potential QAF users, such as anesthetists or other health professionals were often unaware of quality data. They were, however, involved in improvement actions to meet the QAF criteria. In fact, three intertwined factors influenced QAF appropriation by anesthesia teams and impacted practice. The first factor was the action of clinical managers (chief anesthetists and head of department) who helped translate public policy into local practice largely by providing legitimacy by highlighting the scientific evidence underlying QAF, achieving consensus among team members, and pointing out the value of QAF as a means of work recognition. The two other factors related to the socio-material context, namely the coherence of information systems and the quality of interpersonal ties within the department.
Public
 policy tends to focus on the metrological validity of QIs and on ranking methods and overlooks QI implementation. However, effective QI implementation depends on local managerial activity that is often invisible, in interaction with socio-material factors. When developing national quality improvement programs, health authorities might do well to specifically target these clinical managers who act as invaluable mediators. Their key role should be acknowledged and they ought to be provided with adequate resources.
Wound healing is often impaired in diabetic animals and humans. Matrix metalloproteases act as pro-inflammatory agents in physiological wound healing pathways by stimulating cytokines including the interleukins, IL6, IL1A and IL1B, and the tumor necrosis factor and transforming growth factor beta1. Botanicals are traditionally used to assist healing of different types of wounds, because they produce fewer side effects. Our specific aim here was to develop a plant-based recipe supporting effective wound healing in diabetic animals.
Plant materials from Adiantum capillus-veneris, Commiphora molmol, Aloe Vera, and henna were collected for this study, and oven-dried at 60 °C. The dried leaves and resins were then crumbled into a powder and mixed in equal parts with Vaseline as a preservative. This mixture was used as an ointment on wounds induced in 60 diabetic and non-diabetic rats that were divided into 6 subgroups receiving agent or control treatments. Necrotic tissue surrounding the wound was periodically removed during wound healing. RNA was extracted from the healing region of the wound at days 7, 14 and 21 for cDNA synthesis to monitor changes in Tgfb1, Mmp3, Mmp9, Il6 and Tnf α expression using real-time PCR.
The expression of the Mmp3, the Tnf α, and the Tgfb1 genes from wound tissue were significantly different (p < 0.05) between diabetic and non-diabetic (control) rats treated with the herbal mixture after 14 and 21 days. There was no significant difference (p > 0.05) of the Mmp9 gene expression in diabetic and non-diabetic rats treated only with Vaseline after 7, 14, and 21 days. But, the expression of the Mmp9 gene decreased significantly (p < 0.05) in diabetic rats after 14 days in comparison to non-diabetic rats, when the herbal mixture was added to Vaseline.
Our study presents an herbal treatment that alters the gene expression signature at wounds induced in the rat model for type I diabetes in a manner consistent with accelerated healing, and demonstrates that this herbal treatment might be effective to treat wounds in diabetic patients.
We sought to assess physician interest in molecular prognosic testing for patients with early stage colon cancer, and identify factors associated with the likelihood of test adoption.
We identified physicians who care for patients with early-stage (pN0) colon cancer patients, mailed them a survey, and analyzed survey responses to assess clinician receptivity to the use of a new molecular test (GUCY2C) that identifies patients at risk for recurrence, and clinician readiness to act on abnormal test results.
Of 104 eligible potential respondents, 41 completed and returned the survey. Among responding physicians, 56 % were receptive to using the new prognostic test. Multivariable analyses showed that physicians in academic medical centers were significantly more receptive to molecular test use than those in non-academic settings. Forty-one percent of respondents were ready to act on abnormal molecular test results. Physicians who viewed current staging methods as inaccurate and were confident in their capacity to incorporate molecular testing in practice were more likely to say they would act on abnormal test results.
Physician receptivity to molecular diagnostic testing for early-stage colon cancer patients is likely to be influenced by practice setting and perceptions related to delivering quality care to patients.
ClinicalTrials.gov Identifier: NCT01972737.
T1D and AITD are autoimmune disorders commonly occurring in the same family and even in the same individual. The genetic contribution to these disorders is complex making uncovering of susceptibility genes very challenging. The general aim of this study was to identify loci and genes contributing to T1D/AITD susceptibility. Our strategy was to perform linkage and association studies in the relatively genetically homogenous population of northern Sweden. We performed a GWLS to find genomic regions linked to T1D/AITD in families from northern Sweden and we performed an association study in the families to test for association between T1D/AITD and variants in previously published candidate genes as well as a novel candidate gene, CD247.
DNA prepared from 459 individuals was used to perform a linkage and an association study. The ABI PRISM Linkage Mapping Set v2.5MD10 was employed for an initial 10-cM GWLS, and additional markers were added for fine mapping. Merlin was used for linkage calculations. For the association analysis, a GoldenGate Custom Panel from Illumina containing 79 SNPs of interest was used and FBAT was used for association calculations.
Our study revealed linkage to two previously identified chromosomal regions, 4q25 and 6p22, as well as to a novel chromosomal region, 1q23. The association study replicated association to PTPN22, HLA-DRB1, INS, IFIH1, CTLA4 and C12orf30. Evidence in favor of association was also found for SNPs in the novel susceptibility gene CD247.
Several risk loci for T1D/AITD identified in published association studies were replicated in a family material, of modest size, from northern Sweden. This provides evidence that these loci confer disease susceptibility in this population and emphasizes that small to intermediate sized family studies in this population can be used in a cost-effective manner for the search of genes involved in complex diseases. The linkage study revealed a chromosomal region in which a novel T1D/AITD susceptibility gene, CD247, is located. The association study showed association between T1D/AITD and several variants in this gene. These results suggests that common susceptibility genes act in concert with variants of CD247 to generate genetic risk for T1D/AITD in this population.
The advent of genotyping by Next Generation Sequencing has enabled rapid discovery of thousands of single nucleotide polymorphism (SNP) markers and high throughput genotyping of large populations at an affordable cost. Genotyping by sequencing (GBS), a reduced representation library sequencing method, allows highly multiplexed sequencing of genomic subsets. This method has limitations for small organisms with low amounts of genomic DNA, such as the bluetongue virus (BTV) vectors, Culicoides midges.
This study employed the GBS method to isolate SNP markers de novo from whole genome amplified Culicoides brevitarsis genomic DNA. The individuals were collected from regions representing two different Australian patterns of BTV strain distribution: the Northern Territory (NT) and the east coast. We isolated 8145 SNPs using GBS. Phylogenetic analysis conducted using the filtered 3263 SNPs revealed the presence of a distinct C. brevitarsis sub-population in the NT and this was confirmed by analysis of mitochondrial DNA. Two loci showed a very strong signal for selection and were unique to the NT population. Bayesian analysis with STRUCTURE indicated a possible two-population cluster.
The results suggest that genotyping vectors with high density markers in combination with biological and environmental data is useful. However, more extensive sampling over a wider spatial and temporal range is needed. The presence of sub-structure in populations and loci under natural selection indicates the need for further investigation of the role of vectors in shaping the two Australian systems of BTV transmission. The described workflow is transferable to genotyping of small, non-model organisms, including arthropod vectors of pathogens of economic and medical importance.
The raccoon dog (Nyctereutes procyonoides, Canidae, Carnivora) is highly adaptable to urban environments. Populations of carnivorans inhabiting urban areas sometimes differ ecologically and genetically from those in rural areas. However, there is little information on urban raccoon dogs. This study focused on raccoon dog populations in Tokyo, one of the most highly urbanized cities in the world. We examined the genotypes of 10 microsatellites for 101 fecal samples from raccoon dogs inhabiting the grounds of the Imperial Palace, a green space in central Tokyo. We successfully genotyped 58 samples originating from 31 individuals. We also analyzed muscle tissue samples from raccoon dogs from the grounds of the Imperial Palace, the Akasaka Imperial Grounds (a green space close to the Imperial Palace), and the surrounding urban area, and then investigated the genetic structure and diversity of these populations, and the genetic differentiation among them. The population on the grounds of the Imperial Palace was genetically differentiated from that in the Akasaka Imperial Grounds, suggesting that the roads and buildings act as barriers to gene flow. In addition, the population on the grounds of the Imperial Palace showed greater genetic difference from that in the surrounding area than that in the Akasaka Imperial Grounds. We speculate that the moats around the Imperial Palace restrict individual ranges within the palace grounds and limit migration and gene flow to other areas.
Microtubules switch between growing and shrinking states, a feature known as dynamic instability. The biochemical parameters underlying dynamic instability are modulated by a wide variety of microtubule-associated proteins that enable the strict control of microtubule dynamics in cells. The forces generated by controlled growth and shrinkage of microtubules drive
 a large range of processes, including organelle positioning, mitotic spindle assembly, and chromosome segregation. In the past decade, our understanding of microtubule dynamics and microtubule force generation has progressed significantly. Here, we review the microtubule-intrinsic process of dynamic instability, the effect of external factors on this process, and how the resulting forces act on various biological systems. Recently, reconstitution-based approaches have strongly benefited from extensive biochemical and biophysical characterisation of individual components that are involved in regulating or transmitting microtubule-driven forces. We will focus on the current state of reconstituting increasingly complex biological systems and provide new directions for future developments.
Semaphorins are a large family of proteins characterized by sema domains and play a key role not only in the formation of neural circuits, but in the immune system, angiogenesis, tumor progression, and bone metabolism. To date, 15 semaphorins have been reported to be involved in the formation of the peripheral nervous system (PNS) in higher vertebrates. A number of experiments have revealed their functions in the PNS, where they act mainly as axonal guidance cues (as repellents or attractants). Semaphorins also play an important role in the migration of neurons and formation of sensory-motor connections in the PNS. This review summarizes recent knowledge regarding the functions of higher vertebrate semaphorins in the formation of the PNS.
HLA-E products, class Ib human leukocyte antigens, act in the immunology of human reproduction as modulators of the maternal immune system during pregnancy.
To evaluate HLA-E role in the establishment of a viable pregnancy.
HLA-E was genotyped by sequence-based typing (SBT) and analyzed for specific polymorphisms, comparing couples who underwent assisted reproduction treatment (ART) and fertile control couples.
There was a significant difference in HLA-E allele and genotype distributions between ART couples and control couples. The allele HLA-E*01:03 was observed in 63.2% of ART men and in 35.1% of fertile men (P = 0.0032).
These results suggest that HLA-E allelic variants may play a role in the modulation of immune responses in the context of the inability of natural conception and establishment of a viable pregnancy.
Hitherto, most quantitative trait loci (QTL) of maize growth and biomass yield have been identified for a single time point, usually the final harvest stage. Through this approach cumulative effects are detected, without considering genetic factors causing phase-specific differences in growth rates. To assess the genetics of growth dynamics, we employed automated non-invasive phenotyping to monitor the plant sizes of 252 diverse maize inbred lines at eleven different developmental time points. 50 k SNP array genotype data were used for genome wide association mapping and genomic selection. The heritability of biomass was estimated to be over 71 % and the average prediction accuracy amounted to 0.39. Using the individual time point data, 12 main effect marker-trait associations (MTAs) and 6-pairs of epistatic interactions were detected that displayed different patterns of expression at various developmental time points. A subset of them also showed significant effects on relative growth rates in different intervals. The detected MTAs jointly explained up to 12% of the total phenotypic variation, decreasing with developmental progression. Using nonparametric functional mapping and multivariate mapping approaches four additional marker loci affecting growth dynamics were detected. Our results demonstrate that plant biomass accumulation is a complex trait governed by many small effect loci most of which act at certain restricted developmental phases. This highlights the need for investigation of stage-specific growth affecting genes to elucidate important processes operating at different developmental phases. This article is protected by copyright. All rights reserved.
Inhalants are a loosely organized category of abused compounds defined entirely by their common route of administration. Inhalants include volatile solvents, fuels, volatile anesthetics, gasses, and liquefied refrigerants, among others. They are ubiquitous in modern society as ingredients in a wide variety of household, commercial, and medical products. Persons of all ages abuse inhalants but the highest prevalence of abuse is in younger adolescents. Although inhalants have been shown to act upon a host of neurotransmitter receptors, the stimulus effects of the few inhalants which have been trained or tested in drug discrimination procedures suggest that their discriminative stimulus properties are mediated by a few key neurotransmitter receptor systems. Abused volatile solvent inhalants have stimulus effects that are similar to a select group of GABAA positive modulators comprised of benzodiazepines and barbiturates. In contrast the stimulus effects of nitrous oxide gas appear to be at least partially mediated by uncompetitive antagonism of NMDA receptors. Finally, volatile anesthetic inhalants have stimulus effects in common with both GABAA positive modulators as well as competitive NMDA antagonists. In addition to a review of the pharmacology underlying the stimulus effects of inhalants, the chapter also discusses the scientific value of utilizing drug discrimination as a means of functionally grouping inhalants according to their abuse-related pharmacological properties.
Cancer screening is a core component of family medicine but screening inequalities are well documented in Canada for foreign-born persons. Although people of Muslim faith and culture are the fastest growing immigrant population in Canada, there is little information in the literature about their cancer screening practices. Determining screening gaps could inform practice-based quality improvement initiatives. We conducted a retrospective chart review combining patient-level medical record data with self-reported religious affiliation to examine the relationship between religion and cancer screening in a large multi-site urban family practice. Religious affiliation was classified as Muslim, other affiliation, or atheist/no religious affiliation. 5311 patients were included in the study sample. Muslim patients were significantly less likely to prefer English for spoken communication than the other two groups, less likely to be Canadian-born, more likely to have a female family physician, and were over-represented in the lowest income quintile. Muslim women were most likely to be up-to-date on breast cancer screening (85.2 vs. 77.5 % for those with other religions vs. 69.5 % for those with no religious affiliation). There were no significant differences in cancer screening by physician sex. In this pilot study conducted within a primary care practice, we used self-reported data on religious affiliation to examine possible inequities in cancer screening and observed intriguing variations in screening by self-identified religious affiliation. Future efforts to collect and use similar patient-level data should incorporate non-official languages and intensively outreach to patients with less health system contact. Regardless, the family medicine context may be the ideal setting to collect and act on patient-level sociodemographic data such as religious affiliation.
Federal efforts and local initiatives to increase adoption and use of electronic health records (EHRs) continue, particularly since the enactment of the Health Information Technology for Economic and Clinical Health (HITECH) Act. Roughly one in four hospitals not adopted even a basic EHR system. A review of the barriers may help in understanding the factors deterring certain healthcare organizations from implementation. We wanted to assemble an updated and comprehensive list of adoption barriers of EHR systems in the United States. Authors searched CINAHL, MEDLINE, and Google Scholar, and accepted only articles relevant to our primary objective. Reviewers independently assessed the works highlighted by our search and selected several for review. Through multiple consensus meetings, authors tapered articles to a final selection most germane to the topic (n = 27). Each article was thoroughly examined by multiple authors in order to achieve greater validity. Authors identified 39 barriers to EHR adoption within the literature selected for the review. These barriers appeared 125 times in the literature; the most frequently mentioned barriers were regarding cost, technical concerns, technical support, and resistance to change. Despite federal and local incentives, the initial cost of adopting an EHR is a common existing barrier. The other most commonly mentioned barriers include technical support, technical concerns, and maintenance/ongoing costs. Policy makers should consider incentives that continue to reduce implementation cost, possibly aimed more directly at organizations that are known to have lower adoption rates, such as small hospitals in rural areas.
An increased knowledge on the real impacts of ectomycorrhizal symbiosis in forest species is needed to optimize forest sustainable productivity and thus to improve forest services and their capacity to act as carbon sinks. In this study, we investigated the response of an oak species to ectomycorrhizae formation using a proteomics approach complemented by biochemical analysis of carbohydrate levels. Comparative proteome analysis between mycorrhizal and nonmycorrhizal cork oak plants revealed no differences at the foliar level. However, the protein profile of 34 unique oak proteins was altered in the roots. Consistent with the results of the biochemical analysis, the proteome analysis of the mycorrhizal roots suggests a decreasing utilization of
 sucrose for the metabolic activity of mycorrhizal roots which is consistent with an increased allocation of carbohydrates from the plant to the fungus in order to sustain the symbiosis. In addition, a promotion of protein unfolding mechanisms, attenuation of defense reactions, increased nutrient mobilization from the plant-fungus interface (N and P), as well as cytoskeleton rearrangements and induction of plant cell wall loosening for fungal root accommodation in colonized roots are also suggested by the results. The suggested improvement in root capacity to take up nutrients accompanied by an increase of root biomass without apparent changes in aboveground biomass strongly re-enforces the potential of mycorrhizal inoculation to improve cork oak forest resistance capacity to cope with coming climate change.
Inhalation of asbestos fibres is the predominant cause of malignant mesothelioma. Domestic exposure to asbestos is a major community concern in the Australian Capital Territory (ACT) because of loose-fill asbestos home insulation. Little is known about how trends in mesothelioma rates in the ACT compare with those elsewhere. The objective of this study was to describe trends in mesothelioma rates in the ACT and compare them with those for the rest of Australia.
We used de-identified data from the ACT Cancer Registry (1982- 2014), and the Western Australia (WA) Cancer Registry and the Australian Cancer Database (1982-2011). We calculated crude mesothelioma rates, by 3-year periods, for the ACT and for the rest of Australia (excluding WA). We used Poisson regression to analyse mesothelioma trends from 1994 to 2011 (complete reporting period) using an indirect standardisation approach to adjust for age and sex.
There were 140 mesothelioma cases reported to the ACT Cancer Registry between 1982 and 2014 - 81% male and 19% female. Between 1994 and 2011, age- and sex-adjusted mesothelioma rates in the ACT increased over time, on average by 12% per 3-year period (relative risk [RR] 1.12; 95% confidence interval [CI] 0.99, 1.26). Compared with the rest of Australia (excluding WA), ACT rates were, on average, lower (RR 0.84; 95% CI 0.69, 1.02), but they increased at a higher rate (RR 1.12 per 3-year period; 95% CI 0.99, 1.27). These results are strongly influenced by the higher rate of mesothelioma observed in the ACT in 2009-2011, when ACT rates became similar to those for the rest of Australia (excluding WA).
Although mesothelioma rates may have increased more in the ACT than the rest of Australia (excluding WA) during the past two decades, there is considerable uncertainty in the trends. More information is needed regarding the health risks associated with living in a house with loose-fill asbestos insulation. This is the subject of further studies within the ACT Asbestos Health Study.
Elucidation of dynamic interactions between RNA and proteins is essential for understanding the biological processes regulated by RNA, such as RNA interference (RNAi). In this study, the logical chemical probes, comprising 7-bromo-7-deazaadenosine (Br(7)C(7)A) and 3-bromo-3-deazaadenosine (Br(3)C(3)A), to investigate small interfering RNA (siRNA)-RNAi related protein interactions, were developed. The bromo substituents of Br(7)C(7)A and Br(3)C(3)A are expected to be located in the major and the minor grooves, respectively, and to act as a steric hindrance in each groove when these chemical probes are incorporated into siRNAs. A comprehensive investigation using siRNAs containing these chemical probes revealed that (i) Br(3)C(3)A(s) at the 5'-end of the passenger strand enhanced their RNAi activity, and (ii) the direction of RISC assembly is determined by the interaction between Argonaute2, which is the main component of RISC, and siRNA in the minor groove near the 5'-end of the passenger strand. Utilization of these chemical probes enables the investigation of the dynamic interactions between RNA and proteins.
Matched molecular pair analysis was used to evaluate the ability of a tetrazolone group to act as a bioisostere of a carboxylic acid. Compound 7, a tetrazolone of the anti-hypertensive drug, telmisartan 6, was shown to be a potent AT1 antagonist (Kb = 0.14 nM), with activity comparable to telmisartan itself (Kb = 0.44 nM). Additionally, compound 9, a tetrazolone congener of the marketed anti-cancer agent, bexarotene 8, was shown to be an agonist at the retinoid X receptor alpha (EC50 = 64 nM). Compounds containing a tetrazolone group showed similar microsomal stability and plasma protein binding to marketed acid counterparts, while also reducing the value for clog P. Furthermore, compound 7 displayed an improved rat pharmacokinetic profile cf. telmisartan 6. Taken together, the results demonstrate that a tetrazolone group may serve as a bioisostere for a carboxylic acid.
In a recent work we showed that magnesium (Mg(II)) plays an important role in industrial ethanol production, overcoming the negative effect of the excess of minerals, particularly copper, present in sugarcane juice, with a consequent increase in ethanol yield. This cation has been reported to be involved in several steps of yeast metabolism, acting mainly as a co-factor of several enzymes of fermentation metabolism and protecting yeast cells from stressful conditions. However, despite many physiological investigations, its effect in the molecular mechanisms that control such metabolic activities remains unclear and to date no information concerning its influence on gene expression has been provided. The present work took advantage of the DNA microarray technology to analyse the global gene expression in yeast cells upon fermentation in Mg(II)-supplemented medium. The results of the fermentation parameters confirmed the previous report on the increase in ethanol yield by Mg(II). Moreover, the gene expression data revealed an unexpected set of up-regulated genes currently assigned as being negatively-regulated by glucose, which belong to respiratory and energy metabolism, the stress response and the glyoxalate cycle. On the other hand, genes involved in ribosome biogenesis were down-regulated. Computational analysis provided evidence for a regulatory network commanded by key transcriptional factors that may be responsible for the biological action of Mg(II) in yeast cells. In this scenario, Mg(II) seems to act by reprogramming the yeast metabolism by releasing many genes from glucose catabolite repression with positive consequences for ethanol production and maintenance of cell viability.
Precise positioning of a plasmonic nanoparticle (NP) near a small dielectric surface is not only necessary for understanding gap-dependent interactions between a metal and dielectric but it is also a critical component in building ultrasensitive molecular rulers and force sensing devices. In this study we investigate the gap-dependent scattering of gold and silver NPs by controllably depositing them on an atomic force microscope (AFM) tip and monitoring their scattering within the evanescent field of a tin dioxide nanofiber waveguide. The enhanced distance-dependent scattering profiles due to plasmon-dielectric coupling effects show similar decays for both gold and silver NPs given the strong dependence of the coupling on the decaying power in the near-field. Experiments and simulations also demonstrate that the NPs attached to the AFM tips act as free NPs, eliminating optical interference typically observed from secondary dielectric substrates. With the ability to reproducibly place individual plasmonic NPs on an AFM tip, and optically monitor near-field plasmon-dielectric coupling effects, this approach allows a wide-variety of light-matter interactions studies to be carried out on other low-dimensional nanomaterials.
Smart hydrogels are useful elements in microfluidic systems because they respond to environmental stimuli and are capable of storing reagents. We present here a concept of using hydrogels (poly(N-isopropylacrylamide)) as an interface between continuous and discontinuous microfluidics. Their swelling and shrinking capabilities allow them to act as storage elements for reagents absorbed in the swelling process. When the swollen hydrogel collapses in an oil-filled channel, the incorporated water and molecules are expelled from the hydrogel and form a water reservoir. Water-in-oil droplets can be released from the reservoir generating different sized droplets depending on the flow regime at various oil flow rates (dispensing functionality). Different hydrogel sizes and microfluidic structures are discussed in terms of their storage and droplet formation capabilities. The time behaviour of the hydrogel element is investigated by dynamic swelling experiments and computational fluid dynamics simulations. By precise temperature control, the device acts as an active droplet generator and converts continuous to discontinuous flows.
Young men who have sex with men (YMSM) report higher rates of substance use than their heterosexual peers and minority stress has been posited as a risk factor for substance use. The associations between specific types of minority stress and substance use have been inconsistent throughout the literature and few studies have examined mechanisms underlying these associations. Drawing on minority stress theory and the motivational model of alcohol use, we propose that one mechanism underlying these associations may be people's motivations for using substances, including using substances to cope with negative emotions and to enhance pleasure. The goals of the current study were: (1) to examine the associations among minority stressors, substance use motives, and substance use problems; and (2) to examine substance use motives as mediators of the associations between minority stressors and substance use problems. Baseline self-report data were used from
 a cohort of 370 YMSM enrolled in a larger study of substance use and sexual behavior. Results indicated that using marijuana to cope mediated the association between victimization and marijuana use problems. Using other drugs to cope mediated the associations between victimization and drug use problems and between internalized stigma and drug use problems. Drinking to cope and to enhance pleasure mediated the association between internalized stigma and alcohol use problems. In sum, substance use motives, especially using substances to cope, act as mechanisms through which certain types of minority stress influence substance use problems among YMSM.
RGS14 is a multifunctional scaffolding protein possessing two distinct G protein interaction sites including a regulator of G protein signaling (RGS) domain that acts as a GTPase activating protein (GAP) to deactivate Gαi/o-GTP proteins, and a G protein regulatory (GPR) motif that binds inactive Gαi1/3-GDP proteins independent of Gβγ. GPR interactions with Gαi recruit RGS14 to the plasma membrane to interact with Gαi-linked GPCRs and regulate Gαi signaling. While RGS14 actions on Gα proteins are well characterized, consequent effects on Gβγ signaling remain unknown. Conventional RGS proteins act as dedicated GAPs to deactivate Gα and Gβγ signaling following receptor activation. RGS14 may do the same or, alternatively, may coordinate its actions to deactivate Gα-GTP with the RGS domain and then capture the same Gα-GDP via its GPR motif to prevent heterotrimer reassociation and prolong Gβγ signaling. To test this idea, we compared the regulation of G protein activation and deactivation kinetics by a conventional RGS protein, RGS4, and RGS14 in response to GPCR agonist/antagonist treatment utilizing bioluminescence resonance energy transfer (BRET). Co-expression of either RGS4 or RGS14 inhibited the release of free Gβγ after agonist stimulation and increased the deactivation rate of Gα, consistent with their roles as GTPase activating proteins (GAPs). Overexpression of inactive Gαi1 to recruit RGS14 to the plasma membrane did not alter RGS14's capacity to act as a GAP for a second Gαo protein. These results demonstrate the role of RGS14 as a dedicated GAP and suggest that the G protein regulatory (GPR) motif functions independently of the RGS domain and is silent in regulating GAP activity in a cellular context.
Plant 14-3-3 proteins act as critical components of various cellular signaling processes and play an important role in regulating multiple physiological processes. However, less information is known about the 14-3-3 gene family in banana. In this study, 25 14-3-3 genes were identified from the banana genome. Based on the evolutionary analysis, banana 14-3-3 proteins were clustered into ε and non-ε groups. Conserved motif analysis showed that all identified banana 14-3-3 genes had the typical 14-3-3 motif. The gene structure of banana 14-3-3 genes showed distinct class-specific divergence between the ε group and the non-ε group. Most banana 14-3-3 genes showed strong transcript accumulation changes during fruit development and postharvest ripening in two banana varieties, indicating that they might be involved in regulating fruit development and ripening. Moreover, some 14-3-3 genes also showed great changes after osmotic, cold, and salt treatments in two banana varieties, suggested their potential role in regulating banana response to abiotic stress. Taken together, this systemic analysis reveals the involvement of banana 14-3-3 genes in fruit development, postharvest ripening, and response to abiotic stress and provides useful information for understanding the functions of 14-3-3 genes in banana.
The GENOMES UNCOUPLED 1 (GUN1) gene has been reported to encode a chloroplast-localized pentatricopeptide-repeat protein, which acts to integrate multiple indicators of plastid developmental stage and altered plastid function, as part of chloroplast-to-nucleus retrograde communication. However, the molecular mechanisms underlying signal integration by GUN1 have remained elusive, up until the recent identification of a set of GUN1-interacting proteins, by co-immunoprecipitation and mass-spectrometric analyses, as well as protein-protein interaction assays. Here, we review the molecular functions of the different GUN1 partners and propose a major role for GUN1 as coordinator of chloroplast translation, protein import, and protein degradation. This regulatory role is implemented through proteins that, in most cases, are part of multimeric protein complexes and whose precise functions vary depending on their association states. Within this framework, GUN1 may act as a platform to promote specific functions by bringing the interacting enzymes into close proximity with their substrates, or may inhibit processes by sequestering particular pools of specific interactors. Furthermore, the interactions of GUN1 with enzymes of the tetrapyrrole biosynthesis (TPB) pathway support the involvement of tetrapyrroles as signaling molecules in retrograde communication.
Speech sound perception is one of the most fascinating tasks performed by the human brain. It involves a mapping from continuous acoustic waveforms onto the discrete phonological units computed to store words in the mental lexicon. In this article, we review the magnetoencephalographic studies that have explored the timing and morphology of the N1m component to investigate how vowels and consonants are computed and represented within the auditory cortex. The neurons that are involved in the N1m act to construct a sensory memory of the stimulus due to spatially and temporally distributed activation patterns within the auditory cortex. Indeed, localization of auditory fields maps in animals and humans suggested two levels of sound coding, a tonotopy dimension for spectral properties and a tonochrony dimension for temporal properties of sounds. When the stimulus is a complex speech sound, tonotopy and tonochrony data may give important information to assess whether the speech sound parsing and decoding are generated by pure bottom-up reflection of acoustic differences or whether they are additionally affected by top-down processes related to phonological categories. Hints supporting pure bottom-up processing coexist with hints supporting top-down abstract phoneme representation. Actually, N1m data (amplitude, latency, source generators, and hemispheric distribution) are limited and do not help to disentangle the issue. The nature of these limitations is discussed. Moreover, neurophysiological studies on animals and neuroimaging studies on humans have been taken into consideration. We compare also the N1m findings with the investigation of the magnetic mismatch negativity (MMNm) component and with the analogous electrical components, the N1 and the MMN. We conclude that N1 seems more sensitive to capture lateralization and hierarchical processes than N1m, although the data are very preliminary. Finally, we suggest that MEG data should be integrated with EEG data in the light of the neural oscillations framework and we propose some concerns that should be addressed by future investigations if we want to closely line up language research with issues at the core of the functional brain mechanisms.
The bZIP transcription factor (TF) act as an important regulator for the abscisic acid (ABA) mediated abiotic stresses signaling pathways in plants. Here, we reported the cloning and characterization of GhABF2, encoding for typical cotton bZIP TF. Overexpression of GhABF2 significantly improved drought and salt stress tolerance both in Arabidopsis and cotton. However, silencing of GhABF2 made transgenic cotton sensitive to PEG osmotic and salt stress. Expression of GhABF2 was induced by drought and ABA treatments but repressed by high salinity. Transcriptome analysis indicated that GhABF2 increases drought and salt tolerance by regulating genes related to ABA, drought and salt response. The proline contents, activity of superoxide dismutase (SOD) and catalase (CAT) were also significantly increased in GhABF2-overexpression cottons in comparison to wild type after drought and salt treatment. Further, an increase in fiber yield under drought and saline-alkali wetland exhibited the important role of GhABF2 in enhancing the drought and salt tolerance in transgenic lines. In conclusion, manipulation of GhABF2 by biotechnological tools could be a sustainable strategy to deploy drought and salt tolerance in cotton.
Homing of endothelial progenitor cells (EPC) to the ischemic tissues is a key event in neovascularization and tissue regeneration. In response to ischemic insult, injured tissues secrete several chemo-cytokines, including stromal cell-derived factor-1α (SDF-1α), which triggers mobilization and homing of bone marrow-derived EPC (BMD-EPC). We previously reported that SDF-1α-induced EPC homing is mediated by a panel of adhesion molecules highly or selectively expressed on the activated endothelium in ischemic tissues, including E-selectin. Elevated E-selectin on wound vasculature serve as docking sites for circulating EPC, which express counterpart E-selectin ligands. Here, we show that SDF-1α presented in wound tissue and released into circulation can act both locally and remotely to induce ischemic tissue endothelium and BMD-EPC to express both E-selectin and its ligands. By performing BM transplantation using E-selectin(-/-) and E-selectin(+/+) mice as the donors and recipients respectively, we demonstrate that upregulated dual E-selectin/ligand pairs reciprocally expressed on ischemic tissue endothelium and BMD-EPC act as double-locks to secure targeted EPC- endothelium interactions by which to facilitate EPC homing and promote neovascularization and tissue repair. These findings describe a novel mechanism for BMD-EPC homing and indicate
 that dual E-selectin/ligand pairs may be effective targets/tools for therapeutic neovascularization and targeted cell delivery.
Growth hormone receptor (GHR) played key roles in human and animal growth. Both human laron type dwarfism and sex linked dwarf chicken were caused by the mutation of GHR gene. In this study, we identified an endogenously expressed long non-coding natural antisense transcript, GHR-AS, which overlapped with the GHR mRNA (GHR-S) in a tail to tail manner. Spatial and temporal expression analyses indicated that GHR-AS were highly expressed in chicken liver and displayed ascending with the development of chicken from E10 to 3 w of age. Interfering GHR-AS caused GHR-S decreasing, accompanied with increasing of the inactive gene indicator, H3K9me2, in the GHR-S promoter regions in LMH cells. RNase A experiment exhibited that GHR-AS and GHR-S can form double strand RNAs at the last exon of GHR gene in vivo and in vitro, which hinted they could act on each other via the region. In addition, the levels of GHR-S and GHR-AS can be affected by DNA methylation. Compared the normal chicken with the dwarfs, the negative correlation trends were showed between the GHR-S promoter methylation status and the GHR-AS levels. This is the first report of that GHR gene possessed natural antisense transcript and the results presented here further highlight the fine and complicated regulating mechanism of GHR gene in chicken development.
Oncogene-induced senescence is thought to act as a barrier to tumorigenesis by arresting cells at risk of malignant transformation. Nevertheless, numerous findings suggest that senescent cells may conversely promote tumor progression through the development of the senescence-associated secretome they produce. It is likely that the composition and the physiological consequences mediated by the senescence secretome are dependent on the oncogenes that trigger the senescence program. Breast cancer represents a heterogenous disease that can be divided into breast cancer subtypes due to different subsets of genetic and epigenetic abnormalities. As tumor initiation and progression of these breast cancer subtypes is triggered by diverse oncogenic stimuli, differences in the senescence secretomes within breast tumors might be responsible for tumor initiation, progression, metastasis and therapeutic response. Many studies have addressed the role of senescence as a barrier to tumor progression using murine xenograft models. However, few investigations have been performed to elucidate the degree to which senescent tumor cells are present within untreated human tumors, and if present, whether these senescent tumor cells may play a role in disease progression. In the present study we analysed the appearance of senescent cells within invasive breast cancers. Detection of cellular senescence by the use of SAβ-galactosidase (SAβ-gal) staining within invasive breast carcinoms from 129 untreated patients revealed differences in the amount of SAβ-gal+ tumor cells between breast cancer subtypes. The highest percentages of SAβ-gal+ tumor cells were found in HER2-positive and luminal A breast carcinomas whereas triple negative tumors showed either little or no positivity.
The covalent coupling of cognate amino acid-tRNA pairs by corresponding aminoacyl-tRNA synthetases (aaRS) defines the genetic code and provides aminoacylated tRNAs for ribosomal protein synthesis. Besides the cognate substrate, some non-cognate amino acids may also compete for tRNA aminoacylation. However, their participation in protein synthesis is generally prevented by an aaRS proofreading activity located in the synthetic site and in a separate editing domain. These mechanisms, coupled with the ability of certain aaRSs to discriminate well against non-cognate amino acids in the synthetic reaction alone, define the accuracy of the aminoacylation reaction. aaRS quality control may also act as a gatekeeper for the standard genetic code and prevents infiltration by natural amino acids that are not normally coded for protein biosynthesis. This latter finding has reinforced interest in understanding the principles that govern discrimination against a range of potential non-cognate amino acids. This paper presents an overview of the kinetic assays that have been established for monitoring synthetic and editing reactions with cognate and non-cognate amino acid substrates. Taking into account the peculiarities of non-cognate reactions, the specific controls needed and the dedicated experimental designs are discussed in detail. Kinetic partitioning within the synthetic and editing sites controls the balance between editing and aminoacylation. We describe in detail steady-state and single-turnover approaches for the analysis of synthetic and editing reactions, which ultimately enable mechanisms of amino acid discrimination to be determined.
Extracellular DNA (eDNA) is an essential constituent of the extracellular matrix of biofilms of many microorganisms. In spite of many studies, it has long remained unclear how exactly eDNA exerts its role in biofilm formation. Here, we describe recent advances that have been made in understanding biofilm formation in the human pathogen Neisseria meningitidis. Several cell-surface-exposed proteins have been identified that bind DNA and other negatively charged polymers, such as heparin, by electrostatic interactions. By virtue of these proteins, eDNA can act as an adhesive that binds the bacteria together. We provide examples that indicate that the mechanism of binding eDNA via DNA/heparin-binding proteins is a conserved feature in biofilms of many different microorganisms, including fungi.
The Affordable Care Act has the potential to significantly affect access to care for previously uninsured patients in need of emergency general surgical care. Our objective was to determine the relationship between insurance status and disease complexity at presentation among a national sample of emergency general surgical patients.
Data from the National Emergency Department Sample from 2006-2009 were queried to identify all patients aged 18-64 years old admitted through the emergency department with a primary diagnosis of appendicitis, diverticulitis, inguinal hernia, or bowel obstruction. Primary outcome of complex presentation was defined as also presenting with generalized peritonitis, intra-abdominal abscess, perforated bowel, intestinal gangrene, or other disease-specific measures of complexity. We used multivariable logistic regression to determine the independent association between insurance status and complex presentation. Models accounted for patient- and hospital-level covariates. Counterfactual models were used to estimate the risk of complex presentation attributable to lack of insurance.
A total of 1,373,659 patients were included, with an overall uninsured rate of 12.3%. Uninsured patients had significantly higher, unadjusted rates of complex presentation, and uninsured payer status was independently associated with complex presentation (odds ratio 1.38, 95% confidence interval: 1.34-1.42). Counterfactual models suggest that having insurance would result in a 22.37% (95% confidence interval: 22.35-22.39%) relative decline in risk of complex emergency general surgical presentation among the uninsured population.
Insurance status is independently associated with severity of disease at presentation among emergency general surgical conditions nationally. In light of recently reaffirmed Affordable Care Act insurance expansion provisions, these results anticipate increased timely access to operative care for newly insured patients and a corresponding decline in complex, emergency general surgical presentations.
The safety net that immigrants face today differs significantly from the immediate post-Welfare Reform era in terms of eligibility and economic context. To inform debates on immigrant access to the safety net, this paper examines implications of the 2002 Farm Security and Rural Investment Act, which restored food stamp eligibility to nearly two-thirds of immigrants who lost eligibility under Welfare Reform. Using data from the 1995-2013 Current Population Survey and a difference-in-difference design, I examine how restoration efforts have influenced food stamp participation and food insecurity rates among low-income Mexican immigrant households with children. I then examine trends in food stamp receipt across policy and economic changes since Welfare Reform. Overall, results suggest that immigrant restoration efforts have reversed some but not all of the negative consequences of Welfare Reform and that immigrant households' use of food stamps has increased, particularly in the wake of the Great Recession.
In stated preference studies it is assumed that individuals' answers reflect true preferences and are stable over time. We test these two assumptions of validity and reliability using as an example a choice experiment study on ethical consumption that measures preferences for a Peace Product jointly produced by Israeli and Palestinian producers as well as for organic products. In a web survey conducted in Germany, we investigate the validity assumption by manipulating the question context and presenting one group of respondents with questions on anti-Semitic and anti-Arabic attitudes before the choice tasks, and presenting another group with these questions after the choice tasks. In order to test the assumption of temporal stability, the same experimental set-up was repeated in a second survey based on a new sample ten months after the first. However, prior to the second survey an external event, a major violent dispute between Israelis and the Palestinians occurred. Overall, we find evidence for a context effect but not for temporal instability. In both surveys, the placement of the attitudinal questions
 before the choice tasks has a positive effect on the valuation of products from Israel, Palestinian products and the Peace Product (i.e. a directional context effect). The respondents seem to act according to an anti-discrimination norm. In line with this reasoning, we find an attention shift caused by the attitudinal questions. Organic products are valued much less positively if discriminatory attitudes are surveyed before the choice tasks. Furthermore, despite the violent dispute, stated preferences are very stable over time. This indicates high reliability of stated preference studies and encourages the use of study results by private and public decision makers.
Sleep disorders and neurodegenerative diseases are commonly encountered in primary care. A common, but underdiagnosed sleep disorder, rapid eye movement sleep behavior disorder (RBD), is highly associated with Parkinson disease and related disorders. Rapid eye movement sleep behavior disorder is common. It is estimated to affect 0.5% of the general population and more than 7% of individuals older than 60 years; however, most cases go unrecognized. Rapid eye movement sleep behavior disorder presents as dream enactment, often with patients thrashing, punching, and kicking while they are sleeping. Physicians can quickly assess for the presence of RBD with high sensitivity and specificity by asking patients the question "Have you ever been told that you act out your dreams, for example by punching or flailing your arms in the air or screaming and shouting in your sleep?" Patients with RBD exhibit subtle signs of neurodegenerative disease, such as mild motor slowing, constipation, or changes in sense of smell. These signs and symptoms may predict development of a neurodegenerative disease within 3 years. Ultimately, most patients with RBD develop a neurodegenerative disease, highlighting the importance of serial neurological examinations to assess for the presence of parkinsonism and/or cognitive impairment and prognostic counseling for these patients. Rapid eye movement sleep behavior disorder is treatable with melatonin (3-6 mg before bed) or clonazepam (0.5-1 mg before bed) and may be the most common, reversible cause of sleep-related injury. Thus, it is important to identify patients at risk of RBD in a primary care setting so that bedroom safety can be addressed and treatment may be initiated.
Coronaviruses are animal and human pathogens that can cause lethal zoonotic infections like SARS and MERS. They have polycistronic plus-stranded RNA genomes and belong to the order Nidovirales, a diverse group of viruses for which common ancestry was inferred from the common principles underlying their genome organization and expression, and from the conservation of an array of core replicase domains, including key RNA-synthesizing enzymes. Coronavirus genomes (~26-32 kilobases) are the largest RNA genomes known to date and their expansion was likely enabled by acquiring enzyme functions that counter the commonly high error frequency of viral RNA polymerases. The primary functions that direct coronavirus RNA synthesis and processing reside in nonstructural protein (nsp) 7 to nsp16, which are cleavage products of two large replicase polyproteins translated from the coronavirus genome. Significant progress has now been made regarding their structural and functional characterization, stimulated by technical advances like improved methods for bioinformatics and structural biology, in vitro enzyme characterization, and site-directed mutagenesis of coronavirus genomes. Coronavirus replicase functions include more or less universal activities of plus-stranded RNA viruses, like an RNA polymerase (nsp12) and helicase (nsp13), but also a number of rare or even unique domains involved in mRNA capping (nsp14, nsp16) and fidelity control (nsp14). Several smaller subunits (nsp7-nsp10) act as crucial cofactors of these enzymes and contribute to the emerging "nsp interactome." Understanding the structure, function, and interactions of the RNA-synthesizing machinery of coronaviruses will be key to rationalizing their evolutionary success and the development of improved control strategies.
To investigate relevant aspects of functioning and disability, and environmental factors in people with adolescent idiopathic scoliosis according to patients' self-reports based on the International Classification of Functioning, Disability and Health for Children and Youth (ICF-CY).
Multicentre, empirical, cross-sectional study.
Four departments of orthopaedics in 4 hospitals, and 5 departments of rehabilitation medicine in 5 hospitals.
Semi-structured interviews were conducted with 975 patients with adolescent idiopathic scoliosis from 5 hospitals according to the patients' self-reporting. In addition, patients were divided into 3 groups according to clinical outcome. Participant information included demographic and disease-related characteristics. Three adolescent idiopathic scoliosis groups were then compared with respect to the problems identified. Interviews were transcribed verbatim. Categories identified by qualitative analysis were subsequently mapped to the ICF-CY using established linking rules. In order to enrich these findings, we also translated the Scoliosis Research Society 22 Patient Questionnaire (SRS-22 PQ) into the language of the ICF-CY, based on ICF linking rules.
A total of 1278 themes that linked to 54 ICF-CY cate-gories from 18 chapters were identified. Twenty-two (41%) categories were identified as Body Functions, 7 (13%) as Body Structures, 15 (27%) as Activities and Participation, and 10 (19%) as Environmental Factors. Of the 54 categories, 45 (83%) were second-level, 5 (9%) were third-level, and 4 (7%) were fourth-level. Differences between the SRS-22 PQ results and our findings were observed for several ICF-CY categories.
Patients with AIS reported activity limitations and participation restrictions combined with impaired body structures and functions. Environmental factors may act as a barrier to, or facilitator of, patient functioning in daily life. The ICF-CY provides a valuable framework for representing the complexity and multifaceted impact of AIS, and for comparing and examining the content of the SRS-22 PQ for AIS in children and adolescents. These results will be used to develop ICF Core Sets for AIS in China.
Polyphenols act by scavenging reactive oxygen species during oxidative stress and hence are useful in the treatment of metabolic disorders including diabetes. This study describes the effect of polyphenol rich mulberry and jamun wines fed to streptozotocin-induced diabetic rats. To male adult Wistar rats, divided into groups (n = 10 per group) intraperitoneal injection was administered with streptozotocin at 38 mg per kg body weight for inducing diabetes. After confirmation of diabetes, rats divided into groups were fed each day with 5.7 milliliter per kg body weight of mulberry, jamun, white and red grape wines for 6 weeks. One group of animals received resveratrol at 20 mg per kg body weight. After six weeks of treatment, blood glucose, urinary profile, lipid profile, plasma, liver, kidney, brain and eye antioxidant enzyme activities, lipid peroxidation, non-esterified fatty acids (NEFA) and hepatic glutathione (GSH) content were determined. Though wine and resveratrol feeding did not improve the glycemic status of diabetic rats, increases in antioxidant enzymes and GSH content accompanied by reduced NEFA and lipid peroxidation were observed. The kidneys and brains of resveratrol fed rats showed significant reduction in malondialdehyde equivalents, exhibited an improved antioxidant status of tissues and an increased glutathione content. The findings suggested that the wines can ameliorate the consequences of diabetes due to their antioxidants.
Imidazolonepropionase (HutI, EC 3.5.2.7) catalyzes the hydrolytic cleavage of carbon-nitrogen bond in 4-imidazolone-5-propionic acid (IPA) to yield l-formiminoglutamic acid, which is the third step in the universal histidine degradation pathway. In this article, using a combined quantum mechanics and molecular mechanics (QM/MM) approach, the specificity and catalytic mechanism of HutI from Bacillus subtilis have been explored by considering the four isomers of (S)- and (R)-enantiomers of IPA ((S)IPA-1, (S)IPA-2, (R)IPA-1 and (R)IPA-2). Our calculations reveal that the activation of hydrolytic water (a zinc-bound water) is performed by residue E252 via a "bridging" water molecule, which occurs before binding of the substrate. After the substrate binding, this activation channel is blocked by the substrate, and the other two residues (D324 and H272) cannot act as the general base to activate the hydrolytic water. For the two (S)-enantiomers of IPA, HutI can specifically convert one isomer of (S)-enantiomer ((S)IPA-1) to l-formiminoglutamic acid with an energy barrier of 16.6 kcal mol(-1). The conversion of another (S)-enantiomer ((S)IPA-2) corresponds to the energy barrier of 21.9 kcal mol(-1). However, for the two isomers of (R)-enantiomer, (R)IPA-1 corresponds to a higher energy barrier (21.8 kcal mol(-1)), and (R)IPA-2 is associated with a weak binding in the active site compared to (S)IPA-2. Thus, on the basis of our calculations, (S)IPA-1 is suggested to be the most favorable substrate for HutI, whereas the hydrolytic cleavage of (S)IPA-2 may require a preliminary isomerization to (S)IPA-1.
We interpreted the mechanisms of energy harvesting and conversion for intrinsic upconverted mechano-persistent luminescence in CaZnOS through a native point defects study. We found that vacancy defects such as Zn and O vacancies, as well as Schottky pair defects, act as energy harvesting centers; they are very readily formed and very active. They are found to be extra deep electron or hole trap levels near the valence
 or conduction band edges, respectively. This leads to a coupling and exchange effect to continuously collect and transport host charges along a path via localized states to deep recombination levels. The initiating energy barrier is small and can be overcome by ambient thermal stimulation or quantum tunneling. Native activators such as V, V, and V function as energy conversion centers to transfer energy into photon emissions. This gives a solid theoretical reference for developing upconverted mechano-persistent luminescence.
Ab initio calculations predict that pyridine (Py) can act as a photo-catalyst to split water by the absorption of a UV photon following the reaction Py-H2O + hν → PyH˙ + OH˙. To test this prediction, we performed two types of experiments: in the first, we characterize the electronic spectroscopy of the PyH˙ radical in the gas phase. In the second, we evidence the reaction through the UV excitation of molecular Py-(H2O)n clusters obtained in a supersonic expansion and monitoring the PyH˙ reaction product. The results show unambiguously that PyH˙ is produced, and thus that water is split using pyridine as a photo-catalyst.
We have demonstrated that the annealing process for cleaning pyrite surfaces is a critical parameter in promoting ordering on the surface and driving surface reactivity. Furthermore, we describe a spectroscopic surface characterization of the presence or absence of the surface ordering, as indicated by the Low Energy Electron Diffraction (LEED) pattern, as a function of the surface annealing process. Complementary X-ray photoemission spectroscopy (XPS) results provide evidence that longer annealing processes of over 3 hours repair the sulfur vacancies in the pyrite, making FeS species partially disappear in favor of FeS2 species. These features play an important role in molecular adsorption. We show that in the case of the cystine amino acid on the (100) pyrite surface, the substrate structure is responsible for the chemical adsorption form. The presence of an ordered structure on the surface, as indicated by the LEED pattern, favors the cystine NH3(+) chemical form, whereas the absence of the surface ordering promotes cystine NH2 adsorption due to the sulfur-deficient surface. The cystine molecule could then act by changing its chemical functionalities to compensate for the iron surface coordination. The chemical molecular adsorption form can be selected by the surface annealing conditions, implying that environmental conditions could drive molecular adsorption on mineral surfaces. These findings are relevant in several surface processes, and they could play a possible role in prebiotic chemistry surface reactions and iron-sulfur scenarios.
The confinement effect on the complexation process of Cu(ii) by 3-hydroxyflavone (3HF) was investigated by studying 3HF incorporation in channel-type copper-containing ZSM-5 and mordenite (MOR) zeolites characterized by different pore diameters. Complementary electronic and vibrational spectroscopy techniques point out two distinct behaviors upon 3HF sorption and subsequent complexation depending on the channel diameter in CuZSM-5 and CuMOR. To determine the influence of the internal environment on the interaction between the copper cation and the guest molecule, and to predict the structure of the complexes formed within the narrow-pore ZSM-5 and in the larger pore mordenite, the vibrational spectra of the complexes were calculated using quantum chemical calculations at the DFT level. From the calculations, it is derived that the Cu(3HF)(+) chelate is formed in CuMOR indicating a weak interaction with the pore walls. In contrast, due to high confinement in CuZSM-5, interactions between copper cations and the narrower pore walls are assumed to take place in addition to 3HF metal complexation. To emphasize the fact that zeolites act as a solid solvent, 3HF complexation was also investigated in methanol solution. In such liquid media, a stable complex Cu(3HF)2 of 1 : 2 stoichiometry resulting in a double chelation with the metal cation was found to coexist with a minor species [Cu(3HF)(MeOH)2](+) of 1 : 1 stoichiometry. These two complexes show striking analogy with those observed in CuZSM-5 and CuMOR, respectively. Thus, it appears clearly that zeolites can constitute an ideal tool to control and orientate molecular reactivity for the guest in the isolated state.
Hepcidin is the key regulator of systemic iron availability that acts by controlling the degradation of the iron exporter ferroportin. It is expressed mainly in the liver and regulated by iron, inflammation, erythropoiesis and hypoxia. The various agents that control its expression act mainly via the BMP6/SMAD signaling pathway. Among them are exogenous heparins, which are strong hepcidin repressors with a mechanism of action not fully understood but that may involve the competition with the structurally similar endogenous Heparan Sulfates (HS). To verify this hypothesis, we analyzed how the overexpression of heparanase, the HS degrading enzyme, modified hepcidin expression and iron homeostasis in hepatic cell lines and in transgenic mice. The results showed that transient and stable overexpression of heparanase in HepG2 cells caused a reduction of hepcidin expression and of SMAD5 phosphorylation. Interestingly, the clones showed also altered level of TfR1 and ferritin, indices of a modified iron homeostasis. The heparanase transgenic mice showed a low level of liver hepcidin, an increase of serum and liver iron with a decrease in spleen iron content. The hepcidin expression remained surprisingly low even after treatment with the inflammatory LPS. The finding that modification of HS structure mediated by heparanase overexpression affects hepcidin expression and iron homeostasis supports the hypothesis that HS participate in the mechanisms controlling hepcidin expression.
Heritable epigenetic changes underlie the ability of cells to differentiate into distinct cell types. Here, we demonstrate that the fungal pathogen Candida tropicalis exhibits multipotency, undergoing stochastic and reversible switching between three cellular states. The three cell states exhibit unique cellular morphologies, growth rates, and global gene expression profiles. Genetic analysis identified six transcription factors that play key roles in regulating cell differentiation. In particular, we show that forced expression of Wor1 or Efg1 transcription factors can be used to manipulate transitions between all three cell states. A model for tristability is proposed in which Wor1 and Efg1 are self-activating but mutually antagonistic transcription factors, thereby forming a symmetrical self-activating toggle switch. We explicitly test this model and show that ectopic expression of WOR1 can induce white-to-hybrid-to-opaque switching, whereas ectopic expression of EFG1 drives switching in the opposite direction, from opaque-to-hybrid-to-white cell states. We also address the stability of induced cell states and demonstrate that stable differentiation events require ectopic gene expression in combination with chromatin-based cues. These studies therefore experimentally test a model of multistate stability and demonstrate that transcriptional circuits act synergistically with chromatin-based changes to drive cell state transitions. We also establish close mechanistic parallels between phenotypic switching in unicellular fungi and cell fate decisions during stem cell reprogramming.
Colonization of the human gastric mucosa by Helicobacter pylori requires its high motility, which depends on the helical cell shape. In H. pylori, several genes (csd1, csd2, csd3/hdpA, ccmA, csd4, csd5, and csd6) play key roles in determining the cell shape by alteration of cross-linking or by trimming of peptidoglycan stem peptides. H. pylori Csd1, Csd2, and Csd3/HdpA are M23B metallopeptidase family members and may act as d,d-endopeptidases to cleave the d-Ala4-mDAP3 peptide bond of cross-linked dimer muropeptides. Csd3 functions also as the d,d-carboxypeptidase to cleave the d-Ala4-d-Ala5 bond of the muramyl pentapeptide. To provide a basis for understanding molecular functions of Csd1 and Csd2, we have carried out their structural characterizations. We have discovered that (i) Csd2 exists in monomer-dimer equilibrium and (ii) Csd1 and Csd2 form a heterodimer. We have determined crystal structures of the Csd2121-308 homodimer and the heterodimer between Csd1125-312 and Csd2121-308. Overall structures of Csd1125-312 and Csd2121-308 monomers are similar to each other, consisting of a helical domain and a LytM domain. The helical domains of both Csd1 and Csd2 play a key role in the formation of homodimers or heterodimers. The Csd1 LytM domain contains a catalytic site with a Zn2+ ion, which is coordinated by three conserved ligands and two water molecules, whereas the Csd2 LytM domain has incomplete metal ligands and no metal ion is bound. Structural knowledge of these proteins sheds light on the events that regulate the cell wall in H. pylori.
To develop a process to improve patient outcomes from deep brain stimulation (DBS) surgery for Parkinson disease (PD), essential tremor (ET), and dystonia.
We employed standard quality improvement methodology using the Plan-Do-Study-Act process to improve patient selection, surgical DBS lead implantation, postoperative programming, and ongoing assessment of patient outcomes.
The result of this quality improvement process was the development of a neuromodulation network. The key aspect of this program is rigorous patient assessment of both motor and non-motor outcomes tracked longitudinally using a REDCap database. We describe how this information is used to identify problems and to initiate Plan-Do-Study-Act cycles to address them. Preliminary outcomes data is presented for the cohort of PD and
 ET patients who have received surgery since the creation of the neuromodulation network.
Careful outcomes tracking is essential to ensure quality in a complex therapeutic endeavor like DBS surgery for movement disorders. The REDCap database system is well suited to store outcomes data for the purpose of ongoing quality assurance monitoring.
Metal-on-Metal (MoM) total hip arthroplasties (THA) are associated with pseudotumor formation and high revision rates. This prospective study analysed the clinical and wear analyses of 9 large Metal-on-Metal (MoM) total hip arthroplasties (THA) to understand the underlying mechanisms of failure. The MoM bearings were revised for multiple reasons; the main reason was pseudotumor formation.
From 2006 till 2010 the Reinier de Graaf Hospital implanted 160 large head M2a-Magnum™ (Biomet Inc. Warsaw, Indiana, USA) THAs in 150 patients. The first year, 9 bearings were revised and analysed at the Biomechanics Section, Hamburg University of Technology, Germany. We performed clinical (Harris Hip Score, radiographic analysis, blood cobalt and chromium) and wear analysis (implant, tissue and fluid) of the 9 bearings. Since this study did not fall under the scope of the Medical Research Involving Human Subjects Act in The Netherlands, no ethical approval was necessary. In this prospective study all patient details were anonymized by the corresponding author, all other authors were blinded during the research and wear analyses. Patients with bilateral MoM implants were excluded.
The 9 bearings had a median (IQR) survival of 41.0 (25) months in situ. From these bearings, three showed no noticeable wear. The median (IQR) head wear volume was 3.2 (3.6) mm3 and maximum wear depth 0.02 (0.02) mm. For the cup the median (IQR) wear volume was 0.23 (0.3) mm3 with a maximum wear depth of 0.03 (0.05) mm.
An early identification of parameters related to failure of the MoM THA, such as pain, decreased range of motion, radiographic changes and high levels of blood cobalt and chromium is of great importance for patient's quality of life. Especially now patients and surgeons face the long term effects of all these bearings still in situ. This study reports the clinical and wear analyses of 9 MoM THA. In the majority of this group the reason for revision was pseudotumor formation. Most bearings showed signs of wear, however with a great diversity in clinical analysis, in inclination angle, serum cobalt and chromium levels as well as wear analysis. For a better understanding of the underlying mechanisms related with failure, more wear analyses of revised MoM bearings are necessary as well as a frequent follow-up of the patients with a MoM bearing.
Using finite element micromagnetic simulations, we study how resonant magnetisation dynamics in thin magnetic discs with perpendicular anisotropy are influenced by magnetostatic coupling to a magnetic nanoparticle. We identify resonant modes within the disc using direct magnetic eigenmode calculations and study how their frequencies and spatial profiles are changed by the nanoparticle's stray magnetic field. We demonstrate that particles can generate shifts in the resonant frequency of the disc's fundamental mode which exceed resonance linewidths in recently studied spin torque oscillator devices. Importantly, it is shown that the simulated shifts can be maintained over large field ranges (here up to 1 T). This is because the resonant dynamics (the basis of nanoparticle detection here) respond directly to the nanoparticle stray field, i.e. detection does not rely on nanoparticle-induced changes to the magnetic ground state of the disc. A consequence of this is that in the case of small disc-particle separations, sensitivities to the particle are highly mode- and particle-position-dependent, with frequency shifts being maximised when the intense stray field localised directly beneath the particle can act on a large proportion of the disc's spins that are undergoing high amplitude precession.
Iodine is a part of thyroid hormones and has been reported to act directly as an antioxidant or induce indirectly antioxidant enzymes. This study aimed to assess the urinary iodine concentration and its relationship between the antioxidant and oxidative stress capacity in healthy school-aged children.
In total, 196 students from five primary schools, randomly selected between 9 and 12 years (mean age: 10.2±1.2 years), were enrolled in the study. Urinary iodine levels were measured by spectrophotometry with the Sandell-Kolthoff reaction. Total antioxidant status (TAS) and total oxidant status (TOS) were analysed from urine samples. The ratio of TOS to TAS was regarded as an oxidative stress index (OSI), an indicator of the degree of oxidative status.
Fifty-four percentage (107) of the children had iodine deficiency (ID) and the majority of them (30%) had mild ID. There was no severe-ID child in the population (<20 μg/L). Urine TAS levels were significantly lower in the moderate-ID group than in the mild-ID group (6.5±4.1 vs. 11.3±4.1 mmol, p<0.001) and the iodine-sufficient group (11.0±5.3 μmol, p<0.001). TOS levels and OSI were found higher in the moderate-ID group than in the mild-ID group (4.8±2.1 vs. 3.7±2.1 μmol, p<0.001) and the iodine-sufficient group (4.8±2.1 vs. 3.4±2.5 mmol, p<0.001). In the moderate-ID group, low urine iodine levels exhibited significant negative correlations with OSI (r=-0.660) and TOS (r=-0.248) and a positive correlation with TAS (r=0.475).
We found that children with moderate ID were exposed to more oxidative burden than children with mild ID or iodine sufficiency. Increased systemic oxidative stress induced by moderate ID could cause development of ID-related complications and diseases. Iodine supplementation could have a beneficial role in the prevention of oxidative stress.
Recently, deep eutectic solvents (DESs) have shown their new and interesting ability for chemistry through their involvement in variety of applications. This study introduces carbon nanotubes (CNTs) functionalized with DES as a novel adsorbent for Hg(2+) from water. Allyl triphenyl phosphonium bromide (ATPB) was combined with glycerol as the hydrogen bond donor (HBD) to form DES, which can act as a novel CNTs functionalization agent. The novel adsorbent was characterized using Raman, FTIR, XRD, FESEM, EDX, BET surface area, TGA, TEM and Zeta potential. Response surface methodology was used to optimize the removal conditions for Hg(2+). The optimum removal conditions were found to be pH 5.5, contact time 28 min, and an adsorbent dosage of 5 mg. Freundlich isotherm model described the adsorption isotherm of the novel adsorbent, and the maximum adsorption capacity obtained from the experimental data was 186.97 mg g(-1). Pseudo-second order kinetics describes the adsorption rate order.
The ability of phosphonium cations to act as intracellular transport vectors is well-established. Phosphonioalkylthiosulfate zwitterions, and ω-thioacetylalkylphosphonium salts, which act as 'masked thiolate' ligands, are useful precursors for the formation of phosphonium-functionalised gold nanoparticles, enabling the nanoparticles to be transported into cells for diagnostic and therapeutic purposes. In this study we have completed cytotoxicity studies of ω-thioacetylpropylphosphonium salts derived from triphenylphosphine and tri(4-fluorophenyl)phosphine, which show that the compounds are only toxic towards PC3 prostate cancer cells at high concentrations and at prolonged incubation periods and display IC50 values of 67 μM and 252 μM respectively, significantly higher than those of other phosphonium salts. MALDI-TOF-MS has been used to investigate the uptake of the compounds by PC3 cells and to quantify detectable levels of the compounds inside the cells. The structures of ω-thioacetylpropyl(tri-4-fluorophenyl) phosphonium bromide and the corresponding tri(4-fluorophenyl)phosphoniopropylthiosulfate zwitterion have been investigated by single crystal X-ray crystallography. The results show that molecules of the zwitterion are held together through an extensive array of electrostatic and non-covalent interactions. The unit cell of ω-thioacetylpropyl(tri-4-fluorophenyl)phosphonium bromide contains eight cations together with eight bromide anions and two waters of crystallisation, all held together through a complex network of hydrogen bonds. The differences in the molecular packing of the two compounds may account for the lower solubility of the zwitterion in aqueous solutions, compared with that of the phosphonium salt.
Leaves are flat determinate organs derived from indeterminate shoot apical meristems. The presence of a specific leaf meristem is debated, as anatomical features typical of meristems are not present in leaves. Here we demonstrate that multiple NGATHA (NGA) and CINCINNATA-class-TCP (CIN-TCP) transcription factors act redundantly, shortly after leaf initiation, to gradually restrict the activity of a leaf meristem in Arabidopsis thaliana to marginal and basal domains, and that their absence confers persistent marginal growth to leaves, cotyledons and floral organs. Following primordia initiation, the restriction of the broadly acting leaf meristem to the margins is mediated by the juxtaposition of adaxial and abaxial domains and maintained by WOX homeobox transcription factors, whereas other marginal elaboration genes are dispensable for its maintenance. This genetic framework parallels the morphogenetic program of shoot apical meristems and may represent a relic of an ancestral shoot system from which seed plant leaves evolved.
Increased oxidative stress in adipose tissue emerges as an inducer of obesity-linked insulin resistance. Here we tested whether free-radical derived oxysterols are formed by, and accumulate in, human adipocytes. Moreover, we asked whether increased accumulation
 of oxysterols characterizes the adipose cells of obese patients with type 2 diabetes (T2D) (OBT2D) compared with lean, nondiabetic controls (CTRLs). Finally, we studied the effects of the free radical-derived oxysterols on adipogenic differentiation of adipose-derived stem cells (ASCs).
Adipocytes and ASCs were isolated from sc abdominal adipose tissue biopsy in four OBT2D and four CTRL subjects. Oxysterols in adipocytes were detected by gas chromatography/mass spectrometry. The cellular and molecular effects of oxysterols were then evaluated on primary cultures of ASCs focusing on cell viability, adipogenic differentiation, and "canonical" WNT and MAPK signaling pathways.
7-ketocholesterol (7κ-C) and 7β-hydroxycholesterol were unambiguously detected in adipocytes, which showed higher oxysterol accumulation (P < .01) in OBT2D, as compared with CTRL individuals. Notably, the accumulation of oxysterols in adipocytes was predicted by the adipose cell size of the donor (R(2) = 0.582; P < .01). Challenging ASCs with free radical-derived type I (7κ-C) and type II (5,6-Secosterol) oxysterols led to a time- and concentration-dependent decrease of cell viability. Meaningfully, at a non-toxic concentration (1μM), these bioactive lipids hampered adipogenic differentiation of ASCs by sequential activation of WNT/β-catenin, p38-MAPK, ERK1/2, and JNK signaling pathways.
Free radical-derived oxysterols accumulate in the "diabetic" fat and may act as novel adipokines modulating the adipogenic potential of undifferentiated adipose precursor cells.
A unique composite of the copper-based metal-organic framework (Cu-benzene tricarboxylic acid (BTC)) with oxidized graphitic carbon nitride nanospheres is synthesized. For comparison, a hybrid material consisting of g-C3 N4 and Cu-BTC is also obtained. Their surface features are analyzed using Fourier transform infrared spectroscopy, X-ray diffraction, sorption of nitrogen, thermal analysis, scanning electron microscopy, photoluminescence, and diffuse reflectance UV-Vis spectroscopy. The results suggest that the formed nanospheres of oxidized g-C3 N4 act as linkers between the copper sites, playing a crucial role in the composite building process. Their incorporation to the Cu-BTC framework causes the development of new mesoporosity. Remarkable alterations in the optical properties, as a result of the coordination of oxygen containing functional groups of the oxidized graphitic carbon nitride to the copper atoms of the framework, suggest an increase in photoreactivity. On the other hand, for the hybrid material consisting of Cu-BTC and g-C3 N4 , the unaltered pore volume and optical properties support the formation of a physical mixture rather than of a composite. The tests on reactive adsorption and detoxification of G-series organophosphate nerve agent surrogate show the enhanced performance of the composite as catalysts and photocatalyst in visible light.
Dating violence is an important problem. Evidence suggests that women are more likely to perpetrate dating violence.
The present study investigates the prevalence of dating violence compared with cohabiting violence in a community sample of men and women and assesses to what extent child and adolescent explanatory factors predict this behaviour. A secondary aim is to construct a risk score for dating violence based on the strongest risk factors.
The Cambridge Study in Delinquent Development is a prospective longitudinal survey of 411 men (generation 2) born in the 1950s in an inner London area. Most recently, their sons and daughters [generation 3 (G3)] have been interviewed regarding their perpetration of dating and cohabiting violence, utilising the Conflict Tactics Scale. Risk factors were measured in four domains (family, parental, socio-economic and individual).
A larger proportion of women than men perpetrated at least one act of violence towards their dating partner (36.4 vs 21.7%). There was a similar pattern for cohabiting violence (39.6 vs 21.4%). A number of risk factors were significantly associated with the perpetration of dating violence. For G3 women, these included a convicted father, parental conflict, large family size and poor housing. For G3 men, these included having a young father or mother, separation from the father before age 16, early school leaving, frequent truancy and having a criminal conviction. A risk score for both men and women, based on 10 risk factors, significantly predicted dating violence.
Risk factors from four domains were important in predicting dating violence, but they were different for G3 men and women. It may be important to consider different risk factors and different risk assessments for male compared with female perpetration of dating violence. Early identification and interventions are recommended. Copyright © 2016 John Wiley & Sons, Ltd.
The demographic ageing of New Zealand society, as elsewhere in the developed world, has dramatically increased the proportion of older people (aged 65 years and over) in the population. This has major policy implications for the future organisation of social care. Our objective was to test the effects on social care use, first, of putative changes in the overall disability profile of older people, and second, of alterations to the balance of their care, i.e. whether it was community-based or residential. In order to undertake these experiments, we developed a microsimulation model of the later life course using individual-level data from two official national survey series on health and disability, respectively, to generate a synthetic version which replicated original data and parameter settings. A baseline projection under current settings from 2001 to 2021 showed moderate increases in disability and associated social care use. Artificially decreasing disability levels, below the baseline projection, only moderately reduced the use of community care (both informal and formal). Scenarios implemented by rebalancing towards informal care use moderately reduced formal care use. However, only moderate compensatory increases in community-based care were required to markedly decrease the transition to residential care. The disability impact of demographic ageing may not have a major negative effect on system resources in developed countries like New Zealand. As well as healthy ageing, changing the balance of social care may alleviate the impact of increasing demand due to an expanding population of older people.
Fungal mitochondrial genomes act as "reservoirs" for homing endonucleases. These enzymes with their DNA site-specific cleavage activities are attractive tools for genome editing, targeted mutagenesis and gene therapy applications. Herein, we present strategies where homing endonuclease open reading frames (HEases ORFs) are interrupted with group II intron sequences. The ultimate goal is to achieve in vivo expression of HEases that can be regulated by manipulating the splicing efficiency of the HEase ORF-embedded group II introns. That addition of exogenous magnesium chloride (MgCl2) appears to stimulate splicing of nonnative group II introns in Escherichia coli and the addition of cobalt chloride (CoCl2) to the growth medium antagonizes the expression of HEase activity (i.e., splicing). Group II introns are potentially autocatalytic self-splicing elements and thus can be used as molecular switches that allow for temporal regulated HEase expression. This should be useful in precision genome engineering, mutagenesis, and minimizing off-target activities.
Flower-like NiO with a highly hierarchical porous structure was synthesized and used as a cathode material for Li-O2 batteries. The disordered porous structure and specific pathways for O2 and Li ions led to an outstanding cycling performance over 80 cycles at a high current density of 200 mA g(-1).
Cerebral vascular pathology may contribute to cognitive decline experienced by some elderly near death. Given evidence for mixed neuropathologies in advanced age, preventing or reducing cerebrovascular burden in late life may be beneficial.
To correlate measures of cerebral vascular pathology with cognitive trajectories.
Observational study.
A cohort of 2,274 individuals who came to autopsy at a mean age of 89.3 years and 82 percent of whom had at least two cognitive assessments within the last six years of life was compiled from six centers conducting longitudinal studies.
For each cognitive domain: immediate and delayed memory, language, and naming, three trajectories were examined: good, intermediate, and poor cognition. The probability of a participant belonging to each trajectory was associated with measures of cerebral vascular pathology after adjustment for demographics, APOE, and Alzheimer neuropathology.
A large proportion of the cohort (72-94%) experienced good or intermediate cognition in the four domains examined. The presence of arteriolosclerosis and the presence of lacunar infarcts doubled the odds of belonging to the poor cognitive trajectory for language when compared to the good trajectory. The presence of lacunar infarcts increased the odds of an intermediate or poor trajectory for immediate and delayed recall while the presence of large artery infarcts increased the odds of poor trajectories for all four cognitive domains examined. Microinfarcts and cerebral amyloid angiopathy had little effect on the trajectories.
Indicators of cerebral vascular pathology act differently on late life cognition.
Worldwide the demands on emergency and primary health care services are increasing. General practitioners and accident and emergency departments are often used unnecessarily for the treatment of minor ailments. Community pharmacy is often the first port of call for patients in the provision of advice on minor ailments, advising the patient on treatment or referring the patient to an appropriate
 health professional when necessary. The potential for community pharmacists to act as providers of triage services has started to be recognised, and community pharmacy triage services (CPTS) are emerging in a number of countries. This review aimed to explore whether key components of triage services can be identified in the literature surrounding community pharmacy, to explore the evidence for the feasibility of implementing CPTS and to evaluate the evidence for the appropriateness of such services.
Systematic searches were conducted in MEDLINE, EMBASE and International Pharmaceutical Abstracts (IPA) databases from 1980 to March 2016.
Key elements of community pharmacy triage were identified in 37 studies, which were included in the review. When a guideline or protocol was used, accuracy in identifying the presenting condition was high, with concordance rates ranging from 70 % to 97.6 % between the pharmacist and a medical expert. However, when guidelines and protocols were not used, often questioning was deemed insufficient. Where other health professionals had reviewed decisions made by pharmacists and their staff, e.g. around advice and referral, the decisions were considered to be appropriate in the majority of cases. Authors of the included studies provided recommendations for improving these services, including use of guidelines/protocols, education and staff training, documentation, improving communication between health professional groups and consideration of privacy and confidentiality.
Whilst few studies had specifically trialled triage services, results from this review indicate that a CPTS is feasible and appropriate, and has the potential to reduce the burden on other healthcare services. Questions still remain on issues such as ensuring the consistency of the service, whether all pharmacies could provide this service and who will fund the service.
Corals are very efficient at using solar radiation, with photosynthetic quantum efficiencies approaching theoretical limits. Here, we investigated potential mechanisms underlying such outstanding photosynthetic performance through extracting inherent optical properties of the living coral tissue and skeleton in a massive faviid coral. Using Monte Carlo simulations developed for medical tissue optics it is shown that for the investigated faviid coral, the coral tissue was a strongly light scattering matrix with a reduced scattering coefficient of μs' = 10 cm(-1) (at 636 nm). In contrast, the scattering coefficient of the coral skeleton was μs' = 3.4 cm(-1), which facilitated the efficient propagation of light to otherwise shaded coral tissue layers, thus supporting photosynthesis in lower tissues. Our study provides a quantification of coral tissue optical properties in a massive faviid coral and suggests a novel light harvesting strategy, where tissue and skeletal optics act in concert to optimize the illumination of the photosynthesizing algal symbionts embedded within the living coral tissue.
Individual players act as a coherent unit during team sports performance, forming a team synergy. A synergy is a collective property of a task-specific organization of individuals, such that the degrees of freedom of each individual in the system are coupled, enabling the degrees of freedom of different individuals to co-regulate each other. Here, we present an explanation for the emergence of such collective behaviors, indicating how these can be assessed and understood through the measurement of key system properties that exist, considering the contribution of each individual and beyond These include: to (i) dimensional compression, a process resulting in independent degree of freedom being coupled so that the synergy has fewer degrees of freedom than the set of components from which it arises; (ii) reciprocal compensation, if one element do not produce its function, other elements should display changes in their contributions so that task goals are still attained; (iii) interpersonal linkages, the specific contribution of each element to a group task; and (iv), degeneracy, structurally different components performing a similar, but not necessarily identical, function with respect to context. A primary goal of our analysis is to highlight the principles and tools required to understand coherent and dynamic team behaviors, as well as the performance conditions that make such team synergies possible, through perceptual attunement to shared affordances in individual performers. A key conclusion is that teams can be trained to perceive how to use and share specific affordances, explaining how individual's behaviors self-organize into a group synergy. Ecological dynamics explanations of team behaviors can transit beyond mere ratification of sport performance, providing a comprehensive conceptual framework to guide the implementation of diagnostic measures by sport scientists, sport psychologists and performance analysts. Complex adaptive systems, synergies, group behaviors, team sport performance, ecological dynamics, performance analysis.
Roads are a potential threat to bat conservation. In addition to the direct risk of collision of bats with vehicles, roads could pose a threat to bat populations as a result of habitat loss, degradation and fragmentation, and could act as barriers to movements of bats between habitats.We performed a systematic review of the literature and conducted meta-analyses to assess the threat posed by roads to bats as a result of 1) collisions between bats and vehicles and 2) roads acting as barriers to movements of bats.Based on collated records of 1207 bat road casualties in Europe, we found that low-flying species are more prone to collisions than high-flying species, and that juveniles are more vulnerable to collisions than adults. In addition, meta-analysis identified a significant bias towards male casualties. Casualties included rare species such as Barbastella barbastellus and geographically restricted species such as Rhinolophus species.The bias towards male casualties could be indicative of greater natal philopatry or lower dispersal among females, or of sexual segregation in habitats of varying quality, i.e. females may occupy better quality habitats than males, and road density may be lower in better quality habitats.Whether or not roads act as barriers to the movement of bats depends on a complex interplay of habitat and species-specific behaviour. For example, the presence of favourable habitat for bats - notably woodland - was found in this review to be linked with significantly reduced barrier effects but a heightened risk of collision.Our data suggest that roads do pose a threat to bats. Future research should assess the contribution of traffic noise and street lighting to the barrier effect of roads. Where new road schemes are monitored by ecological practitioners, it is vital that consistent protocols are employed to ensure that bat activity can be compared before and after the road is built. Evidence from such research should be used to minimize the risks for bats of any roads built in the future, and to design safe crossing points for bats.
The opportunistic pathogen Staphylococcus aureus is recognized as one of the most frequent causes of biofilm-associated infections. The recently discovered phenol soluble modulins (PSMs) are small α-helical amphipathic peptides that act as the main molecular effectors of staphylococcal biofilm maturation, promoting the formation of an extracellular fibril structure with amyloid-like properties. Here, we combine computational, biophysical and in cell analysis to address the specific contribution of individual PSMs to biofilm structure. We demonstrate that despite their highly similar sequence and structure, contrary to what it was previously thought, not all PSMs participate in amyloid fibril formation. A balance of hydrophobic/hydrophilic forces and helical propensity seems to define the aggregation propensity of PSMs and control their assembly and function. This knowledge would allow to target specifically the amyloid properties of these peptides. In this way, we show that Epigallocatechin-3-gallate (EGCG), the principal polyphenol in green tea, prevents the assembly of amyloidogenic PSMs and disentangles their preformed amyloid fibrils.
Textile-structured solar cells are frequently discussed in the literature due to their prospective applications in wearable devices and in building integrated solar cells that utilize their flexibility, mechanical robustness, and aesthetic appearance, but the current approaches for textile-based solar cells-including the preparation of fibre-type solar cells woven into textiles-face several difficulties from high friction and tension during the weaving process. This study proposes a new structural concept and fabrication process for monolithic-structured textile-based dye-sensitized solar cells that are fabricated by a process similar to the cloth-making process, including the preparation of wires and yarns that are woven for use in textiles, printed, dyed, and packaged. The fabricated single-layered textile-based dye-sensitized solar cells successfully act as solar cells in our study, even under bending conditions. By controlling the inter-weft spacing and the number of Ti wires for the photoelectrode conductor, we have found that the performance of this type of dye-sensitized solar cell was notably affected by the spacing between photoelectrodes and counter-electrodes, the exposed areas of Ti wires to photoelectrodes, and photoelectrodes' surface morphology. We believe that this study provides a process and concept for improved textile-based solar cells that can form the basis for further research.
Vaccinia virus (VACV) oncolytic therapy has been successful in a number of tumor models. In this study our goal was to generate a double recombinant vaccinia
 virus (VV-GMCSF-Lact) with enhanced antitumor activity that expresses exogenous proteins: the antitumor protein lactaptin and human granulocyte-macrophage colony-stimulating factor (GM-CSF). Lactaptin has previously been demonstrated to act as a tumor suppressor in mouse hepatoma as well as MDA-MB-231 human adenocarcinoma cells grafted into SCID mice. VV-GMCSF-Lact was engineered from Lister strain (L-IVP) vaccinia virus and has deletions of the viral thymidine kinase and vaccinia growth factor genes. Cell culture experiments revealed that engineered VV-GMCSF-Lact induced the death of cultured cancer cells more efficiently than recombinant VACV coding only GM-CSF (VV-GMCSF-dGF). Normal human MCF-10A cells were resistant to both recombinants up to 10 PFU/cell. The selectivity index for breast cancer cells measured in pair cultures MCF-7/MCF-10A was 200 for recombinant VV-GMCSF-Lact coding lactaptin and 100 for VV-GMCSF-dGF. Using flow cytometry we demonstrated that both recombinants induced apoptosis in treated cells but that the rate in the cells with active caspase-3 and -7 was higher after treatment with VV-GMCSF-Lact than with VV-GMCSF-dGF. Tumor growth inhibition and survival outcomes after VV-GMCSF-Lact treatment were estimated using immunodeficient and immunocompetent mice models. We observed that VV-GMCSF-Lact efficiently delays the growth of sensitive and chemoresistant tumors. These results demonstrate that recombinant VACVs coding an apoptosis-inducing protein have good therapeutic potential against chemoresistant tumors. Our data will also stimulate further investigation of coding lactaptin double recombinant VACV in clinical settings.
Transcription factor EKLF (Erythroid Krüppel-Like Factor) belongs to the group of Krüppellike factors, which regulate proliferation, differentiation, development and apoptosis of mammalian cells. EKLF factor is present in erythroid cells, where it participates in regulation of hematopoiesis, expression of genes encoding transmembrane proteins (including blood group antigens), and heme biosynthesis enzymes. It is also a key factor in downregulation of γ-globins and activation of β-globin gene expression. The EKLF factor consists of two domains: proline-rich transactivation domain and DNA-binding domain containing three zinc finger motifs, which recognize DNA. EKLF can act as a transcription activator (for example in the case of β-globin gene) or repressor, which depends on the type of posttranslational modification (phosphorylation, SUMOylation, ubiquitination and acetylation). Mutations in the gene encoding EKLF may cause hemoglobinopathies, such as hereditary persistence of fetal hemoglobin and β-thalassemia intermedia, and congenital dyserythropoietic anemia type IV, which is a hematopoietic disorder. These changes may impede invasion of red blood cells by malaria merozoites and cause faster removal of invaded erythrocytes. In addition, mutations in KLF1 may decrease the number of erythrocyte surface antigens that belong to blood group systems such as MN, P1PK, Lutheran, Duffy, Diego and OK. Such antigens can be receptors for protozoans (such as Plasmodium falciparum or Plasmodium vivax), bacteria (like uropathogenic strains of Escherichia coli, Neisseria meningitidis), and toxins (Shiga toxins), which may cause several dangerous diseases including malaria, pyelonephritis, hemorrhagic colitis, hemolytic uremic syndrome (HUS) and meningitis. Here, we propose a hypothesis on possible liaisons between mutations in the gene encoding EKLF and resistance to pathogens.
The constant growth of medical knowledge and the increases in specialization in clinical practice have created a significant need to share and access patient information with speed and efficiency. However, current technology is centered on processing data, rather than gathering information. To realize the potential of modern technology in improving patient health, merely collecting and storing data are insufficient: one must convert these data into information and knowledge. In this article, I present an overview of 2 recent advances in technology and their assimilation into the practice of medicine, in the attempt to make clinical data meaningful and then to learn from aggregated clinical data. We address the emergence of clinical data warehouses (CDWs) and health information exchanges (HIEs), as features of the Health Information Technology for Economic and Clinical Health (HITECH) Act. This act, enacted in the United States as part of the American Recovery and Reinvestment Act of 2009, was signed into law on February 17, 2009, to promote the adoption and meaningful use of health information technology.
Recombinase enzymes promote DNA repair by homologous recombination. The genes that encode them are ancestral to life, occurring in all known dominions: viruses, Eubacteria, Archaea and Eukaryota. Bacterial recombinases are also present in viruses and eukaryotic groups (supergroups), presumably via ancestral events of lateral gene transfer. The eukaryotic recA genes have two distinct origins (mitochondrial and plastidial), whose acquisition by eukaryotes was possible via primary (bacteria-eukaryote) and/or secondary (eukaryote-eukaryote) endosymbiotic gene transfers (EGTs). Here we present a comprehensive phylogenetic analysis of the recA genealogy, with substantially increased taxonomic sampling in the bacteria, viruses, eukaryotes and a special focus on the key eukaryotic supergroup Amoebozoa, earlier represented only by Dictyostelium We demonstrate that several major eukaryotic lineages have lost the bacterial recombinases (including Opisthokonta and Excavata), whereas others have retained them (Amoebozoa, Archaeplastida and the SAR-supergroups). When absent, the bacterial recA homologues may have been lost entirely (secondary loss of canonical mitochondria) or replaced by other eukaryotic recombinases. RecA proteins have a transit peptide for organellar import, where they act. The reconstruction of the RecA phylogeny with its EGT events presented here retells the intertwined evolutionary history of eukaryotes and bacteria, while further illuminating the events of endosymbiosis in eukaryotes by expanding the collection of widespread genes that provide insight to this deep history.
Research is limited on mechanisms of action in restorative justice interventions. This multimethods study delineates the change processes underlying a successful in-prison group treatment program by (a) examining shifts in offenders' self-schemas and (b) identifying key program components that influence this movement. Researchers assigned to small groups as "co-facilitators" gathered data using participant observation, semi-structured interviews, and psychological assessments at three time points. Mechanisms of action include group norms and behaviors that contrast with prior experiences and uncover offenders' self-schemas through intrapsychic processes, which prompt them to test and act upon new possible selves through the group process.
Traditional Indian medicine (ayurveda) is becoming increasingly popular, with many chronic conditions responding to it well. Most patients begin to take conventional medications as soon as their diagnoses are made, so ayurvedic treatments are usually undergone alongside and/or after conventional medical approaches. A detailed knowledge of the action of food, spices, and medicinal plants is needed in order to understand their potential influence fully. While societal use of ayurvedic plants and Indian spices is commonplace, without ill effect, the use of more concentrated products made from single plants, often in the form of teas or tablets, is of more concern. The mechanisms by which polyherbal drugs and their extracts act differ in many respects from the actions of single substances or synthetic drugs. Despite the fact that ayurvedic medicines are based on natural herbal materials, their safety depends on their method of administration, taking into account individuals' needs and their specific disease conditions.
Plasmodium knowlesi occurs across Southeast Asia and is the most common cause of malaria in Malaysia. High parasitaemias can develop rapidly, and the risk of severe disease in adults is at least as high as in falciparum malaria. Prompt initiation of effective treatment is therefore essential. Intravenous artesunate is highly effective in severe knowlesi malaria and in those with moderately high parasitaemia but otherwise uncomplicated disease. Both chloroquine and artemisinin-combination therapy (ACT) are highly effective for uncomplicated knowlesi malaria, with faster parasite clearance times and lower anaemia rates with ACT. Given the difficulties with microscope diagnosis of P. knowlesi, a unified treatment strategy of ACT for all Plasmodium species is recommended in coendemic regions.
An Accountable Care Organization (ACO) is a network of providers that collaborates to manage care and is financially incentivized to realize cost savings while also optimizing standards of care. Since its introduction as part of the 2010 Patient Protection and Affordable Care Act, ACOs have grown to include 16% of Medicare beneficiaries and currently represent Medicare's largest payment initiative. Although ACOs are still in the pilot phase with multiple structural models being assessed, incentives are being introduced to encourage specialist participation, and dermatologists will have the opportunity to influence both the cost savings and quality standard aspects of these organizations. In this article, part of a health care policy series targeted to dermatologists, we review what an ACO is, its relevance to dermatologists, and essential factors to consider when joining and negotiating with an ACO.
Forest ecosystems may act as sinks or sources of nitrogen (N) and carbon (C) compounds, such as the climate
 relevant trace gases nitrous oxide (N2O), nitric oxide (NO) and methane (CH4). Forest edges, which catch more atmospheric deposition, have become important features in European landscapes and elsewhere. Here, we implemented a fully automated measuring system, comprising static and dynamic measuring chambers determining N2O, NO and CH4 fluxes along an edge-to-interior transect in an oak (Q. robur) and a pine (P. nigra) forest in northern Belgium. Each forest was monitored during a 2-week measurement campaign with continuous measurements every 2h. NO emissions were 9-fold higher than N2O emissions. The fluxes of NO and CH4 differed between forest edge and interior, but not for N2O. This edge effect was more pronounced in the oak than in the pine forest. In the oak forest, edges emitted less NO (on average 60%) and took up more CH4 (on average 177%). This suggests that landscape structure can play a role in the atmospheric budgets of these climate relevant trace gases. Soil moisture variation between forest edge and interior was a key variable explaining the magnitude of NO and CH4 fluxes in our measurement campaign. To better understand the environmental impact of N and C trace gas fluxes from forest edges, additional and long-term measurements in other forest edges are required.
Encephalitozoon cuniculi is an opportunist intracellular pathogen of mammals. The adaptive immune response is essential to eliminate E. cuniculi, but evidence is mounting that the response initiated by the innate immune response may ultimately define whether or not the parasite can survive. B-1 cells may act as antigen-presenting cells or differentiate into phagocytes, playing different roles in many infection models. However, the role of these cells in the dynamics of Encephalitozoon sp. infections is still unknown. To investigate the role of B-1 cells in E. cuniculi infection, BALB/c and BALB/c XID (B-1 cells deficient) mice were infected with E. cuniculi spores. Cytometric analyses of peritoneal cells showed that B-1 cells and macrophages increased significantly in infected BALB/c mice compared to uninfected controls. Despite the increase in the number of CD4(+) and CD8(+) lymphocytes in XID mice, these animals were more susceptible to infection as evidenced histologically with more prominent inflammatory lesions and parasite burden. Pro-inflammatory cytokines increased in both infected BALB/c and BALB/c XID mice. To confirm B-1 cells role in encephalitozoonosis, we adoptively transferred B-1 cells to BALB/c XID mice and this group showed few symptoms and microscopic lesions, associated with an increased in cytokines. Together, these results suggest that B-1 cells may increase the resistance of BALB/c mice to encephalitozoonosis, evidencing for the first time the important role of B-1 lymphocytes in the control of microsporidia infection.
Global efforts to end female genital mutilation (FGM) have intensified in recent decades because of the rising awareness that such a practice is an act of extreme violence against women and girls. Articles on FGM have been published highlighting the combined efforts of international and non-governmental organizations, governments, as well as religious and civil society groups to end the practice. However, the consequences of this research are not well known, and it seems that the socioeconomic aspects of the practice are underreported.
This review aims to characterize over a 40-year period the scientific output on the consequences of FGM in African countries, the most affected region known for the high prevalence of FGM, and review data on the socioeconomic consequences of the practice.
A systematic review of literature was done, looking at the following databases: PubMed, Embase, CINAHL, BDSP, Web of Science, PsycINFO, FRANCIS, Sociological Abstracts, WHOLIS, RERO, and SAPHIR. The analysis was limited to articles concerning the African continent, published in English and French, from January 1, 1972, to December 31, 2011.
One hundred ninety-eight articles were reviewed. More than half of the articles were published during the last decade of the study period. The majority of papers were published in biomedical journals (64.1%). Most studies looked at Africa as a region (33.3%). Nigeria was the single country most investigated (19.2%), followed by Egypt (10.6%). Most first authors were affiliated to non-African countries (60.6%): among them 21.2% were US-based, 4% were from African institutions, and 16.2% from Nigeria.The medical and psychological consequences (51.5%) and the prevalence and ethics of the practice (34.4%) were the most frequently investigated topics. The socioeconomic consequences were addressed in a minority of the papers (14.1%): they were classified into direct economic consequences (2.5%), school attendance (1%), marriageability (2%), sexual and marital consequences (3.5%), fertility (2.5%), domestic violence (1%), and discrimination (1.5%).
The publication of articles on the consequences of FGM is increasing, but there is little research on the socioeconomic consequences of the practice. More scientific data focusing on this dimension is necessary to strengthen prevention, advocacy, and intervention campaigns.
Addiction to alcohol and drugs is a major social and economic problem, and there is considerable interest in understanding the molecular mechanisms that promote addictive drives. A number of proteins have been identified that contribute to expression of addictive behaviors. NMDA receptors (NMDARs), a subclass of ionotropic glutamate receptors, have been of particular interest because their physiological properties make them an attractive candidate for gating induction of synaptic plasticity, a molecular change thought to mediate learning and memory. NMDARs are generally inactive at the hyperpolarized resting potentials of many neurons. However, given sufficient depolarization, NMDARs are activated and exhibit long-lasting currents with significant calcium permeability. Also, in addition to stimulating neurons by direct depolarization, NMDARs and their calcium signaling can allow strong and/or synchronized inputs to produce long-term changes in other molecules (such as AMPA-type glutamate receptors) which can last from days to years, binding internal and external stimuli in a long-term memory trace. Such memories could allow salient drug-related stimuli to exert strong control over future behaviors and thus promote addictive drives. Finally, NMDARs may themselves undergo plasticity, which can alter subsequent neuronal stimulation and/or the ability to induce plasticity. This review will address recent and past findings suggesting that NMDAR activity promotes drug- and alcohol-related behaviors, with a particular focus on GluN2B subunits as possible central regulators of many addictive behaviors, as well as newer studies examining the importance of non-canonical NMDAR subunits and endogenous NMDAR cofactors.
The corticospinal tract (CST) plays a major role in cortical control of spinal cord activity. In particular, it is the principal motor pathway for voluntary movements. Here, we discuss: (i) the anatomic evolution and development of the CST across mammalian species, focusing on its role in motor functions; (ii) the molecular mechanisms regulating corticospinal tract formation and guidance during mouse development; and (iii) human disorders associated with abnormal CST development. A comparison of CST anatomy and development across mammalian species first highlights important similarities. In particular, most CST axons cross the anatomical midline at the junction between the brainstem and spinal cord, forming the pyramidal decussation. Reorganization of the pattern of CST projections to the spinal cord during evolution led to improved motor skills. Studies of the molecular mechanisms involved in CST formation and guidance in mice have identified several factors that act synergistically to ensure proper formation of the CST at each step of development. Human CST developmental disorders can result in a reduction of the CST, or in guidance defects associated with abnormal CST anatomy. These latter disorders result in altered midline crossing at the pyramidal decussation or in the spinal cord, but spare the rest of the CST. Careful appraisal of clinical manifestations associated with CST malformations highlights the critical role of the CST in the lateralization of motor control. © 2016 Wiley Periodicals, Inc. Develop Neurobiol, 2016.
To examine how communication between nurses and doctors occurred for managing medications in inpatient paediatric settings.
Communication between health professionals influences medication incidents' occurrence and safe care.
An ethnographic study was undertaken.
Semi-structured interviews, observations and focus groups were conducted in three clinical areas of an Australian tertiary paediatric hospital. Data were transcribed verbatim and thematically analysed using the Medication Communication Model.
The actual communication act revealed professionals' commitment to effective medication management and the influence of professional identities on medication communication. Nurses and doctors were dedicated to providing safe, effective medication therapy for children, within their scope of practice and perceived role responsibilities. Most nurses and junior doctors used tentative language in their communication while senior doctors tended to use direct language. Irrespective of language style, nurses actively engaged with doctors to promote patients' needs. Yet, the medical hierarchical structure, staffing and attendant expectations influenced communication for medication management, causing frustration among nurses and doctors. Doctors' lack of verbal communication of documented changes to medication orders particularly troubled nurses. Nurses persisted
 in their efforts to acquire appropriate orders for safe medication administration to paediatric patients.
Collaborative practice between nurses and doctors involved complex, symbiotic relationships. Their dedication to providing safe medication therapy to paediatric patients facilitated effective medication management. At times, shortcomings in inter-disciplinary communication impacted on potential and actual medication incidents.
Understanding of the complexities affecting medication communication between nurses and doctors helps to ensure inter-professional respect for each other's roles and inherent demands. Interdisciplinary education delivered in health care organisations would facilitate greater clarity in communication related to medications. Encouraging the use of concise, clear words in communication would help to promote improved understanding between parties, and accuracy and efficacy of medication management. This article is protected by copyright. All rights reserved.
Saponins are naturally-occurring units with broad diversity and are usually recognized as phytoanticipins. In order to develop new saponin chemical entities with high activity against Magnaporthe oryzae, we selected oleanolic acid (OA), which has wide natural distribution and rich content in plants. We used the ability of OA to act as an aglycone for glycosylation to obtain information on the structure-activity relationship (SAR) for rational molecular pesticide design. Oleanolic mono- or di-glycosides were synthesized at either the C3-hydroxy and/or C28-carboxyl position, using trichloroacetimidate or glycosyl bromide donors, respectively. Structures were confirmed by [(1)H]-,[(13)C]-NMR. Furthermore, the activity of the synthesized glycosides against M. oryzae was assessed in vitro, based on the mycelium growth rate. The twenty five oleanolic mono- or di-glycosides comprised fourteen saponins with 3-monosaccharide residue 1a-1n, six saponins with 28-monosaccharide residue 2a-2f, and five saponins with 3, 28-monosaccharide residue 3a-3e; all showed different activities against M. oryzae according to their different structures. We concluded that the optimal oleanolic mono- and di-glycoside structure for activity against M. oryzae is a C3 connection of a hexose such as mannose, galactose, or glucose, in combination with a C28 connection to a small group such as allyl or a C3 connection to a pentose accompanied by a larger group such as another pentose or heptenyl at C28.
Pecan (Carya illinoensis) has been introduced to East China for over one hundred years, but its planting is still only occurring at a small scale. The key limiting factor is its low yield. To enhance the yield pecan in East China, two pecan cultivars, Mahan and Western, were examined. Twenty traits describing phasic development, yield, nut quality, and cultural practice were investigated. We found that pecan cultivar Mahan gives a higher yield and nut quality than cultivar Western. We recommend interplanting of cultivar Pawnee to act as a pollinator tree. Appropriate cultivation practices that can be implemented to enhance fruit yield of cultivars Mahan and Western include soil-applied paclobutrazol (PBZ) at certain concentrations, pinching, and supplementary pollination. For example, the addition of 1.25 g/m(2) of PBZ inhibits pecan branch growth and stimulates short bearing branches, which promotes fruit yield. We found that soil-applied PBZ reached optimal performance 82 days after application. A pinching length of 40 cm resulted in a fruit yield increase. In addition, grafting and transplantation may promote male flowering, but delays female flowering. These cultural practices may provide insights that can be used to improve pecan cultivation in East China.
Significant ties exist between clinicians and industry. Little is known about the characteristics of industry payments to dermatologists.
To analyze the nature and extent of industry payments to dermatologists.
This was a retrospective review using the publicly available Centers for Medicare and Medicaid Services (CMS) Sunshine Act Open Payment database. Data were downloaded from the publically available CMS website under General Payment and Research Payment data sets. All payments to dermatologists from companies making products reimbursed by a government-run health program were reviewed.
Mean, median, and range of payments made, including quantity and total sum of payments, per clinician. Total payments and number of transactions per category of payment, geographic region, and payment source were also assessed.
A total of 8333 dermatologists received 208 613 payments totaling more than $34 million. The median total payment per dermatologist was $298 with an interquartile range of $99 to $844. The top 10% of dermatologists (n = 833) received more than $31.2 million, 90% of the total payments. The top 1% each (n = 83) received at least $93 622 and accounted for 44% of total payments. While 83% of payment entries were for food and beverage, they accounted for only 13% of total amount of payments. Speaker fees (31.7%), consulting fees (21.6%), and research payments (16.5%) comprised 69.8% of total payment amount. The top 15 companies were all pharmaceutical manufacturers and paid dermatologists $28.7 million, representing 81% of total disbursement.
Dermatologists received substantial payments from the pharmaceutical industry. The nature and amount of payments varied widely. The impact of the data on patient care, physicians practice patterns, and patient perception of physicians is unclear.
Layer Vb pyramidal cells are the major output neurons of the neocortex and transmit the outcome of cortical columnar signal processing to distant target areas. At the same time they contribute to local tactile information processing by emitting recurrent axonal collaterals into the columnar microcircuitry. It is, however, not known how exactly the two types of pyramidal cells, called slender-tufted and thick-tufted, contribute to the local circuitry. Here, we investigated in the rat barrel cortex the detailed quantitative morphology of biocytin-filled layer Vb pyramidal cells in vitro, which were characterized for their intrinsic electrophysiology with special emphasis on their action potential firing pattern. Since we stained the same slices for cytochrome oxidase, we could also perform layer- and column-related analyses. Our results suggest that in layer Vb the unambiguous action potential firing patterns "regular spiking (RS)" and "repetitive burst spiking (RB)" (previously called intrinsically burst spiking) correlate well with a distinct morphology. RS pyramidal cells are somatodendritically of the slender-tufted type and possess numerous local intralaminar and intracolumnar axonal collaterals, mostly reaching layer I. By contrast, their transcolumnar projections are less well developed. The RB pyramidal cells are somatodendritically of the thick-tufted type and show only relatively sparse local axonal collaterals, which are preferentially emitted as long horizontal or oblique infragranular collaterals. However, contrary to many previous slice studies, a substantial number of these neurons also showed axonal collaterals reaching layer I. Thus, electrophysiologically defined pyramidal cells of layer Vb show an input and output pattern which suggests RS cells to be more "locally segregating" signal processors whereas RB cells seem to act more on a "global integrative" scale.
Koumine is a kind of alkaloid extracted from Gelsemium elegans (G. elegans). Benth, which has shown promise as an anti-tumor, anxiolytic, and analgesic agent. In our present study, the effect of koumine on lipopolysaccharide (LPS)-mediated RAW 264.7 cell apoptosis was evaluated. MTT assays showed that koumine obviously increased cell viability in LPS-mediated RAW 264.7 macrophages. Preincubation with koumine ameliorated LPS-medicated apoptosis by decreasing reactive oxygen species (ROS) production, which resulted in a significant decrease in the levels of nitric oxide (NO) and inducible nitric oxide synthase (iNOS). In addition, koumine-pretreated RAW 264.7 macrophages exhibited reduction of LPS-induced levels of TNF-α, IL-1β, and IL-6 mRNA. Furthermore, pretreatment with koumine suppressed LPS-mediated p53 activation, loss of mitochondrial membrane potential, caspase-3 activation, decrease of Bcl-2 expression, and elevation of Bax and caspase-3 expressions, suggesting that koumine might act directly on RAW 264.7 cells to inhibit LPS-induced apoptosis. It seems as though the mechanism that koumine possesses is the anti-apoptotic effect mediated by suppressing production of ROS, activation of p53, and mitochondrial apoptotic pathways in RAW 264 cells. Koumine could potentially serve as a protective effect against LPS-induced apoptosis.
In this study, we determined efficient head model sizes relative to predicted current densities in transcranial direct current stimulation (tDCS).
Efficiency measures were defined based on a finite element (FE) simulations performed using nine human head models derived from a single MRI data set, having extents varying from 60%-100% of the original axial range. Eleven tissue types, including anisotropic white matter, and three electrode montages (T7-T8, F3-right supraorbital, Cz-Oz) were used in the models.
Reducing head volume extent from 100% to 60%, that is, varying the model's axial range from between the apex and C3 vertebra to one encompassing only apex to the superior cerebellum, was found to decrease the total modeling time by up to half. Differences between current density predictions in each model were quantified by using a relative difference measure (RDM). Our simulation results showed that [Formula: see text] was the least affected (a maximum of 10% error) for head volumes modeled from the apex to the base of the
 skull (60%-75% volume).
This finding suggested that the bone could act as a bioelectricity boundary and thus performing FE simulations of tDCS on the human head with models extending beyond the inferior skull may not be necessary in most cases to obtain reasonable precision in current density results.
Overexpression of the oncogene yes-associated-protein-1 (YAP1) is associated with increased cell proliferation in human cancers. YAP1 is a potential target of the Wnt/beta-catenin pathway, which plays an important role in adrenocortical tumors (ACT). The role of YAP1 in adrenocortical tumorigenesis has not been assessed.
To evaluate YAP1 expression in normal adrenals and pediatric ACT and its association with disease outcome. To investigate the interaction between YAP1 and the Wnt/beta-catenin pathway in adrenocortical cells.
Strong YAP1 staining was present in fetal adrenals and pediatric ACT but weak in postnatal adrenals. In pediatric ACT, YAP1 mRNA overexpression was associated with death, recurrent/metastatic disease and lower overall survival. The inhibition of the Wnt/beta-catenin pathway increased YAP1 mRNA expression. siYAP1 increased CTNNB1/beta-catenin expression and nuclear staining regardless of DLV2, moreover, it decreased cell growth and impaired cell migration.
We assessed in 42 pediatric ACT samples the YAP1 protein expression by immunohistochemistry and mRNA expression by RT-qPCR and analyzed their association with outcome. As controls, we resort 32 fetal and postnatal normal adrenals for IHC and 10 normal adrenal cortices for RT-qPCR. The interaction between YAP1 and the Wnt/beta-catenin pathway was assessed in NCI-H295 adrenocortical cells by inhibiting the TCF/beta-catenin complex and by knocking down YAP1.
YAP1 overexpression is a marker of poor prognosis for pediatric patients with ACT. In adrenocortical cells, there is a close crosstalk between YAP1 and Wnt/beta-catenin. These data open the possibility of future molecular therapies targeting Hippo/YAP1 signaling to treat advanced ACT.
Recent genome-wide omics studies have confirmed the early embryogenesis strictly dependent on the rigorous spatiotemporal activation and multilevel regulation. However, the full effect of functional pathway was not considered. To obtain complete understanding of the gene activation during early development, we performed systematic comparisons based on differential co-expression analysis for bovine preimplantation embryo development (PED). The results confirmed that the functional pathways actively transcribes as early as the 2-cell and 4-cell waves, which Basal transcription factor, Endocytosis and Spliceosome pathway can represent first signs of embryonic activity. Endocytosis act as one of master activators for uncovering a series of successive waves of maternal pioneer signal regulator with the help of Spliceosome complex. Furthermore, the results showed that pattern recognition receptors began to perform its essential function at 4-cell stage, which might be needed to coordinate the later major activation. And finally, our work presented a probable dynamic landscape of key functional pathways for embryogenesis. A clearer understanding of early embryo development will be helpful for Assisted Reproductive Technology (ART) and Regenerative Medicine (RM).
Previously, we reported that height is an indicator of the capacity of vascular repair in elderly men, especially hypertensive men. On the other hand, hemoglobin could act as a possible biochemical index of hypertension-induced vascular damage. However, no studies have clarified the correlation between height and hematopoietic activity. We conducted a cross-sectional study of 249 men aged 65-69 undergoing a general health check-up. Reticulocyte was used to evaluate hematopoietic activity. Because hemoglobin concentration should influence hematopoietic activity, analyses stratified by hemoglobin level were performed. Independent of known cardiovascular risk factors and other hematological parameters (white blood cell count), a significant positive correlation was seen between height and reticulocytes for total subjects and subjects with a high hemoglobin concentration (≥14.5 g/dL), but not in subjects with a low hemoglobin concentration (<14.5 g/dL). The standardized parameter estimates (β) were β=0.18, p=0.003 for total subjects, β=0.28, p=0.001 for subjects with a high hemoglobin concentration, and β=0.03, p=0.717 for subjects with low hemoglobin. Independently, height is significantly positively correlated with reticulocyte in elderly Japanese men, particularly in men with a high hemoglobin concentration. These results indicate that subjects with a short stature might have lower hematopoietic capacity than those with a high stature.
Oreochromis niloticus has been exposed to diclofenac (DCF), a nonsteroidal anti-inflammatory drug prevalent in the aquatic environment, for 80 days post-hatch (dph). Concentrations ranged from environmentally relevant (0.1 μg L(-1) and 1 μg L(-1) DCF) up to 100-fold thereof. Population relevant endpoints (hatching, survival, growth) as well as gill histopathology were analyzed. On this level of examination only gills exhibited mild to moderate alterations. On the contrary, biomarkers associated with reproduction were affected due to DCF exposure, indicating the potential to affect sexual differentiation and gametogenesis by acting as an estrogenic endocrine disrupting compound (EDC) in tilapia. Vitellogenin (VTG) gene expression was significantly induced at 1 μg L(-1) DCF. In order to find an explanation, gene expression patterns of key enzymes of the biotransformation phases I, II, and III have been analyzed. It seems very likely that the detoxification metabolism is induced in a dose dependent manner at higher concentrations of DCF leading to the expression pattern of VTG mRNA. Our results suggest that DCF at environmentally relevant concentrations adversely affects O. niloticus gill histopathology and pituitary gene expression, and has the potential to act as an estrogenic EDC. The sensitivity of various endpoints, however, differs and therefore these endpoints should be linked.
Predicting the water quality at mine sites is of significant importance for developing mines with respect for the environment. Acid mine drainage (AMD) occurs when sulfides are in contact with oxygen and water, and several parameters and mechanisms influence final drainage quality. Galvanic interactions influence the reactivity of sulfide minerals, which act as semi-conductors. These galvanic interactions have been insufficiently studied in the context of AMD generation. In this study, the influence of pyrite on the reactivity of sphalerite and chalcopyrite was investigated. Five blends, comprised of free grains of quartz/pyrite, quartz/chalcopyrite, quartz/sphalerite, quartz/pyrite/chalcopyrite, and quartz/pyrite/sphalerite, were subjected to geochemical testing. Five weathering cells were monitored over a 200-day period during which they were leached twice weekly. Leachates were analyzed for pH, Eh, electrical conductivity, and sulfate and metal concentrations. The results of these analyses showed that galvanic interactions occurred between free sulfide grains. Pyrite was galvanically protected over the full testing period in the quartz/pyrite/chalcopyrite blend, and partially protected in the quartz/pyrite/sphalerite blend. Moreover, the release of Cu from chalcopyrite and Zn, Mn, and Cd from sphalerite was accelerated in the presence of pyrite. This work provides a better understanding of the influence of pyrite on chalcopyrite and sphalerite reactivity by highlighting the galvanic effects. In the future, to improve the reliability of AMD prediction tests, galvanic interactions should be considered in both the prediction of the acid generation potential and the estimation of metal and metalloid release rates.
Proline dehydrogenase (PRODH), which degrades L-proline, resides within the schizophrenia-linked 22q11.2 deletion suggesting a role in disease. Supporting this, elevated L-proline levels have been shown to increase risk for psychotic disorders. Despite the strength of data linking PRODH and L-proline to neuropsychiatric diseases, targets of disease-relevant concentrations of L-proline have not been convincingly described. Here, we show that Prodh-deficient mice with elevated CNS L-proline display specific deficits in high-frequency GABA-ergic transmission and gamma-band oscillations. We find that L-proline is a GABA-mimetic and can act at multiple GABA-ergic targets. However, at disease-relevant concentrations, GABA-mimesis is limited to competitive blockade of glutamate decarboxylase leading to reduced GABA production. Significantly, deficits in GABA-ergic transmission are reversed by enhancing net GABA production with the clinically relevant compound vigabatrin. These findings indicate that accumulation of a neuroactive metabolite can lead to molecular and synaptic dysfunction and help to understand mechanisms underlying neuropsychiatric disease.
Fast excitatory synaptic signaling in the mammalian brain is mediated by AMPA-type ionotropic glutamate receptors. In neurons, AMPA receptors co-assemble with auxiliary proteins, such as stargazin, which can markedly alter receptor trafficking and gating. Here, we used luminescence resonance energy transfer measurements to map distances between the full-length, functional AMPA receptor and stargazin expressed in HEK293 cells and to determine the ensemble structural changes in the receptor due to stargazin. In addition, we used single-molecule fluorescence resonance energy transfer to study the structural and conformational distribution of the receptor and how this distribution is affected by stargazin. Our nanopositioning data place stargazin below the AMPA receptor ligand-binding domain, where it
 is well poised to act as a scaffold to facilitate the long-range conformational selection observations seen in single-molecule experiments. These data support a model of stargazin acting to stabilize or select conformational states that favor activation.
Toxoplasma gondii and Neospora caninum are widespread cyst-forming coccidian parasites of the subfamily Toxoplasmatinae that infect a wide range of wild and domestic animals. Whereas T. gondii is a zoonotic disease, N. caninum is restricted to nonhuman animals. Some chiropteran species can be infected by T. gondii and present fatal toxoplasmosis. In most cases, T. gondii -infected bats are believed to remain asymptomatic and to act as an infection source to other animals. It is not known whether N. caninum can infect bats. We determined infection rates of T. gondii and N. caninum in free-living bats in the state of Bahia, Brazil. Brain samples from 97 bats of seven species, captured in 2008-15, were analyzed by PCRs for T. gondii and N. caninum . Two of the 97 samples were positive for T. gondii DNA. None of the samples were positive for N. caninum DNA, suggesting that the bats were not susceptible to N. caninum infection or that its prevalence was very low.
This study determined the relationship between self-reported and objective measurements of physical activity with adiposity markers in a randomly sample of community-dwelling older adults. The sample included 439 individuals over 65 years (age 71.1±7.8; 54.2% women). Regular physical activity information was collected using self-reported (questionnaire, 7-day-PAR) and objective measurements (accelerometer ActiGraph GT3X) over 7 days. Anthropometric parameters included body mass index, body fat percentage and waist circumference. The number of patients considered active was 28% according to the results of 7-day-PAR, and 69% according to objective measures of accelerometry. With every daily increase of 10 minutes of sedentary activity, the BMI, body fat percentage and waist circumference values increased by 0.04 units, 0.14% and 0.14 cm respectively. According to the accelerometry data, being active was a protective factor for presenting obesity criteria (OR=0.34, CI95 % 0.19-0.59). Objective but non self-reported physical activity was associated with adiposity markers in older adults.
The purpose of this study was to investigate the effects of the addition of a dual task to multicomponent training on cognition of active older adults. Eighty physically active older adults were divided into an intervention group (IG) and a control group (CG). Both groups performed multicomponent training over 12 weeks. The IG simultaneously performed exercises and cognitive tasks. The Mini-Mental State Examination, the Montreal Cognitive Assessment and the Clock Drawing Test were used for cognitive assessments. The Timed Up and Go Test (TUGT) associated with a cognitive task was used for dual task assessment. Significant interactions were not observed between groups in terms of the cognitive variables or the single cognitive task. An interaction was observed only for TUGT performance, which was better in the CG than in the IG. Active older adults showed no improvement in cognition following the addition of the dual task to the multicomponent training.
Positive physiologic and cognitive responses to aerobic exercise have resulted in a proposed cardiorespiratory (CR) fitness hypothesis in which fitness gains drive changes leading to cognitive benefit. The purpose of this study was to directly assess the CR fitness hypothesis. Using data from an aerobic exercise trial, we examined individuals who completed cardiopulmonary and cognitive testing at baseline and 26 weeks. Change in cognitive test performance was not related to CR fitness change (r(2)=0.06, p=0.06). However, in the subset of individuals who gave excellent effort during exercise testing, change in cognitive test performance was related to CR fitness change (r(2)=0.33, p<0.01). This was largely due to change in the cognitive domain of Attention (r(2)=0.36, p<0.01). The magnitude of change was not explained by duration of exercise. Our findings support further investigation of the CR fitness hypothesis and mechanisms by which physiologic adaptation may drive cognitive change.
The aim of this study was to identify determinants of walking and whether walking maintained mobility among women as they transition from their mid-70s to their late 80s. We used 12 years of follow-up data (baseline 1999) from the Australian Longitudinal Study on Women's Health (n=10,322). Fifteen determinants of walking were included in the analysis and three indicators of mobility. Longitudinal data analyses techniques were employed. Thirteen of the 15 determinants were significant predictors of walking. Women in their mid-70s who walked up to one hour per week were less likely to experience loss of mobility in very old age, including reduced likelihood of using a mobility aid. Hence, older women who do no walking should be encouraged to walk to maintain their mobility and their independence as they age, particularly women in their 70s and 80s who smoke, are overweight, have arthritis or who have had a recent fall.
The purpose of this study was to examine age-related gait characteristics and their associations with balance function in older adults. A total of 51 adult volunteers participated. All subjects underwent locomotion analysis using a 3D motion analysis and 12-channel dynamic electromyography system. Dynamic balance function was assessed by the Berg Balance Scale. Older adults showed a higher level of muscle activation than young adults, and there were significant positive correlations between increased age and activation of the trunk and thigh muscles in the stance and swing phase of the gait cycle. In particular, back extensor muscle activity was mostly correlated with the dynamic balance in older adults. Thus, back extensor muscle activity in walking may provide a clue for higher falling risk in older adults. This study demonstrates that the back extensor muscles play very important roles with potential for rehabilitation training to improve balance and gait in older adults.
There is now general agreement that neurokinin B (NKB) acts via neurokinin-3-receptor (NK3R) to stimulate secretion of GnRH and LH in several species, including rats, mice, sheep, and humans. However, the roles of two other tachykinins, substance P (SP) and neurokinin A, which act primarily via NK1R and NK2R, respectively, are less clear. In rodents, these signaling pathways can stimulate LH release and substitute for NKB signaling; in humans, SP is colocalized with kisspeptin and NKB in the mediobasal hypothalamus. In this study, we examined the possible role of these tachykinins in control of the reproductive axis in sheep. Immunohistochemistry was used to describe the expression of SP and NK1R in the ovine diencephalon and determine whether these proteins are colocalized in kisspeptin or GnRH neurons. SP-containing cell bodies were largely confined to the arcuate nucleus, but NK1R-immunoreactivity was more widespread. However, there was very low coexpression of SP or NK1R in kisspeptin cells and none in GnRH neurons. We next determined the minimal effective dose of these three tachykinins that would stimulate LH secretion when administered into the third ventricle of ovary-intact anestrous sheep. A much lower dose of NKB (0.2 nmol) than of neurokinin A (2 nmol) or SP (10 nmol) consistently stimulated LH secretion. Moreover, the relative potency of these three neuropeptides parallels the relative selectivity of NK3R. Based on these anatomical and pharmacological data, we conclude that NKB-NK3R signaling is the primary pathway for the control of GnRH secretion by tachykinins in ewes.
Corrosion-protective coatings for silicate glass based on the transfer of one or two layers of graphene grown on copper by chemical vapor deposition have been demonstrated. The effectiveness of graphene to act as a glass corrosion inhibitor was evaluated by water immersion testing. After 120 days of immersion in water, bare glass samples had a significant increase in surface roughness and defects, which resulted in a marked reduction in fracture strength. In contrast, the single- and double-layer graphene-coated glasses experienced negligible changes in both fracture strength and surface roughness. The anticorrosion mechanism was also studied.
The loading of noble-metal nanoparticles (NMNPs) onto various carriers to obtain stable and highly efficient catalysts is currently an important strategy in the development of noble metal (NM)-based catalytic reactions and their applications. We herein report a nanowire supramolecular assembly constructed from the surfactant-encapsulating polyoxometalates (SEPs) CTAB-PW12 , which can act as new carriers for NMNPs. In this case, the Ag NPs are loaded onto the SEP nanowire assembly with a narrow size distribution from 5 to 20 nm in diameter; the average size is approximately 10 nm. The Ag NPs on the nanowire assemblies are well stabilized and the over agglomeration of Ag NPs is avoided owing to the existence of well-arranged polyoxometalate (POM) units in the SEP assembly and the hydrophobic surfactant on the surface of the nanowire assembly. Furthermore, the loading amount of the Ag NPs can be adjusted by controlling the concentration of the AgNO3 aqueous solution. The resultant Ag/CTAB-PW12 composite materials exhibit high activity and good stability for the catalytic reduction of 4-nitrophenol (4-NP) with NaBH4 in isopropanol/H2 O solution. The NMNPs-loaded SEP nanoassembly may represent a new composite catalyst system for application in NM-based catalysis.
Extinctions typically have ecological drivers, such as habitat loss. However, extinction events are also influenced by policy and management
 settings that may be antithetical to biodiversity conservation, inadequate to prevent extinction, insufficiently resourced, or poorly implemented. Three endemic Australian vertebrate species-the Christmas Island pipistrelle (Pipistrellus murrayi), Bramble Cay melomys (Melomys rubicola), and Christmas Island forest skink (Emoia nativitatis)-became extinct from 2009 to 2014. All 3 extinctions were predictable and probably preventable. We sought to identify the policy, management, research, and other shortcomings that contributed to their extinctions or failed to prevent them. These included a lack within national environmental legislation and policy of explicit commitment to the prevention of avoidable extinctions, lack of explicit accountability, inadequate resources for conservation (particularly for species not considered charismatic or not of high taxonomic distinctiveness), inadequate biosecurity, a slow and inadequate process for listing species as threatened, recovery planning that failed to consider the need for emergency response, inability of researchers to identify major threatening factors, lack of public engagement and involvement in conservation decisions, and limited advocacy. From these 3 cases, we recommend: environmental policy explicitly seeks to prevent extinction of any species and provides a clear chain of accountability and an explicit requirement for public inquiry following any extinction; implementation of a timely and comprehensive process for listing species as threatened and for recovery planning; reservation alone not be assumed sufficient to maintain species; enhancement of biosecurity measures; allocation of sufficient resources to undertake actions necessary to prevent extinction; monitoring be considered a pivotal component of the conservation response; research provides timely identification of factors responsible for decline and of the risk of extinction; effective dissemination of research results; advocacy by an informed public for the recovery of threatened species; and public involvement in governance of the recovery process. These recommendations should be applicable broadly to reduce the likelihood and incidence of extinctions.
Diabetic patients have a higher fracture risk than expected by their bone mineral density (BMD). Poor bone quality is the most suitable and explainable cause for the elevated fracture risk in this population. Advanced glycation end products (AGEs), which are diverse compounds generated via a non-enzymatic reaction between reducing sugars and amine residues, physically affect the properties of the bone material, one of a component of bone quality, through their accumulation in the bone collagen fibers. On the other hand, these compounds biologically act as agonists for these receptors for AGEs (RAGE) and suppress bone metabolism. The concentrations of AGEs and endogenous secretory RAGE, which acts as a "decoy receptor" that inhibits the AGEs-RAGE signaling axis, are associated with fracture risk in a BMD-independent manner. AGEs are closely associated with the pathogenesis of this unique clinical manifestation through physical and biological mechanisms in patients with diabetes mellitus.
This piece returns to the writer's memoir essays about her mother's chronic lung disease to examine the relationship between the act of caregiving and the act of writing. In arguing for important differences between the clinical, healing imperatives of narrative medicine and the primacy for the writer of self-reflection, personal need and career, the essay demonstrates how writing remains in many ways at odds with the obligations and the hopes of caregiving. At the same time, the essay argues that writing her mother's stories of illness holds the potential for both honor and mutuality-and can, in fact, constitute a form of caregiving.
High mobility group box 1 (HMGB1) is a DNA-binding protein that facilitates gene transcription and may act extracellularly as a late mediator of inflammation. The roles of HMGB1 in the pathogenesis of the spiral ganglion neurons (SGNs) of the cochlea are currently unknown. In the present study, we tested the hypothesis that early phenotypical changes in the SGNs of the amikacin-poisoned rat cochlea are mediated by HMGB1. Our results showed that a marked downregulation of HMGB1 had occurred by completion of amikacin treatment, coinciding with acute damage at the dendrite extremities of the SGNs. A few days later, during the recovery of the SGN dendrites, the protein was re-expressed and transiently accumulated within the nuclei of the SGNs. The phosphorylated form of the transcription factor c-Jun (p-c-Jun) was concomitantly detected in the nuclei of the SGNs where it often co-localized with HMGB1, while the anti-apoptotic protein BCL2 was over-expressed in the cytoplasm. In animals co-treated with amikacin and the histone deacetylase inhibitor trichostatin A, both HMGB1 and p-c-Jun were exclusively found within the cytoplasm. The initial disappearance of HMGB1 from the affected SGNs may be due to its release into the external medium, where it may have a cytokine-like function. Once re-expressed and translocated into the nucleus, HMGB1 may facilitate the transcriptional activity of p-c-Jun, which in turn may promote repair mechanisms. Our study therefore suggests that HMGB1 can positively influence the survival of SGNs following ototoxic exposure via both its extracellular and intranuclear functions.
Since the listing of Acropora palmata and A. cervicornis under the US Endangered Species Act in 2006, increasing investments have been made in propagation of listed corals (primarily A. cervicornis, A. palmata to a much lesser extent) in offshore coral nurseries and outplanting cultured fragments to reef habitats. This investment is superimposed over a spatiotemporal patchwork of ongoing disturbances (especially storms, thermal bleaching, and disease) as well as the potential for natural population recovery. In 2014 and 2015, we repeated broad scale (>50 ha), low precision Acropora spp. censuses (i.e., direct observation by snorkelers documented via handheld GPS) originally conducted in appropriate reef habitats during 2005-2007 to evaluate the trajectory of local populations and the effect of population enhancement. Over the decade-long study, A. palmata showed a cumulative proportional decline of 0.4 -0.7x in colony density across all sites, despite very low levels of outplanting at some sites. A. cervicornis showed similar proportional declines at sites without outplanting. In contrast, sites that received A. cervicornis outplants showed a dramatic increase in density (over 13x). Indeed, change in A. cervicornis colony density was significantly positively correlated with cumulative numbers of outplants across sites. This study documents a substantive reef-scale benefit of Acropora spp. population enhancement in the Florida Keys, when performed at adequate levels, against a backdrop of ongoing population decline.
The volume of the hippocampus is reduced in patients with schizophrenia, and this deficit tends to become more pronounced with chronicity. Newer antipsychotics may protect against the progressive reductions in hippocampal volume while preliminary data offer hope that specific antipsychotics may act to reverse it.
None.
© The Royal College of Psychiatrists 2016. This is an open access article distributed under the terms of the Creative Commons Non-Commercial, No Derivatives (CC BY-NC-ND) licence.
Bacteroides fragilis, member from commensal gut microbiota, is an important pathogen associated to endogenous infections and metronidazole remains a valuable antibiotic for the treatment of these infections, although bacterial resistance is widely reported. Considering the need of a better understanding on the global mechanisms by which B. fragilis survive upon metronidazole exposure, we performed a RNA-seq transcriptomic approach with validation of gene expression results by qPCR. Bacteria strains were selected after in vitro subcultures with subinhibitory concentration (SIC) of the drug. From a wild type B. fragilis ATCC 43859 four derivative strains were selected: first and fourth subcultures under metronidazole exposure and first and fourth subcultures after drug removal. According to global gene expression analysis, 2,146 protein coding genes were identified, of which a total of 1,618 (77%) were assigned to a Gene Ontology term (GO), indicating that most known cellular functions were taken. Among these 2,146 protein coding genes, 377 were shared among all strains, suggesting that they are critical for B. fragilis survival. In order to identify distinct expression patterns, we also performed a K-means clustering analysis set to 15 groups. This analysis allowed us to detect the major activated or repressed genes encoding for enzymes which act in several metabolic pathways involved in metronidazole response such as drug activation, defense mechanisms against superoxide ions, high expression level of multidrug efflux pumps, and DNA repair. The strains collected after metronidazole removal were functionally more similar to those cultured under drug pressure, reinforcing that drug-exposure lead to drastic persistent changes in the B. fragilis gene expression patterns. These results may help to elucidate B. fragilis response during metronidazole exposure, mainly at SIC, contributing with information about bacterial survival strategies under stress conditions in their environment.
Depression is a major mental disorder, and is currently recognized as the second-leading cause of disability worldwide. However, the therapeutic effect of antidepressants remains unsatisfactory. For centuries, Chinese herbal formulas (CHFs) have been widely used in the treatment of depression, achieving better therapeutic effects than placebo and having fewer side effects
 than conventional antidepressants. Here, we review the ethnopharmacology, phytochemistry, and pharmacology studies of nine common CHFs: "banxia houpo" decoction, "chaihu shugansan", "ganmaidazao" decoction, "kaixinsan", "shuganjieyu" capsules, "sinisan", "wuling" capsules, "xiaoyaosan", and "yueju". Eight clinical trials and seven meta-analyses have supported the theory that CHFs are effective treatments for depression, decreasing Hamilton Depression Scale scores and showing few adverse effects. Evidence from 75 preclinical studies has also elucidated the multitarget and multipathway mechanisms underlying the antidepressant effect of the nine CHFs. Decoctions, capsules, and pills all showed antidepressant effects, ranked in descending order of efficacy. According to traditional Chinese medicine theory, these CHFs have flexible compatibility and mainly act by soothing the liver and relieving depression. This review highlights the effective treatment choices and candidate compounds for patients, practitioners, and researchers in the field of traditional Chinese medicine. In summary, the current evidence supports the efficacy of CHFs in the treatment of depression, but additional large-scale randomized controlled clinical trials and sophisticated pharmacology studies should be performed.
Heritable microbes represent an important component of the biology, ecology and evolution of many plants, animals and fungi, acting as both parasites and partners. In this review, we examine how heritable symbiont-host interactions may alter host thermal tolerance, and how the dynamics of these interactions may more generally be altered by thermal environment. Obligate symbionts, those required by their host, are considered to represent a thermally sensitive weak point for their host, associated with accumulation of deleterious mutations. As such, these symbionts may represent an important determinant of host thermal envelope and spatial distribution. We then examine the varied relationship between thermal environment and the frequency of facultative symbionts that provide ecologically contingent benefits or act as parasites. We note that some facultative symbionts directly alter host thermotolerance. We outline how thermal environment will alter the benefits/costs of infection more widely, and additionally modulate vertical transmission efficiency. Multiple patterns are observed, with symbionts being cold sensitive in some species and heat sensitive in others, with varying and non-coincident thresholds at which phenotype and transmission are ablated. Nevertheless, it is clear that studies aiming to predict ecological and evolutionary dynamics of symbiont-host interactions need to examine the interaction across a range of thermal environments. Finally, we discuss the importance of thermal sensitivity in predicting the success/failure of symbionts to spread into novel species following natural/engineered introduction.Heredity advance online publication, 5 October 2016; doi:10.1038/hdy.2016.71.
In coordination chemistry and crystal engineering, many factors influence the construction of coordination polymers and the final frameworks depend greatly on the organic ligands used. N-Donor ligands with diverse coordination modes and conformations have been employed to assemble metal-organic frameworks. Carboxylic acid ligands can deprotonate completely or partially when bonding to metal ions and can also act as donors or acceptors of hydrogen bonds and are thus good candidates for the construction of supramolecular architectures. Two new transition metal complexes, namely poly[diaqua(μ4-1,4-bis{[1-(pyridin-3-ylmethyl)-1H-benz[d]imidazol-2-yl]methoxy}benzene)bis(μ2-isophthalato)dicobalt(II)], [Co(C8H4O4)(C34H28N6O2)0.5(H2O)]n, (1), and poly[diaqua(μ4-1,4-bis{[1-(pyridin-3-ylmethyl)-1H-benz[d]imidazol-2-yl]methoxy}benzene)bis(μ2-isophthalato)dicadmium(II)], [Cd(C8H4O4)(C34H28N6O2)0.5(H2O)]n, have been constructed using a symmetric N-donor ligand and a carboxylate ligand under hydrothermal conditions. X-ray crystallographic studies reveal that complexes (1) and (2) are isostructural, both of them exhibiting three-dimensional supramolecular architectures built by hydrogen bonds in which the coordinated water molecules serve as donors, while the O atoms of the carboxylate groups act as acceptors. Furthermore, (1) and (2) have been characterized by elemental, IR spectroscopic, powder X-ray diffraction (PXRD) and thermogravimetric analyses. The UV-Vis absorption spectrum of complex (1) has also been investigated.
To investigate the antimicrobial resistance and assess the molecular characteristics of β-lactamases (ESBLs, AmpC β-lactamases and carbapenemases) among Enterobacteriaceae isolates that caused intra-abdominal infections (IAIs) in patients hospitalized in the Asia-Pacific region during 2008-14.
Multiplex PCR was used to detect the specific types of β-lactamase in 2893 isolates with MICs of ertapenem >0.5 mg/L. In-hospital acquisition times for most isolates were also delineated.
Among 2728 (94.3%) isolates proven with β-lactamase production, the rates of non-susceptibility to imipenem were low (average = 7.9%) among IAI Enterobacteriaceae isolates from all Asia-Pacific countries except Vietnam (17.7%) and the Philippines (10.2%). A stepwise and significant increase in annual rates of carbapenemase production among these isolates was noted. CTX-M-15 and CTX-M-14 were the dominant ESBL variants in most IAI Enterobacteriaceae species. The most abundant AmpC β-lactamase variants were blaCMY-2 among isolates of Escherichia coli and blaDHA-1 among isolates of Klebsiella pneumoniae. In addition, the IAI Enterobacteriaceae isolates harbouring a blaCMY-2 or blaDHA-1 allele were associated with high community-acquired rates (38.0% and 42.6%, respectively). AmpC ACT and MIR variants were mostly detected in Enterobacter species. The blaNDM-1,4,5,7-harbouring isolates of E. coli, K. pneumoniae and Enterobacter cloacae were most commonly identified among IAI isolates from Vietnam and the Philippines. Also of note, blaOXA-48-harbouring IAI Enterobacteriaceae isolates were detected exclusively in Vietnam.
The high resistance burden in Vietnam and the Philippines warrants aggressive control policies to combat the worsening trend in antimicrobial resistance among Enterobacteriaceae species causing IAIs.
In C4 species, the major β-carbonic anhydrase (β-CA) localized in the mesophyll cytosol catalyses the hydration of CO2 to HCO3(-), which phosphoenolpyruvate carboxylase uses in the first step of C4 photosynthesis. To address the role of CA in C4 photosynthesis, we generated transgenic Setaria viridis depleted in β-CA. Independent lines were identified with as little as 13% of wild-type CA. No photosynthetic defect was observed in the transformed lines at ambient CO2 partial pressure (pCO2). At low pCO2, a strong correlation between CO2 assimilation rates and CA hydration rates was observed. C(18)O(16)O isotope discrimination was used to estimate the mesophyll conductance to CO2 diffusion from the intercellular air space to the mesophyll cytosol (gm) in control plants, which allowed us to calculate CA activities in the mesophyll cytosol (Cm). This revealed a strong relationship between the initial slope of the response of the CO2 assimilation rate to cytosolic pCO2 (ACm) and cytosolic CA activity. However, the relationship between the initial slope of the response of CO2 assimilation to intercellular pCO2 (ACi) and cytosolic CA activity was curvilinear. This indicated that in S. viridis, mesophyll conductance may be a contributing limiting factor alongside CA activity to CO2 assimilation rates at low pCO2.
The introduction of health insurance Marketplaces under the Affordable Care Act has been associated with growth of restricted provider networks. The value of this plan design strategy, including its association with lower premiums, is uncertain. We used data from all silver plans offered in the 2014 health insurance exchanges in the fifty states and the District of Columbia to estimate the association between the breadth of a provider network and plan premiums. We found that within a market, for plans of otherwise equivalent design and controlling for issuer-specific pricing strategy, a plan with an extra-small network had a monthly premium that was 6.7 percent less expensive than that of a plan with a large network. Because narrow networks remain an important strategy available to insurance companies to offer lower-cost plans on health insurance Marketplaces, the success of health insurance coverage expansions may be tied to the successful implementation of narrow networks.
The Children's Health Insurance Program (CHIP) is a success story. CHIP has contributed greatly to ensuring affordable insurance and access to medical services for millions of children. The 2015 two-year extension of CHIP funding appeared to confirm its longstanding status as a bipartisan program. Yet that appearance obscures important changes in CHIP politics. In recent years, there have been calls to end the program, and its bipartisan coalition has frayed. In this article we analyze CHIP's funding extension, explore its shifting political environment, and discuss the implications for the program's future.
Changes in insurance coverage over time, or "churning," may have adverse consequences, but there has been little evidence on churning since implementation of the major coverage expansions in the Affordable Care Act (ACA) in 2014. We explored the frequency and implications of churning through surveying 3,011 low-income adults in Kentucky, which used a traditional expansion of Medicaid; Arkansas, which chose a "private option" expansion that enrolled beneficiaries in private Marketplace plans; and Texas, which opted not to expand. We also compared 2015 churning rates in these states
 to survey data from 2013, before the coverage expansions. Nearly 25 percent of respondents in 2015 changed coverage during the previous twelve months-a rate lower than some previous predictions. We did not find significantly different churning rates in the three states over time. Common causes of churning were job-related changes and loss of eligibility for Medicaid or Marketplace subsidies. Churning was associated with disruptions in physician care and medication adherence, increased emergency department use, and worsening self-reported quality of care and health status. Even churning without gaps in coverage had negative effects. Churning remains a challenge for many Americans, and policies are needed to reduce its frequency and mitigate its negative impacts.
The Affordable Care Act transformed health care in the United States. What hasn't changed is the partisan landscape in which it became law.
The model 3-D structure of xylanase KRICT PX3 (JF320814) identified by DNA sequence analysis revealed a catalytic domain and CBM4-9 which functions as a xylan binding domain (XBD). To identify its role in xylan hydrolysis, six expression plasmids were constructed encoding the N-terminal CBM plus the catalytic domain or different glycosyl hydrolases, and the biochemical properties of the recombinant enzymes were compared to the original structure of PX3 xylanase. All six of the recombinant xylanases with the addition of CBM in the pIVEX-GST expression vector showed no improved PX3 hydrolytic activity. However, the absence of the CBM domain resulted in a decrement of 40% in thermostability, movement of the optimal temperature from 55°C to 45°C, alteration of the optimal pH range from 5-10 to 6-8, and reduction of the enzymatic activity to one-second under the same condition, respectively. The putative XBD in PX3 comprises a new N-terminal domain homologous to the catalytic thermostabilizing domains from other xylanases. Analysis of the main products released from xylan indicate that the recombinant enzymes act as endo-1,4-β-xylanases but differ in their hydrolysis of xylan from beech wood, birch wood, and oat spelt.
Before the introduction of the Dutch Human Fertilisation (Donor Information) Act (in Dutch: Wet Donorgegevens Kunstmatige Bevruchting) in 2004, approximately 40,000 donor-conceived offspring were born in the Netherlands. The majority is conceived by means of artificial insemination with anonymous donor sperm (in Dutch: kunstmatige inseminatie met anoniem donorzaad - KID). This means that they have little or no access to information about their genetic origins. Through the Fiom KID-DNA Databank, established in 2010 in association with the Canisius Wilhelmina Hospital, it is possible for these donor-conceived offspring and donors to search for one another. DNA profiles are used to match donor-conceived offspring, donors and half-siblings. It is expected that the number of donor-related searches will increase. The experiences with matching and counselling of donor-conceived offspring and donors presented in this paper will help donor-conceived offspring and donors who start a search in the future. Moreover, they provide guidance for forming a meaningful relationship between those involved.
Lifestyle and family history are two of the most important risk factors for breast cancer (BC). However, these risk factors cannot explain the differences in the incidence and early BC onset among Chinese females compared to their western counterparts. We propose in this hypothesis the potential mechanism of indirect oncogenesis of hepatitis B virus (HBV) in causing BC through its persistence as occult infection and continuous replication with long term subtle liver damage. Estrogen is mainly deactivated in the liver and long term necro-inflammatory damage to liver may result in persistent high level of estrogen, which is a dominant risk factor for BC. HBV may also directly affect the breast cells through its cis and trans effects of HBx which may act as oncoprotein. Given the recognised aetiologic association between oestrogen and breast cancer risk, there is biological plausibility that dietary soy and vegetable intake which is rich in the Chinese diet may have anti-carcinogenic effect on the breast. The seemingly conflicting phenomenon of early age onset and lower BC incidence in China might be due to wide imbalance in the amount of exposure to carcinogenic factor (e.g., HBV infection) for decades and the carcinoprotective exposure levels (e.g., isoflavonoids and flavonoids intake). For example, the increase in carcinoprotective levels would lead to lower incidence of breast cancer and vice versa. Although the focus of this personal view is on HBV, this by no means negates the roles of other known risk factors in breast-cancer development. Characterisation of the role of HBV in BC could potentially benefit Chinese females by decreasing incidence and increasing overall survival.
A series of encapsulated and non-encapsulated bulk heterojunction photovoltaic devices containing poly(3-hexylthiophene) (P3HT) and [6,6]-phenyl C61 butyric acid methyl ester (PCBM) with different P3HT:PCBM ratios were investigated using traditional steady state as well as non-steady state intensity modulated photocurrent spectroscopy (IMPS) techniques. The steady state J-V measurements showed that PCBM content did not have a significant effect on the efficiency for freshly prepared devices, whereas aged non-encapsulated devices exhibited a strong dependence on PCBM content. IMPS measurements showed a significant contribution of interfacial non-geminate recombination in non-encapsulated devices, which increased with decreasing PCBM content in the photoactive layer and cell aging. It was related to the formation of interfacial states at the P3HT/PCBM interface due to atmospheric contamination, which act as recombination centers. Device encapsulation was found to be effective in preventing the occurrence of interfacial recombination. Our results suggest that IMPS can be used as a diagnostic tool to predict the performance of bulk heterojunction organic solar cells. If a solar cell shows the presence of interfacial states as indicated by semicircle arcs in quadrant I of the IMPS complex plane plots, it is most likely that its performance will deteriorate with time due to enhanced interfacial recombination, even without further exposure to atmospheric contaminations. We conclude that interfacial non-geminate recombination is an important degradation mechanism in organic solar cells, especially in case of exposure to atmospheric contaminants.
In this account, studies on the photosensitizing electron transfer of nanocarbons, such as fullerenes, single-walled carbon nanotubes (SWCNTs), and carbon nanohorns (CNH), performed in our laboratory for about 15 years in the early 21st century have been briefly reviewed. These novel nanocarbons act as excellent electron acceptors, when they are linked to light-absorbing electron donors, such as porphyrins or phthalocyanines. For such molecule-nanocarbon hybrids, the direct confirmation of fast, transient, electron-transfer phenomena must be performed with time-resolved spectroscopic methods, such as transient absorption spectral measurements, in addition to fluorescence time-profile measurements in the wide-wavelength regions. Careful use of these methods affords useful information to understand photoinduced electron-transfer mechanisms. In addition, kinetic data obtained by these methods can assist in the construction of light-active devices, such as photovoltaic cells and solar H2 -generation systems.
Artemisinin resistance observed in Southeast Asia threatens the continued use of artemisinin-based combination therapy in endemic countries. Additionally, the diversity of chemical mode of action in the global portfolio of marketed antimalarials is extremely limited. Addressing the urgent need for the development of new antimalarials, a chemical class of potent antimalarial compounds with a novel mode of action was recently identified. Herein, the preclinical characterization of one of these compounds, ACT-451840, conducted in partnership with academic and industrial groups is presented.
The properties of ACT-451840 are described, including its spectrum of activities against multiple life cycle stages of the human malaria parasite Plasmodium falciparum (asexual and sexual) and Plasmodium vivax (asexual) as well as oral in vivo efficacies in two murine malaria models that permit infection with the human and the rodent parasites P. falciparum and Plasmodium berghei, respectively. In vitro, ACT-451840 showed a 50% inhibition concentration of 0.4 nM (standard deviation [SD]: ± 0.0 nM) against the drug-sensitive P. falciparum NF54 strain. The 90% effective doses in the in vivo efficacy models were 3.7 mg/kg against P. falciparum (95% confidence interval: 3.3-4.9 mg/kg) and 13 mg/kg against P. berghei (95% confidence interval: 11-16 mg/kg). ACT-451840 potently prevented male gamete formation from the gametocyte stage with a 50% inhibition concentration of 5.89 nM (SD: ± 1.80 nM) and dose-dependently blocked oocyst development in the mosquito with a 50% inhibitory concentration of 30 nM (range: 23-39). The compound's preclinical safety profile is presented and is in line with the published results of the first-in-man study in healthy male participants, in whom ACT-451840 was well tolerated. Pharmacokinetic/pharmacodynamic (PK/PD) modeling was applied using efficacy in the murine models (defined either as antimalarial activity or as survival) in relation to area under the concentration versus time curve (AUC), maximum observed plasma concentration (Cmax), and time above a threshold concentration. The determination of the dose-efficacy relationship of ACT-451840 under curative conditions in rodent malaria models allowed prediction
 of the human efficacious exposure.
The dual activity of ACT-451840 against asexual and sexual stages of P. falciparum and the activity on P. vivax have the potential to meet the specific profile of a target compound that could replace the fast-acting artemisinin component and harbor additional gametocytocidal activity and, thereby, transmission-blocking properties. The fast parasite reduction ratio (PRR) and gametocytocidal effect of ACT-451840 were recently also confirmed in a clinical proof-of-concept (POC) study.
We provide a taxonomic revision of the genus Crenadactylus, a group of very small clawless geckos from western and central Australia, with currently only one recognized species and four subspecies. Morphological comparisons were made on genotyped specimens from two recent genetic studies, then with an expanded sample to encompass all specimens to determine diagnostic characters in addition to morphological and geographic boundaries. Based on our findings, we           elevate the subspecies Crenadactylus ocellatus ocellatus from south-western Australia and C. o. horni from the Central Uplands to full species. Consultation of the types of Diplodactylus (= Crenadactylus) bilineatus indicate they are                 C. ocellatus based on a dorsal pattern with intermixing of dark and pale scales not shared with any other taxa; we therefore maintain synonymy of 'D.' bilineatus with 'D.' ocellatus. We describe three new Western Australian species formerly      allocated to C. o. horni: C. occidentalis sp. nov. from the western coast, C. tuberculatus sp. nov. from the Cape Range and C. pilbarensis sp. nov. from the Pilbara region. To stabilize the Kimberley taxa, we also raise C. ocellatus rostralis and C. ocellatus naso, both monophyletic taxa from the monsoonal tropics, to full species, while acknowledging further work is required on the C. naso species complex. All new species treated here possess distinctive morphological characters to diagnose them, including enlarged dorsal tubercles in C. tuberculatus sp. nov., a single enlarged supranasal in C. horni and a single enlarged postmental in C. pilbarensis sp. nov. Pattern was relatively conserved among taxa, with highly  contrasting dark and pale longitudinal lines, with the exception of the type species C. ocellatus that possesses intermixed dark and pale scales and ocelli. Crenadactylus species are separated by deep genetic divergences and are usually allopatrically distributed. This indicates that despite being Australia's smallest geckos, or possibly because of it, these      diminutive lizards have a long history of localised persistence through major climatic changes over millions of years.
A facile and efficient enzymatic reconstitution methodology has been proposed for high-catalysis peroxidase mimics by remolding the redox active centers of heme-containing proteins with the in-site biomineralized gold using hemoglobin (Hb) as a model. Catalytic hemin (Hem) was extracted from the active centers of Hb for the gold biomineralization and then reconstituted into apoHb to yield the Hem-Au@apoHb nanocomposites showing dramatically improved intrinsic catalysis and electrocatalysis over natural Hb and Hem. The biomineralized gold, on the one hand, would act as "nanowires" to promote the electron transferring of the nanocomposites. On the other hand, it would create a reactivity pathway to pre-organize and accumulate more substrates towards the active sites of the peroxidase mimics. Steady-state kinetics studies indicate that Hem-Au@apoHb could present much higher substrate affinity (lower Michaelis constants) and intrinsic catalysis even than some natural peroxidases. Moreover, the application feasibility of the prepared artificial enzymes was demonstrated by colorimetric assays and direct electrocatalysis for H2O2 sensing, showing a detection limitation low as 0.45μM. Importantly, such a catalysis active-center reconstitution protocol may circumvent the substantial improvement of the intrinsic catalysis and electrocatalysis of diverse heme-containing proteins or enyzmes toward the extensive applications in the chemical, enviromental, and biomedical catalysis fields.
One effect that illustrates how people adjust aspects of their grasping according to situational constraints is the grasp height effect; when reaching for objects positioned at different heights, adults' grasp height (vertical position of the hand on the object) tends to correlate negatively with object height. This indicates that grasp positions are planned so that they facilitate later placements of the object. The current study investigated the development of the grasp height effect with 3-year-old children, 5-year-old children, and adults. This paradigm allows for studying efficient action planning in the context of a simple task with relatively low motor requirements. Other tasks used so far for studying this issue involved relatively complex adjustments of hand position that younger children might have found difficult to perform. Usually, preschoolers' performance on these tasks was relatively low. We expected that, due to the lower motor requirements of the grasp height paradigm, clearer evidence of efficient planning might be found in preschool children. A second focus of this study was to explore children's behavior in different movement phases of the grasping task. Whereas the task of placing an object at different heights involves planning, putting the object back to its original position seems to depend on recall. The results indicate a significant grasp height effect in all age groups but also significant development across the studied age range. Regarding the second movement phase, when participants were required to put the objects back on the original home shelf, 3- and 5-year-olds did not seem to act based on recall in this context.
Nowadays our planet suffers from the accumulation of the plastic products which have a potential to cause a great harm to the environment in the form of air, water and land pollution. Plastic water bottles have become a great problem in the environment because of the mass numbers consumed throughout the world. Certain types of plastic bottles can be recycled but most of them are not. This paper describes an economical solvent free process that converts polyethyleneterephtalate (PET) bottles waste into carbon nanostructure materials via thermal dissociation in a closed system under autogenic pressure together with additives and/or catalyst which can act as cluster nuclei for carbon nanostructure materials as fullerenes and carbon nanotube. This research succeeded in producing and controlling the microstructure of various forms of carbon nanoparticles from the PET waste by optimizing the preparation parameters as time, additives and amounts of catalyst. Implications Plastic water bottles are becoming a growing segment of the municipal solid waste stream in the world; some are recycled but many are left in landfill sites. By recycling PET bottles waste, it can positively impact the environment in several ways for instance reduced waste, resource conservation, energy conservation, reduced greenhouse gas emissions and decrease the amount of pollution in the air and water sources. The main novelty of the present work is based on the acquisition of a high value carbon based nanomaterials from PET waste by a free solve-chemical simple technique. Thus, the prepared materials are considered to be a promising, cheap eco-friendly materials may use in different applications.
Recent reports have indicated that a manganese oxide spinel component, when embedded in a relatively small concentration in layered xLi2MnO3●(1-x)LiMO2 (M=Ni, Mn, Co) electrode systems, can act as a stabilizer that increases their capacity, rate capability, cycle life, and first-cycle efficiency. These findings prompted us to explore the possibility of exploiting lithiated cobalt oxide spinel stabilizers by taking advantage of (1) the low mobility of cobalt ions relative to manganese and nickel ions in close-packed oxides and (2) their higher potential (~3.6 V vs. Li(0)) relative to manganese oxide spinels (~2.9 V vs. Li(0)) for the spinel-to-lithiated spinel electrochemical reaction. In particular, we have revisited the structural and electrochemical properties of lithiated spinels in the LiCo1-xNixO2 (0≤x≤0.2) system, first reported almost 25 years ago, by means of high-resolution (synchrotron) X-ray diffraction, transmission electron microscopy, nuclear magnetic resonance spectroscopy, electrochemical cell tests, and theoretical calculations. The results provide a deeper understanding of the complexity of intergrown layered/lithiated spinel LiCo1-xNixO2 structures, when prepared in air between 400 and 800 °C, and the impact of structural variations on their electrochemical behavior. These structures, when used in low concentration, offer the possibility of improving the cycling stability, energy, and power of high energy (≥3.5 V) lithium-ion cells.
The aim of this study was to describe prehospital use of ketamine by ACT Ambulance Service, and frequency of endotracheal intubation.
This was a retrospective study of patients receiving prehospital ketamine between 1 January and 31 December 2013. Episodes were identified from the prehospital electronic patient care records, then linkage to ED records at two receiving hospitals. Demographics, dose, indication and occasions of intubation were analysed.
A total of 163 episodes were identified; 10 of these were excluded because of lack of identifying data or missing records (age 1-97 years [mean: 43, standard deviation: 21.7], 56% men). Median total dose was 60 mg (interquartile range 70; 5-400 mg) in three doses (interquartile range 3; 1-14 mg). For patients with a weight recorded (63%), median dose was 0.73 mg/kg. Indications were analgesia 68%,
 agitation/combative 25%, rapid sequence intubation 5% and others 2%. A total of 26 patients were endotracheally intubated, 11 prehospital (seven as an intended rapid sequence intubation and four combative patients with return of spontaneous circulation) and 15 in the ED. Of ED intubations, 10 were trauma patients and five were drug ingestion related. Patients receiving ketamine for combativeness were more likely to be intubated than those receiving it for analgesia (25 vs 7.2%; odds ratio: 3.46; 95% confidence interval: 1.12, 10.71). In those with a weight recorded, the mg/kg dose was not associated with subsequent intubation.
Median dose for analgesia was comparable with other studies; dose for sedation was less than reported elsewhere. Intubation rate for patients receiving prehospital ketamine was 17%. Further study is recommended to assess the ED course of the non-intubated group of patients, and consideration should be given to non-weight-based methods of dose selection.
Women victims of IPV are more likely insecurely attached and have experienced childhood abuse, which according to the attachment theory is deeply related to disorganized attachment. This case-control study was performed with the aim to compare the attachment status and the defensive processing patterns of women victims of IPV (cases) with women with no experiences of IPV (controls).
Cases were 16 women with an age range from 26 years to 51 years. The control group included 16 women with an age range from 26 years to 59 years. Women's states of mind in regard to attachment were evaluated with the Adult Attachment Projective Picture System, which allows classifying attachment status and defensive mechanisms.
Compared with control group, most IPV women resulted having an unresolved attachment status and describing characters less capable to draw upon internal resources, that is, internalized secure base, and less capable to act than controls. Women victims of IPV used significantly more words referring danger and failed protection than controls.
The results evidenced the strong effectiveness of the AAP on analysing the psychological attitudes of women victims of IPV. The dramatic events lived by the women victims of IPV are so dominant in their minds that they invade their stories. This could represent a clue of emotional dysregulation.
The use of AAP improves the understanding of the agency of self and of the specific levels of trauma experienced by IPV victims, on clarifying their frightening/frightened dynamic, typical of the disorganized attachment relationship, which undermines their activity of mentalization. The therapist will assume the stance of a secure base and then both promoting exploration and contrasting impotence, humiliation, and subordination that IPV women have experienced. This therapeutic interpersonal context will be functional to reach two different but related therapeutic goals: (1) to facilitate the rebuilding of agency (through an activation of subject to explore concrete strategies for exiting from IPV), (2) to explore attachment-related segregated systems from awareness, and to integrate them in memory.
Farmed Atlantic salmon (Salmo salar) is a globally important production species, including in Australia where breeding and selection has been in progress since the 1960s. The recent development of SNP genotyping platforms means genome-wide association and genomic prediction can now be implemented to speed genetic gain. As a precursor, this study collected genotypes at 218 132 SNPs in 777 fish from a Tasmanian breeding population to assess levels of genetic diversity, the strength of linkage disequilibrium (LD) and imputation accuracy. Genetic diversity in Tasmanian Atlantic salmon was lower than observed within European populations when compared using four diversity metrics. The distribution of allele frequencies also showed a clear difference, with the Tasmanian animals carrying an excess of low minor allele frequency variants. The strength of observed LD was high at short distances (<25 kb) and remained above background for marker pairs separated by large chromosomal distances (hundreds of kb), in sharp contrast to the European Atlantic salmon tested. Genotypes were used to evaluate the accuracy of imputation from low density (0.5 to 5 K) up to increased density SNP sets (78 K). This revealed high imputation accuracies (0.89-0.97), suggesting that the use of low density SNP sets will be a successful approach for genomic prediction in this population. The long-range LD, comparatively low genetic diversity and high imputation accuracy in Tasmanian salmon is consistent with known aspects of their population history, which involved a small founding population and an absence of subsequent introgression. The findings of this study represent an important first step towards the design of methods to apply genomics in this economically important population.
Parkinson's disease (PD) is a common neurodegenerative disease which begins in adulthood. Its incidence in Mexico is estimated to be 40-50 cases per 100,000 inhabitants/year and is the fourth reason for medical care in the National Institute of Neurology and Neurosurgery. The protein alpha-synuclein, SNCA, plays a key role in the pathology of PD, and its polymorphisms have been associated with an increased risk of developing the disease.
To evaluate the risk of PD represented by the polymorphisms rs2619364, rs2619363, rs2736990, rs7684318, rs17016074, rs356219, rs356220 and rs356203 of SNCA in a sample of Mexican subjects.
Altogether 171 patients diagnosed with PD and 171 gender- and age-paired controls were assessed by means of real-time polymerase chain reaction, and a statistical analysis was performed to determine the association between the polymorphisms and the disease.
The SNCA variants rs356220, rs356203, rs7684318 and rs2736990 were associated with the disease and form two haplotypes with a high risk of developing sporadic PD in the Mexican population.
Variations in SNCA are a risk factor for the development of PD and can act as specific genetic biomarkers as a diagnostic support tool in sporadic PD for Mexican mestizo patients.
Hydrothermal characteristics of a temperature-sensitive magnetic nanofluid between two parallel plates are investigated in the presence of magnetic field produced by one or multiple line dipole(s) using the two-phase mixture model. As the nanofluid reaches the region where the magnetic field is applied, a rotation is developed due to the dependency of magnetization on temperature. This can lead to mixing in the flow and more uniform distribution of temperature due to the disturbance caused in the boundary layer, and consequently, enhancement in convective heat transfer. The results indicate that the disturbance in boundary layer adjacent to the lower wall is more significant than the upper wall. By application of the magnetic field, the convective heat transfer increases locally for both walls. Due to the intensified mixing, a sudden pressure drop occurs when the fluid reaches the region where the magnetic field is applied. For greater magnetic field strengths and lower Reynolds numbers, the improvement in convective heat transfer is more significant. For small magnetic field strengths, the effect of applying magnetic field on the upper wall is much smaller than that on the lower wall; however, this effect becomes almost the same for both walls at great magnetic field strengths.
Genetic mutations on signaling pathways are found in patients with T-cell acute lymphoblastic leukemia (T-ALL) and act as markers of high-risk leukemia. Mutations in dynamin 2 (DNM2) have been reported in T-ALL, particularly in early T-cell precursor-ALL. In the present study, DNM2 mutations were screened by sequencing DNM2 exons obtained by polymerase chain reaction amplification and gel purification in adult T-ALL patients. A total of 4 novel DNM2 mutations were identified in adult T-ALL patients, with a mutation rate of 9.5%, and the DNM2 mutations were found to co-exist with NOTCH1 and PHD finger protein 6, and were also associated with high-risk leukemia. A high rate of silent mutation was also found in the patients, but no significant association was found between the silent mutations and patients' clinical features. The present findings suggested the DNM2 mutations may be involved in the oncogenesis of T-ALL.
The aim of the present study was to investigate the expression of tazarotene-induced gene 2 (TIG2) and evaluate the clinicopathological variables and prognostic value for non-small cell lung cancer (NSCLC) patients. Reverse transcription-polymerase chain reaction and western blotting were utilized to detect TIG2 expression in NSCLC specimens and adjacent noncancerous tissue. Furthermore, the present study investigated the protein expression and the clinicopathological significance of TIG2 in 98 paraffin-embedded NSCLC samples by using immunohistochemistry. The results of the present study demonstrated that the expression of TIG2 mRNA (P=0.003) and protein (P=0.0024) was significantly reduced in NSCLC compared with corresponding noncancerous tissue. TIG2 protein expression in NSCLC was significantly associated with lymph node metastasis (P=0.006), Tumor-Node-Metastasis stage (P=0.021) and degree of differentiation (P=0.025). The Kaplan-Meier method and log-rank test revealed that high TIG2 expression was significantly associated with increased survival of NSCLC patients (P=0.003). Multivariate analysis revealed that TIG2 expression was an independent prognostic factor of the overall survival of NSCLC patients. Decreased expression of TIG2 may be useful as a biomarker for poor prognosis in NSCLC carcinogenesis and may act as a target for gene therapy for the treatment of NSCLC patients.
Deregulated expression of C-terminal-binding protein 2 (CTBP2) has
 been observed previously in a number of tumors, such as hepatocellular carcinoma and prostatic cancer, in the colorectal cancer SW480 cell line and in the human embryonic kidney 293 cell line. In the present study, western blot analysis and immunohistochemistry were performed to investigate whether gliomas exhibit deregulated CTBP2 expression. Kaplan-Meier survival analyses were performed to evaluate the associations between CTBP2 expression, clinicopathological data and patient survival in glioma patients. The results revealed that CTBP2 expression was significantly upregulated in high grade glioma tissues compared with that in low grade glioma and normal brain tissues. Furthermore, increased CTBP2 expression in gliomas was significantly associated with a higher World Health Organization (WHO) tumor grade (P<0.005) and poorer disease-specific survival (P<0.005). In conclusion, these results suggest that CTBP2 may act as an intrinsic regulator of progression in glioma cells and thus may serve as an important prognostic factor for the disease.
The epileptic state, or status epilepticus (SE), is the most serious situation manifested by individuals with epilepsy, and SE events can lead to neuronal damage. An understanding of the molecular, biochemical and physiopathological mechanisms involved in this type of neurological disease will enable the identification of specific central targets, through which novel agents may act and be useful as SE therapies. Currently, studies have focused on the association between oxidative stress and SE, the most severe epileptic condition. A number of these studies have suggested the use of antioxidant compounds as alternative therapies or adjuvant treatments for the epileptic state.
Aim. The incidence of diabetic osteoporosis (DOP) is increasing due to lack of effective management over the past few decades. This review aims to summarize traditional Chinese medicine (TCM) suitability in the pathogenesis and clinical and preclinical management of DOP. Methods. Literature sources used were from Medline (Pubmed), CNKI (China Knowledge Resource Integrated Database), and CSTJ (China Science and Technology Journal Database) online databases. For the consultation, keywords such as diabetic osteoporosis (DOP), TCM, clinical study, animal experiment, toxicity, and research progress were used in various combinations. Around 100 research papers and reviews were visited. Results. Liver-spleen-kidney insufficiency may result in development of DOP. 18 clinical trials are identified to use TCM compound prescriptions for management of patients with DOP. TCM herbs and their active ingredients are effective in preventing the development of DOP in streptozotocin (STZ) and alloxan as well as STZ combined with ovariectomy insulted rats. Among them, most frequently used TCM herbs in clinical trials are Radix Astragali, Radix et Rhizoma Salviae Miltiorrhizae, Radix Rehmanniae Preparata, and Herba Epimedii. Some of TCM herbs also exhibit toxicities in clinical and preclinical research. Conclusions. TCM herbs may act as the novel sources of anti-DOP drugs by improving bone and glucolipid metabolisms. However, the pathogenesis of DOP and the material base of TCM herbs still merit further study.
Background: Carpal tunnel syndrome (CTS) is the most common compressive neuropathy found in clinical practice. Recent studies evaluated which external factors could be involved in the CTS symptoms, including prolonged exposure to vibration, especially in the upper limb. This study investigated signs and symptoms in patients with CTS after using urban transport on (1) both upper limbs, (2) how long before these symptoms appear, and (3) the hands position or body reaction during the act of pressing the safety bars. Methods: The study was conducted from July 2012 to April 2013. A total of 205 (178 women and 27 men) patients were evaluated. CTS was diagnosed in 285 hands. All participants answered a questionnaire formulated by the authors. The questionnaire was applied by researchers who were single-blinded and not involved in the research. Results: Most of the participants (87%) were women, but there was no statistical significance in age between groups (women = 51.24 ± 8.47 years, men = 51.10 ± 6.52 years, P > .05). The symptoms appeared significantly in the first 15 minutes after boarding when compared with patients who had no symptoms during the journey. There was no difference between hands position along the journey and the onset of symptoms. Conclusions: The onset of symptoms in patients with CTS using urban public transportation most commonly occurred in the first 15 minutes after boarding. Public transport vibration seems to be, at least in part, directly related to the development of symptoms. Questionnaires for the assessment of paresthesia symptoms during the use of public transport may be useful for CTS diagnosis.
Around 20%-30% of breast cancers overexpress the proto-oncogene human epidermal growth receptor 2 (HER2), and they are characterized by being very invasive. Therefore, many current studies are focused on testing new therapies against tumors that overexpress this receptor. In particular, there exists major interest in new strategies to fight breast cancer resistant to trastuzumab (Tmab), a humanized antibody that binds specifically to HER2 interfering with its mitogenic signaling. Our team has previously developed immunostimulating complexes (ISCOMs) as nanocapsules functionalized with lipid vinyl sulfones, which can incorporate protein A and bind to G immunoglobulins that makes them very flexible nanocarriers.
The aim of this in vitro study was to synthesize and evaluate a drug delivery system based on protein A-functionalized ISCOMs to target HER2-overexpressing cells. We describe the preparation of ISCOMs, the loading with the drugs doxorubicin and paclitaxel, the binding of ISCOMs to alkyl vinyl sulfone-protein A, the coupling of Tmab, and the evaluation in both HER2-overexpressing breast cancer cells (HCC1954) and non-overexpressing cells (MCF-7) by flow cytometry and fluorescence microscopy. Results show that the uptake is dependent on the level of overexpression of HER2, and the analysis of the cell viability reveals that targeted drugs are selective toward HCC1954, whereas MCF-7 cells remain unaffected.
Protein A-functionalized ISCOMs are versatile carriers that can be coupled to antibodies that act as targeting agents to deliver drugs. When coupling to Tmab and loading with paclitaxel or doxorubicin, they become efficient vehicles for the selective delivery of the drug to Tmab-resistant HER2-overexpressing breast cancer cells. These nanoparticles may pave the way for the development of novel therapies for poor prognosis resistant patients.
Macrophage-mediated innate immune responses play crucial roles in host defense against pathogens. Recent years have seen an explosion of host proteins that act as restriction factors blocking viral replication in infected cells. However, the essential factors restricting Mycobacterium tuberculosis (Mtb) and their regulatory roles during mycobacterial infection remain largely unknown. We previously reported that Mtb tyrosine phosphatase PtpA, a secreted effector protein required for intracellular survival of Mtb, inhibits innate immunity by co-opting the host ubiquitin system. Here, we identified a new PtpA-interacting host protein TRIM27, which is reported to possess a conserved RING domain and usually acts as an E3 ubiquitin ligase that interferes with various cellular processes. We further demonstrated that TRIM27 restricts survival of mycobacteria in macrophages by promoting innate immune responses and cell apoptosis. Interestingly, Mtb PtpA could antagonize TRIM27-promoted JNK/p38 MAPK pathway activation and cell apoptosis through competitively binding to the RING domain of TRIM27. TRIM27 probably works as a potential restriction factor for Mtb and its function is counteracted by Mtb effector proteins such as PtpA. Our study suggests a potential tuberculosis treatment via targeting of the TRIM27-PtpA interfaces.
Gene regulation by base pairing between small noncoding RNAs (sRNAs) and their mRNA targets is an important mechanism that allows bacteria to maintain homeostasis and respond to dynamic environments. In Gram-negative bacteria, sRNA pairing and regulation are mediated by several RNA-binding proteins, including the sRNA chaperone Hfq and polynucleotide phosphorylase (PNPase). PNPase and its homolog RNase PH together represent the two 3' to 5' phosphorolytic exoribonucleases found in Escherichia coli; however, the role of RNase PH in sRNA regulation has not yet been explored and reported. Here, we have examined in detail how PNPase and RNase PH interact to support sRNA stability, activity, and base pairing in exponential and stationary growth conditions. Our results indicate that these proteins facilitate the stability and regulatory function of the sRNAs RyhB, CyaR, and MicA during exponential growth. PNPase further appears to contribute to pairing between RyhB and its mRNA targets. During stationary growth, each sRNA responded differently to the absence or presence of PNPase and RNase PH. Finally, our results suggest that PNPase and RNase PH stabilize only Hfq-bound sRNAs. Taken together, these results confirm and extend previous findings that PNPase participates in sRNA regulation and reveal that RNase PH serves a similar, albeit more limited, role as well. These proteins may, therefore, act to protect sRNAs from spurious degradation while also facilitating regulatory pairing with their targets.
In many bacteria, Hfq-dependent base-pairing sRNAs facilitate rapid changes in gene expression that are critical for maintaining homeostasis and responding to stress and environmental changes. While a role for Hfq in this process was identified more than
 2 decades ago, the identity and function of the other proteins required for Hfq-dependent regulation by sRNAs have not been resolved. Here, we demonstrate that PNPase and RNase PH, the two phosphorolytic RNases in E. coli, stabilize sRNAs against premature degradation and, in the case of PNPase, also accelerate regulation by sRNA-mRNA pairings for certain sRNAs. These findings are the first to demonstrate that RNase PH influences and supports sRNA regulation and suggest shared and distinct roles for these phosphorolytic RNases in this process.
Hyperactivity of the renin-angiotensin-aldosterone system through the angiotensin II (Ang II)/Ang II type 1 receptor (AT1-R) axis constitutes a hallmark of hypertension. Recent findings indicate that only a subset of AT1-R signaling pathways is cardiodeleterious, and their selective inhibition by biased ligands promotes therapeutic benefit. To date, only synthetic biased ligands have been described, and whether natural renin-angiotensin-aldosterone system peptides exhibit functional selectivity at AT1-R remains unknown. In this study, we systematically determined efficacy and potency of Ang II, Ang III, Ang IV, and Ang-(1-7) in AT1-R-expressing HEK293T cells on the activation of cardiodeleterious G-proteins and cardioprotective β-arrestin2. Ang III and Ang IV fully activate similar G-proteins than Ang II, the prototypical AT1-R agonist, despite weaker potency of Ang IV. Interestingly, Ang-(1-7) that binds AT1-R fails to promote G-protein activation but behaves as a competitive antagonist for Ang II/Gi and Ang II/Gq pathways. Conversely, all renin-angiotensin-aldosterone system peptides act as agonists on the AT1-R/β-arrestin2 axis but display biased activities relative to Ang II as indicated by their differences in potency and AT1-R/β-arrestin2 intracellular routing. Importantly, we reveal Ang-(1-7) a known Mas receptor-specific ligand, as an AT1-R-biased agonist, selectively promoting β-arrestin activation while blocking the detrimental Ang II/AT1-R/Gq axis. This original pharmacological profile of Ang-(1-7) at AT1-R, similar to that of synthetic AT1-R-biased agonists, could, in part, contribute to its cardiovascular benefits. Accordingly, in vivo, Ang-(1-7) counteracts the phenylephrine-induced aorta contraction, which was blunted in AT1-R knockout mice. Collectively, these data suggest that Ang-(1-7) natural-biased agonism at AT1-R could fine-tune the physiology of the renin-angiotensin-aldosterone system.
Gut microbiota have been implicated in the development of colorectal cancer (CRC). We evaluated the utility of fecal bacterial marker candidates identified by our metagenome sequencing analysis for CRC diagnosis.
439 subjects (203 CRC and 236 healthy subjects) from two independent Asian cohorts were included. Probe-based duplex quantitative PCR (qPCR) assays were established for quantification of bacterial marker candidates.
Candidates identified by metagenome sequencing, including Fusobacterium nucleatum (Fn), Bacteroides clarus (Bc), Roseburia intestinalis (Ri), Clostridium hathewayi (Ch), and one undefined species (labeled as m7), were examined in fecal samples of 203 CRC patients and 236 healthy controls by duplex-qPCR. Strong positive correlations were demonstrated between the quantification of each candidate by our qPCR assays and metagenomics approach (r=0.801~0.934, all P<0.0001). Fn was significantly more abundant in CRC than controls (P<0.0001), with area under receiver operating curve (AUROC) of 0.868 (P<0.0001). At the best cutoff value maximizing sum of sensitivity and specificity, Fn discriminated CRC from controls with a sensitivity of 77.7%, and specificity of 79.5% in cohort I. A simple linear combination of four bacteria (Fn+Ch+m7-Bc) showed an improved diagnostic ability compared to Fn alone (AUROC=0.886, P<0.0001) in cohort I. These findings were further confirmed in an independent cohort II. In particular, improved diagnostic performances of Fn alone (sensitivity 92.8%, specificity 79.8%) and four-bacteria (sensitivity 92.8%, specificity 81.5%) were achieved in combination with fecal immunochemical test (FIT) for the detection of CRC.
Stool-based CRC-associated bacteria can serve as novel non-invasive diagnostic biomarkers for CRC.
When used effectively, health information technology (HIT) can transform clinical care and contribute to new research discoveries. Despite advances in HIT and increased electronic health record adoption, many challenges to optimal use, interoperability, and data sharing exist. Data standardization across systems is limited, and scanned medical note documents result in unstructured data that make reporting on quality measures for reimbursement burdensome. Different policies and initiatives, including the Health Information Technology for Economic and Clinical Health Act, the Medicare Access and CHIP Reauthorization Act, and the National Cancer Moonshot initiative, among others, all recognize the impact that HIT can have on cancer care. Given the growing role HIT plays in health care, it is vital to have effective and efficient HIT systems that can exchange information, collect credible data that is analyzable at the point of care, and improves the patient-provider relationship. In June 2016, NCCN hosted the Emerging Issues and Opportunities in Health Information Technology Policy Summit. The summit addressed challenges, issues, and opportunities in HIT as they relate to cancer care. Keynote presentations and panelists discussed moving beyond Meaningful Use, HIT readiness to support and report on quality care, the role of HIT in precision medicine, the role of HIT in the National Cancer Moonshot initiative, and leveraging HIT to improve quality of clinical care.
Better knowledge about tuberculosis (TB) and latent TB infection (LTBI) epidemiology is a crucial step for the development of effective strategies towards the control and elimination of this deadliest and persistent health threat. No study has investigated LTBI epidemiology in policemen who act as an interface with cross-border migrants.
A survey to measure the LTBI prevalence and assess the demographic, professional and clinical features potentially associated with tuberculin skin test (TST) positivity was performed in Italian State Police (ISP) employees engaged, even occasionally, in relief activities, hospitality, photographical identification, escorting and accompanying of migrants, regardless of contact with active TB cases. Variables potentially associated with TST positivity were evaluated with univariate and multivariate analysis.
From September to December 2014, 4225 ISP workers underwent TST screening and completed the questionnaire for data collection, according to study procedures. The TST was positive in 9.9% of individuals: no active TB cases were registered among the entire study population. Age, previous BCG vaccination and work category resulted independently associated with TST positivity.
This is the first study providing updated data about LTBI epidemiology among ISP employees engaged in assistance to migrants and furnish preliminary evidence of possible associations between TST positivity and different conditions that need to be deeply investigated with prospective studies.
Haemophagocytic lymphohistiocytosis is a rare inflammatory condition. It can present in adult general medical patients and is a challenging diagnostic conundrum. This article provides an overview of the pathophysiology and clinical presentation of the syndrome for the general physician who will be rarely confronted with this problem but will have to act promptly when the situation arises. Treatment is also briefly discussed, although this usually occurs in a specialist setting after the diagnosis has been established.
Tafenoquine is in development as a single-dose treatment for relapse prevention in individuals with Plasmodium vivax malaria. Tafenoquine must be coadministered with a blood schizonticide, either chloroquine or artemisinin-based combination therapy (ACT). This open-label, randomized, parallel-group study evaluated potential drug interactions between tafenoquine and two ACTs: dihydroartemisinin-piperaquine and artemether-lumefantrine. Healthy volunteers of either sex aged 18 to 65 years without glucose-6-phosphate dehydrogenase deficiency were randomized into five cohorts (n = 24 per cohort) to receive tafenoquine on day 1 (300 mg) plus once-daily dihydroartemisinin-piperaquine on days 1, 2, and 3 (120 mg/960 mg for 36 to <75 kg of body weight and 160 mg/1,280 mg for ≥75 to 100 kg of body weight), or plus artemether-lumefantrine (80 mg/480 mg) in two doses 8 h apart on day 1 and then twice daily on days 2 and 3, or each drug alone. The pharmacokinetic parameters of tafenoquine, piperaquine, lumefantrine, artemether, and dihydroartemisinin were determined by using noncompartmental methods. Point estimates and 90% confidence intervals were calculated for area under the concentration-time curve (AUC) and maximum observed plasma concentration (Cmax) comparisons of tafenoquine plus ACT versus tafenoquine or ACT. All subjects receiving dihydroartemisinin-piperaquine experienced QTc prolongation (a known risk with this drug), but tafenoquine coadministration had no clinically relevant additional effect. Tafenoquine coadministration had no clinically relevant effects on dihydroartemisinin, piperaquine, artemether, or lumefantrine pharmacokinetics. Dihydroartemisinin-piperaquine coadministration increased the tafenoquine Cmax by 38% (90% confidence interval, 25 to 52%), the AUC from time zero to infinity (AUC0-∞) by 12% (1 to 26%), and the half-life (t1/2) by 29% (19 to 40%), with no effect on the AUC from time zero to the time of the last nonzero concentration (AUC0-last). Artemether-lumefantrine coadministration had no effect on tafenoquine pharmacokinetics. Tafenoquine
 can be coadministered with dihydroartemisinin-piperaquine or artemether-lumefantrine without dose adjustment for any of these compounds. (This study has been registered at ClinicalTrials.gov under registration no. NCT02184637.).
Beta-tricalcium phosphate (β-TCP) is widely used for bone substitution in clinical practice. Particles of calcium phosphate ceramics including β-TCP act as an inflammation mediators, which is an unfavorable characteristic for a bone substituent or a prosthetic coating material. It is thought that the stimulatory effect of β-TCP on the immune system could be utilized as an immunomodulator. Here, in vitro effects of β-TCP on primary cultured murine dendritic cells (DCs) and macrophages were investigated. β-TCP particles enhanced expression of costimulatory surface molecules, including CD86, CD80, and CD40 in DCs, CD86 in macrophages, and MHC class II and class I molecules in DCs. DEC205 and CCR7 were up-regulated in β-TCP-treated DCs. Production of cytokines and chemokines, including CCL2, CCL3, CXCL2, and M-CSF, significantly increased in DCs; CCL2, CCL3, CCL4, CCL5, CXCL2, and IL-11ra were up-regulated in macrophages. The results of the functional assays revealed that β-TCP caused a prominent reduction in antigen uptake by DCs, and that conditioned medium from DCs treated with β-TCP facilitated the migration of splenocytes in the transwell migration assay. Thus, β-TCP induced phenotypical and functional maturation/activation of DCs and macrophages; these stimulating effects may contribute to the observed in vivo effect where β-TCP induced extensive migration of immune cells. When compared to lipopolysaccharide (LPS), an authentic TLR ligand, the stimulatory effect of β-TCP on the immune systems is mild to moderate; however, it may have some advantages as a novel immunomodulator. This is the first report on the direct in vitro effects of β-TCP against bone marrow-derived DCs and macrophages.
Sphingolipids are the main components of the lipid membrane. They also perform structural functions and participate in many signal transmission processes. One of the bioactive sphingolipids is sphingosine-1-phosphate (S1P), a ligand for five G protein-coupled receptors (S1PRs1-5), which can also act as an intracellular second messenger. S1P is responsible for the stimulation of progenitor cells in the brain, but it can also induce apoptosis of mature neurons. This study is aimed at assessing the effect of pre- and neonatal exposure to permissible Pb concentrations on S1P levels and S1PR1 (EDG1) expression in the prefrontal cortex, cerebellum, and hippocampus of rats. The concentrations of S1P were determined by RP-HPLC, S1PR1 expression was determined by RT PCR and Western Blot, and receptor immunolocalization was determined by immunohistochemistry method. Our results showed that even low blood Pb concentrations, i.e. within the acceptable limit of 10 μg/dL caused changes in the concentration of S1P in the cerebellum, prefrontal cortex, and hippocampus. Our data also showed a significant decrease in the level of S1PR1 in all studied part of brain, without significant changes in S1PR1 gene expression. Pre- and neonatal exposure to Pb also resulted in a decrease in the expression of S1PR1 in glial cells in all regions of the Cornu Ammonis (CA1-CA4) and Dentate Gyrus in the hippocampus, as well as in all layers of the cerebellum and prefrontal cortex, compared to the unexposed control group.
With the implementation of the Affordable Care Act, the U.S. government committed to a transition in payment policy for health care services linking reimbursement to improved health outcomes rather than the volume of services provided. To accomplish this goal, the Department of Health and Human Services is designing and implementing new payment models intended to improve the quality of health care while reducing its cost. Collectively, these novel payment models and programs have been characterized under the moniker of value-based purchasing (VBP), and although many of these models retain a fundamental fee-for-service (FFS) structure, they are seen as essential tools in the evolution away from volume-based health care financing toward a health system that provides "better care, smarter spending, and healthier people." In 2014, approximately 20% of Medicare provider FFS payments were linked to a VBP program. The Department of Health and Human Services has committed to a four-year plan to link 90% of Medicare provider FFS payments to value-based purchasing by 2018. To achieve this goal, all items and services currently reimbursed under Medicare FFS programs will need to be evaluated in the context of VBP. To this end, the Medicare Hospice benefit appears to be appropriate for inclusion in a model of VBP. This policy analysis proposes an adaptable model for a VBP program for the Medicare Hospice benefit linking payment to quality and efficiency in a manner consistent with statutory requirements established in the Affordable Care Act.
Periodontitis is a polymicrobial, chronic, and degenerative disease that can lead to destruction of the teeth-supporting tissues and eventually to loss of teeth. Aggregatibacter actinomycetemcomitans is predominantly associated with periodontal diseases. Outer membrane protein (Omp) 100 is a more important virulence factor of A. actinomycetemcomitans due to the effect of adhesion and invasion into human gingival epithelial cells. Attachment of A. actinomycetemcomitans inhibition is significant in the treatment process.
We evaluated the capacity of Omp100 in A. actinomycetemcomitans as a novel target for photodynamic therapy (PDT) using a range of bioinformatic tools. In silico analysis was used to predict molecular modeling, the hierarchical nature of protein structure and backbone, and sub-cellular localization.
The results showed that Omp100 is most similar to thiamine-phosphate pyrophosphorylase [Haemophilus influenzae PittGG], with a 74% similarity. The predicted structure of Omp100 displayed that it is a protein with positive charge (10.4) in pH 7 and alpha helix dominates other secondary structures located outside the cell. Protein-protein interaction network showed that Omp100 interacted with extracellular matrix protein adhesion, glycoside hydrolase, Omp 64, phospholipase D/Transphosphatidylase, Flp pilus assembly protein, and heme acquisition system receptor.
According to the results, anionic indocyanine green tends to interact with Omp100 during PDT as a major target.
Breathing is a life-sustaining behavior that in mammals is accomplished by activation of dedicated muscles responsible for inspiratory and expiratory forces acting on the lung and chest wall. Motor control is exerted by specialized pools of motoneurons in the medulla and spinal cord innervated by projections from multiple centers primarily in the brainstem that act in concert to generate both the rhythm and pattern of ventilation. Perturbations that prevent the accomplishment of the full range of motor behaviors by respiratory muscles commonly result in significant morbidity and increased mortality. Recent developments in gene therapy and novel targeting strategies have contributed to deeper understanding of the organization of respiratory motor systems. Gene therapy has received widespread attention and substantial progress has been made in recent years with the advent of improved tools for vector design. Genes can be delivered via a variety of plasmids, synthetic or viral vectors and cell therapies. In recent years, adeno-associated viruses (AAV) have become one of the most commonly used vector systems, primarily because of the extensive characterization conducted to date and the versatility in targeting strategies. Recent studies highlight the power of using AAV to selectively and effectively transduce respiratory motoneurons and muscle fibers with promising therapeutic effects. This brief review summarizes current evidence for the use of gene therapy in respiratory disorders with a primary focus on interventions that address motor control and neuroplasticity, including regeneration, in the respiratory system.
Hydrogen sulfide (H2S) has been traditionally considered to be a toxic molecule for mammals. However, it can be formed endogenously and exert physiological effects with potential health benefits. H2S can partition two-fold in biological membranes and traverse them rapidly, diffusing between compartments. H2S reactivity has similarities to that of thiols, although it is less nucleophilic than thiols and it can form different products. H2S can react with oxidants derived from the partial reduction of oxygen, but direct scavenging is unlikely to explain H2S protective actions. Important effects are exerted on mitochondria including the stimulation or the inhibition of the electron transport chain. Possible mechanisms for unleashing biological consequences are the reactions with metal centers and with thiol oxidation products. The reactions of H2S with disulfides (RSSR) and sulfenic acids (RSOH) lead to the formation of persulfides (RSSH). Persulfides have enhanced nucleophilicity with respect to the corresponding thiol, consistent with the alpha effect. Besides, the inner and outer sulfurs can both act as electrophiles. In this review, we describe the reactions of H2S with oxidized thiol products and the properties of the persulfides formed in the context of the chemical biology of H2S.
Triggering receptor expressed on myeloid cells-1 (TREM-1) has been highlighted as a key amplifier of inflammatory response in various diseases. To determine the contribution of TREM-1 in the inflammatory cascade after subarachnoid hemorrhage (SAH), concentrations of soluble TREM-1 (sTREM-1) in cerebrospinal fluid (CSF) from 30 SAH patients and 9 healthy volunteers were measured by enzyme-linked immunosorbent assay. It was shown
 that the CSF sTREM-1 levels of SAH patients increased significantly than that of the volunteers (P<0.05). Interestingly, the levels were up-regulated dynamically over time with an early increase within 2days and a late peak at day 6 after SAH onset. In addition, it was found that the early sTREM-1 levels (within 3days post-SAH) were negatively correlated with Glasgow Coma Scale (r=-0.550, P=0.022) and positively correlated with the Hunt and Hess scale (r=0.603, P=0.010) respectively conducted on admission, also the early sTREM-1 levels were negatively correlated with Glasgow Outcome Scale (r=-0.505, P=0.039) and positively correlated with modified Rankin Scale (r=0.557, P=0.020) respectively conducted one month after SAH. Altogether, this is the first study showing CSF sTREM-1 dynamics in SAH patients, and exploring the correlations of early CSF sTREM-1 levels to patients' severity and prognosis, which suggests that TREM-1 may play an important role in the inflammatory cascade after SAH and act as a monitoring biomarker facilitated to assess the severity and prognosis of SAH patients.
Mycobacterium tuberculosis is recognised as the primary cause of human tuberculosis worldwide. However, substantial evidence suggests that the burden of Mycobacterium bovis, the cause of bovine tuberculosis, might be underestimated in human beings as the cause of zoonotic tuberculosis. In 2013, results from a systematic review and meta-analysis of global zoonotic tuberculosis showed that the same challenges and concerns expressed 15 years ago remain valid. These challenges faced by people with zoonotic tuberculosis might not be proportional to the scientific attention and resources allocated in recent years to other diseases. The burden of zoonotic tuberculosis in people needs important reassessment, especially in areas where bovine tuberculosis is endemic and where people live in conditions that favour direct contact with infected animals or animal products. As countries move towards detecting the 3 million tuberculosis cases estimated to be missed annually, and in view of WHO's end TB strategy endorsed by the health authorities of WHO Member States in 2014 to achieve a world free of tuberculosis by 2035, we call on all tuberculosis stakeholders to act to accurately diagnose and treat tuberculosis caused by M bovis in human beings.
For casework applications, understanding the source processes used to create a material and the effects of those sources on the results obtained by Isotope Ratio Mass Spectrometry (IRMS) of a bulk material is important. Likewise, understanding the effect of environment, home/office printing processes and some forensic testing in at least a basic context, ensures that in casework, enough information on the effects of these variables is available during comparison and interpretation. In this study, which focuses on oxygen isotopic abundance measurements, both fractionation and mixing effects were observed within the pulping and production process. Also observed in the carbon isotopic experiments, sampling that included toner changed the measured isotopic abundance values of the paper and should be avoided in casework. Inkjet printing processes were not shown to have an effect on the paper oxygen abundance values. Samples that were treated for fingerprints using 1,2-Indandione-Zn prior to sampling showed the greatest risk for misinterpretation of whether two samples had originated from the same source. While this study provides a good basis and understanding of the effects of a range of factors on document paper oxygen isotope values, further testing for a range of specific casework scenarios is required and should be undertaken on a case by case basis as the need arises.
We present the results of a collaborative study for the establishment of a replacement International Standard (IS) for diphtheria toxoid for use in flocculation test and its calibration in Lf units. Calibration was performed using Ramon flocculation method, standardized using the 2nd IS. The candidate standard was assigned a unitage of 1870 Lf/ampoule based on results from 25 laboratories in 15 different countries and was established as the 3rd IS for diphtheria toxoid for use in flocculation test by the WHO Expert Committee on Biological Standardization (ECBS) in October 2015. The study also assessed the use of alternative methods for measuring Lf. Participants were asked to determine the Lf value of the candidate standard using an Enzyme Linked Immunosorbent Assay (ELISA) established at NIBSC, or other suitable in-house method. 10 laboratories performed ELISA according to the NIBSC protocol, 1 laboratory performed flocculation using laser-light scattering according to an in-house protocol, and 1 laboratory performed another in-house ELISA. Results suggest these methods may provide suitable alternatives to the Ramon flocculation test, subject to validation, and that the new standard could act as a suitable reference preparation in these methods.
Recent research has revealed that the activity of adipose tissue (BAT) in adult humans is higher than previously thought, and that obese patients show abnormally low levels of brown fat activity. Studies in experimental animals have shown that BAT is a site of energy expenditure, and that BAT activity protects against obesity and associated metabolic diseases. The action of the sympathetic nervous activity on BAT depots is considered the main regulator of BAT activity in rodent models and possibly also in humans. However, recent research has revealed the existence of additional hormonal factors, produced by distinct peripheral tissues or present in the diet, that influence the amount and activity of BAT. These hormonal factors may act on BAT directly, but also indirectly by targeting the brain and determining the intensity of sympathetic action upon BAT. Identification and characterization of novel factors that control BAT may provide clues for the development of new strategies to treat obesity and metabolic diseases.
Gonadotropins (LH, FSH, and hCG) act in concert in the regulation of female reproductive system. Exploiting this influence, they are part of the assisted reproductive technique protocols. In this review we analyze the effectiveness of the different available gonadotropin formulations and the consequent adverse events. Moreover, different protocols for poor-responders and polycystic ovary syndrome affected women are explored. All these clinical different approaches have specific molecular bases, covered in this review starting from evolution and population genetics, getting to in vitro studies of gonadotropins action. Beyond their application in assisted reproductive technique, gonadotropins have also been largely studied for their intertwined network of interactions with other hormones, which all together contribute to the functioning of the reproductive system and other hormonal axes. In particular, there is both clinical and molecular evidence of interaction between thyroid hormones and insulin growth factors with gonadotropins. Finally, gonadotropins are widely studied for their role in the maintenance of the proper balance between cell proliferation and differentiation, and therefore in cancer.
The long-held belief that pituitary hormones act solely on master targets was first questioned when we documented G protein-coupled receptors for thyroid-stimulating hormone, follicle-stimulating hormone, adrenocorticotrophic hormone, oxytocin, and vasopressin on bone cells. These evolutionarily conserved hormones and their receptors are known to have primitive roles, and exist in invertebrate species as far down as coelenterates. It is not surprising therefore that each such hormone has multiple hitherto unrecognized functions in mammalian integrative physiology, and hence, becomes a potential target for therapeutic intervention. Here we discuss the skeletal actions of pituitary hormones.
The ability of a neuron to regenerate its axon after injury depends in part on its intrinsic regenerative potential. Here, we identify novel intrinsic regulators of axon regeneration: poly(ADP-ribose) glycohodrolases (PARGs) and poly(ADP-ribose) polymerases (PARPs). PARGs, which remove poly(ADP-ribose) from proteins, act in injured C. elegans GABA motor neurons to enhance axon regeneration. PARG expression is regulated by DLK signaling, and PARGs mediate DLK function in enhancing axon regeneration. Conversely, PARPs, which add poly(ADP-ribose) to proteins, inhibit axon regeneration of both C. elegans GABA neurons and mammalian cortical neurons. Furthermore, chemical PARP inhibitors improve axon regeneration when administered after injury. Our results indicate that regulation of poly(ADP-ribose) levels is a critical function of the DLK regeneration pathway, that poly-(ADP ribosylation) inhibits axon regeneration across species, and that chemical inhibition of PARPs can elicit axon regeneration.
Health anxiety is prevalent (5-9%) in all healthcare settings and in the general population, may have an early onset, and a poor prognosis is seen in severe cases if untreated. Research shows that health anxiety is rarely diagnosed though it causes great suffering for the individual and constitutes a substantial socio-economic burden. Studies have shown that individual cognitive behavioural therapy can relieve health anxiety, but these studies are affected by methodological problems, among others, struggling with patients declining participation, high dropout rates, and some patients not responding to the treatment. Moreover, the impact of health anxiety on sick leave is only scarcely examined. This thesis examines the effect of a new treatment approach, group-based Acceptance & Commitment Therapy (ACT-G) for patients with severe health anxiety in an uncontrolled pilot study and a randomised controlled study (RCT)
 on ACT-G compared with a 10-month waitlist control condition (paper I and II). Also, the thesis comprises a study on sick leave in patients with health anxiety compared with the general population during a 5-year period and the effect of ACT-G on sick leave. The findings from this study are described in paper III. Patients (age 20-60 years) consecutively referred from general practitioners from Jutland and Funen in the period of March 2010 - April 2012  (approx. 2.5 million citizens) to the Research Clinic for Functional Disorders and Psychosomatics, Aarhus University Hospital, were included. The pilot study included 34 patients, the RCT on ACT-G included 126 patients. In the RCT, patients were block-randomised to either ACT-G and received treatment in 7 groups of each 9 patients in the period of December 2010 - October 2012, or to a 10-month waitlist control group. The primary outcome measure was the Whiteley-7 paper and pencil index for illness worrying. The last paper is based on data on sickness-related benefits from the DREAM social register of transfer benefits and also includes a matched general population register control cohort (n=12,600). In this thesis, we wish to answer the following questions: 1) Is ACT-G an acceptable, feasible and effective treatment approach for patients with severe health anxiety? 2) Can ACT-G improve severe illness worry compared with a waitlist control condition, and are the recently introduced diagnostic criteria for health anxiety acceptable for the patients? 3) Do patients with health anxiety show more sick leave than the general population during a 5-year period, and can ACT-G reduce sick leave measured by transfer benefits (weeks on sickness-related benefits) at 1-year follow-up? As ACT has not previously been examined as treatment approach for health anxiety, we initially conducted an uncontrolled pilot study to test the newly developed manualised program (ACT-G). The study included 34 patients with severe health anxiety and showed very low dropout and high treatment satisfaction. Significant improvements in self-reported illness worry were demonstrated post-treatment, and the results were sustained and further improved at 3- and 6-months follow-up compared to baseline. The subsequent RCT found high acceptance of the diagnosis of health anxiety. All patients (except 1) accepted the diagnosis as the right diagnosis to fit their ailment, and the majority of the patients found that the diagnosis helped them to better understand their symptoms. In an intention-to-treat analysis, ACT-G showed significant effect in the improvement of self-reported illness worry and other secondary measures compared with a waitlist control condition, both post-treatment and at 10-month follow-up (6 months post-treatment). The results were considered clinically significant as 2/3 of the patients in ACT-G at follow-up had demonstrated a pre-defined treatment response, and ¼ of the patients were considered to no longer have clinical case status. Furthermore, the number needed to treat was found to be 2.4. Patients with severe health anxiety showed significantly more weeks on sickness-related benefits than matched individuals from the general population during the 5 years prior to entering the RCT. This difference was stable until an estimated cut-point at 1 year before enrolment, where patients with health anxiety showed further increase in sickness-related-benefits. At one-year follow-up (8 months post-treatment), we did not find a significant difference between ACT-G and the waitlist group in weeks on sickness-related benefits. Post-hoc analysis, however, revealed a significant decrease in weeks on sickness-related benefits for ACT-G during the 2 years after randomisation. In conclusion, the thesis suggests that ACT-G is both an acceptable and effective treatment approach for patients with severe health anxiety. Hopefully, these findings can contribute to the future research and identification of which treatment approaches are the most effective and for which patients and contribute to tailored, early interventions. This may possibly prevent development of otherwise chronic symptoms, increase the quality of life for the patients, and potentially reduce socio-economic costs.
HIV-associated lipodystrophy syndrome frequently presents as a relative lack of peripheral adipose tissue storage combined with an increase in visceral fat, associated with insulin resistance and dyslipidaemia. This thesis discusses explanations for the links between abnormalities in glucose metabolism, the steroid synthesis pathway, the growth hormone-insulin growth factor-1 axis, and chronic changes in adipose tissue distribution. Specifically, the mechanisms by which low-grade inflammation may affect the normal stimulatory effect of insulin on glucose and fat storage are reviewed. We propose that both chronic low-grade inflammation from HIV infection and treatment with HAART trigger cellular homeostatic stress responses with adverse effects on glucose metabolism. The physiological outcome is such that the total energy storage in the adipocytes is decreased, and the remaining adipocytes resist further energy storage. The excess circulating and dietary lipid metabolites, normally metabolised by adipose tissue, are deposited ectopically in the muscle, liver, or visceral adipose tissue, where they impair insulin action. This deposition of lipid metabolites leads to a vicious circle of insulin resistance and lipotoxicity leading to lipoatrophy or a mixed-type with increased visceral adipose tissue and a clinical phenotype of HIV-associated lipodystrophy syndrome with an elevated waist-to-hip ratio. This HIV-associated inflamm-ageing syndrome can provide a platform for further studies in HIV-infected patients and act as a model for biological accelerated ageing.
Cigarette smoke (CS) accounts for the outcome of several pathologies, even including lung cancer, cardiovascular disease and chronic obstructive pulmonary disease (COPD). Under healthy conditions, lung immune system becomes tolerant in response to various external stimuli. CS exposure alters the pulmonary immune equilibrium, thus leading to a condition of hyper activation of the local innate and adaptive immunity. COPD is one of the major complications of chronic CS exposure where a pro-inflammatory profile of the pulmonary and systemic immunity is predominant. In this review, alternative treatments with natural products to mitigate CS-mediated pulmonary inflammation are proposed. In particular, polyphenols, a class of natural compounds largely present in fruits and vegetables, have been shown to act as anti-inflammatory agents. Accordingly, recent experimental and clinical evidences support polyphenol-mediated potential health benefits in smokers. For instance, pomegranate juice is able to attenuate the damage provoked by CS on cultured human alveolar macrophages. In addition, maqui beery extract has been proven to normalize H2O2 and interleukin-6 levels in exhaled breath condensate in healthy smokers. However, some limitations of alternative treatments are represented by a better knowledge of the mechanism(s) of action exerted by polyphenols and by the lack of animal models of COPD. In any case, the potential targets of polyphenols in the course of COPD will be outlined with special reference to the activation of T regulatory cells as well as to the inhibition of the polymorphonuclear cell and monocyte respiratory burst and of the NF-kB pathway, respectively.
Our recent findings have demonstrated that electromagnetic radiations (EMR) (1.8 GHz radiofrequency) are able to in vitro induce morphometrical and morphological modifications of human leukocytes from normal donors. In view of the evidence that polyphenols exert many beneficial effects on plants, animals and humans, we reasoned that they may act as protective agents against EMR-mediated alterations of human leukocytes. In this direction, our data will show that 1 h pre-treatment of human healthy leukocytes with two polyphenol preparations from red grape before EMR exposure (1.8 GHz) reverts to normality their morphology in comparison to irradiated cells only. Conversely, leukocyte morphometry seems to be not affected by this treatment. Quite interestingly, we have previously found that some leukocyte samples from blood donors exhibited morphometrical and morphological alterations before EMR exposure. Here, we demonstrate that polyphenols are also able to normalize leukocyte morphology per se altered before as well as after irradiation. Finally, a working hypothesis aimed at clarifying the protective mechanisms exerted by polyphenols on irradiated leukocytes will be illustrated.
An increasing number of research evidences indicate linkage between type 2 diabetes mellitus (T2DM) and Alzheimer's disease (AD); the two most common diseases of aging. In addition, T2DM and AD also share some common pathophysiological features. Therefore, dual therapy that targets both the diseases can be regarded as a beneficial approach. Acetylcholinesterase (AChE) and beta-secretase (BACE) have been considered as potential therapeutic targets for AD. Accordingly, the piece of work presented here describes the binding of anti-diabetic drugs (Jardiance, Suiny and Nesina) with AChE and BACE so as to further investigate connecting bridges concerning the treatment of these two diseases. We have used "Autodock 4.2" for docking experiments. Both, hydrogen bond and hydrophobic interactions were found to be involved in the proper positioning of these diabetic drugs within the catalytic site (CAS) of AChE and BACE enzymes to permit docking. Free energy of binding (ΔG) for 'Jardiance-AChE', 'uiny-AChE' and 'Nesina-AChE' CAS interactions were found to be -9.21, -7.32 and -10.66 kcal/mol, respectively; while for 'Jardiance-BACE', 'Suiny -BACE' and
 'Nesina-BACE' CAS interactions the same were determined to be -8.91, -8.58 and -10.40 kcal/mol, respectively. Hence, these diabetic drugs might act as potent dual inhibitors for the treatment of diabetes-associated neurological disorders. Consequently, the results described herein may form the basis of future dual therapy against the same.
Cancer is a multifactorial disease and most of its types still remain incurable, in spite of enormous efforts to explicate various tumor pathophysiology. The anti-cancer drug discovery paradigm "one-compound-one-target" has failed and subsequently shifted to two-drug cocktail and recently the "multi-target approach" in order to design and develop agents able to act simultaneously on multiple intracellular constituents and signaling pathways. Novel hybrid compounds are now designed by incorporating two covalently linked independently acting pharmacores, each efficient at combating cancer. They can deliver synergistic effects from the dual action of both independently acting moieties by interacting with multiple targets. These composite molecules are also less prone to drug resistance, leading to an improved pharmacological potency than each individual moiety. As indole nucleus is a central component of many natural and synthetic molecules with extensive biological activity, this review incorporates a variety of such hybrid compounds with indole moiety as one of the active units, where better therapeutic effect has been successfully achieved, by either simultaneous or sequential action of individual functional pharmacore. The current limitations and challenges encountered in the development of these hybrid agents are also discussed.
Finding high quality beginning compounds is a critical job at the start of the lead generation stage for multi-target drug discovery (MTDD). Designing hybrid compounds as a selective multi-target chemical entity is a challenge, opportunity, and new idea to better act against specific multiple targets. One hybrid molecule is formed by two (or more) pharmacophore group's participation. So, these new compounds often exhibit two or more activities going about as multi-target drugs (mt-drugs) and may have superior safety or efficacy. Application of integrating a range of information and sophisticated new in silico, bioinformatics, structural biology, pharmacogenomics methods may be useful to discover/design, and synthesis of the new hybrid molecules. In this regard, many rational and screening approaches have followed by medicinal chemists for the lead generation in MTDD. Here, we review some popular lead generation approaches that have been used for designing multiple ligands (DMLs). This paper focuses on dual- acting chemical entities that incorporate a part of two drugs or bioactive compounds to compose hybrid molecules. Also, it presents some of key concepts and limitations/strengths of lead generation methods by comparing combination framework method with screening approaches. Besides, a number of examples to represent applications of hybrid molecules in the drug discovery are included.
5-LOX - 5-lipoxygenase; ACT - artemisinin-based combination therapies; ADME - absorption, distribution, metabolism and excretion; BAL - broncho alveolar lavage; CABP - community acquired bacterial pneumonia; cAMP - cyclic adenosine monophosphate; CAP - community-acquired pneumonia; CF - cystic fibrosis, BOS bronchiolitis obliterans syndrome; cGMP - cyclic guanosine monophosphate; COPD - chronic obstructive pulmonary disease; COX - cyclooxygenase; DPB - diffuse panbronchiolitis; HDACs - histone deacetylases; IBD - inflammatory bowel disease; IL-1p - interleukin 1p; IL-6 - interleukin 6; MIC - minimal inhibitory concentrations; MLSB - macrolide, lincosamide, streptogramin B; NSAIDs - non-steroidal anti-inflammatory drugs; OVA - ovalbumin; PDE4 - phosphodiesterase 4; PMA - phorbol 12-myristate 13-acetate; RA - rheumatoid arthritis; RTI - respiratory tract infections; SAHA - suberoylanilide hydroxamic acid; SAR - structure-activity-relationship; Th1 - type 1 helper T-cell; TNBS - trinitrobenzene sulfonic acid; TNF-α - tumour necrosis factor α; UN - United Nations, WHO - World Health Organisation.
Swelling of polymeric hydrogels is sensitive to their crosslink densities. Here, we exploit this principle to prepare self-rupturing gels, which are based on an commonly-used, non-toxic and inexpensive polyelectrolyte, poly(acrylic acid) (PAA) and are prepared through a simple and low-cost thermoinitiated polymerization-based technique. The self-rupture of these covalently crosslinked gels is achieved by preparing them to have highly non-uniform crosslink densities. This heterogeneity in crosslinking leads to highly non-uniform swelling, which generates stresses that are high enough to induce gel rupture. The time required for this rupture to occur depends on the difference in the crosslink densities between the adjoining gel regions, gel size, order in which the variably-crosslinked gel segments are synthesized (as well as the ambient pH and ionic strength). Furthermore, when these self-rupturing gels are prepared to have liquid-filled (capsule-like) morphologies, they can act as timed/delayed release devices. The self-rupture of these capsules provides a burst payload release after a pre-programmed delay, which is on the timescale of days and can be easily tuned by varying the rupture time - i.e., by varying either the crosslink nonuniformity, or the pH and ionic strength of the release media.
In this work we describe the synthesis, thermal and rheological characterization, hot-melt extrusion and three-dimensional printing (3DP) of poly(2-vinylpyridine) (P2VP). We investigate the effect of thermal processing conditions on physical properties of produced filaments in order to achieve high quality, 3D- printable filaments for fused deposition modeling (FDM). We 3D-print P2VP filaments using an affordable 3D printer. The pyridine moieties are crosslinked and quaternized post-printing to form 3D-printed pH-responsive hydrogels. The printed objects exhibited dynamic and reversible pH-dependent swelling. These hydrogels act as flow regulating valves, controlling the flow rate with pH. Additionally, a macroporous P2VP membrane was 3D-printed and the coordinating ability of the pyridyl groups was harassed to immobilize silver precursors on its surface. After the reduction of silver ions, the structure was used to catalyze the reduction of 4-nitrophenol to 4-aminophenol with a high efficiency. This is a facile technique to print recyclable catalytic objects.
Your department has had a good track record over many years for preparing trainees to successfully sit for the ACEM Fellowship exam. On average the pass rate for your trainees is over 80%. Then, to your dismay, suddenly only two of five of your trainees pass the latest Fellowship exam. Does this anomaly necessitate an urgent review of your department's training programme, or is it just a statistical quirk? Let us suppose you can prepare candidates so that they all have at least an 80% chance of passing. The probability that all five candidates would have passed is 32.8% (or 0.8(5) ) based on the multiplication rule of probability for independent events. The probability that only two of five passed is 5.1% (or 10 × 0.8(2) × 0.2(3) ) based on the binomial distribution, which is a probability distribution analogous to the normal distribution. The construction of the binomial distribution depends on two parameters: (i) number of candidates sitting ('n'), and (ii) probability of passing for any individual candidate ('P'). The distribution gives the probability that 'x' number of individuals will pass when 'n' number of individuals sit. Thus despite an 80% pass rate historically, the probability that only two of five candidates will pass is not negligible at 5.1%. It is an anomaly, which we may choose not to act on unless it is recurrent, noting it will be expected to occur naturally about one time out of 20. The real challenge is to maintain or increase that individual probability at 80% or higher.
Drug-paired environments can act as stimuli that elicit drug craving. In humans, drug craving is influenced by the amount of time abstinent, number of past periods of abstinence, and inadvertent exposure to the previously abused drug. The current experiments were designed to determine the effects of (i) the duration of abstinence on expression of ethanol (EtOH)-seeking; (ii) EtOH priming following a short and long abstinence period; and (iii) repeated deprivation cycles on relapse drinking and EtOH-seeking.
Rats were allowed to self-administer 15% EtOH, processed through extinction training, maintained in a home cage for a designated EtOH-free period, and then reintroduced to the operant context in the absence of EtOH. The experiments examined the effects of: (i) various home-cage duration periods (1 to 8 weeks), (ii) priming injections of EtOH in the Pavlovian spontaneous recovery (PSR; 14 days after extinction) and reinstatement of responding (RoR; 1 day after extinction) models, and (iii) exposure to repeated cycles of EtOH access-deprivation on relapse drinking and EtOH-seeking behavior.
Highest expression of EtOH-seeking was observed following 6 weeks of home-cage maintenance. Priming injections of EtOH were more efficacious at stimulating/enhancing EtOH-seeking in the PSR than RoR model. Exposure to repeated cycles of EtOH deprivation and access enhanced and prolonged relapse drinking and the expression of EtOH-seeking (318 ± 22 responses), which was not observed in rats given equivalent consistent exposure to EtOH (66 ± 11 responses).
Overall, the data indicated that the PSR model has ecological validity; factors that enhance EtOH craving in humans enhance the expression of EtOH-seeking in the PSR test. The data also detail factors that
 need to be examined to determine the biological basis of EtOH-seeking (e.g., neuroadaptations that occur during the incubation period and following repeated cycles of EtOH drinking and abstinence).
Green tea has been found to increase the lifespan of various experimental animal models including the fruit fly, Drosophila melanogaster. High in polyphenolic content, green tea has been shown to reduce oxidative stress in part by its ability to bind free iron, a micronutrient that is both essential for and toxic to all living organisms. Due to green tea's iron-binding properties, we questioned whether green tea acts to increase the lifespan of the fruit fly by modulating iron regulators, specifically, mitoferrin, a mitochondrial iron transporter, and transferrin, found in the hemolymph of flies. Publicly available hypomorph mutants for these iron regulators were utilized to investigate the effect of green tea on lifespan and fertility. We identified that green tea could not increase the lifespan of mitoferrin mutants but did rescue the reduced male fertility phenotype. The effect of green tea on transferrin mutant lifespan and fertility were comparable to w(1118) flies, as observed in our previous studies, in which green tea increased male fly lifespan and reduced male fertility. Expression levels in both w(1118) flies and mutant flies, supplemented with green tea, showed an upregulation of mitoferrin but not transferrin. Total body and mitochondrial iron levels were significantly reduced by green tea supplementation in w(1118) and mitoferrin mutants but not transferrin mutant flies. Our results demonstrate that green tea may act to increase the lifespan of Drosophila in part by the regulation of mitoferrin and reduction of mitochondrial iron.
The core skeletal muscle ryanodine receptor (RyR1) calcium release complex extends through three compartments of the muscle fibre, linking the extracellular environment through the cytoplasmic junctional gap to the lumen of the internal sarcoplasmic reticulum (SR) calcium store. The protein complex is essential for skeletal excitation-contraction (EC-) coupling and skeletal muscle function. Its importance is highlighted by perinatal death if any one of the EC-coupling components are missing and by myopathies associated with mutation of any of the proteins. The proteins essential for EC-coupling include the DHPR α1S subunit in the transverse tubule membrane, the DHPR β1a subunit in the cytosol and the RyR1 ion channel in the SR membrane. The other core proteins are triadin and junctin and calsequestrin, associated mainly with SR. These SR proteins are not essential for survival but exert structural and functional influences that modify the gain of EC-coupling and maintain normal muscle function. This review summarises our current knowledge of the individual protein/protein interactions within the core complex and their overall contribution to EC-coupling. We highlight significant areas that provide a continuing challenge for the field. Additional important components of the Ca(2+) release complex, such as FKBP12, calmodulin, S100A1 and Stac3 are identified and reviewed elsewhere.(3) This article is protected by copyright. All rights reserved.
Transfusion of a single unit of stored red blood cells (RBCs) has been hypothesized to induce supra-physiological levels of non-transferrin bound iron (NTBI), which may enhance inflammation and act as a nutrient for bacteria. We investigated the relation between RBC storage time and iron levels in a clinically relevant "two-hit" human transfusion model.
Eighteen healthy male volunteers (ages 18-35 years) were infused with 2 ng lipopolysaccharide (LPS)/kg to induce systemic inflammatory response syndrome. Two hours later, each participant received either 1 unit of 2-day stored (2D) autologous RBCs, 35-day stored (35D) autologous RBCs, or an equal volume of saline. Every 2 hours up to 8 hours after LPS infusion, hemoglobin, hemolysis parameters, and iron parameters, including NTBI, were measured.
Transfusion of both 2D and 35D RBCs caused increases in hemoglobin, plasma iron, and transferrin saturation; whereas levels remained stable in the saline group. Transfusion of 35D RBCs did not result in hemolysis nor did it lead to increased levels of NTBI compared with 2D RBCs or saline. LPS induced increases in ferritin, haptoglobin, bilirubin, and lactate dehydrogenase that were similar in all three groups.
We conclude that 35D autologous RBCs do not cause hemolysis or increased levels of NTBI during human endotoxemia.
Both enchondroma and atypical cartilaginous tumors (ACT) are not considered malignant, so inactive and asymptomatic tumors might not need surgery. To the best of our knowledge, this is the first study that has been done to evaluate the natural course of conservative-treated enchondroma and ACT in the long bones.
For this retrospective study, we analyzed the results of patients in whom we refrained from surgery and only regularly performed radiological follow-up of the tumor. Minimal follow-up after initial diagnosis was 24 months.
Forty-nine patients were included in this study. Eight out of forty-nine cases received surgical treatment during follow-up of the tumor. The reasons for this surgery were radiologic growth of the tumor in two cases, pain in one case, patient request in three cases, another indication for surgery in the same limb in two cases.
In this small series of conservatively treated enchondroma and ACT, only 6% of the patients had a medical indication for surgery. This study shows that indication for surgery should be discussed more thoroughly. Based on our results, we would recommend annual radiologic follow-up for asymptomatic enchondroma or ACT in the long bones, irrespective of tumor size. J. Surg. Oncol. © 2016 Wiley Periodicals, Inc.
Assessment of minimal residual disease (MRD) is becoming standard diagnostic care for potentially curable neoplasms such as some acute leukemias as well as chronic myeloid and lymphocytic leukemia. Although multiple myeloma (MM) remains as an incurable disease, around half of the patients achieve complete remission (CR), and recent data suggests increasing rates of curability with "total-therapy-like" programs. This landscape is likely to be improved with the advent of new antibodies and small molecules. Therefore, conventional serological and morphological techniques have become suboptimal for sensitive evaluation of highly effective treatment strategies. Although, existing data suggests that MRD could be used as a biomarker to evaluate treatment efficacy, help on therapeutic decisions, and act as surrogate for overall survival, the role of MRD in MM is still a matter of extensive debate. Here, we review the different levels of remission used to define depth of response in MM and their clinical significance, as well as the prognostic value and unique characteristics of MRD detection using immunophenotypic, molecular, and imaging techniques. Key facts The higher efficacy of new treatment strategies for MM demand the incorporation of highly sensitive techniques to monitor treatment efficacy MRD could be used as a more potent surrogate biomarker for survival than standard CR We need to understand the pros and cons of the different MRD techniques The time has come to incorporate highly sensitive, cost-effective, readily available, and standardized MRD techniques into clinical trials to assess its role in therapeutic decisions.
Many cathinone analogs act as substrates or inhibitors at dopamine, norepinephrine, and serotonin transporters (DAT, NET, SERT, respectively). Drug selectivity at DAT vs. SERT is a key determinant of abuse potential for monoamine transporter substrates and inhibitors, such that potency at DAT > SERT is associated with high abuse potential, whereas potency at DAT < SERT is associated with low abuse potential. Quantitative structure-activity relationship (QSAR) studies with a series of 4-substituted methcathinone analogs identified volume of the 4-position substituent on the methcathinone phenyl ring as one structural determinant of both DAT vs. SERT selectivity and abuse-related behavioral effects in an intracranial self-stimulation procedure in rats. Subsequent modeling studies implicated specific amino acids in DAT and SERT that might interact with 4-substituent volume to determine effects produced by this series of cathinone analogs. These studies illustrate use of QSAR analysis to investigate pharmacology of cathinones and function of monoamine transporters.
Caterpillar hairs are thought to act as a physical barrier against natural enemies, including parasitoids. However, very few studies have experimentally demonstrated how hairs protect caterpillars from parasitoid oviposition. To clarify the importance of caterpillar hairs as an anti-parasitoid defence, we observed the generalist endoparasitoid Meteorus pulchricornis (Hymenoptera: Braconidae) attacking both smooth and hairy caterpillars under laboratory conditions. A female Meteorus pulchricornis uses its ovipositor to inject venom and lay a single egg inside host larvae. We placed a smooth Spodoptera litura (Lepidoptera: Noctuidae) caterpillar or a hairy Lymantria dispar japonica (Lepidoptera: Erebidae) caterpillar in front of parasitoid females. We observed that 100 % and 84 % of the parasitoids could successfully stab their ovipositors into the smooth larvae of S. litura and first instars of the hairy caterpillar L. dispar japonica, respectively. However, only 24 % of parasitoids could successfully stab their ovipositors into second-instar L. dispar japonica. A higher rate of successful stabs (94 %) by parasitoids was obtained by cutting the hairs of second instar L. dispar japonica much shorter than the parasitoid ovipositor. The results demonstrate that the long, thick hairs of second and later instars
 of L. dispar japonica function as a physical barrier against parasitoid oviposition.
Social interaction and communication are complex behavioral paradigms involving many components. Many different neurotransmitters, hormones, sensory inputs, and brain regions are involved in the act of social engagement and verbal or nonverbal communication. Autism Spectrum Disorder (ASD) and schizophrenia are two neurodevelopmental disorders that have social and language deficits as hallmark symptoms, but show very different etiologies. The output of social dysfunction is common to both ASD and schizophrenia, but this likely arises from very different pathophysiological means. This review will attempt to compile and interpret human and animal studies showing the neurobiological basis for the development of social and language deficits in ASD and schizophrenia as well as a comparison of the two disorders.
The properties of cellular membranes are critical for most cellular functions and are influenced by several parameters including phospholipid composition, integral and peripheral membrane proteins, and environmental conditions such as temperature. We previously showed that the C. elegans paqr-2 and iglr-2 mutants have a defect in membrane homeostasis and exhibit several distinct phenotypes, including a characteristic tail tip defect and cold intolerance. In the present study we report that screening for novel mutants with these 2 defects can lead to the identification of genes that are important contributors to membrane properties. In particular we isolated 3 novel alleles of sma-1, the C. elegans homolog of βH spectrin, and 2 novel alleles of dpy-23, which encodes the C. elegans homolog of the AP2 μ subunit. We also show that sma-1 and dpy-23 act on membrane properties in pathways distinct from that of paqr-2 and iglr-2.
C. elegans spe-9 class genes are male germline-enriched in their expression and indispensable during sperm-oocyte fusion. Identification of mammalian orthologs that exhibit similar functions to these C. elegans genes has been a challenge. The mouse Izumo1 gene encodes a sperm-specific, immunoglobulin (Ig)-like transmembrane (TM) protein that is required for gamete fusion. We recently identified the C. elegans spe-45 gene, which shows male germline-enriched expression and encodes an Ig-like TM protein. spe-45 mutant worms produced otherwise normal spermatozoa that cannot fuse with oocytes, causing essentially the same phenotype as that seen in the Izumo1-knockout mice. By counting the number of self-sperm in the spermatheca of spe-45 hermaphrodites, it was found that this gene might be involved in sperm guidance from the uterus into the spermatheca, as well as gamete fusion. Moreover, we discovered that SPE-45 and IZUMO1 share certain functions for gamete fusion, which are presumably related to binding with cis- and/or trans-partners. Intriguingly, various organisms have Ig-like TM proteins that act during gamete interactions, indicating the wide-spread utility of Ig-like domains during fertilization.
Elevated bone marrow adiposity (BMA) is defined as an increase in the proportion of the bone marrow (BM) cavity volume occupied by adipocytes. This can be caused by an increase in the size and/or number of adipocytes. BMA increases with age in a bone-site-specific manner. This increase may be linked to certain pathophysiological situations. Osteoporosis or compromised bone quality is frequently associated with high BMA. The involvement of BM adipocytes in bone loss may be due to commitment of mesenchymal stem cells to the adipogenic pathway rather than the osteogenic pathway. However, adipocytes may also act on their microenvironment by secreting factors with harmful effects for the bone health. Here, we review evidence that in a context of energy deficit (such as anorexia nervosa (AN) and restriction rodent models) bone alterations can occur in the absence of an increase in BMA. In severe cases, bone alterations are even associated with gelatinous BM transformation. The relationship between BMA and energy deficit and the potential regulators of this adiposity in this context are also discussed. On the basis of clinical studies and preliminary results on animal model, we propose that competition between differentiation into osteoblasts and differentiation into adipocytes might trigger bone loss at least in moderate-to-severe AN and in some calorie restriction models. Finally, some of the main questions resulting from this hypothesis are discussed.
Our mental representations of our body are continuously updated through multisensory bodily feedback as we move and interact with our environment. Although it is often assumed that these internal models of body-representation are used to successfully act upon the environment, only a few studies have actually looked at how body-representation changes influence goal-directed actions, and none have looked at this in relation to body-representation changes induced by sound. The present work examines this question for the first time. Participants reached for a target object before and after adaptation periods during which the sounds produced by their hand tapping a surface were spatially manipulated to induce a representation of an elongated arm. After adaptation, participants' reaching movements were performed in a way consistent with having a longer arm, in that their reaching velocities were reduced. These kinematic changes suggest auditory-driven recalibration of the somatosensory representation of the arm morphology. These results provide support to the hypothesis that one's represented body size is used as a perceptual ruler to measure objects' distances and to accordingly guide bodily actions.
Nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) signaling pathways are involved in cell immune responses, apoptosis and infections. In multiple sclerosis (MS), NF-κB pathways are changed, leading to increased levels of NF-κB activation in cells. This may indicate a key role for NF-κB in MS pathogenesis. NF-κB signaling is complex, with many elements involved in its activation and regulation. Interestingly, current MS treatments are found to be directly or indirectly linked to NF-κB pathways and act to adjust the innate and adaptive immune system in patients. In this review, we will first focus on the intricacies of NF-κB signaling, including the activating pathways and regulatory elements. Next, we will theorize about the role of NF-κB in MS pathogenesis, based on current research findings, and discuss some of the associated therapeutic implications. Lastly, we will review four new MS treatments which interrupt NF-κB pathways-fingolimod, teriflunomide, dimethyl fumarate (DMF) and laquinimod (LAQ)-and explain their mechanisms, and the possible strategy for MS treatments in the future.
Fractional exhaled nitric oxide (FENO) is a biomarker of airway inflammation in asthma. The measurement of FENO is utilized to assist in the diagnosis and treatment of children with asthma, especially for those treated with inhaled corticosteroids.
The aims of this study were to evaluate the correlations between FENO and atopic status, blood eosinophil levels, FCER2 mutation, and asthma control in Vietnamese children.
This was a prospective and descriptive study approved by the local Ethical Board. All children with uncontrolled asthma, seen in the National Hospital of Pediatrics (Hanoi, Vietnam), were included. Exhaled breath FENO, blood eosinophils, skin prick test, total IgE, asthma control test (ACT), and FCER2 gene polymorphism were performed at inclusion. They were followed up at 3 months to evaluate clinical status, FENO levels, and ACT.
Forty-two children with uncontrolled asthma with a mean age of 10±3 years (6-16 years) were included. The male/female ratio was 2.5/1. The mean FENO levels were 26±25 ppb. FENO was significantly higher in patients with a positive skin prick test for respiratory allergens (P<0.05). FENO was significantly correlated with blood eosinophil levels (r=0.5217; P=0.0004). Five of the 32 subjects (15.6%) had a mutation of FCER2 gene (rs28364072 SNP). In this group, the levels of FENO were highest (37±10 ppb; P<0.05). The levels of FENO were significantly decreased after 3 months of treatment (17±8 ppb vs 26±25 ppb; P<0.05). Significant correlations between inhaled corticosteroid doses and FENO levels occurred at 1 and 3 months (r=0.415, P=0.007; r=0.396, P=0.010; respectively). There were no correlations between FENO levels, ACT, and daily use of salbutamol. After 3 months, asthma remained uncontrolled in 22.2% of children.
The measurement of FENO levels is a useful and feasible tool to predict clinical, biological, and asthma control in Vietnamese children.
Wedgies-the upward yanking of another's underpants from the rear to wedge them between the buttocks-can be administered playfully, maliciously, or adventurously; at forces ranging from gentle to "atomic"; and with or without the foreknowledge or consent of the recipient. Wedgies have been documented anecdotally in the popular Internet literature, with chief emphasis on their sensation-seeking or momentary entertainment value to the giver and recipient. Most participants are typically young; however, we report the case of a 50-year-old man who sustained chronic, painless radiculitis after he received an unanticipated wedgie of moderate force. This report-apparently the first of its kind in the medical literature-serves as notice that exchanging wedgies is not merely a juvenile act or immature prank: the outcome can be injurious.
The presumptive approach of confirming malaria in health facilities leads to over-diagnosis of malaria, over use of anti-malaria drugs and the risk of drug resistance development. WHO recommends parasitological confirmation before treatment with artemisinin-based combination
 therapy (ACT) in all suspected malaria patients. The use of malaria rapid diagnostic tests (mRDTs) would make it possible for prescribers to diagnose malaria at point-of-care and better target the use of antimalarials. Therefore, a cost-effectiveness analysis was performed on the introduction of mRDTs for management of malaria in under-five children in a high transmission area in Ghana where presumptive diagnosis was the norm in public health centres.
A cluster-randomised controlled trial where thirty-two health centres were randomised into test-based diagnosis of malaria using mRDTs (intervention) or clinical judgement (control) was used to measure the effect of mRDTs on appropriate treatment: 'a child with a positive reference diagnosis prescribed a course of ACT or a child with a negative reference diagnosis not given an ACT'. Cost data was collected from five purposively selected health centres and used to estimate the health sector costs of performing an mRDT and treat children for malaria and other common febrile illnesses. Costs of training healthcare personnel and supervision in the study period were also collected. A sample of caregivers to children participating in the trial was interviewed about household cost incurred on transport, drugs, fees, and special food during a period of one week after the health centre visit as well as days unable to work. A decision model approach was used to calculate the incremental cost-effectiveness ratios (ICERs). Univariate and multivariate sensitivity analyses were applied to assess the robustness of ICERs.
The availability of mRDTs for malaria diagnosis resulted in fewer ACT treatments compared to the clinical judgement approach (73% versus 81%) and more children appropriately treated (70% versus 57%). The introduction of mRDT-based diagnosis would cost the Ministry of Health US$18.6 per extra appropriately treated child under five compared to clinical judgement while the ICER from a societal perspective was lower at US$11.0 per appropriately treated child. ICERs were sensitive to a decrease in adherence to negative mRDTs, malaria positivity rate and specificity of the mRDT.
The introduction of mRDTs is likely to be considered cost-effective in this high transmission setting as this intervention increased the number of appropriately treated children at low cost.
ClinicalTrials.gov NCT00832754.
Insulin like growth factor (IGF)-I can act on a variety of cells involved in cartilage and bone repair, yet IGF-I has not been studied extensively in the context of inflammatory arthritis. The objective of this study was to investigate whether IGF-I overexpression in the osteoblast lineage could lead to increased reparative or pathological bone formation in rheumatoid arthritis and/or spondyloarthritis respectively.
Mice overexpressing IGF-I in the osteoblast lineage (Ob-IGF-I+/-) line 324-7 were studied during collagen induced arthritis and in the DBA/1 aging model for ankylosing enthesitis. Mice were scored clinically and peripheral joints were analysed histologically for the presence of hypertrophic chondrocytes and osteocalcin positive osteoblasts.
90-100% of the mice developed CIA with no differences between the Ob-IGF-I+/- and non-transgenic littermates. Histological analysis revealed similar levels of hypertrophic chondrocytes and osteocalcin positive osteoblasts in the ankle joints. In the DBA/1 aging model for ankylosing enthesitis 60% of the mice in both groups had a clinical score 1<. Severity was similar between both groups. Histological analysis revealed the presence of hypertrophic chondrocytes and osteocalcin positive osteoblasts in the toes in equal levels.
Overexpression of IGF-I in the osteoblast lineage does not contribute to an increase in repair of erosions or syndesmophyte formation in mouse models for destructive and remodeling arthritis.
Phenylalanine hydroxylase (PAH) is a key tyrosine-biosynthetic enzyme involved in neurological and melanin-associated physiological processes. Despite extensive investigations in holometabolous insects, a PAH contribution to insect embryonic development has never been demonstrated. Here, we have characterized, for the first time, the PAH gene in a hemimetabolous insect, the aphid Acyrthosiphon pisum. Phylogenetic and sequence analyses confirmed that ApPAH is closely related to metazoan PAH, exhibiting the typical ACT regulatory and catalytic domains. Temporal expression patterns suggest that ApPAH has an important role in aphid developmental physiology, its mRNA levels peaking at the end of embryonic development. We used parental dsApPAH treatment to generate successful knockdown in aphid embryos and to study its developmental role. ApPAH inactivation shortens the adult aphid lifespan and considerably affects fecundity by diminishing the number of nymphs laid and impairing embryonic development, with newborn nymphs exhibiting severe morphological defects. Using single nymph HPLC analyses, we demonstrated a significant tyrosine deficiency and a consistent accumulation of the upstream tyrosine precursor, phenylalanine, in defective nymphs, thus confirming the RNAi-mediated disruption of PAH activity. This study provides first insights into the role of PAH in hemimetabolous insects and demonstrates that this metabolic gene is essential for insect embryonic development.
Drug resistance has emerged as one of the greatest challenges facing malaria control. The recent emergence of resistance to artemisinin (ART) and its partner drugs in ART-based combination therapies (ACT) is threatening the efficacy of this front-line regimen for treating Plasmodium falciparum parasites. Thus, an understanding of the molecular mechanisms that underlie the resistance to ART and the partner drugs has become a high priority for resistance containment and malaria management. Using genome-wide association studies, we investigated the associations of genome-wide single nucleotide polymorphisms with in vitro sensitivities to 10 commonly used antimalarial drugs in 94 P. falciparum isolates from the China-Myanmar border area, a region with the longest history of ART usage. We identified several loci associated with various drugs, including those containing pfcrt and pfdhfr. Of particular interest is a locus on chromosome 10 containing the autophagy-related protein 18 (ATG18) associated with decreased sensitivities to dihydroartemisinin, artemether and piperaquine - an ACT partner drug in this area. ATG18 is a phosphatidylinositol-3-phosphate binding protein essential for autophagy and recently identified as a potential ART target. Further investigations on the ATG18 and genes at the chromosome 10 locus may provide an important lead for a connection between ART resistance and autophagy.
The invasive pathogen, ash dieback fungus Hymenoscyphus fraxineus, is spreading rapidly across Europe. It shows high levels of outcrossing and limited population structure, even at the epidemic front. The anamorphic (asexual) form produces prolific conidia, thought to function solely as spermatia (male gametes), facilitating gene flow between sympatric strains. Here, we show that conidia are capable of germination on ash leaves and in vitro, and can infect seedlings via leaves or soil. In leaves, germlings form structures resembling fruiting bodies. Additionally, H. fraxineus colonises ash debris and grows in soil in the absence of ash tissues. We propose an amended life-cycle in which wind-dispersed, insect-vectored or water-spread conidia infect ash and may sporulate in planta, as well as in forest debris. This amplifies inoculum levels of different strains in ash stands. In combination with their function as spermatia, conidia thus act to maximise gene flow between sympatric strains, including those originally present at low inoculum. Such mixing increases evolutionary potential, as well as enhancing the likelihood of gene introgression from closely-related strains or assimilation of further genetic diversity from parental Asian populations. This scenario increases the adaptability of H. fraxineus to new climates and, indeed, onto new host species.
Gastric cancer (GC) is one of the most common types of cancer worldwide, and it involves extensive local tumour invasion, metastasis and poor prognosis. Understanding the mechanisms regulating the progression of GC is necessary for the development of effective therapeutic strategies. Transducin (β)-like 1 X-linked receptor 1 (TBL1XR1) is an important regulator controlling gene activation and repression, which has been thought to be involved in tumorigenesis. However, the role of TBL1XR1 in human GC remains largely unknown. Here, we find that TBL1XR1 is aberrantly expressed in human GC tissues, and TBL1XR1 levels are highly correlated with local tumour invasion, late tumor, lymph node, metastasis ( TNM) stage and poor prognosis. Knockdown of TBL1XR1 by shRNA inhibits GC cell proliferation, migration, invasion, epithelial-mesenchymal transition (EMT) in vitro, as well as tumorigenesis and peritoneal metastasis in vivo, whereas overexpression of TBL1XR1 produces the opposite effects. These effects are mediated by activation of the ERK1/2 signalling pathway, and inhibition of this pathway with a specific ERK1/2 inhibitor (U0126) significantly impairs the tumour-promoting effects induced by TBL1XR1. Moreover, TBL1XR1 mediated ERK1/2 activation is dependent on the β-catenin/MMP7/EGFR signalling pathway. In conclusion, TBL1XR1 contributes to GC tumorigenesis and progression through the activation of the β-catenin/MMP7/EGFR/ERK signalling pathway and may act as a new therapeutic target for GC.Oncogene advance online publication, 3 October 2016; doi:10.1038/onc.2016.352.
The MDMX (MDM4) oncogene is amplified or overexpressed in a significant percentage of human tumors. MDMX is thought to function as an oncoprotein by binding p53
 tumor suppressor protein to inhibit p53-mediated transcription, and by complexing with MDM2 oncoprotein to promote MDM2-mediated degradation of p53. However, down-regulation or loss of functional MDMX has also been observed in a variety of human tumors that are mutated for p53, often correlating with more aggressive cancers and a worse patient prognosis. We have previously reported that endogenous levels of MdmX can suppress proliferation and promote pseudo-bipolar mitosis in primary and tumor cells derived from p53-deficient mice, and that MdmX-p53 double deficient mice succumb to spontaneously formed tumors more rapidly than p53-deficient mice. These results suggest that the MdmX oncoprotein may act as a tumor-suppressor in cancers with compromised p53 function. By using orthotopic transplantation and lung colonization assays in mice we now establish a p53-independent anti-oncogenic role for MdmX in tumor progression. We also demonstrate that the roles of MdmX in genome stability and in proliferation are two distinct functions encoded by the separate MdmX protein domains. The central Zn-finger domain suppresses multipolar mitosis and chromosome loss, whereas the carboxy-terminal RING domain suppresses proliferation of p53-deficient cells. Furthermore, we determine that it is the maintenance of genome stability that underlies MdmX role in suppression of tumorigenesis in hyperploid p53 mutant tumors. Our results offer a rationale for the increased metastatic potential of p53 mutant human cancers with aberrant MdmX function and provide a caveat for the application of anti-MdmX treatment of tumors with compromised p53 activity.
National/social health insurance schemes have increasingly been seen in many low- and middle-income countries (LMICs) as a vehicle to universal health coverage (UHC) and a viable alternative funding mechanism for the health sector. Several countries, including Ghana, have thus introduced and implemented mandatory national health insurance schemes (NHIS) as part of reform efforts towards increasing access to health services. Ghana passed mandatory national health insurance (NHI) legislation (ACT 650) in 2003 and commenced nationwide implementation in 2004. Several peer review studies and other research reports have since assessed the performance of the scheme with positive rating while challenges also noted. This paper contributes to the literature on economic and political implementation challenges based on empirical evidence from the perspectives of the different category of actors and institutions involved in the process.
Qualitative in-depth interviews were held with 33 different category of participants in four selected district mutual health insurance schemes in Southern (two) and Northern (two) Ghana. This was to ascertain their views regarding the main challenges in the implementation process. The participants were selected through purposeful sampling, stakeholder mapping, and snowballing. Data was analysed using thematic grouping procedure.
Participants identified political issues of over politicisation and political interference as main challenges. The main economic issues participants identified included low premiums or contributions; broad exemptions, poor gatekeeper enforcement system; and culture of curative and hospital-centric care.
The study establishes that political and economic factors have influenced the implementation process and the degree to which the policy has been implemented as intended. Thus, we conclude that there is a synergy between implementation and politics; and achieving UHC under the NHIS requires political stewardship. Political leadership has the responsibility to build trust and confidence in the system by providing the necessary resources and backing with minimal interference in the operations. For sustainability of the scheme, authorities need to review the exemption policy, rate of contributions, especially, from informal sector employees and recruitment criteria of scheme workers, explore additional sources of funding and re-examine training needs of employees to strengthen their competences among others.
Good drug regulation requires an effective system for monitoring and inspection of manufacturing and sales units. In India, despite widespread agreement on this principle, ongoing shortages of drug inspectors have been identified by national committees since 1975. The growth of India's pharmaceutical industry and its large export market makes the problem more acute.
The focus of this study is a case study of Maharashtra, which has 29% of India's manufacturing units and 38% of its medicines exports. India's regulations were reviewed, comparing international, national and state inspection norms with the actual number of inspectors and inspections. Twenty-six key informant interviews were conducted to ascertain the causes of the shortfall.
In 2009-2010, 55% of the sanctioned posts of drug inspectors in Maharashtra were vacant. This resulted in a shortfall of 83%, based on the Mashelkar Committee's recommendations. Less than a quarter of the required inspections of manufacturing and sales units were undertaken. The Indian Drugs and Cosmetics Act and its Rules and Regulations make no provisions for drug inspectors and workforce planning norms, despite the growth and increasing complexity of India's pharmaceutical industry.
The Maharashtra Food and Drug Administration (FDA) falls short of the Mashelkar Committee's recommended workforce planning norms. Legislation and political and operational support are required to produce needed changes.
We aimed to explore aspects of the removal of hanging points from correctional facilities.
An argument can be made that individuals have a right to die/suicide. The United Nations holds that except for freedom of movement, prisoners have the same rights as non-prisoners. The rights of the individual and the duty of many custodial institutions are in conflict. This introduces a conundrum; when all hanging points are removed from correctional facilities, prisoners without mental disorder, but with a sustained wish to die, will not be able to achieve that end, while non-prisoners will be well able to do so.
This study aims to explore the effects of tranexamic acid on the coagulation indexes of patients undergoing heart valve replacement surgery under the condition of cardiopulmonary bypass (CPB). One hundred patients who conformed to the inclusive criteria were selected and divided into a tranexamic acid group and a non-tranexamic acid group. They all underwent heart valve replacement surgery under CPB. Patients in the tranexamic acid group were intravenously injected with 1 g of tranexamic acid (100 mL) at the time point after anesthesia induction and before skin incision and at the time point after the neutralization of heparin. Patients in the non-tranexamic acid group were given 100 mL of normal saline at corresponding time points, respectively. Then the coagulation indexes of the two groups were analyzed. The activated blood clotting time (ACT) of the two groups was within normal scope before CPB, while four coagulation indexes including prothrombin time (PT), activated partial thromboplastin time (APTT), international normalized ratio (INR), and fibrinogen (FIB) had significant increases after surgery; the PT and INR of the tranexamic acid group had a remarkable decline after surgery. All the findings suggest that the application of tranexamic acid in heart valve replacement surgery under CPB can effectively reduce intraoperative and postoperative blood loss.
There has been considerable interest in images of medicine in popular science fiction and in representations of doctors in television fiction. Surprisingly little attention has been paid to doctors administering space medicine in science fiction. This article redresses this gap. We analyse the evolving figure of 'the doctor' in different popular science fiction television series. Building upon debates within Medical Sociology, Cultural Studies and Media Studies we argue that the figure of 'the doctor' is discursively deployed to act as the moral compass at the centre of the programme narrative. Our analysis highlights that the qualities, norms and ethics represented by doctors in space (ships) are intertwined with issues of gender equality, speciesism and posthuman ethics. We explore the signifying practices and political articulations that are played out through these cultural imaginaries. For example, the ways in which 'the simple country doctor' is deployed to help establish hegemonic formations concerning potentially destabilising technoscientific futures involving alternative sexualities, or military dystopia. Doctors mostly function to provide the ethical point of narrative stability within a world in flux, referencing a nostalgia for the traditional, attentive, humanistic family physician. The science fiction doctor facilitates the personalisation of technological change and thus becomes a useful conduit through which societal fears and anxieties concerning medicine, bioethics and morality in a 'post 9/11' world can be expressed and explored.
Amplified and/or mutated MET can act as both a primary oncogenic driver and as a promoter of tyrosine kinase inhibitor (TKI) resistance in non-small cell lung cancer (NSCLC). However, the landscape of MET-specific targeting agents remains underdeveloped, and understanding of mechanisms of resistance to MET TKIs is limited. Here, we present a case of a patient with lung adenocarcinoma harboring both a mutation in EGFR and an amplification of MET, who after progression on erlotinib responded dramatically to combined MET and EGFR inhibition with savolitinib and osimertinib. When resistance developed to this combination, a new MET kinase domain mutation, D1228V, was detected. Our in vitro findings demonstrate that MET(D1228V)
 induces resistance to type I MET TKIs through impaired drug binding, while sensitivity to type II MET TKIs is maintained. Based on these findings, the patient was treated with erlotinib combined with cabozantinib, a type II MET inhibitor, and exhibited a response.
With several structurally distinct MET inhibitors undergoing development for treatment of NSCLC, it is critical to identify mechanism-based therapies for drug resistance. We demonstrate that an acquired MET(D1228V) mutation mediates resistance to type I, but not type II, MET inhibitors, having therapeutic implications for the clinical use of sequential MET inhibitors. Cancer Discov; 6(12); 1334-41. ©2016 AACR.See related commentary by Trusolino, p. 1306This article is highlighted in the In This Issue feature, p. 1293.
Acridine dyes, including proflavine and acriflavine, were commonly used as antiseptics before the advent of penicillins in the mid-1940s. While their mode of action on pathogens was originally attributed to their DNA intercalating activity, work in the early 1970s suggested involvement of the host immune responses, characterized by induction of interferon (IFN)-like activities through an unknown mechanism. We demonstrate here that sub-toxic concentrations of a mixture of acriflavine and proflavine instigate a cyclic-GMP-AMP (cGAMP) synthase (cGAS)-dependent type-I IFN antiviral response. This pertains to the capacity of these compounds to induce low level DNA damage and cytoplasmic DNA leakage, resulting in cGAS-dependent cGAMP-like activity. Critically, acriflavine:proflavine pre-treatment of human primary bronchial epithelial cells significantly reduced rhinovirus infection. Collectively, our findings constitute the first evidence that non-toxic DNA binding agents have the capacity to act as indirect agonists of cGAS, to exert potent antiviral effects in mammalian cells.
Odontogenic ameloblast-associated protein (ODAM), an acidic matricellular protein, has been implicated in several epithelial neoplasms. However, its biological functions and molecular mechanisms in cancer progression, particular colorectal carcinoma (CRC), remain unknown. Here we demonstrated that ODAM was significantly down-regulated in CRC tissues compared with their normal counterparts. Then, we established that ODAM expression level was closely correlated with CRC development and patient prognosis. The abnormal expression of ODAM dramatically affected CRC cell growth in vitro and in vivo. We further revealed that the inhibitory effects of ODAM on CRC cell growth were associated with PTEN elevation and PI3K/AKT signaling inactivation. Furthermore, we determined that silencing of PTEN expression yielded recovery of AKT activity in ODAM-expressing CRC cells. Our study suggests matricellular protein ODAM may serve as a novel prognostic marker and act as a CRC growth suppressor.
We present a comprehensive scientific assessment of the environmental impacts of an Antarctic wastewater ocean outfall, at Davis station in East Antarctica. We assessed the effectiveness of current wastewater treatment and disposal requirements under the Protocol on Environmental Protection to the Antarctic Treaty. Macerated wastewater has been discharged from an outfall at Davis since the failure of the secondary treatment plant in 2005. Water, sediment and wildlife were tested for presence of human enteric bacteria and antibiotic resistance mechanisms. Epibiotic and sediment macrofaunal communities were tested for differences between sites near the outfall and controls. Local fish were examined for evidence of histopathological abnormalities. Sediments, fish and gastropods were tested for uptake of sewage as measured by stable isotopes of N and C. Escherichia coli carrying antibiotic resistance determinants were found in water, sediments and wildlife (the filter feeding bivalve Laternula eliptica). Fish (Trematomus bernacchii) within close proximity to the outfall had significantly more severe and greater occurrences of histopathological abnormalities than at controls, consistent with exposure to sewage. There was significant enrichment of (15)N in T. bernacchii and the predatory gastropod Neobuccinum eatoni around the outfall, providing evidence of uptake of sewage. There were significant differences between epibiotic and sediment macrofaunal communities at control and outfall sites (<1.5 km), when sites were separated into groups of similar habitat types. Benthic community composition was also strongly related to habitat and environmental drivers such as sea ice. The combined evidence indicated that the discharge of wastewater from the Davis outfall is causing environmental impacts. These findings suggest that conditions in Antarctic coastal locations, such as Davis, are unlikely to be conducive to initial dilution and rapid dispersal of wastewater as required under the Protocol on Environmental Protection to the Antarctic Treaty. Current minimum requirements for wastewater treatment and disposal in Antarctica are insufficient to ameliorate these risks and are likely to lead to accumulation of contaminants and introduction of non-native microbes and associated genetic elements. This new understanding suggests that modernised approaches to the treatment and disposal of wastewater are required in Antarctica. The most effective solution is advanced levels of wastewater treatment, which are now possible, feasible and a high priority for installation. As a direct outcome of the study, a new advanced treatment system is being installed at Davis, effectively avoiding environmental risks.
In all three kingdoms of life, RNA is not only involved in the expression of genetic information, but also carries out extremely diverse cellular functions. This versatility is essentially due to the fact that RNA molecules can exploit the power of base pairing to allow them to fold into a wide variety of structures through which they can perform diverse roles, but also to selectively target and bind to other nucleic acids. This is true in particular for bacterial small regulatory RNAs that act by imperfect base-pairing with target mRNAs, and thereby control their expression through different mechanisms. Here we outline an overview of in vivo and in vitro approaches that are currently used to gain mechanistic insights into how these sRNAs control gene expression in bacteria.
Irisin, the product of fibronectin type III domain-containing protein 5 (FNDC5) gene, is well-documented to be a regulator of energy metabolism. At present, not much is known about its biological function in non-mammalian species. In this study, a full-length tilapia FDNC5 was cloned and its tissue expression pattern has been confirmed. Based on the sequence obtained, we produced and purified recombinant irisin which could induce uncoupling protein 1 (UCP1) gene expression in tilapia hepatocytes. Further, the rabbit polyclonal irisin antiserum was produced and its specificity was confirmed by antiserum preabsorption. In tilapia pituitary cells, irisin inhibited growth hormone (GH) gene expression and secretion and triggered rapid phosphorylation of Akt, Erk1/2, and p38 MAPK. Furthermore, irisin-inhibited GH mRNA expression could be prevented by inhibiting PI3K/Akt, MEK1/2, and p38 MAPK, respectively. Apparently, fish irisin can act directly at the pituitary level to inhibit GH transcript expression via multiple signaling pathways.
Matrix stiffness is known to play a pivotal role in cellular differentiation. Studies have shown that soft scaffolds (<2-3kPa) promote cellular aggregation and chondrogenesis, whereas, stiffer ones (>10kPa) show poor chondrogenesis in vitro. In this work we investigated if fibrin matrix from clotted blood can act as a soft surrogate which nullifies the influence of the underlying stiff scaffold, thus promoting chondrogenesis irrespective of bulk scale scaffold stiffness. For this we performed in vitro chondrogenesis on soft (∼1.5kPa) and stiff (∼40kPa) gelatin scaffolds in the presence and absence of pericellular plasma clot. Our results demonstrated that in absence of pericellular plasma clot, chondrocytes showed efficient condensation and cartilaginous matrix secretion only on soft scaffolds, whereas, in presence of pericellular plasma clot, cell rounding and cartilaginous matrix secretion was observed in both soft and stiff scaffolds. More specifically, significantly higher collagen II, chondroitin sulfate and aggrecan deposition was observed in soft scaffolds, and soft and stiff scaffolds with pericellular plasma clot as compared to stiff scaffolds without pericellular plasma clot. Moreover, collagen type I, a fibrocartilage/bone marker was significantly higher only in stiff scaffolds without plasma clot. Therefore, it can be concluded that chondrocytes surrounded by a soft fibrin network were unable to sense the stiffness of the underlying scaffold/substrate and hence facilitate chondrogenesis even on stiff scaffolds. This understanding can have significant implications in the design of scaffolds for cartilage tissue engineering.
Cell fate is influenced by the mechanical properties of cell culture substrates. Outside the body, cartilage progenitor cells express significant amounts of cartilage-specific markers on soft scaffolds but not on stiff scaffolds. However, when implanted in joints, stiff scaffolds show equivalent expression of markers as seen in soft scaffolds. This disparity in existing literature prompted our study. Our results suggest that encapsulation of cells in a soft plasma clot, present in any surgical intervention, prevents their perception of stiffness of the underlying scaffold, and hence the ability to distinguish between soft and stiff scaffolds vanishes. This finding would aid the design of new scaffolds that elicit cartilage-like biochemical properties while simultaneously being mechanically
 comparable to cartilage tissue.
The classical pathway of vitamin D activation follows the sequence D3→25(OH)D3→1,25(OH)2D3 with the final product acting on the receptor for vitamin D (VDR). An alternative pathway can be started by the action of CYP11A1 on the side chain of D3, primarily producing 20(OH)D3, 22(OH)D3, 20,23(OH)2D3, 20,22(OH)2D3 and 17,20,23(OH)3D3. Some of these metabolites are hydroxylated by CYP27B1 at C1α, by CYP24A1 at C24 and C25, and by CYP27A1 at C25 and C26. The products of these pathways are biologically active. In the epidermis and/or serum or adrenals we detected 20(OH)D3, 22(OH)D3, 20,22(OH)2D3, 20,23(OH)2D3, 17,20,23(OH)3D3, 1,20(OH)2D3, 1,20,23(OH)3D3, 1,20,22(OH)3D3, 20,24(OH)2D3, 1,20,24(OH)3D3, 20,25(OH)2D3, 1,20,25(OH)3D3, 20,26(OH)2D3 and 1,20,26(OH)3D3. 20(OH)D3 and 20,23(OH)2D3 are non-calcemic, while the addition of an OH at C1α confers some calcemic activity. Molecular modeling and functional assays show that the major products of the pathway can act as "biased" agonists for the VDR with high docking scores to the ligand binding domain (LBD), but lower than that of 1,25(OH)2D3. Importantly, cell based functional receptor studies and molecular modeling have identified the novel secosteroids as inverse agonists of both RORα and RORγ receptors. Specifically, they have high docking scores using crystal structures of RORα and RORγ LBDs. Furthermore, 20(OH)D3 and 20,23(OH)2D3 have been tested in a cell model that expresses a Tet-on RORα or RORγ vector and a RORE-LUC reporter (ROR-responsive element), and in a mammalian 2-hybrid model that test interactions between an LBD-interacting LXXLL-peptide and the LBD of RORα/γ. These assays demonstrated that the novel secosteroids have ROR-antagonist activities that were further confirmed by the inhibition of IL17 promoter activity in cells overexpressing RORα/γ. In conclusion, endogenously produced novel D3 hydroxy-derivatives can act both as "biased" agonists of the VDR and/or inverse agonists of RORα/γ. We suggest that the identification of large number of endogenously produced alternative hydroxy-metabolites of D3 that are biologically active, and of possible alternative receptors, may offer an explanation for the pleiotropic and diverse activities of vitamin D, previously assigned solely to 1,25(OH)2D3 and VDR.
Among the gastrointestinal hormones that regulate food intake and energy homeostasis, ghrelin plays a unique role as the first one identified to increases appetite and stimulate GH secretion. This review highlights the latest mechanism by which ghrelin modulates body growth, appetite and energy metabolism by exploring pharmacological actions of the hormone and consequences of genetic or pharmacological blockade of the ghrelin/GHS-R (Growth Hormone Secretagogue Receptor) system on physiological responses in specific nutritional situations. Within the hypothalamus, novel mechanisms of action of this hormone involve its interaction with other ghrelin-derived peptides, such as desacyl ghrelin and obestatin, which are thought to act as functional ghrelin antagonists, and possible modulation of the GHS-R with other G-protein coupled receptors. During chronic undernutrition such as anorexia nervosa, variations of ghrelin-derived peptides may be an adaptative metabolic response to maintain normal glycemic control. Interestingly, some of ghrelin's metabolic actions are thought to be relayed through modulation of GH, an anabolic and hyperglycemic agent.
It was first discovered in 1992 that P-glycoprotein (Pgp, ABCB1), an ATP binding cassette (ABC) transporter, can transport phospholipids such as phosphatidylcholine, -ethanolamine and -serine as well as glucosylceramide and glycosphingolipids. Subsequently, many other ABC transporters were identified to act as lipid transporters. For substrate transport by ABC transporters, typically a classic, alternating access model with an ATP-dependent conformational switch between a high and a low affinity substrate binding site is evoked. Transport of small hydrophilic substrates can easily be imagined this way, as the molecule can in principle enter and exit the transporter in the same orientation. Lipids on the other hand need to undergo a 180° degree turn as they translocate from one membrane leaflet to the other. Lipids and lipidated molecules are highly diverse, so there may be various ways how to achieve their flipping and flopping. Nonetheless, an increase in biophysical, biochemical and structural data is beginning to shed some light on specific aspects of lipid transport by ABC transporters. In addition, there is now abundant evidence that lipids affect ABC transporter conformation, dynamics as well as transport and ATPase activity in general. In this review, we will discuss different ways in which lipids and ABC transporters interact and how lipid translocation may be achieved with a focus on the techniques used to investigate these processes.
Anemia often develops in rheumatoid arthritis (RA) patients. In the present study, we examined the association between the therapeutic effectiveness of the biologic agent tocilizumab (TCZ) and potential predictors of therapeutic effectiveness. We focused on the amelioration of anemia of chronic inflammation through the mechanism of direct inhibition of Interleukin (IL)-6 receptor-mediated signals by TCZ. Serum hepcidin-25, which is expressed in an IL-6 dependent manner and is a major cause of anemia of chronic inflammation, was measured in 10 RA patients, before and after administration of TCZ. We compared the findings with IL-6 and changes in clinical data, to assess whether hepcidin-25 could act as a predictor of the effectiveness of TCZ. A high level of serum hepcidin-25 was observed in most RA patients, and a decrease was noted after administration of TCZ; most patients had favorable treatment responses. A subgroup of patients had normal or low serum hepcidin-25 levels before administration, increased levels after administration, and poor treatment responses to TCZ. These results suggest that hepcidin-25 may be a predictor of clinical response to TCZ.
Mosquitoes (Diptera: Culicidae) act as vectors of medical and veterinary importance, due to their ability to transmit many pathogens and parasites. Renewed interest has been recently devoted to the potential of sterile insect technique (SIT) for mosquito suppression. However, the success of the SIT is mostly dependent on the ability of sterile males to compete for mates with the wild ones in the field. Nevertheless, little is known on the sexual chemical ecology of mosquitoes, with special reference to the role of chemical signals in males. We reviewed the current knowledge on mosquito sexual chemical ecology and other key cues affecting courtship and mating behavior. The information available on the aggregation and sex pheromones in mosquito males is rather limited. To the best of our knowledge, the components of the aggregation pheromone stimulating swarming mechanisms have been fully characterized only for Aedes aegypti, while evidence for aggregation pheromones in other mosquito species remains elusive. Further research on this issue is needed, as well as to dissect the relative importance of visual (with special reference to swarming landmarks), vibrational, olfactory and tactile cues perceived during swarming and mate. On the other hand, more knowledge is available for cuticular hydrocarbons, which modulate mating behavior in several species of economic importance. These compounds, coupled with volatile aggregation components, have potential interest for the development of monitoring and trapping systems. In addition, the analyses of cuticular hydrocarbons are essential for discrimination between closely related mosquito species and/or populations.
Riverine systems act as important aquatic conduits for carbon transportation between atmospheric, terrestrial and oceanic pools, yet the magnitude of these exports remain poorly constrained. Interconnected creek and river sites (n=28) were sampled on a quarterly basis in three subcatchments of the subtropical Richmond River Catchment (Australia) to investigate spatial and temporal dynamics of dissolved inorganic carbon (DIC), dissolved organic carbon (DOC), carbon dioxide (CO2), methane (CH4), and carbon stable isotope ratios (δ(13)C). The study site is an area of high interest due to potential unconventional gas (coal seam gas or coal bed methane) development. DIC exports were driven by groundwater discharge with a small contribution by in situ DOC remineralization. The DIC exports showed seasonal differences ranging from 0.10 to 0.27mmolm(-2)catchmentd(-1) (annual average 0.17mmolm(-2)catchmentd(-1)) and peaked during winter when surface water discharge was highest. DOC exports (sourced from terrestrial organic matter) had an annual average 0.07mmolm(-2)catchmentd(-1) and were 1 to 2 orders of magnitude higher during winter compared to spring and summer. CO2 evasion rates (annual average of 347mmolm(-2)water aread(-1)) were ~2.5 fold higher during winter compared to spring. Methane was always supersaturated (0.19 to 62.13μM), resulting from groundwater discharge and stream-bed methanogenesis. Methane evasion was highly variable across the seasons with an annual average of 3.05mmolm(-2)water aread(-1). During drier conditions, stable isotopes implied enhanced CH4 oxidation. Overall, carbon losses from the catchment were dominated by CO2 evasion (60%) followed by DIC exports (30%), DOC exports (9%) and CH4 evasion (<1%). Our results demonstrated broad catchment scale spatial and temporal variability in carbon dynamics, and that groundwater discharge and rain events controlled carbon exports.
Practical use of many bioelectronic and bioanalytical devices is limited by the need of expensive materials and time consuming fabrication. Here we demonstrate
 the use of nickel electrodes as a simple and cheap solid support material for bioelectronic applications. The naturally nanostructured electrodes showed a surprisingly high electromagnetic surface enhancement upon light illumination such that immobilization and electron transfer reactions of the model redox proteins cytochrome b5 (Cyt b5) and cytochrome c (Cyt c) could be followed via surface enhanced resonance Raman spectroscopy. It could be shown that the nickel surface, when used as received, promotes a very efficient binding of the proteins upon preservation of their native structure. The immobilized redox proteins could efficiently exchange electrons with the electrode and could even act as an electron relay between the electrode and solubilized myoglobin. Our results open up new possibility for nickel electrodes as an exceptional good support for bioelectronic devices and biosensors on the one hand and for surface enhanced spectroscopic investigations on the other hand.
The etiology of autism spectrum disorders (ASD) is complex and multifactorial, and the roles of genetic and environmental factors in its emergence have been well documented. Current research tends to indicate that these two factors act in a synergistic manner. The processes underlying this interaction are still poorly known, but epigenetic modifications could be the mediator in the gene/environment interface. The epigenetic mechanisms have been implicated in susceptibility to stress and also in the pathogenesis of psychiatric disorders including depression and schizophrenia. Currently, several studies focus on the consideration of the etiological role of epigenetic regulation in ASD.
The object of this review is to present a summary of current knowledge of an epigenetic hypothesis in ASD, outlining the recent findings in this field.
Using Pubmed, we did a systematic review of the literature researching words such as: autism spectrum disorders, epigenetics, DNA methylation and histone modification.
Epigenetic refers to the molecular process modulating gene expression without changes in the DNA sequence. The most studied epigenetic mechanisms are those that alter the chromatin structure including DNA methylation of cytosine residues in CpG dinucleotides and post-translational histone modifications. In ASD several arguments support the epigenetic hypothesis. In fact, there is a frequent association between ASD and genetic diseases whose epigenetic etiologies are recognized. A disturbance in the expression of genes involved in the epigenetic regulation has also been described in this disorder. Some studies have demonstrated changes in the DNA methylation of several autism candidate genes including the gene encoding the oxytocin receptor (OXTR), the RELN and the SHANK3 genes. Beyond the analysis of candidate genes, recent epigenome-wide association studies have investigated the methylation level of several other genes and showed hypomethylation of the whole DNA in brain and blood samples of autistic patients. The changes in epigenetic marks following exposure to environmental factors known as autism risk factors are also discussed in many reports. They include nutritional (vitamin D and folate) and toxic (sodium valproate, bisphenol A) factors. Despite a considerable contribution to understanding the complexity of ASD etiology, the epigenetic studies suffer from numerous methodological biases that limit the scope of their results and make their interpretation difficult. The cell samples used in the psychiatric studies are mostly from the post-mortem tissue of the central nervous system, and factors that might change the epigenome (age, gender, treatments received…) are not taken into account. The use of blood and buccal epithelium samples raises in turn the question as to whether the epigenome of these cells reflects that of the nerve cells. DNA methylation can also be influenced by cell subcomposition variability, transcriptional variability and by DNA sequence variants.
These recent discoveries in epigenetics are the beginnings of an etiopathogenic research revolution in neurodevelopmental disorders. The conceptualization of epigenetic processes is in its early stages and despite its limited means will help integrate disparate data factors previously involved in autism. It could also be the target for the development of new therapeutic modalities.
Haemonchus contortus is an important gastrointestinal parasite on sheep farms in tropical regions. The resistance of the parasite against most anthelmintic drugs represents a great economic problem to sheep farming and is a major challenge that needs to be overcome. The searches for new anthelmintic agents that act on different stages of the parasite's life cycle are necessary for the development of new therapeutic options. The aim of this study was to evaluate the in vitro and in vivo anthelmintic activity of Thymus vulgaris essential oil against H. contortus and of its main component, the monoterpene thymol. Despite the relative ineffectiveness of the oil in the in vivo test, which may be corrected in the future after technical improvements to increase the oil's bioavailability, the in vitro results validated the popular use of T. vulgaris oil as an anthelmintic agent, at least against H. contortus. In fact, both the essential oil and thymol, which accounts for 50.22% of the oil composition, were effective against the three main stages of H. contortus. The oil and thymol were able to inhibit egg hatching by 96.4-100%, larval development by 90.8-100%, and larval motility by 97-100%. Similar to the positive control (levamisole 20mg/mL), the oil and thymol completely inhibited the motility of H. contortus adults within the first 8h of the experiment. Since thymol reproduces the anthelmintic effects of the oil and because it is the main component of the oil, it is reasonable to assume that thymol is the most important compound responsible for the anthelmintic effect of T. vulgaris. These results are of ethnopharmacological importance and may contribute to the development of new drugs and even herbal medicines, increasing treatment options for the farm breeding.
The role that parasites play in regulating animal populations is debated, however recent research hints at their pervasiveness among free-living animal populations. Parasites exert both direct and indirect effects on host populations, and can act to regulate populations. The Ring-necked pheasant is an important game-bird species in the UK, and large numbers of birds are released annually. The impact of the ubiquitous tracheal nematode, Syngamus trachea on pheasant populations through effects on host condition was assessed on two pheasant estates in the south west of England. Pheasants infected with S. trachea demonstrated a significant reduction in host condition compared with uninfected controls, with as few as one pair of worms per bird. Although there was no difference in worm burden between sexes, analysis of regression slopes revealed there was a significant difference between sexes in the magnitude of the effect of increasing worm burden on host condition, with detectable effects observed in hosts with one and three pairs of worms for males and females respectively. The observed reductions in host condition in birds with even sub-clinical infections could be the cause of poor reproductive success and survival of pheasants post-release.
Dendritic cell (DC)-based immune therapy (IT) against HIV showed variable results. It is known that different factors influence host response to DC-IT. Exosomes derived from DC are regulators of the immune system. In this context, here we hypothesize about the role of the DC-derived exosomes on the DC-IT response. Based on data from RT-PCR array genes expression (focused on the TSG101 gene, an exosome marker) and flow cytometry experiments of a DC-IT against HIV-1 clinical trial, we hypothesize that: During the DC-IT exosomes are used as an additional tool for immune system modulation. In addition, we believe that a low release of exosomes can be more beneficial for the DC-IT response than a high release of exosomes. Our data reinforce the concept that exosomes can act as an immune regulatory tool, however not in a generalized manner, but in a highly precise way. Our hypothesis is based in preliminary experimental data, thus, it should be tested using experimental and functional strategies involving a great number of patients. Once the hypothesis confirmed, the immunomodulatory role of the exosomes during DC-IT must be considered as an important factor in the (I) evaluation, (II) modulation, and (III) success of DC-IT against HIV.
Precocious puberty which impacts children physically and psychologically has become one of the health problem over the world. However, the mechanism and preventive measures of precocious puberty is still not clear. Recent studies suggested that leptin may act as the 'permissive factor' to initiate the puberty by regulating gonadotrophin-releasing hormone secretion. Previous evidence from animal and human studies found that tea polyphenols can reduce serum leptin levels in vivo and inhibit the expression of leptin in adipose tissue. This article focus on whether tea polyphenols could delay the onset of puberty by reducing leptin levels. To verify the possibility of tea polyphenols on preventing precocious puberty, animal experiment can be used. Our hypothesis that tea polyphenols could prevent the precocious puberty may provide important potential way for the prevention and control of children precocious puberty.
This retrospective study aimed at evaluating long-term effects of Omalizumab in elderly asthmatics in a real-life setting.
105 consecutive severe asthmatics (GINA step 4-5; mean FEV1% predicted:66 ± 15.7) treated with Omalizumab for at least 1 year (treatment mean duration
 35.1 ± 21.7 months) were divided into 3 groups according to their age at Omalizumab treatment onset: 18-39, 40-64 and ≥ 65 years.
Comorbidities, number of overweight/obese subjects and patients with late-onset asthma were more frequent among older people. A similar reduction of inhaled corticosteroids dosage and SABA on-demand therapy was observed in all groups during Omalizumab treatment; a similar FEV1 increased was also observed. Asthma Control Test (ACT) improved significantly (p < 0.001) in the three groups, increasing from 15 [IQR:12-18] to 24 [IQR:22-25] in younger subjects, from 14 [IQR:10-16] to 21 [IQR:20-23] in the 40-64-year-group and from 15 [IQR:12-16] to 20 [IQR:18-22] in elderly patients where improvement was lower (p = 0.039) compared to younger people. Asthma exacerbations decreased significantly after Omalizumab but the percentage of exacerbation-free patients was higher in younger people (76.9%) compared to middle aged patients (49.2%) and the elderly (29%) (p = 0.049). After Omalizumab treatment, the risk for exacerbations was lower in subjects aged 40-64 (OR = 0.284 [CI95% = 0.098-0.826], p = 0.021) and 18-39 (OR = 0.133 [CI95% = 0.026-0.678], p = 0.015), compared to elderly asthmatics. Also, a significantly reduced ACT improvement (β = -1.070; p = 0.046) passing from each age class was observed.
Omalizumab improves all asthma outcomes independently of age, although the magnitude of the effects observed in the elderly seems to be lower than in the other age groups.
The yeast homolog of DJ-1, Hsp31, is a multifunctional protein that is involved in several cellular pathways including detoxification of the toxic metabolite methylglyoxal and as a protein deglycase. Prior studies ascribed Hsp31 as a molecular chaperone that can inhibit α-Syn aggregation in vitro and alleviate its toxicity in vivo. It was also shown that Hsp31 inhibits Sup35 aggregate formation in yeast, however, it is unknown if Hsp31 can modulate [PSI(+)] phenotype and Sup35 prionogenesis. Other small heat shock proteins, Hsp26 and Hsp42 are known to be a part of a synergistic proteostasis network that inhibits Sup35 prion formation and promotes its disaggregation. Here, we establish that Hsp31 inhibits Sup35 [PSI(+)] prion formation in collaboration with a well-known disaggregase, Hsp104. Hsp31 transiently prevents prion induction but does not suppress induction upon prolonged expression of Sup35 indicating that Hsp31 can be overcome by larger aggregates. In addition, elevated levels of Hsp31 do not cure [PSI(+)] strains indicating that Hsp31 cannot intervene in a pre-existing prion oligomerization cycle. However, Hsp31 can modulate prion status in cooperation with Hsp104 because it inhibits Sup35 aggregate formation and potentiates [PSI(+)] prion curing upon overexpression of Hsp104. The absence of Hsp31 reduces [PSI(+)] prion curing by Hsp104 without influencing its ability to rescue cellular thermotolerance. Hsp31 did not synergize with Hsp42 to modulate the [PSI(+)] phenotype suggesting that both proteins act on similar stages of the prion cycle. We also showed that Hsp31 physically interacts with Hsp104 and together they prevent Sup35 prion toxicity to greater extent than if they were expressed individually. These results elucidate a mechanism for Hsp31 on prion modulation that suggest it acts at a distinct step early in the Sup35 aggregation process that is different from Hsp104. This is the first demonstration of the modulation of [PSI(+)] status by the chaperone action of Hsp31. The delineation of Hsp31's role in the chaperone cycle has implications for understanding the role of the DJ-1 superfamily in controlling misfolded proteins in neurodegenerative disease and cancer.
Metastatization is a complex multistep process requiring fine-tuned regulated cytoskeleton re-modeling, mediated by the cross-talk of actin with interacting partners, such as the Rho GTPases. Our expanding knowledge of invadopodia, small invasive membrane protrusions composed of a core of F-actin, actin regulators and actin-binding proteins, and hotspots for secretion of extracellular matrix (ECM) proteinases, contributes to clarify critical steps of the metastatic program. Growth factor receptors and their intermediate signaling molecules, along with matrix adhesion and rigidity, pH and hypoxia, act as drivers of cytoskeleton changes and invadopodia formation. We recently pro-posed a novel route map by which cancer cells regulates invadopodia dynamics supporting metastasis as response to the endothelin A receptor (ETAR), among the highly druggable G-protein coupled receptors in cancer. The metastatic behavior exhibited by ovarian cancer cells overe-xpressing ETAR is now explained by the interplay with β-arrestin1 (β-arr1), a scaffold protein acting as signal-integrating module of RhoC and cofilin signaling for specific invadopodia formation, accomplished by its interaction with a Rho guanine nucleotide exchange factor (GEF), PDZ-RhoGEF, in a G-protein independent manner. Here, we summarize this novel activation of the RhoC pathway from ETAR/β-arr1 signaling that may be exploited therapeutically and discuss new perspectives for future directions of investigations.
Neutron and X-ray reflection measurements have been used to study the structure of the adsorbed layer of a chelating surfactant at the air/liquid interface. The chelating surfactant 2-dodecyldiethylenetriaminepentaacetic acid (C12-DTPA) has a large head group containing eight donor atoms that can participate in the coordination of metal ions. The donor atoms are also titrating, resulting in an amphoteric surfactant that can adopt a number of differently charged species depending on the pH. Very strong coordination complexes are formed with metal ions, where the metal ion can be considered as part of the surfactant structure, in contrast to monovalent cations that act as regular counter-ions to the negative net charge. Adsorption was investigated over a large concentration interval, from well below the critical micelle concentration (cmc) to five times the cmc. The most striking result is the maximum in the surface excess found around the cmc, which is consistent with previous indications from surface tension measurements. Adding divalent metal ions has a limited effect on the adsorption at the air/liquid interface. The reason is the coordination of the metal ion, resulting in compensating deprotonation of the complex. Small variations in the head group area of different metal complexes are found, correlating to the conditional stability constants. Adding sodium chloride has a significant effect on the adsorption behavior and the results indicate that the protonation equilibrium is more important than the ionic strength effects. From combined fits of the neutron and X-ray data, a model that consists of a thick head group region and a relatively thin dehydrated tail region is found, and it indicates that the tails are not fully extended and that the limiting area per molecule is determined by the bulky head group.
To evaluate a new dark-blood late gadolinium enhancement (LGE) technique called "T(Rho) And Magnetization transfer and INvErsion Recovery" (TRAMINER) for the ability to detect myocardial LGE versus standard "bright-blood" inversion recovery (SIR) imaging.
This Institutional Review Board (IRB)-approved, Health Insurance Portability and Accountability Act (HIPAA)-compliant prospective study included 40 patients (62 ± 14 years [mean ± standard deviation (SD)], 29 males) with suspected myocardial infarction (MI) referred for the assessment of myocardial viability. The patients underwent a 1.5T cardiac magnetic resonance imaging (MRI) including postcontrast SIR and TRAMINER acquisitions. Normalized images were evaluated by two readers. Subjective (3-point Likert scale) and objective image qualities were compared using Mann-Whitney U-test and paired t-test, respectively. Interobserver agreement, LGE detection rate, and level of certainty were compared using Cohen's kappa, Wilcoxon-test, and Mann-Whitney U-test, respectively. Results are reported as mean ± SD or mean [95% confidence interval].
Overall, image quality was rated similar between TRAMINER and SIR; however, TRAMINER performed better on a visual assessment of the ability to differentiate LGE from blood (Likert scale: 3.0 [3.0-3.0] vs. 2.0 [1.7-2.2], P < 0.0001). TRAMINER provided significantly higher signal intensity range (69.8 ± 10.2 vs. 9.6 ± 7.6, P < 0.0001) and a 4-fold higher signal intensity ratio (4.2 ± 1.9 vs. 1.1 ± 0.1, P < 0.0001) between LGE and blood signals. TRAMINER detected more patients (19/40 vs. 17/40) and segments (91/649 vs. 79/649) with LGE with higher level of certainty (2.9 [2.8-3.0] vs. 2.7 [2.5-2.8], P = 0.0185). Interobserver agreement was good to excellent for LGE detection.
TRAMINER provides better contrast between LGE and blood and consequently may have increased ability to discriminate thin subendocardial and papillary muscle enhancement from the blood signal, which can have an indistinct appearance using SIR.
2 J. Magn. Reson. Imaging 2016.
In the nearly 30 years since the passage of the Technology-Related Assistance to Individuals with Disabilities Act of 1988, technology-mediated instruction has been implemented successfully with both students without disabilities and students with a range of disabilities to help them meet the demands of instruction. In this special issue of Assistive Technology, a number of noted scholars contribute research findings designed to add to the growing body of knowledge validating the use of assistive and instructional technology in the classroom.
The new age of nanotechnology has signaled a stream of entrepreneurial possibilities in various areas, form industry to medicine. Drug delivery has benefited the most by introducing nanostructured systems in the transport
 and controlled release of therapeutic molecules at targeted sites associated with a particular disease. As many nanosized particles reach the gastrointestinal tract by various means, their interactions with the molecular components of this highly active niche are intensively investigated. The well-characterized antimicrobial activities of numerous nanoparticles are currently being considered as a reliable and efficient alternative to the eminent world crisis in antimicrobial drug discovery. The interactions of nanosystems present in the gastrointestinal route with host microbiota is unavoidable; hence, a major research initiative is needed to explore the mechanisms and effects of these nanomaterials on microbiota and the impact that microbiota may have in the outcome of therapies entailing drug delivery nanosystems through the gastrointestinal route. These coordinated studies will provide novel techniques to replace or act synergistically with current technologies and help develop new treatments for major diseases via the discovery of unique antimicrobial molecules.
In the mobile computing era, smartphones have become instrumental tools to develop innovative mobile context-aware systems. In that sense, their usage in the vehicular domain eases the development of novel and personal transportation solutions. In this frame, the present work introduces an innovative mechanism to perceive the current kinematic state of a vehicle on the basis of the accelerometer data from a smartphone mounted in the vehicle. Unlike previous proposals, the introduced architecture targets the computational limitations of such devices to carry out the detection process following an incremental approach. For its realization, we have evaluated different classification algorithms to act as agents within the architecture. Finally, our approach has been tested with a real-world dataset collected by means of the ad hoc mobile application developed.
Evidence-based clinical practice guidelines recommend physical activity for people with lung cancer, however evidence has not translated into clinical practice and the majority of patients do not meet recommended activity levels.
To identify factors (barriers and enablers) that influence clinicians' translation of the physical activity guidelines into practice.
Qualitative study involving 17 participants (three respiratory physicians, two thoracic surgeons, two oncologists, two nurses, and eight physical therapists) who were recruited using purposive sampling from five hospitals in Melbourne, Victoria, Australia. Nine semistructured interviews and a focus group were conducted, transcribed verbatim, and independently cross-checked by a second researcher. Thematic analysis was used to analyze data.
Five consistent themes emerged: (1) the clinicians perception of patient-related physical and psychological influences (including symptoms and comorbidities) that impact on patient's ability to perform regular physical activity; (2) the influence of the patient's past physical activity behavior and their perceived relevance and knowledge about physical activity; (3) the clinicians own knowledge and beliefs about physical activity; (4) workplace culture supporting or hindering physical activity; and (5) environmental and structural influences in the healthcare system (included clinicians time, staffing, protocols and services). Clinicians described potential strategies, including: (1) the opportunity for nurse practitioners to act as champions of regular physical activity and triage referrals for physical activity services; (2) opportunistically using the time when patients are in hospital after surgery to discuss physical activity; and (3) for all members of the multidisciplinary team to provide consistent messages to patients about the importance of physical activity.
Key barriers to implementation of the physical activity guidelines in lung cancer are diverse and include both clinician- and healthcare system-related factors. A combined approach to target a number of these factors should be used to inform research, improve clinical services, and develop policies aiming to increase physical activity and improve survivorship outcomes for patients with lung cancer.
In this study, the commercial zero-valent copper (ZVC) was investigated to activate the molecular oxygen (O2) for the degradation of acetaminophen (ACT). 50 mg/L ACT could be completely decomposed within 4 h in the ZVC/air system at initial pH 3.0. The H2O2, hydroxyl radical (OH) and superoxide anion radical (O2(-)) were identified as the main reactive oxygen species (ROSs) generated in the above reaction; however, only OH caused the decomposition and mineralization of ACT in the copper-catalyzed O2 activation process. In addition, the in-situ generated Cu(+) from ZVC dissolution not only activated O2 to produce H2O2, but also initiated the decomposition of H2O2 to generate OH. Meanwhile, the H2O2 could also be partly decomposed into O2(-), which served as a mediator for copper cycling by reduction of Cu(2+) to Cu(+) in the ZVC/air system. Therefore, OH could be continuously generated; and then ACT was effectively degraded. Additionally, the effect of solution pH and the dosage of ZVC were also investigated. As a result, this study indicated the key behavior of the O2(-) during Cu-catalyzed activation of O2, which further improved the understanding of O2 activation mechanism by zero-valent metals.
This article aims to present a fractographic analysis of an anterior tooth restored with a glass fiber post with parallel fiber arrangement, taking into account force vectors, finite element analysis, and scanning electron microscopy (SEM).
A patient presented at the Faculty of Dentistry (Federal University of Santa Maria, Brazil) with an endodontically treated tooth (ETT), a lateral incisor that had a restorable fracture. The treatment was performed, and the fractured piece was analyzed using stereomicroscopy, SEM, and finite element analysis.
The absence of remaining coronal tooth structure might have been the main factor for the clinical failure. We observed different stresses actuating in an ETT restored with a fiber post as well as their relationship with the ultimate fracture. Tensile, compression, and shear stresses presented at different levels inside the restored tooth. Tensile and compressive stresses acted together and were at a maximum in the outer portions and a minimum in the inner portions. In contrast, shear stresses acted concomitantly with tensile and compressive stresses. Shear was higher in the inner portions (center of the post), and lower in the outer portions. This was confirmed by finite element analysis. The SEM analysis showed tensile and compression areas in the fiber post (exposed fibers=tensile areas=lingual surface; nonexposed fibers=compression areas=buccal surface) and shear areas inside the post (scallops and hackle lines). Stereomicroscopic analysis showed brown stains in the crown/root interface, indicating the presence of microleakage (tensile area=lingual surface).
We concluded that glass fiber posts with parallel fibers (0°), when restoring anterior teeth, present a greater fracture potential by shear stress because parallel fibers are not mechanically resistant to support oblique occlusal loads. Factors such as the presence of remaining coronal tooth structure and occlusal stability assist in the biomechanical equilibrium of stresses that act upon anterior teeth.
Drug repurposing (=drug repositioning) is an effective way to cut costs for the development of new therapeutics and to reduce the time-to-market time-span. Following this concept a small library of compounds was screened for their ability to act as inhibitors of acetyl- and butyrylcholinesterase. Picloxydine, an established antiseptic, was shown to be an inhibitor for both enzymes. Systematic variation of the aryl substituents led to analogs possessing almost the same good properties as gold standard galantamine hydrobromide.
Microwave (MW) therapy, as a promising type of thermal therapy, has been attracting more and more attention from scientists. The combination of thermal and chemotherapy is of great significance in the latest studies of synergistic tumor therapy. However, the research on the MW therapy mechanism, especially the nonthermal effect applied in the combined cancer therapy, is not thorough enough. Pleasantly, we have discovered that nonthermal MW irradiation can promote the cellular uptake of nanoparticles and anticancer drugs via experiments in vitro and in vivo. Therefore, multifunctional nanoplatforms have been designed for enhanced tumor inhibition by loading ionic liquids (ILs), doxorubicin hydrochloride (DOX), and phase change materials (PCMs) into ZrO2 hollow nanoparticles. PCMs act as MW switches. The as-made IL-DOX-PCM@ZrO2 nanoplatforms were injected into H22-tumor-bearing mice via the tail vein. Mild microwave irradiation (0.9 W, 450 MHz) was then applied. The thermal effect of MW could cause the temperature of the tumor site to rise (58 °C). On the other hand, it will trigger the MW switch to open and release DOX when the temperature is high enough. At the same time as drug release, a MW nonthermal effect could improve the cellular uptake of nanomaterials and anticancer drugs. The multisynergistic effect can promote the survival rate of the IL-DOX-PCM@ZrO2+MW group to 100%. The results of the tumor therapy experiment in vivo demonstrated that as-made multifunctional IL-DOX-PCM@ZrO2 nanoplatforms could enhance the therapeutic outcome of combined thermal and chemotherapy under mild MW irradiation.
In intensive care units far-reaching decisions are often made at short notice that require the consent of the informed patient. If this is not possible due to the patient's condition, physicians and legal representatives must ascertain the
 previously expressed or presumed will of the patient and act accordingly. The legal principles are specified in the Patient Advance Directives Act and the Patient Rights Act. Any indications for medical treatment need a clearly defined aim of the therapy, which can be questioned during the progress of the disease. To avoid conflicts between patient autonomy and medical treatment, the aims of therapy must be regularly discussed with the patient, representatives or relatives and documented in a written form. Checklists can be useful for structured consultations, to promote transparency and to avoid misunderstandings. Ethics consultations can help to deescalate critical situations.
We have recently shown that tubular form of rotavirus (RV) recombinant VP6 protein has an in vivo adjuvant effect on the immunogenicity of norovirus (NoV) virus-like particle (VLP) vaccine candidate. In here, we investigated in vitro effect of VP6 on antigen presenting cell (APC) activation and maturation and whether VP6 facilitates NoV VLP uptake by these APCs. Mouse macrophage cell line RAW 264.7 and dendritic cell line JAWSII were used as model APCs. Internalization of VP6, cell surface expression of CD40, CD80, CD86, and major histocompatibility class II molecules, and cytokine and chemokine production were analyzed. VP6 nanotubes were efficiently internalized by APCs. VP6 upregulated the expression of cell surface activation and maturation molecules and induced secretion of several proinflammatory cytokines and chemokines. The mechanism of VP6 action was shown to be partially dependent on lipid raft-mediated endocytic pathway as shown by methyl-β-cyclodextrin inhibition on tumor necrosis factor α secretion. These findings add to the understanding of mechanism by which VP6 exerts its immunostimulatory and immunomodulatory actions and further support its use as a part of nonlive RV-NoV combination vaccine.
The skull of leporids (rabbits and hares) is highly transformed, typified by pronounced arching of the dorsal skull and ventral flexion of the facial region (i.e., facial tilt). Previous studies show that locomotor behavior influences aspects of cranial shape in leporids, and here we use an extensive 3D geometric morphometrics dataset to further explore what influences leporid cranial diversity. Facial tilt angle, a trait that strongly correlates with locomotor mode, significantly predicts the cranial shape variation captured by the primary axis of cranial shape space, and describes a small proportion (13.2%) of overall cranial shape variation in the clade. However, locomotor mode does not correlate with overall cranial shape variation in the clade, because there are two district morphologies of generalist species, and saltators and cursorial species have similar morphologies. Cranial shape changes due to phyletic size change (evolutionary allometry) also describes a small proportion (12.5%) of cranial shape variation in the clade, but this is largely driven by the smallest living leporid, the pygmy rabbit (Brachylagus idahoensis). By integrating phylogenetic history with our geometric morphometric data, we show that the leporid cranium exhibits weak phylogenetic signal and substantial homoplasy. Though these results make it difficult to reconstruct what the 'ancestral' leporid skull looked like, the fossil records suggest that dorsal arching and facial tilt could have occurred before the origin of the crown group. Lastly, our study highlights the diversity of cranial variation in crown leporids, and highlights a need for additional phylogenetic work that includes stem (fossil) leporids and includes morphological data that captures the transformed morphology of rabbits and hares.
Hawai'i had high insurance coverage rates even before the Affordable Health Care Act and continues to have a high percentage of the population with health insurance today. However, high insurance rates can disguise wide variation in what is covered and what it costs. In this essay, an Australian Masters in Public Health student from the University of Hawai'i considers the strengths and weaknesses of insurance coverage in the US health-care system when her friend "Peter" becomes seriously ill.
Evolution of cancer cells is characterized by large scale and rapid changes in the chromosomal  landscape. The fluorescence in situ hybridization (FISH) technique provides a way to measure the copy numbers of preselected genes in a group of cells and has been found to be a reliable source of data to model the evolution of tumor cells. Chowdhury et al. (Bioinformatics 29(13):189-98, 23; PLoS Comput Biol 10(7):1003740, 24) recently develop a computational model for tumor progression driven by gains and losses in cell count patterns obtained by FISH probes. Their model aims to find the rectilinear Steiner minimum tree (RSMT) (Chowdhury et al. in Bioinformatics 29(13):189-98, 23) and the duplication Steiner minimum tree (DSMT) (Chowdhury et al. in PLoS Comput Biol 10(7):1003740, 24) that describe the progression of FISH cell count patterns over its branches in a parsimonious manner. Both the RSMT and DSMT problems are NP-hard and heuristics are required to solve the problems efficiently.
In this paper we propose two approaches to solve the RSMT problem, one inspired by iterative methods to address the "small phylogeny" problem (Sankoff et al. in J Mol Evol 7(2):133-49, 27; Blanchette et al. in Genome Inform 8:25-34, 28), and the other based on maximum parsimony phylogeny inference. We further show how to extend these heuristics to obtain solutions to the DSMT problem, that models large scale duplication events.
Experimental results from both simulated and real tumor data show that our methods outperform previous heuristics (Chowdhury et al. in Bioinformatics 29(13):189-98, 23; Chowdhury et al. in PLoS Comput Biol 10(7):1003740, 24) in obtaining solutions to both RSMT and DSMT problems.
The methods introduced here are able to provide more parsimony phylogenies compared to earlier ones which are consider better choices.
Chaetognatha is a minor phylum, comprising transparent marine invertebrates varying in size from 0.5 to 12 cm. The exact phylogenetic position of Chaetognatha in Metazoa has not been deciphered as some embryological characteristics place chaetognaths among deuterostomes and some morphological characteristics place these among protostomes. In this study, the major factors that drive synonymous codon usage bias (SCUB) in the mitogenomes of representative species of Chaetognatha and chosen species of other closely related phyla were analyzed. Spearman's rank correlation analyses of nucleotide contents suggested that mutational pressure and selection were acting in all examined mitogenomes but with varying intensities. The quantification of SCUB using effective number of codons vs. GC composition at the third codon position (GC3) plot suggested that mutational pressure due to GC compositional constraints might be one of the major influencing forces driving the SCUB in all chaetognaths except Sagitta enflata. However, neutrality plots revealed no significant correlation between GC3 and cumulative GC content at first and second codon positions (GC12) in all other species, except in Daphnia pulex. The parity rule 2 bias plot showed that significant compositional differences existed between C and G, as well as between A and T, contents in most of the protein-coding genes (PCGs) and, comparatively, A and T contents were used more proportionally than C and G contents in all chosen mitogenomes. Chi-square analysis revealed the presence of putative optimal codons in all species, except in S. enflata. The correspondence analysis identified that mutational pressure and selection act on the mitogenomes of the selected chaetognaths and other phyla with varying intensities. The cluster analysis based on relative synonymous codon usage (RSCU) values revealed that RSCU variations in the PCGs of mitogenomes of chaetognaths are more comparable with those of protostomes. Apart from mutational pressure and selection, certain unknown selective forces might be acting on the PCGs in the analyzed mitogenomes as the phenomenon of SCUB could not be explained by mutational pressure, by selection, or by both.
Zoonotic cutaneous leishmaniasis (ZCL) is transmitted to humans by phlebotomine sand fly bites. ZCL is a major health problem in Iran, where basic knowledge gaps about sand fly species diversity persist in some ZCL-endemic areas. This paper describes the richness and spatial distribution of sand fly species, collected with sticky traps, in Qom province, a ZCL-endemic area in central Iran, where sand fly fauna has been poorly studied. Collected species were mapped on urban and rural digital maps based on a scale of 1/50,000. All analyses were undertaken with rural- and urban-level precision, i.e., rural and urban levels were our basic units of analysis. After identifying the sand flies, high-risk foci were determined. For spatial analysis of vector species population, the entomological sampling sites were geo-referenced using GPS. Arc GIS 9.3 software was used to determine the foci with leishmaniasis vector species. Following the analyses, two genera (Phlebotomus and Sergentomyia) and 14 species were identified. Based on the mapping and sand fly dispersion analysis, the rural districts were categorized into three groups-infection reported, without infection, and no report. Based on Geographical Information System analyses, Kahak and Markazi districts were identified as high-risk foci with leishmaniasis vector species. These findings can act as a help guide to direct active control measures to the identified high-risk foci and, eventually, lead to reduction in incidence of the disease.
The majority of terrestrial vascular plants are capable of forming mutualistic associations with obligate
 biotrophic arbuscular mycorrhizal (AM) fungi from the phylum Glomeromycota. This mutualistic symbiosis provides carbohydrates to the fungus, and reciprocally improves plant phosphate uptake. AM fungal transporters can acquire phosphate from the soil through the hyphal networks. Nevertheless, the precise functions of AM fungal phosphate transporters, and whether they act as sensors or as nutrient transporters, in fungal signal transduction remain unclear. Here, we report a high-affinity phosphate transporter GigmPT from Gigaspora margarita that is required for AM symbiosis. Host-induced gene silencing of GigmPT hampers the development of G. margarita during AM symbiosis. Most importantly, GigmPT functions as a phosphate transceptor in G. margarita regarding the activation of the phosphate signaling pathway as well as the protein kinase A signaling cascade. Using the substituted-cysteine accessibility method, we identified residues A(146) (in transmembrane domain [TMD] IV) and Val(357) (in TMD VIII) of GigmPT, both of which are critical for phosphate signaling and transport in yeast during growth induction. Collectively, our results provide significant insights into the molecular functions of a phosphate transceptor from the AM fungus G. margarita.
Aerobic respiration is a fundamental physiological trait dependent on coordinated interactions between gene products of the mitochondrial and nuclear genomes. Mitonuclear mismatch in interspecific hybrids may contribute to reproductive isolation by inducing reduced viability (or even complete inviability) due to increased metabolic costs. However, few studies have tested for effects of mitonuclear mismatch on respiration at the whole-organism level. We explored how hybridization affects metabolic rate in closely related species of grasshopper mice (genus Onychomys) to better understand the role of metabolic costs in reproductive isolation. We measured metabolic rate across a range of temperatures to calculate basal metabolic rate (BMR) and cold-induced metabolic rate (MRc) in O. leucogaster, O. torridus and O. arenicola, and in reciprocal F1 hybrids between the latter two species. Within the genus, we found a negative correlation between mass-specific BMR and body mass. Although O. arenicola was smaller than O. torridus, hybrids from both directions of the cross resembled O. arenicola in body mass. In contrast, hybrid BMR was strongly influenced by the direction of the cross: reciprocal F1 hybrids were different from each other but indistinguishable from the maternal species. In addition, MRc was not significantly different between hybrids and either parental species. These patterns indicate that metabolic costs are not increased in Onychomys F1 hybrids and, while exposure of incompatibilities in F2 hybrids cannot be ruled out, suggest that mitonuclear mismatch does not act as a primary barrier to gene flow. Maternal matching of BMR is suggestive of a strong effect of mitochondrial genotype on metabolism in hybrids. Together, our findings provide insight into the metabolic consequences of hybridization, a topic that is understudied in mammals.
Glycoside hydrolases are divided into two groups, known as inverting and retaining enzymes, based on their hydrolytic mechanisms. Glycoside hydrolase family 63 (GH63) is composed of inverting α-glycosidases, which act mainly on α-glucosides. We previously found that Escherichia coli GH63 enzyme, YgjK, can hydrolyze 2-O-α-d-glucosyl-d-galactose. Two constructed glycosynthase mutants, D324N and E727A, which catalyze the transfer of a β-glucosyl fluoride donor to galactose, lactose, and melibiose. Here, we determined the crystal structures of D324N and E727A soaked with a mixture of glucose and lactose at 1.8- and 2.1-Å resolutions, respectively. Because glucose and lactose molecules are found at the active sites in both structures, it is possible that these structures mimic the enzyme-product complex of YgjK. A glucose molecule found at subsite -1 in both structures adopts an unusual (1)S3 skew-boat conformation. Comparison between these structures and the previously determined enzyme-substrate complex structure reveals that the glucose pyranose ring might be distorted immediately after nucleophilic attack by a water molecule. These structures represent the first enzyme-product complex for the GH63 family, as well as the structurally-related glycosidases, and it may provide insight into the catalytic mechanism of these enzymes.
DNA topoisomerases are essential during transcription and replication. The therapeutic mechanism of action of topoisomerase inhibitors is enzyme poisoning rather than catalytic inhibition. Tyrosyl-DNA phosphodiesterases 1 or 2 were found as DNA repair enzymes hydrolyzing the covalent bond between the tyrosyl residue of topoisomerases I or II and the 3'- or 5'-phosphate groups in DNA, respectively. Tyrosyl-DNA phosphodiesterase 1 is a key enzyme in DNA repair machinery and a promising target for antitumor and neurodegenerative therapy. Inhibitors of tyrosyl-DNA phosphodiesterase 1 could act synergistically with topoisomerase I inhibitors and thereby potentiate the effects of topoisomerase I poisons. Tyrosyl-DNA phosphodiesterase 2 is an enzyme that specifically repairs DNA damages induced by topoisomerase II poisons and causes resistance to these drugs. Selective inhibition of tyrosyl-DNA phosphodiesterase 2 may be a novel approach to overcome intrinsic or acquired resistance to topoisomerase II-targeted drug therapy. Thus, agents that inhibit tyrosyl-DNA phosphodiesterases 1 and 2 have many applications in biochemical and physiological research and they have the potential to become anticancer and antiviral drugs. The structures, mechanism of action and therapeutic rationale of tyrosyl-DNA phosphodiesterase inhibitors and their development for combinations with topoisomerase inhibitors and DNA damaging agents are discussed.
The enzyme acid sphingomyelinase-like phosphodiesterase 3B (SMPDL3B) was shown to act as a negative regulator of innate immune signaling, affecting cellular lipid composition and membrane fluidity. Furthermore, several reports identified this enzyme as an off target of the therapeutic antibody rituximab, with implications in kidney disorders. However, structural information for this protein is lacking. Here we present the high resolution crystal structure of murine SMPDL3B, which reveals a substrate binding site strikingly different from its paralogs. The active site is located in a narrow boot-shaped cavity. We identify a unique loop near the active site that appears to impose size constraints on incoming substrates. A structure in complex with phosphocholine indicates that the protein recognizes this head group via an aromatic box, a typical choline-binding motif. Although a potential substrate for SMPDL3B is sphingomyelin, we identify other possible substrates such as CDP-choline, ATP, and ADP. Functional experiments employing structure-guided mutagenesis in macrophages highlight amino acid residues potentially involved in recognition of endogenous substrates. Our study is an important step toward elucidating the specific function of this poorly characterized enzyme.
Animal venoms are complex mixtures containing simple organic molecules, proteins, peptides, and other bioactive elements with extraordinary biological properties associated with their ability to act on a number of molecular receptors in the process of incapacitating their target organisms. In such a context, arthropod venoms are invaluable sources of bioactive substances, with therapeutic interest but the limited availability of some venom such as those from ants, has restricted the potential that these biomolecules could represent. We investigated for the first time transcriptomic expression from the ant species Tetramorium bicarinatum. Four hundred randomly selected clones from cDNA libraries were sequenced and a total of 374 expressed sequence tags (ESTs) were generated. Based on the results of BLAST searches, these sequences were clustered and assembled into 269 contigs. About 72% (269) of these matched BLASTx hits with an interesting diversity and unusual abundance of cellular transcripts (48%) related to gene and protein expression reflecting the specialization of this tissue. In addition, transcripts encoding transposases were relatively highly expressed (14%). It may be that transposable elements are present and that their presence accounts for some of the variation in venom toxins. About twenty per cent of the ESTs were categorized as putative toxins, the major part represented by allergens (48% of the total venom toxins) such as pilosulin 5, sol i 3 and Myp p I and II. Several contigs encoding enzymes, including zinc-metalloproteases (17%) that are likely involved in the processing and activation of venom proteins/peptides, were also identified from the library. In addition, a number of sequences (8%) had no significant similarity to any known sequence which indicates a potential source of for the discovery of new toxins. In order to provide a global insight on the transcripts expressed in the venom gland of the Brazilian ant species Tetramorium bicarinatum and to unveil the potential of their products, high-throughput expressed sequence tags were generated using Illumina paired-end sequencing technology. A total of 212 371 758 pairs of quality-filtered, 100-base-pair Illumina reads were obtained. The de novo assemblies yielded 36 042 contigs for which 27 873 have at least one predicted ORF among which 59.77% produce significant hits in the available databases. The investigation of the read mapping toxin class revealed and confirmed a high diversification with the major part consistent with the classical hymenopteran venom protein signature represented by venom allergen (33.3%) followed by a diverse toxin-expression
 profile including several distinct isoforms of phospholipase A1 and A2, venom serine protease, hyaluronidase, protease inhibitor and secapin. Moreover, our results revealed for the first time the presence of toxin-like peptides that have been previously identified from unrelated venomous animals such as waprin-like (snakes) and agatoxins (spiders and conus). These studies provide a first insight of the gene expression scenario of the venom gland of T. bicarinatum which might contribute to acquiring a more comprehensive view about the origin and functional diversity of venom proteins of this ant. Based on such results, we conducted cytotoxic tests from the crude venom of T.bicarinatum ant and reported toxic effect on tumoral cells lines from one of the fifth of the most frequently occurring cancers with a 3-year survival rate of only 30%. In such a context, new therapeutic strategies are essential and the discovery of new molecules in ant venom could be one possible avenue. Thus our project aims to characterize, from the crude venom of T.bicarinatum, the molecule(s) which have potential anti-cancerous toxicity as well as their mechanisms of action.
It is well known that radiation exposure to the heart and the use of non-steroidal anti-inflammatory drugs (NSAIDs) increase the risk of myocardial infarction (MI). Some NSAIDs are also known to act synergistically with ionizing radiation and have radio-sensitizing effects in radiotherapy. These evidences suggest that NSAIDs may affect the risk of MI after radiation exposure to the heart. In the present study, we investigated effects of NSAIDs on radiation-induced expression of cell adhesion molecules and COX-2, which are associated with inflammation and an increased risk of MI, in human endothelial cells.
Effects of NSAIDs on radiation-induced expression of ICAM-1, VCAM-1, E-selectin, and COX-2 were investigated in human umbilical vein endothelial cells (HUVECs). As NSAIDs, diclofenac, etodolac, indomethacin, ketoprofen, meloxicam, and rofecoxib were used.
Irradiation with 10 Gy increased expression of ICAM-1 and COX-2, but it did not affect expression of VCAM-1 or E-selectin. All the NSAIDs upregulated radiation-induced expression of ICAM-1 and COX-2. The extent of upregulation varied depending on the types of NSAIDs. Indomethacin, diclofenac, and meloxicam highly upregulated radiation-induced expression of ICAM-1 and COX-2. The extent of upregulation was not related to the degree of COX-2 selectivity. An NF-κB inhibitor BAY 11-7082 suppressed radiation-induced expression of ICAM-1, but it did not suppress upregulated expression of ICAM-1 or COX-2 by combination treatment with X-irradiation and meloxicam, suggesting the existence of NF-κB-independent pathways for ICAM-1 and COX-2 induction.
Indomethacin, diclofenac, and meloxicam highly upregulated radiation-induced expression of ICAM-1 and COX-2 in HUVECs, which suggests that use of these NSAIDs may increase the effects of ionizing radiation and affect the risk of MI after radiation exposure to the heart.
The Wnt signalling pathway in beta-cells has been linked to the development of type 2 diabetes. Investigating the impact of a non-canonical Wnt ligand, Wnt4, on beta-cell function we found that in INS-1 cells, Wnt4 was able to completely block Wnt3a stimulated cell growth and insulin secretion. However, despite high levels of Wnt4 protein being detected in INS-1 cells, reducing the expression of Wnt4 had no impact on cell growth or Wnt3a signalling. As such, the role of the endogenously expressed Wnt4 in beta-cells is unclear, but the data showing that Wnt4 can act as a negative regulator of canonical Wnt signalling in beta-cells suggests that this pathway could be a potential target for modulating beta-cell function.
Opioids are important for surgical pain control but may not be appropriate for patients with narcotic abuse histories or opioid intolerance. We describe a laparoscopic bilateral inguinal herniorrhaphy performed without perioperative or postoperative narcotics. Postoperative analgesia involves a novel technique using 2 different bupivacaine formulations that act synergistically to avoid lag time and provide extended pain relief during the acute surgical recovery phase.
Despite progress in drug development, a quantitative and physiological understanding of how small-molecule inhibitors act on cells is lacking. Here, we measure the signalling and proliferative response of individual primary T-lymphocytes to a combination of antigen, cytokine and drug. We uncover two distinct modes of signalling inhibition: digital inhibition (the activated fraction of cells diminishes upon drug treatment, but active cells appear unperturbed), versus analogue inhibition (the activated fraction is unperturbed whereas activation response is diminished). We introduce a computational model of the signalling cascade that accounts for such inhibition dichotomy, and test the model predictions for the phenotypic variability of cellular responses. Finally, we demonstrate that the digital/analogue dichotomy of cellular response as revealed on short (signal transduction) timescales, translates into similar dichotomy on longer (proliferation) timescales. Our single-cell analysis of drug action illustrates the strength of quantitative approaches to translate in vitro pharmacology into functionally relevant cellular settings.
Members of the TrmB family act as global transcriptional regulators for the activation or repression of sugar ABC transporters and central sugar metabolic pathways, including glycolytic, gluconeogenic, and other metabolic pathways, and also as chromosomal stabilizers in archaea. As a relatively newly classified transcriptional regulator family, there is limited experimental evidence for their role in Thermococcales, halophilic archaeon Halobacterium salinarum NRC1, and crenarchaea Sulfolobus strains, despite being one of the extending protein families in archaea. Recently, the protein structures of Pyrococcus furiosus TrmB and TrmBL2 were solved, and the transcriptomic data uncovered by microarray and ChIP-Seq were published. In the present review, recent evidence of the functional roles of TrmB family members in archaea is explained and extended to bacteria.
Functional brain imaging has revealed much about the neuroanatomical substrates of higher cognition, including music, language, learning, and memory. The technique lends itself to studying of groups of individuals. In contrast, the nature of expert performance is typically studied through the examination of exceptional individuals using behavioral case studies and retrospective biography. Here, we combined fMRI and the study of an individual who is a world-class expert musician and composer in order to better understand the neural underpinnings of his music perception and cognition, in particular, his mental representations for music. We used state of the art multivoxel pattern analysis (MVPA) and representational dissimilarity analysis (RDA) in a fixed set of brain regions to test three exploratory hypotheses with the musician Sting: (1) Composing would recruit neutral structures that are both unique and distinguishable from other creative acts, such as composing prose or visual art; (2) listening and imagining music would recruit similar neural regions, indicating that musical memory shares anatomical substrates with music listening; (3) the MVPA and RDA results would help us to map the representational space for music, revealing which musical pieces and genres are perceived to be similar in the musician's mental models for music. Our hypotheses were confirmed. The act of composing, and even of imagining elements of the composed piece separately, such as melody and rhythm, activated a similar cluster of brain regions, and were distinct from prose and visual art. Listened and imagined music showed high similarity, and in addition, notable similarity/dissimilarity patterns emerged among the various pieces used as stimuli: Muzak and Top 100/Pop songs were far from all other musical styles in Mahalanobis distance (Euclidean representational space), whereas jazz, R&B, tango and rock were comparatively close. Closer inspection revealed principaled explanations for the similarity clusters found, based on key, tempo, motif, and orchestration.
The discovery of catalytic RNA (ribozymes) more than 30 years ago significantly widened the horizon of RNA-based functions in natural systems. Similarly to the activity of protein enzymes that are often modulated by the presence of an interaction partner, some examples of naturally occurring ribozymes are influenced by ligands that can either act as cofactors or allosteric modulators. Recent discoveries of new and widespread ribozyme motifs in many different genetic contexts point toward the existence of further ligand-dependent RNA catalysts. In addition to the presence of ligand-dependent ribozymes in nature, researchers have engineered ligand dependency into natural and artificial ribozymes. Because RNA functions can often be assembled in a truly modular way, many different systems have been obtained utilizing different ligand-sensing domains and ribozyme activities in diverse applications. We summarize the occurrence of ligand-dependent ribozymes in nature and the many examples realized by researchers that engineered ligand-dependent catalytic RNA motifs. We will also highlight methods for obtaining ligand dependency as well as discuss the many interesting applications of ligand-controlled catalytic RNAs. For further resources related to this article, please visit the WIREs website.
Sociocognitive research has demonstrated that power affects how people feel, think, and act. In this article, I review literature from social psychology, neuroscience, management, and animal research and propose an integrated framework of power
 as an intensifier of goal-related approach motivation. A growing literature shows that power energizes thought, speech, and action and orients individuals toward salient goals linked to power roles, predispositions, tasks, and opportunities. Power magnifies self-expression linked to active parts of the self (the active self ), enhancing confidence, self-regulation, and prioritization of efforts toward advancing focal goals. The effects of power on cognitive processes, goal preferences, performance, and corruption are discussed, and its potentially detrimental effects on social attention, perspective taking, and objectification of subordinates are examined. Several inconsistencies in the literature are explained by viewing power holders as more flexible and dynamic than is usually assumed. Expected final online publication date for the Annual Review of Psychology Volume 68 is January 03, 2017. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.
Outcome of low-grade glioma (WHO grade II) is highly variable, reflecting molecular heterogeneity of the disease. We compared two different, single-modality treatment strategies of standard radiotherapy versus primary temozolomide chemotherapy in patients with low-grade glioma, and assessed progression-free survival outcomes and identified predictive molecular factors.
For this randomised, open-label, phase 3 intergroup study (EORTC 22033-26033), undertaken in 78 clinical centres in 19 countries, we included patients aged 18 years or older who had a low-grade (WHO grade II) glioma (astrocytoma, oligoastrocytoma, or oligodendroglioma) with at least one high-risk feature (aged >40 years, progressive disease, tumour size >5 cm, tumour crossing the midline, or neurological symptoms), and without known HIV infection, chronic hepatitis B or C virus infection, or any condition that could interfere with oral drug administration. Eligible patients were randomly assigned (1:1) to receive either conformal radiotherapy (up to 50·4 Gy; 28 doses of 1·8 Gy once daily, 5 days per week for up to 6·5 weeks) or dose-dense oral temozolomide (75 mg/m(2) once daily for 21 days, repeated every 28 days [one cycle], for a maximum of 12 cycles). Random treatment allocation was done online by a minimisation technique with prospective stratification by institution, 1p deletion (absent vs present vs undetermined), contrast enhancement (yes vs no), age (<40 vs ≥40 years), and WHO performance status (0 vs ≥1). Patients, treating physicians, and researchers were aware of the assigned intervention. A planned analysis was done after 216 progression events occurred. Our primary clinical endpoint was progression-free survival, analysed by intention-to-treat; secondary outcomes were overall survival, adverse events, neurocognitive function (will be reported separately), health-related quality of life and neurological function (reported separately), and correlative analyses of progression-free survival by molecular markers (1p/19q co-deletion, MGMT promoter methylation status, and IDH1/IDH2 mutations). This trial is closed to accrual but continuing for follow-up, and is registered at the European Trials Registry, EudraCT 2004-002714-11, and at ClinicalTrials.gov, NCT00182819.
Between Sept 23, 2005, and March 26, 2010, 707 patients were registered for the study. Between Dec 6, 2005, and Dec 21, 2012, we randomly assigned 477 patients to receive either radiotherapy (n=240) or temozolomide chemotherapy (n=237). At a median follow-up of 48 months (IQR 31-56), median progression-free survival was 39 months (95% CI 35-44) in the temozolomide group and 46 months (40-56) in the radiotherapy group (unadjusted hazard ratio [HR] 1·16, 95% CI 0·9-1·5, p=0·22). Median overall survival has not been reached. Exploratory analyses in 318 molecularly-defined patients confirmed the significantly different prognosis for progression-free survival in the three recently defined molecular low-grade glioma subgroups (IDHmt, with or without 1p/19q co-deletion [IDHmt/codel], or IDH wild type [IDHwt]; p=0·013). Patients with IDHmt/non-codel tumours treated with radiotherapy had a longer progression-free survival than those treated with temozolomide (HR 1·86 [95% CI 1·21-2·87], log-rank p=0·0043), whereas there were no significant treatment-dependent differences in progression-free survival for patients with IDHmt/codel and IDHwt tumours. Grade 3-4 haematological adverse events occurred in 32 (14%) of 236 patients treated with temozolomide and in one (<1%) of 228 patients treated with radiotherapy, and grade 3-4 infections occurred in eight (3%) of 236 patients treated with temozolomide and in two (1%) of 228 patients treated with radiotherapy. Moderate to severe fatigue was recorded in eight (3%) patients in the radiotherapy group (grade 2) and 16 (7%) in the temozolomide group. 119 (25%) of all 477 patients had died at database lock. Four patients died due to treatment-related causes: two in the temozolomide group and two in the radiotherapy group.
Overall, there was no significant difference in progression-free survival in patients with low-grade glioma when treated with either radiotherapy alone or temozolomide chemotherapy alone. Further data maturation is needed for overall survival analyses and evaluation of the full predictive effects of different molecular subtypes for future individualised treatment choices.
Merck Sharpe & Dohme-Merck & Co, Canadian Cancer Society, Swiss Cancer League, UK National Institutes of Health, Australian National Health and Medical Research Council, US National Cancer Institute, European Organisation for Research and Treatment of Cancer Cancer Research Fund.
A palliative care charity has devised a new approach to end of life care based on the Human Rights Act.
Conducting federally mandated community health needs assessments through academic-practice partnerships provides new opportunities for developing population health nursing competencies.
The purpose of this article was to describe how a baccalaureate practicum experience within such an assessment process, involving health care system partners, re-affirms the importance of community and population health assessment in the development of future nursing leaders.
Student evaluations indicated an emerging appreciation for the social determinants of health, the power of partnerships, and the importance of diversity. Integrating health care and public health system perspectives on assessment meets both public health and nursing accreditation standards and extends student leadership experiences. Such integration also improves regional capacity for improving population health.
Federal mandates for community health needs assessments provide opportunities to advance leadership roles for nursing graduates throughout the health care system, and for confirming the importance of community assessment as an essential nursing competency.
Although accumulated evidence supports the notion that mesenchymal stem cells (MSCs) act in a paracrine manner, the mechanisms are still not fully understood. Recently, MSC-derived exosomes (MSC-Exos), a type of microvesicle released from MSCs, were thought to carry functional proteins and RNAs to recipient cells and play therapeutic roles. In the present study, we intravitreally injected MSCs derived from either mouse adipose tissue or human umbilical cord, and their exosomes to observe and compare their functions in a mouse model of laser-induced retinal injury. We found that both MSCs and their exosomes reduced damage, inhibited apoptosis, and suppressed inflammatory responses to obtain better visual function to nearly the same extent in vivo. Obvious down-regulation of monocyte chemotactic protein (MCP)-1 in the retina was found after MSC-Exos injection. In vitro, MSC-Exos also down-regulated MCP-1 mRNA expression in primarily cultured retinal cells after thermal injury. It was further demonstrated that intravitreal injection of an MCP-1-neutralizing antibody promoted the recovery of retinal laser injury, whereas the therapeutic effect of exosomes was abolished when MSC-Exos and MCP-1 were administrated simultaneously. Collectively, these results suggest that MSC-Exos ameliorate laser-induced retinal injury partially through down-regulation of MCP-1.
Platelet count (PC) and fatty liver are both associated with metabolic syndrome (MS), obesity, and type 2 diabetes. While PC increases in obesity and type 2 diabetes, the severity of hepatic fibrosis caused by fatty liver reduces PC. We aimed to investigate the correlation of PC and MS in patients with and without fatty liver.
We enrolled consecutive patients who received health check-ups at Taipei Veterans General Hospital from 2002 to 2009. Ultrasonography was used to diagnose fatty liver, and MS was diagnosed according to the criteria defined by the International Diabetes Federation Task Force on Epidemiology and Prevention.
Among the 29,797 patients, MS was present in 28.74%. Higher PC was correlated with MS using multivariate analysis, while fatty liver had the strongest association with MS. After dividing the patients by the presence or absence of fatty liver, higher PC was still associated with MS in both groups. The patients were further stratified by age and gender, and MS was correlated with PC among all age groups in women and in men under 60 years of age; however, the association between PC and MS did not reach statistical difference in men older than 60 years.
There is a significant correlation between PC and MS, and the correlation exists independent of gender, age, and fatty liver. PC may act as a surrogate marker for MS, and physicians should be concerned with the presence of MS among patients with high PC.
The volume of a protein can be estimated from its molecular weight. This approach has also been applied in force microscopy experiments.
 Two factors contribute to the determination of the volume from a force microscope image, the applied force and the tip radius. Those factors act in opposite directions. Here, we demonstrate that in the optimum conditions to image a protein, the apparent volume deduced from an AFM image overestimates the real protein volume. The lateral broadening due to the tip finite size, makes the simulated volume to exceed the real protein volume value, while the force applied by the tip tends to decrease the measured volume. The measured volume could coincide with the real volume for either a point-size tip at zero force or when the compression exerted by the tip compensates its dilation effects. The interplay between the above factors make unsuitable to apply the molecular weight method to determine the volume of a protein from AFM data.
Amyloids consist of repetitions of a specific polypeptide chain in a regular cross-β-sheet conformation. Amyloid propensity is largely determined by the protein sequence, the aggregation process being nucleated by specific and short segments. Prions are special amyloids that become self-perpetuating after aggregation. Prions are responsible for neuropathology in mammals, but they can also be functional, as in yeast prions. The conversion of these last proteins to the prion state is driven by prion forming domains (PFDs), which are generally large, intrinsically disordered, enriched in glutamines/asparagines and depleted in hydrophobic residues. The self-assembly of PFDs has been thought to rely mostly on their particular amino acid composition, rather than on their sequence. Instead, we have recently proposed that specific amyloid-prone sequences within PFDs might be key to their prion behaviour. Here, we demonstrate experimentally the existence of these amyloid stretches inside the PFDs of the canonical Sup35, Swi1, Mot3 and Ure2 prions. These sequences self-assemble efficiently into highly ordered amyloid fibrils, that are functionally competent, being able to promote the PFD amyloid conversion in vitro and in vivo. Computational analyses indicate that these kind of amyloid stretches may act as typical nucleating signals in a number of different prion domains.
Patients admitted to a psychiatric hospital commonly suffer from comorbid medical problems which sometimes require urgent medical attention. Twenty-two percent of emergency medical transfers from the Institute of Mental Health (IMH) to the emergency rooms of general hospitals were preventable and could be managed at IMH itself. We undertook a quality improvement project to understand the reasons behind such preventable referrals and implemented changes to address this.
Using the model for improvement, we deconstructed our processes and analysed root causes for such preventable referrals. Thereafter changes were implemented with Plan-Do-Study-Act (PDSA) cycles to analyse their outcomes.
During the 6-month study period, we achieved a 100% reduction in preventable referrals through strategies aimed at reducing pressure on our on-call physicians in the making of medical decisions, maximising usage of our medical resources, constant education and raising awareness of this issue.
Reducing preventable transfer of inpatients from a psychiatric hospital to the emergency departments of general hospitals is a worthwhile endeavour. Such initiatives optimise use of healthcare resources, improve patient care and increase satisfaction.
Programmed cell death occurs as a normal part of oocyte development in Drosophila. For each egg that is formed, 15 germline-derived nurse cells transfer their cytoplasmic contents into the oocyte and die. Disruption of apoptosis or autophagy only partially inhibits the death of the nurse cells, indicating that other mechanisms significantly contribute to nurse cell death. Recently, we demonstrated that the surrounding stretch follicle cells non-autonomously promote nurse cell death during late oogenesis and that phagocytosis genes including draper, ced-12, and the JNK pathway are crucial for this process. When phagocytosis genes are inhibited in the follicle cells, events specifically associated with death of the nurse cells are impaired. Death of the nurse cells is not completely blocked in draper mutants, suggesting that other engulfment receptors are involved. Indeed, we found that the integrin subunit, αPS3, is enriched on stretch follicle cells during late oogenesis and is required for elimination of the nurse cells. Moreover, double mutant analysis revealed that integrins act in parallel to draper. Death of nurse cells in the Drosophila ovary is a unique example of programmed cell death that is both non-apoptotic and non-cell autonomously controlled.
To explore the association between HOTAIR rs4759314 and cancer risk.
A comprehensive online search was conducted using PubMed, EMBASE, and CNKI databases to identify relevant studies. The case-control studies related to HOTAIR rs4759314 polymorphism and cancer risk were selected according to the inclusion and exclusion criteria. The retrieval time was until November 2015. After extracting the basic data information and performing an evaluation of the quality of the literature, the meta-analysis was performed using STATA 12.0 software, by calculating the odds ratio (OD) and 95% confidence interval (95% CI), and further subgroup analysis, literature publication bias testing, and sensitivity analysis.
The studies included a total of 5025 patients with cancer and 5657 controls. The results found no significant association between the HOTAIR rs4759314 polymorphism and cancer risk in a Chinese population (G vs A, OR=1.06, 95% CI :0.87-1.30 ; GG/GA vs AA, OR=1.07, 95% CI: 0.87-1.32; GG vs GA/AA, OR=0.75, 95% CI:0.39-1.43; GA vs AA, OR=1.08, 95% CI: 0.88-1.33; GG vs AA, OR=0.76, 95% CI:0.39-1.45) (all p<0.05). However, A allelic gene was associated with lower risk of gastric cancer, while G allelic gene may act as a genetic susceptibility factor for gastric cancer in Chinese population.
No significant association was noted between the HOTAIR rs4759314 polymorphism and cancer risk in a Chinese population.
Cancer cells have an increased demand for amino acids and require transport even of non-essential amino acids to support their increased proliferation rate. Besides their major role as protein synthesis precursors, the two proteinogenic sulfur-containing amino acids, methionine and cysteine, play specific biological functions. In humans, methionine is essential for cell growth and development and may act as a precursor for cysteine synthesis. Cysteine is a precursor for the biosynthesis of glutathione, the major scavenger for reactive oxygen species.
We study the effect of K-ras oncogene activation in NIH3T3 mouse fibroblasts on transport and metabolism of cysteine and methionine. We show that cysteine limitation and deprivation cause apoptotic cell death (cytotoxic effect) in both normal and K-ras-transformed fibroblasts, due to accumulation of reactive oxygen species and a decrease in reduced glutathione. Anti-oxidants glutathione and MitoTEMPO inhibit apoptosis, but only cysteine-containing glutathione partially rescues the cell growth defect induced by limiting cysteine. Methionine limitation and deprivation has a cytostatic effect on mouse fibroblasts, unaffected by glutathione. K-ras-transformed cells-but not their parental NIH3T3-are extremely sensitive to methionine limitation. This fragility correlates with decreased expression of the Slc6a15 gene-encoding the nutrient transporter SBAT1, known to exhibit a strong preference for methionine-and decreased methionine uptake.
Overall, limitation of sulfur-containing amino acids results in a more dramatic perturbation of the oxido-reductive balance in K-ras-transformed cells compared to NIH3T3 cells. Growth defects induced by cysteine limitation in mouse fibroblasts are largely-though not exclusively-due to cysteine utilization in the synthesis of glutathione, mouse fibroblasts requiring an exogenous cysteine source for protein synthesis. Therapeutic regimens of cancer involving modulation of methionine metabolism could be more effective in cells with limited methionine transport capability.
Assessment methods of surface disinfection based on international standards (Environmental Protection Agency, European Norms, etc) do not correspond to hospital reality. New evaluation methods of surfaces disinfection are proposed to choose the most suitable disinfectant to act against clinically relevant microorganisms detected on the surfaces of burn units. 1) "Immediate effect": 6 products were compared using a glass germ-carrier and 20 recently isolated microorganisms from different patients in the intensive care units. Disinfectants were applied with microfiber cloths. Log10 reductions were calculated for colony forming units produced after 15 minutes of disinfectant application. 2) "Residual effect": the glass germ-carriers were previously impregnated with one of the studied disinfectants. After a 30-minute wait period, they were then contaminated with 1 microorganism (from the 20 above-mentioned). After 15 minutes, the disinfectant was inhibited and the log10 reduction of colony forming units was assessed. The immediate effect (disinfection and microorganism drag and transfer to the cloth) produced complete elimination of the inoculums for all products used except one (a diluted quaternary ammonium). The average residual effect found on the 20 microorganisms was moderate: 2 to 3 log10 colony forming unit reduction with chlorine dioxide or 0.5% chlorhexidine (and lower with the other products), obtaining surfaces refractory to recontamination, at least, during 30 minutes. Two tests should be performed before advising surface disinfectant: 1) direct effect and 2) residual efficacy. These characteristics should be considered
 when a new surface disinfectant is chosen. Chlorine dioxide has a similar or better direct effect than sodium hypochlorite and a similar residual effect than chlorhexidine.
The antineoplastic role of peroxisome proliferator-activated receptor gamma (PPARγ) ligandshas previously been demonstrated in several gastric cancer cell lines. Activation of PPARγ by polyunsaturated fatty acids (PUFAs) inhibits growth and proliferationof tumor cells. In this double-blind clinical study, we evaluate the effect of PUFAs on PPARγ mRNA expression in patients with gastric adenocarcinoma.
A total of 34 chemotherapy-naive patients diagnosed with gastric adenocarcinoma were enrolled in the present study. According to treatment strategies, all subjects were divided into two groups, the first group (17 individuals) received cisplatin without supplements and the second group (17 individuals) received cisplatin plus orally administered PUFAs supplements for 3 weeks. The gastric biopsy samples were obtained from all participants before and after treatment, and PPARγ mRNA expression levels were evaluated by quantitative real-time polymerase chain reaction using validated reference genes.
Our findings revealed that PPARγ mRNA expression is significantly upregulated in group II afterreceiving cisplatin plus orally administered PUFAs supplements for three weeks (p < 0.0001), whereas PPARγ mRNA expression did not show significant alteration in group I after receiving cisplatin alone.
The results of the study evidence that PPARγ may act as a potential target for the therapy of human gastric adenocarcinoma.
The hexaploid wheat (Triticum aestivum) adult plant resistance gene, Lr34/Yr18/Sr57/Pm38/Ltn1, provides broad spectrum resistance to wheat leaf rust (Lr34), stripe rust (Yr18), stem rust (Sr57) and powdery mildew (Pm38) pathogens, and has remained effective in wheat crops for many decades. The partial resistance provided by this gene is only apparent in adult plants and not effective in seedlings under standard growth conditions. Lr34 also causes leaf tip necrosis (Ltn1) in mature adult plant leaves when grown under field conditions. This D genome encoded bread wheat gene was transferred to tetraploid durum wheat (T. turgidum) cultivar Stewart by transformation. Transgenic durum lines were produced with elevated gene expression levels when compared with the endogenous hexaploid gene. Unlike nontransgenic hexaploid and durum control lines, these transgenic plants showed robust seedling resistance to pathogens causing wheat leaf rust, stripe rust and powdery mildew disease. The effectiveness of seedling resistance against each pathogen correlated with the level of transgene expression. No evidence of accelerated leaf necrosis or upregulation of senescence gene markers was apparent in these seedlings suggesting senescence is not required for Lr34 resistance. Several abiotic stress response genes were upregulated in these seedling in the absence of rust infection as previously observed in adult plant flag leaves of hexaploid wheat. Photoperiod and light intensity had significant effects on Lr34 phenotypes. These data demonstrate that expression of a highly durable, broad spectrum adult plant resistance gene can be modified to provide seedling resistance in durum wheat. This article is protected by copyright. All rights reserved.
Lung cancer remains the leading cancer killer around the world. It's crucial to identify newer mechanism-based targets to effectively manage lung cancer. Annexin A5 (ANXA5) is a protein kinase C inhibitory protein and calcium dependent phospholipid-binding protein, which may act as an endogenous regulator of various pathophysiological processes. However, its molecular mechanism in lung cancer remains poorly understood. This study was designed to determine the mechanism of ANXA5 in lung cancer with a hope to obtain useful information to provide a new therapeutic target. We used a stable isotope dimethyl labeling based quantitative proteomic method to identify differentially expressed proteins in NSCLC cell lines after ANXA5 transfection. Out of 314 proteins, we identified 26 and 44 proteins that were down- and up-regulated upon ANXA5 modulation, respectively. The IPA analysis revealed that glycolysis and gluconeogenesis were the predominant pathways modulated by ANXA5. Multiple central nodes, namely HSPA5, FN1, PDIA6, ENO1, ALDOA, JUP and KRT6A appeared to occupy regulatory nodes in the protein-protein networks upon ANXA5 modulation. Taken together, ANXA5 appears to have pleotropic effects, as it modulates multiple key signaling pathways, supporting the potential usefulness of ANXA5 as a potential target in lung cancer. This study might provide a new insight into the mechanism of ANXA5 in lung cancer.
This study aimed to determine the effects of a functional training and ankle stretching program in triceps surae torque, passive stiffness index and in risk for fall indicators in older adults. Twenty women (73.4 ± 7.3 years) were allocated into intervention or control group. The 12-week intervention consisted of functional training and calf stretching exercises performed twice a week. Measurements of peak passive and active torque, passive stiffness, maximum dorsiflexion angle and indexes of risk for fall (Timed Up and go, Functional reach test e QuickScreen-test) were collected. There were no significant differences for all variables, except the maximum dorsiflexion angle, which increased in the intervention group from 33.78 ± 8.57° to 38.89 ± 7.52°. The exercise program was not sufficient to enhance performance on functional tests and decrease the risk for falls of older adults. The significant increase in the maximum dorsiflexion indicates a positive impact of stretching exercises.
Alcohol use is a leading risk factor for the global disease burden including liver diseases. However, the combined effect of alcohol use and body mass index (BMI) on alcohol-related diseases has seldom been examined. We examined whether alcohol consumption and BMI could act together to increase mortality from nonneoplastic liver diseases, upper aero-digestive tract (UADT) cancers, and alcohol use disorders (AUD) in middle-aged Korean men.107,735 men (mean age, 58.8 years) participated in a postal survey in 2004 and were followed until 2010, by linkage to national death records. Hazard ratios (HRs) of cause-specific death were calculated after adjustment for confounders.Each 5-drink (approximately 45 g alcohol) higher weekly alcohol consumption was associated with increased mortality, by approximately 70% for nonneoplastic liver disease mortality (HR = 1.70, P < 0.001), approximately 60% for UADT cancer mortality (HR = 1.64, P < 0.001), and approximately 70% for AUD mortality (HR = 1.71, P < 0.001). Generally, BMI was inversely associated with these alcohol-related diseases (HR per each 5 kg/m higher BMI = 0.18-0.46, P < 0.001 for each cause), while, in participants with BMI ≥25 kg/m, each 5 kg/m higher BMI was also associated with an elevated mortality from nonneoplastic liver diseases of approximately 150% (HR = 2.52, P = 0.001). Men with BMI < 21 kg/m and weekly alcohol consumption ≥14 drinks showed markedly higher mortality from nonneoplastic liver diseases (HR = 5.7), alcoholic liver diseases (HR = 9.3), UADT cancers (HR = 10.5), and esophageal cancer (HR = 15.5), compared to men drinking less than 1 drink/wk with BMI ≥25 kg/m. The combined effect of low BMI and high weekly alcohol consumption was 2.25- to 3.29-fold greater than the additive effect of each factor for these alcohol-related diseases (P < 0.05 for each cause).Alcohol consumption and low BMI were related to deaths from nonneoplastic liver diseases, UADT cancers, and AUD, with evidence of a supra-additive combined effect of both factors. High BMI was also related to deaths from nonneoplastic liver diseases. Men with a low BMI (<23 kg/m) are suggested to be prone to the harmful effects of alcohol.
Hydrogen sulfide (H2S) has been verified as an important biological mediator in human physiological activities, but its rapid and accurate detection is remaining a challenge. Based on our early work, Eu-containing polyoxometalate/ionic liquid-type gemini surfactant hybrid nanoparticles fabricated by EuW10O36·32H2O (Eu-POM) and 1,2-bis(3-hexadecylimidazolium-1-yl) ethane bromide ([C16-2-C16im]Br2) via ionic self-assembly (ISA) strategy, we modified the hybrids with copper (II) ion and used them as a novel turn-off supramolecular fluorescence probe for H2S immediate response. Although copper (II) ions can cause decrease of the fluorescence intensity, the probe with moderate amount of copper (II) still has a high performance in emission property. The copper (II) ion-modified supramolecular sensor (CSS) shows dual signals in the fluorescence intensity and absorbance for H2S detection, and the detection limit is about1.25μM. Furthermore, CSS displays high selectivity for H2S in the presence of other anions and species (e.g. Cl(-), Br(-), I(-), SO4(2-), SO3(2-), S2O3(2-), AC(-), H2O2, HCO3(-), l-cysteine, homocysteine and l-glutathione), and also have potential for preferential imaging in vivo. Besides, the fluorescence quenching mechanism of CSS in the presence of H2S was explored. CuS generated by the reaction between Cu(2+) and H2S was testified to act as a quencher, and the nonradiative resonance energy transfer mechanism was speculated to be responsible for fluorescence quenching. It is anticipated that the as-prepared CSS will be used as an efficient chemosensor for the rapid detection of H2S, which is critical for the diagnosis of some diseases, e.g. Alzhermer's disease, Down's syndrome, and diabetes, etc.
In the post-Affordable Care Act era marked by interorganizational collaborations and availability of large amounts of electronic data from other community partners, it is imperative
 to assess the interoperability of information systems used by the local health departments (LHDs).
To describe the level of interoperability of LHD information systems and identify factors associated with lack of interoperability.
This mixed-methods research uses data from the 2015 Informatics Capacity and Needs Assessment Survey, with a target population of all LHDs in the United States. A representative sample of 650 LHDs was drawn using a stratified random sampling design. A total of 324 completed responses were received (50% response rate). Qualitative data were used from a key informant interview study of LHD informatics staff from across the United States. Qualitative data were independently coded by 2 researchers and analyzed thematically. Survey data were cleaned, bivariate comparisons were conducted, and a multivariable logistic regression was run to characterize factors associated with interoperability.
For 30% of LHDs, no systems were interoperable, and 38% of LHD respondents indicated some of the systems were interoperable. Significant determinants of interoperability included LHDs having leadership support (adjusted odds ratio [AOR] = 3.54), control of information technology budget allocation (AOR = 2.48), control of data systems (AOR = 2.31), having a strategic plan for information systems (AOR = 1.92), and existence of business process analysis and redesign (AOR = 1.49).
Interoperability of all systems may be an informatics goal, but only a small proportion of LHDs reported having interoperable systems, pointing to a substantial need among LHDs nationwide.
Corexit-EC9500A and Corexit-EC9527A are two chemical dispersants that have been used to remediate the impact of the 2010 Deepwater Horizon oil spill. Both dispersants are composed primarily of organic solvents and surfactants and act by emulsifying the crude oil to facilitate biodegradation. The potential adverse effect of the Corexit chemicals on mammalian embryonic development remains largely unknown. Retinol (vitamin A) signaling, mediated by all-trans retinoic acid (RA), is essential for neural tube formation and the development of many organs in the embryo. The physiological levels of RA in cells and tissues are maintained by the retinol signaling pathway (RSP), which controls the biosynthesis of RA from dietary retinol and the catabolism of RA to polar metabolites for removal. RA is a potent activating ligand for the RAR/RXR nuclear receptors. Through RA and the receptors, the RSP modulates the expression of many developmental genes; interference with the RSP is potentially teratogenic. In this study the mouse P19 embryonal pluripotent cell, which contains a functional RSP, was used to evaluate the effects of the Corexit dispersants on retinol signaling and associated neuronal differentiation. The results showed that Corexit-EC9500A was more cytotoxic than Corexit-EC9527A to P19 cells. At non-cytotoxic doses, Corexit-EC9527A inhibited retinol-induced expression of the Hoxa1 gene, which encodes a transcription factor for the regulation of body patterning in the embryo. Such inhibition was seen in the retinol- and retinal- induced, but not RA-induced, Hoxa1 up-regulation, indicating that the Corexit chemicals primarily inhibit RA biosynthesis from retinal. In addition, Corexit-EC9527A suppressed retinol-induced P19 cell differentiation into neuronal cells, indicating potential neurotoxic effect of the chemicals under the tested conditions. The surfactant ingredient, dioctyl sodium sulfosuccinate (DOSS), may be a major contributor to the observed effect of Corexit-EC9527A in the cell.
In vitro transcription assays have been developed and widely used for many years to study the molecular mechanisms involved in transcription. This process requires multi-subunit DNA-dependent RNA polymerase (RNAP) and a series of transcription factors that act to modulate the activity of RNAP during gene expression. Sequencing gel electrophoresis of radiolabeled transcripts is used to provide detailed mechanistic information on how transcription proceeds and what parameters can affect it. In this paper we describe the protocol to study how the essential elongation factor NusA regulates transcriptional pausing, as well as a method to identify an antibacterial agent targeting transcription initiation through inhibition of RNAP holoenzyme formation. These methods can be used a as platform for the development of additional approaches to explore the mechanism of action of the transcription factors which still remain unclear, as well as new antibacterial agents targeting transcription which is an underutilized drug target in antibiotic research and development.
Systemic inflammatory parameters, such as the elevator PLR (platelet-lymphocyte ratio), the NLR (neutrophil-lymphocyte ratio) and the platelet count (PLT), have been found to be associated with the prognosis in gastric cancer; however, these results, especially those relating to the PLR, remain inconsistent. So we aimed to evaluate the prognostic role of the PLR in gastric cancer by conducting and presenting the findings of this meta-analysis.
We conducted a systematic literature search in PubMed, Embase and the Cochrane Library to evaluate the prognostic value of the PLR in gastric cancer. The quality of the included studies was evaluated using the Newcastle Ottawa Quality Assessment Scale (NOS). The hazard ratio (HR) /Odds Ratio (OR) and its 95% confidence were pooled using a random effects model. A funnel plot based on overall survival was used to evaluate the publication bias.
It total, 8 studies comprising 4513 patients with gastric cancer met the pre-setting inclusion criteria. In comparison to the normal PLR, an elevated PLR was correlated with a higher risk of lymph node metastasis with an OR of 1.50 (95% Cl:1.24-1.82; I2 = 17%) and serosal invasion (T3 +T4) risk with an OR of 2.01 (95% Cl: 1.49-2.73; I2 = 55%), and an elevated PLR also increased the advanced stage (III +IV) risk with an OR of 1.99 (95% Cl: 1.60-2.46; I2 = 28%). An elevated PLR was not a reliable predictor for OS with an HR of 0.99 (95% CI: 0.9-1.1; I2 = 12%).
An elevated PLR was correlated with a higher risk of lymph node metastasis, serosal invasion and advanced stage (III +IV) risk in gastric cancer; however, the PLR may not act as a negative predictor for the overall survival of gastric cancer.
The growth of a child and the amount of weight gained across the life course is associated with risk for many chronic degenerative diseases. The life course approach to this area of epidemiological research has burgeoned over the last 25 years, since the initial observation of an inverse relationship between birth weight and coronary heart disease. We review the substantial amount of published research to demonstrate which age-related body size trajectories are indicative of increased risk of cardio-metabolic diseases such as coronary heart disease, stroke, and type two diabetes. Association does not mean causation. The chapter thus also provides an overview of the key sociocultural and other factors responsible for deleterious trajectories, and the biological pathways through which they act, to show how the trajectories are driven by biology but modifiable by the environment. Attention is paid to critical periods and transitions, both biological (e.g., puberty) and behavioural (e.g., marriage), and the influences that these might have on an individual’s trajectory. We highlight the importance of life course trajectories of body size and their associations with trajectories of markers of cardio-metabolic health such as blood pressure and lipids, and the need to integrate biological and social research to move towards a more complete understanding of cardio-metabolic disease processes and, ultimately, how to delay the onset of disease.
In Singapore, tissue donation is covered under the Medical (Therapy, Education and Research) Act. The objective of this study is to review the demographic and psychosocial factors, which may cause hesitation/unwillingness amongst healthcare professionals towards tissue donation.
A survey comprising 18-items was conducted at the Singapore General Hospital and National Heart Centre Singapore. A total of 521 individuals participated in the survey. Descriptive statistics were performed for the demographic profiles of participants, the factors leading to the support of tissue donation, reasons for hesitation/reluctance to donate tissue and motivating factors to discuss tissue donation with next-of-kin. Pearson's chi-square and Fisher's exact tests were employed to assess possible association between various factors and support towards tissue donation. Analyses were performed using Statistical Package for Social Sciences V.21.0 software.
A total of 64.9% of participants had heard about skin donation; 48.9% had heard about heart valve donation; 4.5% were tissue pledgers. The primary reason for pro-donation was the altruism of "improving someone's quality of life". However, a majority stated they "can decide this in the later part of life" as their main reason for hesitation; 82.3% were willing to discuss their tissue donation wish with next-of-kin, while 53.1% were likely to make the decision of donation on behalf of their deceased next-of-kin.
RESULTS highlighted important psychosocial and professional factors that influence the hesitation/ reluctance towards donation. Hence, there is a need to re-strategise educational efforts in accordance with the target audiences and address specific misconceptions and concerns.
It has become clear that mitochondrial reactive oxygen species (mtROS) are not simply villains and mitochondria the hapless targets of their attacks. Rather, it appears that mitochondrial dysfunction itself and the signaling function of mtROS can have positive effects on lifespan, helping to extend longevity.
 If events in the mitochondria can lead to better cellular homeostasis and better survival of the organism in ways beyond providing ATP and biosynthetic products, we can conjecture that they act on other cellular components through appropriate signaling pathways. We describe recent advances in a variety of species which promoted our understanding of how changes of mtROS generation are part of a system of signaling pathways that emanate from the mitochondria to impact organism lifespan through global changes, including in transcriptional patterns. In unraveling this, many old players in cellular homeostasis were encountered. Among these, maybe most strikingly, is the intrinsic apoptotic signaling pathway, which is the conduit by which at least one class of mtROS exercise their actions in the nematode Caenorhabditis elegans. This is a pathway that normally contributes to organismal homeostasis by killing defective or otherwise unwanted cells, and whose various compounds have also been implicated in other cellular processes. However, it was a surprise that that appropriate activation of a cell killing pathway can in fact prolong the lifespan of the organism. In the soma of adult C. elegans, all cells are post-mitotic, like many of our neurons and possibly some of our immune cells. These cells cannot simply be killed and replaced when showing signs of dysfunction. Thus, we speculate that it is the ability of the apoptotic pathway to pull together information about the functional and structural integrity of different cellular compartments that is the key property for why this pathway is used to decide when to boost defensive and repair processes in irreplaceable cells. When this process is artificially stimulated in mutants with elevated mtROS generation or with drug treatments it leads to lifespan prolongations beyond the normal lifespan of the organism.
Oral mucosal Langerhans cells (LC) are likely to play important roles in host defense against infection by human cytomegalovirus (CMV). We previously showed that in vitro-differentiated immature LC (iLC) populations contain smaller amounts of infected cells but produce higher yields than mature LC (mLC) cultures, obtained by iLC stimulation with fetal bovine serum (FBS), CD40 ligand (CD40L) and lipopolysaccharide (LPS). Here, we sought to determine if exposure to select stimuli can improve LC permissiveness to infection, if specific components of the mLC cocktail are responsible for lowering viral yields, if this is due to defects in progeny production or release, and if these restrictions are also effective against reactivated virus. None of the stimuli tested extended the proportion of infected cells to 100%, suggesting that the block to infection onset cannot be fully removed. While CD40L and FBS exerted positive effects on viral progeny production per cell, stimulation with LPS alone or in combination with CD40L was detrimental. Reductions in viral titers were not due to defects in progeny release, and the permissive or restrictive intracellular environment established upon exposure to each stimulus appeared to act in a somewhat similar way toward lytic and latent infections.
To explore the role of elevated feelings of anger and desires to escape (fight/flight), which are experienced as inhibited, blocked, and arrested (i.e., arrested anger and arrested flight/escape leading to feelings of entrapment). This descriptive study developed measures of arrested anger and arrested flight and explored these in the context of a recent self-harm event in people presenting to a Hospital's Emergency Department (ED).
Fifty-eight individuals presenting to an ED following an act of self-harm were recruited. Participants completed newly developed measures of arrested flight, arrested anger and anger with self in regard to self-harm, and suicide intent and depression.
Ninety-three percent of participants presented after self-poisoning. The majority (95%) reported having experienced high escape motivation that felt blocked (arrested flight) with 69% reporting feeling angry with someone but unable to express it (arrested anger). For many participants (53.7%), strong desires to escape from current situations and/or to express anger did not diminish immediately after the act.
As with many studies, a select group of participants agreed to take part and we did not keep records of how many refused. There are no other validated measures of arrested escape and arrested anger and so for this study, our short item-focused measures rely on face validity.
Arrested defenses of fight and flight, and self-criticism are common in those who have self-harmed and may continue after acts of self-harm. Many participants revealed that talking about their experiences of escape motivation and blocked anger (using our measures) was helpful to them.
Feelings of entrapment and arrested anger are common in people who self-harmClinicians could benefit from increased awareness and measures of arrested flight and arrested angerDiscussing these concepts and experiences appears to be useful to people who have self-harmedFurther research is needed on how best to help people with such experiences.
Since a large proportion of medical decisions are based on laboratory results, clinical laboratories should meet the increasing demand of clinicians and their patients. Huge central laboratories may process over 10 million tests annually; they act as production factories, measuring emergency and routine tests with sufficient speed and accuracy. At the same time, they also serve as specialized diagnostic centers where well-trained experts analyze and interpret special test results. It is essential to improve and constantly monitor this complex laboratory service, by several methods. Sample transport by pneumatic tube system, use of an advanced laboratory information system and point-of-care testing may result in decreased total turnaround time. The optimization of test ordering may result in a faster and more cost-effective laboratory service. Autovalidation can save time for laboratory specialists, when the analysis of more complex results requires their attention. Small teams of experts responsible for special diagnostic work, and their interpretative reporting according to predetermined principles, may help to minimize subjectivity of these special reports. Although laboratory investigations have become so diversely developed in the past decades, it is essential that the laboratory can provide accurate results relatively quickly, and that laboratory specialists can support the diagnosis and monitoring of patients by adequate interpretation of esoteric laboratory methods.
Despite extensive knowledge about effective tobacco control interventions, the prevalence of tobacco use in many middle- and low-income countries continues to rise. In these countries, public appreciation of levels of protection provided by laws and regulations on tobacco use and exposure to tobacco smoke is limited. After ratification of the Framework Convention on Tobacco Control, Kenya enacted the Tobacco Control Act, 2007, banning smoking in public places except in designated smoking areas.
To assess adherence to the Tobacco Control Act, 2007 by determining the presence of a workplace policy on tobacco use in bars and restaurants.
A survey of 176 liquor licensed bars and restaurants in Nairobi County was carried out. Their managers were asked about the presence of a workplace policy governing smoking of tobacco, and observations made on provisions that determine adherence to the Tobacco Control Act, 2007.
Smoking took place in almost all bars and restaurants (150 (85%)). Half the establishments (86 (49%)) had a workplace policy governing tobacco use among employees, although a difference between bars (11 (23%)) and restaurants (75 (58%)) was recorded (p<0.001). Establishments at which managers had lower levels of education were less likely to have a workplace policy (p<0.001) and less likely to have 'no smoking' signs and designated smoking areas (p<0.005).
Kenya's implementation of the Tobacco Control Act, 2007 does not provide sufficient protection of patrons and workers in bars and restaurants. It is important to sensitise hospitality workers to the dangers of tobacco smoke. Bar and restaurants managers should have a minimum post-secondary education level. The Tobacco Control Act, 2007 requires strengthening to ensure that bars and restaurants have a smoke-free environment.
Reactive oxygen species (ROS) are potentially toxic, but they are also signaling molecules that modulate aging. Recent observations that ROS can promote longevity have to be reconciled with the numerous claims about the benefits of antioxidants on lifespan. Here, three antioxidants [N-acetylcysteine (NAC), vitamin C, and resveratrol (RSV)] were tested on Caenorhabditis elegans mutants that alter drug uptake, mitochondrial function, and ROS metabolism. We observed that like pro-oxidants, antioxidants can both lengthen and shorten lifespan, dependent on concentration, genotypes, and conditions. The effects of antioxidants thus reveal an inverted U-shaped dose-response relationship between ROS levels and lifespan. In addition, we observed that RSV can act additively to both NAC and paraquat, to dramatically increase lifespan. This suggests that the effect of compounds that modulate ROS levels can be additive when their loci of action or mechanisms of action are sufficiently distinct.
Both endothelin-1 and oxidative stress have important roles in the development of cardiovascular diseases such as hypertension and atherosclerosis. Limited information is available on the interaction between oxidative stress, the glutathione system and endothelin-1 in humans. We aimed to investigate the association of endothelin-1 with markers of oxidative stress and the antioxidant capacity in a biethnic
 South African cohort. This cross-sectional study included 195 black and 198 white South Africans. Serum endothelin-1 levels and oxidative stress-related markers such as reactive oxygen species (measured as serum peroxides), glutathione peroxidase, glutathione reductase, superoxide dismutase and catalase were measured. In single, partial and multiple regression analyses endothelin-1 correlated positively with glutathione reductase activity (adj. R(2)=0.10; β=0.232; P=0.020) and negatively with antihypertension medication (P=0.02) and tended to correlate with glutathione reductase-to-glutathione peroxidase ratio (adj. R(2)=0.10; β=0.19; P=0.057) in black men. In white men, endothelin-1 correlated positively with ROS (adj. R(2)=0.09; β=0.26; P=0.01) and negatively with glutathione peroxidase activity (adj. R(2)=0.05; β=-0.23; P=0.02). In black women, endothelin-1 correlated negatively with total glutathione (adj. R(2)=0.22; β=-0.214; P=0.026). Endothelin-1 may contribute to glutathione reductase upregulation through increased reactive oxygen species production mediated via endothelin-1 in black men. In white men, we observed a negative association between glutathione peroxidase and endothelin-1, describing the expected physiological relationship between endothelin-1 and reactive oxygen species. Higher total glutathione levels may act as a counter-regulatory mechanism to protect against oxidative vascular damage attributed by endothelin-1 in black women.Hypertension Research advance online publication, 29 September 2016; doi:10.1038/hr.2016.128.
The Swedish welfare debate increasingly focuses on market liberal notions and its healthcare perspective aims for more patient-centered care. This article examines the new Swedish Patient Act describing and analyzing how the patient is constructed in government documents. This study takes a Foucauldian discourse analysis approach following Willig's analysis guide. The act contains an entitlement discourse for patients and a requirement discourse for healthcare personnel. These two discourses are governed by a values-based healthcare discourse. Neo-liberal ideology, in the form of New Public Management discourse, focusing on the value of efficiency and competition, is given a hegemonic position as laws and regulations are used to strengthen it. The new Swedish Patient Act seems to further strengthen this development. The Act underlines the increased entitlement for patients, but it is not legally binding as it offers patients only indirect entitlement to influence and control their care. To safeguard the patient's entitlement under the Patient Act, healthcare personnel should be made aware of the contents of the Act, so that they can contribute to the creation of systems and working methods that facilitate respect of the Act's provisions in daily healthcare work.
Dirofilaria immitis, a filarial parasite, causes cardiopulmonary dirofilariasis in dogs, cats and wild canids. The macrocyclic lactone (ML) class of drugs has been used to prevent heartworm infection. There is confirmed ML resistance in D. immitis and thus there is an urgent need to find new anthelmintics that could prevent and/or control the disease. Targeting ion channels of D. immitis for drug design has obvious advantages. These channels, present in the nematode nervous system, control movement, feeding, mating and respond to environmental cues which are necessary for survival of the parasite. Any new drug that targets these ion channels is likely to have a motility phenotype and should act to clear the worms from the host. Many of the successful anthelmintics in the past have targeted these ion channels and receptors. Knowledge about genetic variability of the ion channel and receptor genes should be useful information for drug design as receptor polymorphism may affect responses to a drug. Such information may also be useful for anticipation of possible resistance development. A total of 224 ion channel genes/subunits have been identified in the genome of D. immitis. Whole genome sequencing data of parasites from eight different geographical locations, four from ML-susceptible populations and the other four from ML-loss of efficacy (LOE) populations, were used for polymorphism analysis. We identified 1762 single nucleotide polymorphic (SNP) sites (1508 intronic and 126 exonic) in these 224 ion channel genes/subunits with an overall polymorphic rate of 0.18%. Of the SNPs found in the exon regions, 129 of them caused a non-synonymous type of polymorphism. Fourteen of the exonic SNPs caused a change in predicted secondary structure. A few of the SNPs identified may have an effect on gene expression, function of the protein and resistance selection processes.
Horizontal gene transfer (HGT) is a driving force to the evolution of bacteria. The fast emergence of antimicrobial resistance reflects the ability of genetic adaptation of pathogens. Acinetobacter baumannii has emerged in the last few decades as an important opportunistic nosocomial pathogen, in part due to its high capacity of acquiring resistance to diverse antibiotic families, including to the so-called last line drugs such as carbapenems. The rampant selective pressure and genetic exchange of resistance genes hinder the effective treatment of resistant infections. A. baumannii uses all the resistance mechanisms to survive against carbapenems but production of carbapenemases are the major mechanism, which may act in synergy with others. A. baumannii appears to use all the mechanisms of gene dissemination. Beyond conjugation, the mostly reported recent studies point to natural transformation, transduction and outer membrane vesicles-mediated transfer as mechanisms that may play a role in carbapenemase determinants spread. Understanding the genetic mobilization of carbapenemase genes is paramount in preventing their dissemination. Here we review the carbapenemases found in A. baumannii and present an overview of the current knowledge of contributions of the various HGT mechanisms to the molecular epidemiology of carbapenem resistance in this relevant opportunistic pathogen.
Biofilm matrices of two Klebsiella pneumoniae clinical isolates, KpTs101 and KpTs113, were investigated for their polysaccharide composition and protective effects against antimicrobial peptides. Both strains were good biofilm producers, with KpTs113 forming flocs with very low adhesive properties to supports. Matrix exopolysaccharides were isolated and their monosaccharide composition and glycosidic linkage types were defined. KpTs101 polysaccharide is neutral and composed only of galactose, in both pyranose and furanose ring configurations. Conversely, KpTs113 polysaccharide is anionic due to glucuronic acid units, and also contains glucose and mannose residues. The susceptibility of the two strains to two bovine cathelicidin antimicrobial peptides, BMAP-27 and Bac7(1-35), was assessed using both planktonic cultures and biofilms. Biofilm matrices exerted a relevant protection against both antimicrobials, which act with quite different mechanisms. Similar protection was also detected when antimicrobial peptides were tested against planktonic bacteria in the presence of the polysaccharides extracted from KpTs101 and KpTs113 biofilms, suggesting sequestering adduct formation with antimicrobials. Circular dichroism experiments on BMAP-27 in the presence of increasing amounts of either polysaccharide confirmed their ability to interact with the peptide and induce an α-helical conformation.
Most cells in the body have a constant supply of nutrients, which are required to sustain cellular metabolism and functions. In contrast, cells of the immune system can encounter conditions with a limited nutrient supply during the course of an immune response. Cells of the immune system frequently operate in complex nutrient restricted microenvironments such as tumour or inflammatory sites. The concentrations of key nutrients such as glucose and certain amino acids, can be low at these sites, and this can have an impact upon immune cell function. Nutrient sufficiency is important to supply the metabolic and biosynthetic pathways of immune cells. In addition nutrients can also act as important cues that influence immunological signalling pathways to affect the function of immune cells. This review will describe the various nutrient sensing signalling pathways and discuss the evidence that nutrients are critical signals that shape immune responses.
Emerging evidence shows that microRNAs (miRNAs) act as critical regulators in the progression and chemoresistance of multiple tumors, including osteosarcoma (OS). In this study, we found that the level of miR-24 was increased in OS patients' serum, tumor tissues and OS cell lines. Furthermore, we found that knockdown of miR-24 by its specific inhibitors significantly increased the therapeutic effect of doxorubicin (DOX) on OS cell lines (MG-63 and HOS). Moreover, miR-24 inhibitors resensitized the doxorubicin-resistant MG-63 cells (MG-63/R) and HOS cells (HOS/R) to DOX. As the gene of Bcl-2 interacting mediator of cell death (BIM) was proved to be a target of miR-24 in MG-63/R cells, we further observed that the miR-24 inhibitors promoted the DOX-induced apoptosis via mitochondrial pathway. In addition, results of immunoprecipitation showed the release of second mitochondria derived activator of caspase/ direct IAP binding protein with low pI (Smac/DIABLO) abolished the biological activity of X-linked inhibitor of apoptosis protein (XIAP) by binding with it, which subsequently induced the activation of caspase 9, 7 and 3. In summary, those results strongly suggest that the miR-24-BIM-Smac/DIABLO axis might be a novel target for the treatment of OS.
Estrogens have a modulatory effect on several immune responses, many of which are correlated to autoimmune diseases.
 Estrogens act through binding to their receptors, and an overexpression of these receptors has been identified in patients with different autoimmune diseases. Here we analyzed the association of a putative functional genetic variant in the main estrogen receptor (ERα) gene (ESR1), and the susceptibility to clinical findings and severity of SLE.
A total of 426 individuals (266 healthy controls and 160 SLE patients) were genotyped for the polymorphism rs2234693 in the ESR1 gene. Allele and genotype frequencies were calculated and analyzed between cases and controls using Unphased software.
The SNP rs2234693 was not associated with SLE per se but the minor allele rs2234693-C was correlated with the presence of nephritis and discoid skin rash. On the other hand, the rs2234693-CC genotype was correlated with the absence of arthritis as well as anti-ANA and anti-RNP autoantibodies. The comprehensive clinical analysis of these patients revealed a more severe status of the disease, characterized by a younger age of onset and higher number of organs involved when compared to European populations.
Minor allele rs2234693-C was associated with renal and cutaneous involvement, as well as the absence of arthritis, anti-ANA and anti-RNP autoantibodies.
FGF21 improves the metabolic profile of obese animals through its actions on adipocytes. To elucidate the signaling network responsible for mediating these effects, we quantified dynamic changes in the adipocyte phosphoproteome following acute exposure to FGF21. FGF21 regulated a network of 821 phosphosites on 542 proteins. A major FGF21-regulated signaling node was mTORC1/S6K. In contrast to insulin, FGF21 activated mTORC1 via MAPK rather than through the canonical PI3K/AKT pathway. Activation of mTORC1/S6K by FGF21 was surprising because this is thought to contribute to deleterious metabolic effects such as obesity and insulin resistance. Rather, mTORC1 mediated many of the beneficial actions of FGF21 in vitro, including UCP1 and FGF21 induction, increased adiponectin secretion, and enhanced glucose uptake without any adverse effects on insulin action. This study provides a global view of FGF21 signaling and suggests that mTORC1 may act to facilitate FGF21-mediated health benefits in vivo.
Purpose The purpose of this paper is to test and measure the outcome of a community hospital in implementing the Affordable Care Act (ACA) through a co-management arrangement. RQ1: do the benefits of a co-management arrangement outweigh the costs? RQ2: does physician alignment aid in the effective implementation of the ACA directives set for hospitals? Design/methodology/approach A case study of a 350-bed non-profit community hospital co-management company. The quantitative data are eight quarters of quality metrics prior and eight quarters post establishment of the co-management company. The quality metrics are all based on standardized national requirements from the Joint Commission and Centers for Medicare and Medicaid Services guidelines. These measures directly impact the quality initiatives under the ACA that are applicable to all healthcare facilities. Qualitative data include survey results from hospital employees of the perceived effectiveness of the co-management company. A paired samples difference of means t-test was conducted to compare the timeframe before co-management and post co-management. Findings The findings indicate that the benefits of a co-management arrangement do outweigh the costs for both the physicians and the hospital ( RQ1). The physicians benefit through actual dollar payout, but also with improved communication and greater input in running the service line. The hospital benefits from reduced cost - or reduced penalties under the ACA - as well as better communication and greater physician involvement in administration of the service line. RQ2: does physician alignment aid in the effective implementation of the ACA directives set for hospitals? The hospital improved in every quality metric under the co-management company. A paired sample difference of means t-test showed a statistically significant improvement in five of the six quality metrics in the study. Originality/value Previous research indicates the potential effectiveness of co-management companies in improving healthcare delivery and hospital-physician relations (Sowers et al., 2013). The current research takes this a step further to show that the data do in fact support these concepts. The hospital and the physicians carrying out the day-to-day actions have shared goals, better communication, and improved quality metrics under the co-management company. As the number of co-management companies increases across the USA, more research can be directed at determining their overall impact on quality care.
Curcuminoids of the spice turmeric and their enhanced derivatives have much potential as cancer treatments. They act on a wide variety of biological pathways, including those regulating cell division and circadian rhythms. It is known that circadian clocks can modify cancer therapy effectiveness, according to studies aimed at optimizing treatments based on the circadian cycle. It is therefore important to determine whether treatments with curcumin or similar chemotherapeutic agents are regulated by circadian timing. Similarly, it is important to characterize any effects of curcumin on timing abilities of the circadian clocks within cancer cells.
We examined the circadian clock's impact on the timing of cell death and cell division in curcumin-treated C6 rat glioma cells through continuous video microscopy for several days. To evaluate its persistence and distribution in cancer cells, curcumin was localized within cell compartments by imaging its autofluorescence. Finally, HPLC and spectroscopy were used to determine the relative stabilities of the curcumin congeners demethoxycurcumin and bisdemethoxycurcumin that are present in turmeric.
Circadian rhythms in cell death were observed in response to low (5 μM) curcumin, reaching a peak several hours before the peak in rhythmic expression of mPER2 protein, a major circadian clock component. These results revealed a sensitive phase of the circadian cycle that could be effectively targeted in patient therapies based on curcumin or its analogs. Curcumin fluorescence was observed in cell compartments at least 24 h after treatment, and the two congeners displayed greater stability than curcumin in cell culture medium.
We propose a mechanism whereby curcuminoids act in a sustained manner, over several days, despite their tendency to degrade rapidly in blood and other aqueous media. During cancer therapy, curcumin or its analogs should be delivered to tumor cells at the optimal phase for highest efficacy after identifying the circadian phase of the cancer cells. We confirmed the greater stability of the curcumin congeners, suggesting that they may produce sustained toxicity in cancer cells and should be considered for use in patient care.
Scholars examining homosexual television characters have typically come to one of two conclusions: either exposure to homosexual characters can lead to increased acceptance, or homosexual characters serve to reaffirm negative stereotypes. We seek to bridge these two bodies of research by introducing the concept of stereotyped identification-the idea that cognitively and emotionally identifying with fictional characters can increase acceptance of minorities, while reinforcing implicit stereotypes about how they look, act, and talk. Results from our national survey (N = 972) offer support for this hypothesis.
Viruses are one of the main drivers of the decline of domesticated and wild bees but the mechanisms of antiviral immunity in pollinators are poorly understood. Recent work has suggested that next to the small interfering RNA (siRNA) pathway other immune-related pathways play a role in the defense of the bee hosts against viral infection. In addition, Vago plays a role in the cross-talk between the innate immune pathways in Culex mosquito cells. Here we describe the Vago orthologue in bumblebees of Bombus terrestris, and investigated its role upon the infection of two different bee viruses, the virulent Israeli acute paralysis virus (IAPV) and the avirulent slow bee paralysis virus (SBPV). Our results showed that BtVago was downregulated upon the infection of IAPV that killed all bumblebees, but not with SBPV where the workers survived the virus infection. Thus, for the first time, Vago/Vago-like expression appears to be associated with the virulence of virus and may act as a modulator of antiviral immunity.
The purpose of this study is to identify the optimal screening mammography recall rate range on the basis of cancer detection rates among breast imaging specialists at an academic institution.
Medical outcome audit data collected in accordance with the Mammography Quality Standards Act from September 1, 2007, through August 31, 2012, were reviewed. Cancer detection rates were calculated from 984 screen-detected cancers identified in 188,959 total digital screening mammograms. The percentages of minimally invasive and early-stage cancers were also calculated. The 75 annual recall rates were analyzed two ways. First, they were separated into recall groups to assess cancer detection rate variation by the recall categories using rate ratios: less than 10%, 10% to less than 12%, 12% to less than 14%, and 14% or higher. Next, a linear regression with bootstrap bias correction was performed to assess changes in cancer detection rate with each unit increase in the recall rate up to 20%, with the recall category of less than 7% taken as reference. Annual cancer detection rates for a physician were grouped according to annual percentage recall rate.
Statistically significantly higher cancer detection rates were seen for recall rates
 12% or higher, with rate ratios of 1.75 (95% CI, 1.40-2.19) and 2.06 (95% CI, 1.72-2.46) for the recall groups 12% to less than 14% and 14% and higher, respectively, compared with the less than 10% group. When taking the category 12% to less than 14% as the reference, there were no statistically significant differences between recall groups 12% to less than 14% and 14% or higher in cancer detection rate. A statistically significant increase in the cancer detection rate with each unit increase in the recall rate was seen only for recall rates 12% or higher.
These observations suggest that the sweet spot for optimal cancer detection is in the recall rate range 12% to less than 14% with the incremental benefit above this to be relatively small. A recall rate less than 10% may be too low.
We present the fabrication and characterization of an opto-electronic fiber device which can allow for both electromechanical functionality and optical waveguiding capability. The air holes of a photonic crystal fiber are selectively sealed and then pumped with molten metal under pressure. The metal filled holes act as electrodes to which individual carbon nanotubes (CNT) are attached precisely by a laser-welding technique or a focused ion beam assisted pick-and-bond technique. The optical modal profile and the group velocity dispersion of the fabricated device are studied both numerically and experimentally. We also present preliminary experimental proof showing the feasibility of electric actuation of a pair of nanotubes by applying up to 40 V potential difference between the filled electrodes. Furthermore, numerical simulations are carried out which agree with the experimentally observed displacement of the CNT upon electric actuation. The unique aspect of our device is that it provides optical waveguiding and electromechanical nano-probing capability in a single package. Such combined functionality can potentially enable simultaneous electrical and optical manipulation and interrogation at the nanoscale.
In this work, highly luminescent carbon dots (CDs) were synthesized by the hydrothermal method at 170 °C for 12 h using pasteurized milk as a carbon source. The prepared CDs exhibited bright blue fluorescence under UV light illumination at 365 nm. The CDs show fluorescence life time of ~4.89 ns at excitation wavelength of 370 nm. The effect of different solvents on the fluorescence property of CDs was also investigated. The lisinopril (Lis)-loaded CDs were fabricated by self-assembly of lisinopril on the surfaces of CDs, which were characterized by UV-visible and FT-IR spectroscopic techniques. The controlled release of lisinopril from the Lis-CDs was realized at pH values of 5.2, 6.2 and 7.4, respectively. The results of the cytotoxicity and confocal laser scanning microscopic images indicate that the Lis-CDs were successfully uptaken by HeLa cells without apparent cytotoxicity. The synthesized CDs show great potential as drug vehicles with good biocompatibility, sustained release of lisinopril from CDs, indicating that the CDs can act as a promising drug delivery system for therapeutic delivery and/or bioimaging applications.
The method to generate bioengineered skin constructs was pioneered several decades ago, and nowadays these constructs are used regularly for the treatment of severe burns and non-healing wounds. Commonly, these constructs are comprised of skin fibroblasts within a collagen scaffold, forming the skin dermis, and stratified keratinocytes overlying this, forming the skin epidermis. In the past decade there has been a surge of interest in bioengineered skins, with researchers searching for alternative cell sources, or scaffolds, from which constructs can be established, and for more biomimetic equivalents with skin appendages.
In this manuscript we wanted to evaluate whether human hair follicle dermal cells can act as an alternative cell source for engineering the dermal component of engineered skin constructs.
We established in vitro skin constructs by incorporating into the collagenous dermal compartment either primary interfollicular dermal fibroblasts, hair follicle dermal papilla, or hair follicle dermal sheath cells. In vivo skins were established by mixing dermal cells and keratinocytes in chambers on top of immunologically compromised mice.
All fibroblast subtypes were capable of supporting growth of overlying epithelial cells, both in vitro and in vivo. However, we found hair follicle dermal sheath cells to be superior to fibroblasts in their capacity to influence the establishment of a basal lamina.
Human hair follicle dermal cells can be readily interchanged with interfollicular fibroblasts, and used as an alternative cell source for establishing the dermal component of engineered skin both in vitro and in vivo. This article is protected by copyright. All rights reserved.
Premature ejaculation (PE) is a common ejaculatory complaint. The estimated rates among Turkish men reached 20%, although the severest type of PE (lifelong PE) usually does not exceed 2.3%. This could be seen in line with two survey studies involving five nations. They revealed that 2.5% of men had an intravaginal ejaculation latency time of <1 min and 6% of <2 min. Rapid ejaculation may be treated pharmacologically with a variety of different medications that act either centrally or locally to delay ejaculation and subsequent orgasm. Antidepressants, particularly members of the selective serotonin reuptake inhibitor class, retard ejaculation significantly. Recently, it was postulated that men with lifelong PE might result from a combination of polymorphisms of the serotonergic transporter and receptors, and other neurotransmitters and/or receptors. Our findings augment the significant effect of paroxetine in delaying ejaculation in the responders (P<0.001). Meanwhile, the findings do not suggest a positive association between such response and serotonin transporter gene promoter polymorphism.International Journal of Impotence Research advance online publication, 29 September 2016; doi:10.1038/ijir.2016.36.
Estrogens and leptins act in the hypothalamus to maintain reproduction and energy homeostasis. Neurogenesis in the adult mammalian hypothalamus has been implicated in the regulation of energy homeostasis. Recently, high-fat diet (HFD) and estradiol (E2) have been shown to alter cell proliferation and the number of newborn leptin-responsive neurons in the hypothalamus of adult female mice. The current study tested the hypothesis that new cells expressing estrogen receptor α (ERα) are generated in the arcuate nucleus (ARC) and the ventromedial nucleus of the hypothalamus (VMH) of the adult female mouse, hypothalamic regions that are critical in energy homeostasis. Adult mice were ovariectomized and implanted with capsules containing E2 or oil. Within each hormone group, mice were fed an HFD or standard chow for 6 weeks and treated with BrdU to label new cells. Newborn cells that respond to estrogens were identified in the ARC and VMH, of which a subpopulation was leptin sensitive, indicating that the subpopulation consists of neurons. Moreover, there was an interaction between diet and hormone with an effect on the number of these newborn ERα-expressing neurons that respond to leptin. Regardless of hormone treatment, HFD increased the number of ERα-expressing cells in the ARC and VMH. E2 decreased hypothalamic fibroblast growth factor 10 (Fgf10) gene expression in HFD mice, suggesting a role for Fgf10 in E2 effects on neurogenesis. These findings of newly created estrogen-responsive neurons in the adult brain provide a novel mechanism by which estrogens can act in the hypothalamus to regulate energy homeostasis in females.
Until the 1950s, Ascaris was regarded as an essential part of life which controls every aspect of human physiology among Koreans. Therefore, Ascaris should not be removed from human body. Efforts from medical professionals and the Korean government officials who wished to push forward the parasite control program, had to constantly contest with this perception of Ascaris among ordinary Koreans. In 1966, the 'Parasitic Disease Prevention Act' was promulgated and 'the Korean Association for Parasite Eradication (KAPE)' established in Korea. From the 1970s, Korea mobilized 15 million people each year to achieve the eradication goal. Such mass mobilization could not be possible without public awareness on necessity of parasite eradication. Until the early 1960s, however, Korean people were not sympathetic to the needs of eradication of parasites, especially that of Ascaris. Then, what changed the social perception towards Ascaris during the 1960s? What contributing factors allowed the mass mobilization and public involvement for that campaign? Employing newspaper articles and periodicals, this paper analyzes how social perception on Ascariasis changed during the 1960s, when the 'Parasitic Disease Prevention Act' was established. During the 1960s, Ascariasis became a shameful disease for Koreans. A series of events made Ascariasis more visible and shameful to Koreans. First event happened with Korean miners who were dispatched to Germany in 1963. When the miners turned out to have been infected with intestinal parasites, they were prohibited from work at the mines by the authorities in Germany and quarantined for several weeks. This humiliating experience of Korean expatriate people having bodies swarmed with parasites became a national shame to Koreans. The parasite infected bodies of Korean workers were revealed to the World through German newspapers. Second event happened when a child died of intestinal obstruction due to Ascariasis. The doctor retrieved 1,063 Ascaris from the bowel of the 9 year-old girl, and the photo of the 1,063 worms was published in several newspapers. It was a shocking visualization of Ascariasis
 in Korean society. Through these visualizations of Ascariasis, the Korean society began to perceive Ascariasis as a shame of the nation as well as that of an individual.
Emotional Intelligence (EI) has been associated with several indicators of psychosocial adjustment, including aggressive behavior, but the relevant research has been mostly cross-sectional, focused on adults, and limited to trait EI measures (García-Sancho, Salguero & Fernández-Berrocal, 2014; Mayer, Roberts & Barsade, ). The present work explored the relationship between Ability Emotional Intelligence (AEI) and aggression in both adults and adolescents using cross-sectional and longitudinal designs. We conducted two studies. Study 1 aimed to provide preliminary evidence about the relationship between AEI and aggression in adults. As literature has shown personality traits act as a strong predictor of aggression, study 1 also examined the potential incremental validity of AEI beyond personality traits in 474 undergraduate students (M = 22.76, SD = 5.13). The results indicated AEI explains a significant amount of unique variance for physical aggression, but not for verbal aggression after controlling personality traits. Study 2 aimed a longitudinal analysis of the relationship between EI and aggression in 151 adolescents (M = 14.74, SD = 0.84). AEI predicted physical aggression over time, but it did not predict verbal aggression. Results from both studies suggest a negative and significant relationship between AEI and physical aggression, however contrary our expectations, it did not for verbal aggression. These results highlight the important explanatory role of emotional abilities in physical aggressive conducts and the implications of these findings are discussed.
Nutrition can generate oxidative stress and trigger a cascade of molecular events that can disrupt oxidative and hormonal balance. Nutrient ingestion promotes a major inflammatory and oxidative response at the cellular level in the postprandial state, altering the metabolic state of tissues. A domino of unfavorable metabolic changes is orchestrated in the main metabolic organs, including adipose tissue, skeletal muscle, liver and pancreas, where subclinical inflammation, endothelial dysfunction, mitochondrial deregulation and impaired insulin response and secretion take place. Simultaneously, in reproductive tissues, nutrition-induced oxidative stress can potentially violate delicate oxidative balance that is mandatory to secure normal reproductive function. Taken all the above into account, nutrition and its accompanying postprandial oxidative stress, in the unique context of female hormonal background, can potentially compromise normal metabolic and reproductive functions in women and may act as an active mediator of various metabolic and reproductive disorders.
The cytokine interleukin-22 (IL-22), which is a member of the IL-10 family, is produced exclusively by immune cells and activates signal transducer and activator of transcription 3 (STAT3) in nonimmune cells, such as hepatocytes, keratinocytes, and colonic epithelial cells, to drive various processes central to tissue homeostasis and immunosurveillance. Dysregulation of IL-22 signaling causes inflammatory diseases. IL-22 binding protein (IL-22BP; encoded by IL22RA2) is a soluble IL-22 receptor, which antagonizes IL-22 activity and has genetic associations with autoimmune diseases. Humans have three IL-22BP isoforms, IL-22BPi1 to IL-22BPi3, which are generated by alternative splicing; mice only have an IL-22BPi2 homolog. We showed that, although IL-22BPi3 had less inhibitory activity than IL-22BPi2, IL-22BPi3 was more abundant in various human tissues under homeostatic conditions. IL-22BPi2 was more effective than IL-22BPi3 at blocking the contribution of IL-22 to cooperative gene induction with the inflammatory cytokine IL-17, which is often present with IL-22 in autoimmune settings. In addition, we found that IL-22BPi1 was not secreted and therefore failed to antagonize IL-22 signaling. Furthermore, IL-22BPi2 was the only isoform that was increased in abundance when myeloid cells were activated by Toll-like receptor 2 signaling or retinoic acid, a maturation factor for myeloid cells. These data suggest that the human IL-22BP isoforms have distinct spatial and temporal roles and coordinately fine-tune IL-22-dependent STAT3 responses in tissues as a type of rheostat.
Surface acting (faking emotions) is one of the stressors experienced by contact employees during service interactions with customers, and it has implications for workers' exhaustion. One challenge of research and practice is to identify moderators that help to better understand the positive relationships between surface acting and exhaustion. The present study proposes the two dimensions of eudaimonia beliefs about well-being (self-development and contribution-to-others beliefs) as moderators between surface acting and exhaustion. We performed regression analyses with 817 contact employees working in 118 health-care organizations providing services to people with intellectual disability. Results confirmed the hypotheses, showing that contribution-to-others strengthens the link from surface acting to exhaustion, whereas self-development weakens this relationship. Therefore, self-development beliefs act as a protector for workers when they have to deal with situations that require surface acting.
Gold nanoparticles with a core size of 2nm covalently coated with glycans to maintain solubility, targeting molecules for brain endothelium, and cargo molecules hold great potential for delivery of therapies into the CNS. They have low toxicity, pass through brain endothelium in vitro and in vivo, and move rapidly through the brain parenchyma. Within minutes of infusion the nanoparticles can be detected in neurons and glia. These nanoparticles are relatively easy to synthesize in association with their surface ligands. They can be detected by electron microscopy, ICP-mass spectrometry, and spectroscopy. However, modification of the basic gold nanoparticle is required for in vivo imaging by MR or radioactive methods. Depending on their surface coat, the nanoparticles cross the brain endothelium by the plasma membrane/cytosolic route (passive transport) or by vesicular transcytosis (active transport). A primary aim of current research is to improve the biodistribution of the nanoparticles for CNS drug delivery. Smaller gold nanoparticles are removed rapidly via the kidney, while larger nanoparticles are taken up by mononuclear phagocytes in various tissues. Receptors selectively located on brain endothelium can act as targets for the nanoparticles, to increase their delivery to the brain.
Breast cancer is the most common cancer in women worldwide. Despite the information provided by anatomopathological assessment and molecular markers (such as receptor expression ER, PR, HER2), breast cancer therapies and prognostics depend on the metabolic properties of tumor cells. However, metabolomics have not provided a robust and congruent biomarker yet, likely because individual metabolite contents are insufficient to encapsulate all of the alterations in metabolic fluxes. Here, we took advantage of natural (13)C and (15)N isotope abundance to show there are isotopic differences between healthy and cancer biopsy tissues or between healthy and malignant cultured cell lines. Isotope mass balance further suggests that these differences are mostly related to lipid metabolism, anaplerosis and urea cycle, three pathways known to be impacted in malignant cells. Our results demonstrate that the isotope signature is a good descriptor of metabolism since it integrates modifications in C partitioning and N excretion altogether. Our present study is thus a starting point to possible clinical applications such as patient screening and biopsy characterization in every cancer that is associated with metabolic changes.
Glioblastoma is the deadliest type of brain cancer. Treatment could target the Matrix metalloproteinase-2 (MMP-2), which is known to be involved in the invasion process of glioblastoma cells. But current available inhibitors are not selective to MMP-2 due to their interaction with the catalytic binding site, which is highly conserved in all MMPs structures. Interestingly, members of the chloride channel blocker scorpion toxins, such as chlorotoxin (ClTx) and AaCTx, inhibit glioblastoma cell invasion and show a promising therapeutic potential. Indeed, it has been shown that CITx inhibits selectively MMP-2 and was also able to cross the blood brain and tissue barriers. Although ClTx and AaCTx show high sequence similarity, AaCTx is ten times less active than ClTx. By using molecular modeling, molecular dynamics and MM-PB(GB)SA free energy estimation, we present the first computational study reporting the interaction mode of ClTx/AaCTx with MMP-2. We found that the two peptides probably act on an exosite of MMP-2 comprising mainly residues from the collagen binding domain, a feature that could be exploited to enhance the selectivity toward MMP-2. van der Waals and hydrophobic forces are the primary mediators of this interaction. The N- and C-termini of the two peptides harbor the key residues of the interaction spread across a conserved amino acid patch. In particular, F6 contributes mostly to the binding free energy in ClTx. We also suggest that the lack of the C-terminal arginine and the residues P10 and R24, might be responsible for altering the activity of AaCTx toward glioblastoma cells compared to ClTx.
To understand the biochemistry of methylmercury (MeHg) that leads to the formation of mercury-selenium (Hg-Se) clusters is a long outstanding challenge that promises to deepen our knowledge of MeHg detoxification and the role Se plays in this process. Here, we show that mercury selenide
 (HgSe) nanoparticles in the liver and brain of long-finned pilot whales are attached to Se-rich structures and possibly act as a nucleation point for the formation of large Se-Hg clusters, which can grow with age to over 5 μm in size. The detoxification mechanism is fully developed from the early age of the animals, with particulate Hg found already in juvenile tissues. As a consequence of MeHg detoxification, Se-methionine, the selenium pool in the system is depleted in the efforts to maintain essential levels of Se-cysteine. This study provides evidence of so far unreported depletion of the bioavailable Se pool, a plausible driving mechanism of demonstrated neurotoxic effects of MeHg in the organism affected by its high dietary intake.
The recently determined crystal structures of the sequence-specific transcription factor NF-Y have illuminated the structural mechanism underlying transcription at the CCAAT box. NF-Y is a trimeric protein complex composed by the NF-YA, NF-YB, and NF-YC subunits. NF-YB and NF-YC contain a histone-like domain and assemble on a head-to-tail fashion to form a dimer, which provides the structural scaffold for the DNA sugar-phosphate backbone binding (mimicking the nucleosome H2A/H2B-DNA assembly) and for the interaction with NF-YA. The NF-YA subunit hosts two structurally extended α-helices; one is involved in NF-YB/NF-YC binding and the other inserts deeply into the DNA minor groove, providing exquisite sequence-specificity for recognition and binding of the CCAAT box. The analysis of these structural data is expected to serve as a powerful guide for future experiments aimed at understanding the role of post-translational modification at NF-Y regulation sites and to unravel the three-dimensional architecture of higher order complexes formed between NF-Y and other transcription factors that act synergistically for transcription activation. Moreover, these structures represent an excellent starting point to challenge the formation of a stable hybrid nucleosome between NF-Y and core histone proteins, and to rationalize the fine molecular details associated with the wide combinatorial association of plant NF-Y subunits. This article is part of a Special Issue entitled: Nuclear Factor Y in Development and Disease, edited by Prof. Roberto Mantovani.
As humans expand into natural environments, populations of wild organisms may become relegated to marginal habitats at the boundaries of their distributions. In the ocean, mesophotic coral ecosystems (30-150 m) at the depth limit of photosynthetic reefs are hypothesized to act as refuges that are buffered from anthropogenic and natural disturbances, yet the viability and persistence of subpopulations in these peripheral habitats remains poorly understood. To assess the potential for mesophotic reefs to support robust coral reef fish populations, we compared population density and structure, growth, size, and reproductive output of the bicolor damselfish (Stegastes partitus) from shallow (<10 m), deep shelf (20-30 m), and mesophotic reefs (60-70 m) across the Florida Platform. Population densities decreased and size and age distributions shifted toward older and larger individuals in deeper habitats. Otolith-derived ages indicated that S. partitus found on mesophotic reefs reach larger asymptotic sizes and have longer lifespans than fish in shallower habitats. Based on measurements of oocyte area and batch fecundity, mesophotic fish also have higher reproductive investment. These demographic patterns indicate that mesophotic fish populations composed of large, fecund individuals produce high condition larvae and rely on longevity of individuals for population persistence and viability.
Sometimes it is easy to do the right thing. But often, people act morally only after overcoming competing immoral desires. How does learning about someone's inner moral conflict influence children's and adults' moral judgments about that person? Across four studies, we discovered a striking developmental difference: When the outcome is held constant, 3- to 8-year-old children judge someone who does the right thing without experiencing immoral desires to be morally superior to someone who does the right thing through overcoming conflicting desires-but adults have the opposite intuition. This developmental difference also occurs for judgments of immoral actors: Three- to 5-year-olds again prefer the person who is not conflicted, whereas older children and adults judge that someone who struggles with the decision is morally superior. Our findings suggest that children may begin with the view that inner moral conflict is inherently negative, but, with development, come to value the exercise of willpower and self-control.
Products containing psychoactive synthetic cathinones, such as mephedrone and 3,4-methylenedioxypyrovalerone (MDPV) are prevalent in our society. Synthetic cathinones are structurally similar to methamphetamine, and numerous synthetics have biological activity at dopamine, serotonin, and norepinephrine transporters. Importantly, monoamine transporters co-transport sodium ions along with their substrate, and movement of substrates and ions through the transporter can generate measurable ionic currents. Here we review how electrophysiological information has enabled us to determine how synthetic cathinones affect transporter-mediated currents in cells that express these transporters. Specifically, drugs that act as transporter substrates induce inward depolarizing currents when cells are held near their resting membrane potential, whereas drugs that act as transporter blockers induce apparent outward currents by blocking an inherent inward leak current. We have employed the two-electrode voltage-clamp technique in Xenopus laevis oocytes overexpressing monoamine transporters to determine whether synthetic cathinones found in the so-called bath salts products behave as blockers or substrates. We also examined the structure-activity relationships for synthetic cathinone analogs related to the widely abused compound MDPV, a common constituent in "bath salts" possessing potent actions at the dopamine transporter.
Several fibroblast growth factor (FGF) isoforms act to stimulate epithelial-mesenchymal transition (EMT) during cancer progression. FGF4 and FGF7 are two ligands of FGF receptor 2 (FGFR2). Using two lung adenocarcinoma (ADC) cell lines, A549 and H1299, we showed that FGF4, but not FGF7, altered cell morphology, promoted EMT-associated protein expression, and enhanced cell proliferation, migration/invasion and colony initiation. In addition, FGF4 increased store-operated calcium entry (SOCE) and expression of the calcium signal-associated protein Orai1. The SOCE inhibitor 2,5-di-tert-butylhydroquinone (BHQ) or Orai1 knockdown reversed all of the EMT-promoting effects of FGF4. BHQ also inhibited FGF4-induced EMT in a mouse xenograft model. Finally, 60 human lung ADC samples and 21 sets of matched specimens (primary and metastatic foci in lymph nodes from one patient) were used to confirm the clinicopathologic significance of FGF4 and its correlation with E-cadherin, Vimentin and Orai1 expression. Our study thus shows that FGF4 induces EMT by elevating SOCE in lung ADC.
We have analyzed the binding of the liver-specific microRNA-122 (miR-122) to three conserved target sites of hepatitis C virus (HCV) RNA, two in the non-structural protein 5B (NS5B) coding region and one in the 3' untranslated region (3'UTR). miR-122 binding efficiency strongly depends on target site accessibility under conditions when the range of flanking sequences available for the formation of local RNA secondary structures changes. Our results indicate that the particular sequence feature that contributes most to the correlation between target site accessibility and binding strength varies between different target sites. This suggests that the dynamics of miRNA/Ago2 binding not only depends on the target site itself but also on flanking sequence context to a considerable extent, in particular in a small viral genome in which strong selection constraints act on coding sequence and overlapping cis-signals and model the accessibility of cis-signals. In full-length genomes, single and combination mutations in the miR-122 target sites reveal that site 5B.2 is positively involved in regulating overall genome replication efficiency, whereas mutation of site 5B.3 showed a weaker effect. Mutation of the 3'UTR site and double or triple mutants showed no significant overall effect on genome replication, whereas in a translation reporter RNA, the 3'UTR target site inhibits translation directed by the HCV 5'UTR. Thus, the miR-122 target sites in the 3'-region of the HCV genome are involved in a complex interplay in regulating different steps of the HCV replication cycle.
Consumers often do not understand nutrition labels or do not perceive their usefulness. In addition, price can be a barrier to healthy food choices, especially for socio-economically disadvantaged individuals.
A 6-month intervention combined shelf labeling and marketing strategies (signage, prime placement, taste testing) to draw attention to inexpensive foods with good nutritional quality in two stores located in a disadvantaged neighborhood in Marseille (France). The inexpensive foods with good nutritional quality were identified based on their nutrient profile and their price. Their contribution to customers' spending on food was assessed in the two intervention stores and in two control stores during the intervention, as well as in the year preceding the intervention (n = 6625). Exit survey (n = 259) and in-depth survey (n = 116) were used to assess customers' awareness of and perceived usefulness of the program, knowledge of nutrition, understanding of the labeling system, as well as placement-, taste- and preparation-related
 attractiveness of promoted products. Matched purchasing data were used to assess the contribution of promoted products to total food spending for each customer who participated in the in-depth survey.
The contribution of inexpensive foods with good nutritional quality to customers' total food spending increased between 2013 and 2014 for both the control stores and the intervention stores. This increase was significantly higher in the intervention stores than in the control stores for fruits and vegetables (p = 0.001) and for starches (p = 0.011). The exit survey revealed that 31 % of customers had seen the intervention materials; this percentage increased significantly at the end of the intervention (p < 0.001). The in-depth survey showed that customers who had seen the intervention materials scored significantly higher on quizzes assessing nutrition knowledge (p < 0.001) and understanding of the labeling system (p = 0.024).
A social marketing intervention aimed at increasing the visibility and attractiveness of inexpensive foods with good nutritional quality may improve food purchasing behaviors in disadvantaged neighborhoods.
Innate lymphoid cells (ILCs) are increasingly acknowledged as important mediators of immune homeostasis and pathology. ILCs act as early orchestrators of immunity, responding to epithelium-derived signals by expressing an array of cytokines and cell-surface receptors, which shape subsequent immune responses. As such, ILCs make up interesting therapeutic targets for several diseases. In patients with allergy and asthma, group 2 innate lymphoid cells produce high amounts of IL-5 and IL-13, thereby contributing to type 2-mediated inflammation. Group 3 innate lymphoid cells are implicated in intestinal homeostasis and psoriasis pathology through abundant IL-22 production, whereas group 1 innate lymphoid cells are accumulated in chronic inflammation of the gut (inflammatory bowel disease) and lung (chronic obstructive pulmonary disease), where they contribute to IFN-γ-mediated inflammation. Although the ontogeny of mouse ILCs is slowly unraveling, the development of human ILCs is far from understood. In addition, the growing complexity of the human ILC family in terms of previously unrecognized functional heterogeneity and plasticity has generated confusion within the field. Here we provide an updated view on the function and plasticity of human ILCs in tissue homeostasis and disease.
The natural compound camptothecin (CPT) derivatives have widely been used for anti-cancer treatments, including lung cancer. However, many chemoresistant cancer cells often develop a relatively higher threshold for inducing apoptosis, causing a limited efficacy of anti-cancer drugs. Likewise, lung cancer cells acquire chemoresistance against CPT analogs, such as irinotecan and topotecan, finally resulting in an unsatisfied outcome and poor prognosis of lung cancer patients. TFPP is a quinone-containing compound as a candidate for CPT-based combination chemotherapy. In this study, we examined the effect of TFPP and CPT cotreatment on non-small cell lung cancer (NSCLC) cells. Cell proliferation and flow cytometry-based Annexin-V/PI staining assays demonstrated the synergistic effect of TFPP on CPT-induced apoptosis in both NSCLC A549 and H1299 cells. The results of CPT and TFPP cotreatment cause the regulation of the ERK-Bim axis and the activation of mitochondrial-mediated caspase cascade, including caspase-9 and caspase-3. Besides, TFPP significantly enhanced CPT-induced endogenous reactive oxygen species (ROS) in the two NSCLC cells. In contrast, the treatment of N-acetyl-L-cysteine (NAC), an ROS scavenger, rescues the apoptosis of NSCLC cells induced by TFPP and CPT cotreatment, suggesting that the synergistic effect of TFPP on CPT-induced anti-NSCLC cells is through upregulating ROS production. Consequently, our results suggest that TFPP sensitizes NSCLC towards CPT-based chemotherapy may act through decreasing the apoptosis-initiating threshold. Therefore, TFPP may be a promising chemosensitizer for lung cancer treatment, and the underlying mechanism warrants further.
Rehabilitation of the upper-limb by means of a brain computer interface (BCI) is based on detecting an "intention to act" in the brain and transforming this intention into actual movement by using a motorized orthesis. The visual and proprioceptive feedback that results from the systems' generated movement following the subjects' captured intention, is thought to close the sensori-motor loop. Closing the loop is a key feature of BCI-systems that is thought to induce cerebral plasticity and thereby facilitating rehabilitation.
Ten chronic patients post-stroke with a severe upper-limb motor deficit and 10 healthy controls were included in the study. To mobilize wrist and finger movement, we used a pneumatic orthesis that was controlled by the BCI during a wrist flexion/extension task. The main objective was to evaluate the systems' CPS capacity to "classify" the observed brain activation as either movement or rest. Activation was registered with a 27-channel g tec EEG during two series of 40 randomized trials (20 rest, 20 movements). The sample frequency was 256Hz.
The BCI classifier was capable to distinguish between movements and rest with comparable performance for patients and controls and equal levels of true positives and negatives (78% vs 77% for patients and 81% vs 80% for controls). The CSP classifier used a wide 8-30Hz-frequency band filter to evaluate EEG activity. By cutting this large band into smaller sub-units, we showed that the systems' performance could be optimized by using subject-specific smaller frequency bands. The pneumatic orthesis should be improved.
The present closed-loop BCI-system for rehabilitation of the paretic upper-limb was well able to recognize intention of movement in the brain. Its practical interest for rehabilitation post-stroke needs to be confirmed by a longitudinal efficiency study.
There is no consensus on the question of pain induced by injections of botulinum toxin in children. The objective of this study is the evaluation of our practice as well as the resources, which are employed to relieve children, in order to improve a better management of pain.
This was a six month prospective observational monocentric study. The consent was obtained for each child. The main criterion was the hetero-evaluation of injection related pain with the modified scale FLACC. In parallel, parents evaluated their child pain as well as their anxiety; and injectors evaluated the quality of their act.
Overall, 47 children from 2 to 18 years old, concerned with an indication of botulinum toxin injections, were included. Four hundred and twenty-two children were given during 49 sessions. Seventy-one percent of children received a premedication associating hydroxyzine, MEOPA(®) and EMLA(®). Eight children were also accompanied by hypnoanalgesia, the others, distraction. The average pain during the injections was estimated with the FLACC to 2,632 (sd 1,892), the Digital Scale with 2.591 (sd 2,67). Children who presented an intense pain (FLACC>7) during the session of injections were 14,28%. Thirty-three percent of children were worried or very worried. Injectors were unsatisfied with 33% of their sessions. No link was established between pain and: sex, prematurity, epilepsy, motor disability, premedication, injection's volume, localisation of injection, hypnotherapy or distraction support. Anxiety and pain were linked.
Anxiety must be detected and prevented as well as pain is. Progress is possible, but appropriate studies are still needed to help us to define collectively a protocol more adapted.
In the face of the progressive implementation of the Affordable Care Act (ACA), a significant regulatory regime, and the Merit-Based Incentive Payment System (MIPS), the Centers for Medicare and Medicaid Services (CMS) released its proposed 2017 hospital outpatient department (HOPD) and ambulatory surgery center (ASC) payment rules on July 14, 2016, and the physician payment schedule was released July 15, 2016. U.S. health care costs continue to increase, occupying 17.5% of the gross domestic product (GDP) in 2014 and surpassing $3 trillion in overall health care expenditure. Solo and independent practices face unique challenges and many are being acquired by hospitals or larger groups. This transfer of services to hospital settings is indisputably leading to an increase in the net cost to the system. Comparison of facility payments for interventional techniques in HOPD, ASC, and in-office settings shows wide variation for multiple interventional techniques. Major discrepancies in payment schedules are related to higher payments for hospitals than comparable treatments in in-office settings and ASCs. In-office procedures, which have been converted to ASC procedures, are reimbursed at as high as 1,366% higher than ASCs and 2,156% higher than in-office settings. The Medicare Payment Advisory Commission (MedPAC) has made recommendations on avoiding the discrepancies and site-of-service differentials in in-office settings, hospital outpatient settings, and ASCs. These have not been implemented by CMS. In addition, there have been slow reductions in reimbursements over the recent years, which continue to accumulate, leading to significant reductions in paymentsIn conclusion, equalization of site-of-service differentials will simultaneously improve reimbursement patterns for interventional pain management procedures, increase access and quality of care, and finally, reduce costs for CMS, extending Medicare solvency.
Hospital outpatient departments, ambulatory surgery centers, physician in-office services, interventional pain management, interventional techniques.
The Centers for Medicare and Medicaid Services (CMS) released the proposed 2017
 Medicare physician fee schedule on July 7, 2016, addressing Medicare payments for physicians providing services either in an office or facility setting, which also includes payments for office expenses and quality provisions for physicians. This proposed rule occurs in the context of numerous policy changes, most notably related to the Medicare Access & CHIP Reauthorization Act of 2015 (MACRA) and its Merit-Based Incentive Payment System (MIPS). The proposed rule affects interventional pain management specialists in reimbursement for evaluation and management services, as well as procedures performed in a facility or in-office setting.Changes in the proposed fee schedule impacting interventional pain management practices include adjustments to the meaningful use (MU) program, care management in patient-centered services, identification and review of potentially misvalued services, evaluation of moderate sedation services, Medicare telehealth services, updated geographic practice cost index, data collection on resources used in furnishing global services, reporting of modifier 25 for zero day global services, Medicare Advantage Part C provider and supplier enrollment, appropriate use criteria (AUC) for advanced imaging services, and Medicare shared savings programs. The proposed schedule has provided rates for new epidural codes with or without imaging (fluoroscopy or computed tomography [CT]) and a fee schedule for a new code covering endoscopic spinal decompression. Review of payment rates show major discrepancies in payment schedules with high payments for hospitals, 2,156% higher than in-office procedures. Some procedures which were converted from in-office settings to ambulatory surgery centers (ASCs) are being reimbursed at 1,366% higher than ASCs. The Medicare Payment Advisory Commission (MedPAC) recommendation on avoiding the discrepancies and site-of-service differentials in in-office settings, hospital outpatient settings, and ASCs has not been agreed to by CMS. Thus, even though the changes appear to be minor in physician services and in-office service payment, these changes cumulatively have been reducing payments for interventional procedures. Further, in-office reimbursement is overall significantly lower than ASCs and hospital outpatient departments (HOPDs) specifically for intraarticular injections, peripheral nerve blocks, and peripheral neurolytic injections. The significant advantage also continues for hospitals in their reimbursement for facility fee for evaluation and management services.This health policy review describes various issues related to health care expenses, health care reform, and finally its effects on physician payments for all services and also for the services provided in an office setting.
The Merit-based Incentive Payment System (MIPS) was created by the Medicare Access and CHIP Reauthorization Act of 2015 (MACRA) to improve the health of all Americans by providing incentives and policies to improve patient health outcomes. MIPS combines 3 existing programs, Meaningful Use (MU), now called Advancing Care Information (ACI), contributing 25% of the composite score; Physician Quality Reporting System (PQRS), changed to Quality, contributing 50% of the composite score; and Value-based Payment (VBP) system to Resource Use or cost, contributing 10% of the composite score. Additionally, Clinical Practice Improvement Activities (CPIA), contributing 15% of the composite score, create multiple strategic goals to design incentives that drive movement toward delivery system reform principles with inclusion of Advanced Alternative Payment Models (APMs). Under the present proposal, the Centers for Medicare and Medicaid Services (CMS) has estimated approximately 30,000 to 90,000 providers from a total of over 761,000 providers will be exempt from MIPS. About 87% of solo practitioners and 70% of practitioners in groups of less than 10 will be subjected to negative payments or penalties ranging from 4% to 9%. In addition, MIPS also will affect a provider's reputation by making performance measures accessible to consumers and third-party physician rating Web sites.The MIPS composite performance scoring method, at least in theory, utilizes weights for each performance category, exceptional performance factors to earn bonuses, and incorporates the special circumstances of small practices.In conclusion, MIPS has the potential to affect practitioners negatively. Interventional Pain Medicine practitioners must understand the various MIPS measures and how they might participate in order to secure a brighter future.
Medicare Access and CHIP Reauthorization Act of 2015, merit-based incentive payment system, quality performance measures, resource use, clinical practice improvement activities, advancing care information performance category.
The effective mass of electrons and holes in semiconductors is pivotal in determining the dynamics of carriers and their confinement energy in nanostructured materials. Surprisingly, this quantity is still unknown in wurtzite (WZ) nanowires (NWs) made of III-V compounds (e.g., GaAs, InAs, GaP, InP), where the WZ phase has no bulk counterpart. Here, we investigate the magneto-optical properties of InP WZ NWs grown by selective-area epitaxy that provides perfectly ordered NWs featuring high-crystalline quality. The combined analysis of the energy of free exciton states and impurity levels under magnetic field (B up to 29 T) allows us to disentangle the dynamics of oppositely charged carriers from the Coulomb interaction and thus to determine the values of the electron and hole effective mass. By application of B⃗ along different crystallographic directions, we also assess the dependence of the transport properties with respect to the NW growth axis (namely, the WZ ĉ axis). The effective mass of electrons along ĉ is me(∥) = (0.078 ± 0.002) m0 (m0 is the electron mass in vacuum) and perpendicular to ĉ is me(⊥) = (0.093 ± 0.001) m0, resulting in a 20% mass anisotropy. Holes exhibit a much larger (∼320%) and opposite mass anisotropy with their effective mass along and perpendicular to ĉ equal to mh(∥) = (0.81 ± 0.18) m0 and mh(⊥) = (0.250 ± 0.016) m0, respectively. While no full consensus is found with current theoretical results on WZ InP, our findings show trends remarkably similar to the experimental data available in WZ bulk materials, such as InN, GaN, and ZnO.
Although the use of radioisotopes in Ghana began in 1952, the Radiation Protection Board of Ghana was established in 1993 and served as the national competent authority for authorization and inspection of practices and activities involving radiation sources until 2015. The law has been superseded by an Act of Parliament, Act 895 of 2015, mandating the Nuclear Regulatory Authority of Ghana to take charge of the regulation of radiation sources and their applications. The Radiation Protection Institute in Ghana provided technical support to the regulatory authority. Regulatory and service activities that were undertaken by the Institute include issuance of permits for handling of a radiation sources, authorization and inspection of radiation sources, radiation safety assessment, safety assessment of cellular signal towers, and calibration of radiation-emitting equipment. Practices and activities involving application of radiation are brought under regulatory control in the country through supervision by the national competent authority.
A report on the rapid change of activity of hypocretin/orexin cells in response to contact rather than digestion of food delivers new insights into the behavioral control of food intake and systemic energy expenditure.
The aim of the present study was explore perceptions of group-based walking and gather suggestions to inform the development of a group-based walking intervention among older adults in retirement villages. Twenty-four physically inactive residents (16 female, 8 male; age range: 69-88) and 4 managers from four retirement villages were interviewed. Inductive thematic analysis revealed 6 broad themes: lack of motivation, values versus constraints, fears and confidence, need for structure, creating a sense of belonging, and the physical environment as a double-edged sword. Proposed intervention strategies included using trained walk leaders, using small groups, planning for flexibility, setting attainable goals, creating a routine, creating opportunities for sharing experiences, and planning a variety of walks. Group-based walking programs may be used to promote physical activity but careful planning of such programs is needed in order to make it appealing and feasible to a diverse group of residents.
Despite continued research efforts, the threat of drug resistance from a variety of bacteria continues to plague clinical communities. Discovery and validation of novel biochemical targets will facilitate development of new drugs to combat these organisms. The methylerythritol phosphate (MEP) pathway to make isoprene units is a biosynthetic pathway essential to many bacteria. We and others have explored inhibitors of the MEP pathway as novel antibacterial agents. Mycobacterium tuberculosis, the causative agent of tuberculosis, and Yersinia pestis, resulting in the plague or "black death", both rely on the MEP pathway for isoprene production. 1-Deoxy-d-xylulose 5-phosphate reductoisomerase (Dxr) catalyzes the first committed step in the MEP pathway. We examined two series of Dxr inhibitors based on the parent structure of the retrohydroxamate natural product FR900098. The compounds contain either an extended N-acyl or O-linked alkyl/aryl group and are designed to act as bisubstrate inhibitors of the enzyme. While nearly all of the compounds inhibited both Mtb and Yp Dxr to some extent, compounds generally displayed more potent inhibition against the Yp homologue, with the
 best analogs displaying nanomolar IC50 values. In bacterial growth inhibition assays, the phosphonic acids generally resulted in poor antibacterial activity, likely a reflection of inadequate permeability. Accordingly, diethyl and dipivaloyloxymethyl (POM) prodrug esters of these compounds were made. While the added lipophilicity did not enhance Yersinia activity, the compounds showed significantly improved antitubercular activities. The most potent compounds have Mtb MIC values of 3-12 μg/mL. Taken together, we have uncovered two series of analogs that potently inhibit Dxr homologues from Mtb and Yp. These inhibitors of the MEP pathway, termed MEPicides, serve as leads for future analog development.
The purpose of this study was to explore the role of swimming on Paralympic athletes' perceptions of self and identity development.
A hermeneutic phenomenological approach was taken. During semi-structured interviews, five Paralympic swimmers (aged 20-24 years) were asked questions about their swimming career, perceptions of self, integration, and impairment. Interviews were audio-recorded and transcribed verbatim.
An Interpretative Phenomenological Analysis yielded three superordinate themes: (a) "One of the crowd"; none of the participants viewed themselves as disabled, nor as supercrips; these perceptions stemmed from family-, school-, and swimming-related experiences, (b) "Becoming me"; participation in swimming facilitated self- and social-acceptance, and identity development, and c) "A badge of honor"; swimming presented opportunity to present and reinforce a positive identity.
Swimming experiences enabled the participants to enhance personal and social identities, integrate through pro-social mechanisms, and to develop a career path following retirement from competition. Implications for rehabilitation Offering equal sporting opportunities for people with/without physical disability can help facilitate social integration and act as a buffer against stigmatization. Our research suggests that participation in sport had afforded the participants a heightened sense of self-concept, independence, ability and corresponding pride. When working with individuals with physical disabilities, rehabilitation professionals could utilize sport as a means of increasing an individual's feelings of independence, confidence and normalization. As such, part of rehabilitation should be to ensure opportunities for sport participation for people with physical disability are available for people of all ages.
The comparative clinical benefit of nonstatin therapies that reduce low-density lipoprotein cholesterol (LDL-C) remains uncertain.
To evaluate the association between lowering LDL-C and relative cardiovascular risk reduction across different statin and nonstatin therapies.
The MEDLINE and EMBASE databases were searched (1966-July 2016). The key inclusion criteria were that the study was a randomized clinical trial and the reported clinical outcomes included myocardial infarction (MI). Studies were excluded if the duration was less than 6 months or had fewer than 50 clinical events. Studies of 9 different types of LDL-C reduction approaches were included.
Two authors independently extracted and entered data into standardized data sheets and data were analyzed using meta-regression.
The relative risk (RR) of major vascular events (a composite of cardiovascular death, acute MI or other acute coronary syndrome, coronary revascularization, or stroke) associated with the absolute reduction in LDL-C level; 5-year rate of major coronary events (coronary death or MI) associated with achieved LDL-C level.
A total of 312 175 participants (mean age, 62 years; 24% women; mean baseline LDL-C level of 3.16 mmol/L [122.3 mg/dL]) from 49 trials with 39 645 major vascular events were included. The RR for major vascular events per 1-mmol/L (38.7-mg/dL) reduction in LDL-C level was 0.77 (95% CI, 0.71-0.84; P < .001) for statins and 0.75 (95% CI, 0.66-0.86; P = .002) for established nonstatin interventions that work primarily via upregulation of LDL receptor expression (ie, diet, bile acid sequestrants, ileal bypass, and ezetimibe) (between-group difference, P = .72). For these 5 therapies combined, the RR was 0.77 (95% CI, 0.75-0.79, P < .001) for major vascular events per 1-mmol/L reduction in LDL-C level. For other interventions, the observed RRs vs the expected RRs based on the degree of LDL-C reduction in the trials were 0.94 (95% CI, 0.89-0.99) vs 0.91 (95% CI, 0.90-0.92) for niacin (P = .24); 0.88 (95% CI, 0.83-0.92) vs 0.94 (95% CI, 0.93-0.94) for fibrates (P = .02), which was lower than expected (ie, greater risk reduction); 1.01 (95% CI, 0.94-1.09) vs 0.90 (95% CI, 0.89-0.91) for cholesteryl ester transfer protein inhibitors (P = .002), which was higher than expected (ie, less risk reduction); and 0.49 (95% CI, 0.34-0.71) vs 0.61 (95% CI, 0.58-0.65) for proprotein convertase subtilisin/kexin type 9 inhibitors (P = .25). The achieved absolute LDL-C level was significantly associated with the absolute rate of major coronary events (11 301 events, including coronary death or MI) for primary prevention trials (1.5% lower event rate [95% CI, 0.5%-2.6%] per each 1-mmol/L lower LDL-C level; P = .008) and secondary prevention trials (4.6% lower event rate [95% CI, 2.9%-6.4%] per each 1-mmol/L lower LDL-C level; P < .001).
In this meta-regression analysis, the use of statin and nonstatin therapies that act via upregulation of LDL receptor expression to reduce LDL-C were associated with similar RRs of major vascular events per change in LDL-C. Lower achieved LDL-C levels were associated with lower rates of major coronary events.
In this study, we show that an adaptation of the spinning test can be used as a model to study the exercise-exhaustion-recovery paradigm in fish. This forced swimming test promotes a wide range of changes in the hypothalamus-pituitary-interrenal axis functioning, intermediary metabolism, as well in fish behavior at both exercise and recovery periods. Our results pointed that this adapted spinning test can be considered a valuable tool for evaluating drugs and contaminant effects on exercised fish. This can be a suitable protocol both to environmental-to evaluate contaminants that act in fish energy mobilization and recovery after stressors-and translational perspectives-effects of drugs on exercised or stressed humans.
A novel three-dimensional lanthanide-organic framework {[Eu(BTB)(phen)]·4.5DMF·2H2O}n (1) has been synthesized. Structural characterization suggests that framework 1 possesses one-dimensional channels with potential pore volume, and the large channels in the framework can capture CO2. Interestingly, investigations on the cycloaddition reaction of CO2 and epoxides reveal that compound 1 can be considered as an efficient catalyst for CO2 fixation with epoxides under 1 atm pressure. Importantly, 1 can be reused at least five times without any obvious loss in catalytic activity. Furthermore, the luminescent explorations of 1 reveal that 1 can act as a recyclable sensor of Al(3+), and the corresponding detection limit can reach 5 × 10(-8) M (1.35 ppb), which is obviously lower than the United States Environmental Protection Agency's recommended level of Al(3+) in drinking water (200 ppb). These results show that 1 has a level of sensitivity higher than that of other reported MOF-based sensors of Al(3+).
A number of persons with an intractable disease (ID) experience work-related problems that could lead to job loss. The aim of this study was to ascertain perceptions regarding a range of work-related issues and corresponding support needs of individuals with an ID. Potential participants were people ages 15 to 64 with one of the 130 intractable chronic diseases designated in the Act to Comprehensively Support the Daily and Social Activities of Persons with Disabilities (Comprehensive Support for the Disabled Act). Participants completed a self-administered questionnaire. With the assistance of patients' organizations, 3,000 questionnaires were mailed to potential participants. Questions included demographic characteristics, family concerns, employment/supported employment, work accommodations, and other aspects of life. Responses were received from 889 (29.6%) participants, and respondents had 57 IDs. Forty-six-point-seven percent of respondents reported being unemployed due to fatigue and/or long-term treatment. Nearly half of the unemployed respondents reported that they had been unable to work despite their willingness to do so. Common requests for accommodation included flexible work hours, working at home, and job/workplace modifications. Only 30% of respondents knew about job training programs and supported work available for persons with disabilities. The results of the study are relevant for employees, employers, and occupational health/human resource professionals. The issue of reasonable accommodations for persons with an ID needs to be addressed in future research in order to promote continued work by those persons.
The specific genetic changes through which plants adapt to the multitude of environmental stresses are possible because of the molecular regulations in the system. These intricate regulatory mechanisms once unveiled will surely raise interesting questions. Polyamines and hydrogen peroxide have been suggested to be important signaling molecules during biotic and abiotic stresses. Hydrogen peroxide plays a versatile role from orchestrating physiological processes to stress response. It helps to achieve acclimatization and tolerance to stress by coordinating intra-cellular and systemic signaling systems. Polyamines, on the other hand, are low molecular weight polycationic aliphatic amines, which have been implicated in various stress responses. It is quite interesting to note that both hydrogen
 peroxide and polyamines have a fine line of inter-relation between them since the catabolic pathways of the latter releases hydrogen peroxide. In this review we have tried to illustrate the roles and their multifaceted functions of these two important signaling molecules based on current literature. This review also highlights the fact that over accumulation of hydrogen peroxide and polyamines can be detrimental for plant cells leading to toxicity and pre-mature cell death.
The K-12 classroom applications of mindfulness as developed by Ellen Langer are discussed in a case study of a first-year charter school. Langerian Mindfulness, which is the act of drawing distinctions and noticing novelty, is deeply related to well-being and creativity, yet its impact has yet to be tested at the primary or secondary school level. The objective of the article is to display how Langerian Mindfulness strategies could increase 21st century skills and Social-Emotional Learning in primary classrooms. The New School San Francisco, an inquiry-based, socioeconomically and racially integrated charter school, serves as a model for mindful teaching and learning strategies. It is concluded that when mindful strategies are implemented, students have significant opportunities to exercise the 21st century skills of creativity, collaboration, communication and critical thinking. Langerian Mindfulness is also considered as a tool for increasing Social-Emotional Learning in integrated classrooms. It is recommended that mindful interventions be further investigated in the primary and secondary school context.
The role of bile acids in colorectal cancer has been well documented, but their role in pancreatic cancer remains unclear. In this review, we examined the risk factors of pancreatic cancer. We found that bile acids are associated with most of these factors. Alcohol intake, smoking, and a high-fat diet all lead to high secretion of bile acids, and bile acid metabolic dysfunction is a causal factor of gallstones. An increase in secretion of bile acids, in addition to a long common channel, may result in bile acid reflux into the pancreatic duct and to the epithelial cells or acinar cells, from which pancreatic adenocarcinoma is derived. The final pathophysiological process is pancreatitis, which promotes dedifferentiation of acinar cells into progenitor duct-like cells. Interestingly, bile acids act as regulatory molecules in metabolism, affecting adipose tissue distribution, insulin sensitivity and triglyceride metabolism. As a result, bile acids are associated with three risk factors of pancreatic cancer: obesity, diabetes and hypertriglyceridemia. In the second part of this review, we summarize several studies showing that bile acids act as cancer promoters in gastrointestinal cancer. However, more question are raised than have been solved, and further oncological and physiological experiments are needed to confirm the role of bile acids in pancreatic cancer carcinogenesis.
Biofilms are ubiquitous and when mature have a complex structure of microcolonies in an extracellular polysaccharide and extracellular DNA matrix. Indwelling medical devices harbour biofilms which have been shown to cause infections and act as reservoirs for pathogens. Urinary catheters are often in place for considerable periods of time and are susceptible to both encrustation and biofilm formation. Strategies for minimising biofilm occurrence underpin an active research area in biomedicine. Manuka honey has, inter alia, well-established antibacterial properties. This study aims to assess the influence of honey on early biofilm formation in an established in vitro model.
An established model of early biofilm formation using static bacterial cultures in vinyl 96-well plates was used to grow Escherichia coli, strain ATC 25922 and Proteus mirabilis, strain 7002. Planktonic cells were removed and the residual biofilm was stained with crystal violet, which were subsequently eluted and quantified spectrophotometrically. Manuka honey (Unique Manuka Factor 15+) was added either with the bacteria or up to 72 hours after.
Biofilms in this model was developed over 3 days, after which growth stalled. Mixed (1:1) cultures of E. coli and P. mirabilis grew slower than monocultures. In mixed cultures, honey gave a dose-dependent reduction in biofilm formation (between 3.3 and 16.7%w/v). At 72 hours, all concentrations inhibited maximally (p<0.001). Application of honey to cultures after 24 and 48 hours also reduced the adherent bacterial biomass (p<0.05-p<0.01).
Manuka honey at dilutions as low as 3.3% w/v in some protocols and at 10% or above in all protocols tested significantly inhibits bacterial attachment to a vinyl substrate and reduces further early biofilm development. No augmentation of growth over untreated controls was observed in any experiment.
The objectives of this study were to provide a quantitative description of the long-term effects of environmental variability on xylem functional traits, in order to better assess xylem capacity to change in response to climate change. Twenty-six sites throughout the world, primarily in Europe, were chosen where results from long-term measurements of anatomical traits were previously published. Published data on long-term xylem anatomy (conduit size and density) and ring width variability were compiled across a range of tree species, which was subsequently related to variability in temperature, precipitation and nitrogen deposition rates across the study sites using generalized additive models and Bayesian methods. We found some appreciable relationships between xylem traits (conduit area Ac and conduit density Dc) and environmental variables; whereas combined trait indices (lumen fraction: Ac × Dc and vessel composition: Ac/Dc) were found to be rather constant across a wide range of environmental conditions and to be decoupled from tree growth rates. Overall, results suggested xylem traits coordinated towards a homeostasis in xylem function, which appeared to act across a wide range of environmental conditions. Results showed also nitrogen deposition was associated with xylem traits and vessel composition: increased nitrogen availability due to nitrogen deposition might facilitate construction of a xylem structure efficient for water transport, and concurrently provide capacity to withstand the risks of drought-induced embolism.
Asymmetric divisions produce daughter cells with different fates, and thus are critical for animal development. During asymmetric divisions, the mitotic spindle must be positioned on a polarized axis to ensure the differential segregation of cell fate determinants into the daughter cells. In many cell types a cortically localized complex consisting of Gα, GPR-1/2, and LIN-5 (Gαi/Pins/Mud, Gαi/LGN/NuMA) mediates the recruitment of dynactin/dynein, which exerts pulling forces on astral microtubules to physically position the spindle. The conserved PAR polarity proteins are known to regulate both cytoplasmic asymmetry and spindle positioning in many cases. However, spindle positioning also occurs in response to cell signaling cues that appear to be PAR-independent. In the four-cell Caenorhabditis elegans embryo, Wnt and Mes-1/Src-1 signaling pathways act partially redundantly to align the spindle on the anterior/posterior axis of the EMS cell. It is unclear how those extrinsic signals individually contribute to spindle positioning and whether either pathway acts via conserved spindle-positioning regulators. Here, we genetically test the involvement of Gα, LIN-5, and their negative regulator LET-99, in transducing EMS spindle positioning polarity cues. We also examined whether the C. elegans ortholog of another spindle positioning regulator, DLG-1, is required. We show that LET-99 acts in the Mes-1/Src-1 pathway for spindle positioning. LIN-5 is also required for EMS spindle positioning, possibly through a Gα and DLG-1 independent mechanism.
Cancer treatment has a far greater chance of success if the neoplasm is diagnosed before the onset of metastasis to vital organs. Hence, cancer early diagnosis is extremely important and remains a major challenge in modern therapeutics. In this contribution, facile and new method for rapid multimodal tumor bioimaging is reported by using biosynthesized iron complexes and gold nanoclusters via simple introduction of AuCl4(-) and Fe(2+) ions. The observations demonstrate that the biosynthesized Au nanoclusters may act as fluorescent and computed tomography probes for cancer bioimaging while the iron complexes behave as effective contrast agent for magnetic resonance imaging. The biosynthesized iron complexes and gold nanoclusters are found biocompatible in vitro (MTT (3-(4, 5-dimethylthiazol-2-yl)-2, 5-diphenyltetrazolium bromide) assay) and in vivo for all the vital organs of circulatory and excretory system. These observations raise the possibility that the biosynthesized probes may find applications in future clinical diagnosis for deep seated early neoplasms by multimodal imaging.
The aim of this study was to investigate whether p75NTR (p75 neurotrophin receptor) regulates differential mineralization capacity of rEMSCs (rat ectomesenchymal stem cells) and underlying mechanisms associated with Mage-D1 (melanoma-associated antigens-D1).
Immunohistochemical staining of p75NTR in developing tooth germs was performed on E12.5d (embryonic 12.5 days) and E19.5d (embryonic 19.5 days). E12.5d EMSCs and E19.5d EMSCs were isolated in the same pregnant Sprague-Dawley rats from embryonic maxillofacial processes and tooth germs. p75NTR small-interfering RNA, p75NTR overexpression plasmid, Mage-D1 small-interfering RNA and recombined rat NGF were used to transfect cells.
p75NTR was expressed in epithelial-mesenchymal interaction areas at E12.5d and E19.5d tooth germ development stages.
 E19.5d EMSCs had higher p75NTR expression levels and differential mineralization capacity but lower levels of cell proliferation. Under induction by mineralized culture medium, the potential of differential mineralization had identical trends in regulation of p75NTR in EMSCs; Mage-D1 did not fluctuate and TrkA was not expressed. Binding of p75NTR and Mage-D1 were detected. Mage-D1 knockdown significantly down-regulated expression of related genes, which NGF could not rescue.
p75NTR participated in tooth germ development stages and mediated differential mineralization of EMSCs. p75NTR played a critical role in regulating the potential of differential mineralization of EMSCs. Mage-D1 seemed to act as a bridge in the underlying mechanism of effects of p75NTR.
Disaster and pandemic response events require an interprofessional team of health care responders to organize and work together in high-pressure, time-critical situations. Civilian oral health care professionals have traditionally been limited to forensic identification of human remains. However, after the bombing of the Twin Towers in New York, federal agencies realized that dentists can play significant roles in disaster and immunization response, especially on interprofessional responder teams. Several states have begun to incorporate dentists into the first responder community. This article discusses the roles of dental responders and highlights legislative advancements and advocacy efforts supporting the dental responder.
Seasonal emerging infectious diseases such as influenza A impose substantial risk and need new translational strategies to achieve active immunomodulation. Here, a novel injectable pathogen-mimicking hydrogel (iPMH) that can enhance both cellular and humoral immune responses is suggested. By the help of poly(γ-glutamic acid) that has abundant carboxylate groups and dispersion helper function, hydrophobic immunostimulatory 3-O-desacyl-4'-monophosphoryl lipid A (MPLA) molecules and viral antigens (PR8, W150) can be successfully combined as pathogen-mimicking adjuvants. Polyelectrolyte complex between the poly(γ-glutamic acid)-based adjuvants and collagens generate in situ gel-forming hydrogel at physiological temperature. When the iPMH are immunized, they act as a pathogen-mimicking (MPLA, H1N1, H5N1) immune priming center and a depot for continuous stimulation of immune system, resulting in the induction of high levels (8.5 times higher) of antigen-specific IgG titers in the sera of mice and the increased number of IFN-γ-producing cells (7.3 times higher) compared with those in the groups immunized with antigen plus clinically used aluminum gels. Following the intranasal infection of the mouse adapted virus (emerging infectious 2009 H1N1 and highly pathogenic 2006 H5N1) at 50 times the 50% lethal dose, the mice immunized with viral antigens plus iPMH exhibit 100% protective immunity against lethal virus challenge.
Fetuin-A/AHSH is a novel hepatokine that acts as a vascular calcification inhibitor and as an endogenous TLR-4 ligand. Fetuin-A may act as a positive or negative acute phase protein (APP) in disease conditions. The relationship between circulatory fetuin-A and inflammatory biomarkers in type-2 diabetes (T2D) remains controversial. Therefore, the purpose of this study was to determine the plasma fetuin-A levels in 53 T2D (BMI = 29.7 ± 4.5 kg/m(2)) and 72 non-diabetic individuals (BMI = 28.2 ± 5.8 kg/m(2)) using premixed 38-plex MAP human cytokine/chemokine magnetic bead immunoassays and the data (mean ± SEM) were statistically analyzed to determine Pearson's correlation (r) between fetuin-A and detected analytes; P-values ≤0.05 were considered significant.
The data show that plasma fetuin-A levels were comparable in both groups (P = 0.27) and in T2D individuals, fetuin-A associated negatively (P ≤ 0.05) with a large number of proinflammatory cytokines/chemokines and activation biomarkers including TNF-α, IFN-α2, IFN-γ, IL-1α, IL-1β, IL-1RA, IL-3, IL-4, IL-7, IL-9, IL-12p40/p70, IL-15, CCL-2, CCL-4, CCL-11, CCL-22, CXCL-8, CX3CL-1, EFF-2, EGF, G-CSF, GM-CSF, GRO, sCD40L, and VEGF. In non-diabetics, fetuin-A also correlated positively with certain TH2 cytokines (IL-5, IL-13) and chemokines (CCL-3, CCL-5, CCL-7). Notably, in vitro fetuin-A production was significantly suppressed in HepG2 cells treated with TNF-α, IL-1β, and IFN-γ which supported the clinical findings of a negative association between fetuin A and inflammatory mediators.
The negative association between circulatory fetuin-A and systemic inflammatory mediators in T2D patients suggests that plasma fetuin-A may have predictive significance as a negative APP in metabolic disease.
Sources and sinks of methane (CH4 ) are critical for understanding global biogeochemical cycles and their role in climate change. A growing number of studies have reported that CH4 concentrations in cave ecosystems are depleted, leading to the notion that these subterranean environments may act as sinks for atmospheric CH4 . Recently, it was hypothesized that this CH4 depletion may be caused by radiolysis, an abiotic process whereby CH4 is oxidized via interactions with ionizing radiation derived from radioactive decay. An alternate explanation is that the depletion of CH4 concentrations in caves could be due to biological processes, specifically oxidation by methanotrophic bacteria. We theoretically explored the radiolysis hypothesis and conclude that it is a kinetically constrained process that is unlikely to lead to the rapid loss of CH4 in subterranean environments. We present results from a controlled laboratory experiment to support this claim. We then tested the microbial oxidation hypothesis with a set of mesocosm experiments that were conducted in two Vietnamese caves. Our results reveal that methanotrophic bacteria associated with cave rocks consume CH4 at a rate of 1.3-2.7 mg CH4  · m(-2)  · d(-1) . These CH4 oxidation rates equal or exceed what has been reported in other habitats, including agricultural systems, grasslands, deciduous forests, and Arctic tundra. Together, our results suggest that depleted concentrations of CH4 in caves are most likely due to microbial activity, not radiolysis as has been recently claimed. Microbial methanotrophy has the potential to oxidize CH4 not only in caves, but also in smaller-size open subterranean spaces, such as cracks, fissures, and other pores that are connected to and rapidly exchange with the atmosphere. Future studies are needed to understand how subterranean CH4 oxidation scales up to affect local, regional, and global CH4 cycling.
Salt stress triggers a simultaneous transcriptional repression and aquaporin internalization to modify root cell water conductivity. Plasma membrane intrinsic proteins (PIPs) are involved in the adjustment of plant water balance in response to changing environmental conditions. In this study, Arabidopsis wild-type (Col-0) and transgenic lines overexpressing PIP2;7 were used to investigate and compare their response to salt stress. Hydraulic conductivity measurements using a high-pressure flowmeter (HPFM) revealed that overexpression of PIP2;7 induced a sixfold increase in root hydraulic conductivity of four week-old Arabidopsis thaliana plants compared to WT. Exposure to a high salt stress (150 mM NaCl) triggered a rapid repression of overall aquaporin activity in both genotypes. Response to salt stress was also investigated in 8 day-old seedlings. Exposure to salt led to a repression of PIP2;7 promoter activity and a significant decrease in PIP2;7 mRNA abundance within 2 h. Concomitantly, a rapid internalization of fluorescently-tagged PIP2;7 proteins was observed but removal from the cell membrane was not accompanied by further degradation of the protein within 4 h of exposure to salinity stress. These data suggest that PIP transcriptional repression and channel internalization act in concert during salt stress conditions to modulate aquaporin activity, thereby significantly altering the plant hydraulic parameters in the short term.
Hypoxia-inducible factor (HIF)-α isoforms regulate key macrophage (MΦ) functions during ischemic inflammation. HIF-2α drives proinflammatory cytokine production; however, the requirements for HIF-2α during other key MΦ functions, including phagocytosis, are unknown. In contrast to HIF-1α, HIF-2α was not required for hypoxic phagocytic uptake. Surprisingly, basal HIF-2α levels under nonhypoxic conditions were necessary and sufficient to suppress phagocytosis. Screening approaches revealed selective induction of the scavenger receptor MARCO, which was required for enhanced engulfment. Chromatin immunoprecipitation identified the antioxidant NRF2 as being directly responsible for inducing Marco Concordantly, Hif-2α(-/-) MΦs exhibited reduced antioxidant gene expression, and inhibition of mitochondrial reactive oxygen species suppressed Marco expression and phagocytic uptake. Ex vivo findings were recapitulated in vivo; the enhanced engulfment phenotype resulted in increased bacterial clearance and cytokine suppression. Importantly, natural induction of Hif-2α by IL-4 also suppressed MARCO-dependent phagocytosis. Thus, unlike most characterized prophagocytic regulators, HIF-2α can act as a phagocytic repressor. Interestingly, this occurs in resting MΦs through tempering of steady-state mitochondrial reactive oxygen species. In turn, HIF-2α promotes MΦ quiescence by blocking a MARCO bacterial-response pathway. IL-4 also drives HIF-2α suppression of MARCO, leading to compromised bacterial immunosurveillance in vivo.
The cell-to-cell transport of signaling molecules is essential for multicellular organisms to coordinate the action of their cells. Recent studies identified DWARF14 (D14) as a receptor of strigolactones (SLs), molecules that act as plant hormones and inhibit shoot branching.
 Here, we demonstrate that RAMOSUS3, a pea ortholog of D14, works as a graft-transmissible signal to suppress shoot branching. In addition, we show that D14 protein is contained in phloem sap and transported through the phloem to axillary buds in rice. SLs are not required for the transport of D14 protein. Disruption of D14 transport weakens the suppression of axillary bud outgrowth of rice. Taken together, we conclude that the D14 protein works as an intercellular signaling molecule to fine-tune SL function. Our findings provide evidence that the intercellular transport of a receptor can regulate the action of plant hormones.
The 14-3-3 family of adaptor proteins regulate diverse cellular functions including cell proliferation, metabolism, adhesion and apoptosis. Platelets express numerous 14-3-3 isoforms, including 14-3-3ζ, which has previously been implicated in regulating GPIbα function. Here we show an important role for 14-3-3ζ in regulating arterial thrombosis. Interestingly, this thrombosis defect is not related to alterations in von Willebrand factor (VWF)-GPIb adhesive function or platelet activation, but instead associated with reduced platelet phosphatidylserine (PS) exposure and procoagulant function. Decreased PS exposure in 14-3-3ζ-deficient platelets is associated with more sustained levels of metabolic ATP and increased mitochondrial respiratory reserve, independent of alterations in cytosolic calcium flux. Reduced platelet PS exposure in 14-3-3ζ-deficient mice does not increase bleeding risk, but results in decreased thrombin generation and protection from pulmonary embolism, leading to prolonged survival. Our studies define an important role for 14-3-3ζ in regulating platelet bioenergetics, leading to decreased platelet PS exposure and procoagulant function.
Justice-involved youth have high rates of psychiatric diagnoses, and these youth are often placed out-of-home, although evidence identifies several negative implications of juvenile confinement, especially for youth with psychopathology. Furthermore, youth in the justice system may be processed differently based on gender. As males and females tend to manifest symptoms differently, the psychopathology of youth may act to moderate the relationship between gender and placement in the juvenile justice system. The present study used a large, diverse sample (n = 9 851, 19.8 % female) to examine whether youth placed in various types of out-of-home facilities differed in terms of externalizing, internalizing, substance use, or comorbid disorders, and to determine the predictive value of mental health diagnoses in placement decisions. The moderation effect of psychopathology and substance use on the relationship between gender and placement also was explored. The results indicated that each type of disorder differed across placements, with internalizing being most prevalent in non-secure, and externalizing, comorbid, and substance use being most prevalent in secure settings. Mental health diagnoses improved the prediction of placement in each out-of-home placement beyond legal and demographic factors such that externalizing and substance use disorders decreased the likelihood of placement in non-secure settings, and internalizing, externalizing, and substance use disorders increased the likelihood of placement in secure and state-secure facilities. The relationship between internalizing pathology and placement in more secure facilities was moderated by externalizing pathology. The relationship between gender and placement was significantly moderated by mental health such that females with mental health diagnoses receive less secure placements. Implications for policymakers and practitioners are discussed, as well as implications for reforming juvenile justice within a developmental approach.
The effect of plasma applied to mulungu (Erythrina velutina) seeds was studied to verify its influence on the germination, water absorption, wettability and structure of the seeds. The plasma jet used in this study was produced by dielectric barrier discharge (DBD) in a helium gas flow of 0.03 L/s at a distance of 13 mm for 60 s. The plasma treatment significantly affected the seed germination rate, which was approximately 5% higher than that of the untreated group. Micropyle and hilum contributed a greater proportion to uptake. When sealed in the hilar or micropyle regions the amount of water absorbed into the seed decreased approximately 75% compared to the unsealed seed. This difference suggests that these two regions together act cooperatively in the water absorption. However, when plasma treated seed was blocked in the micropyle region, water absorption was higher higher than in seeds blocked hilum. This difference suggests that the plasma treatment changed the wettability of the hilum more effectively than it changed the micropyle. These results indicate that plasma can significantly change the hydrophilicity, water absorption and percentage of seed germination in E. velutina.
H2 metabolism is proposed to be the most ancient and diverse mechanism of energy-conservation. The metalloenzymes mediating this metabolism, hydrogenases, are encoded by over 60 microbial phyla and are present in all major ecosystems. We developed a classification system and web tool, HydDB, for the structural and functional analysis of these enzymes. We show that hydrogenase function can be predicted by primary sequence alone using an expanded classification scheme (comprising 29 [NiFe], 8 [FeFe], and 1 [Fe] hydrogenase classes) that defines 11 new classes with distinct biological functions. Using this scheme, we built a web tool that rapidly and reliably classifies hydrogenase primary sequences using a combination of k-nearest neighbors' algorithms and CDD referencing. Demonstrating its capacity, the tool reliably predicted hydrogenase content and function in 12 newly-sequenced bacteria, archaea, and eukaryotes. HydDB provides the capacity to browse the amino acid sequences of 3248 annotated hydrogenase catalytic subunits and also contains a detailed repository of physiological, biochemical, and structural information about the 38 hydrogenase classes defined here. The database and classifier are freely and publicly available at http://services.birc.au.dk/hyddb/.
Small cell lung cancers (SCLC) are tumors of neuroendocrine origin. Previous in vitro studies from our laboratory showed that SCLC expresses high levels of the transmembrane dense core vesicle protein IA-2 (islet cell antigen-2) as compared to normal lung cells. IA-2, through its effect on dense core vesicles (DCVs), is known to be involved in the secretion of hormones and neurotransmitters. It is believed that the dysregulated release of the neurotransmitter Acetylcholine (ACh) by DCVs has an autocrine effect on SCLC cell growth. Recently, we found that IA-2 is a target of the microRNA miR-342 and that miR-342 mimics suppress the expression of IA-2. The present experiments were initiated to see whether IA-2 and/or miR-342 affect the growth of SCLC.
SCLC cell growth was evaluated following the knockdown of endogenous IA-2 with RNAi or by overexpressing miR-342 with a mimic. The secretion and content of ACh in SCLC cells was analyzed using a human acetylcholine ELISA (enzyme-linked immunosorbent assay) kit.
The knockdown of endogenous IA-2 by RNAi reduced SCLC cell growth within 4 days by 40 % or more. Similar results were obtained when these cell lines were transfected with a miR-342 mimic. The knockdown of IA-2 by RNAi or miR-342 with a mimic also resulted in a significant decrease in the secretion of ACh, one of the autocrine hormones secreted by SCLC. Further studies revealed that the growth of SCLC cell lines that had been treated with the miR-342 mimic was restored to nearly normal levels by treatment with ACh.
Our studies show for the first time that both miR-342 and its target gene IA-2 are involved in the growth process of SCLC cells and act by their effect on autocrine secretion. These findings point to possible new therapeutic approaches for the treatment of autocrine-induced tumor proliferation.
Patient-centered care for individuals with myotonic dystrophy (DM1) and Huntington's disease (HD)-chronic, progressive, and life-limiting neurological conditions-may be challenged by patients' cognitive and behavioral impairments. However, no research has explored health care providers' (HCPs') perspectives about patient-centered care provision for these patients along their disease trajectory.
Constructivist grounded theory informed the iterative data collection and analysis process. Eleven DM1 or HD HCPs participated in semistructured interviews, and three stages of coding were used to analyze their interview transcripts. Codes were collapsed into themes and categories.
Three categories including an evolving care approach, fluid roles, and making a difference were identified. Participants described that their clinical care approach evolved depending on the patient's disease stage and caregivers' degree of involvement. HCPs described that their main goal was to provide hope to patients and caregivers through medical management, crisis prevention, support, and advocacy. Despite the lack of curative treatments, HCPs perceived that patients benefited from ongoing clinical care provided by proactive clinicians.
Providing care for individuals with DM1 and HD is a balancing act. HCPs must strike a balance between (1) the frustrations and rewards of patient-centered care provision, (2) addressing symptoms and preventing and managing crises while focusing on patients' and caregivers' quality of life concerns, and (3) advocating for patients while addressing caregivers' needs. This raises important questions: Is patient-centered care possible for patients with cognitive decline? Does chronic neurological care need to evolve to
 better address patients' and caregivers' complex needs?
Takeaway food has a relatively poor nutritional profile. Providing takeaway outlets with reduced-holed salt shakers is one method thought to reduce salt use in takeaways, but effects have not been formally tested. We aimed to determine if there was a difference in sodium content of standard fish and chip meals served by Fish & Chip Shops that use standard (17 holes) versus reduced-holed (5 holes) salt shakers, taking advantage of natural variations in salt shakers used.
We conducted a cross-sectional study of all Fish & Chip Shops in two local government areas (n = 65), where servers added salt to meals as standard practice, and salt shaker used could be identified (n = 61). Standard fish and chip meals were purchased from each shop by incognito researchers and the purchase price and type of salt shaker used noted. Sodium content of full meals and their component parts (fish, chips, and fish batter) was determined using flame photometry. Differences in absolute and relative sodium content of meals and component parts between shops using reduced-holed versus standard salt-shakers were compared using linear regression before and after adjustment for purchase price and area.
Reduced-holed salt shakers were used in 29 of 61 (47.5 %) included shops. There was no difference in absolute sodium content of meals purchased from shops using standard versus reduced-holed shakers (mean = 1147 mg [equivalent to 2.9 g salt]; SD = 424 mg; p > 0.05). Relative sodium content was significantly lower in meals from shops using reduced-holed (mean = 142.5 mg/100 g [equivalent to 0.4 g salt/100 g]; SD = 39.0 mg/100 g) versus standard shakers (mean = 182.0 mg/100 g; [equivalent to 0.5 g salt/100 g]; SD = 68.3 mg/100 g; p = 0.008). This was driven by differences in the sodium content of chips and was extinguished by adjustment for purchase price and area. Price was inversely associated with relative sodium content (p < 0.05).
Using reduced-holed salt shakers in Fish & Chip Shops is associated with lower relative sodium content of fish and chip meals. This is driven by differences in sodium content of chips, making our results relevant to the wide range of takeaways serving chips. Shops serving higher priced meals, which may reflect a more affluent customer base, may be more likely to use reduced-holed shakers.
Pulmonary arterial hypertension (PAH) is a relatively rare disease which due to its chronic nature has always been difficult to treat effectively. Selexipag is an oral prostacyclin (PGI2) agonist, which was approved by US Food and Drug Administration (US FDA) in December 2015 for the treatment of PAH. After its success in Phase 1 and Phase 2 clinical trials regarding the convenient oral twice daily dosing and low side-effect profile, selexipag raised the hope of controlling the disease progression in PAH patients. In the recently completed multi-centered Phase 3 study (GRIPHON), selexipag has been shown to reduce the death and hospitalization due to PAH significantly, the effect being consistent across different ranges of maintenance dose. In the same study, selexipag use was also associated with an increase in 6-minute walk distance (a measure of symptom severity) from baseline, but no significant improvement in all-cause mortality could be observed. The results of the ongoing phase 3 studies (TRITON and TRANSIT-1) are expected to throw some more light on its safety and efficacy of this novel molecule across various treatment scenarios. Hence, our article aims to summarize all the available information from preclinical and clinical studies published till date on the pharmacodynamics, pharmacokinetics, efficacy, safety (in general and in scenarios like hepatic and renal function impairment), significant drug interactions (with warfarin and antiretroviral drugs), and clinical significance of oral selexipag in patients with PAH. This article is protected by copyright. All rights reserved.
Sleep is an important contributor to physical and mental health; however, chronic sleep deprivation has become common in adolescents, especially on weekdays. Adolescents aged 14-17 years are recommended to sleep between 8 and 10 h per night to maximize overall health and well-being. Although sleep needs may vary between individuals, sleep duration recommendations are important for surveillance and help inform policies, interventions, and the population of healthy sleep behaviors. Long sleepers are very rare among teenagers and sleeping too much is not a problem per se; only insufficient sleep is associated with adverse health outcomes in the pediatric population. Causes of insufficient sleep are numerous and chronic sleep deprivation poses a serious threat to the academic success, health and safety of adolescents. This article focuses on the link between insufficient sleep and obesity in adolescents.
This "call to action" article argues that sleep should be taken more seriously by the public health community and by our society in general, i.e., given as much attention and resources as nutrition and physical activity. Not only that having a good night's sleep is as important as eating a healthy diet and being regularly physically active for overall health, but sleeping habits also impact eating and screen time behaviors and, therefore, can influence body weight control. Short sleep duration, poor sleep quality, and late bedtimes are all associated with excess food intake, poor diet quality, and obesity in adolescents. Sleep, sedentary behavior, physical activity and diet all interact and influence each other to ultimately impact health. A holistic approach to health (i.e., the whole day matters) targeting all of these behaviors synergistically is needed to optimize the impact of our interventions. Sleep is not a waste of time and sleep hygiene is an important factor to consider in the prevention and treatment of obesity.
Strongly hydrogen-bonded motifs provide structural stability and can act as proton transfer relays to drive chemical processes in biological and chemical systems. However, structures with medium and strong hydrogen bonds are difficult to study due to their characteristically broad vibrational bands and large anharmonicity. This is further complicated by strong interactions between the high-frequency hydrogen-bonded vibrational modes, fingerprint modes, and low-frequency intradimer modes that modulate the hydrogen-bonding. Understanding these structures and their associated dynamics requires studying much of the vibrational spectrum. Here, mid-IR continuum spectroscopy of the cyclic 7-azaindole-acetic acid (7AI-AcOH) heterodimer reveals the vibrational relaxation dynamics and couplings of this complex hydrogen-bonded system. Within this dimer, the NH bond of 7AI exhibits a band at 3250 cm(-1) caused by a medium strength hydrogen bond, while the strongly hydrogen-bonded OH modes of acetic acid exhibit a broad double-peaked vibrational feature spanning 1750 to 2750 cm(-1). Transient IR and 2D IR experiments were performed using three excitation frequencies, centered on the high-frequency OH and NH modes, and probed with a mid-IR continuum to measure the spectral response from 1000 to 3500 cm(-1). While the NH stretch is observed to relax in 300 fs, the strongly hydrogen-bonded OH modes relax within the time resolution of the experiment (sub-100 fs). The difference in the strength of the hydrogen bonds is also reflected in the coupling pattern in the fingerprint region observed with 2D IR spectroscopy. Here the NH is strongly coupled to fingerprint modes involving the 7AI monomer, while the OH vibrations are strongly coupled to vibrational modes across the entire dimer. Together, the results show strong coupling and rapid energy transfer across the hydrogen-bonded interface and through the structure of the 7-azaindole-acetic acid heterodimer, highlighting the need to study the full vibrational spectrum for strongly hydrogen-bonded systems.
Liver X receptors α (LXRα) and β (LXRβ) are essential for protection against cardiovascular diseases. LXRs are members of the nuclear receptor superfamily of DNA-binding transcription factors and act as sensors of cholesterol homeostasis. In this review, we introduce LXRs and briefly describe the roles of LXRs in reverse cholesterol transport and trans-intestinal cholesterol efflux. We discuss LXR agonists and the downstream genes of LXRs that are involved in the regulation of cholesterol transport. In addition, we describe the cardioprotective effects of LXRs against atherosclerosis, myocardial ischemia/reperfusion injury, diabetic cardiomyopathy, and myocardial hypertrophy. Finally, we expand our discussion to the actions of LXRs in atherosclerosis and suggest several potential research avenues that may be of interest to clinicians and basic scientists. The information included herein may be useful for the design of future experimental research studies and may advance the investigation of LXRs as therapeutic targets.
From 1943, when Leo Kanner originally described autism, and to the first objective criteria for "infantile autism" in DSM-III and the inclusion of Asperger's disorder in DSM-IV, the subsequent classification scheme for autistic disorders has led to a substantial change with the 2013 issuance of the DSM-5 by including subcategories into one umbrella diagnosis of autism spectrum disorder (ASD) (Baker, 2013). ASD is a lifelong neurodevelopmental disorder, characterized by social and communication impairments and restricted, stereotypical patterns of behavior (Baker, 2013). It is currently expected that most, or all of the actual cases of ASD, are identified in a timely way (i.e. in early childhood). However, there are many undiagnosed older adults who may have met the current diagnostic criteria for ASD as children, but never received
 such a diagnosis due to the fact it had yet to be established. In addition, some patients with relatively less impairing phenotypes may escape formal diagnosis in childhood, only to later be diagnosed in adulthood. Nevertheless, the first generation of diagnosed patients with ASD is now in old age. Many such ASD patients have needed family and institutional support for their lives subsequent to childhood diagnosis. Due to aging and death of their parents and other supportive figures leading to a loss of social structures, there is no better time than now for the medical community to act.
Oxidative stress occurs when the production of oxidants surpasses the antioxidant capacity in living cells. Oxidative stress is implicated in a number of pathological conditions such as cardiovascular and neurodegenerative diseases but it also has crucial roles in the regulation of cellular activities. Over the last few decades, many studies have identified significant connections between oxidative stress, inflammation and healing. In particular, increasing evidence indicates that the production of oxidants and the cellular response to oxidative stress are intricately connected to the fate of implanted biomaterials. This review article provides an overview of the major mechanisms underlying the link between oxidative stress and the biocompatibility of biomaterials. ROS, RNS and lipid peroxidation products act as chemo-attractants, signalling molecules and agents of degradation during the inflammation and healing phases. As chemo-attractants and signalling molecules, they contribute to the recruitment and activation of inflammatory and healing cells, which in turn produce more oxidants. As agents of degradation, they contribute to the maturation of the extracellular matrix at the healing site and to the degradation of the implanted material. Oxidative stress is itself influenced by the material properties, such as by their composition, their surface properties and their degradation products. Because both cells and materials produce and react with oxidants, oxidative stress may be the most direct route mediating the communication between cells and materials. Improved understanding of the oxidative stress mechanisms following biomaterial implantation may therefore help the development of new biomaterials with enhanced biocompatibility.
The multispecific transcription factor and tumor suppressor FOXO3 is an important mediator of apoptosis, but the mechanisms that control its proapoptotic function are poorly understood. There has long been evidence that acetylation promotes FOXO3-driven apoptosis and recently a specific JNK (c-Jun N-terminal kinase)-dependent S574 phosphorylated form (p-FOXO3) has been shown to be specifically apoptotic. This study examined whether acetylation and S574 phosphorylation act independently or in concert to regulate the apoptotic function of FOXO3. We observed that both sirtuins 1 and 7 (SIRT1 and SIRT7) are able to deacetylate FOXO3 in vitro and in vivo, and that lipopolysaccharide (LPS) treatment of THP-1 monocytes induced a rapid increase of FOXO3 acetylation, partly by suppression of SIRT1 and SIRT7. Acetylation was required for S574 phosphorylation and cellular apoptosis. Deacetylation of FOXO3 by SIRT activation or SIRT1 or SIRT7 overexpression prevented its S574 phosphorylation and blocked apoptosis in response to LPS. We also found that acetylated FOXO3 preferentially bound JNK1, and a mutant FOXO3 lacking four known acetylation sites (K242, 259, 290 and 569R) abolished JNK1 binding and failed to induce apoptosis. This interplay of acetylation and phosphorylation also regulated cell death in primary human peripheral blood monocytes (PBMs). PBMs isolated from alcoholic hepatitis patients had high expression of SIRT1 and SIRT7 and failed to induce p-FOXO3 and apoptosis in response to LPS. PBMs from healthy controls had lower SIRT1 and SIRT7 and readily formed p-FOXO3 and underwent apoptosis when similarly treated. These results reveal that acetylation is permissive for generation of the apoptotic form of FOXO3 and the activity of SIRT1 and particularly SIRT7 regulate this process in vivo, allowing control of monocyte apoptosis in response to LPS.Oncogene advance online publication, 26 September 2016; doi:10.1038/onc.2016.359.
Small-molecule inhibitors of Inhibitor of Apoptosis proteins such as Smac mimetics have been reported to provide a promising tool to sensitize glioblastoma (GBM) cells to cytotoxic therapies including chemotherapeutic drugs. However, the underlying molecular mechanisms of action have not yet been fully unraveled. In the present study, we therefore investigated the role of reactive oxygen species (ROS) in the regulation of Smac mimetic/temozolomide (TMZ)-induced cell death in GBM cells. Here, we show that the Smac mimetic BV6 and TMZ act in concert to stimulate the production of both cytosolic and mitochondrial ROS. This accumulation of ROS contributes toward the activation of the proapoptotic factor BAX upon BV6/TMZ cotreatment as several ROS scavengers (i.e. N-acetyl-L-cysteine, MnTBAP, or α-tocopherol) protect GBM cells against BV6/TMZ-mediated BAX activation. In addition, ROS scavengers significantly rescue GBM cells from BV6/TMZ-triggered cell death, indicating that ROS generation is required for the induction of cell death. By showing that ROS play an important role in the regulation of Smac mimetic/TMZ-induced cell death, our work sheds light on the crucial role of the oxidative system in the cooperative antitumor activity of Smac mimetic/TMZ combination therapy against GBM cells.
Recent passage of the Massachusetts law, An Act Relative to Substance Use, Treatment, Education, and Prevention, represents an admirable public health approach to substance use disorder (SUD), a stigmatized chronic disease that affects some of society's most vulnerable people. With its seven-day supply limit on first-time opioid prescriptions, this legislation takes an unusual approach to state government involvement in health care. By intervening in individual physicians' practices, state legislators have entered a space traditionally reserved for clinical teams. The seven-day supply limit and the process through which it was developed highlight competing priorities and dialogue between physicians and legislators, limits of physician self-regulation, and standards of evidence in policy making and health care. Addressing these issues requires both physicians and legislators to recognize and fulfill new responsibilities in order to better assist the populations they serve.
The exocyst complex is a large conserved hetero-oligomeric complex that consists of Sec3, Sec5, Sec6, Sec8, Sec10, Sec15, Exo70 and Exo84 subunits. It has been implicated in the targeting of vesicles for regulated exocytosis in various cell types, and is also important for targeted exocytosis of post-Golgi transport vesicles to the plasma membrane. The exocyst complex is essential for membrane growth, secretion and function during exocytosis and endocytosis. Moreover, the individual components of the complex are thought to act on specific biological processes, such as cytokinesis, ciliogenesis, apoptosis, autophagy and epithelial-mesenchymal transition (EMT). As a result, recent studies suggest that the exocyst complex may be involved in several diseases such as kidney disease, neuropathogenesis, diabetes, and cancer. In this review, we focus on the diverse functions and cellular signaling pathways of the exocyst complex in various tumors. This article is protected by copyright. All rights reserved.
The Medicare Modernization Act of 2003 (Medicare Part D) added prescription drug coverage for senior citizens aged 65 years and older and applied managed care approaches to contain costs. The Patient Protection and Affordable Care Act of 2010 (ACA) had the goals of expanding health care insurance coverage and slowing growth in health care expenditures.
To (a) describe the proportion of senior citizens who had prescription drug insurance coverage and the proportion who experienced financial hardship from purchasing medications in 2015, and (b) compare the findings with those collected in 1998 and 2001.
Data were obtained in 1998 and 2001 via surveys mailed to national random samples of seniors. Of 2,434 deliverable surveys, 946 (39%) were returned, and 700 (29%) provided usable data. Data were collected in 2015 via an online survey sent to a national sample of adults. Of 26,173 usable responses, 3,933 were aged 65 years or older. Descriptive statistics and logistic regression analyses described relationships among study variables.
Results showed that the proportion of seniors without prescription coverage was 9% in 2015, a decrease from 29% in 2001 and 32% in 1998. The proportion of senior citizens reporting financial hardship from medication purchases was 36% in 2015, a rise from 31% in 2001 and 19% in 1998. For those without prescription drug coverage, 34%, 55%, and 49% reported financial hardship in 1998, 2001, and 2015, respectively. For those with drug coverage, 12%, 22%, and 35% reported financial hardship in 1998, 2001, and 2015, respectively.
After implementation of Medicare Part D and the ACA, the proportion of seniors without prescription drug coverage decreased. However, self-reported financial hardship from purchasing medications increased. Senior citizens with prescription drug insurance may be experiencing financial hardship from increasing out-of-pocket costs for insurance premiums, cost sharing, and full-cost obligation for some medications.
Funding was provided by the American Association of Colleges of Pharmacy New Investigator Program, the University of Minnesota Grant-in-Aid of Research Program, and the Peters Endowment for Pharmacy Practice Innovation. The authors have no conflicts of interest to declare. Schommer,
 Mott, and Brown contributed to study design and collected the data, with assistance from Olson. Data interpretation was performed by Olson, Schommer, Mott, and Brown. The manuscript was written and revised by Olson, Schommer, Mott, and Brown.
Azobenzene-contained glycolipids GlyAzoCns, newly structured azobenzene derivatives, which have an azobenzene moiety between the galactosyl and carbon chains of various sizes, have been synthesized. The GlyAzoCns undergo reversible photo-induced isomerization in both ethanol solution (free state) and liposomal bilayer (restricted state) upon irradiation with UV and Vis-light alternately. The drug release of Liposome@Gly induced by isomerization was found to be an instantaneous behavior. The photo-induced control of DOX release from liposome was investigated in various modes. The Liposome@Glys have been found to keep the entrapped DOX stably in dark with less than 10 % leakage in 10 h but release nearly 100 % of cargos instantaneously with UV-irradiation. Molecular structure of GlyAzoCns and property of liposomal bilayer were considered as important factors influencing drug release. Among the synthesized GlyAzoCns, GlyAzoC7 showed to be the most efficient photosensitive actuator for controlling drug release. A lower proportion of cholesterol in Liposome@Glys was conducive to promote the release amount. Results indicated that the synthesized GlyAzoCns could act as a role of smart actuators in the liposome bilayer and control the drug to release temporarily and quantitatively.
Selective localization of biomolecules at the hot spots of a plasmonic nanoparticle is an attractive strategy to exploit the light-matter interaction due to the high field concentration. Current approaches for hot spot targeting are time-consuming and involve prior knowledge of the hot spots. Multiphoton plasmonic lithography is employed to rapidly immobilize bovine serum albumin (BSA) hydrogel at the hot spot tips of a single gold nanotriangle (AuNT). Regioselectivity and quantity control by manipulating the polarization and intensity of the incident laser are also established. Single AuNTs are tracked using dark-field scattering spectroscopy and scanning electron microscopy to characterize the regioselective process. Fluorescence lifetime measurements further confirm BSA immobilization on the AuNTs. Here, the AuNT-BSA hydrogel complexes, in conjunction with single-particle optical monitoring, can act as a framework for understanding light-molecule interactions at the subnanoparticle level and has potential applications in biophotonics, nanomedicine, and life sciences.
Putative human chemosignals have been shown to influence mood states and emotional processing, but the connection between these effects and higher-order cognitive processing is not well established. This study utilized an economic game (Dictator Game) to test whether androstadienone (AND), an odorous compound derived from testosterone, impacts on altruistic behavior. We predicted that the female participants would act more generously in the AND condition, exhibiting a significant interaction effect between gender and AND on Dictator Game contributions. We also expected that the presence of AND should increase the positive mood of the female participants, compared to a control odor condition and also compared to the mood of the male participants. The results confirm our hypotheses: for women the subliminal perception of AND led to larger monetary donations, compared to a control odor, and also increased positive mood. These effects were absent or significantly weaker in men. Our findings highlight the capacity of human putative chemosignals to influence emotions and higher cognitive processes - in particular the processes used in the context of economic decisions - in a gender-specific way.
The perennial grass species that are being developed as biomass feedstock crops harbor extensive genotypic diversity, but the effects of this diversity on biomass production are not well understood. We investigated the effects of genotypic diversity in switchgrass (Panicum virgatum) and big bluestem (Andropogon gerardii) on perennial biomass cropping systems in two experiments conducted over 2008-2014 at a 5.4-ha fertile field site in northeastern Illinois, USA. We varied levels of switchgrass and big bluestem genotypic diversity using various local and nonlocal cultivars - under low or high species diversity, with or without nitrogen inputs - and quantified establishment, biomass yield, and biomass composition. In one experiment ('agronomic trial'), we compared three switchgrass cultivars in monoculture to a switchgrass cultivar mixture and three different species mixtures, with or without N fertilization. In another experiment ('diversity gradient'), we varied diversity levels in switchgrass and big bluestem (1, 2, 4, or 6 cultivars per plot), with one or two species per plot. In both experiments, cultivar mixtures produced yields equivalent to or greater than the best cultivars. In the agronomic trial, the three switchgrass mixture showed the highest production overall, though not significantly different than best cultivar monoculture. In the diversity gradient, genotypic mixtures had one-third higher biomass production than the average monoculture, and none of the monocultures were significantly higher yielding than the average mixture. Year-to-year variation in yields was lowest in the three-cultivar switchgrass mixtures and Cave-In-Rock (the southern Illinois cultivar) and also reduced in the mixture of switchgrass and big bluestem relative to the species monocultures. The effects of genotypic diversity on biomass composition were modest relative to the differences among species and genotypes. Our findings suggest that local genotypes can be included in biomass cropping systems without compromising yields and that genotypic mixtures could help provide high, stable yields of high-quality biomass feedstocks.
Medicinal plants provide indigenous and peasant communities worldwide with means to meet their healthcare needs. Homegardens often act as medicine cabinets, providing easily accessible medicinal plants for household needs. Social structure and social exchanges have been proposed as factors influencing the species diversity that people maintain in their homegardens. Here, we assess the association between the exchange of medicinal knowledge and plant material and medicinal plant richness in homegardens. Using Tsimane' Amazonian homegardens as a case study, we explore whether social organization shapes exchanges of medicinal plant knowledge and medicinal plant material. We also use network centrality measures to evaluate people's location and performance in medicinal plant knowledge and plant material exchange networks. Our results suggest that social organization, specifically kinship and gender relations, influences medicinal plant exchange patterns significantly. Homegardens total and medicinal plant species richness are related to gardeners' centrality in the networks, whereby people with greater centrality maintain greater plant richness. Thus, together with agroecological conditions, social relations among gardeners and the culturally specific social structure seem to be important determinants of plant richness in homegardens. Understanding which factors pattern general species diversity in tropical homegardens, and medicinal plant diversity in particular, can help policy makers, health providers, and local communities to understand better how to promote and preserve medicinal plants in situ. Biocultural approaches that are also gender sensitive offer a culturally appropriate means to reduce the global and local loss of both biological and cultural diversity.
Wnt signalling has been implicated in the regulation of stem cell self-renewal and differentiation; however, the majority of in vitro studies are carried out using monolayer 2D culture techniques. Here, we used mesenchymal stromal cell (MSC) EGFP reporter lines responsive to Wnt pathway activation in a 3D spheroid culture system to mimic better the in vivo environment. Endogenous Wnt signalling was then investigated under basal conditions and when MSCs were induced to undergo osteogenic and adipogenic differentiation. Interestingly, endogenous Wnt signalling was only active during 3D differentiation whereas 2D cultures showed no EGFP expression throughout an extended differentiation time-course. Furthermore, exogenous Wnt signalling in 3D adipogenic conditions inhibited differentiation compared to unstimulated controls. In addition, suppressing Wnt signalling by Dkk-1 restored and facilitated adipogenic differentiation in MSC spheroids. Our findings indicate that endogenous Wnt signalling is active and can be tracked in 3D MSC cultures where it may act as a molecular switch in adipogenesis. The identification of the signalling pathways that regulate MSCs in a 3D in vivo-like environment will advance our understanding of the molecular mechanisms that control MSC fate.
Gene-environment (G×E) interactions play key roles in many complex diseases. An increasing number of epidemiological studies have shown the combined effect of multiple environmental exposures on disease risk. However, no appropriate statistical models have been developed to conduct a rigorous assessment of such combined effects when G×E interactions are considered. In this paper, we propose a partial linear varying multi-index coefficient model (PLVMICM) to assess how multiple environmental factors act jointly to modify individual genetic risk on complex disease. Our model includes the varying-index coefficient model as a special case, where discrete variables are admitted as the linear part. Thus PLVMICM allows one to study nonlinear interaction effects between genes and continuous environments as well as linear interactions
 between genes and discrete environments, simultaneously. We derive a profile method to estimate parametric parameters and a B-spline backfitted kernel method to estimate nonlinear interaction functions. Consistency and asymptotic normality of the parametric and nonparametric estimates are established under some regularity conditions. Hypothesis testing for the parametric coefficients and nonparametric functions are conducted. Results show that the statistics for testing the parametric coefficients and the non-parametric functions asymptotically follow a χ(2)-distribution with different degrees of freedom. The utility of the method is demonstrated through extensive simulations and a case study.
At the end of 2006, a new System for Promotion of Personal Autonomy and Assistance for Persons in a Situation of Dependency (SAAD) was established in Spain through the approval of the Act 39/2006 of 14th December (the Dependency Act, DA). The DA acknowledged the universal entitlement of Spanish citizens to social services. The recent economic crisis added degrees of uncertainty to several dimensions of the SAAD implementation process. Firstly, the political consensus on which its foundation rested upon has weakened. Secondly, implementation of the SAAD was hampered by several challenges that emerged in the context of the economic crisis. Thirdly, the so-called "dependency limbo" (i.e. the existence of a large number of people eligible for benefits but who do not receive them) has become a structural feature of the system. Finally, contrary to the spirit of the DA, monetary benefits have become the norm rather than a last resort. High heterogeneity across regions regarding the number of beneficiaries covered and services provided reveal the existence of regional inequity in access to long-term care services in the country. Broadly, the current evidence on the state of the SAAD suggests the need to improve the quality of governance, to enhance coordination between health and social systems, to increase the system's transparency, to foster citizens' participation in decision-making and to implement a systematic monitoring of the system.
Knockout mice studies implicate the mammalian short-chain fatty acid (SCFA) receptors, FFAR2 and FFAR3- in colitis, arthritis and asthma. However, the correlation with human biology is uncertain. Here, we detected FFAR2 and FFAR3 expression in human monocytes via immunohistochemistry. Upon treatment with acetate SCFA or FFAR2- and FFAR3-specific synthetic agonists, human monocytes displayed elevated p38 phosphorylation and attenuated C5, CCL1, CCL2, GM-CSF, IL-1α, IL-1β and ICAM-1 inflammatory cytokine expression. Acetate and FFAR2 agonist treatment also repressed Akt and ERK2 signalling. Surprisingly, mouse monocytes displayed a distinct response to acetate treatment, elevating GM-CSF, IL-1α, and IL-1β cytokine expression. This effect persisted in FFAR2/3-knockout mouse monocytes and was not reproduced by synthetic agonists, suggesting a FFAR2/3 independent mechanism in mice. Collectively, we show that SCFAs act via FFAR2/3 to modulate human monocyte inflammatory responses- a pathway that is absent in mouse monocytes.
The purpose of this review was to identify the characteristics and consequences of perioperative patient advocacy.
An integrative review method was employed.
A database search to identify peer-reviewed articles that focused on perioperative patient advocacy was conducted in PubMed and CINAHL, followed by a manual search for additional articles. Studies were selected if they reported original empirical research findings with regard to perioperative patient advocacy. The data abstraction and synthesis were achieved with an inductive qualitative content analysis.
The analysis resulted in seven categories, two subthemes, and one main theme. The main theme, "Doing good for another human being-a balancing act between philanthropy and personal gratification," was the core of perioperative patient advocacy.
Perioperative patient advocacy is part of the professional role of the perioperative nurse, and it affects the perioperative nurse emotionally. This advocacy shares similarities with descriptions of patient advocacy in general nursing.
Highly repetitive tandem arrays at the centromeric and pericentromeric regions in chromosomes, previously considered silent, are actively transcribed, particularly in cancer. This aberrant expression occurs even in K-ras-mutated pancreatic intraepithelial neoplasia (PanIN) tissues, which are precancerous lesions. To examine the biological roles of the satellite RNAs in carcinogenesis, we construct mouse PanIN-derived cells expressing major satellite (MajSAT) RNA and show increased malignant properties. We find an increase in frequency of chromosomal instability and point mutations in both genomic and mitochondrial DNA. We identify Y-box binding protein 1 (YBX1) as a protein that binds to MajSAT RNA. MajSAT RNA inhibits the nuclear translocation of YBX1 under stress conditions, thus reducing its DNA-damage repair function. The forced expression of YBX1 significantly decreases the aberrant phenotypes. These findings indicate that during the early stage of cancer development, satellite transcripts may act as 'intrinsic mutagens' by inducing YBX1 dysfunction, which may be crucial in oncogenic processes.
Loneliness and social isolation are emerging health conditions in the elderly population, in particular widows, high frequency users of health services and those with chronic problems and depression. Loneliness is the subjective feeling of having less affection and closeness than that desired in the intimate or relational field. Social isolation is an objective situation of having minimal contact with other people. Its contribution to increased morbidity and mortality is comparable to other well known risk factors that we deal with daily as Primary Care teams. Strategies to identify these problems in our patients and to perform scientific evidence based studies at individual and community level in cooperation with other community resources and interventions are discussed. The Primary Care team must promote the autonomy of these patients, facilitating their sociability, and act on their social maladaptive thoughts that hinder their social integration.
Staphylococcus aureus (S. aureus) is a common Gram-positive bacterium that causes serious infections in human and animals. With the continuous emergence of the methicillin-resistant S. aureus (MRSA) strains, antibiotics have limited efficacy in treating MRSA infections. Accordingly, novel agents that act on new targets are desperately needed to combat these infections. S. aureus alpha-hemolysin plays an indispensable role in its pathogenicity. In this study, we demonstrate that sclareol, a fragrant chemical compound found in clary sage, can prominently decrease alpha-hemolysin secretion in S. aureus strain USA300 at sub-inhibitory concentrations. Hemolysis assays, western-blotting and RT-PCR were used to detect the production of alpha-hemolysin in the culture supernatant. When USA300 was co-cultured with and A549 epithelial cells, sclareol could protect A549 cells at a final concentration of 8 µg/ml. The protective capability of sclareol against the USA300-mediated injury of A549 cells was further shown by cytotoxicity assays and live/dead analysis. In conclusion, sclareol was shown to inhibit the production of S. aureus alpha-hemolysin. Sclareol has potential for development as a new agent to treat S. aureus infections.
This work describes the first observations of the ionisation of neon in a metastable atomic state utilising a strong-field, few-cycle light pulse. We compare the observations to theoretical predictions based on the Ammosov-Delone-Krainov (ADK) theory and a solution to the time-dependent Schrödinger equation (TDSE). The TDSE provides better agreement with the experimental data than the ADK theory. We optically pump the target atomic species and measure the ionisation rate as the a function of different steady-state populations in the fine structure of the target state which shows significant ionisation rate dependence on populations of spin-polarised states. The physical mechanism for this effect is unknown.
The purely aqueous system of phospholipase D (PLD)-mediated transphosphatidylation using pre-existing carriers for the adsorption of phosphatidylcholine (PC) to act as an "artificial interface" was introduced to replace the liquid-liquid system. Toxic organic solvents are avoided during the reaction, and the free enzyme can be simply reused by centrifugation. Special attention has been paid to the effect of the pore diameter and surface area of silica gel 60H covered with PC molecules on the yield of phosphatidylserine (PS). Results indicated that the highest PS yield of 99.5% was achieved. Moreover, 73.6% of the yield of PS was obtained after being used for six batches. This is the first description of the remarkably high reusability of free enzymes for enzymatic synthesis of PS as well. The excellent results make the aqueous-solid system more promising candidates for the industrial production of PS.
The Netherlands has established a high quality system of child health care based on a unique standardized digital preventive child health program underpinned by legislation. Stringent assessment of the implementation of the new Youth Act is needed to fulfill the United Nations' child rights to health. The impact of national child health care systems on the well-being of children with long-term conditions should be evaluated by using international (World Health Organization) comparable coding to document the benefit of preventive child health care programs and their outcomes.
The flavoenzyme DprE1 catalyses a crucial step in arabinan production for cell wall biosynthesis in Mycobacterium tuberculosis
 and is a highly vulnerable drug target. It was first discovered using benzothiazinones (BTZ): exquisitely potent bactericidal agents that are being developed as drugs to treat tuberculosis. Subsequently, many compounds with diverse scaffolds were found to act as either covalent or noncovalent DprE1 inhibitors. Covalent inhibitors, like the BTZ, are all nitroaromatic compounds that serve as suicide substrates after DprE1-mediated nitroreduction. Here, we describe how high-resolution structures of DprE1, alone and in complex with various ligands, explain enzyme activity and inhibition.
Safeguarding is about the protection of the most vulnerable people in our society. This article presents a case history of the author's experience of a patient with a colostomy and high-output abdominal fistula, who was involved in a safeguarding alert. It explores the roles and responsibilities of nurses, regardless of specialty, to increase their awareness, understanding and knowledge of safeguarding, and the processes in place to protect the most vulnerable people they care for.
We previously showed that prepubertal chronic caffeine exposure adversely affected the development of the testes in male rats. Here we investigated dose- and time-related effects of caffeine consumption on the testis throughout sexual maturation in prepubertal rats. A total of 80 male SD rats were randomly divided into four groups: controls and rats fed 20, 60, or 120 mg caffeine/kg/day, respectively, via gavage for 10, 20, 30, or 40 days. Preputial separation was monitored daily before the rats were sacrificed. Terminal blood samples were collected for hormone assay, and testes were grossly evaluated and weighed. One testis was processed for histological analysis, and the other was collected to isolate Leydig cells. Caffeine exposure significantly increased the relative weight of the testis in a dose-related manner after 30 days of exposure, whereas the absolute testis weight tended to decrease at the 120-mg dose of caffeine. The mean diameter of the seminiferous tubules and height of the germinal epithelium significantly decreased in the caffeine-fed groups after 40 days of caffeine exposure, which was accompanied by a reduced BrdU incorporation rate in germ cells. In addition, caffeine intake significantly reduced in vivo and ex vivo testosterone production in a dose-related manner. Our results demonstrate that caffeine exposure during sexual maturation alter the testicular microarchitecture and also slow germ cell proliferation even at the 20-mg dose level. Furthermore, caffeine may act directly on Leydig cells and interfere with testosterone production in a dose-related manner, consequently delaying onset of sexual maturation.
There is increasing recognition that organisations, particularly in key infrastructure sectors, are potentially vulnerable to climate change and extreme weather events, and require organisational responses to ensure they are resilient and adaptive. However, detailed evidence of how adaptation is facilitated, implemented and reported, particularly through legislative mechanisms is lacking. The United Kingdom Climate Change Act (2008), introduced the Adaptation Reporting Power, enabling the Government to direct so-called reporting authorities to report their climate change risks and adaptation plans. We describe the authors' unique role and experience supporting the Department for Environment, Food and Rural Affairs (Defra) during the Adaptation Reporting Power's first round. An evaluation framework, used to review the adaptation reports, is presented alongside evidence on how the process provides new insights into adaptation activities and triggered organisational change in 78% of reporting authorities, including the embedding of climate risk and adaptation issues. The role of legislative mechanisms and risk-based approaches in driving and delivering adaptation is discussed alongside future research needs, including the development of organisational maturity models to determine resilient and well adapting organisations. The Adaptation Reporting Power process provides a basis for similar initiatives in other countries, although a clear engagement strategy to ensure buy-in to the process and research on its long-term legacy, including the potential merits of voluntary approaches, is required.
There is accumulating evidence that the emerging burden of global climate change threatens the fidelity of routine indicators for disease detection and management of risks to public health. The threat partially reflects the conservative character of the health sector and the reluctance to adopt new indicators, despite the growing awareness that existing environmental health indicators were developed to respond to risks that may no longer be relevant, and are too simplistic to also act as indicators for newer global-scale risk factors. This study sought to understand the scope of existing health indicators, while aiming to discover new indicators for building resilience against three climate sensitive diseases (cerebro spinal meningitis, malaria and diarrhea). Therefore, new potential indicators derived from human and biophysical origins were developed to complement existing health indicators, thereby creating climate-sensitive battery of robust composite indices of resilience in health planning. Using Ghana's health sector as a case study systematic international literature review, national expert consultation, and focus group outcomes yielded insights into the relevance, sensitivity and impacts of 45 indicators in 11 categories in responding to climate change. In total, 65% of the indicators were sensitive to health impacts of climate change; 24% acted directly; 31% synergistically; and 45% indirectly, with indicator relevance strongly associated with type of health response. Epidemiological indicators (e.g. morbidity) and health demographic indicators (e.g. population structure) require adjustments with external indicators (e.g. biophysical, policy) to be resilient to climate change. Therefore, selective integration of social and ecological indicators with existing public health indicators improves the fidelity of the health sector to adopt more robust planning of interdependent systems to build resilience. The study highlights growing uncertainties in translating research into protective policies when new indicators associated with non-health sources are needed to complement existing health indicators that are expected to respond to climate change.
Metal chelates strongly influence the nature and magnitude of pharmacological activities in flavonoids. In recent years, studies have shown that a promising class of flavanone-metal ion complexes can act as selective cholinesterase inhibitors (ChEIs), which has led our group to synthesize a new series of flavanone derivatives (hesperidin, hesperetin, naringin, and naringenin) complexed to either copper (II) or zinc (II) and to evaluate their potential use as selective ChEIs. Most of the synthesized complexes exhibited greater inhibitory activity against acetylcholinesterase (AChE) than against butyrylcholinesterase (BChE). Nine of these complexes constituted potent, reversible, and selective ChEIs with inhibitory potency (IC50) and inhibitory constant (Ki) ranging from 0.02 to 4.5μM. Copper complexes with flavanone-bipyridine derivatives afforded the best inhibitory activity against AChE and BChE. The complex Cu(naringin)(2,2'-bipyridine) (11) gave IC50 and Ki values of 0.012±0.002 and 0.07±0.01μM for huAChE, respectively, which were lower than the inhibitory values obtained for standard galanthamine (IC50=206±30.0 and Ki=126±18.0μM). Evaluation of the inhibitory activity of this complex against butyrylcholinesterase from human serum (huBChE) gave IC50 and Ki values of 8.0±1.4 and 2.0±0.1μM, respectively. A Liquid Chromatography-Immobilized Capillary Enzyme Reactor by UV detection (LC-ICER-UV) assay allowed us to determine the IC50 and Ki values and the type of mechanism for the best inhibitors.
Unilateral peripheral nerve chronic constriction injury (CCI) has been widely used as a research model of human neuropathic pain. Recently, CCI has been shown to induce spinal cord adult neurogenesis, which may contribute to the chronic increase in nociceptive sensitivity. Here, we show that CCI also induces rapid and profound asymmetrical anatomical rearrangements in the adult rodent cerebellum and pons. This remodelling occurs throughout the hindbrain, and in addition to regions involved in pain processing, also affects other sensory modalities. We demonstrate that these anatomical changes, partially reversible in the long term, result from adult neurogenesis. Neurogenic markers Mash1, Ngn2, doublecortin and Notch3 are widely expressed in the rodent cerebellum and pons, both under normal and injured conditions. CCI-induced hindbrain structural plasticity is absent in Notch3 knockout mice, a strain with impaired neuronal differentiation, demonstrating its dependence on adult neurogenesis. Grey matter and white matter structural changes in human brain, as a result of pain, injury or learned behaviours have been previously detected using non-invasive neuroimaging techniques. Because neurogenesis-mediated structural plasticity is thought to be restricted to the hippocampus and the subventricular zone, such anatomical rearrangements in other parts of the brain have been thought to result from neuronal plasticity or glial hypertrophy. Our findings suggest the presence of extensive neurogenesis-based structural plasticity in the adult mammalian brain, which may maintain a memory of basal sensory levels, and act as an adaptive mechanism to changes in sensory inputs.
The continued growth in world population necessitates increases in both the quantity and quality of agricultural production. Triticeae members, particularly
 wheat and barley, make an important contribution to world food reserves by providing rich sources of carbohydrate and protein. These crops are grown over diverse production environments that are characterized by a range of environmental or abiotic stresses. Abiotic stresses such as drought, heat, salinity, or nutrient deficiencies and toxicities cause large yield losses resulting in economic and environmental damage. The negative effects of abiotic stresses have increased at an alarming rate in recent years and are predicted to further deteriorate due to climate change, land degradation, and declining water supply. New technologies have provided an important tool with great potential for improving crop tolerance to the abiotic stresses: microRNAs (miRNAs). miRNAs are small regulators of gene expression that act on many different molecular and biochemical processes such as development, environmental adaptation, and stress tolerance. miRNAs can act at both the transcriptional and post-transcriptional levels, although post-transcriptional regulation is the most common in plants where miRNAs can inhibit the translation of their mRNA targets via complementary binding and cleavage. To date, expression of several miRNA families such as miR156, miR159, and miR398 has been detected as responsive to environmental conditions to regulate stress-associated molecular mechanisms individually and/or together with their various miRNA partners. Manipulation of these miRNAs and their targets may pave the way to improve crop performance under several abiotic stresses. Here, we summarize the current status of our knowledge on abiotic stress-associated miRNAs in members of the Triticeae tribe, specifically in wheat and barley, and the miRNA-based regulatory mechanisms triggered by stress conditions. Exploration of further miRNA families together with their functions under stress will improve our knowledge and provide opportunities to enhance plant performance to help us meet global food demand.
With the implementation of the Patient Protection and Affordable Care Act, cost-effectiveness analyses are becoming increasingly important for resource allocation, and particularly for the justification of costly procedures, such as total knee and total hip arthroplasties (TKAs and THAs). Therefore, using the Short Form-6D (SF-6D) utility values, the purpose of this study was to determine (1) the quality-adjusted life years (QALYs) gained and (2) and the cost-effectiveness of undergoing THA and TKA.
A total of 844 patients (357 men, 487 women) who had a mean age of 65 years (range, 39 to 80 years) underwent primary TKA, and 224 patients who had a mean age of 69 years (range, 44 to 88 years) underwent primary THAs at 7 institutions. The SF-6D values were derived for each patient preoperatively and at 1-year follow-up. QALYs were estimated at 1 year, and lifetime QALYs gained were determined using predicted life-expectancy values, at a discounted rate of 3% per year of life expectancy, to reflect a diminishing gain with time. National-level costs were determined using the 2011 Nationwide Inpatient Sample, and incremental cost-effectiveness ratios (ICER) were deduced for both groups.
The preoperative SF-6D values for the THA and TKA cohorts were 0.614 (range, 0.37 to 1) and 0.62 (range, 0.3 to 0.93). Postoperatively, SF-6D values improved significantly at 1 year in both groups. One-year QALYs for TKA and THA were 0.768 and 0.799. Lifetime QALYs gained for the groups were 2.07 and 1.85 (1.39 and 1.34 if discounted at a rate of 3% per year). The estimated ICER for TKA vs baseline presurgery was $43,107 per QALY, and $39,453 per QALY for THA vs baseline presurgery.
The ICER showed that THA and TKA are cost-effective, compared to the $50,000 USD/QALY threshold for cost-effectiveness, and justify resources allocated to these surgeries. The SF-6D can utilize existing functional outcome data, which makes these cost calculations considerably easier and more feasible for practicing orthopedists.
5-HT3 receptor antagonists play a key role in the management of psychiatric disorders such as, depression and anxiety. They may act through modulation of serotonergic transmission. In the present study, a novel and potential 5-HT3 receptor antagonist, 6g (4-benzylpiperazin-1-yl)(3-methoxyquinoxalin-2-yl) methanone, which exhibited good log P (3.08) and pA2 (7.5) values was screened for its anxiolytic property in lipopolysaccharide (LPS) induced anxiety models.
LPS, an endotoxin, present in the cell wall of Gram negative bacteria was injected 0.83 mg/kg, i.p. as a single dose to induce anxiety-like symptoms in mice. Compound 6g (1 and 2 mg/kg, p.o.) and standard fluoxetine (FLX) (20 mg/kg, p.o.) were injected to treatment groups for 7 days and evaluated in various behavioral paradigms such as elevated plus maze (EPM), light and dark (L/D) test, and open field test (OFT). Their effects on serotonin levels in mice brain were also examined.
The results showed that LPS induced anxiety-like symptoms in mice, as indicated by a significantly decreased percentage open arm entries and percentage time spent in open arms in EPM; decreased time spent in light area and number of transition between chambers in L/D test; decreased ambulation and rearing scores in OFT. Compound 6g (1 and 2 mg/kg, p.o., 7 days) and FLX treatment (20 mg/kg, p.o., 7 days) reversed the LPS-induced behavioral changes and significantly affected all the behavioral parameters mentioned above. In addition 6g (1 and 2 mg/kg, p.o., 7 days) and FLX treatment (20 mg/kg, p.o., 7 days) increased the levels of serotonin in mice brain.
Compound 6g produced anxiolytic-like effects in various anxiety paradigms in LPS-treated mice as well as restored the decreased serotonin levels in mice brain.
Phyllosticta citricarpa is the epidemiological agent of Citrus Black Spot (CBS) disease, which is responsible for large economic losses worldwide. CBS is characterized by the presence of spores (pycnidiospores) in dark lesions of fruit, which are also responsible for short distance dispersal of the disease. The identification of genes involved in asexual reproduction of P. citricarpa can be an alternative for directional disease control. We analyzed a library of mutants obtained through Agrobacterium tumefaciens transformation system, looking for alterations in growth and reproductive structure formation. Two mutant strains were found to have lost the ability to form pycnidia. The flanking T-DNA insertion regions were identified on P. citricarpa genome by using blast analysis and further gene prediction. The predicted genes containing the T-DNA insertions were identified as Spindle Poison Sensitivity Scp3, Ion Transport protein, and Cullin Binding proteins. The Ion Transport and Cullin Binding proteins are known to be correlated with sexual and asexual reproduction in fungi; however, the exact mechanism by which these proteins act on spore formation in P. citricarpa needs to be better characterized. The Scp3 proteins are suggested here for the first time as being associated with asexual reproduction in fungus. This protein is associated with microtubule formation, and as microtubules play an essential role as spindle machinery for chromosome segregation and cytokinesis, insertions in this gene can lead to abnormal formations, such as that observed here in P. citricarpa. We suggest these genes as new targets for fungicide development and CBS disease control, by iRNA.
Pseudomonas aeruginosa ATCC 27853 and Pseudomonas sp. 593 use the phosphatidylcholine synthase pathway (Pcs-pathway) for the biosynthesis of phosphatidylcholine (PC). Both bacterial strains contain the phoA and lapA genes encoding alkaline phosphatases (ALP) and display strong ALP activities. The PhoA and LapA enzymes are thought to be independently secreted via the Xcp and Hxc type II secretion system (T2SS) subtypes, in which the Hxc system may act as a complementary mechanism when the Xcp pathway becomes limiting. Inactivation of the pcs gene in both bacteria abolished PC synthesis and resulted in approximately 50% less ALP activity in the cell-free culture. Analysis by western blotting showed that LapA protein content in the wild type and the pcs- mutant was unchanged in the cytoplasmic, periplasmic or extracellular protein fractions. In contrast, the PhoA protein in the pcs- mutant was less prevalent among extracellular proteins but was more abundant in the periplasmic protein fraction compared to the wild type. Semi- quantitative reverse transcriptase PCR showed that phoA, lapA and 12 xcp genes were equally expressed at the transcriptional level in both the wild types and the pcs- mutants. Our results demonstrate that the absence of PC in bacterial membrane phospholipids does not interfere with the transcription of the phoA and lapA genes but primarily affects the export of PhoA from the cytoplasm to the extracellular environment via the Xcp T2SS.
We have coupled gold nanoparticles (AuNPs) with silver nanoparticles (AgNPs) to assemble a plasmonic sensing platform for colorimetric detection of glucose. In this system, small AuNPs (~4nm) can act as glucose oxidase (GOD) mimic enzyme to catalytically oxidize glucose in the presence of oxygen, producing hydrogen peroxide, which dissolves AgNPs to lead the color changes. Glucose can be detected not only by naked eyes (from yellow to red) but also by spectrophotometer in the concentration range of 5-70μM, with detection limit of 3μM. More importantly, we found that l-cysteine added in the system can markedly improve the selectivity for the detection of glucose. The proposed method was used to application for the detection of glucose in human serum with satisfactory results. This system is simple and low cost without using any enzymes and organic chromogenic agents.
Formation of the G-quadruplex in the human telomeric
 DNA is an effective way to inhibit telomerase activity. Therefore, screening ligands of G-quadruplex has potential applications in the treatment of cancer by inhibit telomerase activity. Although several techniques have been explored for screening of telomeric G-quadruplexes ligands, high-throughput screening method for fast screening telomere-binding ligands from the large compound library is still urgently needed. Herein, a label-free fluorescence strategy has been proposed for high-throughput screening telomere-binding ligands by using DNA-copper nanoparticles (DNA-CuNPs) as a signal probe. In the absence of ligands, human telomeric DNA (GDNA) hybridized with its complementary DNA (cDNA) to form double stranded DNA (dsDNA) which can act as an efficient template for the formation of DNA-CuNPs, leading to the high fluorescence of DNA-CuNPs. In the presence of ligands, GDNA folded into G-quadruplex. Single-strdanded cDNA does not support the formation of DNA-CuNP, resulting in low fluorescence of DNA-CuNPs. Therefore, telomere-binding ligands can be high-throughput screened by monitoring the change in the fluorescence of DNA-CuNPs. Thirteen traditional chinese medicines were screened. Circular dichroism (CD) measurements demonstrated that the selected ligands could induce single-stranded telomeric DNA to form G-quadruplex. The telomere repeat amplification protocol (TRAP) assay demonstrated that the selected ligands can effectively inhibit telomerase activity. Therefore, it offers a cost-effective, label-free and reliable high-throughput way to identify G-quadruplex ligands, which holds great potential in discovering telomerase-targeted anticancer drugs.
The Centers for Medicare and Medicaid Services (CMS) defines "adverse quality events" as the incidence of certain complications such as postsurgical hematoma or iatrogenic pneumothorax during an inpatient stay. Patient safety indicators (PSI) are a means to measure the incidence of these adverse events. When adverse events occur, reimbursement to the hospital decreases. The incidence of adverse quality events among patients hospitalized for primary spinal neoplasms is unknown. Similarly, it is unclear what the impact of insurance status is on adverse care quality among this patient population.
We aimed to determine the incidence of PSI among patients admitted with primary spinal neoplasms, and to determine the association between insurance status and the incidence of PSI in this population.
This is a retrospective cohort study.
We included all patients, 18 years and older, in the Nationwide Inpatient Sample (NIS) who were hospitalized for primary spine neoplasms from 1998 to 2011.
Incidence of PSI from 1998 to 2011 served as outcome variable.
The NIS was queried for all hospitalizations with a diagnosis of primary spinal neoplasm during the inpatient episode from 1998 to 2011. Incidence of PSI was determined using publicly available lists of International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM) diagnosis codes. Logistic regression models were used to determine the effect of primary payer status on PSI incidence. All comparisons were made between privately insured patients and Medicaid or self-pay patients.
We identified 6,095 hospitalizations in which a primary spinal neoplasm was recorded during the inpatient episode. We excluded patients younger than 18 years and those with "other" or "missing" primary insurance status, leaving 5,880 patients for analysis. After adjusting for patient demographics and hospital characteristics, Medicaid or self-pay patients had significantly greater odds of experiencing one or more PSI (odds ratio [OR] 1.81 95% confidence interval [CI] 1.11-2.95) relative to privately insured patients.
Among patients hospitalized for primary spinal neoplasms, primary payer status predicts the incidence of PSI, an indicator of adverse health-care quality used to determine hospital reimbursement by the CMS. As reimbursement continues to be intertwined with reportable quality metrics, identifying vulnerable populations is critical to improving patient care.
Under the Sunshine Act, pharmaceutical and product industry payments to physicians are reported in a public database. We sought to characterize payments received by pediatricians in the first full year of disclosures in 2014. We used the National Centers for Medicare and Medicaid Services Open Payment files to identify pediatricians who received payments. Payment characteristics were stratified, and descriptive statistical analysis was performed, including mean, median, and ranges of payments. Between January 1, 2014, and December 31, 2014, 35 697 pediatricians received payments amounting to $30 031 960. General pediatricians received the majority of payments (71%). Median payment was $15 (interquartile range = $12-$24), mostly in the form of noncash items and services (84%). Significant diversity was observed in median payments among specialty providers. In conclusion, 42% of US pediatricians received industry payments in 2014. These data provide a foundation for future research regarding the influence of the Sunshine Act on pediatric clinical practices.
Regional flood risk caused by intensive rainfall under extreme climate conditions has increasingly attracted global attention. Mapping and evaluation of flood hazard are vital parts in flood risk assessment. This study develops an integrated framework for estimating spatial likelihood of flood hazard by coupling weighted naïve Bayes (WNB), geographic information system, and remote sensing. The north part of Fitzroy River Basin in Queensland, Australia, was selected as a case study site. The environmental indices, including extreme rainfall, evapotranspiration, net-water index, soil water retention, elevation, slope, drainage proximity, and density, were generated from spatial data representing climate, soil, vegetation, hydrology, and topography. These indices were weighted using the statistics-based entropy method. The weighted indices were input into the WNB-based model to delineate a regional flood risk map that indicates the likelihood of flood occurrence. The resultant map was validated by the maximum inundation extent extracted from moderate resolution imaging spectroradiometer (MODIS) imagery. The evaluation results, including mapping and evaluation of the distribution of flood hazard, are helpful in guiding flood inundation disaster responses for the region. The novel approach presented consists of weighted grid data, image-based sampling and validation, cell-by-cell probability inferring and spatial mapping. It is superior to an existing spatial naive Bayes (NB) method for regional flood hazard assessment. It can also be extended to other likelihood-related environmental hazard studies.
Non-small cell lung cancer (NSCLC) has become the leading cause of cancer-related deaths. It is therefore urgent that we identify new molecular targets to help cure NSCLC patients. Here, we identified ZIC5 as a potential novel oncogene.
We detected the expression of ZIC5 in tumor and normal tissues of NSCLC patients using quantitative real-time PCR and explored its clinical appearance. We then knocked down ZIC5 to observe changes in NSCLC cell proliferation and metastasis. Nude mouse xenograft models were established to measure ZIC5's function in vivo.
Our results revealed that ZIC5 was expressed at dramatically higher levels in NSCLC tumor tissues than in normal tissues. High levels of ZIC5 expression were associated with a higher primary tumor grade. ZIC5 expression was significantly inhibited by small interfering RNA. After silencing ZIC5, the metastatic capacity of NSCLC cells was clearly lower. Knocking down ZIC5 significantly inhibited the proliferation of NSCLC cells, causing the cell cycle to be arrested in G2 phase. Xenograft tumor models showed that knocking down ZIC5 also inhibited tumor growth in vivo. Q-PCR and western blot analysis revealed that ZIC5 expression was closely associated with CCNB1 and CDK1 complex expression, while other cell cycle-related genes showed no significant correlation with ZIC5.
Our experiment show that ZIC5 is highly upregulated in NSCLC tumor tissues and suggest that ZIC5 may act as an oncogene by influencing CCNB1 and CDK1 complex expression. ZIC5 may therefore be a potential biomarker and therapeutic target for NSCLC patients.
Although guidelines do not recommend adjuvant chemotherapy (ACT) for stage II colon cancer, many state that ACT may be considered in high-risk disease. Here we describe practice patterns and outcomes associated with ACT in the general population.
All cases of colon cancer diagnosed in Ontario 2002-2008 were identified using the Ontario Cancer Registry, which was linked to electronic treatment records. Pathology reports were obtained for a 25% random sample of cases. High-risk disease was defined as: T4 tumours, <12 lymph nodes, poorly differentiated histology, lymphovascular invasion. Modified Poisson regression was used to evaluate factors associated with ACT. The Cox proportional hazards model was used to explore the association between ACT and cancer-specific (CSS) and overall survival.
The study population included 2488 patients with stage II colon cancer; 1175 (47%) with high-risk disease. ACT was delivered to 18% of all patients and 24% of patients with high-risk disease. ACT rates were higher among younger patients (51% age 20-49 years versus 16% age 70-79, P < 0.001) and varied considerably across geographic regions (range 10-39%, P < 0.001). Among all patients with stage II colon cancer, ACT was not associated with improved CSS (hazard ratio 1.41, 95% confidence interval 1.09-1.82) or overall survival (hazard ratio 1.16, 95% confidence interval 0.94-1.42). Stratified survival analysis for patients with high-risk disease did not show benefit to
 ACT (CSS hazard ratio 1.14, 95% confidence interval 0.84-1.55; overall survival hazard ratio 1.02, 95% confidence interval 0.79-1.31).
ACT use varies across age groups and geographic regions. ACT is not associated with improved survival among patients with stage II colon cancer including those with high-risk disease.
Ethical culture construction is beneficial to maximize policy following behavior (PFB) and avoid accidents of coal miners in an economic downturn. This paper examines the congruence between coal mine ethical culture values (ECVs) and miners' moral values (MVs) and the relationship with PFB. To shed light on this relationship, supervisor moral values (SMVs) act as a key moderator. We build on the initial structure of values to measure ECVs, MVs, and SMVs. At the same time, available congruence was defined to describe the relationship between the two values. Drawing upon a survey of 267 miners in Chinese large state-owned coal mining enterprises, results revealed that ECVs-MVs congruence had a linear relationship with intrinsic PFB (IPFB) and a non-linear relationship with extrinsic PFB. These findings demonstrate that SMVs had a moderating effect on the relationship between ECVs-MVs congruence and extrinsic PFB. Thus, we continued to calculate the available congruence scope in tested enterprises. Furthermore, this study gives relative management proposals and suggestions to improve miners' moral standards and to reduce coal mine accidents.
Most studies of infectious diseases in East African cattle have concentrated on gastro-intestinal parasites and vector-borne diseases. As a result, relatively little is known about viral diseases, except for those that are clinically symptomatic or which affect international trade such as foot and mouth disease, bluetongue and epizootic haemorrhagic disease. Here, we investigate the seroprevalence, distribution and relationship between the viruses involved in respiratory disease, infectious bovine rhinotracheitis virus (IBR), bovine parainfluenza virus Type 3 (PIV3) and bovine viral diarrhoea virus (BVDV) in East African Shorthorn Zebu calves. These viruses contribute to the bovine respiratory disease complex (BRD) which is responsible for major economic losses in cattle from intensive farming systems as a result of pneumonia. We found that calves experience similar risks of infection for IBR, PIV3, and BVDV with a seroprevalence of 20.9%, 20.1% and 19.8% respectively. We confirm that positive associations exist between IBR, PIV3 and BVDV; being seropositive for any one of these three viruses means that an individual is more likely to be seropositive for the other two viruses than expected by chance.
Orf virus (ORFV) causes contagious ecthyma, a non-systemic skin disease in sheep and goat. Bioinformatics analysis showed that ORFV125 has Bcl-2-like homologous domain and 3D structurally, it is generally known that Bcl-2 protein is known to be a key protein to control cell apoptosis. Maybe ORFV125 act as a Bcl-2-like manner to control cell apoptosis, but its exact function isn't very clear. So in this study, we use yeast two-hybrid system to identity the putative host cell protein interacting partners of ORFV125, and meanwhile using the data obtained from the Gene Ontology, Uniprot, and Kyoto Encyclopedia of Genes and Genomes databases to analysis the functions and pathways associated with them. Finally, five host proteins were shown to be interacted with ORFV125, including cytochrome b (cytb) gene, GUCY2C, BIRC5, GTF3C6 and SERBP1, we also found that BIRC5 has complex biological functions, can inhibit apoptosis, promote cell transformation and are involved in mitosis, and the interaction network of BIRC5 and ORFV125 were constructed. These findings provide a foundation to better understand the biology of the interactions between ORFV125 and the host proteins with which it directly interacts with and resultant downstream events.
Common health problems observed during peripartum include milk fever, mastitis, fatty liver disease, ketosis, dystocia, retained placenta, metritis, hypomagnesaemia and abomasal displacements. The increased incidence of health problems observed during the periparturient period can be partly attributed to suboptimal immune responses. Factors contributing to decreased periparturient immunity include the act of parturition itself, impaired leukocytic activity, effects of colostrogenesis and lactogenesis, and associated hypocalcemia and negative energy balance. Nutritional and other management strategies represent a relevant short-term strategy aimed at improving the health and welfare of the transitioning cow. Additionally, it is important to consider improving the health of dairy herds through the genetic selection of animals with enhanced robustness by identifying those with superior disease resistance or resilience in the face of infection. As a consequence these animals are better able to cope with the production and environmental stresses. These may provide long-term selection strategies for improving the health and welfare of the transitioning cow particularly when combined with sound management practices, allowing dairy cattle to reach their full genetic potential.
The acquisition of reproductive competence is organized and activated by steroid hormones acting upon the hypothalamus during critical windows of development. This review describes the potential role of epigenetic processes, particularly DNA methylation, in the regulation of sexual differentiation of the hypothalamus by hormones. We examine disruption of these processes by endocrine-disrupting chemicals (EDCs) in an age-, sex-, and region-specific manner, focusing on how perinatal EDCs act through epigenetic mechanisms to reprogram DNA methylation and sex steroid hormone receptor expression throughout life. These receptors are necessary for brain sexual differentiation and their altered expression may underlie disrupted reproductive physiology and behavior. Finally, we review the literature on histone modifications and non-coding RNA involvement in brain sexual differentiation and their perturbation by EDCs. By putting these data into a sex and developmental context we conclude that perinatal EDC exposure alters the developmental trajectory of reproductive neuroendocrine systems in a sex-specific manner.
We study changes in crop cover under future climate and socio-economic projections. This study is not only organised around the global and regional adaptation or vulnerability to climate change but also includes the influence of projected changes in socio-economic, technological and biophysical drivers, especially regional gross domestic product. The climatic data are obtained from simulations of RCP4.5 and 8.5 by four global circulation models/earth system models from 2000 to 2100. We use Random Forest, an empirical statistical model, to project the future crop cover. Our results show that, at the global scale, increases and decreases in crop cover cancel each other out. Crop cover in the Northern Hemisphere is projected to be impacted more by future climate than the in Southern Hemisphere because of the disparity in the warming rate and precipitation patterns between the two Hemispheres. We found that crop cover in temperate regions is projected to decrease more than in tropical regions. We identified regions of concern and opportunities for climate change adaptation and investment.
Patients with pancreatic carcinoma have a grim prognosis. Here, we examine the induction of an in vitro antibody response of human B cells to pancreatic carcinoma antigens.
Cells of five cultured pancreatic ductal adenocarcinoma lines were lysed and their plasma membrane fragments isolated in an aqueous two-phase-system. The plasma membrane fragments were then added to cultures of isolated peripheral blood mononuclear cells from healthy volunteers for 14 days to act as a tumor antigen. Also, we added combinations of IL-2, IL-4, IL-21, anti-CD40 mAb and varying protein concentrations of the plasma membrane fragments to these cultures. We then tested characteristics and binding of resulting IgG and IgM against aforementioned tumor plasma membrane fragments and their respective cells using ELISAs.
The combination of IL-2, IL-4 and anti-CD40 mAb elicited IgM production showing significant binding (p<0.05) to plasma membrane fragments. PANC-1 antigen and the combination of IL-4, IL-21 and anti-CD40 mAb was able to produce a significant and specific IgG formation against PANC-1 plasma membrane fragments (p<0.05). Tumor antigen, interleukins and anti-CD40 mAb had a significant impact on the binding capacity of these antibodies (p<0.05). IgG binding pancreatic carcinoma cells was observed when the tumor antigen concentration was increased during stimulation (p<0.05). BxPC3 plasma membrane fragments showed inhibitory effects on IgG binding BxPC3 antigens (p<0.05).
A human anti-tumor antibody formation can be induced in vitro using PANC-1 antigens and B cell stimulating agents. This response has the potential to generate antibodies specific to PANC-1 antigens. PRéCIS: The concept presented is novel and a promising approach to eliciting a specific B cell response to tumor antigen. The method may prove useful in understanding and developing anti-tumor immunity.
Multimorbidity has been recognized as a major public health issue, negatively affecting health-related quality of life, including physical, functional, mental, emotional, and social domains, as well as increasing health care utilization. This exploratory study examines selected health outcomes associated with multimorbidity across older age groups/cohorts and gender, comparing Canada and Australia.
Data were drawn from the 2008/09 Canadian Community Health Survey and the 2009 Australian HILDA survey. Seven major chronic conditions were identical across
 the two data sets, and were combined into an additive measure of multimorbidity. OLS and logistic regression models were performed within age group (45-54, 55-64, 65-74, 75+) and gender to estimate associations between multimorbidity and several health-related outcomes, including: loneliness, life satisfaction, perceived health, mobility restriction, and hospital stays, adjusting for marital status, education and foreign born status.
Overall, country-level differences were identified for perceptions of loneliness, life satisfaction, and perceived health. Australians tended to experience a greater risk of loneliness and lower self-rated health in the face of multimorbidity than Canadians, especially among older men. Canadians tended to experience lower life satisfaction associated with multimorbidity than Australians. No country-level differences were identified for associations between multimorbidity and hospital stays or mobility limitations.
The associations between multimorbidity and health are similar between the two countries but are variable depending on population, age group/cohort, and gender. The strongest country-level associations are for indicators of health-related quality of life, rather than health care or mobility limitation outcomes.
As implementation of the US Affordable Care Act (ACA) advances, many domestic health systems are considering major changes in how the healthcare workforce is organized. The purpose of this study is to explore the dynamic processes and interactions by which workforce planning and development (WFPD) is evolving in this new environment.
Informed by the theory of loosely coupled systems (LCS), we use a case study design to examine how workforce changes are being managed in Kaiser Permanente and Montefiore Health System. We conducted site visits with in-depth interviews with 8 to 10 stakeholders in each organization.
Both systems demonstrate a concern for the impact of change on their workforce and have made commitments to avoid outsourcing and layoffs. Central workforce planning mechanisms have been replaced with strategies to integrate various stakeholders and units in alignment with strategic growth plans. Features of this new approach include early and continuous engagement of labor in innovation; the development of intermediary sense-making structures to garner resources, facilitate plans, and build consensus; and a whole system perspective, rather than a focus on single professions. We also identify seven principles underlying the WFPD processes in these two cases that can aid in development of a new and more adaptive workforce strategy in healthcare.
Since passage of the ACA, healthcare systems are becoming larger and more complex. Insights from these case studies suggest that while organizational history and structure determined different areas of emphasis, our results indicate that large-scale system transformations in healthcare can be managed in ways that enhance the skills and capacities of the workforce. Our findings merit attention, not just by healthcare administrators and union leaders, but by policymakers and scholars interested in making WFPD policies at a state and national level more responsive.
Reversible phosphorylation of proteins is a delicate yet dynamic balancing act between kinases and phosphatases, the disturbance of which underlies numerous disease processes. While our understanding of protein kinases has grown tremendously over the past decades, relatively little is known regarding protein phosphatases. This may be because protein kinases are great in number and relatively specific in function, and thereby amenable to be studied in isolation, whereas protein phosphatases are much less abundant and more nonspecific in their function. To achieve subcellular localization and substrate specificity, phosphatases depend on partnering with a large number of regulatory subunits, protein scaffolds and/or other interactors. This added layer of complexity presents a significant barrier to their study, but holds the key to unexplored opportunities for novel pharmacologic intervention. In this review we focus on serine/threonine protein phosphatase type-1 (PP1), which plays an important role in cardiac physiology and pathophysiology. Although much work has been done to investigate the role of PP1 in cardiac diseases including atrial fibrillation and heart failure, most of these studies were limited to examining and manipulating the catalytic subunit(s) of PP1 without adequately considering the PP1 interactors, which give specificity to PP1's functions. To complement these studies, three unbiased methods have been developed and applied to the mapping of the PP1 interactome: bioinformatics approaches, yeast two-hybrid screens, and affinity-purification mass spectrometry. The application of these complementary methods has the potential to generate a detailed cardiac PP1 interactome, which is an important step in identifying novel and targeted pharmacological interventions.
War captivity may affect spouses of former-prisoners-of-war (ex-POWs) in many ways, including posttraumatic stress symptoms (PTSS) and somatic difficulties manifested in negative perceived health. This is generally known as secondary traumatization. Theory suggests that development of secondary traumatization occurs through the relationship with the primary trauma survivor Figley (1986) , thus implying that the ability to keep balanced emotional distance in the relationship may play a pivotal role. Notwithstanding, the contribution of self-differentiation to secondary somatic disturbances remains largely uninvestigated. The current study fills this gap.
Ex-POWs' wives (n=143) and control former-combatants' wives (n=102), were assessed prospectively 30 (T1) and 38 (T2) years after the 1973 Yom Kippur War. Self-differentiation and PTSS were assessed at both time-points, while perceived health measures were assessed at T2.
Wives of ex-POWs endorsed higher PTSS, lower self-differentiation and negative perceived health, compared to control wives. Indirect exposure to war captivity was related to low self-differentiation and elevated PTSS, which predicted negative perceived health. Furthermore, self-differentiation characterized by fusion-with-others fully mediated the relation between indirect exposure to war captivity and perceived health, beyond the effects of PTSS as a mechanism.
Results suggest that tendencies towards fusion-with-others within the marital relationship, act as a risk factor not only for psychological distress but also for somatic distress among secondary trauma survivors. Hence, clinical interventions may seek to improve indirect trauma survivor's self-differentiation capacities, thus potentially facilitating the prevention of secondary somatic distress.
Transcriptional enhancers are DNA regulatory elements that are bound by transcription factors and act to positively regulate the expression of nearby or distally located target genes. Enhancers have many features that have been discovered using genomic analyses. Recent studies have shown that active enhancers recruit RNA polymerase II (Pol II) and are transcribed, producing enhancer RNAs (eRNAs). GRO-seq, a method for identifying the location and orientation of all actively transcribing RNA polymerases across the genome, is a powerful approach for monitoring nascent enhancer transcription. Furthermore, the unique pattern of enhancer transcription can be used to identify enhancers in the absence of any information about the underlying transcription factors. Here, we describe the computational approaches required to identify and analyze active enhancers using GRO-seq data, including data pre-processing, alignment, and transcript calling. In addition, we describe protocols and computational pipelines for mining GRO-seq data to identify active enhancers, as well as known transcription factor binding sites that are transcribed. Furthermore, we discuss approaches for integrating GRO-seq-based enhancer data with other genomic data, including target gene expression and function. Finally, we describe molecular biology assays that can be used to confirm and explore further the function of enhancers that have been identified using genomic assays. Together, these approaches should allow the user to identify and explore the features and biological functions of new cell type-specific enhancers.
Glial cells, also known as neuroglia or glia, are non-neuronal cells providing support and protection for neurons in the central nervous system (CNS). They also act as supportive cells in the brain. Among a variety of glial cells, the star-shaped glial cells, i.e., astrocytes, are the largest cell population in the brain. The important role of astrocyte such as neuronal synchronization, synaptic information regulation, feedback to neural activity and extracellular regulation make the astrocytes play a vital role in brain disease. This paper presents a modified complete neuron-astrocyte interaction model that is more suitable for efficient and large scale biological neural network realization on digital platforms. Simulation results show that the modified complete interaction model can reproduce biological-like behavior of the original neuron-astrocyte mechanism. The modified interaction model is investigated in terms of digital realization feasibility and cost targeting a low cost hardware implementation. Networking behavior of this interaction is investigated and compared between two cases: i) the neuron spiking mechanism without astrocyte effects, and ii) the effect of astrocyte in regulating the neurons behavior and synaptic transmission via controlling the LTP and LTD processes. Hardware implementation on FPGA shows that the modified model mimics the main mechanism of neuron-astrocyte communication with higher performance and considerably lower
 hardware overhead cost compared with the original interaction model.
The aim of this study was to investigate ventilation in mild to moderate asthmatic patients and age-matched controls using hyperpolarized (HP) Xenon magnetic resonance imaging (MRI) and correlate findings with pulmonary function tests (PFTs).
This single-center, Health Insurance Portability and Accountability Act-compliant prospective study was approved by our institutional review board. Thirty subjects (10 young asthmatic patients, 26 ± 6 years; 3 males, 7 females; 10 older asthmatic patients, 64 ± 6 years; 3 males, 7 females; 10 healthy controls) were enrolled. After repeated PFTs 1 week apart, the subjects underwent 2 MRI scans within 10 minutes, inhaling 1-L volumes containing 0.5 to 1 L of Xe. Xe ventilation signal was quantified by linear binning, from which the ventilation defect percentage (VDP) was derived. Differences in VDP among subgroups and variability with age were evaluated using 1-tailed t tests. Correlation of VDP with PFTs was tested using Pearson correlation coefficient. Reproducibility of VDP was assessed using Bland-Altman plots, linear regression (R), intraclass correlation coefficient, and concordance correlation coefficient.
Ventilation defect percentage was significantly higher in young asthmatic patients versus young healthy subjects (8.4% ± 3.2% vs 5.6% ± 1.7%, P = 0.031), but not in older asthmatic patients versus age-matched controls (16.8% ± 10.3% vs 11.6% ± 6.6%, P = 0.13). Ventilation defect percentage was found to increase significantly with age (healthy, P = 0.05; asthmatic patients, P = 0.033). Ventilation defect percentage was highly reproducible (R = 0.976; intraclass correlation coefficient, 0.977; concordance correlation coefficient, 0.976) and significantly correlated with FEV1% (r = -0.42, P = 0.025), FEF25%-75% (r = -0.45, P = 0.019), FEV1/FVC (r = -0.71, P < 0.0001), FeNO (r = 0.69, P < 0.0001), and RV/TLC (r = 0.51, P = 0.0067). Bland-Altman analysis showed a bias for VDP of -0.88 ± 1.52 (FEV1%, -0.33 ± 7.18).
Xenon MRI is able to depict airway obstructions in mild to moderate asthma and significantly correlates with PFTs.
Recently, microRNA (miR)-33b has been demonstrated to act as a tumor suppressor in osteosarcoma. However, the regulatory mechanism of miR-33b in osteosarcoma cell proliferation and migration remains largely unknown. In this study, real-time PCR showed that miR-33b was significantly downregulated in osteosarcoma tissues compared to their matched adjacent non-tumor tissues. Its expression was also decreased in several common osteosarcoma cell lines, including Saos-2, MG63, U2OS, and SW1353, when compared to normal osteoblast cell line hFOB. Overexpression of miR-33b suppressed U2OS cell proliferation and migration. HIF-1α was further identified as a target of miR-33b, and its protein levels were reduced after overexpression of miR-33b in U2OS cells. Moreover, overexpression of HIF-1α significantly reversed the suppressive effect of miR-33b on U2OS cell proliferation and migration. In addition, HIF-1α was found to be significantly upregulated in osteosarcoma tissues compared to adjacent non-tumor tissues, and their expression levels were inversely correlated to the miR-33b levels in osteosarcoma tissues. According to these findings, miR-33b plays a suppressive role in the regulation of osteosarcoma cell proliferation and migration via directly targeting HIF-1α. Therefore, we suggest that the miR-33b/HIF-1α axis may become a promising therapeutic target for osteosarcoma.
The cis/trans isomerization of X-Pro peptide bonds in proteins in some instances acts as a molecular switch in biological pathways. Our prior work suggests that the cis isomer of the phospho-Thr668-Pro669 motif, located in the cytoplasmic domain of the amyloid-β protein precursor (AβPP), is correlated with an increase in amyloidogenic processing of AβPP and production of amyloid-beta (Aβ), the neurotoxic peptide fragment in Alzheimer's disease (AD). We designed a 100% cis-locked cyclic dipeptide composed of cyclized phospho-Thr-Pro (pCDP) as a mimic for this putative pathological conformation, and three phosphate-blocked derivatives (pCDP-diBzl, pCDP-Bzl, and pCDP-diPOM). Two H4 neuroglioma cell lines were established as AD cell models for use in testing these compounds: H4-AβPP695 for stable overexpression of wild-type AβPP695, and H4-BACE1 for stable overexpression of β-site AβPP cleaving enzyme-1 (BACE1). The level of the secreted AβPP fragment resulting from BACE1 activity, sAβPPβ, served as a key proxy for amyloidogenic processing, since cleavage of AβPP by BACE1 is a requisite first step in Aβ production. Of the compounds tested, pCDP-diBzl decreased sAβPPβ levels in both cell lines, while pCDP-diPOM decreased sAβPPβ levels in only H4-BACE1 cells, all with similar dose-dependences and patterns of proteolytic AβPP fragments. Enzymatic assays showed that none of the pCDP derivatives directly inhibit BACE1 catalytic activity. These results suggest a model in which pCDP-diBzl and pCDP-diPOM act at a common point to inhibit entry of AβPP into the amyloidogenic AβPP processing pathway but through different targets, and provide important insights for the development of novel AD therapeutics.
In the present study a series of fifteen 2-heteroarylidene-1-indanone derivatives were synthesised and evaluated as inhibitors of recombinant human monoamine oxidase (MAO) A and B. These compounds are structurally related to series of heterocyclic chalcone derivatives which have previously been shown to act as MAO-B specific inhibitors. The results document that the 2-heteroarylidene-1-indanones are in vitro inhibitors of MAO-B, displaying IC50 values of 0.0044-1.53μM. Although with lower potencies, the derivatives also inhibit the MAO-A isoform with IC50 values as low as 0.061μM. An analysis of the structure-activity relationships for MAO-B inhibition indicates that substitution with the methoxy group on the A-ring leads to a significant enhancement in MAO-B inhibition compared to the unsubstituted homologues while the effect of the heteroaromatic substituent on activity, in decreasing order is: 5-bromo-2-furan>5-methyl-2-furan>2-pyridine≈2-thiophene>cyclohexyl>3-pyridine≈2-furan. It may therefore be concluded that 2-heteroarylidene-1-indanone derivatives are promising leads for the design of MAO inhibitors for the treatment of Parkinson's disease and possibly other neurodegenerative disorders.
Bacterial small RNAs (sRNAs) have been implicated in various aspects of post-transcriptional gene regulation. Here, we demonstrate that sRNAs also act at the level of transcription termination. We use the rpoS gene, which encodes a general stress sigma factor σ(S), as a model system, and show that sRNAs DsrA, ArcZ, and RprA bind the rpoS 5'UTR to suppress premature Rho-dependent transcription termination, both in vitro and in vivo. sRNA-mediated antitermination markedly stimulates transcription of rpoS during the transition to the stationary phase of growth, thereby facilitating a rapid adjustment of bacteria to global metabolic changes. Next generation RNA sequencing and bioinformatic analysis indicate that Rho functions as a global "attenuator" of transcription, acting at the 5'UTR of hundreds of bacterial genes, and that its suppression by sRNAs is a widespread mode of bacterial gene regulation.
Layered two-dimensional (2D) materials display great potential for a range of applications, particularly in electronics. We report the large-scale synthesis of thin films of platinum diselenide (PtSe2), a thus far scarcely investigated transition metal dichalcogenide. Importantly, the synthesis by thermally assisted conversion is performed at 400 °C, representing a breakthrough for the direct integration of this material with silicon (Si) technology. Besides the thorough characterization of this 2D material, we demonstrate its promise for applications in high-performance gas sensing with extremely short response and recovery times observed due to the 2D nature of the films. Furthermore, we realized vertically stacked heterostructures of PtSe2 on Si which act as both photodiodes and photovoltaic cells. Thus, this study establishes PtSe2 as a potential candidate for next-generation sensors and (opto-)electronic devices, using fabrication protocols compatible with established Si technologies.
We demonstrate polarization-selective microlensing and waveguiding of laser beams by birefringent profiles in bulk nematic fluids using numerical modelling. Specifically, we show that radial escaped nematic director profiles with negative birefringence focus and guide light with radial polarization, whereas the opposite - azimuthal - polarization passes through unaffected. A converging lens is realized in a nematic with negative birefringence, and a diverging lens in a positive birefringence material. Tuning of such single-liquid lenses by an external low-frequency electric field and by adjusting the profile and intensity of the beam itself is demonstrated, combining external control with intrinsic self-adaptive focusing. Escaped radial profiles of birefringence are shown to act as single-liquid waveguides with a single distinct eigenmode and low attenuation. Finally, this work is an approach towards creating liquid photonic elements for all-soft matter photonics.
Space-division multiplexing allows unprecedented scaling of bandwidth density for optical communication. Routing spatial channels among transmission ports is critical for future scalable optical network, however, there is still no characteristic parameter to label the overlapped optical carriers. Here we propose a free-space optical flow routing (OFR) scheme by using optical orbital angular moment (OAM) states to label optical flows and simultaneously steer each flow according to their OAM states. With
 an OAM multiplexer and a reconfigurable OAM demultiplexer, massive individual optical flows can be routed to the demanded optical ports. In the routing process, the OAM beams act as data carriers at the same time their topological charges act as each carrier's labels. Using this scheme, we experimentally demonstrate switching, multicasting and filtering network functions by simultaneously steer 10 input optical flows on demand to 10 output ports. The demonstration of data-carrying OFR with nonreturn-to-zero signals shows that this process enables synchronous processing of massive spatial channels and flexible optical network.
We develop and implement what we believe is the first conceptually valid health-inclusive poverty measure (HIPM) - a measure that includes health care or insurance in the poverty needs threshold and health insurance benefits in family resources - and we discuss its limitations. Building on the Census Bureau's Supplemental Poverty Measure, we construct a pilot HIPM for the under-65 population under ACA-like health reform in Massachusetts. This pilot demonstrates the practicality, face validity and value of a HIPM. Results suggest that public health insurance benefits and premium subsidies accounted for a substantial, one-third reduction in the health inclusive poverty rate.
It has been hypothesised that, if ingested, plastic debris could act as vector for the transfer of chemical contaminants from seawater to organisms, yet modelling suggest that, in the natural environment, chemical transfer would be negligible compared to other routes of uptake. However, to date, the models have not incorporated consideration of the role of gut surfactants, or the influence of pH or temperature on desorption, whilst experimental work has shown that these factors can enhance desorption of sorbed contaminants several fold. Here, we modelled the transfer of sorbed organic contaminants dichlorodiphenyltrichloroethane (DDT), phenanthrene (Phe) and bis-2-ethylhexyl phthalate (DEHP) from microscopic particles of polyvinylchloride (PVC) and polyethylene (PE) to a benthic invertebrate, a fish and a seabird using a one-compartment model OMEGA (Optimal Modelling for EcotoxicoloGical Applications) with different conditions of pH, temperature and gut surfactants. Environmental concentrations of contaminants at the bottom and the top of published ranges were considered, in combination with ingestion of either 1 or 5% by weight of plastic. For all organisms, the combined intake from food and water was the main route of exposure for Phe, DEHP and DDT with a negligible input from plastic. For the benthic invertebrate, predictions including the presence of contaminated plastic resulted in very small increases in the internal concentrations of DDT and DEHP, while the net change in the transfer of Phe was negligible. While there may be scenarios in which the presence of plastic makes a more important contribution, our modelling study suggests that ingestion of microplastic does not provide a quantitatively important additional pathway for the transfer of adsorbed chemicals from seawater to biota via the gut.
Fullerenes are carbon based nanoparticles that may enter the environment as a consequence of both natural processes and human activities. Although little is known about the presence of these chemicals in the environment, recent studies suggested that soil may act as a sink. The aim of the present work was to investigate the presence of fullerenes in soils collected in The Netherlands. Samples (n = 91) were taken from 6 locations and analyzed using a new developed LC-QTOF-MS method. The locations included highly trafficked and industrialized as well as urban and natural areas. In general, C60 was the most abundant fullerene found in the environment, detected in almost a half of the samples and at concentrations in the range of ng/kg. Other fullerenes such as C70 and an unknown structure containing a C60 cage were detected to a lower extent. The highest concentrations were found in the proximity of combustion sites such as a coal power plant and an incinerator, suggesting that the nanoparticles were unintentionally produced during combustions processes and reached the soil through atmospheric deposition. Consistent with other recent studies, these results show that fullerenes are widely present in the environment and that the main route for their entrance may be due to human activities. These data will be helpful in the understanding of the distribution of fullerenes in the environment and for the study of their behavior and fate in soil.
Existing examples of Peierls-type 1D systems on surfaces involve depositing metallic overlayers on semiconducting substrates, in particular, at step edges. Here we propose a new class of Peierls system on the (101[over ¯]0) surface of metal-anion wurtzite semiconductors. When the anions are bonded to hydrogen or lithium atoms, we obtain rows of threefold coordinated metal atoms that act as one-atom-wide metallic structures. First-principles calculations show that the surface is metallic, and below a certain critical temperature the surface will condense to a semiconducting state. The idea of surface scaffolding is introduced in which the rows are constrained to move along simple up-down and/or sideways displacements, mirroring the paradigm envisioned in Peierls's description. We predict that this type of insulating state should be visible in the partially hydrogenated (101[over ¯]0) surface of many wurtzite compounds.
To compare the effect of 2 different playground environments on the physical activity of children with ambulatory cerebral palsy during their playground play.
Five 7- to 8-year-old children with cerebral palsy (Gross Motor Functional Classification System [GMFCS] level II) participated. Using an alternating treatment, single-subject design, stride patterns were obtained using an activity monitor on an Americans with Disabilities Act (ADA)-compliant and noncompliant playground. Visual and statistical analysis of the stride data was used to analyze the effect of the playground environments.
Four of the 5 participants increased the number of strides on an ADA-compliant playground.
Children with cerebral palsy (GMFCS II) may benefit from an ADA-compliant playground to increase their physical activity.
Health literacy is the ability to obtain, comprehend, and act on medical information and is an independent predictor of health outcomes in patients with chronic health conditions. However, little has been reported regarding the potential association of health literacy and surgical outcomes. We hypothesized that patient complications after radical cystectomy would be associated with health literacy. In a sample of 368 patients, we found that higher health literacy scores (as determined by the Brief Health Literacy Screen) were associated with decreased odds of developing minor complications (odds ratio = 0.90, 95% confidence interval [0.83, 0.97]). Health literacy should be considered when caring for patients undergoing radical cystectomy and should serve as a potential indicator of the need for additional resources to improve postoperative outcomes.
Anticoagulation treatment during extracorporeal membrane oxygenation (ECMO) treatment is unavoidable. However, discontinuation of heparin infusion is necessary when challenges associated with the use of heparin, such as bleeding and thrombocytopenia, are encountered. The medical records of 94 adult (age ≥ 18 years) patients treated with ECMO from January 2011 to March 2015, at Chung-Ang University Hospital, Seoul, Korea, were reviewed. Among the 94 patients, 55 patients underwent ECMO treatment for 3 or more days. In 52.7% of these patients (n=29, group A), heparin was stopped for 3 or more days due to thrombocytopenic events (<50,000 cells/mm), higher than target range (>230 sec) activated clotting time (ACT), bleeding complications or the need for other surgical procedures. In 43.6% of patients (n=24, group B), heparin was continuously infused during the entire ECMO process. The mean length of ECMO support after the initiation of heparin discontinuation in patients in group A was 10.2 ± 14.7 days. There were no intracardiac, intravascular, or intra-circuit thrombotic complications in group A. There was no difference in the ECMO weaning success rate between the two groups(41.4% in group A vs. 54.2% in group B, p=0.353). Heparin discontinuation can be considered in a select group of patients with coagulation abnormalities and/or bleeding.
Ricin is an A-B ribosome inactivating protein (RIP) toxin composed of an A-chain subunit (RTA) that contains a catalytic N-glycosidase and a B-chain (RTB) lectin domain that binds cell surface glycans. Ricin exploits retrograde transport to enter into the Golgi and the endoplasmic reticulum, and then dislocates into the cytoplasm where it can reach its substrate, the ribosomal RNA. A subset of isolated antibodies (Abs) raised against the RTA subunit protect against ricin intoxication, and RTA-based vaccine immunogens have been shown to provide long-lasting protective immunity against the holotoxin. Anti-RTA Abs are unlikely to cross a membrane and reach the cytoplasm to inhibit the enzymatic activity of the A-chain. Moreover, there is not a strict correlation between the apparent binding affinity (Ka) of anti-RTA Abs and their ability to successfully neutralize ricin toxicity. Some anti-RTA antibodies are toxin-neutralizing, whereas others are not. We hypothesize that neutralizing anti-RTA Abs may interfere selectively with conformational change(s) or partial unfolding required for toxin internalization. To test this hypothesis, we measured the melting temperatures (Tm) of neutralizing single-domain Ab (sdAb)-antigen (Ag) complexes relative to the Tm of the free antigen (Tm-shift = Tm(complex) - Tm(Ag)),
 and observed increases in the Tm(complex) of 9-20 degrees. In contrast, non-neutralizing sdAb-Ag complexes shifted the Tm(Complex) by only 6-7 degrees. A strong linear correlation (r(2) = 0.992) was observed between the magnitude of the Tm-shift and the viability of living cells treated with the sdAb and ricin holotoxin. The Tm-shift of the sdAb-Ag complex provided a quantitative biophysical parameter that could be used to predict and rank-order the toxin-neutralizing activities of Abs. We determined the first structure of an sdAb-RTA1-33/44-198 complex, and examined other sdAb-RTA complexes. We found that neutralizing sdAb bound to regions involved in the early stages of unfolding. These Abs likely interfere with steps preceding or following endocytosis that require conformational changes. This method may have utility for the characterization or rapid screening of other Ab that act to prevent conformational changes or unfolding as part of their mechanism of action.
Plants often experience various biotic and abiotic stresses during their life cycle. The abiotic stresses include mainly drought, salt, temperature (low/high), flooding and nutritional deficiency/excess which hamper crop growth and yield to a great extent. In view of a projection 50% of the crop loss is attributable to abiotic stresses. However, abiotic stresses cause a myriad of changes in physiological, molecular and biochemical processes operating in plants. It is now widely reported that several proteins respond to these stresses at pre- and post-transcriptional and translational levels. By knowing the role of these stress inducible proteins, it would be easy to comprehensively expound the processes of stress tolerance in plants. The proteomics study offers a new approach to discover proteins and pathways associated with crop physiological and stress responses. Thus, studying the plants at proteomic levels could help understand the pathways involved in stress tolerance. Furthermore, improving the understanding of the identified key metabolic proteins involved in tolerance can be implemented into biotechnological applications, regarding recombinant/transgenic formation. Additionally, the investigation of identified metabolic processes ultimately supports the development of antistress strategies. In this review, we discussed the role of proteomics in crop stress tolerance. We also discussed different abiotic stresses and their effects on plants, particularly with reference to stress-induced expression of proteins, and how proteomics could act as vital biotechnological tools for improving stress tolerance in plants.
Numerous studies have found that people tend to commit prosocial acts subsequent to previous immoral acts, as a response to the latter. This phenomenon is called moral cleansing or moral compensation. However, the specific mechanism how previous immoral acts motivate moral compensatory behaviors is still not fully understood. This study aimed to examine the roles of guilt and moral identity in the relation between previous immoral acts and subsequent prosocial behaviors to clarify the mechanism. Based on the extant research, the current study proposed a moderated mediation model to illustrate the process of moral cleansing. Specifically, a previous immoral act motivates guilt, which further leads to subsequent prosocial behaviors, while moral identity facilitates this process. The participants were primed by a recalling task (immoral act vs. a neutral event). The results support the hypothesized model and provide a framework that explains moral cleansing by integrating the roles of guilt and moral identity. These findings highlight the dynamic nature of people's morality with regard to how people adapt moral behaviors to protect their moral self-image.
The Neptune grass, Posidonia oceanica (L.) Delile, 1813, is the most widespread seagrass of the Mediterranean Sea. This foundation species forms large meadows that, through habitat and trophic services, act as biodiversity hotspots. In Neptune grass meadows, amphipod crustaceans are one of the dominant groups of vagile invertebrates, forming an abundant and diverse taxocenosis. They are key ecological components of the complex, pivotal, yet critically endangered Neptune grass ecosystems. Nevertheless, comprehensive qualitative and quantitative data about amphipod fauna found in Mediterranean Neptune grass meadows remain scarce, especially in insular locations.
Here, we provide in-depth metadata about AxIOM, a sample-based dataset published on the GBIF portal. AxIOM is based on an extensive and spatially hierarchized sampling design with multiple years, seasons, day periods, and methods. Samples were taken along the coasts of Calvi Bay (Corsica, France) and of the Tavolara-Punta Coda Cavallo Marine Protected Area (Sardinia, Italy). In total, AxIOM contains 187 samples documenting occurrence (1775 records) and abundance (10720 specimens) of amphipod crustaceans belonging to 72 species spanning 29 families. The dataset is available at http://ipt.biodiversity.be/resource?r=axiom.
An intricate interplay between innate and adaptive immune cells is crucial for an effective immune response during disease, infection and vaccination. This interplay is manly performed by dendritic cells (DCs), which are professional antigen presenting cells (APCs) with unparalleled capacity to translate innate to adaptive immunity. They effectively recognize and uptake antigens, migrate to lymphoid tissues, and activate naïve T-cells. To enable rapid pathogen detection DCs utilize numerous germline encoded pattern recognition receptors (PRR) that recognize conserved pathogen associated molecular patterns (PAMPs) or danger associated molecular patterns (DAMPs). While some PRRs like Toll-like receptors (TLRs) recognize PAMPs and DAMPs at the cell surface and in endosomal/lysosomal compartments, others, such as NOD-like receptors (NLRs), act as cytosolic sensors. NLRs represent therefore a second line of protection against microorganisms or danger signals that were not sensed by cell surface and endocytic PRRs. NLRs activation through recognition of PAMPs and DAMPs leads to the assembly of signaling multimeric protein complexes named inflammasomes. Inflammasomes are important regulators of caspase 1, the enzyme responsible for the proteolytically cleavage of precursors' pro-IL-1β and pro-IL-18 into their active form. Considering the importance of DCs in immune response, it is of utmost importance to unveil how inflammasomes are related to maturation, migration, antigen presenting function and DCs ability to fine tune adaptive immune responses. In this review, we first revise, at a glance, the immunobiology of DCs and then we systematize the evidence for inflammasome activity shaping of DCs functions. Secondly, the mechanisms behind inflammasome activation in DCs during infection, disease and vaccination are also reviewed. Finally, the pharmacological intervention on the inflammasome pathway is also highlighted.
Ascertaining stroke severity in claims data-based studies is difficult because clinical information is unavailable. We assessed the predictive validity of a claims-based stroke severity index (SSI) and determined whether it improves case-mix adjustment.
We analyzed patients with acute ischemic stroke (AIS) from hospital-based stroke registries linked with a nationwide claims database. We estimated the SSI according to patient claims data. Actual stroke severity measured with the National Institutes of Health Stroke Scale (NIHSS) and functional outcomes measured with the modified Rankin Scale (mRS) were retrieved from stroke registries. Predictive validity was tested by correlating SSI with mRS. Logistic regression models were used to predict mortality.
The SSI correlated with mRS at 3 months (Spearman rho = 0.578; 95 % confidence interval [CI], 0.556-0.600), 6 months (rho = 0.551; 95 % CI, 0.528-0.574), and 1 year (rho = 0.532; 95 % CI 0.504-0.560). Mortality models with the SSI demonstrated superior discrimination to those without. The AUCs of models including the SSI and models with the NIHSS did not differ significantly.
The SSI correlated with functional outcomes after AIS and improved the case-mix adjustment of mortality models. It can act as a valid proxy for stroke severity in claims data-based studies.
Surface acoustic wave mediated transductions have been widely used in the sensors and actuators applications. In this study, a shear horizontal surface acoustic wave (SHSAW) was used for the detection of food pathogenic Escherichia coli O157:H7 (E.coli O157:H7), a dangerous strain among 225 E. coli unique serotypes. A few cells of this bacterium are able to cause young children to be most vulnerable to serious complications. Presence of higher than 1cfu E.coli O157:H7 in 25g of food has been considered as a dangerous level. The SHSAW biosensor was fabricated on 64° YX LiNbO3 substrate. Its sensitivity was enhanced by depositing 130.5nm thin layer of SiO2 nanostructures with particle size lesser than 70nm. The nanostructures act both as a waveguide as well as a physical surface modification of the sensor prior to biomolecular immobilization. A specific DNA sequence from E. coli O157:H7 having 22 mers as an amine-terminated probe ssDNA was immobilized on the thin film sensing area through chemical functionalization [(CHO-(CH2)3-CHO) and APTES; NH2-(CH2)3-Si(OC2H5)3]. The high-performance of sensor was shown with the specific oligonucleotide target and attained the sensitivity of 0.6439nM/0.1kHz and detection limit was down to 1.8femto-molar (1.8×10(-15)M). Further evidence was provided by specificity analysis using single mismatched and complementary oligonucleotide sequences.
Polycomb group (PcG) proteins are master regulators of proliferation and development that play essential roles in human pathologies including
 cancers. PcGs act as gatekeepers of cellular identity, maintaining repression of a multitude of target genes. However, these properties have only been recently uncovered thanks to technological advances, first of all chromatin immunoprecipitations (ChIP), that allowed a systematic characterization of the activity of these factors in an unbiased manner at a genome-wide level. Using PcG protein as example, this chapter introduces the readers to the use of chromatin analysis (ChIP assays and replication timing) and how to move these approaches to a level of genome-wide interpretation.
Innate immunity is the host first line of defense against pathogens. However, only in recent years, we are beginning to better understand the ways it operates. A key player is this branch of the immune response that are the phagocytes, as macrophages, dendritic cells and neutrophils. These cells act as sentinels, employing specialized receptors in the sensing of invaders and host injury, and readily responding to them by production of inflammatory mediators. They afford protection not only by ingesting and destroying pathogens, but also by providing a suitable biochemical environment that shapes the adaptive response. In this review, we aim to present a broad perspective about the role of phagocytes in dermatophytosis, focusing on the mechanisms possibly involved in protective and non-protective responses. A full understanding of how phagocytes fit in the pathogenesis of these infections may open the venue for the development of new and more effective therapeutic approaches.
Paclitaxel, a taxane, is a cytotoxic chemotherapeutic agent that targets microtubules. It has become a front-line therapy for a broad range of malignancies, including lung, breast, gastric, esophageal, and bladder carcinomas. Although paclitaxel can inhibit tumor development and improve survival, poor solubility, myelotoxicity, allergic reactions, and drug resistance have restricted its clinical application. Paclitaxel is frequently combined with other chemotherapeutics to enhance the antitumor effects and reduce side effects. We synthesized geridonin, a derivative of oridonin, and demonstrate that geridonin and paclitaxel act synergistically to inhibit the growth of gastric cancer cells. Importantly, geridonin enhanced the antitumor effects of paclitaxel without increasing toxicity in vivo. Mechanistic analysis revealed that administration of geridonin in combination with paclitaxel up-regulated the tumor suppressor PTEN and inhibited phosphorylation of Akt and MDM2. This led to the accumulation of p53 and induced apoptosis though the mitochondrial pathway. Thus, geridonin in combination with paclitaxel is a new treatment strategy for gastric cancer.
Routine monitoring of depression symptoms and suicide risk is essential for appropriate treatment planning and risk management, but not well implemented by clinicians. We developed a brief online monitoring tool to address this issue.
To investigate whether the online tool can feasibly improve monitoring; whether it is acceptable and useful for young people and their clinicians; and to determine whether a shorter tool could be implemented.
In a naturalistic longitudinal cohort study, 101 young people with depression completed the online tool on a tablet, prior to their consultation. Their results were immediately available to their clinician. Clients and clinicians answered questionnaires about acceptability and usefulness.
The tool was feasible to implement. Young people and clinicians found the tool acceptable and useful for understanding symptoms and risk. A brief three-item suicidal ideation screening measure correlated well with a validated measure of suicidal ideation.
The online tool facilitates the quick exchange of key information about suicide risk, allowing clinicians to immediately address this. This level of responsiveness is likely to improve treatment outcomes. The brief version allows full integration into clinical practice to support clinicians managing those at risk of suicide.
Liprin-α1 and ERC1 are interacting scaffold proteins regulating the motility of normal and tumor cells. They act as part of plasma membrane-associated platforms at the edge of motile cells to promote protrusion by largely unknown mechanisms. Here we identify an amino-terminal region of the liprin-α1 protein (liprin-N) that is sufficient and necessary for the interaction with other liprin-α1 molecules. Similar to liprin-α1 or ERC1 silencing, expression of the liprin-N negatively affects tumor cell motility and extracellular matrix invasion, acting as a dominant negative by interacting with endogenous liprin-α1 and causing the displacement of the endogenous ERC1 protein from the cell edge. Interfering with the localization of ERC1 at the cell edge inhibits the disassembly of focal adhesions, impairing protrusion. Liprin-α1 and ERC1 proteins colocalize with active integrin β1 clusters distinct from those colocalizing with cytoplasmic focal adhesion proteins, and influence the localization of peripheral Rab7-positive endosomes. We propose that liprin-α1 and ERC1 promote protrusion by displacing cytoplasmic adhesion components to favour active integrin internalization into Rab7-positive endosomes.
Bone remodeling is a physiological process by which bone constantly adapts its structure to changes in long-term loading manifested by interactions between osteoclasts and osteoblasts. This process can be influenced by many local factors, via effects on bone cells differentiation and proliferation, which are produced by bone cells and act in a paracrine or autocrine way. The aim of the current work is to provide mechanobiological finite elements modeling coupling both cellular activities and mechanical behavior in order to investigate age and gender effects on bone remodeling evolution. A series of computational simulations have been performed on a 2D and 3D human proximal femur. An age- and gender-related impacts on bulk density alteration of trabecular bone have been noticed, and the major actors responsible of this phenomenon have been then discussed.
Single nanowire (NW) green InGaN/GaN light-emitting diodes (LEDs) were fabricated by top-down etching technology. The electroluminescence (EL) peak wavelength remains approximately constant with an increasing injection current in contrast to a standard planar LED, which suggests that the quantum-confined Stark effect is significantly reduced in the single NW device. The strain relaxation mechanism is studied in the single NW LED using Raman scattering analysis. As compared to its planar counterpart, the EL peak of the NW LED shows a redshift, due to electric field redistribution as a result of changes in the cavity mode pattern after metallization. Our method has important implication for single NW optoelectronic device applications.
Toll-like receptors (TLRs) act as initiators and conductors responsible for both innate and adaptive immune responses in organ transplantation. The mammalian target of rapamycin (mTOR) is one of the most critical signaling kinases that affects broad aspects of cellular functions including metabolism, growth, and survival. Recipients (BALB/c) were treated with MyD88, TRIF and mTOR siRNA vectors, 3 and 7 days prior to heart transplantation and 7, 14 and 21 days after transplantation. After siRNA treatment, recipients received a fully MHC-mismatched C57BL/6 heart. Treatment with mTOR siRNA significantly prolonged allograft survival in heart transplantation. Moreover, the combination of mTOR siRNA with MyD88 and TRIF siRNA further extended the allograft survival; Flow cytometric analysis showed an upregulation of FoxP3 expression in spleen lymphocytes and a concurrent downregulation of CD40, CD86 expression, upregulation of PD-L1 expression in splenic dendritic cells in MyD88, TRIF and mTOR treated mice. There is significantly upregulated T cell exhaustion in T cells isolated from tolerant recipients. This study is the first demonstration of preventing immune rejection of allogeneic heart grafts through concurrent gene silencing of TLR and kinase signaling pathways, highlighting the therapeutic potential of siRNA in clinical transplantation.
Woody plants host diverse communities of associated organisms, including wood-inhabiting fungi. In this group, host effects on species richness and interaction network structure are not well understood, especially not at large geographical scales. We investigated ecological, historical and evolutionary determinants of fungal species richness and network modularity, that is, subcommunity structure, across woody hosts in Denmark, using a citizen science data set comprising > 80 000 records of > 1000 fungal species on 91 genera of woody plants. Fungal species richness was positively related to host size, wood pH, and the number of species in the host genus, with limited influence of host frequency and host history, that is, time since host establishment in the area. Modularity patterns were unaffected by host history, but largely reflected host phylogeny. Notably, fungal communities differed substantially between angiosperm and gymnosperm hosts. Host traits and evolutionary history appear to be more important than host frequency and recent history in structuring interactions between hosts and wood-inhabiting fungi. High wood acidity appears to act as a stress factor reducing fungal species richness, while large host size, providing increased niche diversity, enhances it. In some fungal groups that are known to interact with live host cells in the establishment phase, host selectivity is common, causing a modular community structure.
T-type calcium channels are key contributors to neuronal physiology where they shape electrical activity of nerve cells and contribute to the release of neurotransmitters. Enhanced T-type channel expression
 has been causally linked to a number of pathological conditions including peripheral painful diabetic neuropathy. Recently, it was demonstrated that asparagine-linked glycosylation not only plays an essential role in regulating cell surface expression of Cav3.2 channels, but may also support glucose-dependent potentiation of T-type currents. However, the underlying mechanisms by which N-glycosylation and glucose levels modulate the expression of T-type channels remain elusive. In the present study, we show that site-specific N-glycosylation of Cav3.2 is essential to stabilize expression of the channel at the plasma membrane. In contrast, elevated external glucose concentration appears to potentiate intracellular forward trafficking of the channel to the cell surface, resulting in an increased steady-state expression of the channel protein at the plasma membrane. Collectively, our study indicates that glucose and N-glycosylation act in concert to control the expression of Cav3.2 channels, and that alteration of these mechanisms may contribute to the altered expression of T-type channels in pathological conditions.
Since one of the most important disadvantages of soft drinks includes their adverse effect on mineral content of enamel because of their low pH, this study examined the microhardness of enamel before and after exposure to a soft drink containing different concentrations of nano-hydroxyapatite (nano-HA) as an additive.
Sixty caries free human premolars were mounted in epoxy resin. After polishing, the baseline micro-hardness was recorded three times for each specimen using a Vickers indenter at 50 gm load. Subsequently, the samples were divided into six groups, which were treated for 5 minutes at 9°C by a cola-based drink contacting 0, 0.5, 1, 5, and 10 wt.% of nano-HA while the control group was immersed in artificial saliva. Ultimately, the final microhardness was assessed three times again for each specimen.
Paired t-test showed that in groups containing 0 and 0.5 wt.% of nano-HA, the microhardness was significantly reduced after treatment protocol (p = 0.00 and 0.01 respectively). Whereas in the other groups the microhardness was not significantly changed after treatment (p > 0.05).
Pure cola-based drink has a pronounced adverse effect on enamel microhardness, while admixing it with nano-HA could act as a protective factor.
Although soft beverages are hazardous to tooth structure, some additives could compensate their adverse effect.
Preclinical studies have suggested that the pancreatic tumor microenvironment both inhibits and promotes tumor development and growth. Here we establish the role of stromal fibroblasts during acinar-to-ductal metaplasia (ADM), an initiating event in pancreatic cancer formation. The transcription factor V-Ets avian erythroblastosis virus E26 oncogene homolog 2 (ETS2) was elevated in smooth muscle actin-positive fibroblasts in the stroma of pancreatic ductal adenocarcinoma (PDAC) patient tissue samples relative to normal pancreatic controls. LSL-Kras(G12D/+); LSL-Trp53(R172H/+); Pdx-1-Cre (KPC) mice showed that ETS2 expression initially increased in fibroblasts during ADM and remained elevated through progression to PDAC. Conditional ablation of Ets-2 in pancreatic fibroblasts in a Kras(G12D)-driven mouse ADM model decreased the amount of ADM events. ADMs from fibroblast Ets-2-deleted animals had reduced epithelial cell proliferation and increased apoptosis. Surprisingly, fibroblast Ets-2 deletion significantly altered immune cell infiltration into the stroma, with an increased CD8+ T-cell population, and decreased presence of regulatory T cells (Tregs), myeloid-derived suppressor cells, and mature macrophages. The mechanism involved ETS2-dependent chemokine ligand production in fibroblasts. ETS2 directly bound to regulatory sequences for Ccl3, Ccl4, Cxcl4, Cxcl5, and Cxcl10, a group of chemokines that act as potent mediators of immune cell recruitment. These results suggest an unappreciated role for ETS2 in fibroblasts in establishing an immune-suppressive microenvironment in response to oncogenic Kras(G12D) signaling during the initial stages of tumor development.
New determinants of quality of life in schizophrenia need to be identified. As sensory gating deficit is core impairment in schizophrenia, the present study hypothesized that sensory gating deficit is a determinant of impaired quality of life in schizophrenia. This study therefore investigated the relationship between sensory gating deficit and quality of life in patients with schizophrenia after adjusting for key confounding factors.
Sensory gating was assessed with the auditory event-related potential method by measuring P50 amplitude changes in a double-click conditioning-testing procedure, perceptual impairments related to sensory gating deficit was assessed with the SGI questionnaire and quality of life was assessed with the SQoL 18 questionnaire in 39 patients with schizophrenia.
Patients with sensory gating deficit (n=14) had a lower subjective quality of life on the psychological well-being dimension evaluated with SQoL 18 questionnaire (p=0.008) compared to those without it (n=25). This result remained significant (B=-0.45, Wald=4.84, p=0.02) after taking into account 7 potential confounding factors (gender, age, level of education, duration of disorder, positive symptoms, depressive symptoms and anxiety symptoms). Poorer psychological well-being was related to a higher score on the SGI (rho=-0.40, p=0.01), in particular on the Distractibility dimension (rho=-0.47, p=0.001).
These findings suggest that sensory gating deficit may be a determinant of impaired quality of life in schizophrenia. Further studies are needed to address the causal relationship between sensory gating deficit, perceptual impairments, attentional deficit and impaired quality of life in schizophrenia in order to act more efficiently on the quality of life of patients with this disorder.
State agencies play a critical role in addressing the mental health needs of children and youth. Significant changes underway throughout the nation at the federal and state levels have led to questions about the role of state children's mental health (CMH) agencies and the effects of these changes on children's services. The purpose of this study was to examine the current status of state offices for CMH with regard to structure and responsibilities and to identify what state CMH directors express as opportunities and challenges for CMH at the state level. CMH directors or their representatives from 46 states, 1 US territory, and D.C. completed an online survey developed to address the specific aims of this study. Findings highlight the importance of a strong state structure to support CMH and opportunities for reform and system change, particularly related to the Affordable Care Act and expansion of Systems of Care.
To determine whether restrictions on the availability of alcohol in two inner-city entertainment areas in Sydney, Australia (1) reduced the incidence of assault in those areas, (2) increased the incidence of assault in nearby areas (where the restrictions did not apply), (3) resulted in a net reduction in overall levels of assault (4) and/or whether the reductions in assault were most pronounced during the daily time-periods when liquor trading restrictions were in operation.
Structural time-series modelling was used to estimate and compare trends in assault in areas/times affected by the new restrictions on alcohol availability with trends in assault in areas unaffected by the new restrictions.
Sydney, Australia.
The primary outcome measure was the police-recorded monthly incidence of non-domestic assault in the 78 months between January 2009 and June 2015.
Following the reforms, we found reductions in assaults of 45% [beta = -0.599, 95% confidence interval (CI) = -1.107, -0.091] and 22% (beta =0.260, 95% CI = -0.397, -0.123), respectively, in the Kings Cross and Sydney CBD Entertainment Precincts. In the Kings Cross Entertainment Precinct, reductions in assault were observed in all three daily time-periods. In the Sydney CBD Entertainment Precinct reductions in assault were observed only in the second and third daily time-periods. Assaults did not increase in entertainment areas adjacent to or within easy reach of the target areas.
Restrictions on the availability of alcohol appear to reduce the incidence of assault.
The coordinated orientation of cells across the tissue plane, known as planar cell polarity (PCP), is manifested by the segregation of core PCP proteins to different sides of the cell. Secreted Wnt ligands are involved in many PCP-dependent processes, yet whether they act as polarity cues has been controversial. We show that in Xenopus early ectoderm, the Prickle3/Vangl2 complex was polarized to anterior cell edges and this polarity was disrupted by several Wnt antagonists. In midgastrula embryos, Wnt5a, Wnt11, and Wnt11b, but not Wnt3a, acted across many cell diameters to orient Prickle3/Vangl2 complexes away from their sources regardless of their positions relative to the body axis. The planar polarity of endogenous Vangl2 in the neuroectoderm was similarly redirected by an ectopic Wnt source and disrupted after depletion of Wnt11b in the presumptive posterior region of the embryo. These observations provide evidence for the instructive role of Wnt ligands in vertebrate PCP.
Parasites are recorded from the red squirrel, Sciurus vulgaris, from Cheongju, the Republic of Korea. A total of 5 road-killed squirrels were thoroughly examined for internal and external parasites from November 2011 to May 2014. Total 4 parasite species, including 1 tapeworm and 3 ectoparasite species were recovered. They were morphologically identified as Catenotaenia dendritica (Cestoda: Catenotaeniidae), Hirstionyssus sciurinus, Leptotrombidium
 pallidum, and Ceratophyllus (Monopsyllus) indages. Among them, C. dendritica and H. sciurinus are recorded for the first time in the Korean parasite fauna. In addition, the possibility that the red squirrel could act as a reservoir host for a zoonotic disease like tsutsugamushi disease with L. pallidum as its vector has been raised.
The beautiful structural colors in bird feathers are some of the brightest colors in nature, and some of these colors are created by arrays of melanin granules that act as both structural colors and scattering absorbers. Inspired by the color of bird feathers, high-visibility structural colors have been created by altering four variables: size, blackness, refractive index, and arrangement of the nano-elements. To control these four variables, we developed a facile method for the preparation of biomimetic core-shell particles with melanin-like polydopamine (PDA) shell layers. The size of the core-shell particles was controlled by adjusting the core polystyrene (PSt) particles' diameter and the PDA shell thicknesses. The blackness and refractive index of the colloidal particles could be adjusted by controlling the thickness of the PDA shell. The arrangement of the particles was controlled by adjusting the surface roughness of the core-shell particles. This method enabled the production of both iridescent and non-iridescent structural colors from only one component. This simple and novel process of using core-shell particles containing PDA shell layers can be used in basic research on structural colors in nature and their practical applications.
This final rule details the requirements for submitting registration and summary results information, including adverse event information, for specified clinical trials of drug products (including biological products) and device products and for pediatric postmarket surveillances of a device product to ClinicalTrials.gov, the clinical trial registry and results data bank operated by the National Library of Medicine (NLM) of the National Institutes of Health (NIH). This rule provides for the expanded registry and results data bank specified in Title VIII of the Food and Drug Administration Amendments Act of 2007 (FDAAA) to help patients find trials for which they might be eligible, enhance the design of clinical trials and prevent duplication of unsuccessful or unsafe trials, improve the evidence base that informs clinical care, increase the efficiency of drug and device development processes, improve clinical research practice, and build public trust in clinical research. The requirements apply to the responsible party (meaning the sponsor or designated principal investigator) for certain clinical trials of drug products (including biological products) and device products that are regulated by the Food and Drug Administration (FDA) and for pediatric postmarket surveillances of a device product that are ordered by FDA.
The controlled activation of proteins in living cells is an important goal in protein-design research, but to introduce an artificial activation switch into membrane proteins through rational design is a significant challenge because of the structural and functional complexity of such proteins. Here we report the allosteric activation of two types of membrane-bound neurotransmitter receptors, the ion-channel type and the G-protein-coupled glutamate receptors, using coordination chemistry in living cells. The high programmability of coordination chemistry enabled two His mutations, which act as an artificial allosteric site, to be semirationally incorporated in the vicinity of the ligand-binding pockets. Binding of Pd(2,2'-bipyridine) at the allosteric site enabled the active conformations of the glutamate receptors to be stabilized. Using this approach, we were able to activate selectively a mutant glutamate receptor in live neurons, which initiated a subsequent signal-transduction pathway.
A significant function of the immune system is the surveillance and elimination of aberrant cells that give rise to cancer. Even when tumors are well established and metastatic, immune-mediated spontaneous regressions have been documented. While there are have been various forms of immunotherapy, one of the most widely studied for almost 40 years is adoptive cellular immunotherapy, but its success has yet to be fully realized. Adoptive cell transfer (ACT) is a therapeutic modality that has intrigued physicians and researchers for its many theoretical benefits. Preclinical investigations and human trials have utilized natural killer (NK) cells, dendritic cells (DC), macrophages, T-cells or B-cells for ACT with the most intense research focused on T-cell ACT. T-cells are exquisitely specific to the target of its T-cell receptor (TCR), thus potentially reducing the amount of collateral damage and off-target effects from treatment. T-cells also possess a memory subset that may reduce the risk of recurrence of a cancer after the successful treatment of the primary disease. There are several options for the source of T-cells used in the generation of cells for ACT. Perhaps the most widely known source is T-cells generated from tumor-infiltrating lymphocytes (TILs). However, studies have also employed peripheral blood mononuclear cells (PBMCs), lymph nodes, and even induced pluripotent stem cells (IPSCs) as a source of T-cells. Several important technical considerations exist regarding benefits and limitations of each source of T-cells. Unique aspects of T-cells factor into their ability to be efficacious in ACT including the total number of cells available for ACT, the anti-tumor efficacy on a per cell basis, the repertoire of TCRs specific to tumor cells, and their ability to traffic to various organs that harbor tumor. Current research is attempting to unlock the full potential of these cells to effectively and safely treat cancer.
Antimicrobial peptides (AMPs) have remarkably different structures as well as biological activity profiles, whereupon most of these peptides are supposed to kill bacteria via membrane damage. In order to understand their molecular mechanism and target cell specificity for Gram-positive bacteria, it is essential to consider the architecture of their cell envelopes. Before AMPs can interact with the cytoplasmic membrane of Gram-positive bacteria, they have to traverse the cell wall composed of wall- and lipoteichoic acids and peptidoglycan. While interaction of AMPs with peptidoglycan might rather facilitate penetration, interaction with anionic teichoic acids may act as either a trap for AMPs or a ladder for a route to the cytoplasmic membrane. Interaction with the cytoplasmic membrane frequently leads to lipid segregation affecting membrane domain organization, which affects membrane permeability, inhibits cell division processes or leads to delocalization of essential peripheral membrane proteins. Further, precursors of cell wall components, especially the highly conserved lipid II, are directly targeted by AMPs. Thereby, the peptides do not inhibit peptidoglycan synthesis via binding to proteins like common antibiotics, but form a complex with the precursor molecule, which in addition can promote pore formation and membrane disruption. Thus, the multifaceted mode of actions will make AMPs superior to antibiotics that act only on one specific target.
Microglia are considered to be the resident immune cells of the central nervous system and contribute significantly to ongoing neuroinflammation in a variety of neurodegenerative diseases. Recently, we and others identified that voltage-gated sodium channels (VGSC) are present on microglia cells and contribute to excessive accumulation of intracellular Na(+) and release of major pro-inflammatory cytokine tumor necrosis factor alpha (TNF-α). Based on this finding and the fact that pyrethroid pesticides act on VGSC, we hypothesized that exposure of microglia to the pyrethroid pesticides, permethrin and deltamethrin, would activate microglia and increase the release of TNF-α. BV2 cells or primary microglia were treated with 0-5 μM deltamethrin or permethrin in the presence or absence of tetrodotoxin (TTX), a VGSC blocker for 24-48 hr. Both pyrethroids caused a rapid Na(+) influx and increased accumulation of intracellular sodium [(Na+)i] in the microglia in a dose- and time-dependent manner, which was significantly reduced by TTX. Furthermore, deltamethrin and permethrin increased the release of TNF-α in a dose- and time-dependent manner, which was significantly reduced by pre-treatment of cells with TTX. These results demonstrate that pyrethroid pesticides may directly activate microglial cells through their interaction with microglial VGSC. Because neuroinflammation plays a key role in many neurodegenerative diseases, these data provide an additional mechanism by which exposure to pyrethroid insecticides may contribute to neurodegeneration.
Silicon nanowires (SiNWs) show strong resonant wavelength enhancement in terms of absorption as well as scattering of light. However, in most optoelectronic device concepts the SiNWs should be surrounded by a contact layer. Ideally, such a layer can also act as an index matching layer which could nearly halve the strong reflectance of light by silicon. Our results show that this reduction can be overcome at the nanometer scale, i.e. SiNWs embedded in a silica (SiO x ) layer can not only maintain their high scattering cross sections but also their strong polarization dependent scattering. Such effects can be useful for light harvesting or optoelectronic applications. Moreover, we show that it is possible to optically determine the diameters of the embedded nanoscale silicon (Si) cores.
In the United States, authoritative legal guidance remains sparse on whether or when clinicians may stop life-sustaining treatment without consent. Fortunately,
 several significant legislative and judicial developments over the past two years offer some clarity. We group these legal developments into the following seven categories: 1. Lawsuits for Damages 2. Amendments to the Texas Advance Directives Act 3. Constitutional Attack on TADA 4. Legislation Prohibiting Clinicians 5. Legislation Authorizing Clinicians 6. Cases from Canada 7. Cases from the United Kingdom.
As practicing clinicians, physicians are expected to uphold the ethical norms of their profession, including fidelity to patients and respect for patients' self-determination. At the same time, as individuals, physicians are moral agents in their own right and, like their patients, are informed by and committed to diverse cultural, religious, and philosophical traditions and beliefs. In some circumstances, the expectation that physicians will put patients' needs and preferences first may be in tension with the need to sustain the sense of moral integrity and continuity that grounds a physician's personal and professional life. This article examines the implications for patients, physicians, and the medical profession when tensions arise between a physician's professional commitments and his or her deeply held personal moral beliefs. It offers guidance on when a physician's professional commitments should outweigh personal beliefs as well as when physicians should have freedom to act according to the dictates of conscience while still protecting patients' interests.
Complex older patients represent about half of all acute public hospital admissions in Australia. People with dementia are a classic example of complex older patients, and have been identified to have higher rates of hospital-acquired complications. Complications contribute to poorer patient outcomes, and increase length of stay and cost to hospitals. The care for older people with dementia is complex, and this has been attributed to: their cognitive response to being hospitalised; their limited ability to self-care; and lack of nursing engagement with the family caregiver. Registered nurses can offer simultaneous assessment and intervention to prevent or mitigate hospital-acquired complications. However, it is known that when demand for nursing care exceeds supply, care is prioritised according to acute medical need. Consequently some basic but essential nursing care activities such as patient mobility, communication, skin care, hydration and nutrition are implicitly rationed. This paper offers a theoretical proposition of 'Failure to Maintain' as a conceptual framework to indicate implicit care rationing by nurses. Care rationing contributes to functional and cognitive decline of complex older patients, which then contributes to higher rates of hospital acquired complications. Four key hospital acquired complications: pressure injuries, pneumonia, urinary tract infections and delirium are proposed as measurable indicators of 'Failure to Maintain'. Hospital focus on throughput constrains nurses to privilege predictable, solvable and medically-related procedures and processes that will lead to efficient discharge over patient mobility, communication, skin care, hydration and nutrition. This privileging, also known as implicit rationing, is theoretically and physiologically associated with a rise in the incidence of complications such as pressure injuries, pneumonia, urinary tract infection, and delirium. Complex older patients, including those with dementia, are at higher risk of the complications, therefore should have higher delivery of prophylactic intervention (ie have higher care needs). 'Failure to Maintain' offers a conceptual framework that is inclusive of, and sensitive to, this vulnerable population. Implicit rationing is occurring and it likely contributes to functional and cognitive decline in complex older patients and hospital-acquired complications. However, the lack of patient functional ability data at admission and discharge for hospitalised patients, and lack of usable ward and hospital level nurse staffing and workload data makes it difficult to monitor, understand and improve quality of care. Current research in the fields of acute geriatrics and nursing work environments show promise through enabling multidisciplinary team communication, and facilitating clinical autonomy to provide patient focussed care, and avoid 'Failing to Maintain'. The research field of acute geriatrics can understand and act on the risk modification role of nurses, including controlling for nurse staffing and work environment variables in intervention studies. The research field of nurse sensitive outcomes should incorporate the different profile of complex older patients, by including age brackets and functional ability as variables in their studies. Clinically, nursing work environments can be designed to recognise the different profile of complex older patients by adapting practices to privilege mobility, hydration, nutrition, skin care and communication in the midst of acute care interventions.
Cutaneous leishmaniasis has various outcomes, ranging from self-healing reddened papules to extensive open ulcerations that metastasise to secondary sites and are often resistant to standard therapies. In the case of L. guyanensis (L.g), about 5-10% of all infections result in metastatic complications. We recently showed that a cytoplasmic virus within L.g parasites (LRV1) is able to act as a potent innate immunogen, worsening disease outcome in a murine model. In this study, we investigated the immunophenotype of human patients infected by L.g and found a significant association between the inflammatory cytokine IL-17A, the presence of LRV1 and disease chronicity. Further, IL-17A was inversely correlated to the protective cytokine IFN-γ. These findings were experimentally corroborated in our murine model, where IL-17A produced in LRV1+ L.g infection contributed to parasite virulence and dissemination in the absence of IFN-γ. Additionally, IL-17A inhibition in mice using digoxin or SR1001, showed therapeutic promise in limiting parasite virulence. Thus, this murine model of LRV1-dependent infectious metastasis validated markers of disease chronicity in humans and elucidated the immunologic mechanism for the dissemination of Leishmania parasites to secondary sites. Moreover, it confirms the prognostic value of LRV1 and IL-17A detection to prevent metastatic leishmaniasis in human patients.
Previous research has demonstrated that Latino young adults are uninsured at higher rates relative to other ethnoracial groups. Recent implementation of the 2010 Affordable Care Act (ACA) has increased access to health insurance for young adults, in part by maintaining health coverage through their parents until age 26. This paper examines patterns of Latino young adults' insurance coverage during early ACA implementation by addressing three questions: 1) To what extent do Latino young adults remain uninsured relative to their peers of other ethnoracial groups? 2) How do young adults' family socioeconomic background, immigrant characteristics, college enrollment, and employment status mediate their coverage? And, 3) do patterns of insurance coverage differ for employer-provided coverage versus other sources of coverage (including parents' health insurance)? Using a 2011 representative sample of U.S.-born and 1.5-generation immigrant young adults in California, we find that Latinos are more likely than other ethnoracial groups to remain uninsured. While they are as likely as similar peers to obtain employer-provided health insurance, they are less likely to possess insurance through other sources (including their parents). This study contributes to our understanding of the limits of the ACA in reducing disparities in insurance coverage for Latinos by highlighting the importance of family socioeconomic background, immigrant characteristics, college enrollment, and employment in shaping coverage among this age group.
Cytomegalovirus (CMV) infection can generate debilitating disease in immunocompromised individuals and neonates. It is also the most common infectious cause of congenital birth defects in infected fetuses. Available anti-CMV drugs are partially effective but are limited by some toxicity, potential viral resistance, and are not recommended for fetal exposure. Valproate, valpromide, and valnoctamide have been used for many years to treat epilepsy and mood disorders. We report for the first time that, in contrast to the virus-enhancing actions of valproate, structurally related valpromide and valnoctamide evoke a substantial and specific inhibition of mouse and human CMV in vitro. In vivo, both drugs safely attenuate mouse CMV, improving survival, body weight, and developmental maturation of infected newborns. The compounds appear to act by a novel mechanism that interferes with CMV attachment to the cell. Our work provides a novel potential direction for CMV therapeutics through repositioning of agents already approved for use in psychiatric disorders.
Although research has explored between-person traits that may account for the co-occurrence of non-suicidal self-injury (NSSI) and disordered eating (DE), little is known about within-person processes that predict when each behavior occurs. This study describes the socioemotional contexts of NSSI and DE behaviors during a two-week daily diary period. Young adults (aged 18-35) who reported ≥1 episode of NSSI and ≥1 episode of DE (binge eating, purging, or fasting) during the diary period were included (N=25). NSSI and DE co-occurred approximately one third of the time. Participants were more likely to act on NSSI thoughts following arguments and feelings of rejection. They were more likely to act on binge eating/purging thoughts after eating or watching television, and when they felt self-hatred. They were more likely
 to act on fasting thoughts after discussing upsetting memories, and when they were in a public setting. NSSI days were marked by more intense negative mood in the evenings relative to fasting days, and greater fatigue in the morning relative to binge eating/purging days. This study underscores the utility of using experience-sampling methods to develop and test within-person models to advance our understanding of co-occurring behaviors.
This paper introduces the Fuzzy Logic Hypercube Interpolator (FLHI) and demonstrates applications in control of multiple-input single-output (MISO) and multiple-input multiple-output (MIMO) processes with Hammerstein nonlinearities. FLHI consists of a Takagi-Sugeno fuzzy inference system where membership functions act as kernel functions of an interpolator. Conjunction of membership functions in an unitary hypercube space enables multivariable interpolation of N-dimensions. Membership functions act as interpolation kernels, such that choice of membership functions determines interpolation characteristics, allowing FLHI to behave as a nearest-neighbor, linear, cubic, spline or Lanczos interpolator, to name a few. The proposed interpolator is presented as a solution to the modeling problem of static nonlinearities since it is capable of modeling both a function and its inverse function. Three study cases from literature are presented, a single-input single-output (SISO) system, a MISO and a MIMO system. Good results are obtained regarding performance metrics such as set-point tracking, control variation and robustness. Results demonstrate applicability of the proposed method in modeling Hammerstein nonlinearities and their inverse functions for implementation of an output compensator with Model Based Predictive Control (MBPC), in particular Dynamic Matrix Control (DMC).
Like RAS proteins, the aberrant function of RHO family small GTPases has been implicated in driving cancer development and growth. However, unlike the RAS family, where gain-of-function missense mutations are found in ∼25% of all human cancers, missense mutations are relatively rare in RHO proteins. Instead, altered RHO activity in cancer more commonly arises through the aberrant functions of RHO GTPase regulators. In many cancer types, altered expression and/or mutation of RHO-selective guanine nucleotide exchange factors (RHOGEFs) or GTPase-activating proteins (RHOGAPs), which activate or inactivate RHO GTPases, respectively, is observed. For example, deletion or loss of expression of the RHOA GAP DLC1 is well-established to drive cancer growth. Recently, we identified high expression of 2 RHOGAPs, ARHGAP11A and RACGAP1, in the basal-like breast cancer subtype. Unexpectedly, both of these RHOA GAPs exhibited properties of oncoproteins rather than tumor suppressors, in contrast to DLC1. In this commentary, we summarize our findings and speculate that different RHOA GAPs can play distinct roles in cancer depending on their spatial regulation and cancer type context. We also evaluate our results in light of recently-described cancer genome sequencing studies that have identified loss-of-function mutations of RHOA in specific cancer types.
Cyclin-dependent kinase 2 (CDK2), a member of Cyclin-dependent kinases (CDKs), plays an important role in cell division and DNA replication. It is regarded as a desired target to treat cancer and tumor by interrupting aberrant cell proliferation. Compared to lower subtype selectivity of CDK2 ATP-competitive inhibitors, CDK2 allosteric inhibitor with higher subtype selectivity has been used to treat CDK2-related diseases. Recently, the first crystal structure of CDK2 with allosteric inhibitor has been reported, which provides new opportunities to design pure allosteric inhibitors of CDK2. The binding site of the ATP-competition inhibitors and the allosteric inhibitors are partially overlapped in space position, so the same compound might interact with the two binding sites. Thus a novel screening strategy was essential for the discovery of pure CDK2 allosteric inhibitors. In this study, pharmacophore and molecular docking were used to screen potential CDK2 allosteric inhibitors and ATP-competition inhibitors from Traditional Chinese Medicine (TCM). In the docking result of the allosteric site, the compounds which can act with the CDK2 ATP site were discarded, and the remaining compounds were regarded as the potential pure allosteric inhibitors. Among the results, prostaglandin E1 and nordihydroguaiaretic acid (NDGA) were available and their growth inhibitory effect on human HepG2 cell lines was determined by MTT assay. The two compounds could substantially inhibit the growth of HepG2 cell lines with an estimated IC50 of 41.223 μmol/L and 45.646 μmol/L. This study provides virtual screening strategy of allosteric compounds and a reliable method to discover potential pure CDK2 allosteric inhibitors from TCM. Prostaglandin E1 and NDGA could be regarded as promising candidates for CDK2 allosteric inhibitors.
Flavonoids are a group of compounds that are commonly found in various plants, where they play important roles in many processes, including free radical scavenging and UV protection. These compounds can also act as chemical messengers, physiological regulators or protectants against pathogens in the defense reactions of plants. Flavonoid activity is regulated by the addition of various substituents, usually mono- or oligosaccharides of common sugars, such as glucose, rhamnose or galactose. In some plants, glucuronic acid is attached, and this sugar is often acylated by phenylpropanoic acids. Identification of these compounds and their derivatives is of great importance to understanding their role in plant metabolism and defense mechanisms; this research is important because flavonoids are frequently a significant constituent of the human diet. In this study, we identify the flavonoid conjugates present in Axyris amaranthoides L. extracts and demonstrate the usefulness of high-resolution mass spectrometry (HRMS) analyzers for the differentiation of isobaric compounds and the utility of fragmentation spectra for the differentiation of isomeric structures. According to our knowledge, some of the structures, especially dehydrodiferulated conjugates of tricin, whose structures are proposed here have been found for the first time in plant material.
Palonosetron is a potent 5-HT3 receptor antagonist and an effective therapeutic agent against emesis. Here we identify the molecular determinants of compound recognition in the receptor binding site by obtaining a high resolution structure of palonosetron bound to an engineered acetylcholine binding protein that mimics the 5-HT3 receptor binding site, termed 5-HTBP, and by examining the potency of palonosetron in a range of 5-HT3 receptors with mutated binding site residues. The structural data indicate that palonosetron forms a tight and effective wedge in the binding pocket, made possible by its rigid tricyclic ring structure and its interactions with binding site residues; it adopts a binding pose that is distinct from the related antiemetics granisetron and tropisetron. The functional data show many residues previously shown to interact with agonists and antagonists in the binding site are important for palonosetron binding, and indicate those of particular importance are W183 (a cation-π interaction and a hydrogen bond) and Y153 (a hydrogen bond). This information, and the availability of the structure of palonosetron bound to 5-HTBP, should aid the development of novel and more efficacious drugs that act via 5-HT3 receptors.
Background: Recent data show that among persons who needed substance abuse treatment (SAT) and made an effort to obtain it, the most often reported reason for not receiving SAT was lack of health coverage and inability to afford the cost of treatment (38.2%). High unemployment rates have been associated with declines in the number of clients entering SAT. It has been estimated that about 9 million Americans lost their health insurance due to unemployment during the 2007 to 2009 recession. Methods: This report describes the social and economic characteristics of SAT admissions between 2006 and 2011 using Treatment Episode Data Set (TEDS) such as employment status of admissions at treatment entry and health insurance status of treatment admissions and expected source of payment by treatment admissions. Data from the National Survey of Substance Abuse Treatment Services (N-SSATS) was used to identify the types of client payment or insurance accepted by facilities and ancillary services provided by treatment facilities during the same time period. Results: The percentage of SAT admissions reporting unemployment at treatment entry increased from 33.2% in 2006 to 41.6% in 2011; during this time, over one-third of facilities offered employment counseling or training services. Between 2006 and 2011, about 6 in 10 admissions reported having no health insurance coverage at treatment entry. Over 6 in 10 facilities offered sliding fee scales to clients who could not afford to pay for treatment. About half of admissions aged 22 or older expected to pay for their treatment using Medicaid, Medicare, or other government payment; over half of the SAT facilities accepted Medicaid between 2006 (52%) and 2011 (57%). Conclusion: This report shows that from 2006 to 2011, a high percentage of SAT admissions aged 22 or older lacked health insurance coverage and were not employed. In light of these economic barriers, the acceptance of Medicaid reported by a large proportion of facilities may play a crucial role in facilitating access to SAT for individuals experiencing economic hardship. As the Affordable Care Act is implemented through 2014, it is anticipated that there will be upward trends in Medicaid coverage as the program has been expanded
 to include those individuals who were formerly ineligible. Moreover, access to health care services for substance use is expected to improve as the previously uninsured gain health insurance coverage.
Those convicted of homicide were hanged on the public gallows before being dissected under the Murder Act in Georgian England. Yet, from 1752, whether criminals actually died on the hanging tree or in the dissection room remained a medical mystery in early modern society. Dissecting the Criminal Corpse takes issue with the historical cliché of corpses dangling from the hangman’s rope in crime studies. Some convicted murderers did survive execution in early modern England. Establishing medical death in the heart-lungs-brain was a physical enigma. Criminals had large bull-necks, strong willpowers, and hearty survival instincts. Extreme hypothermia often disguised coma in a prisoner hanged in the winter cold. The youngest and fittest were capable of reviving on the dissection table. Many died under the lancet. Capital legislation disguised a complex medical choreography that surgeons staged. They broke the Hippocratic Oath by executing the Dangerous Dead across England from 1752 until 1832.
Adoptive cellular therapy (ACT) is a form of immunotherapy whereby antigen-specific T cells are isolated or engineered, expanded ex vivo, and transferred back to patients. Clinical benefit after ACT has been obtained in treatment of infection, various hematological malignancies, and some solid tumors; however, due to poor functionality and persistence of the transferred T cells, the efficacy of ACT in the treatment of most solid tumors is often marginal. Hence, much effort is undertaken to improve T cell function and persistence in ACT and significant progress is being made. Herein, we will review strategies to improve ACT success rates in the treatment of cancer and infection. We will deliberate on the most favorable phenotype for the tumor-specific T cells that are infused into patients and on how to obtain T cells bearing this phenotype by applying novel ex vivo culture methods. Moreover, we will discuss T cell function and persistence after transfer into patients and how these factors can be manipulated by means of providing costimulatory signals, cytokines, blocking antibodies to inhibitory molecules, and vaccination. Incorporation of these T cell stimulation strategies and combinations of the different treatment modalities are likely to improve clinical response rates further.
We translated the Canadian residential long term care versions of the Alberta Context Tool (ACT) and the Conceptual Research Utilization (CRU) Scale into German, to study the association between organizational context factors and research utilization in German nursing homes. The rigorous translation process was based on best practice guidelines for tool translation, and we previously published methods and results of this process in two papers. Both instruments are self-report questionnaires used with care providers working in nursing homes. The aim of this study was to assess the factor structure, reliability, and measurement invariance (MI) between care provider groups responding to these instruments. In a stratified random sample of 38 nursing homes in one German region (Metropolregion Rhein-Neckar), we collected questionnaires from 273 care aides, 196 regulated nurses, 152 allied health providers, 6 quality improvement specialists, 129 clinical leaders, and 65 nursing students. The factor structure was assessed using confirmatory factor models. The first model included all 10 ACT concepts. We also decided a priori to run two separate models for the scale-based and the count-based ACT concepts as suggested by the instrument developers. The fourth model included the five CRU Scale items. Reliability scores were calculated based on the parameters of the best-fitting factor models. Multiple-group confirmatory factor models were used to assess MI between provider groups. Rather than the hypothesized ten-factor structure of the ACT, confirmatory factor models suggested 13 factors. The one-factor solution of the CRU Scale was confirmed. The reliability was acceptable (>0.7 in the entire sample and in all provider groups) for 10 of 13 ACT concepts, and high (0.90-0.96) for the CRU Scale. We could demonstrate partial strong MI for both ACT models and partial strict MI for the CRU Scale. Our results suggest that the scores of the German ACT and the CRU Scale for nursing homes are acceptably reliable and valid. However, as the ACT lacked strict MI, observed variables (or scale scores based on them) cannot be compared between provider groups. Rather, group comparisons should be based on latent variable models, which consider the different residual variances of each group.
Adverse intra- and extracellular effects of toxic α-synuclein are believed to be central to the pathogenesis in Parkinson's disease and other disorders with Lewy body pathology in the nervous system. One of the physiological roles of α-synuclein relates to the regulation of neurotransmitter release at the presynapse, although it is still unclear whether this mechanism depends on the action of monomers or smaller oligomers. As for the pathogenicity, accumulating evidence suggest that prefibrillar species, rather than the deposits per se, are responsible for the toxicity in affected cells. In particular, larger oligomers or protofibrils of α-synuclein have been shown to impair protein degradation as well as the function of several organelles, such as the mitochondria and the endoplasmic reticulum. Accumulating evidence further suggest that oligomers/protofibrils may have a toxic effect on the synapse, which may lead to disrupted electrophysiological properties. In addition, recent data indicate that oligomeric α-synuclein species can spread between cells, either as free-floating proteins or via extracellular vesicles, and thereby act as seeds to propagate disease between interconnected brain regions. Taken together, several lines of evidence suggest that α-synuclein have neurotoxic properties and therefore should be an appropriate molecular target for therapeutic intervention in Parkinson's disease and other disorders with Lewy pathology. In this context, immunotherapy with monoclonal antibodies against α-synuclein oligomers/protofibrils should be a particularly attractive treatment option.
This study aims to compare the periapical healing of teeth with asymptomatic apical periodontitis treated either by conventional apical preparation (CAP) or apical clearing technique (ACT).
Twenty subjects with bilateral nonvital similar teeth exhibiting comparable periapical index (PAI) score were enrolled and randomly allocated. Group I (CAP, n = 20): Apical preparation three sizes greater (master apical file [MAF]) than the first binding file at the established working length. Group II (ACT, n = 20): Apical preparation three sizes greater than the MAF that was followed by dry reaming. Root canal therapy was accomplished in single-visit for all the teeth. They were pursued radiographically at 3, 6, 9 and 12 months. Pre- and post-treatment PAI scores were compared. To ascertain the proportion of healed teeth between the two groups, McNemar Chi-square test was applied.
At 3, 6, and 9 months' time interval the proportion of healed teeth for Group II (ACT) was greater in comparison to Group I (CAP) (P < 0.05). However, at 12 months follow-up period this difference was not significant (P = 0.08).
ACT enhanced the healing kinetics. However, the long-term (12 months) radiographic outcome was similar for either technique.
Experience with sexual behavior causes cross-sensitization of amphetamine reward, an effect dependent on a period of sexual reward abstinence. We previously showed that ΔFosB in the nucleus accumbens (NAc) is a key mediator of this cross-sensitization, potentially via dopamine receptor activation. However, the role of mesolimbic dopamine for sexual behavior or cross-sensitization between natural and drug reward is unknown. This was tested using inhibitory designer receptors exclusively activated by designer drugs in ventral tegmental area (VTA) dopamine cells. rAAV5/hSvn-DIO-hm4D-mCherry was injected into the VTA of TH::Cre adult male rats. Males received clozapine N-oxide (CNO) or vehicle injections before each of 5 consecutive days of mating or handling. Following an abstinence period of 7 d, males were tested for amphetamine conditioned place preference (CPP). Next, males were injected with CNO or vehicle before mating or handling for analysis of mating-induced cFos, sex experience-induced ΔFosB, and reduction of VTA dopamine soma size. Results showed that CNO did not affect mating behavior. Instead, CNO prevented sexual experience-induced cross-sensitization of amphetamine CPP, ΔFosB in the NAc and medial prefrontal cortex, and decreases in VTA dopamine soma size. Expression of hm4D-mCherry was specific to VTA dopamine cells and CNO blocked excitation and mating-induced cFos expression in VTA dopamine cells. These findings provide direct evidence that VTA dopamine activation is not required for initiation or performance of sexual behavior. Instead, VTA dopamine directly contributes to increased vulnerability for drug use following loss of natural reward by causing neuroplasticity in the mesolimbic pathway during the natural reward experience.
Drugs of abuse act on the neural pathways that mediate natural reward learning and memory. Exposure to natural reward behaviors can alter subsequent drug-related reward. Specifically, experience with sexual behavior, followed by a period of abstinence from sexual behavior, causes increased reward for amphetamine in male rats. This study demonstrates that activation of ventral tegmental area dopamine neurons during sexual experience regulates cross-sensitization
 of amphetamine reward. Finally, ventral tegmental area dopamine cell activation is essential for experience-induced neural adaptations in the nucleus accumbens, prefrontal cortex, and ventral tegmental area. These findings demonstrate a role of mesolimbic dopamine in the interaction between natural and drug rewards, and identify mesolimbic dopamine as a key mediator of changes in vulnerability for drug use after loss of natural reward.
During peripheral inflammation, both spinal TNF-α and IL-6 are released within the spinal cord and support the generation of inflammation-evoked spinal hyperexcitability. However, whether spinal TNF-α and IL-6 act independently in parallel or in a functionally dependent manner has not been investigated. In extracellular recordings from mechanonociceptive deep dorsal horn neurons of normal rats in vivo, we found that spinal application of TNF-α increased spinal neuronal responses to mechanical stimulation of knee and ankle joints. This effect was significantly attenuated by either sgp130, which blocks IL-6 trans-signaling mediated by IL-6 and its soluble receptor IL-6R (sIL-6R); by an antibody to the IL-6 receptor; or by minocycline, which inhibits the microglia. IL-6 was localized in neurons of the spinal cord and, upon peripheral noxious stimulation in the presence of spinal TNF-α, IL-6 was released spinally. Furthermore, TNF-α recruited microglial cells to provide sIL-6R, which can form complexes with IL-6. Spinal application of IL-6 plus sIL-6R, but not of IL-6 alone, enhanced spinal hyperexcitability similar to TNF-α and the inhibition of TNF-α-induced hyperexcitability by minocycline was overcome by coadministration of sIL-6R, showing that sIL-6R is required. Neither minocycline nor the TNF-α-neutralizing compound etanercept inhibited the induction of hyperexcitability by IL-6 plus sIL-6R. Together, these data show that the induction of hyperexcitability of nociceptive deep dorsal horn neurons by TNF-α largely depends on the formation of IL-6/sIL-6R complexes that are downstream of TNF-α and requires the interactions of neurons and microglia orchestrated by TNF-α.
Both spinal TNF-α and IL-6 induce a state of spinal hyperexcitability. We present the novel finding that the full effect of TNF-α on the development of spinal hyperexcitability depends on IL-6 trans-signaling acting downstream of TNF-α. IL-6 trans-signaling requires the formation of complexes of IL-6 and soluble IL-6 receptor. Spinal TNF-α furthers the release of IL-6 from neurons in the spinal cord during peripheral noxious stimulation and recruits microglial cells to provide soluble IL-6 receptor, which can form complexes with IL-6. Therefore, a specific interaction between neurons and microglia is required for the full development of TNF-α-induced hyperexcitability of nociceptive deep horsal horn neurons.
Bin/Amphiphysin/Rvs (BAR) domain proteins control the curvature of lipid membranes in endocytosis, trafficking, cell motility, the formation of complex subcellular structures, and many other cellular phenomena. They form 3D assemblies that act as molecular scaffolds to reshape the membrane and alter its mechanical properties. It is unknown, however, how a protein scaffold forms and how BAR domains interact in these assemblies at protein densities relevant for a cell. In this work, we use various experimental, theoretical, and simulation approaches to explore how BAR proteins organize to form a scaffold on a membrane nanotube. By combining quantitative microscopy with analytical modeling, we demonstrate that a highly curving BAR protein endophilin nucleates its scaffolds at the ends of a membrane tube, contrary to a weaker curving protein centaurin, which binds evenly along the tube's length. Our work implies that the nature of local protein-membrane interactions can affect the specific localization of proteins on membrane-remodeling sites. Furthermore, we show that amphipathic helices are dispensable in forming protein scaffolds. Finally, we explore a possible molecular structure of a BAR-domain scaffold using coarse-grained molecular dynamics simulations. Together with fluorescence microscopy, the simulations show that proteins need only to cover 30-40% of a tube's surface to form a rigid assembly. Our work provides mechanical and structural insights into the way BAR proteins may sculpt the membrane as a high-order cooperative assembly in important biological processes.
Vascular endothelial growth factor receptor-1 (VEGFR-1) is a tyrosine kinase transmembrane receptor that has also a soluble isoform containing most of the extracellular ligand binding domain (sVEGFR-1). VEGF-A binds to both VEGFR-2 and VEGFR-1, whereas placenta growth factor (PlGF) interacts exclusively with VEGFR-1. In this study we generated an anti-VEGFR-1 mAb (D16F7) by immunizing BALB/C mice with a peptide that we had previously reported to inhibit angiogenesis and endothelial cell migration induced by PlGF. D16F7 did not affect binding of VEGF-A or PlGF to VEGFR-1, thus allowing sVEGFR-1 to act as decoy receptor for these growth factors, but it hampered receptor homodimerization and activation. D16F7 inhibited both the chemotactic response of human endothelial, myelomonocytic and melanoma cells to VEGFR-1 ligands and vasculogenic mimicry by tumor cells. Moreover, D16F7 exerted in vivo antiangiogenic effects in a matrigel plug assay. Importantly, D16F7 inhibited tumor growth and was well tolerated by B6D2F1 mice injected with syngeneic B16F10 melanoma cells. The antitumor effect was associated with melanoma cell apoptosis, vascular abnormalities and decrease of both monocyte/macrophage infiltration and myeloid progenitor mobilization. For all the above, D16F7 may be exploited in the therapy of metastatic melanoma and other tumors or pathological conditions involving VEGFR-1 activation.
Renal Cell Carcinoma (RCC) in humans is positively influenced by oxidative stress status in kidneys. We recently reported that adaptive response to low level of chronic oxidative stress induces malignant transformation of immortalized human renal tubular epithelial cells. Epigenetic alterations in human RCC are well documented, but its role in oxidative stress-induced malignant transformation of kidney cells is not known. Therefore, the objective of this study was to evaluate the potential role of epigenetic changes in chronic oxidative stress-induced malignant transformation of HK-2, human renal tubular epithelial cells. The results revealed aberrant expression of epigenetic regulatory genes involved in DNA methylation (DNMT1, DNMT3a and MBD4) and histone modifications (HDAC1, HMT1 and HAT1) in HK-2 cells malignantly transformed by chronic oxidative stress. Additionally, both in vitro soft agar assay and in vivo nude mice study showing decreased tumorigenic potential of malignantly transformed HK-2 cells following treatment with DNA de-methylating agent 5-aza 2' dC further confirmed the crucial role of DNA hypermethyaltion in oxidative stress-induced malignant transformation. Changes observed in global histone H3 acetylation (H3K9, H3K18, H3K27 and H3K14) and decrease in phospho-H2AX (Ser139) also suggest potential role of histone modifications in increased survival and malignant transformation of HK-2 cells by oxidative stress. In summary, the results of this study suggest that epigenetic reprogramming induced by low levels of oxidative stress act as driver for malignant transformation of kidney epithelial cells. Findings of this study are highly relevant in potential clinical application of epigenetic-based therapeutics for treatments of kidney cancers.
In biomedical applications where the size and complexity of SNOMED CT become problematic, using a smaller subset that can act as a reasonable substitute is usually preferred. In a special class of use cases-like ontology-based quality assurance, or when performing scaling experiments for real-time performance-it is essential that modules show a similar shape than SNOMED CT in terms of concept distribution per sub-hierarchy. Exactly how to extract such balanced modules remains unclear, as most previous work on ontology modularization has focused on other problems. In this study, we investigate to what extent extracting balanced modules that preserve the original shape of SNOMED CT is possible, by presenting and evaluating an iterative algorithm.
We used a graph-traversal modularization approach based on an input signature. To conform to our definition of a balanced module, we implemented an iterative algorithm that carefully bootstraped and dynamically adjusted the signature at each step. We measured the error for each sub-hierarchy and defined convergence as a residual sum of squares <1.
Using 2000 concepts as an initial signature, our algorithm converged after seven iterations and extracted a module 4.7 % the size of SNOMED CT. Seven sub-hierarhies were either over or under-represented within a range of 1-8 %.
Our study shows that balanced modules from large terminologies can be extracted using ontology graph-traversal modularization techniques under certain conditions: that the process is repeated a number of times, the input signature is dynamically adjusted in each iteration, and a moderate under/over-representation of some hierarchies is tolerated. In the case of SNOMED CT, our results conclusively show that it can be squeezed to less than 5 % of its size without any sub-hierarchy losing its shape more than 8 %, which is likely sufficient in most use cases.
To investigate the influencing factors for asthma control level in children and the practicability of evaluation indicators for asthma.
A total of 185 children with asthma were enrolled. Questionnaires and pulmonary function test were used to evaluate the asthma control level and the factors influencing the control level. The correlation between evaluation
 indicators and asthma control level was analyzed.
Among the 185 children with asthma, 139 (75.1%) achieved full control, 36 (19.5%) achieved partial control, and 10 (5.4%) had uncontrolled asthma. Application of inhaled corticosteroids and eosinophil count showed significant effects on asthma control level (P<0.05). There were significant differences in the percentage of forced expiratory volume in 1 second (FEV1%), fractional exhaled nitric oxide (FeNO), childhood asthma control test (C-ACT) questionnaire score, and pediatric asthma quality of life questionnaire (PAQLQ) score between the full control, partial control, and uncontrolled groups (P<0.05). In the children with asthma, FEV1% was positively correlated with C-ACT and PAQLQ scores (P<0.05), while there was no significant correlation between FEV1% and FeNO (P=0.214).
Application of inhaled corticosteroids and eosinophil count are factors influencing asthma control in children. A combination of FEV1%, FeNO, C-ACT score, and PAQLQ score helps with the evaluation of asthma control level.
Hepatic stellate cells (HSCs), also known as perisinusoidal cells, are pericytes found in the perisinusoidal space of the liver. HSCs are the major cell type involved in liver fibrosis, which is the formation of scar tissue in response to liver damage. When the liver is damaged, stellate cells can shift into an activated state, characterized by proliferation, contractility and chemotaxis. The activated HSCs secrete collagen scar tissue, which can lead to cirrhosis. Recent studies have shown that in vivo activation of HSCs by fibrogenic agents can eventually lead to senescence of these cells, which would contribute to reversal of fibrosis although it may also favor the insurgence of liver cancer. HSCs in their non-active form store huge amounts of retinoic acid derivatives in lipid droplets, which are progressively depleted upon cell activation in injured liver. Retinoic acid is a metabolite of vitamin A (retinol) that mediates the functions of vitamin A, generally required for growth and development. The precise function of retinoic acid and its alterations in HSCs has yet to be elucidated, and nonetheless in various cell types retinoic acid and its receptors (RAR and RXR) are known to act synergistically with peroxisome proliferator-activated receptor gamma (PPAR-gamma) signaling through the activity of transcriptional heterodimers. Here, we review the recent advancements in the understanding of how retinoic acid signaling modulates the fibrogenic potential of HSCs and proposes a synergistic combined action with PPAR-gamma in the reversal of liver fibrosis.
Allergic drug reactions are currently a major public health problem affecting patient health and increasing healthcare costs. They are caused by interactions between a drug and the human immune system and result in symptoms ranging from urticaria or angioedema to those more serious such as anaphylaxis or anaphylactic shock. The most commonly accepted mechanism for immunological activation is based on the hapten hypothesis. Drugs are low molecular weight substances that cannot cause an immune response on their own. However, they can act as haptens and form covalent adducts with proteins. The resulting hapten-carrier (drug-protein) conjugate can induce the production of IgE antibodies or T cells. An epitope, or antigenic determinant, is the part of the drug-protein antigen that is specifically recognized by the immune system. This may involve not only the drug derivative but also part of the carrier protein. Understanding the way in which drugs are metabolized after protein conjugation is vital in order to make progresses in the diagnosis of clinical allergy. In this review, recent advances in the identification of the chemical structures of antigenic determinants involved in immediate allergic reactions to drugs are presented. We have focused on drugs that most commonly elicit these reactions: betalactam and quinolone antibiotics and the non-steroidal anti-inflamatory drug pyrazolone. This will be discussed from a chemical point of view, relating our understanding of drug structure, chemical reactivity and immune recognition.
An extensive series of 44 radiocarbon (14C) and 37 optically stimulated luminescence (OSL) ages have been obtained from the site of Riwi, south central Kimberley (NW Australia). As one of the earliest known Pleistocene sites in Australia, with archaeologically sterile sediment beneath deposits containing occupation, the chronology of the site is important in renewed debates surrounding the colonization of Sahul. Charcoal is preserved throughout the sequence and within multiple discrete hearth features. Prior to 14C dating, charcoal has been pretreated with both acid-base-acid (ABA) and acid base oxidation-stepped combustion (ABOx-SC) methods at multiple laboratories. Ages are consistent between laboratories and also between the two pretreatment methods, suggesting that contamination is easily removed from charcoal at Riwi and the Pleistocene ages are likely to be accurate. Whilst some charcoal samples recovered from outside hearth features are identified as outliers within a Bayesian model, all ages on charcoal within hearth features are consistent with stratigraphy. OSL dating has been undertaken using single quartz grains from the sandy matrix. The majority of samples show De distributions that are well-bleached but that also include evidence for mixing as a result of post-depositional bioturbation of the sediment. The results of the two techniques are compared and evaluated within a Bayesian model. Consistency between the two methods is good, and we demonstrate human occupation at this site from 46.4-44.6 cal kBP (95.4% probability range). Importantly, the lowest archaeological horizon at Riwi is underlain by sterile sediments which have been dated by OSL making it possible to demonstrate the absence of human occupation for between 0.9-5.2 ka (68.2% probability range) prior to occupation.
Marek's disease virus, or Gallid herpesvirus 2 (GaHV-2), is an avian alphaherpesvirus that induces T-cell lymphoma in chickens. During transcriptomic studies of the RL region of the genome, we characterized the 7.5 kbp gene of the ERL lncRNA (edited repeat-long, long non-coding RNA), which may act as a natural antisense transcript (NAT) of the major GaHV-2 oncogene meq and of two of the three miRNA clusters. During infections in vivo and in vitro, we detected hyperediting of the ERL lncRNA that appeared to be directly correlated with ADAR1 expression levels. The ERL lncRNA was expressed equally during the lytic and latent phases of infection and during viral reactivation, but its hyperediting increased only during the lytic infection of chicken embryo fibroblasts. We also showed that chicken ADAR1 expression was controlled by the JAK/STAT IFN-response pathway, through an inducible promoter containing IFN-stimulated response elements that were functional during stimulation with IFN-α or poly(I:C). Like the human and murine miR-155-5p, the chicken gga-miR-155-5p and the GaHV-2 analogue mdv1-miR-M4-5p deregulated this pathway by targeting and repressing expression of suppressor of cytokine signalling 1, leading to the upregulation of ADAR1. Finally, we hypothesized that the natural antisense transcript role of the ERL lncRNA could be disrupted by its hyperediting, particularly during viral lytic replication, and that the observed deregulation of the innate immune system by mdv1-miR-M4-5p might contribute to the viral cycle.
The mechanisms that underlie the control of bimanual actions in which the two hands act separately to manipulate different objects (uncoupled independent control) has been well studied. In contrast, much less is known about how the central nervous system controls bimanual actions that require the two hands act cooperatively to manipulate a single object (dynamically coupled control). Furthermore, there is scant research into the manual lateralization and role assignment in the processing of visual and haptic feedback during dynamically coupled bimanual tasks. In this experiment, we examined the role of the dominant and non-dominant hands during a dynamically coupled bimanual task in which visual and haptic feedback regarding object penetration were manipulated. Twelve subjects performed a bimanual grasp and reach task towards different target locations in the workspace by using two identical wrist robotic devices. Results showed haptic feedback is necessary for task completion, and that hand specialization plays a fundamental role in spatial and temporal coordination between the two limbs.
This paper distinguishes a rare subset of myeloid dendritic-like cells found in mouse spleen from conventional (c) dendritic cells (DC) in terms of phenotype, function and gene expression. These cells are tentatively named "L-DC" since they resemble dendritic-like cells produced in longterm cultures of spleen. L-DC can be distinguished on the basis of their unique phenotype as CD11bhiCD11cloMHCII-CD43+Ly6C-Ly6G-Siglec-F- cells. They demonstrate similar ability as cDC to uptake and retain complex antigens like mannan via mannose receptors, but much lower ability to endocytose and retain soluble antigen. While L-DC differ from cDC by their inability to activate CD4+ T cells, they are capable of antigen cross-presentation for activation of CD8+ T cells, although less effectively so than the cDC subsets. In terms of gene expression, CD8- cDC and CD8+ cDC are quite distinct from L-DC. CD8+ cDC are distinguishable from the other two subsets by expression of CD24a, Clec9a, Xcr1 and Tlr11, while CD8- cDC are distinguished by expression of Ccnd1 and H-2Eb2. L-DC are distinct from the two cDC subsets through upregulated expression of Clec4a3, Emr4, Itgam, Csf1r and CD300ld. The L-DC gene profile is quite distinct from
 that of cDC, confirming a myeloid cell type with distinct antigen presenting properties.
Ocean microbes drive biogeochemical cycling on a global scale. However, this cycling is constrained by viruses that affect community composition, metabolic activity, and evolutionary trajectories. Owing to challenges with the sampling and cultivation of viruses, genome-level viral diversity remains poorly described and grossly understudied, with less than 1% of observed surface-ocean viruses known. Here we assemble complete genomes and large genomic fragments from both surface- and deep-ocean viruses sampled during the Tara Oceans and Malaspina research expeditions, and analyse the resulting 'global ocean virome' dataset to present a global map of abundant, double-stranded DNA viruses complete with genomic and ecological contexts. A total of 15,222 epipelagic and mesopelagic viral populations were identified, comprising 867 viral clusters (defined as approximately genus-level groups). This roughly triples the number of known ocean viral populations and doubles the number of candidate bacterial and archaeal virus genera, providing a near-complete sampling of epipelagic communities at both the population and viral-cluster level. We found that 38 of the 867 viral clusters were locally or globally abundant, together accounting for nearly half of the viral populations in any global ocean virome sample. While two-thirds of these clusters represent newly described viruses lacking any cultivated representative, most could be computationally linked to dominant, ecologically relevant microbial hosts. Moreover, we identified 243 viral-encoded auxiliary metabolic genes, of which only 95 were previously known. Deeper analyses of four of these auxiliary metabolic genes (dsrC, soxYZ, P-II (also known as glnB) and amoC) revealed that abundant viruses may directly manipulate sulfur and nitrogen cycling throughout the epipelagic ocean. This viral catalog and functional analyses provide a necessary foundation for the meaningful integration of viruses into ecosystem models where they act as key players in nutrient cycling and trophic networks.
Evidence-informed decision-making is essential to ensure that health programs and services are effective and offer value for money; however, barriers to the use of evidence persist. Emerging systems science approaches and advances in technology are providing new methods and tools to facilitate evidence-based decision-making. Simulation modelling offers a unique tool for synthesising and leveraging existing evidence, data and expert local knowledge to examine, in a robust, low risk and low cost way, the likely impact of alternative policy and service provision scenarios. This case study will evaluate participatory simulation modelling to inform the prevention and management of gestational diabetes mellitus (GDM). The risks associated with GDM are well recognised; however, debate remains regarding diagnostic thresholds and whether screening and treatment to reduce maternal glucose levels reduce the associated risks. A diagnosis of GDM may provide a leverage point for multidisciplinary lifestyle modification interventions. This research will apply and evaluate a simulation modelling approach to understand the complex interrelation of factors that drive GDM rates, test options for screening and interventions, and optimise the use of evidence to inform policy and program decision-making.
The study design will use mixed methods to achieve the objectives. Policy, clinical practice and research experts will work collaboratively to develop, test and validate a simulation model of GDM in the Australian Capital Territory (ACT). The model will be applied to support evidence-informed policy dialogues with diverse stakeholders for the management of GDM in the ACT. Qualitative methods will be used to evaluate simulation modelling as an evidence synthesis tool to support evidence-based decision-making. Interviews and analysis of workshop recordings will focus on the participants' engagement in the modelling process; perceived value of the participatory process, perceived commitment, influence and confidence of stakeholders in implementing policy and program decisions identified in the modelling process; and the impact of the process in terms of policy and program change.
The study will generate empirical evidence on the feasibility and potential value of simulation modelling to support knowledge mobilisation and consensus building in health settings.
Transient receptor potential vanilloid type 1 (TRPV1) is a major nociceptive ion channel implicated in bladder physiology and/or pathophysiology. However, the precise expression of TRPV1 in neuronal vs. nonneuronal bladder cells is uncertain. Here we used reporter mouse lines (TRPV1-Cre:tdTomato and TRPV1(PLAP-nlacZ)) to map expression of TRPV1 in postnatal bladder. TRPV1 was not detected in the urothelium, however, we found marked expression of TRPV1 lineage in sensory nerves, and surprisingly, in arterial/arteriolar smooth muscle (ASM) cells. Tomato fluorescence was prominent in the vesical arteries and in small-diameter (15-40 μm) arterioles located in the suburothelial layer with a near equal distribution in bladder dome and base. Notably, arteriolar TRPV1 expression was greater in females than in males and increased in both sexes after 90 days of age, suggesting sex hormone and age dependency. Analysis of whole bladder and vesical artery TRPV1 mRNA revealed a similar sex and developmental dependence. Pharmacological experiments confirmed functional TRPV1 protein expression; capsaicin increased intracellular Ca(2+) in ∼15% of ASM cells from wild-type female bladders, but we observed no responses to capsaicin in bladder arterioles isolated from TRPV1-null mice. Furthermore, capsaicin triggered arteriole constriction that was rapidly reversed by the TRPV1 antagonist, BCTC. These data show that predominantly in postpubertal female mice, bladder ASM cells express functional TRPV1 channels that may act to constrict arterioles. TRPV1 may therefore play an important role in regulating the microcirculation of the female bladder, and this effect may be of significance during inflammatory conditions.
The Swedish Healthcare Act prescribes that healthcare should be provided according to needs and with respect for each person's human dignity. The goal is equity in health for the whole population. In spite of this, studies have revealed that Swedish healthcare is not always provided equally. This has also been observed in telephone nursing. Therefore, the aim of the present study was to investigate if and how an educational intervention can improve awareness of equity in healthcare among telephone nurses.
The study had a quasi-experimental design, with one intervention group and one control group. A base-line measurement was performed before an educational intervention and a follow-up measurement was made afterwards in both groups, using a study specific questionnaire in which fictive persons of different age, gender and ethnicity were assessed concerning, e.g., power over one's own life, quality of life and experience of discrimination. The educational intervention consisted of a web-based lecture, literature and a seminar, covering aspects of inequality in healthcare related to gender, age and ethnicity, and gender and intersectionality theories as explaining models for these conditions.
The results showed few significant differences before and after the intervention in the intervention group. Also in the control group few significant differences were found in the second measurement, although no intervention was performed in that group. The reason might be that the instrument used was not sensitive enough to pick up an expected raised awareness of equity in healthcare, or that solely the act of filling out the questionnaire can create a sort of intervention effect. Fictive persons born in Sweden and of young age were assessed to have a higher Good life-index than the fictive persons born outside Europe and of higher age in all assessments.
The results are an imperative that equity in healthcare still needs to be educated and discussed in different healthcare settings. The intervention and questionnaire were designed to fit telephone nurses, but could easily be adjusted to suit other professional groups, who need to increase their awareness of equity in healthcare.
The structure and dynamics of promoter chromatin have a profound effect on the expression levels of genes. Yet, the contribution of DNA sequence, histone post-translational modifications, histone variant usage and other factors in shaping the architecture of chromatin, and the mechanisms by which this architecture modulates expression of specific genes are not yet completely understood. Here we use optical tweezers to study the roles that DNA sequence and the histone variant H2A.Z have in shaping the chromatin landscape at the promoters of two model genes, Cga and Lhb. Guided by MNase mapping of the promoters of these genes, we reconstitute nucleosomes that mimic those located near the transcriptional start site and immediately downstream (+1), and measure the forces required to disrupt these nucleosomes, and their mobility along the DNA sequence. Our results indicate that these genes are basally regulated by two distinct strategies, making use of H2A.Z to modulate separate phases of transcription, and highlight how DNA sequence, alternative histone variants and remodelling machinery act synergistically to modulate gene expression.
The Philippine government established the Traditional and Alternative Medicine Act in 1997 to promote traditionally used herbal products and to provide an effective yet affordable alternative to conventional medicines. However, government regulation of herbal medicinal products (HMPs) is not stringent,
 relying only on submitted quality data from the manufacturer. In this study we validated the taxonomic identity of 26 plant samples contained within 22 HMPs, each produced by different local manufacturers, through DNA barcoding of the nuclear internal transcribed spacer-2 (ITS2) region. We recovered 19 ITS2 barcodes from 26 samples. These were compared to sequences in GenBank using MEGABLAST, but ambiguous results (similar max scores for different species) were phylogenetically analyzed. Twelve of the 19 samples matched the indicated species on the product label, three were equivocal in specific identity but were placed in the expected genus, and four other samples from three manufacturers contained contamination and/or substitution. GenBank's reference database was at times problematic because some sequences were lacking or were misidentified, but the database was still useful. Overall, ITS2 barcoding was successful in authenticating the HMPs, and it is recommended during the premarket evaluation process so as to obtain a certificate of registration from the government. The government should also develop a comprehensive database of barcodes for Philippine plants, and should prioritize the development of the traditional pharmacopeia because many locally produced HMPs are not indigenous.
The RNA exosome is a 3'-5' ribonuclease complex that is composed of nine core subunits and an essential catalytic subunit, Rrp44. Two distinct conformations of Rrp44 were revealed in previous structural studies, suggesting that Rrp44 may change its conformation to exert its function. In the channeling conformation, (Rrp44(ch)), RNA accesses the active site after traversing the central channel of the RNA exosome, whereas in the other conformation, (Rrp44(da)), RNA gains direct access to the active site. Here, we show that the Rrp44(da) exosome is important for nuclear function of the RNA exosome. Defects caused by disrupting the direct access conformation are distinct from those caused by channel-occluding mutations, indicating specific functions for each conformation. Our genetic analyses provide in vivo evidence that the RNA exosome employs a direct-access route to recruit specific substrates, indicating that the RNA exosome uses alternative conformations to act on different RNA substrates.
Alternative activation of macrophages promotes wound healing but weakens antimicrobial defenses against intracellular pathogens. The mechanisms that suppress macrophage function to create a favorable environment for pathogen growth remain elusive. We show that interleukin (IL)-4 triggers a metallothionein 3 (MT3)- and Zn exporter SLC30A4-dependent increase in the labile Zn(2+) stores in macrophages and that intracellular pathogens can exploit this increase in Zn to survive. IL-4 regulates this pathway by shuttling extracellular Zn into macrophages and by activating cathepsins that act on MT3 to release bound Zn. We show that IL-4 can modulate Zn homeostasis in both human monocytes and mice. In vivo, MT3 can repress macrophage function in an M2-polarizing environment to promote pathogen persistence. Thus, MT3 and SLC30A4 dictate the size of the labile Zn(2+) pool and promote the survival of a prototypical intracellular pathogen in M2 macrophages.
The present study is a microscopic interfacial characterization of a series of lung surfactant materials performed with the micropipette technique. The advantages of this technique include the measurement of equilibrium and dynamic surface tensions while acquiring structural and dynamic information at microscopic air-water interfaces in real time and upon compression. Here, we characterized a series of animal-derived and synthetic lung surfactant formulations, including native surfactant obtained from porcine lungs (NS); the commercial Curosurf, Infasurf, and Survanta; and a synthetic Super Mini-B (SMB)-containing formulation. It was observed that the presence of the natural hydrophobic proteins and, more strikingly, the peptide SMB, promoted vesicle condensation as thick membrane stacks beneath the interface. Only in the presence of SMB, these stacks underwent spontaneous structural transformations, consisting of the nucleation and growth of microtubes and in some cases their subsequent coiling into helices. The dimensions of these tubes (2-15 μm diameter) and their linear (2-3 μm/s) and volumetric growth rates (20-30 μm(3)/s) were quantified, and no specific effects were found on them for increasing SMB concentrations from 0.1 to 4%. Nevertheless, a direct correlation between the number of tubes and SMB contents was found, suggesting that SMB molecules are the promoters of tube nucleation in these membranes. A detailed analysis of the tube formation process was performed following previous models for the growth of myelin figures, proposing a combined mechanism between dehydration-rehydration of the lipid bilayers and induction of mechanical defects by SMB that would act as nucleation sites for the tubes. The formation of tubes was also observed in Infasurf, and in NS only after subsequent expansion and compression but neither in the other clinical surfactants nor in protein-free preparations. Finally, the connection between this data and the observations from the lung surfactant literature concerning the widely reported "near-zero surface tension" for lung surfactant films and intact alveolar surfaces is also discussed.
To investigate trends in five key aspects of Australian food practice which have been implicated in diet-related health risks, specifically energy intake. They are: the replacement of home-prepared foods by commercially prepared foods; consumer reliance on ultra-processed foods; de-structured dining; increased pace of eating; and a decline in commensal eating.
Data were from repeated cross-sections from the national Household Expenditure and Time Use Surveys. Trends in food practice aspects were examined using indicators of food expenditure across different food groups and time spent eating and cooking, including where, when and with whom eating activities took place.
Australia, 1989-2010.
Nationally representative samples of Australian households.
The share of the total food budget spent on food away from home rose steadily from 22·8 % in 1989 to 26·5 % in 2010, while spending on ultra-processed foods increased. The basic patterning of meals and the pace of eating changed little, although people spent more time eating alone and at restaurants. Cooking time declined considerably, particularly for women.
These changes have occurred over the same time that obesity and diet-related, non-communicable diseases have increased rapidly in Australia. Some aspects are implicated more than others: particularly the shift from domestic cooking to use of pre-prepared and ultra-processed foods, a reduction in time spent in food preparation and cooking, as well as an upsurge in time and money devoted to eating away from home. These are all likely to operate through the higher energy content of commercially prepared, compared with unprocessed or lightly processed, foods.
Post-transplant complications such as graft-versus-host disease and graft ischemia-reperfusion injury are crucial challenges in transplantation. Hydrogen can act as a potential antioxidant, playing a preventive role against post-transplant complications in animal models of multiple organ transplantation. Herein, the authors review the current literature regarding the effects of hydrogen on graft ischemia-reperfusion injury and graft-versus-host disease. Existing data on the effects of hydrogen on ischemia-reperfusion injury related to organ transplantation are specifically reviewed and coupled with further suggestions for future work. The reviewed studies showed that hydrogen (inhaled or dissolved in saline) improved the outcomes of organ transplantation by decreasing oxidative stress and inflammation at both the transplanted organ and the systemic levels. In conclusion, a substantial body of experimental evidence suggests that hydrogen can significantly alleviate transplantation-related ischemia-reperfusion injury and have a therapeutic effect on graft-versus-host disease, mainly via inhibition of inflammatory cytokine secretion and reduction of oxidative stress through several underlying mechanisms. Further animal experiments and preliminary human clinical trials will lay the foundation for hydrogen use as a drug in the clinic.
Surface patterning provides a powerful tool to the diagnosis of platelet adhesion. However, the current methodologies of constructing platelet-patterned surfaces require laborious and complicated steps. Herein, a novel and simple platelet-repellent surface was reported by metal (Fe(3+) ions)-polyphenol (tannic acid, TA) coordination interaction. The platelet-repellent effect was significantly better than that of poly(ethylene glycol) (PEG) in a long-term. Moreover, the platelet-repellent behavior could extend to other polyphenols-functionalized surfaces. On the basis of these observations, a TA-based micropattern was fabricated in situ by one-step microcontact printing for well-defined platelet adhesion, which can effectively avoid the traditional introduction of inert hydrophilic polymers and bioactive ligands. Afterward, the TA-based micropattern was applied to monitor the adhesion of defective platelets treated with an antiplatelet drug (tirofiban). This work provided a facile, versatile, and environmentally friendly strategy to construct platelet-repellent polyphenolic surfaces and their micropattern. We expect that this simple micropattern could act as a low-cost and label-free platform for biomaterials and biosensors, and could be widely used in the clinical diagnoses of platelet adhesive functions and the evaluation of antiplatelet therapies.
Many genes are candidates for involvement in epileptic encephalopathy
 (EE) because one or a few possibly pathogenic variants have been found in patients, but insufficient genetic or functional evidence exists for a definite annotation.
To increase the number of validated EE genes, we sequenced 26 known and 351 candidate genes for EE in 360 patients. Variants in 25 genes known to be involved in EE or related phenotypes were followed up in 41 patients. We prioritized the candidate genes, and followed up 31 variants in this prioritized subset of candidate genes.
Twenty-nine genotypes in known genes for EE (19) or related diseases (10), dominant as well as recessive or X-linked, were classified as likely pathogenic variants. Among those, likely pathogenic de novo variants were found in EE genes that act dominantly, including the recently identified genes EEF1A2, KCNB1 and the X-linked gene IQSEC2. A de novo frameshift variant in candidate gene HNRNPU was the only de novo variant found among the followed-up candidate genes, and the patient's phenotype was similar to a few recent publications.
Mutations in genes described in OMIM as, for example, intellectual disability gene can lead to phenotypes that get classified as EE in the clinic. We confirmed existing literature reports that de novo loss-of-function HNRNPUmutations lead to severe developmental delay and febrile seizures in the first year of life.
ADHD is the most common neuropsychiatric condition affecting individuals of all ages. Long-term outcomes of affected individuals and association with severe comorbidities as SUD or conduct disorders are the main concern. Genetic associations have been extensively described. Multiple studies show that intronic variants harbored in the ADGRL3 (LPHN3) gene are associated with ADHD, especially associated with poor outcomes.
In this study, we evaluated this association in the Multimodal Treatment Study of children with ADHD (MTA), initiated as a 14-month randomized clinical trial of 579 children diagnosed with DSM-IV ADHD-Combined Type (ADHD-C), that transitioned to a 16-year prospective observational follow-up, and 289 classmates added at the 2-year assessment to serve as a local normative comparison group (LNCG). Diagnostic evaluations at entry were based on the Diagnostic Interview Schedule for Children-Parent (DISC-P), which was repeated at several points over the years. For an add-on genetic study, blood samples were collected from 232 in the MTA group and 139 in the LNCG.
For the 205 MTA participants, 14.6% retained the DISC-P diagnosis of ADHD-C in adolescence. For 127 LNCG participants, 88.2% remained undiagnosed by the DISC-P. We genotyped 15 polymorphic SNP markers harbored in the ADGRL3 gene, and compared allele frequencies for the 30 cases with continued diagnosis of ADHD-C in adolescence to the other participants. Replication of the association of rs2345039 ADGRL3 variant was observed (P value = 0.004, FDR corrected = 0.03; Odds ratio = 2.25, upper CI 1.28-3.97).
The detection of susceptibility conferred by ADGRL3 variants in the extreme phenotype of continued diagnosis of ADHD-C from childhood to adolescence provides additional support that the association of ADGRL3 and ADHD is not spurious. Exploring genetic effects in longitudinal cohorts, in which refined, age-dependent phenotypes are documented, is crucial to understand the natural history of ADHD.
Wingless-type protein (Wnt) signaling pathway plays a crucial role in the development of human malignancies, such as epithelial-to-mesenchymal transition (EMT) and the maintenance of cancer stem cells (CSCs). Several studies have shown that the expression levels of Wnt proteins, ligands of Wnt signaling pathway, are related to clinical outcomes of non-small cell lung cancer (NSCLC) patients. This meta-analysis aimed to assess the prognostic value of Wnts proteins in patients with NSCLC.
A multiple electronic literature search was conducted to identify all articles referring to the prognostic value of Wnt proteins in patients of NSCLC up to July 2016. Eligible studies were included in a meta-analysis in order to summarize the extracted data in terms of pooled hazard ratios (HRs) and their 95% confidence intervals (95% CIs).
Ten studies published between 2005 and 2015 were eligible for this meta-analysis. The total number of patients included was 1,805. The combined HR for all eligible studies evaluating the overall survival (OS) of NSCLC patients with positive Wnt expression was 1.60 (95% CI: 1.39-1.84). The subgroup analysis showed both Wnt1 and Wnt5a are associated with clinical outcome of NSCLC patients.
Overexpression of Wnt proteins, as well as Wnt1 or Wnt5a alone, was markedly associated with adverse OS in lung cancer patients, suggesting that Wnts may act as a prognostic marker among NSCLCs.
A theory of the Value/Utility of information and knowledge (K) is not really there. This would require a theory of the centrality of Goals in minds, and of the role of K relative to Goals and their dynamics. K value is a notion relative to Goal value. Inf/K is precisely a resource, a means and the value of means depends on the value of their possible functions and uses. The claim of this paper is that Ks have a Value and Utility, they can be more or less 'precious'; they have a cost and imply some risks; they can be not only useful but negative and dangerous. We also examine the 'quality' of this resource: its reliability; and its crucial role in goal processing: activating goals, abandoning, choosing, planning, formulating intentions, decide to act. 'Relevance theory', Information theory, Epistemic Utility theory, etc. are not enough for providing a theory of the Value/Utility of K. And also truthfulness is not 'the' Value of K. Even true information can be noxious for the subject.
Climate change (CC) is an urgent and highly relevant topic that must be integrated into the school curriculum. Literature on CC integration, however, is scarce, let alone literature on integrating climate-smart rice agriculture (CSRA). Bringing CSRA lessons into the classroom means the chance is higher that climate-smart technologies on rice will reach even the most far-flung areas of the Philippines, which stand to be among the most vulnerable as regards the negative impacts of CC. This paper shares experiences drawn from three high schools in the Philippines on integrating CSRA into their curriculum. The research centers on appropriate teaching tools/strategies, push and exogenous factors in CSRA integration, and the types of information that are likely to be shared by the students with their farmer-parents or other farmers in their communities. Surveys among participating students (n = 155) and three focus group discussions among key school officials were conducted. Different teaching methods and/or tools were found to be generally useful in various contexts. Photos and videos, however, emerged as the most effective tools across sites. The livelihood source of the students does have a bearing on the complexity of messages that they can convey. Students from rice-farming households can competently discuss even highly complex adaptation and mitigation information with their farmer-parents or other farmers. Thorough message-framing is necessary to maximize student involvement as well as to increase production of education-entertainment (edutainment) materials to be utilized in teaching. This study, in general, contributes to CC education by bringing in best-fit practices in teaching tools and strategies to mobilize students to act on urgent matters relating to the impacts of CC. It also advises on considering exogenous factors that might affect CC education by taking into account those that are equally capable of shaping students' perception and knowledge.
Although various studies have indicated that high residential density may affect health and psychological outcomes, to our knowledge, there have been no studies regarding the predictive nature of crowded living conditions on binge eating and the use of the Internet as coping strategies.
A total of 1048 Chinese college students (540 males and 508 females) were randomly selected and asked to complete a battery of questionnaires that included the Zung's Self-Rating Anxiety Scale, the Internet Addiction Test, and Rosenbaum's Self-Control Scale. Binge eating behaviors and compensatory behaviors were also reported, and variables about residential density were measured.
Among female participants, binge eating scores were significantly predicted by anxiety caused by high-density living conditions (P = 0.008), and similarly, the frequency of compensatory behaviors was significantly predicted by anxiety caused by high-density living conditions (P = 0.000) and self-control (P = 0.003). Furthermore, the Internet Addiction Test scores were significantly predicted by the anxiety caused by high -density living conditions (P = 0.000) and self-control (P = 0.000). Among male participants, not only were the binge eating scores significantly predicted by the anxiety caused by high-density living conditions (P = 0.000) and self-control (P = 0.000), but the frequency of compensatory behaviors was also significantly predicted by the anxiety caused by high-density living conditions (P = 0.000) and self-control (P = 0.01). Furthermore, Internet Addiction Test scores were significantly predicted by anxiety caused by high-density living conditions (P = 0.000) and self-control (P = 0.000). It was further found that for both genders, subjective factors such as self-control, and the anxiety caused by high-density living conditions had a stronger impact on Internet addiction than objective factors, such as the size of the student's dormitory room. Moreover, self-control was found to act as a moderator in the relationship between anxiety and Internet addiction among male participants.
Binge eating and Internet use could be considered coping
 strategies for Chinese college students facing high residential density in their dormitories.
Molecular docking is a bioinformatics tool used to study and analyse ligand receptor interactions. This helps in identifying the receptors (molecular targets) for different ligands. Using these technologies, compound isolation and drug discovery from herbals is achieved. Herbs are widely used in treatment of various ailments from time immemorial. Phytochemists and drug developers are now interestingly working in developing new molecules that can act effectively than conventional drugs. As they are developing it mostly from herbs they are found to be effective and safer drugs and quantity to be used become minimum. Rotula aquatica Lour is a plant distributed widely in India and used for urinary disorders. The plant root was extracted and studied for its active compounds that possess antiurolithiatic activity. After performing various preliminary phytochemical studies and applying chromatographic methods, molecular docking was carried out with isolated bioactive compound and Tamm-Horsfall protein (THP). By docking analysis the bioactive compound 3-O-acetyl-11-keto-β-boswellic acid interacted with THP and it may inhibit calcium oxalate crystallization.
This article measures the probability that out-of-pocket expenses in the United States exceed a threshold share of income. It calculates this probability separately by individuals' health condition, income, and elderly status and estimates changes occurring in these probabilities between 2010 and 2013.
This article uses nationally representative household survey data on 344,000 individuals. Logistic regressions estimate the probabilities that out-of-pocket expenses exceed 5% and alternatively 10% of income in the two study years. These probabilities are calculated for individuals based on their income, health status, and elderly status.
Despite favorable changes in both health policy and the economy, large numbers of Americans continue to be exposed to high out-of-pocket expenditures. For instance, the results indicate that in 2013 over a quarter of nonelderly low-income citizens in poor health spent 10% or more of their income on out-of-pocket expenses, and over 40% of this group spent more than 5%. Moreover, for Americans as a whole, the probability of spending in excess of 5% of income on out-of-pocket costs increased by 1.4 percentage points between 2010 and 2013, with the largest increases occurring among low-income Americans; the probability of Americans spending more than 10% of income grew from 9.3% to 9.6%, with the largest increases also occurring among the poor.
The magnitude of out-of-pocket's financial burden and the most recent upward trends in it underscore a need to develop good measures of the degree to which health care policy exposes individuals to financial risk, and to closely monitor the Affordable Care Act's success in reducing Americans' exposure to large medical bills.
The discovery of the central monoamine neurons not only demonstrated novel types of brain stem neurons forming global terminal networks all over the brain and the spinal cord, but also to a novel type of communication called volume transmission. It is a major mode of communication in the central nervous system that takes places in the extracellular fluid and the cerebral spinal fluid through diffusion and flow of molecules, like neurotransmitters and extracellular vesicles. The integration of synaptic and volume transmission takes place through allosteric receptor-receptor interactions in heteroreceptor complexes. These heterocomplexes represent major integrator centres in the plasma membrane and their protomers act as moonlighting proteins undergoing dynamic changes and their structure and function. In fact, we propose that the molecular bases of learning and memory can be based on the reorganization of multiples homo and heteroreceptor complexes into novel assembles in the post-junctional membranes of synapses.
Breast cancer is the leading cause of death in women. Epirubicin and cyclophosphamide (EC) is one of the chemotherapeutic regimens used for the treatment of breast cancer. We describe a case treated with EC regimen and who presented to us with symptoms suggestive of diabetes mellitus postchemotherapy. Absence of family history of diabetes and normal blood sugar level, prechemotherapy points toward drug-induced hyperglycemia. These chemotherapeutic agents capable of altering immune response and might act synergistically to cause immunological damage to the islets of pancreas which might precipitate diabetes mellitus. Causality analysis on Naranjo's scale indicates a possible association with regimen.
Sea ice has been suggested to be an important factor for dispersal of vascular plants in the Arctic. To assess its role for postglacial colonization in the North Atlantic region, we compiled data on the first Late Glacial to Holocene occurrence of vascular plant species in East Greenland, Iceland, the Faroe Islands and Svalbard. For each record, we reconstructed likely past dispersal events using data on species distributions and genetics. We compared these data to sea-ice reconstructions to evaluate the potential role of sea ice in these past colonization events and finally evaluated these results using a compilation of driftwood records as an independent source of evidence that sea ice can disperse biological material. Our results show that sea ice was, in general, more prevalent along the most likely dispersal routes at times of assumed first colonization than along other possible routes. Also, driftwood is frequently dispersed in regions that have sea ice today. Thus, sea ice may act as an important dispersal agent. Melting sea ice may hamper future dispersal of Arctic plants and thereby cause more genetic differentiation. It may also limit the northwards expansion of competing boreal species, and hence favour the persistence of Arctic species.
The present study was a direct test of the cheater-hawk hypothesis which argues that psychopathy is related to two potentially adaptive interpersonal strategies: cheating and aggression. As expected, the measures of cheater and hawk behaviors comprised a single factor, according to a maximum-likelihood factor analysis. As hypothesized, psychopathic traits exhibited large positive correlations with measures of both cheater (entitlement, exploitiveness, and short-term mating orientation) and hawk (vengeance and aggression) behaviors. Furthermore, psychopathic traits were associated with the tendency of using individualistic and competitive tactics in an altruism game and being less likely to act in a prosocial manner. Finally, scores on the combined-cheater hawk variable were significantly correlated with psychopathic traits. As hypothesized, individuals scoring high on Factor 1 of psychopathy were more likely to utilize behaviors and strategies associated with the cheater-hawk designation, whether or not they scored high on Factor 2 of psychopathy. In general, the findings support the conceptualization that psychopathy represents a fast life-history strategy characterized by seeking personal gain over others, including exploitiveness (cheater), aggression (hawk), and risk taking. Results also indicate that cheater and hawk behaviors are part of a single strategy more often employed by those higher on psychopathic traits. Implications for treatment success are discussed.
Glycosylation of certain proteins at the mammalian cell surface is an essential event in carcinogenesis. Sialylation, one type of glycosylation, can act on multiple cell-behaviors, such as migration, growth, and malignant invasion. Two polysialyltransferases, ST8Sia II (STX) and ST8Sia IV (PST), are responsible for synthesis of polysialic acid on neural cell adhesion molecule. We showed previously that STX and PST are oppositely expressed in normal murine mammary gland cells undergoing transforming growth factor-β-induced epithelial-mesenchymal transition. The molecular basis for regulation of STX and PST remained unclear. In the present study, we observed that transcription factor Pax3 upregulates STX expression, downregulates PST expression, and modulates upregulated expression of PSA, which attaches primarily to neural cell adhesion molecule to form PSA-NCAM. Overexpression of Pax3 in normal murine mammary gland cells transformed the expression of epithelial-mesenchymal transition markers E-cadherin and N-cadherin, and significantly promoted cell migration, but had no effect on cell proliferation.
Medicaid coverage increases access to care and improves health outcomes for disadvantaged populations. Yet disparities in enrollment and access to care persist. To understand the facilitators and barriers of Medicaid enrollment and accessing care under the Affordable Care Act for disadvantaged Asian Americans and Pacific Islanders. Focus groups and key informant interviews were conducted. Informational barriers to accessing care were pervasive among most new enrollees. Immigrants with limited English proficiency experienced disproportionate difficulties in enrolling and accessing care post enrollment. The simplified, income-based Medicaid eligibility streamlined the enrollment process, but system errors in determining Medicaid eligibility denied coverage for some eligible individuals. To improve access to care, health plans, government agencies, and community organizations might coordinate more closely. Federal and state laws that mandate language assistance by health plans might be enforced to improve access to care for linguistic minorities.
The nervous system is highly enriched with long-chain polyunsaturated fatty acids (PUFAs). Essential fatty acids, namely, ω-6 (n - 6) and ω-3 (n - 3) PUFA, and their metabolites are critical components of cell structure and function and
 could therefore influence stem cell fate. The available supporting experimental data reveal that n - 6 and n - 3 PUFA and their metabolites can act through multiple mechanisms to promote the proliferation and differentiation of various stem cell types. PUFAs and their mediators regulate several processes within the brain, such as neurotransmission, cell survival and neuroinflammation, and thereby mood and cognition. PUFA levels and the signaling pathways that they regulate are altered in various neurological disorders, including Alzheimer's disease and major depression. Therefore, elucidating the role of PUFAs and their metabolites in stem cell fate regulation is important for stem cell biology as well as stem cell therapy. PUFA-based interventions to generate a positive environment for stem cell proliferation or differentiation might be a promising and practical approach to controlling stem cell fate for clinical applications.
Gastric cancer (GC) is a common and deadly disease worldwide. Outcomes of patients are poor largely due to chemoresistance or recurrence. Thus, identifying novel biomarkers to predict response to therapy and/or prognosis are urgently needed. RAD51B, a key player in DNA repair/recombination, has the potential to be a candidate oncogene and biomarker for cancer diagnosis and prognosis. However, its relationship with GC remains unclear. To evaluate clinicopathological and prognostic significance of RAD51B in GC, we examined messenger RNA (mRNA) and protein expression via quantitative real-time polymerase chain reaction (qRT-PCR) from 69 and tissue microarray from 144 GC patients, respectively. Our results showed that RAD51B mRNA expression was significantly up-regulated in tumors compared to that of matched noncancerous tissues (P < 0.001). In parallel, RAD51B protein showed a mainly nucleus-staining pattern, and the positive rate in tumors and stomach atypical hyperplasia was significantly higher than that in matched noncancerous tissues (P = 0.015). Moreover, high level of RAD51B protein was correlated with advanced stage (P = 0.009), aggressive differentiation (P = 0.022), and lymph node metastasis (P = 0.001). Further, Kaplan-Meier analysis indicated that patients with high level of RAD51B expression exhibited worse overall survival compared to patients with low level (P = 0.040). A multivariate Cox regression analysis suggested that RAD51B may be an independent prognostic factor for GC patients in Chinese population (P = 0.004). Additionally, functional studies indicated that over-expression of RAD51B promoted cell proliferation, aneuploidy, and drug resistance, while RAD51B knockdown led to G1 arrest and sensitized cells to 5-fluorouracil (5-FU). In conclusion, RAD51B may act as an oncogene during GC progression, and its hyper-expression may be a potential biomarker for early detection and poor prognosis of GC.
Mental health policy includes a clear expectation that consumers will participate in all aspects of the design and delivery of mental health services. This edict has led to employment roles for people with lived experience of significant mental health challenges and service use. Despite the proliferation of these roles, research into factors impacting their success or otherwise is limited. This paper presents findings from a grounded theory study investigating the experiences of Lived Experience Practitioners in the context of their employment. In-depth interviews were conducted with 13 Lived Experience Practitioners. Risk was identified as a core category, and included sub-categories: vulnerability, 'out and proud', fear to disclose, and self-care. Essentially participants described the unique vulnerabilities of their mental health challenges being known, and while there were many positives about disclosing there was also apprehension about personal information being so publically known. Self-care techniques were important mediators against these identified risks. The success of lived experience roles requires support and nurses can play an important role, given the size of the nursing workforce in mental health, the close relationships nurses enjoy with consumers and the contribution they have made to the development of lived experience roles within academia.
Cancer staging is critical for prognostication, treatment planning, and determining clinical trial eligibility. Electronic health records (EHRs) have structured staging modules, but physician use is inconsistent. Typically, stage is entered as unstructured free text in clinical notes and cannot easily be used for reporting.
We created an Epic Best Practice Advisory (BPA) decision support tool that requires physicians to enter cancer stage in a structured module. If certain conditions are met, the BPA is triggered as a hard stop, and the physician cannot chart until staging is complete or a reason for not staging is selected. We used Plan, Do, Study, Act methodology to inform the intervention and compared preexisting staging rates to rates at 4, 8, and 12 months postintervention.
For 12 months before BPA implementation, 1,480 of 5,222 (28%) patients had cancer stage structured within the Epic problem list. From 1 to 4 months after the BPA 2,057 of 1,788 (115%) cases were staged in Epic. In the 5- to 8-month period after the BPA, 1,057 of 1,893 (56%) cases were staged, and 9 to 12 months after the BPA 1,082 of 1,817 (60%) were staged.
Electronic decision support improves the rate of structured cancer staging at our institution. The staging rates between 56% and 60% for the 5- to 8-month and 9- to 12-month periods likely reflect accurate postintervention staging rates, whereas the initial 115% rate for 1 to 4 months is inflated by providers staging cancers diagnosed before the BPA.
To provide guidance for the organisation and delivery of clinical services and the clinical management of patients who deliberately self-harm, based on scientific evidence supplemented by expert clinical consensus and expressed as recommendations.
Articles and information were sourced from search engines including PubMed, EMBASE, MEDLINE and PsycINFO for several systematic reviews, which were supplemented by literature known to the deliberate self-harm working group, and from published systematic reviews and guidelines for deliberate self-harm. Information was reviewed by members of the deliberate self-harm working group, and findings were then formulated into consensus-based recommendations and clinical guidance. The guidelines were subjected to successive consultation and external review involving expert and clinical advisors, the public, key stakeholders, professional bodies and specialist groups with interest and expertise in deliberate self-harm.
The Royal Australian and New Zealand College of Psychiatrists clinical practice guidelines for deliberate self-harm provide up-to-date guidance and advice regarding the management of deliberate self-harm patients, which is informed by evidence and clinical experience. The clinical practice guidelines for deliberate self-harm is intended for clinical use and service development by psychiatrists, psychologists, physicians and others with an interest in mental health care.
The clinical practice guidelines for deliberate self-harm address self-harm within specific population sub-groups and provide up-to-date recommendations and guidance within an evidence-based framework, supplemented by expert clinical consensus.
For several decades, regulatory testing schemes for genetic damage have been standardized where the tests being utilized examined mutations and structural and numerical chromosomal damage. This has served the genetic toxicity community well when most of the substances being tested were amenable to such assays. The outcome from this testing is usually a dichotomous (yes/no) evaluation of test results, and in many instances, the information is only used to determine whether a substance has carcinogenic potential or not. Over the same time period, mechanisms and modes of action (MOAs) that elucidate a wider range of genomic damage involved in many adverse health outcomes have been recognized. In addition, a paradigm shift in applied genetic toxicology is moving the field toward a more quantitative dose-response analysis and point-of-departure (PoD) determination with a focus on risks to exposed humans. This is directing emphasis on genomic damage that is likely to induce changes associated with a variety of adverse health outcomes. This paradigm shift is moving the testing emphasis for genetic damage from a hazard identification only evaluation to a more comprehensive risk assessment approach that provides more insightful information for decision makers regarding the potential risk of genetic damage to exposed humans. To enable this broader context for examining genetic damage, a next generation testing strategy needs to take into account a broader, more flexible approach to testing, and ultimately modeling, of genomic damage as it relates to human exposure. This is consistent with the larger risk assessment context being used in regulatory decision making. As presented here, this flexible approach for examining genomic damage focuses on testing for relevant genomic effects that can be, as best as possible, associated with an adverse health effect. The most desired linkage for risk to humans would be changes in loci associated with human diseases, whether in somatic or germ cells. The outline of a flexible approach and associated considerations are presented in a series of nine steps, some of which can occur in parallel, which was developed through a collaborative effort by leading genetic toxicologists from academia, government, and industry through the International Life Sciences Institute (ILSI) Health and Environmental Sciences Institute (HESI) Genetic Toxicology Technical Committee (GTTC). The
 ultimate goal is to provide quantitative data to model the potential risk levels of substances, which induce genomic damage contributing to human adverse health outcomes. Any good risk assessment begins with asking the appropriate risk management questions in a planning and scoping effort. This step sets up the problem to be addressed (e.g., broadly, does genomic damage need to be addressed, and if so, how to proceed). The next two steps assemble what is known about the problem by building a knowledge base about the substance of concern and developing a rational biological argument for why testing for genomic damage is needed or not. By focusing on the risk management problem and potential genomic damage of concern, the next step of assay(s) selection takes place. The work-up of the problem during the earlier steps provides the insight to which assays would most likely produce the most meaningful data. This discussion does not detail the wide range of genomic damage tests available, but points to types of testing systems that can be very useful. Once the assays are performed and analyzed, the relevant data sets are selected for modeling potential risk. From this point on, the data are evaluated and modeled as they are for any other toxicology endpoint. Any observed genomic damage/effects (or genetic event(s)) can be modeled via a dose-response analysis and determination of an estimated PoD. When a quantitative risk analysis is needed for decision making, a parallel exposure assessment effort is performed (exposure assessment is not detailed here as this is not the focus of this discussion; guidelines for this assessment exist elsewhere). Then the PoD for genomic damage is used with the exposure information to develop risk estimations (e.g., using reference dose (RfD), margin of exposure (MOE) approaches) in a risk characterization and presented to risk managers for informing decision making. This approach is applicable now for incorporating genomic damage results into the decision-making process for assessing potential adverse outcomes in chemically exposed humans and is consistent with the ILSI HESI Risk Assessment in the 21st Century (RISK21) roadmap. This applies to any substance to which humans are exposed, including pharmaceuticals, agricultural products, food additives, and other chemicals. It is time for regulatory bodies to incorporate the broader knowledge and insights provided by genomic damage results into the assessments of risk to more fully understand the potential of adverse outcomes in chemically exposed humans, thus improving the assessment of risk due to genomic damage. The historical use of genomic damage data as a yes/no gateway for possible cancer risk has been too narrowly focused in risk assessment. The recent advances in assaying for and understanding genomic damage, including eventually epigenetic alterations, obviously add a greater wealth of information for determining potential risk to humans. Regulatory bodies need to embrace this paradigm shift from hazard identification to quantitative analysis and to incorporate the wider range of genomic damage in their assessments of risk to humans. The quantitative analyses and methodologies discussed here can be readily applied to genomic damage testing results now. Indeed, with the passage of the recent update to the Toxic Substances Control Act (TSCA) in the US, the new generation testing strategy for genomic damage described here provides a regulatory agency (here the US Environmental Protection Agency (EPA), but suitable for others) a golden opportunity to reexamine the way it addresses risk-based genomic damage testing (including hazard identification and exposure). Environ. Mol. Mutagen., 2016. © 2016 The Authors. Environmental and Molecular Mutagenesis Published by Wiley Periodicals, Inc.
Aptamers for whole cell detection are selected mostly by the Cell-SELEX procedure. Alternatively, the use of specific cell surface epitopes as target during aptamer selections allows the development of aptamers with ability to bind whole cells. In this study, we integrated a formerly selected Protein A-binding aptamer PA#2/8 in an assay format called ELONA (Enzyme-Linked OligoNucleotide Assay) and evaluated the ability of the aptamer to recognise and bind to Staphylococcus aureus presenting Protein A on the cell surface. The full-length aptamer and one of its truncated variants could be demonstrated to specifically bind to Protein A-expressing intact cells of S. aureus, and thus have the potential to expand the portfolio of aptamers that can act as an analytical agent for the specific recognition and rapid detection of the bacterial pathogen. The functionality of the aptamer was found to be based on a very complex, but also highly variable structure. Two structural key elements were identified. The aptamer sequence contains several G-clusters allowing folding into a G-quadruplex structure with the potential of dimeric and multimeric assembly. An inverted repeat able to form an imperfect stem-loop at the 5'-end also contributes essentially to the aptameric function.
Good culturing methods play an important role in the study of insect behavior and its application to pest management. Here, we describe and validate a new method for rearing the parasitoid wasp, Diachasmimorpha kraussii, which attacks some of the world's worst fruit fly pests and is an internationally used biological control agent. Our method differs from standard culturing approaches by presenting adult wasps with host-infested artificial media within a "culturing bag," which mimics a natural (fruit) oviposition substrate. In laboratory trials using wild collected D. kraussii, the culturing bag method was compared to the use of host-infested nectarines, and a commonly used laboratory method of presenting host-infested artificial media within Petri dishes. The culturing bag method proved to be a significant improvement on both methods, combining the advantages of high host survival in artificial media with parasitism levels that were the equivalent to those recorded using host-infested fruits. In our field study, culturing bags infested with the Queensland fruit fly, Bactrocera tryoni, and hung in a mixed peach and nectarine orchard proved to be effective "artificial fruits" attracting wild D. kraussii for oviposition. Significantly more adult wasps were reared from the culturing bags compared to field collected fruits. This was shown to be due to higher fruit fly larval density in the bags, as similar percentage parasitism rates were found between the culturing bags and ripe fruits. We discuss how this cheap, time-efficient method could be applied to collecting and monitoring wild D. kraussii populations in orchards, and assist in maintaining genetic variability in parasitoid laboratory cultures.
Several inflammatory response biomarkers, including lymphocyte-to-monocyte ratio (LMR), neutrophil-to-lymphocyte ratio (NLR), and platelet-to-lymphocyte ratio (PLR) have been reported to predict survival in various cancers. The aim of this study is to evaluate the clinical value of these biomarkers in patients undergoing curative resection for esophageal cancer.
The LMR, NLR and PLR were calculated in 147 consecutive patients who underwent esophagectomy between January 2006 and February 2015. We examined the prognostic significance of the LMR, NLR, and PLR in both elderly and non-elderly patients. We evaluated the cancer-specific survival (CSS), with the cause of death determined from the case notes or computerized records.
Univariate analyses demonstrated that TNM pStage (p < 0.0001), tumor size (p = 0.0014), operation time (p = 0.0209), low LMR (p = 0.0008), and high PLR (p = 0.0232) were significant risk factors for poor prognosis. Meanwhile, TNM pStage (p < 0.0001) and low LMR (p = 0.0129) were found to be independently associated with poor prognosis via multivariate analysis. In non-elderly patients, univariate analyses demonstrated that TNM pStage (p < 0.0001), tumor size (p = 0.0001), operation time (p = 0.0374), LMR (p < 0.0001), and PLR (p = 0.0189) were significantly associated with a poorer prognosis. Multivariate analysis demonstrated that TNM pStage (p = 0.001) and LMR (p = 0.0007) were independent risk factors for a poorer prognosis. In elderly patients, univariate analysis demonstrated that that TNM pStage (p = 0.0023) was the only significant risk factor for a poor prognosis.
LMR was associated with cancer-specific survival (CSS) of esophageal cancer patients after curative esophagectomy. In particular, a low LMR was a significant and independent predictor of poor survival in non-elderly patients. The LMR was convenient, cost effective, and readily available, and could thus act as markers of survival in esophageal cancer.
The study of the stability enhancement of a peroxidase immobilized onto mesoporous silicon/silica microparticles is presented. Peroxidases tend to get inactivated in the presence of hydrogen peroxide, their essential co-substrate, following an auto-inactivation mechanism. In order to minimize this inactivation, a second protein was co-immobilized to act as an electron acceptor and thus increase the stability against self-oxidation of peroxidase. Two heme proteins were immobilized into the microparticles: a fungal commercial peroxidase and cytochrome c from equine heart. Two types of biocatalysts were prepared: one with only covalently immobilized peroxidase (one-protein system) and another based on covalent co-immobilization of peroxidase and cytochrome c (two-protein system), both immobilized by using carbodiimide chemistry. The amount of immobilized protein was estimated spectrophotometrically, and the characterization of the biocatalyst support matrix was performed using Brunauer-Emmett-Teller (BET), scanning electron microscopy with energy-dispersive X-ray spectroscopy
 (SEM-EDX), and Fourier transform infrared (FTIR) analyses. Stability studies show that co-immobilization with the two-protein system enhances the oxidative stability of peroxidase almost four times with respect to the one-protein system. Thermal stability analysis shows that the immobilization of peroxidase in derivatized porous silicon microparticles does not protect the protein from thermal denaturation, whereas biogenic silica microparticles confer significant thermal stabilization.
The identification of biomarkers of transition from the at-risk mental state (ARMS) to psychotic disorder is important because early treatment of psychosis is associated with improved outcome. Increasing evidence points to an inflammatory contribution to psychosis. We questioned whether raised levels of plasma inflammatory markers predict transition from ARMS to psychotic disorder and whether any such predictors could be reduced by omega-3 (ω-3) polyunsaturated fatty acids (PUFAs).
We measured the levels of 40 neuroinflammation biomarkers using a commercially available immunoassay kit. Firstly, we compared inflammatory markers in subjects in the ARMS who transitioned to psychotic disorder (n = 11) compared to subjects who did not (n = 28). Then we compared inflammatory markers in all subjects before and after ω-3 PUFA treatment (n = 40).
Our data provides preliminary evidence that elevations in the baseline plasma levels of the inflammatory marker IL12/IL23p40 are associated with transition from ARMS to psychotic disorder. IL12/IL23p40 levels did not change following 12 weeks administration of ω-3 PUFAs. These findings provide evidence that elevated plasma IL12/IL23p40 is a potential biomarker of increased risk for transition to psychotic disorder.
Further studies are required to confirm and extend this finding. Our results do not provide support for the possibility that administration of ω-3 PUFAs act to reduced transition to psychotic disorder by reducing blood levels of IL12/IL23p40.
ClinicalTrials.gov, a service of the U.S. National Institutes of Health, Identifier: NCT00396643 , last updated December 20, 2007. Retrospectively registered.
Tuberculosis (TB) is a global epidemic associated increasingly with resistance to first- and second-line antitubercular drugs. The magnitude of this global health threat underscores the urgent need to discover new antimycobacterial agents that have novel mechanisms of action (MOA). In this review, we highlight some of the key advances that have enabled the strengths of target-led and phenotypic approaches to TB drug discovery to be harnessed both independently and in combination. Critically, these promise to fuel the front-end of the TB drug pipeline with new, pharmacologically validated drug targets together with lead compounds that act on these targets.
The Hill Burton Act, which was signed into law in 1946 and ended in 1997, was one of the most significant forces that shaped the health care system we have today. Providing grants and loans for the construction and expansion of hospitals across the country, it required beneficiary hospitals to give some amount of uncompensated care to the poor and uninsured in return. The act not only led to our health care system's current emphasis on the acute-care hospital as the primary site of health care delivery, but it also had a profound effect on nursing, fully involving the profession in an acute-care world. The act created jobs for nurses at an unprecedented level. There are over 3.4 million nurses in the United States, and in 2013, 63 percent of all nurses worked for hospitals. Nursing education continues to emphasize acute care, despite the calls for shifting the curriculum to more community-based content and experiences that focus on health promotion and wellness for individuals, families, and communities. It is my premise that the nursing profession and all who profess to be committed to promoting health have a moral obligation to help the nation adopt a Hill-Burton Act of the twenty-first century that will focus on building healthy communities, supporting families in ways that promote health, and helping individuals to live healthier lives. This would require a shift in resources from a costly health care system to investing in community development, whether job creation, building safe places to play and exercise, providing access to affordable and nutritious foods, advancing the quality of education, or other approaches to addressing and improving the social determinants of health. Making this kind of investment would speak to the principles of beneficence, least harm, and justice, particularly for socioeconomically stressed communities.
Numerous studies have revealed that health care transitions for chronically ill older adults are frequently poorly managed, often with devastating human and economic consequences. And poorly managed transitions and their consequences also occur among younger, relatively healthy individuals who have adequate resources and are prepared to advocate on their own behalf. Despite the rich base of research confirming that evidence-based transitional care enhances patients' experiences, improves health and quality of life, and reduces costs, organizational, regulatory, financial, and cultural barriers have, until recently, prevented widespread adoption of these proven approaches. Provisions of the Affordable Care Act, such as reductions in Medicare payments to hospitals with very high thirty-day rehospitalization rates, have reduced barriers, but uptake of evidence-based transitional care beyond demonstration projects continues to be sporadic and far too slow. With a rich understanding about how to better anticipate and respond to the compelling problems experienced by patients, family caregivers, and health care professionals throughout episodes of acute illness, the time has come to frame transitional care as a system's ethical responsibility in an aging society. Embedding transitional care within the ethical obligations of a health care system requires the perspectives and involvement of nurses and nursing because of this profession's integral role in every aspect of care transitions.
Statins are used for treatment of hypercholestremia. Common adverse reports associated with use of statins are generalized bodyache, rhabdomyolysis, muscles weakness and gastrointestinal disorders. The current work is an attempt to explain how smooth muscles of gastrointestinal tissues are affected by the current statins (Simvastatin, atorvastatin, fluvastatin and rosuvastatin).
Effects of the current statins were studied on spontaneous activity of isolated rabbits' jejunal preparations. Different molar concentrations (10(-12)-10(-2)M) of the statins were applied on spontaneously contracting rabbits' jejunal preparations. As statins relaxed spontaneous activity, so we tested the statins on KCl (80 mM) induced contractions in similar test concentrations. Positive relaxant statins were tested again through construction of Calcium Concentration Response Curves (CCRCs) in the absence and presence of the statins using verapamil, a standard calcium channel blocker. CCRCs of statins were compared with CCRCs of verapamil.
Simvastatin, atorvastatin, fluvastatin and rosuvastatin relaxed the spontaneous and KCl-induced contractions. IC50 for simvastatin on spontaneous rabbit's jejunal preparations is -5.08 ± 0.1 Log 10 M. Similarly, IC50 for KCl-induced contractions is -4.25 ± 0.01 Log 10 M. Mean IC50 (Log 10 M) for atorvastatin on spontaneous rabbit's jejunal preparations and KCl-induced contractions are -5.19 ± 0.07 and -4.37 ± 0.09, respectively. Fluvastatin relaxed spontaneous activity of rabbits' jejunal preparations with an IC50 (Log 10 M) -4.5 ± 0.03. Rosuvastatin relaxed spontaneous as well as KCl (80 mM) induced contractions with respective IC50 (Log 10 M) -3.62 ± 0.04 and -4.57 ± 0.06. In case of CCRCs, tissues pre-treated with 4.6 μg/ml of simvastatin, have IC50 = -1.84 ± 0.03 [log (Ca(++)) M] vs control IC50 = -2.54 ± 0.04 [log (Ca(++)) M]. Similarly, atorvastatin, fluvastatin and rosuvastatin produced significant right shift in IC50 for CCRCs (P ≤ 0.05). In case of verapamil, IC50 for control curves is -2.45 ± 0.06 [log (Ca (++)) M], while IC50 in presence of verapamil (0.1 μM) is -1.69 ± 0.05 [log (Ca (++)) M]. Statins produced right shift in the IC50 of CCRCs. The effects of statins are like that of effects of verapamil, a standard calcium channel blocker.
Our findings suggest that current statins have calcium antagonistic effects that act on voltage gated calcium channels that may provide a rationale for cause muscle weakness and gastrointestinal disorders.
The Department of Health and Human Services has issued far-reaching regulations to implement the nondiscrimination requirement of the Affordable Care Act. Now commonly called "Section 1557," this ACA provision prohibits discrimination by "any health program or activity, any part of which is receiving Federal financial assistance," on grounds prohibited under previously enacted federal antidiscrimination statutes. The DHHS Office of Civil Rights enforces Section 1557. These new regulations and accompanying commentary give warning of the standards the agency will use in its enforcement efforts. Courts will also give some deference to the DHHS regulations in interpreting the statute in lawsuits by individuals claiming damages against covered health care providers for illegal discrimination under Section 1557. Three central issues are the nature of the rights created in Section 1557 and their relation to the listed federal antidiscrimination statutes, the sorts of health care programs and activities that are covered by Section 1557, and the definition of the personal characteristics, including sexual orientation and gender identity, against which discrimination is prohibited.
Women
 who are pregnant and homeless constitute a unique group at significant risk of adverse foetal and maternal outcomes. Despite this heightened risk profile, social housing support to this group of women is less than satisfactory. Concerted effort and more collaborative working is needed by all who provide social, and healthcare services to homeless pregnant women, to improve the lot of these women. Clear definitions and legislative provisions in respect of the homeless will go a long way in reducing ambiguity and close loopholes which currently act to deny the homeless pregnant woman social housing support at a time when it is most needed.
A series of three new isostructural metal-organic frameworks (MOFs) of nickel(II), [{Ni(muco)(bpa)(2H2O)}·2H2O] (1), [{Ni(muco)(bpe)(2H2O)}·2.5H2O] (2), and [{Ni(muco)(azopy)(2H2O)}·2H2O] (3) [where muco = trans,trans-muconate dianion, bpa = 1,2-bis(4-pyridyl)ethane, bpe = 1,2-bis(4-pyridyl)ethylene, and azopy = 4,4'-bis(azobipyridine)], have been synthesized and characterized by single-crystal X-ray diffraction analysis and other physicochemical methods. Compounds 1-3 exhibit an interesting 3-fold-interpenetrated three-dimensional pillar-layered framework structure constituted of 4-coordinating (4-c) Ni(II) nodes with {6(6)}-neb net topology. Remarkably, in spite of 3-fold interpenetration, the structures possess one-dimensional channels with dimensions of ∼8.05 × 5.25 Å(2). Gas (N2, Ar, H2, and CO2) adsorption studies of compounds 2 and 3 revealed selective adsorption properties for CO2 over other gases. In all three structures, the 4-c Ni(II) node has two coordinated H2O molecules that can be reversibly removed by high-temperature treatment to generate a dehydrated framework composed of highly unsaturated, Lewis acidic Ni(II) ions. Further, the activated compounds of 1-3 act as efficient recyclable catalysts for heterogeneous cycloaddition of CO2 with styrene oxide, resulting in cyclic carbonate with high conversion and selectivity. Interestingly, the cycloaddition reactions of CO2 with bulky epoxides show a decrease in the activity with an increase in the alkyl chain length of the substrate due to confinement of the pore size of the MOF. The high catalytic efficiency and size-dependent selectivity for smaller epoxides show the potential utility of 1 as a promising heterogeneous catalyst for the cycloaddition of CO2. Furthermore, the catalyst can be easily separated and reused for several cycles without significant reduction in the catalytic activity as well as structural rigidity. Compounds 1-3 represent rare examples of interpenetrated MOFs exhibiting selective storage and conversion of CO2 at mild conditions.
Stress, via corticosteroids release, influences bone mass density. Hypericum perforatum (Hp) a traditional remedy possess antidepressive activity (serotonin reuptake inhibitor) and wound healing properties. Hp preparation contains mainly hypericin, hyperforin, hyperoside and flavonoids exerting oestrogen-mimetic effect. Cold swimming represents an experimental model of stress associating mental strain and corporal exhaustion.
This study investigates the Hp effect on femur and mandible bone mass changes in rats under cold forced swimming procedure.
30 male Wistar rats were randomized into three groups. Group A was treated with Methanolic extract of Hp (Jarsin®) via gastroesophageal catheter, and was submitted to cold swimming stress for 10 min/daily. Group B was submitted to cold stress, since group C served as control. Experiment duration was 10 days. Haematocrite and serum free fatty acids (FFA) were estimated. Furthermore volume and specific weight of each bone as well as bone mass density via dual energy X-Ray absorptiometry (DEXA) were measured. Statistic analysis by t-test.
Hp treatment restores the stress injuries. Adrenals and bone mass density regain their normal values.
Injuries occurring by forced swimming stress in the rats are significantly improved by Hp treatment. Estrogen-like effects of Hp flavonoids eventually may act favorable in bone remodeling.
Cyclophosphamide (CY) is a commonly-used nitrogen mustard alkylating agent, but its clinical application is severely limited by its cardiotoxicity. Since the development of metabolomics, the change of metabolite profiles caused by cyclophosphamide has been studied by metabolomics and has gained much attention. In this study, we analyzed rat plasma samples collected one, three and five days after cyclophosphamide administration using ultra-performance liquid chromatography quadrupole time-of-flight mass spectrometry (UPLC/Q-TOF-MS). Multiple statistical analyses, such as principal component analysis (PCA) and partial least squares - discriminant analysis (PLS-DA), were used to examine metabolite profile changes in plasma samples in order to screen for potential cardiotoxicity biomarkers and metabolic pathways. Levels of a dozen of metabolites changed significantly in plasma from the CY-treated group after one, three, and five days compared with the control group treated with normal saline (NS). Receiver operator characteristic (ROC) curve analysis suggested that the total 16 metabolites play important roles in different times of CY-induced cardiotoxicity respectively. Our results suggest that these metabolites in linoleic acid metabolism and glycerol phospholipid metabolism may be related to CY-induced cardiotoxicity. These metabolites could act as sensitive biomarkers for CY-induced cardiotoxicity and be useful for investigating toxic mechanisms. They may also lay a foundation for clinical use of cyclophosphamide.
To explore how nurses navigate communication with families during withdrawal of life-sustaining treatment in intensive care.
Death in the intensive care unit is seldom unexpected and often happens following the withdrawal of life-sustaining treatment. A family-centred approach to care relies on the development of a therapeutic relationship and understanding of what is happening to the patient. Whilst previous research has focused on the transition from cure to palliation and the nurse's role in supporting families, less is known about how nurses navigate communication with families during treatment withdrawal.
A qualitative descriptive approach was used. Semi-structured focus groups were conducted with adult critical care nurses from four intensive care units, two in Australia and two in New Zealand.
Twenty-one nurses participated in the study. Inductive content analysis revealed five key themes relating to how nurses navigate family communication: (1) establishing the WHO; (2) working out HOW; (3) judging WHEN; (4) assessing the WHAT; and (5) WHERE these skills were learnt.
Navigating an approach to family communication during treatment withdrawal is a complex and multifaceted nursing activity that is known to contribute to family satisfaction with care. There is need for support and ongoing education opportunities that develop the art of communication in this frequently encountered aspect of end-of-life care.
How nurses navigate communication with families during treatment withdrawal is just as important as what is communicated. Nurses need access to supports and education opportunities in order to be able to perform this vital role.
This study sought to examine the extent to which undergraduates' experiences with and attitudes relevant to rejection may be associated with their emotional and behavioral responses to ambiguous social situations in which rejection might be inferred. Undergraduate students completed questionnaires that assessed their experiences with and attitudes relevant to being rejected. Next, each participant read six hypothetical scenarios that described various situations that could be interpreted as interpersonal rejection. Following each scenario, participants completed questionnaires that assessed their emotional and behavioral responses to the hypothetical situation. Analyses revealed that the participants' experiences with rejection (and, to a lesser extent, their rejection-relevant attitudes) were associated with a negative emotional response and some negative behavioral responses. In sum, when another individual's interpersonal behavior has an uncertain intent, undergraduates' prior experiences with rejection may be especially important in determining the extent to which they feel and act as if they have been rejected.
The Affordable Care Act (ACA) has profoundly restructured American health care. Numerous social work authors have commented on the importance of the ACA's reforms to social work practice, education, and research. This article summarizes the literature, adds relevant information, and makes recommendations for future actions. The policy, opinion, and peer-reviewed literatures were systematically reviewed. Sixty-three publications appeared between 2010 and 2015 are included. Five themes emerged, as follows: 1) the crucial provisions of the ACA, 2) the natural affinity of social work and the ACA reforms, 3) curricular adaptations needed to address changing workforce needs, 4) areas for continued social work advocacy, and 5) opportunities for high-impact social work research. This article provides a comprehensive introduction to the ACA, its reforms, and opportunities for social work to assume a high visibility leadership role in implementing the reforms, with particular emphasis on needed curricular changes and opportunities for research.
Objective The objective of this study was to determine the time to hematologic recovery and the incidence of secondary sepsis and mortality among neutropenic infants treated or not treated with granulocyte colony-stimulating factor (G-CSF). Study Design We identified all neutropenic infants discharged from 348 neonatal intensive care units from 1997 to 2012. Neutropenia was defined as an absolute neutrophil count ≤ 1,500/µL
 for ≥ 1 day during the first 120 days of life. Incidence of secondary sepsis and mortality and number of days required to reach an absolute neutrophil count > 1,500/µL for infants exposed to G-CSF were compared with those of unexposed infants. Results We identified 30,705 neutropenic infants, including 2,142 infants (7%) treated with G-CSF. Treated infants had a shorter adjusted time to hematologic recovery (hazard ratio: 1.36, 95% confidence interval [CI]: 1.30-1.44) and higher adjusted odds of secondary sepsis (odds ratio [OR]: 1.50, 95% CI: 1.20-1.87), death (OR: 1.33, 95% CI: 1.05-1.68), and the combined outcome of sepsis or death (OR: 1.41, 95% CI: 1.19-1.67) at day 14 compared with untreated infants. These differences persisted at day 28. Conclusion G-CSF treatment decreased the time to hematologic recovery but was associated with increased odds of secondary sepsis and mortality in neutropenic infants. G-CSF should not routinely be used for infants with neutropenia.
It remains a challenge to synthesize Ag nanocubes in an aqueous system, although the polyol process was successfully adopted more than one decade ago. Here, we report an aqueous method for the synthesis of Ag nanocubes with an average edge length of 35-95 nm. It involves the formation of AgCl octahedra by mixing CF3COOAg with cetyltrimethylammonium chloride, followed by the nucleation and growth of Ag nanocrystals in the presence of ascorbic acid (AA) and FeCl3. The Fe(3+)/Fe(2+) redox pair is responsible for the removal of multiply twinned seeds through oxidative etching. The Cl(-) ions play two critical roles in the nucleation and growth of Ag nanocubes with a single-crystal structure. First, the Cl(-) ions react with Ag(+) ions to generate nanometer-sized AgCl octahedra in the initial stage of a synthesis. In the presence of room light and a proper reducing agent such as AA, the AgCl can be reduced to generate Agn nuclei followed by their evolution into single-crystal seeds and then Ag nanocrystals. Second, the Cl(-) ions can act as a specific capping agent toward the Ag(100) surface, enabling the formation of Ag nanocubes with sharp corners and edges. Based on the results from a set of time-lapse studies and control experiments, we formulate a plausible mechanism to account for the formation of Ag nanocubes that resembles the formation and development of latent image centers in silver halide grains in the photographic process.
Nowadays, intelligent systems applied to vehicles have grown very rapidly; their goal is not only the improvement of safety, but also making autonomous driving possible. Many of these intelligent systems are based on making use of computer vision in order to know the environment and act accordingly. It is of great importance to be able to estimate the pose of the vision system because the measurement matching between the perception system (pixels) and the vehicle environment (meters) depends on the relative position between the perception system and the environment. A new method of camera pose estimation for stereo systems is presented in this paper, whose main contribution regarding the state of the art on the subject is the estimation of the pitch angle without being affected by the roll angle. The validation of the self-calibration method is accomplished by comparing it with relevant methods of camera pose estimation, where a synthetic sequence is used in order to measure the continuous error with a ground truth. This validation is enriched by the experimental results of the method in real traffic environments.
Resveratrol, a dietary polyphenol, is under consideration as chemopreventive and chemotherapeutic agent for several diseases, including cancer. However, its mechanisms of action and its effects on non-tumor cells, fundamental to understand its real efficacy as chemopreventive agent, remain largely unknown. Proline-rich tyrosine kinase 2 (PYK2), a non-receptor tyrosine kinase acting as signaling mediator of different stimuli, behaves as tumor-suppressor in prostate. Since, PYK2 and RSV share several fields of interaction, including oxidative stress, we have investigated their functional relationship in human non-transformed prostate EPN cells and in their tumor-prone counterpart EPN-PKM, expressing a PYK2 dead-kinase mutant. We show that RSV has a strong biological activity in both cell lines, decreasing ROS production, inducing morphological changes and reversible growth arrest, and activating autophagy but not apoptosis. Interestingly, the PYK2 mutant increases basal ROS and autophagy levels, and modulates the intensity of RSV effects. In particular, the anti-oxidant effect of RSV is more potent in EPN than in EPN-PKM, whereas its anti-proliferative and pro-autophagic effects are more significant in EPN-PKM. Consistently, PYK2 depletion by RNAi replicates the effects of the PKM mutant. Taken together, our results reveal that PYK2 and RSV act on common cellular pathways and suggest that RSV effects on prostate cells may depend on mutational-state or expression levels of PYK2 that emerges as a possible mediator of RSV mechanisms of action. Moreover, the observation that resveratrol effects are reversible and not associated to apoptosis in tumor-prone EPN-PKM cells suggests caution for its use in humans.
Rubinstein-Taybi syndrome (RSTS) is a developmental disorder characterized by a typical face and distal limbs abnormalities, intellectual disability, and a vast number of other features. Two genes are known to cause RSTS, CREBBP in 60% and EP300 in 8-10% of clinically diagnosed cases. Both paralogs act in chromatin remodeling and encode for transcriptional co-activators interacting with >400 proteins. Up to now 26 individuals with an EP300 mutation have been published. Here, we describe the phenotype and genotype of 42 unpublished RSTS patients carrying EP300 mutations and intragenic deletions and offer an update on another 10 patients. We compare the data to 308 individuals with CREBBP mutations. We demonstrate that EP300 mutations cause a phenotype that typically resembles the classical RSTS phenotype due to CREBBP mutations to a great extent, although most facial signs are less marked with the exception of a low-hanging columella. The limb anomalies are more similar to those in CREBBP mutated individuals except for angulation of thumbs and halluces which is very uncommon in EP300 mutated individuals. The intellectual disability is variable but typically less marked whereas the microcephaly is more common. All types of mutations occur but truncating mutations and small rearrangements are most common (86%). Missense mutations in the HAT domain are associated with a classical RSTS phenotype but otherwise no genotype-phenotype correlation is detected. Pre-eclampsia occurs in 12/52 mothers of EP300 mutated individuals versus in 2/59 mothers of CREBBP mutated individuals, making pregnancy with an EP300 mutated fetus the strongest known predictor for pre-eclampsia. © 2016 Wiley Periodicals, Inc.
This study examined symptom-based subgroups of metastatic breast cancer (MBC) patients and the extent to which they differed across key constructs of acceptance and commitment therapy (ACT).
Eighty women with MBC completed self-report surveys assessing 10 common symptoms and several ACT variables (ie, activity engagement, psychological inflexibility, value obstruction, and value progress) during a single time point.
A cluster analysis yielded 3 patient subgroups: low symptoms, low-moderate symptoms, and moderate-high symptoms. Relative to the subgroup with low symptoms, the other subgroups reported less activity engagement. In addition, compared with patients with low symptoms, the subgroup with moderate-high symptoms reported greater psychological inflexibility (ie, avoidance of unwanted internal experiences) and greater difficulty living consistently with their values.
Women with MBC show heterogeneity in their symptom profiles, and those with higher symptom burden are more likely to disengage from valued activities and avoid unwanted experiences (eg, thoughts, feelings, and bodily sensations). Findings are largely consistent with the ACT model and provide strong justification for testing ACT to address symptom interference in MBC patients.
The gastrointestinal (GI) tract, which hosts hundreds of bacteria species, becomes the most exciting organ for the emerging microbiome research. Some of these GI microbes are hostile and cause a variety of diseases. These bacteria colonize in different segments of the GI tract dependent on the local physicochemical and biological factors. Therefore, selectively locating therapeutic or imaging agents to specific GI segments is of significant importance for studying gut microbiome and treating various GI-related diseases. Herein, we demonstrate an enteric micromotor system capable of precise positioning and controllable retention in desired segments of the GI tract. These motors, consisting of magnesium-based tubular micromotors coated with an enteric polymer layer, act as a robust nanobiotechnology tool for site-specific GI delivery. The micromotors can deliver payload to a particular location via dissolution of their enteric coating to activate their propulsion at the target site toward localized tissue penetration and retention.
Drugs capable of trapping topoisomerase II (Top2), an essential enzyme that cleaves DNA to remove naturally occurring knots and tangles, can serve as potent anticancer agents. The monofunctional platinum agent phenanthriplatin, cis-[Pt(NH3)2(phenanthridine)Cl](NO3), is shown here to trap Top2 in addition to its known modes of inhibition of DNA and RNA polymerases. Its potency therefore combines diverse modes of action by which phenanthriplatin kills cancer cells. The observation that phenanthriplatin can act as a Top2 poison highlights opportunities to design
 nonclassical platinum anticancer agents with this novel mechanism of action. Such complexes have the potential to overcome current limitations with chemotherapy, such as resistance, and to provide treatment options for cancers that do not respond well to classical agents. Covalent DNA-platinum lesions implicated in Top2 poisoning are distinctive from those generated by known therapeutic topoisomerase poisons, which typically exert their action by reversible binding at the interface of Top2-DNA cleavage complexes.
The South-southern zone of Nigeria is one of the zones in the country that has reported consistent high prevalent rates of HIV/AIDS pandemic in the last decade. In spite of bio-medical reasons adduced for the spread of the pandemic, socio-cultural factors may be major issues in the access to both prevention and treatment services especially for women. Hence, this study investigated the socio-cultural factors, which influence the access of women to HIV/AIDS prevention and treatment services in Nigeria.
We utilised the social survey viz. the unstructured interviews and the focus group discussions (FGDs) as methods for collecting data.
Socio-cultural norms, stereotypes and expectations still influence the access of women to these services. Such socio-cultural barriers are not significantly reduced by urbanization and the deadly threat of the epidemic. These socio-cultural variables, which impede the access of women to these services, are webbed around the dominant narratives of male superiority and the immorality culturally ascribed to women who openly discuss safe sex or seek prevention devices like the condom.
There is need for more emphasis on gender equality in sexuality and for HIV/AIDS programme planners and policy makers to think and act outside the box of the narratives of male superiority sponsored by socio-cultural norms in addressing the peculiar challenges of women in accessing HIV/AIDS services.
The mechanistic Target Of Rapamycin Complex 1 (mTORC1) is central to the cellular response to changes in nutrient signals such as amino acids. CASTOR1 is shown to be an arginine sensor, which plays an important role in the activation of the mTORC1 pathway. In the deficiency of arginine, CASTOR1 interacts with GATOR2, which together with GATOR1 and Rag GTPases controls the relocalization of mTORC1 to lysosomes. The binding of arginine to CASTOR1 disrupts its association with GATOR2 and hence activates the mTORC1 signaling. Here, we report the crystal structure of CASTOR1 in complex with arginine at 2.5 Å resolution. CASTOR1 comprises of four tandem ACT domains with an architecture resembling the C-terminal allosteric domains of aspartate kinases. ACT1 and ACT3 adopt the typical βαββαβ topology and function in dimerization via the conserved residues from helices α1 of ACT1 and α5 of ACT3; whereas ACT 2 and ACT4, both comprising of two non-sequential regions, assume the unusual ββαββα topology and contribute an arginine-binding pocket at the interface. The bound arginine makes a number of hydrogen-bonding interactions and extensive hydrophobic contacts with the surrounding residues of the binding pocket. The functional roles of the key residues are validated by mutagenesis and biochemical assays. Our structural and functional data together reveal the molecular basis for the arginine-binding specificity of CASTOR1 in the arginine-dependent activation of the mTORC1 signaling.
Increasing parity may be a risk factor for the development of type 2 diabetes mellitus and the metabolic alterations during a normal pregnancy induces a prediabetic state; thus, multiple pregnancies may act as a risk factor for development of type 2 diabetes if these physiological alterations in glucose homeostasis are not reversed postpartum. We hypothesize that multiple pregnancies may lead to β-cell exhaustion and that the insulin resistance that occurs during pregnancy may persist after multiple births.
A total of 28 healthy premenopausal women were recruited: 15 high parity women (≥4 children) and 13 body mass index (BMI)-matched and age-matched low parity women (1 and 2 children). The study consisted of an intravenous glucose tolerance test for assessment of β-cell function followed by a hyperinsulinemic euglycemic clamp for assessment of insulin sensitivity. Dual-energy X-ray absorptiometry was performed to assess body composition.
All anthropometric measures, measures of body composition and baseline blood samples were comparable between the 2 groups. Neither first phase insulin release (0-10 min, p=0.92) nor second phase insulin release (10-60 min, p=0.62), both measured as area under the curve, differed between the 2 groups. The M-value, calculated as the mean glucose infusion rate during the last 30 min of the clamp period, was 8.66 (7.70 to 9.63) mg/kg/min in the high parity group compared with 8.41 (7.43 to 9.39) mg/kg/min in the low parity group (p=0.69).
We did not detect any effects of increasing parity on insulin sensitivity or β-cell function.
Sexual traits are often the most divergent characters among closely related species, suggesting an important role of sexual traits in speciation. However, to prove this, we need to show that sexual trait differences accumulate before or during the speciation process, rather than being a consequence of it. Here, we contrast patterns of divergence among putative male sex pheromone (pMSP) composition and the genetic structure inferred from variation in the mitochondrial cytochrome oxidase 1 and nuclear CAD loci in the African butterfly Bicyclus anynana (Butler, 1879) to determine whether the evolution of "pheromonal dialects" occurs before or after the differentiation process. We observed differences in abundance of some shared pMSP components as well as differences in the composition of the pMSP among B. anynana populations. In addition, B. anynana individuals from Kenya displayed differences in the pMSP composition within a single population that appeared not associated with genetic differences. These differences in pMSP composition both between and within B. anynana populations were as large as those found between different Bicyclus species. Our results suggest that "pheromonal dialects" evolved within and among populations of B. anynana and may therefore act as precursors of an ongoing speciation process.
Fusion of joints as well as intervertebral spaces by the formation of bony spurs appearing as syndesmophytes and osteophytes are the hallmark of spondyloarthropathies which accounts for disability. The aim of this study was to assess the serum level of bone morphogenetic protein (BMP)-7 in ankylosing spondylitis and its relationship with disease activity and the radiographic damage.
This longitudinal case control study was conducted in Ain Shams University Hospitals (Egypt). A total of 55 subjects were included in two case groups and one control group. Group I included 20 patients with Ankylosing Spondylitis (AS) assessed at baseline (defined as Ia and after 18 months defined as Ib). Group II included 20 patients with Rheumatoid Arthritis (RA) and Group III included 15 healthy subjects as controls. Patients with other forms of seronegative spondyloarthropathies, bone forming diseases were excluded from the study. The Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) and the Bath Ankylosing Spondylitis Metrology Index (BASMI) were used to assess disease activity in AS patients. RA disease activity was assessed using the disease activity score 28 (DAS28). Radiographic changes were assessed using the Bath AS Radiographic Index (BASRI) in AS and Larsen scores in RA. Laboratory investigations included: Complete blood picture (CBC), Erythrocyte sedimentation rate (ESR), quantitative CRP, serum calcium, phosphorus and alkaline phosphatase. Determination of serum bone morphogenetic protein-7 level (BMP-7) was done using enzyme linked immunosorbent assay (ELISA). Sample collections, clinical and radiological assessments were performed at baseline for all groups and after a mean follow-up of 18 months for Group I. Data were analyzed by SPSS 17, using t-test, Kruskal-Wallis, Mann-Whitney, Fischer exact test, Chi square, and Pearson Product-Moment Correlation Coefficient.
There were statistically significant differences between the 3 groups as regard baseline BMP-7 levels; the mean BMP-7 level of AS patients was significantly higher than that of RA patients and controls and significantly higher in the RA group than that of controls. BMP-7 levels were not associated with any of the clinical or drug related variables either in AS or RA. In AS BMP-7 levels showed significant increase after follow up and significant positive correlation with serum alkaline phosphatase (both at baseline and after follow up) and BASDAI score (after follow up) respectively. Despite the parallel increase of BMP7 and BASRI score during the follow-up period no statistically significant correlation was detected. There were no significant correlations between BMP7 level and patient's age or any disease related characteristics in the RA group.
A significant progressive increase in serum BMP-7 was noted in AS patients that correlated with serum markers of bone formation. Such a biomarker measurement may not only act as a surrogate marker for the disease but has the potential to contribute to the pathogenesis of AS that may provide a complementary or alternative therapeutic approach.
Osteopontin (OPN) is an essential cytokine involved in immune cell recruitment and an important regulator of inflammation. The purpose of this study was to examine differences in OPN plasma levels between before and after antibiotic treatment in hospitalized adult patients with community-acquired pneumonia (CAP). OPN levels were measured in 93 patients with CAP and 54 healthy controls using a commercial enzyme-linked immunosorbent
 assay (ELISA). The CURB-65, Pneumonia Severity Index (PSI), and Acute Physiology and Chronic Health Evaluation II (APACHE II) scores were used to determine the CAP severity in patients upon initial hospitalization. A decline in the number of white blood cells (WBCs) and neutrophils, and decreases in the levels of OPN and C-reactive protein (CRP) were observed after antibiotic treatment. Only the plasma level of OPN, but not CRP, was correlated with the severity of CAP based on the PSI (r = 0.514, p < 0.001), CURB-65 (r = 0.396, p < 0.001), and APACHE II scores (r = 0.473, p < 0.001). The OPN level also showed a significant correlation with the length of hospital stay (r = 0.210, p = 0.044). In conclusion, plasma level of OPN may act as diagnostic adjuvant biomarkers for CAP and further play a role in clinical assessment of the severity of CAP, which could potentially guide the development of treatment strategies.
Cellulose, often touted as the most abundant biopolymer on Earth, is a critical component of the plant cell wall and is synthesized by plasma membrane-spanning cellulose synthase (CESA) enzymes, which in plants are organized into rosette-like CESA complexes (CSCs). Plants construct two types of cell walls, primary cell walls (PCWs) and secondary cell walls (SCWs), which differ in composition, structure, and purpose. Cellulose in PCWs and SCWs is chemically identical but has different physical characteristics. During PCW synthesis, multiple dispersed CSCs move along a shared linear track in opposing directions while synthesizing cellulose microfibrils with low aggregation. In contrast, during SCW synthesis, we observed swaths of densely arranged CSCs that moved in the same direction along tracks while synthesizing cellulose microfibrils that became highly aggregated. Our data support a model in which distinct spatiotemporal features of active CSCs during PCW and SCW synthesis contribute to the formation of cellulose with distinct structure and organization in PCWs and SCWs of Arabidopsis thaliana This study provides a foundation for understanding differences in the formation, structure, and organization of cellulose in PCWs and SCWs.
Tools to evaluate oncogenic kinase activity in small clinical samples have the power to guide precision medicine in oncology. Existing platforms have demonstrated impressive insights into the activity of protein kinases, but these technologies are unsuitable for the study of kinase behavior in large numbers of primary human cells. To address these limitations, we developed an integrated analysis system that utilizes a light-programmable, cell-permeable reporter deliverable simultaneously to many cells. The reporter's ability to act as a substrate for Akt, a key oncogenic kinase, was masked by a 2-4,5-dimethoxy 2-nitrobenzyl (DMNB) moiety. Upon exposure to ultraviolet light and release of the masking moiety, the substrate sequence enabled programmable reaction times within the cell cytoplasm. When coupled to automated single-cell capillary electrophoresis, statistically significant numbers of primary human cells were readily evaluated for Akt activity.
The history of Neurocinema includes neuroethics, and this theme was first used in 2 films released in the 1940s in both Germany and the United States. Ich Klage An (I Accuse) is about "terminal" multiple sclerosis in a young woman and the decision to determine one's own fate. The protagonist anticipates becoming "deaf, blind, and idiotic" and asks her husband to administer a toxic drug dose, which he does. The film disturbingly suggests that the diagnosis of multiple sclerosis is tantamount to a death sentence. Ich Klage An (1941) played during the medical murders era ("Aktion T-4" program) but has few references to National Socialism, except for judges with Nazi emblems on their robes making a brief Nazi salute and a jury chamber with a bust of Hitler. Party leadership agreed that the film made a deep impression, but the intended effect on the viewing public is largely unknown. An Act of Murder (1948) involves another young woman with an inoperable brain tumor. When her condition worsens during a trip, her husband deliberately crashes the car, killing her but surviving himself. A subsequent trial finds that she died of an overdose rather than the crash. The trial judge dismisses the murder charge, but the film argues the morals of mercy killing. These films came out during the Nazi euthanasia program and founding of the Euthanasia Society of America in 1938. The choice of neurologic disease by these filmmakers and scriptwriters to defend euthanasia is remarkable.
Previous studies have supported acceptance and commitment therapy (ACT) for reducing impairment related to various chronic conditions. ACT may possibly be beneficial for bipolar disorder (BD) with co-existing anxiety, which is associated with a poorer treatment outcome. Efforts are needed to identify suitable psychological interventions for BD and co-existing anxiety. In this open clinical trial, we included 26 patients with BD type 1 or 2 at an outpatient psychiatric unit specializing in affective disorders. The intervention consisted of a 12-session manualized group treatment that included psychoeducation, mindfulness, engaging in values-based behaviour, cognitive defusion, acceptance and relapse prevention modules. Participants completed four self-report questionnaires covering anxiety symptoms (Beck Anxiety Inventory - BAI), depressive symptoms (Beck Depression Inventory - BDI-II), quality of life (Quality of Life Inventory - QOLI) and psychological flexibility (Acceptance and Action Questionnaire - AAQ-2) before, during and after the treatment. At post-treatment, the participants reported significant improvements in all outcome measures, with large effects (Cohen's d between 0.73 and 1.98). The mean reduction in anxiety symptoms was 45%. At post-treatment, 96% of the patients were classified as responders on at least one of the outcome measures. A limitation is that the trial is uncontrolled. The results suggest that ACT has the potential to be an effective treatment for BD patients with co-existing anxiety. Further randomized studies are warranted.
Artemisinin-based combination therapy (ACT) introduced in the mid-1990s has been recommended since 2005 by the World Health Organization as first-line treatment against Plasmodium falciparum in all endemic countries. In 2010, the combination dihydroartemisinin-piperaquine (DP) was recommended for the treatment of uncomplicated P. falciparum malaria. DP is one of the first-line treatments used by the French army since 2013.
A case of P. falciparum clinical failure with DP at day 20 was described in a 104 kg French soldier deployed in Djibouti. He was admitted to hospital for supervision of oral treatment with DP [40 mg dihydroartemisinin (DHA) plus 320 mg piperaquine tetraphosphate (PPQ)]. This corresponded to a cumulative dose of 4.6 mg/kg DHA and 37 mg/kg PPQ in the present patient, which is far below the WHO recommended ranges. No mutation was found in the propeller domain of the Kelch 13 (k13) gene, which is associated with artemisinin resistance in Southeast Asia. Pfmdr1 N86, 184F, S1034 and N1042 polymorphisms and haplotype 72-76 CVIET for the pfcrt gene were found in the present case. There was no evidence of resistance to DP.
This case confirms the risk of therapeutic failure with dihydroartemisinin-piperaquine by under-dosing in patients weighing more than 100 kg. This therapeutic failure with DP by under-dosing highlighted the importance of appropriate dosing guidelines and the need of research data (efficacy, pharmacokinetics and pharmacodynamics) in over-weight patient group.
The diet polyphenols are a secondary metabolites of plants able to act on inflammation process. Their anti-inflammatory activity is articulated through several mechanisms that are related to their antioxidative and radical scavengers properties. Our work is focused on a novel approach to inflammatory disease management, based on anti-glycative and matrix metalloproteinases (MMPs) inhibition effects, as a connected phenomena. To better understand these correlation, polyphenols Structure-Activity Relationship (SAR) studies were also reported. The antioxidant polyphenols inhibit the AGEs at different levels of the glycation process in the following ways: 1) prevention of Amadori adduct oxidation; 2) trapping reactive dycarbonyl compounds; 3) attenuation of receptor for AGEs (RAGE) expression. Moreover, several flavonoids with radical scavenging property showed also MMPs inhibition interact directly with MMPs or indirectly via radical scavengers and AGEs reduction. The essential polyphenols features involved in these mechanisms are C2-C3 double bond and number and position of hydroxyl, glycosyl and O-methyl groups. These factors induce a change in molecular planarity interfering with the hydrogen bond formation, electron delocalization and metal ion chelation. In particular, C2-C3 double bond improve the antioxidant and MMPs inhibition, while the hydroxylation, glycosylation and methylation induce a positive and negative correlation respectively.
Juvenile idiopathic arthritis (JIA) is the most common chronic rheumatic disease in children. Genetics and inflammatory elements seem to act as major underlying factors in its pathogenesis. The aim of this study is to identify the associations between interleukin-6 (IL-6) gene polymorphisms and individuals' vulnerability to JIA in a group of Iranian pediatric patients. Fifty-four patients with JIA were enrolled in this investigation and compared with 139 healthy individuals. Using polymerase chain reaction with sequence-specific primers, cytokine genotyping was performed. The allele and genotype frequencies of two single nucleotide polymorphisms (SNPs) within the IL-6 gene at -174 and +565 positions
 were assessed. A significant positive association was observed for IL -6 -174 G allele in the patient group (p = 0.02). Furthermore, a positive association was observed in patients with JIA for the GG genotype at the same position (p < 0.01), thus revealing a predisposing effect in JIA patients. On the other hand, a significant negative association was found for IL-6 -174 CG genotype (p < 0.01) in the case group. No significant difference was discovered in both the allelic and genotypic frequencies of IL-6 +565 position between patients and controls. Additionally, haplotype analysis divulged over representation of IL-6 GG haplotype in patient group (p < 0.01) as well as IL-6 CG haplotype in healthy controls (p < 0.01). Certain allele, genotype, and haplotype in IL-6 gene were over expressed in patients with JIA, which probably could render individuals more susceptible to this disease.
It is known that there are mechanistic links between circadian clocks and metabolic cycles. Reduced nicotinamide adenine dinucleotide (NADH) is a key metabolic cofactor in all living cells; however, it is not known whether levels of NADH oscillate or not. Here we employed REX, a bacterial NADH-binding protein, fused to the VP16 activator to convert intracellular endogenous redox balance into transcriptional readouts by a reporter gene in mammalian cells. EMSA results show that the DNA binding activity of both T- and S-REX::VP16 fusions is decreased with a reduced-to-oxidized cofactor ratio increase. Transient and stabilized cell lines bearing the REX::VP16 and the REX binding operator (ROP) exhibit two circadian luminescence cycles. Consistent with these results, NADH oscillations are observed in host cells, indicating REX can act as a NADH sensor to report intracellular dynamic redox homeostasis in mammalian cells in real time. NADH oscillations provide another metabolic signal for coupling the circadian clock and cellular metabolic states.
All nicotinic acetylcholine receptors (nAChRs) evolved from homomeric nAChRs in which all five subunits are involved in forming acetylcholine (ACh) binding sites at their interfaces. Heteromeric α4β2* nAChRs typically have two ACh binding sites at α4/β2 interfaces and a fifth accessory subunit surrounding the central cation channel. β2 accessory subunits do not form ACh binding sites, but α4 accessory subunits do at the α4/α4 interface in (α4β2)2α4 nAChRs. α5 and β3 are closely related subunits that had been thought to act only as accessory subunits and not take part in forming ACh binding sites. The effect of agonists at various subunit interfaces was determined by blocking homologous sites at these interfaces using the thioreactive agent 2-((trimethylammonium)ethyl) methanethiosulfonate (MTSET). We found that α5/α4 and β3/α4 interfaces formed ACh binding sites in (α4β2)2α5 and (α4β2)2β3 nAChRs. The α4/α5 interface in (β2α4)2α5 nAChRs also formed an ACh binding site. Blocking of these sites with MTSET reduced the maximal ACh evoked responses of these nAChRs by 30-50%. However, site-selective agonists NS9283 (for the α4/α4 site) and sazetidine-A (for the α4/β2 site) did not act on the ACh sites formed by the α5/α4 or β3/α4 interfaces. This suggests that unorthodox sites formed by α5 and β3 subunits have unique ligand selectivity. Agonists or antagonists for these unorthodox sites might be selective and effective drugs for modulating nAChR function to treat nicotine addiction and other disorders.
EU policy documents and health scholars point out that in order to understand the complexity of modern health systems, as well as to devise appropriate policy responses, considering micro, meso, and macro levels is indispensable. This article aims to develop an analytical framework for how rehabilitation as an interdisciplinary field can be framed in such a three-level framework.
This is a conceptual paper based on recent contributions to the development of a theory of rehabilitation. The paper applies sociological theory to build an analytical framework for a holistic understanding of rehabilitation.
Three groups of agents in the field of rehabilitation are identified: individuals with disabilities, professionals, and governmental authorities. The paper systematizes how these agents are positioned and act at micro, meso, and macro levels. In the intersection between the three levels of society and the three groups of actors, a nine-cell table emerges. In the cells of the table, key examples of important social processes to study in the field of disability and rehabilitation are identified. At the micro level, individuals experience a daily life relevant to rehabilitation, professionals ask what works in therapy, and policy authorities promote a strong work ethic. At the meso level, individuals with disabilities act as service user groups, professionals develop organizational designs and the policy authorities ask for cost-effective services. At the macro level, organizations representing people with disabilities lobby, professionals negotiate authorization issues, and the policymaking authorities must identify what can count as just distribution of services. The nine cells of the table are elaborated on by presenting relevant current studies exemplifying each cell.
To systematize societal levels and agents involved is to enhance the understanding of rehabilitation as an interdisciplinary field of research. Implications for rehabilitation Rehabilitation practice and research must relate to different levels of society and identify different social agents. Service users are not only individuals receiving therapy, but also organized agents influencing the organization of rehabilitation services as well as priorities made at the level of policy development. Both the results produced by health professionals doing a clinical trial and political scientists studying rehabilitation policy disputes will improve when placed in a wide frame of knowledge production.
The Qianhua Mutton Merino (QHMM) is a new sheep (Ovis aries) variety with better meat performance compared with the traditional local variety Small Tail Han (STH) sheep. We aimed to evaluate the transcriptome regulators associated with muscle growth and development between the QHMM and STH. We used RNA-Seq to obtain the transcriptome profiles of the longissimus muscle from the QHMM and STH. The results showed that 960 genes were differentially expressed (405 were up-regulated and 555 were down-regulated). Among these, 463 differently expressed genes (DEGs) were probably associated with muscle growth and development and were involved in biological processes such as skeletal muscle tissue development and muscle cell differentiation; molecular functions such as catalytic activity and oxidoreductase activity; cellular components such as mitochondrion and sarcoplasmic reticulum; and pathways such as metabolic pathways and citrate cycle. From the potential genes, a gene-act-network and co-expression-network closely related to muscle growth and development were identified and established. Finally, the expressions of nine genes were validated by real-time PCR. The results suggested that some DEGs, including MRFs, GXP1 and STAC3, play crucial roles in muscle growth and development processes. This genome-wide transcriptome analysis of QHMM and STH muscle is reported for the first time.
Although heparin administration has reduced the incidence of radial artery occlusion (RAO) during the transradial coronary angiography (TRCA), the effective activated clotting time (ACT) value for guiding unfractionated heparin dosing in patients undergoing TRCA is unknown. Four hundred thirty-two patients who were scheduled for elective TRCA were enrolled in our prospective study. All the patients received a standard dose of 5,000 IU unfractionated heparin. Anticoagulation level was assessed by ACT measurements that were taken at the end of the procedure just before the sheath removal. The day after TRCA, all patients were evaluated by color Doppler ultrasound to detect RAO. RAO was found in 29 patients (6.7%). A median ACT of 205 seconds in the RAO group and 265 seconds in the radial artery patent group were detected (p <0.001). Mean procedure duration was significantly longer in the RAO group than in the radial artery patent group (18.55 ± 9.80 vs 11.24 ± 7.07 minutes, p <0.001). There was a negative correlation between end-procedural ACT and procedure duration (r = -0.117, p = 0.015). In multivariate analysis, end-procedural ACT (odds ratio 0.981, 95% confidence interval [CI] 0.972 to 0.989, p <0.001), procedure duration (odds ratio 1.076, 95% CI, 1.037 to 1.116, p <0.001), and radial artery diameter (odds ratio 0.240, 95% CI 0.063 to 0.907, p = 0.035) were found as independent predictors of RAO. In conclusion, shorter end-procedural ACT levels, longer procedural duration, and smaller radial arterial diameter were independently associated with RAOs after TRCA with standard-dose heparin. In prolonged procedures, ACT-based heparin dosing may be useful to overcome RAO.
Microemulsion electrokinetic chromatography (MEEKC) is a special mode of capillary electrophoresis employing a microemulsion as carrier electrolyte. Analytes may partition between the aqueous phase of the microemulsion and its oil droplets which act as a pseudostationary phase. The technique is well suited for the separation of neutral species, in which case charged oil droplets (obtained by addition of an anionic or cationic surfactant) are present. A single set of separation parameters may be sufficient for separation of a wide range of analytes belonging to quite different chemical classes. Fine-tuning of resolution and analysis time may be achieved by addition of organic solvents, by changes in the nature of the surfactants (and cosurfactants) used to stabilize the microemulsion, or by various additives that may
 undergo some additional interactions with the analytes. Besides the separation of neutral analytes (which may be the most important application area of MEEKC), it can also be employed for cationic and/or anionic species. In this chapter, MEEKC conditions are summarized that have proven their reliability for routine analysis. Furthermore, the mechanisms encountered in MEEKC allow an efficient on-capillary preconcentration of analytes, so that the problem of poor concentration sensitivity of ultraviolet absorbance detection is circumvented.
Our immune system is engaged in a continuous battle against invading pathogens, many of which have evolved to survive in intracellular niches of mammalian hosts. A variety of cellular processes are involved in preventing bacterial invasion or in killing bacteria that successfully invade host cells. Recently, the Rab GTPase Rab32 emerged as critical regulator of a host defense pathway that can eliminate bacterial pathogens. Salmonella enterica is an intracellular bacterium and a major cause of infections and deaths in humans. Rab32 and its guanine nucleotide exchange factor BLOC-3 are essential to prevent the growth of the human-restricted Salmonella enterica serovar Typhi (S. Typhi) in mice, a non-susceptible host. The importance of the Rab32/BLOC-3 pathway has been recently confirmed by the finding that broad-host Salmonella enterica serovars deliver 2 bacterial effectors to neutralize this pathway and infect mice. Rab32 has also been shown to control infection by Listeria monocytogenes, another medically relevant intracellular pathogen. In addition, genetic evidence indicate a possible role of Rab32 in controlling leprosy, a disease caused by Mycobacterium leprae in humans, suggesting that a Rab32-dependent pathway can also act as a host defense pathway in humans. The Rab32 role in bacterial pathogen restriction is discussed here and compared to the function of this GTPase in other cellular processes.
Front-of-pack (FOP) nutrition labelling has received growing attention from public health authorities, as a tool to promote healthier diets in the population. Recently, the French Health law introduced the principle of implementing a FOP nutrition labelling system. A scientific proposal has put forward the 5-Colour Nutrition Label (5-CNL), a five-category colour-coded summary system supported by research suggesting that it is well perceived and understood in the population. Our objective was to investigate the impact of the 5-CNL on the nutritional quality of purchases in experimental supermarkets.
Participants (n = 901) were recruited using quota sampling between September and December 2015 and evenly distributed in three experimental conditions: 1) control situation; 2) Application of the 5-CNL on all food products in three specific sections: breakfast cereals, sweet biscuits and appetizers; 3) introduction of the 5-CNL accompanied by consumer information on use and understanding of the label. Main outcome was the nutritional quality of the shopping cart in the three sections combined, measured using the United Kingdom Food Standards Agency nutrient profiling system (FSA score).
Significantly higher mean nutritional quality of the purchased items per section were observed for the sweet biscuits category in the intervention combining the label + communication (overall FSA score 21.01 vs. 20.23, P = 0.02). No significant effects were observed for the general mean over the three sections combined or other food categories. The results observed on purchase may be related to the high level of recall, self-reported and objective understanding of the label that were observed in the intervention groups as they are pre-requisites for use of a label in purchasing situations.
These results suggest that the 5-CNL FOP nutrition label may have a limited impact on purchases, leading to healthier food choices in some food categories such as sweet biscuits.
The trial was registered on Clinicaltrials.gov under the number NCT02546505 .
MS is widely considered to be a T cell-mediated disease although T cell immunotherapy has consistently failed, demonstrating distinct differences with experimental autoimmune encephalomyelitis (EAE), an animal model of MS in which T cell therapies are effective. Accumulating evidence has highlighted that B cells also play key role in MS pathogenesis. The high frequency of oligoclonal antibodies in the CSF, the localization of immunoglobulin in brain lesions and pathogenicity of antibodies originally pointed to the pathogenic role of B cells as autoantibody producing plasma cells. However, emerging evidence reveal that B cells also act as antigen presenting cells, T cell activators and cytokine producers suggesting that the strong efficacy of anti-CD20 antibody therapy observed in people with MS may reduce disease progression by several different mechanisms. Here we review the evidence and mechanisms by which B cells contribute to disease in MS compared to findings in the EAE model.
Narrative review.
This review provides an overview of the etiological factors and consequences of vitamin D insufficiency in relation to spinal cord injury (SCI) as well as important considerations for vitamin D supplementation.
Montreal, Canada.
Literature search.
Vitamin D insufficiency is common in SCI individuals owing to the presence of many contributing factors including limited sun exposure and intake, use of medication and endocrine perturbations. Although there are several biological plausible mechanisms by which vitamin D may act upon musculoskeletal and cardiometabolic health, the impact of vitamin D insufficiency on such systems remains ill defined in SCI. In the absence of guidelines for the management of vitamin D insufficiency in this high-risk population and in an attempt to provide clinical guidance, considerations for vitamin D supplementation such as the type of vitamin D, dosing regimens and toxicity are discussed and tentative recommendations suggested with particular reference to issues faced by SCI patients.
Although high rates of vitamin D insufficiency are encountered in SCI individuals, its consequences and the amount of vitamin D required to prevent insufficiency are still unknown, indicating a need for more intervention studies with well-defined outcome measures. Routine screening and monitoring of vitamin D as well as treatment of suboptimal status should be instituted in both acute and chronic setting. The close interactions between vitamin D and related bone minerals should be kept in mind when supplementing SCI individuals, and practices should be individualized with clinical conditions.
The biosynthesis of coenzyme A (CoA) from pantothenate and the utilization of CoA in essential biochemical pathways represent promising antimalarial drug targets. Pantothenamides, amide derivatives of pantothenate, have potential as antimalarials, but a serum enzyme called pantetheinase degrades pantothenamides, rendering them inactive in vivo In this study, we characterize a series of 19 compounds that mimic pantothenamides with a stable triazole group instead of the labile amide. Two of these pantothenamides are active against the intraerythrocytic stage parasite with 50% inhibitory concentrations (IC50s) of ∼50 nM, and three others have submicromolar IC50s. We show that the compounds target CoA biosynthesis and/or utilization. We investigated one of the compounds for its ability to interact with the Plasmodium falciparum pantothenate kinase, the first enzyme involved in the conversion of pantothenate to CoA, and show that the compound inhibits the phosphorylation of [(14)C]pantothenate by the P. falciparum pantothenate kinase, but the inhibition does not correlate with antiplasmodial activity. Furthermore, the compounds are not toxic to human cells and, importantly, are not degraded by pantetheinase.
Iron plays an essential role in balancing the various metabolism in the body. It is also involved in the synthesis of several neurotransmitters. Nutritional iron deficiency is one of the most widespread worldwide; it poses a great health challenge due to the consequences it entails.
The aim of this research study is to explore the percentage of psychiatric patients who have a deficiency in iron. In addition, the study investigates the efficacy of iron administered by oral treatment on psychiatric symptomatology among iron deficient patients. The research study utilized the martial biological results, which involved the observation of the level of iron deficiency among the outpatients of a local psychiatrist and assessor from the period of January 2012 until December 2013.
Out of 412 patients, 295 were women and 117 men. The age of the participants ranged from 16 to 89years, with an average age of 45years. The only exclusion criterion was a patient's refusal or inability to take the prescribed iron assessment test. We considered a transferrin saturation coefficient (TSC)<30% and/or a serum ferritin level≤50ng/mL to be "indicative" of obvious iron deficiency, and a ferritin level between 51 and 100ng/mL to be "suggestive" of iron deficiency. A plasma ferritin assay was performed at least once on all of the participants prior to any proposed iron treatment. A calculation of the TSC in 138 patients was requested due to suspected iron deficiency despite a blood ferritin level of>100ng/ml. A single method was utilized in the various laboratories to analyse the blood samples to determine whether there was a deficiency in iron. Only those patients with blood ferritin levels ≤100ng/mL and/or a TSC of<30% (335 patients) were subsequently given exclusively an oral iron treatment prescribed on its own or as a supplement or simultaneously with psychotropic treatment. The daily administered dose of elemental iron varied between 50 and 200mg a day.
About half of the women - 145 (35.19% of
 the subjects) - and 15 men (3.64% of the subjects) certainly had a deficiency in iron (blood ferritin level≤50ng/mL). Ninety women and 24 men (27.6% of the subjects) had blood ferritin levels between 51 and 100ng/mL indicating iron deficiency, and 28 women and 33 men (14.8% of the subjects) had a TSC of<30% despite a blood ferritin level of>100ng/mL. Overall, 335 patients (81.3% of the subjects) showed an iron deficiency based on the criteria we set. In the remaining 77 patients (18.7% of the subjects), all of them had blood ferritin levels>100ng/mL and some had TSC≤30%, while the remaining patients' TSC was unknown because it was not measured. The results indicated that there is an iron deficiency in 198 out of 240 patients suffering mostly from mood and behavioural disorders, in 101 out of 126 patients suffering mostly from anxiety disorders, in 18 out of 27 patients suffering mostly from sleep disorders, in 14 out of 15 patients suffering mostly from delusions of persecution, and in the 4 patients suffering mostly from burn out. There was evidence of regression/remission of psychiatric symptoms in 193 responsive patients whereas the remaining 142 patients were considered non-responsive. In the responsive patient category, 37 participants were treated with just iron, 52 received iron supplemented to the initial psychotropic treatment which was not fully effective, and 104 patients were treated with iron and prescribed psychotropic drugs simultaneously. The iron treatment seems to bring about a reduction - particularly through its mono-aminergic neurotransmitter synthesis-promoting action - in hyperemotivity, anxiety, irritability, aggressiveness, sadness, anhedonia, apathy, asthenia, sleep disorders, dysautonomia symptoms, eating disorders, restless-leg syndrome, cognitive performance and the likelihood of resorting to psychiatric admission. A daily elemental iron dose intake between 50 and 200mg/day by deficient patients appears to likely enhance the effects of the psychotropic drugs and even to act as an actual antidepressant. Many patients who received a prescription for iron and antidepressants showed few side effects related to antidepressants and a small number required psychiatric hospitalization. Patients considered unresponsive to iron therapy were those who left the study, were not assessed because the study's timeframe ended, still had an iron deficiency because they did not continuously take the medication, or suffered from somatic diseases which explains their resistance to treat the low iron level (nutritional imbalance, digestive or urinary or gynecological or iatrogenic diseases, sleep apnea).
Our clinical observation of two years in a local psychiatrist's clinic revealed that over 80% of patients had iron deficiency. Although the low iron level cannot explain all physical and psychiatric symptoms in patients, it is useful to note that more than half of the iron deficient patients responded favorably after an oral treatment of iron. This result leads to further investigation of the level of iron in psychiatric patients and to reconsider the iron range placed by the laboratories. In addition, it is crucial not to eliminate the possibility of iron deficiency in psychiatric patients. Further research studies are needed to set more specific and detailed criteria to determine the range of iron deficiency in order to support the findings of this study and optimize the care given to patients suffering from various disorders and psychiatric syndromes.
Inflammation is a complex and highly regulated biological process, crucial for a variety of functions in the human body, from host response against infectious agents to initiation of repair/regeneration of injured tissues. In the context of tissue repair, the action of different immune cell populations and their interplay with tissue specific cells, including stem cells, is still being uncovered. Extracellular Vesicles (EV) are small membrane vesicles secreted by cells in a controlled manner, which can act locally and systemically. The ability of EV to influence tissue repair and regeneration has been proposed as a physiologically intelligent and targeted strategy of cell communication. Herein, the role of EV in tissue repair is reviewed, summarising first their contribution to the regulation of immune cell function, and discussing the implications for the resolution of inflammation during repair. Next, the impact of EV on cell proliferation and differentiation, and on extracellular matrix remodelling, key aspects of the subsequent phases of tissue repair, is addressed. Finally, EV-based therapies are discussed, focusing on the application of naturally produced EV, and the use of EV as delivery vehicles.
Muscular injuries that destroy the basal lamina result in poor functional recovery of skeletal muscle. This is due, in part, to the deposition of structural fibrotic proteins such as fibronectin and collagen by fibroblasts and other cells. Transforming growth factor-β (TGF-β) promotes fibrosis, whereas the proteoglycan decorin is known to act as an anti-fibrotic agent, in part via the binding and neutralization of TGF-β. We have previously established that decorin can alter the migratory response of skeletal muscle myoblasts to the extracellular matrix (ECM) factor collagen, but not fibronectin. We have also shown that TGF-β reduces myoblast migration. In the current study we demonstrate that decorin can dramatically alter the inhibitory role of TGF-β on human myoblast migration and go on to shown that the extracellular matrix can significantly modify this effect. Decorin and TGF-β2 in combination were observed to significantly increase the rate of human myoblast migration, despite the inhibitory effect of TGF-β2 on its own. Furthermore, in the presence of fibronectin, TGF-β2 and decorin no longer acted synergistically to promote migration; while in the presence of collagen I, TGF-β2 failed to inhibit migration. These studies show, for the first time, that decorin can alter the bioactivity of TGF-β2 on human myoblast migration and emphasize the crucial regulatory role of the extracellular matrix in determining the response of skeletal muscle myoblasts to migratory cues.
Adolescents under the age of 18 are not recognized in the law as adults, nor do they have the fully developed capacity of adults. Yet teens regularly enter into contractual arrangements with operators of websites to send and post information about themselves. Their level of development limits their capacity to understand the implications of online communications, yet the risks are real to adolescents' privacy and reputations. This article explores an apparent contradiction in the law: that in areas other than online communications, U.S. legal systems seek to protect minors from the limitations of youth. The Children's Online Privacy Protection Act provides some protection to the privacy of young people, but applies only to children under age 13, leaving minors of ages 13 to 17 with little legal protection in their online activities. In this article, we discuss several strategies to mitigate the risks of adolescent online activity.
Acceptance and commitment therapy (ACT) increases the psychological exibility of people afflicted with cancer, and consequently improves their adaptability. The present research was conducted with the aim of determining the effectiveness of ACT for people afflicted with cancer.
The present research was of semi-pilot type with a pre-test and post-test plan for the proof group. The demographics of the community were composed of all the women with cancer who were under treatment in Tehran's Dehshpour therapeutic center in 2015. The sample was composed of 24 people who were selected as available and chosen randomly in two groups of test and proof. All the participants responded to Snyder questionnaire in two pre-test and post-test stages, and the test group participated in treatment sessions after conducting the pre-test.
After collecting the information, data analysis was conducted in two description and inferential levels. The test results of covariance analysis showed that the two groups' hope was meaningfully different. Hope in the test group, compared to the proof group, increased meaningfully.
The results show that the ACT is effective in increasing hope of patients with cancer.
Curcumin, a polyphenolic compound isolated from the rhizomes of an herbaceous perennial plant, Curcuma longa, is known to possess anticancerous activity. However, the mechanism of apoptosis induction in cancers differs. In this study, we have (1) investigated the anticancerous activity of curcumin on REH and RS4;11 leukemia cells and (2) studied the chemo-sensitizing potential of curcumin for doxorubicin, a drug presently used for leukemia treatment. It was found that curcumin induced a dose dependent decrease in cell viability because of apoptosis induction as visualized by annexin V-FITC/ PI staining. Curcumin-induced apoptosis of leukemia cells was mediated by PARP-1 cleavage. An increased level of caspase-3, apoptosis inducing factor (AIF), cleaved PARP-1 and decreased level of Bcl2 was observed in leukemia cells after 24h of curcumin treatment. In addition, curcumin at doses lower than the IC50 value significantly enhanced doxorubicin induced cell death. Therefore, we conclude that curcumin induces apoptosis in leukemia cells via PARP-1 mediated caspase-3 dependent pathway and further may act as a potential chemo-sensitizing agent for doxorubicin. Our study highlights the chemo-preventive and chemo-sensitizing role of curcumin.
Adipokines are bioactive proteins that mediate metabolism, inflammation and angiogenesis. Changes in the secretion of key serum adipokines - adiponectin and letpin - may be associated with obesity, cancer and metabolic disorders. Thyroid cancer is one of the
 most important types of endocrine cancer. Therefore, investigating the association between serum levels of adiponectin and leptin and thyroid cancer might be important. The purpose of this study was to assess adiponectin and leptin levels in medullary thyroid carcinoma (MTC) cases in order to identify novel tumor markers.
This research was based on a case-control study, including 45 patients with medullary thyroid cancer (21 men and 24 women) and 45 healthy controls (24 males and 21 females). Adiponectin and leptin levels were measured by ELISA in both groups. Height and weight were measured and body mass index (kg/m2) was calculated.
Adiponectin and leptin levels were not significantly different between medullary thyroid carcinomas and the control group. Also, there was no correlation among age and body mass index and the disease.
These results suggest that changes in serum adiponectin and leptin levels do not play an important role in the diagnosis or could act as as biomarkers for medullary thyroid cancer.
Podocytes are terminally differentiated epithelial cells in the kidney glomeruli that act as a key component of the glomerular filtration barrier. Although the inciting injury to the podocyte may vary between various glomerular diseases, the inevitable consequence of podocyte injury results in their loss, leading to progressive kidney disease. Here, we report that the expression of CCAAT/enhancer binding protein-α (C/EBP-α), a transcription factor known to interact with and activate PPAR-γ and NF-κB, is suppressed in the glomerular cells, particularly in podocytes, in human kidneys with focal segmental glomerulosclerosis. Genetic ablation of C/EBP-α in podocytes resulted in increased proteinuria, increased podocyte foot process effacement, and to decreased podocyte number in the setting of Adriamycin (ADR)-induced nephropathy. Overexpression of C/EBP-α in human podocytes in vitro led to an inhibition of MCP-1 and IL-6 expression in response to TNF-α and IL-1β treatments. Conversely, augmented production of MCP-1 and IL-6 was observed in the glomeruli of C/EBP-α knockout mice and was associated increased infiltration of macrophages in vivo. Together, our data suggest that C/EBP-α mediates anti-inflammatory effects in podocytes to confer protection against podocyte injury and loss that may contribute to worsening glomerulosclerosis.
microRNAs (miRNAs) act as a major regulator of acquired chemo-resistance in various types of cancer therapeutics. This study investigated the contribution of miRNAs in influencing multiple drug resistance in esophageal squamous cell carcinoma (ESCC). The sensitivity of four ESCC cell lines (EC109, EC9706, TE-1 and KYSE-150) to 5-fluorouracil (5-FU) and oxaliplatin (OX) was determined by MTT assay. A 5-FU and OX-resistant subline, EC9706R, was established by continuous exposure to stepwise increasing concentration of 5-FU and OX. Microarray technology was used to compare the differential expression of miRNAs between resistant cells and parental cells. Chemo-sensitivity assay was performed to evaluate drug response in EC9706R cells transfected with miRNA mimic or inhibitor. The direct targets of miRNA were identified by employing pathway analysis and then confirmed with luciferase assay. Sixty ESCC tissue samples and their paired adjacent normal tissues were collected to validate the expression of identified miRNA. Mouse models were further utilized to investigate the function of miRNA on acquired chemo-resistance. MicroRNA panel results indicated that a total of 12 miRNAs were differentially expressed and miR-141-3p was highly over expressed in resistant cells. Inhibition of miR-141-3p reversed acquired chemo-resistance in EC9706R cells by stimulating apoptosis. The expression of miR-141-3p was significantly increased in ESCC tissue samples compared to their matched distant normal tissues. In addition, the elevated miR-141-3p expression was found to be associated with ESCC differentiation status and TNM stage. Moreover, Phosphatase and tensin homolog (PTEN) was identified as direct target of miR-141-3p. Western blot exhibited altered protein levels of PTEN, Akt, and PI3k with miR-141-3p inhibitor. An inverse correlation between PTEN expression and miR-141-3p expression was also observed in tissue samples. EC9706R xenograft mouse model became sensitized to 5-FU and OX treatment following miR-141-3p inhibitor transfection in vivo. Our study demonstrated that miR-141-3p contributed to an acquired chemo-resistance through PTEN modulation both in vitro and in vivo.
Synaptic signaling to NG2-expressing oligodendrocyte precursor cells (NG2 cells) could be key to rendering myelination of axons dependent on neuronal activity, but it has remained unclear whether NG2 glial cells integrate and respond to synaptic input. Here we show that NG2 cells perform linear integration of glutamatergic synaptic inputs and respond with increasing dendritic calcium elevations. Synaptic activity induces rapid Ca(2+) signals mediated by low-voltage activated Ca(2+) channels under strict inhibitory control of voltage-gated A-type K(+) channels. Ca(2+) signals can be global and originate throughout the cell. However, voltage-gated channels are also found in thin dendrites which act as compartmentalized processing units and generate local calcium transients. Taken together, the activity-dependent control of Ca(2+) signals by A-type channels and the global versus local signaling domains make intracellular Ca(2+) in NG2 cells a prime signaling molecule to transform neurotransmitter release into activity-dependent myelination.
Dialeurodes citri is a major pest in citrus producing areas, and large-scale outbreaks have occurred increasingly often in recent years. Lecanicillium attenuatum is an important entomopathogenic fungus that can parasitize and kill D. citri. We separated the fungus from corpses of D. citri larvae. However, the sound immune defense system of pests makes infection by an entomopathogenic fungus difficult. Here we used RNA sequencing technology (RNA-Seq) to build a transcriptome database for D. citri and performed digital gene expression profiling to screen genes that act in the immune defense of D. citri larvae infected with a pathogenic fungus. De novo assembly generated 84,733 unigenes with mean length of 772 nt. All unigenes were searched against GO, Nr, Swiss-Prot, COG, and KEGG databases and a total of 28,190 (33.3%) unigenes were annotated. We identified 129 immunity-related unigenes in transcriptome database that were related to pattern recognition receptors, information transduction factors and response factors. From the digital gene expression profile, we identified 441 unigenes that were differentially expressed in D. citri infected with L. attenuatum. Through calculated Log2Ratio values, we identified genes for which fold changes in expression were obvious, including cuticle protein, vitellogenin, cathepsin, prophenoloxidase, clip-domain serine protease, lysozyme, and others. Subsequent quantitative real-time polymerase chain reaction analysis verified the results. The identified genes may serve as target genes for microbial control of D. citri.
Excessive production of oxygen free radicals has been regarded as a causative common denominator of many pathological processes in the animal kingdom. Hydroxyl and nitrosyl radicals represent the major cause of the destruction of biomolecules either by a direct reaction or by triggering a chain reaction of free radicals. Scavenging of free radicals may act preventively or therapeutically. A number of substances that preferentially react with free radicals can serve as scavengers, thus increasing the internal capacity/activity of endogenous antioxidants and protecting cells and tissues against oxidative damage. Molecular hydrogen (H(2)) reacts with strong oxidants, such as hydroxyl and nitrosyl radicals, in the cells, that enables utilization of its potential for preventive and therapeutic applications. H(2) rapidly diffuses into tissues and cells without affecting metabolic redox reactions and signaling reactive species. H(2) reduces oxidative stress also by regulating gene expression, and functions as an anti-inflammatory and anti-apoptotic agent. There is a growing body of evidence based on the results of animal experiments and clinical observations that H(2) may represent an effective antioxidant for the prevention of oxidative stress-related diseases. Application of molecular hydrogen in situations with excessive production of free radicals, in particular, hydroxyl and nitrosyl radicals is relatively simple and effective, therefore, it deserves special attention.
Autoimmune neurology is a rapidly evolving new subspecialty driven by the discovery of novel neural- (neuronal- or glial-) specific autoantibodies and their target antigens. The neurologic manifestations affecting the central nervous system include encephalitis, dementia, epilepsy, and movement and sleep disorders. Laboratory testing is now available for most of these neural-specific autoantibodies, which serve as diagnostic markers, in some instances directing the physician toward specific cancer types (e.g., N-methyl-D-aspartic acid receptor antibodies for teratoma, collapsin response mediator protein 5 for small-cell lung cancer) and assisting in therapeutic decision making. Antibodies targeting intracellular proteins serve as markers of cytotoxic effector T-cell-mediated injury, which is generally poorly responsive to immunotherapy. By contrast, antibodies targeting extracellular plasma membrane proteins may act as pathogenic effectors and often infer good responses to immunotherapy. Diagnosing these conditions and implementing treatment as early into the clinical course as possible ensures the best possible clinical outcomes. An adequate immunotherapy trial to assess maximum
 reversibility of symptoms, as assessed through objective functional measures, is crucial and can help to determine whether maintenance therapy is needed.
Jasmonates (JAs) are a class of plant hormones that play essential roles in response to tissue wounding. They act on gene expression to slow down growth and to redirect metabolism towards producing defense molecules and repairing damage. These responses are systemic and have dramatic impacts on yields, making JAs a very active research area. JAs interact with many other plant hormones and therefore also have essential functions throughout development, notably during plant reproduction, leaf senescence and in response to many biotic and abiotic stresses.
Ballasted aggregation, a process using the addition of a ballasting agent to improve the settling performance of flocs, appears particularly appropriate for the treatment of humic rich waters that leads to low-density aggregates. In that context, using an aquagenic humic acid coagulated by ferric chloride in the presence of pozzolana particles as ballasting agent, we show that the origin of improved floc settling in ballasted aggregation is not simply related to an increased specific weight of flocs, but also to a significant restructuring of flocs to a more compact structure induced by the added particles. The floc restructuring is evidenced from the increased lag time before measurable floc growth in the presence of the ballasting agent, the higher fractal dimension of flocs above the micron scale range after incorporation of the particles into the aggregates, and a much smaller sediment volume after settling. A simple model of floc compaction based on the turbulent viscous effects that act on an elastic floc, is described.
Lytic polysaccharide monooxygenases (LPMOs) represent a recent addition to the carbohydrate-active enzymes and are classified as auxiliary activity (AA) families 9, 10, 11, and 13. LPMOs are crucial for effective degradation of recalcitrant polysaccharides like cellulose or chitin. These enzymes are copper-dependent and utilize a redox mechanism to cleave glycosidic bonds that is dependent on molecular oxygen and an external electron donor. The electrons can be provided by various sources, such as chemical compounds (e.g., ascorbate) or by enzymes (e.g., cellobiose dehydrogenases, CDHs, from fungi). Here, we demonstrate that a fungal CDH from Myriococcum thermophilum (MtCDH), can act as an electron donor for bacterial family AA10 LPMOs. We show that employing an enzyme as electron donor is advantageous since this enables a kinetically controlled supply of electrons to the LPMO. The rate of chitin oxidation by CBP21 was equal to that of cosubstrate (lactose) oxidation by MtCDH, verifying the usage of two electrons in the LPMO catalytic mechanism. Furthermore, since lactose oxidation correlates directly with the rate of LPMO catalysis, a method for indirect determination of LPMO activity is implicated. Finally, the one electron reduction of the CBP21 active site copper by MtCDH was determined to be substantially faster than chitin oxidation by the LPMO. Overall, MtCDH seems to be a universal electron donor for both bacterial and fungal LPMOs, indicating that their electron transfer mechanisms are similar.
Fipronil (FIP) is widely used across the world as a broad-spectrum phenylpyrazole insecticide and veterinary drug. FIP was the insecticide to act by targeting the γ-aminobutyric acid (GABA) receptor and has favorable selective toxicity towards insects rather than mammals. However, because of accidental exposure, incorrect use of FIP or widespread FIP use leading to the contamination of water and soil, there is increasing evidence that FIP could cause a variety of toxic effects on animals and humans, such as neurotoxic, hepatotoxic, nephrotoxic, reproductive, and cytotoxic effects on vertebrate and invertebrates. In the last decade, oxidative stress has been suggested to be involved in the various toxicities induced by FIP. To date, few reviews have addressed the toxicity of FIP in relation to oxidative stress. The focus of this article is primarily intended to summarize the progress in research associated with oxidative stress as a possible mechanism for FIP-induced toxicity as well as metabolism. The present review reports that studies have been conducted to reveal the generation of reactive oxygen species (ROS) and oxidative stress as a result of FIP treatment and have correlated them with various types of toxicity. Furthermore, the metabolism of FIP was also reviewed, and during this process, various CYP450 enzymes were involved and oxidative stress might occur. The roles of various compounds in protecting against FIP-induced toxicity based on their anti-oxidative effects were also summarized to further understand the role of oxidative stress in FIP-induced toxicity.
Objective: Cross-sectional studies have revealed that high levels of optimism can protect against high levels of posttraumatic stress after exposure to trauma. However, this is the first study to explore (a) the protective role of optimism in a longitudinal perspective and (b) optimism's protective effects on specific symptom clusters within the posttraumatic stress symptomatology. Method: This study used prospective survey data from ministerial employees (n = 256) collected approximately 1, 2, and 3 years after the 2011 Oslo bombing. To examine relationships between optimism and development of posttraumatic stress, we applied a series of latent growth curve analyses of both overall posttraumatic stress and the 5 clusters within the posttraumatic stress symptomatology (intrusions, avoidance, numbing, dysphoric arousal, and anxious arousal) with predictors and interaction terms. Results: The results showed that levels of exposure and optimism had main effects on starting levels of all clusters of posttraumatic stress. In addition, optimism had a protective-stabilizing effect on starting levels of avoidance, numbing, and dysphoric arousal. No associations between optimism and rate of change in symptoms clusters were found. Conclusion: These results suggest that optimism may help to neutralize the effects of high exposure on levels of symptoms of avoidance, numbing, and dysphoric arousal but not on the symptoms of intrusions and anxious arousal. Thus, individuals high in optimism still experience intrusions and anxious arousal after trauma, but may be better equipped to cope with these so they do not develop into avoidance, numbing and dyshorical arousal. (PsycINFO Database Record
To describe the measure review and evaluation process used to identify new measures of care coordination for children with behavioral health needs conducted as part of Massachusetts' Children's Health Insurance Program Reauthorization Act Quality Demonstration Grant.
The Massachusetts Child Health Quality Coalition identified a shortage of pediatric measures of care coordination in behavioral health. After an extensive literature review, the Measure Development Committee applied the Care Coordination Key Elements Framework (Framework), which was designed as part of the grant work, and used a modified RAND Delphi method to conduct feasibility and validity evaluation and propose the new candidate measures for further rigorous testing.
Thirty-two measures were evaluated. One existing Healthcare Effectiveness Data and Information Set and 8 newly proposed measures met the criteria for feasibility and reliability. These measures represented each of the key elements contained in the Framework. The measures need further testing to ensure scientific acceptability and wide usability.
A multipronged methodology was used to propose measures of care coordination in the space of pediatric behavioral health to fill the identified gaps in existing measures.
Prediabetes is a major epidemic and is associated with adverse cardio-cerebrovascular outcomes. Early identification of patients who will develop rapid progression of atherosclerosis could be beneficial for improved risk stratification. In this paper, we investigate important factors impacting the prediction, using several machine learning methods, of rapid progression of carotid intima-media thickness in impaired glucose tolerance (IGT) participants.
In the Actos Now for Prevention of Diabetes (ACT NOW) study, 382 participants with IGT underwent carotid intima-media thickness (CIMT) ultrasound evaluation at baseline and at 15-18 months, and were divided into rapid progressors (RP, n = 39, 58 ± 17.5 μM change) and non-rapid progressors (NRP, n = 343, 5.8 ± 20 μM change, p < 0.001 versus RP). To deal with complex multi-modal data consisting of demographic, clinical, and laboratory variables, we propose a general data-driven framework to investigate the ACT NOW dataset. In particular, we first employed a Fisher Score-based feature selection method to identify the most effective variables and then proposed a probabilistic Bayes-based learning method for the prediction. Comparison of the methods and factors was conducted using area under the receiver operating characteristic curve (AUC) analyses and Brier score.
The experimental results show that the proposed learning methods performed well in identifying or predicting RP. Among the methods, the performance of Naïve Bayes was the best (AUC 0.797, Brier score 0.085) compared to multilayer perceptron (0.729, 0.086) and random forest (0.642, 0.10). The results also show that feature selection has a significant positive impact on the data prediction performance.
By dealing with multi-modal data, the proposed learning methods show effectiveness in predicting prediabetics at risk for rapid atherosclerosis progression. The proposed framework demonstrated utility in outcome prediction in a typical multidimensional clinical dataset with a relatively small number of subjects, extending
 the potential utility of machine learning approaches beyond extremely large-scale datasets.
This paper presents 800-μm thick, biocompatible sensing skins composed of arrays of pressure sensors. The arrays can be configured to conform to the surface of medical instruments so as to act as disposable sensing skins. In particular, the fabrication of cylindrical geometries is considered here for use on endoscopes. The sensing technology is based on polydimethylsiloxane synthetic silicone encapsulated microchannels filled with a biocompatible salt-saturated glycerol solution, functioning as the conductive medium. A multi-layer manufacturing approach is introduced that enables stacking sensing microchannels, mechanical stress concentration features, and electrical routing via flexcircuits in a thickness of less than 1 mm. The proposed approach is inexpensive and does not require clean room tools or techniques. The mechanical stress concentration features are implemented using a patterned copper layer that serves to improve sensing range and sensitivity. Sensor performance is demonstrated experimentally using a sensing skin mounted on a neuroendoscope insertion cannula and is shown to outperform previously developed non-biocompatible sensors.
A fibrinolytic enzyme was produced by the medicinal mushroom, Cordyceps militaris using submerged fermentation. The enzyme was purified from culture supernatant by hydrophobic interaction, ion exchange and gel filtration chromatographies. It was purified by 36 fold, with a specific activity of 1,467.4U/mg protein and the final yield was 5.8%. The molecular weight of the enzyme as determined by SDS-PAGE and gel filtration was 28kDa and 24.5kDa, respectively, and its isoelectric point (pI) was 9.0±0.2. It was found to be a glycoprotein with carbohydrate content of 1.67% (w/v). The enzyme was optimally active at 37°C and pH 7.2. The enzyme activity was strongly inhibited by soybean trypsin inhibitor (SBTI) and aprotinin which indicated it to be a serine protease, while other inhibitors like N-α-tosyl-l-phenylalanine chloromethyl ketone (TPCK), phenyl methane sulfonyl fluoride (PMSF), pepstatin and metal chelator EDTA did not inhibit its activity. Amino acid sequences of the purified enzyme were determined partially by Q-TOF2 and they were IEDFPYQVDLR; ANCGGTVISEK; YVLTAGHCAEGYTGLNIR; TNYASVTPITADMICAGFPEGK; KDSCSGDSGGPLVTGGK; VVGIVSFGTGCAR; ANKPGVYSSVASAEIR. Sequences of the seven peptides completely matched with those of a trypsin-like serine protease from Cordyceps militaris CM01 (accession no. EGX95217.1). The purified enzyme degraded α chains of fibrinogen first and then β and γ chains and also activated plasminogen into plasmin. It can act as an anticoagulant and prevent clot formation by degrading fibrinogen. Based on these studies, the purified enzyme has great potential to be developed as a natural agent for prevention and treatment of thrombolytic diseases.
Prior studies have shown that overexpression of ACT A can lead to ventricular remodeling in rat models of heart failure. Furthermore, recently work studying demonstrated that stimulation of activin An expression in rat aortic smooth muscle (RASM) cells by angiotensin II (Ang II). Ramipril is a recently developed angiotensin converting enzyme (ACE) inhibitor. To investigate the effects of Ramipril on expression of ACT A-FS, we established the rat model of heart failure after myocardial infarction (MI), and divided into either a sham operation (SO), MI, or MI-Ramipril group. We found that Ramipril significantly attenuates collagen-I and III deposition (col-I and III). Notably, we determined that expression of ACT A and II activin receptor (ActRII) were significantly down-regulated in the non-infarcted area of the left ventricle in the Ramipril group, whereas the mRNA and protein levels of FS were markedly up-regulated. Our data suggested that Ramipril benefited left ventricular remodeling by reducing fibrosis and collagen accumulation in the left ventricle of rats after myocardial infarction. This observation was also associated with down-regulation of ACT A expression. This study elucidated a new protective mechanism of Ramipril and suggests a novel strategy for treatment of post-infarct remodeling and subsequent heart failure.
Liver transplant (LT) patients are at high risk for readmission. This study sought to identify predictors of readmission following liver transplantation and to evaluate their impact on survival in a region with prolonged waiting list times.
A single center review of adult deceased donor LT's from 2005 to 2015 was performed, with linkage to the UNOS Standard Transplant Analysis and Research registry. Readmission was defined as hospitalization within 90 days of discharge. Logistic regression was used to identify independent predictors of readmission and Kaplan-Meier analysis for survival.
325 patients underwent LT with an overall 90-day readmission rate of 46%. Upon adjusted analysis, predictors of readmission were age (OR 0.97 per year), male gender (OR 0.48), hospital length of stay (OR 1.03 per day), and hepatitis C liver failure (OR 2.37). Readmitted patients demonstrated a significantly lower 5-year survival (75% vs. 88%, p = 0.008) with only one patient (0.7%) dying during initial readmission.
Nearly half of all patients are readmitted after LT. As readmission portents decreased survival, an emphasis should be placed on identifying and optimizing those at increased risk. If readmission does occur, however, it presents an opportunity to intervene, as virtually no patients died during initial readmission.
Benzalkonium chloride is a quaternary ammonium cationic detergent present in a number of household products, which can act as a major skin irritant. We present the case of six children who developed granular parakeratosis after exposure to benzalkonium chloride in laundry rinse aids, presenting as a brightly erythematous, tender but minimally pruritic, intertriginous eruption followed by superficial desquamation. The eruptions resolved over 3-4 weeks after cessation of exposure.
We propose an all dielectric metamaterial that acts as a perfect terahertz absorber without a ground plane. The unit cell consists of a dielectric cylinder embedded in a low index material. In order to achieve near-perfect terahertz absorption (99.5%) we employ impedance matching of the electric and magnetic resonances within the cylinders of the Huygens' metasurface. The impedance matching is controlled by changing the aspect ratio between the height and diameter of the cylinder. We show that the absorption resonance can be tuned to particular frequencies from 0.3 to 1.9 THz via changing the geometry of the structure while keeping a nearly constant aspect ratio of the cylinders.
It may seem odd to be talking about winter pressures now, but there are signs that the next 6-8 months are going to be challenging in the extreme. A report from the RCN and the Royal College of Emergency Medicine suggests that emergency department staff are locked in a cycle of permanent crisis. Add a spell of icy weather into the mix and the NHS could collapse under the strain.
The protein density in biological membranes can be extraordinarily high, but the impact of molecular crowding on the diffusion of membrane proteins has not been studied systematically in a natural system. The diversity of the membrane proteome of most cells may preclude systematic studies. African trypanosomes, however, feature a uniform surface coat that is dominated by a single type of variant surface glycoprotein (VSG). Here we study the density-dependence of the diffusion of different glycosylphosphatidylinositol-anchored VSG-types on living cells and in artificial membranes. Our results suggest that a specific molecular crowding threshold (MCT) limits diffusion and hence affects protein function. Obstacles in the form of heterologous proteins compromise the diffusion coefficient and the MCT. The trypanosome VSG-coat operates very close to its MCT. Importantly, our experiments show that N-linked glycans act as molecular insulators that reduce retarding intermolecular interactions allowing membrane proteins to function correctly even when densely packed.
The initial steps of viral infections are mediated by interactions between viral proteins and cellular receptors. Blocking the latter with high-affinity ligands may inhibit infection. DC-SIGN, a C-type lectin receptor expressed by immature dendritic cells and macrophages, mediates human immunodeficiency virus (HIV) infection by recognizing mannose clusters on the HIV-1 gp120 envelope glycoprotein. Mannosylated glycodendrimers act as HIV entry inhibitors thanks to their ability to block this receptor. Previously, an amphoteric, but prevailingly cationic polyamidoamine named AGMA1 proved effective as infection inhibitor for several heparan sulfate proteoglycan-dependent viruses, such as human papilloma virus HPV-16 and herpes simplex virus HSV-2. An amphoteric, but prevailingly anionic PAA named ISA23 proved inactive. It was speculated that the substitution of mannosylated units for a limited percentage of AGMA1 repeating units, while imparting anti-HIV activity, would preserve the fundamentals of its HPV-16 and HSV-2 infection inhibitory activity. In this work, four biocompatible linear PAAs carrying different amounts of mannosyl-triazolyl pendants, Man-ISA7, Man-ISA14, Man-AGMA6.5 and Man-AGMA14.5, were prepared by reaction of 2-(azidoethyl)-α-D-mannopyranoside and differently propargyl-substituted AGMA1 and ISA23. All mannosylated PAAs inhibited HIV infection. Both Man-AGMA6.5 and Man-AGMA14.5 maintained the HPV-16 and HSV-2 activity of the parent polymer, proving broad-spectrum, dual action mode virus infection inhibitors.
Environmental drug resistance constitutes a serious impediment for therapeutic intervention in
 multiple myeloma. Tumor-promoting cytokines, such as tumor necrosis factor (TNF), induce nuclear factor-κB (NFκB)- driven expression of pro-survival factors, which confer resistance in myeloma cells to apoptotic insults from TNF-related apoptosis-inducing ligand (TRAIL) and other chemotherapeutic drugs. It is thought that RelA:p50 dimer, activated from IκBα-inhibited complex in response to TNF-induced canonical NFκB signal, mediates the pro-survival NFκB function in cancerous cells. Myeloma cells additionally acquire gain-of-function mutations in the non-canonical NFκB module, which induces partial proteolysis of p100 into p52 to promote RelB:p52/NFκB activation from p100-inhibited complex during immune cell differentiation. However, role of non-canonical NFκB signaling in the drug resistance in multiple myeloma remains unclear. Here we report that myeloma-associated non-canonical aberrations reinforce pro-survival TNF signaling in producing a protracted TRAIL-refractory state. These mutations did not act through a typical p52 NFκB complex, but completely degraded p100 to reposition RelB under IκBα control, whose degradation during TNF signaling induced an early RelB:p50 containing NFκB activity. More so, autoregulatory RelB synthesis prolonged this TNF-induced RelB:p50 activity in myeloma cells harboring non-canonical mutations. Intriguingly, TNF-activated RelB:p50 dimer was both necessary and sufficient, and RelA was not required, for NFκB-dependent pro-survival gene expressions and suppression of apoptosis. Indeed, high RelB mRNA expressions in myeloma patients correlated with the augmented level of pro-survival factors and resistance to therapeutic intervention. In sum, we provide evidence that cancer-associated mutations perpetuate TNF-induced pro-survival NFκB activity through autoregulatory RelB control and thereby exacerbate environmental drug resistance in multiple myeloma.Oncogene advance online publication, 19 September 2016; doi:10.1038/onc.2016.309.
Chronic behavioral stress and beta-adrenergic signaling have been shown to promote cancer progression, whose underlying mechanisms are largely unclear, especially the involvement of epigenetic regulation. Histone deacetylase-2 (HDAC2), an epigenetic regulator, is critical for stress-induced cardiac hypertrophy. It is unknown whether it is necessary for beta-adrenergic signaling-promoted cancer progression. Using xenograft models, we showed that chronic behavioral stress and beta-adrenergic signaling promote angiogenesis and prostate cancer progression. HDAC2 was induced by beta-adrenergic signaling in vitro and in mouse xenografts. We next uncovered that HDAC2 is a direct target of cAMP response element-binding protein (CREB) that is activated by beta-adrenergic signaling. Notably, HDAC2 is necessary for beta-adrenergic signaling to induce angiogenesis. We further demonstrated that, upon CREB activation, HDAC2 represses thrombospondin-1 (TSP1), a potent angiogenesis inhibitor, through epigenetic regulation. Together, these data establish a novel pathway that HDAC2 and TSP1 act downstream of CREB activation in beta-adrenergic signaling to promote cancer progression.Oncogene advance online publication, 19 September 2016; doi:10.1038/onc.2016.319.
Mesenchymal stromal cells (MSCs) are multipotent progenitor cells and there is much interest in how MSCs contribute to the regulation of the tumor microenvironment. Whether MSCs exert a supportive or suppressive effect on tumor progression is still controversial, but is likely dependent on a variety of factors that are tumor-type dependent. Multiple myeloma (MM) is characterized by growth of malignant plasma cells in the bone marrow. It has been shown that the progression of MM is governed by MSCs, which act as a stroma of the myeloma cells. Although stroma is created via mutual communication between myeloma cells and MSCs, the mechanism is poorly understood. Here we explored the role of lysophosphatidic acid (LPA) signaling in cellular events where MSCs were converted into either MM-supportive or MM-suppressive stroma. We found that myeloma cells stimulate MSCs to produce autotaxin, an indispensable enzyme for the biosynthesis of LPA, and LPA receptor 1 (LPA1) and 3 (LPA3) transduce opposite signals to MSCs to determine the fate of MSCs. LPA3-silenced MSCs (siLPA3-MSCs) exhibited cellular senescence-related phenotypes in vitro, and significantly promoted progression of MM and tumor-related angiogenesis in vivo. In contrast, siLPA1-MSCs showed resistance to cellular senescence in vitro, and efficiently delayed progression of MM and tumor-related angiogenesis in vivo. Consistently, anti-MM effects obtained by LPA1-silencing in MSCs were completely reproduced by systemic administration of Ki6425, an LPA1 antagonist. Collectively, our results indicate that LPA signaling determines the fate of MSCs and has potential as a therapeutic target in MM. Stem Cells 2016.
Although it is well documented that infectious diseases can pose threats to biodiversity, the potential long-term consequences of pathogen exposure on individual fitness and its effects on population viability have rarely been studied. We tested the hypothesis that pathogen exposure causes physiological carry-over effects with a pathogen that is uniquely suited to this question because the infection period is specific and time limited. The fungus Pseudogymnoascus destructans causes white-nose syndrome (WNS) in hibernating bats, which either die due to the infection while hibernating or recover following emergence from hibernation. The fungus infects all exposed individuals in an overwintering site simultaneously, and bats that survive infection during hibernation clear the pathogen within a few weeks following emergence. We quantified chronic stress during the active season, when bats are not infected, by measuring cortisol in bat claws. Free-ranging Myotis lucifugus who survived previous exposure to P. destructans had significantly higher levels of claw cortisol than naïve individuals. Thus, cryptic physiological carry-over effects of pathogen exposure may persist in asymptomatic, recovered individuals. If these effects result in reduced survival or reproductive success, they could also affect population viability and even act as a third stream in the extinction vortex. For example, significant increases in chronic stress, such as those indicated here, are correlated with reduced reproductive success in a number of species. Future research should directly explore the link between pathogen exposure and the viability of apparently recovered populations to improve understanding of the true impacts of infectious diseases on threatened populations.
High-throughput and sensitive detection of proteins are essential for clinical diagnostics and biomarker discovery. We develop a novel high-throughput, multiplexed, sensitive mass spectrometric (MS) immunoassay method, which utilizes antibody-modified phospholipid bilayer coated gold nanoparticles (PBL-AuNPs) as the detection label and antibody-immobilized magnetic beads as the capture reagent. This method enables magnetic enrichment of the PBL-AuNPs label specific to target protein, allowing sensitive surface enhanced laser desorption ionization (SELDI)-TOF MS detection of the protein via its specific label. AuNPs act as not only the support but also the matrix for the phospholipids in SELDI TOF MS detection. Moreover, with phospholipids with varying molecular weights as the encoded MS reporters, this method allows multiplexed detection of multiple proteins. With the use of a predefined phospholipids internal standard, this method also affords excellent reproducibility in protein quantification. We have demonstrated this method using the assays of two tumor biomarkers, and the results reveal that it provides a sensitive platform for multiplexed protein detection with detection limits in the picomolar ranges. This method may provide a useful platform for high-throughput and sensitive detection of protein biomarkers for clinical diagnostics.
This article outlines the steps to success in quality improvement and explains how quality improvement can help you, your patients and your institution. Although many tactics can be used to drive quality improvement, some tactics deliver results that are short term and unsustainable and that fail to embed a culture of quality improvement within organizations. Consensus is emerging that a bottom-up approach may be better - where the intrinsic motivations of clinical staff are harnessed to drive quality improvement. This is an ideal opportunity for clinical staff at all levels to join in. The steps involved in quality improvement include choosing a topic, choosing tools to measure the problem, using plan, do, study, act cycles to drive improvement, and then writing up and sharing the project. Quality improvement projects can achieve multiple outcomes including improved patient experience and saved costs.
The importance of the construction of gene-gene interaction (GGI) network to better understand breast cancer has previously been highlighted. In this study, we propose a novel GGI network construction method called linear and probabilistic relations prediction (LPRP) and used it for gaining system level insight into breast cancer mechanisms. We construct separate genome-wide GGI networks for tumor and normal breast samples, respectively, by applying LPRP on their gene expression datasets profiled by The Cancer Genome Atlas. According to our analysis, a large loss of gene interactions in the tumor GGI network was observed (7436; 88.7 % reduction), which also contained fewer functional genes (4757; 32 % reduction) than the normal network. Tumor GGI network was characterized by a bigger network diameter and a longer characteristic path length but a smaller clustering coefficient and much
 sparse network connections. In addition, many known cancer pathways, especially immune response pathways, are enriched by genes in the tumor GGI network. Furthermore, potential cancer genes are filtered in this study, which may act as drugs targeting genes. These findings will allow for a better understanding of breast cancer mechanisms.
The establishment of a regulated legal market for new psychoactive substances (NPS, 'legal highs') under New Zealand's Psychoactive Substances Act (PSA) 2013 created a new commercial sector for psychoactive products, previously limited to alcohol and tobacco.
To explore how the newly-recognised 'legal high' industry (LHI) viewed and responded to the changing regulatory and market environment.
In-depth interviews with six key informants (KI) from the LHI: a leading entrepreneur, chemist, industry spokesperson, retailer, product buyer and a researcher commissioned by the LHI - were conducted, transcribed and analysed thematically. Formative work for the study included review of official LHI documents (websites, public submissions, self-regulation documents).
The LHI stakeholders espoused an idealistic mission of shifting recreational users of alcohol, tobacco and illegal drugs towards "safer alternatives". Passage of the PSA was viewed as a success after years of lobbying led by pioneering LHI actors. The growth and professionalisation of the LHI resulted in an increasingly commercial market which challenged idealistic views of the original operators. LHI KI reported the targeting of young and low income customers, price cutting and increasing the strength of products as business strategies. Attempts by the LHI to self-regulate did not prevent escalation in the strength of products and fall in retail prices. The LHI reported outsourcing of manufacturing and exporting of their products to other countries, demonstrating an international business model.
There was a tension between profit and idealistic motivations within the LHI and this increased as the sector became more commercialised. While the LHI distanced itself from both alcohol and tobacco, they reported the use of similar marketing, business and political lobbying strategies. Rules for engagement with new 'addictive consumption industries' are required to clarify the role they are permitted to play in the development of regulatory regimes for new psychoactive substances.
The act of deliberate injury to one's own body without the help of others is a well-known phenomenon in psychiatric patients. Insertion of foreign bodies into one or more orifices is not uncommon but insertion into a body cavity or the gastrointestinal tract by self-inflicted injury is quite rare.
A 32-year-old Ethiopian psychiatric patient presented with left lower abdominal pain of three months' duration following the insertion of foreign bodies via a self-inflicted wound in the left lower quadrant of his abdomen. Radiological evaluation demonstrated the presence of foreign bodies. A laparotomy revealed two metallic and three wooden materials in his sigmoid colon and a hole in his sigmoid that was tightly sealed with omentum. The foreign bodies were successfully removed, the hole was closed primarily, and our patient was discharged uneventfully.
This case illustrates that a foreign body can be inserted into the colon through a self-inflicted wound in psychiatric patients, and patients may present months later without having developed generalized peritonitis.
Our research is exploiting the marsupial as a model to understand the signals required for lung development. Marsupials have a unique reproductive strategy, the mother gives birth to altricial neonate with an immature lung and the changes in milk composition during lactation in marsupials appears to provide bioactives that can regulate diverse aspects of lung development, including branching morphogenesis, cell proliferation and cell differentiation. These effects are seen with milk collected between 25 and 100days postpartum. To better understand the temporal effects of milk composition on postnatal lung development we used a cross-fostering technique to restrict the tammar pouch young to milk composition not extending beyond day 25 for 45days of its early postnatal life. These particular time points were selected as our previous study showed that milk protein collected prior to ~day 25 had no developmental effect on mouse embryonic lungs in culture.The comparative analysis of the foster group and control young at day 45 postpartum demonstrated that foster pouch young had significantly reduced lung size. The lungs in fostered young were comprised of large intermediate tissue, had a reduced size of airway lumen and a higher percentage of parenchymal tissue. In addition, expression of marker genes for lung development (BMP4, WNT11, AQP-4, HOPX and SPB) were significantly reduced in lungs from fostered young. Further, to identify the potential bioactive expressed by mammary gland that may have developmental effect on pouch young lungs, we performed proteomics analysis on tammar milk through mass-spectrometry and listed the potential bioactives (PDGF, IGFBP5, IGFBPL1 and EGFL6) secreted in milk that may be involved in regulating pouch young lung development. The data suggest that postnatal lung development in the tammar young is most likely regulated by maternal signalling factors supplied through milk.
Anthracycline-induced cardiotoxicity (ACT) is a severe complication in children and young adults that may lead to congestive heart failure. Some risk factors have been identified: high anthracycline cumulative dose, high radiation dose delivered on the cardiac area, or young age during the treatment. Primary prevention is not clearly defined in children. The dexrazoxane iron chelator seems to be interesting based on its short-term cardioprotective property in patients receiving doxorubicin-containing regimens. However, its long-term benefits remain to be determined, as well as the risk of secondary cancer. Childhood cancer survivors treated with anthracyclines are annually followed in the long-term. Trans-thoracic echocardiography is classically performed every 2 to 5 years for assessing the ventricular hemodynamics and function. Recent modern techniques including echocardiography with strain assessment and cardiac MRI seems to be promising for an early detection of myocardial impairment. Further studies are mandatory for validating their usefulness in the setting of anthracycline-induced cardiomyopathy. Recently, ACT predisposing variants in genes involved in oxydative stress and in metabolism and transport of anthracyclines have been identified. Their use in clinical practice could improve ACT risk stratification of children treated with anthracyclines-containing regimens. Predictive models combining replicated genetic variants and clinical factors need to be validated with the challenge to identify patients at high risk of cardiomyopathy. The objective is to personalize treatment strategy according to individual genetic background.
This paper analyzes the interplay between soil fertility, crop biodiversity, and farmers' revenues. We use a large, original, farm-level panel dataset. Findings indicate that both crop biodiversity and soil fertility have positive effects on farmers' revenues. It is also shown that crop biodiversity and soil fertility may act as substitutes. These results provide evidence for the important role of diversity in the resilience of agroecosystems. Crop diversification can be a potential strategy to support productivity when soils are less fertile.
Depression is a leading cause of disease burden across the world. However, in low-middle income countries (LMICs), access to mental health services is severely limited because of the insufficient number of mental health professionals available. The WHO initiated the Mental Health Gap Action Program (mhGAP) aiming to provide a coherent strategy for closing the gap between what is urgently needed and what is available in LMICs. Internet-based treatment is a promising strategy that can be made available to a large number of people now that Internet access is increasing rapidly throughout the world. The present study will investigate whether such an Internet-based treatment for depression is effective in Indonesia.
An Internet-based behavioral activation treatment, with support by lay counselors who will provide online feedback on the assignments and supportive phone contact to encourage participants to work in the program (Guided Act and Feel Indonesia/GAF-ID), is compared to an online-delivered minimal psychoeducation without any support (psychoeducation/PE). Initial assessment for inclusion is based on a Patient Health Questionnaire-9 (PHQ-9) score of at least 10 and meeting criteria for major depressive disorder or persistent depressive disorder as assessed using the Structured Clinical Interview for DSM-5 (SCID-5). Participants with depression (N = 312) will be recruited and randomly assigned to GAF-ID or PE. Overall assessments will be done at baseline, post intervention (10 weeks from baseline) and follow-ups (3 months and 6 months from baseline). The primary outcome is the reduction of depression symptoms as measured by the PHQ-9 after 10 weeks from baseline.
To our knowledge, this is the first study in Indonesia that examines the effectiveness of an Internet-based intervention for depression in a randomized controlled trial. The hope is that it can serve as a starting point for bridging the mental health gap in Indonesia and other LMICs.
Nederlands Trial Register ( www.trialregister.nl ): NTR5920 , registered on 1 July 2016.
Angiogenesis is the process of formation of new blood vessels, which is essential to human biology, and also plays a crucial role in several pathologies such as tumor growth and metastasis, exudative age-related
 macular degeneration, and ischemia. Vascular endothelial growth factor (VEGF), in particular, VEGF-A165 is the most important pro-angiogenic factor for angiogenesis. Thus, blocking the interaction between VEGFs and their receptors is considered an effective anti-angiogenic strategy. We demonstrate for that first time that bovine serum albumin-capped graphene oxide (BSA-GO) exhibits high stability in physiological saline solution and possesses ultrastrong binding affinity towards VEGF-A165 [dissociation constant (Kd) ∼3 × 10(-12) M], which is at least five orders of magnitude stronger than that of high-abundant plasma proteins such as human serum albumin, fibrinogen, transferrin, and immunoglobulin G. Due to the surprising binding specificity of BSA-GO for VEGF-A165 in complex plasma fluid, we have also studied the anti-angiogenic effects in vitro and in vivo. Results show that BSA-GO not only effectively inhibits the proliferation, migration and tube formation of human umbilical vein endothelial cells, but also strongly disturbs the physiological process of angiogenesis in chick chorioallantoic membrane and blocks VEGF-A165-induced blood vessel formation in rabbit corneal neovascularization. Our findings indicate that GO nanomaterials can potentially act as therapeutic anti-angiogenic agents via ultrastrong VEGF adsorption and its activity suppression.
Curing spinal cord injury (SCI) is challenging because of the onset of multiple and irreversible pathological responses to such injury. To suppress the responses, we employed an advanced cell transplantation technology integrating three-dimensional spheroid cell transplantation with non-viral gene transfection using biodegradable polycations. Brain-derived neurotrophic factor (BDNF)-transfected mesenchymal stem cell (MSC) spheroids were transplanted at thoraces level (Th9) to SCI region in mice. BDNF-transfected MSC spheroid transplantation led to a significantly enhanced recovery of hindlimb motor function in acute phase of SCI with myelinated axons preserved at the SCI region, while use of either technology in isolation, BDNF transfection or spheroid culture, exerted only a limited therapeutic effect, demonstrating the importance of integrated approaches. Secretion of endogenous therapeutic proteins, such as anti-inflammatory factors, was greater in MSC spheroids than in monolayer culture MSCs, and these factors appeared to act synergistically alongside BDNF secretion in SCI treatment. This study forms a basis for cell therapy regulating complex pathophysiologic processes.
The effects of multiple stressors on marine diatom assemblages are still poorly understood. The interactive effects of metals and nutrients were assessed in two coastal biofilms grown at a reference site and a historically contaminated site. The biofilms were exposed in situ to pulse exposures of metals (Zn and Pb) and nutrients (N and P) individually and in combination to mimic patterns of discharge in the study area. The reference community's structure (composition and abundance of taxa) was modified after metals and/or nutrients exposure, but each stressor acted in different way. Irrespective of the stressors or scenario, the abundance of the dominant species Opephora krumbeinii declined, and it is proposed as sensitive species. Nutrient supply favoured the proliferation of certain species with high nutrient tolerances (Fragilaria famelica, Tabularia ktenoeides), whereas metals promoted the colonisation of metal-tolerant species, e.g., Berkeleya fennica, Opephora marina. Simultaneous exposure induced an amplification of levels of accumulated metals, chlorophyll a and EPS contents and triggered the succession of species towards tolerant species with specific growth. Metals seemed to act as a selective factor of metal-tolerant species, and nutrients favoured the proliferation of those species forming zig-zag colonies (Neosynedra provincialis), mucous tubes (Berkeleya spp.) and motile diatoms (Navicula salinicola, Nitzschia incognita), resulting in biofilms with a more complex architecture. The diatom communities from the historically contaminated site were more resistant to pulse exposure, but metals or nutrients loads induced overproduction of mucilage. We propose that growth forms may complement taxonomic approaches and provide a quick and easy way to detect community changes related to metal and nutrient pollution.
Smallpox was eradicated by a global program of inoculation with Vaccinia virus (VV). Robust VV-specific CD4 T-cell responses during primary infection are likely essential to controlling VV replication. Although there is increasing interest in cytolytic CD4 T-cells across many viral infections, the importance of these cells during acute VV infection is unclear.
We undertook a detailed functional and genetic characterization of CD4 T-cells during acute VV-infection of humans. VV-specific T-cells were identified by up-regulation of activation markers directly ex vivo and through cytokine and co-stimulatory molecule expression. At day-13-post primary inoculation with VV, CD38highCD45RO+ CD4 T-cells were purified by cell sorting, RNA isolated and analysed by microarray. Differential expression of up-regulated genes in activated CD4 T-cells was confirmed at the mRNA and protein levels. We compared analyses of VV-specific CD4 T-cells to studies on 12 subjects with primary HIV infection (PHI). VV-specific T-cells lines were established from PBMCs collected post vaccination and checked for cytotoxicity potential.
A median 11.9% CD4 T-cells were CD38highCD45RO+ at day-13 post-VV inoculation, compared to 3.0% prior and 10.4% during PHI. Activated CD4 T-cells had an up-regulation of genes related to cytolytic function, including granzymes K and A, perforin, granulysin, TIA-1, and Rab27a. No difference was seen between CD4 T-cell expression of perforin or TIA-1 to VV and PHI, however granzyme k was more dominant in the VV response. At 25:1 effector to target ratio, two VV-specific T-cell lines exhibited 62% and 30% cytotoxicity respectively and CD107a degranulation.
We show for the first time that CD4 CTL are prominent in the early response to VV. Understanding the role of CD4 CTL in the generation of an effective anti-viral memory may help develop more effective vaccines for diseases such as HIV.
Glucagon-like peptide 1 (GLP-1) receptor agonists (GLP-1-RAs) act on multiple tissues, in addition to the pancreas. Recent studies suggest that GLP-1-RAs act on liver and adipose tissue to reduce insulin resistance (IR). Thus, we evaluated the acute effects of exenatide (EX) on hepatic (Hep-IR) and adipose (Adipo-IR) insulin resistance and glucose uptake. Fifteen male subjects (age = 56 ± 8 years; body mass index = 29 ± 1 kg/m(2) ; A1c = 5.7 ± 0.1%) were studied on two occasions, with a double-blind subcutaneous injection of EX (5 μg) or placebo (PLC) 30 minutes before a 75-g oral glucose tolerance test (OGTT). During OGTT, we measured hepatic (HGU) and adipose tissue (ATGU) glucose uptake with [(18) F]2-fluoro-2-deoxy-D-glucose/positron emission tomography, lipolysis (RaGly) with [U-(2) H5 ]-glycerol, oral glucose absorption (RaO) with [U-(13) C6 ]-glucose, and hepatic glucose production (EGP) with [6,6-(2) H2 ]-glucose. Adipo-IR and Hep-IR were calculated as (FFA0-120min ) × (Ins0-120min ) and (EGP0-120min ) × (Ins0-120min ), respectively. EX reduced RaO, resulting in reduced plasma glucose and insulin concentration from 0 to 120 minutes postglucose ingestion. EX decreased Hep-IR (197 ± 28 to 130 ± 37; P = 0.02) and increased HGU of orally administered glucose (23 ± 4 to 232 ± 89 [μmol/min/L]/[μmol/min/kg]; P = 0.003) despite lower insulin (23 ± 5 vs. 41 ± 5 mU/L; P < 0.02). EX enhanced insulin suppression of RaGly by decreasing Adipo-IR (23 ± 4 to 13 ± 3; P = 0.009). No significant effect of insulin was observed on ATGU (EX = 1.16 ± 0.15 vs. PLC = 1.36 ± 0.13 [μmol/min/L]/[μmol/min/kg]).
Acute EX administration (1) improves Hep-IR, decreases EGP, and enhances HGU and (2) reduces Adipo-IR, improves the antilipolytic effect of insulin, and reduces plasma free fatty acid levels during OGTT. (Hepatology 2016;64:2028-2037).
The core symptoms of venous disease include leg discomfort or pain accompanied by sensations of heavy, weighty, or swollen legs. This suggests the presence of a cause and effect relationship between swelling and pain, resulting in the assumption that a venous disorder is responsible. The aim of this study was to investigate the relationship between leg volume increase and symptoms provoked by a period of stationary standing and also to investigate the effect of medical compression stockings (MCS).
Healthy volunteers were subject to stationary standing. Lower leg volume and the intensity and nature of the emerging symptoms were assessed seven times during 10 minutes.
Of 46 subjects analyzed after an initial test with bare legs, 18 (39%) developed no or few symptoms (≤2 on a Numeric Rating Scale [NRS] of 0 to 10). However, their leg volume increased as much as in the 28 subjects who experienced more symptoms. Oligosymptomatic subjects scored lower in a baseline questionnaire on leg symptoms of somatic and psychic origin than did volunteers with more symptoms. The oligosymptomatic subjects were excluded from the tests with MCS. In the 24 subjects who completed the whole study, the lower leg volume increased in two phases, reaching an increment of 44 mL (standard deviation [SD], 18) or 1.73% (SD, 0.65) after 10 minutes. Symptoms emerged and increased in a linear fashion, reaching a mean score of 2.93 NRS points (SD, 1.52) at 10 minutes. The most prominent symptom was tingling (NRS, 5.07; SD, 3.05), followed by feelings of pressure and tension (NRS, 2.17; SD, 1.87). No correlation was found between volume increase and symptoms. MCS exerting an ankle pressure of 10 to 15 mm Hg reduced
 the volume increase to 32 mL (SD, 20), and MCS exerting 23 to 32 mm Hg reduced it to 24 mL (SD, 20; both P < .001; difference between stockings, P = .06). Symptom intensity was reduced to NRS 2.06 (SD, 1.52) and 2.21 (SD, 1.23; both P < .001), respectively. Both MCS reduced the symptoms equally (P = .38). Symptom reduction was not correlated with the prevention of volume increase.
On prolonged stationary standing, leg volume increase and symptoms occur independently. MCS reduce volume increase according to the pressure they exert. Symptoms are reduced independent of the pressure exerted and the volume increase prevented. This suggests that MCS act in more ways than by a simple reduction in volume.
Two genetic variants in apolipoprotein L1 (APOL1) are associated with increased risk of focal segmental glomerulosclerosis as well as other glomerular phenotypes. These risk variants are common in individuals of African ancestry but absent in other racial groups. Yet, the majority of individuals with two APOL1 risk alleles [high-risk (HR) genotype] do not have renal disease. It is critical to identify environmental and secondary genetic influences that, when combined with these alleles, lead to kidney disease. In a recent study of black children with glomerular disease enrolled in the Nephrotic Syndrome Study Network (NEPTUNE) and Chronic Kidney Disease in Children Study (n = 104), we found that subjects with an HR genotype had a 4.6-fold increase in the odds of preterm birth as compared to those with a low risk (LR) genotype [odds ratio 4.6 (CI 1.4-15.5)]. There are known racial disparities in preterm birth, which itself is a known risk factor for chronic kidney disease and focal segmental glomerulosclerosis. Thus, we questioned whether an HR APOL1 genotype is associated with prematurity in the general African American population.
We analyzed two publically available genetic datasets of preterm birth in African Americans, including 867 infants and 519 mothers from the Gene Environment Association Studies (GENEVA) study of preterm delivery and 960 mothers from the Boston Medical Center genome-wide association study of preterm birth. We performed multivariable analyses testing for association between HR APOL1 and birth outcomes.
In both studies, there was no association between HR APOL1 in mothers and prematurity, gestational age or birthweight. Additionally, in the GENEVA study, we saw no association between infant HR APOL1 and prematurity, gestational age or birthweight.
From these data, we conclude that the previously observed association between HR APOL1 and prematurity is specific to those with glomerular disease, suggesting prematurity may act as an additional risk factor in APOL1-associated renal disease.
The effects of acute tryptophan depletion on human decision-making suggest that serotonin modulates the processing of rewards and punishments. However, few studies have assessed which of the many types of serotonin receptors are responsible.
Using a within-subject, double-blind, sham-controlled design in 26 subjects, we examined whether individual differences in serotonin system gene transcription, measured in peripheral blood, predicted the effect of acute tryptophan depletion on decision-making. Participants performed a task in which they chose between successive pairs of fixed, lower-stakes (control) and variable, higher-stakes (experimental) gambles, each involving wins or losses. In 21 participants, mRNA from 9 serotonin system genes was measured in whole blood prior to acute tryptophan depletion: 5-HT1B, 5-HT1F, 5-HT2A, 5-HT2B, 5-HT3A, 5-HT3E, 5-HT7 (serotonin receptors), 5-HTT (the serotonin transporter), and tryptophan hydroxylase 1.
Acute tryptophan depletion did not significantly influence participants' sensitivity to probability, wins, or losses, although there was a trend for a lower tendency to choose experimental gambles overall following depletion. Significant positive correlations, which survived correction for multiple comparisons, were detected between baseline 5-HT1B mRNA levels and acute tryptophan depletion-induced increases in both the overall tendency to choose the experimental gamble and sensitivity to wins. No significant relationship was observed with any other peripheral serotonin system markers. Computational analyses of decision-making data provided results consistent with these findings.
These results suggest that the 5-HT1B receptor may modulate the effects of acute tryptophan depletion on risky decision-making. Peripheral levels of serotonin markers may predict response to treatments that act upon the serotonin system, such as selective serotonin reuptake inhibitors.
A large proportion of justice-involved individuals have mental health issues and substance use disorders (SUD) that are often untreated due to high rates of uninsurance. However, roughly half of justice-involved individuals were estimated to be newly eligible for health insurance through the Affordable Care Act (ACA).
We aimed to assess health insurance trends among justice-involved individuals before and after implementation of the ACA's key provisions, the dependent coverage mandate and Medicaid expansion, and to examine the relationship between health insurance and treatment for behavioral health conditions.
Repeated and pooled cross-sectional analyses of data from the National Survey on Drug Use and Health (NSDUH).
Nationally representative sample of 15,899 adults age 19-64 years between 2008 and 2014 with a history of justice involvement during the prior 12 months.
Uninsurance rates between 2008 and 2014 are reported. Additional outcomes include adjusted treatment rates for depression, serious mental illness, and SUD by insurance status.
The dependent coverage mandate was associated with a 13.0 percentage point decline in uninsurance among justice-involved individuals age 19-25 years (p < 0.001). Following Medicaid expansion, uninsurance declined among justice involved individuals of all ages by 9.7 percentage points (p < 0.001), but remained 16.3 percentage points higher than uninsurance rates for individuals without justice involvement (p < 0.001). In pooled analyses, Medicaid, relative to uninsurance and private insurance, was associated with significantly higher treatment rates for illicit drug abuse/dependence and depression.
Given the high prevalence of mental illness and substance use disorders among justice-involved populations, persistently elevated rates of uninsurance and other barriers to care remain a significant public health concern. Sustained outreach is required to reduce health insurance disparities between individuals with and without justice involvement. Public insurance appears to be associated with higher treatment rates, relative to uninsurance and private insurance, among justice-involved individuals.
The ribosomally synthesized and post-translationally modified peptide (RiPP), pyrroloquinoline quinone (PQQ), is a dehydrogenase cofactor synthesized by, but not exclusively used by, certain prokaryotes. RiPPs represent a rapidly expanding and diverse class of natural products-many of which have therapeutic potential-and the biosynthetic pathways for these are gaining attention. Five gene products from the pqq operon (PqqA, PqqB, PqqC, PqqD, and PqqE) are essential for PQQ biosynthesis. The substrate is the peptide PqqA, which is presented to the radical SAM enzyme PqqE by the small protein PqqD. PqqA is unstructured in solution, and only binds to PqqE when in complex with PqqD. PqqD is a member of a growing family of RiPP chaperone proteins (or domains in most cases) that present their associated peptide substrates to the initial RiPP biosynthesis enzymes. An X-ray crystal structure exists for dimeric Xanthomonas campestris PqqD (PDB ID: 3G2B), but PqqD is now known to act as a monomer under physiological conditions. In this study, the PqqD truncation from naturally fused Methylobacterium extorquens (Mex) PqqCD was overexpressed in Escherichia coli and MexPqqA was chemically synthesized. Solution NMR (1)H-,(15)N-HSQC chemical shift studies have identified the PqqD residues involved in binding PqqA, and (1)H, (13)C, and (15)N peak assignments for PqqD alone and for PqqD bound to PqqA are reported herein.
Immunotherapeutic treatment strategies including adoptive cell transfer (ACT) for metastatic melanoma are capable of mediating complete and durable responses, as well as partial responses and prolonged disease stabilization. Unfortunately, many patients ultimately develop progressive disease. The role of salvage metastasectomy in managing these patients has not been evaluated.
Records of patients with metastatic melanoma treated with ACT at a single institution between 2000 and 2014 were reviewed. Patients with an objective response by RECIST criteria or disease stabilization of at least 6 months and who subsequently developed progressive melanoma and were managed with metastasectomy as the next therapeutic strategy were studied for progression-free survival (PFS) and overall survival (OS). Five additional clinical parameters were also reviewed for association with outcomes.
Of 115 patients treated with ACT who met our response criteria and then developed progressive disease, 26 (23%) had surgery. There were no mortalities related to surgical intervention. Median follow-up after surgery was 62 months. Median PFS after surgery was 11 months and five-year OS was 57%. The development of a new site of metastasis after ACT was associated with poor PFS and OS.
Surgery after immunotherapy is safe. Long PFS and OS can be achieved by metastasectomy in selected patients with progressive melanoma following treatment with ACT. Clinical variables important for patient selection for metastasectomy after immunotherapy remain largely undefined. Improvements in immunotherapeutic treatment strategies may increase
 the role of surgery for patients with advanced disease.
Intravenous and subcutaneous immunoglobulin preparations, consisting of IgG class antibodies, are increasingly used to treat a broad range of pathological conditions, including humoral immune deficiencies, as well as acute and chronic inflammatory or autoimmune disorders. A plethora of Fab- or Fc-mediated immune regulatory mechanisms has been described that might act separately or in concert, depending on pathogenesis or stage of clinical condition. Attempts have been undertaken to improve the efficacy of polyclonal IgG preparations, including the identification of relevant subfractions, mild chemical modification of molecules, or modification of carbohydrate side chains. Furthermore, plasma-derived IgA or IgM preparations may exhibit characteristics that might be exploited therapeutically. The need for improved treatment strategies without increase in plasma demand is a goal and might be achieved by more optimal use of plasma-derived proteins, including the IgA and the IgM fractions. This article provides an overview on the current knowledge and future strategies to improve the efficacy of regular IgG preparations and discusses the potential of human plasma-derived IgA, IgM, and preparations composed of mixtures of IgG, IgA, and IgM.
Patients with chronic rhinosinusitis (CRS) often have comorbid asthma. Prior studies have not examined the impact of CRS or endoscopic sinus surgery (ESS) upon asthma quality of life (QOL) and asthma control using validated outcome metrics.
Patients with CRS, both with and without polyps, and comorbid asthma completed the Mini Asthma QOL Questionnaire (miniAQLQ) and Asthma Control Test (ACT) at baseline and 6 months postoperatively as part of a multi-institutional, prospective study.
Baseline metrics were available on 86 patients. Patients undergoing ESS reported improved miniAQLQ [0.5 (SD ±1.1), 95% CI: 0.2-0.7; P = 0.002] and ACT scores [1.3 (±4.1), 95% CI: 0.2-2.4; P = 0.025]. Uncontrolled baseline asthma (ACT < 20) was present in 51% of patients undergoing ESS. In uncontrolled patients, ESS resulted in a minimal clinically important difference 57% of the time for miniAQLQ scores (≥0.5 points) and 50% of the time for ACT scores (≥3.0 points). After adjustment with linear regression, baseline miniAQLQ scores were worse in patients with comorbid allergy (P = 0.045) and chronic obstructive pulmonary disease (COPD; P = 0.015). Adjusted baseline ACT scores were worse in patients with COPD (P = 0.004). Covariates associated with changes in miniAQLQ scores after ESS were pre-operative corticosteroid dependency (P = 0.011) and change in total SNOT-22 score (P = 0.010). Covariate associated with significantly less improvement in ACT scores was obstructive sleep apnea (P = 0.016).
Patients with CRS often present with uncontrolled asthma, and ESS improves both miniAQLQ and ACT. Approximately half of patients with uncontrolled asthma improve after ESS, yet there are few CRS-specific factors associated with asthma QOL or control or ESS outcomes.
Some supporters of electronic cigarettes have argued that they should be considered a form of harm reduction, analogous to that which has been successful with narcotics. In this viewpoint, we contend that this argument is based on highly selective use of the evidence, coupled with a fundamental misunderstanding of a comprehensive harm minimisation strategy. This includes not only harm reduction but also reduction in demand and supply-two elements that are explicitly rejected by many advocates of electronic cigarettes. We contend that, in the absence of all three elements, there is a danger that electronic cigarettes will delay the achievement of a tobacco-free world.
Birds can act as reservoirs of West Nile virus (WNV) with a key role in its epidemiology. WNV lineage 1 associated fatal cases of human encephalitis in 2011 and acute flaccid paralysis in 2013 were reported in Alappuzha district, Kerala, India. But no information is available on WNV circulation in domestic ducks, which are abundant, cohabit with humans and occupy wetlands and water bodies in the region. To determine the extent of WNV infection, we investigated 209 sera, 250 oral and 350 cloacal swab samples from local Chara and Chemballi domestic ducks (Anas platyrhynchos var domesticus) in the districts of Alappuzha, Kottayam, Kollam and Pathanamthitta collected during January and March 2015. The serum samples were tested for WNV antibodies first by a competition ELISA and then by a micro virus neutralization test (micro-VNT), while oral and cloacal swabs were subjected to WNV real-time RT-PCR. Ninety five ducks showed evidence of flavivirus antibodies by ELISA. End point neutralizing antibody titre against WNV and Japanese encephalitis virus (JEV) revealed WNV specific antibodies in 24 (11.5%) ducks in 3 districts, JEV specific antibodies in 21 (10%) ducks in 2 districts and flavivirus specific antibodies in 19 (9%) ducks. However, no WNV genomic RNA could be detected. The results of this study demonstrate evidence of widespread WNV and JEV infection in domestic ducks in Kuttanad region, Kerala with a higher seroprevalence to WNV than JEV. Additionally, it highlights the utility of domestic ducks as a surveillance tool to detect WNV/JEV circulation in a region.
The aim of this study was to evaluate seric NTPDase and 5'nucleotidase activities of cattle naturally infected by Eurytrema coelomanticum, as well as to correlate them to histopathological lesions in the pancreas and the degree of parasitism. Blood samples and pancreas of 51 bovines were collected on a slaughterhouse in Southern Brazil: 33 from cattle naturally infected by E. coelomanticum (the Group A), and 18 from uninfected animals (the Group B). Infected animals showed an average of 532 parasites per pancreas. In the pancreatic histology, ducts displayed hyperplasia, stenosis, proliferation of fibrous tissue, and interstitial inflammatory infiltration of lymphocytes. The serum from infected animals showed an increase in NTPDase activity when ATP was used as substrate (P<0.001). For the ADP substrate, there was no difference between groups regarding NTPDase activity (P=0.37), as well as 5'-nucleotidase activity (P=0.27). Correlating NTPDase activity (ATP substrate) with the degree of histopathological lesions (rho=0.66, P<0.001) and the parasitic load on the pancreas (rho=0.65, P<0.001), a positive correlation was observed. Similar results were found between the degree of histopathological lesions and NTPDase activity (ADP substrate; rho=0.29, P=0.03), and 5'nucleotidase activity (rho=0.35, P=0.01). Based on the results of NTPDase and 5'nucleotidase enzymes in cattle naturally infected by E. coleomanticum, it is possible to suggest that these enzymes are involved in the modulation of inflammation, and they can act as markers of inflammatory response.
Infections caused by thermotolerant Campylobacter spp. and Salmonella spp. are the leading causes of human gastroenteritis worldwide. Wild birds can act as reservoirs of both pathogens. A survey was carried out to determine the prevalence, genetic diversity and antimicrobial resistance of thermotolerant Campylobacter and Salmonella in waterfowl used as decoys and wild raptors in Andalusia (Southern Spain). The overall prevalence detected for Campylobacter was 5.9% (18/306; CI95%: 3.25-8.52) in decoys and 2.3% (9/387; CI95%: 0.82-3.83) in wild raptors. Isolates were identified as C. jejuni, C. coli and C. lari in both bird groups. Salmonella was isolated in 3.3% (10/306; CI95%: 2.3-4.3) and 4.6% (18/394; CI95%: 3.5-5.6) of the decoys and raptors, respectively. Salmonella Enteritidis and Typhimurium were the most frequently identified serovars, although Salmonella serovars Anatum, Bredeney, London and Mikawasima were also isolated. Pulsed-field gel electrophoresis analysis of isolates showed higher genetic diversity within Campylobacter species compared to Salmonella serovars. Campylobacter isolates showed resistance to gentamicin, ciprofloxacin and tetracycline, while resistance to erythromycin and tetracycline was found in Salmonella isolates. The results indicate that both decoys and raptors can act as natural carriers of Campylobacter and Salmonella in Spain, which may have important implications for public and animal health.
Streptococcus milleri group (SMG) is a group of three streptococcal species (S. anginosus, intermedius and constellatus) that act as opportunist pathogens, among others in cystic fibrosis. Due to their fastidious character, they are both difficult to cultivate and to differentiate from less pathogenic streptococcal species, therefore being most probably underdiagnosed. Semi-selective McKay agar and NAS agar were developed to facilitate SMG recovery from clinical samples; however, direct comparison of recovery rates has not been published yet. We tested the performance of both media on 123 patient samples and demonstrated general superiority of NAS agar for SMG recovery during primary cultivation convincingly. This observation was also confirmed by quantitative drop tests during subculture. Despite the undisputed overall superiority of NAS agar over McKay agar, a smaller fraction of strains grew better on McKay agar. Inter-strain differences were the most probable explanation. Therefore, when economic conditions are not limiting and maximum recovery rate is desirable, both plates are advised to be used in parallel for primary cultivation of clinical samples.
A defining feature of mycobacterial redox metabolism is the use of an unusual deazaflavin cofactor, F420 This cofactor enhances the persistence of environmental and pathogenic mycobacteria, including following antimicrobial treatment, though the molecular basis for this remains to be understood. In this work, we explored our hypothesis that F420 enhances
 persistence by serving as a cofactor in antimicrobial-detoxifying enzymes. To test this, we performed a series of phenotypic, biochemical, and analytical chemistry studies in relation to the model soil bacterium Mycobacterium smegmatis Mutant strains unable to synthesize or reduce F420 were found to be more susceptible to a wide range of antibiotic and xenobiotic compounds. Compounds from three classes of antimicrobial compounds traditionally resisted by mycobacteria inhibited growth of F420 mutant strains at subnanomolar concentrations, namely furanocoumarins (e.g. methoxsalen), arylmethanes (e.g. malachite green), and quinone analogues (e.g. menadione). We demonstrated that promiscuous F420H2-dependent reductases directly reduce these compounds by a mechanism consistent with hydride transfer. Moreover, M. smegmatis strains unable to make F420H2 lost the capacity to reduce and detoxify representatives of the furanocoumarin and arylmethane compound classes in whole-cell assays. By contrast, mutant strains were only slightly more susceptible to clinical antimycobacterials and this appeared to be due to indirect effects of F420 loss-of-function (e.g. redox imbalance) rather than loss of a detoxification system. Together, these data show that F420 enhances antimicrobial resistance in mycobacteria and suggest that one function of the F420H2-dependent reductases is to broaden the range of natural products that mycobacteria and possibly other environmental actinobacteria can reductively detoxify.
This study reveals that a unique microbial cofactor, F420, is critical for antimicrobial resistance in the environmental actinobacterium Mycobacterium smegmatis We show that a superfamily of redox enzymes, the F420H2-dependent reductases, can reduce diverse antimicrobials in vitro and in vivo M. smegmatis strains unable to make or reduce F420 become sensitive to inhibition by these antimicrobial compounds. This suggests that mycobacteria have harnessed the unique properties of F420 to reduce structurally diverse antimicrobials as part of the antibiotics arm race. The F420H2-dependent reductases that facilitate this process represent a new class of antimicrobial-detoxifying enzymes with potential applications in bioremediation and biocatalysis.
The UK 2007 floods resulted in damages estimated to exceed over £4 billion. This triggered a national review of strategic flood risk management (Pitt, 2008) with its recommendations informing and implemented by the Flood and Water Management, Act (FWMA, 2010). Estimating that up to two-thirds of properties flooded in the 2007 event as a direct result of overloaded sewer systems, the FWMA set out an ambitious overhaul of flood risk management approaches including identifying bodies responsible for the management of local flood risk (local municipalities) and the development of over-arching Lead Local Flood Authorities (LLFAs) at a regional level. LLFAs duties include developing local flood risk management strategies and, aligned with this, many LLFAs and local municipalities produced sustainable drainage system (SUDS) guidance notes. In parallel, changes to the national planning policy framework (NPPF) in England give priority to the use of SUDS in new major developments, as does the related Town and Country Planning Order (2015). However, whilst all three pieces of legislation refer to the preferential use of SUDs, these requirements remain "economically proportionate" and thus the inclusion of SUDS within development controls remain desirable - but not mandatory - obligations. Within this dynamic policy context, reignited most recently by the December 2015 floods, this paper examines some of the challenges to the implementation of SUDS in England and Wales posed by the new regulatory frameworks. In particular, it examines how emerging organisational procedures and processes are likely to impact on future SUDS implementation, and highlights the need for further cross-sectoral working to ensure opportunities for cross-sectoral benefits- such as that accrued by reducing stormwater flows within combined sewer systems for water companies, property developers and environmental protection - are not lost.
Institutional theory has been widely debated by scholars. A part of literature examines how institutional pressures act on company choices regarding proactive environmental strategies. However, the institutional perspective has still not completely clarified the influence of these pressures on the effectiveness of environmental management systems (EMSs) in achieving goals in terms of eco-innovation, competitiveness and corporate reputation. This paper analyses the role played by coercive, mimetic and normative forces in stimulating innovative and competitive responses by firms with an environmental certification. Using the results of a survey on 242 European EMAS-registered organisations, the paper highlights the more positive influence of mimetic and normative pressures than coercive ones. The paper contributes to the literature debate on EMSs analysed through the lens of institutional theory.
Under the Patient Protection and Affordable Care Act (ACA), the Centers for Medicare and Medicaid Services' Innovation was chartered to develop new models of health care delivery. The changes meant a drastic need to restructure the health care system. To minimize costs and optimize quality, new laws encourage continuity in health care delivery within an integrated system. Affordable care organizations provided a model of high-quality care while reducing costs. Bundled payments can have a substantial effect on the national expenditures. This article examines new developments in bundle payments, affordable care organizations, and gainsharing agreements as they pertain to arthroplasty.
The US health care system has been fragmented for more than 40 years; this model created a need for modification. Sociopoliticomedical system-related factors led to the Affordable Care Act (ACA) and a restructuring of health care provision/delivery. The ACA increases access to high-quality "affordable care" under cost-effective measures. This article provides a comprehensive review of health reform and the motivating factors that drive policy to empower arthroplasty providers to effectively advocate for the field of orthopedics as a whole, and the patients served.
Experimental studies indicate that some chemicals with UV blocking properties (known as UV filters) can act as endocrine disruptors. UV filters are used in sunscreens and other cosmetic- and personal care products, as well as in other consumer products such as food packaging, clothing and furniture textiles to protect the products against UV radiation. Here we present the urinary excretion of suspected endocrine active UV filters in Danish children and adolescents recruited from the general population.
The content of benzophenone (BP), benzophenone-1 (BP-1), benzophenone-2 (BP-2), benzophenone-3 (BP-3), 5-chloro-2- hydroxybenzophenone (BP-7), 4-hydroxybenzophenone (4-HBP), 4-methyl-benzophenone (4-MBP), 3-(4- methylbenzylidene)-camphor (4-MBC) and 3-benzylidene camphor (3-BC) were monitored in 24h urine and two consecutive first morning samples from 129 healthy Danish children and adolescents (6-21 yrs). All 387 samples were collected during the autumn (Nov. 2007) and were analyzed by a new on-line TurboFlow-LC-MS/MS method developed for simultaneous biomonitoring of these nine UV filters in urine.
BP-3 and BP-1 were detected in more than 80% of the 24h samples and were significantly correlated (R(2)=0.815). BP, 4-HBP and BP-2 were found in 43, 15 and 5% of the samples, respectively. The median (range) concentrations of the UV-filters in 24-h urine were as follows: BP-3, 0.92 (LOD-115); BP-1, 0.54 (LOD-44.6); BP,<LOD (LOD-48.5); 4-HBP,<LOD (LOD-10.5); and BP-2,<LOD (LOD-8.43) ng/mL. In general BP-1 and BP-3 were higher in girls compared to boys and were also higher in the group of adolescent girls (16-21 yrs) compared to the younger age groups of girls. None of the other UV filters; BP-7, 4-MBP, 4-MBC or 3-BC were detected in urine. A highly significant correlation between first morning and 24h urine levels of BP-3, BP-1 and 4-HBP from the same day was observed.
Our project on UV filters analyzed by a new robust and sensitive LC-MS/MS method in Danish children and adolescents showed that almost all individuals were exposed to UV filters. Sun protection products have been claimed to be a major source of exposure to sunscreens. However since all children in the present study were exposed during autumn where sunscreens are not needed in Denmark our study also indicates that other sources and routes of exposure might be of relevance.
Physician-industry relationships have come a long way since serious debates began after a 1990 Senate Committee on Labor and Human Resources report on the topic. On one side, the Sun Shine Act of 2007, now a part of the Patient Protection and Affordable Care Act that mandates disclosure of payments and gifts to the physicians, has injected more transparency into the relationships, and on the other side, numerous voluntary self-regulation guidelines have been instituted to protect patients. However, despite these commendable efforts, problem persists. Taking the specific case of physician-pharmaceutical sales representative (PSR) interactions, also called as detailing, where the PSRs lobby physicians to prescribe their brand drugs while bringing them gifts on the side, an August 2016 article concluded that gifts as small as $20 are associated with higher prescribing rates. A close examination reveals the intricacies of the relationships. Though PSRs ultimately want to push their drugs, more than gifts, they also bring the ready-made synthesized knowledge about the drugs, something the busy physicians, starving for time to read the literature
 themselves, find hard to let go. Conscientious physicians are not unaware of the marketing tactics. And yet, physicians too are humans. It is also the nature of their job that requires an innate cognitive dissonance to be functional in medical practice, a trait that sometimes works against them in case of PSR interactions. Besides, PSRs too follow the dictates of the shareholders of their companies. Therefore, if they try to influence physicians using social psychology, it is a job they are asked to do. The complexity of relationships creates conundrums that are hard to tackle. This commentary examines various dimensions of these relationships. In the end, a few suggestions are offered as a way forward.
Deleted in malignant brain tumors 1 (DMBT1) is deleted during cancer progression and as a potential tumor-suppressor gene in various types of cancer. However, its role in Gallbladder cancer remains poorly understood. DMBT1 has low-expression and deletion of copy number were detected in normal tissues and GBC cancer tissues by qRT-PCR. Knockdown of DMBT1 increased migration and invasion and overexpressed DMBT1 impaired migration and invasion in GBC cells. We also evaluated the molecular mechanism of DMBT1 by RNA sequencing and GSEA analysis. RNA-Pulldown and RIP assay authenticated CRNDE can specified binding with DMBT1 and c-IAP1. Downregulation of DMBT1 resulted in significant change of gene expression (at least 2-fold) in PI3K-AKT pathway, increased expression of MMP-9, JUK-1, ERK and AKT, activating PI3K-AKT pathway lead to GBC carcinogenesis.We for the first time reported, DMBT1 as a prognosis biomarker, is low-expressed in GBC tumors, and CRNDE act as a scaffold to recruit the DMBT1 and c-IAP1, promotes the PI3K-AKT pathway. Our study reveals DMBT1 may be an important contributor to GBC cancer development.
Pseudomonas aeruginosa is an opportunistic bacterial pathogen and a primary cause of nosocomial infection in humans. The rate of antibiotic resistance in P. aeruginosa is increasing worldwide leading to an unmet need for discovery of new chemical compounds distinctly different from present antimicrobials. Protein synthesis is an essential metabolic process and a validated target for the development of new antibiotics. Initiation factor 1 from P. aeruginosa (Pa-IF1) is the smallest of the three initiation factors that act to establish the 30S initiation complex during initiation of protein biosynthesis. Here we report the characterization and solution NMR structure of Pa-IF1. Pa-IF1 consists of a five-stranded β-sheet with an unusual extended β-strand at the C-terminus and one short α-helix arranged in the sequential order β1-β2-β3-α1-β4-β5. The structure adopts a typical β-barrel fold and contains an oligomer-binding motif. A cluster of basic residues (K39, R41, K42, K64, R66, R70, and R72) located on the surface of strands β4 and β5 near the short α-helix may compose the binding interface with the 30S subunit.
Amyloid plaques, although inducing damage to the immediately surrounding neuropil, have been proposed to provide a relatively innocuous way to deposit toxic soluble amyloid-β (Aβ) species. Here we address this hypothesis by exploring spread and absorption of fluorescent Aβ to pre-existing amyloid plaques after local application in wild-type mice versus APP/PS1 transgenic mice with amyloid plaques. Local intracortical or intracerebroventricular injection of fluorescently-labeled Aβ in APP/PS1 mice with a high plaque density resulted in preferential accumulation of the peptide in amyloid plaques in both conventional postmortem histology and in live imaging using two-photon microscopy. These findings support the contention that amyloid plaques may act as buffers to protect neurons from the toxic effects of momentary high concentrations of soluble Aβ oligomers.
A simple eco-friendly approach for the hasty synthesis of stable, potent and benign silver nanoparticles (AgNPs) using seagrass, Syringodium isoetifolium was proposed and described here. The UV-Vis, DLS, XRD, AFM, FESEM, EDX and HRTEM analysis highly characterized and confirmed the presence of polydispersed (2-50nm) spherical and stable AgNPs. FT-IR and phytochemical analysis suggested that the proteins act as reducing and also as capping agent. A hypothetical approach using bioinformatics tools revealed that the Phytochrome B protein of S. isoetifolium might be responsible for the biosynthesis of NPs. Furthermore, biosynthesized AgNPs showed magnificent antibacterial activity against thirteen clinical bacterial pathogens with maximum zone of inhibition of 14.3±0.12mm due to their smaller size and longer stability even at minimal nanomolar (nM) concentration. In addition, the MIC and MBC values also suggested the same. Moreover, the percentage of haemolysis (8.49±3.10 to 73.34±1.79%) and haemolytic index revealed the satisfactory biocompatibility of AgNPs that showed less/no haemolysis up to 3nM concentration. Further, the toxicity effect of biosynthesized AgNPs against the brine shrimp, Artemia salina exhibited significantly increasing mortality (13±4.7 to 100%) with LC50 value at 4nM concentration. Thus, the optical property, crystal structure, size, shape, stability, bactericidal activity, cytotoxicity, and biocompatibility apparently proved that the biologically synthesized AgNPs have typical properties of nanomaterials.
Friction and wear decrease the efficiency and lifetimes of mechanical devices. Solving this problem will potentially lead to a significant reduction in global energy consumption. We show that multilayer polyethylenimine/graphene oxide thin films, prepared via a highly scalable layer-by-layer (LbL) deposition technique, can be used as solid lubricants. The tribological properties are investigated in air, under vacuum, in hydrogen, and in nitrogen gas environments. In all cases the coefficient of friction (COF) significantly decreased after application of the coating, and the wear life was enhanced by increasing the film thickness. The COF was lower in dry environments than in more humid environments, in contrast to traditional graphite and diamond-like carbon films. Superlubricity (COF < 0.01) was achieved for the thickest films in dry N2. Microstructural analysis of the wear debris revealed that carbon nanoparticles were formed exclusively in dry conditions (i.e., N2, vacuum), and it is postulated that these act as rolling asperities, decreasing the contact area and the COF. Density functional theory (DFT) simulations were performed on graphene oxide sheets under pressure, showing that strong hydrogen bonding occurs in the presence of intercalated water molecules compared with weak repulsion in the absence of water. It is suggested that this mechanism prevents the separation graphene oxide layers and subsequent formation of nanostructures in humid conditions.
Ever since the introduction of the Market Restructuring Act, the evaluation and price negotiations of drugs have been controversial. While the Federal Joint Committee considers that the process is transparent and in accordance with clear evidence-based criteria, representatives of pharmaceutical companies are particularly critical of the fact that the central association of statutory health insurance is involved in both the determination of added therapeutic benefit of drugs as well as in the subsequent price negotiation. In this study, we investigate these 2 contradictory assessments empirically. For this purpose, we model the benefit assessment and price negotiation processes under AMNOG and analyze their relationship. We show that the number of patients in the target population, and the annual cost of therapy for the appropriate comparator therapy have a negative influence on the determination of the added benefit of the new therapy. The added value itself has a positive (negative) effect on the mark-up for the appropriate comparator therapy (price discount), while the annual treatment costs of the new therapy (which appropriate comparator therapy) have a positive (negative) influence. We find clues, but no significant evidence for the hypothesis that the decisions on the added value of new medicines and the subsequent price negotiations are interdependent.
Over the past 30 years, there has been a dramatic rise in global obesity prevalence, resulting in significant economic and social consequences. Attempts to develop pharmacological agents to treat obesity have met with many obstacles including the lack of long-term effectiveness and the potential for adverse effects. Historically, there have been limited treatment options for overweight and obesity; however, since 2012, a number of new drugs have become available. A number of peptides produced in the gut act as key mediators of the gut-brain axis, which is involved in appetite regulation. This review discusses the role of the gut-brain axis in appetite regulation with special focus on glucagon-like peptide-1. Liraglutide 3.0 mg, a glucagon-like peptide-1 receptor agonist that targets this pathway, is now approved for the treatment of obesity and overweight (body mass index ≥27 kg/m(2) ) with comorbidities such as type 2 diabetes, high blood pressure, high cholesterol or obstructive sleep apnoea. In addition, other glucagon-like peptide-1 receptor agonists offer promise for obesity management in the future. This review examines how glucagon-like peptide-1 receptor agonists promote weight loss and summarizes the clinical data on weight loss with glucagon-like peptide-1 receptor agonists.
Delayed fat digestion might help to fight obesity. Fat digestion begins in the stomach by adsorption of gastric lipases to oil/water interfaces. In this study we show how biopolymer covered interfaces can act as a physical barrier for recombinant dog gastric lipase (rDGL) adsorption and thus gastric lipolysis. We used β-lactoglobulin
 (β-lg) and thermosensitive methylated nanocrystalline cellulose (metNCC) as model biopolymers to investigate the role of interfacial fluid dynamics and morphology for interfacial displacement processes by rDGL and polysorbate 20 (P20) under gastric conditions. Moreover, the influence of the combination of the flexible β-lg and the elastic metNCC was studied. The interfaces were investigated combining interfacial techniques, such as pendant drop, interfacial shear and dilatational rheology, and neutron reflectometry. Displacement of biopolymer layers depended mainly on the fluid dynamics and thickness of the layers, both of which were drastically increased by the thermal induced gelation of metNCC at body temperature. Soft, thin β-lg interfaces were almost fully displaced from the interface, whereas the composite β-lg-metNCC layer thermogelled to a thick interfacial layer incorporating β-lg as filler material and therefore resisted higher shear forces than a pure metNCC layer. Hence, with metNCC alone lipolysis by rDGL was inhibited, whereas the layer performance could be increased by the combination with β-lg.
Acetochlor (ACT) has been frequently detected in the aquatic environment and implicated in disruption of the immune system in fish, the mechanisms of which, especially at enantiomeric levels, remains unclear. In the present study, embryonic zebrafish were exposed to ACT and its enantiomers at concentrations of 0, 2, 8, 15, 30 and 60 μM from 2 h post-fertilization (hpf) to 72 hpf. We demonstrated that ACT and its enantiomers could cause time- and concentration-dependent mortality (72 h LC50 ranged from 48.4 to 53.1 μM) and developmental malformations (e.g., 48 h EC50 for yolk sac edema ranged from 36.7 to 54.1 μM), as well as increase transcription of the key genes involved in the innate immune system. A consistent enantioselectivity in these endpoints was observed with (-)-R-ACT showed stronger effects than (+)-S-ACT, and the transcription levels of il-1β exhibited significant enantioselectivity at concentrations as low as 8 μM. Further Western blot analysis revealed that significant elevations of Il-1β protein expression in all (-)-R-ACT treatment groups. According to the molecular docking and molecular dynamics simulations, the enantioselectivity between ACT enantiomers was attributed to the distinct binding affinity to Il-1β. Overall, our in vivo and in silico studies uniquely disclosed the enantioselective immunotoxicity of ACT and its underlying mechanisms and highlighted the need to evaluate the environmental risk of chiral chloroacetamide herbicide in aquatic organisms at enantiomeric levels.
Cytokines play important roles in the wound healing process through various signalling pathways. The JAK-STAT pathway is utilised by most cytokines for signal transduction and is regulated by a variety of molecules, including suppressor of cytokine signalling (SOCS) proteins. SOCS are associated with inflammatory diseases and have an impact on cytokines, growth factors and key cell types involved in the wound healing process. SOCS, a negative regulator of cytokine signalling, may hold the potential to regulate cytokine induced signalling in the chronic wound healing process. Wound edge tissues were collected from chronic venous leg ulcer patients and classified as non-healing and healing wounds. The expression pattern of seven SOCSs members, at the transcript and protein level, were examined in these tissues using qPCR and immunohistochemistry. Significantly higher levels of SOCS3 (P=0.0284) and SOCS4 (P=0.0376) in non-healing chronic wounds compared to the healing/healed chronic wounds were observed at the transcript level. Relocalisation of SOCS3 protein in the non-healing wound environment was evident in the investigated chronic biopsies. Thus, the results show that the expression of SOCS transcript indicated that SOCS members may act as a prognostic biomarker of chronic wounds.
Long-term health insurance provides consumers with protection against persistent, negative health shocks. While the stochastic rise in medical spending growth may make some health risks harder to insure, financial assets could act as a hedge for medical spending growth risk. The purpose of this research was to determine whether such hedges exist. The results of this study were two-fold. First, the asset classes with the strongest statistical evidence as hedges were bonds, not stocks. Second, any strategy to hedge medical spending growth involved shorting assets i.e. betting against the bond or stock market. Health insurers writing long-term contracts should combine the use of hedges in the bond market with of portfolio diversification, and may benefit from health policies to moderate the uncertainty of medical spending growth.
We have an incomplete understanding of the differences between cancer stem cells (CSCs) in human papillomavirus-positive (HPV-positive) and -negative (HPV-negative) head and neck squamous cell cancer (HNSCC). The PI3K pathway has the most frequent activating genetic events in HNSCC (especially HPV-positive driven), but the differential signaling between CSCs and non-CSCs is also unknown.
We addressed these unresolved questions using CSCs identified from 10 HNSCC patient-derived xenografts (PDXs). Sored populations were serially passaged in nude mice to evaluate tumorigenicity and tumor recapitulation. The transcription profile of HNSCC CSCs was characterized by mRNA sequencing, and the susceptibility of CSCs to therapy was investigated using an in vivo model. SOX2 transcriptional activity was used to follow the asymmetric division of PDX-derived CSCs. All statistical tests were two-sided.
CSCs were enriched by high aldehyde dehydrogenase (ALDH) activity and CD44 expression and were similar between HPV-positive and HPV-negative cases (percent tumor formation injecting ≤ 1x10(3) cells: ALDH(+)CD44(high) = 65.8%, ALDH(-)CD44(high) = 33.1%, ALDH(+)CD44(high) = 20.0%; and injecting 1x10(5) cells: ALDH(-)CD44(low) = 4.4%). CSCs were resistant to conventional therapy and had PI3K/mTOR pathway overexpression (GSEA pathway enrichment, P < .001), and PI3K inhibition in vivo decreased their tumorigenicity (40.0%-100.0% across cases). PI3K/mTOR directly regulated SOX2 protein levels, and SOX2 in turn activated ALDH1A1 (P < .001 013C and 067C) expression and ALDH activity (ALDH(+) [%] empty-control vs SOX2, 0.4% ± 0.4% vs 14.5% ± 9.8%, P = .03 for 013C and 1.7% ± 1.3% vs 3.6% ± 3.4%, P = .04 for 067C) in 013C and 067 cells. SOX2 enhanced sphere and tumor growth (spheres/well, 013C P < .001 and 067C P = .04) and therapy resistance. SOX2 expression prompted mesenchymal-to-epithelial transition (MET) by inducing CDH1 (013C P = .002, 067C P = .01), followed by asymmetric division and proliferation, which contributed to tumor formation.
The molecular link between PI3K activation and CSC properties found in this study provides insights into therapeutic strategies for HNSCC. Constitutive expression of SOX2 in HNSCC cells generates a CSC-like population that enables CSC studies.
Recently, studies have reported that long noncoding RNAs (lncRNAs) can act as modulators of mRNAs through competitively binding to microRNAs (miRNAs) and have relevance to tumorigenesis as well as other diseases. Identify lncRNA competitively regulated subpathway not only can gain insight into the initiation and progression of disease, but also help for understanding the functional roles of lncRNAs in the disease context. Here, we present an effective method, Subpathway-LNCE, which was specifically designed to identify lncRNAs competitively regulated functions and the functional roles of these competitive regulation lncRNAs have not be well characterized in diseases. Moreover, the method integrated lncRNA-mRNA expression profile and pathway topologies. Using prostate cancer datasets and LUAD data sets, we confirmed the effectiveness of our method in identifying disease associated dysfunctional subpathway that regulated by lncRNAs. By analyzing kidney renal clear cell carcinoma related lncRNA competitively regulated subpathway network, we show that Subpathway-LNCE can help uncover disease key lncRNAs. Furthermore, we demonstrated that our method is reproducible and robust. Subpathway-LNCE provide a flexible tool to identify lncRNA competitively regulated signal subpathways underlying certain condition, and help to expound the functional roles of lncRNAs in various status. Subpathway-LNCE has been developed as an R package freely available at https://cran.rstudio.com/web/packages/SubpathwayLNCE/.
Adverse early-life events induce behavioral psychopathologies and sleep changes in adulthood. In order to understand the molecular level mechanisms by which the maltreatment modifies sleep, valid animal models are needed. Changing pups between mothers at early age (cross-fostering) may satisfyingly model adverse events in human childhood.
Cross-fostering (CF) was used to model mild early-life stress in male and female Wistar rats. Behavior and BDNF gene expression in the basal forebrain (BF), cortex, and hypothalamus were assessed during adolescence and adulthood. Spontaneous sleep, sleep homeostasis, and BF extracellular adenosine levels were assessed in adulthood.
CF rats demonstrated increased number of REM sleep onsets in light and dark periods of the day. Total REM and NREM sleep duration was also increased during the light period. While sleep homeostasis was not severely affected, basal level of adenosine in the BF of both male and female CF rats was lower than in controls. CF did not lead to considerable changes in behavior.
Even when the consequences of adverse early-life events are not observed in tests for anxiety and depression, they leave a molecular mark in the brain, which can act as a vulnerability factor for psychopathologies in later life. Sleep is
 a sensitive indicator for even mild early-life stress.
Adoptive cell therapy (ACT) trials to date have focused on transfer of autologous tumor-specific cytotoxic CD8(+) T cells; however, the potential of CD4(+) T helper (Th) cells for ACT is gaining interest. While encouraging results have been reported with IFNγ-producing Th1 cells, tumor-specific Th2 cells have been largely neglected for ACT due to their reported tumor-promoting properties. In this study, we tested the efficacy of idiotype-specific Th2 cells for the treatment of mice with MHC class II-negative myeloma. Th2 ACT efficiently eradicated subcutaneous myeloma in an antigen-specific fashion. Transferred Th2 cells persisted in vivo and conferred long-lasting immunity. Cancer eradication mediated by tumor-specific Th2 cells did not require B cells, natural killer T cells, CD8(+) T cells, or IFNγ. Th2 ACT was also curative against B-cell lymphoma. Upon transfer, Th2 cells induced a type II inflammation at the tumor site with massive infiltration of M2-type macrophages producing arginase. In vivo blockade of arginase strongly inhibited Th2 ACT, consistent with a key role of arginase and M2 macrophages in myeloma elimination by Th2 cells. These results illustrate that cancer eradication may be achieved by induction of a tumor-specific Th2 inflammatory immune response at the tumor site. Thus, ACT with tumor-specific Th2 cells may represent a highly efficient immunotherapy protocol against cancer. Cancer Res; 76(23); 6864-76. ©2016 AACR.
Mitochondrial dysfunction is a newly established risk factor for the development of renal fibrosis. Cell survival and injury repair is facilitated by mitochondrial biogenesis. Nuclear respiratory factor 1 (NRF-1) is a transcriptional regulation factor that plays a central role in the regulation of mitochondrial biogenesis. However, the transcription factor of this process in renal fibrosis is unknown. Thus, we hereby discussed the correlations of NRF-1 and renal interstitial fibrosis.
In vitro fibrosis model was established by treatment with transforming growth factor-β1 (TGF-β1) in NRK-49F (Normal Rat kidney fibroblast). We investigated the ROS production, mitochondrial biogenesis and fibrogenic marker (e.q. fibronectin) during the progression of renal fibrosis by kit and Western blotting assay. Here, we used that two distinct mechanisms regulate NRF-1 activation and degradation of NRF-1. NRF-1 was transfect by pcDNA-NRF-1 overexpression gene to evaluate the NRF-1 activity of the therapeutic effect in renal fibrosis. In addition, NRF-1 was silenced by shRNA-NRF-1 to evaluate the significance of NRF-1. ELISA was used to evaluate the secreted fibronectin. Immunofluorescence staining was used to assay the in situ expression of proteins (e.g. fibronectin, NRF-1).
Under renal fibrosis conditions, TGF-β1 (5ng/ml) increased ROS. Simultaneously, TGF-β1-induced extracellular fibronectin by ELISA assay. In addition, TGF-β1 decreased expression of mitochondrial biogenesis. This is the first time to demonstrate that expression of NRF-1 is significantly decreased in renal fibrosis. However, NRK49F was a transfection with pcDNA-NRF-1 (2μg/ml) expression vector dramatically reverse TGF-β1-induced cellular fibrosis concomitantly with the suppression of fibronectin (both intracellular and extracellular fibronectin). More importantly, transfection with shRNA-NRF-1 (2μg/ml) significantly increased the expression of fibronectin of both intercellular and extracellular origins in NRK-49F cells.
These finding suggest that NRF-1 plays a pivotal role on renal cellular fibrosis. Moreover, NRF-1 might act as a novel renal fibrosis antagonist by down-regulating fibrosis signaling in renal fibroblast cells.
With the development of mHealth, it is possible to treat patients in their natural environment. Mobile technology helps to bridge the gap between the therapist's office and the "real world." The ACT in Daily Life training (ACT-DL) was designed as an add-on intervention to help patients practice with acceptance and commitment therapy in their daily lives. The ACT-DL consists of two main components: daily monitoring using experience sampling and ACT training in daily life.
To assess the acceptability and feasibility of the ACT-DL in a general outpatient population. A secondary objective was to conduct a preliminary examination of the effectiveness of the ACT-DL.
An observational comparative study was conducted. The experimental group consisted of 49 patients who volunteered for ACT-DL, and the control group consisted of 112 patients who did not volunteer. As part of an inpatient treatment program, both groups received a 6-week ACT training. Participants went home to continue their treatment on an outpatient basis, during which time the experimental group received the 4-week add-on ACT-DL. Acceptability and feasibility of the ACT-DL was assessed weekly by telephone survey. Effectiveness of the ACT-DL was evaluated with several self-report questionnaires ( Flexibility Index Test (FIT-60): psychological flexibility, Brief Symptom Inventory: symptoms, Utrechtse Coping List: coping, and Quality of life visual analog scale (QoL-VAS): quality of life).
More than three-quarters of the participants (76%) completed the full 4-week training. User evaluations showed that ACT-DL stimulated the use of ACT in daily life: participants practiced over an hour a week (mean 78.8 minutes, standard deviation 54.4), doing 10.4 exercises (standard deviation 6.0) on average. Both ACT exercises and metaphors were experienced as useful components of the training (rated 5 out of 7). Repeated measures ANCOVA did not show significant effects of the ACT-DL on psychological flexibility (P=.88), symptoms (P=.39), avoidant coping (P=.28), or quality of life (P=.15).
This is the first study that uses experience sampling to foster awareness in daily life in combination with acceptance and commitment therapy to foster skill building. Adherence to the ACT-DL was high for an intensive mHealth intervention. ACT-DL appears to be an acceptable and feasible mHealth intervention, suitable for a broad range of mental health problems. However, short-term effectiveness could not be demonstrated. Additional clinical trials are needed to examine both short-term and long-term effects.
The case of Ms. L. provides a wonderful opportunity to highlight the underlying value commitments that often deeply influence decisionmaking in medicine and more specifically in innovative neurosurgical procedures. In order to give a fair opinion on how Dr. Impf, as clinician and researcher, should act, a much richer and thicker understanding of the actual perspectives of the stakeholders would be necessary. Because this is not available, I highlight three important elements: the terms under which the deep brain stimulation (DBS) is implanted, the proper goals of a healthcare team, and the fallacy of a "natural" or immutable self. These elements are brought together in this case by a set of unexpected effects on the patient that were not intended and that are judged and categorized differently by various stakeholders within the case. In the end, I hope that there was full transparency and agreement about obligations, responsibilities, and outcomes prior to the implantation of the DBS between the physician and patient. Further, it is important to remember that just because a result is serendipitous does not mean that it should be discounted as a proper benefit. Finally, each person authors variations on their own self that are molded by environment and social networks. If Ms. L. continues to demonstrate an ability to author a desired self, the DBS is no more inappropriate a tool than many other artifacts that are used regularly by others to mold themselves.
Artemisinin-based combination therapy (ACT) has been adopted as national policy for the first-line treatment in large number of malaria-endemic regions. However, artemisinin-resistant parasites have emerged and are spreading, with slow-cleaning parasites being reported in patients treated with ACT. It means that more parasites are exposed to the partner drug alone and the risk of developing resistant parasites against the partner drug is increasing. Therefore, the development of a new method to enhance the effect of artemisinin is required. In this study, the potential effect of probucol as a combination drug of dihydroartemisinin (DHA), an artemisinin derivative, was examined.
C57BL/6 J mice infected with Plasmodium yoelii XL-17 were treated with probucol and/or DHA. The mice were fed with a probucol mixed diet from 2 weeks before infection and through infection period. DHA was injected to mice three to 5 days post infection once a day. In addition, 0.5 % (w/w) probucol was mixed with vitamin E supplemented diet (800 mg/kg) and fed to mice infected with P. yoelii XL-17 to examine the mechanisms of probucol on murine malaria. Furthermore, 8-OHdG, a biomarker of oxidized DNA, was detected in infected red blood cells (iRBC) taken from infected mice by immunofluorescent staining.
With dose-dependent manner, both probucol and DHA decreased parasitaemia and increased survival rate of mice infected with P. yoelii XL-17. A significantly larger amount of 8-OHdG was detected in iRBC taking from probucol-treated mice than control mice. In addition, a large amount of vitamin E supplementation eliminated the effect of probucol against P. yoelii XL-17 infection and lowered the effect of probucol on host plasma vitamin E concentration. The effective doses for probucol and DHA were 0.5 % and 30 mg/kg, respectively, in each single treatment. While the combination treatment of 0.25 % probucol and 7.5 mg/kg DHA was effective in all mice from P. yoelii XL-17 infection.
This study demonstrated that probucol has some impact on malaria by oxidative stress through the induction of host plasma
 vitamin E deficiency. Moreover, the effective dose of DHA on malaria was decreased by prophylactic treatment of probucol. This finding indicates that probucol might be a candidate for a prophylactic treatment drug to enhance the effect of DHA.
The literature on human and animal learning suggests that individuals attend to and act on cues differently based on the order in which they were learned. Recent studies have proposed that one specific type of learning outcome, the highlighting effect, can serve as a framework for understanding a number of early cognitive milestones. However, little is known how this learning effect itself emerges among children, whose memory and attention are much more limited compared to adults. Two experiments were conducted using different versions of the general highlighting paradigm: Experiment 1 tested 3 to 6 year olds with a newly developed image-based version of the paradigm, which was designed specifically to test young children. Experiment 2 tested the validity of an image-based implementation of the highlighting paradigm with adult participants. The results from Experiment 1 provide evidence for the highlighting effect among children 3-6 years old, and they suggest age-related differences in dividing attention among multiple cues during learning. Experiment 2 replicated results from previous studies by showing robust biases for both image-based and text-based versions of the highlighting task. This study suggests that sensitivity to learning order emerges early through the process of cued attention, and the role of the highlighting effect in early language learning is discussed.
The diversity of sex chromosomes among amniotes is the product of independent evolution of different systems in different lineages, defined by novel sex-determining genes. Convergent evolution is very common, suggesting that some genes are particularly adept at taking on a sex-determining role. Comparative gene mapping, and more recently whole genome sequencing, have now turned up other surprising relationships; different regions of the amniote genome that have become sex determining in some taxa seem to share synteny, or share sequence, in others. Is this, after all, evidence that these regions were once linked in a super-sex chromosome that underwent multiple fission in different ways in different amniote lineages? Or does it signify that special properties of sex chromosomes (paucity of active genes, low recombination, epigenetic regulation to achieve dosage compensation) predispose particular chromosomes to a sex-determining role?
Recent research has demonstrated that the endogenous cannabinoid system is central to the brain's response to stress. As part of an ongoing collaboration, we sought to examine the effects of prenatal and early postnatal rearing and housing conditions on developing endocannabinoid systems. We compare brain cannabinoid receptors (CBR) in offspring of either prenatal vehicle intubated or non-treated dams (Experiment 1) or in rats derived from a vendor and shipped at weaning to a collaborating lab (Experiment 2). From postnatal day (PND) 23, all rats were either housed in isolated conditions or enriched conditions with 3 rats/cage and a variety of stimulus objects changed twice a week. All rats underwent 5days of handling as controls for a behavior study and all rats were sacrificed at approximately PND48-50 within 2hours of the last behavioral test. All brains were processed together for CB1 receptor binding using (3)H CP55,940 in prefrontal cortex, striatum, amygdala and hippocampus. Conditions in the two labs were as similar as possible since the two studies were intentionally designed to be comparable and contemporary. Results show that 1) comparing offspring of non-treated dams to offspring of dams receiving daily vehicle intubations, males show decreased CB1 binding in most brain regions while females only showed alterations in the hippocampus and these were increases in the offspring of the vehicle-intubated dams. 2) When comparing offspring of non-treated dams in NY with those derived from a vendor, shipped and maintained in the collaborating lab, this latter group showed reduced CB1 binding in prefrontal cortex in males and increased binding in all four brain regions in females. Therefore, overall, both prenatal handling (intubations) and being vendor-derived, shipped and maintained in a collaborating facility reduced CB1 receptors in males and increased them in females in key limbic brain regions. Effects of environmental enrichment or isolation were minor with only the prefrontal cortex showing an increase in binding in the isolated animals that were offspring of the vehicle-intubated dams. These results support the ideas that prenatal/early postnatal conditions produce different effects in males and females and override the effects of enrichment/isolation on cannabinoid receptors. Behavioral responses to cannabinoid challenges would therefore be expected to vary depending on sex, prenatal/early postnatal history and postweaning conditions of the rats. Since exogenous cannabinoids act through the CBR, the present data may provide a molecular basis for discrepant behavioral effects reported across various labs in the literature as well as sex differences seen following stress and/or manipulation of the cannabinoid system.
Green tea has been shown to have beneficial effects against a variety of diseases such as cancer, obesity, diabetes, cardiovascular disease, and neurodegenerative diseases. Through cellular, animal, and human experiments, green tea and its major component, epigallocatechin-3-gallate (EGCG) have been demonstrated to have anti-inflammatory effects. Our previous findings have indicated that green tea and EGCG suppress the gene and/or protein expression of inflammatory cytokines and inflammation-related enzymes.
Using bibliographic databases, particularly PubMed (provided by the US National Library of Medicine, National Institutes of Health, United States), we examined the potential usefulness of green tea/EGCG for the prevention and treatment of inflammatory diseases in human clinical and epidemiological studies. We also reviewed results from cellular and animal experiments and proposed action mechanisms.
Most of the results from the human studies indicated the beneficial effects of green tea and tea catechins against inflammatory diseases. The cellular and animal studies also provided evidence for the favorable effects of green tea/EGCG. These results are compatible with our previous findings and can be largely explained by a mechanism wherein green tea/EGCG acts as an antioxidant to scavenge reactive oxygen species, leading to attenuation of nuclear factor-κB activity.
Since green tea and EGCG have multiple targets and act in a pleiotropic manner, we may consider their usage to improve the quality of life in patients with inflammatory disease. Green tea and EGCG have beneficial health effects and no severe adverse effects; however, care should be taken to avoid overdosage, which may induce deleterious effects including hepatic injury.
Glucose-1-Phosphate Thymidylyltransferase (RmlA) is one of the enzymes in rhamnose biosynthesis pathway, where rhamnose act as linker of peptidoglycan and arabinogalacton in the cell wall, therefore RmlA is a potential enzyme for the survival of Mycobacterium tuberculosis (Mtb). To go into the depth of the structure for exploring binding regions, homology model of RmlA was built in Prime, Schrodinger v9.2. The model with lowest Discrete Optimized Potential Energy (DOPE) score of -35524.17 kcal/mol and RMSD of 0.1 Å with the template (1H5R_B) was subjected to Molecular Dynamics Simulation (MDS) for 5 ns to achieve its stable folding state. The tertiary structure of the proposed model is composed of α/β/α sandwich type protein with quasi-Rossmann type folding pattern. The substrate, deoxy Thymidine tri phosphate (dTTP) comprises of triphosphate (R1) and methyl (R2) side chains where, R1 is highly essential for the survival of Mtb. Therefore, nineteen side chain analogues of dTTP were designed by substituting R1 and R2 chain of dTTP using Combi Glide, Schrodinger v9.2 and docked with the target RmlA protein. Out of which two analogues that is, 6-[(2R,3S,5R)-5-[5-(2-aminoethyl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidin-1-yl]-3-hydroxyoxolan-2 yl] hexanoic acid (COMP-11) and 4-(2-{1-[(1S,3S,4S)-3-(5-carboxypentyl)-4-hydroxy-2-methylidenecyclopentyl]-2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl}ethyl)morpholin-4-ium (COMP-12) showed the highest GLIDE score (-12.55 Kcal/mol and -11.58 Kcal/mol respectively) than that of substrate (-9.725 Kcal/mol). During simulations, hydrogen bonding profile between the two top hits and protein ranges up to 5 strong polar contacts which were much stronger than that of substrate. Similarly, the computational binding free energy of both the analogues was found to be less than -70 Kcal/mol which is much lower than that of substrate (-52.84 Kcal/mol). All these results suggest that these two compounds have more stable interaction than that of substrate inside the solvent condition and can be used as competitive inhibitors.
Ecological speciation occurs when populations evolve reproductive isolation as a result of divergent natural selection. This isolation can be influenced by many potential reproductive barriers, including selection against hybrids, selection against migrants and assortative mating. How and when these barriers act and interact in nature is understood for relatively few empirical systems. We used a mark-recapture experiment in a contact zone between lake and stream three-spined sticklebacks (Gasterosteus aculeatus, Linnaeus) to evaluate the occurrence of hybrids (allowing inferences about mating isolation), the interannual survival of hybrids (allowing inferences about selection against
 hybrids) and the shift in lake-like vs. stream-like characteristics (allowing inferences about selection against migrants). Genetic and morphological data suggest the occurrence of hybrids and no selection against hybrids in general, a result contradictory to a number of other studies of sticklebacks. However, we did find selection against more lake-like individuals, suggesting a barrier to gene flow from the lake into the stream. Combined with previous work on this system, our results suggest that multiple (most weakly and often asymmetric) barriers must be combining to yield substantial restrictions on gene flow. This work provides evidence of a reproductive barrier in lake-stream sticklebacks and highlights the value of assessing multiple reproductive barriers in natural contexts.
Migration is a key cellular function with important implications in cell physiology. Impairment of such function is observed in angiogenesis, cancer, central nervous system development, and many other physiological and pathological events. Serum is considered among the most potent physiological chemotactic stimuli. Transglutaminase 2 (TG2) is involved in most of the mentioned processes, suggesting the hypothesis that TG2 may modulate cell movement and chemotaxis by acting on serum factors. Cell biology and biochemistry studies confirmed this hypothesis, showing that human serum contains potent chemotactic signals significantly impaired by activated TG2. Bioinformatics studies indicated that one potent serum factor potential substrate of TG2-dependent transamidation is platelet-derived growth factor-BB (PDGF-BB). Cell biology and immunometric experiments carried out with U87MG human glioma cell line showed that human recombinant PDGF-BB pre-incubated with calcium-activated TG2 lost about 70 % of its chemotactic activity and antigenicity. These data indicate that PDGF-BB is a substrate of TG2-transamidating activity, and such modification may play a key role in the modulation of PDGF's chemotactic features. Further, these findings suggest a novel point of view to study the extracellular functions of TG2 and to understand how protein signals, such as growth factors and cytokines, act in the extracellular space to reach their specific targets.
Functional somatic syndromes (FSS) are common in adolescents, characterised by severe disability and reduced quality of life. Behavioural treatments such as acceptance and commitment therapy (ACT) has shown promising results in children and adolescents with FSS, but has focused on specific syndromes such as functional pain. The current study will compare the efficacy of group-based ACT with that of enhanced usual care (EUC) in adolescents with a range of FSS operationalised by the unifying construct of multiorgan bodily distress syndrome (BDS).
A total of 120 adolescents aged 15-19 and diagnosed with multiorgan BDS, of at least 12 months duration, will be assessed and randomised to either: (1) EUC: a manualised consultation with a child and adolescent psychiatrist and individualised treatment plan or (2) manualised ACT-based group therapy plus EUC. The ACT programme consists of 9 modules (ie, 27 hours) and 1 follow-up meeting (3 hours). The primary outcome is physical health, assessed by an Short Form Health Survey (SF-36) aggregate score 12 months after randomisation. Secondary outcomes include self-reported symptom severity, symptom interference, depression and anxiety, illness worry, perceived stress and global improvement; as well as objective physical activity and bodily stress response measured by heart rate variability, hair cortisol and inflammatory biomarkers. Process measures are illness perception, illness-related behaviour and psychological flexibility.
The study is conducted in accordance with Helsinki Declaration II. Approval has been obtained from the Science Ethics Committee of the Central Denmark Region and the Danish Data Protection. The results will be sought to be published according to the CONSORT statement in peer-reviewed journals.
This is one of the first larger randomised clinical trials evaluating the effect of a group-based intervention for adolescents with a range of severe FSS.
NCT02346071; Pre-results.
Caudatin, a C-21 steroidal glyco-side isolated from Chinese herbs, has a long history of use for the treatment of multiple diseases, including cancers. However, the precise mechanisms of actions of caudatin in human uterine cancer cells remain unclear. In this study, we investigated the molecular mechanisms by which caudatin inhibits cell growth in human cervical carcinoma cell line (HeLa) and endometrial carcinoma cell line (HEC-1A). Treatment with caudatin promoted cell morphology change, inhibited cell proliferation, colony formation, migration and spheroid formation, and induced cell apoptosis. Our results showed that the expression of tumor necrosis factor; α-induced protein 1 (TNFAIP1) was downregulated in uterine cancer cells and tissues compared to paired adjacent non-tumor uterine tissues. Further molecular mechanism study showed that caudatin can directly regulate TNFAIP1 expression in a concentration-dependent manner and also associated with the downregulation of NF-κB and upregulation of BAX/BcL-2 ratio and caspase-3. Moreover, we found that overexpression of TNFAIP1 inhibits the growth and invasion, and induces apoptosis in uterine cancer cells through inhibition of the NF-κB pathway, suggesting that TNFAIP1 may act as a potential therapeutic target for the treatment of cancer. We found that caudatin inhibited tumorigenicity and upregulated TNFAIP1 in vivo. Taken together, caudatin impacts on cell proliferation, migration and apoptosis of uterine cancer cells by regulating several carcinogenesis-related processes, including a novel mechanism involving the targeting of TNFAIP1/NF-κB signaling. Our findings provide new insights into understanding the anticancer mechanisms of caudatin in human uterine cancer therapy.
We have previously shown that a non-structural protein 1 (NS1)-binding monoclonal antibody, termed as 2H6, can significantly reduce influenza A virus (IAV) replication when expressed intracellularly. In this study, we further showed that 2H6 binds stronger to the NS1 of H5N1 than A/Puerto Rico/8/1934(H1N1) because of an amino acid difference at residue 48. A crystal structure of 2H6 fragment antigen-binding (Fab) has also been solved and docked onto the NS1 structure to reveal the contacts between specific residues at the interface of antibody-antigen complex. In one of the models, the predicted molecular contacts between residues in NS1 and 2H6-Fab correlate well with biochemical results. Taken together, residues N48 and T49 in H5N1 NS1 act cooperatively to maintain a strong interaction with mAb 2H6 by forming hydrogen bonds with residues found in the heavy chain of the antibody. Interestingly, the pandemic H1N1-2009 and the majority of seasonal H3N2 circulating in humans since 1968 has N48 in NS1, suggesting that mAb 2H6 could bind to most of the currently circulating seasonal influenza A virus strains. Consistent with the involvement of residue T49, which is well-conserved, in RNA binding, mAb 2H6 was also found to inhibit the interaction between NS1 and double-stranded RNA.
One important benefit gained by the millions of Americans with health insurance through the Affordable Care Act (ACA) is protection from high out-of-pocket health spending. While Medicaid unambiguously reduces out-of-pocket premium and medical costs for low-income people, it is less certain that marketplace coverage and other types of insurance purchased to comply with the law's individual mandate also protect from high health spending. Goal: To compare out-of-pocket spending in 2014 to spending in 2013; assess how this spending changed in states where many people enrolled in the marketplaces relative to states where few people enrolled; and project the decline in the percentage of people paying high amounts out-of-pocket. Methods: Linear regression models were used to estimate whether people under age 65 spent above certain thresholds. Key findings and conclusions: The probability of incurring high out-of-pocket costs and premium expenses declined as marketplace enrollment increased. The percentage reductions were greatest among those with incomes between 250 percent and 399 percent of poverty, those who were eligible for premium subsidies, and those who previously were uninsured or had very limited nongroup coverage. These effects appear largely attributable to marketplace enrollment rather than to other ACA provisions or to economic trends.
With the issuance of this final rule, the Drug Enforcement Administration places quinolin-8-yl 1-pentyl-1H-indole-3-carboxylate (PB-22; QUPIC), quinolin-8-yl 1-(5-fluoropentyl)-1H-indole-3-carboxylate (5-fluoro-PB-22; 5F-PB-22), N-(1-amino-3-methyl-1-oxobutan-2-yl)-1-(4-fluorobenzyl)-1H-indazole-3-carboxamide (AB-FUBINACA) and N-(1-amino-3,3-dimethyl-1-oxobutan-2-yl)-1-pentyl-1H-indazole-3-carboxamide (ADB-PINACA), including their salts, isomers, and salts of isomers whenever the existence of such salts, isomers, and salts of isomers is possible, into schedule I of the Controlled Substances Act. This scheduling action is pursuant to the Controlled Substances Act which requires that such actions be made on the record after opportunity for a hearing through formal rulemaking. This action imposes the regulatory controls and administrative, civil, and criminal sanctions applicable to schedule I controlled substances on persons who handle (manufacture, distribute, reverse distribute, import, export, engage in research, conduct instructional activities or chemical analysis, or possess), or propose to handle PB-22, 5F-PB-22, AB-FUBINACA, or ADB-PINACA.
The federal Mental Health Parity and Addiction Equity Act (MHPAEA) sought to eliminate historical
 disparities between insurance coverage for behavioral health (BH) treatment and coverage for medical treatment. Our objective was to evaluate MHPAEA's impact on BH expenditures and utilization among "carve-in" enrollees.
We received specialty BH insurance claims and eligibility data from Optum, sampling 5,987,776 adults enrolled in self-insured plans from large employers. An interrupted time series study design with segmented regression analysis estimated monthly time trends of per-member spending and use before (2008-2009), during (2010), and after (2011-2013) MHPAEA compliance (N=179,506,951 member-month observations). Outcomes included: total, plan, patient out-of-pocket spending; outpatient utilization (assessment/diagnostic evaluation visits, medication management, individual and family psychotherapy); intermediate care utilization (structured outpatient, day treatment, residential); and inpatient utilization.
MHPAEA was associated with increases in monthly per-member total spending, plan spending, assessment/diagnostic evaluation visits [respective immediate increases of: $1.05 (P=0.02); $0.88 (P=0.04); 0.00045 visits (P=0.00)], and individual psychotherapy visits [immediate increase of 0.00578 visits (P=0.00) and additional increases of 0.00017 visits/mo (P=0.03)].
MHPAEA was associated with modest increases in total and plan spending and outpatient utilization; for example, in July 2012 predicted per-enrollee plan spending was $4.92 without MHPAEA and $6.14 with MHPAEA. Efforts should focus on understanding how other barriers to BH care unaddressed by MHPAEA may affect access/utilization. Future research should evaluate effects produced by the Affordable Care Act's inclusion of BH care as an essential health benefit and expansion of MHPAEA protections to the individual and small group markets.
Biological metal ions, including Co, Cu, Fe, Mg, Mn, Mo, Ni and Zn ions, are necessary for the survival and the growth of all microorganisms. Their biological functions are linked to their particular chemical properties: they play a role in structuring macromolecules and/or act as co-factors catalyzing diverse biochemical reactions. These metal ions are also essential for microbial pathogens during infection: they are involved in bacterial metabolism and various virulence factor functions. Therefore, during infection, bacteria need to acquire biological metal ions from the host such that there is competition for these ions between the bacterium and the host. Evidence is increasingly emerging of "nutritional immunity" against pathogens in the hosts; this includes strategies making access to metals difficult for infecting bacteria. It is clear that biological metals play key roles during infection and in the battle between the pathogens and the host. Here, we summarize current knowledge about the strategies used by Pseudomonas aeruginosa to access the various biological metals it requires. P. aeruginosa is a medically significant Gram-negative bacterial opportunistic pathogen that can cause severe chronic lung infections in cystic fibrosis patients and that is responsible for nosocomial infections worldwide.
To report the results of vitrectomy with platelet-rich plasma (PRP) application and gas tamponade as a rescue therapy in previously vitrectomized eyes with optic disk pit (ODP) maculopathy.
Three patients with visual loss due to persistent or recurrent ODP maculopathy who had undergone previous vitrectomy were offered application of PRP. Platelet-rich plasma was obtained by centrifugation of a blood sample from each patient. Surgery consisted of vitrectomy and internal limiting membrane peeling if the membrane had not been already removed (in two eyes). After fluid/air exchange, three drops of PRP were applied on the ODP followed by 8% C3F8 tamponade. Immediately after surgery, the patient remained supine for 30 minutes and then kept a face-down position for 2 weeks.
Optic disk pit maculopathy improved as soon as two weeks after surgery and resolved in all eyes between six and eight months after PRP application. Patients were followed up for three years, with no recurrences. Visual acuity remained stable in one eye and improved in two eyes.
Vitrectomy with PRP application may be useful as a rescue therapy in patients with refractory ODP maculopathy. Platelet-rich plasma may act by promoting the closure of the communication between the vitreous and the intraretinal/subretinal space at the pit. This treatment may avoid potentially harmful maneuvers that have been used to treat ODP maculopathy.
Therapy-related consequences of treatment for type 1 diabetes mellitus (T1DM), such as weight gain and hypoglycaemia, act as a barrier to attaining optimal glycaemic control, indirectly influencing the incidence of vascular complications and associated morbidity and mortality. This study quantifies the individual and combined contribution of changes in hypoglycaemia frequency, weight and HbA1c to predicted quality-adjusted life-years (QALYs) within a T1DM population.
We describe the Cardiff Type 1 Diabetes (CT1DM) Model, originally informed by the Diabetes Control and Complications Trial (DCCT) and updated with the Epidemiology of Diabetes Interventions and Complications (EDIC) study and Swedish National Diabetes Registry for microvascular and cardiovascular complications respectively. We report model validation results and the QALY impact of HbA1c, weight and hypoglycaemia changes.
Validation results demonstrated coefficients of determination for clinical endpoints of R2 = 0.863 (internal R2 = 0.999; external R2 = 0.823), costs R2 = 0.980 and QALYs R2 = 0.951. Achieving and maintaining a 1% HbA1c reduction was estimated to provide 0.61 additional discounted QALYs. Weight changes of ±1kg, ±2kg or ±3kg led to discounted QALY changes of ±0.03, ±0.07 and ±0.10 respectively, while modifying hypoglycaemia frequency by -10%, -20% or -30% resulted in changes of -0.05, -0.11 and -0.17. The differences in discounted costs, life-years and QALYs associated with HbA1c 6% versus 10% were -£19,037, 2.49 and 2.35 respectively.
Using a model updated with contemporary epidemiological data, this study presents an outcome-focused perspective to assessing the health economic consequences of differing levels of glycaemic control in T1DM with and without weight and hypoglycaemia effects.
Steroid hormones and their nuclear receptors play a major role in the development and progression of breast cancer. MCF-7 cells are triple-positive breast cancer cells expressing estrogen receptor (ER), progesterone receptor (PR), and glucocorticoid receptor (GR). However, interaction and their role in expression pattern of activator protein (AP-1) transcription factors (TFs) are not completely understood. Hence, in our study, MCF-7 cells were used as an in vitro model system to study the interplay between the receptors and hormones. MCF-7 cells were treated with estradiol-17β (E2), progesterone (P4), and dexamethasone (Dex), alone or in combination, to study the proliferation of cells and expression of AP-1 genes. MTT assay results show that E2 or P4 induced the cell proliferation by more than 35 %, and Dex decreased the proliferation by 26 %. E2 and P4 are found to increase ERα by more than twofold and c-Jun, c-Fos, and Fra-1 AP-1 TFs by more than 1.7-fold, while Dex shows opposite effect of E2- or P4-induced effect as well as effect on the expression of nuclear receptors and AP-1 factors. E2 antagonist Fulvestrant (ICI 182,780) found to reduce proliferation and E2-induced expression of AP1-TFs, while P4 or Dex antagonist Mifepristone (RU486) is found to block GR-mediated expression of NRs and AP-1 mRNAs. Results suggest that E2 and P4 act synergistically, and Dex acts as an antagonist of E2 and P4.
To determine the effect of wearing compression socks between repeated running bouts on perceptual, physiological and performance-based parameters.
Twelve well-trained male runners (mean ± SD; 5km time 19:24 ± 1:19 mm:ss) recorded their perceptions on the efficacy of compression socks for recovery prior to completion of two experimental sessions. Each session consisted of two 5km running time trials (TT1 and TT2) on a treadmill, with a one-hour recovery period between each TT. In a randomised cross-over design, one session required participants to wear compression socks during the recovery period (COMP), while no compression socks were worn between TTs in the other session (CON).
Running performance between TT1 and TT2 in COMP was similar between TTs (mean Δ ± SD; 5.3 ± 20.7s, d=0.07, p=0.20) while for CON, performance significantly decreased in the second TT (mean Δ; 15.9 ± 13.3s, d=0.19, p<0.01). When grouped by perception of efficacy for compression socks, participants with strong beliefs (n=7) experienced improved subsequent running performance with COMP (mean Δ; -3.6 ± 19.2s, d=0.05, p=0.32) compared to those with neutral or negative perceptions (n=5, mean Δ; 17.9 ± 17.0s, d=0.19, p=0.04). Cross-sectional area of the calf and muscle soreness were significantly reduced during the recovery period with the use of COMP (p<0.01), while ratings of fatigue showed no difference between conditions.
Wearing compression socks between repeated running bouts can aid recovery and subsequent performance. Furthermore, subsequent exercise performance may be even further enhanced when athletes believe in the efficacy of compression socks to assist in recovery between exercise bouts.
Glioblastoma (GBM) is the most frequent and aggressive tumour in the central nervous system. Many studies have demonstrated that upregulation of the NF-κB onco-pathway is accompanied by the acquisition of Temozolomide (TMZ) resistance in GBM cells. Here, we show that RGFP109, a selective histone deacetylase (HDAC1 and HDAC3) inhibitor, overcomes TMZ resistance and downregulates the expression of NF-κB-regulated
 pro-survival genes in a TMZ-resistant (TR) GBM cell line. RGFP109 did not alter the phosphorylation levels of NF-κB/p65 or inhibitory κBα (IκBα). Immunofluorescence microscopy showed that RGFP109 does not block the nuclear translocation of NF-κB/p65. However, co-immunoprecipitation assays revealed that RGFP109 induces the hyperacetylation of NF-κB/p65 and histones, and blocks interactions between NF-κB/p65 and its coactivators, p300 and p300/CBP-associated factor (PCAF). These results indicate that RGFP109-mediated post-translational nuclear acetylation may be involved in the regulation of NF-κB. Electrophoretic mobility shift assays revealed that RGFP109 reduces NF-κB/p65 binding to κB-DNA and decreased the transcriptional level of κB-mediated genes, suggesting that RGFP109-induced hyperacetylation leads to attenuated transcription of the κB gene. In addition, RGFP109 elevates the expression of inhibitor of growth 4 (ING4), which is typically downregulated in GBM cells. Importantly, we found that RGFP109 enhances ING4 recognition and binding to NF-κB/p65, which may be positively correlated with reduced interactions between NF-κB/p65 and p300/PCAF, thereby effecting transcription of the κB gene. Finally, we show that knockdown of ING4 with plasmids containing pcDNA3.1-ING4 shRNA abolished the effect of RGFP109. Therefore, ING4 may act as a corepressor and facilitate RGFP109-triggered suppression of the NF-κB pathway. Taken together, our data show that RGFP109, an HDAC inhibitor, in combination with TMZ may be a therapeutic candidate for patients with temozolomide-resistant GBM.
In animal communication, signallers and recipients are typically different: each signal is given by one subset of individuals (members of the same age, sex, or social rank) and directed towards another. However, there is scope for signaller-recipient interchangeability in systems where most signals are potentially relevant to all age-sex groups, such as great ape gestural communication. In this study of wild bonobos (Pan paniscus), we aimed to discover whether their gestural communication is indeed a mutually understood communicative repertoire, in which all individuals can act as both signallers and recipients. While past studies have only examined the expressed repertoire, the set of gesture types that a signaller deploys, we also examined the understood repertoire, the set of gestures to which a recipient reacts in a way that satisfies the signaller. We found that most of the gestural repertoire was both expressed and understood by all age and sex groups, with few exceptions, suggesting that during their lifetimes all individuals may use and understand all gesture types. Indeed, as the number of overall gesture instances increased, so did the proportion of individuals estimated to both express and understand a gesture type. We compared the community repertoire of bonobos to that of chimpanzees, finding an 88 % overlap. Observed differences are consistent with sampling effects generated by the species' different social systems, and it is thus possible that the repertoire of gesture types available to Pan is determined biologically.
This study aims to determine the factors that act as barriers to Saudi cancer patients in participating in a clinical trial (CT). A total of 244 patients from two different tertiary level hospitals (King Khalid University Hospital and King Fahad Medical City Hospital) in Riyadh, Saudi Arabia, participated in this cross-sectional study. The participants were interviewed by a trained researcher between September and November 2015. All respondents answered a three-part questionnaire which includes demographics, clinical information, and questions related to awareness of CTs, willingness to participate, and factors affecting participation in CTs. The mean age of the participants was 50.83, and 57 % of the participants were females. Most of the participants (63.5 %) were currently being treated for cancer, and 28 % were diagnosed with breast cancer followed by colorectal cancer. Health status or quality of life was self-reported as acceptable by 27.9 % of the participants, and 25 % of the participants at stage II of cancer. The factors that act as barriers to Saudi cancer patients in participating in a CT can be categorized into patient- and physician-related factors. Patient factors include lack of awareness, misconception and fear in participating in CTs; physician-related factors comprise of lack of encouragement from physician to patients in participating in a CT. The study identified few major barriers to participation in CTs. Increased patient awareness and recruitment strategies are required to increase accrual of patients including training for physicians and disseminating easy-to-read tools to the public.
SUMO-specific proteases, known as Ulps in baker's yeast and SENPs in humans, have important roles in controlling the dynamics of SUMO-modified proteins. They display distinct modes of action and specificity, in that they may act on the SUMO precursor, mono-sumoylated, and/or polysumoylated proteins, and they might be specific for substrates with certain SUMO paralogs. SUMO chains may be dismantled either by endo or exo mechanisms. Biochemical characterization of a protease usually requires purification of the protein of interest. Developing a purification protocol, however, can be very difficult, and in some cases, isolation of a protease in its pure form may go along with a substantial loss of activity. To characterize the reaction mechanism of Ulps, we have developed an in vitro assay, which makes use of substrates endowed with artificial poly-SUMO chains of defined lengths, and S. cerevisiae Ulp enzymes in crude extract from E. coli. This fast and economic approach should be applicable to SUMO-specific proteases from other species as well.
Enterococci are considered as transient constituent components of the oral microbiome that may cause a variety of oral and systemic infections. As there is sparse data on the oral enterococcal prevalence, we evaluated the Enterococcus spp. and their virulence attributes including antimicrobial resistance in a healthy Brazilian cohort. A total of 240 individuals in different age groups were studied (children 4-11 yrs, adolescents 12-17 yrs, young adults 18-29 yrs, adults 30-59 yrs, elderly over 60 yrs). Oral rinses were collected and isolates were identified by API 20 Strep and confirmed by 16S rDNA sequencing. E. faecalis isolates, in particular, were evaluated for virulence attributes such as their biofilm formation potential, and susceptibility to antimicrobials and an antiseptic, chlorhexidine gluconate. A total of 40 individuals (16.6%) and 10% children, 4% adolescents, 14% young adults, 30% adults, and 25% elderly carried oral enterococci. The oral enterococcal burden in adolescents was significantly lower than in the adults (p = 0.000) and elderly (p = 0.004). The proportion of carriers was higher among females (p = 0.001). E. faecalis was the most frequent isolate in all the age groups (p = 0.000), followed by E. durans and E. faecium. Whilst all the clinical isolates were able to form biofilms, only a proportion of them were able to produce lipase (92%), hemolysin (38%), and gelatinase (39%). Of all the isolates 53.8% were resistant to tetracycline, 12.3% to amoxicillin, 16.0% to ampicillin, 20.8% to chloramphenicol and 43.4% to erythromycin. None of the isolates were resistant to vancomycin. Our data suggest that in this Brazilian cohort the oral cavity may act as a significant reservoir of rather virulent and antibiotic resistant enterococci, with an increasing degree of carriage in the adults and elderly. Hence clinicians should be cognizant of this silent reservoir of virulent enterococci that may pose a particular threat of nosocomial infection.
The study proposes a possible roadmap for the ethical assessment of sham surgery clinical trials (CTs), focusing on methodological aspects, as a result of the lack of this type of practical tool in the literature/practice.
Surgical procedures are frequently conducted without closely controlled studies. For this reason, these procedures are less rigorous than those for drug/device clinical trials. The aim of a sham (placebo) surgery CT is to carry out a surgical CT with a legitimate control group. The use of sham surgery is controversial from an ethical point of view.
This evaluation system is set up according to ICH/GCP, World Medical Association Declaration of Helsinki, CONSORT 2010 standards. The proposed roadmap is based on the following 4 steps/levels: safety/clinical indications; adequacy of trial methodology/design adopted for a sham surgery CT; specific informed consent, and economic issues.
A flowchart is proposed which can be used at two levels: as a basic guideline for the design of a surgical protocol representing a benchmark level of care; and a multiaxial assessment considering the first two sources of morality of human acts according to Aristotelian ethics: the object of the act (step 1) and some of its circumstances (steps 2-4).
The use of a placebo and of double-blind control groups in surgery CTs would improves the quality of results, providing that an accurate ethical assessment procedure is in place, firstly to ensure patient safety and secondly to prevent abuses/procedural biases. Future testing of the proposed flowchart is outlined.
To examine President Obama's fiscal commitment to the Ryan White Program (formerly Ryan White Comprehensive AIDS Resource Emergency Act), which provides funding for economically disadvantaged people and families affected by HIV.
We analyzed budgetary request and congressional appropriation data from 2009 to 2016. The data are available from the Health Resources and Services Administration and the Henry J. Kaiser Family Foundation.
Increased coverage for people living
 with HIV/AIDS provided by the Affordable Care Act most likely led the Obama administration to request small increases and at times decreases in funding for the Ryan White Program. Congress passed either small increases or decreases in appropriations for the Ryan White Program.
Decreases or small increases in the Ryan White Program funding risk progress made in treating HIV among economically disadvantaged patients.
Pursuant to passage of the Patient Protection and Affordable Care Act, the National Center for Health Statistics has enhanced the content of the National Health Interview Survey (NHIS)-the primary source of information for monitoring health and health care use of the US population at the national level-in several key areas and has positioned the NHIS as a source of population health information at the national and state levels. We review recent changes to the NHIS that support enhanced health reform monitoring, including new questions and response categories, sampling design changes to improve state-level analysis, and enhanced dissemination activities. We discuss the importance of the NHIS, the continued need for state-level analysis, and suggestions for future consideration.
The Texas Medicaid 1115 Transformation Waiver reforms the state's safety net systems by creating a Delivery System Reform Incentive Payment incentive pool for innovative healthcare delivery. The Waiver supports the design and implementation of transformative projects. As part of the Waiver requirements, regions created Learning Collaboratives to collaborate on project implementation and outcomes. This paper describes the experience of one region in adapting the Institute for Healthcare Improvement Breakthrough Series (IHI BTS) model, as a framework for their Learning Collaborative. Implementation of the Learning Collaborative was systematic, multidimensional, and regularly evaluated. Some features of the IHI model were adapted, specifically longer Plan-Do-Check-Act cycles and the lack of a single clinical focus. This experience demonstrates the ability of a region to improve health from a more diverse perspective than the traditional IHI BTS Collaboratives. Within the region, organizations are connecting, agencies are building continuums of care, and stakeholders are involved in healthcare delivery. The initial stages show a remarkable increase in communication and enhanced relationships between providers. At the end of the 5-year Waiver, evaluation of the impact of the regional and cohort Learning Collaboratives will determine how well the adapted IHI BTS model facilitated improvements in the community's health.
Inflammasome-associated innate immune receptors sense host-cell targeting by the type III secretion system (T3SS) of pathogenic Yersinia. In this issue of Cell Host & Microbe, Chung et al. (2016) show that the Yersinia T3SS effector protein YopM counteracts this recognition pathway by restricting the pyrin inflammasome, thus increasing bacterial fitness.
Little is known about the effects that climatic conditions, especially extreme heat, have on physical activity (PA) levels. The aim of this 2-year cohort analysis undertaken in the Arabian Gulf region was to assess changes in objectively-assessed PA as a result of changes in climatic conditions.
A total of 2088 adults (1390 men and 698 women) from many regions of the world were enrolled in a community health program in Qatar, were included in this study. For 2 years participants recorded daily step count using an Omron HJ-720 ITC pedometer. Daily climate parameters included temperature, relative humidity and other conditions.
From linear mixed model analysis it was evident that higher average temperature and humidity, and the Wet bulb Globe Temperature (WbGT), resulted in a reduction of the number of steps taken per day. Analysis of interaction effects also revealed that the effects of heat stress were equivalent across gender, age, and the region participants came from according to a World Health Organization classification scheme.
Increased temperature and humidity are associated with a reduction in the number of steps taken per day. Community-based PA programs in hot hot/humid climates should consider novel approaches to increase PA levels.
In 2008 the Human Fertilisation and Embryology Act amendments made deliberately choosing to bring disability into the world, using assisted reproduction, a criminal offence. This paper considers whether the legal prohibition above, should influence other policy areas concerning the welfare of future children such as new possibilities presented by foetal surgery and in utero gene therapy. If we have legal duties to avoid disability in one context should this influence our avoidance of disability in this other context? This paper investigates whether the State might have a stake in wider promotion of practices to reduce the degree of disability in foetuses that will come to exist (as opposed to those that will be aborted). Not selecting for disability does not affect the welfare of any future individual, whereas treating in utero abnormalities can optimize the eventual child's welfare; antenatal interventions stand to improve clinical outcomes and welfare should that specific child be born. I explore why the State may want to intervene in the antenatal setting and to what extent, if at all; the State should implement these technologies. I argue that if the State is justified in intervening to outlaw the choosing to create disabled lives using assisted reproductive techniques, it is also justified in putting pressure on prospective parents to accept therapies in utero to help their child be born less disabled. However, I qualify this with the argument that the State is not justified in using force or the criminal law in this situation during pregnancy.
To evaluate the effects of naloxone on opioid-induced side effects, the present meta-analysis was constructed.
Electronic databases including PubMed, EMBASE, and CNKI (China National Knowledge Internet) were used for literature search. Studies on comparison of opioid-side effects between naloxone-treated group and placebo or normal saline-related group were included in the meta-analysis. Heterogeneity analysis was performed with Chi-square and I test. Pooled analysis was based on fixed-effects model, if heterogeneity between the eligible studies was negligible (I < 50%, P > 0.05), otherwise, random-effects model was used. Sensitivity analysis was applied to assess the robustness of the results and publication bias was evaluated by Begg and Egger test.
Thirteen studies including 1138 patients were included in the meta-analysis. Pooled analysis indicated that naloxone could significantly reduce the occurrence of pruritus (RR [risk ratio] = 0.252, 95% CI [confidence interval] = 0.137-0.464), nausea (RR = 0.323, 95% CI = 0.245-0.428), and vomiting (RR = 0.338, 95% CI = 0.192-0.593) which were induced by opioids. However, naloxone did not relieve pain (standardized mean difference [SMD] = -0.052, 95% CI = -0.453 to 0.348) and somnolence (RR = 0.561, 95% CI = 0.287 to 1.097) in patients received opioid treatment. Additionally, there were no significant publication bias between the included studies (Begg test, P = 0.602; Egger test, P = 0.388).
Addition of naloxone might act as an effective treatment for prophylaxis of opioid-induced pruritus, nausea, and vomiting in clinical practice.
Background: More than 9.6 million adults in the United States are enrolled in both Medicaid and Medicare (referred to as "dual eligible adults") in fiscal year 2010. More than $250 billion in federal and state health care benefits were estimated to have been spent for dual eligible individuals in 2009. Dual eligible individuals represented 14% of Medicaid enrollment, but accounted for 36% of Medicaid expenditures in 2010. Similarly, dual eligible individuals represented 20% of Medicare enrollment and accounted for 31% of Medicare expenditures in 2008. Dual eligible individuals were more likely to have chronic conditions than individuals who were not dually eligible and had a high proportion of potentially avoidable hospitalizations totaling an estimated $5.4 billion of Medicare and Medicaid costs in 2009. This report focuses on dual eligible adults younger than the age of 65 and the prevalence of behavioral health conditions (mental illness and/or substance use disorder). Methods: The Medical Expenditure Panel Survey (MEPS) is an ongoing household survey that yields national estimates of health care use, expenditures, insurance coverage, sources of payment, access to care, and health care quality. Using pooled years of data from the MEPS (2008-11) this report presents estimates of the average annual proportion of adults with behavioral health conditions among both the dual eligible and those not dual eligible. The report also presents estimates of average annual total health care expenditures for these respective groups. Results: Approximately 2.5 million adults aged 18 to 64 were dual eligible during any given year from 2008 to 2011. Approximately 49% of dual eligible adults aged 18 to 64 were identified as having any mental illness or substance use disorder (behavioral health conditions) within the past year, compared with 14% among adults who were not dually eligible. The average annual total health care expenditures for dual eligible adults aged 18 to 64 were $15,203, compared with $3,540 for adults who were not dually eligible. The average yearly health care expenditures for dual eligible adults aged 18 to 64 who received treatment for their behavioral health conditions were $16,803; this was twice as high as average health care expenditures among adults who were not dually eligible and received treatment for behavioral health conditions ($7,860). Conclusion: This report is one of the few to focus on describing
 the potential behavioral health needs of dual eligible adults aged 18 to 64. This report identified that close to half of adults aged 18 to 64 who were dually eligible for Medicaid and Medicare reported having behavioral health conditions in the past year; a considerably higher proportion than observed among adults who were not dually eligible. In addition, the data show that among adults aged 18 to 64 who received behavioral health care services those dually eligible have significantly greater yearly health care expenditures than adults not dually eligible. Despite some differences in data collection methods and definitions of mental illness and substance abuse these findings are predominately consistent with what has been reported from other data sources. Health care providers may want to consider the higher prevalence of behavioral health conditions when working with dual eligible adults younger than the age of 65. The Affordable Care Act (ACA) includes a number of provisions that attempt to enhance care for dual eligible recipients (e.g., establishing federal entities to improve coordination between Medicare and Medicaid and encouraging integrated care for dual eligible individuals. The implementation of ACA is expected to improve behavioral health care for these dual eligible adults.
Estimates indicate that as many as 1 in 4 Americans will experience a mental health problem or will misuse alcohol or drugs in their lifetimes. These disorders are among the most highly stigmatized health conditions in the United States, and they remain barriers to full participation in society in areas as basic as education, housing, and employment. Improving the lives of people with mental health and substance abuse disorders has been a priority in the United States for more than 50 years. The Community Mental Health Act of 1963 is considered a major turning point in America's efforts to improve behavioral healthcare. It ushered in an era of optimism and hope and laid the groundwork for the consumer movement and new models of recovery. The consumer movement gave voice to people with mental and substance use disorders and brought their perspectives and experience into national discussions about mental health. However over the same 50-year period, positive change in American public attitudes and beliefs about mental and substance use disorders has lagged behind these advances. Stigma is a complex social phenomenon based on a relationship between an attribute and a stereotype that assigns undesirable labels, qualities, and behaviors to a person with that attribute. Labeled individuals are then socially devalued, which leads to inequality and discrimination. This report contributes to national efforts to understand and change attitudes, beliefs and behaviors that can lead to stigma and discrimination. Changing stigma in a lasting way will require coordinated efforts, which are based on the best possible evidence, supported at the national level with multiyear funding, and planned and implemented by an effective coalition of representative stakeholders. Ending Discrimination Against People with Mental and Substance Use Disorders: The Evidence for Stigma Change explores stigma and discrimination faced by individuals with mental or substance use disorders and recommends effective strategies for reducing stigma and encouraging people to seek treatment and other supportive services. It offers a set of conclusions and recommendations about successful stigma change strategies and the research needed to inform and evaluate these efforts in the United States.
A critical component of the nation's economic vitality is ensuring that all Americans can contribute and prosper. Such contributions presuppose an intentional focus on achieving the highest levels of health possible, which requires that conditions in communities, schools workplaces, and other settings promote health and address the social determinants of health for all community members. Many organizations, in both the private and public sectors, have been establishing partnerships to further healthy workplaces and health equity in general. Many are taking the lead in producing economic growth that is inclusive and responsive to the nation's diverse needs and populations. Increasingly, private–public partnerships are emerging as ways of doing business. Additionally, a variety of new developments in health, health care, and community benefits obligations that are part of the Affordable Care Act have contributed to this interest in economic growth and health and in the creation of new partnerships. To examine past successes and future opportunities, the National Academies of Sciences, Engineering, and Medicine held a workshop in November 2015. The workshop focused on the potential of the private sector to produce a triple bottom line: economic opportunity (including workforce development) and growth, healthy work and community environments, and improved employee health. At the same time, participants looked beyond the private sector to public–private partnerships and to public-sector actions that combine opportunities for economic growth and good health for all. This publication summarizes the presentations and discussions from the workshop.
Chondrocytes are the exclusive cells residing in cartilage and maintain the functionality of cartilage tissue. Series of biocomponents such as different growth factors, cytokines, and transcriptional factors regulate the mesenchymal stem cells (MSCs) differentiation to chondrocytes. The number of chondrocytes and dedifferentiation are the key limitations in subsequent clinical application of the chondrocytes. Different culture methods are being developed to overcome such issues. Using tissue engineering and cell based approaches, chondrocytes offer prominent therapeutic option specifically in orthopedics for cartilage repair and to treat ailments such as tracheal defects, facial reconstruction, and urinary incontinence. Matrix-assisted autologous chondrocyte transplantation/implantation is an improved version of traditional autologous chondrocyte transplantation (ACT) method. An increasing number of studies show the clinical significance of this technique for the chondral lesions treatment. Literature survey was carried out to address clinical and functional findings by using various ACT procedures. The current study was conducted to study the pharmacological significance and biomedical application of chondrocytes. Furthermore, it is inferred from the present study that long term follow-up studies are required to evaluate the potential of these methods and specific positive outcomes.
The objective of this study is to identify high-risk groups for industrial accidents by setting up 2003 as the base year and conducting an in-depth analysis of the trends of major industrial accident indexes the index of industrial accident rate, the index of occupational injury rate, the index of occupational illness and disease rate per 10,000 people, and the index of occupational injury fatality rate per 10,000 people for the past 10 years.
This study selected industrial accident victims, who died or received more than 4 days of medical care benefits, due to occupational accidents and diseases occurring at workplaces, subject to the Industrial Accident Compensation Insurance Act, as the study population.
According to the trends of four major indexes by workplace characteristics, the whole industry has shown a decreasing tendency in all four major indexes since the base year (2003); as of 2012, the index of industrial accident rate was 67, while the index of occupational injury fatality rate per 10,000 people was 59.
The manufacturing industry, age over 50 years and workplaces with more than 50 employees showed a high severity level of occupational accidents. Male workers showed a higher severity level of occupational accidents than female workers. The employment period of < 3 years and newly hired workers with a relatively shorter working period are likely to have more occupational accidents than others. Overall, an industrial accident prevention policy must be established by concentrating all available resources and capacities of these high-risk groups.
Cognitive and behavioral treatments (CBT) for sleep problems and chronic pain have shown good results, although these results could improve. More recent developments based on the psychological flexibility model, the model underlying Acceptance and Commitment Therapy (ACT) may offer a useful addition to traditional CBT. The aim of this study was to examine whether an ACT-based treatment for chronic pain is associated with improved sleep. Secondly, we examined the associations between changes on measures of psychological flexibility and sleep-related outcomes.
The study used an observational cohort methodology. Participants were 252 patients (73.8% female) attending a 4-week, interdisciplinary, pain management program in London, United Kingdom. Participants completed standard self-report measures of pain and functioning, sleep outcomes, and processes of psychological flexibility. Pre- to post-treatment, and pre-treatment to follow-up measures were examined for statistically significant differences using paired samples t-tests. Secondarily, hierarchical multiple regression analyses were conducted to examine change in process measures in relation to change in treatment outcome.
Participants showed statistically significant improvements (all p < 0.001) at post-treatment on measures of insomnia severity (d = 0.45), sleep interference (d = 0.61), and sleep efficiency (d = 0.32). Significant improvements in insomnia severity and sleep interference were also observed at 9-month follow up. Small to medium effect sizes were observed across the sleep outcomes. Statistically significant changes were also observed on measures of
 psychological flexibility, and these improvements were significantly associated with improvements on sleep-related outcomes, independently contributing up to 19% of unique variance.
This study supports the potential usefulness of ACT-based treatments for chronic pain for addressing co-occurring sleep difficulties. Further research is needed to determine how to improve the impact of this treatment for co-morbid pain and sleep difficulties, possibly using a randomized-controlled trial design.
Various types of non-neuronal cells, including tumors, are able to produce acetylcholine (ACh), which acts as an autocrine/paracrine growth factor. T lymphocytes represent a key component of the non-neuronal cholinergic system. T cells-derived ACh is involved in a stimulation of their activation and proliferation, and acts as a regulator of immune response. The aim of the present work was to summarize the data about components of cholinergic machinery in T lymphocytes, with an emphasis on the comparison of healthy and leukemic T cells. Cell lines derived from acute lymphoblastic leukemias of T lineage (T-ALL) were found to produce a considerably higher amount of ACh than healthy T lymphocytes. Additionally, ACh produced by T-ALL is not efficiently hydrolyzed, because acetylcholinesterase (AChE) activity is drastically decreased in these cells. Up-regulation of muscarinic ACh receptors was also demonstrated at expression and functional level, whereas nicotinic ACh receptors seem to play a less important role and not form functional channels in cells derived from T-ALL. We hypothesized that ACh over-produced in T-ALL may act as an autocrine growth factor and play an important role in leukemic clonal expansion through shaping of intracellular Ca(2+) signals. We suggest that cholinergic machinery may be attractive targets for new drugs against T-ALL. Specifically, testing of high affinity antagonists of muscarinic ACh receptors as well as antagomiRs, which interfere with miRNAs involved in the suppression of AChE expression, may be the first choice options.
Large conductance calcium-activated potassium channels (or BK channels) fulfil a multitude of roles in the central nervous system. At the soma of many neuronal cell types they control the speed of action potential (AP) repolarization and therefore they can have an impact on neuronal excitability. Due to their presence in nerve terminals they also regulate transmitter release. BK channels have also been shown to be present in the dendrites of some neurons where they can regulate the magnitude and duration of dendritic spikes. Here, we investigate the impact of modulating the activation of BK channels at different locations on the cellular excitability of cortical layer 5 pyramidal neurons. We find that while somatic BK channels help to repolarize APs at the soma and mediate the fast after-hyperpolarization, dendritic BK channels are responsible for repolarization of dendritic calcium spikes and thereby regulate somatic AP burst firing. We found no evidence for a role of dendritic BK channels in the regulation of backpropagating AP amplitude or duration. These experiments highlight the diverse roles of BK channels in regulating neuronal excitability and indicate that their functional impact depends on their subcellular location.
Telehealth is becoming mainstream in the U.S., as more consumers, employers, hospital systems, and even insurers adopt the technology. The authors explore the challenges of regulation, reimbursement, and licensing as the modality evolves.
Organ donation awareness is very poor in India. We have a high demand for transplant organs with poor supply. Apnea test is the confirmatory test for brain death in our country. The Transplantation of Human Organs Act does not support any ancillary testing for the confirmation of brain death in our country. Radionuclide scan is used widely in western countries as a confirmatory test. We in our institution used this as a tool for family counseling with successful conversion rate.
The treatment of acute myeloid leukemia (AML) has made significant progress in the last 30 years; however, numerous factors affect outcomes in patients with AML. Well-known risk factors are age, cytogenetics, and treatment intensity. The purpose of our study was to investigate the effects of insurance status on the outcome of AML; age, Carlson comorbidity index, distance travelled to the treatment center, and type of treatment center were adjusted by analyzing data from National Cancer Database (NCDB). In the wake of the Affordable Care Act, and its impact on insurance coverage, evaluating the effect having insurance has on health outcome is urgently necessary.
Data were analyzed from 67,443 men and women (≥18 years of age), who were registered in the NCDB and diagnosed with AML between 1998 and 2011 with follow-up to the end of 2012. The primary predictor variable was payer status, and the outcome variable was overall survival. Additional variables addressed and adjusted, included: sex, age, race, Charleston Comorbidity index, level of education, income, distance traveled, facility type, diagnosing/treating facility, treatment delay, and chemotherapy.
In multivariate analysis, after adjusting for other predictor variables, payer status was a statistically significant predictor of overall survival for AML. Relative to privately insured patients, patients with Medicaid had a 17% increased risk, those without insurance had a 21% increased risk, those with Medicare had a 19% increased risk and those with unknown insurance status had a 22% increased risk of mortality from AML. The percentage of patients surviving from AML after 24 months was 37.6%, 31.4%, 32.3%, 31.8%, and 33.1% for patients with private, unknown, Medicare, uninsured, and Medicaid payer status, respectively. All factors investigated were found to be significant predictors of AML survival except distance traveled.
We observed that payer status has a statistically significant relationship with overall survival from AML.
Vascular surgical patients have a high rate of readmission, and the cost of readmission for these patients has not been described. Herein, we characterize and compare institutional index hospitalization and 30-day readmission cost following open and endovascular vascular procedures.
The American College of Surgeons National Surgical Quality Improvement Program database was used to identify inpatient open and endovascular procedures at a single institution, from January 2011 through June 2012. Variable and fixed costs for index hospitalization and unplanned 30-day readmissions were obtained using SAP BusinessObjects. Patient characteristics and outcome variables were analyzed using Student t tests or Wilcoxon rank-sum nonparametric tests for continuous variables and Fisher exact tests for categorical variables.
One thousand twenty-six inpatient procedures were included in the analysis. There were 605 (59%) open and 421 (41%) endovascular procedures with a 30-day unplanned readmission rate of 16.9% and 17.8%, respectively (P = .679). The mean index hospitalization costs for open and endovascular procedures were US$27 653 and US$23 999, respectively (P = .146). The mean costs for 30-day unplanned readmission for open and endovascular procedures were US$19 117 and US$17 887, respectively (P = .635). Among open procedures, the mean cost for patients not readmitted was US$28 321 compared to US$31 115 for those readmitted (P = .003). Among endovascular procedures, the mean cost for patients not readmitted was US$26 908 compared to US$32 262 for those readmitted (P = .028).
The cost of index hospitalization and 30-day unplanned readmission are similar for open and endovascular procedures. Readmitted patients had a higher mean index hospitalization cost irrespective of open or endovascular procedure.
Despite American Academy of Pediatrics (AAP) recommendations, many hospitalized infants are not observed in the appropriate safe sleep environment. Caregivers tend to model sleep patterns observed in a hospital setting. This project assessed the change in infant safe sleep practices within 6 children's hospitals after the implementation of a statewide quality improvement program.
The AAP recruited hospitalists from each of the state's children's hospitals and asked them to form "safe sleep teams" within their institutions. Teams used a standardized data tool to collect information on the infant's age and sleep position/environment. They collected baseline data and then weekly for the duration of the 12-month project. Teams were required to implement at least 3 Plan-Do-Study-Act cycles. We calculated changes in safe sleep practices over time. Providers received Maintenance of Certification Part IV credit for participation.
Teams collected 5343 audits at all participating sites. At baseline, only 279 (32.6%) of 856 of the sleeping infants were observed to follow AAP recommendations, compared with 110 (58.2%) of 189 (P < .001) at the project's conclusion. The presence of empty cribs was the greatest improvement (38.1% to 67.2%) (P < .001). Removing loose blankets (77.8% to 50.0%) (P < .001) was the most common change made. Audits also showed an increase in education of families about safe sleep practices from 48.2% to 75.4% (P < .001).
Multifactorial interventions by hospitalist teams in a multi-institutional program within 1 state's children's hospitals improved observed infant safe sleep behaviors and family report of safe sleep education. These behavior changes may lead to more appropriate safe sleep practices at home.
Selectively bred diet-induced obese (DIO) rats become obese on a high-fat diet and are leptin resistant before becoming obese. Compared with diet-resistant (DR) neonates, DIO neonates have impaired leptin-dependent arcuate (ARC) neuropeptide Y/agouti-related peptide
 (NPY/AgRP) and α-melanocyte-stimulating hormone (α-MSH; from proopiomelanocortin (POMC) neurons) axon outgrowth to the paraventricular nucleus (PVN). Using phosphorylation of STAT3 (pSTAT3) as a surrogate, we show that reduced DIO ARC leptin signaling develops by postnatal day 7 (P7) and is reduced within POMC but not NPY/AgRP neurons. Since amylin increases leptin signaling in adult rats, we treated DIO neonates with amylin during postnatal hypothalamic development and assessed leptin signaling, leptin-dependent ARC-PVN pathway development, and metabolic changes. DIO neonates treated with amylin from P0-6 and from P0-16 increased ARC leptin signaling and both AgRP and α-MSH ARC-PVN pathway development, but increased only POMC neuron number. Despite ARC-PVN pathway correction, P0-16 amylin-induced reductions in body weight did not persist beyond treatment cessation. Since amylin enhances adult DIO ARC signaling via an IL-6-dependent mechanism, we assessed ARC-PVN pathway competency in IL-6 knockout mice and found that the AgRP, but not the α-MSH, ARC-PVN pathway was reduced. These results suggest that both leptin and amylin are important neurotrophic factors for the postnatal development of the ARC-PVN pathway. Amylin might act as a direct neurotrophic factor in DIO rats to enhance both the number of POMC neurons and their α-MSH ARC-PVN pathway development. This suggests important and selective roles for amylin during ARC hypothalamic development.
Four papers on fine particulate matter (PM2.5 ) by Anenberg et al., Fann et al., Shin et al., and Smith contribute to a growing body of literature on estimated epidemiological associations between ambient PM2.5 concentrations and increases in health responses relative to baseline notes. This article provides context for the four articles, including a historical review of provisions of the U.S. Clean Air Act as amended in 1970, requiring the setting of National Ambient Air Quality Standards (NAAQS) for criteria pollutants such as particulate matter (PM). The substantial improvements in both air quality for PM and population health as measured by decreased mortality rates are illustrated. The most recent revision of the NAAQS for PM2.5 in 2013 by the Environmental Protection Agency distinguished between (1) uncertainties in characterizing PM2.5 as having a causal association with various health endpoints, and as all-cause mortality, and (2) uncertainties in concentration--excess health response relationships at low ambient PM2.5 concentrations below the majority of annual concentrations studied in the United States in the past. In future reviews, and potential revisions, of the NAAQS for PM2.5 , it will be even more important to distinguish between uncertainties in (1) characterizing the causal associations between ambient PM2.5 concentrations and specific health outcomes, such as all-source mortality, irrespective of the concentrations, (2) characterizing the potency of major constituents of PM2.5 , and (3) uncertainties in the association between ambient PM2.5 concentrations and specific health outcomes at various ambient PM2.5 concentrations. The latter uncertainties are of special concern as ambient PM2.5 concentrations and health morbidity and mortality rates approach background or baseline rates.
Lung cancer is the most frequent cancer in the world. Previous studies have shown that ubiquitin-specific protease 39 (USP39) is upregulated in several cancers and associated with tumor malignant characters. However, the effects of USP39 in lung cancer have not been well understood. In the present study, we found USP39 was generally expressed higher in human lung cancer tissues than in normal tissues by Oncomine database mining, qRT-PCR, and western blot assay. Knockdown of USP39 expression markedly reduced the proliferative and colony-forming ability of lung cancer cell lines 95D and A549. Flow cytometric analysis showed that USP39 knockdown induced cell cycle arrest at G2/M phase and enhanced cell apoptosis in 95D cells. Moreover, depletion of USP39 blocked activation of Akt, mTOR, p53, and PARP signaling pathways. Taken together, our study indicates that USP39 may be functionally involved in lung cancer growth and act as a potential molecular target for human lung cancer diagnosis and treatment.
: Glioblastoma (GBM), an aggressive grade IV astrocytoma, is the most common primary malignant adult brain tumor characterized by extensive invasiveness, heterogeneity, and angiogenesis. Standard treatment options such as radiation and chemotherapy have proven to be only marginally effective in treating GBM because of its invasive nature. Therefore, extensive efforts have been put forth to develop tumor-tropic stem cells as viable therapeutic vehicles with potential to treat even the most invasive tumor cells that are harbored within areas of normal brain. To this end, we discovered a newly described NG2-expressing cell that we isolated from a distinct pericyte subtype found abundantly in cultures derived from peripheral muscle. In this work, we show the translational significance of these peripherally derived neural-like stem cells (NLSC) and their potential to migrate toward tumors and act as therapeutic carriers. We demonstrate that these NLSCs exhibit in vitro and in vivo GBM tropism. Furthermore, NLSCs did not promote angiogenesis or transform into tumor-associated stromal cells, which are concerns raised when using other common stem cells, such as mesenchymal stem cells and induced neural stem cells, as therapeutic carriers. We also demonstrate the potential of NLSCs to express a prototype therapeutic, tumor necrosis factor α-related apoptosis-inducing ligand and kill GBM cells in vitro. These data demonstrate the therapeutic potential of our newly characterized NLSC against GBM.
Radiation and chemotherapy have failed to cause significant therapeutic benefit in glioblastoma patients because of their limitations. This has spurred investigations into the use of engineered stem cells to deliver antitumor drugs as a complementary strategy. This study reports that neural-like stem cells isolated from skeletal muscles show tumor-tropism and can be engineered to secrete therapeutics but do not form tumors and do not transform into tumor- associated cells or cause angiogenesis, in contrast to commonly used stem cells. These advantages coupled with the therapeutic potential of neural-like stem cells highlights their ability to be used as therapeutic carriers against glioblastomas.
Visual motion responses in the brain are shaped by two distinct sources: the physical movement of objects in the environment and motion resulting from one's own actions. The latter source, termed visual reafference, stems from movements of the head and body, and in primates from the frequent saccadic eye movements that mark natural vision. To study the relative contribution of reafferent and stimulus motion during natural vision, we measured fMRI activity in the brains of two macaques as they freely viewed >50 hours of naturalistic video footage depicting dynamic social interactions. We used eye movements obtained during scanning to estimate the level of reafferent retinal motion at each moment in time. We also estimated the net stimulus motion by analyzing the video content during the same time periods. Mapping the responses to these distinct sources of retinal motion, we found a striking dissociation in the distribution of visual responses throughout the brain. Reafferent motion drove fMRI activity in the early retinotopic areas V1, V2, V3, and V4, particularly in their central visual field representations, as well as lateral aspects of the caudal inferotemporal cortex (area TEO). However, stimulus motion dominated fMRI responses in the superior temporal sulcus, including areas MT, MST, and FST as well as more rostral areas. We discuss this pronounced separation of motion processing in the context of natural vision, saccadic suppression, and the brain's utilization of corollary discharge signals.
Visual motion arises not only from events in the external world, but also from the movements of the observer. For example, even if objects are stationary in the world, the act of walking through a room or shifting one's eyes causes motion on the retina. This "reafferent" motion propagates into the brain as signals that must be interpreted in the context of real object motion. The delineation of whole-brain responses to stimulus versus self-generated retinal motion signals is critical for understanding visual perception and is of pragmatic importance given the increasing use of naturalistic viewing paradigms. The present study uses fMRI to demonstrate that the brain exhibits a fundamentally different pattern of responses to these two sources of retinal motion.
In this study, electrospun fiber scaffolds based on biodegradable and bioabsorbable polymers and showing a similar structure to that of the extracellular matrix (ECM) present in the neural tissues were prepared. The effects of electrospun-based scaffolds processed from poly(lactic acid) (PLA)/poly(lactide-b-ethylene glycol-b-lactide) block copolymer (PELA) and PLA/polyethylene glycol (PEG) (50:50 by wt) blends on the morphology, wettability, and mechanical properties, as well as on neural stem cell (NSC) behavior, were investigated. Thus, PLA/PELA and PLA/PEG fiber mats composed of PEG with different chain lengths were evaluated for optimal use as tissue engineering scaffolds. In both cases, the hydrophilic character of the scaffold surface was increased from the introduction of PEG homopolymer or PEG-based block copolymer compared with neat PLA. A microphase separation and a surface erosion of PLA/PEG blend-based electrospun fibers were highlighted, whereas PLA/PELA blend-based fibers displayed a moderate hydrophilic surface and a tunable balance between
 surface erosion and bulk degradation. Even if the mechanical properties of PLA fibers containing PEG or PELA decreased slightly, an excellent compromise between stiffness and the ability to sustain large deformation was found for PLA/PELA(2k), which displayed a significant increase in strain at break, that is, up to 500%. Our results suggest that both neat PLA and PLA/PELA blends supplemented with growth factors may mimic neural-like constructs and provide structural stability. Nonetheless, electrospun PLA/PELA blends have a suitable surface property, which may act synergistically in the modulation of biopotential for implantable scaffolding in neural tissue engineering.
As a major organic component in aquatic sediments, black carbon (BC) could act as super surface sorbent for contaminants in soils or sediments due to its relatively structured carbon matrix with high degree of porosity and extensive surface area. In this work, the adsorption characteristics of Pb(2+) were studied using BCs as adsorbents, which were extracted from four particle sizes of sediment from Lake Wuliangsuhai (WLSH), under conditions of different pH, BC content, and ionic strength. The results showed BC content near to 1 % of sediments from WLSH, in which BC1, BC2, BC3, and BC4 composited about 1.8, 1.6, 1.1, and 0.8 % in the sediment fractions of >180, 180-63, 63-32, and <32 μm, respectively. The specific surface area and the Pb(2+) sorption capacity were increased with decreasing the particle size of BCs. Correspondingly, the adsorption percentage of Pb(2+) increased with increasing initial pH and BC content but declined as the increase of ionic strengths. The Pb(2+) sorption capacity was reached maximum at pH 5-6. Compared pre- to post-sorption BCs by SEM-EDS and FTIR, although the carboxyl (C=O) and phenol (OH) groups on BC fractions contributed to Pb(2+) sorption, the main adsorption mechanism of BCs was the surface sorption at pH <6. Relatively, the contribution of BCs accounted for about 18 % of Pb(2+) sorption capacity on sediments. This work is helpful to understand the environmental effects of different size fractions BCs extracted from natural sediments.
The human leucine-rich repeats and immunoglobulin like domains (LRIG) are evolutionary conserved family of single-pass transmembrane proteins. LRIG gene family includes three members, LRIG1 (formerly LIG1), LRIG2 and LRIG3, all of which are differentially expressed in human tissues and have long been proposed to be tumor suppressors. However, recently accumulated evidence on LRIG protein expression in human cancer appears to be inconsistent with this belief, as LRIG proteins have been found to be upregulated in certain tumors. Moreover, LRIG3 has been shown to act in an opposite manner to LRIG1 and LRIG1, in turn, has been shown to attenuate LRIG3 activity by its proteolytic degradation. These remarkable observations underline and reveal the previously unappreciated complexity of LRIG family dynamics. In the current review, the role of LRIG proteins in various human cancers is summarized and their differential regulation and expression is brought to light in order to understand how these proteins are involved in the genesis and progression of human cancers. Moreover, this is the first compilation that highlights the therapeutic potential of LRIG1 and suggests the same to be undertaken for LRIG2 and LRIG3. By virtue of their potential in prognosis of several cancer types, as well as their role as probable therapeutic proteins or in enhancing the receptiveness of the cancer cells to anti-tumor agents, it is strongly proposed that LRIG analysis should be undertaken and consequently be employed as a part of potential cancer treatment strategies.
A brief description of the history of Cancer Control in Japan was presented for the first time. The establishment of the National Cancer Center and Comprehensive 10-year Strategy for Cancer Control Program, which has been implemented for 30 years, is most important. In response to the concerns raised by cancer patients, their families, and lay people, such as elimination of disparity arising from where they live or which hospital they attend, and asymmetrical cancer information, the Cancer Control Act was established in 2006 and executed in 2007. The Basic Plan to Promote Cancer Control Programs was started in 2007 as a 10-year plan. Hospitals that specialize in cancer treatment, nearly 400 in total, were appointed all over Japan. Hospitals that specialize in pediatric cancer were also appointed all over Japan. Cancer education for children and special issues, including employment of cancer patients, were stressed. Since the establishment of the Cancer Control Act, the Cancer Control Strategy in this country has been achieved remarkably as a frame. Henceforth, all items should be elucidated by giving importance to the opinion of patients, their families, and lay people.
Although the Patient Protection and Affordable Care Act and other laws have promoted the use of shared decision making (SDM) in recent years, few specific policies have addressed the opportunities and challenges of utilizing SDM in the emergency department (ED). Policies relating to physician payment, quality measurement, and medical-legal risks each present unique challenges to adoption of SDM in the ED. This article summarizes findings from a health policy breakout session of the 2016 Academic Emergency Medicine Consensus Conference "Shared Decision Making in the Emergency Department: Development of a Policy-relevant, Patient-centered Research Agenda." The objectives were to 1) describe federal and state policies that influence utilization or assessment of SDM; 2) identify policies and policy-focused knowledge gaps that serve as barriers to adoption of ED SDM; and 3) to define a consensus-based, policy-focused research agenda to support adoption of SDM in emergency care.
To develop chiral anticancer drug candidates for molecular target DNA, the synthesis and characterization of a novel enantiomerically pure copper(II) complex [Cu 1 Cl 2 ] (2) of an optically pure ligand N-(pyridin-2-ylmethylene) dehydroabietylamine (1) was carried out. The coordination geometry of the copper center is a distorted square-planar arrangement. The interactions of 1 and 2 with salmon sperm DNA were investigated by viscosity measurements, UV, fluorescence and circular dichroism (CD) spectroscopic techniques. All the results reveal that 1 and 2 interacted with DNA through intercalation and 2 exhibited a higher DNA binding ability. Further, 1 and 2 could cleave supercoiled pBR322 DNA by single strand and 2 displayed stronger cleavage ability in the presence of ascorbic acid. In vitro cytotoxicity of 1 and 2 against HeLa, SiHa, HepG-2 and A431 cancer cell lines was studied using CCK-8 assay. The results indicate that 2 had a superior cytotoxicity than 1 and the widely used drug cisplatin under identical conditions. Flow cytometry analysis demonstrates 2 produced death of HeLa cancer cells through an apoptotic pathway. Cell cycle analysis shows that 2 mainly arrested HeLa cells at the S phase. A novel enantiomerically pure copper(II) complex [Cu 1 Cl 2 ] (2) of an optically pure ligand N-(pyridin-2-ylmethylene) dehydroabietylamine (1), based on natural product rosin has been synthesized. 2 has the potential to act as effective anticancer drug.
The synthesis and structure of the first 1,2-bis(NHSi)-substituted ortho-carborane [(LSi:)C]2 B10 H10 (termed SiCCSi) is reported (NHSi=N-heterocyclic silylene; L=PhC(NtBu)2 ). Its suitability to serve as a reliable bis(silylene) chelating ligand for transition metals is demonstrated by the formation of [SiCCSi]NiBr2 and [SiCCSi]Ni(CO)2 complexes. The CO stretching vibration modes of the latter indicate that the Si(II) atoms in the SiCCSi ligand are even stronger σ donors than the P(III) atoms in phosphines and C(II) atoms in N-heterocyclic carbene (NHC) ligands. Moreover, the strong donor character of the [SiCCSi] ligand enables [SiCCSi]NiBr2 to act as an outstanding precatalyst (0.5 mol % loading) in the catalytic aminations of arenes, surpassing the activity of previously known molecular Ni-based precatalysts (1-10 mol %).
Although associated with anti-oxidative properties, genistein has been reported to induce DNA strand breaks, whereby oxidative stress and topoisomerase poisoning are considered as potential mechanisms. In contrast, delphinidin, a catalytic topoisomerase inhibitor, is known to suppress the DNA-damaging properties of several topoisomerase poisons. Recently, alternariol, a mycotoxin produced by Alternaria spp., was found not only to induce oxidative stress but also to act as a topoisomerase poison. As both, polyphenols and mycotoxins, might occur in our nutrition simultaneously, the question was addressed whether potential combinatory effects on DNA integrity have to be considered.
We determined combinatory effects of either genistein or delphinidin with alternariol in HT-29 cells. Cytotoxicity was assessed by WST-1 and SRB assays, whereby only weak interactions were observed. The comet assay revealed significant antagonistic interactions of both polyphenols with the genotoxicity of AOH. The underlying mechanism comprises the suppression of alternariol-mediated stabilization of DNA/topoisomerase-II-intermediates, as observed in the ICE assay. Furthermore, DEL but not GEN was found to suppress AOH-mediated oxidative stress.
Our data indicate that a respective polyphenol-rich diet might aid to protect against genotoxic damages caused by AOH, whereby bioactive concentrations of DEL are predominantly expected locally in the intestines.
Functional synapse formation requires tight coordination between pre- and post-synaptic termini. Previous studies have shown that postsynaptic expression of heparan sulfate proteoglycan syndecan-2 (SDC2) induces
 dendritic spinogenesis. Those SDC2-induced dendritic spines are frequently associated with presynaptic termini. However, how postsynaptic SDC2 accelerates maturation of corresponding presynaptic termini is unknown. Because fibroblast growth factor 22 (FGF22), a heparan sulfate binding growth factor, has been shown to act as a presynaptic organizer released from the postsynaptic site, it seems possible that postsynaptic SDC2 presents FGF22 to the presynaptic FGF receptor to promote presynaptic differentiation. Here, we show that postsynaptic SDC2 uses its ectodomain to interact with and facilitate dendritic filopodial targeting of FGF22, triggering presynaptic maturation. Since SDC2 also enhances filopodial targeting of NMDAR via interaction with the CASK-mLIN7-MINT1 adaptor complex, presynaptic maturation promoted by FGF22 further feeds back to activate NMDAR at corresponding postsynaptic sites through increased neurotransmitter release and, consequently, promotes the dendritic filopodia-spines (F-S) transition. Meanwhile, via regulation of the KIF17 motor, CaMKII (activated by the NMDAR pathway) may further facilitate FGF22 targeting to dendritic filopodia that receive presynaptic stimulation. Our study suggests a positive feedback that promotes the coordination of postsynaptic and presynaptic differentiation.
The nucleosomal protein high-mobility group box-1 (HMGB1), which has recently been established as a late mediator of lethal systemic inflammation, has a relatively wide therapeutic window for pharmacological interventions. Compounds produced by marine-derived microbes have been widely investigated for their potential use as bioactive natural products. Cyclic dipeptides, which are also known as diketopiperazines, are molecules that are frequently found in marine-derived microorganisms. While their pharmacological potential has been well established, their biological activities against septic responses have not yet been reported. Here, three diketopiperazines (1-3) isolated from two strains of marine-derived bacteria were investigated for their potential activities against HMGB1-mediated septic responses. The data showed that 1-3 effectively inhibited the lipopolysaccharide (LPS)-induced release of HMGB1 and suppressed the HMGB1-mediated septic responses, including hyperpermeability, leukocyte adhesion and migration, and cell adhesion molecule expression. In addition, 1-3 inhibited the HMGB1-mediated production of tumor necrosis factor-[Formula: see text] (TNF-[Formula: see text] and interleukin (IL)-6 and the activation of nuclear factor-[Formula: see text]B (NF-[Formula: see text]B) and extracellular signal-regulated kinase (ERK) 1 and ERK2. Collectively, these results indicated that 1-3 might act as potential therapeutic agents for various severe vascular inflammatory diseases through the inhibition of the HMGB1 signaling pathway.
Turbulence in integrable systems exhibits a noticeable scientific advantage: it can be expressed in terms of the nonlinear modes of these systems. Whether the majority of the excitations in the system are breathers or solitons defines the properties of the turbulent state. In the two extreme cases we can call such states "breather turbulence" or "soliton turbulence." The number of rogue waves, the probability density functions of the chaotic wave fields, and their physical spectra are all specific for each of these two situations. Understanding these extreme cases also helps in studies of mixed turbulent states when the wave field contains both solitons and breathers, thus revealing intermediate characteristics.
Pulmonary arterial hypertension (PAH) is a progressive and rapidly fatal disease with a high mortality rate. PAH manifests by proliferation/apoptosis imbalance of pulmonary vascular cells leading to remodeling of small pulmonary arteries (PA), increased PA pressure, elevated right ventricular afterload, right heart failure and death. Emerging evidence from many research groups indicates that PAH may be viewed as a proliferative disease with a cancer-like nature and shares an incredible number of pathogenic signaling mechanisms with human cancers. This offers exciting opportunity to employ certain cancer-specific strategies as well as re-purpose anti-cancer agents for treatment of PAH. In this review, we discuss various signal transduction pathways that act as "central signaling hubs" in PAH and cancer, particularly those that have a crucial role in driving pulmonary vascular cell proliferation and survival, summarize recent progress in cellular, pre-clinical and clinical studies focused on proliferative/anti-apoptotic component, and discuss the opportunities for re-purposing or cross-development of anti-cancer agents that can be used in improving PAH care.  .
The Ori region of bacterial genomes is segregated early in the replication cycle of bacterial chromosomes. Consequently, Ori region positioning plays a pivotal role in chromosome dynamics. The Ori region of the E. coli chromosome is organized as a macrodomain with specific properties concerning DNA mobility, segregation of loci and long distance DNA interactions. Here, by using strains with chromosome rearrangements and DNA mobility as a read-out, we have identified the MaoP/maoS system responsible for constraining DNA mobility in the Ori region and limiting long distance DNA interactions with other regions of the chromosome. MaoP belongs to a group of proteins conserved in the Enterobacteria that coevolved with Dam methylase including SeqA, MukBEF and MatP that are all involved in the control of chromosome conformation and segregation. Analysis of DNA rings excised from the chromosome demonstrated that the single maoS site is required in cis on the chromosome to exert its effect while MaoP can act both in cis and in trans. The position of markers in the Ori region was affected by inactivating maoP. However, the MaoP/maoS system was not sufficient for positioning the Ori region at the ¼-¾ regions of the cell. We also demonstrate that the replication and the resulting expansion of bulk DNA are localized centrally in the cell. Implications of these results for chromosome positioning and segregation in E. coli are discussed.
Predicting the timing and order of future events is an essential feature of cognition in higher life forms. We propose a neural mechanism to nondestructively translate the current state of spatiotemporal memory into the future, so as to construct an ordered set of future predictions almost instantaneously. We hypothesize that within each cycle of hippocampal theta oscillations, the memory state is swept through a range of translations to yield an ordered set of future predictions through modulations in synaptic connections. Theoretically, we operationalize critical neurobiological findings from hippocampal physiology in terms of neural network equations representing spatiotemporal memory. Combined with constraints based on physical principles requiring scale invariance and coherence in translation across memory nodes, the proposition results in Weber-Fechner spacing for the representation of both past (memory) and future (prediction) timelines. We show that the phenomenon of phase precession of neurons in the hippocampus and ventral striatum correspond to the cognitive act of future prediction.
The new Patients' Rights Act does not reflect rights of patients as professional obligations of physicians for the first time. It adopted common longtime jurisdiction, but in some respects it is going beyond. This law clearly extended the documentation requirements of physicians, especially concerning the extent of documentation. In surgical fields the requirements for enlightening physicians were more strongly worded than in previous jurisdiction. In medical facilities it is now mandatory to establish an internal quality management system.
Morphine is an agonist of the µ and k receptors, whose activation results in analgesia. Morphine-like agonists act through the µ opioid receptors to cause pain relief, sedation, euphoria and respiratory depression. Morphine is glucuronidated and sulfated at positions 3 and 6; the plasma concentration ratios correlate positively with birth weight, which probably reflects increased liver weight with increasing birth weight. Moreover, morphine clearance correlates positively with gestational age and birth weight. Steady-state morphine plasma concentrations are achieved after 24-48 hours of infusion, but the glucuronide metabolite plasma concentrations do not reach steady state before 60 hours. The morphine-3-glucuronide metabolite has lower clearance, a shorter half-life and a smaller distribution volume compared with the morphine-6 metabolite, which is the most active morphine-like agonist. Ordinary doses cause constipation, urinary retention and respiratory depression. Neonatal pain relief may require a blood level of approximately 120 ng/ml, whereas lower levels (20-40 ng/ml) seem adequate for children. A bibliographic search was performed using the PubMed database and the keywords "morphine metabolism neonate" and "morphine pharmacokinetics neonate". The initial and final cutoff points were January 1990 and September 2015, respectively. The results indicate that morphine is extensively glucuronidated and sulfated at positions 3 and 6, and that the glucuronidation rate is lower in younger neonates compared with older infants. Although much is known about morphine in neonates, further research will be required to ensure that recommended therapeutic doses for analgesia in neonates are evidence based.
Data published from the United States have demonstrated that the use of cervical cerclage has fallen in the period 1998-2013. This is in contrast to recommendations in Australia. We examined this trend using data from the Australian Institute of Health and Welfare (AIHW).
Retrospective
 population-based study.
Data from the Australian Institute of Health and Welfare procedural database were used to determine the total number of cervical cerclage sutures inserted during the period 2004 to 2013. Population datasets were used to calculate age-stratified incidence rates of cerclage.
There was a significant increase in the rate of cervical cerclage in women aged 25 to 34 years and in the 35 years and older age group. The incidence of preterm birth was stable for gestations of 32 to 36 weeks, but slightly increased in the 20 to 27 week and 28 to 31 week gestational age groups. Further research into cervical cerclage and the use of vaginal progesterone for the prevention of preterm birth would be valuable.
Quorum sensing (QS) is the process by which bacteria produce and detect signal molecules to coordinate their collective behavior. This intercellular communication is a relevant target for anti-biofilm therapies. Here we have optimized a screening-applicable assay to search for new quorum sensing inhibitors from natural compound libraries. In this system, QS is correlated with the production of violacein, which is directly controlled by the LuxI/LuxR system in Chromobacterium violaceum ATCC 31532. The parallel use of C. violaceum Tn5-mutant CV026, which depends on auto-inducer addition, allows simultaneous discrimination of compounds that act as quenchers of the AHL signal (quorum quenchers). The incorporation of a redox stain into the platform allowed further distinction between QS inhibitors, quorum quenchers and antibacterial compounds. A pilot screening was performed with 465 natural and synthetic flavonoids. All the most active compounds were flavones and they displayed potencies (IC50) in the range of 3.69 to 23.35 μM. These leads were particularly promising as they inhibited the transition from microcolonies into mature biofilms from Escherichia coli and Pseudomonas aeruginosa strains. This approach can be very effective in identifying new antimicrobials posing lesser risks of resistance.
Although lysine acetylation is now recognized as a general protein modification for both histones and non-histone proteins, the mechanisms of acetylation-mediated actions are not completely understood. Acetylation of the C-terminal domain (CTD) of p53 (also known as TP53) was an early example of non-histone protein acetylation and its precise role remains unclear. Lysine acetylation often creates binding sites for bromodomain-containing 'reader' proteins. Here we use a proteomic screen to identify the oncoprotein SET as a major cellular factor whose binding with p53 is dependent on CTD acetylation status. SET profoundly inhibits p53 transcriptional activity in unstressed cells, but SET-mediated repression is abolished by stress-induced acetylation of p53 CTD. Moreover, loss of the interaction with SET activates p53, resulting in tumour regression in mouse xenograft models. Notably, the acidic domain of SET acts as a 'reader' for the unacetylated CTD of p53 and this mechanism of acetylation-dependent regulation is widespread in nature. For example, acetylation of p53 also modulates its interactions with similar acidic domains found in other p53 regulators including VPRBP (also known as DCAF1), DAXX and PELP1 (refs. 7, 8, 9), and computational analysis of the proteome has identified numerous proteins with the potential to serve as acidic domain readers and lysine-rich ligands. Unlike bromodomain readers, which preferentially bind the acetylated forms of their cognate ligands, the acidic domain readers specifically recognize the unacetylated forms of their ligands. Finally, the acetylation-dependent regulation of p53 was further validated in vivo by using a knock-in mouse model expressing an acetylation-mimicking form of p53. These results reveal that acidic-domain-containing factors act as a class of acetylation-dependent regulators by targeting p53 and, potentially, other proteins.
Black Lives Matter was first articulated just a few years ago, but it has been the leitmotif of antiracist struggles for generations. The Movement for Black Lives extends the work of previous movements that challenged forms of oppression that act on Black bodies with impunity. It should be understood in the context of Ida B. Wells' anti-lynching campaign, Fannie Lou Hamer's reproductive justice demands, and the Black Panther Party's health activism. The 50th anniversary of the Black Panther Party is an occasion to recall that its work confronted the callous neglect and the corporeal surveillance and abuse of poor Black communities. Similar demands have been the centrifugal force of social movements that for centuries have refused to have Black lives cast beyond the human boundary.
Some reports have evaluated the prognostic relevance of microRNAs (miRNAs) in patients with pancreatic cancer (PC). However, most studies focused on limited miRNAs with small number of patients. The aim of the study is to identify a panel of miRNA signature that could predict prognosis in PC with the data from The Cancer Genome Atlas (TCGA). A total of 167 PC patients with the corresponding clinical data were enrolled in our study. The miRNAs significantly associated with overall survival (OS) in PC patients were identified with Cox proportional regression model. A risk score formula was developed to evaluate the prognostic value of the miRNA signature in PC. Thirteen miRNAs were identified to be significantly related with OS in PC patients. Patients with high risk score suffered poor overall survival compared with patients who had low risk score. The multivariate Cox regression analyses showed that the miRNA signature could act as an independent prognostic indicator. In addition, the signature might serve as a predicator for treatment outcome. Our study identified a miRNA signature including 13 miRNAs which could serve as an independent marker in prognosis of PC.
Surprising events may be relevant or irrelevant for behavior, requiring either flexible adjustment or stabilization of our model of the world and according response strategies. Cognitive flexibility and stability in response to environmental demands have been described as separable cognitive states, associated with activity of striatal and lateral prefrontal regions, respectively. It so far remains unclear, however, whether these two states act in an antagonistic fashion and which neural mechanisms mediate the selection of respective responses, on the one hand, and a transition between these states, on the other. In this study, we tested whether the functional dichotomy between striatal and prefrontal activity applies for the separate functions of updating (in response to changes in the environment, i.e., switches) and shielding (in response to chance occurrences of events violating expectations, i.e., drifts) of current predictions. We measured brain activity using fMRI while 20 healthy participants performed a task that required to serially predict upcoming items. Switches between predictable sequences had to be indicated via button press while sequence omissions (drifts) had to be ignored. We further varied the probability of switches and drifts to assess the neural network supporting the transition between flexible and stable cognitive states as a function of recent performance history in response to environmental demands. Although flexible switching between models was associated with activation in medial pFC (BA 9 and BA 10), we found that stable maintenance of the internal model corresponded to activation in the lateral pFC (BA 6 and inferior frontal gyrus). Our findings extend previous studies on the interplay of flexibility and stability, suggesting that different prefrontal regions are activated by different types of prediction errors, dependent on their behavioral requirements. Furthermore, we found that striatal activation in response to switches and drifts was modulated by participants' successful behavior toward these events, suggesting the striatum to be responsible for response selections following unpredicted stimuli. Finally, we observed that the dopaminergic midbrain modulates the transition between different cognitive states, thresholded by participants' individual performance history in response to temporal environmental demands.
3-Deoxy-β-d-manno-oct-2-ulosonic acid (β-Kdo) glycosides are mainly found in capsular polysaccharides and extracellular exopolysaccharides from Gram-negative bacteria. These compounds have profound biological implications in immune response and act as virulence factors. We have developed a novel methodology for the stereoselective synthesis of β-Kdo glycosides via the use of a 4'-methoxyphenacyl (Phen) auxiliary group at the C1 position of a peracetylated β-Kdo thioglycoside. Under the promotion of NIS/AgOTf in acetonitrile, a series of Kdo glycosides was synthesized in good yield and β-selectivity while minimizing the formation of undesirable glycals. Stereoselectivity of the glycosylation was shown to be modulated by various factors such as promotor, solvent, anomeric ratio of donor, nature of acceptor, and Phen substitution. Chemoselective cleavage of the Phen group was performed under the action of Zn/HOAc. DFT calculations together with experimental results suggested that α-triflate and a six-membered α-spiroPhen are plausible intermediates of the reaction, accounting for the enhanced formation of β-Kdo glycosides. The developed methodology could be applied to the synthesis of β-Kdo-containing glycans from pathogenic bacteria.
A solitary fibrous tumor (SFT) is an extremely rare, distinct otological soft-tissue tumor. Only two such tumors in the external auditory canal have been reported. A SFT related to hemangiopericytomas (HPC), which commonly arise in the central nervous system. HPCs act malignant in many cases, while SFTs at other sites are
 mainly benign. A 25-year-old female presented with highly vascular tumor at the right external auditory meatus and bleeding from the mass when a crust was removed from its surface. After excisional biopsy followed by pre-operative embolization, this tumor confirmed with SFT. The recurrence rate of SFT is very low after complete resection, with a slightly increased risk of recurrence with extrathoracic tumors. We describe the third case of SFT in the external auditory canal and review the literature.
Novel action beta-blockers combine many different pharmacological effects. The espindolol exhibits effects through β and central 5-HT1α receptors to demonstrate pro-anabolic, anti-catabolic, and appetite-stimulating actions. In the ACT-ONE trial, espindolol reversed weight loss and improved handgrip strength in patients with cachexia due to non-small cell lung cancer or colorectal cancer. With this trial, another frontier of cachexia management is in sight. Nonetheless, more efficacy and safety data is needed before new therapeutic indications for novel action beta-blockers can be endorsed.
Phytonutrients and pigments present in cyanobacteria act as antioxidants, which facilitate the formation of body's defense mechanism against free radical damage to cells. The aim of this investigation was to study the total phenolic content (TPC), total flavonoid content (TFC), antioxidant activity, phycobiliproteins (PBPs), and active compounds in four cyanobacterial species, that is, Oscillatoria sp., Lyngbya sp., Microcystis sp., and Spirulina sp. isolated from fresh water bodies of Sri Lanka. In this study, Lyngbya sp., showed highest TPC (5.02 ± 0.20 mg/g), TFC (664.07 ± 19.76 mg/g), and total PBPs (127.01 mg/g) value. The ferric reducing antioxidant power (FRAP) was recorded highest in Oscillatoria sp. (39.63 ± 7.02), whereas the 2,2-diphenyl-1-picrylhydrazyl (DPPH) radical scavenging activity was also reported the highest in Oscillatoria sp. (465.31 ± 25.76) followed by Lyngbya sp. (248.39 ± 11.97). In FTIR spectroscopy, Lyngbya sp. does not show any N-H stretching band which is ultimately responsible for the inhibition of antioxidant activity. The study revealed that Lyngbya sp. and Oscillatoria sp. can be an excellent source for food, pharmaceutical, and other industrial uses.
The Affordable Care Act (ACA) healthcare reforms, centered on achieving the Centers for Medicare & Medicaid Services (CMS) Triple Aim goals of improving patient care quality and satisfaction, improving population health, and reducing costs, have led to increasing partnerships between hospitals and insurance companies and the implementation of employee wellness programs. Hospitals and insurance companies have opted to partner to distribute the risk and resources and increase coordination of care.
To examine the ACA's impact on the health and wellness programs that have resulted from the joint ventures of hospitals and health plans based on the published literature.
We conducted a review of the literature to identify successful mergers and best practices of health and wellness programs. Articles published between January 2007 and January 2015 were compiled from various search engines, using the search terms "corporate," "health and wellness program," "health plan," "insurance plan," "hospital," "joint venture," and "vertical merger." Publications that described consolidations or wellness programs not tied to health insurance plans were excluded. Noteworthy characteristics of these programs were summarized and tabulated.
A total of 44 eligible articles were included in the analysis. The findings showed that despite rising healthcare costs, joint ventures prevent hospitals from trading-off quality and services for cost reductions. Administrators believed that partnering would allow the companies to meet ACA standards for improving clinical outcomes at reduced costs. Before the implementation of the ACA, some employers had wellness programs, but these were not standardized and did not need to produce measurable results. The ACA encouraged improvement of employee wellness programs by providing funding for expanded health services and by mandating quality care. Successful workplace health and wellness programs have varying components, but all include monetary incentives and documented outcomes.
The concurrent growth of hospital health plans (especially those emerging from vertical mergers and partnerships) and wellness programs in the United States provides a unique opportunity for employees and patient populations to promote wellness and achieve the Triple Aim goals as initiated by CMS.
Several studies have shown that workplace violence in the emergency department (ED) is common. Residents may be among the most vulnerable staff, as they have the least experience with these volatile encounters. The goal for this study was to quantify and describe acts of violence against emergency medicine (EM) residents by patients and visitors and to identify perceived barriers to safety.
This cross-sectional survey study queried EM residents at multiple New York City hospitals. The primary outcome was the incidence of violence experienced by residents while working in the ED. The secondary outcomes were the subtypes of violence experienced by residents, as well as the perceived barriers to safety while at work.
A majority of residents (66%, 78/119) reported experiencing at least one act of physical violence during an ED shift. Nearly all residents (97%, 115/119) experienced verbal harassment, 78% (93/119) had experienced verbal threats, and 52% (62/119) reported sexual harassment. Almost a quarter of residents felt safe "Occasionally," "Seldom" or "Never" while at work. Patient-based factors most commonly cited as contributory to violence included substance use and psychiatric disease.
Self-reported violence against EM residents appears to be a significant problem. Incidence of violence and patient risk factors are similar to what has been found previously for other ED staff. Understanding the prevalence of workplace violence as well as the related systems, environmental, and patient-based factors is essential for future prevention efforts.
Alterations in the cyclic (c)AMP-dependent signaling pathway have been implicated in the majority of benign adrenocortical tumors (ACTs) causing Cushing syndrome (CS). Phosphodiesterases (PDEs) are enzymes that regulate cyclic nucleotide levels, including cyclic adenosine monophosphate (cAMP). Inactivating mutations and other functional variants in PDE11A and PDE8B, two cAMP-binding PDEs, predispose to ACTs. The involvement of these two genes in ACTs was initially revealed by a genome-wide association study in patients with micronodular bilateral adrenocortical hyperplasia. Thereafter, PDE11A or PDE8B genetic variants have been found in other ACTs, including macronodular adrenocortical hyperplasias and cortisol-producing adenomas. In addition, downregulation of PDE11A expression and inactivating variants of the gene have been found in hereditary and sporadic testicular germ cell tumors, as well as in prostatic cancer. PDEs confer an increased risk of ACT formation probably through, primarily, their action on cAMP levels, but other actions might be possible. In this report, we review what is known to date about PDE11A and PDE8B and their involvement in the predisposition to ACTs.
The objective was to determine the accuracy of sequential organ failure assessment (SOFA) score in predicting outcome of patients in Intensive Care Unit (ICU).
Forty-four consecutive patients between 15 and 80 years admitted to ICU over 8 weeks period were studied prospectively. Three patients were excluded. SOFA score was determined 24 h postadmission to ICU and subsequently every 48 h for the first 10 days. Patients were followed till discharge/death/transfer from the ICU. Initial SOFA score, highest and mean SOFA scores were calculated and correlated with mortality and duration of stay in ICU.
The mortality rate was 39% and the mean duration of stay in the ICU was 9 days. The maximum score in survivors (3.92 ± 2.17) was significantly lower than nonsurvivors (8.9 ± 3.45). The initial SOFA score had a strong statistical correlation with mortality. Cardiovascular score on day 1 and 3, respiratory score on day 7, and coagulation profile on day 3 correlated significantly with the outcome. Duration of the stay did not correlate with the survival (P = 0.461).
SOFA score is a simple, but effective prognostic indicator and evaluator for patient progress in ICU. Day 1 SOFA can triage the patients into risk categories. For further management, mean and maximum score help determine the severity of illness and can act as a guide for the intensity of therapy required for each patient.
The elucidation of the superficial fascial system (SFS) by Lockwood in 1991 has been the cornerstone of our understanding of abdominal excisional dynamics for the last 25 years. The SFS can be used for closure and, appropriately mobilized, for tension transmission in abdominoplasty, and lower body lifts. The pattern of SFS adhesion to muscle fascia and the zones of adhesion was also described but there are inconsistencies between the description and clinical experience.
This study was performed to better describe the pattern of subcutaneous tissue adhesion to the trunk.
Twenty pre-abdominoplasty patients were studied. A series of points were marked around the trunk and the skin moved in four opposing directions. The excursions were measured and the median plotted on a diagram. Two fresh cadavers were also dissected, removing all subcutaneous tissue circumferentially from the trunk muscle fascia and marking the strength of the adhesion with a colored pin. Three grades of adhesion were mapped.
In the current study, maximal laxity was shown in the mid-lower abdomen and the anterior and lateral
 chest. Laxity was limited in the anterior and posterior midlines, over the lower back, and the lateral upper thigh. The cadaver dissection mapped adhesion which correlated with the skin laxity diagram.
The detailed skin adhesion map better explains features of surface anatomy. Incorporating this understanding a tension vector of abdominoplasty closure obliquely inwards is proposed to maximally harvest the laxity of the anterior and lateral chest and to create further lowering and narrowing of the waist.
Plant aerial epidermal tissues, like animal epithelia, act as load-bearing layers and hence play pivotal roles in development. The presence of tension in the epidermis has morphogenetic implications for organ shapes but it also constantly threatens the integrity of this tissue. Here, we explore the multi-scale relationship between tension and cell adhesion in the plant epidermis, and we examine how tensile stress perception may act as a regulatory input to preserve epidermal tissue integrity and thus normal morphogenesis. From this, we identify parallels between plant epidermal and animal epithelial tissues and highlight a list of unexplored questions for future research.
Decisions concerning the appropriate listing status of species under the United States Endangered Species Act (ESA) can be controversial even among conservationists. These decisions may not only determine whether a species persists in the near term, they can also have long-lasting social and political ramifications. Given the ESA's mandate that such decisions be based upon the best available science, it is important to examine what factors contribute to experts' judgments concerning the listing of species. We examined how a variety of factors influenced experts' judgments concerning the appropriate listing status of the Greater Yellowstone grizzly bear (U. arctos horribilis). Although experts' assessment of the threats to this species was strongly correlated with their listing status recommendation, this relationship disappears when other cognitive factors are included in the model. Specifically, our results indicate that values related to human use of wildlife and norms (i.e., one's expectation of peers' assessments) were most influential in listing status recommendations. These results suggest that experts' decisions about listing, like all human decisions, are subject to the use of heuristics (i.e., decision short-cuts). An understanding of how heuristics and related biases affect decisions under uncertainty can help inform decision making about threatened and endangered species and may be useful in designing more effective processes when determining protections for imperiled species. This article is protected by copyright. All rights reserved.
Health insurance is among the most important financial and health-related decisions that people make. Choosing a health insurance plan that offers sufficient risk protection is difficult, in part because total expected health care costs are not transparent. This study examines the effect of providing total costs estimates on health insurance decisions using a series of hypothetical choice experiments given to 7,648 individuals responding to the fall 2015 Health Reform Monitoring Survey. Participants were given two health scenarios presented in random order asking which of three insurance plans would best meet their needs. Half received total estimated costs, which increased the probability of choosing a cost-minimizing plan by 3.0 to 10.6 percentage points, depending on the scenario (p < .01). With many consumers choosing or failing to switch out of plans that offer insufficient coverage, incorporating insights on consumer decision making with personalized information to estimate costs can improve the quality of health insurance choices.
The Affordable Care Act is expected to profoundly affect inpatient hospital utilization, both as a result of expansions in insurance coverage as well as payment and delivery system reforms. The objective of this study is to examine changes in inpatient utilization between 2010 and 2013 in California, following a Medicaid expansion and implementation of the Delivery System Reform Incentive Payment program. Findings show that between 2010 and 2013: (a) the overall number of inpatient admissions increased, mainly because an increase in Medicaid admissions exceeded the decrease in uninsured admissions; (b) the number of preventable admissions did not change; (c) preventable admissions decreased at safety net hospitals that received Delivery System Reform Incentive Payment funds relative to other safety net hospitals. The results suggest that delivery system reforms may help offset the upward pressures on utilization and costs due to coverage expansions.
Regulator of G protein signaling (RGS) proteins act as negative modulators of G protein signaling. RGS4 has been shown to negatively modulate G protein signaling mediated by the delta opioid receptor (DOPr) in vitro. However, the role of RGS4 in modulating DOPr-mediated behaviors in vivo has not been elucidated.
The aim of this study was to compare the ability of the DOPr agonist SNC80 to induce DOPr-mediated antinociception, antihyperalgesia, antidepressant-like effects, and convulsions in wild-type and RGS4 knockout mice.
Antinociception was assessed in the acetic acid stretch assay. Antihyperalgesia was measured in a nitroglycerin-induced thermal hyperalgesia assay. Antidepressant-like effects were evaluated in the forced swim and tail suspension tests. Mice were also observed for convulsive activity post-SNC80 treatment. SNC80-induced phosphorylation of MAP kinase in striatal tissue from RGS4 wild-type and knockout mice was quantified by Western blot. DOPr number from forebrain tissue was measured using [(3)H]DPDPE saturation binding.
Elimination of RGS4 potentiated SNC80-induced antinociception and antihyperalgesia. SNC80-induced antidepressant-like effects were potentiated in RGS4 knockout mice in the forced swim test but not in the tail suspension test. Additionally, RGS4 knockout did not alter SNC80-induced convulsions. SNC80-induced phosphorylation of MAP kinase was potentiated in striatum from RGS4 knockout mice. Loss of RGS4 did not affect total DOPr number.
Overall, these findings demonstrate that reduction of RGS4 functionally may increase the therapeutic index of SNC80. These results provide the first evidence of differential regulation of DOPr-mediated behaviors by RGS proteins and G protein signaling pathways.
The current emphasis on fiscally responsible health spending in the era of the Affordable Care Act and other health care reform necessitates cost-conscious delivery of care. "Value" in health care is defined as the quality of care divided by the cost. As such, health systems optimize value by providing the most cost-effective care possible without sacrificing safety or outcomes. Elective, minimal risk surgical procedures in children may be value-enhanced by moving from an operating room (OR) to a more cost-efficient setting. The purpose of this study was to assess the safety and cost of performing the removal of implantable central venous access devices ("ports") in locations other than the main OR.
We compared port removal at three sites: 1. Main OR, 2. Satellite OR, and 3. Clinic Procedure Room. This was a mixed-methods study including a retrospective review of medical records and prospective observation/interviewing. To calculate cost without the inherent biases of hospital charges, costs, and payments, we utilized the methodology of time-driven activity based costing. Specifically, we recorded time spent by the patient in hospital facilities and with health care personnel. This duration was then weighted with the hourly cost of each health care professional and hospital space. The Mann-Whitney U test compared time and cost across the three sites. Overall cost at each site was divided by overall cost at the referent site (Main OR) to obtain a ratio of cost savings.
A total of 120 patients (40 per site) were included in the analysis. Demographic and clinical factors were not significantly different between sites. No complication occurred with port removal at any site. Time of the entire care episode was significantly decreased in the Clinic (median 161min, 95% confidence interval [CI] 134-188min), compared to the Main OR (median 235min, 95% confidence interval [CI] 209-251min) or Satellite OR (median 228min, 95% confidence interval [CI] 211-245min). Overall cost was decreased by 25% (95% CI: 13-34%) at the Clinic and by 6% (95% CI: -2-11%) at the Satellite OR, compared to the Main OR (referent, P<0.01).
In our study, port removal in the Clinic Procedure Room was not associated with increased risk of negative outcomes. Shifting port removal from the Main OR to the Clinic may result in substantial cost savings.
Microglia act as the resident immune cells of the central nervous system, including the retina. In response to damaging stimuli microglia adopt an activated state, which can progress into a phagocytic phenotype and play a potentially harmful role by eliciting the expression and release of pro-inflammatory cytokines. The aim of the present study was to assess longitudinal changes in microglia during retinal degeneration in the homozygous P23H rat, a model of dominant retinitis pigmentosa. Microglial phenotypes, morphology and density were analyzed by immunohistochemistry, flow cytometry, and cytokine antibody array. In addition, we performed electroretinograms to evaluate the retinal response. In the P23H retina, sclera, choroid and ciliary body, inflammatory cells increased in number compared with the control at all ages analyzed. As the rats became older, a higher number of amoeboid MHC-II(+) cells were observed in the P23H retina, which correlated with an increase in the expression of pro-inflammatory
 cytokines. These findings suggest that, in the P23H model, retinal neuroinflammation persists throughout the rat's life span even after photoreceptor depletion. Therefore, the inclusion of anti-inflammatory drugs at advanced stages of the neurodegenerative process may provide better retinal fitness so the remaining cells could still be used as targets of cellular or gene therapies.
Characterising and predicting the effects of ionising radiation on cells remains challenging, with the lack of robust models of the underlying mechanism of radiation responses providing a significant limitation to the development of personalised radiotherapy. In this paper we present a mechanistic model of cellular response to radiation that incorporates the kinetics of different DNA repair processes, the spatial distribution of double strand breaks and the resulting probability and severity of misrepair. This model enables predictions to be made of a range of key biological endpoints (DNA repair kinetics, chromosome aberration and mutation formation, survival) across a range of cell types based on a set of 11 mechanistic fitting parameters that are common across all cells. Applying this model to cellular survival showed its capacity to stratify the radiosensitivity of cells based on aspects of their phenotype and experimental conditions such as cell cycle phase and plating delay (correlation between modelled and observed Mean Inactivation Doses R(2) > 0.9). By explicitly incorporating underlying mechanistic factors, this model can integrate knowledge from a wide range of biological studies to provide robust predictions and may act as a foundation for future calculations of individualised radiosensitivity.
Amyloid-β (Aβ) peptides are the main components of the plaques found in the brains of patients with Alzheimer's disease. However, Aβ peptides are also detectable in secretory compartments and peripheral blood contains a complex mixture of more than 40 different modified and/or N- and C-terminally truncated Aβ peptides. Recently, anti-infective properties of Aβ peptides have been reported. Here, we investigated the interaction of Aβ peptides of different lengths with various bacterial strains and the yeast Candida albicans. The amyloidogenic peptides Aβ1-42, Aβ2-42, and Aβ3p-42 but not the non-amyloidogenic peptides Aβ1-40 and Aβ2-40 bound to microbial surfaces. As observed by immunocytochemistry, scanning electron microscopy and Gram staining, treatment of several bacterial strains and Candida albicans with Aβ peptide variants ending at position 42 (Aβx-42) caused the formation of large agglutinates. These aggregates were not detected after incubation with Aβx-40. Furthermore, Aβx-42 exerted an antimicrobial activity on all tested pathogens, killing up to 80% of microorganisms within 6 h. Aβ1-40 only had a moderate antimicrobial activity against C. albicans. Agglutination of Aβ1-42 was accelerated in the presence of microorganisms. These data demonstrate that the amyloidogenic Aβx-42 variants have antimicrobial activity and may therefore act as antimicrobial peptides in the immune system.
Macrocyclic compounds have received increasing attention in recent years. With their large surface area, they hold promise for inhibiting protein-protein interactions, a chemical space that was thought to be undruggable. Although many chemical methods have been developed for peptide macrocyclization, enzymatic methods have emerged as a promising new economical approach. Thus far, most enzymes have been shown to act on l-peptides; their ability to cyclize d-amino-acid-containing peptides has rarely been documented. Herein we show that macrocycles consisting of d-amino acids, except for the Asn residue at the ligating site, were efficiently synthesized by butelase 1, an Asn/Asp-specific ligase. Furthermore, by using a peptide-library approach, we show that butelase 1 tolerates most of the d-amino acid residues at the P1'' and P2'' positions.
Klebsiella pneumoniae is a Gram-negative pathogen responsible for a wide range of infections, including pneumonia and bacteremia, and is rapidly acquiring antibiotic resistance. K. pneumoniae requires secretion of siderophores, low-molecular-weight, high-affinity iron chelators, for bacterial replication and full virulence. The specific combination of siderophores secreted by K. pneumoniae during infection can impact tissue localization, systemic dissemination, and host survival. However, the effect of these potent iron chelators on the host during infection is unknown. In vitro, siderophores deplete epithelial cell iron, induce cytokine secretion, and activate the master transcription factor hypoxia inducible factor-1α (HIF-1α) protein that controls vascular permeability and inflammatory gene expression. Therefore, we hypothesized that siderophore secretion by K. pneumoniae directly contributes to inflammation and bacterial dissemination during pneumonia. To examine the effects of siderophore secretion independently of bacterial growth, we performed infections with tonB mutants that persist in vivo but are deficient in siderophore import. Using a murine model of pneumonia, we found that siderophore secretion by K. pneumoniae induces the secretion of interleukin-6 (IL-6), CXCL1, and CXCL2, as well as bacterial dissemination to the spleen, compared to siderophore-negative mutants at an equivalent bacterial number. Furthermore, we determined that siderophore-secreting K. pneumoniae stabilized HIF-1α in vivo and that bacterial dissemination to the spleen required alveolar epithelial HIF-1α. Our results indicate that siderophores act directly on the host to induce inflammatory cytokines and bacterial dissemination and that HIF-1α is a susceptibility factor for bacterial invasion during pneumonia.
Klebsiella pneumoniae causes a wide range of bacterial diseases, including pneumonia, urinary tract infections, and sepsis. To cause infection, K. pneumoniae steals iron from its host by secreting siderophores, small iron-chelating molecules. Classically, siderophores are thought to worsen infections by promoting bacterial growth. In this study, we determined that siderophore-secreting K. pneumoniae causes lung inflammation and bacterial dissemination to the bloodstream independently of bacterial growth. Furthermore, we determined that siderophore-secreting K. pneumoniae activates a host protein, hypoxia inducible factor (HIF)-1α, and requires it for siderophore-dependent bacterial dissemination. Although HIF-1α can protect against some infections, it appears to worsen infection with K. pneumoniae Together, these results indicate that bacterial siderophores directly alter the host response to pneumonia in addition to providing iron for bacterial growth. Therapies that disrupt production of siderophores could provide a two-pronged attack against K. pneumoniae infection by preventing bacterial growth and preventing bacterial dissemination to the blood.
Under conditions of tight coupling between translation and transcription, the ribosome enables synthesis of full-length mRNAs by preventing both formation of intrinsic terminator hairpins and loading of the transcription termination factor Rho. While previous studies have focused on transcription factors, we investigated the role of Escherichia coli elongation factor P (EF-P), an elongation factor required for efficient translation of mRNAs containing consecutive proline codons, in maintaining coupled translation and transcription. In the absence of EF-P, the presence of Rho utilization (rut) sites led to an ~30-fold decrease in translation of polyproline-encoding mRNAs. Coexpression of the Rho inhibitor Psu fully restored translation. EF-P was also shown to inhibit premature termination during synthesis and translation of mRNAs encoding intrinsic terminators. The effects of EF-P loss on expression of polyproline mRNAs were augmented by a substitution in RNA polymerase that accelerates transcription. Analyses of previously reported ribosome profiling and global proteomic data identified several candidate gene clusters where EF-P could act to prevent premature transcription termination. In vivo probing allowed detection of some predicted premature termination products in the absence of EF-P. Our findings support a model in which EF-P maintains coupling of translation and transcription by decreasing ribosome stalling at polyproline motifs. Other regulators that facilitate ribosome translocation through roadblocks to prevent premature transcription termination upon uncoupling remain to be identified.
Bacterial mRNA and protein syntheses are often tightly coupled, with ribosomes binding newly synthesized Shine-Dalgarno sequences and then translating nascent mRNAs as they emerge from RNA polymerase. While previous studies have mainly focused on the roles of transcription factors, here we investigated whether translation factors can also play a role in maintaining coupling and preventing premature transcription termination. Using the polyproline synthesis enhancer elongation factor P, we found that rapid translation through potential stalling motifs is required to provide efficient coupling between ribosomes and RNA polymerase. These findings show that translation enhancers can play an important role in gene expression by preventing premature termination of transcription.
In this work, we assessed the anti-inflammatory effects of paeonol (PAE) in LPS-activated N9 microglia cells, as well as its underlying molecular mechanisms. PAE had no adverse effect on the viability of murine microglia N9 cell line within a broad range (0.12∼75 μM). When N9 cell line was activated by LPS, PAE (0.6, 3, 15 μM) significantly suppressed the release of proinflammatory products, such as nitric oxide (NO), interleukin-1β (IL-1β), and prostaglandin E2 (PGE2), demonstrated by the ELISA assay. Moreover, the
 levels of cyclooxygenase-2 (COX-2) and inducible nitric oxide synthase (iNOS) were significantly reduced in PAE-treated N9 microglia cells. We also examined some proteins involved in immune signaling pathways and found that PAE treatment significantly decreased the expression of TLR4, MyD88, IRAK4, TNFR-associated factor 6 (TRAF6), p-IkB-α, and NF-kB p65, as well as the mitogen-activated protein kinase (MAPK) pathway molecules p-P38, p-JNK, and p-ERK, indicating that PAE might act on these signaling pathways to inhibit inflammatory responses. Overall, we found that PAE had anti-inflammatory effect on LPS-activated N9 microglia cells, possibly via inhibiting the TLR4 signaling pathway, and it could be a potential drug therapy for inflammation-associated neurodegenerative diseases.
Adults with poor mental health may want and need insurance to obtain care, but symptoms may impede enrollment into public health insurance. This study compares Medicaid enrollment responses to eligibility expansions by mental health status using a sample of non-elderly adults in both the 2000-2011 Medical Expenditure Panel Survey and the National Health Interview Survey (N = 27,494). The impact of Medicaid income eligibility thresholds (defined as the maximum family income level allowed in each state to be considered eligible for Medicaid) on Medicaid enrollment was estimated from linear regression models allowing for differential enrollment responses by mental and physical health status. Increasing income eligibility thresholds by 100% of the federal poverty level (FPL) was associated with a five-percentage-point increase in the probability of Medicaid enrollment in the non-disabled population under 300% FPL. The enrollment response to Medicaid expansions prior to the Affordable Care Act was stronger for adults symptomatic of psychological distress compared with adults without distress and compared to adults with chronic physical health problems.
Obesity continues to be a major global problem. Various cancers are related to obesity and proper understanding of their aetiology, especially their molecular tumour biology is important for early diagnosis and better treatment. Genes play an important role in the development of obesity. Few genes such as leptin, leptin receptor encoded by the db (diabetes), pro-opiomelanocortin, AgRP and NPY and melanocortin-4 receptors and insulin-induced gene 2 were linked to obesity. MicroRNAs control gene expression via mRNA degradation and protein translation inhibition and influence cell differentiation, cell growth and cell death. Overexpression of miR-143 inhibits tumour growth by suppressing B cell lymphoma 2, extracellular signal-regulated kinase-5 activities and KRAS oncogene. Cancers of the breast, uterus, renal, thyroid and liver are also related to obesity. Any disturbance in the production of sex hormones and insulin, leads to distortion in the balance between cell proliferation, differentiation and apoptosis. The possible mechanism linking obesity to cancer involves alteration in the level of adipokines and sex hormones. These mediators act as biomarkers for cancer progression and act as targets for cancer therapy and prevention. Interestingly, many anti-cancerous drugs are also beneficial in treating obesity and vice versa. We also reviewed the possible link in the mechanism of few drugs which act both on cancer and obesity. The present review may be important for molecular biologists, oncologists and clinicians treating cancers and also pave the way for better therapeutic options.
Cocaine use leads to health, social and legal problems. The aim of this paper is to discuss cocaine action, addicts characteristics, use patterns and consequences, as well as addiction treatment methods. A literature review was based on the Medline, PubMed, Polish Medical Bibliography databases and the Silesian Library resources. The Police and Central Statistical Office statistics, as well as the World Health Organization, the European Monitoring Centre for Drugs and Drug Addiction and the National Office for Combating Drug Addiction reports were used. Cocaine leads to mood improvement, appetite decrease, physical and intellectual activity enhancement, euphoria, inflated self-esteem, social networking ease and increased sexual desire. Cocaine hydrochloride is mainly used intranasaly, but also as intravenous and subcutaneous injections. Cocaine use and first addiction treatment fall in later age compared to other psychoactive substances. There is a high men to women ratio among addicts. There is a relationship between cocaine addiction, the presence of other disorders and genetic predisposition to addiction development. Polish reports indicate higher popularity of cocaine among people with a high economic and social status. Although Poland is a country with the low percentage of cocaine use, its popularity is growing. The consequences of cocaine use concern somatic and mental health problems, socioeconomic and legal conditions. The drug plays a role in crimes and traffic accidents. Because of the risks associated with cocaine use, it has been listed in a register of drugs attached to the Act on Counteracting Drug Addiction. Addiction treatment includes psychological, pharmacological and harm reduction strategies. Med Pr 2016;67(4):537-544.
Używanie kokainy niesie konsekwencje zdrowotne, społeczne i prawne. Celem publikacji jest omówienie działania kokainy, charakterystyki osób używających, schematów i konsekwencji uzależnienia oraz metod leczenia. Przeglądu literatury dokonano, używając baz bibliograficznych Medline, PubMed i Polskiej Bibliografii Lekarskiej oraz zasobów Biblioteki Śląskiej. Korzystano również ze statystyk policji i Głównego Urzędu Statystycznego oraz raportów Światowej Organizacji Zdrowia (World Health Organization), Europejskiego Centrum Monitorowania Narkotyków i Narkomanii (European Monitoring Centre for Drugs and Drug Addiction) oraz polskiego Krajowego Biura ds. Przeciwdziałania Narkomanii. Kokaina powoduje poprawę samopoczucia, zmniejszenie łaknienia, wzrost aktywności fizycznej i intelektualnej, euforię, zawyżoną samoocenę, łatwość nawiązywania kontaktów i nasilenie popędu seksualnego. Chlorowodorek kokainy stosuje się głównie donosowo, ale także w postaci wstrzyknięć dożylnych i podskórnych. Pierwsze zażycie kokainy i pierwsze leczenie odwykowe przypadają w późniejszym wieku niż w przypadku pozostałych nielegalnych substancji psychoaktywnych. Wśród osób uzależnionych od kokainy znacząco przeważają mężczyźni. Stwierdzono związek kokainizmu z obecnością innych zaburzeń psychicznych i somatycznych oraz genetyczną predyspozycję do rozwoju uzależnienia. Polskie doniesienia wskazują na większe rozpowszechnienie tego narkotyku wśród osób o wysokim statusie ekonomicznym i społecznym. Mimo że Polska należy do krajów o niskim odsetku stosowania kokainy, jej popularność rośnie. Konsekwencje używania kokainy dotyczą zdrowia somatycznego i psychicznego oraz warunków socjalnych, społeczno- ekonomicznych i prawnych. Używanie kokainy niejednokrotnie było przyczyną przestępstw i wypadków komunikacyjnych. Z uwagi na zagrożenia związane ze stosowaniem kokainy została ona umieszczona w wykazie środków odurzających w Ustawie o przeciwdziałaniu narkomanii. Leczenie uzależnienia obejmuje terapię psychologiczną i farmakologiczną oraz strategię redukcji szkód. Med. Pr. 2016;67(4):537–544.
To learn, obtain reward and survive, humans and other animals must monitor, approach and act on objects that are associated with variable or unknown rewards. However, the neuronal mechanisms that mediate behaviours aimed at uncertain objects are poorly understood. Here we demonstrate that a set of neurons in an internal-capsule bordering regions of the primate dorsal striatum, within the putamen and caudate nucleus, signal the uncertainty of object-reward associations. Their uncertainty responses depend on the presence of objects associated with reward uncertainty and evolve rapidly as monkeys learn novel object-reward associations. Therefore, beyond its established role in mediating actions aimed at known or certain rewards, the dorsal striatum also participates in behaviours aimed at reward-uncertain objects.
Aging is an inevitable process influenced by genetic, lifestyle and environmental factors. Indirect evidence shows that several phytochemicals can have anti-aging capabilities, although direct evidence in this field is still limited. This report aims to provide a critical review on aspects related to the use of novel phytochemicals as anti-aging agents, to discuss the obstacles found when performing most anti-aging study protocols in humans, and to analyze future perspectives. In addition to the extensively studied resveratrol, epicatechin, quercetin and curcumin, new phytochemicals have been reported to act as anti-aging agents, such as the amino acid L-theanine isolated from green tea, and the lignans arctigenin and matairesinol isolated from Arctium lappa seeds. Furthermore, this review discusses the application of several new extracts rich in phytochemicals with potential use in anti aging therapies. Finally, this review also discusses the most important biomarkers to test anti-aging interventions, the necessity of conducting epidemiological studies and the need of clinical trials with adequate study protocols for humans.
Treatment failures of human cystic echinococcosis (CE) with albendazole (ABZ) have attributed to its low solubility and poor drug absorption rate, resulting in low drug level in plasma. The scolicidal effects of ABZ-loaded liposome nanoparticles have recently evaluated; however, these particles have several challenges due to their low encapsulated load. This investigation was designed to evaluate and compare in vitro apoptotic activities of ABZ sulfoxide (ABZs) and ABZs-loaded poly(lactic-co-glycolic
 acid) (PLGA)-PEG against protoscoleces (PSCs). ABZs-loaded PLGA-PEG was prepared by a double-emulsion method (W1/O/W2). Various concentrations of ABZs and ABZs-loaded PLGA-PEG (50, 100, 150, and 200 μg/ml) were experimentally tested against PSC of CE at different exposure times (5, 10, 20, 30, and 60 min). ABZs-loaded PLGA-PEG at concentrations of 150 and 200 μg/ml was able to act at a 100 % scolicidal rate in all exposure times (5 to 60 min), while ABZs at a concentration of 200 μg/ml demonstrated 94, 100, and 100 % mortality rates following 20, 30, and 60 min of exposure times, respectively. The messenger RNA (mRNA) expression of caspase-3 was assessed by semi-quantitative RT-PCR after 15 h of exposure. Caspase-3 mRNA expression was higher in both PSC treated with ABZs and PSC treated with ABZs-loaded PLGA-PEG than that in control groups (P < 0.05). No significant difference was observed between the apoptotic intensity of PSC treated with ABZs and that of PSC treated with ABZs-loaded PLGA-PEG (P > 0.05). DNA fragmentation assay and ultrastructural changes revealed that ABZs and ABZs-loaded PLGA-PEG induced the apoptosis of PSC by activation of caspase-3. The higher permeability and scolicidal rate of ABZs-loaded PLGA-PEG can be addressed as an effectual alternative strategy to improve the treatment of human CE.
Several sparsity-constrained algorithms, such as orthogonal matching pursuit (OMP) or the Frank-Wolfe (FW) algorithm, with sparsity constraints work by iteratively selecting a novel atom to add to the current nonzero set of variables. This selection step is usually performed by computing the gradient and then by looking for the gradient component with maximal absolute entry. This step can be computationally expensive especially for large-scale and high-dimensional data. In this paper, we aim at accelerating these sparsity-constrained optimization algorithms by exploiting the key observation that, for these algorithms to work, one only needs the coordinate of the gradient's top entry. Hence, we introduce algorithms based on greedy methods and randomization approaches that aim at cheaply estimating the gradient and its top entry. Another of our contribution is to cast the problem of finding the best gradient entry as a best-arm identification in a multiarmed bandit problem. Owing to this novel insight, we are able to provide a bandit-based algorithm that directly estimates the top entry in a very efficient way. Theoretical observations stating that the resulting inexact FW or OMP algorithms act, with high probability, similar to their exact versions are also given. We have carried out several experiments showing that the greedy deterministic and the bandit approaches we propose can achieve an acceleration of an order of magnitude while being as efficient as the exact gradient when used in algorithms, such as OMP, FW, or CoSaMP.
Immune system deregulation and evasion play a key role in cancers' evolution and progression, including squamous cell carcinoma of the head and neck (SCCHN). Development of basic research proposed a whole new vision of cancer treatment, based on a strong biological rational, and targeting intrinsic deregulations. Immunotherapies provide an encouraging strategy for patients' improved outcomes. Immune-based therapies could act on cancer growth and/or development throughout many pathways. If cetuximab is for now the only monoclonal antibody approved for SCCHN management, other strategies, e.g. immune checkpoints openers, are arousing enthusiasm. Clinical trials are multiplying in patients with recurrent/metastatic SCCHN and primary results offer promising outcomes. Prospects of combining various immunotherapies with more established treatments, such as chemotherapy and radiotherapy, seem very encouraging and could provide synergistic benefits. Ongoing phase III clinical trials should soon enlighten us on the next "standard of care" for SCCHN. In the present review we summarized the different immunotherapy strategies that are currently under clinical investigation for SCCHN' medical care.
Functional fitness (FF) and gait ability in older populations have been associated with increased survival rates, fall prevention and quality of life. One possible intervention for the improvement of FF is well-structured exercise programs. However, there are inconsistent findings regarding the effects of exercise interventions in the maintenance of gait parameters. The aim of this protocol is to develop a community-based exercise intervention targeting an older population. The intervention aim is the improvement of gait parameters and FF. A control trial with follow-up will be performed. The primary outcome variables will be plantar pressure gait parameters. The secondary outcome variables will be aerobic endurance, lower limb strength, agility, and balance. These variables will be recorded at baseline and after 12, 24 and 36 weeks, in the intervention and control groups. If effective, this protocol can be used by exercise professionals in improving community exercise programs.
This study investigated the relationships between muscle echo intensity (EI), physical activity (PA) and functional mobility in 108 Japanese (88-92 years). We measured EI and muscle thickness (MT) at the midpoint of the anterior superior iliac spine and patella using B-mode ultrasound. Light and moderate to vigorous PA (LPA and MVPA) were assessed with a tri-axial accelerometer. Timed up and go (TUG) test was measured for functional mobility. EI, but not MT, was significantly associated with both TUG scores (β=0.17, p=0.047) and MVPA (β=-0.31, p=0.01) adjusted by potential confounders. However, association between EI and TUG was disappeared after adjusted by MVPA. Meanwhile, MVPA was significantly associated with TUG scores independent of EI (β=-0.35, p<0.001). Although EI of anterior thigh muscles might be a weaker predictor of functional morbidity than MVPA, it is a non-invasive and practical approach for assessing muscle quality in the very old.
We tested a social cognitive model of physical activity (PA) in the cultural context of the Czech Republic, a post-communist central European country. In total, 546 older Czech adults (mean age=68 years, data collected in 2013) completed a battery of questionnaires assessing indicators of PA and related social cognitive constructs, including self-efficacy, social support, and self-regulation strategies. Subsequently, a structural equation model was used to test the relationship between the social cognitive constructs and PA. Our analyses indicated an acceptable fit of the proposed model (CFI=.911; SRMR=.046; RMSEA=.073). Self-regulation was predicted by self-efficacy (β=.67) and social support (β =.23), which predicted PA (β=.45). The model explained 60.4% of the variance in PA self-regulation and 20.5% of the variance in PA participation. The results provide further evidence for the role of self-efficacy and social support in enabling PA in older adults, and suggest that this relationship is partially mediated by self-regulation.
Bacterial biofilms are problematic in natural and anthropogenic environments, and they confer protective properties on their constituent cells, making them difficult to treat with conventional antibiotics. Antibiofilm strategies, therefore, represent a promising direction of research for treating biofilm infections. Natural autodispersal and interspecies dispersal signaling pathways provide insight into cell-cell communication mechanisms, species dynamics in mixed communities, and potential targets for infection therapies. Here, we describe a novel interspecies dispersal signaling pathway between Pseudomonas aeruginosa and Escherichia coli. E. coli biofilms disperse in response to compounds in P. aeruginosa culture supernatant. Two components of the P. aeruginosa Las and Rhl quorum sensing systems, N-(3-oxo-dodecanoyl) homoserine lactone (3oxoC12HSL) and rhamnolipids, are found to act cooperatively to disperse E. coli biofilms. Our results indicate that rhamnolipids do not affect growth, biofilm development, or dispersal in E. coli but instead complement 3oxoC12HSL signaling by inducing selective permeability of the E. coli membrane. The increased target cell permeability is consistent with rhamnolipid-mediated removal of lipopolysaccharide from E. coli membranes and appears to selectively increase the permeability of lipophilic acyl homoserine lactones. This work suggests that rhamnolipids play a critical role in P. aeruginosa-E. coli interspecies signaling. Rhamnolipids and other biosurfactants may have similar effects in other intra- and interspecies chemical signaling pathways.
A core component of family-centred nursing care during the provision of end-of-life care in intensive care settings is information sharing with families. Yet little is known about information provided in these circumstances.
To identify information most frequently given by critical care nurses to families in preparation for and during withdrawal of life-sustaining treatment.
An online cross-sectional survey.
During May 2015, critical care nurses in Australia and New Zealand were invited to complete the Preparing Families for Treatment Withdrawal questionnaire. Data analysis included descriptive statistics to identify areas of information most and least frequently shared with families. Cross tabulations with demographic data were used to explore any associations in the data.
From the responses of 159 critical care nurses, information related to the emotional care and support of the family was most frequently provided to families in preparation for and during withdrawal of life-sustaining treatment. Variation was noted in the frequency of provision of information across body systems and their associated physical changes during the dying process. Significant associations (p<0.05)
 were identified between the variables gender, nursing experience and critical care experiences and some of the information items most and least frequently provided.
The provision of information during end-of-life care reflects a family-centred care approach by critical care nurses with information pertaining to emotional care and support of the family paramount. The findings of this study provide a useful framework for the development of interventions to improve practice and support nurses in communicating with families at this time.
The efficacy of the use of an upper body compression garment (UBCG) as an ergogenic aid to reduce thermoregulatory strain in older adults remains unknown. The aim of this study was to evaluate the effects of UBCG on thermoregulatory, cardiorespiratory and perceptual responses during cycling in a temperate environment (~25ºC, 66% rh) in trained older adults. Twelve cyclists aged 66±2 years performed an intermittent 1-h cycling trial at 50% of the peak power output followed by 10 min of passive recovery. Participants were provided with either commercially available UBCG or control garment in a randomized order. UBCG increased thermoregulatory strain during exercise, as indicated by a significantly higher core temperature (38.1±0.3ºC vs. 37.9±0.3ºC;p=.04), body temperature (36.9±0.2ºC vs. 36.7±0.2ºC;p=.01) and thermal sensation (8.0±0.4 vs. 7.5±1.0;p=.02). These results suggest that the use of UBCG in trained older adults does not reduce the thermoregulatory strain during moderate exercise.
Participation in surfing has evolved to include all age groups. Therefore, the purpose of this study was to determine whether activity levels and cardiovascular responses to surfing change with age. Surfing time and heart rate (HR) were measured for the total surfing session and within each activity of surfing (paddling, sitting, wave-riding and miscellaneous). Peak oxygen consumption (VO2peak) was also measured during a laboratory-based simulated surfboard paddling on a modified swim bench ergometer. VO2peak decreased with age during simulated paddling (r=-0.455, p<0.001, n=68). Total time surfing (p=0.837) and time spent within each activity of surfing did not differ with age (n=160). Mean HR during surfing significantly decreased with age (r=-0.231, p=0.004). However, surfing HR expressed as a percent of age-predicted maximum increased significantly with age. Therefore, recreational surfers across the age spectrum are achieving intensities and durations that are consistent with guidelines for cardiovascular health.
Natural oils are extremely complex mixtures containing compounds of different chemical nature. Some of them have physiological or therapeutic activities that may act either alone or in synergy. Therefore, they are used in the pharmaceutical, agronomic, food, sanitary and cosmetic industries. Today, the interest in bioactive natural oils is growing due to their immense potential to prevent and treat numerous human diseases. Formulation in microemulsions (MEs) containing natural oils appeared suitable to improve pharmaceutical and biopharmaceutical properties of bioactive compound derivatives from these oils. Microemulsion systems are thermodynamically stable, transparent, and are isotropic dispersions consisting of oil and water stabilized by an interfacial film of surfactants, typically in combination with a cosurfactant. They can protect labile compounds from premature degradation, control release, increase solubility and hence enhance the bioavailability of poorly bioavailable compounds. The aim of this work was to review the various advantages of bioactive compounds presented in natural oil loaded ME systems to be used as delivery systems. First, the state of the art of the parameters involved in the ME formation, including the basic concepts of the physicochemical formulation of the ME systems, and the main aspects of production and the energy responsible for their formation were reported. The second section describes the use of ME systems and reviews the recent applications of natural oil-loaded in the ME systems as the bioactive compound in the formulation.
The purpose of study was to demonstrate age-related changes during gait initiation (GI). Therefore, displacement, velocity, total power, mean and median frequency of COP trajectories were measured during phases of GI in anteroposterior (AP) and mediolateral (ML) directions. The older group demonstrated the slower and lesser displacement in comparison to the younger group during anticipatory phase in AP direction and during locomotor phase in AP and ML directions. Also, the median and mean frequency were greater in the older relative to the younger group during anticipatory phase in AP direction, while these were lesser in older than younger group during locomotor phase in AP and ML directions. Moreover, total power was greater among older than younger adults during the anticipatory phase in ML direction and during all phases in AP direction. This study suggests that COP-related parameters extracted from time and frequency domains have the ability to demonstrate age-related changes.
The Texas Medical Association has made recommendations to improve the Centers for Medicare &amp; Medicaid Services&#39; proposed rule to implement the Medicare Access and CHIP Reauthorization Act (MACRA), which results in numerous compliance and administrative hassles.
Advances in the knowledge of acromegaly are leading to an increase in the survival rate of acromegalic subjects. This study was conducted to evaluate balance control, risk of falls, and peripheral muscle function in the acromegalic elderly. Seventeen elderly subjects with acromegaly (67 (63-73) years) and twenty paired control subjects were evaluated with balance scales, force platform, and knee isokinetic dynamometry tests. There were significant differences between the groups on several balance and gait scales, with a worse performance and risk of falls in the acromegalic elderly. The acromegalic elderly had lower values for peak torque, maximum repetition of the total work, and total work in extension at 240º/s. The acromegalic elderly have higher values in the medial-lateral range. Acromegaly elderly subjects had lateral instability that compromises their body balance and increases the risk of falls. Moreover, there is a propensity for muscle fatigue in these individuals.
In the JAPA supplement (JAPA 24[Suppl.], June 2016), which contained the abstracts for the 9th World Congress on Active Ageing, an incorrect abstract appears on page S102. This abstract, "An Australian Unique Way of Addressing the Research-Selling Health and Wellness to the Over 60s with Active Life Weekends", by B. Lord, was a duplicate of an earlier printed abstract. The correct abstract appears below. We apologize for this error. The online version has been corrected.
No abstract available for this article.
The coagulation system provides a primitive but effective defense against hemorrhage. Soluble fibrinogen (Fg) monomers, composed of α, β and γ chains, are recruited to provide structural support for the formation of a hemostatic plug. Fg binds to platelets and is processed into a cross-linked fibrin polymer by the enzymatic clotting factors, thrombin and Factor XIII (FXIII). The newly formed fibrin-platelet clot can act as barrier to protect against pathogens from entering the bloodstream. Further, injuries caused by bacterial infections can be confined to the initial wound site. Many pathogenic bacteria have Fg-binding adhesins that can circumvent the coagulation pathway and allow the bacteria to sidestep containment. Fg expression is upregulated during lung infection providing an attachment surface for bacteria with the ability to produce Fg-binding adhesins. Fg binding by leptospira might play a crucial factor in Leptospira-associated pulmonary hemorrhage, the main factor contributing to lethality in severe cases of leptospirosis. The 12th domain of Leptospira immunoglobulin-like protein B (LigB12), a leptospiral adhesin, interacts with the C-terminus of FgαC (FgαCC). In this study, the binding site for LigB12 was mapped to the final 23 amino acids at the C-terminal end of FgαCC (FgαCC8). The association of FgαCC8 with LigB12 (ELISA, KD = 0.76 μM; SPR, KD = 0.96 μM) was reduced by mutations of both charged residues (R608, R611 and H614 from FgαCC8; D1061 from LigB12) and hydrophobic residues (I613 from FgαCC8; F1054 and A1065 from LigB12). Additionally, LigB12 bound strongly to FXIII and also inhibited fibrin formation, suggesting that LigB can disrupt coagulation by suppressing FXIII activity. Here, the detailed binding mechanism of a leptospiral adhesin to a host hemostatic factor is characterized for the first time and should provide better insight into the pathogenesis of leptospirosis.
To investigate differences in self-reported health among Australian women with a history of intimate partner violence (IPV) in relation to rurality of residence.
Data were drawn from six survey waves of the Australian Longitudinal Study on Women's Health 1973-78 birth cohort. Self-reported general and mental health scores derived from the SF-36 scale were compared for women with a history of IPV living in metropolitan, regional and rural areas. Multivariable generalised estimating equations were constructed adjusting for income hardship, number of children, education, social support, age and marital status.
Women with a history of IPV living in regional and rural areas had no significant differences in self-reported general health scores compared to their metropolitan counterparts. Rural women affected by IPV had slightly better self-reported mental health than equivalent women living in metropolitan or regional areas. The socio-demographic factors with the strongest association with self-reported health were income,
 education, social support, and number of children.
Women in regional and rural areas were no more disadvantaged, in terms of self-reported general health or mental health, than IPV affected women living in major cities in Australia.
Delta/Notch-like EGF-related receptor (DNER) has been reported to act as a Notch ligand, despite lacking a Delta/Serrate/Lag (DSL) binding domain common to all other known ligands. The established Notch ligand Delta-like 1 (DLL1), but not DNER, activated Notch1 in a luciferase assay, prevented the differentiation of myoblasts through Notch signaling, and bound Notch-fc in a cell-based assay. DNER is not a Notch ligand and its true function remains unknown.
Adoptive cell transfer therapy has emerged as a powerful treatment for metastatic melanoma, but efficacy is limited by an inhospitable tumor microenvironment. In this issue of Cancer Cell, Marigo et al. demonstrate that therapy requires induced expression of nitric oxide synthase 2 in monocyte-derived dendritic cells.
Research toward renewable and sustainable energy has identified specific terpenes capable of supplementing or replacing current petroleum-derived fuels. Despite being naturally produced and stored by many plants, there are few examples of commercial recovery of terpenes from plants because of low yields. Plant terpene biosynthesis is regulated at multiple levels, leading to wide variability in terpene content and chemistry. Advances in the plant molecular toolkit, including annotated genomes, high-throughput omics profiling, and genome editing, have begun to elucidate plant terpene metabolism, and such information is useful for bioengineering metabolic pathways for specific terpenes. We review here the status of terpenes as a specialty biofuel and discuss the potential of plants as a viable agronomic solution for future terpene-derived biofuels.
General practice registrars in Australia are expected to identify and address their knowledge or skills gaps during consultations. The content and frequency of registrars seeking assistance and the factors that influence this have been studied for 84,723 consultations. Term 1 registrars asked their supervisor for help in 11.0% of consultations, but by term 4 this reduced to 1.2% of consultations. Assistance was most often for skin or musculoskeletal conditions, and more often about management than diagnosis.
This article discusses the implications of this information for Australian general practice training.
Registrars asked their supervisors for assistance despite having ready access to electronic information. Practices can anticipate supervisor interruptions approximately every tenth registrar consultation. The greater input required by registrars from supervisors earlier in training should be acknowledged by more flexible standards and payments to practices. A priority for general practice supervisor professional development is how to teach the management of complex patients, dermatology and musculoskeletal medicine.
Aeromonas spp. cause various intestinal and extraintestinal diseases. These bacteria are usually isolated from fecal samples, especially in children under five years old. The aim of this study was to assess the prevalence of Aeromonas spp. and their antimicrobial resistance profile in children with diarrhea referred to the Children Medical Center in Tehran, between 2013 and 2014.
A total number of 391 stool samples were collected from children with ages between 1 day and 14 years old, with diarrhea (acute or chronic), referred to the Children Hospital, Tehran, Iran, between 2013 and 2014. Samples were enriched in alkaline peptone water broth for 24 hours at 37 °C and then cultured. Suspicious colonies were analyzed through biochemical tests. Furthermore, antimicrobial susceptibility tests were carried out for the isolates. Isolates were further studied for act, ast, alt, aerA and hlyA virulence genes using polymerase chain reaction.
In total, 12 isolates (3.1%) were identified as Aeromonas spp.; all were confirmed using the API-20E test. Of these isolates, five A. caviae (42%), four A. veronii (33%) and three A. hydrophila (25%) were identified in cases with gastroenteritis. Second to ampicillin (which was included in the growth medium used), the highest rate of antimicrobial resistance was seen against nalidixic acid and trimethoprim-sulfamethoxazole (5 isolates each, 41.6%) and the lowest rate of antimicrobial resistance was seen against gentamicin, amikacin and cefepime (none of the isolates). Results included 76.4% act, 64.7% ast, 71.5% alt, 83.3% aerA and 11.7% hlyA genes.
Aeromonas spp. are important due to their role in diarrhea in children; therefore, isolation and identification of these fecal pathogens should seriously be considered in medical laboratories. Since virulence genes play a significant role in gastroenteritis symptoms caused by these bacteria, Aeromonas species that include virulence genes are potentially suspected to cause severe infections. Moreover, bacterial antimicrobial resistance is increasing, especially against trimethoprim-sulfamethoxazole and nalidixic acid.
In theory, the immunotherapy of cancer should induce the selective destruction of cancer cells and a long-term specific protection, based on the specificity and memory of immunity. This contrasts with the collateral damages of conventional therapies and their toxic effects on host tissues. However, recent data suggest that chemotherapy may potentiate ongoing immune responses, through homeostatic mechanisms. Massive tumor death, empty "immune" niches and selected cytokines may act as a danger signal, alerting the immune system and amplifying pre-existing antitumor reactivity.
To evaluate the role of computed tomography (CT) in preoperative diagnosis of intrathymic cyst and small thymoma, and determine the best CT threshold for distinguish intrathymic cyst from small thymoma.
We retrospectively reviewed the medical records of 30 patients (17 intrathymic cyst and 13 small thymoma) who had undergone mediastinal masses resection (with diameter less than 3 cm) under thoracoscope between January 2014 and July 2015 at our hospital. Clinical and CT features were compared and receiver-operating characteristics curve (ROC) analysis was performed.
The CT value of small thymoma [39.5 HU (IQR, 33.7-42.2 HU)] was significantly higher than intrathymic cyst [25.8 HU (IQR, 22.3-29.3 HU), P=0.004]. When CT value was 31.2 HU, it could act as a threshold for identification of small thymoma and intrathymic cyst (the sensitivity and specificity was 92.3% and 82.4%, respectively). The ΔCT value of enhanced CT value with the non-enhanced CT value was significantly different between small thymoma [18.7 HU (IQR, 10.9-19.0 HU)] and intrathymic cyst [4.3 HU (IQR, 3.0-11.7 HU), P=0.04]. The density was more homogenous in intrathymic cyst than small thymoma, and the contour of the intrathymic cyst was more smoothly than small thymoma.
Preoperative CT scans could help clinicians to identify intrathymic cyst and small thymoma, and we recommend 31.2 HU as the best thresholds. Contrast-enhanced CT scans is useful for further identification of the two diseases.
Polymorphisms in the type III interferon IFN-λ3 and the killer cell immunoglobulin-like receptor (KIR) genes controlling the activity of natural killer (NK) cells can predict spontaneous resolution of acute hepatitis C virus (HCV) infection. We hypothesized that IFN-λ3 polymorphism may modulate NK cell function during acute HCV.
We monitored the plasma levels of type III IFNs in relation to the phenotype and the function of NK cells in a cohort of people who inject drugs (PWID) during acute HCV infection with different outcomes.
Early acute HCV was associated with high variability in type III IFNs plasma levels and the favorable IFN-λ3 CC genotype was associated with higher viral loads. Reduced expression of Natural Killer Group Protein 2A (NKG2A) was associated with lower IFN-λ3 plasma levels and the CC genotype. IFN-γ production by NK cells was higher in individuals with the CC genotype during acute infection but this did not prevent viral persistence. IFN-λ3 plasma levels did not correlate with function of NK cells and IFN-λ3 prestimulation did not affect NK cell activation and function.
These results suggest that IFN-λ3 polymorphism indirectly influences NK cell phenotype and function during acute HCV but other factors may act in concert to determine the outcome of the infection.
This review discusses the status, antimicrobial mechanisms, application, and regulation of natural preservatives in livestock food systems. Conventional preservatives are synthetic chemical substances including nitrates/nitrites, sulfites, sodium benzoate, propyl gallate, and potassium sorbate. The use of artificial preservatives is being reconsidered because of concerns relating to headache, allergies, and cancer. As the demand for biopreservation in food systems has increased, new natural antimicrobial compounds of various origins are being developed, including plant-derived products (polyphenolics, essential oils, plant antimicrobial peptides (pAMPs)), animal-derived products (lysozymes, lactoperoxidase, lactoferrin, ovotransferrin, antimicrobial peptide (AMP), chitosan and others), and microbial metabolites (nisin, natamycin, pullulan, ε-polylysine, organic acid, and others). These natural preservatives act by inhibiting microbial cell walls/membranes, DNA/RNA replication and transcription, protein synthesis, and metabolism. Natural preservatives have been recognized for their safety; however, these substances can influence color, smell, and toxicity in large amounts while being effective as a food preservative. Therefore, to evaluate the safety and toxicity of natural preservatives, various trials including combinations of other substances or different food preservation
 systems, and capsulation have been performed. Natamycin and nisin are currently the only natural preservatives being regulated, and other natural preservatives will have to be legally regulated before their widespread use.
Previously, we found that the expression of decoy receptor 3 (DcR3) in gliomas was significantly upregulated compared to normal brain tissues. However, the effect of DcR3-specific small interfering RNA (siRNA) on cell biological function of glioma cells remains incompletely understood.
The aim of this study was to explore the effect of DcR3 siRNA on cell growth and apoptosis of glioma cells and to investigate the potential downstream pathways affected by DcR3.
DcR3-specific siRNA was transfected into three glioma cell lines (U251MG, LN-308, and U87MG) using combiMAGnetofection method. MTS tetrazolium assay and fluorimetric resorufin viability assay were used to assess the growth of glioma cells. Then, apoptosis was examined using the Hoechst 33342/propidium iodide double-staining assay and fluorescent caspase-3/7 assay. Meanwhile, Western blot was performed to explore the probable pathway by which DcR3-specific siRNA acts in glioma cells. Also, microarray dataset analysis was applied to analyze the potential function of DcR3 in glioma.
The DcR3-specific siRNA had a potent effect on cell growth and apoptosis of all three glioma cells tested, and the effects were time dependent. Among these three glioma cell lines, U251MG had the most significant effect with regard to growth inhibition and apoptosis induction. MTS assay showed that the proliferation rate at 72 and 96 hours after the transfection was 76.333%±5.131% (t=7.611, P=0.002) and 64.333%±5.859% (t=10.983, P<0.001), respectively. The viability rate of U251MG cells was 80.667%±2.309% (t=12.302, P<0.001) and 62.333%±2.082% (t=21.213, P<0.001) at 72 and 96 hours posttreatment, respectively. The caspase-3/7 activity of U251MG cells was 2.76 (t=-6.601, P=0.003) and 4.75 (t=-9.189, P=0.001) folds that of the mock control at 72 and 96 hours, respectively. The apoptosis rate was increased to 1.85 (t=-2.496, P=0.067) and 3.93 (t=-12.587, P<0.001) folds at 72 and 96 hours after transfection, respectively. Furthermore, the levels of phospho-ERK1/2 and phospho-AKT were significantly downregulated after DcR3 silencing.
The DcR3-specific siRNA could efficiently inhibit growth and induce apoptosis of cells via affecting ERK and AKT. Hence, DcR3-specific siRNA treatment could act as a supplementary targeted therapy strategy for gliomas.
Hepatocellular carcinoma (HCC) is one of the deadliest cancers in the world and is associated with a high risk of recurrence. The development of a wide range of new therapies is therefore essential. In this study, from the perspective of supportive therapy for the prevention of HCC recurrence and preservation of liver function in HCC patients, we surveyed a variety of different therapeutic agents. We show that branched chain amino acids (BCAA) supplementation and late evening snack with BCAA, strategies that address issues of protein-energy malnutrition, are important for liver cirrhotic patients with HCC. For chemoprevention of HCC recurrence, we show that viral control after radical treatment is important. We also reviewed the therapeutic potential of antiviral drugs, sorafenib, peretinoin, iron chelators. Sorafenib is a kinase inhibitor and a standard therapy in the treatment of advanced HCC. Peretinoin is a vitamin A-like molecule that targets the retinoid nuclear receptor to induce apoptosis and inhibit tumor growth in HCC cells. Iron chelators, such as deferoxamine and deferasirox, act to prevent cancer cell growth. These chelators may have potential as combination therapies in conjunction with peretinoin. Finally, we review the potential inhibitory effect of bone marrow cells on hepatocarcinogenesis.
The update of the global burden of disease attributable to the environment is presented. The study focuses on modifiable risks to show the potential health impact from environmental interventions.
Systematic literature reviews on 133 diseases and injuries were performed. Comparative risk assessments were complemented by more limited epidemiological estimates, expert opinion and information on disease transmission pathways. Population attributable fractions were used to calculate global deaths and global disease burden from environmental risks.
Twenty-three percent (95% CI: 13-34%) of global deaths and 22% (95% CI: 13-32%) of global disability adjusted life years (DALYs) were attributable to environmental risks in 2012. Sixty-eight percent of deaths and 56% of DALYs could be estimated with comparative risk assessment methods. The global disease burden attributable to the environment is now dominated by noncommunicable diseases. Susceptible ages are children under five and adults between 50 and 75 years. Country level data are presented.
Nearly a quarter of global disease burden could be prevented by reducing environmental risks. This analysis confirms that eliminating hazards and reducing environmental risks will greatly benefit our health, will contribute to attaining the recently agreed Sustainable Development Goals and will systematically require intersectoral collaboration to be successful.
Horizontal acquisition of novel chromosomal genes is considered to be a key process in the evolution of bacterial pathogens. However, the identification of gene presence or absence could be hindered by the inconsistencies in bacterial genome annotations. Here, we performed a cross-annotation of omnipresent core and mosaic accessory genes in the chromosome of Salmonella enterica serovar Typhimurium across a total of 20 fully assembled genomes deposited into GenBank. Cross-annotation resulted in a 32% increase in the number of core genes and a 3-fold decrease in the number of genes identified as mosaic genes (i.e., genes present in some strains only) by the original annotation. Of the remaining noncore genes, the vast majority were prophage genes, and 255 of the nonphage genes were actually of core origin but lost in some strains upon the emergence of the S Typhimurium serovar, suggesting that the chromosomal portion of the S Typhimurium genome acquired a very limited number of novel genes other than prophages. Only horizontally acquired nonphage genes related to bacterial fitness or virulence were found in four recently sequenced isolates, all located on three different genomic islands that harbor multidrug resistance determinants. Thus, the extensive use of antimicrobials could be the main selection force behind the new fitness gene acquisition and the emergence of novel Salmonella pathotypes.
Significant discrepancies in the annotations of bacterial genomes could mislead the conclusions about evolutionary origin of chromosomal genes, as we demonstrate here via a cross-annotation-based analysis of Salmonella Typhimurium genomes from GenBank. We conclude that despite being able to infect a broad range of vertebrate hosts, the genomic diversity of S Typhimurium strains is almost exclusively limited to gene loss and the transfer of prophage DNA. Only nonphage chromosomal genes acquired after the emergence of the serovar are linked to the genomic islands harboring multidrug resistance factors. Since the fitness factors could lead to increased virulence, this poses an important research question: could overuse or misuse of antimicrobials act as selection forces for the emergence of more pathogenic strains of Salmonella?
Sphingosine-1-phosphate (S1P), a simple, bioactive sphingolipid metabolite, plays a key role, both intracellularly and extracellularly, in various cellular processes such as proliferation, survival, migration, inflammation, angiogenesis, and endothelial barrier integrity. The cellular S1P level is low and is tightly regulated by its synthesis and degradation. Sphingosine Kinases (SphKs) 1 and 2, catalyze the ATP-dependent phosphorylation of sphingosine to S1P, while the degradation is mediated by the reversible dephosphorylation catalyzed by the S1P phosphatases and lipid phosphate phosphatases and the irreversible degradation to hexadecenal and ethanolamine phosphate by sphingosine-1-phosphate lyase (S1PL). As a ligand for specific G-protein-coupled receptors, S1P1-5, which are differentially expressed in different cell types, S1P generates downstream signals that play crucial role in developmental and disease related pathologies. In addition to acting extracellularly on receptors located on the plasma membrane, S1P can also act intracellularly, independently of S1P1-5, affecting calcium homeostasis and cell proliferation. The SphKs /S1P /S1PL metabolic pathway is implicated in numerous human pathologies including respiratory disorders, thereby raising the possibility that manipulating intracellular S1P levels could offer therapeutic potential in ameliorating lung diseases. This review focuses on the prospects of targeting S1P signaling and S1P metabolizing enzymes using small molecule inhibitors, receptor agonists, and antagonists in the treatment of lung diseases.
The purpose of this study was to explore how adults with prediabetes perceive their risk of developing diabetes and examine their preferences for evidence-based treatment options to prevent diabetes.
A qualitative study was conducted in 2 large Midwest primary care practices, involving in-depth semistructured interviews with 35 adult patients with prediabetes.
This ethnically diverse (77% nonwhite) sample of middle-aged primary care patients exhibited multiple diabetes risk factors. Knowledge gaps about prediabetes and its medical management were pervasive. Most patients overestimated the risk of developing diabetes and were not familiar with evidence-based treatment options for prediabetes. They suggested that receiving brief, yet specific information about
 these topics during the study interview motivated them to act. The majority of participants considered both intensive lifestyle intervention and metformin acceptable treatment options. Many preferred initial treatment with intensive lifestyle intervention but would take metformin if their efforts at lifestyle change failed and their primary care physician recommended it. Some participants expressed wanting to combine both treatments.
This qualitative study highlights potential opportunities to promote patient-centered dialogue about prediabetes in primary care settings. Providing patients specific information about the risk of developing diabetes and evidence-based treatment options to prevent or delay its onset may encourage action. Physicians' prediabetes counseling efforts should be informed by the finding that most patients consider both intensive lifestyle intervention and metformin acceptable treatment options.
Biochar incorporated into soil has been known to affect soil nutrient availability and act as a habitat for microorganisms, both of which could be related to its particle size. However, little is known about the effect of particle size on soil microbial community structure and function. To investigate short-term soil microbial responses to biochar addition having varying particle sizes and addition rates, we established a laboratory incubation study. Biochar produced via pyrolysis of bamboo was ground into three particle sizes (diameter size<0.05mm (fine), 0.05-1.0mm (medium) and 1.0-2.0mm (coarse)) and amended at rates of 0% (control), 3% and 9% (w/w) in an intensively managed bamboo (Phyllostachys praecox) plantation soil. The results showed that the fine particle biochar resulted in significantly higher soil pH, electrical conductivity (EC), available potassium (K) concentrations than the medium and coarse particle sizes. The fine-sized biochar also induced significantly higher total microbial phospholipid fatty acids (PLFAs) concentrations by 60.28% and 88.94% than the medium and coarse particles regardless of addition rate, respectively. Redundancy analysis suggested that the microbial community structures were largely dependent of particle size, and that improved soil properties were key factors shaping them. The cumulative CO2 emissions from biochar-amended soils were 2-56% lower than the control and sharply decreased with increasing addition rates and particle sizes. Activities of α-glucosidase, β-glucosidase, β-xylosidase, N-acetyl-β-glucosaminidase, peroxidase and dehydrogenase decreased by ranging from 7% to 47% in biochar-amended soils over the control, indicating that biochar addition reduced enzyme activities involved carbon cycling capacity. Our results suggest that biochar addition can affect microbial population abundances, community structure and enzyme activities, that these effects are particle size and rate dependent. The fine particle biochar may additionally produce a better habitat for microorganisms compared to the other particle sizes.
Due to the light excitation, the valence band electron of the copper (I) sulfide quantum dot transfer to the conduction band and act as a scavenger of the terminal proton of the alkyne in the presence of organic azide with the formation of 1,4-disubstituted 1,2,3-triazoles, where the copper(I) species of Cu2S act as a catalyst for the reaction. The above cycloaddition reaction between alkyne and azide is commonly known as the Click reaction. In this study, experiments were carried out under the exposure of ultra-violate and daylight and also dark environment. According to the original recommendation for the Click reaction, the role of the base was also considered for this experiment. We found that the effect of conduction band electron is more efficient than the recommended conventional base mediated reaction procedure.
This study examined associations between perceived neighborhood environment and physical activity among frail older adults and whether these associations are moderated by fear of falling. Participants were 238 frail older adults. Daily step counts and duration of moderate-to-vigorous physical activity were measured using an accelerometer. Participants completed the abbreviated Neighborhood Environment Walkability Scale; fear of falling and demographic and health-related factors were measured by a questionnaire. The interaction between crime safety and fear of falling was significantly associated with step count (p = 0.009) and moderate-to-vigorous physical activity (p = 0.018) in multiple regression analysis. Stratified according to fear of falling, crime safety was significantly associated with steps (p = 0.007) and moderate-to-vigorous physical activity (p = 0.030) in the low fear of falling group. The results suggest that crime safety is associated with physical activity among frail older adults, and this association is moderated by fear of falling.
Antimicrobial resistance is one of the most serious health threats. Cell-wall remodeling processes are tightly regulated to warrant bacterial survival and in some cases are directly linked to antibiotic resistance. Remodeling produces cell-wall fragments that are recycled but can also act as messengers for bacterial communication, as effector molecules in immune response and as signaling molecules triggering antibiotic resistance. This review is intended to provide state-of-the-art information about the molecular mechanisms governing this process and gather structural information of the different macromolecular machineries involved in peptidoglycan recycling in Gram-negative bacteria. The growing body of literature on the 3D structures of the corresponding macromolecules reveals an extraordinary complexity. Considering the increasing incidence and widespread emergence of Gram-negative multidrug-resistant pathogens in clinics, structural information on the main actors of the recycling process paves the way for designing novel antibiotics disrupting cellular communication in the recycling-resistance pathway.
As a population, middle-aged and older adults are not meeting national guidelines for exercise. The purpose of this study was to describe factors associated with exercise adherence in an 8-month program offered as part of a research study testing the effects of exercise on cognitive performance for persons with a family history of Alzheimer's disease (AD). After completion of the program, participants provided open-ended responses indicating their reasons for adhering to the exercise program, and they completed the Motives for Physical Activities Measure-Revised. Results indicated that adherence was tied to an interest in contributing to our understanding of AD, the opportunity to join an exercise program, perceived exercise benefits, and social support. Additionally, participants reported high levels of extrinsic (fitness-related) and intrinsic (interest/enjoyment) motivation. Other possible motivating factors which emerged from day-to-day observations in the program were identified. Findings suggest directions for exercise professionals with respect to exercise adherence.
MicroRNAs (miRNAs) represent an important class of small regulatory RNAs that control gene expression posttranscriptionally by targeting mRNAs for degradation or translation inhibition. Early studies have revealed a complex role for miRNAs in major biological processes such as development, differentiation, growth and metabolism. MiR-137 in particular, has been of great interest due to its critical role in brain function and putative involvement in the etiology of both neuropsychiatric disorders and cancer. Several lines of evidence suggest that development, differentiation and maturation of the nervous system is strongly linked to the expression of miR-137 and its regulation of a large number of downstream target genes in various pathways. Dysregulation of this molecule has also been implicated in major mental illnesses through its position in a variant allele highly associated with schizophrenia in the largest mega genome-wide association studies. Interestingly, miR-137 has also been shown to act as a tumor suppressor, with numerous studies finding reduced expression in neoplasia including brain tumor. Restoration of miR-137 expression has also been shown to inhibit cell proliferation, migration and metastasis, and induce cell cycle arrest, differentiation and apoptosis. These properties of miR-137 propose its potential for prognosis, diagnosis and as a therapeutic target for treatment of several human neurological and neoplastic disorders. In this review, we provide details on the discovery, targets, function, regulation and disease involvement of miR-137 with a broad look at recent discovery in this area.Molecular Psychiatry advance online publication, 13 September 2016; doi:10.1038/mp.2016.150.
Neutrophils are essential components of immunity and are rapidly recruited to infected or injured tissue. Upon their activation, neutrophils release granules to the cell's exterior, through a process called degranulation. These granules contain proteins with antimicrobial properties that help combat infection. The enteropathogenic bacterium Yersinia pseudotuberculosis successfully persists as an extracellular bacterium during infection by virtue of its translocation of virulence effectors (Yersinia outer proteins [Yops]) that act in the cytosol of host immune cells to subvert phagocytosis and proinflammatory responses. Here, we investigated the effect of Y. pseudotuberculosis on neutrophil degranulation upon cell contact. We found that virulent Y. pseudotuberculosis was able to prevent secondary granule release. The blocking effect was general, as the release of primary and tertiary granules was also reduced. Degranulation of secondary granules was also blocked in primed neutrophils, suggesting that this mechanism
 could be an important element of immune evasion. Further, wild-type bacteria conferred a transient block on neutrophils that prevented their degranulation upon contact with plasmid-cured, avirulent Y. pseudotuberculosis and Escherichia coli Detailed analyses showed that the block was strictly dependent on the cooperative actions of the two antiphagocytic effectors, YopE and YopH, suggesting that the neutrophil target structures constituting signaling molecules needed to initiate both phagocytosis and general degranulation. Thus, via these virulence effectors, Yersinia can impair several mechanisms of the neutrophil's antimicrobial arsenal, which underscores the power of its virulence effector machinery.
The purpose of this systematic review and meta-analysis was to determine the effects of supervised resistance and/or aerobic training physical activity interventions on performance-based measures of physical functioning among community-dwelling older adults, and to identify factors impacting intervention effectiveness. Diverse search strategies were used to identify eligible studies. Standardized mean difference effect sizes (d, ES) were synthesized using a random effects model. Moderator analyses were conducted using subgroup analyses and meta-regression. Twenty-eight studies were included. Moderator analyses were limited by inconsistent reporting of sample and intervention characteristics. The overall mean ES was 0.45 (k=38, p=<.01), representing a clinically meaningful reduction of 0.92 seconds in the Timed Up and Go for treatment versus control. More minutes per week (p<.01) and longer intervention session duration (p<0.01) were associated with larger effects. Interventions were especially effective among frail participants (d=1.09). Future research should clearly describe sample and intervention characteristics and incorporate frail populations.
The expansive goals of the Health Information Technology for Economic and Clinical Health (HITECH) Act required the simultaneous development of a complex and interdependent infrastructure and a wide range of relationships, generating points of vulnerability. While federal legislation can be a powerful stimulus for change, its effectiveness also depends on its ability to accommodate state and local policies and private health care markets. Ambitious goals require support over a long time horizon, which can be challenging to maintain. The future of health information technology (health IT) support nationally is likely to depend on the ability of the technology to satisfy its users that its functionalities address the interests policymakers and other stakeholders have in using technology to promote better care, improved outcomes, and reduced costs.
The Health Information Technology for Economic and Clinical Health (HITECH) Act set ambitious goals for developing electronic health information as one tool to reform health care delivery and improve health outcomes. With HITECH's grant funding now mostly exhausted but statutory authority for standards remaining, this article looks back at HITECH's experience in the first 5 years to assess its implementation, remaining challenges, and lessons learned.
This review derives from a global assessment of the HITECH Act. Earlier, we examined the logic of HITECH and identified interdependencies critical to its ultimate success. In this article, we build on that framework to review what has and has not been accomplished in building the infrastructure authorized by HITECH since it was enacted. The review incorporates quantitative and qualitative evidence of progress from the global assessment and from the evaluations funded by the Office of the National Coordinator for Health Information Technology (ONC) of individual programs authorized by the HITECH Act.
Our review of the evidence provides a mixed picture. Despite HITECH's challenging demands, its complex programs were implemented, and important changes sought by the act are now in place. Electronic health records (EHRs) now exist in some form in most professional practices and hospitals eligible for HITECH incentive payments, more information is being shared electronically, and the focus of attention has shifted from adoption of EHRs toward more fundamental issues associated with using health information technology (health IT) to improve health care delivery and outcomes. In some areas, HITECH's achievements to date have fallen short of the hopes of its proponents as it has proven challenging to move meaningful use beyond the initial low bar set by Meaningful Use Stage 1. EHR products vary in their ability to support more advanced functionalities, such as patient engagement and population-based care management. Many barriers to interoperability persist, limiting electronic communication across a diverse set of largely private providers and care settings.
Achieving the expansive goals of HITECH required the simultaneous development of a complex and interdependent infrastructure and a wide range of relationships, some better positioned to move forward than others. To date, it has proven easier to get providers to adopt EHRs, perhaps in response to financial incentives to do so, than to develop a robust infrastructure that allows the information in EHRs to be used effectively and shared not only within clinical practices but also across providers. Effective exchange of data is necessary to drive the kinds of delivery and payment reforms sought nationwide.
Monocytes are precursors of macrophages and key players during inflammation and pathogen challenge in the periphery, whereas intestinal resident macrophages act as innate effector cells to engulf and clear bacteria, secrete cytokines, and maintain intestinal immunity and homeostasis. However, perturbation of toll-like receptor signaling pathway in intestinal macrophages has been associated with tolerance breakdown in autoimmune diseases. In the present review, we have summarized and discussed the role of toll-like receptor signals in human intestinal macrophages, and the role of human intestinal macrophages in keeping human intestinal immunity, homeostasis, and autoimmune diseases.
Regular participation in resistance training is important for older people to maintain their health and independence, yet participation rates are low. The study aimed to identify motivators and barriers to older people participating in resistance training. A systematic review was conducted including quantitative, qualitative and mixed-method studies. Searches generated 15,920 citations from six databases, with 14 studies (n=1,937 participants) included. In total, 92 motivators and 24 barriers were identified. Motivators specific to participating in resistance training included preventing deterioration (disability), reducing risk of falls, building (toning) muscles, feeling more alert and better concentration. Looking too muscular and thinking participation increased the risk of having a heart attack, stroke or death, despite the minimal likelihood of these occurring, were barriers. The analysis indicates that increasing participation in resistance training among older people should focus on the specific benefits valued by older people and the dissemination of accurate information to counter misperceptions.
The purpose of this study was to determine if bone health at the femoral neck (FN) and lumbar spine (LS) can be predicted from objectively-measured sedentary behavior and physical activity data in post-menopausal women. Waist-mounted ActiGraph GT1M and GT3X devices were used to quantify levels of sedentary and moderate-to-vigorous intensity behavior during a 7-day period in 44 older females. Bone health (normal and osteopenia/osteoporosis) of FN and LS was derived from T scores generated using dual energy x-ray absorptiometry. Binomial logistic regression analysis indicated that sedentary time and number of breaks in sedentary behavior were significant predictors of osteopenia/osteoporosis at the FN, but not at the LS. Adherence to physical activity guidelines was not a significant predictor of bone health at the FN or LS. Our findings suggest that more frequent interruptions in sedentary behavior are associated with improved bone health in post-menopausal women.
Many international agencies recommend using 40% of VO2reserve to individually prescribe moderate aerobic intensity to achieve health benefits. Few studies have evaluated the walking cadence needed to reach that intensity for older adults. 121 apparently healthy adults with an average age of 69 years old and an average VO2peak of 24.1 ± 6.7 ml/kg/min (women) and 28.9 ± 9.1 ml/kg/min (men) were studied. Walking cadence at moderate intensity was established when participants reached 40% of VO2reserve on an indoor flat surface using a portable metabolic cart. Other clinical variables potentially associated with walking cadence were collected to create a clinical algorithm. Mean walking cadence to reach moderate intensity was 115 ± 10 steps per minute. The best algorithm to predict the walking cadence needed to reach moderate intensity in this sample was 113.6 - 0.23 (body weight in kg) + 0.21 (self-selected walking cadence in steps per minute).
We studied the impact of a Housing First (HF) intervention on housing, contact with the justice system, healthcare usage and health outcomes among At Home/Chez Soi randomised trial participants in Toronto, a city with an extensive service network for social and health services for individuals who are experiencing homelessness and mental illness.
Participants identified as high needs were randomised to receive either the intervention which provided them with housing and supports by an assertive community treatment team (HF+ACT) or treatment as usual (TAU). Participants (N=197) had in-person interviews every 3 months for 2 years.
The HF+ACT group spent more time
 stably housed compared to the TAU group with the mean difference between the groups of 45.8% (95% CI 37.1% to 54.4%, p<0.0001). Accounting for baseline differences, HF+ACT group showed significant improvements over TAU group for community functioning, selected quality-of-life subscales and arrests at some time points during follow-up. No differences between HF+ACT and TAU groups over the follow-up were observed for health service usage, community integration and substance use.
HF for individuals with high levels of need increased housing stability and selected health and justice outcomes over 2 years in a city with many social and health services.
ISRCTN42520374.
Biological approach to synthesis of metal nanoparticles using aqueous leaf extract is a highly relevant and recent theme in nanotechnological research. Phytosynthesized AgNPs have better inhibitory and antimicrobial effects compared to aqueous leaf extract and silver nitrate. In the present investigation crystalline silver nanoparticles (AgNPs) with size of 10nm have been successfully synthesized using aqueous leaf extract (AQLE) of Ziziphus oenoplia (L.) Mill., which act as both reducing as well as capping agent. The particles were characterized using UV Visible spectroscopy, HRTEM-EDAX, XRD, FT-IR and DLS. An evaluation of the anti bacterial activity was carried out using Agar well diffusion method and MIC determination against four bacterial strains, Klebsiella pneumoniae, Pseudomonas aeruginosa, Escherichia coli and Salmonella typhi; the AgNPs exhibited quite high antibacterial activity. Furthermore, bactericidal studies with TEM at different time intervals after AgNPs treatment showed the presence of AgNPs near cell membrane of bacteria at about 30min exposure and the bacterial-lysis was found completed at 24h. This gave an insight on the mechanism of bacterial-lysis by direct damage to the cell membrane.
Darwin was the first to recognize that sexual selection is a strong evolutionary force. Exaggerated traits allow same-sex individuals to compete over access to mates and provide a mechanism by which mates are selected. It is relatively easy to appreciate how inter- and intrasexual selection work in organisms with the sensory capabilities to perceive physical or behavioural traits that signal mate quality or mate compatibility, and to assess the relative quality of competitors. It is therefore not surprising that most studies of sexual selection have focused on animals with separate sexes and obvious adaptations that function in the context of reproductive competition. Yet, many sexual organisms are both male and female at the same time, often lack sexual dimorphism and never come into direct contact at mating. How does sexual selection act in such species, and what can we learn from them? Here, we address these questions by exploring the potential for sexual selection in simultaneous hermaphrodites, sperm- and broadcast spawners, plants and fungi. Our review reveals a range of mechanisms of sexual selection, operating primarily after gametes have been released, which are common in many of these groups and also quite possibly in more familiar (internally fertilizing and sexually dimorphic) organisms.This article is part of the themed issue 'Weird sex: the underappreciated diversity of sexual reproduction'.
Saturated free fatty acids (FFAs) act as lipid mediators and induce insulin resistance in skeletal muscle. Specifically, in obesity-related diseases such as type 2 diabetes, FFAs directly reduce insulin sensitivity and glucose uptake in skeletal muscle. However, the knowledge of how FFAs mediate inflammation and subsequent tissue disorders, including fibrosis in skeletal muscle, is limited. FFAs are a natural ligand for toll-like receptor 2 (TLR2) and TLR4, and induce chronic low-grade inflammation that directly stimulates skeletal muscle tissue. However, persistent inflammatory stimulation in tissues could induce pro-fibrogenic processes that ultimately lead to perturbation of the tissue architecture and dysfunction. Therefore, blocking the link between inflammatory primed skeletal muscle tissue and connective tissue might be an efficient therapeutic option for treating obesity-induced muscle inactivity. In this study, we investigated the impact of conditioned medium obtained from human palatine tonsil-derived mesenchymal stem cells (T-MSCs) on the interaction between skeletal muscle cells stimulated with palmitic acid (PA) and fibroblasts. We found that PA-treated skeletal muscle cells actively secreted interleukin-1β (IL-1β) and augmented the migration, proliferation and expression of fibronectin in L929 fibroblasts. Furthermore, T-CM inhibited the skeletal muscle cell-derived pro-fibrogenic effect via the production of the interleukin-1 receptor antagonist (IL-1Ra), which is an inhibitor of IL-1 signalling. Taken together, our data provide novel insights into the therapeutic potential of T-MSC-mediated therapy for the treatment of pathophysiological processes that occur in skeletal muscle tissues under chronic inflammatory conditions.
Adoptive transfer of tumor-specific T cells, expanded from tumor-infiltrating lymphocytes or from peripheral blood, is a promising immunotherapeutic approach for the treatment of cancer. Here, we studied whether the tumor-draining lymph nodes (TDLN) of patients with human papillomavirus (HPV)-induced cervical cancer can be used as a source for ACT. The objectives were to isolate lymph node mononuclear cells (LNMC) from TDLN and optimally expand HPV-specific CD4+ and CD8+ T cells under clinical grade conditions. TDLN were isolated from 11 patients with early-stage cervical cancer during radical surgery. Isolated lymphocytes were expanded in the presence of HPV16 E6 and E7 clinical grade synthetic long peptides and IL-2 for 22 days and then analyzed for HPV16 specificity by proliferation assay, multiparameter flow cytometry and cytokine analysis as well as for CD25 and FoxP3 expression. Stimulation of LNMC resulted in expansion of polyclonal HPV-specific T cells in all patients. On average a 36-fold expansion of a CD4+ and/or CD8+ HPV16-specific T cell population was observed, which maintained its capacity for secondary expansion. The T helper type 1 cytokine IFNγ was produced in all cell cultures and in some cases also the Th2 cytokines IL-10 and IL-5. The procedure was highly reproducible, as evidenced by complete repeats of the stimulation procedures under research and under full good manufacturing practice conditions. In conclusion, TDLN represent a rich source of polyclonal HPV16 E6- and E7-specific T cells, which can be expanded under clinical grade conditions for adoptive immunotherapy in patients with cervical cancer.
Recent pharmacokinetic studies have revealed that ginsenosides, the major ingredients of ginseng (the roots of Panax ginseng), are present in the plasma collected from subjects receiving ginseng, and speculated that ginsenosides might be actively transported via glucose transporters. We evaluated whether ginsenosides Rb1 and Rg1, and their metabolites from enteric bacteria act as substrates of sodium-glucose cotransporter (SGLT) 1, the major glucose transporter expressed on the apical side of intestinal epithelial cells. First, we evaluated the competing effects of ginseng extract and ginsenosides on the uptake of [(14)C]methyl-glucose, a substrate of SGLT1, by SGLT1-overexpressing HEK293 cells. A boiling water extract of ginseng inhibited SGLT1 in a concentration-dependent manner with an IC50 value of 0.85 mg/ml. By activity-guided fractionation, we determined that the fraction containing ginsenosides displayed an inhibitory effect on SGLT1. Of the ginsenosides evaluated, protopanaxatriol-type ginsenosides were not found to inhibit SGLT1, whereas protopanaxadiol-type ginsenosides, including ginsenosides Rd, Rg3, Rh2, F2 and compound K, exhibited significant inhibitory effects on SGLT1, with ginsenoside F2 having the highest activity with an IC50 value of 23.0 µM. Next, we measured the uptake of ginsenoside F2 and compound K into Caco-2 cells, a cell line frequently used to evaluate the intestinal absorption of drugs. The uptake of ginsenoside F2 and compound K into Caco-2 cells was not competitively inhibited by glucose. Furthermore, the uptake of ginsenoside F2 and compound K into SGLT1-overexpressing HEK293 cells was not significantly higher than into mock cells. Ginsenoside F2 and compound K did not appear to be substrates of SGLT1, although these compounds could inhibit SGLT1. Ginsenosides might be absorbed by passive diffusion through the intestinal membrane or actively transported via unknown transporters other than SGLT1.
Bitter is a taste modality associated with toxic substances evoking aversive behaviour in most animals, and the valence of different taste modalities is conserved between mammals and Drosophila. Despite knowledge gathered in the past on the peripheral perception of taste, little is known about the identity of taste interneurons in the brain. Here we show that hugin neuropeptide-containing neurons in the Drosophila larval brain are necessary for avoidance behaviour to caffeine, and when activated, result in cessation of feeding and mediates a bitter taste signal within the brain. Hugin neuropeptide-containing neurons project to the neurosecretory region of the protocerebrum and functional imaging demonstrates that these neurons are activated by bitter stimuli and by activation of bitter sensory receptor neurons. We propose that hugin neurons projecting to the protocerebrum act as gustatory interneurons relaying bitter taste information to higher brain centres in Drosophila larvae.
In recent years, efforts have been made in catalysis related surface science studies to explore the possibilities to perform experiments at conditions closer to those of a technical catalyst,
 in particular at increased pressures. Techniques such as high pressure scanning tunneling/atomic force microscopy (HPSTM/AFM), near ambient pressure x-ray photoemission spectroscopy (NAPXPS), surface x-ray diffraction (SXRD) and polarization-modulation infrared reflection absorption spectroscopy (PM-IRAS) at semi-realistic conditions have been used to study the surface structure of model catalysts under reaction conditions, combined with simultaneous mass spectrometry (MS). These studies have provided an increased understanding of the surface dynamics and the structure of the active phase of surfaces and nano particles as a reaction occurs, providing novel information on the structure/activity relationship. However, the surface structure detected during the reaction is sensitive to the composition of the gas phase close to the catalyst surface. Therefore, the catalytic activity of the sample itself will act as a gas-source or gas-sink, and will affect the surface structure, which in turn may complicate the assignment of the active phase. For this reason, we have applied planar laser induced fluorescence (PLIF) to the gas phase in the vicinity of an active model catalysts. Our measurements demonstrate that the gas composition differs significantly close to the catalyst and at the position of the MS, which indeed should have a profound effect on the surface structure. However, PLIF applied to catalytic reactions presents several beneficial properties in addition to investigate the effect of the catalyst on the effective gas composition close to the model catalyst. The high spatial and temporal resolution of PLIF provides a unique tool to visualize the on-set of catalytic reactions and to compare different model catalysts in the same reactive environment. The technique can be applied to a large number of molecules thanks to the technical development of lasers and detectors over the last decades, and is a complementary and visual alternative to traditional MS to be used in environments difficult to asses with MS. In this article we will review general considerations when performing PLIF experiments, our experimental set-up for PLIF and discuss relevant examples of PLIF applied to catalysis.
We applied a fluorescein-containing oligonucleotide (ON) to probe surface properties of oxidized graphene (oxo-G) and observed that graphene-like patches are formed upon aging of oxo-G, indicated by enhanced probe binding and by FTIR spectroscopic analysis. By using a recently developed fluorogenic endoperoxide (EP) probe, we confirmed that during the aging process the amount of EPs on the oxo-G surface is reduced. Furthermore, aging was found to strongly affect cell membrane carrier properties of this material. In particular, freshly prepared oxo-G does not act as a carrier, whereas oxo-G aged for 28 days at 4 °C is an excellent carrier. Based on these data we prepared an optimized oxo-G, which has a low-defect density, binds ONs, is not toxic, and acts as cell membrane carrier. We successfully applied this material to design fluorogenic probes of representative intracellular nucleic acids 28S rRNA and β-actin-mRNA. The results will help to standardize oxidized graphene derivatives for biomedical and bioanalytical applications.
Breast cancer is the primary reason for cancer-related death in women worldwide and the development of new formulations to treat breast cancer patients is crucial. Curcumin (Cur), a natural product, exerts promising anticancer activities against various cancer types. However, its therapeutic efficacy is hindered as a result of poor water solubility, instability, and low bioavailability. The aim of this work is to assess the curative effect of a novel nanoformulation, i.e., Cur-loaded and calcium-doped dendritic mesoporous silica nanoparticles modified with folic acid (Cur-Ca@DMSNs-FA) for breast cancer therapy. The results manifested that Cur-Ca@DMSNs-FA dispersed very well in aqueous solution, released Cur with a pH-responsible profile, and targeted efficiently to human breast cancer MCF-7 cells. Further investigations indicated that Cur-Ca@DMSNs-FA effectively inhibited cell proliferation, increased intracellular ROS generation, decreased mitochondrial membrane potential, and enhanced cell cycle retardation at G2/M phase, leading to a higher apoptosis rate in MCF-7 compared to free Cur. Moreover, the Western blotting analysis demonstrated that Cur-Ca@DMSNs-FA were more active than free Cur through suppression of PI3K/AKT/mTOR and Wnt/β-catenin signaling, and activation of the mitochondria-mediated apoptosis pathway. In addition, hemolysis assay showed that the Ca@DMSNs-FA exhibited good biocompatibility. Last, in vivo studies indicated that when Cur was encapsulated in Ca@DMSNs-FA, the Cur concentration in blood serum and tumor tissues was increased after 1 h intraperitoneal injection. In conclusion, Cur-Ca@DMSNs-FA might act as a potential anticancer drug formulation for breast cancer therapy.
Solventogenic clostridia are native producers of ethanol and many higher alcohols employing a broad range of cheap renewable substrates, such as lignocellulosic materials and C1 gases (CO and CO2). These characteristics enable solventogenic clostridia to act as flexible microbial platforms for the production of liquid biofuels. With the rapid development of genetic tools in recent years, the intrinsic intractability of clostridia has been largely overcome, thus, engineering clostridia for production of chemicals and fuels has attracted increasing interests. Here, we provide an overview of recent progress in the production of alcohols based on solventogenic clostridia. Saccharolytic, cellulolytic and gas-fermenting clostridia are discussed, with a special focus on strategies for metabolic engineering to enable and to improve clostridia for the production of higher alcohols.
Despite efforts to improve malaria management for children, a substantial gap remains between policy and practice in Uganda. The aim of this study was to create quantitative profiles of assets and challenges facing caregivers in Butaleja District when managing malaria in children aged 5 years and under. The objectives were: (1) to estimate caregivers' assets and challenges during an acute episode; and, (2) to ascertain which caregiver attributes influenced receipt of an appropriate anti-malarial the most.
Data from a 2011 cross-sectional, household survey and ten psychometrically justified scales were used to estimate caregivers' assets and challenges. The scales scores were simple counts across a series of items, for example, the number of times a caregiver answered a knowledge item correctly or the number of times a caregiver relied on a credible source for information. Since high scores on six of the scales reflected attributes that eased the burden of caregiving, these were labelled 'caregiver assets'. Similarly, high scores on four of the measures signalled that a caregiver was having trouble managing the malaria episode, thereby reflecting deficits, and these were labelled 'caregiver challenges'. ANOVAs were used to compare scale scores between caregivers of children who received an appropriate anti-malarial versus those who did not.
On the six asset scales, caregivers averaged highest on knowledge (65 %), followed by correct episode management (48 %), use of trustworthy information sources (40 %), ability to initiate or redirect their child's treatment (37 %), and lowest on possible encounters with health professionals to assist in treatment decisions (33 %). Similarly, the average caregiver reported problems with 74 % of the issues they might encounter in accessing advice, and 56 % of the problems in obtaining the best anti-malarial. Caregivers whose children received an appropriate anti-malarial demonstrated greater assets and fewer challenges than those whose child did not, with important regional differences existing. Overall, no one region performed particularly well across all ten scales.
Findings from this study suggest that the low use of artemisinin-based combination therapy (ACT) in Butaleja for children 5 years and under may result from caregivers' high perceived barrier to accessing ACT and low perceived benefits from ACT.
Mitochondrial dysfunction is one of the leading causes of neurological disorders in humans. Mitochondrial perturbations lead to adaptive mechanisms that include HIF-1 stabilization, though the consequences of increased levels of HIF-1 following mitochondrial stress remain poorly understood.
Using Caenorhabditis elegans, we show that a hif-1 loss-of-function mutation confers resistance towards the mitochondrial toxin ethidium bromide (EtBr) and suppresses EtBr-induced production of ROS. In mammals, the PD-related gene DJ-1 is known to act as a redox sensor to confer protection against antioxidants and mitochondrial inhibitors. A deletion mutant of the C. elegans homolog djr-1.1 also showed increased resistance to EtBr. Furthermore, our data implicates p38 MAP kinase as an indispensable factor for survival against mitochondrial stress in both hif-1 and djr-1.1 mutants.
We propose that EtBr-induced HIF-1 activates pathways that are antagonistic in conferring protection against EtBr toxicity and that blocking HIF-1 activity may promote survival in cells with compromised mitochondrial function.
Excitatory neurotransmission plays a key role in epileptogenesis. Correspondingly, AMPA-subtype ionotropic glutamate receptors, which mediate the majority of excitatory neurotransmission and contribute to seizure generation and spread, have emerged as promising targets for epilepsy therapy. The most potent and well-tolerated AMPA receptor inhibitors act via a noncompetitive mechanism, but many of them produce adverse side effects. The design of better drugs is hampered by the lack of a structural understanding of noncompetitive
 inhibition. Here, we report crystal structures of the rat AMPA-subtype GluA2 receptor in complex with three noncompetitive inhibitors. The inhibitors bind to a novel binding site, completely conserved between rat and human, at the interface between the ion channel and linkers connecting it to the ligand-binding domains. We propose that the inhibitors stabilize the AMPA receptor closed state by acting as wedges between the transmembrane segments, thereby preventing gating rearrangements that are necessary for ion channel opening.
Chlorophyll degradation is an intricate process that is critical in a variety of plant tissues at different times during the plant life cycle. Many of the photoactive chlorophyll degradation intermediates are exceptionally cytotoxic necessitating that the pathway be carefully coordinated and regulated. The primary regulatory step in the chlorophyll degradation pathway involves the enzyme pheophorbide a oxygenase (PAO), which oxidizes the chlorophyll intermediate pheophorbide a, that is eventually converted to non-fluorescent chlorophyll catabolites. There is evidence that PAO is differentially regulated across different environmental and developmental conditions with both transcriptional and post-transcriptional components, but the involved regulatory elements are uncertain or unknown. We hypothesized that transcription factors modulate PAO expression across different environmental conditions, such as cold and drought, as well as during developmental transitions to leaf senescence and maturation of green seeds. To test these hypotheses, several sets of Arabidopsis genomic and bioinformatic experiments were investigated and re-analyzed using computational approaches. PAO expression was compared across varied environmental conditions in the three separate datasets using regression modeling and correlation mining to identify gene elements co-expressed with PAO. Their functions were investigated as candidate upstream transcription factors or other regulatory elements that may regulate PAO expression. PAO transcript expression was found to be significantly up-regulated in warm conditions, during leaf senescence, and in drought conditions, and in all three conditions significantly positively correlated with expression of transcription factor Arabidopsis thaliana activating factor 1 (ATAF1), suggesting that ATAF1 is triggered in the plant response to these processes or abiotic stresses and in result up-regulates PAO expression. The proposed regulatory network includes the freezing, senescence, and drought stresses modulating factor ATAF1 and various other transcription factors and pathways, which in turn act to regulate chlorophyll degradation by up-regulating PAO expression.
High-level ab initio calculations have been used to calculate the standard and inherent radical stabilities (RSEs) of a test set of 41 sulfur-centered radicals, chosen for their relevance in fields as diverse as combustion, atmospheric chemistry, polymer chemistry, and biochemistry. Radical stability was shown to be profoundly affected by substituents, varying over a 30 kcal mol(-1) range for the test set studied. Like carbon-centered radicals, substituent effects on sulfur-centered radical stabilities result from the competition between the stabilizing effect of electron delocalization by lone pair donation and π-acceptance, and the destabilizing effect of σ withdrawal. However, in contrast to carbon-centered radicals, the heavier thiyl radicals are better able to undergo resonance and lone-pair donor interactions with heavier substituents. In particular, sulfur-containing lone pair donor and π-acceptor substituents have the greatest stabilizing effect, whereas σ-withdrawing substituents such as carbonyls and pyridines are the least stabilizing. The stabilities predicted using the standard definition and Zavitsas's inherent RSEZ scheme are shown to be in surprisingly good agreement with one another for most species tested. The RSEZ values have also been shown to be capable of making chemically accurate estimates of bond energies by comparing our calculated values with 34 currently available experimental ones.
Plant cell walls undergo dynamic structural and chemical changes during plant development and growth. Floral organ abscission and lateral root emergence are both accompanied by cell wall remodeling which involves the INFLORESCENCE DEFICIENT IN ABSCISSION (IDA)-derived peptide and its receptors, HAESA (HAE) and HAESA-LIKE2 (HSL2). Plant cell walls also act as barriers against pathogenic invaders. Thus, the cell wall remodeling during plant development could have influence on plant resistance to phytopathogens. Here, we identified IDA-like 6 (IDL6), a gene which is prominently expressed in Arabidopsis leaves. IDL6 expression in Arabidopsis leaves is significantly upregulated when the plant suffering from attacks of the bacterial Pseudomonas syingae pv. tomato (Pst) DC3000. IDL6 overexpression and knock-down lines respectively decrease and increase the Arabidopsis resistance to Pst DC3000, indicating that the gene promotes the Arabidopsis susceptibility to Pst DC3000. Moreover, IDL6 promotes the expression of a polygalacturonase (PG) gene, ADPG2, and increases PG activity in Arabidopsis leaves, which in turn reduces leaf pectin content and leaf robustness. ADPG2 overexpression restrains Arabidopsis resistance to Pst DC3000, whereas ADPG2 loss-of-function mutants increase the resistance to the bacterium. Pst DC3000 infection elevates the ADPG2 expression partially through HAE and HSL2. Taken together, our results suggest that IDL6-HAE/HSL2 facilitates the ingress of Pst DC3000 by promoting pectin degradation in Arabidopsis leaves, and Pst DC3000 might enhance its infection by manipulating the IDL6-HAE/HSL2-ADPG2 signaling pathway. This article is protected by copyright. All rights reserved.
Medicaid payments tend to be less than the cost of care. Federal Disproportionate Share Hospital (DSH) payments help hospitals recover such uncompensated costs of Medicaid-insured and uninsured patients. The Patient Protection and Affordable Care Act reduces DSH payments in anticipation of fewer uninsured patients and therefore decreased uncompensated care. However, unlike adults, few hospitalized children are uninsured, while many have Medicaid coverage. Therefore, DSH payment reductions may expose extensive Medicaid financial losses for hospitals serving large absolute numbers of children.
To identify types of hospitals with the highest Medicaid losses from pediatric inpatient care and to estimate the proportion of losses recovered through DSH payments.
This retrospective cross-sectional analysis evaluated Medicaid-insured hospital discharges of patients 20 years and younger from 23 states in the 2009 Kids' Inpatient Database. The dates of the analysis were March to September 2015. Hospitals were categorized as freestanding children's hospitals (FSCHs), children's hospitals within general hospitals, non-children's hospital teaching hospitals, and non-children's hospital nonteaching hospitals. Financial records of FSCHs in the data set were used to estimate the proportion of Medicaid losses recovered through DSH payments.
Hospital financial losses from inpatient care of Medicaid-insured children (defined as the reimbursement minus the cost of care) were compared across hospital types. For our subsample of FSCHs, Medicaid-insured inpatient financial losses were calculated with and without each hospital's DSH payment.
The 2009 Kids' Inpatient Database study population included 1485 hospitals and 843 725 Medicaid-insured discharges. Freestanding children's hospitals had a higher median number of Medicaid-insured discharges (4082; interquartile range [IQR], 3524-5213) vs non-children's hospital teaching hospitals (674; IQR, 258-1414) and non-children's hospital nonteaching hospitals (161; IQR, 41-420). Freestanding children's hospitals had the largest median Medicaid losses from pediatric inpatient care (-$9 722 367; IQR, -$16 248 369 to -$2 137 902). Smaller losses were experienced by non-children's hospital teaching hospitals (-$204 100; IQR, -$1 014 100 to $14 700]) and non-children's hospital nonteaching hospitals (-$28 310; IQR, -$152 370 to $9040]). Disproportionate Share Hospital payments to FSCHs reduced their Medicaid losses by almost half.
Estimated financial losses from pediatric inpatients covered by Medicaid were much larger for FSCHs than for other hospital types. For children's hospitals, small anticipated increases in insured children are unlikely to offset the reductions in DSH payments.
Remodeling DNA methylation in mammalian genomes can be global, as seen in preimplantation embryos and primordial germ cells (PGCs), or locus specific, which can regulate neighboring gene expression. In PGCs, global and locus-specific DNA demethylation occur in sequential stages, with an initial global decrease in methylated cytosines (stage I) followed by a Tet methylcytosine dioxygenase (Tet)-dependent decrease in methylated cytosines that act at imprinting control regions (ICRs) and meiotic genes (stage II). The purpose of the two-stage mechanism is unclear. Here we show that Dnmt1 preserves DNA methylation through stage I at ICRs and meiotic gene promoters and is required for the pericentromeric enrichment of 5hmC. We discovered that the functional consequence of abrogating two-stage DNA demethylation in PGCs was precocious germline differentiation leading to hypogonadism and infertility. Therefore, bypassing stage-specific DNA demethylation has significant consequences for progenitor germ cell differentiation and the ability to transmit DNA from parent to offspring.
Mass media campaigns can be effective in tobacco control but may widen health inequalities if they fail to engage disadvantaged smokers. This qualitative study explored
 how parents with young children living in disadvantaged circumstances engaged with a national campaign which aimed to raise awareness of the importance of smokefree homes. Individual semi-structured interviews were carried out with 17 parents before and after the Scottish 2014 "Right Outside" mass media campaign. A conceptual framework exploring meaningful exposure (recall and understanding), motivational responses (protecting children from secondhand smoke (SHS)) and opportunities to act (barriers) was used to thematically analyse the findings. Campaign recall and engagement, and motivation to protect children were high. Parents identified with the dramatized scenario and visual impact of SHS harm to children in the TV advertisement. Some reported changed smoking practices. However, supervising young children in limited accommodation when caring alone constrained opportunities to smoke outside. Instead, parents described actions other than smoking outside that they had taken or were planning to take to create smokefree homes. Mass media campaigns using emotive, real-life circumstances can be effective in engaging parents about SHS. However, the behavioural impact may be limited because of difficult home environments and circumstances.
LoRa is a long-range, low-power, low-bitrate, wireless telecommunications system, promoted as an infrastructure solution for the Internet of Things: end-devices use LoRa across a single wireless hop to communicate to gateway(s), connected to the Internet and which act as transparent bridges and relay messages between these end-devices and a central network server. This paper provides an overview of LoRa and an in-depth analysis of its functional components. The physical and data link layer performance is evaluated by field tests and simulations. Based on the analysis and evaluations, some possible solutions for performance enhancements are proposed.
Photonic nanoarchitectures occurring in the scales of Blue butterflies are responsible for their vivid blue wing coloration. These nanoarchitectures are quasi-ordered nanocomposites which are constituted from a chitin matrix with embedded air holes. Therefore, they can act as chemically selective sensors due to their color changes when mixing volatile vapors in the surrounding atmosphere which condensate into the nanoarchitecture through capillary condensation. Using a home-built vapor-mixing setup, the spectral changes caused by the different air + vapor mixtures were efficiently characterized. It was found that the spectral shift is vapor-specific and proportional with the vapor concentration. We showed that the conformal modification of the scale surface by atomic layer deposition and by ethanol pretreatment can significantly alter the optical response and chemical selectivity, which points the way to the efficient production of sensor arrays based on the knowledge obtained through the investigation of modified butterfly wings.
The dynamic instability of microtubules is characterized by slow growth phases stochastically interrupted by rapid depolymerizations called catastrophes. Rescue events can arrest the depolymerization and restore microtubule elongation. However, the origin of these rescue events remains unexplained. Here we show that microtubule lattice self-repair, in structurally damaged sites, is responsible for the rescue of microtubule growth. Tubulin photo-conversion in cells revealed that free tubulin dimers can incorporate along the shafts of microtubules, especially in regions where microtubules cross each other, form bundles or become bent due to mechanical constraints. These incorporation sites appeared to act as effective rescue sites ensuring microtubule rejuvenation. By securing damaged microtubule growth, the self-repair process supports a mechanosensitive growth by specifically promoting microtubule assembly in regions where they are subjected to physical constraints.
To complete its life cycle, the hepatitis C virus (HCV) induces changes to numerous aspects of its host cell. As kinases act as regulators of many pathways utilized by HCV, they are likely enzyme targets for virally induced inhibition or activation. Herein, we used activity-based protein profiling (ABPP), which allows for the identification of active enzymes in complex protein samples and the quantification of their activity, to identify kinases that displayed differential activity in HCV-expressing cells. We utilized an ABPP probe, wortmannin-yne, based on the kinase inhibitor wortmannin, which contains a pendant alkyne group for bioconjugation using bioorthogonal chemistry. We observed changes in the activity of kinases involved in the mitogen-activated protein kinase pathway, apoptosis pathways, and cell cycle control. These results establish changes to the active kinome, as reported by wortmannin-yne, in the proteome of human hepatoma cells actively replicating HCV. The observed changes include kinase activity that affect viral entry, replication, assembly, and secretion, implying that HCV is regulating the pathways that it uses for its life cycle through modulation of the active kinome.
Dissolved organic matter (DOM) can act as a photosensitizer and an inhibitor in the phototransformation of several nitrogen-containing organic contaminants in surface waters. The present study was performed to select a probe molecule that is suitable to measure these antagonistic properties of DOM. Out of nine studied nitrogen-containing aromatic compounds, 4-cyanoaniline, N,N-dimethyl-4-cyanoaniline (DMABN), sotalol (a β-blocker) and sulfadiazine (a sulfonamide antibiotic) exhibited a marked photosensitized transformation that could be substantially inhibited by addition of phenol as a model antioxidant. The photosensitized transformation of DMABN, the selected probe compound, was characterized in detail under UV-A and visible irradiation (λ > 320 nm) to avoid direct phototransformation. Low reactivity of DMABN with singlet oxygen was found (second-order rate constant <2 × 10(7) M(-1) s(-1)). Typically at least 85% of the reactivity of DMABN could be inhibited by DOM or the model antioxidant phenol. The photosensitized transformation of DMABN mainly proceeded (>72%) through demethylation yielding N-methyl-4-cyanoaniline and formaldehyde as primary products. In solutions of standard DOM extracts and their mixtures the phototransformation rate constant of DMABN was shown to vary nonlinearly with the DOM concentration. Model equations describing the dependence of such rate constants on DOM and model antioxidant concentrations were successfully used to fit experimental data.
To systematically review epidemiologic and laboratory studies on the etiology of high myopia and its links to pathologic myopia.
Regular Medline searches have been performed for the past 20 years, using "myopia" as the basic search term. The abstracts of all articles have been scrutinized for relevance, and where necessary, translations of articles in languages other than English were obtained.
Systematic review shows that there is an epidemic of myopia and high myopia in young adults in East and Southeast Asia, with similar but smaller trends in other parts of the world. This suggests an impending epidemic of pathologic myopia. High myopia in young adults in East and Southeast Asia is now predominantly associated with environmental factors, rather than genetic background. Recent clinical trials show that the onset of myopia can be reduced by increasing the time children spend outdoors, and methods to slow the progression of myopia are now available.
High myopia is now largely associated with environmental factors that have caused the epidemic of myopia in East and Southeast Asia. An important clinical question is whether the pathologic consequences of acquired high myopia are similar to those associated with classic genetic high myopia. Increased time outdoors can be used to slow the onset of myopia, whereas methods for slowing progression are now available clinically. These approaches should enable the current epidemics of myopia and high myopia to be turned around, preventing an explosion of pathologic myopia.
Biomolecules can act as functional templates for the organization of inorganic particles. Here we use two protein containers, engineered with opposite surface charge, as building blocks for the construction of a new type of biohybrid material. Binary structures with crystalline order were obtained, adopting a tetragonal lattice. Moreover, the cavity of the engineered protein containers can be filled with inorganic nanoparticles. The controlled assembly of these protein-nanoparticle composites yields highly ordered binary nanoparticle superlattices as free-standing crystals, with up to a few hundred micrometers in size. Because the structure and lattice parameters of the protein-nanoparticle crystals are independent of their nanoparticle cargo, the binary protein material may serve as a generally applicable matrix for the assembly of a variety of nanoparticles types.
The mammalian neocortex has a repetitious, laminar structure and performs functions integral to higher cognitive processes, including sensory perception, memory, and coordinated motor output. What computations does this circuitry subserve that link these unique structural elements to their function? Potjans and Diesmann (2014) parameterized a four-layer, two cell type (i.e. excitatory and inhibitory) model of a cortical column with homogeneous populations and cell type dependent connection probabilities. We implement a version of their model using a displacement integro-partial differential equation (DiPDE) population density model. This approach, exact in the limit of large homogeneous populations, provides a fast numerical method to solve equations describing the full probability density distribution of neuronal membrane
 potentials. It lends itself to quickly analyzing the mean response properties of population-scale firing rate dynamics. We use this strategy to examine the input-output relationship of the Potjans and Diesmann cortical column model to understand its computational properties. When inputs are constrained to jointly and equally target excitatory and inhibitory neurons, we find a large linear regime where the effect of a multi-layer input signal can be reduced to a linear combination of component signals. One of these, a simple subtractive operation, can act as an error signal passed between hierarchical processing stages.
Nanoclay can be incorporated into emerging dual functional drug delivery systems (DDSs) to promote efficiency in drug delivery and reduce the toxicity of doxorubicin (DOX) used for thyroid cancer treatment. This paper reports the expansion of the basal spacing of kaolinite nanoclay was expanded from 0.72 nm to 0.85 nm, which could provide sufficiently spacious site for hosting doxorubicin molecules and controlling the diffusion rate. A targeted design for papillary thyroid cancer cells was achieved by introducing KI, which is consumed by the sodium-iodide symporter (NIS). As indicated by MTT assays, confocal laser scanning microscopy and bio-TEM observations, methoxy-intercalated kaolinite (KaolinMeOH) exhibited negligible cytotoxicity against papillary thyroid cancer cells. By contrast, DOX-KaolinMeOH showed dose-dependent therapeutic effects in vitro, and KI@DOX-KaolinMeOH was found to act as a powerful targeted therapeutic drug. Furthermore, active and passive targeting strategies played a role in the accumulation of the drug molecules, as verified by an in vivo bio-distribution analysis.
Humans are meta-organisms that maintain a diverse population of microorganisms on their barrier surfaces, collectively named the microbiota. Since most pathogens either cross or inhabit barrier surfaces, the microbiota plays a critical and often protective role during infections, both by modulating immune system responses and by mediating colonization resistance. However, the microbiota can also act as a reservoir for opportunistic microorganisms that can 'bloom', significantly complicating diseases of barrier surfaces by contributing to inflammatory immune responses. This review discusses our current understanding of the complex interactions between the host, its microbiota, and pathogenic organisms, focusing in particular on the intestinal mucosa.
Malaria is a life-threatening disease caused by different species of the protozoan parasite Plasmodium, with P. falciparum being the deadliest. Increasing parasitic resistance to existing antimalarials makes the necessity of novel avenues to treat this disease an urgent priority. The enzymes responsible for the synthesis of phosphatidylcholine and phosphatidylethanolamine are attractive drug targets to treat malaria as their selective inhibition leads to an arrest of the parasite's growth and cures malaria in a mouse model. We present here a detailed study that reveals a mode of action for two P. falciparum choline kinase inhibitors both in vitro and in vivo. The compounds present distinct binding modes to the choline/ethanolamine-binding site of P. falciparum choline kinase, reflecting different types of inhibition. Strikingly, these compounds primarily inhibit the ethanolamine kinase activity of the P. falciparum choline kinase, leading to a severe decrease in the phosphatidylethanolamine levels within P. falciparum, which explains the resulting growth phenotype and the parasites death. These studies provide an understanding of the mode of action, and act as a springboard for continued antimalarial development efforts selectively targeting P. falciparum choline kinase.
Rabbit haemorrhagic disease virus (RHDV) is a lagovirus that can cause fatal hepatitis (rabbit haemorrhagic disease, RHD) with mortality of 80-90% in farmed and wild rabbits. Since 1986, RHDV has caused outbreaks in rabbits (Oryctolagus cuniculus) in Europe, but never in European brown hares (Lepus europaeus, EBH). In 2010, a new RHDV-related virus, called RHDV2, emerged in Europe, causing extended epidemics because it largely overcame the immunity to RHDV present in most rabbit populations. RHDV2 also was identified in Cape hare (Lepus capensis subsp. mediterraneus) and in Italian hare (Lepus corsicanus). Here, we describe two distinct incidents of RHDV2 infection in EBH that occurred in Italy (2012) and Spain (2014). The two RHDV2 strains caused macroscopic and microscopic lesions similar to European brown hare syndrome (EBHS) in hares, and they were genetically related to other RHDV2 strains in Europe. EBHs are common in Europe, often sharing habitat with rabbits. They likely have been exposed to high levels of RHDV2 during outbreaks in rabbits in recent years, yet only two incidents of RHDV2 in EBHs have been found in Italy and Spain, suggesting that EBHs are not a primary host. Instead, they may act as spillover hosts in situations when infection pressure is high and barriers between rabbits and hares are limited, resulting in occasional infections causing EBHS-like lesions. The serological survey of stocked hare sera taken from Italian and Spanish hare populations provided an understanding of naturally occurring RHDV2 infection in the field confirming its sporadic occurrence in EBH. Our findings increase the knowledge on distribution, host range and epidemiology of RHDV2.
Herein we describe two new species of the skink genus Lerista from north-eastern Queensland, based on morphological and genetic data.  Additionally, we redescribe L. cinerea as this species is morphologically more variable than previously suggested.  We allocate these three species to the L. wilkinsi group (Greer et al. 1983) which is here identified as an endemic Queensland radiation, comprising L. ameles, L. cinerea, L. hobsoni sp. nov., L. storri, L. vanderduysi sp. nov., L. vittata and L. wilkinsi.  A number of these species have strong associations with semi-evergreen vine thickets, listed as an endangered habitat under the Australian Environment Protection and Biodiversity Conservation Act (1999).
Two of the three recognized genera of Sericothripinae are known from the Neotropics, and 14 new species from this area are here described in this subfamily. Illustrated keys are provided to females of seven species of Hydatothrips, and 41 species of Neohydatothrips, mainly from Brazil but including all recorded species south of the border between Mexico and USA. Plant species on which breeding has been recorded are indicated where possible, notes are provided on the few species of economic importance, and a key is appended to second instar larvae of seven species. Neohydatothrips burungae (Hood) stat. rev. and N. aztecus Johansen stat. rev. are recalled from synonymy with Neohydatothrips signifer (Priesner), and N. denigratus (De Santis) syn. n. is synonymized with N. burungae. Hydatothrips williamsi (Hood) comb. n. is relocated from Neohydatothrips, and as this produces a homonym in the genus, Hydatothrips tareei nom. nov. is proposed for Hydatothrips williamsi Mound & Tree from Australia.
This note resolves homonymy among three genera of beetles described by myself (Ślipiński 1988, 1990), John F. Lawrence (Ślipiński & Lawrence 1997), and Hermes E. Escalona (Ślipiński & Escalona 2016). I propose new replacement names in accordance with the International Code of Zoological Nomenclature (ICZN 1999). Two anonymous reviewers are thanked for making valuable suggestions on an earlier version of this manuscript.
Ferredoxin:NADP(H) oxidoreductase (FNR) plays a key role in redox metabolism in plastids. Whereas leaf FNR (LFNR) is required for photosynthesis, root FNR (RFNR) is believed to provide electrons to ferredoxin (Fd)-dependent enzymes, including nitrite reductase (NiR) and Fd-glutamine-oxoglutarate aminotransferase (Fd-GOGAT) in non-photosynthetic conditions. In some herbal species, however, most nitrate reductase activity is located in photosynthetic organs, and ammonium in roots is assimilated mainly by Fd-independent NADH-GOGAT. Therefore, RFNR might have a limited impact on N assimilation in roots grown with nitrate or ammonium nitrogen sources. AtRFNR genes are rapidly induced by application of toxic nitrite. Thus, we tested the hypothesis that RFNR could contribute to nitrite reduction in roots by comparing Arabidopsis thaliana seedlings of the wild type with loss-of-function mutants of RFNR2 When these seedlings were grown under nitrate, nitrite or ammonium, only nitrite nutrition caused impaired growth and nitrite accumulation in roots of rfnr2 Supplementation of nitrite with nitrate or ammonium as N sources did not restore the root growth in rfnr2 Also, a scavenger for nitric oxide (NO) could not effectively rescue the growth impairment. Thus, nitrite toxicity, rather than N depletion or nitrite-dependent NO production, probably causes the rfnr2 root growth defect. Our results strongly suggest that RFNR2 has a major role in reduction of toxic nitrite in roots. A specific set of genes related to nitrite reduction and the supply of reducing power responded to nitrite concomitantly, suggesting that the products of these genes act co-operatively with RFNR2 to reduce nitrite in roots.
Notch signaling has been reported to be involved in several types of malignant tumors. However, the role and activation mechanisms of Notch signaling in oral squamous cell carcinoma (OSCC) remain poorly characterized. The present review focuses on the dual role of Notch signaling in OSCC. A number of expression and functional analyses demonstrated that Notch1 plays a crucial role in development and progression of OSCC. On the other hand, a tumor suppressive role of Notch1 was also suggested from studies, based on deep sequencing of cancer genomes.
 Interestingly, although some Notch1 mutations overlap in tumors from Caucasian and Asian patients, the overall spectrum of such mutations is vastly different between these cohorts. Accumulating evidence suggests that variation of Notch1 mutation signature may determine the role of Notch signaling in OSCC. As Notch is thought to act as an oncogene in a subset of OSCC, but also has a tumor suppression role, the role of Notch in OSCC seems to be highly context dependent.
What is your job? I act as an expert resource, supporting acute and community teams to provide safe and timely transition home for children on long-term ventilation (LTV) across London and the south east region. I provide parental and professional education and training, and take part in patient involvement projects, for example to ensure feedback is responded to. As a WellChild nurse I link into the established WellChild nurses' national network, which helps me seek support, share ideas and experiences with other nurses, contribute to research and undertake study days.
To assess the adherence of women's health providers in New Mexico to the Women's Preventive Services Guidelines and to examine how providers' knowledge, attitudes, and external barriers are associated with adherence.
Cross-sectional, descriptive survey.
New Mexico.
Women's health providers in New Mexico, including nurse practitioners, certified nurse-midwives, and family practice and obstetrician-gynecologist physicians.
Participants completed a self-administered survey to measure knowledge, attitudes, external barriers, and adherence to each of the eight guidelines. Adherence was defined as following a guideline more than 90% of the time.
The response rate was 22% (399/1,798). Among the eight guidelines, participant adherence ranged from 17.2% to 88.4%. Only 39.7% of participants indicated adherence to most of the guidelines (four or more). Overall, provider adherence was directly associated with familiarity with the guidelines (odds ratio = 3.69; 95% confidence interval [1.96, 6.96]), self-efficacy to implement them (odds ratio = 4.25; 95% confidence interval [2.21, 8.20]), and younger age (odds ratio = 0.97; 95% confidence interval [0.94, 1.00]).
Adherence to the Women's Preventive Services Guidelines by providers in New Mexico is variable and, for many recommended practices, less than optimal. New targeted implementation strategies are needed to address barriers to adherence.
Uterine inflammatory processes trigger prolabor pathways and orchestrate on-time labor onset. Although essential for successful labor, inflammation needs to be regulated to avoid uncontrolled amplification and resolve postpartum. During labor, myometrial smooth muscle cells generate ATP mainly via anaerobic glycolysis, resulting in accumulation of lactate. Aside from its metabolic function, lactate has been shown to activate a G protein-coupled receptor, GPR81, reported to regulate inflammation. We therefore hypothesize that lactate produced during labor may act via GPR81 in the uterus to exert in a feedback manner antiinflammatory effects, to resolve or mitigate inflammation.
We sought to investigate the role of lactate produced during labor and its receptor, GPR81, in regulating inflammation in the uterus.
We investigated the expression of GPR81 in the uterus and the pharmacological role of lactate acting via GPR81 during labor, using shRNA-GPR81 and GPR81(-/-) mice.
(1) Uterine lactate levels increased substantially from 2-9 mmol/L during labor. (2) Immunohistological analysis revealed expression of GPR81 in the uterus with high expression in myometrium. (3) GPR81 expression increased during gestation, and peaked near labor. (4) In primary myometrial smooth muscle cell and ex vivo uteri from wild-type mice, lactate decreased interleukin-1β-induced transcription of key proinflammatory Il1b, Il6, Ccl2, and Pghs2; suppressive effects of lactate were not observed in cells and tissues from GPR81(-/-) mice. (5) Conversely, proinflammatory gene expression was augmented in the uterus at term in GPR81(-/-) mice and wild-type mice treated intrauterine with lentiviral-encoded shRNA-GPR81; GPR81 silencing also induced proinflammatory gene transcription in the uterus when labor was induced by endotoxin (lipopolysaccharide). (6) Importantly, administration to pregnant mice of a metabolically stable specific GPR81 agonist, 3,5-dihydroxybenzoic acid, decreased endotoxin-induced uterine inflammation, preterm birth, and associated neonatal mortality.
Collectively, our data uncover a novel link between the anaerobic glycolysis and the control of uterine inflammation wherein the high levels of lactate produced during labor act on uterine GPR81 to down-regulate key proinflammatory genes. This discovery may represent a novel feedback mechanism to regulate inflammation during labor, and conveys a potential rationale for the use of GPR81 agonists to attenuate inflammation and ensued preterm birth.
The incidence of pulmonary nodules is increasing with the movement toward screening for lung cancer by low-dose computed tomography. Given the large number of benign nodules detected by computed tomography, an adjunctive test capable of distinguishing malignant from benign nodules would benefit practitioners. The ability of the EarlyCDT-Lung blood test (Oncimmune Ltd., Nottingham, United Kingdom) to make this distinction by measuring autoantibodies to seven tumor-associated antigens was evaluated in a prospective registry.
Of the members of a cohort of 1987 individuals with Health Insurance Portability and Accountability Act authorization, those with pulmonary nodules detected, imaging, and pathology reports were reviewed. All patients for whom a nodule was identified within 6 months of testing by EarlyCDT-Lung were included. The additivity of the test to nodule size and nodule-based risk models was explored.
A total of 451 patients (32%) had at least one nodule, leading to 296 eligible patients after exclusions, with a lung cancer prevalence of 25%. In 4- to 20-mm nodules, a positive test result represented a greater than twofold increased relative risk for development of lung cancer as compared with a negative test result. Also, when the "both-positive rule" for combining binary tests was used, adding EarlyCDT-Lung to risk models improved diagnostic performance with high specificity (>92%) and positive predictive value (>70%).
A positive autoantibody test result reflects a significant increased risk for malignancy in lung nodules 4 to 20 mm in largest diameter. These data confirm that EarlyCDT-Lung may add value to the armamentarium of the practitioner in assessing the risk for malignancy in indeterminate pulmonary nodules.
Ageing is generally associated with deterioration of organ function and regenerative potential. In the case of pancreatic β-cells, an age-related decline in proliferative potential is well documented, and was proposed to contribute to the increased prevalence of type 2 diabetes in the elderly. The effects of ageing on β-cell function, namely glucose-stimulated insulin secretion (GSIS), have not been studied as extensively. Recent work revealed that, surprisingly, β-cells of mature mice and humans secrete more insulin than young β-cells in response to high glucose concentrations, potentially serving to counteract age-related peripheral insulin resistance. This functional change appears to be orchestrated by p16(Ink4A) -driven cellular senescence and downstream remodelling of chromatin structure and DNA methylation, enhancing the expression of genes controlling β-cell function. We propose that activation of the cellular senescence program drives life-long functional maturation of β-cells, due to β-cell hypertrophy, enhanced glucose uptake and more efficient mitochondrial metabolism, in parallel to locking these cells in a non-replicative state. We speculate that the beneficial aspects of this process can be harnessed to enhance GSIS. Other age-related mechanisms, which are currently poorly understood, act to increase basal insulin secretion levels also in low glucose conditions. This leads to an overall reduction in the amplitude of insulin secretion between low and high glucose at old age, which may contribute to a deterioration in metabolic control.
Biological barrier plays a crucial role for organisms against the possible toxicity from engineered nanomaterials (ENMs). Graphene oxide (GO) has been proven to cause potential toxicity on organisms. However, the molecular mechanisms for intestinal barrier of animals against GO toxicity are largely unclear. Using in vivo assay system of Caenorhabditis elegans, we found that mutation of genes encoding core p38 mitogen-activated protein kinase (MAPK) signaling pathway caused susceptible property to GO toxicity and enhanced translocation of GO into the body of nematodes. Genetic assays indicated that SKN-1/Nrf functioned downstream of p38 MAPK signaling pathway to regulate GO toxicity and translocation. Transcription factor of SKN-1 could regulate GO toxicity and translocation at least through function of its targeted gene of gst-4 encoding one of phase II detoxification proteins. Moreover, intestine-specific RNA interference (RNAi) assay demonstrated that the p38 MAPK-SKN-1/Nrf signaling cascade could function in intestine to regulate GO toxicity and intestinal permeability in GO exposed nematodes. Therefore, p38 MAPK-SKN-1/Nrf signaling cascade may act as an important molecular basis for intestinal barrier against GO toxicity in organisms. Exposure to GO induced significantly increased expression of genes encoding p38 MAPK-SKN-1/Nrf signaling cascade, which further implies that the identified p38 MAPK-SKN-1/Nrf signaling cascade may encode a protection mechanism for nematodes in intestine to be against GO toxicity.
Cat fleas (Ctenocephalides felis (Bouché)) are a common
 flea species mostly found on cats and dogs. They not only cause discomfort to pets and their owners but also act as important vectors for human and pet zoonoses. Over the past 15 yr, the control of cat fleas on pets has been revolutionized through the use of various treatments. At present, fipronil and imidacloprid are used for flea control in Taiwan and are available in spot-on and spray formulations. Outside Taiwan, spinosad in tablet form is also available. In this study, we examined the effects of the aforementioned three insecticides on laboratory-reared and field-collected cat flea larvae. We developed a new technique for detecting flea susceptibility using a single larval bioassay with 96-well microtiter plates via contact and oral applications. Compared to the lab strain, the field strain exhibited lower susceptibility to fipronil, with the latter showing resistance levels two to four times higher than that of the former. By contrast, no difference in susceptibility was found between the two strains when tested with spinosad and imidacloprid. Our new technique was found to be stable, standardized, more efficient, convenient, and reproducible when compared to present techniques.
The purpose of this quality improvement project was to implement and evaluate a postpartum depression screening program using the Edinburgh Postnatal Depression Scale (EPDS) during well-child appointments up to 1 year of age at a private, faith-based primary care clinic.
The Plan-Do-Study-Act framework was used in this quality improvement project. The EPDS was administered to mothers ages 19 years and older at their infants' well-child appointments at a faith-based clinic in the Midwest. A score of 10 or higher was considered a positive result. The results were reviewed, and protocol changes were implemented every 2 weeks using the Plan-Do-Study-Act framework.
A total of 35 mothers completed the EPDS during the 9-week implementation period. Of 37 mothers asked to participate, nearly all agreed (97.3%); there was one refusal (2.7%). Staff compliance rate with administering the EPDS was 78.7%; there were 10 missed opportunities (21.3%). There were five positive EPDS results (14.3%). Mothers who screened positive were between the ages of 20 and 44 years. Infant ages were between 2 weeks and 12 months.
Screening mothers at well-child appointments can identify women with postpartum depression. Not doing so is a missed opportunity. The results of this project support the identification of postpartum depression by screening using the EPDS during well-child appointments up to 1 year of age.
Pro-inflammatory mediators including TNF-alpha, IL-6, and nitric oxide are important for the regulation of the immune response when an infection is present, but when overproduced, it can be responsible for the development of tissue and organ injury seen in sepsis, as well as severe asthma, and autoimmune diseases such as Crohn's disease and rheumatoid arthritis. Data from our lab to characterize the novel compound enaminone E121 have suggested that macrophages stimulated with lipopolysaccharide (LPS) release significantly decreased levels of TNF-alpha and IL-6 as measured by enzyme-linked immunosorbent assay as compared to the DMSO control group. Additionally, functional experiments in a mouse model of asthma have shown that E121 is efficacious in decreasing airway hyperresponsiveness. A new set of compounds synthesized in our lab (JODI) have an N-aryl piperazino motif incorporated on the aromatic side of the enaminone pharmacophore. It was hypothesized that this would enhance their immunosuppressive activity as anti-inflammatory agents by also acting as a chemokine receptor antagonist. Our studies suggest that JODI appears to suppress TNF-alpha and IL-6 in a dose-dependent manner. The JODI compounds were also more effective in reducing TNF-alpha after LPS stimulation when compared to dexamethasone. Lastly, studies using MCP-1 suggest that the JODI compounds, and not E121, are able to block CCR2 signaling as evidenced by decreased total ERK1/2. These studies indicate that E121 and its corresponding piperazino analogs could act as strong anti-inflammatory agents in asthma or other autoimmunities where efficacious therapeutic options are needed.
The study aimed to confirm the presence of historic oyster banks of Qatar and code the biotopes present. The research also collated historical records and scientific publications to create a timeline of fishery activity. The oyster banks where once an extremely productive economic resource however, intense overfishing, extreme environmental conditions and anthropogenic impacts caused a fishery collapse. The timeline highlighted the vulnerability of ecosystem engineering bivalves if overexploited. The current status of the oyster banks meant only one site could be described as oyster dominant. This was unexpected as the sites were located in areas which once supported a highly productive oyster fishery. The research revealed the devastating effect that anthropogenic impacts can have on a relatively robust marine habitat like an oyster bed and it is hoped these findings will act as a driver to investigate and map other vulnerable habitats within the region before they too become compromised.
Temozolomide is a chemotherapeutic agent that is used in the treatment of glioblastoma and other malignant gliomas. It acts through DNA alkylation, but treatment is limited by its systemic toxicity and neutralization of DNA alkylation by upregulation of the O(6)-methylguanine-DNA methyltransferase gene. Both of these limiting factors can be addressed by achieving higher concentrations of TMZ in the brain. Our research has led to the discovery of new analogs of temozolomide with improved brain:plasma ratios when dosed in vivo in rats. These compounds are imidazotetrazine analogs, expected to act through the same mechanism as temozolomide. With reduced systemic exposure, these new agents have the potential to improve efficacy and therapeutic index in the treatment of glioblastoma.
In this paper we explore the suitability of concept mapping as a method for integrating knowledge from science, practice, and policy. In earlier research we described and analysed five cases of concept mapping procedures in the Netherlands, serving different purposes and fields in public health. In the current paper, seven new concept mapping studies of co-produced work are added to extend this analysis. For each of these twelve studies we analysed: (1) how the method was able to integrate knowledge from practice with scientific knowledge by facilitating dialogue and collaboration between different stakeholders in the field of public health, such as academic researchers, practitioners, policy-makers and the public; (2) how the method was able to bring theory development a step further (scientific relevance); and (3) how the method was able to act as a sound basis for practical decision-making (practical relevance). Based on the answers to these research questions, all but one study was considered useful for building more evidence-based public health, even though the extent to which they underpinned actual decision-making varied. The chance of actually being implemented in practice seems strongly related to the extent to which the responsible decision-makers are involved in the way the concept map is prepared and executed.
Dry periods are predicted to become more frequent and severe in the future in some parts of the tropics, including Amazonia, potentially causing reduced productivity, higher tree mortality and increased emissions of stored carbon. Using a long-term (12 year) through-fall exclusion (TFE) experiment in the tropics, we test the hypothesis that trees produce leaves adapted to cope with higher levels of water stress, by examining the following leaf characteristics: area, thickness, leaf mass per area, vein density, stomatal density, the thickness of palisade mesophyll, spongy mesophyll and both of the epidermal layers, internal cavity volume and the average cell sizes of the palisade and spongy mesophyll. We also test whether differences in leaf anatomy are consistent with observed differential drought-induced mortality responses among taxa, and look for relationships between leaf anatomy, and leaf water relations and gas exchange parameters. Our data show that trees do not produce leaves that are more xeromorphic in response to 12 years of soil moisture deficit. However, the drought treatment did result in increases in the thickness of the adaxial epidermis (TFE: 20.5 ± 1.5 µm, control: 16.7 ± 1.0 µm) and the internal cavity volume (TFE: 2.43 ± 0.50 mm(3) cm(-2), control: 1.77 ± 0.30 mm(3) cm(-2)). No consistent differences were detected between drought-resistant and drought-sensitive taxa, although interactions occurred between drought-sensitivity status and drought treatment for the palisade mesophyll thickness (P = 0.034) and the cavity volume of the leaves (P = 0.025). The limited response to water deficit probably reflects a tight co-ordination between leaf morphology, water relations and photosynthetic properties. This suggests that there is little plasticity in these aspects of plant anatomy in these taxa, and that phenotypic plasticity in leaf traits may not facilitate the acclimation of Amazonian trees to the predicted future reductions in dry season water availability.
In the natural environment, Daphnia spp. are constantly exposed to a complex matrix of biomolecules, especially during cyanobacterial bloom events. When cyanobacterial cells decay, not only are toxic secondary metabolites known as cyanotoxins released, but also multiple other secondary metabolites, some of which act as enzyme inhibitors. The present study examined the effects of such a natural toxin matrix (crude extract from a bloom) versus artificial toxin mixtures
 in terms of oxidative stress in Daphnia pulex. The results indicate that there is no significant effect on the survival of D. pulex. However, exposure to the bloom extract resulted in increased lipid peroxidation over a shorter exposure period and reduced antioxidative enzyme activities when compared to the artificial mixtures. The daphnids also needed a longer recovery time to reduce the increased cellular hydrogen peroxide concentration associated with the exposure to the crude extract than with the artificial mixtures. The results indicate a significant difference between the bloom crude extract and the two synthetic mixtures for all stress markers tested, indicating enhanced toxicity of the bloom extract.
A significant number of consumer goods and building materials can act as emission sources of flame retardants (FRs) in the indoor environment. We investigate the relationship between the emission source strength and the levels of 19 brominated flame retardants (BFRs) and seven organophosphate flame retardants (OPFRs) in air and dust collected in 38 indoor microenvironments in Norway. We use modeling methods to back-calculate emission rates from indoor air and dust measurements and identify possible indications of an emission-to-dust pathway. Experimentally based emission estimates provide a satisfactory indication of the relative emission strength of indoor sources. Modeling results indicate an up to two orders of magnitude enhanced emission strength for OPFRs (median emission rates of 0.083 and 0.41 μg h(-1) for air-based and dust-based estimates) compared to BFRs (0.52 and 0.37 ng h(-1) median emission rates). A consistent emission-to-dust signal, defined as higher dust-based than air-based emission estimates, was identified for four of the seven OPFRs, but only for one of the 19 BFRs. It is concluded, however, that uncertainty in model input parameters could potentially lead to the false identification of an emission-to-dust signal.
The transcriptional cofactor receptor-interacting protein 140 (RIP140) is known as a deleterious regulator of cardiac mitochondrial function and energy metabolic homeostasis. This study revealed that RIP140 repressed Sirtuin 3 (SIRT3), a mitochondrial deacetylase that plays an important role in regulating cardiac function.
RIP140 was overexpressed by adenovirus infection or was knocked down by RNA interference in neonatal rat cardiomyocytes.
RIP140 overexpression repressed, while RIP140 silencing elevated the expression and activity of SIRT3. Ad-RIP140 enhanced the expressions of the cardiac hypertrophic markers and increased cardiomyocyte surface area, whereas SIRT3 overexpression prevented the effect of Ad-RIP140. Additionally, SIRT3 overexpression reversed Ad-RIP140-induced mitochondrial dysfunction and energy metabolic dysfunction, such as increase in oxidative stress, decrease in mitochondrial membrane potential and ATP production, as well as downregulation of mitochondrial DNA-encoded genes and genes related to mitochondrial genome replication and transcription, mitochondrial oxidative phosphorylation and fatty acid oxidation. In contrast, SIRT3 silencing exacerbated RIP140-induced cardiomyocyte hypertrophy and mitochondrial dysfunction. Furthermore, the repression of SIRT3 by RIP140 was dependent on estrogen-related receptor-α (ERRα). The involvement of peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α) was ruled out of SIRT3 suppression by RIP140. RIP140 and PGC-1α might act as functional antagonists on the regulation of SIRT3.
This study indicates that suppression of SIRT3 by RIP140 facilitates the development of cardiomyocyte hypertrophy, mitochondrial dysfunction and energy metabolic dysfunction. Strategies targeting inhibition of RIP140 and upregulation of SIRT3 might improve cardiac energy metabolism and suggest therapeutic potential for heart diseases.
SHP-1, the Src homology-2 (SH2) domain-containing phosphatase 1, is a cytosolic protein-tyrosine phosphatase (PTP) predominantly expressed in hematopoietic-derived cells. Previous studies have focused on the involvement of SHP-1 in osteoclastogenesis. Using primary cultured mouse fetal calvaria-derived osteoblasts as a model, this study aims to investigate the effects of SHP-1 on differentiation and mineralization of osteoblasts and elucidate the signaling pathways responsible for these effects. We found that osteoblasts treated by osteogenic media showed significant increase in SHP-1 expression, which contributed to osteoblastic differentiation and mineralization. Using immunoprecipitation assay, we found that a direct association between SHP-1 and glycogen synthase kinase (GSK)-3β could be detected in differentiated osteoblasts and was significantly inhibited by SHP-1 inhibitor NSC87877. Inhibition of SHP-1 activated GSK3β, thereby leading to suppression of osteoblast differentiation and mineralization, which could be rescued by the inhibitor of GSK3β. In addition, we found that rosiglitazone (RSG) treatment led to significant decrease in SHP-1 expression. Overexpression of SHP-1 reversed RSG-induced GSK3β activation, thus rescuing the inhibitory effect of RSG on osteoblast differentiation and mineralization. These findings suggest that protein tyrosine phosphatase SHP-1 may act as a positive regulator of osteoblast differentiation through direct association with and dephosphorylation of GSK3β. Downregulation of SHP-1 may contribute to RSG-induced inhibition of mouse calvaria osteoblast differentiation by activating GSK3β-dependent pathway.
Emotive health messages are widely used tools in tobacco control. However, under some circumstances, they can be less effective than desired by eliciting defensive responses in smokers.
This study tests whether enhancing a currently used emotive graphic smoking health warning with a self-affirmation component reduces cigarette consumption and whether potential effects are stronger in heavier smokers, as suggested by previous research.
Participants (n = 265) were randomly allocated to a self-affirmation (reflecting on personal values and positive traits using a questionnaire) or matched control condition before viewing an emotive graphic health message from a current Australian government public health campaign. The primary outcome (cigarettes per day [CPD]) was assessed both before and a week following the intervention.
No main effect of self-affirmation on smoking, but as hypothesized, a significant interaction between baseline smoking and self-affirmation was found that showed that heavier smokers (>21 CPD) who self-affirmed significantly reduced CPD compared to nonaffirmed smokers.
These findings support the use of self-affirmation to enhance smoking awareness campaigns in heavier smokers.
This study shows that enhancing emotive graphic smoking health messages with self-affirmation (the act of reflecting on positive aspects of oneself) increases their effectiveness in heavier smokers. This suggests that self-affirmation might be a particularly useful tool for health promotion targeting heavier smokers. This study adds to previous research in that it is the first to test the add-on effects of self-affirmation to current graphic health messages on smoking rather than smoking-related cognitions.
Esophageal squamous cell carcinoma (ESCC) is a fatal disease contributed by both genetic and epigenetic factors. The epigenetic alteration of protein tyrosine phosphatase non-receptor type 22 (PTPN22) and its clinical significance in ESCC were still not yet clarified. A quantitative methylation study of PTPN22 and its expression were conducted in 121 and 31 paired tumor and adjacent normal tissue (ANT), respectively. Moreover, the association between PTPN22 methylation and clinicopathological parameters was evaluated. We found that the methylation level of PTPN22 was significantly elevated in tumor tissues (66.3%) relative to ANT (62.1%) (p=0.005). The methylation level of non-smoking ANT (59.1%) was significant lower than smoking ESCC tissue (65.8%) (p=0.03); similarly, the methylation levels in ANT with no lymph node invasion (57.6%) were significant lower than tumor tissues with lymph node invasion (67.5%) (p=0.001). PTPN22 expression in ESCC was lower than normal tissues, however the difference was not statistically significant (p=0.55). Lower expression was more frequently occurred in N1-3 and III stage patients, while higher expression was more likely to occur in N0 and I-II stage patients. Lower expression of PTPN22 was associated with poor overall survival (p=0.04). Taken together, PTPN22 was hypermethylationed in ESCC. Hypermethylation was associated with lymph node invasion. The PTPN22 expression may act as a prognostic biomarker to identify patients at risk of high grade.
NumbL, or Numb-like, is a close homologue of Numb, and is part of an evolutionary conserved protein family implicated in some important cellular processes. Numb is a protein involved in cell development, in cell adhesion and migration, in asymmetric cell division, and in targeting proteins for endocytosis and ubiquitination. NumbL exhibits some overlapping functions with Numb, but its role in tumorigenesis is not fully known. Here we showed that the downregulation of NumbL alone is sufficient to increase NICD nuclear translocation and induce Notch pathway activation. Furthermore, NumbL downregulation increases epithelial-mesenchymal transition (EMT) and cancer stem cell (CSC)-related gene transcripts and CSC-like phenotypes, including an increase in the CSC-like pool. These data suggest that NumbL can act independently as a tumor suppressor gene. Furthermore, an absence of NumbL induces chemoresistance in tumor cells. An analysis of human tumors indicates that NumbL is downregulated in a variable percentage of human tumors, with lower levels of this gene correlated with worse prognosis in
 colon, breast and lung tumors. Therefore, NumbL can act as an independent tumor suppressor inhibiting the Notch pathway and regulating the cancer stem cell pool.
Long non-coding RNAs (lncRNAs) have emerged recently as key regulators of tumor development and progression. Our previous study identified an NF-KappaB interacting lncRNA (NKILA) which was negatively correlated with breast cancer metastasis and patient prognosis. However, its clinical significance and potential role in Tongue squamous cell carcinoma (TSCC) remain unclear. Here we show that NKILA is down-regulated in TSCC cancer tissues than that in matched adjacent noncancerous tissues. And low NKILA expression in TSCC is significantly correlated with tumor metastasis and poor patient prognosis. In vitro, overexpression of NKILA decreases TSCC cells migration and invasion. Mechanistic study shows that NKILA inhibits the phosphorylation of IκBα and NF-κB activation as well as the induction of the epithelial-mesenchymal transition (EMT) process. Ectopic expression of NKILA in Tscca cells inhibits NF-κB activator TNF-α-promoted cell migration and invasion, while applying NF-κB inhibitor Bay-117082 or JSH-23 in NKILA silenced CAL27 cells reverses cell migration capacity to lower level. In vivo experimental metastasis model also demonstrates NKILA inhibits lung metastasis of NOD/SCID mice with TSCC tumors. These results suggested that NKILA is a vital determinant of TSCC migration and invasion and NF-κB signaling pathway mediates this effect. Given the above mentioned function of NKILA, it could act as a potential predictor for overall survival in patients with TSCC and a potential therapeutic target for TSCC intervention.
A range of pesticides are available in Australia for use in agricultural and domestic settings to control pests, including organophosphate and pyrethroid insecticides, herbicides, and insect repellents, such as N,N-diethyl-meta-toluamide (DEET). The aim of this study was to provide a cost-effective preliminary assessment of background exposure to a range of pesticides among a convenience sample of Australian residents. De-identified urine specimens stratified by age and sex were obtained from a community-based pathology laboratory and pooled (n = 24 pools of 100 specimens). Concentrations of urinary pesticide biomarkers were quantified using solid-phase extraction coupled with isotope dilution high-performance liquid chromatography-tandem mass spectrometry. Geometric mean biomarker concentrations ranged from <0.1 to 36.8 ng/mL for organophosphate insecticides, <0.1 to 5.5 ng/mL for pyrethroid insecticides, and <0.1 to 8.51 ng/mL for all other biomarkers with the exception of the DEET metabolite 3-diethylcarbamoyl benzoic acid (4.23 to 850 ng/mL). We observed no association between age and concentration for most biomarkers measured but noted a "U-shaped" trend for five organophosphate metabolites, with the highest concentrations observed in the youngest and oldest age strata, perhaps related to age-specific differences in behavior or physiology. The fact that concentrations of specific and non-specific metabolites of the organophosphate insecticide chlorpyrifos were higher than reported in USA and Canada may relate to differences in registered applications among countries. Additional biomonitoring programs of the general population and focusing on vulnerable populations would improve the exposure assessment and the monitoring of temporal exposure trends as usage patterns of pesticide products in Australia change over time.
Hospitalisations are the prime contributor to healthcare expenditure, with older adults often identified as high hospital users. Despite the apparent high use of hospitals at the end of life, limited evidence currently exists regarding reasons for hospitalisation. Understanding complex end of life care needs is required for future health care planning as the global population ages. This study aimed to investigate patterns of hospitalisation in the last year of life by cause of death (COD) as well as reasons for admission and short-term predictors of hospital use.
Survey data from 1,205 decedents from the 1921-1926 cohort of the Australian Longitudinal Study on Women's Health were matched with the state-based hospital records and the National Death Index. Hospital patterns based on COD were graphically summarised and multivariate logistic regression models examined the impact of short-term predictors of length of stay (LOS).
85 % of women had at least one admission in the last year of life; and 8 % had their first observed admission during this time. Reasons for hospitalisation, timing of admissions and LOS differed by COD. Women who died of cancer, diabetes and 'other' causes were admitted earlier than women who died of organ failure, dementia and influenza. Women who died of organ failure overall spent the longest time in hospital, and women with cancer had the highest median LOS. Longer LOS was associated with previous short- and medium-term- hospitalisations and type of hospital separation.
Reducing acute care admissions and LOS at the end of life is complex and requires a shift in perceptions and treatment regarding end of life care and chronic disease management.
During bioethanol fermentation process, Saccharomyces cerevisiae cell membrane is the first target to be attacked by the accumulated ethanol. In such a prominent position, S. cerevisiae cell membrane could reversely provide protection through changing fluidity or elasticity secondary to remodeled membrane components or structure during the fermentation process. However, there is yet to be a direct observation of the real effect of the membrane compositional change. In this study, atomic force microscope-based strategy was performed to determine Young's modulus of S. cerevisiae to directly clarify ethanol stress-associated changes and roles of S. cerevisiae cell membrane fluidity and elasticity. Cell survival rate decreased while the cell swelling rate and membrane permeability increased as ethanol concentration increased from 0% to 20% v/v. Young's modulus decreased continuously from 3.76MPa to 1.53MPa while ethanol stress increased from 0% to 20% v/v, indicating that ethanol stress induced the S. cerevisiae membrane fluidity and elasticity changes. Combined with the fact that membrane composition varies under ethanol stress, to some extent, this could be considered as a forced defensive act to the ethanol stress by S. cerevisiae cells. On the other hand, the ethanol stress induced loosening of cell membrane also caused S. cerevisiae cell to proactively remodel membrane to make cell membrane more agreeable to the increase of environmental threat. Increased ethanol stress made S. cerevisiae cell membrane more fluidized and elastic, and eventually further facilitated yeast cell's survival.
Prostate cancer is a key health concern for men with its etiology still under investigation. Recently, the role of dietary supplements has been noted to have a major inhibitory effect on prostate cancer and numerous studies have been conducted in this regard. This review provides a summary on numerous recent studies conducted in this field. Some of the studies reviewed revealed a protective role for supplements, and others showed no correlation while some even had an adverse effect. The mechanism of how these supplements act on the prostate is still not clear. Further studies are warranted especially for supplements that have been shown to have a potential inhibitory role in prostate cancer.
Artemisinins are the most rapidly acting of currently available antimalarial drugs. Artesunate has become the treatment of choice for severe malaria, and artemisinin-based combination therapies (ACTs) are the foundation of modern falciparum malaria treatment globally. Their safety and tolerability profile is excellent. Unfortunately, Plasmodium falciparum infections with mutations in the 'K13' gene, with reduced ring-stage susceptibility to artemisinins, and slow parasite clearance in patients treated with ACTs, are now widespread in Southeast Asia. We review clinical efficacy data from the region (2000-2015) that provides strong evidence that the loss of first-line ACTs in western Cambodia, first artesunate-mefloquine and then DHA-piperaquine, can be attributed primarily to K13 mutated parasites. The ring-stage activity of artemisinins is therefore critical for the sustained efficacy of ACTs; once it is lost, rapid selection of partner drug resistance and ACT failure are inevitable consequences. Consensus methods for monitoring artemisinin resistance are now available. Despite increased investment in regional control activities, ACTs are failing across an expanding area of the Greater Mekong subregion. Although multiple K13 mutations have arisen independently, successful multidrug-resistant parasite genotypes are taking over and threaten to spread to India and Africa. Stronger containment efforts and new approaches to sustaining long-term efficacy of antimalarial regimens are needed to prevent a global malaria emergency.
Good laboratory practice standards are US federal regulations enacted as part of the Federal Insecticide, Fungicide, and Rodenticide Act (40 CFR Part 160), the Toxic Substance Control Act (40 CFR Part 792), and the Good Laboratory Practice for Nonclinical Laboratory Studies (21 CFR Part 58) to support protection of public health in the areas of pesticides, chemicals, and drug investigations in response to allegations of inaccurate data acquisition. Essentially, good laboratory practices (GLPs) are a system of management controls for nonclinical research studies involving animals to ensure the uniformity, consistency, reliability, reproducibility, quality, and integrity of data collected as part of chemical (including pharmaceuticals) tests, from in vitro through acute
 to chronic toxicity tests. The GLPs were established in the United States in 1978 as a result of the Industrial Bio-Test Laboratory scandal which led to congressional hearings and actions to prevent fraudulent data reporting and collection. Although the establishment of infrastructure for GLPs compliance is labor-intensive and time-consuming, achievement and maintenance of GLP compliance ensures the accuracy of the data collected from each study, which is critical for defending results, advancing science, and protecting human and animal health. This article describes how and why those in the US Army Medical Department responsible for protecting the public health of US Army and other military personnel made the policy decision to have its toxicology laboratory achieve complete compliance with GLP standards, the first such among US Army laboratories. The challenges faced and how they were overcome are detailed.
Parkinson's disease, dementia with Lewy bodies and multiple system atrophy are characterised by abnormal neuroglial α-synuclein accumulation. These α-synucleinopathies have in common parkinsonism and non-motor features including orthostatic hypotension (OH) and cognitive impairment. However, the nature of the relationship between OH and cognitive impairment is unclear. We therefore systematically reviewed the literature for evidence of an association between OH and cognitive impairment in α-synucleinopathies and discuss possible mechanisms and implications of this relationship. Abstracts from 313 original research articles were surveyed, and a total of 132 articles were considered for this review. Articles were stratified as: 'direct-evidence studies' based on the direct assessment for a relationship between OH and cognitive impairment in α-synucleinopathies, and 'indirect-evidence studies' based on an association being referred to as a secondary outcome. Ten 'direct-evidence papers' were identified, seven of which reported a positive association between OH and cognitive impairment, while seven of 12 'indirect-evidence papers' similarly did as well. The papers that reported no association between OH and cognitive impairment used less sensitive measures of cognition. A relationship between OH and cognitive impairment in patients with α-synucleinopathies exists, but the underlying mechanisms remain unclear. Three hypotheses are proposed: (1) OH and cognitive impairment occur concurrently due to diffuse brain and peripheral deposition of α-synuclein, (2) OH-mediated cerebral hypoperfusion impairs cognition and (3) the two act synergistically to accelerate cognitive decline. Longitudinal neuroimaging studies and clinical trials may help clarify the nature of this relationship.
Blood flow restriction (BFR) under low-intensity resistance training (LIRT) can produce similar effects upon muscles to that of high-intensity resistance training (HIRT) while overcoming many of the restrictions to HIRT that occurs in a clinical setting. However, the potential molecular mechanisms of BFR induced muscle hypertrophy remain largely unknown. Here, using a BFR rat model, we aim to better elucidate the mechanisms regulating muscle hypertrophy as induced by BFR and reveal possible clinical therapeutic targets for atrophy cases. We performed genome wide screening with microarray analysis to identify unique differentially expressed genes during rat muscle hypertrophy. We then successfully separated the differentially expressed genes from BRF treated soleus samples by comparing the Affymetrix rat Genome U34 2.0 array with the control. Using qRT-PCR and immunohistochemistry (IHC) we also analyzed other related differentially expressed genes. Results suggested that muscle hypertrophy induced by BFR is essentially regulated by the rate of protein turnover. Specifically, PI3K/AKT and MAPK pathways act as positive regulators in controlling protein synthesis where ubiquitin-proteasome acts as a negative regulator. This represents the first general genome wide level investigation of the gene expression profile in the rat soleus after BFR treatment. This may aid our understanding of the molecular mechanisms regulating and controlling muscle hypertrophy and provide support to the BFR strategies aiming to prevent muscle atrophy in a clinical setting.
DNA-based technologies such as RNAi, chemical-genetic profiling, or gene expression profiling by DNA microarrays combined with other biochemical methods are established strategies for surveying drug mechanisms. Such approaches can provide mechanistic information on how drugs act and affect cellular pathways. By studying how cancer cells compensate for the drug treatment, novel targets used in a combined treatment can be designed. Furthermore, toxicity effects on cells not targeted can be obtained on a molecular level. For example, drug companies are particularly interested in studying the molecular side effects of drugs in the liver. In addition, experiments with the purpose of elucidating liver toxicity can be studied using samples obtained from animal models exposed to different concentrations of a drug over time. More recently considerable advances in mass spectrometry (MS) technologies and bioinformatics tools allows informative global drug profiling experiments to be performed at a cost comparable to other large-scale technologies such as DNA-based technologies. Moreover, MS-based proteomics provides an additional layer of information on the dynamic regulation of proteins translation and particularly protein degradation. MS-based proteomics approaches combined with other biochemical methods delivers information on regulatory networks, signaling cascades, and metabolic pathways upon drug treatment. Furthermore, MS-based proteomics can provide additional information on single amino acid polymorphisms, protein isoform distribution, posttranslational modifications, and subcellular localization. In this chapter, we will share our experience using MS based proteomics as a pharmacoproteomics strategy to characterize drug mechanisms of action in single drug therapy or in multidrug combination. Finally, the emergence of integrated proteogenomics analysis, such as "The Cancer Genome Atlas" program, opened interesting perspectives to extend this approach to drug target discovery and validation.
Tandem ubiquitin-binding entities (TUBEs) act as molecular traps to isolate polyubiquitylated proteins facilitating the study of this highly reversible posttranslational modification. We provide here sample preparation and adaptations required for TUBE-based enrichment of the ubiquitin proteome from tumor cell lines or primary cells. Our protocol is suitable to identify ubiquitin substrates, enzymes involved in the ubiquitin proteasome pathway, as well as proteasome subunits by mass spectrometry. This protocol was adapted to prepare affinity columns, reduce background, and improve the protein recovery depending on the sample source and necessities.
Because of our current crisis of resistance, particularly in nosocomial pathogens, the discovery and development of new antimicrobial agents has become a societal imperative. Changes in regulatory pathways by the Food and Drug Administration and the European Medicines Agency place great emphasis on the use of preclinical models coupled with pharmacokinetic/pharmacodynamic analysis to rapidly and safely move new molecular entities with activity against multi-resistant pathogens through the approval process and into the treatment of patients. In this manuscript, the use of the murine pneumonia system and the Hollow Fiber Infection Model is displayed and the way in which the mathematical analysis of the data arising from these models contributes to the robust choice of dose and schedule for Phase 3 clinical trials is shown. These data and their proper analysis act to de-risk the conduct of Phase 3 trials for anti-infective agents. These trials are the most expensive part of drug development. Further, given the seriousness of the infections treated, they represent the riskiest element for patients. Consequently, these preclinical model systems and their proper analysis have become a central part of accelerated anti-infective development. A final contention of this manuscript is that it is possible to embed these models and in particular, the Hollow Fiber Infection Model earlier in the drug discovery/development process. Examples of 'dynamic driver switching' and the impact of this phenomenon on clinical trial outcome are provided. Identifying dynamic drivers early in drug discovery may lead to improved decision making in the lead optimization process, resulting in the best molecules transitioning to clinical development.
In the treatment of severe oculo-orbital traumas, intraocular malignancies or other life-threatening conditions it is sometimes necessary to surgically remove the patient's diseased eye. Following the removal of the eye, an orbital implant is inserted into the anophthalmic socket in order to provide satisfactory volume replacement and restore the aesthetic appearance of a normal eye. Over the last decades, the implant design and the criteria of materials selection evolved from simple non-porous polymeric sphere to devices with more complex shape and functionalities for ensuring better clinical outcomes in the long-term. Polymeric and ceramic porous implants have gained prominence since their highly interconnected porous architecture allows them to act as a passive framework for fibrovascular in-growth offering reduced complication rates and the possibility of pegging to enhance the motility of the artificial eye. However, there are still drawbacks to these materials. Some critical aspects of today's orbital implants include the risk of migration and extrusion, postoperative infections and low motility transmitted to the aesthetic ocular prosthesis. Hence,
 the development of novel biomaterials with enhanced functionalities (e.g. angiogenesis, antibacterial effect, in situ mouldability) which enable an improved outcome of eye replacement is more than ever desirable and represents one of the most challenging topics of research in the field of ocular implants. This review summarizes the evolution of orbital implants and provides an overview of the most recent advances in the field as well as some critical remarks for materials design, selection, characterization and translation to clinical applications.
In this study, a composite film based on TEMPO-oxidized cellulose nanofibers (TOCN), polyvinyl alcohol (PVA) and polypyrrole (PPy) was synthesized in situ by a chemical polymerization, resulting in the induced absorption of PPy on the surface of the TOCN. The composite films were investigated with scanning electron microscopy, thermogravimetric analysis, contact angle measurements, mechanical tests, and evaluation of antibacterial properties. The developed composite has nearly identical Young modulus (3.4GPa), elongation (2.6%) and tensile stress (about 51MPa) to TOCN even if PPy, which as poor properties by itself, was incorporated. From the energy-dispersive X-ray spectroscopy (EDX) results, it was shown that PPy is mainly located on the composite surface. Results confirmed by an increase from 54.5 to 83° in contact angle, an increased heat protection (Thermogravimetric analysis) and a decrease in surface energy. The nanocomposites were also evaluated for antibacterial activity against bacteria occasionally found in food: Gram-positive Bacillus subtilis (B. subtilis) and Gram-negative bacteria Escherichia coli (E. coli). The results indicate that the nanocomposites are effective against all of the bacteria studied as shown by the decrease of 5.2logcolonyformingunits (CFU) for B. subtilis and 6.5logCFU for E. coli. Resulting in the total destruction of the studied bacteria. The perfect match between the resulting inhibition zone and the composite surface area has demonstrated that our composite was contact active with a slight leaching of PPy. Our composite was successful as an active packaging on meat (liver) as bacteria were killed by contact, thereby preventing the spread of possible diseases. While it has not been tested on bacteria found in medicine, TOCN/PVA-PPy film may be able to act as an active sterile packaging for surgical instruments.
Stimuli-responsive and self-healing materials have a wide range of potential uses, and some significant research has focused on cross-linking of hydrogel materials by means of reversible coordination bonding. The resulting materials, however, tend to have poor mechanical properties with pronounced weakness and brittleness. In this work, we present a novel mussel-inspired graphene oxide(GO)-containing hydrogel based on modified polyaspartamide with γ-amino butyric acid (GABA), 3.4-dihydroxyphenethylamine (DOPA), and ethanolamine (EA), termed PolyAspAm(GABA/DOPA/EA). Here both GO nanosheets and boric acid (H3BO3) act as cross-linkers, interacting with polar functional groups of the PolyAspAm(GABA/DOPA/EA). Compared to PolyAspAm(GABA/DOPA/EA)/B(3+) gel without GO, the same containing 5wt% of GO yielded a 10-fold increase in both the storage and loss moduli, as well as 134% and 104% increases in the tensile and compressive strengths, respectively. In addition, the GO-containing polyaspartamide hydrogel exhibited rapid and autonomous self-healing property. Two types of bonding, boron-catechol coordination and strong hydrogen bonding interactions between PolyAspAm side chains and GO nanosheets, would impart the enhanced mechanical strength and good reversible gelation behavior upon pH stimulation to the hydrogel, making this biocompatible hydrogel a promising soft matter for biomedical applications.
The purpose of this study was  to identify demographic, clinical, psychosocial, physical and environmental factors that are associated with participation in and adherence to a combined resistance and endurance exercise program among cancer survivors, shortly after completion of primary cancer treatment. Data from the randomized controlled Resistance and Endurance exercise After ChemoTherapy (REACT) study were used for this study.
The participants of the REACT study were randomly allocated to either a high intensity (HI) or low-to-moderate intensity (LMI) exercise program. Patients' participation rate was defined as the cancer survivors' decision to participate in the REACT study. Exercise adherence reflected participants' attendance to the scheduled exercise sessions and their compliance to the prescribed exercises. High session attendance rates were defined as attending at least 80 % of the sessions. High compliance rates were defined as performing at least of 90 % of the prescribed exercise across all sessions. Correlates of exercise adherence were studied separately for HI and LMI exercise. Demographic, clinical, and physical factors were assessed using self-reported questionnaires. Relevant clinical information was extracted from medical records. Multivariable logistic regression analyses were applied to identify correlates that were significantly associated with participation, high session attendance, high compliance with resistance and high compliance with endurance exercises.
Participants were more likely to have higher education, be non-smokers, have lower psychological distress, higher outcome expectations, and perceive more exercise barriers than non-participants. In HI exercise, higher self-efficacy was significantly associated with high session attendance and high compliance with endurance exercises, and lower psychological distress was significantly associated with high compliance with resistance exercises. In LMI exercise, being a non-smoker was significantly associated with high compliance with resistance exercises and higher BMI was significantly associated with high compliance with resistance and endurance exercises. Furthermore, breast cancer survivors were less likely to report high compliance with resistance and endurance exercises in LMI exercise compared to survivors of other types of cancer. The discriminative ability of the multivariable models ranged from 0.62 to 0.75.
Several demographic, clinical and psychosocial factors were associated with participation in and adherence to exercise among cancer survivors. Psychosocial factors were more strongly associated with adherence in HI than LMI exercise.
This study was registered at the Netherlands Trial Register [ NTR2153 ] on the 5(th) of January 2010.
Molybdoenzymes are an ancient protein family found in phylogenetically and ecologically diverse prokaryotes. Under anaerobic conditions, respiratory molybdoenzymes catalyze redox reactions that transfer electrons to a variety of substrates that act as terminal electron acceptors for energy generation. Here, we used probe sequences to conduct an extensive genomic survey and phylogenetic inference for NarG, DmsA, TorA and nine other respiratory molybdoenzyme subfamilies. Our analysis demonstrates their abundance in 60% of prokaryotic phyla. In contrast to many other autonomic genetic units in prokaryotes, the major route of evolution of their predominant subfamilies is vertical gene transfer, gene duplication and divergence. Our results show the robustness of genomic co-occurrence of respiratory molybdoenzymes genes, found in the majority of studied species, for most of the enzyme subfamilies. Genomes which encode for multiple respiratory molybdoenzymes are also enriched in genes regulating replication, recombination and mobility of genetic elements. Respiratory molybdoenzymes were found in prokaryotes associated with diverse environments occupying terrestrial, aquatic, food and host-related habitats, emphasizing their essential role in adaptation of prokaryotes to changing environments. Interestingly, host-associated prokaryotes such as human pathogens more frequently carry multiple respiratory molybdoenzyme genes compared with non-host-associated prokaryotes, highlighting the importance of metabolic flexibility in host-microbiome environments.
Expert medical opinions are necessary in pretrial cases and other legal matters. They act as means of evidence for administrative bodies and courts. It may be necessary to adapt the method of evaluation depending upon the issue or subject matter to be evaluated. We report on a social court case, which needed to answer the question of the medical necessity of a functional electrical stimulation orthosis prescribed to improve the function of a drop foot accompanied by an atactic gait disorder. The claimant suffered from a stroke, which had occurred several years before. Her aids were an ankle-foot-orthosis for foot lift and a wheeled walker. The current treatment was to be augmented by the disputed device. The statutory health insurance declined to meet the costs. They failed to find relevant benefits after analysis of video tapes of the patient's gait while using an electrical stimulation orthosis. The social court requested an expert opinion to answer the question as to whether or not there was a relevant functional benefit to using functional electrical stimulation over the existing orthosis or to an alternative treatment. Video documentation was desired by the court. We used the clinic's gait analysis laboratory, which is equipped with a gait course and the claimed video documentation. Standardised video documentation offers substantial advantages for answering forensic questions such as these. It assures reproducibility and comparability of all tested scenarios, with objectification of the individual advantages or limitations. This gain in both validity and reliability fulfills the scientific requirements placed upon an expert assessment.
The cardiac ryanodine receptor (RyR2)
 is an intracellular ion channel that regulates Ca2+ release from the sarcoplasmic reticulum (SR) during excitation-contraction coupling in the heart. The glutathione transferases (GSTs) are a family of phase II detoxification enzymes with additional functions including the selective inhibition of RyR2, with therapeutic implications. The C-terminal half of GSTM2 (GSTM2C) is essential for RyR2 inhibition, and mutations F157A and Y160A within GSTM2C prevent the inhibitory action. Our objective in this investigation was to determine whether GSTM2C can enter cultured rat neonatal ventricular cardiomyocytes and influence contractility. We show that oregon green-tagged GSTM2C (at 1 μM) is internalized into the myocytes and it reduces spontaneous contraction frequency and myocyte shortening. Field stimulation of myocytes evoked contraction in the same percentage of myocytes treated either with media alone or media plus 15 μM GSTM2C. Myocyte shortening during contraction was significantly reduced by exposure to 15 μM GSTM2C, but not 5 and 10 μM GSTM2C and was unaffected by exposure to 15 μM of the mutants Y160A or F157A. The amplitude of the Ca2+ transient in the 15 μM GSTM2C - treated myocytes was significantly decreased, the rise time was significantly longer and the decay time was significantly shorter than in control myocytes. The Ca2+ transient was not altered by exposure to Y160A or F157A. The results are consistent with GSTM2C entering the myocytes and inhibiting RyR2, in a manner that indicates a possible therapeutic potential for treatment of arrhythmia in the neonatal heart.
Certain behavior types can drive the emergence of an unsafe act at the workplace which may be reflected by workers' perceptions toward safety climate.
The purpose of this study was to explore the relationship between workers' safety climate perceptions (NOSACQ-50 questionnaire) and their behavior types (based on DISC personality traits: Dominance, Influence, Steadiness, and Conscientiousness).
NOSACQ-50 and DISC assessment questionnaires were distributed on employees of four different companies (N = 755) working at hazardous workplaces in different occupational fields: fertilizer, coal mining, and oil & gas.
Four of the 48 correlation coefficients were statistically significant in which the strongest correlation was found between safety commitment and Influence (I) trait in public self (r = -0.119, p < 0.01). There were two groups of DISC's profile that have a lower perception toward safety climate. The first group was indicated by high scores on Influence (I) trait in public self (17.2% of respondents), and the latter was characterized by low scores on Dominance (D) trait and high scores on Conscientiousness (C) trait in private self (2.8% of respondents).
Lower perception toward safety climate was found to be correlated with two groups of DISC's profile. Workers characterized with these two profiles are considered to have priority needs for training or to be assigned to less a hazardous workplace.
Schistosomiasis is a debilitating disease that affects over 240 million people worldwide and is considered the most important neglected tropical disease following malaria. Free-swimming freshwater cercariae, one of the six morphologically distinct schistosome life stages, infect humans by directly penetrating through the skin. Cercariae identify and seek the host by sensing chemicals released from human skin. When they reach the host, they burrow into the skin with the help of proteases and other contents released from their acetabular glands and transform into schistosomula, the subsequent larval worm stage upon skin infection. Relative to host invasion, studies have primarily focused on the nature of the acetabular gland secretions, immune response of the host upon exposure to cercariae, and cercaria-schistosomulum transformation methods. However, the molecular signaling pathways involved from host-seeking through the decision to penetrate skin are not well understood. We recently observed that heat shock factor 1 (Hsf1) is localized to the acetabular glands of infectious schistosome cercariae, prompting us to investigate a potential role for heat shock proteins (HSPs) in cercarial invasion. In this study, we report that cercarial invasion behavior, similar to the behavior of cercariae exposed to human skin lipid, is regulated through an Hsp70-dependent process, which we show by using chemical agents that target Hsp70. The observation that biologically active protein activity modulators can elicit a direct and clear behavioral change in parasitic schistosome larvae is itself interesting and has not been previously observed. This finding suggests a novel role for Hsp70 to act as a switch in the cercaria-schistosomulum transformation, and it allows us to begin elucidating the pathways associated with cercarial host invasion. In addition, because the Hsp70 protein and its structure/function is highly conserved, the model that Hsp70 acts as a behavior transitional switch could be relevant to other parasites that also undergo an invasion process and can apply more broadly to other organisms during morphological transitions. Finally, it points to a new function for HSPs in parasite/host interactions.
Previously, metallodielectric Janus particles have been shown to travel with their dielectric hemisphere forward under low frequency applied electric fields as a result of asymmetric induced-charge electroosmotic flow. Here, it is demonstrated that at high frequencies, well beyond the charge relaxation time of the electric double layer induced around the particle, rather than the velocity decaying to zero, the Janus particles reverse direction, traveling with their metallic hemisphere forward. It is proposed that such motion is the result of a surface force, arising from localized nonuniform electric field gradients, induced by the dual symmetry-breaking of an asymmetric particle adjacent to a wall, which act on the induced dipole of the particle to drive net motion even in a uniform AC field. Although the field is external, since the driving gradient is induced on the particle level, it may be considered an active colloid. We have thus termed this propulsion mechanism "self-dielectrophoresis", to distinguish from traditional dielectrophoresis where the driving nonuniform field is externally fixed and the particle direction is restricted. It is demonstrated theoretically and experimentally that the critical frequency at which the particle reverses direction can be characterized by a nondimensional parameter which is a function of electrolyte concentration and particle size.
Organic-inorganic hybrid nanoparticles are prepared by free-radical copolymerization of methyl methacrylate (MMA) with the structurally well-defined methacrylate-functionalized zirconium oxocluster Zr4O2(methacrylate)12. The polymerization process occurs in the confined space of miniemulsion droplets. The formation of covalent chemical bonds between the organic and the inorganic counterparts improves the distribution of the guest species (oxoclusters) in the polymer particles, overcoming problems related to migration, leaching, and stability. Because of the presence of a high number of double bonds (12 per oxocluster), the oxoclusters act as efficient cross-linking units for the resulting polymer matrix, thus ruling its swelling behavior in organic solvents. The synthesized hybrid nanostructures are applied as heterogeneous systems in the catalytic oxidation of an organic sulfide to the corresponding sulfoxide and sulfone by hydrogen peroxide, displaying quantitative sulfide conversion in 4-24 h, with overall turnover numbers (TON) up to 8000 after 4 cycles.
Spermatogenesis and sperm maturation in the male reproductive tract is dictated by a variety of proteins secreted in the testis and epididymis. Though the proteome of these tissues is known, the functional role of many of these proteins remains uncharacterized. In this study, we characterize the rat Lysozyme-like (Lyzl) genes and proteins.
In silico tools were used to predict the primary, secondary and tertiary structures. Reverse transcription PCR, immunofluorescence and immunoblotting were used to determine the expression pattern. Lysozyme like enzyme activity was assessed by standard assays.
Six rat Lyzl genes namely Lyzl1, Lyzl3, Lyzl4, Lyzl5, Lyzl6 and Lyzl7 were found to be highly conserved among the vertebrates with higher homology to mouse counterparts than with human counterparts. All the LYZL proteins contained the characteristic 4 disulfide bridges similar to c-type lysozyme. Only LYZL 1 and 6, conserved the active site amino acids of the lysozyme. Molecular modeling studies indicated that LYZL proteins exhibit strikingly similar three-dimensional structures among themselves. The secondary structure analysis of the recombinant LYZL proteins indicated the presence of α-helix, β-sheet and random coil with α-helix being the majority. Docking studies indicated the peptidoglycan binding nature of LYZL proteins. All the rat Lyzl mRNA transcripts (Lyzl1, Lyzl3, Lyzl4, Lyzl5, Lyzl6 and Lyzl7) are predominantly expressed in testes though some of them are expressed in tissues other than reproductive tract. Their expression was androgen independent. The rat LYZL proteins are localized in the germinal epithelium and on the spermatozoa. Recombinant LYZL1 and 6 possessed muramidase, isopeptidase and antibacterial activities. The mechanism of antibacterial action of LYZL1 and LYZL6 involved bacterial membrane damage and leakage of cellular contents. Only LYZL1 and 6 possess peptidoglycan binding ability, whereas LYZL3, LYZL4 and LYZL5 possess hyaluronan binding ability suggesting a possible functional divergence of these proteins. LYZL3, LYZL4 and LYZL7 possessed free radical scavenging property, suggesting that they may act as antioxidants.
The
 divergent properties of LYZL proteins indicate that they may have a role in sperm function, innate immunity and other physiological process as well.
To study the impact of rising bilateral mastectomy rates among neoadjuvant chemotherapy (NAC) recipients in California.
NAC for operable breast cancer (BC) can downstage disease and facilitate breast conservation. We assessed trends in NAC use and surgical procedures in California from January 1, 1998 to December 31, 2012 using statewide population-based cancer registry data.
A total of 236,797 females diagnosed with stage I-III BC were studied. Information regarding NAC, adjuvant chemotherapy (aCT), breast conserving surgery (BCS), bilateral mastectomy (BLM), and unilateral mastectomy (ULM) was abstracted from the medical records. Multivariable polytomous logistic regression was used to estimate odds ratios (OR) of receiving NAC and of type of surgery after NAC.
Approximately, 40.1% (94,980) of patients received chemotherapy: 87% (82,588) aCT and 13.0% (12,392) NAC. NAC use more than doubled over time and increased with stage (Stage I, 0.7%; Stage III, 29.9%). Multivariable predictors of NAC treatment were stage (III), younger age (<40 yrs), Black or Hispanic race/ethnicity versus non-Hispanic White (OR 1.10, 95% confidence interval (CI) 1.05-1.16), and care at a National Cancer Institute (NCI)-designated center (OR 1.70, CI 1.58-1.82). Most NAC recipients (68.4%) had mastectomies, and 14.3% of them underwent BLM. In contrast, 47.9% aCT patients had mastectomies with 7.3% BLM. The only independent predictor of BCS after NAC was care at a NCI-designated center (OR 1.28, CI 1.10-1.49), and of BLM, age <40 years versus 50 to 64 years (OR 2.59, CI 2.21-3.03), or residence in the highest socioeconomic neighborhood quintile versus lowest (OR 2.10, CI 1.67-2.64).
NAC use remains low. Predictors of surgery type after NAC were sociodemographic rather than clinical, raising concern for disparities in care access.
In this paper, we apply an original scientometric analyses to a corpus comprising synthetic biology (SynBio) publications in Thomson Reuters Web of Science to characterize the emergence of this new scientific field. Three results were drawn from this empirical investigation. First, despite the exponential growth of publications, the study of population level statistics (newcomers proportion, collaboration network structure) shows that SynBio has entered a stabilization process since 2010. Second, the mapping of textual and citational networks shows that SynBio is characterized by high heterogeneity and four different approaches: the central approach, where biobrick engineering is the most widespread; genome engineering; protocell creation; and metabolic engineering. We suggest that synthetic biology acts as an umbrella term allowing for the mobilization of resources, and also serves to relate scientific content and promises of applications. Third, we observed a strong intertwinement between epistemic and socio-economic dynamics. Measuring scientific production and impact and using structural analysis data, we identified a core set of mostly American scientists. Biographical analysis shows that these central and influential scientists act as "boundary spanners," meaning that their importance to the field lies not only in their academic contributions, but also in their capacity to interact with other social spaces that are outside the academic sphere.
Genetically determined artemisinin resistance in Plasmodium falciparum has been described in Southeast Asia. The relevance of recently described Kelch 13-propeller mutations for artemisinin resistance in Sub-Saharan Africa parasites is still unknown. Southeast Asia parasites have low genetic diversity compared to Sub-Saharan Africa, where parasites are highly genetically diverse. This study attempted to elucidate whether genetics provides a basis for discovering molecular markers in response to artemisinin drug treatment in P. falciparum in Kenya. The genetic diversity of parasites collected pre- and post- introduction of artemisinin combination therapy (ACT) in western Kenya was determined. A panel of 12 microsatellites and 91 single nucleotide polymorphisms (SNPs) distributed across the P. falciparum genome were genotyped. Parasite clearance rates were obtained for the post-ACT parasites. The 12 microsatellites were highly polymorphic with post-ACT parasites being significantly more diverse compared to pre-ACT (p < 0.0001). The median clearance half-life was 2.55 hours for the post-ACT parasites. Based on SNP analysis, 15 of 90 post-ACT parasites were single-clone infections. Analysis revealed 3 SNPs that might have some causal association with parasite clearance rates. Further, genetic analysis using Bayesian tree revealed parasites with similar clearance phenotypes were more closely genetically related. With further studies, SNPs described here and genetically determined response to artemisinin treatment might be useful in tracking artemisinin resistance in Kenya.
Re-pigmentation and stabilization are the two ultimate goals of any re-pigmenting plan designed for vitiligo management. Furthermore, whether the improvement of some vitiligo lesions could be considered a guarantee for a similar response and/or stabilization of the rest of the lesions or not, remains to be clarified. To evaluate the behavior of non-segmental vitiligo (NSV), while on narrow band-ultraviolet B (NB-UVB) phototherapy. 25 patients with stable generalized NSV were included and received NB-UVB twice weekly. For the sake of ensuring accuracy of follow up, up to four lesions were randomly chosen in each patient and regularly measured using the point counting technique. The over-all point counting technique of all included patients showed a significant reduction (18.5 ± 8.4 cm(2) to 8.2± 3.1 cm(2) ) after 6 months of therapy (p < .001). Nine patients (36%), showed mixed response in the different lesions. Improvement was documented in some lesions, while other lesions showed no response or even worsening. No significant correlations were detected between the behavior of vitiligo during NB-UVB and any of the demographic or clinical data of the patients. NB-UVB is a pillar in the management of vitiligo, however close follow-up of the patient as a whole and his lesions, by both subjective and objective measures are mandatory to detect activity as early as possible, as vitiligo at many times may not act as one unit. This early detection of activity and the subsequent change in the treatment policy may ultimately change the final outcome of treatment.
We demonstrate, experimentally and theoretically, a Talbot effect for hybrid light-matter waves-an exciton-polariton condensate formed in a semiconductor microcavity with embedded quantum wells. The characteristic "Talbot carpet" is produced by loading the exciton-polariton condensate into a microstructured one-dimensional periodic array of mesa traps, which creates an array of phase-locked sources for coherent polariton flow in the plane of the quantum wells. The spatial distribution of the Talbot fringes outside the mesas mimics the near-field diffraction of a monochromatic wave on a periodic amplitude and phase grating with the grating period comparable to the wavelength. Despite the lossy nature of the polariton system, the Talbot pattern persists for distances exceeding the size of the mesas by an order of magnitude. Thus, our experiment demonstrates efficient shaping of the two-dimensional flow of coherent exciton polaritons by a one-dimensional "flat lens."
The objective of our study was to reduce variation in image quality of orthogonal reformatted images generated from long-z-axis CT angiography (CTA) studies of the upper and lower extremities.
Upper and lower extremity CTA studies were targeted at a single health care system. A correctly performed CTA examination was defined as one that met the following three criteria: Sagittal and coronal reformats were obtained, a high-resolution matrix greater than 512 × 512 was used, and reformatted images were available in a distance-measurable format. Baseline data were collected from February 1, 2014, through September 30, 2014. Corrective actions were implemented during three consecutive plan-do-check-act (PDCA) cycles from October 1, 2014, through July 31, 2015, that addressed human, technical, and systematic variations. A 3-month maintenance period followed in which no intervention was performed. Longitudinal data were analyzed monthly using a statistical process control chart (p-chart).
The total number of long-z-axis extremity CTA studies analyzed was as follows: 351 CTA studies were analyzed at baseline, 94 at the first PDCA cycle, 92 at the second PDCA cycle, 114 at the third PDCA cycle, and 138 during the maintenance period. The monthly rate of correctly performed studies ranged from 7% to 51% (mean, 38% ± 13% [SD]) during the baseline period, 32-59% (mean, 46% ± 14%) during the first PDCA cycle, 40-81% (mean, 61% ± 21%) during the second PDCA cycle, and 80-82% (mean, 81% ± 0.9%) during the third PDCA cycle. The monthly rate improved to 90-91% (mean, 91% ± 0.5%) during the maintenance period. The upper and lower control limits of the p-chart were upshifted after the second and third PDCA cycles. Correcting systematic and technical variations led to the greatest improvements in reformat accuracy.
Obtaining consistently and correctly reformatted images from long-z-axis CTA studies is achievable using iterative PDCA cycles.
This article presents information on illicitly used synthetic cannabinoids. Synthetic cannabinoids are structurally heterogeneous and commonly used drugs of abuse that act as full agonists of the cannabinoid type-1 receptor but have a variety of additional pharmacologic effects. There are numerous cases of patient harm and death in
 the United States, Europe, and Australia with many psychological, neurological, cardiovascular, pulmonary, and renal adverse events. Although most users prefer using cannabis, there are convenience, legal, and cost reasons driving the utilization of synthetic cannabinoids. Clinicians should be aware of pharmacologic and clinical similarities and differences between synthetic cannabinoid and cannabis use, the limited ability to detect synthetic cannabinoids in the urine or serum, and guidance to treat adverse events.
Presenteeism, a concept that has recently undergone active study, is the act of attending work while sick. This study investigates the association between presenteeism and various psychosocial factors within workplaces.
This study analyzed 29246 wage earners from the third Korean Working Conditions Survey (KWCS, 2011) data using the logistic regression analysis to investigate the association between presenteeism and various psychosocial factors within workplaces.
Among the 29246 wage earners, 6347 (21.7 %) showed presenteeism. Those who experienced age discrimination at work (adjusted odds ratio (aOR) 1.77: 95 % CI 1.56-2.00), educational background discrimination (aOR 1.35: 95 % CI 1.22-1.51), regional discrimination (aOR 1.55: 95 % CI 1.31-1.83), sexual discrimination (aOR 1.65: 95 % CI 1.41-1.94), employment type discrimination (aOR 2.13: 95 % CI 1.89-2.40), physical violence (aOR 1.92: 95 % CI 1.45-2.55), sexual harassment (aOR 2.90: 95 % CI 2.01-4.19), job insecurity (aOR 1.36: 95 % CI 1.18-1.56), work-life imbalance (aOR 1.38: 95 % CI 1.29-1.47), low job satisfaction (aOR 2.04: 95 % CI 1.91-2.17), no colleague support (aOR 1.11: 95 % CI 1.02-1.21), job stress (aOR 1.89: 95 % CI 1.76-2.02), emotional labor (aOR 1.50: 95 % CI 1.41-1.60), high work intensity (aOR 1.31: 95 % CI 1.23-1.38), and 3 groups of job strain that are passive group (aOR 1.09: 95 % CI 1.00-1.18), active group (aOR 1.39: 95 % CI 1.28-1.51), and high strain group (aOR 1.35: 95 % CI 1.24-1.46) showed an increased risk of presenteeism compared to their respective counterparts (p < 0.01).
The study results confirmed the association between presenteeism and various psychosocial factors within workplaces. Considering that presenteeism negatively affects productivity and the mental and physical health of individuals, managing various psychosocial factors within workplaces is proposed to reduce presenteeism.
프리젠티즘은 최근 활발히 연구되고 있는 개념으로 건강하지 않은 상태로 출근하여 일하는 것을 의미한다. 본 연구는 프리젠티즘과 다양한 직장 내 사회 심리적 요인들의 관계를 파악하기 위하여 수행되었다.
이 연구에서는 2011 년 실시된 제 3 차 근로환경조사 자료를 이용하여 임금 근로자 29,246 명을 대상으로 분석을 실시하였다. 프리젠티즘과 직장 내 사회 심리적 요인의 관계를 알아보기 위해 로지스틱 회귀분석을 사용하였다.
29,246 명의 임금근로자 중 프리젠티즘이 있는 근로자는 6,347 명 (21.7 %), 프리젠티즘이 없는 근로자는 22,899 명 (78.3 %) 이었다. 개인적 특성과 직업적 요인들을 보정하여 분석한 결과 프리젠티즘이 있는 경우가 없는 경우에 비해 연령차별이 있는 경우 1.77 배 (95 % CI 1.56-2.00), 학벌차별이 있는 경우 1.35 배 (95 % CI 1.22-1.51), 출신지역차별이 있는 경우 1.55 배 (95 % CI 1.31-1.83), 성차별이 있는 경우 1.65 배 (95 % CI 1.41-1.94), 고용형태차별이 있는 경우 2.13 배 (95 % CI 1.89-2.40), 신체적 폭력이 있는 경우 1.92 배 (95 % CI 1.45-2.55), 성희롱이 있는 경우 2.90 배 (95 % CI 2.01-4.19), 직무 불안정이 있는 경우 1.36 배 (95 % CI 1.18-1.56), 일-생활 균형이 맞지 않는 경우 1.38 배 (95 % CI 1.29-1.47), 직무 만족도가 낮은 경우 2.04 배 (95 % CI 1.91-2.17), 동료의 지지를 받지 못하는 경우 1.11 배 (95 % CI 1.02-1.21), 업무 스트레스를 받는 경우 1.89 배 (95 % CI 1.76-2.02), 감정 노동의 경우 1.50 배 (95 % CI 1.41-1.60), 직무 요구도가 높은 경우 1.31 배 (95 % CI 1.23-1.38), 직무 긴장도는 낮은 긴장도 그룹을 기준으로 수동적 그룹이 1.09 배 (95 % CI 1.00-1.18), 능동적 그룹이 1.39 배 (95 % CI 1.28-1.51), 높은 긴장도 그룹이 1.35 배 (95 % CI 1.24-1.46) 높게 나타났다.
본 연구 결과, 프리젠티즘과 직장 내 사회 심리적 요인들의 연관성을 확인할 수 있었다. 프리젠티즘이 생산성 및 개인의 정신적, 육체적 건강에 큰 영향을 미치는 만큼, 프리젠티즘을 줄이기 위한 여러 가지 방안 중 하나로 직장 내 사회 심리적 요인의 관리를 제시할 수 있을 것이다.
Immuno-oncology has changed the landscape of cancer treatment in recent years. Immune checkpoint inhibitors (ICI) have shown survival advantage with long term remissions in a variety of cancers. However, there is another approach to harnessing the power of the immune system in combating cancer: the adoptive cell therapy (ACT) strategy. Although ACT is restricted to small specialized centres and has yet to deliver as much success as ICI, some important results were presented at this year's ASCO meeting. Important lessons have been learned from these studies, including the prospects and challenges ahead. In this editorial, we summarize the important studies on ACT presented at the ASCO 2016 meeting and discuss the way forward.
"Entotheonella" (phylum "Tectomicrobia") is a filamentous symbiont that produces almost all known bioactive compounds derived from the Lithistida sponge Theonella swinhoei. In contrast to the comprehensive knowledge of its secondary metabolism, knowledge of its lifestyle, resilience, and interaction with the sponge host and other symbionts remains rudimentary. In this study, we obtained two "Entotheonella" genomes from T. swinhoei from the South China Sea through metagenome binning, and used a RASTtk pipeline to achieve better genome annotation. The high average nucleotide index values suggested they were the same phylotypes as the two "Entotheonella" phylotypes from T. swinhoei from the Japan Sea. Genomic features related to utilization of various carbon sources, peptidase secretion, CO2 fixation, sulfate reduction, anaerobic respiration, and denitrification indicated the mixotrophic nature of "Entotheonella." The endospore-forming potential along with metal- and antibiotic resistance indicated "Entotheonella" was highly resilient to harsh conditions. The potential for endospore formation also explained the widespread distribution of "Entotheonella" to some extent. The discovery of Type II (general secretion pathway proteins and the Widespread Colonization Island) and Type VI secretion systems in "Entotheonella" suggested it could secrete extracellular hydrolases, form tight adhesion, act against phagocytes, and kill other prokaryotes. Overall, the newly discovered genomic features suggest "Entotheonella" is a highly competitive member of the symbiotic community of T. swinhoei.
Sean Wensley believes there are sound justifications for the profession to act.
We directly measured at the single-molecule level the forces and lifetimes of DNA base-pair stacking interactions for all stack sequence combinations. Our experimental approach combined dual-beam optical tweezers with DNA origami components to allow positioning of blunt-end DNA helices so that the weak stacking force could be isolated. Base-pair stack arrays that lacked a covalent backbone connection spontaneously dissociated at average rates ranging from 0.02 to 500 per second, depending on the sequence combination and stack array size. Forces in the range from 2 to 8 piconewtons that act along the helical direction only mildly accelerated the stochastic unstacking process. The free-energy increments per stack that we estimate from the measured forward and backward kinetic rates ranged from -0.8 to -3.4 kilocalories per mole, depending on the sequence combination. Our data contributes to understanding the mechanics of DNA processing in biology, and it is helpful for designing the kinetics of DNA-based nanoscale devices according to user specifications.
The anthracnose caused by Colletotrichum species is an important disease that primarily causes fruit rot in pepper. Eighty-eight strains representing seven species of Colletotrichum were obtained from rotten pepper fruits in Sichuan Province, China, and characterized according to morphology and the glyceraldehyde-3-phosphate dehydrogenase (GAPDH) sequence. Fifty-two strains were chosen for identification by phylogenetic analyses of multi-locus sequences, including the nuclear ribosomal internal transcribed spacer (ITS) region and the β-tubulin (TUB2), actin (ACT), calmodulin (CAL) and GAPDH genes. Based on the combined datasets, the 88 strains were identified as Colletotrichum gloeosporioides, C. siamense, C. fructicola, C. truncatum, C. scovillei, and C. brevisporum, and one new species was detected, described as Colletotrichum sichuanensis. Notably, C. siamense and C. scovillei were recorded for the first time as the causes of anthracnose in peppers in China. In addition, with the exception of C. truncatum, this is the first report of all of the other Colletotrichum species studied in pepper from Sichuan. The fungal species were all non-host-specific, as the isolates were able to infect not only Capsicum spp. but also Pyrus pyrifolia in pathogenicity tests. These findings suggest that the fungal species associated with anthracnose in pepper may inoculate other hosts as initial inoculum.
Society is failing in its moral obligation to improve the standard of healthcare provided to vulnerable populations, such as people who lack decision making capacity, by a misguided paternalism that seeks to protect them by excluding them from medical research. Uncertainties surround the basis on which decisions about research participation is made under dual regulatory regimes, which adds further complexity. Vulnerable individuals' exclusion from research as a result of such regulation risks condemning such populations to poor quality care as a result of 'evidence biased' medicine.
This paper explores the research regulation provisions for proxy decision making for those unable to provide informed consent for themselves, and the subsequent legal and practical difficulties for decision-makers. There are two separate regulatory regimes governing research involving adults who lack capacity to consent in England and Wales. The Mental Capacity Act 2005 governs how incapacitated adults can be involved in research, however clinical trials of medicinal products are separately regulated by the Medicines for Human Use (Clinical Trials) Regulations 2004. There are significant differences under these dual regimes in the provisions for those lacking capacity to participate in medical research. The
 level of risk permitted differs, with a greater requirement for justification for participation in a clinical trial than other types of research. Who acts as proxy decision maker, how much information is provided to the person lacking capacity, and whether they retain the power of veto also significantly differs.
The development of two separate regulatory regimes has resulted in significant differences between the provisions for clinical trials and other forms of research, and from usual medical practice. The resulting uncertainty has reinforced the tendency of those approving and conducting research to exclude adults lacking capacity to avoid difficult decisions about seeking consent for their participation. Future developments, such as the incoming EU Regulations, may address some of these differences, however the justification and level of risk permitted requires review to ensure that requirements are appropriate and proportionate to the burdens and risks for the individual, and also to the benefits for the wider population represented.
The evaporation of quinacridone from a stainless steel Knudsen cell leads to the partial decomposition of this molecule in the cell, due to its comparably high sublimation temperature. At least one additional type of molecules, namely indigo, could be detected in the effusion flux. Thermal desorption spectroscopy and atomic force microscopy have been used to study the co-deposition of these molecules on sputter-cleaned and carbon-covered silicon dioxide surfaces. Desorption of indigo appears at temperatures of about 400 K, while quinacridone desorbs at around 510 K. For quinacridone, a desorption energy of 2.1 eV and a frequency factor for desorption of 1 × 10(19) s(-1) were calculated, which in this magnitude is typical for large organic molecules. A fraction of the adsorbed quinacridone molecules (∼5%) decomposes during heating, nearly independent of the adsorbed amount, resulting in a surface composed of small carbon islands. The sticking coefficients of indigo and quinacridone were found to be close to unity on a carbon covered SiO2 surface but significantly smaller on a sputter-cleaned substrate. The reason for the latter can be attributed to insufficient energy dissipation for unfavorably oriented impinging molecules. However, due to adsorption via a hot-precursor state, the sticking probability is increased on the surface covered with carbon islands, which act as accommodation centers.
Porcine reproductive and respiratory syndrome virus (PRRSV) is recognized worldwide as an important and economically devastating pathogen in pig production. Although PRRSV is widespread in domestic swine, there is a lack of information regarding PRRSV infection in European wild boars (Sus scrofa). Currently available information does not provide conclusive evidence that wild boars are a reservoir of PRRSV. Nevertheless, wild boars may be likely to become infected by domestic swine through occasional direct or indirect contact. Furthermore, wild boars can act as a reservoir for infectious diseases of domestic pigs. Therefore, the objectives of the present study were to determine the virus prevalence and further explore the epidemiology and diversity of PRRSV strains present in Lithuanian wild boars over a 5-year period. A total of 1597 tissue and serum samples from wild boars inhabiting 44 districts and ten counties in Lithuania were analysed using conventional nested reverse transcription polymerase chain reaction (RT-PCR) and real-time Taqman RT-PCR for the detection of PRRSV-specific open reading frame (ORF) 1 and 6 sequences.
PRRSV was highly prevalent in Lithuanian wild boar populations, with an average rate of 18.66 % using conventional RT-PCR and 19.54 % using real-time RT-PCR. PRRSV was detected in 36.71 and 41.77 % of 237 hunting grounds tested by conventional RT-nPCR and real-time RT-PCR, respectively. No statistically significant differences in PRRSV prevalence were observed by geographic area in the ten Lithuanian counties. Animals infected with PRRSV were identified in all age groups; however, significantly higher prevalence rates were identified in subadult and adult wild boars than in juveniles up to 12 months old. No positive results were obtained using conventional PCR with Type 2 specific primers. Phylogenetic analysis of the partial ORF5 region revealed that ten wild boars harboured virus sequences belonging to genetic subtypes 3 and 4 and may therefore pose a serious threat to Lithuanian pig farms in which only subtype two strains are circulating.
The results of virus prevalence and phylogenetic analyses strongly support the role of wild boars as a possible natural reservoir for PRRSV in Lithuania.
Sini Powder (SP), a traditional Chinese herbal formula, has long been used to treat depression in patients, although the underlying mechanisms remain to be elucidated. In the present study, we found that rats treated with SP extract for 7 days showed a significant increase in swimming time and reduction in immobility time in forced swimming test in a dose-dependent manner, without changes in locomotion. These effects could be attributed to SP's modulation of the hypothalamus-pituitary-adrenal axis, because a single pretreatment of SP extract could rescue increased serum corticosterone and plasma adrenocorticotropin levels induced by acute elevated platform stress. A single pretreatment of SP extract could also elevate the mRNA expression of hippocampal glucocorticoid receptors. In conclusion, our results suggest that SP extract may act as an anti-stress medication to produce antidepressant-like effects.
Highly stable, luminescent, and printable/paintable supramolecular egg white hydrogel-based surface enhanced Raman scattering (SERS) matrix is created by an in situ synthesis of gold clusters inside a luminescent egg white hydrogel (Au-Gel). The synthesis of stable luminescent egg-white-based hydrogel, where the hydrogel can act as a three dimensional (3D) matrix, using a simple cross-linking chemistry, has promising application in the biomedical field including in 3D cell culturing. Furthermore, this functional hydrogel is demonstrated for micromolar-level detection of Rhodamine 6G using the SERS technique, where Au-Gel is painted over a flexible cellulose pad.
Despite several national coordinated research networks, enrollment in many cerebrovascular trials remains challenging. An electronic tool was needed that would improve the efficiency and efficacy of screening for multiple simultaneous acute clinical stroke trials by automating the evaluation of inclusion and exclusion criteria, improving screening procedures and streamlining the communication process between the stroke research coordinators and the stroke clinicians.
A multidisciplinary group consisting of physicians, study coordinators, and biostatisticians designed and developed an electronic clinical trial screening tool on a HIPAA (Health Insurance Portability and Accountability Act)-compliant platform.
A web-based tool was developed that uses branch logic to determine eligibility for simultaneously enrolling clinical trials and automatically notifies the study coordinator teams about eligible patients. After 12 weeks of use, 225 surveys were completed, and 51 patients were enrolled in acute stroke clinical trials. Compared with the 12 weeks before implementation of the tool, there was an increase in enrollment from 16.5% of patients screened to 23.4% of patients screened (P<0.05). Clinicians and coordinators reported increased satisfaction with the process and improved ease of screening.
We created a semiautomated electronic screening tool that uses branch logic to screen patients for stroke clinical trials. The tool has improved efficiency and efficacy of screening, and it could be adapted for use at other sites and in other medical fields.
Acute kidney injury (AKI) is an important clinical issue that is associated with significant morbidity and mortality. Despite research advances over the past decades, the complex pathophysiology of AKI is not fully understood. The regulatory mechanisms underlying post-AKI repair and fibrosis have not been clarified either. Furthermore, there is no definitively effective treatment for AKI. MicroRNAs (miRNAs) are endogenous single-stranded noncoding RNAs of 19~23 nucleotides that have been shown to be crucial to the post-transcriptional regulation of various cellular biological functions, including proliferation, differentiation, metabolism, and apoptosis. In addition to being fundamental to normal development and physiology, miRNAs also play important roles in various human diseases. In AKI, some miRNAs appear to act pathogenically by promoting inflammation, apoptosis, and fibrosis, while others may act protectively by exerting anti-inflammatory, anti-apoptotic, anti-fibrotic, and pro-angiogenic effects. Thus, miRNAs have not only emerged as novel biomarkers for AKI; they also hold promise to be potential therapeutic targets.
Malaria is one of the most widespread infectious diseases around the world with 214 million cases and 438,000 deaths in 2015. In the early twentieth century it was described for the first time the resistance to quinine and, since then, drug resistance to antimalarial drugs has spread up to represent a global challenge in the fight and control of malaria. Understanding the mechanisms, geography and monitoring tools that we can act against resistance to antimalarial drugs is critical to prevent its expansion.
The assembly of plasmonic metal nanoparticles into hot spot surface-enhanced Raman scattering (SERS) nanocluster probes is a powerful, yet challenging approach for ultrasensitive biosensing. Scaffolding strategies based on self-complementary peptides and proteins are of increasing interest for these assemblies, but the electronic and the photonic properties
 of such hybrid nanoclusters remain difficult to predict and optimize. Here, split-green fluorescence protein (sGFP) fragments are used as molecular glue and the GFP chromophore is used as a Raman reporter to assemble a variety of gold nanoparticle (AuNP) clusters and explore their plasmonic properties by numerical modeling. It is shown that GFP seeding of plasmonic nanogaps in AuNP/GFP hybrid nanoclusters increases near-field dipolar couplings between AuNPs and provides SERS enhancement factors above 10(8) . Among the different nanoclusters studied, AuNP/GFP chains allow near-infrared SERS detection of the GFP chromophore imidazolinone/exocyclic CC vibrational mode with theoretical enhancement factors of 10(8) -10(9) . For larger AuNP/GFP assemblies, the presence of non-GFP seeded nanogaps between tightly packed nanoparticles reduces near-field enhancements at Raman active hot spots, indicating that excessive clustering can decrease SERS amplifications. This study provides rationales to optimize the controlled assembly of hot spot SERS nanoprobes for remote biosensing using Raman reporters that act as molecular glue between plasmonic nanoparticles.
Intrinsic emission from nonconjugated polymers has attracted considerable attention owing to its fundamental importance and intensive applications in diverse fields. The emission mechanism, however, is still in debate. Herein, nonconjugated polyacrylonitrile (PAN) molecules are found to be virtually nonluminescent in dilute solutions, while being highly emissive when concentrated or aggregated as nanosuspensions, solid powders, and films, exhibiting distinct aggregation-induced emission (AIE) characteristics. Moreover, triplet emissions of delayed fluorescence and room temperature phosphorescence are detected from the solid powders. Such unique emission of nonconjugated PAN is ascribed to the formation of cyano clusters, which act as the exact chromophores. In these clusters, through space electronic interactions, namely overlap of π and lone pair (n) electrons among cyano groups extend the conjugation and meanwhile rigidify the molecular conformations, thus offering remarkable emission upon irradiation. The AIE phenomenon can also be well rationalized by the formation of cyano clusters together with conformation rigidification. And the triplet emissions shall be originated from the n-π* transition owing to the presence of lone pairs. It is believed that such clustering-triggered emission mechanism is instructive for further development of unorthodox luminogens.
Riboswitches are RNA elements that act on the mRNA with which they are cotranscribed to modulate expression of that mRNA. These elements are widely found in bacteria, where they have a broad impact on gene expression. The defining feature of riboswitches is that they directly recognize a physiological signal, and the resulting shift in RNA structure affects gene regulation. The majority of riboswitches respond to cellular metabolites, often in a feedback loop to repress synthesis of the enzymes used to produce the metabolite. Related elements respond to the aminoacylation status of a specific tRNA or to a physical parameter, such as temperature or pH. Recent studies have identified new classes of riboswitches and have revealed new insights into the molecular mechanisms of signal recognition and gene regulation. Application of structural and biophysical approaches has complemented previous genetic and biochemical studies, yielding new information about how different riboswitches operate.
Autism spectrum disorders (ASD) are characterized by disturbed social interaction and communication as well as stereotyped or repetitive behaviors and interests. Although adults with ASD often acquire complex compensatory strategies that help them master social situations in a rule-based fashion, they still show impairments in intuitive processing of social signals and especially nonverbal communication in complex everyday situations. This constitutes a particular challenge for the psychotherapy of ASD. Psychotherapists are required to explicitly inform and act as an agent of the non-autistic world to enable patients to acquire the ability to take different perspectives. The overall aim of cognitive behavioral therapy interventions addressing ASD in adulthood is to extend the patients' behavioral repertoire to improve their quality of life. Thus, besides psychoeducation on ASD and its frequently associated comorbidities, psychotherapy for adults with ASD should focus on the training and development of social-communicative skills. Furthermore, dealing with stress in everyday situations is an important aspect of psychotherapy of these patients.
The heart of patients with hypertension and cardiac hypertrophy is more vulnerable to ischemia-reperfusion injury (IRI). Here we discuss the main mechanisms of IRI and possible targets for cardioprotection. In particular, we consider the viewpoint that hypertension and cardiac hypertrophy may act synergistically in increasing the predisposition to cardiovascular accidents and in worsening IRI. There is no doubt that hypertrophic hearts may be redirected to be less vulnerable to IRI. Some experimental evidences suggest that antihypertensive drugs may have beneficial effects, some of which are not directly related to hypertension-lowering effect. However, more thorough experimental and clinical studies are necessary to understand the mechanisms and to maximize the beneficial effects of reperfusion after a heart attack in the presence of comorbidities, such as hypertension and cardiac hypertrophy.
The continued activation of androgen receptor (AR) transcription and elevated expression of AR and transcriptional intermediary factor 2 (TIF2) coactivator observed in prostate cancer (CaP) recurrence and the development of castration-resistant CaP (CRPC) support a screening strategy for small-molecule inhibitors of AR-TIF2 protein-protein interactions (PPIs) to find new drug candidates. Small molecules can elicit tissue selective effects, because the cells of distinct tissues express different levels and cohorts of coregulatory proteins. We reconfigured the AR-TIF2 PPI biosensor (PPIB) assay in the PC-3 CaP cell line to determine whether AR modulators and hits from an AR-TIF2 PPIB screen conducted in U-2 OS cells would behave differently in the CaP cell background. Although we did not observe any significant differences in the compound responses between the assay performed in osteosarcoma and CaP cells, the U-2 OS AR-TIF2 PPIB assay would be more amenable to screening, because both the virus and cell culture demands are lower. We implemented a testing paradigm of counter-screens and secondary hit characterization assays that allowed us to identify and deprioritize hits that inhibited/disrupted AR-TIF2 PPIs and AR transcriptional activation (AR-TA) through antagonism of AR ligand binding or by non-specifically blocking nuclear receptor trafficking. Since AR-TIF2 PPI inhibitor/disruptor molecules act distally to AR ligand binding, they have the potential to modulate AR-TA in a cell-specific manner that is distinct from existing anti-androgen drugs, and to overcome the development of resistance to AR antagonism. We anticipate that the application of this testing paradigm to characterize the hits from an AR-TIF2 PPI high-content screening campaign will enable us to prioritize the AR-TIF2 PPI inhibitor/disruptor leads that have potential to be developed into novel therapeutics for CaP and CRPC.
Background: In 2011, an estimated 19.3 million Americans aged 12 or older needed but did not receive substance abuse treatment (SAT). Among the estimated 281,000 people who believed they needed SAT, made an effort to obtain SAT, but ultimately did not receive SAT, the most common reason for not receiving SAT was lack of health insurance & inability to afford the cost of SAT (37.3%); an additional 10.1% said that they had health insurance, but did not cover SAT. Method: The 2011 Treatment Episode Data Set (TEDS), a census of all admissions to treatment facilities reported to the Substance Abuse and Mental Health Services Administration (SAMHSA). Type of health insurance is a data item reported by 34 States and jurisdictions for 2011. Data presented in this report are restricted to those 34 States and jurisdictions. TEDS does not record whether the health insurance covers SAT or whether the insurance was used to pay for SAT. Four categories of health insurance status are used in this report: no health insurance; private insurance, (e.g., Blue Cross/Blue Shield, HMO); Medicaid; & other insurance (e.g., Medicare, CHAMPUS, Tricare). Results: In 2011, 59.6% of SAT admissions aged 26 or older reported having no health insurance, 21.3% reported having Medicaid, and 10.5% reported having private insurance. For admissions aged 26 or older, a higher proportion of male admissions than female admissions reported having no health insurance (63.8 vs. 51.2%). 67.5% of admissions aged 26 or older that were referred to SAT by the criminal justice system had no health insurance, which substantially exceeded the percentages for most other referral sources. Conclusion: The goal of this report is to provide baseline characteristics for health insurance coverage among adults for future comparison. This report shows that prior to the implementation of the Patient Protection and Affordable Care Act and the Health Care and Education Reconciliation Act of 2010 (together referred to as the Affordable Care Act, or "ACA"), 3 out of 5 SAT admissions aged 26 or older had no health insurance, and that these admissions differed by several demographic and socio-economic characteristics. With full ACA implementation, access to affordable insurance will increase among the uninsured. As eligibility for Medicaid coverage expands under ACA in many States
 to those who were not previously eligible (e.g., low-income adults without children and the criminal justice population), the composition of SAT admissions reporting Medicaid coverage might change.
The term “Advanced Practice Registered Nurse” (APRN) encompasses the Nurse Practitioner (NP), Certified Registered Nurse Anesthetist (CRNA), Clinical Nurse Specialist (CNS), and Nurse Midwife (NM).1 Today, most NPs practice in primary care. Autonomy or independence has always been central to the concept of a nurse practitioner as a primary care provider.2 The National Council of State Boards of Nursing defines “independence” as practicing with “no requirement for a written collaborative agreement, no supervision, [and] no conditions for practice.”3 Although the authority to diagnose and prescribe are the most frequently mentioned aspects of independence, the concept encompasses other dimensions including entry into practice; authority to bill for services independently; access to diagnostic services and hospital admitting privileges; and recognition as primary care providers.4 Medical licensing is a state function and APRN scope-of-practice (SOP) laws vary from state to state. 5 In 16 states, APRNs have the authority to practice without a written agreement with a supervising physician, 9 states require physician involvement to prescribe but not to diagnose and treat, and in 24 states physician oversight is required to prescribe, diagnose, and treat.6 The definition of “oversight,” however, varies by state, and most states allow collaboration or supervision to occur remotely.7 There is also variation in SOP laws regarding APRNs' authority to supervise clinical staff. For example, one article notes a requirement in sections 2069–71 of the California Business and Professions Code that doctors and selected other professions— but not registered nurses—may supervise California medical assistants.8 While there is disagreement about whether APRNs should practice independently, the seemingly arbitrary variation in SOP laws among the states is nearly universally criticized. As an editorial from the Commonwealth Fund put it, “objectively interpreted data on the competencies of professionals should guide policy, not rigid, often antiquated state laws.”9 The National Governors Association10 and the Institute of Medicine (IOM)11 have criticized variation in SOP regulations among the states, and both argue that nurses should be able to practice to the “full extent of their education and training” in order to adapt to the changing health care system after the implementation of the Affordable Care Act (ACA), which authorizes nurse-managed health clinics and other innovations. In March, 2014, a report from the Federal Trade Commission, relying in large part on the IOM report, argued that physician supervision or collaborative practice agreement requirements “may sometimes restrict competition unnecessarily, which can be detrimental to health care consumers and have broader public health consequence,” that is, “decreased access to health care services, higher health care costs, reduced quality of care, and less innovation in health care delivery.”12 In the context of the ACA, one emergent issue is whether some patient care teams should be led by a nurse practitioner instead of only a medical doctor. Other advocates for change argue that, nationally, removing restrictions on NP practice would improve access to primary care and allow NPs to emerge as leaders of the integrated teams that are an important component of new models for delivering primary care.8,13,14THE IMPACT OF STATE SOP REGULATION: Despite the strong statements from multiple groups, there has been very little formal study of the impact of SOP laws on access to and quality of care. The National Governors Association report, supporting the elimination of most SOP restrictions for APRNs, notes: More restrictive SOP rules are probably associated with slower growth in the number of NPs15 and in the number of Medicare patients cared for by NPs.16 In both 2006 and 2010, the odds of having an NP as a primary care provider were 2.5 times higher in the least restrictive states compared to the most restrictive states.16 These findings have not been directly associated with overall access to primary care, and it is unclear whether SOP rules exert this effect directly, or indirectly via the policies of state and private payers. In an extensive provider survey, “at the point of care, scope-of-practice laws were not found to have substantial impact across the study states on what services NPs can deliver, despite significant differences across states in the level of NP autonomy…”17 Rather, the study found that payer policies had more impact than SOP laws on how and where NPs can practice.17 Payers in states with restrictive SOP laws often add additional restrictions, such as not recognizing NPs as primary care providers, that make independent NP practice difficult. In addition, Medicare policies do not permit a NP to order home health care or durable medical equipment, even in states in which NPs practice independently. Other arguments made by advocates for APRNs about the adverse effects of SOP restrictions are based on hypothetical reasoning or on anecdotes concerning inefficient use of time and, in some cases, delay in needed care because a physician's approval was required to prescribe, order equipment, or admit a patient to the hospital. PHYSICIAN GROUP PERSPECTIVES: Physician groups that support SOP restrictions envision a system in which physicians delegate the care of less complex patients to (supervised) nurse practitioners; one physician advocacy group has estimated that “nurse practitioners and physician assistants are capable of providing 70% or more of the care required for adults and 90% in pediatrics.”18 According to J.K. Iglehart, the AMA supports team-based care but argues that teams should be led by medical doctors, as integrated systems such as Geisinger, Kaiser Permanente, and the VA have done. 5 These groups also argue that physicians may be better able to manage complicated diagnostic problems, patients with multiple chronic conditions, and unstable patients. These claims are plausible—as Blumenthal and Abrams note, “[p]hysicians and nurse practitioners receive very different training, and it would be surprising if their competencies were identical.”9 However, no studies have been done to examine the validity of these beliefs. Physician groups also argue that policymakers should take into account that patients prefer having a medical doctor as a primary care provider and that use of the title “doctor” by APRNs who have completed doctoral training could confuse patients about the training of their provider.19 Evidence about patients' preferences regarding the type of provider is conflicting. VETERANS HEALTH ADMINISTRATION PRACTICE ENVIRONMENT AND PREVIOUS RESEARCH: In the Veterans Health Administration (VHA), the use of APRNs in the delivery of health care, including primary, specialty, acute, and home health care, expanded greatly after the implementation of the Veterans Integrated Service Network (VISN) structure in October 1995 and the Veterans Health Care Eligibility Reform Act in 1996 (Public Law 104-262).20 These changes resulted in a shift to local and regional networks grounded in ambulatory and primary care,21 an increase in the number of patients served by the VHA, and an increase in the percentage of patients seeking primary care services: 20% in fiscal year 1994 to 76% in fiscal year 1996. In 1996, 75% of VHA primary care practices reported using NPs and by 1999, this proportion had risen to 90%.22 Today the VHA employs over 4,700 nurse practitioner full time equivalents, 786 CRNAs, and 482 CNSs.23 Currently, although a single unrestricted license allows APRNs to work at any VA facility, the VHA observes state-by-state rules regarding prescribing and admission privileges and physician supervision for APRNs. Each VA institution establishes its own policies regarding all other aspects of scope of practice. Advocates for “federal supremacy” argue that overriding state laws would “increase access to health care services, reduce costs and improve the quality and availability of health care” for Veterans by eliminating bureaucratic complexity and “artificial barriers” such as supervisory requirements.23,24 They note that varying regulations for diagnosing and prescribing can delay appropriate care and waste time and resources, particularly for CNSs in cardiology and other specialties working in VA facilities that serve patients from more than one state. Research on APRNs in the VHA has been sporadic, and has focused on NPs rather than CRNAs or CNSs. From 1995 to 1999, the VHA HSR&D conducted one single-center RCT25 and several observational studies of the impact of NPs on access to specialty care, continuity of care, and resource use.26-29 Some studies demonstrated improved continuity of and access to care after implementation of an interdisciplinary firm system,27-29 however, little research was conducted in the 2000s.20,30 The best recent data are from a 2011 cross-sectional study of all VISN 11 primary care patients who had hypertension and/or diabetes.20 VISN 11 includes 2 states (Illinois, Michigan) with very restrictive scope of practice laws and 2 states (Ohio, Indiana) with moderately restrictive laws. The main findings were: A survey of VISN 11 NPs and MD providers was also part of this study. The main findings were: A 2012 ESP report reviewed the evidence on the role of primary care providers' skill level (MD vs NP/PA) in ambulatory care settings in influencing patient outcomes from a VHA perspective.31 The authors of the ESP report stated that they “did not review studies that examined the effect of skill levels on patient quality of care or patient
 safety as it is widely accepted that medical school or more training increases quality of care.” The best evidence the ESP identified came from 2 randomized controlled trials which consistently found no difference in patient satisfaction with provider interaction when seeing a NP/PA instead of an MD. The ESP report also noted that a large VA study of patient satisfaction among 1.6 million veterans seen in 21 VISNs provided some limited information about impact of skill level: patient satisfaction increased in 3 VISNs that hired more NP/PAs. USE OF EVIDENCE IN POLICY DEBATES: In a policy paper, Newhouse and colleagues state “[o]nce the issue of comparability between APRN care and that delivered by physicians is set aside in favor of an integrated team concept, disciplines can focus on…overarching goals” such as developing patient-centered team care, reducing quality gaps, and educating an interprofessional workforce.32 Their recent systematic review of RCTs and observational studies supports the emphasis on team care outlined in their policy paper. Including all types of APRNs, intermediate and health outcomes, and various patient populations and settings, Newhouse et al concluded that the outcomes of care provided by APRNs in collaboration with specialist or primary care physicians are similar to, or in some cases better than, the outcomes of care provided by a physician alone.33 Although Newhouse et al's emphasis on the role of APRNs in integrated teams is more relevant to the current organization of primary care services in VHA, policy discussions about over-riding state SOP laws invoke the argument that APRNs working independently provide the same quality of care as medical doctors.11,24,34 The Institute of Medicine, for example, claims that a large body of evidence “does not support the conclusion that APRNs are less able than physicians to provide safe, effective, and efficient care.”11 Similarly, a publication from the Robert Wood Johnson Foundation (RWJF) asserts that “health outcomes are comparable for patients treated by primary care NPs and MDs.”24 Most articles about the role of APRNs do not explicitly define the autonomy of the nurses, compare non-autonomous nurses with physicians, or evaluate nurse-direct protocol-driven care for patients with specific conditions.35 However, studies like these are often cited in support of the claim that APRNs practicing autonomously provide the same quality of primary care as medical doctors. For example, the RWJF publication quoted above refers to a review by Naylor and Kurtzman14 that relied on 2 systematic reviews published in 2002 and 200536,37 and 2additional randomized trials published in 2009. Many of the trials included in 2 older systematic reviews were considered by Naylor and Kurtzman.36,37 The first additional trial comparing NP and general physician care was conducted 2 months after the NPs successfully completed a Masters-level training program. As nurses were not permitted to prescribe independently, physicians were “always available for consultation and to validate prescriptions and referrals.”38 The second randomized trial included in the Naylor and Kurtzman review evaluated a 4-visit, computer-guided, nurse-led intervention for overweight and obese patients conducted in 11 general practice (GP) locations.39 Most research on APRNs has evaluated team models of care or interventions designed to enhance care for patients with specific conditions (eg, incontinence, bronchiectasis, heart failure, etc.).36,37,40,41 The evidence supporting the contributions of APRNs in team models of care, protocol-driven care and nurse-led intervention focusing on a specific patient population is relevant to VHA and reasonably up-to-date.33,35 VA-ESP recently published a report that concluded there is strong evidence that nurse-managed protocols help to improve health outcomes among patients with moderate severity of diabetes, hypertension, hyperlipidemia, and chronic heart failure.42 Nevertheless, the issue of the comparability of health outcomes of autonomous APRNs and physicians continues to be a cornerstone of the debate regarding state SOP rules. Because no previous systematic review has focused on this issue, the VHA Office of Quality, Safety and Value commissioned the VA Evidence-based Synthesis Program (ESP) Coordinating Center to reevaluate recent, original studies that reported health outcomes.
In large organizations such as the VA, mandatory training has become an integral part of workforce learning.1 Some common reasons for adopting mandatory training for all employees include showing employees management's commitment to the topic area,2 promoting positive change,3 promoting overall staff safety,1 and legal or compliance considerations.3 In some cases, such as for the topic of diversity, mandatory training efforts are directly tied to federal requirements instituted in response to employee wrongdoings that resulted in corporate lawsuits.4 Numerous courts have held that to avoid punitive damages, employers must provide training to their employees on harassment and discrimination prevention. (187 F.3d 1241 (10(th) Cir. 1999); 270 F.3d 794 (9(th) Cir. 2001); 281 F.3d 452 (4(th) Cir. 2002)) The Tenth Circuit Court of Appeals stated that “the extent to which an employer has adopted antidiscrimination policies and educated its employees about the requirement of [the discrimination laws] is important in deciding whether it is insulated from vicarious punitive liability.” (187 F.3d 1241 (10(th) Cir. 1999)) The costs associated with mandatory training program management can be quite high, resulting in annual expenditures in the hundreds of millions of dollars across U.S. organizations.4 The laws that motivate mandatory compliance training are often broad in nature and generally do not set standards on training content or evaluation.2 This leaves organizations with the ability to implement training in a compulsory manner to serve a symbolic purpose, with little attention to whether their training methods are actually effective.4 Unfortunately, training implemented merely to serve a symbolic purpose may be creating a false sense of organizational security.5 Research has found that the mere existence of an anti-harassment policy is not always sufficient to protect the employer from liability6 (239 F.3d 848 (7(th) Cir. 2001)). Likewise, in an article on the effectiveness of diversity training, a Harvard sociologist indicated that there is no history of any court giving an employer credit for the mere existence of diversity training.4 Mandatory training is traditionally unpopular,1 and there is a perception that it is ineffective and decreases motivation to learn. Some education theory-related barriers to learning that may reduce the effectiveness of mandatory training include employee resentment about their lack of control, lack of interest, perception of irrelevancy to their specific workplace context, and workplace time pressures.1 Considering the high cost associated with mandatory training and doubts about its effectiveness, organizations would be well served to more closely consider the benefits of their programs. An extensive literature on general organizational training research is available to inform decisions about how to design, implement, and evaluate training in a variety of settings.7,8 The design and evaluation of training is based on a wide variety of theoretical frameworks. There is a good deal of consensus about the best practices that organizations should engage in before, during, and after training in order to maximize effectiveness.8 Pre-training factors associated with training effectiveness include individual characteristics such as cognitive ability,9 self-effcacy,7,10 and motivation9,10 and needs assessments. Experts recommend that one of the most important steps in developing training is to conduct a pre-training needs analysis to identify the competencies needed, training priorities, and who needs the training.8 Factors that matter during training include individual characteristics and instructional strategies and principles. In recent years, group training, distance learning, and computer-based training have become common training delivery systems in many work organizations. Post-training factors associated with effectiveness include the ability to use skills and knowledge gained from training,11 delay between training and use of skills and knowledge,7 social, peer, subordinate, and supervisor support and training evaluation efforts.12 The Kirkpatrick Model of Training Evaluation is commonly used as a framework for evaluating training programs.13 Organizations have struggled to conduct training evaluation due to the labor and costs involved, and difficulty with credible field evaluation.7 Since most empirical research is still relying on surveys to measure learning outcomes,8 there is still a need for more research using formal experimental designs to evaluate training effectiveness. Although there has been an increase in general training-related research,7 it is unclear whether the best practices identified in the general training literature have their desired effect on outcomes in the mandatory training domain. The VA currently requires all employees to undergo mandatory training on the topics of Government Ethics, Prevention of Workplace Harassment/No Fear Act, and Privacy and Information Security Awareness and Rules of Behavior (http://www.valu.va.gov/Home/MandatoryTraining). Table 1 summarizes content and timing details for each of these training topics. The requirements for the three trainings that are mandatory for all VA employees originate from Executive Orders, Congressional mandates, the Office of Personnel Management, regulatory bodies, and VA department-level requirements. These regulatory directives do not specify requirements about
 the format, content, or method of delivery of training material. Originally, the VA provided local facility leadership with the flexibility to locally manage their mandatory training processes, including tracking and recording employee attendance. This allowed local facilities to customize their approach to meeting the training mandates based on the local culture, which included a variety of training formats including face-to-face sessions, videos, handouts, or multiple modalities. Eventually, national tracking became more of a priority for the VA, and this led to centralization and standardization of mandatory training. Currently, all VA mandatory training is computer-based, and it is delivered and tracked via the VA Learning University Training Management System (VALU-TMS). In order to evaluate the use and outcomes of mandatory training in the VHA, the National Leadership Council's Human Resource Committee chartered the Mandatory Training Workgroup in November 2008. The workgroup was designated as a standing subcommittee in October 2010. The goal of the Subcommittee is to “envision a strategic evidence-based approach to Mandatory Training that linked employee learning to organizational outcomes.” The workgroup envisions “that mandatory training, used sparingly, would become meaningful, focused, effective, flexible, and satisfying to all employees.” The Subcommittee has suggested various revisions to the VA's current mandatory training approach that include rescinding the requirements entirely, changing the requirements to “highly recommended” instead of mandatory, combining topics, reducing course length and/or frequency, limiting target audience, substituting a competency-based or stepped training approach, and adding additional delivery formats to allow learners to select resources that best fit their individual learning styles. The theoretical advantages of computer-based training include convenience, flexibility in scheduling, consistency of material presented, and tracking and documentation capabilities.15 But what is not taken into consideration by computer-based methods is that people learn in different ways. In their 2009 report on the burden of VA mandatory training, the Mandatory Training Subcommittee raised questions about the value of the VA's mandatory training program.16 The Subcommittee estimated that VHA spends $40 million a year just for the three core trainings mandated for VA employees (Table 1).16 Despite these high estimated costs, the Mandatory Training Subcommittee did not identify any studies in VA or otherwise of the effectiveness of any VA mandatory training programs. Additionally, the Subcommittee's qualitative evaluation of employee perceptions found universal unhappiness about the mandatory training requirements. Common themes include criticism that the mandatory trainings take up too much time, are not optimally accessible (including the varying locations and usability of courses), vary in quality, lack alternatives to online courses, and do not adapt to an individual's role and his or her existing knowledge on the subject.16 The Subcommittee report concluded that, given the enormous burdens of cost and negative employee perceptions, the VA would be well served to more closely consider the benefits of their mandatory training programs. In January 2009, the Mandatory Training Workgroup asked the VA Technology Assessment Program (TAP) to conduct a Brief Overview of evidence on the organizational effectiveness of mandatory learning strategies.17 The VA TAP Brief identified very little evidence on the subject and their main findings were that volition may be an important determinant of organizational learning and that training effectiveness may vary as a function of evaluation criteria, training delivery method, the subject being taught, and the criterion used to operationalize effectiveness. In February, 2014, to maintain the currency of knowledge about evidence on mandatory learning strategies, the Mandatory Training Workgroup requested that the VA Evidence-based Synthesis Program Coordinating Center (ESP CC) conduct an updated Evidence Brief on this topic. An evidence brief differs from a full systematic review in that the scope is narrowly defined and the traditional review methods are streamlined in order to synthesize evidence within a shortened timeframe. An evidence brief does not outline the full context in which the information is to be used and does not present a comprehensive assessment of knowledge on the topic. Brief or rapid review methodology is still developing and there is not yet consensus on what represents best practice.SCOPE: The objective of this Evidence Brief is to synthesize the literature on the effectiveness of mandatory online employee compliance training. The ESP Coordinating Center investigators and representatives of the VHA Mandatory Training Subcommittee worked together to identify the population, comparator, outcome, timing, setting, and study design characteristics of interest. The VHA Mandatory Training Subcommittee approved the following key questions and eligibility criteria to guide this review:KEY QUESTIONS: INCLUSION CRITERIA: The ESP included studies that met the following criteria: This Evidence Brief will not include the following:
Applied behavior analysts work with many populations including individuals with developmental and intellectual disabilities. Although behavior analysts have a variety of empirically supported treatments to implement when working with individuals with disabilities, sometimes, other variables may adversely impact treatment effectiveness. The degree to which problematic thoughts and feelings (private events) influence behavior may be a variable that contributes to treatment efficacy. Traditional behavior analytic services are not always equipped to successfully address the private events influencing client behavior. In such cases, it may be beneficial for behavior analysts to consider additional philosophically aligned treatments for private events. One such treatment, acceptance and commitment therapy, may be a useful tool for behavior analysts to incorporate into their toolbox in order to help clients. The purpose of this paper is to introduce behavior analysts to a potential solution to the problem of effectively addressing private events in behavior analytic services. We then propose a model for thinking about private events in relation to clients with disabilities and present a guide for taking steps to address private events in the clinical setting. We conclude this paper with a call for research and present a possible research agenda for behavior analysts.
To investigate the knowledge and use of asthma control measurement (ACM) tools in the management of asthma among doctors working in family and internal medicine practice in Nigeria.
A questionnaire based on the global initiative on asthma (GINA) guideline was self-administered by 194 doctors. It contains 12 test items on knowledge of ACM tools and its application. The knowledge score was obtained by adding the correct answers and classified as good if the score ≥ 9, satisfactory if score was 6-8 and poor if < 6.
The overall doctors knowledge score of ACM tools was 4.49±2.14 (maximum of 12). Pulmonologists recorded the highest knowledge score of 10.75±1.85. The majority (69.6%) had poor knowledge score of ACM tools. Fifty (25.8%) assessed their patients' level of asthma control and 34(17.5%) at every visit. Thirty-nine (20.1%) used ACM tools in their consultation, 29 (15.0%) of them used GINA defined control while 10 (5.2 %) used asthma control test (ACT). The use of the tools was associated with pulmonologists, having attended CME within six months and graduated within five years prior to the survey.
The results highlight the poor knowledge and use of ACM tools and the need to address the knowledge gap.
Dynamic regulation of stomatal aperture is essential for plants to optimize water use and CO2 uptake. Stomatal opening or closure is accompanied by the modulation of guard cell turgor. Among the events leading to stomatal closure by plant hormones or microbial elicitors, three signaling components stand out as the major converging points. These are reactive oxygen species (ROS), cytosolic free Ca(2+), and ion channels. Once formed, the ROS and free Ca(2+) of guard cells regulate both downstream and upstream events. A major influence of ROS is to increase the levels of NO and cytosolic free Ca(2+) in guard cells. Although the rise in NO is an important event during stomatal closure, the available evidences do not support the description of NO as the point of convergence. The rise in ROS and NO would cause an increase of free Ca(2+) and modulate ion channels, through a network of events, in such a way that the guard cells lose K(+)/Cl(-)/anions. The efflux of these ions decreases the turgor of guard cells and leads to stomatal closure. Thus, ROS, NO, and cytosolic free Ca(2+) act as points of divergence. The other guard cell components, which are modulated during stomatal closure are G-proteins, cytosolic pH, phospholipids, and sphingolipids. However, the current information on the role of these components is not convincing so as to assign them as the points of convergence or divergence. The interrelationships and interactions of ROS, NO, cytosolic pH, and free Ca(2+) are quite complex and need further detailed examination. Our review is an attempt to critically assess the current status of information on guard cells, while emphasizing the convergence and divergence of signaling components during stomatal closure. The existing gaps in our knowledge are identified to stimulate further research.
Increasing evidence suggests that cognitive-control processes can be configured to optimize either persistence of information processing (by amplifying competition between
 decision-making alternatives and top-down biasing of this competition) or flexibility (by dampening competition and biasing). We investigated whether high-frequency binaural beats, an auditory illusion suspected to act as a cognitive enhancer, have an impact on cognitive-control configuration. We hypothesized that binaural beats in the gamma range bias the cognitive-control style toward flexibility, which in turn should increase the crosstalk between tasks in a dual-task paradigm. We replicated earlier findings that the reaction time in the first-performed task is sensitive to the compatibility between the responses in the first and the second task-an indication of crosstalk. As predicted, exposing participants to binaural beats in the gamma range increased this effect as compared to a control condition in which participants were exposed to a continuous tone of 340 Hz. These findings provide converging evidence that the cognitive-control style can be systematically biased by inducing particular internal states; that high-frequency binaural beats bias the control style toward more flexibility; and that different styles are implemented by changing the strength of local competition and top-down bias.
The Medical Treatment and Supervision Act (MTSA) was enacted in 2005 in Japan to promote the reintegration of clinical offenders with mental disorders into society. Under the MTSA, individuals who committed serious crimes in a state of insanity or diminished responsibility are diverted from the criminal justice system to the mental health system. Based on court decisions about MTSA-based treatment, clinical offenders have an obligation to engage in rehabilitation within their local community under the guidance of mental health professionals. However, patients under MTSA-based clinical treatments have faced various problems in the course of treatment, because of psychiatric as well as other static or dynamic factors, and sometimes have committed problematic behaviors, such as violence and medical non-compliance. Hence, this study aimed to clarify factors related to patients' inclusion in MTSA-based outpatient treatment and additionally, their commitment of problematic behaviors, based on confidential data acquired during a four-year government survey period (National Center of Neurology and Psychiatry) from MTSA enactment (July 15, 2005) to December 31, 2009. In total, we recruited 441 clinical offenders receiving MTSA-based outpatient treatment from 158 nationwide facilities. To evaluate related factors, we collected demographic, psychiatric, forensic, clinical treatment, and social service information. Statistical analyses demonstrated that predominant profiles of patients included male gender, younger age, low school history, psychiatric diagnoses (F1, F2, and F3), and no correctional or outpatient history before MTSA-based treatment. F1 or substance use diagnosis, in particular, was increasingly correlated with other factors, such as male gender, older age, and correctional history before MTSA treatment. Among the 441 patients, 189 (43%) committed problematic behaviors in the course of the MTSA-based outpatient treatment. Risk factors for patients' commitment of problematic behaviors comprised F1 diagnosis and inpatient history before MTSA-based treatment inclusion. In summary, reduction of overall problematic behaviors under the MTSA outpatient likely makes progress by focal attention to patients with psychiatric disorders caused by substance use and/or a past inpatient history for more severe psychiatric symptoms. This work is of ongoing and future importance in the domain of forensic community treatment, to connect risk-enhancing factors with risk management.
Cryptosporidium parvum is an important zoonotic protozoan parasite that infects the gastrointestinal tract of vertebrate animals and man. The current study was contemplated for molecular detection of Cryptosporidium species prevalent in dairy calves in Punjab, India. A total of 302 faecal samples were screened by modified Ziehl-Neelsen staining technique for the detection of Cryptosporidium oocysts. Molecular characterisation was done using PCR followed by sequence analysis of the representative isolates. An overall prevalence of 26.15 % was obtained with the highest prevalence obtained in 0-30 day old calves in both diarrhoeic and non-diarrhoeic animals. PCR analysis revealed the expected bands at 1,325 and 835 bp from all the isolates for primary and secondary/nested PCR respectively. Ten representative samples were sequenced in both directions. Phylogenetic analysis revealed the presence of C. parvum in all the samples. The high rate of calves infected with C. parvum can act as a great source of zoonotic cryptosporidiosis which indicates a potential risk of zoonotic transmission from animal to human beings in Punjab (India).
A sociologist chronicles how uninsurance and health reform have affected one Texas family for over a decade.
Rural hospitals differ from urban hospitals in many ways. For example, rural hospitals are more reliant on public payers and have lower operating margins. In addition, enrollment in the health insurance Marketplaces of the Affordable Care Act (ACA) has varied across rural and urban areas. This study employed a difference-in-differences approach to evaluate the average effect of Medicaid expansion in 2014 on payer mix and profitability for urban and rural hospitals, controlling for secular trends. For both types of hospitals, we found that Medicaid expansion was associated with increases in Medicaid-covered discharges. However, the increases in Medicaid revenue were greater among rural hospitals than urban hospitals, and the decrease in the proportion of costs for uncompensated care were greater among urban hospitals than rural hospitals. This preliminary analysis of the early effects of Medicaid expansion suggests that its financial impacts may be different for hospitals in urban and rural locations.
The Medicare Access and CHIP Reauthorization Act of 2015 (MACRA) established a new framework for Medicare physician payment. Designed to stabilize uncertain payment rates for Medicare's fee-for-service (FFS) system and incentivize physicians to move into new alternative payment systems, MACRA contains several uncertainties of its own. In a textbook illustration of why it's important to be careful what you wish for, it's increasingly easy to predict that implementation of MACRA will be delayed as a result of both regulatory and legislative breaches of its statutory timeline. This article traces the contemporary history of the Medicare physician payment system and efforts to implement additional changes.
The oral contraceptive pill is the contraceptive method most commonly used by US women, but inconsistent use of the pill is a contributor to high rates of unintended pregnancy. The relationship between consumer cost sharing and consistent use of the pill is not well understood, and the impact of the elimination of cost sharing for oral contraceptive pills in a mandate in the Affordable Care Act (ACA) is not yet known. We analyzed insurance claims for 635,075 women with employer-sponsored insurance who were initiating use of the pill, to examine rates of discontinuation and nonadherence, their relationship with cost sharing, and trends before and during the first year after implementation of the ACA mandate. We found that cost sharing for oral contraceptives decreased markedly following implementation, more significantly for generic than for brand-name versions. Higher copays were associated with greater discontinuation of and nonadherence to generic pills than was the case with zero copayments. Discontinuation of the use of generic or brand-name pills decreased slightly but significantly following ACA implementation, as did nonadherence to brand-name pills. Our findings suggest a modest early impact of the ACA on improving consistent use of oral contraceptives among women initiating their use.
Patient cost sharing for contraceptive prescriptions was eliminated for certain insurance plans as part of the Affordable Care Act. We examined the impact of this change on women's patterns of choosing prescription contraceptive methods. Using claims data for a sample of midwestern women ages 18-46 with employer-sponsored coverage, we examined the contraceptive choices made by women in employer groups whose coverage complied with the mandate, compared to the choices of women in groups whose coverage did not comply. We found that the reduction in cost sharing was associated with a 2.3-percentage-point increase in the choice of any prescription contraceptive, relative to the 30 percent rate of choosing prescription contraceptives before the change in cost sharing. A disproportionate share of this increase came from increased selection of long-term contraception methods. Thus, the removal of cost as a barrier seems to be an important factor in contraceptive choice, and our findings about long-term methods may have implications for rates of unintended pregnancy that require further study.
Expansions of eligibility for Medicaid under the Affordable Care Act may have increased the number of Medicaid drug prescriptions. However, the expansions did not drive Medicaid spending on prescription drugs overall in 2014.
The Orphan Drug Act of 1983 established incentives for the development of drugs that treat rare, or orphan, diseases. We used the IMS Health MIDAS database of audited biopharmaceutical sales to measure US annual spending on orphan drugs in the period 2007-13, and we estimated spending on the drugs for the period 2014-18. We identified 356 brand-name orphan drugs that were approved by the Food and Drug Administration in the period 1983-2013. While we included orphan drugs with both orphan and other indications, we adjusted spending to include
 only spending for orphan indications. In 2014 dollars, expenditures on orphan drugs totaled $15 billion in 2007 and $30 billion in 2013-representing 4.8 percent and 8.9 percent of total pharmaceutical expenditures, respectively. Our future trend analysis for the period 2014-18 suggests a slowing in the growth of orphan drug expenditures. The overall impact of orphan drugs on payers' drug budgets is relatively small, and spending on orphan drugs as a percentage of total pharmaceutical expenditures has remained fairly stable. Concerns that growth in orphan drug expenditures may lead to unsustainable drug expenditures do not appear to be justified.
The Affordable Care Act (ACA) includes provisions to reduce Medicare beneficiaries' out-of-pocket spending for prescription drugs by gradually closing the coverage gap between the initial coverage limit and the catastrophic coverage threshold (known as the doughnut hole) beginning in 2011. However, Medicare beneficiaries who take specialty pharmaceuticals could still face a large out-of-pocket burden because of uncapped cost sharing in the catastrophic coverage phase. Using 2008-12 pharmacy claims data from a 20 percent sample of Medicare beneficiaries, we analyzed trends in total and out-of-pocket spending among Medicare beneficiaries who take at least one high-cost specialty drug from the top eight specialty drug classes in terms of spending. Annual total drug spending per specialty drug user studied increased considerably during the study period, from $18,335 to $33,301, and the proportion of expenditures incurred while in the catastrophic coverage phase increased from 70 percent to 80 percent. We observed a 26 percent decrease in mean annual out-of-pocket expenditures incurred below the catastrophic coverage threshold, likely attributable to the ACA's doughnut hole cost-sharing reductions, but increases in mean annual out-of-pocket expenditures incurred while in the catastrophic coverage phase offset these reductions almost entirely. Policy makers should consider implementing limits on patients' out-of-pocket burden.
Identification of pro-cell-survival signaling pathways has implications for cancer, cardiovascular and neurodegenerative disease. We show that the Caenorhaditis elegans epidermal growth factor receptor LET-23 has a pro-survival function in counteracting excitotoxicity, and we identify novel molecular players required for this pro-survival signaling. uv1 sensory cells in the C. elegans uterus undergo excitotoxic death in response to activation of the OSM-9/OCR-4 TRPV channel by the endogenous agonist nicotinamide. Activation of LET-23 EGFR can effectively prevent this excitotoxic death. We investigate the roles of signaling pathways known to act downstream of LET-23 EGFR in C. elegans and find that the LET-60 Ras / MAPK pathway, but not the IP3 receptor pathway, is required for efficient LET-23 EGFR activity in its pro-survival function. However, activation of LET-60 Ras / MAPK pathway does not appear to be sufficient to fully mimic LET-23 EGFR activity. We screen for genes that are required for EGFR pro-survival function and uncover a role for phosphatidylcholine biosynthetic enzymes in EGFR pro-survival function. Finally we show that exogenous application of phosphatidylcholine is sufficient to prevent some deaths in this excitotoxicity model. Our work implicates regulation of lipid synthesis downstream of EGFR in cell survival and death decisions.
Müller glia (MG) are the principal glial cell type in the vertebrate retina. Recent work has identified the LIM homeodomain factor encoding gene Lhx2 as necessary for both Notch signaling and MG differentiation in late-stage retinal progenitor cells (RPCs). However, the extent to which Lhx2 interacts with other intrinsic regulators of MG differentiation is unclear. We investigated this question by investigating the effects of overexpression of multiple transcriptional regulators that are either known or hypothesized to control MG formation, in both wildtype and Lhx2-deficient RPCs. We observe that constitutively elevated Notch signaling, induced by N1ICD electroporation, inhibited gliogenesis in wildtype animals, but rescued MG development in Lhx2-deficient retinas. Electroporation of Nfia promoted the formation of cells with MG-like radial morphology, but did not drive expression of MG molecular markers. Plagl1 and Sox9 did not induce gliogenesis in wildtype animals, but nonetheless activated expression of the Müller marker P27(Kip1) in Lhx2-deficient cells. Finally, Sox2, Sox8, and Sox9 promoted amacrine cell formation in Lhx2-deficient cells, but not in wildtype retinas. These findings demonstrate that overexpression of individual gliogenic factors typically regulates only a subset of characteristic MG markers, and that these effects are differentially modulated by Lhx2.
Brain development involves multiple levels of molecular coordination in forming a functional nervous system. The hippocampus is a brain area that is important for memory formation and spatial reasoning. During early postnatal development of the hippocampal circuit, Fibroblast growth factor 22 (FGF22) and FGF7 act to establish a balance of excitatory and inhibitory tone. Both FGFs are secreted from CA3 dendrites, acting on excitatory or inhibitory axon terminals formed onto CA3 dendrites, respectively. Mechanistically, FGF22 utilizes FGFR2b and FGFR1b to induce synaptic vesicle recruitment within axons of dentate granule cells (DGCs), and FGF7 utilizes FGFR2b to induce synaptic vesicle recruitment within interneuron axons. FGF signaling eventually induces gene expression in the presynaptic neurons; however, the effects of FGF22-induced gene expression within DGCs and FGF7-induced gene expression within interneurons in the context of a developing hippocampal circuit have yet to be explored. Here, we propose one hypothetical mechanism of FGF22-induced gene expression in controlling adult neurogenesis.
Ticagrelor is an antagonist of the platelet P2Y12 receptor for ADP, approved for the prevention of thromboembolic events in patients with acute coronary syndrome. Previous studies showed that ticagrelor has no significant activity versus P1 receptors for adenosine and other known P2Y receptors, with the exception of P2Y13, which was not tested. The P2Y12 antagonist cangrelor has been shown to also inhibit P2Y13 and to decrease the P2Y13-regulated capacity of megakaryocytes to produce pro-platelets. We tested whether or not ticagrelor inhibits P2Y13 signalling and function. The in vitro effects of ticagrelor, its active (TAM) and inactive (TIM) metabolites, cangrelor and the P2Y13 antagonist MRS2211 were tested in two experimental models: 1) a label-free cellular response assay in P2Y13-transfected HEK293 T-REx cells; and 2) pro-platelet formation by human megakaryocytes in culture. Ticagrelor, TAM, cangrelor and MRS2211, but not TIM, inhibited the cellular responses in P2Y13-transfected cells. In contrast, only MRS2211 and cangrelor, confirming previous results, inhibited pro-platelet formation by megakaryocytes in vitro. The platelet count of patients randomised to treatment with ticagrelor in the PLATO trial did not change during treatment and was comparable to those of patients randomised to clopidogrel. In conclusion, ticagrelor and TAM act as P2Y13 antagonists in a transfected cell system in vitro but this does not translate into any impact on pro-platelet formation in vitro or altered platelet count in patients.
During mouse preimplantation embryo development, the classically described second cell-fate decision involves the specification and segregation, in blastocyst inner cell mass (ICM), of primitive endoderm (PrE) from pluripotent epiblast (EPI). The active role of fibroblast growth factor (Fgf) signalling during PrE differentiation, particularly in the context of Erk1/2 pathway activation, is well described. However, we report that p38 family mitogen-activated protein kinases (namely p38α/Mapk14 and p38β/Mapk11; referred to as p38-Mapk14/11) also participate in PrE formation. Specifically, functional p38-Mapk14/11 are required, during early-blastocyst maturation, to assist uncommitted ICM cells, expressing both EPI and earlier PrE markers, to fully commit to PrE differentiation. Moreover, functional activation of p38-Mapk14/11 is, as reported for Erk1/2, under the control of Fgf-receptor signalling, plus active Tak1 kinase (involved in non-canonical bone morphogenetic protein (Bmp)-receptor-mediated PrE differentiation). However, we demonstrate that the critical window of p38-Mapk14/11 activation precedes the E3.75 timepoint (defined by the initiation of the classical 'salt and pepper' expression pattern of mutually exclusive EPI and PrE markers), whereas appropriate lineage maturation is still achievable when Erk1/2 activity (via Mek1/2 inhibition) is limited to a period after E3.75. We propose that active p38-Mapk14/11 act as enablers, and Erk1/2 as drivers, of PrE differentiation during ICM lineage specification and segregation.
Attention Deficit Hyperactivity Disorder (ADHD) is a common childhood disorder with international prevalence estimates of 5 % in childhood, yet significant evidence exists that far fewer children receive ADHD services. In many countries, ADHD is assessed and diagnosed in specialist mental health or neuro-developmental paediatric clinics, to which referral by General (Family) Practitioners (GPs) is required. In such 'gatekeeper' settings, where GPs act as a filter to diagnosis and treatment, GPs may either not recognise potential ADHD cases, or may be reluctant to refer. This study systematically reviews the literature regarding GPs' views of ADHD in such settings.
A search of nine major databases was conducted, with wide search parameters; 3776 records were initially retrieved. Studies were included if they
 were from settings where GPs are typically gatekeepers to ADHD services; if they addressed GPs' ADHD attitudes and knowledge; if methods were clearly described; and if results for GPs were reported separately from those of other health professionals.
Few studies specifically addressed GP attitudes to ADHD. Only 11 papers (10 studies), spanning 2000-2010, met inclusion criteria, predominantly from the UK, Europe and Australia. As studies varied methodologically, findings are reported as a thematic narrative, under the following themes: Recognition rate; ADHD controversy (medicalisation, stigma, labelling); Causes of ADHD; GPs and ADHD diagnosis; GPs and ADHD treatment; GP ADHD training and sources of information; and Age, sex differences in knowledge and attitudes.
Across times and settings, GPs practising in first-contact gatekeeper settings had mixed and often unhelpful attitudes regarding the validity of ADHD as a construct, the role of medication and how parenting contributed to presentation. A paucity of training was identified, alongside a reluctance of GPs to become involved in shared care practice. If access to services is to be improved for possible ADHD cases, there needs to be a focused and collaborative approach to training.
To estimate health care expenditure trends among young adults ages 19-25 before and after the 2010 implementation of the Affordable Care Act (ACA) provision that extended eligibility for dependent private health insurance coverage.
Nationally representative Medical Expenditure Panel Survey data from 2008 to 2012.
We conducted repeated cross-sectional analyses and employed a difference-in-differences quantile regression model to estimate health care expenditure trends among young adults ages 19-25 (the treatment group) and ages 27-29 (the control group).
Our results show that the treatment group had 14 percent lower overall health care expenditures and 21 percent lower out-of-pocket payments compared with the control group in 2011-2012. The overall reduction in health care expenditures among young adults ages 19-25 in years 2011-2012 was more significant at the higher end of the health care expenditure distribution. Young adults ages 19-25 had significantly higher emergency department costs at the 10th percentile in 2011-2012. Differences in the trends of costs of private health insurance and doctor visits are not statistically significant.
Increased health insurance enrollment as a consequence of the ACA provision for dependent coverage has successfully reduced spending and catastrophic expenditures, providing financial protections for young adults.
While dual usage of US Department of Veterans Affairs (VA) and non-VA health services increases access to care and choice for veterans, it is also associated with a number of negative consequences including increased morbidity and mortality. Veterans with multiple health conditions, such as the homeless, may be particularly susceptible to the adverse effects of dual use. Homeless veteran dual use is an understudied yet timely topic given the Patient Protection and Affordable Care Act and Veterans Choice Act of 2014, both of which may increase non-VA care for this population. The study purpose was to evaluate homeless veteran dual use of VA and non-VA health care by describing the experiences, perspectives, and recommendations of community providers who care for the population.
Three semi-structured focus group interviews were conducted with medical, dental, and behavioral health providers at a large, urban Health Care for the Homeless (HCH) program. Qualitative content analysis procedures were used.
HCH providers experienced challenges coordinating care with VA medical centers for their veteran patients. Participants lacked knowledge about the VA health care system and were unable to help their patients navigate it. The HCH and VA medical centers lacked clear lines of communication. Providers could not access the VA medical records of their patients and felt this hampered the quality and efficiency of care veterans received.
Substantial challenges exist in coordinating care for homeless veteran dual users. Our findings suggest recommendations related to education, communication, access to electronic medical records, and collaborative partnerships. Without dedicated effort to improve coordination, dual use is likely to exacerbate the fragmented care that is the norm for many homeless persons.
Staphylococcus aureus expresses two distinct but closely related multifunctional cell wall-anchored (CWA) proteins that bind to the host glycoprotein fibronectin. The fibronectin binding proteins FnBPA and FnBPB comprise two distinct domains. The C-terminal domain comprises a tandem array of repeats that bind to the N-terminal type I modules of fibronectin by the tandem β-zipper mechanism. This causes allosteric activation of a cryptic integrin binding domain, allowing fibronectin to act as a bridge between bacterial cells and the α5β1 integrin on host cells, triggering bacterial uptake by endocytosis. Variants of FnBPA with polymorphisms in fibronectin binding repeats (FnBRs) that increase affinity for the ligand are associated with strains that infect cardiac devices and cause endocarditis, suggesting that binding affinity is particularly important in intravascular infections. The N-terminal A domains of FnBPA and FnBPB have diverged into seven antigenically distinct isoforms. Each binds fibrinogen by the 'dock, lock and latch' mechanism characteristic of clumping factor A. However, FnBPs can also bind to elastin, which is probably important in adhesion to connective tissue in vivo. In addition, they can capture plasminogen from plasma, which can be activated to plasmin by host and bacterial plasminogen activators. The bacterial cells become armed with a host protease which destroys opsonins, contributing to immune evasion and promotes spreading during skin infection. Finally, some methicillin-resistant S. aureus (MRSA) strains form biofilm that depends on the elaboration of FnBPs rather than polysaccharide. The A domains of the FnBPs can interact homophilically, allowing cells to bind together as the biofilm accumulates.
The neurobiological mechanisms mediating an increased risk to develop affective disorders remain poorly understood. In a group of individuals with a family history of major depressive (MDD) or bipolar disorder (BD), we investigated the microstructural properties of white matter fiber tracts, that is, cingulum bundle, uncinate fasciculus, anterior limb of the internal capsule, and corpus callosum, that facilitate the communication between brain regions implicated in affective disorders.
Eighty-nine healthy mono- or dizygotic twins with a co-twin diagnosed with MDD or BD (high-risk) and 57 healthy twins with a co-twin with no familial history of affective disorders (low-risk) were included in a diffusion tensor imaging study.
The high-risk group showed decreased fractional anisotropy (FA), a measure of water diffusion directionality, and increased radial diffusivity in the anterior region of corpus callosum compared to the low-risk group. This abnormality was not associated with zygosity or type of depressive disorder of co-twin.
The observed decreased anterior callosal fiber FA in the high-risk group may be indicative of a compromised interhemispheric communication between left and right frontal regions critically involved in mood regulation. Reduced anterior callosal FA may act as a vulnerability marker for affective disorders in individuals at familial risk.
Renal denervation (RDN) has been shown in several studies to reduce blood pressure (BP) in patients with resistant hypertension (RH). Data on potential biomarkers associated with BP changes remain scarce. We evaluated whether soluble vascular endothelial growth factor receptor (sVEGFR-1) is affected by the procedure. A total of 57 patients with RH participated in this study. BP and heart rate were recorded at baseline and at 3 months follow-up, at which time blood samples were collected to determine the levels of sVEGFR-1, VEGF-A, VEGF-C, nitric oxide (NO), soluble vascular adhesion molecule 1 and soluble intracellular adhesion molecule 1. None of the biomarkers had a predictive value that could identify responders vs non-responders to RDN. However, sVEGFR-1 concentration was dramatically reduced after RDN (5913±385 vs 280±57 pg ml(-1), P<0.001). At the same time VEGF-A levels were significantly increased (10.0±3.0 vs 55.5±7.9 pg ml(-1), P<0.001), without significant changes in VEGF-C. NO levels were significantly increased after RDN in the whole group (82.6±6.2 vs 106.9±7.8 μM, P=0.021). Interestingly, the elevation in NO levels at 3 months was only seen in patients who demonstrated a reduction in systolic BP of ⩾10 mm Hg (78.9±8.3 vs 111.6±11.7 μM, P=0.018). We report a significant reduction in sVEGFR-1 levels after RDN procedure, which was accompanied by a significant increase in VEGF-A concentration as well as NO. Changes in plasma cytokines were not quantitatively linked to magnitude of BP reduction. An RDN-induced reduction in sVEGFR-1 plasma levels and increase in VEGF-A would raise the VEGF-A/sVEGFR-1 ratio, thereby increasing VEGF-A bioavailability to act on its full-length receptor and may contribute to the BP-lowering effect potentially via NO-mediated pathways.Journal of Human Hypertension advance online publication, 8 September 2016; doi:10.1038/jhh.2016.64.
There are international concerns in relation to the management of patient deterioration which has led to a body of evidence known as the 'failure to rescue' literature. Nursing staff are known to miss cues of deterioration and often fail to call for assistance. Medical Emergency Teams (Rapid Response Teams) do improve the management of acutely deteriorating patients, but first responders need the requisite
 skills to impact on patient safety.
In this study we aim to address these issues in a mixed methods interventional trial with the objective of measuring and comparing the cost and clinical impact of face-to-face and web-based simulation programs on the management of patient deterioration and related patient outcomes. The education programs, known as 'FIRST(2)ACT', have been found to have an impact on education and will be tested in four hospitals in the State of Victoria, Australia. Nursing staff will be trained in primary (the first 8 min) responses to emergencies in two medical wards using a face-to-face approach and in two medical wards using a web-based version FIRST(2)ACTWeb. The impact of these interventions will be determined through quantitative and qualitative approaches, cost analyses and patient notes review (time series analyses) to measure quality of care and patient outcomes.
In this 18 month study it is hypothesised that both simulation programs will improve the detection and management of deteriorating patients but that the web-based program will have lower total costs. The study will also add to our overall understanding of the utility of simulation approaches in the preparation of nurses working in hospital wards. (ACTRN12616000468426, retrospectively registered 8.4.2016).
A glycosaminoglycan mimetic was attached to the surface of solid and mesoporous silica nanoparticles to create novel antiviral agents against herpes simplex type 1 and type 2 viruses. The nanoparticles act as viral entry inhibitors that appear to block viral attachment and penetration into susceptible cells.
Magnetic interactions in magnetic nanostructures are critical to nanomagnetic and spintronic explorations. Here we demonstrate an extremely sensitive magnetic yoking effect and tunable interactions in FePt based hard/soft bilayers mediated by the soft layer. Below the exchange length, a thin soft layer strongly exchange couples to the perpendicular moments of the hard layer; above the exchange length, just a few nanometers thicker, the soft layer moments turn in-plane and act to yoke the dipolar fields from the adjacent hard layer perpendicular domains. The evolution from exchange to dipolar-dominated interactions is experimentally captured by first-order reversal curves, the ΔM method, and polarized neutron reflectometry, and confirmed by micromagnetic simulations. These findings demonstrate an effective yoking approach to design and control magnetic interactions in wide varieties of magnetic nanostructures and devices.
Psychosocial interventions have an important role in promoting recovery in people with persisting psychotic disorders such as schizophrenia. Readily available, digital technology provides a means of developing therapeutic resources for use together by practitioners and mental health service users. As part of the Self-Management and Recovery Technology (SMART) research program, we have developed an online resource providing materials on illness self-management and personal recovery based on the Connectedness-Hope-Identity-Meaning-Empowerment (CHIME) framework. Content is communicated using videos featuring persons with lived experience of psychosis discussing how they have navigated issues in their own recovery. This was developed to be suitable for use on a tablet computer during sessions with a mental health worker to promote discussion about recovery.
This is a rater-blinded randomised controlled trial comparing a low intensity recovery intervention of eight one-to-one face-to-face sessions with a mental health worker using the SMART website alongside routine care, versus an eight-session comparison condition, befriending. The recruitment target is 148 participants with a schizophrenia-related disorder or mood disorder with a history of psychosis, recruited from mental health services in Victoria, Australia. Following baseline assessment, participants are randomised to intervention, and complete follow up assessments at 3, 6 and 9 months post-baseline. The primary outcome is personal recovery measured using the Process of Recovery Questionnaire (QPR). Secondary outcomes include positive and negative symptoms assessed with the Positive and Negative Syndrome Scale, subjective experiences of psychosis, emotional symptoms, quality of life and resource use. Mechanisms of change via effects on self-stigma and self-efficacy will be examined.
This protocol describes a novel intervention which tests new therapeutic methods including in-session tablet computer use and video-based peer modelling. It also informs a possible low intensity intervention model potentially viable for delivery across the mental health workforce.
NCT02474524 , 24 May 2015, retrospectively registered during the recruitment phase.
Outcomes for very old patients (≥ 80 years) referred but not admitted to an intensive care unit have not been described in Australia and New Zealand.
To ascertain long-term (12-month) outcomes for very old patients urgently referred for ICU support at a tertiary referral hospital.
A retrospective, medical record review of 1240 very old patients (≥ 80 years) who were urgently referred to an Australian, 31-bed ICU over a 40-month period from March 2011 to August 2014. Referrals were divided into those who were "too well" for the ICU, admitted to the ICU, and "too sick" for the ICU. Data and main outcome measures: Data were extracted from hospital records, the ICU patient database and the Australian Institute of Health and Welfare National Death Index, and our main outcome measures were health status and destination at hospital discharge, and 12-month mortality rates.
Urgent admissions of very old patients accounted for 6.9% of total ICU admissions (443/6415). The hospital mortality rate was 16.0% (93/583) for patients who were too well, 32.1% (142/443) for those admitted to the ICU, and 69.2% (148/214) for those too sick (P ≥ 0.001). Mortality rates 12 months after referral were 40.8% (238/583), 46.0% (204/443) and 88.3% (189/214), respectively (P ≥ 0.001).
Very old patients considered too well for the ICU have a significantly lower hospital mortality rate than those admitted to the ICU after urgent referral. However, 12 months after referral, patients considered too well for ICU admission have a mortality rate approaching that of very old patients admitted to the ICU. Over half of very old patients urgently referred to the ICU die within 12 months.
Craniotomy pain may be severe and is often undertreated. Pain management following craniotomy is a balancing act of achieving adequate analgesia but avoiding sedation, respiratory depression, hypercapnia, nausea and vomiting, and hypertension. Opioids are a first-line analgesic therapy; however, concern that opioid-related adverse effects (sedation, respiratory depression) may interfere with neurologic assessment and increase intracranial pressure has limited use of these drugs for intracranial surgery. Non-opioid analgesics avoid these effects and may be useful as part of a multimodal regimen for post-craniotomy pain. Regional scalp blocks, paracetamol, and non-steroidal anti-inflammatory drugs are beneficial in the early post-operative period. Recent studies suggest a role for novel analgesics: dexmedetomidine, gabapentinoids, and ketamine, though additional studies are necessary.
Recognition and timely action around "warning signs" of illness exacerbation is central to the self-management of bipolar disorder. Due to its heterogeneity and fluctuating course, passive and active mobile technologies have been increasingly evaluated as adjunctive or standalone tools to predict and prevent risk of worsening of course in bipolar disorder. As predictive analytics approaches to big data from mobile health (mHealth) applications and ancillary sensors advance, it is likely that early warning systems will increasingly become available to patients. Such systems could reduce the amount of time spent experiencing symptoms and diminish the immense disability experienced by people with bipolar disorder. However, in addition to the challenges in validating such systems, we argue that early warning systems may not be without harms. Probabilistic warnings may be delivered to individuals who may not be able to interpret the warning, have limited information about what behaviors to change, or are unprepared to or cannot feasibly act due to time or logistic constraints. We propose five essential elements for early warning systems and provide a conceptual framework for designing, incorporating stakeholder input, and validating early warning systems for bipolar disorder with a focus on pragmatic considerations.
Stromal cells in secondary lymphoid organs (SLOs) are non-hematopoietic cells involved in the regulation of adaptive immune responses. Three major stromal populations have been identified in adult SLOs: fibroblastic reticular cells (FRCs), follicular dendritic cells (FDCs) and marginal reticular cells (MRCs). The properties of these individual populations are not clearly defined, mainly due to the lack of appropriate genetic tools, especially for MRCs. Here, we analyzed stromal cell targeting in SLOs from a transgenic mouse strain that expresses Cre recombinase under the CollagenVI promoter, using lineage tracing approaches. We show that these mice target specifically MRCs and FDCs, but not FRCs in Peyer's patches and isolated lymphoid follicles in the intestine. In contrast, stromal cells in lymph nodes and the spleen do not express the transgene, which renders ColVI-cre mice ideal for the specific targeting of stromal cells in the gut-associated lymphoid tissue (GALT). This funding further supports the hypothesis of organ-specific stromal precursors in SLOs. Interestingly, in all tissues analyzed, there was also high specificity for perivascular cells, which have been proposed to act
 as FDC precursors. Taken together, ColVI-Cre mice are a useful new tool for the dissection of MRC- and FDC-specific functions and plasticity in the GALT.
Given the increase of antibiotic resistant bacteria the requirement for hospitals and ambulatory services to collect and analyze antibiotic consumption data was stipulated in the Protection against Infection Act (IfSG) in 2011. It is the duty of the public health offices to supervise the compliance with these specifications. Below, the antibiotic consumption data of all hospitals in Frankfurt am Main between 2012 and 2014 are reported and the supervisory activities presented.
Hospitals collect the antibiotic consumption data according to the legal requirements and provide the data in the form of defined daily doses (DDD) per active substance as suggested in the recommendations for the implementation of the law by the Robert Koch-Institute. Given the number of patient days the DDD/100 patient days could be calculated allowing a comparison between the hospitals. In 2015 the public health office additionally collected organizational and structural data on antimicrobial consumption.
With more than 1.5 million patient days per year and over a million DDD, the consumption in the year 2012 was 67.5 DDD/100 patient days (pt days) and 66.0 DDD/100 pt days in the year 2014, with a range of 26.4 to 86.7 DDD/100 pt days in the individual hospitals. In 2012 Cefuroxim made up for 24 % of total consumption with 256,343 DDD, followed by Ciprofloxacin, Ceftriaxon and Levofloxacin with over 6 % each and with no significant changes from 2012 through 2014. In 2012 the carbapenems were the fourth most frequently prescribed group of antibiotics with 65,772 DDD or 4.1 DDD/100 pt days after the cephalosporins (408,519 DDD; 25.7 DDD/100 pt days), penicillins (215,591 DDD; 13.5 DDD/100 pt days) and the fluoroquinolones (144,195 DD; 9.1 DDD/100 pt days). However, the consumption of carbapenems increased up to 2014 by 24 % to 82,007 DDD. All 16 hospitals had established an antibiotic consumption surveillance system including the evaluation of the data, however, the availability for the entire staff was not yet fully implemented.
This is the first report of antibiotic consumption data from the hospitals of an entire city. After compilation and processing of the data the public health office fed back this information to the facilities during on-site visits in 2015 - in an anonymized comparison with other hospitals of the region. This forces the hospitals to deal intensely with the data, with the goal of using antibiotics more appropriately in order to minimize the selective pressure due to mis- and overuse of antibiotics. The forthcoming years will clarify the effect of the antibiotic surveillance on antibiotic consumption in these hospitals.
Metformin, a natural product from Galga officinalis, is an oral drug, now in the forefront of the therapeutic management of type-2 diabetes mellitus. A series of clinical observations of the last decades, support that metformin may contribute to lowering the risk of cancer development in diabetic patients, and also to improvement of response-to-therapy and survival in individuals with certain types of malignancies. Moreover, several preclinical in-vitro and in-vivo data indicate that metformin indeed exerts anti-proliferative capacities upon tumor cells mediated through a variety of mechanisms. Interestingly, metformin has been shown to act in synergy with certain anti-cancer agents and also to overcome chemo- and/or radio-resistance of various types of tumors, providing a hopeful rationale for novel therapeutic strategies against cancer development and progression. However, this remains an issue of controversy, since significant contradictions exist among the available data. Limitations of preclinical studies and caveats of epidemiological works, together with significant variances among the several types of cancer and the fact that the mode of metformin's action is largely unknown, make longitudinal surveys urgently needed. Now, a plethora of large clinical trials are active worldwide, aiming at determining the effect of metformin in the prevention or prognosis of a variety of human cancers. If encouraging results arise, metformin will be an attractive candidate adjuvant in the management of human neoplasias, due to its safety, tolerability and low-cost, expected to mitigate adverse effects and no-response parameters of current anti-cancer therapeutics, thus improving the quality of life and survival of cancer patients.
Improving a patient's ability to form and maintain satisfactory interpersonal relations is an important goal in many therapies. A mentalization-based approach to treatment is ideally suited to achieve this end to the extent it's designed to help improve a patient's ability to form more nuanced guesses about why others act as they do, based on a more accurate "read" of that individual's beliefs and desires. Interpersonal difficulties often issue when patients remain insistent on their own interpretation of another's motives that fly in the face of that individual's understanding of what is "driving" them. Helping patients explore the basis upon which they'd formed their conclusions about others goes a ways toward opening their mind to the possibility that things are a bit more complicated than first imaged. This in turn leads to greater curiosity and willingness to explore their own narratives and perceptions.
Emotional control may be observed to be (1) too excessive as in avoidant behaviors during psychotherapy, (2) suitable to a frank expression of feelings, or (3) lacking in regulation causing too intense affective experiences. This article offers a theory that may help clinicians make observations about this range of possible states, formulate the patient's defensive processes, and choose if, how, and when to act. The observations and formulations presented focus on specific and present moment situations rather than habitual defense mechanisms.
The WRKY family of transcription factors orchestrate the reprogrammed expression of the complex network of defense genes at various biotic and abiotic stresses. Within the last 96 million years, three rounds of Musa polyploidization events had occurred from selective pressure causing duplication of MusaWRKYs with new activities. Here, we identified a total of 153 WRKY transcription factors available from the DH Pahang genome. Based on their phylogenetic relationship, the MusaWRKYs available with complete gene sequence were classified into the seven common WRKY sub-groups. Synteny analyses data revealed paralogous relationships, with 17 MusaWRKY gene pairs originating from the duplication events that had occurred within the Musa lineage. We also found 15 other MusaWRKY gene pairs originating from much older duplication events that had occurred along Arecales and Poales lineage of commelinids. Based on the synonymous and nonsynonymous substitution rates, the fate of duplicated MusaWRKY genes was predicted to have undergone sub-functionalization in which the duplicated gene copies retain a subset of the ancestral gene function. Also, to understand the regulatory roles of MusaWRKY during a biotic stress, Illumina sequencing was performed on resistant and susceptible cultivars during the infection of root lesion nematode, Pratylenchus coffeae. The differential WRKY gene expression analysis in nematode resistant and susceptible cultivars during challenged and unchallenged conditions had distinguished: 1) MusaWRKYs participating in general banana defense mechanism against P.coffeae common to both susceptible and resistant cultivars, 2) MusaWRKYs that may aid in the pathogen survival as suppressors of plant triggered immunity, 3) MusaWRKYs that may aid in the host defense as activators of plant triggered immunity and 4) cultivar specific MusaWRKY regulation. Mainly, MusaWRKY52, -69 and -92 are found to be P.coffeae specific and can act as activators or repressors in a defense pathway. Overall, this preliminary study in Musa provides the basis for understanding the evolution and regulatory mechanism of MusaWRKY during nematode stress.
The putative oxyallyl cation intermediate generated following Nazarov cyclization of dienone has been successfully intercepted with potassium alkynyltrifluoroborates which act as σ-nucleophiles in the presence of BF3·Et2O. This new trapping modality allowed unprecedented introduction of an alkynyl moiety to the cyclopentanone framework by means of an interrupted Nazarov reaction. The α-alkynyl cyclopentanone product can be further transformed into an array of densely functionalized cyclic compounds.
Human 8-oxoguanine DNA glycosylase (hOGG1) is known to play an important role in the prevention of carcinogenesis, including gastric cancer (GC). We performed a case-control study to investigate whether single nucleotide polymorphisms (SNPs) of hOGG1 are associated with GC risk in a Chinese population. Two potential functional tagSNPs (rs159153 and rs1052133) and a previously reported risk SNP (rs125701) were genotyped in 1,275 GC patients and 1,436 controls. We found that SNP rs125701 G > A was significantly associated with the increased GC risk [adjusted odds ratio (OR) = 1.38, 95% confidence interval (CI) = 1.05-1.79 in additive model]. Besides, the functional studies demonstrated that the minor A allele of rs125701 significantly reduced the transcriptional activity of hOGG1 promoter and enhanced the methylation level of CpG site of cg15357639. In conclusion, our results suggested that the SNP rs125701 in hOGG1 promoter was associated with the elevated GC risk, which could act as a new potential biomarker for GC susceptibility. Further functional verification of rs125701 in GC pathogenesis is warranted.
The crucial role of Toll-like Receptors (TLRs) in innate and adaptive
 immune systems is well discussed in the literature. In cancer, TLRs act as a double-edged sword that can promote or suppress tumor growth. Areas covered: In this article, the authors uncover the potential role of TLRs in lymphomas, which are cancers related to the lymphatic system and blood cells. TLRs are de facto inflammation-inducing receptors that can either worsen disease or ameliorate lymphoma treatment. From this perspective, the usage of TLRs to modulate the immune system toward lymphoma regression is desirable. Various strategies have been used so far, and novel ways are being sought out to cure lymphoma. Expert opinion: TLR ligands have successfully been used to improve patient health; however, these receptors must be finely tuned to further optimize therapy. For a better outcome, novel specific ligands, improved pharmacodynamics, and unique targets should be discerned. Ligands with conjugated molecules, nanoparticles, and targeted drug delivery can highly optimize the therapy for lymphoma with various etiologies.
Many signaling pathways act through shared components, where different ligand molecules bind the same receptors or activate overlapping sets of response regulators downstream. Nevertheless, different ligands acting through cross-wired pathways often lead to different outcomes in terms of the target cell behavior and function. Although a number of mechanisms have been proposed, it still largely remains unclear how cells can reliably discriminate different molecular ligands under such circumstances. Here we show that signaling via ligand-induced receptor dimerization-a very common motif in cellular signaling-naturally incorporates a mechanism for the discrimination of ligands acting through the same receptor.
The metabolome is a collection of small molecules resulting from multiple cellular and biological processes that can act as biomarkers of disease, and African-Americans exhibit high levels of genetic diversity. Exome sequencing of a sample of deeply phenotyped African-Americans allowed us to analyze the effects of annotated loss-of-function (LoF) mutations on 308 serum metabolites measured by untargeted liquid and gas chromatography coupled with mass spectrometry. In an independent sample, we identified and replicated four genes harboring six LoF mutations that significantly affected five metabolites. These sites were related to a 19 to 45% difference in geometric mean metabolite levels, with an average effect size of 25%. We show that some of the affected metabolites are risk predictors or diagnostic biomarkers of disease and, using the principle of Mendelian randomization, are in the causal pathway of disease. For example, LoF mutations in SLCO1B1 elevate the levels of hexadecanedioate, a fatty acid significantly associated with increased blood pressure levels and risk of incident heart failure in both African-Americans and an independent sample of European-Americans. We show that SLCO1B1 LoF mutations significantly increase the risk of incident heart failure, thus implicating the metabolite in the causal pathway of disease. These results reveal new avenues into gene function and the understanding of disease etiology by integrating -omic technologies into a deeply phenotyped population study.
Epididymo-orchitis (EO) potentially results in reduced fertility in up to 60% of affected patients. The anti-inflammatory effects of Korean red ginseng (KRG) and its ability to act as an immunoenhancer in parallel with the beneficial effects of this ancient herbal medicine on the reproductive systems of animals and humans led us to evaluate its protective effects against acute EO.
This animal experimental study was conducted in the Department of Anatomical Sciences, Faculty of Medicine, Zanjan University of Medical Sciences (ZUMS), Zanjan, Iran during 2013-2015. We divided 50 Wistar rats into five following groups (n=10 per group): i. Control-intact animals, ii. Vehicle-phosphate buffered saline (PBS) injection into the vas deferens, iii. KRG-an intraperitoneal (IP) injection of KRG, iv. EO-an injection of uropathogenic Escherichia coli (UPEC) strain M39 into the vas defer- ens, and v. EO/ KRG-injections of both UPEC strain M39 and KRG. The treatment lasted seven days. We then evaluated sperm parameters, number of germ cell layers, Johnson's criteria, germ cell apoptosis, body weight and relative sex organs weight.
Acute EO increased the relative weight of prostate and seminal vesicles (P≤0.05). It also reduced sperm quality such as total motility, sperm concentration (P≤0.01), and the percentage of normal sperm (P≤0.001). Moreover, acute EO decreased Miller's (P≤0.05) and Johnsen's scores and increased apoptotic indexes of spermatogenic cells (P≤0.001). KRG treatment decreased prostate weight gain (P≤0.05) and improved the percentage of sperm with normal morphology, total motility (P≤0.01), and progressive motility (P≤0.05). The apoptotic indexes of spermatogenic cells reduced (P≤0.001), whereas both Johnsen's (P≤0.01) and Miller's criteria increased in the KRG-treated EO testis (P≤0.05).
Consequently, KRG ameliorated the devastating effects of EO on the sperm retrieved from either epididymis or testicle in rats.
The blacklegged tick Ixodes scapularis is widely distributed in the United States and transmits multiple pathogens to humans, wildlife and domestic animals. Recently, several novel viruses in the family Bunyaviridae (South Bay virus (SBV) and Blacklegged tick phlebovirus (BTPV)) were identified infecting female I. scapularis ticks collected in New York State. We used metagenomic sequencing to investigate the distribution of viruses infecting male and female I. scapularis ticks collected in Centre County, Pennsylvania. We identified both SBV and BTPV in both male and female ticks from all collection locations. The role of male I. scapularis in pathogen epidemiology has been overlooked because they rarely bite and are not considered important pathogen vectors. However, males may act as reservoirs for pathogens that can then be transmitted to females during mating. Our data highlight the importance of examining all potential avenues of pathogen maintenance and transmission throughout the vector-pathogen life cycle in order to understand the epidemiology of tick-borne pathogens.
Recently, numerous studies have observed changes in bird vocalizations-especially song-in urban habitats. These changes are often interpreted as adaptive, since they increase the active space of the signal in its environment. However, the proximate mechanisms driving cross-generational changes in song are still unknown. We performed a captive experiment to identify whether noise experienced during development affects song learning and the development of song-control brain regions. Zebra finches (Taeniopygia guttata) were bred while exposed, or not exposed, to recorded traffic urban noise (Study 1) or pink noise (Study 2). We recorded the songs of male offspring and compared these to fathers' songs. We also measured baseline corticosterone and measured the size of song-control brain regions when the males reached adulthood (Study 1 only). While male zebra finches tended to copy syllables accurately from tutors regardless of noise environment, syntax (the ordering of syllables within songs) was incorrectly copied affected by juveniles exposed to noise. Noise did not affect baseline corticosterone, but did affect the size of brain regions associated with song learning: these regions were smaller in males that had been had been exposed to recorded traffic urban noise in early development. These findings provide a possible mechanism by which noise affects behaviour, leading to potential population differences between wild animals occupying noisier urban environments compared with those in quieter habitats.
Bacterial communities associated with healthy corals produce antimicrobial compounds that inhibit the colonization and growth of invasive microbes and potential pathogens. To date, however, bacteria-derived antimicrobial molecules have not been identified in reef-building corals. Here, we report the isolation of an antimicrobial compound produced by Pseudovibrio sp. P12, a common and abundant coral-associated bacterium. This strain was capable of metabolizing dimethylsulfoniopropionate (DMSP), a sulfur molecule produced in high concentrations by reef-building corals and playing a role in structuring their bacterial communities. Bioassay-guided fractionation coupled with nuclear magnetic resonance (NMR) and mass spectrometry (MS), identified the antimicrobial as tropodithietic acid (TDA), a sulfur-containing compound likely derived from DMSP catabolism. TDA was produced in large quantities by Pseudovibrio sp., and prevented the growth of two previously identified coral pathogens, Vibrio coralliilyticus and V. owensii, at very low concentrations (0.5 μg/mL) in agar diffusion assays. Genome sequencing of Pseudovibrio sp. P12 identified gene homologs likely involved in the metabolism of DMSP and production of TDA. These results provide additional evidence for the integral role of DMSP in structuring coral-associated bacterial communities and underline the potential of these DMSP-metabolizing microbes to contribute to coral disease prevention.
Accelerated degradation of the wetlands and fragmentation of surrounding vegetation in the Andean-Orinoco Piedmont are the main threats to diversity and ecological integrity of these ecosystems; however, information on this topic is of limited availability. In this region, we evaluated the value of 37 lentic wetlands as reservoirs of woody and aquatic plants and analyzed diversity and changes in species composition within and among groups defined according to management given by: (1) type (swamps, heronries, rice fields, semi-natural lakes, constructed lakes and fish farms) and (2) origins
 (natural, mixed and artificial). A total of 506 plant species were recorded: 80% woody and 20% aquatic. Of these, 411 species (81%) were considered species typical of the area (Meta Piedmont distribution). Diversity patterns seem to be driven by high landscape heterogeneity and wetland management. The fish farms presented the highest diversity of woody plants, while swamps ranked highest for aquatic plant diversity. Regarding wetland origin, the artificial systems were the most diverse, but natural wetlands presented the highest diversity of typical species and can therefore be considered representative ecosystems at the regional scale. Our results suggest that lentic wetlands act as refuges for native vegetation of Meta Piedmont forest, hosting 55% of the woody of Piedmont species and 29% of the aquatic species of Orinoco basin. The wetlands showed a high species turnover and the results indicated that small wetlands (mean ± SD: size = 11 ± 18.7 ha), with a small area of surrounding forest (10 ± 8.6 ha) supported high local and regional plant diversity. To ensure long-term conservation of lentic wetlands, it is necessary to develop management and conservation strategies that take both natural and created wetlands into account.
Osteopontin (OPN) has an important role in urolithiasis. However, few studies have explored the association between OPN genetic variants and urolithiasis risk. In the present study, three single-nucleotide polymorphisms (SNPs) (rs28357094, rs11439060 and rs11730582) located on the promoter of OPN were genotyped in a total of 480 individuals, including 230 nephrolithiasis patients and 250 matched healthy controls, and the associations between these SNPs and nephrolithiasis risk in different genetic models was assessed. No significant differences were identified in the genotype and allele frequencies of OPN rs28357094 or rs11730582 (P=0.805 for rs28357094; P=0.577 for rs11730582, respectively). However, carriers with the OPN rs11439060 insertion (ins) types (ins/deletion and ins/ins) were overrepresented in urolithiasis patients compared with the controls [odds ratio (OR), 1.55; 95% confidence interval (CI), 1.08-2.22]. In the stratified analysis, the increased risk was more evident among younger subjects (adjusted OR, 1.68; 95% CI, 1.01-2.81), females (2.15; 1.14-4.08), overweight subjects (1.80; 1.07-3.05), normotensive subjects (2.48; 1.02-6.00), abnormal blood sugar subjects (1.58; 1.08-2.30), smokers (1.63; 1.02-2.60), and ever-drinkers (1.98; 1.10-3.60).. These findings revealed that the OPN rs11439060 polymorphism may act as genetic biomarker for the detection of high-risk nephrolithiasis patients.
Suicide is a global phenomenon in all regions of the world affecting people of all age groups. It has detrimental consequences on patients, their families, and the community as a whole. There have been numerous risk factors described for suicide including mental illness, stressful life situations, loss of social support, and general despair. The association of suicide with Islam has not been extensively studied. The common impression from clinical practice is that being a practicing Muslim reduces the risk of suicide. Another factor associated with suicide is starting a patient on antidepressants. However, this has been questioned recently. This report describes a middle-aged man with depression and multiple social stressors who survived a serious suicide attempt. The discussion will focus on the factors that lead him to want to end his life and the impact of the assumed protective factors such as religious belief and family support on this act of self-harm. Such patients can be on the edge when there is an imbalance between risk factors (such as depression, insomnia, and psychosocial stressors) and protective factors (like religious affiliation and family support). All physicians are advised to assess the suicide risk thoroughly in patients with depression regardless of any presumed protective factor.
The aim of the present study was to investigate the pathogenesis of Candida albicans in human umbilical vein endothelial cells (HUVECs) and to screen for aberrantly expressed genes during the process of infection. GSE7355 (accession no.) was downloaded from the National Center of Biotechnology Information Gene Expression Omnibus database and used to identify the differentially-expressed genes (DEGs) between the two groups, which included 4 samples from an untreated HUVEC control group, and 4 samples from HUVECs exposed to C. albicans. Subsequently, the gene ontology (GO) function package was used to perform GO and pathway enrichment analysis, prior to the extraction of DEG correlations in the Kyoto Encyclopedia of Genes and Genomes. A protein-protein interaction (PPI) network was constructed using the String database. In total, 77 DEGs were identified, including 69 upregulated and 8 downregulated DEGs in the C. albicans-infected HUVEC samples. DEGs were significantly enriched in response to external stimuli and chemokine activity. In addition, DEG FBJ murine osteosarcoma viral oncogene homolog (FOS) and interleukin (IL)-6 were significantly enriched in the Toll-like receptor signaling pathway. Nuclear factor κ light polypeptide gene enhancer in B cells 2 (NFKB2) was significantly enriched in the mitogen-activated protein kinase signaling pathway. In the interaction network of DEGs, according data included in the KEGG database, FOS and NFKB2 had higher connectivity degrees. Notably, FOS, IL-6 and intercellular adhesion molecule 1 were demonstrated to have higher connectivity degrees in the PPI network. FOS, IL-6 and NFKB2 may be important genes for C. albicans infection in HUVECs, and these genes may act as therapeutic targets to treat patients infected with C. albicans.
Plant hormones have become appropriate candidates for driving functional plant mycorrhization programs, including the processes that regulate the formation of arbuscules in arbuscular mycorrhizal (AM) symbiosis. Here, we examine the role played by ABA/GA interactions regulating the formation of AM in tomato. We report differences in ABA and GA metabolism between control and mycorrhizal roots. Active synthesis and catabolism of ABA occur in AM roots. GAs level increases as a consequence of a symbiosis-induced mechanism that requires functional arbuscules which in turn is dependent on a functional ABA pathway. A negative interaction in their metabolism has been demonstrated. ABA attenuates GA-biosynthetic and increases GA-catabolic gene expression leading to a reduction in bioactive GAs. Vice versa, GA activated ABA catabolism mainly in mycorrhizal roots. The negative impact of GA3 on arbuscule abundance in wild-type plants is partially offset by treatment with ABA and the application of a GA biosynthesis inhibitor rescued the arbuscule abundance in the ABA-deficient sitiens mutant. These findings, coupled with the evidence that ABA application leads to reduce bioactive GA1, support the hypothesis that ABA could act modifying bioactive GA level to regulate AM. Taken together, our results suggest that these hormones perform essential functions and antagonize each other by oppositely regulating AM formation in tomato roots.
Type II pyridoxal phosphate-dependent decarboxylase (PLP_deC) enzymes play important metabolic roles during nitrogen metabolism. Recent evolutionary profiling of these genes revealed a sharp expansion of histidine decarboxylase genes in the members of Solanaceae family. In spite of the high sequence homology shared by PLP_deC orthologs, these enzymes display remarkable differences in their substrate specificities. Currently, limited information is available on the gene repertoires and substrate specificities of PLP_deCs which renders their precise annotation challenging and offers technical challenges in the immediate identification and biochemical characterization of their full gene complements in plants. Herein, we explored their evolutionary trails in a comprehensive manner by taking advantage of high-throughput data accessibility and computational approaches. We discussed the premise that has enabled an improved reconstruction of their evolutionary lineage and evaluated the factors offering constraints in their rapid functional characterization, till date. We envisage that the synthesized information herein would act as a catalyst for the rapid exploration of their biochemical specificity and physiological roles in more plant species.
The majority of herbivorous insects are specialized feeders restricted to a plant family, genus, or species. The evolution of specialized insect-plant interactions is generally considered to be a result of trade-offs in fitness between possible hosts. Through the course of natural selection, host plants that maximize insect fitness should result in optimal, specialized, insect-plant associations. However, the extent to which insects are tracking plant phylogeny or key plant traits that act as herbivore resistance or acceptance characters is uncertain. Thus, with regard to the evolution of host plant specialization, we tested if insect performance is explained by phylogenetic relatedness of potential host plants, or key plant traits that are not phylogenetically related. We tested the survival (naive first instar to adult) of the oligophagous leaf-feeding beetle, Cassida rubiginosa, on 16 selected representatives of the Cardueae tribe (thistles and knapweeds), including some of the worst weeds in temperate grasslands of the world in terms of the economic impacts caused by lost productivity. Leaf traits (specific leaf area, leaf pubescence, flavonoid concentration, carbon and nitrogen content) were measured as explanatory variables and tested in relation to survival of the beetle, and the phylogenetic signal of the traits were examined. The survival of C. rubiginosa decreased
 with increasing phylogenetic distance from the known primary host plant, C. arvense, suggesting that specialization is a conserved character, and that insect host range, to a large degree is constrained by evolutionary history. The only trait measured that clearly offered some explanatory value for the survival of C. rubiginosa was specific leaf area. This trait was not phylogenetically dependant, and when combined with phylogenetic distance from C. arvense gave the best model explaining C. rubiginosa survival. We conclude that the specialization of the beetle is explained by a combination of adaptation to an optimal host plant over evolutionary time, and key plant traits such as specific leaf area that can restrict or broaden host utilization within the Cardueae lineage. The phylogenetic pattern of C. rubiginosa fitness will aid in predicting the ability of this biocontrol agent to control multiple Cardueae weeds.
Plant innate immunity serves as a surveillance system by providing the first line of powerful weapons to fight against pathogen attacks. Beneficial microorganisms and Microbial-Associated Molecular Patterns might act as signals to trigger this immunity. Burkholderia phytofirmans PsJN, a highly efficient plant beneficial endophytic bacterium, promotes growth in a wide variety of plants including grapevine. Further, the bacterium induces plant resistance against abiotic and biotic stresses. However, no study has deciphered triggered-mechanisms during the tripartite interaction between grapevine, B. phytofirmans PsJN and Botrytis cinerea. Herein, we showed that in contrast with classical rhizobacteria, which are restricted in the root system and act through ISR, B. phytofirmans PsJN is able to migrate until aerial part and forms at leaves surface a biofilm around B. cinerea mycelium to restrict the pathogen. Nevertheless, considering the endophytic level of PsJN in leaves, the plant protection efficacy of B. phytofirmans PsJN could not be explained solely by its direct antifungal effect. Deeper investigations showed a callose deposition, H2O2 production and primed expression of PR1, PR2, PR5, and JAZ only in bacterized-plantlets after pathogen challenge. The presence of PsJN modulated changes in leaf carbohydrate metabolism including gene expression, sugar levels, and chlorophyll fluorescence imaging after Botrytis challenge. Our findings indicated that protection induced by B. phytofirmans PsJN was multifaceted and relied on a direct antifungal effect, priming of defense mechanisms as well as the mobilization of carbon sources in grapevine leaf tissues.
Executive functions (EFs) is an umbrella term for various cognitive processes controlled by a complex neural activity, which allow the production of different types of behaviors seeking to achieve specific objectives, one of them being inhibitory control. There is a wide consensus that clinical and behavioral alterations associated with EF, such as inhibitory control, are present in various neuropsychiatric disorders. This paper reviews the research literature on the relationship between executive dysfunction, frontal-subcortical neural circuit changes, and the psychopathological processes associated with attention deficit hyperactivity disorder (ADHD) and post-traumatic stress disorder (PTSD). A revision on the role of frontal-subcortical neural circuits and their presumable abnormal functioning and the high frequency of neuropsychiatric symptoms could explain the difficulties with putting effector mechanisms into action, giving individuals the necessary tools to act efficiently in their environment. Although, neuronal substrate data about ADHD and PTSD has been reported in the literature, it is isolated. Therefore, this review highlights the overlapping of neural substrates in the symptomatology of ADHD and PTSD disorders concerning EFs, especially in the inhibitory component. Thus, the changes related to impaired EF that accompany disorders like ADHD and PTSD could be explained by disturbances that have a direct or indirect impact on the functioning of these loops. Initially, the theoretical model of EF according to current neuropsychology will be presented, focusing on the inhibitory component. In a second stage, this component will be analyzed for each of the disorders of interest, considering the clinical aspects, the etiology and the neurobiological basis. Additionally, commonalities between the two neuropsychiatric conditions will be taken into consideration from the perspectives of cognitive and emotional inhibition. Finally, the implications and future prospects for research and interventions in the area will be outlined, with the intention of contributing scientific reference information that encompasses the knowledge and understanding of executive dysfunction and its relationship with these treated disorders.
Myofibroblasts are fibroblasts with smooth muscle-like features characterized by the presence of a contractile apparatus and found in the connective tissue stroma of normal tissues such as blood vessels and lymph nodes. They are now thought to play a role in the synthesis and reorganization of extracellular matrix, which could contribute to the aggressive biologic behavior of the lesions.
To compare the mean number of stromal myofibroblasts in dentigerous cysts (DCs), keratocystic odontogenic tumor (KCOT) and ameloblastoma; and to derive a correlation between the stromal myofibroblasts and the known biologic behavior of the lesions.
A cross-sectional immunohistochemical analysis of cases of DC, KCOT and ameloblastoma.
Twenty paraffin-embedded tissue blocks each of DC, KCOT and multicystic ameloblastoma were selected for the study and diagnosis confirmed through hematoxylin and eosin staining. Tissue sections were analyzed for the number of myofibroblasts using alpha smooth muscle actin (α-SMA) immunostaining.
Differences in the mean number of α-SMA positive cells in each group were analyzed using one-way ANOVA test. Intergroup comparisons of mean values of α-SMA positive cells were performed using Mann-Whitney U-test.
Ameloblastoma showed the highest number of myofibroblasts, whereas DC showed the lowest. Among the groups, there were significant differences between the myofibroblast counts among DC and KCOT and between DC and ameloblastoma, whereas the difference in counts was not statistically significant between KCOT and ameloblastoma. A positive correlation was observed between the myofibroblast count and the known biologic behavior of the lesions.
Myofibroblasts may act in close association with the epithelial cells to bring about changes in stromal microenvironment, favorable to the growth and progression of the lesion. They may be of great value in predicting the biologic behavior and growth potential of such lesions.
RG7787 is a mesothelin-targeted immunotoxin designed to have low-immunogenicity, high-cytotoxic activity and fewer side effects. RG7787 kills many types of mesothelin-expressing cancer cells lines and causes tumor regressions in mice. Safety and immunogenicity of RG7787 is now being assessed in a phase I trial. To enhance the antitumor activity of RG7787, we screened for clinically used drugs that can synergize with RG7787. Actinomycin D is a potent transcription inhibitor that is used for treating several cancers. We report here that actinomycin D and RG7787 act synergistically to kill many mesothelin-positive cancer cell lines and produce major regressions of pancreatic and stomach cancer xenografts. Analyses of RNA expression show that RG7787 or actinomycin D alone and together increase levels of TNF/TNFR family members and NF-κB-regulated genes. Western blots revealed the combination changed apoptotic protein levels and enhanced cleavage of Caspases and PARP.
Recombinant attenuated Salmonella enterica serovar Typhimurium strains are believed to act as powerful live vaccine carriers that are able to elicit protection against various pathogens. Auxotrophic mutations, such as a deletion of aroA, are commonly introduced into such bacteria for attenuation without incapacitating immunostimulation. In this study, we describe the surprising finding that deletion of aroA dramatically increased the virulence of attenuated Salmonella in mouse models. Mutant bacteria lacking aroA elicited increased levels of the proinflammatory cytokine tumor necrosis factor alpha (TNF-α) after systemic application. A detailed genetic and phenotypic characterization in combination with transcriptomic and metabolic profiling demonstrated that ΔaroA mutants display pleiotropic alterations in cellular physiology and lipid and amino acid metabolism, as well as increased sensitivity to penicillin, complement, and phagocytic uptake. In concert with other immunomodulating mutations, deletion of aroA affected flagellin phase variation and gene expression of the virulence-associated genes arnT and ansB Finally, ΔaroA strains displayed significantly improved tumor therapeutic activity. These results highlight the importance of a functional shikimate pathway to control homeostatic bacterial physiology. They further highlight the great potential of ΔaroA-attenuated Salmonella for the development of vaccines and cancer therapies with important implications for host-pathogen interactions and translational medicine.
Recombinant attenuated bacterial vector systems based on genetically engineered Salmonella have been developed as highly potent vaccines. Due to the pathogenic properties of Salmonella, efficient attenuation is required for clinical applications. Since the hallmark study by Hoiseth and Stocker in 1981 (S. K. Hoiseth and B. A. D. Stocker, Nature 291:238-239, 1981, http://dx.doi.org/10.1038/291238a0), the auxotrophic ΔaroA mutation has been generally considered safe and universally used to attenuate bacterial strains. Here, we are presenting the
 remarkable finding that a deletion of aroA leads to pronounced alterations of gene expression, metabolism, and cellular physiology, which resulted in increased immunogenicity, virulence, and adjuvant potential of Salmonella. These results suggest that the enhanced immunogenicity of aroA-deficient Salmonella strains might be advantageous for optimizing bacterial vaccine carriers and immunotherapy. Accordingly, we demonstrate a superior performance of ΔaroA Salmonella in bacterium-mediated tumor therapy. In addition, the present study highlights the importance of a functional shikimate pathway to sustain bacterial physiology and metabolism.
Nonsteroidal antiinflammatory drugs, including ibuprofen, are among the most commonly used medications and produce their antiinflammatory effects by blocking cyclooxygenase (COX)-2. Their use is associated with increased risk of heart attacks caused by blocking COX-2 in the vasculature and/or kidney, with our recent work implicating the endogenous NOS inhibitor asymmetric dimethylarginine (ADMA), a cardiotoxic hormone whose effects can be prevented by l-arginine. The ibuprofen salt ibuprofen arginate (Spididol) was created to increase solubility but we suggest that it could also augment the NO pathway through codelivery of arginine. Here we investigated the idea that ibuprofen arginate can act to simultaneously inhibit COX-2 and preserve the NO pathway. Ibuprofen arginate functioned similarly to ibuprofen sodium for inhibition of mouse/human COX-2, but only ibuprofen arginate served as a substrate for NOS. Ibuprofen arginate but not ibuprofen sodium also reversed the inhibitory effects of ADMA and N(G)-nitro-l-arginine methyl ester on inducible NOS (macrophages) and endothelial NOS in vitro (aorta) and in vivo (blood pressure). These observations show that ibuprofen arginate provides, in one preparation, a COX-2 inhibitor and NOS substrate that could act to negate the harmful cardiovascular consequences mediated by blocking renal COX-2 and increased ADMA. While remarkably simple, our findings are potentially game-changing in the nonsteroidal antiinflammatory drug arena.-Kirkby, N. S., Tesfai, A., Ahmetaj-Shala, B., Gashaw, H. H., Sampaio, W., Etelvino, G., Leão, N. M., Santos, R. A., Mitchell, J. A. Ibuprofen arginate retains eNOS substrate activity and reverses endothelial dysfunction: implications for the COX-2/ADMA axis.
Identifying casual peer influence is a long-standing challenge to social scientists. Using data from a natural experiment of randomly-assigned college roommates (N = 2,059), which removes the threat of friend selection, we investigate peer effects on aggressive behavior, smoking, and concurrent sexual partnering. The findings suggest that the magnitude and direction of peer influence depend on predisposition, gender, and the nature of the behavior. Peer effects on individuals predisposed toward a given behavior tend to be larger than peer effects on individuals without such a predisposition. We find that the influence of roommates on aggressive behavior is more pronounced among male students than among female students; roommate effects on smoking are negative among female students and male students who did not smoke before college. For concurrent sexual partnering, a highly private behavior, we find no evidence of peer effects.
Like many federal statutes, the U.S. Endangered Species Act (ESA) contains vague or ambiguous language. Scientists can make invaluable contributions to the interpretation of the ESA when vague or ambiguous language contains scientific words or refers to scientific concepts. For scientists wanting to assist with statutory interpretation, I provide a primer on statutory interpretation. I then explain potential roles of scientists and describe how scientists have contributed to the interpretation of a particular vague and ambiguous phrase in the ESA: "significant portion of its range" (SPOIR). The role of scientists in statutory interpretation raises two professional issues - advocacy and competency. I argue that 1) disputes over the ESA's interpretation are already replete with advocates, and therefore, scientists' most constructive role is that of an unbiased, objective source of scientific information and guidance, and 2) most conservation scientists lack demonstrable competence in statutory interpretation, and therefore, should collaborate with lawyers when interpreting the ESA's vague or ambiguous language. In addition, I recommend that professional scientific societies remain policy neutral and present all interpretations of the unclear statutory language; explain the semantics, science, legislative history, and case law both supporting and contradicting each interpretation; and describe the potential consequences (ecological, social, economic) of implementing each interpretation. This article is protected by copyright. All rights reserved.
Psychoactive substances are subject to several international and national conventions and laws that have emphasised the importance of the 'war on drugs' and supply reduction. At the same time, it is increasingly clear that evidence-based, balanced policies are needed, which address the important differences between alcohol, tobacco, marijuana and other psychoactive substances or drugs. The Prevention of and Treatment for Substance Abuse Act 70 of 2008 speaks to the National Drug Master Plan, which emphasises a range of strategies for addressing the excessive use of alcohol, tobacco, marijuana and other psychoactive substances.
The locus coeruleus-norepinephrine (LC-NE) system is thought to act as a reset signal allowing brain network reorganization in response to salient information in the environment. However, no direct evidence of NE-dependent whole-brain reorganization has ever been described. We used resting-state functional magnetic resonance imaging in monkeys to investigate the impact of NE-reuptake inhibition on whole-brain connectivity patterns. We found that boosting NE transmission changes functional connectivity between and within resting-state networks. It modulated the functional connectivity pattern of a brainstem network including the LC region and interactions between associative and sensory-motor networks as well as within sensory-motor networks. Among the observed changes, those involving the fronto-parietal attention network exhibited a unique pattern of uncoupling with other sensory-motor networks and correlation switching from negative to positive with the brainstem network that included the LC nucleus. These findings provide the first empirical evidence of NE-dependent large-scale brain network reorganization and further demonstrate that the fronto-parietal attention network represents a central feature within this reorganization.
The scale-up of antiretroviral therapy (ART) in Malawi was based on a public health approach adapted to its resource-poor setting, with principles and practices borrowed from the successful tuberculosis control framework. From 2004 to 2015, the number of new patients started on ART increased from about 3000 to over 820,000. Despite being a small country, Malawi has made a significant contribution to the 15 million people globally on ART and has also contributed policy and service delivery innovations that have supported international guidelines and scale up in other countries. The first set of global guidelines for scaling up ART released by the World Health Organization (WHO) in 2002 focused on providing clinical guidance. In Malawi, the ART guidelines adopted from the outset a more operational and programmatic approach with recommendations on health systems and services that were needed to deliver HIV treatment to affected populations. Seven years after the start of national scale-up, Malawi launched a new strategy offering all HIV-infected pregnant women lifelong ART regardless of the CD4-cell count, named Option B+. This strategy was subsequently incorporated into a WHO programmatic guide in 2012 and WHO ART guidelines in 2013, and has since then been adopted by the majority of countries worldwide. In conclusion, the Malawi experience of ART scale-up has become a blueprint for a public health response to HIV and has informed international efforts to end the AIDS epidemic by 2030.
We report on the results of a respondent-driven sampling survey among men who have sex with men (MSM) in Kampala, Uganda, where same-sex behavior is criminalized and highly stigmatized. We enrolled 608 MSM aged 18 + years and residing in greater Kampala from June 2012-November 2013. Anonymous data were collected through audio-computer assisted self-interviews; blood was tested for HIV-1 antibodies, CD4 + T cell counts, and viral load. Estimated HIV prevalence was 12.2 % (95 % confidence interval [CI] 8.0-16.1), increasing with age. One in five (19.6 %) stated knowing their HIV-positive status and a similar proportion of HIV-infected MSM were virally suppressed (19.3 %; 95 % CI 3.3-33.1). HIV-related risk behaviors included unprotected anal sex (35.8 % at last sex act), selling sex (38.5 %), having multiple steady (54.3 %) or casual (63.6 %) partners, and ever injecting drugs (31.6 %). Forty percent experienced homophobic abuse; 44.5 % ever experienced suicide ideation. HIV prevalence among MSM remains high whereas knowledge of seropositive status and suppression of viral load remains low. MSM report a wide range of high risk behaviors, frequent homophobic abuse, poor mental health, as well as low levels of testing and treatment. Better access to tailored prevention and treatment services to improve population-level viral load suppression are warranted.
There are many inputs during development that influence an organism's fit to current or upcoming environments. These include genetic effects, transgenerational epigenetic influences, environmental cues and developmental
 noise, which are rarely investigated in the same formal framework. We study an analytically tractable evolutionary model, in which cues are integrated to determine mature phenotypes in fluctuating environments. Environmental cues received during development and by the mother as an adult act as detection-based (individually observed) cues. The mother's phenotype and a quantitative genetic effect act as selection-based cues (they correlate with environmental states after selection). We specify when such cues are complementary and tend to be used together, and when using the most informative cue will predominate. Thus, we extend recent analyses of the evolutionary implications of subsets of these effects by providing a general diagnosis of the conditions under which detection and selection-based influences on development are likely to evolve and coexist.
This study responds to a rural community's concern that, despite national initiatives, malaria management in young children falls short of national guidelines in their district. This study aimed to: (1) describe caregivers' treatment-seeking behaviors in the rural district of Butaleja, (2) estimate the percentage of children who received an appropriate antimalarial, and (3) determine factors that maximized the likelihood of receiving an appropriate antimalarial. Appropriate antimalarial in this study is defined as having received only the Uganda's age-specific first-line malaria treatment for uncomplicated and severe malaria during the course of the febrile illness.
A household survey design was used in 2011 to interview 424 caregivers with a child aged five and under who had fever within the two weeks preceding the survey. The survey evaluated factors that included: knowledge about malaria and its treatment, management practices, decision-making, and access to artemisinin combination therapy (ACT) and information sources. Bivariate analysis, followed by logistic regression, was used to determine predictors of the likelihood of receiving an appropriate antimalarial.
Home management was the most common first action, with most children requiring a subsequent action to manage their fever. Overall, 20.9 % of children received a blood test, 68.4 % received an antimalarial, and 41.0 % received an ACT. But closer inspection showed that only 31.6 % received an appropriate antimalarial. These results confirm that ACT usage and receipt of an appropriate antimalarial in Butaleja remain well below the 2010/2015 target of 85 %. While nine survey items differentiated significantly whether a child had or had not received an appropriate antimalarial, our logistic regression model identified four items as independent predictors of likelihood that a child would receive an appropriate antimalarial: obtaining antimalarials from regulated outlets (OR = 14.99); keeping ACT in the home for future use (OR = 6.36); reporting they would select ACT given the choice (OR = 2.31); and child's age older than four months (OR = 5.67).
Few children in Butaleja received malaria treatment in accordance with national guidelines. This study highlighted the importance of engaging the full spectrum of stakeholders in the management of malaria in young children - including licensed and unlicensed providers, caregivers, and family members.
It has been observed that the efficacy of dipeptidyl peptidase-4 (DPP-4) inhibitors as compared to the placebo groups in some clinical trials conducted in China is weaker than that in trials conducted outside China, leading to the suspicion that this may be caused by differential Glycosylated Hemoglobin (HbA1c) response in the placebo arm of DPP-4 inhibitor clinical trials conducted in China compared to other countries.
We searched published articles and other documents related to phase III placebo-control trials of DPP-4 inhibitors in Type 2 diabetes mellitus (T2DM). We included studies from different countries and compared those conducted in China to those conducted in other countries. Meta-regression analysis was used to analyze the HbA1c response in the placebo arms.
A total of 66 studies met the inclusion criteria and 10 were conducted within China. There were a total of 8303 participants (mean age 56, male 57 %) in placebo groups. The pooled change in HbA1c for the placebo groups of 10 trials conducted in patients with T2DM in China was 0.26 % (95 % CI [-0.36 %, -0.16 %], p-value < 0.001), compared to 0.015 % (95 % CI [-0.05 %, 0.08 %], p-value is 0.637) for 56 trials conducted outside of China. The difference of placebo effect between trials conducted in and outside China is -0.273 % (95 % CI [-0.42 %, -0.13 %], p-value is less than 0.001) while after excluding trials conducted in Japan, the difference is -0.203 % (95 % CI [-0.35 %, -0.06 %], p-value is 0.005). They are both statistically significant.
The meta-analysis in the article demonstrates that there is statistically significant difference in the HbA1c response in the placebo arm of DPP-4 inhibitor clinical trials conducted in China compared to other countries. This differential HbA1c response in the placebo arm should be taken into consideration by both experimenters and medical decision makers when future DPP-4 studies are conducted in China.
Natural selection favors individuals to act in their own interests, implying that wild animals experience a competitive psychology. Animals in the wild also express helping behaviors, presumably at their own expense and suggestive of a more compassionate psychology. This apparent paradox can be partially explained by ultimate mechanisms that include kin selection, reciprocity, and multilevel selection, yet some theorists argue such ultimate explanations may not be sufficient and that an additional "stake in others" is necessary for altruism's evolution. We suggest this stake is the "camaraderie effect," a by-product of two highly adaptive psychological experiences: social motivation and empathy. Rodents can derive pleasure from access to others and this appetite for social rewards motivates individuals to live together, a valuable psychology when group living is adaptive. Rodents can also experience empathy, the generation of an affective state more appropriate to the situation of another compared to one's own. Empathy is not a compassionate feeling but it has useful predictive value. For instance, empathy allows an individual to feel an unperceived danger from social cues. Empathy of another's stance toward one's self would predict either social acceptance or ostracism and amplify one's physiological sensitivity to social isolation, including impaired immune responses and delayed wound healing. By contrast, altruistic behaviors would promote well-being in others and feelings of camaraderie from others, thereby improving one's own physiological well-being. Together, these affective states engender a stake in others necessary for the expression of altruistic behavior.
Drosophila border cells undergo a straightforward and stereotypical collective migration during egg development. However, a complex genetic program underlies this process. A variety of approaches, including biochemical, genetic, and imaging strategies have identified many regulatory components, revealing layers of control. This complexity suggests that the active processes of evaluating the environment, remodeling the cytoskeleton, and coordinating movements among cells, demand rapid systems for modulating cell behaviors. Multiple signaling inputs, nodes of integration, and feedback loops act as molecular rheostats to fine-tune gene expression levels and physical responses. Since key genetic regulators of border cell migration have been shown to be required in other types of cell migration, this model system continues to provide an important avenue for genetic discovery.
MicroRNA-21 (miR-21) was reported to act as an oncogene during the development of many human tumors. However, little was revealed about the function of miR-21 in retinoblastoma (RB). In this study, we examined the expression of miR-21 in RB tissues and explored the relationship between miR-21 and phosphatase and tensin homolog (PTEN)/phosphatidylinositol-3-OH kinase (PI3K)/AKT signal. Quantitative real-time PCR (qRT-PCR) results showed that the level of miR-21 in RB tissues was higher than that in retinal normal tissues. In Weri-Rb-1 cells, miR-21 inhibitor suppressed the expression of miR-21 and cell viability, but improved cell apoptotic rates by modulating the levels of PDCD4, Bax, and Bcl-2. Meanwhile, miR-21 inhibitor suppressed cell migration and invasion via inhibiting the protein levels of MMP2 and MMP9 and significantly affected the expression of PTEN, PI3K, and p-AKT. Taken together, miR-21 inhibitor suppressed cell proliferation, migration, and invasion via the PTEN/PI3K/AKT signal. These findings revealed the molecular basis of miR-21 functioning in the progression of RB and provided a new means for cell therapy in RB.
Mesoporous silica nanoparticles (MSNs) with large surface area, tunable pore size, and low toxicity can act as suitable vehicles for drug and gene delivery. An MSN/DNA/PEI complex delivery system was prepared by using MSNs to hold plasmid DNA coated with polyethyleneimine (PEI), and the dry powder formulation was produced by freeze-drying with trehalose as lyoprotectant. The MSN/DNA/PEI complexes successfully enhanced the gene expression with about 1.5-fold higher efficiency as compared with the control, and even better effects and lower toxicity were achieved at lower content of PEI. Also, this gene delivery system showed nearly sixfold higher efficiency in the serum-containing condition than the control, so further application of these vehicles in vivo is highly appreciated. Besides, the trehalose containing lyophilized formulation could hold the availability for at least 4 months of storing at room temperature,
 presenting the potential for industrial production and transportation of gene therapy.
Variations in FTO are the strongest common genetic determinants of adiposity, and may partly act by influencing dopaminergic signalling in the brain leading to altered reward processing that promotes increased food intake. Therefore, we investigated the impact of such an interaction on body composition, and peripheral and brain insulin sensitivity.
Participants from the Tübingen Family study (n = 2245) and the Malmö Diet and Cancer study (n = 2921) were genotyped for FTO SNP rs8050136 and ANKK1 SNP rs1800497. Insulin sensitivity in the caudate nucleus, an important reward area in the brain, was assessed by fMRI in 45 participants combined with intranasal insulin administration.
We found evidence of an interaction between variations in FTO and an ANKK1 polymorphism that associates with dopamine (D2) receptor density. In cases of reduced D2 receptor availability, as indicated by the ANKK1 polymorphism, FTO variation was associated with increased body fat and waist circumference and reduced peripheral insulin sensitivity. Similarly, altered central insulin sensitivity was observed in the caudate nucleus in individuals with the FTO obesity-risk allele and diminished D2 receptors.
The effects of variations in FTO are dependent on dopamine D2 receptor density (determined by the ANKK1 polymorphism). Carriers of both risk alleles might, therefore, be at increased risk of obesity and diabetes.
Tight junctions are the outermost structures of intercellular junctions and are classified as transmembrane proteins. These factors form selective permeability barriers between cells, act as paracellular transporters and regulate structural and functional polarity of cells. Although tight junctions have been previously studied, comparison of the transcriptional translational levels of these molecules in canine organs remains to be investigated. In the present study, organ specific expression of the tight junction proteins, claudin, occludin, junction adhesion molecule A and zona occludens 1 was examined in the canine duodenum, lung, liver and kidney. Results of immunohistochemistry analysis demonstrated that the tight junctions were localized in intestinal villi and glands of the duodenum, bronchiolar epithelia and alveolar walls of the lung, endometrium and myometrium of the hepatocytes, and the distal tubules and glomeruli of the kidney. These results suggest that tight junctions are differently expressed in organs, and therefore may be involved in organ specific functions to maintain physiological homeostasis.
There is substantial evidence that stress increases multiple sclerosis disease activity, but limited evidence on its association with the onset of multiple sclerosis.
To examine the association between stressful life events and risk of first demyelinating event (FDE).
This was a multicentre incident case-control study. Cases (n = 282 with first diagnosis of central nervous system (CNS) demyelination, including n = 216 with 'classic FDE') were aged 18-59 years. Controls without CNS demyelination (n = 558) were matched to cases on age, sex and study region. Stressful life events were assessed using a questionnaire based on the Social Readjustment Rating Scale.
Those who suffered from a serious illness in the previous 12 months were more likely to have an FDE (odds ratio (OR) = 2.35 (1.36, 4.06), p = 0.002), and when we limited our reference group to those who had no stressful life events, the magnitude of effect became stronger (OR = 5.41 (1.80, 16.28)). The total stress number and stress load were not convincingly associated with the risk of an FDE.
Cases were more likely to report a serious illness in the previous 12 months, which could suggest that a non-specific illness provides an additional strain to an already predisposed immune system.
In this study, protein profiling was performed on gastric cancer tissue samples in order to identify proteins that could be utilized for an effective diagnosis of this highly heterogeneous disease and as targets for therapeutic approaches. To this end, 16 pairs of postoperative gastric adenocarcinomas and adjacent non-cancerous control tissues were analyzed on microarrays that contain 813 antibodies targeting 724 proteins. Only 17 proteins were found to be differentially regulated, with much fewer molecules than the numbers usually identified in studies comparing tumor to healthy control tissues. Insulin-like growth factor-binding protein 7 (IGFBP7), S100 calcium binding protein A9 (S100A9), interleukin-10 (IL-10) and mucin 6 (MUC6) exhibited the most profound variations. For an evaluation of the proteins' capacity for discriminating gastric cancer, a Receiver Operating Characteristic curve analysis was performed, yielding an accuracy (area under the curve) value of 89.2% for distinguishing tumor from non-tumorous tissue. For confirmation, immunohistological analyses were done on tissue slices prepared from another cohort of patients with gastric cancer. The utility of the 17 marker proteins, and particularly the four molecules with the highest specificity for gastric adenocarcinoma, is discussed for them to act as candidates for diagnosis, even in serum, and targets for therapeutic approaches.
Rotaviruses (RVs) are a major cause of severe diarrhea in humans and animals. Five of the nine RV groups (RVA, RVB, RVC, RVE, and RVH) have been previously detected in pigs; however, in pig herds worldwide, most studies highlight diarrhea outbreaks caused by RVA. In the present study, we describe detection and characterization of RV groups A, B, C, and H in fecal samples from pigs with single and mixed infections during a post-weaning diarrhea outbreak. The outbreak occurred in a single pig herd routinely vaccinated with an inactivated commercial vaccine for neonatal diarrhea control that included the RVA OSU (G5P[7]) strain. RVC (78%) was the most prevalent group found in single (34%) and mixed (44%) infections, followed by RVA (46%), RVB (32%), and RVH (18%). Phylogenetic analysis of three RVA strains allowed the characterization of two distinct G/P genotypes represented by G5P[13] and G9P[23], different from G5P[7] found in vaccines. Regardless of the RV group, mixed infections (54%) were more prevalent than single infections. Detection of RVB or RVH was associated with the presence of other RV groups, suggesting a secondary action of these RV groups in the reported outbreak. The detection of RV groups B, C, and H in the same pig herd suggests that these RVs act as causative agents of diarrhea and should be included in the diagnostic tests of porcine enteric diseases. These data provide new epidemiological information on RV diversity that need to be addressed in future studies for a better understanding and prevention of RV infections.
The differential availability of iron during hypoxia is presumed to affect the functioning of cardiac and skeletal myocytes. Rat H9C2 cardiomyocytes and L6G8C5 myocytes were cultured for 48 h in normoxic or hypoxic conditions at the optimal, reduced or increased iron concentration. The mRNA expression levels of markers of apoptosis [B cell lymphoma 2 (Bcl2; inhibition) and Bcl 2 activated X protein (Bax; induction)], atrophy (Atrogin), glycolysis (pyruvate kinase 2; PKM2) and iron metabolism [transferrin receptor 1 (TfR1; iron importer), ferroportin 1 (FPN1; iron exporter), ferritin heavy chain (FTH; iron storage protein) and hepcidin (HAMP; iron regulator)] were determined using reverse transcription quantitative polymerase chain reaction, and cell viability was measured using an tetrazolium reduction assay. Cardiomyocytes and myocytes, when exposed to hypoxia, demonstrated an increased Bax/Bcl 2 gene expression ratio (P<0.05). Additional deferoxamine (DFO) treatment resulted in further increases in Bax/Bcl 2 in each cell type (P<0.001 each) and this was associated with the 15% loss in viability. The analogous alterations were observed in both cell types upon ammonium ferric citrate (AFC) treatment during hypoxia; however, the increased Bax/Bcl 2 ratio and associated viability loss was lower compared with that in case of DFO treatment (P<0.05 each). Under hypoxic conditions, myocytes demonstrated an increased expression of PKM2 (P<0.01). Additional DFO treatment caused an increase in the mRNA expression levels of PKM2 and Atrogin 1 (P<0.001 and P<0.05, respectively), whereas AFC treatment caused an increased mRNA expression of PKM2 (P<0.01) and accompanied decreased mRNA expression of Atrogin 1 (P<0.05). The expression augmentation of PKM2 during hypoxia was greater upon low iron compared with that of ferric salt treatment (P<0.01). Both cell types upon DFO during hypoxia demonstrated the increased expression of TfR1 and HAMP (all P<0.05), which was associated with the increased Bax/Bcl 2 ratio (all R>0.6 and P<0.05). In conclusion, during hypoxia iron deficiency impairs the viability of cardiomyocytes and myocytes more severely compared with iron excess. In myocytes, during hypoxia iron may act in a protective manner, since the level of atrophy is decreased in the iron salt treated cells.
In developing countries, there is a need for access to affordable inhaled respiratory medicines. This study tested the clinical non-inferiority of fluticasone propionate/salmeterol combination (FSC) 50/250 μg Rotacaps(®)/Rotahaler(®) compared with FSC 50/250 μg Diskus(®).
A multi-centre, randomised, double-blind, double-dummy study evaluated 12 weeks, twice daily treatment of FSC 50/250 μg administered using Rotacaps/Rotahaler or Diskus inhaler in a crossover design in patients with asthma (pre-bronchodilator forced expiratory volume in 1 s (FEV1) 40%-85% of predicted, FEV1 reversibility ≥12%, prior stable dose with inhaled corticosteroid (ICS) or ICS/long acting beta-agonist). The primary
 efficacy endpoint, change from baseline in trough morning FEV1 at Day 85, was analysed using a model for repeated measures analysis. The pre-defined criterion for non-inferiority was the lower limit of the CI (0.025, one-sided significance level) for the treatment difference (Rotacaps/Rotahaler-Diskus) in least squares (LS) mean change from baseline, being greater than -125 mL. Secondary endpoints included serial FEV1 measurements, morning peak expiratory flow (PEF), rescue medication use, day- and night-time asthma symptoms, Asthma Control Test (ACT) scores, and serial cortisol measured over 12 h (area under the curve (AUC0-12)).
Treatment with FSC 50/250 μg via Rotacaps/Rotahaler or Diskus resulted in a similar LS mean increase from baseline in trough FEV1 at Day 85 (231 mL and 203 mL respectively). The difference in the model-adjusted LS mean change was 28 mL (95% CI -24 mL, 80 mL), fulfilling the criterion for non-inferiority. Data for all secondary endpoints were similar for the two treatments, supporting the primary endpoint findings. Both treatments were well tolerated and demonstrated similar safety profiles.
This study demonstrated the clinical non-inferiority of FSC 50/250 μg when administered using Rotacaps/Rotahaler compared with administration using Diskus in patients with asthma, and suggests there is no difference in the risk:benefit profile between the two FSC inhalers.
The antimalarial drug Pyrimethamine has been suggested to exert an antitumor activity by inducing apoptotic cell death in cancer cells, including metastatic melanoma cells. However, the dose of Pyrimethamine to be considered as an anticancer agent appears to be significantly higher than the maximum dose used as an antiprotozoal drug.
Hence, a series of Pyrimethamine analogs has been synthesized and screened for their apoptosis induction in two cultured metastatic melanoma cell lines. One of these analogs, the Methylbenzoprim, was further analyzed to evaluate cell-cycle and the mechanisms of cell death. The effects of Methylbenzoprim were also analyzed in a severe combined immunodeficiency (SCID)-mouse xenotransplantation model.
Low dose of Methylbenzoprim was capable of inducing cytotoxic activity and a potent growth-inhibitory effect by arresting cell cycle in S-phase in melanoma cells. Methylbenzoprim was also detected as powerful antineoplastic agents in SCID-mouse although used at very low dose and as a single agent.
Our screening approach led to the identification of a "low cost" newly synthesized drug (methylbenzoprim), which is able to act as an antineoplastic agent in vitro and in vivo, inhibiting melanoma tumor growth at very low concentrations.
The read-write genome idea predicts that mobile DNA elements will act in evolution to generate adaptive changes in organismal DNA. This prediction was examined in the context of mammalian adaptations involving regulatory non-coding RNAs, viviparous reproduction, early embryonic and stem cell development, the nervous system, and innate immunity. The evidence shows that mobile elements have played specific and sometimes major roles in mammalian adaptive evolution by generating regulatory sites in the DNA and providing interaction motifs in non-coding RNA. Endogenous retroviruses and retrotransposons have been the predominant mobile elements in mammalian adaptive evolution, with the notable exception of bats, where DNA transposons are the major agents of RW genome inscriptions. A few examples of independent but convergent exaptation of mobile DNA elements for similar regulatory rewiring functions are noted.
Disability retirement is an economic, public health and work life issue causing costs for employees, workplaces and society. Adopting physical activity at middle-age has been associated with reduced risk of sickness absence and mortality. The aim of this study was to examine how changes over time in leisure time physical activity are associated with subsequent disability retirement among midlife employees.
The Helsinki Health Study cohort baseline (phase 1) mail questionnaire survey data were collected in 2000, 2001 and 2002 among 40-60-year-old employees of the City of Helsinki, Finland. A phase 2 survey was conducted in 2007 (N = 3943). Respondents were classified into three groups: 1. low-active (<14 MET-hours/week), 2. moderately active (> = 14 MET-hours/week in moderate-intensity physical activity) and 3. vigorously active (> = 14 MET-hours/week including vigorous physical activity) at both phases. This yielded nine groups for describing stability and change of leisure time physical activity. Disability retirement data were derived from the registry of the Finnish Centre for Pensions until the end of 2013. A Cox regression analysis was used to calculate hazard ratios (HR) and their 95 % confidence intervals (CI) adjusting for covariates.
During the follow-up, 264 (6.7 %) participants retired due to disability. Compared with those who were persistently low-active, those who increased their physical activity from low to vigorous had a lower risk of subsequent disability retirement (HR = 0.38, 95 % CI = 0.15-0.97) when adjusting for age, gender, occupational social class, strenuousness of work, smoking and binge drinking. Similarly, compared with those who were persistently moderately active, those increasing from moderate to vigorous (HR = 0.50, 95 % CI = 0.28-0.86) had a reduced risk. In contrast, those decreasing their physical activity from vigorous to low (HR = 2.42, 95 % CI = 1.32-4.41) or moderate (HR = 1.70, 95 % CI = 1.03-2.82) had an increased risk, compared with those who were persistently vigorously active. Adjusting for BMI, limiting longstanding illness and prior sickness absence somewhat attenuated the associations.
Adopting vigorous physical activity was associated with a reduced risk of disability retirement. Promoting vigorous physical activity among midlife employees may help prevent disability retirement.
This article draws on a prospective longitudinal study in which Assertive Community Treatment (ACT) model fidelity and patient outcomes were assessed in twenty outpatient treatment teams. 530 severely mentally ill patients participated in the study. Delinquency outcomes were assessed three times during a two-year follow-up period. At baseline, 49% of the patients had a recent criminal history, meaning that they had at least one reported contact with the police and/or the justice system in the past year. Patients with a recent criminal history had more serious psychosocial problems at baseline compared to those without a recent criminal history. Delinquency outcomes showed improvement over time, but this was not associated with ACT model fidelity. The study shows an association for homelessness and criminal activity. The persistent criminal activities of some of the patients showed that for this group extra interventions are needed that specifically target reduction of criminal behavior.
Antibody-based anti-cancer immunotherapy was recently recognized as one of the truly effective therapies for cancer patients. Antibodies against cell surface cancer antigens, such as CD20, and also those against immune-inhibitory molecules called "immune checkpoint blockers", such as CTLA4 or PD1, have emerged. Large-scale clinical trials have confirmed that, in some cases, antibody-based drugs are superior to conventional chemotherapeutic agents. These antibody-based drugs are now being manufactured employing a mass-production system by pharmaceutical companies. Anti-cancer therapy by immune cells, i.e. cell-based immunotherapy, is expected to be more effective than antibody therapy, because immune cells can recognize, infiltrate, and act in cancer tissues more directly than antibodies. In order to achieve cell-based anti-cancer immunotherapy, it is necessary to develop manufacturing systems for mass-production of immune cells. Our group has been studying immunotherapy with myeloid cells derived from ES cells or iPS cells. These pluripotent stem cells can be readily propagated under constant culture conditions, with expansion into a large quantity. We consider these stem cells to be the most suitable cellular source for mass-production of immune cells. This review introduces our studies on anti-cancer therapy with iPS cell-derived dendritic cells and iPS cell-derived macrophages.
Decades of practice under a system that set the financial interests of physicians and insurers at odds, has resulted in physician distrust of insurers being cited a key obstacle to value-based arrangements. Insurers must work to shift the insurer-provider relationship from one that's transactional to a partnership built on trust. Even when physicians and insurers agree philosophically on quality over quantity, there are practical challenges. Insurers can provide the data, systems and analytical insights that help inform the physician's care strategy. Implementing value-based payments requires the two groups to build trust and work together to change long-established systems.
Ag nanorods coated with an ultrathin HfO2 shell (Ag NRs@HfO2) were prepared for the synthesis of a versatile, robust, and easily recyclable surface-enhanced Raman scattering (SERS) substrate. This substrate maximizes the high melting point of the HfO2 shell and thus ensures the excellent plasmonic efficiency of Ag NRs. Therefore, it possesses extraordinary thermal stability and SERS activity, which could act as a reusable and cost-effective SERS detector. After SERS detection, the regeneration of Ag NRs@HfO2 was achieved by annealing the substrate within several seconds. This procedure led to the thermal release of adsorbed molecules and resulted in a refreshed substrate for subsequent measurements. The composite substrate maintained its SERS efficiency well during multiple "detection-heating" cycles, hence demonstrating the stability
 and recyclability of Ag NRs@HfO2. Furthermore, in addition to revealing the feasibility of SERS sensing in liquids, Ag NRs@HfO2 also provided continuous real-time monitoring of vapor-phase samples at ultralow concentrations. This work provides a robust and renewable SERS sensor with advantages of high sensitivity, stability, cost effectiveness, and easy operation, which can be implemented for both aqueous and gaseous analyte detection and is thus an intriguing candidate for practical applications in environmental, industrial, and homeland security sensing fields.
Recently, a novel pathway for heme b biosynthesis in Gram-positive bacteria has been proposed. The final poorly understood step is catalyzed by an enzyme called HemQ and includes two decarboxylation reactions leading from coproheme to heme b. Coproheme has been suggested to act as both substrate and redox active cofactor in this reaction. In the study presented here, we focus on HemQs from Listeria monocytogenes (LmHemQ) and Staphylococcus aureus (SaHemQ) recombinantly produced as apoproteins in Escherichia coli. We demonstrate the rapid and two-phase uptake of coproheme by both apo forms and the significant differences in thermal stability of the apo forms, coproheme-HemQ and heme b-HemQ. Reduction of ferric high-spin coproheme-HemQ to the ferrous form is shown to be enthalpically favored but entropically disfavored with standard reduction potentials of -205 ± 3 mV for LmHemQ and -207 ± 3 mV for SaHemQ versus the standard hydrogen electrode at pH 7.0. Redox thermodynamics suggests the presence of a pronounced H-bonding network and restricted solvent mobility in the heme cavity. Binding of cyanide to the sixth coproheme position is monophasic but relatively slow (∼1 × 10(4) M(-1) s(-1)). On the basis of the available structures of apo-HemQ and modeling of both loaded forms, molecular dynamics simulation allowed analysis of the interaction of coproheme and heme b with the protein as well as the role of the flexibility at the proximal heme cavity and the substrate access channel for coproheme binding and heme b release. Obtained data are discussed with respect to the proposed function of HemQ in monoderm bacteria.
The present study aimed to explore the nature of parental involvement in the intervention of children with hearing loss, as experienced by parents.
A qualitative descriptive methodology was adopted to conduct semi-structured in-depth interviews with a purposive sample of parents who have a child with hearing loss.
Seventeen parents of 11 children aged 6-9 years participated in this study.
The overarching theme of parents taking the central role was identified using thematic analysis. This overarching theme connected five themes which described the nature of parental involvement: (1) parents work behind the scenes; (2) parents act as 'case managers'; (3) parents always have their child's language development in mind; (4) parents' role extends to advocacy for all children with hearing loss; and (5) parents serve a number of roles, but at the end of the day, they are parents.
The results indicate that parental involvement in the intervention of children with hearing loss is multifaceted in nature and incorporates a broad range of behaviours and practices. These findings have important implications for the provision of family-centred practices.
The commercialization of Zn-air batteries has been impeded by the lack of low-cost, highly active, and durable catalysts that act independently for oxygen electrochemical reduction and evolution. Here, we demonstrate excellent performance of NiCo nanoparticles anchored on porous fibrous carbon aerogels (NiCo/PFC aerogels) as bifunctional catalysts toward the Zn-air battery. This material is designed and synthesized by a novel K2Ni(CN)4/K3Co(CN)6-chitosan hydrogel-derived method. The outstanding performance of NiCo/PFC aerogels is confirmed as a superior air-cathode catalyst for a rechargeable Zn-air battery. At a discharge-charge current density of 10 mA cm(-2), the NiCo/PFC aerogels enable a Zn-air battery to cycle steadily up to 300 cycles for 600 h with only a small increase in the round-trip overpotential, notably outperforming the more costly Pt/C+IrO2 mixture catalysts (60 cycles for 120 h). With the simplicity of the synthetic method and the outstanding electrocatalytic performance, the NiCo/PFC aerogels are promising electrocatalysts for Zn-air batteries.
Granzyme A (GzmA) is elevated in the plasma and synovium in RA patients suggesting the involvement of the protease in its pathogenesis. GzmA contributes to sepsis by regulating pro-inflammatory cytokine production. We evaluated the contribution of GzmA to the pathogenesis of RA in vivo and the possibility that GzmA via TNF-α stimulates osteoclastogenesis.
Inflammatory arthritis induced by type II collagen was evaluated in wild type, GzmA deficient and perforin deficient mice. Osteoclastogenic potential of GzmA was evaluated in vitro on bone marrow and CFU-GM cells and in vivo using GzmA deficient mice.
Gene deletion of GzmA attenuates CIA, including pro-inflammatory cytokines in serum and join damage and bone erosion in affected mice, suggesting that osteoclast activity is reduced in the absence of GzmA. Accordingly, GzmA-treated bone marrow cells produce multinucleated cells that fulfill criteria for mature osteoclasts: tartrate-resistant acid phosphatase activity, β-integrin and calcitonin receptor expression plus resorptive activity on dentine slices. GzmA appears to act without accessory cells and its activity is not affected by osteoprotegerin suggesting a minor contribution of RANKL. It also induces expression and secretion of TNF-α and neutralization of TNF-α or stimulation of CFU-GM cells from TNF-α(-/-) mice prevents GzmA-induced osteoclastogenesis. Finally, GzmA deficient mice presented reduced osteoclastogenesis in vivo (less calcitonin receptor positive mutinucleated cells and less transcripts for cathepsin K, MMP-9 and TRAP in joints) and reduced levels of CTX-I in serum.
GzmA contributes, in part by promoting osteoclast differentiation, to the joint destruction in RA. This article is protected by copyright. All rights reserved.
Professor Giuseppe Moscati (1880-1927) was canonized by the Catholic Church in 1987. This act recognized the extraordinary qualities of a doctor who, considering his work as a "sublime mission", dedicated his life to helping the sick. The fame of the "Holy doctor" or "doctor of the poor", as people called him, was soon widespread and, immediately after his death, made him the subject of several biographies. These treatises, mainly written by religious hagiographers, have little analyzed Moscati as a doctor and scientist, or, in rare cases, privileged the description of his medical career, touching only marginally salient aspects of his work as a scientist and researcher. The purpose of this paper is to provide an insight into the figure of Moscati as a scientist, contextualizing his research activities in the scientific fields of biochemistry and physiology, which were flourishing in the early twentieth century. By a more careful analysis, his scientific production appears original for the resource-poor context and the innovative research method. The Italian scientist, combining physiological chemistry and biochemistry at the clinic, anticipated the birth of modern branches as the "Laboratory Medicine" and the "Clinical Pathology". In particular, he carried out studies on diabetes, storage diseases, metabolism, toxicology, pathology, nephrology and occupational diseases. Moreover, he anticipated the concept of modern laboratory in the oncological field as means for the characterization of the "nature" of neoplasms and related therapeutic approaches. Therefore, even if Moscati was rarely mentioned by the sources of the history of medicine, it is safe to assume that the fame of the Saint has paradoxically eclipsed that of the scientist, preventing him from receiving the necessary reward.
Il prof. Giuseppe Moscati (1880-1927) è stato canonizzato dalla Chiesa Cattolica il 25 ottobre 1987. Con tale atto venivano riconosciute le straordinarie doti di umanità di un medico che dedicò la sua vita all’assistenza degli infermi, considerando la sua opera una “sublime missione”. La fama del “medico santo” o del “medico dei poveri”, come il popolo lo definiva, era diffusissima e subito dopo la sua morte egli è stato oggetto di numerose biografie. Queste trattazioni, opera soprattutto di agiografi religiosi, hanno poco analizzato il Moscati medico e scienziato e, nei pochi casi in cui ciò è avvenuto, è stata comunque privilegiata la descrizione del Moscati medico, toccando solo marginalmente gli aspetti salienti della sua attività di scienziato e ricercatore. Lo scopo del presente elaborato è di fornire un approfondimento sulla figura del Moscati scienziato, contestualizzando la sua attività scientifica nell’ambito dei filoni di ricerca biochimica e fisiologica fiorenti all’inizio del XX secolo. Da una più attenta analisi, questa copiosa e articolata produzione scientifica ci appare originale per i contenuti delle ricerche e per il metodo scientifico utilizzato. Pertanto, anche se Moscati non ha prodotto scoperte scientifiche sensazionali e la sua figura di ricercatore è stata raramente citata dalle fonti di storia della medicina, non è azzardato ritenere che la fama del Santo ha paradossalmente offuscato quella dello scienziato, non consentendogli di ricevere i dovuti riconoscimenti.
The evaluation of contracted two-electron integrals over a Gaussian geminal operator is pivotal to diverse quantum chemistry methods. In this article, using the unique factorization properties and the sparsity of these integrals, a novel, near-optimal computation algorithm is presented. Our method employs a combination of recently developed upper
 bounds, recurrence relations in the spirit of the Head-Gordon-Pople approach, and late- and early-contraction paths in the PRISM style. A detailed study of the FLOP (floating-point operations) cost reveals that the new algorithm is computationally much cheaper than any other previous scheme.
Community health assessments (CHAs) are a core function of local health departments (LHDs). Recently, completing a CHA has become a prerequisite for LHDs seeking accreditation by the Public Health Accreditation Board (PHAB). Similarly, under the Affordable Care Act, nonprofit hospitals are required to conduct periodic community health needs assessments (CHNAs). Opportunities thus exist for LHDs and hospitals to jointly complete CHAs/CHNAs.
This study examined existing LHD-hospital collaborations around CHAs/CHNAs, focusing specifically on the relationship between LHDs' level of engagement with PHAB accreditation activities and their collaboration with hospitals around CHAs/CHNAs.
Data came from the 2013 NACCHO (National Association of County & City Health Officials) Profile Study and the Area Health Resource File. Complete data were available for 1332 LHDs that participated in the 2013 NACCHO Profile Study. Logistic regression explored the relationship between LHDs' completion of accreditation prerequisites, in particular completion of a CHA, community health improvement plan, and strategic plan, and their involvement in collaborations with tax-exempt hospitals around CHAs/CHNAs.
LHDs that collaborated with tax-exempt hospitals on CHAs/CHNAs were larger, more likely to be locally governed, and more likely to have a local board of health. Bivariate analysis showed that CHA/CHNA-related collaboration with hospitals was significantly correlated (P < .01) with an LHD's completion of accreditation prerequisites. In multivariate regression analysis, completion of all 3 PHAB accreditation prerequisites significantly increased the odds of LHDs collaborating with hospitals when controlling for other LHD and community-level characteristics.
PHAB accreditation prerequisites together with IRS requirements for hospitals foster potential for collaboration around CHAs/CHNAs. Joint completion of CHAs/CHNAs not only allows partners to complete the assessment more efficiently but has also been shown to produce higher-quality assessments, thus building a strong foundation for continued collaboration to improve community health.
Despite implementation of the Affordable Care Act (ACA), as of 2015, about 25.8 million working-age Americans remained uninsured and vulnerable to premature death because of poor health care access. The ACA-mandated phasing out of disproportionate share hospital payments that supported charity care may aggravate care access for the residual uninsured.
To estimate excess deaths among the uninsured and the potential ACA impact on the basis of a recent cohort's mortality experience. We hypothesized a higher uninsured mortality risk than the available pre-2000 estimate because of worsening of care disparities owing to technology-driven advances in life-saving care.
We conducted a retrospective cohort study of the 1999 to 2002 National Health and Nutrition Examination Survey respondents observed through 2011. We estimated (a) weighted Cox proportional mortality hazard of uninsured working-age adults adjusted for demographics, comorbidity, and lifestyle behaviors, (b) weighted mortality rates among the uninsured and insured within age and comorbidity strata, and (c) excess deaths because of uninsurance using the Institute of Medicine methodology.
Noninstitutionalized US population.
Adults aged 20 to 64 years.
Mortality.
Of 7274 study-eligible respondents, 20.6% were uninsured and 478 died during follow-up, for an adjusted uninsured mortality hazard ratio of 1.57 (95% confidence interval, 1.12-2.21) versus privately insured, translating to 48 529 excess deaths among the population aged 25 to 64 years in 2011 (7.8% of total deaths in this age group). The estimated proportion of excess deaths was 52% higher than the pre-2000 cohort study. The mortality disparity increased with age and comorbidity.
Findings support our hypotheses, and indicate that post-ACA, a residual 4.7% excess mortality among working-age adults will continue, about 30 428 excess deaths annually. Restoration of disproportionate share hospital supports and continued advocacy for universal health care coverage are needed to reduce avoidable deaths.
An important workforce development effort during the past 25 years has been developing competency sets. Several of the sets rely on the concepts of Senge's Learning Organization and Burns' Transformational Leadership. The authors' experiences and study in designing and implementing a curriculum for a public health leadership institute based on these concepts raised several important questions about competency development and application.
To summarize the use of the Senge and Burns frameworks in several competency sets and the practice literature and to assess the status of competency development for those frameworks and for competency development generally.
The authors reviewed several commonly used competency sets and textbooks and searched 3 leading public health practice journals (Journal of Public Health Management and Practice, Public Health Reports, and American Journal of Public Health) for Senge and Burns framework terms. They also reviewed efforts to implement competency sets in public health education and practice.
(1) The extent to which the articles and texts demonstrated understanding of the frameworks and reported their implementation and (2) whether competency statements and their uses in the literature contained precise definitions of competencies (knowledge, skills, behaviors, and attitudes associated with them), the standards by which competence is to be measured, and the means for measuring their attainment.
"Learning Organization" and "Transformational Leadership" terms were used often and viewed favorably. However, the terms were rarely defined as Senge and Burns had, the uses generally did not indicate the complexity and difficulty of implementation, and there was only one report of even partial implementation. The review of competency development efforts found there is virtually no attention to the definitional and measurement issues in the literature.
Unless public health organizations recognize the need for a common understanding of competencies and how to measure their attainment and act on that understanding, it will be impossible to say with confidence that there is agreement on which individuals are competent, whether public health agencies have competent personnel, or that the public health workforce itself is competent.
Kinase enzymes are an important class of drug targets, particularly in cancer. Cell-based kinase assays are needed to understand how potential kinase inhibitors act on their targets in a physiologically relevant context. Current cell-based kinase assays rely on antibody-based detection of endogenous substrates, inaccurate disease models, or indirect measurements of drug action. Here we expand on previous work from our lab to introduce a 96-well plate compatible approach for measuring cell-based kinase activity in disease-relevant human chronic myeloid leukemia cell lines using an exogenously added, multi-functional peptide substrate. Our cellular models natively express the BcrAbl oncogene and are either sensitive or have acquired resistance to well-characterized BcrAbl tyrosine kinase inhibitors. This approach measures IC50 values comparable to established methods of assessing drug potency, and its robustness indicates that it can be employed in drug discovery applications. This medium-throughput assay could bridge the gap between single target focused, high-throughput in vitro assays and lower-throughput cell-based follow-up experiments.
Glucosinolates (GSL) of cruciferous plants comprise a major group of structurally diverse secondary compounds which act as deterrents against aphids and microbial pathogens and have large commercial and ecological impacts. While the transcriptional regulation governing the biosynthesis and modification of GSL is now relatively well understood, post-translational regulatory components that specifically determine the structural variation of indole glucosinolates have not been reported. We show that the cytoplasmic protein phosphatase 2A regulatory subunit B'γ (PP2A-B'γ) physically interacts with indole glucosinolate methyltransferases and controls the methoxylation of indole glucosinolates and the formation of 4-methoxy-indol-3-yl-methyl glucosinolate in Arabidopsis leaves. By taking advantage of proteomic approaches and metabolic analysis we further demonstrate that PP2A-B'γ is required to control the abundance of oligomeric protein complexes functionally linked with the activated methyl cycle and the trans-methylation capacity of leaf cells. These findings highlight the key regulatory role of PP2A-B'γ in methionine metabolism and provide a previously unrecognized perspective for metabolic engineering of glucosinolate metabolism in cruciferous plants.
Epigenetics describes mechanisms which control gene expression and cellular processes without changing the DNA sequence. The main mechanisms in epigenetics are DNA methylation in CpG-rich promoters, histone modifications and non-coding RNAs (ncRNAs). DNA methylation modifies the function of the DNA and correlates with gene silencing. Histone modifications including acetylation/deacetylation and phosphorylation act in diverse biological processes such as transcriptional activation/inactivation and DNA repair. Non-coding RNAs play a large part in epigenetic regulation of gene expression in addition to their roles at the transcriptional and post-transcriptional level. Osteoporosis is the most
 common skeletal disorder, characterized by compromised bone strength and bone micro-architectural deterioration that predisposes the bones to an increased risk of fracture. It is most often caused by an increase in bone resorption that is not sufficiently compensated by a corresponding increase in bone formation. Nowadays it is well accepted that osteoporosis is a multifactorial disorder and there are genetic risk factors for osteoporosis and bone fractures. Here we review emerging evidence that epigenetics contributes to the machinery that can alter DNA structure, gene expression, and cellular differentiation during physiological and pathological bone remodeling.
The incorporation of evidence-based practice (EBP) is widely recognised as a necessary process for entry-level health professional training. Accreditation documents reflect the practice standards of health professions. No previous study has assessed the extent to which EBP has been taken up by chiropractic regulatory/licencing authorities, known as Councils on Chiropractic Education (CCEs), around the world. The purposes of this study were to examine CCEs' educational standards for signs of a positive and negative approach to EBP as indicated by the prevalence and use of the words evidence, research, subluxation and vitalism, and to make recommendations if significant deficiencies were found.
We undertook a systematic audit of the educational standard documents of the various CCEs. CCEs were selected on the basis of the World Health Organisation. Two investigators identified the occurrences of terms explicitly related to EBP: evidence, evidence-based, research, subluxation and vitalism. This information was tabulated for comparative purposes. The date of the study was March 2016.
Occurrences of the term evidence, as it related to EBP, was highest in the CCE-Europe (n = 6), followed by CCE-Australia (n = 2), and CCE-USA (n = 1). None were found in the CCE-International or CCE-Canada documents. The term research appeared most frequently in the CCE-Europe documents (n = 43), followed by CCE-USA (n-32), CCE-Australia (n = 29), CCE-Canada (n = 9) and CCE-International (n = 8). The term subluxation was found only once (CCE-USA) and vitalism did not appear in any educational standard documents.
Accreditation bodies are powerfully positioned to act as a driver for education providers to give greater priority to embedding EBP into entry-level programs and shaping future directions within the profession. Terminology relating explicitly to EBP appears to be lacking in the educational standard documentation of CCEs. Therefore, future revisions of accreditation standards should address lack of terminology.
As a typical microfluidic cell sorting technique, the size-dependent cell sorting has attracted much interest in recent years. In this paper, a size-dependent cell sorting scheme is presented based on a controllable asymmetric pinched flow by employing an immersed boundary-lattice Boltzmann method (IB-LBM). The geometry of channels consists of 2 upstream branches, 1 transitional channel, and 4 downstream branches (D-branches). Simulations are conducted by varying inlet flow ratio, the cell size, and the ratio of flux of outlet 4 to the total flux. It is found that, after being randomly released in one upstream branch, the cells are aligned in a line close to one sidewall of the transitional channel due to the hydrodynamic forces of the asymmetric pinched flow. Cells with different sizes can be fed into different downstream D-branches just by regulating the flux of one D-branch. A principle governing D-branch choice of a cell is obtained, with which a series of numerical cases are performed to sort the cell mixture involving two, three, or four classes of diameters. Results show that, for each case, an adaptive regulating flux can be determined to sort the cell mixture effectively.
In this study, Listeria (L.) monocytogenes isolated from milk and milk products in Kaduna, Nigeria, were subjected to a multiplex PCR assay to identify virulence-associated genes (such as prf A, inl A, hly A, act A, and iap). Of the 36 isolates, 9 (25%) were positive for one or two virulence-associated genes. Based on the sample type, 6 (16.9%) of the isolates that possessed virulence-associated genes were obtained from raw milk, 2 (3.2%) from "Manshanu," and 1 (2.8%) from "Kindrimo." Sequence and phylogenetic analysis based on the 16S rRNA revealed that Nigerian L. monocytogenes isolates (NGA 34A, NGA 35A, NGA 41A, and NGA 38A), when compared with reference L. monocytogenes, were grouped into two distinct clusters, A and B, with sequence (NGA 34A, NGA 35A, and NGA 41A) phylogenetically closer to J1776; N1-011A; R2-502; J1816; and J2-031, whereas L. monocytogenes isolate (NGA 38A) clustered with EDG; J1-220; J1926; J1817; and J2-1091. The separation of the Nigerian L. monocytogenes isolates into linage A (responsible for epidemic listeriosis) and lineage B (responsible for sporadic cases of listeriosis) is of public health concern and that local isolates might have potentials for human food borne listeriosis based on the virulence factors so far identified.
Mononuclear Ru(III) complexes of the type [Ru(LL)Cl2(H2O)] (LL = monobasic tridentate Schiff base anion: (1Z)-N'-(2-{(E)-[1-(2,4-dihydroxyphenyl)ethylidene]amino}ethyl)-N-phenylethanimidamide [DAE], 4-[(1E)-N-{2-[(Z)-(4-hydroxy-3-methoxybenzylidene)amino]ethyl}ethanimidoyl]benzene-1,3-diol [HME], 4-[(1E)-N-{2-[(Z)-(3,4-dimethoxybenzylidene)amino]ethyl}ethanimidoyl]benzene-1,3-diol [MBE], and N-(2-{(E)-[1-(2,4-dihydroxyphenyl)ethylidene]amino}ethyl)benzenecarboximidoyl chloride [DEE]) were synthesized and characterized using the microanalytical, conductivity measurements, electronic spectra, and FTIR spectroscopy. IR spectral studies confirmed that the ligands act as tridentate chelate coordinating the metal ion through the azomethine nitrogen and phenolic oxygen atom. An octahedral geometry has been proposed for all Ru(III)-Schiff base complexes. In vitro anticancer studies of the synthesized complexes against renal cancer cells (TK-10), melanoma cancer cells (UACC-62), and breast cancer cells (MCF-7) was investigated using the Sulforhodamine B assay. [Ru(DAE)Cl2(H2O)] showed the highest activity with IC50 valves of 3.57 ± 1.09, 6.44 ± 0.38, and 9.06 ± 1.18 μM against MCF-7, UACC-62, and TK-10, respectively, order of activity being TK-10 < UACC-62 < MCF-7. The antioxidant activity by DPPH and ABTS inhibition assay was also examined. Scavenging ability of the complexes on DPPH radical can be ranked in the following order: [Ru(DEE)Cl2(H2O)] > [Ru(HME)Cl2(H2O)] > [Ru(DAE)Cl2(H2O)] > [Ru(MBE)Cl2(H2O)].
Ephrin receptors interact with membrane-bound ephrin ligands to regulate contact-mediated attraction or repulsion between opposing cells, thereby influencing tissue morphogenesis. Cell repulsion requires bidirectional trans-endocytosis of clustered Eph-ephrin complexes at cell interfaces, but the mechanisms underlying this process are poorly understood. Here, we identified an actin-regulating pathway allowing ephrinB(+) cells to trans-endocytose EphB receptors from opposing cells. Live imaging revealed Rac-dependent F-actin enrichment at sites of EphB2 internalization, but not during vesicle trafficking. Systematic depletion of Rho family GTPases and their regulatory proteins identified the Rac subfamily and the Rac-specific guanine nucleotide exchange factor Tiam2 as key components of EphB2 trans-endocytosis, a pathway previously implicated in Eph forward signaling, in which ephrins act as in trans ligands of Eph receptors. However, unlike in Eph signaling, this pathway is not required for uptake of soluble ligands in ephrinB(+) cells. We also show that this pathway is required for EphB2-stimulated contact repulsion. These results support the existence of a conserved pathway for EphB trans-endocytosis that removes the physical tether between cells, thereby enabling cell repulsion.
How do people use memories to make inferences about real-world objects? We tested three strategies based on predicted patterns of response times and blood-oxygen-level-dependent (BOLD) responses: one strategy that relies solely on recognition memory, a second that retrieves additional knowledge, and a third, lexicographic (i.e., sequential) strategy, that considers knowledge conditionally on the evidence obtained from recognition memory. We implemented the strategies as computational models within the Adaptive Control of Thought-Rational (ACT-R) cognitive architecture, which allowed us to derive behavioral and neural predictions that we then compared to the results of a functional magnetic resonance imaging (fMRI) study in which participants inferred which of two cities is larger. Overall, versions of the lexicographic strategy, according to which knowledge about many but not all alternatives is searched, provided the best account of the joint patterns of response times and BOLD responses. These results provide insights into the interplay between recognition and additional knowledge in memory, hinting at an adaptive use of these two sources of information in decision making. The results highlight the usefulness of implementing models of decision making within a cognitive architecture to derive predictions on the behavioral and neural level.
Nonribosomal peptide synthetases (NRPSs) produce a wide variety of peptide natural products. During synthesis, the multidomain NRPSs act as an assembly line, passing the growing product from one module to the next. Each module generally consists of an integrated peptidyl carrier protein, an amino acid-loading adenylation domain, and a condensation domain that catalyzes peptide bond formation. Some adenylation domains interact with small partner proteins called MbtH-like proteins (MLPs) that enhance solubility or activity. A
 structure of an MLP bound to an adenylation domain has been previously reported using a truncated adenylation domain, precluding any insight that might be derived from understanding the influence of the MLP on the intact adenylation domain or on the dynamics of the entire NRPS module. Here, we present the structures of the full-length NRPS EntF bound to the MLPs from Escherichia coli and Pseudomonas aeruginosa These new structures, along with biochemical and bioinformatics support, further elaborate the residues that define the MLP-adenylation domain interface. Additionally, the structures highlight the dynamic behavior of NRPS modules, including the module core formed by the adenylation and condensation domains as well as the orientation of the mobile thioesterase domain.
Social capital is a valuable resource that has received little attention in the prison context. Differences in the construct and accessibility of bonding, bridging, and linking social capital exist for Aboriginal Australians in mainstream society, but were previously unexplored in prison. This study seeks to understand contextual differences of social capital for Australian Aboriginal and non-Aboriginal men in prison. Thirty male inmates participated in qualitative interviews across three New South Wales (NSW) correctional centres. Interviews were completed between November 2014 and March 2015. Experiences of bonding and linking social capital varied among Aboriginal and non-Aboriginal participants. Opportunities for bridging social capital were limited for all participants. There is greater scope for building bonding social capital among male inmates than either bridging or linking social capital. Bonding social capital, particularly among Aboriginal men in prison, should be utilised to promote health and other programs to inmates.
The aim of the present study was to construct a cost-effective noninvasive diagnostic index for prediction of hepatic steatosis in patients with hepatitis B virus(HBV) infection. From January 2011 to January 2015, a total of 364 consecutive subjects who underwent liver biopsies were enrolled. The Receiver-operating characteristic(ROC) curves and Obuchowski measure were constructed to evaluate the diagnostic accuracy of the new index. The AUROCs of steatosis index of patients with HBV infection (SIHBV) in predicting of steatosis were 0.929 (95% confidence interval:0.889-0.970, P < 0.05) in the model group and 0.855 (0.794-0.917, P < 0.05) in the validation group respectively. Comparisons of AUROCs demonstrated that SIHBV was significantly superior to Korean Score, fatty liver index (FLI), hepatic steatosis index (HSI), lipid accumulation product(LAP), and fatty liver disease (FLD) index for prediction of hepatic steatosis in model group and validation group(all P < 0.01). Especially for patients with hepatic steatosis percentage of 5.0-9.9% and 10.0-19.9%, SIHBV had a sensitivity of 63.6% and 79.2%, whereas it were 29.1% and 45.8% for Ultrasonography (all P < 0.05). In conclusion, as a cost-effective, simple, noninvasive, and readily available method, SIHBV may act as a massive screening tool before further examinations such as MRI, CT, transient elastography, or liver biopsy, especially for developing countries.
Skeletal tissue growth anomalies (STAs) of corals are capable of causing considerable degradation of reef health. This study is the first report of growth anomalies in Turbinaria corals and the first descriptive study of Indian corals. T. mesenterina colonies at 2 sites were affected by small, round to irregularly shaped growth anomalies. Prevalence of STAs was observed to be higher in T. mesenterina colonies with larger diameters. Prevalence of STAs on T. mesenterina was 71% at Site 1 and 40% at Site 2. Affected colonies were seen to be undergoing tissue damage and infiltration by filamentous algae. We describe the gross morphology of growth anomalies which can act as baseline data for growth anomalies from this region, but further investigation is needed to understand the form and etiology of this coral disease.
Southern right whales Eubalaena australis from Peninsula Valdés, Argentina, show wounds produced by kelp gulls Larus dominicanus that feed on the whales' dorsal skin and blubber. During the 2013 whale season, several calves were reported showing kelp gull injuries with a swollen area surrounded by rhomboid-shaped raised edges. Samples from 9 calves were taken in order to establish the etiology of these rhomboid-shaped wounds; 2 calves (one living, one dead) showed gull-inflicted injuries with rhomboid-shaped edges. Samples from the dead calf were histologically characterized by the presence of dermal congestion, suppurative dermatitis and panniculitis, necrotizing vasculitis and vascular thrombosis. Erysipelothrix rhusiopathiae was detected by culture and PCR in samples from both calves. In this study we report, for the first time to our knowledge, the isolation of E. rhusiopathiae from wounds produced by gull attacks on southern right whale calves, supplying evidence that these wounds may act as an entry route for pathogens. This work provides new information about the consequences of gull-inflicted injuries for whale health.
Plasmodium falciparum uncomplicated malaria can successfully be treated with an artemisinin-based combination therapy (ACT). However resistance is spreading to the different ACT compounds; the artemisinin derivative and the partner drug. Studies of P. falciparum polymorphisms associated with drug resistance can provide a useful tool to track resistance and guide treatment policy as well as an in-depth understanding of the development and spread of resistance.
The role of P. falciparum molecular markers in selection of reinfections was assessed in an efficacy trial comparing artesunate-amodiaquine fixed-dose combination with artemether-lumefantrine to treat malaria in Nimba County, Liberia 2008-2009. P. falciparum polymorphisms in pfcrt 76, pfmdr1 86, 184 and 1246, and pfmrp1 876 and 1466 were analysed by PCR-RFLP and pyrosequencing.
High baseline prevalence of pfmdr1 1246Y was found in Nimba county (38 %). Pfmdr1 1246Y and pfmdr1 86+184+1246 haplotypes NYY and YYY were selected in reinfections in the artesunate-amodiaquine arm and pfcrt K76, pfmdr1 N86 and pfmdr1 haplotype NFD were selected in artemether-lumefantrine reinfections. Parasites harbouring pfmdr1 1246Y could reinfect earlier after treatment with artesunate-amodiaquine and parasites carrying pfmdr1 N86 could reinfect at higher lumefantrine concentrations in patients treated with artemether-lumefantrine.
Although treatment is highly efficacious, selection of molecular markers in reinfections could indicate a decreased sensitivity or tolerance of parasites to the current treatments and the baseline prevalence of molecular markers should be closely monitored. Since individual drug levels and the day of reinfection were demonstrated to be key determinants for selection of reinfections, this data needs to be collected and taken into account for accurate evaluation of molecular markers for anti-malarial treatments. The protocols for the clinical trial was registered with Current Controlled Trials, under the Identifier Number ISRCTN51688713 on 9 October 2008.
Orbital angular momentum (OAM) has been widely studied in fibre and short-range communications. The implementation of millimetre waves with OAM is expected to increase the communication capacity. Most experiments demonstrate the distinction of OAM modes by receiving all of the energy in the surface vertical to the radiation axis in space. However, the reception of OAM is difficult in free space due to the non-zero beam angle and divergence of energy. The reception of OAM in the space domain in a manner similar to that in optical fibres (i.e., receiving all of the energy rings vertical to the radiation axis) is impractical, especially for long-distance transmission. Here, we fabricate a prototype of the antenna and demonstrate that rather than in the space domain, the OAM can be well received in the time domain via a single antenna by rotating the OAM wave at the transmitter, i.e., the radio wave with rotational OAM. The phase and frequency measured in the experiment reveal that for different OAM modes, the received signals act as a commonly used orthogonal frequency division multiplexing (OFDM) signal in the time domain. This phase rotation has promising prospects for use in the practical reception of different OAMs of millimetre waves in long-distance transmission.
After decades of internal discussion, the Government of Jamaica recently amended its laws to create a regulated and licensed cannabis industry for medical and scientific purposes. The new law also decriminalizes personal possession and use of cannabis; allows cannabis to be used by individuals for religious, medical, scientific and therapeutic purposes; and permits home cultivation of up to five plants.
We first describe the statutory changes under the Dangerous Drugs (Amendment) Act of 2015 and compare it with other jurisdictions. We provide an analytical framework for understanding how the DDA Amendment affects key populations and achieves its stated goals, drawing on publicly available information and unstructured interviews with non-governmental stakeholders in Jamaica.
The Amendment's primary goals are to deliver economic impact and reduce criminal justice costs. A relaxed policy of enforcement toward possession and use seems to have occurred even before the law's passage; after the law's passage, enforcement remains limited. To access medical cannabis under the DDA residents must receive authorization from a certified health professional in Jamaica; tourists may self-declare their medical need; and Rastafarians may grow and exchange non-commercially for religious purposes.
Internally, many see "ganja"
 as an industry sorely needed to drive economic growth in Jamaica. Indeed, the potential impacts could be large, especially if Jamaica draws additional tourism or creates a viable export industry. A growing cannabis-related tourism industry seems more realistic. We maintain that policymakers and observers should proceed in an orderly fashion, continuing to identify and resolve remaining uncertainties, initiate new types of data collection, and make decisions based on realistic assessments of potentials for economic impact.
The opportunistic pathogen Staphylococcus aureus expresses transcription factors (TFs) and regulatory small RNAs (sRNAs) which are essential for bacterial adaptation and infectivity. Until recently, the study of S. aureus sRNA gene expression regulation was under investigated, but it is now an expanding field. Here we address the regulation of Srn_3610_SprC sRNA, an attenuator of S. aureus virulence. We demonstrate that SarA TF represses srn_3610_sprC transcription. DNase I footprinting and deletion analyses show that the SarA binding site on srn_3610_sprC belongs to an essential 22 bp DNA region. Comparative analysis also revealed another possible site, this time in the srn_9340 promoter. SarA specifically binds these two sRNA promoters with high affinity in vitro and also represses their transcription in vivo Chromatin immunoprecipitation (ChIP) assays confirmed SarA attachment to both promoters. ChIP and electrophoretic mobility shift assays targeting σ(A) RNA polymerase subunit or using bacterial RNA polymerase holoenzyme suggested that SarA and the σ(A) bind srn_3610_sprC and srn_9340 promoters in a mutually exclusive way. Beyond the mechanistic study of SarA repression of these two sRNAs, this work also suggests that some S. aureus sRNAs belong to the same regulon and act jointly in responding to environmental changes.
The mode of dental antibacterial resin-based materials can be divided into two types, namely, single and combined antibacterial mode. With regard to single antibacterial mode, only one kind of antibacterial agent is added into the resin, which can be released or act as contacting antibacterial agent. The single mode resin has limitation in sterilization methods and effect. As for combined antibacterial mode, it is a combination of different types of biocides and thus maximizes the sterilizing effect, including the releasing antibacterial agent incorporated with the contacting antibacterial agent or antibacterial agents combined with calcium compound possessing biological mineralization function. In this paper, current status and further prospects of dental resin-based materials with antibacterial properties are reviewed from the perspectives of single and combined antibacterial modes to provide guidance for dental antibacterial resin material research.
In ovarian cancer (OC) cells, Snail was reported to induce the epithelial-to-mesenchymal transition (EMT), which is a critical step in OC metastasis. At present little is known about controlling Snail expression in OC cells by using specific microRNAs (miRNAs).
We first used a computational target prediction analysis to identify 6 candidate miRNAs that bind to the 3'-untranslated region (3'-UTR) region of the Snail mRNA. Among these miRNAs, two miRNAs (miR-137 and miR-34a) with a potential to regulate Snail were validated by quantitative real-time PCR, Western blot analysis, and Snail 3'-UTR reporter assays. We assessed the effects of miR-137 and miR-34a on EMT, invasion and sphere formation in OC cells. We also evaluated the expression of miR-137 and miR-34a in OC tissues and adjacent normal tissues and analyzed the relationship between their expression and patient survival.
We report that OC tissues possess significantly decreased levels of miR-137 and miR-34a and increased expression of Snail when compared to their adjacent normal tissues, and lower miR-137 and miR-34a expression correlates with worse patient survival. Using luciferase constructs containing the 3'-UTR region of Snail mRNA combined with miRNA overexpression and mutagenesis, we identified miR-137 and miR-34a as direct suppressors of Snail in OC cells. The introduction of miR-137 and miR-34a resulted in the suppression of Snail at both the transcript and protein levels, and effectively suppressed the EMT phenotype and sphere formation of OC cells. However, the inhibition of miR-137 and miR-34a with antisense oligonucleotides promoted EMT and OC cell invasion. Moreover, ectopic expression of Snail significantly reversed the inhibitory effects of miR-137 and miR-34a on OC cell invasion and sphere formation.
These findings suggest that both miR-137 and miR-34a act as Snail suppressors to negatively regulate EMT, invasive and sphere-forming properties of OC cells.
Implementation of intersectoral community approaches often fails due to a translational gap between the approach as intended and the approach as implemented in practice. Knowledge about the implementation determinants of such approaches is needed to facilitate future implementation processes.
The implementation of five EPODE-derived intersectoral community approaches was studied longitudinally. Semi-structured interviews were held with 189 community stakeholders from four sectors to elucidate which determinants influenced implementation, and if an to which extent determinants differed across communities, sectors and over time. A framework approach was used to analyze our data.
Twenty-two key determinants of implementation were identified. Facilitators named were mostly proximal (stakeholder level), and barriers were mostly distal (context level). Key determinants varied greatly across sectors and over time, especially between the educational & health care sector and the private, welfare & sports sector. Only 'perceived importance of IACO goals' was identified as an universal implementation facilitator.
Striking differences in determinants were found across sectors and over time. Also, stakeholders expressed that possibilities to adapt the approach to the local context were needed to improve implementation. We therefore propose to develop sector- and time specific leads for implementation, which should be approved and amended (over time) by stakeholders. This so-called 'mutual adaptation' allows for the use of both scientific insights and practice-based knowledge, enabling program management and community stakeholders to collaboratively improve their implementation efforts.
Adipose-derived stem cells (ADSCs) are multipotent cells that have attracted much recent attention and emerged as therapeutic approaches in several medical fields. Although current knowledge of the biological impacts of ADSCs in cancer research is greatly improved, the underlying effects of ADSCs in tumor development remain controversial and cause the safety concerns in clinical utilization. Hence, we isolated primary ADSCs from the abdominal fat of mice and conducted interaction of ADSCs with Lewis lung carcinoma cells in culture and in mice to investigate the impacts of ADSCs on tumor development. Cytokine array and neutralizing antibody were further utilized to identify the key regulator and downstream signaling pathway. In this study, we demonstrated that ADSCs enhance the malignant characteristics of LLC1 cells, including cell growth ability and especially cancer stem cell property. ADSCs were then identified to promote tumor formation and growth in mice. We further determined that ADSC interaction with LLC1 cells stimulates increased secretion of interleukin-6 mainly from ADSCs, which then act in a paracrine manner on LLC1 cells to enhance their malignant characteristics. Interleukin-6 was also identified to regulate genes related to cell proliferation and cancer stem cell, as well as to activate JAK2/STAT3, a predominant interleukin-6-activated pathway, in LLC1 cells. Collectively, we demonstrated that ADSCs play a pro-malignant role in tumor development of Lewis lung carcinoma cells by particularly promoting cancer stem cell property through interleukin-6 paracrine circuit, which is important for safety considerations regarding the clinical application of ADSCs.
Species in the cycad genus Encephalartos are listed in CITES Appendix I and as Threatened or Protected Species in terms of South Africa's National Environmental Management: Biodiversity Act (NEM:BA) of 2004. Despite regulations, illegal plant harvesting for medicinal trade has continued in South Africa and resulted in declines in cycad populations and even complete loss of sub-populations. Encephalartos is traded at traditional medicine markets in South Africa in the form of bark strips and stem sections; thus, determining the species traded presents a major challenge due to a lack of characteristic plant parts. Here, a case study is presented on the use of DNA barcoding to identify cycads sold at the Faraday and Warwick traditional medicine markets in Johannesburg and Durban, respectively. Market samples were sequenced for the core DNA barcodes (rbcLa and matK) as well as two additional regions: nrITS and trnH-psbA. The barcoding database for cycads at the University of Johannesburg was utilized to assign query samples to known species. Three approaches were followed: tree-based, similarity-based, and character-based (BRONX) methods. Market samples identified were Encephalartos ferox (Near Threatened), Encephalartos lebomboensis (Endangered), Encephalartos natalensis (Near Threatened), Encephalartos senticosus (Vulnerable), and Encephalartos villosus (Least Concern). Results from this study are crucial for making appropriate assessments and decisions on how to manage these markets.
Office workers spend a large proportion of their working hours sitting. This may contribute to an increased risk of chronic disease and premature mortality. While there is growing interest
 in workplace interventions targeting prolonged sitting, few qualitative studies have explored workers' perceptions of reducing occupational sitting outside of an intervention context. This study explored barriers to reducing office workplace sitting, and the feasibility and acceptability of strategies targeting prolonged sitting in this context.
Semi-structured interviews were conducted with a convenience sample of 20 office workers (50 % women), including employees and managers, in Melbourne, Australia. The three organisations (two large, and one small organisation) were from retail, health and IT industries and had not implemented any formalised approaches to sitting reduction. Questions covered barriers to reducing sitting, the feasibility of potential strategies aimed at reducing sitting, and perceived effects on productivity. Interviews were audiotaped and transcribed verbatim. Data were analysed using thematic analysis.
Participants reported spending most (median: 7.2 h) of their working hours sitting. The nature of computer-based work and exposure to furniture designed for a seated posture were considered to be the main factors influencing sitting time. Low cost strategies, such as standing meetings and in-person communication, were identified as feasible ways to reduce sitting time and were also perceived to have potential productivity benefits. However, social norms around appropriate workplace behaviour and workload pressures were perceived to be barriers to uptake of these strategies. The cost implications of height-adjustable workstations influenced perceptions of feasibility. Managers noted the need for an evidence-based business case supporting action on prolonged sitting, particularly in the context of limited resources and competing workplace health priorities.
While a number of low-cost approaches to reduce workplace sitting are perceived to be feasible and acceptable in the office workplace, factors such as work demands and the organisational social context may still act as barriers to greater uptake. Building a supportive organisational culture and raising awareness of the adverse health effects of prolonged sitting may be important for improving individual-level and organisational-level motivation for change.
Triadin isoforms, splice variants of one gene, maintain healthy Ca(2+) homeostasis in skeletal muscle by subserving several functions including an influence on Ca(2+) release through the ligand-gated ryanodine receptor (RyR1) ion channels. The predominant triadin isoform in skeletal muscle, Trisk 95, activates RyR1 in vitro via binding to previously unidentified amino acids between residues 200 and 232. Here, we identify three amino acids that influence Trisk 95 binding to RyR1 and ion channel activation, using peptides encompassing residues 200-232. Selective alanine substitutions show that K(218), K(220), and K(224) together facilitate normal Trisk 95 binding to RyR1 and channel activation. Neither RyR1 binding nor activation are altered by alanine substitution of K(220) alone or of K(218) and K(224). Therefore K(218), K(220), and K(224) contribute to a robust binding and activation site that is disrupted only when the charge on all three residues is neutralized. We suggest that charged pair interactions between acidic RyR1 residues D(4878), D(4907), and E(4908) and Trisk 95 residues K(218), K(220), and K(224) facilitate Trisk 95 binding to RyR1 and channel activation. Since K(218), K(220), and K(224) are also required for CSQ binding to RyRs (Kobayashi et al. 17, J Biol Chem 275, 17639-17646), the results suggest that Trisk 95 may not simultaneously bind to RyR1 and CSQ, contrary to the widely held belief that triadin monomers form a quaternary complex with junctin, CSQ and RyR1. Therefore, the in vivo role of triadin monomers in modulating RyR1 activity is likely unrelated to CSQ.
RNAi is broadly used as a technique for specific gene silencing in insects but few studies have investigated the factors that can affect its efficiency. Viral infections have the potential to interfere with RNAi through their production of viral suppressors of RNAi (VSRs) and the production of viral small RNAs that can saturate and inactivate the RNAi machinery. In this study, the impact of persistent infection of the RNA viruses Flock house virus (FHV) and Macula-like virus (MLV) on RNAi efficiency was investigated in selected lepidopteran cell lines. Lepidopteran cell lines were found to be readily infected by both viruses without any apparent pathogenic effects, with the exception of Bombyx-derived Bm5 and BmN4 cells, which could not be infected by FHV. Because Sf21 cells were free from both FHV and MLV and Hi5-SF were free from FHV and only contained low levels of MLV, they were tested to evaluate the impact of the presence of the virus. Two types of RNAi reporter assays however did not detect a significant interference with gene silencing in infected Sf21 and Hi5-SF cells when compared to virus-free cells. In Hi5 cells, the presence of FHV could be easily cleared through the expression of an RNA hairpin that targets its VSR gene, confirming that the RNAi mechanism was not inhibited. Sequencing indicated that the B2 RNAi inhibitor gene of FHV and a putative VSR gene from MLV were intact in persistently infected cell lines, indicating that protection against RNAi remains essential for virus survival. It is proposed that infection levels of persistent viruses in the cell lines are too low to have an impact on RNAi efficiency in the lepidopteran cell lines and that encoded VSRs act locally at the sites of viral replication (mitochondrial membranes) without affecting the rest of the cytoplasm.
Asthma affects a large number of patients in China, but relatively little is known about asthma management among Chinese patients. This study aims to estimate asthma control rate among adult Chinese patients and to identify predictors associated with uncontrolled asthma.
A total of 4125 asthma patients aged ⩾17 years and representing all regions of mainland China except Tibet were surveyed. Asthma control status was assessed using the Asthma Control Test (ACT) and classified as controlled (ACT score ⩾ 20) and uncontrolled (ACT score ⩽ 19). A multivariate logistic regression model was used to identify predictors associated with uncontrolled asthma from the factors including demographics, rhinitis, allergic rhinitis, and treatment adherence.
Asthma was controlled in 44.9%, and uncontrolled in 55.1% of the study participants. High rates of uncontrolled asthma were found in patients with treatment nonadherence (77.3%), poor adherence (66.2%), no schooling (64.8%), or obesity (62.9%). The risk of uncontrolled asthma was much higher in the treatment nonadherence group than the complete adherence group [odds ratio (OR) = 4.55 (3.68-5.62), p < 0.001]. Other predictors for uncontrolled asthma included concomitant rhinitis [OR = 1.31 (1.14-1.50), p < 0.001], obesity [OR = 1.31 (1.05-1.64), p = 0.019], asthma duration > 3 years [OR = 1.22 (1.07-1.39), p = 0.004] and age ⩾ 45 years [OR = 1.23 (1.07-1.41), p = 0.004].
About half of the participants in this study had uncontrolled asthma. Treatment nonadherence is one of the significant predictors, which is very strongly associated with uncontrolled asthma. Efforts should be prioritized to promote patients' treatment adherence to improve asthma control while attention is needed on rhinitis or obesity.
There are indications that low S-25(OH)D is associated with increased disease severity in psychotic disorder. Our first aim was to investigate the relations between low S-25(OH)D and positive, negative and depressive symptoms. Our second aim was to explore if associations between S-25(OH)D and symptoms were influenced by levels of inflammatory markers.
Participants (N=358) with a medical history of one or more psychotic episodes were recruited. Current symptomatology was assessed by The Structured Interview for the Positive and Negative Syndrome Scaleanalyzed by a five-factor model. The Calgary Depression Scale for Schizophrenia was used to assess depression and suicidal ideation. Blood samples were analyzed for S-25(OH)D, CRP, sTNF-R1, IL-Ra and OPG. We performed bivariate correlations and multiple regression models to evaluate the effect of S-25(OH)D on the outcomes.
Low S-25(OH)D was significantly associated with negative symptoms (adjusted R(2)=0.113, F(6,357)=8.58, p<0.001) and with depression (adjusted R(2)=0.045, F(4,357)=5.233, p<0.001) when adjusting for possible confounding factors (i.e. gender, education, diagnose, hospitalization status, ethnicity, season and thyroid status). CRP was correlated with both S-25(OH)D (rho=-0.13, p=0.02) and negative symptoms (rho=0.14, p=0.01), but did not act as a mediator. The correlations between S-25(OH)D and the inflammatory markers sTNF-R1, IL-Ra and OPG were not significant.
There is a strong association between low S-25(OH)D and higher negative and depressive symptoms in psychotic disorders. Randomized controlled trials should be performed to investigate the effect of vitamin D supplementation as adjuvant treatment strategy in patients with prominent negative or depressive symptoms.
We have developed peptides that are able to distinguish between subgroups of polyclonal antibodies. These β-hairpin peptides act as conformational epitopes with specific shape and flexibility; they have been analyzed by NMR and CD spectroscopy, and have been shown to identify known disease markers. As a standalone mini β-sheet, a hairpin is stabilized by alternating pairs of hydrogen-bonded and non-bonded amino acids on its two opposing peptide strands. A single d mutation disrupts this secondary structure, the correlated double-d mutation of two opposing amino acids compensates for this destabilizing effect. The designed kink was introduced into both hydrogen-bonded
 and -non-bonded positions of an all-l hairpin that is a known conformational epitope in molecular recognition. Our peptides enabled the discrimination of different human rheumatoid arthritis autoantibodies in an ELISA assay.
Before pandemic H1N1 vaccines were available, the potential benefit of existing seasonal trivalent inactivated influenza vaccines (IIV3s) against influenza due to the 2009 pandemic H1N1 influenza strain was investigated, with conflicting results. This study assessed the efficacy of seasonal IIV3s against influenza due to 2008 and 2009 seasonal influenza strains and against the 2009 pandemic H1N1 strain.
This observer-blind, randomized, placebo-controlled study enrolled adults aged 18-64years during 2008 and 2009 in Australia and New Zealand. Participants were randomized 2:1 to receive IIV3 or placebo. The primary objective was to demonstrate the efficacy of IIV3 against laboratory-confirmed influenza. Participants reporting an influenza-like illness during the period from 14days after vaccination until 30 November of each study year were tested for influenza by real-time reverse transcription polymerase chain reaction.
Over a study period of 2years, 15,044 participants were enrolled (mean age±standard deviation: 35.5±14.7years; 54.4% female). Vaccine efficacy of the 2008 and 2009 IIV3s against influenza due to any strain was 42% (95% confidence interval [CI]: 30%, 52%), whereas vaccine efficacy against influenza due to the vaccine-matched strains was 60% (95% CI: 44%, 72%). Vaccine efficacy of the 2009 IIV3 against influenza due to the 2009 pandemic H1N1 strain was 38% (95% CI: 19%, 53%). No vaccine-related deaths or serious adverse events were reported. Solicited local and systemic adverse events were more frequent in IIV3 recipients than placebo recipients (local: IIV3 74.6% vs placebo 20.4%, p<0.001; systemic: IIV3 46.6% vs placebo 39.1%, p<0.001).
The 2008 and 2009 IIV3s were efficacious against influenza due to seasonal influenza strains and the 2009 IIV3 demonstrated moderate efficacy against influenza due to the 2009 pandemic H1N1 strain. Funded by CSL Limited, ClinicalTrials.gov identifier NCT00562484.
Women from disadvantaged socio-economic groups access assisted reproductive technology treatment less than women from more advantaged groups. However, women from disadvantaged groups tend to start families younger, making them less likely to suffer from age-related subfertility and potentially have less need for fertility treatment. Whether socio-economic disparities in access to assisted reproductive technology treatment persist after controlling for the need for treatment, has not been previously explored. This population based study demonstrates that socio-economic disparities in access to assisted reproductive technology treatment persist after adjusting for several confounding factors, including age at first birth (used as a measure of delayed childbearing, hence a proxy for need for fertility treatment), geographic remoteness and Australian jurisdiction. Assisted reproductive technology access progressively decreased as socio-economic quintiles became more disadvantaged, with a 15.8% decrease in access in the most disadvantaged quintile compared with the most advantaged quintile after controlling for confounding factors. The adjusted rate of access to assisted reproductive technology treatment also decreased by 12.3% for women living in regional and remote areas compared with those in major cities. These findings indicate that financial and sociocultural barriers to assisted reproductive technology treatment remain in disadvantaged groups after adjusting for need.
Adherence with asthma medications is less than optimal, measuring approximately 30-50%. Several factors have been shown to contribute to medication non-adherence including low-socioeconomic status, low literacy, medication cost, access to care, and language barriers. Community Health Clinic Ole has attempted to reduce medication adherence barriers associated with cost, access to care, and language by 1) allowing medications to be obtained from the clinic at a reduced cost via the 340B drug pricing program and patient assistance programs, and 2) providing one-on-one consultations from bilingual Spanish-speaking clinicians. Limited evidence is available regarding chronic disease-state medication adherence among Spanish-speaking individuals presenting to a Federally Qualified Health Center (FQHC).
The purpose of this study is to assess asthma medication adherence and determine predictors of non-adherence in the underserved population at an FQHC.
Adult patients with a diagnosis of persistent asthma receiving medication refills from clinic between October 1, 2011 and October 31, 2012 were identified (N = 121). Individuals with intermittent or seasonal asthma only, exercise-induced asthma only, or mixed asthma/COPD; individuals who have not picked up at least one fill of inhaled corticosteroid in the past one-year; and individuals without active prescriptions for asthma controller medications were excluded. Medication adherence was assessed by using the medication possession ratio (MPR) for asthma controller medications (e.g. inhaled corticosteroids, long-acting beta-2 agonists, leukotriene modifiers, and theophylline). Patients were categorized into two adherence groups: medium-high (MPR ≥ 0.5) and low (MPR < 0.5).
Approximately one-third of individuals were identified with medium-high adherence to asthma medications, of which only 8.3% of individuals were found to be fully adherent (MPR ≥ 0.8). The majority of individuals (66.1%) were identified with low adherence, despite efforts to reduce medication adherence barriers associated with drug cost, access to care, and language. Patients with low adherence were younger (39.3 vs. 45.4 yo; P < 0.012), had fewer medication refills (2.1 vs. 5.3; P < 0.001), had fewer primary care provider (PCP) visits (3.4 vs. 5.0; P < 0.05), lower baseline Asthma Control Test (ACT) scores (13.1 vs. 17.3; P < 0.001), and lower asthma medication ratios (AMR) (0.7 vs. 0.9; P < 0.001) than patients with medium-high adherence. No significant differences in MPR rates were found between Hispanics and non-Hispanics. The average MPR in both groups was 0.55.
Our findings demonstrate that asthma medication adherence remains poor among all underserved patients despite improved access to care via reduced medication pricing and the provision of Spanish-speaking medication consultations at refill pick-ups. Poor adherence rates remained common among both the Non-Hispanic and Hispanic, younger, and lower-socioeconomic patients in our study. Future studies may wish to explore whether providing a service that encompasses healthcare team support, optimal medication counseling, and utilization of patient-centered communication strategies improves asthma medication adherence in the Hispanic population.
The use of selective serotonin-reuptake inhibitors (SSRIs) has been associated with an increased risk of bone fracture, raising concerns about their increasingly broader usage. This deleterious effect is poorly understood, and thus strategies to avoid this side effect remain elusive. We show here that fluoxetine (Flx), one of the most-prescribed SSRIs, acts on bone remodeling through two distinct mechanisms. Peripherally, Flx has anti-resorptive properties, directly impairing osteoclast differentiation and function through a serotonin-reuptake-independent mechanism that is dependent on intracellular Ca(2+) levels and the transcription factor Nfatc1. With time, however, Flx also triggers a brain-serotonin-dependent rise in sympathetic output that increases bone resorption sufficiently to counteract its local anti-resorptive effect, thus leading to a net effect of impaired bone formation and bone loss. Accordingly, neutralizing this second mode of action through co-treatment with the β-blocker propranolol, while leaving the peripheral effect intact, prevents Flx-induced bone loss in mice. Hence, this study identifies a dual mode of action of SSRIs on bone remodeling and suggests a therapeutic strategy to block the deleterious effect on bone homeostasis from their chronic use.
Oxidation of glucose is the major source of obtaining cell energy, this process requires glucose transport into the cell. However, cell membranes are not permeable to polar molecules such as glucose; therefore its internalization is accomplished by transporter proteins coupled to the cell membrane. In eukaryotic cells, there are two types of carriers coupled to the membrane: 1) cotransporter Na+-glucose (SGLT) where Na+ ion provides motive power for the glucose´s internalization, and 2) the glucotransporters (GLUT) act by facilitated diffusion. This review will focus on the 14 GLUT so far described. Despite the structural homology of GLUT, different genetic alterations of each GLUT cause specific clinical entities. Therefore, the aim of this review is to gather the molecular and biochemical available information of each GLUT as well as the particular syndromes and pathologies related with GLUT´s alterations and their clinical approaches.
Redox balance is associated with the regulation of several cell signalling pathways and functions. In fact, under physiological conditions, cells maintain a balance between oxidant and antioxidant systems, and reactive oxygen species (ROS) can act as second messengers to regulate cell proliferation, cell death, and other physiological processes. Cancer tissues usually contain higher levels of ROS than normal tissues, and this ROS overproduction is associated with tumor development. Neoplastic tissues are very heterogeneous systems, composed of tumor cells and microenvironment that has a critical role in tumor progression. Cancer associated fibroblasts (CAFs) represent the main cell type of tumor microenvironment, and
 they contribute to tumor growth by undergoing an irreversible activation process. It is known that ROS can be transferred from cancer cells to fibroblasts. In particular, ROS affect the behaviour of CAFs by promoting the conversion of fibroblasts to myofibroblasts that support tumor progression and dissemination. Furthermore, the wrecking of redox homeostasis in cancer cells and tumor microenvironment induces a metabolic reprogramming in tumor cells and cancer associated fibroblasts, giving advantage to cancer growth. This review describes the role of ROS in tumor growth, by focusing on CAFs activation and metabolic interactions between cancer cells and stromal fibroblasts.
Osteoporosis is a common musculoskeletal disease of the elderly population characterized by decreased bone mineral density and subsequent fractures. Bisphosphonates are a widely accepted drug therapy which act through inhibition of bone resorption and prevent fractures. However, in long-term use, atypical bisphosphonate induced fractures may occur, particularly involving the lower weight bearing extremity. Atypical ulna fracture associated with long-term bisphosphonate use is rarely reported in current literature. We present a 62-year-old woman with atypical ulna due to long-term alendronate therapy without a history of trauma or fall. Clinicians should be aware of stress fracture in a patient who has complaints of upper extremity pain and history of long-term bisphosphonate therapy.
Background. Tuberculosis of the liver without active pulmonary or miliary tuberculosis is considered as an uncommon diagnosis. The aim of the present study was to determine the etiological role of tuberculosis in adult patients presenting with features of liver abscess. Methods. A total of 40 patients with liver abscess were included in the study. The liver abscess aspirate was subjected to microscopy, culture, and polymerase chain reaction to determine the role of tuberculosis as an etiological factor in liver abscess. Results. Of the 40 patients enrolled, 25% (10/40) were diagnosed with having tubercular liver abscess. In a total of 40 specimens, 2.5% (1/40) were positive for acid fast bacilli by Ziehl-Neelsen method, while 10% (4/40) were positive for M. tuberculosis by culture using BACTEC 460 and the yield increased to 25% (10/40) by polymerase chain reaction for M. tuberculosis. Conclusion. 25% of the patients presenting with liver abscess had tubercular etiology without features of active pulmonary or miliary tuberculosis. Liver can act as the primary site of involvement in the absence of activity elsewhere in the body. Tuberculosis should be considered as an important differential diagnosis of liver abscess irrespective of evidence of active tuberculosis elsewhere in the body.
Antisense non-coding RNA in the INK4 locus (ANRIL) fixed genetic variants have consistently been linked with coronary heart disease (CHD) risk. We investigated relationships between perinatal ANRIL promoter DNA methylation and CHD risk markers in children aged 9 years. Genetic variants in the non-coding RNA ANRIL identify it as an important CHD risk locus. Increasing evidence suggests that the early life environment may act through epigenetic processes to influence later CHD risk markers such as increased arterial pulse wave velocity (PWV, a measure of arterial stiffness) blood pressure or heart rate.
Using pyrosequencing, ANRIL DNA methylation at nine CpG sites was measured in the umbilical cord from 144 children in a UK mother-offspring cohort and related to the descending aorta PWV measured by velocity-encoded phase contrast MRI at age 9 years. Perinatal methylation was not associated with child's later blood pressure, but higher methylation at CpG5 was associated with increased childhood PWV (β = 0.066 m/s/10 % methylation increase [95 % CI, 0.004 to 0.128], p = 0.037); 10 % decreases in methylation at CpG1 and CpG2 were associated with increased heart rate (CpG1 β = 1.93 [0.07 to 3.8] beats/min, p = 0.041; CpG2 β = 2.30 [0.18 to 4.41] beats/min, p = 0.033, accounting for potential confounding variables). The associations with perinatal ANRIL promoter methylation were independent of neighbouring fixed genetic variants.
Our findings suggest developmental epigenetic regulation of ANRIL promoter methylation as a factor in later CHD risk in children.
Emerging wildlife pathogens are an increasing threat to biodiversity. One of the most serious wildlife diseases is chytridiomycosis, caused by the fungal pathogen, Batrachochytrium dendrobatidis (Bd), which has been documented in over 500 amphibian species. Amphibians vary greatly in their susceptibility to Bd; some species tolerate infection, whereas others experience rapid mortality. Reservoir hosts-species that carry infection while maintaining high abundance but are rarely killed by disease-can increase extinction risk in highly susceptible, sympatric species. However, whether reservoir hosts amplify Bd in declining amphibian species has not been examined. We investigated the role of reservoir hosts in the decline of the threatened northern corroboree frog (Pseudophryne pengilleyi) in an amphibian community in southeastern Australia. In the laboratory, we characterized the response of a potential reservoir host, the (nondeclining) common eastern froglet (Crinia signifera), to Bd infection. In the field, we conducted frog abundance surveys and Bd sampling for both P. pengilleyi and C. signifera. We built multinomial logistic regression models to test whether Crinia signifera and environmental factors were associated with P. pengilleyi decline. C. signifera was a reservoir host for Bd. In the laboratory, many individuals maintained intense infections (>1000 zoospore equivalents) over 12 weeks without mortality, and 79% of individuals sampled in the wild also carried infections. The presence of C. signifera at a site was strongly associated with increased Bd prevalence in sympatric P. pengilleyi. Consistent with disease amplification by a reservoir host, P. pengilleyi declined at sites with high C. signifera abundance. Our results suggest that when reservoir hosts are present, population declines of susceptible species may continue long after the initial emergence of Bd, highlighting an urgent need to assess extinction risk in remnant populations of other declined amphibian species.
The need for twisting wires is an integral aspect of maxillofacial surgery. The act of using the commonly available wire twister exposes the operating surgeon as well as the patient to injury by the sharp edges of wire turning around. Pencil wire twister is advantageous in being safer for both the patient as well as the surgeon. In this paper, the authors discuss the feasibility of wider use of this immensely useful instrument.
A series of N,N-dimethylcarbamates containing a N,N-dibenzylamino moiety was synthesized and tested to evaluate their ability to inhibit Acetylcholinesterase (AChE). The most active compounds 4 and 8, showed 85 and 69% of inhibition at 50 μM, respectively. Furthermore, some basic SAR rules were outlined: an alkyl linker of six methylene units is the best spacer between the carbamoyl and dibenzylamino moieties; electron-withdrawal substituents on aromatics rings of the dibenzylamino group reduce the inhibitory power. Compound 4 produces a slow onset inhibition of AChE and this is not due to the carbamoylation of the enzyme, as demonstrated by the time-dependent inhibition assay of AChE with compound 4 and by MALDI-TOF MS analysis of trypsinized AChE inhibited by compound 4. Instead, compound 4 could act as a slow-binding inhibitor of AChE, probably because of its high conformational freedom due to the linear alkyl chain.
DNA-binding compounds are of extraordinary importance in medicine, accounting for a substantial portion of antitumor drugs in clinical usage. However, their mechanisms of action remain sometimes incompletely understood. This review critically examines two broad classes of molecules that bind noncovalently to DNA: intercalators and groove binders. Intercalators bind to DNA by inserting their chromophore moiety between two consecutive base pairs, whereas groove binders fit into the grooves of DNA. Noncovalent DNA-interactive drugs can recognize certain supramolecular DNA structures such as the G-quadruplexes found in telomeres and in numerous gene promoters, and they can act as topoisomerase I and II poisons. We discuss how DNA-binding compounds affect transcription and compete with protein factors for binding to consensus binding sites in gene promoters both in vitro and in cultured cancer cells. Moreover, we comment on the design of molecules that can tightly and specifically bind to any desired target DNA, such as various hairpin polyamides which efficacy as chemotherapeutic agents is being evaluated. At present, genome-wide studies, which provide details of events that may influence both cancer progression and therapeutic outcome, are a common way used to analyze the effects of DNA-binding compounds. A conclusive feature that emerges from reviewing the information on DNA-binding compounds is that both natural sources and chemical approaches can be productively used to obtain drugs to manipulate gene expression in cancer cells.
Much has been written on the successful lesbian, gay, bisexual, transgender, and intersex movement in South Africa, and the resulting institutionalization of sexual minority rights. Comparatively less has been written about the forms of activism undertaken specifically by Black lesbians that are not oriented toward legal change. In this article, I assert the need to examine public demonstrations of mourning as an act of Black lesbian resistance to violence in South Africa. Based on in-depth interviews with members of Free Gender, a Black lesbian organization, I argue that members' conceptualizations
 of mourning as providing community support force a reconsideration of what it means to be human. In order to grasp the decolonial potential of Free Gender's activism, I draw on Sylvia Wynter's argument that a singular Western bourgeois conception of human has come to dominate globally.
Iron oxide nanoparticles are one of the most promising types of nanoparticles for biomedical applications, primarily in the context of nanomedicine-based diagnostics and therapy; hence, great attention should be paid to their bio-safety. Here, we investigate the ability of surface-modified magnetite nanoparticles (MNPs) to produce chromosome damage in human alveolar A549 cells. Compared to control cells, all the applied MNPs increased the level of micronuclei moderately but did not cause structural chromosomal aberrations in exposed cells. A rise in endoreplication, polyploid and multinuclear cells along with disruption of tubulin filaments, downregulation of Aurora protein kinases and p53 protein activation indicated the capacity of these MNPs to impair the chromosomal passenger complex and/or centrosome maturation. We suppose that surface-modified MNPs may act as aneugen-like spindle poisons via interference with tubulin polymerization. Further studies on experimental animals revealing mechanisms of therapeutic-aimed MNPs are required to confirm their suitability as potential anti-cancer drugs.
The extracellular matrix is produced by the resident cells in tissues and organs, and secreted into the surrounding medium to provide biophysical and biochemical support to surrounding cells due to its containing of diverse bioactive molecules. Recently, the extracellular matrix has been used as a promising approach for tissue engineering. Emerging studies demonstrate that extracellular matrix scaffolds are able to create a favorable regenerative microenvironment, promote tissue-specific remodeling, and act as an inductive template for the repair and functional reconstruction of skin, bone, nerve, heart, lung, liver, kidney, small intestine, and other organs. In the current review, we will provide a critical overview of the structure and function of various types of extracellular matrix, the construction of three-dimensional extracellular matrix scaffolds, and their tissue engineering applications, with a focus on translation of these novel tissue engineered products to the clinic. We will also present an outlook on future perspectives of the extracellular matrix in tissue engineering and regenerative medicine.
The purpose of this study was to explore the use of iterative decomposition of water and fat with echo asymmetry and least-squares estimation Carr-Purcell-Meiboom-Gill (IDEAL-CPMG) to simultaneously measure skeletal muscle apparent fat fraction and water T2 (T2,w) in patients with Duchenne muscular dystrophy (DMD). In twenty healthy volunteer boys and thirteen subjects with DMD, thigh muscle apparent fat fraction was measured by Dixon and IDEAL-CPMG, with the IDEAL-CPMG also providing T2,w as a measure of muscle inflammatory activity. A subset of subjects with DMD was followed up during a 48-week clinical study. The study was in compliance with the Patient Privacy Act and approved by the Institutional Review Board. Apparent fat fraction in the thigh muscles of subjects with DMD was significantly increased compared to healthy volunteer boys (p <0.001). There was a strong correlation between Dixon and IDEAL-CPMG apparent fat fraction. Muscle T2,w measured by IDEAL-CPMG was independent of changes in apparent fat fraction. Muscle T2,w was higher in the biceps femoris and vastus lateralis muscles of subjects with DMD (p <0.05). There was a strong correlation (p <0.004) between apparent fat fraction in all thigh muscles and six-minute walk distance (6MWD) in subjects with DMD. IDEAL-CPMG allowed independent and simultaneous quantification of skeletal muscle fatty degeneration and disease activity in DMD. IDEAL-CPMG apparent fat fraction and T2,w may be useful as biomarkers in clinical trials of DMD as the technique disentangles two competing biological processes.
Drowning is a leading cause of death among infants and toddlers. Unique physiological and behavioural factors contribute to high mortality rates. Drowning incidents predominantly occur during warmer months and holidays. Recent studies link high socio-economic status and drowning, in contrast to earlier studies. Cardiac arrhythmias, epilepsy and autism are strong risk factors for drowning incidents. Prevention strategies have substantially lowered drowning rates. While legislation-compliant pool fencing substantially reduces drowning risk, compliance levels are low, and penalties are minor. Active supervision education for parents and carers is an effective drowning prevention strategy. Bystanders provide basic life support in only 30% of cases; strategies to increase training uptake are needed. Fencing costs should be a mandatory inclusion for pool installations, with high penalties for non-compliance. Basic life support training should be compulsory for pool owners, and tax incentives should be used as a lever to increase training uptake.
We set students' learning goal of basic life support (BLS) education at "being able to describe all the steps of BLS in an appropriate order", and objectively analyzed the appropriateness of the learning goal we set and educational effects of lecture contents. Before delivering a lecture, we provided students with an assignment which asked them to "Describe the steps of BLS in an appropriate order", and investigated students' levels of acquiring knowledge on BLS. As the results, the majority of students failed to perform this assignment. Since many students did not understand the process of BLS correctly, the learning goal was considered appropriate in the sense of promoting students' understanding of BLS. We also investigated whether the contents of BLS education was effective to achieve the learning goal. We provided students with the same assignment after the lecture, and the results showed that most students successfully performed the assignment. Furthermore, the time required for students to recall the whole process of BLS was significantly reduced after receiving the lecture, showing that the BLS lecture was effective in improving students' "ability to act to save lives".
It is well documented that emotionally arousing experiences are better remembered than mundane events. This is thought to occur through hippocampus-amygdala crosstalk during encoding, consolidation, and retrieval. Here we investigated whether emotional events (context) also cause a memory benefit for simultaneously encoded non-arousing contents and whether this effect persists after a delay via recruitment of a similar hippocampus-amygdala network. Participants studied neutral pictures (content) encoded together with either an arousing or a neutral sound (that served as context) in two study sessions three days apart. Memory was tested in a functional magnetic resonance scanner directly after the second study session. Pictures recognised with high confidence were more often thought to have been associated with an arousing than with a neutral context, irrespective of the veridical source memory. If the retrieved context was arousing, an area in the hippocampus adjacent to the amygdala exhibited heightened activation and this area increased functional connectivity with the parahippocampal gyrus, an area known to process pictures of scenes. These findings suggest that memories can be shaped by the retrieval act. Memory structures may be recruited to a higher degree when an arousing context is retrieved, and this may give rise to confident judgments of recognition for neutral pictures even after a delay.
Aortic arch reconstruction after hypoplastic left heart syndrome (HLHS) palliation can vary widely in shape and dimensions between patients. Arch morphology alone may affect cardiac function and outcome. We sought to uncover the relationship of arch three-dimensional shape features with functional and short-term outcome data after total cavopulmonary connection (TCPC).
Aortic arch shape models of 37 patients with HLHS (age, 2.89 ± 0.99 years) were reconstructed from magnetic resonance data before TCPC completion. A novel, validated statistical shape analysis method was used to compute a three-dimensional anatomic mean shape from the cohort and calculate the deformation vectors of the mean shape toward each patient's specific anatomy. From these deformations, three-dimensional shape features most related to ventricular ejection fraction, indexed end-diastolic volume, and superior cavopulmonary pressure were extracted by partial least-square regression analysis. Shape patterns relating to intensive care unit and hospital lengths of stay after TCPC were assessed.
Distinct deformation patterns, which result in an acutely mismatched aortic root and ascending aorta, and a gothic-like transverse arch, correlated with increased indexed end-diastolic volume and higher superior cavopulmonary pressure but not with ejection fraction. Specific arch morphology with pronounced transverse arch and descending aorta mismatch also correlated with longer intensive care unit and hospital lengths of stay after TCPC completion.
Independent of hemodynamically important arch obstruction, altered aortic morphology in HLHS patients appears to have important associations with higher superior cavopulmonary pressure and with short-term outcomes after TCPC completion as highlighted by statistical shape analysis, which could act as adjunct to risk assessment in HLHS.
To systematically evaluate the clinical effect of cultured milk products as adjunctive therapy in the anti- Helicobacter pylori (H. pylori) treatment.

The randomized controlled trials (RCT) and Quasi-randomized controlled clinical trials (Quasi-RCT),
 which were used to evaluate the efficacy and safety of eradicating H. pylori by fermented milk-based routine treatment, were searched and collected in Pubmed, Embase, CNKI (China National Knowledge Infrastructure), CBM (Chinese BioMedical Literature Database), Wangfang Database, VIP (VIP Citation Database) from establishment of these database to February 2015. The combined relative risk (RR) of H. pylori eradication rate and the rate of side effects were analyzed. Sub-group and sensitivity analysis was performed, and the publication bias was also tested. 

A total of 9 studies including 1 644 cases were identified. The H. pylori eradication rate was 79.5% in fermented milk products combined with routine therapy, and 67.0% in routine therapy. The combined RR of H. pylori eradication rate was 1.186 (95% CI 1.118-1.257), and the combined RR of total side effects was 0.706 (95% CI 0.373-1.340).

Cultured milk products as adjunctive therapy is effective in improving the eradication rate during eradication therapy for H. pylori. However, it could not effectively decrease the risk of side effects.
目的：系统评价发酵乳联合常规治疗方案清除幽门螺杆菌(Helicobacter pylori，H. pylori)感染的临床疗效。
方法：通过检索Pubmed，Embase，中国知网，中国生物医学文献数据库，万方知网和维普等数据库，收集各数据库建库至2015年2月间与发酵乳辅助治疗H. pylori感染相关研究的随机试验或半随机对照试验，分析根除率与不良反应发生率的合并RR值，并进行亚组、敏感性分析和发表偏倚检测。结果：共纳入9项(1 644例)研究，发酵乳联合常规根除疗法与单独常规根除疗法H. pylori根除率分别为79.5%和67.0%，其合并RR为1.186(95%CI: 1.118~1.257)。总不良反应发生率的合并RR为0.706(95%CI: 0.373~1.340)。结论：益生菌可提高常规疗法对H. pylori的根除率，但不能有效降低不良反应的发生风险。.
The available coefficient of friction (ACOF) is a measure of the friction available between two surfaces, which for human gait would be the footwear-floor interface. It is often compared to the required coefficient of friction (RCOF) to determine the likelihood of a slip in gait. Both the ACOF and RCOF are stochastic by nature meaning that neither should be represented by a deterministic value, such as the sample mean. Previous research has determined that the RCOF can be modelled well by either the normal or lognormal distributions, but previous research aimed at determining an appropriate distribution for the ACOF was inconclusive. This study focuses on modelling the stochastic nature of the ACOF by fitting eight continuous probability distributions to ACOF data for six scenarios. In addition, the data were used to study the effect that a simple housekeeping action such as sweeping could have on the ACOF. Practitioner Summary: Previous research aimed at determining an appropriate distribution for the ACOF was inconclusive. The study addresses this issue as well as looking at the effect that an act such as sweeping has on the ACOF.
Glucocorticoids are steroid hormones widely used to control many inflammatory conditions. These effects are primarily attributed to glucocorticoid receptor transrepressional activities but with concomitant receptor transactivation associated with considerable side effects. Accordingly, there is an immediate need for selective glucocorticoid receptor agonists able to dissociate transactivation from transrepression. Triterpenoids have structural similarities with glucocorticoids and exhibit anti-inflammatory and apoptotic activities via mechanisms that are not well-defined. In this study, we examined whether echinocystic acid and its 3-O-glucoside derivative act, at least in part, through the regulation of glucocorticoid receptor and whether they can constitute selective receptor activators. We showed that echinocystic acid and its glucoside induced glucocorticoid receptor nuclear translocation by 75% and 55%. They suppressed the nuclear factor-kappa beta transcriptional activity by 20% and 70%, respectively, whereas they have no glucocorticoid receptor transactivation capability and stimulatory effect on the expression of the phosphoenolopyruvate carboxykinase target gene in HeLa cells. Interestingly, their suppressive effect is diminished in glucocorticoid receptor low level COS-7 cells, verifying the receptor involvement in this process. Induced fit docking calculations predicted favorable binding in the ligand binding domain and structural characteristics which can be considered consistent with the experimental observations. Further, glucocorticoids exert apoptotic activities; we have demonstrated here that the echinocystic acids in combination with the synthetic glucocorticoid, dexamethasone, induce apoptosis. Taken together, our results indicate that echinocystic acids are potent glucocorticoid receptor regulators with selective transrepressional activities (dissociated from transactivation), highlighting the potential of echinocystic acid derivatives as more promising treatments for inflammatory conditions.
A series of new bis-1,2,3-triazole linked ciprofloxacin conjugates was designed, synthesized and evaluated in vitro antibacterial activity against a panel of clinically relevant bacteria. A significant part of the compounds displayed enhanced activity against both Gram-positive and Gram-negative species of bacteria as compared to the parent drug. Additionally, negligible toxicity profile of compounds indicates that they may act a good antibiotic in future. Despite relatively small number of synthesized conjugates, it was possible to observe important dependences between their structure and activity.
In marine environments characterised by habitat-forming plants, the relative allocation of resources into vegetative growth and flowering is an important indicator of plant condition and hence ecosystem health. In addition, the production and abundance of seeds can give clues to local resilience. Flowering density, seed bank, biomass and epiphyte levels were recorded for the temperate seagrass Zostera nigricaulis in Port Phillip Bay, south east Australia at 14 sites chosen to represent several regions with different physicochemical conditions. Strong regional differences were found within the large bay. Spathe and seed density were very low in the north of the bay (3 sites), low in the centre of the bay (2 sites) intermediate in the Outer Geelong Arm (2 sites), high in Swan Bay (2 sites) and very high in the Inner Geelong Arm (3 sites). In the south (2 sites) seed density was low and spathe density was high. These regional patterns were largely consistent for the 5 sites sampled over the three year period. Timing of flowering was consistent across sites, occurring from August until December with peak production in October, except during the third year of monitoring when overall densities were lower and peaked in November. Seagrass biomass, epiphyte load, canopy height and stem density showed few consistent spatial and temporal patterns. Variation in spathe and seed density and morphology across Port Phillip Bay reflects varying environmental conditions and suggests that northern sites may be restricted in their ability to recover from disturbance through sexual reproduction. In contrast, sites in the west and south of the bay have greater potential to recover from disturbances due to a larger seed bank and these sites could act as source populations for sites where seed production is low.
Transmission pathways have fundamental influence on microbial symbiont persistence and evolution. For example, the core gut microbiome of honey bees is transmitted socially and via hive surfaces, but some non-core bacteria associated with honey bees are also found on flowers, and these bacteria may therefore be transmitted indirectly between bees via flowers. Here, we test whether multiple flower and wild megachilid bee species share microbes, which would suggest that flowers may act as hubs of microbial transmission. We sampled the microbiomes of flowers (either bagged to exclude bees or open to allow bee visitation), adults, and larvae of seven megachilid bee species and their pollen provisions. We found a Lactobacillus operational taxonomic unit (OTU) in all samples but in the highest relative and absolute abundances in adult and larval bee guts and pollen provisions. The presence of the same bacterial types in open and bagged flowers, pollen provisions, and bees supports the hypothesis that flowers act as hubs of transmission of these bacteria between bees. The presence of bee-associated bacteria in flowers that have not been visited by bees suggests that these bacteria may also be transmitted to flowers via plant surfaces, the air, or minute insect vectors such as thrips. Phylogenetic analyses of nearly full-length 16S rRNA gene sequences indicated that the Lactobacillus OTU dominating in flower- and megachilid-associated microbiomes is monophyletic, and we propose the name Lactobacillus micheneri sp. nov. for this bacterium.
Asthma is a public health problem that is responsible for significant symptomatology and in extreme cases, premature deaths among adolescents. Lack of knowledge of the disease contributes to both its morbidity and mortality. In this manuscript, we discuss school interventions in asthma, in particular their impacts on improving knowledge of the disease and their ability to both make the school environment safer and reduce morbidity indicators. These interventions have been successful when implemented in higher income countries. Thus, to address the lack of interventions in low and middle income countries, we present an example of an alternative asthma intervention in the school curriculum developed in South America. The model has been proven to be both feasible and relatively inexpensive. It is easily structured by utilizing the staff of the school itself and is capable of being adapted to other countries.
Chromium (III) has been shown to act as a pharmacological agent improving insulin sensitivity in rodent models of obesity, insulin resistance, and diabetes. To act in beneficial fashion, chromium must reach insulin-sensitive tissues. Chromium is transported from the bloodstream to the tissues by
 the iron-transport protein transferrin. When blood concentrations of glucose are high (as in a diabetic subject), transferrin can be glycated, modifying its ability to bind and transport iron. However, the effects of glycation of transferrin on its ability to bind and transport Cr have not been examined previously. Storage of transferrin at 37°C in the presence and absence of glucose has significant effects on the binding of Cr. Transferrin stored in the absence of glucose only binds one equivalent of Cr tightly, compared to the normal binding of two equivalents of Cr by transferrin. Glycated transferrin (stored in the presence of glucose) binds two equivalents of Cr but the changes in its extinction coefficient at 245nm that accompany binding suggest that the Cr-bound transferrin possesses a conformation that deviates appreciably from untreated transferrin. These changes have dramatic effects, greatly reducing the ability of transferrin to transport Cr in vivo in rats. The results suggest that glycation of transferrin in subjects with high blood glucose concentrations should reduce the ability of Cr from pharmacological agents to enter tissues.
As part of the National Institute for Health and Care Excellence's (NICE) Single Technology Appraisal (STA) process, ruxolitinib was assessed to determine the clinical and cost effectiveness of its use in the treatment of disease-related splenomegaly or symptoms in adults with myelofibrosis. Ruxolitinib had previously been assessed as part of the STA process and was not recommended in NICE guidance issued in June 2013 (TA289). A review of TA289 was commissioned following the availability of new longer-term survival data; a price discount patient access scheme (PAS) was also introduced. The Centre for Reviews and Dissemination (CRD) and Centre for Health Economics (CHE) Technology Appraisal Group at the University of York was commissioned to act as the independent Evidence Review Group (ERG). This article provides a summary of the manufacturer or sponsor of the technology's (referred to as the company) submission, the ERG review and the resulting NICE guidance issued in March 2016. The main clinical effectiveness data were derived from two good-quality multicentre randomised controlled trials (RCTs): COMFORT-II compared ruxolitinib with best available therapy (BAT) and COMFORT-I compared ruxolitinib with placebo. Both RCTs demonstrated a statistically significant reduction in splenomegaly and its associated symptoms in intermediate-2 and high-risk myelofibrosis patients. Overall survival was statistically significantly improved with ruxolitinib compared with BAT at 3.5 years of follow-up in the COMFORT-II trial (hazard ratio 0.58, 95 % CI 0.36-0.93). Grade 3-4 adverse events were more frequent in the ruxolitinib group than in the BAT group; 42 % compared with 25 %. Evidence relating to patients with lower-risk disease or low platelet counts (50-100 × 10(9)/L) was less robust. The company's economic model was well-presented and had an appropriate model structure. The base-case incremental cost-effectiveness ratio (ICER) was estimated to be around £45,000 per quality-adjusted life-year (QALY) gained (including the PAS discount). Extensive sensitivity and scenario analyses were presented, demonstrating that the estimated ICER was robust to a range of input values and assumptions made in the model. Alternative scenarios presented by the ERG showed only modest increases in the estimated ICER, primarily as a result of including an element of drug wastage within the model. Alternative scenarios resulted in estimated ICERs ranging from around £45,000 to £49,000 per QALY gained (including the PAS discount). At the first appraisal meeting, the NICE Appraisal Committee concluded that ruxolitinib was clinically effective and was a cost effective use of National Health Service (NHS) resources for patients with high-risk myelofibrosis who meet NICE's end-of-life criteria. Following the consultation, the company offered a revised PAS, resulting in a revised base-case ICER of £31,229 per QALY gained. The company also presented new evidence on the cost effectiveness of ruxolitinib in intermediate-2 and high-risk subgroups and a revised version of the model. The NICE Appraisal Committee considered the new evidence and recommended ruxolitinib for the treatment of patients with intermediate-2-risk disease as well as patients with high-risk disease, based on International Prognostic Scoring System (IPSS) prognostic factors.
Adenosine deaminase (ADA) is an enzyme involved in purine metabolism. ADA converts adenosine to inosine and liberates ammonia. Because of their critical role in the differentiation and maturation of cells, the regulation of ADA activity is considered as a potential therapeutic approach to prevent malignant and inflammatory disorders. In the present study, the inhibitory activity of a plant flavonoid, hibifolin on ADA is investigated using enzyme kinetic assay and isothermal titration calorimetry. The inhibitory constant of hibifolin was found to be 49.92μM±3.98 and the mode of binding was reversible. Isothermal titration calorimetry showed that the compound binds ADA with binding energy of -7.21Kcal/mol. The in silico modeling and docking studies showed that the bound ligand is stabilized by hydrogen bonds with active site residues of the enzyme. The study reveals that hibifolin can act as a potential inhibitor of ADA.
Metazoan embryos undergo a maternal-to-zygotic transition (MZT) during which maternal gene products are eliminated and the zygotic genome becomes transcriptionally active. During this process RNA-binding proteins (RBPs) and the microRNA-induced silencing complex (miRISC) target maternal mRNAs for degradation. In Drosophila, the Smaug (SMG), Brain tumor (BRAT) and Pumilio (PUM) RBPs bind to and direct the degradation of largely distinct subsets of maternal mRNAs. SMG has also been shown to be required for zygotic synthesis of mRNAs and several members of the miR-309 family of microRNAs (miRNAs) during the MZT. Here we have carried out global analysis of small RNAs both in wild type and in smg mutants. Our results show that 85% all miRNA species encoded by the genome are present during the MZT. Whereas loss of SMG has no detectable effect on Piwi-interacting RNAs (piRNAs) or small interfering RNAs (siRNAs), zygotic production of more than 70 species of miRNAs fails or is delayed in smg mutants. SMG is also required for the synthesis and stability of a key miRISC component, Argonaute 1 (AGO1), but plays no role in accumulation of the Argonaute-family proteins associated with piRNAs or siRNAs. In smg mutants, maternal mRNAs that are predicted targets of the SMG-dependent zygotic miRNAs fail to be cleared. BRAT and PUM share target mRNAs with these miRNAs but not with SMG itself. We hypothesize that SMG controls the MZT, not only through direct targeting of a subset of maternal mRNAs for degradation but, indirectly, through production and function of miRNAs and miRISC, which act together with BRAT and/or PUM to control clearance of a distinct subset of maternal mRNAs.
To analyze whether there was an increase in retirement or in part-time work among older workers after January 2014, when new health insurance coverage options became available because of the Affordable Care Act (ACA).
We analyze trends in retirement and part-time work for individuals aged 50-64 years in the basic monthly Current Population Survey from January 2008 through June 2016. We test for a break in trend in January 2014. We also test for differences in trends, both before and after 2014, in states that expanded their Medicaid programs in January 2014 under the ACA compared with those that did not.
We find that there was no change in the probability of retirement or part-time work among older workers in 2014 and later, either overall or in Medicaid expansion states relative to nonexpansion states.
Although many observers had predicted that an unintended consequence of health reform would be reduced labor supply, we find no evidence of this for older workers in the first 2.5 years after the law's major coverage provisions took effect.
In this work, we designed and synthesized a carbazole-type molecule that can form carbazolyl radicals in chloroform solution under the irradiation of UV light. The process is accompanied by an obvious change in the emission color from blue to bright green. The radicals and the neutral molecules assemble together and form nanospheres through synergistic effect of π-π stacking, intermolecular hydrogen bonds and charge transfer interaction. High resolution-transmission electron microscopy (HR-TEM) is used to confirm the nanospheres. The radius sizes of the nanospheres are mainly in 80-100nm. Further, these nanospheres act as the fluorescence sensor for explosives detection, and they exhibit high selectivity and sensitivity to 2, 4, 6-trinitrophenol (TNP). The limit of detection for nanospheres is 1.2×10(-7)M.
The exposure of phosphatidylserine (PS) on the surface membrane of apoptotic cells triggers the recruitment of phagocytic receptors and subsequently results in uptake by phagocytes. Here we describe how apoptotic cells can use intercellular membrane nanotubes to transfer exposed PS to neighboring viable cells, and thus deposit an "eat-me" tag on the viable cells. Tunneling nanotubes (TNTs) connected UV-treated apoptotic rat pheochromocytoma PC12 cells with neighboring untreated cells. These TNTs were composed of PS-exposed plasma membrane and facilitated the transfer of the membrane from apoptotic to viable cells. Other pro-phagocytic signals, such as oxidized phospholipids and calreticulin, were also transferred to viable cells. In addition, anti-phagocytic signal CD47 presenting on the plasma membrane of viable cells was masked by the transferred PS-membrane.
 Confocal imaging revealed an increase of phagocytosis of viable PC12 cells by murine RAW264.7 macrophages when the viable PC12 cells were cocultured with UV-treated PC12 cells. Treatment with 50 nM cytochalasin D would abolish TNTs and correspondingly inhibit this phagocytosis of the viable cells. Our study indicates that exposed-PS membrane is delivered from apoptotic to viable cells through TNTs. This transferred membrane may act as a pro-phagocytic signal for macrophages to induce phagocytosis of viable cells in a situation where they are in the vicinity of apoptotic cells. This article is protected by copyright. All rights reserved.
One of the most demanding DNA extractions is from bones and teeth due to the robustness of the material and the relatively low DNA content. The greatest challenge is due to the manifold nature of the material, which is defined by various factors, including age, storage, environmental conditions, and contamination with inhibitors. However, most published protocols do not distinguish between different types or qualities of bone material, but are described as being generally applicable. Our laboratory works with two different extraction methods based on silica membranes or the use of silica beads. We compared the amplification success of the two methods from bone samples with different qualities and in the presence of inhibitors. We found that the DNA extraction using the silica membrane method results an in higher DNA yield but also in a higher risk of co-extracting impurities, which can act as inhibitors. In contrast the silica beads method shows decreased co-extraction of inhibitors but also less DNA yield. Related to our own experiences it has to be considered that each bone material should be reviewed independently regarding the analysis and extraction method. Therefore, the most ambitious task is determining the quality of the bone material, which requires substantial experience.
The Community Development Learning Initiative (CDLI) in Calgary, Alberta, Canada aims to be a network that brings together neighbourhood residents, community development practitioners and other supporters to learn and act on neighbourhood-based, citizen-led community development projects. In 2013, the CDLI initiated The Evaluation for Learning and Dialogue Project to provide the opportunity for organizations and supporters to work together to establish a shared vision and goals through discussions about evaluation learning and outcomes. It was intended that the project would be a useful learning tool for participating organizations by enabling them to engage in an evaluative methodological process, and record relevant information and to compare and learn from each other's projects. Outcome Harvesting was chosen as the evaluation methodology for the project. This article reviews critical learning from the project on the use of Outcome Harvesting methodology in the evaluation learning and outcomes of local community development projects, and it provides lessons for other jurisdictions interested in implementing this methodology.
The nuclear envelope is much more than a simple barrier between nucleoplasm and cytoplasm. Nuclear envelope bridging complexes are protein complexes spanning both the inner and outer nuclear envelope membranes, thus directly connecting the cytoplasm with the nucleoplasm. In metazoans, they are involved in connecting the cytoskeleton with the nucleoskeleton, and act as anchoring platforms at the nuclear envelope for the positioning and moving of both nuclei and chromosomes. Recently, nucleocytoplasmic bridging complexes have also been identified in more evolutionarily diverse organisms, including land plants. Here, I discuss similarities and differences among and between eukaryotic supergroups, specifically of the proteins forming the cytoplasmic surface of these complexes. I am proposing a structure and function for a hypothetical ancestral nucleocytoplasmic bridging complex in the last eukaryotic common ancestor, with the goal to stimulate research in more diverse emerging model organisms.
Working memory is associated with persistent activity in the prefrontal cortex (PFC). The neuromodulator dopamine, which is released by midbrain neurons projecting into the frontal lobe, influences PFC neurons and networks via the dopamine D1 (D1R) and the D2 receptor (D2R) families. Although behavioral, clinical and computational evidence suggest an involvement of D2Rs in working memory, a neuronal explanation is missing. We report an enhancement of persistent working memory responses of PFC neurons after iontophoretically stimulating D2Rs in monkeys memorizing the number of items in a display. D2R activation improved working memory representation at the population level and increased population dynamics during the transition from visual to mnemonic representations. Computational modeling suggests that D2Rs act by modulating interneuron-to-pyramidal signaling. By increasing the population's response dynamics, D2Rs might put PFC networks in a more flexible state and enhance the neurons' working memory coding, thereby controlling dynamic cognitive control.
: Cardiomyocytes can be differentiated from human pluripotent stem cells (hPSCs) in defined conditions, but efficient and consistent cardiomyocyte differentiation often requires expensive reagents such as B27 supplement or recombinant albumin. Using a chemically defined albumin-free (E8 basal) medium, we identified heparin as a novel factor that significantly promotes cardiomyocyte differentiation efficiency, and developed an efficient method to differentiate hPSCs into cardiomyocytes. The treatment with heparin helped cardiomyocyte differentiation consistently reach at least 80% purity (up to 95%) from more than 10 different hPSC lines in chemically defined Dulbecco's modified Eagle's medium/F-12-based medium on either Matrigel or defined matrices like vitronectin and Synthemax. One of heparin's main functions was to act as a Wnt modulator that helped promote robust and consistent cardiomyocyte production. Our study provides an efficient, reliable, and cost-effective method for cardiomyocyte derivation from hPSCs that can be used for potential large-scale drug screening, disease modeling, and future cellular therapies.
Using a new method, heparin was identified as a novel reagent that promotes cardiomyocyte differentiation. Albumin was not necessary for cardiac differentiation when heparin was present. Heparin has biphasic regulations of Wnt signaling during cardiac differentiation. This study reports that the heparin-based cardiac differentiation method is easier in terms of quality control and is cost-effective for large-scale production and potential clinical applications.
Modulation of neurotransmission by the monoamines dopamine (DA), norepinephrine (NE), and serotonin (5-HT) is critical for normal nervous system function. Precise temporal and spatial control of this signaling in mediated in large part by the actions of monoamine transporters (DAT, NET, and SERT, respectively). These transporters act to recapture their respective neurotransmitters after release, and disruption of clearance and reuptake has significant effects on physiology and behavior and has been linked to a number of neuropsychiatric disorders. To ensure adequate and dynamic control of these transporters, multiple modes of control have evolved to regulate their activity and trafficking. Central to many of these modes of control are the actions of protein kinases, whose actions can be direct or indirectly mediated by kinase-modulated protein interactions. Here, we summarize the current state of our understanding of how protein kinases regulate monoamine transporters through changes in activity, trafficking, phosphorylation state, and interacting partners. We highlight genetic, biochemical, and pharmacological evidence for kinase-linked control of DAT, NET, and SERT and, where applicable, provide evidence for endogenous activators of these pathways. We hope our discussion can lead to a more nuanced and integrated understanding of how neurotransmitter transporters are controlled and may contribute to disorders that feature perturbed monoamine signaling, with an ultimate goal of developing better therapeutic strategies.
Fifteen galectins, β-galactose-binding animal lectins, are known to be distributed throughout the body. We herein summarize current knowledge on the tissue- and cell-specific localization of galectins and their potential functions in health and disease. Galectin-3 is widely distributed in epithelia, including the simple columnar epithelium in the gut, stratified squamous epithelium in the gut and skin, and transitional epithelium and several regions in nephrons in the urinary tract. Galectin-2 and galectin-4/6 are gut-specific, while galectin-7 is found in the stratified squamous epithelium in the gut and skin. The reproductive tract mainly contains galectin-1 and galectin-3, and their expression markedly changes during the estrous/menstrual cycle. The galectin subtype expressed in the corpus luteum (CL) changes in association with luteal function. The CL of women and cows displays a "galectin switch" with coordinated changes in the major galectin subtype and its ligand glycoconjugate structure. Macrophages express galectin-3, which may be involved in phagocytotic activity. Lymphoid tissues contain galectin-3-positive macrophages, which are not always stained with the macrophage marker, F4/80. Subsets of neurons in the brain and dorsal root ganglion express galectin-1 and galectin-3, which may contribute to the regeneration of damaged axons, stem cell differentiation, and pain control. The subtype-specific contribution of galectins to implantation, fibrosis, and diabetes are also discussed. The function of galectins may differ depending on the tissues or
 cells in which they act. The ligand glycoconjugate structures mediated by glycosyltransferases including MGAT5, ST6GAL1, and C2GnT are important for revealing the functions of galectins in healthy and disease states.
The Family Smoking Prevention and Tobacco Control Act authorized the FDA to reduce the nicotine content in cigarettes. Research is needed to guide proposed regulations, including evaluation of consequences to public health. This study evaluated how a reduced nicotine product standard might be moderated by and impact cannabis use.
Secondary analysis of a controlled clinical trial examining the effects of nicotine content in cigarettes in adult daily smokers. Linear regression assessed whether baseline cannabis use moderated behavioral, subjective, or physiological effects of smoking very low nicotine content (VLNC) versus normal nicotine content (NNC) cigarettes. Repeated measures analysis of associations between nicotine condition and prevalence and frequency of cannabis use was completed using generalized estimating equations (GEE).
Cannabis use did not moderate most of the following effects of VLNC cigarettes: Among cannabis users and non-users, smokers randomized to VLNC cigarettes reported lower nicotine dependence, cigarettes per day, biomarkers of nicotine exposure, and craving compared to smokers randomized to NNC cigarettes. Non-cannabis using smokers randomized to VLNC cigarettes also reported lower smoking dependence motives and had lower tobacco-specific nitrosamine exposure and total puff volume versus smokers randomized to NNC cigarettes. For cannabis users, smokers randomized to VLNC cigarettes reported decreased positive affect. VLNC cigarette use did not impact the prevalence or frequency of cannabis use.
Findings provide evidence that nicotine reduction in cigarettes could have beneficial effects on cigarette smoking regardless of cannabis use. Results suggest that transitioning to VLNC cigarettes is unlikely to alter current rates of cannabis use.
The modern built environment (BE) design creates unique ecological niches ideal for the survival and mutual interaction of microbial communities. This investigation focused on the synergistic relations between Legionella and the fungal species commonly found in BEs and the impact of these synergistic relationships on the survival and transmission of Legionella.
A field study was conducted to identify the types and concentrations of fungi in BEs. The fungal isolates purified from BEs were cocultured with Legionella to study their synergistic association. Cocultured Legionella cells were aerosolized in an air-tight chamber to evaluate the efficacy of ultraviolet (UV) to inactivate these cells.
Aspergillus, Alternaria, and Cladosporium were the most common fungi detected in samples that tested positive for Legionella. After coculturing, Legionella cells were detected inside fungal hyphae. The microscopic observations of Legionella internalization in fungal hyphae were confirmed by molecular analyses. UV disinfection of the aerosolized Legionella cells that were cocultured with fungi indicated that fungal spores and propagules act as a shield against UV radiation. The shield effect of fungal spores on Legionella cells was quantified at >2.5 log10.
This study provides the first evidence, to our knowledge, of Legionella cell presence inside fungi detected in an indoor environment. This symbiotic relationship with fungi results in longer survival of Legionella under ambient conditions and provides protection against UV rays.
Biglycan (BGN) is an important component of the extracellular matrix (ECM) that is implicated in a variety of human cancers. In our previous study, we reported that BGN was overexpressed in gastric cancer (GC) tissues and promoted cancer metastasis. Moreover, the tubular formation capacity in HUVECs was promoted by stimulation with culture media from BGN-overexpressing GC cells, but the exact underlying mechanism is still unknown. The purpose of this study was to determine the role and molecular mechanism of BGN in VEGF expression in endothelial cells. We found that BGN stimulation of endothelial cells increased the interaction between NF-kB and the HIF-1α promoter, leading to enhanced promoter activity and increased HIF-1α mRNA levels, as well as augmented HIF-1 activity that resulted in VEGF expression. All of this was dependent on the interaction of BGN with its receptors, TLR2 and TLR4. Moreover, we found that BGN enhanced endothelial cell migration and proliferation, as well as tube formation, in a TLR signaling pathway-dependent manner. In addition, endothelial cell-derived VEGF in turn was found to act on GC cells and promotes their migration. The combined findings of our current and previous studies suggest that BGN secreted from GC cells into the tumor stroma promotes GC development, as well as its progression, potentially through the chronic activation of tumor angiogenesis.
Patients with resected oral squamous cell carcinoma (OSCC) harboring extracapsular extension (ECE) of the involved lymph node, show poor and heterogeneous outcomes. We aim to improve their prognostic stratification by combining genetic information from next-generation sequencing (NGS) using traditional clinicopathological prognosticators. The hotspot mutation regions of 45 cancer-related genes were investigated using NGS with an ultra-deep (>1000×) sequencing approach in formalin-fixed paraffin-embedded samples obtained from 201 patients with resected OSCC harboring ECE. Adjuvant chemoradiotherapy (CRT) and the number of nodes with ECE were the most important traditional prognosticators for disease-specific survival (DSS). The 5-year DSS for patients with CRT versus without, was 55% versus 21% (P < 0.001), and that for 1-3 versus ≥ 4 ECEs was 60% versus 25% (P = 0.001), respectively. Multivariate analysis in patients who received adjuvant CRT for 1-3 ECEs (i.e., those with a favorable expected prognosis) identified the following adverse prognostic factors: 1) margin of < 5 mm for locoregional failure (66% versus 30%, P = 0.007) and DSS (42% versus 63%, P = 0.039); 2) HRAS mutation for distant failure (55% versus 25%, P = 0.007) and DSS (36% versus 63%, P = 0.024); and 3) TP53 DNA-binding domain missense mutations for DSS (52% versus 71%, P = 0.025) and overall survival (39% versus 61%, P = 0.007).We conclude that genetic information from NGS may improve the prognostic stratification offered by traditional prognosticators in resected OSCC patients with ECE. Our findings will contribute to implementation of precision medicine in OSCC patients.
The efficacy of pharmacological perturbation to the signaling transduction network depends on the network topology. However, whether and how signaling dynamics mediated by crosstalk contributes to the drug resistance are not fully understood and remain to be systematically explored. In this study, motivated by a realistic signaling network linked by crosstalk between EGF/EGFR/Ras/MEK/ERK pathway and HGF/HGFR/PI3K/AKT pathway, we develop kinetic models for several small networks with typical crosstalk modules to investigate the role of the architecture of crosstalk in inducing drug resistance. Our results demonstrate that crosstalk inhibition diminishes the response of signaling output to the external stimuli. Moreover, we show that signaling crosstalk affects the relative sensitivity of drugs, and some types of crosstalk modules that could yield resistance to the targeted drugs were identified. Furthermore, we quantitatively evaluate the relative efficacy and synergism of drug combinations. For the modules that are resistant to the targeted drug, we identify drug targets that can not only increase the relative drug efficacy but also act synergistically. In addition, we analyze the role of the strength of crosstalk in switching a module between drug-sensitive and drug-resistant. Our study provides mechanistic insights into the signaling crosstalk-mediated mechanisms of drug resistance and provides implications for the design of synergistic drug combinations to reduce drug resistance.
Vaccines targeting enterohaemorrhagic Escherichia coli (EHEC) O157:H7 shedding in cattle are only partially protective. The correlates of protection of these vaccines are unknown, but it is probable that they reduce bacterial adherence at the mucosal surface via the induction of blocking antibodies. Recent studies have indicated a role for cellular immunity in cattle during colonisation, providing an impetus to understand the bacterial epitopes recognised during this response. This study mapped the epitopes of 16 EHEC O157:H7 proteins recognised by rectal lymph node CD4(+) T-cells from calves colonised with Shiga toxin producing EHEC O157:H7 strains. 20 CD4(+) T-cell epitopes specific to E. coli from 7 of the proteins were identified. The highly conserved N-terminal region of Intimin, including the signal peptide, was consistently recognised by mucosal CD4(+) T-cell populations from multiple animals of different major histocompatibility complex class II haplotypes. These T-cell epitopes are missing from many Intimin constructs used in published vaccine trials, but are relatively conserved across a range of EHEC serotypes, offering the potential to develop cross protective vaccines. Antibodies recognising H7 flagellin have been consistently identified in colonised calves; however CD4(+) T-cell epitopes from H7 flagellin were not identified in this study, suggesting that H7 flagellin may act as a T-cell independent antigen. This is the first time that the epitopes recognised by CD4(+) T-cells following colonisation with an attaching and effacing pathogen have been characterised in any species. The findings have implications for the design of antigens used in the next generation of EHEC O157:H7 vaccines.
Porcine reproductive and respiratory
 syndrome virus (PRRSV) is responsible for one of the most economically important diseases in swine worldwide. It causes reproductive failure in sows and pneumonia in pigs that predisposes them to secondary bacterial infections. Methods to control PRRSV and/or limit secondary bacterial infections are desired to reduce the impact of this virus on animal health. Neutrophils play a major role in combatting infection; they can act as phagocytes as well as produce and release lytic enzymes that have potent antimicrobial effects leading to the destruction and clearance of bacterial pathogens. Granulocyte-colony stimulating factor (G-CSF) is a cytokine that controls the production, differentiation and function of granulocytes (including neutrophils) from the bone marrow. Recent work from our laboratory has shown that encoding porcine G-CSF in a replication-defective adenovirus (Ad5-G-CSF) and delivering a single dose to pigs induced a neutrophilia lasting more than two weeks. As secondary bacterial infection is a common occurrence following PRRSV infection, particularly following challenge with highly pathogenic (HP)-PRRSV, the aim of the current study was to evaluate the effectiveness of a single prophylactic dose of adenovirus-encoded G-CSF to mitigate secondary bacterial disease associated with HP-PRRSV infection. Administration of Ad5-G-CSF induced a significant neutrophilia as expected. However, between 1 and 2days following HP-PRRSV challenge the number of circulating neutrophils decreased dramatically in the HP-PRRSV infected group, but not the non-infected Ad5-G-CSF group. Ad5-G-CSF administration induced monocytosis as well, which was also reduced by HP-PRRSV challenge. There was no difference in the progression of disease between the Ad5-G-CSF and Ad5-empty groups following HP-PRRSV challenge, with pneumonia and systemic bacterial infection occurring in both treatment groups. Given the impact of HP-PRRSV infection on the neutrophilia induced by the Ad5-G-CSF administration, additional studies are warranted to evaluate the timing of Ad5-G-CSF induced neutrophilia and multiple G-CSF inoculations on protection against secondary bacterial infection following PRRSV infection. Nevertheless, this study may provide insight into the pathogenesis of HP-PRRSV.
Dessert and cooking bananas are vegetatively propagated crops of great importance for both the subsistence and the livelihood of people in developing countries. A wide diversity of diploid and triploid cultivars including AA, AB, AS, AT, AAA, AAB, ABB, AAS and AAT genomic constitutions exists. Within each of this genome groups, cultivars are classified into subgroups that are reported to correspond to varieties clonally derived from each other after a single sexual event. The number of those founding events at the basis of the diversity of bananas is a matter of debate.
We analysed a large panel of 575 accessions, 94 wild relatives and 481 cultivated accessions belonging to the section Musa with a set of 498 DArT markers previously developed.
DArT appeared successful and accurate to describe Musa diversity and help in the resolution of cultivated banana genome constitution and taxonomy, and highlighted discrepancies in the acknowledged classification of some accessions. This study also argues for at least two centres of domestication corresponding to South-East Asia and New Guinea, respectively. Banana domestication in New Guinea probably followed different schemes that those previously reported where hybridization underpins the emergence of edible banana. In addition, our results suggest that not all wild ancestors of bananas are known, especially in M. acuminata subspecies. We also estimate the extent of the two consecutive bottlenecks in edible bananas by evaluating the number of sexual founding events underlying our sets of edible diploids and triploids, respectively.
The attribution of clone identity to each sample of the sets allowed the detection of subgroups represented by several sets of clones. Although morphological characterization of some of the accessions is needed to correct potentially erroneous classifications, some of the subgroups seem polyclonal.
Several evidences indicate that hormones and neuropeptides function as immunomodulators. Among these, growth hormone (GH) is known to act on the thymic microenvironment, supporting its role in thymocyte differentiation. The aim of this study was to evaluate the effect of GH on human thymocytes and thymic epithelial cells (TEC) in the presence of laminin.
GH increased thymocyte adhesion on BSA-coated and further on laminin-coated surfaces. The number of migrating cells in laminin-coated membrane was higher in GH-treated thymocyte group. In both results, VLA-6 expression on thymocytes was constant. Also, treatment with GH enhanced laminin production by TEC after 24 h in culture. However, VLA-6 integrin expression on TEC remained unchanged. Finally, TEC/thymocyte co-culture model demonstrated that GH elevated absolute number of double-negative (CD4(-)CD8(-)) and single-positive CD4(+) and CD8(+) thymocytes. A decrease in cell number was noted in double-positive (CD4(+)CD8(+)) thymocytes.
The results of this study demonstrate that GH is capable of enhancing the migratory capacity of human thymocytes in the presence of laminin and promotes modulation of thymocyte subsets after co-culture with TEC.
Human lipoxygenases (LOXs) have been emerging as effective therapeutic targets for inflammatory diseases. In this study, we found that four natural 2-arylbenzo[b]furan derivatives isolated from Artocarpus heterophyllus exhibited potent inhibitory activities against human LOXs, including moracin C (1), artoindonesianin B-1 (2), moracin D (3), moracin M (4). In our in vitro experiments, compound 1 was identified as the most potent LOX inhibitor and the moderate subtype selective inhibitor of 12-LOX. Compounds 1 and 2 act as competitive inhibitors of LOXs. Moreover, 1 significantly inhibits LTB4 production and chemotactic capacity of neutrophils, and is capable of protecting vascular barrier from plasma leakage in vivo. In addition, the preliminary structure-activity relationship analysis was performed based on the above four naturally occurring (1-4) and six additional synthetic 2-arylbenzo[b]furan derivatives. Taken together, these 2-arylbenzo[b]furan derivatives, as LOXs inhibitors, could represent valuable leads for the future development of therapeutic agents for inflammatory diseases.
Wnt proteins are modified and inactivated by two extracellular enzymatic antagonists, Tiki and Notum. Tiki proteins act as membrane-tethered metalloproteases to cleave a fragment from the amino terminus of Wnt proteins. Notum is a Wnt deacylase that removes the lipid modification that is essential for Wnt activities. Here, we provide detailed procedures for preparing enzymatic active Tiki and Notum proteins and the in vitro enzymatic reactions. We also describe a metabolic labeling and click chemistry method for detection of Wnt protein acylation.
Wnt proteins act as potent morphogens in various aspects of embryonic development and adult tissue homeostasis. However, in addition to its physiological importance, aberrant Wnt signaling has been linked to the onset and progression of different types of cancer. On the cellular level, the secretion of Wnt proteins involves trafficking of lipid-modified Wnts from the endoplasmic reticulum (ER) to Golgi and further compartments via the Wnt cargo receptor evenness interrupted. Others and we have recently shown that Wnt proteins are secreted on extracellular vesicles (EVs) such as microvesicles and exosomes. Although more details about specific regulation of Wnt secretion steps are emerging, it remains largely unknown how Wnt proteins are channeled into different release pathways such as lipoprotein particles, EVs and cytonemes. Here, we describe protocols to purify and quantify Wnts from the supernatant of cells by either assessing total Wnt proteins in the supernatant or monitoring Wnt proteins on EVs. Purified Wnts from the supernatant as well as total cellular protein content can be investigated by immunoblotting. Additionally, the relative activity of canonical Wnts in the supernatant can be assessed by a dual-luciferase Wnt reporter assay. Quantifying the amount of secreted Wnt proteins and their activity in the supernatant of cells allows the investigation of intracellular trafficking events that regulate Wnt secretion and the role of extracellular modulators of Wnt spreading.
This study investigates prospective associations of anthropometrical and lifestyle indices with insulin resistance (IR) in European children from the IDEFICS cohort. Insulin resistance (IR) is a growing concern in childhood obesity and a central aspect of the metabolic syndrome (MS). It most likely represents the link between obesity and type 2 diabetes.
This longitudinal study included 3348 preadolescent children aged 3 to 10.9 years from 8 European countries who were observed from 2007/2008 to 2009/2010. The main outcome measure in the present analysis is HOMA-IR (homeostasis model assessment as a common proxy indicator to quantify IR) at follow-up and in its longitudinal development. Anthropometrical measures and lifestyle indices, including objectively determined physical activity, were considered, among others factors, as determinants of IR. Prospective associations between IR at follow-up and anthropometrical and lifestyle indices were estimated by logistic regression models.
Country-specific prevalence rates of IR in the IDEFICS cohort of European children showed a positive trend with weight category. Prospective multivariate analyses showed the strongest positive associations of IR with BMI z-score (OR = 2.6 for unit change from the mean, 95 % CI 2.1-3.1) and z-score of waist circumference (OR = 2.2 for
 unit change from the mean, 95 % CI 1.9-2.6), which were analysed in separate models, but also for sex (OR = 2.2 for girls vs. boys, 95 % CI 1.5-3.1 up to OR 2.5, 95 % CI 1.8-3.6 depending on the model), audio-visual media time (OR = 1.2 for an additional hour per day, 95 % CI 1.0-1.4 in both models) and an inverse association of objectively determined physical activity (OR = 0.5 for 3(rd) compared to 1(st) quartile, 95 % CI 0.3-0.9 in both models). A longitudinal reduction of HOMA-IR was accompanied with a parallel decline in BMI.
This study is, to our knowledge, the first prospective study on IR in a preadolescent children's population. It supports the common hypothesis that overweight and obesity are the main determinants of IR. Our data also indicate that physical inactivity and a sedentary lifestyle are likewise associated with the development of IR, independent of weight status. The promotion of physical activity should thus be considered as an equal option to dietary intervention for the treatment of IR in the paediatric practice.
Multiple simultaneous exposures to electromagnetic signals induced adjustments in mammal nervous systems. In this study, we investigated the non-thermal SAR (Specific Absorption Rate) in the cerebral or cerebellar hemispheres of rats exposed in vivo to combined electromagnetic field (EMF) signals at 900 and 2450 MHz.Forty rats divided into four groups of 10 were individually exposed or not exposed to radiation in a GTEM chamber for one or two hours. After radiation, we used the Chemiluminescent Enzyme-Linked Immunosorbent Assay (ChELISA) technique to measure cellular stress levels, indicated by the presence of heat shock proteins (HSP) 90 and 70, as well as caspase-3-dependent pre-apoptotic activity in left and right cerebral and cerebellar hemispheres of Sprague Dawley rats.Twenty-four hours after exposure to combined or single radiation, significant differences were evident in HSP 90 and 70 but not in caspase 3 levels between the hemispheres of the cerebral cortex at high SAR levels. In the cerebellar hemispheres, groups exposed to a single radiofrequency (RF) and high SAR showed significant differences in HSP 90, 70 and caspase-3 levels compared to control animals. The absorbed energy and/or biological effects of combined signals were not additive, suggesting that multiple signals act on nervous tissue by a different mechanism.
NR6A1/CT150, as an orphan receptor, is a novel member of the cancer-testis (CT) antigen family. Here, we investigated the expression and function of NR6A1 and its underlying mechanisms in prostate cancer (PCa) patients who underwent radical prostatectomy. A total of 303 cases of prostate cancer after radical prostatectomy were analysed in a tissue microarray (TMA) for NR6A1 immunohistochemistry-based protein expression. Kaplan-Meier/log-rank analysis and Cox regression analysis were used to investigate the relationship between NR6A1 expression and clinicopathological factors in PCa. NR6A1 mRNA expression was examined by reversing transcriptase-polymerase chain reaction (RT-PCR). Knockdown of NR6A1 by small interfering RNA mediated gene silencing and overexpression of NR6A1 through lentivirus were utilized to investigate its potential role in prostate cancer cells. NR6A1 protein expression was 29.7% (90/303) and mRNA expression was 28.1%(9/32) in PCa patients. NR6A1 expression was significantly associated with Gleason score (GS) (P=0.003) and tumor stage (P=0.042). The patients with positive NR6A1 expression have a shorter biochemical recurrence-free survival. NR6A1 predicted biochemical recurrence in univariate (P=0.0159) and multivariate models (P=0.0317). In addition, gene silencing of NR6A1 resulted in G0/G1 phase cell cycle arrest, and decreased metastatic and invasive potential of prostate cancer cells DU145 and PC3. In contrast, overexpression of NR6A1 reduced G0/G1 phase cell cycle arrest, and promoted metastatic and invasive potential of prostate cancer cells 22RV1. And overexpression of NR6A1 significantly promoted tumor growth in vivo. What's more, down regulation of NR6A1 could reverse epithelial-to-mesenchymal transition (EMT) process in DU145 and PC3 cell lines, and the overexpression could enhance EMT process in 22RV1 cell line. NR6A1 played a prominent role in migration and invasion of PCa cells, and it is indicated that NR6A1 may act as a novel marker for biochemical recurrence after radical prostatectomy.
Three organotin complexes containing furosemide as a ligand (L), Ph₃SnL, Me₂SnL₂ and Bu₂SnL₂, were synthesized and characterized. Octahedral geometry was proposed for the Me₂SnL₂ and Bu₂SnL₂, while the Ph₃SnL complex has trigonal bipyramid geometry. The synthesized organotin complexes (0.5% by weight) were used as additives to improve the photostability of poly(vinyl chloride), PVC, (40 μm thickness) upon irradiation. The changes imposed on functional groups, weight loss and viscosity average molecular weight of PVC films were monitored. The experimental results show that the rate of photodegradation was reduced in the presence of the organotin additives. The quantum yield of the chain scission was found to be low (9.8 × 10(-7)) when Ph₃SnL was used as a PVC photostabilizer compared to controlled PVC (5.18 × 10(-6)). In addition, the atomic force microscope images for the PVC films containing Ph₃SnL₂ after irradiation shows a smooth surface compared to the controlled films. The rate of PVC photostabilization was found to be highest for Ph₃SnL followed by Bu₂SnL₂ and Me₂SnL₂. It has been suggested that the organotin complexes could act as hydrogen chloride scavengers, ultraviolet absorbers, peroxide decomposers and/or radical scavengers.
Bi2Se3 is a prominent narrow gap semiconductor with a rhombohedral crystal structure and potential applications in thermoelectric and spintronic technologies. Its electrical conduction is ruled by native point defects inducing an n-type degenerate behavior. Here, we present a first principles study of the point defects in Bi2Se3, focusing on the relevance of the interstitial sites. A density functional methodology was employed with van der Waals correction and spin-orbit coupling in order to achieve a better description of the defects. The results indicate that interstitial Bi atoms in octahedral sites between two consecutive quintuple layers have a lower formation energy than selenium vacancies and that these interstitials could act as a possible source of free electron carriers. In addition, we show that the utilization of an experimental or strained lattice constant in the calculations may lead to an under- or overestimation of the defect formation energies.
OBJECTIVE The author describes the creation, structuring, and development of a pediatric neurosurgery telemedicine clinic (TMC) to provide telehealth across geographical, time, social, and cultural barriers. METHODS In July 2009 the University of Florida (UF) Division of Pediatric Neurosurgery received a request from the Southeast Georgia Health District (Area 9-2) to provide a TMC to meet regional needs. The Children's Medical Services (CMS) of the State of Georgia installed telemedicine equipment and site-to-site connectivity. Audiovisual connectivity was performed in the UF Pediatric Neurosurgery office, maintaining privacy and HIPAA (Health Insurance Portability and Accountability Act) requirements. Administrative steps were taken with documentation of onsite training of the secretarial and nursing personnel of the CMS clinic. Patient preregistration and documentation were performed as required by the UF College of Medicine-Jacksonville. Monthly clinics are held with the CMS nursing personnel presenting the pertinent clinical history and findings to the pediatric neurosurgeon in the presence of the patient/parents. Physical findings and diagnostic studies are discussed, and management decisions are made. RESULTS The first TMC was held in August 2011. A total of 40 TMC sessions have been held through January 2016, with a total of 43 patients seen: 13 patients once; 13 patients twice; 8 patients for 3 visits; 2 for 4 visits; 2 for 6 visits; 2 for 5 visits; 2 for 7 visits; and 1 patient has been seen 8 times. CONCLUSIONS Pediatric patients in areas of the continental US and its territories with limited access to pediatric neurosurgery services could benefit from this model, if other pediatric neurosurgery centers provide telehealth services.
We developed a silver decahedral nanoparticles (Ag10NPs)-enhanced ratiometric Fluorescence Resonance Energy Transfer (FRET) nanosensor based on two adjustable FRET modes. Alexa Fluor 488 (Alexa) and Cyanine3 (Cy3)-aptamer-Black hole quencher-2 (BHQ-2) were bound with Ag10NPs to form the ratiometric FRET nanosensor (Ag-Alexa/Cy3/BHQ-2). Alexa act as donor and Cy3 as acceptor in the FRET mode 1 while Cy3 was donor and BHQ-2 was acceptor in the FRET mode 2. In the absence of platelet-derived growth factor (PDGF-BB), the fluorescence intensity of Alexa was lowest while that of Cy3 was highest. Upon the addition of PDGF-BB, Cy3-aptamer-BHQ-2 binds with PDGF-BB resulting in the change of structure of aptamer. The fluorescence intensity of Alexa increased while that of Cy3 decreased. In addition, the fluorescence intensity ratio of Alexa to Cy3 increased remarkably with PDGF-BB concentration in the range of 0.4-400ng/mL. A good linear response was obtained when the PDGF-BB concentrations were in the range of 3.1-200ng/mL, with the limit of detection at 0.4ng/mL. When compared to sensors without Ag10NPs (Alexa/Cy3/BHQ-2) and one without BHQ-2 (Ag-Alexa/Cy3), the new nanosensor Ag-Alexa/Cy3/BHQ-2 showed remarkable increase in sensitivity.
Suboptimal asthma control during pregnancy may impact perinatal outcomes. U.S. guidelines recommend questionnaires to assess asthma control including the Asthma Control Test (ACT).
 It is unknown in a research setting to what extent recall differs by the time between symptom occurrence and the administration of the questionnaire.
Between 2009-2014, 196 pregnant asthmatic women were recruited by the Organization of Teratology Information Specialists (OTIS) MotherToBaby Pregnancy Studies. Participants were administered the ACT at enrollment, gestational weeks 20 and 32, and shortly after delivery. The same women were also administered the ACT retrospectively at approximately 6 months postpartum.
The Pearson correlation coefficients between the in-pregnancy and retrospective continuous ACT scores for the 1st, 2nd and 3rd trimesters were: 0.67 (95% CI: 0.58, 0.74), 0.61 (0.52, 0.70) and 0.65 (0.56, 0.72), respectively. When dichotomized into well-controlled asthma (ACT score ≥ 20) versus otherwise, the chi-square test for all three trimesters resulted in p values <0.0001. Cohen's Kappa statistics for the same dichotomized scores were 0.51, 0.45 and 0.40 for each trimester respectively. There was no evidence that adverse outcome of pregnancy (recall bias) influenced postpartum responses.
The retrospectively recalled ACT score obtained postpartum was substantially different compared to in-pregnancy administration of the same questionnaire which could reflect test-retest variability as well as attenuation of recall. Documentation of the magnitude and direction of these differences could be useful in interpretation of the impact of asthma control when the ACT is used in retrospective case-control studies for pregnancy outcomes.
Nanoscale wrinkling on the surfaces of polymer-based materials can be precisely controlled by depositing thin metal films of varying thicknesses. The deposition of these films fundamentally alters the mechanical properties of the substrates in ways that are not simply described using traditional continuum mechanical frameworks. In particular, we find, by modeling within a finite element analysis approach, that the very act of depositing a metal film may alter the Young's modulus of the polymer substrate to depths of up to a few hundred nanometers, creating a modified interfacial skin layer. We find that simulated wrinkle patterns reproduce the experimentally observed features only when the modulus of this surface layer varies by more than ∼500 nm and is described using a sigmoidal gradient multiplier.
In the United States, over three million people use a wheelchair for their primary means of mobility and they rely on functional and accessible pathways to participate in their communities. The Americans with Disabilities Act Accessibility Guidelines related to pathway roughness are currently ambiguous, subjective and therefore unable to be measured. Consequently, many public pathways are sufficiently rough to result in harmful vibrations and discomfort for wheelchair users. In previous research, subjective ratings and root-mean-square accelerations were reported from subjects traveling over surfaces with various roughnesses in their own wheelchairs. The purpose of the current study is to use previous data to propose roughness thresholds by correlating the roughness of surfaces to vibration data and subjective ratings from wheelchair users. The results suggest a pathway roughness index threshold of ≤50 mm/m (1.2 in./ft) for a surface segment of 100 m (328 ft) in length, and ≤100 mm/m (1.2 in./ft) for a surface segment of 3 m (9.8 ft) in length would protect wheelchair users against discomfort and possible health risks due to vibration exposure. For surfaces of different lengths, a 3 m (9.8 ft) and 100 m (328 ft) moving window should be used.
Fish embryos have become a popular model in ecotoxicology and toxicology. The fish embryo acute toxicity test (FET) with the zebrafish embryo was recently adopted by the OECD as technical guideline TG 236 and a large database of concentrations causing 50% lethality (LC50) is available in the literature. Quantitative Structure-Activity Relationships (QSARs) of baseline toxicity (also called narcosis) are helpful to estimate the minimum toxicity of chemicals to be tested and to identify excess toxicity in existing data sets. Here, we analyzed an existing fish embryo toxicity database and established a QSAR for fish embryo LC50 using chemicals that were independently classified to act according to the non-specific mode of action of baseline toxicity. The octanol-water partition coefficient Kow is commonly applied to discriminate between non-polar and polar narcotics. Replacing the Kow by the liposome-water partition coefficient Klipw yielded a common QSAR for polar and non-polar baseline toxicants. This developed baseline toxicity QSAR was applied to compare the final mode of action (MOA) assignment of 132 chemicals. Further, we included the analysis of internal lethal concentration (ILC50) and chemical activity (La50) as complementary approaches to evaluate the robustness of the FET baseline toxicity. The analysis of the FET dataset revealed that specifically acting and reactive chemicals converged towards the baseline toxicity QSAR with increasing hydrophobicity. The developed FET baseline toxicity QSAR can be used to identify specifically acting or reactive compounds by determination of the toxic ratio and in combination with appropriate endpoints to infer the MOA for chemicals.
Negative urgency-the tendency to act rashly during negative affective states-is a risk factor for regular cigarette smoking. This human laboratory study tested a novel theoretical model of the underlying mechanisms linking negative urgency and smoking motivation, which purports that smokers with high negative urgency are at increased susceptibility to abstinence-induced increases in negative affect, which, in turn, provokes the urge to smoke to suppress negative affect.
Smokers (N = 180, >10 cigarettes/day) attended a baseline session at which they completed self-report measures of negative urgency and other co-factors and subsequently attended two counterbalanced within-subject experimental sessions (i.e., 16 hours of smoking abstinence or smoking as usual). At both experimental sessions, self-reported tobacco withdrawal symptoms, affect, and smoking urge were assessed.
Negative urgency was associated with larger abstinence-induced increases in tobacco withdrawal symptoms, negative affect, and urge to smoke to alleviate negative affect, both with and without controlling for anxiety, depression, tobacco dependence, and sensation seeking (βs > .18, ps < .05). The association between negative urgency and abstinence-induced increases in urge to smoke to alleviate negative affect was mediated by greater abstinence-induced increases in negative affect (βs > .062, ps = .01).
These results provide initial support of this model by providing evidence that smokers with higher (vs. lower) negative urgency may be more prone to greater negative affect during withdrawal, which in turn may promote urge to smoke to suppress negative emotion. Research extending this model to other settings, measures, and methodological approaches may be fruitful.
Prostate cancer (PCa) is a leading cause of male cancer-related deaths. A significant fraction of prostate tumors are very aggressive, often metastasizing to bone, causing significant morbidity and mortality. Also, PCa is associated with high rates of recurrence, often attributed to the existence of cancer stem cells. Epithelial-mesenchymal transition (EMT), a process characterized by decreased expression of epithelial genes and increased expression of mesenchymal genes, plays a critical role in tumor invasion, metastasis and recurrence. In PCa, EMT has been implicated particularly in the context of metastatic disease and microRNAs have emerged as critical post-transcriptional regulators of PCa EMT. In this review, we summarize the role of miRNAs in PCa EMT that play a role in progression, metastasis and recurrence. Studies till date suggest that microRNAs mediate efficient and reversible control of PCa EMT via multiple mechanisms including either by (i) directly repressing single or multiple EMT-TFs or regulating cytoskeletal components (epithelial/mesenchymal genes) or (ii) regulating key signaling pathways involved in EMT. Oncogenic microRNAs often act as EMT promoters by repressing epithelial characteristics and tumor suppressive miRNAs act by inhibiting mesenchymal progression. Further, EMT is mechanistically linked to stem cell signatures in PCa and several miRNAs implicated in EMT have been reported to influence PCa stem cells. Loss of EMT-inhibiting miRNAs and/or gain of EMT promoting miRNAs lead to induction of PCa EMT, leading to tumor progression, metastasis and recurrence. Restoring expression of tumor suppressive miRNAs and inhibiting oncogenic miRNAs represent potential therapeutic opportunities to prevent disease metastasis and recurrence.
Our recent study has shown that αA-crystallin appears to act as a tumor suppressor in pancreas. Here, we analyzed expression patterns of αA-crystallin in the pancreatic tumor tissue and the neighbor normal tissue from 74 pancreatic cancer patients and also pancreatic cancer cell lines. Immunocytochemistry revealed that αA-crystallin was highly expressed in the normal tissue from 56 patients, but barely detectable in the pancreatic tumor tissue. Moreover, a low level of αA-crystallin predicts poor prognosis for patients with pancreatic duct adenocarcinoma (PDAC). In the 12 pancreatic cell lines analyzed, except for Capan-1 and Miapaca-2 where the level of αA-crystallin was about 80% and 65% of that in the control cell line, HPNE, the remaining pancreatic cancer cells have much lower αA-crystallin levels. Overexpression of αA-crystallin in MiaPaca-1 cells lacking endogenous αA-crystallin significantly decreased its tumorigenicity ability as shown in the colony formation and wound healing assays.
 In contrast, knockdown of αA-crystallin in the Capan-1 cells significantly increased its tumorigenicity ability as demonstrated in the above assays. Together, our results further demonstrate that αA-crystallin negatively regulates pancreatic tumorigenesis and appears to be a prognosis biomarker for PDAC.
Non-steroidal anti-inflammatory drugs (NSAIDs) may act through others mechanisms, in addition to inhibition of prostaglandin synthesis. These includes cholinergic, NO, serotonergic and opioids pathways.
The aim of this work was to evaluate the effect of systemic action of (S)-+-ketoprofen (dexketoprofen, DEX) on pain behaviors using the orofacial formalin test in mice and the potential involvement of cholinergic, NO, serotonergic and opioids pathways.
The pretreatment of the mice with 1mg/kg ip of atropine or opoid antagonists: 1mg/kg, ip of NTX or 1mg/kg ip of NTI or 1mg/kg of NOR-BNI ip, did not produce significant change in the ED50 values of the antinociception to orofacial test induced by DEX. The pretreatment of the mice with 0.5mg/kg ip tropisetron, increased in a significant fashion the values of ED50 of DEX. When the mice were treated with 5mg/kg ip of L-NAME or 25mg/kg ip of aminoguanidine or 50mg/kg ip of 7-nitroindazole reversed the antinociception of DEX.
The findings of this study demonstrate activation of NO and 5-HTpathways play important roles in the systemic antinociceptive effect of DEX in a murine model of inflammatory pain.
Adoptive cell therapies (ACTs) using tumor-reactive T cells have shown clinical benefit and potential for cancer treatment. While the majority of the current ACT are focused on using CD8(+) cytotoxic T lymphocytes (CTL), others have shown that the presence of tumor-reactive CD4(+) T helper (Th) cells can greatly enhance the anti-tumor activity of CD8(+) CTL. However, difficulties in obtaining adequate numbers of CD4(+) Th cells through in vitro expansion can limit the application of CD4 Th cells in ACT. This study aims to optimize the culture conditions for mouse CD4 T cells to provide basic information for animal studies of ACT using CD4 T cells. Taking advantage of the antigen-specificity of CD4(+) Th cells from OT-II transgenic mice, we examined different methodologies for generating antigen-specific CD4(+) Th1 cells in vitro. We found that cells grown in complete advanced-DMEM/F12 medium supplemented with low-dose IL-2 and IL-7 induced substantial cell expansion. These Th cells were Th1-like, as they expressed multiple Th1-cytokines and exhibited antigen-specific cytotoxicity. In addition co-transfer of these CD4(+) Th1-like cells with CD8(+) CTL significantly enhanced tumor regression, leading to complete cure in 80% of mice bearing established B16-OVA. These observations indicate that the CD4(+) Th1-like cells generated using the method we optimized are functionally active to eliminate their target cells, and can also assist CD8(+) CTL to enhance tumor regression. The findings of this study provide valuable data for further research into in vitro expansion of CD4(+) Th1-like cells, with potential applications to cancer treatment involving ACT.
T-helper (Th) 0 cell differentiation into Th1 or Th2 cells is dependent on a number of transcription factors that act at specific time points to regulate gene expression. Th17 cells, a subset of interleukin (IL)-17-producing T cells distinct from Th1 or Th2 cells, are considered to exhibit a critical function in inflammation and autoimmune diseases, as well as cancer development. In the present study, the expression of Th1-, Th2- and Th17-associated cytokines in laryngeal cancer and pericarcinoma tissues obtained from 57 laryngeal carcinoma patients was investigated. The association between Th1, Th2 and Th17 infiltration and tumor development was also evaluated. Reverse transcription-polymerase chain reaction and western blotting results revealed that the mRNA and protein expression of Th2 cytokines was lower, while the expression of Th1 and Th17 cytokines was higher in tumor tissues than in pericarcinoma tissues. Furthermore, the early stage cancer patients exhibited a higher level of interferon-γ, IL-2 and IL-17 mRNA expression than those at advanced stages. Cancer tissues exhibited higher Th17 cytokine expression than pericarcinoma tissues. By contrast, Th1 cytokine expression was increased in pericarcinoma tissues compared with cancer tissues. These results indicate that high expression of Th1- and Th17-associated cytokines in laryngeal carcinoma may contribute to suppression of cancer development and a relatively good prognosis.
Studies that only assess differentially-expressed (DE) genes do not contain the information required to investigate the mechanisms of diseases. A complete knowledge of all the direct and indirect interactions between proteins may act as a significant benchmark in the process of forming a comprehensive description of cellular mechanisms and functions. The results of protein interaction network studies are often inconsistent and are based on various methods. In the present study, a combined network was constructed using selected gene pairs, following the conversion and combination of the scores of gene pairs that were obtained across multiple approaches by a novel algorithm. Samples from patients with and without lung adenocarcinoma were compared, and the RankProd package was used to identify DE genes. The empirical Bayesian (EB) meta-analysis approach, the search tool for the retrieval of interacting genes/proteins database (STRING), the weighted gene coexpression network analysis (WGCNA) package and the differentially-coexpressed genes and links package (DCGL) were used for network construction. A combined network was also constructed with a novel rank-based algorithm using a combined score. The topological features of the 5 networks were analyzed and compared. A total of 941 DE genes were screened. The topological analysis indicated that the gene interaction network constructed using the WGCNA method was more likely to produce a small-world property, which has a small average shortest path length and a large clustering coefficient, whereas the combined network was confirmed to be a scale-free network. Gene pairs that were identified using the novel combined method were mostly enriched in the cell cycle and p53 signaling pathway. The present study provided a novel perspective to the network-based analysis. Each method has advantages and disadvantages. Compared with single methods, the combined algorithm used in the present study may provide a novel method to analyze gene interactions, with increased credibility.
Caloric restriction (CR), defined as decreased nutrient intake without causing malnutrition, has been documented to increase both health and lifespan across numerous organisms, including humans. Many drugs and other compounds naturally occurring in our diet (nutraceuticals) have been postulated to act as mimetics of caloric restriction, leading to a wave of research investigating the efficacy of these compounds in preventing age-related diseases and promoting healthier, longer lifespans. Although well studied at the biochemical level, there are still many unanswered questions about how CR and CR mimetics impact genome function and structure. Here we discuss how genome function and structure are influenced by CR and potential CR mimetics, including changes in gene expression profiles and epigenetic modifications and their potential to identify the genetic fountain of youth.
In the first few years of life children spend a good proportion of time sleeping as well as acquiring the meanings of hundreds of words. There is now ample evidence of the effects of sleep on memory in adults and the number of studies demonstrating the effects of napping and nocturnal sleep in children is also mounting. In particular, sleep appears to benefit children's memory for recently-encountered novel words. The effect of sleep on children's generalization of novel words across multiple items, however, is less clear. Given that sleep is polyphasic in the early years, made up of multiple episodes, and children's word learning is gradual and strengthened slowly over time, it is highly plausible that sleep is a strong candidate in supporting children's memory for novel words. Importantly, it appears that when children sleep shortly after exposure to novel word-object pairs retention is better than if sleep is delayed, suggesting that napping plays a vital role in long-term word retention for young children. Word learning is a complex, challenging, and important part of development, thus the role that sleep plays in children's retention of novel words is worthy of attention. As such, ensuring children get sufficient good quality sleep and regular opportunities to nap may be critical for language acquisition.
Somatostatin analogs (SSA) are the mainstay of pharmacological treatment for pituitary adenomas. However, some patients escape from therapy with octreotide, a somatostatin receptor 2 (sst2)-preferring SSA, and pasireotide, a novel multi-sst-preferring SSA, may help to overcome this problem. It has been proposed that correspondence between sst1-sst5 expression pattern and SSA-binding profile could predict patient's response. To explore the cellular/molecular features associated with octreotide/pasireotide response, we performed a parallel comparison of their in vitro effects, evaluating sst1-sst5 expression, intracellular Ca(2+) signaling ([Ca(2+)]i), hormone secretion and cell viability, in a series of 85 pituitary samples. Somatotropinomas expressed sst5>sst2, yet octreotide reduced [Ca(2+)]i more efficiently than pasireotide, while both SSA similarly decreased growth hormone release/expression and viability. Corticotropinomas predominantly expressed sst5, but displayed limited response to pasireotide, while octreotide
 reduced functional endpoints. Non-functioning adenomas preferentially expressed sst3 but, surprisingly, both SSA increased cell viability. Prolactinomas mainly expressed sst1 but were virtually unresponsive to SSA. Finally, both SSA decreased [Ca(2+)]i in normal pituitaries. In conclusion, both SSA act in vitro on pituitary adenomas exerting both similar and distinct effects; however, no evident correspondence was found with the sst1-sst5 profile. Thus, it seems plausible that additional factors, besides the simple abundance of a given sst, critically influence the SSA response.
We report here a genome sequence for Rhodococcus sp. isolate UM008 isolated from the renal/interrenal tissue of the winter skate Leucoraja ocellata Genome sequence analysis suggests that Rhodococcus bacteria may act in a novel mutualistic relationship with their elasmobranch host, serving as biocatalysts in the steroidogenic pathway of 1α-hydroxycorticosterone.
Genome-wide mechanisms that coordinate expression of subsets of functionally related genes are largely unknown. Recent studies show that receptor tyrosine kinases and components of signal transduction cascades including the extracellular signal-regulated protein kinase (ERK), once thought to act predominantly in the vicinity of plasma membrane and in the cytoplasm, can be recruited to chromatin encompassing transcribed genes. Genome-wide distribution of these transducers and their relationship to transcribing RNA polymerase II (Pol2) could provide new insights about co-regulation of functionally related gene subsets. Chromatin immunoprecipitations (ChIP) followed by deep sequencing, ChIP-Seq, revealed that genome-wide binding of epidermal growth factor receptor, EGFR and ERK pathway components at EGF-responsive genes was highly correlated with characteristic mitogen-induced Pol2-profile. Endosomes play a role in intracellular trafficking of proteins including their nuclear import. Immunofluorescence revealed that EGF-activated EGFR, MEK1/2 and ERK1/2 co-localize on endosomes. Perturbation of endosome internalization process, through the depletion of AP2M1 protein, resulted in decreased number of the EGFR containing endosomes and inhibition of Pol2, EGFR/ERK recruitment to EGR1 gene. Thus, mitogen-induced co-recruitment of EGFR/ERK components to subsets of genes, a kinase module possibly pre-assembled on endosome to synchronize their nuclear import, could coordinate genome-wide transcriptional events to ensure effective cell proliferation.
In 2005, Public Act No. 161 (PA 161) was passed in Michigan, allowing dental hygienists to practice in approved public dental prevention programs to provide services for underserved populations while utilizing a collaborative agreement with a supervising dentist. The aims of this study were to assess how well dental and dental hygiene students and faculty members and practicing dental hygienists have been educated about PA 161, what attitudes and knowledge about the act they have, and how interested they are in additional education about it. University of Michigan dental and dental hygiene students and faculty members, students in other Michigan dental hygiene programs, and dental hygienists in the state were surveyed. Respondents (response rate) were 160 dental students (50%), 63 dental hygiene students (82%), 30 dental faculty members (26%), and 12 dental hygiene faculty members (52%) at the University of Michigan; 143 dental hygiene students in other programs (20%); and 95 members of the Michigan Dental Hygienists' Association (10%). The results showed that the dental students were less educated about PA 161 than the dental hygiene students, and the dental faculty members were less informed than the dental hygiene faculty members and dental hygienists. Responding dental hygiene faculty members and dental hygienists had more positive attitudes about PA 161 than did the students and dental faculty members. Most of the dental hygiene faculty members and dental hygienists knew a person providing services in a PA 161 program. Most dental hygiene students, faculty members, and dental hygienists wanted more education about PA 161. Overall, the better educated about the program the respondents were, the more positive their attitudes, and the more interested they were in learning more.
The aggregation of α-synuclein (α-syn) into amyloid fibrils is associated with neurodegenerative diseases, collectively referred to as the α-synucleinopathies. In vivo, molecular chaperones, such as the small heat-shock proteins (sHsps), normally act to prevent protein aggregation; however, it remains to be determined how aggregation-prone α-syn evades sHsp chaperone action leading to its disease-associated deposition. This work examines the molecular mechanism by which two canonical sHsps, αB-crystallin (αB-c) and Hsp27, interact with aggregation-prone α-syn to prevent its aggregation in vitro Both sHsps are very effective inhibitors of α-syn aggregation, but no stable complex between the sHsps and α-syn was detected, indicating that the sHsps inhibit α-syn aggregation via transient interactions. Moreover, the ability of these sHsps to prevent α-syn aggregation was dependent on the kinetics of aggregation; the faster the rate of aggregation (shorter the lag phase), the less effective the sHsps were at inhibiting fibril formation of α-syn. Thus, these findings indicate that the rate at which α-syn aggregates in cells may be a significant factor in how it evades sHsp chaperone action in the α-synucleinopathies.
Histamine seems to act, via H2 receptor, on inflammatory process stimulating interleukin-6 (IL-6) and matrix metalloproteinases (MMPs) release. As cimetidine is a H2 receptor antagonist, we hypothesize that this antiulcer drug reduces IL-6, MMP-1 and MMP-9 immunoexpression in the gingiva with induced periodontal disease (PD). To confirm a possible modulatory role of IL-6 on MMPs, the relationship between IL-6/MMP-1 and IL-6/MMP-9 immunoexpression was evaluated.
Forty-six male rats were distributed into cimetidine group (CimG): received daily intraperitoneal injections of 100mg/kg bw of cimetidine; and saline (SG). PD was induced by cotton ligature around the upper left first molars (PDSG and PDCimG); the right molars were used as controls (SG and CimG). After 7, 15, 30 and 50 days, the maxillary fragments were processed for paraffin-embedding or for transmission electron microscopy. Tartrate-resistant acid phosphatase (TRAP)-positive osteoclasts in the alveolar process surface, and the number of IL-6, MMP-1 and MMP-9-immunolabeled cells in the gingival mucosa were quantified. Statistical analyses were performed (p≤0.05).
In PDSG and PDCimG, the gingival mucosa exhibited few collagen fibers among numerous inflammatory cells. In PDCimG, the number of TRAP-positive osteoclasts and IL-6, MMP-1 and MMP-9-immunolabeled cells was significantly lower than in PDSG, at all periods. A positive correlation between IL-6/MMP-1 and IL-6/MMP-9 was detected in PDSG and PDCimG.
Cimetidine decreases bone loss through reduction of osteoclast number, and induces reduction of IL-6, MMP-1 and MMP-9 immunoexpression, reinforcing that the beneficial effect of cimetidine in PD may be due to reduction of IL-6 immunolabeling in the inflamed gingival mucosa.
Estuaries generally act as sediment traps and may retain a range of contaminants associated to this matrix. Aliphatic hydrocarbons (AHs) were investigated in Capibaribe Estuarine System and adjacent shelf, Northeast of Brazil, to evaluate the contamination and to better understand its functionality related to the coast. Fourteen sediment samples were analyzed, using gas chromatography with flame ionization detection. Total AHs concentrations ranged from 7.5 to 190.3μgg(-1) and n-alkanes ranged from below detection limit (<DL) to 9.47μgg(-1). The highest concentrations were in the upper portion of the estuary, which receives domestic and industrial effluents. The observed UCM and other geochemical markers, indicated contamination by petroleum hydrocarbons. The concentration decrease (about 90%) towards the adjacent shelf suggested an estuarine high retention capacity but dilution and degradation processes cannot be neglected. Similar AHs characteristics reported in sediments from the adjacent shelf suggested that this system may also export contaminants.
In Germany the structures of generalized and specialized palliative care services have considerably increased over the last decade with respect to the number, quality and differentiation. The goal is to improve or to maintain the quality of life for patients with life-threatening illnesses.
The current structures of generalized and specialized palliative care services in Germany are presented.
The structures of healthcare services are presented primarily based on the S3 guidelines on palliative care for patients with incurable cancer. An extrapolation to all patients with incurable illnesses and limited life-expectancy has been carried out.
Palliative care in Germany can be differentiated into two sectors. Generalized palliative care provides care for patients with a low or moderately complex situation on general hospital and oncology wards, in long-term care facilities and in the domestic environment. Specialized palliative care services manage patients with a highly complex situation in palliative care units, by a palliative care support team in hospitals or in palliative medical day care centers and as outpatients in specialized outpatient palliative home care, in specialized palliative outpatient clinics or day care hospices. Inpatient hospices and the outpatient hospice services are overlapping sectors and can be assigned to both generalized and specialized palliative care.
Despite a good development in recent years, a nationwide and sufficient provision of palliative care services has
 still not been achieved and some services have hardly been developed, e. g. palliative outpatient clinics. Hospital palliative care support teams should soon be available in all hospitals caring for patients with life-threatening illnesses, due to the requirements of the Hospice and Palliative Care Act from 2015.
Telomeres are specific structures that protect chromosome ends and act as a biological clock, preventing normal cells from replicating indefinitely. Mammalian telomeres are replicated throughout S-phase in a predetermined order. However, the mechanism of this regulation is still unknown. We wished to investigate this phenomenon under physiological conditions in a changing environment, such as the immortalization process to better understand the mechanism for its control. We thus examined the timing of human telomere replication in normal and SV40 immortalized cells, which are cytogenetically very similar to cancer cells. We found that the timing of telomere replication was globally conserved under different conditions during the immortalization process. The timing of telomere replication was conserved despite changes in telomere length due to endogenous telomerase reactivation, in duplicated homologous chromosomes, and in rearranged chromosomes. Importantly, translocated telomeres, possessing their initial subtelomere, retained the replication timing of their homolog, independently of the proportion of the translocated arm, even when the remaining flanking DNA is restricted to its subtelomere, the closest chromosome-specific sequences (inferior to 500 kb). Our observations support the notion that subtelomere regions strongly influence the replication timing of the associated telomere.
This work presents an experimental design for studying low-velocity collisions into granular surfaces in low-gravity. In the experiment apparatus, reduced-gravity is simulated by releasing a free-falling projectile into a surface container with a downward acceleration less than that of Earth's gravity. The acceleration of the surface is controlled through the use of an Atwood machine, or a system of pulleys and counterweights. The starting height of the surface container and the initial separation distance between the projectile and surface are variable and chosen to accommodate collision velocities up to 20 cm/s and effective accelerations of ∼0.1 to 1.0 m/s(2). Accelerometers, placed on the surface container and inside the projectile, provide acceleration data, while high-speed cameras capture the collision and act as secondary data sources. The experiment is built into an existing 5.5 m drop tower frame and requires the custom design of all components, including the projectile, surface sample container, release mechanism, and deceleration system. Data from calibration tests verify the efficiency of the experiment's deceleration system and provide a quantitative understanding of the performance of the Atwood system.
Fundamental details concerning the interaction between H2 and CH3-Si(111) have been elucidated by the combination of diffractive scattering experiments and electronic structure and scattering calculations. Rotationally inelastic diffraction (RID) of H2 and D2 from this model hydrocarbon-decorated semiconductor interface has been confirmed for the first time via both time-of-flight and diffraction measurements, with modest j = 0 → 2 RID intensities for H2 compared to the strong RID features observed for D2 over a large range of kinematic scattering conditions along two high-symmetry azimuthal directions. The Debye-Waller model was applied to the thermal attenuation of diffraction peaks, allowing for precise determination of the RID probabilities by accounting for incoherent motion of the CH3-Si(111) surface atoms. The probabilities of rotationally inelastic diffraction of H2 and D2 have been quantitatively evaluated as a function of beam energy and scattering angle, and have been compared with complementary electronic structure and scattering calculations to provide insight into the interaction potential between H2 (D2) and hence the surface charge density distribution. Specifically, a six-dimensional potential energy surface (PES), describing the electronic structure of the H2(D2)/CH3-Si(111) system, has been computed based on interpolation of density functional theory energies. Quantum and classical dynamics simulations have allowed for an assessment of the accuracy of the PES, and subsequently for identification of the features of the PES that serve as classical turning points. A close scrutiny of the PES reveals the highly anisotropic character of the interaction potential at these turning points. This combination of experiment and theory provides new and important details about the interaction of H2 with a hybrid organic-semiconductor interface, which can be used to further investigate energy flow in technologically relevant systems.
Frugivorous tephritid fruit flies have lineages with high levels of host generalism. These insects use olfaction to locate fruits, but how they are able to recognize the odors of so many different host species is poorly understood. We used a series of behavioral experiments to investigate the role of fruit ripening volatiles as host cues in the Queensland fruit fly, Bactrocera tryoni (Froggatt), a polyphagous pest in Australia. Odors of mature guava (Psidium guajava) attracted female and male flies more strongly than three other ripening stages and guava pulp. We analyzed volatiles from guava odor and selected eleven compounds, all of which elicited an electrophysiological response in the antenna of female flies. Three of these, ethyl acetate, ethyl butyrate, and ethyl propionate, were released at the highest rates from the most attractive ripening stage. In behavioral trials, these three esters were not attractive individually, whereas a combination was necessary and sufficient in attracting female flies. The three-component blend was as attractive as the entire 11-component blend, which without these key volatiles was not attractive. Moreover, injecting low ranking hosts (squash and cucumber) with the three volatiles increased attraction in ovipositing female flies. These fruit flies are classed as generalists, but like many polyphagous insects they could be regarded as resource specialists, preferring specific plant reproductive stages with predictable odor cues. Exploring olfaction from this perspective could improve our understanding of host choice in polyphagous insects, and the selection of volatiles to be used as attractants in insect pest management.
The cellular response to various stresses is a universal phenomenon and involves a common set of stress responses that are largely independent of the type of stress. The response to stress is complex and cells can activate multiple signaling pathways that act in concert to influence cell fate and results in a specific cellular outcome, including reduction in macromolecular synthesis by shared pathways, cell cycle arrest, DNA repair, senescence and/or apoptosis. Whether cells mount a protective response or die depends to a great degree on the nature and duration of the stress and the particular cell type. Helicases play essential roles in DNA replication, repair, recombination, transcription and translation, and also participate in RNA metabolic processes including pre-mRNA processing, ribosome biogenesis, RNA turnover, export, translation, surveillance, storage and decay. In order to survive in the human host, the malaria parasite Plasmodium falciparum has to handle variety of stresses, which it encounters during the erythrocytic stages of its life cycle. In recent past the role of helicases in imparting various stress responses has emerged. Therefore in the present review an attempt has been made to highlight the emerging importance of helicases in stress responses in malaria parasite and their comparison with human host is also presented. It is noteworthy that PfDHX33 and PfDDX60 are larger in size and different in sequence as compared to the HsDHX33 and HsDDX60. The study suggests that helicases are multifunctional and play major role in helping the cells to combat various stresses.
Heart rhythms arise from electrical activity generated by precisely timed opening and closing of ion channels in individual cardiac myocytes. Opening of the primary cardiac voltage-gated sodium (NaV1.5) channel initiates cellular depolarization and the propagation of an electrical action potential that promotes coordinated contraction of the heart. The regularity of these contractile waves is critically important since it drives the primary function of the heart: to act as a pump that delivers blood to the brain and vital organs. When electrical activity goes awry during a cardiac arrhythmia, the pump does not function, the brain does not receive oxygenated blood, and death ensues. Perturbations to NaV1.5 may alter the structure, and hence the function, of the ion channel and are associated downstream with a wide variety of cardiac conduction pathologies, such as arrhythmias.
The objective of this study was to determine the ability of spermine to act as an antioxidant in scavenging reactive oxygen species (ROS), maintaining sperm function and decreasing cryocapacitation after cryopreservation. Although motility did not increase with spermine treatment, values for membrane integrity were significantly increased (P < 0.05). Higher percentages of linearity and straightness with a lower amplitude of lateral head displacement (ALH) indicated that spermine inhibits hyperactivation. Concentrations of intracellular and extracellular ROS were decreased in the treatment group (P < 0.05). Higher expression of an anti-apoptotic gene (Bcl-2) and lower expression of a pro-apoptotic gene (Bax), together with decreased expression of the mitochondrial ROS
 modulator ROMO1, DNA repair due to oxidative damage (OGG1), spermine synthase (SMS), NADPH oxidase associated with motility (NOX5) and spermine amino oxidase (SMOX), all showed that 5.0 mM spermine treatment was beneficial to spermatozoa. Furthermore, the proportion of live spermatozoa with intact acrosomes after thawing in the treatment group was higher than in the control. After incubation in canine capacitating medium, numbers of live capacitated spermatozoa with reacted acrosomes were higher than in the control. Our results indicate that 5.0 mM spermine is an optimal concentration for maintaining sperm function, reducing ROS production, preventing apoptosis and adverse effects of cryocapacitation during canine sperm cryopreservation.
Multiple animal species exhibit morphological asymmetries in male genitalia. In insects, left-right genital asymmetries evolved many times independently and have been proposed to appear in response to changes in mating position. However, little is known about the relationship between mating position and the interaction of male and female genitalia during mating, and functional analyses of asymmetric morphologies in genitalia are virtually non-existent. We investigated the relationship between mating position, asymmetric genital morphology and genital coupling in the fruit fly Drosophila pachea, in which males possess an asymmetric pair of external genital lobes and mate in an unusual right-sided position on top of the female.
We examined D. pachea copulation by video recording and by scanning electron microscopy of genital complexes. We observed that the interlocking of male and female genital organs in D. pachea is remarkably different from genital coupling in the well-studied D. melanogaster. In D. pachea, the female oviscapt valves are asymmetrically twisted during copulation. The male's asymmetric lobes tightly grasp the female's abdomen in an asymmetric 'locking' position, with the left and right lobes contacting different female structures. The male anal plates, which grasp the female genitalia in D. melanogaster, do not contact the female in D. pachea. Experimental lobe amputation by micro-surgery and laser-ablation of lobe bristles led to aberrant coupling of genitalia and variable mating positions, in which the male was tilted towards the right side of the female.
We describe, for the first time, how the mating position depends on coupling of male and female genitalia in a species with asymmetric genitalia and one-sided mating position. Our results show that D. pachea asymmetric epandrial lobes do not act as a compensatory mechanism for the change from symmetric to one-sided mating position that occurred during evolution of D. pachea's ancestors, but as holding devices with distinct specialized functions on the left and right sides.
This study aimed to evaluate whether GSTM1 and GSTT1 (presents or nulls), GSTP1 c.313A>G and NQO2 c.-102A>C polymorphisms, involved in xenobiotic detoxification pathways, alter outcomes of epithelial ovarian cancer (EOC) patients. DNA from 84 EOC patients diagnosed at the University of Campinas Academic Hospital from January 1995 and July 2007 was analyzed by polymerase chain reaction and restriction fragment length polymorphism assays. The prognostic impact of genotypes of polymorphisms on progression-free survival and overall survival (OS) of EOC patients was examined using the Kaplan-Meier probability estimates and univariate and multivariate Cox proportional hazard ratio (HR) regression analyses. The significant results of Cox analyses were validated using a bootstrap resampling study (1000 replications). At 60 months of follow-up, lower OS was seen in patients with GSTT1 null genotype (50.0 vs. 76.7 %, P = 0.02) compared with the other genotype (Kaplan-Meier estimate). This outcome remained the same in univariate Cox analysis (HR 2.22, P = 0.02). After multivariate Cox analysis, patients with GSTT1 null (HR 2.11, P = 0.04, P bootstrap = 0.04) and NQO2 AA (HR 2.13, P = 0.03, P bootstrap = 0.04) genotypes were under greater risks of progressing to death when compared with those with others genotypes. Our data suggest, for the first time, that inherited abnormalities in xenobiotic detoxification pathway related to GSTT1 and NQO2 c.-102A>C polymorphisms act as independent prognostic factors for OS of EOC patients.
Two cases of hospital-acquired listeriosis were linked to a commercially produced, pasteurized ice cream mix. Manufacturers should implement safety measures from the Food Safety Modernization Act to minimize the risk of Listeria contamination. Dietary guidelines for persons at high risk of listeriosis may need revision to recognize the potential risk from pasteurized products.
The integration of inorganic nanoparticles into polymer matrices allows for the modification of physical properties as well as the implementation of new features for unexplored application fields. Here, we propose the study of a new metal/polymer nanocomposite fabricated by dispersing pure Ti nanoparticles into a poly(methylmetacrilate) matrix via solvent casting process, to investigate its potential use as new biomaterial for biomedical applications. We demonstrated that Ti nanoparticles embedded in the poly(methylmetacrilate) matrix can act as reinforcing agent, not negatively influencing the biological response of human mesenchymal stem cell in terms of cytotoxicity and cell viability. As a function of relative amount and surface treatment, Ti nanoparticles may enhance mechanical strength of the composite-ranging from 31.1 ± 2.5 to 43.7 ± 0.7 MPa-also contributing to biological response in terms of adhesion and proliferation mechanisms. In particular, for 1 wt% Ti, treated Ti nanoparticles improve cell materials recognition, as confirmed by higher cell spreading-quantified in terms of cell area via image analysis-locally promoting stronger interactions at cell matrix interface. At this stage, these preliminary results suggest a promising use of pure Ti nanoparticles as filler in polymer composites for biomedical applications.
During larval molts, C. elegans exhibits a sleep-like state (termed lethargus) that is characterized by the absence of feeding and profound locomotion quiescence. The rhythmic pattern of locomotion quiescence and arousal linked to the molting cycle is mediated by reciprocal changes in sensory responsiveness, whereby arousal is associated with increased responsiveness. Sensory neurons arouse locomotion via release of a neuropeptide (PDF-1) and glutamate. Here we identify a second arousing neuropeptide (FLP-2). We show that FLP-2 acts via an orexin-like receptor (FRPR-18), and that FLP-2 and PDF-1 secretion are regulated by reciprocal positive feedback. These results suggest that the aroused behavioral state is stabilized by positive feedback between two neuropeptides.
To determine the efficacy of pioglitazone to prevent type 2 diabetes in older compared to younger adults with pre-diabetes. Six hundred two participants with impaired glucose tolerance (IGT) were randomized in double blind fashion to placebo or pioglitazone for diabetes prevention in the ACT NOW study (NEJM 364:1104-1115, 2011). Cox proportional hazard regression was used to compare time to development of diabetes over a mean of 2 years between older (≥61 years) and younger participants. We compared effects of pioglitazone versus placebo on metabolic profiles, inflammatory markers, adipokines, β cell function (disposition index), insulin sensitivity (Matsuda index), and body composition by ANOVA. Diabetes incidence was reduced by 85 % in older and 69 % in younger subjects (p = 0.41). β cell function (disposition index) increased by 35.0 % in the older and 26.7 % in younger subjects (p = 0.83). Insulin sensitivity (Matsuda index) increased by 3.07 (5.2-fold) in older and by 2.54 (3.8-fold) in younger participants (p = 0.58). Pioglitazone more effectively increased adiponectin in older versus younger subjects (22.9 ± 3.2 μg/mL [2.7-fold] vs. 12.7 ± 1.4 μg/mL [2.2-fold], respectively; p = 0.04). Younger subjects tended to have a greater increase in whole body fat mass compared to older subjects (3.6 vs. 3.1 kg; p = 0.061). Younger and older subjects had similar decreases in bone mineral density (0.018 ± 0.0071 vs. 0.0138 ± 0.021 g/cm(2)). Younger and older pre-diabetic adults taking pioglitazone had similar reductions in conversion to diabetes and older adults had similar or greater improvements in metabolic risk factors, demonstrating that pioglitazone is useful in preventing diabetes in older adults.
The era of the Obama Administration draws to a close at the end of 2016, leaving behind a signature achievement in the form of the Patient Protection and Affordable Care Act (ACA) that became law in 2010. Beginning with that year, I have contributed an annual essay to the Journal of Allied Health describing various aspects of this legislation. The current essay initially will start down that same path, but then take a sharp detour to discuss related aspects of what is occurring in the broader health domain.
The increase in access to healthcare through the Affordable Care Act highlights the need to track where women seek their office-based care. The objectives of this study were to examine the types of physicians sought by women beyond their customary reproductive years and before being elderly.
This retrospective cohort study involved an analysis of national data from the Medical Expenditure Panel Survey (MEPS) between 2002 and 2012. Women between 45 and 64 years old (n = 44,830) were interviewed, and reviews of corresponding office visits (n = 330,114) were undertaken.
In 2002, women aged 45-64 years (62%) went to a family or internal medicine physician only and this reached 72% in 2012. The percentage of women who went to an obstetrician-gynecologist (ob-gyn) only decreased
 from 20% in 2002 to 12% in 2012. Most went to a family physician or general internist for a general checkup or for diagnosis or treatment. By contrast, visits to ob-gyn physicians were predominantly for general checkups. Those who went to an ob-gyn office were more likely to have a higher family income, live in the Northeast, and describe their overall health as being excellent.
Women aged 45-64 years were substantially more likely to obtain care exclusively at offices of family physicians or general internists than of ob-gyn physicians. Overlap in care provided at more than one physician's office requires continued surveillance in minimizing redundant cost and optimizing resource utilization.
Population and family-based genetic studies typically result in the identification of genetic variants that are statistically associated with a clinical disease or phenotype. For many diseases and traits, most variants are non-coding, and are thus likely to act by impacting subtle, comparatively hard to predict mechanisms controlling gene expression. Here, we describe a general strategic approach to prioritize non-coding variants, and screen them for their function. This approach involves computational prioritization using functional genomic databases followed by experimental analysis of differential binding of transcription factors (TFs) to risk and non-risk alleles. For both electrophoretic mobility shift assay (EMSA) and DNA affinity precipitation assay (DAPA) analysis of genetic variants, a synthetic DNA oligonucleotide (oligo) is used to identify factors in the nuclear lysate of disease or phenotype-relevant cells. For EMSA, the oligonucleotides with or without bound nuclear factors (often TFs) are analyzed by non-denaturing electrophoresis on a tris-borate-EDTA (TBE) polyacrylamide gel. For DAPA, the oligonucleotides are bound to a magnetic column and the nuclear factors that specifically bind the DNA sequence are eluted and analyzed through mass spectrometry or with a reducing sodium dodecyl sulfate polyacrylamide gel electrophoresis (SDS-PAGE) followed by Western blot analysis. This general approach can be widely used to study the function of non-coding genetic variants associated with any disease, trait, or phenotype.
Photoelectrochemical water splitting with metal oxide semiconductors offers a cost-competitive alternative for the generation of solar fuels. Most of the materials studied so far suffer from poor charge-transfer kinetics at the semiconductor/liquid interface, making compulsory the use of catalytic layers to overcome the large overpotentials required for the water oxidation reaction. Herein, we report a very soft electrolytic synthesis deposition method, which allows remarkably enhanced water oxidation kinetics of BiVO4 photoanodes by the sequential addition of Zr and Fe precursors. Upon a heat treatment cycle, these precursors are converted into monoclinic ZrO2 and α-Fe2 O3 nanoparticles, which mainly act as catalysts, leading to a five-fold increase of the water oxidation photocurrent of BiVO4 . This method provides a versatile platform that is easy to apply to different semiconductor materials, fully reproducible, and facile to scale-up on large area conductive substrates with attractive implications for technological deployment.
The Centers for Medicare & Medicaid Services (CMS) has released a proposed rule that details a consolidated pay-for-performance provider payment system within the Medicare Access and CHIP Reauthorization Act. This proposed rule establishes policy for the new provider Merit-Based Incentive System and Alternative Payment Models. While the rule is extremely complex, and not yet finalized, there are significant implications for nursing and advanced practice providers. This proposed rule intends to drastically change the current provider payment system and reward providers who demonstrate better quality outcomes at a lower cost. It also aligns with the current administration's intention to reform the payment and delivery system to a value-based methodology. Within the proposed rule, there is much at stake and will likely transform the way in which providers are reimbursed for Medicare beneficiaries. There are many strategies that can be deployed to help drive success within this new legislation. Among them are a renewed focus on quality outcomes, knowledge of clinical performance, care coordination, and deploying new models of care that address a lower cost structure. It is imperative that nurses and advanced practice providers are aware of this new legislation and how their practice will be implicated by payment reform.
As a result of the Affordable Care Act, innovative strategies must be developed and initiated to work with the Affordable Care Act in order to diminish fragmentation of care delivery and thereby improve quality and reduce costs. It is imperative for health care organizations to explore options from mergers and acquisitions to affiliation agreements in order to prepare for business transformation. Since financial strength combined with independent governance and retention of cultural identity may be optimal, a legal transactional structure such as an affiliation is sometimes the best course of action for a health system. This article explores the affiliation process for health care organizations.
Today's dynamic health care environment is exceedingly complex, and health care facilities across the United States are struggling to respond to changes in technology, health care reimbursement, the Affordable Care Act, and the much-anticipated nursing shortage. Mergers, acquisitions, and integrations are the current health care reality. These are proposed to increase efficiency, efficacy, quality, satisfaction, and safety while effectively reducing cost to the consumer and stabilizing the economy of the health care system. Many of these projects fail to achieve objectives, even years after the formal change in status. Clinical education departments in merged organizations are often operated in the single-facility mindset, or contain an element of the shared services model. They are not truly integrated. Development of skills in complex analysis of current state, identification of desired scope of service and expectations of performance, and articulation of the benefits of the desired future state are all essential to nursing executive practice. This article describes an experience integrating 3 legacy education departments across 21 facilities into a centralized education system. The complexity of integration activities is illustrated and outcome measures of success are discussed. Barriers, facilitators, and risks of the project are identified and evaluated.
Topological insulators (TIs) are renowned for their exotic topological surface states (TSSs) that reside in the top atomic layers, and hence, detailed knowledge of the surface top atomic layers is of utmost importance. Here we present the remarkable morphology changes of Bi2Te3 surfaces, which have been freshly cleaved in air, upon subsequent systematic annealing in ultrahigh vacuum and the resulting effects on the local and area-averaging electronic properties of the surface states, which are investigated by combining scanning tunneling microscopy (STM), scanning tunneling spectroscopy (STS), and Auger electron spectroscopy (AES) experiments with density functional theory (DFT) calculations. Our findings demonstrate that the annealing induces the formation of a Bi bilayer atop the Bi2Te3 surface. The adlayer results in n-type doping, and the atomic defects act as scattering centers of the TSS electrons. We also investigated the annealing-induced Bi bilayer surface on Bi2Te3 via voltage-dependent quasi-particle-interference (QPI) mapping of the surface local density of states and via comparison with the calculated constant-energy contours and QPI patterns. We observed closed hexagonal patterns in the Fourier transform of real-space QPI maps with secondary outer spikes. DFT calculations attribute these complex QPI patterns to the appearance of a "second" cone due to the surface charge transfer between the Bi bilayer and the Bi2Te3. Annealing in ultrahigh vacuum offers a facile route for tuning of the topological properties and may yield similar results for other topological materials.
Over the past decades, the dichotomy between innate and adaptive immune responses has largely dominated our understanding of immunology. Upon primary encounter with microbial pathogens, differentiation of adaptive immune cells into functional effectors usually takes several days or even longer, making them contribute to host protection only late during primary infection. However, once generated, antigen-experienced T lymphocytes can persist in the organism and constitute a pool of memory cells that mediate fast and effective protection to a recall infection with the same microbial pathogen. Herein, we challenge this classical paradigm by highlighting the "innate nature" of memory CD8+ T cells. First, within the thymus or in the periphery, naïve CD8+ T cells may acquire phenotypic and functional characteristics of memory CD8+ T cells independently of challenge with foreign antigens. Second, both the "unconventional" and the "conventional" memory cells can rapidly express protective effector functions in response to sets of inflammatory cytokines and chemokines signals, independent of cognate antigen triggering. Third, memory CD8+ T cells can act by orchestrating the recruitment, activation, and licensing of innate cells, leading to broad antimicrobial states. Thus, collectively, memory CD8+ T cells may represent important actors of innate immune defenses.
Human success and even survival depends on our ability to predict what others will do by guessing what they are thinking. If I accelerate, will he yield? If I propose, will she accept?
 If I confess, will they forgive? Psychologists call this capacity "theory of mind." According to current theories, we solve this problem by assuming that others are rational actors. That is, we assume that others design and execute efficient plans to achieve their goals, given their knowledge. But if this view is correct, then our theory of mind is startlingly incomplete. Human action is not always a product of rational planning, and we would be mistaken to always interpret others' behaviors as such. A wealth of evidence indicates that we often act habitually-a form of behavioral control that depends not on rational planning, but rather on a history of reinforcement. We aim to test whether the human theory of mind includes a theory of habitual action and to assess when and how it is deployed. In a series of studies, we show that human theory of mind is sensitive to factors influencing the balance between habitual and planned behavior.
It has long been known that breakfast skipping is associated with obesity; however, well controlled clinical trials have only recently been conducted to determine a causative relationship.
Skipping breakfast is likely to be detrimental for insulin sensitivity; however, randomized trials suggest that it does not play a large role in weight gain or weight loss. Specific breakfast strategies such as certain types of breakfast, and consuming more calories in the morning relative to the evening, however, may produce greater weight loss.
The act of eating breakfast, compared to skipping it, does not appear to have a large impact on body weight. More specific strategies regarding the size and type of breakfast may be required for a substantial effect on weight loss, and improving glycemic regulation may be an important reason to consume breakfast rather than skipping it.
Chemical denaturants are the most commonly used agents for unfolding proteins and are thought to act by better solvating the unfolded state. Improved solvation is expected to lead to an expansion of unfolded chains with increasing denaturant concentration, providing a sensitive probe of the denaturant action. However, experiments have so far yielded qualitatively different results concerning the effects of chemical denaturation. Studies using Förster resonance energy transfer (FRET) and other methods found an increase in radius of gyration with denaturant concentration, but most small-angle X-ray scattering (SAXS) studies found no change. This discrepancy therefore challenges our understanding of denaturation mechanism and more generally the accuracy of these experiments as applied to unfolded or disordered proteins. Here, we use all-atom molecular simulations to investigate the effect of urea and guanidinium chloride on the structure of the intrinsically disordered protein ACTR, which can be studied by experiment over a wide range of denaturant concentration. Using unbiased molecular simulations with a carefully calibrated denaturant model, we find that the protein chain indeed swells with increasing denaturant concentration. This is due to the favorable association of urea or guanidinium chloride with the backbone of all residues and with the side-chains of almost all residues, with denaturant-water transfer free energies inferred from this association in reasonable accord with experimental estimates. Interactions of the denaturants with the backbone are dominated by hydrogen bonding, while interactions with side-chains include other contributions. By computing FRET efficiencies and SAXS intensities at each denaturant concentration, we show that the simulation trajectories are in accord with both experiments on this protein, demonstrating that there is no fundamental inconsistency between the two types of experiment. Agreement with experiment also supports the picture of chemical denaturation described in our simulations, driven by weak association of denaturant with the protein. Our simulations support some assumptions needed for each experiment to accurately reflect changes in protein size, namely, that the commonly used FRET chromophores do not qualitatively alter the results and that possible effects such as preferential solvent partitioning into the interior of the chain do not interfere with the determination of radius of gyration from the SAXS experiments.
In bacteria, two-component systems act as signaling systems to respond to environmental stimuli. Two-component systems generally consist of a sensor histidine kinase and a response regulator, which work together through histidyl-aspartyl phosphorelay to result in gene regulation. One of the two-component systems in Escherichia coli, CusS-CusR, is known to induce expression of cusCFBA genes at increased periplasmic Cu(I) and Ag(I) concentrations to help maintain metal ion homeostasis. CusS is a membrane-associated histidine kinase with a periplasmic sensor domain connected to the cytoplasmic ATP binding and catalytic domains through two transmembrane helices. The mechanism of how CusS senses increasing metal ion concentrations and activates CusR is not yet known. Here, we present the crystal structure of the Ag(I)-bound periplasmic sensor domain of CusS at a resolution of 2.15 Å. The structure reveals that CusS forms a homodimer with four Ag(I) binding sites per dimeric complex. Two symmetric metal binding sites are found at the dimeric interface, which are each formed by two histidines and one phenylalanine with an unusual cation-π interaction. The other metal ion binding sites are in a nonconserved region within each monomer. Functional analyses of CusS variants with mutations in the metal sites suggest that the metal ion binding site at the dimer interface is more important for function. The structural and functional data provide support for a model in which metal-induced dimerization results in increases in kinase activity in the cytoplasmic domains of CusS.
Loach minnow (Rhinichthys cobitis) and spikedace (Meda fulgida) are legally protected with the status of Endangered under the U.S. Endangered Species Act and are endemic to the Gila River basin of Arizona and New Mexico. Efficient and sensitive methods for monitoring these species' distributions are critical for prioritizing conservation efforts. We developed quantitative PCR assays for detecting loach minnow and spikedace DNA in environmental samples. Each assay reliably detected low concentrations of target DNA without detection of non-target species, including other cyprinid fishes with which they co-occur.
Suture is the surgical final act in most of oral surgery's procedures. Quality of advisable healing after the operation depends on its efficiency. Suture must not be cause of inflammation, both in direct way and indirect. The objective of this study is to compare the bacterial colonization on different suture's materials after a third molar's extraction.
30 patients were randomly selected among people going under third molar extraction; they were divided into 3 groups and one suture type was used on each group. After 7 days distal stitches were removed by a single operator, placed in physiologic solution and analyzed after 2 or 3 hours. Patients followed the same post surgical protocols; materials used were: Silk 4/0 ETHICON, Dafilon©️ BIBRAUN 4/0, Safil©️ BIBRAUN 4/0.
The amount of cocci and bacilli on the sutures analyzed shows that silk (Silk by ETHICON®) is the higher level of retention material where monofilament (Dafilon by BIBraun®) is the lower. There is a difference between monofilament and poliglicolic material (Safil by BIBraun®): the first one is less retentive but not statistically significant.
A less plaque retention, and consequently a fewer bacterial presence, is crucial to minimize the inflammatory process and allow a better tissue healing. Since the capability of brushing and, of course, the final personal hygiene is dependent from different variables, we must use surgical protocols able to minimize the effect of improper cleaning on the healing process: this statement implies the use of low plaque retention materials. Suture is the final surgical act and deliver a suture with monofilament or poliglicolic threads can help reducing bacterial concentration and therefore allow a faster and better healing.
Mountain pine beetle (Dendroctonus ponderosae) has killed millions of hectares of pine forests in western North America. Beetle success is dependent upon a community of symbiotic fungi comprised of Grosmannia clavigera, Ophiostoma montium, and Leptographium longiclavatum. Factors regulating the dynamics of this community during pine infection are largely unknown. However, fungal volatile organic compounds (FVOCs) help shape fungal interactions in model and agricultural systems and thus may be important drivers of interactions among bark beetle-associated fungi. We investigated whether FVOCs can mediate interspecific interactions among mountain pine beetle's fungal symbionts by affecting fungal growth and reproduction. Headspace volatiles were collected and identified to determine species-specific volatile profiles. Interspecific effects of volatiles on fungal growth and conidia production were assessed by pairing physically-separated fungal cultures grown either on a carbon-poor or -rich substrate, inside a shared-headspace environment. Fungal VOC profiles differed by species and influenced the growth and/or conidia production of the other species. Further, our results showed that FVOCs can be used as carbon sources for fungi developing on carbon-poor substrates. This is the first report demonstrating that FVOCs can drive interactions among bark beetle fungal symbionts, and thus are important factors in beetle attack success.
Immunization is the process or the act of making individuals immune, which is usually done during childhood. Everyone is aware about immunization during childhood,
 however, very few know about adult immunization. This led us to review the adult immunization literature for the preventive strategies through various vaccination protocols. Adults do require vaccination protocols with booster doses for hepatitis B, Shingles, communicable diseases, traveler's diseases, etc. In this context, this article revises much of the available adult immunization literature and presents comprehensive guidelines. This article will increase the awareness regarding the importance of vaccination for adults to prevent a variety of conditions prevalent in our country as well as epidemics. The article comprehensively provides insights into the available vaccination and preventive strategy of human papilloma virus (HPV), hepatitis, and human immunodeficiency virus (HIV) infection in this part of the review. We strongly recommend all the health care professionals to educate their co-professionals and the public to use the benefits of adult immunization. It is the need of the hour and reduces the burden of treatment and increases productivity.
This study examined in real time the role of sleep and daydreaming as potentiating states for subsequent dissociation in depersonalization/derealization disorder (DDD). Research and theory suggests that dissociation may be exacerbated and maintained by a labile sleep-wake cycle in which "dream-like" mentation intrudes into waking life and fuels dissociative symptoms. We explore and extend this idea by examining the state of daydreaming in dissociation. Daydreaming is a state of consciousness between dreaming and waking cognition that involves stimulus-independent and task-unrelated mentation. We report the results of a unique intensive N = 1 study with an individual meeting diagnostic criteria for DDD. Using experience-sampling methodology, the participant rated (six times daily for 40 days) current daydreaming, mood, and dissociative symptoms. At the start of each day sleep quality and duration was also rated. Daydreaming was reported on 45% of occasions and significantly predicted greater dissociation, in particular when daydreams were repetitive and negative (but not fanciful) in content. These relationships were mediated by feelings of depression and anxiety. Sleep quality but not duration was a negative predictor of daily dissociation and also negatively predicted depression but not anxiety. Findings offer initial evidence that the occurrence and content of daydreams may act as potentiating states for heightened, in the moment, dissociation. The treatment implications of targeting sleep and daydreaming for dissociative disorders are discussed.
Compared with acute pain that arises suddenly in response to a specific injury and is usually treatable, chronic pain persists over time, and is often resistant to medical treatment. Because of the heterogeneity of chronic pain origins, satisfactory therapies for its treatment are lacking, leading to an urgent need for the development of new treatments. The leading approach in drug design is selective compounds, though they are often less effective and require chronic dosing with many side effects. Herein, we review novel approaches to drug design for the treatment of chronic pain represented by dual-acting compounds, which operate at more than one biological target. A number of studies suggest the involvement of the cannabinoid and vanilloid receptors in pain. Interestingly cannabinoid system is in interrelation with other systems that comprise lipid mediators: prostaglandins, produced by COX enzyme. Therefore, in the present review, we summarize the role of dual-acting molecules (FAAH/TRPV1 and FAAH/COX-2 inhibitors) that interact with endocannabinoid and endovanillinoid systems and act as analgesics by elevating the endogenously produced endocannabinoids and dampening the production of pro-inflammatory prostaglandins. The plasticity of the endocannabinoid system (ECS) and the ability of a single chemical entity to exert an activity on two receptor systems has been developed and extensively investigated. Here, we review up-to-date pharmacological studies on compounds interacting with FAAH enzyme together with TRPV1 receptor or COX-2 enzyme respectively. Multi-target pharmacological intervention for treating pain may lead to the development of original and efficient treatments.
The tangerine pathotype of Alternaria alternata produces the A. citri toxin (ACT) and is the causal agent of citrus brown spot that results in significant yield losses worldwide. Both the production of ACT and the ability to detoxify reactive oxygen species (ROS) are required for A. alternata pathogenicity in citrus. In this study, we report the 34.41 Mb genome sequence of strain Z7 of the tangerine pathotype of A. alternata. The host selective ACT gene cluster in strain Z7 was identified, which included 25 genes with 19 of them not reported previously. Of these, 10 genes were present only in the tangerine pathotype, representing the most likely candidate genes for this pathotype specialization. A transcriptome analysis of the global effects of H2O2 on gene expression revealed 1108 up-regulated and 498 down-regulated genes. Expressions of those genes encoding catalase, peroxiredoxin, thioredoxin and glutathione were highly induced. Genes encoding several protein families including kinases, transcription factors, transporters, cytochrome P450, ubiquitin and heat shock proteins were found associated with adaptation to oxidative stress. Our data not only revealed the molecular basis of ACT biosynthesis but also provided new insights into the potential pathways that the phytopathogen A. alternata copes with oxidative stress.
The recent discovery of multiple giant dsDNA viruses blurred the consensual distinction between viruses and cells due to their size, as well as their structural and genetic complexity. A dramatic feature revealed by these viruses as well as by many positive-strand RNA viruses is their ability to rapidly form elaborate intracellular organelles, coined viral factories where viral progeny are continuously generated. Here we report the first isolation of viral factories at progressive post-infection time-points. The isolated factories were subjected to mass spectrometry-based proteomics, bioinformatics and imaging analyses. These analyses reveal that numerous viral proteins are present in the factories but not in mature virions, thus implying that multiple and diverse proteins are required to promote the efficiency of viral factories as 'production lines' of viral progeny. Moreover, our results highlight the dynamic and highly complex nature of viral factories, provide new and general insights into viral infection, and substantiate the intriguing notion that viral factories may represent the living state of viruses.
Large dsDNA viruses such as Vaccinia and the giant Mimivirus, as well as many positive-strand RNA viruses, generate elaborate cytoplasmic organelles in which the multiple and diverse transactions required for viral replication and assembly occur. These organelles, which were coined 'viral factories', are attracting much interest due to the increasing realization that the rapid and continuous production of viral progeny is a direct outcome of the elaborate structure and composition of the factories, which act as efficient 'production lines'. To get new insights into the nature and function of viral factories, we devised a method that allows, for the first time, the isolation of these organelles. Analyses of the isolated factories generated at different times post-infection by mass spectrometry-based proteomics provide new perceptions on their role and reveal the highly dynamic nature of these organelles.
Hyperglycaemia in diabetes is either caused by reduced availability of insulin (type 1 diabetes, T1D) or insulin resistance to the cells (type 2 diabetes, T2D). In recent years, the prevalence of T2D has increased to an alarming proportion, encompassing 95 percent of the total diabetic burden, probably due to economy-driven changes in lifestyle. Recent epidemiological studies show comorbid depression, anxiety and related mental illness. To explore the molecular mechanisms underlying this comorbid conditions, we used Sprague-Dawley rats on high-fructose diet for 8 weeks to induce prediabetic condition. Rats with this metabolic syndrome also showed hyper-anxiety when they were subjected to anxiety-related behavioural assays. Rats were administered with resveratrol, an activator of sirtuins, and metformin, a standard antidiabetic drug, simultaneously with fructose. We observed that resveratrol was more effective in protecting from both the metabolic (prediabetic) and affective (anxiety) disorders than metformin. Molecular studies showed that recovery was associated with the upregulation of few nuclear sirtuins that act epigenetically - Sirt 1 and 7, which were significantly attenuated in the striatum of prediabetic rats. In conclusion, our study showed that hyper-anxiety associated with prediabetic condition is ameliorated by resveratrol through modulation of sirtuins, which is more or less similar to metformin.
Emerging diseases are a major challenge to public health. Revealing the evolutionary processes that allow novel pathogens to adapt to new hosts, also the potential barriers to host adaptation, is central to understanding the drivers of disease emergence. In particular, it is unclear how the genetics and ecology of pathogens interact to shape the likelihood of successful cross-species transmission. To better understand the determinants of host adaptation and emergence, we modelled key aspects of pathogen evolutionary dynamics at both intra- and inter-host scales, using parameter values similar to those observed in influenza virus. We considered the possibility of acquiring the necessary host adaptive mutations both
 before ('off-the-shelf' emergence) and after ('tailor-made' emergence) a virus is transmitted from a donor to a new recipient species. Under both scenarios, population bottlenecks at inter-host transmission act as a major barrier to host adaptation, greatly limiting the number of adaptive mutations that are able to cross the species barrier. In addition, virus emergence is hindered if the fitness valley between the donor and recipient hosts is either too steep or too shallow. Overall, our results reveal where in evolutionary parameter space a virus could adapt to and become transmissible in a new species.
With the introduction of the Youth Act in 2015, the Dutch Ministry of Health has taken a step back from child and adolescent mental health care (CAMHC). This act placed CAMHC under the responsibility of the municipalities, as part of a programme of integrated youth care. Care at municipal level offers unique possibilities for the timely identification of problems and disturbances in adolescence. However, the prevalence of severe mental disorder in adolescents (2%), is too low for specialised CAMHC to be offered in each of the 390 Dutch municipalities. CAMHC needs to be organised at a supraregional level. Since the introduction of the Youth Act there has been a disturbing lack of coherence and a time- and money-devouring new bureaucracy at this level that threatens the survival of CAMHC. The Ministry of Health should step forward to safeguard the efforts of the Association of Netherlands Municipalities and CAMHC professional organisations to maintain and foster supraregional services.
Longevity assurance homolog 2 of yeast LAG1 (LASS2) has been reported to act as an important tumor suppressor in the development of human cancers. However, little is known about the prognostic value of LASS2 in hepatocellular carcinoma (HCC) . In the present study, we analyzed correlation between LASS2 and TGF-β1 levels, and evaluated their prognostic values in HCC patients. We first analyzed the expression of LASS2 and TGF-β1 in two independent cohorts (test cohort: 184 HCC patients; validation cohort: 118 HCC patients) using immunohistochemistry (IHC). Kaplan-Meier survival and Cox regression analyses were executed to evaluate the prognosis of HCC. The results of IHC analysis revealed a positive correlation between the expression of LASS2 and TGF-β1. HCC Patients with low expression of LASS2 and TGF-β1 had shorter overall survival (OS) and time to recurrence (TTR) than patients with high expression of LASS2 and TGF-β1. Furthermore, combination of LASS2 and TGF-β1 was an independent and significant risk factor for OS and TTR. In conclusion, low expression of LASS2 and TGF-β1 contributes to the aggressiveness and poor prognosis of HCC, and may represent a novel prognostic biomarker for HCC patients.
Regulatory CD4+ Foxp3+ T cells (Tregs) are critical in controlling immunity and tolerance. Thus, preserving Treg numbers and function in transplanted patients is essential for the successful minimization of maintenance immunosuppression. Multiple cellular signals control the development, differentiation, and function of Tregs. Many of these signals are shared with conventional Foxp3(-) T cells (Tconv) and are targeted by immunosuppressive drugs, negatively affecting both Tregs and Tconv. Because intracellular signals vary in optimal intensity in different T cell subsets, improved specificity in immunosuppressive regimens must occur to benefit long-term transplant outcomes. In this regard, recent advances are gradually uncovering differences in the signals required in Tregs and Tconv biology, opening the door to new potential therapeutic approaches to either enhance or spare Tregs. In this review, we will explain the prominent cell signaling pathways critical for Treg maintenance and function, while reporting the effects of immunosuppressive drugs targeting these signaling pathways in clinical transplantation settings.
In order to investigate the chiral benzedrine molecules corresponding to their different characteristics in biochemical systems, we studied their interaction with D3 R using the docking method, molecular dynamic simulation, and quantum chemistry. The obtained results indicate that the active residues for R-benzedrine (RAT) bound with D3 R are Ala132, Asp133, and Tyr55, while Asn57, Asp133, Asp168, Cys172, Gly54, Trp24, and Vall136 act as the active residues for S-benzedrine (SAT). The different active pockets are observed for ART or SAT because they possess different active residues. The binding energies between RAT and SAT with D3 R were determined to be -44.0 kJ.mol(-1) and -71.2 kJ.mol(-1) , respectively. These results demonstrate that SAT within the studied pocket of D3 R has a stronger capability of binding with D3 R, while it is more feasible for RAT to leave from the interior positions of D3 R. In addition, the results suggest that the D3 R protein can recognize chiral benzedrine molecules and influence their different addictive and pharmacological effects in biochemical systems. Chirality 28:674-685, 2016. © 2016 Wiley Periodicals, Inc.
p21-activated kinase 1 (Pak1)-a key node protein kinase regulating various cellular process including angiogenesis-has been recognised to be a therapeutic target for multitude of diseases, and hence, various small molecule inhibitors targeting its activity have been tested. However, the direct toxic and anti-angiogenic effects of these pharmacologic agents have not been examined. In this study, we evaluate the translational efficacy of Pak1 inhibitor IPA-3 using zebrafish toxicity model system to stratify its anti-angiogenic potential and off-target effects to streamline the compound for further therapeutic usage. The morphometric analysis has shown explicit delay in hatching, tail bending, pericardial sac oedema and abnormal angiogenesis. We provide novel evidence that Pak1 inhibitor could act as anti-angiogenic agents by impeding the development of sub-intestinal vessel (SIV) and intersegmental vessels (ISVs) by suppressing the expression of vascular endothelial growth factor (VEGF), VEGF receptor 2 (VEGFR2), neurophilin 1 (NRP1) and its downstream genes matrix metalloproteinase (MMP)-2 and MMP-9. Knockdown studies using 2-O-methylated oligoribonucleotides targeting Pak1 also revealed similar phenotypes with inhibition of angiogenesis accompanied with deregulation of major angiogenic factor and cardiac-specific genes. Taken together, our findings indicate that Pak1 signalling facilitates enhanced angiogenesis and also advocated the design and use of small molecule inhibitors of Pak1 as potent anti-angiogenic agents and suggest their utility in combinatorial therapeutic approaches targeting anomalous angiogenesis.
The bran from polished rice grains can be used to produce rice bran oil (RBO). High oleic (HO) RBO has been generated previously through RNAi down-regulation of OsFAD2-1. HO-RBO has higher oxidative stability and could be directly used in the food industry without hydrogenation, and is hence free of trans fatty acids. However, relative to a classic oilseed, lipid metabolism in the rice grain is poorly studied and the genetic alteration in the novel HO genotype remains unexplored.
Here, we have undertaken further analysis of role of OsFAD2-1 in the developing rice grain. The use of Illumina-based NGS transcriptomics analysis of developing rice grain reveals that knockdown of Os-FAD2-1 gene expression was accompanied by the down regulation of the expression of a number of key genes in the lipid biosynthesis pathway in the HO rice line. A slightly higher level of oil accumulation was also observed in the HO-RBO.
Prominent among the down regulated genes were those that coded for FatA, LACS, SAD2, SAD5, caleosin and steroleosin. It may be possible to further increase the oleic acid content in rice oil by altering the expression of the lipid biosynthetic genes that are affected in the HO line.
The aim of this study is to investigate how socioeconomic position (SEP) is associated with multidimensional measures of successful aging (SA), and how this varies and accumulates across the life-course.
Using data from 1,733 Scottish men and women from two cohorts aged around 57 and 76, respectively, we explored associations of SA, based on the Rowe-Kahn model, with 10 measures of SEP measured in childhood and, distally and proximally, in adulthood.
Individual SEP associations with SA score were generally consistent across different indicators and life stages: Respondents with the most versus least favorable SEP had two additional positive SA dimensions. There was also a strong association between SA and cumulative SEP based on all 10 measures combined; respondents with the most versus least favorable lifelong SEP had four additional positive SA dimensions.
SEP advantages/disadvantages act and accumulate across the life-course, resulting in widening socioeconomic inequalities in SA in later life.
Sharon Wilson is a community organizer for the nonprofit organization Earthworks. After leaving her office job managing data for the oil and gas industry, she started organizing in response to negative impacts from unconventional oil and gas extraction methods near her Texas home and throughout the state. She describes the environmental health impacts of oil and gas development aided by new technologies and regulatory exemptions set forth by the 2005 Energy Policy Act. Production has spread to previously unexplored regions over the last decade, including her property on the Barnett Shale in North Texas, where she has interacted with energy corporations and observed the intensification of residents' health issues. I structured the questions in this interview to highlight her unique perspective on organizing in relation to current regulatory loopholes, health impacts of oil and gas development, and
 the experiences individuals have had with representatives from the industry.
Recent genetic studies yielded conflicting results regarding a role for the variant chromogranin B (CHGB)(P413L) allele as a disease modifier in ALS. Moreover, potential deleterious effects of the CHGB(P413L) variant in ALS pathology have not been investigated. Here we report that in transfected cultured cells, the variant CHGB(L413) protein exhibited aberrant properties including mislocalization, failure to interact with mutant superoxide dismutase 1 (SOD1) and defective secretion. The CHGB(L413) transgene in SOD1(G37R) mice precipitated disease onset and pathological changes related to misfolded SOD1 specifically in female mice. However, the CHGB(L413) variant also slowed down disease progression in SOD1(G37R) mice, which is in line with a very slow disease progression that we report for a Swedish woman with ALS who is carrier of two mutant SOD1(D90A) alleles and two variant CHGB(P413L) and CHGB(R458Q) alleles. In contrast, overexpression of the common CHGB(P413) allele in SOD1(G37R) mice did not affect disease onset but significantly accelerated disease progression and pathological changes. As in transgenic mice, the CHGB(P413L) allele conferred an earlier ALS disease onset in women of Japanese and French Canadian origins with less effect in men. Evidence is presented that the sex-dependent effects of CHGB(L413) allelic variant in ALS may arise from enhanced neuronal expression of CHGB in females because of a sex-determining region Y element in the gene promoter. Thus, our results suggest that CHGB variants may act as modifiers of onset and progression in some ALS populations and especially in females because of higher expression levels compared to males.
An increase in global temperatures will impact future crop yields. In the cereal crops wheat and barley, high temperatures accelerate reproductive development, reducing the number of grains per plant and final grain yield. Despite this relationship between temperature and cereal yield, it is not clear what genes and molecular pathways mediate the developmental response to increased temperatures. The plant circadian clock can respond to changes in temperature and is important for photoperiod-dependent flowering, and so is a potential mechanism controlling temperature responses in cereal crops. This study examines the relationship between temperature, the circadian clock, and the expression of flowering-time genes in barley (Hordeum vulgare), a crop model for temperate cereals. Transcript levels of barley core circadian clock genes were assayed over a range of temperatures. Transcript levels of core clock genes CCA1, GI, PRR59, PRR73, PRR95, and LUX are increased at higher temperatures. CCA1 and PRR73 respond rapidly to a decrease in temperature whereas GI and PRR59 respond rapidly to an increase in temperature. The response of GI and the PRR genes to changes in temperature is lost in the elf3 mutant indicating that their response to temperature may be dependent on a functional ELF3 gene.
A mixed-method study was conducted in the Rift Valley of Kenya to characterise drug-dispensing practices amongst staff at animal health outlets and to explore perceptions of veterinary medicines amongst pastoralists and farmers. Forty structured questionnaires were administered to staff at animal health outlets, including franchise outlets of 'Sidai Africa Ltd.', and two focus group discussions were facilitated to explore the perceptions of local animal health services by a Maasai pastoralist group and a dairy farmer cooperative. Differences were detected in the characteristics of Sidai outlets, agrovets, pharmacies and dukas. A greater proportion of Sidai outlet staff selected drugs based on principles of responsible drug use than staff at other types of outlet, and technical qualifications and training were associated with responsible drug use. Across all outlet types, staff knowledge and training gaps were identified, including in the correct administration of medicines. The majority of drug sales are accompanied by verbal advice to farmers. Members of the Maasai pastoralist group were concerned about accidental self-medication, withdrawal periods, drug residues and the misuse of drugs due to a lack of quality information and advice. The dairy farmer group raised similar concerns, reporting under-dosing as a common mistake amongst farmers. This study concludes that current knowledge, attitudes and practices of many service providers and livestock owners in the sale, purchase and use of veterinary medicines present risks of drug misuse and therefore the emergence of antimicrobial resistance. There is a clear demand from livestock keepers for accessible, affordable and quality animal health services and products in Kenya, and animal health practitioners have the potential to provide increased support to livestock-based livelihoods and act as stewards of our existing portfolio of animal and human medicines.
Consumption of sugar-sweetened beverages (SSBs) is associated with increased risk of obesity, diabetes, heart disease and dental caries. Our aim was to assess the effects of plain packaging, warning labels, and a 20 % tax on predicted SSB preferences, beliefs and purchase probabilities amongst young people.
A 2 × 3 × 2 between-group experimental study was conducted over a one-week period in August 2014. Intervention scenarios were delivered, and outcome data collected, via an anonymous online survey. Participants were 604 New Zealand young people aged 13-24 years who consumed soft drinks regularly. Participants were randomly allocated using a computer-generated algorithm to view one of 12 experimental conditions, specifically images of branded versus plain packaged SSBs, with either no warning, a text warning, or a graphic warning, and with or without a 20 % tax. Participant perceptions of the allocated SSB product and of those who might consume the product were measured using seven-point Likert scales. Purchase probabilities were measured using 11-point Juster scales.
Six hundred and four young people completed the survey (51 % female, mean age 18 (SD 3.4) years). All three intervention scenarios had a significant negative effect on preferences for SSBs (plain packaging: F (6, 587) = 54.4, p <0.001; warning label: F (6, 588) = 19.8, p <0.001; 20 % tax: F (6, 587) = 11.3, p <0.001). Plain packaging and warning labels also had a significant negative impact on reported likelihood of purchasing SSB's (p = <0.001). A 20 % tax reduced participants' purchase probability but the difference was not statistically significant (p = 0.2).
Plain packaging and warning labels significantly reduce young people's predicted preferences for, and reported probability of purchasing, SSBs.
The Food and Drug Administration (FDA) is amending its regulations governing drug establishment registration and drug listing. These amendments reorganize, modify, and clarify current regulations concerning who must register establishments and list human drugs, human drugs that are also biological products, and animal drugs. The final rule requires electronic submission, unless waived in certain circumstances, of registration and listing information. This rulemaking pertains to finished drug products and to active pharmaceutical ingredients (APIs) alone or together with one or more other ingredients. The final rule describes how and when owners or operators of establishments at which drugs are manufactured or processed must register their establishments with FDA and list the drugs they manufacture or process. In addition, the rule makes certain changes to the National Drug Code (NDC) system. We are taking this action to improve management of drug establishment registration and drug listing requirements and make these processes more efficient and effective for industry and for us. This action also supports implementation of the electronic prescribing provisions of the Medicare Prescription Drug, Improvement, and Modernization Act of 2003 (MMA) and the availability of current drug labeling information through DailyMed, a computerized repository of drug information maintained by the National Library of Medicine.
The recent reform of the English National Health Service (NHS) through the Health and Social Care Act of 2012 introduced important changes in the organization, management, and provision of public health services in England. This study aims to analyze the NHS reforms in the historical context of predominance of neoliberal theories since 1980 and to discuss the "liberalization" of the NHS. The study identifies and analyzes three phases: (i) gradual ideological and theoretical substitution (1979-1990) - transition from professional and health logic to management and commercial logic; (ii) bureaucracy and incipient market (1991-2004) - structuring of the bureaucracy focused on administration of the internal market and expansion of pro-market measures; and (iii) opening to the market, fragmentation, and discontinuity of services (2005-2012) - weakening of the territorial health model and consolidation of health as an open market for public and private providers. This gradual but constant liberalization has closed services and restricted access, jeopardizing the system's comprehensiveness, equity, and universal healthcare entitlement in the NHS.
Recent studies indicate that long noncoding RNAs (lncRNAs) can act as competing endogenous RNAs (ceRNAs) to indirectly regulate mRNAs through shared microRNAs, which represents a novel layer of RNA crosstalk and plays critical roles in the development of tumor. However, the global regulation landscape and characterization of these lncRNA related ceRNA crosstalk in cancers is still largely unknown. Here, we systematically characterized the lncRNA related ceRNA interactions across 12 major cancers
 and the normal physiological states by integrating multidimensional molecule profiles of more than 5000 samples. Our study suggest the large difference of ceRNA regulation between normal and tumor states and the higher similarity across similar tissue origin of tumors. The ceRNA related molecules have more conserved features in tumor networks and they play critical roles in both the normal and tumorigenesis processes. Besides, lncRNAs in the pan-cancer ceRNA network may be potential biomarkers of tumor. By exploring hub lncRNAs, we found that these conserved key lncRNAs dominate variable tumor hallmark processes across pan-cancers. Network dynamic analysis highlights the critical roles of ceRNA regulation in tumorigenesis. By analyzing conserved ceRNA interactions, we found that miRNA mediate ceRNA regulation showed different patterns across pan-cancer; while analyzing the cancer specific ceRNA interactions reveal that lncRNAs synergistically regulated tumor driver genes of cancer hallmarks. Finally, we found that ceRNA modules have the potential to predict patient survival. Overall, our study systematically dissected the lncRNA related ceRNA networks in pan-cancer that shed new light on understanding the molecular mechanism of tumorigenesis.
The Rags represent a unique family of evolutionarily conserved, heterodimeric, lysosome-localized small GTPases that play an indispensible role in regulating cellular metabolism in response to various amino acid signaling mechanisms. Rapid progress in the field has begun to unveil a picture in which Rags act as central players in translating information regarding cellular amino acid levels by modulating their nucleotide binding status through an ensemble of support proteins localized in and around the lysosomes. By cooperating with other signaling pathways that converge on the lysosomes, Rags promote anabolic processes through positively affecting mTORC1 signaling in the presence of abundant amino acids. Conversely, Rag inactivation plays an indispensible role in switching cellular metabolism into a catabolic paradigm by promoting the activity of the master lysosomal/autophagic transcription factors TFEB and TFE3. Precise control of Rag signaling is necessary for cells to adapt to constantly changing cellular demands and emerging evidence has highlighted their importance in a wide variety of developmental and pathological conditions.
The natural killer cell receptor NKG2D activates NK cells by engaging one of several ligands (NKG2DLs) belonging to either the MIC or ULBP families. Human cytomegalovirus (HCMV) UL16 and UL142 counteract this activation by retaining NKG2DLs and US18 and US20 act via lysomal degradation but the importance of NK cell evasion for infection is unknown. Since NKG2DLs are highly conserved in rhesus macaques, we characterized how NKG2DL interception by rhesus cytomegalovirus (RhCMV) impacts infection in vivo. Interestingly, RhCMV lacks homologs of UL16 and UL142 but instead employs Rh159, the homolog of UL148, to prevent NKG2DL surface expression. Rh159 resides in the endoplasmic reticulum and retains several NKG2DLs whereas UL148 does not interfere with NKG2DL expression. Deletion of Rh159 releases human and rhesus MIC proteins, but not ULBPs, from retention while increasing NK cell stimulation by infected cells. Importantly, RhCMV lacking Rh159 cannot infect CMV-naïve animals unless CD8+ cells, including NK cells, are depleted. However, infection can be rescued by replacing Rh159 with HCMV UL16 suggesting that Rh159 and UL16 perform similar functions in vivo. We therefore conclude that cytomegaloviral interference with NK cell activation is essential to establish but not to maintain chronic infection.
Although the Affordable Care Act has been successful in expanding Medicaid to >17 million people, insurance alone may not translate into access to health care. Even among the insured, substantial barriers to accessing services inhibit health care utilization.
We examined the effect of selected barriers to health care access and the magnitude of those barriers on health care utilization.
Data come from a 2008 survey of adult enrollees in Minnesota's public health care programs. We used multivariate logistic regression to estimate the effects of perceived patient, provider, and system-level barriers on past year delayed, foregone, and lack of preventive care.
A total of 2194 adults enrolled in Minnesota Health Care Programs who were mostly female (66%), high school graduates (76%), unemployed (62%), and living in metro areas (67%) were included in the analysis.
Reporting problems across all barriers increased the odds of delayed care from 2 times for provider-related barriers (OR=2.0; 95% CI, 1.2-3.3) to >6 times for access barriers (OR=6.2; 95% CI, 3.8-10.2) and foregone care from 2.6 times for family/work barriers (OR=2.6; 95% CI, 1.3-5.1) to >7 times for access barriers (OR=7.1; 95% CI, 3.9-13.1). Perceived discrimination was the only barrier consistently associated with all 3 utilization outcomes.
Multiple types of barriers are associated with delayed and foregone care. System-level barriers and discrimination have the greatest effect on health care seeking behavior.
Children's Full Service Partnerships (FSP), created through California's Mental Health Services Act of 2004 are comprehensive treatment and support programs incorporating a wraparound model designed to serve undertreated families with children who have a serious emotional disturbance and are at risk for suicide, violence, residential instability, criminal justice involvement, or involuntary hospitalization.
This study investigated whether FSP programs resulted in reduced crisis-related mental health emergency services (MHES) for the children they served.
Using a statewide data set for 464,880 children and youth ages 11to <18 served by California's county mental health systems between 2004 and 2012, the study compared age-related trajectories of MHES use for FSP-served children before and after treatment alongside children in usual care. Estimates were made within stratified age groups (11 to <15 and 15 to <18), utilizing propensity score adjusted random effects for each child's increasing age to control individual differences in MHES likelihood and trajectory, while controlling for age, cohort, county of service, and clinical and demographic covariates.
Before treatment in FSP, FSP-served children showed higher and increasing MHES rates initially, reflecting greater severity. After FSP treatment, FSP-served children's MHES trajectory declined more rapidly than those of controls.
There is strong evidence for the success of FSP's aggressive approach in reducing dangerous, increasing trajectories in MHES use. More research is needed, but key efficacious components within the program may be candidates for broader application when providing community-based, crisis-averting care for the most socially and economically vulnerable, seriously mentally ill children and youth.
By 2050, adults aged 80 years and over will represent around 20% of the global population. Little is known about how adults surviving into very old age use hospital services over time.
The objective of the study was to examine patterns of hospital usage over a 10-year period for women who were aged 84 to 89 in 2010 and examine factors associated with increased use.
Survey data from 1936 women from the 1921 to 1926 cohort of the Australian Longitudinal Study on Women's Health were matched with the state-based Admitted Patients Data Collection. Hospital use profiles were determined using repeated measures latent class analysis.
Four latent class trajectories were identified. One-quarter of the sample were at low risk of hospitalization, while 20.6% demonstrated increased risk of hospitalization and a further 38.1% had moderate hospitalization risk over time. Only 16.8% of the sample was classified as having high hospitalization risk. Correlates of hospital use for very old women differed according to hospital use class and were contingent on the timing of exposure (ie, short-term or long-term).
Despite the perception that older adults place a significant burden on health care systems, the majority of women demonstrated relatively low hospital use over an extended period, even in the presence of chronic health conditions. High hospitalization risk was found to be concentrated among a small minority of these long-term survivors. The findings suggest the importance of service planning and treatment regimes that take account of the diverse trajectories of hospital use into and through advanced old age.
Although Hmgn5 is involved in the regulation of cellular proliferation and differentiation, its physiological function during decidualization is still unknown. Here we showed that Hmgn5 was highly expressed in the decidual cells. Silencing of Hmgn5 expression by specific siRNA reduced the proliferation of uterine stromal cells and expression of Ccnd3 and Cdk4 in the absence or presence of estrogen and progesterone, whereas overexpression of Hmgn5 exhibited the opposite effects. Simultaneously, Hmgn5 might induce the expression of Prl8a2 and Prl3c1 which were 2 well-known differentiation markers for decidualization. In the uterine stromal cells, cAMP analog 8-Br-cAMP and progesterone could up-regulate the expression of Hmgn5, but the up-regulation was impeded by H89 and RU486, respectively. Attenuation of Hmgn5 expression could block the differentiation of uterine stromal cells in response to cAMP and progesterone. Further studies found that regulation of cAMP and progesterone on Hmgn5 expression was mediated by Hoxa10. During in vitro decidualization, knockdown of Hmgn5 could abrogate Hoxa10-induced upregulation of Prl8a2 and Prl3c1, while overexpression of Hmgn5 reversed the inhibitory effects of Hoxa10 siRNA on the expression of Prl8a2
 and Prl3c1. In the stromal cells undergoing decidualization, Hmgn5 might act downstream of Hoxa10 to regulate the expression of Cox-2, Vegf and Mmp2. Collectively, Hmgn5 may play an important role during mouse decidualization.
The Medicare Modernization Act, with its requirements for Medicare Part D to comply with electronic prescribing (e-prescribing), bolstered the adoption of e-prescribing, which increased to 73% in 2013. Therefore, understanding whether electronic prescriptions are less likely to be picked up is important as e-prescribing continues to be emphasized.
To assess whether prescription origin is among the factors associated with initial medication adherence, using claim reversals as a proxy measure.
A cross-sectional study was completed using a sample of reversed claims from the Pharmaceutical Assistance Contract for the Elderly (PACE) program for September 2014. The total number of reversed claims for new prescriptions (15,966) was categorized by prescription origin (written, telephone, electronic, fax, and pharmacy). Using a chi-square analysis, the reversed claims were compared among prescription origin to determine if there is a difference in the proportion of electronic prescriptions reversed compared with those from other origins.
When compared with all other prescription origins, electronic prescriptions (E) were more likely to be reversed at day 0 (E = 50%, any other [AO] = 49%, P < 0.05) and after day 0 (E = 58%, AO = 42%, P < 0.05).
Electronic prescriptions are associated with a higher rate of claim reversals and may reflect poorer initial adherence. Electronic prescriptions may more likely be forgotten or not picked up because they were not presented to the pharmacy by the patient. The growing adoption of electronic prescriptions merits particular attention, since it may be a factor in initial medication adherence in the elderly.
This study was not supported by any funding. Peterson reports advisory board and consultancy fees from IMS Health and Pfizer and employment by Genentech. Klaiman is currently employed by AccessMatters. No other financial or other conflicts of interests were reported. Study concept and design were primarily contributed by Forestal, along with Klaiman and Peterson. Heller took the lead in data collection, along with Forestal, and data interpretation was performed by Forestal, Klaiman, and Peterson. Forestal, Klaiman, and Heller were responsible for manuscript preparation.
Clinical inertia, which has been defined as the recognition of a problem with a patient's management but failing to act, is a concern in type 2 diabetes (T2D) because it places the patient at risk of diabetes-related complications. Despite managed care organizations making significant investment in this area, little is known about the impact of educational programs aimed at aligning patients and their physicians with diabetes guidelines and thus overcoming clinical inertia.
To assess the impact of an educational intervention specifically designed to align patients and their physicians with 2012 American Diabetes Association (ADA) guidelines on glycated hemoglobin (A1c) testing frequency and insulin initiation.
The "Act on Threes" educational intervention was a 12-month, randomized controlled prospective study that included Medicare Advantage patients aged 18-85 years with T2D, who received ≥ 3 oral antidiabetes drugs (OADs) and/or had A1c not at goal and/or had no recent A1c evaluation over 12 months, as identified through the analysis of administrative claims data (May 1, 2011-April 30, 2013) from the Humana database. Identified patients were randomized 3:1 to receive the Act on Threes educational intervention in conjunction with standard care (intervention group) or standard care alone (control group). For the educational intervention, patients and physicians were simultaneously mailed general and targeted information aimed at aligning them to 3 vital aspects of A1c control: timely measurement of A1c every 3 months; timely treatment intensification to meet A1c goals with treatment intensification every 3 months if A1c is not at goal; and insulin initiation when appropriate, including patients receiving ≥ 3 OADs with A1c not at goal. Control patients were only enrolled if the treating physician was not involved in the care of any patients in the intervention group. The primary outcome measures were A1c testing frequency based on the ADA standard for compliance of ≥ 2 tests per year and insulin initiation in the 12-month postintervention period. A1c levels were evaluated for the subgroup of patients with available A1c measurements in the pre- and postintervention periods. Descriptive statistics were used to analyze differences between the intervention and control groups. Multiple logistic regression analysis was used to identify determinants of insulin initiation in the full study cohort.
6,243 patients (mean age 70 years; 43.5% female) were identified: 4,555 were randomized to the intervention group and 1,688 to the control group. The percentage of patients with ≥ 2 A1c tests per year was not significantly different postintervention for patients in the intervention and control groups (47.7% vs. 46.8%, respectively; P = 0.995). Intriguingly, the frequency of A1c testing increased significantly from pre- to postintervention in the intervention and control groups. Change in A1c level from pre- to postintervention was also similar for the 2 groups (P = 0.240). A similar percentage of patients in the intervention and control groups initiated insulin during the postintervention period (6.3% vs. 7.6%, respectively; P = 0.059).
This randomized controlled study demonstrated that, compared with standard care, the Act on Threes educational intervention combined with standard care did not result in any significant differences in the frequency of A1c testing or in the initiation of insulin in patients with T2D. These findings are in contrast to uncontrolled comparative studies showing significant improvements in outcomes postintervention and reinforce the importance of study design in evaluating the effectiveness of educational programs.
This study was funded by Sanofi U.S. Reynolds, Davis, Kamble, and Uribe are employees of Comprehensive Health Insights, which was contracted by Sanofi U.S. to conduct, publish, and present this study. Bieszk and Wei are employees of Sanofi U.S. Reynolds and Uribe provided expertise and key clinical insights for the study design and methodology, provided interpretations of the data, contributed to the discussion, and reviewed the manuscript. Bieszk and Wei codeveloped the study design, researched data, contributed to discussion, and reviewed the manuscript. Davis and Kamble collected the data, provided study design, clinical insights, statistical and analytic reflections of the data, drafted the study reports, and reviewed the manuscript. All authors had full access to all the data in the study. Reynolds is the guarantor of this work and, as such, takes responsibility for the integrity of the data and the accuracy of the data analysis.
Writing/editorial support in the preparation of this manuscript, which was funded by Sanofi U.S., was provided by Rosalie Gadiot, PhD, of Excerpta Medica, who wrote the initial draft of the manuscript.
This research article reports on factors influencing initial voluntary uptake of community-based health insurance (CBHI) schemes in low- and middle-income countries (LMIC), and renewal decisions.
Following PRISMA protocol, we conducted a comprehensive search of academic and gray literature, including academic databases in social science, economics and medical sciences (e.g., Econlit, Global health, Medline, Proquest) and other electronic resources (e.g., Eldis and Google scholar). Search strategies were developed using the thesaurus or index terms (e.g., MeSH) specific to the databases, combined with free text terms related to CBHI or health insurance. Searches were conducted from May 2013 to November 2013 in English, French, German, and Spanish. From the initial search yield of 15,770 hits, 54 relevant studies were retained for analysis of factors influencing enrolment and renewal decisions. The quantitative synthesis (informed by meta-analysis) and the qualitative analysis (informed by thematic synthesis) were compared to gain insight for an overall synthesis of findings/statements.
Meta-analysis suggests that enrolments in CBHI were positively associated with household income, education and age of the household head (HHH), household size, female-headed household, married HHH and chronic illness episodes in the household. The thematic synthesis suggests the following factors as enablers for enrolment: (a) knowledge and understanding of insurance and CBHI, (b) quality of healthcare, (c) trust in scheme management. Factors found to be barriers to enrolment include: (a) inappropriate benefits package, (b) cultural beliefs, (c) affordability, (d) distance to healthcare facility, (e) lack of adequate legal and policy frameworks to support CBHI, and (f) stringent rules of some CBHI schemes. HHH education, household size and trust in the scheme management were positively associated with member renewal decisions. Other motivators were: (a) knowledge and understanding of insurance and CBHI, (b) healthcare quality, (c) trust in scheme management, and (d) receipt of an insurance payout the previous year. The barriers to renewal decisions were: (a) stringent rules of some CBHI schemes, (b) inadequate legal and policy frameworks to support CBHI and (c) inappropriate benefits package.
The demand-side factors positively affecting enrolment in CBHI include education, age, female household heads, and the socioeconomic status of households. Moreover, when individuals understand how their CBHI functions they are more likely to enroll and when people have a positive
 claims experience, they are more likely to renew. A higher prevalence of chronic conditions or the perception that healthcare is of good quality and nearby act as factors enhancing enrolment. The perception that services are distant or deficient leads to lower enrolments. The second insight is that trust in the scheme enables enrolment. Thirdly, clarity about the legal or policy framework acts as a factor influencing enrolments. This is significant, as it points to hitherto unpublished evidence that governments can effectively broaden their outreach to grassroots groups that are excluded from social protection by formulating supportive regulatory and policy provisions even if they cannot fund such schemes in full, by leveraging people's willingness to exercise voluntary and contributory enrolment in a community-based health insurance.
Emerging data support a role for antibody Fc-mediated antiviral activity in vaccine efficacy and in the control of HIV-1 replication by broadly neutralizing antibodies. Antibody-mediated virus internalization is an Fc-mediated function that may act at the portal of entry whereby effector cells may be triggered by pre-existing antibodies to prevent HIV-1 acquisition. Understanding the capacity of HIV-1 antibodies in mediating internalization of HIV-1 virions by primary monocytes is critical to understanding their full antiviral potency. Antibody isotypes/subclasses differ in functional profile, with consequences for their antiviral activity. For instance, in the RV144 vaccine trial that achieved partial efficacy, Env IgA correlated with increased risk of HIV-1 infection (i.e. decreased vaccine efficacy), whereas V1-V2 IgG3 correlated with decreased risk of HIV-1 infection (i.e. increased vaccine efficacy). Thus, understanding the different functional attributes of HIV-1 specific IgG1, IgG3 and IgA antibodies will help define the mechanisms of immune protection. Here, we utilized an in vitro flow cytometric method utilizing primary monocytes as phagocytes and infectious HIV-1 virions as targets to determine the capacity of Env IgA (IgA1, IgA2), IgG1 and IgG3 antibodies to mediate HIV-1 infectious virion internalization. Importantly, both broadly neutralizing antibodies (i.e. PG9, 2G12, CH31, VRC01 IgG) and non-broadly neutralizing antibodies (i.e. 7B2 mAb, mucosal HIV-1+ IgG) mediated internalization of HIV-1 virions. Furthermore, we found that Env IgG3 of multiple specificities (i.e. CD4bs, V1-V2 and gp41) mediated increased infectious virion internalization over Env IgG1 of the same specificity, while Env IgA mediated decreased infectious virion internalization compared to IgG1. These data demonstrate that antibody-mediated internalization of HIV-1 virions depends on antibody specificity and isotype. Evaluation of the phagocytic potency of vaccine-induced antibodies and therapeutic antibodies will enable a better understanding of their capacity to prevent and/or control HIV-1 infection in vivo.
Patients with anorexia nervosa (AN) are at high risk of reduced bone mass. Osteocalcin (OC), a bone formation marker, has been proposed to act as a link between bone and energy metabolism. We investigated how the 3 forms of OC respond during a 12-week intensive nutrition therapy in AN patients, in whom large changes in energy metabolism are expected.Twenty-two female AN patients, mean 20.9 years of age, with a starting mean body mass index (BMI) 15.5 kg/m(2) (minimum-maximum) (13.4-17.3 kg/m(2)) completed the study. Biochemical markers, body composition, bone mass by DXA, and pQCT were assessed. Subjects gained in median 9.9 kg (5.5-17.0 kg), and BMI increased from median 15.4 kg/m(2) (13.4-17.3 kg/m(2)) to 19.0 kg/m(2) (16.2-20.6 kg/m(2)), p<0.0001. Fat mass increased from median 11.4% (4.4-24.8%) to 26.7% (16.9-39.8%). Total OC, carboxylated OC (cOC), undercarboxylated OC (ucOC), and bone-specific alkaline phosphatase (BALP) increased during the study period. No change was observed for the resorption marker carboxy-terminal cross-linking telopeptide of type I collagen (CTX). Total body bone mineral content (BMC) increased, but no changes were found for whole body or lumbar spine bone mineral density. Tibial trabecular density measured by pQCT decreased. Total OC, cOC, and ucOC were not associated with BMI, insulin or body composition parameters. This prospective study demonstrates that all 3 forms of OC (total OC, cOC, ucOC) increase during rapid weight gain. BALP increased while the resorption marker CTX was unchanged, which corroborate with the increased total body BMC.
The GMA committee for dentistry of the German Society for Medical Education (GMA) considers its' main purpose the representation and interconnection of all aspects of dentistry with and within the GMA. Teaching and assessing practical skills during training is traditionally of great importance in dental education. This is also reflected in the National Competence Based Catalogue of Learning Objectives for Dental Education (NKLZ). Practical skills are not comprised in a separate chapter as they are in the National Competence Based Catalogue of Learning Objectives for Medical Education (NKLM), but are considered in all sections of the NKLZ for the purpose of interdisciplinary patient- or disease-specific application, targeting the educational level of acting competency. The implementation of the associated joined interdisciplinary integrated educational concept has undoubtedly been a challenge for dental curriculum development against the backdrop of German Dental Licensure Act dating back to 1955.
Der Ausschuss Zahnmedizin der Gesellschaft für Medizinische Ausbildung (GMA) sieht seine Hauptaufgabe in der themenübergreifenden Vertretung und Vernetzung des Faches Zahnmedizin mit und innerhalb der GMA. In der Zahnmedizin ist die Vermittlung und Überprüfung praktischer Fertigkeiten traditionell von großer Bedeutung in der Ausbildung. Dies spiegelt sich auch im Nationalen Lernzielkatalog Zahnmedizin (NKLZ) wieder. Die praktischen Fertigkeiten sind nicht wie im Nationalen Lernzielkatalog Medizin (NKLM) in einem eigenen Kapitel zusammengefasst, sondern finden im Sinne einer fachübergreifenden patienten- bzw. erkrankungsspezifischen Anwendung in allen Abschnitten des NKLZ Berücksichtigung, und es wird häufig der Ausbildungslevel der Handlungskompetenz angestrebt. Die Umsetzung des damit verbundenen integrierten fachübergreifenden Ausbildungskonzeptes stellt für die zahnärztliche Curriculumsentwicklung vor dem Hintergrund einer seit 1955 gültigen Approbationsordnung zweifellos eine Herausforderung dar.
Interleukin-33 (IL-33), the most recently discovered member of the IL-1 superfamily, has been linked to several human pathologies including autoimmune diseases, sepsis, and allergy through its specific IL-1 receptor ST2. However, there is little information regarding the role of IL-33 in gout. In this study, we investigated the potential role of IL-33 in gout patients. The serum level of IL-33 was measured by ELISA, and the clinical and laboratory parameters, serum creatinine, urea, and lipid, were extracted from medical record system. The serum IL-33 expression was predominantly increased in gout patients compared to healthy controls, and the IL-33 levels were higher in patients without kidney injury. Furthermore, IL-33 showed a negative correlation with biomarkers of kidney injury, such as CRE and urea. The lipid metabolism dysfunction, tophi, and hypertension are the common reasons for kidney injury in gout. Interestingly, inverse and positive correlation of IL-33 expression was observed in LDL and HDL, respectively. However, there was no significant alteration in the gout patients with hypertension and tophi. These data suggested that IL-33 might act as a protective role in kidney injury through regulating the lipid metabolism in gout.
Gamma-aminobutyric acid type-A receptors (GABAARs) belong to multisubunit membrane spanning ligand-gated ion channels (LGICs) which act as the principal mediators of rapid inhibitory synaptic transmission in the human brain. Therefore, the category prediction of GABAARs just from the protein amino acid sequence would be very helpful for the recognition and research of novel receptors. Based on the proteins' physicochemical properties, amino acids composition and position, a GABAAR classifier was first constructed using a 188-dimensional (188D) algorithm at 90% cd-hit identity and compared with pseudo-amino acid composition (PseAAC) and ProtrWeb web-based algorithms for human GABAAR proteins. Then, four classifiers including gradient boosting decision tree (GBDT), random forest (RF), a library for support vector machine (libSVM), and k-nearest neighbor (k-NN) were compared on the dataset at cd-hit 40% low identity. This work obtained the highest correctly classified rate at 96.8% and the highest specificity at 99.29%. But the values of sensitivity, accuracy, and Matthew's correlation coefficient were a little lower than those of PseAAC and ProtrWeb; GBDT and libSVM can make a little better performance than RF and k-NN at the second dataset. In conclusion, a GABAAR classifier was successfully constructed using only the protein sequence information.
Metformin can act in muscle, inhibiting the complex I of the electron transport chain and decreasing mitochondrial reactive oxygen species. Our hypothesis is that the inhibition of complex I can minimize damage oxidative in muscles of hypoinsulinemic rats. The present study investigated the effects of insulin and/or metformin treatment on oxidative stress levels in the gastrocnemius muscle of diabetic rats. Rats were rendered diabetic (D) with an injection of streptozotocin and were submitted to treatment with insulin (D+I), metformin (D+M), or insulin plus metformin (D+I+M) for 7 days. The body weight, glycemic control, and insulin resistance were evaluated.
 Then, oxidative stress levels, glutathione antioxidant defense system, and antioxidant status were analyzed in the gastrocnemius muscle of hypoinsulinemic rats. The body weight decreased in D+M compared to ND rats. D+I and D+I+M rats decreased the glycemia and D+I+M rats increased the insulin sensitivity compared to D rats. D+I+M reduced the oxidative stress levels and the activity of catalase and superoxide dismutase in skeletal muscle when compared to D+I rats. In conclusion, our results reveal that dual therapy with metformin and insulin promotes more benefits to oxidative stress control in muscle of hypoinsulinemic rats than insulinotherapy alone.
Jie-Geng-Tang (JGT), a classic and famous traditional Chinese medicine (TCM) prescription composed of Platycodon grandiflorum (Jacq.) A. DC. (PG) and Glycyrrhiza uralensis Fisch. (GU), is well known for "clearing heat and relieving toxicity" and its ability to "diffuse the lung and relieve sore throat." However, the mechanism underlying its action remains unclear. In this study, potential anti-inflammatory ingredients were screened and submitted to PharmMapper and the KEGG bioinformatics website to predict the target proteins and related pathways, respectively. Differentially expressed candidate proteins from acute lung injury (ALI) mice treated with JGT were identified by isobaric tags for relative and absolute quantitation (iTRAQ) and LC Triple-TOF. Eleven potential anti-inflammatory ingredients were found, including the derivatives of glycyrrhizic acid, licorice-saponin, liquiritin, and platycodigenin. A total of sixty-seven differentially expressed proteins were confirmed after JGT treatment with four therapeutic functions, including immunoregulation, anti-inflammation, ribosome, and muscle contraction. PG and GU comediate PI3K/Akt signal pathway inhibition of NF-κB, VCAM1, and ICAM1 release which primarily act on PI3K, PDK1, AKT, and GSK3β. GU markedly inhibits the ERK/MAPK signaling pathways and primarily acts on LCK, RAS, and MEK. A network was constructed using bioactive ingredients, targets, and pathways to determine the mechanism underlying JGT treatment of ALI.
Tumor angiogenesis plays very important roles for tumorigenesis, tumor development, metastasis, and prognosis. Targeting T1/T2 dual modality magnetic resonance (MR) imaging of the tumor vascular endothelial cells (TVECs) with MR molecular probes can greatly improve diagnostic sensitivity and specificity, as well as helping to make an early diagnosis of tumor at the preclinical stage. In this study, a new T1 and T2 dual modality nanoprobe was successfully fabricated. The prepared nanoprobe comprise peptides CL 1555, poly(ε-caprolactone)-block-poly(ethylene glycol) amphiphilic copolymer shell, and dozens of manganese ferrite (MnFe2O4) nanoparticle core. The results showed that the hydrophobic MnFe2O4 nanoparticles were of uniform spheroidal appearance and narrow size distribution. Due to the self-assembled nanomicelles structure, the prepared probes were of high relaxivity of 281.7 mM(-1) s(-1), which was much higher than that of MnFe2O4 nanoparticles (67.5 mM 1 s(-1)). After being grafted with the targeted CD105 peptide CL 1555, the nanomicelles can combine TVECs specifically and make the labeled TVECs dark in T2-weighted MR imaging. With the passage on, the Mn(2+) ions were released from MnFe2O4 and the size decreased gradually, making the signal intensity of the second and third passage of labeled TVECs increased in T1-weighted MR imaging. Our results demonstrate that CL-poly(ethylene glycol)-MnFe2O4 can conjugate TVECs and induce dark and bright contrast in MR imaging, and act as a novel molecular probe for T1- and T2-enhanced MR imaging of tumor angiogenesis.
Excessive bleeding and allogeneic transfusion during adult post-cardiotomy venoarterial extracorporeal membrane oxygenation (ECMO) are potentially harmful and expensive. Balancing the inhibition of clotting and distinguishing surgical from non-surgical bleeding in post-operative period is difficult. The sensitivity of coagulation tests including Thromboelastography(®) (TEG) to predict chest tube drainage in the early hours of ECMO was examined with the use of receiver-operating characteristics (ROC). The results are useful to incorporate in clinical evidence-based algorithms to guide management decisions. In the eighth hour of ECMO, 26 of the 53 adult patients (49%) studied were identified as non-bleeders (less than 2.0 mL/kg/h). All had experienced various types of cardiac surgical procedures. Fifty-two percent were female and the group was 54 ± 19 (mean ± 1 SD) years old. The coagulation parameter threshold with the maximum sensitivity and specificity to predict non-bleeding at 8 hours on ECMO was the kaolin plus heparinase TEG maximum amplitude (KH-TEG MA) at a significant ROC threshold (t) > 50 mm. The activated partial thromboplastin time (aPTT) t < 49 seconds, KH-TEG alpha-angle t > 51°, and the kaolin activated clotting time (ACT) t < 148 seconds were sensitive predictors of non-bleeders. The whole-blood KH-TEG MA was superior to the plasma-based aPTT or International Normalization Ratio (INR) to predict bleeding in the eighth hour of ECMO. Using coagulation laboratory thresholds that predict non-bleeding can begin a process of identifying patients earlier that are likely to bleed. Awareness of these parameter thresholds may improve care through patient protection from unnecessary transfusion and prolonging the life of the ECMO circuit. An algorithm incorporating the ROC thresholds was created to help recognize surgical bleeding to minimize unnecessary transfusions.
Epimorphic regeneration proceeds with or without formation of a blastema, as observed for the limb and skin, respectively. Inhibition of epimorphic regeneration provides a means to interrogate the cellular and molecular mechanisms that regulate it. In this study, we show that exposing amputated limbs to beryllium nitrate disrupts blastema formation and causes severe patterning defects in limb regeneration. In contrast, exposing full-thickness skin wounds to beryllium only causes a delay in skin regeneration. By transplanting full-thickness skin from ubiquitous GFP-expressing axolotls to wild-type hosts, we demonstrate that beryllium inhibits fibroblast migration during limb and skin regeneration in vivo Moreover, we show that beryllium also inhibits cell migration in vitro using axolotl and human fibroblasts. Interestingly, beryllium did not act as an immunostimulatory agent as it does in Anurans and mammals, nor did it affect keratinocyte migration, proliferation or re-epithelialization, suggesting that the effect of beryllium is cell type-specific. While we did not detect an increase in cell death during regeneration in response to beryllium, it did disrupt cell proliferation in mesenchymal cells. Taken together, our data show that normal blastema organogenesis cannot occur without timely infiltration of local fibroblasts and highlights the importance of positional information to instruct pattern formation during regeneration. In contrast, non-blastemal-based skin regeneration can occur despite early inhibition of fibroblast migration and cell proliferation.
The prevalence and the characteristics of poor asthma control among adults treated with combinations of inhaled corticosteroids (ICS) and long-acting beta-agonists (LABA) are not completely understood.
Data from adult patients in Germany with self-reported asthma treated with an ICS-LABA combination in the National Health and Wellness Survey (NHWS) were analysed. Patients with well-controlled and not well-controlled asthma according to the Asthma Control Test (ACT) score were compared, with respect to socio-demographic characteristics, attitudes, adherence and outcomes.
Among the German patients with self-reported asthma (5.2% of the respondents), 16.2% (382 patients) were treated with an ICS-LABA combination and did not report concomitant chronic obstructive pulmonary disease, chronic bronchitis or emphysema. In this subgroup, 55.8% had not well-controlled asthma (ACT < 20). ICS-LABA treated patients with not well-controlled asthma were more likely to report emergency visits (16.4% vs. 8.9%), missed more time from work (absenteeism: 12.9% vs. 4.3%), were more impaired while at work (presenteeism: 29.0% vs. 14.9%) and were more likely to be women (69.0% vs. 57.4%), compared with well-controlled patients. There were no significant differences in age, body mass index, smoking, income, education or self-reported adherence between the two groups, but different attitudes regarding the patient-physician relationship.
A substantial proportion of patients treated with ICS and LABA had not well-controlled asthma. These patients did not differ from well-controlled patients in terms of education or self-reported adherence, but in terms of their attitudes regarding the patient-physician relationship.
Patients with aspirin-exacerbated respiratory disease (AERD) also recently known as nonsteroidal anti-inflammatory drug (NSAID) exacerbated respiratory disease (NERD) must avoid aspirin and all other oral NSAIDs. The effect of topical NSAID (tNSAID), especially salicylates which are commonly present in topical medicated preparations, on asthma control of this phenotype is studied.
The study inclusion criteria were adults with: 1) NSAID hypersensitivity; 2) nasal polyposis/chronic rhinosinusitis; 3) not well-/poorly controlled asthma and 4) exposure to tNSAID. Patients were given verbal and written instructions to cease tNSAIDs exposure and asthma control was evaluated during the 6 months prior and after intervention.
There were eleven patients (ten females) with a mean age of 56.5 (range 37-71) years. Prior known oral NSAIDs hypersensitivity included aspirin (5), mefenamic acid (2), diclofenac (2), Synflex (2) and ibuprofen (1).
 All, except 2, had arthropathies or spinal disorders and were using tNSAID for a mean of 4.2 years. One, four and six patients were using over-the-counter medicated oil containing salicylates, NSAID gel/plasters and both respectively. All patients had cutaneous, with 4 having concomitant inhalational exposure to these tNSAIDs. The mean duration of asthma diagnosis and uncontrolled asthma were 25.2 and 4.5 years respectively. Except for 2 patients, there was no change in asthma maintenance medications pre and post-intervention. Asthma control significantly (p < 0.05) improved based on pre and post-intervention ACT score, number of exacerbations, FEV1 were 14.9 and 22.1, 1.9 and 0.43, 1.28L and 1.67L respectively.
It is paramount to eliminate not only oral but topical NSAID exposure in NERD phenotype asthmatic patients. When a long-standing asthma progressed to uncontrolled, a meticulous evaluation of tNSAIDs exposure is warranted especially if the patient has developed chronic pain.
A carbon dioxide imprinted solid amine adsorbent (IPEIA-R) with polyethylenimine (PEI) as a skeleton was conveniently prepared by using glutaraldehyde to cross-link carbon dioxide-preadsorbed PEI. As confirmed by FTIR, FT-Raman, and (13) C NMR spectroscopy, CO2 preadsorbed on PEI could occupy the reactive sites of amino groups and act as a template for imprinting in the cross-linking process. The imino groups formed from the cross-linking reaction between glutaraldehyde and PEI could be reduced by NaBH4 to form CO2 -adsorbable amino groups. The adsorption results indicated that CO2 imprinting and reduction of imino groups by NaBH4 endowed the adsorbent with a higher CO2 adsorption capacity. Compared with PEI-supported mesoporous adsorbents, the solid amine adsorbent with PEI as a skeleton can avoid serious pore blockage and CO2 diffusion resistance, even with a high amine content. The solid amine adsorbent with PEI as a skeleton showed a remarkable CO2 adsorption capacity (8.56 mmol g(-1) ) in the presence of water at 25 °C, owing to the high amine content and good swelling properties. It also showed promising regeneration performance and could maintain almost the same CO2 adsorption capacity after 15 adsorption-desorption cycles.
Mesenchymal stem or stromal cells (MSCs) act on different components of the immune response including macrophages (MΦs). Therefore this study has been committed to explore how MSCs may modify the effect of MΦ polarization upon an inductive environment using mouse bone marrow (BM)-derived "naïve", unpolarized MΦs. Phagocytosis of various MΦ subtypes was different since M1 and M2b showed poorer, while M2a higher rate of phagocytosis. MSCs significantly promoted yeast ingestion by M1 and M2b and diminished it by M2a cells. Under polarizing conditions, MSCs profoundly affected the TNFα production of MΦ subtypes since M1 and M2b MΦs produced less and M2a produced higher amount of TNFα while the amount of IL-10 was not affected. The most striking effect of MSCs was registered on M2b cells since the inflammatory TNFα dominance remarkably shifted to the immunosuppressive IL-10. Prepolarized M1 cells readily converted to M2a and M2b states when polarizing conditions changed from M1 to M2a or M2b induction, respectively. Repolarizing from M1 to M2a resulted in the decline of IL-10 and TNFα and defined elevation of Ym1 similar to levels characteristic to M2a primarily polarized from naïve BM-MΦs. Similarly, polarization of M1 to M2b MΦs was successful showing increase in IL-10 and reduction in TNFα levels characteristic to M2b cells. However, when co-culturing with MSCs, M1-M2a or M1-M2b transition was not affected. Crosstalk between MΦs and MSCs depended on PGE-2 since COX-2 inhibition reduced the effect of MSCs to establish an IL-10-dominant cytokine production by MΦs.
In South Africa children under the age of 18 are legal minors and considered not fully capable of acting independently. However, in certain defined circumstances the law has granted minors the capacity to act independently, including regarding their sexual and reproductive health (SRH). This study explored the perspectives and practices of 17 social workers from KwaZulu-Natal on legislation relevant to adolescents' evolving sexual and reproductive health and rights and the decriminalisation of consensual underage sex. A key finding was that many social workers have conservative views about adolescent access to SRH advice and services and many were critical of the recent decriminalisation of underage consensual sex. In the main, social workers were concerned that adolescents lack the capacity to make SRH care decisions and that liberal laws promote underage sex rather than protect adolescents. Despite antagonistic views of SRH laws related to adolescents, many social workers felt that they are able to uphold their professional rather than personal views in their work. These findings are important given that a key barrier to adolescent access and uptake of SRH advice and services relates to concerns that they will be judged. Therefore service providers need to be regularly updated on adolescent SRH issues (including rights, laws, and policies) and be engaged in critical thinking about conflicting cultural, moral and personal judgements around adolescent sexuality. Such training should include counselling and communication skills that address issues on confidentiality, adolescents' dignity, privacy and best interests.
A very large number of fatty acids play wide range of physiological roles in cellular growth and function in placental as well as fetal growth. However, docosahexaenoic acid (DHA), in addition to its critical role in cellular membranes, is known to act as a ligand for several nuclear receptors and regulates the activity of transcription factor families like peroxisome proliferator-activated receptor, liver X receptor (LXR), retinoid X receptor (RXR), and sterol regulatory element binding protein (SREBP). These transcription factors and DHA are known to regulate the placental and fetal growth and development.
The objective of the present study was to examine the fatty acids and transcription factors in the placenta of women delivering low birth weight (LBW) babies.
The present study examines the fatty acid and mRNA levels of various transcription factors in the placentae of women delivering normal birth weight (NBW) (n = 38) and women delivering LBW (n = 36). Placental fatty acids were analyzed using gas chromatography. Placental mRNA levels of PPARα, PPARγ, SREBP-1c, LXRα, RXRα, and RXRγ were examined using quantitative real time PCR.
Placental DHA levels and mRNA levels of placental PPARγ and LXRα were lower (P < .05 for all) in women delivering LBW babies. There was a positive association of placental PPARγ mRNA levels and placental DHA levels with baby weight (P < .05 for both).
Our data suggest that lower placental DHA and transcription factors may have a vital role in the etiology of LBW babies.
Abdominopelvic washings (APW) performed during gynecologic surgeries have become a common specimen evaluated by cytopathologists. Their role in staging of female genital tract tumors has changed significantly since they were first described, and continue to evolve. The ability of these washings to detect microscopic disease, even in the absence of gross disease, warrants the critical role that these washings play in the staging of certain female gynecologic tract tumors, allowing for optimal staging and subsequent treatment of the patient. Irrespective of the underlying pathology, the gamut of cytomorphologic findings that may be observed in APW is extensive, and ranges from benign lesions that may act as mimickers of malignancy, to both common and rare malignancies. This review discusses the changing role of APW in the staging of gynecologic tumors, and highlights the salient cytomorphologic features of these lesions, with emphasis in their correct identification, including cautionary notes to avoid over or misinterpretation. Diagn. Cytopathol. 2016;44:1039-1057. © 2016 Wiley Periodicals, Inc.
We report the long-term follow-up in patients with locally advanced cervical cancer treated with neoadjuvant chemotherapy (NACT) + radical surgery (RS) + adjuvant chemotherapy (ACT) analyzing prognostic factors which may more influence, in a long time, the survival outcome using univariate and multivariate analysis. In this study, we included all patients with diagnosis of locally advanced cervical cancer (IB2-IIB) treated with NACT + RS + ACT from June 2000 and February 2007 as previously described by Angioli et al. (Gynecol Oncol 127(2):290-6, 2012). The primary end-point of the study was overall survival (OS) in patients with node metastases and in those without positive lymph nodes at the end of 10-year follow-up in order to confirm the prognostic role of nodes involvement for a long period. Moreover, we analyzed the impact of other prognostic factors, such as histotype, tumor size, grading and parametrial invasion. Secondary end-point was evaluated in the subgroup of patients with positive nodes the following prognostic factors: number of positive lymph nodes and site of positive lymph nodes. In the subgroup of patients with positive nodes, the OS was 63 %, and in that with negative nodes, the OS was 75 %. On multivariate analysis, the number of nodal metastases, parametrial involvement, grading and the lesion diameter were noted to be significant factors in determining OS. Neither the histotype nor the lymph nodal site is related to survival. Results suggest that CT alone may be an alternative postoperative therapy for patients with cervical cancer.
Infection by hepatitis C virus (HCV) can result in the development of liver fibrosis and may eventually progress into cirrhosis and hepatocellular carcinoma. However, the molecular mechanisms for this process
 are not fully known. Several genome-wide association studies have been carried out to pinpoint causative variants in HCV-infected patient cohorts, but these variants are usually not the functional ones. The aim of this study was to identify the regulatory single nucleotide polymorphism associated with the risk of HCV-induced liver fibrosis and elucidate its molecular mechanism.
We utilized a bioinformatics approach to identify a non-coding regulatory variant, located in an intron of the MERTK gene, based on differential transcription factor binding between the alleles. We validated the results using expression reporter assays and electrophoresis mobility shift assays.
Chromatin immunoprecipitation sequencing indicated that transcription factor(s) bind stronger to the A allele of rs6726639. Electrophoresis mobility shift assays supported these findings and suggested that the transcription factor is interferon regulatory factor 1 (IRF1). Luciferase report assays showed lower enhancer activity from the A allele and that IRF1 may act as a repressor.
Treatment of hepatitis C with interferon-α results in increased IRF1 levels and our data suggest that this leads to an allele-specific downregulation of MERTK mediated by an allelic effect on the regulatory element containing the functional rs6726639. This variant also shows the hallmarks for being the driver of the genome-wide association studies for reduced risk of liver fibrosis and non-alcoholic fatty liver disease at MERTK.
Major depressive disorder (MDD) is predicted to be the second leading cause of global disease burden by 2030. A large number of MDD patients do not respond to the currently available medication because of its poorly understood etiology. Recently, studies of microRNAs (miRNAs), which act as a molecular switch of gene expression, have shown promise in identifying a molecular network that could provide significant clues to various psychiatric illnesses. Using an in vitro system, a rodent depression model, and a human postmortem brain, we investigated the role of a brain-enriched, neuron-specific miRNA, miR-124-3p, whose expression is highly dysregulated in stressed rodents, and identified a set of target genes involved in stress response and neural plasticity. We also found that miR-124-3p is epigenetically regulated and its interaction with the RNA-induced silencing complex (RISC) is compromised in MDD. Using blood serum, we found similar dysregulation of miR-124-3p in antidepressant-free MDD subjects. Altogether, our study demonstrates potential contribution of miR-124-3p in the pathophysiology of MDD and suggests that this miRNA may serve as a novel target for drug development and a biomarker for MDD pathogenesis.Neuropsychopharmacology advance online publication, 5 October 2016; doi:10.1038/npp.2016.175.
We previously demonstrated that dehydroevodiamine•HCl (DHED), which was purified from Evodia rutaecarpa Bentham (Rutaceae), has beneficial effects on memory impairment and neuronal damage in three disease models. To investigate the preventive action of DHED in Alzheimer's disease (AD), a progressive neurodegenerative disorder characterized by memory decline, amyloid-β (Aβ) protein-containing neuritic plaques and neurofibrillary tangles, in this study, we proposed that DHED may be therapeutically effective against the memory impairment and disease-related neurochemical changes that occur in Tg2576 (Tg) mice. DHED (0.5 mg/kg) was intraperitoneally administered to 7-month-old Tg and wild type mice for 4 months. In passive avoidance and water maze tests, DHED improved memory impairment of Tg mice after 4 months of administration. DHED also reduced cortical levels of soluble Aβ40, soluble Aβ42 and total Aβ peptides in the Tg mice. Additionally, we investigated whether DHED may be a β-secretase inhibitor that affects the production of Aβ related to the formation of neuritic plaques. DHED directly inhibited β-secretase activity in a concentrationdependent manner. The concentration required for 50 % enzyme inhibition (IC50) was 40.96 μM, and DHED may act as a competitive inhibitor of β-secretase. Moreover, DHED interacted strongly with BACE1 (β-secretase 2QP8), as demonstrated in the analysis of the binding mode of DHED in the active site of human BACE1. In conclusion, DHED may exhibit therapeutic effects for AD as a β-secretase inhibitor.
This updated edition provides a quick guide to Mental Health Act assessments and the relevant legal frameworks.
The cost of dialysis for the estimated 6500 dialysis-dependent undocumented individuals with kidney failure in the United States is high, the quality of dialysis care they receive is poor, and their treatment varies regionally. Some regions use state and matched federal funds to cover regularly scheduled dialysis treatments, while others provide treatment only in emergent life-threatening conditions. Nephrologists caring for patients who receive emergent dialysis are tasked with the difficult moral dilemma of determining "who gets dialysis that day." Without a path to citizenship and by exclusion from the federal marketplace exchanges, undocumented individuals have limited options for their treatment. A novel opportunity to provide scheduled dialysis for this population is through the purchase of insurance off the exchange. Plans purchased off the exchange must still abide by the 2014 provision of the Patient Protection and Affordable Care Act, which prohibits insurance companies from denying coverage based on a preexisting health condition. In 2015 and 2016, >100 patients previously receiving only emergent dialysis at the two largest safety-net hospital systems in Texas obtained off-the-exchange commercial health insurance plans. These undocumented patients now receive scheduled dialysis treatments, which has improved their care and quality of life, as well as decompressed the overburdened hospital systems. The long-term sustainability of this option is not known. Socially responsive and visionary policymakers allowing the move into this bold, new direction deserve special appreciation.
No systemic evaluation of asthma control in Jilin Province has been reported. Asthma control might provide the basis for asthma management in this region. A multicenter hospital-based cross-sectional study was performed to investigate the asthma control and related factors for severe asthma exacerbations in patients with moderate or severe asthma in Jilin Province, China.
The study enrolled 1546 patients in five grade one general hospitals from January to December 2013. Asthma medication, patient self-management, asthma control test (ACT) scores and frequency of severe asthma exacerbations during the follow-up (12 months) were collected via a follow-up questionnaire.
In the study, 889 patients provided a complete follow-up questionnaire. Severe asthma exacerbations occurred in 54.89 % of patients. ACT score ≤15, asthma medication ≤ 3 months, severe asthma, income level lower than average Per Capita Disposable Income (PCDI) and a lower educational level were risk factors of a severe exacerbation.
Poor adherence to asthma medication, poor asthma symptom control, lower income, a low educational level might be possible reasons for the high incidence of severe asthma exacerbations and poor asthma control in Jilin Province of China.
Ginsenoside Rb1 (GS-Rb1) is one of the most important active pharmacological extracts of the Traditional Chinese Medicine ginseng, with extensive evidence of its cardioprotective properties. Mir-208 has been shown to act as a biomarker of acute myocardial infarction in vivo studies including man. However the impact of miR-208 on the protective effect of GS-Rb1 in hypoxia/ischemia injured cardiomyocytes remains unclear. The current study aims to investigate the target gene of miR-208 and the impact on the protective effect of GS-Rb1 in hypoxia/ischemia (H/I) injuried cardiomyocytes.
Primary cultures of neonatal rat cardiomyocytes (NRCMs) was subjected to the H/I conditions with or without GS-Rb1. Cell viability was calculated by MTT assay and confirmed by flow cytometry analysis. Mir-208 was then detected by qRT-PCR. Luciferase reporter assay was carried out to detect the target gene of Mir-208. Then the NRCMs were transfected with miR-208 mimics and inhibitors to evaluate the impact on cardioprotective properties of Rb1.
The miR-208 expression level was clearly upregulated in the H/I treated NRCMs accompanied by the percentage of the apoptotic cells which could be reversed by GS-Rb1 pretreatment. The nemo-like kinase (NLK) mRNA and protein expression levels were decreased in H/I group measured by RT-PCR and western blotting. Luciferase activity assay was then carried out to identify that NLK may be a direct target of mir-208. MTT assay showed that miR-208 inhibitor slightly decreased the protective effect of Rb1 on the H/I impaired NRCMs. However, results showed no statistical difference.
These findings proved that NLK was a direct target of mir-208 and miR-208 act indirectly during Rb1 protecting H/I impaired NRCMs and further researches were needed to explore the relationship that microRNAs and other signal pathways in the protective effect of GS-Rb1 on the hypoxia/ischemia injuries in cardiomyocytes.
High sea surface temperature accompanied by high levels of solar irradiance is responsible for the disruption of the symbiosis between cnidarians and their symbiotic dinoflagellates from the genus Symbiodinium. This phenomenon, known as coral bleaching, is one of the major threats affecting coral reefs around the world. Because an important molecular trigger to bleaching appears related to the production of reactive oxygen species (ROS), it is critical to understand the function of the antioxidant network of Symbiodinium species. In this study we investigated the response of two Symbiodinium species, from
 contrasting environments, to a chemically induced oxidative stress. ROS produced during this oxidative burst reduced photosynthesis by 30 to 50% and significantly decreased the activity of superoxide dismutase. Lipid peroxidation levels and carotenoid concentrations, especially diatoxanthin, confirm that these molecules act as antioxidants and contribute to the stabilization of membrane lipids. The comparative analysis between the two Symbiodinium species allowed us to highlight that Symbiodinium sp. clade A temperate was more tolerant to oxidative stress than the tropical S. kawagutii clade F. These differences are very likely a consequence of adaptation to their natural environment, with the temperate species experiencing conditions of temperature and irradiance much more variable and extreme.
Patient-centred care and patient engagement are not the "flavour of the month" nor just buzz phrases. The role of the patient voice in the review of the Quality of Care Information Protection Act and the creation of the Health Information Protection Act 2016 (Bill 119) was significant and transformative. Engaging patients and families whether at the bedside in a hospital, at the decision-making table in a healthcare organization, or in the creation of policy at the provincial and national levels is changing our healthcare system.
Moxifloxacin (MOX) is a Mycobacterium tuberculosis DNA gyrase inhibitor. Due to its intense hydrophilicity, MOX is cleared from the body within 24 h and required for repetitive doses which may then result in hepatotoxicity and acquisition of MOX resistant-TB, related with its use. To overcome the aforementioned limitations, the current study aimed to develop PLGA nanoparticles (PLGA NPs), to act as an efficient carrier for controlled delivery of MOX. To achieve a substantial extension in blood circulation, a combined design, affixation of polyethylene glycol (PEG) to MOX-PLGA NPs and adsorption of water-soluble chitosan (WSC) (cationic deacetylated chitin) to particle surface, was rose for surface modification of NPs. Surface modified NPs (MOX-PEG-WSC NPs) were prepared to provide controlled delivery and circulate in the bloodstream for an extended period of time, thus minimizing dosing frequency. In vivo pharmacokinetic and in vivo biodistribution following oral administration were investigated. NP surface charge was closed to neutral +4.76 mV and significantly affected by the WSC coating. MOX-PEG-WSC NPs presented striking prolongation in blood circulation, reduced protein binding, and long-drawn-out the blood circulation half-life with resultant reduced liver sequestration vis-à-vis MOX-PLGA NPs. The studies, therefore, indicate the successful formulation development of MOX-PEG-WSC NPs that showed sustained release behavior from nanoparticles which indicates low frequency of dosing.
α-l-Fucosyl residues are frequently found in oligosaccharides, polysaccharides and glycoconjugates which play fundamental roles in various biological processes. α-l-Fucosidases, glycoside hydrolases for catalyzing the removal of α-l-fucose, can serve as desirable tools in the study and the modification of fucose-containing biomolecules. In this study, an α-l-fucosidase named as Alf1_Wf was purified from a marine bacterium Wenyingzhuangia fucanilytica by using a combination of chromatographic procedures. The sequence of Alf1_Wf was identified via proteomics analysis against the predicted proteome of the bacterium. Recombinant Alf1_Wf with 6×His tag was expressed in E. coli and showed α-l-fucosidase activity. Sequence annotation revealed that Alf1_Wf contained a combination of GH29 catalytic domain and CBM35 accessory domain. Alf1_Wf was confirmed as a member of GH29-A subfamily based on the phylogenetic analysis. Furthermore, biochemical properties and kinetic characteristics of the enzyme were also determined. Substrate specificity determination showed that Alf1_Wf was capable in hydrolyzing α1,4-fucosidic linkage and synthetic substrate pNP-fucose. Besides, Alf1_Wf could act on partially degraded fucoidan. This study successfully purified, identified, cloned, expressed and characterized a novel α-l-fucosidase, and meanwhile revealed a new multidomain structure of glycoside hydrolase. The knowledge gained from this study should facilitate the further research and application of α-l-fucosidases.
Over 500 000 Washingtonians gained health insurance under the Affordable Care Act (ACA). As more patients gain insurance, community health centers (CHCs) expect to see an increase in demand for their services. This article studies the CHCs in Washington State to examine how the increase in patients has been impacting their workload and staffing. We found a reported mean increase of 11.7% and 5.4% in new Medicaid and Exchange patients, respectively. Half of the CHCs experienced large or dramatic workload impact from the ACA. Our findings suggest that CHCs need further workforce support to meet the expanding patient demand.
I. II. III. IV. V. VI. VII. References SUMMARY: In the 21(st) century, the wheat stripe rust fungus has evolved to be the largest biotic limitation to global wheat production. New pathogen genotypes are more aggressive and able to infect previously resistant wheat varieties, leading to rapid pathogen migration across and between continents. We now know the full life cycle, microevolutionary relationships and past migration routes on a global scale. Current sequencing technologies have provided the first fungal draft genomes and simplified plant resistance gene cloning. Yet, we know nothing about the molecular and microevolutionary mechanisms that facilitate the infection process and cause new devastating pathogen races. These are the questions that need to be addressed by exploiting the synergies between novel 21(st) century biology tools and decades of dedicated pathology work.
Although ICP4 is the only essential transcription activator of herpes simplex virus 1 (HSV-1), its mechanisms of action are still only partially understood. We and others propose a model in which HSV-1 genomes are chromatinized as a cellular defense to inhibit HSV-1 transcription. To counteract silencing, HSV-1 would have evolved proteins that prevent or destabilize chromatinization to activate transcription. These proteins should act as HSV-1 transcription activators. We have shown that HSV-1 genomes are organized in highly dynamic nucleosomes and that histone dynamics increase in cells infected with wild type HSV-1. We now show that whereas HSV-1 mutants encoding no functional ICP0 or VP16 partially enhanced histone dynamics, mutants encoding no functional ICP4 did so only minimally. Transient expression of ICP4 was sufficient to enhance histone dynamics in the absence of other HSV-1 proteins or HSV-1 DNA. The dynamics of H3.1 were increased in cells expressing ICP4 to a greater extent than those of H3.3. The dynamics of H2B were increased in cells expressing ICP4, whereas those of canonical H2A were not. ICP4 preferentially targets silencing H3.1 and may also target the silencing H2A variants. In infected cells, histone dynamics were increased in the viral replication compartments, where ICP4 localizes. These results suggest a mechanism whereby ICP4 activates transcription by disrupting, or preventing the formation of, stable silencing nucleosomes on HSV-1 genomes.
Thiopeptides are structurally complex, bioactive natural products derived from ribosomally synthesized and post-translationally modified peptides. A remarkable set of enzymes were recently revealed to catalyze the formation of the core trithiazolylpyridine of thiopeptides via a formal [4 + 2] cycloaddition. These pyridine synthases typically act late in thiopeptide biosynthesis to affect macrocyclization and cleavage of the N-terminal leader peptide, making them potentially useful biocatalysts for preparation of new thiopeptide variants. Herein we investigate the leader peptide requirements for TclM from thiocillin biosynthesis in Bacillus cereus ATCC 14579. Through a series of truncations, we define a minimum recognition sequence (RS) that is necessary and sufficient for TclM activity. This RS can be readily synthesized and ligated to linear thiopeptide cores prepared via solid-phase peptide synthesis (SPPS), giving an efficient and modular route to thiopeptide variants. We exploit this strategy to define C-terminal core peptide requirements and explore the differences in promiscuity of two pyridine synthases, TclM and TbtD, ultimately examining their ability to access new structural variants.
Peucedanum japonicum Thunb is a medicinal plant belonging to the family Umbelliferae. This study evaluated the anti-diabetic and anti-obesity effects of cis-3',4'-diisovalerylkhellactone (cDIVK) isolated from Peucedanum japonicum Thunb leaves. cDIVK (30 and 50μM) effectively inhibited adipocyte differentiation and fat accumulation, whereas it stimulated glucose uptake compared with the control in 3T3-L1 cells. cDIVK significantly increased AMPK activation and suppressed protein and mRNA expression of major adipogenic transcriptional factors such as C/EBPα, PPARγ and SREBP-1c in 3T3-L1 cells. In addition, cDIVK had potential α-glucosidase inhibitory activity. These results indicated that cDIVK may act as a natural dual therapeutic agent for diabetes and obesity.
Combining hydraulic- and carbon-related measurements helps to understand drought-induced plant mortality. Here, we investigated the role that plant respiration (R) plays in determining carbon budgets under drought. We measured the hydraulic conductivity of stems and roots, and gas exchange and nonstructural carbohydrate (NSC) concentrations of leaves, stems and roots of seedlings of two resprouting species exposed to drought or well-watered conditions: Ulmus minor (riparian tree) and Quercus ilex (dryland tree). With increasing
 water stress (occurring more rapidly in larger U. minor), declines in leaf, stem and root R were less pronounced than that in leaf net photosynthetic CO2 uptake (Pn ). Daytime whole-plant carbon gain was negative below -4 and -6 MPa midday xylem water potential in U. minor and Q. ilex, respectively. Relative to controls, seedlings exhibiting shoot dieback suffered c. 80% loss of hydraulic conductivity in both species, and reductions in NSC concentrations in U. minor. Higher drought-induced depletion of NSC reserves in U. minor was related to higher plant R, faster stomatal closure, and premature leaf-shedding. Differences in drought resistance relied on the ability to maintain hydraulic conductivity during drought, rather than tolerating conductivity loss. Root hydraulic failure elicited shoot dieback and precluded resprouting without root NSC reserves being apparently limiting for R.
Artificial photosynthesis is an attractive approach for renewable fuel generation because it offers the prospect of a technology suitable for deployment on highly abundant, non-arable land. Recent leaps forward in the development of efficient and durable light absorbers and catalysts for oxygen evolution and the growing attention to catalysts for carbon dioxide activation brings into focus the tasks of hierarchically integrating the components into assemblies for closing of the photosynthetic cycle. A particular challenge is the efficient coupling of the multi-electron processes of CO2 reduction and H2O oxidation. Among the most important requirements for a complete integrated system are catalytic rates that match the solar flux, efficient charge transport between the various components, and scalability of the photosynthetic assembly on the unprecedented scale of terawatts in order to have impact on fuel consumption. To address these challenges, we have developed a heterogeneous inorganic materials approach with molecularly precise control of light absorption and charge transport pathways. Oxo-bridged heterobinuclear units with metal-to-metal charge-transfer transitions absorbing deep in the visible act as single photon, single charge transfer pumps for driving multi-electron catalysts. A photodeposition method has been introduced for the spatially directed assembly of nanoparticle catalysts for selective coupling to the donor or acceptor metal of the light absorber. For CO2 reduction, a Cu oxide cluster is coupled to the Zr center of a ZrOCo light absorber, while coupling of an Ir nanoparticle catalyst for water oxidation to the Co donor affords closing of the photosynthetic cycle of CO2 conversion by H2O to CO and O2. Optical, vibrational, and X-ray spectroscopy provide detailed structural knowledge of the polynuclear assemblies. Time resolved visible and rapid-scan FT-IR studies reveal charge transfer mechanisms and transient surface intermediates under photocatalytic conditions for guiding performance improvements. Separation of the water oxidation and carbon dioxide reduction half reactions by a membrane is essential for efficient photoreduction of CO2 by H2O to liquid fuel products. A concept of a macroscale artificial photosystem consisting of arrays of Co oxide-silica core-shell nanotubes is introduced in which each tube operates as a complete, independent photosynthetic unit with built-in membrane separation. The ultrathin amorphous silica shell with embedded molecular wires functions as a proton conducting, molecule impermeable membrane. Photoelectrochemical and transient optical measurements confirm tight control of charge transport through the membrane by the orbital energetics of the wire molecules. Hierarchical arrangement of the components is accomplished by a combination of photodeposition, controlled anchoring, and atomic layer deposition methods.
The conduct of research regardless of the subject or methods employed brings responsibilities and challenges. These are greater when dealing with sensitive topics and vulnerable groups and therefore researchers must navigate a range of complex issues and make choices in relation to practical, ethical and philosophical concerns. While literature dealing with research methodologies and research design may assist to some degree, it cannot provide a clear pathway or template as each research project must respond to a unique set of circumstances. We can however, also learn from sharing our stories and critical reflections on our research processes.
The purpose of this article is to highlight the practical and methodological issues arising from researching a sensitive topic with vulnerable women experiencing an Assumption of Care.
Research involving topics that are deeply personal and private combined with a vulnerable population can be complex and challenging for the researcher. Although some issues were anticipated from the literature, others encountered in this study were unexpected. Special considerations and prerequisites were necessary to build mutual trust and share power with women who had experienced an Assumption of Care at birth. Narrative Inquiry was a good methodological fit for this study as it privileged the voices of women and insisted that their experiences be considered within the context of their lives.
Although Narrative Inquiry is a suitable choice for researching sensitive topics with vulnerable women specific considerations are still required to ensure the benefits of this research for both participants and researchers. Family and Community Service (FACS) have now replaced the formerly known Department of Community Services (DoCS) and in consideration of the timing of this study this article uses the terminology as DoCS.
On 29 December 1970, the Occupational Safety and Health Act of 1970 established the Occupational Safety and Health Administration (OSHA). This article on OSHA, Title 29, Part 1910.1096 Ionizing Radiation standard was written to increase awareness of the employer, the workforce, state and federal governments, and those in the radon industry who perform radon testing and radon mitigation of the existence of these regulations, particularly the radon relevant aspect of the regulations. This review paper was also written to try to explain what can sometimes be complicated regulations. As the author works within the Radon Division of the Pennsylvania Department of Environmental Protection, Bureau of Radiation Protection, the exclusive focus of the article is on radon. The 1910.1096 standard obviously covers many other aspects of radiation and radiation safety in the work place.
We report a theory capable of describing conformational transitions for single polymer adsorption in a poor solvent. We show that an additional molecular confinement effect near the contact line can act exactly like line tension, playing a critical role in the behavior of an absorbed polymer chain. Using this theory, distinct conformational states: desorbed globule (DG), surface attached cap (SAC), and adsorbed lens (AL), can be vividly revealed, resembling the drying-wetting transition of a nanodroplet. But the transitions between these states can behave rather differently from those in the usual wetting transitions. The DG-SAC transition is discrete, occurring at the adsorption threshold when the globule size at the desorbed state is equal to the adsorption blob. The SAC-AL transition is smooth for finite chain lengths, but can change to discontinuous in the infinite chain limit, characterized by the different end-to-end exponent 3/8 and the unique crossover exponent 1/4. Distinctive critical exponents near this transition are also determined, indicating that it is an additional universality class of phase transitions. This work also sheds light on nanodrop spreading, wherein the important role played by line tension might simply be a manifestation of the local molecular confinement near the contact line.
We study the modeling and prediction of dynamical systems based on conventional models derived from measurements. Such algorithms are highly desirable in situations where the underlying dynamics are hard to model from physical principles or simplified models need to be found. We focus on symbolic regression methods as a part of machine learning. These algorithms are capable of learning an analytically tractable model from data, a highly valuable property. Symbolic regression methods can be considered as generalized regression methods. We investigate two particular algorithms, the so-called fast function extraction which is a generalized linear regression algorithm, and genetic programming which is a very general method. Both are able to combine functions in a certain way such that a good model for the prediction of the temporal evolution of a dynamical system can be identified. We illustrate the algorithms by finding a prediction for the evolution of a harmonic oscillator based on measurements, by detecting an arriving front in an excitable system, and as a real-world application, the prediction of solar power production based on energy production observations at a given site together with the weather forecast.
Analysis of short-pulse propagation in positive dispersion media, e.g., in optical fibers and in shallow water, requires assorted high-order derivative terms. We present an infinite-order "dark" hierarchy of equations, starting from the basic defocusing nonlinear Schrödinger equation. We present generalized soliton solutions, plane-wave solutions, and periodic solutions of all orders. We find that "even"-order equations in the set affect phase and "stretching factors" in the solutions, while "odd"-order equations affect the velocities. Hence odd-order equation solutions can be real functions, while even-order equation solutions are complex. There are various applications in optics and water waves.
Act-and-wait modification of a time-delayed feedback control (TDFC)
 algorithm is proposed to stabilize unstable periodic orbits in nonautonomous dynamical systems. Due to periodical switching on and off the control perturbation, an infinite-dimensional function space of the TDFC system is reduced to the finite-dimensional state space. As a result the number of Floquet exponents defining the stability of the controlled orbit remains the same as for the control-free system. The values of these exponents can be effectively manipulated by the variation of control parameters. We demonstrate the advantages of the modification for the chaotic nonautonomous Duffing oscillator with diagonal and nondiagonal control matrices. In both cases very deep minima of the spectral abscissa of Floquet exponents have been attained. The advantage of the modification is particularly remarkable for the nondiagonal coupling; in this case the conventional TDFC fails, whereas the modified version works.
We investigate the stochastic thermodynamics of a two-particle Langevin system. Each particle is in contact with a heat bath at different temperatures T_{1} and T_{2} (<T_{1}), respectively. Particles are trapped by a harmonic potential and driven by a linear external force. The system can act as an autonomous heat engine performing work against the external driving force. Linearity of the system enables us to examine thermodynamic properties of the engine analytically. We find that the efficiency of the engine at maximum power η_{MP} is given by η_{MP}=1-sqrt[T_{2}/T_{1}]. This universal form has been known as a characteristic of endoreversible heat engines. Our result extends the universal behavior of η_{MP} to nonendoreversible engines. We also obtain the large deviation function of the probability distribution for the stochastic efficiency in the overdamped limit. The large deviation function takes the minimum value at macroscopic efficiency η=η[over ¯] and increases monotonically until it reaches plateaus when η≤η_{L} and η≥η_{R} with model-dependent parameters η_{R} and η_{L}.
In perspective of reducing the mortality of cancer, there is a high interest in compounds which act on multiple cellular targets and therefore prevent the appearance of cancer resistances. Saponins and α-hederin, an oleanane-type saponin, induce cancer cell death through different pathways, including apoptosis and membrane permeabilization. Unfortunately, the mechanism by which cell death is induced is unknown. We hypothesized that the activity of α-hederin mainly depends on its interaction with membrane cholesterol and therefore investigated the cholesterol and saponin-structure dependency of apoptosis and membrane permeabilization in two malignant monocytic cell lines. Apoptotic cell death and membrane permeabilization were significantly reduced in cholesterol-depleted cells. Permeabilization further depended upon the osidic side chain of α-hederin and led to extracellular calcium influx and nuclear fragmentation, with only the latter being susceptible to caspase inhibitors. Membrane order, measured by laurdan generalized polarization imaging, was neither reduced by α-hederin nor its aglycone hederagenin suggesting that their activity was not related to membrane cholesterol extraction. However, a radical change in morphology, including the disappearance of pseudopodes was observed upon incubation with α-hederin. Our results suggest that the different activities of α-hederin mainly depend on its interaction with membrane cholesterol and consequent pore formation.
Mast cell-mediated anaphylactic reactions are involved in many allergic diseases, including asthma and allergic rhinitis. In Korea, where it has been used as a traditional medicine, Rosae Multiflorae fructus (RMF) is known to have potent antioxidative, analgesic, and anti-inflammatory activities and to have no obvious acute toxicity. However, its specific effect on asthma is still unknown. In this study, we evaluated whether or not RMF hot water extracts (RMFW) could inhibit ovalbumin (OVA)-induced allergic asthma and evaluated compound 48/80-induced mast cell activation to elucidate the mechanisms of asthma inhibition by RMFW. Oral administration of RMFW decreased the number of eosinophils and lymphocytes in the lungs of mice challenged by OVA and downregulated histological changes such as eosinophil infiltration, mucus accumulation, goblet cell hyperplasia, and collagen fiber deposits. In addition, RMFW significantly reduced T helper 2 cytokines, TNF-α, IL-4, and IL-6 levels in the BAL fluid of mice challenged by OVA. Moreover, RMFW suppressed compound 48/80-induced rat peritoneal mast cell degranulation and inhibited histamine release from mast cells induced by compound 48/80 in a dose-dependent manner. These results suggest that RMFW may act as an antiallergic agent by inhibitingTh2 cytokine production from Th2 cells and histamine release from mast cells, and could be used as a therapy for patients with Th2-mediated or mast cell-mediated allergic diseases.
The spatial distributions and fates of selected legacy and emerging compounds were investigated and compared in surface sediments sampled along the Adriatic mud-wedge and in deep-sea regions from the southern Adriatic basin. Results indicated that the concentrations of legacy contaminants (PAHs, PCBs and DDTs) and emerging contaminants (tonalide, galaxolide, EHMC, octocrylene, BP3 and NP) ranged from 0.1 to 572 ng g(-1) and from <LOD to 40.7 ng g(-1), respectively. In general, higher concentrations and estimated burdens were detected in the northern Adriatic, highlighting the importance of the Po River as the major contributor for the inputs of legacy and emerging contaminants to sediments in the Adriatic Sea. Nevertheless, the prevalence of some UV filters and fragrances in the central and southern Adriatic indicates that the proximity to tourist areas and WWTPs discharges seems to affect the distribution of those compounds. The accumulation of contaminants in the deep-sea areas supports the inference that this region may act as an important repository for contaminants within the Adriatic Sea. Estimated annual contaminant accumulation reveals that both, legacy and emerging contaminants accumulate preferentially in the northern Adriatic (40-60% of the total annual contaminant accumulation), where the presence of legacy, and to a lesser extent emerging contaminants, are likely to pose an immediate or long-term hazard to resident biota.
The Medicare Modernization Act, with its requirements for Medicare Part D to comply with electronic prescribing (e-prescribing), bolstered the adoption of e-prescribing, which increased to 73% in 2013. Therefore, understanding whether electronic prescriptions are less likely to be picked up is important as e-prescribing continues to be emphasized.
To assess whether prescription origin is among the factors associated with initial medication adherence, using claim reversals as a proxy measure.
A cross-sectional study was completed using a sample of reversed claims from the Pharmaceutical Assistance Contract for the Elderly (PACE) program for September 2014. The total number of reversed claims for new prescriptions (15,966) was categorized by prescription origin (written, telephone, electronic, fax, and pharmacy). Using a chi-square analysis, the reversed claims were compared among prescription origin to determine if there is a difference in the proportion of electronic prescriptions reversed compared with those from other origins.
When compared with all other prescription origins, electronic prescriptions (E) were more likely to be reversed at day 0 (E = 50%, any other [AO] = 49%, P < 0.05) and after day 0 (E = 58%, AO = 42%, P < 0.05).
Electronic prescriptions are associated with a higher rate of claim reversals and may reflect poorer initial adherence. Electronic prescriptions may more likely be forgotten or not picked up because they were not presented to the pharmacy by the patient. The growing adoption of electronic prescriptions merits particular attention, since it may be a factor in initial medication adherence in the elderly.
This study was not supported by any funding. Peterson reports advisory board and consultancy fees from IMS Health and Pfizer and employment by Genentech. Klaiman is currently employed by AccessMatters. No other financial or other conflicts of interests were reported. Study concept and design were primarily contributed by Forestal, along with Klaiman and Peterson. Heller took the lead in data collection, along with Forestal, and data interpretation was performed by Forestal, Klaiman, and Peterson. Forestal, Klaiman, and Heller were responsible for manuscript preparation.
Clinical inertia, which has been defined as the recognition of a problem with a patient's management but failing to act, is a concern in type 2 diabetes (T2D) because it places the patient at risk of diabetes-related complications. Despite managed care organizations making significant investment in this area, little is known about the impact of educational programs aimed at aligning patients and their physicians with diabetes guidelines and thus overcoming clinical inertia.
To assess the impact of an educational intervention specifically designed to align patients and their physicians with 2012 American Diabetes Association (ADA) guidelines on glycated hemoglobin (A1c) testing frequency and insulin initiation.
The "Act on Threes" educational intervention was a 12-month, randomized controlled prospective study that included Medicare Advantage patients aged 18-85 years with T2D, who received ≥ 3 oral antidiabetes drugs (OADs) and/or had A1c not at goal and/or had no recent A1c evaluation over 12 months, as identified through the analysis of administrative claims data (May 1, 2011-April 30, 2013) from the Humana database. Identified patients were randomized 3:1 to receive the Act on Threes
 educational intervention in conjunction with standard care (intervention group) or standard care alone (control group). For the educational intervention, patients and physicians were simultaneously mailed general and targeted information aimed at aligning them to 3 vital aspects of A1c control: timely measurement of A1c every 3 months; timely treatment intensification to meet A1c goals with treatment intensification every 3 months if A1c is not at goal; and insulin initiation when appropriate, including patients receiving ≥ 3 OADs with A1c not at goal. Control patients were only enrolled if the treating physician was not involved in the care of any patients in the intervention group. The primary outcome measures were A1c testing frequency based on the ADA standard for compliance of ≥ 2 tests per year and insulin initiation in the 12-month postintervention period. A1c levels were evaluated for the subgroup of patients with available A1c measurements in the pre- and postintervention periods. Descriptive statistics were used to analyze differences between the intervention and control groups. Multiple logistic regression analysis was used to identify determinants of insulin initiation in the full study cohort.
6,243 patients (mean age 70 years; 43.5% female) were identified: 4,555 were randomized to the intervention group and 1,688 to the control group. The percentage of patients with ≥ 2 A1c tests per year was not significantly different postintervention for patients in the intervention and control groups (47.7% vs. 46.8%, respectively; P = 0.995). Intriguingly, the frequency of A1c testing increased significantly from pre- to postintervention in the intervention and control groups. Change in A1c level from pre- to postintervention was also similar for the 2 groups (P = 0.240). A similar percentage of patients in the intervention and control groups initiated insulin during the postintervention period (6.3% vs. 7.6%, respectively; P = 0.059).
This randomized controlled study demonstrated that, compared with standard care, the Act on Threes educational intervention combined with standard care did not result in any significant differences in the frequency of A1c testing or in the initiation of insulin in patients with T2D. These findings are in contrast to uncontrolled comparative studies showing significant improvements in outcomes postintervention and reinforce the importance of study design in evaluating the effectiveness of educational programs.
This study was funded by Sanofi U.S. Reynolds, Davis, Kamble, and Uribe are employees of Comprehensive Health Insights, which was contracted by Sanofi U.S. to conduct, publish, and present this study. Bieszk and Wei are employees of Sanofi U.S. Reynolds and Uribe provided expertise and key clinical insights for the study design and methodology, provided interpretations of the data, contributed to the discussion, and reviewed the manuscript. Bieszk and Wei codeveloped the study design, researched data, contributed to discussion, and reviewed the manuscript. Davis and Kamble collected the data, provided study design, clinical insights, statistical and analytic reflections of the data, drafted the study reports, and reviewed the manuscript. All authors had full access to all the data in the study. Reynolds is the guarantor of this work and, as such, takes responsibility for the integrity of the data and the accuracy of the data analysis.
Writing/editorial support in the preparation of this manuscript, which was funded by Sanofi U.S., was provided by Rosalie Gadiot, PhD, of Excerpta Medica, who wrote the initial draft of the manuscript.
The past 25 years have seen a substantial increase in the effect of specialty drugs on patient care. These agents were initially not considered financially viable because they often served a comparatively small market of patients. However, the extended monopoly afforded to manufacturers of these drugs by the Orphan Drug Act of 1983 has made treatment of rare diseases, which specialty drugs often target, a more viable option. As a result, pharmaceutical companies began to increase research and development expenditures in this area, and the pipeline of specialty drugs began to grow in the late 1980s.
To analyze the annual change in wholesale acquisition cost (WAC) pricing of specialty drugs sold over a period of 11 years.
Pharmacy claims data, including date and WAC, were collected for each specialty drug transaction that occurred from 2002 through 2013 at the University of Illinois at Chicago Ambulatory Care Pharmacy Department. The data were organized to create a chronological sequence of WAC values from the initial to final sales of each available drug. Those values were then used to calculate annual percentage of change in WAC. These results were grouped into subsets and graphed in order to illustrate the effects that various factors had on the annual changes in price.
The price of the specialty drugs studied has generally shown a greater rate of increase since experiencing a trough rate increase in 2009 of 4.08%. The economic crisis of 2008 created a short pause in this overall trend, but increases in the rate of price growth have since rebounded. WACs increased at a rate of 7.03% or greater from 2010 through the end of the study period. There was a clear increase over the last few years of the study in the number of drugs with more than 10% annual increases in WAC, which has also shown a rebound after the economic crisis at the end of the last decade.
Specialty drugs are getting more expensive at a faster rate over time. The period from 2010 to 2013, the final year of this study, has also seen biologic agents take a more prominent role in driving these annual increases in WAC.
No funding was provided for the commission of this study. The source data was provided by the University of Illinois at Chicago Ambulatory Care Pharmacy Department and described de-identified data from customer transactions from 2002 through 2013. The authors report no conflicts of interest. Study concept and design and data interpretation were contributed by Stubbings and Penington. The manuscript was written primarily by Penington with assistance from Stubbings.
Morphological information on the reproductive system allows the understanding of ecological and behavioural aspects of different species as well as supports the development of conservational strategies. Unfortunately, for many species, not enough relevant and precise information is available. In the present study, we describe for the first time the macroscopic and histological aspects of female genital organs and external female genitalia of Saimiri macrodon, Saimiri cassiquiarensis and Saimiri vanzolinii. We perform a comparison between these three peripatric species and investigate the possibility of their reproductive morphology to act as a factor of reproductive isolation. We have found that these species share many similarities in most of the analysed organs. Although some important differences were identified that may play an important role in the evolution of the components of the reproductive system of these species, those differences are not enough to compose a mechanism of reproductive isolation for these three species of Saimiri. The results of this study may be used to support the development of biotechnological approaches of reproduction and strategies for conservation programmes and management of threatened species of this genus, particularly S. vanzolinii, considered to be a vulnerable species to extinction.
Treatment with high iodine concentrations can delay oncogenic activation effects, reduce cell growth and return thyroid-specific gene and protein expression levels to normal. During rearranged during transfection (RET)/papillary thyroid carcinoma (PTC) 3 activation, excess iodine can act as a protective agent in thyroid follicular cells. The chemokine receptor CCR7 serves a critical role in lymphocyte trafficking into and within lymph nodes, the preferential metastatic site for PTC. However, the potential associations between chemokine (C C motif) ligand 21 (CCL21)/C C chemokine receptor type 7 (CCR7) interaction and iodine concentrations in primary cultures of PTC with RET/PTC expression remain unclear. Proliferation assays of primary cultures of PTC cells with RET/PTC1 and RET/PTC3 expression indicated that CCR7 activation by its specific ligand, CCL21, was associated with significantly increased cell proliferation. Flow cytometry data indicated that CCL21/CCR7 interaction significantly increased the fraction of cells in the G2/M phase of the cell cycle. Western blotting indicated that CCL21/CCR7 interaction significantly upregulated cyclin A, cyclin B1 and cyclin dependent kinase 1 (CDK1) expression. Western blotting determined that CCL21/CCR7 interaction significantly enhanced the levels of phosphorylated extracellular signal regulated kinase (P ERK). Co-immunoprecipitation confirmed that there was interaction between P ERK and cyclin A, cyclin B1 or CDK1, particularly in the presence of CCL21. Sodium iodide (NaI, 10-5 M) significantly abolished the effects of exogenous CCL21. These results suggest that CCL21/CCR7 interaction contributes to G2/M progression of RET/PTC expressing cells via the ERK pathway in association with 10 5 M NaI.
Dietary calorie restriction is a broadly acting intervention that extends the lifespan of various organisms from yeast to mammals. On another front, magnesium (Mg(2+)) is an essential biological metal critical to fundamental cellular processes and is commonly used as both a dietary supplement and treatment for some clinical conditions. If connections exist between calorie restriction and Mg(2+) is unknown. Here, we show that Mg(2+), acting alone or in response to dietary calorie restriction, allows eukaryotic cells to combat genome-destabilizing and lifespan-shortening
 accumulations of RNA-DNA hybrids, or R-loops. In an R-loop accumulation model of Pbp1-deficient Saccharomyces cerevisiae, magnesium ions guided by cell membrane Mg(2+) transporters Alr1/2 act via Mg(2+)-sensitive R-loop suppressors Rnh1/201 and Pif1 to restore R-loop suppression, ribosomal DNA stability and cellular lifespan. Similarly, human cells deficient in ATXN2, the human ortholog of Pbp1, exhibit nuclear R-loop accumulations repressible by Mg(2+) in a process that is dependent on the TRPM7 Mg(2+) transporter and the RNaseH1 R-loop suppressor. Thus, we identify Mg(2+) as a biochemical signal of beneficial calorie restriction, reveal an R-loop suppressing function for human ATXN2 and propose that practical magnesium supplementation regimens can be used to combat R-loop accumulation linked to the dysfunction of disease-linked human genes.
Forgery is an act of modifying a document, product, image or video, among other media. Video tampering detection research requires an inclusive database of video modification. This paper aims to discuss a comprehensive proposal to create a dataset composed of modified videos for forensic investigation, in order to standardize existing techniques for detecting video tampering. The primary purpose of developing and designing this new video library is for usage in video forensics, which can be consciously associated with reliable verification using dynamic and static camera recognition. To the best of the author's knowledge, there exists no similar library among the research community. Videos were sourced from YouTube and by exploring social networking sites extensively by observing posted videos and rating their feedback. The video tampering dataset (VTD) comprises a total of 33 videos, divided among three categories in video tampering: (1) copy-move, (2) splicing, and (3) swapping-frames. Compared to existing datasets, this is a higher number of tampered videos, and with longer durations. The duration of every video is 16s, with a 1280×720 resolution, and a frame rate of 30 frames per second. Moreover, all videos possess the same formatting quality (720p(HD).avi). Both temporal and spatial video features were considered carefully during selection of the videos, and there exists complete information related to the doctored regions in every modified video in the VTD dataset. This database has been made publically available for research on splicing, Swapping frames, and copy-move tampering, and, as such, various video tampering detection issues with ground truth. The database has been utilised by many international researchers and groups of researchers.
In September 2015, 80 litres of a viscous, light-red liquid, described as hair product, was seized by the Australian Border Force (ABF). Initial testing by ABF indicated that the liquid was the 3,4-methylenedioxymethamphetamine (MDMA) precursor chemical safrole and custody of the material was transferred to the Australian Federal Police (AFP) who coordinated all subsequent investigations. Initial gas chromatography-mass spectrometry (GC-MS) analysis by the AFP indicated that the material was not safrole and samples of the liquid were transferred to the National Measurement Institute Australia (NMIA) for identification. Using a combination of nuclear magnetic resonance spectroscopy (NMR), GC-MS, infrared spectroscopy, and synthesis, the unknown substance was identified as N-tert.-butoxycarbonyl-MDMA (t-BOC-MDMA). The substance was also converted in high yield to MDMA (aqueous HCl, 80 °C, 30 min). The possibility that the t-BOC-MDMA may act as a pro-drug following ingestion was explored by exposure to simulated gastric juice (pH 1.5) and monitored by NMR (37 °C) at various intervals. The majority of t-BOC-MDMA was converted to MDMA after 305 min, which suggested that this derivatized form might serve as a pro-drug in vivo. An investigation into the chemistry of potential pro-drugs showed that t-BOC derivatives of methamphetamine, pseudoephedrine and 4-methylmethcahtinone (mephedrone) could also be prepared using di-tert.-butyl dicarbonate. The appearance of t-BOC-derivatives on the drug market requires further monitoring. © 2016 Commonwealth of Australia. Drug Testing and Analysis © 2016 John Wiley & Sons, Ltd.
Ensuring that older patients are discharged from hospital in a safe and appropriate manner is a fundamental aspect of nursing care. However, it is clear from the literature and clinical practice that determining people's capacity and whether they are able to decide where they live on discharge is a significant challenge. There is variation in practice despite the legal framework provided by the Mental Capacity Act (MCA) 2005, covering England and Wales, which raises questions about adherence to the legislation. Using a case study, this article explores aspects of the MCA and clinical practice that affect older patients' outcomes on discharge from general hospital settings. It demonstrates how effective multidisciplinary working, using the legal frameworks available, can ensure that an individual's independence and well-being are maintained.
To understand the action and mechanism of hypotaurine, an immediate precursor of taurine, on orofacial nociceptive processing, we examined the direct effects and receptor types involved in hypotaurine-induced responses using the whole-cell patch clamp technique in the substantia gelatinosa (SG) neurons of the trigeminal subnucleus caudalis (Vc) of immature mice. Under the condition of high-chloride pipette solution, hypotaurine elicited inward currents or upward deflections of membrane potential, which increased in a concentration-dependent manner (30-3000 μM) with the EC50 of 663.8 and 337.6 μM, respectively. The responses to 300 µM hypotaurine were reproducible and recovered upon washout. The 300 µM hypotaurine-induced currents were maintained in the presence of TTX, CNQX, and AP5, indicating direct postsynaptic action of hypotaurine on SG neurons. Responses to both low (300 µM) and high (1 or 3 mM) concentrations of hypotaurine were completely and reversibly blocked by the glycine receptor antagonist strychnine (2 µM), but unaffected by the GABAA receptor antagonist gabazine (3 µM) which blocks synaptic GABAA receptors at low concentration. Furthermore, responses to 300 µM hypotaurine and a maximal concentration of glycine (3 mM) were not additive, indicating that hypotaurine and glycine act on the same receptor. Hypotaurine-induced currents were partially antagonized by picrotoxin (50 µM) which blocks homomeric glycine receptors and by bicuculline (10 µM) which is an antagonist of α2 subunit-containing glycine receptors. These results suggest that hypotaurine-induced responses were mediated by glycine receptor activation in the SG neurons and hypotaurine might be used as an effective therapeutics for orofacial pain.
Epigenetic alterations such as DNA methylation, histone modifications and non-coding RNA (including microRNA) associated gene silencing have been identified as a major characteristic in human cancers. These alterations may occur more frequently than genetic mutations and play a key role in silencing tumor suppressor genes or activating oncogenes, thereby affecting multiple cellular processes. In recent years, studies have shown that microRNAs, that act as posttranscriptional regulators of gene expression are frequently deregulated in colorectal cancer (CRC), via aberrant DNA methylation. Over the past decade, technological advances have revolutionized the field of epigenetics and have led to the identification of numerous epigenetically dysregulated miRNAs in CRC, which are regulated by CpG island hypermethylation and DNA hypomethylation. In addition, aberrant DNA methylation of miRNA genes holds a great promise in several clinical applications such as biomarkers for early screening, prognosis, and therapeutic applications in CRC.
One of the long-standing principles of molecular biology is that DNA acts as a template for transcription of messenger RNAs, which serve as blueprints for protein translation. A rapidly growing number of exceptions to this rule have been reported over the past decades: they include long known classes of RNAs involved in translation such as transfer RNAs and ribosomal RNAs, small nuclear RNAs involved in splicing events, and small nucleolar RNAs mainly involved in the modification of other small RNAs, such as ribosomal RNAs and transfer RNAs. More recently, several classes of short regulatory non-coding RNAs, including piwi-associated RNAs, endogenous short-interfering RNAs and microRNAs have been discovered in mammals, which act as key regulators of gene expression in many different cellular pathways and systems. Additionally, the human genome encodes several thousand long non-protein coding RNAs >200 nucleotides in length, some of which play crucial roles in a variety of biological processes such as epigenetic control of chromatin, promoter-specific gene regulation, mRNA stability, X-chromosome inactivation and imprinting. In this chapter, we will introduce several classes of short and long non-coding RNAs, describe their diverse roles in mammalian gene regulation and give examples for known modes of action.
The evolution of sensory systems has let mammals develop complicated tactile end organs to enable sophisticated sensory tasks, including social interaction, environmental exploration, and tactile discrimination. The Merkel disc, a main type of tactile end organ consisting of Merkel cells (MCs) and Aβ-afferent endings, are highly abundant in fingertips, touch domes, and whisker hair follicles of mammals. The Merkel disc has high tactile acuity for an object's physical features, such as texture, shape, and edges. Mechanisms underlying the tactile function of Merkel discs are obscured as to how MCs transmit tactile signals to Aβ-afferent endings
 leading to tactile sensations. Using mouse whisker hair follicles, we show herein that tactile stimuli are transduced by MCs into excitatory signals that trigger vesicular serotonin release from MCs. We identify that both ionotropic and metabotropic 5-hydroxytryptamine (5-HT) receptors are expressed on whisker Aβ-afferent endings and that their activation by serotonin released from MCs initiates Aβ-afferent impulses. Moreover, we demonstrate that these ionotropic and metabotropic 5-HT receptors have a synergistic effect that is critical to both electrophysiological and behavioral tactile responses. These findings elucidate that the Merkel disc is a unique serotonergic synapse located in the epidermis and plays a key role in tactile transmission. The epidermal serotonergic synapse may have important clinical implications in sensory dysfunctions, such as the loss of tactile sensitivity and tactile allodynia seen in patients who have diabetes, inflammatory diseases, and undergo chemotherapy. It may also have implications in the exaggerated tactile sensations induced by recreational drugs that act on serotoninergic synapses.
Collective sensing by interacting cells is observed in a variety of biological systems, and yet, a quantitative understanding of how sensory information is collectively encoded is lacking. Here, we investigate the ATP-induced calcium dynamics of monolayers of fibroblast cells that communicate via gap junctions. Combining experiments and stochastic modeling, we find that increasing the ATP stimulus increases the propensity for calcium oscillations, despite large cell-to-cell variability. The model further predicts that the oscillation propensity increases with not only the stimulus, but also the cell density due to increased communication. Experiments confirm this prediction, showing that cell density modulates the collective sensory response. We further implicate cell-cell communication by coculturing the fibroblasts with cancer cells, which we show act as "defects" in the communication network, thereby reducing the oscillation propensity. These results suggest that multicellular networks sit at a point in parameter space where cell-cell communication has a significant effect on the sensory response, allowing cells to simultaneously respond to a sensory input and the presence of neighbors.
Recent evidence has implicated steroid hormones, specifically estrogens, in the rapid modulation of cognitive processes. Songbirds have been a useful model system in the study of complex cognitive processes including birdsong, a naturally learned vocal behavior regulated by a discrete steroid-sensitive telencephalic circuitry. Singing behavior is known to be regulated by long-term actions of estrogens but rapid steroid modulation of this behavior has never been examined. We investigated if acute actions of estrogens regulate birdsong in canaries (Serinus canaria). In the morning, male canaries sing within minutes after light onset. Birds were injected with fadrozole, a potent aromatase inhibitor, or vehicle within 2-5 minutes after lights on to implement a within-subjects experimental design. This single injection of fadrozole reduced the motivation to sing as well as song acoustic stereotypy, a measure of consistency over song renditions, on the same day. By the next day, however, all song measures that were affected had returned to baseline. This study indicates that estrogens also act in a rapid fashion to regulate two distinct features of song, a learned vocal behavior.
The neglected tropical disease priority review voucher (PRV) program ("tropical disease voucher," "voucher") is a U.S. government program intended to enlarge the number of products approved for tropical diseases in the United States. Ridley and others noted that "Infectious and parasitic diseases create enormous health burdens, but because most of the people suffering from these diseases are poor, little is invested in developing treatments." In 2006, these academicians proposed, and in 2007, the U.S. Congress enacted a new section 524 to the Federal Food, Drug, and Cosmetic Act (21 U.S.C. 360n) that provides financial incentives for sponsors of tropical disease products. If a sponsor achieves approval of a new drug application (NDA) or biologics licensing application (BLA) for a new chemical entity (NCE) that constitutes a significant improvement for one of at least 16 listed tropical diseases, the sponsor receives a PRV which can be used for priority review of any subsequent NDA/BLA. "Priority review" means that the Food and Drug Administration (FDA) review occurs with a target of 6 months rather than the standard review period of 10 months. The PRV is transferable and can be sold for use with any other product. An approximately 4-month shorter FDA review time for a future NDA/BLA has clear monetary value providing sufficient financial incentives to develop novel tropical disease products. Note that the creation of this financial incentive costs the U.S. taxpayer essentially nothing: use of a voucher puts drug "X" supported by the voucher at the front of the FDA review line, with the extra voucher user fee paid by the sponsor of drug X compensating the FDA for the extra review effort.
In ecosystems where large-scale disturbances are infrequent, the mode of succession may be difficult to discern and floristic surveys alone cannot be used determine the underlying processes causing vegetation change. To determine the causes of vegetation change in response to a large-scale fire event, we combined traditional floristic survey data, plant functional traits and environmental variables in a model-based solution to the fourth-corner problem. This approach allowed us to describe the trait-environment relationship and provides an intuitive matrix of environment by trait interaction coefficients. We could then quantify the strength and direction of associations between plant traits, species life-forms and environmental factors in two alpine plant communities over nine years post-fire. Initially, the fire drastically reduced vegetation cover and species density to very low levels. The fourth-corner analysis interaction coefficients indicated that over the course of the nine-year study a high abundance of graminoids, a low abundance of shrubs, tall species and those with high leaf dry matter content had the strongest associations with the two plant communities. We also found evidence for functional homogenisation between these two communities using this novel technique. Analysing plant traits and species responses post-fire in this manner can be used to infer the ecological processes driving shifts in vegetation.
The reduced and oxidized states of an open-shell diindeno[b,i]anthracene (DIAn) derivative have been investigated by experimental and theoretical techniques. As a result of moderate biradical character and the ability of cyclopenta-fused scaffolds to stabilize both positive and negative charges, DIAn exhibits rich redox chemistry with four observable and isolable charged states. Structural and electronic properties of the DIAn system are brought to light by UV-vis-NIR and Raman spectroelectrochemical measurements. Aromatization of the diindeno-fused anthracene core upon successive single-electron injections is revealed through single-crystal X-ray diffraction of radical anion and dianion salts. We present a rare case where the pseudoaromatic/quinoidal ground state of a neutral biradical polycyclic hydrocarbon leads to a stable cascade of five redox states. Our detailed investigation of the transformation of molecular structure along all four redox events provides a clearer understanding of the nature of charge carriers in ambipolar organic field-effect transistors.
Non-small cell lung cancer (NSCLC) is a potentially fatal disease and the incidence is increasing annually. In order to diagnose and treat NSCLC effectively, greater understanding of its molecular mechanism is required. In the present study, 36 NSCLC tissues and 10 normal tissues were selected. Reverse transcription quantitative polymerase chain reaction (RT qPCR) was used to analyze the CD44 mRNA expression level in NSCLC tissue and DNA sequencing was performed to further verify the CD44 expression level. Differentially expressed genes between tumor tissues and controls were determined by DNA sequencing and the Gene_act_net between CD44 and its associated genes was constructed. Gene Ontology (GO) term enrichment analysis of the differentially expressed genes was performed by the Biological Networks Gene Ontology tool. Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis was performed based on the Expression Analysis Systematic Explorer test applied in the Database for Annotation, Visualization and Integrated Discovery. RT qPCR results showed that CD34 was overexpressed in 21 of the 36 NSCLC tissues (58.3%). The Gene_act_net indicated that there were 20 differentially expressed genes with 17 upregulated and 3 downregulated. Among them, CD44, MET, ERBB2, EGFR, AKT1, IQGAP1 and STAT3 were associated with the occurrence and migration of NSCLC. In KEGG pathway analysis, extracellular matrix receptor interaction and hematopoietic cell lineage pathways were the most affected by overexpressed CD44; and thus may be important in the development and migration of NSCLC. In conclusion, CD44 was overexpressed in NSCLC and the overexpression was associated with the occurrence of NSCLC and migration of NSCLC cells.
Physicians in small physician-owned practices in the United States have been slower to adopt EHRs than physicians in large practices or practices owned by large organizations. The Health Information Technology for Economic and Clinical Health (HITECH) Act of 2009 included provisions intended to address many of the potential barriers to EHR adoption cited in the literature,
 including a financial incentives program that has paid physicians and other professionals $13 billion through December 2015.
Given the range of factors that may be influencing physicians' decisions on whether to adopt an EHR, and given the level of HITECH expenditures to date, there is significant policy value in assessing whether the HITECH incentives have actually had an impact on EHR adoption decisions among U.S. physicians in small, physician-owned practices. This study addresses this question by analyzing physicians' own views on the influence of the HITECH incentives as well as other potential considerations in their decision-making on whether to adopt an EHR.
Using data from a national survey of physicians, five composite scales were created from groups of survey items to reflect physician views on different potential facilitators and barriers for EHR adoption as of 2011, after the launch of the HITECH incentives program. Multinomial and binary logistic regression models were specified to test which of these physician-reported considerations have a significant relationship with EHR adoption status among 1043 physicians working in physician-owned practices with no more than 10 physicians.
Physicians' views on the importance of the HITECH financial incentives are strongly associated with EHR adoption during the first three years of the HITECH period (2010-2012). In the study's primary model, a one-point increase on a three-point scale for physician-reported influence of the HITECH financial incentives increases the relative risk of being in the process of adoption in 2011, compared to the risk of remaining a non-adopter, by a factor of 4.02 (p<0.001, 95% CI of 2.06-7.85). In a second model which excludes pre-HITECH adopters from the data, a one-point increase on the incentives scale increases the relative risk of having become a new EHR user in 2010 or 2011, compared to the risk of remaining a non-adopter, by a factor of 3.98 (p<0.01, 95% CI of 1.48-10.68) and also increases the relative risk of being in the process of adoption in 2011 by a factor of 5.73 (p<0.001, 95% CI of 2.57-12.76), compared to the risk of remaining a non-adopter in 2011. In contrast, a composite scale that reflects whether physicians viewed choosing a specific EHR vendor as challenging is not associated with adoption status.
This study's principal finding is that the HITECH financial incentives were influential in accelerating EHR adoption among small, physician-owned practices in the United States. A second finding is that physician decision-making on EHR adoption in the United States has not matched what would be predicted by the literature on network effects. The market's failure to converge on a dominant design in the absence of interoperability means it will be difficult to achieve widespread exchange of patients' clinical information among different health care provider organizations.
Insulin-like peptides (ILPs) act through a conserved insulin signaling pathway and play crucial roles in insect metabolism, growth, reproduction, and aging. Application of bovine insulin is able to increase vitellogenin (Vg) mRNA and protein levels in female insects. Here, we first show that injection of bovine insulin into previtellogenic Chrysopa septempunctata female adults promoted ovarian growth, increased Vg protein abundance, elevated reproductive performance, and enhanced protease activity. These data suggested that ILPs play crucial roles in reproductive regulation of the green lacewing, C. septempunctata.
Extreme intentional and deliberate violence against innocent people, including acts of terror and school shootings, poses various ethical challenges, some related to the practice of medicine. We discuss a dilemma relating to deliberate violence, in this case the aftermath of a terror attack, in which there are multiple injured individuals, including the terror perpetrator. Normally, the priority of medical treatment is determined based on need. However, in the case of a terror attack, there is reason to question this. Should the perpetrator of extreme violence receive medical treatment on the scene before the victims if he or she is designated as the most seriously injured? Or rather, should victims receive medical care priority if they are also in some life-threatening danger, although not at the same level of severity as the perpetrator? We present two opposing approaches: the conventional 'no-exceptions' approach, which gives priority to the terrorist, and the justice-oriented 'victim first' approach, which gives priority to the victims. Invoking concepts of retributive justice, distributive justice and corrective justice, this latter approach suggests that 'value-neutrality' can lead to injustice. Perpetrators of terror-like violence should be treated as an act of humanism and good ethical medical practice. However, in clear and obvious terror-like situations, to treat the perpetrators of violence before their victims may be unjust. Thus, in some specific situations, the 'victim first' approach may be considered a legitimate alternative triage policy.
Estrogen has been closely associated with breast cancer. Several studies reported that Ca2+ signal and Ca2+ channels act in estrogen-modulated non-genomic pathway of breast cancer, however little was revealed on the function of L-type Ca2+ channels. The L-type Ca2+ channel subunit α 1D, named Cav1.3 was found in breast cancer cells. We aimed to investigate the expression and activity of Cav1.3 in human breast cancer, and reveal the effect of estrogen in regulating the expression of Cav1.3. The qRT-PCR and western blotting were employed to show that Cav1.3 was highly expressed in breast cancer tissues. E2 exposure rapidly upregulated the expression of Cav1.3 in dosage- and time-dependent manner, and promoted Ca2+ influx. The silencing of G protein-coupled estrogen receptor 30 (GPER1/GPR30) using siRNA transfection inhibited the upregulation of Cav1.3 and Ca2+ influx induced by E2. Moreover, the inhibition of Cav1.3 by siRNA transfection suppressed E2-induced second peak of Ca2+ signal, the expression of p-ERK1/2, and the cell proliferation. Ultrasound-targeted microbubble destruction (UTMD) of Cav1.3 siRNA was used in MCF-7 cells in vitro and in the tumor xenografts mice in vivo. The application of UTMD significantly suppressed the tumor growth and promoted the survival rate. In conclusion, E2 upregulated the expression of Cav1.3 for Ca2+ influx to promote the expression of p-ERK1/2 for cell proliferation. The study confirmed that the mechanism of E2 inducing the expression of Cav1.3 through a non-genomic pathway, and highlighted that UTMD of Cav1.3 siRNA is a powerful promising technology for breast cancer gene therapy.
We report a novel approach for patterning thermoresponsive hydrogels based on N,N-diethylacrylamide (DEAAm) and bifunctional Jeffamine ED-600 by dip-pen nanolithography (DPN). The direct writing of micron-sized thermoresponsive polymer spots was achieved with efficient control over feature size. A Jeffamine-based ink prepared through the combination of organic polymers, such as DEAAm, in an inorganic silica network was used to print thermosensitive arrays on a thiol-silanized silicon oxide substrate. The use of a Jeffamine hydrogel, acting as a carrier matrix, allowed a reduction in the evaporation of ink molecules with high volatility, such as DEAAm, and facilitated the transfer of ink from tip to substrate. The thermoresponsive behavior of polymer arrays which swell/deswell in aqueous solution in response to a change in temperature was successfully characterized by atomic force microscopy (AFM) and Raman spectroscopy: a thermally induced change in height and hydration state was observed, respectively. Finally, we demonstrate that cells can adhere to and interact with these dynamic features and exhibit a change in behavior when cultured on the substrates above and below the transition temperature of the Jeffamine/DEAAm thermoresponsive hydrogels. This demonstrates the potential of these micropatterned hydrogels to act as a controllable surface for cell growth.
Hepatic fibrosis is a scarring process that may progress to hepatic cirrhosis and even hepatic carcinoma if left untreated. Hepatic stellate cells (HSCs) play essential roles in the development of hepatic fibrosis. The tumor suppressor protein p53 is a transcription factor that is involved in cell proliferation, cell cycle regulation, apoptosis and DNA repair. Recombinant human adenovirus-p53 (Ad-p53) has been demonstrated to act as a promising antitumor gene therapy in various types of cancer. However, there is limited infomration regarding the therapeutic effect of Ad-p53 on the regression of hepatic fibrosis. In order to examine the underlying molecular mechanism responsible for the effects of Ad-p53 on HSCs, a rat model of hepatic fibrosis was established and HSC-T6 cells were cultured under different conditions. The expression of p53, transforming growth factor (TGF-β1) and α-smooth muscle actin (α-SMA), which is a marker of activated HSCs, was detected by immunohistochemical assays and RT-qPCR. In vitro, five different concentrations (1x106, 5x106, 1x107, 2x107 and 5x107 PFU/ml) of Ad-p53 were selected for use in the MTT assay to analyze the proliferation of HSCs at 0, 24, 48 and 72 h. Flow cytometric analysis was applied to determine the effect of three different concentrations of Ad-p53 (5x106, 1x107 and 2x107 PFU/ml) on the cell cycle and the apoptosis of HSC-T6 cells at 24 and 48 h. The results of immunohistochemical studies and RT-qPCR showed that Ad-p53 upregulated the expression of p53, and downregulated the expression of TGF-β1 and α-SMA. The MTT assay revealed that when treated with various doses of Ad-p53, the proliferation of HSCs was inhibited within a certain range of concentrations and time periods.
 Analysis of flow cytometric data showed that Ad-p53 arrested the cell cycle in G1 phase and significantly induced apoptosis. Taken together, these findings suggest that Ad-p53 promotes apoptosis and inhibits the proliferation of HSCs in a time  and dose-dependent manner by modulating the expression of p53, TGF-β1 and α-SMA.
T-705 (favipiravir) is a new antiviral agent in advanced clinical development for influenza therapy. It is supposed to act as an alternative substrate for the viral polymerase, causing inhibition of viral RNA synthesis or virus mutagenesis. These mechanisms were also proposed for ribavirin, an established and broad antiviral drug that shares structural similarity with T-705. We here performed a comparative analysis of the effects of T-705 and ribavirin on influenza virus and host cell functions. Influenza virus-infected cell cultures were exposed to T-705 or ribavirin during single or serial virus passaging. The effects on viral RNA synthesis and infectious virus yield were determined and mutations appearing in the viral genome were detected by whole-genome virus sequencing. Besides, the cellular nucleotide pools were quantified as well as direct inhibition of the viral polymerase enzyme. We demonstrate that the anti-influenza effect of ribavirin is based on IMP dehydrogenase inhibition, which results in fast and profound GTP depletion and an imbalance in the nucleotide pools. In contrast, T-705 acts as a potent and GTP-competitive inhibitor of the viral polymerase. In infected cells, viral RNA synthesis is completely inhibited by T-705 or ribavirin at ≥50 μM, whereas exposure to lower drug concentrations induces formation of non-infectious particles and accumulation of random point mutations in the viral genome. This mutagenic effect is two-fold higher for T-705 than for ribavirin. Hence, T-705 and ribavirin both act as purine pseudobases, but profoundly differ with regard to the mechanism behind their antiviral and mutagenic effects on influenza virus.
MicroRNA-45 (miR-145) has been demonstrated to be downregulated in various cancer types including colorectal cancer (CRC). However, the function of miR 145 in CRC has not been clearly elucidated. In this study, we examined miR-145 expression by quantitative real time PCR (qRT PCR) in CRC cell lines as well as tumors and corresponding normal mucosa, and the results were correlated to the clinicopathological parameters. In addition, using computational algorithms we investigated putative miR 145 targets. The role of miR 145 was further examined in studies in vitro. In our study miR 145 was significantly decreased in CRC tissues and cell lines compared with non cancerous colorectal mucosa, especially lymph node or distance metastasis cases. Based on computational algorithms, we assumed that ERG was directly modulated by miR 145 in colorectal cancer cells. For the first time, we demonstrated that ERG was highly expressed in CRC tissues compared with normal ones by qRT PCR. The inverse correlation between the expression of miR 145 and ERG was observed in CRC tissues. Dual Luciferase assays demonstrated the direct interaction between miR 145 and 3' UTR of ERG mRNA. Ectopic expression of miR 145 suppressed the proliferation and invasion ability of colorectal cancer cells, while ERG knockdown partially restored the tumor suppressive effect of miR 145. These results suggested that miR 145 might act as a tumor suppressor during the process of CRC malignant transformation by interacting with ERG.
Cultural beliefs about breast cancer may act as a barrier to Latina women seeking preventive services or timely follow-up for breast symptoms regardless of access. This study examines the association between factors and breast cancer cultural beliefs and the extent to which cultural beliefs are associated with delays in breast cancer care. Participants who were Latina, ages 30-79, and had been diagnosed with a primary breast cancer were examined (n = 181). Interviews included a 15-item cultural beliefs scale spanning beliefs inconsistent with motivation to seek timely healthcare. Self-reported date of symptom discovery, date of first medical presentation, and date of first treatment were used to construct measures of prolonged patient, clinical, and total delay. Logistic regression with model-based standardization was used to estimate crude and confounder-adjusted prevalence differences for prolonged delay by number of cultural beliefs held. Women held a mean score of three cultural beliefs. The belief most commonly held was, "Faith in God can protect you from breast cancer" (48 %). Holding three or more cultural beliefs was associated with lower acculturation, lower socioeconomic status and less access to care (p < 0.01). After adjusting for age, education, income, acculturation, trust, and insurance, likelihood of prolonged total delay remained 21 percentage points higher in women who held a higher number cultural beliefs (p = 0.02). Cultural beliefs may predispose Latina women to prolong delays in seeking diagnosis and treatment for breast symptoms. Cultural beliefs represent a potential point of intervention to decrease delays among Latina breast cancer patients.
The discovery of antibiotics is one of the most significant milestones in modern medicine. Upon the advent of the antibiotic era, invasive surgical procedures, which were previously deemed too risky because of the possibility of bacterial infection, became a reality. In the process, medicine as a whole made great strides that led to the rise of the average human life span by almost three decades. Unfortunately, over the course of time bacteria have started to evolve resistance to antibiotic agents being administered, thus rendering many of these drugs ineffective (or on the verge of being ineffective). Today, the number of antibiotic-resistant bacteria continues to escalate and yet the number of new antibiotics being approved for clinical use has drastically decreased. The combination of these two factors has brought about a primary public health crisis for the 21st century. In order to maintain the status quo of modern medicine, new antibiotics need to be discovered and developed. Two emerging new strategies that hold considerable promise is the use of immunomodulator antibiotics and infection tolerance agents. Rather than targeting the bacteria directly, as traditional antibiotics do, these agents function to clear or tolerate infections by interfering with the bacterial colonization process and by stimulating the immune system of infected host. This review focuses on the different types of immunomodulation antibiotics and infection tolerance strategies that have been discovered over the last two decades and the mechanisms by which they act upon the host system to effectively combat bacterial infections.
The use of consumer products and pharmaceuticals that act as contaminants entering waterways through runoff and wastewater effluents alters aquatic ecosystem health. Traditional toxicological endpoints may underestimate the toxicity of contaminants, as lethal concentrations are often orders of magnitude higher than those found within freshwater ecosystems. While newer techniques examine the metabolic responses of sublethal contaminant exposure, there has been no direct comparison with ontogeny in Daphnia. It was hypothesized that Daphnia magna would have distinct metabolic changes after 3 different sublethal contaminant exposures, because of differences in the toxic mode of action and ontogeny. To test this hypothesis, the proton nuclear magnetic resonance metabolomic profiles were measured in D. magna aged day 0 and 18 after exposure to 28% of the lethal concentration of 50% of organisms tested (LC50) of atrazine, propranolol, and perfluorooctanesulfonic acid (PFOS) for 48 h. Principal component analysis revealed significant separation of contaminants from the control daphnids in both neonates and adults exposed to propranolol and PFOS. In contrast, atrazine exposure caused separation from the controls in only the adult D. magna. Minimal ontogenetic changes in the targeted metabolites were seen after exposure to propranolol. For both atrazine and PFOS exposures ontogeny exhibited unique changes in the targeted metabolites. These results indicate that, depending on the contaminant studied, neonates and adults respond uniquely to sublethal contaminant exposure. Environ Toxicol Chem 2016;9999:1-9. © 2016 SETAC.
Entecavir and tenofovir potently suppress hepatitis B virus (HBV) replication so that serum HBV DNA levels <20 IU/mL can be achieved after 2 years. Despite this, inadequate suppression is reported in >20% of cases for unclear reasons.
We tested whether 4-week (wk) viral load (VL) assessment could improve 96-wk treatment outcome.
Data on all chronic hepatitis B patients treated with entecavir or tenofovir between 2005-2014 were entered prospectively. Full data capture included pre-treatment, weeks 4, 24, 48 and 96 HBV DNA titre, HBeAg, age, gender, antiviral agent and dose escalation. Compliance data were compiled from pharmacy records, doctors' letters and clinic bookings/attendance. Time to achieve complete viral suppression (HBV DNA <20 IU/mL) was graphed using Kaplan-Meier curves. Factors affecting this were examined using a multivariate Cox Proportional Hazard model.
Amongst 156 patients treated, 72 received entecavir and 84 tenofovir. Pre-treatment HBV DNA titre, 4wk assessment and compliance impacted significantly on time to complete viral suppression. At 96wk, 90% of those assessed as compliant by 4wk HBV DNA had complete viral suppression versus 50% followed by 6 month VL estimation. Continuing care by the same physician was related to 4wk VL testing and optimal compliance.
Medium-term outcomes of HBV antiviral therapy are improved by early on-treatment VL testing, facilitating patient
 engagement and improved compliance. The observation that 90% complete viral suppression after 2 years monotherapy is achievable in a routine clinic setting questions the need for combination therapy in HBV cases with suboptimal response.
The human skin is a well-organized organ bearing different types of cells in a well-structured interference to each other including epidermal and follicular keratinocytes, sebocytes, melanocytes, dermal papilla cells and fibroblasts, endothelial cells, sweat gland cells as well as nerves. Several hormones act on different cell types of the skin, while it is also considered an endocrine organ secreting hormones that act at several sites of the organism. GH receptors are found in almost all cell types forming the skin, while IGF-1 receptors' expression is restricted to the epidermal keratinocytes. Both Growth Hormone (GH) excess, as in the case of Acromegaly in adults, or Gigantism in growing children, and GH deficiency states lead to skin manifestations. In case of GH excess the main dermatological findings are skin thickening, coarsening of facial features, acrochordons, puffy hands and feet, oily skin and hyperhidrosis, while GH deficiency, on the contrary, is characterized by thin, dry skin and disorder of normal sweating. Moreover, special disorders associated with GH excess may have specific characteristics, as is the case of café-au-lait spots in Neurofibromatosis, or big café-au-lait skin hyperpigmented regions with irregular margins, as is the case in McCune-Albright syndrome. Meticulous examination of the skin may therefore contribute to the final diagnosis in cases of GH-induced disorders.
Changing demographics and an increasing burden of multiple chronic comorbidities in western countries dictate refocusing of heart failure (HF) services from acute in-hospital care to better support the long inter-critical out-of-hospital phases of HF. The needs of the HF population are not adequately addressed by current HF outpatient services, as documented by differences in age, gender, comorbidities and recommended therapies between patients discharged for hospitalized HF and those followed up at HF clinics.The Working Group on Heart Failure of the Italian Association of Hospital Cardiologists (ANMCO) has drafted a consensus document for the organization of a national HF care network. The aims of this document are to describe tasks and requirements of the different health system points of contact for HF patients, and to define how diagnosis, management and care processes should be documented and shared among healthcare professionals. In this document, HF clinics are classified into three groups: 1) community HF clinics, devoted to the management of stable patients in strict liaison with primary care, regular re-evaluation of emerging clinical needs and prompt treatment of impending destabilizations, 2) hospital HF clinics, that target both new-onset and chronic HF patients for diagnostic assessment, treatment planning and early post-discharge follow-up. They act as main referral for medicine units and community clinics; 3) advanced HF clinics, directed at patients with severe disease or persistent clinical instability, candidates to advanced treatment options such as heart transplant or mechanical circulatory support. These different types of HF clinics are integrated in a dedicated network for the management of HF patients on a regional basis, according to geographic features. By sharing predefined protocols and communication systems, these HF networks integrate multiprofessional providers to ensure continuity of care. This consensus document is expected to promote a more efficient organization of HF care, in particular for elderly patients and in transition phases from acute to chronic HF, by networking outpatient cardiology offer and primary care.
Rational optimization of catalytic performance has been one of the major challenges in catalysis. Here we report a bottom-up study on the ability of TiO2 and ZrO2 to optimize the CO2 conversion to methanol on Cu, using combined density functional theory (DFT) calculations, kinetic Monte Carlo (KMC) simulations, in situ diffuse reflectance infrared Fourier transform spectroscopy (DRIFTS) measurements, and steady-state flow reactor tests. The theoretical results from DFT and KMC agree with in situ DRIFTS measurements, showing that both TiO2 and ZrO2 help to promote methanol synthesis on Cu via carboxyl intermediates and the reverse water-gas-shift (RWGS) pathway; the formate intermediates, on the other hand, likely act as a spectator eventually. The origin of the superior promoting effect of ZrO2 is associated with the fine-tuning capability of reduced Zr(3+) at the interface, being able to bind the key reaction intermediates, e.g. *CO2, *CO, *HCO, and *H2CO, moderately to facilitate methanol formation. This study demonstrates the importance of synergy between theory and experiments to elucidate the complex reaction mechanisms of CO2 hydrogenation for the realization of a better catalyst by design.
The eyes of an individual act as an indispensable communication medium during human social interactions. Functional neuroimaging studies have revealed that several brain regions are activated in response to eyes and eye gaze direction changes. However, it remains unclear whether the temporal pole is one of these regions. Furthermore, if the temporal pole is activated by these stimuli, the timing and manner in which it is activated also remain unclear. To investigate these issues, we analyzed intracranial electroencephalographic data from the temporal pole that were obtained during the presentation of eyes and mosaics in averted or straight directions and their directional changes. Time-frequency statistical parametric mapping analyses revealed that the bilateral temporal poles exhibited greater gamma-band activation beginning at 215 ms in response to eyes compared with mosaics, irrespective of the direction. Additionally, the right temporal pole showed greater gamma-band activation beginning at 197 ms in response to directional changes of the eyes compared with mosaics. These results suggest that gamma-band oscillations in the temporal pole were involved in the processing of the presence of eyes and changes in eye gaze direction at a relatively late temporal stage compared with the posterior cortices.
Neural circuitry has evolved to form distributed networks that act dynamically across large volumes. Conventional microscopy collects data from individual planes and cannot sample circuitry across large volumes at the temporal resolution relevant to neural circuit function and behaviors. Here we review emerging technologies for rapid volume imaging of neural circuitry. We focus on two critical challenges: the inertia of optical systems, which limits image speed, and aberrations, which restrict the image volume. Optical sampling time must be long enough to ensure high-fidelity measurements, but optimized sampling strategies and point-spread function engineering can facilitate rapid volume imaging of neural activity within this constraint. We also discuss new computational strategies for processing and analyzing volume imaging data of increasing size and complexity. Together, optical and computational advances are providing a broader view of neural circuit dynamics and helping elucidate how brain regions work in concert to support behavior.
Difficulties of walking and deficits of cognitive functions appear to be associated in the elderly. Thus, clinical assessment in geriatry and neurology should focus on: (1) diagnostic approaches covering both domains of everyday functioning; (2) therapeutic interventions that take into account possible interactions and synergies of both domains.
In order to assess the capability for motor-cognitive interactions in the elderly it is recommended to investigate walking patterns during dual-tasks (e.g. walking and counting backwards, walking and naming words) and to examine clinical tests of everyday mobility tasks, such as the Timed-up-and-go-Test and spatial navigation tasks. Patients with cognitive disorders often perform inferior with a reduction of walking speed and an increase of stepping variability. Dual-task performance appears to be a reliable parameter for long-term observations of the course of the disease. Moreover, it might improve the quality of the gait examination during diagnostic or therapeutic interventions (e.g. the spinal tap test in patients with NPH). Several studies further highlight gait deficits during dual-task walking as a marker for the everyday functioning and the quality of life in elderly persons and patients with cognitive disorders.Therapeutic approaches in this context comprise complex motor-cognitive interventions, such as Thai Chi and Dalcroze rhythmic exercises. These interventions appear to act synergistically in motor and cognitive domains. First evidence for the efficacy for improving executive functions and reducing the fall risk of patients with cognitive impairments is given, thought randomized, controlled trials are rare.
Laws governing abortion provision are proliferating throughout the United States, yet little is known about how these laws affect providers. We investigated the experiences of abortion providers in North Carolina practicing under the 2011 Women's Right to Know Act, which mandates that women receive counseling with specific, state-prescribed information at least 24 hours prior to an abortion. We focus here on a subset of the data to examine one strategy by which providers worked to minimize moral conflicts generated by the counseling procedure. Drawing on Erving Goffman's work on language and social interaction, we highlight how providers communicated moral objections and layered meanings through a practice that we call prefacing the script.
We conducted
 semi-structured interviews with 31 physicians, nurses, physician assistants, and clinic managers who provide abortion care in North Carolina. Audio-recorded interviews were transcribed verbatim and analyzed using an inductive, iterative analytic approach, which included reading for context, interpretive memo-writing, and focused coding.
Roughly half of the participants (14/31) reported that they or the clinicians who performed the counseling in their institution routinely prefaced the counseling script with qualifiers, disclaimers, and apologies that clarified their relationship to the state-mandated content. We identified three performative functions of this practice: 1) enacting a frame shift from a medical to a legal interaction, 2) distancing the speaker from the authorial voice of the counseling script, and 3) creating emotional alignment.
Prefacing state-mandated abortion counseling scripts constitutes a practical strategy providers use to balance the obligation to comply with state law with personal and professional responsibilities to provide tailored care, emotional support, and serve the patient's best interests. Our findings suggest that language constitutes a powerful resource for navigating and minimizing moral conflicts in healthcare.
Alzheimer's disease (AD) and Parkinson's disease (PD) are the most common age-related neurodegenerative disorders and hence pose remarkable socio-economical burdens to both families and state. Although AD and PD have different clinical and neuropathological features, they share common molecular mechanisms that appear to be triggered by multi-factorial events, such as protein aggregation, mitochondrial dysfunction, oxidative stress (OS), and neuroinflammation, ultimately leading to neuronal cell death. Currently, there are no established and validated disease-modifying strategies for either AD or PD. Among the various lifestyle factors that may prevent or slow age-related neurodegenerative diseases, epidemiological studies on moderate consumption of red wine, especially as part of a holistic Mediterranean diet, have attracted increasing interest. Red wine is particularly rich in specific polyphenolic compounds that appear to affect the biological processes of AD and PD, such as quercetin, myricetin, catechins, tannins, anthocyanidins, resveratrol, and ferulic acid. Indeed, there is now a consistent body of in vitro and in vivo data on the neuroprotective effects of red wine polyphenols (RWP) showing that they do not merely possess antioxidant properties, but may additionally act upon, in a multi-target manner, the underlying key mechanisms featuring in both AD and PD. Furthermore, it is important that bioavailability issues are addressed in order for neuroprotection to be relevant in a clinical study scenario. This review summarizes the current knowledge about the major classes of RWP and places into perspective their potential to be considered as nutraceuticals to target neuropathology in AD and PD.
Automated label-free quantitative imaging of biological samples can greatly benefit high throughput diseases diagnosis. Digital holographic microscopy (DHM) is a powerful quantitative label-free imaging tool that retrieves structural details of cellular samples non-invasively. In off-axis DHM, a proper spatial filtering window in Fourier space is crucial to the quality of reconstructed phase image. Here we describe a region-recognition approach that combines shape recognition with an iterative thresholding method to extracts the optimal shape of frequency components. The region recognition technique offers fully automated adaptive filtering that can operate with a variety of samples and imaging conditions. When imaging through optically scattering biological hydrogel matrix, the technique surpasses previous histogram thresholding techniques without requiring any manual intervention. Finally, we automate the extraction of the statistical difference of optical height between malaria parasite infected and uninfected red blood cells. The method described here paves way to greater autonomy in automated DHM imaging for imaging live cell in thick cell cultures.
The Health Information Technology for Economic and Clinical Health (HITECH) Act proposes the meaningful use of interoperable electronic health records throughout the United States health care delivery system as a critical national goal. As we have moved from medical records on paper to interoperable electronic health records, the rapid and easy sharing of medical data through the Internet makes medical data insecure. Electronic data is easy to share but many steps to ensure security of the data need to be taken. Beyond medical data security, we need to ethically acquire, use and manage data so that all people involved with the data from producer to data manager are recognized and respected. This paper advocates that sharing medical data can be ethically the right choice for everyone in health care if data sharing guidelines are available for people to use, modify and strengthen for specific purposes.
Clinical and Translational Science Award (CTSA) recipients have a need to create research data marts from their clinical data warehouses, through research data networks and the use of i2b2 and SHRINE technologies. These data marts may have different data requirements and representations, thus necessitating separate extract, transform and load (ETL) processes for populating each mart. Maintaining duplicative procedural logic for each ETL process is onerous. We have created an entirely metadata-driven ETL process that can be customized for different data marts through separate configurations, each stored in an extension of i2b2 's ontology database schema. We extended our previously reported and open source Eureka! Clinical Analytics software with this capability. The same software has created i2b2 data marts for several projects, the largest being the nascent Accrual for Clinical Trials (ACT) network, for which it has loaded over 147 million facts about 1.2 million patients.
Immunoactivation is less evident in secondary progressive MS (SPMS) compared to relapsing-remitting disease. MicroRNA (miRNA) expression is integral to the regulation of gene expression; determining their impact on immune-related cell functions, especially CD4+ T cells, during disease progression will advance our understanding of MS pathophysiology. This study aimed to compare miRNA profiles of CD4+ T cells from SPMS patients to healthy controls (HC) using whole miRNA transcriptome next-generation sequencing (NGS). Total RNA was extracted from CD4+ T cells and miRNA expression patterns analyzed using Illumina-based small-RNA NGS in 12 SPMS and 12 HC samples. Results were validated in a further cohort of 12 SPMS and 10 HC by reverse transcription quantitative polymerase chain reaction (RT-qPCR).
The ten most dysregulated miRNAs identified by NGS were selected for qPCR confirmation; five (miR-21-5p, miR-26b-5p, miR-29b-3p, miR-142-3p, and miR-155-5p) were confirmed to be down-regulated in SPMS (p < 0.05). SOCS6 is targeted by eight of these ten miRNAs. Consistent with this, SOCS6 expression is up-regulated in SPMS CD4+ T cells (p < 0.05). This is of particular interest as SOCS6 has previously been shown to act as a negative regulator of T cell activation.
Ninety-seven percent of miRNA candidates identified by NGS were down-regulated in SPMS. The down-regulation of miRNAs and increased expression of SOCS6 in SPMS CD4+ T cells may contribute to reduced immune system activity in progressive MS.
Retirement is not always associated with greater engagement in physical activity. Previous interventions informed by possible selves, a type of future-oriented self-representation, proved useful to increase physical activity in young adults. We thus wanted to explore if a similar intervention would yield favorable outcomes in new retirees. We also examined whether possible selves could help increase identity relative to the physical activity context. Identity circumscribes the meanings which help individuals define who they are in a given role (i.e., what it means to be a physically active person). The strength of identification as a physically active person increases when individuals endorse these meanings more strongly. Possible selves may be tied to identity as they allow individuals to imagine themselves as physically active, which has been argued to incite changes to one's sense of self. Hence, the overall aim of this study was to determine whether a possible selves intervention would increase physical activity behaviour and physical activity identity in a group of newly-retired individuals.
A total of 294 participants were randomized into one of three groups: (a) a repeated group with three possible selves image generation exposures, (b) a one-time group with one possible selves image generation exposure, or (c) a control group. Participants completed self-report measures at baseline and follow-up assessments were taken at weeks 4, 8, and 12 of the study. The measures for the outcomes of interest were the Godin Leisure Time Exercise Questionnaire and the modified Exercise Identity Scale.
Repeated measures mixed-effects models analyses with maximum likelihood estimation revealed no significant differences between groups on physical activity behaviour (p = 0.34) or physical activity identity (p = 0.97) at follow-up time points. However, a time effect was found for physical activity (p <.01) and physical activity identity (p <.01), which increased across time (baseline-to-12-week follow-up) in all three groups. Such a time effect (inconsequential to group assignment) suggests that the observed increases in physical activity and identity cannot be attributed to an exposure to a possible selves intervention.
While the intervention failed to significantly increase physical
 activity identity and physical activity in newly retired individuals, we suggest future research directions for interventions targeting new retired individuals.
Cells make use of molecular motors to transport small molecules, macromolecules and cellular organelles to target region to execute biological functions, which is utmost important for polarized cells, such as neurons. In particular, cytoskeleton motors play fundamental roles in neuron polarization, extension, shape and neurotransmission. Cytoskeleton motors comprise of myosin, kinesin and cytoplasmic dynein. F-actin filaments act as myosin track, while kinesin and cytoplasmic dynein move on microtubules. Cytoskeleton motors work together to build a highly polarized and regulated system in neuronal cells via different molecular mechanisms and functional regulations. This review discusses the structures and working mechanisms of the cytoskeleton motors in neurons.
Genital self-mutilation (GSM) is a much rare finding and more commonly associated with psychosis when it comes to comparison with self-mutilation as a whole. There have been anecdotal case reports of GSM in psychotic disorders with most of them being in long standing psychoses. We describe herein a case of GSM during the first episode of psychosis where multiple phenomenological variables were seen responsible for the act.
The aim of this study was to purify, characterize and evaluate the antibacterial activity of bioactive compound against methicillin-resistant Staphylococcus aureus (MRSA). The anti-MRSA compound was produced by a halophilic bacterial strain designated as MHB1. The MHB1 strain exhibited 99 % similarity to Bacillus amyloliquefaciens based on 16S rRNA gene analysis. The culture conditions of Bacillus amyloliquefaciens MHB1 were optimized using nutritional and environmental parameters for enhanced anti-MRSA compound production. The pure bioactive compound was isolated using silica gel column chromatography and Semi-preparative High-performance liquid chromatography (Semi-preparative HPLC). The Thin layer chromatography, Fourier transform infrared spectroscopy and proton NMR ((1)H NMR) analysis indicated the phenolic nature of the compound. The molecular mass of the purified compound was 507 Da as revealed by Liquid chromatography-mass spectrometry (LC-MS) analysis. The compound inhibited the growth of MRSA with minimum inhibitory concentration (MIC) of 62.5 µg mL(-1). MRSA bacteria exposed to 4× MIC of the compound and the cell viability was determined using flow cytometric analysis. Scanning electron microscope and Transmission electron microscope analysis was used to determine the ultrastructural changes in bacteria. This is the first report on isolation of anti-MRSA compound from halophilic B. amyloliquefaciens MHB1 and could act as a promising biocontrol agent.
Food intake occurs in bouts or meals, and numerous meal-generated signals have been identified that act to limit the size of ongoing meals. Hormones such as cholecystokinin (CCK) are secreted from the intestine as ingested food is being processed, and in addition to aiding the digestive process, they provide a signal to the brain that contributes to satiation, limiting the size of the meal. The potency of CCK to elicit satiation is enhanced by elevated levels of adiposity signals such as insulin. In the present experiments we asked whether CCK and insulin interact at the level of the blood-brain barrier (BBB). We first isolated rat brain capillary endothelial cells that comprise the BBB and found that they express the mRNA for both the CCK1R and the insulin receptor, providing a basis for a possible interaction. We then administered insulin intraperitoneally to another group of rats and 15min later administered CCK-8 intraperitoneally to half of those rats. After another 15min, CSF and blood samples were obtained and assayed for immunoreactive insulin. Plasma insulin was comparably elevated above baseline in both the CCK-8 and control groups, indicating that the CCK had no effect on circulating insulin levels given these parameters. In contrast, rats administered CCK had CSF-insulin levels that were more than twice as high as those of control rats. We conclude that circulating CCK greatly facilitates the transport of insulin into the brain, likely by acting directly at the BBB. These findings imply that in circumstances in which the plasma levels of both CCK and insulin are elevated, such as during and soon after meals, satiation is likely to be due, in part, to this newly-discovered synergy between CCK and insulin.
Cellular components of synaptic circuits have been adjusted for increased human brain size, neural cell density, energy consumption and developmental duration. How does the human brain make these accommodations? There is evidence that astrocytes are one of the most divergent neural cell types in primate brain evolution and it is now becoming clear that they have critical roles in controlling synaptic development, function and plasticity. Yet, we still do not know how the precise developmental appearance of these cells and subsequent astrocyte-derived signals modulate diverse neuronal circuit subtypes. Here, we discuss what is currently known about the influence of glial factors on synaptic maturation and focus on unique features of human astrocytes including their potential roles in regenerative and translational medicine. Human astrocyte distinctiveness may be a major contributor to high level neuronal processing of the human brain and act in novel ways during various neuropathies ranging from autism spectrum disorders, viral infection, injury and neurodegenerative conditions.
Arginine vasotocin (AVT) is known to play an important role in the regulation of social behavior in a number of vertebrate species. Nevertheless, the relationship between AVT and intraspecific interactions appears complex and in some cases contradictory. Moreover, AVT influences other behaviors, which are not primarily social including exploratory behavior, locomotion and thermoregulation. Some of these behavioral effects may be side-effects from a general influence of AVT on physiology. Indeed AVT can regulate metabolism and osmoregulation. Because most studies have been conducted using mammals and birds, its role in modulating behavior in other vertebrate groups is largely unknown. In this study we examined the effect of AVT on the social behavior of male common lizards, Zootoca vivipara. Moreover, considering the variety of pathways AVT could be involved in, we investigated its consequences on thermoregulatory behavior and physiological performance. In mid-June 2010, 74 males were captured from field sites (Mont-Lozère, South-eastern France) and kept in the laboratory for three weeks to obtain behavioral (reaction to conspecific odors, thermoregulation) and physiological (endurance, testosterone level) measurements. We demonstrated that injection of AVT reduced testosterone level and affected social behavior in different ways depending on the size of an individual. Specifically, small males injected with AVT were less attracted by conspecific odors than small control males, and no effect was detected in large males. Moreover, AVT promoted thermoregulatory behavior and enhanced endurance. These results are concordant with previous results obtained in this species in studies on stress suggesting that AVT may act through its influence on corticosterone secretion.
To study in vitro anti-hydatic and immunomodulatory effects of ginger and [6]-gingerol as an alternative therapy for cystic echinococcosis.
Effect of a commonly used herbal product and ginger (Zingiber officinale) towards protoscoleces (PSC) and cyst wall in vitro was studied. The effect of [6]-gingerol, and the pungent constituent of ginger, was also evaluated on PSC culture. Furthermore, the activity of both extracts in association with interferon-gamma (IFN-γ) on PSC co-cultured with mononuclear cells of hydatic patients was evaluated. The nitric oxide (NO) production was measured in each co-culture.
Ginger exhibited a concentration- and time-dependent cytotoxic effect against PSC and cyst wall. Interestingly, ginger was more effective than the [6]-gingerol. Moreover, additional parasitic effect between extracts and IFN-γ are also observed in co-cultures. Furthermore, both extracts attenuated the NO production elicited by this infection or by the IFN-γ.
Ginger has an important anti-hydatic effect in vitro. This effect is amplified in the presence of IFN-γ. Moreover, this herbal product may protect against host's cell death by reducing the high levels of NO. Ginger may act, at least, through the [6]-gingerol. All our data suggest the promising use of ginger in the treatment of Echinococcus granulosus infection.
Self-incompatibility (SI) is a self/non-self discrimination system found widely in angiosperms and, in many species, is controlled by a single polymorphic S-locus. In the Solanaceae, Rosaceae and Plantaginaceae, the S-locus encodes a single S-RNase and a cluster of S-locus F-box (SLF) proteins to control the pistil and pollen expression of SI, respectively. Previous studies have shown that their cytosolic interactions determine their recognition specificity, but the physical force between their interactions remains unclear. In this study, we show that the electrostatic potentials of SLF contribute to the pollen S specificity through a physical mechanism of 'like charges repel and unlike charges attract' between SLFs and S-RNases in Petunia hybrida. Strikingly, the alteration of a single C-terminal amino acid of SLF reversed its surface electrostatic potentials and subsequently the pollen S specificity. Collectively, our results reveal that the electrostatic potentials act as a major physical force between cytosolic SLFs and S-RNases, providing a mechanistic insight into
 the self/non-self discrimination between cytosolic proteins in angiosperms.
Carbapenem-resistant Acinetobacter baumannii (CRAB) is a serious threat for hospitalized patients and it can survive for long periods in hospital settings, particularly on inanimate surfaces. The environment occupied by these resistant and resilient isolates may act as a reservoir for cross-colonization and outbreaks. Here, we aimed to determine the distribution of CRAB in the hospital environment and to characterize their clonal relatedness, susceptibility profile, carriage of blaOXA genes, and biofilm formation. A total of 1080 samples were collected from various environmental surfaces and equipment of two referral hospitals in Tehran, Iran. The A. baumannii isolates were subjected to gyrB multiplex PCR, antibiotic susceptibility testing, biofilm formation assay, pulsed field gel electrophoresis (PFGE), and multiplex PCR for blaOXA-58, blaOXA-24, and blaOXA-23 genes. Eighteen Acinetobacter spp. were isolated; 8 were identified as A. baumannii and 10 as A. lwoffii. Five of A. baumannii isolates were CRAB and exhibited the multidrug-resistant (MDR) phenotype as well. All CRAB isolates produced biofilm, albeit with different levels. Four of CRAB isolates harbored the blaOXA-23. The CRAB isolates were clustered into 3 distinct pulsotypes (PTs). The CRAB isolates belonging to PT1 were detected in two geographically distinct hospitals whereas those belonging to PT3 were found in two different units of same hospital. This study revealed the presence of clonally related OXA-23-producing CRAB in high risk units of referral hospitals as inter- or intra-hospital dissemination. The distribution of multiresistant A. baumannii on several surfaces and areas may increase the risk of transmission of resistant isolates to vulnerable patients.
Isoprenoids such as geranylgeranyl pyrophosphate (GGPP) influence various biological processes. Here we show that GGPP inhibits adipocyte differentiation via the liver X receptors (LXRs) pathway. Intracellular GGPP levels and GGPP synthase (Ggps) mRNA expression increases during adipocyte differentiation. Ggps expression also increases in white adipose tissue of obese mice. GGPP addition reduces the expression of adipogenic marker genes such as adipocyte fatty acid binding protein, peroxisome proliferator-activated receptor γ, and insulin-stimulated glucose uptake. Similarly, over-expressing Ggps inhibits adipocyte differentiation. In contrast, Ggps knockdown promotes adipocyte differentiation. Inhibition of adipocyte differentiation by GGPP was partially reduced by LXR agonist T0901317. Furthermore, Ggps knockdown up-regulates LXR target genes during adipocyte differentiation. These results suggest that GGPP may act as an endogenous regulator of adipocyte differentiation and maturation through a mechanism partially dependent on the LXR pathway.
Certain cytotoxic chemotherapeutic drugs are immunogenic, stimulating tumor immunity through mechanisms that are not completely understood. Here we show how the DNA-damaging drug cisplatin modulates tumor immunity. At the maximum tolerated dose (MTD), cisplatin cured 50% of mice with established murine TC-1 or C3 tumors, which are preclinical models of human papillomavirus (HPV)-associated cancer. Notably, the curative benefit of cisplatin relied entirely upon induction of tumor-specific CD8(+) T cells. Mechanistic investigations showed that cisplatin stimulated tumor infiltration of inflammatory antigen-presenting cells (APC) expressing relatively higher levels of the T-cell costimulatory ligands CD70, CD80, and CD86. Cell death triggered by cisplatin was associated with the release of at least 19 proteins in the tumor environment that could act as damage-associated molecular patterns and upregulate costimulatory molecules, either alone or in concert, but the responsible proteins remain unknown. Essentially, the curative effect of cisplatin was abrogated in mice lacking expression of CD80 and CD86 on APCs. Furthermore, cisplatin treatment was improved by CTLA-4 blockade, which increases the availability of CD80/86 to bind to CD28. In contrast, there was no effect of CD27 stimulation, which replaces CD70 interaction. At the cisplatin MTD, cure rates could also be increased by vaccination with synthetic long peptides, whereas cures could also be achieved at similar rates at 80% of the MTD with reduced side effects. Our findings reveal an essential basis for the immunogenic properties of cisplatin, which are mediated by the induction of costimulatory signals for CD8(+) T-cell-dependent tumor destruction. Cancer Res; 76(20); 6017-29. ©2016 AACR.
Since the therapeutic treatment of depression is far from being satisfactory, new therapeutic strategies ought to be pursued. In addition, further investigation on brain areas involved in the action mechanism of antidepressants can shed light on the aetiology of depression. We have previously reported that typical and atypical antidepressants strongly stimulate catecholamine transmission in the bed nucleus of stria terminalis (BNST). In this study, we have built on that work to examine the effect of ketamine, an unusual antidepressant that can produce a fast-acting and long-lasting antidepressant effect after administration of a single sub-anaesthetic dose. Ketamine is an antagonist of the ionotropic N-methyl-D-aspartate (NMDA) receptor but can also act through its metabolite (2R-6R)-hydroxynorketamine. Using the microdialysis technique in freely moving rats, we monitored the acute effect of ketamine on catecholamine release in the BNST to gain clues to its prompt antidepressant effect. Male Sprague-Dawley rats were implanted with a microdialysis probe in the BNST and 48h later, were injected with ketamine (10, 20, and 40mg/kg, i.p.). Ketamine increased norepinephrine (127%, 155%, 186%) and dopamine (114%, 156%, 176%) extracellular concentration above basal in a time and dose dependent manner, without significantly modifying motility. Since the effect of ketamine, although lower, was not substantially different from that produced by classical antidepressants, we suggest that catecholamine increase in BNST is not likely to be related to a rapid ketamine antidepressant effect, though it might be related to its performance in predictive tests of antidepressant properties.
We examine emergency department (ED) use and hospitalizations through the ED after Patient Protection and Affordable Care Act (ACA) health insurance expansion in Illinois, a Medicaid expansion state.
Using statewide hospital administrative data from 2011 through 2015 from 201 nonfederal Illinois hospitals for patients aged 18 to 64 years, mean monthly ED visits were compared before and after ACA implementation by disposition from the ED and primary payer. Visit data were combined with 2010 to 2014 census insurance estimates to compute payer-specific ED visit rates. Interrupted time-series analyses tested changes in ED visit rates and ED hospitalization rates by insurance type after ACA implementation.
Average monthly ED visit volume increased by 14,080 visits (95% confidence interval [CI] 4,670 to 23,489), a 5.7% increase, after ACA implementation. Changes by payer were as follows: uninsured decreased by 24,158 (95% CI -27,037 to -21,279), Medicaid increased by 28,746 (95% CI 23,945 to 33,546), and private insurance increased by 9,966 (95% 6,241 to 13,690). The total monthly ED visit rate increased by 1.8 visits per 1,000 residents (95% CI 0.6 to 3.0). The monthly ED visit rate decreased by 8.7 visit per 1,000 uninsured residents (95% CI -11.1 to -6.3) and increased by 10.2 visit per 1,000 Medicaid beneficiaries (95% CI 4.4 to 16.1) and 1.3 visits per 1,000 privately insured residents (95% CI 0.6 to 1.9). After adjusting for baseline trends and season, these changes remained statistically significant. The total number of hospitalizations through the ED was unchanged.
ED visits by adults aged 18 to 64 years in Illinois increased after ACA health insurance expansion. The increase in total ED visits was driven by an increase in visits resulting in discharge from the ED. A large post-ACA increase in Medicaid visits and a modest increase in privately insured visits outpaced a large reduction in ED visits by uninsured patients. These changes are larger than can be explained by population changes alone and are significantly different from trends in ED use before ACA implementation.
The dorsal medial striatum is a crucial part of the neural network that subserves dynamic, goal-directed behaviors. Functional output of this nucleus is shaped, in part, by the influence of glutamatergic inputs. Striatal cholinergic systems have the capacity to modulate these excitatory inputs through presynaptic nicotinic acetylcholine receptors (nAChRs); however, the individual contribution of the two major nicotinic receptor subtypes, α4β2 and α7, to such modulation is not well characterized. In the present experiments, glutamate biosensors were used to monitor nAChR-dependent glutamate release with high temporal precision in the dorsal medial striatum of rats. Both α4β2 and α7 nAChRs were found to potently modulate glutamate release; however the two receptor subtypes do so in strikingly different ways. α7 nAChRs appear to enhance release from glutamatergic terminals. In contrast, α4β2 nAChRs act as a brake on glutamate release via an interaction with local dopaminergic inputs and D2 receptors. Combined, the present data reveal the capacity of local striatal cholinergic signaling to dynamically modulate excitatory inputs through nAChRs.
As the central pacemaker in mammals, the circadian clock in the suprachiasmatic nucleus (SCN) of the hypothalamus is a heterogeneous structure consisting of multiple types of GABAergic neurons with distinct chemical identities [1, 2]. Although individual cells have
 a cellular clock driven by autoregulatory transcriptional/translational feedback loops of clock genes, interneuronal communication among SCN clock neurons is likely essential for the SCN to generate a highly robust, coherent circadian rhythm [1]. However, neuronal mechanisms that determine circadian period length remain unclear. The SCN is composed of two subdivisions: a ventral core region containing vasoactive intestinal peptide (VIP)-producing neurons and a dorsal shell region characterized by arginine vasopressin (AVP)-producing neurons. Here we examined whether AVP neurons act as pacemaker cells that regulate the circadian period of behavior rhythm in mice. The deletion of casein kinase 1 delta (CK1δ) specific to AVP neurons, which was expected to lengthen the period of cellular clocks [3-6], lengthened the free-running period of circadian behavior as well. Conversely, the overexpression of CK1δ specific to SCN AVP neurons shortened the free-running period. PER2::LUC imaging in slices confirmed that cellular circadian periods of the SCN shell were lengthened in mice without CK1δ in AVP neurons. Thus, AVP neurons may be an essential component of circadian pacemaker cells in the SCN. Remarkably, the alteration of the shell-core phase relationship in the SCN of these mice did not impair the generation per se of circadian behavior rhythm, thereby underscoring the robustness of the SCN network.
The clustering of neurons sharing similar functional properties and connectivity is a common organizational feature of vertebrate nervous systems. Within motor networks, spinal motor neurons (MNs) segregate into longitudinally arrayed subtypes, establishing a central somatotopic map of peripheral target innervation. MN organization and connectivity relies on Hox transcription factors expressed along the rostrocaudal axis; however, the developmental mechanisms governing the orderly arrangement of MNs are largely unknown. We show that Pbx genes, which encode Hox cofactors, are essential for the segregation and clustering of neurons within motor columns. In the absence of Pbx1 and Pbx3 function, Hox-dependent programs are lost and the remaining MN subtypes are unclustered and disordered. Identification of Pbx gene targets revealed an unexpected and apparently Hox-independent role in defining molecular features of dorsally projecting medial motor column (MMC) neurons. These results indicate Pbx genes act in parallel genetic pathways to orchestrate neuronal subtype differentiation, connectivity, and organization.
The Drug Enforcement Administration is placing the substance thiafentanil (4-(methoxycarbonyl)-4-(N-phenmethoxyacetamido)-1-[2-(thienyl)ethyl]piperidine), including its isomers, esters, ethers, salts and salts of isomers, esters and ethers as possible, into schedule II of the Controlled Substances Act. This scheduling action is pursuant to the Controlled Substances Act, as revised by the Improving Regulatory Transparency for New Medical Therapies Act which was signed into law on November 25, 2015.
Reproductive isolation between rice of different ploidy levels is manifested as endosperm and embryo abortion in seeds produced by interploidy crosses. Genomic imprinting is considered to be the underlying mechanism establishing the post-zygotic hybridization barrier. We characterized disrupted seed development in reciprocal crosses between a diploid Japonica rice and a tetraploid Indica rice.
Triploid seeds from these crosses had aborted development and could not germinate in soil but could be rescued in culture medium with significantly more seeds developing to seedlings in the 4n × 2n (♀-♂) cross with excess maternal genomes than in the 2n × 4n cross with excess paternal genome. Consistent with previous findings, precocious endosperm cellularization and bigger embryos were observed in the seeds from the maternal excess cross, whereas absence of cellularization and arrested globular embryos were found in the seeds from the paternal excess cross, supporting the idea that endosperm cellularization is an important transition for embryo development. Moreover, we found that starch granules were persistently deposited in the pericarp parenchyma cells of the paternal excess cross, while pericarp starch gradually decreased and relocated to the developing endosperm in balanced and maternal excess crosses in which cellularization and starch deposition occur in endosperm, suggesting that parental genome balance influences pericarp starch relocation via cellularization and starch deposition. Loss of imprinting, or altered expression of imprinted genes and epigenetic regulators, OsFIE2 and OsMET1b were observed, implying the potential role of imprinting and epigenetic mechanisms in regulating the differential parental genome dosage effects on endosperm development.
Our results support the hypothesis that the maternal genome dosage promotes endosperm cellularization and the paternal genome dosage delays or inhibits cellularization via contributing different sets of imprinted genes.
Sugarcane smut is caused by the fungus Sporisorium scitamineum (Ustilaginales/Ustilaginomycotina/Basidiomycota), which is responsible for losses in sugarcane production worldwide. Infected plants show a profound metabolic modification resulting in the development of a whip-shaped structure (sorus) composed of a mixture of plant tissues and fungal hyphae. Within this structure, ustilospores develop and disseminate the disease. Despite the importance of this disease, a detailed histopathological analysis of the plant-pathogen interaction is lacking.
The whip-shaped sorus was investigated using light microscopy, scanning and transmission electron microscopy, histochemical tests and epifluorescence microscopy coupled with deconvolution.
Sorus growth is mediated by intercalary meristem activity at the base of the sorus, where the fungus causes partial host cell wall degradation and formation of intercellular spaces. Sporogenesis in S. scitamineum is thallic, with ustilospore initials in intercalary or terminal positions, and mostly restricted to the base of the sorus. Ustilospore maturation is centrifugal in relation to the ground parenchyma and occurs throughout the sorus median region. At the apex of the sorus, the fungus produces sterile cells and promotes host cell detachment. Hyphae are present throughout the central axis of the sorus (columella). The plant cell produces callose around the intracellular hyphae as well as inside the papillae at the infection site.
The ontogeny of the whip-shaped sorus suggests that the fungus can cause the acropetal growth in the intercalary meristem. The sporogenesis of S. scitamineum was described in detail, demonstrating that the spores are formed exclusively at the base of the whip. Light was also shed on the nature of the sterile cells. The presence of the fungus alters the host cell wall composition, promotes its degradation and causes the release of some peripheral cells of the sorus. Finally, callose was observed around fungal hyphae in infected cells, suggesting that deposition of callose by the host may act as a structural response to fungal infection.
Wnt/LRP6 signaling is best known for the β-catenin-dependent regulation of target genes. However, pathway branches have recently emerged, including Wnt/STOP signaling, which act independently of β-catenin and transcription. We review here the molecular mechanisms underlying β-catenin-independent Wnt/LRP6 signaling cascades and their implications for cell biology, development, and physiology.
Objective The aim of the study was to improve the engagement of professional interpreters for women during labour.Methods The quality improvement initiative was co-designed by a multidisciplinary group at one Melbourne hospital and implemented in the birth suite using the plan-do-study-act framework. The initiative of offering women an interpreter early in labour was modified over cycles of implementation and scaled up based on feedback from midwives and language services data.Results The engagement of interpreters for women identified as requiring one increased from 28% (21/74) at baseline to 62% (45/72) at the 9th month of implementation.Conclusion Improving interpreter use in high-intensity hospital birth suites is possible with supportive leadership, multidisciplinary co-design and within a framework of quality improvement cycles of change.What is known about the topic? Despite Australian healthcare standards and policies stipulating the use of accredited interpreters where needed, studies indicate that services fall well short of meeting these during critical stages of childbirth.What does the paper add? Collaborative approaches to quality improvement in hospitals can significantly improve the engagement of interpreters to facilitate communication between health professionals and women with low English proficiency.What are the implications for practice? This language services initiative has potential for replication in services committed to improving effective communication between health professionals and patients.
The eastern Mediterranean region is comprised of 22 countries: Afghanistan, Bahrain, Djibouti, Egypt, Iran, Iraq, Jordan, Kuwait, Lebanon, Libya, Morocco, Oman, Pakistan, Palestine, Qatar, Saudi Arabia, Somalia, Sudan, Syria, Tunisia, the United Arab Emirates, and Yemen. Since our Global Burden of Disease Study 2010 (GBD 2010), the region has faced unrest as a result of revolutions, wars, and the so-called Arab uprisings. The objective of this study was to present the burden of diseases, injuries, and risk factors in the eastern Mediterranean region as of 2013.
GBD 2013 includes an annual assessment covering 188 countries from 1990 to 2013. The study covers 306 diseases and injuries, 1233 sequelae, and 79 risk factors. Our GBD 2013 analyses included the addition of
 new data through updated systematic reviews and through the contribution of unpublished data sources from collaborators, an updated version of modelling software, and several improvements in our methods. In this systematic analysis, we use data from GBD 2013 to analyse the burden of disease and injuries in the eastern Mediterranean region specifically.
The leading cause of death in the region in 2013 was ischaemic heart disease (90·3 deaths per 100 000 people), which increased by 17·2% since 1990. However, diarrhoeal diseases were the leading cause of death in Somalia (186·7 deaths per 100 000 people) in 2013, which decreased by 26·9% since 1990. The leading cause of disability-adjusted life-years (DALYs) was ischaemic heart disease for males and lower respiratory infection for females. High blood pressure was the leading risk factor for DALYs in 2013, with an increase of 83·3% since 1990. Risk factors for DALYs varied by country. In low-income countries, childhood wasting was the leading cause of DALYs in Afghanistan, Somalia, and Yemen, whereas unsafe sex was the leading cause in Djibouti. Non-communicable risk factors were the leading cause of DALYs in high-income and middle-income countries in the region. DALY risk factors varied by age, with child and maternal malnutrition affecting the younger age groups (aged 28 days to 4 years), whereas high bodyweight and systolic blood pressure affected older people (aged 60-80 years). The proportion of DALYs attributed to high body-mass index increased from 3·7% to 7·5% between 1990 and 2013. Burden of mental health problems and drug use increased. Most increases in DALYs, especially from non-communicable diseases, were due to population growth. The crises in Egypt, Yemen, Libya, and Syria have resulted in a reduction in life expectancy; life expectancy in Syria would have been 5 years higher than that recorded for females and 6 years higher for males had the crisis not occurred.
Our study shows that the eastern Mediterranean region is going through a crucial health phase. The Arab uprisings and the wars that followed, coupled with ageing and population growth, will have a major impact on the region's health and resources. The region has historically seen improvements in life expectancy and other health indicators, even under stress. However, the current situation will cause deteriorating health conditions for many countries and for many years and will have an impact on the region and the rest of the world. Based on our findings, we call for increased investment in health in the region in addition to reducing the conflicts.
Bill & Melinda Gates Foundation.
Control of lipid levels is one of the most effective strategies for cardiovascular (CV) event prevention. In fact, many clinical trials have clearly demonstrated that low-density lipoprotein cholesterol (LDL-C) lowering, primarily with statins, reduces major CV events and mortality. The evidence from these trials has been useful in designing the cholesterol treatment guidelines, which are mainly aimed at preventing and managing cardiovascular disease (CVD). However, available data indicate that a large proportion of patients fail to achieve lipid goals, and this is particularly frequent in patients at high or very high CV risk. Furthermore, owing to side effects, a significant percentage of patients cannot tolerate statin treatment. Hence, researchers have focused their attention on novel LDL-C-lowering agents that act via mechanisms distinct from that of statins. Among the new compounds under investigation, the monoclonal antibodies to proprotein convertase subtilisin/kexin type 9 (PCSK9) seem particularly promising, having recently been shown to be well tolerated and highly effective at lowering LDL-C, with a possible effect on the occurrence of CV events. Currently, alirocumab is approved by the US Food and Drug Administration (FDA) as an adjunct to diet and maximally tolerated statin therapy for use in adults with heterozygous familial hypercholesterolemia (FH) or those with atherosclerotic CV disease who require additional LDL-C lowering; it has also been recently approved by the European Medicines Agency (EMA) for use in patients with heterozygous FH, non-familial hypercholesterolemia or mixed dyslipidemia in whom statins are ineffective or not tolerated. Evolocumab is approved by the FDA as an adjunct to diet and maximally tolerated statins for adults with hetero- and homozygous FH and those with atherosclerotic CV disease who require additional lowering of LDL-C, and by the EMA in adults with primary hypercholesterolemia or mixed dyslipidemia, as an adjunct to diet, in combination with a statin or a statin with other lipid lowering therapies in patients unable to reach LDL-C goals with the maximum tolerated dose of a statin; alone or in combination with other lipid lowering therapies in patients who are statin-intolerant, or those for whom a statin is contraindicated. Evolocumab is also indicated in adults and adolescents aged 12 years and over with homozygous familial hypercholesterolemia in combination with other lipid-lowering therapies.
DDT and pyrethroid insecticides were among the earliest neurotoxins identified to act on voltage-gated sodium channels. In the 1960s, equipped with, at the time, new voltage-clamp techniques, Professor Narahashi and associates provided the initial evidence that DDT and allethrin (the first commercial pyrethroid insecticide) caused prolonged flow of sodium currents in lobster and squid giant axons. Over the next several decades, continued efforts by Prof. Narahashi's group as well as other laboratories led to a comprehensive understanding of the mechanism of action of DDT and pyrethroids on sodium channels. Fast forward to the 1990s, genetic, pharmacological and toxicological data all further confirmed voltage-gated sodium channels as the primary targets of DDT and pyrethroid insecticides. Modifications of the gating kinetics of sodium channels by these insecticides result in repetitive firing and/or membrane depolarization in the nervous system. This mini-review focuses on studies from Prof. Narahashi's pioneer work and more recent mutational and computational modeling analyses which collectively elucidated the elusive pyrethroid receptor sites as well as the molecular basis of differential sensitivities of insect and mammalian sodium channels to pyrethroids.
Seabirds are ideal model organisms to track mercury (Hg) through marine food webs as they are long-lived, broadly distributed, and are susceptible to biomagnification due to foraging at relatively high trophic levels. However, using these species as biomonitors requires a solid understanding of the degree of species, sexual and age-specific variation in foraging behaviors which act to mediate their dietary exposure to Hg. We combined stomach content analysis along with Hg and stable isotope analyses of blood, feathers and common prey items to help explain inter and intra-specific patterns of dietary Hg exposure across three sympatric Pygoscelis penguin species commonly used as biomonitors of Hg availability in the Antarctic marine ecosystem. We found that penguin tissue Hg concentrations differed across species, between adults and juveniles, but not between sexes. While all three penguins species diets were dominated by Antarctic krill (Euphausia superba) and to a lesser extent fish, stable isotope based proxies of relative trophic level and krill consumption could not by itself sufficiently explain the observed patterns of inter and intra-specific variation in Hg. However, integrating isotopic approaches with stomach content analysis allowed us to identify the relatively higher risk of Hg exposure for penguins foraging on mesopelagic prey relative to congeners targeting epipelagic or benthic prey species. When possible, future seabird biomonitoring studies should seek to combine isotopic approaches with other, independent measures of foraging behavior to better account for the confounding effects of inter and intra-specific variation on dietary Hg exposure.
Outer membrane proteins (OMPs) are a class of proteins that reside in the outer membrane of Gram-negative bacteria. OMPs act as epitopes and are potential vaccine candidates. Outer membrane protein N (OmpN) is a component of the outer membrane of Edwardsiella ictaluri (E. ictaluri). In a previous study, the OmpN1-, OmpN2-, OmpN3-encoding genes of E. ictaluri were cloned, and here they were expressed in Escherichia coli. Western blotting showed that these three proteins had molecular weights of ∼60kDa. Channel catfish were immunized with recombinant OmpNs (rOmpNs) and then challenged with E. ictaluri. The results showed that rOmpN1, rOmpN2, and rOmpN3, as well as a mixture of all three proteins (in a ratio of 1:1:1) generated moderate immune protection (relative percentage of survival=62.5, 62.5, 67.5, and 75%, respectively). In an agglutination antibody titer assay, fish antisera showed an antibody titer of 1:128. Furthermore, each of the proteins stimulated high levels of lysozyme activity. In addition, a real-time polymerase chain reaction analysis revealed significant up-regulation of immune-related genes encoding major histocompatibility complex class I (MHC I), MHC II, CD4L, tumor necrosis factor-α, and interferon-γ after 24 and 48h of challenge, compared with the levels stimulated by phosphate-buffered saline. Taken together, we conclude that rOmpNs may elicit immune responses and generate protection against E. ictaluri in channel catfish. Thus, rOmpNs could be promising vaccine candidates against E. ictaluri.
Childhood vaccination programs are considered one of the most beneficial public health programs in modern history. In the United States, the increasing use of non-medical exemptions (NMEs) from school entry vaccination requirements has garnered attention
 and scrutiny in the popular press, academic literature, and policy forums. In 2016, California law SB277 goes into effect, eliminating the NME option for students attending the state's public and private schools. Whereas SB277 is a strong move to increase vaccination coverage within California's schools, the new law contains an important caveat - students already having a valid NME (obtained prior to the 2016 school year) are "grandfathered" in until their next grade checkpoint (seventh grade). Although no new students will enter the California school system with a NME after 2016, the law's grandfather clause will allow NMEs to persist within the state school system until 2022. This analysis demonstrates how the past "build up" of students with pre-SB277 NMEs and the law's grandfather clause will act in combination to affect NME rates across the state after the implementation of SB277. We construct spatially explicit, yearly models of all students (K-12) enrolled in the California school system from 2011 to 2022. Our analysis finds that, although all regions of the state will eventually reach an NME rate of 0% by 2022, SB277's effect will be highly spatially and temporally variable. Some school districts will continue to experience elevated NME rates and increased risk of disease outbreak for years after SB277 is implemented. Our analysis highlights the potential spatially variant consequences of SB277's grandfather clause, providing important information for other states considering similar policy initiatives.
An efficient ratiometric electrochemical biosensor for Cu(2+) determination was constructed using dual hydroxyl-functionalized poly (ionic liquid) (DHF-PIL) as the catalyst support. The DHF-PIL exhibited typical macroporous structure, which provided a high surface area of 39.31m(2)/g for the sufficient loading of biomolecules. The specific recognition of Cu(2+) was accomplished by employing neurokinin B (NKB) for the first time, which could bind to Cu(2+) to form a [Cu(II)(NKB)2] complex with high specificity. Meanwhile, a common redox mediator, 2, 2'-Azinobis-(3-ethylbenzthiazoline-6-sulfonate) (ABTS) was modified into DHF-PIL by electrostatic interactions to act as an inner reference molecule, which provided a built-in correction for environmental effects and improving the detection accuracy. With this strategy, the developed electrochemical biosensor was capable of determining Cu(2+) with a linear range between 0.9 and 36.1μM and low detection limit (LOD) and quantification limit (LOQ) of 0.24 and 0.6μM, respectively. The sensor also displayed a satisfactory selectivity against a series of interferences in the brain, including metal ions, amino acids and other endogenous compounds. Accordingly, the present biosensor was successfully applied to evaluate Cu(2+) levels in normal and AD rats.
Arginine play numerous roles in several biological processes, and also act as a precursor for many biomolecules. Arginine derived biomolecules were found to involve in many of the events that lead to diseases and therefore selective detection of Arg in biological fluids has an enormous impact on disease diagnosis and in the drug development. Although number of methods were developed for the selective detection of Arg, the colorimetric method has an advantage over these methods due to their operational simplicity, high selectivity, and speediness. Herein, silver nanoparticles ensemble with Zn(II) complex of α-liopoic acid conjugated terpyridine (ZnLATP-AgNPs) were developed for the selective colorimetric detection of Arg. The nanoparticle ensemble exhibited selectivity towards Arg by showing distinguishable colour change from yellow to orange, among all the other naturally occurring amino acids studied. The new ZnLATP-AgNPs assay allows detection of Arg down to 200±15nM, provides an easy and sensitive method to detect Arg visually. The current approach was further validated by the quantification of Arg in supplement tablets.
Appropriate and accurate determination of HER2 status in women with breast cancer is critical for stratifying anti-HER2 therapies, and for access to subsidised treatment in the Australian setting. We conducted a regulated, nationwide program providing HER2 in situ hybridisation (ISH) testing for patients with newly diagnosed breast cancer. Cases with equivocal or non-diagnostic ISH test results at the local laboratory were sent to a high volume central testing laboratory for analysis using fluorescence ISH (FISH). We tested 78,408 early breast cancers and 3469 metastatic cancers using ISH. Of these, 12,405 early breast cancers (15.8%) and 798 metastatic cancers (23.0%) were HER2 positive. During the testing period, the proportion of core biopsy samples increased, the number of repeat tests remained stable and testing turnaround time declined. Discordant 3+ IHC, ISH negative results dropped from 20% to 13% in early breast cancers and from 35% to 8% among metastatic breast cancers. Following central laboratory FISH testing only 87 samples remained non-diagnostic (1.9% of FISH-tested samples, 0.1% of the whole cohort), most being decalcified specimens. This is a successful story of a cohesive service determining HER2 status in women with breast cancer in a 'real-world' setting.
OBJECTIVES : In the midst of large-scale changes across our nation's health care system, including the Affordable Care Act and Patient-Centered Medical Home initiatives, integrated primary care models afford important opportunities for those in the field of pediatric psychology. Despite the extensive and growing attention, this subspecialty has received in recent years, a comprehensive set of core professional competencies has not been established. METHODS : A subset of an Integrated Primary Care Special Interest Group used two well-established sets of core competencies in integrated primary care and pediatric psychology as a basis to develop a set of integrated pediatric primary care-specific behavioral anchors. CONCLUSIONS : The current manuscript describes these behavioral anchors and their development in the context of professional training as well as with regard to Triple Aim goals and securing psychology's role in integrated pediatric primary care settings.
Accumulation of selected heavy metals (Cd, Pb, Ni, Cr, Fe, and Zn) and phenolic metabolites (total soluble phenols, cichoric and caftaric acid) in dandelion organs (leaves, roots, inflorescences/anthodia) collected from six localities within the industrial town Košice (eastern Slovakia) were studied. Localities from the vicinity of a steel factory (Cd, Fe) and heavy traffic (Pb, Ni, Cr, Zn) contained the highest amount of individual metals in the soil but a significant correlation between soil and organ metal content was found only for Cr in the leaves (r(2) = 0.7679). The amount of Cd and partially Pb differed among localities in all organs and especially in the leaves and anthodia, indicating probably the impact of atmospheric pollution. The bioaccumulation factor was <1 for almost all metals, suggesting that given dandelion species is not metal accumulator. Translocation factor did not reach values close to or over 1 only for Cd, indicating a root-to-shoot movement of Pb, Ni and Zn though the impact of air pollution on leaves cannot be excluded. A strong correlation between leaf Cd and leaf total phenols, cichoric and caftaric acids was observed (r(2) = 0.7926, 0.8682 and 0.8830, respectively), indicating that phenolic metabolites act in the protection of dandelion against Cd excess. Overall, our data indicate low pollution of urban soil by Cd (5.53-113.8 ng g(-1)) and partially by Cr and the suitability of above-ground organs of dandelion species for the monitoring of air pollution mainly by Cd.
The RNA-binding proteins Zfp36l1 and Zfp36l2 act redundantly to enforce the β-selection checkpoint during thymopoiesis, yet their molecular targets remain largely unknown. In this study, we identify these targets on a genome-wide scale in primary mouse thymocytes and show that Zfp36l1/l2 regulate DNA damage response and cell cycle transcripts to ensure proper β-selection. Double-negative 3 thymocytes lacking Zfp36l1/l2 share a gene expression profile with postselected double-negative 3b cells despite the absence of intracellular TCRβ and reduced IL-7 signaling. Our findings show that in addition to controlling the timing of proliferation at β-selection, posttranscriptional control by Zfp36l1/l2 limits DNA damage responses, which are known to promote thymocyte differentiation. Zfp36l1/l2 therefore act as posttranscriptional safeguards against chromosomal instability and replication stress by integrating pre-TCR and IL-7 signaling with DNA damage and cell cycle control.
Endoplasmic reticulum (ER) stress and unfolded protein response (UPR) are highly activated in cancer and involved in tumorigenesis and resistance to anti-cancer therapy. UPR is becoming a promising target of anti-cancer therapies. Thus, the identification of UPR components that are highly expressed in cancer could offer new therapeutic opportunity.In this study, we demonstrate that Endoplasmic Reticulum Metallo Protease 1 (ERMP1) is broadly expressed in a high percentage of breast, colo-rectal, lung, and ovary cancers, regardless of their stage and grade. Moreover, we show that loss of ERMP1 expression significantly hampers proliferation, migration and invasiveness of cancer cells. Furthermore, we show that this protein is an important player in the UPR and defense against oxidative stress. ERMP1 expression is strongly affected by reticular stress induced by thapsigargin and other oxidative stresses. ERMP1 silencing during reticular stress impairs the activation of PERK, a key sensor of the UPR activation. Loss of ERMP1 also prevents the expression of GRP78/BiP, a UPR stress marker involved in the activation
 of the survival pathway. Finally, ERMP1 silencing in cells exposed to hypoxia leads to inhibition of the Nrf2-mediated anti-oxidant response and to reduction of accumulation of HIF-1, the master transcription factor instructing cells to respond to hypoxic stress. Our results suggest that ERMP1 could act as a molecular starter to the survival response induced by extracellular stresses. Moreover, they provide the rationale for the design of ERMP1-targeting drugs that could act by inhibiting the UPR initial adaptive response of cancer cells and impair cell survival.
Currently used surgical techniques to reconstruct tissue defects after resection of musculoskeletal tumours are associated with high complication rates. This drives a strong demand for innovative therapeutic concepts that are able to improve the clinical outcomes of patients suffering from bone and soft tissue tumours. Tissue engineering and regenerative medicine (TE&RM) provides a technology platform based on biochemical, molecular, cellular and biomaterials modules to selectively direct tissue healing processes for improved defect regeneration. At the same time, precautionary measures have to be taken when these instruments are used in cancer patients to prevent any promotion of tumour growth or metastatic spread. On the other hand, several innovative TE&RM tools are being developed such as multi-functionalized biomaterials, drug-delivering nanomaterials or genetically engineered stem cells that per se have the potential to mediate anti-cancer effects, act synergistically with currently used chemotherapeutics and/or radiotherapy regimens and reduce their side effects. Recently, scientists became conscious that TE&RM strategies may not only be utilized to advance contemporary tissue reconstruction techniques but also to develop personalized diagnostic tools and clinically relevant disease models for cancer patients. Eventually, prospective randomized clinical trials combined with comparative outcome analyses are a conditio sine qua non to shape the benefits of personalized regenerative therapies for the standardized management of patients with musculoskeletal tumours.
Various pesticides in the form of mixtures must be used to keep tobacco crops pest-free. Recent studies have shown a link between occupational exposure to pesticides in tobacco crops and increased damage to the DNA, mononuclei, nuclear buds and binucleated cells in buccal cells as well as micronuclei in lymphocytes. Furthermore, pesticides used specifically for tobacco crops shorten telomere length (TL) significantly. However, the molecular mechanism of pesticide action on telomere length is not fully understood. Our study evaluated the interaction between a complex mixture of chemical compounds (tobacco cultivation pesticides plus nicotine) and proteins associated with maintaining TL, as well as the biological processes involved in this exposure by System Biology tools to provide insight regarding the influence of pesticide exposure on TL maintenance in tobacco farmers. Our analysis showed that one cluster was associated with TL proteins that act in bioprocesses such as (i) telomere maintenance via telomere lengthening; (ii) senescence; (iii) age-dependent telomere shortening; (iv) DNA repair (v) cellular response to stress and (vi) regulation of proteasome ubiquitin-dependent protein catabolic process. We also describe how pesticides and nicotine regulate telomere length. In addition, pesticides inhibit the ubiquitin proteasome system (UPS) and consequently increase proteins of the shelterin complex, avoiding the access of telomerase in telomere and, nicotine activates UPS mechanisms and promotes the degradation of human telomerase reverse transcriptase (hTERT), decreasing telomerase activity.
A visible-light active photocatalyst, CdS/Au/TiO2 nanotube array (NTA) photoelectrode, was prepared by electrodeposition of Au nanoparticles onto TiO2 NTA with subsequent deposition of visible-light absorbable 2.4eV band-gap CdS quantum dots using successive ion layer adsorption and reaction (SILAR). The Au nanoparticles here act as electron sinks facilitating charge carrier separation. Under AM1.5G illumination a photoconversion efficiency of 4.06% was achieved for the CdS/Au/TiO2 NTA photoelectrode, suggesting the promise of the material architecture for achieving high-performance cost-effective materials.
The World Health Organization (WHO) recently recommended the addition of a single low-dose of the gametocytocidal drug primaquine (PQ) to artemisinin-based combination therapy (ACT) in low transmission settings as a component of pre-elimination or elimination programmes. However, it is unclear whether that influences the ACT cure rate. The study assessed treatment outcome of artemether-lumefantrine (AL) plus a single PQ dose (0.25 mg/kg) versus standard AL regimen for treatment of acute uncomplicated Plasmodium falciparum malaria in Tanzania.
A randomized, single-blinded, clinical trial was conducted in Yombo, Bagamoyo district, Tanzania. Acute uncomplicated P. falciparum malaria patients aged ≥1 year, with the exception of pregnant and lactating women, were enrolled and treated with AL plus a single PQ dose (0.25 mg/kg) or AL alone under supervision. PQ was administered together with the first AL dose. Clinical and laboratory assessments were performed at 0, 8, 24, 36, 48, 60, and 72 h and on days 7, 14, 21, and 28. The primary end-point was a polymerase chain reaction (PCR)-adjusted adequate clinical and parasitological response (ACPR) on day 28. Secondary outcomes included: fever and asexual parasitaemia clearance, proportion of patients with PCR-determined parasitaemia on day 3, and proportion of patients with Pfmdr1 N86Y and Pfcrt K76T on days 0, 3 and day of recurrent infection.
Overall 220 patients were enrolled, 110 were allocated AL + PQ and AL, respectively. Parasite clearance by microscopy was fast, but PCR detectable parasitaemia on day 3 was 31/109 (28.4 %) and 29/108 (26.9 %) in patients treated with AL + PQ and AL, respectively (p = 0.79). Day 28 PCR-adjusted ACPR and re-infection rate was 105/105 (100 %) and 101/102 (99 %) (p = 0.31), and 5/107 (4.7 %) and 5/8 (4.8 %) (p = 0.95), in AL + PQ and AL arm, respectively. There was neither any statistically significant difference in the proportion of Pfmdr1 N86Y or Pfcrt K76T between treatment arms on days 0, 3 and day of recurrent infection, nor within treatment arms between days 0 and 3 or day 0 and day of recurrent infection.
The new WHO recommendation of adding a single low-dose of PQ to AL did not compromise treatment outcome of uncomplicated P. falciparum malaria in Tanzania. Trial registration number NCT02090036.
There is increasing evidence of activities of chlorinated by-products of bisphenol A (BPA) on retinoic acid system. Their agonistic and antagonistic activities to human retinoid X receptor (RXR) were assessed by a two-hybrid yeast assay. Aqueous solutions of 1mg/L BPA were chlorinated by sodium hypochlorite (NaClO). It showed that chlorination of BPA increased RXRβ antagonistic activity, while no agonistic activity was detected, showing chlorine might act as a toxic potentiator rather than a toxic deactivator in RXRβ disrupting effects. BPA and its byproducts including 2,2',6,6'-tetrachlorobisphenol A (TCBPA) and 2,4,6-trichlorophenol (TCP) were quantitatively determined by gas chromatography/mass spectrometry (GC/MS). BPA rapidly degraded. With the increasing of ICC and reaction time, concentration of formed TCBPA increased initially then decreased, while concentration of formed TCP increased stably. Using the toxic equivalent (TEQ) approach, the main contributors should be mono-, di- and tri- chlorobisphenol A at initial chlorine concentration (ICC) of 1mg/L. At ICC of 2 and 5mg/L, the main contributors were TCBPA and TCP, being 57.7%-70.7% and 45.3%-59.4%. Molecular docking showed BPA chlorination by-products might have the same mode of action with BPA, forming hydrogen bond and pi-pi interaction with their OH group or hydrophobic ring.
Since the turn of the century, our understanding of the quantities, transport pathways, and fate of persistent organic pollutants (POPs) over the Tibetan Plateau (TP), the largest and highest plateau on Earth, has greatly enhanced. We begin in this article by reviewing the available literature on the levels of POPs over the TP. In general, the levels of most POPs are similar or lower than values reported for other background regions. However, dichlorodiphenyltrichloroethane (DDT) and hexachlorocyclohexane (HCH) levels in air and soil far exceed those measured in other mountainous areas. The East Asian monsoon, Indian Monsoon and westerly winds are responsible for the long-range atmospheric transport (LRAT) and arrival of POPs over the TP. Surface soil and vegetation act as "final sinks" for DDTs and other high molecular weight POPs. Linked to the continuous use of POPs in surrounding counties, LRAT and "cold trapping" by the TP can happen following emission-transport-deposition events, leading to the enrichment of POPs in the TP environment. Bioaccumulation of DDTs and high chlorinated PCBs have been found in Tibetan terrestrial and aquatic food chains, and newly emerging compounds such as polyfluoroalkyl substances and hexabromocyclododecanes have been widely detected in wild fish species. The corresponding ecological risks should be of great concern. Climate change, such as increased temperatures and changing coverage of snow and glaciers, has the potential to affect the behavior and distribution of POPs. Therefore, long-term monitoring data are required. Ineffective regulation regarding POPs has been reported for countries in South Asia, emissions patterns, the outflow of POPs, and their seasonal and inter-annual variability should therefore be clarified. Estimating the loading
 of POPs, as well as how they move, within the TP, especially under the impact of glacial melt and global warming, should be a priority.
The aims of the study were to generate a grounded theory explaining the latent pattern of behavior in transcultural care interactions in the context of pediatric cancer care and to unify previously performed studies.
The basic tenets of classic grounded theory were applied on a theoretical sample of data from previous studies that included 5 focus group interviews with health care professionals (n = 35) and individual interviews with nurses (n = 12) and foreign-born parents (n = 11).
Facading emerged as the core category and is the act of showing an outer appearance that will influence other people's interpretations. In transcultural interactions, facading might be misinterpreted related to different obstacles. Examples are given of different facades explored in pediatric cancer care including strength facading. Facading is a strategy aiming to protect oneself and others emotionally in care and includes: emotional facading and facading-sensitive issues.
This grounded theory could help make health care professionals aware of different meanings of facading across cultures in health care. Also, awareness is needed of different views on emotional facading and facading-sensitive issues to provide a congruent care.
The objective of this experiment was to investigate the mechanisms through which different levels of dietary energy affect postnatal skeletal muscle development in ewe lambs. Twelve Dorper × Small Thin-Tailed crossbred ewe lambs (100 d of age; 20 ± 0.5 kg BW) were selected randomly and divided into 2 groups in a completely randomized design. Animals were offered identical diets at 100% or 65% of ad libitum intake. Lambs were euthanized when BW in the ad libitum group reached 35 kg and the semitendinosus muscle was sampled. Final BW and skeletal muscle weight were decreased (P < 0.01) by feed restriction. Both muscle fiber size distribution and myofibril cross-sectional area were altered by feed restriction. Insulin-like growth factor 1 (IGF-1) messenger RNA (mRNA) content was decreased (P < 0.05) when lambs were underfed, whereas no difference for IGF-2 mRNA expression was observed (P > 0.05). Feed restriction altered phosphor-Akt protein abundance (P < 0.01). Moreover, the mammalian target of rapamycin (mTOR) pathway was inhibited by feed restriction, which was associated with decreased phosphor-mTOR, phosphorylated eukaryotic initiation factor 4E binding protein 1 (phosphor-4EBP1), and phosphorylated ribosomal protein S6 kinase (phosphor-S6K). Both mRNA expression of myostatin and its protein content were elevated in feed-restricted ewe lambs (P < 0.05). In addition, mRNA expression of both muscle RING finger 1 and muscle atrophy F-box was increased when ewe lambs were underfed. In summary, feed restriction in young growing ewe lambs attenuates skeletal muscle hypertrophy by inhibiting protein synthesis and increasing protein degradation, which may act through the Akt-dependent pathway.
Immigrants' perceptions of affordability of insurance and knowledge of insurance after health reform are unknown. We conducted face-to-face surveys with a convenience sample of 1124 patients in three Massachusetts safety net Emergency Departments after the Massachusetts health reform (August 2013-January 2014), comparing immigrants and non-immigrants. Immigrants, as compared to non-immigrants, reported more concern about paying premiums (30 vs. 11 %, p = 0.0003) and about affording the current ED visit (38 vs. 22 %, p < 0.0001). Immigrants were also less likely to report having unpaid medical bills (24 vs. 32 %, p = 0.0079), however this difference was not present among those with any hospitalization in the past year. Insured immigrants were less likely to know copayment amounts (57 vs. 71 %, p = 0.0018). Immigrants were more likely to report that signing up for insurance would be easier with fewer plans (53 vs. 34 %, p = 0.0443) and to lack information about insurance in their primary language (31 vs. 1 %, p < 0.0001) when applying for insurance. Immigrants who sought insurance information via websites or helplines were more likely to find that information useful than non-immigrants (100 vs. 92 %, p = 0.0339). Immigrants seeking care in safety net emergency departments had mixed experiences with affordability of and knowledge about insurance after Massachusetts health reform, raising concern about potential disparities under the Affordable Care Act that is based on the MA reform.
Protein malnutrition (PM) is a major public health problem in developing countries, affecting the inflammatory response and increasing susceptibility to opportunistic infections. For this reason, an adequate nutritional intervention can improve the quality of life of patients. Glutamine (GLN) is a nonessential amino acid, but can be considered "conditionally essential" for macrophage function in stress situations, in which it plays a role in the improvement of the inflammatory response. Concerning this issue, in the current study, it was of interest to evaluate some biological aspects of peritoneal cells from a protein malnutrition (PM) mouse model challenged with lipopolysaccharide (LPS) and treated intravenously with GLN. Two-month-old male Balb/c mice were subjected to a low-protein diet (2 % protein) and stimulated intravenously with LPS 1 h prior to the injection of 0.75 mg/kg GLN. Malnourished animals showed a reduced number of total peritoneal cells. Malnourished animals stimulated with LPS or LPS plus GLN did not show differences in peritoneal cell counts; however, the control group showed increased cellularity after LPS stimulus, which was reversed after GLN injection. Further, in the animals from both groups stimulated with LPS, GLN decreased the circulating levels of TNF-α and the levels of TNF-α produced by peritoneal cells; additionally, GLN decreased the IL-10 circulating levels in the malnourished animals stimulated with LPS. In addition, peritoneal cells of the control and malnourished groups stimulated with LPS showed a negative modulation of the NFkB signaling pathway after GLN injection. In conclusion, this study shows that GLN has the capacity to reduce TNF-α synthesis as well as to act as a negative regulator of NFkB phosphorylation, leading to a positive outcome in the control of TNF-α production.
Implementation science (IS) is the study of methods that successfully integrate best evidence into practice. Although typically applied in healthcare settings to improve patient care and subsequent outcomes, IS also has immediate and practical applications to medical education toward improving physician training and educational outcomes. The objective of this article is to illustrate how to build a research agenda that focuses on applying IS principles in medical education.
We examined the literature to construct a rationale for using IS to improve medical education. We then used a generalizable scenario to step through a process for applying IS to improve team-based care.
IS provides a valuable approach to medical educators and researchers for making improvements in medical education and overcoming institution-based challenges. It encourages medical educators to systematically build upon the research outcomes of others to guide decision-making while evaluating the successes of best practices in individual environments and generate additional research questions and findings.
IS can act as both a driver and a model for educational research to ensure that best educational practices are easier and faster to implement widely.
The aim of this study was to investigate intrinsic antimicrobial activity of three monoterpenes nerol, dimethyl octanol and estragole, against bacteria and yeast strains, as well as, investigate if these compounds are able to inhibit the NorA efflux pump related to fluoroquinolone resistance in Staphylococcus aureus. Minimal inhibitory concentrations (MICs) of the monoterpenes against Staphylococcus aureus, Escherichia coli and Candida albicans strains were determined by micro-dilution assay. MICs of the norfloxacin against a S. aureus strain overexpressing the NorA protein were determined in the absence or in the presence of the monoterpenes at subinhibitory concentrations, aiming to verify the ability of this compounds act as efflux pump inhibitors. The monoterpenes were inactive against S. aureus however the nerol was active against E. coli and C. albicans. The addition of the compounds to growth media at sub-inhibitory concentrations enhanced the activity of norfloxacin against S. aureus SA1199-B. This result shows that bioactives tested, especially the nerol, are able to inhibit NorA efflux pump indicating a potential use as adjuvants of norfloxacin for therapy of infections caused by multi-drug resistant S. aureus strains.
Mild hyperthermia has shown great advantages when combined with chemotherapy. The development of a multifunctional platform for the integration of mild hyperthermia capability into a drug-loading system is a key issue for cancer multimodality treatment application. Herein, a facile one-pot in situ fabrication protocol of docetaxel (DTX)-loaded poly(lactic-co-glycolic acid) (PLGA)/polypyrrole (PPy) nanocomposites was developed. While the PLGA nanoparticles (NPs) allow efficient drug loading, the PPy nanobulges embedded within the surface of the PLGA NPs, formed by in situ pyrrole polymerization without the introduction of other template agents, can act as ideal mediators for photoinduced mild hyperthermia. Physiochemical characterizations of the as-prepared nanocomposites, including structure, morphology, photothermal effects, and an in vitro drug release profile, were systematically investigated. Further, 2-deoxyglucose-terminated poly(ethylene glycol) (PEG)
 was anchored onto the surface of the nanocomposites to endow the nanoplatform with targeting ability to tumor cells, which resulted in a 17-fold increase of NP internalization within human breast cancer cells (MCF-7) as competed with PEG-modified nanocomposites. Mild hyperthermia can be successfully mediated by the nanoplatform, and the temperature can be conveniently controlled by careful modulation of the PPy contents within the nanocomposites or the laser power density. Importantly, we have demonstrated that MCF-7 cells, which are markedly resistant to heat treatment of traditional water-bath hyperthermia, became sensitive to the PLGA/PPy nanocomposite-mediated photothermal therapy under the same mild-temperature hyperthermia. Moreover, DTX-loaded PLGA/PPy-nanocomposite-induced mild hyperthermia can strongly enhance drug cytotoxicity to MCF-7 cells. Under the same thermal dose, photoinduced hyperthermia can convert the interaction between hyperthermia and drug treatment from interference to synergism. This is the first report on the one-pot synthesis of PLGA/PPy nanocomposites by in situ pyrrole polymerization, and such a multifunctional nanoplatform is demonstrated as a high-potential agent for photoinduced mild hyperthermia and enhanced chemotherapy.
Giant vesicles (1-10 μm) were constructed via a facile ionic self-assembly (ISA) strategy using an anionic dye Acid Orange II (AO) and an oppositely charged ionic-liquid-type cationic surfactant 1-tetradecyl-3-methylimidazolium bromide (C14mimBr). This is the first report about preparing giant vesicles through ISA strategy. Interestingly, the giant vesicle could keep the original morphology during the evaporation of solvent and displayed solid-like properties at low concentration. Moreover, giant vesicles with large internal capacity volume and good stability in solution could also be achieved by increasing the concentrations of AO and C14mimBr which contributed to the increase of the other noncovalent cooperative interactions. In order to facilitate comparison, a series of parallel experiments with similar materials were carried out to investigate and verify the driving forces for the formation of these kinds of giant vesicles by changing the hydrophobic moieties or the head groups of the surfactants. It is concluded that the electrostatic interaction, hydrophobic effect and π-π stacking interaction play key roles in this self-assembly process. Importantly, the giant vesicles can act as a smart microcarrier to load and release carbon quantum dot (CQD) under control. Besides, the giant vesicles could also be applied as a microrector to synthesize monodispersed Ag nanoparticles with diameter of about 5-10 nm which exhibited the ability to catalyze reduction of 4-nitroaniline. Therefore, it is indicated that our AO/C14mimBr assemblies hold promising applications in the areas of microencapsulation, catalyst support, and lightweight composites owing to their huge sizes and large microcavities.
Functional magnetic resonance imaging may help in elucidating the pathophysiology of post-traumatic anosmia.
Using an fMRI olfactory stimulus paradigm, this study compared BOLD activation of the brain in a 21-year old male research subject with post-traumatic anosmia and a 19-year old male normal healthy control participant.
A delayed activation of the primary orbitofrontal cortex was found in the subject with traumatic anosmia, which may represent a crucial pathophysiological mechanism in the subject with traumatic anosmia due to axonal injury or traumatic transection at the lamina cribrosa level.
In healthy subjects the activation of secondary cortical areas may be due to the habituation effect in the primary olfactory cortex. This raises the possibility that, in the absence of secondary activation areas-that may act as a feed-back habituation or desensitization in the patient-one of the primary response areas is activated over the longer period of stimulation. The failed activation of these secondary areas in the patient may cause a feed-back habituation or desensitization in the patient and could also play a role in the disturbed perception of odours.
Plants have evolved elaborate mechanisms controlling developmental responses to environmental stimuli. A particularly important stimulus is temperature. Previous work has identified the interplay of PIF4 and ELF3 as a central circuit underlying thermal responses in Arabidopsis thaliana. However, thermal responses vary widely among strains, possibly offering mechanistic insights into the wiring of this circuit. ELF3 contains a polyglutamine (polyQ) tract that is crucial for ELF3 function and varies in length across strains. Here, we use transgenic analysis to test the hypothesis that natural polyQ variation in ELF3 is associated with the observed natural variation in thermomorphogenesis. We found little evidence that the polyQ tract plays a specific role in thermal responses beyond modulating general ELF3 function. Instead, we made the serendipitous discovery that ELF3 plays a crucial, PIF4-independent role in thermoresponsive flowering under conditions more likely to reflect field conditions. We present evidence that ELF3 acts through the photoperiodic pathway, pointing to a previously unknown symmetry between low and high ambient temperature responses. Moreover, in analyzing two strain backgrounds with different thermal responses, we demonstrate that responses may be shifted rather than fundamentally rewired across strains. Our findings tie together disparate observations into a coherent framework in which multiple pathways converge in accelerating flowering in response to temperature, with some such pathways modulated by photoperiod.
Fish oil supplementation is of great medical and public interest with epidemiological evidence of health benefits in humans, in particular by conferring protection against heart diseases. Its anti-inflammatory properties have also been reported. Initial results from short-lived mouse strains showed that fish oil can increase lifespan, affecting pathways like inflammation and oxidation thought to be involved in the regulation of aging. Could fish oil and its omega-3 fatty acids act as geroprotectors? Probably not. A new study by Strong et al. challenges the role for fish oil supplementation in aging. Using a large cohort of genetically heterogeneous mice in three sites, part of the Interventions Testing Program of the NIA, Strong et al. show that fish oil supplementation at either low or high dosages has no effect on the lifespan of male or female mice. Although it is still possible that fish oil supplementation has health benefits for specific age-related diseases, it does not appear to slow aging or have longevity benefits.
Prostate cancer-associated fibroblasts (CAF) can stimulate malignant progression and invasion of prostatic tumour cells via several mechanisms including those active in extracellular matrix;
We isolated CAF from prostate cancer patients of Gleason Score 6-10 and confirmed their cancer-promoting activity using an in vivo tumour reconstitution assay comprised of CAF and BPH1 cells. We tested the effects of heat shock protein 90 (HSP90) inhibitors upon reconstituted tumour growth in vivo. Additionally, CAF contractility was measured in a 3D collagen contraction assay and migration was measured by scratch assay;
HSP90 inhibitors dipalmitoyl-radicicol and 17-dimethylaminoethylamino-17-demethoxygeldanamycin (17-DMAG) reduced tumour size and proliferation in CAF/BPH1 reconstituted tumours in vivo. We observed that the most contractile CAF were derived from patients with lower Gleason Score and of younger age compared with the least contractile CAF. HSP90 inhibitors radicicol and 17-DMAG inhibited contractility and reduced the migration of CAF in scratch assays. Intracellular levels of HSP70 and HSP90 were upregulated upon treatment with HSP90 inhibitors. Inhibition of HSP90 also led to a specific increase in transforming growth factor beta 2 (TGFβ2) levels in CAF;
We suggest that HSP90 inhibitors act not only upon tumour cells, but also on CAF in the tumour microenvironment.
Childhood obesity is a major global issue. Its incidence is constantly increasing, thereby offering a threatening public health perspective. The risk of developing the numerous chronic diseases associated with this condition from very early in life is significant. Although complex and multi-factorial, the pathophysiology of obesity recognizes essential roles of nutritional and metabolic aspects. Particularly, several risk factors identified as possible determinants of later-life obesity act within the first 1000 days of life (i.e., from conception to age 2 years). The purpose of this manuscript is to review those key mechanisms for which a role in predisposing children to obesity is supported by the most recent literature. Throughout the development of the human feeding environment, three different stages have been identified: (1) the prenatal period; (2) breast vs. formula feeding; and (3) complementary diet. A deep understanding of the specific nutritional challenges presented within each phase might foster the development of future preventive strategies.
This paper reports the synthesis and fabrication of aligned electrospun nanofibers derived out of multiwalled carbon nanotubes (MWCNTs) embedded SU-8 photoresist, which are targeted towards ultrasensitive biosensor applications. The ultrasensitivity (detection in the range of fg/mL) and the specificity of these biosensors were achieved by complementing the inherent advantages of MWCNTs such as high surface to volume ratio and excellent electrical and transduction properties with the ease of surface functionalization of SU-8. The electrospinning process was optimized to precisely align nanofibers in between two electrodes of a copper microelectrode array.
 MWCNTs not only enhance the conductivity of SU-8 nanofibers but also act as transduction elements. In this paper, MWCNTs were embedded way beyond the percolation threshold and the optimum percentage loading of MWCNTs for maximizing the conductivity of nanofibers was figured out experimentally. As a proof of concept, the detection of myoglobin, an important biomarker for on-set of Acute Myocardial Infection (AMI) has been demonstrated by functionalizing the nanofibers with anti-myoglobin antibodies and carrying out detection using a chemiresistive method. This simple and robust device yielded a detection limit of 6 fg/mL.
Mitochondria are important organelles in cellular metabolism. Several crucial metabolic pathways such as the energy producing electron transport chain or the tricarboxylic acid cycle are hosted inside the mitochondria. The proper function of mitochondria depends on the import of proteins, which are encoded in the nucleus and synthesized in the cytosol. Micro-ribonucleic acids (miRNAs) are short non-coding ribonucleic acid (RNA) molecules with the ability to prevent messenger RNA (mRNA)-translation or to induce the degradation of mRNA-transcripts. Although miRNAs are mainly located in the cytosol or the nucleus, a subset of ~150 different miRNAs, called mitomiRs, has also been found localized to mitochondrial fractions of cells and tissues together with the subunits of the RNA-induced silencing complex (RISC); the protein complex through which miRNAs normally act to prevent translation of their mRNA-targets. The focus of this review is on miRNAs and mitomiRs with influence on mitochondrial metabolism and their possible pathophysiological impact.
We present experimental observations of visible wavelength second- and third-harmonic generation on single plasmonic nanowires of variable widths. We identify that near-infrared surface plasmon polaritons, which are guided along the nanowire, act as the source of the harmonics generation. We discuss the underlying mechanism of this nonlinear process, using a combination of spatially resolved measurements and numerical simulations to show that the visible harmonics are generated via a combination of both local and propagating plasmonic modes. Our results provide the first demonstration of nanoscale nonlinear optics with guided, propagating plasmonic modes on a lithographically defined chip, opening up new routes toward integrated optical circuits for information processing.
Identifying care needs for newly enrolled or newly insured individuals is important under the Affordable Care Act. Systematically collected patient-reported information can potentially identify subgroups with specific care needs prior to service use.
We conducted a retrospective cohort investigation of 6,047 individuals who completed a 10-question needs assessment upon initial enrollment in Kaiser Permanente Colorado (KPCO), a not-for-profit integrated delivery system, through the Colorado State Individual Exchange. We used responses from the Brief Health Questionnaire (BHQ), to develop a predictive model for cost for receiving care in the top 25 percent, then applied cluster analytic techniques to identify different high-cost subpopulations. Per-member, per-month cost was measured from 6 to 12 months following BHQ response.
BHQ responses significantly predictive of high-cost care included self-reported health status, functional limitations, medication use, presence of 0-4 chronic conditions, self-reported emergency department (ED) use during the prior year, and lack of prior insurance. Age, gender, and deductible-based insurance product were also predictive. The largest possible range of predicted probabilities of being in the top 25 percent of cost was 3.5 percent to 96.4 percent. Within the top cost quartile, examples of potentially actionable clusters of patients included those with high morbidity, prior utilization, depression risk and financial constraints; those with high morbidity, previously uninsured individuals with few financial constraints; and relatively healthy, previously insured individuals with medication needs.
Applying sequential predictive modeling and cluster analytic techniques to patient-reported information can identify subgroups of individuals within heterogeneous populations who may benefit from specific interventions to optimize initial care delivery.
Various ginger compounds improve gastrointestinal problems and motion sickness. The main effects of ginger allocate to some phenolics such as gingerols and shogaols that act as their active agents. Chewing gums are among convenient dosage forms which patients prefer due to their advantages. Hence, this study tried to design, formulate, and evaluate ginger chewing gum of favorable taste and texture to avoid motion sickness and have gastro-protective and anti-oxidant effect.
Dried ginger rhizomes were percolated to extract ginger compounds. Total phenolics were measured in 70% hydro-alcoholic extract of ginger by gallic and tannic acid standards using Folin-Ciocalteu's reagent. Chewing gums containing 50 mg of concentrated extract were prepared. Content uniformity, weight variation, release pattern, organoleptic, and mechanical properties were evaluated.
Phenolic content was measured 61.50 ± 5.27 mg/g and 76.75 ± 5.45 mg/g of concentrated extract as gallic acid and tannic acid equivalents, respectively. Release pattern of formulations with different gum bases and sweeteners demonstrated almost 100% release of drug. Evaluation of organoleptic properties was on 10 healthy volunteers and later prepared formulations exhibited better characteristics. Formulations without any flavorants have higher acceptability. Evaluation of mechanical properties showed higher stiffness of F15.
Ginger chewing gum comprises admissible properties to be used as a modern drug delivery system due to its advantageous results in motion sickness. It passed all the specified tests for an acceptable chewing gum. Thus, it may be successfully produced to help GI problems.
In this paper, we investigate the effectiveness of a CRF-based learning method for identifying necessary Web of Things (WoT) application components that would satisfy the users' requests issued in natural language. For instance, a user request such as "archive all sports breaking news" can be satisfied by composing a WoT application that consists of ESPN breaking news service and Dropbox as a storage service.
We built an engine that can identify the necessary application components by recognizing a main act (MA) or named entities (NEs) from a given request. We trained this engine with the descriptions of WoT applications (called recipes) that were collected from IFTTT WoT platform. IFTTT hosts over 300 WoT entities that offer thousands of functions referred to as triggers and actions. There are more than 270,000 publicly-available recipes composed with those functions by real users. Therefore, the set of these recipes is well-qualified for the training of our MA and NE recognition engine.
We share our unique experience of generating the training and test set from these recipe descriptions and assess the performance of the CRF-based language method. Based on the performance evaluation, we introduce further research directions.
Patient participation is required by law in Norway and in several western countries. Current participation ideology is based on individualism, which may conflict with the older generation's commonly held values of solidarity and community. Hence, different values and ideologies may come in conflict when older patients receive treatment and rehabilitation in geriatric wards. Participation is a guiding principle in rehabilitation. Criteria for admission of older patients to geriatric wards are complex health problems, acute illness and/or acute physical and/or cognitive functional failure. The ideal is an active and engaged patient. The aim of the study was to describe the difficulties experienced by older patients on acute geriatric wards when involving themselves with their own treatment and care.
In this qualitative study older patients were interviewed during hospitalization in geriatric wards and asked to tell about their experiences with participation. Data analysis was conducted using a phenomenological hermeneutic method.
The patients experienced difficulties in participating in decisions and care. They linked their difficulties to their own diminishing capabilities, and cited the ward's busy schedule as a reason for abstaining from participation. However, despite their reservations, they did participate in decisions in different ways. Their participatory practices appeared ambiguous and they employed various strategies to put themselves in a position of influence. The most important of these involved their relatives. The patients delegated to family the tasks of seeking, receiving and giving information to the nurses and the staff, and, to some extent, for the dialogues with hospital staff about their needs and plan of care. The family appeared to accept the responsibility willingly.
The patients addressed their difficulties by authorizing family members to act and participate on their behalf. This underlines the family's important role in patient participation and the role that nurses and other staff must play in collaborating with the patient and their family to facilitate participation independently of the patients' performances of participation.
The activated spliceosome (B(act)) is in a catalytically inactive state and is remodeled into a catalytically active machine by the RNA helicase Prp2, but the mechanism is unclear. Here, we describe a 3D electron cryomicroscopy structure of the Saccharomyces cerevisiae B(act) complex at 5.8-angstrom resolution. Our model reveals that in B(act), the catalytic U2/U6 RNA-Prp8 ribonucleoprotein core is already
 established, and the 5' splice site (ss) is oriented for step 1 catalysis but occluded by protein. The first-step nucleophile-the branchsite adenosine-is sequestered within the Hsh155 HEAT domain and is held 50 angstroms away from the 5'ss. Our structure suggests that Prp2 adenosine triphosphatase-mediated remodeling leads to conformational changes in Hsh155's HEAT domain that liberate the first-step reactants for catalysis.
Mitochondria and mitochondrial debris are found in the brain's extracellular space, and extracellular mitochondrial components can act as damage associated molecular pattern (DAMP) molecules. To characterize the effects of potential mitochondrial DAMP molecules on neuroinflammation, we injected either isolated mitochondria or mitochondrial DNA (mtDNA) into hippocampi of C57BL/6 mice and seven days later measured markers of inflammation. Brains injected with whole mitochondria showed increased Tnfα and decreased Trem2 mRNA, increased GFAP protein, and increased NFκB phosphorylation. Some of these effects were also observed in brains injected with mtDNA (decreased Trem2 mRNA, increased GFAP protein, and increased NFκB phosphorylation), and mtDNA injection also caused several unique changes including increased CSF1R protein and AKT phosphorylation. To further establish the potential relevance of this response to Alzheimer's disease (AD), a brain disorder characterized by neurodegeneration, mitochondrial dysfunction, and neuroinflammation we also measured App mRNA, APP protein, and Aβ1-42 levels. We found mitochondria (but not mtDNA) injections increased these parameters. Our data show that in the mouse brain extracellular mitochondria and its components can induce neuroinflammation, extracellular mtDNA or mtDNA-associated proteins can contribute to this effect, and mitochondria derived-DAMP molecules can influence AD-associated biomarkers.
Antifungal susceptibilities of non-Aspergillus filamentous fungal pathogens cannot always be inferred from their identification. Here we determined, using the Sensititre(®) YeastOne(®) YO10 panel, the in vitro activities of nine antifungal agents against 52 clinical isolates of emergent non-Aspergillus moulds representing 17 fungal groups in Australia. Isolates comprised Mucorales (n = 14), Scedosporium/Lomentospora spp. (n = 18) and a range of hyaline hyphomycetes (n = 9) and other dematiaceous fungi (n = 11). Excluding Verruconis gallopava, echinocandins demonstrated poor activity (MICs generally >8 mg/L) against these moulds. Lomentospora prolificans (n = 4) and Fusarium spp. (n = 6) demonstrated raised MICs to all antifungal drugs tested, with the lowest being to voriconazole and amphotericin B (AmB), respectively (geometric mean MICs of 3.4 mg/L and 2.2 mg/L, respectively). All Scedosporium apiospermum complex isolates (n = 14) were inhibited by voriconazole concentrations of ≤0.25 mg/L, followed by posaconazole and itraconazole at ≤1 mg/L. Posaconazole and AmB were the most active agents against the Mucorales, with MIC90 values of 1 mg/L and 2 mg/L, respectively, for Rhizopus spp. For dematiaceous fungi, all isolates were inhibited by itraconazole and posaconazole concentrations of ≤0.5 mg/L (MIC90, 0.12 mg/L and 0.25 mg/L, respectively), but voriconazole and AmB also had in vitro activity (MIC90, 0.5 mg/L and 1 mg/L, respectively). Differences in antifungal susceptibility within species and between species within genera support the need for testing individual patient isolates to guide therapy. The Sensititre(®) YeastOne(®) offers a practical alternative to the reference methodology for susceptibility testing of moulds.
High-temperature tolerance in plants is important in a warming world, with extreme heat waves predicted to increase in frequency and duration, potentially leading to lethal heating of leaves. Global patterns of high-temperature tolerance are documented in animals, but generally not in plants, limiting our ability to assess risks associated with climate warming. To assess whether there are global patterns in high-temperature tolerance of leaf metabolism, we quantified Tcrit (high temperature where minimal chlorophyll a fluorescence rises rapidly and thus photosystem II is disrupted) and Tmax (temperature where leaf respiration in darkness is maximal, beyond which respiratory function rapidly declines) in upper canopy leaves of 218 plant species spanning seven biomes. Mean site-based Tcrit values ranged from 41.5 °C in the Alaskan arctic to 50.8 °C in lowland tropical rainforests of Peruvian Amazon. For Tmax , the equivalent values were 51.0 and 60.6 °C in the Arctic and Amazon, respectively. Tcrit and Tmax followed similar biogeographic patterns, increasing linearly (˜8 °C) from polar to equatorial regions. Such increases in high-temperature tolerance are much less than expected based on the 20 °C span in high-temperature extremes across the globe. Moreover, with only modest high-temperature tolerance despite high summer temperature extremes, species in mid-latitude (~20-50°) regions have the narrowest thermal safety margins in upper canopy leaves; these regions are at the greatest risk of damage due to extreme heat-wave events, especially under conditions when leaf temperatures are further elevated by a lack of transpirational cooling. Using predicted heat-wave events for 2050 and accounting for possible thermal acclimation of Tcrit and Tmax , we also found that these safety margins could shrink in a warmer world, as rising temperatures are likely to exceed thermal tolerance limits. Thus, increasing numbers of species in many biomes may be at risk as heat-wave events become more severe with climate change.
Experimental studies of group selection show that higher levels of selection act on indirect genetic effects, making the response to group and community selection qualitatively different from that of individual selection. This suggests that multilevel selection plays a key role in the evolution of supersocial societies. Experiments showing the effectiveness of community selection indicate that we should consider the possibility that selection among communities may be important in the evolution of supersocial species.
Anemia is frequent in oncology. We debate the decision-making process of erythrocyte transfusion in palliative care situation from a case report. A patient with a prostatic metastatic cancer was in palliative situation with asthenia and coronary symptom. We analyze, in this particular case that does not describe reality of normal practice, the decision-making process of erythrocyte transfusion. These transfusions were based, in this case, on the evaluation of oncology prognosis, the short-term vital threats, life project and clinical safety of the transfusion. The patient has received 5 erythrocyte transfusions in 4 months until a multidisciplinary meeting decided to stop transfusion because of poor prognostic situation and bad tolerance of the act. This patient could be a collegial model used to measure the reasonable nature of prescription depending on the purpose and the goal of the patient but does not allow generalization. Although there is low risk of erythrocyte shortage, it seems important to train doctors to reduce abusive transfusion and define transfusion thresholds. Different levels of erythrocyte transfusion security would raise the issue of management of several stocks. Erythrocyte transfusion in palliative care can be considered subject to prognostic information and the palliative aim of the transfusions, multidisciplinary decision-making, during short hospitalizations and with evaluation of the act and consequences for the patient.
As a highly consequential biological trait, a memory "bottleneck" cannot escape selection pressures. It must therefore co-evolve with other cognitive mechanisms rather than act as an independent constraint. Recent theory and an implemented model of language acquisition suggest that a limit on working memory may evolve to help learning. Furthermore, it need not hamper the use of language for communication.
The use of artemisinin as a monotherapy resulted in the emergence of artemisinin resistance in 2005 in Southeast Asia. Monitoring of artemisinin combination therapy (ACT) is critical in order to detect and prevent the spread of resistance in endemic areas. Ex vivo studies and genotyping of molecular markers of resistance can be used as part of this routine monitoring strategy. One gene that has been associated in some ACT partner drug resistance is the Plasmodium falciparum multidrug resistance protein 1 (pfmdr1) gene. The purpose of this study was to assess the drug susceptibility of P. falciparum populations from Thiès, Senegal by ex vivo assay and typing molecular markers of resistance to drug components of ACT currently used for treatment.
The ex vivo susceptibility of 170 P. falciparum isolates to chloroquine, amodiaquine, lumefantrine, artesunate, and artemether was determined using the DAPI ex vivo assay. The high resolution melting technique was used to genotype the pfmdr1 gene at codons 86, 184 and 1246.
A significant decrease in IC50 values was observed between 2012 and 2013: from 13.84 to 6.484 for amodiaquine, 173.4 to 113.2 for lumefantrine, and 39.72 to 18.29 for chloroquine, respectively. Increase of the wild haplotype NYD and the decrease of the mutant haplotype NFD (79 and 62.26 %) was also observed. A correlation was observed between the wild type allele Y184 in pfmdr1 and higher IC50 for all drugs, except amodiaquine.
This study has shown an increase in sensitivity over the span of two transmission seasons, marked by an increase in the WT alleles at pfmdr1. Continuous the monitoring of the ACT used for treatment of uncomplicated malaria will be helpful.
Many factors can negatively affect honey bee (Apis mellifera L.) health including the pervasive use of systemic
 neonicotinoid insecticides. Through direct consumption of contaminated nectar and pollen from treated plants, neonicotinoids can affect foraging, learning, and memory in worker bees. Less well studied are the potential effects of neonicotinoids on queen bees, which may be exposed indirectly through trophallaxis, or food-sharing. To assess effects on queen productivity, small colonies of different sizes (1500, 3000, and 7000 bees) were fed imidacloprid (0, 10, 20, 50, and 100 ppb) in syrup for three weeks. We found adverse effects of imidacloprid on queens (egg-laying and locomotor activity), worker bees (foraging and hygienic activities), and colony development (brood production and pollen stores) in all treated colonies. Some effects were less evident as colony size increased, suggesting that larger colony populations may act as a buffer to pesticide exposure. This study is the first to show adverse effects of imidacloprid on queen bee fecundity and behavior and improves our understanding of how neonicotinoids may impair short-term colony functioning. These data indicate that risk-mitigation efforts should focus on reducing neonicotinoid exposure in the early spring when colonies are smallest and queens are most vulnerable to exposure.
In 2006 The Dutch Health Care system changed to a market oriented system. The GP remuneration changed from ± 2/3 capitation patients and 1/3 private patients before 2006 to a mixed payment scheme. From 2006 onward every patient was insured and the GP received partly capitation, partly fees for consultations and for specific services. This change coincided with many other organisational changes in General Practice care. Our research question was if during the years after 2006 patient experiences of Dutch family practice had changed. We also wanted to explore the influence of patient and practice characteristics on patient experiences. Data on patient experiences were available from 2007 to 2012.
In a series of annual cross sectional patient surveys the performance of GPs and practices was measured. Patient sampling took place as a part of the Dutch accreditation program in 1657 practices involving 2966 GPs. Patients' experiences, gender, age, health status, and number of annual consultations were documented as well as the type and location of practices. Linear regression analysis was used to examine time trends in patient experiences and the impact of patient and practice characteristics.
78,985 patients assessed the performance of 2966 GPs, and 45,773 patients assessed the organisation of 1657 practices. The number of patients with positive experiences increased significantly between 2007 and 2012; respectively 4.8 % for GPs (beta 0.20 and p < 0.0001) and 6.6 % for practices (beta 0.10, p < 0.004). Higher age, having no chronic illness, more frequent consultations and attending single-handed practices, predicted better patient experiences.
In our evaluation of patient experiences with general practice care from 2007 to 2012 we found an increase of 4.8 % for GPs and 6.6 % for practices respectively. This improvement is significant. While no direct causation can be made, possible explanations may be found in the various reforms in Dutch family practice since 2006. More insight is needed into key determinants of this improvement before policymakers and care providers can attribute the improvement to these reforms.
The development of hypersensitivity following spinal cord injury can result in incurable persistent neuropathic pain. Our objective was to examine the effect of red light therapy on the development of hypersensitivity and sensorimotor function, as well as on microglia/macrophage subpopulations following spinal cord injury.
Wistar rats were treated (or sham treated) daily for 30 min with an LED red (670 nm) light source (35 mW/cm(2)), transcutaneously applied to the dorsal surface, following a mild T10 hemicontusion injury (or sham injury). The development of hypersensitivity was assessed and sensorimotor function established using locomotor recovery and electrophysiology of dorsal column pathways. Immunohistochemistry and TUNEL were performed to examine cellular changes in the spinal cord.
We demonstrate that red light penetrates through the entire rat spinal cord and significantly reduces signs of hypersensitivity following a mild T10 hemicontusion spinal cord injury. This is accompanied with improved dorsal column pathway functional integrity and locomotor recovery. The functional improvements were preceded by a significant reduction of dying (TUNEL(+)) cells and activated microglia/macrophages (ED1(+)) in the spinal cord. The remaining activated microglia/macrophages were predominantly of the anti-inflammatory/wound-healing subpopulation (Arginase1(+)ED1(+)) which were expressed early, and up to sevenfold greater than that found in sham-treated animals.
These findings demonstrate that a simple yet inexpensive treatment regime of red light reduces the development of hypersensitivity along with sensorimotor improvements following spinal cord injury and may therefore offer new hope for a currently treatment-resistant pain condition.
The hitherto unknown role of saponin in the regulation of thyrotoxicosis has been revealed in chemically-induced thyrotoxic rats. l-T4 (l-thyroxine) administration at pre-standardized dose of 500-μg/kg body weight for 12days increased the levels of thyroid hormones, enhanced the activity of hepatic 5'-monodeiodinase I (5'DI) and glucose-6-phosphatase (G-6Pase) as well as lipid peroxidation (LPO) with a parallel decrease in the levels of antioxidative enzymes. However, administration of the isolated saponin for 15days ameliorated the T4-induced alterations in serum thyroid hormones, hepatic LPO, G-6-Pase and 5'DI activity, and improved the cellular antioxidant status, indicating its antithyroidal and antioxidative potential. These effects of the test compound were comparable to a reference antithyroid drug, Propylthiouracil (PTU), suggesting that the test saponin may act as a potent anti-thyroid agent.
Calorie restriction (CR) is a broadly effective environmental intervention that extends life by operating through numerous biological processes. Here, we discuss how non-coding RNA (ncRNA) molecules act as mediators and targets of lifespan-extending CR. We also highlight how these RNA molecules connect CR to its effects on genome stability, cell metabolism, programmed cell death, senescence, cancer, and neurodegeneration. We anticipate that an advanced understanding of the connections between CR and non-coding RNA will provide unique insights into aging mechanisms while pointing to novel approaches aimed at modulating aging and age-related diseases.
The production of the L/T channel blocker ACT-280778 required the enantiomerically pure 5-phenylbicyclo[2.2.2]oct-5-en-2-one (1) as key building block. As the published routes towards 1 are very low yielding (<0.5% yield) and comprise many steps that are not acceptable for scale-up, a series of processes to 1 was developed to match the increasing requirements from first kg-batches to clinical supplies. The three routes are characterized by an individual asset. (1) The first route contains a scale-up of a Diels-Alder reaction with highly reactive reagents and afforded 90 kg enantiomerically pure 1. To mitigate safety risks, a flow reactor was developed for the high-temperature Diels-Alder reaction. This route relied on an efficient enantiomer separation on a ¼-ton scale by HPLC. (2) A Crystallization Induced Diastereomer Transformation (CIDT) during an intramolecular aldol reaction was the pivotal step of a first enantioselective route that starts with the Shibasaki reaction. (3) The 2(nd) enantioselective route represents a rare example of organocatalysis on scale and allowed to skip six out of nine steps with a significant impact on the cost of goods. This simple way to 1 opened up a short synthesis of Hayashi's chiral diene ligands (bod*) that were so far lacking an affordable access. Some of these novel C1-symmetrical dienes have shown very high enantioselectivities in Rh-catalyzed additions of arylboronates.
There is substantial expert disagreement about the use of mammography to screen for breast cancer, and this disagreement routinely plays out in the media. Evidence suggests that some women are aware of the controversy over mammography, but less is known about whether immigrant and other underserved women have heard about it and, if so, how they react to it.
To explore immigrant women's awareness of and reactions to mammography controversy.
Community-engaged qualitative study: we conducted six focus groups with 53 women aged 35-55 from three immigrant communities (Somali, Latina and Hmong) in a major US metropolitan area. A grounded theory approach was used to identify themes; NVivo 10 was used to enhance analyses.
Several themes emerged: (i) low awareness of mammography controversy across groups, despite self-reported attention to health information; (ii) high intentions to be screened, even after being told about the controversy; (iii) few reported discussions of mammography's risks and benefits with clinicians; (iv) substantial interest in learning more about mammography and breast cancer, but some low self-efficacy to obtain such information; and (v) questions about whether health recommendations matter and what qualifies as evidence.
Given on-going expert disagreement about mammography screening, it is important for clinicians to help women understand mammography's risks and benefits so they can make an informed choice. This is particularly critical for immigrant and other underserved women, who may be less able to access, attend to, process, retain and act on health information (a phenomenon known as communication inequality).
Tissue engineering is a recently emerging line of act which assists
 the regeneration of damaged tissues, unable to self-repair themselves and in turn, enhances the natural healing potential of patients. The repair of injured tissue can be induced with the help of some artificially created polymer scaffolds for successful tissue regeneration. The pullulan composite scaffolds can be used to enhance the proliferation and differentiation of cells for tissue regeneration. The unique pattern of pullulan with α-(1→4) and α-(1→6) linkages along with the presence of nine hydroxyl groups on its surface, endows the polymer with distinctive physical features required for tissue engineering. Pullulan can be used for vascular engineering, bone repair and skin tissue engineering. Pullulan composite scaffolds can also be used for treatment of injured femoral condyle bone, skull bone and full thickness skin wound of murine models, transversal mandibular and tibial osteotomy in goat, etc. This review article highlights the latest developments on applications of pullulan and its derivatives in tissue engineering.
As people are living longer, they are being encouraged to work longer. While it is assumed that extended employment will be good for health, the evidence has been mixed. This study considers whether employment and job quality exert an influence on four indicators of health status in older workers.
Data for this study came from 836 older workers (440 men and 396 women) aged 50-59 years at baseline who participated in the Household, Income and Labour Dynamics in Australia (HILDA) Survey. Using linear regression, we examine within-person change in self-rated, physical and mental health and one health behaviour (physical activity) at two time points over a nine year follow-up period.
There were minimal differences in the way health changed for older adults who continued working compared to those who retired voluntarily. However, when we decomposed employment in terms of job quality, health outcomes diverged. Compared to voluntary retirees, older workers who had worked in good quality jobs reported marginally better self-rated health (0.14,-0.02-0.29); but did not differ in their physical (2.31,-1.09-5.72) or mental health (0.51,-1.84-2.87). In contrast, older workers who held poor quality jobs for most of the follow-up period declined in their self-rated (-1.13,-0.28 - -0.02), physical (-4.90, 8.52- - 1.29) and mental health (-4.67, 7.69- - 1.66) relative to voluntary retirees. Older workers who held poor quality jobs for just some of the follow-up period did not differ from voluntary retirees in terms of their health. However there was evidence of a linear relationship between length of exposure to poor quality jobs and decline in health outcomes.
Extended working lives mean that people will be 'exposed' to work for longer, and this exposure will occur at a life stage characterised by declining health for many. Our findings show that ensuring older workers have access to secure jobs which allow for control over work time, skill use and fair rewards will be essential if policy goals to boost participation and productivity, as well as reduce the health and care costs of the elderly, are to be met.
Signal transduction is the process through which cells communicate with the external environment, interpret stimuli and respond to them. This mechanism is controlled by signaling cascades, which play the role of intracellular transmitter, being able to transmit biochemical information between cell membrane and nucleus. In theory as well as in practice, it has been shown that a perturbation can propagate upstream (and not only downstream) a cascade, by a mechanism known as retroactivity. This study aims to compare the conditions on biochemical parameters which favor one or the other direction of signaling in such a cascade.
From a mathematical point of view, we show that the steady states of a cascade of arbitrary length n are described by an iterative map of second order, meaning that the cascade tiers are actually coupled three-by-three. We study the influence of the biochemical parameters in the control of the direction of transmission - upstream and/or downstream - along a signaling cascade. A numerical and statistical approach, based on the random scan of parameters describing a 3-tier signaling cascade, provides complementary findings to the analytical study. In particular, computing the likelihood of parameters with respect to various signaling regimes, we identify conditions on biochemical parameters which enhance a specific direction of propagation corresponding to forward or retro-signaling regimes. A compact graphical representation is designed to relay the gist of these conditions.
The values of biochemical parameters such as kinetic rates, Michaelis-Menten constants, total concentrations of kinases and of phosphatases, determine the propensity of a cascade to favor or impede downstream or upstream signal transmission. We found that generally there is an opposition between parameter sets favoring forward and retro-signaling regimes. Therefore, on one hand our study supports the idea that in most cases, retroactive effects can be neglected when a cascade which is efficient in forward signaling, is perturbed by an external ligand inhibiting the activation at some tier of the cascade. This result is relevant for therapeutic methodologies based on kinase inhibition. On the other hand, our study highlights a less-known part of the parameter space where, although the forward signaling is inefficient, the cascade can interestingly act as a retro-signaling device.
Early childhood is a critical time for establishing physical activity and sedentary behaviours. Identifying modifiable predictors of physical activity and sedentary behaviours in the early life stages can inform the development of early intervention programs. The aim of this study was to identify modifiable predictors of outdoor play (a proxy of physical activity) and screen-time in 2- to 5-year-olds.
A longitudinal data analysis was conducted using 5-year follow-up data from the Healthy Beginnings Trial undertaken in Sydney, Australia from 2007 to 2013. A total of 667 pregnant women were recruited for the study. Information on mothers' demographics, physical activity, screen-time, knowledge of child development, and awareness of childhood obesity during pregnancy (at baseline); children's tummy time (a colloquial term describing the time when a baby is placed on his or her stomach while awake and supervised) at 6 months old and screen-time at 1 year old was collected via interviews with participating mothers as potential modifiable predictors. Main outcomes were children's outdoor playtime and screen-time at ages 2, 3.5, and 5 years. Mixed linear and logistic regression models were built to determine these modifiable predictors.
Mothers' screen-time during pregnancy (β = 2.1, 95 % CI 0.17-4.12; P = 0.030) and children's daily screen-time at age 1 year (β = 15.2, 95 % CI 7.28-23.11; P < 0.0001) predicted children's daily screen-time across ages 2 to 5 years after controlling for confounding factors. Practising tummy time daily (β = 13.4, 95 % CI 1.26-25.52; P = 0.030), mother's physical activity level (β = 3.9, 95 % CI 0.46-7.28; P = 0.026), and having been informed about playing with child at baseline (β = 11.6, 95 % CI 1.56-21.54; P = 0.023) predicted children's outdoor playtime across ages 2 to 5 years.
Mothers played an important role in their children's outdoor play and screen-time in the first years of live. Children's early exposure to screen devices could be associated with their later screen-time. Early interventions to improve young children's physical activity and sedentary behaviour should focus on improving pregnant women's physical activity, awareness of playing with their child, reducing their own screen-time as well as practicing daily tummy time for infants after giving birth.
The Healthy Beginnings Trial is registered with the Australian Clinical Trial Registry ( ACTRNO12607000168459 ). Registered 13 March 2007. Prospectively registered.
To investigate the protein profiling of buffalo oocytes at the germinal vesicle (GV) stage and metaphase II (MII) stage, an iTRAQ-based strategy was applied. A total of 3,763 proteins were identified, which representing the largest buffalo oocytes proteome dataset to date. Among these proteins identified, 173 proteins were differentially expressed in GV oocytes and competent MII oocytes, and 146 proteins were differentially abundant in competent and incompetent matured oocytes. Functional and KEGG pathway analysis revealed that the up-regulated proteins in competent MII oocytes were related to chromosome segregation, microtubule-based process, protein transport, oxidation reduction, ribosome, and oxidative phosphorylation, etc., in comparison with GV and incompetent MII oocytes. This is the first proteomic report on buffalo oocytes from different maturation stages and developmental competent status. These data will provide valuable information for understanding the molecular mechanism underlying buffalo oocyte maturation, and these proteins may potentially act as markers to predict developmental competence of buffalo oocyte during in vitro maturation.
Complex interactions exist between cytokines, and the interleukin family plays a fundamental role in inflammation. Particularly circulating IL-1β, IL-6 and IL-8 are unregulated in systemic and chronic inflammatory conditions. Hypercoagulability is an important hallmark of inflammation, and these cytokines are critically involved in abnormal clot formation, erythrocyte pathology and platelet hyper-activation, and these three cytokines have known receptors on platelets. Although these cytokines are always unregulated in inflammation, we do not know how the individual cytokines act upon the structure of erythrocytes and platelets, and which
 of the viscoelastic clot parameters are changed. Here we study the effects of IL-1β, IL-6 and IL-8 at low physiological levels, representative of chronic inflammation, by using scanning electron microscopy and thromboelastography. All three interleukins caused the viscoelastic properties to display an increased hypercoagulability of whole blood and pathology of both erythrocytes and platelets. The most pronounced changes were noted where all three cytokines caused platelet hyper-activation and spreading. Erythrocyte structure was notably affected in the presence of IL-8, where the morphological changes resembled that typically seen in eryptosis (programmed cell death). We suggest that erythrocytes and platelets are particularly sensitive to cytokine presence, and that they are excellent health indicators.
Gatekeeper suicide prevention programs train staff to increase the identification and referral of suicidal individuals to the appropriate resources.
We evaluated Act on FACTS: Making Educators Partners in Youth Suicide Prevention (MEP), which is an online training program designed to enhance the knowledge of suicide risk factors and warning signs as well as improve participants' attitudes and self-efficacy/confidence.
School personnel (N = 700) completed a survey administered before and immediately after the training to assess gains in training outcomes and to evaluate participants' satisfaction with the training.
Results indicated that MEP participants demonstrated significant increases in suicide knowledge, attitudes, and self-efficacy. Moreover, exploratory analyses revealed moderating effects of professional role on pre-/posttest changes in self-efficacy, but not suicide knowledge or attitudes. Specifically, guidance counselors demonstrated significantly smaller increases in self-efficacy/confidence compared with teachers and classroom aids, whereas teachers demonstrated significantly larger increases in self-efficacy/confidence compared with administrators. The majority of school personnel who completed the MEP program were satisfied with the training content and experience.
Although the current findings are promising, more rigorous evaluations employing randomized controlled research designs are warranted to adequately determine the effectiveness of the MEP program.
The concept of competitive endogenous RNA (ceRNA) was first proposed by Salmena and colleagues. Evidence suggests that pseudogene RNAs can act as a 'sponge' through competitive binding of common miRNA, releasing or attenuating repression through sequestering miRNAs away from parental mRNA. In theory, ceRNAs refer to all transcripts such as mRNA, tRNA, rRNA, long non-coding RNA, pseudogene RNA and circular RNA, because all of them may become the targets of miRNA depending on spatiotemporal situation. As binding of miRNA to the target RNA is not 100% complementary, it is possible that one miRNA can bind to multiple target RNAs and vice versa. All RNAs crosstalk through competitively binding to miRNAvia miRNA response elements (MREs) contained within the RNA sequences, thus forming a complex regulatory network. The ratio of a subset of miRNAs to the corresponding number of MREs determines repression strength on a given mRNA translation or stability. An increase in pseudogene RNA level can sequester miRNA and release repression on the parental gene, leading to an increase in parental gene expression. A massive number of transcripts constitute a complicated network that regulates each other through this proposed mechanism, though some regulatory significance may be mild or even undetectable. It is possible that the regulation of gene and pseudogene expression occurring in this manor involves all RNAs bearing common MREs. In this review, we will primarily discuss how pseudogene transcripts regulate expression of parental genes via ceRNA network and biological significance of regulation.
Autosomal Dominant Polycystic Kidney Disease (ADPKD) is a common genetic disease that leads to progressive renal cyst growth and loss of renal function, and is caused by mutations in the genes encoding polycystin-1 (PC1) and polycystin-2 (PC2), respectively. The PC1/PC2 complex localizes to primary cilia and can act as a flow-dependent calcium channel in addition to numerous other signaling functions. The exact functions of the polycystins, their regulation and the purpose of the PC1/PC2 channel are still poorly understood. PC1 is an integral membrane protein with a large extracytoplasmic N-terminal domain and a short, ~200 amino acid C-terminal cytoplasmic tail. Most proteins that interact with PC1 have been found to bind via the cytoplasmic tail. Here we report that the PC1 tail has homology to the regulatory domain of myosin heavy chain including a conserved calmodulin-binding motif. This motif binds to CaM in a calcium-dependent manner. Disruption of the CaM-binding motif in PC1 does not affect PC2 binding, cilia targeting, or signaling via heterotrimeric G-proteins or STAT3. However, disruption of CaM binding inhibits the PC1/PC2 calcium channel activity and the flow-dependent calcium response in kidney epithelial cells. Furthermore, expression of CaM-binding mutant PC1 disrupts cellular energy metabolism. These results suggest that critical functions of PC1 are regulated by its ability to sense cytosolic calcium levels via binding to CaM.
Despite increased focus on the role of spiritual care in palliative care, there is limited knowledge about spirituality/religiosity among dying patients in secularized cultures such as Denmark. This study aims through semi-structured interviews with Danish hospice patients and participant observation to elucidate how hospice patients reflect and act upon their potential faith. The results demonstrate three dimensions of faith: (1) "Knowing" (cognition), (2) "doing" (praxis) and (3) "being" (meaning). The article concludes that most patients had a hesitant, but according to their situation, important faith although it was not something they knew much about, let alone discussed or practiced much.
Photoinitiated polymerization has been the subject of continued research efforts due to the numerous applications in which this polymerization technique is involved (coatings, inks, adhesives, optoelectronic, laser imaging, stereolithography, nanotechnology, etc.). More recently, photopolymerization has received renewed interest due to the emergence of 3D-printing technologies. However, despite current academic and industrial interest in photopolymerization methodologies, a major limitation lies in the slow rates of photopolymerization. The development of new photoinitiating systems aimed at addressing this limitation is an active area of research. Photopolymerization occurs through the exposure of a curable formulation to light, generating radical and/or cationic species to initiate polymerization. At present, photopolymerization is facing numerous challenges related to safety, economic and ecological concerns. Furthermore, practical considerations such as the curing depth and the competition for light absorption between the chromophores and other species in the formulation are key parameters drastically affecting the photopolymerization process. To address these issues, photoinitiating systems operating under low intensity visible light irradiation, in the absence of solvents are highly sought after. In this context, the use of photoredox catalysis can be highly advantageous; that is, photoredox catalysts can provide high reactivities with low catalyst loading, permitting access to high performance photoinitiating systems. However, to act as efficient photoredox catalysts, specific criteria have to be fulfilled. A strong absorption over the visible range, an ability to easily oxidize or reduce as well as sufficient photochemical stability are basic prerequisites to make these molecules desirable candidates for photoredox catalysis. Considering the similarity of requirements between organic electronics and photopolymerization, numerous materials initially designed for applications in organic electronics have been revisited in the context of photopolymerization. Organic electronics is a branch of electronics and materials science focusing on the development of semiconductors devoted to three main research fields; organic light-emitting diodes (OLEDs), organic field-effect transistors (OFETs), and organic solar cells (OSCs). The contribution of organic electronics to the field of electronics is important as it paves the way toward cheaper, lighter, and more energy efficient devices. In the present context of photopolymerization, materials that were investigated as photocatalysts were indifferently organic semiconductors used for transistors, charge-transport materials, and light-emitting materials used in electroluminescent devices or conjugated polymers and small molecule dyes for solar cells. In this Account, we summarize our latest developments in elaborating on photocatalytic systems based on these new classes of compounds. Through an in-depth understanding of the parameters governing their reactivities and our efforts to incorporate these materials into photoinitiating systems, we provide new knowledge and a valuable insight for future prospects.
microRNAs (miRNAs) are a broad group of endogenous small non-coding molecules that reduce the transcription of mRNA and play a key role in post-transcriptional gene processes. miRNAs are involved in onset and progression of several human disorders such as infectious and immune non-infectious diseases, cancers, metabolic and cardiovascular disorders. They regulate the expression of gene targets (e.g. oncogenes and tumor suppressor genes) and act as gene repressors with mRNA binding and cleavage. The increasing evidence that miRNAs play a key role in the pathogenesis of cardiovascular conditions
 could radically change the future management approach to these disorders. This review focuses on current knowledge about the influence of miRNAs on cardiovascular disease, with particular regard to common conditions such as atherosclerosis, diabetes and migraine. Key messages miRNAs are a group of endogenous small non-coding RNA segments measuring 19-25 nucleotides that are involved in physiologic processes and onset and progression of disorders such as infectious and immune non-infectious diseases, cancers, metabolic and cardiovascular disorders. miRNAs expression guarantees vascular integrity, by regulating apoptosis, VEGF pathway and VCAM 1 expression (-126), and is involved in atherosclerotic plaque formation process and progression. Hyperglycemia, overt diabetes, and their complications are associated with overexpression of several miRNAs. An altered expression of miRNAs has also been postulated in migraine patients, although only a few preliminary studies have so far been performed with this respect.
During early September 2014, the Arkansas Department of Health identified an increased number of tuberculosis (TB) cases among a unique population in a well-circumscribed geographical area in northwest Arkansas. The Compact of Free Association Act of 1985 (Public Law 99-239, amended in 2003 by Public Law 108-188) established the Republic of the Marshall Islands (RMI) as an independent nation, and persons from the RMI can travel freely (with valid RMI passport) to and from the United States as nonimmigrants without visas (1). Marshallese started settling in northwest Arkansas during the early 1990s because of employment and educational opportunities (2). According to the 2010 Census, an estimated 4,300 Marshallese resided in Arkansas (2), mostly within one county which ranked 6th in the United States for counties with the highest percentage of Native Hawaiians and Other Pacific Islanders (3). It is estimated that this number has been growing steadily each year since the 2010 Census; however, obtaining an accurate count is difficult. The RMI is a TB high-incidence country, with a case-rate of 212.7 per 100,000 persons for 2014, whereas the case-rate was 3.1 per 100,000 persons in Arkansas and 2.9 per 100,000 persons in the United States (4,5). Screening for either active TB or latent TB infection (LTBI) is not required for Marshallese entry to the United States (1).
To understand how cells form tissues, we need to understand how the tyrosine kinases are involved in controlling cell mechanics, whether they act directly as parts of mechanosensing machines or indirectly. Cells test the critical parameter of matrix rigidity by locally contracting ("pinching") matrices and measuring forces, and the depletion of contractile units causes transformation. We report here that knocking down the receptor tyrosine kinases (RTKs), AXL, and ROR2, alters rigidity sensing and increases the magnitude or duration of local contraction events, respectively. Phospho-AXL and ROR2 localize to contraction units and bind major contractile components, tropomyosin 2.1 (AXL), myosin IIA (AXL), and filamin A (ROR2). At a molecular level, phosphorylated AXL localizes to active myosin filaments and phosphorylates tropomyosin at a tyrosine critical for adhesion formation. ROR2 binding of ligand is unnecessary, but binding filamin A helps function. Thus, AXL and ROR2 alter rigidity sensing and consequently morphogenic processes by directly controlling local mechanosensory contractions without ligands.
Inpatient falls (IF) are the most commonly reported safety incidents. The high rate of inpatient falls was reported in a newly built hospital, within Aneurin Bevan University Health Board, Wales (UK). The aim of the project is to reduce the incidence of IF and associated adverse clinical outcomes in a hospital with 100% single rooms. The key mechanism for improvement was education and training of nursing staff around falls risk factors. A Plan-Do-Study-Act methodology was used and a geriatrician-led, systematic nurse training programme on the understanding and correct use of existing multifactorial falls risk assessment (FRA) tool was implemented in April 2013. Pre-training baseline data revealed inadequate falls assessment and low completion rates of the FRA tool. Subsequent, post-training data showed improvement in compliance with all aspects of FRA. Concurrent with nurse training, the actual falls incidence/1000 patient-bed-days fell significantly from the baseline of 18.19±3.46 (Nov 2011-March 2013) to 13.36±2.89 (p<0.001) over next 12 months (April 2013-March 2014) and remained low (mean falls 12.81±2.85) until November 2015. Improved clinical outcomes have been observed in terms of a reduction of length of stay and new care home placements, making total annualised savings of £642,055.
Standardization of Inflammatory Bowel Disease (IBD) care through participation in the ImproveCareNow (ICN) Network has improved outcomes for pediatric patients with IBD, but under the current care model, our improvements have plateaued. Current ICN model care guidelines recommend health supervision visits every six months. We identified a gap in our practice's ability to ensure either a routine six month follow-up or a rapid follow-up after a disease flare, and a significant number of patients with active disease status during a six month period lacked timely reassessment after interventions or medication changes. Telemedicine provides an alternative method of care delivery to address these gaps, but has had limited use in patients with IBD. A multi-step approach to offer alternative follow-up care options via telemedicine was developed with potential impact on remission rates and quality of life. Short term goals of the pilot were to improve telemedicine access for patients with IBD were to 1) increase the percent of patients with active disease with a follow-up completed within two months of a visit from 40% to 70%, 2) increase the percent of patients with a visit scheduled within two months of their last sick visit from 20% to 70% (interim measure), 3) increase the number of eVisits from zero visits per month to two visits per month during pilot phase, 4) increase electronic communication with patients from zero messages per month to 200 messages per month, 5) no change in complications or adverse events (defined as an unplanned visit or ED (emergency department) encounter within 30 days of an eVisit. The expected outcomes of the e-visit model were to: maintain baseline care standards and health screening capabilities, improve access to care, and provide equivalent care delivery (no increase in the number of unplanned clinical encounters). Using the IHI model for improvement (Plan-Do-Study-Act) we have seen a progressive increase in the rate of patient signups for the electronic medical record patient portal, with a baseline median of 20% per clinic compared with a current median of approximately 70% after six months. We successfully implemented e-messaging in its pilot form among five providers and have seen steady uptake in patient use from 5 patient initiated messages during the first month to 76 messages/month over the past three months. E-visits have replaced a total of 32 visits to date. Medications, nutrition, and disease activity were appropriately screened and managed electronically without the need for a physical office visit by the treating gastroenterologist. Access to care was improved in that all patients completed their e-visits from their homes without missing school or work and did not require a physical office visit. One visit successfully identified worsening of the patient's clinical course and resulted in a scheduled office visit request, but no unplanned office visits or ED visits have occurred. This report represents the first description of telemedicine use in routine clinical care in children with IBD. We anticipate continuing use of this novel mode of health care delivery in pediatrics in an effort to increase the proportion of patients seen for interval follow-up, after IBD diagnosis, or mild flare in an effort to target early treatment changes that should result in improved remission and patient reported outcomes. E-visits are less expensive and time consuming than traditional visits and may serve as an additional method of cost savings by matching care to a patient's individual needs.
Inflammatory Bowel Disease (IBD) is a chronic autoimmune inflammatory disease of the intestine which can lead to malnutrition, poor quality of life, and colon cancer.(1-4) Although there is no cure for the disease, clinical remission is the primary goal.(5) The Center for Inflammatory Bowel Disease at MassGeneral Hospital for Children (MGHfC) adopted a Previsit Planning (PVP) model to identify and discuss symptomatic patients prior to their appointments to identify specific issues that impact disease management.(6-8) The Registry from ImproveCareNow (ICN), the international Quality Improvement Collaborative for the management of Crohn's Disease and Ulcerative Colitis in pediatric and adolescent patients, was used to capture information from each ambulatory visit and hospitalization. Using the Model for Improvement framework, the team began a weekly review and made care recommendations of patients with active disease who were cared for by one physician. Interventions were modified over multiple Plan-Do-Study-Act (PDSA) improvement cycles to increase the number of providers and to include patients with mild or moderate disease activity.(9) Feedback from the providers regarding this process was elicited via a REDCap survey and the clinical remission rate was tracked using the ICN Registry. The clinical remission rate for the Center's patients increased from 77% (n=597) in September 2014 to 83% (n=585) in August 2015 and has been maintained. 78% of responding
 providers indicated that they found the PVP recommendations helpful "all of the time". One hundred percent who responded to the survey said that they have used at least one recommendation provided to them. PVP for management of a chronic disease in pediatrics is feasible, even in a high volume practice. This process at MGHfC has resulted in the improvement of clinical remission rate. PDSA cycles were used to document successes and failures to help guide the work. Ongoing expansion of this PVP practice to all providers continues with the anticipation of including input from patients and their families, as well.
Selective estrogen receptor modulators (SERMs) are now being used as a treatment for breast cancer, osteoporosis and postmenopausal symptoms, as these drugs have features that can act as an estrogen agonist and an antagonist, depending on the target tissue. After tamoxifen, raloxifene, lasofoxifene and bazedoxifene SERMs have been developed and used for treatment. The clinically decisive difference among these drugs (i.e., the key difference) is their endometrial safety. Compared to bisphosphonate drug formulations for osteoporosis, SERMs are to be used primarily in postmenopausal women of younger age and are particularly recommended if there is a family history of invasive breast cancer, as their use greatly reduces the incidence of this type of cancer in women. Among the above mentioned SERMs, raloxifene has been widely used in prevention and treatment of postmenopausal osteoporosis and vertebral compression fractures, and clinical studies are now underway to test the comparative advantages of raloxifene with those of bazedoxifene, a more recently developed SERM. Research on a number of adverse side effects of SERM agents is being performed to determine the long-term safety of this class of compouds for treatment of osteoporosis.
Reproductive functions may be altered by the exposure to a multitude of endogenous and exogenous agents, drug or environmental pollutants, which are known to affect gene transcription through the peroxisome proliferator-activated receptors (PPARs) activation. PPARs act as ligand activated transcription factors and regulate metabolic processes such as lipid and glucose metabolism, energy homeostasis, inflammation, and cell proliferation and differentiation. All PPARs isotypes are expressed along the hypothalamic-pituitary-gonadal axis and are strictly involved in reproductive functions. Since female fertility and energy metabolism are tightly interconnected, the research on female infertility points towards the exploration of potential PPARs activating/antagonizing compounds, mainly belonging to the class of thiazolidinediones (TZDs) and fibrates, as useful agents for the maintenance of metabolic homeostasis in women with ovarian dysfunctions. In the present review, we discuss the recent evidence about PPARs expression in the hypothalamic-pituitary-gonadal axis and their involvement in female reproduction. Finally, the therapeutic potential of their manipulation through several drugs is also discussed.
Narcolepsy with cataplexy is a rare, but important differential diagnosis for daytime sleepiness and atonic paroxysms in an adolescent. A recent increase in incidence in the pediatric age group probably linked to the use of the Pandemrix influenza vaccine in 2009, has increased awareness that different environmental factors can "trigger" narcolepsy with cataplexy in a genetically susceptible population. Here, we describe the case of a 13-year-old boy with narcolepsy following yellow fever vaccination. He carries the HLA DQB1*0602 haplotype strongly associated with narcolepsy and cataplexy. Polysomnography showed rapid sleep onset with rapid eye movement (REM) latency of 47 min, significant sleep fragmentation and a mean sleep latency of 1.6 min with sleep onset REM in four out of four nap periods. Together with the clinical history, these findings are diagnostic of narcolepsy type 1. The envelope protein E of the yellow fever vaccine strain 17D has significant amino acid sequence overlap with both hypocretin and the hypocretin receptor 2 receptors in protein regions that are predicted to act as epitopes for antibody production. These findings raise the question whether the yellow fever vaccine strain may, through a potential molecular mimicry mechanism, be another infectious trigger for this neuro-immunological disorder.
Dominance solvability is one of the most straightforward solution concepts in game theory. It is based on two principles: dominance (according to which players always use their dominant strategy) and iterated dominance (according to which players always act as if others apply the principle of dominance). However, existing experimental evidence questions the empirical accuracy of dominance solvability. In this study, we study the relationships between the key facets of dominance solvability and two cognitive skills, cognitive reflection, and fluid intelligence. We provide evidence that the behaviors in accordance with dominance and one-step iterated dominance are both predicted by one's fluid intelligence rather than cognitive reflection. Individual cognitive skills, however, only explain a small fraction of the observed failure of dominance solvability. The accuracy of theoretical predictions on strategic decision making thus not only depends on individual cognitive characteristics, but also, perhaps more importantly, on the decision making environment itself.
People can speak, and this provides opportunities to analyze human emotions using perceived experiences communicated via language, as well as through measurement and imaging techniques that are also applicable to other higher animal species. Here I compare four qualitative methodological approaches to test if, and how, thrill depends on fear. I use eight high-risk, high-skill, real-life outdoor adventure recreation activities to provide the test circumstances. I present data from: >4000 person-days of participant observation; interviews with 40 expert practitioners; retrospective autoethnography of 50 critical incidents over 4 decades; and experimental autoethnography of 60 events. Results from different methods are congruent, but different approaches yield different insights. The principal findings are as follows. Individuals differ in their fear and thrill responses. The same individual may have different responses on different occasions. Fear boosts performance, but panic causes paralysis. Anxiety or apprehension prior to a risky action or event differs from fear experienced during the event itself. The intensity of pre-event fear generally increases with the immediacy of risk to life, and time to contemplate that risk. Fear must be faced, assessed and overcome in order to act. Thrill can occur either during or after a high-risk event. Thrill can occur without fear, and fear without thrill. Below a lower threshold of perceived risk, thrill can occur without fear. Between a lower and upper threshold, thrill increases with fear. Beyond the upper threshold, thrill vanishes but fear remains. This there is a sawtooth relation between fear and thrill. Perceived danger generates intense focus and awareness. Fear and other emotions can disappear during intense concentration and focus. Under high risk, the usual emotional sequence is fear before the action or event, then focus during the action or event, then thrill, relief, or triumph afterward. The emotionless state persists only during the most intense concentration. For events long enough to differentiate time within the events, fear and thrill can arise and fade in different fine-scale sequences.
The prevalence of metabolic syndrome, a clustering of three or more risk factors that include abdominal obesity, increased blood pressure, and high levels of glucose, triglycerides, and high-density lipoproteins, has reached dangerous and costly levels worldwide. Increases in morbidity and mortality result from a combination of factors that promote altered glucose metabolism, insulin resistance, and metabolic dysfunction. Although diet and exercise are commonly touted as important determinants in the development of metabolic dysfunction, other environmental factors, including circadian clock disruption and activation of the aryl hydrocarbon receptor (AhR) by dietary or other environmental sources, must also be considered. AhR binds a range of ligands, which prompts protein-protein interactions with other Per-Arnt-Sim (PAS)-domain-containing proteins and subsequent transcriptional activity. This review focuses on the reciprocal crosstalk between the activated AhR and the molecular circadian clock. AhR exhibits a rhythmic expression and time-dependent sensitivity to activation by AhR agonists. Conversely, AhR activation influences the amplitude and phase of expression of circadian clock genes, hormones, and the behavioral responses of the clock system to changes in environmental illumination. Both the clock and AhR status and activation play significant and underappreciated roles in metabolic homeostasis. This review highlights the state of knowledge regarding how AhR may act together with the circadian clock to influence energy metabolism. Understanding the variety of AhR-dependent mechanisms, including its interactions with the circadian timing system that promote metabolic dysfunction, reveals new targets of interest for maintenance of healthy metabolism.
The pain associated with cancer is highly detrimental to the quality of life of the affected individuals. It also contributes to the anxiety of the patient. There is a need for a nonpharmacological approach in addition to the pharmacological therapy for the management of the pain for a more holistic improvement in the individual. With this study, we wish to achieve this through music.
To assess the effect of music
 therapy on pain scores and anxiety levels of cancer patients with pain.
In this quantitative study, a comparative study was done on fourteen cancer patients admitted for pain relief under the Department of Pain and Palliative Medicine, of a tertiary care hospital, having moderate to severe pain (numerical pain rating scale [NRS] - of 4 to 10).
Convenience sampling was used. Patients were allocated to test group or control group nonrandomly. The test group patients were subjected to music therapy for 20 min while the control group patients were kept occupied by talking to them for 20 min. The NRS scale was used to assess the pre- and post-interventional pain scores and the Hamilton anxiety rating scale was used to assess the pre- and post-interventional anxiety scores in the two groups.
Student's t-test was used for comparing the pre- and post-interventional data. Two sample t-test was used to compare the data obtained from the control and study groups.
Statistically significant reduction seen in the pain scores in the test group after music therapy (P = 0.003). No statistically significant reduction seen in the pain score in the control group (P = 0.356). There was a statistically significant reduction in the postintervention pain scores in the test group compared to the control group (P = 0.034). The reduction in anxiety levels in both groups after intervention was not statistically significant.
Music therapy was found to lower the pain score of a patient who had received standard palliative care for pain reduction. It was also more effective than the act of talking in reducing the pain score. A study with a larger sample size should be undertaken to conclude that, music therapy can be used in addition to morphine and other painkillers to reduce pain as a part of a more holistic approach to palliative care strategies.
NMDA receptors are ligand-gated ion channels that underlie transmission at excitatory synapses and play an important role in regulating synaptic strength and stability. Functional NMDA receptors require two copies of the GluN1 subunit coassembled with GluN2 (and/or GluN3) subunits into a heteromeric tetramer. A diverse array of allosteric modulators can upregulate or downregulate NMDA receptor activity. These modulators include both synthetic compounds and endogenous modulators, such as cis-unsaturated fatty acids, 24(S)-hydroxycholesterol, and various neurosteroids. To evaluate the structural requirements for the formation and allosteric modulation of NMDA receptor pores, we have replaced portions of the rat GluN1, GluN2A, and GluN2B subunits with homologous segments from the rat GluK2 kainate receptor subunit. Our results with these chimeric constructs show that the NMDA receptor transmembrane domain is sufficient to account for most pore properties, but that regulation by some allosteric modulators requires additional cytoplasmic or extracellular domains.
Glutamate receptors mediate excitatory synaptic transmission by forming cation channels through the membrane that open upon glutamate binding. Although many compounds have been identified that regulate glutamate receptor activity, in most cases the detailed mechanisms that underlie modulation are poorly understood. To identify what parts of the receptor are essential for pore formation and sensitivity to allosteric modulators, we generated chimeric subunits that combined segments from NMDA and kainate receptors, subtypes with distinct pharmacological profiles. Surprisingly, our results identify separate domain requirements for allosteric potentiation of NMDA receptor pores by pregnenolone sulfate, 24(S)-hydroxycholesterol, and docosahexaenoic acid, three endogenous modulators derived from membrane constituents. Understanding where and how these compounds act on NMDA receptors should aid in designing better therapeutic agents.
The spatial and temporal control of microtubule dynamics is fundamentally important for proper spindle assembly and chromosome segregation. This is achieved, in part, by the multitude of proteins that bind to and regulate spindle microtubules, including kinesin superfamily members, which act as microtubule-destabilizing enzymes. These fall into two general classes: the kinesin-13 proteins, which directly depolymerize microtubules, and the kinesin-8 proteins, which are plus end-directed motors that either destabilize microtubules or cap the microtubule plus ends. Here we analyze the contribution of a PtK kinesin-8 protein, Kif18B, in the control of mitotic microtubule dynamics. Knockdown of Kif18B causes defects in spindle microtubule organization and a dramatic increase in astral microtubules. Kif18B-knockdown cells had defects in chromosome alignment, but there were no defects in chromosome segregation. The long astral microtubules that occur in the absence of Kif18B are limited in length by the cell cortex. Using EB1 tracking, we show that Kif18B activity is spatially controlled, as loss of Kif18B has the most dramatic effect on the lifetimes of astral microtubules that extend toward the cell cortex. Together our studies provide new insight into how diverse kinesins contribute to spatial microtubule organization in the spindle.
Microtubule dynamics is regulated by plus end-tracking proteins (+TIPs), which localize to the plus ends of microtubules (MTs). We previously showed that TACC1 and TACC3, members of the transforming acidic coiled-coil protein family, can act as +TIPs to regulate MT dynamics in Xenopus laevis Here we characterize TACC2 as a +TIP that localizes to MT plus ends in front of EB1 and overlapping with TACC1 and TACC3 in multiple embryonic cell types. We also show that TACC2 can promote MT polymerization in mesenchymal cells but not neuronal growth cones, thus displaying cell-type specificity. Structure-function analysis demonstrates that the C-terminal region of TACC2 is both necessary and sufficient to localize to MT plus ends and promote increased rates of MT polymerization, whereas the N-terminal region cannot bind to MT plus ends but can act in a dominant-negative capacity to reduce polymerization rates. Finally, we analyze mRNA expression patterns in Xenopus embryos for each TACC protein and observe neural enrichment of TACC3 expression compared with TACC1 and TACC2, which are also expressed in mesodermal tissues, including somites. Overall these data provide a novel assessment of all three TACC proteins as a family of +TIPs by highlighting the unique attributes of each, as well as their collective characteristics.
Individuals who are deaf and hard-of-hearing (DHH) are underrepresented in science, technology, engineering, and mathematics (STEM) professions, and this may be due in part to their level of preparation in the development and retention of mathematical and problem-solving skills. An approach was developed that incorporates experiential learning and best practices of STEM instruction to give first-year DHH students enrolled in a postsecondary STEM program the opportunity to develop problem-solving skills in real-world scenarios. Using an industrial engineering laboratory that provides manufacturing and warehousing environments, students were immersed in real-world scenarios in which they worked on teams to address prescribed problems encountered during the activities. The highly structured, Plan-Do-Check-Act approach commonly used in industry was adapted for the DHH student participants to document and communicate the problem-solving steps. Students who experienced the intervention realized a 14.6% improvement in problem-solving proficiency compared with a control group, and this gain was retained at 6 and 12 months, post-intervention.
Despite a long-standing debate about the utility of species-centered conservation approaches (Roberge & Angelstam 2004), surrogate species remain popular by providing useful-or even necessary-"shortcuts" for successful conservation programs (Caro 2010). Flagship species, as one prime example of surrogates, are primarily intended to promote public awareness and to raise funds for conservation (Veríssimo et al. 2011). In contrast, the protection of umbrella species is expected to benefit a wide range of co-occurring species (Roberge & Angelstam 2004; Caro 2010). Accordingly, the main criteria for selecting flagships should be based on socio-cultural considerations, whereas umbrellas are principally chosen based on ecological criteria (Caro 2010; Veríssimo et al. 2011; see Table 1). Since these two concepts are often confused or mistakenly used interchangeably, Caro (2010, p. 248) coined the term "flagship umbrellas" for those species that explicitly integrate both functions. Indeed, Li and Pimm (2016) recently demonstrated that the classic flagship species, the giant panda (Ailuropoda melanoleuca), can simultaneously act as an umbrella species, as its protection benefits many co-occurring endemic mammals, birds and amphibians. This challenges the often held views that: (i) the umbrella concept has to be abandoned as it is not efficiently working at local scales (Caro 2015); (ii) most flagship species are weak predictors for efficient reserve planning (Caro 2010); and (iii) ecosystem- or landscape-based conservation approaches should consequentially be favored over species-based approaches whenever feasible (Roberge & Angelstam 2004; Caro 2010). Further commotion in the discussion is the increasingly demanded paradigm shift in conservation strategies to specifically target hidden or neglected biodiversity for its intrinsic value and its contribution to ecosystem processes (Dougherty et al. 2016). This article is protected by copyright. All rights reserved.
The need for effective interventions to improve mental health and emotional well-being at a population level are gaining prominence both in the United Kingdom and globally. Advances in technology and widespread
 adoption of Internet capable devices have facilitated rapid development of Web-delivered psychological therapies. Interventions designed to manage a range of affective disorders by applying diverse therapeutic approaches are widely available.
The main aim of this review was to evaluate the evidence base of acceptance and commitment therapy (ACT) in a Web-based delivery format.
A systematic review of the literature and meta-analysis was conducted. Two electronic databases were searched for Web-delivered interventions utilizing ACT for the management of affective disorders or well-being. Only Randomized Controlled Trials (RCTs) were included.
The search strategy identified 59 articles. Of these, 10 articles met the inclusion criteria specified. The range of conditions and outcome measures that were identified limited the ability to draw firm conclusions about the efficacy of Web-delivered ACT-based intervention for anxiety or well-being.
ACT in a Web-based delivery format was found to be effective in the management of depression. Rates of adherence to study protocols and completion were high overall suggesting that this therapeutic approach is highly acceptable for patients and the general public.
Macrophages are key players involved in numerous pathophysiological pathways and an in-depth characterization of their gene regulatory networks can help in better understanding how their dysfunction may impact on human diseases. We here conducted a cross-species network analysis of macrophage gene expression data between human and mouse to identify conserved networks across both species, and assessed whether such networks could reveal new disease-associated regulatory mechanisms. From a sample of 684 individuals processed for genome-wide macrophage gene expression profiling, we identified 27 groups of coexpressed genes (modules). Six modules were found preserved (P < 10(-4)) in macrophages from 86 mice of the Hybrid Mouse Diversity Panel. One of these modules was significantly [false discovery rate (FDR) = 8.9 × 10(-11)] enriched for genes belonging to the oxidative phosphorylation (OXPHOS) pathway. This pathway was also found significantly (FDR < 10(-4)) enriched in susceptibility genes for Alzheimer, Parkinson, and Huntington diseases. We further conducted an expression quantitative trait loci analysis to identify SNP that could regulate macrophage OXPHOS gene expression in humans. This analysis identified the PARK2 rs192804963 as a trans-acting variant influencing (minimal P-value = 4.3 × 10(-8)) the expression of most OXPHOS genes in humans. Further experimental work demonstrated that PARK2 knockdown expression was associated with increased OXPHOS gene expression in THP1 human macrophages. This work provided strong new evidence that PARK2 participates to the regulatory networks associated with oxidative phosphorylation and suggested that PARK2 genetic variations could act as a trans regulator of OXPHOS gene macrophage expression in humans.
Binge eating is characterized by repeated intermittent bouts of compulsive overconsumption of food. Treatment is challenging given limited understanding of the mechanisms underlying this type of disordered eating. The hypothesis that dysregulation of mesocortical dopaminergic and GABAergic systems underlie binge eating was tested.
Analysis of gene expression within the ventral tegmental area and its terminal mesocortical regions was examined in bingeing rats before and after bingeing occurred. In addition, alterations in binge-type behavior induced by pharmacological inactivation of subnuclei of the prefrontal cortex (PFC) and by pharmacological activation and inhibition of cortical D1 and D2 receptors were examined.
Correlative and functional evidence demonstrates dysregulated neurotransmitter processing by the PFC and ventral tegmental area, but not the amygdala or nucleus accumbens, in bingeing rats. Either GABAergic inactivation or D2-like receptor activation within the PFC increased consumption in bingeing rats, but not controls, suggesting that the PFC, and D2 receptors in particular, functions as a behavioral brake to limit bingeing.
The act of bingeing resolved some gene expression differences that preceded binge onset, further suggesting that bingeing may partially serve to self-medicate a system driving this maladaptive behavior. However, the failure of bingeing to resolve other dopaminergic/GABAergic differences may render individuals vulnerable to future binge episodes.
Activated immune cell populations contribute to hypertension in part through inciting damage to the kidney and by provoking inappropriate sodium reabsorption in the nephron. Inflammatory mediators called cytokines produced by T lymphocytes and macrophages act on specific sodium transporters in the kidney, augmenting their activity or expression, with consequent expansion of intravascular fluid volume and cardiac output. The overlapping functions of these cytokines, each of which may activate multiple receptors, present challenges in precisely targeting inflammatory signaling cascades in hypertension. Moreover, broad immune suppression could expose the hypertensive patient to disproportional risks of infection or malignancy. Nevertheless, the possibility that incisive immunomodulatory therapies could provide cardiovascular and renal protection through both blood pressure-dependent and -independent mechanisms justifies comprehensive investigation into the relevant signaling pathways and tissue sites in which inflammatory cytokines function to exaggerate blood pressure elevation and target organ damage in hypertension.
We investigate the failure of bacterial floc mediated streamers in a microfluidic device in a creeping flow regime using both experimental observations and analytical modeling. The quantification of streamer deformation and failure behavior is possible due to the use of 200 nm fluorescent polystyrene beads which firmly embed in the extracellular polymeric substance (EPS) and act as tracers. The streamers, which form soon after the commencement of flow begin to deviate from an apparently quiescent fully formed state in spite of steady background flow and limited mass accretion indicating significant mechanical nonlinearity. This nonlinear behavior shows distinct phases of deformation with mutually different characteristic times and comes to an end with a distinct localized failure of the streamer far from the walls. We investigate this deformation and failure behavior for two separate bacterial strains and develop a simplified but nonlinear analytical model describing the experimentally observed instability phenomena assuming a necking route to instability. Our model leads to a power law relation between the critical strain at failure and the fluid velocity scale exhibiting excellent qualitative and quantitative agreeing with the experimental rupture behavior.
Negative feedback in combination with time delay can bring about both sustained oscillations and adaptive behaviour in cellular networks. Here, we study which design features of systems with delayed negative feedback shape characteristic response patterns with special emphasis on the role of time delay. To this end, we analyse generic two-dimensional delay differential equations describing the dynamics of biochemical signal-response networks.
We investigate the influence of several design features on the stability of the model equilibrium, i.e., presence of auto-inhibition and/or mass conservation and the kind and/or strength of the delayed negative feedback. We show that auto-inhibition and mass conservation have a stabilizing effect, whereas increasing abruptness and decreasing feedback threshold have a de-stabilizing effect on the model equilibrium. Moreover, applying our theoretical analysis to the mammalian p53 system we show that an auto-inhibitory feedback can decouple period and amplitude of an oscillatory response, whereas the delayed feedback can not.
Our theoretical framework provides insight into how time delay and design features of biochemical networks act together to elicit specific characteristic response patterns. Such insight is useful for constructing synthetic networks and controlling their behaviour in response to external stimulation.
Melanoma patients treated with oncogenic BRAF inhibitors can develop cutaneous squamous cell carcinoma (cSCC) within weeks of treatment, driven by paradoxical RAS/RAF/MAPK pathway activation. Here we identify frequent TGFBR1 and TGFBR2 mutations in human vemurafenib-induced skin lesions and in sporadic cSCC. Functional analysis reveals these mutations ablate canonical TGFβ Smad signalling, which is localized to bulge stem cells in both normal human and murine skin. MAPK pathway hyperactivation (through Braf(V600E) or Kras(G12D) knockin) and TGFβ signalling ablation (through Tgfbr1 deletion) in LGR5(+ve) stem cells enables rapid cSCC development in the mouse. Mutation of Tp53 (which is commonly mutated in sporadic cSCC) coupled with Tgfbr1 deletion in LGR5(+ve) cells also results in cSCC development. These findings indicate that LGR5(+ve) stem cells may act as cells of origin for cSCC, and that RAS/RAF/MAPK pathway hyperactivation or Tp53 mutation, coupled with loss of TGFβ signalling, are driving events of skin tumorigenesis.
Evolution-in-materio concerns the computer controlled manipulation of material systems using external stimuli to train or evolve the material to perform a useful function. In this paper we demonstrate the evolution of a disordered composite material, using voltages as the external stimuli, into a form where a simple computational problem can be solved. The material consists of single-walled carbon nanotubes suspended in liquid crystal; the nanotubes act as a conductive network, with the liquid crystal providing a host medium to allow the conductive network to reorganise
 when voltages are applied. We show that the application of electric fields under computer control results in a significant change in the material morphology, favouring the solution to a classification task.
Francisella tularensis in an intracellular bacterial pathogen that causes a potentially lethal disease called tularemia. Studies performed nearly 100 years ago revealed that neutrophil accumulation in infected tissues correlates directly with the extent of necrotic damage during F. tularensis infection. However, the dynamics and details of bacteria-neutrophil interactions have only recently been studied in detail. Herein, we review current understanding regarding the mechanisms that recruit neutrophils to F. tularensis-infected lungs, opsonization and phagocytosis, evasion and inhibition of neutrophil defense mechanisms, as well as the ability of F. tularensis to prolong neutrophil lifespan. In addition, we discuss distinctive features of the bacterium, including its ability to act at a distance to alter overall neutrophil responsiveness to exogenous stimuli, and the evidence which suggests that macrophages and neutrophils play distinct roles in tularemia pathogenesis, such that macrophages are major vehicles for intracellular growth and dissemination, whereas neutrophils drive tissue destruction by dysregulation of the inflammatory response.
The Mental Health Act 2007 (NSW) (MHA) was recently reformed in light of the recovery movement and the United Nations Convention on the Rights of Persons with Disabilities. We analyse the changes and describe the impact that these reforms should have upon clinical practice.
The principles of care and treatment added to the MHA place a strong onus on clinicians to monitor patients' decision-making capacity, institute a supported decision-making model and obtain consent to any treatment proposed. Patients competently refusing treatment should only be subject to involuntary treatment in extraordinary circumstances. Even when patients incompetently refuse treatment, clinicians must make every effort reasonably practicable to tailor management plans to take account of any views and preferences expressed by them or made known via friends, family or advance statements.
It is an emerging focus to develop a simple and straightforward strategy to synthesize multifunctional nanomedicines for cancer imaging and treatment. In this work, a new carbon dot (named CyCD) with intrinsic theranostic properties was prepared from a hydrophobic cyanine dye [2-((E)-2-((E)-2-chloro-3-((E)-2-(1-(2-hydroxyethyl)-3,3-dimethylindolin-2-ylidene) ethylidene)cyclohex-1-en-1-yl)vinyl)-1-(2-hydroxyethyl)-3,3-dimethyl-3H-indol-1-ium iodide, CyOH] and poly(ethylene glycol) (PEG800) via a simple solvothermal process. The as-prepared CyCD is well dispersed in water media with an average diameter of 2.9 ± 0.5 nm; it possesses favorable hydrophilicity and excellent photostability. More importantly, the strong absorption and near-IR (NIR) emission within the range from 600 to 900 nm, along with preferential uptake at tumors and high photothermal conversion efficiency (η = 38.7%), facilitate CyCD to act as an ideal theranostic agent for NIR fluorescent imaging and photothermal therapy in vitro and in vivo. This work highlights theranostic CDs as an excellent candidate for efficient cancer imaging and therapy.
Prion diseases are fatal transmissible diseases, where conversion of the endogenous prion protein (PrP(C) ) into a misfolded isoform (PrP(Sc) ) leads to neurodegeneration. Microglia, the immune cells of the brain, are activated in neurodegenerative disorders including prion diseases; however, their impact on prion disease pathophysiology is unclear with both beneficial PrP(Sc) -clearing and detrimental potentially neurotoxic effects. Moreover, monocytes entering the brain from the periphery during disease course might add to disease pathophysiology. Here, the degree of microglia activation in the brain of prion infected mice with and without an additional intraperitoneal retrovirus infection was studied. Peripheral murine retrovirus infection leads to activation of parenchymal microglia without recruitment of monocytes. This activation correlated with transient clearance or delay in accumulation of infectious prions specifically from the brain at early time points in the diseases course. Microglia expression profiling showed upregulation of genes involved in protein degradation coinciding with prion clearance. This enforces a concept where microglia act beneficial in prion disease if adequately activated. Once microglia activation has ceased, prion disease reemerges leading to disease kinetics undistinguishable from the situation in prion-only infected mice. This might be caused by the loss of microglial homeostatic function at clinical prion disease.
Gliomas are the most common type of brain tumor and have a poor prognosis. MicroRNAs (miRNAs) are a class of small, endogenous, and non-coding RNAs that play crucial roles in cell proliferation, survival, and invasion. Deregulated expression of miR-206 has been investigated in many cancers. However, the role of miR-206 in glioblastoma is still unclear. In the present study, we found that the expression of miR-206 was decreased in cancer tissues compared with normal tissues. However, the expression level of BCL-2 was higher in cancer tissues than that in normal tissues (all p < 0.001). Statistically, the expression level of BCL-2 was inversely correlated with the miR-206. In addition, the overall survival of glioblastoma patients with lower miR-206 expression was significantly shorter than those with high miR-206 expression (p < 0.001). Besides, the expression of miR-206 was also decreased in U87 and U251 cells. In vitro assays showed that ectopic miR-206 expression affected the proliferation, cell cycle, and invasion in U87 and U251 cells. Importantly, we identified BCL-2 as a direct target of miR-206 in U87 and U251 cells using luciferase assay. Overexpression of BCL-2 partially attenuated the miR-206-mediated cell proliferation. In vivo, overexpression of miR-206 suppressed the progression of glioblastoma cells using mice xenograft model. In conclusion, this study suggested that miR-206 could act as a tumor suppressor gene through inhibiting BCL-2 in the development of glioblastoma.
To explore the experiences of individuals who have had a severe traumatic brain injury (TBI) and their carers in the first month post-discharge from in-patient rehabilitation into living in the community.
Using a qualitative approach underpinned by critical realism, we explored the narratives of 10 patients and nine carers using semi-structured interviews approximately one month post-discharge. Thematic analysis was carried out independently by two researchers.
Firstly, perceptions of support were mixed but many patients and carers felt unsupported in the inpatient phase, during transitions between units and when preparing for discharge. Secondly, they struggled to accept a new reality of changed abilities, loss of roles and loss of autonomy. Thirdly, early experiences post-discharge exacerbated fears for the future.
Most patients and carers struggled to identify a cohesive plan that supported their transition to living in the community. Access to services required much persistence on the part of carers and tended to be short-term, and therefore did not meet their long-term needs. We propose the need for a case manager to be involved at an early stage of their rehabilitation and act as a key point for information and access to on-going rehabilitation and other support services. Implications for Rehabilitation Traumatic Brain Injury (TBI) is a major cause of long-term disability. It can affect all areas of daily life and significantly reduce quality of life for both patient and carer. Professionals appear to underestimate the change in abilities and impact on daily life once patients return home. Community services maintain a short-term focus, whereas patients and carers want to look further ahead - this dissonance adds to anxiety. The study's findings on service fragmentation indicate an urgent need for better integration within health services and across health, social care and voluntary sectors. A link person/case manager who oversees the patient journey from admission onwards would help improve integrated care and ensure the patient, and carer, are at the center of service provision.
Acetaminophen (ACT) is one of the most frequently detected pharmaceuticals in aqueous environments, and treatment of ACT were generally carried out by photocatalytic degradations under high energy UV irradiation. In this study, potassium ferricyanide was utilized as a quadruple-elemental dopant in a TiO2 photocatalyst in order to enhance its visible-light activity. Two critical parameters (amounts of dopants and durations of calcination) of the synthesis of the photocatalyst by a sol-gel method were systematically evaluated. Crystal structure of the doping TiO2 was examined by X-ray diffraction while the effects of the two parameters on the photocatalytic activity were elucidated by various characterizations. Increasing the amount of dopant or the duration of calcination red-shifted the UV-vis DRS of the doped TiO2. The estimated band gap energy of the doped TiO2 decreased slightly as the amount of dopant increased, but it increased as the duration of calcination increased. The FT-IR yielded characteristic peaks that revealed the effects of the two parameters, whereas the SEM images revealed the morphological evolutions of each effect. The photocatalyst, synthesized at optimum conditions was able to remove 99.1 % acetaminophen with rate constant of 7.9 × 10(-3) min(-1), which was 4.88 times greater than virgin TiO2. In general, this study not only optimized synthetic conditions of the new visible-light
 active photocatalyst for ACT degradation but also presented characterizations conducted by SEM, XRD, UV-vis DRS, and FTIR to elucidate the relationship between modified structure and the photocatalytic activity. Graphical abstract Effects of doping amounts of K3[Fe(CN)6] and calcunation duration on visible light absorbance of TiO2 photocatalysts.
MicroRNAs (miRNAs) are short non-coding RNAs that act as important regulators of gene expression as part of the epigenetic machinery. In addition to posttranscriptional gene silencing by miRNAs, the epigenetic mechanisms also include DNA methylation, histone modifications and their crosstalk. Epigenetic modifications were reported to play an important role in many disease onsets and progressions and can be used to explain several features of complex diseases, such as late onset and fluctuation of symptoms. However, miRNAs not only function as a part of epigenetic machinery, but are also epigenetically modified by DNA methylation and histone modification like any other protein-coding gene. There is a strong connection between epigenome and miRNome, and any dysregulation of this complex system can result in various physiological and pathological conditions. In addition, miRNAs play an important role in toxicogenomics and may explain the relationship between toxicant exposure and tumorigenesis. The present review provides information on 63 miRNA genes shown to be epigenetically regulated in association with 21 diseases, including 11 cancer types: cardiac fibrosis, cardiovascular disease, preeclampsia, Hirschsprung's disease, rheumatoid arthritis, systemic sclerosis, systemic lupus erythematosus, temporal lobe epilepsy, autism, pulmonary fibrosis, melanoma, acute myeloid leukemia, chronic lymphocytic leukemia, colorectal, gastric, cervical, ovarian, prostate, lung, breast, and bladder cancer. The review revealed that hsa-miR-34a, hsa-miR-34b, and hsa-miR-34c are the most frequently reported epigenetically dysregulated miRNAs. There is a need to further study molecular mechanisms of various diseases to better understand the crosstalk between epigenetics and gene expression and to develop new therapeutic options and biomarkers.
Prohibitin (PHB) is overtly conserved evolutionarily and ubiquitously expressed protein with pleiotropic functions in diverse cellular compartments. However, regulation and function of these proteins in different cells, tissues and in various diseases is different as evidenced by expression of these proteins which is found to be reduced in heart diseases, kidney diseases, lung disease, Crohn's disease and ulcerative colitis but this protein is highly expressed in diverse cancer diseases. The mechanism by which this protein acts at the molecular level in different subcellular localizations or in different cells or tissues in different conditions (diseases or normal) has remained poorly understood. There are several studies reported to understand and decipher PHB's role in diseases and/or cancers of ovary, lung, stomach, thyroid, liver, blood, prostrate, gastric, esophagus, glioma, breast, bladder etc where PHB is shown to act through mechanisms by acting as oncogene, tumor suppressor, antioxidant, antiapoptotic, induction of angiogenesis, autophagy etc. Since cardiovascular disease (CVD) may lead to heart failure and disability worldwide, this review mainly focuses on the functional role and regulatory mechanism of PHB at the molecular level in CVD or impairments to understand and elucidate its direct/indirect involvement in cellular protection of cardiac cells/tissue or in disease progression.
Protein farnesyltransferase (PFT) inhibitors have emerged as a potent target for the malaria treatment caused by the Plasmodium falciparum (Pf) parasite. In this review, various scaffolds as Pf-PFT inhibitors are reported. Seven inhibitor scaffolds based on ethylenediamine, peptidomimetic, benzophenone, benzamide, tetrahydroquinoline, naphthyridine and oxy-tetrahydroquinoline, have been developed. These inhibitors act against Pf-PFT target and have proved their therapeutic potential as antimalarial agents. This review is primarily meant for suggesting new drugs against malaria.
The aim of this pilot study was to conduct a nontargeted exploratory proteomics profiling analysis on sera obtained from patients diagnosed with diffuse large B-cell lymphoma (DLBCL) with the goal of identifying disease-specific biomarkers.
Sera from 87 participants (57 chemotherapy-naïve diffuse DLBCL patients, 30 controls frequency-matched by age group and World Health Organization (WHO) BMI categories) that were part of a large San Francisco Bay Area case-control study of non-Hodgkin lymphoma were analyzed by liquid chromatography combined with tandem mass spectrometry.
Thirty-five proteins (p-adjusted <0.05) were identified as differentially abundant between the DLBCL patients at various disease stages as compared to the controls. Of these, five proteins were randomly selected for further confirmation by ELISA: adiponectin (AdipoQ), cluster of differentiation 14 (CD14), heparin sulfate proteoglycan core protein (HSPG2), extracellular matrix 1 (ECM1), and alpha-1-antichymotrypsin (ACT). These proteins were statistically significantly elevated by 68.8, 37.0, 61.6, 68.0, and 32.0%, respectively, in DLBCL patient sera as compared to controls.
These preliminary data when combined with other cancer-related data regarding these proteins warrant continued research in clinical and large prospective studies to clarify the role for these biomarkers in DLBCL pathogenesis and/or prognosis.
Two-thirds of the people with multiple sclerosis (pwMS) experience pain. Medications provide minimal relief, and current non-pharmacological interventions lack a clear conceptualization of MS pain. This study explored the potential efficacy of a telephone-supported hybrid cognitive behavior therapy and acceptance and commitment therapy self-management intervention for pwMS based on an empirically supported model of MS pain using a replicated single-case series design.
Seven pwMS with varied demographic and disease characteristics completed the 8-week home-based program alongside 3 hours of telephone support. Online questionnaires were completed every four days for 16 weeks (4-weeks baseline, 8-weeks treatment, 4-weeks follow-up). The primary outcomes were pain severity and pain interference. Psychological process variables drawn from the MS pain model were also completed, and post-treatment qualitative interviews conducted.
Simulation modeling analysis (SMA) showed three patients had large improvements in pain outcomes, two showed no change and two worsened. Five participants showed significant change on various psychological process variables. Change in pain catastrophizing was the most consistent finding.
The findings suggest a self-management program for MS pain with minimal therapy support may be effective for some pwMS, but not those with more complex comorbidities. The participants suggested web-based delivery may simplify the approach, and therapist telephone contact was highly valued. Implications for Rehabilitation This case series suggests a hybrid CBT/ACT self-management workbook program for MS pain improves severity and impact of pain in some pwMS. Pain-related catastrophizing reduced in most pwMS, whilst change in other ACT and CBT process variables varied across the individuals. PwMS feedback suggests a tailored web-based delivery of the program with therapist telephone support may be optimal. PwMS with serious co-morbid depression and very advanced disease may not respond well to this self-management approach.
Autotaxin (ATX; also known as ENPP2), the lysophospholipase responsible for generating the lipid receptor agonist lysophosphatidic acid (LPA), is a secreted enzyme. Here we show that, once secreted, ATX can bind to the surface of cell-secreted exosomes. Exosome-bound ATX is catalytically active and carries generated LPA. Once bound to a cell, through specific integrin interactions, ATX releases the LPA to activate cell surface G-protein-coupled receptors of LPA; inhibition of signalling by the receptor antagonist Ki1642 suggests that these receptors are LPAR1 and LPAR3. The binding stimulates downstream signalling, including phosphorylation of AKT and mitogen-activated protein kinases, the release of intracellular stored Ca(2+) and cell migration. We propose that exosomal binding of LPA-loaded ATX provides a means of efficiently delivering the lipid agonist to cell surface receptors to promote signalling. We further propose that this is a means by which ATX-LPA signalling operates physiologically.
Escitalopram is one of the most commonly prescribed selective serotonin reuptake inhibitors (SSRIs). It is thought to act by blocking the serotonin transporter (SERT). However, its dose-SERT occupancy relationship is not well known, so it is not clear what level of SERT blockade is achieved by currently approved doses.
To determine the dose-occupancy relationship, we measured serial SERT occupancy using [(11)C]DASB [3-amino-4-(2-dimethylaminomethylphenylsulfanyl)-benzonitrile] positron emission tomography (PET) and plasma drug concentrations after the administration of escitalopram in 12 healthy volunteers. We then built a pharmacokinetic-pharmacodynamic model to characterize the dose-occupancy relationship in the putamen and the dorsal raphe nucleus.
Escitalopram at approved doses occupied less SERT than expected and the SERT occupancy showed regional effects [occupancy was higher in the dorsal raphe nucleus than in the putamen (p < 0.001)]. The drug concentration when 50 % of receptors are occupied (EC50) value and Hill coefficient were significantly different between the putamen (EC50 4.30, Hill coefficient 0.459) and the dorsal raphe nucleus (EC50 2.89, Hill coefficient 0.817).
Higher doses of
 escitalopram than 20 mg are needed to achieve 80 % or greater SERT occupancy. Higher occupancy by escitalopram in the dorsal raphe nucleus relative to the striatum may explain the delayed onset of action of SSRIs by modulating autoreceptor function. The prevention of the 5-HT1A autoreceptor-mediated negative feedback could be a strategy for accelerating the clinical antidepressant effects.
Frequently observed phenotypes of tumours include high metabolic activity, hypoxia and poor perfusion; these act to produce an acidic microenvironment. Cellular function depends on pH homoeostasis, and thus, tumours become dependent on pH regulatory mechanisms. Many of the proteins involved in pH regulation are highly expressed in tumours, and their expression is often of prognostic significance. The more acidic tumour microenvironment also has important implications with regard to chemotherapeutic and radiotherapeutic interventions. In addition, we review pH-sensing mechanisms, the role of pH regulation in tumour phenotype and the use of pH regulatory mechanisms as therapeutic targets.
Lupins are important grain legume crops that form a critical part of sustainable farming systems, reducing fertilizer use and providing disease breaks. It has a basal phylogenetic position relative to other crop and model legumes and a high speciation rate. Narrow-leafed lupin (NLL; Lupinus angustifolius L.) is gaining popularity as a health food, which is high in protein and dietary fibre but low in starch and gluten-free. We report the draft genome assembly (609 Mb) of NLL cultivar Tanjil, which has captured >98% of the gene content, sequences of additional lines and a dense genetic map. Lupins are unique among legumes and differ from most other land plants in that they do not form mycorrhizal associations. Remarkably, we find that NLL has lost all mycorrhiza-specific genes, but has retained genes commonly required for mycorrhization and nodulation. In addition, the genome also provided candidate genes for key disease resistance and domestication traits. We also find evidence of a whole-genome triplication at around 25 million years ago in the genistoid lineage leading to Lupinus. Our results will support detailed studies of legume evolution and accelerate lupin breeding programmes.
Epilepsy is a serious chronic health condition with a high morbidity impairing the life of patients and afflicted families. Many epileptic conditions, especially those affecting children, are rare disorders generating an urgent medical need for more efficacious therapy options. Therefore, we assessed the output of the US and European orphan drug legislations.
Quantitative analysis of the FDA and EMA databases for orphan drug designations according to STrengthening the Reporting of OBservational studies in Epidemiology (STROBE) criteria.
Within the US Orphan Drug Act 40 designations were granted delivering nine approvals, i.e. clobazam, diazepam viscous solution for rectal administration, felbamate, fosphenytoin, lamotrigine, repository corticotropin, rufinamide, topiramate, and vigabatrin. Since 2000 the EMA granted six orphan drug designations whereof two compounds were approved, i.e. rufinamide and stiripentol. In the US, two orphan drug designations were withdrawn. Orphan drugs were approved for conditions including Lennox-Gastaut syndrome, infantile spasms, Dravet syndrome, and status epilepticus. Comparing time to approval for rufinamide, which was approved in the US and the EU to treat rare seizure conditions, the process seems faster in the EU (2.2 years) than in the US (4.3 years).
Orphan drug development in the US and in the EU delivered only few molecular entities to treat rare seizure disorders. The development programs focused on already approved antiepileptic drugs or alternative pharmaceutical formulations. Most orphan drugs approved in the US are not approved in the EU to treat rare seizures although some were introduced after 2000 when the EU adopted the Orphan Drug Regulation.
Clinical proteomics application aims at solving a specific clinical problem within the context of a clinical study. It has been growing rapidly in the field of biomarker discovery, especially in the area of cancer diagnostics. Until recently, protein isoform has not been viewed as a new class of early diagnostic biomarkers for clinical proteomics. A protein isoform is one of different forms of the same protein. Different forms of a protein may be produced from single-nucleotide polymorphisms (SNPs), alternative splicing, or post-translational modifications (PTMs). Previous studies have shown that protein isoforms play critical roles in tumorigenesis, disease diagnosis, and prognosis. Identifying and characterizing protein isoforms are essential to the study of molecular mechanisms and early detection of complex diseases such as breast cancer. However, there are limitations with traditional methods such as EST sequencing, Microarray profiling (exon array, Exon-exon junction array), mRNA next-generation sequencing used for protein isoform determination: 1) not in the protein level, 2) no connectivity about connection of nonadjacent exons, 3) no SNPs and PTMs, and 4) low reproducibility. Moreover, there exist the computational challenges of clinical proteomics studies: 1) low sensitivity of instruments, 2) high data noise, and 3) high variability and low repeatability, although recent advances in clinical proteomics technology, LC-MS/MS proteomics, have been used to identify candidate molecular biomarkers in diverse range of samples, including cells, tissues, serum/plasma, and other types of body fluids.
Therefore, in the paper, we presented a peptidomics method for identifying cancer-related and isoform-specific peptide for clinical proteomics application from LC-MS/MS. First, we built a Peptidomic Database of Human Protein Isoforms, then created a peptidomics approach to perform large-scale screen of breast cancer-associated alternative splicing isoform markers in clinical proteomics, and lastly performed four kinds of validations: biological validation (explainable index), exon array, statistical validation of independent samples, and extensive pathway analysis.
Our results showed that alternative splicing isoform makers can act as independent markers of breast cancer and that the method for identifying cancer-specific protein isoform biomarkers from clinical proteomics application is an effective one for increasing the number of identified alternative splicing isoform markers in clinical proteomics.
A graded-index multilayer thin-film stack is optimized to act as a cladding layer on top of a silicon (Si) nanowaveguide and also a collimator for chip coupling where the waveguide ends. The numerical example shows an optimized graded-index profile from 2.35 to 1.45 provides an optical coupling to the standard single-mode fiber with efficiency close to 90% while retaining tight light confinement for the Si nanowaveguide. The corresponding material realization of a graded-index profile with a Si-rich nitride SiN<sub>x</sub>/SiON/SiO<sub>2</sub> system is explored using inductively coupled plasma chemical vapor deposition, and a SiN<sub>x</sub> cladded Si waveguide is demonstrated.
Ca(2+) antagonist drugs are widely used in therapy of cardiovascular disorders. Three chemical classes of drugs bind to three separate, but allosterically interacting, receptor sites on CaV1.2 channels, the most prominent voltage-gated Ca(2+) (CaV) channel type in myocytes in cardiac and vascular smooth muscle. The 1,4-dihydropyridines are used primarily for treatment of hypertension and angina pectoris and are thought to act as allosteric modulators of voltage-dependent Ca(2+) channel activation, whereas phenylalkylamines and benzothiazepines are used primarily for treatment of cardiac arrhythmias and are thought to physically block the pore. The structural basis for the different binding, action, and therapeutic uses of these drugs remains unknown. Here we present crystallographic and functional analyses of drug binding to the bacterial homotetrameric model CaV channel CaVAb, which is inhibited by dihydropyridines and phenylalkylamines with nanomolar affinity in a state-dependent manner. The binding site for amlodipine and other dihydropyridines is located on the external, lipid-facing surface of the pore module, positioned at the interface of two subunits. Dihydropyridine binding allosterically induces an asymmetric conformation of the selectivity filter, in which partially dehydrated Ca(2+) interacts directly with one subunit and blocks the pore. In contrast, the phenylalkylamine Br-verapamil binds in the central cavity of the pore on the intracellular side of the selectivity filter, physically blocking the ion-conducting pathway. Structure-based mutations of key amino-acid residues confirm drug binding at both sites. Our results define the structural basis for binding of dihydropyridines and phenylalkylamines at their distinct receptor sites on CaV channels and offer key insights into their fundamental mechanisms of action and differential therapeutic uses in cardiovascular diseases.
Patterning of colloidal particles with chemically or topographically distinct surface domains (patches) has attracted intense research interest. Surface-patterned particles act as colloidal analogues of atoms and molecules, serve as model systems in studies of phase transitions in liquid systems, behave as 'colloidal surfactants' and function as templates for the synthesis of hybrid particles. The generation of micrometre- and submicrometre-sized patchy colloids is now efficient, but surface patterning of inorganic colloidal nanoparticles with dimensions of the order of tens of nanometres is uncommon. Such nanoparticles exhibit size- and shape-dependent optical, electronic and magnetic properties, and their assemblies
 show new collective properties. At present, nanoparticle patterning is limited to the generation of two-patch nanoparticles, and nanoparticles with surface ripples or a 'raspberry' surface morphology. Here we demonstrate nanoparticle surface patterning, which utilizes thermodynamically driven segregation of polymer ligands from a uniform polymer brush into surface-pinned micelles following a change in solvent quality. Patch formation is reversible but can be permanently preserved using a photocrosslinking step. The methodology offers the ability to control the dimensions of patches, their spatial distribution and the number of patches per nanoparticle, in agreement with a theoretical model. The versatility of the strategy is demonstrated by patterning nanoparticles with different dimensions, shapes and compositions, tethered with various types of polymers and subjected to different external stimuli. These patchy nanocolloids have potential applications in fundamental research, the self-assembly of nanomaterials, diagnostics, sensing and colloidal stabilization.
An individual's access to health insurance influences the amount and type of health services a patient receives for prevention and treatment, and, ultimately, influences survival. The North American Association of Central Cancer Registries (NAACCR) Item #630, Primary Payer at DX, is a required field intended to document health insurance status for the purpose of supporting patterns-of-care studies and other research. However, challenges related to the uniformity of collection and availability of data needed to populate this field diminish the value of the Primary Payer at DX data. A NAACCR taskforce worked on issues surrounding the collection of Primary Payer at DX; including proposing a crosswalk between Primary Payer at DX and the new Public Health Payment Typology standard, often available in hospital discharge databases. However, there are issues with compatibility between coding systems, intent of data collection, timelines for coding insurance, and changes in insurance coverage (partly due to the Affordable Care Act) that continue to complicate the collection and use of Primary Payer at DX data.
Wound healing is a dynamic process whereby cells, growth factors (GFs), and the extracellular matrix (ECM) interact to restore the architecture of damaged tissue. Chronic wounds can be difficult to treat due to the increased presence of inflammatory cells that degrade the ECM, GF, and cells necessary for wound healing to occur. Cellular and acellular matrix products can be used in the management of a variety of chronic wounds including venous, diabetic, and pressure ulcers and other conditions such as burns, epidermolysis bullosa, pyoderma gangrenosum, and surgical wounds. These matrices provide cells, GF, and other key elements that act as a scaffold and promote reepithelialization and revascularization of the wound bed.
This article focuses on cellular and acellular matrix products that have been well-studied clinically with positive results in randomized clinical trials and widely available matrices for chronic nonhealing wounds. We present trial results as well as their indications, techniques, and outcomes.
There are a variety of matrix products available on the market. Some of these products are used to treat chronic wounds, for example, diabetic foot ulcers, venous leg ulcers, pyoderma gangrenosum, and pressure ulcers. In this review, we found that wounds of different etiologies have been treated with a variety of matrices, with successful outcomes compared with standard wound care.
Both cellular and acellular matrix products are useful in the management of a variety of chronic wounds. These matrices provide cells, GF, and other key elements that promote reepithelialization and revascularization of the wound bed while preventing degradation of the ECM. The treatment of chronic wounds with matrix products in combination with standard wound care has been proven to aid in wound healing when added to standard of care.
Alternating electric fields at an intermediate frequency (100~300 kHz), referred to as tumour-treating fields (TTF), are believed to interrupt the process of mitosis via apoptosis and to act as an inhibitor of cell proliferation. Although the existence of an antimitotic effect of TTF is widely known, the proposed apoptotic mechanism of TTF on cell function and the efficacy of TTF are controversial issues among medical experts. To resolve these controversial issues, a better understanding of the underlying molecular mechanisms of TTF on cell function and the differences between the effects of TTF alone and in combination with other treatment techniques is essential. Here, we report experimental evidence of TTF-induced apoptosis and the synergistic antimitotic effect of TTF in combination with ionizing radiation (IR). For these experiments, two human Glioblastoma multiforme (GBM) cells (U373 and U87) were treated either with TTF alone or with TTF followed by ionizing radiation (IR). Cell apoptosis, DNA damage, and mitotic abnormalities were quantified after the application of TTF, and their percentages were markedly increased when TTF was combined with IR. Our experimental results also suggested that TTF combined with IR synergistically suppressed both cell migration and invasion, based on the inhibition of MMP-9 and vimentin.
Pancreatic cancer, one of the most lethal cancers, has very poor 5-year survival partly due to gemcitabine resistance. Recently, it was reported that chemotherapeutic agents may act as stressors to induce adaptive responses and to promote chemoresistance in cancer cells. During long-term drug treatment, the minority of cancer cells survive and acquire an epithelial-mesenchymal transition phenotype with increased chemo-resistance and metastasis. However, the short-term response of most cancer cells remains unclear. This study aimed to investigate the short-term response of pancreatic cancer cells to gemcitabine stress and to explore the corresponding mechanism. Our results showed that gemcitabine treatment for 24 hours enhanced pancreatic cancer cell invasion. In gemcitabine-treated cells, HAb18G/CD147 was up-regulated; and HAb18G/CD147 down-regulation or inhibition attenuated gemcitabine-enhanced invasion. Mechanistically, HAb18G/CD147 promoted gemcitabine-enhanced invasion by activating the EGFR (epidermal growth factor receptor)-STAT3 (signal transducer and activator of transcription 3) signaling pathway. Inhibition of EGFR-STAT3 signaling counteracted gemcitabine-enhanced invasion, and which relied on HAb18G/CD147 levels. In pancreatic cancer tissues, EGFR was highly expressed and positively correlated with HAb18G/CD147. These data indicate that pancreatic cancer cells enhance cell invasion via activating HAb18G/CD147-EGFR-pSTAT3 signaling. Our findings suggest that inhibiting HAb18G/CD147 is a potential strategy for overcoming drug stress-associated resistance in pancreatic cancer.
Complicated health care policy decisions are generally made by elected officials. The officials making these complicated decisions are elected by the people, and citizens' participation in the voting process is one of the basic tenets of democracy. Voters in the United States, who are also patients in the health care system, receive enormous amounts of information throughout election cycles. This information is generally delivered in sound bites often intended to elicit an emotional reaction rather than simply inform. From April through July 2016, the author-an academic physician-rode a bicycle across the United States and met with people in small rural towns to ask them their understanding of the Affordable Care Act and the impact it has had on their lives. In this Commentary the author shares some of those stories, which are often informed by sound bites and misinformation. The author argues that it is the role of academic physicians to educate not only students and residents but also patients. In addition to providing information about patients' medical problems, physicians can educate them about the health care policy issues that are decided by elected officials.A doctor can help educate patients about these issues to facilitate their making informed decisions in elections. Physicians have a role and responsibility in society as a knowledgeable person to make the health care system be the best it can be for the most people.
The intersection of small molecular weight drugs and antibody-based therapeutics is rarely studied in large scale. Both types of agents are currently part of the cancer armamentarium. However, very little is known about how to combine them in optimal ways. Immunotoxins are antibody-toxin gene fusion proteins engineered to target cancer cells via antibody binding to surface antigens. For fusion proteins derived from Pseudomonas exotoxin (PE), potency relies on the enzymatic domain of the toxin which catalyzes the ADP-ribosylation of EF2 causing inhibition of protein synthesis leading to cell death. Candidate immunotoxins have demonstrated clear value in clinical trials but generally have not been curative as single agents. Therefore we undertook three screens to discover effective combinations that could act synergistically. From the MIPE-3 library of compounds we identified various enhancers of immunotoxin action and at least one major class of inhibitor. Follow-up experiments confirmed the screening data and suggested that immunotoxins when administered with everolimus or nilotinib exhibit favorable combinatory activity and would be candidates for preclinical development. Mechanistic studies revealed that everolimus-immunotoxin combinations acted synergistically on elements of the protein synthetic machinery, including S61 kinase and 4E-BP1 of the mTORC1 pathway. Conversely, PARP inhibitors antagonized immunotoxins
 and also blocked the toxicity due to native ADP-ribosylating toxins. Thus, our goal of investigating a chemical library was justified based on the identification of several approved compounds that could be developed preclinically as 'enhancers' and at least one class of mitigator to be avoided.
Consuming carbohydrate- and antioxidant-rich fruits during exercise as a means of supporting and enhancing both performance and health is of interest to endurance athletes. Watermelon (WM) contains carbohydrate, lycopene, l-citrulline, and l-arginine. WM may support exercise performance, augment antioxidant capacity, and act as a countermeasure to exercise-induced inflammation and innate immune changes. Trained cyclists (n = 20, 48 ± 2 years) participated in a randomized, placebo controlled, crossover study. Subjects completed two 75 km cycling time trials after either 2 weeks ingestion of 980 mL/day WM puree or no treatment. Subjects drank either WM puree containing 0.2 gm/kg carbohydrate or a 6% carbohydrate beverage every 15 min during the time trials. Blood samples were taken pre-study and pre-, post-, 1 h post-exercise. WM ingestion versus no treatment for 2-weeks increased plasma l-citrulline and l-arginine concentrations (p < 0.0125). Exercise performance did not differ between WM puree or carbohydrate beverage trials (p > 0.05), however, the rating of perceived exertion was greater during the WM trial (p > 0.05). WM puree versus carbohydrate beverage resulted in a similar pattern of increase in blood glucose, and greater increases in post-exercise plasma antioxidant capacity, l-citrulline, l-arginine, and total nitrate (all p < 0.05), but without differences in systemic markers of inflammation or innate immune function. Daily WM puree consumption fully supported the energy demands of exercise, and increased post-exercise blood levels of WM nutritional components (l-citrulline and l-arginine), antioxidant capacity, and total nitrate, but without an influence on post-exercise inflammation and changes in innate immune function.
In Corsica, extensive pig breeding systems allow frequent interactions between wild boars and domestic pigs, which are suspected to act as reservoirs of several zoonotic diseases including hepatitis E virus (HEV). In this context, 370 sera and 166 liver samples were collected from phenotypically characterized as pure or hybrid wild boars, between 2009 and 2012. In addition, serum and liver from 208 domestic pigs belonging to 30 farms were collected at the abattoir during the end of 2013. Anti-HEV antibodies were detected in 26% (21%-31.6%) of the pure wild boar, 43.5% (31%-56.7%) of hybrid wild boar and 88% (82.6%-91.9%) of the domestic pig sera. In addition, HEV RNA was detected in five wild boars, three hybrid wild boars and two domestic pig livers tested. Our findings provide evidence that both domestic pig and wild boar (pure and hybrid) act as reservoirs of HEV in Corsica, representing an important zoonotic risk for Corsican hunters and farmers but also for the large population of consumers of raw pig liver specialties produced in Corsica. In addition, hybrid wild boars seem to play an important ecological role in the dissemination of HEV between domestic pig and wild boar populations, unnoticed to date, that deserves further investigation.
Mutations the in human DJ-1 (hDJ-1) gene are associated with early-onset autosomal recessive forms of Parkinson's disease (PD). hDJ-1/parkinsonism associated deglycase (PARK7) is a cytoprotective multi-functional protein that contains a conserved cysteine-protease domain. Given that cysteine-proteases can act on both amide and ester substrates, we surmised that hDJ-1 possessed cysteine-mediated esterase activity. To test this hypothesis, hDJ-1 was overexpressed, purified and tested for activity towards 4-nitrophenyl acetate (pNPA) as µmol of pNPA hydrolyzed/min/mg·protein (U/mg protein). hDJ-1 showed maximum reaction velocity esterase activity (Vmax = 235.10 ± 12.00 U/mg protein), with a sigmoidal fit (S0.5 = 0.55 ± 0.040 mM) and apparent positive cooperativity (Hill coefficient of 2.05 ± 0.28). A PD-associated mutant of DJ-1 (M26I) lacked activity. Unlike its protease activity which is inactivated by reactive oxygen species (ROS), esterase activity of hDJ-1 is enhanced upon exposure to low concentrations of hydrogen peroxide (<10 µM) and plateaus at elevated concentrations (>100 µM) suggesting that its activity is resistant to oxidative stress. Esterase activity of DJ-1 requires oxidation of catalytic cysteines, as chemically protecting cysteines blocked its activity whereas an oxido-mimetic mutant of DJ-1 (C106D) exhibited robust esterase activity. Molecular docking studies suggest that C106 and L126 within its catalytic site interact with esterase substrates. Overall, our data show that hDJ-1 contains intrinsic redox-sensitive esterase activity that is abolished in a PD-associated mutant form of the hDJ-1 protein.
A designed nanostructure with MoS2 nanosheets (NSs) perpendicularly grown on graphene sheets (MoS2/G) is achieved by a facile and scalable hydrothermal method, which involves adsorption of Mo7O24(6-) on a graphene oxide (GO) surface, due to the electrostatic attraction, followed by in situ growth of MoS2. These results give an explicit proof that the presence of oxygen-containing groups and pH of the solution are crucial factors enabling formation of a lamellar structure with MoS2 NSs uniformly decorated on graphene sheets. The direct coupling of edge Mo of MoS2 with the oxygen from functional groups on GO (C-O-Mo bond) is proposed. The interfacial interaction of the C-O-Mo bonds can enhance electron transport rate and structural stability of the MoS2/G electrode, which is beneficial for the improvement of rate performance and long cycle life. The graphene sheets improve the electrical conductivity of the composite and, at the same time, act not only as a substrate to disperse active MoS2 NSs homogeneously but also as a buffer to accommodate the volume changes during cycling. As an anode material for lithium-ion batteries, the manufactured MoS2/G electrode manifests a stable cycling performance (1077 mAh g(-1) at 100 mA g(-1) after 150 cycles), excellent rate capability, and a long cycle life (907 mAh g(-1) at 1000 mA g(-1) after 400 cycles).
Prostate cancer (PCa) is a leading cause of mortality among males. Long non-coding RNAs (lncRNAs) are subclass of noncoding RNAs that may act as biomarkers and therapeutic targets. In this study, we firstly conducted analysis of global lncRNA expression patterns by using our own cohort (GSE73397) and two public available gene expression datasets: The Cancer Genome Atlas (TCGA) and GSE55909. Next, we performed microarray to observe genome-wide lncRNAs' expressions under dihydrotestosterone (DHT) stimulation in LNCaP cells (GSE72866), and overlapped the result with ChIPBase data to predict androgen-responsive lncRNAs with ARE. Combined the two results, a total of 44 androgen-responsive lncRNAs with ARE were found to be over-expressed in PCa samples. Ten lncRNAs were selected for further validation by examining their expressions in LNCaP cells under DHT stimulation, and in PCa samples and cell lines. Among them, RP1-4514.2, LINC01138, SUZ12P1 and KLKP1 were validated as directly AR-targeted lncRNAs by ChIP-PCR. Then we conducted a bioinformatic analysis to identify lncRNAs as putative prognostic and therapeutic targets by using TCGA data. Three androgen-responsive lncRNAs, LINC01138, SUZ12P1 and SNHG1 showed association with gleason score and pT-stage. The biological functions of LINC01138 and SUZ12P1 were also evaluated, both lncRNAs promoted the proliferation and inhibited apoptosis of PCa. These results provide potent information for exploring potential biomarkers and therapeutic targets for prostate cancer, especially for castration-resistant PCa.
The paper discusses the governmental draft of the Act on counteracting threats of sexual offences. It assumes the creation of the Registry of Sex Offenders in a version with a limited access and a version available to the public. The registry is supplemented with a publically available map of sexual crime threats, which includes the places of sexual offences and the places of residence of offenders. Criticising the proposed solutions, the authors point out the lack of integration with other interventions conducted in Poland against sex offenders, noncompliance with the recommendations of the most important expert circles in the field, as well as the research results showing the lack of effectiveness of the planned measures to reduce sexual offences. Anumber of negative consequences of making the sex offenders'data available to the public was also highlighted in the form of a clear deterioration of social rehabilitation prognoses, additional stigmatisation, as well as social exclusion of the offenders themselves and the victims of sexual violence. The summary emphasises the need to counteract the problem of sexual offences in a systematic way and the need to diversify the interventions undertaken against the offenders, depending on the level of risk of sexual recidivism.
Aberrant activation of signal transduction pathways can transform a normal cell to a malignant one and can impart survival properties that render cancer cells resistant to therapy. A diverse set of cascades have been implicated in various cancers including those mediated by serine/threonine kinases such RAS, PI3K/AKT, and PKC. Signal transduction is a dynamic process involving both "On" and "Off" switches. Activating mutations of RAS or PI3K can be viewed as the switch being stuck in the "On" position resulting in continued signaling by a survival and/or proliferation pathway. On the other hand, inactivation of protein phosphatases such as the PP2A family can be seen as the defective "Off"
 switch that similarly can activate these pathways. A problem for therapeutic targeting of PP2A is that the enzyme is a hetero-trimer and thus drug targeting involves complex structures. More importantly, since PP2A isoforms generally act as tumor suppressors one would want to activate these enzymes rather than suppress them. The elucidation of the role of cellular inhibitors like SET and CIP2A in cancer suggests that targeting these proteins can have therapeutic efficacy by mechanisms involving PP2A activation. Furthermore, drugs such as FTY-720 can activate PP2A isoforms directly. This review will cover the current state of knowledge of PP2A role as a tumor suppressor in cancer cells and as a mediator of processes that can impact drug resistance and immune surveillance.
Due to frequent cases of alveolar echinococcosis (AE) in captive primates in Europe, 141 samples of food, which consisting of vegetables and fruits, were investigated for contamination with egg-DNA of taeniids. Each sample consisted of at least 40 heads of lettuce as well as various vegetables and fruits. The samples were purchased at different times of the year: either from September to November (autumn), originating from greenhouses or fields in the Basel region in the North of Switzerland, or in April and May (spring) when fruit and vegetables are sourced from throughout Europe from various wholesalers. Each sample was washed, and the washing water sieved through mesh apertures of 50 μm and 21 μm, respectively. The debris, including taeniid eggs, collected on the 21 μm sieve were investigated by a multiplex PCR-analysis followed by direct sequencing. In 17 (18%) of the 95 samples collected in autumn, taeniid-DNA was detected (Taenia hydatigena in four, Taenia ovis in three, Taenia polyacantha in two and Hydatigera (Taenia) taeniaeformis in five cases). Similarly, in 13 (28%) of the 46 samples collected during spring taeniid-DNA was detected (Echinococcus granulosus s.l. in two, Taenia crassiceps in one, T. hydatigena in two, Taenia multiceps/Taenia serialis in two, Taenia saginata in one and H. taeniaeformis in five cases). Although DNA of Echinococcus multilocularis was not found specifically in this study, the detection of other fox taeniids reveals that vegetables and fruit fed to the primates at the Zoo Basel at different times of the year and from different origin are contaminated with carnivore's faeces and therefore act as a potential source of AE infections.
Texting while driving is a dangerous activity that is on the rise in the United States (U.S.). Since 2011 there has been a 17% increase in the number of people injured in a motor vehicle crash involving a distracted driver. Bans on the act of texting and driving have already taken place in 46 states in the U.S., but studies have shown that they are ineffective. An unstudied method of reducing texting while driving is sticker reminders. Sticker reminders have already been proven to be an effective intervention in the realm of driver safety; one study found that a "Buckle-Up" dashboard sticker doubled the use of safety belts by front seat passengers. In this study, 104 medical students aged 21 - 29, from the University of Central Florida (UCF) College of Medicine were randomly divided into two groups, an interventional group receiving a "Drive in the Moment" windshield sticker, and a control group not receiving the sticker. Both groups took a pre- and post-survey that recorded self-reported texting and driving frequency. The results showed that the sticker intervention significantly reduced reported rates of sending texts while driving, reading texts while driving, and using social media while driving (p < 0.05). The results of this study suggest that a novel sticker-intervention could potentially serve as a point of attack when addressing the growing and dangerous texting while driving the epidemic.
The species-rich genus Peperomia (Black Pepper relatives) is the only genus among early diverging angiosperms where epiphytism evolved. The majority of fruits of Peperomia release sticky secretions or exhibit hook-shaped appendages indicative of epizoochorous dispersal, which is in contrast to other flowering plants, where epiphytes are generally characterized by fruit morphological adaptations for anemochory or endozoochory. We investigate fruit characters using Cryo-SEM. Comparative phylogenetic analyses are applied for the first time to include life form and fruit character information to study diversification in Peperomia. Likelihood ratio tests uncover correlated character evolution. We demonstrate that diversification within Peperomia is not homogenous across its phylogeny, and that net diversification rates increase by twofold within the most species-rich subgenus. In contrast to former land plant studies that provide general evidence for increased diversification in epiphytic lineages, we demonstrate that the evolution of epiphytism within Peperomia predates the diversification shift. An epiphytic-dependent diversification is only observed for the background phylogeny. An elevated frequency of life form transitions between epiphytes and terrestrials and thus evolutionary flexibility of life forms is uncovered to coincide with the diversification shift. The evolution of fruits showing dispersal related structures is key to diversification in the foreground region of the phylogeny and postdates the evolution of epiphytism. We conclude that the success of Peperomia, measured in species numbers, is likely the result of enhanced vertical and horizontal dispersal ability and life form flexibility but not the evolution of epiphytism itself.
Research on socially aware systems requires fine-grained knowledge of the mechanisms of persuasion in order to promote civic knowledge and aware political participation. Within humor studies, political parody is generally considered a simple pleasant weapon for political evaluation, currently explained by referring to the so called "just a joke effect" (Nabi et al., 2007). Indeed the funny side of parody can induce positive emotions, but it also includes a discrediting act that sometimes produces a "bitter laughter." The present study aims to understand the role played by negative and moral emotions aroused by parody. A parody is defined as a communicative behavior (a discourse, text, body movement, song) that imitates a communicative behavior or trait displayed by some Target by reproducing it in a distorted way, with the aim of making fun of the Target. Based on a socio-cognitive approach, a distinction is made between "surface" and "deep" parody (Poggi and D'Errico, 2013), with the former simply imitating behaviors actually displayed by the Target, and the latter implying a (humorous) re-categorization of the Target. The paper studies the effect of these two different types of parody on persuasion processes. Results show that the deep parody, as opposed to surface parody, triggers more negative emotions, and in particular indignation, that in turn lead to more negative evaluations of the Target. Moreover, the moral priming of parody is influenced by the Target politician's gender.
Owing to the reports of microcephaly as a consistent outcome in the fetuses of pregnant women infected with ZIKV in Brazil, Zika virus (ZIKV)-microcephaly etiomechanistic relationship has recently been implicated. Researchers, however, are still struggling to establish an embryological basis for this interesting causal handcuff. The present study reveals robust evidence in favor of a plausible ZIKV-microcephaly cause-effect liaison. The rationale is based on: (1) sequence homology between ZIKV genome and the response element of an early neural tube developmental marker "retinoic acid" in human DNA and (2) comprehensive similarities between the details of brain defects in ZIKV-microcephaly and retinoic acid embryopathy. Retinoic acid is considered as the earliest factor for regulating anteroposterior axis of neural tube and positioning of structures in developing brain through retinoic acid response elements (RARE) consensus sequence (5'-AGGTCA-3') in promoter regions of retinoic acid-dependent genes. We screened genomic sequences of already reported virulent ZIKV strains (including those linked to microcephaly) and other viruses available in National Institute of Health genetic sequence database (GenBank) for the RARE consensus repeats and obtained results strongly bolstering our hypothesis that ZIKV strains associated with microcephaly may act through precipitation of dysregulation in retinoic acid-dependent genes by introducing extra stretches of RARE consensus sequence repeats in the genome of developing brain cells. Additional support to our hypothesis comes from our findings that screening of other viruses for RARE consensus sequence repeats is positive only for those known to display neurotropism and cause fetal brain defects (for which maternal-fetal transmission during developing stage may be required). The numbers of RARE sequence repeats appeared to match with the virulence of screened positive viruses. Although, bioinformatic evidence and embryological features are in favor of our hypothesis, additional studies including animal models are warranted to validate our proposition. Such studies are likely to unfold ZIKV-microcephaly association and may help in devising methods to combat it.
Plants possess intracellular immune receptors designated "nucleotide-binding domain and leucine-rich repeat" (NLR) proteins that translate pathogen-specific recognition into disease-resistance signaling. The wheat immune receptors Sr33 and Sr50 belong to the class of coiled-coil (CC) NLRs. They confer resistance against a broad spectrum of field isolates of Puccinia graminis f. sp. tritici, including the Ug99 lineage, and are homologs of the barley powdery mildew-resistance protein
 MLA10. Here, we show that, similarly to MLA10, the Sr33 and Sr50 CC domains are sufficient to induce cell death in Nicotiana benthamiana Autoactive CC domains and full-length Sr33 and Sr50 proteins self-associate in planta In contrast, truncated CC domains equivalent in size to an MLA10 fragment for which a crystal structure was previously determined fail to induce cell death and do not self-associate. Mutations in the truncated region also abolish self-association and cell-death signaling. Analysis of Sr33 and Sr50 CC domains fused to YFP and either nuclear localization or nuclear export signals in N benthamiana showed that cell-death induction occurs in the cytosol. In stable transgenic wheat plants, full-length Sr33 proteins targeted to the cytosol provided rust resistance, whereas nuclear-targeted Sr33 was not functional. These data are consistent with CC-mediated induction of both cell-death signaling and stem rust resistance in the cytosolic compartment, whereas previous research had suggested that MLA10-mediated cell-death and disease resistance signaling occur independently, in the cytosol and nucleus, respectively.
Accumulating evidence indicates that odontoblasts act as sensor cells, capable of triggering action potentials in adjacent pulpal nociceptive axons, suggesting a paracrine signaling via a currently unknown mediator. Since glutamate can mediate signaling by non-neuronal cells, and peripheral axons may express glutamate receptors (GluR), we hypothesized that the expression of high levels of glutamate, and of sensory receptors in odontoblasts, combined with an expression of GluR in adjacent pulpal axons, is the morphological basis for odontoblastic sensory signaling. To test this hypothesis, we investigated the expression of glutamate, the thermo- and mechanosensitive ion channels transient receptor potential vanilloid 1 (TRPV1), transient receptor potential ankyrin 1 (TRPA1), and TWIK-1-related K+channel (TREK-1), and the glutamate receptor mGluR5, in a normal rat dental pulp, and following dentin injury. We also examined the glutamate release from odontoblast in cell culture. Odontoblasts were enriched with glutamate, at the level as high as in adjacent pulpal axons, and showed immunoreactivity for TRPV1, TRPA1, and TREK-1. Pulpal sensory axons adjacent to odontoblasts expressed mGluR5. Both the levels of glutamate in odontoblasts, and the expression of mGluR5 in nearby axons, were upregulated following dentin injury. The extracellular glutamate concentration was increased significantly after treating of odontoblast cell line with calcium permeable ionophore, suggesting glutamate release from odontoblasts. These findings lend morphological support to the hypothesis that odontoblasts contain glutamate as a potential neuroactive substance that may activate adjacent pulpal axons, and thus contribute to dental pain and hypersensitivity.
The familial forms of early onset pre-eclampsia and related syndromes (HELLP) present with hypertension and proteinuria in the mother and growth restriction of the fetus. Genetically, these clinically similar entities are caused by different founder-dependent, placentally-expressed paralogous genes. All susceptibility genes (STOX1, lincHELLP, INO80B) identified so far are master control genes that regulate an essential trophoblast differentiation pathway, but act at different entry points. Many genes remain to be identified. Here we demonstrate that a long non-coding RNA (lncRNA) within intron 3 of the STOX2 gene on 4q35.1 acts as a permissive cis-acting regulator of alternative splicing of STOX2. When this lncRNA is mutated or absent, an alternative exon (3B) of STOX2 is included. This introduces a stop codon resulting in the deletion of a highly conserved domain of 64 amino acids in the C-terminal of the STOX2 protein. A mutation present within a regulatory region within intron 1 of STOX2 has the same effect after blocking with CRISPR technology: transcripts with exon 3B are upregulated. This proces appears related to transcriptional control by a chromatin-splicing adaptor complex as described for FGFR2. For STOX2, CHD5, coding for a chromodomain helicase DNA binding protein, qualifies as the chromatin modifier in this process.
In 1970, it was well accepted that the central role of lipids was in energy storage and metabolism, and it was assumed that amphipathic lipids simply served a passive structural role as the backbone of biological membranes. As a result, the scientific community was focused on nucleic acids, proteins, and carbohydrates as information-containing molecules. It took considerable effort until scientists accepted that lipids also "encode" specific and unique biological information and play a central role in cell signaling. Along with this realization came the recognition that the enzymes that act on lipid substrates residing in or on membranes and micelles must also have important signaling roles, spurring curiosity into their potentially unique modes of action differing from those acting on water-soluble substrates. This led to the creation of the concept of "surface dilution kinetics" for describing the mechanism of enzymes acting on lipid substrates, as well as the demonstration that lipid enzymes such as phospholipase A2 (PLA2) contain allosteric activator sites for specific phospholipids as well as for membranes. As our understanding of phospholipases advanced, so did the understanding that many of the lipids released by these enzymes are chiral information-containing signaling molecules; for example, PLA2 regulates the generation of precursors for the biosynthesis of eicosanoids and other bioactive lipid mediators of inflammation and resolution underlying disease progression. The creation of the LIPID MAPS initiative in 2003 and the ensuing development of the lipidomics field have revealed that lipid metabolites are central to human metabolism. Today lipids are recognized as key mediators of health and disease as we enter a new era of biomarkers and personalized medicine. This article is my personal "reflection" on these scientific advances.
Glycoside hydrolases (GHs) are key enzymes in the depolymerization of plant-derived cellulose, a process central to the global carbon cycle and the conversion of plant biomass to fuels and chemicals. A limited number of GH families hydrolyze crystalline cellulose, often by a processive mechanism along the cellulose chain. During cultivation of thermophilic cellulolytic microbial communities, substantial differences were observed in the crystalline cellulose saccharification activities of supernatants recovered from divergent lineages. Comparative community proteomics identified a set of cellulases from a population closely related to actinobacterium Thermobispora bispora that were highly abundant in the most active consortium. Among the cellulases from T. bispora, the abundance of a GH family 12 (GH12) protein correlated most closely with the changes in crystalline cellulose hydrolysis activity. This result was surprising since GH12 proteins have been predominantly characterized as enzymes active on soluble polysaccharide substrates. Heterologous expression and biochemical characterization of the suite of T. bispora hydrolytic cellulases confirmed that the GH12 protein possessed the highest activity on multiple crystalline cellulose substrates and demonstrated that it hydrolyzes cellulose chains by a predominantly random mechanism. This work suggests that the role of GH12 proteins in crystalline cellulose hydrolysis by cellulolytic microbes should be reconsidered.
Cellulose is the most abundant organic polymer on earth, and its enzymatic hydrolysis is a key reaction in the global carbon cycle and the conversion of plant biomass to biofuels. The glycoside hydrolases that depolymerize crystalline cellulose have been primarily characterized from isolates. In this study, we demonstrate that adapting microbial consortia from compost to grow on crystalline cellulose generated communities whose soluble enzymes exhibit differential abilities to hydrolyze crystalline cellulose. Comparative proteomics of these communities identified a protein of glycoside hydrolase family 12 (GH12), a family of proteins previously observed to primarily hydrolyze soluble substrates, as a candidate that accounted for some of the differences in hydrolytic activities. Heterologous expression confirmed that the GH12 protein identified by proteomics was active on crystalline cellulose and hydrolyzed cellulose by a random mechanism, in contrast to most cellulases that act on the crystalline polymer in a processive mechanism.
Pericytes, resident fibroblasts, and mesenchymal stem cells are poorly described cell populations. They have recently been characterized in much greater detail in rodent lungs and have been shown to play important roles in development, homeostasis, response to injury and pathogens, as well as recovery from damage. These closely related mesenchymal cell populations form extensive connections to the lung's internal structure, as well as its internal and external surfaces. They generate and remodel extracellular matrix, coregulate the vasculature, help maintain and restore the epithelium, and act as sentries for the immune system. In this review, we revisit these functions in light of significant advances in characterizing and tracking lung fibroblast populations in rodents. Lineage tracing experiments have mapped the heritage, identified functions that discriminate lung pericytes from resident fibroblasts, identified a subset of mesenchymal stem cells, and shown these populations to be the predominant progenitors of pathological fibroblasts and myofibroblasts in lung diseases. These findings point to the importance of resident lung mesenchymal populations as therapeutic targets in acute lung injury as well as fibrotic
 and degenerative diseases. Far from being passive and quiescent, pericytes and resident fibroblasts are busily sensing and responding, through diverse mechanisms, to changes in lung health and function.
Pretreatment serum pseudocholinesterase (PChE) has been reported to be a prognostic predictor in several cancers. However, the prognostic significance of serum PChE level in patients with upper tract urothelial carcinoma (UTUC) remains unknown.
A total of 180 patients who underwent radical nephroureterectomy (RNU) for UTUC were included in this retrospective analysis. The associations of pretreatment serum PChE levels with clinicopathological characteristics and clinical outcomes were assessed.
The median (IQR) pretreatment serum PChE level was 6385 (5449-7260) IU/L, and an optimal cutoff value of 5336 IU/L was set according to ROC analysis. Decreased pretreatment serum PChE levels were significantly correlated with older patient age, higher preoperative chronic kidney disease (CKD) stage and pT stage (all P < 0.05). On multivariate analysis, adjusting for preoperative variables, decreased pretreatment serum PChE levels independently predicted higher pT stage (P = 0.011). Moreover, Kaplan-Meier curves suggested that patients with PChE levels <5336 IU/L were predicted to have a shorter overall survival (OS) and cancer-specific survival (CSS) than those with PChE levels ≥5336 IU/L (both P < 0.001). On multivariate analysis, decreased pretreatment serum PChE levels were significantly associated with shorter OS (HR 0.553; 95 %CI 0.322-0.951; P = 0.032) and CSS (HR 0.484; 95 %CI 0.269-0.870; P = 0.015).
Decreased pretreatment serum PChE level is an independent predictor for higher pT stage, shorter OS and CSS in patients with UTUC. Pretreatment serum PChE levels may act as a simple and effective parameter to predict prognosis for UTUC patients after RNU.
People with intellectual disability often have few friends and experience social exclusion. Recognising this gap, supported social groups with the aim of inclusion and interdependence were created by a supported employment provider.
Interviews were undertaken with 10 adults with intellectual disability exploring their lived experiences of a supported social group. Data were analysed using descriptive phenomenology.
Two themes emerged (i) supported engagement fosters wellbeing, and (ii) developing social belonging and connectedness. Participants not only acknowledged the support that they needed to participate, but also that the social group had changed their lives in many ways.
Adults with intellectual disability want to socialise, have friends and be part of their community. For this to be achieved, they recognise the need to seek some form of support. With appropriate and targeted support, adults with intellectual disability can move from social exclusion towards supported inclusion and experience richer lives.
Calmodulin is a representative calcium-binding protein comprised of four Ca(2+) -binding motifs with a helix-loop-helix structure (EF-hands). In this study, we clarified the potential of peptide segments derived from the third and fourth EF-hands (EF3 and EF4) to act as recognition tags. Through an analysis of the mode of disulfide formation among cysteines inserted at the N- or C-terminus of these peptide segments, EF3 and EF4 peptides were suggested to form a heterodimer with a topology similar to that in the wild-type protein. Heterodimer formation was shown to be a function of the Ca(2+) concentration, suggesting that these structures may be used as Ca(2+) -switchable recognition tags. An example of an 'EF-tag' system involving the membrane fusion of liposomes decorated with EF3 and EF4 peptides is presented. This article is protected by copyright. All rights reserved.
Directional proton transport along 'wires' that feed biochemical reactions in proteins is poorly understood. Amino-acid residues with high pKa are seldom considered as active transport elements in such wires because of their large classical barrier for proton dissociation. Here, we use the light-triggered proton wire of the green fluorescent protein to study its ground-electronic-state proton-transport kinetics, revealing a large temperature-dependent kinetic isotope effect. We show that 'deep' proton tunnelling between hydrogen-bonded oxygen atoms with a typical donor-acceptor distance of 2.7-2.8 Å fully accounts for the rates at all temperatures, including the unexpectedly large value (2.5 × 10(9) s(-1)) found at room temperature. The rate-limiting step in green fluorescent protein is assigned to tunnelling of the ionization-resistant serine hydroxyl proton. This suggests how high-pKa residues within a proton wire can act as a 'tunnel diode' to kinetically trap protons and control the direction of proton flow.
Harmful algal blooms (HABs) and marine pathogens - like Vibrio spp. - are increasingly common due to climate change. These stressors affect the growth, viability and development of bivalve larvae. Little is known, however, about the potential for interactions between these two concurrent stressors. While some mixed exposures have been performed with adult bivalves, no such work has been done with larvae which are generally more sensitive. This study examines whether dinoflagellates and bacteria may interactively affect the viability and immunological resilience of blue mussel Mytilus edulis larvae. Embryos were exposed to environmentally relevant concentrations (100, 500, 2500 & 12,500 cells ml(-1)) of a dinoflagellate (Alexandrium minutum, Alexandrium ostenfeldii, Karenia mikimotoi, Protoceratium reticulatum, Prorocentrum cordatum, P. lima or P. micans), a known pathogen (Vibrio coralliilyticus/neptunius-like isolate or Vibrio splendidus; 10(5) CFU ml(-1)), or both. After five days of exposure, significant (p < 0.05) adverse effects on larval viability and larval development were found for all dinoflagellates (except P. cordatum) and V. splendidus. Yet, despite the individual effect of each stressor, no significant interactions were found between the pathogens and harmful algae. The larval viability and the phenoloxidase innate immune system responded independently to each stressor. This independence may be related to a differential timing of the effects of HABs and pathogens.
The goal of this study is to better understand the characteristics of men who act as primary caregivers of maltreated children. We examined differences between male primary caregivers (fathers) for youth involved in the child welfare system and female primary caregivers (mothers). We conducted secondary data analyses of the National Survey of Child and Adolescent Well-Being-II baseline data. Overall, primary caregiving fathers and mothers were more similar than different, though a few differences were revealed. Compared to mothers, fathers tended to be older and were more likely to be employed, with a higher household income and older children. Fathers and mothers did not differ in terms of depression or parenting behavior, but there was evidence that mothers have more problems with drug use compared to fathers. Compared to fathers, mothers reported higher levels of internalizing and externalizing problems in their children. Children with male primary caregivers were more likely to have experienced physical abuse but less likely to have experienced emotional abuse or witnessed domestic violence than children with female primary caregivers. These findings may help to inform researchers, practitioners, and policy makers on how to address the needs of male caregivers and their children.
ADAMs are transmembrane multifunctional proteins that contain disintegrin and metalloprotease domains. ADAMs act in a diverse set of biological processes, including fertilization, inflammatory responses, myogenesis, cell migration, cell proliferation and ectodomain cleavage of membrane proteins. These proteins also have additional functions in pathological processes as cancer and metastasis development. ADAM9 is a member of ADAM protein family that is overexpressed in several types of human carcinomas. The aim of this study was to investigate the role of ADAM9 in hematogenous and lymphatic tumor cell dissemination assisting the development of new therapeutic tools. The role of ADAM9 in the interaction of breast tumor cells (MDA-MB-231) and endothelial cells was studied through RNA silencing. ADAM9 silencing in MDA-MB-231 cells had no influence in expression of several genes related to the metastatic process such as ADAM10, ADAM12, ADAM17, cMYC, MMP9, VEGF-A, VEGF-C, osteopontin and collagen XVII. However, there was a minor decrease in ADAM15 expression but an increase in that of MMP2. Moreover, ADAM9 silencing had no effect in the adhesion of MDA-MB-231 cells to vascular (HMEC-1 and HUVEC) and lymphatic cells (HMVEC-dLyNeo) under flow condition. Nevertheless, siADAM9 in MDA-MB-231 decreased transendothelial cell migration in vitro through HUVEC, HMEC-1 and HMVEC-dLyNeo (50%, 40% and 32% respectively). These results suggest a role for ADAM9 on the extravasation step of the metastatic cascade through both blood and lymph vessels.
Many Americans with metastasised colon cancer do not receive indicated palliative chemotherapy. We examined the effects of health insurance and physician supplies on such chemotherapy in California.
We analysed registry data for 1199 people with metastasised colon cancer diagnosed between 1996 and 2000 and followed for 1 year. We obtained data on health insurance, census tract-based socioeconomic status and county-level physician supplies. Poor neighbourhoods were oversampled and the criterion was receipt of chemotherapy. Effects were described with rate ratios (RR) and tested with logistic regression models.
Palliative chemotherapy was received by less than half of the participants (45%). Facilitating effects
 of primary care (RR=1.23) and health insurance (RR=1.14) as well as an impeding effect of specialised care (RR=0.86) were observed. Primary care physician (PCP) supply took precedence. Adjusting for poverty, PCP supply was the only significant and strong predictor of chemotherapy (OR=1.62, 95% CI 1.02 to 2.56). The threshold for this primary care advantage was realised in communities with 8.5 or more PCPs per 10 000 inhabitants. Only 10% of participants lived in such well-supplied communities.
This study's observations of facilitating effects of primary care and health insurance on palliative chemotherapy for metastasised colon cancer clearly suggested a way to maximise Affordable Care Act (ACA) protections. Strengthening America's system of primary care will probably be the best way to ensure that the ACA's full benefits are realised. Such would go a long way towards facilitating access to palliative care.
Histone deacetylases (HDACs) critically regulate gene expression by determining the acetylation status of histones. Studies have increasingly focused on the activities of HDACs, especially involving non-histone proteins, and their various biological effects. Aberrant HDAC expression observed in several kinds of human tumors makes HDACs potential targets for cancer treatment. Several preclinical studies have suggested that HDAC inhibitors show some efficacy in the treatment of acute myelogenous leukemia with AML1-ETO, which mediates transcriptional repression through its interaction with a complex including HDAC1. Recurrent mutations in epigenetic regulators are found in T-cell lymphomas (TCLs), and HDAC inhibitors and hypomethylating agents were shown to act cooperatively in the treatment of TCLs. Preclinical modeling has suggested that persistent activation of the signal transducer and activator of transcription signaling pathway could serve as a useful biomarker of resistance to HDAC inhibitor in patients with cutaneous TCL. Panobinostat, a pan-HDAC inhibitor, in combination with bortezomib and dexamethasone, has achieved longer progression-free survival in patients with relapsed/refractory multiple myeloma (MM) than the placebo in combination with bortezomib and dexamethasone. Panobinostat inhibited MM cell growth by degrading protein phosphatase 3 catalytic subunit α (PPP3CA), a catalytic subunit of calcineurin. This degradation was suggested to be mediated by the blockade of the chaperone function of heat shock protein 90 due to HDAC6 inhibition. Aberrant PPP3CA expression in advanced MM indicated a possible correlation between high PPP3CA expression and the pathogenesis of MM. Furthermore, PPP3CA was suggested as a common target of panobinostat and bortezomib.
Cities are complex adaptive systems whose responses to policy initiatives emerge from feedback interactions between their parts. Urban policy makers must routinely deal with both detail and dynamic complexity, coupled with high levels of diversity, uncertainty and contingency. In such circumstances, it is difficult to generate reliable predictions of health-policy outcomes. In this paper we explore the potential for low-order system dynamics (LOSD) models to make a contribution towards meeting this challenge. By definition, LOSD models have few state variables (≤5), illustrate the non-linear effects caused by feedback and accumulation, and focus on endogenous dynamics generated within well-defined boundaries. We suggest that experience with LOSD models can help practitioners to develop an understanding of basic principles of system dynamics, giving them the ability to 'see with new eyes'. Because efforts to build a set of LOSD models can help a transdisciplinary group to develop a shared, coherent view of the problems that they seek to tackle, such models can also become the foundations of 'powerful ideas'. Powerful ideas are conceptual metaphors that provide the members of a policy-making group with the a priori shared context required for effective communication, the co-production of knowledge, and the collaborative development of effective public health policies.
There is an on-going debate about whether health products, such as insecticide-treated bednets (ITNs) for protection against malaria, should be distributed for free or at a positive price to maximize ownership and use. One argument in favour of free distribution is related to positive externalities. Like vaccines, individual use of ITNs provides a community-wide protective effect against malaria even for non-users. In addition, price may act as a barrier to ownership particularly among those most at-risk who are frequently poor. Alternatively, charging a positive price may reduce donor dependence, more efficiently allocate nets to those most at risk of malaria, and encourage use through a hypothesized sunk cost effect, where individuals are more likely to use goods they pay for. Using a randomized experiment in Madagascar, we evaluate the impact of price on demand for and use of ITNs. We find that price negatively affects both demand and use of ITNs. When price increases by $0.55, demand falls by 23.1% points (CI 19.6-26.6; P < 0.01) and effective coverage falls by 23.1% points (CI 19.6-26.6; P < 0.01). We fail to find evidence of a screening effect for prices greater than zero, but households eligible for free ITNs are more likely to use them if they have more self-reported fevers in the household at baseline. We also fail to find evidence of a sunk cost effect, meaning that households are not more likely to use nets that they pay for. Our results suggest that: (1) only partially subsidizing ITNs significantly limits ownership and (2) distributing ITNs for free or at a small nominal price will maximize demand and effective coverage. Alternative sources of financing should be identified to completely (or almost completely) subsidize the cost of ITNs in order to maximize coverage of ITNs among poor populations at risk of malaria.
Low rainfall is a major limitation to expanding the dairy industry in semi-arid environments in East Africa. In such dry areas, plants need to keep their tissues hydrated and stomata open for carbon exchange and to grow. On this basis, we assessed the productivity of 10 lines of Napier grass (Pennisetum purpureum Schum.), which formed three yield clusters: low yielding (LYC), moderate yielding (MYC), and high yielding (HYC), in a wet highland (Muguga) and semi-arid lowland (Katumani) of Kenya. Stomatal conductance (gs ), leaf water potential (LWP) and relative water content (RWC) were monitored, and water use simulated, over four growth cycles in 2012. These were used with measurements of leaf area index (LAI) and plant dry weight to explore the possible use of these physiological parameters for assessing productivity potential of Napier grass accessions.
The plants were less stressed at Muguga, where gs was 700-1000 mmol m(-2) s(-1) , LWP -0.4 to -0.9 MPa and RWC was 82-95%; these values at Katumani were 450-750 mmol m(-2) s(-1) , -0.7 to -1.4 MPa and 74-93%, respectively. Total water use at Katumani was of the order HYC ≈ MYC (390 mm) > LYC (370 mm), and water use efficiency (WUE, kg ha(-1) mm(-1) ) followed the same order HYC (34.3) > MYC (32.6) > LYC (24.9); whereas at Muguga water use averaged 710 mm for HYC and MYC, greater than 676 mm for LYC, and WUE (kg ha(-1) mm(-1) ) averaged 29.2 for HYC and MYC, and 19.4 for LYC.
The three water stress indices were poor, whereas vigorous early canopy development (determined as LAI) was a more reliable predictor of productivity potential of Napier grasses. In these dry environments, therefore, early rapid canopy development can be an effective indicator of yield potential and a credible selection criterion. © 2016 Society of Chemical Industry.
The freshwater zooplankton Daphnia magna has been extensively employed in chemical toxicity tests such as OECD Test Guidelines 202 and 211. Previously, it has been demonstrated that the treatment of juvenile hormones (JHs) or their analogues to female daphnids can induce male offspring production. Based on this finding, a rapid screening method for detection of chemicals with JH-activity was recently developed using adult D. magna. This screening system determines whether a chemical has JH-activity by investigating the male offspring inducibility. Although this is an efficient high-throughput short-term screening system, much remains to be discovered about JH-responsive pathways in the ovary, and whether different JH-activators act via the same mechanism. JH-responsive genes in the ovary including developing oocytes are still largely undescribed. Here, we conducted comparative microarray analyses using ovaries from Daphnia magna treated with fenoxycarb (Fx; artificial JH agonist) or methyl farnesoate (MF; a putative innate JH in daphnids) to elucidate responses to JH agonists in the ovary, including developing oocytes, at a JH-sensitive period for male sex determination. We demonstrate that induction of hemoglobin genes is a well-conserved response to JH even in the ovary, and a potential adverse effect of JH agonist is suppression of vitellogenin gene expression, that might cause reduction of offspring number. This is the first report demonstrating different transcriptomics profiles from MF and an artificial JH agonist in D. magna ovary, improving understanding the tissue-specific mode-of-action of JH. Copyright © 2016 John Wiley & Sons, Ltd.
Reactive oxygen species can modify the structure and function of proteins and may also act as important signaling molecules in various cellular processes. Cysteine thiol groups of proteins are particularly susceptible to oxidation. Meanwhile, their reversible oxidation is of critical roles for redox regulation and signaling. Recently, several computational tools have been developed for predicting redox-sensitive cysteines; however, those
 methods either only focus on catalytic redox-sensitive cysteines in thiol oxidoreductases, or heavily depend on protein structural data, thus cannot be widely used.
In this study, we analyzed various sequence-based features potentially related to cysteine redox-sensitivity, and identified three types of features for efficient computational prediction of redox-sensitive cysteines. These features are: sequential distance to the nearby cysteines, PSSM profile and predicted secondary structure of flanking residues. After further feature selection using SVM-RFE, we developed Redox-Sensitive Cysteine Predictor (RSCP), a SVM based classifier for redox-sensitive cysteine prediction using primary sequence only. Using 10-fold cross-validation on RSC758 dataset, the accuracy, sensitivity, specificity, MCC and AUC were estimated as 0.679, 0.602, 0.756, 0.362 and 0.727, respectively. When evaluated using 10-fold cross-validation with BALOSCTdb dataset which has structure information, the model achieved performance comparable to current structure-based method. Further validation using an independent dataset indicates it is robust and of relatively better accuracy for predicting redox-sensitive cysteines from non-enzyme proteins.
In this study, we developed a sequence-based classifier for predicting redox-sensitive cysteines. The major advantage of this method is that it does not rely on protein structure data, which ensures more extensive application compared to other current implementations. Accurate prediction of redox-sensitive cysteines not only enhances our understanding about the redox sensitivity of cysteine, it may also complement the proteomics approach and facilitate further experimental investigation of important redox-sensitive cysteines.
Tobacco pricing impacts use, yet military retailers sell discounted cigarettes. No systematic research has examined how military retail stores use internal community comparisons to set prices. We analysed data obtained through a Freedom of Information Act request on community price comparisons used by military retail to set cigarette prices.
Data on cigarette prices were obtained directly from military retailers (exchanges) from January 2013 to March 2014. Complete pricing data were obtained from exchanges on 114 military installations.
The average price for a pack of Marlboro cigarettes in military exchanges was US$5.51, which was similar to the average lowest community price (US$5.45; mean difference=-0.06; p=0.104) and almost a US$1.00 lower than the average highest price (US$6.44). Military retail prices were 2.1%, 6.2% and 13.7% higher than the lowest, average and highest community comparisons, respectively, and 18.2% of exchange prices violated pricing instructions. There was a negative correlation (r=-0.21, p=0.02) between the number of community stores surveyed and exchange cigarette prices.
There was no significant difference between prices for cigarettes on military installations and the lowest average community comparison, and in some locations, the prices violated Department of Defense (DoD) policy. US Marine Corps exchanges had the lowest prices, which is of concern given that the Marines also have the highest rates of tobacco use in the DoD. Given the relationship between tobacco product prices and demand, a common minimum (or floor) shelf price for tobacco products should be set for all exchanges and discount coupon redemptions should be prohibited.
Two cell lines derived from a single Trypanosoma cruzi clone by long-term passaging generated a highly virulent (C8C3hvir) and a low virulent (C8C3lvir) cell line. The C8C3hvir cell line was highly infective and lethal to Balb/c mice, and the C8C3lvir cell line was three- to five-fold less infective to mouse cardiomyocytes than C8C3hvir. The highly virulent T. cruzi cell line abundantly expressed the major cysteine proteinase cruzipain (Czp), complement regulatory protein (CRP) and trans-sialidase (TS), all of which are known to act as virulence factors in this parasite. The in vitro invasion capacity and in vivo Balb/c mouse infectiveness of the highly virulent strain was strongly reduced by pre-treatment with antisense oligonucleotides targeting TS or CRP or with E64d. Based on these results, we conclude that decreased levels of TS, CRP and Czp expression could contribute to loss of T. cruzi trypomastigote virulence.
The gut hormone, glucagon like peptide-1 (GLP-1) exerts anti-inflammatory effects. However, its clinical use is limited by its short half-life. Previously, we have shown that GLP-1 as a nanomedicine (GLP-1 in sterically stabilized phospholipid micelles, GLP-1-SSM) has increased in vivo stability. The current study was aimed at testing the efficacy of this GLP-1 nanomedicine in alleviating colonic inflammation and associated diarrhea in dextran sodium sulfate (DSS) induced mouse colitis model. Our results show that GLP-1-SSM treatment markedly alleviated the colitis phenotype by reducing the expression of pro-inflammatory cytokine IL-1β, increasing goblet cells and preserving intestinal epithelial architecture in colitis model. Further, GLP-1-SSM alleviated diarrhea (as assessed by luminal fluid) by increasing protein expression of intestinal chloride transporter DRA (down regulated in adenoma). Our results indicate that GLP-1 nanomedicine may act as a novel therapeutic tool in alleviating gut inflammation and associated diarrhea in inflammatory bowel disease (IBD).
Alterations in neurotransmitter phenotypes of specific neurons can cause imbalances in excitation and inhibition in the central nervous system (CNS), leading to diseases. Therefore, the correct specification and maintenance of neurotransmitter phenotypes is vital. As with other neuronal properties, neurotransmitter phenotypes are often specified and maintained by particular transcription factors. However, the specific molecular mechanisms and transcription factors that regulate neurotransmitter phenotypes remain largely unknown.
In this paper we use single mutant, double mutant and transgenic zebrafish embryos to elucidate the functions of Lmx1ba and Lmx1bb in the regulation of spinal cord interneuron neurotransmitter phenotypes.
We demonstrate that lmx1ba and lmx1bb are both expressed in zebrafish spinal cord and that lmx1bb is expressed by both V0v cells and dI5 cells. Our functional analyses demonstrate that these transcription factors are not required for neurotransmitter fate specification at early stages of development, but that in embryos with at least two lmx1ba and/or lmx1bb mutant alleles there is a reduced number of excitatory (glutamatergic) spinal interneurons at later stages of development. In contrast, there is no change in the numbers of V0v or dI5 cells. These data suggest that lmx1b-expressing spinal neurons still form normally, but at least a subset of them lose, or do not form, their normal excitatory fates. As the reduction in glutamatergic cells is only seen at later stages of development, Lmx1b is probably required either for the maintenance of glutamatergic fates or to specify glutamatergic phenotypes of a subset of later forming neurons. Using double labeling experiments, we also show that at least some of the cells that lose their normal glutamatergic phenotype are V0v cells. Finally, we also establish that Evx1 and Evx2, two transcription factors that are required for V0v cells to acquire their excitatory neurotransmitter phenotype, are also required for lmx1ba and lmx1bb expression in these cells, suggesting that Lmx1ba and Lmx1bb act downstream of Evx1 and Evx2 in V0v cells.
Lmx1ba and Lmx1bb function at least partially redundantly in the spinal cord and three functional lmx1b alleles are required in zebrafish for correct numbers of excitatory spinal interneurons at later developmental stages. Taken together, our data significantly enhance our understanding of how spinal cord neurotransmitter fates are regulated.
People living with HIV in Sub-Saharan Africa face significant challenges accessing care. Community-based peer support groups can increase linkage to treatment, though the effectiveness of structured, scalable groups has not been demonstrated. This study aimed to measure the impact of the structured Integrated Access to Care and Treatment intervention on clients' knowledge, attitudes, and practice regarding HIV/AIDS, including their experiences of stigma, in KwaZulu-Natal, South Africa. Data collection involved pre-/post-tests and client interviews. Pre-/post-test data from 66 clients were collected. 17 participants were interviewed. Paired t-tests did not detect significant changes in the main outcomes. Qualitative results suggested a psychosocial benefit as participants connected with their peers, expressed themselves openly, and re-engaged with their communities. Unfortunately, this study did not quantitatively measure psychosocial changes, and the results have limited generalizability to men. I ACT may be an effective complement to clinic-based support services, though further study should quantify the psychosocial benefit.
Mosquitoes are insects of huge public health importance, since they act as vectors for important pathogens and parasites. Here, we focused on the possibility of using the neem cake in the fight against mosquito vectors. The neem cake chemical composition significantly changes among producers, as evidenced by our HPTLC (High performance thin layer chromatography) analyses of different marketed products. Neem cake extracts were tested to evaluate the ovicidal, larvicidal and adulticidal activity against the rural malaria vector Anopheles culicifacies. Ovicidal activity of both types of extracts was statistically significant, and 150 ppm completely inhibited egg hatching. LC50 values were extremely low against fourth instar larvae, ranging from 1.321 (NM1) to 1.818 ppm (NA2). Adulticidal
 activity was also high, with LC50 ranging from 3.015 (NM1) to 3.637 ppm (NM2). This study pointed out the utility of neem cake as a source of eco-friendly mosquitocides in Anopheline vector control programmes.
Large multicentre randomised controlled trials (RCTs) in the Netherlands are increasingly being impeded by major differences between local approval procedures. However, no national agenda exists as yet to improve this situation. The existence of major local differences in processing time and documentation required has been reported previously but little is known about the costs incurred and whether or not specific certifications and research contracts are mandatory. The current study evaluated these aspects of local procedures for obtaining approval of two oncological multicentre RCTs.
Retrospective, descriptive.
All local procedures for obtaining approval of two randomised clinical trials were evaluated: the CAIRO5 and CHARISMA trials initiated by the Dutch Colorectal Cancer Group (DCCG). We objectified time between approval by the Medical Ethics Review Committee (METC) and final approval by the Board of Directors (RvB), the type and number of documents needed, and costs charged.
The median time interval between the approval by the Medical Ethics Review Committee and the approval by the Board of Directors was 90 days (range 4-312). The number of documents required per centre ranged from 6-20. The costs charged ranged from € 0-€ 1750, and amounted to € 8575 for all procedures combined. No costs were charged by the majority of the centres.
The approval procedures for multicentre clinical trials in the Netherlands demonstrate major differences. Processing times, documentation required and costs are unpredictable; greater uniformity is highly desirable in this context.
The liver and pancreas are the prime digestive and metabolic organs in the body. After emerging from the neighboring domains of the foregut endoderm, they turn on distinct differentiation and morphogenesis programs that are regulated by hierarchies of transcription factors. Members of SOX family of transcription factors are expressed in the liver and pancreas throughout development and act upstream of other organ-specific transcription factors. They play key roles in maintaining stem cells and progenitors. They are also master regulators of cell fate determination and tissue morphogenesis. In this review, we summarize the current understanding of SOX transcription factors in mediating liver and pancreas development. We discuss their contribution to adult organ function, homeostasis and injury responses. We also speculate how the knowledge of SOX transcription factors can be applied to improve therapies for liver diseases and diabetes.
Integrative strategy of health services delivery has been proven to be effective in economically developed countries, where the healthcare systems have enough qualified primary care providers. However rural China lacks such providers to act as gatekeeper, besides, Chinese rural hypertensive patients are usually of old age, more likely to be exposed to health risk factors and they experience a greater socio-economic burden. All these Chinese rural setting specific features make the effectiveness of integrative strategy of health services in improving health related quality of life among Chinese rural hypertensive patients uncertain.
In order to assess the impact of integrative strategy of health services delivery on health related quality of life among Chinese rural hypertensive patients, a two-year quasi-experimental trial was conducted in Chongqing, China. At baseline the sample enrolled 1006 hypertensive patients into intervention group and 420 hypertensive patients into control group. Physicians from village clinics, town hospitals and county hospitals worked collaboratively to deliver multidisciplinary health services for the intervention group, while physicians in the control group provided services without cooperation. The quality of life was studied by SF-36 Scale. Blood pressures were reported by town hospitals. The Difference-in-Differences model was used to estimate the differences in SF-36 score and blood pressure of both groups to assess the impact.
The study showed that at baseline there was no statistical difference in SF-36 scores between both groups. While at follow-up the intervention group scored higher in overall SF-36, Role Physical, Body Pain, Social Functioning and Role Emotional than the control group. The Difference-in-Differences result demonstrated that there were statistical differences in SF-36 total score (p = 0.011), Role Physical (p = 0.027), Social Functioning (p = 0.000), Role Emotional (p = 0.002) between both groups. Integrative services delivery improved the score of SF-36 by 4.591 ± 1.794, and also improved the score in domains of Role Physical, Social Functioning and Role Emotional by 8.289 ± 3.753, 9.762 ± 2.019 and 12.534 ± 4.083, respectively.
Patients in the intervention group obtained lower systolic blood pressure and diastolic blood pressure. Integrative strategy of health services delivery improved health related quality of life and blood pressure control among rural Chinese hypertensive patients.
The Ethics Committee of Tongji Medical College, Huazhong University of Science and Technology, ChiCTR-OOR-14005563, Registered on 7 June 2011.
Obesity is defined as a chronic and excessive growth of adipose tissue. It is increasingly recognized as an oncogenic factor. Adipose tissue, originally thought as a passive depot for fat metabolism, is now identified as an endocrine organ, secreting a wide array of bioactive molecules known as adipocytokines, which act as key mediators in several obesity-associated diseases. Among these adipocytokines, adiponectin has been proposed as having a key role in the pathogenesis of cardiovascular disease and type 2 diabetes along with other diseases such as obesity-associated malignancies, including breast cancer. New insights into the molecular mechanisms linking adiponectin and mammary tumorigenesis could be useful to identify novel therapeutic approaches to be exploited, particularly in obese women.
Despite significant investment in mental health and suicide intervention strategies in Australia, the extent of change in suicide rates over the last decade is unclear. This paper analyses sex and age trajectories in suicide rates over the last decade in Australia. Age Standardized Suicide Rates from 2004 to 2013 were obtained from the Australian Bureau of Statistics and reflect rates of suicide per 100,000 within age and sex cohorts. Age-related suicide rates were consistent over the last decade. For both males and females, there were increases in mid-life suicide rates before declining around 55-65 years of age. However, rates of suicide in men increased in late-life with rates for those aged 70-79 comparable with those in mid-life. Rates amongst men aged 85+ were consistently the highest rates over the decade. Positively, there was decline in suicide rates among younger men aged 20-34 years. However, more consistently, for both sexes across most age cohorts, there were either increases or no change in suicide rate. Apart from declines in younger-adult males, analysis of age-standardized suicide rates indicate no improvement in suicide rates. High suicide rates amongst middle-aged and older males remain a significant public health issue that needs to be addressed.
Polypharmacology, which refers to the ability of a molecule to simultaneously interact with multiple target proteins, is shifting the drug discovery process from a 'one-drug-one-target' paradigm to a conceptual framework in which the multitarget profile of small molecules is proactively pursued. Nicotinic acetylcholine receptors (nAChRs) appear as attractive targets for the design of polypharmacological agents. These proteins participate in the regulation of multiple physiological processes and impressive progress has been made regarding their structure and function. Moreover, they contain several ligand binding sites, and a number of compounds including orthosteric and allosteric ligands, have been described.
The authors provide an overview of some of these topics and briefly discuss the mechanisms of action of some known promiscuous drugs that act at nAChRs, with the idea that this analysis will serve to guide the development of novel polypharmacological agents with a wide spectrum of actions.
The authors anticipate that many innovative drugs will be compounds intentionally designed to have polypharmacological properties. Furthermore, the authors suggest that although the search for multitarget drugs acting at the orthosteric site of nAChRs will remain an interesting option, allosteric sites of these receptors exhibit a much greater polypharmacological potential.
The allure of integrating the tunable properties of soft nanomaterials with the unique optical and electronic properties of metal nanoparticles has led to the development of organic-inorganic hybrid nanomaterials. A promising method for the synthesis of such organic-inorganic hybrid nanomaterials is afforded by the in situ generation of metal nanoparticles within a host organic template. Due to their tunable surface morphology and porosity, soft organic materials such as gels, liquid crystals, and polymers that are derived from various synthetic or natural compounds can act as templates for the synthesis of metal nanoparticles of different shapes and sizes. This method provides stabilization to the metal nanoparticles by the organic soft material and advantageously precludes the use of external reducing or capping agents in many instances. In this Account, we exemplify the green chemistry approach for synthesizing these materials, both in the choice of gelators as soft material frameworks and in the reduction mechanisms
 that generate the metal nanoparticles. Established herein is the core design principle centered on conceiving multifaceted amphiphilic soft materials that possess the ability to self-assemble and reduce metal ions into nanoparticles. Furthermore, these soft materials stabilize the in situ generated metal nanoparticles and retain their self-assembly ability to generate metal nanoparticle embedded homogeneous organic-inorganic hybrid materials. We discuss a remarkable example of vegetable-based drying oils as host templates for metal ions, resulting in the synthesis of novel hybrid nanomaterials. The synthesis of metal nanoparticles via polymers and self-assembled materials fabricated via cardanol (a bioorganic monomer derived from cashew nut shell liquid) are also explored in this Account. The organic-inorganic hybrid structures were characterized by several techniques such as UV-visible spectroscopy, scanning electron microscopy (SEM), and transmission electron microscopy (TEM). Utilization of silver nanoparticle-based hybrid nanomaterials as an antimicrobial material is another illustration of the advantage of hybrid nanomaterials. We envision that the results summarized in this Account will help the scientific community to design and develop diverse organic-inorganic hybrid materials using environmentally benign methods and that these materials will yield advanced properties that have multifaceted applications in various research fields.
Organ-to-organ communication is indispensable for higher organisms to maintain homeostasis over their entire life. Recent findings have uncovered that plants, like animals, mediate organ-to-organ communication by long-distance signaling through the vascular system. In particular, xylem-mobile secreted peptides have attracted much attention as root-to-shoot long-distance signaling molecules in response to fluctuating environmental nutrient status. Several leguminous CLE peptides induced by rhizobial inoculation act as 'satiety' signals in long-distance negative feedback of nodule formation. By contrast, Arabidopsis CEP family peptides induced by local nitrogen (N)-starvation behave as systemic 'hunger' signals to promote compensatory N acquisition in other parts of the roots. Xylem sap peptidomics also implies the presence of still uncharacterized long-distance signaling peptides. This review highlights the current understanding of and new insights into the mechanisms and functions of root-to-shoot long-distance peptide signaling during environmental responses.
Single-emitter microscopy has emerged as a promising method of imaging nanostructures with nanoscale resolution. This technique uses the centroid position of an emitter's far-field radiation pattern to infer its position to a precision that is far below the diffraction limit. However, nanostructures composed of high-dielectric materials such as noble metals can distort the far-field radiation pattern. Previous work has shown that these distortions can significantly degrade the imaging of the local density of states in metallic nanowires using polarization-resolved imaging. But unlike nanowires, nanoparticles do not have a well-defined axis of symmetry, which makes polarization-resolved imaging difficult to apply. Nanoparticles also exhibit a more complex range of distortions, because in addition to introducing a high dielectric surface, they also act as efficient scatterers. Thus, the distortion effects of nanoparticles in single-emitter microscopy remains poorly understood. Here we demonstrate that metallic nanoparticles can significantly distort the accuracy of single-emitter imaging at distances exceeding 300 nm. We use a single quantum dot to probe both the magnitude and the direction of the metallic nanoparticle-induced imaging distortion and show that the diffraction spot of the quantum dot can shift by more than 35 nm. The centroid position of the emitter generally shifts away from the nanoparticle position, which is in contradiction to the conventional wisdom that the nanoparticle is a scattering object that will pull in the diffraction spot of the emitter toward its center. These results suggest that dielectric distortion of the emission pattern dominates over scattering. We also show that by monitoring the distortion of the quantum dot diffraction spot we can obtain high-resolution spatial images of the nanoparticle, providing a new method for performing highly precise, subdiffraction spatial imaging. These results provide a better understanding of the complex near-field coupling between emitters and nanostructures and open up new opportunities to perform super-resolution microscopy with higher accuracy.
To examine national changes in rates of cost-related prescription nonadherence (CRN) by age group, we used data from the 1999-2015 Sample Adult and Sample Child National Health Interview Surveys (n = 768 781). In a logistic regression analysis of 2015 data, we identified subgroups at risk for cost-related nonadherence. The proportion of all Americans who did not fill a prescription in the previous 12 months because they could not afford it grew from 1999 to 2009, peaking at 8.3% at the height of the Great Recession and dropping to 5.2% by 2015. CRN among seniors, however, peaked in 2004 at 5.4% and dropped to 3.6% after implementation of Medicare Part D in 2006. CRN is responsive to improved access related to implementation of Medicare Part D and the Affordable Care Act.
Waterpipe smoking has been dramatically increasing among youth worldwide and in the United States. Despite its general association with misperceptions of reduced harm, evidence suggests this is a harmful and dependence-inducing tobacco use method that represents a threat to public health. Waterpipe products continue to be generally unregulated, which likely has contributed to their spread. The Family Smoking Prevention and Tobacco Control Act of 2009 granted the US Food and Drug Administration (FDA) the authority to regulate waterpipe products, and the FDA finalized a rule extending its authority over waterpipe products in May 2016. This critical step in addressing the alarming increase in waterpipe smoking in the United States has created urgency for research to provide the evidence needed for effective regulatory initiatives for waterpipe products. We aim to stimulate such research by providing a framework that addresses the scope of waterpipe products and their unique context and use patterns. The proposed framework identifies regulatory targets for waterpipe product components (i.e., tobacco, charcoal, and device), the waterpipe café setting, and its marketing environment dominated by Internet promotion.
Central venous port devices made of two different polymeric materials, thermoplastic polyurethane (TPU) and silicone rubber (SiR), were compared due their material properties. Both naïve catheters as well as catheters after removal from patients were investigated. In lab experiments the influence of various chemo-therapeutic solutions on material properties was investigated, whereas the samples after removal were compared according to the implanted time in patient. The macroscopic, mechanical performance was assessed with dynamic, specially adapted tests for elasticity. The degradation status of the materials was determined with common tools of polymer characterisation, such as infrared spectroscopy, molecular weight measurements and various methods of thermal analysis. The surface morphology was analysed using scanning electron microscopy. A correlation between material properties and clinical performance was proposed. The surface morphology and chemical composition of the polyurethane catheter materials can potentially result in increased susceptibility of the catheter to bloodstream infections and thrombotic complications. The higher mechanic failure, especially with increasing implantation time of the silicone catheters is related to the lower mechanical performance compared to the polyurethane material as well as loss of barium sulphate filler particles near the surface of the catheter. This results in preformed microscopic notches, which act as predetermined sites of fracture.
The neuroregulator system in humans controls organ and system functioning. This system comprises a set of neural centres that are distributed along the spinal cord and act independently together with their nerve interconnections. The centres involved in this task were isolated in previous studies through investigations of the functioning and composition of the neuroregulator system of the lower urinary tract to elucidate their individual performances and enable the creation of a general neuroregulator system model capable of operating at the neuronal level. Although the long-term goal of our research is the development of a system on chip (SoC) capable of behaving as a fully programmable neuroregulator system, this work is another step in which we test the viability of the hardware design of one of these neuroregulator centres (specifically the cortical-diencephalic centre) to achieve a first prototype and architectural proposal. To this end, the behaviour of this centre has been isolated, a hardware design implemented on FPGA has been proposed to create a prototype, a simulation environment has been built for the evaluation, and finally, the results have been analysed. This system verified that the functional behaviour corresponded to the expected behaviour in humans and that the operational requirements for the implementation were technically and architecturally viable.
Osteoporosis is a major co-morbidity of COPD, but the mechanistic links between diseases of the lung and the bone remain elusive. Human neutrophils express the osteoclast activation factor RANKL (receptor activator of NF-kB ligand) and act directly on osteoclasts to promote bone loss. Given that
 neutrophils are key effector cells in the pathogenesis of COPD, these same cells, by expressing RANKL, may be involved in osteoporosis of COPD.
We enrolled 59 male patients with COPD, 32 smokers with normal lung function and 25 healthy non-smokers of the same gender as controls. The expression of RANKL on peripheral neutrophils was detected by flow cytometry. The plasma concentrations of pro-inflammatory cytokines were measured by ELISA. We analysed the association of RANKL (+) neutrophils with bone mineral density (BMD), lung function and the levels of cytokines.
RANKL (+) neutrophils in the blood of COPD patients were increased as compared to smokers and healthy controls, and the percentage of RANKL (+) neutrophils was higher in patients with low BMD as compared to those with normal BMD. The percentage of RANKL (+) neutrophils showed negative correlations with BMD and forced expiratory volume in 1 s (FEV1) % predicted. Further analysis showed that activated neutrophils were increased and expressed a higher level of RANKL in COPD patients. Plasma levels of IL-1β, IL-6 and IL-8 were increased in COPD patients and correlated with RANKL expression by neutrophils.
Our results show that RANKL-expressing neutrophils are increased in male patients with COPD and associated with BMD and lung function, suggesting that these cells may play a role in osteoclastogenesis in COPD.
In their active GTP-bound form, Rab proteins interact with proteins termed effector molecules. In this study, we have thoroughly characterized a Rab effector domain that is present in proteins of the Mical and EHBP families, both known to act in endosomal trafficking. Within our study, we show that these effectors display a preference for Rab8 family proteins (Rab8, 10, 13 and 15) and that some of the effector domains can bind two Rab proteins via separate binding sites. Structural analysis allowed us to explain the specificity towards Rab8 family members and the presence of two similar Rab binding sites that must have evolved via gene duplication. This study is the first to thoroughly characterize a Rab effector protein that contains two separate Rab binding sites within a single domain, allowing Micals and EHBPs to bind two Rabs simultaneously, thus suggesting previously unknown functions of these effector molecules in endosomal trafficking.
Dehydrins (DHNs) play a crucial role in enhancing abiotic stress tolerance in plants. Although DHNs have been identified and characterized in many plants, there is little known about Capsicum annuum L., one of the economically important vegetable crops. In this study, seven CaDHNs in the pepper genome were identified, which could be divided into two classes: YnSKn- and SKn-type, based on their highly conserved domains. Quantitative real-time PCR (qRT-PCR) results showed that the seven DHN genes were expressed in all tissues and might be involved in the growth and development of pepper. The gene expression profiles analysis suggested that most of the CaDHN genes were induced by various stresses (low temperature, salt and mannitol) and signaling molecules (ABA, SA and MeJA). Furthermore, the CaDHN3 (YSK2)-silenced pepper plants showed obvious lower resistance to abiotic stresses (cold, salt and mannitol) than the control plants (TRV2:00). So the CaDHN3 might act as a positive role in resisting abiotic stresses. This study lays the foundation for further studies into the regulation of their expression under various conditions.
Treatment guidelines for rheumatoid arthritis (RA) recommend early, aggressive treatment with nonbiologic and biologic disease-modifying antirheumatic drugs (DMARDs) to minimize long-term disability. We aimed to assess differences in medical resource utilization, drug therapy, and health outcomes among RA patients by insurance type in the United States.
Individuals with a self-reported diagnosis of RA were identified in the Medical Expenditure Panel Survey (MEPS) database, 2006-2009. Data regarding sociodemographic characteristics, insurance type and status, and outcomes (including health care resource utilization, prescription medication use, health status, and patient-reported barriers to health care) were extracted. Multivariable regression analyses were used to examine the impact of insurance type (private, Medicare, Medicaid, or uninsured) on outcome measures while controlling for age group, sex, and race/ethnicity.
A total of 693 individuals with a self-reported diagnosis of RA during the study period were identified; 423 were aged 18-64 years and 270 were aged ≥65 years. Among patients aged 18-64, those with Medicaid or who were uninsured were less likely than those with private insurance to visit a rheumatologist (adjusted odds ratio [aOR] 0.13 and 0.17, respectively; p < .001) and to receive biologic DMARDS (aOR 0.09 [p < .001] and 0.16 [p < .01], respectively); those with Medicaid were also less likely to receive nonbiologic DMARDS (aOR 0.26 [p < .01]). Those with Medicaid were more likely than those with private insurance to be unable/delayed in getting prescription drugs (aOR 2.9 [p < .05]), to experience cognitive, social, and physical limitations (aOR 8.7 [p < .001], 4.7 [p < .001], and 2.5 [p < .05], respectively); they also reported significantly lower general health and health-related quality of life. Patients aged ≥65 experienced greater equity in care and outcomes.
Younger RA patients with Medicaid (including those who receive coverage under the Medicaid expansion component of the Affordable Care Act) may be at risk for inadequate treatment.
Measles virus (MeV) is a highly contagious virus that still causes annual epidemics in developing countries despite the availability of a safe and effective vaccine. Additionally, importation from endemic countries causes frequent outbreaks in countries where it has been eliminated. The M protein of MeV plays a key role in virus assembly and cytopathogenesis; interestingly, M is localised in nucleus, cytoplasm and membranes of infected cells. We have used transient expression of M in transfected cells and in-cell transcription assays to show that only some MeV M localizes to the nucleus, in addition to cell membranes and the cytoplasm as previously described, and can inhibit cellular transcription via binding to nuclear factors. Additionally, MeV M was able to inhibit in vitro transcription in a dose-dependent manner. Importantly, a proportion of M is also localized to nucleus of MeV infected cells at early times in infection, correlating with inhibition of cellular transcription. Our data show, for the first time, that MeV M may play a role early in infection by inhibiting host cell transcription.
A change in the delicate equilibrium between apoptosis and survival regulates the neurons fate during the development of nervous system and its homeostasis in adulthood. Signaling pathways promoting or protecting from apoptosis are activated by multiple signals, including those elicited by neurotrophic factors, and depend upon specific transcriptional programs. To decipher the rescue program induced by substance P (SP) in cerebellar granule neurons, we analyzed their whole-genome expression profiles after induction of apoptosis and treatment with SP. Transcriptional pathways associated with the survival effect of SP included genes encoding for proteins that may act as pharmacological targets. Inhibition of one of these, the Myc pro-oncogene by treatment with 10058-F4, reverted in a dose-dependent manner the rescue effect of SP. In addition to elucidate the transcriptional mechanisms at the intersection of neuronal apoptosis and survival, our systems biology-based perspective paves the way towards an innovative pharmacology based on targets downstream of neurotrophic factor receptors.
Mitochondrial antiviral signalling protein (MAVS) acts as a critical adaptor protein to transduce antiviral signalling by physically interacting with activated RIG-I and MDA5 receptors. MAVS executes its functions at the outer membrane of mitochondria to regulate downstream antiviral signalling, indicating that the mitochondria provides a functional platform for innate antiviral signalling transduction. However, little is known about whether and how MAVS-mediated antiviral signalling contributes to mitochondrial homeostasis. Here we show that the activation of MAVS is sufficient to induce autophagic signalling, which may mediate the turnover of the damaged mitochondria. Importantly, we find MAVS directly interacts with LC3 through its LC3-binding motif 'YxxI', suggesting that MAVS might act as an autophagy receptor to mediate mitochondrial turnover upon excessive activation of RLR signalling. Furthermore, we provide evidence that both MAVS self-aggregation and its interaction with TRAF2/6 proteins are important for MAVS-mediated mitochondrial turnover. Collectively, our findings suggest that MAVS acts as a potential receptor for mitochondria-associated autophagic signalling to maintain mitochondrial homeostasis.
Recent developments in pain rehabilitation emphasise the importance of promoting psychological flexibility. Acceptance and Commitment Therapy (ACT) is one approach that has been shown to be effective for the treatment of chronic musculoskeletal pain. However, studies have shown that introducing innovative approaches such as ACT into established health care can cause some anxiety for professional groups. We used Action Research to evaluate the implementation of ACT to a physiotherapy-led pain rehabilitation programme.
All staff in the pain service were invited to participate. Participants took part in focus groups, engaged in reflective sessions/meetings and completed reflective diaries. The analysis was undertaken by an experienced qualitative researcher using constant comparison. Participants reviewed emerging themes and validated the findings.
Four key
 themes emerged from the study: (a) the need to see pain as an embodied, rather than dualistic, experience; (b) the need for a more therapeutic construction of 'acceptance'; (c) value-based goals as profound motivation for positive change; and (d) it's quite a long way from physiotherapy. Integral to a therapeutic definition of acceptance was the challenge of moving away from 'fixing' towards 'sitting with'. Participants described this as uncomfortable because it did not fit their biomedical training.
This article describes how Action Research methodology was used in the introduction of ACT to a physiotherapy-led pain rehabilitation programme. The innovation of this study is that it helps us to understand the potential barriers and facilitators to embedding an ACT philosophy within a physiotherapy setting.
Different sources of epigenetic changes can increase the range of phenotypic options. Environmentally induced epigenetic changes and stochastic epimutations are, respectively, associated with phenotypic plasticity and diversifying bet-hedging. Their relative contribution is thus expected to reflect the capacity of a genotype to face distinct changes since these strategies are differentially selected according to environmental uncertainty. To test this hypothesis, we assessed the sources of epigenetic changes on clonal fish from predictable (lakes) or unpredictable (intermittent streams) environments. DNA methylation of clones from natural conditions revealed contrasting contribution of environmentally induced versus stochastic changes according to their origins. These differences were validated in common garden experiments. Consistent with theoretical models, distinct sources of epigenetic variation prevail according to the environmental uncertainty. However, both sources act conjointly, suggesting that plasticity and random processes are complementary strategies. This represents a rigorous approach for further exploring the capacity of organisms to respond to environmental conditions.
Atopic dermatitis (AD) is a Th2-dominated inflammatory skin disease characterized by epidermal thickening. Serum levels of IL-22, a cytokine known to induce keratinocyte proliferation, are elevated in AD, and Th22 cells infiltrate AD skin lesions. We show that application of antigen to mouse skin subjected to tape stripping, a surrogate for scratching, induces an IL-22 response that drives epidermal hyperplasia and keratinocyte proliferation in a mouse model of skin inflammation that shares many features of AD. DC-derived IL-23 is known to act on CD4(+) T cells to induce IL-22 production. However, the mechanisms that drive IL-23 production by skin DCs in response to cutaneous sensitization are not well understood. We demonstrate that IL-23 released by keratinocytes in response to endogenous TLR4 ligands causes skin DCs, which selectively express IL-23R, to up-regulate their endogenous IL-23 production and drive an IL-22 response in naive CD4(+) T cells that mediates epidermal thickening. We also show that IL-23 is released in human skin after scratching and polarizes human skin DCs to drive an IL-22 response, supporting the utility of IL-23 and IL-22 blockade in AD.
Desiccation tolerance (DT) is a remarkable process that allows seeds in the dry state to remain viable for long periods of time that in some instances exceed 1,000 y. It has been postulated that seed DT evolved by rewiring the regulatory and signaling networks that controlled vegetative DT, which itself emerged as a crucial adaptive trait of early land plants. Understanding the networks that regulate seed desiccation tolerance in model plant systems would provide the tools to understand an evolutionary process that played a crucial role in the diversification of flowering plants. In this work, we used an integrated approach that included genomics, bioinformatics, metabolomics, and molecular genetics to identify and validate molecular networks that control the acquisition of DT in Arabidopsis seeds. Two DT-specific transcriptional subnetworks were identified related to storage of reserve compounds and cellular protection mechanisms that act downstream of the embryo development master regulators LEAFY COTYLEDON 1 and 2, FUSCA 3, and ABSCICIC ACID INSENSITIVE 3. Among the transcription factors identified as major nodes in the DT regulatory subnetworks, PLATZ1, PLATZ2, and AGL67 were confirmed by knockout mutants and overexpression in a desiccation-intolerant mutant background to play an important role in seed DT. Additionally, we found that constitutive expression of PLATZ1 in WT plants confers partial DT in vegetative tissues.
Transient spine enlargement (3- to 5-min timescale) is an important event associated with the structural plasticity of dendritic spines. Many of the molecular mechanisms associated with transient spine enlargement have been identified experimentally. Here, we use a systems biology approach to construct a mathematical model of biochemical signaling and actin-mediated transient spine expansion in response to calcium influx caused by NMDA receptor activation. We have identified that a key feature of this signaling network is the paradoxical signaling loop. Paradoxical components act bifunctionally in signaling networks, and their role is to control both the activation and the inhibition of a desired response function (protein activity or spine volume). Using ordinary differential equation (ODE)-based modeling, we show that the dynamics of different regulators of transient spine expansion, including calmodulin-dependent protein kinase II (CaMKII), RhoA, and Cdc42, and the spine volume can be described using paradoxical signaling loops. Our model is able to capture the experimentally observed dynamics of transient spine volume. Furthermore, we show that actin remodeling events provide a robustness to spine volume dynamics. We also generate experimentally testable predictions about the role of different components and parameters of the network on spine dynamics.
Maternal inheritance of mitochondria and mtDNA is a universal principle in human and animal development, guided by selective ubiquitin-dependent degradation of the sperm-borne mitochondria after fertilization. However, it is not clear how the 26S proteasome, the ubiquitin-dependent protease that is only capable of degrading one protein molecule at a time, can dispose of a whole sperm mitochondrial sheath. We hypothesized that the canonical ubiquitin-like autophagy receptors [sequestosome 1 (SQSTM1), microtubule-associated protein 1 light chain 3 (LC3), gamma-aminobutyric acid receptor-associated protein (GABARAP)] and the nontraditional mitophagy pathways involving ubiquitin-proteasome system and the ubiquitin-binding protein dislocase, valosin-containing protein (VCP), may act in concert during mammalian sperm mitophagy. We found that the SQSTM1, but not GABARAP or LC3, associated with sperm mitochondria after fertilization in pig and rhesus monkey zygotes. Three sperm mitochondrial proteins copurified with the recombinant, ubiquitin-associated domain of SQSTM1. The accumulation of GABARAP-containing protein aggregates was observed in the vicinity of sperm mitochondrial sheaths in the zygotes and increased in the embryos treated with proteasomal inhibitor MG132, in which intact sperm mitochondrial sheaths were observed. Pharmacological inhibition of VCP significantly delayed the process of sperm mitophagy and completely prevented it when combined with microinjection of autophagy-targeting antibodies specific to SQSTM1 and/or GABARAP. Sperm mitophagy in higher mammals thus relies on a combined action of SQSTM1-dependent autophagy and VCP-mediated dislocation and presentation of ubiquitinated sperm mitochondrial proteins to the 26S proteasome, explaining how the whole sperm mitochondria are degraded inside the fertilized mammalian oocytes by a protein recycling system involved in degradation of single protein molecules.
Organismal evolution tends to be closely associated with ecological conditions. However, the extent to which this association constrains adaptation or diversification into new habitats remains unclear. We studied habitat evolution in the hyper-diverse angiosperm clade Saxifragales.
We used species-level phylogenies for approx. 950 species to analyse the evolution of habitat shifts as well as their influence on plant diversification. We combined habitat characterization based on floristic assignments and state-of-the art phylogenetic comparative methods to estimate within- and across-habitat diversification patterns.
Our analyses showed that Saxifragales diversified into multiple habitats from a forest-inhabiting ancestor and that this diversification is governed by relatively rare habitat shifts. Lineages are likely to stay within inferred ancestral ecological conditions. Adaptation to some habitat types (e.g. aquatic, desert) may be canalizing events that lineages do not escape. Although associations between increased diversification rates and shifts in habitat preferences are occasionally observed, extreme macroevolutionary rates are closely associated with specific habitats. Lineages occurring in shrubland, and especially tundra and rock cliffs, exhibit comparatively high diversification, whereas forest, grassland, desert and aquatic habitats are associated with low diversification.
The likelihood of occupation of new habitats appears to be asymmetric. Shifts to aquatic and desert habitats may be canalizing events. Other habitats, such as tundra, might act as evolutionary sources, while forests provide the only habitat seemingly colonized easily by lineages originating elsewhere. However, habitat shifts are very rare, and any major environmental alteration is expected to have dramatic evolutionary consequences.
The impact of the Affordable Care Act (ACA) on HIV care patients,
 aged 18-64, was evaluated in three jurisdictions with Medicaid expansion (Chicago, New York State, and Washington) and three jurisdictions without Medicaid expansion (Georgia, Texas, and Virginia) using data from the Medical Monitoring Project. Multivariate regression models were used to evaluate insurance status that was reported pre- and post-ACA; self-reported impact of ACA on HIV care was explored with descriptive statistics. The likelihood of having insurance was significantly greater post-ACA compared to pre-ACA in Chicago (aRR = 1.33, 95%CI = 1.20, 1.47), Washington (aRR = 1.15, 95%CI = 1.08, 1.22), and Virginia (aRR = 1.14, 95%CI = 1.00, 1.29). In Washington and Chicago, the likelihood of being Medicaid-insured was greater post-ACA compared to pre-ACA implementation (Chicago: aRR = 1.25, 95%CI = 1.03,1.53; Washington: aRR = 1.66 95% CI = 1.30, 2.13). No other significant differences were observed. Only a subset of HIV care patients (range: 15-35%) reported a change in insurance that would have coincided with the implementation of ACA; and within this subset, a change in medical care costs was the most commonly noted issue. In conclusion, the influence of ACA on insurance coverage and other factors affecting HIV care likely varies by jurisdiction.
Death certificates and autopsy reports contain personal identifying information and clinical information protected under the Health Insurance Portability and Accountability Act (HIPAA) of 1996. These documents are used, for example, by the families of the deceased for settling estates, bereavement and closure, and genetic counseling of relatives. Insurance companies, public health and law enforcement officials, and the legal community also have legitimate claims to this information. Critical ethical questions have not yet been settled about whether and when this information should be public and under which circumstances making this kind of information public incurs benefits, harms, or both. Additional considerations include which organizations-the media, academic institutions, or government agencies, for example-are best suited to interpret these questions and respond to them.
The detection of plagiarism in scholarly articles is a complex process. It requires not just quantitative analysis with the similarity recording by anti-plagiarism software but also assessment of the readers' opinion, pointing to the theft of ideas, methodologies, and graphics. In this article we describe a blatant case of plagiarism by Chinese authors, who copied a Russian article from a non-indexed and not widely visible Russian journal, and published their own report in English in an open-access journal indexed by Scopus and Web of Science and archived in PubMed Central. The details of copying in the translated English article were presented by the Russian author to the chief editor of the index journal, consultants from Scopus, anti-plagiarism experts, and the administrator of the Committee on Publication Ethics (COPE). The correspondents from Scopus and COPE pointed to the decisive role of the editors' of the English journal who may consider further actions if plagiarism is confirmed. After all, the chief editor of the English journal retracted the article on grounds of plagiarism and published a retraction note, although no details of the complexity of the case were reported. The case points to the need for combining anti-plagiarism efforts and actively seeking opinion of non-native English-speaking authors and readers who may spot intellectual theft which is not always detected by software.
Preclinical and clinical evidence indicate that the proimmune effects of radiotherapy can be synergistically augmented with immunostimulatory mAbs to act both on irradiated tumor lesions and on distant, nonirradiated tumor sites. The combination of radiotherapy with immunostimulatory anti-PD1 and anti-CD137 mAbs was conducive to favorable effects on distant nonirradiated tumor lesions as observed in transplanted MC38 (colorectal cancer), B16OVA (melanoma), and 4T1 (breast cancer) models. The therapeutic activity was crucially performed by CD8 T cells, as found in selective depletion experiments. Moreover, the integrities of BATF-3-dependent dendritic cells specialized in crosspresentation/crosspriming of antigens to CD8(+) T cells and of the type I IFN system were absolute requirements for the antitumor effects to occur. The irradiation regimen induced immune infiltrate changes in the irradiated and nonirradiated lesions featured by reductions in the total content of effector T cells, Tregs, and myeloid-derived suppressor cells, while effector T cells expressed more intracellular IFNγ in both the irradiated and contralateral tumors. Importantly, 48 hours after irradiation, CD8(+) TILs showed brighter expression of CD137 and PD1, thereby displaying more target molecules for the corresponding mAbs. Likewise, PD1 and CD137 were induced on tumor-infiltrating lymphocytes from surgically excised human carcinomas that were irradiated ex vivo These mechanisms involving crosspriming and CD8 T cells advocate clinical development of immunotherapy combinations with anti-PD1 plus anti-CD137 mAbs that can be synergistically accompanied by radiotherapy strategies, even if the disease is left outside the field of irradiation. Cancer Res; 76(20); 5994-6005. ©2016 AACR.
Rust fungi are an important group of plant pathogens that cause devastating losses in agricultural, silvicultural and natural ecosystems. Plants can be protected from rust disease by resistance genes encoding receptors that trigger a highly effective defence response upon recognition of specific pathogen avirulence proteins. Identifying avirulence genes is crucial for understanding how virulence evolves in the field.
To facilitate avirulence gene cloning in the flax rust fungus, Melampsora lini, we constructed a high-density genetic linkage map using single nucleotide polymorphisms detected in restriction site-associated DNA sequencing (RADseq) data. The map comprises 13,412 RADseq markers in 27 linkage groups that together span 5860 cM and contain 2756 recombination bins. The marker sequences were used to anchor 68.9 % of the M. lini genome assembly onto the genetic map. The map and anchored assembly were then used to: 1) show that M. lini has a high overall meiotic recombination rate, but recombination distribution is uneven and large coldspots exist; 2) show that substantial genome rearrangements have occurred in spontaneous loss-of-avirulence mutants; and 3) identify the AvrL2 and AvrM14 avirulence genes by map-based cloning. AvrM14 is a dual-specificity avirulence gene that encodes a predicted nudix hydrolase. AvrL2 is located in the region of the M. lini genome with the lowest recombination rate and encodes a small, highly-charged proline-rich protein.
The M. lini high-density linkage map has greatly advanced our understanding of virulence mechanisms in this pathogen by providing novel insights into genome variability and enabling identification of two new avirulence genes.
Fusarium mycotoxins, deoxynivalenol (DON) and nivalenol (NIV) act as virulence factors and are essential for symptom development after initial infection in wheat. To date, 16 genes have been identified in the DON biosynthesis pathway. However, a comparative gene expression analysis in different chemotypes of Fusarium graminearum in response to Fusarium head blight infection remains to be explored. Therefore, in this study, nine genes that involved in trichothecene biosynthesis were analyzed among 3-acetyldeoxynivalenol (3-ADON), 15-acetyldeoxynivalenol (15-ADON) and nivalenol producing F. graminearum strains in a time course study. Quantitative reverse transcription polymerase chain reaction revealed that the expression of all examined TRI gene transcripts initiated at 2 days post-inoculation (dpi), peaked at three to four dpi and gradually decreased at seven dpi. The early induction of TRI genes indicates that presence of high levels of TRI gene transcripts at early stages is important to initiate the biosynthetic pathway of DON and NIV. Comparison of gene expression among the three chemotypes showed that relative expression of TRI genes was higher in 3-ADON producing strains compared with 15-ADON and NIV strains. Comparatively higher levels of gene expression may contribute to the higher levels of DON produced by 3-ADON strains in infected grains.
Controlled drug delivery systems are an encouraging solution to some drug disadvantages such as reduced solubility, deprived biodistribution, tissue damage, fast breakdown of the drug, cytotoxicity, or side effects. Self-ordered nanoporous anodic alumina is an auspicious material for drug delivery due to its biocompatibility, stability, and controllable pore geometry. Its use in drug delivery applications has been explored in several fields, including therapeutic devices for bone and dental tissue engineering, coronary stent implants, and carriers for transplanted cells. In this work, we have created and analyzed a stimuli-responsive drug delivery system based on layer-by-layer pH-responsive polyelectrolyte and nanoporous anodic alumina. The results demonstrate that it is possible to control the drug release using a polyelectrolyte multilayer coating that will act as a gate.
A thorough understanding of the ecological and evolutionary mechanisms that drive the phenotypic evolution of neoplastic cells is a timely and key challenge for the cancer research community. In this respect, mathematical modelling can complement experimental cancer research by offering alternative means of understanding the results of in vitro and in vivo experiments, and by allowing for a quick and easy exploration of a variety of biological scenarios through in silico studies.
To elucidate the roles of phenotypic plasticity and selection pressures in tumour
 relapse, we present here a phenotype-structured model of evolutionary dynamics in a cancer cell population which is exposed to the action of a cytotoxic drug. The analytical tractability of our model allows us to investigate how the phenotype distribution, the level of phenotypic heterogeneity, and the size of the cell population are shaped by the strength of natural selection, the rate of random epimutations, the intensity of the competition for limited resources between cells, and the drug dose in use.
Our analytical results clarify the conditions for the successful adaptation of cancer cells faced with environmental changes. Furthermore, the results of our analyses demonstrate that the same cell population exposed to different concentrations of the same cytotoxic drug can take different evolutionary trajectories, which culminate in the selection of phenotypic variants characterised by different levels of drug tolerance. This suggests that the response of cancer cells to cytotoxic agents is more complex than a simple binary outcome, i.e., extinction of sensitive cells and selection of highly resistant cells. Also, our mathematical results formalise the idea that the use of cytotoxic agents at high doses can act as a double-edged sword by promoting the outgrowth of drug resistant cellular clones. Overall, our theoretical work offers a formal basis for the development of anti-cancer therapeutic protocols that go beyond the 'maximum-tolerated-dose paradigm', as they may be more effective than traditional protocols at keeping the size of cancer cell populations under control while avoiding the expansion of drug tolerant clones.
This article was reviewed by Angela Pisco, Sébastien Benzekry and Heiko Enderling.
We have investigated the capability of nanoparticle-assisted laser desorption ionization mass spectrometry (NP-LDI MS), matrix-assisted laser desorption ionization (MALDI) MS, and gas cluster ion beam secondary ion mass spectrometry (GCIB SIMS) to provide maximum information available in lipid analysis and imaging of mouse brain tissue. The use of Au nanoparticles deposited as a matrix for NP-LDI MS is compared to MALDI and SIMS analysis of mouse brain tissue and allows selective detection and imaging of groups of lipid molecular ion species localizing in the white matter differently from those observed using conventional MALDI with improved imaging potential. We demonstrate that high-energy (40 keV) GCIB SIMS can act as a semi-soft ionization method to extend the useful mass range of SIMS imaging to analyze and image intact lipids in biological samples, closing the gap between conventional SIMS and MALDI techniques. The GCIB SIMS allowed the detection of more intact lipid compounds in the mouse brain compared to MALDI with regular organic matrices. The 40 keV GCIB SIMS also produced peaks observed in the NP-LDI analysis, and these peaks were strongly enhanced in intensity by exposure of the sample to trifluororacetic acid (TFA) vapor prior to analysis. These MS techniques for imaging of different types of lipids create a potential overlap and cross point that can enhance the information for imaging lipids in biological tissue sections. Graphical abstract Schematic of mass spectral imaging of a mouse brain tissue using GCIB-SIMS and MALDI techniques.
Independent of physical activity levels, youth sedentary behaviors (SB) have negative health outcomes. SB prevalence estimates during discretionary periods of the day (e.g., after-school), inform the need for targeted period-specific interventions. This systematic review aimed to determine children's and adolescents' SB prevalence during the after-school period.
A computerized search was conducted in October 2015 (analysed November 2015). Inclusion criteria were: published in a peer-reviewed English journal; participants aged 5-18 years; measured overall after-school sedentary time (ST) objectively, and/or specific after-school SBs (e.g., TV viewing) objectively or subjectively; and provided the percentage of the after-school period spent in ST/SB or duration of behavior and period to calculate this. Where possible, findings were analyzed by location (e.g., after-school care/'other' locations). The PRISMA guidelines were followed.
Twenty-nine studies were included: 24 included children (≤12 years), four assessed adolescents (>12 years) and one included both; 20 assessed ST and nine assessed SB. On average, children spent 41% and 51% of the after-school period in ST when at after-school care and other locations respectively. Adolescents spent 57% of the after-school period in ST. SBs that children and adolescents perform include: TV viewing (20% of the period), non-screen based SB (including homework; 20%), screen-based SB (including TV viewing; 18%), homework/academics (13%), motorised transport (12%), social SB (9%), and screen-based SB (excluding TV viewing; 6%).
Children spent up to half of the after-school period in ST and this is higher among adolescents. A variety of screen- and non-screen based SBs are performed after school, providing key targets for interventions.
PROSPERO registration number CRD42015010437.
Invasive alien species (IAS) threaten human livelihoods and biodiversity globally. Increasing globalization facilitates IAS arrival, and environmental changes, including climate change, facilitate IAS establishment. Here we provide the first global, spatial analysis of the terrestrial threat from IAS in light of twenty-first century globalization and environmental change, and evaluate national capacities to prevent and manage species invasions. We find that one-sixth of the global land surface is highly vulnerable to invasion, including substantial areas in developing economies and biodiversity hotspots. The dominant invasion vectors differ between high-income countries (imports, particularly of plants and pets) and low-income countries (air travel). Uniting data on the causes of introduction and establishment can improve early-warning and eradication schemes. Most countries have limited capacity to act against invasions. In particular, we reveal a clear need for proactive invasion strategies in areas with high poverty levels, high biodiversity and low historical levels of invasion.
Few school-based interventions have been successful in reducing physical activity decline and preventing overweight and obesity in adolescent populations. As a result, few cost effectiveness analyses have been reported. The aim of this paper is to report the cost and cost effectiveness of the Physical Activity 4 Everyone (PA4E1) intervention which was a multi-component intervention implemented in secondary schools located in low-income communities. Cost effectiveness was assessed using both the physical activity and weight status trial outcomes.
Intervention and Study Design: The PA4E1 cluster randomised controlled trial was implemented in 10 Australian secondary schools (5 intervention: 5 control) and consisted of intervention schools receiving seven physical activity promotion strategies and six additional strategies that supported school implementation of the intervention components. Costs associated with physical activity strategies, and intervention implementation strategies within the five intervention schools were estimated and compared to the costs of usual physical activity practices of schools in the control group. The total cost of implementing the intervention was estimated from a societal perspective, based on the number of enrolled students in the target grade at the start of the intervention (Grade 7, n = 837). Economic Outcomes: The economic analysis outcomes were cost and incremental cost effectiveness ratios for the following: minutes of moderate-to-vigorous physical activity (MVPA) per day gained, MET hours gained per person/day; Body Mass Index (BMI) unit avoided; and 10% reduction in BMI z-score.
The intervention cost AUD $329,952 over 24 months, or AUD$394 per student in the intervention group. This resulted in a cost effectiveness ratio of AUD$56 ($35-$147) per additional minute of MVPA, AUD$1 ($0.6-$2.7) per MET hour gained per person per day, AUD$1408 ($788-$6,570) per BMI unit avoided, and AUD$563 ($282-$3,942) per 10% reduction in BMI z-score.
PA4E1 is a cost effective intervention for increasing the physical activity levels and reducing unhealthy weight gain in adolescence, a period in which physical activity typically declines. Additional modelling could explore the potential economic impact of the intervention on morbidity and mortality.
Australian New Zealand Clinical Trials Registry ACTRN12612000382875.
Studies exploring the potential of Chaos Game Representations (CGR) of genomic sequences to act as "genomic signatures" (to be species- and genome-specific) showed that CGR patterns of nuclear and organellar DNA sequences of the same organism can be very different. While the hypothesis that CGRs of mitochondrial DNA sequences can act as genomic signatures was validated for a snapshot of all sequenced mitochondrial genomes available in the NCBI GenBank sequence database, to our knowledge no such extensive analysis of CGRs of nuclear DNA sequences exists to date.
We analyzed an extensive dataset, totalling 1.45 gigabase pairs, of nuclear/nucleoid genomic sequences (nDNA) from 42 different organisms, spanning all major kingdoms of life. Our computational experiments indicate that CGR signatures of nDNA of two different origins cannot always be differentiated, especially if they originate from closely-related species such as H. sapiens and P. troglodytes or E. coli and E. fergusonii. To address this issue, we propose the general concept of additive DNA signature of a set (collection) of DNA sequences. One particular instance, the composite DNA signature, combines information from nDNA fragments and organellar (mitochondrial, chloroplast, or plasmid)
 genomes. We demonstrate that, in this dataset, composite DNA signatures originating from two different organisms can be differentiated in all cases, including those where the use of CGR signatures of nDNA failed or was inconclusive. Another instance, the assembled DNA signature, combines information from many short DNA subfragments (e.g., 100 basepairs) of a given DNA fragment, to produce its signature. We show that an assembled DNA signature has the same distinguishing power as a conventionally computed CGR signature, while using shorter contiguous sequences and potentially less sequence information.
Our results suggest that, while CGR signatures of nDNA cannot always play the role of genomic signatures, composite and assembled DNA signatures (separately or in combination) could potentially be used instead. Such additive signatures could be used, e.g., with raw unassembled next-generation sequencing (NGS) read data, when high-quality sequencing data is not available, or to complement information obtained by other methods of species identification or classification.
Availability of Emergency Obstetric Care (EmOC) is crucial to avert maternal death due to life-threatening complications potentially arising during delivery. Research on the determinants of utilization of EmOC has neglected urban settings, where traffic congestion can pose a significant barrier to the access of EmOC facilities, particularly for the urban poor due to costly and limited transportation options. This study investigates the impact of travel time to EmOC facilities on the utilization of facility-based delivery services among mothers living in urban poor settlements in Sylhet, Bangladesh.
A cross-sectional EmOC health-seeking behavior survey from 39 poor urban clusters was geo-spatially linked to a comprehensive geo-referenced dataset of EmOC facility locations. Geo-spatial techniques and logistic regression were then applied to quantify the impact of travel time on place of delivery (EmOC facility or home), while controlling for confounding socio-cultural and economic factors.
Increasing travel time to the nearest EmOC facility is found to act as a strong deterrent to seeking care for the urban poor in Sylhet. Logistic regression results indicate that a 5-min increase in travel time to the nearest EmOC facility is associated with a 30 % decrease (0.655 odds ratio, 95 % CI: 0.529-0.811) in the likelihood of delivery at an EmOC facility rather than at home. Moreover, the impact of travel time varies substantially between public, NGO and private facilities. A 5-min increase in travel time from a private EmOC facility is associated with a 32.9 % decrease in the likelihood of delivering at a private facility, while for public and Non-Government Organizations (NGO) EmOC facilities, the impact is lower (28.2 and 28.6 % decrease respectively). Other strong determinants of delivery at an EmOC facility are the use of antenatal care and mother's formal education, while Muslim mothers are found to be more likely to deliver at home.
Geospatial evidence points to the need to strengthen referral and emergency transport systems in order to reduce urban travel time, and establish or relocate EmOC facilities closer to where the poor reside. However, female education and antenatal care coverage remain the most important determinants of facility delivery.
Occupational therapy practitioners must advocate for clients in multiple ways. The Occupational Therapy Practice Framework: Domain and Process as well as the Occupational Therapy Code of Ethics lend support to advocacy. Recognizing one's responsibility to provide advocacy for clients is different from knowing how to provide that advocacy. One aspect of health care affected by the Patient Protection and Affordable Care Act (ACA) is the definition and implementation of medical necessity. This article outlines some major concepts around medical necessity, particularly in relation to the passage of the ACA, and outlines guidance on how to advocate effectively to meet both individual and community needs.
Dynamic nuclear polarization (DNP) is a powerful method to enhance sensitivity especially of solid-state magic-angle spinning (MAS) NMR by up to several orders of magnitude. The increased interest both from a practical as well as theoretical viewpoint has spawned several fields of active research such as the development of new polarizing agents with improved or unique properties and description of the underlying DNP mechanisms such as solid effect (SE) and cross effect (CE). Even though a novel class of unique polarizing agents based on high-spin metal ions such as Gd(iii) and Mn(ii) has already been utilized for MAS DNP a theoretical description of the involved DNP mechanism is still incomplete. Here, we review several aspects of DNP-relevant electron-paramagnetic resonance (EPR) properties of the general class of these half-integer high-spin metal ions with isotropic Zeeman interaction but significant zero-field splitting (ZFS). While the SE can be relatively easily described similar to that of a S = 1/2 system and is assumed to be effective only for polarizing agents featuring a narrow central EPR transitions (i.e., mS = -1/2 → +1/2) with respect to the nuclear Larmor frequency, the CE between two high-spin ions requires a more detailed theoretical investigation due to a multitude of possible transitions and matching conditions. This is especially interesting in light of recent understanding of CE being induced by MAS-driven level anti-crossings (LACs) between dipolar-coupled electron spins. We discuss the requirements of such CE-enabling LACs to occur due to anisotropy of ZFS, the expected adiabaticity, and the resulting possibilities of high-spin metal ion pairs to act as polarizing agents for DNP. This theoretical description serves as a framework for a detailed experimental study published directly following this work.
Mobile colloids can act as carriers for low-solubility contaminants in the environment. However, the dominant mechanism for this colloid-facilitated transport of chemicals is unclear. Therefore, we developed a bead-based microfluidic platform of sediment analogues and measured both single and population transport of model colloids. The porous medium is assembled through a bead-by-bead injection method. This approach has the versatility to build both electrostatically homogeneous and heterogeneous media at the pore scale. A T-junction at the exit also allowed for encapsulation and enumeration of colloids effluent at single particle resolution to give population dynamics. Tortuosity calculated from pore-scale trajectory analysis and its comparison with lattice Boltzmann simulations revealed that transport of colloids was influenced by the size exclusion effect. The porous media packed by positively and negatively charged beads into two layers showed distinctive colloidal particle retention and significant remobilization and re-adsorption of particles during water flushing. We demonstrated the potential of our method to fabricate porous media with surface heterogeneities at the pore scale. With both single and population dynamics measurement, our platform has the potential to connect pore-scale and macroscale colloid transport on a lab scale and to quantify the impact of grain surface heterogeneities that are natural in the subsurface environment.
The aim of the study was to determine whether embedding into the radiology report a patient-specific plan in the event of gastrojejunostomy (GJ) tube dysfunction reduces the need for after-hours utilization of pediatric interventional radiology resources for the replacement of GJ tubes.
This is a Health Insurance Portability and Accountability Act compliant, institutional review board-approved retrospective repeated cross-sectional study of patients requiring after-hours (5 PM-7 AM) or weekend (Saturday and Sunday) GJ tube replacement at a dedicated children's hospital, before and after the inclusion of a patient-specific plan in the radiology report as part of the electronic medical record.
During a 6-month period before the inclusion of a patient-specific plan, there were 242 total GJ tube changes performed by the pediatric interventional radiology service under image guidance. Twenty-six (10.7%) of these procedures were performed outside of standard operating hours at the request of the emergency department (ED) (6/26), inpatient service (8/26), or patient/caregiver (12/26). Of the 8 inpatients, 3 were admitted from the ED for the sole purpose of tube replacement. Data were again collected for 6 months following inclusion of a patient-specific plan during the same seasonal period of the following year. During this period, 240 total image-guided changes were performed. Fifteen (6.2%) were performed outside of standard operating hours at the request of the ED (2/15), inpatient service (4/15), or patient/caregiver (9/15). No patients were admitted for GJ tube replacement procedures following implementation of the enhanced reporting policy. These data indicate a trend toward reduced after-hours resource utilization for GJ tube replacement requests by the ED (23.1%-13.3%), inpatient service (30.8%-26.7%), and all patients (14.7%-11%). Fewer after-hours GJ tube changes reduced cost by proportionately reducing hourly compensation for interventional radiology nurses and technicians.
Our single-center data suggest that the inclusion of patient-specific recommendations at the end of each radiology GJ tube procedure note, generated in collaboration with the feeding service or primary medical provider, reduces off-hour resource utilization in patients who could otherwise have their tubes replaced during standard operating hours with image guidance. Avoidance of tube-related admissions is likely the greatest source of cost savings, followed by lower radiology
 technical support costs. Cost savings related to improved ED workflow and reduced patient/family anxiety are difficult to quantify, but likely significant. Future studies should be designed to quantify these savings and to assess the effect of this intervention on patient/caregiver satisfaction.
As they assemble, retroviruses encapsidate both their genomic RNAs and several types of host RNA. Whereas limited amounts of messenger RNA (mRNA) are detectable within virion populations, the predominant classes of encapsidated host RNAs do not encode proteins, but instead include endogenous retroelements and several classes of non-coding RNA (ncRNA), some of which are packaged in significant molar excess to the viral genome. Surprisingly, although the most abundant host RNAs in retroviruses are also abundant in cells, unusual forms of these RNAs are packaged preferentially, suggesting that these RNAs are recruited early in their biogenesis: before associating with their cognate protein partners, and/or from transient or rare RNA populations. These RNAs' packaging determinants differ from the viral genome's, and several of the abundantly packaged host ncRNAs serve cells as the scaffolds of ribonucleoprotein particles. Because virion assembly is equally efficient whether or not genomic RNA is available, yet RNA appears critical to the structural integrity of retroviral particles, it seems possible that the selectively encapsidated host ncRNAs might play roles in assembly. Indeed, some host ncRNAs appear to act during replication, as some transfer RNA (tRNA) species may contribute to nuclear import of human immunodeficiency virus 1 (HIV-1) reverse transcription complexes, and other tRNA interactions with the viral Gag protein aid correct trafficking to plasma membrane assembly sites. However, despite high conservation of packaging for certain host RNAs, replication roles for most of these selectively encapsidated RNAs-if any-have remained elusive.
Lung cancer may be prevented by a diet rich in fruits and vegetables as they are enriched with dietary antioxidant polyphenols, such as flavonoids, proanthocyanidins, lignans, stilbenes, and phenolic acids. Dietary polyphenols exert a wide range of beneficial biological functions beyond their antioxidative properties and are involved in regulation of cell survival pathways leading to anticarcinogenic and antimutagenic functions. There are sufficient evidence from in vitro, in vivo, and epidemiological studies to suggest that the dietary intervention of polyphenols in cancer prevention, including the chemopreventive ability of dietary polyphenols, act against lung carcinogens. Cohort and epidemiological studies in selected risk populations have evaluated clinical effects of polyphenols. Polyphenols have demonstrated three major actions: antioxidative activity, regulation of phase I and II enzymes, and regulation of cell survival pathways against lung carcinogenesis. They have also shown an inverse association of lung cancer occurrences among high risk populations who consumed considerable amounts of fruits and vegetables in their daily diet. In in vitro cell culture experimental models, polyphenols bind with electrophilic metabolites from carcinogens, inactivate cellular oxygen radicals, prevent membrane lipid peroxidation and DNA oxidative damage, and adduct formation. Further, polyphenols enhance the detoxifying enzymes such as the phase II enzymes, glutathione transferases and glucuronosyl transferases.
Globalization phenomena and Information Communication Technology (ICT) are producing deep changes worldwide. The economic environment and society where firms both cooperate and compete with each other are rapidly changing leading firms towards recognizing the role of intangible resources as a source of fresh competitive advantage. Experience, innovation and the ability to create new knowledge completely arise from the act of human resources inviting firms to focus on how to generate and shape knowledge. Therefore, the future of firms depends greatly on how managers are able to explore and exploit human resources. However, without a clear understanding of the nature of human beings and the complexity behind human interactions, we cannot understand the theory of organizational knowledge creation. Thus, how can firms discover, manage and valorize this "human advantage"? Neuroscience can increase the understanding of how cognitive and emotional processes work; in doing so, we may be able to better understand how individuals involved in a business organization make decisions and how external factors influence their behavior, especially in terms of commitment activation and engagement level. In this respect, a neuroscientific approach to business can support managers in decision-making processes. In a scenario where economic humanism plays a central role in the process of fostering firms' competitiveness and emerging strategies, we believe that a neuroscience approach in a business organization could be a valid source of value and inspiration for manager decision-making processes.
Many conflicting results have been reported related to the antioxidant and oxidant activities of nanoceria. On the basis of this research, many factors might affect the antioxidant activity of nanoceria. However, all of the factors reported only affect the antioxidant activity of nanoceria to a limited extent or cause the antioxidant activity to be lost. We found that several factors can induce conversion between the protective effect and toxicity of nanoceria. At low concentrations of hydroxyl radicals (•OH) and nanomaterials, nanoceria exhibited antioxidant activity but could produce greater amounts of •OH at higher •OH or nanomaterial concentrations and subsequently exhibit oxidant activity. Moreover, the morphology and size of nanoceria can also affect this conversion. We found that high concentrations of •OH and nanoceria could introduce a high amount of Ce(3+) in the system, which might be the reason that nanoceria converted from exhibiting antioxidant to oxidant activity. Under this condition, nanoceria act as a catalyst similar to Fe(2+) to promote •OH production in a Fenton system and also as a catalyst promoter to boost Fe(2+) production of additional •OH during the redox reaction. These conclusions support a better understanding of conflicting reports on medicinal applications for nanoceria and promote their practical application.
In mammals, adenosine 3', 5'-cyclic monophosphate (cAMP) is known to play highly important roles in sperm motility and acrosomal exocytosis. It is known to act through protein phosphorylation via PRKA and through the activation of guanine nucleotide exchange factors like EPAC. Sperm intracellular cAMP levels depend on the activity of adenylyl cyclases, mostly SACY, though transmembrane-containing adenylyl cyclases are also present, and on the activity of cyclic nucleotide phosphodiesterases (PDE) whose role is to degrade cAMP into 5'-AMP. The PDE superfamily is subdivided into 11 families (PDE1 to 11), which act on either cAMP or cGMP, or on both cAMP and cGMP although with different enzymatic properties. PDE10, which is more effective on cAMP than cGMP, has been known for almost 15 years and is mostly studied in the brain where it is associated with neurological disorders. Although a high level of PDE10A gene expression is observed in the testis, information on the identity of the isoforms or on the cell type that express the PDE10 protein is lacking. The objective of this study was to identify the PDE10A isoforms expressed in the testis and germ cells, and to determine the presence and localization of PDE10A in mature spermatozoa. As a sub-objective, since PDE10A transcript variants were reported strictly through analyses of bovine genomic sequence, we also wanted to determine the nucleotide and amino acid sequences by experimental evidence. Using RT-PCR, 5'- and 3'-RACE approaches we clearly show that PDE10A transcript variants X3 and X5 are expressed in bovine testis as well as in primary spermatocytes and spermatids. We also reveal using a combination of immunological techniques and proteomics analytical tools that the PDE10A isoform X4 is present in the area of the developing acrosome of spermatids and of the acrosome of mature spermatozoa.
The Affordable Care Act (ACA) include provisions that reduce beneficiaries' cost sharing and eventually closes the coverage gap-known as the "doughnut hole"-that was originally part of Medicare prescription drug coverage implemented in 2006.
This study examines changes in overall prescription drug utilization and out-of-pocket spending as well as by manufacturer type (brand vs. generic), through 2013 as a result of the doughnut hole provisions of the ACA.
This analysis is based on data from Medical Expenditure Panel Survey and the sample for this analysis includes all individuals 55 years of age and older. A difference-in-differences methodology was adopted to measure changes in drug utilization and out-of-pocket spending among both the treatment group and the comparison group after the ACA.
The findings from this study suggest that overall out-of-pocket spending significantly decreased after closing the coverage gap, mainly because of a significant reduction in out-of-pocket spending on brand-name drugs. Conversely, the results show that generic drug utilization increased after closing the coverage gap. As expected, the effects were considerably larger for people who fell into the doughnut hole.
The ACA doughnut hole provisions likely contributed to a reduction in out-of-pocket spending for prescription drugs for part D beneficiaries, especially for people who fell into the doughnut hole.
On a sunny Thursday morning, June 25, 2015, President Obama strode into the Rose Garden and declared a victory for the Affordable Care Act (ACA)
 by stating that the act was working exactly the way it was supposed to work. He further reinforced that ACA has enabled young Americans up to the age of 26 to remain on their parents' health plans. It disallows the insurance companies from denying coverage based on preexisting conditions. Above all, an expansion of Medicaid has also brought an additional 16 million Americans under health coverage in a span of less than 2 years. The ACA went into full effect on January 1, 2014, ushering in health insurance reforms and new health coverage options across the country. As the states expand Medicaid and provide new coverage options through the federal health insurance marketplace, they are busy streamlining application and enrollment processes for coverage programs. This article highlights the positive impact of the ACA on uninsured and the challenges that not-for-profit and public hospitals are facing as they navigate the new health care landscape.
The nicotinamide-nucleotide adenylyltransferase protein Nmnat1 is a potent inhibitor of axonal degeneration in models of acute axonal injury. Hyperphosphorylation and aggregation of the microtubule-associated protein Tau are associated with neurodegeneration in Alzheimer's Disease and other disorders. Previous studies have demonstrated that other Nmnat isoforms can act both as axonoprotective agents and have protein chaperone function, exerting protective effects in drosophila and mouse models of tauopathy. Nmnat1 targeted to the cytoplasm (cytNmnat1) is neuroprotective in a mouse model of neonatal hypoxia-ischemia, but the effect of cytNmnat1 on tauopathy remains unknown.
We examined the impact of overexpression of cytNmnat1 on tau pathology, neurodegeneration, and brain functional connectivity in the P301S mouse model of chronic tauopathy.
Overexpression of cytNmnat1 preserved cortical neuron functional connectivity in P301S mice in vivo. However, whereas Nmnat1 overexpression decreased the accumulation of detergent-insoluble tau aggregates in the cerebral cortex, it exerted no effect on immunohistochemical evidence of pathologic tau phosphorylation and misfolding, hippocampal atrophy, or inflammatory markers in P301S mice.
Our results demonstrate that cytNmnat1 partially preserves neuronal function and decreases biochemically insoluble tau in a mouse model of chronic tauopathy without preventing tau phosphorylation, formation of soluble aggregates, or tau-induced inflammation and atrophy. Nmnat1 might thus represent a therapeutic target for tauopathies.
The hedgehog (Hh) signalling pathway is conserved throughout metazoans and plays an important regulatory role in both embryonic development and adult homeostasis. Many levels of regulation exist that control the release, reception, and interpretation of the hedgehog signal. The fatty nature of the Shh ligand means that it tends to associate tightly with the cell membrane, and yet it is known to act as a morphogen that diffuses to elicit pattern formation. Heparan sulfate proteoglycans (HSPGs) play a major role in the regulation of Hh distribution outside the cell. Inside the cell, the primary cilium provides an important hub for processing the Hh signal in vertebrates. This review will summarise the current understanding of how the Hh pathway is regulated from ligand production, release, and diffusion, through to signal reception and intracellular transduction.
Studies on hematopoietic stem cells (HSCs) and leukemia stem cells (LSCs) have helped to establish the paradigms of normal and cancer stem cell concepts. For both HSCs and LSCs, specific gene expression programs endowed by their epigenome functionally distinguish them from their differentiated progenies. MicroRNAs (miRNAs), as a class of small non-coding RNAs, act to control post-transcriptional gene expression. Research in the past decade has yielded exciting findings elucidating the roles of miRNAs in control of multiple facets of HSC and LSC biology. Here we review recent progresses on the functions of miRNAs in HSC emergence during development, HSC switch from a fetal/neonatal program to an adult program, HSC self-renewal and quiescence, HSC aging, HSC niche, and malignant stem cells. While multiple different miRNAs regulate a diverse array of targets, two common themes emerge in HSC and LSC biology: miRNA mediated regulation of epigenetic machinery and cell signaling pathways. In addition, we propose that miRNAs themselves behave like epigenetic regulators, as they possess key biochemical and biological properties that can provide both stability and alterability to the epigenetic program. Overall, the studies of miRNAs in stem cells in the hematologic contexts not only provide key understandings to post-transcriptional gene regulation mechanisms in HSCs and LSCs, but also will lend key insights for other stem cell fields.
Developmental studies on butterfly wing color patterns often focus on eyespots. A typical eyespot (such as that of Bicyclus anynana) has a few concentric rings of dark and light colors and a white spot (called a focus) at the center. The prospective eyespot center during the early pupal stage is known to act as an organizing center. It has often been assumed, according to gradient models for positional information, that a white spot in adult wings corresponds to an organizing center and that the size of the white spot indicates how active that organizing center was. However, there is no supporting evidence for these assumptions. To evaluate the feasibility of these assumptions in nymphalid butterflies, we studied the unique color patterns of Calisto tasajera (Nymphalidae, Satyrinae), which have not been analyzed before in the literature.
In the anterior forewing, one white spot was located at the center of an eyespot, but another white spot associated with either no or only a small eyespot was present in the adjacent compartment. The anterior hindwing contained two adjacent white spots not associated with eyespots, one of which showed a sparse pattern. The posterior hindwing contained two adjacent pear-shaped eyespots, and the white spots were located at the proximal side or even outside the eyespot bodies. The successive white spots within a single compartment along the midline in the posterior hindwing showed a possible trajectory of a positional determination process for the white spots. Several cases of focus-less eyespots in other nymphalid butterflies were also presented.
These results argue for the uncoupling of white spots from eyespot bodies, suggesting that an eyespot organizing center does not necessarily differentiate into a white spot and that a prospective white spot does not necessarily signify organizing activity for an eyespot. Incorporation of these results in future models for butterfly wing color pattern formation is encouraged.
Background. This work examines the relationship between emotional intelligence (EI) and depressive symptomatology in institutionalized older adults, delving into the mechanisms underlying this relationship. Considering that previous evidence of the variation of the EI-depression relationship depending on whether the emotional ability or the perception of that ability is evaluated, a model of multiple mediation was tested in which the dimensions of emotional self-efficacy (ESE) act as mediators in the relationship between ability EI and depressive symptomatology. Methods. The sample consisted of 115 institutionalized older adults (47.82% women; 80.3 ± 7.9 years of age) from the province of Jaén (Spain) who completed a test of ESE, a measure of ability EI, and a self-administered questionnaire of depressive symptoms. Results. The results showed a positive association between older adults' emotional performance and depressive symptomatology, finding stronger associations with ESE than with EI abilities. In addition, multiple mediation analyses showed that two of the four dimensions of ESE fully mediated the relationship between ability EI and depressive symptoms. Discussion. These findings suggest that older adults' high levels of emotional competence generate a feeling of ESE which can protect them against depressive symptoms. This work supports the predictive validity of emotional abilities and ESE for the mental health of a group that is particularly vulnerable to depression, institutionalized older adults. The limitations of the work are discussed, and future lines of research were considered.
Although atrial fibrillation (AF), a common arrhythmia, frequently presents in patients with underlying valvular disease, its hemodynamic contributions are not fully understood. The present work aimed to computationally study how physical conditions imposed by pathologic valvular anatomy act on AF hemodynamics.
We simulated AF with different severity grades of left-sided valvular diseases and compared the cardiovascular effects that they exert during AF, compared to lone AF. The fluid dynamics model used here has been recently validated for lone AF and relies on a lumped parameterization of the four heart chambers, together with the systemic and pulmonary circulation. The AF modelling involves: (i) irregular, uncorrelated and faster heart rate; (ii) atrial contractility dysfunction. Three different grades of severity (mild, moderate, severe) were analyzed for each of the four valvulopathies (AS, aortic stenosis, MS, mitral stenosis, AR, aortic regurgitation, MR, mitral regurgitation), by varying-through the valve opening angle-the valve area.
Regurgitation was hemodynamically more relevant than stenosis, as the latter led to inefficient cardiac flow, while the former introduced more drastic fluid dynamics variation. Moreover, mitral valvulopathies were more significant than aortic ones. In case of aortic valve diseases, proper mitral functioning damps out changes at atrial and pulmonary levels. In the case
 of mitral valvulopathy, the mitral valve lost its regulating capability, thus hemodynamic variations almost equally affected regions upstream and downstream of the valve. In particular, the present study revealed that both mitral and aortic regurgitation strongly affect hemodynamics, followed by mitral stenosis, while aortic stenosis has the least impact among the analyzed valvular diseases.
The proposed approach can provide new mechanistic insights as to which valvular pathologies merit more aggressive treatment of AF. Present findings, if clinically confirmed, hold the potential to impact AF management (e.g., adoption of a rhythm control strategy) in specific valvular diseases.
One of the most challenging questions in neuroscience is to dissect how learning and memory, the foundational pillars of cognition, are grounded in stable, yet plastic, gene expression states. All known epigenetic mechanisms such as DNA methylation and hydroxymethylation, histone modifications, chromatin remodelling, and noncoding RNAs regulate brain gene expression, both during neurodevelopment and in the adult brain in processes related to cognition. On the other hand, alterations in the various components of the epigenetic machinery have been linked to well-known causes of intellectual disability disorders (IDDs). Two examples are Down Syndrome (DS) and Fragile X Syndrome (FXS), where global and local epigenetic alterations lead to impairments in synaptic plasticity, memory, and learning. Since epigenetic modifications are reversible, it is theoretically possible to use epigenetic drugs as cognitive enhancers for the treatment of IDDs. Epigenetic treatments act in a context specific manner, targeting different regions based on cell and state specific chromatin accessibility, facilitating the establishment of the lost balance. Here, we discuss epigenetic studies of IDDs, focusing on DS and FXS, and the use of epidrugs in combinatorial therapies for IDDs.
Activated in energy depletion conditions, AMP-activated protein kinase (AMPK) acts as a cellular energy sensor and regulator in both central nervous system and peripheral organs. Hypothalamic AMPK restores energy balance by promoting feeding behavior to increase energy intake, increasing glucose production, and reducing thermogenesis to decrease energy output. Besides energy state, many hormones have been shown to act in concert with AMPK to mediate their anorexigenic and orexigenic central effects as well as thermogenic influences. Here we explore the factors that affect hypothalamic AMPK activity and give the underlying mechanisms for the role of central AMPK in energy homeostasis together with the physiological effects of hypothalamic AMPK on energy balance restoration.
The red alga Polysiphonia morrowii, native to the North Pacific (Northeast Asia), has recently been reported worldwide. To determine the origin of the French and Argentine populations of this introduced species, we compared samples from these two areas with samples collected in Korea and at Hakodate, Japan, the type locality of the species. Combined analyses of chloroplastic (rbcL) and mitochondrial (cox1) DNA revealed that the French and Argentine populations are closely related and differ substantially from the Korean and Japanese populations. The genetic structure of P. morrowii populations from South Atlantic and North Atlantic, which showed high haplotype diversity compared with populations from the North Pacific, suggested the occurrence of multiple introduction events from areas outside of the so-called native regions. Although similar, the French and Argentine populations are not genetically identical. Thus, the genetic structure of these two introduced areas may have been modified by cryptic and recurrent introduction events directly from Asia or from other introduced areas that act as introduction relays. In addition, the large number of private cytoplasmic types identified in the two introduced regions strongly suggests that local populations of P. morrowii existed before the recent detection of these invasions. Our results suggest that the most likely scenario is that the source population(s) of the French and Argentine populations was not located only in the North Pacific and/or that P. morrowii is a cryptogenic species.
Indazole-derived synthetic cannabinoids (SCs) featuring an alkyl substituent at the 1-position and l-valinamide at the 3-carboxamide position (e.g., AB-CHMINACA) have been identified by forensic chemists around the world, and are associated with serious adverse health effects. Regioisomerism is possible for indazole SCs, with the 2-alkyl-2H-indazole regioisomer of AB-CHMINACA recently identified in SC products in Japan. It is unknown whether this regiosiomer represents a manufacturing impurity arising as a synthetic byproduct, or was intentionally synthesized as a cannabimimetic agent. This study reports the synthesis, analytical characterization, and pharmacological evaluation of commonly encountered indazole SCs AB-CHMINACA, AB-FUBINACA, AB-PINACA, 5F-AB-PINACA and their corresponding 2-alkyl-2H-indazole regioisomers. Both regioisomers of each SC were prepared from a common precursor, and the physical properties, (1)H and (13)C nuclear magnetic resonance spectroscopy, gas chromatography-mass spectrometry, and ultraviolet-visible spectroscopy of all SC compounds are described. Additionally, AB-CHMINACA, AB-FUBINACA, AB-PINACA, and 5F-AB-PINACA were found to act as high potency agonists at CB1 (EC50 = 2.1-11.6 nM) and CB2 (EC50 = 5.6-21.1 nM) receptors in fluorometric assays, while the corresponding 2-alkyl-2H-indazole regioisomers demonstrated low potency (micromolar) agonist activities at both receptors. Taken together, these data suggest that 2-alkyl-2H-indazole regioisomers of AB-CHMINACA, AB-FUBINACA, AB-PINACA, and 5F-AB-PINACA are likely to be encountered by forensic chemists and toxicologists as the result of improper purification during the clandestine synthesis of 1-alkyl-1H-indazole regioisomers, and can be distinguished by differences in gas chromatography-mass spectrometry fragmentation pattern.
Large-panicle rice cultivars often fail to reach their yield potential due to the poor grain filling of inferior spikelets (IS). Thus, it is important to determine the causes of poor IS grain filling. In this study, we attempted to identify whether inferior grain filling of large panicles is restricted by superior spikelets (SS) and their physiological mechanism. SS were removed from two homozygous japonica rice strains (W1844 and WJ165) during flowering in an attempt to force photosynthate transport to the IS. We measured the effects of SS removal on seed setting rate, grain weight, grain filling rate, sucrose content, as well as hormone levels, activities of key enzymes, and expression of genes involved in sucrose to starch metabolism in rice IS during grain filling. The results showed that SS removal improved IS grain filling by increasing the seed setting rate, grain weight, sucrose content, and hormone levels. SS removal also enhanced the activities of key enzymes and the expression levels of genes involved in sucrose to starch metabolism. These results suggest that sucrose and several hormones act as signal substances and play a vital role in grain filling by regulating enzyme activities and gene expression. Therefore, IS grain filling is restricted by SS, which limit assimilate supply and plant hormones, leading to poor grain filling of IS.
The present study investigates the developmental aspect of stimulus-response compatibility (SRC) effect in 8-11-years-old children. The task consisted in manually responding to the color of a pawn presented on a chessboard at different distances. Manual responses were provided by reaching a proximal or distal location depending on the color of the stimulus. We found that reaction time was affected by the conflict generated by the response suggested by the location of the stimulus and the response required according to its color. This was not the case for movement time despite we found a higher rate of long duration movements in the incongruent than in the congruent spatial condition. The SRC effect was, however, observed in children older than 10 years old. These findings provide additional evidence for a reorganization of the perceptual system during the period of 8-10 years, integrating progressively multimodal information and preparing more efficiently the body to act in the environment.
In humans and rodents, loss of brain orexin/hypocretin (OH) neurons causes pathological sleepiness [1-4], whereas OH hyperactivity is associated with stress and anxiety [5-10]. OH cell control is thus of considerable interest. OH cells are activated by fasting [11, 12] and proposed to stimulate eating [13]. However, OH cells are also activated by diverse feeding-unrelated stressors [14-17] and stimulate locomotion and "fight-or-flight" responses [18-20]. Such OH-mediated behaviors presumably preclude concurrent eating, and loss of OH cells produces obesity, suggesting that OH cells facilitate net energy expenditure rather than energy intake [2, 21-23]. The relationship between OH cells and eating, therefore, remains unclear. Here we investigated this issue at the level of natural physiological activity of OH cells. First, we monitored eating-associated dynamics of OH cells using fiber photometry in free-feeding mice. OH cell activity decreased within milliseconds after eating onset, and remained in a down state during eating. This OH inactivation occurred with foods of diverse tastes and textures, as well as with calorie-free "food," in both fed and fasted mice, suggesting that it is driven by the act of eating itself. Second, we probed the implications of natural OH cell signals for eating and weight in a new conditional OH cell-knockout model. Complete
 OH cell inactivation in adult brain induced a hitherto unrecognized overeating phenotype and caused overweight that was preventable by mild dieting. These results support an inhibitory interplay between OH signals and eating, and demonstrate that OH cell activity is rapidly controllable, across nutritional states, by voluntary action.
Fep1, the iron-responsive GATA factor from the methylotrophic yeast Pichia pastoris, has been characterised both in vivo and in vitro. This protein has two Cys2-Cys2 type zinc fingers and a set of four conserved cysteines arranged in a Cys-X5-Cys-X8-Cys-X2-Cys motif located between the two zinc fingers. Electronic absorption and resonance Raman spectroscopic analyses in anaerobic and aerobic conditions indicate that Fep1 binds iron in the form of a [2Fe-2S] cluster. Site-directed mutagenesis shows that replacement of the four cysteines with serine inactivates this transcriptional repressor. Unexpectedly, the inactive mutant is still able to bind a [2Fe-2S] cluster, employing two cysteine residues belonging to the first zinc finger. These two cysteine residues can act as alternative cluster ligands selectively in aerobically purified Fep1 wild type, suggesting that oxygen could play a role in Fep1 function by causing differential localization of the [Fe-S] cluster.
Parrots are largely considered plant antagonists as they usually destroy the seeds they feed on. However, there is evidence that parrots may also act as seed dispersers. We evaluated the dual role of parrots as predators and dispersers of the Critically Endangered Parana pine (Araucaria angustifolia). Eight of nine parrot species predated seeds from 48% of 526 Parana pines surveyed. Observations of the commonest parrot indicated that 22.5% of the picked seeds were dispersed by carrying them in their beaks. Another five parrot species dispersed seeds, at an estimated average distance of c. 250 m. Dispersal distances did not differ from those observed in jays, considered the main avian dispersers. Contrary to jays, parrots often dropped partially eaten seeds. Most of these seeds were handled by parrots, and the proportion of partially eaten seeds that germinated was higher than that of undamaged seeds. This may be explained by a predator satiation effect, suggesting that the large seeds of the Parana pine evolved to attract consumers for dispersal. This represents a thus far overlooked key plant-parrot mutualism, in which both components are threatened with extinction. The interaction is becoming locally extinct long before the global extinction of the species involved.
Electronic cigarettes as possibly healthier alternative to conventional cigarettes are gaining popularity worldwide, although they are still hazardous to human health. Partly it is caused by unregulated advertising and online sales. Unfortunately it is more and more popular for youth to try electronic cigarettes.
The aim of the study was to assess the marketing claims used by Polish websites offering electronic cigarettes.
A search using Google search engine was performed in July 2015 for two keywords: e-papierosy [e-cigarettes] and elektroniczne papierosy [electronic cigarettes]. First 150 websites (15 pages) were listed. After initial review 86 pages met all inclusion criteria and were included in the study. Pages were searched for presence of 13 selected marketing claims as well as age-related warning and any social websites connections.
Age-related warning was present on only 33.72% (n=29) websites. Two thirds has its own Facebook fan-page with average 1922.09 ± 3634.86 likes. Articles about health are available on 10.46% (n=9) websites, 53.49% (n=46) states that e-cigarettes are healthier than conventional ones, 39.53% (n=34) emphasized that during usage of e-cigarettes no tarry substances are produced. Two pages had special article in which conventional and electronic cigarettes were compared. Almost half (44.19%) remarked that e-cigarettes are cheaper in usage than conventional, one third pointed out the simplicity of usage. 32.56% advertised e-cigarettes as aid in quitting smoking. One fourth stated that e-cigarettes are harmless for surroundings. 33.72% marketed them as a way of bypassing public smoking act. 56.98% remarked the variety of liquid tastes offered.
Electronic cigarettes and their rising popularity create another new possible threat for public health as the widely available information emphasize safety of e-cigarettes usage and as their availability and usage is not limited or restricted by law.
electronic cigarettes, e-cigarettes, internet retail websites.
The synthesis of various new structures of a library of 11-substituted 6-amino-11,12-dihydrobenzo[c]phenanthridines (BP) and 11-substituted 6-aminobenzo[c]phenanthridines (BP-D) is presented. These structures, further synthetic modifications, and the preparation of follow-up products which delivered about 40 new derivatives are described. Their potential as antiproliferative drug candidates was investigated by comparison of NCI 60 developmental therapeutics program (DTP) human tumor cell line screening data based on the results of in vitro tumor cell growth inhibition, including about 40 hitherto unpublished compound test results with up to 60 cancer cell lines. NCI-COMPARE studies helped to suggest the modes of action of the highly active antiproliferative drugs. These findings are supported by in vitro biological investigations showing either inhibition of tubulin polymerization and depolymerization or topoisomerase inhibition. Together with physicochemical parameters of the drug candidates, structure-activity relationships are critically discussed. Tubulin interaction or inhibition of topoisomerase I and IIα/β activity are two rationales that can explain the antiproliferative activity observed in the NCI 60 DTP human tumor cell line screen. However, it can also be reasonably assumed that these compounds address several targets, thus prohibiting the identification of simple structure-activity relationships. The new structures described herein are thought to act as so-called multitarget drugs, thus being of special interest in the area of multidrug resistance.
Anisotropic particles have attracted interest for decades and have been studied for many aspects, ranging from fundamental phase behavior to photonic properties. In addition, magnetic fields have been heavily used for external manipulation of colloidal particles for separation, for assembly, and even for photonic applications. Here we use magnetic field microgradients established in a paramagnetic fluid to act as templates for the assembly of both nonmagnetic and magnetic anisotropic colloidal particles. We embed the assembled structure in a polymer matrix in order to obtain a composite where the spatial distribution of the reinforcing particles are preprogrammed. By using a mixture of paramagnetic and diamagnetic particles with different mechanical strengths, a periodical modulation of reinforcement by the variation of the particle type at different locations is achieved. Furthermore, we introduce a similar method for assembly of paramagnetic particles, where we use magnetic gradients of permanent magnet arrays to obtain field gradients and modulate spatially the particle concentration, and thus reinforcement, through the macroscopic samples in three dimensions.
Climate change is expected to impact all aspects of marine ecosystems, including fisheries. Here, we use output from a suite of 11 earth system models to examine projected changes in two ecosystem-defining variables: temperature and food availability. In particular, we examine projected changes in epipelagic temperature and, as a proxy for food availability, zooplankton density. We find that under RCP8.5, a high business-as-usual greenhouse gas scenario, increasing temperatures may alter the spatial distribution of tuna and billfish species richness across the North Pacific basin. Furthermore, warmer waters and declining zooplankton densities may act together to lower carrying capacity for commercially valuable fish by 2-5% per decade over the 21st century. These changes have the potential to significantly impact the magnitude, composition, and distribution of commercial fish catch across the pelagic North Pacific. Such changes will in turn ultimately impact commercial fisheries' economic value. Fishery managers should anticipate these climate impacts to ensure sustainable fishery yields and livelihoods.
Prostate cancer is a multifocal disease with characteristic heterogeneity and foci that can range from low grade indolent to aggressive disease. The latter is characterised by the well-established histopathological Gleason grading system used in the current clinical care. Nevertheless, a large discrepancy exists on initial biopsy and after the final radical prostatectomy. Moreover, there is no reliable imaging modality to study these foci, in particular at the level of the cells and surrounding matrix. Extracellular matrix (ECM) remodelling is significant in cancer progression with collagen as the dominant structural component providing mechanical strength and flexibility of tissue. In this study, the collagen assembly in prostate tissue was investigated with second harmonic generation (SHG) microscopy: malignant foci demonstrated a reticular pattern, with a typical collagen pattern for each Gleason score. The orientation of collagen for each biopsy was computed by applying a ratio of the anisotropic and isotropic collagen fibres. This value was found to be distinct for each Gleason score. The findings suggest that this approach can not only be used to detect prostate cancer, but also can act as a potential biomarker for cancer aggressiveness.
Previous research suggests that messages promoting active behavior change may inadvertently increase food consumption by promoting
 a general goal to act. We suggest that this is only the case for active-approach behaviors and that messages promoting active-avoidance behaviors may be used to effectively decrease food consumption.
Participants were presented with healthy eating messages pretested to vary on the dimensions of direction (approach vs. avoid) and amount (action vs. inaction) of behavior. After viewing the messages, participants selected and consumed a healthy or unhealthy snack during a taste test.
There were no differences in snack selection (healthy vs. unhealthy) across message conditions. For messages promoting more active behavior, however, there was a significant difference in snack consumption such that participants viewing active-approach messages consumed significantly more food than participants viewing active-avoidance messages. This happened regardless of whether participants selected a healthy or unhealthy snack. For messages promoting less active behavior there was no difference in consumption between approach and avoidance based messages.
These findings suggest that when viewing health messages that promote active behavior change, individuals are sensitive to the direction of action advocated by the message (approach vs. avoidance) and modulate consumption accordingly.
Amyotrophic lateral sclerosis is an incurable, relentlessly progressive disease primarily affecting motor neurons. The cause of the disease, except for the mutations identified in a small fraction of patients, is unknown. The major mechanisms contributing to the degeneration of motor neurons have already been disclosed and characterized, including excitotoxicity, oxidative stress, mitochondrial dysfunction, and immune/inflammatory processes. During the progression of the disease these toxic processes are not discrete, but each facilitates the deleterious effect of the other. However, due to their common reciprocal calcium dependence, calcium ions may act as a common denominator and through a positive feedback loop may combine the individual pathological processes into a unified escalating mechanism of neuronal destruction. This mini-review provides an overview of the mutual calcium dependence of the major toxic mechanisms associated with amyotrophic lateral sclerosis.
In a recent issue of Nature Communications Ukleja and co-workers reported a cryo-EM 3D reconstruction of the Ccr4-Not complex from Schizosaccharomyces pombe with an immunolocalization of the different subunits. The newly gained architectural knowledge provides cues to apprehend the functional diversity of this major eukaryotic regulator. Indeed, in the cytoplasm alone, Ccr4-Not regulates translational repression, decapping and deadenylation, and the Not module additionally plays a positive role in translation. The spatial distribution of the subunits within the structure is compatible with a model proposing that the Ccr4-Not complex interacts with the 5' and 3' ends of target mRNAs, allowing different functional modules of the complex to act at different stages of the translation process, possibly within a circular constellation of the mRNA. This work opens new avenues, and reveals important gaps in our understanding regarding structure and mode of function of the Ccr4-Not complex that need to be addressed in the future.
It is difficult to achieve bone union in case of non-union with non-invasive techniques. MicroRNAs (miRNAs) are short, non-coding RNAs that act as repressors of gene expression at the level of post-transcriptional regulation. This study focuses on microRNA (miR)-222 as it is known to be a negative modulator of angiogenesis, an essential component of fracture healing. The purpose of this study was to analyze the effects of miR-222 on osteogenic and chondrogenic differentiation in human mesenchymal stromal cell (MSC)s in vitro, and to determine whether local administration of miR-222 inhibitor into the fracture site could achieve bone union in vivo.
miR-222 expression in human bone marrow mesenchymal stem cells (hMSCs), and osteogenic differentiation in hMSCs, were investigated. The gain or loss of miR-222 function was examined, in order to assess the effects of miR-222 on osteogenic and chondrogenic differentiation in hMSCs. A femoral transverse fracture was completed in rats, and the periosteum at the fracture site was cauterized. Then, either an miR-222 inhibitor or an miR-222 mimics, mixed with atelocollagen, was administered into the fracture site. A non-functional inhibitor negative control was administered to the control group. At 2, 4, 6, and 8 weeks, radiographs of the fractured femurs were obtained. Immunohistochemistry was performed at 2 weeks to evaluate the capillary density. At 8 weeks, micro-computed tomography (μCT) imaging analysis and histological evaluations were performed.
The expression of miR-222 significantly decreased as osteogenic differentiation of hMSCs proceeded. Inhibition of miR-222 promoted osteogenic differentiation, and over expression of miR-222 inhibited osteogenic differentiation in hMSCs, which was confirmed by measuring expression of Runx2, collagen type 1A1 (COL1A1), and osteocalcin. Inhibition of miR-222 promoted chondrogenic differentiation in hMSCs, which was confirmed by measuring expression of collagen type II (COL2A1), aggrican, and SOX9. Bone union at the fracture site was achieved in only the groups treated with the miR-222 inhibitor, confirmed by radiographic, μCT and histological evaluation at 8 weeks after administration. Immunohistochemistry showed that capillary density in the miR-222 inhibitor group was significantly higher than that in the control group and in the miR-222 mimics group.
Local administration of miR-222 inhibitor can accelerate bone healing by enhancing osteogenesis, chondrogenesis, and angiogenesis in the rat refractory model.
Accurate quantum chemical calculations were employed to investigate the mechanism of ozone-initiated oxidation of C-H bonds of saturated hydrocarbons and polymers. Step wise hydrogen atom abstraction generates the first resting state the trihydroxide -COOOH, which undergoes decomposition to produce the free radical species alkoxyl -CO˙ and peroxyl ˙OOH thereby setting off a complex chain of radical processes. The H transfer from peroxyl radical to alkoxyl allows formation of inactive alcohol and the singlet excited dioxygen. Other competitive processes include the self fragmentation or β-scission of the alkoxyl -CO˙ to give rise to a carbonyl (ketone or aldehyde) and a C-centred free radical species. Tertiary C-H bonds are most susceptible to O3 oxidation followed by secondary and primary. Among the polymers studied, poly(styrene) is the least resistant to C-H bond ozonation, followed by poly(propylene), poly(methacrylate), poly(methyl methacrylate) and poly(vinyl chloride). Calculations also reveal catalytic effects of water in promoting the C-H bond oxidation process in polymer systems without competing H-bond donor groups.
Guidelines recommend routine monitoring of unfractionated heparin (UFH) with activated clotting time (ACT) during percutaneous coronary intervention (PCI). However, the optimal ACT for patients undergoing PCI is unclear.
We sought to determine the association of peak ACT during PCI with 30-day major adverse cardiac events (MACE; all-cause mortality, myocardial infarction, and revascularization) and bleeding events. We searched the Cochrane Central Register of Controlled Trials, EMBASE, and Medline for randomized controlled trials (RCTs) evaluating UFH through May 2015. Only patients randomized to UFH alone or to UFH with a glycoprotein IIb/IIIa inhibitor (GPI) were analyzed using Bayesian meta-regression.
Among 13 included RCTs (n = 17455), eight (n = 5521) included study arms of UFH alone and 12 (n = 11934) included arms of UFH with a GPI. Peak ACT ranged from 201 to 460 sec for UFH alone and 248-317 sec for UFH with a GPI. With UFH alone, the probability of MACE was 7.0% (95% credible interval [CrI] 1.5, 31.5) for a peak ACT of 200 sec and 5.8% (95% CrI 2.6, 12.0) for 300 sec. Among UFH with a GPI, the probability of MACE was 2.8% (95% CrI 0.8, 6.8) for a peak ACT of 200 sec and 7.2% (95% CrI 5.4, 9.7) for 300 sec.
Among individual RCTs, the probability of MACE and major bleeding events associated with low versus high values of peak ACT is inconsistent. Our meta-regression results are inconclusive, emphasizing the need for RCTs comparing low versus high doses of UFH. © 2016 Wiley Periodicals, Inc.
Earlier work suggested that telephone follow-up could be used in lieu of in-person follow-up after surgery, saving patients time and travel and maximizing use of scarce surgeon and facility resources. We report our experience implementing and evaluating telephone postoperative follow-up within an integrated health system.
We conducted a pre-post evaluation of a general surgery telephone postoperative clinic at a tertiary care Veterans Affairs facility from April 2015 to February 2016. Patients were offered a telephone postoperative visit from a surgical provider in lieu of an in-person clinic visit. Telephone clinic operating procedures were refined through iterative cycles of change using the Plan-Do-Study-Act method. The study period included 2 months pre-intervention and 9 months post-intervention. The primary end point was mean number of clinic visits per eligible patient before and after telephone clinic implementation. Secondary outcomes were rates of emergency department visits and readmissions before vs after telephone clinic implementation and complication rates in patients scheduled for telephone vs in-person postoperative care.
During the study period, 200 patients underwent eligible operations, 29 pre-intervention and 171 post-intervention. In-person clinic use decreased from 0.83 visits per eligible patient pre-intervention to 0.40 after implementation
 of the telephone clinic (p < 0.01). There was no difference in rates of emergency department presentation or readmission in eligible patients (0.17 visits/patient pre-intervention vs 0.12 post-intervention; p = 0.36). Complication rates were comparable for eligible patients who were and were not scheduled for telephone care (6% vs 8%; p = 0.31).
Telephone postoperative care can be used in select populations as a triage tool to identify patients who require in-person care and decrease overall in-person clinic use.
Football injuries are responsible for many of the maxillofacial injuries sustained during sporting activities. In the Australian Capital Territory (ACT), the four major types of Australian football are played in large numbers and up to a high standard. Our objective was to analyse maxillofacial fractures that were sustained during rugby league, rugby union, Australian rules, and soccer matches. We retrospectively studied 134 patients with maxillofacial fractures during the five-year period 2010-14. All patients were assessed and treated at Canberra Hospital, the major trauma centre in the ACT. Data collected from patients' records included type of football, age, sex, mechanism of injury, site of injury, and treatment. The number of people registered to play was obtained from each football governing body to find out the incidence of fractures. League had the highest incidence of facial fractures, followed by union, Australian rules, and soccer. High speed and high collision football (league and union) had a higher rate of mandibular fractures than high speed and low contact football (Australian rules and soccer) (n=43, 45% compared with n=7, 21%). Australian rules and soccer had a higher incidence of midface fractures than league and union (n=26, 79%, compared with n=52, 55%). Clash of heads was the leading cause of fractures. Collisions against other players' shoulders and forearms were more likely to cause mandible fractures. Ninety-four patients (70%) required surgical intervention. Football-related maxillofacial fractures occur regularly, and different types of football have predictable patterns of injury. Padding of the heads and elbows of players may reduce the number and seriousness of facial fractures.
We are revising the Medicare hospital inpatient prospective payment systems (IPPS) for operating and capital-related costs of acute care hospitals to implement changes arising from our continuing experience with these systems for FY 2017. Some of these changes will implement certain statutory provisions contained in the Pathway for Sustainable Growth Reform Act of 2013, the Improving Medicare Post-Acute Care Transformation Act of 2014, the Notice of Observation Treatment and Implications for Care Eligibility Act of 2015, and other legislation. We also are providing the estimated market basket update to apply to the rate-of-increase limits for certain hospitals excluded from the IPPS that are paid on a reasonable cost basis subject to these limits for FY 2017. We are updating the payment policies and the annual payment rates for the Medicare prospective payment system (PPS) for inpatient hospital services provided by long-term care hospitals (LTCHs) for FY 2017. In addition, we are making changes relating to direct graduate medical education (GME) and indirect medical education payments; establishing new requirements or revising existing requirements for quality reporting by specific Medicare providers (acute care hospitals, PPS-exempt cancer hospitals, LTCHs, and inpatient psychiatric facilities), including related provisions for eligible hospitals and critical access hospitals (CAHs) participating in the Electronic Health Record Incentive Program; updating policies relating to the Hospital Value-Based Purchasing Program, the Hospital Readmissions Reduction Program, and the Hospital-Acquired Condition Reduction Program; implementing statutory provisions that require hospitals and CAHs to furnish notification to Medicare beneficiaries, including Medicare Advantage enrollees, when the beneficiaries receive outpatient observation services for more than 24 hours; announcing the implementation of the Frontier Community Health Integration Project Demonstration; and making technical corrections and changes to regulations relating to costs to related organizations and Medicare cost reports; we are providing notice of the closure of three teaching hospitals and the opportunity to apply for available GME resident slots under section 5506 of the Affordable Care Act. We are finalizing the provisions of interim final rules with comment period that relate to a temporary exception for certain wound care discharges from the application of the site neutral payment rate under the LTCH PPS for certain LTCHs; application of two judicial decisions relating to modifications of limitations on redesignation by the Medicare Geographic Classification Review Board; and legislative extensions of the Medicare-dependent, small rural hospital program and changes to the payment adjustment for low-volume hospitals.
In multicellular organisms, relations among parts and between parts and the whole are contextual and interdependent. These organisms and their cells are ontogenetically linked: an organism starts as a cell that divides producing non-identical cells, which organize in tri-dimensional patterns. These association patterns and cells types change as tissues and organs are formed. This contextuality and circularity makes it difficult to establish detailed cause and effect relationships. Here we propose an approach to overcome these intrinsic difficulties by combining the use of two models; 1) an experimental one that employs 3D culture technology to obtain the structures of the mammary gland, namely, ducts and acini, and 2) a mathematical model based on biological principles. The typical approach for mathematical modeling in biology is to apply mathematical tools and concepts developed originally in physics or computer sciences. Instead, we propose to construct a mathematical model based on proper biological principles. Specifically, we use principles identified as fundamental for the elaboration of a theory of organisms, namely i) the default state of cell proliferation with variation and motility and ii) the principle of organization by closure of constraints. This model has a biological component, the cells, and a physical component, a matrix which contains collagen fibers. Cells display agency and move and proliferate unless constrained; they exert mechanical forces that i) act on collagen fibers and ii) on other cells. As fibers organize, they constrain the cells on their ability to move and to proliferate. The model exhibits a circularity that can be interpreted in terms of closure of constraints. Implementing the mathematical model shows that constraints to the default state are sufficient to explain ductal and acinar formation, and points to a target of future research, namely, to inhibitors of cell proliferation and motility generated by the epithelial cells. The success of this model suggests a step-wise approach whereby additional constraints imposed by the tissue and the organism could be examined in silico and rigorously tested by in vitro and in vivo experiments, in accordance with the organicist perspective we embrace.
A biomimetic strategy was developed in order to prepare organically modified hydroxyapatite (ormoHAP) with spherical shape. The technical approach is based on electric field-assisted migration of calcium ions and phosphate ions into a hydrogel composed of carboxymethylated gelatin. The electric field as well as the carboxymethylation using glucuronic acid (GlcA) significantly accelerates the mineralization process, which makes the process feasible for lab scale production of ormoHAP spheres and probably beyond. A further process was developed for gentle separation of the ormoHAP spheres from the gelatin gel without compromising the morphology of the mineral. The term ormoHAP was chosen since morphological analyses using electron microscopy (SEM, TEM) and element analysis (EDX, FT-IR, XRD) confirmed that carboxymethylated gelatin molecules use to act as organic templates for the formation of nanocrystalline HAP. The hydroxyapatite (HAP) crystals self-organize to form hollow spheres with diameters ranging from 100 to 500nm. The combination of the biocompatible chemical composition and the unique structure of the nanocomposites is considered to be a useful basis for future applications in functionalized degradable biomaterials.
A novel bioinspired mineralization process was developed based on electric field-assisted migration of calcium and phosphate ions into biochemically carboxymethylated gelatin acting as organic template. Advantages over conventional hydroxyapatite include particle size distribution and homogeneity as well as achievable mechanical properties of relevant composites. Moreover, specifically developed calcium ion or phosphate ion release during degradation can be useful to adjust the fate of bone cells in order to manipulate remodeling processes. The hollow structure of the spheres can be useful for embedding drugs in the core, encapsulated by the highly mineralized outer shell. In this way, controlled drug release could be achieved, which enables advanced strategies for threating bone-related diseases, e.g. osteoporosis and multiple myeloma.
Current US guidelines recommend the Asthma Control Test (ACT) for assessing disease control and selecting treatment.
The goal of this study was to prospectively assess the ACT and its component questions for their utility in predicting the risk of severe asthma exacerbations.
Individuals were participants in the Study of Asthma Phenotypes and Pharmacogenomic Interactions by Race-Ethnicity, and those included in the current analysis had the following
 characteristics: age 18 years or more, physician-diagnosed asthma, and longitudinal care received at a large health system in southeastern Michigan. Study participants underwent a baseline evaluation, which included answering the ACT. A severe asthma exacerbation was defined as one requiring oral steroids, an emergency department visit, or inpatient admission. Receiver-operator characteristic curves were used to measure and compare the predictive utility of the ACT and its component questions for severe asthma exacerbations.
Of 1180 participants, 354 (30.0%) experienced a severe asthma exacerbation within 6 months of their baseline evaluation. When compared with the individual questions that composed the ACT, the composite score was significantly better at predicting severe exacerbations with 1 exception; the composite ACT score and the question assessing rescue medication use were not significantly different (P = .580). Pharmacy-based records of metered-dose inhaler short-acting beta-agonist use and asthma severity were also not significantly different from the composite ACT score.
Our study demonstrates that although the ACT is modestly predictive for exacerbations, the composite score may not be superior to assessing rescue medication use alone for predicting the risk of severe asthma exacerbations.
The occurrence of harmful cyanobacterial blooms in surface waters is often accompanied by the production of a variety of cyanotoxins, and these toxins are designed to target in humans specific organs on which they act. When introduced into the soil ecosystem by spray irrigation of crops, they may affect the same molecular pathways in plants having identical or similar target organs, tissues, cells, or biomolecules. There are also several indications that terrestrial plants, including crops, can bioaccumulate cyanotoxins and present, therefore, potential health hazards for humans. During this project, for monitoring purposes, water samples were collected from lake Occhito, in which there was an algal bloom (Planktothrix rubescens) in 2009, and from three tanks which acted as hydraulic junctions. In addition, crop samples irrigated with water from the three tanks mentioned above were also picked. Finally, the characterization of principal cyanobacteria was performed, to determine the presence of cyanotoxins such as microcystins and validate a method of screening ELISA for the determination of microcystins in vegetable samples and a confirmatory method by HPLC-ESI-MS/MS. Graphical abstract Occhito lake (left), microcystin LR (center), Tomato field in Foggia (right); figures below: ELISA (left), HPLC-MS/MS (right).
Chinese hamster ovary (CHO) cell lines are widely used for therapeutic protein production. When a transgene is integrated into the genome of a CHO cell, the expression level is highly dependent on the site of integration because of positional effects such as gene silencing. To overcome negative positional effects and establish stable CHO cell lines with high productivity, several regulatory DNA elements are used in vector construction. Previously, we established the CHO DR1000L-4N cell line, a stable and high copy number Dhfr gene-amplified cell line. It was hypothesized that the chromosomal location of the exogenous gene-amplified region in the CHO DR1000L-4N genome contains regulatory motifs for stable protein production. Therefore, we isolated DNA regulatory motifs from the CHO DR1000L-4N cell line and determined whether these motifs act as an insulator. Our results suggest that stable expression of a transgene can be promoted by the CHO genome sequence, and it would be a powerful tool for therapeutic protein manufacturing.
Breastfeeding has many known benefits yet its support across Australian health systems was suboptimal throughout the 20th Century. The World Health Organization launched a global health promotion strategy to help create a 'breastfeeding culture'. Research on the programme has revealed multiple barriers since implementation.
To analyse the sociopolitical challenges associated with implementing a global programme into a national setting via an examination of the influences on the early period of implementation of the Baby Friendly Hospital Initiative in Australia.
A focused historical document analysis was attended as part of an instrumental case study. A purposeful sampling strategy obtained a comprehensive sample of public and private documents related to the introduction of the BFHI in Australia. Analysis was informed by a 'documents as commentary' approach to gain insight into individual and collective social practices not otherwise observable.
Four major themes were identified: "a breastfeeding culture"; "resource implications"; "ambivalent support for breastfeeding and the BFHI" and "business versus advocacy". "A breastfeeding culture" included several subthemes. No tangible support for breastfeeding generally, or the Baby Friendly Hospital Initiative specifically, was identified. Australian policy did not follow international recommendations. There were no financial or policy incentives for BFHI implementation.
Key stakeholders' decisions negatively impacted on the Baby Friendly Hospital Initiative at a crucial time in its implementation in Australia. The potential impact of the programme was not realised, representing a missed opportunity to establish and provide sustainable standardised breastfeeding support to Australian women and their families.
Lignin forms a large part of plant biomass. It is a highly heterogeneous polymer of 4-hydroxyphenylpropanoid units and is embedded within polysaccharide polymers forming lignocellulose. Lignin provides strength and rigidity to plants and is rather resilient towards degradation. To improve the (bio)processing of lignocellulosic feedstocks, more effective degradation methods of lignin are in demand. Nature has found ways to fully degrade lignin through the production of dedicated ligninolytic enzyme systems. While such enzymes have been well thoroughly studied for ligninolytic fungi, only in recent years biochemical studies on bacterial enzymes capable of lignin modification have intensified. This has revealed several types of enzymes available to bacteria that enable them to act on lignin. Two major classes of bacterial lignin-modifying enzymes are DyP-type peroxidases and laccases. Yet, recently also several other bacterial enzymes have been discovered that seem to play a role in lignin modifications. In the present review, we provide an overview of recent advances in the identification and use of bacterial enzymes acting on lignin or lignin-derived products.
Conscience and conscientious objections are important issues in medical law and ethics. However, discussions tend to focus on a particular type of conscience-based claim. These types of claims are based upon predictable, generalizable rules in which an individual practitioner objects to what is otherwise standard medical treatment (for example, the objections recognised in the Abortion Act). However, not all conscience based claims are of this type. There are other claims which are based not on an objection to a treatment in general but in individual cases. In other words, these cases may involve practices which the doctor does not usually object to but does so in this instance on these facts. This paper will explore these types of conscience-based claims in two ways. First, it will explore whether these types of individualised conscience-based claims are really conscience claims at all. Second, it will explore how these claims interact with the other sorts of judgements we expect doctors to make in these cases (things like professional standards, clinical judgment and the best interests of the patient).
In continuation of our previous efforts directed towards the development of potent and selective inhibitors of aldose reductase (ALR2), and to control the diabetes mellitus (DM), a chronic metabolic disease, we synthesized novel coumarin-thiazole 6(a-o) and coumarin-oxadiazole 11(a-h) hybrids and screened for their inhibitory activity against aldose reductase (ALR2), for the selectivity against aldehyde reductase (ALR1). Compounds were also screened against ALR1. Among the newly designed compounds, 6c, 11d, and 11g were selective inhibitors of ALR2. Whereas, (E)-3-(2-(2-(2-bromobenzylidene)hydrazinyl)thiazol-4-yl)-2H-chromen-2-one 6c yielded the lowest IC50 value of 0.16±0.06μM for ALR2. Moreover, compounds (E)-3-(2-(2-benzylidenehydrazinyl)thiazol-4-yl)-2H-chromen-2-one (6a; IC50=2.94±1.23μM for ARL1 and 0.12±0.05μM for ARL2) and (E)-3-(2-(2-(1-(4-bromophenyl)ethylidene)hydrazinyl)thiazol-4-yl)-2H-chromen-2-one (6e; IC50=1.71±0.01μM for ARL1 and 0.11±0.001μM for ARL2) were confirmed as dual inhibitors. Furthermore, compounds 6i, 6k, 6m, and 11b were found to be selective inhibitors for ALR1, among which (E)-3-(2-(2-((2-amino-4-chlorophenyl)(phenyl)methylene)hydrazinyl)thiazol-4-yl)-2H-chromen-2-one (6m) was most potent (IC50=0.459±0.001μM). Docking studies performed using X-ray structures of ALR1 and ALR2 with the given synthesized inhibitors showed that coumarinyl thiazole series lacks the carboxylate function that could interact with the anionic binding site being a common ALR1/ALR2 inhibitors trait. Molecular docking study with dual inhibitor 6e also suggested plausible binding modes for the ALR1 and ALR2 enzymes. Hence, the results of this study revealed that coumarinyl thiazole and oxadiazole derivatives could act as potential ALR1/ALR2 inhibitors.
The simultaneous uptake of PDMPO and Rhodamine B as two fluorescent dyes forming a Förster transfer pair by the diatom Cyclotella meneghiniana is demonstrated by in vivo-fluorochromation. The incorporation density in the cell walls was high enough for achieving resonant energy transfer between the two dyes as detected by fluorescence
 and excitation spectroscopy. The mean fluorescence lifetime of the donor is shortened in the presence of the acceptor by a factor of 0.75. By determining the mean lifetime from the fluorescence decay fitted by three eponentials, the efficiency of the energy transfer and the acceptor concentration is calculated assuming a homogenous distribution. For an initial concentration of both dyes of 5μM in the culture medium which is at the saturation limit of incorporation, an acceptor incorporation density of 0.6mM is obtained. In addition to such quantitative determinations, efficient emitting systems based on resonant energy transfer between two laser dyes may be useful in photonic applications of the hybrid biomineral. By achieving stimulated emission, the presence of optical modes in diatom frustules, which may act as photonic resonators due to the refractive index contrast to the environment in combination with the more or less regular pore pattern, may be characterized further.
To determine the outcome of a bailout procedure using the right ventricle to re-assist the left ventricle in neonates after technically adequate coarctectomy but a failing borderline left heart.
The surgical procedure was performed on bypass. A 'reversed' 6-mm surgical shunt was inserted between the pulmonary trunk and the descending aorta together with bilateral branch pulmonary artery banding.
Over a 10-year period, 89 neonates presented with coarctation and small left hearts. In 9 neonates, a hybrid procedure was performed at the outset. The remaining 80 underwent extended end-to-end coarctectomy. Two of these, despite adequate coarctectomy, developed retrograde cardiac failure with supra-systemic pulmonary hypertension, dilating right ventricles and progressive cardiogenic shock. The progressively dilating right ventricles inhibited left ventricular filling. Reversed surgical shunts were performed at 9 and 7 days post-coarctectomy. Both infants recovered rapidly and could be extubated after 4 and 7 days, respectively. Patient 1 proceeded to a univentricular repair and Patient 2 to a biventricular repair.
Reversed surgical shunt with bilateral banding of the branch pulmonary arteries after neonatal coarctectomy can be successfully employed as a bailout procedure in cases where a borderline left heart with growth potential cannot tolerate a biventricular circulation. It may act as an acute life-saving measure as well as a bridge to later repair. If high risk for backward failure exists in a borderline left heart with catch-up growth potential, a primary hybrid procedure is probably a more elegant and predictable strategy.
Myasthenia gravis (MG) is a chronic humoral immunity-mediated autoimmune disorder of the neuromuscular junction characterized by muscle weakness. Follicular helper T (Tfh) cells may be the key Th cell subset that promotes MG development, as their major function is helping B cell activation and Ab production. Aberrance of thymus-derived Tfh cells might be implicated in autoimmune diseases including MG; just how circulating Tfh cells, especially those from patients with a normal thymus, contribute to MG pathogenesis remains to be uncovered. In this article, we characterize a population of circulating CD4(+)CXCR5(+)PD-1(+) Tfh cells in ocular and generalized MG patients without thymic abnormalities and demonstrate that the circulating Tfh cells are significantly enriched in generalized MG patients but not in ocular MG patients compared with healthy subjects, whereas a proportion of follicular regulatory T cells decreased in MG patients. In addition, the frequency of plasma cells and B cells was higher and the serum levels of IL-6/IL-21 were also elevated in these MG patients. The activated Tfh1 and Tfh17 in Tfh cells are the major source for IL-21 production in MG patients. A strong correlation between Tfh cells and the plasma cell frequency and anti-acetylcholine receptor Ab titers was evident in generalized MG patients. In particular, we found that Tfh cells derived from MG patients promoted B cells to produce Abs in an IL-21 signaling-dependent manner. Collectively, our results suggest that circulating Tfh cells may act on autoreactive B cells and thus contribute to the development of MG in patients without thymic abnormalities.
The aim of this study was to qualitatively explore the barriers and enablers to implementing healthy workplace initiatives in a sample of workplaces based in Perth, Western Australia. In-depth interviews were conducted with representatives from 31 organizations representing small, medium and large businesses in the Perth metropolitan area which reported having healthy workplace initiatives. In total, 43 factors were mentioned as influencing the implementation of healthy workplace initiatives. Factors appearing to exert the most influence on the implementation of health promoting initiatives in this sample were culture; support from managers and staff; collaboration with industry providers; financial resources circumstances and the physical environment. These factors appeared to be mutually reinforcing and interconnected. Findings suggest there may be merit in applying an organizational development lens to the implementation of workplace health promotion initiatives as this could assist in leveraging enablers and minimizing barriers.
In search of more effective chemotherapeutics for the treatment of castration-resistant prostate cancer and inspired by curcumin analogues, twenty five (1E,3E,6E,8E)-1,9-diarylnona-1,3,6,8-tetraen-5-ones bearing two identical terminal heteroaromatic rings have been successfully synthesized through Wittig reaction followed by Horner-Wadsworth-Emmons reaction. Twenty-three of them are new compounds. The WST-1 cell proliferation assay was employed to assess their anti-proliferative effects toward both androgen-sensitive and androgen-insensitive human prostate cancer cell lines. Eighteen out of twenty-five synthesized compounds possess significantly improved potency as compared with curcumin. The optimal compound, 78, is 14- to 23-fold more potent than curcumin in inhibiting prostate cancer cell proliferation. It can be concluded from our data that 1,9-diarylnona-1,3,6,8-tetraen-5-one can serve as a new potential scaffold for the development of anti-prostate cancer agents and that pyridine-4-yls and quinolin-4-yl act as optimal heteroaromatic rings for the enhanced potency of this scaffold. Two of the most potent compounds, 68 and 75, effectively suppress PC-3 cell proliferation by activating cell apoptosis and by arresting cell cycle in the G0/G1 phase.
Nations with emerging deceased-donor liver transplantation programs, such as India, face problems associated with poor donor maintenance. Cold ischemic time (CIT) is typically maintained short by matching donor organ recovery and recipient hepatectomy to achieve maximum favorable outcome. We analyzed different extended criteria donor factors including donor acidosis, which may act as a surrogate marker of poor donor maintenance, to quantify the risk of primary nonfunction (PNF) or initial poor function (IPF).
A single-center retrospective outcome analysis of prospectively collected data of patients undergoing deceased-donor liver transplantation over 2 years to determine the impact of different extended criteria donor factors on IPF and PNF.
From March 2013 to February 2015, a total of 84 patients underwent deceased-donor liver transplantation. None developed PNF. Thirteen (15.5%) patients developed IPF. Graft macrosteatosis and donor acidosis were only related to IPF (P = .002 and P = .032, respectively). Cold ischemic time was tried to be maintained short (81 cases ≤8 hours, maximum 11 hours) in all cases.
Poor donor maintenance as evidenced by donor acidosis and graft macrosteatosis had significant impact in developing IPF when CIT is kept short. Similar study with larger sample size is required to establish extended criteria cutoff values.
Common diseases like diabetes, hypertension, and atrial fibrillation are probable risk factors for dementia, suggesting that their treatments may influence the risk and rate of cognitive and functional decline. Moreover, specific therapies and medications may affect long-term brain health through mechanisms that are independent of their primary indication. While surgery, benzodiazepines, and anti-cholinergic drugs may accelerate decline or even raise the risk of dementia, other medications act directly on the brain to potentially slow the pathology that underlies Alzheimer's and other dementia. In other words, the functional and cognitive decline in vulnerable patients may be influenced by the choice of treatments for other medical conditions. Despite the importance of these questions, very little research is available. The Alzheimer's Drug Discovery Foundation convened an advisory panel to discuss the existing evidence and to recommend strategies to accelerate the development of comparative effectiveness research on how choices in the clinical care of common chronic diseases may protect from cognitive decline and dementia.
One of the most characteristic pathological changes in cats that have succumbed to feline infectious peritonitis (FIP) is a multifocal granulomatous phlebitis. Although it is now well established that leukocyte extravasation elicits the inflammation typically associated with FIP lesions, relatively few studies have aimed at elucidating this key pathogenic event. The upregulation of adhesion molecules on the endothelium is a prerequisite for stable leukocyte-endothelial cell (EC) adhesion that necessarily precedes leukocyte diapedesis. Therefore, the present work focused on the expression of the EC adhesion molecules and possible triggers of EC activation during the development of FIP. Immunofluorescence analysis revealed that the endothelial expression of P-selectin,
 E-selectin, intercellular adhesion molecule 1 (ICAM-1) and vascular cell adhesion molecule 1 (VCAM-1) was elevated in veins close to granulomatous infiltrates in the renal cortex of FIP patients compared to non-infiltrated regions and specimens from healthy cats. Next, we showed that feline venous ECs become activated when exposed to supernatant from feline infectious peritonitis virus (FIPV)-infected monocytes, as indicated by increased adhesion molecule expression. Active viral replication seemed to be required to induce the EC-stimulating activity in monocytes. Finally, adhesion assays revealed an increased adhesion of naive monocytes to ECs treated with supernatant from FIPV-infected monocytes. Taken together, our results strongly indicate that FIPV activates ECs to increase monocyte adhesion by an indirect route, in which proinflammatory factors released from virus-infected monocytes act as key intermediates.
Against a backdrop of non-ideal political and legal conditions, this article examines the health capability paradigm and how its principles can help determine what aspects of health care might legitimately constitute positive health care rights-and if indeed human rights are even the best approach to equitable health care provision. This article addresses the long American preoccupation with negative rights rather than positive rights in health care. Positive health care rights are an exception to the overall moral range and general thrust of U.S. legal doctrine. Some positive rights to health care have arisen from U.S. Constitutional Eighth Amendment cases and federal and state laws like Medicare, Medicaid, the State Children's Health Insurance Program, the Emergency Medical Treatment and Active Labor Act, and the Patient Protection and Affordable Care Act. Finally, this article discusses some of the difficulties inherent in implementing a positive right to health care in the U.S.
The metabotropic glutamate receptor 5 (mGluR5) and the cannabinoid receptor 1 (CB1) exhibit a functional interaction, as CB1 regulates pre-synaptic glutamate release and mGluR5 activation increases endocannabinoid synthesis at the post-synaptic site. Since both mGluR5 and CB1 promote neuroprotection, we delineated experiments to investigate a possible link between CB1 and mGluR5 activation in the induction of neuroprotection using primary cultured corticostriatal neurons. We find that either the pharmacological blockade or the genetic ablation of either mGluR5 or CB1 can abrogate both CB1- and mGluR5-mediated neuroprotection against glutamate insult. Interestingly, decreased glutamate release and diminished intracellular Ca(2+) do not appear to play a role in CB1 and mGluR5-mediated neuroprotection. Rather, these two receptors work cooperatively to trigger the activation of cell signaling pathways to promote neuronal survival, which involves MEK/ERK1/2 and PI3K/AKT activation. Interestingly, although mGluR5 activation protects postsynaptic terminals and CB1 the presynaptic site, intact signaling of both receptors is required to effectively promote neuronal survival. In conclusion, mGluR5 and CB1 act in concert to activate neuroprotective cell signaling pathways and promote neuronal survival.
MicroRNA (miR)-20a, a member of the miR-17-92 cluster related to cardiac development, was obviously downregulated in myocardially differentiated P19 cells compared with normal P19 cells. Smoothened (SMO) is a member of the Hh pathway. Hh signaling induces cardiac differentiation in P19 cells, and SMO mediates the Hh pathway during embryonic development. Using bioinformatic prediction software Targetscan (http://www.targetscan.org/), PicTar (http://pictar.bio.nyu.edu), and miRBase (http://microrna.sanger.ac.uk/), miR-20a and the 3'-untranslated region (3'-UTR) of SMO mRNA were predicted to have complementary binding regions. Accordingly, we inferred that miR-20a might act as a regulator of SMO, and regulate proliferation, differentiation and apoptosis in P19 cells. We determined the expression of miR-20a, SMO and marker proteins of cardiomyocytes (cTnT, GATA4 and desmin) by quantitative real-time PCR (qRT-PCR) and western blot assays, and found that P19 cells had differentiated into cardiomyocytes successfully at differentiation day 10, and downregulation of miR-20a and upregulation of SMO existed in myocardially differentiated P19 cells. Cell proliferation, differentiation and apoptosis detection showed that miR-20a upregulation inhibited proliferation and differentiation and enhanced apoptosis in P19 cells. Moreover, we verified that miR-20a directly targeted SMO and knockdown of SMO and miR-20a overexpression had similar effects on P19 cell proliferation, differentiation and apoptosis, which verified the speculation that miR-20a inhibits proliferation and differentiation and enhances apoptosis in P19 cells by directly targeting SMO. Our results suggest that miR-20a may be a potential target against congenital heart diseases.
To evaluate the shear bond strengths of two gingiva-colored materials (an indirect composite material and a denture base acrylic resin) to zirconia ceramics and determine the effects of surface treatment with various priming agents.
A gingiva-colored indirect composite material (CER) or denture base acrylic resin (PAL) was bonded to zirconia disks with unpriming (UP) or one of seven priming agents (n=11 each), namely, Alloy Primer (ALP), Clearfil Photo Bond (CPB), Clearfil Photo Bond with Clearfil Porcelain Bond Activator (CPB+Act), Metal Link (MEL), Meta Fast Bonding Liner (MFB), MR. bond (MRB), and V-Primer (VPR). Shear bond strength was determined before and after 5000 thermocycles. The data were analyzed with the Kruskal-Wallis test and Steel-Dwass test.
The mean pre-/post-thermalcycling bond strengths were 1.0-14.1MPa/0.1-12.1MPa for the CER specimen and 0.9-30.2MPa/0.1-11.1MPa for the PAL specimen. For the CER specimen, the ALP, CPB, and CPB+Act groups had significantly higher bond strengths among the eight groups, at both 0 and 5000 thermocycles. For the PAL specimen, shear bond strength was significantly lower after thermalcycling in all groups tested. After 5000 thermocycles, bond strengths were significantly higher in the CPB and CPB+Act groups than in the other groups.
For the PAL specimens, bond strengths were significantly lower after thermalcycling in all groups tested. The MDP functional monomer improved bonding of a gingiva-colored indirect composite material and denture base acrylic resin to zirconia ceramics.
The microR159 (miR159) - GAMYB pathway is conserved in higher plants, where GAMYB, expression promotes programmed cell death in seeds (aleurone) and anthers (tapetum). In cereals, restriction of GAMYB expression to seeds and anthers is mainly achieved transcriptionally, whereas in Arabidopsis this is achieved post-transcriptionally, as miR159 silences GAMYB (MYB33 and MYB65) in vegetative tissues, but not in seeds and anthers. However, we cannot rule out a role for miR159-MYB33/65 pathway in Arabidopsis vegetative tissues; a loss-of-function mir159 Arabidopsis mutant displays strong pleiotropic defects and numerous reports have documented changes in miR159 abundance during stress and hormone treatments. Hence, we have investigated the functional role of this pathway in vegetative tissues.
It was found that the miR159-MYB33/65 pathway was ubiquitously present throughout rosette development. However, miR159 appears to continuously repress MYB33/MYB65 expression to levels that have no major impact on rosette development. Inducible inhibition of miR159 resulted in MYB33/65 de-repression and associated phenotypic defects, indicating that a potential role in vegetative development is only possible through MYB33 and MYB65 if miR159 levels decrease. However, miR159 silencing of MYB33/65 appeared extremely robust; no tested abiotic stress resulted in strong miR159 repression. Consistent with this, the stress responses of an Arabidopsis mutant lacking the miR159-MYB33/65 pathway were indistinguishable from wild-type. Moreover, expression of viral silencing suppressors, either via transgenesis or viral infection, was unable to prevent miR159 repression of MYB33/65, highlighting the robustness of miR159-mediated silencing.
Despite being ubiquitously present, molecular, genetic and physiological analysis failed to find a major functional role for the miR159-MYB33/65 pathway in Arabidopsis rosette development or stress response. Although it is likely that this pathway is important for a stress not tested here or in different plant species, our findings argue against the miR159-MYB33/65 pathway playing a major conserved role in general stress response. Finally, in light of the robustness of miR159-mediated repression of MYB33/65, it appears unlikely that low fold-level changes of miR159 abundance in response to stress would have any major physiological impact in Arabidopsis.
The U.S. federal Every Student Succeeds Act (ESSA) was enacted with goals of closing achievement gaps and providing all students with access to equitable and high-quality instruction. One requirement of ESSA is annual statewide testing of students in grades 3-8 and once in high school. Some students, including many deaf or hard-of-hearing (D/HH) students, are eligible to use test supports, in the form of accommodations and accessibility tools, during state testing. Although technology allows accommodations and accessibility tools to be embedded within a digital assessment system, the success of this approach depends on the ability of test developers to appropriately represent content in accommodated forms. The Guidelines for Accessible Assessment Project (GAAP) sought to develop evidence- and consensus-based guidelines for representing test content in American Sign Language. In this article, we present an overview of GAAP, review of the
 literature, rationale, qualitative and quantitative research findings, and lessons learned.
The Small Archaeal Modifier Proteins (SAMPs) from Haloferax volcanii belong to the group of ubiquitin like proteins (Ubls) that act both as protein modifiers and sulfur carriers. The E1-like enzyme UbaA is essential for SAMP activation and therefore required for both sampylation and sulfur transfer. Here, we provide a commentary on the thorough characterization of UbaA by J. Maupin-Furlow and colleagues.
Obesity prevention interventions targeting 'at-risk' adolescents are urgently needed. The aim of this study is to evaluate the sustained impact of the 'Active Teen Leaders Avoiding Screen-time' (ATLAS) obesity prevention program.
Cluster RCT in 14 secondary schools in low-income communities of New South Wales, Australia. Participants were 361 adolescent boys (aged 12-14 years) 'at risk' of obesity. The intervention was based on Self-Determination Theory and Social Cognitive Theory and involved: professional development, fitness equipment for schools, teacher-delivered physical activity sessions, lunch-time activity sessions, researcher-led seminars, a smartphone application, and parental strategies. Assessments for the primary (body mass index [BMI], waist circumference) and secondary outcomes were conducted at baseline, 8- (post-intervention) and 18-months (follow-up). Analyses followed the intention-to-treat principle using linear mixed models.
After 18-months, there were no intervention effects for BMI or waist circumference. Sustained effects were found for screen-time, resistance training skill competency, and motivational regulations for school sport.
There were no clinically meaningful intervention effects for the adiposity outcomes. However, the intervention resulted in sustained effects for secondary outcomes. Interventions that more intensively target the home environment, as well as other socio-ecological determinants of obesity may be needed to prevent unhealthy weight gain in adolescents from low-income communities.
Australian Clinical Trial Registry ACTRN12612000978864.
This study was designed to evaluate the possible potentiation of survival protection afforded by relatively low-dose amifostine prophylaxis against total body irradiation in combination with a protective, less toxic agent, gamma-tocotrienol (GT3). Mice were administered amifostine and/or GT3, then exposed to 9.2 Gy (60)Co γ-irradiation and monitored for survival for 30 days. To investigate cytokine stimulation, mice were administered amifostine or GT3; serum samples were collected and analyzed for cytokines. Survival studies show single treatments of GT3 or amifostine significantly improved survival, compared to the vehicle, and combination treatments resulted in significantly higher survival compared to single treatments. In vivo studies with GT3 confirmed prior work indicating GT3 induces granulocyte colony-stimulating factor (G-CSF). This approach, the prophylactic combination of amifostine and GT3, which act through different mechanisms, shows promise and should be investigated further as a potential countermeasure for acute radiation syndrome.
Mandatory employer-based insurance coverage of contraception in the US has been a controversial component of the Affordable Care Act (ACA). Prior research has examined the cost-effectiveness of contraception in general; however, no studies have developed a formal decision model in the context of the new ACA provisions. As such, this study aims to estimate the relative cost-effectiveness of insurance coverage of contraception under employer-sponsored insurance coverage taking into consideration newer regulations allowing for religious exemptions.
A decision model was developed from the employer perspective to simulate pregnancy costs and outcomes associated with insurance coverage. Method-specific estimates of contraception failure rates, outcomes and costs were derived from the literature. Uptake by marital status and age was drawn from a nationally representative database.
Providing no contraception coverage resulted in 33 more unintended pregnancies per 1000 women (95% confidence range: 22.4; 44.0). This subsequently significantly increased the number of unintended births and terminations. Total costs were higher among uninsured women owing to higher costs of pregnancy outcomes. The effect of no insurance was greatest on unmarried women 20-29 years old.
Denying female employees' full coverage of contraceptives increases total costs from the employer perspective, as well as the total number of terminations.
Insurance coverage was found to be significantly associated with women's choice of contraceptive method in a large nationally representative sample. Using a decision model to extrapolate to pregnancy outcomes, we found a large and statistically significant difference in unintended pregnancy and terminations. Denying women contraception coverage may have significant consequences for pregnancy outcomes.
The time available to act is a crucial factor affecting the probable success of interventions to manage opiate overdose. We analyse opiate users' accounts of non-fatal overdose incidents to (i) construct a proto-typology of non-fatal opiate overdose onset and (ii) assess the implications for overdose management and prevention of fatalities.
Re-analysis of a subset of data from a large qualitative study of non-fatal opiate overdose conducted from 1997 to 1999. Data were generated from semi-structured interviews undertaken with opiate users who had experienced a non-fatal overdose in the previous 24 hours. Forty-four participants (30 men; 14 women; aged 16-47 years) provided sufficient information for in-depth analysis. Data relating to 'memory of the moment of overdose', 'time to loss of consciousness' and 'subjective description of the overdose experience' were scrutinised using iterative categorization.
Four types of overdose onset were identified: type A 'amnesic' (n = 8), characterized by no memory, rapid loss of consciousness and no description of the overdose experience; type B 'conscious' (n = 17), characterized by some memory, sustained consciousness and a description of the overdose in terms of feeling unwell and symptomatic; type C 'instant' (n = 14), characterized by some memory, immediate loss of consciousness and no description of the overdose experience; and type D 'enjoyable' (n = 5), characterized by some memory, rapid loss of consciousness and a description of the overdose experience as pleasant or positive.
The identification of different types of overdose onset highlights the complexity of overdose events, the need for a range of interventions and the challenges faced in managing incidents and preventing fatalities. Opiate overdose victims who retain consciousness for a sustained period and recognize the negative signs and symptoms of overdosing could summon help or self-administer naloxone, thus indicating that opiate overdose training should incorporate self-management strategies.
Myeloid-derived suppressor cells (MDSCs) play a pivotal role in promoting tumor growth and metastasis and can even decrease the efficacy of immunotherapy. In breast cancer, MDSCs are recruited mainly by breast cancer cells to form a tumor-favoring microenvironment to suppress the anti-tumor immune response. In addition, MDSCs can react directly with breast cancer cells. In this paper, we describe several ways to recruit MDSCs in breast cancer, including breast cancer cell-derived cytokines and chemokines. The intracellular pathways in MDSCs during recruitment are classified as the STAT3-NF-κB-IDO pathway, the STAT3/IRF-8 pathway and the PTEN/Akt pathway. MDSCs act on T cells and NK cells to suppress the body's immunity, and via IL-6 trans-signaling, promote breast cancer directly. We further describe MDSC-targeted immune therapies for breast cancer, which are classified as: preventing the formation of MDSCs, eliminating MDSDCs, and reducing the products of MDSCs. Furthermore, MDSC-targeted immunotherapy potentiates the effect of the other immunotherapies. Based on the facts that MSDCs have significant roles in breast cancer malignant behaviors and can be suppressed by various strategies, we do believe MDSC-targeted immunotherapy presents a broad prospect in the future.
Mel-18, a polycomb group protein, has been reported to act as a tumor suppressor and be down-regulated in several human cancers including gastric cancer. It was also found that Mel-18 negatively regulates self-renewal of hematopoietic stem cells and breast cancer stem cells (CSCs). This study aimed to clarify its role in gastric CSCs and explore the mechanisms. We found that low-expression of Mel-18 was correlated with poor prognosis and negatively correlated with overexpression of stem cell markers Oct4, Sox2, and Gli1 in 101 gastric cancer tissues. Mel-18 was down-regulated in cultured spheroid cells, which possess CSCs, and overexpression of Mel-18 inhibits cells sphere-forming ability and tumor growth in vivo. Besides, Mel-18 was lower-expressed in ovary metastatic lesions compared with that in primary lesions of gastric cancer, and Mel-18 overexpression inhibited the migration ability of gastric cancer cells. Interestingly, overexpression of Mel-18 resulted in down-regulation of miR-21 in gastric cancer cells and the expression of Mel-18 was negatively correlated with the expression of miR-21 in gastric cancer tissues. Furthermore, miR-21 overexpression partially restored sphere-forming ability, migration potential and chemo-resistance in Mel-18 overexpressing gastric cancer cells. These results suggests Mel-18 negatively regulates stem cell-like properties through downregulation of miR-21 in gastric cancer cells.
Forests are expected to expand into alpine areas due to global climate change. It has recently been shown that temperature
 alone cannot realistically explain this process and that upslope tree advance in a warmer scenario may depend on the availability of sites with adequate geomorphic/topographic characteristics. Here, we show that, besides topography (slope and aspect), climate itself can produce a braking effect on the upslope advance of subalpine forests and that tree limit is influenced by non-linear and non-monotonic contributions of the climate variables which act upon treeline upslope advance with varying relative strengths. Our results suggest that global climate change impact on the upslope advance of subalpine forests should be interpreted in a more complex way where climate can both speed up and slow down the process depending on complex patterns of contribution from each climate and non-climate variable.
Solanum lycopersicum auxin response factor 10 (SlARF10) is post-transcriptionally regulated by Sl-miR160. Overexpression of a Sl-miR160-resistant SlARF10 (mSlARF10) resulted in narrower leaflet blades with larger stomata but lower densities. 35S:mSlARF10-6 plants with narrower excised leaves had greater water loss, which was in contrast to the wild type (WT). Further analysis revealed that the actual water loss was not consistent with the calculated stomatal water loss in 35S:mSlARF10-6 and the WT under the dehydration treatment, indicating that there is a difference in hydraulic conductance. Pretreatment with abscisic acid (ABA) and HgCl2 confirmed higher hydraulic conductance in 35S:mSlARF10, which is related to the larger stomatal size and higher activity of aquaporins (AQPs). Under ABA treatment, 35S:mSlARF10-6 showed greater sensitivity, and the stomata closed rapidly. Screening by RNA sequencing revealed that five AQP-related genes, fourteen ABA biosynthesis/signal genes and three stomatal development genes were significantly altered in 35S:mSlARF10-6 plants, and this result was verified by qRT-PCR. The promoter analysis showed that upregulated AQPs contain AuxRE and ABRE, implying that these elements may be responsible for the high expression levels of AQPs in 35S:mSlARF10-6. The three most upregulated AQPs (SlTIP1-1-like, SlPIP2;4 and SlNIP-type-like) were chosen to confirm AuxRE and ABRE function. Promoters transient expression demonstrated that the SlPIP2;4 and SlNIP-type-like AuxREs and SlPIP2;4 and SlTIP1-1-like ABREs could significantly enhance the expression of the GUS reporter in 35S:mSlARF10-6, confirming that AuxRE and ABRE may be the main factors inducing the expression of AQPs. Additionally, two upregulated transcription factors in 35S:mSlARF10-6, SlARF10 and SlABI5-like were shown to directly bind to those elements in an electromobility shift assay and a yeast one-hybrid assay. Furthermore, transient expression of down-regulated ARF10 or up-regulated ABI5 in tomato leaves demonstrated that ARF10 is the direct factor for inducing the water loss in 35S:mSlARF10-6. Here, we show that although SlARF10 increased the ABA synthesis/signal response by regulating stomatal aperture to mitigate water loss, SlARF10 also influenced stomatal development and AQP expression to affect water transport, and both act cooperatively to control the loss of leaf water in tomato. Therefore, this study uncovers a previously unrecognized leaf water loss regulatory factor and a network for coordinating auxin and ABA signalling in this important process. In an evolutionary context, miR160 regulates ARF10 to maintain the water balance in the leaf, thus ensuring normal plant development and environmental adaptation.
Subjection of the resorcylic ester 16 to a Nozaki-Hiyama-Kishi reaction afforded the 12-membered lactone 17, while treatment of it under the Loh-type α-allylation conditions using indium metal gave the isomeric, 14-membered macrolide 18. Compound 18 was readily elaborated to the resorcylic acid lactone type natural products paecilomycin F and cochliomycin C.
Ficus tikoua (F. tikoua) was a promising species for Antimony (Sb) phyto-remediation due to widely growing in mining area. However, little was known on its tolerance mechanisms towards Sb. The determination of the distribution and chemical speciation of Sb in F. tikoua is essential for understanding the mechanisms involved in Sb accumulation, transportation, and detoxification. The present study investigated the subcellular distribution and chemical forms of Sb in F. tikoua. The plant was exposed to different Sb concentrations (0, 30, 90 and 180 μmol/L) for 30 days. The results showed that F. tikoua possessed a marked ability to tolerate and accumulate Sb. The proportional Sb increased with increasing Sb concentration in the solution, and the highest Sb concentration occurred in roots (1274.5-1580.9 mg/kg), followed by stems (133.5-498.9 mg/kg) and leaves (4.1-15.7 mg/kg). In the subcellular sequestration of Sb in F. tikoua, the largest accumulation of Sb occurred in cell walls (72.4-87.5%) followed by cytoplasmic organelles (8.2-18.6%) and cytoplasmic supernatant. The results suggested that cell walls act as important protective barriers against Sb toxicity in F. tikoua. Although Sb in all plant tissues found primarily in the fractions extracted by ethanol and distilled water, the current study found that the Sb amounts in the HAc-extractable fraction, HCl-extractable fraction and residue fraction increased at the highest Sb level (180 μmol/L) compared to that under lower Sb levels. These results indicate that excessive Sb accumulated in F. tikoua under Sb stress is bound to non-dissolved or low-bioavailable compounds, a biochemical mechanism that benefits F. tikoua because it helps alleviate Sb toxicity.
The history of informed consent dates back as early as the 16th century (Selek, 2010). The current tenets of informed consent pertaining to the ethical conduct of research on human participants predominately stems from the 1947 Nuremberg Code (National Institutes of Health, 2016), which was created following the Nuremberg trials at the end of World War II. The unethical conduct of research on human participants during the Holocaust, coupled with experiments (e.g., the Tuskegee syphilis study), prompted a more formalized structure for ensuring the well-being and autonomy of human participants in research studies. The World Medical Association (2013) created the Declaration of Geneva in 1948 (Fischer, 2006), followed by the Declaration of Helsinki in 1964, to apply ethical principles to medical research involving human participants (Fischer, 2006; Rickham, 1964). A decade later, on July 12, 1974, the National Research Act was signed into law (U.S. Department of Health and Human Services [HHS], 1979). Through this act, the National Commission for the Protection of Human Subjects of Biomedical and Behavioral Research was formed and charged with developing guidelines for the conduct of biomedical and behavioral research. The guidelines were established in the Belmont Report (HHS, 1979; U.S. Department of Health, Education, and Welfare, 1979), which continues to be periodically updated. The Belmont Report describes the general principles of respect for persons, beneficence, and justice, and it outlines the process of obtaining informed consent to ensure that these principles are followed (HHS, 1979). In 1998, an informed consent checklist was instituted (HHS, 1998). Although clearly outlined, defined, and described in consent forms, it is beneficial to revisit how informed participants are when they enter research studies, particularly for patients undergoing treatment for cancer. This article will provide an overview of several areas for consideration. 
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Endocrine active compounds (EACs) remain an important group of chemicals that require additional evaluation to determine their environmental impacts. While estrogens and androgens were previously demonstrated to impact organisms during environmental exposures, progestagens have recently been shown to have strong impacts on aquatic organisms. To gain an understanding of the impacts of these types of chemicals on aquatic species, experiments evaluating the mechanisms of action of progestagen exposure were conducted with the Eastern Mosquitofish (Gambusia holbrooki). The objective of this study was to conduct hepatic microarray analysis of male and female G. holbrooki exposed to progestins and anti-progestagens. In addition, we evaluated the ability of levonorgestrel, a synthetic progesterone (progestin), to induce anal fin elongation and to determine how anal fin growth is modulated during co-exposures with progesterone and androgen receptor antagonists. Gene expression analyses were conducted on male and female G. holbrooki exposed for 48h to the agonist levonorgestrel, the antagonist mifepristone, or a mixture of the two chemicals. Microarray analysis revealed that mifepristone does not act as an anti-progestagen in G. holbrooki in liver tissues, and that levonorgestrel elicits strong effects on the processes of embryo development and lipid transport. Levonorgestrel was also demonstrated to induce male secondary sexual characteristic formation in females, and co-exposure of either an androgen or levonorgestrel in the presence of the anti-androgen flutamide prevented anal fin elongation. These results provide indications as to the potential impacts of progestins, including non-target effects such as secondary sexual characteristic formation, and demonstrate the importance of this class of chemicals on aquatic organisms.
MiR-200c has been confirmed to display remarkable effects on proliferation inhibition and apoptosis induction of certain cancer cells, but the main challenge for its successful translation into the clinic remains its effective delivery to the action site in vivo. In this study, a novel composite polyphosphazene vesicle system composed of amphiphilic [NP(PEG)0.3(EAB)1.7]n (PEEP) and weakly cationic [NP(PEG)0.5(DPA)1.5]n
 (PEDP) was prepared via a very simple dialysis method. The loading of miR-200c was accomplished with high efficiency by taking advantage of the combination effect of physical encapsulation and electrostatic interaction between vectors and miR-200c. The resultant miR-200c-loaded PEEP-PEDP polymersome (Nano-ED-200c) displayed suitable particle size, electric neutrality, excellent Ribonuclease stability and hemocompatibility. We also evaluated its subsequent miR-200c function in paclitaxel resistance human lung cancer (A549/T) cells in culture and tumor xenografts in nude mice. The results showed that Nano-ED-200c could achieve a higher miR-200c level and the enhanced antitumor efficacy with 68% tumor inhibition ratio at a very low dose of 1.0 mg/kg than PEEP nanoparticle, PEDP nanoparticle, even than Lipo2000. All these evidences indicated that this miR-200c delivery via polyphosphazene vesicles could act as a potential new therapeutic option for paclitaxel resistant human lung cancer.
High levels of stress and burnout have been reported among mental health professionals worldwide, including Singapore, with concerning potential implications for the quality of patient care. Mindfulness has been associated with decreased stress and burnout; however, associations between mindfulness, stress, and burnout have not been examined in Singapore. The aim of this study was to investigate whether mindfulness is associated with stress and burnout among healthcare professionals working in a mental health setting in Singapore. A total of 224 Singaporean mental health professionals completed a cross-sectional survey which included measures of: mindfulness (observe, describe, act with awareness, non-judge, and non-react), stress, and burnout (exhaustion and disengagement). Using multiple regression, significant negative associations were found between each of the mindfulness facets and: stress, exhaustion, and disengagement, while controlling for years of experience. Of the five mindfulness facets, act with awareness demonstrated the strongest negative association with all three variables. This study showed that mental health professionals in Singapore who have higher levels of mindfulness also have lower levels stress and burnout (disengagement and exhaustion). Future longitudinal research is warranted to better understand the directionality of these associations, with implications for the development of interventions aimed to reduce stress and burnout within this population.
The secreted protein HbpS, the membrane-embedded sensor kinase SenS and the cytoplasmic response regulator SenR from streptomycetes have been shown to form a novel type of signaling pathway. Based on structural biology as well as different biochemical and biophysical approaches, redox stress-based post-translational modifications in the three proteins were shown to modulate the activity of this signaling pathway. In this study, we show that the homologous system, named here HbpSc-SenSc-SenRc, from the model species Streptomyces coelicolor A3(2) provides this bacterium with an efficient defense mechanism under conditions of oxidative stress. Comparative analyses of the transcriptomes of the Streptomyces coelicolor A3(2) wild-type and the generated hbpSc-senSc-senRc mutant under native and oxidative-stressing conditions allowed to identify differentially expressed genes, whose products may enhance the anti-oxidative defense of the bacterium. Amongst others, the results show an up-regulated transcription of genes for biosynthesis of cysteine and vitamin B12, transport of methionine and vitamin B12, and DNA synthesis and repair. Simultaneously, transcription of genes for degradation of an anti-oxidant compound is down-regulated in a HbpSc-SenSc-SenRc-dependent manner. It appears that HbpSc-SenSc-SenRc controls the non-enzymatic response of Streptomyces coelicolor A3(2) to counteract the hazardous effects of oxidative stress. Binding of the response regulator SenRc to regulatory regions of some of the studied genes indicates that the regulation is direct. The results additionally suggest that HbpSc-SenSc-SenRc may act in concert with other regulatory modules such as a transcriptional regulator, a two-component system and the Streptomyces B12 riboswitch. The transcriptomics data, together with our previous in vitro results, enable a profound characterization of the HbpS-SenS-SenR system from streptomycetes. Since homologues to HbpS-SenS-SenR are widespread in different actinobacteria with ecological and medical relevance, the data presented here will serve as a basis to elucidate the biological role of these homologues.
An ethics of permission can be helpful in framing a response to the ethical differences surrounding the California End of Life Option Act. Law does not define morality, and reaching a moral understanding demands thorough reflection. An ethics of permission examines the ethical demands of a permissive law for both clinician and patient. Serving the good of the patient, respecting professional conscience, and following the law are three ethical elements. Although developing an ethics of permission includes these three elements, these elements do not exhaust all the moral implications involved. An ethics of permission also includes the importance of exercising professional tolerance in the honoring of clinicians who choose to participate or refuse to participate. In addition, an ethics of permission also provides insight in implementing just and fair behavior among medical professionals.
This study investigated change processes resulting from a randomized controlled trial smartphone-delivered maintenance intervention with daily electronic diaries and personalized written feedback based on acceptance and commitment therapy (ACT) following a rehabilitation program for patients with chronic widespread pain.
This study included 48 women who during a 5-week period completed electronic diaries three times daily, totaling 3372 entries. In response to the completed diaries, they received daily feedback from a therapist for 4 weeks (excluding weekends), totaling 799 feedback messages. To analyze the change processes, we explored the associations between feedback and daily ratings of participants' physical activities, positive emotions, pain fear and avoidance, pain acceptance, and self-management. Commitment to physical activities and the participants' evaluation of feedback were also analyzed. Multilevel models were used in the statistical analyses.
Participants' average pain fear and avoidance decreased over the intervention period (mean -0.019, P = 0.05). Self-management, pain acceptance, and positive feelings increased (mean -0.030, P < 0.01; mean -0.015, P < 0.01; and mean -0.011, P = 0.01, respectively). Participants' performance of physical activities decreased slightly over time, but the level of commitment was high and they evaluated the feedback as supportive for staying sufficiently active. No correlation between diary contents and feedback messages was found, even though most of the participants evaluated the feedback as supportive.
No support was found for an association between diary content and feedback based on ACT. However, diary measures were consistent with the ACT model and may have influenced positively the change processes.
Understanding the processes that influence range expansions during climate warming is paramount for predicting population extirpations and preparing for the arrival of non-native species. While climate warming occurs over a background of variation due to cyclical processes and irregular events, the temporal structure of the thermal environment is largely ignored when forecasting the dynamics of non-native species. Ecological theory predicts that high levels of temporal autocorrelation in the environment - relatedness between conditions occurring in close temporal proximity - will favor populations that would otherwise have an average negative growth rate by increasing the duration of favorable environmental periods. Here, we invoke such theory to explain the success of biological invasions and evaluate the hypothesis that sustained periods of high environmental temperature can act synergistically with increases in mean temperature to favor the establishment of non-native species. We conduct a 60-day field mesocosm experiment to measure the population dynamics of the non-native cladoceran zooplankter Daphnia lumholtzi and a native congener Daphnia pulex in ambient temperature environments (control), warmed with recurrent periods of high environmental temperatures (uncorrelated-warmed), or warmed with sustained periods of high environmental temperatures (autocorrelated-warmed), such that both warmed treatments exhibited the same mean temperature but exhibited different temporal structures of their thermal environments. Maximum D. lumholtzi densities in the warmed-autocorrelated treatment were threefold and eightfold higher relative to warmed-uncorrelated and control treatments, respectively. Yet, D. lumholtzi performed poorly across all experimental treatment(s) relative to D. pulex and were undetectable (by) the end of the experiment. Using mathematical models, we show that this increase in performance can occur alongside increasing temporal autocorrelation and should occur over a broad range of warming scenarios. These results provide both empirical and theoretical evidence that the temporal structure of the environment can influence the performance of species undergoing range expansions due to climate warming.
Hemagglutinin (HA), the membrane-bound fusion protein of the influenza virus, enables the entry of virus into host cells via a structural rearrangement. There is strong evidence that the primary trigger for this rearrangement is the low pH environment of a late endosome. To understand the structural basis and the
 dynamic consequences of the pH trigger, we employed explicit-solvent molecular dynamics simulations to investigate the initial stages of the HA transition. Our results indicate that lowered pH destabilizes HA and speeds up the dissociation of the fusion peptides (FPs). A buried salt bridge between the N-terminus and Asp1122 of HA stem domain locks the FPs and may act as one of the pH sensors. In line with recent observations from simplified protein models, we find that, after the dissociation of FPs, a structural order-disorder transition in a loop connecting the central coiled-coil to the C-terminal domains produces a highly mobile HA. This motion suggests the existence of a long-lived asymmetric or "symmetry-broken" intermediate during the HA conformational change. This intermediate conformation is consistent with models of hemifusion, and its early formation during the conformational change has implications for the aggregation seen in HA activity.
The case of Jahi McMath has reignited a discussion concerning how society should define death. Despite pronouncing McMath brain dead based on the American Academy of Neurology criteria, the court ordered continued mechanical ventilation to accommodate the family's religious beliefs. Recent case law suggests that the potential for a successful challenge to the neurologic criteria of death provisions of the Uniform Determination of Death Act are greater than ever in the majority of states that have passed religious freedom legislation. As well, because standard ethical claims regarding brain death are either patently untrue or subject to legitimate dispute, those whose beliefs do not comport with the brain death standard should be able to reject it.
Multiplex bioassays have drawn more and more attention for the development of novel analytical techniques. Herein, we used photonic crystal (PC) and surface enhanced Raman scattering (SERS) as two encoding elements in different modes for the dual encoding of multiplex bioassays. In practice, PC beads and SERS nanotags act as carriers and labels, respectively, for the multiplex detection of antigens in a sandwich format. Except for the amplified capacity by two encoding modes, we also demonstrated that fine stability, low background and high sensitivity were realized for the quantitative analysis of multiple analytes, which holds great promise in biomedical applications like protein biomarker analysis.
Dietary lectins have been shown to affect the proliferation of human cancer cell lines. The anti-proliferative effects of lectins from varied sources have been extensively studied and in some cases, the underlying mechanism has been explored. Except for peanut agglutinin (PNA), the mitogenic effects of no other lectins have been studied in detail. In the present study, we have shown that jacalin, lectin purified from jackfruit (Artocarpus integrifolia) seeds act as a mitogen for K562, the Bcr-Abl expressing erythroleukemia cell line (K562) and the effect was found to be dose dependent. K562 cells remained in the proliferative state for a longer period even after the withdrawal of jacalin stimulation, thus jacalin was found to induce sustained mitogenic effect on K562 cells. Further, conditioned media from K562 cells treated with jacalin were observed to have the similar mitogenic effect even in the presence of galactose. Importantly, galactose which is a known ligand for jacalin will interact with functionally active jacalin present in the conditioned media and neutralise its effect. In addition, jacalin treatment also resulted in increased mRNA expression levels of pro-inflammatory cytokines including IL-1β, IL-6 and IFN-γ. Our results indicate that jacalin induces secretion of soluble molecules, which maybe responsible for this observed increased proliferation of K562 cells.
Environmental health researchers, government agencies, and community groups have endorsed long-term community-academic partnerships as an effective strategy to support science-based improvements in environmental health. Social sciences concepts, approaches, and methods are fundamental to these translational partnerships. However, appropriate roles for academic partners vary throughout the process of changing systems (policies, practices, programs, etc.). This can complicate planning, evaluating, and sustaining such partnerships. We set forth a conceptual framework for academic partners' roles at different stages of systems change. We apply this framework to three longstanding academic-community partnerships involving National Institute of Environmental Health Sciences Community Outreach and Engagement Cores. We conclude by discussing how the framework can help academic partners tap appropriate expertise, redefine their roles, and evaluate their contributions to community efforts to improve environmental health.
Infection with Bacillus anthracis, the causative agent of anthrax, can lead to persistence of lethal secreted toxins in the bloodstream, even after antibiotic treatment. VHH single-domain antibodies have been demonstrated to neutralize diverse bacterial toxins both in vitro and in vivo, with protein properties such as small size and high stability that make them attractive therapeutic candidates. Recently, we reported on VHHs with in vivo activity against the protective antigen component of the anthrax toxins. Here, we characterized a new set of 15 VHHs against the anthrax toxins that act by binding to the edema factor (EF) and/or lethal factor (LF) components. Six of these VHHs are cross-reactive against both EF and LF and recognize the N-terminal domain (LFN, EFN) of their target(s) with subnanomolar affinity. The cross-reactive VHHs block binding of EF/LF to the protective antigen C-terminal binding interface, preventing toxin entry into the cell. Another VHH appears to recognize the LF C-terminal domain and exhibits a kinetic effect on substrate cleavage by LF. A subset of the VHHs neutralized against EF and/or LF in murine macrophage assays, and the neutralizing VHHs that were tested improved survival of mice in a spore model of anthrax infection. Finally, a bispecific VNA (VHH-based neutralizing agent) consisting of two linked toxin-neutralizing VHHs, JMN-D10 and JMO-G1, was fully protective against lethal anthrax spore infection in mice as a single dose. This set of VHHs should facilitate development of new therapeutic VNAs and/or diagnostic agents for anthrax.
Oncostatin M (OSM) and leukemia inhibitory factor (LIF) are IL-6 family members with a wide range of biological functions. Human OSM (hOSM) and murine LIF (mLIF) act in mouse cells via a LIF receptor (LIFR)-glycoprotein 130 (gp130) heterodimer. In contrast, murine OSM (mOSM) signals mainly via an OSM receptor (OSMR)-gp130 heterodimer and binds with only very low affinity to mLIFR. hOSM and mLIF stimulate bone remodeling by both reducing osteocytic sclerostin and up-regulating the pro-osteoclastic factor receptor activator of NF-κB ligand (RANKL) in osteoblasts. In the absence of OSMR, mOSM still strongly suppressed sclerostin and stimulated bone formation but did not induce RANKL, suggesting that intracellular signaling activated by the low affinity interaction of mOSM with mLIFR is different from the downstream effects when mLIF or hOSM interacts with the same receptor. Both STAT1 and STAT3 were activated by mOSM in wild type cells or by mLIF/hOSM in wild type and Osmr(-/-) cells. In contrast, in Osmr(-/-) primary osteocyte-like cells stimulated with mOSM (therefore acting through mLIFR), microarray expression profiling and Western blotting analysis identified preferential phosphorylation of STAT3 and induction of its target genes but not of STAT1 and its target genes; this correlated with reduced phosphorylation of both gp130 and LIFR. In a mouse model of spontaneous osteopenia caused by hyperactivation of STAT1/3 signaling downstream of gp130 (gp130(Y757F/Y757F)), STAT1 deletion rescued the osteopenic phenotype, indicating a beneficial effect of promoting STAT3 signaling over STAT1 downstream of gp130 in this low bone mass condition, and this may have therapeutic value.
Multi-modal imaging-guided cancer photothermal therapy (PTT) with advanced theranostic nanoagents can efficiently improve therapeutic efficacy and reduce treatment side effects. Herein, we have developed a theranostic nanoagent based on indocyanine green (ICG)-loaded polydopamine (PDA)-iron ions coordination nanoparticles (PDA-Fe(3+)-ICG NPs), which are used for photoacoustic (PA) and magnetic resonance (MR) dual-modal imaging-guided cancer PTT treatments. In this nanoplatform, ICG molecules, the U.S. Food and Drug Administration approved near-infrared (NIR) dye, absorbing on PDA NPs (a melanin-like biopolymer) to significantly increase the NIR optical absorption of PDA NPs nearly 6 times and decreases their fluorescence emission, which can improve the PA contrast ability and promote the photothermal conversion efficiency of PDA NPs. Meanwhile, Fe(3+) ions chelated on the PDA NPs act as a T1-weighted MRI contrast agent (r1 = 14 mM(-1) s(-1)). In a mouse 4T1 breast tumor model, PA/MRI dual-modal imaging and highly efficient PTT treatments with low laser density were achieved with remarkable therapeutic efficiency and minimal side effects. This study illustrates that the highly integrated and biocompatible PDA-based NPs can serve as a versatile nanoplatform by loading different imaging molecules and drugs for multi-modal imaging and cancer combination therapy.
As sessile organisms, plants rely on their environment for cues indicating imminent herbivory. These cues can originate from tissues on the same plant or from different individuals. Since parasitic plants form vascular connections with their host, parasites have the potential to receive cues from hosts that allow them to adjust defenses against future herbivory.
 However, the role of plant communication between hosts and parasites for herbivore defense remains poorly investigated. Here, we examined the effects of damage to lupine hosts (Lupinus texensis) on responses of the attached hemiparasite (Castilleja indivisa), and indirectly, on a specialist herbivore of the parasite, buckeyes (Junonia coenia). Lupines produce alkaloids that act as defenses against herbivores that can be taken up by the parasite. We found that damage to lupine host plants by beet armyworm (Spodoptera exigua) significantly increased jasmonic acid (JA) levels in both the lupine host and parasite, suggesting uptake of phytohormones or priming of parasite defenses by using host cues. However, lupine host damage did not induce changes in alkaloid levels in the hosts or parasites. Interestingly, the parasite had substantially higher concentrations of JA and alkaloids compared to lupine host plants. Buckeye herbivores consumed more parasite tissue when attached to damaged compared to undamaged hosts. We hypothesize that increased JA due to lupine host damage induced higher iridoid glycosides in the parasite, which are feeding stimulants for this specialist herbivore. Our results demonstrate that damage to hosts may affect both parasites and associated herbivores, indicating cascading effects of host damage on multiple trophic levels.
Anti-microbial peptides (AMPs) were originally thought to exert protecting actions against bacterial infection by disintegrating bacterial membranes. Upon identification of internal bacterial targets, the view changed and moved toward inhibition of prokaryote-specific biochemical processes. However, the level of none of these activities can explain the robust efficacy of some of these peptides in animal models of systemic and cutaneous infections. A rapidly growing panel of reports suggests that AMPs, now called host-defense peptides (HDPs), act through activating the immune system of the host. This includes recruitment and activation of macrophages and mast cells, inducing chemokine production and altering NF-κB signaling processes. As a result, both pro- and anti-inflammatory responses are elevated together with activation of innate and adaptive immunity mechanisms, wound healing, and apoptosis. HDPs sterilize the systemic circulation and local injury sites significantly more efficiently than pure single-endpoint in vitro microbiological or biochemical data would suggest and actively aid recovering from tissue damage after or even without bacterial infections. However, the multiple and, often opposing, immunomodulatory functions of HDPs require exceptional care in therapeutic considerations.
Mutations in LRRK2 gene cause inherited Parkinson's disease (PD) and variations around LRRK2 act as risk factor for disease. Similar to sporadic disease, LRRK2-linked cases show late onset and, typically, the presence of proteinaceous inclusions named Lewy bodies (LBs) in neurons. Recently, defects on ceramide (Cer) metabolism have been recognized in PD. In particular, heterozygous mutations in the gene encoding for glucocerebrosidase (GBA1), a lysosomal enzyme converting glucosyl-ceramides (Glc-Cer) into Cer, increase the risk of developing PD. Although several studies have linked LRRK2 with membrane-related processes and autophagic-lysosomal pathway regulation, whether this protein impinges on the Cer pathway has not been addressed. Here, using a targeted lipidomics approach, we report an altered sphingolipid composition in Lrrk2(-/-) mouse brains. In particular, we observe a significant increase of Cer levels in Lrrk2(-/-) mice and direct effects on GBA1. Collectively, our results suggest a link between LRRK2 and Cer metabolism, providing new insights into the possible role of this protein in sphingolipids metabolism, with implications for PD therapeutics.
Pancreatic ductal adenocarcinoma (PDAC) is an aggressive malignancy with a very poor prognosis, and excessive resistance to chemotherapy. MicroRNAs have been shown to play important roles in PDAC oncogenesis as they can act as both oncogenes and tumor suppressor molecules. Altered expression of specific microRNAs in PDAC has diagnostic and prognostic implications. There is growing body of evidence showing the important role of miR-486-5p and miR-938 for discrimination of PDAC patients from healthy subjects and those with chronic pancreatitis. Additionally the diagnostic features of miR-486-5p were comparable with CA 19-9 for the detection of PDAC patients, suggesting its diagnostic value as a blood-based miRNA in PDAC, although further investigations are warranted for validation of these markers. In addition to these applications, several studies have suggested therapeutic potential of some miRNAs in PDAC. In particular, modulations of let-7, miR-29a, miR-17-5p, miR-365, miR-181b, miR-21, miR-221 and miR-96 are reported to be associated with chemotherapy resistance/sensitivity. Moreover, enforced expression of miR-17-92 inhibits tumourigenicity and increased chemoresistance in PDAC cancer stem cells via TGF-β1 pathway, while miR-96 could targets KRAS. In this review we attempt to give an overview about recent preclinical and clinical studies that have addressed the potential use of circulating microRNAs as diagnostic and prognostic biomarkers, their use as therapeutic agents and finally, we discuss the possible role of microRNAs in PDAC chemoresistance.
The Ebola epidemic has claimed thousands of lives in Africa, and there has been a mounting pressure on the healthcare systems around the globe to prepare for the showing up of patients infected with this virus. Junior clinicians are at the forefront of medical teams, often coming into contact with patients first, during clerking and admissions. This study assesses the level of knowledge of Ebola virus disease (EVD) among dental students at Semmelweis University, Budapest, Hungary.
A cross-sectional survey of 257 dental students was carried out across five different courses. Each of the students was asked to fill out a detailed questionnaire comprising of 11 questions, to assess their knowledge about signs and symptoms, investigations, management, and sequelae of the virus and the outbreak.
This study highlighted that there is an overall lack of knowledge about critical aspects of EVD among dental students. We found that the participating students scored less than 60% for 8 of the 11 questions, including those assessing their recognition and subsequent management of EVD.
These results are concerning and the medical universities and dental schools need to act fast to prepare the Hungary's dental (and medical) students and junior doctors for an inevitable influx of infected patients.
Characterization of membrane proteins is challenging due to the difficulty in mimicking the native lipid bilayer with properly folded and functional membrane proteins. Recently, styrene-maleic acid (StMA) copolymers have been shown to facilitate the formation of disc-like lipid bilayer mimetics that maintain the structural and dynamic integrity of membrane proteins. Here we report the controlled synthesis and characterization of StMA containing block copolymers. StMA polymers with different compositions and molecular weights were synthesized and characterized by size exclusion chromatography (SEC). These polymers act as macromolecular surfactants for 1-Palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine (POPC)/1-palmitoyl-2-oleoyl-sn-glycero-3-phospho-(1'-rac-glycerol (POPG) lipids, forming disc like structures of the lipids with the polymer wrapping around the hydrophobic lipid edge. A combination of dynamic light scattering (DLS), solid-state nuclear magnetic resonance (SSNMR) spectroscopy, and transmission electron microscopy (TEM) was used to characterize the size of the nanoparticles created using these StMA polymers. At a weight ratio of 1.25:1 StMA to lipid, the nanoparticle size created is 28+1nm for a 2:1 ratio, 10+1nm for a 3:1 StMA ratio and 32+1nm for a 4:1 StMA ratio independent of the molecular weight of the polymer. Due to the polymer acting as a surfactant that forms disc like nanoparticles, we term these StMA based block copolymers "RAFT SMALPs". RAFT SMALPs show promise as a new membrane mimetic with different nanoscale sizes, which can be used for a wide variety of biophysical studies of membrane proteins.
In response to increasing fiscal pressures, the Affordable Care Act (ACA) sought to reduce Medicare Advantage plan expenses by restructuring the bidding and payment processes. The purpose of this study is to assess the effects of the ACA's payment freeze and restructuring of the bidding and payment processes on favorable risk selection in Medicare Advantage plan enrollment (objective 1) and changes in the health status of beneficiaries enrolled in Medicare Advantage plans over time (objective 2).
We used the Medicare Health Outcome Survey baseline data (2007→2013) for analyses of the first objective (7 cohorts, 1.7 million beneficiaries) and the linked baseline and follow-up data (2007-2009→2011-2013) for analyses of the second objective (5 cohorts, 0.5 million beneficiaries). To examine favorable risk selection we used the following outcomes: self-rated health, falls, balance problems, falls management, frailty, and morbidity. To examine changes in beneficiary health status over time, we examined changes (over time) in these same outcomes. The focal independent variable is the policy implementation measure, which is time dependent and measures the accumulation of changes to Medicare Advantage payment policies resulting from the ACA. Multiple regression models were developed to examine the relationship between ACA implementation and outcomes of interest.
In terms of favorable selection, individuals enrolled in Medicare Advantage plans post-ACA have, on average, better self-rated health (b = 0.003,
 p < 0.01), lower odds of falls (AOR = 0.981, p < 0.001), higher odds of falls management (AOR = 1.040, p < 0.001), lower frailty risks (IRR = 0.983, p < 0.001), and lower risks of comorbidities (IRR = 0.989, p < 0.001). In terms of health status changes over time, the results indicate that in the post-ACA period, beneficiaries reported better self-rated health (b = 0.028, p < 0.001), lower odds of falls (AOR = 0.965, p < 0.001), lower odds of balance problems (AOR = 0.958, p < 0.001), lower odds of falls management (AOR = 0.981, p < 0.05), lower frailty risks (IRR = 0.944, p < 0.001), and lower risks of comorbidity (IRR = 0.986, p < 0.001) at follow up compared to the same risks at baseline.
These findings suggest that as the Medicare Advantage payment policies in the ACA were being implemented, plans may have engaged in favorable selection activities, yet beneficiaries exhibited more favorable health outcomes.
Fleas and ticks are parasites of wild and domestic mammals, and can be vectors of several pathogens. In rural areas, domestic carnivores such as the domestic dog (Canis lupus familiaris L.), may act as a "bridge" between natural areas and human settlements where ectoparasites can be used as a metric of such link. The aim of this study was to identify fleas, ticks, and Rickettsia spp., collected from domestic and wild carnivores in a natural reserve and surrounding human settlements in Central Chile, using morphological keys and molecular analysis. We surveyed 170 households from which 107 dogs and eight cats were sampled. From the natural reserve, we sampled two chilla foxes (Pseudalopex griseus Gray), two lesser grison (Galictis cuja Molina), three kodkods (Leopardus guigna Molina), and four dogs. From dogs, we collected Ctenocephalides felis Bouché, Ctenocephalides canis Curtis, Pulex irritans L., and Rhipicephalus sanguineus s.l. Latreille; C. felis was the most frequent ectoparasite. Cats were infested only by C. felis and Rh. sanguineus s.l. From wild carnivores, we obtained C. canis and P. irritans, the latter being most frequent. Molecular analysis of P. irritans detected 10 haplotypes and two main clades, which tended to separate fleas from wild and domestic hosts. Molecular analysis of ompA and ompB genes confirmed the presence of Rickettsia felis in fleas collected from owned dogs and cats, which could represent a potential risk factor of R. felis transmission in the area.
Artesunate-amodiaquine (AS-AQ) and artemether-lumefantrine (AL) are first- and second-line treatments for uncomplicated Plasmodium falciparum malaria in Gabon. AL remains highly efficacious, but its widespread use has led to molecular selection of the NFD haplotype on Pfmdr1 and K76 in Pfcrt. In this study, plasmodial infection characteristics and the distribution of the Pfmdr1 and Pfcrt genotypes involved in reduced efficacy of artemisinin-based combination therapy (ACT) were investigated in four Gabonese localities.
A cross-sectional study was conducted in the paediatric units of rural (Lastourville and Fougamou), semi-urban (Koula-Moutou) and urban (Franceville) areas. Malaria was diagnosed with the rapid diagnostic test Optimal-IT(®) and confirmed by blood smear. Pfmdr1 codons 86, 184 and 1246 and Pfcrt codon 76 were genotyped by PCR-RFLP and sequencing.
Among 1129 included children, the prevalence of plasmodial infection was 79.5 % at Lastourville, 53.6 % at Fougamou, 36.1 % at Koula-Moutou, and 21.2 % at Franceville. The prevalence was significantly higher among children over 60 months of age in both semi-urban (p = 0.01) and urban (p = 0.004) areas. The prevalence of Pfmdr1 wild-type N86 differed significantly between Lastourville (57.8 %) and Koula-Moutou (45.4 %) (p = 0.039). No difference in 184F-carrying parasites was found between Lastourville (73.8 %), Fougamou (81.6 %), Koula-Moutou (83.2 %), and Franceville (80.6 %) (p = 0.240). The prevalence of wild-type D1246 was significantly different between Lastourville (94.1 %), Koula-Moutou (85.6 %) and Franceville (87.3 %) (p = 0.01). The frequency of wild-type K76 was not significantly different across the four sites: Lastourville (16.5 %), Fougamou (27.8 %), Koula-Moutou (17.4 %), and Franceville (29.4 %) (p = 0.09). The mixed genotypes were only found in Lastourville and Franceville. The NFD, YFD and NYD haplotypes were mainly Lastourville (46.6, 25.8, 14.0 %), Fougamou (45.5, 9.1, 42.4 %), Koula-Moutou (35, 6.7, 40.4 %), and Franceville (40.0, 16.0, 32.0 %).
This study shows an increase in the prevalence of childhood plasmodial infection in Gabon according to the low socio-economic level, and a high frequency of markers associated with AL treatment failure. Close monitoring of ACT use is needed.
Malaria case management remains a vital component of malaria control strategies. Despite the introduction of national malaria treatment guidelines and scale-up of malaria control interventions in Nigeria, anecdotal evidence shows some deviations from the guidelines in malaria case management. This study assessed factors influencing adherence to malaria diagnosis and treatment guidelines among healthcare workers in public and private sectors in Ogun State, Nigeria.
A comparative cross-sectional study was carried out among 432 (216 public and 216 private) healthcare workers selected from nine Local Government Areas using a multistage sampling technique. A pre-tested interviewer administered questionnaire was used to collect information on availability and use of malaria Rapid Diagnostic Test (mRDT) and artemisinin combination therapy (ACT), for management of uncomplicated malaria. Adherence was defined as when choice of antimalarials for parasitological confirmed malaria cases was restricted to recommended antimalarial medicines. Association between adherence and independent variables were tested using Chi-square at 5 % level of significance.
Malaria RDT was available in 81.9 % of the public health facilities and 19.4 % of the private health facilities (p = 0.001). Its use was higher among public healthcare workers (85.2 %) compared to 32.9 % in private facilities (p = 0.000). Presumptive diagnosis of malaria was higher among private healthcare workers (94.9 %) compared to 22.7 % public facilities (p = <0.0001). The main reason for non-usage of mRDT among private healthcare workers was its perceived unreliability of mRDT (40.9 %). Monotherapy including artesunate (58.3 % vs 12.5 %), amodiaquine (38.9 % vs 8.3 %) and chloroquine (26.4 % vs 4.2 %) were significantly more available in private than public health facilities, respectively. Adherence to guidelines was significantly higher among public healthcare workers (60.6 %) compared to those in private facilities (27.3 %). Availability of antimalarial medicine was the main factor that influenced treatment prescription in both healthcare settings (p = 0.27). However, drug promotion by manufactures (45.8 %) has a major influence on private healthcare workers' prescription practice.
The findings of this study demonstrate significant difference between public and private healthcare workers on adherence to national malaria diagnosis and treatment guidelines. Interventions to improve private sector engagement in implementation of the guidelines, training and supply of recommended antimalarial medicines should be intensified.
In this paper, we have studied the equilibrium unfolding transitions of cytochrome c from Pseudomonas aeruginosa (cytc551), a small bacterial protein. Similar to eukaryotic cytochrome c, cytc551 folds sequentially, although significant differences exist in the order of folding units (foldons). There are two regions of cytc551 (N-terminal helix with residue number 3 to 10 and the loop 2 region containing residues 34 to 45), in which no foldon unit could be assigned. In addition, the helix containing the Cys-X-X-Cys-His motif, adjacent to the N-terminal helix (residue number 3 to 10), shows unexplained ultra-fast collapse. To obtain further insights, we have studied cytc551 site-directed mutants using fluorescence correlation spectroscopy (FCS) and molecular dynamics simulation. We have found out that cytc551 unfolds through the formation of a fluorescently dark intermediate state and the amplitude of the dark component depends on the position of labeling. We have utilized this position dependence to propose a shape change model during the unfolding of cytc551. The present results show that the N-terminal helix remains in a collapsed position even in the completely unfolded state and this helix may act as a rigid support to guide the folding of its adjacent helix. This rigid support may be responsible for the ultra-fast collapse of the adjacent helix region, which occurs during the initial events of folding. The present results also show that the C-terminal end of loop 2 traverses a large distance during unfolding compared to the N-terminal end, which justifies the observed flexibility of the loop 2 region.
This study sought to understand the role of plants and animals in traditional medical systems and evaluate the capacity of these systems to absorb impacts and maintain their identity by determining the existence of functional substitutes.
Ethnobiological data were collected through semi-structured interviews and free lists at a rural community in the semiarid region of northeastern Brazil. The data were subjected to the utilitarian redundancy model and analyzed by tests of proportion and variance.
We found that most of the therapeutic targets treated with animal-based remedies were also treatable by plant-based remedies; these targets were perceived as very usual, although they were not considered dangerous. Furthermore, people considered the plants and animals to be equally effective at curing overlapping therapeutic targets, but the plant remedies were used more frequently. The findings show that local knowledge
 about medicinal plants and animals follows similar patterns regarding the utilitarian redundancy, with high functional overlap among these features. However, the ease of access to the medicinal resource influences the choice of treatment, leading to an increased preference for plants over animals. In addition, we suggest that during the cultural evolution process, people concentrated their efforts on experimenting with different resources for the treatment of diseases that were very frequent locally, even if not very severe, which contributed to the resilience of the local medical system.
Furthermore, we infer that plants may effectively perform the function of healing, whereas animals act as reserves of resilience for the system, maintaining system function in the face of disturbances that may affect the availability of plant species.
In 2012, alarmingly high rates of oral artemisinin monotherapy availability and use were detected along Eastern Myanmar, threatening efforts to halt the spread of artemisinin resistance in the Greater Mekong Subregion (GMS), and globally. The aim of this paper is to exemplify how the use of supply side evidence generated through the ACTwatch project shaped the artemisinin monotherapy replacement malaria (AMTR) project's design and interventions to rapidly displace oral artemisinin monotherapy with subsidized, quality-assured ACT in the private sector.
The AMTR project was implemented as part of the Myanmar artemisinin resistance containment (MARC) framework along Eastern Myanmar. Guided by outlet survey and supply chain evidence, the project implemented a high-level subsidy, including negotiations with a main anti-malarial distributor, with the aim of squeezing oral artemisinin monotherapy out of the market through price competition and increased availability of quality-assured artemisinin-based combinations. This was complemented with a plethora of demand-creation activities targeting anti-malarial providers and consumers. Priority outlet types responsible for the distribution of oral artemisinin monotherapy were identified by the outlet survey, and this evidence was used to target the AMTR project's supporting interventions.
The widespread availability and use of oral artemisinin monotherapy in Myanmar has been a serious threat to malaria control and elimination in the country and across the region. Practical anti-malarial market evidence was rapidly generated and used to inform private sector approaches to address these threats. The program design approach outlined in this paper is illustrative of the type of evidence generation and use that will be required to ensure effective containment of artemisinin drug resistance and progress toward regional and global malaria elimination goals.
Derailed inflammation causes severe damage to the normal tissues resulting in various pathological conditions such as auto-inflammatory disorders, neurodegenerative diseases and cancer. Cure of inflammatory diseases is a big challenge. Medicinal herbs used traditionally represent the best option for obtaining effective anti-inflammatory therapeutics. Present review provides a thorough insight about various pathways, consequences and therapeutic strategies of inflammation with prime focus to expose indigenous anti-inflammatory herbal compounds along with their structures and diverse range of mechanisms of action. Over hundred medicinal plants with scientifically reported anti-inflammatory properties were reviewed. Different parts of the plants like roots, stem, bark, leaves, flowers and seeds contain active compounds with potential anti-inflammatory properties. Such compounds act at multiple targets in the inflammatory response pathways and regulate multitude of chemical mediators, enzymes, genes or cellular functions to alleviate inflammation. Although a large number of antiinflammatory herbal compounds have been isolated but the mechanism of action of bulk of compounds has not been elucidated comprehensively. Besides there is need for conducting well designed clinical trials so that the promising compounds could be used as effective antiinflammatory therapeutic agents in future.
Malignant gliomas are the most common form of primary intracranial tumors with the highest mortality rates. Various gene alterations are considered as prognostic markers in glioma. But, the relevant molecular mechanisms in this setting are not well-understood.
The aim of this study was to assess the association and prognostic value of TLR9 and NFKBIA with clinical significance and also their impact on patient survival in human glioma.
Expression of TLR9 and NFKBIA mRNA in the tissues was determined by immunohistochemistry and qRT-PCR methods. Kaplan-Meier curves and Cox proportional hazards regression model were used to assess the association of TLR9 and NFKBIA with clinical outcomes of patients.
Quantitative real-time PCR analysis showed that TLR9 mRNAs is markedly expressed in glioma tissues than in non-neoplastic tissues (mean±SD: 3.26±0.40 vs. 0.71±0.36, P<0.001). There was also a significant difference between TLR9 mRNAs and high grade glioma (P<0.001).NFKBIA mRNAs was significantly identified in non-neoplastic tissues compared with glioma specimens (mean±SD: 2.76±0.30 vs. 0.94±0.35, P<0.001). Lower levels of NFKBIA mRNA were significantly related to advanced grade of gliomas (P<0.001). Furthermore, Immunoreactivity for high expression of TLR9 was detected in 65% of cases (26/40) that was associated with high grade glioma (P=0.001). No statistically significant correlation was found between TLR9 and other clinical parameters (P>0.05). Immunoreactivity for high expression of NFKBIA was observed in 32.5% (13/40) of cases and NFKBIA expression was decreased in patients with high grad glioma (P=0.014). There was no significant correlation between NFKBIA protein expression and age, sex, and relapse. The Kaplan-Meier analysis indicated that patients with high expression of TLR9 and low expression of NFKBIA are significantly related to poorer OS (P<0.001). In addition, the multivariate Cox regression model revealed that TLR9 and NFKBIA protein expressions (low/high) and tumor grade were potentially an independent predictor of survival in patients (hazard ratio, 2.132, 2.411, 2.13 [95% confidence interval, 1.825-3.782, 1.61-3.231, 1.542-3.92]; P=0.012,P=0.018, P=0.001).
These data indicate that TLR9 and NFKBIA protein expressions act as independent predictor of survival for the diagnosis of glioma and a prognostic biomarker for those with a tumor at an advanced pathological grade.
Early identification of physical activity (PA) opportunities in the home and neighborhood environment may help obesity prevention efforts in households with young children. This cross-sectional study's purpose was to develop a brief, easy-to-use, self-report inventory called Home Opportunities for Physical activity check-Up (HOP-Up), to evaluate the availability and accessibility of PA space and equipment in and near homes with preschool children, and establish its validity and reliability.
The HOP-Up was field tested by two trained researchers and parents of preschool-aged children (n = 50; 71% white). To establish criterion validity, researchers were the 'gold standard' and visited participants' homes to assess their PA environments using the HOP-Up, while participants separately completed their HOP-Up. Two weeks later, parents completed the HOP-Up online for test-retest reliability. After minor survey refinements, exploratory and confirmatory factor analysis using a split-half cross validation procedure was conducted in a larger sample of participants (n = 655, 60% white) who completed the HOP-Up online to examine its factor structure. To establish convergent validity, correlations were conducted to compare HOP-Up scales from the factor solution generated with PA behavior and cognitions, and reported screen time.
Intra-class correlations (ICCs) examining HOP-Up item agreement between researcher and parents revealed slight to substantial agreement (range 0.22 to 0.81) for all items. ICCs for all HOP-Up items ranged from fair to substantial agreement between parent responses at both time points (range 0.42 to 0.95). Exploratory factor analysis revealed a five factor solution (18 items), supported eigen values, scree plots, review for contextual sense, and confirmatory factor analysis. Additionally, there were significant (p < 0.05) positive correlations among nearly all five HOP-Up scales with parent and child physical activity levels (range 0.08 to 0.35), and values parents placed on PA for self and child (range 0.16 to 0.35), and negative correlations of Neighborhood Space & Supports for PA scale with parent and child reported screen time (r = -0.11, r = -0.13, respectively).
Findings support the psychometric properties of this brief, easy-to-use, HOP-Up questionnaire, which may help parents, prevention researchers, residential planners, and practitioners increase their understanding of how the home environment-inside, outside, and the neighborhood- impacts preschool children's physical activity levels.
The construction of a p-n heterojunction is an efficient strategy to resolve the limited light absorption and serious charge-carrier recombination in semiconductors and enhance the photocatalytic activity. However, the promotion effect is greatly limited by poor interfacial charge transfer efficiency as well as reduced redox ability of charge carriers. In this work, we demonstrate that the embedding of metal Pd into the interface between n-type C3N4 and p-type Cu2O can further enhance the interfacial charge transfer and increase the redox ability of charge carriers through the design of the C3N4-Pd-Cu2O stack nanostructure. The embedded Pd nanocubes in the stack structure not only trap the charge carriers from the semiconductors in promoting the
 electron-hole separation but also act as a Z-scheme "bridge" in keeping the strong reduction/oxidation ability of the electrons/holes for surface reactions. Furthermore, Pd nanocubes also increase the bonding strength between the two semiconductors. Enabled by this unique design, the hydrogen evolution achieved is dramatically higher than that of its counterpart C3N4-Cu2O structure without Pd embedding. The apparent quantum efficiency (AQE) is 0.9% at 420 nm for the designed C3N4-Pd-Cu2O. This work highlights the rational interfacial design of heterojunctions for enhanced photocatalytic performance.
Current clinical procedures for rotator cuff tears need to be improved, as a high rate of failure is still observed. Therefore, new approaches have been attempted to stimulate self-regeneration, including biophysical stimulation modalities, such as low-frequency pulsed electromagnetic fields, which are alternative and non-invasive methods that seem to produce satisfying therapeutic effects. While little is known about their mechanism of action, it has been speculated that they may act on resident stem cells. Thus, the purpose of this study was to evaluate the effects of a pulsed electromagnetic field (PST®) on human tendon stem cells (hTSCs) in order to elucidate the possible mechanism of the observed therapeutic effects.
hTSCs from the rotator cuff were isolated from tendon biopsies and cultured in vitro. Then, cells were exposed to a 1-h PST® treatment and compared to control untreated cells in terms of cell morphology, proliferation, viability, migration, and stem cell marker expression.
Exposure of hTSCs to PST® did not cause any significant changes in proliferation, viability, migration, and morphology. Instead, while stem cell marker expression significantly decreased in control cells during cell culturing, PST®-treated cells did not have a significant reduction of the same markers.
While PST® did not have significant effects on hTSCs proliferation, the treatment had beneficial effects on stem cell marker expression, as treated cells maintained a higher expression of these markers during culturing. These results support the notion that PST® treatment may increase the patient stem cell regenerative potential.
Pancreatic cancer (PC) is one of the most aggressive diseases. Only 10 % of all PC cases are thought to be due to genetic factors. Here, we analyzed the most recently published case-control association studies, meta-analyses, and cohort studies with the aim to summarize the main environmental factors that could have a role in PC. Among the most dangerous agents involved in the initiation phase, there are the inhalation of cigarette smoke, and the exposure to mutagenic nitrosamines, organ-chlorinated compounds, heavy metals, and ionizing radiations. Moreover, pancreatitis, high doses of alcohol drinking, the body microbial infections, obesity, diabetes, gallstones and/or cholecystectomy, and the accumulation of asbestos fibers seem to play a crucial role in the progression of the disease. However, some of these agents act both as initiators and promoters in pancreatic acinar cells. Protective agents include dietary flavonoids, marine omega-3, vitamin D, fruit, vegetables, and the habit of regular physical activity. The identification of the factors involved in PC initiation and progression could be of help in establishing novel therapeutic approaches by targeting the molecular signaling pathways responsive to these stimuli. Moreover, the identification of these factors could facilitate the development of strategies for an early diagnosis or measures of risk reduction for high-risk people.
The number of uninsured people in the United States has declined by an estimated 20 million since the Affordable Care Act went into effect in 2010. Yet, an estimated 24 million people still lack health insurance. Goal: To examine the characteristics of the remaining uninsured adults and their reasons for not enrolling in marketplace plans or Medicaid. Methods: Analysis of the Commonwealth Fund ACA Tracking Survey, February--April 2016. Key findings and conclusions: There have been notable shifts in the demographic composition of the uninsured since the law's major coverage expansions went into effect in 2014. Latinos have become a growing share of the uninsured, rising from 29 percent in 2013 to 40 percent in 2016. Whites have become a declining share, falling from half the uninsured in 2013 to 41 percent in 2016. The uninsured are very poor: 39 percent of uninsured adults have incomes below the federal poverty level, twice the rate of their overall representation in the adult population. Of uninsured adults who are aware of the marketplaces or who have tried to enroll for coverage, the majority point to affordability concerns as a reason for not signing up.
Background: Non-occupational post-exposure prophylaxis (NPEP) is available to people with a potential risk for HIV exposure within the preceding 72h. We sought to determine if men who have sex with men (MSM) and receive NPEP had a significantly different risk profile (before the preceding 72h) from MSM not receiving NPEP. If this is the case, NPEP consultations may act as a cue for also discussing pre-exposure prophylaxis. Methods: We conducted a retrospective analysis to compare the demographic characteristics, sexual practices and clinical diagnoses of MSM who were NPEP users and those who were non-NPEP users attending Melbourne Sexual Health Centre from January 2008 to December 2014. Univariate and multivariate logistic regression models were used to examine the association between NPEP use and risk practices. Generalised estimating equations were used to adjust for within-individual correlations related to multiple visits of the same individual. Results: Of the 40395 MSM consultations included in the study, 1776 consultations (4%) were related to NPEP prescription. NPEP prescribing was associated with ever having injected drugs (adjusted odds ratio (AOR) 1.8, 95% confidence interval (CI): 1.4-2.3), sex with males only (AOR 1.9, 95% CI: 1.6-2.3), more than three male partners in the past 3 months (AOR 1.5, 95% CI: 1.4-1.7) and inconsistent condom use with these partners within the past 3 months (AOR 2.1, 95% CI: 1.9-2.4). Sex workers (AOR 0.6, 95% CI: 0.3-0.9), and men reporting sex overseas within the past 12 months (AOR 0.7, 95% CI: 0.6-0.8) were less likely to receive NPEP. MSM who used NPEP were more likely to test positive for any sexually transmissible infection (AOR 1.2, 95% CI: 1.0-1.4). Conclusions: MSM receiving NPEP generally had a higher risk profile than MSM not requesting NPEP, indicating that NPEP was used by MSM at higher risk for HIV. Therefore, consultations for NPEP may be an opportune time for also discussing pre-exposure prophylaxis for HIV.
Thiazines are a group of heterocyclic organic compounds that are still largely unexplored for their pharmacological activities. There are different available methods for the synthesis of thiazine derivatives in the literature. In this review, we discuss available methods of thiazine preparation through green synthesis methods. Beside their synthesis, many thiazine derivatives are biologically active and play an important role in the treatment of various diseases and show promising results of varying degrees, where they act as antibacterial, antifungal, antitumor, antimalarial, antineoplastic, antiviral, anti-inflammatory, analgesic and anticancer agents and thus they represent an interesting class of heterocyclic medicinal compounds worthy of further exploration.
1-Deoxy-d-xylulose 5-phosphate synthase (DXS) is a thiamin diphosphate (TDP) dependent enzyme that marks the beginning of the methylerythritol 4-phosphate isoprenoid biosynthesis pathway. The mechanism of action for DXS is still poorly understood and begins with the formation of a thiazolium ylide. This TDP activation step is thought to proceed through an intramolecular deprotonation by the 4'-aminopyrimidine ring of TDP; however, this step would occur only after an initial deprotonation of its own 4'-amino group. The mechanism of the initial deprotonation has been hypothesized, by analogy to transketolases, to occur via a histidine or an active site water molecule. Results from hybrid quantum mechanical/molecular mechanical (QM/MM) reaction path calculations reveal an ∼10 kcal/mol difference in transition state energies, favoring a water mediated mechanism over direct deprotonation by histidine. This difference was determined to be largely governed by electrostatic changes induced by conformational variations in the active site. Additionally, mutagenesis studies reveal DXS to be an evolutionarily resilient enzyme. Particularly, we hypothesize that residues H82 and H304 may act in a compensatory fashion if the other is lost due to mutation. Further, nucleus-independent chemical shifts (NICSs) and aromatic stabilization energy (ASE) calculations suggest that reduction in TDP aromaticity also serves as a factor for regulating ylide formation and controlling reactivity.
Venous thromboembolism (VTE) is a common and potentially fatal disease. Fondaparinux is a synthetic agent able to act on single factors involved in the coagulation network, which could be administered at fixed doses and with a more predictable response.
This review will focus on the efficacy and safety of fondaparinux in the treatment of major VTE (deep vein thrombosis and pulmonary embolism) and in the treatment of superficial vein thrombosis (SVT).
Results of high quality randomized controlled trials have clearly shown the efficacy and safety of fondaparinux in comparison to conventional treatment in patients with a major VTE. There are limited evidences on the safety and efficacy of different options in patients presenting with SVT. Fondaparinux has been evaluated in a large population
 of patients presenting with a SVT. Results of this high quality RCT provided the evidence on the efficacy and safety of fondaparinux 2.5 mg s.c./day for 45 days in this setting. Thus, considering the evidence of the literature and thanks to its pharmacokinetic and pharmacodynamic characteristics, fondaparinux represent a valid treatment option for both the acute management of patients with major VTE, and for the treatment of SVT.
MicroRNA-214 (miR-214) has been shown to act as a tumour suppressor in human cervical and colorectal cancer cells. The aim of this study was to experimentally validate high mobility group AT-hook 1 as a novel target for miR-214-mediated suppression of growth and motility.
HMGA1 and miR-214 expression levels were estimated in cervical and colorectal clinical specimens using qPCR. HMGA1 3' untranslated region luciferase assays were performed to validate HMGA1 as a target of miR-214. Effect of altering the expression of miR-214 or HMGA1 on proliferation, migration and invasion of human cervical and colorectal cancer cells was investigated.
miR-214 expression was poor while that of HMGA1 was high in cervical and colorectal cancer tissues. miR-214-re-expression or HMGA1 downregulation inhibited proliferation, migration and invasion of cancer cells while miR-214 inhibition had opposite effects. miR-214 was demonstrated to bind to the wild-type 3' untranslated region of HMGA1 but not with its mutant.
Low expression of miR-214 concurrent with elevated levels of HMGA1 may contribute to cervical and colorectal cancer progression. miR-214-mediated regulation of HMGA1 is a novel mechanism for its tumour-suppressive actions in human cervical and colorectal cancer cells and opens up avenues for novel therapeutic strategies for these two cancers.
Chronic non-progressive pneumonia, a disease that has become a worldwide epidemic has caused considerable loss to sheep industry. Mycoplasma ovipneumoniae (M. ovipneumoniae) is the causative agent of interstitial pneumonia in sheep, goat and bighorn. We here have identified by immunogold and immunoblotting that elongation factor Tu (EF-Tu) and heat shock protein 70 (HSP 70) are membrane-associated proteins on M. ovipneumonaiea. We have evaluated the humoral and cellular immune responses in vivo by immunizing BALB/c mice with both purified recombinant proteins rEF-Tu and rHSP70. The sera of both rEF-Tu and rHSP70 treated BALB/c mice demonstrated increased levels of IgG, IFN-γ, TNF-α, IL-12(p70), IL-4, IL-5 and IL-6. In addition, ELISPOT assay showed significant increase in IFN-γ+ secreting lymphocytes in the rHSP70 group when compared to other groups. Collectively our study reveals that rHSP70 induces a significantly better cellular immune response in mice, and may act as a Th1 cytokine-like adjuvant in immune response induction. Finally, growth inhibition test (GIT) of M. ovipneumoniae strain Y98 showed that sera from rHSP70 or rEF-Tu-immunized mice inhibited in vitro growth of M. ovipneumoniae. Our data strongly suggest that EF-Tu and HSP70 of M. ovipneumoniae are membrane-associated proteins capable of inducing antibody production, and cytokine secretion. Therefore, these two proteins may be potential candidates for vaccine development against M. ovipneumoniae infection in sheep.
In this work, we developed a new pH- and temperature-responsive nanochemotherapeutic system based on Doxorubicin (DOX) noncovalently bound to biosynthesized gelatin-coated gold nanoparticles (DOX-AuNPs@gelatin). The real-time release profile of DOX was evaluated at different pH values (7.4, 5.3, and 4.6) and temperatures (22-45 °C) in aqueous solutions, and its therapeutic performance was examined in vitro against MCF-7 breast cancer cells. TEM, dark-field scattering, and wide-field fluorescence microscopy indicated the effective uptake of nanochemotherapeutics with the subsequent release and progressive accumulation of DOX in cell nuclei. MTT assays clearly showed the effectiveness of the treatment by inhibiting the growth of MCF-7 breast cancer cells for a loaded drug concentration of 5 μg/mL. The most informative data about the dynamic release and localization were provided by scanning confocal microscopy using time-resolved fluorescence and surface-enhanced Raman scattering (SERS) techniques. In particular, fluorescence-lifetime imaging (FLIM) recorded under 485 nm pulsed diode laser excitation revealed the bimodal distribution of DOX in cells. The shorter fluorescence lifetime of DOX localized in nuclei (1.52 ns) than in the cytoplasm (2.4 ns) is consistent with the cytotoxic mechanism induced by DOX-DNA intercalation. Remarkably, the few DOX molecules captured between nanoparticles ("electromagnetic hotspots") after most drug is released act as SERS reporters for the localization of plasmonic nanocarriers in MCF-7 cells. The high drug loading capacity and effective drug release under pH control combined with the advantage of multimodal visualization inside cells clearly indicate the high potential of our DOX-AuNPs@gelatin delivery system for implementation in nanomedicine.
Cascade reactions represent a class of ideal organic reactions because they empower efficiency, elegance, and novelty. However, development of cascade reactions remains a daunting task for synthetic chemists. Radicals are known to be well suited for cascade reactions. Compared with widely used carbon-based radicals, nitrogen-based radicals, such as neutral aminyl radicals and protonated aminyl radicals (amine radical cations), are underutilized, although they are behind some notable synthetic methods such as the Hofmann-Löffler-Freytag reaction. The constraint on their usage is generally attributed to the limited number of available stable precursors. Since amine radical cations offer increased reactivity and selectivity in chemical transformations compared with neutral aminyl radicals, their generation is of utmost importance. Recently, a surge of reports has been revealed using visible light photoredox catalysis. It has been demonstrated that amines can act as an electron donor in a reductive quenching cycle while the amine itself is oxidized to the amine radical cation. Although a number of methods exist to generate amine radical cations, the photochemical formation of these species offers many practical advantages. In this Account, we discuss our journey to the development of annulation reactions with various π-bonds and electrophilic addition reactions to alkenes using photogenerated amine radical cations. Various carbocycles and heterocycles are produced by these reactions. In our annulation work, we first show that single electron photooxidation of cyclopropylanilines to the amine radical cations triggers ring opening of the strained carbocycle, producing distonic radical cations. These odd-electron species are shown to react with alkenes and alkynes to yield the corresponding cyclopentanes and cyclopentenes in an overall redox neutral process. Further development of this annulation reaction allows us to achieve the [4 + 2] annulation of cyclobutylanilines with alkynes. In our work on electrophilic addition reactions to alkenes, we reveal that photogenerated amine radical cations are capable of undergoing the electrophilic addition reactions to alkenes to form a variety of indoles and indolines. This chemistry represents a rare oxidative C-N bond-forming reaction using visible light. Conclusions drawn from observational results and proposed mechanisms are outlined in this Account. Additionally, open discussion of our successes and deficiencies in our experiences will give readers helpful insights as to how these species tend to react. The overall utility of photogenerated amine radical cations has yet to reach its full potential. With our current results, we anticipate more new transformations can still be derived from the ring opening processes of cyclopropylanilines and cyclobutylanilines under visible light photocatalysis. Additionally, since utilizing photogenerated amine radical cations in C-N bond-forming reactions has practically been absent in literature, we are confident more new reactions have yet been exploited.
Smokeless tobacco has been actively promoted by tobacco companies using endorsements by major sport figures, and research indicates that tobacco advertising can lead to youth initiation of tobacco use (1,2). Television and radio advertisements for cigarettes and smokeless tobacco have been prohibited since 1969,* and the 1998 Master Settlement Agreement(†) further prohibited tobacco companies from targeting youths with tobacco product advertisements in specified areas. In 2010, the Food and Drug Administration (FDA), under authority of the 2009 Family Smoking Prevention and Tobacco Control Act (FSPTCA), prohibited tobacco-brand sponsorship (i.e., sponsorship of sports and entertainment events or other social or cultural events using the tobacco brand name or anything identifiable with any brand of cigarettes or smokeless tobacco).(§) However, corporate-name tobacco sponsorship (i.e., sponsorship using the name of the corporation that manufactures regulated tobacco products) is still permitted under certain conditions.(¶) To monitor tobacco advertising and promotional activities in sports in the United States, CDC analyzed trends in sports-related marketing expenditures for cigarettes and smokeless tobacco during 1992-2013 using data from the Federal Trade Commission (FTC). During 1992-2013, sports-related marketing expenditures, adjusted by the consumer price index to constant 2013 dollars, decreased significantly for both cigarettes (from $136 million in 1992 to $0 in 2013) and smokeless tobacco (from $34.8 million in 1992 to $2.1 million in 2013). During 2010-2013, after the prohibition of tobacco-brand sponsorship in sports under the FSPTCA, cigarette manufacturers reported no
 spending (i.e., $0) on sports-related advertising and promotional activities; in contrast, smokeless tobacco manufacturers reported expenditures of $16.3 million on advertising and promoting smokeless tobacco in sports during 2010-2013. These findings indicate that despite prohibitions on brand sponsorship, smokeless tobacco products continue to be marketed in sports in the United States, potentially through other indirect channels such as corporate-name sponsorship. Enhanced measures are warranted to restrict youth-oriented tobacco marketing and promotional activities that could lead to tobacco initiation and use among children and adolescents (2). Reducing tobacco industry promotion through sponsorship of public and private events is an evidence-based strategy for preventing youth initiation of tobacco use (3). In addition, other proven interventions (e.g., tobacco price increases, anti-tobacco mass media campaigns, tobacco-free policies inclusive of smokeless tobacco, and barrier-free access to cessation services), could help reduce smokeless tobacco use in the United States (1).
Inflammation is a hallmark of almost all forms of renal injury and the activation of the innate immune system is of importance in the development of many kidney diseases. Pattern recognition receptors (PRRs) act as sensors of the innate immune system to detect pathogen- or damage-associated molecular patterns, which initiate immune responses to resolve infections and repair damaged tissues. Abnormalities in PRR activation will lead to excessive inflammation.
Nucleotide oligomerization domain (NOD)-like receptors (NLRs) are recently identified intracellular PRRs that are essential to innate immune responses and tissue homeostasis. A better understanding of the function of NLRs will provide unexpected opportunities to develop new therapies for kidney diseases by modulation of the innate immune system.
NLRs are constitutively expressed in the kidney and emerging evidence has shown that activation of NLRs plays an important role in the pathogenesis of renal injury. Among NLRs, NOD2 and NLRP3 inflammasome are the best characterized members in the kidney. In this review, we summarize current knowledge about the pathological mechanisms that are related to NOD2 and NLRP3 inflammasome in various kidney diseases by their canonical and non-canonical effects and discuss the opportunities of pharmacological targeting of NLR-mediated signaling pathways at multiple levels for the treatment of renal disease.
Fat grafting is an increasingly popular method of augmentation/reconstruction of soft tissue defects. However, the clinical unpredictability and high resorption rates of the grafts remain problematic. Cellular stress from the harvest and the ensuing ischemic episode may be the cause of this. Cellular stress activates the p38 mitogen-activated protein kinase (MAPK) signaling pathway. In response to cellular stress, the p38 pathway can lead to apoptosis and can negatively regulate cell proliferation. Inhibition of p38 in ex vivo experiments has been shown to promote the expansion of human cord blood hematopoietic stem cell and improve the adipogenesis process through its upstream regulator, Shp2. Because of its wide-ranging cell regulation and antiinflammatory properties, large-scale clinical trials using p38 inhibitors are also currently being performed, especially for therapeutic effect in chronic obstructive pulmonary disease and asthma. The rationale for our study was that the treatment of fat grafts with p38 inhibitor would (a) prevent apoptosis of adipose-derived stem cells in the fat grafts, (b) increase adipose-derived stem cells proliferation, and (c) stimulate the release of several angiogenic factors and promote revascularization.
Clinical and histological testing was performed on 5 fat-transplanted (1 mL) CD-1 nude mice compared with the test group of 5 mice, which were injected with a p38 MAPK inhibitor at 1, 3, 6, and 9 days after the fat transplantation.
The weights and volumes of the control group grafts were significantly higher than those of the p38 MAPK inhibitor-treated grafts. Average volume resorption was 36% in the control group and 92% in the test group. Histological evaluation of the grafts revealed significantly improved integration, with a significant reduction of fibrosis and inflammation in the control group versus the treated group.
This preliminary study suggests that as opposed to our hypothesis, inhibition of p38 significantly increases fat graft resorption. The dramatic effects observed in our study may suggest that p38 may act differently on the numerous cell types that constitute the fat graft, and further investigation is necessary.
A new hydrated yttrium copper tellurite nitrate, yttrium(III) copper(II) bis-[trioxidotellurate(IV)] nitrate trihydrate, has been synthesized hydro-thermally in a Teflon-lined autoclave and structurally determined using synchrotron radiation. The new phase is the first example containing yttrium, copper and tellurium in one structure. Its crystal structure is unique, with relatively strongly bound layers extending parallel to (020), defined by YO8, CuO4 and TeO3 polyhedra, while the NO3 (-) anions and one third of the water mol-ecules lie between those layers. The structural unit consists of [Cu2(TeO3)4](4-) loop-branched chains of {Cu⋯Te⋯Cu⋯Te} squares running parallel to [001], which are linked further into layers only through Y(O,H2O)8 polyhedra. Weak 'secondary' Te bonds and O-H⋯O hydrogen-bonding inter-actions, involving water mol-ecules and layer O atoms, link the layers and inter-layer species. IR spectroscopic data are also presented.
In the title compound, [Fe(C48H36N4)(C4H6N2)2]ClO4·1.5C4H8O, the iron(III) metal is coordinated in a distorted octa-hedral geometry by four pyrrole N atoms of the porphyrin ligand in the equatorial plane and two N atoms of 2-methyl-imidazole ligands in the axial sites. The complex has a highly ruffled porphyrin core with mean absolute core-atom displacements C a, C b, C m and C av of 0.25 (5), 0.17 (12), 0.432 (16) and 0.25 (13) Å, respectively. One of the four phenyl groups of the porphyrin is disordered over two sets of sites with refined occupancy ratio of 0.718 (7):0.282 (7). The mean Fe-Np (Np is a porphyrin N atom) bond length [1.975 (9) Å] indicates the low-spin state of the iron atom. The two 2-methyl-imidazole ligands are nearly perpendicular and form a dihedral angle of 86.93 (10)°. The dihedral angles between the 2-methyl-imidazole ligands and the closest Fe-Np vector are 38.04 (9) and 35.00 (7)°. In the crystal, the complex cations inter-act with the perchlorate anions through N-H⋯O hydrogen bonds, forming chains running parallel to [110].
Visceral leishmaniasis is a severe form of the disease, caused by Leishmania infantum in the New World. Patients present an anergic immune response that favors parasite establishment and spreading through tissues like bone marrow and liver. On the other hand, Leishmania braziliensis causes localized cutaneous lesions, which can be self-healing in some individuals. Interactions between host and parasite are essential to understand disease pathogenesis and progression. In this context, dendritic cells (DCs) act as essential bridges that connect innate and adaptive immune responses. In this way, the aim of this study was to compare the effects of these two Leishmania species, in some aspects of human DCs' biology for better understanding of the evasion mechanisms of Leishmania from host innate immune response. To do so, DCs were obtained from monocytes from whole peripheral blood of healthy volunteer donors and from those infected with L. infantum or L. braziliensis for 24 h. We observed similar rates of infection (around 40%) as well as parasite burden for both Leishmania species. Concerning surface molecules, we observed that both parasites induced CD86 expression when DCs were infected for 24 h. On the other hand, we detected a lower surface expression of CD209 in the presence of both L. braziliensis and L. infantum, but only the last one promoted the survival of DCs after 24 h. Therefore, DCs infected by both Leishmania species showed a higher expression of CD86 and a decrease of CD209 expression, suggesting that both enter DCs through CD209 molecule. However, only L. infantum had the ability to inhibit DC apoptotic death, as an evasion mechanism that enables its spreading to organs like bone marrow and liver. Lastly, L. braziliensis was more silent parasite, once it did not inhibit DC apoptosis in our in vitro model.
Gilles de la Tourette Syndrome (TS) is a childhood-onset neurodevelopmental disorder that is characterized by multiple motor and phonic tics. It has a complex etiology with multiple genes likely interacting with environmental factors to lead to the onset of symptoms. The genetic basis of the disorder remains elusive. However, multiple resources and large-scale projects are coming together, launching a new era in the field and bringing us on the verge of discovery. The large-scale efforts outlined in this report are complementary and represent a range of different approaches to the study of disorders with complex inheritance. The Tourette Syndrome Association International Consortium for Genetics (TSAICG) has focused on large families, parent-proband trios and cases for large case-control designs such as genomewide association studies (GWAS), copy number variation (CNV) scans, and exome/genome sequencing. TIC Genetics targets rare, large effect size mutations in simplex trios, and multigenerational families. The European Multicentre Tics in Children Study (EMTICS) seeks to elucidate gene-environment interactions including the involvement of infection and immune mechanisms in TS etiology. Finally, TS-EUROTRAIN, a Marie Curie Initial Training Network, aims to act as a platform to unify
 large-scale projects in the field and to educate the next generation of experts. Importantly, these complementary large-scale efforts are joining forces to uncover the full range of genetic variation and environmental risk factors for TS, holding great promise for identifying definitive TS susceptibility genes and shedding light into the complex pathophysiology of this disorder.
Ants of the Australian genus Myrmecia partition their foraging niche temporally, allowing them to be sympatric with overlapping foraging requirements. We used histological techniques to study the light and dark adaptation mechanisms in the compound eyes of diurnal (Myrmecia croslandi), crepuscular (M. tarsata, M. nigriceps) and nocturnal ants (M. pyriformis). We found that, except in the day-active species, all ants have a variable primary pigment cell pupil that constricts the crystalline cone in bright light to control for light flux. We show for the nocturnal M. pyriformis that the constriction of the crystalline cone by the primary pigment cells is light dependent whereas the opening of the aperture is regulated by an endogenous rhythm. In addition, in the light-adapted eyes of all species, the retinular cell pigment granules radially migrate towards the rhabdom, a process that in both the day-active M. croslandi and the night-active M. pyriformis is driven by ambient light intensity. Visual system properties thus do not restrict crepuscular and night-active ants to their temporal foraging niche, while day-active ants require high light intensities to operate. We discuss the ecological significance of these adaptation mechanisms and their role in temporal niche partitioning.
Argonaute2 (Ago2) is a rapidly evolving nuclease in the Drosophila melanogaster RNA interference (RNAi) pathway that targets viruses and transposable elements in somatic tissues. Here we reconstruct the history of Ago2 duplications across the D. obscura group and use patterns of gene expression to infer new functional specialization. We show that some duplications are old, shared by the entire species group, and that losses may be common, including previously undetected losses in the lineage leading to D. pseudoobscura We find that while the original (syntenic) gene copy has generally retained the ancestral ubiquitous expression pattern, most of the novel Ago2 paralogs have independently specialized to testis-specific expression. Using population genetic analyses, we show that most testis-specific paralogs have significantly lower genetic diversity than the genome-wide average. This suggests recent positive selection in three different species, and model-based analyses provide strong evidence of recent hard selective sweeps in or near four of the six D. pseudoobscura Ago2 paralogs. We speculate that the repeated evolution of testis specificity in obscura group Ago2 genes, combined with their dynamic turnover and strong signatures of adaptive evolution, may be associated with highly derived roles in the suppression of transposable elements or meiotic drive. Our study highlights the lability of RNAi pathways, even within well-studied groups such as Drosophila, and suggests that strong selection may act quickly after duplication in RNAi pathways, potentially giving rise to new and unknown RNAi functions in nonmodel species.
Interband tunnelling of carriers through a forbidden energy gap, known as Zener tunnelling, is a phenomenon of fundamental and technological interest. Its experimental observation in the Esaki p-n semiconductor diode has led to the first demonstration and exploitation of quantum tunnelling in a condensed matter system. Here we demonstrate a new type of Zener tunnelling that involves the resonant transmission of electrons through zero-dimensional (0D) states. In our devices, a narrow quantum well of the mid-infrared (MIR) alloy In(AsN) is placed in the intrinsic (i) layer of a p-i-n diode. The incorporation of nitrogen in the quantum well creates 0D states that are localized on nanometer lengthscales. These levels provide intermediate states that act as "stepping stones" for electrons tunnelling across the diode and give rise to a negative differential resistance (NDR) that is weakly dependent on temperature. These electron transport properties have potential for the development of nanometre-scale non-linear components for electronics and MIR photonics.
Among the members of the genus Burkholderia, Burkholderia tropica has the ability to fix nitrogen and promote sugarcane plant growth as well as act as a biological control agent. There is little information about how this bacterium metabolizes carbohydrates as well as those carbon sources found in the sugarcane juice that accumulates in stems during plant growth. Reverse transcription quantitative PCR (RT-qPCR) can be used to evaluate changes in gene expression during bacterial growth on different carbon sources. Here we tested the expression of six reference genes, lpxC, gyrB, recA, rpoA, rpoB, and rpoD, when cells were grown with glucose, fructose, sucrose, mannitol, aconitic acid, and sugarcane juice as carbon sources. The lpxC, gyrB, and recA were selected as the most stable reference genes based on geNorm and NormFinder software analyses. Validation of these three reference genes during strain Ppe8 growth on the same carbon sources showed that genes involved in glycogen biosynthesis (glgA, glgB, glgC) and trehalose biosynthesis (treY and treZ) were highly expressed when Ppe8 was grown in aconitic acid relative to other carbon sources, while otsA expression (trehalose biosynthesis) was reduced with all carbon sources. In addition, the expression level of the ORF_6066 (gluconolactonase) gene was reduced on sugarcane juice. The results confirmed the stability of the three selected reference genes (lpxC, gyrB, and recA) during the RT-qPCR and also their robustness by evaluating the relative expression of genes involved in glycogen and trehalose biosynthesis when strain Ppe8 was grown on different carbon sources and sugarcane juice.
The base-assisted oxidation of an aniline-Ru-quinone complex produced an anilinyl radical-Ru-semiquinone. Furthermore, base-assisted oxidation of the radical complex resulted in selective C-N bond formation through an intermolecular coupling between nitrogen and carbon atoms at the para-position of the anilinyl ligand.
Air pollution in transportation cabins has recently become a public concern. However, few studies assessed the exposure levels of suspected air pollutants including Volatile Organic Compounds (VOCs). This paper studied the exposure levels of in-carriage VOCs (benzene, toluene, ethylbenzene, xylene, styrene, formaldehyde, acetaldehyde, acetone and acrolein) in Shanghai, China and estimated the health risk in different conditions. The results indicated that VOCs concentrations in metro carriages varied from different train models, due to the difference in carriage size and ventilation system. The concentrations of aromatic VOCs in old metro carriage were 1-2 times higher than the new ones, as better paintings were used in new trains. Poor air circulation and ventilation in the underground track was likely to be the cause of higher VOCs levels (~10%) than the above-ground track. Lower aromatic compounds levels and higher carbonyls levels were observed in metro carriages at suburban areas than those at urban areas, likely due to less aromatic emission sources and more carbonyls emission sources in suburban areas. Acetone and acrolein were found to increase from 7.71 to 26.28μg/m(3) with number of commuters increasing from 40 to 200 in the carriages. According to the acceptable level proposed by the World Health Organization (1×10(-6)-1×10(-5)), the life carcinogenic risk of commuters by subway (8.5×10(-6)-4.8×10(-5)) was little above the acceptable level in Shanghai. Further application of our findings is possible to act as a reference in facilitating regulations for metro systems in other cities around world, so that in-carriage air quality might be improved.
Lung cancer has not traditionally been viewed as an immune-responsive tumor. However, it is becoming evident that tumor-induced immune suppression is vital to malignant progression. Immunotherapies act by enhancing the patient's innate immune response and hold promise for inducing long-term responses in select patients with non-small cell lung cancer (NSCLC) and small cell lung cancer (SCLC). Immune checkpoint inhibitors, in particular, inhibitors to cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) and programmed death 1 (PD-1) and programmed death receptor ligand 1 (PD-L1) have shown promise in early studies and are currently in clinical trials in both small cell lung cancer and non-small cell lung cancer patients. Two large randomized phase III trials recently demonstrated superior overall survival (OS) in patients treated with anti-PD-1 therapy compared to chemotherapy in the second-line setting.
Medicaid is often associated with longer hospitalizations and higher in-hospital mortality than other insurance types.
To characterize the impact of state Medicaid expansion status under the Affordable Care Act (ACA) on payer mix, length of stay (LOS), and in-hospital mortality.
Retrospective cohort study of general medicine patients discharged from academic medical centers (AMCs) within the University HealthSystem Consortium from October 1, 2012 to September 30, 2015.
Hospitals were stratified according to state Medicaid expansion status. The proportion of discharges by primary payer, LOS index, and mortality index were compared between Medicaid-expansion and nonexpansion hospitals before and after ACA implementation. ACA implementation was defined as January 1, 2014, for all states except Michigan, New Hampshire, Pennsylvania, and Indiana, which had unique dates of Medicaid expansion.
We identified 3,144,488
 discharges from 156 hospitals in 24 Medicaid-expansion states and Washington, DC, and 1,114,464 discharges from 55 hospitals in 14 nonexpansion states during the study period. Hospitals in Medicaid-expansion states experienced a significant 3.7% increase in Medicaid discharges (P = 0.013) and a 2.9% decrease in uninsured discharges (P < 0.001) after ACA implementation, whereas hospitals in nonexpansion states saw no significant change in payer mix. In a difference-in-differences analysis, the changes in LOS and mortality indices pre- to post-ACA implementation did not differ significantly between hospitals in Medicaid-expansion versus nonexpansion states.
The differential shift in payer mix between Medicaid-expansion and nonexpansion states under the ACA did not influence LOS or in-hospital mortality for general medicine patients at AMCs in the United States. Journal of Hospital Medicine 2015;11:847-852. © 2015 Society of Hospital Medicine.
Exercise is crucial in the management of diabetes mellitus and its associated complications. However, individuals with diabetes have a heightened risk of musculoskeletal problems, including tendon pathologies. Diabetes has a significant impact on the function of tendons due to the accumulation of advanced glycation end-products in the load-bearing collagen. In addition, tendon vascularity and healing may be reduced due to diabetes-induced changes in the peripheral vascular system, and impaired synthesis of collagen and glycosaminoglycan. The current chapter presents an evidence-based discussion of considerations for the rehabilitation of tendon problems in people with diabetes. The following conditions are discussed in detail - calcific tendinopathy, tenosynovitis, tendon rupture, and non-calcifying tendinopathy. Common diabetes-related findings are presented, along with their potential impact on tendinopathy management and suggested modifications to standard tendinopathy treatment protocols. A holistic approach should be used to optimize musculotendinous function, including a comprehensive exercise prescription addressing strength, flexibility, and aerobic fitness.
Hyperuricemia, particularly gout, and the immune inflammatory response are highly integrated. Both, long standing hyperuricemia and monosodium urate (MSU) crystal deposition can challenge tendon homeostasis because of their potential to cause inflammation to the host. Knowledge is emerging from clinical imaging research depicting where MSU crystals deposit, including patellar tendon, triceps and quadriceps tendons. Remarkably, subclinical tendon inflammation and damage are also present in asymptomatic hyperuricemia. Monosodium urate crystals act as danger activating molecular patterns (DAMPs), activating the inflammasome and inducing the secretion of IL-1beta, a key mediator of the inflammatory response. The crucial role of IL-1beta in driving the inflammatory events during gout attacks is supported by the clinical efficacy of IL-1beta blockade. Some data implicating IL-1beta as an initiator of tendinopathy exist, but the link between hyperuricemia and the development of tendinopathy remains to be validated. Further knowledge about the interactions of uric acid with both innate immune and tendon cells, and their consequences may help to determine if there is a subclass of hyperuricemic-tendinopathy.
Identification of mechanisms that allow some species to outcompete others is a fundamental goal in ecology and invasive species management. One useful approach is to examine congeners varying in invasiveness in a comparative framework across native and invaded ranges. Acacia species have been widely introduced outside their native range of Australia, and a subset of these species have become invasive in multiple parts of the world. Within specific regions, the invasive status of these species varies. Our study examined whether a key mechanism in the life history of Acacia species, the legume-rhizobia symbiosis, influences acacia invasiveness on a regional scale. To assess the extent to which species varying in invasiveness correspondingly differ with regard to the diversity of rhizobia they associate with, we grew seven Acacia species ranging in invasiveness in California in multiple soils from both their native (Australia) and introduced (California) ranges. In particular, the aim was to determine whether more invasive species formed symbioses with a wider diversity of rhizobial strains (i.e. are more promiscuous hosts). We measured and compared plant performance, including aboveground biomass, survival, and nodulation response, as well as rhizobial community composition and richness. Host promiscuity did not differ among invasiveness categories. Acacia species that varied in invasiveness differed in aboveground biomass for only one soil and did not differ in survival or nodulation within individual soils. In addition, acacias did not differ in rhizobial richness among invasiveness categories. However, nodulation differed between regions and was generally higher in the native than introduced range. Our results suggest that all Acacia species introduced to California are promiscuous hosts and that host promiscuity per se does not explain the observed differences in invasiveness within this region. Our study also highlights the utility of assessing potential mechanisms of invasion in species' native and introduced ranges.
Objective While the Affordable Care Act improves access to lactation services for many women across the US, low-income mothers in states without Medicaid expansion lack coverage for lactation support. As these states consider individual Medicaid reimbursement policies, the availability, effectiveness, and cost-benefit of lactation services must be evaluated. We conducted such an analysis for low-income mothers in North Carolina (NC), providing a model for other states. Methods First, we analyzed the distribution of NC International Board Certified Lactation Consultants (IBCLCs) and county-level breastfeeding rates among low-income infants. Logistic regression was used to examine the association between IBCLC density and 6-week breastfeeding duration. Finally, state advocates collaborated on a cost-benefit analysis of Medicaid coverage of IBCLCs. Results Maps of the NC breastfeeding support landscape indicate that IBCLCs are available to provide services to low-income women across the state. Compared to counties with no IBCLCs, those with high IBCLC density were found to have a 6-week breastfeeding prevalence ratio of 1.20 (95 % CI 1.12, 1.28). Medicaid reimbursement of IBCLCs showed an estimated annual cost savings of $2.33 million. Conclusions for Practice In one state without Medicaid expansion, we found that breastfeeding support resources are available across the state, high density IBCLC support is associated with increased breastfeeding by low-income mothers, and services are cost-effective. Our model for Medicaid reimbursement in NC provides a framework for states to improve equity in access to optimal lactation support.
This article provides a collaborative perspective of the discussions and conclusions from the fifth international workshop of combined positron emission tomorgraphy (PET)/magnetic resonance imaging (MRI) that was held in Tübingen, Germany, from February 15 to 19, 2016. Specifically, we summarise the second part of the workshop made up of invited presentations from active researchers in the field of PET/MRI and associated fields augmented by round table discussions and dialogue boards with specific topics. This year, this included practical advice as to possible approaches to moving PET/MRI into clinical routine, the use of PET/MRI in brain receptor imaging, in assessing cardiovascular diseases, cancer, infection, and inflammatory diseases. To address perceived challenges still remaining to innovatively integrate PET and MRI system technologies, a dedicated round table session brought together key representatives from industry and academia who were engaged with either the conceptualisation or early adoption of hybrid PET/MRI systems. Discussions during the workshop highlighted that emerging unique applications of PET/MRI such as the ability to provide multi-parametric quantitative and visual information which will enable not only overall disease detection but also disease characterisation would eventually be regarded as compelling arguments for the adoption of PET/MR. However, as indicated by previous workshops, evidence in favour of this observation is only growing slowly, mainly due to the ongoing inability to pool data cohorts from independent trials as well as different systems and sites. The participants emphasised that moving from status quo to status go entails the need to adopt standardised imaging procedures and the readiness to act together prospectively across multiple PET/MRI sites and vendors.
Nanotopography modulates cell characteristics and cell behavior. Nanotopological cues can be exploited to investigate the in-vivo modulation of cell characteristics by the cellular microenvironment. However, the studies explaining the modulation of tumor cell characteristics and identifying the transition step in cancer progressiveness are scarce. Here, we engineered nanochips comprising of Tantalum oxide nanodot arrays of 10, 50, 100 and 200 nm as artificial microenvironments to study the modulation of cancer cell behavior. Clinical samples of different types of Ovarian cancer at different stages were obtained, primary cultures were established and then seeded on different nanochips. Immunofluorescence (IF) was performed to compare the morphologies and cell characteristics. Indices corresponding to cell characteristics were defined. A statistical comparison of the cell characteristics in response to the nanochips was performed. The cells displayed differential growth parameters.
 Morphology, Viability, focal adhesions, microfilament bundles and cell area were modulated by the nanochips which can be used as a measure to study the cancer progressiveness. The ease of fabrication of nanochips ensures mass-production. The ability of the nanochips to act as artificial microenvironments and modulate cell behavior may lead to further prospects in the markerless monitoring of the progressiveness and ultimately, improving the prognosis of Ovarian cancer.
A growing body of literature describes how the Affordable Care Act (ACA) has expanded health insurance coverage. What is less well known is how these coverage gains have affected populations that are at risk for high health spending. To investigate this issue, we used prescription transaction data for a panel of 6.7 million prescription drug users to compare changes in coverage, prescription fills, plan spending, and out-of-pocket spending before and after the implementation of the ACA's coverage expansion. We found a 30 percent reduction in the proportion of this population that was uninsured in 2014 compared to 2013. Uninsured people who gained private coverage filled, on average, 28 percent more prescriptions and had 29 percent less out-of-pocket spending per prescription in 2014 compared to 2013. Those who gained Medicaid coverage had larger increases in fill rates (79 percent) and reductions in out-of-pocket spending per prescription (58 percent). People who gained coverage who had at least one of the chronic conditions detailed in our study saw larger decreases in out-of-pocket spending compared to those who did not have at least one condition. These results demonstrate that by reducing financial barriers to care, the ACA has increased treatment rates while reducing out-of-pocket spending, particularly for people with chronic conditions.
The long-term survival of relict populations depends on the accessibility of appropriate sites (microrefugia). In recent times, due to the mass extinction of rare species that has resulted from the loss of natural habitats, the question is - Are there any human-made sites that can act as refugial habitats? We examined forest roadside populations of the mountain plant Pulsatilla vernalis in the last large lowland refugium in Central Europe. We compared the habitat conditions and community structure of roadsides with P. vernalis against the forest interior. Light availability and bryophyte composition were the main factors that distinguished roadsides. Pulsatilla occurred on sites that had more light than the forest interior, but were also more or less shaded by trees, so more light came as one-side illumination from the road. Roadsides had also a lower coverage of bryophytes that formed large, dense carpets. At the same time, they were characterised by a greater richness of vascular plants and 'small' bryophytes, which corresponds to a higher frequency of disturbances. In a warming and more fertile Anthropocene world, competition plays the main role in the transformation of forest communities, which is why relict populations have found refugia in extensively disturbed human-made habitats.
Punch injuries are a form of self-harm characterised by the intentional act of striking an object with a closed fist. We aimed to describe the characteristics and trends in young people presenting with injuries sustained via the punch mechanism. A comprehensive retrospective review of medical records was completed of all young people aged 10-18 years presenting to our Central London Emergency Department over a 12-month period. A subset of the total group was identified as the punch injury subgroup. A total of 78 punch injury presentations were identified. In this subgroup, the male:female ratio is 4.57:1; 37.18% of presentations were associated with a fracture (n = 29) and 35.90% (n = 28) of patients re-presented following another punch injury, as a victim of violence, or by other psychiatric presentation. In conclusion, a male preponderance was observed, with frequent re-presentations, often in high-risk circumstances. An opportunity for screening, including mental health, social and substance misuse, was identified. Further research is needed to enable targeted effective interventions in this group.
The micronutrients folate and vitamin B12 are essential for the proper development of the central nervous system, and their deficiency during pregnancy has been associated with a wide range of disorders. They act as methyl donors in the one-carbon metabolism which critically influences epigenetic mechanisms. In order to depict further underlying mechanisms, we investigated the role of let-7 and miR-34, two microRNAs regulated by methylation, on a rat model of maternal deficiency. In several countries, public health policies recommend periconceptional supplementation with folic acid. However, the question about the duration and periodicity of supplementation remains. We therefore tested maternal supply (3 mg/kg/day) during the last third of gestation from embryonic days (E) 13 to 20. Methyl donor deficiency-related developmental disorders at E20, including cerebellar and interhemispheric suture defects and atrophy of selective cerebral layers, were associated with increased brain expression (by 2.5-fold) of let-7a and miR-34a, with subsequent downregulation of their regulatory targets such as Trim71 and Notch signaling partners, respectively. These processes could be reversed by siRNA strategy in differentiating neuroprogenitors lacking folate, with improvement of their morphological characteristics. While folic acid supplementation helped restoring the levels of let-7a and miR-34a and their downstream targets, it led to a reduction of structural and functional defects taking place during the perinatal period. Our data outline the potential role of let-7 and miR-34 and their related signaling pathways in the developmental defects following gestational methyl donor deficiency and support the likely usefulness of late folate supplementation in at risk women.
"Universal design provides a blueprint for maximum inclusion of all people" [7]. This statement is now nearly 20 years old. The present collection of papers from the 3rd International Conference on Universal Design (UD 2016) is testament to the fact that Universal Design is now benefitting from a climate that is more knowledgeable about, and possibly more accommodating of, individual differences between people. However, there are still many open issues, and much to be learnt from exchanging experiences between all stakeholders interested in Universal Design, be they policy makers, practitioners or researchers. This is due to the many changes in society, the environment and technology that have occurred in the last two decades. In this collection of papers from the conference, we cover many areas of theory and practice of Universal Design, with applications from the built environment and tangible products, to communication, services, and system design issues. There are also papers about advocating and teaching Universal Design, debates about policy, and about codes, regulations and standards. We hope the collection is a useful way for policy makers, practitioners and researchers interested in these different strands of work to learn and exchange ideas and best practices, and to break down the "silos" that inevitably emerge in any group attempting to address a topic of mutual interest from many perspectives. In gathering together these different strands, we also need to reflect on the current manifestations of Universal Design, and what implications there are for the years to come. We need to look back to where we came from, and to look forward to the future shaping of Universal Design. With the benefit of nearly 20 years since the publication of the Principles of Universal Design <fnr rid="fn001" /><fn id="fn001">Principles of Universal Design Version 2.0 4/1/97. © Copyright 1997 NC State University, The Center for Universal Design, an initiative of the College of Design. Compiled by advocates of universal design, listed in alphabetical order: Bettye Rose Connell, Mike Jones, Ron Mace, Jim Mueller, Abir Mullick, Elaine Ostroff, Jon Sanford, Ed Steinfeld, Molly Story, &amp; Gregg Vanderheiden https://www.ncsu.edu/project/design-projects/sites/cud/content/principles/principles.html. </fn>, we can review some of the terminology and its development around the concept of Universal Design. From the outset, the term referred to a broad spectrum of applications. It covered the design of buildings, products and environments, and the need for these to be inherently accessible to older people, people without disabilities, and people with disabilities. More specifically, the term Universal Design was defined in 1997 as "the design of products and environments to be usable by all people, to the greatest extent possible, without the need for adaptation or specialized design" <fnr rid="fn002" /><fn id="fn002">https://www.ncsu.edu/ncsu/design/cud/about_ud/about_ud.htm. </fn>. As with all concise definitions, it has been necessary to emphasise and add to this statement, for instance: • Universal Design is really about including all people and not a euphemism for "design for those with a disability". It is about products, services, and environments being usable, to the greatest extent possible, by everyone, regardless of their age, ability, cultural background or status in life [1]. • The phrase "to the greatest extent possible" was added to counter criticism that Universal Design was a utopian ideal, and to underscore that Universal Design is a practical as well as conceptual approach. • The focus of Universal Design is on mainstream products, services, and environments and not on adaptations or specialist products, services, and environments. • Universal Design emphasises the need to design from
 the outset for the widest possible range of users, rather than try to make modifications later on, whether during the design process or after release. • Products, services, and environments should also be aesthetically pleasing as well as non-discriminatory and non-stigmatising. Most of these elaborations are enshrined in the Principles of Universal Design. This is a set of seven principles that were developed to lay out guidance for the design of environments, products and communications, to evaluate existing designs, and to educate both designers and consumers about the characteristics of more usable products and environments. In addition, other terms have come into being, responding to the need to explain different aspects of the Universal Design spectrum. In 1998, at the "Designing for the 21st Century Conference" Ron Mace's presentation differentiated between the meanings and practices associated with the terms "Barrier-Free Design", "Assistive Technology" and "Universal Design" [2]. At the turn of the millennium, "Design for All" was the term adopted by the European Commission which focused on ensuring that environments, products, services and interfaces of the Information Society Technologies (ISTs) work for people of all ages and abilities in different situations and under various circumstances [6, 8]. It spelt out the "adaptation or specialized design" with a three-part strategy: • Design of IST products, services and applications which are demonstrably suitable for most of the potential users without any modifications. • Design of products which are easily adaptable to different users (e.g. by incorporating adaptable or customisable user interfaces). • Design of products which have standardised interfaces, capable of being accessed by specialised user interaction devices [6]. Alongside setting out this strategy, the definition of Design for All made a conscious effort to make the concept more widely acceptable by explaining how Design for All could benefit not just consumers of ISTs, but also producers, and give wider social and economic benefit. Amongst other things, adopting a Design for All approach would help deal proactively with the demographic trend of the aging population, and benefit businesses with increased sales of innovatively designed products that everyone could use. In short, Design for All advocated a policy of mutual benefit, where the "for all" descriptor included more than the user population. However, as with the term Universal Design, Design for All was misinterpreted, and accused firstly of the impractical aim of trying to accommodate everyone without exception. Secondly, there was a confusion that Design for All in its insistence on minimizing adaptation, was advocating a "one design fits all" stance, evidenced by the question posed at the time "Could you imagine a pair of shoes being designed in such way that everybody would want to wear them?" A preferred term to Design for All in the English-speaking European literature is "Inclusive Design". Coined by Roger Coleman in 1994 <fnr rid="fn003" /><fn id="fn003">RICA (Research Institute for Consumer Affairs) (2016) Inclusive Design: manufacturing, design, and retail expert views available from rica.org.uk. </fn>, this was an elegant apposition to the marketing term "exclusive design" as well as being a way of bringing in the notion of social equity that is part of the ethos of Universal Design and enshrined in the first of the seven Principles of Universal Design. Interestingly, in 2005, the British Standards Institute described Inclusive Design in its "Guide to Managing Inclusive Design" as "comprehensive, integrated design which encompasses all aspects of a product used by consumers of diverse age and capability in a wide range of contexts" <fnr rid="fn004" /><fn id="fn004">BS 7000-6:2005, Design management systems. Managing inclusive design. Guide. </fn>. The emphasis is firmly on products, as noted by the compilers of the Inclusive Design Toolkit <fnr rid="fn005" /><fn id="fn005">Inclusive Design Toolkit, What is Inclusive Design, Section: Comparison with Universal Design, http://www.inclusivedesigntoolkit.com/betterdesign2/whatis/whatis.html#p3b. </fn>. However in the guide itself, the definition is widened to include services: "the design of mainstream products and/or services that are accessible to, and usable by, as many people as reasonably possible without the need for special adaptation or specialised design" <fnr rid="fn006" /><fn id="fn006">BS 7000-6, 2005. Design Management Systems: Managing Inclusive Design, BSi, London, UK. http://shop.bsigroup.com/en/ProductDetail/?pid=000000000030142267. </fn>. With the term Inclusive Design, the notion that the design is of mutual benefit to all stakeholders, as in Design for All, was lost. It is perhaps telling that the Scandinavian countries with their tradition of collaborative and participatory design are the main supporters of the term Design for All as the most appropriate one to use [6]. It is a term no longer in such evident use by the European Commission. However, it is notable that in the proposal for what is being more commonly referred to as the European Accessibility Act, there is a somewhat awkward paraphrase "Accessibility following a 'design for all' approach" <fnr rid="fn007" /><fn id="fn007">Section 1.2, European Commission (2015) COM(2015) 615 final2015/0278 (COD) Proposal for a Directive of the European Parliament and of the Council on the approximation of the laws, regulations and administrative provisions of the Member States as regards the accessibility requirements for products and services. </fn> which could be understood as an attempt to keep the "mutual benefit" notion, since the Directive is not calling for human rights non-discriminatory legislation directly, but for support of the Single Market. (ABSTRACT TRUNCATED)
Democratic rights are granted by its nations legislation and systems, but needs enforcement by its institutions to be effective. This also relates to Universal Design. The refugee crisis in Europe raises questions as to how planning in the societies can be designed and implemented to include the new groups of the population. The Norwegian Planning and Building Act (PBA) put weight on the individual's or a group's right to influence public assessment and decision making processes. In this article a case from the Veitvet-Sletteløkka area in the ward of Bjerke, Oslo, is presented to show how these principles can be put into practice. The case clearly demonstrates how the presence of representatives from the ward and planning authority built trust to the various parts of the local community by a consistent and inclusive approach. Also, to further enhance inclusion and effectiveness in planning, the case illustrates the need for adapting new technologies, communication modes and perspectives.
The concept of Universal Design has received increasing appreciation over the past two decades. Yet, there are very few existing designs that cater to the needs of extraordinary users who experience some form of physical challenge. Previous work has shown promising results on involving users with physical challenges as lead users - users who have the potential to identify needs that could be latent among the general population. It has also been shown that older adults can act as such lead users. They can help design universal product ideas that satisfy both older adults and the general population. In this paper we build on this and examine if involving older adults in the design phase can result in universal products, products preferred by both older adults and the general population over a current option. Eighty-nine older adult participants and thirty-four general population participants took part in the study. Products were redesigned and prototyped based on the needs of older adults and tested among both populations. Results show that, although older adults and the general population did share certain needs and demands, the majority of older adults had needs and demands that were different from those of the general population. However, even though the needs differed between the populations, on average 89% of the general population participants preferred products designed based on design needs expressed by older adults over the current option. This provides further evidence supporting the use of older adults in designing products for all.
In Sweden, governmental agencies and bodies are required to implement a higher level of accessibility in their buildings than that stipulated by the National Building and Planning Act (PBL). The Swedish Agency for Participation (MFD, Myndigheten för delaktighet) develops holistic guidelines in order to conceptualize this higher level of accessibility. In conjunction to these guidelines, various checklist protocols have been produced. The present study focuses on the efficiency of such checklist protocols. The study revolved around the use of a checklist protocol in assessments of two buildings in Stockholm: the new head office for the National Authority for Social Insurances (ASI) and the School of Architecture at the Royal Institute of Technology (KTH). The study included three groups: Group 1 and Group 2 consisted of 50 real estate managers employed by the ASI, while Group 3 consisted of three participants in a course at the KTH. The results were similar in all of the groups. The use of the checklist protocol generated queries, which related mainly to two factors: (1) the accompanying factsheet consisted of textual explanations with no drawings, photographs or illustrations and (2) the order of the questions in the checklist protocol was difficult to correlate with the two buildings' spatial logic of accessing, egressing and making use of the built space.
The Norwegian state has been working for more than fifteen
 years on various ways of improving accessibility for the general public. An important part of this work has been to develop new legislation and other forms of formal guidelines to reduce physical barriers. The new Anti-Discrimination and Accessibility Act, Obligation to ensure general accommodation (universal design), came into force January 2009, and introduces some complicated dilemmas, especially when it states: "When assessing whether the design or accommodation entails an undue burden, particular importance shall be attached to the effect of the accommodation on the dismantling of disabling barriers, the necessary costs associated with the accommodation, the undertaking's resources, whether the normal function of the undertaking is of a public nature, safety considerations and cultural heritage considerations." What is an "undue burden" in relation to architectural visual qualities and to the historical heritage expressed in buildings and townscapes? This paper will look into these dilemmas by discussing specific cases from some cities in different countries. What kinds of procedure are suitable and decisive when it comes to these complicated questions? Is this a task exclusively reserved for professionals, or should the voice of lay people be heard and taken into consideration? By presenting examples from architecture and landscape architecture, I will show how universal design even can be implemented in old buildings and environments. The paper will argue for more focus on procedures than just physical solutions. The procedures should be based on accepted principles for changing historical monuments, such as wholeness, readability, reversibility and sustainability.
Deregulation is on the political agenda in the European countries. The Norwegian building code related to universal design and accessibility is challenged. To meet this, the Norwegian Building Authority have chosen to examine established truths and are basing their revised code on scientific research and field tests. But will this knowledge-based deregulation comply within the framework of the anti-discrimination act and, and if not: who suffers and to what extent?
Solution-phase syntheses of three bioactive natural products of mixed polypeptide-polyketide biogenesis, fellutamides A, B, and C, have been achieved. Three peptide bonds are generated without the use of coupling reagents in each synthesis of the fellutamides, which act against proteasomes.
Topoisomerase II is an essential nuclear enzyme involved in regulating DNA topology to facilitate replication and cell division. Disruption of topoisomerase II function by chemotherapeutic agents is in use as an effective strategy to fight cancer. Etoposide is an anticancer therapeutic that disrupts the catalytic cycle of topoisomerase II and stabilizes enzyme-bound DNA strand breaks. Etoposide is metabolized into several species including active quinone and catechol metabolites. Our previous studies have explored some of the details of how these compounds act against topoisomerase II. In our present study, we extend those analyses by examining several effects of etoposide quinone on topoisomerase IIα including whether the quinone impacts ATP hydrolysis, DNA ligation, cleavage complex persistence, and enzyme/DNA binding. Our results demonstrate that the quinone inhibits relaxation at 100-fold lower levels of drug when compared to that of etoposide. Further, the quinone inhibits ATP hydrolysis by topoisomerase IIα. The quinone does appear to stabilize single-strand breaks similar to etoposide suggesting a traditional poisoning mechanism. However, there is minimal difference in cleavage complex persistence in the presence of etoposide or etoposide quinone. In contrast to etoposide, we find that etoposide quinone blocks enzyme/DNA binding, which provides an explanation for previous data showing the ability of the quinone to inactivate the enzyme over time. Finally, etoposide quinone is able to stabilize the N-terminal protein clamp implying an interaction between the compound and this portion of the enzyme. Taken together, the evidence supports a two-mechanism model for the effect of the quinone on topoisomerase II: (1) interfacial poison and (2) covalent poison that interacts with the N-terminal clamp and impacts the binding of DNA.
Transport of cholesterol derived from hydrolysis of lipoprotein associated cholesteryl esters out of late endosomes depends critically on the function of the Niemann Pick C1 (NPC1) and C2 (NPC2) proteins. Both proteins bind cholesterol but also various other sterols and both with strongly varying affinity. The molecular mechanisms underlying this multiligand specificity are not known. On the basis of the crystal structure of NPC2, we have here investigated structural details of NPC2-sterol interactions using molecular mechanics Poisson-Boltzmann surface area (MM-PBSA) calculations. We found that an aliphatic side chain in the sterol ligand results in strong binding to NPC2, while side-chain oxidized sterols gave weaker binding. Estradiol and the hydrophobic amine U18666A had the lowest affinity of all tested ligands and at the same time showed the highest flexibility within the NPC2 binding pocket. The binding affinity of all ligands correlated highly with their calculated partitioning coefficient (logP) between octanol/water phases and with the potential of sterols to stabilize the protein backbone. From molecular dynamics simulations, we suggest a general mechanism for NPC2 mediated sterol transfer, in which Phe66, Val96, and Tyr100 act as reversible gate keepers. These residues stabilize the sterol in the binding pose via π-π stacking but move transiently apart during sterol release. A computational mutation analysis revealed that the binding of various ligands depends critically on the same specific amino acid residues within the binding pocket providing shape complementary to sterols, but also on residues in distal regions of the protein.
Boron-doped derivatives of graphene have been intensely investigated because of their electronic and catalytic properties. The maximum experimentally observed concentration of boron atoms in graphite was 2.35% at 2350 K. By employing quantum chemistry coupled with molecular dynamics, we identified the theoretical doping limit for single-layer graphene at different temperatures, demonstrating that it is possible to achieve much higher boron doping concentrations. According to the calculations, 33.3 mol% of boron does not significantly undermine thermal stability, whereas 50 mol% of boron results in critical backbone deformations, which occur when three or more boron atoms enter the same six-member ring. Even though boron is less electro-negative than carbon, it tends to act as an electron acceptor in the vicinity of C-B bonds. The dipole moment of B-doped graphene depends strongly on the distribution of dopant atoms within the sheet. Compared with N-doped graphene, the dopant-dopant bonds are less destructive in the present system. The reported results motivate efforts to synthesize highly B-doped graphene for semiconductor and catalytic applications. The theoretical predictions can be validated through direct chemical synthesis.
To gain an understanding of how next of kin experience the transition of their older relatives from hospital to municipal health care.
During the care transition of their older relatives, next of kin experience a period of ill-defined roles and expectations. Successful transition lays the ground for postdischarge treatment and care, in which next of kin have important roles.
A descriptive, exploratory design was used to gain a greater understanding of the experiences of next of kin during their older relatives' care transitions.
We conducted qualitative interviews of 13 next of kin of patients aged ≥80 years who had been discharged from the hospital to municipal care. Qualitative content analysis was used to analyse interviews.
The main theme, 'Next of kin balance multiple tasks during older relatives' care transitions', emerged from two subthemes: 'Next of kin strive to fulfil informational needs during care transition' and 'Next of kin take responsibility for the older relative during care transition'.
Next of kin have the challenging role of letting their older relative manage self-care during transition, when able, while being prepared to act on behalf of their relative as needed. Insufficient information and significant responsibilities contribute to unnecessary concerns and worries among next of kin.
Nurses in both hospitals and municipal health care will benefit from knowing more about the experiences of next of kin; this may ensure continuity of care during transitions and diminish unnecessary worries and concerns. Clinical nurses should be sensitive to the next of kin's need for support so the next of kin can better manage their older relatives' care after homecoming.
A trusting relationship is fundamental to effective nursing practice. Patients need to feel safe in your care and believe you will act in their best interest at all times.
To facilitate staff transition from an open plan to a two cot Neonatal Intensive Care Unit (NICU) design.
In 2012, an Australian regional NICU transitioned from an open plan to a two cot NICU design. Research has reported single and small room NICU design may negatively impact on the distances nurses walk, reducing the time they spend providing direct neonatal care. Studies have also reported nurses feel isolated and need additional support and education in such NICUs. Staff highlighted their concerns regarding the impact of the new design on workflow and clinical practice.
A Participatory Action Research (PAR) approach.
A participatory action group titled the Change and Networking (CAN) Group collaborated with staff over a four year period (2009-2013) to facilitate
 the transition. The CAN Group utilised a collaborative, cyclical process of planning, gathering data, taking action, and reviewing the results in order to plan the next action. Data Sources included: meeting and workshop minutes, newsletters, feedback boards, sub group reports and a staff satisfaction survey.
The study findings include a description of 1) how the PAR cycles were utilised by the CAN Group: providing examples of projects and strategies undertaken; and 2) evaluations of PAR methodology and Group by NICU staff and CAN members.
This study has described the benefits of using PAR to facilitate staff transition from an open plan to a two cot NICU design. PAR methodology enabled the inclusion of staff to find solutions to design and linical practice questions. Future research is required to assess the long term effect of NICU design on staff workload, maintaining and supporting a skilled workforce as well as the impact of the a new NICU design on the NICU culture. This article is protected by copyright. All rights reserved.
The unique properties of macroporous, mesoporous, and microporous systems, including their ability to accommodate molecules of different sizes inside their pores and to act as drug delivery systems, have been the object of extensive studies. In this work, mesoporous silica with hexagonal structure was obtained by template synthesis via the sol-gel process. The resulting material was used as support to accommodate the anti-inflammatory agent indomethacin. The alkaline route was used to prepare the mesoporous silica; cetyltrimethylammonium bromide was employed as porogenic agent. The silica particles were functionalized with 3-aminopropyltriethoxysilane alkoxide (APTES) by the sol-gel post-synthesis method. Indomethacin was incorporated into the silica functionalized with APTES and into non-functionalized silica. The resulting systems were characterized by x-ray diffraction (XRD), specific area, infrared spectroscopy, and thermal analyses (TGA). XRD attested to formation of mesoporous silica with hexagonal structure. This structure remained after silica functionalization with APTES and incorporation of indomethacin. Typical infrared spectroscopy vibrations and organic material decomposition during TGA confirmed silica functionalization and drug incorporation. The specific surface area and pore volume of the functionalized material incorporated with indomethacin decreased as compared with the specific surface area and pore volume of the non-functionalized silica containing no drug, suggesting both the functionalizing agent and the drug were present in the silica. Cytotoxicity tests conducted on normal fibroblasts (GM0479A) cells attested that the silica matrix containing indomethacin was less toxic than the free drug.
To elicit the perspectives of carers of people with mental illness regarding access to, and experience with, physical health care services for mental health consumers.
People diagnosed with mental illness have increased risks of physical illness and earlier death, problems able to be addressed through better physical health services. Carers of people with mental illness play a significant role in the mental health care system yet research examining their views is lacking.
QUALITATIVE EXPLORATORY: METHODS: Indepth interviews were conducted with 13 mental health carers. They were asked to describe their views and experiences pertaining to the physical health and availability of physical health care for of the people they care for. Data were analysed using the framework of Braun and Clarke.
Analysis of carer responses identified two important themes: responsiveness and access, and a shortage of care co-ordination. Carers felt alienated from physical health care providers and were compelled to fill gaps in available care through persistence in ensuring access to physical health care services.
The findings identify carers as key stakeholders in the physical health care of the people they care for. Their involvement in accessing and co-ordinating care provides vital perspective on health service capacity which requires further consideration in the practice and research domains.
Carers of people diagnosed with mental illness are crucial to the effective delivery of mental health services. Their perspectives must be central to their research agenda and contribute to the development of initiatives to improve clinical practice and promote improved physical health care. This article is protected by copyright. All rights reserved.
Advances in neonatal care have allowed premature infants to survive at earlier gestational ages, but they are often afflicted with neurological delays or deficits. Maternal inflammation has been identified as a major risk factor for premature birth and once born, infants often require supplemental oxygen for survival. Nurr1 (NR4A2) is an orphan nuclear receptor with no known binding site and is essential for the growth of midbrain dopamine neurons. Others have reported that Nurr1 can act as an anti-inflammatory transcription factor in microglia and astrocytes and respond lipopolysaccharide (LPS). We have previously reported decreased numbers of oligodendrocytes and increased numbers of microglia in the mice exposed to both maternal inflammation and neonatal hyperoxia in the perinatal period. These studies tested the hypothesis that the combined exposures to inflammation and hyperoxia would increase Nurr1 expression in microglia in our mouse model and in an immortalized microglia cell line, BV2 cells. Our data indicate that Nurr1 protein expression is increased at postnatal day 0 and postnatal day 28 in whole-brain homogenates from mice exposed to LPS and hyperoxia. Alternatively, Nurr1 message is decreased at postnatal day 60 in isolated microglia, indicating that the increases in whole-brain homogenates may be due to other cell types. In BV2 cells, Nurr1 message in increased by exposure to hyperoxia, but this increase is attenuated in cells exposed to both LPS and hyperoxia. Although Nurr1 regulation is not straightforward, these data indicate that Nurr1 expression is increased in whole-brain homogenates in response to inflammation, but is decreased in isolated primary microglia and BV2 cells in response to similar inflammation. Our data support the hypothesis that Nurr1 expression may play a significant role in regulating inflammation in the brain and understanding the complex regulation of Nurr1 could lead to new therapeutic strategies.
Under the Affordable Care Act (ACA), more than 30 states have expanded Medicaid, with some states choosing to expand private insurance instead (the "private option"). In addition, while coverage gains from the ACA's Medicaid expansion are well documented, impacts on utilization and health are unclear.
To assess changes in access to care, utilization, and self-reported health among low-income adults in 3 states taking alternative approaches to the ACA.
Differences-in-differences analysis of survey data from November 2013 through December 2015 of US citizens ages 19 to 64 years with incomes below 138% of the federal poverty level in Kentucky, Arkansas, and Texas (n = 8676). Data analysis was conducted between January and May 2016.
Medicaid expansion in Kentucky and use of Medicaid funds to purchase private insurance for low-income adults in Arkansas (private option), compared with no expansion in Texas.
Self-reported access to primary care, specialty care, and medications; affordability of care; outpatient, inpatient, and emergency utilization; receiving glucose and cholesterol testing, annual check-up, and care for chronic conditions; quality of care, depression score, and overall health.
Among the 3 states included in the study, Arkansas (n=2890), Kentucky (n=2898, and Texas (n=2888), there were no differences in sex, income, or marital status. Respondents from Texas were younger, more urban, and disproportionately Latino compared with those in Arkansas and Kentucky. Significant changes in coverage and access were more apparent in 2015 than in 2014. By 2015, expansion was associated with a 22.7 percentage-point reduction in the uninsured rate compared with nonexpansion (P < .001). Expansion was associated with significantly increased access to primary care (12.1 percentage points; P < .001), fewer skipped medications due to cost (-11.6 percentage points; P < .001), reduced out-of-pocket spending (-29.5%; P = .02), reduced likelihood of emergency department visits (-6.0 percentage points, P = .04), and increased outpatient visits (0.69 visits per year; P = .04). Screening for diabetes (6.3 percentage points; P = .05), glucose testing among patients with diabetes (10.7 percentage points; P = .03), and regular care for chronic conditions (12.0 percentage points; P = .008) all increased significantly after expansion. Quality of care ratings improved significantly (-7.1 percentage points with "fair/poor quality of care"; P = .03), as did the share of adults reporting excellent health (4.8 percentage points; P = .04). Comparisons of Arkansas vs Kentucky showed increased private coverage in the former (21.7 percentage points; P < .001), increased Medicaid in the latter (21.3 percentage points; P  < .001), and higher diabetic glucose testing rates in Kentucky (11.6 percentage points; P = .04), but no other statistically significant differences.
In the second year of expansion, Kentucky's Medicaid program and Arkansas's private option were associated with significant increases in outpatient utilization, preventive care, and improved health care quality; reductions in emergency department use; and improved self-reported health. Aside from the type of coverage obtained, outcomes were similar for nearly all other outcomes between the 2 states using alternative approaches to expansion.
Determining the speed at which a task is performed
 (i.e., reaction time) can be a valuable tool in both research and clinical assessments. However, standard computer hardware employed for measuring reaction times (e.g., computer monitor, keyboard, or mouse) can add nonrepresentative noise to the data, potentially compromising the accuracy of measurements and the conclusions drawn from the data. Therefore, an assessment of the accuracy and precision of measurement should be included along with the development of computerized tests and assessment batteries that rely on reaction times as the dependent variable. This manuscript outlines three methods for assessing the temporal accuracy of reaction time data (one employing external chronometry). Using example data collected from the Dalhousie Computerized Attention Battery (DalCAB) we discuss the detection, measurement, and correction of nonrepresentative noise in reaction time measurement. The details presented in this manuscript should act as a cautionary tale to any researchers or clinicians gathering reaction time data, but who have not yet considered methods for verifying the internal chronometry of the software and or hardware being used.
Thousands of workers are engaged in textile industry worldwide. Textile industry involves the use of different kinds of dyes which are known to possess carcinogenic properties. Solvents used in these industries are also associated with different health related hazards including cancer. In previous studies on textile and iron industries, the authors have reported genotoxicity among them and observed occurrence of cancer deaths among textile industry workers. Thus, an attempt has been made to compile the studies on the prevalence of different types of cancers among textile industry workers.
A wide literature search has been done for compiling the present paper. Papers on cancer occurrence among textile industry workers have been taken from 1976 to 2015. A variety of textile dyes and solvents, many of them being carcinogenic, are being used worldwide in the textile industry. The textile industry workers are therefore, in continuous exposure to these dyes, solvents, fibre dusts and various other toxic chemicals. The present study evaluates the potential of different chemicals and physical factors to be carcinogenic agents among occupationally exposed workers by going through various available reports and researches. Papers were collected using different databases and a number of studies report the association of textile industry and different types of cancer including lung, bladder, colorectal and breast cancer. After going through the available reports, it can be concluded that workers under varied job categories in textile industries are at a higher risk of developing cancer as various chemicals used in the textile industry are toxic and can act as potential health risk in inducing cancer among them. Assessing the cancer risk at different job levels in textile industries may be found useful in assessing the overall risk to the workers and formulating the future cancer preventive strategies.
We describe a bias in moral judgment in which the mere existence of other victims reduces assessments of the harm suffered by each harmed individual. Three experiments support the seemingly paradoxical relationship between the number of harmed individuals and the perceived severity of the harming act. In Experiment 1a, participants expressed lower punitive intentions toward a perpetrator of an unethical act that hurt multiple people and assigned lower monetary compensation to each victim than did those who judged a similar act that harmed only one person. In Experiment 1b, participants displayed greater emotional involvement in the case of a single victim than when there were multiple victims, regardless of whether the victims were unrelated and unaware of each other or constituted a group. Experiment 2 measured the responses of the victims themselves. Participants received false performance feedback on a task before being informed that they had been deceived. Victims who were deceived alone reported more negative feelings and judged the deception as more immoral than did those who knew that others had been deceived as well. Taken together, these results suggest that a victim's plight is perceived as less severe when others share it, and this bias is common to both third-party judges and victims.
This essay argues that it matters for the fate of health policies challenged in court whether courts consider health merely as a policy goal that must be subordinate to law, or as a legal norm warranting legal weight and consideration. Applying population-based legal analysis, this article demonstrates that courts have traditionally treated health as a legal norm. However, this norm appears to have weakened in recent years, a trend evident in the Supreme Court's first two decisions concerning the Affordable Care Act, NFIB v. Sebelius and Burwell v. Hobby Lobby However, in its more recent Affordable Care Act decision, King v. Burwell, the health legal norm is once again evident. Whether the Court will continue to treat health as a legal norm will prove critical to the deference and weight it grants health policies in the future.
The recent increase in our knowledge of human gut microbiota has changed our view on antibiotics. Antibiotics are, indeed, no longer considered only beneficial, but also potentially harmful drugs, as their abuse appears to play a role in the pathogenesis of several disorders associated with microbiota impairment (eg, Clostridium difficile infection or metabolic disorders). Both drug-related factors (such as antibiotic class, timing of exposure or route of administration) and host-related factors appear to influence the alterations of human gut microbiota produced by antibiotics. Nevertheless, antibiotics are nowadays considered a reliable therapy for some non-communicable disorders, including IBS or hepatic encephalopathy. Moreover, some antibiotics can also act positively on gut microbiota, providing a so-called 'eubiotic' effect, by increasing abundance of beneficial bacteria. Therefore, antibiotics appear to change, for better or worse, the nature of several disorders, including IBS, IBD, metabolic disorders or liver disease. This reviews aims to address the potential of antibiotics in the development of major non-communicable disorders associated with the alteration of gut microbiota and on newly discovered therapeutic avenues of antibiotics beyond the cure of infectious diseases.
Intimate partner violence (IPV) during pregnancy may be common in settings where HIV is prevalent but there are few data on IPV in populations of HIV-infected pregnant women in Southern Africa. We examined the prevalence and correlates of IPV among HIV-infected pregnant women.
A primary care antenatal clinic in Cape Town, South Africa.
623 consecutive HIV-infected pregnant women initiating lifelong antiretroviral therapy.
IPV, depression, substance use and psychological distress were assessed using the 13-item WHO Violence Against Women questionnaire, the Edinburgh Postnatal Depression Scale (EPDS), Alcohol and Drug Use Disorders Identification Tests (AUDIT/DUDIT) and the Kessler 10 (K-10) scale, respectively.
The median age in the sample was 28 years, 97% of women reported being in a relationship, and 70% of women reported not discussing and/or agreeing on pregnancy intentions before conception. 21% of women (n=132) reported experiencing ≥1 act of IPV in the past 12 months, including emotional (15%), physical (15%) and sexual violence (2%). Of those reporting any IPV (n=132), 48% reported experiencing 2 or more types. Emotional and physical violence was most prevalent among women aged 18-24 years, while sexual violence was most commonly reported among women aged 25-29 years. Reported IPV was less likely among married women, and women who experienced IPV were more likely to score above threshold for substance use, depression and psychological distress. In addition, women who reported not discussing and/or not agreeing on pregnancy intentions with their partner prior to conception were significantly more likely to experience violence.
HIV-infected pregnant women in the study reported experiencing multiple forms of IPV. While the impact of IPV on maternal and child health outcomes in the context of HIV infection requires further research attention, IPV screening and support services should be considered within the package of routine care for HIV-infected pregnant women.
NCT01933477.
Silicon-based microelectronics forms a major foundation of our modern society. Small lithium-ion batteries act as the key enablers of its success and have revolutionised portable electronics used in our all everyday's life. While large-scale LIBs are expected to help establish electric vehicles, on the other end of device size chip-integrated Si-based μ-batteries may revolutionise microelectronics once more. In general, Si is regarded as one of the white hopes since it offers energy densities being ten times higher than conventional anode materials. The use of monocrystalline, wafer-grade Si, however, requires several hurdles to be overcome since it its volume largely expands during lithiation. Here, we will show how 3D patterned Si wafers, prepared by the sophisticated techniques from semiconductor industry, are to be electrochemically activated to overcome these limitations and to leverage their full potential being reflected in stable charge capacities (>1000 mAhg(-1)) and high Coulomb efficiencies (98.8%).
To allow for greater coverage of the uninsured, the Affordable Care Act expanded Medicaid coverage in 2014. Accessing financial data of state health insurers from the National Association of Insurance Commissioners, this data trend study compares the financial performance and solvency of Medicaid-focused health insurers
 prior to and after the first year expansion of Medicaid coverage. After the first year of Medicaid expansion, there was a significant increase in operating profit margin ratio for Medicaid-focused health insurers within expansion states. Lower medical loss ratio as well as no change in administrative costs contributed to this profitable position. The risk-based capital ratio for solvency increased significantly for health insurers in nonexpansion states while there was no change in this ratio for health insurers in expansion states. Conversely, the other important solvency ratio of cash flow margin increased significantly for health insurers in expansion states but not for insurers in nonexpansion states.
The concept of resident-facility fit has largely been used to illustrate whether a residential care facility and a resident are together able to meet requirements set by only the hampering functional abilities of the latter. The purpose of this paper is to study how assisted living residents perceive resident-facility fit. The data were gathered ethnographically from both observations and resident interviews in a sheltered home in Finland during 2013-2014. Perceived resident-facility fit is based on several relational factors that connect to both the residents as individuals and their surroundings. This fit seems also to be partly conditional and indeed depends on residents' trust in having their own potential to act. Good resident-facility fit results in feeling at home in a facility, whereas poor fit can even result in residents' feeling imprisoned. Care providers can thus utilize our results to affirm residents' quality of life in residential facilities.
This article offers an as yet unexplored dimension of our current understanding of the ageing body in the context of contemporary South Korea. Drawing on interviews with twenty elderly women living in the greater Seoul metropolitan area, this article explores the role of appearance, body work, and the presentation of self in the women's everyday lived experiences. Existing research on the ageing female body in South Korea has primarily focused on the so-called noin munjae ('the elderly issue') discourse, within which the ageing body is framed as passive, undesirable, or out-of-control. Contrary to this, the elderly women's own narratives of everyday beauty practices suggest that the act of sustaining well-ordered appearance in later life allows for the enforcing of positive selves in the context of personal beauty and body work. Maintaining a positive appearance was shown to play an important part of their everyday lives, and functioned as a ritual of not only presenting an appearance that signified control over the ageing body, but to continue to enjoy it. The carefully calculated engagement with various non-surgical and surgical beauty practices also emerged as an embodied practice of mediating intersubjective social encounters through which self-esteem was engendered by evidencing the self's efforts to show respect to others. The findings of this study challenge dominant discourses in the west which present body work on the ageing female body as primarily self-indulgent, or driven by anxiety about the body's inability to fit within existing youthful beauty ideals.
A species sensitivity distribution (SSD) is a probability model of the variation of species sensitivities to a stressor, in particular chemical exposure. The SSD approach has been used as a decision support tool in environmental protection and management since the 1980s, and the ecotoxicological, statistical, and regulatory basis and applications continue to evolve. This article summarizes the findings of a 2014 workshop held by the European Centre for Toxicology and Ecotoxicology of Chemicals and the UK Environment Agency in Amsterdam, The Netherlands, on the ecological relevance, statistical basis, and regulatory applications of SSDs. An array of research recommendations categorized under the topical areas of use of SSDs, ecological considerations, guideline considerations, method development and validation, toxicity data, mechanistic understanding, and uncertainty were identified and prioritized. A rationale for the most critical research needs identified in the workshop is provided. The workshop reviewed the technical basis and historical development and application of SSDs, described approaches to estimating generic and scenario-specific SSD-based thresholds, evaluated utility and application of SSDs as diagnostic tools, and presented new statistical approaches to formulate SSDs. Collectively, these address many of the research needs to expand and improve their application. The highest priority work, from a pragmatic regulatory point of view, is to develop a guidance of best practices that could act as a basis for global harmonization and discussions regarding the SSD methodology and tools. Integr Environ Assess Manag 2016;12:000-000. © 2016 SETAC.
Propofol biotransformation occurs in the liver via hydroxylation by CYP450 enzymatic complex and by glucuronidation, however extra-hepatic metabolism has also been described.
To better understand the metabolic pathways involved in propofol biotransformation, the expression of CYP1A1, CYP1A2, the enzymatic and non-enzymatic antioxidant activity and the amount of propofol and its non-conjugated metabolites were investigated.
Twenty-one NewZealand rabbits were allocated into three groups continuously treated for 20h. Each group received: NaCl 0.9%, vehicle (SMOFlipid) and propofol 2% (Lipuro). At the end, liver and kidney samples were collected for histopathology and immunohistochemistry and plasma for quantification of propofol and its metabolites.
CYP1A1 and CYP1A2 were observed in zone 1 and zone 3 regions of the liver acinus. The propofol and saline groups showed a higher expression of CYP1A1 when compared to vehicle group. Propofol significantly increased CYP1A2 expression, compared to saline. CYP1A1 and CYP1A2 immunoexpression were observed in the kidney but no differences were registered between groups.
This suggests that propofol may act as selective inhibitor of CYP1A1 and an inducer of CYP1A2 expression in different regions of the liver. Propofol seems to have an antioxidative protective effect on liver parenchyma, comparatively to the emulsion alone. In the rabbit, extra-hepatic propofol biotransformation may also occur in the kidney.
The human ability to perform joint actions is often attributed to high-level cognitive processes. For example, the finding that action leaders act faster when imitated by their partners has been interpreted as evidence for anticipation of the other's actions (Pfister, Dignath, Hommel, & Kunde, 2013). In two experiments, we showed that a low-level mechanism can account for this finding. Action leaders were faster when imitated than when counterimitated, but only if they could observe their partner's actions (Exp. 1). Crucially, when due to our manipulation the partner's imitative actions became slower than the counterimitative actions, leaders also became slower when they were imitated, and faster when counterimitated (Exp. 2). Our results suggest that spontaneous temporal adaptation is a key mechanism in joint action tasks. We argue for a reconsideration of other phenomena that have traditionally been attributed solely to high-level processes.
The donor artery after a long-standing arteriovenous fistula (AVF) for hemodialysis usually evolves exceptionally toward a true aneurysmal degeneration (AD). The purpose of this article was to describe true brachial artery AD in end-stage renal disease patients after AVF creation, as well as its influencing factors and treatment strategies.
We present a retrospective, observational, single-center study realized in Caen University Hospital's Vascular Surgery Department from May 1996 to November 2015. The inclusion criteria were true AD of the brachial artery after a vascular access for hemodialysis. A literature research, using the same criteria, was performed on the articles published between 1994 and 2015. The used databases included MEDLINE (via PubMed), EMBASE via OVID, Cochrane Library Database, and ResearchGate.
Our series includes 5 patients. Twenty-one articles were found in the literature: 17 case reports, 3 series, and 1 review. The same triggering factors for AD (high flow and immunosuppressive treatment) were found. The mean age at the time of AVF creation, first renal transplantation, and AD's diagnosis were respectively 26 (range 15-49), 29.2, and 48.6 years (range 37-76) in our series versus 34 (range 27-39), 40.4 (range 28-55), and 55.5 years (range 35-75) in cases found in the literature. The time spread after AVF creation and aneurysmal diagnosis was about 20.6 years (range 18-25) in our study versus 20.5 years (range 9-29) in the case reports. Our surgical attitude corresponds principally to that described in the literature. Nevertheless, we describe for the first time one case of arterial transposition to exclude the brachial aneurysm using superficial femoral artery.
Arterial aneurysm is a rare, but significant complication after a long-term creation of hemodialysis access. High flow and immunosuppression may accelerate this process. Young age of the patients may act as a benefic factor and delay the AD. Arterial transposition could be an option in the absence of any venous conduit, if anatomy does not permit the use of prosthetic grafts.
TNF (tumor necrosis factor) is both a pro-inflammatory and anti-inflammatory cytokine that is central to the development of autoimmune disease, cancer, and protection against infectious pathogens. As well as a myriad other activities, TNF can be a product of T cells and can act on T cells. Here we review old and new data on the importance of TNF produced by T cells and how TNF signaling via TNFR2 may directly impact
 alternate aspects of T cell biology. TNF can promote the activation and proliferation of naïve and effector T cells, but also can induce apoptosis of highly activated effector T cells, further determining the size of the pathogenic or protective conventional T cell pool. Moreover, TNF can have divergent effects on regulatory T cells. It can both downregulate their suppressive capacity, but also contribute in other instances to their development or accumulation. Biologics that block TNF or stimulate TNFR2 therefore have the potential to strongly modulate the balance between effector T cells and Treg cells which could impact disease in both positive and negative manners.
This report outlines the need for the development of an advanced course in mass-casualty life support (MCLS) and introduces the course content. The current problems with education on disasters involving chemical agents, biological agents, radiation/nuclear attacks, or explosives (CBRNE) in Japan are presented. This newly developed "MCLS-CBRNE" program was created by a Ministry of Health, Labour, and Welfare (Tokyo, Japan) research group based on these circumstances. Modifications were then made after a trial course. Training opportunities for relevant organizations to learn how to act at a CBRNE disaster site currently are lacking. The developed course covers initial responses at a disaster site. This one-day training course comprises lectures, three tabletop simulations, and practical exercises in pre-decontamination triage and post-decontamination triage. With regard to field exercises conducted to date, related organizations have experienced difficulties in understanding each other and adapting their approaches. Tabletop simulations provide an opportunity for participants to learn how organizations working on-site, including fire, police, and medical personnel, act with differing goals and guiding principles. This course appears useful as a means for relevant organizations to understand the importance of developing common guidelines. The MCLS-CBRNE training is proposed to support CBRNE disaster control measures during future events. Anan H , Otomo Y , Kondo H , Homma M , Koido Y , Morino K , Oshiro K , Harikae K , Akasaka O . Development of mass-casualty life support-CBRNE (MCLS-CBRNE) in Japan. Prehosp Disaster Med. 2016;31(5):547-550.
Of all the aquatic organisms, algae are a good source of biomolecules. Since algae contain pigments, proteins, carbohydrates, fats, nucleic acids and secondary metabolites such as alkaloids, some aromatic compounds, macrolides, peptides and terpenes, they act as reducing agents to produce nanoparticles from metal salts without producing any toxic by-product. Once the algal biomolecules are identified, the nanoparticles of desired shape or size may be fabricated. The metal and metal oxide nanoparticles thus synthesized have been investigated for their antimicrobial activity against several gram-positive and gram-negative bacterial strains and fungi. Their dimension is controlled by temperature, incubation time, pH and concentration of the solution. In this review, we have attempted to update the procedure of nanoparticle synthesis from algae, their characterization by UV-vis, Fourier transform infrared spectroscopy, transmission electron microscopy, scanning electron microscopy, x-ray diffraction, energy-dispersive x-ray spectroscopy, dynamic light scattering and application in cutting-edge areas.
Impulsivity as a tendency to act quickly without considering future consequences has been proposed as a dimensional factor in bipolar disorder. It can be measured using behavioral tasks and self-report questionnaires. Previous findings revealed patients to show worse performance on at least one behavioral measure of impulsivity. Additionally, self-reported impulsivity seems to be higher among bipolar patients, both parameters being possibly associated with a more severe course of illness. In this study, our primary aim was to investigate the relationship between these two constructs of impulsivity among bipolar patients.
A total of 40 euthymic patients with bipolar disorder (21 female, 22 Bipolar I) and 30 healthy controls were recruited for comprehensive neuropsychological assessment. To assess inhibition control as a behavioral measure of impulsivity, the Stroop Color and Word Test (Stroop) was used. Additionally, both groups completed the Barratt Impulsiveness Scale (BIS) as a self-report of impulsivity. To compare the groups' performance on the Stroop and ratings on the BIS, the non-parametric Mann-Whitney U test was used. Within the bipolar group, we additionally examined the possibility of an association between Stroop performance and BIS total scores using Pearson's Correlation r.
Patients and controls differed significantly on the Stroop and BIS, with patients performing worse on the Stroop and scoring higher on the BIS. However, there was no association between the Stroop and BIS within the bipolar group. As an exploratory analysis, a positive correlation between Stroop performance and number of episodes was found. Further, we detected a statistical trend in the direction of poorer Stroop performance among patients treated with polypharmacy.
Both difficulties with behavioral inhibition and self-reported impulsivity were observed to be higher in bipolar patients than controls in the current study. However, within the patient group we did not observe an association between patients' behavioral performance and self-report. This indicates that the parameters likely constitute distinct, dimensional factors of bipolar disorder. In future research, studies with larger samples should investigate which of the two markers constitutes the better marker for the illness and is more suitable to differentiate the most severe patients.
Snake venoms are rich and intriguing sources of biologically-active molecules that act on target cells, modulating a diversity of physiological functions and presenting promising pharmacological applications. Lys49 phospholipase A2 is one of the multifunctional proteins present in these complex secretions and, although catalytically inactive, has a variety of biological activities, including cytotoxic, antibacterial, inflammatory, antifungal activities. Herein, a Lys49 phospholipase A2, denominated CoaTx-II from Crotalus oreganus abyssus, was purified and structurally and pharmacologically characterized. CoaTx-II was isolated with a high degree of purity by a combination of two chromatographic steps; molecular exclusion and reversed-phase high performance liquid chromatography. This toxin is dimeric with a mass of 13868.2 Da (monomeric form), as determined by mass spectrometry. CoaTx-II is rich in Arg and Lys residues and displays high identity with other Lys49 PLA2 homologues, which have high isoelectric points. The structural model of dimeric CoaTx-II shows that the toxin is non-covalently stabilized. Despite its enzymatic inactivity, in vivo CoaTx-II caused local muscular damage, characterized by increased plasma creatine kinase and confirmed by histological alterations, in addition to an inflammatory activity, as demonstrated by mice paw edema induction and pro-inflammatory cytokine IL-6 elevation. CoaTx-II also presents antibacterial activity against gram negative (Pseudomonas aeruginosa 31NM, Escherichia coli ATCC 25922) and positive (Staphyloccocus aureus BEC9393 and Rib1) bacteria. Therefore, data show that this newly purified toxin plays a central role in mediating the degenerative events associated with envenomation, in addition to demonstrating antibacterial properties, with potential for use in the development of strategies for antivenom therapy and combating antibiotic-resistant bacteria.
Mutilation is a rare and unusual act performed on a victim, especially in cases of homicide. Knowledge on mutilation homicide is scarce as the base rate of this type of homicide is very low. Moreover, previous studies examining this specific criminal behavior have been mainly descriptive, neglecting to look at other factors related to the act of mutilation. Furthermore, depending on the cultural context and country of origin, the infliction of mutilation pre-, per-, or post-homicide translates into different meanings. Therefore, it is important to examine mutilation homicide in the context of non-Western countries. Using crime and forensic examination reports subjected to forensic examination and convicted for a homicide between 1995 and 2011 (N = 1,200) in Korea, the rate of mutilation homicide was estimated. Based on the 65 cases (5.4%) identified, information on the offenses and offenders were described. Moreover, using a series of bivariate analyses, the current study compared cases of mutilation homicides in Korea with other countries. Findings revealed interesting differences and similarities between mutilation homicide cases from Korea and the other countries. For instance, offender-victim relationship, victim's gender, and criminal history were significantly different from the comparison groups. In addition, compared with Korea, mutilation homicide cases were significantly more likely to involve an accomplice in Finland, suggesting the need to carry the body over a long distance. Investigators and researchers need to understand the cultural context in which these acts are committed as the infliction of mutilation may serve different purposes across different countries.
Genetic participation in gynaecological oncology multidisciplinary team meetings (MDT) may identify the sentinel cancer in women with hereditary breast-ovarian cancer syndrome or Lynch syndrome.
To identify the changing patterns of genetic referral from 2010 to 2014 and the outcomes of referrals through clinical MDT case review.
Medical records of cases of gynaecological cancer presented at the MDT meetings and genetics databases
 were reviewed to determine the frequency and outcomes of recommendations for genetic referral between 2010 and 2014.
Four hundred and sixty-two women of 2523 cases reviewed were recommended for referral, increasing from 8% in 2010 to 25% in 2014. However, 167 of 462 patients (36%) had not registered with a Hereditary Cancer Clinic in NSW/ACT, including 11 women with high-grade serous ovarian cancer and seven women with abnormal MMR immunohistochemistry. Mutations were identified in 40 of 165 women (24%) undergoing breast cancer BRCA1/2 testing and in ten of 25 women (40%) who underwent MMR genetic testing. Eighty-one first- or second-degree relatives of these women have undergone predictive testing, identifying 48 mutation carriers and 33 non-carriers.
Changing indications and increased participation by a genetic consultant in the weekly MDT meeting has led to increasing genetic referrals over the last five years. Follow up of referrals needs to be addressed. With decreasing costs of genetic testing and use of readily transportable DNA collected through saliva or mouth swabs, we propose that distance should not be a barrier to this model being extended to all centres providing care to gynaecological cancer patients.
Bortezomib (BTZ) is used for the treatment of multiple myeloma (MM). However, a significant proportion of patients may be refractory to the drug. This study aimed to investigate whether the endothelin (ET-1) axis may act as an escape mechanism to treatment with bortezomib in MM cells.
NCI-H929 and RPMI-8226 (human MM cell lines) were cultured with or without ET-1, BTZ, and inhibitors of the endothelin receptors. ET-1 levels were determined by ELISA, while the protein levels of its receptors and of the PI3K and MAPK pathways' components by western blot. Effects of ET-1 on cell proliferation were studied by MTT and on the ubiquitin proteasome pathway by assessing the chymotryptic activity of the 20S proteasome in cell lysates.
Endothelin receptors A and B (ETAR and ETBR, respectively) were found to be expressed in both cell lines, with the RPMI-8226 cells that are considered resistant to BTZ, expressing higher levels of ETBR and in addition secreting ET-1. Treatment of the NCI-H929 cells with ET-1 increased proliferation, while co-incubation of these cells with ET-1 and BTZ decreased BTZ efficacy with concomitant upregulation of 20S proteasomal activity. Si-RNA silencing or chemical blockade of ETBR abrogated the protective effects of ET-1. Finally, data suggest that the predominant signaling pathway involved in ET-1/ETBR-induced BTZ resistance in MM cells may be the MAPK pathway.
Our data suggest a possible role of the ET-1/ETBR axis in regulating the sensitivity of MM cells to BTZ. Thus, combining bortezomib with strategies to target the ET-1 axis could prove to be a novel promising therapeutic approach in MM.
Chromosome stability models are usually qualitative models derived from molecular-genetic mechanisms for DNA repair, DNA synthesis, and cell division. While qualitative models are informative, they are also challenging to reformulate as precise quantitative models. In this report we explore how (A) laboratory experiments, (B) quantitative simulation, and (C) seriation algorithms can inform models of chromosome stability. Laboratory experiments were used to identify 19 genes that when over-expressed cause chromosome instability in the yeast Saccharomyces cerevisiae To better understand the molecular mechanisms by which these genes act, we explored their genetic interactions with 18 deletion mutations known to cause chromosome instability. Quantitative simulations based on a mathematical model of the cell cycle were used to predict the consequences of several genetic interactions. These simulations lead us to suspect that the chromosome instability genes cause cell-cycle perturbations. Cell-cycle involvement was confirmed using a seriation algorithm, which was used to analyze the genetic interaction matrix to reveal an underlying cyclical pattern. The seriation algorithm searched over 10(14) possible arrangements of rows and columns to find one optimal arrangement, which correctly reflects events during cell cycle phases. To conclude, we illustrate how the molecular mechanisms behind these cell cycle events are consistent with established molecular interaction maps.
Although the inhibition of return (IOR) effect is primarily studied when people act individually, IOR is also observed in social environments where a person observes a partner's response before executing their own response (social or sIOR). Specifically, an observer takes longer to initiate a response to a target at a location that another individual has just responded to than to another location. The present study was conducted to determine if sIOR emerges when two individuals execute different actions-one participant executed keypress responses and the other completed aiming movements to the same set of stimuli. The two conditions in the present experiment were designed to separate the effects of observing a co-actor's target information from observing their subsequent response. In the Full Vision condition, observers saw both the target stimuli and the response of the partner. In the Partial Vision condition, observers witnessed the response of the partner, but did not see the target stimulus or any other potentially attention capturing event at the target location. It was found that, although sIOR emerged in the Full Vision condition, sIOR did not emerge in the Partial Vision condition. These and other previous findings on the impact of action goal on sIOR are discussed with reference to the potential contributions of attention and action co-representation mechanisms to the sIOR effect.
(1) To implement a new policy-driven referral program, Opt-to-Quit, using electronic data transfer from the electronic health record (EHR) to the New York State Smokers' Quitline (NYSSQL) and (2) to improve referrals to the NYSSQL for smoking caregivers of children admitted to a children's hospital.
Smoking caregivers of pediatric patients were referred to the NYSSQL through a standardized template built into the EHR, during the child's hospitalization or emergency department encounter. Direct data exchange was based on a point-to-point protocol, without dependence on any external centralized processing service. Input and oversight were provided by a multidisciplinary task force, which included physician and nursing leadership, information technology specialists, Health Insurance Portability and Accountability Act compliance personnel and legal counsel, and NYSSQL staff. The process was refined through several iterative plan-do-study-act cycles, using a single-armed, prospective cohort study design, including surveys of nursing staff and continued input of information technology experts on both hospital and Quitline sides.
In 2013, 193 smokers were identified in 2 pilot units; 62% (n= 119) accepted referral to the NYSSQL. In 2014, after expansion to all inpatient units and the emergency department, 745 smokers were identified, and 36% (n = 266) accepted referral. Over the 2 years, overall increase in referrals was 124%; as of the first quarter of 2015, referral rate was sustained at 34%.
Hospital-wide implementation of the Opt-to-Quit program through our EHR was feasible and sustainable and has significantly improved referrals to the NYSSQL.
Adult hippocampal neurogenesis is decreased in type 2 diabetes, and this impairment appears to be important in cognitive dysfunction. Previous studies suggest that ghrelin gene products (acylated ghrelin (AG), unacylated ghrelin (UAG) and obestatin (OB)) promote neurogenesis. Therefore, we hypothesize that ghrelin gene products may reduce the harmful effects of high glucose (HG) on hippocampal neural stem cells (NSCs). The aim of this study was to investigate the role of these peptides on the survival of cultured hippocampal NSCs exposed to HG insult. Treatment of hippocampal NSCs with AG, UAG or OB inhibited HG-induced cell death and apoptosis. Exposure of cells to the growth hormone secretagogue receptor 1a antagonist abolished the protective effects of AG against HG toxicity, whereas those of UAG or OB were preserved. All three peptides attenuated HG-induced decrease in BrdU-labeled and phosphohistone-H3-labeled cells. We also investigated the effects of ghrelin gene products on the regulation of apoptosis at the mitochondrial level. AG, UAG or OB rescued hippocampal NSCs from HG insult by inhibiting intracellular and mitochondrial reactive oxygen species generation and stabilizing mitochondrial transmembrane potential. In addition, cells treated with ghrelin gene products showed an increased Bcl-2 and decreased Bax levels, thereby increasing the Bcl-2/Bax ratio, inhibiting cytochrome c release and preventing caspase-3 activation. Finally, AG-, UAG- or OB-mediated protection was dependent on the activities of adenosine monophosphate-activated protein kinase/uncoupling protein 2 pathway. Our data indicate that ghrelin gene products may act as survival factors that preserve mitochondrial function and inhibit oxidative stress-induced apoptosis.
Cancer is primarily considered a disease of old age. Immunosenescence refers to the age-associated changes in the immune system, and its contribution to the increased risk of cancer in old individuals has been discussed for many years. Natural killer (NK) cells are cytotoxic innate immune cells specialized in defence against tumour and virus-infected cells. NK cell cytotoxicity is the result of a fine balance between activating and inhibitory receptors. Several activating receptors have been identified that recognize different ligands frequently found over-expressed on tumour cells or virus-infected cells. The most important NK cell inhibitory receptors interact with major
 histocompatibility complex class I molecules expressed on almost all nucleated cells preventing NK cell-mediated lysis of healthy cells. NK cell immunosenescence is characterized by a redistribution of NK cell subsets, a diminished expression of several activating receptors and lower per-cell cytotoxicity. Altered expression of activating receptors has also been described in young and elderly cancer patients probably due to chronic exposure to ligands on tumour cells. Thus, the effect of both age and cancer may act synergistically to diminish NK cell-mediated tumour immunosurveillance. Different strategies harnessing the power of NK cells to target tumour cells have been designed including adoptive therapy with autologous or allogeneic expanded NK cells. In addition, checkpoint blockade of inhibitory receptors and the use of agonist antibodies to stimulate activating receptors are emerging areas of research. In this context, the effect of immunosenescence should be considered to improve the efficiency of cancer immunotherapy.
Dye-sensitized solar cells (DSSCs) are devices that convert light to electrical energy. Nowadays, researchers have focused on the understanding of the performance of dyes in solar cells. In this way, new efficient dyes have been obtained which can act as efficient light-harvesting compounds where the combination and the balance of acceptor(A)-bridge-donor(D) architectures confer suitable attributes and properties to the dye. Herein, we have carried out a DFT study on the optical and electronic properties of eight different A motifs and their influence on the electron photo-injection (PI) mechanisms through type I (indirect) or type II (direct) pathways in A-bridge-D dyes in DSSCs. The models consisted of thiophene as a bridge and triphenylamine as a D anchored to a TiO2 anatase cluster. All geometry optimizations were calculated using the B3LYP, CAM-B3LYP and BHandHLYP functionals combined with the 6-31G(d,p) basis set for C, H, N, O and S and the LANL2DZ pseudopotential for Ti atoms. Most of the A dyes display optoelectronic properties consistent with a type-I (indirect) mechanism except for the A5 dye where the results suggest a type-II (direct) PI pathway. In addition, molecular dynamics (MD) simulations have been carried out in order to describe the formation of dye dimers and analyze the stability of the aggregates due to intermolecular interactions. The observed trends indicate that dyes with A2 and A5 anchoring groups have less tendency to dimerize due to weaker intermolecular interactions resulting in less stable dimer complexes. Specifically, we found that the A motif influences the PI by a dye and the dimerization profiles.
To facilitate research involving marijuana and its chemical constituents, DEA is adopting a new policy that is designed to increase the number of entities registered under the Controlled Substances Act (CSA) to grow (manufacture) marijuana to supply legitimate researchers in the United States. This policy statement explains how DEA will evaluate applications for such registration consistent with the CSA and the obligations of the United States under the applicable international drug control treaty.
This final rule will update the prospective payment rates for inpatient rehabilitation facilities (IRFs) for federal fiscal year (FY) 2017 as required by the statute. As required by section 1886(j)(5) of the Act, this rule includes the classification and weighting factors for the IRF prospective payment system's (IRF PPS's) case-mix groups and a description of the methodologies and data used in computing the prospective payment rates for FY 2017. This final rule also revises and updates quality measures and reporting requirements under the IRF quality reporting program (QRP).
The Office of Personnel Management is issuing final regulations to implement the Wounded Warriors Federal Leave Act of 2015, which establishes a separate new leave category, to be known as "disabled veteran leave," available during a 12-month period beginning on the first day of employment to be used by an employee who is a veteran with a service-connected disability rated at 30 percent or more for purposes of undergoing medical treatment for such disability. We are also rescinding two obsolete leave-related regulations.
The influence of plant traits on forest fire behaviour has evolutionary, ecological and management implications, but is poorly understood and frequently discounted. We use a process model to quantify that influence and provide validation in a diverse range of eucalypt forests burnt under varying conditions. Measured height of consumption was compared to heights predicted using a surface fuel fire behaviour model, then key aspects of our model were sequentially added to this with and without species-specific information. Our fully specified model had a mean absolute error 3.8 times smaller than the otherwise identical surface fuel model (p < 0.01), and correctly predicted the height of larger (≥1 m) flames 12 times more often (p < 0.001). We conclude that the primary endogenous drivers of fire severity are the species of plants present rather than the surface fuel load, and demonstrate the accuracy and versatility of the model for quantifying this.
Photoluminescent defect states introduced by sp(3) functionalization of semiconducting carbon nanotubes are rapidly emerging as important routes for boosting emission quantum yields and introducing new functionality. Knowledge of the relaxation dynamics of these states is required for understanding how functionalizing agents (molecular dopants) may be designed to access specific behaviors. We measure photoluminescence (PL) decay dynamics of sp(3) defect states introduced by aryl functionalization of the carbon nanotube surface. Results are given for five different nanotube chiralities, each doped with a range of aryl functionality. We find that the PL decays of these sp(3) defect states are biexponential, with both components relaxing on time scales of ∼100 ps. Exciton trapping at defects is found to increases PL lifetimes by a factor of 5-10, in comparison to those for the free exciton. A significant chirality dependence is observed in the decay times, ranging from 77 ps for (7,5) nanotubes to >600 ps for (5,4) structures. The strong correlation of time constants with emission energy indicates relaxation occurs via multiphonon decay processes, with close agreement to theoretical expectations. Variation of the aryl dopant further modulates decay times by 10-15%. The aryl defects also affect PL lifetimes of the free E11 exciton. Shortening of the E11 bright state lifetime as defect density increases provides further confirmation that defects act as exciton traps. A similar shortening of the E11 dark exciton lifetime is found as defect density increases, providing strong experimental evidence that dark excitons are also trapped at such defect sites.
To qualitatively and quantitatively compare abdominal computed tomography (CT) images reconstructed with a new version of model-based iterative reconstruction (Veo 3.0; GE Healthcare) to those created with Veo 2.0.
This retrospective study was approved by our institutional review board and was Health Insurance Portability and Accountability Act compliant. The raw data from 29 consecutive patients who had undergone CT abdomen scanning was used to reconstruct 4 sets of 3.75-mm axial images: Veo 2.0, Veo 3.0 standard, Veo 3.0 5% resolution preference (RP), and Veo 3.0 20% RP. A slice thickness optimization of 3.75 mm and texture feature was selected for Veo 3.0 reconstructions.The images were reviewed by 3 independent readers in a blinded, randomized fashion using a 5-point Likert scale and 5-point comparative scale.Multiple 2-dimensional circular regions of interest were defined for noise and contrast-to-noise ratio measurements. Line profiles were drawn across the 7 lp/cm bar pattern of the CatPhan 600 phantom for spatial resolution evaluation.
The Veo 3.0 standard image set was scored better than Veo 2.0 in terms of artifacts (mean difference, 0.43; 95% confidence interval [95% CI], 0.25-0.6; P < 0.0001), overall image quality (mean difference, 0.87; 95% CI, 0.62-1.13; P < 0.0001) and qualitative resolution (mean difference, 0.9; 95% CI, 0.69-1.1; P < 0.0001). Although the Veo 3.0 standard and RP05 presets were preferred across most categories, the Veo 3.0 RP20 series ranked best for bone detail. Image noise and spatial resolution increased along a spectrum with Veo 2.0 the lowest and RP20 the highest.
Veo 3.0 enhances imaging evaluation relative to Veo 2.0; readers preferred Veo 3.0 image appearance despite the associated mild increases in image noise. These results provide suggested parameters to be used clinically and as a basis for future evaluations, such as focal lesion detection, in the oncology setting.
Xanthomonas euvesicatoria is the causal agent of bacterial spot disease in pepper and tomato. X. euvesicatoria bacteria interfere with plant cellular processes by injecting effector proteins into host cells through the type III secretion (T3S) system. About 35 T3S effectors have been identified in X. euvesicatoria 85-10, and a few of them were implicated in suppression of pattern-triggered immunity (PTI). We used an Arabidopsis thaliana pathogen-free protoplast-based assay to identify X. euvesicatoria 85-10 effectors that interfere with PTI signaling induced by the bacterial peptide flg22. Of 33 tested effectors, 17 inhibited activation of a PTI-inducible promoter. Among them, nine effectors also interfered with activation of an abscisic acid-inducible promoter. However, effectors that inhibited flg22-induced signaling did not affect phosphorylation of mitogen-activated protein (MAP) kinases acting downstream of flg22 perception. Further investigation of selected effectors revealed that
 XopAJ, XopE2, and XopF2 inhibited activation of a PTI-inducible promoter by the bacterial peptide elf18 in Arabidopsis protoplasts and by flg22 in tomato protoplasts. The effectors XopF2, XopE2, XopAP, XopAE, XopH, and XopAJ inhibited flg22-induced callose deposition in planta and enhanced disease symptoms caused by attenuated Pseudomonas syringae bacteria. Finally, selected effectors were found to localize to various plant subcellular compartments. These results indicate that X. euvesicatoria bacteria utilize multiple T3S effectors to suppress flg22-induced signaling acting downstream or in parallel to MAP kinase cascades and suggest they act through different molecular mechanisms.
The changes in structure during the digestion of highly concentrated methyl cellulose (MC) O/W emulsions and of hydrated MC were investigated. The effect of human saliva and in vitro stomach digestion was attributed to a dilution effect, rather than to pH or pepsin activity. After in vitro intestine incubation, a decrease in viscoelasticity and an increase in fat globule size were observed. The fat released after the digestion of the MC emulsion was 49.8% of the initial fat, indicating the existence of a big physical impediment. In comparison with an O/W whey protein emulsion with fat content equal to the fat released during the MC emulsion digestion, a 12% reduction in free fatty acid formation was found, which indicates that the decrease in fat bioaccessibility in the MC emulsion should be attributed not only to a physical effect against fat release but also to a further impediment related to the fat digestion process. Fat released quantification informs about the physical retention of fat in the emulsion matrix structure. Enzymes may not act if fat is not released and solubilized. Free fatty acid quantification is the real indicator of fat digestion, but contrary to the total fat released, it is affected by a wide variety of enzymatic factors, which should be considered for the correct comparison of systems of different properties, for example systems where the amount of fat release during the digestion may be different or initially unknown.
The syntheses, crystal structures and catalytic activities of the polymers derived from 2-(2-pyridylmethyleneamino)benzenesulfonic acid (HL), viz. [CuL(H2tma)]n (1) and [{Cu2L2(H2pma)}·(8H2O)]n (2) [H3tma = benzene-1,3,5-tricarboxylic (trimesic) acid and H4pma = benzene-1,2,4,5-tetracarboxylic (pyromellitic) acid], are presented. Despite the comparable combinations and compositions of ligands (sulfonate and carboxylate) in these two polymers the bridging moiety in 1 is sulfonate while in 2 it is carboxylate. Complexes 1 and 2 act as catalysts in the peroxidative oxidation of cyclohexane under mild conditions using either the ionic liquid 1-butyl-3-methylimidazolium hexafluorophosphate [bmim][PF6] or acetonitrile as the solvent. The ionic liquid medium leads to increases in the yields and in the turnover numbers, achieved in shorter reaction times in comparison with those when using the conventional acetonitrile solvent. A simple recycling of the catalysts in the ionic liquid medium is achieved without loss of activity and selectivity.
Little is known about how adverse events are summarised and reported in trials, as detailed information is usually considered confidential. We have acquired clinical study reports (CSRs) from the European Medicines Agency through the Freedom of Information Act. The CSRs describe the results of studies conducted as part of the application for marketing authorisation for the slimming pill orlistat. The purpose of this study was to study how adverse events were summarised and reported in study protocols, CSRs, and published papers of orlistat trials.
We received the CSRs from seven randomised placebo controlled orlistat trials (4,225 participants) submitted by Roche. The CSRs consisted of 8,716 pages and included protocols. Two researchers independently extracted data on adverse events from protocols and CSRs. Corresponding published papers were identified on PubMed and adverse event data were extracted from this source as well. All three sources were compared. Individual adverse events from one trial were summed and compared to the totals in the summary report. None of the protocols or CSRs contained instructions for investigators on how to question participants about adverse events. In CSRs, gastrointestinal adverse events were only coded if the participant reported that they were "bothersome," a condition that was not specified in the protocol for two of the trials. Serious adverse events were assessed for relationship to the drug by the sponsor, and all adverse events were coded by the sponsor using a glossary that could be updated by the sponsor. The criteria for withdrawal due to adverse events were in one case related to efficacy (high fasting glucose led to withdrawal), which meant that one trial had more withdrawals due to adverse events in the placebo group. Finally, only between 3% and 33% of the total number of investigator-reported adverse events from the trials were reported in the publications because of post hoc filters, though six of seven papers stated that "all adverse events were recorded." For one trial, we identified an additional 1,318 adverse events that were not listed or mentioned in the CSR itself but could be identified through manually counting individual adverse events reported in an appendix. We discovered that the majority of patients had multiple episodes of the same adverse event that were only counted once, though this was not described in the CSRs. We also discovered that participants treated with orlistat experienced twice as many days with adverse events as participants treated with placebo (22.7 d versus 14.9 d, p-value < 0.0001, Student's t test). Furthermore, compared with the placebo group, adverse events in the orlistat group were more severe. None of this was stated in the CSR or in the published paper. Our analysis was restricted to one drug tested in the mid-1990s; our results might therefore not be applicable for newer drugs.
In the orlistat trials, we identified important disparities in the reporting of adverse events between protocols, clinical study reports, and published papers. Reports of these trials seemed to have systematically understated adverse events. Based on these findings, systematic reviews of drugs might be improved by including protocols and CSRs in addition to published articles.
Flavonoids are crucial signaling molecules in the symbiosis between legumes and their nitrogen-fixing symbionts, the rhizobia. The primary function of flavonoids in the interaction is to induce transcription of the genes for biosynthesis of the rhizobial signaling molecules called Nod factors, which are perceived by the plant to allow symbiotic infection of the root. Many legumes produce specific flavonoids that only induce Nod factor production in homologous rhizobia, and therefore act as important determinants of host range. Despite a wealth of evidence on legume flavonoids, relatively few have proven roles in rhizobial infection. Recent studies suggest that production of key "infection" flavonoids is highly localized at infection sites. Furthermore, some of the flavonoids being produced at infection sites are phytoalexins and may have a role in the selection of compatible symbionts during infection. The molecular details of how flavonoid production in plants is regulated during nodulation have not yet been clarified, but nitrogen availability has been shown to play a role.
Neurodegenerative diseases may have distinct genetic etiologies and pathological manifestations, yet share common cellular mechanisms underpinning neuronal damage and dysfunction. These cellular mechanisms include excitotoxicity, calcium dysregulation, oxidative damage, ER stress and neuroinflammation. Recent data have identified a dual role in these events for glial cells, such as microglia and astrocytes, which are able both to induce and to protect against damage induced by diverse stresses. Cyclo(His-Pro), a cyclic dipeptide derived from the hydrolytic removal of the amino-terminal pyroglutamic acid residue of the hypothalamic thyrotropin-releasing hormone, may be important in regulating the nature of the glial cell contribution. Cyclo(His-Pro) is ubiquitous in the central nervous system and is a key substrate of organic cation transporters, which are strongly linked to neuroprotection. The cyclic dipeptide can also cross the brain-blood-barrier and, once in the brain, can affect diverse inflammatory and stress responses by modifying the Nrf2-NF-κB signaling axis. For these reasons, cyclo(His-Pro) has striking potential for therapeutic application by both parenteral and oral administration routes and may represent an important new tool in counteracting neuroinflammation-based degenerative pathologies. In this review, we discuss the chemistry and biology of cyclo(His-Pro), how it may interact with the biological mechanisms driving neurodegenerative disease, such as amyotrophic lateral sclerosis, and thereby act to preserve or restore neuronal function.
Periodontal disease is an inflammatory disease caused by bacterial infection of tooth-supporting structures, which results in the destruction of alveolar bone. Osteoclasts play a central role in bone destruction. Osteoclasts are tartrate-resistant acid phosphatase (TRAP)-positive multinucleated giant cells derived from hematopoietic stem cells. Recently, we and other researchers revealed that microRNAs are involved in osteoclast differentiation. MicroRNAs are novel, single-stranded, non-coding, small (20-22 nucleotides) RNAs that act in a sequence-specific manner to regulate gene expression at the post-transcriptional level through cleavage or translational repression of their target mRNAs. They regulate
 various biological activities such as cellular differentiation, apoptosis, cancer development, and inflammatory responses. In this review, the roles of microRNAs in osteoclast differentiation and function during alveolar bone destruction in periodontal disease are described.
During development and homeostasis, cells integrate multiple signals originating either from neighboring cells or systemically. In turn, responding cells can produce signals that act in an autocrine, paracrine, or endocrine manner. Although the nature of the signals and pathways used in cell-cell communication are well characterized, we lack, in most cases, an integrative view of signaling describing the spatial and temporal interactions between pathways (e.g., whether the signals are processed sequentially or concomitantly when two pathways are required for a specific outcome). To address the extent of cross-talk between the major metazoan signaling pathways, we characterized immediate transcriptional responses to either single- or multiple pathway stimulations in homogeneous Drosophila cell lines. Our study, focusing on seven core pathways, epidermal growth factor receptor (EGFR), bone morphogenetic protein (BMP), Jun kinase (JNK), JAK/STAT, Notch, Insulin, and Wnt, revealed that many ligands and receptors are primary targets of signaling pathways, highlighting that transcriptional regulation of genes encoding pathway components is a major level of signaling cross-talk. In addition, we found that ligands and receptors can integrate multiple pathway activities and adjust their transcriptional responses accordingly.
Nucleic acid-containing debris released from dead and dying cells can be recognized as damage-associated molecular patterns (DAMPs) or pattern-associated molecular patterns (PAMPs) by the innate immune system. Inappropriate activation of the innate immune response can engender pathological inflammation and autoimmune disease. To combat such diseases, major efforts have been made to therapeutically target the pattern recognition receptors (PRRs) such as the Toll-like receptors (TLRs) that recognize such DAMPs and PAMPs, or the downstream effector molecules they engender, to limit inflammation. Unfortunately, such strategies can limit the ability of the immune system to combat infection. Previously, we demonstrated that nucleic acid-binding polymers can act as molecular scavengers and limit the ability of artificial nucleic acid ligands to activate PRRs. Herein, we demonstrate that nucleic acid scavengers (NASs) can limit pathological inflammation and nucleic acid-associated autoimmunity in lupus-prone mice. Moreover, we observe that such NASs do not limit an animal's ability to combat viral infection, but rather their administration improves survival when animals are challenged with lethal doses of influenza. These results indicate that molecules that scavenge extracellular nucleic acid debris represent potentially safer agents to control pathological inflammation associated with a wide range of autoimmune and infectious diseases.
A major barrier to transitions to environmental sustainability is that consumers lack information about the full environmental footprints of their purchases. Sellers' incentives do not support reducing the footprints unless customers have such information and are willing to act on it. We explore the potential of modern information technology to lower this barrier by enabling firms to inform customers of products' environmental footprints at the point of purchase and easily offset consumers' contributions through bundled purchases of carbon offsets. Using online stated choice experiments, we evaluated the effectiveness of several inexpensive features that firms in four industries could implement with existing online user interfaces for consumers. These examples illustrate the potential for firms to lower their overall carbon footprints while improving customer satisfaction by lowering the "soft costs" to consumers of proenvironmental choices. Opportunities such as these likely exist wherever firms possess environmentally relevant data not accessible to consumers or when transaction costs make proenvironmental action difficult.
Heterotrimeric G proteins are localized to the plasma membrane where they transduce extracellular signals to intracellular effectors. G proteins also act at intracellular locations, and can translocate between cellular compartments. For example, Gαs can leave the plasma membrane and move to the cell interior after activation. However, the mechanism of Gαs translocation and its intracellular destination are not known. Here we use bioluminescence resonance energy transfer (BRET) to show that after activation, Gαs rapidly associates with the endoplasmic reticulum, mitochondria, and endosomes, consistent with indiscriminate sampling of intracellular membranes from the cytosol rather than transport via a specific vesicular pathway. The primary source of Gαs for endosomal compartments is constitutive endocytosis rather than activity-dependent internalization. Recycling of Gαs to the plasma membrane is complete 25 min after stimulation is discontinued. We also show that an acylation-deacylation cycle is important for the steady-state localization of Gαs at the plasma membrane, but our results do not support a role for deacylation in activity-dependent Gαs internalization.
Despite considerable interest in the role of spatial intelligence in science, technology, engineering, and mathematics (STEM) achievement, little is known about the ontogenetic origins of individual differences in spatial aptitude or their relation to later accomplishments in STEM disciplines. The current study provides evidence that spatial processes present in infancy predict interindividual variation in both spatial and mathematical competence later in development. Using a longitudinal design, we found that children's performance on a brief visuospatial change-detection task administered between 6 and 13 months of age was related to their spatial aptitude (i.e., mental-transformation skill) and mastery of symbolic-math concepts at 4 years of age, even when we controlled for general cognitive abilities and spatial memory. These results suggest that nascent spatial processes present in the first year of life not only act as precursors to later spatial intelligence but also predict math achievement during childhood.
It is now clear that milk has multiple functions; it provides the most appropriate nutrition for growth of the newborn, it delivers a range of bioactives with the potential to stimulate development of the young, it has the capacity to remodel the mammary gland (stimulate growth or signal cell death) and finally milk can provide protection from infection and inflammation when the mammary gland is susceptible to these challenges. There is increasing evidence to support studies using an Australian marsupial, the tammar wallaby (Macropus eugenii), as an interesting and unique model to study milk bioactives. Reproduction in the tammar wallaby is characterized by a short gestation, birth of immature young and a long lactation. All the major milk constituents change substantially and progressively during lactation and these changes have been shown to regulate growth and development of the tammar pouch young and to have roles in mammary gland biology. This review will focus on recent reports examining the control of lactation in the tammar wallaby and the timed delivery of milk bioactivity.
Macroautophagy, hereafter referred to as autophagy, is a catabolic process that results in the lysosomal degradation of cytoplasmic contents ranging from abnormal proteins to damaged cell organelles. It is activated  under diverse conditions, including nutrient deprivation and hypoxia. During autophagy, members of the core autophagy-related (ATG) family of proteins mediate membrane rearrangements, which lead to the engulfment and degradation of cytoplasmic cargo. Recently, the nuclear regulation of autophagy, especially by transcription factors and histone modifiers, has gained increased attention. These factors are not only involved in rapid responses to autophagic stimuli, but also regulate the long-term outcome of autophagy. Now there are more than 20 transcription factors that have been shown to be linked to the autophagic process. However, their interplay and timing appear enigmatic as several have been individually shown to act as major regulators of autophagy. This Cell Science at a Glance article and the accompanying poster highlights the main cellular regulators of transcription involved in mammalian autophagy and their target genes.
BubR1 is a key component of the spindle assembly checkpoint (SAC). Mutations that reduce BubR1 abundance cause aneuploidization and tumorigenesis in humans and mice, whereas BubR1 overexpression protects against these. However, how supranormal BubR1 expression exerts these beneficial physiological impacts is poorly understood. Here, we used Bub1b mutant transgenic mice to explore the role of the amino-terminal (BubR1(N)) and internal (BubR1(I)) Cdc20-binding domains of BubR1 in preventing aneuploidy and safeguarding against cancer. BubR1(N) was necessary, but not sufficient to protect against aneuploidy and cancer. In contrast, BubR1 lacking the internal Cdc20-binding domain provided protection against both, which coincided with improved microtubule-kinetochore attachment error correction and SAC activity. Maximal SAC reinforcement occurred when both the Phe- and D-box of BubR1(I) were disrupted. Thus, while under- or overexpression of most mitotic regulators impairs chromosome segregation fidelity, certain manipulations of BubR1 can positively impact this process and therefore be therapeutically exploited.
The illegal wildlife trade may increase the risk of infectious disease transmission, and
 it may not only cause disease outbreaks in humans but also threaten livestock, native wild populations, and ecosystems' health. Bird species may act as carriers in the transmission of enteric pathogens. However, epidemiological studies on zoonotic bacteria in wild birds are rare in Brazil. From March 2011 to March 2012, we investigated the frequency of Enterobacteriaceae in cloacal swab samples from 109 birds of the passerine and Psittacidae families. These birds were recovered from illegal trade in Rio de Janeiro, Brazil, and sent to a rehabilitation center. Gram-negative bacteria were isolated from 86 wild birds (78.9%). A mean (±SD) of 1.68 (±1.30) different bacterial species were isolated per bird, with a maximum of five bacterial species from three bird species. The most frequently isolated bacteria were Escherichia coli, followed by Enterobacter spp., Klebsiella pneumoniae and other enteric bacteria. Salmonella ser. Typhimurium was isolated from a Temminck's seedeater (Sporophila falcirostris), and two Salmonella ser. Panama were isolated from two specimens of chestnut-capped blackbird (Chrysomus ruficapillus). Of the 70 selected bacterial isolates, 60 exhibited antibiotic resistance. The resistance patterns varied from one to nine of the antibiotics tested. Resistance to ceftiofur was the most prevalent, followed by ampicillin and ceftriaxone. The dissemination potential of resistant strains in situations typically seen in the management of captive birds may become a problem for the conservation of natural bird populations and for public health.
In line with our previous studies, we have developed through a rational design approach novel morpholine and benzoxa(or thia)zine lead compounds that modulate a multiplicity of targets against atherosclerosis. We have evaluated the most promising compounds for their efficiency to a) interact and scavenge free radicals, b) inhibit the metal ion (Cu2+)-induced LDL oxidation c) act intracellularly as antioxidants in THP- 1 monocytes from a leukemic patient and d) inhibit the pro-inflammatory enzymes cycloxygenase-1 (COX-1) and -2 (COX-2) in vitro. Furthermore, two representative compounds were tested for their potential to decrease lipidemic parameters (TC, LDL and TG) in hyperlipidemic mice. Most derivatives indicated a remarkable antioxidant activity, while at the same time exhibited a significant in vitro anti-inflammatory activity, inhibiting COX-1 or/and COX-2 activity at 20 μΜ. Furthermore, after their long-term administration, compounds 6 and 8 afforded a considerable activity in a chronic experimental animal model of hyperlipidemia (after high fat diet administration). The multifunctional pharmacological profile exhibited by the compounds of this study renders them interesting lead compounds for the development of novel agents against atherosclerosis.
Molecularly targeted anticancer therapy involves the use of drugs or other substances affecting specific molecular targets that play a part in the development, progression and spread of a given neoplasm. By contrast, the majority of classical chemotherapeutics act on all rapidly proliferating cells, both healthy and cancerous ones. Target anticancer drugs are designed to achieve a particular aim and they usually act cytostatically, not cytotoxically like classical chemotherapeutics. At present, more than 300 biological molecular targets have been identified. The proteins involved in cellular metabolism include (among others) receptor proteins, signal transduction proteins, mRNA thread matrix synthesis proteins participating in neoplastic transformation, cell cycle control proteins, functional and structural proteins. The receptor proteins that are targeted by currently used anticancer drugs comprise the epithelial growth factor receptor (EGFR), platelet-derived growth factor receptor (PDGFR) and vascular endothelial growth factor receptor(VEGFR). Target anticancer drugs may affect extracellular receptor domains (antibodies) or intracellular receptor domains (tyrosine kinase inhibitors). The blocking of the mRNA thread containing information about the structure of oncogenes (signal transduction proteins) is another molecular target of anticancer drugs. That type of treatment, referred to as antisense therapy, is in clinical trials. When the synthesis of genetic material is disturbed, in most cases the passage to the next cycle phase is blocked. The key proteins responsible for the blockage are cyclines and cycline-dependent kinases (CDK). Clinical trials are focused on natural and synthetic substances capable of blocking various CDKs. The paper discusses the molecular targets and chemical structure of target anticancer drugs that have been approved for and currently applied in antineoplastic therapy together with indications and contraindications for their application.
Prostate cancer (PC) is one of the most common solid tumors in men. However, the molecular mechanism of PC remains unclear. Numerous studies have demonstrated that long noncoding RNA (lncRNA) can act as microRNA (miRNA) sponge, one type of competing endogenous RNAs (ceRNAs), which offers a novel viewpoint to elucidate the mechanisms of PC. Here, we proposed an integrative systems biology approach to infer the gain and loss of ceRNAs in PC. First, we re-annotated exon microarray data to obtain lncRNA expression profiles of PC. Second, by integrating mRNA and miRNA expression, as well as miRNA targets, we constructed lncRNA-miRNA-mRNA ceRNA networks in cancer and normal samples. The lncRNAs in these two ceRNA networks tended to have a longer transcript length and cover more exons than the lncRNAs not involved in ceRNA networks. Next, we further extracted the gain and loss ceRNA networks in PC. We found that the gain ceRNAs in PC participated in cell cycle, and the loss ceRNAs in PC were associated with metabolism. We also identified potential prognostic ceRNA pairs such as MALAT1-EGR2 and MEG3-AQP3. Finally, we inferred a novel mechanism of known drugs, such as cisplatin, for the treatment of PC through gain and loss ceRNA networks. The potential drugs such as 1,2,6-tri-O-galloyl-beta-D-glucopyranose (TGGP) could modulate lncRNA-mRNA competing relationships, which may uncover new strategy for treating PC. In summary, we systematically investigated the gain and loss of ceRNAs in PC, which may prove useful for identifying potential biomarkers and therapeutics for PC.
In this paper, I describe dividing practices in making up a specific medical-legal category-the revolving door patient-to identify, label, and direct the actions of particular people living with mental illness. The revolving door patient was a category that had been spoken of for some time, but became a formal legal subject with the introduction of the Alberta Mental Health Act 2010 and Community Treatment Orders (CTOs). I demonstrate how a rationale of control over unpredictable and dangerous individuals was primary in creating this new category, and that the characterization of the revolving door patient required a disciplinary technology to reduce danger. I argue that the CTO is a medical-legal technology that solves the problem of governing a subject in order to produce a patient that manages mental illness. I conclude by reflecting on how the narrative of the revolving door patient, and of mental illness more broadly, has implications for personal identity and tensions between care and control. Dans cet article, je décris comment des 'pratiques divisées' ont créé une catégorie spécifique médico-légale - le « revolving door patient » - afin d'identifier, d'étiqueter et de contrôler les comportements de certains individus vivants avec une maladie mentale. Le «revolving door patient», une catégorie dont on avait parlé depuis un certain temps, est devenu un sujet juridique formel par l'introduction de la loi de la santé mentale de l'Alberta 2010 et de l'Ordre de Traitement Communautaire (OCT). Je démontre comment une logique de contrôle sur les individus imprévisibles et dangereux eu un rôle prépondérant lors de la création de cette catégorie et que la caractérisation du «revolving door patient», entant que telle, a nécessité une technologie disciplinaire pour réduire le danger social. Je soutiens que le OTC est une technologie médico-légale qui résout le problème de contrôle d'un sujet en produisant un patient qui gère une maladie mentale. Je conclus en démontrant de quelle façon le «revolving door patient», et la maladie mentale en général, a des répercussions sur l'identité personnelle et produisent des tensions entre les soins et le contrôle.
We conducted a systematic review and meta-analysis to investigate the clinical values, including clinicopathology, prognosis, and diagnosis of different long non-coding RNAs (lncRNAs) in renal cell carcinoma (RCC). A total of 14 eligible studies, including 10 on clinicopathological features, 11 on prognosis, and 3 on diagnosis were identified. Results revealed that metastasis-associated lung adenocarcinoma transcript 1(MALAT1) expression was associated with tumor stage (odds ratio [OR], 3.46; 95% confidence interval [CI], 1.63-7.36; p=0.001). The high expression of MALAT1 could be considered a biomarker of the early detection of lymph node metastasis and predictor of poor survival in RCC patients, who likely manifested short overall survival (OS; hazard ratio [HR], 2.97; 95% CI, 1.68-5.28; p<0.001). For diagnostic value, the pooled result showed that lncRNA maintained a sensitivity of 0.89 and specificity of 0.91 in RCC diagnosis, The area under the curve of 0.94 (95% CI, 0.92-0.96) for lncRNA in RCC diagnosis also indicated a significant advantage over other biomarkers. Our systematic review and meta-analysis demonstrated that lncRNAs could be considered biomarkers to detect lymph node metastasis and distant metastasis in early stages. LncRNAs
 could function as potential prognostic markers in RCC. LncRNAs could also display high accuracy for RCC diagnosis.
Endometrial cancers expressing estrogen and progesterone receptors respond to hormonal therapy. The disappearance of steroid hormone receptor expression is common in patients with recurrent disease, ultimately hampering the clinical utility of hormonal therapy. Here, we demonstrate for the first time that nucleophosmin (NPM1/B23) suppression can restore the expression of estrogen receptor α (ESR1/ERα) in endometrial cancer cells. Mechanistically, B23 and activator protein-2γ (TFAP2C/AP2γ) form a complex that acts as a transcriptional repressor of ERα. Our results indicate that B23 or AP2γ knockdown can restore ERα levels and activate ERα-regulated genes (e.g., cathepsin D, EBAG9, and TFF1/pS2). Moreover, AP2γ knockdown in a xenograft model sensitizes endometrial cancer cells to megesterol acetate through the upregulation of ERα expression. An increased immunohistochemical expression of AP2γ is an adverse prognostic factor in endometrial cancer. In summary, B23 and AP2γ may act in combination to suppress ERα expression in endometrial cancer cells. The inhibition of B23 or AP2γ can restore ERα expression and can serve as a potential strategy for sensitizing hormone-refractory endometrial cancers to endocrine therapy.
Acquired aortopulmonary fistulation is a rare condition in humans. It usually results as a late complication of a true or pseudoaneurysm of the thoracic aorta. It is most commonly associated with trauma or surgery, less commonly with atherosclerosis, inflammation, hypertension or Marfan's syndrome. Aortopulmonary fistulation is also seen as a rare complication of acute aortic dissection. On rare occasions, acquired aortopulmonary fistulation is reported in aged patients without any of the above mentioned triggering factors. Thus, these cases should be considered as idiopathic aortopulmonary fistulation. Clearly, the pathogenesis of this condition is not yet completely understood. Friesian horses are highly inbred and are affected by several genetic conditions. Rupture of the thoracic aorta has a relatively high prevalence in Friesian horses and is often characterized by the formation of a pseudoaneurysm with subsequent fistulation into the pulmonary artery. Affected animals may survive for several weeks to months.
Here we performed vascular casting in three affected Friesian horses. In all three cases, an aortic rupture at the caudoventral side of the aorta was connected with a rupture of the main pulmonary artery just proximal to its bifurcation.
Affected Friesians show a consistent location and configuration of the aortic rupture site, very similar to the human condition and therefore could act as a spontaneous model to study this disease.
After fertilization, rapid changes of the Caenorhabditis elegans cytoskeleton occur in the transition from meiosis to mitosis, requiring precise regulation. The MEI-1/MEI-2 katanin microtubule-severing complex is essential for meiotic spindle formation but must be quickly inactivated to allow for proper formation of the mitotic spindle. MEI-1/MEI-2 inactivation is dependent on multiple redundant pathways. The primary pathway employs the MEL-26 substrate adaptor for the CUL-3/cullin-based E3 ubiquitin ligase, which targets MEI-1 for proteosomal degradation. Here, we used quantitative antibody staining to measure MEI-1 levels to determine how other genes implicated in MEI-1 regulation act relative to CUL-3/MEL-26 The anaphase-promoting complex/cyclosome, APC/C, the DYRK (Dual-specificity tyrosine-regulated kinase), MBK-2, and the CUL-2-based E3 ubiquitin ligase act together to degrade MEI-1, in parallel to MEL-26/CUL-3 CUL-2 is known to keep MEL-26 low during meiosis, so CUL-2 apparently changes its target from MEL-26 in meiosis to MEI-1 in mitosis. RFL-1, an activator of cullin E3 ubiquitin ligases, activates CUL-2 but not CUL-3 for MEI-1 elimination. HECD-1 (HECT/Homologous to the E6AP carboxyl terminus domain) E3 ligase acts as a MEI-1 activator in meiosis but functions as an inhibitor during mitosis, without affecting levels of MEI-1 or MEI-2 Our results highlight the multiple layers of MEI-1 regulation that are required during the switch from the meiotic to mitotic modes of cell division.
The malaria situation in India is complex as a result of diverse socio-environmental conditions. India contributes a substantial burden of malaria outside sub-Saharan Africa, with the third highest Plasmodium vivax prevalence in the world. Successful malaria control in India is likely to enhance malaria elimination efforts in the region. Despite modest gains, there are many challenges for malaria elimination in India, including: varied patterns of malaria transmission in different parts of the country demanding area-specific control measures; intense malaria transmission fuelled by favourable climatic and environment factors; varying degrees of insecticide resistance of vectors; antimalarial drug resistance; a weak surveillance system; and poor national coordination of state programmes. Prevention and protection against malaria are low as a result of a weak health-care system, as well as financial and socioeconomic constraints. Additionally, the open borders of India provide a potential route of entry for artesunate-resistant parasites from southeast Asia. This situation calls for urgent dialogue around tackling malaria across borders-between India's states and neighbouring countries-through sharing of information and coordinated control and preventive measures, if we are to achieve the aim of malaria elimination in the region.
Treat-to-target is the recommended strategy for the management of rheumatoid arthritis (RA) and involves regular assessment of disease activity using validated measures and subsequent adjustment of medical therapy if patients are not in remission or low disease activity. Recommendations published in 2012 detailed the preferred disease activity measures but there have been few publications on implementation of disease activity measures in a real-world clinic setting.
Plan-Do-Study-Act (PDSA) methodology was used over two cycles with a goal of increasing provider measurement of disease activity during all RA patient visits. In PDSA cycle 1, we implemented a paper-based form to help providers assess disease activity in RA patients. PDSA cycle 2 included the creation of separate patient and physician forms for collection of information, identification of patients prior to their clinic visit and incorporation of medical assistants into the workflow.
The first PDSA cycle improved the number of RA patients with documented disease activity measures from 24 % over a 4-week period, to an average of 44 % over an 8-week period. The second PDSA cycle showed a sustained and dramatic improvement, with 85 % of patients having a disease activity measure recorded over a 27-week period.
Implementation of disease activity measurement in a typical academic rheumatology clinic can be achieved by standardizing workflow using a simple paper form.
The plants are always subjected to various environmental stress, because of plant sessile growth. qRT-PCR is a sensitive and reliable technology, and the normalization of target gene expression with suitable reference genes is very important for obtaining accurate data. Halostachys caspica is an extremely salt-tolerant halophyte belonging to Chenopodiaceae and a good candidate to explore the stress-physiological and molecular mechanism. To get truly the expression profiles of coding genes and miRNAs in H. caspica in response to salt and drought stress using qRT-PCR, suitable reference genes need to be confirmed. In this study, 10 candidate genes including ACT, UBC10, UBC13, TUB2, TUB3, EF1α, 5S rRNA, tRNA, U6 and miR1436 from H. caspica are chosen, and among them, the former nine are commonly used as internal control genes, and miR1436 with high sequence copies is no significant difference expression in high salinity-treated and untreated small RNA libraries of this species. The three softwares are used to analyze expression stability. The results showed that EF1α and TUB3 were the most stable under salt and drought stress, respectively, and UBC10 was the most constant aross all the samples with the both stressed combination. This work will benefit deep studies on abiotic tolerance in H. caspica.
The aim of this study was to examine changes in the psychosocial backgrounds and clinical features of patients with psychiatric disorders associated with new psychoactive substances (NPS) between 2012 and 2014 in Japan.
Clinical features of patients with NPS-related disorders were compared using data from the Nationwide Mental Hospital Surveys on Drug-related Psychiatric Disorders undertaken in 2012 and 2014. NPS patients were compared with a control group comprising patients with methamphetamine-related disorders, using data from the same period.
In NPS patients, changes were observed in the following three areas between 2012 and 2014: (i) a decrease in the number of employed patients; (ii) an increase in the ratio of patients diagnosed with dependence syndrome; and (iii) a decrease in the ratio of patients diagnosed with psychotic disorder. In methamphetamine patients, only one change was observed: protective custody or arrest record relating to the Pharmaceutical Affairs Act.
This study suggests that the number of patients dependent upon NPS, and those exhibiting social dysfunction, increased between 2012 and 2014. There is a need to focus future measures against NPS dependence: not only on stopping the supply of drugs, but also on reducing the demand for them.
Secondary data analysis from the cross-sectional survey of the Swiss Spinal Cord Injury Cohort Study.
To explore associations with physical activity (PA) levels in people
 with spinal cord injury (SCI) with the specific aim to identify aspects that potentially explain being physically active (PHYS-ACT) and the achievement of the World Health Organization recommendations on PA.
Community sample (n=485).
Participants who completely answered four items of the Physical Activity Scale for Individuals with Physical Disabilities were included. Two outcome measures were defined: (1) being PHYS-ACT vs being completely inactive and (2) achieving WHO recommendations on PA (ACH-WHO-REC) (at least 2.5 h per week of at least moderate intensity) vs performing less. Independent variables were selected from the original questionnaire by applying the ICF framework. Multivariate logistic regression analyses were conducted.
In the participants (aged 52.8±14.8; 73.6% male) older age decreased, but being a manual wheelchair user increased the odds of achieving both outcomes. Social support and self-efficacy increased the odds of being PHYS-ACT. Use of an intermittent catheter increased, whereas dependency in self-care mobility and coping with emotions decreased the odds for ACH-WHO-REC. Experiencing hindrances due to accessibility is associated with increased odds for ACH-WHO-REC.
Being PHYS-ACT at all and achieving the WHO recommendations on PA are associated with different aspects. Applying the ICF framework contributes to a comprehensive understanding of PA behavior in people with SCI, which can tailor the development of interventions. Longitudinal studies should be initiated to test these associations for causal relationships.Spinal Cord advance online publication, 16 August 2016; doi:10.1038/sc.2016.126.
The Hippo signalling pathway has recently emerged as an important regulator of cell apoptosis and proliferation with significant implications in human diseases. In mammals, the pathway contains the core kinases MST1/2, which phosphorylate and activate LATS1/2 kinases. The pro-apoptotic function of the MST/LATS signalling axis was previously linked to the Akt and ERK MAPK pathways, demonstrating that the Hippo pathway does not act alone but crosstalks with other signalling pathways to coordinate network dynamics and cellular outcomes. These crosstalks were characterised by a multitude of complex regulatory mechanisms involving competitive protein-protein interactions and phosphorylation mediated feedback loops. However, how these different mechanisms interplay in different cellular contexts to drive the context-specific network dynamics of Hippo-ERK signalling remains elusive. Using mathematical modelling and computational analysis, we uncovered that the Hippo-ERK network can generate highly diverse dynamical profiles that can be clustered into distinct dose-response patterns. For each pattern, we offered mechanistic explanation that defines when and how the observed phenomenon can arise. We demonstrated that Akt displays opposing, dose-dependent functions towards ERK, which are mediated by the balance between the Raf-1/MST2 protein interaction module and the LATS1 mediated feedback regulation. Moreover, Ras displays a multi-functional role and drives biphasic responses of both MST2 and ERK activities; which are critically governed by the competitive protein interaction between MST2 and Raf-1. Our study represents the first in-depth and systematic analysis of the Hippo-ERK network dynamics and provides a concrete foundation for future studies.
Clinical genetic testing for Mendelian disorders is standard of care in many cases; however, it is less clear to what extent and in which situations clinical genetic testing may improve preventive efforts, diagnosis and/or prognosis of complex disease. One challenge is that much of the reported research relies on tag single nucleotide polymorphisms (SNPs) to act as proxies for assumed underlying functional variants that are not yet known. Here we use coronary artery disease and melanoma as case studies to evaluate how well reported genetic risk variants tag surrounding variants across population samples in the 1000 Genomes Project Phase 3 data. We performed a simulation study where we randomly assigned a "functional" variant and evaluated how often this simulated functional variant was correctly tagged in diverse population samples. Our results indicate a relatively large error rate when generalizing increased genetic risk of complex disease across diverse population samples, even when generalizing within geographic regions. Our results further highlight the importance of including diverse populations in genome-wide association studies. Future work focused on identifying functional variants will eliminate the need for tag SNPs; however, until functional variants are known, caution should be used in the interpretation of genetic risk for complex disease using tag SNPs.
We recently demonstrated that the aquaglyceroporins (AQGPs) could act as potent transporters for orthosilicic acid (H4SiO4). Although interesting, this finding raised the question of whether water and H4SiO4, the transportable form of Si, permeate AQGPs by interacting with the same region of the pore, especially in view of the difference in molecular radius between the two substrates. Here, our goal was to identify residues that endow the AQGPs with the ability to facilitate Si diffusion by examining the transport characteristics of mutants in which residues were interchanged between a water-permeable but Si-impermeable channel (aquaporin 1 [AQP1]) and a Si-permeable but water-impermeable channel (AQP10). Our results indicate that the composition of the arginine filter (XX/R), known to include three residues that play an important role in water transport, may also be involved in Si selectivity. Interchanging the identities of the nonarginine residues within this filter causes Si transport to increase by approximately sevenfold in AQP1 and to decrease by approximately threefold in AQP10, whereas water transport and channel expression remain unaffected. Our results further indicate that two additional residues in the AQP arginine filter may be involved in substrate selectivity: replacing one of the residues has a profound effect on water permeability, and replacing the other has a profound effect on Si permeability. This study has thus led to the identification of residues that could play a key role in Si transport by the AQGPs and shown that substrate selectivity is likely ensured by more than one checkpoint within or near the pore.
Coherent network oscillations (GDPs), generated in the immature hippocampus by the synergistic action of GABA and glutamate, both depolarizing and excitatory, play a key role in the construction of neuronal circuits. In particular, GDPs-associated calcium transients act as coincident detectors for enhancing synaptic efficacy at emerging GABAergic and glutamatergic synapses. Here, we show that, immediately after birth, in the CA3 hippocampal region of the BTBR T+tf/J mouse, an animal model of idiopathic autism, GDPs are severely impaired. This effect was associated with an increased GABAergic neurotransmission and a reduced neuronal excitability. In spite its depolarizing action on CA3 pyramidal cells (in single channel experiments EGABA was positive to Em), GABA exerted at the network level an inhibitory effect as demonstrated by isoguvacine-induced reduction of neuronal firing. We implemented a computational model in which experimental findings could be interpreted as the result of two competing effects: a reduction of the intrinsic excitability of CA3 principal cells and a reduction of the shunting activity in GABAergic interneurons projecting to principal cells. It is therefore likely that premature changes in neuronal excitability within selective hippocampal circuits of BTBR mice lead to GDPs dysfunction and behavioral deficits reminiscent of those found in autistic patients.
A photodetector with a high spectrum selectivity and enhanced responsivity has been realized in the ZnO NPs coated Au/ZnO/Au structure. In this structure, the ZnO NPs act as the "filter" that filtrates out the short-wavelength photons to ensure the high spectrum selectivity of the photodetector, whereas on the other hand they act as the "scatterer" to scatter incident light in order to increase the absorption of the ZnO film and consequently enhance the responsivity of the photodetector. In this way, a photodetector with a response width of only 10 nm has been obtained, and the responsivity of the photodetector is 0.052 A W(-1) at 3 V at the wavelength of 376 nm, which is higher than that of the bare Au/ZnO/Au structured photodetector (0.028 A W(-1)). The results reported in this paper may provide a facile route to a highly spectrum-selective photodetector without performance degradation.
Knowledge about the pathophysiology of psoriasis has evolved substantially in recent years, since the identification of the T helper 17 (Th17) cells. Cytokines produced by these cells appear to play major roles in psoriatic inflammation. The cytokine interleukin (IL)-23 appears to promote regulatory T cells to differentiate into Th17 cells. Available and investigational therapies act on targets within these pathways.
Recently, we identified the primo-vascular system (PVS), a novel vascular network, in rat subcutaneous tissues. Little is known about the subcutaneous PVS (sc-PVS). Here, we examined the ultrastructure of the sc-PVS in the hypodermis at the rat abdominal midline by electron microscopy. On the surface of sc-PVS, we observed three types of cells: microcells (5-6 μm), large elliptical cells (>20 μm), and erythrocyte (3-4 μm). The inside of the sc-PVS was filled with numerous cells, which can be classified into three major groups: leucocytes, mast cells, and erythrocytes. The dense leucocytes and mast cells were easily noticed. The extracellular matrix of the sc-PVS was mainly composed of extensive
 fibers (79 ± 6.5 nm) tightly covered by micro- (0.5-1 μm) and nanoparticles (10-100 nm). In conclusion, the ultrastructural features, such as the resident cells on and in the sc-PVS and fiber meshwork covered by particles, indicate that sc-PVS might act as a circulatory channel for the flow and delivery of numerous cells and particles. Our findings will help understand the nature of various sc-PVS beneath-the-skin layers and how they relate to acupuncture meridians.
Plasma aldosterone is elevated in type 2 diabetes and obesity in experimental and clinical studies and can act to inhibit both glucose-stimulated insulin secretion by the β-cell and insulin signaling. Currently mineralocorticoid receptor antagonism is the best characterized treatment to ameliorate aldosterone-mediated effects. A second alternative is inhibition of aldosterone synthase, an approach with protective effects on end-organ damage in heart or kidney in animal models. The effect of aldosterone synthase inhibition on metabolic parameters in type 2 diabetes is not known. Therefore, male Zucker diabetic fatty (ZDF) rats were treated for 11 weeks with the aldosterone synthase inhibitor FAD286, beginning at 7 weeks of age. Results were compared with the mineralocorticoid receptor antagonist eplerenone. Plasma aldosterone was abolished by FAD286 and elevated more than 9-fold by eplerenone. The area under the curve calculated from an oral glucose tolerance test (OGTT) was lower and overall insulin response during OGTT was increased by FAD286. In contrast, eplerenone elevated blood glucose levels and blunted insulin secretion during the OGTT. Fasting glucose was lowered and fasting insulin was increased by FAD286 in the prediabetic state. Glycated hemoglobin was lowered by FAD286, whereas eplerenone showed no effect. We conclude that aldosterone synthase inhibition, in contrast to mineralocorticoid receptor antagonism, has the potential for beneficial effects on metabolic parameters in type 2 diabetes.
Second-generation antipsychotics occupy dopamine D2 receptors and act as antagonists or partial agonists at these receptors. While these drugs alleviate positive symptoms in patients with schizophrenia, they are less effective for treating cognitive deficits and negative symptoms. Dopamine D3 receptors are highly expressed in areas of the brain thought to play a role in the regulation of motivation and reward-related behavior. Consequently, the dopamine D3 receptor has become a target for treating negative symptoms in combination with D2 antagonism to treat positive symptoms in patients with schizophrenia.
The purpose of this study was to determine the cariprazine receptor occupancies in brain for D2 and D3 receptors in patients with schizophrenia.
Using [(11)C]-(+)-PHNO as a radioligand, positron emission tomography (PET) scans were performed in eight patients at baseline and postdose on days 1, 4, and 15. Plasma and cerebrospinal fluid (CSF) samples were analyzed for cariprazine concentrations.
A monotonic dose-occupancy relationship was observed for both receptor types. After 2 weeks of treatment, near complete (∼100 %) occupancies were observed for both receptors at a dose of 12 mg/day. At the lowest cariprazine dose (1 mg/day), mean D3 and D2 receptor occupancies were 76 and 45 %, respectively, suggesting selectivity for D3 over D2 receptors at low doses. An exposure-response analysis found a ∼3-fold difference in EC50 (D3 = 3.84 nM and D2 = 13.03 nM) in plasma after 2 weeks of dosing.
This PET imaging study in patients with schizophrenia demonstrated that cariprazine is a D3-preferring dual D3/D2 receptor partial agonist.
Bcl-xL, a member of the Bcl-2 family of proteins, remains distributed over the cytosol and the mitochondrial membrane, maintaining a balance between apoptosis and the survival of the cell. Passage to the membrane is essential for its biological functions (e.g. to antagonize pro-apoptotic proteins of the Bcl2 family), which is known to be initiated by the insertion of the C-terminal segment into the membrane. This tail, composed of ∼24 residues, is reported to act as a pseudo-inhibitor of the protein itself, adapting a helical conformation. It gets released from the confinement when Bcl-xL approaches the membrane. This article reports the events associated with the insertion of the helical tail into an explicitly modeled all-atom membrane, which reveals a partial unfolding to refolding cycle of the peptide, correlating with the early insertion, to a fully inserted state. The polar interactions have been found to have a dominant role in steering the peptide towards the membrane at the desired orientation. The landscape of the potential of mean force (PMF) is consistent with the proposed mechanism. Molecular dynamics further brings the insight that the peptide insertion is associated with the encapsulation of a thin water layer around the peptide throughout the course of insertion, which motivates the protein to refold once the insertion is complete.
A previous study has revealed that miR-29c functions as a tumor suppressor in hepatocellular carcinoma (HCC), but the clinical significance and prognostic value of miR-29c in HCC have not been investigated. Paired human HCC tissues and adjacent noncancerous tissues were obtained from 91 patients, between 2008 to 2014. Quantitative real-time PCR (qRT-PCR) was used to analyze miR-29c expression. Kaplan-Meier survival plots and log-rank tests were used to assess differences in the overall survival of different subgroups of HCC patients. It was observed that miR-29c expression was remarkably decreased in HCC tissues relative to that in normal hepatic tissues (P < 0.001). The low miR-29c level was significantly associated with histologic grade (P = 0.001), microvascular invasion (P = 0.005), and tumor stage (P < 0.001). Kaplan-Meier analysis showed that decreased miR-29c expression correlated with shorter overall survival (P = 0.002). Multivariate Cox regression analysis showed that decreased miR-29c expression (hazard ratio = 2.19, 95%CI = 1.361-6.779, P = 0.025) was independently associated with poor survival in HCC. Our findings demonstrate that miR-29c expression is significantly downregulated in HCC patients and that miR-29c can act as an independent predictor of unfavorable clinical outcome.
We present here the results of a technological and typological analysis of the Acheulian and early Middle Paleolithic assemblages from Torre in Pietra (Latium, Italy) together with comparisons with the Acheulian small tools of Castel di Guido. The assemblages were never chronometrically dated before. We have now 40Ar/39Ar dates and ESR-U-series dates, within a geomorphological framework, which support correlations to marine isotope stages. The Acheulian (previously correlated to MIS 9) is now dated to MIS 10 while the Middle Paleolithic is dated to MIS 7. Lithic analyses are preceded by taphonomic evaluations. The Levallois method of the Middle Paleolithic assemblage is an innovation characterized by the production of thin flake blanks without cortex. In contrast, the small tool blanks of the Acheulian were either pebbles or thick flakes with some cortex. They provided a relatively easy manual prehension. The choice of Levallois thin flake blanks in the Middle Paleolithic assemblage suggest that the new technology is most likely related to the emergence of hafting. Accordingly, the oldest direct evidence of hafting technology is from the site of Campitello Quarry in Tuscany (Central Italy) where birch-bark tar, found on the proximal part of two flint flakes, is dated to the end of MIS 7. Nevertheless, a peculiar feature of the Middle Paleolithic at Torre in Pietra is the continuous presence of small tool blanks on pebbles and cores and on thick flake albeit at a much lower frequency than in the older Acheulian industries. The adoption of the new technology is thus characterized by innovation combined with a degree of stability. The persistence of these habits in spite of the introduction of an innovative technique underlies the importance of cultural transmission and conformity in the behavior of Neandertals.
Voltage-gated calcium channels are key regulators of brain function, and their dysfunction has been associated with multiple conditions and neurodegenerative diseases because they couple membrane depolarization to the influx of calcium-and other processes such as gene expression-in excitable cells. L-type calcium channels, one of the three major classes and probably the best characterized of the voltage-gated calcium channels, act as an essential calcium binding proteins with a significant biological relevance. It is well known that estradiol can activate rapidly brain signaling pathways and modulatory/regulatory proteins through non-genomic (or non-transcriptional) mechanisms, which lead to an increase of intracellular calcium that activate multiple kinases and signaling cascades, in the same way as L-type calcium channels responses. In this context, estrogens-L-type calcium channels signaling raises intracellular calcium levels and activates the same signaling cascades in the brain probably through estrogen receptor-independent modulatory mechanisms. In this review, we discuss the available literature on this area, which seems to suggest that estradiol exerts dual effects/modulation on these channels in a concentration-dependent manner (as a potentiator of these channels in pM concentrations and as an inhibitor in nM concentrations). Indeed, estradiol may orchestrate multiple neurotrophic responses, which open a new avenue for the development of novel estrogen-based therapies to alleviate different neuropathologies. We also highlight that it is essential to determine through computational and/or experimental approaches the interaction between estradiol and L-type calcium channels to assist
 these developments, which is an interesting area of research that deserves a closer look in future biomedical research.
Genome-wide association studies (GWAS) have identified a region at chromosome 1p21.3, containing the microRNA MIR137, to be among the most significant associations for schizophrenia. However, the mechanism by which genetic variation at this locus increases risk of schizophrenia is unknown. Identifying key regulatory regions around MIR137 is crucial to understanding the potential role of this gene in the aetiology of psychiatric disorders. Through alignment of vertebrate genomes, we identified seven non-coding regions at the MIR137 locus with conservation comparable to exons (>70 %). Bioinformatic analysis using the Psychiatric Genomics Consortium GWAS dataset for schizophrenia showed five of the ECRs to have genome-wide significant SNPs in or adjacent to their sequence. Analysis of available datasets on chromatin marks and histone modification data showed that three of the ECRs were predicted to be functional in the human brain, and three in development. In vitro analysis of ECR activity using reporter gene assays showed that all seven of the selected ECRs displayed transcriptional regulatory activity in the SH-SY5Y neuroblastoma cell line. This data suggests a regulatory role in the developing and adult brain for these highly conserved regions at the MIR137 schizophrenia-associated locus and further that these domains could act individually or synergistically to regulate levels of MIR137 expression.
With regard to jurisdiction, the Patients' Rights Act and the Medical Association's professional code of conduct in Germany, correct informed consent in a timely manner has to be assured by the physician. Omissions concerning informed consent may lead to conviction including compensation for damages and for pain and suffering if the patient is able to prove such omissions. Mistakes during treatment or gaps of the informed consent must not to be told to the patient, but facts must be correctly answered.
Superantigens (SAgs) are microbial proteins produced by various microorganisms that elicit excessive and strong stimulation of T cells via an unconventional mechanism. They cause polyclonal activation of T cells in a non-specific manner, by binding to a particular variable-beta (Vβ) chain of T-cell receptor (TCR) and MHC class II molecule, in unprocessed form and outside of peptide-binding cleft, forming a bridge between the antigen presenting cell and the T cell. SAgs are classified into three groups, namely 1) exogenous (soluble proteins and exotoxins secreted by microorganisms), 2) endogenous (transmembrane proteins encoded by viruses which are integrated into the genome) and 3) B-cell SAgs (proteins which stimulate predominantly B cells). The best characterized and mostly studied SAgs are staphylococcal and streptococcal exotoxins, however it is well-known that many other microorganisms also possess SAg activities. Despite the presence of several viruses that cause severe infections in humans, the number of viruses that have proteins identified with SAg property in their pathogenesis, is relatively low. To date, the defined viruses that encoded SAgs are as follows; mouse mammary tumor virus (MMTV) (Marrack, et al. 1991), rabies virus (Lafon, et al. 1992), Epstein-Barr virus (EBV) (Sutkowski, et al. 1996), human endogenous retrovirus (HERV) (Conrad, et al. 1997), human immunodeficiency virus (HIV) (Posnett, et al. 1995; Torres, et al. 1996; Townsley-Fuchs, et al. 1997) and Ebola virus (Leroy, et al. 2011). SAgs were first described in the MMTV, a polymorphic B-type retrovirus that is either contained in the genome as an endogenous provirus (germline transmission) or exogenous infectious virus that transmits vertically via breast milk. Both MMTV forms encode SAgs. The SAg-mediated massive T cell activation is required for the spread of exogenous MMTV from intestines to mammary glands, facilitating the transmission of infectious virus. On the other hand, expression of endogenous SAgs leads to thymic deletion of responding T cells (bearing Vβ6-9+ TCR) due to self-tolerance induction during the fetal life, and protects the host against future exogenous MMTV infections. The SAg of rabies virus is the N protein found in nucleocapsid structure and stimulates Vβ8+TCR-bearing T cells. The SAg-induced polyclonal activation of T cells leads to turn-off the specific immune response, to enhance the immunopathogenesis and facilitates viral transmission from the initial site of infection (the muscle tissue) to the nerve endings. In case of EBV-associated SAg that activates Vβ13+TCR-bearing T cells, it was detected that the SAg activity was not encoded by EBV itself, but instead was due to the transactivation of HERV-K18 by EBV latent membrane proteins, whose env gene encodes the SAg (Sutkowski, et al. 2001). It has been denoted that EBV-induced SAg expression plays a role in the long-term persistence and latency of virus in memory B cells, in the development of autoimmune diseases and in the oncogenesis mechanisms. The proteins which are identified as SAgs of HIV are Nef and gp120. It is believed that, the massive activation of CD4+ T cells (selectively with Vβ-12+, Vβ-5.3+ and Vβ-18+ TCRs) in early stages of infection and clonal deletion, anergy and apoptosis of bystander T cells in the late stages may be due to SAg property of Nef protein, as well as the other mechanisms. However there are some studies indicating that Nef does not act as a SAg (Lapatschek, et al. 2001). HIV gp120 glycoprotein is a B-cell SAg that binds to VH3-expressing B cell receptors and causes polyclonal B cell activation. In addition, binding of gp120 to IgE on the surface of basophiles and mast cells causes activation of those cells, secretion of high level proinflammatory mediators leading to allergic reactions and tissue damage. In a recent study, the depletion (anergy or deletion) of T cell populations bearing Vβ12+, Vβ13+ and Vβ17+ TCR have been shown, in patients infected with Zaire Ebola virus, whatever the clinical outcome (death or recovery), these results also suggest the presence of SAg activity. In this review article, following a brief description of the general characteristics of SAgs, virus-encoded SAgs and their roles in the diseases have been discussed.
The austere setting of the intensive care unit (ICU) can suppress expressions of spirituality.
To describe how family members and clinicians experience and express spirituality during the dying process.
21 bed medical-surgical ICU Methods: Reflecting the care of 70 dying patients, we conducted 208 semi-structured qualitative interviews with 76 family members and 150 clinicians participating in the 3 Wishes Project. Interviews were recorded and transcribed verbatim. Data were analyzed by 3 investigators using qualitative interpretive description.
Participants characterize dying as a spiritual event. Spirituality is an integral part of the life narrative of the patient before, during, and after death. Experiences and expressions of spirituality for patients, families and clinicians during end-of-life care in the ICU are supported by eliciting and implementing wishes in several ways. Eliciting wishes stimulates conversations for people of diverse spiritual orientations to respond to death in personally meaningful ways that facilitate continuity and closure, and ease emotional trauma. Soliciting wishes identifies positive aspirations, which provide comfort in the face of death. The act of soliciting wishes brings clinician humanity to the fore. Wishing makes individual spiritual preferences and practices more accessible. Wishes may be grounded in spiritual goals such as peace, comfort, connections and tributes; they may seek a spiritually-enhanced environment, or represent specific spiritual interventions.
Family members and clinicians consider spirituality an important dimension of end-of-life care. The 3 Wishes Project invites and supports the expression of myriad forms of spirituality during the dying process in the ICU.
Polycystic ovary syndrome (PCOS), a multigenic endocrine disorder, is highly associated with low-grade chronic inflammation, however its etiology remains unclear. In this study, we employed dehydroepiandrosterone (DHEA)-treated mice to reveal the molecular mechanism of inflammation and its correlation with oxidative stress in PCOS patients.
miR-21 and miR-146a expression levels were measured using quantitative real-time polymerase chain reaction (qRT-PCR). DNA strand breakage frequency was measured using the single cell gel electrophoresis (SCGE) assay (comet assay) and micronucleus test (MN). CRP levels were measured by ELISA method and ESR values were measured by means of Micro-Dispette (Fisher No: 02-675-256) tubes according to the manufacturer's instructions. Data were analyzed using one-way ANOVA in SPSS 21.0 software.
Our results showed that miR-21 and miR-146a as inflammation markers were upregulated in the sample group in comparison with control group. Erythrocyte sedimentation rate (ESR) and C- reactive protein (CRP) levels were also increased in mouse models of PCOS (p < 0.000). Micronucleated polychromatic erythrocyte (MNPCE) rates per 1000 polychromatic erythrocyte (PCE) significantly increased in DHEA treated mice (6.22 ± 3.28) in comparison with the controls (2.33 ± 2.23, p < 0.000). Moreover, mean arbitrary unit in DHEA treated animals (277 ± 92) was significantly higher than that in controls (184 ± 76, p = 0.005).
To conclude, increased DNA strand breakage frequency and increased expression levels of miR-21 and miR-146a in DHEA administrated animals suggest that low grade chronic inflammation and oxidative stress can act as the main etiologies of PCOS.
Exon-skipping via synthetic antisense oligonucleotides represents one of the most promising
 potential therapies for Duchenne muscular dystrophy (DMD), yet this approach is highly sequence-specific and thus each oligonucleotide is of benefit to only a subset of patients. The discovery that dystrophin mRNA is subject to translational suppression by the microRNA miR31, and that miR31 is elevated in the muscle of DMD patients, raises the possibility that the same oligonucleotide chemistries employed for exon skipping could be directed toward relieving this translational block. This approach would act synergistically with exon skipping where possible, but by targeting the 3'UTR it would further be of benefit to the many DMD patients who express low levels of in-frame transcript. We here present investigations into the feasibility of combining exon skipping with several different strategies for miR31-modulation, using both in vitro models and the mdx mouse (the classical animal model of DMD), and monitoring effects on dystrophin at the transcriptional and translational level. We show that despite promising results from our cell culture model, our in vivo data failed to demonstrate similarly reproducible enhancement of dystrophin translation, suggesting that miR31-modulation may not be practical under current oligonucleotide approaches. Possible explanations for this disappointing outcome are discussed, along with suggestions for future investigations.
Dbx1 is a homeodomain transcription factor involved in neuronal fate specification belonging to a widely conserved family among bilaterians. In mammals, Dbx1 was proposed to act as a transcriptional repressor by interacting with the Groucho corepressors to allow the specification of neurons involved in essential biological functions such as locomotion or breathing.
Sequence alignments of Dbx1 proteins from different species allowed us to identify two conserved domains related to the Groucho-dependent Engrailed repressor domain (RD), as well as a newly described domain composed of clusterized acidic residues at the C-terminus (Cter) which is present in tetrapods but also several invertebrates. Using a heterologous luciferase assay, we showed that the two putative repressor domains behave as such in a Groucho-dependent manner, whereas the Cter does not bear any intrinsic transcriptional activity. Consistently with in vitro data, we found that both RDs are involved in cell fate specification using in vivo electroporation experiments in the chick spinal cord. Surprisingly, we show that the Cter domain is required for Dbx1 function in vivo, acting as a modulator of its repressive activity and/or imparting specificity.
Our results strongly suggest that the presence of a Cter domain among tetrapods is essential for Dbx1 to regulate neuronal diversity and, in turn, nervous system complexity.
Retrotransposons have generated about 40 % of the human genome. This review examines the strategies the cell has evolved to coexist with these genomic "parasites", focussing on the non-long terminal repeat retrotransposons of humans and mice. Some of the restriction factors for retrotransposition, including the APOBECs, MOV10, RNASEL, SAMHD1, TREX1, and ZAP, also limit replication of retroviruses, including HIV, and are part of the intrinsic immune system of the cell. Many of these proteins act in the cytoplasm to degrade retroelement RNA or inhibit its translation. Some factors act in the nucleus and involve DNA repair enzymes or epigenetic processes of DNA methylation and histone modification. RISC and piRNA pathway proteins protect the germline. Retrotransposon control is relaxed in some cell types, such as neurons in the brain, stem cells, and in certain types of disease and cancer, with implications for human health and disease. This review also considers potential pitfalls in interpreting retrotransposon-related data, as well as issues to consider for future research.
Transition metals such as iron, copper, zinc, or molybdenum are essential nutrients for plants. These elements are involved in almost every biological process, including photosynthesis, tolerance to biotic and abiotic stress, or symbiotic nitrogen fixation. However, plants often grow in soils with limiting metallic oligonutrient bioavailability. Consequently, to ensure the proper metal levels, plants have developed a complex metal uptake and distribution system, that not only involves the plant itself, but also its associated microorganisms. These microorganisms can simply increase metal solubility in soils and making them more accessible to the host plant, as well as induce the plant metal deficiency response, or directly deliver transition elements to cortical cells. Other, instead of providing metals, can act as metal sinks, such as endosymbiotic rhizobia in legume nodules that requires relatively large amounts to carry out nitrogen fixation. In this review, we propose to do an overview of metal transport mechanisms in the plant-microbe system, emphasizing the role of arbuscular mycorrhizal fungi and endosymbiotic rhizobia.
Though antihypertensive drugs have been in use for many decades, the mechanisms by which they act chronically to reduce blood pressure remain unclear. Over long periods, mean arterial blood pressure must match the perfusion pressure necessary for the kidney to achieve its role in eliminating the daily intake of salt and water. It follows that the kidney is the most likely target for the action of most effective antihypertensive agents used chronically in clinical practice today. Here we review the long-term renal actions of antihypertensive agents in human studies and find three different mechanisms of action for the drugs investigated. (i) Selective vasodilatation of the renal afferent arteriole (prazosin, indoramin, clonidine, moxonidine, α-methyldopa, some Ca(++)-channel blockers, angiotensin-receptor blockers, atenolol, metoprolol, bisoprolol, labetolol, hydrochlorothiazide, and furosemide). (ii) Inhibition of tubular solute reabsorption (propranolol, nadolol, oxprenolol, and indapamide). (iii) A combination of these first two mechanisms (amlodipine, nifedipine and ACE-inhibitors). These findings provide insights into the actions of antihypertensive drugs, and challenge misconceptions about the mechanisms underlying the therapeutic efficacy of many of the agents.
While the intention of endurance athletes undertaking short term heat training protocols is to rapidly gain meaningful physical adaption prior to competition in the heat, it is currently unclear whether or not this process also presents an overt, acute challenge to the immune system. The aim of this study was therefore to examine the effects of heat training on both endurance performance and biomarkers associated with inflammatory and immune system responses.
Moderately-actively males (n = 24) were allocated randomly to either HOT (n = 8, 35°C, and 70% RH; NEUTRAL (n = 8, 20°C, and 45% RH); or a non-exercising control group, (CON, n = 8). Over the 18 day study HOT and NEUTRAL performed seven training sessions (40 min cycling at 55 of VO2 max) and all participants completed three heat stress tests (HST) at 35°C and 70% RH. The HST protocol comprised three × sub-maximal intervals followed by a 5 km time trial on a cycle ergometer. Serum samples were collected before and after each HST and analyzed for interleukin-6, immunoglobulin M and lipopolysaccharide.
Both HOT and NEUTRAL groups experienced substantial improvement to 5 km time trial performance (HOT -33 ± 20 s, p = 0.02, NEUTRAL -39 ± 18 s, p = 0.01) but only HOT were faster (-45 ± 25 s, and -12 s ± 7 s, p = 0.01) in HST3 compared to baseline and HST2. Interleukin-6 was elevated after exercise for all groups however there were no significant changes for immunoglobulin M or lipopolysaccharide.
Short-term heat training enhances 5 km cycling time trial performance in moderately-fit subjects by ~6%, similar in magnitude to exercise training in neutral conditions.Three top-up training sessions yielded a further 3% improvement in performance for the HOT group. Furthermore, the heat training did not pose a substantial challenge to the immune system.
The muscle segment homeogenes Msx1 and Msx2 play a major role in tooth and bone formation. Periodontal osteoclast impairment also occurs in Msx2 null mutant mice, which is restored by overexpression of the receptor activator of NF-κB targeted in osteoclast lineage. Here, we investigated the role of Msx2 in dentinogenesis. Experiments were performed on Msx2(-/-) mice and the MDPC-23 odontoblastic cell line. After Msx2 gene silencing, real-time quantitative RT-PCR data showed significant overexpression of Runx2, Bglap, Dspp, and Alpl. Of three inhibitors of Wnt/β-catenin signaling (Dkk1, SostDc1, and Sost/Sclerostin), only Sost was expressed in postnatal teeth and overexpressed in Msx2(-/-) tooth samples. Initial crown dentin formation-primary dentinogenesis-occurred fairly normally in Msx2(-/-) teeth, albeit with distorted cusp patterns. Later stages of tooth development were characterized by a deviation from secondary toward tertiary dentinogenesis with osteodentin formation and impaired dentin deposition leading to limited root elongation. In Msx2(-/-)/receptor activator of NF-κB-transgenic double mutants, the dentin phenotype, notably in the roots, was rescued and sclerostin levels were normalized. These data suggest that Msx2 may act indirectly on dentinogenesis by controlling osteoclast activity and the signaling network related to eruption, supporting and further extending the concept that Msx2 controls formation of mineralized tissues by inhibition of the Wnt/β-catenin pathway; Sost in dentin and Dkk1 in bone, as previously demonstrated.
Primary care access (PCA) for the homeless can prove challenging, especially during periods of economic distress. In the United States, the most recent recession may have presented additional barriers
 to accessing care. Limited safety-net resources traditionally used by the homeless may have also been used by the non-homeless, resulting in delays in seeking treatment for the homeless. Using hospitalizations for ambulatory care sensitivity (ACS) conditions as a proxy measure for PCA, this study investigated the recession's impact on PCA for the homeless and non-homeless in four states. The State Inpatient Databases were used to identify ACS admissions. Findings from this study indicate the recession was a barrier to PCA for homeless people who were uninsured. Ensuring that economically-disadvantaged populations have the ability to obtain insurance coverage is crucial to facilitating PCA. With targeted outreach efforts, the Affordable Care Act provides an opportunity for expanding coverage to the homeless.
For the working rural mother, one key source of support for breastfeeding is the employer. The purpose of this article was to examine workplace barriers and facilitators to breastfeeding in a small rural American community following the passage of the Affordable Care Act in 2010. We used a qualitative research design: semi-structured interviews with major employers and low-income working breastfeeding mothers, and a focus-group with another group of employed and unemployed breastfeeding low-income mothers. While some businesses accommodate breastfeeding mothers, few actively promote breastfeeding. Lack of compliance with the new law, inadequate breastfeeding information for mothers, and lack of support from co-workers and supervisors emerged as the main barriers to successful workplace breastfeeding. To improve workplace breastfeeding support significantly there is need for authentic collaboration among maternal-child and rural health agencies and businesses in creating breastfeeding-tolerant, flexible, and forward-looking work environments that, at a minimum, satisfy the law.
The chaperone-like activity of αA-crystallin has an important role in maintaining lens transparency. Previously we identified residues 70-88 as a chaperone site in αA-crystallin. In this study, we deleted the chaperone site residues to generate αAΔ70-76 and αAΔ70-88 mutants and investigated if there are additional substrate-binding sites in αA-crystallin. Both mutant proteins when expressed in E. coli formed inclusion bodies, and on solubilizing and refolding, they exhibited similar structural properties, with a 2- to 3-fold increase in molar mass compared to the molar mass of wild-type protein. The deletion mutants were less stable than the wild-type αA-crystallin. Functionally αAΔ70-88 was completely inactive as a chaperone, while αAΔ70-76 demonstrated a 40-50% reduction in anti-aggregation activity against alcohol dehydrogenase (ADH). Deletion of residues 70-88 abolished the ADH binding sites in αA-crystallin at physiological temperature. At 45°C, cryptic ADH binding site(s) became exposed, which contributed subtly to the chaperone-like activity of αAΔ70-88. Both of the deletion mutants were completely inactive in suppressing aggregation of βL-crystallin at 53°C. The mutants completely lost the anti-apoptotic property that αA-crystallin exhibits while they protected ARPE-19 (a human retinal pigment epithelial cell line) and primary human primary lens epithelial (HLE) cells from oxidative stress. Our studies demonstrate that residues 70-88 in αA-crystallin act as a primary substrate binding site and account for the bulk of the total chaperone activity. The β3 and β4 strands in αA-crystallin comprising 70-88 residues play an important role in maintenance of the structure and in preventing aggregation of denaturing proteins.
Antidepressant medications represent the most common treatment option for major depressive disorder (MDD), but the neuro-psychological mechanisms by which antidepressants act to improve depressive symptoms remain under-specified. We designed this study to assess the effects of escitalopram treatment on spontaneous brain activity of MDD patients using functional magnetic resonance imaging (fMRI). Twenty first-episode drug-naive MDD patients received resting-state fMRI scans before and after 8 weeks of treatment with a selective serotonin reuptake inhibitor - escitalopram. Twenty age- and gender-matched healthy controls were also scanned twice with an 8-week interval. The fractional amplitude of low-frequency fluctuation (fALFF) was used to characterize the spontaneous brain activity. The analysis of covariance (ANCOVA) was performed to determine treatment-related changes in fALFF. The symptoms were significantly improved in MDD patients after treatment. We observed significant group-by-time interaction on fALFF in the left dorsomedial prefrontal cortex, the right middle frontal gyrus, and the left putamen. Post-hoc analyses showed that the fALFF values in these regions were significantly higher in the MDD patients compared to healthy controls at baseline and were reduced after treatment. The findings suggest that abnormalities in the brain areas involved in emotional processing and regulation could be normalized by effective antidepressant treatment with escitalopram in the MDD patients and free of a task situation.
Worldwide, bacterial resistance to chemical antibiotics has reached such a high level that endangers public health. Presently, the adoption of alternative strategies that promote the elimination of resistant microbial strains from the environment is of utmost importance. This review discusses and analyses several (potential) alternative strategies to current chemical antibiotics. Bacteriophage (or phage) therapy, although not new, makes use of strictly lytic phage particles as an alternative, or a complement, in the antimicrobial treatment of bacterial infections. It is being rediscovered as a safe method, because these biological entities devoid of any metabolic machinery do not possess any affinity whatsoever to eukaryotic cells. Lysin therapy is also recognized as an innovative antimicrobial therapeutic option, since the topical administration of preparations containing purified recombinant lysins with amounts in the order of nanograms, in infections caused by Gram-positive bacteria, demonstrated a high therapeutic potential by causing immediate lysis of the target bacterial cells. Additionally, this therapy exhibits the potential to act synergistically when combined with certain chemical antibiotics already available on the market. Another potential alternative antimicrobial therapy is based on the use of antimicrobial peptides (AMPs), amphiphilic polypeptides that cause disruption of the bacterial membrane and can be used in the treatment of bacterial, fungal and viral infections, in the prevention of biofilm formation, and as antitumoral agents. Interestingly, bacteriocins are a common strategy of bacterial defense against other bacterial agents, eliminating the potential opponents of the former and increasing the number of available nutrients in the environment for their own growth. They can be applied in the food industry as biopreservatives and as probiotics, and also in fighting multi-resistant bacterial strains. The use of antibacterial antibodies promises to be extremely safe and effective. Additionally, vaccination emerges as one of the most promising preventive strategies. All these will be tackled in detail in this review paper.
AMP-activated protein kinase (AMPK) in the ventromedial nucleus of the hypothalamus (VMH) and orexin (OX) in the lateral hypothalamic area (LHA) modulate brown adipose tissue (BAT) thermogenesis. However, whether these two molecular mechanisms act jointly or independently is unclear. Here, we show that the thermogenic effect of bone morphogenetic protein 8B (BMP8B) is mediated by the inhibition of AMPK in the VMH and the subsequent increase in OX signaling via the OX receptor 1 (OX1R). Accordingly, the thermogenic effect of BMP8B is totally absent in ox-null mice. BMP8B also induces browning of white adipose tissue (WAT), its thermogenic effect is sexually dimorphic (only observed in females), and its impact on OX expression and thermogenesis is abolished by the knockdown of glutamate vesicular transporter 2 (VGLUT2), implicating glutamatergic signaling. Overall, our data uncover a central network controlling energy homeostasis that may be of considerable relevance for obesity and metabolic disorders.
The advancement of surgical science relies on educating new generations of surgeon-scientists. Career development awards (K Awards) from the National Institutes of Health, often considered a marker of early academic success, are one way physician-scientists may foster skills through a mentored research experience. This study aimed to develop a conceptual framework to understand institutional support and other factors leading to a K Award.
A national, qualitative study was conducted with academic surgeons. Participants included 15 K Awardees and 12 surgery department Chairs. Purposive sampling ensured a diverse range of experiences. Semistructured, in-depth telephone interviews were conducted. Interviews were audio recorded and transcribed verbatim, and 2 reviewers analyzed the transcripts using Grounded Theory methodology.
Participants described individual and institutional factors contributing to success. K Awardees cited personal factors such as perseverance and team leadership skills. Chairs described the K Awardee as an institutional "investment" requiring protected time for research, financial support, and mentorship. Both K Awardees and Chairs identified a number of challenges unique to the surgeon-scientist, including financial strains and competing clinical demands.
Institutional support for surgeons pursuing K Awards is a complex investment with significant initial costs to the department. Chairs act as stewards of institutional resources and support those surgeon-scientists
 most likely to be successful. Although the K Award pathway is one way to develop surgeon-scientists, financial burdens and challenges may limit its usefulness. These findings, however, may better prepare young surgeons to develop career plans and identify new mechanisms for academic productivity.
Through the use of conjugate ring-rich pyrazine and quinoxaline derivatives, five new Keggin polymolybdate based compounds, [Ag(I)3L(1)2(H2O)2(PMo12O40)] (1), [Ag(I)4L(1)5(SiMo12O40)] (2), [Ag(I)6L(2)6(PMo12O40)2] (3), [Ag(I)2L(2)2(C16H36N)2](SiMo12O40)] (4), [Cu(I)3L(2)3(PMo12O40)] (5) (L(1) = 2,3-diphenylpyrazine, L(2) = 2,3-diphenylquinoxaline, C16H36N = tetrabutylammonium), were synthesized under hydrothermal conditions and characterized by single-crystal X-ray diffraction. In compound 1, three Ag(I) ions are fused by two L(1) molecules to form a [Ag3L(1)2](3+) subunit, and these subunits link the PMo12 anions to construct two kinds of 1D chains (I and II). Chains I and II connect to each other by sharing the same PMo12 anions and a 2D grid-like layer is built. The asymmetric unit of compound 2 is linked to form a dimer by sharing Ag ions, and a 1D double strand is formed. The SiMo12 anions connect adjacent 1D double strands through Ag3-O23 bonds and a 2D network is built. In compound 3, there exists a 1D ladder-like double chain with PMo12 anions as linking bars. A 2D layer is formed by linkage Ag2-O24 between adjacent chains. In compound 4, the PMo12 anions act as inorganic linkages to connect adjacent zigzag chains through Ag1-O3 bonds to construct a 2D grid-like layer. In compound 5 two Cu(I)-L(2) lines are fused by PMo12 anions to build a 1D ladder-like chain. Additionally, the electrochemical and photocatalytic properties of the title compounds have been studied.
This study sought to describe the extent to which psychiatrists, prior to insurance expansions under the Affordable Care Act (ACA), reported currently participating or being likely to participate in integrated services delivery models, to assume new roles, to accept new reimbursement structures, and to use electronic health records (EHRs).
A cross-sectional probability survey of U.S. psychiatrists was fielded from September to December 2013. In total, 2,800 psychiatrists were randomly selected from the AMA Physician Masterfile, and 45% responded. Of these, 93% (N=1,099) reported treating patients, forming the sample.
Overall, 29% reported practicing in new ACA or integrated models, and 64% reported assuming at least one new role. Forty-two percent reported currently receiving a salary; other capitated and risk-based reimbursement was rarely used. Half (53%) reported current use of EHRs for clinical functions not limited to billing or practice management; only 21% reported participating in the Medicare or Medicaid EHR Incentive Program. Those who reported currently practicing or being very likely to practice in primary care or integrated treatment settings, to assume at least one ACA role, to receive a salary, or to use an EHR were younger and more racially-ethnically diverse and more likely to see Medicaid and public outpatient clinic patients Conclusions: Although substantial proportions of psychiatrists reported current practice in ACA services delivery models and ACA roles, the findings highlight opportunities for workforce development, training, and technical assistance to strengthen participation in these activities. The findings also underscore the need to prepare psychiatrists for merit-based payment reforms and use of EHRs.
Medications for treatment of substance use disorders are underutilized in treatment programs in the United States. Little is known about how insurance enrollment within states affects treatment program decisions about whether to offer medications. The primary objective of the study was to examine the impact of health insurance enrollment on availability of substance use disorder medications among treatment programs.
Data from the 2012 National Survey of Substance Abuse Treatment Services, National Survey on Drug Use and Health, American Community Survey, Area Health Resource File, and the Substance Abuse and Mental Health Services Administration were combined to examine the impact of state insurance enrollment on availability of substance use disorder medications in treatment programs (N=9,888). A two-level, random-intercept logistic regression model was estimated to account for potential unobserved heterogeneity among treatment programs nested in states.
The percentage of state residents with employer-based insurance and Medicaid was associated with greater odds of offering at least one medication among treatment programs. A 5% increase in the rate of private insurance enrollment was associated with a 7.7% increase in the probability of offering at least one medication, and a 5% increase in the rate of state Medicaid enrollment was associated with a 9.3% increase in the probability of offering at least one medication.
Results point to the potential significance of health insurance enrollment in shaping the availability of substance use disorder medications. Significant expansions in health insurance enrollment spurred by the Affordable Care Act have the potential to increase access to medications for many Americans.
Intestinal microfold (M) cells are epithelial cells primarily present on Peyer's patches (PPs) in the small intestine. The ability of M cells to shuttle antigens into the PP for appropriate immune responses makes M cells a target for next-generation oral vaccine delivery. In this regard, discovery of M cell-specific receptors are of great interest, which could act as molecular tags for targeted delivery of cargo to M cells. Here, using a monoclonal antibody we generated to the Sialic acid-binding immunoglobulin-like lectin F (Siglec-F), we show that Siglec-F is expressed on mouse M cells in the small intestine. Immunohistochemical analysis of the PP tissue sections shows that Siglec-F is expressed on the surface of the M cell membrane exposed to the intestinal lumen. Anti-Siglec-F antibody injected into the mouse small intestine bound to M cells, demonstrating the potential to target M cells via Siglec-F.
The ubiquitin system comprises enzymes that are responsible for ubiquitination and deubiquitination, as well as ubiquitin receptors that are capable of recognizing and deciphering the ubiquitin code, which act in coordination to regulate almost all host cellular processes, including host-pathogen interactions. In response to pathogen infection, the host innate immune system launches an array of distinct antimicrobial activities encompassing inflammatory signaling, phagosomal maturation, autophagy and apoptosis, all of which are fine-tuned by the ubiquitin system to eradicate the invading pathogens and to reduce concomitant host damage. By contrast, pathogens have evolved a cohort of exquisite strategies to evade host innate immunity by usurping the ubiquitin system for their own benefits. Here, we present recent advances regarding the ubiquitin system-mediated modulation of host-pathogen interplay, with a specific focus on host innate immune defenses and bacterial pathogen immune evasion.
Silicon micromachined neural electrode arrays, which act as an interface between bioelectronic devices and neural tissues, play an important role in chronic implants, in vivo. The biological compatibility of chronic microelectrode arrays (MEA) is an essential factor that must be taken into account in their design and fabrication. In order to improve biocompatibility of the MEAs, the surface of the electrodes was coated with polyethylene glycol (PEG) and parylene-C, which are biocompatible polymers. An in vitro study was performed to test the capacity of poly-d-lysine (PDL) to improve neural-cell adhesion and proliferation. Increased proliferation of the neuroblast cells on the microelectrodes was observed in the presence of the PDL. The presence of the peptide on the electrode surface was confirmed using Fourier transform infrared spectroscopy and scanning electron microscopy (SEM). The impedance of the electrodes was not changed significantly before and after PDL deposition. Mouse neuroblast cells were seeded and cultured on the PDL coated and uncoated neural MEAs with different tip-coatings such as platinum, molybdenum, gold, sputtered iridium oxide, and carbon nanotubes. The neuroblast cells grew preferentially on and around peptide coated-microelectrode tips, as compared to the uncoated microelectrodes.
Recently obtained evidence indicated that an orthologue of the O. savignyi TSGP4 salivary lipocalin was present in the saliva of O. moubata. TSGP4 is known to act as a cysteinyl leukotrienes scavenger helping in the prevention of inflammation and oedema at the tick bite site. Since this function seems to be crucial for successful tick feeding, the novel O. moubata TSGP4 turned into a potential vaccine target. The purposes of the current work were: (i) to clone and characterize the O. moubata TSGP4 and, (ii) to produce it as recombinant to evaluate its protective efficacy as vaccine antigen. The results of these experiments indicated that the O. moubata TSGP4 shows high sequence and structural identity with the O. savignyi orthologue suggesting identical function in the physiology of the tick-host relationship. The mature native TSGP4 is not immunogenic when it is inoculated to host with tick saliva during feeding, but host vaccination with the recombinant protein TSGP4 in Freund's adjuvants induced strong humoral immune responses that recognized both the recombinant and native TSGP4 and protected the host with a 14.1% efficacy. So, the O. moubata TSGP4 can be considered a silent salivary antigen; however, in the light of the current results, its inclusion in the current repertory of protective antigens to be targeted by anti-tick
 vaccines could be controversial.
Canine leishmaniasis (CanL) is a parasite-borne disease mainly induced by Leishmania infantum in the Old World and Leishmania chagasi (infantum) in the New World. CanL is a zoonosis transmitted by the bite of infected Phlebotominae flies that act as vectors. CanL is a very serious disease that usually produces death when remains untreated and can be a focus of transmission to other dogs or humans. Infected dogs and other domestic and wild animals act as reservoirs and are a real threat to uninfected/healthy dogs and humans in endemic areas where the sand flies are present. Prevention of new infections in dogs can help to stop the current increase of the disease in humans, reinforcing the concept of "One Health" approach. The management of CanL is being performed using prophylactic measures in healthy dogs - insecticides impregnated in collars or immunostimulants applied by spot-on devices - and chemotherapy in animals that suffer from the disease. Antimonials as first-line monotherapy have proven efficacy in reducing most of the clinical signs of CanL, but they need to be administered during several days, and no complete parasite clearance is achieved, favouring the presence of relapses among treated dogs. Therefore, new drugs, such as miltefosine, or combinations of this drug or antimonials with allopurinol are in the pipeline of clinical treatment of CanL. Recently, there has been an emergence of protective - prophylactic - and curative - autogenous vaccines - immunotherapy tools to face CanL, whose results are still under study. This review highlights the current use of preventive and eradicative weapons to fight against this disease, which is a scourge for dogs and a continuous threat to human beings.
Psoriasis is a chronic inflammatory disease of the skin with an unknown aetiology. The disease manifests itself as red and silvery scaly plaques distributed over the scalp, lower back and extensor aspects of the limbs. After receiving scant consideration for quite a few years, psoriasis has now become a prominent focus for new drug development. A group of closely connected and differentially co-expressed genes may act in a network and may serve as molecular signatures for an underlying phenotype. A weighted gene coexpression network analysis (WGCNA), a system biology approach has been utilized for identification of new molecular targets for psoriasis. Gene coexpression relationships were investigated in 58 psoriatic lesional samples resulting in five gene modules, clustered based on the gene coexpression patterns. The coexpression pattern was validated using three psoriatic datasets. 10 highly connected and informative genes from each module was selected and termed as psoriasis specific hub signatures. A random forest based binary classifier built using the expression profiles of signature genes robustly distinguished psoriatic samples from the normal samples in the validation set with an accuracy of 0.95 to 1. These signature genes may serve as potential candidates for biomarker discovery leading to new therapeutic targets. WGCNA, the network based approach has provided an alternative path to mine out key controllers and drivers of psoriasis. The study principle from the current work can be extended to other pathological conditions.
Homeodomain-leucine zipper proteins (HD-ZIPs) form a plant-specific family of transcription factors functioning as homo- or heterodimers. Certain members of all four classes of this family are involved in embryogenesis, the focus of this review. They support auxin biosynthesis, transport and response, which are in turn essential for the apical-basal patterning of the embryo, radicle formation and outgrowth of the cotyledons. They transcriptionally regulate meristem regulators to maintain the shoot apical meristem once it is initiated. Some members are specific to the protoderm, the outermost layer of the embryo, and play a role in shoot apical meristem function. Within classes, homeodomain-leucine zippers tend to act redundantly during embryo development, and there are many examples of regulation within and between classes of homeodomain-leucine zippers. This indicates a complex network of regulation that awaits future experiments to uncover.
In this article I examine a recent approach to regulating assisted reproduction, whereby use of some kind of medical intervention 'triggers' laws governing legal parenthood that are more favourable to intending parents and sperm providers. I argue that although perhaps an improvement on the previous legal framework, these laws are problematic for three important reasons. First, they are prone to violating parental rights and unjustly imposing substantial burdens on individuals. Second, they are discriminatory. Third, even if we take a pragmatic approach to the question of parenthood in these cases, these laws fail to properly consider the welfare interests of children. Finally, I conclude by showing that my argument does not entail adopting a laissez-fair attitude to conception using third-party sperm.
The plant hormone abscisic acid (ABA) plays many important roles in controlling plant development and physiology, from flowering to senescence. ABA is now known to exert its effects through a family of soluble ABA receptors, which in Arabidopsis thaliana has 13 members divided into three clades. Homologues of these receptors are present in other plants, also in relatively large numbers. Investigation of the roles of each homologue in mediating the diverse physiological roles of ABA is hampered by this genetic redundancy. We report herein the in vitro screening of a targeted ABA-like analogue library and identification of novel antagonist hits, including the analogue PBI686 that had been developed previously as a probe for identifying ABA-binding proteins. Further in vitro characterization of PBI686 and development of second-generation leads yielded both receptor-selective and universal antagonist hits. In planta assays in different species have demonstrated that these antagonist leads can overcome various ABA-induced physiological changes. While the general antagonists open up a hitherto unexplored avenue for controlling plant growth through inhibition of ABA-regulated physiological processes, the receptor-selective antagonist can be developed into chemical probes to explore the physiological roles of individual receptors.
A ∼1.7 kDa antimicrobial peptide was purified from the acidified body extract of the Lugworm, Marphysa sanguinea, by preparative acid-urea-polyacrylamide gel electrophoresis and C18 reversed-phase high performance liquid chromatography (HPLC). The identified peptide is composed of 14 amino acids with the N-terminal acetylation. Comparison of the identified amino acid sequences and molecular weight of this peptide with those of other known proteins or peptides revealed that this peptide had high identity to the N-terminus of hemerythrin of marine invertebrates and named the msHemerycin. The full-length hemerythrin cDNA of Lugworm was contained 1027-bp, including a 5'-untranslated region (UTR) of 60-bp, a 3'-UTR of 595-bp, and an open reading frame of 372-bp encoding 123 amino acids including the msHemerycin at the N-terminus. Tissue distribution of the msHemerycin mRNA suggests that it is constitutively expressed as a non-tissue-specific manner, however, a relatively higher expression level was observed in muscle (6.8-fold) and brain (6.3-fold), and the lowest level in digestive gland. The secondary structural prediction and homology modeling studies indicate that the msHemerycin might form an unordered structure and might act via unconventional mechanism. Our results suggest that the msHemerycin might be an innate immune component related to the host defenses in the Lugworm. This is the first report on the antimicrobial function of the peptide derived from the N-terminus of hemerythrin in the Lugworm, Marphysa sanguinea.
In the 1980s, Chile adopted a mixed (public and private) model for health insurance coverage similar to the one recently outlined by the Affordable Care Act in the United States (US). In such a system, a mix of public and private health plans offer nearly universal coverage using a combined approach of managed competition and subsidies for low-income individuals. This paper uses a "most different" case study design to compare policies implemented in Chile and the US to address self-selection into private insurance. We argue that the implementation of a mixed health insurance system in Chile without the appropriate regulations was complex, and it generated a series of inequities and perverse incentives. The comparison of Chile and the US healthcare reforms examines the different approaches that both countries have used to manage economic competition, address health insurance self-selection and promote solidarity. Copyright © 2015 John Wiley & Sons, Ltd.
Manduca sexta, known as the tobacco hornworm or Carolina sphinx moth, is a lepidopteran insect that is used extensively as a model system for research in insect biochemistry, physiology, neurobiology, development, and immunity. One important benefit of this species as an experimental model is its extremely large size, reaching more than 10 g in the larval stage. M. sexta larvae feed on solanaceous plants and thus must tolerate a substantial challenge from plant allelochemicals, including nicotine. We report the sequence and annotation of the M. sexta genome, and a survey of gene expression in various tissues and developmental stages. The Msex_1.0 genome assembly resulted in a total genome size of 419.4 Mbp. Repetitive sequences accounted for 25.8% of the assembled genome. The official gene set is comprised of 15,451 protein-coding genes, of which 2498 were manually curated. Extensive RNA-seq data from many tissues and developmental
 stages were used to improve gene models and for insights into gene expression patterns. Genome wide synteny analysis indicated a high level of macrosynteny in the Lepidoptera. Annotation and analyses were carried out for gene families involved in a wide spectrum of biological processes, including apoptosis, vacuole sorting, growth and development, structures of exoskeleton, egg shells, and muscle, vision, chemosensation, ion channels, signal transduction, neuropeptide signaling, neurotransmitter synthesis and transport, nicotine tolerance, lipid metabolism, and immunity. This genome sequence, annotation, and analysis provide an important new resource from a well-studied model insect species and will facilitate further biochemical and mechanistic experimental studies of many biological systems in insects.
Nucleic acids are generally regarded as the payload in gene therapy, often requiring a carrier for intracellular delivery. With the recent discovery that spherical nucleic acids enter cells rapidly, we demonstrate that nucleic acids also have the potential to act as a delivery vehicle. Herein, we report an amphiphilic DNA-paclitaxel conjugate, which forms stable micellar nanoparticles in solution. The nucleic acid component acts as both a therapeutic payload for intracellular gene regulation and the delivery vehicle for the drug component. A bioreductively activated, self-immolative disulfide linker is used to tether the drug, allowing free drug to be released upon cell uptake. We found that the DNA-paclitaxel nanostructures enter cells ∼100 times faster than free DNA, exhibit increased stability against nuclease, and show nearly identical cytotoxicity as free drug. These nanostructures allow one to access a gene target and a drug target using only the payloads themselves, bypassing the need for a cocarrier system.
Present financial consequences imposed by the Affordable Care Act, along with practice challenges to address rates of 30-day readmission among patients with heart failure, emphasize the need for effective interventions. Healthcare workers must identify effective interventions to reduce readmission of patients with heart failure while providing high-quality care.
Moderate exercise positively impacts innate immune functions, bringing about a better resistance against infections and general immunosurveillance. Exercise of high workloads (i.e., high intensity and/or duration) such as elite marathon, on the other hand, may have detrimental effects over immune function, but neither how long nor how intense should be the exercise sessions to be deleterious is known, this being a matter of intense dispute. Exercise is, at the same time, one of the most powerful inducers of the 70 kDa family of heat shock proteins (HSPAs, formerly known as HSP70s), which are protein chaperones characterized by a marked anti-inflammatory potency, when located intracellularly (iHSPA), but may act as pro-inflammatory cytokines if in the extracellular space (eHSPA). The above observations led us to suppose that short-term exercise could impose long-lasting effects on macrophage function that should be related to the eHSPA-to-iHSPA ratio, viz. H-index. Sedentary adult male Wistar rats were then submitted to 20 min swimming sessions with an overload (as a percentage of body weight attached to the tail base) of either 2, 4, 6, or 8 %. Control animals were maintained at rest in shallow water. Monocyte/macrophage functions (phagocytic capacity, nitric oxide [NO], and hydrogen peroxide [H2O2]) were assessed just after and 12 h after exercise and compared with HSPA status and oxidative stress markers. The results showed that exercise increased phagocytosis and H2O2 immediately after the bouts in a workload-dependent way. This was accompanied by increased H-index but no alteration in the redox status. Enhanced phagocytic capacity persisted for up to 12 h, when a marked rise in NO production was also observed, but H-index resumes its control values, suggesting that immune alertness returned to basal levels. Of note was the detection of the cognate form of eHSPA (encoded by hspa8 gene and formerly known as HSP73) in the rat sera. In total, acute exercise may evoke 12 h long workload-dependent effects associated with HSPA status.
To understand the activation patterns of the trunk musculature, it is also important to consider the implications of adjacent structures such as the upper limbs, and the muscles that act to move the arms. This study investigated the effects of arm positions on the activation patterns and co-activation of the trunk musculature and muscles that move the arm during trunk range-of-motion movements (maximum trunk axial twist, flexion, and lateral bend). Fifteen males and fifteen females, asymptomatic for low back pain, performed maximum trunk range-of-motion movements, with three arm positions for axial twist (loose, crossed, abducted) and two positions for flexion and lateral bend (loose, crossed). Electromyographical data were collected for eight muscles bilaterally, and activation signals were cross-correlated between trunk muscles and the muscles that move the arms (upper trapezius, latissimus dorsi). Results revealed consistently greater muscle co-activation (higher cross-correlation coefficients) between the trunk muscles and upper trapezius for the abducted arm position during maximum trunk axial twist, while results for the latissimus dorsi-trunk pairings were more dependent on the specific trunk muscles (either abdominal or back) and latissimus dorsi muscle (either right or left side), as well as the range-of-motion movement. The findings of this study contribute to the understanding of interactions between the upper limbs and trunk, and highlight the influence of arm positions on the trunk musculature. In addition, the comparison of the present results to those of individuals with back or shoulder conditions may ultimately aid in elucidating underlying mechanisms or contributing factors to those conditions.
Geographers have long grappled with how their research can positively impact individuals, communities and society. Demonstrating research impact is an increasingly important aspect of academic life internationally. In this paper we argue that agendas for encouraging 'impact' would be well-served if impact through teaching was identified and stimulated more explicitly, and if academics better recognised and seized the opportunities that already exist for such impact. We take engagement between health geography and nurse education as an example of how social scientists could demonstrate research impact through inter-disciplinary involvement in the education of health care professionals, and specifically student nurses. We begin by showing how the UK's Research Excellence Framework (widely regarded as the key reference point for research performance management regimes internationally) has tended to produce an undervaluation of impact via education in many disciplines. A comprehensive overview of international scholarship at the intersection between geography and nursing is then presented. Here we trace three 'waves of enquiry' that have focused on research interactions before calling for a fourth focused on critical pedagogy. To illustrate the possibilities of this fourth wave, we sketch a case study that outlines how engagement with research around blood donation could help provide a foundation for critical pedagogy that challenges student nurses to practice reflexively, think geographically and act justly. Finally, we call for closer engagement between health geography and nurse education, by encouraging educators to translate, teach, and transfuse ideas and people between health geography and nurse education. In so doing, we argue that work at this interface can be mutually beneficial and demonstrate impact both within and beyond research assessment rubrics. Hence, our ideas are relevant beyond nurse education and geography insofar as this paper serves as an example of how reframing research impact can recover the importance of impact through education.
Rivers and streams are important reservoirs of freshwater for human consumption. These ecosystems are threatened by increasing urbanization, because raw sewage discharged into them alters their nutrient content and may affect the composition of their microbial community. In the present study, we investigate the taxonomic and functional profile of the microbial community in an urban lotic environment. Samples of running water were collected at two points in the São Pedro stream: an upstream preserved and non-urbanized area, and a polluted urbanized area with discharged sewage. The metagenomic DNA was sequenced by pyrosequencing. Differences were observed in the community composition at the two sites. The non-urbanized area was overrepresented by genera of ubiquitous microbes that act in the maintenance of environments. In contrast, the urbanized metagenome was rich in genera pathogenic to humans. The functional profile indicated that the microbes act on the metabolism of methane, nitrogen and sulfur, especially in the urbanized area. It was also found that virulence/defense (antibiotic resistance and metal resistance) and stress response-related genes were disseminated in the urbanized environment. The structure of the microbial community was altered by uncontrolled anthropic interference, highlighting the selective pressure imposed by high loads of urban sewage discharged into freshwater environments.
Objective To address the role of transthoracic echocardiography in inferior vena cava (IVC) monitoring in the management of haemodynamically unstable elderly patients subjected to lower limb orthopaedic surgery under spinal anesthesia. Possible implications in the postoperative care unit (PACU) length of stay (LOS) are investigated. Methods 41 elderly patients
 with cardiac diseases were recruited. Patients experiencing intraoperative haemodynamic instability (diastolic blood pressure ≤ 60 mmHg) were divided into two groups according to right atrial pressure (RAP), (RAP < 5 mmHg and RAP between 5 and 10 mmHg) as measured by inferior vena cava collapsibility index (IVCCI). Haemodynamic instability was treated with normal saline infused at a constant rate supplemented by phenylephrine (PHE) infusions titrated to normal blood pressure values. Intraoperatively comparisons of peak PHE infusion rates and all episodes of hypotension, including in the PACU, were recorded among groups. The patients' PACU LOS and associated factors were assessed. Results The intraoperative peak PHE infusion rate and the incidence of haemodynamic instability in the postoperative period were significantly higher in patients with RAP < 5 mmHg. The total PHE consumption was also higher in patients with RAP < 5 mmHg postoperatively. The primary risk factor for a prolonged stay in PACU, as determined by multiple regression analysis was RAP. Conclusions Patients with high dynamic collapsibility of the IVC may require aggressive treatment to restore their haemodynamic status. Additionally, intraoperative levels of RAP, as measured by IVCCI, can act as a predictor for increased LOS in the PACU.
Potential synergetic interaction between chemicals, climate change and the emergence of opportunistic diseases is of utmost concern within the amphibian decline scenario. Understand the structure and dynamic of this microbiome and how environmental stressors act on this community is a priority. The present study aimed to: i) characterize the skin microbiome of Pelophylax perezi frog by looking for variations between populations in reference and under stress conditions (one metal contaminated and another with salinity fluctuations) and ii) evaluate the tolerance of skin-isolated bacteria to chemical contamination. Skin swabs were collected from frog populations inhabiting three reference sites (LB, VA and AM), one metal-rich contaminated (TP) and one brackish lentic aquatic system (SL). The frogs' skin microbiome was characterized by culture independent method (DGGE) and by cultivation methods. DGGE showed a characteristic profile in frogs from TP population. Results of recovered communities revealed low morphotype diversity and density (Colony Forming Units per frog) on individuals from TP population, comparatively to the other sampled populations. Isolated bacteria identified based on 16S rRNA gene sequence belong mainly to the classes Actinobacteria and Alphaproteobacteria. Ecotoxicological assays with acid-metal contaminated effluent (ETP) showed that the percentage of tolerant strains was higher in frogs from TP population than in SL and LB populations. In conclusion, results suggest that: a) environmental specific characteristics, as the presence of chemical contaminants, influence the composition of amphibian microbiome, comparing with sites without such contaminants; b) there are differences in microbiome composition between populations; and c) bacteria historically exposed to effluent may evolve tolerance to this kind of contamination.
Metals have strong toxic effects in humans and can act as immunoregulatory factors. The purpose of our study was to determine whether the concentrations of metals are associated with the clinical course of nasal polyposis (NP). We measured the concentrations of 10 metals and non-metal (Zn, Mn, Se, Fe, Cr, Ni, Pb, Al, Cd, and Cu) in 58 patients with NP, and 29 controls with a healthy nasal mucosa. We used electron microscopy to compare the ultrastructural features of the nasal mucosa between NP patients and healthy controls. Concentrations of metals in nasal polyps and healthy mucosa were determined by mass spectrometry. Transmission electron microscopic (TEM) and scanning electron microscopic (SEM) images of the nasal mucosa were obtained. The mean tissue concentrations of all 10 metals and non-metal were significantly lower in NP patients than in healthy controls (P < 0.05).TEM and SEM revealed changes in the mucosal ultrastructure in NP with progressive fibrosis, devascularisation, and inflammation. Tissue concentrations of metals were lower in NP patients than in healthy controls, and this was particularly evident in massive polyposis.
How infants observe a goal-directed instrumental action provides a unique window into their understanding of others' behavior. In this study, we investigated eye-gaze patterns while infants observed events in which an actor used a tool on an object. Comparisons among 4-, 7-, 10-, and 12-month-old infants and adults reveal changes in infants' looking patterns with age; following an initial face bias, infants' scan path eventually shows a dynamic integration of both the actor's face and the objects on which they act. This shift may mark a transition in infants' understanding of the critical components of tool-use events and their understanding of others' behavior.
Bioremediation of polycyclic aromatic hydrocarbons (PAHs) is extremely challenging when they coexist with heavy metals. This constrain has led to adsorption-based techniques that help immobilize the metals and reduce toxicity. However, the adsorbents can also non-selectively bind the organic compounds, which reduces their bioavailability. In this study we developed a surface-engineered organoclay (Arquad(®) 2HT-75-bentonite-palmitic acid) which enhanced bacterial proliferation and adsorbed cadmium, but elevated phenanthrene bioavailability. Adsorption models of single and binary solutes revealed that the raw bentonite adsorbed cadmium and phenanthrene non-selectively at the same binding sites and sequestrated phenanthrene. In contrast, cadmium selectively bound to the deprotonated state of carboxyl groups in the organoclay and phenanthrene on the outer surface of the adsorbent led to a microbially congenial microenvironment with a higher phenanthrene bioavailability. This study provided valuable information which would be highly important for developing a novel clay-modulated bioremediation technology for cleaning up PAHs under mixed-contaminated situations.
Pathological buying is characterized by irrepressible buying behaviour and its negative consequences. A possible mechanism contributing to its development and maintenance is that buying episodes act as a maladaptive strategy to cope with negative emotions. Accordingly, pathological buying has been repeatedly associated with impulsivity, in particular with the tendency to experience strong reactions under negative affect. Relying on an experimental mood induction procedure, the present study tested in a sample of 100 individuals (a) whether individuals with pathological buying symptoms respond more impulsively in the Go/No-Go Task (as a measure of the behavioural inhibition aspect of impulsivity) and (b) whether this association is more pronounced in a negative mood. While controlling for comorbidities, the results show that pathological buying is associated with faster responses and a larger number of commission errors. Moreover, a significant interaction indicated that the association between pathological buying and performance the Go/No-Go Task was stronger in the negative mood condition. The present study thus shows that pathological buying is associated with deficits in the behavioural inhibition component of impulsivity. These deficits are most pronounced when mood is negative; in turn, this provides an explanation for the occurrence of excessive buying episodes following negative affect.
A dairy wastewater treatment system composed of the 1st segment (no aeration) equipped with a facility for the destruction of milk fat particles, four successive aerobic treatment segments with activated sludge and a final sludge settlement segment was developed. The activated sludge is circulated through the six segments by settling sediments (activated sludge) in the 6th segment and sending the sediments beck to the 1st and 2nd segments. Microbiota was examined using samples from the non-aerated 1st and aerated 2nd segments obtained from two farms using the same system in summer or winter. Principal component analysis showed that the change in microbiota from the 1st to 2nd segments concomitant with effective wastewater treatment is affected by the concentrations of activated sludge and organic matter (biological oxygen demand [BOD]), and dissolved oxygen (DO) content. Microbiota from five segments (1st and four successive aerobic segments) in one location was also examined. Although the activated sludge is circulating throughout all the segments, microbiota fluctuation was observed. The observed successive changes in microbiota reflected the changes in the concentrations of organic matter and other physicochemical conditions (such as DO), suggesting that the microbiota is flexibly changeable depending on the environmental condition in the segments. The genera Dechloromonas, Zoogloea and Leptothrix are frequently observed in this wastewater treatment system throughout the analyses of microbiota in this study.
The skin protects our body from external assaults like pathogens, xenobiotics or UV irradiation. In addition, it prevents the loss of water and solutes. To fulfill these important tasks, a complex barrier system has developed which comprises the stratum corneum, tight junctions, the microbiome, the chemical barrier and the immunological barrier. These barriers do not act separately, but influence each other e.g. after external manipulation or in skin diseases. Especially the two mechanical barriers, i.e. stratum corneum and tight junctions, are of great interest for drug delivery, because they are the first interaction partners of drug delivery systems and play the major role in skin absorption. Tight junctions are of special interest,
 as they are centrally localized in this complex barrier system in the outermost viable layer - the stratum granulosum of the interfollicular epidermis and the companion cell layer of the hair follicle - and because they can react very quickly to stimuli. We summarize here our current knowledge about tight junction barrier function in mammalian interfollicular epidermis and hair follicles, and the interaction of tight junctions with other skin barrier components in health and disease. Furthermore, we discuss their relevance for drug delivery and provide examples for tight junction modulators.
Among various compounds used in research and clinic for degenerative bone diseases, low level laser therapy (LLLT), comprising low level lasers (LLL) and light emitting diodes (LEDs), has been investigated regarding its effects on bone metabolism. They have specific wavelengths but in general act as a cellular biomodulator, and as a therapeutic agent, rebalancing and normalizing their activity. However, they are not standardized yet, since their parameters of use are relevant for the effects and mechanisms of action. Therefore, the aim of this study was to compare the influence of two spectrums of LLL and LED phototherapy, at the same energy densities (10 and 50J/cm(2)), on human osteoblasts proliferation and differentiation. The involvement of ERK signaling on proliferation was also investigated by evaluating its activation during proliferation under different phototherapies by western blotting and CFSE-based osteoblast proliferation was measured in a presence or absence of the ERK-specific inhibitor. Osteogenic differentiation was evaluated through in vitro mineralization and gene expression of type I collagen (COL1A1) and osteonectin (SPARC) by Real Time- PCR. Increases in viable cells and proliferation were obtained after irradiation, regardless of LLLT type. However, only red at 10J/cm(2) and infrared at both doses, but not LED, induced ERK1/2 activation. In the presence of ERK inhibitor, the LLL-induced proliferation was prevented. In addition, while COL1A1 gene expression was upregulated by red laser, SPARC does so by infrared stimulation. However, LED, at both doses, increased both COL1A1 and SPARC expression. All LLLT increased mineralization, dependent on the dose and time. Thus, LLL and LED differently modulated the metabolism of human osteoblasts, increasing proliferation by mechanism dependent or not of ERK signaling activation and osteogenic differentiation markers.
The aim of this study was to identify the perceptions of blood donors and recipients regarding the act of donating blood.
This descriptive study with a survey design focuses on subjective and cultural aspects. Twenty donors and 20 recipients in the blood bank at the time of data collection participated in the study. Interviews were analyzed according to deductive thematic analysis.
Two themes emerged - perceptions of donors and perceptions of recipients. Both groups saw the act of donating blood as something positive, though donors associated their reports with the experiences of people close to them who needed blood transfusions, while the recipients associated donations with the maintenance of their lives as, for them, a blood transfusion was a necessary medical treatment.
Perceptions regarding blood donations are culturally constructed, as the participants associated knowledge acquired in the social world with moral issues and their life experiences. Hence, in addition to helping others, these individuals feel socially and morally rewarded.
In order to efficiently obtain blood from their vertebrate hosts, bloodsucking arthropods have undergone an evolutionary selection process leading to specialist adaptations in their feeding apparatus (mouthparts and suction pumps) and salivary molecules. These adaptations act to counteract haemostasis, inflammation, and immune responses in their vertebrate hosts. The association of haematophagous arthropods with vertebrate hosts during a blood feed allows the transmission of pathogens between their hosts and vectors in a tripartite interaction. Feeding mechanisms in haematophagous arthropod species have been the subject of studies over at least eight decades worldwide, as a consequence of the importance of vector-borne diseases and their impact on human health. Here we review studies of the feeding mechanisms of triatomine bugs, with a particular focus on factors that influence their feeding performance when obtaining a blood meal from different vertebrate hosts.
Identification of the key ingredients and essential processes required to achieve perfect tissue regeneration in humans has so far remained elusive. Injury in vertebrates induces an obligatory wound response that will precede or overlap any regeneration specific program or scarring outcome. This process shapes the cellular and molecular landscape of the tissue, influencing the success of endogenous repair pathways or for potential clinical intervention. The involvement of immune cells is also required for aspects of development extending beyond the initial inflammatory phase of wounding. It has now become clear from amphibian, fish and mammalian models of tissue injury that the type of immune response and the profile of immune cells attending the site of injury can act as the gatekeepers that determine wound repair quality. The heterogeneity among innate and adaptive immune cell populations, along with the developmental origin of these cells, form key ingredients affecting the potential for downstream repair and the suppression of fibrosis. Cell-to-cell interactions between immune cells, such as macrophages and T cells, with stem cells and mesenchymal cells are critically important for shaping this process and these exchanges, are in turn influenced by the type of injury, tissue location and developmental stage of the organism. Developmentally, mouse cardiac regeneration is restricted to early stages of postnatal life where the balance of innate to adaptive immune cells may be poised towards regeneration. In the injured adult mouse liver, specific macrophage subsets improve repair while other bone marrow derived cells can exacerbate injury. Other studies using genetically diverse mice have shown enhanced regeneration in certain strains, restricted to specific tissues. This enhanced repair is linked with expression of genes such as Insulin-like Growth Factor- 1 (IGF-1) and activin (Act 1), that both play important roles in shaping the immune system. Immune cells are now appreciated to have powerful influences on critical cell types required for regeneration success. The winning recipe for tissue regeneration is likely to be found ultimately by identifying the genetic elements and specific cell populations that limit or allow intrinsic potential. This will be essential for developing therapeutic strategies for tissue regeneration in humans.
Macrophages are present in all tissues, either as resident cells or monocyte-derived cells that infiltrate into tissues. The tissue site largely determines the phenotype of tissue-resident cells, which help to maintain tissue homeostasis and act as sentinels of injury. Both tissue resident and recruited macrophages make a substantial contribution to wound healing following injury. In this review, we evaluate how macrophages in two fundamentally distinct tissues, i.e. the lung and the skin, differentially contribute to the process of wound healing. We highlight the commonalities of macrophage functions during repair and contrast them with distinct, tissue-specific functions that macrophages fulfill during the different stages of wound healing.
IL-33 is a member of the IL-1 family of cytokines. IL-33 is predominantly located within the nucleus of cells where it plays a role in gene regulation. Given the right combination of signals and cellular damage, stored IL-33 is released from the cell where it can interact with its receptor ST2, triggering danger-associated responses and act as a cellular "alarmin". Whilst IL-33/ST2 signalling has been shown to induce potent pro-inflammatory responses that can be detrimental in certain disease states, a dichotomous, protective role of IL-33 in promoting wound healing has also emerged in multiple tissues types. This review will explore the current literature concerning this homeostatic role of IL-33/ST2 in tissue repair and also review its role in uncontrolled wound responses as seen in both fibrosis and tumorigenesis.
Dopamine was first identified as a neurotransmitter localized to the midbrain over 50 years ago. The dopamine transporter (DAT; SLC6A3) and the vesicular monoamine transporter 2 (VMAT2; SLC18A2) are regulators of dopamine homeostasis in the presynaptic neuron. DAT transports dopamine from the extracellular space into the cytosol of the presynaptic terminal. VMAT2 then packages this cytosolic dopamine into vesicular compartments for subsequent release upon neurotransmission. Thus, DAT and VMAT2 act in concert to move the transmitter efficiently throughout the neuron. Accumulation of dopamine in the neuronal cytosol can trigger oxidative stress and neurotoxicity, suggesting that the proper compartmentalization of dopamine is critical for neuron function and risk of disease. For decades, studies have examined the effects of reduced transporter function in mice (e.g. DAT-KO, VMAT2-KO, VMAT2-deficient). However, we have only recently been able to assess the effects of elevated transporter expression using BAC transgenic methods (DAT-tg, VMAT2-HI mice). Complemented with in vitro work and neurochemical techniques to assess dopamine compartmentalization, a new focus on the importance of transporter proteins as both models of human disease and potential drug targets has emerged. Here, we review the importance of DAT and VMAT2 function in the delicate balance of neuronal dopamine.
We
 have established a clinically relevant animal model of hepatocellular cancer (HCC) in immune competent mice to elucidate the complex dialog between host immunity and tumors during HCC initiation and progression. Mechanistic findings have been leveraged to develop a clinically feasible anti-tumor chemoimmunotherapeutic strategy.
Intraperitoneal injection of carbon tetrachloride and intrasplenic inoculation of oncogenic hepatocytes were combined to induce progressive HCCs in fibrotic livers of immunocompetent mice. Immunization and adoptive cell transfer (ACT) were used to dissect the tumor antigen-specific immune response. The ability of the tyrosine kinase inhibitor sunitinib to enhance immunotherapy in the setting of HCC was evaluated.
This new mouse model mimics human HCC and reflects its typical features. Tumor-antigen-specific CD8(+) T cells maintained a naïve phenotype and remained responsive during early-stage tumor progression. Late tumor progression produced circulating tumor cells, tumor migration into draining lymph nodes, and profound exhaustion of tumor-antigen-specific CD8(+) T cells associated with accumulation of programmed cell death protein 1 (PD-1)(hi) CD8(+) T cells and regulatory T cells (Tregs). Sunitinib-mediated tumoricidal effect and Treg suppression synergized with antibody-mediated blockade of PD-1 to powerfully suppress tumor growth and activate anti-tumor immunity.
Treg accumulation and upregulation of PD-1 provide two independent mechanisms to induce profound immune tolerance in HCC. Chemoimmunotherapy using Food and Drug Administration-approved sunitinib with anti-PD-1 antibodies achieved significant tumor control, supporting translation of this approach for the treatment of HCC patients.
In the current study, we have established a clinically relevant mouse model which mimics human liver cancer. Using this unique model, we studied the response of the immune system to this aggressive cancer. Findings from this trial have led to the development of an innovative and clinically feasible chemoimmunotherapeutic strategy.
The vascular endothelium is a critical interface, which separates the organs from the blood and its contents. The endothelium has a wide variety of functions and maintenance of endothelial homeostasis is a multi-dimensional active process, disruption of which has potentially deleterious consequences if not reversed. Vascular injury predisposes to endothelial apoptosis, dysfunction and development of atherosclerosis. Endothelial dysfunction is an end-point, a central feature of which is increased ROS generation, a reduction in endothelial nitric oxide synthase and increased nitric oxide consumption. A dysfunctional endothelium is a common feature of diseases including rheumatoid arthritis, systemic lupus erythematosus, diabetes mellitus and chronic renal impairment. The endothelium is endowed with a variety of constitutive and inducible mechanisms that act to minimise injury and facilitate repair. Endothelial cytoprotection can be enhanced by exogenous factors such as vascular endothelial growth factor, prostacyclin and laminar shear stress. Target genes include endothelial nitric oxide synthase, heme oxygenase-1, A20 and anti-apoptotic members of the B cell lymphoma protein-2 family. In light of the importance of endothelial function, and the link between its disruption and the risk of atherothrombosis, interest has focused on therapeutic conditioning and reversal of endothelial dysfunction. A detailed understanding of cytoprotective signalling pathways, their regulation and target genes is now required to identify novel therapeutic targets. The ultimate aim is to add vasculoprotection to current therapeutic strategies for systemic inflammatory diseases, in an attempt to reduce vascular injury and prevent or retard atherogenesis.
Multidrug resistance is the major obstacle for successful treatment of breast cancer, prompting the investigation of novel anticancer compounds.
In this study, we tested whether LQB-223, an 11a-N-Tosyl-5-deoxi-pterocarpan newly synthesized compound, could be effective toward breast cancer cells.
Human breast cell lines MCF-7, MDA-MB-231, HB4a and MCF-7 Dox(R) were used as models for this study. Cell culture, MTT and clonogenic assay, flow cytometry and Western blotting were performed.
The LQB-223 decreased cell viability, inhibited colony formation and induced an expressive G2/M arrest in breast cancer cells. There was an induction in p53 and p21(Cip1) protein levels following treatment of wild-type p53 MCF-7 cells, which was not observed in the mutant p53 MDA-MB-231 cell line, providing evidence that the compound might act to modulate the cell cycle regardless of p53 status. In addition, LQB-223 resulted in decreased procaspase levels and increased annexin V staining, suggesting that the apoptotic cascade is also triggered. Importantly, LQB-223 treatment was shown to be less cytotoxic to non-neoplastic breast cells than docetaxel and doxorubicin. Strikingly, exposure of doxorubicin-resistant MCF-7-Dox(R) cells to LQB-223 resulted in suppression of cell viability and proliferation in levels comparable to MCF-7. Of note, MCF-7-Dox(R) cells have an elevated expression of the P-glycoprotein efflux pump when compared to MCF-7.
Together, these results show that LQB-223 mediates cytotoxic effects in sensitive and resistant breast cancer cells, while presenting low toxicity to non-neoplastic cells. The new compound might represent a potential strategy to induce toxicity in breast cancer cells, especially chemoresistant cells.
This study evaluated the effects of deficient IGF-I expression in osteocytes on fracture healing. Transgenic mice with conditional knockout (cKO) of Igf1 in osteocytes were generated by crossing Dmp1-Cre mice with Igf1 flox mice. Fractures were created on the mid-shaft of tibia of 12-week-old male cKO mice and wild-type (WT) littermates by three-point bending. At 21 and 28days post-fracture healing, the increases in cortical bone mineral density, mineral content, bone area, and thickness, as well as sub-cortical bone mineral content at the fracture site were each greater in cKO calluses than in WT calluses. There were 85% decrease in the cartilage area and >2-fold increase in the number of osteoclasts in cKO calluses at 14days post-fracture, suggesting a more rapid remodeling of endochondral bone. The upregulation of mRNA levels of osteoblast marker genes (cbfa1, alp, Opn, and Ocn) was greater in cKO calluses than in WT calluses. μ-CT analysis suggested an accelerated bony union of the fracture gap in cKO mice. The Sost mRNA level was reduced by 50% and the Bmp2 mRNA level was increased 3-fold in cKO fractures at 14days post-fracture, but the levels of these two mRNAs in WT fractures were unchanged, suggesting that the accelerated fracture repair may in part act through the Wnt and/or BMP signaling. In conclusion, conditional deletion of Igf1 in osteocytes not only did not impair, but unexpectedly enhanced, bony union of the fracture gap. The accelerated bony union was due in part to upregulation of the Wnt and BMP2 signaling in response to deficient osteocyte-derived IGF-I expression, which in turn favors intramembranous over endochondral bone repair.
Patients with systemic sclerosis (SSc) are endagered by tissue fibrosis and by microvasculopathy, with the latter caused by endothelial cell expansion/proliferation. SSc-associated fibrosis potentially results from mesenchymal transdifferentiation of endothelial cells. Early Endothelial Progenitor Cells (eEPCs) act proangiogenic under diverse conditions. Aim of the study was to analyze eEPC regeneration and mesenchymal transdifferentiation in patients with limited and diffuse SSs (lSSc and dSSc).
Patients with both, lSSc and dSSc were included into the study. The following parameters were evaluated: eEPC numbers and regeneration, concentrations of vasomodulatory mediators, mesenchymal properties of blood-derived eEPC. Serum samples of healthy subjects and SS patients were used for stimulation of cultured human eEPC, subsequently followed by analysis of mesenchymal cell characteristics and mobility.
Twenty-nine patients were included into the study. Regenerative activity of blood-derived eEPCs did not differ between Controls and patients. Circulating eEPC were significantly lower in all patients with SSc, and in limited and diffuse SSc (lSSc/dSSc). Serum concentrations of promesenchymal TGF-b was elevated in all patients with SSc. Cultured mononuclear cells from SS patients displayed higher abundances of CD31 and of CD31 and aSMA combined. Finally, serum from SSc patients inhibited migration of cultured eEPCs and the cells showed lower sensitivity towards the endothelin antagonist Bosentan.
The eEPC system, which represents an essential element of the endogenous vascular repair machinery is affected in SSc. The increased appearance of mesenchymal properties in eEPC may indicate that alterations of the cells potentially contribute to the accumulation of connective tissue and to vascular malfunction.
Cell proliferation is crucial to the growth of multicellular organisms, and thus the proper control of cell division is important to prevent developmental arrest or overgrowth. Nevertheless, tools for controlling cell proliferation are still poor in plant. To develop novel tools, we focused on a specific compound family, triarylmethanes, whose members show various antiproliferative activities in animals. By combining organic chemistry to create novel and diverse compounds containing the triarylmethyl moiety and biological screens based on live-cell imaging of a fluorescently labeled tobacco Bright Yellow-2 (BY-2) culture cell line (Nicotiana tabacum), we isolated (3-furyl)diphenylmethane as a strong but partially reversible inhibitor of plant cell division. We also found that this agent had
 efficient antiproliferative activity in developing organs of Arabidopsis thaliana without causing secondary defects in cell morphology, and induced rapid cell division arrest independent of the cell cycle stage. Given that (3-furyl)diphenylmethane did not affect the growth of a human cell line (HeLa) and a budding yeast (Saccharomyces cerevisiae), it should act specifically on plants. Taking our results together, we propose that the combination of desired chemical synthesis and detailed biological analysis is an effective tool to create novel drugs, and that (3-furyl)diphenylmethane is a specific antiproliferative agent for plants.
To determine if the T1 relaxation time of the pancreas can detect parenchymal changes in mild chronic pancreatitis (CP).
This Institutional Review Board (IRB)-approved, Health Insurance Portability and Accountability Act (HIPAA)-compliant retrospective study analyzed 98 patients with suspected mild CP. Patients were grouped as normal (n = 53) or mild CP (n = 45) based on history, presenting symptomatology, and concordant findings on both the secretin-enhanced magnetic resonance cholangiopancreatography (S-MRCP) and endoscopic retrograde cholangiopancreatography (ERCP). T1 maps were obtained in all patients using the same 3D gradient echo technique on the same 3T scanner. T1 relaxation times, fat signal fraction (FSF), and anterior-posterior (AP) diameter were correlated with the clinical diagnosis of CP.
There was a significant difference (P < 0.0001) in the T1 relaxation times between the control (mean = 797 msec, 95% confidence interval [CI]: 730, 865) and mild CP group (mean = 1099 msec, 95% CI: 1032, 1166). A T1 relaxation time threshold value of 900 msec was 80% sensitive (95% CI: 65, 90) and 69% specific (95% CI: 56, 82) for the diagnosis of mild CP (area under the curve [AUC]: 0.81). Multiple regression analysis showed that T1 relaxation time was the only statistically significant variable correlating with the diagnosis of CP (P < 0.0001). T1 relaxation times showed a weak positive correlation with the pancreatic FSF (ρ = 0.33, P = 0.01) in the control group, but not in the mild CP group.
The T1 relaxation time of the pancreatic parenchyma was significantly increased in patients with mild CP. Therefore, T1 mapping might be used as a practical quantitative imaging technique for the evaluation of suspected mild CP. J. Magn. Reson. Imaging 2016.
Alternative splicing events that result in the production of multiple gene isoforms reveals important molecular mechanisms. Gene isoforms are often differentially expressed across organs and tissues, developmental stages, and disease conditions. Specifically, recent studies show that aberrant regulation of alternative splicing frequently occurs in cancer to affect tumor cell transformation and growth. While analysis of isoform expression is important for discovering tumor-specific isoform signatures and interpreting relevant genomic mutations, there is currently no web-based, easy-to-use, and publicly available platform for this purpose.
We developed ISOexpresso to provide information regarding isoform existence and expression, which can be grouped by cancer vs. normal conditions, cancer types, and tissue types. ISOexpresso implements two main functions: First, the Isoform Expression View function creates visualizations for condition-specific RNA/isoform expression patterns upon query of a gene of interest. With this function, users can easily determine the major isoform (the most expressed isoform in a sample) of a gene with respect to the condition and check whether it matches the known canonical isoform. ISOexpresso outputs expression levels of all known transcripts to check alterations of expression landscape and to find potential tumor-specific isoforms. Second, the User Data Annotation function supports annotation of genomic variants to determine the most plausible consequence of a variation (e.g., an amino acid change) among many possible interpretations. As most coding sequence mutations are effective through the subsequent transcription and translation, ISOexpresso automatically prioritizes transcripts that act as backbones for mutation effect prediction by their relative expression. By employing ISOexpresso, we could investigate the consistency between the most expressed and known canonical/principal isoforms, as well as infer candidate tumor-specific isoforms based on their expression levels. In addition, we confirmed that ISOexpresso could easily reproduce previously known isoform expression patterns: recurrent observation of a major isoform across tissues, differential isoform expression patterns in a given tissue, and switching of major isoform during tumorigenesis.
ISOexpresso serves as a web-based, easy-to-use platform for isoform expression and alteration analysis based on large-scale cancer database. We anticipate that ISOexpresso will expedite formulation and confirmation of novel hypotheses by providing isoform-level perspectives on cancer research. The ISOexpresso database is available online at http://wiki.tgilab.org/ISOexpresso/ .
Multi-atlas fusion is a promising approach for computer-assisted segmentation of anatomic structures. The purpose of this study was to evaluate the accuracy and time efficiency of multi-atlas segmentation for estimating spleen volumes on clinically acquired computed tomography (CT) scans.
Under an institutional review board approval, we obtained 294 de-identified (Health Insurance Portability and Accountability Act-compliant) abdominal CT scans on 78 subjects from a recent clinical trial. We compared five pipelines for obtaining splenic volumes: Pipeline 1 - manual segmentation of all scans, Pipeline 2 - automated segmentation of all scans, Pipeline 3 - automated segmentation of all scans with manual segmentation for outliers on a rudimentary visual quality check, and Pipelines 4 and 5 - volumes derived from a unidimensional measurement of craniocaudal spleen length and three-dimensional splenic index measurements, respectively. Using Pipeline 1 results as ground truth, the accuracies of Pipelines 2-5 (Dice similarity coefficient, Pearson correlation, R-squared, and percent and absolute deviation of volume from ground truth) were compared for point estimates of splenic volume and for change in splenic volume over time. Time cost was also compared for Pipelines 1-5.
Pipeline 3 was dominant in terms of both accuracy and time cost. With a Pearson correlation coefficient of 0.99, average absolute volume deviation of 23.7 cm(3), and time cost of 1 minute per scan, Pipeline 3 yielded the best results. The second-best approach was Pipeline 5, with a Pearson correlation coefficient of 0.98, absolute deviation of 46.92 cm(3), and time cost of 1 minute 30 seconds per scan. Manual segmentation (Pipeline 1) required 11 minutes per scan.
A computer-automated segmentation approach with manual correction of outliers generated accurate splenic volumes with reasonable time efficiency.
A new antibiotic natural product, ravynic acid, has been isolated from a Penicillium sp. of fungus, collected from Ravensbourne National Park. The 3-acylpolyenyne tetramic acid structure was definitively elucidated via synthesis. Highlights of the synthetic method include the heat induced formation of the 3-acylphosphorane tetramic acid and a selective Wittig cross-coupling to efficiently prepare the natural compounds carbon skeleton. The natural compound was shown to inhibit the growth of Staphylococcus aureus down to concentrations of 2.5 µg mL(-1).
Thirty-one different 3-O-acetyl-OA derived amides have been prepared and screened for their cytotoxic activity. In the SRB assays nearly all the carboxamides displayed good cytotoxicity in the low μM range for several human tumor cell lines. Low EC50 values were obtained especially for the picolinylamides 14-16, for a N-[2-(dimethylamino)-ethyl] derivative 27 and a N-[2-(pyrrolinyl)-ethyl] carboxamide 28. These compounds were submitted to an extensive biological testing and proved compound 15 to act mainly by an arrest of the tumor cells in the S phase of the cell cycle. Cell death occurred by autophagy while compounds 27 and 28 triggered apoptosis.
PurposeIt is known that microRNAs (miRNAs) are a class of small, noncoding RNAs that act as key regulators in various physiological and pathological processes. However, the regulatory mechanisms involving miRNAs in retinoblastoma (RB) remain largely unknown. The miRNA miR-125b is dysregulated in various human cancers such as breast cancer, human hepatocellular carcinoma, ovarian cancer, and colorectal cancer. However, the significance of miR-125b in RB has not been sufficiently investigated. Our objective was to explore the role of the miR-125b in RB.MethodsIn this study, we measured miR-125b levels using real-time polymerase chain reaction in human RB cell lines, including HXO-Rb44, Y79, SO-RB50, and the normal human retinal pigment epithelial cell line ARPE-19; a total of 38 pairs of primary RB tissues and adjacent noncancerous tissues were also measured. In addition, overexpression of miR-125b in RB cell lines was performed to determine the role of miR-125b in RB.ResultsWe found that miR-125b is significantly upregulated in RB, and closely associated with tumor cell proliferation and apoptosis. In addition, overexpression of miR-125b apparently promotes RB cell proliferation and migration in vitro. Gain-of-function in vitro experiments further showed that the miR-125b mimic significantly suppressed RB cell apoptosis. A subsequent dual-luciferase reporter assay identified the suppressor gene DRAM2 as direct target of miR-125b.ConclusionsOur data collectively demonstrate that miR-125b is a suppressor gene miRNA that can promote RB cell proliferation and migration by downregulating the suppressor gene DRAM2, indicating that miR-125b
 may represent a new potential diagnostic and therapeutic target for RB treatment.
Supernumerary teeth and tooth agenesis are common morphological anomalies in humans. We previously obtained evidence that supernumerary maxillary incisors form as a result of the successive development of the rudimentary maxillary incisor tooth germ in Usag-1 null mice. The development of tooth germs is arrested in Runx2 null mice, and such mice also exhibit lingual epithelial buds associated with the upper molars and incisors. The aim of this study is to investigate the potential crosstalk between Usag-1 and Runx2 during tooth development. In the present study, three interesting phenomena were observed in double null Usag-1-/-/Runx2-/- mice: the prevalence of supernumerary teeth was lower than in Usag-1 null mice; tooth development progressed further compared than in Runx2 null mice; and the frequency of molar lingual buds was lower than in Runx2 null mice. Therefore, we suggest that RUNX2 and USAG-1 act in an antagonistic manner. The lingual bud was completely filled with odontogenic epithelial Sox2-positive cells in the Usag-1+/+/Runx2-/- mice, whereas almost no odontogenic epithelial Sox2-positive cells contributed to supernumerary tooth formation in the rudimentary maxillary incisors of the Usag-1-/-/Runx2+/+ mice. Our findings suggest that RUNX2 directly or indirectly prevents the differentiation and/or proliferation of odontogenic epithelial Sox2-positive cells. We hypothesize that RUNX2 inhibits the bone morphogenetic protein (BMP) and/or Wnt signaling pathways regulated by USAG-1, whereas RUNX2 expression is induced by BMP signaling independently of USAG-1.
It is now well documented that peptides with enhanced or alternative functionality (termed cryptides) can be liberated from larger, and sometimes inactive, proteins. A primary example of this phenomenon is the oxygen-transport protein hemoglobin. Aside from respiration, hemoglobin and hemoglobin-derived peptides have been associated with immune modulation, hematopoiesis, signal transduction and microbicidal activities in metazoans. Likewise, the functional equivalents to hemoglobin in invertebrates, namely hemocyanin and hemerythrin, act as potent immune effectors under certain physiological conditions. The purpose of this review is to evaluate the true extent of oxygen-transport protein dynamics in innate immunity, and to impress upon the reader the multi-functionality of these ancient proteins on the basis of their structures. In this context, erythrocyte-pathogen antibiosis and the immune competences of various erythroid cells are compared across diverse taxa.
Protein growth factors have demonstrated great potential for tissue repair, but their inherent instability and large size prevents meaningful presentation to biologically protected nervous tissue. Here, we create a nanofibrous network from a self-assembling peptide (SAP) hydrogel to carry and stabilize the growth factors. We significantly reduced growth factor degradation to increase their lifespan by over 40 times. To control the temporal release profile we covalently attached polysaccharide chitosan molecules to the growth factor to increase its interactions with the hydrogel nanofibers and achieved a 4 h delay, demonstrating the potential of this method to provide temporally controlled growth factor delivery. We also describe release rate based analysis to examine the growth factor delivery in more detail than standard cumulative release profiles allow and show that the chitosan attachment method provided a more consistent release profile with a 60% reduction in fluctuations. To prove the potential of this system as a complex growth factor delivery platform we demonstrate for the first time temporally distinct release of multiple growth factors from a single tissue specific SAP hydrogel: a significant goal in regenerative medicine.
Tall buildings are concentrated in urban areas. The outer walls of buildings are vertically erected to the ground and almost flat. Therefore, the vertical corners that meet the vertical planes are present everywhere in urban areas. These corners act as convenient landmarks, which can be extracted by using the light detection and ranging (LIDAR) sensor. A vertical corner feature based precise vehicle localization method is proposed in this paper and implemented using 3D LIDAR (Velodyne HDL-32E). The vehicle motion is predicted by accumulating the pose increment output from the iterative closest point (ICP) algorithm based on the geometric relations between the scan data of the 3D LIDAR. The vertical corner is extracted using the proposed corner extraction method. The vehicle position is then corrected by matching the prebuilt corner map with the extracted corner. The experiment was carried out in the Gangnam area of Seoul, South Korea. In the experimental results, the maximum horizontal position error is about 0.46 m and the 2D Root Mean Square (RMS) horizontal error is about 0.138 m.
Many environmental incidents affect large areas, often in rough terrain constrained by natural obstacles, which makes intervention difficult. New technologies, such as unmanned aerial vehicles, may help address this issue due to their suitability to reach and easily cover large areas. Thus, unmanned aerial vehicles may be used to inspect the terrain and make a first assessment of the affected areas; however, nowadays they do not have the capability to act. On the other hand, ground vehicles rely on enough power to perform the intervention but exhibit more mobility constraints. This paper proposes a multi-robot sense-act system, composed of aerial and ground vehicles. This combination allows performing autonomous tasks in large outdoor areas by integrating both types of platforms in a fully automated manner. Aerial units are used to easily obtain relevant data from the environment and ground units use this information to carry out interventions more efficiently. This paper describes the platforms and sensors required by this multi-robot sense-act system as well as proposes a software system to automatically handle the workflow for any generic environmental task. The proposed system has proved to be suitable to reduce the amount of herbicide applied in agricultural treatments. Although herbicides are very polluting, they are massively deployed on complete agricultural fields to remove weeds. Nevertheless, the amount of herbicide required for treatment is radically reduced when it is accurately applied on patches by the proposed multi-robot system. Thus, the aerial units were employed to scout the crop and build an accurate weed distribution map which was subsequently used to plan the task of the ground units. The whole workflow was executed in a fully autonomous way, without human intervention except when required by Spanish law due to safety reasons.
The brain has high-order functions and is composed of several kinds of cells, such as neurons and glial cells. It is becoming clear that many kinds of neurodegenerative diseases are more-or-less influenced by astrocytes, which are a type of glial cell. Aquaporin-4 (AQP4), a membrane-bound protein that regulates water permeability is a member of the aquaporin family of water channel proteins that is expressed in the endfeet of astrocytes in the central nervous system (CNS). Recently, AQP4 has been shown to function, not only as a water channel protein, but also as an adhesion molecule that is involved in cell migration and neuroexcitation, synaptic plasticity, and learning/memory through mechanisms involved in long-term potentiation or long-term depression. The most extensively examined role of AQP4 is its ability to act as a neuroimmunological inducer. Previously, we showed that AQP4 plays an important role in neuroimmunological functions in injured mouse brain in concert with the proinflammatory inducer osteopontin (OPN). The aim of this review is to summarize the functional implication of AQP4, focusing especially on its neuroimmunological roles. This review is a good opportunity to compile recent knowledge and could contribute to the therapeutic treatment of autoimmune diseases through strategies targeting AQP4. Finally, the author would like to hypothesize on AQP4's role in interaction between reactive astrocytes and reactive microglial cells, which might occur in neurodegenerative diseases. Furthermore, a therapeutic strategy for AQP4-related neurodegenerative diseases is proposed.
ChIP-seq experiments detect the chromatin occupancy of known transcription factors in a genome-wide fashion. The comparisons of several species-specific ChIP-seq libraries done for different transcription factors have revealed a complex combinatorial and context-specific co-localization behavior for the identified binding regions. In this study we have investigated human derived ChIP-seq data to identify common cis-regulatory principles for the human transcription factor c-Fos. We found that in four different cell lines, c-Fos targeted proximal and distal genomic intervals show prevalences for either AP-1 motifs or CCAAT boxes as known binding motifs for the transcription factor NF-Y, and thereby act in a mutually exclusive manner. For proximal regions of co-localized c-Fos and NF-YB binding, we gathered evidence that a characteristic configuration of repeating CCAAT motifs may be responsible for attracting c-Fos, probably provided by a nearby AP-1 bound enhancer. Our results suggest a novel regulatory function of NF-Y in gene-proximal regions. Specific CCAAT dimer repeats bound by the transcription factor NF-Y define this novel cis-regulatory module. Based on this behavior we propose a new enhancer promoter interaction model based on AP-1 motif defined enhancers which interact with CCAAT-box characterized promoter regions.
To determine whether pre-activation of the cardiac
 catheterization lab by Emergency Health Services (EHS) with a single call system in the field was associated with reduced time to reperfusion in patients with ST-Elevation Myocardial Infarction (STEMI) undergoing primary percutaneous coronary intervention (PPCI).
Consecutive STEMI patients identified by EHS and subsequently taken to the Queen Elizabeth II Health Sciences Center (QEIIHSC) for PPCI between February 1, 2011 and January 30, 2013 were examined. Patients who had pre-activation of the catheterization lab from the field (pre-act group) after the acquisition of the LifeNet® system (Physio Control, Redmond Washington) were compared to those who had usual activation (routine group) prior to the acquisition of the LifeNet® system, for outcomes including treatment timeline data and mortality.
271 patients were included in the analysis, 149 patients in the pre-act group and 122 patients in the routine group. Door-to-device (DTD) times of less than 90min were achieved more frequently in the Pre-act group (91.9% vs. 62.2%; P<0.001). DTD time was shorter in the Pre-act group (48min IQR: 38 to 63min vs. 78min IQR: 64-101min; p=0.001) as was first medical contact-to-device (FMCTD) time (91min IQR: 78 to 106min vs. 115min IQR: 90 to 139min; P<0.001). False activation of the catheterization lab was infrequent (1.3%).
Implementation of catheterization lab pre-activation using the LifeNet® system was associated with more efficient reperfusion times as measured by reduced FMCTD and DTD times without excess false activation rates.
Trehalose is an important disaccharide that is used as a cellular protectant by many different organisms, helping these organisms better survive extreme conditions, such as dehydration, oxidative stress, and freezing temperatures. Methods to detect and accurately measure trehalose from different organisms will help us gain a better understanding of the mechanisms behind trehalose's ability to act as a cellular protectant. A liquid chromatography-tandem mass spectrometry (LC-MS/MS) assay using selected reaction monitoring mode for the detection and quantification of trehalose using maltose as an internal standard has been developed. This assay uses a commercially available LC column for trehalose separation and a standard triple quadrupole mass spectrometer, thus allowing many scientists to take advantage of this simple assay. The calibration curve from 3 to 100μM trehalose was fit best by a single polynomial. This LC-MS/MS assay directly detects and accurately quantifies trehalose, with an instrument limit of detection (LOD) that is 2-1000 times more sensitive than the most commonly-used assays for trehalose detection and quantification. Furthermore, this assay was used to detect and quantify endogenous trehalose produced by Escherichia coli (E. coli) cells, which were found to have an intracellular concentration of 8.5±0.9mM trehalose. This method thus shows promise for the reliable detection and quantification of trehalose from different biological sources.
E26 transformation-specific (ETS) transcription factor EHF plays a tumor suppressor role in prostate cancer and esophageal squamous cell carcinoma (ESCC), whereas it is overexpressed and may act as an oncogene in ovarian and mammary cancers. However, its biological role in thyroid cancer remains totally unknown. The aim of this study was to explore the biological functions of EHF and its potential as a therapeutic target in thyroid cancer. Using quantitative RT-PCR (qRT-PCR) assay, we evaluated mRNA expression of EHF in a cohort of primary papillary thyroid cancers (PTCs) and matched non-cancerous thyroid tissues. The functions of knockdown and ectopic expression of EHF in thyroid cancer cells were determine by a series of in vitro and in vivo experiments. Moreover, dual-luciferase reporter and chromatin immunoprecipitation (ChIP) assays were performed to identify its downstream targets. Our data showed that EHF expression was significantly increased in PTCs compared with matched non-cancerous thyroid tissues. EHF knockdown significantly inhibited thyroid cancer cell proliferation, colony formation, migration, invasion and tumorigenic potential in nude mice and induced cell cycle arrested and apoptosis by modulating the PI3K/Akt and MAPK/Erk signaling pathways. On the other hand, ectopic expression of EHF in thyroid cancer cells notably promoted cell growth and invasiveness. Importantly, EHF was identified as a new transcription factor for HER2 and HER3, contributing to thyroid tumorigenesis. Altogether, our findings suggest that EHF is a novel functional oncogene in thyroid cancer by transcriptionally regulating HER2 and HER3, and may represent a potential therapeutic target for this cancer.
The peer review processes as outlined in the Health Care Quality Improvement Act (HCQIA) is meant ensure quality standard of care through a self-policing mechanism by the medical community. This process grants immunity for people filing a peer review, which is meant to protect whistleblowers. However, it also creates a loophole that can be used maliciously to hinder competition. This is accentuated when surgeons are integrating new technologies, such as robotic surgery, into their practice. With more than 2000 da Vinci robots in use and more than 300 new units being shipped each year, robotic surgery has become a mainstay in the surgical field. The applications for robots continue to expand as surgeons discover their expanding capability. We need a better peer review process. That ensures the peer review is void of competitive bias. Peer reviewers need to be familiar with the procedure and the technology. The current process could stymie innovation in the name of competition.
Global consciousness on climate change problems and adaptation revolves around the disparity of information sharing and communication gap between theoretical scientific knowledge at academic end and practical implications of these at the vulnerable populations' end. Coastal communities facing socio-economic stress, like densely populated Sundarbans, are the most affected part of the world, exposed to climate change problems and uncertainties. This article explores the successes of a socio-environmental project implemented at Indian Sundarbans targeted towards economic improvement and aims at communicating environmental conservation through organized community participation.
Participatory rural appraisal (PRA) and the wealth rank tool (WRT) were used to form a "group based organization" with 2100 vulnerable families to give them knowledge about capacity building, disaster management, resource conservation and sustainable agriculture practices. Training was conducted with the selected group members on resource conservation, institution building, alternative income generation activities (AIGA) like, Poultry, Small business, Tricycle van, Organic farming and disaster management in a participatory mode. The climate change 'problems-solutions' were communicated to this socio-economically marginalized and ostracized community through participatory educational theater (PET).
WRT revealed that 45 % of the population was under economic stress. Out of 2100 beneficiaries', 1015 beneficiaries' started organic farming, 133 beneficiaries' adopted poultry instead of resource exploitive livelihood and 71 beneficiaries' engaged themselves with small business, which was the success stories of this project. To mitigate disaster, 10-committees were formed and the endemic knowledge about climate change was recorded by participatory method validated through survey by structured questionnaire. As a part of this project 87 ha of naked deforested mudflat was reclaimed with endangered mangroves involving target community members aimed to sequester CO2, control soil erosion and act as a barrier during natural disasters.
This case study concluded that participatory method of communication, aiming not only to communicate theoretical knowledge, but also to devise adaptation strategies through conservation of endemic knowledge, popularizing sustainability through Micro Finance Institutions and promoting AIGA along with motivating vulnerable community to restore degraded forest lands, could be a effective solution to practically combat climate change problems.
Tropical forests currently play a key role in regulating the terrestrial carbon cycle and abating climate change by storing carbon in wood. However, there remains considerable uncertainty as to whether tropical forests will continue to act as carbon sinks in the face of increased pressure from expanding human activities. Consequently, understanding what drives productivity in tropical forests is critical. We used permanent forest plot data from the Gola Rainforest National Park (Sierra Leone) - one of the largest tracts of intact tropical moist forest in West Africa - to explore how (1) stand basal area and tree diversity, (2) past disturbance associated with past logging, and (3) underlying soil nutrient gradients interact to determine rates of aboveground wood production (AWP). We started by statistically modeling the diameter growth of individual trees and used these models to estimate AWP for 142 permanent forest plots. We then used structural equation modeling to explore the direct and indirect pathways which shape rates of AWP. Across the plot network, stand basal area emerged as the strongest determinant of AWP, with densely packed stands exhibiting the fastest rates of AWP. In addition to stand packing density, both tree diversity and soil phosphorus content were also positively related to productivity. By contrast, historical logging activities negatively impacted AWP through the removal of large trees, which contributed disproportionately to productivity. Understanding what determines variation in wood production across tropical forest landscapes
 requires accounting for multiple interacting drivers - with stand structure, tree diversity, and soil nutrients all playing a key role. Importantly, our results also indicate that logging activities can have a long-lasting impact on a forest's ability to sequester and store carbon, emphasizing the importance of safeguarding old-growth tropical forests.
The 2003 Medicare Modernization Act (MMA) increased payments to Medicare Advantage plans and instituted a new risk-adjustment payment model to reduce plans' incentives to enroll healthier Medicare beneficiaries and avoid those with higher costs. Whether the MMA reduced risk selection remains debatable. This study uses mortality differences, nursing home utilization, and switch rates to assess whether the MMA successfully decreased risk selection from 2000 to 2012. We found no decrease in the mortality difference or adjusted difference in nursing home use between plan beneficiaries pre- and post the MMA. Among beneficiaries with nursing home use, disenrollment from Medicare Advantage plans declined from 20% to 12%, but it remained 6 times higher than the switch rate from traditional Medicare to Medicare Advantage. These findings suggest that the MMA was not associated with reductions in favorable risk selection, as measured by mortality, nursing home use, and switch rates.
The facile synthesis of Group 9 Rh(III) porphyrin-aza-BODIPY conjugates that are linked through an orthogonal Rh-C(aryl) bond is reported. The conjugates combine the advantages of the near-IR (NIR) absorption and intense fluorescence of aza-BODIPY dyes with the long-lived triplet states of transition metal rhodium porphyrins. Only one emission peak centered at about 720 nm is observed, irrespective of the excitation wavelength, demonstrating that the conjugates act as unique molecules rather than as dyads. The generation of a locally excited (LE) state with intramolecular charge-transfer (ICT) character has been demonstrated by solvatochromic effects in the photophysical properties, singlet oxygen quantum yields in polar solvents, and by the results of density functional theory (DFT) calculations. In nonpolar solvents, the Rh(III) conjugates exhibit strong aza-BODIPY-centered fluorescence at around 720 nm (ΦF =17-34 %), and negligible singlet oxygen generation. In polar solvents, enhancements of the singlet-oxygen quantum yield (ΦΔ =19-27 %, λex =690 nm) have been observed. Nanosecond pulsed time-resolved absorption spectroscopy confirms that relatively long-lived triplet excited states are formed. The synthetic methodology outlined herein provides a useful strategy for the assembly of functional materials that are highly desirable for a wide range of applications in material science and biomedical fields.
Recent studies have indicated that innate immune signalling molecules are involved in late-onset Alzheimer's disease (LOAD) risk. Amyloid beta (Aβ) accumulates in AD brain, and has been proposed to act as a trigger of innate immune responses. Caspase-4 is an important part of the innate immune response. We recently characterized transgenic mice carrying human CASP4, and observed that the mice manifested profound innate immune responses to lipopolysaccharide (LPS). Since these inflammatory processes are important in the aetiology of AD, we have now analysed the correlation of expression of caspase-4 in human brain with AD risk genes, and studied caspase-4 effects on AD-related phenotypes in APPswe/PS1deltaE9 (APP/PS1) mice. We observed that the expression of caspase-4 was strongly correlated with AD risk genes including TYROBP, TREM2, CR1, PSEN1, MS4A4A and MS4A6A in LOAD brains. Caspase-4 expression was upregulated in CASP4/APP/PS1 mice in a region-specific manner, including hippocampus and prefrontal cortex. In APP/PS1 mice, caspase-4 expression led to impairments in the reversal phase of a Barnes maze task and in hippocampal synaptic plasticity, without affecting soluble or aggregated Aβ levels. Caspase-4 was expressed predominantly in microglial cells, and in the presence of CASP4, more microglia were clustered around amyloid plaques. Furthermore, our data indicated that caspase-4 modulates microglial cells in a manner that increases proinflammatory processes. We propose that microglial caspase-4 expression contributes to the cognitive impairments in AD, and that further study of caspase-4 will enhance our understanding of AD pathogenesis and may lead to novel therapeutic targets in AD.
Neural networks that regulate binge eating remain to be identified, and effective treatments for binge eating are limited.
We combined neuroanatomic, pharmacologic, electrophysiological, Cre-lox, and chemogenetic approaches to investigate the functions of 5-hydroxytryptamine (5-HT) 2C receptor (5-HT2CR) expressed by dopamine (DA) neurons in the regulation of binge-like eating behavior in mice.
We showed that 5-HT stimulates DA neural activity through a 5-HT2CR-mediated mechanism, and activation of this midbrain 5-HT→DA neural circuit effectively inhibits binge-like eating behavior in mice. Notably, 5-HT medications, including fluoxetine, d-fenfluramine, and lorcaserin (a selective 5-HT2CR agonist), act on 5-HT2CRs expressed by DA neurons to inhibit binge-like eating in mice.
We identified the 5-HT2CR population in DA neurons as one potential target for antibinge therapies, and provided preclinical evidence that 5-HT2CR agonists could be used to treat binge eating.
Fucoidan was purified from seaweed, Turbinaria conoides. Isolated fragments were characterized with NMR ((13)C, (1)H), Gas Chromatography-Mass Spectronomy (GC-MS) and HPLC analysis. The autohydrolysate of fucoidans consisted of sulfated fuco-oligosaccharides having the backbone of α-(1, 3)-linked fuco-pyranose derivatives and minor components of galactose, glucose, mannose and xylose sugars. Fucoidan induced a dose-dependent reduction in cell survival of lung cancer A549 cells by MTT assay (GI50, 75μg/mL). However, it was not cytotoxic to a non-tumorigenic human keratinocyte cell line of skin tissue (HaCaT) (GI50>1.0mg/mL). The apoptotic cells in fucoidan-treated A549 cells were visualized by laser confocal microscopy and cell cycle analysis showed induction of G0/G1 phase arrest of the cell progression cycle. Further, CFSE labeling and flow cytometry highlighted that fucoidan significantly (P<0.05) inhibited the proliferation rate of A549 cells by up to 2-fold compared with the control cells. It is concluded that fucoidan has the potential to act as an anti-proliferative agent on lung carcinoma (A549) cells.
South Africa is undergoing epidemiological and nutrition transitions with associated increases in the incidence of overweight, obesity and diet-related chronic diseases. With the emergence of the nutrition transition in South Africa, there is an urgent need for interventions to prevent overweight and obesity in children and adolescents as risk factors for chronic diseases in adolescence may track throughout later life. This research explored the potential for faith-based organisations (FBOs) to be used as community organisations for overweight and obesity prevention interventions in adolescents by assessing the readiness of religious leaders to engage in such interventions.
Surveys and focus group discussions (FGDs) were conducted with 51 religious leaders in Johannesburg and Soweto. The Community Readiness Model (CRM) survey was chosen to determine the stage of readiness of this community regarding overweight and obesity prevention. Six different dimensions were assessed in the CRM (community efforts, knowledge of efforts, leadership, community climate, knowledge of the issue, resources). The surveys were scored according to the CRM protocol. The survey data were supplemented with findings from FGDs. Thematic analysis was used to analyse the FGDs.
The mean community readiness score was 2.57 ± 0.76 which equates with the "denial/resistance stage". The mean readiness score for resources was the highest of all the dimensions (3.77 ± 0.28), followed by knowledge of the issue (3.20 ± 0.51). The lowest score was seen for community knowledge of efforts (1.77 ± 1.50), followed by community climate (2.00 ± 0.64). FGDs helped interpret the CRM scores. FGDs showed that religious leaders were enthusiastic and recognised that their role was not limited solely to spiritual guidance and mentoring, but also to physical well-being.
Religious leaders recognised that they act as role models within the community and thus have a role to play in improving adolescent health. They have some knowledge about the overweight/obesity issue and some of the resources could be made available to support overweight/obesity prevention-related initiatives. However, the low community knowledge of efforts and the negative prevailing attitude of the community towards overweight and obesity highlight the need to increase awareness of this issue prior to implementing initiatives on overweight and obesity prevention.
The first elateroid fossils from the Upper Jurassic Talbragar Fish Bed in Australia are described and illustrated. Wongaroo amplipectorale gen. et sp. n., based on two specimens, is placed in the family Cerophytidae due to its convex, posteriorly weakly angled and laterally carinate pronotum obscuring the head in dorsal view, its relatively long, pointed elytra and slender legs, its 9-striate elytra with deep basal pits and the absence of metacoxal plates. Beattieellus jurassicus gen. et sp. n., described from one specimen, possesses the acutely angled pronotum without a carina on the posterolateral angles and the ventral click apparatus typical of Eucnemidae and is classified in this family. Assignment of it to a eucnemid subfamily is impossible because of the insufficient preservation of relevant characters in the fossil. Four other elateroid fossils, possibly representing
 eucnemids and elaterids, are illustrated and briefly described but not named, due to their insufficient preservation. These fossils represent the first of their kind in Australia and in the Southern Hemisphere, and Beattieellus is also the oldest eucnemid fossil known and extends the fossil record of Eucnemidae into the Upper Jurassic. The discovery of elateroid fossils in the Talbragar Fish Bed adds to the coleopteran diversity of this ancient lake ecosystem, indicating that it was well wooded and provided suitable habitats of rotten wood for the development of the larvae of these taxa.
Effective pest management relies on accurate delimitation of species and, beyond this, on accurate species identification. Mitochondrial COI sequences are useful for providing initial indications in delimiting species but, despite acknowledged limitations in the method, many studies involving COI sequences and species problems remain unresolved. Here we illustrate how such impasses can be resolved with microsatellite and nuclear sequence data, to assess more directly the amount of gene flow between divergent lineages. We use a population genetics approach to test for random mating between two 8 ± 2% divergent COI lineages of the rusty grain beetle, Cryptolestes ferrugineus (Stephens). This species has become strongly resistant to phosphine, a fumigant used worldwide for disinfesting grain. The possibility of cryptic species would have significant consequences for resistance management, especially if resistance was confined to one mitochondrial lineage. We find no evidence of restricted gene flow or nonrandom mating across the two COI lineages of these beetles, rather we hypothesize that historic population structure associated with early Pleistocene climate changes likely contributed to divergent lineages within this species.
Tumor necrosis factor alpha (TNF) is increased in depression and clinical-trial evidence indicates that blocking peripheral TNF has some antidepressant efficacy. In rodents, peripheral or intracerebroventricular TNF results in sickness e.g. reduced body weight, altered emotional behavior and impaired memory. However, the underlying pathways and responsible brain regions are poorly understood. The aim of this mouse study was to increase understanding by comparing the effects of sustained increases in TNF in the circulation, in brain regions impacted by increased circulating TNF, or specific brain regions. Increased peripheral TNF achieved by repeated daily injection (IP-TNF) or osmotic pump resulted in decreased body weight, decreased saccharin (reward) consumption, and increased memory of an aversive conditioned stimulus. These effects co-occurred with increased plasma interleukin-6 and increased IP-derived TNF in brain peri-ventricular regions. An adenovirus-associated viral TNF vector (AAV-TNF) was constructed, brain injection of which resulted in dose-dependent, sustained and region-specific TNF expression, and was without effect on blood cytokine levels. Lateral ventricle AAV-TNF yielded increased TNF in the same brain regions as IP-TNF. In contrast to IP-TNF it was without effect on body weight, saccharin consumption and fear memory, although it did increase anxiety. Hippocampal AAV-TNF led to decreased body weight. It increased conditioning to but not subsequent memory of an aversive context, suggesting impaired consolidation; it also increased anxiety. Amygdala AAV-TNF was without effect on body weight and aversive stimulus learning-memory, but reduced saccharin consumption and increased anxiety. This study adds significantly to the evidence that both peripheral and brain region-specific increases in TNF lead to both sickness and depression- and anxiety disorder-relevant behavior and do so via different pathways. It thereby highlights the complexity in terms of indirect and direct pathways via which increased TNF can act and which need to be taken into account when considering it as a therapeutic target.
Climate change is expected to cause extensive shifts in the epidemiology of infectious and vector-borne diseases. Scenarios on the effects of climate change typically attribute altered distribution of communicable diseases to a rise in average temperature and altered incidence of infectious diseases to weather extremes.
Recent evaluations of the effects of climate change on Hawaii have not explored this link. It may be expected that Hawaii's natural geography and robust water, sanitation, and health care infrastructure renders residents less vulnerable to many threats that are the focus on smaller, lesser developed, and more vulnerable Pacific islands. In addition, Hawaii's communicable disease surveillance and response system can act rapidly to counter increases in any disease above baseline and to redirect resources to deal with changes, particularly outbreaks due to exotic pathogens.
The evidence base examined in this article consistently revealed very low climate sensitivity with respect to infectious and mosquito-borne diseases.
A community resilience model is recommended to increase adaptive capacity for all possible climate change impacts rather an approach that focuses specifically on communicable diseases. (Disaster Med Public Health Preparedness. 2016;page 1 of 8).
The transfer process of graphene onto the surface of oxide substrates is well known. However, for many devices, we require high quality oxide thin films on the surface of graphene. This step is not understood. It is not clear why the oxide should adopt the epitaxy of the underlying oxide layer when it is deposited on graphene where there is no lattice match. To date there has been no explanation or suggestion of mechanisms which clarify this step. Here we show a mechanism, supported by first principles simulation and structural characterisation results, for the growth of oxide thin films on graphene. We describe the growth of epitaxial SrTiO3 (STO) thin films on a graphene and show that local defects in the graphene layer (e.g. grain boundaries) act as bridge-pillar spots that enable the epitaxial growth of STO thin films on the surface of the graphene layer. This study, and in particular the suggestion of a mechanism for epitaxial growth of oxides on graphene, offers new directions to exploit the development of oxide/graphene multilayer structures and devices.
Accessory attachments of the levator scapulae (LS) muscle have been described in the literature in previous cadaveric studies, but there is little knowledge about the incidence and distribution. Knowledge of LS accessory attachments is relevant to clinicians working in the fields of radiology, surgery, neurology, and musculoskeletal medicine. The purpose of this study was to explore the incidence and spectrum of LS caudal accessory attachments in vivo using magnetic resonance (MR) imaging in a young cohort.
MR images of the cervical spine were obtained from 37 subjects (13 males and 24 females) aged 18-36 years using an axial T1-weighted spin echo sequence acquired from a 3-Tesla MR scanner. The LS muscle was identified, and the presence of caudal accessory attachments was recorded and described.
LS caudal accessory attachments were identified in 16 subjects (4 right, 6 left, and 6 bilateral; 12 female). Ten had unilateral accessory attachments to the serratus anterior, serratus posterior superior or the first/second rib. Four had bilateral accessory attachments to serratus anterior. One had bilateral accessory attachments to serratus posterior superior and unilateral accessory attachment to serratus anterior. One had bilateral attachments to both muscles.
Both unilateral and bilateral LS caudal accessory attachments were present in nearly half of the subjects examined. They were relatively more frequent in females than males. The findings indicate that these accessory attachments are common, and in some cases, those accessory attachments can occur bilaterally and to more than one site.
Metal-organic frameworks have shown interesting features for biomedical applications, such as drug delivery and imaging agents. The benchmarked mesoporous iron(III) trimesate MIL-100 MOF nanocarrier combines progressive release of high drug cargoes with absence of visible in vivo toxicity. Although in a previous study pharmacokinetics and biodistribution of MIL-100 nanoparticles were evaluated in the long term (from 24h to 1 month), the crucial times for drug targeting and delivery applications are shorter (up to 24h). Thus, this work aims to study the blood circulating profile and organ accumulation of MIL-100 nanocarrier at early times after administration. For this purpose, after intravenous administration to rats, both constitutive components of MIL-100 (trimesate and iron) were quantified by high performance liquid chromatography and a spectrophotometric method, respectively. The pharmacokinetic profile suggested that the nanoparticles act as a depot in the blood stream during the first hours before being cleared. Accumulation took mainly place in the liver and, in some extent, in the spleen. Nevertheless, histological studies demonstrated the absence of morphological alterations due to the presence of the particles in these organs. Liver function was however slightly altered as reflected by the increased plasma aspartate aminotransferase concentrations. Finally trimesate was progressively eliminated in urine.
Direct interaction between Red blood cells (RBCs) and platelets is known for a long time. The bleeding time is prolonged in anemic patients independent of their platelet count and could be corrected by transfusion of RBCs, which indicates that RBCs play an important role in hemostasis and platelet activation. However, in the last few years, opposing mechanisms of platelet inhibition by RBCs derived nitric oxide (NO) were proposed. The aim of our study was to identify whether RBCs
 could produce NO and activate soluble guanylate cyclase (sGC) in platelets.
To test whether RBCs could activate sGC under different conditions (whole blood, under hypoxia, or even loaded with NO), we used our well-established and highly sensitive models of NO-dependent sGC activation in platelets and activation of purified sGC. The activation of sGC was monitored by detecting the phosphorylation of Vasodilator Stimulated Phosphoprotein (VASP(S239)) by flow cytometry and Western blot. ANOVA followed by Bonferroni's test and Student's t-test were used as appropriate.
We show that in the whole blood, RBCs prevent NO-mediated inhibition of ADP and TRAP6-induced platelet activation. Likewise, coincubation of RBCs with platelets results in strong inhibition of NO-induced sGC activation. Under hypoxic conditions, incubation of RBCs with NO donor leads to Hb-NO formation which inhibits sGC activation in platelets. Similarly, RBCs inhibit activation of purified sGC, even under conditions optimal for RBC-mediated generation of NO from nitrite.
All our experiments demonstrate that RBCs act as strong NO scavengers and prevent NO-mediated inhibition of activated platelets. In all tested conditions, RBCs were not able to activate platelet or purified sGC.
Intracellular accumulation of free zinc contributes to neuronal death in brain injuries such as ischemia and epilepsy. Pyruvate, a glucose metabolite, has been shown to block zinc neurotoxicity. However, it is largely unknown how pyruvate shows such a selective and remarkable protective effect. In this study, we sought to find a plausible mechanism of pyruvate protection against zinc toxicity. Pyruvate almost completely blocked cortical neuronal death induced by zinc, yet showed no protective effects against death induced by calcium (ionomycin, NMDA) or ferrous iron. Of the TCA cycle intermediates, citrate, isocitrate, and to a lesser extent oxaloacetate, protected against zinc toxicity. We then noted with LC-MS/MS assay that exposure to pyruvate, and to a lesser degree oxaloacetate, increased levels of citrate and isocitrate, which are known zinc chelators. While pyruvate added only during zinc exposure did not reduce zinc toxicity, citrate and isocitrate added only during zinc exposure, as did extracellular zinc chelator CaEDTA, completely blocked it. Furthermore, addition of pyruvate after zinc exposure substantially reduced intracellular zinc levels. Our results suggest that the remarkable protective effect of pyruvate against zinc cytotoxicity may be mediated indirectly by the accumulation of intracellular citrate and isocitrate, which act as intracellular zinc chelators.
The activity of the hypothalamus-pituitary-thyroid axis (HPT) is coordinated by hypophysiotropic thyrotropin releasing hormone (TRH) neurons present in the paraventricular nucleus of the hypothalamus. Hypophysiotropic TRH neurons act as energy sensors. TRH controls the synthesis and release of thyrotropin, which activates the synthesis and secretion of thyroid hormones; in target tissues, transporters and deiodinases control their local availability. Thyroid hormones regulate many functions, including energy homeostasis. This review discusses recent evidence that covers several aspects of TRH role in HPT axis regulation. Knowledge about the mechanisms of TRH signaling has steadily increased. New transcription factors engaged in TRH gene expression have been identified, and advances made on how they interact with signaling pathways and define the dynamics of TRH neurons response to acute and/or long-term influences. Albeit yet incomplete, the relationship of TRH neurons activity with positive energy balance has emerged. The importance of tanycytes as a central relay for the feedback control of the axis, as well as for HPT responses to alterations in energy balance, and other stimuli has been reinforced. Finally, some studies have started to shed light on the interference of prenatal and postnatal stress and nutrition on HPT axis programing, which have confirmed the axis susceptibility to early insults.
Mitogen activated protein kinases (MAPK) pathways play a key role in orchestrating the eukaryotic cellular response to different stimuli. In this process, phosphorylation of both conserved threonine and tyrosine residues of MAPKs is essential for their activation. Identification of tyrosine and dual specificity protein phosphatases capable of dephosphorylating these phosphosites is thus critical to gain insight into their regulation. Due to the conservation of pivotal elements in eukaryotic signaling, yeast has turned into a valuable tool to increase the knowledge of MAPK signaling in other cell types. Here we describe an in vivo method to evaluate the capacity of a protein, from yeast or other origin, to act as a MAPK phosphatase. It relies on the ability of the phosphatase to reduce, when overexpressed, both the amount of activated MAPK and the transcription from a specific promoter regulated by the corresponding pathway. To this end, the pathway has to be previously activated, preferentially through overexpression of a hyperactive allele of an upstream component within the MAPK module. Additionally, the ability of an overexpressed "trapping" inactive phosphatase version to modify these readouts is also analyzed. Western blotting analysis with specific anti-phospho MAPK antibodies and flow cytometry-based determination of fluorescence produced by GFP whose expression is driven by MAPK-regulated promoters are the selected techniques for monitoring these readouts.
In this work, we developed a simple yet robust single particle scattering intensity measurement method for the quantification of cancer-related biomarkers. The design is based on the plasmonic coupling effect between noble metal nanoparticles. First, the primary and secondary antibodies were conjugated onto the surface of 60 nm gold nanoparticles (AuNPs, act as capture probes) and 50 nm silver nanoparticles (AgNPs, act as signal amplification probes) respectively. In the presence of corresponding antigen, a sandwiched immunocomplex was formed, resulting a significantly enhanced scattering intensity in contrast to that of individual probes. By measuring the intensity change of the particles with a dark-field microscope (DFM), the amount of target protein could be accurately quantified. As a proof of concept experiment, quantification of three types of antigens, including carcinoembryonic antigen (CEA), prostate-specific antigen (PSA) and alpha fetoprotein (AFP) by this platform was demonstrated with limit of detection (LOD) of 1.7, 3.3, and 5.9 pM, respectively, with a linear dynamic range of 0 to 300 pM. Furthermore, to elucidate the potential in clinical application, the content of antigens in a serum sample was also quantified directly without additional sample pretreatment. In order to validate the reliability of this method, the measured result was also compared with that obtained by regular enzyme-linked immunosorbent assay (ELISA) kit, showing good consistency between these two data sets. Therefore, owing to the simplicity and accuracy of this method, it could be potentially applied for massive disease screening in clinical assay in the future.
ATP-binding cassette (ABC) transporters are a huge family of ATP-dependent transmembrane proteins whose main function is exporting or importing substances or molecules through the cell membranes, plasma cell membrane, or inner membranes in organelles. They fulfill these functions by maintaining cell integrity, metabolism, and homeostasis. They are expressed in a variety of tissues as they transport numerous essential compounds including lipids and other signaling molecules. ABC transporters became widely studied since the discovery of their ability to carry a multitude of xenobiotics, including therapeutic drugs, and in light of the fact that they represent a hurdle for the treatment of resistant cancers. In contrast, the role of ABC transporters in neurological diseases like Alzheimer`s and Parkinson`s, depression, schizophrenia, and epilepsy remains controversial and their mechanism of action in these pathologies remains elusive, thus hindering the implementation of therapies aimed at modulating the functions of these transporters. To date, a number of natural and synthetic compounds are known to act as inhibitors, substrates, and even inducers of these transporters, being able to modulate their expression and/or function; however, their implication as therapeutic agents is far from reaching wide clinical utilization. This review highlights the importance of overcoming the challenges posed by ABC transporters in drug development.
The treatment of microbial infections is becoming increasingly challenging because of limited therapeutic options and the growing number of pathogenic strains that are resistant to current antibiotics. There is an urgent need to identify molecules with novel modes of action to facilitate the development of new and more effective therapeutic agents. The anti-mycobacterial activity of the C17 diyne natural products falcarinol and panaxydol has been described previously; however, their mode of action remains largely undetermined in microbes. Gene expression profiling was therefore used to determine the transcriptomic response of Mycobacterium smegmatis upon treatment with falcarinol and panaxydol to better characterize the mode of action of these C17 diynes.
Our analyses identified 704 and 907 transcripts that were differentially expressed in M. smegmatis after treatment with falcarinol and panaxydol respectively. Principal component analysis suggested that the C17 diynes exhibit a mode of action that is distinct to commonly used antimycobacterial drugs. Functional enrichment analysis and pathway enrichment analysis revealed that cell processes such as ectoine biosynthesis
 and cyclopropane-fatty-acyl-phospholipid synthesis were responsive to falcarinol and panaxydol treatment at the transcriptome level in M. smegmatis. The modes of action of the two C17 diynes were also predicted through Prediction of Activity Spectra of Substances (PASS). Based upon convergence of these three independent analyses, we hypothesize that the C17 diynes inhibit fatty acid biosynthesis, specifically phospholipid synthesis, in mycobacteria.
Based on transcriptomic responses, it is suggested that the C17 diynes act differently than other anti-mycobacterial compounds in M. smegmatis, and do so by inhibiting phospholipid biosynthesis.
Anticoagulation using intravenous bolus administration of unfractionated heparin (UFH) aims to prevent thromboembolic complications in children undergoing cardiac catheterization (CC). Optimal UFH dosage is needed to reduce bleeding complications. We analyzed the effect of bolus UFH on activated clotting time (ACT) in children undergoing CC focusing on age-dependent, anesthesia-related, or disease-related influencing factors. This retrospective single-center study of 183 pediatric patients receiving UFH during CC analyzed ACT measured at the end of CC. After bolus administration of 100 IU UFH/kg body weight, ACT values between 105 and 488 seconds were reached. Seventy-two percent were within target level of 160 to 240 seconds. Age-dependent differences were not obtained (P = .407). The ACT values were lower due to hemodilution (total fluid and crystalloid administration during CC, both P < .001), with premedication of acetylsalicylic acid (P = .014) and low-molecular-weight heparin (P = .049). Arterial thrombosis (3.85%), venous thrombosis (0.55%), and bleeding (1.65%) following CC did not correlate with ACT values but occurred more frequently in children between 1 month and 1 year of age (91%). In conclusion, with a bolus of 100 IU UFH/kg, an ACT target level of 160 to 240 seconds can be achieved during CC in children in 72%, which is influenced by hemodilution and anticoagulant and antiplatelet premedication but not by age.
This guideline summarizes the current view of the European Association of Nuclear Medicine Drug Development Committee. The purpose of this guideline is to guarantee a high standard of PET studies that are aimed at measuring target occupancy in the brain within the framework of development programs of drugs that act within the central nervous system (CNS drugs). This guideline is intended to present information specifically adapted to European practice. The information provided should be applied within the context of local conditions and regulations.
Legumes form symbiotic associations with either nitrogen-fixing bacteria or arbuscular mycorrhizal fungi. Formation of these two symbioses is regulated by a common set of signalling components that act downstream of recognition of rhizobia or mycorrhizae by host plants. Central to these pathways is the calcium and calmodulin-dependent protein kinase (CCaMK)-IPD3 complex which initiates nodule organogenesis following calcium oscillations in the host nucleus. However, downstream signalling events are not fully understood. Here we show that Medicago truncatula DELLA proteins, which are the central regulators of gibberellic acid signalling, positively regulate rhizobial symbiosis. Rhizobia colonization is impaired in della mutants and we provide evidence that DELLAs can promote CCaMK-IPD3 complex formation and increase the phosphorylation state of IPD3. DELLAs can also interact with NSP2-NSP1 and enhance the expression of Nod-factor-inducible genes in protoplasts. We show that DELLA is able to bridge a protein complex containing IPD3 and NSP2. Our results suggest a transcriptional framework for regulation of root nodule symbiosis.
The scope of FDA's jurisdiction over laboratory-developed tests (LDTs), and whether FDA has such jurisdiction at all, has been a heavily debated issue over the past several years. If FDA moves forward with its guidance, or Congress takes action to reform LDT and IVD regulation, a fundamental question that needs to be answered is how to divide activities regulated by FDCA from those regulated by CLIA. In this article, we consider FDA's authority to regulate LDTs and the policy implications of regulation, and discuss an idea for a fact-driven framework to distinguish FDCA- and CLIA- activities.
The tobacco calmodulin-like protein rgs-CaM is involved in host defense against virus and is reported to possess an associated RNA silencing suppressor activity. Rgs-CaM is also believed to act as an antiviral factor by interacting and targeting viral silencing suppressors for autophagic degradation. Despite these functional data, calcium interplay in the modulation of rgs-CaM is still poorly understood. Here we show that rgs-CaM displays a prevalent alpha-helical conformation and possesses three functional Ca(2+)-binding sites. Using computational modeling and molecular dynamics simulation, we demonstrate that Ca(2+) binding to rgs-CaM triggers expansion of its tertiary structure with reorientation of alpha-helices within the EF-hands. This conformational change leads to the exposure of a large negatively charged region that may be implicated in the electrostatic interactions between rgs-CaM and viral suppressors. Moreover, the kd values obtained for Ca(2+) binding to the three functional sites are not within the affinity range of a typical Ca(2+) sensor.
The Affordable Care Act (ACA) Medicaid expansion varies in availability across states.
We compared characteristics of low-income uninsured residents in both Medicaid nonexpanding and expanding states with respect to their dietary quality, health risk factors, and access to care.
Data from the 2007-2012 National Health and Nutrition Examination Survey was matched with the Kaiser Family Foundation Medicaid expansion data. Bivariate and multivariate regressions were estimated to assess differences across expanding and non-expanding states.
The non-expansion group had a lower Healthy Eating Index score (41.8 vs. 44.1, p-value=0.006), a higher Body Mass Index (29.9 vs. 28.9, p-value=0.032), higher obesity prevalence (41% vs. 33%, p-value=0.007), and lower asthma prevalence (14.8% vs. 19.7%, p-value=0.037) compared with the expansion group.
Differences across states in Medicaid coverage under the ACA may lead to widening disparities in health outcomes between expanding and non-expanding states.
Designing supported well-defined bis(carbene) complexes remains a key challenge in heterogeneous catalysis. The reaction of W(≡CtBu)(CH2 tBu)3 with amine-modified mesoporous SBA15 silica, which has vicinal silanol/silylamine pairs [(≡SiOH)(≡SiNH2 )], leads to [(≡SiNH2 -)(≡SiO-)W(≡CHtBu)(CH2 tBu)2 ] and [(≡SiNH2 -)(≡SiO-)W(=CHtBu)2 (CH2 tBu). Variable temperature, (1) H-(1) H 2D double-quantum, (1) H-(13) C HETCOR, and HETCOR with spin diffusion solid-state NMR spectroscopy demonstrate tautomerization between the alkyl alkylidyne and the bis(alkylidene) on the SBA15 surface. Such equilibrium is possible through the coordination of W to the surface [(≡Si-OH)(≡Si-NH2 )] groups, which act as a [N,O] pincer ligand. DFT calculations provide a rationalization for the surface-complex tautomerization and support the experimental results. This direct observation of such a process shows the strong similarity between molecular mechanisms in homogeneous and heterogeneous catalysis. In propane metathesis (at 150 °C), the tungsten bis(carbene) tautomer is favorable, with a turnover number (TON) of 262. It is the highest TON among all the tungsten alkyl-supported catalysts.
Climate change can drive major shifts in community composition and interactions between resident species. However, the magnitude of these changes depends on the type of interactions and the biome in which they take place. We review the existing conceptual framework for how climate change will influence tropical plant-herbivore interactions and formalize a similar framework for the temperate zone. We then conduct the first biome-specific tests of how plant-herbivore interactions change in response to climate-driven changes in temperature, precipitation, ambient CO2, and ozone. We used quantitative meta-analysis to compare predicted and observed changes in experimental studies. Empirical studies were heavily biased toward temperate systems, so testing predicted changes in tropical plant-herbivore interactions was virtually impossible. Furthermore, most studies investigated the effects of CO2 with limited plant and herbivore species. Irrespective of location, most studies manipulated only one climate change factor despite the fact that different factors can act in synergy to alter responses of plants and herbivores. Finally, studies of belowground plant-herbivore interactions were also rare; those conducted suggest that climate change could have major effects on belowground subsystems. Our results suggest that there is a disconnection between the growing literature proposing how climate change will influence plant-herbivore interactions and the studies testing these predictions. General conclusions will also be hampered without better integration of above- and belowground systems, assessing the effects of multiple climate change factors simultaneously, and using greater diversity of species in experiments.
Corneal neuropathy is a recently described disease process that is not well understood and is likely underdiagnosed as a result. This is the first reported case of an acquired corneal neuropathy associated with malposition of an Ex-PRESS shunt.
A single case report.
We report the case of a 50-year-old man with a history of multiple procedures for glaucoma who subsequently developed photoallodynia and corneal neuropathy in association with malposition of an Ex-PRESS shunt in the peripheral cornea. Laser confocal
 microscopy (HRT3/RCM) of the cornea showed the presence of neuromas, decreased nerve density, and a significant increase of dendritiform immune cells consistent with our diagnosis. Initial treatment with steroid pulse therapy did not result in decreased inflammation or symptomatic improvement leading to surgical explantation of the shunt. One month after surgery, there was noticeable improvement in the patient's pain and photoallodynia (approximately 40%) as well as the abnormalities seen on confocal microscopy.
We hypothesize that poor Ex-PRESS shunt positioning can act as a nidus for corneal inflammation, resulting in corneal neuropathy and lowering of the nociception threshold.
Salsolinol (1-methyl-6,7-dihydroxy-1,2,3,4-tetrahydroisoquinoline) is thought to regulate dopaminergic neurons and to act as a mediator in the neuroendocrine system. We have previously reported that exogenous salsolinol evokes enteric neuronal cell death, leading to the impairment of myenteric neurons density and abnormal intestinal transit in rats. We also observed significant reduction of body weight, related to the disrupted gastrointestinal homeostasis. e aim of current study was to evaluate the influence of prolonged salsolinol administration body weight, food intake, adipose tissue accumulation and fad pad adipocyte morphological parameters assessed by image analysis. Male Wistar rats were subjected to continuous intraperitoneal low dosing of salsolinol - 200 mg/kg in total with ALZET osmotic mini-pumps (Durtec, USA) for 2 or 4 weeks with either normal or high-fat diet. Appropriate groups served as the controls. Food intake, body weight were measured each morning. Both epididymal fat pads were dissected, weighted and processed for routine hematoxylin and eosin staining. e following parameters: cell area, perimeter, long and short axis, aspect ratio and circularity factor were assessed in stained specimens with the image analysis system (Multiscan, Poland). Salsolinol administration significantly reduced total body mass with no differences in total food intake between the groups. The epididymal fat pad weight over final body mass ratio was lower in salsolinol treated rats on high fat diet in comparison with the control groups. e area, perimeter, short and long axis of the fad pad adipocytes were significantly decreased in salsolinol treated animals in comparison with relevant controls. Salsolinol targets some regulatory mechanisms concerned with the basic rat metabolism. Prolonged peripheral salsolinol administration in rats significantly decreases the adipocyte size, and such effect is related to the weight loss and reduced adipose tissue accumulation.
Increasing evidence suggests that discrete neural networks that mediate emotion processing are activated when mothers respond to infant's images or cries. Accumulating data also indicate that natural variation in maternal caregiving behavior is related to maternal oxytocin (OT) levels. However, brain activation to infant cues has not been studied comparing mothers at disparate ends of the "maternal sensitivity" spectrum. Based on observed mother-infant play interaction at 4-6 months postpartum in 80 antenatally recruited mothers, 15 mothers with the highest sensitivity (HSMs) and 15 mothers with the lowest sensitivity (LSMs) were followed at 7-9 months using functional magnetic resonance imaging (fMRI) to examine brain responses to viewing videos of their "own" versus an "unknown" infant in 3 affect states (neutral, happy, and sad). Plasma OT measurements were taken from mothers following play interactions with their infant. Compared with LSMs, HSMs showed significantly greater brain activation in right superior temporal gyrus (STG) in response to own versus unknown neutral infant and to own happy versus neutral control. Changes in brain activation were significantly negatively correlated with plasma OT responses in HSMs mothers. Conversely, compared with HSMs, LSMs showed no significant activation difference in response to own infant separately or in contrast to unknown infant. Activation of STG may index sensitive maternal response to own infant stimuli. Sensitive parenting may have its unique profile in relation to brain responses which can act as biomarkers for future intervention studies that enhance sensitivity of maternal care. (PsycINFO Database Record
The success of quantitative real-time reverse transcription polymerase chain reaction (RT-qPCR) to quantify gene expression depends on the stability of the reference genes used for data normalization. To date, systematic screening for reference genes in persimmon (Diospyros kaki Thunb) has never been reported. In this study, 13 candidate reference genes were cloned from 'Nantongxiaofangshi' using information available in the transcriptome database. Their expression stability was assessed by geNorm and NormFinder algorithms under abiotic stress and hormone stimulation. Our results showed that the most suitable reference genes across all samples were UBC and GAPDH, and not the commonly used persimmon reference gene ACT. In addition, UBC combined with RPII or TUA were found to be appropriate for the "abiotic stress" group and α-TUB combined with PP2A were found to be appropriate for the "hormone stimuli" group. For further validation, the transcript level of the DkDREB2C homologue under heat stress was studied with the selected genes (CYP, GAPDH, TUA, UBC, α-TUB, and EF1-α). The results suggested that it is necessary to choose appropriate reference genes according to the test materials or experimental conditions. Our study will be useful for future studies on gene expression in persimmon.
Plant volatiles play important roles in attraction of certain pollinators and in host location by herbivorous insects. Virus infection induces changes in plant volatile emission profiles, and this can make plants more attractive to insect herbivores, such as aphids, that act as viral vectors. However, it is unknown if virus-induced alterations in volatile production affect plant-pollinator interactions. We found that volatiles emitted by cucumber mosaic virus (CMV)-infected tomato (Solanum lycopersicum) and Arabidopsis thaliana plants altered the foraging behaviour of bumblebees (Bombus terrestris). Virus-induced quantitative and qualitative changes in blends of volatile organic compounds emitted by tomato plants were identified by gas chromatography-coupled mass spectrometry. Experiments with a CMV mutant unable to express the 2b RNA silencing suppressor protein and with Arabidopsis silencing mutants implicate microRNAs in regulating emission of pollinator-perceivable volatiles. In tomato, CMV infection made plants emit volatiles attractive to bumblebees. Bumblebees pollinate tomato by 'buzzing' (sonicating) the flowers, which releases pollen and enhances self-fertilization and seed production as well as pollen export. Without buzz-pollination, CMV infection decreased seed yield, but when flowers of mock-inoculated and CMV-infected plants were buzz-pollinated, the increased seed yield for CMV-infected plants was similar to that for mock-inoculated plants. Increased pollinator preference can potentially increase plant reproductive success in two ways: i) as female parents, by increasing the probability that ovules are fertilized; ii) as male parents, by increasing pollen export. Mathematical modeling suggested that over a wide range of conditions in the wild, these increases to the number of offspring of infected susceptible plants resulting from increased pollinator preference could outweigh underlying strong selection pressures favoring pathogen resistance, allowing genes for disease susceptibility to persist in plant populations. We speculate that enhanced pollinator service for infected individuals in wild plant populations might provide mutual benefits to the virus and its susceptible hosts.
Few population-based studies have assessed the effectiveness of adjuvant chemotherapy (ACT) in stage III colon cancer patients according to age. We sought to quantify the prevalence of ACT use and the absolute and relative survival benefit of ACT overall and by age in a population-based cohort.
Stage III patients with adenocarcinoma of the colon identified by the Georgia Comprehensive Cancer Registry for the years 2000-07 were eligible (final N=3057). We utilized Poisson regression to obtain adjusted mortality rates (MR) and Cox proportional hazards models to obtain adjusted hazard ratios (HRs) for 5-year overall survival. We evaluated control of confounding by comparing HRs obtained via multivariable modeling (MM), propensity score weighting (PSW), and propensity score matching (PSM).
Just over one-third of colon cancer patients did not receive ACT, and the proportion increased with age. Overall, receipt of ACT conferred an absolute (MR difference [No ACT rate-ACT rate] 25.4 deaths/1000 person-years [py], 95% confidence interval [CI]: 19.1-32.7 deaths/1000 py) and relative (MM HR=0.67, 95% CI: 0.59-0.76) survival benefit. The survival benefit was demonstrated across age groups. MM and propensity score methods yielded highly similar HRs.
Unless contraindicated, efforts to ensure receipt of ACT for stage III colon cancer patients up to 84 years of age are needed to improve the prognosis of patients with node-positive disease.
20-30% of patients with inflammatory bowel disease (IBD) present before age 18 years, eventually requiring transfer to adult care. Vulnerability during transfer may be exacerbated by loss of insurance. A provision of the Affordable Care Act (ACA) allows young adults (YAs) to remain on parental private insurance through age 25 years. There has been a decrease in uninsured YAs since its implementation in 2010. Little is known about whether insurance coverage of YAs with IBD has been affected.
To determine whether proportion of uninsured
 YAs with IBD has changed following implementation of extended dependent eligibility under the ACA.
We conducted a cross-sectional analysis of hospitalized patients with IBD, identified in the Nationwide Inpatient Sample (NIS) using diagnostic codes, to estimate proportions of insurance coverage during the years 2006-2013. We compared 19-25 year olds(yo) to 2-18 and 26-35 yo, unaffected by the provision, to account for underlying trends.
From 2006-2010 19-25 yo had the highest proportion uninsured, peaking at 14.1% in 2010. In 2011, the proportion decreased to 10.1%, below the proportion of uninsured 26-35 yo (13.1%), remaining in this range through 2013. Private coverage increased in 2011 for 19-25 yo, remaining stable for 26-35 yo.
Previous research cited 5% uninsured among all hospitalized patients with IBD. Our study indicates a higher proportion for YAs, decreasing after the ACA. Lack of insurance increases vulnerability during transfer, but may be modifiable through policy change. Further research should analyze effects of Medicaid expansion and health care exchanges.
The US Food and Drug Administration (FDA) Safety and Innovation Act (FDASIA, 2012) introduced the Breakthrough Therapy Designation (BTD), a new tool to expedite development of medicines to treat serious or life-threatening diseases. The majority of BTDs have gone to oncology drugs, and a recent publication by Shea et al.(1) reviewed the impact of BTD on oncology drug development. This article reviews the impact of BTD on development strategies and timelines for nononcology drugs.
Light alkali metal hydridotriphenylborates M[HBPh3] (M = Li, Na, K), characterized as tris{2-(dimethylamino)ethyl}amine (L) complexes [(L)M][HBPh3], act as efficient catalysts for the chemoselective hydroboration of a wide range of aldehydes and ketones using pinacolborane HBpin. The lithium derivative showed a remarkably high TOF of ≥17 s(-1). These compounds also catalyze the hydroborative reduction of CO2 to give formoxyborane HCO2Bpin without any over-reduction.
Understanding and managing the biological invasion threats posed by aquatic plants under current and future climates is a growing challenge for biosecurity and land management agencies worldwide. Eichhornia crassipes is one of the world's worst aquatic weeds. Presently, it threatens aquatic ecosystems, and hinders the management and delivery of freshwater services in both developed and developing parts of the world. A niche model was fitted using CLIMEX, to estimate the potential distribution of E. crassipes under historical and future climate scenarios. Under two future greenhouse gas emission scenarios for 2080 simulated with three Global Climate Models, the area with a favourable temperature regime appears set to shift polewards. The greatest potential for future range expansion lies in Europe. Elsewhere in the northern hemisphere temperature gradients are too steep for significant geographical range expansion under the climate scenarios explored here. In the Southern Hemisphere, the southern range boundary for E. crassipes is set to expand southwards in Argentina, Australia and New Zealand; under current climate conditions it is already able to invade the southern limits of Africa. The opportunity exists to prevent its spread into the islands of Tasmania in Australia and the South Island of New Zealand, both of which depend upon hydroelectric facilities that would be threatened by the presence of E. crassipes. In Europe, efforts to slow or stop the spread of E. crassipes will face the challenge of limited internal biosecurity capacity. The modelling technique demonstrated here is the first application of niche modelling for an aquatic weed under historical and projected future climates. It provides biosecurity agencies with a spatial tool to foresee and manage the emerging invasion threats in a manner that can be included in the international standard for pest risk assessments. It should also support more detailed local and regional management.
Periodontitis impairs the osteogenic differentiation of human periodontal mesenchymal stem cells (hPDLSCs), but the underlying molecular mechanisms are still poorly understood. Long noncoding RNAs (lncRNAs) have been demonstrated to have significant roles under both physiologic and pathological conditions. In this study, we performed comprehensive lncRNA profiling by lncRNA microarray analysis and identified a novel lncRNA, osteogenesis impairment-related lncRNA of PDLSCs from periodontitis patients (lncRNA-POIR), the expression of which was significantly decreased in PDLSCs from periodontitis patients (pPDLSCs) and was upregulated by osteogenic induction. To study the functions of lncRNA-POIR, we prepared cells with overexpression and knockdown of lncRNA-POIR and found that lncRNA-POIR positively regulated osteogenic differentiation of hPDLSCs and pPDLSCs both in vitro and in vivo. Using quantitative real-time PCRs (qPCRs) and luciferase reporter assays, we demonstrated that lncRNA-POIR may act as a competing endogenous RNA (ceRNA) for miR-182, leading to derepression of its target gene, FoxO1. In this process, lncRNA-POIR and miR-182 suppress each other and form a network to regulate FoxO1. FoxO1 increased bone formation of pPDLSCs by competing with TCF-4 for β-catenin and inhibiting the canonical Wnt pathway. Finally, inflammation increases miR-182 expression through the nuclear factor-κB pathway, and the miR-182 overexpression in the inflammatory microenvironment resulted in an imbalance in the lncRNA-POIR-miR-182 regulatory network. In conclusion, our results provide novel evidence that this lncRNA-miRNA (microRNA) regulatory network has a significant role in osteogenic differentiation of pPDLSCs and that it has potential as a therapeutic target in mesenchymal stem cells during inflammation.
Autosomal dominant polycystic kidney disease (ADPKD) is a common genetic renal disease, which is caused by pathogenic mutations of either PKD1 (85%) or PKD2 (15%) genes, encoding for polycystin-1 (PC1) or polycystin-2 (PC2), respectively. These two proteins hetero-dimerize in renal primary cilia to act as a calcium channel. Primary cilia that protrude from cell membranes have a microtubule-based finger-like structure and are found on most mammalian cells. Primary cilia in the kidney have no motility but act as mechanosensors to sense fluid flow through renal tubules. In addition, various signaling proteins related to Hedgehog (Hh) and platelet-derived growth factor receptor alpha (PDGFRα) are localized to the cilia to detect changes in the extracellular environment. Recent studies have demonstrated that many ADPKD animal models have defective cilia in the epithelial cells that line the cysts. Also, animal models targeting ciliary genes show abnormal phenotypes such as polycystic kidneys and developmental defects. These findings reveal that ciliary malfunction is sufficient to cause ADPKD. In this chapter, we will review the putative roles of cilia in cyst formation and development in ADPKD.
Recent health care payment reforms aim to improve the alignment of Medicare payment strategies with goals to improve the quality of care provided, patient experiences with health care, and health outcomes, while also controlling costs. These efforts move Medicare away from the volume-based payment of traditional fee-for-service models and toward value-based purchasing, in which cost control is an explicit goal in addition to clinical and quality goals. Specific payment strategies include pay-for-performance and other quality incentive programs that tie financial rewards and sanctions to the quality and efficiency of care provided and accountable care organizations in which health care providers are held accountable for both the quality and cost of the care they deliver. Accounting For Social Risk Factors in Medicare Payment: Criteria, Factors, and Methods is the third in a series of five brief reports that aim to inform ASPE analyses that account for social risk factors in Medicare payment programs mandated through the IMPACT Act. This report builds on the conceptual relationships and empirical associations between social risk factors and performance indicators used in value-based payment identified in the first report to provide guidance on which factors could be considered for Medicare accounting purposes, criteria to identify these factors, and methods to do so in ways that can improve care and promote greater health equity for socially at-risk patients.
Aims and method To develop a simple, pragmatic typology to characterise the nature of liaison interventions delivered by a liaison service in a National Health Service setting. We carried out a retrospective electronic case-note review of referrals to a ward-based liaison psychiatry service. Results Three hundred and forty-four patients were referred to the service over a 12-month period. Ten different types of liaison interventions were identified, with the most common interventions being diagnosis (112 patients, 32.6%), medication management (57 patients, 16.6%), risk assessment and treatment (56 patients, 16.3% each). Mental Health Act work accounted for the greatest number of contacts per patient (median 7). Clinical implications There are inherent limitations in any single-site observational study, as site-specific results cannot be generalised to other liaison services. The intervention categories we developed, however, are easy to use and will provide a way of comparing and benchmarking the range of interventions delivered by different liaison psychiatry services.
Although the Representation of the People Act 2000 permits most psychiatric in-patients to register on the electoral register, transferred prisoners and those admitted to hospital under hospital orders remain disenfranchised by law. This article clarifies the voting
 rights of individuals receiving in-patient psychiatric care and contends that the selective disenfranchisement of some mentally disordered offenders is problematic, discriminatory and may breach international human rights law. There are therefore strong arguments for the UK government to address this long-standing inequality before the next general election.
Papaya (Carica papaya L.) is a fleshy fruit that presents a rapid pulp softening during ripening. However, the timeline on how papaya pectinases act in polysaccharide solubilization and the consequent modification of the cell wall fractions during ripening is still not clear. In this work, the gene expression correlations between, on one hand, 16 enzymes potentially acting during papaya cell wall disassembling and, on the other hand, the monosaccharide composition of cell wall fractions during papaya ripening were evaluated. In order to explain differences in the ripening of papaya samplings, the molecular mass distribution of polysaccharides from water-soluble and oxalate-soluble fractions (WSF and OSF, respectively), as well as the oligosaccharide profiling from the WSF fraction, were evaluated by high performance size exclusion chromatography coupled to a refractive index detector and high performance anion-exchange chromatography coupled to pulse amperometric detection analyses, respectively. Results showed that up-regulated polygalacturonase and β-galactosidase genes were positively correlated with some monosaccharide profiles. In addition, an overall increase in the retention time of high molecular weight (HMW) and low molecular weight (LMW) polysaccharides in WSF and OSF was shown. The apparent disappearance of one HMW peak of the OSF may result from the conversion of pectin that were crosslinked with calcium into more soluble forms through the action of PGs, which would increase the solubilization of polysaccharides by lowering their molecular weight. Thus, the results allowed us to propose a detailed process of papaya cell wall disassembling that would affect sensorial properties and post-harvesting losses of this commercially important fruit.
The mechanical properties of tendon play a fundamental role to passively transmit forces from muscle to bone, withstand sudden stretches, and act as a mechanical buffer allowing the muscle to work more efficiently. The use of non-invasive imaging methods for the assessment of human tendon's mechanical, structural, and biochemical properties in vivo is relatively young in sports medicine, clinical practice, and basic science. Non-invasive assessment of the tendon properties may enhance the diagnosis of tendon injury and the characterization of recovery treatments. While ultrasonographic imaging is the most popular tool to assess the tendon's structural and indirectly, mechanical properties, ultrasonographic elastography, and ultra-high field magnetic resonance imaging (UHF MRI) have recently emerged as potentially powerful techniques to explore tendon tissues. This paper highlights some methodological cautions associated with conventional ultrasonography and perspectives for in vivo human Achilles tendon assessment using ultrasonographic elastography and UHF MRI.
Effective handovers are critical for patient care and safety. Electronic handover tools are increasingly used today to provide an effective and standardized platform for information exchange. The implementation of an electronic handover system in tertiary hospitals can be a major challenge. Previous efforts in implementing an electronic handover tool failed due to poor compliance and buy-in from end-users. A new electronic handover tool was developed and incorporated into the existing electronic medical records (EMRs) for medical patients in Singapore General Hospital (SGH).
There was poor compliance by on-call doctors in acknowledging electronic handovers, and lack of adherence to safety rules, raising concerns about the safety and efficiency of the electronic handover tool. Urgent measures were needed to ensure its safe and sustained use.
A quality improvement group comprising stakeholders, including end-users, developed multi-faceted interventions using rapid PDSA (P-Plan, D-Do, S-Study, A-Act ) cycles to address these issues.
Innovative solutions using media and online software provided cost-efficient measures to improve compliance.
The percentage of unacknowledged handovers per day was used as the main outcome measure throughout all PDSA cycles. Doctors were also assessed for improvement in their knowledge of safety rules and their perception of the electronic handover tool.
An electronic handover tool complementing daily clinical practice can be successfully implemented using solutions devised through close collaboration with end-users supported by the senior leadership. A combined 'bottom-up' and 'top-down' approach with regular process evaluations is crucial for its long-term sustainability.
Long-term respiratory conditions such as asthma and chronic obstructive pulmonary disease (COPD) are common, and cause high levels of morbidity and mortality. Supporting self-management is advocated for both asthma and increasingly so for COPD, and there is growing interest in the potential role of a range of new technologies, such as smartphone apps, the web or telehealth to facilitate and promote self-management in these conditions. Treatment goals for both asthma and COPD include aiming to control symptoms, maintain activities, achieve the best possible quality of life and minimize risks of exacerbation. To do this, health professionals should be (a) helping patients to recognize deteriorating symptoms and act appropriately; (b) promoting adherence to maintenance therapy; (c) promoting a regular review where triggers can be established, and strategies for managing such triggers discussed; and (d) promoting healthy lifestyles and positive self-management of symptoms. In particular, low uptake of asthma action plans is a modifiable contributor to morbidity and possibly also to mortality in those with asthma and should be addressed as a priority. Using technology to support self-management is an evolving strategy that shows promise. This review provides an overview of self-management support and discusses how newer technologies may help patients and health professionals to meet key treatment goals.
Two closely related caliciviruses cocirculate in Australia: rabbit hemorrhagic disease virus (RHDV) and rabbit calicivirus Australia 1 (RCV-A1). RCV-A1 causes benign enteric infections in the European rabbit (Oryctolagus cuniculus) in Australia and New Zealand, while its close relative RHDV causes a highly pathogenic infection of the liver in the same host. The comparison of these viruses provides important information on the nature and trajectory of virulence evolution, particularly as highly virulent strains of RHDV may have evolved from nonpathogenic ancestors such as RCV-A1. To determine the evolution of RCV-A1 we sequenced the full-length genomes of 44 RCV-A1 samples isolated from healthy rabbits and compared key evolutionary parameters to those of its virulent relative, RHDV. Despite their marked differences in pathogenicity and tissue tropism, RCV-A1 and RHDV have evolved in a very similar manner. Both viruses have evolved at broadly similar rates, suggesting that their dynamics are largely shaped by high background mutation rates, and both exhibit occasional recombination and an evolutionary environment dominated by purifying selection. In addition, our comparative analysis revealed that there have been multiple changes in both virulence and tissue tropism in the evolutionary history of these and related viruses. Finally, these new genomic data suggest that either RCV-A1 was introduced into Australia after the introduction of myxoma virus as a biocontrol agent in 1950 or there was drastic reduction of the rabbit population, and hence of RCV-A1 genetic diversity, perhaps coincident with the emergence of myxoma virus.
The comparison of closely related viruses that differ profoundly in propensity to cause disease in their hosts offers a powerful opportunity to reveal the causes of changes in virulence and to study how such changes alter the evolutionary dynamics of these pathogens. Here we describe such a novel comparison involving two closely related RNA viruses that cocirculate in Australia, the highly virulent rabbit hemorrhagic disease virus (RHDV) and the nonpathogenic rabbit calicivirus Australia 1 (RCV-A1). Both viruses infect the European rabbit, but they differ in virulence, tissue tropism, and mechanisms of transmission. Surprisingly, and despite these fundamental differences, RCV-A1 and RHDV have evolved at very similar (high) rates and with strong purifying selection. Furthermore, candidate key mutations were identified that may play a role in virulence and/or tissue tropism and therefore warrant further investigation.
During meiosis, programmed double-strand breaks (DSBs) are generated to initiate homologous recombination, which is crucial for faithful chromosome segregation. In yeast, Radiation sensitive1 (RAD1) acts together with Radiation sensitive9 (RAD9) and Hydroxyurea sensitive1 (HUS1) to facilitate meiotic recombination via cell-cycle checkpoint control. However, little is known about the meiotic functions of these proteins in higher eukaryotes. Here, we characterized a RAD1 homolog in rice (Oryza sativa) and obtained evidence that O. sativa RAD1 (OsRAD1) is important for meiotic DSB repair. Loss of OsRAD1 led to abnormal chromosome association and fragmentation upon completion of homologous pairing and synapsis. These aberrant chromosome associations were independent of OsDMC1. We found that classical nonhomologous end-joining mediated by Ku70 accounted for most of the ectopic associations in Osrad1 In addition, OsRAD1 interacts directly
 with OsHUS1 and OsRAD9, suggesting that these proteins act as a complex to promote DSB repair during rice meiosis. Together, these findings suggest that the 9-1-1 complex facilitates accurate meiotic recombination by suppressing nonhomologous end-joining during meiosis in rice.
The γ/γ' interface dislocation network is reported to improve the high temperature creep resistance of single crystal superalloys and is usually found to deposit in {001} interface. In this work, a new type of dislocation network was found in {111} γ/γ' interface at a single crystal model superalloy crept at 1100 °C/100 MPa. The dislocations in the network are screw with Burgers vectors of 1/2 a<110> and most interestingly, they exhibit a pair-coupling structure. Further investigation indicates that the formation of {111} interface dislocation network occurs when the γ' raft structure begins to degrade by the dislocations cutting into the rafted γ' through the interface. In this condition, the pair-coupling structure is established by the dislocations gliding in a single {111} plane of γ', in order to remove the anti-phase boundary in γ'; these dislocations also act as diffusion channels for dissolving of the γ' particle that is unstable under the interfacial stress from lattice misfit, which leads to the formation of {111}-type zigzag interface. The formation of this network arises as a consequence of more negative misfit, low-alloying γ' particle and proper test conditions of temperature and stress.
Rheumatoid arthritis is characterised by synovial inflammation and proliferation of fibroblast-like synoviocytes. The induction of apoptosis has long been proposed as a target for proliferative autoimmune diseases, and has further been shown to act as a successful treatment of experimental models of arthritis, such as collagen-induced arthritis. Here we examined the effects of specific oral small-molecule inhibitors of the transcription regulating cyclin-dependent kinase 9 on the development and progression of collagen-induced arthritis. DBA/1 mice were immunised with bovine collagen type II and treated orally with specific CDK9 inhibitors. The effects of CDK9 inhibition on RNA levels and protein expression, apoptosis induction, caspase activation and lymphocyte phenotype were further analysed. Mice showed a significant delay in disease onset and a reduction in disease severity following treatment with CDK9 inhibitors. Inhibiting CDK9 activity in peripheral blood mononuclear cells resulted in the loss of Mcl-1 expression at both the protein and RNA levels, along with a subsequent increase in apoptosis. CDK9 specific inhibitors may be a potential alternative treatment not only of cancer, but also for autoimmune- and inflammatory diseases. Taken together, these results show that transient inhibition of CDK9 induces apoptosis in leukocyte subsets and modulates the immune response.
The emergence of mobile health (mHealth) offers unique and varied opportunities to address some of the most difficult problems of health. Some of the most promising and active efforts of mHealth involve the engagement of mobile phone technology. As this technology has spread and as this technology is still evolving, we begin a conversation about the core characteristics of mHealth relevant to any mobile phone platform. We assert that the relevance of these characteristics to mHealth will endure as the technology advances, so an understanding of these characteristics is essential to the design, implementation, and adoption of mHealth-based solutions. The core characteristics we discuss are (1) the penetration or adoption into populations, (2) the availability and form of apps, (3) the availability and form of wireless broadband access to the Internet, and (4) the tethering of the device to individuals. These collectively act to both enable and constrain the provision of population health in general, as well as personalized and precision individual health in particular.
High-level ab initio calculations are used to identify the mechanism of secondary (and primary) alkylperoxyl radical termination and explain why their reactions are much faster than their tertiary counterparts. Contrary to existing literature, the decomposition of both tertiary and non-tertiary tetroxides follows the same asymmetric two-step bond cleavage pathway to form a caged intermediate of overall singlet multiplicity comprising triplet oxygen and two alkoxyl radicals. The alpha hydrogen atoms of non-tertiary species facilitate this process by forming unexpected CHO hydrogen bonds to the evolving O2. For non-tertiary peroxyls, subsequent alpha hydrogen atom transfer then yields the experimentally observed non-radical products, ketone, alcohol and O2, whereas for tertiary species, this reaction is precluded and cage escape of the (unpaired) alkoxyl radicals is a likely outcome with important consequences for autoxidation.
Gastric carcinoma (GC) ranks as the second most common cause of cancer associated mortality worldwide. Emerging evidence has suggested a potential novel therapeutic strategy based on the ability of cancer stem cells (CSCs) to trigger tumorigenesis. MicroRNAs (miRNAs) have previously been implicated in CSC formation and regulation of their functional characteristics. In the current study, a significant upregulation of miR 483 5p levels was demonstrated in spheroid body forming cells (P<0.01) by reverse transcription quantitative polymerase chain reaction, which were isolated from the MKN 45 gastric cancer cell line and possessed gastric CSC (GCSC) properties. An MTT assay demonstrated that overexpression of miR 483 5p by transfection with miR 483 5p mimics significantly increased cell proliferation and Annexin V propidium iodide staining indicated the suppression of cell apoptosis, suggesting that miR 483 5p has an important function in GCSC growth. Notably, Transwell and sphere formation assays demonstrated that miR 483 5p elevation promoted GCSC invasion and cell self renewal ability, respectively. Further western blotting assays demonstrated that miR 483 5p upregulation induced an increase in the protein expression levels of β catenin and its downstream target molecules, including cyclin D1, Bcl 2 and matrix metalloproteinase 2, indicating that miR 483 5p activates Wnt/β catenin signaling. Inhibition of this pathway by β catenin small interfering RNA transfection attenuated the miR 483 5p induced effects on cell growth, invasion and self renewal. These results demonstrate that miR 483 5p may act as an oncogene to promote the development of GC by regulating GCSC growth, invasion and self renewal via the Wnt/β catenin signaling pathway. Thus, the present study suggests that miR 483 5p may be a promising therapeutic target against GC.
Intermediate neural progenitors (INPs) need to avoid both dedifferentiation and differentiation during neurogenesis, but the underlying mechanisms are not well understood. In Drosophila, the Ets protein Pointed P1 (PntP1) is required to generate INPs from type II neuroblasts. Here, we investigated how PntP1 promotes INP generation. By generating pntP1-specific mutants and using RNAi knockdown, we show that the loss of PntP1 leads to both an increase in type II neuroblast number and the elimination of INPs. The elimination of INPs results from the premature differentiation of INPs due to ectopic Prospero expression in newly generated immature INPs (imINPs), whereas the increase in type II neuroblasts results from the dedifferentiation of imINPs due to loss of Earmuff at later stages of imINP development. Furthermore, reducing Buttonhead enhances the loss of INPs in pntP1 mutants, suggesting that PntP1 and Buttonhead act cooperatively to prevent premature INP differentiation. Our results demonstrate that PntP1 prevents both the premature differentiation and the dedifferentiation of INPs by regulating the expression of distinct target genes at different stages of imINP development.
Genomic variations are associated with the metabolism and the occurrence of adverse reactions of many therapeutic agents. The polymorphisms on over 2000 locations of cytochrome P450 enzymes (CYP) due to many factors such as ethnicity, mutations, and inheritance attribute to the diversity of response and side effects of various drugs. The associations of the single nucleotide polymorphisms (SNPs), the internal pharmacokinetic patterns and the vulnerability of specific adverse reactions become one of the research interests of pharmacogenomics. The conventional genomewide association studies (GWAS) mainly focuses on the relation of single or multiple SNPs to a specific risk factors which are a one-to-many relation. However, there are no robust methods to establish a many-to-many network which can combine the direct and indirect associations between multiple SNPs and a serial of events (e.g. adverse reactions, metabolic patterns, prognostic factors etc.). In this paper, we present a novel deep learning model based on generative stochastic networks and hidden Markov chain to classify the observed samples with SNPs on five loci of two genes (CYP2D6 and CYP1A2) respectively to the vulnerable population of 14 types of adverse reactions.
A supervised deep learning model is proposed in this study. The revised generative stochastic networks (GSN) model with transited by the hidden Markov chain is used. The data of the training set are collected from clinical observation. The training set is composed of 83 observations of blood samples with the genotypes respectively on CYP2D6*2, *10, *14 and CYP1A2*1C, *1 F. The samples are genotyped by the polymerase chain reaction (PCR) method. A hidden Markov chain is used as the transition operator to simulate the probabilistic distribution. The model can perform learning at lower cost compared to the conventional maximal likelihood method because the
 transition distribution is conditional on the previous state of the hidden Markov chain. A least square loss (LASSO) algorithm and a k-Nearest Neighbors (kNN) algorithm are used as the baselines for comparison and to evaluate the performance of our proposed deep learning model.
There are 53 adverse reactions reported during the observation. They are assigned to 14 categories. In the comparison of classification accuracy, the deep learning model shows superiority over the LASSO and kNN model with a rate over 80 %. In the comparison of reliability, the deep learning model shows the best stability among the three models.
Machine learning provides a new method to explore the complex associations among genomic variations and multiple events in pharmacogenomics studies. The new deep learning algorithm is capable of classifying various SNPs to the corresponding adverse reactions. We expect that as more genomic variations are added as features and more observations are made, the deep learning model can improve its performance and can act as a black-box but reliable verifier for other GWAS studies.
The stabilization of o/w Pickering emulsions in cases of weak adsorption of solid particles at the surface of oil droplets is addressed. Though the adsorption is usually very strong and irreversible when partial wetting conditions are fulfilled, electrostatic repulsions between charged solid particles act against the adsorption. The regime of weak adsorption was reached using charged silica nanoparticles at high pH and low ionic strength. O/w Pickering emulsions of the diisopropyl adipate oil were stabilized by colloidal nanoparticles of Ludox® AS40 consisting of non-aggregated particles of bare silica (hydrophilic). The combination of stability assessment, droplet size and electrokinetic potential measurements at various pH values, adsorption isotherms and cryo-SEM observations of the adsorbed layers disclosed the specificities of the stabilization of Pickering emulsions by adsorption of solid nanoparticles against strong electrostatic repulsions. Not only the long-term stability of emulsions was poor under strong electrostatic repulsions at high pH, but emulsification failed since full dispersion of oil could not be achieved. Emulsion stability was ensured by decreasing electrostatic repulsions by lowering the pH from 9 to 3. Stable emulsions were stabilized by a monolayer of silica particles at 54% coverage of the oil droplet surface at low silica content and an adsorption regime as multilayers was reached at higher concentrations of silica although there was no aggregation of silica in the bulk aqueous phase.
miRNAs act as important regulators of gene expression by promoting mRNA degradation or by attenuating protein translation. Since miRNAs are stably expressed in bodily fluids, there is growing interest in profiling these miRNAs, as it is minimally invasive and cost-effective as a diagnostic matrix. A technical hurdle in studying miRNA dynamics is the ability to reliably extract miRNA as small sample volumes and low RNA abundance create challenges for extraction and downstream applications. The purpose of this study was to develop a pipeline for the recovery of miRNA using small volumes of archived serum samples. The RNA was extracted employing several widely utilized RNA isolation kits/methods with and without addition of a carrier. The small RNA library preparation was carried out using Illumina TruSeq small RNA kit and sequencing was carried out using Illumina platform. A fraction of five microliters of total RNA was used for library preparation as quantification is below the detection limit. We were able to profile miRNA levels in serum from all the methods tested. We found out that addition of nucleic acid based carrier molecules had higher numbers of processed reads but it did not enhance the mapping of any miRBase annotated sequences. However, some of the extraction procedures offer certain advantages: RNA extracted by TRIzol seemed to align to the miRBase best; extractions using TRIzol with carrier yielded higher miRNA-to-small RNA ratios. Nuclease free glycogen can be carrier of choice for miRNA sequencing. Our findings illustrate that miRNA extraction and quantification is influenced by the choice of methodologies. Addition of nucleic acid- based carrier molecules during extraction procedure is not a good choice when assaying miRNA using sequencing. The careful selection of an extraction method permits the archived serum samples to become valuable resources for high-throughput applications.
The design of a melt synthesis of the first air-stable formulation of the metastable form III of paracetamol is derived from thermo-spectroscopic and thermo-diffraction experiments. Melt crystallisation in the presence of β-1,4-saccharides produces form III selectively and the excipients appear to act as stabilising 'active' templates of the metastable polymorph.
This retrospective study was designed to evaluate the importance of tissue expressions of caveolin-1 (Cav-1) and AT-rich interactive domain 1 alpha (ARID-1A) which are known as signal regulator and tumor suppressor in differential diagnosis of uterine smooth muscle tumors (SMTs).
Thirty patients recently diagnosed as uterine SMTs at the Tepecik Training and Research Hospital were identified using pathology databases. Immunohistochemical stains for Cav-1 and ARID-1A were performed.
In this series, there were 10 leiomyosarcomas (LMSs), 10 uterine smooth muscle tumors of uncertain malignant potentials (STUMPs), and 10 leiomyomas (LMs). Cav-1 expression located cytoplasmic or perivascular area. Cytoplasmic Cav-1 expression was determined in 5 LMSs and 2 STUMPs while perivascular Cav-1 expression was determined in 9 LMSs and 2 STUMPs. Statistically, it was determined that if the tumor becomes malignant and more invasive, it gains the perivascular Cav-1 expression (P = 0.029). On the other hand, the mean nuclear staining rate for ARID-1A in LMSs (63 ± 23.4%) was higher than both STUMPs (60 ± 18.5%) and LMs (34.5 ± 16.5%). Statistically, it was determined that the expression of ARID-1A was significantly downregulated in LMs when compared with STUMPs and LMSs (P = 0.004).
Our findings were demonstrated that perivascular Cav-1 expression was seen to be a marker for malignancy of uterine SMTs. Similarly, we found to link of ARID-1A expression and the aggressiveness of SMTs. Therefore, it may be suggested that Cav-1 and ARID-1A may act as predictive biomarkers in uterine SMTs.
The Hand, Foot and Mouth Disease (HFMD) is caused by Enterovirus 71 (EV-A71) and Coxsackieviruses. Common HFMD symptoms are high fever (≥ 39C), rashes, and ulcers but complications due to virulent EV-A71 may arise leading to cardiopulmonary failure and death. The lack of vaccines and antiviral drugs against EV-A71 highlights the urgency of developing preventive and treatment agents. Recent studies have reported the emergence of novel antiviral agents and vaccines that utilize microRNAs (miRNAs). They belong to a class of small (19-24 nt) non coding RNA molecules. As miRNAs play a major role in the host regulatory system, there is a huge opportunity for interplay between host miRNAs and EV-A71 expressions. A total of 42 out of 64 miRNAs were up-regulated in EV-A71-infected cells. There was consistent up-regulation of miR-1246 gene expression that targeted the DLG3 gene which contributes to neurological pathogenesis. In contrast, miR-30a that targets calcium channels for membrane transportation was down-regulated. This leads to repression of EV-A71 replication. The impact of host miRNAs on immune activation, shutdown of host protein synthesis, apoptosis, signal transduction and viral replication are discussed. miRNAs have been used in the construction of live attenuated vaccines (LAV) such as the poliovirus LAV that has miRNA binding sites for let-7a or miR-124a. The miRNA-bearing vaccine will not replicate in neuronal cells carrying the corresponding miRNA but could still replicate in the gastrointestinal tract and hence remains to act as immunogens. As such, miRNAs are attractive candidates to be developed as vaccines and antivirals.
Cholesterol plays a central role in numerous nervous system functions. Cholesterol is the major constituent of myelin sheaths, is essential for synapse and dendrite formation, axon guidance as well as neurotransmission. Among regulators of cholesterol homeostasis, liver X receptors (LXRs), two members of the nuclear receptor superfamily, play a determinant role. LXRs act as cholesterol sensors and respond to high intracellular cholesterol concentration by decreasing plasmatic and intracellular cholesterol content. Beyond their cholesterol-lowering role, LXRs have been proposed as regulators of immunity and anti-inflammatory factors. Dysregulation of cholesterol metabolism combined to neuroinflammatory context have been described in neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS). ALS is characterized by the progressive loss of motoneurons in the brain and spinal cord, leading to severe paralytic condition and death of patients in a median time of 3 years. Motoneuron degeneration is accompanied by chronic neuroinflammatory response, involving microglial and astrocytic activation, infiltration of blood-derived immune cells and release of pro-inflammatory factors. We propose to discuss here the role of LXRs as a molecular link between the central nervous system cholesterol metabolism, neuroinflammation, motoneuron survival and their potential as promising therapeutic candidates for ALS therapy.
The capacity of the bread wheat (Triticum aestivum) genome to tolerate introgression from related genomes can be exploited for wheat improvement. A resistance to powdery mildew expressed by a derivative of the cross-bread wheat cv. Tähti × T. militinae (Tm) is
 known to be due to the incorporation of a Tm segment into the long arm of chromosome 4A. Here, a newly developed in silico method termed rearrangement identification and characterization (RICh) has been applied to characterize the introgression. A virtual gene order, assembled using the GenomeZipper approach, was obtained for the native copy of chromosome 4A; it incorporated 570 4A DArTseq markers to produce a zipper comprising 2132 loci. A comparison between the native and introgressed forms of the 4AL chromosome arm showed that the introgressed region is located at the distal part of the arm. The Tm segment, derived from chromosome 7G, harbours 131 homoeologs of the 357 genes present on the corresponding region of Chinese Spring 4AL. The estimated number of Tm genes transferred along with the disease resistance gene was 169. Characterizing the introgression's position, gene content and internal gene order should not only facilitate gene isolation, but may also be informative with respect to chromatin structure and behaviour studies.
The Wender-Utah Rating Scale (WURS) is a widely used self-report instrument for retrospective assessment of childhood ADHD. However, many WURS items are not specific to ADHD. Here, we investigated the effect of excluding these items on the performance of the WURS in predicting adult ADHD based on previous diagnosis and current clinically significant symptoms. The study was conducted on a sample of adults (n = 1014; 48 % male) participating in a family-based investigation of ADHD. Participants completed the 61-item WURS questionnaire and the 66-item Conners Adult ADHD Rating Scale. Receiver operating characteristic (ROC) curves were used to compare the performance of the eight-item WURS (WURS-8) and the longer WURS-25 in predicting previous ADHD diagnosis and current clinically significant ADHD symptoms. WURS-8 and WURS-25 have approximately the same power to predict adult ADHD, based on either previous diagnosis or current symptoms (area under the ROC curves >0.8). WURS-8 performs at least as well as the longer WURS-25 in predicting adult ADHD. This 8-item questionnaire is thus a valid instrument and is especially useful for screening for ADHD in large epidemiological samples.
Caffeine is associated with procognitive effects in humans by counteracting overactivation of the adenosine A2A receptor (A2AR), which is upregulated in the human forebrain of aged and Alzheimer's disease (AD) patients. We have previously shown that an anti-A2AR therapy reverts age-like memory deficits, by reestablishment of the hypothalamic-pituitary-adrenal (HPA) axis feedback and corticosterone circadian levels. These observations suggest that A2AR over-activation and glucocorticoid dysfunction are key events in age-related hippocampal deficits; but their direct connection has never been explored. We now show that inducing A2AR overexpression in an aging-like profile is sufficient to trigger HPA-axis dysfunction, namely loss of plasmatic corticosterone circadian oscillation, and promotes reduction of GR hippocampal levels. The synaptic plasticity and memory deficits triggered by GR in the hippocampus are amplified by A2AR over-activation and were rescued by anti-A2AR therapy; finally, we demonstrate that A2AR act on GR nuclear translocation and GR-dependent transcriptional regulation. We provide the first demonstration that A2AR is a major regulator of GR function and that this functional interconnection may be a trigger to age-related memory deficits. This supports the idea that the procognitive effects of A2AR antagonists, namely caffeine, on Alzheimer's and age-related cognitive impairments may rely on its ability to modulate GR actions.
Land-use change and intensification threaten bee populations worldwide, imperilling pollination services. Global models are needed to better characterise, project, and mitigate bees' responses to these human impacts. The available data are, however, geographically and taxonomically unrepresentative; most data are from North America and Western Europe, overrepresenting bumblebees and raising concerns that model results may not be generalizable to other regions and taxa. To assess whether the geographic and taxonomic biases of data could undermine effectiveness of models for conservation policy, we have collated from the published literature a global dataset of bee diversity at sites facing land-use change and intensification, and assess whether bee responses to these pressures vary across 11 regions (Western, Northern, Eastern and Southern Europe; North, Central and South America; Australia and New Zealand; South East Asia; Middle and Southern Africa) and between bumblebees and other bees. Our analyses highlight strong regionally-based responses of total abundance, species richness and Simpson's diversity to land use, caused by variation in the sensitivity of species and potentially in the nature of threats. These results suggest that global extrapolation of models based on geographically and taxonomically restricted data may underestimate the true uncertainty, increasing the risk of ecological surprises.
Conservation planning and biodiversity management require information on landscape connectivity across a range of spatial scales from individual home ranges to large regions. Reduction in landscape connectivity due changes in land use or development is expected to act synergistically with alterations to habitat mosaic configuration arising from climate change. We illustrate a multiscale connectivity framework to aid habitat conservation prioritization in the context of changing land use and climate. Our approach, which builds upon the strengths of multiple landscape connectivity methods, including graph theory, circuit theory, and least-cost path analysis, is here applied to the conservation planning requirements of the Mohave ground squirrel. The distribution of this threatened Californian species, as for numerous other desert species, overlaps with the proposed placement of several utility-scale renewable energy developments in the American southwest. Our approach uses information derived at three spatial scales to forecast potential changes in habitat connectivity under various scenarios of energy development and climate change. By disentangling the potential effects of habitat loss and fragmentation across multiple scales, we identify priority conservation areas for both core habitat and critical corridor or stepping stone habitats. This approach is a first step toward applying graph theory to analyze habitat connectivity for species with continuously distributed habitat and should be applicable across a broad range of taxa.
Few estimates of migration rates or descriptions of behavior or survival exist for wild populations of out-migrating Pacific salmon smolts from natal freshwater rearing areas to the ocean. Using acoustic transmitters and fixed receiver arrays across four years (2010-2013), we tracked the migration of > 1850 wild sockeye salmon (Oncorhynchus nerka) smolts from Chilko Lake, British Columbia, to the coastal Pacific Ocean (> 1000 km distance). Cumulative survival to the ocean ranged 3-10% among years, although this may be slightly underestimated due to technical limitations at the final receiver array. Distinct spatial patterns in both behavior and survival were observed through all years. In small, clear, upper-river reaches, downstream migration largely occurred at night at speeds up to 50 km/d and coincided with poor survival. Among years, only 57-78% of smolts survived the first 80 km. Parallel laboratory experiments revealed excellent short-term survival and unhindered swimming performance of dummy-tagged smolts, suggesting that predators rather than tagging effects were responsible for the initial high mortality of acoustic-tagged smolts. Migration speeds increased in the Fraser River mainstem (~220 km/d in some years), diel movement patterns ceased, and smolt survival generally exceeded 90% in this segment. Marine movement rates and survival were variable across years, with among-year segment-specific survival being the most variable and lowest (19-61%) during the final (and longest, 240 km) marine migration segment. Osmoregulatory preparedness was not expected to influence marine survival, as smolts could maintain normal levels of plasma chloride when experimentally exposed to saltwater (30 ppt) immediately upon commencing their migration from Chilko Lake. Transportation of smolts downstream generally increased survival to the farthest marine array. The act of tagging may have affected smolts in the marine environment in some years as dummy-tagged fish had poorer survival than control fish when transitioned to saltwater in laboratory-based experiments. Current fisheries models for forecasting the number of adult sockeye returning to spawn have been inaccurate in recent years and generally do not incorporate juvenile or smolt survival information. Our results highlight significant potential for early migration conditions to influence adult recruitment.
Morbidity and mortality from lung cancer has dramatically increased in women as compared to men over the past few years. Historically, smoking has been considered the major risk factor for lung cancer regardless of gender. Several recent lines of evidence implicate gender differences in the observed differences in prevalence and histologic type which cannot be explained based on the carcinogenic action of nicotine. Several recent studies underscore the importance of reproductive and hormonal factors in the carcinogenesis of lung cancer Lung cancer morbidity and mortality in Bulgaria was 16.2/100000 women and 14.6/ 100000 women, resp. Lung cancer morbidity in Europe was 39/100000 women. Lung cancer is extremely sensitive to estrogens. The latter act directly or as effect modifiers for the relationship
 between smoking and lung cancer. Further research examining the relationship between serum estrogen levels and the estrogen receptor expression in normal and tumor lung tissue samples can help elucidate the importance of reproductive and hormonal (exogenous and endogenous) factors in the carcinogenesis of lung cancer.
A nurse-led Parkinson's service was introduced at Canberra Hospital and Health Services in 2012 with the primary objective of improving the care and self-management of people with a diagnosis of Parkinson's disease (PD) and related movement disorders. Other objectives of the Service included improving the quality of life of patients with PD and reducing their caregiver burden, improving the knowledge and understanding of PD among healthcare professionals, and reducing unnecessary hospital admissions. This article evaluates the first 2 years of this Service.
The Context, Input, Process, and Product Evaluation Model was used to evaluate the Parkinson's and Movement Disorder Service.
The context evaluation was conducted through discussions with stakeholders, review of PD guidelines and care pathways, and assessment of service gaps. Input: The input evaluation was carried out by reviewing the resources and strategies used in the development of the Service.
The process evaluation was undertaken by reviewing the areas of the implementation that went well and identifying issues and ongoing gaps in service provision. Product: Finally, product evaluation was undertaken by conducting stakeholder interviews and surveying patients in order to assess their knowledge and perception of value, and the patient experience of the Service. Admission data before and after implementation of the Parkinson's and Movement Disorder Service were also compared for any notable trends.

Several gaps in service provision for patients with PD in the Australian Capital Territory were identified, prompting the development of a PD Service to address some of them. Input: Funding for a Parkinson's disease nurse specialist was made available, and existing resources were used to develop clinics, education sessions, and outreach services.
Clinics and education sessions were implemented successfully, with positive feedback from patients and healthcare professionals. However, outreach services were limited because of capacity constraints on the Parkinson's disease nurse specialist. Product: The Service has filled an important health need in the local context; 98.3% of patients surveyed reported that the Service met their needs and helped them understand their care plan, achieving the primary objective of improving patient self-management. Interviews with stakeholders provided positive feedback about the value and usefulness of the Service, and healthcare professionals reported improvement in their knowledge about PD management. The evaluation also identified ongoing gaps in service provision and highlighted areas for potential improvement. No discernible trends in admission rates before and after the implementation of the Service were identified.
The introduction of a nurse-led PD service has had a positive impact on the provision of care for patients with PD and is a valued service. The evaluation highlighted some ongoing gaps in service provision and has generated some recommendations to address these.
Two categories of joint overloading cause post-traumatic osteoarthritis (PTOA): single acute traumatic loads/impactions and repetitive overloading due to incongruity/instability. We developed and refined three classes of complementary models to define relationships between joint overloading and progressive cartilage loss across the spectrum of acute injuries and chronic joint abnormalities: explant and whole joint models that allow probing of cellular responses to mechanical injury and contact stresses, animal models that enable study of PTOA pathways in living joints and pre-clinical testing of treatments, and patient-specific computational models that define the overloading that causes OA in humans. We coordinated methodologies across models so that results from each informed the others, maximizing the benefit of this complementary approach. We are incorporating results from these investigations into biomathematical models to provide predictions of PTOA risk and guide treatment. Each approach has limitations, but each provides opportunities to elucidate PTOA pathogenesis. Taken together, they help define levels of joint overloading that cause cartilage destruction, show that both forms of overloading can act through the same biologic pathways, and create a framework for initiating clinical interventions that decrease PTOA risk. Considered collectively, studies extending from explants to humans show that thresholds of joint overloading that cause cartilage loss can be defined, that to at least some extent both forms of joint overloading act through the same biologic pathways, and interventions that interrupt these pathways prevent cartilage damage. These observations suggest that treatments that decrease the risk of all forms of OA progression can be discovered. © 2016 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res.
Degenerative cartilage endplate (CEP) shows decreased chondrification and increased ossification. Cartilage endplate stem cells (CESCs), with the capacity for chondro-osteogenic differentiation, are responsible for CEP restoration. CEP is avascular and hypoxic, while the physiological hypoxia is disrupted in the degenerated CEP. Hypoxia promoted chondrogenesis but inhibited osteogenesis in CESCs. This tissue-specific differentiation fate of CESCs in response to hypoxia was physiologically significant with regard to CEP maintaining chondrification and refusing ossification. MIF, a downstream target of HIF1A, is involved in cartilage and bone metabolisms, although little is known about its regulatory role in differentiation. In CESCs, MIF was identified as a key point through which HIF1A regulated the chondro-osteogenic differentiation. Unexpectedly, unlike the traditionally recognized mode, increased nuclear-expressed MIF under hypoxia was identified to act as a transcriptional regulator by interacting with the promoter of SOX9 and RUNX2. This mode of HIF1A/MIF function may represent a target for CEP degeneration therapy.
To analyze scopes and limits of the use of participatory methodology of evaluation with municipal health managers and administrators.
Qualitative research with health policymakers and managers of the Comissão Intergestores Regional (CIR - Regional Interagency Commission) of a health region of the state of Sao Paulo in Brazil. Representatives from seven member cities participated in seven workshops facilitated by the researchers, with the aim of assessing a specific problem of the care line, which would be used as a tracer of the system integrality. The analysis of the collected empirical material was based on the hermeneutic-dialectic methodology and aimed at the evaluation of the applied participatory methodology, according to its capacity of promoting a process of assessment capable to be used as a support for municipal management.
With the participatory approach of evaluation, we were able to promote in-depth discussions with the group, especially related to the construction of integral care and to the inclusion of the user's perspective in decision-making, linked to the search for solution to concrete problems of managers. By joint exploration, the possibility of using data from electronic information systems was opened, as well as information coming directly from the users of the services, to enhance discussions and negotiations between partners. The participants were disbelievers of the replication potential of this type of evaluation without the direct monitoring of the academy, given the difficulty of organizing the process in everyday life, already taken by emergency and political issues.
Evaluations of programs and services carried out within the Regional Interagency Commission, starting from the local interest and facilitating the involvement of its members by the use of participatory methodologies, can contribute to the construction of integral care. To the extent that the act of evaluating stay invested with greater significance to the local actors, its involvement with the evaluations at the federal level can also be stimulated.
Analisar alcances e limites do uso de metodologia participativa de avaliação junto a gestores e gerentes municipais de saúde.
Pesquisa qualitativa com gestores e gerentes de saúde da Comissão Intergestores Regional de uma região de saúde do estado de São Paulo. Representantes de sete municípios membros participaram de sete oficinas facilitadas pelos pesquisadores, com o objetivo de avaliar um problema específico da linha de cuidados sob a perspectiva da integralidade. A análise do material empírico coletado baseou-se na metodologia hermenêutica-dialética e visou a avaliação da metodologia participativa aplicada, segundo sua capacidade de promover um processo de avaliação passível de ser utilizado como suporte à gestão municipal.
Com a abordagem participativa de avaliação, foi possível promover debates em profundidade com o grupo, principalmente relacionados à construção da integralidade da atenção e à inclusão da perspectiva do usuário na tomada de decisão, de forma vinculada à busca de solução para problemas concretos dos gestores. Mediante a exploração conjunta, foi aberta a possibilidade de utilização de dados advindos dos sistemas eletrônicos de informação, bem como de informações advindas diretamente dos usuários dos serviços, para enriquecer debates e negociações entre parceiros. Os participantes se mostraram descrentes do potencial de replicação deste tipo de avaliação sem o acompanhamento direto da academia, dada a dificuldade de
 organização do processo no cotidiano, já tomado por questões emergenciais e políticas.
Avaliações de programas e serviços realizadas no âmbito da Comissão Intergestores Regional, partindo do interesse local e facilitando o envolvimento de seus membros pelo uso de metodologias participativas, podem contribuir para a construção da integralidade do cuidado. Na medida em que o ato de avaliar fique investido de maior significado para os atores locais, seu envolvimento com as avaliações em nível federal poderá ser também estimulado.
Ligase IV and XRCC4 genes, important molecules in the nonhomologous end-joining pathway for repairing DNA double-strand breaks, may play crucial roles in carcinogenesis. To detect their effects on the risk of human glioma, their gene expression differences between 110 human glioma tissues and 50 healthy brain tissues were determined using quantitative real-time PCR. Furthermore, two tagging single nucleotide polymorphisms (SNPs) in ligase IV and four SNPs in XRCC4 genes were genotyped in 317 glioma patients and 352 healthy controls. The association of glioma and ligase IV/XRCC4 was evaluated using methods for SNP, haplotype, and gene-gene interaction analysis. Compared with those in normal brain tissues, the relative gene expression levels of ligase IV and XRCC4 were significantly downregulated in glioma tissue (P=0.0017 and 0.0006, respectively). Single SNP analysis indicated that only rs10131 in ligase IV remained significantly associated with glioma (P=0.0036) after 10 000 permutation tests. Haplotype analysis showed that the haplotype profiles of ligase IV and XRCC4 were significantly different between glioma patients and healthy controls (P=0.004 and 3.13E-6, respectively). Finally, the gene-gene interaction analysis suggested that the three-locus model (rs1805388, rs10131, and rs2075685) was the best model for ligase IV and XRCC4 to have interaction effects on the risk of glioma. In conclusion, both ligase IV and XRCC4 may act in concert to modulate the development of glioma.
Immune cell recognition of bacterial products usually occurs via specific pattern recognition receptors, but new research recently published in Cell by Wolf et al. (2016) demonstrates that the glycolytic enzyme hexokinase can act as an innate immune sensor by binding to bacterial derived N-acetylglucosamine (NAG).
Dehydrins are a group of intrinsically disordered proteins that protect plants from damage caused by drought, cold, and high salinity. Like other intrinsically disordered proteins, dehydrins can gain structure when bound to a ligand. Previous studies have shown that dehydrins are able to protect liposomes from cold damage, but the interactions that drive membrane binding and the detailed structure of the bound and unbound forms are not known. We use an ensemble-structure approach to generate models of a dehydrin known as K2 in the presence and absence of sodium dodecyl sulfate micelles, and we docked the bound structure to the micelle. The collection of residual dipolar coupling data, amide protection factors, and paramagnetic relaxation enhancement distances, in combination with chemical shifts and relaxation measurements, allows for determining plausible structures that are not otherwise visible in time-averaged structural data. The results show that in the bound structure, the conserved lysines are important for membrane binding, whereas the flanking hydrophobic residues play a lesser role. The unbound structure shows a high level of disorder and an extended structure. We propose that the structural differences between bound and unbound forms allow dehydrins to act as molecular shields in their unbound state and as membrane protectants in their bound state. Unlike α-synuclein, the significant gain of α-helicity in K2 at low concentrations of sodium dodecyl sulfate is not due to a decrease in the critical micelle concentration. The study provides structural insight into how a disordered protein can interact with a membrane surface.
Genome-wide experimental studies in Saccharomyces cerevisiae reveal that autonomous replicating sequence (ARS) requires an essential consensus sequence (ACS) for replication activity. Computational studies identified thousands of ACS like patterns in the genome. However, only a few hundreds of these sites act as replicating sites and the rest are considered as dormant or evolving sites. In a bid to understand the sequence makeup of replication sites, a content and context-based analysis was performed on a set of replicating ACS sequences that binds to origin-recognition complex (ORC) denoted as ORC-ACS and non-replicating ACS sequences (nrACS), that are not bound by ORC. In this study, DNA properties such as base composition, correlation, sequence dependent thermodynamic and DNA structural profiles, and their positions have been considered for characterizing ORC-ACS and nrACS. Analysis reveals that ORC-ACS depict marked differences in nucleotide composition and context features in its vicinity compared to nrACS. Interestingly, an A-rich motif was also discovered in ORC-ACS sequences within its nucleosome-free region. Profound changes in the conformational features, such as DNA helical twist, inclination angle and stacking energy between ORC-ACS and nrACS were observed. Distribution of ACS motifs in the non-coding segments points to the locations of ORC-ACS which are found far away from the adjacent gene start position compared to nrACS thereby enabling an accessible environment for ORC-proteins. Our attempt is novel in considering the contextual view of ACS and its flanking region along with nucleosome positioning in the S. cerevisiae genome and may be useful for any computational prediction scheme.
Neural stem cells (NSCs) are multipotent, self-renewing and undifferentiated cells that have the ability to differentiate to both glial and neuronal lineages. miRNAs act a key role in regulating neuronal fate and self-renewal of NSCs. In this study, we found that ectopic expression of miR-765 promoted NSCs proliferation. Moreover, miR-765 overexpression increased the ki-67 and β-tubulin-III expression inNSCs. Overexpression of miR-765 inhibited the expression of GFAP in NSCs. Furthermore, Hes1 was identified as a direct target gene of miR-765 in NSCs. Overexpression of Hes1 decreased miR-765-induced proliferation of NSCs and inhibited NSCs differentiation to neurons in miR-765-treated NSCs. These results demonstrated that miR-765 acted a crucial role in NSCs differentiation and proliferation by inhibiting Hes1 expression.
Raffinose synthase 5 (AtRS5, At5g40390) was characterized from Arabidopsis as a recombinant enzyme. It has a far higher affinity for the substrates galactinol and sucrose than any other raffinose synthase previously reported. In addition raffinose synthase 5 is also working as a galactosylhydrolase, degrading galactinol, and raffinose under certain conditions. Together with raffinose synthase 4, which is predominantly a stachyose synthase, both enzymes contribute to the raffinose family oligosaccharide (RFO) accumulation in seeds. A double knockout in raffinose synthase 4 and raffinose synthase 5 (ΔAtRS4,5) was generated, which is devoid of RFOs in seeds. Unstressed leaves of 4 week old ΔAtRS4,5 plants showed drastically 23.8-fold increased concentrations of galactinol. Unexpectedly, raffinose appeared again in drought stressed ΔAtRS4,5 plants, but not under other abiotic stress conditions. Drought stress leads to novel transcripts of raffinose synthase 6 suggesting that this isoform is a further stress inducible raffinose synthase in Arabidopsis. ΔAtRS4,5 seeds showed a 5 days delayed germination phenotype in darkness and an elevated expression of the transcription factor phytochrome interacting factor 1 (AtPIF1) target gene AtPIF6, being a repressor of germination. This prolonged dormancy is not seen during germination in the light. Exogenous galactose partially promotes germination of ΔAtRS4,5 seeds in the dark suggesting that RFOs act as a galactose store and repress AtPIF6 transcripts.
This paper describes the methods and conceptual framework for Wave 1 of the Population Assessment of Tobacco and Health (PATH) Study data collection. The National Institutes of Health, through the National Institute on Drug Abuse, is partnering with the Food and Drug Administration's (FDA) Center for Tobacco Products to conduct the PATH Study under a contract with Westat.
The PATH Study is a nationally representative, longitudinal cohort study of 45 971 adults and youth in the USA, aged 12 years and older. Wave 1 was conducted from 12 September 2013 to 15 December 2014 using Audio Computer-Assisted Self-Interviewing to collect information on tobacco-use patterns, risk perceptions and attitudes towards current and newly emerging tobacco products, tobacco initiation, cessation, relapse behaviours and health outcomes. The PATH Study's design allows for the longitudinal assessment of patterns of use of a spectrum of tobacco products, including initiation, cessation, relapse and transitions between products, as well as factors associated with use patterns. Additionally, the PATH Study collects biospecimens from consenting adults aged 18 years and older and measures biomarkers of exposure and potential harm related to tobacco use.
The cumulative, population-based data generated over time by the PATH Study will contribute to the evidence base to inform FDA's regulatory mission under the Family Smoking Prevention and Tobacco Control Act and efforts to reduce the Nation's burden of tobacco-related death and disease.
The myodural bridge was proposed initially in 1995. The myodural bridge is a connective tissue bridge that connects a pair of deep muscles at the suboccipital region to the dura mater. There have been numerous studies concerning the morphology and function of the myodural
 bridge. To determine whether a myodural bridge exists in reptiles, six Siamese crocodiles were investigated using gross anatomy dissection and P45 sheet plastination technologies. As a result, we demonstrated that the posterior occipital muscles of the Siamese crocodile are directly or indirectly connected to the proatlas, atlas, and intermembrane between them. Multiple trabeculae existing in the posterior epidural space extended from the ventral surface of the proatlas, atlas, and intermembrane between them to the dorsal surface of the spinal dura mater. This study showed that the posterior occipital muscle in the suboccipital region of the Siamese crocodile is connected to the spinal dura mater through the proatlas, atlas, and the trabeculae. In conclusion, a myodural bridge-like structure exists in reptiles. This connection may act as a pump to provide cerebrospinal fluid (CSF) circulation at the occipitocervical junction. We hypothesize that a physiologic role of the Siamese crocodile's myodural bridge may be analogous to the human myodural bridge. Anat Rec, 299:1402-1408, 2016. © 2016 Wiley Periodicals, Inc.
The in vivo origin of bone-producing osteoblasts is not fully defined. Skeletal stem cells, a population of mesenchymal stem cells resident in the bone marrow compartment, are thought to act as osteoprogenitors during growth and adulthood. Quiescent bone lining cells (BLCs) have been suggested as a population capable of activation into mature osteoblasts. These cells were defined by location and their morphology and studies addressing their significance have been hampered by their inaccessibility, and lack of markers that would allow for their identification and tracing. Using lineage tracing models, we have observed labeled osteoblasts at time points extending beyond the reported lifespan for this cell type, suggesting continuous reactivation of BLCs. BLCs also make a major contribution to bone formation after osteoblast ablation, which includes the ability to proliferate. In contrast, mesenchymal progenitors labeled by Gremlin1 or alpha smooth muscle actin do not contribute to bone formation in this setting. BLC activation is inhibited by glucocorticoids, which represent a well-established cause of osteoporosis. BLCs express cell surface markers characteristic of mesenchymal stem/progenitors that are largely absent in osteoblasts including Sca1 and Leptin Receptor. BLCs also show different gene expression profiles to osteoblasts, including elevated expression of Mmp13, and osteoclast regulators RANKL and macrophage colony stimulating factor, and retain osteogenic potential upon transplantation. Our findings provide evidence that bone lining cells represent a major source of osteoblasts during adulthood. Stem Cells 2016;34:2930-2942.
To design new tobacco control legislation to achieve the New Zealand Government's 2025 smokefree goal.
An original analysis of the legislative options for New Zealand tobacco control.
'Business as usual' is most unlikely to achieve smoking prevalence that is less than 5% by 2025. Key components of a new Act would ideally include plans and targets with teeth, a focus on the industry, a focus on the product, reduction of supply, and a whole-of-society approach to promote consistency in policy implementation through: i) a public duty on government agencies to act consistently with smokefree law; ii) a general duty on those associated with the tobacco/nicotine industry in relation to tobacco control objectives; and iii) a principle requiring international treaties to be interpreted consistently with tobacco control objectives.
Strategies such as those identified in this Viewpoint should be explored further as part of urgently needed planning to achieve the New Zealand Government's goal for Smokefree Aotearoa by 2025.
Hepcidin, a liver-expressed antimicrobial peptide, has been demonstrated to act as an iron regulatory hormone as well as to exert a wide spectrum of antimicrobial activity. The aim of this work was the expression, as secreted peptide, purification, and characterization of a new recombinant polyHis-tagged camel hepcidin (HepcD-His) in yeast Pichia pastoris. The use of this eukaryotic expression system, for the production of HepcD-His, having 6 histidine residues at its C terminus, was simpler and more efficient compared with the use of the prokaryotic system Escherichia coli. Indeed, a single purification step was required to isolate the soluble hepcidin with purity estimated more that 94% and a yield of 2.8 against 0.2 mg/L for the E coli system. Matrix-assisted laser desorption/ionization time-of-flight (TOF)/TOF mass spectrometry of the purified HepcD-His showed 2 major peaks at m/z 4524.64 and 4634.56 corresponding to camel hepcidin with 39 and 40 amino acids. Evaluation of disulfide bond connectivity with the Ellman method showed an absence of free thiol groups, testifying that the 8 cysteine residues in the peptide are displayed, forming 4 disulfide bridges. Circular dichroism spectroscopy showed that camel hepcidin structure was significantly modified at high temperature of 90°C and returns to its original structure when incubation temperature drops back to 20°C. Interestingly, this peptide showed also a greater bactericidal activity, at low concentration of 9.5μM, against E coli, than the synthetic analog DH3. Thus, the production, at a large scale, of the recombinant camel hepcidin, HepcD-His, may be helpful for future therapeutic applications including bacterial infection diseases.
Both hydrogen sulfide (H2S) and nitric oxide (NO) are important gaseous mediators. We and others previously reported that these two gases react with each other to generate a new mediator, nitroxyl (HNO), and regulate cardiovascular functions. In this study, we demonstrated for the first time that the interaction between the two gases also existed in microglia. The biological functions of HNO in microglial cells were further studied with Angeli's salt (AS), an HNO donor. We found that AS attenuated lipopolysaccharide (LPS)-evoked production of reactive oxygen species (ROS) and pro-inflammatory cytokines (e.g. IL-1β and TNFα) through downregulating the expression of inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2). HNO significantly reduced the phosphorylation of p38 mitogen-activated protein kinase (MAPK) and the activation of nuclear factor-κB (NF-κB) through suppression of phosphorylation p65 and IκBα. The above effects were abolished by l-cysteine, an HNO scavenger, but were not mimicked by nitrite, another product of AS during generating HNO. A Cys-179-to-Ala mutation in inhibitory κB kinase β (IKKβ) mimicked the effect of HNO on LPS-induced NF-κB activation. Interestingly, AS abolished the inflammation in cells overexpressing WT-IKKβ, but had no significant effect in cells overexpressing C179A-IKKβ. These data suggest that HNO may act on C179 to prevent IKKβ-dependent inflammation. Taken together, our data demonstrated for the first time that H2S interacts with NO to generate HNO in microglial cells. HNO produces anti-inflammatory effects through suppressing the IKKβ dependent NF-κB activation and p38 MAPK pathways.
Hospitals in Wales will be legally obliged to implement safe nurse staffing levels from April 2018, the Welsh Assembly has announced.
The advent of 2D materials integration has enabled novel heterojunctions where carrier transport proceeds thrsough different ultrathin layers. We here demonstrate the potential of such heterojunctions on a graphene/dielectric/semiconductor vertical stack that combines several enabling features for optoelectronic devices. Efficient and stable light emission was achieved through carrier tunneling from the graphene injector into prominent states of a luminescent material. Graphene's unique properties enable fine control of the band alignment in the heterojunction. This advantage was used to produce vertical tunneling-injection light-emitting transistors (VtiLET) where gating allows adjustment of the light emission intensity independent of applied bias. This device was shown to simultaneously act as a light detecting transistor with a linear and gate tunable sensitivity. The presented development of an electronically controllable multifunctional light emitter, light detector and transistor open up a new route for future optoelectronics.
Knowledge of integrative physiology is a major challenge for scientists, as even small deregulation could lead to diseases. Cells communicate with each other to control many processes such as growth, migration, survival, or differentiation. Such interaction could be achieved via several mechanisms either through cell-cell interactions and/or through the signaling of molecules that bind to receptors on the membrane or in the target cells. The produced molecules could have either autocrine, paracrine stimulations, or even act on distant organs (endocrine signaling).
Disintegrant is one of the most important components in a typical tablet dosage form. It is responsible for ensuring the break-up of the tablet matrix upon ingestion. Disintegrants act by different mechanisms, and a number of factors may affect their performance. It is important for formulators to understand how disintegrants function so as to be able to judiciously use disintegrants to develop optimized formulations. If the formulator is required to implement the quality by design paradigm while developing a tablet formulation, it would be important to determine the impact of component ranges and process variations on tablet performance and of particular importance, tablet disintegration. Thus, a better understanding of the mechanisms of disintegrants and the tablet disintegration processes can be critical to product design success. This review aims to provide an overview of tablet disintegrants and the disintegration processes
 with particular focus on the factors affecting the functionalities of disintegrants. An updated compendium of different techniques employed to evaluate disintegrant action and measure disintegration time is also provided. The objective of this review is to assemble the knowledge about disintegrants and the measurement of tablet disintegratability so that the information provided could be of help to tablet formulation development.
This review provides a summary of the physiological significance of the TRPV4 ion channel. Although TRPV4 was initially characterized as an osmosensor, we found that TRPV4 can also act as a thermosensor or a mechanosensor in brain neurons or epithelial cells in the urinary bladder. Here, we summarize the newly characterized functions of TRPV4, including the research progress that has been made toward our understanding of TRPV4 physiology, and discuss other recent data pertaining to TRPV4. It is thought that TRPV4 may be an important drug target based on its broad expression patterns and important physiological functions. Possible associations between diseases and TRPV4 are also discussed.
One of the aims of the WHO Global Action Plan for Influenza Vaccines (GAP) was to transfer influenza vaccine production technology to interested manufacturers and governments in developing countries, to enable greater influenza vaccine manufacturing capacity against any pandemic threat or pandemic. For this objective, the GAP was supported by an independent Technical Advisory Group (TAG) to assist WHO to select vaccine manufacturing proposals for funding and to provide programmatic support for successful grantees. While there were many challenges, for both the TAG and grantees, there were also notable successes with an additional capacity of 338-600 million pandemic vaccine doses being made possible by the programme between 2007 and 2015, and a potential capacity of more than 600 million by 2016/17 with up to one billion doses expected by 2018/19. Seasonal vaccine production was also developed in 4 countries with another 4-5 countries expected to be producing seasonal vaccine by 2018/19. The relatively small WHO investments - in time and funding - made in these companies to develop their own influenza vaccine production facilities have had quite dramatic results.
Retigabine is a KCNQ voltage-gated potassium channel opener that was recently approved as an add-on therapeutic for patients with drug-resistant epilepsy. Retigabine exhibits very little specificity between most KCNQ channel subtypes, and there is interest in generating more potent and specific KCNQ channel openers. The present study describes the marked specificity of ICA069673 for KCNQ2 vs. KCNQ3, and exploits this property to investigate determinants of KCNQ subtype specificity. ICA069673 acts on a binding site in the voltage-sensing domain that is distinct from the putative retigabine site in the channel pore. ICA069673 has two separable effects on KCNQ channel activity. We identify two channel residues required for subtype specificity of KCNQ channel openers and show that these are sufficient to generate ICA069673 sensitivity in KCNQ3.
Retigabine (RTG) is the first approved anti-epileptic drug that acts via activation of voltage-gated potassium channels, targeting KCNQ channels that underlie the neuronal M-current. RTG exhibits little specificity between KCNQ2-5 as a result of conservation of a Trp residue in the pore domain that binds to the drug. The RTG analogue ICA-069673 ('ICA73') exhibits much stronger effects on KCNQ2 channels, including a large hyperpolarizing shift of the voltage-dependence of activation, an ∼2-fold enhancement of peak current and pronounced subtype specificity for KCNQ2 over KCNQ3. Based on ICA73 sensitivity of chimeric constructs of the transmembrane segments of KCNQ2 and KCNQ3, this drug appears to interact with the KCNQ2 voltage sensor (S1-S4) rather than the pore region targeted by RTG. KCNQ2 point mutants in the voltage sensor were generated based on KCNQ2/KCNQ3 sequence differences, and screened for ICA73 sensitivity. These experiments reveal that KCNQ2 residues F168 and A181 in the S3 segment are essential determinants of ICA73 subtype specificity. Mutations at either position in KCNQ2 abolish the ICA73-mediated gating shift, but preserve RTG sensitivity. Interestingly, A181P mutant channels show little ICA73-mediated gating shift but retain current potentiation by the drug. Mutations (L198F and P211A), which introduce these critical KCNQ2 residues at corresponding positions in KCNQ3, transplant partial ICA73 sensitivity. These findings demonstrate that RTG and ICA73 act via distinct mechanisms, and also reveal specific residues that underlie subtype specificity of KCNQ channel openers.
Delivery represents a significant barrier to the clinical advancement of oligonucleotide therapeutics for the treatment of neurological disorders, such as Huntington's disease. Small, endogenous vesicles known as exosomes have the potential to act as oligonucleotide delivery vehicles, but robust and scalable methods for loading RNA therapeutic cargo into exosomes are lacking. Here, we show that hydrophobically modified small interfering RNAs (hsiRNAs) efficiently load into exosomes upon co-incubation, without altering vesicle size distribution or integrity. Exosomes loaded with hsiRNAs targeting Huntingtin mRNA were efficiently internalized by mouse primary cortical neurons and promoted dose-dependent silencing of Huntingtin mRNA and protein. Unilateral infusion of hsiRNA-loaded exosomes, but not hsiRNAs alone, into mouse striatum resulted in bilateral oligonucleotide distribution and statistically significant bilateral silencing of up to 35% of Huntingtin mRNA. The broad distribution and efficacy of hsiRNA-loaded exosomes delivered to brain is expected to advance the development of therapies for the treatment of Huntington's disease and other neurodegenerative disorders.
Glycolysis generates methylglyoxal (MGO) as an unavoidable, cytotoxic by-product in plant cells. MGO scavenging is performed by the glyoxalase system, which produces d-lactate as an end product. d-Lactate dehydrogenase (d-LDH) is encoded by a single gene in Arabidopsis (Arabidopsis thaliana; At5g06580). It catalyzes in vitro the oxidation of d-lactate to pyruvate using flavin adenine dinucleotide as a cofactor; knowledge of its function in the context of the plant cell remains sketchy. Blue native-polyacrylamide gel electrophoresis of mitochondrial extracts combined with in gel activity assays using different substrates and tandem mass spectrometry allowed us to definitely show that d-LDH acts specifically on d-lactate, is active as a dimer, and does not associate with respiratory supercomplexes of the inner mitochondrial membrane. The combined use of cytochrome c (CYTc) loss-of-function mutants and respiratory complex III inhibitors showed that CYTc acts as the in vivo electron acceptor of d-LDH. CYTc loss-of-function mutants, as well as the d-LDH mutants, were more sensitive to d-lactate and MGO, indicating that they function in the same pathway. In addition, overexpression of d-LDH and CYTc increased tolerance to d-lactate and MGO Together with fine-localization of d-LDH, the functional interaction with CYTc in vivo strongly suggests that d-lactate oxidation takes place in the mitochondrial intermembrane space, delivering electrons to the respiratory chain through CYTc These results provide a comprehensive picture of the organization and function of d-LDH in the plant cell and exemplify how the plant mitochondrial respiratory chain can act as a multifunctional electron sink for reductant from cytosolic pathways.
Proteins are vital biological molecules driving many fundamental cellular processes. They rarely act alone, but form interacting groups called protein complexes. The study of protein complexes is a key goal in systems biology. Recently, large protein-protein interaction (PPI) datasets have been published and a plethora of computational methods that provide new ideas for the prediction of protein complexes have been implemented. However, most of the methods suffer from two major limitations: First, they do not account for proteins participating in multiple functions and second, they are unable to handle weighted PPI graphs. Moreover, the problem remains open as existing algorithms and tools are insufficient in terms of predictive metrics.
In the present paper, we propose gradually expanding neighborhoods with adjustment (GENA), a new algorithm that gradually expands neighborhoods in a graph starting from highly informative "seed" nodes. GENA considers proteins as multifunctional molecules allowing them to participate in more than one protein complex. In addition, GENA accepts weighted PPI graphs by using a weighted evaluation function for each cluster.
In experiments with datasets from Saccharomyces cerevisiae and human, GENA outperformed Markov clustering, restricted neighborhood search and clustering with overlapping neighborhood expansion, three state-of-the-art methods for computationally predicting protein complexes. Seven PPI networks and seven evaluation datasets were used in total. GENA outperformed existing methods in 16 out of 18 experiments achieving an average improvement of 5.5% when the maximum matching ratio metric was used. Our method was able to discover functionally homogeneous protein clusters and uncover important network modules in a Parkinson expression dataset. When used on the human networks, around 47% of the detected clusters were enriched in gene ontology (GO) terms with depth higher than five in the GO hierarchy.
In the present manuscript, we introduce a new method for the computational prediction of protein complexes by making the realistic assumption that proteins participate in multiple protein complexes and cellular
 functions. Our method can detect accurate and functionally homogeneous clusters.
To determine if changes to the Ontario Highway Traffic Act (OHTA) in 2009 and 2010 had an effect on the proportion of alcohol-related motor vehicle collisions (MVCs) presenting to a trauma centre over a 10-year period.
A retrospective review of the trauma registry at a Level I trauma centre in southwestern Ontario was undertaken. The trauma registry is a database of all trauma patients with an injury severity score (ISS) ≥12 and/or who had trauma team activation. Descriptive statistics were calculated. Interrupted time series analyses with ARIMA modeling were performed on quarterly data from 2004-2013.
A total of 377 drivers with a detectable serum ethanol concentration (SEC) were treated at our trauma centre over the 10-year period, representing 21% of all MVCs. The majority (330; 88%) were male. The median age was 31 years, median SEC was 35.3 mmol/L, and median ISS was 21. A total of 29 (7.7%) drinking drivers died from their injuries after arriving to hospital. There was no change in the proportion of drinking drivers after the 2009 amendment, but there was a significant decline in the average SEC of drinking drivers after changes to the law. There was no difference in the proportion of drinking drivers ≤21 years after introduction of the 2010 amendment for young and novice drivers.
There was a significance decline in the average SEC of all drinking drivers after the 2009 OHTA amendment, suggesting that legislative amendments may have an impact on drinking before driving behaviour.
Chemotactic responses of eukaryotic cells require a signal processing system that translates an external gradient of attractant into directed motion. To challenge the response system to its limits, we increased the size of Dictyostelium discoideum cells by using electric-pulse-induced fusion. Large cells formed multiple protrusions at different sites along the gradient of chemoattractant, independently turned towards the gradient and competed with each other. Finally, these cells succeeded to re-establish polarity by coordinating front and tail activities. To analyse the responses, we combined two approaches, one aimed at local responses by visualising the dynamics of Ras activation at the front regions of reorientating cells, the other at global changes of polarity by monitoring front-to-tail-directed actin flow. Asymmetric Ras activation in turning protrusions underscores that gradients can be sensed locally and translated into orientation. Different to cells of normal size, the polarity of large cells is not linked to an increasing front-to-tail gradient of the PIP3-phosphatase PTEN. But even in large cells, the front communicates with the tail through an actin flow that might act as carrier of a protrusion inhibitor.
The exploitation of optical wireless communication channels in a non-line-of-sight regime is studied for point-to-point and networking configurations considering the use of light-emitting diodes. Two environments with different scattering center densities are considered, assuming operation at 265 nm. The bit error rate performance of both pulsed and multicarrier modulation schemes is examined, using numerical approaches. In the networking scenario, a central node only receives data, one node transmits useful data, and the rest of them act as interferers. The performance of the desirable node's transmissions is evaluated. The access to the medium is controlled by a code division multiple access scheme.
The human visual system uses eye movements to gather visual information. They act as visual scanning processes and can roughly be divided into two different types: small movements around fixation points and larger movements between fixation points. The processes are often modeled as random walks, and recent models based on heavy tail distributions, also known as Levý flights, have been used in these investigations. In contrast to these approaches we do not model the stochastic processes, but we will show that the step lengths of the movements between fixation points follow generalized Pareto distributions (GPDs). We will use general arguments from the theory of extreme value statistics to motivate the usage of the GPD and show empirically that the GPDs provide good fits for measured eye tracking data. In the framework of information geometry the GPDs with a common threshold form a two-dimensional Riemann manifold with the Fisher information matrix as a metric. We compute the Fisher information matrix for the GPDs and introduce a feature vector describing a GPD by its parameters and different geometrical properties of its Fisher information matrix. In our statistical analysis we use eye tracker measurements in a database with 15 observers viewing 1003 images under free-viewing conditions. We use Matlab functions with their standard parameter settings and show that a naive Bayes classifier using the eigenvalues of the Fisher information matrix provides a high classification rate identifying the 15 observers in the database.
In youth, maladaptive personality traits such as urgency (the tendency to act rashly when highly emotional) predict early onset alcohol consumption. In adults, maladaptive behaviors, including substance use, predict negative personality change. This article reports on a test of hypothesized maladaptive, reciprocal prediction between youth drinking and the trait of urgency. In a sample of 1,906 youth assessed every 6 months from the spring of 5th grade through the spring of 8th grade, and again in the spring of 9th grade, the authors found such reciprocal prediction. Over each 6 month and then 12 month time lag, urgency predicted increased subsequent drinking. In addition, over 6 of the 7 time lags, drinking behavior predicted subsequent increases in urgency. During early adolescence, maladaptive personality and dysfunctional behavior each led to increases in the other. The results of this process include cyclically increasing risk for youth drinking and may include increasing risk for the multiple maladaptive behaviors predicted by the trait of urgency. (PsycINFO Database Record
To identify the barriers to and enablers of effective insulin self-titration in people with Type 2 diabetes.
A qualitative semi-structured interview approach was used. Questions were structured according to the Theoretical Domains Framework, which outlines 14 domains that can act as barriers to and enablers of changing behaviour. Interviews were audio-recorded and transcribed verbatim. The data were coded according to the 14 domains, belief statements were created within each domain, and a frequency count of the most reported barriers and enablers was then carried out. Analyses were conducted by two researchers, and discrepancies agreed with a third researcher.
A total of 18 adults with Type 2 diabetes took part in an interview. The majority were of South-Asian ethnicity (n = 8) and were men (n = 12). Their mean age was 61 years old. The mean duration of diabetes was 16 years and time on insulin 9 years. Inter-rater reliability for each of the domains varied (29-100%). The most frequently reported domains were Social Influence and Beliefs about Consequences; the least frequently reported were Optimism and Reinforcement. Interviewees reported receiving support to self-titrate from a range of sources. Self-titrating was perceived to have a range of both positive and negative consequences, as was not titrating.
The findings highlight that those interviewed experienced a range of barriers and enablers when attempting to self-titrate. Improved education and training when initiating insulin treatment among adults with Type 2 diabetes, and throughout their journey on insulin therapy could help identify and address these barriers in order to optimize self-titration.
Images on food and dietary supplement packaging might lead people to infer (appropriately or inappropriately) certain health benefits of those products. Research on this issue largely involves direct questions, which could (a) elicit inferences that would not be made unprompted, and (b) fail to capture inferences made implicitly. Using a novel memory-based method, in the present research, we explored whether packaging imagery elicits health inferences without prompting, and the extent to which these inferences are made implicitly.
In 3 experiments, participants saw fictional product packages accompanied by written claims. Some packages contained an image that implied a health-related function (e.g., a brain), and some contained no image. Participants studied these packages and claims, and subsequently their memory for seen and unseen claims were tested.
When a health image was featured on a package, participants often subsequently recognized health claims that-despite being implied by the image-were not truly presented. In Experiment 2, these recognition errors persisted despite an explicit warning against treating the images as informative. In Experiment 3, these findings were replicated in a large consumer sample from 5 European countries, and with a cued-recall test.
These findings confirm that images can act as health claims, by leading people to infer health benefits without prompting. These inferences appear often to be implicit, and could therefore be highly pervasive. The data underscore the importance of regulating imagery on product packaging; memory-based methods represent innovative ways to measure how leading (or misleading) specific images can be. (PsycINFO Database Record
To investigate the expression of advanced glycation end products (AGEs) and the receptor for AGE (RAGEs) in maternal blood, umbilical blood and placental tissues in women with severe preeclampsia (sPE) as well as any association with inflammatory processes.
The expressions of AGEs, RAGE, tumor necrosis factor-alpha
 (TNF)-α and vascular cell adhesion molecule-1 (VCAM)-1 in placental tissues were measured using immunohistochemistry. The levels of AGEs, RAGE, TNF-α and VCAM-1 in maternal blood, umbilical blood and placental extracts were assessed using enzyme-linked immunosorbent assays. Placental RAGE, TNF-α and VCAM-1 mRNA expression levels were determined by PCR. Placental AGEs, RAGE, TNF-α and VCAM-1 protein levels were determined by western blotting.
The levels of AGEs, TNF-α and VCAM-1 in the maternal tissues and umbilical blood were significantly higher in the sPE group than in the normal pregnancy (NP) controls (p < 0.05). The serum level of sRAGE in the umbilical blood was lower in the sPE group than in the NP controls (p < 0.05), while sRAGE was higher in the maternal blood of sPE than in the NP (p < 0.05). The maternal serum levels of AGEs were positively correlated with that of TNF-α and VCAM-1 in the maternal blood. There were no correlations between the levels of RAGE, TNF-α or VCAM-1 in maternal blood or umbilical serum. There were no correlations between the levels of sRAGE and TNF-α or VCAM-1 in maternal blood or umbilical serum. The levels of AGEs were positively correlated with those of TNF-α and VCAM-1 in placental lysates.
AGEs and RAGE appear to act as important mediators in regulating the inflammatory pathways of preeclampsia.
The Family Smoking Prevention and Tobacco Control Act of 2009 (Public Law 111-31) gave the US Food and Drug Administration (FDA) the responsibility for regulating tobacco products. Nicotine is the primary addictive component of tobacco and its effects can be modulated by additional ingredients in manufactured products. Nicotine acts by mimicking the neurotransmitter acetylcholine on neuronal nicotinic acetylcholine receptors (nAChRs), which function as ion channels in cholinergic modulation of neurotransmission. Subtypes within the family of neuronal nAChRs are defined by their α- and β-subunit composition. The subtype-selective profiles of tobacco constituents are largely unknown, but could be essential for understanding the physiological effects of tobacco products. In this report, we report the development and validation of electrophysiology-based high-throughput screens (e-HTS) for human nicotinic subtypes, α3β4, α3β4α5, α4β2, and α7 stably expressed in Chinese Hamster Ovary cells. Assessment of agonist sensitivity and acute desensitization gave results comparable to those obtained by conventional manual patch clamp electrophysiology assays. The potency of reference antagonists for inhibition of the receptor channels and selectivity of positive allosteric modulators also were very similar between e-HTS and conventional manual patch voltage clamp data. Further validation was obtained in pilot screening of a library of FDA-approved drugs that identified α7 subtype-selective positive allosteric modulation by novel compounds. These assays provide new tools for profiling of nicotinic receptor selectivity.
Human cooperation is enigmatic, as organisms are expected, by evolutionary and economic theory, to act principally in their own interests. However, cooperation requires individuals to sacrifice resources for each other's benefit. We conducted a series of novel experiments in a foraging society where social institutions make the study of social image and punishment particularly salient. Participants played simple cooperation games where they could punish non-cooperators, promote a positive social image or do so in combination with one another. We show that although all these mechanisms raise cooperation above baseline levels, only when social image alone is at stake do average economic gains rise significantly above baseline. Punishment, either alone or combined with social image building, yields lower gains. Individuals' desire to establish a positive social image thus emerges as a more decisive factor than punishment in promoting human cooperation.
Population attributes such as diversity, connectivity, and structure are important components of understanding species persistence and vulnerability to extinction. Hyla wrightorum, the Arizona treefrog, is native to the southwestern United States and Mexico, and an isolated group of populations exists in the Huachuca Mountains and Canelo Hills (HMCH) of southeastern Arizona, USA. Due to concerns about declining observations of the species within the isolated HMCH portion of its range, the HMCH group is currently a candidate for federal protection under the U.S. Endangered Species Act. We present results of a genetic study examining population diversity, structure, and connectivity within the HMCH region. We sampled DNA from H. wrightorum larvae and adults from ten distinct locations, 8 of which were breeding sites and 4 of which were previously undescribed localities for the species. We developed and genotyped 17 polymorphic microsatellite loci and quantified genetic diversity, population differentiation, and landscape influences on population genetic structure. We found evidence of larger than expected effective population sizes, significant genetic differentiation between populations, and evidence of distance being the primary driver of genetic structure of populations with some influence of slope and canopy cover. We found little evidence of recent genetic bottlenecks, and individual-based analyses indicate admixture between populations despite significant genetic differentiation. These patterns may indicate that the breeding sites within the Huachuca Mountains constitute a metapopulation. We suggest that the HMCH region may contain larger and more connected breeding populations than previously understood, but the dynamics of this system and the limited geographic extent of the HMCH group justify current concern for the persistence of the species in this region. Efforts to ensure availability of high-quality breeding habitats and control for local threats such as effects of invasive predators may be critical to the persistence of these unique populations of H. wrightorum.
To determine the accuracy of ferumoxytol-enhanced magnetic resonance angiography (MRA) in assessing the severity of transplant renal artery stenosis (TRAS), using digital subtraction angiography (DSA) as the reference standard.
Our Institutional Review Board approved this retrospective, Health Insurance Portability and Accountability Act-compliant study. Thirty-three patients with documented clinical suspicion for TRAS (elevated serum creatinine, refractory hypertension, edema, and/or audible bruit) and/or concerning sonographic findings (elevated renal artery velocity and/or intraparenchymal parvus tardus waveforms) underwent a 1.5T MRA with ferumoxytol prior to DSA. All DSAs were independently reviewed by an interventional radiologist and served as the reference standard. The MRAs were reviewed by three readers who were blinded to the ultrasound and DSA findings for the presence and severity of TRAS. Sensitivity, specificity, and accuracy for identifying substantial stenoses (>50%) were determined. Intraclass correlation coefficients (ICCs) were calculated among readers. Mean differences between the percent stenosis from each MRA reader and DSA were calculated.
On DSA, a total of 42 stenoses were identified in the 33 patients. The sensitivity, specificity, and accuracy of MRA in detecting substantial stenoses were 100%, 75-87.5%, and 95.2-97.6%, respectively, among the readers. There was excellent agreement among readers as to the percent stenosis (ICC = 0.82). MRA overestimated the degree of stenosis by 3.9-9.6% compared to DSA.
Ferumoxytol-enhanced MRA provides high sensitivity, specificity, and accuracy for determining the severity of TRAS. Our results suggest that it can potentially be used as a noninvasive examination following ultrasound to reduce the number of unnecessary conventional angiograms. J. Magn. Reson. Imaging 2016.
This qualitative study explores the dynamic changes that occur in family interaction patterns when Alzheimer's disease is present. Semi-structured interviews were conducted with 15 participants who have a family member with the disease. Using modified analytic induction, guided by the dimensions of the Family Fundamental Interpersonal Relations Orientation (FIRO) Model, participants shared how Alzheimer's disease affected family structure, control dynamics, and intimacy among family members. Findings demonstrate that (a) families reorganize and restructure based on geographic proximity and shifting roles, act out of filial responsibility, and strive to preserve shared meanings and rituals; (b) decision making increases around care of the person with Alzheimer's disease and shifts to the primary caregiver or other family members based on their abilities; and (c) expressions of intimacy intensify while personality is preserved in the person with the disease. The Family FIRO model can inform practitioners using family-centered care with families with Alzheimer's disease.
Events consist of diverse elements, each processed in specialized neocortical networks, with temporal lobe memory systems binding these elements to form coherent event memories. We provide a novel theoretical analysis of an unexplored consequence of the independence of memory systems for elements and their bindings, 1 that raises the paradoxical prediction that schema-driven false memories can act solely on the binding of event elements despite the superior retrieval of individual elements. This is because if 2, or more, schema-relevant elements are bound together in unexpected conjunctions, the unexpected conjunction will increase attention during encoding to both the elements and their bindings, but only the bindings will receive competition with evoked schema-expected bindings. We test our model by examining memory for object-location bindings in recognition (Study 1)
 and recall (Studies 2 and 3) tasks. After studying schema-relevant objects in unexpected locations (e.g., pan on a stool in a kitchen scene), participants who then viewed these objects in expected locations (e.g., pan on stove) at test were more likely to falsely remember this object-location pairing as correct, compared with participants that viewed a different unexpected object-location pairing (e.g., pan on floor). In recall, participants were more likely to correctly remember individual schema-relevant objects originally viewed in unexpected, as opposed to expected locations, but were then more likely to misplace these items in the original room scene to expected places, relative to control schema-irrelevant objects. Our theoretical analysis and novel paradigm provide a tool for investigating memory distortions acting on binding processes. (PsycINFO Database Record
Mosquitoes (Diptera: Culicidae) are a key threat for millions of people and animals worldwide, since they act as vectors for devastating pathogens and parasites, including malaria, dengue, Japanese encephalitis, filiariasis and Zika virus. Mosquito young instars are usually targeted using organophosphates, insect growth regulators and microbial agents. Indoor residual spraying and insecticide-treated bed nets are also employed. However, these chemicals have negative effects on human health and the environment and induce resistance in a number of vectors. In this scenario, newer and safer tools have been recently implemented to enhance mosquito control. The concrete potential of screening plant species as sources of metabolites for entomological and parasitological purposes is worthy of attention, as recently elucidated by the Y. Tu's example. Here we investigated the toxicity of Heracleum sprengelianum (Apiaceae) leaf essential oil and its major compounds toward third instar larvae of the malaria vector Anopheles subpictus, the arbovirus vector Aedes albopictus and the Japanese encephalitis vector Culex tritaeniorhynchus. GC-MS analysis showed that EO major components were lavandulyl acetate (17.8%) and bicyclogermacrene (12.9%). The EO was toxic to A. subpictus, A. albopictus, and C. tritaeniorhynchus, with LC50 of 33.4, 37.5 and 40.9µg/ml, respectively. Lavandulyl acetate was more toxic to mosquito larvae if compared to bicyclogermacrene. Their LC50 were 4.17 and 10.3µg/ml for A. subpictus, 4.60 and 11.1µg/ml for A. albopictus, 5.11 and 12.5µg/ml for C. tritaeniorhynchus. Notably, the EO and its major compounds were safer to three non-target mosquito predators, Anisops bouvieri, Diplonychus indicus and Gambusia affinis, with LC50 ranging from 206 to 4219µg/ml. Overall, this study highlights that H. sprengelianum EO is a promising source of eco-friendly larvicides against three important mosquito vectors with moderate toxicity against non-target aquatic organisms.
The use of siRNA-based therapies for the treatment of neurodegenerative disease requires efficient, nontoxic distribution to the affected brain parenchyma, notably the striatum and cortex. Here, we describe the synthesis and activity of a fully chemically modified siRNA that is directly conjugated to docosahexaenoic acid (DHA), the most abundant polyunsaturated fatty acid in the mammalian brain. DHA conjugation enables enhanced siRNA retention throughout both the ipsilateral striatum and cortex following a single, intrastriatal injection (ranging from 6-60 μg). Within these tissues, DHA conjugation promotes internalization by both neurons and astrocytes. We demonstrate efficient and specific silencing of Huntingtin mRNA expression in both the ipsilateral striatum (up to 73%) and cortex (up to 51%) after 1 week. Moreover, following a bilateral intrastriatal injection (60 μg), we achieve up to 80% silencing of a secondary target, Cyclophilin B, at both the mRNA and protein level. Importantly, DHA-hsiRNAs do not induce neural cell death or measurable innate immune activation following administration of concentrations over 20 times above the efficacious dose. Thus, DHA conjugation is a novel strategy for improving siRNA activity in mouse brain, with potential to act as a new therapeutic platform for the treatment of neurodegenerative disorders.
In the current work, a new high strain rate tensile testing equipment is proposed. The equipment uses a pendulum device to generate an impact load and a three-bar mechanism to bring that load to act upon a specially designed specimen. As the standard impact testing apparatus uses pendulum device and the well-known SHB high strain rate tester adopts the above-mentioned mechanism, the introduced equipment can be dealt with as an impact apparatus in which the base that supports the V-shape specimen is replaced with the three-bar configuration that the traditional SHB uses. In order to demonstrate the applicability of the new tester, virtual design tools were used to determine the most appropriate configuration for it. Then, a detailed design was created, and a full-scale prototype was produced, calibrated, instrumented and tested. The obtained results demonstrate that the new tester is capable of axially straining steel specimens up to failure at a maximum rate of about 250 s(-1), which is reasonable when compared with a more established high strain rate testers.
Osteopontin (OPN) is a multifunctional adhesive glycoprotein that is implicated in a variety of pro-inflammatory as well as neuroprotective and repair-promoting effects in the brain. As a first step towards understanding the role of OPN in retinal degeneration (RD), we examined changes in OPN expression in a mouse model of RD induced by exposure to a blue light-emitting diode (LED). RD was induced in BALB/c mice by exposure to a blue LED (460 nm) for 2 h. Apoptotic cell death was evaluated by terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) assay. In order to investigate changes in OPN in RD, western blotting and immunohistochemistry were performed. Anti-OPN labeling was compared to that of anti-glial fibrillary acidic protein (GFAP), which is a commonly used marker for retinal injury or stress including inflammation. OPN expression in RD retinas markedly increased at 24 h after exposure, was sustained through 72 h, and subsided at 120 h. Increased OPN expression was observed co-localized with microglial cells in the outer nuclear layer (ONL), outer plexiform layer (OPL), and subretinal space. Expression was restricted to the central retina in which photoreceptor cell death occurred. Interestingly, OPN expression in the ONL/OPL was closely associated with microglia, whereas most of the OPN plaques observed in the subretinal space were not. Immunogold electron microscopy demonstrated that OPN was distributed throughout the cytoplasm of microglia and in nearby fragments of degenerating photoreceptors. In addition, we found that OPN was induced more acutely and with greater region specificity than GFAP. These results indicate that OPN may be a more useful marker for retinal injury or stress, and furthermore act as a microglial pro-inflammatory mediator and a phagocytosis-inducing opsonin in the subretinal space. Taken together, our data suggest that OPN plays an important role in the pathogenesis of RD.
We investigated the best position for shoulder retractor strengthening exercise to maximize middle trapezius activity and minimize rhomboid major activity. Although both trapezius and rhomboids are scapular retractors, rhomboids also act as downward rotators of the scapula, which can worsen subacromial impingement.
Twelve healthy participants (age 30 [SD 6] y) with no history of shoulder pain were recruited for this study, which used fine-wire electromyography to examine maximal muscle activation of the middle trapezius and rhomboid major muscle fibres in four different positions: with the shoulder in 90° abduction with elbow completely extended and (1) shoulder internal rotation, (2) shoulder neutral rotation, (3) shoulder external rotation, and (4) rowing (shoulder neutral rotation and elbow flexed 90°). The ratio of trapezius to rhomboid muscles was compared with Wilcoxon signed-rank tests.
Muscle activation ratio during shoulder retraction exercise was significantly lower by 22% (i.e., rhomboid was more active than middle trapezius) when performed with the shoulder in rowing position (elbow flexed) than with the shoulder in external rotation (elbow extended) position (p=0.031). All four positions produced coactivation of trapezius and rhomboids.
Rowing position may not be the best position for shoulder retractor strengthening in patients with impingement syndrome. The preferable position for maximizing middle trapezius activity and minimizing rhomboid activity may be shoulder external rotation with elbow extended.
Objet: Chercher la meilleure position pour un exercice de renforcement du rétracteur de l'épaule afin de maximiser l'activité du trapèze moyen et de réduire celle du grand rhomboïde au minimum. Même si les deux sont des rétracteurs de l'omoplate, les rhomboïdes font aussi pivoter l'omoplate vers le bas, ce qui peut aggraver la compression subacromiale. Méthodes: On a recruté 12 participants en bonne santé (âgés de 30 [ET 6] ans) sans antécédent de douleur à l'épaule pour cette étude dans le cadre de laquelle on a utilisé l'électromyographie à fil fin pour étudier l'activité maximale des fibres musculaires du trapèze moyen et du grand rhomboïde dans différentes positions: épaule en abduction à 90° avec coude en extension complète et a) rotation de l'épaule vers l'intérieur, b) rotation neutre de l'épaule, c) rotation de l'épaule vers l'extérieur d) mouvement d'aviron (rotation neutre de l'épaule et coude en flexion à 90°). On a comparé le ratio des trapèzes par rapport aux rhomboïdes au moyen du test de Wilcoxon pour observations appariées. Résultats: Le ratio d'activation
 musculaire au cours de l'exercice de rétraction de l'épaule était beaucoup moins élevé de 22% (c.-à-d. que le rhomboïde était plus actif que le trapèze moyen) l'épaule en position d'aviron (coude en flexion) qu'en position de rotation vers l'extérieur (coude en extension) (p=0,031). Les quatre positions ont produit une coactivation du trapèze et des rhomboïdes. Discussion: La position d'aviron n'est peut-être pas la meilleure position pour renforcer le rétracteur de l'épaule chez les patients qui ont un syndrome de pincement. La position préférée pour maximiser l'activité du trapèze moyen et réduire celle des rhomboïdes au minimum peut être la rotation vers l'extérieur, le coude en extension.
Important antimalarial drugs, including quinolines, act against blood schizonts by interfering with hemoglobin metabolism. To reach their site of action, these compounds have to cross the plasma membrane of red blood cells (RBCs). Organic cation transporters (OCTs) and organic anion transporting polypeptides (OATPs) are important uptake transporters and interesting candidates for local drug transport. We therefore studied their interaction with antimalarial compounds (quinine, chloroquine, mefloquine, pyrimethamine, artemisinin, and artesunate) and characterized the expression of OATP1A2 and OATP2B1 in RBCs. Competition assays using transporter-overexpressing Madin-Darby canine kidney (MDCKII) cells and the model substrate estrone-3-sulfate identified quinine and chloroquine as potent inhibitors of OATP1A2 function (IC50 quinine: 0.7 ± 1.2 µM; chloroquine: 1.0 ± 1.5 µM), but no or only moderate effects were observed for OATP2B1. Subsequently, quinine was identified as a substrate of OATP1A2 (Km 23.4 µM). The OATP1A2-mediated uptake was sensitive to the OATP1A2-specific inhibitor naringin. Both OATPs were expressed in human RBCs, and ex vivo transport studies demonstrated naringin-sensitive accumulation of quinine in these cells (60 pmol versus 38 pmol/5 × 10(5) RBCs). Additional transport studies using OCT1-3 and organic cation transporter novel type 1 (OCTN1) indicated only significant quinine uptake by OCT1, which was not detected in RBCs. In conclusion, our data demonstrate expression of OATP2B1 and OATP1A2 in RBCs as well as OATP1A2-mediated uptake of quinine. Therefore, modulation of OATP1A2 function may affect quinine uptake into erythrocytes.
One pillar of the Affordable Care Act (ACA) was its expected impact on the growing burden of uncompensated care costs for the uninsured at hospitals. However, little is known about how this burden changed as a result of the ACA's enactment. We examine how the Affordable Care Act (ACA)'s coverage expansions affected uncompensated care costs at a large, diverse sample of hospitals. We estimate that in states that expanded Medicaid under the ACA, uncompensated care costs decreased from 4.1 percentage points to 3.1 percentage points of operating costs. The reductions in Medicaid expansion states were larger at hospitals that had higher pre-ACA uncompensated care burdens and in markets where we predicted larger gains in coverage through expanded eligibility for Medicaid. Our estimates suggest that uncompensated care costs would have decreased from 5.7 percentage points to 4.0 percentage points of operating costs in nonexpansion states if they had expanded Medicaid. Thus, while the ACA decreased the variation in uncompensated care costs across hospitals within Medicaid expansion states, the difference between expansion and nonexpansion states increased substantially. Policy makers and researchers should consider how the shifting uncompensated care burden affects other hospital decisions as well as the distribution of supplemental public funding to hospitals.
The Affordable Care Act (ACA) imposed new restrictions on the formation and expansion of physician-owned hospitals. These restrictions provided incentives for the hospitals and their owners to take preemptive actions before the effective dates of ACA provisions and modify their operations thereafter. We studied 106 physician-owned hospitals in Texas to determine how they responded to ACA restrictions. We found that there were significant pre-ACA increases in the formation, physician ownership, and physical capacity of physician-owned hospitals, which suggests that they reacted quickly to the policy changes. After the ACA's provisions took effect, the hospitals improved the use of their assets to generate increased amounts of services, revenue, and profits. We found no evidence that existing physician-owned hospitals stopped accepting Medicare to avoid the ACA restrictions, although some investors adopted a seemingly unsuccessful strategy of not accepting Medicare at physician-owned hospitals formed after implementation of the ACA. We conclude that the ACA restrictions effectively eliminated the formation of new physician-owned hospitals, thus accomplishing what previous legislative efforts had failed to do.
Multilevel interventions are those that affect at least two levels of influence-for example, the patient and the health care provider. They can be experimental designs or natural experiments caused by changes in policy, such as the implementation of the Affordable Care Act or local policies. Measuring the effects of multilevel interventions is challenging, because they allow for interaction among levels, and the impact of each intervention must be assessed and translated into practice. We discuss how two projects from the National Institutes of Health's Centers for Population Health and Health Disparities used multilevel interventions to reduce health disparities. The interventions, which focused on the uptake of the human papillomavirus vaccine and community-level dietary change, had mixed results. The design and implementation of multilevel interventions are facilitated by input from the community, and more advanced methods and measures are needed to evaluate the impact of the various levels and components of such interventions.
The Ras/mitogen-activated protein kinase (MAPK) signaling pathway is tightly controlled by negative feedback regulators, such as the tumor suppressor SPRED1. The SPRED1 gene also carries loss-of-function mutations in the RASopathy Legius syndrome. Growth factor stimulation translocates SPRED1 to the plasma membrane, triggering its inhibitory activity. However, it remains unclear whether SPRED1 there acts at the level of Ras or Raf. We show that pharmacological or galectin-1 (Gal-1)-mediated induction of B- and C-Raf-containing dimers translocates SPRED1 to the plasma membrane. This is facilitated in particular by SPRED1 interaction with B-Raf and, via its N terminus, with Gal-1. The physiological significance of these novel interactions is supported by two Legius syndrome-associated mutations that show diminished binding to both Gal-1 and B-Raf. On the plasma membrane, SPRED1 becomes enriched in acidic membrane domains to specifically perturb membrane organization and extracellular signal-regulated kinase (ERK) signaling of active K-ras4B (here, K-ras) but not H-ras. However, SPRED1 also blocks on the nanoscale the positive effects of Gal-1 on H-ras. Therefore, a combinatorial expression of SPRED1 and Gal-1 potentially regulates specific patterns of K-ras- and H-ras-dependent signaling output. More broadly, our results open up the possibility that related SPRED and Sprouty proteins act in a similar Ras and Raf isoform-specific manner.
Dopamine/norepinephrine (DA/NE) reuptake inhibitors have been used to manipulate the central mechanisms affecting arousal and motivation during exercise. Eight healthy, physically active males performed 30min fixed-intensity cycling at 50% Wmax followed by 30min of self paced time trial (TT) with each section interspersed with a 30 s maximal sprint at 9, 19 and 29min. The DA/NE re-uptake inhibitor administered was bupropion (BUP) versus a placebo (PLA) in either warm (32°C, BUP32 or PLA32) or moderate (20°C; BUP20, PLA20) ambient conditions. Core and skin temperature, heart rate and perceptual responses, neuromuscular and hormonal measures were assessed at multiple times throughout the trials and post exercise. Time trial performance remained unchanged across conditions (12.7-13.1km) although core temperature was elevated in the fixed intensity section of the trials for BUP32 and BUP20 but continued to rise only in BUP32 during the time trial reaching 38.6°C (P<0.05). NE increased in all conditions from pre-exercise with BUP32 values peaking at the end of TT to 1245.3±203.1pg/mL (P<0.05) compared to the other conditions. Neuromuscular responses were similar among conditions although peak force was significantly reduced from pre (262±31N) to post (202±31N, P<0.05) exercise along with contraction duration (22%, P<0.05) in BUP20. We conclude that DA/NE re-uptake inhibitors influenced thermoregulation in the heat but not exercise performance. DA/NE re-uptake inhibitors are likely to act centrally to override the inhibitory signals for the cessation of exercise with these drugs acting peripherally to reduce the twitch characteristics of skeletal muscle in cooler conditions.
The present work reports the synthesis and biological activity of a series of 14 benzimidazole derivatives designed to act on the enzyme triosephosphate isomerase of Trypanosoma cruzi (TcTIM). This enzyme is involved in the metabolism of glucose, the only source of energy for the parasite. In this study, we found four compounds that inhibit TcTIM moderately and lack inhibitory activity against human TIM (HsTIM). In vitro studies against T. cruzi epimastigotes showed two compounds that were more active than the reference drug nifurtimox, and these presented a low cytotoxic effect in mouse macrophages (J744 cell line).
Plant adaptive responses to osmotic stress are co-ordinated by restriction of growth and
 developmental processes and by molecular and physiological activities. The phytohormone ABA is the primary regulator that induces and responds to osmotic stress, and its sensitivity markedly influences osmotic stress tolerance levels. Several E3 ubiquitin ligases act as positive or negative regulators of ABA, thereby mediating sensitivity to osmotic stress in higher plants. Here, we report that the C3H2C3-type RING finger E3 ligase, CaAIP1, regulates osmotic stress responses via ABA-mediated signaling. CaAIP1 contains a RING finger motif, which functions during attachment of ubiquitins to the target proteins. Expression of CaAIP1 was induced by ABA, drought and NaCl treatments, suggesting its role in the osmotic stress response. CaAIP1-silenced pepper plants displayed a drought-sensitive phenotype characterized by a high level of transpirational water loss in the drought-treated leaves. CaAIP1-overexpressing (OX) plants exhibited increased sensitivity to ABA, but an NaCl- and mannitol-tolerant phenotype during seed germination and seedling growth. CaAIP1-OX plants further displayed enhanced tolerance to drought stress, characterized by low levels of transpirational water loss via increased stomatal closure and leaf temperature. Our data indicate that CaAIP1 is a positive regulator of the osmotic stress tolerance mechanism.
CpERF9 controls papaya fruit ripening through transcriptional repression of cell-wall-modifying genes CpPME1/2 and CpPG5 by directly binding to their promoters. Papaya fruit ripening is an intricate and highly coordinated developmental process which is controlled by the action of ethylene and expression of numerous ethylene-responsive genes. Ethylene response factors (ERFs) representing the last regulators of ethylene-signaling pathway determine the specificities of ethylene response. However, knowledge concerning the transcriptional controlling mechanism of ERF-mediated papaya fruit ripening is limited. In the present work, a gene-encoding AP2/ERF protein with two ERF-associated amphiphilic repression (EAR) motifs, named CpERF9, was characterized from papaya fruit. CpERF9 was found to localize in nucleus, and possess transcriptional repression ability. CpERF9 expression steadily decreased during papaya fruit ripening, while several genes encoding pectin methylesterases (PMEs) and polygalacturonases (PGs), such as CpPME1/2 and CpPG5, were gradually increased, paralleling the decline of fruit firmness. Electrophoretic mobility shift assay (EMSA) demonstrated a specific binding of CpERF9 to promoters of CpPME1/2 and CpPG5, via the GCC-box motif. Transient expression of CpERF9 in tobacco repressed CpPME1/2 and CpPG5 promoter activities, which was depended on two EAR motifs of CpERF9 protein. Taken together, these findings suggest that papaya CpERF9 may act as a transcriptional repressor of several cell-wall modifying genes, such as CpPME1/2 and CpPG5, via directly binding to their promoters.
The objectives of this study are to assess the levels of serum Interleukin-35 (IL-35) in patients with idiopathic inflammatory myopathies (IIMs) and to evaluate the association between IL-35 levels and IIM-related features. Serum IL-35 was detected in 76 patients with dermatomyositis (DM), 28 patients with polymyositis (PM), 98 disease controls (40 rheumatoid arthritis (RA), 34 systemic lupus erythematosus (SLE), 12 systemic sclerosis (SSc), and 12 sjogren syndrome (SS)), and 43 healthy controls by ELISA. Follow-up was conducted on 34 patients. Serum IL-35 was higher in myositis (PM/DM) patients than in healthy controls (median 76.6 pg/ml [interquartile range (IQR) 57.9-136.2] vs. 29.9 pg/ml (IQR 21.9-65.5), P < 0.001) and disease controls. Serum IL-35 in IIM patients negatively correlated with disease duration moderately (r = -0.35, P < 0.01). Patients with dysphagia had higher IL-35 than those without (median149.35 pg/ml (IQR 87.97-267.32) vs. 70.72 pg/ml (IQR 54.49-123.42), P = 0.001). Cross-sectional correlation analysis showed a weak positive correlation between serum IL-35 and CK (r = 0.293, P = 0.003), moderate positive correlation with erythrocyte sedimentation rate (ESR) (r = 0.304, P = 0.002), serum ferritin (SF) (r = 0.467, P = 0.001) and LDH levels (r = 0.401, P < 0.001). Additionally, serum IL-35 was higher in patients who were positive for anti-HMGCR (median 292.04 pg/ml (IQR 67.9-442.86) vs. 74.66 pg/ml (IQR 57.24-131.32), P = 0.038) and anti-SRP antibody (median 130.33 pg/ml (IQR 88.04-481.28) vs. 73.06 pg/ml (IQR 56.78-134.28), P = 0.009) than in negative patients, respectively. Follow-up study showed that changes in IL-35 levels after treatment correlated with changes in MYOACT scores moderately (r = 0.375, P = 0.029). These data indicate that increased serum IL-35 could act as a disease activity marker and as a risk factor for esophageal involvement in IIM. IL-35 may participate in the pathophysiological processes of IIM, but it still needs further study to confirm.
FoxO proteins are evolutionarily conserved regulators of neuronal structure and function, yet the neuron-specific pathways within which they act are poorly understood. To elucidate neuronal FoxO function in Drosophila melanogaster, we first screened for FoxO's upstream regulators and downstream effectors. On the upstream side, we present genetic and molecular pathway analyses indicating that the Toll-6 receptor, the Toll/interleukin-1 receptor domain adaptor dSARM, and FoxO function in a linear pathway. On the downstream side, we find that Toll-6-FoxO signaling represses the mitotic kinesin Pavarotti/MKLP1 (Pav-KLP), which itself attenuates microtubule (MT) dynamics. We next probed in vivo functions for this novel pathway and found that it is essential for axon transport and structural plasticity in motoneurons. We demonstrate that elevated expression of Pav-KLP underlies transport and plasticity phenotypes in pathway mutants, indicating that Toll-6-FoxO signaling promotes MT dynamics by limiting Pav-KLP expression. In addition to uncovering a novel molecular pathway, our work reveals an unexpected function for dynamic MTs in enabling rapid activity-dependent structural plasticity.
The heparin dose-response (HDR) technique is based on activated clotting time (ACT) response to a fixed-dose heparin bolus, which varies substantially among patients. It is unclear, however, whether hemodilution-associated reductions in coagulation and anticoagulation factors affect the HDR slope.
For in vitro hemodilution, aliquots of whole blood from healthy volunteers were diluted 9:1 and 8:2 v/v with normal saline. For in vivo hemodilution, a prospective observational study was performed on 46 patients who underwent elective cardiovascular surgery with or without cardiopulmonary bypass. HDR slope, antithrombin (AT) activity, complete blood count, and other coagulation parameters were compared after induction of anesthesia and after hemodilution with 500 ml of intravenous fluid.
In vitro 10 and 20 % hemodilution significantly increased the HDR slope relative to baseline, reducing the heparin requirement. Hemodilution of heparinized samples significantly prolonged ACT, whereas there was no significant change in non-heparinized blood. The percent changes in fibrinogen and AT activity were significantly greater at 20 % than those of the other coagulation variables. In vivo, hemodilution significantly increased the HDR slope and reduced heparin requirement. The percent change in fibrinogen due to hemodilution was significantly greater than the change in AT activity. Target ACTs of 300 and 450 s were not achieved in 83.3 and 53.8 % of patients, respectively.
In vitro and in vivo hemodilution significantly increased the HDR slope and reduced the requirement for heparin. In vitro, the HDR slope did not change in parallel but became steeper, depending on the degree of hemodilution.
Immune system related pathologies affect an increasing number of patients every year, having potentially lethal consequences and requiring expensive and difficult tolerated treatments. This area of pathologies offers an excellent potential for the development of innovative solutions such as nanoformulations; this review aims to describe the main categories of nanostructured drug delivery platforms that have been developed in order to achieve a more effective, low toxic treatment in autoimmune pathologies.
We conducted a systematic search of peer-reviewed original studies focusing on nanoformulations suitable for use against autoimmune disorders. Each study was evaluated by at least two reviewers who applied inclusion and exclusion criteria in order to establish the quality of the research reported in the selected papers. The systematic screening of the literature also identified the most recent patents issued in the field of inflammatory/autoimmune diseases which were included in the current paper.
One hundred ninety-seven bibliographic titles were included in the review of which fifty-three recently published patents. Twenty-one papers were selected to define the interaction between nanoformulations and the immune system triggering either immunosuppression or immunostimulation. Thirty-seven papers outlined the characteristics of liposomal formulations that have been reported as treatment for several autoimmune diseases including multiple sclerosis. Twentythree articles provided data on the main lipid nanoparticles of the first and second generation which may include physiological lipids with low cytotoxicity. Gold nanoparticles were described by thirteen papers which highlighted the advantages of the new hybrid organic-inorganic nanoparticles vs. the classical ionic gold compounds. Polymeric nanoformulations were the subject of fifty-nine papers that described their preparation as well as various advantages in the treatment of inflammatory disorders; dendrimers and polymeric micelles
 were included in the study. Thirty-three studies were selected to outline the benefits provided by the use of cyclodextrins as carriers for active drugs. The review also identified the possibility of producing combined nanoformulations (e.g. polymer/cyclodextrin, liposome/polymer) thus achieving superior therapeutic results.
Nanoformulations offer multiple advantages over the classical pharmaceutical formulations, the main ones being the precise targeted therapy with small doses of active drugs, longer circulating time in the bloodstream, and high loading capacity for diagnostic and therapeutic molecules; moreover, the nanoparticles may be functionalized in order to act as nanotheranostics within the larger frame of personalized medicine.
Miombo and mopane woodlands are the dominant land cover in southern Africa. Ecosystem services from these woodlands support the livelihoods of 100 M rural people and 50 M urban dwellers, and others beyond the region. Provisioning services contribute $9 ± 2 billion yr(-1) to rural livelihoods; 76% of energy used in the region is derived from woodlands; and traded woodfuels have an annual value of $780 M. Woodlands support much of the region's agriculture through transfers of nutrients to fields and shifting cultivation. Woodlands store 18-24 PgC carbon, and harbour a unique and diverse flora and fauna that provides spiritual succour and attracts tourists. Longstanding processes that will impact service provision are the expansion of croplands (0.1 M km(2); 2000-2014), harvesting of woodfuels (93 M tonnes yr(-1)) and changing access arrangements. Novel, exogenous changes include large-scale land acquisitions (0.07 M km(2); 2000-2015), climate change and rising CO2 The net ecological response to these changes is poorly constrained, as they act in different directions, and differentially on trees and grasses, leading to uncertainty in future service provision. Land-use change and socio-political dynamics are likely to be dominant forces of change in the short term, but important land-use dynamics remain unquantified.This article is part of the themed issue 'Tropical grassy biomes: linking ecology, human use and conservation'.
Adjuvant chemotherapy (ACT) improved survival in the NCIC Clinical Trials Group JBR.10 trial of resected stage IB/II non-small-cell lung cancer. A prognostic 15-gene expression signature was developed, which may also predict for benefit from ACT. An exploratory economic analysis was conducted to assess the potential cost-effectiveness of using the 15-gene signature in guiding ACT decisions.
A decision analytic model was populated by study patients with quantitative reverse transcription polymerase chain reaction tumor profiling, current costs, and quality-adjusted survival. Analysis was performed over the 6-year follow-up from the perspective of the Canadian public health care system in 2015 Canadian dollars (discounted 5%/year). Incremental cost-effectiveness and cost-utility ratios were determined for ACT versus observation using clinical stage, gene signature, or a combined approach to select treatment.
The mean survival gain of ACT versus observation was higher using the gene signature (1.86 years) compared with clinical stage (1.28 years). Although more costly, ACT guided by the gene signature remained cost-effective at $10,421/life-year gained (95% confidence interval [CI], $466-$19,568 Canadian), comparable to stage-directed selection ($7081/life-year gained; 95% CI, -$2370 to $14,721; P = .52). Incremental cost-utility ratios were $13,452/quality-adjusted life-year (95% CI, $373-$31,949) and $9194/quality-adjusted life-year (95% CI, -$4104 to $23,952), respectively (P = .53). Comparing the standard and test-and-treat approaches, use of the gene signature did not significantly alter survival compared with the standard strategy, but it reduced the ACT rate by 25%.
If validated, the use of the 15-gene expression signature to select patients for ACT may increase the survival gain of treatment in patients with high-risk stage IB/II non-small-cell lung cancer, while avoiding toxicities in low-risk patients.
RNA helicases are involved in almost every aspect of RNA, from transcription to RNA decay. DExD/H-box helicases comprise the largest SF2 helicase superfamily, which are characterized by two conserved RecA-like domains. In recent years, an increasing number of unexpected functions of these proteins have been discovered. They play important roles not only in innate immune response but also in diseases like cancers and chronic hepatitis C. In this review, we summarize the recent literatures on one member of the SF2 superfamily, the DEAD-box protein DDX41. After bacterial or viral infection, DNA or cyclic-di-GMP is released to cells. After phosphorylation of Tyr414 by BTK kinase, DDX41 will act as a sensor to recognize the invaders, followed by induction of type I interferons (IFN). After the immune response, DDX41 is degraded by the E3 ligase TRIM21, using Lys9 and Lys115 of DDX41 as the ubiquitination sites. Besides the roles in innate immunity, DDX41 is also related to diseases. An increasing number of both inherited and acquired mutations in DDX41 gene are identified from myelodysplastic syndrome and/or acute myeloid leukemia (MDS/AML) patients. The review focuses on DDX41, as well as its homolog Abstrakt in Drosophila, which is important for survival at all stages throughout the life cycle of the fly.
Fresh Geobacillus thermoglucosidasius cells grown on soybean-casein digest nutrient agar were inoculated as a parent colony 1 cm in diameter on the surface of an agar gel containing acetate and calcium ions (calcite-promoting hydrogel) and incubated at 60 °C for 4 days, after which magnesium-calcite single crystals of 50-130 µm in size formed within the parent colony. Addition of EDTA, polyacrylic acid or N,N-dicyclohexylcarbodiimide to the calcite-forming hydrogel inhibited the parent colony from forming magnesium-calcite crystals. Inoculation of G. thermoglucosidasius on calcite-forming hydrogel containing 5 µM cadmium and 20 µM zinc resulted in a decrease in the sporulation rate from 55 to 7-8 %. Magnesium-calcite synthesis decreased relative to the sporulation rate. G. thermoglucosidasius exhibited higher adsorption/absorbance of calcium than other Geobacillus sp. that do not mediate calcite formation and higher levels of magnesium accumulation. Calcium ions contained in the calcite-promoting hydrogel and magnesium ions concentrated in G. thermoglucosidasius cells serve as the elements for magnesium-calcite synthesis. The observed decreases in sporulation rate and magnesium-calcite formation support the hypothesis that endospores act as nuclei for the synthesis of magnesium-calcite single crystals.
Frontotemporal dementia is a devastating neurodegenerative disease causing stark alterations in personality and language. Characterized by severe atrophy of the frontal and temporal brain lobes, frontotemporal dementia (FTD) shows extreme heterogeneity in clinical presentation, genetic causes, and pathological findings. Like most neurodegenerative diseases, the initial symptoms of FTD are subtle, but increase in severity over time, as the disease progresses. Clinical progression is paralleled by exacerbation of pathological findings and the involvement of broader brain regions, which currently lack mechanistic explanation. Yet, a flurry of studies indicate that protein aggregates accumulating in neurodegenerative diseases can act as propagating entities, amplifying their pathogenic conformation, in a way similar to infectious prions. In this prion-centric view, FTD can be divided into three subtypes, TDP-43 or FUS proteinopathy and tauopathy. Here, we review the current evidence that FTD-linked pathology propagates in a prion-like manner and discuss the implications of these findings for disease progression and heterogeneity. Frontotemporal dementia (FTD) is a progressive neurodegenerative disease causing severe personality dysfunctions, characterized by profound heterogeneity. Accumulation of tau, TDP-43 or FUS cytoplasmic aggregates characterize molecularly distinct and non-overlapping FTD subtypes. Here, we discuss the current evidence suggesting that prion-like propagation and cell-to-cell spread of each of these cytoplasmic aggregates may underlie disease progression and heterogeneity. This article is part of the Frontotemporal Dementia special issue.
Mobile technology may serve as a cost-effective and scalable tool for delivering behavioral nutrition interventions. This research sought to iteratively develop a theory-driven mobile app, Vegethon, to increase vegetable consumption.
Development of Vegethon followed phases outlined by the IDEAS framework: 1) empathize with users (qualitative interviews, n = 18); 2) specify target behavior; 3) ground in behavioral theory; 4) ideate implementation strategies; 5) prototype potential products; 6) gather user feedback (qualitative interviews, n = 14; questionnaire, n = 41); 7) build minimum viable product; and 8) pilot potential efficacy and usability (pilot RCT, n = 17). Findings from each phase informed subsequent phases. The target population that informed intervention development was 18-50 years of age, had BMIs of 28-40 kg/m(2), and lived in the geographical area surrounding Stanford University. A full description of the final version of Vegethon is included in the paper.
Qualitative findings that shaped initial intervention conception were: participants' interests in accountability without judgment; their desire for simple and efficient dietary self-monitoring; and the importance of planning meals in advance. Qualitative findings identified during intervention refinement were the need for a focus on vegetable self-monitoring; inclusion of vegetable challenges; simplification of features; advice and inspiration
 for eating vegetables; reminder notifications; and peer comparison. Pilot RCT findings suggested the initial efficacy, acceptance, and feasibility of the intervention. The final version of Vegethon enabled easy self-monitoring of vegetable consumption and included a range of features designed to engage the user (e.g., surprise challenges; leaderboard; weekly reports). Vegethon was coded for its inclusion of 18 behavior change techniques (BCTs) (e.g., goal setting; feedback; social comparison; prompts/cues; framing/reframing; identity).
Vegethon is a theory-based, user-informed mobile intervention that was systematically developed using the IDEAS framework. Vegethon targets increased vegetable consumption among overweight adults and is currently being evaluated in a randomized controlled efficacy trial.
Clinical Trials.gov: NCT01826591.
Social workers are leaders in the substance abuse services field and may often work in substance use disorder (SUD) education, prevention, assessment, treatment, or resource coordination and case management roles. As the Patient Protection and Affordable Care Act (ACA) (2010) drives changes in the fields of health and behavioral health, social workers have an opportunity to lead structural changes at the micro and macro levels that will have a positive impact on low-income clients with SUDs. In this article, authors examine the current state of SUDs and health care access, the impact of the ACA on the field, and implications for social work practice and education. Social workers should seek specialized education and credentialing in SUD services, know how to help clients apply for health care coverage, and advocate for integrated substance abuse treatment and health care programs and an expansion of Medicaid in their local communities. Social workers are well positioned to be a voice for clients to ensure that the current structural changes result in a better, integrated system of care that is able to respond to the needs of low-income clients with SUDs.
The mechanisms regulating synapse numbers during development and ageing are essential for normal brain function and closely linked to brain disorders including dementias. Using Drosophila, we demonstrate roles of the microtubule-associated protein Tau in regulating synapse numbers, thus unravelling an important cellular requirement of normal Tau. In this context, we find that Tau displays a strong functional overlap with microtubule-binding spectraplakins, establishing new links between two different neurodegenerative factors. Tau and the spectraplakin Short Stop act upstream of a three-step regulatory cascade ensuring adequate delivery of synaptic proteins. This cascade involves microtubule stability as the initial trigger, JNK signalling as the central mediator, and kinesin-3 mediated axonal transport as the key effector. This cascade acts during development (synapse formation) and ageing (synapse maintenance) alike. Therefore, our findings suggest novel explanations for intellectual disability in Tau deficient individuals, as well as early synapse loss in dementias including Alzheimer's disease.
Cupuassu (Theobroma grandiflorum [Willd. ex Spreng.] Schum) is a species of high economic importance in Brazil with great potential at international level due to the multiple uses of both its seeds and pulp in the industry of sweets and cosmetics. For this reason, the cupuassu breeding program focused on the selection of genotypes with high pulp and seed quality-selection associated with the understanding of the mechanisms involved in fruit formation. Gene expression is one of the most used approaches related to such understanding. In this sense, quantitative real-time PCR (qPCR) is a powerful tool, since it rapidly and reliably quantifies gene expression levels across different experimental conditions. The analysis by qPCR and the correct interpretation of data depend on signal normalization using reference genes, i.e. genes presenting a uniform pattern of expression in the analyzed samples. Here, we selected and analyzed the expression of five genes from cupuassu (ACP, ACT, GAPDH, MDH, TUB) to be used as candidates for reference genes on pulp and seed of young, maturing and mature cupuassu fruits. The evaluation of the gene expression stability was obtained using the NormFinder, geNorm and BestKeeper programs. In general, our results indicated that the GAPDH and MDH genes constituted the best combination as reference genes to analyze the expression of cupuassu samples. To our knowledge, this is the first report of reference gene definition in cupuassu, and these results will support subsequent analysis related to gene expression studies in cupuassu plants subjected to different biotic or abiotic conditions as well as serve as a tool for diversity analysis based on pulp and seed quality.
Lung cancer is the second most prevalent cancer in both women and men with some 221,200 new cases and 158,040 deaths reported in 2015. Almost 90% of these are non-small cell lung cancer (NSCLC) and these patients have a very poor prognosis. Recently a new treatment option for NSCLC appeared that strongly improved treatment responses-immunotherapy. Here we review the various forms of immunotherapy and how immune modification of proteasomes in lung cancer may support the immune system in controlling NSCLC. These immunoproteasomes then support recognition of NSCLC and may act as a biomarker for selecting responding patients to immunotherapy.
In psoriatic arthritis, many patients do not develop permanent joint damage even after a prolonged follow-up. This has led several authors to consider the possibility of a subpopulation of stayers (those who do not have the propensity to experience the event of interest), as opposed to assuming the entire population consist of movers (those who have the propensity to experience the event of interest). In addition, it is recognised that the damaged joints process may act very differently across different joint areas, particularly the hands, feet and large joints. From a clinical perspective, interest lies in identifying possible relationships between the damaged joints processes in these joint areas for the movers and estimating the proportion of stayers in these joint areas, if they exist. For this purpose, this paper proposes a novel trivariate mover-stayer model consisting of mover-stayer truncated negative binomial margins, and patient-level dynamic covariates and random effects in the models for the movers and stayers, respectively. The model is then extended to have a two-level mover-stayer structure for its margins so that the nature of the stayer property can be investigated. A particularly attractive feature of the proposed models is that only an optimisation routine is required in their model fitting procedures. © 2016 The Authors. Statistics in Medicine Published by John Wiley & Sons Ltd.
Bacillus subtilis can enter three developmental pathways to form spores, biofilms or K-state cells. The K-state confers competence for transformation and antibiotic tolerance. Transition into each of these states requires a stable protein complex formed by YlbF, YmcA and YaaT. We have reported that this complex acts in sporulation by accelerating the phosphorylation of the response regulator Spo0A. Phosphorelay acceleration was also predicted to explain their involvement in biofilm formation and the K-state. This view has been challenged in the case of biofilms, by the suggestion that the three proteins act in association with the mRNA degradation protein RNaseY (Rny) to destabilize the sinR transcript. Here, we reaffirm the roles of the three proteins in supporting the phosphorylation of Spo0A for all three developmental pathways and show that in their absence sinR mRNA is not stabilized. We demonstrate that the three proteins also play unknown Spo0A-P-independent roles in the expression of biofilm matrix and in the production of ComK, the master transcription factor for competence. Finally, we show that domesticated strains of B. subtilis carry a mutation in sigH, which influences the expression kinetics of the early spore gene spoIIG, thereby increasing the penetrance of the ylbF, ymcA and yaaT sporulation phenotypes.
To document the existence of primary pancreatic secretinoma in patients with watery diarrhea syndrome (WDS) and achlorhydria and establish secretin as a diarrheogenic hormone.
Vasoactive intestinal peptide (VIP) has been widely accepted as the main mediator of WDS. However, in 1968, Zollinger et al reported 2 female patients with pancreatic neuroendocrine tumors, WDS, and achlorhydria. During surgery on the first, a 24-year-old patient, they noticed distended duodenum filled with fluid and a dilated gallbladder containing dilute bile with high bicarbonate concentration. After excision of the tumor, WDS ceased and gastric acid secretion returned. The second, a 47-year-old, patient's metastatic tumor extract given intravenously in dogs, produced significantly increased pancreatic and biliary fluid rich in bicarbonate. They suggested a secretin-like hormone of islet cell origin explains WDS and achlorhydria. These observations, however, predated radioimmunoassay, immunohistochemical staining, and other molecular studies.
The first patient's tumor tissue was investigated for secretin and VIP. Using both immunohistochemistry and laser microdissection and pressure catapulting technique for RNA isolation and subsequent reverse transcription polymerase chain reaction, the expression levels of secretin, and VIP were measured.
Immunoreactive secretin and its mRNA were predominantly found in the tumor tissue whereas VIP and its mRNA were scarce.
The findings strongly support that the WDS and achlorhydria in this patient may have been caused by secretin as originally proposed in 1968 and that secretin may act as a diarrheogenic
 hormone.
Molecular chaperones act on non-native proteins in the cell to prevent their aggregation, premature folding or misfolding. Different chaperones often exert distinct effects, such as acceleration or delay of folding, on client proteins via mechanisms that are poorly understood. Here we report the solution structure of SecB, a chaperone that exhibits strong antifolding activity, in complex with alkaline phosphatase and maltose-binding protein captured in their unfolded states. SecB uses long hydrophobic grooves that run around its disk-like shape to recognize and bind to multiple hydrophobic segments across the length of non-native proteins. The multivalent binding mode results in proteins wrapping around SecB. This unique complex architecture alters the kinetics of protein binding to SecB and confers strong antifolding activity on the chaperone. The data show how the different architectures of chaperones result in distinct binding modes with non-native proteins that ultimately define the activity of the chaperone.
Studies were carried out to assess the correlation between thermoluminescence (TL) and optically stimulated luminescence (OSL) of this phosphor. It was observed that the OSL and TL glow curve consists of a wide distribution of traps having different photo-ionization cross-sections, trap depths and frequency factors. In case of Al doped sample, some of the traps up to 200°C are assumed to act as a source traps for the observance of OSL due to thermal transfer of charge carriers into the deep traps beyond 480°C. This suggests that Al impurities play an important role in the thermal transfer OSL process. As most of the work on this phenomenon is done on natural materials (mainly quartz) in which aluminum is a natural impurity, this study will explain the role of Al in this phenomenon.
The random mutation and natural selection phenomenon act in a mathematically predictable behavior, which when understood leads to approaches to reduce and prevent the failure of the use of these selection pressures when treating infections and cancers. The underlying principle to impair the random mutation and natural selection phenomenon is to use combination therapy, which forces the population to evolve to multiple selection pressures simultaneously that invoke the multiplication rule of probabilities simultaneously as well. Recently, it has been seen that combination therapy for the treatment of malaria has failed to prevent the emergence of drug-resistant variants. Using this empirical example and the principles of probability theory, the derivation of the equations describing this treatment failure is carried out. These equations give guidance as to how to use combination therapy for the treatment of cancers and infectious diseases and prevent the emergence of drug resistance. Copyright © 2016 John Wiley & Sons, Ltd.
We demonstrate a method for the preparation of fully solution processed inorganic solar cells from a spin and spray coating deposition of nanocrystal inks. For the photoactive absorber layer, colloidal CdTe and CdSe nanocrystals (3-5 nm) are synthesized using an inert hot injection technique and cleaned with precipitations to remove excess starting reagents. Similarly, gold nanocrystals (3-5 nm) are synthesized under ambient conditions and dissolved in organic solvents. In addition, precursor solutions for transparent conductive indium tin oxide (ITO) films are prepared from solutions of indium and tin salts paired with a reactive oxidizer. Layer-by-layer, these solutions are deposited onto a glass substrate following annealing (200-400 °C) to build the nanocrystal solar cell (glass/ITO/CdSe/CdTe/Au). Pre-annealing ligand exchange is required for CdSe and CdTe nanocrystals where films are dipped in NH4Cl:methanol to replace long-chain native ligands with small inorganic Cl(-) anions. NH4Cl(s) was found to act as a catalyst for the sintering reaction (as a non-toxic alternative to the conventional CdCl2(s) treatment) leading to grain growth (136±39 nm) during heating. The thickness and roughness of the prepared films are characterized with SEM and optical profilometry. FTIR is used to determine the degree of ligand exchange prior to sintering, and XRD is used to verify the crystallinity and phase of each material. UV/Vis spectra show high visible light transmission through the ITO layer and a red shift in the absorbance of the cadmium chalcogenide nanocrystals after thermal annealing. Current-voltage curves of completed devices are measured under simulated one sun illumination. Small differences in deposition techniques and reagents employed during ligand exchange have been shown to have a profound influence on the device properties. Here, we examine the effects of chemical (sintering and ligand exchange agents) and physical treatments (solution concentration, spray-pressure, annealing time and annealing temperature) on photovoltaic device performance.
Pest suppression from combinations of tactics is fundamental to pest management and eradication. Interactions may occur among tactical combinations and affect suppression. The best case is synergistic, where suppression from a combination is greater than the sum of effects from single tactics (AB > A+B). We explored how mating disruption and insecticide interacted at field scale, additively or synergistically. Use of a pheromone delivery formulation (SPLAT™) as either a mating disruption treatment (i.e. a two-component pheromone alone) or as a lure and kill treatment (i.e. the two-component pheromone plus a permethrin insecticide) was compared for efficacy against the lightbrown apple moth Epiphyas postvittana. Next, four point-source densities of the SPLAT™ formulations were compared for communication disruption. Finally, the mating disruption and lure and kill treatments were applied with a broadcast insecticide. Population assessment used virgin female traps and synthetic pheromone in replicated 9-ha vineyard plots compared with untreated controls and insecticide-treated plots, to investigate interactions. Lure and kill and mating disruption provided equivalent suppression; no additional benefit accrued from including permethrin with the pheromone suggesting lack of contact. The highest point-source density tested (625/ha) was most effective. The insect growth regulator methoxyfenoxide applied by broadcast application lowered pest prevalence by 70% for the first ten weeks compared to pre-trial. Pheromone addition suppressed the pest further by an estimated 92.5%, for overall suppression of 97.7% from the treatment combination of insecticide plus mating disruption. This was close to that expected for an additive model of interactivity between insecticide and mating disruption (AB = A+B) estimated from plots with single tactics as 98% suppression in a combination. The results indicate the need to examine other tactical combinations to achieve the potential cost-efficiencies of synergistic interactions.
To the authors' knowledge, the impact of insurance status on the survival time of patients with glioblastoma multiforme (GBM) has not been fully understood. The objective of the current study was to clarify the association between insurance status and survival of patients with GBM by analyzing population-based data.
The authors performed a cohort study using data from the Surveillance, Epidemiology, and End Results program. They included adult patients (aged ≥18 years) with GBM as their primary diagnosis from the years 2007 to 2012. Patients without information regarding insurance status were excluded. A survival analysis between insurance status and GBM-related death was performed using an accelerated failure time model. Demographic and clinical variables were included to adjust for confounding effects.
Among the 13,665 adult patients in the study cohort, 558 (4.1%) were uninsured, 1516 (11.1%) had Medicaid coverage, and 11,591 (84.8%) had non-Medicaid insurance. Compared with patients who were uninsured, insured patients were more likely to be older, female, white, married, and with a smaller tumor size at diagnosis. Accelerated failure time analysis demonstrated that older age (hazard ratio [HR], 1.04; P<.001), male sex (HR, 1.08; P<.001), large tumor size at the time of diagnosis (HR, 1.26; P<.001), uninsured status (HR, 1.14; P =.018), and Medicaid insurance (HR, 1.10; P =.006) were independent risk factors for shorter survival among patients with GBM, whereas radiotherapy (HR, 0.40; P<.001) and married status (HR, 0.86; P<.001) indicated a better outcome. The authors discovered an overall yearly progressive improvement in survival in patients with non-Medicaid insurance who were diagnosed from 2007 through 2011 (P =.015), but not in uninsured or Medicaid-insured patients.
Variations existed in insurance status within the GBM population. Uninsured status and Medicaid insurance suggested shorter survival compared with non-Medicaid insurance among a population of patients with GBM. Cancer 2016;122:3157-65. © 2016 American Cancer Society.
Metallic hole arrays have been recently used for color generation and filtering due to their reliability and color tunability. However, color generation is still limited to several microns. Understanding the interaction between the individual elements of the whole nanostructure may push the resolution to the sub-micron level. Herein, we study the hybridization between silver nanocavities in order to obtain active color generation at the micron scale. To do so, we use five identical triangular cavities which are separated by hundreds of nanometers from each other. By tuning either the distance between the cavities or the optical polarization state of the incoming field, the transmitted light through the cavities is actively enhanced at specific frequencies. Consequently, a rainbow of colors is observed from a sub-micron
 scale unit. The reason for this is that the metallic surface plays a vital role in the hybridization between the cavities and contributes to higher frequency modes. Cathodoluminescence measurements have confirmed this assumption and have revealed that these five triangular cavities act as a unified entity surrounded by the propagated surface plasmons. In such plasmonic structures, multi-color tuning can be accomplished and may open the possibility to improve color generation and high-quality pixel fabrication.
People aged 26 to 34 years represent the greatest proportion of the uninsured, and they have the highest incidence of testicular cancers. The aim of this study was to investigate the association between insurance status and cancer outcomes in men diagnosed with germ cell tumors.
The Surveillance, Epidemiology, and End Results database was used to identify 10,211 men diagnosed with germ cell gonadal neoplasms from 2007 to 2011. Associations between insurance status and characteristics at diagnosis and receipt of treatment were examined with log-binomial regression. The association between insurance status and mortality was assessed with Cox proportional hazards regression.
Uninsured patients had an increased risk of metastatic disease at diagnosis (relative risk [RR], 1.26; 95% confidence interval [CI], 1.15-1.38) in comparison with insured patients, as did Medicaid patients (RR, 1.62; 95% CI, 1.51-1.74). Among men with metastatic disease, uninsured and Medicaid patients were more likely to be diagnosed with intermediate/poor-risk disease (RR for uninsured patients, 1.22; 95% CI, 1.04-1.44; RR for Medicaid patients, 1.39; 95% CI, 1.23-1.57) and were less likely to undergo lymph node dissection (RR for uninsured patients, 0.74; 95% CI, 0.57-0.94; RR for Medicaid patients, 0.76; 95% CI, 0.63-0.92) in comparison with insured patients. Men without insurance were more likely to die of their disease (hazard ratio [HR], 1.88; 95% CI, 1.29-2.75) in comparison with insured men, as were those with Medicaid (HR, 1.51; 95% CI, 1.08-2.10).
Patients without insurance and patients with Medicaid have an increased risk of presenting with advanced disease and dying of the disease in comparison with those who have insurance. Future studies should examine whether implementation of the Patient Protection and Affordable Care Act reduces these disparities. Cancer 2016;122:3127-35. © 2016 American Cancer Society.
Glucocorticoid induction of pulmonary surfactant involves a mesenchyme-derived protein first characterized in 1978 by Smith and termed fibroblast-pneumocyte factor (FPF). Despite a number of agents having been postulated as being FPF, its identity has remained obscure. In the past decade, three strong candidates for FPF have arisen. This review examines the evidence that keratinocyte growth factor (KGF), leptin or neuregulin-1β (NRG-1β) act as FPF or components of it. As with FPF production, glucocorticoids enhance the concentration of each of these agents in fibroblast-conditioned media. Moreover, each stimulates the synthesis of surfactant-associated phospholipids and proteins in type II pneumocytes. Further, some have unique activities, for example, KGF also minimizes lung injury through enhanced epithelial cell proliferation and NRG-1β enhances surfactant phospholipid secretion and β-adrenergic receptor activity in type II cells. However, even though these agents have attributes in common with FPF, it is inappropriate to specify any one of these agents as FPF. Rather, it appears that each contributes to separate mesenchymal-epithelial signaling mechanisms involved in different aspects of lung development. Given that the production of pulmonary surfactant is essential for postnatal survival, it is reasonable to suggest that several mechanisms independently regulate surfactant synthesis.
A one-step microwave synthesis of N-doped hydroxyl-functionalized carbon dots (CDs) with ultra-high fluorescence quantum yields (QYs) of 99% is reported. These ultra-high QY CDs were synthesized using citric acid and amino compound-containing hydroxyls like ethanolamine and tris(hydroxylmethyl)aminomethane. Amino and carboxyl moieties can form amides through dehydration condensation reactions, and these amides act as bridges between carboxyl and hydroxyl groups, and modify hydroxyl groups on the surface of the CDs. The entire reaction can be carried out within 5 min. When the molar ratio of reactants is 1 : 1, the hydroxyl and graphitic nitrogen content is the highest, and the synergy leads to a high ratio between the radiative transition rate and nonradiative transition rate as well as a high QY. The developed pathway to N-doped hydroxyl-functionalized CDs can provide unambiguous and remarkable insights into the design of highly luminescent functionalized carbon dots, and expedite the applications of CDs.
The fabrication of polymer-nanoparticle composites is extremely important in the development of many functional materials. Identifying the precise composition of these materials is essential, especially in the design of surface catalysts, where the surface concentration of the active component determines the activity of the material. Antimicrobial materials which utilize nanoparticles are a particular focus of this technology. Recently swell encapsulation has emerged as a technique for inserting antimicrobial nanoparticles into a host polymer matrix. Swell encapsulation provides the advantage of localizing the incorporation to the external surfaces of materials, which act as the active sites of these materials. However, quantification of this nanoparticle uptake is challenging. Previous studies explore the link between antimicrobial activity and surface concentration of the active component, but this is not directly visualized. Here we show a reliable method to monitor the incorporation of nanoparticles into a polymer host matrix via swell encapsulation. We show that the surface concentration of CdSe/ZnS nanoparticles can be accurately visualized through cross-sectional fluorescence imaging. Using this method, we can quantify the uptake of nanoparticles via swell encapsulation and measure the surface concentration of encapsulated particles, which is key in optimizing the activity of functional materials.
The canonical set of amino acids leads to an exceptionally wide range of protein functionality. Nevertheless, the set of residues still imposes limitations on potential protein applications. The incorporation of noncanonical amino acids can enlarge this scope. There are two complementary approaches for the incorporation of noncanonical amino acids. For site-specific incorporation, in addition to the endogenous canonical translational machineries, an orthogonal aminoacyl-tRNA-synthetase-tRNA pair must be provided that does not interact with the canonical ones. Consequently, a codon that is not assigned to a canonical amino acid, usually a stop codon, is also required. This genetic code expansion enables the incorporation of a noncanonical amino acid at a single, given site within the protein. The here presented work describes residue-specific incorporation where the genetic code is reassigned within the endogenous translational system. The translation machinery accepts the noncanonical amino acid as a surrogate to incorporate it at canonically prescribed locations, i.e., all occurrences of a canonical amino acid in the protein are replaced by the noncanonical one. The incorporation of noncanonical amino acids can change the protein structure, causing considerably modified physical and chemical properties. Noncanonical amino acid analogs often act as cell growth inhibitors for expression hosts since they modify endogenous proteins, limiting in vivo protein production. In vivo incorporation of toxic noncanonical amino acids into proteins remains particularly challenging. Here, a cell-free approach for a complete replacement of L-arginine by the noncanonical amino acid L-canavanine is presented. It circumvents the inherent difficulties of in vivo expression. Additionally, a protocol to prepare target proteins for mass spectral analysis is included. It is shown that L-lysine can be replaced by L-hydroxy-lysine, albeit with lower efficiency. In principle, any noncanonical amino acid analog can be incorporated using the presented method as long as the endogenous in vitro translation system recognizes it.
The CRISPR/Cas9 system is a research hotspot in genome editing and regulation. Currently, it is used in genomic silencing and knock-in experiments as well as transcriptional activation and repression. This versatile system consists of two components: a guide RNA (gRNA) and a Cas9 nuclease. Recognition of a genomic DNA target is mediated through base pairing with a 20-base gRNA. The latter further recruits the Cas9 endonuclease protein to the target site and creates double-stranded breaks in the target DNA. Compared with traditional genome editing directed by DNA-binding protein domains, this short RNA-directed Cas9 endonuclease system is simple and easily programmable. Although this system may have off-target effects and in vivo delivery and immune challenges, researchers have employed this system in vivo to establish disease models, study specific gene functions under certain disease conditions, and correct genomic information for disease treatment. In regards to pain research, the CRISPR/Cas9 system may act as a novel tool in gene correction therapy for pain-associated hereditary diseases and may be a new approach for RNA-guided transcriptional activation or repression of pain-related genes. In addition, this system is also applied to loss-of-function mutations in pain-related genes and knockin of reporter genes or loxP tags at pain-related genomic loci. The CRISPR/Cas9 system will likely be carried out widely in both bench work and clinical
 settings in the pain field.
75-year old gentleman presented with acute urinary retention. He had met with road traffic accident 15 years back and sustained pelvic fracture and bladder rupture, underwent bladder repair and open reduction and internal fixation of pubic symphsis. Imaging studies showed the free lying encrusted orthopedic screw in the bladder, which was removed per urethra using nephroscope. Migratory foreign bodies in the urinary bladder are rare. However there is a possibility of longstanding foreign bodies in adjacent structures to erode and perforate into the bladder. Inside the bladder these foreign bodies act as nidus for stone formation.
Design, construction, maintenance and upgrading of civil engineering infrastructure requires fresh thinking to minimize use of materials, energy and labour. This can only be achieved by understanding the performance of the infrastructure, both during its construction and throughout its design life, through innovative monitoring. Advances in sensor systems offer intriguing possibilities to radically alter methods of condition assessment and monitoring of infrastructure. In this paper, it is hypothesized that the future of infrastructure relies on smarter information; the rich information obtained from embedded sensors within infrastructure will act as a catalyst for new design, construction, operation and maintenance processes for integrated infrastructure systems linked directly with user behaviour patterns. Some examples of emerging sensor technologies for infrastructure sensing are given. They include distributed fibre-optics sensors, computer vision, wireless sensor networks, low-power micro-electromechanical systems, energy harvesting and citizens as sensors.
Pranlukast is a leukotriene receptor antagonist (LTRA) that is used as an additional controller of mild to moderate asthma. This study compared the efficacy and side effects of two bioequivalent preparations of pranlukast: original pranlukast (Onon(®); Ono Pharmaceutical, Japan) and a modified formulation of pranlukast (Prakanon(®); Yuhan Co, Korea) in patients with mild to moderate asthma.
Of the 34 subjects screened, 30 patients who were using standard medication to control asthma and scored less than 20 points on the Asthma Control Test(™) (ACT) were assigned randomly to one of the two groups in a prospective, open label, crossover study: group 1 received Prakanon(®) (150 mg/day) and group 2 received Onon(®) (450 mg/day) for 8 weeks each; after a 1-week rest period, the groups were switched to the alternative medication for further 8 weeks and monitored for 2 more weeks without study medication. Evaluation parameters included the ACT, quality of life questionnaire adult Korean asthmatics (QLQAKA), pulmonary function tests, peripheral blood tests, vital signs, and adverse events.
Thirty patients were enrolled and 21 completed the trial: 10 in group 1 and 11 in group 2. The baseline data of the two groups did not differ. No statistical significant differences were observed in efficacy and lung function at each time and in changes from baseline value between the two kinds of pranlukast. The final asthma control rate was 81% with Prakanon(®) and 76% with Onon(®). There were no differences in vital signs and laboratory data at each time and in changes from baseline value between the two drugs. There were no differences in adverse events between the two drugs. The most common side effect was abdominal pain. Drug compliance was high, without differences between the two drugs.
These findings suggest that Prakanon(®) which is an improved formulation of pranlukast at a lower dose than the original formulation, Onon(®), has a similar efficacy and side effect profile in the control of persistent asthma.
Empirical research has demonstrated a link between legal coercion and treatment engagement following conviction among those with severe personality disorder. Legal coercive pressures were often applied by the Indeterminate Sentence for Public Protection (IPP), until it was replaced by the Extended Determinate Sentence by the Legal Aid, Sentencing and Punishment of Offenders Act 2012. In this paper, it is proposed that use of the new determinate sentence will lessen motivation for treatment engagement. One effect of treatment refusal may be greater reliance by the Secretary of State for Justice on his jurisdiction to transfer prisoners due for release to secure hospital transfers under the Mental Health Act 1983. Not only will this risk posturing undermine the principal aim of the Offender Personality Disorder Implementation Pathway to improve treatment engagement among the target group, it will also have negative implications for medical practitioners working in secure forensic hospitals. To demonstrate what is at stake, the paper briefly recapitulates empirical findings familiar to readers of the journal, before drawing on original unpublished data.
To investigate the association of the neutrophil to lymphocyte ratio (NLR) at admission with presence of fracture, comorbid conditions, and its prognostic value for short-term outcomes in orthogeriatric patients.
On 415 consecutive patients (mean age 78.8 ±8.7[SD] years, 281 women, 255 with a non-vertebral bone fracture, including 167 with a hip fracture, HF) admitted to the Department of Orthopaedic Surgery at the Canberra hospital (2010 - 2011) data on clinical and laboratory characteristics were collected prospectively. The validation dataset included 294 consecutive patients (mean age 82.1 ± 8.0 years, 72.1% women) with HF.
Multivariate regression revealed four variables, presence of HF, hypoalbuminaemia (<33g/L), anaemia (<120g/L) and hyperparathyroidism (PTH>6.8 pmol/L), as independent determinants of admission NLR≥5.1. There was a dose-graded relationship between presence of fracture, especially HF, postoperative complications and levels of NLR categorized as tertiles. Compared to patients with NLR<5.1(first tertile), patients with NLR 5.1-8.5 (second tertile) had a 1.8-, 3.1-, 2.6-, and 2.5-fold higher risk for presence of any fracture, HF, developing postoperative myocardial injury (troponin I rise) and a high inflammatory response/infection (CRP>100mg/L after the 3rd postoperative day), respectively, while in subjects with NLR>8.5 (third tertile) these risks were 2.6-, 4.9-, 5.9- and 4.5-times higher, respectively; subjects with NLR>8.5 had a 9.7 times higher chance of dying in the hospital compared to patients with NLR 5.1-8.5; the NLR retained its significance on multivariate analyses. The NLR ≥5.1 predicted postoperative myocardial injury with an area under the curve (AUC) of 0.626, CRP>100mg/L with AUC of 0.631 and the NLR >8.5 predicted in-hospital mortality with an AUC of 0.793, showing moderately high sensitivity (86.7%, 80% and 90%, respectively) and negative predictive value (92.9%, 71.2%, 99.6%, respectively), but low specificity. Admission NLR was superior to other, except hypoalbuminaemia, prognostic markers; combined use of both NLR≥5.1 and albumin<33g/L only moderately increased the accuracy of prediction. The validation study confirmed the prognostic value of the admission NLR.
In orthogeriatric patients, high NLR on admission is an independent indicator of fracture presence, a significant risk factor and moderate predictor of postoperative myocardial injury, high inflammatory response/infection and in-hospital death.
To review current thinking regarding the role of personalized phenotype-driven as opposed to broad guideline-based therapies in asthma and to speculate on the relative contributions of innate (lung) and adaptive (T and B lymphocyte) roles in asthma pathogenesis.
PubMed literature review.
Articles pertaining to asthma pathogenesis, with emphasis on those that included biotherapeutic interventions.
Current methods allow asthma to be divided into phenotypes characterized by the presence or absence of eosinophilic inflammation. Corticosteroids are likely to be only effective in the context of eosinophilic inflammation. Similarly, interventions with biotherapeutic agents currently available or in development have efficacious only when administered to patients with asthma of relevant phenotypes.
The availability of biotherapeutic agents that target IgE, interleukin (IL) 5, and, in the near future, IL-13 is an exciting vindication of molecular medicine. However, these biotherapeutic agents are only effective when targeted to patients with specific asthma phenotypes. In Promising biotherapeutic targets are the airway epithelial-derived cytokines IL-25, IL-33, and thymic stromal lymphopoietin. Targeting these lung epithelial-derived mediators, instead of products of the adaptive immune system, may be more likely to improve day-to-day asthma symptoms in contrast to agents that target the adaptive immune system, approaches that primarily act to ameliorate asthma exacerbations.
Hypoxia-inducible factor (HIF)-1 is a central regulator in the adaptation process of cell response to hypoxia (low oxygen). Emerging evidence has demonstrated that HIF-1 plays an important role in the development and progression of many types of human diseases, including pathogen-associated cancers. In the present review, we summarize the recent understandings of how human pathogenic agents including viruses, bacteria and parasites deregulate cellular HIF-1 signaling pathway in their associated cancer cells, and highlight the common molecular mechanisms of HIF-1 signaling activated by these pathogenic infection, which could act as potential diagnostic markers and new therapeutic strategies against human infectious cancers.
β-Lactamases enable resistance to almost all β-lactam antibiotics. Pioneering work revealed that acyclic boronic acids can act as 'transition state analogue' inhibitors of nucleophilic serine enzymes, including serine-β-lactamases. Here we report
 biochemical and biophysical analyses revealing that cyclic boronates potently inhibit both nucleophilic serine and zinc-dependent β-lactamases by a mechanism involving mimicking of the common tetrahedral intermediate. Cyclic boronates also potently inhibit the non-essential penicillin-binding protein PBP 5 by the same mechanism of action. The results open the way for development of dual action inhibitors effective against both serine- and metallo-β-lactamases, and which could also have antimicrobial activity through inhibition of PBPs.
Oral mucositis (OM) is a common adverse reaction to radiotherapy and chemotherapy in oncology. Its treatment requires oral formulations that enhance therapy compliance, improve administration and ensure drug effectiveness. Solid dosage forms that act by slow dissolution, such as pastilles, are an effective alternative to mouthwashes, for their versatility, ease of administration and extended residence time in the oral cavity. The present work describes the development and stability studies of an innovative formulation of nystatin and lidocaine pastilles for the treatment of oral mucositis. Full pharmaceutical quality testing was carried out, including disintegration and dissolution testing, texture profile analysis, grittiness and an antifungal activity testing. A soft pastille formulation containing 0.25% lidocaine and 78,000 IU nystatin was obtained, presenting suitable pharmaceutical characteristics, as a disintegration time of 17 ± 2 min, dissolution rate and microbiological and physicochemical for 30 days when stored at 2-8 °C under light protection. Palatability was also evaluated, being well accepted by a panel of 38 healthy volunteers. This formulation allows an accurate drug dosing by the prescriber, while enabling the patients to control the retention time of the drugs in the oral cavity and consequently manage their pain treatment.
Type 1 diabetes mellitus (T1D) is an autoimmune disease characterized by insufficient insulin production due to the destruction of insulin secreting β-cells in the Langerhans islets. A variety of factors, including chemicals, viruses, commensal bacteria and diet have been proposed to contribute to the risk of developing the disorder. In the last years, gut microbiota has been proposed as a main factor in T1D pathogenesis. Several alterations of gut microbiota composition were described both in animal model and in humans. The decrease of Firmicutes/Bacteroides ratio was the most frequent pattern described, in particular, in human studies. Furthermore, Bacteroides, Clostridium cluster XIVa, Lactobacillus, Bifidobacterium, and Prevotella relative abundances were different in healthy and affected subjects. Dysbiosis would seem to increase intestinal permeability and thus promote the development of a pro-inflammatory niche that stimulates β-cell autoimmunity in predisposed subjects. Preliminary studies on animal models were realized to investigate the role of gut microbiota modulation as therapy or prevention approach in predisposed animals: promising and stimulating results have been reported. Key message Dietary antigens and microbiota-derived products might act as triggers of T1D by causing a pro-inflammatory and metabolic dysfunctional environment.
Vermicomposting is a biooxidation process in which epigeicearthworms act in synergy with microbial populations to degrade organic matter. Vermicomposting does not go through a thermophilic stage as required by North American legislations for pathogen eradication. We examined the survival of a Green Fluorescent Protein (GFP) labeled Escherichia coli MG1655 as a model for the survival of pathogenic bacteria in both small-scale batch and medium-scale continuously-operated systems to discern the influence of the earthworm Eisenia fetida, nutrient content and the indigenous vermicompost microbial community on pathogen abundance. In batch systems, the microbial community had the greatest influence on the rapid decline of E. coli populations, and the effect of earthworms was only visible in microbially-impoverishedvermicomposts. No significant earthworm density-dependent relationship was observed on E. coli survival under continuous operation. E. coli numbers decreased below the US EPA compost sanitation guidelines of 10(3)Colony Forming Units (CFU)/g (dry weight) within 18-21days for both the small-scale batch and medium-scale continuous systems, but it took up to 51days without earthworms and with an impoverished microbial community to reach the legal limit. Nutrient replenishment (i.e. organic carbon) provided by continuous feed input did not appear to extend E. coli survival. In fact, longer survival of E. coli was noticed in treatments where less total and labile sugars were available, suggesting that sugars may support potentially antagonist bacteria in the vermicompost. Total N, pH and humidity did not appear to affect E. coli survival. Several opportunistic human pathogens may be found in vermicompost, and their populations are likely kept in check by antagonists.
Fluoxetine, a well-known anti-depression agent, may act as a chemosensitizer to assist and promote cancer therapy. However, how fluoxetine regulates cellular signaling to enhance cellular responses against tumor cell growth remains unclear. In the present study, addition of fluoxetine promoted growth inhibition of interferon-alpha (IFN-α) in human bladder carcinoma cells but not in normal uroepithelial cells through lessening the IFN-α-induced apoptosis but switching to cause G1 arrest, and maintaining the IFN-α-mediated reduction in G2/M phase. Activations and signal transducer and transactivator (STAT)-1 and peroxisome proliferator-activated receptor alpha (PPAR-α) were involved in this process. Chemical inhibitions of STAT-1 or PPAR-α partially rescued bladder carcinoma cells from IFN-α-mediated growth inhibition via blockades of G1 arrest, cyclin D1 reduction, p53 downregulation and p27 upregulation in the presence of fluoxetine. However, the functions of both proteins were not involved in the control of fluoxetine over apoptosis and maintained the declined G2/M phase of IFN-α. These results indicated that activation of PPAR-α and STAT-1 participated, at least in part, in growth inhibition of IFN-α in the presence of fluoxetine.
Colorectal cancer (CRC) has one of the highest mortality rates in the worldwide and its incidence has been increasing in recent years. Protein tyrosine kinase-7 (PTK7) is an inactive member of receptor protein tyrosine kinase (RPTK)-like molecules, which is involved in tumorigenesis of a variety of cancers. Our study aimed to investigate expression of PTK7 in colorectal tumors (including benign adenomas and malignant carcinomas), and its potential function in tumorigenesis and prognosis. A total of 209 CRC patients and 28 colonic adenoma patients were included in this study. Reverse transcription polymerase chain reaction (RT-PCR) and quantitative real-time PCR were performed in 14 pairs of fresh frozen tissues to evaluate mRNA expression of PTK7. Expression of PTK7 protein in 209 CRC tissues with paired non-cancerous mucosa and 28 adenoma specimens were tested using immunohistochemistry. The expression difference and its correlation with clinicopathological features and overall survival were assessed by SPSS statistics (version 22). P<0.05 was considered significant. RT-PCR and quantitative real-time PCR showed a higher expression of PTK7 mRNA in CRC compared with non-tumorous mucosa (4.87±3.71 vs. 1.33±1.05; P<0.001). PTK7 expression was significantly higher in adenoma (75%) and CRC (68.3%) than in non-tumorous mucosa (P<0.001). PTK7 expression was correlated with tumor differentiation (P=0.027), lymph node metastasis (P=0.005), distant metastasis (P=0.001) and TNM stage (P=0.028) of CRC patients. Significant correlation between PTK7 overexpression and favorable overall survival of CRC patients was observed (P=0.005). Therefore, it may act as a candidate biomarker to predict the occurrence and prognosis of colorectal tumor.
Phosphorylation of proteins on serine/threonine residues that precede proline (pSer/Thr-Pro) is specifically catalyzed by the peptidyl-prolyl cis-trans isomerase PIN1. PIN1-mediated prolyl-isomerization induces cell cycle arrest and growth inhibition through the regulation of target proteins, including TP53. We examined whether PIN1 acts in a different manner according to TP53 gene status in hepatocellular carcinoma (HCC). We investigated the expression of PIN1 and TP53 proteins in 119 HCC tissue samples. We also analyzed PIN1 expression in combination with TP53 gene mutation and its correlation with the clinical outcome. In addition, we used synthetic small interfering RNA to silence PIN1 gene expression in TP53 wild-type and TP53 mutant HCC cell lines, and then evaluated cell proliferation, migration and invasion. Expression of PIN1 was strongly associated with expression of TP53 protein or TP53 mutation of HCC samples. PIN1 and TP53 expression in TP53 mutant HCC cell lines was higher than that in TP53 wild-type HCC cell lines. Silencing of PIN1 in HLE cells containing mutant TP53 significantly decreased cell proliferation, migration and invasion. In contrast to PIN1 silencing in HLE cells, PIN1 silencing in HepG2 cells containing functional wild-type TP53 resulted in enhanced tumor cell proliferation. HCC patients bearing PIN1 expression with wild-type TP53 were predicted to demonstrate favorable relapse-free survival. Our results suggest that PIN1 plays a role in cancer cell proliferation, migration and invasion in a different manner according to the TP53 gene mutation status in HCC. In particular, interaction of PIN1 with mutant TP53 can act as a tumor promoter and increase its oncogenic activities in HCC.
Energy production in the brain depends almost exclusively on oxidative metabolism.
 Neurons have small energy reserves and require a continuous supply of oxygen (O2). It is therefore not surprising that one of the hallmarks of normal brain function is the tight coupling between cerebral blood flow and neuronal activity. Since capillaries are embedded in the O2-consuming neuropil, we have here examined whether activity-dependent dips in O2 tension drive capillary hyperemia. In vivo analyses showed that transient dips in tissue O2 tension elicit capillary hyperemia. Ex vivo experiments revealed that red blood cells (RBCs) themselves act as O2 sensors that autonomously regulate their own deformability and thereby flow velocity through capillaries in response to physiological decreases in O2 tension. This observation has broad implications for understanding how local changes in blood flow are coupled to synaptic transmission.
Eukaryotic cells can "remember" transient encounters with a wide range of stimuli, inducing lasting states of altered responsiveness. Regulatory T (Treg) cells are a specialized lineage of suppressive CD4 T cells that act as critical negative regulators of inflammation in various biological contexts. Treg cells exposed to inflammatory conditions acquire strongly enhanced suppressive function. Using inducible genetic tracing, we analyzed the long-term stability of activation-induced transcriptional, epigenomic, and functional changes in Treg cells. We found that the inflammation-experienced Treg cell population reversed many activation-induced changes and lost its enhanced suppressive function over time. The "memory-less" potentiation of Treg suppressor function may help avoid a state of generalized immunosuppression that could otherwise result from repeated activation.
Tumor hypoxia is associated with treatment resistance, cell proliferation, and metastatic potential, all of which contribute to a poor prognosis. Resveratrol [RES (trans-3,4',5-trihydroxystilbene)], a naturally occurring polyphenol, is enriched in grapes and red wine. This study investigated whether the resveratrol analog HS-1793 modulates the hypoxic status and the level of perfusion in mouse breast cancer FM3A cells. Our data show that HS-1793 decreased the levels of hypoxia-inducible factor-1α (HIF-1α) and vascular endothelial growth factor protein under hypoxic conditions in FM3A cells. HS-1793 improved perfusion and hypoxic status in tumor tissues and inhibited angiogenesis through HIF-1α suppression in mice. Moreover, HS-1793 inhibited hypoxia-induced cancer stem cell properties and enhanced ionizing radiation-induced apoptosis in hypoxic FM3A cells. Collectively, the resveratrol analog HS-1793 might act as a potent radiosensitizer and be a useful adjuvant agent against radiotherapy-resistant hypoxic cells in solid tumors.
The nature and anatomic location of the protective memory CD8(+) T cell subset induced by intranasal vaccination remain poorly understood. We developed a vaccination model to assess the anatomic location of protective memory CD8(+) T cells and their role in lower airway infections. Memory CD8(+) T cells elicited by local intranasal, but not systemic, vaccination with an engineered non-replicative CD8(+) T cell-targeted antigen confer enhanced protection to a lethal respiratory viral challenge. This protection depends on a distinct CXCR3(LO) resident memory CD8(+) T (Trm) cell population that preferentially localizes to the pulmonary interstitium. Because they are positioned close to the mucosa, where infection occurs, interstitial Trm cells act before inflammation can recruit circulating memory CD8(+) T cells into the lung tissue. This results in a local protective immune response as early as 1 day post-infection. Hence, vaccine strategies that induce lung interstitial Trm cells may confer better protection against respiratory pathogens.
The surface functionality of Au38S2(SAdm)20 nanoclusters (-SAdm = adamantanethiolate) in the presence of α-, β-, and γ-cyclodextrins (CDs) is studied. The supramolecular chemistry and host-guest interactions of CDs and the protecting ligands of nanoclusters are investigated using UV-vis and NMR spectroscopies, MALDI mass spectrometry, and molecular dynamics simulations. In contrast to α- and γ-CDs, the results show that β-CDs are capable of efficiently chemisorbing onto the Au38S2(SAdm)20 nanoclusters to yield Au38S2(SAdm)20-(β-CD)2 conjugates. MD simulations revealed that two -SAdm ligands of the nanoparticle with the least steric hindrance are capable to selectively be accommodated into hydrophobic cavity of β-CDs, as furthermore confirmed by NMR spectroscopy. The conjugates largely improve the stability of the nanoclusters in the presence of strong oxidants (e.g., TBHP). Further, the electrochemical properties of Au38S2(SAdm)20 nanoclusters and Au38S2(SAdm)20-(β-CD)2 conjugates are compared. The charge transfer to the redox probe molecules (e.g., K3Fe(CN)6) in solution was monitored by cyclic voltammetry. It is found that β-CDs act as an umbrella to cover the fragile metal cores of the nanoclusters, thereby blocking direct interaction with destabilizing agents and hence quenching the charge transfer process.
IL-1R2 was the first decoy receptor to be described. Subsequently receptors which act as pure decoys or scavengers or trigger dampening of cytokine signaling have been described for cytokines and chemokines. Here we review the current understanding of the mode of action and significance in pathology of the chemokine atypical receptor ACKR2, the IL-1 decoy receptor IL-1R2 and the atypical IL-1 receptor family IL-1R8. Decoy and scavenger receptors with no or atypical signaling have emerged as a general strategy conserved in evolution to tune the action of cytokines, chemokines and growth factors.
The early diagnosis and successful treatment of breast cancer (BC) is still a challenging task due to the diverse origin and functional heterogeneity of cancer cells. The heterogeneity of BC may likely to explained by molecular BC subtypes, comprises Luminal-A (LA), Luminal-B (LB), Triple-negative (TN) and HER2-positive (HP), which are governed by a variety of cancer associated pathways. To identify protein signatures in different BC subtypes, we performed isobaric tag for absolute and relative quantitation (iTRAQ) of enriched blood plasma samples of BC subtypes (N=32) and healthy subjects (N=8). After analyses of data, 58 proteins were found to be modulated in BC subtypes from healthy subjects (p<0.05) and among these; Fibronectin (FN1), Alpha-2-macroglobulin (A2M), and Complement component-4-binding protein-alpha (C4BPA) and Complement factor-B (CFB) were selected for validation in BC subtypes and healthy subjects in the independent set of blood plasma (N=100) and tissue samples (N=25). Statistical analysis showed the significant modulation of FN1 and C4BPA in LB, and A2M in TN patients in both plasma as well as tissues comparatively control (p<0.05). Further, FN1 and C4BPA in LB subtype revealed a good diagnostic accuracy in plasma level validation. The receiver operating characteristic (ROC) curve and regression analysis demonstrated that these proteins with associated criterion of expression could act as discriminating signatures among BC subtypes with diagnostic and prognostic relevance.
The heterogeneity of breast cancer (BC) has gained many challenges for successful management of BC, thus, the delineating proteomic alterations BC subtypes may provide great clinical values in diagnostic, prognostic and therapeutics of BC. The findings from the present quantitative proteomic study have deciphered the altered proteomic patterns and their possible molecular interactions in each BC subtype. The study showed a strong association of FN1, A2M, C4BPA and CFB in molecular subtypes of BC, in which, C4BPA and A2M demonstrated a potent signature in blood plasma and tissue samples of LB and TN subtypes in BC patients, respectively. The findings also revealed the altered level expressions of these selected proteins could classify BC subtypes through plasma and tissue based expression analysis in patients and control samples. Hence, these proteins could have clinical importance for the diagnosis and prognosis purposes among molecular BC subtypes.
Neuronal oscillations exist across a broad frequency spectrum, and are thought to provide a mechanism of interaction between spatially separated brain regions. Since ongoing mental activity necessitates the simultaneous formation of multiple networks, it seems likely that the brain employs interactions within multiple frequency bands, as well as cross-frequency coupling, to support such networks. Here, we propose a multi-layer network framework that elucidates this pan-spectral picture of network interactions. Our network consists of multiple layers (frequency-band specific networks) that influence each other via inter-layer (cross-frequency) coupling. Applying this model to MEG resting-state data and using envelope correlations as connectivity metric, we demonstrate strong dependency between within layer structure and inter-layer coupling, indicating that networks obtained in different frequency bands do not act as independent entities. More specifically, our results suggest that frequency band specific networks are characterised by a common structure seen across all layers, superimposed by layer specific connectivity, and inter-layer coupling is most strongly associated with this common mode. Finally, using a biophysical model, we demonstrate that there are two regimes of multi-layer network behaviour; one in which different layers are independent and a second in which they operate highly dependent. Results suggest that the healthy human brain operates at the transition point between these regimes, allowing for integration and segregation between layers. Overall, our observations show that a complete picture of global brain
 network connectivity requires integration of connectivity patterns across the full frequency spectrum.
In the present study, we proposed a novel dual-cyclical nucleic acid strand-displacement polymerization (dual-CNDP) based signal amplification system for highly sensitive determination of tumor suppressor genes. The system primarily consisted of a signaling hairpin probe (SHP), a label-free hairpin probe (LHP) and an initiating primer (IP). The presence of target DNA was able to induce one CNDP through continuous process of ligation, polymerization and nicking, leading to extensively accumulation of two nicked triggers (NT1 and NT2). Intriguingly, the NT1 could directly hybridize SHP, while the NT2 could act as the target analog to induce another CNDP. The resulting dual-CNDP contributed the striking signal amplification, and only a very weak blank noise existed since the ligation template of target was not involved. In this case, the target could be detected in a wide linear range (5 orders of magnitude), and a low detection limit (78 fM) was obtained, which is superior to most of the existing fluorescent methods. Moreover, the dual-CNDP sensing system provided a high selectivity towards target DNA against mismatched target and was successfully applied to analysis of target gene extracted from cancer cells or in human serum-contained samples, indicating its great potential for practical applications.
An intracellular cascade amplification strategy for ultrasensitive "off-on" imaging of telomerase activity in living cells was designed. The method was based on fabrication of a dual function module-encapsulated liposome nanoprobe, which consisted of a telomerase-targeting responder-transmitter DNA complex (HPT) module and a catalyzed hairpin assembly (CHA) signal amplification module. Upon transfected into living cells, the released HPT could be specifically recognized and extended by telomerase, leading to the release of the transmitter DNA. The transmitter could act as the initiator and catalyzer of CHA amplification, resulting in the lightening up of the reporter complex. The telomerase activity could be monitored in situ by the fluorescence signal without the need for obtaining cell extracts. Because of the recycling use of the transmitter, multiplied enhancement of signal outputs from one extension event was achieved. The proposed strategy could be employed for in situ monitoring of the change of intracellular telomerase activity in response to drugs to detect drug efficacy. Thus the method has great potential in the study of the molecular mechanisms of telomerase-related life processes.
To identify and describe the steps and strategies that community pharmacies with established medication management services have used to integrate medication management services into their practice settings.
Qualitative case study with semistructured interviews and focus groups.
Community pharmacy organizations in Minnesota.
Pharmacists and pharmacy leadership from 4 different pharmacy organizations including independent, chain, and health system pharmacies.
Not applicable.
Qualitative case study analysis of community pharmacy management and pharmacists' perceptions of the factors that led to the establishment and sustainability of their medication management programs.
Focus groups and interviews were undertaken with 25 pharmacists and pharmacy leaders from 4 distinct community pharmacy organizations from April to June 2015. Five themes emerged, representing specific implementation and continuation stages of medication management services in community practice: Deciding to Act, Setting the Stage, Executing the Service, Sticking to It, and Continuing to Grow.
This study sheds light on key stages that have commonly occurred across community pharmacies that are delivering medication management services. The results of this work may serve as a road map for other community pharmacies looking to integrate medication management services into their own practice settings.
The majority of active agents do not readily permeate into brain due to the presence of the blood-brain barrier and blood-cerebrospinal fluid barrier. Currently, the most innovative and promising non-invasive strategy in brain delivery is the design and preparation of nanocarriers, which can move through the brain endothelium. Niosomes can perform brain delivery, in fact polysorbates, can act as an anchor for apolipoprotein E from blood plasma. The particles mimic LDL and interact with the LDL receptor leading to the endothelial cells uptake. The efficacy of niosomes for anticancer therapeutic applications was correlated to their physicochemical and drug delivery properties. Dimensions and ζ-potential were characterized using dynamic light scattering and asymmetric flow-field fractionation system. Lipid bilayer was characterized measuring the fluidity, polarity and microviscosity by fluorescent probe spectra evaluation. Morphology and homogeneity were characterized using atomic force microscopy. Physicochemical stability and serum stability (45% v/v fetal bovine and human serum) were evaluated as a function of time using dynamic light scattering. U87-MG human glioblastoma cells were used to evaluate vesicle cytotoxicity and internalisation efficiency. From the obtained data, the systems appear useful to perform a prolonged (modified) release of biological active substances to the central nervous system.
Throughout the world, busy waterways near large ports witness heavy vessel traffic in recent decades. The waterways are characterized by high risk in terms of loss of life, property, and pollution to environment. To facilitate maritime safety management with satisfactory efficiency and efficacy, the authors propose a framework of safety indexes to evaluate the risk level in busy waterways according to the accident severity, fatality rate and special indicators of maritime transportation. The safety indexes consist of Safety Evaluation Index (SEI) and Safety Warning Index (SWI), and are derived from the proposed risk criteria of Chinese vessel traffic. As a case study, data on vessel traffic accidents reported in the Western Shenzhen Port, South China from 1995 to 2015 are analyzed. The actual risk level of this area during the period is calculated under the framework. The implementation of the safety indexes indicate that the risk criteria and safety indexes are practicable and effective for the vessel traffic management. The methodology based on long-term accident data can significantly support the risk analysis in the macroscopic perspective for busy ports and waterways, such that SWI can act as threshold to trigger actions, while SEI can act as an indicator to measure safety status.
N-terminal (Nt) acetylation is known to be a highly abundant co-translational protein modification, but the recent discovery of Golgi- and chloroplast-resident N-terminal acetyltransferases (NATs) revealed that it can also be added post-translationally. Nt-acetylation may act as a degradation signal in a novel branch of the N-end rule pathway, whose functions include the regulation of human blood pressure. Nt-acetylation also modulates protein interactions, targeting, and folding. In plants, Nt-acetylation plays a role in the control of resistance to drought and in regulation of immune responses. Mutations of specific human NATs that decrease their activity can cause either the lethal Ogden syndrome or severe intellectual disability and cardiovascular defects. In sum, recent advances highlight Nt-acetylation as a key factor in many biological pathways.
L-type calcium channel (LTCC) gene Cav1.2 is believed to play an important role in the alteration of Ca(2+) homeostasis in brain astrocytes. Increasing evidence shows that alteration of intracellular Ca(2+) concentration is related to the effect of 17β-estradiol (E2) in a variety of neurophysiological and neuropathological conditions. In this study, we measured immunoreactivity of Cav1.2 protein expression in rat primary cortical astrocytes by using Western blots. We demonstrated that E2 upregulated Cav1.2 expression in a dose- and time-dependent manner and the effect of E2 on Cav1.2 expression were blocked by an estrogen receptor (ER) antagonist, ICI-182,780. The ER subtype-selective ERα agonists propylpyrazole triole (PPT) and ERβ agonist diarylpropionitrile (DPN) both increase the expression of Cav1.2 in a dose-dependent manner. Also, the PPT most closely mimicked the upregulation of Cav1.2 protein expression by E2. Similar experiments of 10 nM E2-treated ERα- or ERβ-knockdown astrocytes have also shown that the E2 regulation of Cav1.2 protein expression is mediated through an ERα-dependent pathway. Furthermore, we established that E2 did not change the level of Cav1.2 mRNA. The induction of E2-mediated Cav1.2 expression was inhibited by cycloheximide (CHX) but not by actinomycin D (Act-D), suggesting that E2 regulation of Cav1.2 expression occurred at a posttranscriptional level. We also found that E2 may increase Cav1.2 levels by decreasing its ubiquitination and degradation rate. These findings provide new information about the effect of E2 on Cav1.2 in astrocytes, particularly necessary for the treatment of neurological disease.
Platinum-based chemotherapy is the standard treatment for NSCLC patients with EGFR wild-type, and as alternative to failure to EGFR inhibitors. However, this treatment is aggressive and most patients experience grade 3-4 toxicities. ERCC1, ERCC2, ERCC5, XRCC1, MDM2, ABCB1, MTHFR, MTR, SLC19A1, IL6 and IL16 gene polymorphisms may contribute to individual variation in toxicity to chemotherapy. The aim of this study was to evaluate the effect of these polymorphisms on platinum-based chemotherapy in NSCLC patients. A prospective cohorts study was conducted, including 141 NSCLC patients. Polymorphisms were analyzed
 by PCR Real-Time with Taqman(®) probes and sequencing. Patients with ERCC1 C118T-T allele (p=0.00345; RR=26.05; CI95%=4.33, 515.77) and ERCC2 rs50872-CC genotype (p=0.00291; RR=4.06; CI95%=1.66, 10.65) had higher risk of general toxicity for platinum-based chemotherapy. ERCC2 Asp312Asn G-alelle, ABCB1 C1236T-TT and the IL1B rs12621220-CT/TT genotypes conferred a higher risk to present multiple adverse events. The subtype toxicity analysis also revealed that ERCC2 rs50872-CC genotype (p=0.01562; OR=3.23; CI95%=1.29, 8.82) and IL16 rs7170924-T allele (p=0.01007; OR=3.19; CI95%=1.35, 7.97) were associated with grade 3-4 hematological toxicity. We did not found the influence of ERCC1 C8092A, ERCC2 Lys751Gln, ERCC2 Asp312Asn, ERCC5 Asp1104His, XRCC1 Arg194Trp, MDM2 rs1690924, ABCB1 C3435T, ABCB1 Ala893Ser/Thr, MTHFR A1298C, MTHFR C677T, IL1B rs1143623, IL1B rs16944, and IL1B rs1143627 on platinum-based chemotherapy toxicity. In conclusion, ERCC1 C118T, ERCC2 rs50872, ERCC2 Asp312Asn, ABCB1 C1236T, IL1B rs12621220 and IL16 rs7170924 polymorphisms may substantially act as prognostic factors in NSCLC patients treated with platinum-based chemotherapy.
In this study, we investigated the cognitive processing stages underlying associative recognition using MEG. Over the last four decades, a model of associative recognition has been developed in the ACT-R cognitive architecture. This model was first exclusively based on behavior, but was later evaluated and improved based on fMRI and EEG data. Unfortunately, the limited spatial resolution of EEG and the limited temporal resolution of fMRI have made it difficult to fully understand the spatiotemporal dynamics of associative recognition. We therefore conducted an associative recognition experiment with MEG, which combines excellent temporal resolution with reasonable spatial resolution. To analyze the data, we applied non-parametric cluster analyses and a multivariate classifier. This resulted in a detailed spatio-temporal model of associative recognition. After the visual encoding of the stimuli in occipital regions, three separable memory processes took place: a familiarity process (temporal cortex), a recollection process (temporal cortex and supramarginal gyrus), and a representational process (dorsolateral prefrontal cortex). A late decision process (superior parietal cortex) then acted upon the recollected information represented in the prefrontal cortex, culminating in a late response process (motor cortex). We conclude that existing theories of associative recognition, including the ACT-R model, should be adapted to include these processes.
Immunohistochemical 4 (IHC4) score plus Clinical Treatment Score (CTS) is an inexpensive tool predicting risk of distant recurrence in women with early breast cancer (EBC). IHC4 score is based on ER, PR, HER2 and Ki67 index. This study explores the role of the combined score (IHC4 + CTS) in predicting risk of locoregional recurrence (LRR) in women with EBC who had breast conservation surgery (BCS) without adjuvant radiotherapy (study group). The secondary objective was to evaluate the clinicopathological differences between our study group and women who had adjuvant radiation following BCS (control group).
Patients were selected from the local database over a 13-year period. IHC testing was done where results were missing. Combined scores were calculated using the appropriate formulae.
Patients in the study group (81 patients) had favorable clinicopathological features compared to the control group (1406 patients). The Cox regression indicated a statistically significant association between the combined score and the risk of LRR (p = 0.03). The incidence of LRR was zero, 20% and 33.3% in the low, intermediate and high risk groups respectively (p = 0.007). Margin status was the only variable not included in the combined score. The Cox regression analysis demonstrated that the combined score (p = 0.02) and the ordinal measure of margins (p = 0.03) were significant independent predictors of LRR.
This is the first study of its kind. The IHC4 score + CTS can be used to identify low risk women who can potentially avoid adjuvant radiotherapy.
Highly pathogenic avian influenza is an on-going problem in poultry and a potential human pandemic threat. Pandemics occur suddenly and vaccine production must be fast and effective to be of value in controlling the spread of the virus. In this study we evaluated the potential of a recombinant protein from the extracellular domain of an H5 hemagglutinin protein produced in a yeast expression system to act as an effective vaccine. Protein production was efficient, with up to 200 mg purified from 1 L of culture medium. We showed that the deletion of the multibasic cleavage site from the protein improves oligomerization and, consequentially, its immunogenicity. We also showed that immunization with this deleted protein protected chickens from challenge with a highly pathogenic avian influenza H5N1 virus. Our results suggest that this recombinant protein produced in yeast may be an effective vaccine against H5N1 virus in poultry.
Bone renews itself and changes shape throughout life to account for the changing needs of the body; this requires co-ordinated activities of bone resorbing cells (osteoclasts), bone forming cells (osteoblasts) and bone's internal cellular network (osteocytes). This review focuses on paracrine signaling by the IL-6 family of cytokines between bone cells, bone marrow, and skeletal muscle in normal physiology and in pathological states where their levels may be locally or systemically elevated. These functions include the support of osteoclast formation by osteoblast lineage cells in response to interleukin 6 (IL-6), interleukin 11 (IL-11), oncostatin M (OSM) and cardiotrophin 1 (CT-1). In addition it will discuss how bone-resorbing osteoclasts promote osteoblast activity by secreting CT-1, which acts as a "coupling factor" on osteocytes, osteoblasts, and their precursors to promote bone formation. OSM, produced by osteoblast lineage cells and macrophages, stimulates bone formation via osteocytes. IL-6 family cytokines also mediate actions of other bone formation stimuli like parathyroid hormone (PTH) and mechanical loading. CT-1, OSM and LIF suppress marrow adipogenesis by shifting commitment of pluripotent precursors towards osteoblast differentiation. Ciliary neurotrophic factor (CNTF) is released as a myokine from skeletal muscle and suppresses osteoblast differentiation and bone formation on the periosteum (outer bone surface in apposition to muscle). Finally, IL-6 acts directly on marrow-derived osteoclasts to stimulate release of "osteotransmitters" that act through the cortical osteocyte network to stimulate bone formation on the periosteum. Each will be discussed as illustrations of how the extended family of IL-6 cytokines acts within the skeleton in physiology and may be altered in pathological conditions or by targeted therapies.
A growing body of evidence suggests health-promoting effects of kefir consumption on different nonruminant species, leading to the speculation that kefir may act as a probiotic and benefit calf performance and health. Our objectives were to determine effects of feeding kefir on performance and health of calves in the first 70d of life. Thirty 3-d-old female Holstein calves (body weight=38.2±3.1kg) were blocked by initial body weight and assigned randomly to 1 of 3 treatments (1 calf per pen; 10 pens per treatment). Kefir was added to whole milk (vol/vol) at 0:1 (control; KF0), 1:3 (KF1), or 1:1 (KF2) and fed twice per day (0800 and 1600h) from d3 through 45 and then once per day until weaning, which occurred on d50. Pre- and postweaning intake of starter, daily body weight gain, and gain-to-feed ratio exhibited no difference among treatments. Adding kefir to whole milk fed directly to calves had no effect on concentration of blood metabolites collected on d20, 40, and 70. Body length on d50 (weaning) and 70 was greater in kefir-fed calves. Kefir intake improved fecal scores and reduced days with diarrhea during the first 2wk of life. Apparent digestibility of organic matter, ether extract, crude protein, and neutral detergent fiber remained unaffected by treatment. Overall, it appears that directly feeding kefir to calves during the preweaning period did not improve the performance of calves under the conditions of the current study; however, its consumption marginally improved body length and fecal consistency in the first weeks of life, which is an important concern in intensive calf-rearing systems. Feeding kefir to neonatal calves may be a viable approach to improve the health of calves in commercial calf-rearing operations, although to validate its health-promoting effects additional research is needed to investigate its effects under different calf-rearing conditions.
The incidence of adverse care quality events among patients undergoing cervical fusion surgery is unknown using the definition of care quality employed by the Centers for Medicare and Medicaid Services (CMS). The effect of insurance status on the incidence of these adverse quality events is also unknown.
This study determined the incidence of hospital-acquired conditions (HAC) and patient safety indicators (PSI) in patients with cervical spine fusion and analyzed the association between primary payer status and these adverse events.
This is a retrospective cohort design.
All patients in the Nationwide Inpatient Sample (NIS) aged 18 and older who underwent cervical spine fusion from 1998 to 2011 were included.
Incidence of HAC and PSI from 1998 to 2011 served as outcome variables.
We queried the NIS for all hospitalizations that included a cervical fusion during the inpatient episode from 1998 to 2011. All comparisons were made between privately insured patients and Medicaid
 or self-pay patients because Medicare enrollment is confounded with age. Incidence of nontraumatic HAC and PSI was determined using publicly available lists of International Classification of Disease, Ninth Revision, Clinical Modification (ICD-9-CM) diagnosis codes. We built logistic regression models to determine the effect of primary payer status on PSI and nontraumatic HAC.
We identified 419,424 hospitalizations with cervical fusion performed during an inpatient episode. The estimated national incidences of nontraumatic HAC and PSI were 0.35% and 1.6%, respectively. After adjusting for patient demographics and hospital characteristics, Medicaid or self-pay patients had significantly greater odds of experiencing one or more HAC (odds ratio [OR] 1.51 95% conflict of interest [CI] 1.23-1.84) or PSI (OR 1.52 95% CI 1.37-1.70) than the privately insured cohort.
Among patients undergoing inpatient cervical fusion, primary payer status predicts PSI and HAC (both indicators of adverse health-care quality used to determine hospital reimbursement by CMS). As the US health-care system transitions to a value-based payment model, the cause of these disparities must be studied to improve the quality of care delivered to vulnerable patient populations.
We investigated the role of TRPV4 channels (TRPV4) in regulating the contractility of detrusor smooth muscle (DSM) and muscularis mucosae (MM) of the urinary bladder. Distribution of TRPV4 in DSM and MM of guinea-pig bladders was examined by fluorescence immunohistochemistry. Changes in the contractility of DSM and MM bundles were measured using isometric tension recording. Intracellular Ca(2+) dynamics were visualized by Cal-520 fluorescent Ca(2+) imaging, while membrane potential changes were recorded using intracellular microelectrode technique. DSM and MM expressed TRPV4 immunoreactivity. GSK1016790A (GSK, 1 nM), a TRPV4 agonist, evoked a sustained contraction in both DSM and MM associated with a cessation of spontaneous phasic contractions in a manner sensitive to HC-067047 (10 μM), a TRPV4 antagonist. Iberiotoxin (100 nM) and paxilline (1 μM), large conductance Ca(2+)-activated K(+) (BK) channel blockers restored the spontaneous contractions in GSK. The sustained contractions in DSM and MM were reduced by nifedipine (10 μM), a blocker of L-type voltage-dependent Ca(2+) channels (LVDCCs) by about 40 % and by nominally Ca(2+)-free solution by some 90 %. GSK (1 nM) abolished spontaneous Ca(2+) transients, increased basal Ca(2+) levels and also prevented spontaneous action potential discharge associated with DSM membrane hyperpolarization. In conclusion, Ca(2+) influx through TRPV4 appears to activate BK channels to suppress spontaneous contractions and thus a functional coupling of TRPV4 with BK channels may act as a self-limiting mechanism for bladder contractility during its storage phase. Despite the membrane hyperpolarization in GSK, Ca(2+) entry mainly through TRPV4 develops the tonic contraction.
Impulsivity, or a tendency to act without anticipation of future consequences, is associated with drug abuse. Impulsivity is typically separated into two main measures, impulsive action and impulsive choice. Given the association of impulsivity and drug abuse, treatments that reduce impulsivity have been proposed as an effective method for countering drug addiction. Progesterone has emerged as a promising treatment, as it is associated with decreased addiction-related behaviors and impulsive action. The goal of the present study was to determine the effects of progesterone (PRO) on impulsive action for food: a Go/No-Go task. Female and male rats responded for sucrose pellets during a Go component when lever pressing was reinforced on a variable-interval 30-s schedule. During the alternate No-Go component, withholding a lever press was reinforced on a differential reinforcement of other (DRO) behavior 30-s schedule, where a lever press reset the DRO timer. Impulsive action was operationally defined as the inability to withhold a response during the No-Go component (i.e. the number of DRO resets). Once Go/No-Go behavior was stable, responding between rats treated with PRO (0.5mg/kg) or vehicle was examined. Progesterone significantly decreased the total number of DRO resets in both males and females, but it did not affect VI responding for sucrose pellets. This suggests that PRO decreases motor impulsivity for sucrose pellets without affecting motivation for food. Thus, PRO may reduce motor impulsivity, a behavior underlying drug addiction.
The Kelch-like ECH associated protein 1 (Keap1) is a component of a Cullin3-based Cullin-RING E3 ubiquitin ligase (CRL) multisubunit protein complex. Within the CRL, homodimeric Keap1 functions as the Cullin3 adaptor, and importantly, it is also the critical component of the E3 ligase that performs the substrate recognition. The best-characterized substrate of Keap1 is transcription factor NF-E2 p45-related factor 2 (Nrf2), which orchestrates an elaborate transcriptional program in response to environmental challenges caused by oxidants, electrophiles and pro-inflammatory agents, allowing adaptation and survival under stress conditions. Keap1 is equipped with reactive cysteine residues that act as sensors for endogenously produced and exogenously encountered small molecules (termed inducers), which have a characteristic chemical signature, reactivity with sulfhydryl groups. Inducers modify the cysteine sensors of Keap1 and impair its ability to target Nrf2 for ubiquitination and degradation. Consequently, Nrf2 accumulates, enters the nucleus and drives the transcription of its target genes, which encode a large network of cytoprotective proteins. Here we summarize the early studies leading to the prediction of the existence of Keap1, followed by the discovery of Keap1 as the main negative regulator of Nrf2. We then describe the available structural information on Keap1, its assembly with Cullin3, and its interaction with Nrf2. We also discuss the multiple cysteine sensors of Keap1 that allow for detection of a wide range of endogenous and environmental inducers, and provide fine-tuning and tight control of the Keap1/Nrf2 stress-sensing response.
Guanidinoacetic acid (GAA) is an experimental dietary additive that might act as a creatine source in tissues with high-energy requirements. In this case study, we evaluated brain levels of creatine in white matter, gray matter, cerebellum, and thalamus during 8 wk oral GAA administration in five healthy men and monitored the prevalence and severity of side effects of the intervention.
Volunteers were supplemented daily with 36 mg/kg body weight (BW) of GAA for the first 4 wk of the intervention; afterward GAA dosage was titrated ≤60 mg/kg BW of GAA daily. At baseline, 4, and 8 wk, the participants underwent brain magnetic resonance spectroscopy, clinical chemistry studies, and open-ended questionnaire for side-effect prevalence and severity.
Brain creatine levels increased in similar fashion in cerebellum, and white and gray matter after GAA supplementation, with an initial increase of 10.7% reported after 4 wk, and additional upsurge (7.7%) from the weeks 4 to 8 follow-up (P < 0.05). Thalamus creatine levels decreased after 4 wk for 6.5% (P = 0.02), and increased nonsignificantly after 8 wk for 8% (P = 0.09). GAA induced an increase in N-acetylaspartate levels at 8-wk follow-up in all brain areas evaluated (P < 0.05). No participants reported any neurologic adverse event (e.g., seizures, tingling, convulsions) during the intervention.
Supplemental GAA led to a region-dependent increase of the creatine pool in the human brain. This might be relevant for restoring cellular bioenergetics in disorders characterized by low brain creatine and functional enzymatic machinery for creatine synthesis, including neurodegenerative diseases, brain tumors, or cerebrovascular disease.
C4 photosynthesis exhibits efficient CO2 assimilation in ambient air by concentrating CO2 around ribulose 1,5-bisphosphate carboxylase/oxygenase (Rubisco) through a metabolic pathway called the C4 cycle. It has been suggested that cyclic electron flow (CEF) around PSI mediated by chloroplast NADH dehydrogenase-like complex (NDH), an alternative pathway of photosynthetic electron transport (PET), plays a crucial role in C4 photosynthesis, although the contribution of NDH-mediated CEF is small in C3 photosynthesis. Here, we generated NDH-suppressed transformants of a C4 plant, Flaveria bidentis, and showed that the NDH-suppressed plants grow poorly, especially under low-light conditions. CO2 assimilation rates were consistently decreased in the NDH-suppressed plants under low and medium light intensities. Measurements of non-photochemical quenching (NPQ) of Chl fluorescence, the oxidation state of the reaction center of PSI (P700) and the electrochromic shift (ECS) of pigment absorbance indicated that proton translocation across the thylakoid membrane is impaired in the NDH-suppressed plants. Since proton translocation across the thylakoid membrane induces ATP production, these results suggest that NDH-mediated CEF plays a role in the supply of ATP which is required for C4 photosynthesis. Such a role is more crucial when the light that is available for photosynthesis is limited and the energy production by PET becomes rate-determining for C4 photosynthesis. Our results demonstrate that the physiological contribution of NDH-mediated CEF is greater in C4 photosynthesis than in C3 photosynthesis, suggesting that the mechanism of PET in C4 photosynthesis has changed from that in C3 photosynthesis accompanying the changes in the mechanism of CO2 assimilation.
Plants perceive information from the surroundings and elicit appropriate molecular responses. How plants dynamically respond to combinations of external inputs is yet to be revealed,
 despite the detailed current knowledge of intracellular signaling pathways. We measured dynamics of Response-to-Dehydration 29A (RD29A) expression induced by single or combined NaCl and ABA treatments in Arabidopsis thaliana. RD29A expression in response to a combination of NaCl and ABA leads to unique dynamic behavior that cannot be explained by the sum of responses to individual NaCl and ABA. To explore the potential mechanisms responsible for the observed synergistic response, we developed a mathematical model of the DREB2 and AREB pathways based on existing knowledge, where NaCl and ABA act as the cognate inputs, respectively, and examined various system structures with cross-input modulation, where non-cognate input affects expression of the genes involved in adjacent signaling pathways. The results from the analysis of system structures, combined with the insights from microarray expression profiles and model-guided experiments, predicted that synergistic activation of RD29A originates from enhancement of DREB2 activity by ABA. Our analysis of RD29A expression profiles demonstrates that a simple mathematical model can be used to extract information from temporal dynamics induced by combinatorial stimuli and produce experimentally testable hypotheses.
Given the rarity of in-hospital pediatric emergency events, identification of gaps and inefficiencies in the code response can be difficult. In-situ, simulation-based medical education programs can identify unrecognized systems-based challenges. We hypothesized that developing an in-situ, simulation-based pediatric emergency response program would identify latent inefficiencies in a complex, dual-hospital pediatric code response system and allow rapid intervention testing to improve performance before implementation at an institutional level.
Pediatric leadership from two hospitals with a shared pediatric code response team employed the Institute for Healthcare Improvement's (IHI) Breakthrough Model for Collaborative Improvement to design a program consisting of Plan-Do-Study-Act cycles occurring in a simulated environment. The objectives of the program were to 1) identify inefficiencies in our pediatric code response; 2) correlate to current workflow; 3) employ an iterative process to test quality improvement interventions in a safe environment; and 4) measure performance before actual implementation at the institutional level.
Twelve dual-hospital, in-situ, simulated, pediatric emergencies occurred over one year. The initial simulated event allowed identification of inefficiencies including delayed provider response, delayed initiation of cardiopulmonary resuscitation (CPR), and delayed vascular access. These gaps were linked to process issues including unreliable code pager activation, slow elevator response, and lack of responder familiarity with layout and contents of code cart. From first to last simulation with multiple simulated process improvements, code response time for secondary providers coming from the second hospital decreased from 29 to 7 min, time to CPR initiation decreased from 90 to 15 s, and vascular access obtainment decreased from 15 to 3 min. Some of these simulated process improvements were adopted into the institutional response while others continue to be trended over time for evidence that observed changes represent a true new state of control.
Utilizing the IHI's Breakthrough Model, we developed a simulation-based program to 1) successfully identify gaps and inefficiencies in a complex, dual-hospital, pediatric code response system and 2) provide an environment in which to safely test quality improvement interventions before institutional dissemination.
Although population models are recognized as necessary tools in the ecological risk assessment of pesticides, particularly for species listed under the Endangered Species Act, their application in this context is currently limited to very few cases. The authors developed a detailed, individual-based population model for a threatened plant species, the decurrent false aster (Boltonia decurrens), for application in pesticide risk assessment. Floods and competition with other plant species are known factors that drive the species' population dynamics and were included in the model approach. The authors use the model to compare the population-level effects of 5 toxicity surrogates applied to B. decurrens under varying environmental conditions. The model results suggest that the environmental conditions under which herbicide applications occur may have a higher impact on populations than organism-level sensitivities to an herbicide within a realistic range. Indirect effects may be as important as the direct effects of herbicide applications by shifting competition strength if competing species have different sensitivities to the herbicide. The model approach provides a case study for population-level risk assessments of listed species. Population-level effects of herbicides can be assessed in a realistic and species-specific context, and uncertainties can be addressed explicitly. The authors discuss how their approach can inform the future development and application of modeling for population-level risk assessments of listed species, and ecological risk assessment in general. Environ Toxicol Chem 2016;9999:1-12. © 2016 SETAC.
Improved understanding of the secondary gene pools of crops is essential for advancing genetic gain in breeding programmes. Common bean, Phaseolus vulgaris, is a staple crop with several wild relatives in its secondary gene pool. The year-long bean, P. dumosus, an important crop in Guatemala, is considered particularly closely related to P. vulgaris and a potential source of novel variation. However, the genetic diversity and relationship to other Phaseolus species of P. dumosus remain unclear.
We conducted the first comprehensive investigation of P. dumosus genetic diversity using both nuclear and chloroplast genome markers. Our nuclear marker set included over 700 markers present within the Phaseolus DArT (Diversity Arrays Technology) array, which we applied to P. dumosus and other relatives of P. vulgaris (including every secondary gene pool species: P. acutifolius, P. albescens, P. coccineus and P. costaricensis).
Phaseolus dumosus arose from hybridization of P. vulgaris and P. coccineus, followed by at least two later hybridizations with sympatric congener populations. Existing P. dumosus collections have low genetic diversity.
The under-utilized crop P. dumosus has a complex hybrid origin. Further sampling in the region in which it arose may uncover additional germplasm for introgressing favourable traits into crops within the P. vulgaris gene pool.
Normal breathing in rodents requires activity of glutamatergic Dbx1-derived (Dbx1(+)) preBötzinger Complex (preBötC) neurons expressing somatostatin (SST). We combined in vivo optogenetic and pharmacological perturbations to elucidate the functional roles of these neurons in breathing. In transgenic adult mice expressing channelrhodopsin (ChR2) in Dbx1(+) neurons, photoresponsive preBötC neurons had preinspiratory or inspiratory firing patterns associated with excitatory effects on burst timing and pattern. In transgenic adult mice expressing ChR2 in SST(+) neurons, photoresponsive preBötC neurons had inspiratory or postinspiratory firing patterns associated with excitatory responses on pattern or inhibitory responses that were largely eliminated by blocking synaptic inhibition within preBötC or by local viral infection limiting ChR2 expression to preBötC SST(+) neurons. We conclude that: (1) preinspiratory preBötC Dbx1(+) neurons are rhythmogenic, (2) inspiratory preBötC Dbx1(+) and SST(+) neurons primarily act to pattern respiratory motor output, and (3) SST(+)-neuron-mediated pathways and postsynaptic inhibition within preBötC modulate breathing pattern.
The domestic cat is natural host to both feline immunodeficiency virus and Felis catus gammaherpesvirus 1 (FcaGHV1). Comparative data suggest that these agents might act as synergistic copathogens in feline AIDS-related lymphoma. To identify leucocyte subsets harbouring gammaherpesvirus DNA, whole blood from 5 healthy, FcaGHV1-infected cats was labelled with monoclonal antibodies to feline CD21, CD4, CD8 and CD14 for 4-way fluorescence-activated cell sorting. FcaGHV1gB qPCR was performed on DNA extracted from purified fractions and whole blood longitudinally. FcaGHV1 DNA was detected in CD21+, CD4+, CD8+, but not CD14+ cells. Variation in whole blood load, up to 19,788 copies/10(6)cells, was detected in individual cats over time. FcaGHV1 DNA was undetectable in one cat on one occasion highlighting that qPCR of whole blood from a single time point will not detect all cases of FcaGHV1 infection. Further investigation of the role of FcaGHV1 in feline lymphoid malignancies is warranted.
Indonesia has seen an emergence of local health care financing schemes over the last decade, implemented and operated by district governments. Often motivated by the local political context and characterized by a large degree of heterogeneity in scope and design, the common objective of the district schemes is to address the coverage gaps for the informal sector left by national social health insurance programs. This paper investigates the effect of these local health care financing schemes on access to health care and financial protection. Using data from a unique survey among District Health Offices, combined with data from the annual National Socioeconomic Surveys, the study is based on a fixed effects analysis for a panel of 262 districts over the period 2004-10, exploiting variation in local health financing reforms across districts in terms of type of reform and timing of implementation. Although the schemes had a modest impact on average, they do seem to have provided some contribution
 to closing the coverage gap, by increasing outpatient utilization for households in the middle quintiles that tend to fall just outside the target population of the national subsidized programs. However, there seems to be little effect on hospitalization or financial protection, indicating the limitations of local health care financing policies. In addition, we see effect heterogeneity across districts due to differences in design features.
Although transpiration and aquaporins have long been identified as two key components influencing plant water status, it is only recently that their relations have been investigated in detail. The present review first examines the various facets of aquaporin function in stomatal guard cells and shows that it involves transport of water but also of other molecules such as carbon dioxide and hydrogen peroxide. At the whole plant level, changes in tissue hydraulics mediated by root and shoot aquaporins can indirectly impact plant transpiration. Recent studies also point to a feedback effect of transpiration on aquaporin function. These mechanisms may contribute to the difference between isohydric and anisohydric stomatal regulation of leaf water status. The contribution of aquaporins to transpiration control goes far beyond the issue of water transport during stomatal movements and involves emerging cellular and long-distance signalling mechanisms which ultimately act on plant growth.
An end-of-life vigil is the act of being with another toward death. A family vigil at end-of-life occurs when significant others gather by the bedside of dying individuals in the weeks, days, or hours prior to the death event. It is not unusual for nurses to be present, bear witness, and share in this human experience. This article reviews seminal and current research regarding the meaning and structure of the lived experience of vigil keeping for a dying family member, and translates research to inform nurses regarding family care during the transition at end-of-life.
Polyester polyurethane (PU) coatings are widely used to help protect underlying structural surfaces but are susceptible to biological degradation. PUs are susceptible to degradation by Pseudomonas species, due in part to the degradative activity of secreted hydrolytic enzymes. Microorganisms often respond to environmental cues by secreting enzymes or secondary metabolites to benefit their survival. This study investigated the impact of exposing several Pseudomonas strains to select carbon sources on the degradation of the colloidal polyester polyurethane Impranil DLN (Impranil). The prototypic Pseudomonas protegens strain Pf-5 exhibited Impranil-degrading activities when grown in sodium citrate but not in glucose-containing medium. Glucose also inhibited the induction of Impranil-degrading activity by citrate-fed Pf-5 in a dose-dependent manner. Biochemical and mutational analyses identified two extracellular lipases present in the Pf-5 culture supernatant (PueA and PueB) that were involved in degradation of Impranil. Deletion of the pueA gene reduced Impranil-clearing activities, while pueB deletion exhibited little effect. Removal of both genes was necessary to stop degradation of the polyurethane. Bioinformatic analysis showed that putative Cbr/Hfq/Crc-mediated regulatory elements were present in the intergenic sequences upstream of both pueA and pueB genes. Our results confirmed that both PueA and PueB extracellular enzymes act in concert to degrade Impranil. Furthermore, our data showed that carbon sources in the growth medium directly affected the levels of Impranil-degrading activity but that carbon source effects varied among Pseudomonas strains. This study uncovered an intricate and complicated regulation of P. protegens PU degradation activity controlled by carbon catabolite repression.
Polyurethane (PU) coatings are commonly used to protect metals from corrosion. Microbiologically induced PU degradation might pose a substantial problem for the integrity of these coatings. Microorganisms from diverse genera, including pseudomonads, possess the ability to degrade PUs via various means. This work identified two extracellular lipases, PueA and PueB, secreted by P. protegens strain Pf-5, to be responsible for the degradation of a colloidal polyester PU, Impranil. This study also revealed that the expression of the degradative activity by strain Pf-5 is controlled by glucose carbon catabolite repression. Furthermore, this study showed that the Impranil-degrading activity of many other Pseudomonas strains could be influenced by different carbon sources. This work shed light on the carbon source regulation of PU degradation activity among pseudomonads and identified the polyurethane lipases in P. protegens.
Both LARGE1 (formerly LARGE) and its paralog LARGE2 are bifunctional glycosyltransferases with xylosy- and glucuronyltransferase activities, and are capable of synthesizing polymers composed of a repeating disaccharide [-3Xylα1,3GlcAβ1-]. Post-translational modification of the O-mannosyl glycan of α-dystroglycan (α-DG) with the polysaccharide is essential for it to act as a receptor for ligands in the extracellular matrix (ECM), and both LARGE paralogs contribute to the modification in vivo. LARGE1 and LARGE2 have different tissue distribution profiles and enzymatic properties; however, the functional difference of the homologs remains to be determined, and α-DG is the only known substrate for the modification by LARGE1 or LARGE2. Here we show that LARGE2 can modify proteoglycans (PGs) with the laminin-binding glycan. We found that overexpression of LARGE2, but not LARGE1, mediates the functional modification on the surface of DG(-/-), Pomt1(-/-) and Fktn(-/-) embryonic stem cells. We identified a heparan sulfate-PG glypican-4 as a substrate for the LARGE2-dependent modification by affinity purification and subsequent mass spectrometric analysis. Furthermore, we showed that LARGE2 could modify several additional PGs with the laminin-binding glycan, most likely within the glycosaminoglycan (GAG)-protein linkage region. Our results indicate that LARGE2 can modify PGs with the GAG-like polysaccharide composed of xylose and glucuronic acid to confer laminin binding. Thus, LARGE2 may play a differential role in stabilizing the basement membrane and modifying its functions by augmenting the interactions between laminin globular domain-containing ECM proteins and PGs.
Leptospiral infection is widespread in wildlife. In this context, wild ecosystems in tropical countries hold a vast biodiversity, including several species that may act as potential reservoirs of leptospires. The Pantanal biome presents highly favorable environmental conditions for the occurrence of leptospirosis, such as high temperatures, constant flooding, and high biodiversity. The purpose of this study was to detect wild animals as carriers of Leptospira sp. using direct methods (PCR and culture) in the Pantanal biome, Brazil. A total of 35 animals were studied, namely Cerdocyon thous, Nasua nasua, Ozotoceros bezoarticus, and Sus scrofa species. Blood for serology (MAT) and urine for bacteriological culturing and PCR was sampled. The most prevalent serogroups were Javanica and Djasiman. Additionally, 40.6% of these animals presented PCR positive reactions. Seroreactivity associated with the high frequency of leptospiral carriers among the different studied species suggests a high level of exposure of the studied animals to pathogenic Leptospira strains. Our results are still limited and the actual role of the studied animals in the epidemiology of leptospirosis in the Pantanal region remains to be elucidated.
Chyawanprash (CP), a traditional immune booster recipe, has a long history of ethnic origin, development, household preparation and usage. There are even mythological stories about the origin of this recipe including its nomenclature. In the last six decades, CP, because of entrepreneurial actions of some research Vaidyas (traditional doctors) has grown to industrial production and marketing in packed forms to a large number of consumers/patients like any food or health care product. Currently, CP has acquired a large accepted user base in India and in a few countries out-side India.
Authoritative texts, recognized by the Drugs and Cosmetics Act of India, describe CP as an immunity enhancer and strength giver meant for improving lung functions in diseases with compromised immunity. This review focuses on published clinical efficacy and safety studies of CP for correlation with health benefits as documented in the authoritative texts, and also briefs on its recipes and processes.
Authoritative texts were searched for recipes, processes, and other technical details of CP. Labels of marketing CP products (Indian) were studied for the health claims. Electronic search for studies of CP on efficacy and safety data were performed in PubMed/MEDLINE and DHARA (Digital Helpline for Ayurveda Research Articles), and Ayurvedic books were also searched for clinical studies.
The documented clinical studies from electronic databases and Ayurvedic books evidenced that individuals who consume CP regularly for a definite period of time showed improvement in overall health status and immunity. However, most of the clinical studies in this review are of smaller sample size and short duration. Further, limitation to access and review significant data on traditional products like CP in electronic databases was noted.
Randomized controlled trials of high quality with larger sample size and longer follow-up are needed to have significant evidence on the clinical use of CP as immunity booster. Additional studies involving measurement of current biomarkers of immunity pre- and post-consumption of the product as well as benefits accruing with the use of CP as an adjuvant are suggested.
The
 ability to respond to stressful conditions is essential for most living organisms. In pathogenic organisms, this response is required for effective transition from a saprophytic lifestyle to the establishment of pathogenic interactions within a susceptible host. Hyperosmotic stress has been used as a model to study signal transduction and seems to cause many cellular adaptations, including the alteration of protein expression and cellular volume as well as size regulation. In this work, we evaluated the proteomic profile of Paracoccidioides lutzii Pb01 yeast cells during osmotic stress induced by potassium chloride. We performed a high accuracy proteomic technique (NanoUPLC-MS(E)) to identify differentially expressed proteins during osmotic shock. The data describe an osmoadaptative response of this fungus when subjected to this treatment. Proteins involved in the synthesis of cell wall components were modulated, which suggested cell wall remodeling. In addition, alterations in the energy metabolism were observed. Furthermore, proteins involved in amino acid metabolism and hydrogen peroxide detoxification were modulated during osmotic stress. Our study suggests that P. lutzii Pb01. presents a vast osmoadaptative response that is composed of different proteins that act together to minimize the effects caused by osmotic stress.
Organ, tissue, and cell procurement from deceased donors for transplantation requires consent and authorization, documented donor's positive acceptance, or lack of objection to donation expressed while alive (consent). It also requires the fulfillment of other legal conditions required by law, such as person's legal abilities to act in this field or to obtain approval for donation (authorization). Consent to and authorization of donation from deceased donors requires regulations at the national level. Poland developed an opting-out policy with the Transplantation Act in 1996. The Central Register of Objections (CRO) was introduced on November 1, 1996. The purpose of this article is a formal analysis of all submitted objections and objection withdrawals managed by the CRO since the introduction of the registry in 1996 until the end of 2014.
All data collected by the CRO during 18 years of service was subject to analysis. The objections and withdrawals of objections are summarized in the tables, along with the age, sex, and place of residence of the registered residents.
By December 31, 2014, a total of 29,288 records were registered, including 29,013 registered objections and 275 registered withdrawals of objections; this means that 0.075% of the country's population expressed objection to posthumous tissue and organ donation for transplantation. Legal representatives submitted 4208 declarations (15.6% of all declarations). The largest inflow of objections took place in 1997, the first full year of CRO activity.
CRO is an indispensable option in a country with opt-out system as a part of organ donation authorization protocol. Number of registered objections is extremely low, in practice, this leads to a situation where the will of the deceased most often is obtained from his family.
We determine the incidence of and trends in enforcement of the Emergency Medical Treatment and Labor Act (EMTALA) during the past decade.
We obtained a comprehensive list of all EMTALA investigations conducted between 2005 and 2014 directly from the Centers for Medicare & Medicaid Services (CMS) through a Freedom of Information Act request. Characteristics of EMTALA investigations and resulting citation for violations during the study period are described.
Between 2005 and 2014, there were 4,772 investigations, of which 2,118 (44%) resulted in citations for EMTALA deficiencies at 1,498 (62%) of 2,417 hospitals investigated. Investigations were conducted at 43% of hospitals with CMS provider agreements, and citations issued at 27%. On average, 9% of hospitals were investigated and 4.3% were cited for EMTALA violation annually. The proportion of hospitals subject to EMTALA investigation decreased from 10.8% to 7.2%, and citations from 5.3% to 3.2%, between 2005 and 2014. There were 3.9 EMTALA investigations and 1.7 citations per million emergency department (ED) visits during the study period.
We report the first national estimates of EMTALA enforcement activities in more than a decade. Although EMTALA investigations and citations were common at the hospital level, they were rare at the ED-visit level. CMS actively pursued EMTALA investigations and issued citations throughout the study period, with half of hospitals subject to EMTALA investigations and a quarter receiving a citation for EMTALA violation, although there was a declining trend in enforcement. Further investigation is needed to determine the effect of EMTALA on access to or quality of emergency care.
Specialist palliative care is not a standardised component of service delivery in nursing home care in Australia. Specialist palliative care services can increase rates of advance care planning, decrease hospital admissions and improve symptom management in such facilities. New approaches are required to support nursing home residents in avoiding unnecessary hospitalisation and improving rates of dying in documented preferred place of death. This study examined whether the addition of a proactive model of specialist palliative care reduced resident transfer to the acute care setting, and achieved a reduction in hospital deaths.
A quasi-experimental design was adopted, with participants at 4 residential care facilities. The intervention involved a palliative care nurse practitioner leading 'Palliative Care Needs Rounds' to support clinical decision-making, education and training. Participants were matched with historical decedents using propensity scores based on age, sex, primary diagnosis, comorbidities and the Aged Care Funding Instrument rating. Outcome measures included participants' hospitalisation in the past 3 months of life and the location of death.
The data demonstrate that the intervention is associated with a substantial reduction in the length of hospital stays and a lower incidence of death in the acute care setting. While rates of hospitalisation were unchanged on average, length of admission was reduced by an average of 3.22 days (p<0.01 and 95% CI -5.05 to -1.41), a 67% decrease in admitted days.
The findings have significant implications for promoting quality outcomes through models of palliative care service delivery in residential facilities.
Stingless bees constitute a species-rich tribe of tropical and subtropical eusocial Apidae that act as important pollinators for flowering plants. Many foraging tasks rely on vision, e.g. spatial orientation and detection of food sources and nest entrances. Meliponini workers are usually small, which sets limits on eye morphology and thus quality of vision. Limitations are expected both on acuity, and thus on the ability to detect objects from a distance, as well as on sensitivity, and thus on the foraging time window at dusk and dawn. In this study, we determined light intensity thresholds for flight under dim light conditions in eight stingless bee species in relation to body size in a Neotropical lowland rainforest. Species varied in body size (0.8-1.7 mm thorax-width), and we found a strong negative correlation with light intensity thresholds (0.1-79 lx). Further, we measured eye size, ocelli diameter, ommatidia number, and facet diameter. All parameters significantly correlated with body size. A disproportionately low light intensity threshold in the minute Trigonisca pipioli, together with a large eye parameter P eye suggests specific adaptations to circumvent the optical constraints imposed by the small body size. We discuss the implications of body size in bees on foraging behavior.
Selenium compounds that contain selenol functions or can be metabolized to selenols are toxic via superoxide and H2O2 generation, when ingested at dosages beyond requirement. At supra-nutritional dosages various forms of programmed cell death are observed. At physiological intakes, selenium exerts its function as constituent of selenoproteins, which overwhelmingly are oxidoreductases. Out of those, the glutathione peroxidases counteract hydroperoxide-stimulated signaling cascades comprising inflammation triggered by cytokines or lipid mediators, insulin signaling and different forms of programmed cell death. Similar events are exerted by peroxiredoxins, which functionally depend on the selenoproteins of the thioredoxin reductase family. The thiol peroxidases of both families can, however, also act as sensors for hydroperoxides, thereby initiating signaling cascades. Although the interaction of selenoproteins with signaling events has been established by genetic techniques, the in vivo relevance of these findings is still hard to delineate for several reasons: The biosynthesis of individual selenoproteins responds differently to variations of selenium intakes; selenium is preferentially delivered to privileged tissues via inter-organ trafficking and receptor-mediated uptake, and only half of the selenoproteins known by sequence have been functionally characterized. The fragmentary insights do not allow any uncritical use of selenium for optimizing human health.
Consumer participation in the education of health professionals is increasing, particularly in mental health nursing education and storytelling remains the most frequent approach to consumer involvement. The use of story has tended to be accepted as a legitimate educational tool with limited critique or consideration of its potential consequences presented within the academic literature. A qualitative exploratory research study was undertaken with mental health nurse academics (n = 34) and consumer educators and academics (n = 12), to investigate the perceptions
 and experiences of mental health nurses and consumers regarding the involvement of consumers in mental health nursing education. Data were analysed thematically. Story was a major theme to emerge from consumer participants and received some attention from nurse academics. Consumers and nurses both referred to the power of story to convey the human experience of mental illness diagnosis and service use; and the vulnerability that can result from storytelling. Consumers also described: story as expectation; preparation and support; and the politics of story. All participants supported the value of storytelling in mental health nursing education. Consumers had considered the complexities in far greater detail. The ongoing value of story as an educational technique requires further research. Equally important is considering a broader range of educational roles for mental health consumers.
Rice plant growth is comprised of distinct phases, such as vegetative, reproductive, grain filling and maturity phases. In these phases synthesis and availability of primary and secondary metabolites including volatile organic compounds (VOC's) is highly variable. In scented rice, aroma volatiles are synthesized in aerial plant parts and deposited in mature grains. There are more than 100 VOCs reported to be responsible for flavor in basmati rice. It will be interesting to keep track of aroma volatiles across the developmental stages in scented rice. Therefore, the aroma volatiles contributing in aroma with special reference to the major compound 2 acetyl-1-pyrroline (2AP) were screened at seven developmental stages in scented rice cultivars Basmati-370 and Ambemohar-157 along with non-scented rice cultivar IR-64 as a control following HS-SPME-GC-MS method. In addition, the expression levels of key genes and precursor levels involved in 2AP biosynthesis were studied.
The study indicated that volatilome of scented rice cultivars is more complex than non-scented rice cultivar. N-heterocyclic class was the major distinguishing class between scented from non-scented rice. A total of 14 compounds including, 2AP were detected specifically in scented rice cultivars. Maximum number of compounds were synthesized at seedling stage and decreased gradually at reproductive and maturity. The seedling stage is an active phase of development where maximum number green leaf volatiles were synthesized which are known to act as defense molecules for protection of young plant parts. Among the 14 odor active compounds (OACs), 10 OACs were accumulated at higher concentrations significantly in scented rice cultivars and contribute in the aroma. 2AP content was highest in mature grains followed by at booting stage. Gene expression analysis revealed that reduced expression of betaine aldehyde dehydrogenase 2 (badh2) and glyceraldehyde-3-phosphate dehydrogenase (GAPDH) and elevated level of triose phosphate isomerase (TPI) and Δ1-Pyrolline-5-carboxylic acid synthetase (P5CS) transcript enhances 2AP accumulation.
Most diverse compounds were synthesized at seedling stage and OACs were accumulated more at flowering followed by seedling stage. Distinct accumulation pattern exists for 2AP and other aroma volatiles at various developmental stages. The study revealed the mechanism of 2AP accumulation such that 2AP in mature grains might be transported from leaves and stem sheath and accumulation takes place in grains.
While establishing the diagnosis of Parkinson disease (PD) can be straightforward, it can be challenging in some patients, even for the experienced neurologist. The misdiagnosis rate ranges from 10% to 20% or greater depending on clinician experience.
Despite promise in the search for a biomarker that can establish the presence of PD and act as a marker of its progression, the diagnosis of PD continues to be based on clinical examination. Core criteria, exclusion criteria, and supportive criteria have been developed to aid the clinician in establishing the diagnosis. Nonmotor symptoms of PD are usually present at the time of diagnosis, may precede motor symptoms, and should be specifically sought during evaluation. Ancillary testing can be appropriate, but its indications and utility must be clearly understood.
The diagnosis of PD requires the recognition of the core features of PD and the differentiation of its clinical presentation from other entities with similar and potentially overlapping symptoms. A careful history and examination guided by clinical diagnostic criteria will usually establish the diagnosis of PD or uncover red flags for the possibilities of other diagnoses. Appropriate selection and interpretation of ancillary testing is critical to avoid misdiagnosis and unnecessary tests.
Mycobacterium abscessus subsp. abscessus (MAB) is a highly drug resistant mycobacterium and the most common respiratory pathogen among the rapidly growing non-tuberculous mycobacteria. MAB is also one of the most deadly of the emerging cystic fibrosis (CF) pathogens requiring prolonged treatment with multiple antibiotics. In addition to its "mycobacterial" virulence genes, the genome of MAB harbours a large accessory genome, presumably acquired via lateral gene transfer including homologs shared with the CF pathogens Pseudomonas aeruginosa and Burkholderia cepacia. While multiple genome sequences are available there is little functional genomics data available for this important pathogen.
We report here the first multi-omics approach to characterize the primary transcriptome, coding potential and potential regulatory regions of the MAB genome utilizing differential RNA sequencing (dRNA-seq), RNA-seq, Ribosome profiling and LC-MS proteomics. In addition we attempt to address the genomes contribution to the molecular systems that underlie MAB's adaptation and persistence in the human host through an examination of MABs transcriptional response to a number of clinically relevant conditions. These include hypoxia, exposure to sub-inhibitory concentrations of antibiotics and growth in an artificial sputum designed to mimic the conditions within the cystic fibrosis lung.
Our integrated map provides the first comprehensive view of the primary transcriptome of MAB and evidence for the translation of over one hundred new short open reading frames (sORFs). Our map will act as a resource for ongoing functional genomics characterization of MAB and our transcriptome data from clinically relevant stresses informs our understanding of MAB's adaptation to life in the CF lung. MAB's adaptation to growth in artificial CF sputum highlights shared metabolic strategies with other CF pathogens including P. aeruginosa and mirrors the transcriptional responses that lead to persistence in mycobacteria. These strategies include an increased reliance on amino acid metabolism, and fatty acid catabolism and highlights the relevance of the glyoxylate shunt to growth in the CF lung. Our data suggests that, similar to what is seen in chronically persisting P. aeruginosa, progression towards a biofilm mode of growth would play a more prominent role in a longer-term MAB infection. Finally, MAB's transcriptional response to antibiotics highlights the role of antibiotic modifications enzymes, active transport and the evolutionarily conserved WhiB7 driven antibiotic resistance regulon.
Chronic active Epstein-Barr virus (EBV) infection (CAEBV) is characterized as chronic or recurrent mononucleosis-like symptoms and elevated EBV deoxyribonucleic acid (EBV-DNA) copies. Cardiovascular complications have high morbidity and mortality. The treatment regimen for CAEBV has not been established yet, resulting in poor prognoses. Herein, we present a case of cardiovascular magnetic resonance imaging (CMRI) evaluation with a series of sequences for CAEBV-associated cardiovascular involvement, which has never been reported.
A 16-year-old female (body weight, 55 kg) developed a persistent fever and a positive EBV-DNA level of 28,000 copies/mL. Computed tomography angiography (CTA) showed aneurysms involving the aorta and its major branches, as well as multiple aneurysms and stenoses of the coronary arteries. CMRI of the coronary arteries depicted the dilution and stenosis of the arterial lumen as well as the thickening of the arterial wall. Late gadolinium enhancement (LGE) showed subendocardial and transmural delayed enhancement of the left ventricle, suggesting myocardial infarction.CAEBV and associated cardiovascular complications were diagnosed. After treatment with Medrol and Leflunomide, the clinical manifestation and serological parameters reversed to normal. However, the EBV-DNA level increased again to 13,900 copies/mL 2 months later. A follow-up with aorta CTA showed that the arterial walls of the bilateral common iliac artery aneurysms were thicker with new-onset mural thrombi. The aorta CTA also showed new-onset occlusion of the right coronary artery, but a follow-up of CMRI at the same day did not find new-onset delayed enhancement lesion.
This case reminds clinicians of the vital importance of early diagnosis and close follow-up of CAEBV-associated cardiovascular complications. With cine imaging, coronary artery imaging, LGE imaging, and other novel techniques, CMRI can effectively and comprehensively reveal the early and dynamic changes, and act as an important tool in the field of cardiovascular diseases.
Treatments for chronic rhinosinusitis (CRS) and asthma can affect both conditions, based on the united airway concept. This study aimed to evaluate the link between CRS and asthma, based on disease-specific quality of life measures.We performed a prospective cohort study to investigate the correlations between results from CRS- and asthma-specific questionnaires. Thirty-two patients with asthma and CRS were evaluated before and after undergoing nasal surgery at a tertiary medical center.There
 were significant correlations between the results from the Asthma Control Test (ACT) and the Sino-Nasal Outcome Test-22, as well as between the results of the ACT and Rhinoconjunctivitis Quality of Life Questionnaire, at both the preoperative and 3-month postoperative evaluations (P < 0.01). Moreover, nasal surgery improved the sinonasal symptoms, asthma control, and pulmonary function (P < 0.01).Increasingly severe sinonasal symptoms of CRS were associated with poor asthma control. Therefore, CRS and asthma should be considered and treated as common airway diseases.
MicroRNAs have been shown to act as oncogenes or tumor suppressers via various cellular pathways. Specifically, in breast cancer, upregulation of miR-10b is positively associated with aggressiveness of tumors. However, the mechanism by which miR-10b contributes to cell malignancy is largely unknown. Here we show that at the receiving end of the miR-10b pathway is the proto-oncogene c-Jun, a transcription factor that plays a critical role in stimulation of cell proliferation and tumor progression. c-Jun is known to be translationally activated by loss of cell contacts or restructuring of the cytoskeleton. A comprehensive analysis of miRNA expression exhibited a significant increase in miR-10b expression. This was supported by analysis of breast cancer cells, which showed that loss of E-cadherin in metastatic cells is accompanied by elevation of miR-10b and interestingly, by a marked increase in accumulation of c-Jun. Silencing miR-10b in metastatic breast cancer cells leads to a decline in c-Jun expression, whereas overexpression of miR-10b in HaCaT cells is sufficient to elevate the accumulation of c-Jun. The increase in c-Jun protein accumulation in metastatic cells is not accompanied by an increase in c-Jun mRNA and is not dependent on MAPK activity. Knockdown and overexpression experiments revealed that the increase is mediated by NF1 and RhoC, downstream targets of miR-10b that affect cytoskeletal dynamics through the ROCK pathway. Overall, we show the ability of miR-10b to activate the expression of c-Jun through RhoC and NF1, which represents a novel pathway for promoting migration and invasion of human cancer cells.
Stathmin has been investigated as a tumor biomarker because it appear to be associated with tumorigenesis; however, the effect of stathmin in lung adenocarcinoma (LAC) remains poorly understood. The purpose of this study was to examine the expression of stathmin in lung adenocarcinoma, and to disclose the relationship between them. The expression of stathmin was examined by RT-PCR, IHC and Western blot. Furthermore, small interfering RNA (shRNA)-mediated silencing of stathmin was employed in LAC cells to investigate cell proliferation, invasion and apoptosis. In this study, we showed that overexpression of stathmin was significantly associated with poorly differentiated, lymph node metastasis and advance TNM stages of lung adenocarcinoma. And silencing of stathmin expression inhibited the proliferation, migration and invasion of lung adenocarcinoma PC-9 cells, and retarded the growth of PC-9 cells xenografts in nude mice. Additionally, the anticarcinogenic efficacy of stathmin silencing might be involved in P38 and MMP2 signaling pathways. In conclusion, these results showed that stathmin expression was significantly up-regulated in LAC, which may act as a biomarker for LAC. Furthermore, silence of stathmin inhibiting LAC cell growth indicated that stathmin may be a promising molecular target for LAC therapy.
Non-Hodgkin lymphomas (NHLs) include a heterogeneous group of diseases, which differ in both cellular origin and clinical behavior. Among the aggressive malignancies of this group, the diffuse large B-cell lymphomas (DLBCLs) are the most frequently observed. They are themselves clinically and molecularly heterogeneous and have been further sub-divided in three sub-types according to different cell of origin, mechanisms of oncogenesis and clinical outcome. Among them, the germinal center B-cell-like (GCB) derives from the germinal center and expresses the BCL6 oncogene. We have previously shown that Patz1-knockout mice develop B-cell neoplasias, suggesting a tumor suppressor role for PATZ1 in human NHLs. Here, by immunohistochemical analysis of a tissue-microarray including 170 NHLs, we found that PATZ1 nuclear expression is down-regulated in follicular lymphomas and DLBCLs. Moreover, consistent with our previous results showing a PATZ1-dependent regulation of BCL6 and BAX transcription, we show that low PATZ1 nuclear expression significantly correlates with high BCL6 expression, mainly in DLBCLs, and with low BAX expression, also considering separately follicular lymphomas and DLBCLs. Finally, by analyzing overall and progression-free survival in DLBCL patients that underwent rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone chemotherapy, low levels of PATZ1 were significantly associated to a worst outcome and demonstrated an independent prognostic factor in multivariate analysis, including known prognostic factors of DLBCL, IPI score and cell of origin (GCB/non-GCB). Therefore, we propose PATZ1 as a new prognostic marker of DLBCLs, which may act as a tumor suppressor by enhancing apoptosis through inhibiting and enhancing transcription of BCL6 and BAX, respectively.
MicroRNAs (miRNAs) are vital for many biological processes and have been regarded as cancer biomarkers. Specific and sensitive detection of miRNAs is essential for cancer diagnosis and therapy. Herein, a split recognition mode combined with cascade signal amplification strategy is developed for highly specific and sensitive detection of miRNA. The split recognition mode possesses two specific recognition processes, which are based on toehold-mediated strand displacement reaction (TSDR) and direct hybridization reaction. Two recognition probes, hairpin probe (HP) with overhanging toehold domain and assistant probe (AP), are specially designed. Firstly, the toehold domain of HP and AP recognize part of miRNA simultaneously, accompanied with TSDR to unfold the HP and form the stable DNA Y-shaped junction structure (YJS). Then, the AP in YJS can further act as primer to initiate strand displacement amplification, releasing numerous trigger sequences. Finally, the trigger sequences hybridize with padlock DNA to initiate circular rolling circle amplification and generate enhanced fluorescence responses. In this strategy, the dual recognition effect of split recognition mode guarantees the excellent selectivity to discriminate let-7b from high-homology sequences. Furthermore, the high amplification efficiency of cascade signal amplification guarantees a high sensitivity with the detection limit of 3.2 pM and the concentration of let-7b in total RNA sample extracted from Hela cells is determined. These results indicate our strategy will be a promising miRNA detection strategy in clinical diagnosis and disease treatment.
We utilized the recently published method of passive CLARITY to explore brain astrocytes for the first time with our optimized method. Astrocytes are the fundamental cells in the brain that act to maintain the synaptic activity of neurons, support metabolism of all neurons, and communicate through extensive networks throughout the CNS. They are the defining cell that differentiates lower organisms from humans. From a disease vantage point they are the principal cause of brain tumors and the propagator of neurodegenerative diseases like amyotrophic lateral sclerosis. New methods to study these cells is paramount. Our modified use of CLARITY provides a new way to study these brain cells. To reduce cost, speed up tissue clearing process, reduce human handling error, and to retrieve quantifiable data from single confocal and pseudo-super resolution microscopy we modified and optimized the original protocol.
Using path-integral Monte Carlo simulations, we assess the core structure and mobility of the screw and edge basal-plane dislocations in hcp ^{4}He. Our findings provide key insights into recent interpretations of giant plasticity and mass flow junction experiments. First, both dislocations are dissociated into nonsuperfluid Shockley partial dislocations separated by ribbons of stacking fault, suggesting that they are unlikely to act as one-dimensional channels that may display Lüttinger-liquid-like behavior. Second, the centroid positions of the partial cores are found to fluctuate substantially, even in the absence of applied shear stresses. This implies that the lattice resistance to motion of the partial dislocations is negligible, consistent with the recent experimental observations of giant plasticity. Further results indicate that both the structure of the partial cores and the zero-point fluctuations play a role in this extreme mobility.
As the use of mobile devices and their software applications, or apps, becomes ubiquitous, use amongst agricultural working populations is expanding as well. The smart device paired with a well-designed app has potential for improving workplace health and safety in the hands of those who can act upon the information provided. Many apps designed to assess workplace hazards and implementation of worker protections already exist. However, the abundance and diversity of such applications also presents challenges regarding evaluation practices and assignation of value. This is particularly true in the agricultural workspace, as there is currently little information on the value of these apps for agricultural safety and health. This project proposes a framework for developing and evaluating apps that have potential usefulness in agricultural health and safety. The evaluation framework is easily transferable, with little modification for evaluation of apps in several agriculture-specific areas.
Osteoarthritis
 (OA) is associated with pain, dysfunction and reduced quality of life. Patient education (PE) followed by 12 weekly sessions of Basic Body Awareness Therapy (BBAT) was offered to patients with hip OA, aiming to strengthen their ability to move and act functionally in daily life.
To explore how patients described their experiences and outcome from participating in PE and BBAT.
Individual, semi-structured interviews with five patients, aged 52-78 years, were performed after PE and BBAT at four and ten months. Interview data were analyzed by systematic text condensation.
Three main themes emerged. "Becoming motivated and involved" reflected experiences of encouragement and support from information given and communication with group members. In "Movement awareness learning" patients described becoming aware of and improving functional movement, alleviating symptoms and increasing daily functioning. "Movement and disease in a long-term perspective" reflected patientś experience of increased self-awareness and taking better care of themselves at 10 months after baseline. Practicing basic movement principles, they felt empowered to handle daily life challenges in more functional and energy-economical ways.
PE followed by BBAT in groups may be beneficial to patients with hip OA, and provide lasting benefits regarding daily life function. Implications for Rehabilitation Insight into disease process and relationship to functional movement gained through patient education may empower patients with hip osteoarthritis in management of daily life Movement awareness and exploration of movement quality using principles from Basic Body Awareness Therapy was found to support patients in finding resources for functional movement, implemented in daily actions Movement strategies characterized by adjustment rather than force was experienced by the patients to support their general functioning, despite of prevailing hip pain Implementing group therapeutic factors (Yalom) in physiotherapy was found to strengthen patients' motivation and belief in functional improvement.
A series of compounds with benzothiazole and amide-imidazole scaffolds were designed and synthesized to combat the increasing incidence of drug-resistant fungal infections. The antifungal activity of these compounds was evaluated in vitro, and their structure-activity relationships (SARs) were evaluated. The synthesized compounds showed excellent inhibitory activity against Candida albicans and Cryptococcus neoformans. The most potent compounds 14o, 14p, and 14r exhibited potent activity, with minimum inhibitory concentration (MIC) values in the range of 0.125-2 μg/mL. Preliminary mechanism studies revealed that the compound 14p might act by inhibiting the CYP51 of Candida albicans. The SARs and binding mode established in this study are useful for further lead optimization.
Hand hygiene is one of the fundamental measures necessary for reducing healthcare-associated infections. The adherence of health care workers to safe hand hygiene practices is low worldwide, despite evidence showing compliance with hand hygiene guidelines decreases infection rate. This project focuses on the role of patients in promoting healthcare workers' compliance with hand hygiene practices. Several plan-do-study-act (PDSA) cycles were conducted to test interventions which aimed to empower patients and increase staff members' adherence to hand hygiene practices. The initial findings presented on the run chart demonstrate that compliance among healthcare workers increased with the interventions; there was an increase of 15% compliance during the 10 days of project testing. We will need to collect more data to show continued and sustained improvement. Patients can play an important role in promoting safe care and hand hygiene practices.
Application of inflammatory mediators to the cranial dura has been used as a method to activate and sensitize neurons in the meningeal sensory pathway in preclinical behavioral studies of headache mechanisms. However, the relatively high concentrations and volumes used in these studies raise the question of whether the applied agents might pass through the dura to act directly on central neurons, thus bypassing the dural afferent pathway.
We used a radiolabeling approach to quantify the meningeal permeability of two of the inflammatory mediators, 5-HT and PGE2, when applied to the cranial dura as part of an inflammatory mixture used in preclinical headache models.
Both agents could be detected in samples taken four hours after dural application in the cerebrospinal fluid (CSF) and, in measurements made only for PGE2, in the central nervous system (CNS) as well. Based on our measurements, we made estimates of the CSF and CNS levels that would be attained with the higher concentrations and volumes of 5HT and PGE2 that were exogenously applied in previous pre-clinical headache studies. These estimated levels were comparable to or larger than normal endogenous levels, potentially large enough to have physiological effects.
The finding that the cranial meninges are permeable to the two tested inflammatory mediators PGE2 and 5-HT raises some uncertainty about whether the behavioral changes observed in prior pre-clinical headache studies with these as well as other agents can be attributed entirely to the activation of dural nociceptors, particularly when the agents are applied at concentrations several orders of magnitude above physiological levels.
This study investigated postoperative hemostasis of patients subjected to conventional protamine dosing compared with protamine dosing based on a pharmacokinetic (PK) model following cardiopulmonary bypass.
Retrospective case-control study.
Tertiary university hospital.
Patients undergoing elective cardiac surgery with cardiopulmonary bypass.
In 56 patients, protamine was dosed in a fixed ratio (CD), while 62 patients received protamine based on the PK model.
There was no difference in heparin administration (414±107 mg (CD) v 403±90 mg (PK); p = 0.54), whereas protamine dosing was considerably different with a protamine-to-heparin dosing ratio of 1.1±0.3 for the CD group and 0.5±0.1 for the PK group (p<0.001). The changes in activated coagulation time (ΔACT) values (ACT after protamine minus preoperative ACT;+17±77 s v+6±15 s; p = 0.31) were equal between groups. Yet, the thromboelastometric intrinsically activated coagulation test clotting time (CT; 250±76 s v 203±44 s; p<0.001) and intrinsically activated coagulation test without the heparin effect CT (275±105 v 198±32 s; p<0.001) were prolonged in the CD group. Median packed red blood cell transfusion (0 [0-2] v 0 [0-0]), fresh frozen plasma transfusion (1 [0-2] v 0 [0-0]), and platelet concentrate transfusion (0 [0-1] v 0 [0-0]) were different between the fixed ratio and PK group, respectively (all p<0.001).
This study showed that patient-tailored protamine dosing based on a PK model was associated with a reduction in protamine dosing, with better hemostatic test results when compared with fixed-ratio protamine dosing.
Fibrous dysplasia (FD) is a rare bone disease caused by postzygotic somatic activating mutations in the GNAS gene, which lead to constitutive activation of adenylyl cyclase and elevated levels of cyclic AMP, which act on downstream signaling pathways and cause normal bone to be replaced with fibrous tissue and abnormal (woven) bone. The bone disease may occur in one bone (monostotic), multiple bones (polyostotic), or in combination with hyperfunctioning endocrinopathies and hyperpigmented skin lesions (in the setting of McCune-Albright Syndrome). FD is common in the craniofacial skeleton, causing significant dysmorphic features, bone pain, and dental anomalies. This review summarizes the pathophysiology, clinical findings, and treatment of FD, with an emphasis on the craniofacial and oral manifestations of the disease.
Inappropriate deposition of insoluble aggregates of proteins with abnormal structures is a hallmark of affected organs in protein aggregation disease. Very rare, affected organs avoid aggregation naturally. This concerns atrophic testis in Huntington disease (HD). We aimed to understand how HD testis avoids aggregation. Using HD model R6/1 mice, we demonstrate that affected testis contain rare organelles myelinosomes. Myelinosomes secreted from testis somatic TM4 Sertoli cells provide the release of aggregate-prone mutant, but not normal Huntingtin (Htt) exon1. Myelinosomes also support the release of other aggregate-prone mutant protein responsible for cystic fibrosis (CF), F508delCFTR. The traffic and discharge of myelinosomes is facilitated by multivesicular bodies (MVB)s. Inhibition of MVB excretion induced reversible retention of both misfolded proteins inside TM4 Sertoli cells. We propose that myelinosome-mediated elimination of mutant proteins is an unusual secretory process allowing Sertoli cells getting rid of misfolded proteins to avoid aggregation and to maintain cell proteostasis.
The effect of the aluminium ion (Al(3+)) on the scavenging reaction of a 2,2-diphenyl-1-picrylhydrazyl radical (DPPH˙), as a reactivity model of reactive oxygen species, with hydroquinone (QH2) and its methylated derivatives (MenQH2, n = 1-4) was investigated using stopped-flow and electrochemical techniques in a hydroalcoholic medium. The second-order rate constants (k) for the DPPH˙-scavenging reaction of the hydroquinones increased with the increasing number of methyl substituents. Upon addition of Al(3+), the k values significantly increased depending on the concentration of Al(3+). Such an accelerating effect of Al(3+) on the DPPH˙-scavenging rates of the hydroquinones results from the remarkable positive shift of the one-electron reduction potential (Ered) of DPPH˙ in the presence of Al(3+). These results demonstrate that Al(3+), a strong Lewis
 acid, can act as a radical-scavenging promoter by stabilising the one-electron reduced species of the radical, although Al(3+) is reported not only to act as a pro-oxidant but also to strongly interact with biomolecules, showing toxicities.
Our goal is to investigate flower foraging by capuchin monkeys, a behavior rarely studied in wild primates. We ask what drives seasonal variation in florivory rates: flower quality and abundance or fluctuations in fruit and invertebrate abundances. We explore how capuchins affect the reproductive success of flower food species by quantifying the potential pollination rate.
We followed capuchin groups from dawn to dusk and recorded all flower foraging bouts. Flower food nutritional composition was compared to fruit and invertebrate foods. We recorded overall flower, fruit, and invertebrate abundances and compared the rate of flower foraging to these. We estimated the likelihood of pollination from the proportion of flower patch visits to each plant species that satisfied minimum behavioral requirements.
Flower eating was highly seasonal, and was significantly negatively related to overall fruit and invertebrate abundance but not flower abundance. Although smaller than most fruits, flowers were nutritionally comparable to fruit foods by dry mass and contained higher average concentrations of protein. Capuchins are likely pollinators for Luehea speciosa; most foraging visits to this species occurred in a manner that makes outcrossing or geitonogamous pollination likely.
Flowers are an important seasonal resource for capuchins. Flowers likely act as fallback foods during periods of reduced fruit and invertebrate abundance, and may exert evolutionary pressure disproportionate to their consumption. Capuchin florivory likely affects the reproductive success of some plants, potentially shaping forest structure. Our study illustrates the value of assessing the importance of rare foods in the primate diet.
To describe the role of nurses in the management of symptoms related to spasticity in patients with multiple sclerosis (MS).
A descriptive study was developed based on a questionnaire on spasticity in MS patients. The questionnarie was completed through an anonymous tele-voting system at a national meeting with nurses involved in the management of these patients.
Apart from fatigue, according to the opinion of the participants, the spasticity symptom associated with MS most notified by patients was difficulty in walking, followed by spasms and pain. Participants thought that it is important that nursing takes: 1) a role in identifying these symptoms, 2) should focus on the detection of the triggering or aggravating factors, and 3) on providing support in the assessment of the level of spasticity. It is important to inform about the correct use of anti-spasticity drugs, how to adjust the dosage and side effects of treatments, including cannabinoids via an oromucosal spray, titrating its doses according to each patient, and monitoring its tolerability, efficacy and adherence. Although there are usually resources to follow up these patients, there are still important gaps, including the lack of a specific follow-up protocol.
Although all the participants are experts in the management of patients with MS, there is still diversity in the functions they perform, and the available resources they have in their hospitals. Nurses act as a key element in the process of identification of symptoms, training and monitoring of these patients with spasticity in EM.
The ability for magnetite to act as a recyclable electron donor and acceptor for Fe-metabolizing bacteria has recently been shown. However, it remains poorly understood whether microbe-mineral interfacial electron transfer processes are limited by the redox capacity of the magnetite surface or that of whole particles. Here we examine this issue for the phototrophic Fe(II)-oxidizing bacteria Rhodopseudomonas palustris TIE-1 and the Fe(III)-reducing bacteria Geobacter sulfurreducens, comparing magnetite nanoparticles (d ≈ 12 nm) against microparticles (d ≈ 100-200 nm). By integrating surface-sensitive and bulk-sensitive measurement techniques we observed a particle surface that was enriched in Fe(II) with respect to a more oxidized core. This enables microbial Fe(II) oxidation to occur relatively easily at the surface of the mineral suggesting that the electron transfer is dependent upon particle size. However, microbial Fe(III) reduction proceeds via conduction of electrons into the particle interior, i.e. it can be considered as more of a bulk electron transfer process that is independent of particle size. The finding has potential implications on the ability of magnetite to be used for long range electron transport in soils and sediments.
To describe the post-surgical imaging appearance and complications of high tibial osteotomy in patients with the iBalance implant system (iHTO; Arthrex, Naples, FL, USA).
Retrospective, institutional review board-approved, Health Insurance Portability and Accountability Act-compliant review of imaging after 24 iBalance procedures was performed with attention to: correction of varus malalignment, healing at the osteotomy site, resorption of the osteoinductive compound, and complications.
Immediate correction of the varus deformity was present in all cases. Lobular radiolucency was present in all cases, more pronounced on the lateral knee radiograph, simulating infection or erosive disease. Four radiographic signs of healing were observed: blurring at the opposing osteotomy bony margins and at the osteoinductive compound and the adjacent bone interface, callus formation, and resorption of the osteoinductive compound. Complications were present in 33 % of cases, including fracture through the lateral tibial cortex (21 %), genu varum recurrence (8 %), painful exuberant bone formation (4 %), persistent pain, requiring total knee arthroplasty (4 %), and non-union (after >6 months' follow-up), with suspected infection (4 %).
Radiologists should be aware of the normal radiographic appearance following iBalance high tibial osteotomy, which may be confused with infection. Radiologists should also be aware of potential post-operative complications and compare all post-operative radiographs with the immediate post-operative examination to detect collapse of the osteotomy site and recurrence of varus angulation.
Caffeine has both excitatory and vasoconstrictive effects on central nervous system. Caffeine use might be associated with development and chronification of migraine. We aimed to evaluate the effect of caffeine cessation on the acute treatment of migraine.
We prospectively recruited migraine patients who consumed caffeine drinks daily and instructed them to discontinue their caffeine intake. Triptans were prescribed for acute treatment. Patients were followed up after at least two weeks after screening and evaluated the efficacy of acute treatment with the migraine assessment of current therapy (Migraine-ACT) questionnaire. Excellent efficacy was defined as Migraine-ACT score of 4. Chronic migraine, body mass index, allodynia, depression, anxiety, antiemetic use, and use of prophylactic medication were included in the multivariate analysis if the univariate p < 0.2.
Among 108 patients included, 36 completely discontinued their caffeine intake (abstinence group). The efficacy of acute treatment was assessed at median 34.5 days (interquartile range, 28-89) after the screening. Twenty-six patients (72.2 %) in the abstinence group and 29 (40.3 %) in the non-abstinence group reported an excellent efficacy (p = 0.002). The abstinence group also showed a trend toward greater reduction of headache impact test-6 (HIT-6) scores (p = 0.085). Caffeine abstinence was independently associated with an excellent efficacy of acute treatment (multivariate odds ratio, 3.2; 95 % confidence interval, 1.2-8.4; p = 0.018) after controlling for covariates.
Caffeine abstinence is associated with better efficacy of acute migraine treatment. Our uncontrolled study results encourage a further confirmatory study on this issue.
The coordinated regulation of gene expression at the transcriptional level is fundamental to development and homeostasis. Inducible systems are invaluable when studying transcription because the regulatory process can be triggered instantaneously, allowing the tracking of ordered mechanistic events. Here, we use precision run-on sequencing (PRO-seq) to examine the genome-wide heat shock (HS) response in Drosophila and the function of two key transcription factors on the immediate transcription activation or repression of all genes regulated by HS. We identify the primary HS response genes and the rate-limiting steps in the transcription cycle that GAGA-associated factor (GAF) and HS factor (HSF) regulate. We demonstrate that GAF acts upstream of promoter-proximally paused RNA polymerase II (Pol II) formation (likely at the step of chromatin opening) and that GAF-facilitated Pol II pausing is critical for HS activation. In contrast, HSF is dispensable for establishing or maintaining Pol II pausing but is critical for the release of paused Pol II into the gene body at a subset of highly activated genes. Additionally, HSF has no detectable role in the rapid HS repression of thousands of genes.
The determination of death by neurological criteria remains controversial scientifically, culturally, and legally, worldwide. In the United Kingdom, although the determination of death by neurological criteria is not legally codified, the Code of Practice of the Academy of Medical Royal Colleges is customarily used for neurological (brainstem) death determination and treatment withdrawal. Unlike some states in the US, however, there are no provisions under the law requiring accommodation of and respect for residents' religious
 rights and commitments when secular conceptions of death based on medical codes and practices conflict with a traditional concept well-grounded in religious and cultural values and practices. In this article, we analyse the medical, ethical, and legal issues that were generated by the recent judgement of the High Court of England and Wales in Re: A (A Child) [2015] EWHC 443 (Fam). Mechanical ventilation was withdrawn in this case despite parental religious objection to a determination of death based on the code of practice. We outline contemporary evidence that has refuted the reliability of tests of brainstem function to ascertain the two conjunctive clinical criteria for the determination of death that are stipulated in the code of practice: irreversible loss of capacity for consciousness and somatic integration of bodily biological functions. We argue that: (1) the tests of brainstem function were not properly undertaken in this case; (2) the two conjunctive clinical criteria set forth in the code of practice cannot be reliably confirmed by these tests in any event; and (3) absent authentication of the clinical criteria of death, the code of practice (in fact, although implicitly rather than explicitly) wrongly invokes a secular definition of death based on the loss of personhood. Consequently, the moral obligation of a pluralistic society to honor and respect diverse religious convictions to the greatest extent possible is being violated. Re A (A Child) is contrasted with the US case of Jahi McMath in which the court accommodated parental religious objection to the determination of neurological death codified in the Uniform Determination of Death Act. We conclude that the legal system in the United Kingdom should not favour a secular definition of death over a definition of death that is respectful of religious values about the inviolability and sanctity of life. We recommend the legal recognition of religious accommodation in death determination to facilitate cultural sensitivity and compassionate care to patients and families in a pluralistic society.
To discuss the role of substance-related and addictive disorders (SRAD) that lead patients with attention-deficit hyperactivity disorder (ADHD) to suicide and homicide. <p> Method: Relevant articles were searched via PubMed using several keywords related to this issue. Most of the articles included in this review were published after 2000. <p> Results: Patients with ADHD often fall into crises of catastrophic life events such as suicide or homicide. SRAD play an important role in leading ADHD patients to such events. Because ADHD is characterized by inattentiveness and impulsivity, any kinds of substances, legal or illegal, can deteriorate ADHD symptoms, leading ADHD patients to such catastrophic events. There are several pathways that connect ADHD with SRAD, which are roughly divided into two ways: internalizing mental disorders and externalizing mental disorders. The former includes depression and anxiety disorders characterized by self-inhibition or withdrawal. The latter typically includes conduct disorder or oppositional defiant disorder, as well as antisocial personality disorder, characterized by aggressive or antisocial behaviors or emotions towards others. These comorbid psychiatric disorders are apt to lead ADHD patients to SRAD, and once these patients suffer from SRAD, risk of catastrophic life events seems to increase due to the irreversibility of their adverse mentality. Comorbid mental disorders with ADHD can act, at least partially, as mediators from ADHD to SRAD. <p> Conclusion: SRAD can be a critical risk factor of suicide and homicide among patients with ADHD. Early interventions for families with ADHD and psychiatric comorbidities may work as effective preventive strategies against such events.
Given the large availability of nicotinic acetylcholine receptors (nAChRs) throughout the brain, and the wide range of neurotransmitter systems affected (norepinephrine, serotonin and dopamine), nicotine influences a wide variety of cognitive domains such as sensorial, motor, attentional, executive function, learning and memory. This article reviews current state of the art research on the effects of nicotine upon cognition. There are different neurobiological mechanisms involved in acute/chronic smoking and nicotine abstinence. Smoking reinforcement could be due to the initial cognitive improvement, that is, individuals can learn that smoking temporarily increases cognitive functioning (improving some components of attention and memory). These acute nicotine effects improve (i) cognitive performance above smokers' normal levels, and (ii) cognitive disruption resulting from nicotine abstinence. Both neurobiological effects act as reinforcers to nicotine use, greatly contributing to the development of nicotine dependence. However, heavy smoking is associated with cognitive impairment and cognitive decline in middle age. Future clinical research should investigate the role of positive and negative cognitive effects of nicotine in smoking cessation treatment. This is clearly an important scientific issue, with insufficient current data from which to draw definitive conclusions.
In addition to primary and secondary special care, a special type of care was created in the 2015 German Health Care Strengthening Act [GKV-Versorgungsstärkungsgesetz]: medical care centres for adult people with mental and multiple disabilities (MCAMD). This closed a gap in the German healthcare system and part of Article 25 of the UN Convention on the Rights of Persons with Disabilities was implemented.
Experiences from pilot projects are useful while implementing these centres. The issue is therefore: which are the supporting (s) and inhibiting (i) factors when establishing MCAMDs in the view of health care providers?
Based on open guided expert interviews medical directors and initiators of existing and planned centres were interviewed. Data analysis was done by qualitative content analysis.
Healthcare providers think reducing barriers in people's minds is most important. In the course of approval procedures, reservations from different actors and institutions were considered (i). During financial negotiations, health insurance companies requested a characterisation of the target group using the ICD-lists, which doesn't comply with the needs of the users (i). Implementation was only possible with a great effort from the initiators paired with willingness from actors of the association of statutory health insurance physicians and the health insurances (s).
This paper describes the process used to implement MCAMDs. Potential centre providers can be inspired by these results. Further research on the process of implementation of these medical centres is needed, especially taking into account all involved parties.
The new Federal Government's Report on Participation explores the contexts in which impairments become disabilities for those individuals who experience them. In parallel, it outlines the factors that foster inclusion and opportunities to act for everyone in society - despite existing impairments.From a sociopolitical and health policy perspective, disability refers to unequal opportunities based on impairment. Hence, the focus here is on the equalisation of these participation opportunities to match those of the entire population - but always from differentiated perspectives on the various social arenas. The human rights approach stresses protection against discrimination as well as dignity and self-determination for all. From a human resources angle, the emphasis is on the performance of individuals in favourable conditions and the attainment of personal goals within their actual everyday circumstances.The new reporting concept is indebted to these perspectives and thus focuses on individual life circumstances, while referring to the WHO's International Classification of Functioning, Disability and Health (ICF) - an approach now validated on a global scale. Therefore, it does not only report on measures provided by services for persons with disabilities but, more crucially, investigates determinants on the personal and environmental levels, unequal opportunities and the interdependency between context and competence for particular sections of the population. Two groups are singled out in the process: elderly persons and individuals with mental health impairments.The participation report is part of the National Action Plan to implement the UN Convention on the Rights of Persons with Disabilities (UNCRPD). An independent scientific committee conceptualises the design of the report while accompanying and commenting upon its realisation. Currently, a second federal report on participation is emerging from the new concept.
A role for Hedgehog (Hh) signalling in the development of colorectal cancer (CRC) has been proposed. In CRC and other solid tumours, Hh ligands are upregulated; however, a specific Hh antagonist provided no benefit in a clinical trial. Here we use Hh reporter mice to show that downstream Hh activity is unexpectedly diminished in a mouse model of colitis-associated colon cancer, and that downstream Hh signalling is restricted to the stroma. Functionally, stroma-specific Hh activation in mice markedly reduces the tumour load and blocks progression of advanced neoplasms, partly via the modulation of BMP signalling and restriction of the colonic stem cell signature. By contrast, attenuated Hh signalling accelerates colonic tumourigenesis. In human CRC, downstream Hh activity is similarly reduced and canonical Hh signalling remains predominantly paracrine. Our results suggest that diminished downstream Hh signalling enhances CRC development, and that stromal Hh activation can act as a colonic tumour suppressor.
Thrombospondin 1 (TSP-1) is abundantly expressed
 in visceral adipose tissue and this expression is up-regulated in obese humans and rodents. Recent studies showed that genetic deletion of TSP-1 protects mice from diet-induced insulin resistance. However, the molecular mechanism is largely unknown. In this study, we examined the effect of recombinant TSP-1 on insulin signaling in cultured cells from insulin sensitive tissues to investigate whether TSP-1 could act as an adipokine. Here we show that treatment with recombinant TSP-1 suppressed insulin signaling in cultured muscle cells, which was accompanied by the activation of stress signaling such as JNK, p38, and IKK. These results suggest that TSP-1 acts as an adipokine which is involved in the pathogenesis of obesity-induced insulin resistance. Thus, TSP-1 could be a potential target for the treatment of insulin resistance and metabolic disease related to insulin resistance.
Optical colonoscopy is a prominent procedure by which clinicians examine the surface of the colon for cancerous polyps using a flexible colonoscope. One of the main concerns regarding the quality of the colonoscopy is to ensure that the whole colonic surface has been inspected for abnormalities. In this paper, we aim at estimating areas that have not been covered thoroughly by providing a map from the internal colon surface.
Camera parameters were estimated using optical flow between consecutive colonoscopy frames. A cylinder model was fitted to the colon structure using 3D pseudo stereo vision and projected into each frame. A circumferential band from the cylinder was extracted to unroll the internal colon surface (band image). By registering these band images, drift in estimating camera motion could be reduced, and a visibility map of the colon surface could be generated, revealing uncovered areas by the colonoscope. Hidden areas behind haustral folds were ignored in this study. The method was validated on simulated and actual colonoscopy videos. The realistic simulated videos were generated using a colonoscopy simulator with known ground truth, and the actual colonoscopy videos were manually assessed by a clinical expert.
The proposed method obtained a sensitivity and precision of 98 and 96 % for detecting the number of uncovered areas on simulated data, whereas validation on real videos showed a sensitivity and precision of 96 and 78 %, respectively. Error in camera motion drift could be reduced by almost 50 % using results from band image registration.
Using a simple cylindrical model for the colon and reducing drift by registering band images allows for the generation of visibility maps. The current results also suggest that the provided feedback through the visibility map could enhance clinicians' awareness of uncovered areas, which in return could reduce the probability of missing polyps.
We study experimentally a fine structure of the optical Laue diffraction from two-dimensional periodic photonic lattices. The periodic photonic lattices with the C4v square symmetry, orthogonal C2v symmetry, and hexagonal C6v symmetry are composed of submicron dielectric elements fabricated by the direct laser writing technique. We observe surprisingly strong optical diffraction from a finite number of elements that provides an excellent tool to determine not only the symmetry but also exact number of particles in the finite-length structure and the sample shape. Using different samples with orthogonal C2v symmetry and varying the lattice spacing, we observe experimentally a transition between the regime of multi-order diffraction, being typical for photonic crystals to the regime where only the zero-order diffraction can be observed, being is a clear fingerprint of dielectric metasurfaces characterized by effective parameters.
Growth-regulating factor (GRF) is an important protein in GA-mediated response, with key roles in plant growth and development. However, it is not known whether or how the GRF proteins in citrus to regulate organ size. In this study, nine citrus GRF genes (CsGRF1-9) were validated from the 'Anliu' sweet orange (AL, Citrus sinensis cv. Anliu) by PCR amplification. They all contain two conserved motifs (QLQ and WRC) and have 3-4 exons. The transcript levels of genes were detected by qRT-PCR. Transcript analysis showed that (1) CsGRF 1, 2, 5, 6, 7, and 9 expressed predominantly in young leaf, CsGRF 3 and 4 expressed predominantly in fruit immature juice sacs and CsGRF 8 expressed predominantly in root; (2) all citrus GRF genes had significantly higher expression in young leaves than mature leaf; (3) in juice sacs, the transcript levels of CsGRF1, 4, 5, 6, and 8 increased significantly while the transcript levels of CsGRF2, 3, 7, and 9 had no significant change from 80 DAF to 100 DAF. Besides, GA3 treatment did not affect the transcript levels of CsGRF5 and CsGRF6 but significantly increased the transcript levels of the other seven CsGRF genes in young leaves. These results suggested that all CsGRF genes involve in the leaf development, CsGRF1, 4, 5, 6, and 8 act developmentally whilst CsGRF2, 3, 7, and 9 play fundamental roles in fruit cell enlargement, which may be through GA pathway or GA-independent pathway.
Sialic acids (Sias) are abundantly displayed on the surfaces of vertebrate cells, and particularly on all mucosal surfaces. Sias interact with microbes of many types, and are the targets of specific recognition by many different viruses. They may mediate virus binding and infection of cells, or alternatively can act as decoy receptors that bind virions and block virus infection. These nine-carbon backbone monosaccharides naturally occur in many different modified forms, and are attached to underlying glycans through varied linkages, creating significant diversity in the pathogen receptor forms. Here we review the current knowledge regarding the distribution of modified Sias in different vertebrate hosts, tissues, and cells, their effects on viral pathogens where those have been examined, and outline unresolved questions.
Peat cores were collected from a Sphagnum-dominated Selisoo bog, which is located about 40 km from the large oil shale-fired power plants (PPs) in Estonia. These PPs have been operational from the 1960's and had the largest negative impact on the surrounding environment during the 1970's and 1980's. Nearby ombrotrophic peatlands are good indicators of atmospheric pollution due to their properties of effectively adsorbing mineral matter and pollutants. Collected peat cores (S1 and S2) from Selisoo peat bog were sliced into 1 cm thick layers and measured gamma spectrometrically. In addition, spherical fly ash particles (SFAP) originating from the combustion of the PPs were counted. The maximum concentrations (particles per cm(3)) of the SFAP remained between 7 and 12 cm for core S1 and between 11 and 17 cm for core S2. The concentration profiles of the SFAP reflect the combustion and emission history of the PPs. Pb-210 activity concentrations have the maximum values up to 500 Bq kg(-1) and 413 Bq m(-2) for S1 and for the S2 the values are 441 Bq kg(-1) and 535 Bq m(-2) (dry weight). The unsupported (210)Pb inventory is around 4250 Bq m(-2). This represents a (210)Pb deposition flux of 133 Bq m(-2) y(-1). The estimated (210)Pb deposition via fly ash from the PPs at Selisoo area remains between 0.2 and 2.2 Bq m(-2) y(-1). Considering the annual (210)Pb deposition from the atmosphere (with a precipitation rate of 600 mm y(-1)) between 92 and 133 Bq m(-2), which is regarded as the natural background value, we show that the radiological burden due to the power plants at these distances is negligible. As the peat cores exhibit noticeable differences from each other (in terms of radionuclide concentration distribution), the SFAP can provide a good additional parameter to improve the validity of results obtained only from radiometric methods in the chronological studies. SFAP can also act as a possible tool to estimate the radionuclide deposition rate via fly ash in the vicinity of the PPs.
There are three main reasons for transferring from an existing bioanalytical assay to an alternative chromatographic method: speed, cost and sensitivity. These represent a challenge to the analyst in that there is an interplay between these three considerations and one factor is often improved at the expense of another. These three factors act as drivers to encourage technology development and support its uptake. The more recently introduced chromatographic technologies may show significant improvements against one of more of these factors relative to conventional 4.6-mm id reversed-phase HPLC. In this article, some of these new chromatographic approaches will be considered in terms of what they can offer the bioanalysts.
As one of the predominant protein families within the extracellular matrix both structurally and functionally, laminins have been shown to be heavily involved in tumor progression and drug resistance. Laminins participate in key cellular events for tumor angiogenesis, cell invasion and metastasis development, including the regulation of epithelial-mesenchymal transition and basement membrane remodeling, which are tightly associated with the phenotypic characteristics of stem-like cells, particularly in the context of cancer. In addition, a great deal of studies and reports has highlighted the critical roles of laminins in modulating stem cell phenotype and differentiation, as part of the stem cell niche. Stemming from these discoveries a growing body of literature suggests that laminins may act as regulators of cancer stem cells, a tumor cell subpopulation that plays an instrumental role in long-term cancer maintenance, metastasis development and therapeutic resistance. The accumulating evidence in this emerging research area suggests that laminins represent potential therapeutic targets for anti-cancer treatments
 against cancer stem cells, and that they may be used as predictive and prognostic markers to inform clinical management and improve patient survival.
Exposure to parasites in conservation translocations increases the risks to recipient and translocated populations from disease, and therefore there has been interest in implementing biosecurity methods. Using four case examples we described how biosecurity was applied in practical translocation scenarios prior to and during a translocation and also post-release. We implemented biosecurity, including quarantine barriers, at specific points in the translocation pathway where hazards, identified by the disease risk analysis, had the potential to induce disease. Evidence that biosecurity protected translocated and recipient populations, included an absence of mortality associated with high-risk non-native parasites, a reduction in mortality associated with endemic parasites, the absence of high-risk pathogenic parasites, or associated diseases, at the destination; and the apparent absence of diseases in closely related species at the destination site. The biosecurity protocols did not alter the level or duration of translocated species confinement and therefore probably did not act as a stressor. There is a monetary cost involved in biosecurity but the epidemiological evidence suggests that conservation translocation managers should carefully consider its use. Breakdowns in quarantine have occurred in human hospitals despite considerable investment and training for health professionals, and we therefore judge that there is a need for training in the objectives and maintenance of quarantine barriers in conservation translocations. Biosecurity protocols for conservation translocations should be continually updated in response to findings from disease risk analysis and post-release disease surveillance and we recommend further studies to evaluate their effectiveness.
It is rarely the case that a single electron affects the behaviour of several hundred thousands of atoms. Here we demonstrate a phenomenon where this happens. The key role is played by topological insulators-materials that have surface states protected by time-reversal symmetry. Such states are delocalized over the surface and are immune to its imperfections in contrast to ordinary insulators. For topological insulators, the effects of these surface states will be more strongly pronounced in the case of nanoparticles. Here we show that under the influence of light a single electron in a topologically protected surface state creates a surface charge density similar to a plasmon in a metallic nanoparticle. Such an electron can act as a screening layer, which suppresses absorption inside the particle. In addition, it can couple phonons and light, giving rise to a previously unreported topological particle polariton mode. These effects may be useful in the areas of plasmonics, cavity electrodynamics and quantum information.
HIV-1-infected macrophages are long-lived and act as human immunodeficiency virus 1 (HIV-1) virus reservoirs. Lipopolysaccharide (LPS) has been demonstrated to suppress HIV-1 replication in macrophages, but the mechanism is not clear. Previous research suggested that downregulation of CD4 and CCR5 as well as blockage of the interaction of HIV-1 with cells are major causes of inhibition of HIV-1 replication in macrophages by LPS. In order to study whether LPS blocks the post-entry event of HIV-1 replication, we developed a macrophage HIV-1 infection model by using VSV-G pseudotyped HIV-1-luciferase virus to infect THP-1 differentiated macrophage-like cells. We found that LPS can suppress HIV-1 replication at post-entry steps. Further study suggested that HIV-1 reverse transcription was blocked by LPS, but addition of exogenous deoxyribonucleosides led to only partial recovery of HIV-1 replication. However, the inhibition of pro-inflammatory pathway completely rescued HIV-1 replication. Thus, our study shows that LPS can suppress the events of HIV-1 replication post-entry, including reverse transcription, and this restriction is mediated by more than one mechanism.
The S6 Kinase (S6K) proteins are some of the main downstream effectors of the mammalian Target Of Rapamycin (mTOR) and act as key regulators of protein synthesis and cell growth. S6K is overexpressed in a variety of human tumors and is correlated to poor prognosis in prostate cancer. Due to the current urgency to identify factors involved in prostate cancer progression, we aimed to reveal the cellular functions of three S6K isoforms-p70-S6K1, p85-S6K1 and p54-S6K2-in prostate cancer, as well as their potential as therapeutic targets.
In this study we performed S6K knockdown and overexpression and investigated its role in prostate cancer cell proliferation, colony formation, viability, migration and resistance to docetaxel treatment. In addition, we measured tumor growth in Nude mice injected with PC3 cells overexpressing S6K isoforms and tested the efficacy of a new available S6K1 inhibitor in vitro.
S6Ks overexpression enhanced PC3-luc cell line viability, migration, resistance to docetaxel and tumor formation in Nude mice. Only S6K2 knockdown rendered prostate cancer cells more sensitive to docetaxel. S6K1 inhibitor PF-4708671 was particularly effective for reducing migration and proliferation of PC3 cell line.
These findings demonstrate that S6Ks play an important role in prostate cancer progression, enhancing cell viability, migration and chemotherapy resistance, and place both S6K1 and S6K2 as a potential targets in advanced prostate cancer. We also provide evidence that S6K1 inhibitor PF-4708671 may be considered as a potential drug for prostate cancer treatment.
The present article deals with the Italian Electronic Health Record (hereinafter EHR), recently introduced by Act 221/2012, with a specific focus on personal data protection. Privacy issues--e.g., informed consent, data processing, patients' rights and minors' will--are discussed within the framework of recent e-Health legislation, national Data Protection Code, the related Data Protection Authority pronouncements and EU law. The paper is aimed at discussing the problems arising from a complex, fragmentary and sometimes uncertain legal framework on e-Health.
Team conflict can add value or destroy it. Good conflict fosters respectful debate and yields mutually agreed-upon solutions that are often far superior to those first offered. Bad conflict occurs when team members simply can't get past their differences, killing productivity and stifling innovation. Destructive conflict typically stems not from differences of opinion but from a perceived incompatibility between the way certain team members think and act. The conventional approach to working through such conflict is to respond to clashes as they arise. But this approach routinely fails because it allows frustrations to build for too long, making it difficult to reset negative impressions and restore trust. In their research on team dynamics and experience working with executive teams, Toegel and Barsoux have found a proactive approach to be much more effective. In this article, they introduce a methodology that focuses on how people look, act, speak, think, and feel. Team leaders facilitate five conversations--one focused on each category--before the team gets under way, to build a shared understanding of the process, rather than the content, of work and lay the foundation for effective collaboration.
Most leaders don't have the luxury of building their teams from scratch. Instead they're put in charge of an existing group, and they need guidance on the best way to take over and improve performance. Watkins, an expert on transitions, suggests a three-step approach: Assess. Act quickly to size up the personnel you've inherited, systematically gathering data from one-on-one chats, team meetings, and other sources. Reflect, too, on the business challenges you face, the kinds of people you want in various roles, and the degree to which they need to collaborate. Reshape. Adjust the makeup of the team by moving people to new positions, shifting their responsibilities, or replacing them. Make sure that everyone is aligned on goals and how to achieve them--you may need to change the team's stated direction. Consider also making changes in the way the team operates (reducing the frequency of meetings, for example, or creating new subteams). Then establish ground rules and processes to sustain desired behaviors, and revisit those periodically. Accelerate team development. Set your people up for some early wins. Initial successes will boost everyone's confidence and reinforce the value of your new operating model, thus paving the way for ongoing growth.
The article series provides a written and pictorial account of the Danish pharmaceutical industry's products from their introduction until about 1950. Part 8 deals with products from Lundbeck. Lundbeck which today is known as a considerable international pharmaceutical company could in 2015 celebrate its 100 years' jubilee. Among the early Danish medicinal companies H. Lundbeck & Co. is in many ways an exception as the company was not originally established as a pharmaceutical company. Not until several years after the foundation the company began to import foreign ready-made medicinal products and later-on to manufacture these medicinal products in own factory and even later to do research and development of own innovative products. When Lundbeck was established in 1915 several Danish medicinal companies, not only the well-known such as Alfred Benzon and Løvens kemiske Fabrik (LEO Pharma), but also Skelskør Frugtplantage, Ferrin and Ferraton, had emerged due to the respective enterprising pharmacy owners who had expanded their traditional pharmacy business and even with commercial
 success. Other medicinal companies, such as C.R. Evers & Co., Leerbeck & Holms kemiske Fabriker, Chr. F. Petri, Erslevs kemiske Laboratorium, Edward Jacobsen, Th. Fallesen-Schmidt, and yet other companies which were named after the founder had all been established by pharmacists with the primary intention to manufacture and sell medicinal products. Also for the limited companies Medicinalco, Ferrosan, Pharmacia, and GEA the primary task was to manufacture and sell medicinal products, and also in these companies pharmacists were involved in the foundation. Not until 1924, fully 9 years after the foundation, Lundbeck started to be interested in medicinal products and initiated import and sale of foreign medicinal products manufactured by a.o. German and French companies which had not established their own sales companies in Denmark. Almost all contemporary Danish manufacturers of medicinal products could exclusively determine own proprietary names of the articles and could themselves make their own homogeneous and easily recognisable design, a.o. by frequent use of prefixes as Afa, Asa, Gea, Ido, Leo, and Meco which associated to for instance the company name. However, it goes without saying that Lundbeck had to market the articles in commission according to the different contracts with their partners. Consequently their range of products appeared heterogeneously. The international financial crisis and the consequent unemployment in the 1920s and 1930s had in Denmark a.o. resulted in national regulation in order to complicate import of ready-made goods and thus support the domestic manufacture of such articles. This was one of the reasons why Lundbeck decided to initiate its own manufacture of medicinal products in Denmark instead of continuing only with the import business which had been obstructed by the authorities. This article does not mention all Lundbeck's medicinal products which were marketed in Denmark until 1955 where a new Pharmacy Act came into force though undoubtedly a lot of interest can be written about all of them. The products mentioned in this article have been carefully selected, not only because they are representative for Lundbeck's development during the first decades, but also because the Danish Collection of the History of Pharmacy has acquired consumer packages of many of the articles. Several of these packages include patient information leaflets with an instruction for use and/or other information, and especially these leaflets represent a source material which has not previously been given much attention. It does not appear from the available source material whether these earliest medicinal products from Lundbeck were assembled in Danish packages on the production sites, or whether they were repacked in Copenhagen. It is not unlikely that the assembling originally was finalized abroad, and that instructions for the production of packaging material with Danish text were supplied by Lundbeck to the respective manufacturers. However, it is not unlikely either that the currency restrictions which were made after 1932 encouraged Lundbeck, where possible, first of all to import raw materials and bulk products and then manufacture the finished products in Valby. This was the case with Anusol, which Lundbeck certainly emphazised in the advertisement. It has to be pointed out that at that time there were no legal requirements regarding dating, neither of the user instructions nor of advertisements. Thus it is not due to mistakes or omissions made by Lundbeck that these materials are undated. The user instructions which Lundbeck had inserted in the packages were made and distributed at a time where no legal restrictions were in force neither regarding form nor content of such. The user instructions for products marketed after 1932 had probably been presented to the Pharmacopoeia Commission as this was statutory. It is, however, uncertain whether the Commission has dealt with the contents and the look of the user instructions. The most important task of the Commission was besides of the work with maintaining the Pharmacopoeia to look after the economic interests of the pharmacies so that only new drug substances could be marketed by the pharmaceutical industry, cf. below. In order to find out whether, and if so to which extent, the Pharmacopoeia Commission has been occupied in evaluating the informative and promoting printed matters of the industry, would require studies of the unprinted files of the Commission, and that is outside the scope of this article. At that time it was not against the law to inform in a user instruction that in case of a longer period of treatment, it would be more economical for the patient to buy a larger package. If you look at these patient information leaflets with today's eyes in the light of the present detailed, comprehensive and rigid regulations which the EU Commission has stated regarding patient information leaflets, you will find that Lundbeck's patient information leaflets were both simple and easy to read. On a free sample of Gelonida meant for the prescribing physician Lundbeck stated, besides of indication, dosage and warnings, also that the article was "Manufactured in Denmark". At that time it was not required to print information of production sites on packaging materials, however, it was not unusual to use this sales promoting claim in times of unemployment. In 1949 the original packaging material for Beatin was modified because certain text elements, the therapeutic indications were removed as it appeared that they since 1933 had violated the Pharmacy Act against advertisements for medicinal products aimed at the public. The packaging material for Beatin is a model example of the possibilities to combine practical information about the use of a medicinal product with sales claims in a reliable way. The above text modification and thus the legalisation of the packaging material took place upon request from the company as the violation of the advertising rules of the Pharmacy Act apparently had not resulted in any legal problems. Studies of unpublished files from the National Board of Health may possibly explain the background of this sequence of events, however, that is outside the scope of this article. The paragraph of the Pharmacy Act of 1932, stating that a medicinal product containing a common commodity as the active ingredient could not be marketed as a proprietary medicinal product, was meant to protect the pharmacies against the increasing competition from the industry. At first the paragraph did put a strain on the industry which from then on either had to manufacture own originator products or to copy other originator products without breaking patents. In the long run it has probably caused that not only Lundbeck, but also other Danish pharmaceutical companies became research-oriented and thus have been able to develop a relatively large number of originator products. In this context a product like Lucamid can hardly be regarded as an example of such a compulsory development of an originator product, an acetylsalicylic acid analogue. There were already such products on the market, but the wish to develop a better active ingredient has probably been bigger. From the three first editions of The Tariff of Medicines from 1935, 1937 and 1939 respectively it appears how Lundbeck's business within the area of medicines developed during the last half of the 1930s. In 1935 Lundbeck had placed 36 different medicinal products on the market, and all of them were in-licensing products. 4 years later, in 1939 Lundbeck had placed 40 different medicinal products on the market, and the number of in-licensing products had been reduced to 18 and 22 products were Lundbeck products. However, the increased focus on the development of own new medicinal products as Epicutan and Klianyl did not stop the in-licensing activities. Varex which Lundbeck brought on the market in 1942 came from a German pharmaceutical company with which Lundbeck had not previously collaborated. In Denmark Lundbeck had the intention to market 4 of Goedecke's 6 different medicinal products which all had Gelonida as part of the proprietary name. However, only one of these products got a longer life and with a simplified name, namely Gelonida. The fixed combination with three compounds of acetylsalicylic acid, phenacetin and codeine was without doubt effective, however, already at the end of the 1950s concern was raised about the safety of phenacetin. The Card Index of Medicines is a primary source of knowledge of how Lundbeck marketed the earliest medicinal products to the prescribing physicians. (ABSTRACT TRUNCATED)
The mediator complex-associated cyclin dependent kinase CDK8 regulates β-catenin-dependent transcription following activation of WNT signaling. Multiple lines of evidence suggest CDK8 may act as an oncogene in the development of colorectal cancer. Here we describe the successful optimization of an imidazo-thiadiazole series of CDK8 inhibitors that was identified in a high-throughput screening campaign and further progressed by structure-based design. In several optimization cycles, we improved the microsomal stability, potency, and kinase selectivity. The initial imidazo-thiadiazole scaffold was replaced by a 3-methyl-1H-pyrazolo[3,4-b]-pyridine which resulted in compound 25 (MSC2530818) that displayed excellent kinase selectivity, biochemical and cellular potency, microsomal stability, and is orally bioavailable. Furthermore, we demonstrated modulation of phospho-STAT1, a pharmacodynamic biomarker of CDK8 activity, and tumor growth inhibition in an APC mutant SW620 human colorectal carcinoma xenograft model after oral administration. Compound 25 demonstrated suitable potency and selectivity to progress into preclinical in vivo efficacy and safety studies.
Gorgonian species show
 a high morphological variability in relation to the environment in which they live. In coastal areas, parameters such as temperature, light, currents, and food availability vary significantly with depth, potentially affecting morphology of the colonies and the structure of the populations, as well as their connectivity patterns. In tropical seas, the existence of connectivity between shallow and deep populations supported the hypothesis that the deep coral reefs could potentially act as (reproductive) refugia fostering re-colonization of shallow areas after mortality events. Moreover, this hypothesis is not so clear accepted in temperate seas. Eunicella singularis is one of the most common gorgonian species in Northwestern Mediterranean Sea, playing an important role as ecosystem engineer by providing biomass and complexity to the coralligenous habitats. It has a wide bathymetric distribution ranging from about 10 m to 100 m. Two depth-related morphotypes have been identified, differing in colony morphology, sclerite size and shape, and occurrence of symbiotic algae, but not in mitochondrial DNA haplotypes. In the present study the genetic structure of E. singularis populations along a horizontal and bathymetric gradient was assessed using microsatellites and ITS1 sequences. Restricted gene flow was found at 30-40 m depth between the two Eunicella morphotypes. Conversely, no genetic structuring has been found among shallow water populations within a spatial scale of ten kilometers. The break in gene flow between shallow and deep populations contributes to explain the morphological variability observed at different depths. Moreover, the limited vertical connectivity hinted that the refugia hypothesis does not apply to E. singularis. Re-colonization of shallow water populations, occasionally affected by mass mortality events, should then be mainly fueled by larvae from other shallow water populations.
Children often require transfer to pediatric hospital emergency departments (EDs) after evaluation in community hospital EDs. Such transfers are regulated by the federal Emergency Medical Treatment and Labor Act. Unusual circumstances, such as logistical errors in the physical transfer of the patient, may increase Emergency Medical Treatment and Labor Act-related liability risks for hospitals and ED physicians.
Fructans obtained from agave, called agavins, have recently shown significant benefits for human health including obesity. Therefore, we evaluated the potential of agavins as neuroprotectors and antioxidants by determining their effect on brain-derived neurotrophic factor (BDNF) and glial-derived neurotrophic factor (GDNF) as well as oxidative brain damage in of obese mice.
Male C57BL/6J mice were fed a high-fat diet (HFD) and treated daily with 5% (HFD/A5) or 10% (HFD/A10) of agavins or a standard diet (SD) for 10 weeks. The levels of BDNF and GDNF were evaluated by ELISA. The oxidative stress was evaluated by lipid peroxidation (TBARS) and carbonyls. SCFAs were also measured with GC-FID. Differences between groups were assessed using ANOVA and by Tukey's test considering p < 0.05.
The body weight gain and food intake of mice HFD/A10 group were significantly lower than those in the HFD group. Agavins restored BDNF levels in HFD/A5 group and GDNF levels of HFD/A5 and HFD/A10 groups in cerebellum. Interestingly, agavins decreased TBARS levels in HFD/A5 and HFD/A10 groups in the hippocampus, frontal cortex and cerebellum. Carbonyl levels were also lower in HFD/A5 and HFD/A10 for only the hippocampus and cerebellum. It was also found that agavins enhanced SCFAs production in feces.
Agavins may act as bioactive ingredients with antioxidant and protective roles in the brain.
Asthma in the elderly is severe and associated with poor treatment outcome. Although atopy has an important role in pathogenesis, its role in the elderly is unclear, partly due to immune senescence.
We aimed to examine the associations of Th2-mediated inflammation with asthma severity in the elderly.
Consecutive asthmatics older than 60 years without severe exacerbation within 8 weeks were enrolled. Atopic status was determined by positive serum specific IgE or skin prick test to common aeroallergens. Serum total IgE was measured simultaneously to exhaled fractional concentration of nitric oxide (FeNO). Asthma control level was assessed by using Thai Asthma Control Test (ACT) score.
Total of 44 elderly asthmatic patients were enrolled. The mean age was 68.9 years and mean age of asthma diagnosis was 46.6 years. Seventy-seven percent of patients were female. Atopic status was found in 45.5% of patients. Uncontrolled asthma classified as ACT score < 20 was noted in 25% of elderly asthma, but its association with either high serum total IgE (≥120 IU/mL), high FeNO (≥50 ppb) or atopic status was not detected.
One-fourth of elderly asthmatics were clinically uncontrolled, while atopy was confirmed in 45.5%. Neither high total IgE, high FeNO nor atopic status was associated with uncontrolled asthma in the elderly. Other factors might play role in asthma severity in the elderly, and has to be further investigated.
Standards have a significant role in showing the minimum level of optimal optimum and the expected performance. Since the perfusion technology staffs play an the leading role in providing the quality services to the patients undergoing open heart surgery with cardiopulmonary bypass machine, this study aimed to assess the standards on how Iranian perfusion technology staffs evaluate and manage the patients during the cardiopulmonary bypass process and compare their practice with the recommended standards by American Society of Extracorporeal Technology.
In this descriptive study, data was collected from 48 Iranian public hospitals and educational health centers through a researcher-created questionnaire. The data collection questionnaire assessed the standards which are recommended by American Society of Extracorporeal Technology.
Findings showed that appropriate measurements were carried out by the perfusion technology staffs to prevent the hemodilution and avoid the blood transfusion and unnecessary blood products, determine the initial dose of heparin based on one of the proposed methods, monitor the anticoagulants based on ACT measurement, and determine the additional doses of heparin during the cardiopulmonary bypass based on ACT or protamine titration. It was done only in 4.2% of hospitals and health centers.
Current practices of cardiopulmonary perfusion technology in Iran are inappropriate based on the standards of American Society of Cardiovascular Perfusion. This represents the necessity of authorities' attention to the validation programs and development of the caring standards on one hand and continuous assessment of using these standards on the other hand.
Platelets are essential for physiological hemostasis and are central in pathological thrombosis. These are their traditional and best known activities in health and disease. In addition, however, platelets have specializations that broaden their functional repertoire considerably. These functional capabilities, some of which are recently discovered, include the ability to sense and respond to infectious and immune signals and to act as inflammatory effector cells. Human platelets and platelets from mice and other experimental animals can link the innate and adaptive limbs of the immune system and act across the immune continuum, often also linking immune and hemostatic functions. Traditional and newly recognized facets of the biology of platelets are relevant to defensive, physiological immune responses of the lungs and to inflammatory lung diseases. The emerging view of platelets as blood cells that are much more diverse and versatile than previously thought further predicts that additional features of the biology of platelets and of megakaryocytes, the precursors of platelets, will be discovered and that some of these will also influence pulmonary immune defenses and inflammatory injury.
Improving access to palliative care for older adults living in residential care is recognised internationally as a pressing clinical need. The integration of specialist palliative care in residential care for older adults is not yet standard practice.
This study aimed to understand the experience and impact of integrating a specialist palliative care model on residents, relatives and staff.
Focus groups were held with staff (n=40) and relatives (n=17). Thematic analysis was applied to the data.
Three major themes were identified. The intervention led to (1) normalising death and dying in these settings, (2) timely access to a palliative care specialist who was able to prescribe anticipatory medications aiding symptom management and unnecessary hospitalisations and (3) better decision-making and planned care for residents, which meant that staff and relatives were better informed about, and prepared for, the resident's likely trajectory.
The intervention normalised death and dying and also underlined the important role that specialists play in providing staff education, timely access to medicines and advance care planning. The findings from our study, and the growing wealth of evidence integrating specialist palliative care in residential care for older adults, indicate a number of priorities for care providers, academics and policymakers. Further work on determining the role of primary and specialist palliative care services in residential care settings is needed to inform service delivery models.
Gene regulation relies on the specificity of transcription factor (TF)-DNA interactions. Limited specificity may lead to crosstalk: a regulatory state in which a gene is either incorrectly activated due to noncognate TF-DNA interactions or remains erroneously inactive. As each TF can have numerous
 interactions with noncognate cis-regulatory elements, crosstalk is inherently a global problem, yet has previously not been studied as such. We construct a theoretical framework to analyse the effects of global crosstalk on gene regulation. We find that crosstalk presents a significant challenge for organisms with low-specificity TFs, such as metazoans. Crosstalk is not easily mitigated by known regulatory schemes acting at equilibrium, including variants of cooperativity and combinatorial regulation. Our results suggest that crosstalk imposes a previously unexplored global constraint on the functioning and evolution of regulatory networks, which is qualitatively distinct from the known constraints that act at the level of individual gene regulatory elements.
Tissue homeostasis is dependent on the controlled localization of specific cell types and the correct composition of the extracellular stroma. While the role of the cancer stroma in tumour progression has been well characterized, the specific contribution of the matrix itself is unknown. Furthermore, the mechanisms enabling normal-not cancer-stroma to provide tumour-suppressive signals and act as an antitumorigenic barrier are poorly understood. Here we show that extracellular matrix (ECM) generated by normal fibroblasts (NFs) is softer than the CAF matrix, and its physical and structural features regulate cancer cell proliferation. We find that normal ECM triggers downregulation and nuclear exit of the histone demethylase JMJD1a resulting in the epigenetic growth restriction of carcinoma cells. Interestingly, JMJD1a positively regulates transcription of many target genes, including YAP/TAZ (WWTR1), and therefore gene expression in a stiffness-dependent manner. Thus, normal stromal restricts cancer cell proliferation through JMJD1a-dependent modulation of gene expression.
The inhibition of platelet aggregation is key to preventing conditions such as myocardial infarction and ischemic stroke. Aspirin is the most widely used drug to inhibit platelet aggregation. Aspirin absorption can be improved further to increase its permeability across biologic membranes via esterification or converting the carboxylic acid to an anhydride. There are several reports indicating that ω-3 and ω-6 fatty acids such as linoleic acid, eicosapentaenoic acid (EPA), and docosahexaenoic acid (DHA) separately inhibit platelet aggregation. Herein, we synthesize anhydride conjugates of aspirin with linoleic acid, EPA, and DHA to form aspirin anhydrides that are expected to have higher permeability across cellular membranes. These aspirin-fatty acid anhydrides inhibited platelet aggregation in washed human platelets and platelet-rich plasma in a dose-dependent manner. In particular, the aspirin-DHA anhydride displayed similar effectiveness to aspirin. Platelet aggregation studies conducted in the presence of various platelet agonists indicated that the aspirin-lipid conjugates act through inhibition of the cyclooxygenase (COX)-thromboxane synthase (TXAS) pathway. Hence, we performed detailed biochemical studies using purified COX-1 as well as TXAS stabilized in nanoscale lipid bilayers of nanodiscs to confirm results from the platelet aggregation studies. We show that although all of the aspirin conjugates act through the COX-TXAS pathway by inhibiting COX-1, the parent fatty acids do not act via this pathway. Finally, we studied the hydrolysis of these compounds in buffer and human plasma, and we demonstrate that all of the aspirin-fatty acid conjugates hydrolyze to the parent molecules aspirin and fatty acid in a controlled manner.
Recently, the World Health Organization launched a campaign to eradicate the tropical disease yaws, caused by the bacterium Treponema pallidum subsp. pertenue; however, for decades researchers have questioned whether flies act as a vector for the pathogen that could facilitate transmission.
A total of 207 fly specimens were trapped in areas of Africa in which T. pallidum-induced skin ulcerations are common in wild baboons; 88 flies from Tarangire National Park and 119 from Lake Manyara National Park in Tanzania were analyzed by PCR for the presence of T. pallidum DNA.
We report that in the two study areas, T. pallidum DNA was found in 17-24% of wild-caught flies of the order Diptera. Treponemal DNA sequences obtained from many of the flies match sequences derived from nearby baboon T. pallidum strains, and one of the fly species with an especially high prevalence of T. pallidum DNA, Musca sorbens, has previously been shown to transmit yaws in an experimental setting.
Our results raise the possibility that flies play a role in yaws transmission; further research is warranted, given how important understanding transmission is for the eradication of this disfiguring disease.
The enormous impact of HIV on communities and health services in Sub-Saharan Africa and the Caribbean has especially affected nurses, who comprise the largest proportion of the health workforce in low- and middle-income countries (LMICs). Strengthening action-based leadership for and by nurses is a means to improve the uptake of evidence-informed practices for HIV care.
A prospective quasi-experimental study in Jamaica, Kenya, Uganda and South Africa examined the impact of establishing multi-stakeholder leadership hubs on evidence-informed HIV care practices. Hub members were engaged through a participatory action research (PAR) approach. Three intervention districts were purposefully selected in each country, and three control districts were chosen in Jamaica, Kenya and Uganda. WHO level 3, 4 and 5 health care institutions and their employed nurses were randomly sampled. Self-administered, validated instruments measured clinical practices (reports of self and peers), quality assurance, work place policies and stigma at baseline and follow-up. Standardised average scores ranging from 0 to 1 were computed for clinical practices, quality assurance and work place policies. Stigma scores were summarised as 0 (no reports) versus 1 (one or more reports). Pre-post differences in outcomes between intervention and control groups were compared using the Mantel Haenszel chi-square for dichotomised stigma scores, and independent t tests for other measures. For South Africa, which had no control group, pre-post differences were compared using a Pearson chi-square and independent t test. Multivariate analysis was completed for Jamaica and Kenya. Hub members in all countries self-assessed changes in their capacity at follow-up; these were examined using a paired t test.
Response rates among health care institutions were 90.2 and 80.4 % at baseline and follow-up, respectively. Results were mixed. There were small but statistically significant pre-post, intervention versus control district improvements in workplace policies and quality assurance in Jamaica, but these were primarily due to a decline in scores in the control group. There were modest improvements in clinical practices, workplace policies and quality assurance in South Africa (pre-post) (clinical practices of self-pre 0.67 (95 % CI, 0.62, 0.72) versus post 0.78 (95 % CI, 0.73-0.82), p = 0.002; workplace policies-pre 0.82 (95 % CI, 0.70, 0.85) versus post 0.87 (95 % CI, 0.84, 0.90), p = 0.001; quality assurance-pre 0.72 (95 % CI, 0.67, 0.77) versus post 0.84 (95 % CI, 0.80, 0.88)). There were statistically significant improvements in scores for nurses stigmatising patients (Jamaica reports of not stigmatising-pre-post intervention 33.9 versus 62.4 %, pre-post control 54.7 versus 64.4 %, p = 0.002-and Kenya pre-post intervention 35 versus 51.6 %, pre-post control 34.2 versus 47.8 %, p = 0.006) and for nurses being stigmatised (Kenya reports of no stigmatisation-pre-post intervention 23 versus 37.3 %, pre-post control 15.4 versus 27 %, p = 0.004). Multivariate results for Kenya and Jamaica were non-significant. Twelve hubs were established; 11 were active at follow-up. Hub members (n = 34) reported significant improvements in their capacity to address care gaps.
Leadership hubs, comprising nurses and other stakeholders committed to change and provided with capacity building can collectively identify issues and act on strategies that may improve practice and policy. Overall, hubs did not provide the necessary force to improve the uptake of evidence-informed HIV care in their districts. If hubs are to succeed, they must be integrated within district health authorities and become part of formal, legal organisations that can regularise and sustain them.
Traditionally, a few processes have to be employed in sequence for multi-dye removal, due to the different physical and chemical characteristics of the dyes. In this study, we innovatively developed an integrated adsorption and Fenton oxidation fluidized bed reactor (FBR) based on the hydraulic classification theory, which could efficiently remove dispersed red, acid yellow, and reactive brilliant dyes. The fluidized solids such as ceramsite and activated carbon could be separately fluidized at the bottom and the top part of the FBR, respectively. As a result, Fenton oxidization of dyes was promoted by the fluidization of ceramsite and activated carbon. Besides, adsorption of activated carbon could synergistically act on the dyes. The results showed that the removal efficiencies of acid yellow 2G, disperse red 60, and reactive brilliant blue X-BR could reach 100, 79.8, and 84.9 % in 10 min, respectively. Lots of intermediates with unsaturated bonds were generated during Fenton reaction, which was further removed by adsorption of activated carbon. Consequently, a high COD removal of 93 % was obtained. Interestingly, some of Fe(3+) produced during Fenton reaction was further precipitated and crystallized as FeO(OH) or Fe(OH)3 on the surface of activated carbon and ceramsite, which could be potentially recycled
 for further utilization as a heterogeneous catalyst. Meanwhile, the other Fe(3+) might be removed in the form of ferro-organic complexes by adsorption onto the activated carbon. Thus, only a little iron hydroxide sludge was generated in the FBR. This novel FBR gave us an effective clue to realize multi-reactions for textile wastewater treatment by employing hydraulic classification fluidization.
The brain at rest exhibits a spatio-temporally rich dynamics which adheres to systematic behaviours that persist in task paradigms but appear altered in disease. Despite this hypothesis, many rest state paradigms do not act directly upon the rest state and therefore cannot confirm hypotheses about its mechanisms. To address this challenge, we combined transcranial magnetic stimulation (TMS) and electroencephalography (EEG) to study brain's relaxation toward rest following a transient perturbation. Specifically, TMS targeted either the medial prefrontal cortex (MPFC), i.e. part of the Default Mode Network (DMN) or the superior parietal lobule (SPL), involved in the Dorsal Attention Network. TMS was triggered by a given brain state, namely an increase in occipital alpha rhythm power. Following the initial TMS-Evoked Potential, TMS at MPFC enhances the induced occipital alpha rhythm, called Event Related Synchronisation, with a longer transient lifetime than TMS at SPL, and a higher amplitude. Our findings show a strong coupling between MPFC and the occipital alpha power. Although the rest state is organized around a core of resting state networks, the DMN functionally takes a special role among these resting state networks.
Nodal class TGF-β signalling molecules play essential roles in establishing the vertebrate body plan. In all vertebrates, nodal family members have specific waves of expression required for tissue specification and axis formation. In Xenopus laevis, six nodal genes are expressed before gastrulation, raising the question of whether they have specific roles or act redundantly with each other. Here, we examine the role of Xnr5. We find it acts at the late blastula stage as a mesoderm inducer and repressor of ectodermal gene expression, a role it shares with Vg1. However, unlike Vg1, Xnr5 depletion reduces the expression of the nodal family member xnr1 at the gastrula stage. It is also required for left/right laterality by controlling the expression of the laterality genes xnr1, antivin (lefty) and pitx2 at the tailbud stage. In Xnr5-depleted embryos, the heart field is established normally, but symmetrical reduction in Xnr5 levels causes a severely stunted midline heart, first evidenced by a reduction in cardiac troponin mRNA levels, while left-sided reduction leads to randomization of the left/right axis. This work identifies Xnr5 as the earliest step in the signalling pathway establishing normal heart laterality in Xenopus.
The first known function of Ku70 is as a DNA repair factor in the nucleus. Using neuronal neuroblastoma cells as a model, we have established that cytosolic Ku70 binds to the pro-apoptotic protein Bax in the cytosol and blocks Bax's cell death activity. Ku70-Bax binding is regulated by Ku70 acetylation in that when Ku70 is acetylated Bax dissociates from Ku70, triggering cell death. We propose that Ku70 may act as a survival factor in these cells such that Ku70 depletion triggers Bax-dependent cell death. Here, we addressed two fundamental questions about this model: (1) Does all Bax, which is a cytosolic protein, bind to all cytosolic Ku70? and (2) Is Ku70 a survival factor in cells types other than neuronal neuroblastoma cells? We show here that, in neuronal neuroblastoma cells, only a small fraction of Ku70 binds to a small fraction of Bax; most Bax is monomeric. Interestingly, there is no free or monomeric Ku70 in the cytosol; most cytosolic Ku70 is in complex with other factors forming several high molecular weight complexes. A fraction of cytosolic Ku70 also binds to cytosolic Ku80, Ku70's binding partner in the nucleus. Ku70 may not be a survival factor in some cell types (Ku70-depletion less sensitive) because Ku70 depletion does not affect survival of these cells. These results indicate that, in addition to Ku70 acetylation, other factors may be involved in regulating Ku70-Bax binding in the Ku70-depletion less sensitive cells because Ku70 acetylation in these cells is not sufficient to dissociate Bax from Ku70 or to activate Bax.
Simultaneous administration of phenytoin and isoniazid (INH) in tuberculous meningitis (TBM) or tuberculoma patients with seizures results in higher plasma phenytoin level and thus phenytoin intoxication. N-acetyltransferase 2 (NAT2) enzyme catalyses two acetylation reactions in INH metabolism and NAT2 gene polymorphism leads to slow and rapid acetylators. The present study was aimed to evaluate the effect of allelic variants of N-acetyltransferase 2 (NAT2) gene as a predisposing factor for phenytoin toxicity in patients with TBM or tuberculoma having seizures, and taking INH and phenytoin simultaneously.
Sixty patients with TBM or tuberculoma with seizures and taking INH and phenytoin simultaneously for a minimum period of seven days were included in study. Plasma phenytoin was measured by high performance liquid chromatography. NAT2 gene polymorphism was studied using restriction fragment length polymorphism and allele specific PCR.
The patients were grouped into those having phenytoin intoxication and those with normal phenytoin level, and also classified as rapid or slow acetylators by NAT2 genotyping. Genotypic analysis showed that of the seven SNPs (single nucleotide polymorphisms) of NAT2 gene studied, six mutations were found to be associated with phenytoin intoxication. For rs1041983 (C282T), rs1799929 (C481T), rs1799931 (G857A), rs1799930 (G590A), rs1208 (A803G) and rs1801280 (T341C) allelic variants, the proportion of homozygous mutant was higher in phenytoin intoxicated group than in phenytoin non-intoxicated group.
Homozygous mutant allele of NAT2 gene at 481site may act as a predisposing factor for phenytoin intoxication among TBM or tuberculoma patients having seizures.
The utility of antibody-dependent cellular cytotoxicity (ADCC) for eliminating HIV-1-infected cells is of much interest for the design of both prophylactic vaccines for HIV-1 prevention and therapeutics to eliminate latently infected cells following reactivation. Significant research has been conducted to understand the antibody specificities involved in anti-HIV-1 ADCC responses. Perhaps equally important as the identity of the antibodies mediating these responses are factors regulating the ability of ADCC effector cells, in particular, natural killer (NK) cells, to respond to antibody-coated target cells. Indeed, a plethora of activating and inhibitory receptors expressed on the surface of NK cells might act in conjunction with CD16 to influence ADCC. As the expression of NKG2D and its ligands has been linked to HIV-1 disease progression, we evaluated if signals through NKG2D were involved in anti-HIV-1 ADCC. Utilizing assays measuring cytolysis, we provide the first data implicating NKG2D in antibody-dependent NK cell responses against a target cell line either pulsed with gp120 or infected with HIV-1. These observations are highly significant for understanding antibody-dependent NK cell responses against HIV-1 and might be useful for optimizing prophylactics and therapeutics aiming to utilize antibodies and optimally functional NK cells to control HIV-1.
FasL-mediated cytotoxicity is one of the mechanisms that CTLs use to kill tumor cells. However, human colon carcinoma often deregulates the Fas signaling pathway to evade host cancer immune surveillance. We aimed at testing the hypothesis that novel ceramide analogs effectively modulate Fas function to sensitize colon carcinoma cells to FasL-induced apoptosis. We used rational design and synthesized twenty ceramide analogs as Fas function modulators. Five ceramide analogs, IG4, IG7, IG14, IG17, and IG19, exhibit low toxicity and potent activity in sensitization of human colon carcinoma cells to FasL-induced apoptosis. Functional deficiency of Fas limits both FasL and ceramide analogs in the induction of apoptosis. Ceramide enhances FasL-induced activation of the MAPK, NF-κB, and caspase 8 despite induction of potent tumor cell death. Finally, a sublethal dose of several ceramide analogs significantly increased CTL-mediated and FasL-induced apoptosis of colon carcinoma cells. We have therefore developed five novel ceramide analogs that act at a sublethal dose to enhance the efficacy of tumor-specific CTLs, and these ceramide analogs hold great promise for further development as adjunct agents in CTL-based colon cancer immunotherapy.
A crystal structure of the lutein-binding domain of human StARD3 (StAR-related lipid-transfer protein 3; also known as MLN64) has been refined to 1.74 Å resolution. A previous structure of the same protein determined to 2.2 Å resolution highlighted homology with StARD1 and shared cholesterol-binding character. StARD3 has since been recognized as a carotenoid-binding protein in the primate retina, where its biochemical function of binding lutein with specificity appears to be well suited to recruit this photoprotective molecule. The current and previous structures correspond closely to each other (r.m.s.d. of 0.25 Å), especially in terms of the helix-grip fold constructed around a solvent-filled cavity. Regions of interest were defined with alternate conformations in the current higher-resolution structure, including Arg351 found within the cavity and Ω1, a loop of four residues found just outside the cavity entrance. Models of the complex with lutein generated by rigid-body docking indicate that one of the ionone rings must protrude outside the cavity, and this insight has implications
 for molecular interactions with transport proteins and enzymes that act on lutein. Interestingly, models with the ℇ-ionone ring characteristic of lutein pointing towards the bottom of the cavity were associated with fewer steric clashes, suggesting that steric complementarity and ligand asymmetry may play a role in discriminating lutein from the other ocular carotenoids zeaxanthin and meso-zeaxanthin, which only have β-ionone rings.
The Colombian reform of 1994, through a strange historical sequence, became a model for health reform in Latin America, Europe, and the United States. Officially, the reform aimed to improve access for the uninsured and underinsured, in collaboration with the private, for-profit insurance industry. After several historical attempts at health reform adhering to the neoliberal pattern, favored by international financial institutions and multinational insurance corporations, the Affordable Care Act (ACA) similarly enhanced access by corporations to public-sector trust funds. An ideology favoring for-profit corporations in the marketplace justified these reforms through unproven claims about the efficiency of the private sector and enhanced quality of care under principles of competition and business management. The ACA maintains this historical continuity by dealing with health care as a commodity bought and sold in a marketplace, rather than a fundamental human right to be guaranteed according to principles of social solidarity. As the ACA heads toward probable failure, a space finally will open for a U.S. national health program that does not follow same historical patterns of the neoliberal model.
The reaction mechanism of (E)-methyl 3-(2-aminophenyl)acrylate (A) with phenylisothiocyanate (B) as well as the vital roles of substrate A and solvent water were investigated under unassisted, water-assisted, substrate A-assisted, and water-A-assisted conditions. The reaction proceeds with four processes via nucleophilic addition, deprotonation and protonation, intramolecular cyclization with hydrogen transfer, and keto-enol tautomerization. According to the different H-shift mode, two possible types of H-shift P1 and P2 are carefully investigated to identify the most preferred pathway, differing in the NH2 group deprotonation and CH group of A protonation processes. It is found that substrate A and water not only act as reactant and solvent, but also as catalyst, proton shuttle, and stabilizer in effectively lowering the energy barrier. Therefore, the results demonstrate that the strong donating and accepting ability of NH2 group on A and the presence of bulk water are the keys to the title reaction proceed. © 2016 Wiley Periodicals, Inc.
Phenotypic plasticity has been suggested to act through developmental switches, but little is known about associated molecular mechanisms. In the nematode Pristionchus pacificus, the sulfatase eud-1 was identified as part of a developmental switch controlling mouth-form plasticity governing a predatory versus bacteriovorous mouth-form decision. Here we show that mutations in the conserved histone-acetyltransferase Ppa-lsy-12 and the methyl-binding-protein Ppa-mbd-2 mimic the eud-1 phenotype, resulting in the absence of one mouth-form. Mutations in both genes cause histone modification defects and reduced eud-1 expression. Surprisingly, Ppa-lsy-12 mutants also result in the down-regulation of an antisense-eud-1 RNA. eud-1 and antisense-eud-1 are co-expressed and further experiments suggest that antisense-eud-1 acts through eud-1 itself. Indeed, overexpression of the antisense-eud-1 RNA increases the eud-1-sensitive mouth-form and extends eud-1 expression. In contrast, this effect is absent in eud-1 mutants indicating that antisense-eud-1 positively regulates eud-1. Thus, chromatin remodelling and antisense-mediated up-regulation of eud-1 control feeding plasticity in Pristionchus.
Despite progress in understanding the pathophysiology of the acute respiratory distress syndrome (ARDS), it remains a devastating clinical disorder associated with high mortality rates, and those who survive can experience significant long-term morbidity. Recent advances in the management of ARDS have mostly been achieved in supportive care, including the use of protective mechanical ventilation, neuromuscular blocking agents, prone positioning, and conservative fluid strategies. However, to date, no pharmacologic therapy has been able to act effectively on disease-specific pathways or to reduce mortality. In this context, current advances in understanding the potential roles of alternative approaches, such as cell therapy, offer new hope for ARDS.
This review discusses the use of mesenchymal stromal (stem) cells (MSCs) in pre-clinical experimental models of ARDS and in ongoing clinical trials.
Through the secretion of soluble mediators and extracellular vesicles, MSCs have been shown to modulate inflammation, enhance bacterial clearance, and reduce organ injury and death, making them a potential novel treatment for ARDS. Initial clinical trials have demonstrated the safety of MSC administration in patients with ARDS but further investigations are required to further characterize the efficacy profile of these therapies.
The bacterial magnetic nanoparticles (BMPs) are biomineralized by the magnetotactic bacteria and naturally covered with a layer of biomembrane. Herein, BMPs were isolated and firstly used for the photothermal therapy (PTT) of cancer under the guidance of magnetic resonance imaging (MRI) in vitro and in vivo. The results showed that BMPs could rapidly convert the energy of 808 nm near-infrared (NIR) light into heat. After internalization by the HepG2 tumor cells, BMPs with good biocompatibility could induce an efficient killing effect after NIR light irradiation, along with a change of mitochondrial membrane potential (ΔΨm) and level of intracellular reactive oxygen species (ROS). The in vivo therapy also confirms that PTT with BMPs could effectively and completely ablate the tumor in mice without inducing observable toxicity. T2-weighted MRI showed a clear tumor boundary and a 25% enhancement of negative contrast enhancement at the tumor site, suggesting that BMPs can act as an effective MRI contrast agent for guiding the PTT. Our results indicate that BMPs could be a potential theranostic agent for simultaneous MRI and PTT of cancer.
There are two kinds of adipose tissue in mammals: white adipose tissue - WAT and brown adipose tissue - BAT. The main function of WAT is accumulation of triacylglycerols whereas the function of BAT is heat generation. At present, WAT is also considered to be an endocrine gland that produces bioactive adipokines, which take part in glucose and lipid metabolism. Considering its endocrine function, the adipose tissue is not a homogeneous gland but a group of a few glands which act differently. Studies on the secretory function of WAT began in 1994 after discovery of leptin known as the satiation hormone, which regulates body energy homeostasis and maintainence of body mass. Apart from leptin, the following belong to adipokines: adiponectin, resistin, apelin, visfatin and cytokines: TNF and IL 6. Adiponectin is a polypeptide hormone of antidiabetic, anti-inflammatory and anti-atherogenic activity. It plays a key role in carbohydrate and fat metabolism. Resistin exerts a counter effect compared to adiponectin and its physiological role is to maintain fasting glycaemia. Visfatin stimulates insulin secretion and increases insulin sensitivity and glucose uptake by muscle cells and adipocytes. Apelin probably increases the insulin sensitivity of tissues. TNF evokes insulin resistance by blocking insulin receptors and inhibits insulin secretion. Approximately 30% of circulating IL 6 comes from adipose tissue. It causes insulin resistance by decreasing the expression of insulin receptors, decreases adipogenesis and adiponectin and visfatin secretion, and stimulates hepatic gluconeogenesis. In 2004, Bays introduced the notion of adiposopathy, defined as dysfunction of the adipose tissue, whose main feature is insulin and leptin resistance as well as the production of inflammatory cytokines: TNF and IL 6 and monocyte chemoattractant protein. This means that excess of adipose tissue, especially visceral adipose tissue, leads to the development of a chronic subclinical inflammatory condition, which favours the development of insulin resistance and Type 2 diabetes. Obesity is a systemic illness caused by energy transformation homeostasis disorder which results in an increase in the amount of body fat mass. It effects approximately 40% of dogs and 20% of cats. Illnesses which accompany obesity result, to a great extent, from the secretive role of adipose tissue, which is still little known, which should be included when planning treatment of an obese animal.
The ability of plants to cope with abiotic environmental stresses such as drought, salinity, heat, cold or flooding relies on flexible mechanisms for re-programming gene expression. Over recent years it has become apparent that transcriptional regulation needs to be understood within its structural context. Chromatin, the assembly of DNA with histone proteins, generates a local higher-order structure that impacts on the accessibility and effectiveness of the transcriptional machinery, as well as providing a hub for multiple protein interactions. Several studies have shown that chromatin features such as histone variants and post-translational histone modifications are altered by environmental stress, and they could therefore be primary stress targets that initiate transcriptional stress responses. Alternatively, they could act downstream of stress-induced transcription factors as an integral part of transcriptional activity. A few experimental studies have addressed this 'chicken-and-egg' problem
 in plants and other systems, but to date the causal relationship between dynamic chromatin changes and transcriptional responses under stress is still unclear. In this review we have collated the existing information on concurrent epigenetic and transcriptional responses of plants to abiotic stress, and we have assessed the evidence using a simple theoretical framework of causality scenarios. This article is part of a Special Issue entitled: Plant Gene Regulatory Mechanisms and Networks, edited by Dr. Erich Grotewold and Dr. Nathan Springer.
Tyrosyl-tRNA synthetases (TyrRSs) as essential enzymes for all living organisms are good candidates for therapeutic target in the prevention and therapy of microbial infection. We examined the effect of various polyphenols, alkaloids, and terpenes-secondary metabolites produced by higher plants showing many beneficial properties for the human organism, on bacterial aminoacylation reaction. The most potent inhibitors of Escherichia coli TyrRS are epigallocatechin gallate, acacetin, kaempferide, and chrysin, whereas the enzymes from Staphylococcus aureus and Pseudomonas aeruginosa are inhibited mainly by acacetin and chrysin. Most of them act as competitive inhibitors. Structure-activity relationship showed that the most potent flavonoid inhibitors contain hydroxyl group at position 5 and 7 of A ring and OCH3 group at position 4' of B ring.
Food and feeding-state dependent changes in chemoreceptor gene expression may allow Caenorhabditis elegans to modify their chemosensory behavior, but the mechanisms essential for these expression changes remain poorly characterized. We had previously shown that expression of a feeding state-dependent chemoreceptor gene, srh-234, in the ADL sensory neuron of C. elegans is regulated via the MEF-2 transcription factor. Here, we show that MEF-2 acts together with basic helix-loop-helix (bHLH) transcription factors to regulate srh-234 expression as a function of feeding state. We identify a cis-regulatory MEF2 binding site that is necessary and sufficient for the starvation-induced down regulation of srh-234 expression, while an E-box site known to bind bHLH factors is required to drive srh-234 expression in ADL. We show that HLH-2 (E/Daughterless), HLH-3 and HLH-4 (Achaete-scute homologs) act in ADL neurons to regulate srh-234 expression. We further demonstrate that the expression levels of srh-234 in ADL neurons are regulated remotely by MXL-3 (Max-like 3 homolog) and HLH-30 (TFEB ortholog) acting in the intestine, which is dependent on insulin signaling functioning specifically in ADL neurons. We also show that this intestine-to-neuron feeding-state regulation of srh-234 involves a subset of insulin-like peptides. These results combined suggest that chemoreceptor gene expression is regulated by both cell-autonomous and non-cell-autonomous transcriptional mechanisms mediated by MEF2 and bHLH factors, which may allow animals to fine-tune their chemosensory responses in response to changes in their feeding state.
Magnetic liquid marbles have recently attracted extensive attention for various potential applications. However, conventional liquid marbles based on iron oxide nanoparticles are opaque and inadequate for photo-related applications. Herein, we report the first development of liquid marbles coated with magnetic lanthanide-doped upconversion nanoparticles (UCNPs) that can convert near-infrared light into visible light. Apart from their excellent magnetic and mechanical properties, which are attractive for repeatable tip opening and magnetically directed movements, the resultant UCNP-based liquid marbles can act as ideal miniature reactors for photodynamic therapy of cancer cells. This work opens new ways for the development of liquid marbles, and shows great promise for liquid marbles based on UCNPs to be used in a large variety of potential applications, such as photodynamic therapy for accelerated drug screening, magnetically guided controlled drug delivery and release, and multifunctional actuation.
Recent advances in the treatment of Chagas disease have followed combinations of drugs that act synergistically against infection, predominantly including benznidazole (BNZ) and azoles derivatives. Possible incompatibilities between these drugs, slow dissolution of BNZ and dose adjustment difficulties are technological obstacles to the development of multidrug formulations. Thus, in the present study, BNZ pellets were developed using extrusion spheronization for immediate drug delivery. Preformulation studies were then performed using thermal analysis and infrared spectroscopy and compatibility between the drug and selected excipients (polyethylene glycol 6000, sodium starch glycolate, microcrystalline cellulose and sodium croscarmellose) was investigated. No chemical decomposition of BNZ was observed, even in samples submitted to wet granulation and thermal stress. Subsequently, formulations were elaborated according to a simplex lattice experimental design using polyethylene glycol, sodium starch glycolate and sodium croscarmellose as disintegrating agents. In these experiments, BNZ pellets showed appropriate physicochemical characteristics, including high drug load capacity and excellent flow properties. The mixture experimental design allowed identification of adequate compositions of disintegrating agents and achieved rapid disintegration and dissolution of pellets. Optimum performance was achieved using polyethylene glycol and sodium croscarmellose at 5.0% w/w each. The present BNZ pellets are versatile alternatives to treat Chagas disease and provide insights into the preparation of multidrug systems.
Elegant Z-scheme WO3/Au/In2S3 nanowire arrays were precisely constructed through a facile step-by-step route. Surface potential change on pristine or In2S3-Au coated WO3 single nanowire under dark and illumination detected through a Kelvin probe force microscopy (KPFM) technique indicates that the vectorial holes transfer of In2S3 → Au → WO3 should occur upon the excitation of both WO3 and In2S3. In such charge transfer processes, the embedded Au nanoparticles in the heterojunction systems act as a charge mediator for electrons in the conduction band of WO3 and holes in the valence band of In2S3. The strong charge carrier separation ability of this structure will finally enhance the oxidation ability of WO3 with high concertation of photogenerated holes and, further, leave the free electrons in the In2S3 with long surviving time. Therefore, the unique Z-scheme WO3/Au/In2S3 heterostructure shows great visible-light activity toward photocatalytic reduction of CO2 in the presence of water vapor into renewable hydrocarbon fuel (methane: CH4).
The mechanistic Target of Rapamycin Complex 1 (mTORC1) is a major regulator of eukaryotic growth that coordinates anabolic and catabolic cellular processes with inputs such as growth factors and nutrients, including amino acids. In mammals arginine is particularly important, promoting diverse physiological effects such as immune cell activation, insulin secretion, and muscle growth, largely mediated through activation of mTORC1 (refs 4, 5, 6, 7). Arginine activates mTORC1 upstream of the Rag family of GTPases, through either the lysosomal amino acid transporter SLC38A9 or the GATOR2-interacting Cellular Arginine Sensor for mTORC1 (CASTOR1). However, the mechanism by which the mTORC1 pathway detects and transmits this arginine signal has been elusive. Here, we present the 1.8 Å crystal structure of arginine-bound CASTOR1. Homodimeric CASTOR1 binds arginine at the interface of two Aspartate kinase, Chorismate mutase, TyrA (ACT) domains, enabling allosteric control of the adjacent GATOR2-binding site to trigger dissociation from GATOR2 and downstream activation of mTORC1. Our data reveal that CASTOR1 shares substantial structural homology with the lysine-binding regulatory domain of prokaryotic aspartate kinases, suggesting that the mTORC1 pathway exploited an ancient, amino-acid-dependent allosteric mechanism to acquire arginine sensitivity. Together, these results establish a structural basis for arginine sensing by the mTORC1 pathway and provide insights into the evolution of a mammalian nutrient sensor.
It is increasing evidence that ceRNA activity of long non-coding RNAs (lncRNAs) played critical roles in both normal physiology and tumorigenesis. However, functional roles and regulatory mechanisms of lncRNAs as ceRNAs in pancreatic ductal adenocarcinoma (PDAC), and their potential implications for early diagnosis remain unclear. In this study, we performed a genome-wide analysis to investigate potential lncRNA-mediated ceRNA interplay based on "ceRNA hypothesis". A dysregulated lncRNA-associated ceRNA network (DLCN) was constructed by utilizing sample-matched miRNA, lncRNA and mRNA expression profiles in PDAC and normal samples in combination with miRNA regulatory network. The results of network analysis uncovered seven novel lncRNAs as functional ceRNAs whose aberrant expression will result in the extensive variation in tumorigenic or tumor-suppressive gene expression through DLCN at the post-transcriptional level contributing to PDAC. Therefore, we developed a 7-lncRNA signature (termed LncRisk-7) based on the expression data of seven lncRNAs and SVM algorithm as a novel diagnostic tool to improve early diagnosis of PDAC. The LncRisk-7 achieved high performance in distinguishing PDAC patients from nonmalignant pancreas samples in the discovery cohort and was further confirmed in another two independent validation cohorts. Functional analysis demonstrated that seven lncRNA biomarkers act as ceRNAs involving the regulation of cell death, cell adhesion and cell cycle. This study will help to improve our understanding of the lncRNA-mediated ceRNA regulatory mechanisms in the pathogenesis of PDAC and provide
 novel lncRNAs as candidate diagnostic biomarkers or potential therapeutic targets.
Metacognition is the act of thinking about one's own thought processes. There are long-term gains in learning among students who are trained to understand how the brain works and how they can control their own learning. Wrappers are short questionnaires provided at or near the time of completion of a lecture, assignment, or assessment to coach the student in thinking through the steps of metacognition (planning, monitoring, and adapting). As students completed the second and third of four examinations in a first-year veterinary anatomy course, they were invited to fill out an examination wrapper that asked them questions about examination preparation, where they felt they had had the most trouble with the examination, and what they might do differently before the next examination. Neither percentage change in scores from the second to the third and from the third to the fourth lecture or laboratory examination nor final grade for the course varied between the group of students who completed an examination wrapper and the group that did not. Students did not appear to change their behavior from one examination to the next. This was most likely because students lacked formal training in metacognition and therefore did not understand the value of completing the examination wrapper or the potential benefits of using their reflections. Future work will describe outcomes when learning objectives specific to metacognition are included in coursework in the veterinary curriculum.
Abscisic acid (ABA) and phototropins act antagonistically to control stomatal movements. Here, we investigated the role of ABA in phototropin-directed chloroplast movements in mesophyll cells of Arabidopsis thaliana. We analyzed the expression of phototropins at mRNA and protein level under the influence of ABA. PHOT1 mRNA level was decreased by ABA in the dark while it was insensitive to ABA in light. PHOT2 mRNA level was independent of the hormone treatment. The levels of phototropin proteins were down-regulated by ABA, both in darkness and light. No impact of exogenous ABA on amplitudes and kinetics of chloroplast movements was detected. Chloroplast responses in wild type Arabidopsis and three mutants, abi4, abi2 (abscisic acid insensitive4, 2) and aba1 (abscisic acid1), were measured to account for endogenous ABA signaling. The chloroplast responses were slightly reduced in abi2 and aba1 mutants in strong light. To further investigate the effect, abi2 and aba1 mutants were supplemented with exogenous ABA. In the aba1 mutant, the reaction was rescued but in abi2 it was unaffected. Our results show that ABA is not directly involved in phototropin-controlled chloroplast responses in mature leaves of Arabidopsis. However, the disturbance of ABA biosynthesis and signaling in mutants affects some elements of the chloroplast movement mechanism. In line with its role as a stress hormone, ABA appears to enhance plant sensitivity to light and promote the chloroplast avoidance response.
The G protein-coupled receptors (GPCRs), one of the largest protein families, are essential components of the most commonly used signal-transduction systems in cells. These receptors, often using common pathways, may cooperate in the regulation of signal transmission to the cell nucleus. Recent scientific interests increasingly focus on the cooperation between these receptors, particularly in a context of their oligomerization, e.g. the formation of dimers that are able to change characteristic signaling of each receptor. Numerous studies on kinin and dopamine receptors which belong to this family of receptors have shown new facts demonstrating their direct interactions with other GPCRs. In this review, current knowledge on signaling pathways and oligomerization of these receptors has been summarized. Owing to the fact that kinin and dopamine receptors are widely expressed in cell membranes where they act as mediators of numerous common physiological processes, the information presented here sheds new light on a putative crosstalk of these receptors and provides more comprehensive understanding of possible direct interactions that may change their functions. The determination of such interactions may be useful for the development of new targeted therapeutic strategies against many disorders in which kinin and dopamine receptors are involved.
Focal adhesion kinase (FAK) has known signaling roles in cytoplasmic adhesion structures, but was recently shown to act as a transcriptional regulator in the nucleus. In this issue of Structure, Cardoso et al. (2016) report that mechanical forces translocate FAK to the nucleus of cardiomyocytes, and provide structural insights into how FAK interacts with the MEF2 transcription factor to control cardiac hypertrophy.
FOXP3+ regulatory T cell (Treg) based cellular therapies represent promising therapeutic options in autoimmunity, allergy, transplantation and prevention of Graft Versus Host (GVH) Disease. Among human FOXP3-expressing CD4+T cells, only the CD45RA+ naïve Treg (nTreg) subset is suitable for in vitro expansion. However, FOXP3 expression decays in cells using currently described culture protocols. Rapamycin alone was not able to prevent FOXP3 loss in nTregs cells, as only a half of them maintained FOXP3 expression after 14 days of culture. In contrast we report a novel combined drug regimen that can drastically stabilize FOXP3 expression in cultured Tregs. IL-2, rapamycin, histone deacetylase and DNA methyltransferase inhibitors act in synergy to allow expansion of human regulatory T cells with sustained high expression of FOXP3 and CD15s with potent suppressive capacities in vitro and control of murine xeno-GVH reactions. Of note, an additional subsequent infusion of expanded nTreg cells did not improve survival of mice. Combination of IL-2, rapamycin, histone deacetylase and DNA methyltransferase inhibitors is optimal for the expansion in vitro of pure effective nTreg maintaining high levels of FOXP3 for therapeutic purposes.
Recent research found that Tiron was an effective antioxidant that could act as the intracellular reactive oxygen species (ROS) scavenger or alleviate the acute toxic metal overload in vivo. In this study, we investigated the inhibitory effect of Tiron on matrix metalloproteinase (MMP)-1 and MMP-3 expression in human dermal fibroblast cells. Western blot and ELISA analysis revealed that Tiron inhibited ultraviolet B (UVB)-induced protein expression of MMP-1 and MMP-3. Real-time quantitative PCR confirmed that Tiron could inhibit UVB-induced mRNA expression of MMP-1 and MMP-3. Furthermore, Tiron significantly blocked UVB-induced activation of the MAPK signaling pathway and activator protein (AP)-1 in the downstream of this transduction pathway in fibroblasts. Through the AP-1 binding site mutation, it was found that Tiron could inhibit AP-1-induced upregulation of MMP-1 and MMP-3 expression through blocking AP-1 binding to the AP-1 binding sites in the MMP-1 and MMP-3 promoter region. In conclusion, Tiron may be a novel antioxidant for preventing and treating skin photoaging UV-induced.
Type 5 17β-hydroxysteroid dehydrogenase, aldo-keto reductase 1C3 (AKR1C3) converts Δ(4)-androstene-3,17-dione and 5α-androstane-3,17-dione to testosterone (T) and 5α-dihydrotestosterone, respectively, in castration resistant prostate cancer (CRPC). In CRPC, AKR1C3 is implicated in drug resistance, and enzalutamide drug resistance can be surmounted by indomethacin a potent inhibitor of AKR1C3. We examined a series of naproxen analogues and find that (R)-2-(6-methoxynaphthalen-2-yl)butanoic acid (in which the methyl group of R-naproxen was replaced by an ethyl group) acts as a potent AKR1C3 inhibitor that displays selectivity for AKR1C3 over other AKR1C enzymes. This compound was devoid of inhibitory activity on COX isozymes and blocked AKR1C3 mediated production of T and induction of PSA in LNCaP-AKR1C3 cells as a model of a CRPC cell line. R-Profens are substrate selective COX-2 inhibitors and block the oxygenation of endocannabinoids and in the context of advanced prostate cancer R-profens could inhibit intratumoral androgen synthesis and act as analgesics for metastatic disease.
miR-449a has been reported to act as a tumor suppressor in several cancers, however, it is controversial whether it inhibits tumor growth in colorectal cancer. The mechanisms underlying its expression and functions in colorectal cancers are still largely unknown. SATB2 is a sensitive and specific marker for CRC diagnosis. However, the mechanisms by which the expression and functions of SATB2 are regulated still remain to be clarified. We investigated the expression and functional significance of miR-449a and SATB2 and the mechanisms of their dysregulation in human CRC cells. miR-449a overexpression or SATB2 depletion inhibited tumor growth and promoted apoptosis in colorectal tumor cells in vitro and in xenograft mouse model, partially by downregulating SATB2. Expression of miR-449a was increased epigenetically via knocking down their targets, particularly SATB2. miR-449a was downregulated and STAB2 expression was upregulated in human CRCs. Their expressions were significantly associated with overall survival of CRC patients. Our findings demonstrate the existence of a miR-449a-SATB2 negative feedback loop that maintains low levels of miR-449a as well as high level of SATB2, thereby promoting CRC development.
Tumor-specific immune tolerance represents an obstacle for the development of effective anti-tumor immune responses through cancer vaccines. We here evaluated the efficacy of chemo-immunotherapy in breaking tumor-specific immune tolerance in an almost incurable mouse model of spontaneous carcinogenesis.Transgenic HER-2/neu mice bearing large mammary tumors
 received the adoptive transfer of splenocytes and serum isolated from immune donors, with or without pre-conditioning with cyclophosphamide. Treatment efficacy was assessed by monitoring tumor growth by manual inspection and by magnetic resonance imaging. The same chemo-immunotherapy protocol was tested on tumor-free HER-2/neu mice, to evaluate the effects on tumor emergence.Our data show that chemo-immunotherapy hampered carcinogenesis and caused the regression of large mammary tumor lesions in tumor-bearing HER-2/neu mice. The complete eradication of a significant number of tumor lesions occurred only in mice receiving cyclophosphamide shortly before immunotherapy, and was associated with increased serum anti HER-2/p185 antibodies and tumor leukocyte infiltration. The same protocol significantly delayed the appearance of mammary tumors when administered to tumor-free HER-2/neu mice, indicating that this chemo-immunotherapy approach acted through the elicitation of an effective anti-tumor immune response. Overall, our data support the immune-modulatory role of chemotherapy in overcoming cancer immune tolerance when administered at lymphodepleting non-myeloablative doses shortly before transfer of antigen-specific immune cells and immunoglobulins. These findings open new perspectives on combining immune-modulatory chemotherapy and immunotherapy to overcome immune tolerance in cancer patients.
Bacterial conjugation is a form of type IV secretion used to transport protein and DNA directly to recipient bacteria. The process is cell contact-dependent, yet the mechanisms enabling extracellular events to trigger plasmid transfer to begin inside the cell remain obscure. In this study of plasmid R1 we investigated the role of plasmid proteins in the initiation of gene transfer. We find that TraI, the central regulator of conjugative DNA processing, interacts physically, and functionally with the plasmid partitioning proteins ParM and ParR. These interactions stimulate TraI catalyzed relaxation of plasmid DNA in vivo and in vitro and increase ParM ATPase activity. ParM also binds the coupling protein TraD and VirB4-like channel ATPase TraC. Together, these protein-protein interactions probably act to co-localize the transfer components intracellularly and promote assembly of the conjugation machinery. Importantly these data also indicate that the continued association of ParM and ParR at the conjugative pore is necessary for plasmid transfer to start efficiently. Moreover, the conjugative pilus and underlying secretion machinery assembled in the absence of Par proteins mediate poor biofilm formation and are completely dysfunctional for pilus specific R17 bacteriophage uptake. Thus, functional integration of Par components at the interface of relaxosome, coupling protein, and channel ATPases appears important for an optimal conformation and effective activation of the transfer machinery. We conclude that low copy plasmid R1 has evolved an active segregation system that optimizes both its vertical and lateral modes of dissemination.
Acute kidney injury (AKI) affects ~30% of hospitalized neonates. Critical to advancing our understanding of neonatal AKI is collaborative research among neonatologists and nephrologists. The Neonatal Kidney Collaborative (NKC) is an international, multidisciplinary group dedicated to investigating neonatal AKI. The AWAKEN study (Assessment of Worldwide Acute Kidney injury Epidemiology in Neonates) was designed to describe the epidemiology of neonatal AKI, validate the definition of neonatal AKI, identify primary risk factors for neonatal AKI, and investigate the contribution of fluid management to AKI events and short-term outcomes.
The NKC was established with at least one pediatric nephrologist and neonatologist from 24 institutions in 4 countries (USA, Canada, Australia, and India). A Steering Committee and four subcommittees were created. The database subcommittee oversaw the development of the web-based database (MediData Rave™) that captured all NICU admissions from 1/1/14 to 3/31/14. Inclusion and exclusion criteria were applied to eliminate neonates with a low likelihood of AKI. Data collection included: (1) baseline demographic information; (2) daily physiologic parameters and care received during the first week of life; (3) weekly "snapshots"; (4) discharge information including growth parameters, final diagnoses, discharge medications, and need for renal replacement therapy; and (5) all serum creatinine values.
AWAKEN was proposed as human subjects research. The study design allowed for a waiver of informed consent/parental permission. NKC investigators will disseminate data through peer-reviewed publications and educational conferences.
The purpose of this publication is to describe the formation of the NKC, the establishment of the AWAKEN cohort and database, future directions, and a few "lessons learned." The AWAKEN database includes ~325 unique variables and >4 million discrete data points. AWAKEN will be the largest, most inclusive neonatal AKI study to date. In addition to validating the neonatal AKI definition and identifying risk factors for AKI, this study will uncover variations in practice patterns related to fluid provision, renal function monitoring, and involvement of pediatric nephrologists during hospitalization. The AWAKEN study will position the NKC to achieve the long-term goal of improving the lives, health, and well-being of newborns at risk for kidney disease.
The 2009 Family Smoking Prevention and Tobacco Control Act opened the possibility for tobacco companies to apply to market their products as having "modified" or reduced risks. However, research on how to communicate comparative tobacco risks and how such messages are interpreted is limited. This study aimed to qualitatively examine perceptions of potential modified risk statements presented as warning labels for e-cigarettes. We conducted six focus groups between 2014 and 2015 with 27 adult e-cigarette users and cigarette-only smokers who provided comments on two versions of a modified risk warning for e-cigarettes: 1) "WARNING: No tobacco product is safe, but this product presents substantially lower risks to health than cigarettes" (as proposed by two companies for their smokeless tobacco products) and 2) "WARNING: This product may be harmful to health, but is substantially less harmful than cigarettes" (an alternative developed by our team). Although most personally believed that e-cigarettes are safer than cigarettes and some thought the messages were true and accurate, many were skeptical and uncomfortable with the warnings because they did not "seem like a warning" and because use of the phrase "substantially lower risks" could be misleading and difficult to understand. Several thought the second warning was stronger (e.g., more active, more specific). Modified risk messages about e-cigarettes may impact perceptions and use of the product. More research is needed to identify the framing, wording and placement (e.g. within or in addition to a warning) that could potentially increase population-level benefits and minimize harms.
The 2014 Ebola outbreak in West Africa raised many questions about the control of infectious disease in an increasingly connected global society. Limited availability of contact information made contact tracing diffcult or impractical in combating the outbreak. 
We consider the development of multi-scale public health strategies that act on individual and community levels. We simulate policies for community-level response aimed at early screening all members of a community, as well as travel restrictions to prevent inter-community transmission. 
Our analysis shows the policies to be effective even at a relatively low level of compliance and for a variety of local and long range contact transmission networks. In our simulations, 40% of individuals conforming to these policies is enough to stop the outbreak. Simulations with a 50% compliance rate are consistent with the case counts in Liberia during the period of rapid decline after mid September, 2014. We also find the travel restriction to be effective at reducing the risks associated with compliance substantially below the 40% level, shortening the outbreak and enabling efforts to be focused on affected areas. 
Our results suggest that the multi-scale approach can be used to further evolve public health strategy for defeating emerging epidemics.
The NAM, ATAF1/2, and CUC2 (NAC) domain proteins play various roles in plant growth and stress responses. Arabidopsis NAC transcription factor NAC072 has been reported as a transcriptional activator in Abscisic acid (ABA)-responsive gene expression. However, the exact function of NAC072 in ABA signaling is still elusive. In this study, we present evidence for the interrelation between NAC072 and ABA-responsive element binding factor 3 (ABF3) that act as a positive regulator of ABA-responsive gene expression in Arabidopsis. The transcript of NAC072 is up-regulated by ABF3 in ABA response, and NAC072 protein interacts with ABF3. Enhanced ABA sensitivity occurs in nac072 mutant plants that overexpressed ABF3. However, overexpression of NAC072 weakened the ABA sensitivity in the abf3 mutant plants, but instead of recovering the ABA sensitivity of abf3. NAC072 and ABF3 cooperate to regulate RD29A expression, but are antagonistic when regulating RD29B expression. Therefore, NAC072 displays a dual function in ABF3-mediated ABA-responsive gene regulation.
Protein derivatives and carbohydrates can stimulate plant growth, increase stress tolerance, and activate plant defense mechanisms. However, these molecules can also act as a nutritional substrate for microbial communities living on the plant phyllosphere and possibly affect their biocontrol activity against pathogens. We investigated the mechanisms
 of action of a protein derivative (nutrient broth, NB) against grapevine downy mildew, specifically focusing on the effects of foliar treatments on plant defense stimulation and on the composition and biocontrol features of the phyllosphere microbial populations. NB reduced downy mildew symptoms and induced the expression of defense-related genes in greenhouse- and in vitro-grown plants, indicating the activation of grapevine resistance mechanisms. Furthermore, NB increased the number of culturable phyllosphere bacteria and altered the composition of bacterial and fungal populations on leaves of greenhouse-grown plants. Although, NB-induced changes on microbial populations were affected by the structure of indigenous communities originally residing on grapevine leaves, degrees of disease reduction and defense gene modulation were consistent among the experiments. Thus, modifications in the structure of phyllosphere populations caused by NB application could partially contribute to downy mildew control by competition for space or other biocontrol strategies. Particularly, changes in the abundance of phyllosphere microorganisms may provide a contribution to resistance induction, partially affecting the hormone-mediated signaling pathways involved. Modifying phyllosphere populations by increasing natural biocontrol agents with the application of selected nutritional factors can open new opportunities in terms of sustainable plant protection strategies.
Due to the rapidly increasing prevalence of multidrug-resistant bacterial strains, the need for new antimicrobial drugs to treat infections has become urgent. Bacteriocins, which are antimicrobial peptides of bacterial origin, are considered potential alternatives to conventional antibiotics and have attracted widespread attention in recent years. Among these bacteriocins, lantibiotics, especially two-component lantibiotics, exhibit potent antimicrobial activity against some clinically relevant Gram-positive pathogens and have potential applications in the pharmaceutical industry. In this study, we characterized a novel two-component lantibiotic termed thusin that consists of Thsα, Thsβ, and Thsβ' (mutation of Thsβ, A14G) and that was isolated from a B. thuringiensis strain BGSC 4BT1. Thsα and Thsβ (or Thsβ') exhibit optimal antimicrobial activity at a 1:1 ratio and act sequentially to affect target cells, and they are all highly thermostable (100°C for 30 min) and pH tolerant (pH 2.0 to 9.0). Thusin shows remarkable efficacy against all tested Gram-positive bacteria and greater activities than two known lantibiotics thuricin 4A-4 and ticin A4, and one antibiotic vancomycin against various bacterial pathogens (Bacillus cereus, Listeria monocytogenes, Staphylococcus aureus (MRSA), Staphylococcus sciuri, Enterococcus faecalis, and Streptococcus pneumoniae). Moreover, thusin is also able to inhibit the outgrowth of B. cereus spores. The potent antimicrobial activity of thusin against some Gram-positive pathogens indicates that it has potential for the development of new drugs.
This paper presents a limited case study examining the causal inference of student mobility on standardized test performance, within one middle-class high school in suburban Connecticut. Administrative data were used from a district public high school enrolling 319 10th graders in 2010. Propensity score methods were used to estimate the causal effect of student mobility on Math, Science, Reading, and Writing portions of the Connecticut Academic Performance Test (CAPT), after matching mobile vs. stable students on gender, race/ethnicity, eligibility for free/reduced lunches, and special education status. Analyses showed that mobility was associated with lower performance in the CAPT Writing exam. Follow-up analyses revealed that this trend was only significant among those who were ineligible for free/reduced lunches, but not among eligible students. Additionally, mobile students who were ineligible for free/reduced lunches had lower performance in the CAPT Science exam according to some analyses. Large numbers of students transferring into a school district may adversely affect standardized test performance. This is especially relevant for policies that affect student mobility in schools, given the accountability measures in the No Child Left Behind that are currently being re-considered in the recent Every Student Succeeds Act.
Although the neuropeptide oxytocin has been associated with enhanced prosocial behaviors, it has also been linked to aggression and mental health disorders. Thus, it was suggested that oxytocin might act by increasing the salience of social stimuli, irrespective of whether these are positive or negative, thus increasing vulnerability to negative mental health outcomes. The current study (N = 243), conducted among white university students, examined the relation of trauma, depressive symptoms including suicidal ideation in relation to a single nucleotide polymorphism (SNP) within the oxytocin receptor gene (OXTR), rs53576, and a SNP on the CD38 gene that controls oxytocin release, rs3796863. Individuals with the polymorphism on both alleles (AA genotype) of the CD38 SNP had previously been linked to elevated plasma oxytocin levels. Consistent with the social sensitivity perspective, however, in the current study, individuals carrying the AA genotype displayed elevated feelings of alienation from parents and peers as well as increased levels of suicidal ideation. Moreover, they tended to report elevated depressive symptoms compared to CC homozygotes. It was also observed that the CD38 genotype moderated the relation between trauma and suicidal ideation scores, such that high levels of trauma were associated with elevated suicidal ideation among all CD38 genotypes, but this relationship was stronger among individuals with the AA genotype. In contrast, there was no relationship between the OXTR SNP, rs53576, depression or suicidal ideation. These findings support a social sensitivity hypothesis of oxytocin, wherein the AA genotype of the CD38 SNP, which has been considered the "protective allele" was associated with increased sensitivity and susceptibility to disturbed social relations and suicidal ideation.
The sense of taste is an essential chemosensory modality that enables animals to identify appropriate food sources and control feeding behavior. In particular, the recognition of bitter taste prevents animals from feeding on harmful substances. Feeding is a complex behavior comprised of multiple steps, and food quality is continuously assessed. We here examined the role of pharyngeal gustatory organs in ingestion behavior. As a first step, we constructed a gustatory receptor-to-neuron map of the larval pharyngeal sense organs, and examined corresponding gustatory receptor neuron (GRN) projections in the larval brain. Out of 22 candidate bitter compounds, we found 14 bitter compounds that elicit inhibition of ingestion in a dose-dependent manner. We provide evidence that certain pharyngeal GRNs are necessary and sufficient for the ingestion response of larvae to caffeine. Additionally, we show that a specific pair of pharyngeal GRNs, DP1, responds to caffeine by calcium imaging. In this study we show that a specific pair of GRNs in the pharyngeal sense organs coordinates caffeine sensing with regulation of behavioral responses such as ingestion. Our results indicate that in Drosophila larvae, the pharyngeal GRNs have a major role in sensing food palatability to regulate ingestion behavior. The pharyngeal sense organs are prime candidates to influence ingestion due to their position in the pharynx, and they may act as first level sensors of ingested food.
Literature has demonstrated the adaptive function of identity development and parenting toward manifestation of problem behaviors in adolescence. These dimensions act on both internalizing and externalizing symptoms.
The objective is to investigate the relationship between identity status, parenting, and adolescent problems, which may manifest through internalized (phobias, obsessions, depression, eating disorders, entropy) and externalized modes (alcohol use and school discomfort). The research involved 198 Italian students (104 males and 94 females) in the 4th year (mean =16.94 years, standard deviation =0.35) and 5th year (mean =17.94 years, standard deviation =0.43) of senior secondary schools, who live in Caltanissetta, a town located in Sicily, Italy. The research lasted for 1 school year. The general group consisted of 225 students with a mortality rate of 12%. They completed an anamnestic questionnaire to provide 1) basic information, 2) alcohol consumption attitude in the past 30 days, and 3) their beliefs about alcohol; the "Ego Identity Process Questionnaire" to investigate identity development; the "Parental Bonding Instrument" to measure the perception of parenting during childhood; and the "Constraints of Mind" to value the presence of internalizing symptoms.
Data show that identity status influences alcohol consumption. Low-profile identity and excessive maternal control affect the relational dependence and the tendency to perfectionism in adolescents. Among the predictors of alcohol use, there are socioeconomic status, parental control, and the presence of internalizing symptoms.
Family is the favored context of learning beliefs, patterns, and values that affect the broader regulatory social environment, and for this reason, it is considered the privileged context on which to intervene to reduce the adolescents' behavior problems. This deviance could be an external manifestation of the difficulty in management of internalizing symptoms in adolescence.
Mammalian spermatozoa acquire their fertilizing ability in the female reproductive tract (sperm capacitation). On the other hand, seminal vesicle secretion, which
 is a major component of seminal plasma, inhibits the initiation of sperm capacitation (capacitation inhibition) and reduces the fertility of the capacitated spermatozoa (decapacitation). There are seven major proteins involved in murine seminal vesicle secretion (SVS1-7), and we have previously shown that SVS2 acts as both a capacitation inhibitor and a decapacitation factor, and is indispensable for in vivo fertilization. However, the effects of SVSs other than SVS2 on the sperm have not been elucidated. Since mouse Svs2-Svs6 genes evolved by gene duplication belong to the same gene family, it is possible that SVSs other than SVS2 also have some effects on sperm capacitation. In this study, we examined the effects of SVS3 and SVS4 on sperm capacitation. Our results showed that both SVS3 and SVS4 are able to bind to spermatozoa, but SVS3 alone showed no effects on sperm capacitation. On the other hand, SVS4 acted as a capacitation inhibitor, although it did not show decapacitation abilities. Interestingly, SVS3 showed an affinity for SVS2 and it facilitated the effects of SVS2. Interaction of SVS2 and spermatozoa is mediated by the ganglioside GM1 in the sperm membrane; however, both SVS3 and SVS4 had weaker affinities for GM1 than SVS2. Therefore, we suggest that separate processes may cause capacitation inhibition and decapacitation, and SVS3 and SVS4 act on sperm capacitation cooperatively with SVS2.
Avian leucosis virus subgroup J (ALV-J) can cause lifelong infection and can escape from the host immune defenses in chickens. Since macrophages act as the important defense line against invading pathogens in host innate immunity, we investigated the function and innate immune responses of chicken primary monocyte-derived macrophages (MDM) after ALV-J infection in this study. Our results indicated that ALV-J was stably maintained in MDM cells but that the viral growth rate was significantly lower than that in DF-1 cells. We also found that ALV-J infection significantly increased nitric oxide (NO) production, but had no effect on MDM phagocytic capacity. Interestingly, infection with ALV-J rapidly promoted the expression levels of Myxovirus resistance 1 (Mx) (3 h, 6 h), ISG12 (6 h), and interleukin-1β (IL-1β) (3 h, 12 h) at an early infection stage, whereas it sharply decreased the expression of Mx (24 h, 36 h), ISG12 (36 h), and made little change on IL-1β (24 h, 36 h) production at a late infection stage in MDM cells. Moreover, the protein levels of interferon-β (IFN-β) and interleukin-6 (IL-6) had sharply increased in infected MDM cells from 3 to 36 h post infection (hpi) of ALV-J. And, the protein level of interleukin-10 (IL-10) was dramatically decreased at 36 hpi in MDM cells infected with ALV-J. These results demonstrate that ALV-J can induce host innate immune responses and we hypothesize that macrophages play an important role in host innate immune attack and ALV-J immune escape.
Access to firearms increases the risk of a batterer killing his partner. Moreover, firearms may be more common in homes where intimate partner abuse has occurred. The Violence Against Women Act of 1994 banned possession of firearms by individuals subject to civil protection orders. Yet little research has focused on how this ban is communicated to survivors and batterers. Drawing on systematic observations of protection order hearings, the current study explores factors related to judicial discussion of the ban in court. Implications for improving protection orders and for increasing battered women's safety are discussed.
The sulfate-reducing bacteria of the Desulfovibrio genus make three distinct modified tetrapyrroles, haem, sirohaem and adenosylcobamide, where sirohydrochlorin acts as the last common biosynthetic intermediate along the branched tetrapyrrole pathway. Intriguingly, D. vulgaris encodes two sirohydrochlorin chelatases, CbiK(P) and CbiK(C) , that insert cobalt/iron into the tetrapyrrole macrocycle but are thought to be distinctly located in the periplasm and cytoplasm respectively. Fusing GFP onto the C-terminus of CbiK(P) confirmed that the protein is transported to the periplasm. The structure-function relationship of CbiK(P) was studied by constructing eleven site-directed mutants and determining their chelatase activities, oligomeric status and haem binding abilities. Residues His154 and His216 were identified as essential for metal-chelation of sirohydrochlorin. The tetrameric form of the protein is stabilized by Arg54 and Glu76, which form hydrogen bonds between two subunits. His96 is responsible for the binding of two haem groups within the main central cavity of the tetramer. Unexpectedly, CbiK(P) is shown to bind two additional haem groups through interaction with His103. Thus, although still retaining cobaltochelatase activity, the presence of His96 and His103 in CbiK(P) , which are absent from all other known bacterial cobaltochelatases, has evolved CbiK(P) a new function as a haem binding protein permitting it to act as a potential haem chaperone or transporter.
The von Hippel-Lindau tumor suppressor (VHL; E3 ubiquitin ligase gene) is frequently mutated or undetectable in clear cell renal cell carcinoma (CCRCC), and therefore these tumors are highly resistant to chemotherapeutic agents, including adriamycin (ADM) and sunitinib. A mutation in the tumor protein p53 (TP53) also leads to chemoresistance in tumors; however, in CCRCC, TP53 is frequently functional, yet the tumors remain highly insensitive to chemotherapy. This indicates the possibility of a synergistic effect of VHL and P53 in CCRCC. The present study aimed to detect the chemosensitivity of CCRCC. The expression of VHL in the MZ1257 cell line sensitized these cells to ADM and sunitinib, and a knockdown of VHL in the ACHN cells increased their chemoresistance. To confirm that VHL and P53 are both required for chemosensitivity, VHL and P53 were co expressed in 786 O cells. The results of the functional antagonist assay (which assessed the IC50 values, i.e. the half maximal inhibitory concentration) confirmed that VHL and P53 act in synergy to promote chemosensitivity. Cell cycle arrest was measured by propidium iodide staining following treatment with ADM or sunitinib. Further analysis indicated that co expression of VHL and P53 inhibited cell proliferation by completely inhibiting the cell cycle at the G0/G1 phase, and promoted apoptosis following treatment with ADM or sunitinib. These findings demonstrated that VHL and P53 act synergistically in the regulation of cell proliferation and apoptosis in CCRCC. Overall, VHL and P53 have important roles in the regulation of cell proliferation and apoptosis in CCRCC. Furthermore, the regulatory role of VHL is dependant on the activation P53.
PM10 was sampled at a suburban location affected by traffic and industry in the north of Spain. The samples were analysed to determine the chemical components of PM10 (organic and elemental carbon, soluble chemical species and metals). The aim of this study was to assess the toxicity of PM10 in terms of the bulk analysis and the physico-chemical properties of the particles. Total carbon, sulphates, ammonium, chlorides and nitrates were found to be the major constituents of PM10. The contribution of the last of these was found to increase significantly with PM10 concentration (Pearson coefficient correlation of 0.7, p-value < 0.001). Individual airborne particles were characterised morphologically and chemically via a combination of Scanning Electron Microscopy and Energy-Dispersive X-ray spectroscopy (SEM-EDX). The subsequent image analysis revealed C-rich particles with shapes that pointed to combustion processes. Moreover, carbonaceous particles seemed to act as vehicles for sulphur compounds and metals (S, Na, Fe, Ca, Mg, K, Al, Mn, Zn and Cu). Coarse particles were found to be mainly constituted by crustal material and marine and carbonaceous particles. Although most of the studied individual particles in PM10 samples (86.0%) had a diameter within the 0.1-2.5 μm range, 1.8% of them had sizes lower than 0.1 μm 40.2% of the total studied particles were estimated to be inhaled and deposited in the human respiratory tract; 12.3% of these particles would reach the deepest zones, thereby posing a major risk to human health.
Within a healthcare system with managed competition, health insurers are expected to act as prudent buyers of care on behalf of their customers. To fulfil this role adequately, understanding consumer preferences for health plan characteristics is of vital importance. Little is known, however, about these preferences and how they vary across consumers. Using a discrete choice experiment (DCE) we quantified trade-offs between basic health plan characteristics and analysed whether there are differences in preferences according to age, health status and income. We selected four health plan characteristics to be included in the DCE: (i) the level of provider choice and associated level of reimbursement, (ii) the primary focus of provider contracting (price, quality, social responsibility), (iii) the level of service benefits, and (iv) the monthly premium. This selection was based on a literature study, expert interviews and focus group discussions. The DCE consisted of 17 choice sets, each comprising two hypothetical health plan alternatives. A representative sample (n = 533) of the Dutch adult population, based on age, gender and educational level, completed the online questionnaire during the annual open enrolment period for 2015. The final model with four latent classes showed that being able to choose a care provider freely was by far the most decisive characteristic for respondents aged over 45, those with chronic conditions, and those with a gross income over €3000/month. Monthly premium was the most important choice determinant for young, healthy,
 and lower income respondents. We conclude that it would be very unlikely for half of the sample to opt for health plans with restricted provider choice. However, a premium discount up to €15/month by restricted health plans might motivate especially younger, healthier, and less wealthy consumers to choose these plans.
Somatic missense mutations in the Ser/Thr protein phosphatase 2A (PP2A) Aα scaffold subunit gene PPP2R1A are among the few genomic alterations that occur frequently in serous endometrial carcinoma (EC) and carcinosarcoma, two clinically aggressive subtypes of uterine cancer with few therapeutic options. Previous studies reported that cancer-associated Aα mutants exhibit defects in binding to other PP2A subunits and contribute to cancer development by a mechanism of haploinsufficiency. Here we report on the functional significance of the most recurrent PPP2R1A mutations in human EC, which cluster in Aα HEAT repeats 5 and 7. Beyond predicted loss-of-function effects on the formation of a subset of PP2A holoenzymes, we discovered that Aα mutants behave in a dominant-negative manner due to gain-of-function interactions with the PP2A inhibitor TIPRL1. Dominant-negative Aα mutants retain binding to specific subunits of the B56/B' family and form substrate trapping complexes with impaired phosphatase activity via increased recruitment of TIPRL1. Accordingly, overexpression of the Aα mutants in EC cells harboring wild-type PPP2R1A increased anchorage-independent growth and tumor formation, and triggered hyperphosphorylation of oncogenic PP2A-B56/B' substrates in the GSK3β, Akt, and mTOR/p70S6K signaling pathways. TIPRL1 silencing restored GSK3β phosphorylation and rescued the EC cell growth advantage. Our results reveal how PPP2R1A mutations affect PP2A function and oncogenic signaling, illuminating the genetic basis for serous EC development and its potential control by rationally targeted therapies. Cancer Res; 76(19); 5719-31. ©2016 AACR.
The intersection of HIV-related health outcomes and problem substance use has been well documented. New York City continues to be a focal point of the U.S. HIV epidemic. In 2011, the NYC Department of Health and Mental Hygiene (NYC DOHMH) issued a recommendation that all HIV infected individuals should be offered antiretroviral therapy (ART) regardless of CD4 cell count or other indicators of disease progression. This policy is based in the concept of "treatment as prevention," in which providing ART to people living with HIV (PLWH) greatly reduces the likelihood of HIV transmission, while also improving individual health. The "ART for ALL" (AFA) study was designed to inform modifications to and identify gaps in the implementation of universal ART, and specifically to help guide allocation of resources to obtain local policy goals for increasing viral suppression among PLWH who have problem substance use.
The AFA Study is informed by two complementary frameworks: Glasgow and colleagues' RE-AIM model, a multi-level framework developed to guide the evaluation of implementation of new policies, and Bronfrenbrenner's ecological systems model, which conceptualizes the bi-directional interplay between people and their environment. Using multi-level data and mixed methods, the primary aims of the AFA Study are to assess rates of viral load suppression, using the NYC HIV Surveillance Registry, within 12 months of HIV diagnosis with (a) yearly cohorts of high-risk-to-transmit, difficult-to-treat, substance using patients recruited from NYC Sexually Transmitted Disease clinics and a large detoxification unit and (b) yearly cohorts of all newly HIV diagnosed people in NYC. Further goals include (c) recruiting cross-sectional samples of HIV/AIDS service providers to assess ART initiation with problem substance users and d) examining geographic factors that influence rates of viral load suppression. An Implementation Collaborative Board meets regularly to guide study procedures and interpret results.
The AFA Study has the unique strength of accessing and analyzing data at multiple levels using mixed methodology, taking advantage of NYC DOHMH biomedical surveillance data. If successful, others may benefit from lessons learned to inform local and state policies to improve the health of PLWH and further reduce HIV transmission.
Heavy metals, including cadmium (Cd), lead (Pb) and mercury (Hg) act as nephrotoxic agents, particularly in the renal cortex. The aim of the study was to determine the concentrations of Cd, Pb and Hg in kidneys removed from patients due to lesions of various etiologies and from patients after the rejection of transplanted kidneys. Additionally, we determined the influence of selected biological and environmental factors on the concentrations of toxic metals. The study material consisted of kidneys with tumor lesions (n = 27), without tumors (n = 7) and its extracted grafts (n = 10) obtained from patients belongs to the north-western areas of Poland. The determined metal concentrations in the renal cortex and medulla may be arranged in the following descending order: Cd > Pb > Hg. The highest concentrations of Cd and Hg were found in the cortex, while the maximum content Pb was observed in the medulla. Significant correlations were found in the concentrations of the same metals between cortex and medulla and between Pb and Hg in the renal medulla. Pb content was higher in the renal medulla of men than in the cortex of the elderly (above 60 years of age). The highest concentrations of Pb and Hg were found in the cortex and medulla, of the kidneys had not neoplastic changes, and lower content of these metals were found in the extracted kidney grafts. In summary, renal grafts accumulate less heavy metals than cancerous kidneys, what could have been caused by immunosuppressors taken by the graft recipients. Moreover, sex, age and smoking are key factors responsible for xenobiotics concentrations.
Both the lateral septum (LS) and anterior hypothalamus (AHA) regulate behavioural defense. We tested whether those two interconnected structures act in serial in that regard. Infusions of the GABAA agonist muscimol into one side of the LS and the contralateral (but not ipsilateral) AHA suppressed rats' burying in the shock-probe test whereas none of our muscimol infusion approaches altered their open-arm avoidance in the elevated plus-maze. These results suggest that the LS-AHA circuit serves a specialized role in defensive responses towards discrete, localizable threat stimuli but not towards potential threats.
Carotenoids are precursors of carotenoid derived molecules termed apocarotenoids, which include isoprenoids with important functions in plant-environment interactions such as the attraction of pollinators and the defense against pathogens and herbivores. Apocarotenoids also include volatile aromatic compounds that act as repellents, chemoattractants, growth simulators and inhibitors, as well as the phytohormones abscisic acid and strigolactones. In plants, apocarotenoids can be found in several types of plastids (etioplast, leucoplast and chromoplast) and among different plant tissues such as flowers and roots. The structural similarity of some flower and spice isoprenoid volatile organic compounds (β-ionone and safranal) to carotenoids has led to the recent discovery of carotenoid-specific cleavage oxygenases, including carotenoid cleavage dioxygenases and 9-cis-epoxydioxygenases, which tailor and transform carotenoids into apocarotenoids. The great diversity of apocarotenoids is a consequence of the huge amount of carotenoid precursors, the variations in specific cleavage sites and the modifications after cleavage. Lycopene, β-carotene and zeaxanthin are the precursors of the main apocarotenoids described to date, which include bixin, crocin, picrocrocin, abscisic acid, strigolactone and mycorradicin.The current chapter will give rise to an overview of the biosynthesis and function of the most important apocarotenoids in plants, as well as the current knowledge about the carotenoid cleavage oxygenase enzymes involved in these biosynthetic pathways.
Carotenoids are ubiquitous and essential pigments in photosynthesis. They absorb in the blue-green region of the solar spectrum and transfer the absorbed energy to (bacterio-)chlorophylls, and so expand the wavelength range of light that is able to drive photosynthesis. This is an example of singlet-singlet energy transfer, and so carotenoids serve to enhance the overall efficiency of photosynthetic light reactions. Carotenoids also act to protect photosynthetic organisms from the harmful effects of excess exposure to light. Triplet-triplet energy transfer from chlorophylls to carotenoids plays a key role in this photoprotective reaction. In the light-harvesting pigment-protein complexes from purple photosynthetic bacteria and chlorophytes, carotenoids have an additional role of structural stabilization of those complexes. In this article we review what is currently known about how carotenoids discharge these functions. The molecular architecture of photosynthetic systems will be outlined first to provide a basis from which to describe carotenoid photochemistry, which underlies most of their important functions in photosynthesis.
Drugs used chronically by patients with diseases of the cardiovascular system (group C of the ATC classification) may act on adrenergic receptors and/or certain ion channels, which gives them the potential to interact with the action of local dental anesthetics. The aim of the study was to investigate the effect of systemically administered chronic cardiovascular medication (oral route) on the efficacy of intraoral local anesthesia in patients with diseases of the cardiovascular system.
This was a prospective cohort study which analyzed the efficacy of local terminal anesthesia (onset of anesthesia,
 duration anesthetized area) in the upper jaw of 70 patients: 40 patients on medication for cardiovascular system disorders and 30 patients who were not using these drugs (the control group). The following cardiovascular drugs were used: beta blockers, angiotensin converting enzyme inhibitors, calcium channel blockers, vasodilatators, diuretics, angiotensin receptor blockers, antiarrhythmics, statins and alfa blockers.
The onset of anesthesia on the vestibular side was faster in those taking cardiovascular drugs (40.50±19.87 s) than the control patients (58.93±31.07 s; P = 0.004) and duration of anesthesia on this side was shorter. Although the difference was not significant, it was evident that on vestibular and palatal side the anesthetized area was more rapidly reduced in the patients taking cardiovascular drugs. The duration of cardiovascular therapy also had a significant impact on the anesthetized area.
Drugs acting on cardiovascular system may influence the effect of local anesthetics used in dentistry, possibly through interaction with autonomic receptors and ion channels.
The idea behind ego depletion is that willpower draws on a limited mental resource, so that engaging in an act of self-control impairs self-control in subsequent tasks. To present ego depletion as more than a convenient metaphor, some researchers have proposed that glucose is the limited resource that becomes depleted with self-control. However, there have been theoretical challenges to the proposed glucose mechanism, and the experiments that have tested it have found mixed results. We used a new meta-analytic tool, p-curve analysis, to examine the reliability of the evidence from these experiments. We found that the effect sizes reported in this literature are possibly influenced by publication or reporting bias and that, even within studies yielding significant results, the evidential value of this research is weak. In light of these results, and pending further evidence, researchers and policymakers should refrain from drawing any conclusions about the role of glucose in self-control.
Long noncoding RNAs (lncRNAs) are emerging as regulators of gene expression in pathogenesis, including cancer. Recently, lncRNAs have been implicated in progression of specific subtypes of breast cancer. One aggressive, basal-like subtype associates with increased EGFR signaling, while another, the HER2-enriched subtype, engages a kin of EGFR Based on the premise that EGFR-regulated lncRNAs might control the aggressiveness of basal-like tumors, we identified multiple EGFR-inducible lncRNAs in basal-like normal cells and overlaid them with the transcriptomes of over 3,000 breast cancer patients. This led to the identification of 11 prognostic lncRNAs. Functional analyses of this group uncovered LINC01089 (here renamed LncRNA Inhibiting Metastasis; LIMT), a highly conserved lncRNA, which is depleted in basal-like and in HER2-positive tumors, and the low expression of which predicts poor patient prognosis. Interestingly, EGF rapidly downregulates LIMT expression by enhancing histone deacetylation at the respective promoter. We also find that LIMT inhibits extracellular matrix invasion of mammary cells in vitro and tumor metastasis in vivo In conclusion, lncRNAs dynamically regulated by growth factors might act as novel drivers of cancer progression and serve as prognostic biomarkers.
Bacillus circulans xylanase (BcX), a family 11 glycoside hydrolase, catalyses the hydrolysis of xylose polymers with a net retention of stereochemistry. Glu172 in BcX is believed to act as a general acid by protonating the aglycone during glycosylation, and then as a general base to facilitate the deglycosylation step. The key to the dual role of this general acid/base lies in its protonation states, which depend on its intrinsic pKa value and the specific environment which it resides within. To fully understand the detailed molecular features in BcX to establish the dual role of Glu172, we present a combined study based on both atomistic simulations and empirical models to calculate pKa shifts for the general acid/base Glu172 in BcX at different functional states. Its pKa values and those of nearby residues, obtained based on QM/MM free energy calculations, MCCE and PROPKA, show a good agreement with available experimental data. Additionally, our study provides additional insights into the effects of structural and electrostatic perturbations caused by mutations and chemical modifications, suggesting that the local solvation environment and mutagenesis of the residues adjacent to Glu172 establish its dual role during hydrolysis. The strengths and limitations of various methods for calculating pKas and pKa shifts have also been discussed.
The increasing mortality rates from alcohol-related liver disease (ARLD) are a public health concern. To address this, alcohol care teams (ACT) case-find and lead management of alcohol issues for these patients. Local assessments of ACTs have shown reductions in emergency admissions and emergency department attendances. We examine the impact of ACTs on emergency hospital activity following a diagnosis of ARLD.
Administrative Hospital Episode Statistics (HES) data were extracted. Information on ACT provision at English NHS hospital trusts and sites in 2009/10 was taken from a survey by Public Health England. We undertook a difference-in-difference analysis to compare emergency hospital activity for a cohort of individuals diagnosed with ARLD who presented to hospitals either with or without an ACT in the one year before and after a first ARLD diagnosis during 2009/10.
Over the study period, 9,165 individuals eligible for inclusion in our study had a first diagnosis of ARLD. 4,768 presented to one of 41 hospital trusts with an ACT (59 sites) and 4,397 presented to one of 50 non-ACT hospital trusts (65 sites). Whilst age and sex demographics were similar between the two cohorts, the ACT hospital cohort had a higher proportion of individuals in the most deprived quintile (41.6 % v 28.5 % p < .0001). In the difference-in-difference analysis, the presence of an ACT at a hospital trust was not associated with a change in all-cause emergency admissions (0.020 (95 % CI -0.070, 0.111), p = 0.656), alcohol-related emergency admissions (-0.025 (95 % CI -0.104, 0.054), p = 0.536) or all-cause emergency department attendances (0.042 (95 % CI -0.087, 0.171), p = 0.521). Sensitivity analyses by sex and hospital site did not affect the study findings.
In this study, the presence of an ACT at the NHS hospital trust where individuals have their first recorded diagnosis of ARLD does not appear to be associated with subsequent emergency hospital activity within these populations. Further analysis focussing on the components and specific effects of ACT interventions on individuals and systems both pre- and post-diagnosis of ARLD may reveal important avenues to improve care.
Primary congenital glaucoma (PCG) and early onset glaucomas are one of the major causes of children and young adult blindness worldwide. Both autosomal recessive and dominant inheritance have been described with involvement of several genes including CYP1B1, FOXC1, PITX2, MYOC and PAX6. However, mutations in these genes explain only a small fraction of cases suggesting the presence of further candidate genes.
To elucidate further genetic causes of these conditions whole exome sequencing (WES) was performed in an Italian patient, diagnosed with PCG and retinal detachment, and his unaffected parents. Sanger sequencing of the complete coding region of COL1A1 was performed in a total of 26 further patients diagnosed with PCG or early onset glaucoma. Exclusion of pathogenic variations in known glaucoma genes as CYP1B1, MYOC, FOXC1, PITX2 and PAX6 was additionally done per Sanger sequencing and Multiple Ligation-dependent Probe Amplification (MLPA) analysis.
In the patient diagnosed with PCG and retinal detachment, analysis of WES data identified compound heterozygous variants in COL1A1 (p.Met264Leu; p.Ala1083Thr). Targeted COL1A1 screening of 26 additional patients detected three further heterozygous variants (p.Arg253*, p.Gly767Ser and p.Gly154Val) in three distinct subjects: two of them diagnosed with early onset glaucoma and mild form of osteogenesis imperfecta (OI), one patient with a diagnosis of PCG at age 4 years. All five variants affected evolutionary, highly conserved amino acids indicating important functional restrictions. Molecular modeling predicted that the heterozygous variants are dominant in effect and affect protein stability and thus the amount of available protein, while the compound heterozygous variants act as recessive alleles and impair binding affinity to two main COL1A1 binding proteins: Hsp47 and fibronectin.
Dominant inherited mutations in COL1A1 are known causes of connective tissues disorders such as OI. These disorders are also associated with different ocular abnormalities, although recognition of the common pathology for both features is seldom being recognized. Our results expand the role of COL1A1 mutations in different forms of early-onset glaucoma with and without signs of OI. Thus, we suggest including COL1A1 mutation screening in the genetic work-up of glaucoma cases and detailed ophthalmic examinations with fundus analysis in patients with OI.
Inflammation of tooth supporting structures is referred to as periodontitis. C-reactive proteins (CRP) levels are usually increased in case of chronic inflammatory process like periodontitis. Association of CRP with pregnancy has been observed in the past, which includes most commonly preterm delivery, preeclampsia, etc. Therefore, it can be hypothesized that CRP may act as a link between periodontitis and adverse pregnancy outcomes. Hence, we aim to evaluate the plasma CRP levels in pregnant women with and without periodontal
 pathologies.
The study included 210 pregnant women who reported to the hospital with periodontal problems and for routine checkups. All the patients were divided into three groups based on the presence and absence of periodontal pathologies. Russell's Periodontal Index Score was used for the evaluation of periodontal status of the subjects.
While comparing the mean CRP levels in all the three study groups, statistically significant results were obtained. Statistically significant results were obtained while comparing the mean CRP levels in group C patients before treatment and after treatment therapy. The CRP levels were estimated by taking blood samples. Paired t-test and one-way analysis of variance was used to assess the correlation between the two parameters.
Casual association might exist between the CRP levels and periodontal diseases in pregnant women and the CRP levels may also get elevated in pregnant women.
Although it is known that maternal disordered eating is related to restrictive feeding practices, there is little research exploring mechanisms for this association or its effects on other feeding practices. The purpose of this study was to assess whether maternal emotion responses mediate the association between maternal binge eating (BE) and child feeding practices, in order to identify potential risk factors for feeding practices that influence child weight.
This longitudinal observational study included (n = 260) mothers and children from the STRONG Kids Panel Survey. At Wave 1, children were an average of 37 months old (SD = 6.9), and at Wave 2 children were an average of 57 months old (SD = 8.3). Mothers self-reported their frequency of binge eating behavior (Wave 1), responses to children's negative emotions (Wave 1), feeding practices (Wave 1 and Wave 2), and child height and weight were measured at both time points. Using bias-corrected bootstrapping procedures, we tested the hypothesis that longitudinal associations between maternal BE and nonresponsive parent feeding practices would be mediated by parents' unsupportive responses to children's negative emotion. We also tested a serial mediation model positing that maternal BE predicts child body mass index (BMI) percentile change 18-24 months later, indirectly through unsupportive responses to negative emotion and nonresponsive feeding practices.
Maternal BE predicted use of more nonresponsive feeding practices (e.g. Emotion Regulation, Restriction for Health, Pressure to Eat, and Food as Reward), indirectly through more Distress responses to children's negative emotions. In the serial mediation model, maternal BE was associated with greater use of Distress responses, which indirectly predicted higher child BMI percentile through Food as Reward feeding practices.
These results suggest that maternal eating and emotion responsiveness are important for understanding the interpersonal context of feeding behaviors, and child weight outcomes. Distress responses may serve as a risk factor for use of unhealthful feeding practices among mothers with BE and these responses may increase children's risk for weight gain.
This study used an observational prospective design. Therefore, it has not been registered as a clinical intervention trial.
Eating self-regulatory capacity can help individuals to cope with the obesogenic environment and achieve, as well as maintain, a healthy weight and diet. At present, there is no comprehensive, reliable and valid questionnaire for assessing this capacity and measuring change in response to self-regulation interventions in adults. This paper reports the development of the Self-regulation of Eating Behaviour Questionnaire (SREBQ) for use in UK adults, and presents evidence for its reliability and construct validity. The development of the SREBQ involved generation of an item pool, followed by two pilot studies (Samples 1 and 2) and a test of the questionnaire's underlying factor structure (Sample 3). The final version of the SREBQ was then assessed for reliability and construct validity (Sample 4).
Development of the SREBQ resulted in a 5-item questionnaire. The face validity was satisfactory, as assessed by the pilot studies. The factor structure analysis (Sample 3) suggested that it has a single underlying factor, which was confirmed in a second sample (Sample 4). The SREBQ had strong construct validity, showing a positive correlation with general measures of self-regulation. It was also positively correlated with motivation and behavioural automaticity, and negatively correlated with food responsiveness and emotional over-eating (p < 0.001). It showed good discriminant validity, as it was only weakly associated with satiety responsiveness, food fussiness and slowness in eating.
The SREBQ is a reliable and valid measure for assessment of eating self-regulatory capacity in the general UK adult population.
Cathepsin S (CTSS) is a lysosomal protease whose activity regulation is important for MHC-II signaling and subsequent activation of CD4(+) T cell mediated immune responses. Dysregulation of its enzymatic activity or enhanced secretion into extracellular environments is associated with the induction or progression of several autoimmune diseases. Here we demonstrate that commensal intestinal bacteria influence secretion rates and intracellular activity of host CTSS and that symbiotic bacteria, i.e. Bacteroides vulgatus mpk, may actively regulate this process and help to maintain physiological levels of CTSS activities in order to prevent from induction of pathological inflammation. The symbiont-controlled regulation of CTSS activity is mediated by anticipating reactive oxygen species induction in dendritic cells which, in turn, maintains cystatin C (CysC) monomer binding to CTSS. CysC monomers are potent endogenous CTSS inhibitors. This Bacteroides vulgatus caused and CysC dependent CTSS activity regulation is involved in the generation of tolerant intestinal dendritic cells contributing to prevention of T-cell mediated induction of colonic inflammation. Taken together, we demonstrate that symbionts of the intestinal microbiota regulate host CTSS activity and secretion and might therefore be an attractive approach to deal with CTSS associated autoimmune diseases.
In many parts of the world policy and research interventions to modify sedentary behavior of children and adolescents are now being developed. However, the evidence to inform these interventions (e.g. how sedentary behavior changes across childhood and adolescence) is limited. This study aimed to assess longitudinal changes in sedentary behavior, and examine the degree of tracking of sedentary behavior from age 7y to 15y.
Participants were part of the Gateshead Millennium Study cohort. Measures were made at age 7y (n = 507), 9y (n = 510), 12y (n = 425) and 15y (n = 310). Participants were asked to wear an ActiGraph GT1M and accelerometer epochs were defined as sedentary when recorded counts were ≤25 counts/15 s. Differences in sedentary time and sedentary fragmentation were examined using the Friedman test. Tracking was examined using Spearman's correlation coefficients and trajectories over time were assessed using multilevel linear spline modelling.
Median daily sedentary time increased from 51.3% of waking hours at 7y to 74.2% at 15y. Sedentary fragmentation decreased from 7y to 15y. The median number of breaks/hour decreased from 8.6 to 4.1 breaks/hour and the median bout duration at 50% of the cumulative sedentary time increased from 2.4 min to 6.4 min from 7y to 15y. Tracking of sedentary time and sedentary fragmentation was moderate from 7y to 15y however, the rate of change differed with the steepest increases/decreases seen between 9y and 12y.
In this study, sedentary time was high and increased to almost 75% of waking hours at 15y. Sedentary behavior became substantially less fragmented as children grew older. The largest changes in sedentary time and sedentary fragmentation occurred between 9y to 12y, a period which spans the transition to secondary school. These results can be used to inform future interventions aiming to change sedentary behavior.
T lymphocyte-mediated immune responses are critical for antitumour immunity; however, T cell function is impaired in the tumour environment. MicroRNAs are involved in regulation of the immune system. While little is known about the function of intrinsic microRNAs in CD8(+) T cells in the tumour microenvironment. Here, we found that miR-491 was upregulated in CD8(+) T cells from mice with colorectal cancer. Retroviral overexpression of miR-491 in CD8(+) and CD4(+) T cells inhibited cell proliferation and promoted cell apoptosis and decreased the production of interferon-γ in CD8(+) T cells. We found that miR-491 directly targeted cyclin-dependent kinase 4, the transcription factor T cell factor 1 and the anti-apoptotic protein B-cell lymphoma 2-like 1 in CD8(+) T cells. Furthermore, tumour-derived TGF-β induced miR-491 expression in CD8(+) T cells. Taken together, our results suggest that miR-491 can act as a negative regulator of T lymphocytes, especially CD8(+) T cells, in the tumour environment; thus, this study provides a novel insight on dysfunctional CD8(+) T cells during tumourigenesis and cancer progression. In conclusion, miR-491 may be a new target for antitumour immunotherapy.
Guard cells (GCs) are specialised cells within the plant epidermis which form stomatal pores, through which gas exchange can occur. The GCs derive through a specialised lineage of cell divisions which is specified by the transcription factor SPEECHLESS (SPCH), the expression of which can be detected in undifferentiated epidermal cells prior to asymmetric division. Other transcription factors may act before GC specification and be required for correct GC patterning. Previously, the DOF transcription factor STOMATAL CARPENTER
 1 (SCAP1) was shown to be involved in GC function, by activating a set of GC-specific genes required for GC maturation and activity. It is thus far unknown whether SCAP1 can also affect stomatal development.
Here we show that SCAP1 expression can also be observed in young leaf primordia, before any GC differentiation occurs. The study of transgenic plants carrying a proSCAP1:GUS-GFP transcriptional fusion, coupled with qPCR analyses, indicate that SCAP1 expression peaks in a temporal window which is coincident with expression of stomatal patterning genes. Independent scap1 loss-of-function mutants have a reduced number of GCs whilst SCAP1 over expression lines have an increased number of GCs, in addition to altered GC distribution and spacing patterns. The study of early markers for stomatal cell lineage in a background carrying gain-of-function alleles of SCAP1 revealed that, compared to the wild type, an increased number of protodermal cells are recruited in the GC lineage, which is reflected in an increased number of meristemoids.
Our results suggest an early role for SCAP1 in GC differentiation. We propose that a function of SCAP1 is to integrate different aspects of GC biology including specification, spacing, maturation and function.
Decreased thyroidal hormone production is found during lipopolysaccharide (LPS)-induced endotoxic shock in animals as well as in critically ill patients. Here we studied the role of the thyroid hormone receptors (TRs) in activation of STAT3, NF-κB and ERK, which play a key role in the response to inflammatory cytokines during sepsis. TR knockout mice showed down-regulation of hepatic inflammatory mediators, including interleukin 6 (IL-6) in response to LPS. Paradoxically, STAT3 and ERK activity were higher, suggesting that TRs could act as endogenous repressors of these pathways. Furthermore, hyperthyroidism increased cytokine production and mortality in response to LPS, despite decreasing hepatic STAT3 and ERK activity. This suggested that TRs could directly repress the response of the cells to inflammatory mediators. Indeed, we found that the thyroid hormone T3 suppresses IL-6 signalling in macrophages and hepatocarcinoma cells, inhibiting STAT3 activation. Consequently, the hormone strongly antagonizes IL-6-stimulated gene transcription, reducing STAT3 recruitment and histone acetylation at IL-6 target promoters. In conclusion, TRs are potent regulators of inflammatory responses and immune homeostasis during sepsis. Reduced responses to IL-6 should serve as a negative feedback mechanism for preventing deleterious effects of excessive hormone signaling during infections.
A serious challenge in cancer treatment is to reposition the activity of various already known drug candidates against cancer. There is a need to rewrite and systematically analyze the detailed mechanistic aspect of cellular networks to gain insight into the novel role played by various molecules. Most Human Immunodeficiency Virus infection-associated cancers are caused by oncogenic viruses like Human Papilloma Viruses and Epstein-Bar Virus. As the onset of AIDS-associated cancers marks the severity of AIDS, there might be possible interconnections between the targets and mechanism of both the diseases. We have explored the possibility of certain antiviral compounds to act against major AIDS-associated cancers: Kaposi's Sarcoma, Non-Hodgkin Lymphoma, and Cervical Cancer with the help of systems pharmacology approach that includes screening for targets and molecules through the construction of a series of drug-target and drug-target-diseases network. Two molecules (Calanolide A and Chaetochromin B) and the target "HRAS" were finally screened with the help of molecular docking and molecular dynamics simulation. The results provide novel antiviral molecules against HRAS target to treat AIDS defining cancers and an insight for understanding the pharmacological, therapeutic aspects of similar unexplored molecules against various cancers.
This review assesses the importance of proteostasis in skeletal muscle maintenance with a specific emphasis on autophagy. Skeletal muscle appears to be particularly vulnerable to genetic defects in basal and induced autophagy, indicating that autophagy is co-substantial to skeletal muscle maintenance and adaptation. We discuss emerging evidence that tension-induced protein unfolding may act as a direct link between mechanical stress and autophagic pathways. Mechanistic links between protein damage, autophagy and muscle hypertrophy, which is also induced by mechanical stress, are still poorly understood. However, some mouse models of muscle disease show ameliorated symptoms upon effective targeting of basal autophagy. These findings highlight the importance of autophagy as therapeutic target and suggest that elucidating connections between protein unfolding and mTOR-dependent or mTOR-independent hypertrophic responses is likely to reveal specific therapeutic windows for the treatment of muscle wasting disorders.
Capparis Spinosa L. is an aromatic plant growing wild in dry regions around the Mediterranean basin. Capparis Spinosa was shown to possess several properties such as antioxidant, antifungal, and anti-hepatotoxic actions. In this work, we aimed to evaluate immunomodulatory properties of Capparis Spinosa leaf extracts in vitro on human peripheral blood mononuclear cells (PBMCs) from healthy individuals.
Using MTT assay, we identified a range of Capparis Spinosa doses, which were not toxic. Unexpectedly, we found out that Capparis Spinosa aqueous fraction exhibited an increase in cell metabolic activity, even though similar doses did not affect cell proliferation as shown by CFSE. Interestingly, Capparis Spinosa aqueous fraction appeared to induce an overall anti-inflammatory response through significant inhibition of IL-17 and induction of IL-4 gene expression when PBMCs were treated with the non toxic doses of 100 and/or 500 μg/ml. Phytoscreening analysis of the used Capparis Spinosa preparations showed that these contain tannins; sterols, alkaloids; polyphenols and flavonoids. Surprisingly, quantification assays showed that our Capparis Spinosa preparation contains low amounts of polyphenols relative to Capparis Spinosa used in other studies. This Capparis Spinosa also appeared to act as a weaker scavenging free radical agent as evidenced by DPPH radical scavenging test. Finally, polyphenolic compounds including catechin, caffeic acid, syringic acid, rutin and ferulic acid were identified by HPLC, in the Capparis spinosa preparation.
Altogether, these findings suggest that our Capparis Spinosa preparation contains interesting compounds, which could be used to suppress IL-17 and to enhance IL-4 gene expression in certain inflammatory situations. Other studies are underway in order to identify the compound(s) underlying this effect.
Green nanoparticle synthesis was achieved using environmentally acceptable plant extracts reducing and capping agents. The present study was based on assessments to the anticancer activities to determine the effect of synthesized silver nanoparticles (AgNPs) from three medicinal plants on human liver (HepG2) and prostate (PC3) cancer cell lines. The synthesis of AgNPs using Plumbago zeylanica (Pz), Semecarpus anacardium (Sa) and Terminalia arjuna (Ta) plant extracts in the reaction mixture was monitored by UV-visible spectroscopy. FTIR results clearly illustrated that the plant extracts containing prominent peaks of functional groups and biomolecules viz., tannins, phenols, flavonoids and triterpenoids those act as capping agents and involved in the stabilization of the synthesised silver nanoparticles. Synthesized AgNPs were spherical and cuboid in shape which is determined by SEM. Average size of the AgNPs were between 80-98, 60-95 and 34-70 nm for PzAgNPs, SaAgNPs and TaAgNPs, respectively. Further, the synthesized AgNPs were characterized by XRD, EDX, DLS and Zeta potential analysis. Moreover, the synthesized AgNPs exhibited a dose-dependent cytotoxicity against human liver and prostate cancer cell lines. The inhibitory concentration (IC50) values of HepG2, PC3 and Vero cells were found to be 70.97, 58.61, 96.41; 10.04, 42.77, 83.86; and 28.42, 41.78, 69.48 μg/ml for PzAgNPs, SaAgNPs and TaAgNPs at 48 h incubation. An induction of apoptosis was confirmed by DNA fragmentation, Hoechst, Rhodamine and AO/EtBr staining. The present results strongly suggested that the AgNPs synthesized using P. zeylanica, S. anacardium and T. arjuna extracts showed potential anticancer activity of HepG2 and PC3 cell lines.
Issue: Since enactment of the Affordable Care Act (ACA), many more women have health insurance than before the law, in part because it prohibits insurer practices that discriminate against women. However, gaps in women's health coverage persist. Insurers often exclude health services that women are likely to need, leaving women vulnerable to higher costs and denied claims that threaten their economic security and physical health. Goal: To uncover the types and incidence of insurer exclusions that may disproportionately affect women's coverage. Method: The authors examined qualified health plans from 109 insurers across 16 states for 2014, 2015, or both years. Key findings and conclusions: Six types of services are frequently excluded from insurance coverage: treatment of conditions resulting from noncovered services, maintenance therapy, genetic testing, fetal reduction surgery, treatment of self-inflicted conditions, and preventive services not covered by law. Policy change recommendations include prohibiting variations within states' "essential health benefits" benchmark plans and requiring transparency and simplified language in plan documents.
Preparing data for medical research can be challenging, detail oriented, and time consuming. Transcription
 errors, missing or nonsensical data, and records not applicable to the study population may hamper progress and, if unaddressed, can lead to erroneous conclusions. In addition, study data may be housed in multiple disparate databases and complex formats. Merging methods may be incomplete to obtain temporally synchronized data elements. We created a comprehensive database to explore the general hypothesis that environmental and occupational factors influence health outcomes and risk-taking behavior among active duty Air Force personnel. Several databases containing demographics, medical records, health survey responses, and safety incident reports were cleaned, validated, and linked to form a comprehensive, relational database. The final step involved removing and transforming personally identifiable information to form a Health Insurance Portability and Accountability Act compliant limited database. Initial data consisted of over 62.8 million records containing 221 variables. When completed, approximately 23.9 million clean and valid records with 214 variables remained. With a clean, robust database, future analysis aims to identify high-risk career fields for targeted interventions or uncover potential protective factors in low-risk career fields.
The interaction of gold nanoparticles (AuNP) with human immune-deficiency virus aspartic protease (HIVPR) is modelled using a regime of molecular dynamics simulations. The simulations of the 'docking', first as a rigid-body complex, and eventually through flexible-fit analysis, creates 36 different complexes from four initial orientations of the nanoparticle strategically positioned around the surface of the enzyme. The structural deviations of the enzymes from the initial x-ray crystal structure during each docking simulation are assessed by comparative analysis of secondary structural elements, root mean square deviations, B-factors, interactive bonding energies, dihedral angles, radius of gyration (R g), circular dichroism (CD), volume occupied by C α , electrostatic potentials, solvation energies and hydrophobicities. Normalisation of the data narrows the selection from the initial 36 to one 'final' probable structure. It is concluded that, after computer simulations on each of the 36 initial complexes incorporating the 12 different biophysical techniques, the top five complexes are the same no matter which technique is explored. The significance of the present work is an expansion of an earlier study on the molecular dynamic simulation for the interaction of HIVPR with silver nanoparticles. This work is supported by experimental evidence since the initial 'orientation' of the AgNP with the enzyme is the same as the 'final' AuNP-HIVPR complex generated in the present study. The findings will provide insight into the forces of the binding of the HIVPR to AuNP. It is anticipated that the protocol developed in this study will act as a standard process for the interaction of any nanoparticle with any biomedical target.
Post-exposure prophylaxis (PEP) against rabies infection consists of a combination of passive immunisation with plasma-derived human or equine immune globulins and active immunisation with vaccine delivered shortly after exposure. Since anti-rabies immune globulins are expensive and scarce, there is a need for cheaper alternatives that can be produced more consistently. Previously, we generated potent virus-neutralising VHH, also called Nanobodies, against the rabies glycoprotein that are effectively preventing lethal disease in an in vivo mouse model. The VHH domain is the smallest antigen-binding functional fragment of camelid heavy chain-only antibodies that can be manufactured in microbial expression systems. In the current study we evaluated the efficacy of half-life extended anti-rabies VHH in combination with vaccine for PEP in an intranasal rabies infection model in mice. The PEP combination therapy of systemic anti-rabies VHH and intramuscular vaccine significantly delayed the onset of disease compared to treatment with anti-rabies VHH alone, prolonged median survival time (35 versus 14 days) and decreased mortality (60% versus 19% survival rate), when treated 24 hours after rabies virus challenge. Vaccine alone was unable to rescue mice from lethal disease. As reported also for immune globulins, some interference of anti-rabies VHH with the antigenicity of the vaccine was observed, but this did not impede the synergistic effect. Post exposure treatment with vaccine and human anti-rabies immune globulins was unable to protect mice from lethal challenge. Anti-rabies VHH and vaccine act synergistically to protect mice after rabies virus exposure, which further validates the possible use of anti-rabies VHH for rabies PEP.
DYRK1A is important in neuronal development and function, and its excessive activity is considered a significant pathogenic factor in Down syndrome and Alzheimer's disease. Thus, inhibition of DYRK1A has been suggested to be a new strategy to modify the disease. Very few compounds, however, have been reported to act as inhibitors, and their potential clinical uses require further evaluation. Here, we newly identify CX-4945, the safety of which has been already proven in the clinical setting, as a potent inhibitor of DYRK1A that acts in an ATP-competitive manner. The inhibitory potency of CX-4945 on DYRK1A (IC50=6.8 nM) in vitro was higher than that of harmine, INDY or proINDY, which are well-known potent inhibitors of DYRK1A. CX-4945 effectively reverses the aberrant phosphorylation of Tau, amyloid precursor protein (APP) and presenilin 1 (PS1) in mammalian cells. To our surprise, feeding with CX-4945 significantly restored the neurological and phenotypic defects induced by the overexpression of minibrain, an ortholog of human DYRK1A, in the Drosophila model. Moreover, oral administration of CX-4945 acutely suppressed Tau hyperphosphorylation in the hippocampus of DYRK1A-overexpressing mice. Our research results demonstrate that CX-4945 is a potent DYRK1A inhibitor and also suggest that it has therapeutic potential for DYRK1A-associated diseases.
A variety of inherited animal models with different genetic causes and distinct genetic backgrounds are needed to help dissect the complex genetic etiology of glaucoma. The scarcity of such animal models has hampered progress in glaucoma research. Here, we introduce a new inherited glaucoma model: the inbred mouse strain YBR/EiJ (YBR). YBR mice develop a form of pigmentary glaucoma. They exhibit a progressive age-related pigment-dispersing iris disease characterized by iris stromal atrophy. Subsequently, these mice develop elevated intraocular pressure (IOP) and glaucoma. Genetic mapping studies utilizing YBR as a glaucoma-susceptible strain and C57BL/6J as a glaucoma-resistant strain were performed to identify genetic loci responsible for the iris disease and high IOP. A recessive locus linked to Tyrp1(b) on chromosome 4 contributes to iris stromal atrophy and high IOP. However, this is not the only important locus. A recessive locus on YBR chromosome 17 causes high IOP independent of the iris stromal atrophy. In specific eyes with high IOP caused by YBR chromosome 17, the drainage angle (through which ocular fluid leaves the eye) is largely open. The YBR alleles of genes on chromosomes 4 and 17 underlie the development of high IOP and glaucoma but do so through independent mechanisms. Together, these two loci act in an additive manner to increase the susceptibility of YBR mice to the development of high IOP. The chromosome 17 locus is important not only because it causes IOP elevation in mice with largely open drainage angles but also because it exacerbates IOP elevation and glaucoma induced by pigment dispersion. Therefore, YBR mice are a valuable resource for studying the genetic etiology of IOP elevation and glaucoma, as well as for testing new treatments.
This study examined whether cardiorespiratory fitness (CRF) and body composition are associated with salivary secretory immunoglobulin A (SIgA), a mucosal immunity marker, and salivary alpha-amylase (sAA), a marker of stress-related sympathetic nervous system (SNS) activity, in South African children. Morning (7:30-8:00 a.m.) saliva samples were collected from 132 children (10.05 ± 1.68 years old, 74 females, 58 males). Body composition, resting blood pressure, and predicted maximal aerobic capacity (VO2max) were determined, and SIgA and sAA were quantified. Obese children had significantly higher sAA compared with overweight and normal weight children (p < 0.01). SIgA secretion rate was significantly lower in obese and overweight vs. normal weight children (p < 0.01). Multiple-linear regression analysis revealed that body mass index (BMI) (p < 0.05) and diastolic blood pressure (DBP) (p < 0.05) were independent predictors of sAA with CRF acting as a mitigator. Age and BMI predicted SIgA secretion rate (p < 0.05) with BMI (p < 0.001) found to be an independent predictor of SIgA secretion rate. Obesity, based on BMI, was associated with elevated SNS activity and lowered mucosal immunity. CRF-mitigated sympathetic activation was not associated with mucosal immunity.
Lake Pamvotis (Greece) is a shallow hypereutrophic lake with a natural tendency to eutrophication. Several restoration measures were applied, but with no long-term success. To examine the causes for this an Artificial Neural Network (ANN) was created in order to simulate the chlorophyll-a (Chl-a) levels and to investigate the role of the associated environmental parameters. The ANN managed to simulate with good correlation the simulated Chl-a and can be considered as a reliable predictor. The relative importance of the environmental parameters to the simulated Chl-a was calculated with the use of the "Partial Derivatives" ("PaD") sensitivity method. The water temperature
 (WT) and soluble reactive phosphorus (SRP) had the highest relative importance, with values of 50% and 17%, respectively. The synergistic effect of the paired parameters was calculated with the use of the "PaD2" algorithm. The SRP-WT paired parameter was the most influential, with a relative contribution of 22%. The ANN showed that Lake Pamvotis is prone to suffer the effects of climatic change, because of the major contribution of WT. The ANN also revealed that combined nutrients reduction would improve water quality status. The ANN findings can act as an advisory tool regarding any restoration efforts.
This research was conducted for evaluation of antioxidant activities of four fractions from bamboo shavings extract (BSE) and their antioxidant components. The antioxidant capacities of BSE and four fractions on ABTS, DPPH, FRAP and total antioxidant capacity assays exhibited the following descending order: DF > n-butanol fraction (BF) > BSE ≈ ethyl acetate fraction (AF) > water fraction (WF). Among the identified phenolic compounds, caffeic acid exhibited the highest antioxidant capacities on DPPH, FRAP and total antioxidant capacity assays. An extremely significant positive correlation between the antioxidant activities with the contents of total flavonoids, total phenolic acids, or total phenolics was observed in this study. The result indicated that the bamboo shaving extract and its solvent fractions could act as natural antioxidants in light of their potent antioxidant activities.
Here we report a novel, facile, and sustainable approach for the preparation of spherical submicrometer carbon nitride-based polymer composites by a continuous aerosol-photopolymerization process. In this regard, spherical mesoporous carbon nitride (SMCN) nanoparticles were initially prepared via a nanocasting approach using spray-drying synthesized spherical mesoporous silica (SMS) nanoparticles as hard templates. In addition to experimental characterization, the effect of porosity on the light absorption enhancement and consequently the generation rate of electron-hole pairs inside the SMCN was simulated using a three-dimensional finite difference time-domain (FDTD) method. To produce the carbon nitride-based polymer composite, SMCN nanoparticles exhibit excellent performance in photopolymerization of butyl acrylate (PBuA) monomer in the presence of n-methyldiethanolamine (MDEA) as a co-initiator in a continuous aerosol-based process. In this one-pot synthesis, SMCN nanoparticles act not only as photoinitiators but at the same time as fillers and templates. The average aerosol residence time in the photoreactor is about 90 s. The presented aerosol-photopolymerization process avoids the need for solvent and surfactant, operates at room temperature, and, more importantly, is suitable to produce the spherical composite with hydrophobic polymers. Furthermore, we simulated the condition of SMCN nanoparticles during illumination in the gas phase process, which can freely rotate. The results demonstrated that the hole (h(+)) density is almost equally distributed in the whole part of the SMCN nanoparticles due to their rotation, leading to efficient light harvesting and more homogeneous photoreaction. The combination of the outstanding features of environmentally friendly SMCN, photopolymerization, and aerosol processing might open new avenues, especially in green chemistry, to produce novel polymer composites with multifunctional properties.
Elegant Z-scheme WO3/Au/In2S3 nanowire arrays were precisely constructed through a facile step-by-step route. Surface potential change on pristine or In2S3-Au coated WO3 single nanowire under dark and illumination detected through a Kelvin probe force microscopy (KPFM) technique indicates that the vectorial holes transfer of In2S3 → Au → WO3 should occur upon the excitation of both WO3 and In2S3. In such charge transfer processes, the embedded Au nanoparticles in the heterojunction systems act as a charge mediator for electrons in the conduction band of WO3 and holes in the valence band of In2S3. The strong charge carrier separation ability of this structure will finally enhance the oxidation ability of WO3 with high concertation of photogenerated holes and, further, leave the free electrons in the In2S3 with long surviving time. Therefore, the unique Z-scheme WO3/Au/In2S3 heterostructure shows great visible-light activity toward photocatalytic reduction of CO2 in the presence of water vapor into renewable hydrocarbon fuel (methane: CH4).
Herpes zoster (HZ) is a common condition that increases in incidence with older age but vaccines are available to prevent the disease. However, there are limited data estimating the health system burden attributable to herpes zoster by age.
In this study, we quantified excess healthcare resource usage associated with HZ during the acute/sub-acute period of disease (21days before to 90 days after onset) in 5952 cases and an equal number of controls matched on age, sex, and prior healthcare resource usage. Estimates were adjusted for potential confounders in multivariable regression models. Using population-based estimates of HZ incidence, we calculated the age-specific excess number of health service usage events attributable to HZ in the population.
Per HZ case, there was an average of 0.06 (95% CI 0.04-0.08) excess hospitalisations, 1.61 (95% CI 1.51-1.69) excess general practitioner visits, 1.96 (95% CI 1.86-2.15) excess prescriptions filled and 0.11 (95% CI 0.09-0.13) excess emergency department visits. The average number of healthcare resource use events, and the estimated excess per 100,000 population increased with increasing age but were similar for men and women, except for higher rates of hospitalisation in men. The excess annual HZ associated burden of hospitalisations was highest in adults ≥80 years (N = 2244, 95%CI 1719-2767); GP visits was highest in those 60-69 years (N = 50567, 95%CI 39958-61105), prescriptions and ED visits were highest in 70-79 years (N = 50524, 95%CI 40634-60471 and N = 2891, 95%CI 2319-3449 respectively).
This study provides important data to establish the healthcare utilisation associated with HZ against which detailed cost-effectiveness analyses of HZ immunisation in older adults can be conducted.
The Department of Homeland Security's (DHS) Science and Technology (S&T) Directorate plays a role in public health that extends beyond biodefense. These responsibilities were exercised as part of the 2014-16 Ebola outbreak, leading to productive and beneficial contributions to the international public health response and improved operations in the United States. However, we and others have identified numerous areas for improvement. Based on our successes and lessons learned, we propose a number of ways that DHS, the interagency, and academia can act now to ensure improved responses to future public health crises. These include pre-developing scientific capabilities to respond agnostically to threats, and disease-specific master question lists to organize and inform initial efforts. We are generating DHS-specific playbooks and tools for anticipating future needs and capturing requests from DHS components and our national and international partners, where efforts will also be used to refine and exercise communication and information-sharing practices. These experiences and improvement efforts have encouraged discussions on the role of science in developing government policy, specifically responding to public health crises. We propose specific considerations for both scientists and government decision makers to ensure that the best available science is incorporated into policy and operational decisions to facilitate highly effective responses to future health crises.
Staphylococcus aureus RNAIII is one of the main intracellular effectors of the quorum-sensing system. It is a multifunctional RNA that encodes a small peptide, and its noncoding parts act as antisense RNAs to regulate the translation and/or the stability of mRNAs encoding transcriptional regulators, major virulence factors, and cell wall metabolism enzymes. In this review, we explain how regulatory proteins and RNAIII are embedded in complex regulatory circuits to express virulence factors in a dynamic and timely manner in response to stress and environmental and metabolic changes.
Hydrogen peroxide (H2O2) detection in biological systems is of significant importance, which act as critical second messenger in fundamental biological processes. Here, we report on a chemoselective fluorescent naphthylimide peroxide probe (NPP) for the H2O2 detection in vitro and in vivo. NPP is a phenylboronic acid-caged chromophore that selectively responds to H2O2 through a self-immolate mechanism. NPP exhibited high sensitivity and selectivity to H2O2 with distinctive fluorescence change due to the excellent two-photon excitation property, which permits the facile detection of inflammation produced H2O2 and offers chance to monitor the inflammatory stages in diseased cells.
Cancer is now the leading cause of death in Japan. A rapid increase in cancer mortality is expected as Japan is facing a super-aged society. Many causes of cancer are known to be closely linked to life style factors, such as smoking, drinking, and diet. The oral environment is known to be involved in the pathogenesis and development of various diseases such as bronchitis, pneumonia, diabetes, heart disease, and dementia. Because the oral cavity acts as the bodily entrance for air and food, it is constantly exposed to foreign substances, including bacteria and viruses. A large number of bacteria are endemic to the oral cavity, and indigenous oral flora act to prevent the settlement of foreign bacteria. The oral environment is influenced by local factors, including dental plaque, tartar, teeth alignment, occlusion, an incompatible
 prosthesis, and bad lifestyle habits, and systemic factors, including smoking, consumption of alcohol, irregular lifestyle and eating habits, obesity, stress, hormones, and heredity. It has recently been revealed that the oral environment is associated with cancer. In particular, commensal bacteria in the oral cavity are involved in the development of cancer. Moreover, Candida, human papilloma virus and Epstein-Barr virus as well as commensal bacteria have been reported to be associated with the pathogenesis of cancer. In this review, we introduce recent findings of the correlation between the oral environment and cancer.
This article considers the medical measures of the 1920 Aliens Order barring aliens from Britain. Building on existing local and port public health inspection, the requirement for aliens to be medically inspected before landing significantly expanded the duties of these state agencies and necessitated the creation of a new level of physical infrastructure and administrative machinery. This article closely examines the workings and limitations of alien medical inspection in two of England's major ports-Liverpool and London-and sheds light on the everyday working of the Act. In doing so it reflects on the ambitions, actions and limitations of the state and so extends research by historians of the nineteenth and early twentieth century on the disputed histories of public health and the complexities of statecraft. Overall it suggests the importance of developing nuanced understandings of the gaps and failures arising from the translation of legislation into practice.
People often demand a greater price when selling goods that they own than they would pay to purchase the same goods-a well-known economic bias called the endowment effect. The endowment effect has been found to be muted among experienced traders, but little is known about how trading experience reduces the endowment effect. We show that when selling, experienced traders exhibit lower right anterior insula activity, but no differences in nucleus accumbens or orbitofrontal activation, compared with inexperienced traders. Furthermore, insula activation mediates the effect of experience on the endowment effect. Similar results are obtained for inexperienced traders who are incentivized to gain trading experience. This finding indicates that frequent trading likely mitigates the endowment effect indirectly by modifying negative affective responses in the context of selling.
To determine the appropriate punishment for a harmful action, people must often make inferences about the transgressor's intent. In courtrooms and popular media, such inferences increasingly rely on video evidence, which is often played in "slow motion." Four experiments (n = 1,610) involving real surveillance footage from a murder or broadcast replays of violent contact in professional football demonstrate that viewing an action in slow motion, compared with regular speed, can cause viewers to perceive an action as more intentional. This slow motion intentionality bias occurred, in part, because slow motion video caused participants to feel like the actor had more time to act, even when they knew how much clock time had actually elapsed. Four additional experiments (n = 2,737) reveal that allowing viewers to see both regular speed and slow motion replay mitigates the bias, but does not eliminate it. We conclude that an empirical understanding of the effect of slow motion on mental state attribution should inform the life-or-death decisions that are currently based on tacit assumptions about the objectivity of human perception.
Adherence to the American Academy of Pediatrics safe sleep practice (SSP) recommendations among hospitalized infants is unknown, but is assumed to be low. This quality improvement study aimed to increase adherence to SSPs for infants admitted to a children's hospital general care unit between October 2013 and December 2014.
After development of a hospital policy and redesign of room setup processes, a multidisciplinary team developed intervention strategies based on root cause analysis and implemented changes using iterative Plan-Do-Study-Act cycles. Nurse knowledge was assessed before and after education. SSPs were measured continuously with room audits during sleeping episodes. Statistical process control and run charts identified improvements and sustainability in hospital SSPs. Caregiver home practices after discharge were assessed via structured questionnaires before and after intervention.
Nursing knowledge of SSPs increased significantly for each item (P ≤ .001) except avoidance of bed sharing. Audits were completed for 316 sleep episodes. Simultaneous adherence to all SSP recommendations improved significantly from 0% to 26.9% after intervention. Significant improvements were noted in individual practices, including maintaining a flat, empty crib, with an appropriately bundled infant. The largest gains were noted in the proportion of empty cribs (from 3.4% to 60.3% after intervention, P < .001). Improvements in caregiver home practices after discharge were not statistically significant.
Sustained improvements in hospital SSPs were achieved through this quality improvement initiative, with opportunity for continued improvement. Nurse knowledge increased during the intervention. It is uncertain whether these findings translate to changes in caregiver home practices after discharge.
Resistant bacteria are one of the leading causes of hospital-acquired/ventilator-associated bacterial pneumonia (HABP/VABP). HABP/VABP trials are complex and difficult to conduct due to the large number of medical procedures, adverse events, and concomitant medications involved. Differences in the legislative frameworks between different regions of the world may also lead to excessive data collection. The Clinical Trials Transformation Initiative (CTTI) seeks to advance antibacterial drug development (ABDD) by streamlining clinical trials to improve efficiency and feasibility while maintaining ethical rigor, patient safety, information value, and scientific validity.
In 2013, CTTI engaged a multidisciplinary group of experts to discuss challenges impeding the conduct of HABP/VABP trials. Separate workstreams identified challenges associated with current data collection processes. Experts defined "data collection" as the act of capturing and reporting certain data on the case report form as opposed to recording of data as part of routine clinical care. The ABDD Project Team developed strategies for streamlining safety data collection in HABP/VABP trials using a Quality by Design approach.
Current safety data collection processes in HABP/VABP trials often include extraneous information. More targeted strategies for safety data collection in HABP/VABP trials will rely on optimal protocol design and prespecification of which safety data are essential to satisfy regulatory reporting requirements.
A consensus and a cultural change in clinical trial design and conduct, which involve recognition of the need for more efficient data collection, are urgently needed to advance ABDD and to improve HABP/VABP trials in particular.
Vibrio cholerae is the etiological agent of the acute intestinal disorder cholera. The toxin-coregulated pilus (TCP), a type IVb pilus, is an essential virulence factor of V. cholerae Recent work has shown that TcpB is a large minor pilin encoded within the tcp operon. TcpB contributes to efficient pilus formation and is essential for all TCP functions. Here, we have initiated a detailed targeted mutagenesis approach to further characterize this salient TCP component. We have identified (thus far) 20 residues of TcpB which affect either the steady-state level of TcpB or alter one or more TCP functions. This study provides a solid framework for further understanding of the complex role of TcpB and will be of use upon determination of the crystal structure of TcpB or related minor pilin orthologs of type IVb pilus systems.
Type IV pili, such as the toxin-coregulated pilus (TCP) in V. cholerae, are bacterial appendages that often act as essential virulence factors. Minor pilins, like TcpB, of these pili systems often play integral roles in pilus assembly and function. In this study, we have generated mutations in tcpB to determine residues of importance for TCP stability and function. Combined with a predicted tertiary structure, characterization of these mutants allows us to better understand critical residues in TcpB and the role they may play in the mechanisms underlying minor pilin functions.
The sialic acids (N-acylneuraminates) are a group of nine-carbon keto-sugars existing mainly as terminal residues on animal glycoprotein and glycolipid carbohydrate chains. Bacterial commensals and pathogens exploit host sialic acids for nutrition, adhesion, or antirecognition, where N-acetyl- or N-glycolylneuraminic acids are the two predominant chemical forms of sialic acids. Each form may be modified by acetyl esters at carbon position 4, 7, 8, or 9 and by a variety of less-common modifications. Modified sialic acids produce challenges for colonizing bacteria, because the chemical alterations to N-acetylneuraminic acid (Neu5Ac) confer increased resistance to sialidase and aldolase activities essential for the catabolism of host sialic acids. Bacteria with O-acetyl sialate esterase(s) utilize acetylated sialic acids for growth, thereby gaining a presumed metabolic advantage over competitors lacking this activity. Here, we demonstrate the esterase activity of Escherichia coli NanS after purifying it as a C-terminal HaloTag fusion. Using a similar approach, we show that E. coli strain O157:H7 Stx prophage or prophage remnants invariably include paralogs of nanS often located downstream of the Shiga-like toxin genes. These paralogs may include sequences encoding
 N- or C-terminal domains of unknown function where the NanS domains can act as sialate O-acetyl esterases, as shown by complementation of an E. coli strain K-12 nanS mutant and the unimpaired growth of an E. coli O157 nanS mutant on O-acetylated sialic acid. We further demonstrate that nanS homologs in Streptococcus spp. also encode active esterase, demonstrating an unexpected diversity of bacterial sialate O-acetyl esterase.
The sialic acids are a family of over 40 naturally occurring 9-carbon keto-sugars that function in a variety of host-bacterium interactions. These sugars occur primarily as terminal carbohydrate residues on host glycoproteins and glycolipids. Available evidence indicates that diverse bacterial species use host sialic acids for adhesion or as sources of carbon and nitrogen. Our results show that the catabolism of the diacetylated form of host sialic acid requires a specialized esterase, NanS. Our results further show that nanS homologs exist in bacteria other than Escherichia coli, as well as part of toxigenic E. coli prophage. The unexpected diversity of these enzymes suggests new avenues for investigating host-bacterium interactions. Therefore, these original results extend our previous studies of nanS to include mucosal pathogens, prophage, and prophage remnants. This expansion of the nanS superfamily suggests important, although as-yet-unknown, functions in host-microbe interactions.
Cell walls of grasses, including cereal crops and biofuel grasses, comprise the majority of plant biomass and intimately influence plant growth, development and physiology. However, the functions of many cell wall synthesis genes, and the relationships among and the functions of cell wall components remain obscure. To better understand the patterns of cell wall accumulation and identify genes that act in grass cell wall biosynthesis, we characterized 30 samples from aerial organs of rice (Oryza sativa cv. Kitaake) at 10 developmental time points, 3-100 d post-germination. Within these samples, we measured 15 cell wall chemical components, enzymatic digestibility and 18 cell wall polysaccharide epitopes/ligands. We also used quantitative reverse transcription-PCR to measure expression of 50 glycosyltransferases, 15 acyltransferases and eight phenylpropanoid genes, many of which had previously been identified as being highly expressed in rice. Most cell wall components vary significantly during development, and correlations among them support current understanding of cell walls. We identified 92 significant correlations between cell wall components and gene expression and establish nine strong hypotheses for genes that synthesize xylans, mixed linkage glucan and pectin components. This work provides an extensive analysis of cell wall composition throughout rice development, identifies genes likely to synthesize grass cell walls, and provides a framework for development of genetically improved grasses for use in lignocellulosic biofuel production and agriculture.
This paper explores what the virtual biodiversity e-infrastructure will look like as it takes advantage of advances in 'Big Data' biodiversity informatics and e-research infrastructure, which allow integration of various taxon-level data types (genome, morphology, distribution and species interactions) within a phylogenetic and environmental framework. By overcoming the data scaling problem in ecology, this integrative framework will provide richer information and fast learning to enable a deeper understanding of biodiversity evolution and dynamics in a rapidly changing world. The Atlas of Living Australia is used as one example of the advantages of progressing towards this future. Living in this future will require the adoption of new ways of integrating scientific knowledge into societal decision making.This article is part of the themed issue 'From DNA barcodes to biomes'.
α-Synuclein, which is present as a small, soluble, cytosolic protein in healthy subjects, is converted to amyloid-like fibrils in diseases such as Parkinson's disease (PD), dementia with Lewy bodies (DLB), and multiple system atrophy (MSA). Bulk synthesis of purified α-synuclein has made it more convenient to study the nature of the normal protein and the mechanism of its conversion to an abnormal form in vitro and in vivo. Synthetic α-synuclein fibrils and pathological α-synuclein from diseased brains can act as triggers to convert normal α-synuclein to an abnormal form via prion-like mechanisms. In this article, we describe the experimental pathologies of α-synuclein both in vitro and in vivo in human and animal models. Prion-like spreading of abnormal α-synuclein from cell to cell can account for the progression of these α-synucleinopathies.
Transforming growth factor β (TGF-β) family members signal via heterotetrameric complexes of type I and type II dual specificity kinase receptors. The activation and stability of the receptors are controlled by posttranslational modifications, such as phosphorylation, ubiquitylation, sumoylation, and neddylation, as well as by interaction with other proteins at the cell surface and in the cytoplasm. Activation of TGF-β receptors induces signaling via formation of Smad complexes that are translocated to the nucleus where they act as transcription factors, as well as via non-Smad pathways, including the Erk1/2, JNK and p38 MAP kinase pathways, and the Src tyrosine kinase, phosphatidylinositol 3'-kinase, and Rho GTPases.
To describe our experience of using a confidentiality waiver (Section 251) in the National Health Service (NHS) Act to identify and recruit potential research participants to a cohort study and consider its use in a wider research context.
Methodological discussion.
NHS Trusts in England.
We established a research recruitment process with quality health (QH), administrators of the National Cancer Patient Experience Survey, after an amendment to a Section 251 approval (reference number ECC-8-05d-2011). NHS Trusts agreeing to implement the process were requested to send the details of 16-24-year-olds, identified by a relevant ICD-10 code indicating a cancer diagnosis within a specified time period to QH. QH sent study information and a consent-to-be-contacted form which allowed QH to send details to BRIGHTLIGHT, for BRIGHTLIGHT to contact the treating team confirming eligibility and for an interviewer from Ipsos MORI to contact them. Written consent was to be obtained at interview.
The method was implemented in 98 trusts; 75 supplied patient details. QH sent information to 441 young people, of whom 64 (15%) responded. Of these, 23 had already consented to participate. Adverse events were reported by 6 (1%) invitees: 4 were distressed because they did not have cancer, their details being submitted to QH due to incorrect hospital coding, and 1 young person was distressed about their diagnosis and requested no further contact and 1 young person found out they had cancer from the invitation.
Application of Section 251 of the NHS Act (2006) to directly approach participants can facilitate recruitment to research projects where routinely collected NHS data are available to select eligible patients. The benefits of this method are that it requires fewer resources to recruit across multiple sites, and is quicker. Further information on the impact on bias and adverse event profile are required.
A substantial amount of U.S. teenagers experience physical or sexual abuse within their romantic relationship. With recent technological advances, teenage dating violence can also be perpetrated digitally by harassing or controlling a romantic partner through the Internet or mobile phone. School nurses are naturally positioned to act as first responders for victims of an abusive romantic relationship. As online and offline forms of dating violence are often intertwined, it is imperative that school nurses are able to identify different types of digital dating violence as this could signal the presence of offline forms of dating abuse. Therefore, being able to interpret potential warning signs could help school nurses to play an active role in prevention and intervention of different types of dating violence. In this article, we provide an overview of the recent research on the context and consequences of cyber dating abuse and outline several suggestions for prevention and intervention.
Multiple myeloma (MM) is a plasma cell malignancy, characterized by osteolytic lesions and monoclonal immunoglobulins. The anemia, accompanying the disease is often treated with recombinant human EPO. Diverse non-erythropoietic effects of EPO have led us to question its combined action on the immune system and bone in the 5T33MM mouse model. EPO administration to MM mice attenuated disease progression as demonstrated by a decrease in serum MM IgG2b, splenic CD138 expressing cells, IL-6 and RORγτ transcripts in bone marrow (BM). IFN-γ transcript levels and macrophages (F4/80(+)CD11b(+)) in the BM both increased ~1.5 fold in the EPO-treated MM mice. In-vitro, EPO stimulated phagocytosis of 5T33MM cells (+30%) by BM-derived macrophages. In contrast, high-resolution microCT analysis of distal femurs revealed EPO-associated bone loss in both healthy and 5T33MM mice. EPO significantly increased expression of the osteoclastogenic nuclear factor-kappa B ligand (RANKL) in healthy mice, but not in MM mice, likely due to antagonizing effects on MM progression. Thus, in MM, EPO may act as a double-edged-sword stimulating immune response, while accelerating bone resorption, possibly via direct action on BM macrophages. This study supports a prudent approach of treating anemia in MM patients, aiming to maintain EPO-associated anti-MM effects, while considering bone damage.
To assess the long-term (5 year) efficacy of omalizumab and systemic corticosteroid therapy in allergic and
 non-allergic asthma that could not be controlled by step 4 therapy, respectively.
This single-center study was based on all consecutive step 4 patients with severe persistent uncontrolled allergic and non-allergic asthma who were given omalizumab and systemic corticosteroid (minimum: 4 mg, maximum: 12 mg, median: 8 mg methyl prednisone), respectively, in 2006-2014 and were followed up for at least 5 years. Asthma control test (ACT), FEV1 and exacerbation rates at initial presentation and 1, 2, and 5 years after step 5 treatment initiation were calculated for both groups.
There were 17 and 16 allergic and non-allergic group patients, respectively. Both groups exhibited significant improvements in ACT at the 1st, 2nd, and 5th years relative to baseline (all p< 0.01). The allergic group had significantly better ACTs at 16 weeks, 1 year, and 2 years than the non-allergic group (all p< 0.01). By the 5th year, the exacerbations in the non-allergic group rose significantly by 39.6% (3.3 on average) compared to baseline (2.38 on average, p< 0.001). By contrast, the allergic group continued to have significantly fewer exacerbations at the 5th year (77.1% fewer relative to baseline, p< 0.001). However, 47% of the allergic group patients still presented with one exacerbation in the 5th year.
Adding omalizumab to step 5 therapy improved the control of severe persistent allergic asthma. However, nearly half of the patients in both groups presented at least one exacerbation in the 5th year.
A strong public health infrastructure is necessary to assure that every community is capable of carrying out core public health functions (assessment of population health, assurance of accessible and equitable health resources, and development of policies to address population health) to create healthy conditions. Yet, due to budget cuts and inconsistent approaches to base funding, communities are losing critical prevention and health promotion services and staff that deliver them.
This article describes key components of and current threats to our public health infrastructure and suggests actions necessary to strengthen public health systems and improve population health.
National nursing and public health organizations have a duty to advocate for policies supporting strong prevention systems, which are crucial for well-functioning health care systems and are fundamental goals of the nursing profession.
We propose strengthening alliances between nursing organizations and public health systems to assure that promises of a reformed health system are achieved.
The search for new fluorescent molecules is vital to the advancement of molecular imaging and sensing for the benefit of medical and biological studies. One such class of new fluorescent molecule is fluorescent gold nanoclusters encapsulated in Human Serum Albumin (HSA-AuNC). In order to use this new fluorescent molecule as a sensor or fluorescent marker in biological imaging both in vitro and in vivo it is important to understand whether/how the proteins function is changed by the synthesis and presence of the gold nanoclusters inside the protein. Natural HSA acts as the main drug carrier in the blood stream, carrying a multitude of molecules in two major binding sites (Sudlow I and II). To test the effects of gold on the ability of HSA to act as a drug carrier we employed warfarin, an anticoagulant drug, as a fluorescent probe to detect changes between natural HSA and HSA-AuNCs. AuNCs are found to inhibit the take up of warfarin by HSA. Evidence for this is found from fluorescence spectral and lifetime measurements. Interestingly, the presence of warfarin bound to HSA also inhibits the formation of gold nanoclusters within protein. This research provides valuable insight into how protein function can change upon synthesis of AuNCs and how that will affect their use as a fluorescent probe.
Alcohol use disorder (AUD) and addiction in general is characterized by failures of choice resulting in repeated drug intake despite severe negative consequences. Behavioral change is hard to accomplish and relapse after detoxification is common and can be promoted by consumption of small amounts of alcohol as well as exposure to alcohol-associated cues or stress. While those environmental factors contributing to relapse have long been identified, the underlying psychological and neurobiological mechanism on which those factors act are to date incompletely understood. Based on the reinforcing effects of drugs of abuse, animal experiments showed that drug, cue and stress exposure affect Pavlovian and instrumental learning processes, which can increase salience of drug cues and promote habitual drug intake. In humans, computational approaches can help to quantify changes in key learning mechanisms during the development and maintenance of alcohol dependence, e.g. by using sequential decision making in combination with computational modeling to elucidate individual differences in model-free versus more complex, model-based learning strategies and their neurobiological correlates such as prediction error signaling in fronto-striatal circuits. Computational models can also help to explain how alcohol-associated cues trigger relapse: mechanisms such as Pavlovian-to-Instrumental Transfer can quantify to which degree Pavlovian conditioned stimuli can facilitate approach behavior including alcohol seeking and intake. By using generative models of behavioral and neural data, computational approaches can help to quantify individual differences in psychophysiological mechanisms that underlie the development and maintenance of AUD and thus promote targeted intervention.
Small antisense RNAs like miRNA and siRNA are of crucial importance in cardiac physiology, pathology and, moreover, can be applied as therapeutic agents for the treatment of cardiovascular diseases. Identification of novel strategies for miRNA/siRNA therapy requires a comprehensive understanding of the underlying mechanisms. Emerging data suggest that small RNAs are transferred between cells via gap junctions and provoke gene regulatory effects in the recipient cell. To elucidate the role of miRNA/siRNA as signalling molecules, suitable tools are required that will allow the analysis of these small RNAs at the cellular level. In the present study, we applied 3 dimensional fluorescence recovery after photo bleaching microscopy (3D-FRAP) to visualise and quantify the gap junctional exchange of small RNAs between neonatal cardiomyocytes in real time. Cardiomyocytes were transfected with labelled miRNA and subjected to FRAP microscopy. Interestingly, we observed recovery rates of 21% already after 13min, indicating strong intercellular shuttling of miRNA, which was significantly reduced when connexin43 was knocked down. Flow cytometry analysis confirmed our FRAP results. Furthermore, using an EGFP/siRNA reporter construct we demonstrated that the intercellular transfer does not affect proper functioning of small RNAs, leading to marker gene silencing in the recipient cell. Our results show that 3D-FRAP microscopy is a straightforward, non-invasive live cell imaging technique to evaluate the GJ-dependent shuttling of small RNAs with high spatio-temporal resolution. Moreover, the data obtained by 3D-FRAP confirm a novel pathway of intercellular gene regulation where small RNAs act as signalling molecules within the intercellular network.
The action of tyrosinase on resorcinol and some derivatives (4-ethylresorcinol, 2-methylresorcinol and 4-methylresorcinol) was investigated. If the catalytic cycle is completed with a reductant such as ascorbic acid or an o-diphenol such as 4-tert-butylcatechol, these compounds act as substrates of tyrosinase in all cases. The reaction can also be carried out, adding hydrogen peroxide to the medium. All the above compounds were characterized as substrates of the enzyme and their kinetic constants, KM (Michaelis constant) and kcat (catalytic constant) were determined. Measurement of the activity of the enzyme after pre-incubation with resorcinol, 4-ethylresorcinol or 4-methylresorcinol points to an apparent loss of activity at short times, which could correspond to an enzymatic inactivation process. However, if the measurements are extended over longer times, a burst is observed and the enzymatic activity is recovered, demonstrating that these compounds are not suicide substrates of the enzyme. These effects are not observed with 2-methylresorcinol. The docking results indicate that the binding of met-tyrosinase with these resorcinols occurs in the same way, but not with 2-methylresorcinol, due to steric hindrance.
Ferroelectric (Pb,La)(Zr,Ti)O3 (PLZT) capacitors were fabricated with Pt, Al:ZnO (AZO), or Sn:In2O3 (ITO) top electrodes. Hydrogen- or deuterium-induced degradation was investigated for the three capacitors by annealing in a 3% H2/balance N2 or 3% D2/balance N2 ambient environment at 200 °C and 1 torr. The remnant polarization of all capacitors decreased after annealing in both H2 and D2 ambient after 45 min, and the remnant polarization of the Pt/PLZT/Pt capacitor significantly decreased after 45-min annealing compared with that of the AZO/PLZT/Pt and ITO/PLZT/Pt capacitors, even though the initial remnant polarization for the Pt/PLZT/Pt capacitor was larger. Time-of-flight secondary ion mass spectrometry showed slight differences in hydrogen content for the three different capacitors after H2 annealing. In contrast, the deuterium content of the Pt/PLZT/Pt and AZO/PLZT/Pt or ITO/PLZT/PT capacitors was significantly different after deuterium annealing. Deuterium depth profiles for the Pt/PLZT/Pt capacitor after annealing showed that deuterium conformally exists in the PLZT layer of the Pt/PLZT/Pt capacitor, and deuterium accumulation under the Pt bottom electrode was also observed. This result suggests that
 diffusion of deuterium in Pt was much higher than that in PLZT. AZO and ITO top electrodes could act as a hydrogen barrier layer for ferroelectric films.
Drug release from inorganic supports is a challenge for the scientific community for various reasons, related to the low costs of the systems and the possibility of easily regulating the drug release. In the present work, surface-modified zeolite particles are used as carriers for non steroidal antiflammatory drugs (NSAIDs). The release of the drug has been studied in a solution that simulates the intestinal fluid as well as in a gel-like system, based on a surfactant and a binding salt. In the solution case, the quantity of drug released has been tracked via spectrophotometric assay. Release in the gel has been monitored by rheological methods. The molecular conformation of the NSAIDs is fundamental for the interaction with the zeolite surface, whose modified surface has a strong binding energy. It has been proven that the main mechanism for the drug release is anion exchange. It has been found that the NSAIDs, used in their sodic form, can act as binding salts by themselves in the gel-like system, thus changing the viscoelastic response of the overall solution. Drug release kinetics in the solution compare quantitatively well with the released drug in the gel-like fluid, as measured by rheometry.
The Mental Capacity Act (MCA) is a piece of statutory legislation which is designed to empower and protect those who are assessed as being unable to make decisions for themselves. At the time of implementation, the legislation was described as visionary and it had the potential to change the lives of many. However, a post-legislative scrutiny report published in 2014 concluded that there is a lack of knowledge among professionals of the MCA, and so it is not embedded into daily clinical practice. This review of literature has identified four key themes: assessment, training, knowledge and empowerment. These appear to concur with the findings of the House of Lords report. The successful integration of the MCA into professionals' everyday practice is high on the political agenda, thus reinforcing the message that following the guidance set out in the MCA legislation is mandatory and not a choice. A shift in culture and improvement in knowledge and understanding of the MCA is required in order for it to be used in the correct manner for which it was designed.
Green mould, resulting from Penicillium digitatum, is the most important postharvest disease of citrus. In a previous study, the PdSte12 transcription factor gene was identified, and disruption mutants were obtained. In the present study, the ΔPdSte12 mutants generated through gene replacement showed significantly reduced virulence during citrus fruit infection. Virulence was affected not only in mature fruit but also in immature fruit, and disease severity was markedly reduced when the oranges were stored at 20 or 4°C. In addition, the ΔPdSte12 mutants were defective in asexual reproduction, producing few conidia. The conidiophores of these mutants had longer metulae with fewer branches at the tip of the hyphae. Gene expression analysis revealed that PdSte12 might act as a negative regulator of several transporter-encoding genes and a positive regulator of two sterol demethylases, all of which are involved in fungicide resistance and fungal virulence. Moreover, PdSte12 exhibited the negative regulation of another transcription factor PdMut3, putatively involved in fungal pathogenesis but with no effect on the MAPK SLT2 P. digitatum orthologue belonging to different transcription pathways relevant to cell integrity. These results indicate the PdSte12 transcription factor is functionally conserved in P. digitatum for infection and asexual reproduction, similar to other Ste12 fungal plant pathogens.
Chronic pain places a burden on individuals and the economy. Although there is evidence for the effectiveness of Cognitive Behaviour Therapy, it is recognised that the effects are limited. Acceptance and commitment therapy (ACT), which aims to increase valued action in the presence of pain, has been suggested as an alternative approach. The objective of this review was to determine the clinical effectiveness of ACT for chronic pain in adults when compared to control conditions and other active treatments.
The searches of this systematic review were conducted in the Cochrane library, MEDLINE, EMBASE, CINAHL Plus (EBSCO) and PsycINFO. Grey literature, reference list and reverse citation searches were also completed.
Eleven trials were included. ACT was favoured over controls (no alternative intervention or treatment as usual). Significant, medium to large effect sizes were found for measures of pain acceptance and psychological flexibility, which are typically considered processes of ACT. Significant small to medium effect sizes were found for measures of functioning, anxiety and depression. Measures of pain intensity and quality of life were not significantly different than zero. Generally effect sizes were smaller at follow up.
ACT was more clinically effective than controls on a number of outcomes. It is possible, that methodological limitations, some of which are common to psychological trials, may have led to over-estimated effects. Only a few studies compared ACT to active treatments and while the evidence is promising for ACT in the treatment of chronic pain, further methodologically robust trials are required.
Starting in September of 2010, the Patient Protection and Affordable Care Act required most health insurance policies to cover evidence-based preventive care with no cost-sharing (no copays, coinsurance, or deductibles). It is unknown, however, whether declines in out-of-pocket costs for preventive services are large enough to prompt increases in utilization, the ultimate goal of the policy.
In this study, we use a nationally representative sample of ambulatory care visits to estimate the impact of the zero cost-sharing mandate on out-of-pocket expenditures on well-child and screening mammography visits. Estimates are made using 2-part interrupted time-series models, with well-woman visits serving as the control group because they were not covered under the zero cost-sharing mandate until after our study period.
Results indicate a substantial reduction in out-of-pocket costs attributable to the Affordable Care Act. Between January 2011 and September 2012, the zero cost-sharing mandate reduced per-visit out-of-pocket costs for well-child visits from $18.46 to $8.08 (56%) and out-of-pocket costs for screening mammography visits from $25.43 to $6.50 (74%). No reduction was apparent for well-woman visits.
The Affordable Care Act's zero cost-sharing mandate for preventive care has had a large impact on out-of-pocket expenditures for well-child and mammography visits. To increase preventive service use, research is needed to better understand barriers to obtaining preventive care that are not directly related to cost.
Exploring novel electrode materials is critical for the development of a next-generation rechargeable magnesium battery with high volumetric capacity. Here, we showed that a distinct amorphous molybdenum sulfide, being a coordination polymer of disulfide-bridged (Mo3S11) clusters, has great potential as a rechargeable magnesium battery cathode. This material provided good reversible capacity, attributed to its unique structure with high flexibility and capability of deformation upon Mg insertion. Free-terminal disulfide moiety may act as the active site for reversible insertion and extraction of magnesium.
The advancement of trapping and detection of nano-objects at very low laser powers in the near-infra-red region (NIR) is crucial for many applications. Singular visible-light nano-optics based on abrupt phase changes have recently demonstrated a significant improvement in molecule detection. Here, we propose and demonstrate tunable plasmonic nanodevices, which can improve both the trapping field enhancement and detection of nano-objects using singular phase drops in the NIR range. The plasmonic nanostructures, which consist of gaps with dimensions 50 nm × 50 nm connecting nanorings in arrays is discussed. These gaps act as individual detection and trapping sites. The tunability of the system is evident from extinction and reflection spectra while increasing the aperture size in the arrays. Additionally, in the region where the plasmonic nano-array exhibits topologically-protected, near-zero reflection behaviour, the phase displays a rapid change. Our experimental data predict that, using this abrupt phase changes, one can improve the detection sensitivity by 10 times compared to the extinction spectra method. We finally report experimental evidence of 100 nm polystyrene beads trapping using low incident power on these devices. The overall design demonstrates strong capability as an optical, label-free, non-destructive tool for single molecule manipulation where low trapping intensity, minimal photo bleaching and high sensitivity is required.
Classical hormone receptors reversibly and non-covalently bind active hormone molecules, which are generated by biosynthetic enzymes, to trigger signal transduction. The α/β hydrolase DWARF14 (D14), which hydrolyses the plant branching hormone strigolactone and interacts with the F-box protein D3/MAX2, is probably involved in strigolactone detection. However, the active form of strigolactone has yet to be identified and it is unclear which protein directly binds the active form of strigolactone, and in which manner, to act as the genuine strigolactone receptor. Here we report the crystal structure of the strigolactone-induced AtD14-D3-ASK1 complex, reveal that Arabidopsis thaliana (At)D14 undergoes an open-to-closed state transition to trigger strigolactone signalling,
 and demonstrate that strigolactone is hydrolysed into a covalently linked intermediate molecule (CLIM) to initiate a conformational change of AtD14 to facilitate interaction with D3. Notably, analyses of a highly branched Arabidopsis mutant d14-5 show that the AtD14(G158E) mutant maintains enzyme activity to hydrolyse strigolactone, but fails to efficiently interact with D3/MAX2 and loses the ability to act as a receptor that triggers strigolactone signalling in planta. These findings uncover a mechanism underlying the allosteric activation of AtD14 by strigolactone hydrolysis into CLIM, and define AtD14 as a non-canonical hormone receptor with dual functions to generate and sense the active form of strigolactone.
Protecting healthcare staff against the risk of infection caused by injuries when using sharp or pointed instruments has been placed - as a special, common and difficult type of "biological risk" - at the centre of attention in the investigations, studies and research conducted by various countries and subjects that have led to a convergence between the results able to influence European and supranational legislation. This convergence of results is headed towards the recognition of the great potential of the role of technology and, more specifically, of the "protection devices" of paramount and essential importance, as "technical measures", over the other, nevertheless important "organisational" and "personal" measures. The national and international results of the studies and research, as well as their corresponding conclusions, deserve special space in this journal, given the supranational legislative recognition they received in Directive 2010/32/EU. Indeed, this latter Directive, set forth and classified, with a system of absolutely mandatory regulations, the "Framework agreement" concluded between the organisations that are most representative of the hospital and healthcare sector for the "prevention of cut and prick injuries". On the basis of the "European Union" treaty, Directive 2010/32/EU must be assimilated in the legal system of all the member States of this "Union" with appropriately sanctioned legal provisions in the event of breach by "employers" and/or "directors". In this sense, with Legislative Decree no. 19 of 2014, Italy introduced a dedicated "criminal offence of danger" for the breach of "prevention" regulations intended to prevent the specific "biological risk" in question, regulations that have been incorporated into Legislative Decree 81/08 - "The Occupational Safety and Health Consolidation Act" with a special "Section" (X bis) dedicated exclusively to them.
Noroviruses (NoV) are highly contagious and the leading cause of nonbacterial outbreaks of gastroenteritis worldwide. Individuals who are infected asymptomatically may act as reservoirs and facilitate the transmission of NoV, but the likelihood of workers of becoming infected in outbreak settings has not been systematically studied.
We evaluated the occurrence of norovirus infections among workers exposed to the virus in different outbreak settings.
We screened feces from food handlers and healthcare workers related with gastroenteritis outbreaks, and shedding concentrations over time were calculated from serial samples of infected individuals. Sequence analyses of the capsid P2 domain and region C were used to evaluate linkage between asymptomatic employees and outbreak cases.
Of all employees, 59.1% were positive for NoV, and more than 70% of them were asymptomatic. Asymptomatic infections were significantly more frequent in foodborne compared to person-to-person transmitted outbreaks; and in restaurants and hotels, compared to nursing homes and healthcare institutions. Mean viral loads were similar between symptomatic and asymptomatic individuals, starting at 7.51±1.80 and 6.49±1.93 log10 genome copies/g, respectively, and decreasing to 5.28±0.76 and 4.52±1.45 log10 genome copies/g after 19days.
The likelihood of becoming infected when a NoV outbreak occurs at the work place is high and similar between food handlers and healthcare workers, but asymptomatic infections are more frequently identified among food handlers. Since shed amounts of viruses in the absence of symptoms are also high, reinforcement of hygiene practices among workers is especially relevant to reduce the risk of virus secondary transmissions.
Prisoners have higher rates of chronic diseases such as substance dependence, mental health conditions and infectious disease, as compared to the general population. We projected the number of male state prisoners with a chronic health condition who at release would be eligible or ineligible for healthcare coverage under the Affordable Care Act (ACA). We used ACA income guidelines in conjunction with reported pre-arrest social security benefits and income from a nationally representative sample of prisoners to estimate the number eligible for healthcare coverage at release. There were 643,290 US male prisoners aged 18-64 with a chronic health condition. At release, 73% in Medicaid-expansion states would qualify for Medicaid or tax credits. In non-expansion states, 54% would qualify for tax credits, but 22% (n = 69,827) had incomes of ≤ 100% the federal poverty limit and thus would be ineligible for ACA-mediated healthcare coverage. These prisoners comprise 11% of all male prisoners with a chronic condition. The ACA was projected to provide coverage to most male state prisoners with a chronic health condition; however, roughly 70,000 fall in the "coverage gap" and may require non-routine care at emergency departments. Mechanisms are needed to secure coverage for this at risk group and address barriers to routine utilization of health services.
The impact of external electric potential on the adsorption of a protein to base metal surfaces was examined. Hen egg white lysozyme (LSZ) and six types of base metal plates (stainless steel SUS316L (St), Ti, Ta, Zr, Cr, or Ni) were used as the protein and adsorption surface, respectively. LSZ was allowed to adsorb on the surface under different conditions (surface potential, pH, electrolyte type and concentration, surface material), which was monitored using an ellipsometer. LSZ adsorption was minimized in the potential range above a certain threshold and, in the surface potential range below the threshold, decreasing the surface potential increased the amount of protein adsorbed. The threshold potential for LSZ adsorption was shifted toward a positive value with increasing pH and was lower for Ta and Zr than for the others. A divalent anion salt (K2SO4) as an electrolyte exhibited the adsorption of LSZ in the positive potential range while a monovalent salt (KCl) did not. A comprehensive consideration of the obtained results suggests that two modes of interactions, namely the electric force by an external electric field and electrostatic interactions with ionized surface hydroxyl groups, act on the LSZ molecules and determine the extent of suppression of LSZ adsorption. All these findings appear to support the view that a base metal surface can be controlled for the affinity to a protein by manipulating the surface electric potential as has been reported on some electrode materials.
The flowers of delphinium cultivars owe their coloration to anthocyanins such as delphinidin or pelargonidin derivatives. To date, no delphinium cultivars have been found with red flowers due to the presence of cyanidin derivatives. This suggests that delphiniums do not have cyanidin biosynthesis ability because of the loss of function of flavonoid 3' hydroxylase (F3'H). Here, we show that the wild delphinium species Delphinium zalil (synonym semibarbatum) can accumulate quercetin 3-glucosides in its sepals, presumably through F3'H activity. We isolated F3'H cDNA from D. zalil (DzF3'H) and produced a recombinant enzyme from a yeast transformant. The recombinant DzF3'H protein could convert naringenin, apigenin, dihydrokaempferol and kaempferol to eriodictyol, luteolin, dihydroquercetin and quercetin, respectively. An expression analysis confirmed that blue flowered D. grandiflorum does not express F3'H, and also showed that flavonoid 3',5'-hydroxylase and anthocyanidin synthase do not function in D. zalil sepals. DzF3'H can act as a flavonoid hydroxylase to produce cyanidin accumulation. The introduction of the DzF3'H gene into other delphinium species by conventional breeding may enable development of cultivars with novel flower colors.
Survivor of a ship ground in polar regions may have to wait more than five days before being rescued. Therefore, the purpose of this study was to explore cognitive performance during prolonged cold exposure. Core temperature (T c) and cognitive test battery (CTB) performance data were collected from eight participants during 24 hours of cold exposure (7.5°C ambient air temperature). Participants (recruited from those who have regular occupational exposure to cold) were instructed that they could freely engage in minimal exercise that was perceived to maintaining a tolerable level of thermal comfort. Despite the active engagement, test conditions were sufficient to significantly decrease T c after exposure and to eliminate the typical 0.5-1.0°C circadian rise and drop in core temperature throughout a 24 h cycle. Results showed minimal changes in CTB performance regardless of exposure time. Based on the results, it is recommended that survivors who are waiting for rescue should be encouraged to engage in mild physical activity, which could have the benefit of maintaining metabolic heat production, improve motivation, and act as a distractor from cold discomfort. This recommendation should be taken into consideration during future research and when considering guidelines for mandatory survival equipment regarding cognitive performance.
Survival of the semi-allograft
 fetus during pregnancy opens a new area for the immunological based causes of recurrent spontaneous abortion (RSA). Cytotoxic T lymphocyte-associated antigen 4 (CTLA4) is a negative regulator of the T-cell activation, which may modulate peripheral self-tolerance of the allogeneic fetus. The present study aimed to investigate the +49 A/G CTLA4 genetic polymorphism and predisposition to RSA.
The total participants were 120 women with at least two miscarriages and 120 healthy post-menopausal women as the control group. The +49 A/G polymorphism was genotyped using PCR-RFLP method. Required demographic information was collected through filling out a questionnaire. The obtained data were fed into SPSS software version 16.
The results showed a significant association between the minor alleles (G) with the decreased risk of the RSA. The frequency of the G allele in controls and patients was 25% and 12%, respectively. A GG genotype in the co-dominance model (OR: 0.25, 95%CI: 0.09-0.66) and in the dominant model for allele G (GG+AG vs. AA) (OR: 0.84, 95%CI: 0.8-0.87) showed significant association with RSA by imposing the protective role. The frequency of miscarriage is significantly (p=0.04) higher among the relatives of RSA women (33.3%) in comparison with the women in the control group (21.7%).
It can be concluded that +49G allele may act as a dominant allele and reduce the risk of RSA. Family history of miscarriage increased the risk of RSA among women.
Indigenous children in Australia are more likely than non-Indigenous children to be in contact with the child safety system. A large number of Queensland's Indigenous population live in remote and isolated communities in north Queensland where the state government's Alcohol Management Plans (AMPs) are in effect. In these communities it is an offence to have in one's possession more than the regulated amount and type of alcohol. A breach of these restrictions can result in convictions under the Liquor Act 1992.
During an evaluation of AMPs, influential stakeholders and key service providers voiced their belief that a conviction for a breach of the AMP would impact a person's eligibility to hold a Positive Notice Blue Card (PNBC). On its own, however, a breach of the Liquor Act 1992 will not impact a person's eligibility for a PNBC. A PNBC is required for any person volunteering or working with children. Without a PNBC, a person is ineligible to work in child-related employment, volunteer at child-related activities or provide out-of-home care for children.
This misconception needs to be addressed in these already-disadvantaged communities to ensure that Indigenous community members have every opportunity to hold a PNBC. Focused strategies with evaluation and research are needed in this important policy area.
gamma-Aminobutyric acid (GABA) is a naturally occurring inhibitory neurotransmitter and some of its derivatives showed potential to act as neuroprotective agents. With the aim of developing potential leads for anti-Alzheimer's drugs, in this study we synthesized a novel GABA derivative, methyl 4-(4-((2-(tert-butoxy)-2-oxoethyl)(4-methoxyphenyl)amino)benzamido)butanoate by a unique method of Buchwald-Hartwig cross coupling synthesis; with some modification the yield was significant (97 %) and spectroscopic analysis confirmed that the compound was highly pure (98.8 % by HPLC). The druglikeness properties such as logP, logS, and polar surface area were 3.87, -4.86 and 94.17 Å(2) respectively and it satisfied the Lipinski's rule of five. We examined the binding behavior of the molecule to human serum albumin (HSA) and bovine serum albumin (BSA) which are known as universal drug carrier proteins. The molecule binds to the proteins with low micromolar efficiency and the calculated binding constants were 3.85 and 2.75 micromolar for BSA and HSA, respectively. Temperature dependent study using van't Hoff equation established that the binding was thermodynamically favorable and the changes in the Gibb's free energy, ΔG for the binding process was negative. However, the binding of the molecule to HSA was enthalpy driven and the change of enthalpy (ΔH) was -10.63 kJ/mol, whereas, the binding to BSA was entropy driven and the change in entropy ΔS was 222 J/mol. The molecular docking analysis showed that the binding sites of the molecule lie in the groove between domain I and domain III of BSA, whereas it is within the domain I in case of HSA, which also supported the different thermodynamic nature of binding with HSA and BSA. Molecular dynamics analysis suggested that the binding was stable with time and provided further details of the binding interaction. Molecular dynamics study also highlighted the effect of this ligand binding on the serum albumin structure.
The meteoric metal layers act as unique tracers of chemistry and dynamics in the upper atmosphere. Existing lidar studies from a few locations show that K exhibits a semiannual seasonality (winter and summer maxima), quite unlike the annual seasonality (winter maximum and summer minimum) seen with Na and Fe. This work uses spaceborne observations made with the Optical Spectrograph and InfraRed Imager System instrument on the Odin satellite to retrieve the near-global K layer for the first time. The satellite data (2004 to mid-2013) are used to validate the implementation of a recently proposed potassium chemistry scheme in a whole atmosphere chemistry climate model, which provides a chemical basis for this semiannual seasonal behavior. The satellite and model data show that this semiannual seasonality is near global in extent, with the strongest variation at middle and high latitudes. The column abundance, centroid layer height, and root-mean-square width of the K layer are consistent with the limited available lidar record. The K data set is then used to investigate the impact of polar mesospheric clouds on the metal layers at high latitudes during summer. Finally, the occurrence frequency of sporadic K layers and their possible link to sporadic E layers are examined.
Managers of large, complex wildlife conservation programs need information on the conservation status of each of many species to help strategically allocate limited resources. Oversimplifying status data, however, runs the risk of missing information essential to strategic allocation. Conservation status consists of two components, the status of threats a species faces and the species' demographic status. Neither component alone is sufficient to characterize conservation status. Here we present a simple key for scoring threat and demographic changes for species using detailed information provided in free-form textual descriptions of conservation status. This key is easy to use (simple), captures the two components of conservation status without the cost of more detailed measures (sufficient), and can be applied by different personnel to any taxon (consistent). To evaluate the key's utility, we performed two analyses. First, we scored the threat and demographic status of 37 species recently recommended for reclassification under the Endangered Species Act (ESA) and 15 control species, then compared our scores to two metrics used for decision-making and reports to Congress. Second, we scored the threat and demographic status of all non-plant ESA-listed species from Florida (54 spp.), and evaluated scoring repeatability for a subset of those. While the metrics reported by the U.S. Fish and Wildlife Service (FWS) are often consistent with our scores in the first analysis, the results highlight two problems with the oversimplified metrics. First, we show that both metrics can mask underlying demographic declines or threat increases; for example, ∼40% of species not recommended for reclassification had changes in threats or demography. Second, we show that neither metric is consistent with either threats or demography alone, but conflates the two. The second analysis illustrates how the scoring key can be applied to a substantial set of species to understand overall patterns of ESA implementation. The scoring repeatability analysis shows promise, but indicates thorough training will be needed to ensure consistency. We propose that large conservation programs adopt our simple scoring system for threats and demography. By doing so, program administrators will have better information to monitor program effectiveness and guide their decisions.
Introduction. Despite the efforts of the malaria control programme, malaria morbidity is still a common health problem in Yemen, with 60% of the population at risk. Plasmodium falciparum is responsible for 99% of malaria cases. The emergence in Yemen of parasite resistance to chloroquine (CQ) prompted the adoption of artemisinin combination therapy (ACT) in 2009, which involves the use of artesunate plus sulphadoxine-pyrimethamine (AS + SP). However, CQ was retained as the drug of choice for vivax malaria. To assess the impact of the change in the malaria treatment policy five years after its introduction, the present study investigated the mutations in the CQ resistance transporter (pfcrt) and multidrug resistance 1 (pfmdr1) genes. Method. A molecular investigation of 10 codons of pfcrt (72-76, 220, 271, 326, 356, and 371) and five codons of pfmdr1 (86, 184, 1034, 1042, and 1246) was conducted on P. falciparum isolates from districts with the highest malaria endemicity in the Hodeidah and Al-Mahwit governorates in Tehama region, Yemen. A total of 86 positive cases of falciparum monoinfection were investigated for the presence of mutations related to CQ and other antimalarials using a PCR-RFLP assay. Results. There was a wide prevalence of pfcrt gene mutations with the pfcrt 76T CQ resistance marker being predominant (97.7%). The prevalence of other pfcrt mutations varied from high (75E: 88%) to moderate (74I: 79.1%, 220S: 69.8%,
 271E and 371I: 53.5%) or low (326S: 36%, 72S: 10.5%). Mutated pfcrt 72-76 amino acids haplotypes were highly prevalent (98.8%). Among these, the CVIET classic, old-world African/Southeast Asian haplotype was the most predominant, and was mostly found in the isolates from the Khamis Bani Saad district of Al-Mahwit (93.1%) and the AdDahi district of Hodeidah (88.9%). However, it was only found in 26.3% of the isolates from the Bajil district of Hodeidah. Surprisingly, the SVMNT new-world South American haplotype was exclusively detected in 9.3% of the isolates from the Bajil district of Hodeidah. Mutations at Y184F of pfmdr1 were found in all isolates (100%) from all districts. The mutation for codons 1034C and 86Y were found only in the isolates from the AdDahi and Khamis Bani Saad districts. Overall, the AdDahi and Khamis Bani Saad districts were similar in terms of carrying most of the mutations in the pfcrt and pfmdr1 genes, while there was a lower prevalence of mutation in the isolates from the Bajil district. Conclusion. The high prevalence of mutations in pfcrt 5 years after the official cessation of CQ use against P. falciparum suggests that there is sustained CQ pressure on P. falciparum isolates in the study area. Moreover, the low prevalence of mutations in the pfmdr1 gene could be a good indicator of the high susceptibility of P. falciparum isolates to antimalarials other than CQ. A new strategy to ensure the complete nationwide withdrawal of CQ from the private drug market is recommended.
Chronic ultraviolet (UV) exposure-induced reactive oxygen species (ROS) are commonly involved in the pathogenesis of skin damage by activating the metalloproteinases (MMP) that break down type I collagen. Adenophora remotiflora (AR) is a perennial wild plant that inhabits Korea, China, and Japan. The present study investigated the protective effects of AR against UVB-induced photo-damage in keratinocytes.
An in vitro cell-free system was used to examine the scavenging activity of 2,2-diphenyl-1-picrylhydrazyl (DPPH) free radical and nitric oxide (NO). The effect of AR on ROS formation, antioxidant enzymes, elastase, MMP-1 level, and mRNA expression of MMP-1 were determined in UVB-irradiated human keratinocyte HaCaT cells.
AR demonstrated strong DPPH free radical and NO scavenging activity in a cell-free system exhibiting IC50 values of 1.88 mg/mL and 6.77 mg/mL, respectively. AR pretreatment dose-dependently attenuated the production of UVB-induced intracellular ROS, and antioxidant enzymes (catalase and superoxide dismutase) were enhanced in HaCaT cells. Furthermore, pretreatment of AR prevented UVB-induced elastase and collagen degradation by inhibiting the MMP-1 protein level and mRNA expression. Accordingly, AR treatment elevated collagen content in UVB-irradiated HaCaT cells.
The present study provides the first evidence of AR inhibiting UVB-induced ROS production and induction of MMP-1 as a result of augmentation of antioxidative activity in HaCaT human keratinocytes. These results suggest that AR might act as an effective inhibitor of UVB-modulated signaling pathways and might serve as a photo-protective agent.
Inflammatory bowel diseases (IBDs) are characterized by autoimmune and inflammation-related complications of the large intestine (ulcerative colitis) and additional parts of the digestive tract (Crohn's disease). Complications include pain, diarrhoea, chronic inflammation, and cancer. IBD prevalence has increased during the past decades, especially in Westernized countries, being as high as 1%. As prognosis is poor and medication often ineffective or causing side effects, additional preventive/adjuvant strategies are sought. A possible approach is via diets rich in protective constituents. Polyphenols, the most abundant phytochemicals, have been associated with anti-inflammatory, antioxidant, immunomodulatory, and apoptotic properties. Locally reducing oxidative stress, they can further act on cellular targets, altering gene expression related to inflammation, including NF-κB, Nrf-2, Jak/STAT, and MAPKs, suppressing downstream cytokine formation (e.g., IL-8, IL-1β, and TNF-α), and boosting the bodies' own antioxidant status (HO-1, SOD, and GPx). Moreover, they may promote, as prebiotics, healthy microbiota (e.g., Bifidobacteria, Akkermansia), short-chain fatty acid formation, and reduced gut permeability/improved tight junction stability. However, potential adverse effects such as acting as prooxidants, or perturbations of efflux transporters and phase I/II metabolizing enzymes, with increased uptake of undesired xenobiotics, should also be considered. In this review, we summarize current knowledge around preventive and arbitrary actions of polyphenols targeting IBD.
Theaflavins, the major black tea polyphenols, have been reported to exhibit promising antitumor activities in several human cancers. However, the role of theaflavins in hepatocellular carcinoma (HCC) is still unknown. In this study, we found that theaflavins could significantly inhibit proliferation, migration, and invasion, and induce apoptosis in HCC cells in vitro. Furthermore, we found that theaflavins inhibited the growth and metastasis of HCC in an orthotopic model and a lung metastasis model. Immunohistochemical analyses and terminal deoxynucleotidyl transferase dUTP nick end-labeling assays showed that theaflavins could suppress proliferation and induce apoptosis in vivo. Theaflavins also suppressed constitutive and inducible signal transducer and activator of transcription 3 (STAT3) phosphorylation. The downstream proteins regulated by STAT3, including the antiapoptotic proteins (Bcl-2 and Survivin) and the invasion-related proteins (MMP-2, MMP-9), were also downregulated after theaflavins treatment. Theaflavins induced apoptosis by activating the caspase pathway. Together, our results suggest that theaflavins suppress the growth and metastasis of human HCC through the blockage of the STAT3 pathway, and thus may act as potential therapeutic agents for HCC.
Caregivers of individuals with COPD have a key role in maintaining patient adherence and optimizing patient function. However, no systematic review has examined how the caregiver role has been operationalized in interventions to improve outcomes of individuals with COPD or the quality or effectiveness of these interventions. The aims of this review were to 1) determine whether caregivers have been involved as part of interventions to improve outcomes of individuals with COPD; 2) determine the risk of bias within included intervention studies; and 3) examine the effectiveness of interventions that have involved caregivers in improving outcomes of individuals with COPD. The electronic databases of Medline, Embase, PsycINFO, and Cochrane Library were searched from January 2000 to November 2015. Experimental studies testing interventions that involved a caregiver to improve COPD patient outcomes were eligible. Nine studies involving caregivers met inclusion criteria. No studies reported any intervention components targeted solely at caregivers, with most instead including caregivers in dyadic or group education sessions about COPD delivered by health care professionals. The risk of bias identified in included studies was mixed. Seven of the nine studies were effective in improving a broad range of outcomes. These findings highlight that there is an urgent need for methodologically rigorous interventions to examine the effectiveness of strategies to assist caregivers to provide direct care, encourage adherence to health care provider recommendations, act as a health care advocate, and provide emotional and psychosocial support to individuals with COPD.
Here we describe the molecular basis underlying interference by inhibitors of reporter enzymes for biochemical and cell-based assays. This understanding is used to create strategies to mitigate the confounding effects reporter enzyme inhibitor interference has on interpreting high throughput screening results, and to aid in evaluating chemical probes derived from reporter gene assays. As well, example compounds that act as potent inhibitors of luciferases are described which can serve as useful tools when developing luciferase-based assays.
Extensive study of photorefractive polymeric composites photosensitized with semiconductor nanocrystals has yielded data indicating that the inclusion of such nanocrystals enhances the charge-carrier mobility, and subsequently leads to a reduction in the photorefractive response time. Unfortunately, the included nanocrystals may also act as a source of deep traps, resulting in diminished diffraction efficiencies as well as reduced two beam coupling gain coefficients. Nonetheless, previous studies indicate that this problem is mitigated through the inclusion of semiconductor nanocrystals possessing a relatively narrow band-gap. Here, we fully exploit this property by doping PbS nanocrystals into a newly formulated photorefractive composite based on molecular triphenyldiamine photosensitized with C60. Through this approach, response times of 399 μs are observed, opening the door for video and other high-speed applications. It is further demonstrated that this improvement in response time occurs with little sacrifice in photorefractive efficiency, with internal diffraction efficiencies of 72% and two-beam-coupling gain coefficients of 500 cm(-1) being measured. A thorough analysis of the experimental data is presented, supporting the hypothesized mechanism of enhanced charge mobility without the accompaniment of superfluous traps. It is anticipated that this approach can play a significant role in the eventual commercialization of this class of materials.
Fluoroquinolones (FQs) are highly effective broad-spectrum antibiotics. Clinical data reveal an increased incidence of tendon pain and rupture in those
 taking FQs, yet little is known about tendon structural changes. This review synthesises published data on tendon structural changes in people who have taken FQs. Eight databases were searched for potentially relevant articles (Medline, CINAHL, Biological Abstracts, AMED, Web of Knowledge, SCOPUS, SportDiscus and EMBASE) using MeSH and free-text searches. Inclusion and exclusion criteria determined which articles were used for this review. Twenty-six papers met the eligibility criteria. The Achilles tendon was most commonly affected, and ciprofloxacin and levofloxacin were the most commonly implicated FQs. Mean time to onset of symptoms was 16 days following first FQ dose. Imaging modalities used included magnetic resonance imaging (MRI), B-mode ultrasound (US) and computed tomography (CT). Tendon measurements were rarely reported, and intratendinous imaging findings were not reported in a consistent manner. Few studies imaged tendons bilaterally, and only two studies were longitudinal in design. Future studies should report imaging measures such as thickness and cross-sectional area and use consistent descriptions of intratendinous changes during and post-FQ treatment.
We demonstrate the real-time monitoring of the growth of amyloid-protein aggregates in a semi-rigid gel environment constructed from a 5% w/v gelatin solution. The kinetics of amyloid fibril growth from reduced and carboxy-methylated κ-casein occurring in the gel medium was contrasted against that obtained in a regular solution assay. Aggregation kinetics were recorded using Thioflavin T fluorescence. Transmission electron microscopy was used to confirm the aggregates' existence and morphology. The current demonstration of controlled amyloid growth in a gel environment represents the first step towards development of an experimental model for investigating the role of spatial and medium factors in the kinetics of aggregation-based proteopathies.
Cannabis was introduced to the UK as a medical product in the nineteenth century. However, with questions over its safety, efficacy, and possible harms its medical role diminished and by the 1950s it was viewed as a drug of misuse. Nonetheless, scientific and lay knowledge around cannabis expanded from the 1960s and cannabis re-appeared in different therapeutic forms. In re-medicalizing cannabis, science-policy transfer proved important and was enabled by the developing mechanism of expert committees, most notably the Advisory Council on the Misuse of Drugs (ACMD).
This article draws upon previously unknown archival material on the ACMD held at the National Archives and covers the period 1972-1982. It considers how expert groups were established, their membership, and the evolving discussion over therapeutic cannabis within the broader drug policy debate.
Three distinct periods emerged: 1972-1976 with the creation of the Working Group on Cannabis; 1977-1979 when the Working Group focused on potential amendments to the Misuse of Drugs Act and recommended downgrading cannabis from Class B to Class C; 1980-1982 when the Expert Group on the Effects of Cannabis recommended downgrading cannabis and encouraged research into cannabis as a medicine. Sources reveal that driven by drug control imperatives the ACMD stimulated research on cannabis leading to increased research on medical applications.
Expert advice was critical in the process of re-medicalization. Initially, discourse occurred in the closed expert committees of the ACMD. The drug problem had been framed under the criminal justice system but as the limitations of this were revealed, and there was continuing uncertainty over cannabis' impact, new approaches to cannabis were sought. It was this combination of more relaxed attitudes towards cannabis, research incentives, as well as a developing desire to draw medical needs away from discussion of drug control that was to allow re-medicalization to develop.
The pharmacist's role in home care is increasingly important. We are required to collaborate with multiple other professions. As home care pharmaceutical managers, pharmacists verify the timeline of side effects and the onset of expected effects. It is also important to verify all prescriptions from the pharmaceutical viewpoint, and to point out potential negative interactions or consequences of each prescribed medication, suggesting changes or dosage reduction in drugs as appropriate. Additionally, we verify the cause of unused drugs (i.e. patient non-compliance) and take action. As an effort to provide quality home care, pharmacists share information with other professions for collaborative management of a patient's needs. We act as a bridge between related government, agencies and citizens, assisting in creating a healthy lifestyle for the residents of our community. The days when pharmacists just sit in their pharmacies and dispense drugs are gone. Therefore, we need to collaborate more with medical, nursing care, and governmental professionals in our communities.
SLC17A9 proteins function as a lysosomal ATP transporter responsible for lysosomal ATP accumulation. P2X4 receptors act as lysosomal ion channels activated by luminal ATP. SLC17A9-mediated ATP transport across the lysosomal membrane is suppressed by Bafilomycin A1, the V-ATPase inhibitor. SLC17A9 mainly uses voltage gradient but not pH gradient generated by the V-ATPase as the driving force to transport ATP into the lysosome to activate P2X4.
The lysosome contains abundant ATP which plays important roles in lysosome functions and in cell signalling. Recently, solute carrier family 17 member 9 (SLC17A9, also known as VNUT for vesicular nucleotide transporter) proteins were suggested to function as a lysosomal ATP transporter responsible for lysosomal ATP accumulation, and P2X4 receptors were suggested to be lysosomal ion channels that are activated by luminal ATP. However, the molecular mechanism of SLC17A9 transporting ATP and the regulatory mechanism of lysosomal P2X4 are largely unknown. In this study, we report that SLC17A9-mediated ATP transport across lysosomal membranes is suppressed by Bafilomycin A1, the V-ATPase inhibitor. By measuring P2X4 activity, which is indicative of ATP transport across lysosomal membranes, we further demonstrated that SLC17A9 mainly uses voltage gradient but not pH gradient as the driving force to transport ATP into lysosomes. This study provides a molecular mechanism for lysosomal ATP transport mediated by SLC17A9. It also suggests a regulatory mechanism of lysosomal P2X4 by SLC17A9.
Clearance of misfolded and aggregated proteins is central to cell survival. Here, we describe a new pathway for maintaining protein homeostasis mediated by the proteasome shuttle factor UBQLN2. The 26S proteasome degrades polyubiquitylated substrates by recognizing them through stoichiometrically bound ubiquitin receptors, but substrates are also delivered by reversibly bound shuttles. We aimed to determine why these parallel delivery mechanisms exist and found that UBQLN2 acts with the HSP70-HSP110 disaggregase machinery to clear protein aggregates via the 26S proteasome. UBQLN2 recognizes client-bound HSP70 and links it to the proteasome to allow for the degradation of aggregated and misfolded proteins. We further show that this process is active in the cell nucleus, where another system for aggregate clearance, autophagy, does not act. Finally, we found that mutations in UBQLN2, which lead to neurodegeneration in humans, are defective in chaperone binding, impair aggregate clearance, and cause cognitive deficits in mice.
Microvillus inclusion disease (MVID) is a known congenital cause of intractable diarrhea resulting in permanent intestinal failure. There is need for a lifelong total parenteral nutrition (TPN) from diagnosis and the prognosis is poor. Most patients die by the second decade of life as a result of complications of parenteral alimentation including liver failure or sepsis. The only available treatment at this moment is a small bowel transplantation. But before that moment, the patients often suffer from a persistent failure to thrive and electrolyte disturbances despite continuous TPN.
We report what we believe is a first case of an extensive small bowel resection in a 5-month-old boy with proven MVID to act as a bridge to (liver-) intestinal transplantation to treat failure to thrive and intractable diarrhea.
An extensive small bowel resection can be done to enhance the chance of survival leading up to the transplantation by managing fluid and electrolyte imbalance. It facilitates medical management of these patients and makes a bowel transplantation possible at a later stage.
Characterization of the implanting human fetus as an allograft prompted a field of research in reproductive immunology that continues to fascinate and perplex scientists. Paternal- or partner-derived alloantigens are present in the maternal host at multiple times during the reproductive process. They begin with exposure to semen, continue through implantation and placentation, and may persist for decades in the form of fetal microchimerism. Changes in maternal immune responses that allow allogenic fertilization and survival of semiallogenic concepti to delivery must be balanced with a continued need to respond appropriately to pathogenic invaders, commensals, cell or tissue damage, and any tendency toward malignant transformation. This complex and sophisticated balancing act is essential for survival of mother, fetus, and the species itself. We will discuss concepts of alloimmune recognition, tolerance, and ignorance as they pertain to mammalian reproduction with a focus on human reproduction, maternal immune modulation, and the very earliest events in the reproductive process, fertilization and implantation.
A series of diester containing zwitterionic gemini surfactants, N,N-dimethyl-N-alkyl-2-[[hydroxy
 (alkoxy) phosphinyl]oxy]-alkylammonium designated as C8(-)-S-Cn(+), S = 2 and 3, n = 12, 14 and 16, were synthesized and characterized by instrumental techniques namely FT-IR, (1)H NMR, (13)C NMR, (31)P NMR and Mass spectral studies. These new gemini surfactants further investigated for their various surfactant properties. The critical micelle concentration (cmc) and the effectiveness of surface tension reduction (Πcmc) were determined as a function of surfactant concentration by means of surface tension measurement. Micellization and viscosity properties were investigated by surface tension, electrical conductivity, dye micellization and rheology techniques. The findings of the aqueous surfactant system obtained were impacted by polarity, size and the nature of zwitterions as the surface. The thermodynamic and viscosity properties of these surfactants found to be based on the structures of gemini surfactants.
Although it is well established that the protein α-synuclein (αS) plays an important role in Parkinson's disease, its physiological function remains largely unknown. It has been reported to bind membranes and to play a role in membrane remodeling processes. The mechanism by which αS remodels membranes is still debated; it may either affect its physical properties or act as a chaperone for other membrane associated proteins. To obtain insight into the role of αS in membrane remodeling we investigated the number of αS proteins associated with single small vesicles in a neuronal cell model. Using single-molecule microscopy and photo-bleaching approaches, we most frequently found 70 αS-GFPs per vesicle. Although this number is high enough to modulate physical membrane properties, it is also strikingly similar to the number of synaptobrevins, a putative interaction partner of αS, per vesicle. We therefore hypothesize a dual, synergistic role for αS in membrane remodeling.
Curcumin has received immense attention over the past decades because of its diverse biological activities and recognized as a promising drug candidate in a large number of diseases. However, its clinical application has been hindered due to extremely low aqueous solubility, chemical stability, and cellular uptake. In this study, we discovered quite a new function of curcumin, i.e. pH-responsive endosomal disrupting activity, derived from curcumin's self-assembly. We selected anticancer activity as an example of biological activities of curcumin, and investigated the contribution of pH-responsive property to its anticancer activity. As a result, we demonstrated that the pH-responsive property significantly enhances the anticancer activity of curcumin. Furthermore, we demonstrated a utility of the pH-responsive property of curcumin as delivery nanocarriers for doxorubicin toward combination cancer therapy. These results clearly indicate that the smart curcumin assemblies act as promising nanoplatform for development of curcumin-based therapeutics.
Changes in environmental conditions can act as stressors, with potential consequences for the health and fitness of organisms. Rising levels of carbon dioxide (CO2) is one potential environmental stressor that is occurring more frequently in the environment and can be a stressor for aquatic organisms. In this study, the physiological responses of two species of unionid mussel, Lampsilis siliquoidea and Amblema plicata, were assessed in response to exposure to two levels of elevated partial pressure of CO2 (pCO2) (~20,000 and ~55,000μatm) over a 28d period, followed by a subsequent 14d recovery period. Observations were consistent with responses associated with respiratory acidosis, as demonstrated by changes in hemolymph HCO3(-), Ca(2+), Cl(-), and Na(2+). Both species exposed to elevated pCO2 had elevated hemolymph HCO3(-) during the pCO2 treatment period compared to control mussels, but recovered once pCO2 was removed. Similarly, both species had elevated hemolymph Na(+) during exposure to elevated pCO2, and this returned to control levels for A. plicata but remained elevated for L. siliquoidea once the pCO2 stimuli was removed. Changes in hemolymph Ca(2+) and Cl(-) in response to elevated pCO2 were also observed, but these changes were species-specific. Additional physiological responses to elevated pCO2 (e.g., changes in hemolymph glucose and Mg(2+)) were consistent with a stress response in both species. This study demonstrates the importance of considering inter-specific differences in the response of organisms to stress, and also that responses to elevated pCO2 may be transient and can recover once the stress is removed.
The highly conserved Rho-family GTPase Cdc42 is an essential regulator of polarity in many different cell types. During polarity establishment, Cdc42 becomes concentrated at a cortical site, where it interacts with downstream effectors to orient the cytoskeleton along the front-back axis. To concentrate Cdc42, loss of Cdc42 by diffusion must be balanced by recycling to the front. In Saccharomyces cerevisiae, the guanine nucleotide dissociation inhibitor (GDI) Rdi1 recycles Cdc42 through the cytoplasm. Loss of Rdi1 slowed but did not eliminate Cdc42 accumulation at the front, suggesting the existence of other recycling pathways. One proposed pathway involves actin-directed trafficking of vesicles carrying Cdc42 to the front. However, we found no role for F-actin in Cdc42 concentration, even in rdi1Δ cells. Instead, Cdc42 was still able to exchange between the membrane and cytoplasm in rdi1Δ cells, albeit at a reduced rate. Membrane-cytoplasm exchange of GDP-Cdc42 was faster than that of GTP-Cdc42, and computational modeling indicated that such exchange would suffice to promote polarization. We also uncovered a novel role for the Cdc42-directed GTPase-activating protein (GAP) Bem2 in Cdc42 polarization. Bem2 was known to act in series with Rdi1 to promote recycling of Cdc42, but we found that rdi1Δ bem2Δ mutants were synthetically lethal, suggesting that they also act in parallel. We suggest that GAP activity cooperates with the GDI to counteract the dissipative effect of a previously unappreciated pathway whereby GTP-Cdc42 escapes from the polarity site through the cytoplasm.
MicroRNAs (miRNAs) act as important post-transcriptional regulators of gene expression by targeting the 3'-untranslated region of their target genes. Altered expression of miR-16 is reported in human ulcerative colitis (UC), but its role in the development of the disease remains unclear. Adenosine through adenosine A2a receptor (A2aAR) could inhibit nuclear factor-kappaB (NF-κB) signaling pathway in inflammation. Here we identified overexpression of miR-16 and down-regulation of A2aAR in the colonic mucosa of active UC patients. We demonstrated that miR-16 negatively regulated the expression of the A2aAR at the post-transcriptional level. Furthermore, transfection of miR-16 mimics promoted nuclear translocation of NF-κB p65 protein and expression of pro-inflammatory cytokines, IFN-γ and IL-8 in colonic epithelial cells. Treatment with miR-16 inhibitor could reverse these effects in cells. The A2aAR-mediated effects of miR-16 on the activation of the NF-κB signaling pathway were confirmed by the A2aAR knockdown assay. Our results suggest that miR-16 regulated the immune and inflammatory responses, at least in part, by suppressing the expression of the A2aAR to control the activation of the NF-κB signaling pathway.
Extracts of Ruscus aculeatus are a rich source of bioactive steroidal glycosides, such as ruscogenins which are reported to act against chronic venous disorders. Nowadays, several preparations of its roots, commonly used in traditional medicine, are on the market as food supplements for health care and maintenance. Although spirostanol deglucoruscin is one of the main metabolites in these extracts, literature reports about its pharmacological profile are scarce. In this paper, a multi-disciplinary approach, based on chemical proteomics, molecular modelling and bio-organic assays, has been used to disclose the whole interactome of deglucoruscin and the F0-F1 ATP synthase complex has been found as its main target.
Whether the executive profile is different between obesity (OB) and morbid obesity (MO) remains unclear. Recent evidence suggests that physical activity (PA) can act as a cognitive enhancer. Irisin is a recently discovered hormone associated with some of the positive effects of PA. The objective of the study was to investigate the executive profile in OB and MO, and to explore the role of PA and irisin. 114 participants were included (21 OB, 44 MO and 49 healthy controls-HC) in the study and assessed with the Wisconsin Card Sorting Test, Stroop Color and Word Test, and Iowa Gambling Task. All participants were female, aged between 18 and 60 years. Results showed a similar dysfunctional profile on decision making in OB and MO compared with HC. Thus, no specific neuropsychological profiles between OB and MO can be clearly observed in our sample. However, a negative correlation was found between irisin and executive functioning. These results demonstrate a specific executive profile in OB and a relevant and negative modulation of irisin on executive functioning. Although irisin might be a promising target for the treatment of obesity, its effects on cognition might be considered when thinking about its therapeutic use.
The potential of wastewater treatment plants (WWTPs) to act as sources of poly and perfluoroalkyl substances (PFASs), volatile methyl siloxanes (VMSs) and organic UV-filters to the atmosphere was investigated. Target compounds included: PFASs (fluorotelomer alcohols (FTOHs), perfluorooctane sulfonamides/sulfonamidoethanols (FOSAs/FOSEs), perfluroalkyl sulfonic acids (PFSAs) and perfluroalkyl carboxylic acids (PFCAs)), cyclic VMSs (D3 to D6), linear VMSs (L3 to L5) and eight UV-filters.
 Emissions to air were assessed at eight WWTPs using paired sorbent-impregnated polyurethane foam passive air samplers, deployed during summer 2013 and winter 2014. Samplers were deployed on-site above the active tank and off-site as a reference. Several types of WWTPs were investigated: secondary activated sludge in urban areas (UR-AS), secondary extended aeration in towns (TW-EA) and facultative lagoons in rural areas (RU-LG). The concentrations of target compounds in air were ∼1.7-35 times higher on-site compared to the corresponding off-site location. Highest concentrations in air were observed at UR-AS sites while the lowest were at RU-LG. Higher air concentrations (∼2-9 times) were observed on-site during summer compared to winter, possibly reflecting enhanced volatilization due to higher wastewater temperatures or differences in influent wastewater concentrations. A significant positive correlation was obtained between concentrations in air and WWTP characteristics (influent flow rate and population in the catchment of the WWTP); whereas a weak negative correlation was obtained with hydraulic retention time. Emissions to air were estimated using a simplified dispersion model. Highest emissions to air were seen at the UR-AS locations. Emissions to air (g/year/tank) were highest for VMSs (5000-112,000) followed by UV-filters (16-2000) then ΣPFASs (10-110).
A physician-patient relationship is essential for the well-being of the patient, for without a strong and trusting relationship between both individuals, the patient may not receive the best care that they deserve. There are many legal policies and ethical principles a physician must follow when caring for a patient. It is both the legal and moral duty of the physician to act in the best interests of their patients, while making sure to respect them regardless of background and personal behaviours. The relationship is secured with both trust and respect, for without trust, the patient may hold back from stating their conditions which will result in the physician not providing them with all the care they require. Sometimes, lack of some of these key characteristics of the physician-patient relationship and other circumstances, may cause either the patient or the physician to terminate the relationship. Termination of a relationship creates a difficult situation for the patient, and therefore there are only specific situations where a physician may have permission to follow through and terminate their relationship. Both the law and ethical principles play a role in the decisions made by the physician in regards to their relationship with the patient, but regardless, the physician has the obligation to make sure their patient is receiving care by one means or another.
This final rule establishes requirements for State agencies, local educational agencies, and schools operating the Community Eligibility Provision, a reimbursement option that allows the service of school meals to all children at no-cost in high poverty schools without collecting household applications. By eliminating the household application process and streamlining meal counting and claiming procedures through the Community Eligibility Provision, local educational agencies may substantially reduce administrative burden related to operating the National School Lunch and School Breakfast Programs. This rule codifies many requirements that were implemented through policy guidance following enactment of the Healthy, Hunger-Free Kids Act of 2010, as well as provisions of the proposed rule. These requirements will result in consistent, national implementation of the Community Eligibility Provision.
This final rule requires all local educational agencies that participate in the National School Lunch and School Breakfast Programs to meet expanded local school wellness policy requirements consistent with the requirements set forth in section 204 of the Healthy, Hunger-Free Kids Act of 2010. The final rule requires each local educational agency to establish minimum content requirements for the local school wellness policies, ensure stakeholder participation in the development and updates of such policies, and periodically assess and disclose to the public schools' compliance with the local school wellness policies. These regulations are expected to result in local school wellness policies that strengthen the ability of a local educational agency to create a school nutrition environment that promotes students' health, well-being, and ability to learn. In addition, these regulations will increase transparency for the public with regard to school wellness policies and contribute to integrity in the school nutrition program.
This rule adopts as final, with some modifications, the National School Lunch Program and School Breakfast Program regulations set forth in the interim final rule published in the Federal Register on June 28, 2013. The requirements addressed in this rule conform to the provisions in the Healthy, Hunger-Free Kids Act of 2010 regarding nutrition standards for all foods sold in schools, other than food sold under the lunch and breakfast programs. Most provisions of this final rule were implemented on July 1, 2014, a full year subsequent to publication of the interim final rule. This was in compliance with section 208 of the Healthy, Hunger-Free Kids Act of 2010, which required that State and local educational agencies have at least one full school year from the date of publication of the interim final rule to implement the competitive food provisions. Based on comments received on the interim final rule and implementation experience, this final rule makes a few modifications to the nutrition standards for all foods sold in schools implemented on July 1, 2014. In addition, this final rule codifies specific policy guidance issued after publication of the interim rule. Finally, this rule retains the provision related to the standard for total fat as interim and requests further comment on this single standard.
Bacterial virulence relies on a delicate balance of signals interchanged between the invading microbe and the host. This communication has been extensively perceived as a battle involving harmful molecules produced by the pathogen and host defenses. In this review, we focus on a largely unexplored element of this dialogue, as are toxin-antitoxin (TA) systems of the pathogen. TA systems are reported to respond to stresses that are also found in the host and, as a consequence, could modulate the physiology of the intruder microbe. This view is consistent with recent studies that demonstrate a contribution of distinct TA systems to virulence since their absence alters the course of the infection. TA loci are stress response modules that, therefore, could readjust pathogen metabolism to favor the generation of slow-growing or quiescent cells 'before' host defenses irreversibly block essential pathogen activities. Some toxins of these TA modules have been proposed as potential weapons used by the pathogen to act on host targets. We discuss all these aspects based on studies that support some TA modules as important regulators in the pathogen-host interface.
In large health care systems, decision regarding broad implementation of psychotherapies for inpatients with psychosis require substantial evidence regarding effectiveness and feasibility for implementation. It is important to recognize challenges in conducting research to inform such decisions, including difficulties in obtaining consent from and engaging inpatients with psychosis in research. We set out to conduct a feasibility and effectiveness Hybrid Type I pilot randomized controlled trial of acceptance and commitment therapy (ACT) and a semi-formative evaluation of barriers and facilitators to implementation.
We developed a training protocol and refined an ACT treatment manual for inpatient treatment of psychosis for use at the Veterans Health Administration. While our findings on feasibility were mixed, we obtained supportive evidence of the acceptability and safety of ACT. Identified strengths of ACT included a focus on achievement of valued goals rather than symptoms. Weaknesses included that symptoms may limit patient's understanding of ACT. Facilitators included building trust and multi-stage informed consent processes. Barriers included restrictive eligibility criteria, rigid use of a manualized protocol, and individual therapy format. Conclusions are limited by our randomization of only 18 patient participants (with nine completing all aspects of the study) out of 80 planned.
Future studies should include (1) multi-stage informed consent processes to build trust and alleviate patient fears, (2) relaxation of restrictions associated with obtaining efficacy/effectiveness data, and (3) use of Hybrid Type II and III designs.
Objectives The objective of this study was to describe factors that influence the ability of state Medicaid agencies to report the Centers for Medicare & Medicaid Services' (CMS) core set of children's health care quality measures (Child Core Set). Methods We conducted a multiple-case study of four high-performing states participating in the Children's Health Insurance Program Reauthorization Act (CHIPRA) Quality Demonstration Grant Program: Illinois, Maine, Pennsylvania, and Oregon. Cases were purposively selected for their diverse measurement approaches and used data from 2010 to 2015, including 154 interviews, semiannual grant progress reports, and annual public reports on Child Core Set measures. We followed Yin's multiple-case study methodology to describe how and why each state increased the number of measures reported to CMS. Results All four states increased the number of Child Core Set measures reported to CMS during the grant period. Each took a different approach to reporting, depending on the available
 technical, organizational, and behavioral inputs in the state. Reporting capacity was influenced by a state's Medicaid data availability, ability to link to other state data systems, past experience with quality measurement, staff time and technical expertise, and demand for the measures. These factors were enhanced by CHIPRA Quality Demonstration grant funding and other federal capacity building activities, as hypothesized in our conceptual framework. These and other states have made progress reporting the Child Core Set since 2010. Conclusion With financial support and investment in state data systems and organizational factors, states can overcome challenges to reporting most of the Child Core Set measures.
Drug addiction represents a dramatic dysregulation of motivational circuits that is caused by a combination of exaggerated incentive salience and habit formation, reward deficits and stress surfeits, and compromised executive function in three stages. The rewarding effects of drugs of abuse, development of incentive salience, and development of drug-seeking habits in the binge/intoxication stage involve changes in dopamine and opioid peptides in the basal ganglia. The increases in negative emotional states and dysphoric and stress-like responses in the withdrawal/negative affect stage involve decreases in the function of the dopamine component of the reward system and recruitment of brain stress neurotransmitters, such as corticotropin-releasing factor and dynorphin, in the neurocircuitry of the extended amygdala. The craving and deficits in executive function in the so-called preoccupation/anticipation stage involve the dysregulation of key afferent projections from the prefrontal cortex and insula, including glutamate, to the basal ganglia and extended amygdala. Molecular genetic studies have identified transduction and transcription factors that act in neurocircuitry associated with the development and maintenance of addiction that might mediate initial vulnerability, maintenance, and relapse associated with addiction.
To investigate the safety and efficacy of an adjusted regimen of heparin infusion in cardiopulmonary bypass (CPB) surgery in a Chinese population.
Prospective, single-center, observational study.
University teaching hospital.
Patients having cardiac surgery with CPB were selected for this study using the following criteria: 18 to 75 years of age, undergoing first-time cardiac surgery with conventional median sternotomy, aortic clamping time between 40 and 120 minutes, and preoperative routine blood tests showing normal liver, renal, and coagulation functions. The exclusion criteria include salvage cases, a history of coagulopathy in the family, and long-term use of anticoagulation or antiplatelet drugs.
Sixty patients were divided randomly into a control group (n = 30) receiving a traditional heparin regimen and an experimental group (n = 30) receiving an adjusted regimen.
Activated coagulation time (ACT) was monitored at different time points, ACT>480 seconds was set as the safety threshold of CPB. Heparin doses (initial dose, added dose, and total dose), protamine doses (initial dose, added dose, and total dose), CPB time, aortic clamping time, assisted circulation time, sternal closure time, blood transfusion volume, and drainage volume 24 hours after surgery were recorded. There was no significant difference in achieving target ACT after the initial dose of heparin between the 2 groups; CPB time, aortic clamping time, assisted circulation time, postoperative complication rate, and drainage volume between the 2 groups were not significantly different (p>0.05). However, initial and total dosage of heparin, initial and total dosage of protamine, sternal closure time, and intraoperative blood transfusion volume in the experimental group were significantly lower (p< 0.05).
Adjusted regimen of heparin infusion could be used safely and effectively in Chinese CPB patients, which might reduce the initial and total dosage of heparin and protamine as well as sternal closure time and intraoperative blood transfusion volume.
A motional Stark effect polarimeter insensitive to polarized broadband light is proposed. Partially polarized background light is anticipated to be a significant source of systematic error for the ITER polarimeter. The proposed polarimeter is based on the standard dual photoelastic modulator approach, but with the introduction of a birefringent delay plate, it generates a sinusoidal spectral filter instead of the usual narrowband filter. The period of the filter is chosen to match the spacing of the orthogonally polarized Stark effect components, thereby increasing the effective signal level, but resulting in the destructive interference of the broadband polarized light. The theoretical response of the system to an ITER like spectrum is calculated and the broadband polarization tolerance is verified experimentally.
Bivalve mollusks bioaccumulate toxins via ingestion of toxic dinoflagellates. In this study, Crassostrea gigas was used to investigate the effects related to Prorocentrum lima exposure. Oysters were fed with three diets Isochrysis galbana (2 × 10(6) cell mL(-1)) control treatment; algal mix of I. galbana (2 × 10(6)) and P. lima (3 × 10(3) cell mL(-1)); and P. lima alone (3 × 10(3) cell mL(-1)). Feeding behavior changes, histopathological alterations, and expression patterns changes of genes involved in cell cycle (p21, cafp55, p53), cytoskeleton (tub, act), and inflammatory process (casp1) were evaluated. Results indicated that the presence of diarrheic shellfish poisoning by P. lima cells decreased the clearance rate (p < 0.05), induced structural loss, significantly decreased tubule area of the digestive gland (p < 0.05), and up-regulated in expression all gene (p < 0.05), suggesting that toxic cells might trigger inflammatory tissue process, disturb cell cycle and cytoskeleton representing a risk to oysters integrity.
The storage of water in a landscape lake can act as a buffer zone between reclaimed water production and reuse, but there is still uncertainty about the variation of water quality and toxic effects during the open-storage process. In this study, long-term sample collection, chemical analyses and biotoxicity assessments were conducted on reclaimed water before and after open storage in a landscape lake. The organic contents, in terms of chemical oxygen demand and total organic carbon, were found to be slightly higher in the lake water than that in the reclaimed water, but substantial reduction of the total concentration of 52 trace organic chemicals was obtained and microorganism toxicity, phytotoxicity, aquatic vertebrate toxicity and genotoxicity, were significantly weakened after open storage. Furthermore, the total risk quotient (RQTotal) decreased from 5.12 (potential ecological risk level) in the reclaimed water to 0.18 (negligible ecological risk level) in the lake water. The removal of chlorpyrifos, dichlorphos and tetracycline was identified as the main reason for biotoxicity reduction after open storage. The seminatural environment of the landscape lake would have provided a favorable condition for the decay of toxic trace organic chemicals so that the stored water turned to be safer for further reuse.
We extend a previously introduced model of stochastic gene regulation of cancer to a nonlinear case having both gene and pseudogene messenger RNAs (mRNAs) self-regulated. The model consists of stochastic Boolean genetic elements and possesses noise-induced multistability (multimodality). We obtain analytical expressions for probabilities for the case of constant but finite number of microRNA molecules which act as a noise source for the competing gene and pseudogene mRNAs. The probability distribution functions display both the global bistability regime as well as even-odd number oscillations for a certain range of model parameters. Statistical characteristics of the mRNA's level fluctuations are evaluated. The obtained results of the extended model advance our understanding of the process of stochastic gene and pseudogene expressions that is crucial in regulation of cancer.
Reactive oxygen intermediates (ROI) are metabolites produced by aerobic cells which have been linked to oxidative stress. Evidence reported in vertebrates indicates that ROI can also act as messengers in a variety of cellular signaling pathways, including those involved in innate immunity. In a recent study, an inhibitor of NF-kB transcription factors was identified in the scallop Argopecten purpuratus, and its functional characterization suggested that it may regulate the expression of the big defensin antimicrobial peptide ApBD1. In order to give new insights into the messenger role of ROI in the immune response of bivalve mollusks, the effect of ROI production on gene transcription of ApBD1 was assessed in A. purpuratus. The results showed that 48 h-cultured hemocytes were able to display phagocytic activity and ROI production in response to the β-glucan zymosan. The immune stimulation also induced the transcription of ApBD1, which was upregulated in cultured hemocytes. After neutralizing the ROI produced by the stimulated hemocytes with the antioxidant trolox, the transcription of ApBD1 was reduced near to base levels. The results suggest a potential messenger role of intracellular ROI on the regulation of ApBD1 transcription during the immune response of scallops.
DWCNTs have numerous industrial and biomedical applications and several studies reported that they could act as immunomodulator systems. The immune system is the first line of defence of the human body when exposed to particulate matter. In order to investigate DWCNTs' role on innate immunity, we used THP-1 monocytic cells for the purpose of this study. We showed that DWCNTs were not cytotoxic until 6h, 24h,
 48h and 72h of incubation with THP-1 monocytic cells (concentrations tested from 10 to 50μg/mL). From 6h to 72h of incubation of THP-1 cells with DWCNTs, we measured a significant increase of the baseline cell index using xCELLigence(®) technology showing cell adhesion. After 24h of exposure, DWCNTs agglomerates were localized in THP-1 monocyte cytoplasm and cell adhesion was observed simultaneously with a significant increase in the expression of CD11b and CD14 cell surface proteins. Pro-inflammatory cytokine secretion (IL-1β, IL-6, IL-8, TNF-α and IL-10) was also measured in supernatants after 6h or 24h of exposure to DWCNTs. This pro-inflammatory response was increased in THP-1 monocytic cells pre-treated with LPS. Altogether, our data indicate that DWCNTs induce an increased pro-inflammatory response of THP-1 monocytes and seem to modulate cell surface protein expression confirming that DWCNTs could act as stimulators of innate immunity.
Biofilm formation on fungal hyphae and production of antifungal molecules are strategies of bacteria in their competition with fungi for nutrients. Since these strategies are often coordinated and under control of quorum sensing by the bacteria, interference with this bacterial communication system can be used as a counter-strategy by the fungi in this competition. Hydrolysis of N-acyl-homoserine lactones (HSL), a quorum sensing molecule used by Gram-negative bacteria, by fungal cultures has been demonstrated. However, the enzymes that are responsible for this activity, have not been identified. In this study, we identified and characterized two paralogous HSL hydrolyzing enzymes from the coprophilous fungus Coprinopsis cinerea. The C. cinerea HSL lactonases belong to the metallo-β-lactamase family and show sequence homology to and a similar biochemical activity as the well characterized lactonase AiiA from Bacillus thuringiensis. We show that the fungal lactonases, similar to the bacterial enzymes, are kept intracellularly and act as a sink for the bacterial quorum sensing signals both in C. cinerea and in Saccharomyces cerevisiae expressing C. cinerea lactonases, due to the ability of these signal molecules to diffuse over the fungal cell wall and plasma membrane. The two isogenes coding for the C. cinerea HSL lactonases are arranged in the genome as a tandem repeat and expressed preferentially in vegetative mycelium. The occurrence of orthologous genes in genomes of other basidiomycetes appears to correlate with a saprotrophic lifestyle.
The abolition of the Dutch milk quota system has been accompanied by the introduction of a new manure policy to limit phosphate production (i.e., excretion via manure) on expanding dairy farms. The objective of this study was to evaluate the effect of these recent policy changes on the farm structure, management, labor income, nitrogen and phosphate surpluses, and greenhouse gas emissions of an average Dutch dairy farm. The new manure policy requires that any increase in phosphate production be partly processed and partly applied to additional farmland. In addition, phosphate quotas have been introduced. Herein, we used a whole-farm optimization model to simulate an average farm before and after quota abolition and introduction of the new manure policy. The objective function of the model maximized labor income. We combined the model with a farm nutrient balance and life-cycle assessment to determine environmental impact. Based on current prices, increasing the number of cows after quota abolition was profitable until manure processing or additional land was required to comply with the new manure policy. Manure processing involved treatment so that phosphate was removed from the national manure market. Farm intensity in terms of milk per hectare increased by about 4%, from 13,578kg before quota abolition to 14,130kg after quota abolition. Labor income increased by €505/yr. When costs of manure processing decreased from €13 to €8/t of manure or land costs decreased from €1,187 to €573/ha, farm intensity could increase up to 20% until the phosphate quota became limiting. Farms that had already increased their barn capacity to prepare for expansion after milk quota abolition could benefit from purchasing extra phosphate quota to use their full barn capacity. If milk prices increased from €355 to €420/t, farms could grow unlimited, provided that the availability of external inputs such as labor, land, barn capacity, feed, and phosphate quota at current prices were also unlimited. The milk quota abolition, accompanied by a new manure policy, will slightly increase nutrient losses per hectare, due to an increase in farm intensity. Greenhouse gas emissions per unit of milk will hardly change, so at a given milk production per cow, total greenhouse gas emissions will increase linearly with an increase in the number of cows.
Angiogenesis, the formation of new blood vessels from pre-existing ones, is thought to enhance tumour growth and these blood vessels can act as conduits of tumour cell metastasis. Integrins, the family of cell surface extracellular matrix receptors, can promote endothelial cell migration and survival, both essential features of angiogenesis, and were thus considered good targets for anti-angiogenic therapy. This sparked the development of agents to block integrin function as new cancer therapies. Here, we review the current status of αvβ3-integrin in tumour angiogenesis. Learning from what we now know about integrin conformational changes and endocytosis, we discuss the possible future of targeting blood vessel αvβ3-integrin in the control of cancer.
The hepatotoxin microcystin (MCYST) is produced by a variety of freshwater cyanobacterial species, including Microcystis aeruginosa Interestingly, MCYST-producing M. aeruginosa strains have been shown to outcompete their nontoxic counterparts under iron-limiting conditions. However, the reasons for this are unclear. Here we examined the proteomic response of M. aeruginosa PCC 7806 continuous cultures under different iron and growth regimes. Iron limitation was correlated with a global reduction in levels of proteins associated with energy metabolism and photosynthesis. These proteomic changes were consistent with physiological observations, including reduced chlorophyll a content and reduced cell size. While levels of MCYST biosynthesis proteins did not fluctuate during the study period, both intra- and extracellular toxin quotas were significantly higher under iron-limiting conditions. Our results support the hypothesis that intracellular MCYST plays a role in protecting the cell against oxidative stress. Further, we propose that extracellular MCYST may act as a signaling molecule, stimulating MCYST production under conditions of iron limitation and enhancing the fitness of bloom populations.
Microcystin production in water supply reservoirs is a global public health problem. Understanding the ecophysiology of hepatotoxic cyanobacteria, including their responses to the presence of key micronutrient metals such as iron, is central to managing harmful blooms. To our knowledge, this was the first study to examine proteomic and physiological changes occurring in M. aeruginosa continuous cultures under conditions of iron limitation at different growth rates.
Recently, many states in India have invoked various provisions of the Epidemic Diseases Act of 1897 to control communicable diseases. In this context, the Act was reviewed with reference to its relevance in the current context of surveillance and other relevant Acts and legislations at the national and international levels. It is felt that the Act has major limitations in the current scenario as it is outdated, merely regulatory and not rights-based, and lacks a focus on the people. There is a need for an integrated, comprehensive, actionable and relevant legal provision for the control of outbreaks in India.
Lactic acid bacteria (LAB) produce exopolysaccharides (EPS) that are important for biofilm formation in the mammalian oral cavity and gastrointestinal tract. Sucrose is a well-known substrate for homo-EPS formation by Lactobacillus reuteri glucansucrases (GS). Starch is the main fermentable carbohydrate in the human diet, and often consumed simultaneously with sucrose. Recently we have characterized L. reuteri strains that also possess 4,6-α-glucanotransferases (4,6-α-GTases) that act on starch yielding isomalto-/malto-polysaccharides. In this study we have characterized the EPS formed by L. reuteri 35-5 cells and enzymes from sucrose plus starch. The data show that both in vivo and in vitro the L. reuteri 35-5 GS and 4,6-α-GTase enzymes, incubated with sucrose plus starch, cross-react and contribute to synthesis of the final hybrid EPS products. This may have strong effects on the EPS functional properties, influence biofilm formation, and affect the relationship between dietary intake of sucrose and starch, and dental caries formation.
Inositol pyrophosphates, such as diphosphoinositol pentakisphosphate (IP7), are conserved eukaryotic signaling molecules that possess pyrophosphate and monophosphate moieties. Generated predominantly by inositol hexakisphosphate kinases (IP6Ks), inositol pyrophosphates can modulate protein function by posttranslational serine pyrophosphorylation. Here, we report inositol pyrophosphates as novel regulators of cytoplasmic dynein-driven vesicle transport. Mammalian cells lacking IP6K1 display defects in dynein-dependent trafficking pathways, including endosomal sorting, vesicle movement, and Golgi maintenance. Expression of catalytically active but not inactive IP6K1 reverses these defects, suggesting a role for inositol pyrophosphates in these processes. Endosomes derived from slime mold lacking inositol pyrophosphates also display reduced dynein-directed microtubule transport. We demonstrate
 that Ser51 in the dynein intermediate chain (IC) is a target for pyrophosphorylation by IP7, and this modification promotes the interaction of the IC N-terminus with the p150(Glued) subunit of dynactin. IC-p150(Glued) interaction is decreased, and IC recruitment to membranes is reduced in cells lacking IP6K1. Our study provides the first evidence for the involvement of IP6Ks in dynein function and proposes that inositol pyrophosphate-mediated pyrophosphorylation may act as a regulatory signal to enhance dynein-driven transport.
Marine litter represents a pervasive environmental problem that poses direct threats to wildlife and habitats. Indirectly, litter can also act as a vehicle for the exposure and bioaccumulation of chemicals that are associated with manufactured or processed solids. In this study, we describe the use of a Niton field-portable-x-ray fluorescence (FP-XRF) spectrometer to determine the content of 17 elements in beached plastics, foams, ropes and painted items. The instrument was used in a 'plastics' mode configured for complex, low density materials, and employed a thickness correction algorithm to account for varying sample depth. Accuracy was evaluated by analysing two reference polyethylene discs and was better than 15% for all elements that had been artificially impregnated into the polymer. Regarding the litter samples, limits of detection for a 120s counting time varied between the different material categories and among the elements but were generally lowest for plastics and painted items with median concentrations of less than 10μgg(-1) for As, Bi, Br, Cr, Hg, Ni, Pb, Se and Zn. Concentrations returned by the XRF were highly sensitive to the thickness correction applied for certain elements (Ba, Cl, Cr, Cu, Fe, Sb, Ti, Zn) in all matrices tested, indicating that accurate measurement and application of the correct thickness is critical for acquiring reliable results. An independent measure of the elemental content of selected samples by ICP spectrometry following acid digestion returned concentrations that were significantly correlated with those returned by the XRF, and with an overall slope of [XRF]/[ICP]=0.85. Within the FP-XRF operating conditions, Cl, Cr, Fe, Ti and Zn were detected in more than 50% and Hg and Se in less than 1% of the 376 litter samples analysed. Significant from an environmental perspective were concentrations of the hazardous elements, Cd, Br and Pb, that exceeded several thousand μgg(-1) in many cases.
We aimed to characterize the lipidomic, metabolomic, and transcriptomic profiles in preterm piglets administered enteral (ENT) formula or three parenteral lipid emulsions [parenteral nutrition (PN)], Intralipid (IL), Omegaven (OV), or SMOFlipid (SL), for 14 days. Piglets in all parenteral lipid groups showed differential organ growth versus ENT piglets; whole body growth rate was lowest in IL piglets, yet there were no differences in either energy expenditure or (13)C-palmitate oxidation. Plasma homeostatic model assessment of insulin resistance demonstrated insulin resistance in IL, but not OV or SL, compared with ENT. The fatty acid and acyl-CoA content of the liver, muscle, brain, and plasma fatty acids reflected the composition of the dietary lipids administered. Free carnitine and acylcarnitine (ACT) levels were markedly reduced in the PN groups compared with ENT piglets. Genes associated with oxidative stress and inflammation were increased, whereas those associated with alternative pathways of fatty acid oxidation were decreased in all PN groups. Our results show that new generation lipid emulsions directly enrich tissue fatty acids, especially in the brain, and lead to improved growth and insulin sensitivity compared with a soybean lipid emulsion. In all total PN groups, carnitine levels are limiting to the formation of ACTs and gene expression reflects the stress of excess lipid on liver function.
Molecular chaperones are a very special class of proteins that play essential roles in many cellular processes like folding, targeting and transport of proteins. Moreover, recent evidence indicates that chaperones can act as potentially strong suppressor agents in Alzheimer's disease (AD). Indeed, in vitro experiments demonstrate that several chaperones are able to significantly slow down or suppress aggregation of Aβ peptide and in vivo studies reveal that treatment with specific chaperones or their overexpression can ameliorate some distinct pathological signs characterizing AD.
Here we investigate using a biophysical approach (fluorescence, circular dichroism (CD), transmission electron (TEM) and atomic force (AFM) microscopy, size exclusion chromatography (SEC)) the effect of the human chaperonin Hsp60 on Aβ fibrillogenesis.
We found that Hsp60 powerfully inhibits Aβ amyloid aggregation, by closing molecular pathways leading to peptide fibrillogenesis.
We observe that Hsp60 inhibits Aβ aggregation through a more complex mechanism than a simple folding chaperone action. The action is specifically directed toward the early oligomeric species behaving as aggregation seeds for on-pathway amyloid fibrillogenesis.
Understanding the specificity of the molecular interactions of Hsp60 with amyloid Aβ peptide allowed us to emphasize the important aspects to be taken into consideration when considering the recent promising therapeutic strategies for neurodegeneration.
Recent studies have shown that dysfunctional microRNAs (miRNAs) are involved in the progression of various cancers. Dysfunctional miRNAs may jointly regulate their target genes and further alter the activities of canonical biological pathways. Identification of the pathways regulated by a group of dysfunctional miRNAs could help uncover the pathogenic mechanisms of cancer and facilitate development of new drug targets. Current miRNA-pathway analyses mainly use differentially-expressed miRNAs to predict the shared pathways on which they act. However, these methods fail to consider the level of differential expression level, which could improve our understanding of miRNA function. We propose a novel computational method, MicroRNA Set Enrichment Analysis (MiRSEA), to identify the pathways regulated by dysfunctional miRNAs. MiRSEA integrates the differential expression levels of miRNAs with the strength of miRNA pathway associations to perform direct enrichment analysis using miRNA expression data. We describe the MiRSEA methodology and illustrate its effectiveness through analysis of data from hepatocellular cancer, gastric cancer and lung cancer. With these analyses, we show that MiRSEA can successfully detect latent biological pathways regulated by dysfunctional miRNAs. We have implemented MiRSEA as a freely available R-based package on CRAN (https://cran.r-project.org/web/packages/MiRSEA/).
The ubiquitous small heat shock proteins (sHSPs) are well documented to act in vitro as molecular chaperones to prevent the irreversible aggregation of heat-sensitive proteins. However, the in vivo activities of sHSPs remain unclear. To investigate the two most abundant classes of plant cytosolic sHSPs (class I [CI] and class II [CII]), RNA interference (RNAi) and overexpression lines were created in Arabidopsis (Arabidopsis thaliana) and shown to have reduced and enhanced tolerance, respectively, to extreme heat stress. Affinity purification of CI and CII sHSPs from heat-stressed seedlings recovered eukaryotic translation elongation factor (eEF) 1B (α-, β-, and γ-subunits) and eukaryotic translation initiation factor 4A (three isoforms), although the association with CI sHSPs was stronger and additional proteins involved in translation were recovered with CI sHSPs. eEF1B subunits became partially insoluble during heat stress and, in the CI and CII RNAi lines, showed reduced recovery to the soluble cell fraction after heat stress, which was also dependent on HSP101. Furthermore, after heat stress, CI sHSPs showed increased retention in the insoluble fraction in the CII RNAi line and vice versa. Immunolocalization revealed that both CI and CII sHSPs were present in cytosolic foci, some of which colocalized with HSP101 and with eEF1Bγ and eEF1Bβ. Thus, CI and CII sHSPs have both unique and overlapping functions and act either directly or indirectly to protect specific translation factors in cytosolic stress granules.
It has been hypothesized that selective serotonin reuptake inhibitors (SSRIs), the most common treatment for major depression, affect mood through changes in immune function. However, the effects of SSRIs on inflammatory response are contradictory since these act either as anti- or pro-inflammatory drugs. Previous experimental and clinical studies showed that the quality of the living environment moderates the outcome of antidepressant treatment. Therefore, we hypothesized that the interplay between SSRIs and the environment may, at least partially, explain the apparent incongruence regarding the effects of SSRI treatment on the inflammatory response. In order to investigate such interplay, we exposed C57BL/6 mice to chronic stress to induce a depression-like phenotype and, subsequently, to fluoxetine treatment or vehicle (21days) while being exposed to either an enriched or a stressful condition. At the end of treatment, we measured the expression levels of several anti- and pro-inflammatory cytokines and inflammatory mediators in the whole hippocampus and in isolated microglia. We also determined microglial density, distribution, and morphology to investigate their surveillance state. Results show that the effects of fluoxetine treatment on inflammation and microglial function, as compared to vehicle, were dependent on the quality of the living environment. In particular, fluoxetine administered in the enriched condition increased the expression of pro-inflammatory markers compared to vehicle, while treatment
 in a stressful condition produced anti-inflammatory effects. These findings provide new insights regarding the effects of SSRIs on inflammation, which may be crucial to devise pharmacological strategies aimed at enhancing antidepressant efficacy by means of controlling environmental conditions.
A successful pregnancy depends on the maintenance of tolerance at the fetal-maternal interface; strong inflammation in the placental bed is generally associated with adverse fetal outcomes. Among the mechanisms that foster tolerance and limit inflammation, the fetal immune system favors Th2 or regulatory responses over Th1 responses. The unintended consequence of this functional program is high susceptibility to infections. Human Vδ2 T cells mount innate-like responses to a broad range of microorganisms and are poised for Th1 responses before birth. In infants they likely play a key role in protection against pathogens by exerting early Th1 effector functions, improving function of other innate cells, and promoting Th1 polarization of adaptive responses. However, their propensity to release Th1 mediators may require careful regulation during fetal life to avoid exaggerated proinflammatory responses. We investigated molecules with the potential to act as a rheostat for fetal Vδ2 cells. Programmed death 1 (PD1) is a negative regulator of T cell responses and a determinant of tolerance, particularly at the fetal-maternal interface. Neonatal Vδ2 cells upregulate PD1 shortly after activation and, unlike their adult counterparts, express this molecule for at least 28 d. Engagement of PD1 by one of its ligands, PDL1, effectively dampens TCR-mediated responses (TNF-α production and degranulation) by neonatal Vδ2 cells and may thus help maintain their activity within safe limits. PD1 expression by neonatal Vδ2 cells is inversely associated with promoter DNA methylation. Prolonged PD1 expression may be part of a functional program to control Vδ2 cell inflammatory responses during fetal life.
A decade has passed since the Animal Welfare Act 2006 and the Animal Health and Welfare (Scotland) Act 2006 became law. A session at this year's Animal Welfare Foundation Discussion Forum examined the successes and limitations of the Acts and whether they are working to their full potential. Further discussions centred on the keeping of non-traditional companion animals as pets and whether greater regulation of the pet trade is needed. Laura Honey reports.
Gene editing technologies enable the precise insertion of favourable mutations and performance enhancing trait genes into chromosomes whilst excluding all excess DNA from modified genomes. The technology gives rise to a new class of biotech crops which is likely to have widespread applications in agriculture. Despite progress in the nucleus, the seamless insertions of point mutations and non-selectable foreign genes into the organelle genomes of crops have not been described. The chloroplast genome is an attractive target to improve photosynthesis and crop performance. Current chloroplast genome engineering technologies for introducing point mutations into native chloroplast genes leave DNA scars, such as the target sites for recombination enzymes. Seamless editing methods to modify chloroplast genes need to address reversal of site-directed point mutations by template mediated repair with the vast excess of wild type chloroplast genomes that are present early in the transformation process.
Using tobacco, we developed an efficient two-step method to edit a chloroplast gene by replacing the wild type sequence with a transient intermediate. This was resolved to the final edited gene by recombination between imperfect direct repeats. Six out of 11 transplastomic plants isolated contained the desired intermediate and at the second step this was resolved to the edited chloroplast gene in five of six plants tested. Maintenance of a single base deletion mutation in an imperfect direct repeat of the native chloroplast rbcL gene showed the limited influence of biased repair back to the wild type sequence. The deletion caused a frameshift, which replaced the five C-terminal amino acids of the Rubisco large subunit with 16 alternative residues resulting in a ~30-fold reduction in its accumulation. We monitored the process in vivo by engineering an overlapping gusA gene downstream of the edited rbcL gene. Translational coupling between the overlapping rbcL and gusA genes resulted in relatively high GUS accumulation (~0.5 % of leaf protein).
Editing chloroplast genomes using transient imperfect direct repeats provides an efficient method for introducing point mutations into chloroplast genes. Moreover, we describe the first synthetic operon allowing expression of a downstream overlapping gene by translational coupling in chloroplasts. Overlapping genes provide a new mechanism for co-ordinating the translation of foreign proteins in chloroplasts.
Follicular regulatory T (Tfr) cells are defined as a specialized subset of regulatory T cells (Tregs) that act to control the overactivation of follicular helper T (Tfh) cells and B cells in germinal centers. Accumulating evidence has demonstrated that the dysregulation of either Tfr cells or Tfh cells results in abnormal germinal center responses that contribute to the pathogenesis of autoimmune diseases. However, the role that Tfr cells and Tfh cells play in myasthenia gravis (MG) remains unclear. This study revealed a significantly decreased frequency of CD4(+)CXCR5(+)FOXP3(+) Tfr-like cells and an increased frequency of CD4(+)CXCR5(+)FOXP3(-) Tfh-like cells in the peripheral blood of MG patients compared with healthy controls. Moreover, the Tfr-like/Tfh-like ratio was inversely correlated with the clinical severity of the MG patients. Interestingly, glucocorticoid (GC) treatment can restore the imbalance of circulating Tfr-like/Tfh-like cells, and this restoration is accompanied by reduced clinical symptoms. These results suggested, for the first time, that an imbalance of circulating Tfr-like and Tfh-like cells may be involved in the immunopathogenesis of MG and may provide novel insight for the development of MG therapies.
In the present study we chemically profiled tannin-enriched extracts from strawberries and tested their biological properties in a cell model of gastric inflammation. The chemical and biological features of strawberry tannins after in vitro simulated gastric digestion were investigated as well. The anti-inflammatory activities of pure strawberry tannins were assayed to get mechanistic insights. Tannin-enriched extracts from strawberries inhibit IL-8 secretion in TNFα-treated human gastric epithelial cells by dampening the NF-κB signaling. In vitro simulated gastric digestion slightly affected the chemical composition and the biological properties of strawberry tannins. By using pure compounds, we found that casuarictin may act as a pure NF-κB inhibitor while agrimoniin inhibits IL-8 secretion also acting on other biological targets; in our system procyanidin B1 prevents the TNFα-induced effects without interfering with the NF-κB pathway. We conclude that strawberry tannins, even after in vitro simulated gastric digestion, exert anti-inflammatory activities at nutritionally relevant concentrations.
Bariatric surgery is the most effective way to improve comorbidities related to obesity. Since the introduction of minimally invasive laparoscopic surgery in the bariatric surgery techniques, the number of procedures has increased substantially; advances in techniques and the transition from open to minimally invasive procedures have decreased morbidity and mortality. Multidisciplinary teams in charge of the operative planning, surgical act, and postoperative recovery are determinant in the success of the management of high-risk bariatric patients; careful identification and preoperative management of these higher-risk patients is crucial in decreasing complications after weight loss surgery.
Prostate cancer is a common diagnosis with several treatment options for the newly diagnosed patient, including radiation, surgery, active surveillance, and watchful waiting. Although tailoring of treatment to individual patient needs is an important goal, the recent passage of the Affordable Care Act has placed renewed interest in cost containment and cost-effectiveness. We sought to conduct a literature review of recent US-based studies to analyze the cost-effectiveness of initial local treatments for localized prostate cancer.
We conducted a systematic literature search through PubMed, the Cost-Effectiveness Analysis Registry, and manual cross-referencing of articles. We identified US-based studies with cost analyses starting in 2005 that studied the cost-effectiveness of initial local treatments for localized prostate cancer (surgery, radiation, or observation).
There were eight studies that met our inclusion and exclusion criteria. Most studies took the cost perspective of Medicare, and two studies also considered the societal cost in terms of lost patient time. Most studies also used a Markov model with inputs based on the available literature for the effectiveness and toxicity of the different treatment options. The radiation-focused studies tended to find brachytherapy (BT) or stereotactic body radiation therapy (SBRT) to be more cost-effective than intensity-modulated radiation therapy or proton beam therapy. These findings were primarily based on the lower cost of SBRT or BT with roughly equal efficacy and toxicity. The two studies focused on surgery found surgery to be more cost effective than intensity-modulated radiation therapy, at least for low-risk disease, and one study found BT to be more cost-effective than surgery, and watchful waiting to be the most cost-effective option overall.
Cost-effectiveness analysis is important because it helps
 patients, physicians, and policymakers make quantitatively-based decisions, which balance treatment efficacy, toxicity, and costs. Significant methodological heterogeneity in the studies we found limit the ability to compare their results directly, but most found that for favorable-risk prostate cancer, shorter or simpler treatments tended to be more cost-effective, including no treatment (watchful waiting) in one study.
The actual connectivity between populations of freshwater organisms is largely determined by species biology, but is also influenced by many area- and site-specific factors, such as water pollution and habitat fragmentation. Therefore, the prediction of effective gene flow, even for well-studied organisms, is difficult. The amphipod crustacean Gammarus fossarum is a key invertebrate in freshwater ecosystems and contains many cryptic species. One of these species is the broadly distributed G. fossarum clade 11 (type B). In this study, we tested for factors driving the genetic structure of G. fossarum clade 11 in a human-impacted landscape at local and regional scales. To determine population structure, we analyzed the mitochondrial cytochrome c oxidase 1 (CO1) gene of 2,086 specimens from 54 sampling sites and microsatellite loci of 420 of these specimens from ten sites.
We detected strong overall genetic differentiation between populations at regional and local scales with both independent marker systems, often even within few kilometers. Interestingly, we observed only a weak correlation of genetic distances with geographic distances or catchment boundaries. Testing for factors explaining the observed population structure revealed, that it was mostly the colonization history, which has influenced the structure rather than any of the chosen environmental factors. Whereas the number of in-stream barriers did not explain population differentiation, the few large water reservoirs in the catchment likely act as dispersal barriers.
We showed that populations of Gammarus fossarum clade 11 are strongly isolated even at local scales in the human-impacted region. The observed genetic structure was best explained by the effects of random genetic drift acting independently on isolated populations after historical colonization events. Genetic drift in isolated populations was probably further enhanced by anthropogenic impacts, as G. fossarum is sensitive to many anthropogenic stressors. These findings highlight the importance of small-scale genetic studies to determine barriers restricting gene flow to prevent further loss of genetic diversity and maintain intact freshwater ecosystems.
The United States currently faces the large, logistical undertaking of enrolling millions of Americans into a complex Affordable Care Act (ACA) system within a short period of time. One way states have addressed this implementation challenge is through the development of consumer assistance programs. In these programs, health care professionals-known as "Assistors"-are trained in insurance enrollment services to help consumers navigate the complex application and plan selection process, with the ultimate goal of optimizing enrollment rates.
Cicatelli Associates Inc. (CAI), a non-profit capacity building organization, has served as the Statewide Training Center for New York's Health Insurance Program Initiative since 2013, before the ACA Marketplace roll-out occurred. This article presents a narrative of CAI's experiences and promising practices related to training and developing of the Assistor workforce in New York State (NYS).
By the end of the second enrollment period (February 2015), NYS trained and certified over 11,000 Assistors (1); CAI trained fifteen percent of this total workforce. As a result of this intensive workforce training effort, NYS observed extremely high rates of facilitated enrollment, and overall success with the roll-out process.
Through this initiative, CAI has garnered key insights for other organizations that engage in similar work, as well as state policymakers considering how to integrate and bolster the Assistor programs in their states. These lessons include: the necessity of ensuring that Assistors are armed with all technical concepts and messages; ensuring that Assistors are motivated to work through a change process; the constructive feedback process that can occur when these Assistors directly communicate issues to the state; and the transformation of public opinion that can occur when Assistors provide good customer service and can effectively promote statewide and federal ACA policies and benefits.
The vertebral column has evolved to accommodate the broad range of locomotor pressures found across vertebrate lineages. Xenarthran (armadillos, sloths and anteaters) vertebral columns are characterized by xenarthrous articulations, novel intervertebral articulations located in the posterior trunk that are hypothesized to stiffen the vertebral column to facilitate digging. To determine the degree to which xenarthrous articulations impact vertebral movement, we passively measured compliance and range of motion during ventroflexion, dorsiflexion and lateral bending across the thoracolumbar region of the nine-banded armadillo, Dasypus novemcinctus Patterns of bending were compared with changes in vertebral morphology along the column to determine which morphological features best predict intervertebral joint mechanics. We found that compliance was lower in post-diaphragmatic, xenarthrous vertebrae relative to pre-xenarthrous vertebrae in both sagittal and lateral planes of bending. However, we also found that range of motion was higher in this region. These changes in mechanics are correlated with the transition from pre-xenarthrous to xenarthrous vertebrae, as well as with the transition from thoracic to lumbar vertebrae. Our results thus substantiate the hypothesis that xenarthrous articulations stiffen the vertebral column. Additionally, our data suggest that xenarthrous articulations, and their associated enlarged metapophyses, also act to increase the range of motion of the post-diaphragmatic region. We propose that xenarthrous articulations perform the dual role of stiffening the vertebral column and increasing mobility, resulting in passively stable vertebrae that are capable of substantial bending under appropriate loads.
In 2010, the United Nations (UN) launched the Global Strategy for Women's and Children's Health to accelerate progress on maternal and child health. A UN Commission on Information and Accountability, established to ensure oversight and accountability on women's and children's health, outlined a framework with three processes: monitor, review, and act. This paper assesses progress on these processes. Effective monitoring depends on a functional civil registration and vital statistics system. Review requires counting all deaths and identifying contributing factors. The final, critical step is action to prevent similar deaths. Maternal death surveillance and response includes these steps and strengthens accountability. Strategies are underway to improve accountability for severe maternal morbidity and perinatal mortality. The post-2015 agenda adds greater focus on reducing inequalities, increasing availability of quality, disaggregated data, and accountability for human rights. This agenda requires engagement with communities and health providers - the foundation of accountability for women's and children's health.
Exosomes, which act as biological cargo vessels, are cell-released, phospholipid-enclosed vesicles. In eukaryotic cells, exosomes carry and exchange biological materials or signals for the benefit or detriment to the cells. Thereby, we consider exosomes to be molecular Palkis (carriers). Although exosomes are currently one of the most popularly researched cellular entities, they have remained largely enigmatic and warrant continued investigation into their structure and functions. These membraned vesicles are between 30 and 150 nm in diameter and are actively secreted by all cell types. While initially considered cellular "trash bags," recent years have revealed exosomes to be dynamic and multi-functional vesicles that may play a crucial role in cancer development, progression and metastasis. Thereby, they have the potential to be used in development of therapeutic modalities for cancer and other diseases. As more research studies emerge, it's becoming evident that exosomes are released by cells with a purpose and are representatives of certain cell types and disease conditions. Hence, they may also be used as biomarkers for the detection of cancer initiation, progression and organotropic metastatic growth of cancer cells. This review will focus on the recent developments achieved in identifying the role of exosomes in cancer development and progression as well as therapeutic implications. The review will also discuss the pitfalls of methodologies used for the extraction of exosomes.
Reward and motivation have powerful effects on cognition and brain activity, yet it remains unclear how they affect sustained cognitive performance. We have recently shown that a variety of motivators improve accuracy and reduce variability during sustained attention. In the current study, we investigate how neural activity in task-positive networks supports these sustained attention improvements. Participants performed the gradual-onset continuous performance task with alternating motivated (rewarded) and unmotivated (unrewarded) blocks. During motivated blocks, we observed increased sustained neural recruitment of task-positive regions, which interacted with fluctuations in task performance. Specifically, during motivated blocks, participants recruited these regions in preparation for upcoming targets, and this activation predicted accuracy. In contrast, during unmotivated blocks,
 no such advanced preparation was observed. Furthermore, during motivated blocks, participants had similar activation levels during both optimal (in-the-zone) and suboptimal (out-of-the-zone) epochs of performance. In contrast, during unmotivated blocks, task-positive regions were only engaged to a similar degree as motivated blocks during suboptimal (out-of-the-zone) periods. These data support a framework in which motivated individuals act as "cognitive investors," engaging task-positive resources proactively and consistently during sustaining attention. When unmotivated, however, the same individuals act as "cognitive misers," engaging maximal task-positive resources only during periods of struggle.
The FT/TFL1 gene family controls important aspects of plant development: MFT-like genes affect germination, TFL1-like genes act as floral inhibitors, and FT-like genes are floral activators. Gene duplications produced paralogs with modified functions required by the specific lifestyles of various angiosperm species. We constructed the transcriptome of the weedy annual plant Chenopodium rubrum and used it for the comprehensive search for the FT/TFL1 genes. We analyzed their phylogenetic relationships across Amaranthaceae and all angiosperms. We discovered a very ancient phylogenetic clade of FT genes represented by the CrFTL3 gene of C. rubrum Another paralog CrFTL2 showed an unusual structural rearrangement which might have contributed to the functional shift. We examined the transcription patterns of the FT/TFL1 genes during the vegetative growth and floral transition in C. rubrum to get clues about their possible functions. All the genes except for the constitutively expressed CrFTL2 gene, and the CrFTL3 gene, which was transcribed only in seeds, exhibited organ-specific expression influenced by the specific light regime. The CrFTL1 gene was confirmed as a single floral activator from the FT/TFL1 family in C. rubrum Its floral promoting activity may be counteracted by CrTFL1 C. rubrum emerges as an easily manipulated model for the study of floral induction in weedy fast-cycling plants lacking a juvenile phase.
Adolescence is characterized by low moderate- to vigorous- intensity physical activity (MVPA) levels. Targeting the school setting can increase MVPA among a large proportion of adolescents. However, school-based physical activity interventions for adolescents remain largely ineffective. Therefore, the purpose of this study was to examine how naturally-occurring changes to school physical activity policy, recreational programming, public health resources, and the physical environment, impact adolescent MVPA over a 1-year period.
Quasi-experimental longitudinal data from 18,777 grade 9-12 students (mean age = 15.1 ± 0.02 years), and 86 principals from 86 schools, participating in year 2 (2013-2014) and year 3 (2014-2015) of the COMPASS study (Ontario and Alberta, Canada) was used. Total MVPA over the previous week was self-reported at both time points using the COMPASS Student Questionnaire and average daily MVPA was calculated. Changes to physical activity policies, recreational programming, public health resources, and the physical environment were self-reported by school principals. Changes to the number and condition of physical activity facilities were objectively measured during school audits using the COMPASS School Environment Application. Multi-level modeling was used to examine change in student MVPA between schools that made changes and schools that did not. Models were adjusted for several student and school level confounders.
Over the 1-year period, 61 of 86 schools made physical activity related changes. Of these, 9 significantly changed student MVPA. However, only 4 of 9 schools' changes increased student MVPA, including opening the fitness centre at lunch (β = 17.2, 95% CI: 2.6-31.7), starting an outdoor club (β = 17.8, 95% CI:7.4-28.1), adding a bike rack (β-14.9, 95% CI:0.7-29.1), and adding weightlifting and run/walk clubs, archery, figure skating, increased access to the sports field, and improved condition of the outdoor basketball court (β = 15.5, 95% CI: 5.2-25.7).
Changes such as adding or increasing access to facilities, and adding multiple recreational programs, seemed to be effective for increasing student MVPA over the 1-year period. However, given the specificity of results, a one-size fits all approach may not be effective for increasing MVPA. Instead, school principals need to consider the resources within and surrounding their school, and the interests of the students.
No specific psychotherapy for adult anorexia nervosa (AN) has shown superior effect. Maintenance factors in AN (over-evaluation of control over eating, weight and shape) were addressed via Acceptance and Commitment Therapy (ACT). The study aimed to compare 19 sessions of ACT with treatment as usual (TAU), after 9 to 12 weeks of daycare, regarding recovery and risk of relapse up to five years.
Patients with a full, sub-threshold or partial AN diagnosis from an adult eating disorder unit at a hospital were randomized to ACT (n = 24) and TAU (n = 19). The staff at the hospital, as well as the participants, were unaware of the allocation until the last week of daycare. Primary outcome measures were body mass index (BMI) and specific eating psychopathology. Analyses included mixed model repeated measures and odds ratios.
Groups did not differ regarding recovery and relapse using a metric of BMI and the Eating Disorder Examination Questionnaire (EDE-Q). There were only significant time effects. However, odds ratio indicated that ACT participants were more likely to reach good outcome. The study was underpowered due to unexpected low inflow of patients and high attrition.
Longer treatment, more focus on established perpetuating factors and weight restoration integrated with ACT might improve outcome. Potential pitfalls regarding future trials on AN are discussed. Trial registration number ISRCTN 12106530. Retrospectively registered 08/06/2016.
We demonstrate that human motor memories can be artificially tagged and later retrieved by noninvasive transcranial direct current stimulation (tDCS). Participants learned to adapt reaching movements to two conflicting dynamical environments that were each associated with a different tDCS polarity (anodal or cathodal tDCS) on the sensorimotor cortex. That is, we sought to determine whether divergent background activity levels within the sensorimotor cortex (anodal: higher activity; cathodal: lower activity) give rise to distinct motor memories. After a training session, application of each tDCS polarity automatically resulted in the retrieval of the motor memory corresponding to that polarity. These results reveal that artificial modulation of neural activity in the sensorimotor cortex through tDCS can act as a context for the formation and recollection of motor memories.
Today much is known about cytochrome P450 (P450) enzymes and their catalytic specificity, but the range of reactions catalyzed by each still continues to surprise. Historically, P450s had been considered to be involved in either the metabolism of xenobiotics or endogenous chemicals, in the former case playing a generally protective role and in the latter case a defined physiological role. However, the line of demarcation is sometimes blurred. It is difficult to be completely specific in drug design, and some P450s involved in the metabolism of steroids and vitamins can be off-targets. In a number of cases, drugs have been developed that act on some of those P450s as primary targets, e.g., steroid aromatase inhibitors. Several of the P450s involved in the metabolism of endogenous substrates are less specific than once thought and oxidize several related structures. Some of the P450s that primarily oxidize endogenous chemicals have been shown to oxidize xenobiotic chemicals, even in a bioactivation mode.
Direct laser writing has been utilized to fabricate highly photostable fluorescent nanocluster microstructures in an organic polymer poly(methacrylic acid), where the carboxyl functional group is reported to play a vital role in nanocluster stabilization. In this Letter, we demonstrate that not only the polymer containing the carboxyl functional group, but also the polymer comprising the hydroxyl group, namely polyvinyl alcohol (PVA), can act as an appropriate stabilizer matrix for laser-induced synthesis and patterning of silver nanoclusters. The as-formed nanoclusters in the PVA film exhibit broadband emission and photostability comparable to the nanoclusters formed in the poly(methacrylic acid) polymer. As PVA is a widely used, nontoxic, biocompatible and biodegradable polymer, the technique of patterning fluorescent nanoclusters in PVA thin films is expected to find numerous applications in fields like fluorescence imaging, biolabeling, and sensing.
The Poynting vector S plays a central role in electrodynamics as it is directly related to the power and the momentum carried by an electromagnetic wave. In the presence of multiple electromagnetic waves with different polarizations and propagation directions, the Poynting vector may exhibit solenoidal components which are not associated to any power flow. Here, we demonstrate theoretically and experimentally that the presence of such solenoidal components has physical consequences, and it is not a mere artifact of the gauge invariance of S. In particular, we identify a simple field configuration displaying solenoidal components of S and theoretically show that a judiciously designed scatterer can act as a "Poynting vector detector" which when immersed in such field distribution would experience a transverse optical force orthogonal to the incidence plane. We experimentally validate our theoretical predictions by observing a pronounced asymmetry in the scattering pattern
 of a spherical nanoparticle.
We demonstrate a tunable all-optical gating phenomenon in a single-section quantum dot laser. The free-running operation of the device is emission from the excited state. Optical injection into the ground state of the material can induce a switch to emission from the ground state with complete suppression of the excited state. If the master laser is detuned from the ground-state emitting frequency, a periodic train of ground-state dropouts can be obtained. These dropouts act as gates for excited-state pulsations: during the dropout, the gate is opened and gain is made available for the excited state, and the gate is closed again when the dropout ends. Numerical simulations using a rate equation model are in excellent agreement with experimental results.
Eucalyptus oil is known from antimicrobial properties and due to natural origin and low toxicity it can be applied as a green pesticide. This plant extract is a mixture of compounds among which Eucalyptol prevails strongly over the number of minor components including terpinen-4-ol. However, antimicrobial effect of total extract is stronger than the effect of its major component. The mechanism of action of essential oils involves their incorporation into membrane of pathogenic cell. To investigate the effect of eucalyptus oil components on bacterial membrane in this work the influence of Eucalyptol on model lipid systems of various compositions was studied and then compared with the effect induced by the mixture of Eucalyptol and terpinen-4-ol. The analysis of the lipid monolayer properties modified by the presence of the essential oils evidenced that Eucalyptol reduces the lipids packing and decreases membrane rigidity, however, its influence is determined both by the concentration of this terpene and by the composition of lipid film. As indicated the results of calculation of the surface excess values Eucalyptol molecules tend to adsorb at the interface, however, at higher concentration in the subphase, the molecules undergo desorption at membrane-related surface pressure. By mixing of Eucalyptol and terpinen-4-ol stronger monolayer fluidization and destabilization can be achieved as well as stronger adsorption, even at higher surface pressures, occurs. However, these effects are also determined by the composition of model system. The collected data suggest that these compounds may act by penetrating bacterial membrane. Moreover, it can be proposed that although Eucalyptol is a major component of the Eucalyptus oil the antimicrobial effect of total extract is generated also by a minor component. This may explain stronger antimicrobial effect of Eucalyptus oil as compared to sole Eucalyptol confirmed in biological studies.
The aim of this study was to determine whether a revised heat warning threshold provides an enhanced predictive tool for increases in Emergency Department heat-related presentations in Canberra, Australia. All Emergency Department triage records containing the word "heat", as well as those diagnosing a heat related illness for the summer periods 2013/2014, 2014/2015, and 2015/2016 were searched. Then a medical record review was conducted to confirm that the patient's presentation was related to environmental heat, which was defined by the final clinical diagnosis, presentation complaint and details of the patient's treatment. Researchers then compared this presentation data, to a mean threshold formula. The mean threshold formula included the past three consecutive daily mean temperatures and the last measured temperature upon presentation. This formula was designed to take into account the variance of night-time lows, with concurrent daily ambient temperatures, and was used to determine whether there was a correlation between heat-related presentations and increasing mean temperatures. Heat-related presentations appeared to occur when the mean threshold temperature reached 25 °C (77 °F), with significant increases when the mean threshold reached 30 °C (86 °F). These results confirm that a mean temperature of 30 °C corresponds to a relevant local public health heat-related threat.
Capsaicinoids are plant secondary metabolites, capsaicin being the principal responsible for the pungency of chili peppers. It is biosynthesized through two pathways involved in phenylpropanoid and fatty acid metabolism. Plant capsaicin concentration is mainly affected by genetic, environmental and crop management factors. However, its synthesis can be enhanced by the use of elicitors. Capsaicin is employed as food additive and in pharmaceutical applications. Additionally, it has been found that capsaicin can act as a cancer preventive agent and shows wide applications against various types of cancer. This review is an approach in contextualizing the use of controlled stress on the plant to increase the content of capsaicin, highlighting its synthesis and its potential use as anticancer agent.
Food allergy is a serious problem for infants and young children. Induction of antigen-specific oral tolerance is one therapeutic strategy. Enhancement of oral tolerance induction by diet is a promising strategy to prevent food allergy in infants. Thus, in this study, we evaluate the effect of probiotic Lactobacillus gasseri OLL2809 (LG2809) on oral tolerance induction in a mouse model. The degree of oral tolerance induction was evaluated by measuring the proliferation and level of IL-2 production of splenic CD4+ T cells from DO11.10 mice fed ovalbumin (OVA) alone or OVA with LG2809. Oral administration of LG2809 significantly decreased the rate of proliferation and IL-2 production by CD4+ T cells from OVA-fed mice. LG2809 increased a ratio of CD4+ T-cell population, producing high levels of IL-10 and having strong suppressive activity. Moreover, LG2809 increased a ratio of plasmacytoid dendritic cells (pDCs) among the lamina propria (LP) in small intestine. When used as antigen presenting cells to naïve CD4+ T cells from DO11.10 mice, LP cells from BALB/c mice fed LG2809 induced higher IL-10 production and stronger suppressive activity than those from non-treated mice. These results suggest that oral administration of LG2809 increases the population of pDCs in the LP, resulting in the enhancement of oral tolerance induction by increasing the ratio of effector regulatory T cells. LG2809 could, therefore, act as a potent immunomodulator to prevent food allergies by promoting oral tolerance.
Programmed cell death is an essential aspect of animal development. Mutations in vertebrate genes that mediate apoptosis only mildly perturb development, suggesting that other cell death modes likely have important roles. Linker cell-type death (LCD) is a morphologically conserved cell death form operating during the development of Caenorhabditis elegans and vertebrates. We recently described a molecular network governing LCD in C. elegans, delineating a key role for the transcription factor heat-shock factor 1 (HSF-1). Although HSF-1 functions to protect cells from stress in many settings by inducing expression of protein folding chaperones, it promotes LCD by inducing expression of the conserved E2 ubiquitin-conjugating enzyme LET-70/UBE2D2, which is not induced by stress. Following whole-genome RNA interference and candidate gene screens, we identified and characterized four conserved regulators required for LCD. Here we show that two of these, NOB-1/Hox and EOR-1/PLZF, act upstream of HSF-1, in the context of Wnt signaling. A third protein, NHR-67/TLX/NR2E1, also functions upstream of HSF-1, and has a separate activity that prevents precocious expression of HSF-1 transcriptional targets. We demonstrate that the SET-16/mixed lineage leukemia 3/4 (MLL3/4) chromatin regulation complex functions at the same step or downstream of HSF-1 to control LET-70/UBE2D2 expression. Our results identify conserved proteins governing LCD, and demonstrate that transcriptional regulators influence this process at multiple levels.
The habitat in which proteins exert their function contains up to 400 g/L of macromolecules, most of which are proteins. The repercussions of this dense environment on protein behavior are often overlooked or addressed using synthetic agents such as poly(ethylene glycol), whose ability to mimic protein crowders has not been demonstrated. Here we performed a comprehensive atomistic molecular dynamic analysis of the effect of protein crowders on the structure and dynamics of three proteins, namely an intrinsically disordered protein (ACTR), a molten globule conformation (NCBD), and a one-fold structure (IRF-3) protein. We found that crowding does not stabilize the native compact structure, and, in fact, often prevents structural collapse. Poly(ethylene glycol) PEG500 failed to reproduce many aspects of the physiologically-relevant protein crowders, thus indicating its unsuitability to mimic the cell interior. Instead, the impact of protein crowding on the structure and dynamics of a protein depends on its degree of disorder and results from two competing effects: the excluded volume, which favors compact states, and quinary interactions, which favor extended conformers. Such a viscous environment slows down protein flexibility and restricts the conformational landscape, often biasing it towards bioactive conformations but hindering biologically relevant protein-protein contacts. Overall, the protein crowders used here act as unspecific chaperons that modulate the protein conformational space, thus having relevant consequences for disordered proteins.
HIGHLIGHTS Computational techniques provide accurate descriptions of the structure and dynamics of biological systems, contributing to their understanding at an atomic level.Classical MD simulations are a precious computational tool for the processes where no chemical reactions take place.QM calculations provide
 valuable information about the enzyme activity, being able to distinguish among several mechanistic pathways, provided a carefully selected cluster model of the enzyme is considered.Multiscale QM/MM simulation is the method of choice for the computational treatment of enzyme reactions offering quantitative agreement with experimentally determined reaction parameters.Molecular simulation provide insight into the mechanism of both the catalytic activity and inhibition of monoamine oxidases, thus aiding in the rational design of their inhibitors that are all employed and antidepressants and antiparkinsonian drugs. Aging society and therewith associated neurodegenerative and neuropsychiatric diseases, including depression, Alzheimer's disease, obsessive disorders, and Parkinson's disease, urgently require novel drug candidates. Targets include monoamine oxidases A and B (MAOs), acetylcholinesterase (AChE), butyrylcholinesterase (BChE), and various receptors and transporters. For rational drug design it is particularly important to combine experimental synthetic, kinetic, toxicological, and pharmacological information with structural and computational work. This paper describes the application of various modern computational biochemistry methods in order to improve the understanding of a relationship between the structure and function of large biological systems including ion channels, transporters, receptors, and metabolic enzymes. The methods covered stem from classical molecular dynamics simulations to understand the physical basis and the time evolution of the structures, to combined QM, and QM/MM approaches to probe the chemical mechanisms of enzymatic activities and their inhibition. As an illustrative example, the later will focus on the monoamine oxidase family of enzymes, which catalyze the degradation of amine neurotransmitters in various parts of the brain, the imbalance of which is associated with the development and progression of a range of neurodegenerative disorders. Inhibitors that act mainly on MAO A are used in the treatment of depression, due to their ability to raise serotonin concentrations, while MAO B inhibitors decrease dopamine degradation and improve motor control in patients with Parkinson disease. Our results give strong support that both MAO isoforms, A and B, operate through the hydride transfer mechanism. Relevance of MAO catalyzed reactions and MAO inhibition in the context of neurodegeneration will be discussed.
This study aims to investigate differences between continuous epidural infusion (CEI) and programmed intermittent epidural bolus (IEB) analgesia for the Chinese parturients undergoing spontaneous delivery and to approach their safety to parturients and neonates.
Two hundred healthy American Society of Anesthesiologists class I or II, term (≥37 weeks' gestation), nulliparous women who requested analgesia for labor were recruited. Epidural analgesia was initiated with a solution of 0.15% ropivacaine 10 mL and maintained with 0.1% ropivacaine mixed with sufentanil 0.3 μg/mL by CEI at a rate of 5 mL/h combined with a patient-controlled epidural analgesia (PCEA) bolus of 5 mL of ropivacaine sufentanil mixture or IEB of 5 mL of ropivacaine sufentanil mixture combined with a PCEA bolus of 5 mL of ropivacaine sufentanil mixture. The lockout interval was 20 minutes in each arm between the CEI and the IEB group. After 20 minutes of first dosage, visual analog scale (VAS) score was obtained every 60 minutes. The maternal and fetal outcome and total consumption of analgesic solution were compared.
There was no difference in demographic characteristics, duration of first and second stages, delivery methods, sensory block, fetal Apgar scores, and the maternal outcomes between the CEI and IEB groups. There was a significant difference in VAS scores and epidural ropivacaine total consumption between the two groups (IEB vs CEI: 51.27±9.61 vs 70.44±12.78 mg, P<0.01).
The use of programmed IEB mixed with PCEA improved labor analgesia compared to CEI mixed with PCEA, which could act as maintenance mode for epidural labor analgesia.
During Notch (N)-mediated binary cell fate decisions, cells adopt two different fates according to the levels of N pathway activation: an Noff-dependent or an Non-dependent fate. How cells maintain these N activity levels over time remains largely unknown. We address this question in the cell lineage that gives rise to the Drosophila mechanosensory organs. In this lineage a primary precursor cell undergoes a stereotyped sequence of oriented asymmetric cell divisions and transits through two neural precursor states before acquiring a neuron identity. Using a combination of genetic and cell biology strategies, we show that Escargot and Scratch, two transcription factors belonging to the Snail superfamily, maintain Noff neural commitment by directly blocking the transcription of N target genes. We propose that Snail factors act by displacing proneural transcription activators from DNA binding sites. As such, Snail factors maintain the Noff state in neural precursor cells by buffering any ectopic variation in the level of N activity. Since Escargot and Scratch orthologs are present in other precursor cells, our findings are fundamental for understanding precursor cell fate acquisition in other systems.
An analysis of Sox9 binding profiles in developing chondrocytes identified marked enrichment of an AP-1-like motif. Here, we have explored the functional interplay between Sox9 and AP-1 in mammalian chondrocyte development. Among AP-1 family members, Jun and Fosl2 were highly expressed within prehypertrophic and early hypertrophic chondrocytes. Chromatin immunoprecipitation followed by DNA sequencing (ChIP-seq) showed a striking overlap in Jun- and Sox9-bound regions throughout the chondrocyte genome, reflecting direct binding of each factor to the same enhancers and a potential for protein-protein interactions within AP-1- and Sox9-containing complexes. In vitro reporter analysis indicated that direct co-binding of Sox9 and AP-1 at target motifs promoted gene activity. By contrast, where only one factor can engage its DNA target, the presence of the other factor suppresses target activation consistent with protein-protein interactions attenuating transcription. Analysis of prehypertrophic chondrocyte removal of Sox9 confirmed the requirement of Sox9 for hypertrophic chondrocyte development, and in vitro and ex vivo analyses showed that AP-1 promotes chondrocyte hypertrophy. Sox9 and Jun co-bound and co-activated a Col10a1 enhancer in Sox9 and AP-1 motif-dependent manners consistent with their combined action promoting hypertrophic gene expression. Together, the data support a model in which AP-1 family members contribute to Sox9 action in the transition of chondrocytes to the hypertrophic program.
Intromittent organs are structures that enter the female genital tract and deposit sperm; these organs are found in many animal taxa that use internal fertilization. Despite their shared function, they are fantastically diverse morphologically. Many of their species-specific shape differences are likely the result of sexual selection and coevolution between male and female reproductive tracts, but a growing number of studies have identified other factors that can also affect their functional anatomy. In this symposium, we united scientists who combine morphological methods with contemporary molecular, phylogenetic, and imaging techniques to study the reproductive performance of intromittent organs in invertebrate and vertebrate model systems. The result was a collection of studies discussing competing selective pressures that act on these structures, including the effects of life history, genes and development, sexual conflict, ecological interactions, the biomechanics of copulation, and phenotypic plasticity. There was also an overwhelming consensus that a full understanding of intromittent organ evolution will not be possible without complimentary studies of morphology and function in female reproductive tracts.
More than 40 % of the world's population is at risk of being infected with malaria. Most malaria cases occur in the countries of sub-Saharan Africa, Central and South America, and Asia. Resistance to standard therapy, including artemisinin combinations, is increasing. There is an urgent need for novel antimalarials with new mechanisms of action. In a phenotypic screen, we identified a series of phenylalanine-based compounds that exhibit antimalarial activity via a new and yet unknown mechanism of action. Our optimization efforts culminated in the selection of ACT-451840 [(S,E)-N-(4-(4-acetylpiperazin-1-yl)benzyl)-3-(4-(tert-butyl)phenyl)-N-(1-(4-(4-cyanobenzyl)piperazin-1-yl)-1-oxo-3-phenylpropan-2-yl)acrylamide] for clinical development. Herein we describe our optimization efforts from the screening hit to the potential drug candidate with respect to antiparasitic activity, drug metabolism and pharmacokinetics (DMPK) properties, and in vivo pharmacological efficacy.
Artemisinin resistance in Plasmodium falciparum threatens global efforts in the elimination or eradication of malaria. Several studies have associated mutations in the PfATP6 gene in conjunction with artemisinin resistance, but the underlying molecular mechanism of the resistance remains unexplored. Associated mutations act as a biomarker to measure the artemisinin efficacy. In the proposed work, we have analyzed the binding affinity and efficacy between PfATP6 and artemisinin in the presence of L263D, L263E and L263K mutations. Furthermore, we performed virtual screening to identify potential compounds to inhibit the PfATP6 mutant proteins. In this study, we observed that artemisinin binding affinity with PfATP6 gets affected by L263D, L263E and L263K mutations. This in silico elucidation of artemisinin resistance
 enhanced the identification of novel compounds (CID: 10595058 and 10625452) which showed good binding affinity and efficacy with L263D, L263E and L263K mutant proteins in molecular docking and molecular dynamics simulations studies. Owing to the high propensity of the parasite to drug resistance the need for new antimalarial drugs will persist until the malarial parasites are eventually eradicated. The two compounds identified in this study can be tested in in vitro and in vivo experiments as possible candidates for the designing of new potential antimalarial drugs.
The Netherlands has seen an increase in Δ9-tetrahydrocannabinol (THC) concentrations from approximately 8% in the 1990s up to 20% in 2004. Increased cannabis potency may lead to higher THC-exposure and cannabis related harm. The Dutch government officially condones the sale of cannabis from so called 'coffee shops', and the Opium Act distinguishes cannabis as a Schedule II drug with 'acceptable risk' from other drugs with 'unacceptable risk' (Schedule I). Even in 1976, however, cannabis potency was taken into account by distinguishing hemp oil as a Schedule I drug. In 2011, an advisory committee recommended tightening up legislation, leading to a 2013 bill proposing the reclassification of high potency cannabis products with a THC content of 15% or more as a Schedule I drug. The purpose of this measure was twofold: to reduce public health risks and to reduce illegal cultivation and export of cannabis by increasing punishment. This paper focuses on the public health aspects and describes the (explicit and implicit) assumptions underlying this '15% THC measure', as well as to what extent these are supported by scientific research. Based on scientific literature and other sources of information, we conclude that the 15% measure can provide in theory a slight health benefit for specific groups of cannabis users (i.e., frequent users preferring strong cannabis, purchasing from coffee shops, using 'steady quantities' and not changing their smoking behaviour), but certainly not for all cannabis users. These gains should be weighed against the investment in enforcement and the risk of unintended (adverse) effects. Given the many assumptions and uncertainty about the nature and extent of the expected buying and smoking behaviour changes, the measure is a political choice and based on thin evidence.
The termini of DNA strand breaks induced by reactive oxygen species or by abortive DNA metabolic intermediates require processing to enable subsequent gap filling and ligation to proceed. The three proteins, tyrosyl DNA-phosphodiesterase 1 (TDP1), aprataxin (APTX) and polynucleotide kinase/phosphatase (PNKP) each act on a discrete set of modified strand-break termini. Recently, a series of neurodegenerative and neurodevelopmental disorders have been associated with mutations in the genes coding for these proteins. Mutations in TDP1 and APTX have been linked to Spinocerebellar ataxia with axonal neuropathy (SCAN1) and Ataxia-ocular motor apraxia 1 (AOA1), respectively, while mutations in PNKP are considered to be responsible for Microcephaly with seizures (MCSZ) and Ataxia-ocular motor apraxia 4 (AOA4). Here we present an overview of the mechanisms of these proteins and how their impairment may give rise to their respective disorders.
A checklist of extant species of Psylloidea in New Zealand is presented. The list is structured according to the latest taxonomic classification of families, subfamilies and genera. It includes 99 species, 71 of which are formally described and named, along with information on the host plants and the natural enemies as aspects that are either species-specific or assist in their recognition. An updated distribution of each species is given based on literature records and material held in the major New Zealand entomological collections and databases, including from very recent field surveys. A new record for New Zealand is Phellopsylla formicosa.
Two new species of Tricheops Newman, T. remus sp. nov. and T. guillemeti sp. nov. from Western Australia are described and illustrated. The genus Tricheops is redescribed and a key to species is provided. The structures associated with the unusual three-lobed eyes of Tricheops and Bardistus Newman are discussed.
Elevated nitrogen (N) deposition impacts the structure and functioning of heathland ecosystems across Europe. Calluna plants under high N-inputs are very sensitive to secondary stress factors, including defoliation attacks by the heather beetle. These attacks result in serious damage or death of Calluna, its rapid replacement by grasses, and the subsequent loss of heathland. We know very little about the mechanisms that control the populations and trigger outbreaks of the heather beetle, impeding proper management measures to mitigate the damage. We investigated the effects of N deposition on the relationships between the heather beetle, its host plant, and two arthropod predators at building (rejuvenated through fire) and mature heathlands. The study combines field manipulation experiments simulating a range of N deposition rates (0, 1, 2, 5 g N m(-2) year(-1) for 2 years, and 5.6 g N m(-2) year(-1) for 10 years), and food-choice laboratory experiments testing the preferences of adults and larvae of the heather beetle for N-treated Calluna plants, and the preferences of predators for larvae grown on plants with different N-content. The larvae of the heather beetle achieved the highest abundances after the long-term (10-year) addition of N at mature Calluna plots in the field. Contrary to the adults, the larvae foraged preferentially on the most N-rich Calluna shoots under laboratory conditions. Predators showed no aggregative numerical responses to the accumulation of heather beetle larvae at high N-input experimental plots. During the feeding trials, predators consumed a small number of larvae, both in total and per individual, and systematically avoided eating the larvae reared on high-N Calluna shoots. Our study showed that the most severe defoliation damage by the heather beetle is inflicted at the larval stage under prolonged availability of high-N inputs, and that arthropod predators might not act as effective regulators of the beetle's populations.
CXCR3, a G-protein coupled chemokine receptor, has been found to be overexpressed in many tumors and act as an independent prognostic marker. However, it is still unclear whether CXCR3 is involved in gastric cancer progression. In this study, we found that CXCR3 was markedly expressed in gastric cancer cells and tissues. High CXCR3 expression correlated with advanced tumor stage, vascular invasion, lymph node metastasis and poor survival of gastric cancer patients. Activation of CXCR3 by one of its ligands CXCL10 promoted the invasion and migration of gastric cancer BGC-823 and MGC-803 cells, and increased the secretion and activities of MMP-2 and MMP-9. However, the effects of CXCL10 on gastric cancer cells were attenuated by CXCR3 siRNA transfection. Furthermore, overexpression of CXCR3 enhanced CXCL10-mediated cell invasion and migration of gastric cancer MKN28 cells. In addition, CXCR3 time-dependently induced activation of AKT. PI3K/AKT pathway was required for CXCR3-mediated gastric cancer cell invasion, migration and MMP-2/9 production. Together, our findings suggest that CXCL10/CXCR3 axis promotes gastric cancer cell invasion and migration by upregulating MMP-2 and MMP-9 production via PI3K/AKT pathway. Thus, CXCR3 could be a potential target for the gastric cancer treatment.
Currently, there is no effective vaccine available, and chemotherapy is the main approach for treatment of cutaneous leishmaniasis (CL). During recent decades, studies have demonstrated that a number of plant-derived compounds may act as new therapeutic tools against leishmaniasis. This study was evaluated the antileishmanial, antioxidant, and cytotoxic activities of Quercus infectoria Olivier (oak) extract. The total amount of phenolic and flavonoid compounds was measured in oak extract. High performance liquid chromatography (HPLC) analysis was also performed to determine the amount of quercetin and gallic acid in this plant. This extract (0-80g/mL) was evaluated in vitro against promastigote and intracellular amastigote forms of Leishmania major (MRHO/IR/75/ER) using MTT assay and in a macro-phage model, respectively. Then oak extract was tested on CL in infected male BALB/c mice with L. major in order to evaluate the antileishmanial activity topically. Moreover, cytotoxicity effects of oak in murine macrophage cells were tested by MTT assay. Antioxidative activity of oak was also determined by the 2,2-diphenyl-1,1-picrylhydrazyl (DPPH) scavenging test. The amount of phenolic and flavonoid compounds in the oak extract was 57.50 and 1.86%, respectively. The amount of quercetin and gallic acid in the oak extract was 0.0064 and 0.22%, respectively. The findings revealed that oak significantly (P<0.05) inhibited the growth rate of promastigote of (IC50 12.65μg/mL) and amastigotes (IC50 10.31μg/mL) as a dose-dependent response. In the in vivo assay, after 4 weeks of treatment, 91.6, 66.66, and 50% recovery was observed in the infected mice treated with 20, 10, and 5mg/kg of oak extract, respectively. After treatment of the infected mice with the concentration of 10 and 20mg/kg of oak, the mean diameter of lesions, parasite load and mean number of parasites was significantly (P<0.05) reduced. Selectivity index of greater than 10 for oak revealed that oak extract had no cytotoxic effects on macrophage cells. Moreover, DPPH test demonstrated that radical inhibition occurred at greater power with increasing the concentration of oak. To conclude, the present study showed potent antileishmanial and antioxidant activity of oak extract; whereas this plant had no toxic
 effect on mammalian cells.
MicroRNAs (miRNAs) are short, non-coding RNAs with post-transcriptional regulatory function, playing crucial roles in cancer development and progression of human melanoma. Previous studies have indicated that miR-769 was implicated in diverse biological processes. However, the underlying mechanism of miR-769 in human melanoma has not been intensively investigated. In this present study, we aimed to investigate the role of miR-769 and its target genes in human melanoma. We found that miR-769 expression was strongly increased in human melanoma cells and clinical tissues compared with their corresponding controls. Overexpression of miR-769 promoted cell proliferation in human melanoma cell line A375, whereas miR-769-in reverses the function. Glycogen synthase kinase-3 Beta (GSK3B), a potential target gene of miR-769, and was validated by luciferase assay. Further studies revealed that miR-769 regulated cell proliferation of human melanoma by directly suppressing GSK3B expression and the knockdown of GSK3B expression reversed the effect of miR-769-in on human melanoma cell proliferation. In summary, our data demonstrated that miR-769 might act as a tumor promoter by targeting GSK3B during development of human melanoma.
Cyanide (CN) blood concentration is hardly considered during routine when evaluating smoke gas intoxications and fire victims, although some inflammable materials release a considerable amount of hydrogen cyanide. CN can be significant for the capacity to act and can in the end even be the cause of death. Systematic data concerning the influence of different fire conditions, especially those of various inflammable materials, on the CN-blood concentration of deceased persons do not exist. This study measured the CN level in 92 blood samples of corpses. All persons concerned were found dead in connection with fires and/or smoke gases. At the same time, the carboxyhemoglobin (COHb) level was determined, and the corpses were examined to detect pharmaceutical substances, alcohol and drugs. Furthermore, we analysed autopsy findings and the investigation files to determine the inflammable materials and other circumstances of the fires. Due to the inflammable materials, the highest concentration of CN in the victims was found after enclosed-space fires (n = 45) and after motor-vehicle fires (n = 8). The CN levels in these two groups (n = 53) were in 47 % of the cases toxic and in 13 % of the cases lethal. In victims of charcoal grills (n = 17) and exhaust gases (n = 6), no or only traces of CN were found. Only one case of the self-immolations (n = 12) displayed a toxic CN level. The results show that CN can have considerable significance when evaluating action ability and cause of death with enclosed-space fires and with motor-vehicle fires.
The Little Prince is one of the most famous fables. In this paper, we attempt to look at three bioethical issues through the Little Prince's eyes: the end-of-life context, the patient-physician relationship and prevention/precaution. The fable gives us the basis for a perspective we have called 'Medicine of the Invisible', which is value-focused. The Little Prince suggests that we seek the invisible-the "thing that is important", the "matters of consequence", even on a gnoseological and epistemological level-as a new type of 'clinical data' which may help to make healthcare more ethical and effective. However, this invisible is attainable only within a relationship, in which the physician needs to be tamed by the patient and the patient needs to be tamed by the physician-each one becoming responsible for the other, each one becoming himself through the dialogue with the other. Responsibility is also projected towards the future, against those threats to life that are still unseen and unknown: owning a part of the world entails the ethical imperative to act, in order to safeguard life. But, without a relationship-saturated with lived time, shared experiences, and individual's uniqueness-no meaning and no value can be given. For this reason, the Medicine of the Invisible reminds bioethics that "the thing that is important is the thing that is not seen".
Poly(adenosine diphosphate-ribose) polymerase (PARP) is a group of enzymes with several subtypes and it manages various ailment such as cancer, inflammatory disorders, diabetes mellitus, neuronal injury, HIV infection, Parkinsonism, aging, and ischemia-reperfusion injury. Various PARP inhibitors share a common property of bicyclic lactam in its main structural frame. The core moiety containing bicyclic lactam rings are isoquinolinones, dihydroisoquinolinones, quinazolinediones, phthalazinones, quinazolinones, and phenanthridones. The quinazolinone with diverse substituents displayed low nanomolar inhibition. Quinazolinone is an important and vital molecule in the field of medicinal chemistry possessing multitude pharmacological actions. Though the chemistry of quinazolinones has been discussed through centuries, its concise role on PARP inhibition needed a special consideration. The aim of this review is to discover the effect of quinazolinone substitutents and its role in PARP inhibition. This precise review will discuss the effect of quinazolinones on PARP subtypes such as PARP-1, PARP-2, PARP-5a, and PARP-5b. In addition to its pharmacological actions, PARP inhibitors can also act as a chemosensitizing agent, and it is used in combination with the other anticancer agents. This summarization will definitely be a supportive report for the scientist working toward the novelty in the quinazolinone nucleus and its role in PARP inhibition.
Determining the three-dimensional structure of a protein in living cells remains particularly challenging. We demonstrated that the integration of site-specific tagging proteins and GPS-Rosetta calculations provides a fast and effective way of determining the structures of proteins in living cells, and in principle the interactions and dynamics of protein-ligand complexes.
Nanofibre-based mucoadhesive films were invented for oromucosal administration of nanocarriers used for delivery of drugs and vaccines. The mucoadhesive film consists of an electrospun nanofibrous reservoir layer, a mucoadhesive film layer and a protective backing layer. The mucoadhesive layer is responsible for tight adhesion of the whole system to the oral mucosa after application. The electrospun nanofibrous reservoir layer is intended to act as a reservoir for polymeric and lipid-based nanoparticles, liposomes, virosomes, virus-like particles, dendrimers and the like, plus macromolecular drugs, antigens and/or allergens. The extremely large surface area of nanofibrous reservoir layers allows high levels of nanoparticle loading. Nanoparticles can either be reversibly adsorbed to the surface of nanofibres or they can be deposited in the pores between the nanofibres. After mucosal application, nanofibrous reservoir layers are intended to promote prolonged release of nanoparticles into the submucosal tissue. Reversible adsorption of model nanoparticles as well as sufficient mucoadhesive properties were demonstrated. This novel system appears appropriate for the use in oral mucosa, especially for sublingual and buccal tissues. To prove this concept, trans-/intramucosal and lymph-node delivery of PLGA-PEG nanoparticles was demonstrated in a porcine model. This system can mainly be used for sublingual immunization and the development of "printed vaccine technology".
We evaluated the differences in sonographic parameters in carpal tunnel syndrome (CTS) patients with normal and mildly abnormal nerve conduction studies (NCS). This was a prospective cross-sectional study. We assessed 169 wrists (101 patients) with a clinical diagnosis of carpal tunnel syndrome (CTS), as well as 20 healthy controls (40 wrists). 49 wrists were classified as mild NCS-positive and 38 as NCS-negative based on our laboratory NCS normal values. The cross-sectional area (CSA) of the median nerve at the carpal tunnel inlet and mid-forearm were measured and the wrist-to-forearm ratio (WFR) was calculated. 26% of the NCS-negative group had abnormal CSA. The CSA and WFR also differed significantly between the two groups. There was significant correlation between the sonographic and electrophysiologic variables. Ultrasound was diagnostic for CTS in a third of the NCS-negative wrists. Ultrasound may be useful in clinical CTS patients with normal or borderline NCS.
Monitoring patient experience is essential for stimulating innovation in health care and improving quality and accountability. Internationally, standardised approaches are used to collect patient experience information, but in Australian primary health care (PHC), little is known about which patient experience surveys are used and which aspects of experience they measure. This prevents routine inclusion of patient experience data in quality improvement or system performance measurement. A scoping review was undertaken to identify relevant surveys. Data on survey availability, psychometric properties, target population, method and frequency of administration were extracted. Survey items were mapped against six dimensions of patient experience described internationally. Ninety-five surveys were identified; 34 were developed for use in Australia. Surveys vary in content, size, aspects of experience measured and methods of administration. The quality of data collected and the extent to which it is used in quality improvement is unclear. Collection of patient experience data in Australian PHC is not well developed or standardised and there are few publicly available instruments. There is a need to clearly identify the purposes for which data are to be used and to develop an integrated approach that articulates these collections with other quality and performance data. Some options
 are discussed.
External (to the fetus) stressors may act together with maternal factors as well as fetal and placental factors to increase the risk of stillbirth. Data published in 2011 indicate non-left side sleeping positions, particularly the supine one, is such a stressor; we do not know, however, if this new knowledge has influenced the choice of sleeping position among pregnant women.
Using a web-based questionnaire made available at the home page of the Swedish national infant foundation we collected information on sleeping positions among women who gave birth to a stillborn baby between 2000 and 2014.
The questionnaire was completed by 583 women. About one third of the women reporting their sleeping position stated that they lay down on their the left side when going to bed, and another third reported lying down as often on the left as on the right side. Figures for typically going to bed on the left side the 4 weeks preceding the stillbirth was as follows: 72 (30 %) of 242 between 2011 and 2014 and 86 (27 %) of 313 between 2000 and 2010. Among the 240 women who remembered their position when waking up on the day the stillbirth was diagnosed, 63 (26 %) reported a supine position.
Our data indicate that one third of the women went to bed on the left side the month before the stillbirth. The data are consistent with the notion that efforts in Sweden to advise women to lie on their left side when going to bed may decrease the rate of stillbirth.
Primary Health Networks (PHNs) have been tasked with two key objectives to be achieved through commissioning. Public value aims can be achieved by developing operational capability in the context of an authorising environment. Public value will need to focus on system level outcomes from multiple perspectives, including a consumer perspective. The authorising environment will require policymakers to allow time for PHNs to mature into their role. It will require an environment of effective collaboration amongst multiple stakeholders including consumers. The operational capability will need to ensure highly competent managers and clinical leadership working in a symbiotic relationship. Although some Medicare Locals demonstrated commissioning capacity and capability, this will need to be scaled up at-pace in the new healthcare landscape in order for PHNs to optimally fulfil their roles.
A metal-organic molecular net composed of tannic acid (TA) and iron(iii) was constructed around the brome mosaic virus (BMV) particle to determine whether the added net could act as a transport barrier for water, and if the net could stabilize the virus in physically or chemically challenging environments. This new virus engineering strategy is expected to provide benefits both in the study and technological applications of viruses. For instance, a virus wrapped in a thin molecular layer could be extracted from solution either in air or vacuum, and its structure, composition and even internal dynamics could be interrogated by methods not compatible with a liquid environment. Atomic force microscopy (AFM) studies of Fe(iii)-TA coated BMV in liquid and in air supported a marked resistance to dehydration when compared to wtBMV. Native charge detection mass spectrometry (CDMS), was employed to estimate the number of molecules in the molecular net which wrapped the virus. The CDMS data suggested that less than one molecular monolayer wrapped the virus. Additionally, it was found, that this very thin molecular coat was sufficient to render the coated viruses resistant to storage conditions that typically lead to virus disassembly over time. A temporary coat imparting increased resistance to disassembly could be useful in adding time delay control or alleviate required storage conditions of engineered viruses for therapeutic purposes.
Pleiotrophin (PTN) is a secreted growth factor recently proposed to act as a neuromodulatory peptide in the Central Nervous System. PTN appears to be involved in neurodegenerative diseases and neural disorders, and it has also been implicated in learning and memory. Specifically, PTN-deficient mice exhibit a lower threshold for LTP induction in the hippocampus, which is attenuated in mice overexpressing PTN. However, there is little information about the signaling systems recruited by PTN to modulate neural activity. To address this issue, the gene expression profile in hippocampus of mice lacking PTN was analyzed using microarrays of 22,000 genes. In addition, we corroborated the effect of the absence of PTN on the expression of these genes by silencing this growth factor in primary neuronal cultures in vitro. The microarray analysis identified 102 genes that are differentially expressed (z-score>3.0) in PTN null mice, and the expression of eight of those modified in the hippocampus of KO mice was also modified in vitro after silencing PTN in cultured neurons with siRNAs. The data obtained indicate that the absence of PTN affects AKT pathway response and modulates the expression of genes related with neuroprotection (Mgst3 and Estrogen receptor 1, Ers 1) and cell differentiation (Caspase 6, Nestin, and Odz4), both in vivo and in vitro.
Rotavirus infection has emerged as an important cause of complications in organ transplantation recipients. Immunosuppressants used to prevent alloreactivity can also interfere with virus infection, but the direct effects of the specific type of immunosuppressants on rotavirus infection are still unclear. Here we profiled the effects of different immunosuppressants on rotavirus using a 2D culture model of Caco2 human intestinal cell line and a 3D model of human primary intestinal organoids inoculated with laboratory and patient-derived rotavirus strains. We found that the responsiveness of rotavirus to Cyclosporine A treatment was moderate and strictly regulated in an opposite direction by its cellular targets cyclophilin A and B. Treatment with mycophenolic acid (MPA) resulted in a 99% inhibition of viral RNA production at the clinically relevant concentration (10 μg/ml) in Caco2 cells. This effect was further confirmed in organoids. Importantly, continuous treatment with MPA for 30 passages did not attenuate its antiviral potency, indicating a high barrier to drug resistance development. Mechanistically, the antiviral effects of MPA act via inhibiting the IMPDH enzyme and resulting in guanosine nucleotide depletion. Thus for transplantation patients at risk for rotavirus infection, the choice of MPA as an immunosuppressive agent appears rational.
The cytomolecular discrimination of the A(m)- and A-genome chromosomes facilitates the selection of wheat-Triticum monococcum introgression lines. Fluorescence in situ hybridisation (FISH) with the commonly used DNA probes Afa family, 18S rDNA and pSc119.2 showed that the more complex hybridisation pattern obtained in T. monococcum relative to bread wheat made it possible to differentiate the A(m) and A chromosomes within homoeologous groups 1, 4 and 5. In order to provide additional chromosomal landmarks to discriminate the A(m) and A chromosomes, the microsatellite repeats (GAA)n, (CAG)n, (CAC)n, (AAC)n, (AGG)n and (ACT)n were tested as FISH probes. These showed that T. monococcum chromosomes have fewer, generally weaker, simple sequence repeat (SSR) signals than the A-genome chromosomes of hexaploid wheat. A differential hybridisation pattern was observed on 6A(m) and 6A chromosomes with all the SSR probes tested except for the (ACT)n probe. The 2A(m) and 2A chromosomes were differentiated by the signals given by the (GAA)n, (CAG)n and (AAC)n repeats, while only (GAA)n discriminated the chromosomes 3A(m) and 3A. Chromosomes 7A(m) and 7A could be differentiated by the lack of (GAA)n and (AGG)n signals on 7A. As potential landmarks for identifying the A(m) chromosomes, SSR repeats will facilitate the introgression of T. monococcum chromatin into wheat.
The focus of this paper is on the ethics of the act of wilfully "abandoning" human embryos. I offer a critique of this unique behaviour, which draws on empirical data about who wilfully abandons their surplus embryos and why. I argue that wilful embryo abandonment is in all cases avoidable. Given this, I make three observations which speak to the moral unacceptability of embryo abandonment. The first has to do with the abandoner's unfair treatment of the clinic storing their abandoned embryos, and the second the abandoner's apparent lack of sympathy for the plight of other people like them, who require assistance (e.g. donated embryos) in pursuing their family-building goals. The third observation has to do with the abandoner's failure to meet their responsibility for directing the handling of their embryos, and what their reaction to that responsibility (through abandonment) says about their moral character in certain respects. There is good reason to conclude that wilful embryo abandonment is morally unacceptable. One implication of this normative conclusion is that clinics have reasonable grounds for justifying the design of their policies and practices so as to make wilful embryo abandonment impossible.
Neuropeptides and peptide hormones from non-neuronal tissues play important roles in the regulation of insect life. In recent years, the rapid development of analytical techniques has contributed to the discovery of more than 30 families of peptide neurohormones that differ structurally and functionally. Although the discovery of the first neuropeptide occurred almost forty years ago, our knowledge about their full mode of activities, primary structures, synthesis, interactions with receptors or places of action increases gradually and there is still much to unravel. However, one thing is certain. Neuropeptides perform an extremely diverse range of activities. One neuropeptide can affect physiology in different ways. The neuropeptides
 can act as neurotransmitters, co-transmitters as well as neuromodulators. Most of these molecules have diverse pleiotropic activities on different tissues and organs. Their mode of action includes allatotropic, myotropic, cardiotropic or gonadotropic effects. Activity of some of them is conserved among most of insect species, indicating crucial roles in insect physiology and age of these systems. On the other hand, activity of other neuropeptides and peptide hormones is highly diverse, depending on species or even stages of development. This may indicate that some compounds have taken over the function of others. Insect heart work is regulated in a very complex manner. Myocardium activity undergoes regulation both, by nervous and hormonal way. What is important is that these same compounds can influent on heart as both nervous and hormonal factors. For that reason, the regulation of myocardium is still unclear. In this paper, we summarize the existing knowledge regarding cardioactivity and the involvement of insect neurohormones and some peptide hormones from non-neural tissues to regulation of insect myocardium.
Mesoporous silica nanoparticles (MSNs) are highly attractive as supports in the design of controlled delivery systems that can act as containers for the encapsulation of therapeutic agents, overcoming common issues such as poor water solubility and poor stability of some drugs and also enhancing their bioavailability. In this context, we describe herein the development of polyglutamic acid (PGA)-capped MSNs that can selectively deliver rhodamine B and doxorubicin. PGA-capped MSNs remain closed in an aqueous environment, yet they are able to deliver the cargo in the presence of pronase because of the hydrolysis of the peptide bonds in PGA. The prepared solids released less than 20% of the cargo in 1 day in water, whereas they were able to reach 90% of the maximum release of the entrapped guest in ca. 5 h in the presence of pronase. Studies of the PGA-capped nanoparticles with SK-BR-3 breast cancer cells were also undertaken. Rhodamine-loaded nanoparticles were not toxic, whereas doxorubicin-loaded nanoparticles were able to efficiently kill more than 90% of the cancer cells at a concentration of 100 μg/mL.
In 2005, the Australian Productivity Commission made a recommendation that a national health registration regimen and a consolidated national accreditation regimen be established. On 1 July 2010, the National Registration and Accreditation Scheme (NRAS) for health practitioners came into effect and the Australian Health Practitioner Regulation Agency (AHPRA) became the single national oversight agency for health professional regulation. It is governed by the Health Practitioner Regulation National Law Act (the National Law). While all states and territories joined NRAS for registration and accreditation, NSW did not join the scheme for the handling of complaints, but retained its existing co-regulatory complaint-handling system. All other states and territories joined the national notification (complaints) scheme prescribed in the National Law. Because the introduction of NRAS brings with it new processes and governance around the management of complaints that apply to all regulated health professionals in all states and territories except NSW, where complaints management remains largely unchanged, there is a need for comparative analysis of these differing national and NSW approaches to the management of complaints/notifications about health professionals, not only to allow transparency for consumers, but also to assess consistency of decision making around complaints/notifications across jurisdictions. This paper describes the similarities and differences for complaints/notifications handling between the NRAS and NSW schemes and briefly discusses subsequent and potential changes in other jurisdictions.
β-catenin is a multifunctional protein; it is a key component of the Wnt signaling, and it plays a central role in cadherin-based adhesions. Cadherin loss promotes tumorigenesis by releasing membrane-bound β-catenin, hence stimulating Wnt signaling. Cadherins seem to be involved in tumor development, but these findings are limited in adrenocortical tumors (ACTs). The objective of this study was to evaluate alterations in key components of cadherin/catenin adhesion system and of Wnt pathway. This study included eight normal adrenal samples (NA) and 95 ACT: 24 adrenocortical carcinomas (ACCs) and 71 adrenocortical adenomas (ACAs). β-catenin mutations were evaluated by sequencing, and β-catenin and cadherin (E-cadherin and N-cadherin) expression was analyzed by quantitative reverse transcription PCR (qRT-PCR) and by immunohistochemistry (IHC). We identified 18 genetic alterations in β-catenin gene. qRT-PCR showed overexpression of β-catenin in 50 % of ACC (12/24) and in 48 % of ACA (21/44). IHC data were in accordance with qRT-PCR results: 47 % of ACC (7/15) and 33 % of ACA (11/33) showed increased cytoplasmic or nuclear β-catenin accumulation. N-cadherin downregulation has been found in 83 % of ACC (20/24) and in 59 % of ACA (26/44). Similar results were obtained by IHC: N-cadherin downregulation was observed in 100 % (15/15) of ACC and in 55 % (18/33) of ACA. β-catenin overexpression together with the aberrant expression of N-cadherin may play important role in ACT tumorigenesis. The study of differentially expressed genes (such as N-cadherin and β-catenin) may enhance our understanding of the biology of ACT and may contribute to the discovery of new diagnostic and prognostic tools.
Mobile phone apps offer a promising medium to deliver psychological interventions. A mobile app based on Acceptance and Commitment Therapy (ACT) was developed and studied in a randomized controlled trial (RCT).
To study usage metrics of a mobile ACT intervention and dose-response relationship between usage and improvement in psychological flexibility.
An RCT was conducted to investigate the effectiveness of different lifestyle interventions for overweight people with psychological stress. This paper presents a secondary analysis of the group that received an 8-week mobile ACT intervention. Most of the analyzed 74 participants were female (n=64, 86%). Their median age was 49.6 (interquartile range, IQR 45.4-55.3) years and their mean level of psychological flexibility, measured with the Acceptance and Action Questionnaire II, was 20.4 (95% confidence interval 18.3-22.5). Several usage metrics describing the intensity of use, usage of content, and ways of use were calculated. Linear regression analyses were performed to study the dose-response relationship between usage and the change in psychological flexibility and to identify the usage metrics with strongest association with improvement. Binary logistic regression analyses were further used to assess the role of usage metrics between those who showed improvement in psychological flexibility and those who did not. In addition, associations between usage and baseline participant characteristics were studied.
The median number of usage sessions was 21 (IQR 11.8-35), the number of usage days was 15 (IQR 9.0-24), and the number of usage weeks was 7.0 (IQR 4.0-8.0). The participants used the mobile app for a median duration of 4.7 (IQR 3.2-7.2) hours and performed a median of 63 (IQR 46-98) exercises. There was a dose-response relationship between usage and the change in psychological flexibility. The strongest associations with psychological flexibility (results adjusted with gender, age, and baseline psychological variables) were found for lower usage of Self as context related exercises (B=0.22, P=.001) and higher intensity of use, described by the number of usage sessions (B=-0.10, P=.01), usage days (B=-0.17, P=.008), and usage weeks (B=-0.73, P=.02), the number of exercises performed (B=-0.02, P=.03), and the total duration of use (B=-0.30, P=.04). Also, higher usage of Acceptance related exercises (B=-0.18, P=.04) was associated with improvement. Active usage was associated with female gender, older age, and not owning a smart mobile phone before the study.
The results indicated that active usage of a mobile ACT intervention was associated with improved psychological flexibility. Usage metrics describing intensity of use as well as two metrics related to the usage of content were found to be most strongly associated with improvement.
ClinicalTrials.gov NCT01738256; https://clinicaltrials.gov/ct2/show/NCT01738256 (Archived by WebCite at http://www.webcitation.org/6iTePjPLL).
Defective DNA repair capacity caused by inherited polymorphisms could be associated with cancer susceptibility. One of the major repair pathways is Nucleotide Excision Repair (NER). We investigated Xeroderma Pigmentosum complementation group C (XPC) polymorphisms (Lys939Gln, PAT) with the risk of prostate cancer.
154 confirmed prostate cancer patients and 205 Benign Prostate Hyperplasia (BPH) controls were recruited in this survey. The genotypes were determined by PCR-Restriction Fragment Length Polymorphism (RFLP) method.
Our results indicated that there were no significant differences between the BPH group and patient group for the XPC Lys939Gln in this pathway. However, deletion/insertion (D/I) and insertion/insertion (I/I) of XPC PAT polymorphism in this pathway could decrease the risk of prostate cancer and act as a protective factor.
In this study, XPC Lys939Gln gene polymorphism was not associated with the risk of developing prostate cancer in Iranian patients. There are no association between different alleles of this polymorphism and grades and stages of tumors, but our results indicated the significant association between XPC PAT and reduction of prostate cancer risk in this group of patients. For more significant results, further samples are required.
The fruits of Persea Americana Mill., commonly
 known as Avocado, are traditionally consumed for various health benefits including weight reduction. Here, we studied the effect of hydroalcoholic fruit extract of Persea americana (HAEPA) on high fat diet (HFD) induced obesity in rats. Obesity was induced in male Sprague Dawley rats by feeding HFD for 14 wk. The hypolipidemic effect was evaluated by co-administering 25, 50, 100 and 200 mg/kg body wt. of HAEPA. There was a significant increase in weight gain, body mass index (BMI), blood lipids, low density lipoproteins (LDL), lipid peroxides (LPO) and serum transaminases in HFD fed rats. HFD+HAEPA fed rats showed a significant decrease in blood lipids, LPO, liver lipids and increase in antioxidant status when compared to HFD control rats. The activity of lipid metabolic key enzymes such as fatty acid synthase and HMG CoA reductase in liver were also found to be decreased significantly in HAEPA co-administered rats. Lipoprotein lipase activity was found increased in HFD+HAEPA rats. Among the 4 doses studied, 100 mg of HAEPA/kg body wt. exhibited optimum hypolipidemic activity. Histopathological observations in liver and visceral adipose tissue added more evidence for the lipid lowering effect of HAEPA. It can be concluded that avocado fruit extract can act as hypolipidemic agent probably by modulating the activities of HMG CoA reductase and fatty acid synthase in liver.
For the first time, a series of 25 pseudo-octahedral pyridylphosphinate metal complexes (Ru, Os, Rh, Ir) has been synthesised and assessed in biological systems. Each metal complex incorporates a pyridylphosphinate ligand, a monodentate halide and a capping η(6)-bound aromatic ligand. Solid- and solution-state analyses of two complexes reveal a structural preference for one of a possible two diastereomers. The metal chlorides hydrolyse rapidly in D2O to form a 1 : 1 equilibrium ratio between the aqua and chloride adducts. The pKa of the aqua adduct depends upon the pyridyl substituent and the metal but has little dependence upon the phosphinate R' group. Toxicity was measured in vitro against non-small cell lung carcinoma H460 cells, with the most potent complexes reporting IC50 values around 50 μM. Binding studies with selected amino acids and nucleobases provide a rationale for the variation in toxicity observed within the series. Finally, an investigation into the ability of the chelating amino acid l-His to displace the phosphinate O-metal bond shows the potential for phosphinate complexes to act as prodrugs that can be activated in the intracellular environment.
One application of gene flow science is the policy arena. In this article, we describe two examples in which the topic of gene flow has entered into the U.S. national environmental policymaking process: regulation of genetically engineered crops and clarification of the jurisdictional scope of the Clean Water Act. We summarize both current scientific understanding and the legal context within which gene flow science has relevance. We also discuss the process by which scientific knowledge has been synthesized and communicated to decision-makers in these two contexts utilizing the concept of 'boundary work'. Boundary organizations, the work they engage in to bridge the worlds of science, policy, and practice, and the boundary objects they produce to translate scientific knowledge existed in both examples. However, the specific activities and attributes of the objects produced varied based on the needs of the decision-makers. We close with suggestions for how scientists can contribute to or engage in boundary work with policymakers.
Growing evidence from online credibility research reveals that online users rely on heuristic processes to evaluate the credibility of online information. The current paper, which is based on the construal level theory (CLT), proposes that congruency between the psychological distance of a stimulus and the way it is mentally construed can act as a heuristic for believability. According to CLT, psychologically close (e.g., spatially, temporally, socially) stimuli are represented concretely whereas psychologically distant stimuli are represented abstractly. The level of mental construals and the psychological distance of information have been shown to influence people's truth judgments in offline contexts. This study tests whether congruency between the construal level of people's mindsets (abstract vs. concrete) and the psychological distance implied in an online message (far vs. close) enhances message believability. By partially confirming CLT predictions, we found that believability of an online news item about a distant location increased when people maintained an abstract mindset rather than a concrete one. The effect of a concrete mindset on believability was not significant for the close psychological distance condition. Our findings provide initial evidence that congruency between the construal level of people's mindsets and psychological distance cues in online messages can act as a heuristic for believability. We discuss the potential of applying the CLT framework to the growing literature on online cognitive heuristics in the area of online information credibility.
Preterm birth is a common cause of adverse neonatal and childhood outcomes, in both the short and long term. Preterm labor is commonly associated with inflammation at the maternal-fetal interface. There is some indirect evidence that mast cells (MCs) might represent a link between hormonal influences and local reactions leading to the onset of labor.
The placentas and membranes of 51 uncomplicated spontaneous term births were compared to those from 50 spontaneous preterm births. Immunohistochemical staining for MC tryptase was undertaken allowing MC concentration, location, and degranulation status to be determined. Regression modeling was used to compare results.
There were no significant differences in the demographic characteristics of the two cohorts. There were significantly more MCs in the decidua for term births than preterm births (P=0.03). The presence of histological chorioamnionitis did not affect MC concentrations.
Despite evidence suggesting a possible role for MCs in spontaneous preterm birth, this study found that the concentration of decidual MCs was in fact significantly lower in preterm compared to term birth.
In 2010, the Centers for Disease Control and Prevention funded 50 communities to participate in the Communities Putting Prevention to Work (CPPW) program. CPPW supported community-based approaches to prevent or delay chronic disease and promote wellness by reducing tobacco use and obesity. We collected the direct costs of CPPW for the 44 communities funded through the American Recovery and Reinvestment Act (ARRA) and analyzed costs per person reached for all CPPW interventions and by intervention category.
From 2011 through 2013, we collected quarterly data on costs from the 44 CPPW ARRA-funded communities. We estimated CPPW program costs as spending on labor; consultants; materials, travel, and services; overhead activities; and partners plus the value of in-kind donations. We estimated communities' costs per person reached for each intervention implemented and compared cost allocations across communities that focused on reducing tobacco use, or obesity, or both. Analyses were conducted in 2014; costs are reported in 2012 dollars.
The largest share of CPPW total costs of $363 million supported interventions in communities that focused on obesity ($228 million). Average costs per person reached were less than $5 for 84% of tobacco-related interventions, 88% of nutrition interventions, and 89% of physical activity interventions. Costs per person reached were highest for social support and services interventions, almost $3 for tobacco use interventions and $1 for obesity prevention interventions.
CPPW cost estimates are useful for comparing intervention cost per person reached with health outcomes and for addressing how community health intervention costs vary by type of intervention and by community size.
The availability of clinical-grade cytokines and artificial antigen-presenting cells has accelerated interest in using natural killer (NK) cells as adoptive cellular therapy (ACT) for cancer. One of the technological shortcomings of translating therapies from animal models to clinical application is the inability to effectively and non-invasively track these cells after infusion in patients. We have optimized the nonradioactive isotope fluorine-19 ((19)F) as a means to label and track NK cells in preclinical models using magnetic resonance imaging (MRI). Human NK cells were expanded with interleukin (IL)-2 and labeled in vitro with increasing concentrations of (19)F. Doses as low as 2 mg/mL (19)F were detected by MRI. NK cell viability was only decreased at 8 mg/mL (19)F. No effects on NK cell cytotoxicity against K562 leukemia cells were observed with 2, 4 or 8 mg/mL (19)F. Higher doses of (19)F, 4 mg/mL and 8 mg/mL, led to an improved (19)F signal by MRI with 3 × 10(11) (19)F atoms per NK cell. The 4 mg/mL (19)F labeling had no effect on NK cell function via secretion of granzyme B or interferon gamma (IFNγ), compared to NK cells exposed to vehicle alone. (19)F-labeled NK cells were detectable immediately by MRI after intratumoral injection in NSG mice and up to day 8. When (19)F-labeled NK cells were injected subcutaneously, we observed a loss of signal through time at the site of injection suggesting NK cell migration to distant organs. The (19)F perfluorocarbon is a safe and effective reagent for monitoring the persistence and trafficking of NK cell infusions in vivo, and may have potential for developing novel imaging techniques to monitor ACT for cancer.
A novel approach to immunotherapy is the activation of toll-like receptor 8 (TLR8). Motolimod, a selective
 TLR8 agonist can act in concert with approved immunotherapies to sensitize T cells and augment natural killer (NK) cell function. Despite treatment with chemotherapeutic agents and advance disease, cancer patients remain sensitive to motolimod.
Adoptive cell transfer (ACT) is an emerging anticancer therapy that has shown promise in various malignancies. Redirecting antigen specificity by genetically engineering T cells to stably express receptors has become an effective variant of ACT. A novel extension of this approach is to utilize engineered T cells to produce and deliver anticancer therapeutics that enhance cytotoxic T cell function and simultaneously inhibit immunosuppressive processes. Here, we review the potential of using T cells as therapeutic-secreting vehicles for immunotherapies and present theoretical and established arguments in support of further development of this unique cell-based immunotherapy.
Targeted pulmonary vasoactive substances are the cornerstone of treatment in pulmonary arterial hypertension (PAH). Approved drugs act on various receptors and molecules within the pulmonary arteries, mainly causing pulmonary vasodilation and potentially reversing remodeling with consequent improvement of right ventricular function. A key role is attributed to the prostacyclin pathway and especially the prostacyclin receptor (IP). Selexipag is a recently developed, non-prostanoid, oral IP receptor agonist for the treatment of PAH which has been approved in countries/regions including the USA and Europe.
We review the discovery and development of drugs targeting IP receptors in PAH and describe preclinical and phase I studies of selexipag. Furthermore, we review important phase II and III selexipag studies and place them into the clinical context of previously approved prostanoids.
Oral selexipag offers a promising therapeutic option within the class of available drugs targeting IP receptors. However, its role as first-line therapy based on its efficacy/side-effect profile in current studies is questionable. Most likely, selexipag will be used in combination with other PAH-specific oral drugs. The potential of selexipag to replace or postpone the use of inhaled or parenteral prostanoids needs to be investigated in future trials.
A major current challenge in bioorganic chemistry is the identification of effective mimics of protein secondary structures that act as inhibitors of protein-protein interactions (PPIs). In this work, trans-2-aminocyclobutanecarboxylic acid (tACBC) was used as the key β-amino acid component in the design of α/β/γ-peptides to structurally mimic a native α-helix. Suitably functionalized α/β/γ-peptides assume an α-helix-mimicking 12,13-helix conformation in solution, exhibit enhanced proteolytic stability in comparison to the wild-type α-peptide parent sequence from which they are derived, and act as selective inhibitors of the p53/hDM2 interaction.
In a search for plant homologues of dipeptidyl peptidase III (DPP III) family, we found a predicted protein from the moss Physcomitrella patens (UniProt entry: A9TLP4), which shared 61% sequence identity with the Arabidopsis thaliana uncharacterized protein, designated Nudix hydrolase 3. Both proteins contained all conserved regions of the DPP III family, but instead of the characteristic hexapeptide HEXXGH zinc-binding motif, they possessed a pentapeptide HEXXH, and at the N-terminus, a Nudix box, a hallmark of Nudix hydrolases, known to act upon a variety of nucleoside diphosphate derivatives. To investigate their biochemical properties, we expressed heterologously and purified Physcomitrella (PpND) and Arabidopsis (AtND) protein. Both hydrolyzed, with comparable catalytic efficiency, the isopentenyl diphosphate (IPP), a universal precursor for the biosynthesis of isoprenoid compounds. In addition, PpND dephosphorylated four purine nucleotides (ADP, dGDP, dGTP, and 8-oxo-dATP) with strong preference for oxidized dATP. Furthermore, PpND and AtND showed DPP III activity against dipeptidyl-2-arylamide substrates, which they cleaved with different specificity. This is the first report of a dual activity enzyme, highly conserved in land plants, which catalyzes the hydrolysis of a peptide bond and of a phosphate bond, acting both as a dipeptidyl peptidase III and an atypical Nudix hydrolase.
Glioma amplified sequence 41(GAS41) is a potent transcription factor that play a crucial role in cell proliferation and survival. In glioblastoma, the expression of GAS41 at both transcriptional and post transcriptional level needs to be tightly maintained in response to cellular signals. Micro RNAs (miRNA) are small non coding RNA that act as important regulators for modulating the expression of various target genes. Studies have shown that several miRNAs play role in the post-transcriptional regulation of GAS41. Here we identified GAS41 as a novel target for endogenous miR-203 and demonstrate an inverse correlation of miR-203 expression with GAS41 in glioma cell lines (HNGC2 and U87). Over expression of miR-203 negatively regulates GAS41 expression in U87 and HNGC2 cell lines. Moreover, miR-203 restrained miR-10b action by suppressing GAS41. GAS41 is essential for repressing p53 in tumor suppressor pathway during cell proliferation. Enforced expression of GAS41 produced contradictory effect on miR-203 but was able to enhance p53 tumor suppressor pathway associated protein. It was also found that miR-203 maintains the stability of p53 as knock down of p53 expression using siRNA resulted in down regulation of pri-miR and mature miR-203 expression. Conversely reconstitution of miR-203 expression induced apoptosis and inhibited migratory property of glioma cells. Taken together, we show that miR-203 is a key negative regulator of GAS41 and acts as tumor suppressor microRNA in glioma.
The vasculature of plants act as a channel for transport of signal(s) that facilitate long-distance intraplant communication. In maize, Maize insect resistance1-Cysteine Protease (Mir1-CP), which has homology to papain-like proteases, provides defense to different feeding guilds of insect pests. Furthermore, accumulation of Mir1-CP in the vasculature suggests that Mir1-CP can potentially function as a phloem-mobile protein. In a recent study, we provided evidence that Mir1-CP can curtail the growth of phloem-sap sucking insect, corn leaf aphid (CLA; Rhopalosiphum maidis). Our current study further examined whether aboveground feeding by CLA can induce resistance to subsequent herbivory by belowground feeding western corn rootworm (WCR; Diabrotica virgifera virgifera). Aboveground feeding by CLA systemically induced the accumulation of Mir1-CP in the roots. Furthermore, foliage feeding by CLA provided enhanced resistance to subsequent herbivory by belowground feeding of WCR. Taken together, our previous findings and results presented here indicate that long-distance transport of Mir1-CP is critical for providing enhanced resistance to insect attack in maize.
LARGE is a glycosyltransferase involved in glycosylation of α-dystroglycan (α-DG). Absence of this protein in the LARGEmyd mouse results in α-DG hypoglycosylation, and is associated with central nervous system abnormalities and progressive muscular dystrophy. Up-regulation of LARGE has previously been proposed as a therapy for the secondary dystroglycanopathies: overexpression in cells compensates for defects in multiple dystroglycanopathy genes. Counterintuitively, LARGE overexpression in an FKRP-deficient mouse exacerbates pathology, suggesting that modulation of α-DG glycosylation requires further investigation. Here we demonstrate that transgenic expression of human LARGE (LARGE-LV5) in the LARGEmyd mouse restores α-DG glycosylation (with marked hyperglycosylation in muscle) and that this corrects both the muscle pathology and brain architecture. By quantitative analyses of LARGE transcripts we also here show that levels of transgenic and endogenous LARGE in the brains of transgenic animals are comparable, but that the transgene is markedly overexpressed in heart and particularly skeletal muscle (20-100 fold over endogenous). Our data suggest LARGE overexpression may only be deleterious under a forced regenerative context, such as that resulting from a reduction in FKRP: in the absence of such a defect we show that systemic expression of LARGE can indeed act therapeutically, and that even dramatic LARGE overexpression is well-tolerated in heart and skeletal muscle. Moreover, correction of LARGEmyd brain pathology with only moderate, near-physiological LARGE expression suggests a generous therapeutic window.
The usage of amorphous solids in practical applications, such as in medication, is commonly limited by the poor long-term stability of this state, because unwanted crystalline transitions occur. In this study, three different polymeric coatings are investigated for their ability to stabilize amorphous films of the model drug clotrimazole and to protect against thermally induced transitions. For this, drop cast films of clotrimazole are encapsulated by initiated chemical vapor deposition (iCVD), using perfluorodecyl acrylate (PFDA), hydroxyethyl methacrylate (HEMA), and methacrylic acid (MAA). The iCVD technique operates under solvent-free conditions at low temperatures, thus leaving the solid state of the encapsulated layer unaffected. Optical microscopy and X-ray diffraction data reveal that at ambient conditions of about 22 °C, any of these iCVD layers extends the lifetime of the amorphous state significantly. At higher temperatures (50 or 70 °C), the p-PFDA coating is unable to provide protection, while the p-HEMA and p-MAA strongly reduce the crystallization rate. Furthermore, p-HEMA and p-MAA selectively facilitate a preferential alignment of clotrimazole and, interestingly, even suppress crystallization upon a
 temporary, rapid temperature increase (3 °C/min, up to 150 °C). The results of this study demonstrate how a polymeric coating, synthesized directly on top of an amorphous phase, can act as a stabilizing agent against crystalline transitions, which makes this approach interesting for a variety of applications.
Extensive molecular-dynamics (MD) simulations have been used to investigate DNA-dye and DNA-photosensitizer conjugates, which act as reactants in templated reactions leading to the generation of fluorescent products in the presence of specific desoxyribonucleic acid sequences (targets). Such reactions are potentially suitable for detecting target nucleic acids in live cells by fluorescence microscopy or flow cytometry. The simulations show how the attached dyes/photosensitizers influence DNA structure and reveal the relative orientations of the chromophores with respect to each other. Our results will help to optimize the reactants for the templated reactions, especially length and structure of the spacers used to link reporter dyes or photosensitizers to the oligonucleotides responsible for target recognition. Furthermore, we demonstrate that the structural ensembles obtained from the simulations can be used to calculate steady-state UV-vis absorption and emission spectra. We also show how important quantities describing the quenching of the reporter dye via fluorescence resonance energy transfer (FRET) can be calculated from the simulation data, and we compare these for different relative chromophore geometries.
InAs nanowires (NWs) have been grown on semi-insulating InAs (111)B substrates by metal-organic chemical vapor deposition catalyzed by 50, 100, and 150 nm-sized Au particles. The pure wurtzite (WZ) phase of these NWs has been attested by high-resolution transmission electron microscopy and selected area diffraction pattern measurements. Low temperature photoluminescence measurements have provided unambiguous and robust evidence of a well resolved, isolated peak at 0.477 eV, namely 59 meV higher than the band gap of ZB InAs. The WZ nature of this energy band has been demonstrated by high values of the polarization degree, measured in ensembles of NWs both as-grown and mechanically transferred onto Si and GaAs substrates, in agreement with the polarization selection rules for WZ crystals. The value of 0.477 eV found here for the bandgap energy of WZ InAs agrees well with theoretical calculations.
Allergy has been inferred to contribute to the pathophysiology of chronic rhinosinusitis (CRS) although this role is controversial and the mechanism is debated. Furthermore, the role of aeroallergens in CRS is poorly defined and has been postulated to contribute to CRS through direct penetration in the sinuses or downstream systemic consequences. Common aeroallergens implicated in chronic rhinosinusitis include air pollution/second hand smoke, dust mite and pollen [<citeref rid="ref1">1</citeref>,<citeref rid="ref2">2</citeref>,<citeref rid="ref3">3</citeref>]. One emerging potential mechanism whereby aeroallergens contribute to CRS is through sinonasal epithelial barrier disruption (fig. <figref rid="fig01">1</figref>). Characterization of cytokine disruption of sinonasal epithelial cell barrier has been described including interleukin (IL)-4 and IL-13, as well as aeroallergens such as house dust mite and cigarette smoke. Recent results have demonstrated severe barrier disruption in response to direct application of either particulate matter (PM) or house dust mite (HDM) to sinonasal epithelial cells. Sinonasal epithelial barrier disruption may contribute to CRS by enabling the perpetual and chronic exposure of inflammatory allergens and stimuli. The sinonasal epithelial barrier plays a significant role in innate immune host defense. Mechanisms of innate immune defense include pattern recognition receptors (PRRs), secreted endogenous antimicrobials and inflammatory cytokines that aid in repair mechanisms including IL-33. Here we discuss recent evidence implicating aeroallergens and dysregulated host innate immune responses in the development of CRS. <figure id="fig01"><no>1</no><figcap>Fig. 1. Aeroallergens and inflammatory stimuli disrupt sinonasal epithelial barrier function. These agents act to destabilize the barrier through stimulating endocytosis and destruction of cell junction proteins via oxidative stress and MyD88-dependent mechanisms. Furthermore, aeroallergens and inflammatory stimuli induce secretion of IL-25, IL-33, and TSLP from sinonasal epithelial cells.</figcap><figbody filename="F01" filetype="JPG">F01</figbody></figure>.
Kratom (Mitragyna speciosa) is a plant consumed throughout the world for its stimulant effects and as an opioid substitute (1). It is typically brewed into a tea, chewed, smoked, or ingested in capsules (2). It is also known as Thang, Kakuam, Thom, Ketum, and Biak (3). The Drug Enforcement Administration includes kratom on its Drugs of Concern list (substances that are not currently regulated by the Controlled Substances Act, but that pose risks to persons who abuse them), and the National Institute of Drug Abuse has identified kratom as an emerging drug of abuse (3,4). Published case reports have associated kratom exposure with psychosis, seizures, and deaths (5,6). Because deaths have been attributed to kratom in the United States (7), some jurisdictions have passed or are considering legislation to make kratom use a felony (8). CDC characterized kratom exposures that were reported to poison centers and uploaded to the National Poison Data System (NPDS) during January 2010-December 2015. The NPDS is a national database of information logged by the country's regional poison centers serving all 50 United States, the District of Columbia, and Puerto Rico and is maintained by the American Association of Poison Control Centers. NPDS case records are the result of call reports made by the public and health care providers.
Nanoparticle-liquid crystal (NP-LC) composites based on hydrogen bonding were explored using a model system. The ligand shells of 3 nm diameter zirconium dioxide nanoparticles (ZrO2 NPs) were varied to control their interaction with 4-n-hexylbenzoic acid (6BA). The miscibility and effect of the NPs on the nematic order as a function of particle concentration was characterized by polarized optical microscopy (POM), fluorescence microscopy and (2)H NMR spectroscopy. Nonfunctionalized ZrO2 NPs have the lowest miscibility and strongest effect on the LC matrix due to irreversible binding of 6BA to the NPs via a strong zirconium carboxylate bond. The ZrO2 NPs were functionalized with 6-phosphonohexanoic acid (6PHA) or 4-(6-phosphonohexyloxy)benzoic acid (6BPHA) which selectively bind to the ZrO2 NP surface via the phosphonic acid groups. The miscibility was increased by controlling the concentration of the pendant CO2H groups by adding hexylphosphonic acid (HPA) to act as a spacer group. Fluorescence microscopy of lanthanide doped ZrO2 NPs showed no aggregates in the nematic phase below the NP concentration where aggregates are observed in the isotropic phase. The functionalized NPs preferably concentrate into LC defects and any remaining isotropic liquid but are still present throughout the nematic liquid at a lower concentration.
Black and minority ethnic (BME) service users experience adverse pathways into care. Ethnic differences are evident even at first-episode psychosis (FEP); therefore, contributory factors must operate before first presentation to psychiatric services. The ENRICH programme comprised three interlinked studies that aimed to understand ethnic and cultural determinants of help-seeking and pathways to care.
Study 1: to understand ethnic differences in pathways to care in FEP by exploring cultural determinants of illness recognition, attribution and help-seeking among different ethnic groups. Study 2: to evaluate the process of detention under the Mental Health Act (MHA) and determine predictors of detention. Study 3: to determine the appropriateness, accessibility and acceptability of generic early intervention services for different ethnic groups.
Study 1: We recruited a prospective cohort of FEP patients and their carers over a 2-year period and assessed the chronology of symptom emergence, attribution and help-seeking using semistructured tools: the Nottingham Onset Schedule (NOS), the Emerging Psychosis Attribution Schedule and the ENRICH Amended Encounter Form. A stratified subsample of user–carer NOS interviews was subjected to qualitative analyses. Study 2: Clinical and sociodemographic data including reasons for detention were collected for all MHA assessments conducted over 1 year (April 2009–March 2010). Five cases from each major ethnic group were randomly selected for a qualitative exploration of carer perceptions of the MHA assessment process, its outcomes and alternatives to detention. Study 3: Focus groups were conducted with service users, carers, health professionals, key stakeholders from voluntary sector and community groups, commissioners and representatives of spiritual care with regard to the question: ‘How appropriate and accessible are generic early intervention services for the specific ethnic and cultural needs of BME communities in Birmingham?’
There were no ethnic differences in duration of untreated psychosis (DUP) and duration of untreated illness in FEP. DUP was not related to illness attribution; long DUP was associated with patients being young (< 18 years) and living alone. Black patients had a greater risk of MHA detention, more criminal justice involvement and more crisis presentations than white and Asian groups. Asian carers and users were most likely to attribute symptoms to faith-based or supernatural explanations and to seek help from faith organisations. Faith-based help-seeking, although offering comfort
 and meaning, also risked delaying access to medical care and in some cases also resulted in financial exploitation of this vulnerable group. The BME excess in MHA detentions was not because of ethnicity per se; the main predictors of detention were a diagnosis of mental illness, presence of risk and low level of social support. Early intervention services were perceived to be accessible, supportive, acceptable and culturally appropriate. There was no demand or perceived need for separate services for BME groups or for ethnic matching between users and clinicians.
Statutory health-care organisations need to work closely with community groups to improve pathways to care for BME service users. Rather than universal public education campaigns, researchers need to develop and evaluate public awareness programmes that are specifically focused on BME groups.
The National Institute for Health Research Programme Grants for Applied Research programme.
Ghrelin and cholecystokinin (CCK) are multifunctional peptides. In the current study, complete sequences of ghrelin (800 bp) and CCK (739 bp) were firstly cloned in Columba livia by using rapid amplification of cDNA ends (RACE) method. The open reading frames of ghrelin (351bp) and CCK (393bp) encoded 116 amino acids and 130 amino acids, respectively. Sequence comparison indicated that pigeon ghrelin and CCK shared high identity with those reported in other avian species. Quantitative real-time PCR analysis found that ghrelin and CCK mRNAs expressed in three intestinal segments of pigeon during development. Both ghrelin and CCK showed generally higher expressions at days posthatch than embryonic periods regardless of intestinal segments. In duodenum and ileum, the expressions of ghrelin and CCK mRNA reached the peak values at 8 d posthatch. Jejunum CCK mRNA level increased linearly after hatching, and reached the highest point at posthatch 28 d. Based on documented effects of long chain fatty acids (LCFAs) on pigeon ghrelin and CCK expression were also investigated in vitro. Higher concentrations (50 μM or 250 μM) of linoleic acid, α-linolenic acid or arachidonic acid can significantly increase ghrelin mRNA level in pigeon jejunum. However, for oleic acid, the induction of ghrelin gene expressions needed a lower concentration (5 μM). 5 μM of linoleic acid, α-linolenic acid or arachidonic acid and 250 μM palmitic acid repressed CCK expression significantly. A higher concentration (250 μM) of oleic acid or α-linolenic acid can up-regulate CCK mRNA level significantly. Our results indicated that ghrelin and CCK may act key functions in pigeon intestine development and their expressions could be regulated by LCFAs.
Expression of the human cytomegalovirus (HCMV) IE1 and IE2 proteins is critical for the establishment of lytic infection and reactivation from viral latency. Defining the mechanisms controlling IE1 and IE2 expression is therefore important for understanding how HCMV regulates its replicative cycle. Here we identify several novel transcripts encoding full-length IE1 and IE2 proteins during HCMV lytic replication. Two of the alternative major immediate early (MIE) transcripts initiate in the first intron, intron A, of the previously defined MIE transcript, while others extend the 5' untranslated region. Each of the MIE transcripts associates with polyribosomes in infected cells and therefore contributes to IE1 and IE2 protein levels. Surprisingly, deletion of the core promoter region of the major immediate early promoter (MIEP) from a plasmid containing the MIE genomic locus did not completely abrogate IE1 and IE2 expression. Instead, deletion of the MIEP core promoter resulted in increased expression of alternative MIE transcripts, suggesting that the MIEP suppresses the activity of the alternative MIE promoters. While the canonical MIE mRNA was the most abundant transcript at immediate early times, the novel MIE transcripts accumulated to levels equivalent to that of the known MIE transcript later in infection. Using two HCMV recombinants, we found that sequences in intron A of the previously defined MIE transcript are required for efficient IE1 and IE2 expression and viral replication. Together, our results identify new regulatory sequences controlling IE1 and IE2 expression and suggest that multiple transcription units act in concert to regulate IE1 and IE2 expression during lytic infection.
The HCMV IE1 and IE2 proteins are critical regulators of HCMV replication, both during primary infection and reactivation from viral latency. This study expands our understanding of the sequences controlling IE1 and IE2 expression by defining novel transcriptional units controlling the expression of full-length IE1 and IE2 proteins. Our results suggest that alternative promoters may allow for IE1 and IE2 expression when MIEP activity is limiting, as occurs in latently infected cells.
Specific structures in mRNA modulate translation rate and thus can affect protein folding. Using the protein structures from two eukaryotes and three prokaryotes, we explore the connections between the protein compactness, inferred from solvent accessibility, and mRNA structure, inferred from mRNA folding energy (ΔG). In both prokaryotes and eukaryotes, the ΔG value of the most stable 30 nucleotide segment of the mRNA (ΔGmin) strongly, positively correlates with protein solvent accessibility. Thus, mRNAs containing exceptionally stable secondary structure elements typically encode compact proteins. The correlations between ΔG and protein compactness are much more pronounced in predicted ordered parts of proteins compared to the predicted disordered parts, indicative of an important role of mRNA secondary structure elements in the control of protein folding. Additionally, ΔG correlates with the mRNA length and the evolutionary rate of synonymous positions. The correlations are partially independent and were used to construct multiple regression models which explain about half of the variance of protein solvent accessibility. These findings suggest a model in which the mRNA structure, particularly exceptionally stable RNA structural elements, act as gauges of protein co-translational folding by reducing ribosome speed when the nascent peptide needs time to form and optimize the core structure.
Physical interaction between organelles is a flexible event and essential for cells to adapt rapidly to environmental stimuli. Germinating plants utilize oil bodies and peroxisomes to mobilize storage lipids for the generation of sucrose as the main energy source. Although membrane interaction between oil bodies and peroxisomes has been widely observed, its underlying molecular mechanism is largely unknown. Here we present genetic evidence for control of the physical interaction between oil bodies and peroxisomes. We identified alleles of the sdp1 mutant altered in oil body morphology. This mutant accumulates bigger and more oil body aggregates compared with the wild type and showed defects in lipid mobilization during germination. SUGAR DEPENDENT 1 (SDP1) encodes major triacylglycerol lipase in Arabidopsis Interestingly, sdp1 seedlings show enhanced physical interaction between oil bodies and peroxisomes compared with the wild type, whereas exogenous sucrose supplementation greatly suppresses the interaction. The same phenomenon occurs in the peroxisomal defective 1 (ped1) mutant, defective in lipid mobilization because of impaired peroxisomal β-oxidation, indicating that sucrose production is a key factor for oil body-peroxisomal dissociation. Peroxisomal dissociation and subsequent release from oil bodies is dependent on actin filaments. We also show that a peroxisomal ATP binding cassette transporter, PED3, is the potential anchor protein to the membranes of these organelles. Our results provide novel components linking lipid metabolism and oil body-peroxisome interaction whereby sucrose may act as a negative signal for the interaction of oil bodies and peroxisomes to fine-tune lipolysis.
Dopamine is central to reinforcement processing and exerts this function in species ranging from humans to fruit flies. It can do so via two different types of receptors (i.e., D1 or D2) that mediate either augmentation or abatement of cellular cAMP levels. Whereas D1 receptors are known to contribute to Drosophila aversive odor learning per se, we here show that D2 receptors are specific for support of a consolidated form of odor memory known as anesthesia-resistant memory. By means of genetic mosaicism, we localize this function to Kenyon cells, the mushroom body intrinsic neurons, as well as GABAergic APL neurons and local interneurons of the antennal lobes, suggesting that consolidated anesthesia-resistant memory requires widespread dopaminergic modulation within the olfactory circuit. Additionally, dopaminergic neurons themselves require D2R, suggesting a critical role in dopamine release via its recognized autoreceptor function. Considering the dual role of dopamine in balancing memory acquisition (proactive function of dopamine) and its "forgetting" (retroactive function of dopamine), our analysis suggests D2R as central player of either process.
Dopamine provides different information; while it mediates reinforcement during the learning act (proactive function), it balances memory performance between two antithetic processes thereafter (retroactive function) (i.e., forgetting and augmentation). Such bidirectional design can also be found at level of dopamine receptors, where augmenting D1 and abating D2 receptors are engaged to balance cellular cAMP levels. Here, we report that consolidated anesthesia-resistant memory (ARM), but not other concomitant memory phases, are sensitive to bidirectional dopaminergic signals. By means of genetic mosaicism, we identified widespread dopaminergic modulation within the olfactory
 circuit that suggests nonredundant and reiterating functions of D2R in support of ARM. Our results oppose ARM to its concomitant memory phases that localize to mushroom bodies and propose a decentralized organization of consolidated ARM.
Fission yeast cells treated with low doses of the actin depolymerizing drug, latrunculin A (LatA), delay entry into mitosis via a mechanism that is dependent on both the Clp1p and Rad24p proteins. During this delay, cells remain in a cytokinesis-competent state that is characterized by continuous repair and/or reestablishment of the actomyosin ring. In this manner, cells ensure the faithful completion of the preceding cytokinesis in response to perturbation of the cell division machinery. To uncover other genes with a role in this response, or simply genes with roles in adapting to LatA-induced stress, we carried out a genome-wide screen and identified a group of 38 gene deletion mutants that are hyper-sensitive to the drug. As expected, we found genes affecting cytokinesis and/or the actin cytoskeleton within this set (ain1, acp2, imp2). We also identified genes with roles in histone modification (tra1, ngg1), intracellular transport (apl5, aps3), and glucose-mediated signaling (git3, git5, git11, pka1, cgs2). Importantly, while the identified gene deletion mutants are prone to cytokinesis failure in the presence of LatA, they are nevertheless fully capable of cell division in the absence of the drug. These results indicate that fission yeast cells make use of a diverse set of regulatory modules to counter abnormal cytoskeletal perturbations, and furthermore, that these modules act redundantly to ensure cell survival and proliferation.
The dopaminergic system is implicated in many mental processes and neuropsychiatric disorders. Pharmacologically, drugs with dopamine receptor antagonistic and agonistic effects are used, but their effects on functional brain metabolism are not well known.
In this randomized crossover, placebo-controlled, and rater-blinded study, 25 healthy adults received an acute dose placebo substance (starch), quetiapine (dopamine receptor antagonist), or pramipexole (dopamine agonist of the nonergoline class) 1 hour before the experiment. Background-suppressed 2D pseudo-continuous arterial spin labeling was used to examine whole-brain baseline cerebral blood flow differences induced by the 3 substances.
We found that quetiapine reduced perfusion in the occipital (early visual areas) and bilateral cerebellar cortex relative to placebo. In contrast, quetiapine enhanced cerebral blood flow (relative to placebo) in the striatal system (putamen and caudate nucleus) but also in the supplementary motor area, insular-, prefrontal- as well as in the pre- and postcentral cortex. Pramipexole increased cerebral blood flow compared with placebo in the caudate nucleus, putamen, middle frontal, supplementary motor area, and brainstem (substantia nigra), but reduced cerebral blood flow in the posterior thalamus, cerebellum, and visual areas. Pramipexole administration resulted in stronger cerebral blood flow relative to quetiapine in the hypothalamus, cerebellum, and substantia nigra.
Our results indicate that quetiapine and pramipexole differentially modulate regional baseline cerebral blood flow. Both substances act on the dopaminergic system, although they affect distinct regions. Quetiapine altered dopaminergic function in frontal, striatal, and motor regions. In contrast, pramipexole affected cerebral blood flow of the nigrostriatal (striatum and substantia nigra) dopaminergic, but less the fronto-insular system.
Aggregation of TAR-DNA-binding protein 43 (TDP-43) and of its fragments TDP-25 and TDP-35 occurs in amyotrophic lateral sclerosis (ALS). TDP-25 and TDP-35 act as seeds for TDP-43 aggregation, altering its function and exerting toxicity. Thus, inhibition of TDP-25 and TDP-35 aggregation and promotion of their degradation may protect against cellular damage. Upregulation of HSPB8 is one possible approach for this purpose, since this chaperone promotes the clearance of an ALS associated fragments of TDP-43 and is upregulated in the surviving motor neurones of transgenic ALS mice and human patients. We report that overexpression of HSPB8 in immortalized motor neurones decreased the accumulation of TDP-25 and TDP-35 and that protection against mislocalized/truncated TDP-43 was observed for HSPB8 in Drosophila melanogaster Overexpression of HSP67Bc, the functional ortholog of human HSPB8, suppressed the eye degeneration caused by the cytoplasmic accumulation of a TDP-43 variant with a mutation in the nuclear localization signal (TDP-43-NLS). TDP-43-NLS accumulation in retinal cells was counteracted by HSP67Bc overexpression. According with this finding, downregulation of HSP67Bc increased eye degeneration, an effect that is consistent with the accumulation of high molecular weight TDP-43 species and ubiquitinated proteins. Moreover, we report a novel Drosophila model expressing TDP-35, and show that while TDP-43 and TDP-25 expression in the fly eyes causes a mild degeneration, TDP-35 expression leads to severe neurodegeneration as revealed by pupae lethality; the latter effect could be rescued by HSP67Bc overexpression. Collectively, our data demonstrate that HSPB8 upregulation mitigates TDP-43 fragment mediated toxicity, in mammalian neuronal cells and flies.
Abnormal elevation of low-density lipoprotein (LDL) and triglyceride-rich lipoproteins in plasma as well as dysfunction of anti-atherogenic high-density lipoprotein (HDL) have both been recognized as essential components of the pathogenesis of atherosclerosis and are classified as dyslipidemia. This review describes the arc of development of antisense oligonucleotides for the treatment of dyslipidemia. Chemically-armed antisense candidates can act on various kinds of transcripts, including mRNA and miRNA, via several different endogenous antisense mechanisms, and have exhibited potent systemic anti-dyslipidemic effects. Here, we present specific cutting-edge technologies have recently been brought into antisense strategies, and describe how they have improved the potency of antisense drugs in regard to pharmacokinetics and pharmacodynamics. In addition, we discuss perspectives for the use of armed antisense oligonucleotides as new clinical options for dyslipidemia, in the light of outcomes of recent clinical trials and safety concerns indicated by several clinical and preclinical studies.
Repetition priming is characterized by increased performance as a behavior is repeated. Although this phenomenon is ubiquitous, mediating mechanisms are poorly understood. We address this issue in a model system, the feeding network of Aplysia This network generates both ingestive and egestive motor programs. Previous data suggest a chemical coding model: ingestive and egestive inputs to the feeding central pattern generator (CPG) release different modulators, which act via different second messengers to prime motor activity in different ways. The ingestive input to the CPG (neuron CBI-2) releases the peptides feeding circuit activating peptide and cerebral peptide 2, which produce an ingestive pattern of activity. The egestive input to the CPG (the esophageal nerve) releases the peptide small cardioactive peptide. This model is based on research that focused on a single aspect of motor control (radula opening). Here we ask whether repetition priming is observed if activity is triggered with a neuron within the core CPG itself and demonstrate that it is not. Moreover, previous studies demonstrated that effects of modulatory neurotransmitters that induce repetition priming persist. This suggests that it should be possible to "prime" motor programs triggered from within the CPG by first stimulating extrinsic modulatory inputs. We demonstrate that programs triggered after ingestive input activation are ingestive and programs triggered after egestive input activation are egestive. We ask where this priming occurs and demonstrate modifications within the CPG itself. This arrangement is likely to have important consequences for "task" switching, i.e., the cessation of one type of motor activity and the initiation of another.
The structural complexity of metamaterials is limitless, but, in practice, most designs comprise periodic architectures that lead to materials with spatially homogeneous features. More advanced applications in soft robotics, prosthetics and wearable technology involve spatially textured mechanical functionality, which requires aperiodic architectures. However, a naive implementation of such structural complexity invariably leads to geometrical frustration (whereby local constraints cannot be satisfied everywhere), which prevents coherent operation and impedes functionality. Here we introduce a combinatorial strategy for the design of aperiodic, yet frustration-free, mechanical metamaterials that exhibit spatially textured functionalities. We implement this strategy using cubic building blocks-voxels-that deform anisotropically, a local stacking rule that allows cooperative shape changes by guaranteeing that deformed building blocks fit together as in a three-dimensional jigsaw puzzle, and three-dimensional printing. These aperiodic metamaterials exhibit long-range holographic order, whereby the two-dimensional pixelated surface texture dictates the three-dimensional interior voxel arrangement. They also act as programmable shape-shifters, morphing into spatially complex, but predictable and designable, shapes when uniaxially compressed. Finally, their mechanical response to compression by a textured surface reveals their ability to perform sensing and pattern analysis. Combinatorial design thus opens up a new avenue towards mechanical metamaterials with unusual order and machine-like functionalities.
The factors
 that determine red blood cell (RBC) lifespan and the rate of RBC aging have not been fully elucidated. In several genetic conditions, including sickle cell disease, thalassemia, and G6PD deficiency, erythrocyte lifespan is significantly shortened. Many of these diseases are also associated with protection from severe malaria, suggesting a role for accelerated RBC senescence and clearance in malaria resistance. Here, we report a novel, N-ethyl-N-nitrosourea-induced mutation that causes a gain of function in adenosine 5'-monophosphate deaminase (AMPD3). Mice carrying the mutation exhibit rapid RBC turnover, with increased erythropoiesis, dramatically shortened RBC lifespan, and signs of increased RBC senescence/eryptosis, suggesting a key role for AMPD3 in determining RBC half-life. Mice were also found to be resistant to infection with the rodent malaria Plasmodium chabaudi. We propose that resistance to P. chabaudi is mediated by increased RBC turnover and higher rates of erythropoiesis during infection.
Menopausal estrogen loss leads to an increased bone loss. Soy isoflavones can act as selective estrogen receptor modulators, their role in bone turnover is unclear. The primary outcome was assessing changes in plasma bone turnover markers. The secondary outcomes were assessing changes in cardiovascular risk markers including insulin resistance, blood pressure, and lipid profile. We performed a double-blind randomized parallel study in which 200 women within 2 years after the onset of their menopause were randomized to 15 g soy protein with 66 mg isoflavone (SPI) or 15 g soy protein alone (SP), daily for 6 months. There was a significant reduction in type I collagen crosslinked beta C-telopeptide (βCTX) (bone-resorption marker) with SPI supplementation (0.40 ± 0.17 versus 0.15 ± 0.09 μg/L; p < 0.01) compared to SP supplementation (0.35 ± 0.12 versus 0.35 ± 0.13 μg/L; p = 0.92) after 6 months. There was also a significant reduction in type I procollagen-N-propeptide (P1NP) (bone formation marker) with SPI supplementation (50.5 ± 25.0 versus 34.3 ± 17.6 μg/L; p < 0.01), more marked between 3 and 6 months. Following SPI there was a significant reduction in fasting glucose, fasting insulin, insulin resistance, and systolic blood pressure whereas no significant changes in these parameters was observed with SP. There were no significant changes in fasting lipid profile and diastolic blood pressure with either preparation. There was a significant increase in TSH and reduction in free thyroxine (p < 0.01) with SPI supplementation though free tri-iodothyronine was unchanged. In conclusion, soy protein with isoflavones may confer a beneficial effect on bone health, analogous to the mode of action of antiresorptive agents, albeit to a less magnitude. There was a significant improvement of cardiovascular risk markers, but a significant increase in TSH and reduction in free thyroxine after SPI supplementation indicating a detrimental effect on thyroid function. © 2016 American Society for Bone and Mineral Research.
This study tested the hypothesis that inhibins act in an autocrine manner on Leydig cells using a pre-pubertal Leydig cell line, TM3, as a model of immature Leydig cells. The expression of Inha, Inhba, and Inhbb in TM3 cells was determined by RT-PCR and the production of the inhibin-alpha subunit was confirmed by western blot. Knockdown of Inha expression resulted in significant decreases in the expression of Leydig cell markers Cyp17a1, Cyp11a1, Nr5a1, and Insl3. Western blot showed that activin A, TGFβ1 and TGFβ2 activated SMAD2, and that knockdown of Inha expression in TM3 cells enhanced both activin A- and TGFβ-induced SMAD2 activation. SB431542, a chemical inhibitor of the TGFβ/activin type I receptors, blocked ligand-induced SMAD2 activation and the downregulation of Cyp17a1 expression. Our findings demonstrate that TGFβs and activin A negatively regulate steroidogenic gene expression in TM3 cells via ALK4/5 and SMAD2 and endogenous inhibins can counter this regulation.
Variation in the provision of coronary angiography is associated with health care inefficiency and inequity. We explored geographic, socio-economic, health service and disease indicators associated with variation in angiography rates across Australia.
Australian census and National Health Survey data were used to determine socio-economic, health workforce and service indicators. Hospital separations and coronary deaths during 2011 were identified in the National Hospital Morbidity and Mortality databases. All 61 Medicare Locals responsible for primary care were included, and age- and sex-standardised rates of acute coronary syndrome (ACS) incidence, coronary angiography, revascularisation and mortality were tested for correlations, and adjusted by Bayesian regression.
There were 3.7-fold and 2.3-fold differences between individual Medicare Locals in the lowest and highest ACS and coronary artery disease mortality rates respectively, whereas angiography rates varied 5.3-fold. ACS and death rates within Medicare Locals were correlated (partial correlation coefficient [CC], 0.52; P < 0.001). There was modest correlation between ACS and angiography rates (CC, 0.31; P = 0.018). The proportion of patients undergoing angiography who proceeded to revascularisation was inversely correlated with the total angiogram rate (CC, -0.71; P < 0.001). Socio-economic disadvantage and remoteness were correlated with disease burden, ACS incidence and mortality, but not with angiography rate. In the adjusted analysis, the strongest association with local angiography rates was with admissions to private hospitals (71 additional angiograms [95% CI, 47-93] for every 1000 admissions).
Variation in rates of coronary angiography, not related to clinical need, occurs across Australia. A greater focus on clinical care standards and better distribution of health services will be required if these variations are to be attenuated.
Scotland has a persistently high mortality rate that is not solely due to the effects of socio-economic deprivation. This "excess" mortality is observed across the entire country, but is greatest in and around the post-industrial conurbation of West Central Scotland. Despite systematic investigation, the causes of the excess mortality remain the subject of ongoing debate.
Attachment processes are a fundamental part of human development, and have a profound influence on adult personality and behaviour, especially in response to stressors. Many studies have also shown that childhood adversity is correlated with adult morbidity and mortality. The interplay between childhood adversity and attachment is complex and not fully elucidated, but will include socio-economic, intergenerational and psychological factors. Importantly, some adverse health outcomes for parents (such as problem substance use or suicide) will simultaneously act as risk factors for their children. Data show that some forms of "household dysfunction" relating to childhood adversity are more prevalent in Scotland: such problems include parental problem substance use, rates of imprisonment, rates of suicide and rates of children being taken into care. However other measures of childhood or family wellbeing have not been found to be substantially different in Scotland compared to England. We suggest in this paper that the role of childhood adversity and attachment experience merits further investigation as a plausible mechanism influencing health in Scotland. A model is proposed which sets out some of the interactions between the factors of interest, and we propose parameters for the types of study which would be required to evaluate the validity of the model.
Europe has a growing population of ethnic minority groups whose dietary behaviours are potentially of public health concern. To promote healthier diets, the factors driving dietary behaviours need to be understood. This review mapped the broad range of factors influencing dietary behaviour among ethnic minority groups living in Europe, in order to identify research gaps in the literature to guide future research.
A systematic mapping review was conducted (protocol registered with PROSPERO 2014: CRD42014013549). Nine databases were searched for quantitative and qualitative primary research published between 1999 and 2014. Ethnic minority groups were defined as immigrants/populations of immigrant background from low and middle income countries, population groups from former Eastern Bloc countries and minority indigenous populations. In synthesizing the findings, all factors were sorted and structured into emerging clusters according to how they were seen to relate to each other.
Thirty-seven of 2965 studies met the inclusion criteria (n = 18 quantitative; n = 19 qualitative). Most studies were conducted in Northern Europe and were limited to specific European countries, and focused on a selected number of ethnic minority groups, predominantly among populations of South Asian origin. The 63 factors influencing dietary behaviour that emerged were sorted into seven clusters: social and cultural environment (16 factors), food beliefs and perceptions (11 factors), psychosocial (9 factors), social and material resources (5 factors), accessibility of food (10 factors), migration context (7 factors), and the body (5 factors).
This review identified a broad range of factors and clusters influencing dietary behaviour among ethnic minority groups. Gaps in the literature identified a need for researchers to explore the underlying mechanisms that shape dietary behaviours, which can be gleaned from more holistic, systems-based studies exploring relationships between factors and clusters. The dominance of studies exploring 'differences' between ethnic minority groups and the majority population in terms of the socio-cultural environment and food beliefs
 suggests a need for research exploring 'similarities'. The evidence from this review will feed into developing a framework for the study of factors influencing dietary behaviours in ethnic minority groups in Europe.
Sonoclot analyzer has been widely used in many countries. But the reference intervals provided by the manufacturer were derived from only 45 participants, and there was no cut-off value for transfusion for Sonoclot analysis. This study aimed to establish reference intervals and transfusion criterion for Sonoclot analysis. Volunteers were recruited from healthy Chinese adults and patients undergoing cardiac surgery. Blood samples were withdrawn from forearm vein and measured for activated clotting time (ACT), clot rate (CR), platelet function (PF), activated partial thromboplastin time (APTT), fibrinogen concentration (FIB), and platelet count (PLT). The reference intervals were determined by the nonparametric method. Cut-off values were determined by the receiver operating characteristics curve. A total of 135 healthy volunteers and 281 patients were enrolled. The 95% reference intervals were 96-195 s, 22-51 signal U/min, >1.6 for ACT, CR, PF respectively. In the 281 patients, the results of APTT, FIB, PLT, ACT, CR, and PF ranged from 20.5-300.0 s, 0.28-4.11 g/L, (19.0-387.3)×109/L, 80-514 s, 2.9-74 signal U/min, and 0.1-5.1 respectively. The cut-off values for transfusion were >208, ≤14, and ≤1.3 for ACT, CR, PF respectively. The cut-off values of Sonoclot analysis were within the manufacturer's reference intervals, while they were outside the reference intervals established in this study. The results suggested that the manufacturer's reference intervals were not suitable for Chinese. The reference intervals and cut-off values established in this study will be helpful to Chinese patients.
Limited data exist regarding industry financial relationships in plastic surgery. The Sunshine Act Open Payments Database currently represents the largest repository of these data, but is limited primarily to queries of individual providers. The purpose of this study was to analyze these data and present them in a manner that better delineates these relationships, and to compare plastic surgery with other surgical subspecialties.
A review of the Open Payments Database was performed for the period from January 1, 2014, to December 31, 2014. These data were analyzed with respect to types of payments, characteristics of plastic surgeons and companies, and comparison with other surgical subspecialties.
A total of 49,053 payments from 274 companies were identified that were made to 4812 plastic surgeons (475 academic and 4337 private practice). The total value of payments was $17,091,077. Food and beverage represented the most common type of payment (82.2 percent). Royalties and licensing represented the highest valued type of payment (35.7 percent), but were received by only a minority of plastic surgeons (0.5 percent). No significant differences were identified between academic and private practice plastic surgeons in the value or quantity of payments. Plastic surgery (54.5 percent) exhibited the lowest prevalence of industry financial relationships compared with otolaryngology (57.9 percent), orthopedics (62.4 percent), neurosurgery (87.8 percent), and urology (63.1 percent) (p < 0.001).
Approximately half of all plastic surgeons have industry financial relationships. The prevalence of these relationships is comparatively less than in other surgical subspecialties.
A clear disparity in the pattern and provision of surgical care exists, particularly for patients with vulnerable socioeconomic backgrounds. For hand-injured patients in particular, this discrepancy has been frequently shown in their receiving appropriate care. With the advent of the Affordable Care Act and with Medicaid expansion on the horizon, more patients will be requiring access to care. Safety net programs have been shown to provide equivalent levels of care for patients compared with non-safety net providers, and the survival of these hospitals for the disadvantaged is essential to providing quality care for this growing patient population. In this article, the authors review the factors that affect the barriers to care, the importance of safety net hospitals, the epidemiology of the hand-injured patient, and how the Affordable Care Act will impact these safety net programs.
Understanding the effects of resistance QTL on pathogen development cycle is an important issue for the creation of QTL combination strategies to durably increase disease resistance in plants. The oomycete pathogen Aphanomyces euteiches, causing root rot disease, is one of the major factors limiting the pea crop in the main producing countries. No commercial resistant varieties are currently available in Europe. Resistance alleles at seven main QTL were recently identified and introgressed into pea agronomic lines, resulting in the creation of Near Isogenic Lines (NILs) at the QTL. This study aimed to determine the effect of main A. euteiches resistance QTL in NILs on different steps of the pathogen life cycle.
NILs carrying resistance alleles at main QTL in susceptible genetic backgrounds were evaluated in a destructive test under controlled conditions. The development of root rot disease severity and pathogen DNA levels in the roots was measured during ten days after inoculation. Significant effects of several resistance alleles at the two major QTL Ae-Ps7.6 and Ae-Ps4.5 were observed on symptom appearance and root colonization by A. euteiches. Some resistance alleles at three other minor-effect QTL (Ae-Ps2.2, Ae-Ps3.1 and Ae-Ps5.1) significantly decreased root colonization. The combination of resistance alleles at two or three QTL including the major QTL Ae-Ps7.6 (Ae-Ps5.1/Ae-Ps7.6 or Ae-Ps2.2/Ae-Ps3.1/Ae-Ps7.6) had an increased effect on delaying symptom appearance and/or slowing down root colonization by A. euteiches and on plant resistance levels, compared to the effects of individual or no resistance alleles.
This study demonstrated the effects of single or multiple resistance QTL on delaying symptom appearance and/or slowing down colonization by A. euteiches in pea roots, using original plant material and a precise pathogen quantification method. Our findings suggest that single resistance QTL can act on multiple or specific steps of the disease development cycle and that their actions could be pyramided to increase partial resistance in future pea varieties. Further studies are needed to investigate QTL effects on different steps of the pathogen life cycle, as well as the efficiency and durability of pyramiding strategies using QTL which appear to act on the same stage of the pathogen cycle.
Frailty has been defined in different ways and several diagnostic tools exist, but most of them are not applicable in routine primary care. Nonetheless, general practitioners (GPs) have a natural advantage in identifying frailty, due to their continued access to patients, patient-centered approach and training. GPs have also an advantage in conducting population-based evaluation as consequence of their role of gatekeepers of the health care system. This paper aims to identify those socio-demographic and clinical profiles and the relative information sources that, from the GPs' perspective, act as frailty markers, not solely as a diagnosis of state but as the ability to identify a patient's trajectory, over time, through the aging process.
This study was performed as a survey within a population aged 75 and over, attending 148 GPs in Italy. A total of 23,996 patients were classified by GPs in distinct frailty status, without the use of a specific evaluation tool, but only referring to general indications. Co-morbidity was objectively assessed by a record-linkage with previous hospitalizations, in order to assess the occurrence of previous illnesses that could be associated with the likelihood of being identified as frails or at risk. The methodological approach is based on social network analysis (SNA), suited to explore relational aspects of complex phenomena.
Our findings reveal that GPs are able to perform low cost population-based evaluation, by exploiting the advantages of their approach to patients, combined with the information derived from their daily practice and from other sources currently available.
We believe that informative integration among different sources of available data can provide a comprehensive picture of the health state of patients in a shorter time and at lower cost. The identification of limited patient trajectories based on these observations can enable the development of critical biomarkers/diagnostics and prognostic indicators that will enhance patient care and potentially reduce inappropriate healthcare use. We also believe that network analysis is an extremely flexible research tool and a rich theoretical paradigm, and it may be used in the healthcare planning.
Competition-driven evolution of habitat isolation is an important mechanism of ecological speciation but empirical support for this process is often indirect. We examined how an on-going displacement of pied flycatchers from their preferred breeding habitat by collared flycatchers in a young secondary contact zone is associated with (a) access to an important food resource (caterpillar larvae), (b) immigration of pied flycatchers in relation to habitat quality, and (c) the risk of hybridization in relation to habitat quality. Over the past 12 years, the estimated access to caterpillar larvae biomass in the habitat surrounding the nests of pied flycatchers has decreased by a fifth due to shifted establishment possibilities, especially for immigrants. However, breeding in the high quality habitat has become associated with such a high risk of hybridization for pied flycatchers that overall selection
 currently favors pied flycatchers that were forced to immigrate into the poorer habitats (despite lower access to preferred food items). Our results show that competition-driven habitat segregation can lead to fast habitat isolation, which per se caused an opportunity for selection to act in favor of future "voluntarily" altered immigration patterns and possibly strengthened habitat isolation through reinforcement.
We report a mathematical model for ion transport and electrical impedance in zwitterionic hydrogels, which possess acidic and basic functional groups that carry a net charge at a pH not equal to the isoelectric point. Such hydrogels can act as an electro-mechanical interface between a relatively hard biosensor and soft tissue in the body. For this application, the electrical impedance of the hydrogel must be characterized to ensure that ion transport to the biosensor is not significantly hindered. The electrical impedance is the ratio of the applied voltage to the measured current. We consider a simple model system, wherein an oscillating voltage is applied across a hydrogel immersed in electrolyte and sandwiched between parallel, blocking electrodes. We employ the Poisson-Nernst-Planck (PNP) equations coupled with acid-base dissociation reactions for the charge on the hydrogel backbone to model the ionic transport across the hydrogel. The electrical impedance is calculated from the numerical solution to the PNP equations and subsequently analyzed via an equivalent circuit model to extract the hydrogel capacitance, resistance, and the capacitance of electrical double layers at the electrode-hydrogel interface. For example, we predict that an increase in pH from the isoelectric point, pH = 6.4 for a model PCBMA hydrogel, to pH = 8 reduces the resistance of the hydrogel by ∼40% and increases the double layer capacitance by ∼250% at an electrolyte concentration of 0.1 mM. The significant impact of charged hydrogel functional groups to the impedance is damped at higher electrolyte concentration.
Due to the extremely small dimensions and super high frequency of the rotor in a thermally driven rotary nanomotor made from carbon nanostructures, measuring the rotational frequency of the nanomotor is still an open issue. To this end, a measuring system is constructed in which a spring wing is connected with the rotor to provide collisions with a probe tip whose deflection reflects the rotational frequency of the rotor. The spring wing is formed by connecting an end-tube from a carbon nanotube and a graphene with differently hydrogenated surfaces. Due to the alternative hydrogenation of the two surfaces, the graphene shrinks like a spring. When the rotational frequency increases, the centrifugal force applied on the wing increases and then the spring is stretched (becoming longer). As the end-tube rotates with the rotor and reaches the probe tip, a collision occurs between the end-tube and the probe tip. After collision, the probe tip undergoes a variation of vertical deflection that can be measured through atomic force microscopy. The relation between the maximal deflection of the probe tip and the rotational frequency of the rotor is determined via numerical experiments. The effects of the configuration (namely hydrogenation and length) of graphene on the rotation of the rotor are investigated. The results provide some insight into the fabrication of nanomachines.
To assess the impact of a quality improvement collaborative on quality and efficiency of pediatric discharges.
This was a multicenter quality improvement collaborative including 11 tertiary-care freestanding children's hospitals in the United States, conducted between November 1, 2011 and October 31, 2012. Sites selected interventions from a change package developed by an expert panel. Multiple plan-do-study-act cycles were conducted on patient populations selected by each site. Data on discharge-related care failures, family readiness for discharge, and 72-hour and 30-day readmissions were reported monthly by each site. Surveys of each site were also conducted to evaluate the use of various change strategies.
Most sites addressed discharge planning, quality of discharge instructions, and providing postdischarge support by phone. There was a significant decrease in discharge-related care failures, from 34% in the first project quarter to 21% at the end of the collaborative (P < .05). There was also a significant improvement in family perception of readiness for discharge, from 85% of families reporting the highest rating to 91% (P < .05). There was no improvement in unplanned 72-hour (0.7% vs 1.1%, P = .29) and slight worsening of the 30-day readmission rate (4.5% vs 6.3%, P = .05).
Institutions that participated in the collaborative had lower rates of discharge-related care failures and improved family readiness for discharge. There was no significant improvement in unplanned readmissions. More studies are needed to evaluate which interventions are most effective and to assess feasibility in non-children's hospital settings.
This paper deals with the changes of turbidity that are generated in aqueous solutions of phenol when they are oxidized by using different Fenton technologies. Results revealed that if the Fenton reaction was promoted with UV light, the turbidity that was generated in the water doubled. Alternatively, the use of ultrasonic waves produced an increase in turbidity which initially proceeded slowly, reaching intensities eight times higher than in the conventional Fenton treatment. As well, the turbidity showed a high dependence on pH. It is therefore essential to control acidity throughout the reaction. The maximum turbidity was generated when operating at pH = 2.0, and it slowly decreased with increasing to a value of pH = 3.0, at which the turbidity was the lowest. This result was a consequence of the presence of ferric ions in solution. At pH values greater than 3.5, the turbidity increased almost linearly until at pH = 5.0 reached its maximum intensity. In this range, ferrous ions may generate an additional contribution of radicals that promote the degradation of the phenol species that produce turbidity. Turbidity was enhanced at ratios R = 4.0 mol H2O2/mol C6H6O. This value corresponds to the stoichiometric ratio that leads to the production of turbidity-precursor species. Therefore, muconic acid would be a species that generate high turbidity in solution according to its isomerism. Also, the results revealed that the turbidity is not a parameter to which species contribute additively since interactions may occur among species that would enhance their individual contributions to it. Analyzing the oxidation of phenol degradation intermediates, the results showed that meta-substituted compounds (resorcinol) generate high turbidity in the wastewater. The presence of polar molecules, such as muconic acid, would provide the structural features that are necessary for resorcinol to act as a clip between two carboxylic groups, thus establishing directional hydrogen bonds that would generate an adduct in the 2:2 ratio. In addition, some similarity is observed between the turbidity and the presence of dihydroxybenzoquinone. This molecule has a structure that could establish hydrogen bond links with the carboxylic groups in 1:2 ratio. Such supramolecular structures would possess high molecular weight and robustness that would hinder the passage of light through the water, generating high turbidity.
It has become necessary to re - examine the relevance of diagnostic laparoscopy in the two-stage approach to surgical management of symptomatic women with higher stage endometriosis following emerging evidence demonstrating acceptable diagnostic performance of alternative less invasive and less expensive imaging modalities. We highlight the relative merits of these presurgical diagnostic imaging modalities and propose strategies that address the challenge of transitioning to a new diagnostic paradigm in the management of symptomatic women with higher stage endometriosis.
A major challenge in treating acute asthma exacerbations is the need to open constricted airways rapidly enough to reestablish ventilation and allow delivery of conventional medication to diseased airways. The solution requires a new approach that considers both biophysical and pharmacological aspects of treatments used in acute asthma. The result of testing several formulations was S-1226: carbon dioxide-enriched air delivered in nebulized perflubron, a synthetic surfactant. These agents act synergistically to rapidly reopen closed airways within seconds. The bronchodilator effect is independent of β-adrenergic and cholinergic mediated-signaling pathways, offering a unique mechanism of action. S-1226 has a low toxicity profile and was effective in treating bronchoconstriction in animal models of asthma. The goal of the present study was to evaluate the safety and tolerability of S-1226 in healthy human subjects.
The phase I study was a single-center, randomized, double-blind, placebo-controlled, sequential, single-ascending-dose study conducted in Canada. Thirty-six subjects were distributed into three cohorts. Within each cohort, subjects were randomized to receive a single dose of S-1226 or a matching placebo administered over a 2-minute nebulization period. S-1226 was formulated with perflubron and 4 %, 8 %, or 12 % CO2. The dose of CO2 was sequentially escalated by cohort. The safety and tolerability of S-1226 were evaluated through assessment of adverse events, vital signs, 12-lead electrocardiograms, clinical laboratory parameters, and physical examinations.
S-1226 was safe and well tolerated at all three CO2 levels (4 %, 8 %, and 12 %). A total of 28 adverse events were reported, and all were judged mild in severity. Twenty-four adverse events occurred in the S-1226 cohort,
 of which five were considered remotely related and six possibly related to S-1226.
S-1226 is a novel drug being developed for the treatment of acute asthma exacerbations. It consists of CO2-enriched air and perflubron and has potential to offer rapid and potent bronchodilation. The results of the study indicate that S-1226 is safe and well tolerated. All adverse events were mild, reversible, and likely due to known side effects of CO2 inhalation.
ClinicalTrials.gov NCT02616770 . Registered on 25 November 2015.
The act of retrieving information modifies memory in critical ways. In particular, testing-effect studies have demonstrated that retrieval practice (compared to restudy or to no testing) benefits long-term retention and protects from retroactive interference. Although such testing effects have previously been demonstrated in both between- and within-subjects manipulations of retrieval practice, it is less clear whether one or the other testing format is most beneficial on a final test. In two paired-associate learning experiments conducted under typical testing-effect conditions, we manipulated restudy and test trials using either blocked or mixed practice conditions while equating other factors. Retrieval-practice and restudy trials were presented either separately in different blocks (blocked practice) or randomly intermixed (mixed practice). In Experiment 1, recall was assessed after short and long delay intervals; in Experiment 2, the final memory test occurred after a short delay, but with or without an interfering activity before the final test. In both experiments, typical testing effects emerged, and critically, they were found to be unaffected by practice format. These results support the conclusion that testing effects are robust and emerge to equal extents in both blocked and mixed designs. The generality of testing effects further encourages the application of retrieval practice as a memory enhancer in a variety of contexts, including education.
The effect of a flax straw extract on Al corrosion inhibition in a strong alkaline solution was studied by using electrochemical measurements, weight-loss analysis, SEM, and FTIR spectroscopy. Flax straw extract added (3 vol %) to the 5 m KOH solution to act as a mixed-type Al corrosion inhibitor. The electrochemistry of Al in the presence of a flax straw extract in the alkaline solution, the effect of the extract on the Al morphology and surface films formed, and the corrosion inhibition mechanism are discussed. Finally, the Al-air battery discharge capacity recorded from a cell that used the flax straw extract in the alkaline electrolyte is substantially higher than that with only a pure alkaline electrolyte. This improved sustainability of the Al anode is attributed to Al corrosion inhibition and, consequently, to hydrogen evolution suppression.
A 49-year-old woman with debilitating nystagmus and oscillopsia failed conservative therapy. A titanium T-plate was anchored to the lateral orbital rim and cantilevered into the orbit where it was secured to the inferior rectus muscle tendon with a suture. After the procedure was performed on both eyes, the patient had significant decreases in the amplitudes of her nystagmus and oscillopsia, thereby improving her daily function. She had sustained duration of effect through 7 years of follow up. This novel surgical technique holds promise in the treatment of acquired nystagmus and debilitating oscillopsia for which conventional therapy may be ineffective. The case report is in compliance with the Health Insurance Portability and Accountability Act.
For decades, Swedish dental professionals have collected clinical epidemiological data from the dental records. To supplement the epidemiology, Ostergötland County Council decided to examine patient perceptions of oral health: self-rated knowledge, self-perceived oral health, and opinions about oral health. The aim was to compare self-perceived oral health among 19-year-olds to determine differences between genders, various municipalities and between 2004 and 2011. This study analysed the responses from two cross-sectional surveys of the entire population of 19-year-olds in Ostergötland County, Sweden, performed in 2004 and 2011. Of the 2,413 (53%) (50% men, 50% women) 19-year-olds who responded to the questionnaire in 2004 and the 3,803 (67%) (50% men, 50% women) in 2011, most 19-year-olds (88.1% [2004] and 87.5 % [2011]) reported satisfaction with their oral health. Around half of the respondents rated their knowledge on periodontitis as low. Boys rated their knowledge about avoiding periodontitis higher than girls (p < 0.05 in 2004 and p < 0.001 in 2011). In 2004, 84.7% reported shooting pain. In 2011 that figure was 83.7%.The respondents expressed some uncertainty about the benefits of fluoride toothpaste (7.5% in 2004 and 9.3% in 2011), especially the boys (10.3% in 2004 and 10.5% in 2011). Girls reported both a higher social impact and greater concern about aesthetics related to their oral health. They also reported headache (27.5%) nearly twice as often as boys (14.2%) (p > 0.001). Responses between the municipalities did not differ, with the exception of items regarding periodontitis. Thus, this study found indications that perceptions of oral health and knowledge in Ostergötland County complied with Swedish Dental Act. The study also found patient perceptions of oral health among 19-year-olds to be good.
Pyrethroids are now the fourth most used group of insecticides worldwide. Employed in agriculture and in urban areas, they are detected in waterways at concentrations that are lethally and sublethally toxic to aquatic organisms. Highly lipophilic, pyrethroids accumulate in sediments and bioaccumulate in fishes. Additionally, these compounds are demonstrated to act as endocrine disrupting compounds (or EDCs) in mammals and fishes, and therefore interfere with endocrine signaling by blocking, mimicking, or synergizing endogenous hormones through direct receptor interactions, and indirectly via upstream signaling pathways. Pyrethroid metabolites have greater endocrine activity than their parent structures, and this activity is dependent on the enantiomer present, as some pyrethroids are chiral. Many EDCs studied thus far in fish have known estrogenic or antiestrogenic effects, and as such cause the inappropriate or altered expression of genes or proteins (i.e., Vtg-vitellogenin, Chg-choriogenin), often leading to physiological or reproductive effects. Additionally, these compounds can also interfere with other endocrine pathways and immune response. This review highlights studies that focus on the mechanisms of pyrethroid biotransformation and endocrine toxicity to fishes across a broad range of different pyrethroid types, and integrates literature on the in vitro and mammalian responses that inform these mechanisms.
Traditional therapeutics to treat bacterial infections have given rise to multi-drug resistant pathogens, which pose a major threat to human and animal health. In several pathogens, quorum sensing (QS)-a cell-cell communication system in bacteria-controls the expression of genes responsible for pathogenesis, thus representing a novel target in the fight against bacterial infections. Based on the structure of the autoinducers responsible for QS activity and other QS inhibitors, we hypothesize that β-keto esters with aryl functionality could possess anti-QS activity. A panel of nineteen β-keto ester analogs was tested for the inhibition of bioluminescence (a QS-controlled phenotype) in the marine pathogen Vibrio harveyi. Initial screening demonstrated the need of a phenyl ring at the C-3 position for antagonistic activity. Further additions to the phenyl ring with 4-substituted halo groups or a 3- or 4-substituted methoxy group resulted in the most active compounds with IC50 values ranging from 23 µM to 53 µM. The compounds additionally inhibit green fluorescent protein production by E. coli JB525. Evidence is presented that aryl β-keto esters may act as antagonists of bacterial quorum sensing by competing with N-acyl homoserine lactones for receptor binding. Expansion of the β-keto ester panel will enable us to obtain more insight into the structure-activity relationships needed to allow for the development of novel anti-virulence agents.
The characteristic feature of polarity establishment in MDCK II cells is transcytosis of apical glycoprotein podocalyxin (PCX) from the outer plasma membrane to the newly formed apical domain. This transcytotic event consists of multiple steps, including internalization from the plasma membrane, transport through early endosomes and Rab11-positive recycling endosomes, and delivery to the apical membrane. These steps are known to be tightly coordinated by Rab small GTPases, which act as molecular switches cycling between active GTP-bound and inactive GDP-bound states. However, our knowledge regarding which sets of Rabs regulate particular steps of PCX trafficking was rather limited. Recently, we have performed a comprehensive analysis of Rab GTPase engagement in the transcytotic pathway of PCX during polarity establishment in 2-dimensional (2D) and 3-dimensional (3D) MDCK II cell cultures. In this Commentary we summarize our findings and set them in the context of previous reports.
Glyphosate is the active ingredient of several herbicide formulations. Different reports suggest that glyphosate-based herbicides (GBHs) may act as endocrine disruptors. We evaluated the potential estrogenic effects of a GBH formulation using the uterotrophic assay. Adult ovariectomized rats were sc injected for 3 consecutive days with: saline solution (vehicle control), 2.10(-5)  g E2 /kg/day (uterotrophic dose; UE2 ), 2.10(-7)  g E2 /kg/day (nonuterotrophic dose; NUE2 ), or 0.5, 5, or 50 mg GBH/kg/day of the. Twenty-four hours after the
 last injection, the uterus was removed and weighed and processed for histopathology and mRNA extraction. Epithelial cell proliferation and height and expression of estrogen-responsive genes were evaluated (estrogen receptors, ERα and ERβ; progesterone receptor, PR; complement 3, C3). Uterine weight and epithelial proliferation were not affected by GBH. However, the luminal epithelial cell height increased at GBH0.5. ERα mRNA was downregulated by all GBH doses and E2 groups, whereas PR and C3 mRNA were diminished by GBH0.5. GBH5-, GBH50-, and UE2 -treated rats showed downregulated ERα protein expression in luminal epithelial cells, while the receptor was upregulated in the stroma. GBH upregulated ERβ (GBH0.5-50) and PR (GBH5) expressions in glandular epithelial cells, similar effect to that of NUE2 group. These results indicate that, although the uterine weight was not affected, GBH modulates the expression of estrogen-sensitive genes. © 2016 Wiley Periodicals, Inc. Environ Toxicol, 2016.
A key provision of the American Recovery and Reinvestment Act of 2009 mandated that electronic health records (EHR) be adopted in US healthcare organizations by 2015. The purpose of this study is to examine the communicative processes involved as healthcare workers implement an EHR and make changes, known as workarounds. Guided by theories in social influence, and diffusion of innovations, we conducted a survey of healthcare professionals using an EHR system in an organization. Our structural equation modeling (SEM) and multiple regression results reveal coworker communication, in the form of informal social support and feedback, play an important role in whether people engage in workarounds. Understanding this relationship is important because our study also demonstrates that workarounds predict healthcare employees' overall satisfaction with the EHR system. Specifically, workarounds are associated with higher perceptions of the EHR's relative advantage, higher perceptions of EHR implementation success, and lower levels of resistance to EHR change. This study offers a health communication contribution to the growing research on EHR systems and demonstrates the persuasive effects that coworkers have on new technology use in healthcare organizations.
Emerging evidence indicates that mitochondrial flashes (mitoflashes) are highly conserved elemental mitochondrial signaling events. However, which signal controls their ignition and how they are integrated with other mitochondrial signals and functions remain elusive. In this study, we aimed to further delineate the signal components of the mitoflash and determine the mitoflash trigger mechanism. Using multiple biosensors and chemical probes as well as label-free autofluorescence, we found that the mitoflash reflects chemical and electrical excitation at the single-organelle level, comprising bursting superoxide production, oxidative redox shift, and matrix alkalinization as well as transient membrane depolarization. Both electroneutral H(+)/K(+) or H(+)/Na(+) antiport and matrix proton uncaging elicited immediate and robust mitoflash responses over a broad dynamic range in cardiomyocytes and HeLa cells. However, charge-uncompensated proton transport, which depolarizes mitochondria, caused the opposite effect, and steady matrix acidification mildly inhibited mitoflashes. Based on a numerical simulation, we estimated a mean proton lifetime of 1.42 ns and diffusion distance of 2.06 nm in the matrix. We conclude that nanodomain protons act as a novel, to our knowledge, trigger of mitoflashes in energized mitochondria. This finding suggests that mitoflash genesis is functionally and mechanistically integrated with mitochondrial energy metabolism.
The cryptochrome/photolyase protein family possesses a conserved triad of tryptophans that may act as a molecular wire to transport electrons from the protein surface to the FAD cofactor for activation and/or signaling-state formation. Members from the animal (and animal-like) cryptochrome subclade use this process in a light-induced fashion in a number of exciting responses, such as the (re-)setting of circadian rhythms or magnetoreception; however, electron-transfer pathways have not been explored in detail yet. Therefore, we present an in-depth time-resolved optical and electron-paramagnetic resonance spectroscopic study of two cryptochromes from Chlamydomonas reinhardtii and Drosophila melanogaster. The results do not only reveal the existence of a fourth, more distant aromatic amino acid that serves as a terminal electron donor in both proteins, but also show that a tyrosine is able to fulfill this very role in Chlamydomonas reinhardtii cryptochrome. Additionally, exchange of the respective fourth aromatic amino acid to redox-inactive phenylalanines still leads to light-induced radical pair formation; however, the lifetimes of these species are drastically reduced from the ms- to the μs-range. The results presented in this study open up a new chapter, to our knowledge, in the diversity of electron-transfer pathways in cryptochromes. Moreover, they could explain unique functions of animal cryptochromes, in particular their potential roles in magnetoreception because magnetic-field effects of light-induced radical pairs strongly depend on distance and orientation parameters.
Lithium carbonate, a drug for the treatment of bipolar disorder, provides mood stability to mitigate recurrent episodes of mania and/or depression. Despite its long-term and widespread use, the mechanism by which lithium acts to elicit these psychological changes has remained unknown. Using nuclear magnetic resonance (NMR) methods, in this study we characterized the association of lithium with adenosine triphosphate (ATP) and identified a bimetallic (Mg·Li) ATP complex. Lithium's affinity to form this complex was found to be relatively high (Kd ∼1.6 mM) compared with other monovalent cations and relevant, considering lithium dosing and physiological concentrations of Mg(2+) and ATP. The ATP·Mg·Li complex reveals, for the first time, to the best of our knowledge, that lithium can associate with magnesium-bound phosphate sites and then act to modulate purine receptor activity in neuronal cells, suggesting a molecular mode for in vivo lithium action.
Despite improvements in the diagnosis and treatment of hepatocellular carcinoma (HCC), the prognosis is still poor. Pioneering work has demonstrated a potential role for tumour cell-derived exosomes (TEXs) in HCC. TEXs can mediate immune responses, antigen presentation and intracellular communication by serving as vehicles for the transfer of proteins, viruses, lipids and RNA between cells. An improved understanding of the roles played by exosomes could lead to a powerful new strategy for preventing and treating HCC. In this review, we summarise current understanding on the topic. The literature points to two faces of TEXs in HCC: 1) They can promote invasion, metastasis, immune evasion and modulation and 2) they can act as diagnostic and prognostic biomarkers, and can be used in anti-cancer drug resistance and immunotherapy in the future.
Mitochondria are semi-autonomous organelles of prokaryotic origin that are postulated to have been acquired by eukaryotic cells through an early endosymbiotic event. Except for their main role in energy production, they are also implicated in fundamental cellular processes, including ion homeostasis, lipid metabolism, and initiation of apoptotic cell death. Perturbed mitochondrial function has been correlated with severe human pathologies such as type-2 diabetes, cardiovascular, and neurodegenerative diseases. Thus, proper mitochondrial physiology is a prerequisite for health and survival. Cells have developed sophisticated and elaborate mechanisms to adapt to stress conditions and alterations in metabolic demands, by regulating mitochondrial number and function. Hence, the generation of new and the removal of damaged or unwanted mitochondria are highly regulated processes that need to be accurately coordinated for the maintenance of mitochondrial and cellular homeostasis. Here, we survey recent research findings that advance our understanding and highlight the importance of the underlying molecular mechanisms.
Loss of anchorage to the extracellular matrix leads to apoptosis (anoikis) in normal cells, but cancerous cells are usually resistant to such stress. Here we report the pivotal role of an E3 ubiquitin ligase, ring-finger protein 126 (RNF126), in the resistance of cancer cells to the stress associated with non-adherent conditions. Non-adherent cancer cells exhibited increased flux through the tricarboxylic acid cycle via increased conversion of pyruvate to acetyl-CoA. RNF126 was found to act as a ubiquitin ligase for pyruvate dehydrogenase kinases (PDKs), resulting in their proteasomal degradation. This decrease in PDK levels allowed pyruvate dehydrogenases to catalyze the conversion of pyruvate to acetyl-CoA. Moreover, depletion of RNF126 or increased expression of PDK1 in cancer cells suppressed colony formation in soft agar as well as tumorigenicity in mice. RNF126 expression in cancer cells was found to be under the control of the extracellular signal-regulated kinase signaling pathway, which is essential for anoikis resistance. Thus, RNF126 is an attractive molecule for treating cancer by selectively targeting anchorage-independent growth.
G protein-coupled receptors are allosteric proteins that control transmission of external signals to regulate cellular response. Although agonist binding promotes canonical G protein signalling transmitted through conformational changes, G protein-coupled receptors also interact with other proteins. These include other G protein-coupled receptors, other receptors and channels, regulatory proteins and receptor-modifying proteins, notably receptor
 activity-modifying proteins (RAMPs). RAMPs have at least 11 G protein-coupled receptor partners, including many class B G protein-coupled receptors. Prototypic is the calcitonin receptor, with altered ligand specificity when co-expressed with RAMPs. To gain molecular insight into the consequences of this protein-protein interaction, we combined molecular modelling with mutagenesis of the calcitonin receptor extracellular domain, assessed in ligand binding and functional assays. Although some calcitonin receptor residues are universally important for peptide interactions (calcitonin, amylin and calcitonin gene-related peptide) in calcitonin receptor alone or with receptor activity-modifying protein, others have RAMP-dependent effects, whereby mutations decreased amylin/calcitonin gene-related peptide potency substantially only when RAMP was present. Remarkably, the key residues were completely conserved between calcitonin receptor and AMY receptors, and between subtypes of AMY receptor that have different ligand preferences. Mutations at the interface between calcitonin receptor and RAMP affected ligand pharmacology in a RAMP-dependent manner, suggesting that RAMP may allosterically influence the calcitonin receptor conformation. Supporting this, molecular dynamics simulations suggested that the calcitonin receptor extracellular N-terminal domain is more flexible in the presence of receptor activity-modifying protein 1. Thus, RAMPs may act in an allosteric manner to generate a spectrum of unique calcitonin receptor conformational states, explaining the pharmacological preferences of calcitonin receptor-RAMP complexes. This provides novel insight into our understanding of G protein-coupled receptor-protein interaction that is likely broadly applicable for this receptor class.
The biogenesis of photosystem I (PSI), cytochrome b 6 f (Cytb 6 f) and NADH dehydrogenase (NDH) complexes relies on the spatially and temporally coordinated expression and translation of both nuclear and chloroplast genes. Here we report the identification of photosystem biogenesis regulator 1 (PBR1), a nuclear-encoded chloroplast RNA-binding protein that regulates the concerted biogenesis of NDH, PSI and Cytb 6 f complexes. We identified Ycf1, one of the two largest chloroplast genome-encoded open reading frames as the direct downstream target protein of PBR1. Biochemical and molecular analyses reveal that PBR1 regulates Ycf1 translation by directly binding to its mRNA. Surprisingly, we further demonstrate that relocation of the chloroplast gene Ycf1 fused with a plastid-transit sequence to the nucleus bypasses the requirement of PBR1 for Ycf1 translation, which sufficiently complements the defects in biogenesis of NDH, PSI and Cytb 6 f complexes in PBR1-deficient plants. Remarkably, the nuclear-encoded PBR1 tightly controls the expression of the chloroplast gene Ycf1 at the translational level, which is sufficient to sustain the coordinated biogenesis of NDH, PSI and Cytb 6 f complexes as a whole. Our findings provide deep insights into better understanding of how a predominant nuclear-encoded factor can act as a migratory mediator and undergoes selective translational regulation of the target plastid gene in controlling biogenesis of photosynthetic complexes.
Transient DNA strand break formation has been identified as an effective means to enhance gene expression in living cells. In the muscle lineage, cell differentiation is contingent upon the induction of caspase-mediated DNA strand breaks, which act to establish the terminal gene expression program. This coordinated DNA nicking is rapidly resolved, suggesting that myoblasts may deploy DNA repair machinery to stabilize the genome and entrench the differentiated phenotype. Here, we identify the base excision repair pathway component XRCC1 as an indispensable mediator of muscle differentiation. Caspase-triggered XRCC1 repair foci form rapidly within differentiating myonuclei, and then dissipate as the maturation program proceeds. Skeletal myoblast deletion of Xrcc1 does not have an impact on cell growth, yet leads to perinatal lethality, with sustained DNA damage and impaired myofiber development. Together, these results demonstrate that XRCC1 manages a temporally responsive DNA repair process to advance the muscle differentiation program.
Nitrilase1 was classified as a tumour suppressor in association with the fragile histidine-triad protein Fhit. However, knowledge about nitrilase1 and its tumour suppressor function is still limited. Whereas nitrilase1 and Fhit are discrete proteins in mammals, they are merged in Drosophila melanogaster and Caenorhabditis elegans. According to the Rosetta-Stone hypothesis, proteins encoded as fusion proteins in one organism and as separate proteins in another organism may act in the same signalling pathway. Although a direct interaction of human nitrilase1 and Fhit has not been shown, our previous finding that Fhit interacts with β-catenin and represses its transcriptional activity in the canonical Wnt pathway suggested that human nitrilase1 also modulates Wnt signalling. In fact, human nitrilase1 forms a complex with β-catenin and LEF-1/TCF-4, represses β-catenin-mediated transcription and shows an additive effect together with Fhit. Knockdown of human nitrilase1 enhances Wnt target gene expression. Moreover, our experiments show that β-catenin competes away human nitrilase1 from LEF-1/TCF and thereby contributes to the activation of Wnt-target gene transcription. Inhibitory activity of human nitrilase1 on vertebrate Wnt signalling was confirmed by repression of Wnt-induced double axis formation in Xenopus embryogenesis. In line with this finding, the Drosophila fusion protein Drosophila NitFhit directly binds to Armadillo and represses the Wingless pathway in reporter gene assays. Genetic experiments confirmed the repressive activity of Drosophila NitFhit on Wingless signalling in the Drosophila wing imaginal disc. In addition, colorectal tumour microarray analysis revealed a significantly reduced expression of human nitrilase1 in poorly differentiated tumours. Taken together, repression of the canonical Wnt pathway represents a new mechanism for the human nitrilase1 tumour suppressor function.
As major components of innate immunity, NK cells not only exert cell-mediated cytotoxicity to destroy tumors or infected cells, but also act to regulate the functions of other cells in the immune system by secreting cytokines and chemokines. Thus, NK cells provide surveillance in the early defense against viruses, intracellular bacteria, and cancer cells. However, the effecter function of NK cells must be exquisitely controlled to prevent inadvertent attack against normal "self" cells. In an organ such as the liver, where the distinction between immunotolerance and immune defense against routinely processed pathogens is critical, the plethora of NK cells has a unique role in the maintenance of homeostasis. Once self-tolerance is broken, autoimmune liver disease resulted. NK cells act as a "two-edged weapon" and even play opposite roles with both regulatory and inducer activities in the hepatic environment. That is, NK cells act not only to produce inflammatory cytokines and chemokines, but also to alter the proliferation and activation of associated lymphocytes. However, the precise regulatory mechanisms at work in autoimmune liver diseases remain to be identified. In this review, we focus on recent research with NK cells and their potential role in the development of autoimmune liver disease.
Clubroot, caused by the plasmodiophorid pathogen Plasmodiophora brassicae, is one of the most serious diseases on Brassica crops worldwide and a major threat to canola production in western Canada. Host resistance is the key strategy for clubroot management on canola. Several clubroot resistance (CR) genes have been identified, but the mechanisms associated with these CR genes are poorly understood. In the current study, a label-free shotgun proteomic approach was used to profile and compare the proteomes of Brassica rapa carrying and not carrying the CR gene Rcr1 in response to P. brassicae infection. A total of 527 differentially accumulated proteins (DAPs) were identified between the resistant (with Rcr1) and susceptible (without Rcr1) samples, and functional annotation of these DAPs indicates that the perception of P. brassicae and activation of defense responses are triggered via an unique signaling pathway distinct from common modes of recognition receptors reported with many other plant-pathogen interactions; this pathway appears to act in a calcium-independent manner through a not-well-defined cascade of mitogen-activated protein kinases and may require the ubiquitin-26S proteasome found to be related to abiotic stresses, especially the cold-stress tolerance in other studies. Both up-regulation of defense-related and down-regulation of pathogenicity-related metabolism was observed in plants carrying Rcr1, and these functions may all contribute to the CR mediated by Rcr1. These results, combined with those of transcriptomic analysis reported earlier, improved our understanding of molecular mechanisms associated with Rcr1 and CR at large, and identified candidate metabolites or pathways related to specific resistance mechanisms. Deploying CR genes with different modes of action may help improve the durability of CR.
Lactobacilli are probiotic commensal bacteria and potent modulators of immunity. When present in the gut or supplemented as probiotics, they beneficially modulate ex vivo immune responsiveness. Further, factors derived from several lactobacilli strains act immune regulatory in vitro. In contrast, Staphylococcus aureus (S. aureus) is known to induce excessive T cell activation. In this study, we aimed to investigate S. aureus-induced activation of human
 mucosal-associated invariant T cells (MAIT cells), γδ T cells, NK cells, as well as of conventional CD4(+) and CD8(+) T cells in vitro. Further, we investigated if lactobacilli-derived factors could modulate their activation. PBMC were cultured with S. aureus 161:2 cell-free supernatants (CFS), staphylococcal enterotoxin A or CD3/CD28-beads alone, or in combination with Lactobacillus rhamnosus GG-CFS or Lactobacillus reuteri DSM 17938-CFS and activation of T and NK cells was evaluated. S. aureus-CFS induced IFN-γ and CD107a expression as well as proliferation. Costimulation with lactobacilli-CFS dampened lymphocyte-activation in all cell types analyzed. Preincubation with lactobacilli-CFS was enough to reduce subsequent activation, and the absence of APC or APC-derived IL-10 did not prevent lactobacilli-mediated dampening. Finally, lactate selectively dampened activation of unconventional T cells and NK cells. In summary, we show that molecules present in the lactobacilli-CFS are able to directly dampen in vitro activation of conventional and unconventional T cells and of NK cells. This study provides novel insights on the immune-modulatory nature of probiotic lactobacilli and suggests a role for lactobacilli in the modulation of induced T and NK cell activation.
Running is not unique to humans, but it is seemingly a basic human capacity. This article addresses the evolutionary origins of humans running long distances, the basic physical capability of running, and the neurogenesis of aerobic fitness. This article more specifically speaks to the conditions that set the stage for the act of running, and then looks at brain expression, and longer-term consequences of running within a context of specific morphological features and diverse information molecules that participate in our capacity for running and sport. While causal factors are not known, we do know that physiological factors are involved in running and underlie neural function. Multiple themes about running are discussed in this article, including neurogenesis, neural plasticity, and memory enhancement. Aerobic exercise increases anterior hippocampus size. This expansion is linked to the improvement of memory, which reflects the improvement of learning as a function of running activity in animal studies. Higher fitness is associated with greater expansion, not only of the hippocampus, but of several other brain regions.
Hypothermia is a standard treatment for neonatal encephalopathy, but nearly 50% of treated infants have adverse outcomes. Pharmacological therapies can act through complementary mechanisms with hypothermia improving neuroprotection. Cannabidiol could be a good candidate. Our aim was to test whether immediate treatment with cannabidiol and hypothermia act through complementary brain pathways in hypoxic-ischemic newborn piglets. Hypoxic-ischemic animals were randomly divided into four groups receiving 30 min after the insult: (1) normothermia and vehicle administration; (2) normothermia and cannabidiol administration; (3) hypothermia and vehicle administration; and (4) hypothermia and cannabidiol administration. Six hours after treatment, brains were processed to quantify the number of damaged neurons by Nissl staining. Proton nuclear magnetic resonance spectra were obtained and analyzed for lactate, N-acetyl-aspartate and glutamate. Metabolite ratios were calculated to assess neuronal damage (lactate/N-acetyl-aspartate) and excitotoxicity (glutamate/Nacetyl-aspartate). Western blot studies were performed to quantify protein nitrosylation (oxidative stress), content of caspase-3 (apoptosis) and TNFα (inflammation). Individually, the hypothermia and the cannabidiol treatments reduced the glutamate/Nacetyl-aspartate ratio, as well as TNFα and oxidized protein levels in newborn piglets subjected to hypoxic-ischemic insult. Also, both therapies reduced the number of necrotic neurons and prevented an increase in lactate/N-acetyl-aspartate ratio. The combined effect of hypothermia and cannabidiol on excitotoxicity, inflammation and oxidative stress, and on cell damage, was greater than either hypothermia or cannabidiol alone. The present study demonstrated that cannabidiol and hypothermia act complementarily and show additive effects on the main factors leading to hypoxic-ischemic brain damage if applied shortly after the insult.
G protein-coupled receptor 56 (GPR56) is an adhesion G protein-coupled receptor with essential functions for cell physiology and survival, and its expression correlates with prognosis in a number of malignancies. The aim of this study is to determine the relationship of GPR56 expression with clinicopathological parameters and prognosis in non-small-cell lung carcinoma (NSCLC).
The levels of GPR56 were evaluated by immunohistochemistry in 157 NSCLC tissue samples. The association between GPR56 and clinicopathological parameters was evaluated by χ (2) test. Univariate and multivariate analyses were performed to demonstrate the prognosis role of GPR56. The function of GPR56 in NSCLC cell lines was also explored through overexpression and knockdown studies.
The expression level of GPR56 in tumor tissues was significantly correlated with the TNM stage of NSCLC (P=0.005). Univariate and multivariate analyses revealed that GPR56 can act as an independent prognostic factor for overall survival. Furthermore, through overexpression and knockdown experiments, we confirmed that GPR56 can promote the proliferation and invasion of NSCLC cells.
GPR56 plays an important role in tumor development and may serve as a promising target for prognostic prediction in NSCLC.
Severe chronic obstructive pulmonary disease (COPD) is often associated with secondary pulmonary hypertension (PH), which worsens prognosis. PH can be lowered by oxygen, but also by inhaled nitric oxide (NO), which has the potential to improve the health status of these patients. NO is an important mediator in vascular reactions in the pulmonary circulation. Oral compounds can act through NO-mediated pathways, but delivering pulsed inhaled NO (iNO) directly to the airways and pulmonary vasculature could equally benefit patients. Therefore, a proof-of-concept study was performed to quantify pulmonary blood vessel caliber changes after iNO administration using computed tomography (CT)-based functional respiratory imaging (FRI).
Six patients with secondary PH due to COPD received "pulsed" iNO in combination with oxygen for 20 minutes via a nasal cannula. Patients underwent a high-resolution CT scan with contrast before and after iNO. Using FRI, changes in volumes of blood vessels and associated lobes were quantified. Oxygen saturation and blood pressure were monitored and patients were asked about their subjective feelings.
Pulmonary blood vessel volume increased by 7.06%±5.37% after iNO. A strong correlation (Ω(2) 0=0.32, P=0.002) was obtained between ventilation and observed vasodilation, suggesting that using the pulsed system, iNO is directed toward the ventilated zones, which consequently experience more vasodilation. Patients did not develop oxygen desaturation, remained normotensive, and perceived an improvement in their dyspnea sensation.
Inhalation of pulsed NO with oxygen causes vasodilation in the pulmonary circulation of COPD patients, mainly in the well-ventilated areas. A high degree of heterogeneity was found in the level of vasodilation. Patients tend to feel better after the treatment. Chronic use trials are warranted.
Light chain (AL) amyloidosis is an incurable human disease characterized by the misfolding, aggregation, and systemic deposition of amyloid composed of immunoglobulin light chains (LC). This work describes our studies on potential mechanisms of AL cytotoxicity. We have studied the internalization of AL soluble proteins and amyloid fibrils into human AC16 cardiomyocytes by using real time live cell image analysis. Our results show how external amyloid aggregates rapidly surround the cells and act as a recruitment point for soluble protein, triggering the amyloid fibril elongation. Soluble protein and external aggregates are internalized into AC16 cells via macropinocytosis. AL amyloid fibrils are shown to be highly cytotoxic at low concentrations. Additionally, caspase assays revealed soluble protein induces apoptosis, demonstrating different cytotoxic mechanisms between soluble protein and amyloid aggregates. This study emphasizes the complex immunoglobulin light chain-cell interactions that result in fibril internalization, protein recruitment, and cytotoxicity that may occur in AL amyloidosis.
Our research sought to identify the barriers and facilitators experienced by policymakers and evaluation researchers in the critical early stages of establishing an evaluation of a policy or program. We sought to determine the immediate barriers experienced at the point of initiating or commissioning evaluations and how these relate to broader system factors previously identified in the literature. We undertook 17 semi-structured interviews with a purposive sample of senior policymakers (n=9) and senior evaluation researchers (n=8) in Australia. Six themes were consistently raised by participants: political influence, funding, timeframes, a 'culture of evaluation', caution over anticipated results, and skills of policy agency staff. Participants also reflected on the dynamics of policy-researcher relationships including different motivations, physical and conceptual separation of the policy and researcher worlds, intellectual property concerns, and trust. We found that political and system factors act as macro level barriers to good evaluation practice that are manifested as time and funding constraints and contribute to organisational cultures that can come to fear evaluation. These factors then fed into meso and micro level factors. The dynamics of policy-researcher
 relationship provide a further challenge to evaluating government policies and programs.
Due to the small skin depth in metals at optical frequencies, their plasmonic response is strongly dictated by their surface properties. Copper (Cu) is one of the standard materials of choice for plasmonic applications, because of its high conductivity and CMOS compatibility. However, being a chemically active material, it gets easily oxidized when left in ambient environment, causing an inevitable degradation in its plasmonic resonance. Here, for the first time, we report a strong enhancement in the optical relaxation time in Cu by direct growth of few-layer graphene that is shown to act as an excellent passivation layer protecting Cu surface from any deterioration. Spectroscopic ellipsometry measurements reveal a 40-50% reduction in the total scattering rate in Cu itself, which is attributed to an improvement in its surface properties. We also study the impact of graphene quality and show that high quality graphene leads to an even larger improvement in electron scattering rate. These findings are expected to provide a big push towards graphene-protected Cu plasmonics.
Protamine is used to neutralize heparin after patient separation from cardiopulmonary bypass (CPB). Different bedside tests are used to monitor the adequacy of heparin neutralization. For this study, the interchangeability of the activated coagulation time (ACT) and thromboelastometry (ROTEM; Tem Innovations GmbH, Basel, Switzerland) clotting time (CT) ratios in children undergoing cardiac surgery was assessed.
Single-center, retrospective, cohort study between September 2010 and January 2012.
University children's hospital.
The study comprised children 0 to 16 years old undergoing elective cardiac surgery with CPB. Exclusion criteria were preoperative coagulopathy, Jehovah's witnesses, and children in a moribund condition (American Society of Anesthesiologists score 5).
None.
After heparin neutralization with protamine, the ratio between ACT, with and without heparinase, and the CT measured with INTEM/HEPTEM (intrinsic test activated with ellagic acid was performed without heparinase [INTEM] and with heparinase [HEPTEM]) using tests of ROTEM were calculated. Agreement was evaluated using Cohen's kappa statistics, Passing-Bablok regression, and Bland-Altman analysis. Among the 173 patients included for analysis, agreement between both tests showed a Cohen's kappa statistic of 0.06 (95% CI: -0.02 to 0.14; p = 0.22). Bland-Altman analysis showed a bias of 0.01, with a standard deviation of 0.13, and limits of agreement between -0.24 and 0.26. Passing-Bablok regression showed a systematic difference of 0.40 (95% CI: 0.16-0.59) and a proportional difference of 0.61 (95% CI: 0.42-0.86). The residual standard deviation was 0.11 (95% CI: -0.22 to 0.22), and the test for linearity showed p = 0.10.
ACT, with or without heparinase, and the INTEM/HEPTEM CT ratios are not interchangeable to evaluate heparin reversal after pediatric patient separation from CPB. Therefore, the results of these tests should be corroborated with the absence/presence of bleeding and integrated into center-specific treatment algorithms.
Youth advocacy has been successfully used in substance use prevention but is a novel strategy in obesity prevention. As a precondition for building an evidence base for youth advocacy for obesity prevention, the present study aimed to develop and evaluate measures of youth advocacy mediator, process, and outcome variables.
The Youth Engagement and Action for Health (YEAH!) program (San Diego County, CA) engaged youth and adult group leaders in advocacy for school and neighborhood improvements to nutrition and physical activity environments. Based on a model of youth advocacy, scales were developed to assess mediators, intervention processes, and proximal outcomes of youth advocacy for obesity prevention. Youth (baseline n = 136) and adult group leaders (baseline n = 47) completed surveys before and after advocacy projects. With baseline data, we created youth advocacy and adult leadership subscales using confirmatory factor analysis (CFA) and described their psychometric properties.
Youth came from 21 groups, were ages 9-22, and most were female. Most youth were non-White, and the largest ethnic group was Hispanic/Latino (35.6%). The proposed factor structure held for most (14/20 youth and 1/2 adult) subscales. Modifications were necessary for 6 of the originally proposed 20 youth and 1 of the 2 adult multi-item subscales, which involved splitting larger subscales into two components and dropping low-performing items.
Internally consistent scales to assess mediators, intervention processes, and proximal outcomes of youth advocacy for obesity prevention were developed. The resulting scales can be used in future studies to evaluate youth advocacy programs.
Photoreceptor cell degeneration leads to visual impairment and blindness in several types of retinal disease. However, the discovery of safe and effective therapeutic strategies conferring photoreceptor cell protection remains challenging. Targeting distinct cellular pathways with low doses of different drugs that produce a functionally synergistic effect could provide a strategy for preventing or treating retinal dystrophies. We took a systems pharmacology approach to identify potential combination therapies using a mouse model of light-induced retinal degeneration. We showed that a combination of U.S. Food and Drug Administration-approved drugs that act on different G protein (heterotrimeric guanine nucleotide-binding protein)-coupled receptors (GPCRs) exhibited synergistic activity that protected retinas from light-induced degeneration even when each drug was administered at a low dose. In functional assays, the combined effects of these drugs were stimulation of Gi/o signaling by activating the dopamine receptors D2R and D4R, as well as inhibition of Gs and Gq signaling by antagonizing D1R and the α1A-adrenergic receptor ADRA1A, respectively. Moreover, transcriptome analyses demonstrated that such combined GPCR-targeted treatments preserved patterns of retinal gene expression that were more similar to those of the normal retina than did higher-dose monotherapy. Our study thus supports a systems pharmacology approach to identify treatments for retinopathies, an approach that could extend to other complex disorders.
Environmental factors can act as facilitators of chronic non-communicable diseases. Ambient noise and air pollution collectively outrank all other environmental risk factors in importance, contributing to over 75% of the disease and disability burden associated with known environmental risk factors. In the first part of this review, we discussed the global burden and epidemiologic evidence supporting the importance of these novel risk factors as facilitators of cardiometabolic disease. In this part, we will discuss pathophysiological mechanisms responsible for noise and air pollution-mediated effects. Akin to traditional cardiovascular risk factors, a considerable body of evidence suggests that these environmental agents induce low-grade inflammation, oxidative stress, vascular dysfunction, and autonomic nervous system imbalance, thereby facilitating the development of diseases such as hypertension and diabetes. Through their impact on traditional risk factors and via additional novel mechanisms, environmental risk factors may have much larger impact on cardiovascular events than currently appreciated. In the second part of this review, we discuss deficiencies and gaps in knowledge and opportunities for new research.
A novel approach for the rapid discrimination of bergamot essential oil from other citrus fruits oils is presented. The method was developed using paper spray mass spectrometry (PS-MS) allowing for a rapid molecular profiling coupled with a statistic tool for a precise and reliable discrimination between the bergamot complex matrix and other similar matrices, commonly used for its reconstitution. Ambient mass spectrometry possesses the ability to record mass spectra of ordinary samples, in their native environment, without sample preparation or pre-separation by creating ions outside the instrument. The present study reports a PS-MS method for the determination of oxygen heterocyclic compounds such as furocoumarins, psoralens and flavonoids present in the non-volatile fraction of citrus fruits essential oils followed by chemometric analysis. The volatile fraction of Bergamot is one of the most known and fashionable natural products, which found applications in flavoring industry as ingredient in beverages and flavored foodstuff. The development of the presented method employed bergamot, sweet orange, orange, cedar, grapefruit and mandarin essential oils. PS-MS measurements were carried out in full scan mode for a total run time of 2 min. The capability of PS-MS profiling to act as marker for the classification of bergamot essential oils was evaluated by using multivariate statistical analysis. Two pattern recognition techniques, linear discriminant analysis and soft independent modeling of class analogy, were applied to MS data. The cross-validation procedure has shown excellent results in terms of the prediction ability because both models have correctly classified all samples for each category. Copyright © 2016 John Wiley & Sons, Ltd.
Inflammasomes are macromolecular cytoplasmic complexes that act as signaling platforms for the activation of inflammatory caspases. Their activation triggers the processing and secretion of the pro-inflammatory cytokines IL-1β and IL-18, as well as the induction of a specialized form of inflammatory cell death termed pyroptosis. Here, we review the mechanisms of inflammasome activation triggered by the intracellular pathogen Salmonella enterica serovar
 Typhimurium. We highlight the different inflammasome subfamilies utilized by macrophages, neutrophils, dendritic cells, and intestinal epithelial cells response to a Salmonella infection as well as the Salmonella ligands that trigger each inflammasome's formation. We also discuss the evasion strategies utilized by Salmonella to avoid inflammasome detection. Overall, inflammasomes play a key and multilayered role at distinct stages of host cell defense against Salmonella infection.
The complementary actions of the innate and adaptive immune systems often provide effective host defense against microbial pathogens and harmful environmental agents. Germline-encoded pattern recognition receptors (PRRs) endow the innate immune system with the ability to detect and mount a rapid response against a given threat. Members of several intracellular PRR families, including the nucleotide-binding domain and leucine-rich repeat containing receptors (NLRs), the AIM2-like receptors (ALRs), and the tripartite motif-containing (TRIM) protein Pyrin/TRIM20, nucleate the formation of inflammasomes. These cytosolic scaffolds serve to recruit and oligomerize the cysteine protease caspase-1 in filaments that promote its proximity-induced autoactivation. This oligomerization occurs either directly or indirectly through intervention of the bipartite adaptor protein ASC, apoptosis-associated speck-like protein containing a caspase recruitment domain (CARD), which is needed for the domain interaction. Caspase-1 cleaves the precursors of the inflammatory cytokines interleukin (IL)-1β and IL-18 and triggers their release into the extracellular space, where they act on effector cells to promote both local and systemic immune responses. Additionally, inflammasome activation gives rise to a lytic mode of cell death, named pyroptosis, which is thought to contribute to initial host defense against infection by eliminating replication niches of intracellular pathogens and exposing them to the immune system. Inflammasome-induced host defense responses are the subject of intense investigation, and understanding their physiological roles during infection and the regulatory circuits that are involved is becoming increasingly detailed. Here, we discuss current understanding of the activation mechanisms and biological outcomes of inflammasome activation.
Hybrid vigour (heterosis) has been used for decades in crop industries, especially in the production of maize and rice. Hybrid varieties usually exceed their parents in plant biomass and seed yield. But the molecular basis of hybrid vigour is not fully understood. In this project, we studied heterosis at early stages of seedling development in Arabidopsis hybrids derived from crossing Ler and C24 accessions. We found that early heterosis is associated with non-additive gene expression that resulted from earlier changes in gene expression in the hybrids relative to the parents. The non-additively expressed genes are involved in metabolic pathways, including photosynthesis, critical for plant growth. The early increased expression levels of genes involved in energy production in hybrids is associated with heterosis in the young seedlings that could be essential for biomass heterosis at later developmental stages of the plant.
A novel series of compounds obtained by fusing the acetylcholinesterase (AChE) inhibitor donepezil and the antioxidant melatonin were designed as multi-target-directed ligands for the treatment of Alzheimer's disease (AD). In vitro assay indicated that most of the target compounds exhibited a significant ability to inhibit acetylcholinesterase (eeAChE and hAChE), butyrylcholinesterase (eqBuChE and hBuChE), and β-amyloid (Aβ) aggregation, and to act as potential antioxidants and biometal chelators. Especially, 4u displayed a good inhibition of AChE (IC50 value of 193nM for eeAChE and 273nM for hAChE), strong inhibition of BuChE (IC50 value of 73nM for eqBuChE and 56nM for hBuChE), moderate inhibition of Aβ aggregation (56.3% at 20μM) and good antioxidant activity (3.28trolox equivalent by ORAC assay). Molecular modeling studies in combination with kinetic analysis revealed that 4u was a mixed-type inhibitor, binding simultaneously to catalytic anionic site (CAS) and the peripheral anionic site (PAS) of AChE. In addition, 4u could chelate metal ions, reduce PC12 cells death induced by oxidative stress and penetrate the blood-brain barrier (BBB). Taken together, these results strongly indicated the hybridization approach is an efficient strategy to identify novel scaffolds with desired bioactivities, and further optimization of 4u may be helpful to develop more potent lead compound for AD treatment.
India has high rates of mental health issues among its youth and low-income communities experience a disproportionate amount of depression and suicide. Positive psychology, the act of promoting well-being, could be used as a tool to promote wellness and help improve the mental health of youth living in slum areas of India. A pilot positively psychology program, "The Hero Lab", was conducted in a migratory slum in Worli, Mumbai, with trained Hindu community leaders implementing the interventions toward at-risk Hindu youth. The curriculum's impact showed statistical improvement (p < 0.001) in happiness (General Happiness Scale from 11.24 ± 1.56 to 19.08 ± 3.32), grit (Grit Survey from 2.23 ± 0.34 to 3.24 ± 0.67), empathy (Toronto Empathy Questionnaire from 24.92 ± 3.27 to 41.96 ± 8.41), and gratitude (Gratitude Survey from 16.88 ± 3.47 to 27.98 ± 6.59). While a pilot study, the Hero Lab curriculum demonstrates that positive psychology interventions may be an important tool in improving mental health in at-risk children.
E2F transcription factors have been studied extensively in a broad range of organisms as major regulators of cell cycle, apoptosis, and differentiation. The E2F family includes the atypical member E2F7, which has been rarely studied in gliomas. The aim of this study is to determine the expression status of E2F7 in gliomas, its relationship to clinicopathological features, and patients' outcome. The mRNA levels of E2F7 in the human brain and different grades of gliomas were analysed using datasets from the publically available Oncomine database. One of the most significant co-expression factors, CDK1, together with E2F7, was further validated by immunohistochemistry in 90 different grades of gliomas. Furthermore, univariate and multivariate analyses were performed to identify prognostic variables relative to patient and tumour characteristics and treatment modalities. E2F7 mRNA expression was found to be elevated in gliomas by Oncomine-database analysis. Immunohistochemistry showed an increase in E2F7 labelling index in high- versus low-grade gliomas (62.1±11.8% vs. 18.9±10.2%, p<0.0001). There was a positive correlation between E2F7 and CDK1 immunoreactivity (Spearman r=0.446, p=0.037). Clinicopathological evaluation suggested that E2F7 expression was associated with tumour grade (p<0.0001) and recurrence (p=0.025). In Cox multivariate analysis, pathological classification and recurrence were independent prognostic factors of gliomas, and E2F7 was significantly related to progression-free survival (p=0.011), but not overall survival (p=0.062). Our findings suggested that E2F7 might act as an independent prognostic factor of gliomas and might constitute a potential therapeutic target for this disease.
Breakthrough therapy designation (BTD) is a new approach created by the US Congress and the US Food and Drug Administration (FDA) as part of the FDA Innovation and Safety Act of 2012 to expedite the drug development process for serious illness, including cancer. By law, to qualify for BTD, a new molecular entity must demonstrate substantial clinical improvement over existing therapies. Although the administrative requirements for granting BTD have been made available by the FDA, the actual trial designs, end points, and quantitative therapeutic thresholds involved in the granting process have not been made public. This literature review evaluates nine oncology new molecular entities granted BTD involved in 10 accelerated approvals and summarizes the key factors in clinical trial design leading to successful BTD applications. This information can be used by oncology research teams to set goals for BTD when developing clinical trial designs and thresholds in expedited drug development programs.
Introgressive hybridization represents one of the long-lasting debated genetic consequences of species range expansion. Mitochondrial DNA has been shown to heavily introgress between interbreeding animal species that meet in new sympatric areas and, often, asymmetric introgression from local to the colonizing populations has been observed. Disentangling among the evolutionary and ecological processes that might shape this pattern remains difficult, because they continuously act across time and space. In this context, long-term studies can be of paramount importance. Here, we investigated the dynamics of mitochondrial introgression between two mosquito species (Aedes mariae and Ae. zammitii ) during a colonization event that started in 1986 after a translocation experiment. By analyzing 1,659 individuals across 25 years, we showed that introgression occurred earlier and at a higher frequency in the introduced than in the local species, showing a pattern of asymmetric introgression. Throughout time, introgression increased slowly in the local species, becoming reciprocal at most sites. The rare opportunity to investigate the pattern of introgression across time during a range expansion along with the characteristics of our study-system allowed us to support a role of demographic dynamics in determining the observed introgression pattern.
Microenvironment is being increasingly recognized as a critical
 determinant in tumor progression and metastasis. However, the appropriate regulatory mechanism to maintain the normal balance between differentiation and self-renewal of the cancer cell in microenvironment is not well known.
4T1 breast cancer cells were treated with embryonic stem (ES) cell conditioned medium which was collected from mouse ES cells. Inhibition of tumor cell growth was based on the reduction of cell proliferation and viability, and inhibition of aggressive properties of tumor cells were examined using the wound-healing and mammosphere assays. The expression of stem cell-associated genes was detected by quantitative RT-PCR.
We used a real-time imaging system to investigate the effect of the mouse ES cell microenvironment on aggressive breast cancer cells in vitro and in vivo. Exposure of breast cancer cells in mouse ES cell conditioned medium resulted in inhibition of growth, migration, metastasis, and angiogenesis of cancer cells. For many tumors, aggressive properties were tightly related to Stat3 signaling activation. We specifically discovered that the ES cell microenvironment sufficiently suppressed Stat3 signaling pathway activation in aggressive tumor cells, leading to a reduction in tumorigenesis and invasiveness.
We identified important functions of Stat3 and their implications for antitumor effects of ES cell conditioned medium. Some factors secreted by ES cells could efficiently suppress Stat3 pathway activation in breast cancer cells, and were then involved in cancer cell growth, survival, invasion, and migration. This study may act as a platform to understand tumor cell plasticity and may offer new therapeutic strategies to inhibit breast cancer progression.
Each year, 1-4 % of people with known gallstones become symptomatic, either presenting with biliary colic or as acute cholecystitis. The distinction between both diagnoses remains challenging. To aid the proper diagnosis, the revised 2013 Tokyo Guidelines (TG 2013) were proposed with a self-acclaimed diagnostic accuracy of over 90 %. However, this accuracy has not been verified by others so far.
To determine the accuracy of the TG 2013 guidelines in the diagnosis of acute cholecystitis both in its single components of fever, inflammatory markers and US features and of the combined application of the TG 2013 guidelines as a whole.
A 5-year retrospective analysis equal to the TG 2013 validation process of all emergency cholecystectomies for acute cholecystitis or persistent biliary pain with an ultrasound performed during the same admission. Acute cholecystitis at histology was the golden standard.
Inclusion criteria were met by 169 patients with a prevalence of acute cholecystitis of 52.7 %. The individual features of fever, gallbladder wall thickening and probe tenderness were not significant in univariate analysis. In multivariate analysis only, neutrophil count was an independent predictor. The combined application of the TG 2013 guidelines led to a better sensitivity of 83.1 % at the cost a reduced specificity of 37.5 % compared to neutrophil count alone. The accuracy was therefore only 60.3 %, which was well below the TG 2013 report.
The 2013 Tokyo Guidelines were slightly better in predicting acute cholecystitis but over diagnosed two-thirds of normal gallbladders compared to neutrophil count alone.
Liposarcoma(LPS) is the most common type of soft tissue sarcoma accounting for 20 % of all adult sarcomas. However, the molecular pathogenesis of this malignancy is still poorly understood. Here, we showed that GPS2 expression was downregulated in LPS and correlated with the prognosis of this disease. In vitro study showed that knockdown of GPS2 resulted in enhanced proliferation and migration of LPS cell line SW872, without significant influence of cell death. Conclusively, our results suggest that GPS2 may act as a tumor suppressor in LPS and serve as a potential prognosis marker for this disease.
Gastric cancer (GC) is one of the most aggressive malignancies and has a poor prognosis. Identifying novel diagnostic and prognostic markers is of great importance for the management and treatment of GC. Long non-coding RNAs (lncRNAs), which are involved in multiple processes during the development and progression of cancer, may act as potential biomarkers of GC. Here, by performing data mining using four microarray data sets of GC downloaded from the Gene Expression Omnibus (GEO) database with different classifiers and risk score analyses, we identified a five-lncRNA signature (AK001094, AK024171, AK093735, BC003519 and NR_003573) displaying both diagnostic and prognostic values for GC. The results of the Kaplan-Meier survival analysis and log-rank test showed that the risk score based on this five-lncRNA signature was closely associated with overall survival time (p = 0.0001). Further analysis revealed that the risk score is an independent predictor of prognosis. Quantitative reverse transcription polymerase chain reaction (qRT-PCR) analysis of 30 pairs of GC tissue samples confirmed that the five lncRNAs were dysregulated in GC, and receiver operating characteristic (ROC) curves showed the high diagnostic ability of combining the five lncRNAs, with an area under the curve (AUC) of 0.95 ± 0.025. The five lncRNAs involved in several cancer-related pathways were identified using gene set enrichment analysis (GSEA). These findings indicate that the five-lncRNA signature may have a good clinical applicability for determining the diagnosis and predicting the prognosis of GC.
Remote ischemic preconditioning (RIPC) is an intriguing process whereby transient regional ischemia and reperfusion episodes to remote tissues including skeletal, renal, mesenteric provide protection to the heart against sustained ischemia-reperfusion-induced injury. Clinically, this technique has been used in patients undergoing various surgical interventions including coronary artery bypass graft surgery, abdominal aortic aneurysm repair, percutaneous coronary intervention, and heart valve surgery. The endogenous opioid system is extensively expressed in the brain to modulate pain sensation. Besides the role of opioids in relieving pain, numerous researchers have found their critical involvement in evoking cardioprotective effects. Endogenous opioids including endorphins, enkephalins, and dynorphins are released during RIPC and are critically involved in mediating RIPC-induced cardioprotective effects. It has been suggested that during RIPC, the endogenous opioids may be released into the systemic circulation and may travel via bloodstream that act on the myocardial opioid receptors to induce cardioprotection. The present review describes the potential role of opioids in mediating RIPC-induced cardioprotection.
Based on research carried out over the last decade, it has become increasingly evident that bile acids act not only as detergents, but also as important signaling molecules that exert various biological effects via activation of specific nuclear receptors and cell signaling pathways. Bile acids also regulate the expression of numerous genes encoding enzymes and proteins involved in the synthesis and metabolism of bile acids, glucose, fatty acids, and lipoproteins, as well as energy metabolism. Receptors activated by bile acids include, farnesoid X receptor α, pregnane X receptor, vitamin D receptor, and G protein-coupled receptors, TGR5, muscarinic receptor 2, and sphingosine-1-phosphate receptor (S1PR)2. The ligand of S1PR2, sphingosine-1-phosphate (S1P), is a bioactive lipid mediator that regulates various physiological and pathophysiological cellular processes. We have recently reported that conjugated bile acids, via S1PR2, activate and upregulate nuclear sphingosine kinase 2, increase nuclear S1P, and induce genes encoding enzymes and transporters involved in lipid and sterol metabolism in the liver. Here, we discuss the role of bile acids and S1P signaling in the regulation of hepatic lipid metabolism and in hepatobiliary diseases.
To investigate the inhibitory effects of single and compound phenolic acids on mixed algae.
Salicylic acid, cinnamic acid and pyrogallic acid were chosen individually or in pairs to act on mixed algae of Microcystis aeruginosa and Chlorella pyrenoidosa.
Three phenolic acids that singled or paired showed certain inhibitory effects on the mixed algae, of which were pyrogallic acid > salicylic acid > cinnamic acid in single phenolic acid, the EC50s of the three phenolic acids on the mixture of Microcystis aeruginosa and Chlorella pyrenoidosa were 7.87, 64.90 and 89.34 mg/L at the day 6; and inhibition of the paired phenolic acid group was pyrogallic acid & salicylic acid group > pyrogallic acid & cinnamic acid group > salicylic acid & cinnamic acid, the first 2 groups had synergistic algal inhibitory effects and the last paired group showed additive action.
Some specifically combined phenolic acids can lead to synergistic inhibiting effects on algae, which has better environmental safety for application due to the use of single phenolic acid was massively decreased.
Issue: Nearly 12.7 million individuals signed up for coverage in the Affordable Care Act's (ACA) health insurance marketplaces during the third open enrollment period, and by the end of March there were 11.1 million consumers with active coverage. States that operate their own marketplaces posted a year-to-year enrollment gain of 8.8 percent. To maintain membership and attract new consumers, the state-based marketplaces must sponsor enrollment assistance programs and conduct consumer outreach. These marketplaces relied heavily on such efforts during the third enrollment period, despite declining funding. Goal: To learn which outreach strategies, assistance programs, and other factors marketplace officials viewed as having exerted the greatest influence on enrollment.
 Methods: Survey of officials representing each of the 17 state-based marketplaces (15 responses). Key findings and conclusions: The cost of coverage and low health insurance literacy pose significant barriers to enrollment for many consumers. Marketplaces sought to overcome them by encouraging consumers to obtain in-person enrollment assistance from ACA-created assistance programs and from insurance brokers, and by partnering with community organizations for outreach activities. Many marketplaces also enhanced their web portals to make them easier to navigate and to give consumers better tools with which to evaluate their coverage options.
Starting in 2014, the Affordable Care Act transformed the market for individual health insurance by changing how insurance is sold and by subsidizing coverage for millions of new purchasers. Insurers, who had no previous experience under these market conditions, competed actively but faced uncertainty in how to price their products. This issue brief uses newly available data to understand how health insurers fared financially during the ACA's first year of full reforms. Overall, health insurers' financial performance began to show some strain in 2014, but the ACA's reinsurance program substantially buffered the negative effects for most insurers. Although a quarter of insurers did substantially worse than others, experience under the new market rules could improve the accuracy of pricing decisions in subsequent years.
High altitude exposure can increase resting metabolic rate (RMR) and induce weight loss in obese populations, but there is a lack of research regarding RMR in athletes at moderate elevations common to endurance training camps. The present study aimed to determine whether four weeks of classical altitude training affects RMR in middle-distance runners. Ten highly-trained athletes were recruited for four weeks of endurance training undertaking identical programs at either 2200m in Flagstaff, Arizona (ALT, n=5) or 600m in Canberra, Australia (CON, n=5). RMR, anthropometry, energy intake, and haemoglobin mass (Hbmass) were assessed pre- and post-training. Weekly run distance during the training block was: ALT 96.8±18.3km; CON 103.1±5.6km. A significant interaction for Time*Group was observed for absolute (kJ.day(-1)) (F-statistic, p-value: F(1,8)=13.890, p=0.01) and relative RMR (F(1,8)=653.453, p=0.003) POST-training. No significant changes in anthropometry were observed in either group. Energy intake was unchanged (ALT: 195±3921kJ, p=0.25; CON: 836±7535kJ, p=0.75). A significant main effect for time was demonstrated for total Hbmass (g) (F(1,8)=13.380, p=0.01), but no significant interactions were observed for either variable [Total Hbmass (g): F(1,8)=1.706, p=0.23; Relative Hbmass (g.kg(-1)): F(1,8)=0.609, p=0.46]. These novel findings have important practical application to endurance athletes routinely training at moderate altitude, and those seeking to optimize energy management without compromising training adaptation. Altitude exposure may increase RMR and enhance training adaptation,. During training camps at moderate altitude, an increased energy intake is likely required to support an increased RMR and provide sufficient energy for training and performance.
An organocatalytic asymmetric reaction between 5H-oxazol-4-ones and N-substituted maleimides is disclosed. Employing Takemoto's chiral tertiary amine-thiourea as the catalyst, [4 + 2] annulation reactions were performed with high chemoselectivity, leading to a series of biologically important chiral oxo-bridged piperidone-fused succinimides in good to excellent enantioselectivities (up to >99% ee) and >19:1 dr.
This study describes a new approach in the screening for loss-of-gene mutants in Heavy Ion Bombardment (HIB) mutant populations of genetically complex organisms such as hexaploid bread wheat using multiplexed single-color (SYBR Green) melt curve analyses. The assay was set up for three target genes to test its validity and applicability. For each gene, three genome-specific primer pairs (one for each genome) with distinct melt curves were developed and multiplexed. This allowed screening for "single null mutants" (plants with the target gene deleted in one of the three genomes) for all three genomes in a single reaction. The first two genes (α-Amylase 3 and Epsilon Cyclase) were used to test the approach as HIB null lines for all three genomes were already available for these. The third assay was successfully applied to identify new single null lines of the target gene α-Amylase 2 in an in-house HIB wheat collection. The use of SYBR Green greatly reduced the time and/or cost investment compared to other techniques and the approach proved highly suitable for high-throughput applications.
Multidrug resistance is a hurdle to successful cancer chemotherapy. Over expression of P-glycoprotein (P-gp) is a prime contributing factor for drug resistance. In this study, a disulphide cross-linked pullulan-based cationic polymer (PPSS) was synthesized to act simultaneously as gene delivery vehicle and efflux pump inhibitor. The PPSS nanoplexes were of size <200nm with the zeta potential of +15 to +20mV. The cytotoxicity studies using C6 and L929 cells showed that PPSS polymers are non-toxic even at high polymer concentrations. The PPSS/pDNA nanoplex showed superior uptake in confocal microscopy with 97% uptake by flow cytometry. The efficacy of efflux pump inhibition by the PPSS nanoplex was established by the enhanced intracellular retention of DOX. The enhanced cell death by p53/PPSS/DOX nanoplexes was attributed to the synergistic effect of P-gp inhibition and p53 transfection efficiency. Therefore, this multifunctional polymeric system may have significant promise for therapeutic application against cancer drug resistance.
Under the Physician Payments Sunshine Act, "payments or transfers of value" by biomedical companies to physicians must be disclosed through the Open Payments Program. Designed to provide transparency of financial transactions between medication and device manufacturers and health care providers, the Open Payments Program shows financial relationships between industry and health care providers. Awareness of this program is crucial because its interpretation or misinterpretation by patients, physicians, and the general public can affect patient care, clinical practice, and research. This study evaluated nonresearch payments by industry to orthopedic surgeons. A retrospective cross-sectional review of the first wave of Physician Payments Sunshine Act data (August through December 2013) was performed to characterize industry payments to orthopedic surgeons by subspecialty, amount, type, origin, and geographic distribution. During this 5-month period, orthopedic surgeons (n=14,828) received $107,666,826, which included 3% of those listed in the Open Payments Program and 23% of the total amount paid. Of orthopedic surgeons who received payment, 45% received less than $100 and 1% received $100,000 or more. Median payment (interquartile range) was $119 ($34-$636), and mean payment was $7261±95,887. The largest payment to an individual orthopedic surgeon was $7,849,711. The 2 largest payment categories were royalty or license fees (68%) and consulting fees (13%). During the study period, orthopedic surgeons had substantial financial ties to industry. Of orthopedic surgeons who received payments, the largest proportion (45%) received less than $100 and only 1% received large payments (≥$100,000). The Open Payments Program offers insight into industry payments to orthopedic surgeons. [Orthopedics. 2016; 39(6):e1058-e1062.].
Microglia, immune cells of the brain, originate from erythromyeloid precursors, far from the central nervous system. Xu et al. (2016) in this issue of Developmental Cell and Casano et al. (2016) recently in Cell Reports show that apoptotic neurons act as bait to "trap" microglia into colonizing the developing brain.
There are several case reports of quinine-induced thrombocytopenia but no clinical trials to ascertain its incidence and significance in severe malaria.
The primary objective was to assess the effect of quinine on the platelet count in children with severe malaria and to compare it with artesunate combination therapy (ACT), and the secondary objective was to assess outcome of treatment with quinine and ACT.
An open-labelled, randomised, controlled trial was undertaken in 100 children aged 6 months to 12 years who were diagnosed with malaria by microscopy and/or rapid diagnostic test kits with at least one WHO clinical or laboratory criterion for severe malaria. All subjects were commenced on either quinine or ACT. Clindamycin was added to artesunate as a combination drug (ACT). It was also given to patients on quinine to avoid its confounding effect on the results. Platelet counts were undertaken every 24 hours for 7 consecutive days, temperature and coma score (Blantyre coma score ≥3 in children <4 years or Glasgow coma score ≥13 in children >4 years) was recorded 6-hourly and peripheral smears were taken 12-hourly until two consecutively negative smears were obtained. The primary outcome was a fall in the platelet count by ≥20% from the time of drug initiation until day 7. The secondary outcome was comparison of the efficacy, parasite clearance time, fever clearance time, coma recovery time and adverse effects of quinine vs ACT.
30.4% patients in the quinine group (n = 48) had ≥20% fall in platelet count and 10.8% of patients in the ACT group (n = 46) (P = 0.02). Despite the fall in platelet count, there was no bleeding. The efficacy of ACT was significantly better than quinine but the other treatment outcomes showed insignificant difference.
Quinine should be used with caution in patients with severe malaria because of the potential risk of quinine-induced thrombocytopenia.
Pleural
 lavage cytology (PLC) is considered as a possible tool for assessing prognosis of lung cancer patients. We aimed to comprehensively review the prognosis value of PLC in patients undergoing surgical resection.
We searched 4 electronic databases for relevant studies comparing positive PLC and negative PLC. The primary outcomes included survival rate and recurrence rate at maximum follow-up.
The meta-analysis included 28 studies, with a total of 20,714 patients. For the overall survival rate of all stages, the results demonstrated that positive pre-resection, post-resection and pooled PLC were associated with unfavorable survival: hazard ratio (HR) 2.89 (95% confidence interval [CI] 2.48-3.37), 2.70 (1.90-3.83), and 2.89 (2.52-3.31), respectively. For the stage I survival rate, the combined results also suggested that positive pre-resection, post-resection and pooled PLC were associated with unfavorable survival: HR 3.29 (95% CI 2.55-4.25), 4.85 (2.31-10.20), and 3.16 (2.53-3.94), respectively. Furthermore, a meta-analysis of 14 studies included 14,279 patients showed that positive pre-resection, post-resection and pooled PLC were associated with an increased risk of overall recurrence: risk ratio (RR) 2.45 (95% CI 1.91-3.15), 2.37 (1.11-5.09), and 2.37 (95% CI 2.00-2.80), respectively. Positive PLC was also associated with a high pleural recurrence (RR 4.77; 95% CI 3.13-7.26) or distant recurrence (RR 2.33; 95% CI 1.65-3.29).
Both positive pre- resection and post-resection PLC are associated with not only higher tumor recurrence but also unfavorable survival outcomes in patients with lung cancer resection. This technique can therefore act as a strong prognostic factor for tumor recurrence and adverse survival rates.
The gut microbiota is a complex consortium of microorganisms with the ability to influence important aspects of host health and development. Harnessing this "microbial organ" for biomedical applications requires clarifying the degree to which host and bacterial factors act alone or in combination to govern the stability of specific lineages. To address this issue, we combined bacteriological manipulation and light sheet fluorescence microscopy to monitor the dynamics of a defined two-species microbiota within a vertebrate gut. We observed that the interplay between each population and the gut environment produces distinct spatiotemporal patterns. As a consequence, one species dominates while the other experiences sudden drops in abundance that are well fit by a stochastic mathematical model. Modeling revealed that direct bacterial competition could only partially explain the observed phenomena, suggesting that a host factor is also important in shaping the community. We hypothesized the host determinant to be gut motility, and tested this mechanism by measuring colonization in hosts with enteric nervous system dysfunction due to a mutation in the ret locus, which in humans is associated with the intestinal motility disorder known as Hirschsprung disease. In mutant hosts we found reduced gut motility and, confirming our hypothesis, robust coexistence of both bacterial species. This study provides evidence that host-mediated spatial structuring and stochastic perturbation of communities can drive bacterial population dynamics within the gut, and it reveals a new facet of the intestinal host-microbe interface by demonstrating the capacity of the enteric nervous system to influence the microbiota. Ultimately, these findings suggest that therapeutic strategies targeting the intestinal ecosystem should consider the dynamic physical nature of the gut environment.
An efficient method for synthesizing arylated heteroaromatics has been reported via Pd-catalyzed ligand-free cross-coupling of N-heteroaromatic bromides with iodine(III) reagents under mild conditions. Iodobenzene diacetate, iodosobenzene, and diphenyliodonium salts act as ideal arylated sources in this reaction, producing bioactive aromatic-substituted pyridines and quinolines in moderate to high yields.
The precautionary principle (PP) has been used in the evaluation of the effectiveness and/or cost-effectiveness of interventions designed to prevent future harms in a range of activities, particularly in the area of the environment. Here, we provide details of circumstances under which the PP can be applied to the topic of harm reduction in Public Health. The definition of PP that we use says that the PP reverses the onus of proof of effectiveness between an intervention and its comparator when the intervention has been designed to reduce harm. We first describe the two frameworks used for health-care evaluation: evidence-based medicine (EBM) and decision theory (DT). EBM is usually used in treatment effectiveness evaluation, while either EBM or DT may be used in evaluating the effectiveness of the prevention of illness. For cost-effectiveness, DT is always used. The expectation in Public Health is that interventions employed to reduce harm will not actually increase harm, where "harm" in this context does not include opportunity cost. That implies that an intervention's effectiveness can often be assumed. Attention should therefore focus on its cost-effectiveness. This view is consistent with the conclusions of DT. It is also very close to the PP notion of reversing the onus of proof, but is not consistent with EBM as normally practiced, where the onus is on showing a new practice to be superior to usual practice with a sufficiently high degree of certainty. Under our definitions, we show that where DT and the PP differ in their evaluation is in cost-effectiveness, but only for decisions that involve potential catastrophic circumstances, where the nation-state will act as if it is risk-averse. In those cases, it is likely that the state will pay more, and possibly much more, than DT would allow, in an attempt to mitigate impending disaster. That is, the rules that until now have governed all cost-effectiveness analyses are shown not to apply to catastrophic situations, where the PP applies.
This review revises the reclassification of the membranoproliferative glomerulonephritis (MPGN) after the consensus conference that by 2015 reclassified all the glomerulonephritis basing on etiology and pathogenesis, instead of the histomorphological aspects. After reclassification, two types of MPGN are to date recognized: The immunocomplexes mediated MPGN and the complement mediated MPGN. The latter type is more extensively described in the review either because several of these entities are completely new or because the improved knowledge of the complement cascade allowed for new diagnostic and therapeutic approaches. Overall the complement mediated MPGN are related to acquired or genetic cause. The presence of circulating auto antibodies is the principal acquired cause. Genetic wide association studies and family studies allowed to recognize genetic mutations of different types as causes of the complement dysregulation. The complement cascade is a complex phenomenon and activating factors and regulating factors should be distinguished. Genetic mutations causing abnormalities either in activating or in regulating factors have been described. The diagnosis of the complement mediated MPGN requires a complete study of all these different complement factors. As a consequence, new therapeutic approaches are becoming available. Indeed, in addition to a nonspecific treatment and to the immunosuppression that has the aim to block the auto antibodies production, the specific inhibition of complement activation is relatively new and may act either blocking the C5 convertase or the C3 convertase. The drugs acting on C3 convertase are still in different phases of clinical development and might represent drugs for the future. Overall the authors consider that one of the principal problems in finding new types of drugs are both the rarity of the disease and the consequent poor interest in the marketing and the lack of large international cooperative studies.
Improved survival of human immunodeficiency virus (HIV) infected patients with chronic kidney disease following the introduction of antiretroviral therapy resulted in the need to revisit the topic of kidney transplantation in these patients. Large cohort studies have demonstrated favorable outcomes and proved that transplantation is a viable therapeutic option. However, HIV-infected recipients had higher rates of rejection. Immunosuppressive therapy did not negatively impact the course of HIV infection. Some of the immunosuppressive drugs used following transplantation exhibit antiretroviral effects. A close collaboration between infectious disease specialists and transplant professionals is mandatory in order to optimize transplantation outcomes in these patients. Transplantation from HIV(+) donors to HIV(+) recipients has been a subject of intense debate. The HIV Organ Policy Equity act provided a platform to research this area further and to develop guidelines. The first HIV(+) to HIV(+) kidney transplant in the United States and the first HIV(+) to HIV(+) liver transplant in the world were recently performed at the Johns Hopkins University Medical Center.
Epigenetic processes act as a link between environment and individual development. This pilot study examined the association between socioeconomic status (SES), attachment, and methylation of the promoter region of the serotonin transporter gene (SLC6A4).
Attachment classification and SLC6A4 methylation was determined in 100 late adolescents. We hypothesized that (1) SES would interact with methylation to predict higher unresolved loss (UL) or trauma scores on the Adult Attachment Interview; (2) across SES, participants with unresolved attachment would have lower levels of methylation than organized or secure participants; and (3) within the unresolved classification,
 SES would predict methylation.
Results showed that lower methylation and low-SES were associated with higher UL, and higher methylation and low-SES were associated with higher unresolved trauma. Across SES, unresolved participants had lower levels of methylation than organized participants. Within the unresolved category, low-SES unresolved participants had higher levels of methylation than mid/upper-SES participants. SES was unrelated to methylation within the secure and organized categories.
These results suggest that the quality of attachment relationships may impact epigenetic processes.
Cytochrome P450 monooxygenases (CYP450s) are known to play important roles in biosynthesis of all secondary metabolites, including flavonoids. Despite this, few CYP450s have been functionally characterized in model plants and roles of fewer CYP450s are known in non-model, medicinal, and aromatic plants. Our study in Coleus forskohlii indicates that flavone synthase (CYP93B) and flavonoid 3' monooxygenase (CYP706C) are key enzymes positioned at a metabolic junction, to execute the biosynthesis of different sub-classes of flavonoids (flavones, flavonol, anthocynanin, isoflavones etc.) from a common precursor. Such branch points are favored targets for artificially modulating the metabolic flux toward specific metabolites, through genetic manipulation or use of elicitors that differentially impact the expression of branch point genes. Genkwanin, the only flavone reported from C. forskohlii, is known to possess anti-inflammatory activity. It is biosynthesized from the general flavonoid precursor: naringenin. Two differentially expressed cytochrome P450 genes (CfCYP93B, CfCYP706C), exhibiting maximum expression in leaf tissues, were isolated from C. forskohlii. Mannitol treatment resulted in increased expression of CfCYP93B and decrease in expression of CfCYP706C. Metabolite quantification data showed that genkwanin content increased and anthocyanin levels decreased in response to mannitol treatment. Alignment, phylogenetic analysis, modeling, and molecular docking analysis of protein sequences suggested that CfCYP93B may be involved in conversion of naringenin to flavones (possibly genkwanin via apigenin), while CfCYP706C may act on common precursors of flavonoid metabolism and channel the substrate toward production of flavonols or anthocynanins. Decrease in expression of CfCYP706C and increase in accumulation of genkwanin suggested that mannitol treatment may possibly lead to accumulation of genkwanin via suppression of a competitive branch of flavonoids in C. forskohlii.
Bacillus cereus displays a high diversity of lifestyles and ecological niches and include beneficial as well as pathogenic strains. These strains are widespread in the environment, are found on inert as well as on living surfaces and contaminate persistently the production lines of the food industry. Biofilms are suspected to play a key role in this ubiquitous distribution and in this persistency. Indeed, B. cereus produces a variety of biofilms which differ in their architecture and mechanism of formation, possibly reflecting an adaptation to various environments. Depending on the strain, B. cereus has the ability to grow as immersed or floating biofilms, and to secrete within the biofilm a vast array of metabolites, surfactants, bacteriocins, enzymes, and toxins, all compounds susceptible to act on the biofilm itself and/or on its environment. Within the biofilm, B. cereus exists in different physiological states and is able to generate highly resistant and adhesive spores, which themselves will increase the resistance of the bacterium to antimicrobials or to cleaning procedures. Current researches show that, despite similarities with the regulation processes and effector molecules involved in the initiation and maturation of the extensively studied Bacillus subtilis biofilm, important differences exists between the two species. The present review summarizes the up to date knowledge on biofilms produced by B. cereus and by two closely related pathogens, Bacillus thuringiensis and Bacillus anthracis. Economic issues caused by B. cereus biofilms and management strategies implemented to control these biofilms are included in this review, which also discuss the ecological and functional roles of biofilms in the lifecycle of these bacterial species and explore future developments in this important research area.
The Mississippi River (MR) serves as the primary source of freshwater and nutrients to the northern Gulf of Mexico (nGOM). Whether this input of freshwater also enriches microbial diversity as the MR plume migrates and mixes with the nGOM serves as the central question addressed herein. Specifically, in this study physicochemical properties and planktonic microbial community composition and diversity was determined using iTag sequencing of 16S rRNA genes in 23 samples collected along a salinity (and nutrient) gradient from the mouth of the MR, in the MR plume, in the canyon, at the Deepwater Horizon wellhead and out to the loop current. Analysis of these datasets revealed that the MR influenced microbial diversity as far offshore as the Deepwater Horizon wellhead. The MR had the highest microbial diversity, which decreased with increasing salinity. MR bacterioplankton communities were distinct compared to the nGOM, particularly in the surface where Actinobacteria and Proteobacteria dominated, while the deeper MR was also enriched in Thaumarchaeota. Statistical analyses revealed that nutrients input by the MR, along with salinity and depth, were the primary drivers in structuring the microbial communities. These results suggested that the reduced salinity, nutrient enriched MR plume could act as a seed bank for microbial diversity as it mixes with the nGOM. Whether introduced microorganisms are active at higher salinities than freshwater would determine if this seed bank for microbial diversity is ecologically significant. Alternatively, microorganisms that are physiologically restricted to freshwater habitats that are entrained in the plume could be used as tracers for freshwater input to the marine environment.
To study the spatiotemporal dynamics of neural activity in a cortical population, we implanted a 10 × 10 microelectrode array in the vibrissal cortex of urethane-anesthetized rats. We recorded spontaneous neuronal activity as well as activity evoked in response to sustained and brief sensory stimulation. To quantify the temporal dynamics of activity, we computed the probability distribution function (PDF) of spiking on one electrode given the observation of a spike on another. The spike-triggered PDFs quantified the strength, temporal delay, and temporal precision of correlated activity across electrodes. Nearby cells showed higher levels of correlation at short delays, whereas distant cells showed lower levels of correlation, which tended to occur at longer delays. We found that functional space built based on the strength of pairwise correlations predicted the anatomical arrangement of electrodes. Moreover, the correlation profile of electrode pairs during spontaneous activity predicted the "signal" and "noise" correlations during sensory stimulation. Finally, mutual information analyses revealed that neurons with stronger correlations to the network during spontaneous activity, conveyed higher information about the sensory stimuli in their evoked response. Given the 400-μm-distance between adjacent electrodes, our functional quantifications unravel the spatiotemporal dynamics of activity among nearby and distant cortical columns.
As the precursor of vitellin (Vn), vitellogenin (Vg) has initially been considered as a female-specific protein involved in vitellogenesis, while it was also present in males induced by hormones or organs manipulation. Distinct from vtg1 we previously found in female mud crab Scylla paramamosain, vtg2 was intriguingly detected in male testis under normal physiological conditions in this study. Sequence analysis showed that vtg2 and vtg1 were actually two isoforms of Vg caused by different types of alternative splicing. PCR and in situ hybridization analysis revealed that vtg2 was localized only in the testicular spermatozoa, while Vn was detected in both the spermatozoa of the testis and seminal vesicle. Therefore, we speculated that Vn was initially translated in testicular spermatozoa, then migrated with spermatozoa, and finally stored in the seminal vesicle, where spermatozoa gradually accomplished maturation. We presumed that vtg2/Vn might act as an immune-relevant molecule in the male reproduction system. In the subsequent experiment, the expression of vtg2/Vn in testis was significantly induced in response to lipopolysaccharide (LPS) and lipoteichoic acid (LTA) injection at both transcriptional and translational levels. In the light of the results presented above, we deemed that vtg2/Vn is a novel candidate of immune-relevant molecules involved in immunoprotection during the spermatozoon maturation, and this research helps to open a new avenue for further exploring the role of Vg.
Hematite and goethite are the two most abundant iron oxides in natural environments. Their formation is controlled by multiple environmental factors; therefore, their relative concentration has been used widely to indicate climatic variations. In this study, we aimed to test whether hematite and goethite growth is influenced by ambient magnetic fields of Earth-like values. Ferrihydrite was aged at 95 °C in magnetic fields ranging from ~0 to ~100 μT. Our results indicate a large influence of the applied magnetic field on hematite and goethite growth from ferrihydrite. The synthesized products are a mixture of hematite and goethite for field intensities <~60 μT. Higher fields favour hematite formation by accelerating ferrimagnetic ferrihydrite
 aggregation. Additionally, hematite particles growing in a controlled magnetic field of ~100 μT appear to be arranged in chains, which may be reduced to magnetite keeping its original configuration, therefore, the presence of magnetic particles in chains in natural sediments cannot be used as an exclusive indicator of biogenic magnetite. Hematite vs. goethite formation in our experiments is influenced by field intensity values within the range of geomagnetic field variability. Thus, geomagnetic field intensity could be a source of variation when using iron (oxyhydr-)oxide concentrations in environmental magnetism.
The MYD88(L265P) mutation is found in 2% to 10% of chronic lymphocytic leukemia, 29% of activated B-cell type diffuse large B-cell lymphoma and 90% of Waldenström macroglobulinemia, making it conceptually attractive to treat these malignancies with inhibitors of endosomal Toll-like receptors (TLR9, TLR7) that activate MYD88. Here we show that genetic inhibition of endosomal TLRs has the opposite effect on accumulation of MYD88(L265P) B cells in vitro and in vivo. Activated mature B cells from wild-type, Unc93b1(3d/3d)-mutant, or Tlr9-deficient mice were transduced with retrovirus encoding MYD88(L265P) and analyzed either in vitro or after transplantation into Rag1(-/-) recipient mice. Unc93b1(3d/3d) mutation, which blocks TLR9 and TLR7 signaling, or Tlr9 deficiency suppressed MYD88(L265P) B-cell growth in vitro but paradoxically increased in vivo accumulation of MYD88(L265P) B cells as CD19(low) plasmablasts by 10- to 100-fold. These results reveal an unexpected, powerful inhibitory effect of TLR9 on MYD88(L265P) B-cell proliferation and differentiation that appears independent of TLR7, and they provide a preclinical indicator for caution in clinical trials of TLR7/9 inhibitors for MYD88(L265P) B-cell malignancies.
ABI3, originally discovered as a seed-specific transcription factor is now implicated to act beyond seed physiology, especially during abiotic stress. In non-seed plants, ABI3 is known to act in desiccation stress signaling. Here we show that ABI3 plays a role in dehydration stress response in Arabidopsis. ABI3 gene was upregulated during dehydration stress and its expression was maintained during subsequent stress recovery phases. Comparative gene expression studies in response to dehydration stress and stress recovery were done with genes which had potential ABI3 binding sites in their upstream regulatory regions. Such studies showed that several genes including known seed-specific factors like CRUCIFERIN1, CRUCIFERIN3 and LEA-group of genes like LEA76, LEA6, DEHYDRIN LEA and LEA-LIKE got upregulated in an ABI3-dependent manner, especially during the stress recovery phase. ABI3 got recruited to regions upstream to the transcription start site of these genes during dehydration stress response through direct or indirect DNA binding. Interestingly, ABI3 also binds to its own promoter region during such stress signaling. Nucleosomes covering potential ABI3 binding sites in the upstream sequences of the above-mentioned genes alter positions, and show increased H3 K9 acetylation during stress-induced transcription. ABI3 thus mediates dehydration stress signaling in Arabidopsis through regulation of a group of genes that play a role primarily during stress recovery phase.
Plutella xylostella L. is a notorious pest of cruciferous crops causing worldwide losses of $4-5 billion per year. Developing classical biological control to this pest include an introduction of host plants that act as natural enemies showing deviation from the preference-performance regimen in the evolutionary ecology of plant-insect interactions. The present study was designed to understand the role of glucosinolate-myrosinase system during P. xylostella interactions with a novel host. Adult moth preference and larval performance study were conducted on a novel host Lepidium latifolium L. (LL) that has high sinigrin content and was compared with its laboratory host Arabidopsis thaliana (AT). The glucosinolate-myrosinase system was studied in a time course experiment during larval feeding in choice and no-choice experiments. Adult moths visit and prefers LL over AT for oviposition. Conversely, LL leaves were not preferred and proved detrimental for P. xylostella larvae. Aliphatic and indolic glucosinolates were found to decrease significantly (p≤0.05) in AT during initial 12h of P. xylostella challenge, whereas, they were not affected in LL. Also, MYB transcription factor expression and myrosinase activity in LL do not suggest a typical host response to a specialist insect. This preference-performance mismatch of P. xylostella on LL mediated by glucosinolate pattern suggests that this novel plant could be utilized in P. xylostella management.
Social and political tensions keep on fueling armed conflicts around the world. Although each conflict is the result of an individual context-specific mixture of interconnected factors, ethnicity appears to play a prominent and almost ubiquitous role in many of them. This overall state of affairs is likely to be exacerbated by anthropogenic climate change and in particular climate-related natural disasters. Ethnic divides might serve as predetermined conflict lines in case of rapidly emerging societal tensions arising from disruptive events like natural disasters. Here, we hypothesize that climate-related disaster occurrence enhances armed-conflict outbreak risk in ethnically fractionalized countries. Using event coincidence analysis, we test this hypothesis based on data on armed-conflict outbreaks and climate-related natural disasters for the period 1980-2010. Globally, we find a coincidence rate of 9% regarding armed-conflict outbreak and disaster occurrence such as heat waves or droughts. Our analysis also reveals that, during the period in question, about 23% of conflict outbreaks in ethnically highly fractionalized countries robustly coincide with climatic calamities. Although we do not report evidence that climate-related disasters act as direct triggers of armed conflicts, the disruptive nature of these events seems to play out in ethnically fractionalized societies in a particularly tragic way. This observation has important implications for future security policies as several of the world's most conflict-prone regions, including North and Central Africa as well as Central Asia, are both exceptionally vulnerable to anthropogenic climate change and characterized by deep ethnic divides.
Attention-deficit hyperactivity disorder (ADHD) is a prevalent and highly heritable disorder of childhood with negative lifetime outcomes. Although candidate gene and genome-wide association studies have identified promising common variant signals, these explain only a fraction of the heritability of ADHD. The observation that rare structural variants confer substantial risk to psychiatric disorders suggests that rare variants might explain a portion of the missing heritability for ADHD. Here we believe we performed the first large-scale next-generation targeted sequencing study of ADHD in 152 child and adolescent cases and 188 controls across an a priori set of 117 genes. A multi-marker gene-level analysis of rare (<1% frequency) single-nucleotide variants (SNVs) revealed that the gene encoding brain-derived neurotrophic factor (BDNF) was associated with ADHD at Bonferroni corrected levels. Sanger sequencing confirmed the existence of all novel rare BDNF variants. Our results implicate BDNF as a genetic risk factor for ADHD, potentially by virtue of its critical role in neurodevelopment and synaptic plasticity.Molecular Psychiatry advance online publication, 26 July 2016; doi:10.1038/mp.2016.117.
Melatonin, a lipophilic molecule that is mainly synthesized in the pineal gland, performs various neuroprotective functions. However, the detailed role and mechanisms of promoting neuronal differentiation remains limited. This study demonstrated that 10 μM melatonin led to significant increases in the proliferation and neurite outgrowth of PC12 cells. Increased expression of microtubule-associated protein 2 (MAP2, a neuron-specific protein) was also observed. However, luzindole (melatonin receptor antagonist) and PD98059 (MEK inhibitor) attenuated these increases. LY294002 (AKT inhibitor) inhibited melatonin-mediated proliferation in PC12 cells and did not affect melatonin-induced neural differentiation. The expression of p-ERK1/2/ERK1/2 was increased by melatonin treatment for 14 days in PC12 cells, whereas luzindole or PD98059 reduced the melatonin-induced increase. These results suggest that the activation of both the MEK/ERK and PI3K/AKT signaling pathways could potentially contribute to melatonin-mediated proliferation, but that only the MEK/ERK pathway participates in the melatonin-induced neural differentiation of PC12 cells. Altogether, our study demonstrates for the first time that melatonin may exert a positive effect on neural differentiation via melatonin receptor signalling and that the MEK/ERK1/2 signalling may act down stream from the melatonin pathway.
Tobacco retail sales are prohibited within 100 m of schools in many large cities in China. However, little is known about the enforcement of this zoning regulation. The objectives of this study were to estimate tobacco retailers' compliance with the regulation, examine the density of tobacco retail stores, describe the types of tobacco products sold in stores and how they are marketed, and determine if there are displays of warning messages in retail stores around schools and in neighbourhoods in Changsha, China.
Tobacco retail stores located within 200 m of 36 schools and 36 residential neighbourhoods were audited by trained students with a validated audit form.
On average, there were about 3 tobacco retail stores within 100 m of the front entrance
 of schools. The density of the stores and the types of tobacco products sold in the stores were similar near schools and in neighbourhoods. Over one-fourth of the stores had exterior tobacco advertisements. Interior advertising was slightly less prevalent, and it was most prevalent among tobacco shops (62.5%). Tobacco displays that target children were pervasive, with about 83% of tobacco retail stores displaying cigarettes within 1 m of the floor and 59% displaying cigarettes within 0.3 m of toys and candy. About 40% of stores within 100 m of a school had a visible retail licence. Only 19.6% of the stores had a 'smoke-free' sign and 22.2% had a 'no sales to minors' sign.
We observed low enforcement of the regulation that bans tobacco retail sales near schools and high prevalence of tobacco displays that target children in Changsha, China. Chinese officials should act to effectively enforce the regulation bans of tobacco sales near schools. In addition, regulations are urgently needed to limit tobacco marketing practices at the point of sale, especially those targeting youth.
To examine the functional connectivity of the primary and supplementary motor areas (SMA) in glioma patients using resting-state functional MRI (rfMRI). To correlate rfMRI data with tumor characteristics and clinical information to characterize functional reorganization of resting-state networks (RSN) and the limitations of this method. This study was IRB approved and in compliance with Health Insurance Portability and Accountability Act. Informed consent was waived in this retrospective study. We analyzed rfMRI in 24 glioma patients and 12 age- and sex-matched controls. We compared global activation, interhemispheric connectivity, and functional connectivity in the hand motor RSNs using hemispheric voxel counts, pairwise Pearson correlation, and pairwise total spectral coherence. We explored the relationship between tumor grade, volume, location, and the patient's clinical status to functional connectivity. Global network activation and interhemispheric connectivity were reduced in gliomas (p < 0.05). Functional connectivity between the bilateral motor cortices and the SMA was reduced in gliomas (p < 0.01). High-grade gliomas had lower functional connectivity than low-grade gliomas (p < 0.05). Tumor volume and distance to ipsilateral motor cortex demonstrated no association with functional connectivity loss. Functional connectivity loss is associated with motor deficits in low-grade gliomas, but not in high-grade gliomas. Global reduction in resting-state connectivity in areas distal to tumor suggests that radiological tumor boundaries underestimate areas affected by glioma. Association between motor deficits and rfMRI suggests that rfMRI may accurately reflect functional changes in low-grade gliomas. Lack of association between rfMRI and clinical motor deficits implies decreased sensitivity of rfMRI in high-grade gliomas, possibly due to neurovascular uncoupling.
Soil salinity is becoming an increasingly large problem in agriculture. In this study, we have investigated whether a capacity to withstand salinity can be induced in the salinity sensitive plant species Arabidopsis thaliana, and whether it can be maintained in subsequent generations. To this end, we have used zinc finger artificial transcription factor (ZF-ATFs) mediated genome interrogation. Already within a relatively small collection Arabidopsis lines expressing ZF-ATFs, we found 41 lines that were tolerant to 100 mM NaCl. Furthermore, ZF-ATF encoding gene constructs rescued from the most strongly salinity tolerant lines were indeed found to act as dominant and heritable agents for salinity tolerance. Altogether, our data provide evidence that a silent capacity to withstand normally lethal levels of salinity exists in Arabidopsis and can be evoked relatively easily by in trans acting transcription factors like ZF-ATFs.
Previous studies indicate that Internet searching was a major source of information for the public during the launch of the Affordable Care Act, but little is known about geographic variation in searching. Our objective was to examine factors associated with health insurance-related Google searches in 199 U.S. metro areas during the first open enrollment period (October 2013 through March 2014), by merging data from Google Trends with metro-area-level and state-level characteristics. Our results indicate substantial geographic variation in the volumes of searching across the United States, and these patterns were related to local uninsurance rates. Specifically, areas with higher uninsurance rates were more likely to search in higher volumes for "Obamacare" and "health insurance," after adjusting for sociodemographic, political, and insurance market characteristics. The enormous political, advocacy, and media attention to the Affordable Care Act's launch may have contributed to heightened Internet search activity, particularly in areas characterized by higher uninsurance.
Trends in malpractice awards and adverse actions (e.g., revocation of provider license) following an act or omission constituting medical error or negligence were examined. The National Practitioner Data Bank was used to compare rates of malpractice reports and adverse actions for physicians, physician assistants (PAs), and nurse practitioners (NPs). During 2005 through 2014, there ranged from 11.2 to 19.0 malpractice payment reports per 1,000 physicians, 1.4 to 2.4 per 1,000 PAs, and 1.1 to 1.4 per 1,000 NPs. Physician median payments ranged from 1.3 to 2.3 times higher than PAs or NPs. Diagnosis-related malpractice allegations varied by provider type, with physicians having significantly fewer reports (31.9%) than PAs (52.8%) or NPs (40.6%) over the observation period. Trends in malpractice payment reports may reflect policy enactments to decrease liability.
Forkhead Box P3 (Foxp3) is a regulatory T cells marker, and its expression correlates with prognosis in a number of malignancies. The aim of this study is to determine the relationship of Foxp3 expression with clinicopathological parameters and prognosis in oral squamous cell carcinoma (OSCC).
Foxp3 expression was examined using immunohistochemistry (IHC) in paraffin-embedded tissue samples from 273 OSCC patients. Statistical analysis was performed to evaluate the associations between Foxp3 expression, the clinicopathologic characteristics and prognostic factors in OSCC.
Foxp3 protein expression was significantly associated with lymph node metastasis (P <0.01). Both univariate and multivariate analyses revealed that Foxp3 was an independent factor for both 5 years overall survival (OS) and relapse-free survival (RFS) (both P <0.01). Patients with Foxp3 overexpression had shorter OS and RFS.
Our results determined that elevated Foxp3 protein expression was a predictive factor of outcome in OSCC and could act as a promising therapeutic target.
The number of Medicaid beneficiaries has increased under the Affordable Care Act, improving access to solid organ transplantation in this disadvantaged patient cohort. It is unclear what impact Medicaid expansion will have on transplantation outcomes. We performed a retrospective cohort analysis to measure the frequency and variation in Medicaid transplantation and post-transplantation survival in Medicaid patients.
Adult heart, lung, liver, and renal transplant recipients between 2002 and 2011 (n = 169,194) reported to the Scientific Registry of Transplant Recipients were identified. Transplant recipients were classified based on insurance status (private, Medicare or Medicaid). Outcomes measures included 5-year post-transplantation survival, summarized using Kaplan-Meier curves and compared with log-rank tests. Organ-specific Cox proportional hazards models were used to adjust for donor and recipient factors.
Medicaid patients comprised 8.6% of all organ transplant recipients. Fewer transplantations were performed than expected among Medicaid beneficiaries for all organs except liver (liver: observed to expected ratio = 1.21; 95% CI, 0.68-1.90; heart: observed to expected ratio = 0.89; 95% CI, 0.44-1.49; lung: observed to expected ratio = 0.57; 95% CI, 0.22-1.06; renal: observed to expected ratio = 0.32; 95% CI, 0.08-0.72). Medicaid transplant recipients were listed with more severe organ failure and experienced shorter transplant wait times. Post-transplantation survival was lower in Medicaid patients compared with private insurance for all organs. Post-transplantation survival in Medicaid patients was similar to Medicare patients for heart, liver, and renal but lower in lung.
Medicaid organ transplant beneficiaries had significantly lower survival compared with privately insured beneficiaries. The more severe organ failure among Medicaid beneficiaries at the time of listing, suggested a pattern of late referral, which might account for worse outcomes. Implementation of the Affordable Care Act gives the opportunity to develop the necessary infrastructure to ensure timely transplantation referrals and improve long-term outcomes in this vulnerable population.
Cutaneous squamous cell carcinoma (cSCC) is the second most common skin cancer and frequently progresses from an actinic keratosis (AK), a sun-induced keratinocyte intraepithelial neoplasia (KIN). Epigenetic mechanisms involved in the phenomenon of progression from AK to cSCC remain to be elicited.
Expression of microRNAs in sun-exposed skin, AK and cSCC was analysed by Agilent microarrays. DNA methylation of miR-204 promoter was determined by bisulphite treatment and pyrosequencing. Identification of miR-204 targets and pathways was accomplished in HaCat cells. Immunofluorescence and immunohistochemistry were used to analyze STAT3 activation and PTPN11 expression in human biopsies.
cSCCs display a marked downregulation of miR-204 expression when
 compared to AK. DNA methylation of miR-204 promoter was identified as one of the repressive mechanisms that accounts for miR-204 silencing in cSCC. In HaCaT cells miR-204 inhibits STAT3 and favours the MAPK signaling pathway, likely acting through PTPN11, a nuclear tyrosine phosphatase that is a direct miR-204 target. In non-peritumoral AK lesions, activated STAT3, as detected by pY705-STAT3 immunofluorescence, is retained in the membrane and cytoplasm compartments, whereas AK lesions adjacent to cSCCs display activated STAT3 in the nuclei.
Our data suggest that miR-204 may act as a "rheostat" that controls the signalling towards the MAPK pathway or the STAT3 pathway in the progression from AK to cSCC.
When compared to an Australasian ED, the two major differences in the emergency medicine practice at Teaching Hospital Karapitiya are which patients are selected at triage and how those selected present. These differences have caused me to reflect on emergency medicine practice in Australasia and wonder if this practice is sustainable.
Remarkable interest has risen in the idea that oxidative/nitrosative stress is mediated in the etiology of numerous human diseases. Oxidative/Nitrosative stress is the result of an disequilibrium in oxidant/antioxidant which reveals from continuous increase of Reactive Oxygen and Reactive Nitrogen Species production. The aim of this review is to emphasize with current information the importance of antioxidants which play the role in cellular responce against oxidative/nitrosative stress, which would be helpful in enhancing the knowledge of any biochemist, pathophysiologist, or medical personnel regarding this important issue. Products of lipid peroxidation have commonly been used as biomarkers of oxidative/nitrosative stress damage. Lipid peroxidation generates a variety of relatively stable decomposition end products, mainly α, β-unsaturated reactive aldehydes, such as malondialdehyde, 4-hydroxy-2-nonenal, 2-propenal (acrolein) and isoprostanes, which can be measured in plasma and urine as an indirect index of oxidative/nitrosative stress. Antioxidants are exogenous or endogenous molecules that mitigate any form of oxidative/nitrosative stress or its consequences. They may act from directly scavenging free radicals to increasing antioxidative defences. Antioxidant deficiencies can develop as a result of decreased antioxidant intake, synthesis of endogenous enzymes or increased antioxidant utilization. Antioxidant supplementation has become an increasingly popular practice to maintain optimal body function. However, antoxidants exhibit pro-oxidant activity depending on the specific set of conditions. Of particular importance are their dosage and redox conditions in the cell.
The National Heart Foundation of Australia has updated the Guide to management of hypertension 2008: assessing and managing raised blood pressure in adults (updated December 2010). Main recommendations For patients at low absolute cardiovascular disease risk with persistent blood pressure (BP) ≥ 160/100 mmHg, start antihypertensive therapy. The decision to treat at lower BP levels should consider absolute cardiovascular disease risk and/or evidence of end-organ damage, together with accurate BP assessment. For patients at moderate absolute cardiovascular disease risk with persistent systolic BP ≥ 140 mmHg and/or diastolic BP ≥ 90 mmHg, start antihypertensive therapy. Treat patients with uncomplicated hypertension to a target BP of < 140/90 mmHg or lower if tolerated. Changes in management as a result of the guideline Ambulatory and/or home BP monitoring should be offered if clinic BP is ≥ 140/90 mmHg, as out-of-clinic BP is a stronger predictor of outcome. In selected high cardiovascular risk populations, aiming for a target of < 120 mmHg systolic can improve cardiovascular outcomes. If targeting < 120 mmHg, close follow-up is recommended to identify treatment-related adverse effects including hypotension, syncope, electrolyte abnormalities and acute kidney injury. Why the changes have been made A 2015 meta-analysis of patients with uncomplicated mild hypertension (systolic BP range, 140-169 mmHg) demonstrated that BP-lowering therapy is beneficial (reduced stroke, cardiovascular death and all-cause mortality). A 2015 trial comparing lower with higher blood pressure targets in selected high cardiovascular risk populations found improved cardiovascular outcomes and reduced mortality, with an increase in some treatment-related adverse events.
This study investigated whether use of services of a breast care nurse (BCN) at any time during treatment for breast cancer led to reduced unmet needs and increased self-efficacy among women with breast cancer. A secondary aim was to analyse comparisons between urban and rural and remote dwellers.
Participants were Australian women who completed treatment for breast cancer at least 6 months before the survey date, recruited through two national databases of women diagnosed with breast cancer. The cross-sectional online survey consisted of two well validated measures, the SCNS-SF34 and the CASE-Cancer Scale. Statistical data were analysed using SPSS, with chi-square used to measure statistical significance.
A total of 902 participants responded to the survey. Unmet needs in the psychological domain were most prominent. Respondents who used the services of a BCN were significantly less likely to report unmet needs regarding tiredness, anxiety; future outlook; feelings about death and dying; patient care and support from medical staff; and provision of health systems and information. Scores of self-efficacy showed women using the services of a BCN had significantly higher self-efficacy when seeking and obtaining information (ρ ≤ 0.001) and understanding and participating in care (ρ = 0.032). Urban dwellers were more likely to have choice of health care service, but overall neither unmet needs nor perceived self-efficacy varied statistically significantly by remoteness.
Women with breast cancer experience a range of unmet needs; however those using BCN services demonstrated positive outcomes in terms of decreased unmet needs and increased self-efficacy.
Although a large body of literature exists propounding the importance of space in aged care and care of the older person with dementia, there is, however, only limited exploration of the 'acute care space' as a particular type of space with archetypal constraints that maybe unfavourable to older people with cognitive impairment and nurses wanting to provide care that is person-centred. In this article, we explore concepts of space and examine the implications of these for the delivery of care to older people who are cognitively impaired. Our exploration is grounded in theorisations of space offered by key geographers and phenomenologists, but also draws on how space has been constructed within the nursing literature that refers specifically to acute care. We argue that space, once created, can be created and that nursing has a significant role to play in the process of its recreation in the pursuit of care that is person-centred. We conclude by introducing an alternative logic of space aimed at promoting the creation of more salutogenic spaces that invokes a sense of sanctuary, safeness, and inclusion, all of which are essential if the care provided to the older person with cognitive impairment is apposite to their needs. The concept of 'person-centred space' helps to crystallize the relationship between space and person-centred care and implies more intentional manipulation of space that is more conducive to caring and healing. Significantly, it marks a return to Nightingale's wisdom, that is, to put the person in the best possible conditions for nature to act upon them.
This clinical update review focuses on the classification and description of common neuropsychiatric manifestations in Parkinson's disease (PD).
We conducted a systematic search of the literature using Pubmed and selected the most recent and relevant papers for this review.
Neuropsychiatric manifestations in PD are are very frequent and may arise from an abnormal psychopathological response to the disease, neurobiological changes related to the disease itself, complications of treatments or a combination of all of these.
Neuropsychiatric symptoms may precede the motor clinical presentation of PD. Early recognition is essential.
To evaluate the impact of the 2006 Massachusetts health reform, the model for the Affordable Care Act, on short-term enrollment and utilization in the unsubsidized individual health insurance market.
Seven years of administrative and claims data from Harvard Pilgrim Health Care.
We employed pre-post survival analysis and an interrupted time series design to examine changes in enrollment length, utilization patterns, and use of elective procedures (discretionary inpatient surgeries and infertility treatment) among nonelderly adult enrollees before (n = 6,912) and after (n = 29,207) the MA reform.
The probability of short-term enrollment dropped immediately after the reform. Rates of inpatient encounters (HR = 0.83, 95 percent CI: 0.74, 0.93), emergency department encounters (HR = 0.85, 95 percent CI: 0.80, 0.91), and discretionary inpatient surgeries (HR = 0.66 95 percent CI: 0.45, 0.97) were lower in the postreform period, whereas the rate of ambulatory visits was somewhat higher (HR = 1.04, 95 percent CI: 1.00, 1.07). The rate of infertility treatment was higher after the reform (HR = 1.61, 95 percent CI: 1.33, 1.97), driven by women in individual (vs. family) plans. The reform was not associated with increased utilization among short-term enrollees.
MA health reform was associated with a decrease in short-term enrollment and changes in utilization patterns indicative of reduced adverse selection in the unsubsidized individual market. Adverse
 selection may be a problem for specific, high-cost treatments.
On a global scale, nearly two billion persons are infected with Mycobacterium tuberculosis. From this vast reservoir of latent tuberculosis (TB) infection, a substantial number will develop active TB during their lifetime, with some being able to transmit TB or Multi-drug- resistant (MDR) TB to others. There is clinical evidence pointing to a higher prevalence of infectious diseases including TB among individuals with Diabetes Mellitus (DM). Furthermore, ageing and diabetes mellitus may further aggravate protein-energy malnutrition (PEM), which in turn impairs T-lymphocyte mediated immunologic defenses, thereby increasing the risk of developing active TB and compromising TB treatment. This article aims to a) highlight synergistic mechanisms associated with immunosenescence, DM and PEM in relation to the development of active TB and b) identify nutritional, clinical and epidemiological research gaps.
To explore the synergistic relationship between ageing, DM, tuberculosis and PEM, a comprehensive review was undertaken. The MEDLINE and the Google Scholar databases were searched for articles published from 1990 to March 2015, using different MESH keywords in various combinations.
Ageing and DM act synergistically to reduce levels of interferon gamma (IFN- γ), thereby increasing susceptibility to TB, for which cell mediated immunity (CMI) plays an instrumental role. These processes can set in motion a vicious nutritional cycle which can predispose to PEM, further impairing the CMI and consequently limiting host defenses. This ultimately transforms the latent TB infection into active disease. A clinical diagnostic algorithm and clinical guidelines need to be established for this population.
Given the increase in ageing population with DM and PEM, especially in resource-poor settings, these synergistic tripartite interactions must be examined if a burgeoning TB epidemic is to be averted. Implementation of a comprehensive, all-encompassing approach to curb transmission is clearly indicated. To this end, clinical, nutritional and epidemiological research gaps must be addressed without a delay.
We introduced a simple checklist to act as an aid to memory for our junior medical staff to ensure that every patient in the intensive care unit (ICU) received every appropriate element of a bundle of care every day. The checklist was developed in consultation with our junior doctors and was designed to be completed every morning for every patient by the junior doctor reviewing the patient. The completed checklist was then checked again by the attending intensivist on the main daily ward round to ensure all the appropriate elements of the checklist had been applied to the patient. It was also noted each day which of the elements of the checklist had been forgotten and was therefore prompted to be completed by use of the checklist. Of the 75 patients surveyed there were 99 occasions, in 48 patients, when the checklist detected a forgotten element of the bundle of care (i.e. in 64% of patients). There was a decrease in the incidence of missed elements of the bundle of care the longer the patient stayed in the ICU. Types of missed elements varied with the duration of the ICU stay. We found that the introduction of a simple checklist, developed in collaboration with the junior medical staff who would be using the checklist every day in the ICU, resulted in the detection and correction of missed elements of a bundle of care we had previously introduced in the ICU.
Although organ transplantation is well established for end-stage organ failure, many patients die on waiting lists due to insufficient donor numbers. Recently, there has been renewed interest in donation after circulatory death (DCD). In a retrospective observational study we reviewed the screening of patients considered for DCD between March 2007 and December 2012 in our hospital. Overall, 148 patients were screened, 17 of whom were transferred from other hospitals. Ninety-three patients were excluded (53 immediately and 40 after review by donation staff). The 55 DCD patients were younger than those excluded (P=0.007) and they died from hypoxic brain injury (43.6%), intraparenchymal haemorrhage (21.8%) and subarachnoid haemorrhage (14.5%). Antemortem heparin administration and bronchoscopy occurred in 50/53 (94.3%) and 22/55 (40%) of cases, respectively. Forty-eight patients died within 90 minutes and proceeded to donation surgery. Associations with not dying in 90 minutes included spontaneous ventilation mode (P=0.022), absence of noradrenaline infusion (P=0.051) and higher PaO2:FiO2 ratio (P=0.052). The number of brain dead donors did not decrease over the study period. The time interval between admission and death was longer for DCD than for the 45 brain dead donors (5 [3-11] versus 2 [2-3] days; P<0.001), and 95 additional patients received organ transplants due to DCD. Introducing a DCD program can increase potential organ donors without reducing brain dead donors. Antemortem investigations appear to be acceptable to relatives when included in the consent process.
The school system has been identified as an ideal setting for the implementation of prevention and early intervention programs for suicide. However, in Australia, suicide-prevention programs that are routinely delivered in the schools are lacking. Internationally, evidence exists for the effectiveness of peer-led interventions that take a social connectedness approach to improve help-seeking for suicide. The aim of the current trial is to test the effectiveness of the Sources of Strength program to promote help-seeking for suicide in adolescents in Australian high schools.
This study is a two-arm, cluster-randomised, controlled trial that will compare the evidence-based Sources of Strength program to a wait-list control condition. Sixteen Australian high schools will be recruited to the trial, with all adolescents in years 7 to 10 (12-16 years of age) invited to participate. Peer leaders from intervention-condition schools will receive training in the Sources of Strength program and will integrate positive messages, across 3 months, with the support of adult advisors. Activities may take the form of class presentations, posters, videos, and messages on social media sites and will aim to change help-seeking norms, strengthen youth-adult connections, and promote positive coping. The primary outcome measure for the study is help-seeking intentions, whereas secondary outcomes include help-seeking behaviour, help-seeking attitudes and norms, referral of distressed peers, availability of adult help, positive coping, and suicidal behaviour. Data will be collected pre-intervention, post-intervention (after the initial 3 months of messaging), and at the end of the first (6-month follow-up) and the second year after implementation (18-month follow-up). Primary analyses will compare changes in help-seeking intentions for the intervention condition relative to the wait-list control condition using mixed-effect repeated-measures analyses to account for clustering within schools.
If proven effective, this universal social connectedness program for suicide could be more widely delivered in Australian high schools, providing a valuable new resource. The Sources of Strength program has the potential to significantly contribute to the mental health of young people in Australia by improving help-seeking for suicide. The findings from this research will also contribute to the evidence-base for peer-leadership programs internationally.
Australian New Zealand Clinical Trials Registry, ACTRN12616000048482 . Registered on 19 January 2016.
Formal, structured annual appraisals are now a regulatory requirement for all doctors and must meet the standards stipulated by the General Medical Council (GMC), including connection with a designated body.
To investigate occupational physicians' opinions and experience of the first year of appraisals for revalidation.
Members of the Society of Occupational Medicine (SOM) were surveyed electronically regarding the appraisal process and its software. A quiz tested knowledge of the requirements and underlying principles and regulations of appraisal for revalidation.
In total, 163 responses were received, with 57 free-text comments. Respondents spent a mean of 31h on the appraisal process (range 0-200h). Less than half of respondents said they had a clear understanding of the appraisal process. Most respondents (88 and 92%) reported difficulties with the appraisal process and the appraisal software. Only 22% felt the time taken for the appraisal process was proportionate to the value gained. Overall, there was support for appraisal and in particular for SOM appraisers, but only half of the respondents found it useful. The average quiz score was 11 out of 15 (74%) with only one respondent scoring full marks. About 25% of respondents were not aware that the responsible officer is obliged to act on any concerns raised. The free-text comments suggested that some physicians found the process costly and stressful.
The findings suggest that the time requirements and process of appraisal for occupational physicians could be improved, and clearer, comprehensive and more accessible guidance should be developed.
Environmental biotic stress factors act continuously on plants, through multiple molecular interactions that eventually lead to the establishment and progress of symbiotic or pathogenic complex interactions. Proteins and peptides play noteworthy roles in such biological processes, usually being the main effectors since the initial recognizing and elicitor functions until the following transduction, gene regulation and physiological responses activities. Ranging from specific regulators to direct antimicrobial agents, plant or pathogen proteins
 and peptides comprise the arsenal available to each side in this biological war, resulting from the genetic coding potential inherited by each one. Post-translational research tools have widely contributed with valuable information on how the plant proteome works to achieve, maintain and adjust plant immunity in order to properly cope with the challenging pathogenic derived proteomes. These key proteins and peptides have great biotechnological potential since they represent distinctive features of each pathogen group (fungi, bacteria, viruses and other) in response to molecules of defense of host plants.
Etanercept, a soluble tumor necrosis factor receptor, and acitretin have been shown to be effective in treating psoriasis. Acitretin is widely used in Korea. However, the combination of etanercept plus acitretin has not been evaluated among Korean patients with psoriasis. The objective of this study was to investigate the efficacy and safety of combination therapy with etanercept and acitretin in patients with moderate to severe plaque psoriasis.
Sixty patients with psoriasis were randomized to receive etanercept 50 mg twice weekly (BIW) for 12 weeks followed by etanercept 25 mg BIW for 12 weeks (ETN-ETN); etanercept 25 mg BIW plus acitretin 10 mg twice daily (BID) for 24 weeks (ETN-ACT); or acitretin 10 mg BID for 24 weeks (ACT). The primary efficacy measurement was the proportion of patients achieving 75 % improvement in Psoriasis Area and Severity Index (PASI 75) at week 24. Secondary end points included 50 % improvement in PASI (PASI 50) at week 24 and clear/almost-clear by Physician Global Assessment (PGA) at each visit through week 24.
The proportions of patients achieving PASI 75, PASI 50, and PGA clear/almost-clear at week 24 in the ETN-ETN (52.4, 71.4, and 52.4 %, respectively) and ETN-ACT groups (57.9, 84.2, and 52.6 %, respectively) were higher than in the ACT group (22.2, 44.4, and 16.7 %, respectively). The incidence of adverse events was similar across all arms. This was an open-label study with a small number of patients.
In Korean patients with moderate to severe plaque psoriasis, etanercept alone or in combination with acitretin was more effective than acitretin. All treatments were well tolerated throughout the study.
This study was registered on July 7, 2009 at ClinicalTrials.gov, NCT00936065 .
Developing of new and improved mosquito control methods, that are economically sustainable and effective, is a critical requirement in the management of vector-borne epidemic diseases. Aedes albopictus is one of the main vectors of various important pathogens in the tropics, which now have the potential to also spread in temperate regions, owing to the environmental and climate changes in act. We report about the isolation of steroidal saponins from Dracaena arborea, evidencing their larvicidal activity against A. albopictus by biological essays. In specific, spiroconazole A demonstrated the best larvicidal activity, showing LT50 value of 57.23 hours at 25 ppm. We finally discuss about the value of this finding.
Asthma is a chronic respiratory disease that affects patients' quality of life and work performance. The cost of asthma treatment is a global economic burden. The costs include the direct medical costs and the indirect costs, such as the loss of productivity, which is difficult to quantify.
Analyze the cost of asthma treatment in Thailand.
Seventy-four asthmatic patients who had exacerbation were enrolled in the present study. Self-answer questionnaires were completed by the subjects including characteristics, socioeconomic factors, and level of asthma control by asthma control test (ACT) score. We evaluated the cost of asthma treatment calculated from direct medical, direct non-medical, and indirect medical costs.
The average total cost per month was 2,752 Thai baht (US$ 86). The direct medical, direct non-medical, and indirect medical costs were 52.39%, 20.73%, and 26.88%, respectively. The direct medical costs accounted for quick-relief medications 11.91% and control medications 36.85% of the total medical cost. Loss of productivity, loss of work caused by asthma exacerbation, was the majority cost of non-medical costs. The average cost of treatment in uncontrolled was higher than partly controlled asthmatic patients but without significant difference. Healthcare payment system and age range affected the total costs of asthma treatment.
The direct non-medical costs and indirect medical costs tend to play an important role of asthma treatment. The data suggested that cost savings could be achieved by improving asthma control.
Articular cartilage (AC), tissue with the lowest volumetric cellular density, is not supplied with blood and nerve tissue resulting in limited ability for self-repair upon injury. Because there is no treatment capable of fully restoring damaged AC, tissue engineering is being investigated. The emphasis of this field is to engineer functional tissues in vitro in bioreactors capable of mimicking in vivo envi- ronments required for appropriate cellular growth and differentiation. In a step towards engineering AC, human adipose-derived stem cells were differentiated in a unique centrifugal bioreactor under oscillating hydrostatic pressure (OHP) and supply of transforming growth factor beta 3 (TGF-β3) that mimic in vivo environments. Static micromass and pellet cultures were used as controls. Since withstanding and absorbing loads are among the main functions of an AC, mechanical properties of the engineered AC tissues were assayed using atomic force microscopy (AFM) under a controlled indentation depth of 100 nm. Young's moduli of elasticity were quantified by modeling AFM force-indentation data using the Hertz model of contact mechanics. We found exposure to OHP causes cartilage constructs to have 45-fold higher Young's moduli compared to static cultures. Addition of TGF-β3 further increases Young's moduli in bioreactor samples by 1.9-fold bringing it within 70.6% of the values estimated for native cartilage. Our results imply that OHP and TGF-β3 act synergistically to improve the mechanics of engineered tissues.
We report on the electrical characteristics of field effect transistors fabricated with random networks of single-walled carbon nanotubes with surfaces modified by ZnO nanoparticles. ZnO nanoparticles are directly grown on single-walled carbon nanotubes by atomic layer deposition using diethylzinc (DEZ) and water. Electrical observations show that ZnO nanoparticles act as charge transfer sources that provide electrons to the nanotube channel. The valley position in ambipolar transport of nanotube transistors is negatively shifted for 3V due to the electronic n-typed property of ZnO nanoparticles. However, the Raman resonance remains invariant despite the charge transfer effect produced by ZnO nanoparticles.
We fabricated a series of linker-assisted quantum-dot-sensitized solar cells based on the ex situ self-assembly of CdSe quantum dots (QDs) onto TiO2 electrode using sulfide/polysulfide (S(2-)/Sn(2-)) as an electrolyte and Au cathode. Our cell were combined with single-walled carbon nanotubes (SWNTs) by two techniques; One was mixing SWNTs with TiO2 electrode and the other was spraying SWNTs onto Au electrode. Absorption spectra were used to confirm the adsorption of QDs onto TiO2 electrode. Cell performance was measured on samples containing and not-containing SWNTs. Samples mixing SWNTs with TiO2 showed higher cell efficiency, on the while sample spraying SWNTs onto Au electrode showed lower efficiency compared with pristine sample (not-containing SWNTs). Electrochemical impedance spectroscopy analysis suggested that SWNTs can act as either barriers or excellent carrier transfers according their position and mixing method.
In this paper, we report a simple, cost effective and surfactant-free method for synthesizing different morphology of β-SnWO4 with irregular, spherical, flake-like and leaf-like structures by using sonochemical method followed by calcination. A well dispersed and highly crystalline β-SnWO4 crystallites with various sizes have been prepared. The samples were characterized by using X-ray diffraction (XRD), scanning electron microscope (SEM), UV-vis spectroscopy, particle size and Zeta potential analyser. The SEM images reveal the successful preparation of an irregular, spherical, flake-like and leaf-like structure of β-SnWO4. The absorption maximum of as-prepared different structures of β-SnWO4 was observed in visible region. The degradation efficiency was found to be increased in leaf-like structures compared to irregular, spherical and flake-like structures of β-SnWO4. Further, an enhanced photocatalytic effect was observed in leaf-like β-SnWO4 nanoparticles while the common oxidants such as peroxomonosulphate (PMS), peroxodisulphate (PDS) and hydrogen peroxide (H2O2) were added. The degradation efficiency of these oxidants was found in the order of PMS > H2O2 > PDS. Generally these oxidants act as electron scavengers. From our experimental results, it is found that maximum efficiency of 93% was achieved when PMS was added. This shows the vital role of common oxidants in photocatalytic characteristics and their future applications in waste-water treatment.
A simple, hasty and eco-friendly approach for the synthesis of iron nanoparticles has been developed using the medicinally important Azadirachta indica extract, which act as both reducing and stabilizing agent. The formation and morphological properties of iron nanoparticles as a function of metallic precursor and Azadirachta indica extract concentration have been investigated. The influence of solvent over the size and texture of iron nanoparticles has also been evaluated in detail. The thermal behavior of prepared nanoparticles was identified from thermogravimetric analysis. Furthermore,
 the catalytic activity of prepared iron nanoparticles toward the reduction of p-nitrophenol was analyzed and the reduction process was occurred within 30 sec. The cost and time efficient biosynthesis process and excellent catalytic activity of the prepared iron nanoparticles construct this protocol attractive.
The Affordable Care Act of 2010 launch of Medicare Value-Based Purchasing has become the platform for payment reform. It is a mechanism by which buyers of health care services hold providers accountable for high-quality and cost-effective care. The objective of the study was to examine the relationship between quality of hospital care and hospital competition using the quality-quantity behavioral model of hospital behavior. The quality-quantity behavioral model of hospital behavior was used as the conceptual framework for this study. Data from the American Hospital Association database, the Hospital Compare database, and the Area Health Resources Files database were used. Multivariate regression analysis was used to examine the effect of hospital competition on patient mortality. Hospital market competition was significantly and negatively related to the 3 mortality rates. Consistent with the literature, hospitals located in more competitive markets had lower mortality rates for patients with acute myocardial infarction, heart failure, and pneumonia. The results suggest that hospitals may be more readily to compete on quality of care and patient outcomes. The findings are important because policies that seek to control and negatively influence a competitive hospital environment, such as Certificate of Need legislation, may negatively affect patient mortality rates. Therefore, policymakers should encourage the development of policies that facilitate a more competitive and transparent health care marketplace to potentially and significantly improve patient mortality.
Yacon (Smallanthus sonchifolius), a perennial plant of the family Asteraceae native to the Andean regions of South America, is an abundant source of fructooligosaccharides (FOS). This comprehensive review of the literature addressed the role of yacon supplementation in promoting health and reducing the risk of chronic diseases. According to several preclinical and clinical trials, FOS intake favors the growth of health-promoting bacteria while reducing pathogenic bacteria populations. Moreover, the endproducts of FOS fermentation by the intestinal microbiota, short chain fatty acids (SCFA), act as substrates or signaling molecules in the regulation of the immune response, glucose homeostasis and lipid metabolism. As a result, glycemic levels, body weight and colon cancer risk can be reduced. Based on these findings, most studies reviewed concluded that due to their functional properties, yacon roots may be effectively used as a dietary supplement to prevent and treat chronic diseases.
The chicken upper respiratory tract is the portal of entry for respiratory pathogens, such as avian influenza virus (AIV). The presence of microorganisms is sensed by pathogen recognition receptors (such as Toll-like receptors (TLRs)) of the innate immune defenses. Innate responses are essential for subsequent induction of potent adaptive immune responses, but little information is available about innate antiviral responses of the chicken trachea. We hypothesized that TLR ligands induce innate antiviral responses in the chicken trachea. Tracheal organ cultures (TOC) were used to investigate localized innate responses to TLR ligands. Expression of candidate genes, which play a role in antiviral responses, was quantified. To confirm the antiviral responses of stimulated TOC, chicken macrophages were treated with supernatants from stimulated TOC, prior to infection with AIV. The results demonstrated that TLR ligands induced the expression of pro-inflammatory cytokines, type I interferons and interferon stimulated genes in the chicken trachea. In conclusion, TLR ligands induce functional antiviral responses in the chicken trachea, which may act against some pathogens, such as AIV.
A series of 2'-hydroxy- and 2'-hydroxy-4',6'-dimethoxychalcones was synthesised and evaluated as inhibitors of human acetylcholinesterase (AChE). The majority of the compounds were found to show some activity, with the most active compounds having IC50 values of 40-85 µM. Higher activities were generally observed for compounds with methoxy substituents in the A ring and halogen substituents in the B ring. Kinetic studies on the most active compounds showed that they act as mixed-type inhibitors, in agreement with the results of molecular modelling studies, which suggested that they interact with residues in the peripheral anionic site and the gorge region of AChE.
To act and think, children and adults are continually required to ignore irrelevant visual information to focus on task-relevant items. As real-world visual information is organized into structures, we designed a feature visual search task containing 3-level hierarchical stimuli (i.e., local shapes that constituted intermediate shapes that formed the global figure) that was presented to 112 participants aged 5, 6, 9, and 21 years old. This task allowed us to explore (a) which level is perceptively the most salient at each age (i.e., the fastest detected level) and (b) what kind of attentional processing occurs for each level across development (i.e., efficient processing: detection time does not increase with the number of stimuli on the display; less efficient processing: detection time increases linearly with the growing number of distractors). Results showed that the global level was the most salient at 5 years of age, whereas the global and intermediate levels were both salient for 9-year-olds and adults. Interestingly, at 6 years of age, the intermediate level was the most salient level. Second, all participants showed an efficient processing of both intermediate and global levels of hierarchical stimuli, and a less efficient processing of the local level, suggesting a local disadvantage rather than a global advantage in visual search. The cognitive cost for selecting the local target was higher for 5- and 6-year-old children compared to 9-year-old children and adults. These results are discussed with regards to the development of executive control. (PsycINFO Database Record
Small compound active site interactors receive considerable attention for their ability to positively influence the fold of glycosidases. Endoglycoceramidase II (EGCII) from Rhodococcus sp. is an endo-β-glucosidase releasing the complete glycan from ceramide in glycosphingolipids. Cleavage of the β-glycosidic linkage between glucose and ceramide is also catalyzed by glucocerebrosidase (GBA), the exo-β-glucosidase deficient in Gaucher disease. We demonstrate that established β-glucoside-configured cyclophellitol-type activity-based probes (ABPs) for GBA also are effective, mechanism-based, and irreversible inhibitors of EGCII. The stability of EGCII is markedly enhanced by formation of covalent complexes with cyclophellitol ABPs substituted with hydrophobic moieties, as evidenced by an increased melting temperature, resistance against tryptic digestion, changes in (15)N-(1)H transverse relaxation optimized spectroscopy spectra of the [(15)N]Leu-labeled enzyme, and relative hydrophobicity as determined by 8-anilino-1-naphthalenesulfonic acid fluorescence. The stabilization of EGCII conformation correlates with the shape and hydrophobicity of the substituents of the ABPs. We conclude that the amphipathic active site binders with aliphatic moieties act as a "hydrophobic zipper" on the flexible EGCII protein structure.
Avian nests are frequently concealed or camouflaged, but a number of species builds noticeable nests or use conspicuous materials for nest decoration. In most cases, nest decoration has a role in mate choice or provides thermoregulatory or antiparasitic benefits. In territorial species however, decorations may serve additional or complementary functions, such as extended phenotypic signaling of nest-site occupancy and social status to potential intruders. The latter may benefit both signaler and receiver by minimizing the risk of aggressive interactions, especially in organisms with dangerous weaponry. Support for this hypothesis was recently found in a population of black kites (Milvus migrans), a territorial raptor that decorates its nest with white artificial materials. However, the crucial assumption that nest decorations increased nest-site visibility to conspecifics was not assessed, a key aspect given that black kite nests may be well concealed within the canopy. Here, we used an unmanned aircraft system to take pictures of black kite nests, with and without an experimentally placed decoration, from different altitudes and distances simulating the perspective of a flying and approaching, prospecting intruder. The pictures were shown to human volunteers through a standardized routine to determine whether detection rates varied according the nest decoration status and distance. Decorated nests consistently showed a higher detection frequency and a lower detection-latency, compared to undecorated versions of the same nests. Our results confirm that nest decoration in this species may act as a signaling medium that enhances nest visibility for aerial receivers, even at large distances. This finding complements previous work on this communication system, which showed that nest decoration was a threat informing trespassing conspecifics on the social dominance, territory quality and fighting capabilities of the signaler.
For an adolescent with physical disabilities, intellectual disabilities, or both, and for her caregivers, menstruation can present significant challenges. If, after an evaluation, the adolescent, her family, and the obstetrician-gynecologist
 have decided that menstrual intervention is warranted, advantages and disadvantages of hormonal methods should be reviewed and individualized to each patient's specific needs. Complete amenorrhea may be difficult to achieve, and realistic expectations should be addressed with the patient and her caregivers. The goal in menstrual manipulation should be optimal suppression, which means a reduction in the amount and total days of menstrual flow. Menstrual suppression before menarche and endometrial ablation are not recommended as treatments. Optimal gynecologic health care for adolescents with disabilities is comprehensive; maintains confidentiality; is an act of dignity and respect toward the patient; maximizes the patient's autonomy; avoids harm; and assesses and addresses the patient's knowledge of puberty, menstruation, sexuality, safety, and consent.
For an adolescent with physical disabilities, intellectual disabilities, or both, and for her caregivers, menstruation can present significant challenges. If, after an evaluation, the adolescent, her family, and the obstetrician-gynecologist have decided that menstrual intervention is warranted, advantages and disadvantages of hormonal methods should be reviewed and individualized to each patient's specific needs. Complete amenorrhea may be difficult to achieve, and realistic expectations should be addressed with the patient and her caregivers. The goal in menstrual manipulation should be optimal suppression, which means a reduction in the amount and total days of menstrual flow. Menstrual suppression before menarche and endometrial ablation are not recommended as treatments. Optimal gynecologic health care for adolescents with disabilities is comprehensive; maintains confidentiality; is an act of dignity and respect toward the patient; maximizes the patient's autonomy; avoids harm; and assesses and addresses the patient's knowledge of puberty, menstruation, sexuality, safety, and consent.
Increasing numbers of adults, particularly college students, are misusing prescription stimulants primarily for cognitive/academic enhancement, so it is critical to explore whether empirical findings support neurocognitive benefits of prescription stimulants. Previous meta-analytic studies have supported small benefits from prescription stimulants for the cognitive domains of inhibitory control and memory; however, no meta-analytic studies have examined the effects on processing speed or the potential impairment on other domains of cognition, including planning, decision-making, and cognitive perseveration. Therefore, the present study conducted a meta-analysis of the available literature examining the effects of prescription stimulants on specific measures of processing speed, planning, decision-making, and cognitive perseveration among healthy adult populations. The meta-analysis results indicated a positive influence of prescription stimulant medication on processing speed accuracy, with an overall mean effect size of g = 0.282 (95% CI [0.077, 0.488]; n = 345). Neither improvements nor impairments were revealed for planning time, planning accuracy, advantageous decision-making, or cognitive perseveration; however, findings are limited by the small number of studies examining these outcomes. Findings support that prescription stimulant medication may indeed act as a neurocognitive enhancer for accuracy measures of processing speed without impeding other areas of cognition. Considering that adults are already engaging in illegal use of prescription stimulants for academic enhancement, as well as the potential for stimulant misuse to have serious side effects, the establishment of public policies informed by interdisciplinary research surrounding this issue, whether restrictive or liberal, is of critical importance. (PsycINFO Database Record
Current guidelines for epicardial catheter ablation for ventricular tachycardia (VT) advocate that epicardial access is avoided in anticoagulated patients and should be performed prior to heparinisation. Recent studies have shown that epicardial access may be safe in heparinised patients. However, no data exist for patients on oral anticoagulants. We investigated the safety of obtaining epicardial access on uninterrupted warfarin.
A prospective registry of patients undergoing epicardial VT ablation over two years was analysed. Consecutive patients in whom epicardial access was attempted were included. All patients were heparinised prior to epicardial access with a target activated clotting time (ACT) of 300-350s. Patients who had procedures performed on uninterrupted warfarin (in addition to heparin) were compared to those not taking an oral anticoagulant.
46 patients were included of which 13 were taking warfarin. There was no significant difference in clinical and procedural characteristics (except INR and AF) between the two groups. Epicardial access was achieved in all patients. There were no deaths and no patients required surgery. A higher proportion of patients in the warfarin group had a drop in haemoglobin of >2g/dL compared to the no-warfarin group (38.5% versus 27.3%, p=0.74) and delayed pericardial drain removal (7.8% versus 3.03%, p=0.47). There was no difference in overall procedural complication rate. No patients required warfarin reversal or blood transfusion.
Epicardial access can be achieved safely and effectively in patients' anticoagulated with warfarin and heparinised with therapeutic ACT. This may be an attractive option for patients with a high stroke risk.
Renal ischemia-reperfusion (I/R) injury ranks as the primary cause of acute renal injury with severe morbidity and mortality. Side population (SP) cells have recently drawn increasing attention due to their critical role in injury repair and regeneration. Unfortunately, the underlying mechanism involved in renal I/R remains poorly elucidated. Here, pronounced increases of SDF-1 and its receptor CXCR4 were substantiated in I/R kidneys from C57BL/6 mice subjected to clamp the bilateral renal pedicles to mimic renal ischemia. Similar up-regulation of them was also determined in SP cells upon simulated ischemia/reperfusion (SI/R). In contrast to non-SP cells, SP cells exhibited higher viability, apoptosis resistance, chemotaxis and paracrine actions following SI/R treatment, and these were further enhanced after SDF-1 stimulation. Interestingly, blocking CXCR4 signaling with AMD3100 notably ameliorated the above effects. Mechanism analysis corroborated that SDF-1/CXCR4 further induced the expression of ATP-binding cassette transporter ABCG2, an essential element for SP-mediated kidney regeneration after renal I/R injury. Moreover, AMD3100 pretreatment strikingly attenuated ABCG2 elevation in SP cells. Additionally, sonic hedgehog (SHH)-Gli 1 signaling was involved in SDF-1/CXCR4-mediated ABCG2 expression. When SP cells pretreated with AMD3100 were intravenously injected into I/R mice, SP cell-mediated decreases in blood urea nitrogen (BUN), serum creatinine (Scr) and histological score of kidney (HSK) were noticeably attenuated, indicating that blocking CXCR4 pathway mitigated the therapeutic function of SP cells in renal I/R injury. Together, this research suggests that SDF-1/CXCR4 axis might act, via Shh-Gli1-ABCG2 signaling, as a positive regulator of SP cell-based therapies for renal I/R by Shh-Gli 1-ABCG2 signaling.
Although engagement is generally predictive of positive outcomes in technology-based behavioral change interventions, engagement measures remain largely atheoretical and lack treatment-specificity. This study examines the extent to which adherence measures based on the underlying behavioral change theory of an Acceptance and Commitment Therapy (ACT) app for smoking cessation predict smoking outcomes, and user characteristics associated with adherence.
Study sample was adult daily smokers in a single arm pilot study (n=84). Using the app's log file data, we examined measures of adherence to four key components of the ACT behavior change model as predictors of smoking cessation and reduction. We also examined baseline user characteristics associated with adherence measures that predict smoking cessation.
Fully adherent users (24%) were over four times more likely to quit smoking (OR=4.45; 95% CI=1.13, 17.45; p=0.032). Both an increase in tracking the number of urges passed (OR=1.02; 95% CI=1.00, 1.03; p=0.043) and ACT modules completed (OR=1.27; 95% CI=1.01, 1.60; p=0.042) predicted cessation. Lower baseline acceptance of cravings was associated with over four times higher odds of full adherence (OR=4.59; 95% CI=1.35, 15.54; p=0.014).
Full adherence and use of specific ACT theory-based components of the app predicted quitting. Consistent with ACT theory, users with low acceptance were most likely to adhere to the app. Further research is needed on ways to promote app engagement.
Tuning the ratios of ethanol to water, self-assembling microspheres composed of Co3O4 nanoflakes are synthesized by the hydrothermal method. The scanning electron microscopy (SEM) images of as-grown samples obviously show that the dispersive multilayered structures gradually change into micro/nanobelts and cubic blocks structures, and then into the desired self-assembled microspheres with increasing ratios of ethanol to water. Also, all the x-ray diffraction (XRD) patterns evidently demonstrate that all obtained Co3O4 has cubic crystal structure. The corresponding synthesis mechanism is discussed in detail. More importantly, the unique self-assembling Co3O4 nanoflake microspheres have excellent electrochemical performance with large specific capacitance, good rate capability and excellent cycling performance, evidently presenting a potential capability of Co3O4 nanoflake microspheres to act as electrode materials for supercapacitors in sustainable power sources.
Pesticides are widely
 used to protect crop plants from various insect pests. However, application of pesticides causes phytotoxicity to plants which results in their impaired growth and development. Brassinosteroids are well known to protect plants under abiotic stress conditions. The purpose of the present study was to access the ameliorative role of 24-epibrassinolide (EBR) in Brassica juncea L. under imidacloprid (IMI) toxicity. B. juncea plants were raised from seeds soaked in 0.1, 1 and 100nM of EBR, and grown in soils amended with 250, 300 and 350mgkg(-1) IMI pesticide, and observed for growth, pigments and photosynthetic parameters after 30, 60 and 90 days of seed sowing. The plants grown in soil treated with IMI exhibited a significant reduction in shoot length, number of leaves, chlorophyll contents and photosynthetic parameters like photosynthetic rate, stomatal conductance, inter-cellular CO2 and transpiration rate, when compared with their respective controls. However, pigments which act as antioxidants such as carotenoids, anthocyanins and xanthophylls were increased with IMI stress. Pre-sowing seed treatment with EBR decreased the toxic effects of IMI and increased the growth, pigment biosynthesis and photosynthetic parameters of the plants grown in IMI amended soil. Maximum increase in all the growth and photosynthetic parameters was noticed in plants raised from seeds treated with 100nM EBR and grown in IMI amended soil.
Hydrogen is regarded as a future sustainable and clean energy carrier. Formic acid is a safe and sustainable hydrogen storage medium with many advantages, including high hydrogen content, nontoxicity, and low cost. In this work, a series of highly active catalysts for hydrogen production from formic acid are successfully synthesized by controllably depositing Pd onto Ag nanoplates with different Ag nanofacets, such as Ag{111}, Ag{100}, and the nanofacet on hexagonal close packing Ag crystal (Ag{hcp}). Then, the Pd-Ag nanoplate catalysts are supported on Vulcan XC-72 carbon black to prevent the aggregation of the catalysts. The research reveals that the high activity is attributed to the formation of Pd-Ag alloy nanofacets, such as Pd-Ag{111}, Pd-Ag{100}, and Pd-Ag{hcp}. The activity order of these Pd-decorated Ag nanofacets is Pd-Ag{hcp} > Pd-Ag{111} > Pd-Ag{100}. Particularly, the activity of Pd-Ag{hcp} is up to an extremely high value, i.e., TOF{hcp} = 19 000 ± 1630 h(-1) at 90 °C (lower limit value), which is more than 800 times higher than our previous quasi-spherical Pd-Ag alloy nanocatalyst. The initial activity of Pd-Ag{hcp} even reaches (3.13 ± 0.19) × 10(6) h(-1) at 90 °C. This research not only presents highly active catalysts for hydrogen generation but also shows that the facet on the hcp Ag crystal can act as a potentially highly active catalyst.
Drinking water treatment residue (DWTR) seems to be very promising for controlling lake sediment pollution. Logically, acquisition of the potential toxicity of DWTR will be beneficial for its applications. In this study, the toxicity of DWTR and sediments amended with DWTR to Aliivibrio fischeri was evaluated based on the Microtox(®) solid and leachate phase assays, in combination with flow cytometry analyses and the kinetic luminescent bacteria test. The results showed that both solid particles and aqueous/organic extracts of DWTR exhibited no toxicity to the bacterial luminescence and growth. The solid particles of DWTR even promoted bacterial luminescence, possibly because DWTR particles could act as a microbial carrier and provide nutrients for bacteria growth. Bacterial toxicity (either luminescence or growth) was observed from the solid phase and aqueous/organic extracts of sediments with or without DWTR addition. Further analysis showed that the solid phase toxicity was determined to be related mainly to the fixation of bacteria to fine particles and/or organic matter, and all of the observed inhibition resulting from aqueous/organic extracts was identified as non-significant. Moreover, DWTR addition not only had no adverse effect on the aqueous/organic extract toxicity of the sediment but also reduced the solid phase toxicity of the sediment. Overall, in practical application, the solid particles, the water-soluble substances transferred to surface water or the organic substances in DWTR had no toxicity or any delayed effect on bacteria in lakes, and DWTR can therefore be considered as a non-hazardous material.
This article reports the development of a treatment protocol, based on cognitive behavioral therapy (CBT) principles, for delayed sleep-wake phase disorder (DSWPD). The protocol consists of psycho-education, presenting a CBT model for DSWPD, case formulation, motivational interviewing, registering sleep in a diary, strategies to improve the rhythm of sleep and wakefulness, relaxation training, cognitive restructuring, strategies to cope with daytime symptoms, constructing an individualized CBT program, and learning how to deal with relapses. Qualitative data, focusing on how the patients perceived the protocol, were collected within the realm of a trial exploring the efficacy of the protocol. These findings highlighted several advantages but also disadvantages of the therapy. It is our hope that this paper might act as a platform for further clinical work and future research efforts in patients with DSWPD.
Exercise interventions facilitate odds of quit success among high-anxiety sensitive adults smokers. We examined the dependency of these benefits on the genetic BDNF Val66Met (rs6265) polymorphism; individuals who are Met carriers have lower BDNF responses and reduced associated benefits from exercise. Accordingly, we hypothesized that the efficacy of vigorous exercise for smoking cessation would be specific to high-anxiety sensitive Val/Val carriers.
Participants were adults (N=55) of European ancestry who had participated in a randomized controlled trial comparing a smoking cessation program augmented with exercise vs. augmented with a wellness control treatment. In this secondary analysis, growth curve models for point-prevalence abstinence (PPA) and prolonged abstinence (PA) employed for the main outcome analyses were amended to test the moderator effects of the BDNF Val66Met polymorphism.
Consistent with prediction, the advantage of exercise over control for PPA was significantly greater among high-anxiety sensitive persons with the Val/Val genotype than for those with the Val/Met genotype. This advantage did not reach statistical significance for PA. Differences in abstinence between the exercise and control interventions among low-anxiety sensitive smokers were not dependent on the BDNF Val66Met polymorphism.
We found that the efficacy of exercise for augmenting smoking cessation treatment is intensified among high-anxiety sensitive smokers who are Val/Val carriers. This observation is consistent with findings documenting BDNF mediation of exercise benefits and greater negative affect among smokers who are Val/Val carriers. These data encourage further evaluation of the association between the BDNF polymorphism, exercise, anxiety sensitivity, and smoking cessation.
Depression is a leading cause of disability worldwide, but most depressed individuals do not receive treatment. There is now significant support for physical exercise as an effective alternative treatment for depression, which may be more accessible than traditional psychiatric treatments. Little is known about preferences for exercise as a depression treatment.
A total of 102 individuals (50% female, mean age = 39 (SD=13.1; range: 18-62), 83% Caucasian) with likely major depression completed an online survey of exercise for depression treatment preferences and barriers to increased exercise. Results are reported by gender due to well established gender differences in exercise preferences.
Both genders reported a high level of interest in an exercise for depression program. On average, participants preferred an individual walking program that was coached, asked them to engage in one longer bout multiple times per week, and was provided in home. However, there was significant variability within and between genders. Lack of motivation, mood, and fatigue were reported as barriers to exercise by the majority of participants of both genders.
The majority of those with depression have interest in an exercise for depression program, but symptoms of depression are seen as significant barriers. Future studies should use these results to design exercise for depression programs. The variability and gender differences in our results suggest that flexible programs may be needed.
Social monogamy is a mating strategy rarely employed by mammalian species. Laboratory studies in socially monogamous prairie voles (Microtus ochrogaster) demonstrate that oxytocin and vasopressin act within the mesolimbic dopamine pathway to facilitate pair-bond formation. Species differences in oxytocin receptor (OTR) and vasopressin 1a receptor (V1aR) distribution in this pathway are associated with species differences in mating strategy. Here we characterize the neuroanatomical distribution of OTR and V1aR binding sites in naturally occurring populations of Taiwan voles (M. kikuchii), which purportedly display social monogamy. Live trapping was conducted at two sites in 2009-2010 and receptor autoradiography for OTR and V1aR was performed on brains from 24 animals. OTR binding in two brain regions where OTR signaling regulates pair-bonding were directly compared with that of prairie voles. Our results show that like prairie voles, Taiwan voles exhibit OTR in the prefrontal cortex, insular cortex, claustrum, nucleus accumbens, caudate-putamen, dorsal lateral septal nucleus, central amygdala, and ventromedial hypothalamus. Unlike prairie voles, Taiwan voles exhibit OTR binding in the CA3 pathway of
 the hippocampus, as well as the indusium griseum, which has only previously been documented in tuco-tucos (Ctenomys haigi, C. sociabilis), Syrian hamsters (Mesocricetus auratus) and naked mole-rats (Heterocephalus glaber). V1aR binding was present in the ventral pallidum, lateral septum, nucleus basalis, bed nucleus of the stria terminalis, hippocampus, medial amygdala, and anterior, ventromedial and dorsomedial hypothalamus. Marked individual differences in V1aR binding were noted in the cingulate cortex and several thalamic nuclei, remarkably similar to prairie voles. While pharmacological studies are needed to determine whether oxytocin and vasopressin are involved in pair-bond formation in this species, our results lay a foundation for future investigations into the role of these neuropeptides in Taiwan vole social behavior.
We used a question from the Healthcare Equality Index to explore nurses' knowledge and understanding of medical advance directives, medical power of attorney and other legal documents for lesbian, gay, bisexual and transgender patients.
Until the landmark ruling in Obergefell vs. Hodges, lesbian, gay, bisexual and transgender individuals and same-sex couples have had limited relationship rights as only a few states recognised marriages and provided legal protections for same-sex couples. Health care providers' knowledge of and attitudes towards advance care planning plays a significant role in determining whether or not individuals successfully complete advance directives, yet advance care planning for lesbian, gay, bisexual and transgender individuals is poorly understood among both health care providers and same-sex couples.
These data were part of a larger research study that explored the current state of lesbian, gay, bisexual and transgender-sensitive nursing practice.
Undergraduate nursing students recruited and interviewed nurse key informants (n = 268) about medical advance directives, medical power of attorney and other legal documents for lesbian, gay, bisexual and transgender patients.
Nearly 50% of key informants indicated a lack of knowledge of advance directives, over 26% reported the difficulties nurses face regarding advance directives are the same for both lesbian, gay, bisexual and transgender and heterosexual patients, and nearly 25% indicated difficulties including having to decide who has the legal right to make decisions for the patient.
The study demonstrated the need for education and training for practising nurses in advance care planning for lesbian, gay, bisexual and transgender patients and same-sex couples.
Nurses are in a position to act as educators, advocates and decision makers for their patients. Nurse's lack of understanding of advance care planning may negatively impact the type and quality of care lesbian, gay, bisexual and transgender patients receive.
Targeted HIV cure strategies require definition of the mechanisms that maintain the virus. Here, we tracked HIV replication and the persistence of infected CD4 T cells in individuals with natural virologic control by sequencing viruses, T cell receptor genes, HIV integration sites, and cellular transcriptomes. Our results revealed three mechanisms of HIV persistence operating within distinct anatomic and functional compartments. In lymph node, we detected viruses with genetic and transcriptional attributes of active replication in both T follicular helper (TFH) cells and non-TFH memory cells. In blood, we detected inducible proviruses of archival origin among highly differentiated, clonally expanded cells. Linking the lymph node and blood was a small population of circulating cells harboring inducible proviruses of recent origin. Thus, HIV replication in lymphoid tissue, clonal expansion of infected cells, and recirculation of recently infected cells act together to maintain the virus in HIV controllers despite effective antiviral immunity.
The deregulation of microRNA-185 (miR-185) has been showed to be associated with many cancers and act as a tumor suppressor in many types of human malignancies. We hence tried to find out its role in human colorectal cancer (CRC).
miR-185 expression was investigated by real-time quantitative polymerase chain reaction. We carried out transfections to overexpress or knockdown of miR-185 by mimics or inhibitor, respectively. Functional study like cell counting kit-8 assay was performed to evaluate the proliferation. For addressing the impact of miR-185 on Wnt/β-catenin signaling, we further applied luciferase reporter assay and Western blotting for specific proteins in this pathway.
miR-185 was decreased in CRC cell lines when compared with corresponding control cell line. We also proved that its overexpression in LoVo cells could remarkably suppress cell proliferation whereas knocked it down in SW480 cells has the opposite effect in vitro. Mechanically, we demonstrated that miR-185 could suppress the Wnt/β-catenin signaling and modulate the transcription and translation level of downstream molecules of this pathway, including MYC and CCND1.
Taken together, these results suggested that miR-185 exerts its tumor suppressor activities probably through a negative modulation of the Wnt/β-catenin pathway.
The biological processing - mechanism of cellular uptake, effects on the cytoplasmic and mitochondrial membranes, intracellular sites of localisation and induction of reactive oxygen species - of two dinuclear polypyridylruthenium(ii) complexes has been examined in three eukaryotic cells lines. Flow cytometry was used to determine the uptake of [{Ru(phen)2}2{μ-bb12}](4+) (Rubb12) and [Ru(phen)2(μ-bb7)Ru(tpy)Cl](3+) {Rubb7-Cl, where phen = 1,10-phenanthroline, tpy = 2,2':6',2''-terpyridine and bbn = bis[4(4'-methyl-2,2'-bipyridyl)]-1,n-alkane} in baby hamster kidney (BHK), human embryonic kidney (HEK-293) and liver carcinoma (HepG2) cell lines. The results demonstrated that the major uptake mechanism for Rubb12 and Rubb7-Cl was active transport, although with a significant contribution from carrier-assisted diffusion for Rubb12 and passive diffusion for Rubb7-Cl. Flow cytometry coupled with Annexin V/TO-PRO-3 double-staining was used to compare cell death by membrane damage or apoptosis. Rubb12 induced significant direct membrane damage, particularly with HepG2 cells, while Rubb7-Cl caused considerably less membrane damage but induced greater levels of apoptosis. Confocal microscopy, coupled with JC-1 assays, demonstrated that Rubb12 depolarises the mitochondrial membrane, whereas Rubb7-Cl had a much smaller affect. Cellular localisation experiments indicated that Rubb12 did not accumulate in the mitochondria, whereas significant mitochondrial accumulation was observed for Rubb7-Cl. The effect of Rubb12 and Rubb7-Cl on intracellular superoxide dismutase activity showed that the ruthenium complexes could induce cell death via a reactive oxygen species-mediated pathway. The results of this study demonstrate that Rubb12 predominantly kills eukaryotic cells by damaging the cytoplasmic membrane. As this dinuclear ruthenium complex has been previously shown to exhibit greater toxicity towards bacteria than eukaryotic cells, the results of the present study suggest that metal-based cationic oligomers can achieve selective toxicity against bacteria, despite exhibiting a non-specific membrane damage mechanism of action.
Enhancers can stimulate transcription by a number of different mechanisms which control different stages of the transcription cycle of their target genes, from recruitment of the transcription machinery to elongation by RNA polymerase. These mechanisms may not be mutually exclusive, as a single enhancer may act through different pathways by binding multiple transcription factors. Multiple enhancers may also work together to regulate transcription of a shared target gene. Most of the evidence supporting different enhancer mechanisms comes from the study of single genes, but new high-throughput experimental frameworks offer the opportunity to integrate and generalize disparate mechanisms identified at single genes. This effort is especially important if we are to fully understand how sequence variation within enhancers contributes to human disease.
Oesophageal cancer ranks as the sixth most common malignancy in the world, and recent evidence has shown that its incidence is increasing. ACBPs (Acyl-coA binding proteins) act as intracellular carrier-proteins for medium to long chain acyl-coA, mediating fatty acid transport to the mitochondrion for ß-oxidation. ACBPs are also believed to be putative ligands of PBR (peripheral benzodiazepine receptor), and once they bind to this receptor they facilitate mitochondrial membrane permeabilization, presumably favouring apoptosis. The main aim of the study was to establish the expression patterns of 1- Acyl-coA binding proteins (1-ACBP), B- Acyl-coA binding proteins (B-ACBP), and peripheral bezodiazepine receptor (PBR) in oesophageal cancer, and to link their roles with the disease. In situ hybridization and quantitative real-time PCR methods were performed to determine localization and the expression levels of the three genes in oesophageal cancer. All three genes illustrated substantial up-regulation within the malignant tissue sections as compared to normal oesophageal sections, all three transcripts localized specifically to mast cells, plasma cells and lymphocytes in diseased and normal tissue section. In the diseased tissue B-ACBP and 1-ACBP mRNA localized to endothelial cells of blood vessels in the submucosa. B-ACBP also localized to the nucleus of squamous epithelial cells. PBR localization was indicated in tumour islands of invasive tissue sections. Quantitative RT-PCR also indicated that the expression levels of PBR were higher as compared to the ACBP genes expression in tumours. These results show that 1-ACBP, B-ACBP
 and PBR play a role in the pathogenesis of oesophageal tumours and possibly in carcinogenic angiogenesis.
We report the synthesis of a 2D-layered metal-organic framework incorporating weakly interacting chains designed to aid exfoliation of the layers into nanosheets. Dispersion of the nanosheets exposes labile metal-sites which are shown to exchange solvent molecules allowing the nanosheets to act as sensors in suspension.
Endogenous interferon beta (IFNβ) is an important cytokine involved in several chronic inflammatory diseases, such as Multiple Sclerosis (MS). In spite of the numerous therapeutic approaches available for MS patients, the administration of recombinant IFNβ continues being one of the first line treatment to these patients. The soluble form of IFNβ receptor (sIFNAR2) could act as critical regulator of the endogenous and the systemically administered IFNβ, but whether it functions as an agonist or antagonist of its ligand is not completely elucidated. Morover, the possible role of sIFNAR2 in autoimmune diseases like MS is still unknown and so far overlooked. Here we evaluated the efficacy of the combined therapy of IFNβ and our recombinant protein analogous to human sIFNAR2 as a treatment in a chronic mice model of MS (CP-EAE). We also tested the effect of the sIFNAR2 administered as a monotherapy over these EAE-animals. The results showed that our recombinant sIFNAR2 protein potentiates the immunomodulatory effects of exogenous IFNβ in CP-EAE by increasing the reduction of the induced inflammation and the tissue damage. Furthermore, we demonstrate for the first time that sIFNAR2 shows intrinsic properties by modulating the CP-EAE progression and the neuroinflammation processes related to this disease. Another intrinsic activity showed by sIFNAR2 is the inhibition of the T cells proliferation, which increase its potential as therapeutic molecule.
There is a paucity of information concerning the developmental neurotoxicity (DNT) hazard posed by industrial and environmental chemicals. New testing approaches will most likely be based on batteries of alternative and complementary (non-animal) tests. As DNT is assumed to result from the modulation of fundamental neurodevelopmental processes (such as neuronal differentiation, precursor cell migration or neuronal network formation) by chemicals, the first generation of alternative DNT tests target these processes. The advantage of such types of assays is that they capture toxicants with multiple targets and modes-of-action. Moreover, the processes modelled by the assays can be linked to toxicity endophenotypes, i.e. alterations in neural connectivity that form the basis for neurofunctional deficits in man. The authors of this review convened in a workshop to define criteria for the selection of positive/negative controls, to prepare recommendations on their use, and to initiate the setup of a directory of reference chemicals. For initial technical optimization of tests, a set of >50 endpoint-specific control compounds was identified. For further test development, an additional "test" set of 33 chemicals considered to act directly as bona fide DNT toxicantsis proposed, and each chemical is annotated to the extent it fulfills these criteria. A tabular compilation of the original literature used to select the test set chemicals provides information on statistical procedures, and toxic/non-toxic doses (both for pups and dams). Suggestions are provided on how to use the >100 compounds (including negative controls) compiled here to address specificity, adversity and use of alternative test systems.
E2F transcription factors are important regulators of the cell cycle, and unrestrained activation of E2F-dependent transcription is considered to be an important driver of tumor formation and progression. Although highly expressed in normal skin and skin cancer, the role of the atypical E2Fs, E2F7 and E2F8, in keratinocyte homeostasis, regeneration and tumorigenesis is unknown. Surprisingly, keratinocyte-specific deletion of E2F7 and E2F8 in mice did not interfere with skin development and wound healing. However, the rate for successful isolation and establishment of E2f7/8-deficient primary keratinocyte cultures was much higher than for wild-type keratinocytes. Moreover, E2f7/8-deficient primary keratinocytes proliferate more efficiently under stress conditions, such as low/high confluence or DNA damage. Application of in vivo stress using the DMBA/TPA skin carcinogenesis protocol revealed that combined inactivation of E2f7/8 enhanced tumorigenesis and accelerated malignant progression. Loss of atypical E2Fs resulted in increased expression of E2F target genes, including E2f1. Additional loss of E2f1 did not rescue, but worsened skin tumorigenesis. We show that loss of E2F7/8 triggers apoptosis via induction of E2F1 in response to stress, indicating that the tumor-promoting effect of E2F7/8 inactivation can be partially compensated via E2F1-dependent apoptosis. Importantly, E2F7/8 repressed a large set of E2F target genes that are highly expressed in human patients with skin cancer. Together, our studies demonstrate that atypical E2Fs act as tumor suppressors, most likely via transcriptional repression of cell cycle genes in response to stress.Oncogene advance online publication, 25 July 2016; doi:10.1038/onc.2016.251.
RNA functions through the dynamic formation of complexes with RNA-binding proteins (RBPs) in all clades of life. We determined the RBP repertoire of beating cardiomyocytic HL-1 cells by jointly employing two in vivo proteomic methods, mRNA interactome capture and RBDmap. Together, these yielded 1,148 RBPs, 391 of which are shared with all other available mammalian RBP repertoires, while 393 are thus far unique to cardiomyocytes. RBDmap further identified 568 regions of RNA contact within 368 RBPs. The cardiomyocyte mRNA interactome composition reflects their unique biology. Proteins with roles in cardiovascular physiology or disease, mitochondrial function, and intermediary metabolism are all highly represented. Notably, we identified 73 metabolic enzymes as RBPs. RNA-enzyme contacts frequently involve Rossmann fold domains with examples in evidence of both, mutual exclusivity of, or compatibility between RNA binding and enzymatic function. Our findings raise the prospect of previously hidden RNA-mediated regulatory interactions among cardiomyocyte gene expression, physiology, and metabolism.
Di-(2-propylheptyl) phthalate (DPHP) does not act as a reproductive toxicant or endocrine disruptor in contrast to other phthalates. Considering adverse effects of phthalates to be linked to their metabolism, it was the aim of the present study to investigate in the rat the blood burden of DPHP and its metabolites as a basis for understanding the toxicological behavior of DPHP. Rats were administered single oral doses of DPHP of 0.7 and 100mg/kg body weight. Concentration-time courses of DPHP and metabolites were monitored in blood. The areas under the concentration-time curves in blood (AUCs), normalized for the dose of DPHP, showed the following order: DPHP<mono-(2-propyl-6-oxoheptyl) phthalate<mono-(2-propyl-6-hydroxyheptyl) phthalate=mono-(2-propylheptyl) phthalate<mono-(2-propyl-6-carboxyhexyl) phthalate (cx-MPHP). Glucuronidation of the monoesters accounted for less than 5% of total compounds. The elimination half-lives of the compounds ranged from 2.3h (DPHP) to 8.2h (cx-MPHP). The normalized AUCs of the metabolites were lower at the high dose of DPHP than at the low one indicating saturation kinetics of intestinal DPHP hydrolysis. The absence of toxicity to reproduction of DPHP may be related to the comparatively low bioavailability of the parent compound and its metabolites.
Partitioning-defective (Par) proteins contribute to multiprotein complexes that drive cell polarity and fate in invertebrates. Of these, the ternary Par3-atypical protein kinase C-Par6 polarity complex mediates asymmetry in various systems, whereas Par3 and aPKC/Par6 can also act independently. aPKC-λ has recently been implicated in epidermal differentiation and stem cell fate; however, whether Par3 contributes to the homeostasis of adult stratified epithelia is currently unknown. Here, we provide functional evidence that epidermal Par3 loss disturbed the inside-out skin barrier, coinciding with altered expression and localization of principle tight junction components, and that epidermal differentiation and thickness were increased. Moreover, Par3 inactivation caused an initial expansion and later decline of hair follicle bulge stem cells, accompanied by an enrichment of committed progenitors, formation of hypertrophic sebaceous glands, and increased epidermal differentiation, suggesting aberrant cell fate decisions. Importantly, and opposite to aPKCλ deletion, Par3 loss did not enhance perpendicular cell divisions. Instead, in Par3-deficient hair follicles, spindles were shifted toward planar orientation, indicating that abnormal differentiation after Par3 inactivation is unlikely to be attributed to increased perpendicular spindle orientation. Collectively, mammalian Par3 controls the epidermal barrier, differentiation, and stem cell maintenance in the pilosebaceous unit, which are all essential for the homeostasis of an important barrier-forming epithelium.
Copaifera trapezifolia Hayne occurs in the Atlantic Rainforest, which is considered one of the most important and endangered tropical forests on the planet. Although literature works have described many Copaifera spp., their biological activities remain little known. In the present study, we aimed to evaluate (1) the potential of the hydroalcoholic extract from C. trapezifolia leaves (CTE) to act against the causative agents of tooth decay and apical periodontitis and (2) the cytotoxicity and mutagenicity of CTE to ensure
 that it is safe for subsequent application. Concerning the tested bacteria, the MIC and the minimum bactericidal concentration of CTE varied between 100 and 400 µg ml-1. The time-kill assay conducted at a CTE concentration of 100 µg ml-1 evidenced bactericidal activity against Porphyromonas gingivalis (ATCC 33277) and Peptostreptococcus micros (clinical isolate) within 72 h. CTE at 200 µg ml-1 inhibited Porphyromonas gingivalis and Peptostreptococcus micros biofilm formation by at least 50 %. A combination of CTE with chlorhexidine dichlorohydrate did not prompt any synergistic effects. The colony-forming assay conducted on V79 cells showed that CTE was cytotoxic at concentrations above 156 µg ml-1. CTE exerted mutagenic effect on V79 cells, but the micronucleus test conducted on Swiss mice and the Ames test did not reveal any mutagenicity. Therefore, the use of standardized and safe extracts could be an important strategy to develop novel oral care products with antibacterial action. These extracts could also serve as a source of compounds for the discovery of new promising biomolecules.
Pro-opiomelanocortin deficiency is a rare cause of severe intractable obesity. Two patients have experienced dramatic weight loss in response to setmelanotide, a melanocortin-4 receptor activator. The drug has potential in broader populations, but caution is warranted as it may act at other melanocortin receptors.
Myositis, which means inflammation of the muscles, is a general term used for inflammatory myopathies. Myositis is a rare idiopathic autoimmune disease. It is believed that environmental factors such as virus, bacteria, parasites, direct injuries, drugs side effect can trigger the immune system of genetically susceptible individuals to act against muscle tissues. There are several types of myositis with the same systemic symptoms such as muscle weakness, fatigue, muscle pain and inflammation. These include dermatomyositis, juvenile dermatomyositis, inclusion-body myositis, polymyositis, orbital myositis and myositis ossificans. Juvenile and adult dermatomyositis are chronic, immune-mediated inflammatory myopathies characterized by progressive proximal muscle weakness and typical skin symptoms. The aim of the authors was to compare the symptoms, laboratory and serological findings and disease course in children and adult patients with idiopathic inflammatory myopathy. Early diagnosis and aggressive immunosuppressive treatment improve the mortality of these patients. Myositis-specific autoantibodies have predictive and prognostic values regarding the associated overlap disease, response to treatment and disease course. The authors intend to lighten the clinical and pathogenetic significance of the new target autoantigens. Orv. Hetil., 2016, 157(29), 1179-1184.
Since the first description of the silicateins, a group of enzymes that mediate the formation of the amorphous, hydrated biosilica of the skeleton of the siliceous sponges, much progress has been achieved in the understanding of this biomineralization process. These discoveries include, beside the proof of the enzymatic nature of the sponge biosilica formation, the dual property of the enzyme, to act both as a structure-forming and structure-guiding protein, and the demonstration that the initial product of silicatein is a soft, gel-like material that has to undergo a maturation process during which it achieves its favorable physical-chemical properties allowing the development of various technological or medical applications. This process comprises the hardening of the material by the removal of water and ions, its cast-molding to specific morphologies, as well as the fusion of the biosilica nanoparticles through a biosintering mechanism. The discovery that the enzymatically formed biosilica is morphogenetically active and printable also opens new applications in rapid prototyping and three-dimensional bioprinting of customized scaffolds/implants for biomedical use.
Nuclear aggregates of polyamines (NAPs) are supramolecular compounds generated by the self-assembly of protonated nuclear polyamines (spermine, spermidine and putrescine) and phosphate ions. In the presence of genomic DNA, the hierarchical process of self-structuring ultimately produces nanotube-like polymers that envelop the double helix. Because of their modular nature and their aggregation-disaggregation dynamics, NAPs confer plasticity and flexibility to DNA. Through the disposition of charges, NAPs also enable a bidirectional stream of information between the genome and interacting moieties. High mobility group (HMG) B1 is a non-histone chromosomal protein that binds to DNA and that influences multiple nuclear processes. Because genomic DNA binds to either NAPs or HMGB1 protein, we explored the ability of in vitro self-assembled NAPs (ivNAPs) to mediate the DNA-HMGB1 interaction. To this end, we structured DNA-NAPs-HMGB1 and DNA-HMGB1-NAPs ternary complexes in vitro through opportune sequential incubations. Mobility shift electrophoresis and atomic force microscopy showed that the DNA-ivNAPs-HGMB1 complex had conformational assets supposedly more suitable those of the DNA-HGMB1-ivNAPs to comply with the physiological and functional requirements of DNA. Our findings indicated that ivNAPs act as mediators of the DNA-HMGB1 interaction.
Peptides are known to have diverse biological roles, most prominently as signaling/regulatory molecules in a broad variety of physiological processes including defense, immunity, stress, growth, homeostasis and reproduction. These aspects have been used in the field of dermatology and cosmetology to produce short, stable and synthetic peptides for extracellular matrix synthesis, pigmentation, innate immunity and inflammation. The evolution of peptides over the century, which started with the discovery of penicillin, has now extended to their usage as cosmeceuticals in recent years. Cosmeceutical peptides may act as signal modulators of the extracellular matrix component, as structural peptides, carrier peptides and neurotransmitter function modulators. Transdermal delivery of peptides can be made more effective by penetration enhancers, chemical modification or encapsulation of peptides. The advantages of using peptides as cosmeceuticals include their involvement in many physiological functions of the skin, their selectivity, their lack of immunogenicity and absence of premarket regulatory requirements for their use. However, there are disadvantages: clinical evidence for efficacy is often weak, absorption may be poor due to low lipophilicity, high molecular weight and binding to other ingredients, and prices can be quite high.
Planar cell polarity (PCP) refers to the collective alignment of polarity along the tissue plane. In skin, the largest mammalian organ, PCP aligns over extremely long distances, but the global cues that orient tissue polarity are unknown. Here, we show that Celsr1 asymmetry arises concomitant with a gradient of tissue deformation oriented along the medial-lateral axis. This uniaxial tissue tension, whose origin remains unknown, transiently transforms basal epithelial cells from initially isotropic and disordered states into highly elongated and aligned morphologies. Reorienting tissue deformation is sufficient to shift the global axis of polarity, suggesting that uniaxial tissue strain can act as a long-range polarizing cue. Observations both in vivo and in vitro suggest that the effect of tissue anisotropy on Celsr1 polarity is not a direct consequence of cell shape but rather reflects the restructuring of cell-cell interfaces during oriented cell divisions and cell rearrangements that serve to relax tissue strain. We demonstrate that cell intercalations remodel intercellular junctions predominantly between the mediolateral interfaces of neighboring cells. This restructuring of the cell surface polarizes Celsr1, which is slow to accumulate at nascent junctions yet stably associates with persistent junctions. We propose that tissue anisotropy globally aligns Celsr1 polarity by creating a directional bias in the formation of new cell interfaces while simultaneously aligning the persistent interfaces at which Celsr1 prefers to accumulate.
Sensory dendrite arbors are patterned through cell-autonomously and non-cell-autonomously functioning factors [1-3]. Yet, only a few non-cell-autonomously acting proteins have been identified, including semaphorins [4, 5], brain-derived neurotrophic factors (BDNFs) [6], UNC-6/Netrin [7], and the conserved MNR-1/Menorin-SAX-7/L1CAM cell adhesion complex [8, 9]. This complex acts from the skin to pattern the stereotypic dendritic arbors of PVD and FLP somatosensory neurons in Caenorhabditis elegans through the leucine-rich transmembrane receptor DMA-1/LRR-TM expressed on PVD neurons [8, 9]. Here we describe a role for the diffusible C. elegans protein LECT-2, which is homologous to vertebrate leukocyte cell-derived chemotaxin 2 (LECT2)/Chondromodulin II. LECT2/Chondromodulin II has been implicated in a variety of pathological conditions [10-13], but the developmental functions of LECT2 have remained elusive. We find that LECT-2/Chondromodulin II is required for development of PVD and FLP dendritic arbors and can act as a diffusible cue from a distance to shape dendritic arbors. Expressed in body-wall muscles, LECT-2 decorates neuronal processes and hypodermal cells in a pattern similar to the cell adhesion molecule SAX-7/L1CAM. LECT-2 functions genetically downstream of the MNR-1/Menorin-SAX-7/L1CAM adhesion complex and upstream of the DMA-1 receptor. LECT-2 localization is dependent on SAX-7/L1CAM, but not on MNR-1/Menorin or DMA-1/LRR-TM, suggesting that LECT-2 functions as part of the skin-derived MNR-1/Menorin-SAX-7/L1CAM adhesion complex. Collectively, our findings suggest that LECT-2/Chondromodulin II acts
 as a muscle-derived, diffusible cofactor together with a skin-derived cell adhesion complex to orchestrate the molecular interactions of three tissues during patterning of somatosensory dendrites.
In this column, Sara Wickham takes a sideways look at issues relevant to midwives, students, women and families, inviting us to sit down with a cup of tea and ponder what we think we know. In this article, Sara shares the story of a woman who discovered that the due date calculation made by a machine was considered inalienable, even when another date was known with certainty to be correct. Is this an inevitable consequence of our modern world, or can we act to challenge such situations?
Insect larvae killed by entomopathogenic nematodes are thought to contain bacterial communities dominated by a single bacterial genus, that of the nematode's bacterial symbiont. In this study, we used next-generation sequencing to profile bacterial community dynamics in greater wax moth (Galleria mellonella) larvae cadavers killed by Heterorhabditis nematodes and their Photorhabdus symbionts. We found that, although Photorhabdus strains did initially displace an Enterococcus-dominated community present in uninfected G. mellonella insect larvae, the cadaver community was not static. Twelve days postinfection, Photorhabdus shared the cadaver with Stenotrophomonas species. Consistent with this result, Stenotrophomonas strains isolated from infected cadavers were resistant to Photorhabdus-mediated toxicity in solid coculture assays. We isolated and characterized a Photorhabdus-produced antibiotic from G. mellonella cadavers, produced it synthetically, and demonstrated that both the natural and synthetic compounds decreased G. mellonella-associated Enterococcus growth, but not Stenotrophomonas growth, in vitro Finally, we showed that the Stenotrophomonas strains described here negatively affected Photorhabdus growth in vitro Our results add an important dimension to a broader understanding of Heterorhabditis-Photorhabdus biology and also demonstrate that interspecific bacterial competition likely characterizes even a theoretically monoxenic environment, such as a Heterorhabditis-Photorhabdus-parasitized insect cadaver.
Understanding, and eventually manipulating, both human and environmental health depends on a complete accounting of the forces that act on and shape microbial communities. One of these underlying forces is hypothesized to be resource competition. A resource that has received little attention in the general microbiological literature, but likely has ecological and evolutionary importance, is dead/decaying multicellular organisms. Metazoan cadavers, including those of insects, are ephemeral and nutrient-rich environments, where resource competition might shape interspecific macrobiotic and microbiotic interactions. This study is the first to use a next-generation sequencing approach to study the community dynamics of bacteria within a model insect cadaver system: insect larvae parasitized by entomopathogenic nematodes and their bacterial symbionts. By integrating bioinformatic, biochemical, and classic in vitro microbiological approaches, we have provided mechanistic insight into how antibiotic-mediated bacterial interactions may shape community dynamics within insect cadavers.
Quality-adjusted life years (QALYs) are used to determine how to allocate resources to health programmes or to treatments within those programmes in order to gain maximum utility from those limited, shared healthcare resources. However, if we use those same population- based QALYs when faced with individual treatment decisions we may act unjustly in relation to that individual or in relation to the wider population. A treatment with a population-based incremental cost-effectiveness ratio beyond our willingness to pay threshold may be denied to a patient even if, for that particular patient, the QALYs gained for the cost would fall within that threshold. When considering individual cases, it is proposed that we should take an individualised approach to the cost of treatment and response to treatment ('individualised QALYs') and a personalised approach to the valuation of health states ('personalised QALYs'). Only if we do this, can we maximise utility and give the patient a fair opportunity to benefit. Individualised and personalised QALYs also allow us to express patient choice and religious treatment preferences in terms of utility. Individualised and personalised QALYs are explored in the context of individual funding requests in the National Health Service. In preference to the concept of 'clinical exceptionality', individualised and personalised QALYs provide the potential for better and more consistent decisions and improved utility. Rather than treating unequal patients as if they were equal, individualised and personalised QALYs promote fair and unequal access to resources for some of our most unequal patients. Potential challenges are also considered.
Notwithstanding improvements in door-to-balloon time, adverse event rates after primary PCI have remained steady. We analysed the effect of symptom-to-balloon (STB) time, a reflection of total ischaemic time, on major adverse cardiovascular events (MACE) and explored predictors of prolonged STB time.
The study population included 1002 consecutive patients (22.4% women) with a mean age of 62.3±13.2 years, who underwent primary PCI during 2008-2014. Groups were compared for STB ≤ and >240min. Primary endpoint was one-year MACE, a composite of death, reinfarction, stent thrombosis or target vessel revascularisation.
Symptom-to-balloon time was available in 893 patients of which 588 (65.8%) had STB ≤240min and 305 (34.2%) had STB >240min. The incidence of one-year MACE increased significantly in a stepwise manner with increasing STB time (p for trend=0.003). Symptom-to-balloon time was an independent predictor of one-year MACE along with age >70 years, final TIMI flow <3, three vessel disease, cardiogenic shock and out-of-hospital cardiac arrest. We also performed a multivariate analysis to determine predictors of delayed treatment. Predictors of STB time >240min were age >70 years, female gender, diabetes, absence of prehospital catheter laboratory activation and presentation to a non-PCI centre.
Incidence of MACE was strongly correlated with STB time and STB time was an independent predictor of MACE. We have identified specific subgroups with prolonged STB times (age >70, female gender, diabetes, absence of prehospital activation and presentation to a non-PCI centre). This information should inform future studies and strategies to minimise delays in these subgroups for improved outcomes.
Alpha-amylase/trypsin bi-functional inhibitors (ATIs) are non-gluten protein components of wheat and other cereals that can hypersensitise the human gastrointestinal tract, eventually causing enteropathies in predisposed individuals. These inhibitory proteins can act both directly by targeting specific pro-inflammatory receptors, and indirectly by impairing the activity of digestive enzymes, the latter event causing the accumulation of undigested peptides with potential immunogenic properties. Herein, according to a concerted approach based on in vitro and in silico methods we characterized kinetics, equilibrium parameters and modes of binding of the complexes formed between wheat ATI and two representative mammalian digestive enzymes, namely trypsin and alpha-amylase. Interestingly, we demonstrated ATI to target both enzymes with independent binding sites and with moderately high affinity.
The antioxidant activity of dietary phenols in humans (direct reduction of radicals and other highly oxidizing species) could be largely restricted to fighting postprandial oxidative stress in the gastric compartment. Hence, the development of chemical tests simply modelling this situation is pertinent. In this work, the antioxidant properties of the olive phenols hydroxytyrosol and oleuropein are investigated in pH 5-6 micellar solutions through the reduction of the DPPH radical and the inhibition of the metmyoglobin-induced peroxidation of linoleic acid. In the first test, hydroxytyrosol and oleuropein proved as efficient as common polyphenols and their reactivity was only moderately affected by β-cyclodextrin and bovine serum albumin, taken as models of food macromolecules. In the second test, hydroxytyrosol and oleuropein by themselves came up as relatively weak inhibitors, despite their efficiency at reducing hypervalent haem iron. However, hydroxytyrosol was able to act in synergy with the typical chain-breaking antioxidant α-tocopherol.
A swarm of fish displays a collective behavior (swarm behavior) and moves "en masse" despite the huge number of individual animals. In analogy, organ function is supported by a huge number of cells that act in an orchestrated fashion and this applies also to vascular cells along the vessel length. It is obvious that communication is required to achieve this vital goal. Gap junctions with their modular bricks, connexins (Cxs), provide channels that interlink the cytosol of adjacent cells by a pore sealed against the extracellular space. This allows the transfer of ions and charge and thereby the travel of membrane potential changes along the vascular wall. The endothelium provides a low-resistance pathway that depends crucially on connexin40 which is required for long-distance conduction of dilator signals in the microcirculation. The experimental evidence for membrane potential changes synchronizing vascular behavior is manifold but the functional verification of a physiologic role is still open. Other molecules may also be exchanged that possibly contribute to the synchronization (eg, Ca(2+)). Recent data suggest that vascular Cxs have more functions than just facilitating communication. As
 pharmacological tools to modulate gap junctions are lacking, Cx-deficient mice provide currently the standard to unravel their vascular functions. These include arteriolar dilation during functional hyperemia, hypoxic pulmonary vasoconstriction, vascular collateralization after ischemia, and feedback inhibition on renin secretion in the kidney.
A role for glucose-dependent insulinotropic polypeptide (GIP) in controlling bone resorption has been suspected. However uncertainty remains to identify whether GIP act directly on osteoclasts. The aim of the present study were (i) to identify in different osteoclast differentiation models (human peripheral blood mononuclear cells-PBMC, murine bone marrow macrophage-BMM and murine Raw 264.7 cells) whether GIP was capable of reducing osteoclast formation and resorption; (ii) ascertain whether the highly potent GIP analogue N-AcGIP was capable of inducing a response at lower concentrations and (iii) to decipher the molecular mechanisms responsible for such effects. [d-Ala(2)]-GIP dose-dependently reduced osteoclast formation at concentration as low as 1nM in human PBMC and 10nM in murine BMM cultures. Furthermore, [d-Ala(2)]-GIP also reduced the extent of osteoclast resorption at concentration as low as 1nM in human PBMC and murine BMM cultures. The mechanism of action of [d-Ala(2)]-GIP appeared to be mediated by reduction in intracellular calcium concentration and oscillation that subsequently inhibited calcineurin activity and NFATc1 nuclear translocation. The potency of the highly potent N-AcGIP was determined and highlighted an effect on osteoclast formation and resorption at concentration ten times lower than observed with [d-Ala(2)]-GIP in vitro. Furthermore, N-AcGIP was also capable of reducing the number of osteoclast in ovariectomized mice as well as the circulating level of type I collagen C-telopeptide. Pharmacological concentrations required for reducing osteoclast formation and resorption provide the impetus to design and exploit enzymatically stable GIP analogues for the treatment of bone resorption disorders in humans.
The occurrence of vinyl chloride (VC) is often a main concern at sites contaminated with chlorinated solvents due to its high degree of toxicity and carcinogenicity. VC occurrence in aquifers is most often related to the degradation of higher chlorinated ethenes or ethanes and it is generally detected in plumes along with parent contaminants. However, specific combination of stratigraphic, hydrogeologic and geochemical conditions can enhance the degradation of parents and lead to the formation of plumes almost entirely composed of VC (i.e. VC-only plumes). This paper investigates the causes of VC-only plumes in the aquifers below the city of Ferrara (northern Italy) by combining multiple lines of evidence. The City of Ferrara is located on an alluvial lowland, built by the River Po, and is made up of alternating unconsolidated sandy aquifer and silt-clay aquitard deposits of fluvial origin. This region has been strongly impacted by prior industrial activities, with the occurrence of chlorinated compounds at several sites. VC-only plumes with uncertain source location were found at two contaminated sites. The source zone of a third plume composed of chloroethenes from PCE to VC was investigated for high resolution depositional facies architecture and contaminant distribution (contaminant concentration and Compound Specific Isotope Analysis - CSIA). The investigation suggested that degradation of PCE and TCE takes place during contaminant migration through peat-rich (swamp) layers related to the Holocene transgression, which locally act as a "reactor" for stimulating degradation with the accumulation of VC in the strongly reducing environment of the peat. Regional-scale stratigraphic architecture showed the ubiquitous occurrence of swamp layers at distinct stratigraphic levels in the investigated system and their apparent linkage to the in situ creation of the VC-only plumes.
Toxoplasma gondii is an apicomplexan parasite that secretes a large number of protein kinases and pseudokinases from its rhoptry organelles. Although some rhoptry kinases (ROPKs) act as virulence factors, many remain uncharacterized. In this study, predicted ROPKs were assessed for bradyzoite expression then prioritized for a reverse genetic analysis in the type II strain Pru that is amenable to targeted disruption. Using CRISPR/Cas9, we engineered C-terminally epitope tagged ROP21 and ROP27 and demonstrated their localization to the parasitophorous vacuole and cyst matrix. ROP21 and ROP27 were not secreted from microneme, rhoptry, or dense granule organelles, but rather were located in small vesicles consistent with a constitutive pathway. Using CRISPR/Cas9, the genes for ROP21, ROP27, ROP28, and ROP30 were deleted individually and in combination, and the mutant parasites were assessed for growth and their ability to form tissue cysts in mice. All knockouts lines were normal for in vitro growth and bradyzoite differentiation, but a combined ∆rop21/∆rop17 knockout led to a 50% reduction in cyst burden in vivo. Our findings question the existing annotation of ROPKs based solely on bioinformatic techniques and yet highlight the importance of secreted kinases in determining the severity of chronic toxoplasmosis.
Peripheral nervous system has intrinsic regeneration ability after injury, accompanied with the coordination of numerous cells, molecules and signaling pathways. These post-injury biological changes are complex with insufficient understanding. Thus, to obtain a global perspective of changes following nerve injury and to elucidate the mechanisms underlying nerve regeneration are of great importance. By RNA sequencing, we detected transcriptional changes in dorsal root ganglia (DRG) neurons at 0 h, 3 h, 9 h, 1 d, 4 d and 7 d following sciatic nerve crush injury in rats. Differentially expressed genes were then selected and classified into major clusters according to their expression patterns. Cluster 2 (with genes high expressed before 9 h and then down expressed) and cluster 6 (combination of cluster 4 and 5 with genes low expressed before 1 d and then up expressed) were underwent GO annotation and KEGG pathway analysis. Gene act networks were then constructed for these two clusters and the expression of pivotal genes was validated by quantitative real-time PCR. This study provided valuable information regarding the transcriptome changes in DRG neurons following nerve injury, identified potential genes that could be used for improving axon regeneration after nerve injury, and facilitated to elucidate the biological process and molecular mechanisms underlying peripheral nerve injury.
Ants in the genera Anochetus and Odontomachus belong to one of the largest clades in the subfamily Ponerinae, and are one of four lineages of ants possessing spring-loaded "trap-jaws." Here we present results from the first global species-level molecular phylogenetic analysis of these trap-jaw ants, reconstructed from one mitochondrial, one ribosomal RNA, and three nuclear protein-coding genes. Bayesian and likelihood analyses strongly support reciprocal monophyly for the genera Anochetus and Odontomachus. Additionally, we found strong support for seven trap-jaw ant clades (four in Anochetus and three in Odontomachus) mostly concordant with geographic distribution. Ambiguity remains concerning the closest living non-trap-jaw ant relative of the Anochetus+Odontomachus clade, but Bayes factor hypothesis testing strongly suggests that trap-jaw ants evolved from a short mandible ancestor. Ponerine trap-jaw ants originated in the early Eocene (52.5Mya) in either South America or Southeast Asia, where they have radiated rapidly in the last 30million years, and subsequently dispersed multiple times to Africa and Australia. These results will guide future taxonomic work on the group and act as a phylogenetic framework to study the macroevolution of extreme ant mouthpart specialization.
The act of problem formation is integral to the policymaking process. Moreover, the process by which certain situations, experiences or events are rendered problematic hinges upon the places, spaces and networks through which the issue is made visible and intelligible to policy makers and decision makers. In this paper, we explore these epistemic geographies by unpacking one such example - the Mental Health Commission of Canada's At Home/Chez Soi study - a federally funded, $110 million field trial of the Housing First (HF) model. HF prioritizes rapid rehousing of the chronically homeless, followed by separate support and treatment services. The model has become widespread in Canada since 2005, based in large part on understandings of its cost-effectiveness. In this article, we utilize At Home/Chez Soi as an illustrative case for examining how 'chronic homelessness' is translated into a discourse of costs and benefits, and given an accounting value, through a series of translations. This problematization advances a particular logic - what we refer to as 'bedspace'.
Toxin-antitoxin modules are gene pairs encoding a toxin and its antitoxin, and are found on the chromosomes of many bacteria, including pathogens. Here, we characterize the specific contribution of the TxpA and YqcG toxins in elimination of defective cells from developing Bacillus subtilis biofilms. On nutrient limitation, defective cells accumulated in the biofilm breaking its symmetry. Deletion of the toxins resulted in accumulation of morphologically abnormal cells, and interfered with the proper development of the multicellular community. Dual physiological responses are of significance for TxpA and YqcG activation: nitrogen deprivation enhances the transcription of both TxpA and YqcG toxins, and simultaneously sensitizes the biofilm cells to their activity.
 Furthermore, we demonstrate that while both toxins when overexpressed affect the morphology of the developing biofilm, the toxin TxpA can act to lyse and dissolve pre-established B. subtilis biofilms.
Text messaging services could increase access to psychotherapeutic content for individuals with depression by avoiding barriers to in-person psychotherapy such as cost, transportation, and therapist availability. Determining whether text messages reflecting different psychotherapeutic techniques exhibit differences in acceptability or effectiveness may help guide service development.
We aimed to determine: (1) the feasibility of delivering a psychotherapy-based text messaging service to people with depression identified via the internet, (2) whether there is variation in satisfaction with messages according to the type of psychotherapeutic technique they represent, and (3) whether symptoms of depression vary according to receipt of each message type and participants' satisfaction with the messages they received.
For this study 190 US adults who screened positive for a major depressive episode (Patient Health Questionnaire (PHQ-9) score ≥10) were recruited from online advertisements. Participants received a daily psychotherapy-based text message 6 days per week for 12 weeks. Text messages were developed by a team of psychiatrists, psychologists, and social workers to reflect three psychotherapeutic approaches: acceptance and commitment therapy (ACT), behavioural activation, and cognitive restructuring. Each week the message type for the week was randomly assigned from one of the three types, allowing for repeats. Participants were asked daily to rate each message. On the 7th day of each week, participants completed a two-item depression screener (PHQ-2). Web-based surveys at baseline, 6, and 12 weeks were used as the primary measure of depressive symptoms (PHQ-9).
Of the 190 participants enrolled, 85 (45%) completed the 6-week web survey and 67 (35%) completed the 12-week survey. The mean baseline PHQ-9 score was 19.4 (SD 4.2) and there was a statistically significant mean improvement in PHQ-9 scores of -2.9 (SD 6.0; p < 0.001) at 6 weeks and -4.8 (SD 6.6; p < 0.001) at 12 weeks. Mean satisfaction ratings did not vary across message types. There was generally no association between the number of weeks in which participants received a given message type and PHQ-9 scores at follow-up. However, among individuals with more severe depression at baseline (PHQ-9 ≥ 20; n = 30), the number of weeks of behavioural activation messages received was associated with less symptom improvement (ρ = 0.37; p = 0.04) at 12 weeks. Participants who gave higher satisfaction ratings to messages regardless of type had greater reductions in PHQ-9 scores at 6 weeks.
Study participants exhibited borderline clinically significant improvement in depressive symptoms at 12 weeks suggesting the effects of the intervention, if any, were small. Although there was no overall variation in changes in PHQ-9 according to users' exposure to the three message types, effectiveness among severely depressed participants could potentially be improved by tailoring towards fewer behavioural activation messages. Controlled studies to determine effectiveness of texting interventions such as this one are indicated considering that even small effects may be cost effective given the low cost of delivering text messages.
The effects of combined calcium peroxide (CaO2) oxidation with chemical re-flocculation on dewatering performance and physicochemical properties of waste activated sludge was investigated in this study. The evolutions of extracellular polymeric substances (EPS) distribution, composition and morphological properties were analyzed to unravel the sludge conditioning mechanism. It was found that sludge filtration performance was enhanced by calcium peroxide oxidation with the optimal dosage of 20 mg/gTSS. However, this enhancement was not observed at lower dosages due to the absence of oxidation and the performance deteriorated at higher dosages because of the release of excess EPS, mainly as protein-like substances. The variation in soluble EPS (SEPS) component can be fitted well with pseudo-zero-order kinetic model under CaO2 treatment. At the same time, extractable EPS content (SEPS and loosely bound EPS (LB-EPS)) were dramatically increased, indicating sludge flocs were effectively broken and their structure became looser after CaO2 addition. The sludge floc structure was reconstructed and sludge dewaterability was significantly enhanced using chemical re-flocculation (polyaluminium chloride (PACl), ferric iron (FeCl3) and polyacrylamide (PAM)). The inorganic coagulants performed better in improving sludge filtration dewatering performance and reducing cake moisture content than organic polymer, since they could act as skeleton builders and decrease the sludge compressibility.
Sulfonamides (SAs) are extensively used antibiotics and their residues in the water bodies propose potential threat to the public. In this study, degradation efficiency of sulfanilamide (SAM), which is the precursor of SAs, using WO3 nanoplates and their Ag heterogeneous as photocatalysts was investigated. WO3 nanoplates with uniform size were synthesized by a facile one step hydrothermal method. Different amount of Ag nanoparticles (Ag NPs) were loaded onto WO3 nanoplates using a photo-reduction method to generate WO3/Ag composites. The physio-chemical properties of synthesized nanomaterials were systematically characterized. Photodegradation of SAM by WO3 and WO3/Ag composites was conducted under visible light irradiation. The results show that WO3/Ag composites performed much better than pure WO3 where the highest removal rate was 96.2% in 5h. Ag as excellent antibacterial agent also endows certain antibacterial efficiency to WO3, and 100% removal efficiency against Escherichia Coli and Bacillus subtilis could be achieved in 2h under visible light irradiation for all three WO3/Ag composites synthesized. The improved performance in terms of SAM degradation and antibacterial activity of WO3/Ag can be attributed to the improved electron-hole pair separation rate where Ag NPs act as effective electron trapper during the photocatalytic process.
The 2008 Wellstone and Domenici Mental Health Parity and Addiction Equity Act (MHPAEA) aims to secure parity in private insurance coverage between behavioral and other medical disorders in the United States (U.S.). This legislation represents an important change in the operating field of substance use disorder treatment, but to date, its impact on treatment centers has not been widely examined. The current study measured the extent of center leaders' familiarity with the MHPAEA and their perceptions of its overall impact on their centers.
Using a nationally representative sample of treatment centers in the U.S., we examined the extent of MHPAEA familiarity and its perceived impact as reported by treatment center leaders. We further employed logistic and ordered logistic regressions to determine personal and organizational characteristics associated with their reported familiarity and experienced impacts, including changes in the number of privately-insured clients seeking treatment and in the treatment coverage of those clients.
We found that dissemination of parity information was low. Only 36% of administrators reported high levels of familiarity and 16% used professional sources of information. The majority of administrators (71%) reported no impact of the legislation on their organization, but those that reported any impact were more likely to state positive impact. Greater parity knowledge and perceived positive impacts were associated with administrator and organizational characteristics indicative of greater access to industry-specific knowledge, a medical model orientation, and reliance on private insurance revenue.
This study demonstrates that dissemination of parity information is lacking and that the majority of leaders have yet to experience an impact of the MHPAEA. Leaders of centers with more sophisticated structures are most likely to be familiar with the legislation and perceive a positive impact. Research concerning the effective management of treatment centers, including environmental scanning techniques, continues to be needed.
Based on its wide expression in immune cells, type-2 cannabinoid (CB2) receptors were traditionally thought to act as "peripheral receptors" with an almost exclusively immunomodulatory function. However, their recent identification in mammalian brain areas, as well as in distinct neuronal cells, has opened the way to a re-consideration of CB2 signaling in the context of brain pathophysiology, synaptic plasticity and neuroprotection. To date, accumulated evidence from several independent preclinical studies has offered new perspectives on the possible involvement of CB2 signaling in brain and spinal cord traumatic injury, as well as in the most relevant neurodegenerative disorders like Alzheimer's disease, Parkinson's disease and Huntington's chorea. Here, we will review available information on CB2 in these disease conditions, along with data that support also its therapeutic potential to treat them.
When offered diets with hay ad libitum, rabbits (Oryctolagus cuniculus) clearly prefer open dishes over nipple drinkers, but whether this preference also applies in guinea pigs (Cavia porcellus) is unsure. We tested the drinker preference of 10 guinea pigs when offered open dishes (OD) and nipple drinkers (ND) simultaneously and measured the amount of water consumed by each animal on four different diets (grass hay 100%, or as 10% of intake on diets of fresh parsley, seed mix or pelleted complete feed, respectively) on either of the drinking systems. All animals ingested the hay portion of the combined
 diets first. The amount of water consumed differed significantly between individual animals. Animals drank less water on parsley than on the other diets. Nine of 10 animals clearly preferred ND when having a choice, and eight of these drank more when on ND only. The difference between the drinking systems was not consistent across all diets: on hay, similar amounts of water were drunk when on OD or ND only. Differences in water intake were reflected in urine production. Because drinking from ND in guinea pigs involves jaw movements similar to those in chewing, the results could suggest that when motivation for oral processing behaviour is not satisfied by a diet, animals may respond in using ND beyond physiological water necessity. Whereas physiological water requirements are probably better investigated with other drinking systems due to a possible overestimation when using ND, offering ND to pet guinea pigs most likely offers a form of behavioural enrichment that at the same time may increase water intake and hence act as prophylaxis against urolithiasis.
Field application of livestock manure introduces colloids and veterinary antibiotics, e.g. sulfonamides (SAs), into farmland. The presence of manure colloids may potentially intensify the SAs-pollution to soils and groundwater by colloid-facilitated transport. Transport of three SAs, sulfadiazine (SDZ), sulfamethoxypyridazine (SMPD), and sulfamoxole (SMOX), was investigated in saturated soil columns with and without manure colloids from sows and farrows, weaners, and fattening pigs. Experimental results showed that colloid-facilitated transport of SMOX was significant in the presence of manure colloids from fattening pigs with low C/N ratio, high SUVA280nm and protein C, while manure colloids from sows and farrows and weaners had little effect on SMOX transport. In contrast, only retardation was observed for SDZ and SMPD when manure colloids were present. Breakthrough curves (BTCs) of colloids and SAs were replicated well by a newly developed numerical model that considers colloid-filtration theory, competitive kinetic sorption, and co-transport processes. Model results demonstrate that mobile colloids act as carriers for SMOX, while immobile colloids block SMOX from sorbing onto the soil. The low affinity of SMOX to sorb on immobile colloids prevents aggregation and also promotes SMOX's colloid-facilitated transport. Conversely, the high affinity of SDZ and SMPD to sorb on all types of immobile colloids retarded their transport. Thus, manure properties play a fundamental role in increasing the leaching risk of hydrophobic sulfonamides.
Appropriative water rights allocate surface water to competing users based on seniority. Often water rights vary seasonally with spring runoff, irrigation schedules, or other non-uniform supply and demand. Downscaled monthly Coupled Model Intercomparison Project multi-model, multi-emissions scenario hydroclimate data evaluate water allocation reliability and variability with anticipated hydroclimate change. California's Tuolumne watershed is a study basin, chosen because water rights are well-defined, simple, and include competing environmental, agricultural, and urban water uses representative of most basins. We assume that dedicated environmental flows receive first priority when mandated by federal law like the Endangered Species Act or hydropower relicensing, followed by senior agricultural water rights, and finally junior urban water rights. Environmental flows vary by water year and include April pulse flows, and senior agricultural water rights are 68% larger during historical spring runoff from April through June. Results show that senior water right holders receive the largest climate-driven reductions in allocated water when peak streamflow shifts from snowmelt-dominated spring runoff to mixed snowmelt- and rainfall-dominated winter runoff. Junior water right holders have higher uncertainty from inter-annual variability. These findings challenge conventional wisdom that water shortages are absorbed by junior water users and suggest that aquatic ecosystems may be disproportionally impaired by hydroclimate change, even when environmental flows receive priority.
Wastewater-derived organic nitrogen (org-N) can act as both nutrients and carcinogenic nitrogenous disinfection byproduct precursors. In this study, the concentration, composition, bioavailability, and N-nitrosodimethylamine (NDMA) formation potential of particulate organic nitrogen (PON) from three different municipal wastewater treatment plants were characterized and compared with that of effluent dissolved organic nitrogen (DON). The average effluent PON and DON concentrations ranged from 0.09 to 0.55mgN/L and from 0.91 to 1.88mgN/L, respectively. According to principal component analysis, org-N composition and characterization differed in PON and DON samples (n=20). Compared with DON, PON tended to be enriched in protein and nucleic acids, and showed a more proteinaceous character. Composition of org-N functional groups estimated from the X-ray photoelectron spectroscopy N 1s spectra indicate no significant differences in the molecular weight distribution of the protein-like materials between PON and DON. Moreover, PON exhibited a significantly higher bioavailability (61.0±13.3%) compared to DON (38.5±12.4%, p˂0.05, t-test) and a significantly higher NDMA yields (791.4±404.0ng/mg-N) compared to DON (374.8±62.5ng/mg-N, p˂0.05, t-test). Accordingly, PON contributed to approximately 12.3-41.7% of the total bioavailable org-N and 22.0-38.4% of the total NDMA precursors in wastewater effluents. Thus, the potential adverse effects of PON on wastewater discharge and reuse applications should not be overlooked, even though it only accounted for 7.4-26.8% of the total effluent org-N.
Rapid and efficient synthesis of 23 analogues inspired by bromotyramine derivatives, marine natural products, by means of CuSO4-catalysed [3+2] alkyne-azide cycloaddition is described. The final target was then assayed for anti-biofilm activity against three Gram-negative marine bacteria, Pseudoalteromonas ulvae (TC14), Pseudoalteromonas lipolytica (TC8) and Paracoccus sp. (4M6). Most of the synthesised bromotyramine/triazole derivatives are more active than the parent natural products Moloka'iamine (A) and 3,5-dibromo-4-methoxy-β-phenethylamine (B) against biofilm formation by the three bacterial strains. Some of these compounds were shown to act as non-toxic inhibitors of biofilm development with EC50 < 200 μM without any effect on bacterial growth even at high concentrations (200 μM).
CO2 reduction in aqueous electrolytes suffers efficiency losses because of the simultaneous reduction of water to H2 We combine in situ surface-enhanced IR absorption spectroscopy (SEIRAS) and electrochemical kinetic studies to probe the mechanistic basis for kinetic bifurcation between H2 and CO production on polycrystalline Au electrodes. Under the conditions of CO2 reduction catalysis, electrogenerated CO species are irreversibly bound to Au in a bridging mode at a surface coverage of ∼0.2 and act as kinetically inert spectators. Electrokinetic data are consistent with a mechanism of CO production involving rate-limiting, single-electron transfer to CO2 with concomitant adsorption to surface active sites followed by rapid one-electron, two-proton transfer and CO liberation from the surface. In contrast, the data suggest an H2 evolution mechanism involving rate-limiting, single-electron transfer coupled with proton transfer from bicarbonate, hydronium, and/or carbonic acid to form adsorbed H species followed by rapid one-electron, one-proton, or H recombination reactions. The disparate proton coupling requirements for CO and H2 production establish a mechanistic basis for reaction selectivity in electrocatalytic fuel formation, and the high population of spectator CO species highlights the complex heterogeneity of electrode surfaces under conditions of fuel-forming electrocatalysis.
Deterministic evolutionary theory robustly predicts that populations displaying altruistic behaviors will be driven to extinction by mutant cheats that absorb common benefits but do not themselves contribute. Here we show that when demographic stochasticity is accounted for, selection can in fact act in the reverse direction to that predicted deterministically, instead favoring cooperative behaviors that appreciably increase the carrying capacity of the population. Populations that exist in larger numbers experience a selective advantage by being more stochastically robust to invasions than smaller populations, and this advantage can persist even in the presence of reproductive costs. We investigate this general effect in the specific context of public goods production and find conditions for stochastic selection reversal leading to the success of public good producers. This insight, developed here analytically, is missed by the deterministic analysis as well as by standard game theoretic models that enforce a fixed population size. The effect is found to be amplified by space; in this scenario we find that selection reversal occurs within biologically reasonable parameter regimes for microbial populations. Beyond the public good problem, we formulate a general mathematical framework for models that may exhibit stochastic selection reversal. In this context, we describe a stochastic analog to [Formula: see text] theory, by which small populations can evolve to higher densities in the absence of disturbance.
In 2010, the Affordable Care Act (ACA) extended eligibility for dependent coverage under private health insurance. Emerging evidence shows that young adults, including those with behavioral health disorders (BHDs), have benefited from this expansion.
The objective of this study is to explore the population characteristics
 of the remaining uninsured individuals with and without BHDs and to examine whether the factors that contribute to racial and ethnic disparities in the likelihood of being uninsured were different after the implementation of the ACA provision that extended insurance eligibility for young adults in 2010.
We use cross-sectional data analysis.
We use a nationally representative dataset of the non-institutionalized civilian population in the Medical Expenditure Panel Survey from 2007 to 2012.
We compare population characteristics of the remaining uninsured individuals ages 19-25, before and after the implementation of the ACA expansion in 2010. We use multivariate logistic regression to estimate the predictors (such as family income and English proficiency) that are associated with the likelihood of having no health insurance. We utilize the Fairlie decomposition method to examine the factors that contribute to racial (non-Latino White (White) vs. non-Latino African-American (African-American)) and ethnic (non-Latino White (White) vs. Latino) differences in the probability of being uninsured. Finally, we apply our analysis among populations with and without BHDs respectively, to examine the differences in the predictors of being uninsured between these two groups.
Among individuals with BHDs, after adjusting for covariates, the estimated probabilities of being uninsured for Whites were 0.21 and 0.16 pre- and post- the ACA expansion, respectively. The predicted probabilities of being uninsured for Latinos were 0.29 and 0.26 and for African-American were 0.19 and 0.17 pre- and post- the ACA expansion, respectively. The ethnic disparity between Whites and Latinos was 19 %. The racial disparity was moderate. Reductions in the uninsured rate of individuals without BHDs were observed as well. However, the ethnicity disparity remained at 19 % and the racial disparity increased by 5 %. Overall, our decomposition model explained 63-89 % of the racial and ethnic disparities in insurance coverage. The major factor associated with the ethnic disparity among those with BHDs was the immigrant status of Latinos, and the major factor associated with racial disparity was geographic location. The major factor associated with the ethnic disparity among those without BHDs included the immigrant status of Latinos, lack of English proficiency, and geographic location, whereas the major factor associated with racial disparity was family income.
Our study presents health insurance coverage trends among racial and ethnic minorities after the implementation of insurance expansion, a major provision of the ACA. It is important for policy makers to be aware of differences among the remaining uninsured as they evaluate ways to improve healthcare access and affordability.
Identifying small molecules to activate the Oct-4/Sox2-derived pluripotency network represents a hopeful and safe method to pluripotency without genetic manipulation. Luteolin and apigenin, two major bioactive flavonoids, enhance reprogramming efficiency and increase expression of Oct-4/Sox2/c-Myc, albeit the detailed mechanism regulating pluripotency in dental-derived cells remains unknown. In the present study, to elucidate the effect of luteolin/apigenin on pluripotency of periodontal ligament cells (PDLCs) through interaction with downstream signals, we examined cell cycle, proliferation, apoptosis, expression of Oct-4/Sox2/c-Myc, and multilineage differentiation of PDLCs with luteolin/apigenin treatment. Moreover, we profiled the differentially expressed pluripotency genes by PCR arrays. Our results demonstrated that luteolin/apigenin restrained cell proliferation, increased apoptosis, and arrested PDLCs in G2/M and S phase. Luteolin and apigenin activated expression of Oct-4, Sox2, and c-Myc in a time- and dose-dependent pattern, and repressed lineage-specific differentiation. PCR arrays profiled multiple signals in PDLCs with luteolin/apigenin treatment, among which NFATc1 was the major upregulated gene. Notably, blocking of the NFATc1 signal with INCA-6 significantly decreased mRNA and protein expression of Oct-4, Sox2, and c-Myc in PDLCs with luteolin/apigenin treatment, indicating that NFATc1 may act as an upstream modulator of Oct-4/Sox2 signal. Taken together, this study showed that luteolin and apigenin effectively maintain pluripotency of PDLCs through activation of Oct-4/Sox2 signal via NFATc1.
Arf GTPases assemble protein complexes on membranes to carry out major functions in cellular traffic. An essential step is their activation by guanine nucleotide exchange factors (GEFs), whose Sec7 domain stimulates GDP/GTP exchange. ArfGEFs form 2 major families: ArfGEFs with DCB, HUS and HDS domains (GBF1 and BIG1/BIG2 in humans), which act at the Golgi; and ArfGEFs with a C-terminal PH domain (cytohesin, EFA6 and BRAG), which function at the plasma membrane and endosomes. In addition, pathogenic bacteria encode an ArfGEF with a unique membrane-binding domain. Here we review the allosteric regulation of Arf GTPases and their GEFs at the membrane interface. Membranes contribute several regulatory layers: at the GTPase level, where activation by GTP is coupled to membrane recruitment by a built-in structural device; at the Sec7 domain, which manipulates this device to ensure that Arf-GTP is attached to membranes; and at the level of non-catalytic ArfGEF domains, which form direct or GTPase-mediated interactions with membranes that enable a spectacular diversity of regulatory regimes. Notably, we show here that membranes increase the efficiency of a large ArfGEF (human BIG1) by 32-fold by interacting directly with its N-terminal DCB and HUS domains. The diversity of allosteric regulatory regimes suggests that ArfGEFs can function in cascades and circuits to modulate the shape, amplitude and duration of Arf signals in cells. Because Arf-like GTPases feature autoinhibitory elements similar to those of Arf GTPases, we propose that their activation also requires allosteric interactions of these elements with membranes or other proteins.
This second article of a series of four is aimed to inform dental practitioners about the relevance to provide more formal analysis of economic resources when helping patients make clinical decisions.
The following methods of health economic evaluation are described: Cost-effectiveness-analysis (CEA), cost-utility-analysis (CUA) and cost-benefit-analysis (CBA). CEA compares the effectiveness of different interventions usually based on specific clinical outcome measures, for example pocket depth reduction. CUA evaluates the effectiveness of therapies by taking into account more generic health outcome measures such as quality adjusted life years (QALYs). Cost-benefit-analysis (CBA) is based on measuring patients' actual willingness to pay. Cost-benefit-analysis (CBA) is based on measuring patients' actual willingness to pay, and it offers a method of economic evaluation that values all benefits against all costs. In other words, the total costs of a specific intervention are subtracted from the value of benefits related to that intervention.
This article reported common methods of health economic evaluation that could be taken into account throughout clinical decision-making. Decision makers (patients, practitioners, health policy) should be adequately informed about costs and health outcomes associated with the various therapeutic alternatives in order to act responsibly within scenarios of resource scarcity. Economic evaluations can be informative with respect to whether or not the health outcomes outweigh the costs of an intervention, and hence provide a decision-making tool for decision makers considering treatment alternatives.
The information provided here may help decision makers (patients, practitioners, health policy) to understand economic considerations as an essential component of the decision-making process. Carefulness is advised with regard to interpreting the results from economic evaluation studies.
Fishes have several means of moving water to effect odorant transport to their olfactory epithelium ('olfactory flow'). Here we show that olfactory flow in the adult garpike Belone belone (Belonidae, Teleostei), a fish with an unusual nasal region, can be generated by its motion relative to water (swimming, or an external current, or both). We also show how the unusual features of the garpike's nasal region influence olfactory flow. These features comprise a triangular nasal cavity in which the olfactory epithelium is exposed to the external environment, a papilla situated within the nasal cavity, and an elongated ventral apex. To perform our investigation we first generated life-like plastic models of garpike heads from X-ray scans of preserved specimens. We then suspended these models in a flume and flowed water over them to simulate swimming. By directing filaments of dye at the static models, we were able to visualise flow in the nasal regions at physiologically relevant Reynolds numbers (700-2,000). We found that flow of water over the heads did cause circulation in the nasal cavity. Vortices may assist in this circulation. The pattern of olfactory flow was influenced by morphological variations and the asymmetry of the nasal region. The unusual features of the nasal region may improve odorant sampling in the garpike, by dispersing flow over the olfactory epithelium and by creating favourable conditions for odorant transport (e.g. steep velocity gradients). Unexpectedly, we found that the mouth and the base of the garpike's jaws may assist the sampling process. Thus, despite its apparent simplicity, the garpike's nasal region is likely to act as an effective trap for odorant molecules.
The transforming growth factor-β (TGF-β) family of ligands elicit their biological effects by initiating new programs of gene expression. The best
 understood signal transducers for these ligands are the SMADs, which essentially act as transcription factors that are activated in the cytoplasm and then accumulate in the nucleus in response to ligand induction where they bind to enhancer/promoter sequences in the regulatory regions of target genes to either activate or repress transcription. This review focuses on the mechanisms whereby the SMADs achieve this and the functional implications. The SMAD complexes have weak affinity for DNA and limited specificity and, thus, they cooperate with other site-specific transcription factors that act either to actively recruit the SMAD complexes or to stabilize their DNA binding. In some situations, these cooperating transcription factors function to integrate the signals from TGF-β family ligands with environmental cues or with information about cell lineage. Activated SMAD complexes regulate transcription via remodeling of the chromatin template. Consistent with this, they recruit a variety of coactivators and corepressors to the chromatin, which either directly or indirectly modify histones and/or modulate chromatin structure.
Secondary syringe exchangers (SSEs) are a vital component of harm reduction efforts among persons who inject drugs (PWIDs). However, little research has explored how secondary exchange occurs, nor why SSEs do their work. This study looks at secondary exchange as an act of resilience within the PWID risk environment. It asks how secondary syringe exchangers utilize syringes to improve their mental and material well-being.
This article draws on findings from semi-structured in-depth interviews of 30 SSEs. It is also informed by 4 years of participant observation as a volunteer and site supervisor at the San Francisco Aids Foundation syringe exchange sites, and 1 year of participant observation with SSEs and their clients.
This study finds that SSEs use syringes as a resource to support three discursive practices - those of merchants, public health workers, and samaritans. These discursive practices correlate to their work and educational backgrounds, and to their accounts of charging for syringes, disseminating public health information, and helping their clients in various ways.
SSEs hold heterogeneous motivations and operate in multiple contexts. Many SSEs see themselves as, and behave as, informal health care workers or helpers in their community. They could be utilized, with minimal training and encouragement, to disseminate additional harm reduction information and materials.
The idea of empowerment permeates the occupational therapy literature yet has received little critical reflection from occupational therapy's theorists.
This paper aims to explore the concept of empowerment and highlight a recent definition that resonates with occupational therapists' core values.
Empowerment is generally understood to be a process of bestowing power and giving ability to someone deficient in both. However, a new definition provides a framework for understanding how empowerment might enhance people's capabilities.
The World Bank's depiction of empowerment fits well with occupational therapists' beliefs in the importance of the ability and opportunity to "do," providing a framework for action. This framework focuses on people's capabilities: their freedom-or opportunity-to choose what they wish to do and to be and their ability to act on these wishes. Moreover, the World Bank's assertion that empowered people have freedom of both choice and action suggests empowerment is a relevant concept for occupational therapists.
Mitochondrial permeability transition pore (MPTP) is a protein complex whose opening promotes an abrupt increase in mitochondrial inner membrane permeability. Calcium signaling pathways are described in gametes and are involved in the fertilization process. Although mitochondria may act as Ca(2+) store and have a fast calcium-releasing mechanism through MPTP, its contribution to fertilization remains unclear. The work aimed to investigate the MPTP phenomenon in sea urchin spermatozoa and its role on the fertilization. Several pharmacological tools were used to evaluate the MPTP's physiology. Our results demonstrated that MPTP occurs in male gametes in a Ca(2+) - and voltage-dependent manner and it is sensitive to cyclosporine A. Additionally, our data show that MPTP opening does not alter ROS generation in sperm cells. Inhibition of MPTP in spermatozoa strongly improved the fertilization rate, which may involve mechanisms that increase the spermatozoa lifespan. The present work is the first report of the presence of a voltage- and Ca(2+) -dependent MPTP in gametes of invertebrates and indicates MPTP opening as another evolutionary feature shared by sea urchins and mammals. Studies about MPTP in sea urchin male gametes may contribute to the elucidation of several mechanisms involved in sperm infertility.
Calcium signalling relies on the flux of calcium ions across membranes yet how signals in different compartments are related remains unclear. In particular, similar calcium signals on both sides of the nuclear envelope have been reported and attributed to passive diffusion through nuclear pores. However, observed differing cytosolic and nucleosolic calcium signatures suggest that the signalling machinery in these compartments can act independently.
We adapt the fire-diffuse-fire model to investigate the generation of perinuclear calcium oscillations. We demonstrate that autonomous spatio-temporal calcium patterns are still possible in the presence of nuclear and cytosolic coupling via nuclear pores. The presence or absence of this autonomy is dependent upon the strength of the coupling and the maximum firing rate of an individual calcium channel. In all cases, coupling through the nuclear pores enables robust signalling with respect to changes in the diffusion constant.
We show that contradictory interpretations of experimental data with respect to the autonomy of nuclear calcium oscillations can be reconciled within one model, with different observations being a consequence of varying nuclear pore permeabilities for calcium and refractory conditions of channels. Furthermore, our results provide an explanation for why calcium oscillations on both sides of the nuclear envelope may be beneficial for sustained perinuclear signaling.
The aim of this study was to evaluate the association between menstrual cycle characteristics in early life and adulthood and fecundability.
Pregnancy Study Online (PRESTO) is an Internet-based preconception cohort study of pregnancy planners from the United States and Canada. During the preconception period, we enrolled 2189 female pregnancy planners aged 21-45 years who had been attempting conception for ≤6 cycles. Women self-reported menstrual cycle characteristics via an online baseline questionnaire, and pregnancy status was ascertained through bimonthly follow-up questionnaires. Proportional probabilities models were used to estimate fecundability ratios (FRs) and 95% confidence intervals (CIs), adjusting for potential confounders.
Compared with usual menstrual cycle lengths of 27-29 days, cycle lengths of <25 (FR = 0.81, 95% CI: 0.54-1.22) and 25-26 days (FR = 0.92, 95% CI: 0.75-1.14) were associated with reduced fecundability. Compared with women who reached menarche at the age of 12-13 years, those who reached menarche at <12 years had reduced fecundability (FR = 0.87, 95% CI: 0.76-0.99). Women whose cycles never regularized after menarche (FR = 0.93, 95% CI: 0.81-1.06) had slightly reduced fecundability compared with women whose cycles regularized within 2 years of menarche. Bleed length and heaviness of bleeding were not appreciably associated with fecundability.
Menstrual cycle characteristics, specifically cycle length and age at menarche, may act as markers of fertility potential among pregnancy planners.
Transcription of nonprotein-coding DNA is widespread in eukaryotes and plays important regulatory roles for many genes, including genes that are misregulated in cancer cells. Its pervasiveness presents the potential for a wealth of diverse regulatory roles for noncoding transcription. We previously showed that the act of transcribing noncoding DNA (ncDNA) across the promoter of the protein-coding SER3 gene in Saccharomyces cerevisiae positions nucleosomes over the upstream activating sequences, leading to strong repression of SER3 transcription. To explore the possibility of other regulatory roles for ncDNA transcription, we selected six candidate S. cerevisiae genes that express ncRNAs over their promoters and analyzed the regulation of one of these genes, ECM3, in detail. Because noncoding transcription can lead to changes in the local chromatin landscape that impinge on the expression of nearby coding genes, we surveyed the effects of various chromatin regulators on the expression of ECM3 These analyses identified roles for the Paf1 complex in positively regulating ECM3 transcription through methylation of histone H3 at lysine 4 (K4) and for Paf1 in controlling the pattern of intergenic transcription at this locus. By deleting a putative promoter for the noncoding transcription unit that lies upstream of ECM3, we provide evidence for a positive correlation between intergenic transcription and ECM3 expression. Our results are consistent with a model in which cotranscriptional methylation of histone H3 K4, mediated by the Paf1 complex and noncoding transcription, leads to activation of ECM3 transcription.
Submerged growth of Halobacterium salinarum and therefore synthesis of bacteriorhodopsin (BR) and carotenoids depend greatly on products of both chemical and/or photochemical oxidation of medium components and cellular metabolism which act as inhibitors. Some cultivation variants which allowed eliminating an adverse effect of inhibitors on biomass
 accumulation and BR synthesis are reviewed. The application of activated charcoal or ion exchange resin as adsorbents at preparing inoculums and the main cultivation stages was shown to allow controlling, namely lowering overstress of the halobacterial cells by metabolites. The halobacterial biomass containing BR up to 1,750mgL(-1) and the minimum amount of carotinoids that would BR greatly facilitate isolation was accumulated up to 45gL(-1) during eight-day cultivation with cell recycling through adsorbent suspension in a fed-batch mode. To control BR biosynthesis the express method of BR quantification based on colour shades of cell suspension was developed.
Up-to-date oncological therapy has been accomplished through the results of clinical trials (CTs). We analyzed the overall survival (OS) of patients with non-small cell lung cancer (NSCLC) and its relation to CT enrollment.
The study included 1,042 patients with advanced NSCLC treated at the Instituto Nacional de Cancerología. All patients received treatment according to the national and international guidelines. Data were collected from medical records. Patients were subgrouped on the basis of their CT enrollment as follows: participants in any CT (ACT), exclusively intervention CTs (ICT) or exclusively pharmaceutical-sponsored CTs (PCT).
The CT enrollment effect was assessed through a multivariate Cox proportional hazards model. Thirty percent of the patients were in ACT, 28.3% in ICT and 13.7% in PCT. Female gender (p = 0.001), adenocarcinoma histology (p = 0.018), positive EGFR mutation (p = 0.006), and better ECOG performance status (<2) (p ≤ 0.0001) were more frequent in patients enrolled in CT; further, tobacco smoking (p ≤ 0.0001) and KRAS mutation (p = 0.001) were more frequent in patients who were not enrolled in a CT.
Enrollment in ACT was associated with a better OS (hazard ratio: 0.47-0.74). NSCLC patients enrolled in a CT have an improved survival in an independent manner to other prognostic factors.
In the course of search for selective growth inhibitors against the cancer cells adapted to nutrient starvation, two polybrominated diphenyl ethers, 3,4,5-tribromo-2-(2',4'-dibromophenoxy)-phenol (1) and 3,5-dibromo-2-(2',4'-dibromophenoxy)-phenol (2) were isolated from an Indonesian marine sponge of Dysidea sp. Compounds 1 and 2 showed the anti-proliferative activity against PANC-1 cells under glucose-starved conditions with IC50 values of 2.1 and 3.8 µM, respectively, whereas no growth inhibition was observed up to 30 µM in the general culture conditions. The further mechanistic analysis indicated that compound 1 might act mainly by inhibiting complex II in the mitochondrial electron transport chain.
Cortical thinning is a part of normal ageing. Recent studies suggest that accelerated cortical thinning in vulnerable regions may be a useful biomarker for neuropathologies including Alzheimer's disease (AD). Longitudinal studies, which have largely focused on older adults, have provided estimates of normative rates and patterns of age-related cortical thinning. Very little, however, is known about healthy cortical thinning at midlife. Here we provide longitudinal estimates of age-related cortical thinning observed over 8 years, in a large (n = 404) group of healthy individuals aged 44-49 years at baseline, who were scanned with MRI (1.5T) on up to three occasions. Age-related cortical thinning was assessed across the whole cortex. We measured a mean annual decrease in cortical thickness of 0.26 % on the left and 0.17 % on the right hemisphere, and largely affecting frontal and cingulate cortices. Medial and lateral temporal regions were generally spared. Studying regions that are specifically vulnerable to-or spared from-healthy age-related cortical thinning at midlife may be important for the early identification of neurodegeneration, including AD.
DNA methylation and histone modifications are key epigenetic regulators of gene expression, and tight connections are known between the two. DNA methyltransferases are upregulated in several tumors and aberrant DNA methylation profiles are a cancer hallmark. On the other hand, histone demethylases are upregulated in cancer cells. Previous work on ES cells has shown that the lysine demethylase KDM1A binds to DNMT1, thereby affecting DNA methylation. In cancer cells, the occurrence of this interaction has not been explored. Here we demonstrate in several tumor cell lines an interaction between KDM1A and both DNMT1 and DNMT3B. Intriguingly and in contrast to what is observed in ES cells, KDM1A depletion in cancer cells was found not to trigger any reduction in the DNMT1 or DNMT3B protein level or any change in DNA methylation. In the S-phase, furthermore, KDM1A and DNMT1 were found, to co-localize within the heterochromatin. Using P-LISA, we revealed substantially increased binding of KDM1A to DNMT1 during the S-phase. Together, our findings propose a mechanistic link between KDM1A and DNA methyltransferases in cancer cells and suggest that the KDM1A/DNMT1 interaction may play a role during replication. Our work also strengthens the idea that DNMTs can exert functions unrelated to act on DNA methylation.
Various TRP channels act as polymodal sensors of thermal and chemical stimuli, but the mechanisms whereby chemical ligands impact on TRP channel gating are poorly understood. Here we show that AITC (allyl isothiocyanate; mustard oil) and menthol represent two distinct types of ligands at the mammalian cold sensor TRPM8. Kinetic analysis of channel gating revealed that AITC acts by destabilizing the closed channel, whereas menthol stabilizes the open channel, relative to the transition state. Based on these differences, we classify agonists as either type I (menthol-like) or type II (AITC-like), and provide a kinetic model that faithfully reproduces their differential effects. We further demonstrate that type I and type II agonists have a distinct impact on TRPM8 currents and TRPM8-mediated calcium signals in excitable cells. These findings provide a theoretical framework for understanding the differential actions of TRP channel ligands, with important ramifications for TRP channel structure-function analysis and pharmacology.
Neurons of the medial entorhinal cortex (MEC) provide spatial representations critical for navigation. In this network, the periodic firing fields of grid cells act as a metric element for position. The location of the grid firing fields depends on interactions between self-motion information, geometrical properties of the environment and nonmetric contextual cues. Here, we test whether visual information, including nonmetric contextual cues, also regulates the firing rate of MEC neurons. Removal of visual landmarks caused a profound impairment in grid cell periodicity. Moreover, the speed code of MEC neurons changed in darkness and the activity of border cells became less confined to environmental boundaries. Half of the MEC neurons changed their firing rate in darkness. Manipulations of nonmetric visual cues that left the boundaries of a 1D environment in place caused rate changes in grid cells. These findings reveal context specificity in the rate code of MEC neurons.
Williams syndrome transcription factor (WSTF), which is encoded by the BAZ1B gene, was first identified as a hemizygously deleted gene in patients with Williams syndrome. WSTF protein has been reported to be involved in transcription, replication, chromatin remodeling and DNA damage response, and also functions as a tyrosine protein kinase. However, the function of WSTF in cancer is not known. Here, we show that WSTF overexpression promotes proliferation, colony formation, migration and invasion of lung cancer A549 and H1299 cells. WSTF overexpression also promotes tumor growth and invasive abilities of lung cancer cells in mouse xenograft models. cDNA microarray and subsequent qRT-PCR validation revealed that WSTF overexpression significantly upregulated the expression of EMT (epithelial to mesenchymal transition) marker fibronectin (FN1) and EMT-inducing genes Fos and CEACAM6. The changes of EMT markers including downregulated E-cadherin and upregulated N-cadherin and FN1 were further confirmed at both mRNA and protein levels upon WSTF overexpression, with typical morphological changes of EMT. Furthermore, WSTF activates both PI3K/Akt and IL-6/STAT3 oncogenic signaling pathways. Treatment with PI3K inhibitor ZSTK474 or STAT3 inhibitor niclosamide reversed the effects of WSTF overexpression by inhibiting cell proliferation, migration and invasion, with decreased level of p-Akt, p-STAT3 and IL-6. ZSTK474 and niclosamide also reversed EMT markers and EMT-inducing proteins including Snail, Slug, Twist and CEACAM6 in WSTF-overexpressing A549 cells. Taken together, these results demonstrate that WSTF may act as an oncoprotein in lung cancer to accelerate tumor aggressiveness by promoting EMT via activation of PI3K/Akt and IL-6/STAT3 pathways.
Physical activity and health literacy are topics of utmost importance in the prevention of chronic diseases. The present article describes the study protocol for evaluating a cross-provider workplace-related intervention promoting physical activity and health literacy.
The RE-AIM Framework will be the conceptual framework of the AtRisk study. A controlled natural experiment and a qualitative study will be conducted. The cross-provider intervention is based on the cooperation of the German Pension Fund Rhineland and cooperating German Statutory Health Insurances. It combines two components: a behavior-oriented lifestyle intervention and the assignment of a health coach. The single-provider intervention only includes the behavior-oriented lifestyle intervention. The quantitative study (natural experiment) encompasses three measuring points (T0 = start of the behavior-oriented lifestyle
 intervention (baseline); T1 = end of the behavior-oriented lifestyle intervention (16 weeks); T2 = 6 month follow-up) and will compare the effectiveness of the cross-provider workplace-related intervention compared with the single provider intervention. Participants are employees with health related risk factors. ANCOVA will be used to evaluate the effect of the intervention on the outcome variables leisure time physical (primary outcome) activity and health literacy (secondary outcome). The qualitative study comprises semi-structured interviews, systematic field notes of stakeholder meetings and document analyses.
The AtRisk study will contribute towards the claim for cross-provider interventions and workplace-related approaches described in the new Preventive Health Care Act. The results of this study will inform providers, payers and policy makers about the effectiveness of a cross-provider workplace-related lifestyle intervention compared to a single-provider intervention. Beyond, the study will identify challenges for implementing cross-provider preventive interventions. With respect to the sustainability of preventive interventions the AtRisk study will give insight in the expectations and needs on health coaching from the perspective of different stakeholders.
DRKS00010693 .
Anti-malarial drugs are the major focus in the prevention and treatment of malaria. Artemisinin-based combination therapy (ACT) is the WHO recommended first-line treatment for Plasmodium falciparum malaria across the endemic world. Also ACT is increasingly relied upon in treating Plasmodium vivax malaria where chloroquine is failing. The emergence of artemisinin drug-resistant parasites is a serious threat faced by global malaria control programmes. Therefore, the success of treatment and intervention strategies is highly pegged on understanding the genetic basis of resistance.
Here, resistance in P. falciparum was generated in vitro for artemisinin to produce levels above clinically relevant concentrations in vivo, and the molecular haplotypes investigated. Genomic DNA was extracted using the QIAamp mini DNA kit. DNA sequences of Pfk13, Pfcrt and Pfmdr1 genes were amplified by PCR and the amplicons were successfully sequenced. Single nucleotide polymorphisms were traced by standard bidirectional sequencing and reading the transcripts against wild-type sequences in Codon code Aligner Version 5.1 and NCBI blast.
Exposure of parasite strains D6 and W2 to artemisinin resulted in a decrease in parasite susceptibility to artemisinin (W2 and D6) and lumefantrine (D6 only). The parasites exhibited elevated IC50s to multiple artemisinins, with >twofold resistance to artemisinin; however, the resistance index obtained with standard methods was noticeably less than expected for parasite lines recovered from 50 µg/ml 48 h drug pressure. The change in parasite susceptibility was associated with Pfmdr-185K mutation, a mutation never reported before. The Pfcrt-CVMNK genotype (Pfcrt codons 72-76) was retained and notably, the study did not detect any polymorphisms reported to reduce P. falciparum susceptibility in vivo in the coding sequences of the Pfk13 gene.
This data demonstrate that P. falciparum has the capacity to develop resistance to artemisinin derivatives in vitro and that this phenotype is achieved by mutations in Pfmdr1, the genetic changes that are also underpinning lumefantrine resistance. This finding is of practical importance, because artemisinin drugs in Kenya are used in combination with lumefantrine for the treatment of malaria.
Artemisinin resistance phenotype as has been shown in this work, is a decrease in parasites susceptibility to artemisinin derivatives together with the parasite's ability to recover from drug-induced dormancy after exposure to drug dosage above the in vivo clinical concentrations. The study surmises that Pfmdr1 may play a role in the anti-malarial activity of artemisinin.
The role of adjuvant chemoradiotherapy (ACRT) or adjuvant chemotherapy (ACT) in treating patients with locally advanced upper rectal cancer (URC) after total mesorectal excision (TME) surgery remains unclear. We developed a clinical nomogram and a recursive partitioning analysis (RPA)-based risk stratification system for predicting 5-year cancer-specific survival (CSS) to determine whether these individuals require ACRT or ACT.
This retrospective analysis included 547 patients with primary URC. A nomogram was developed based on the Cox regression model. The performance of the model was assessed by concordance index (C-index) and calibration curve in internal validation with bootstrapping. RPA stratified patients into risk groups based on their tumor characteristics.
Five independent prognostic factors (age, preoperative increased carcinoembryonic antigen and carcinoma antigen 19-9, positive lymph node [PLN] number, tumor deposit [TD], pathological T classification) were identified and entered into the predictive nomogram. The bootstrap-corrected C-index was 0.757. RPA stratification of the three prognostic groups showed obviously different prognosis. Only the high-risk group (patients with PLN ≤ 6 and TD, or PLN > 6) benefited from ACRT plus ACT when compared with surgery followed by ACRT or ACT, and surgery alone (5-year CSS: 70.8% vs. 57.8% vs. 15.6%, P < 0.001).
Our nomogram predicts 5-year CSS after TME surgery for locally advanced rectal cancer and RPA-based stratification indicates that ACRT plus ACT post-surgery may be an important treatment plan with potentially significant survival advantages in high-risk URC. This may help to select candidates of adjuvant treatment in prospective studies.
We investigated dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) contrast enhancement kinetic variables quantified from normal breast parenchyma for association with presence of breast cancer, in a case-control study.
Under a Health Insurance Portability and Accountability Act compliant and Institutional Review Board-approved protocol, DCE-MRI scans of the contralateral breasts of 51 patients with cancer and 51 controls (matched by age and year of MRI) with biopsy-proven benign lesions were retrospectively analyzed. Applying fully automated computer algorithms on pre-contrast and multiple post-contrast MR sequences, two contrast enhancement kinetic variables, wash-in slope and signal enhancement ratio, were quantified from normal parenchyma of the contralateral breasts of both patients with cancer and controls. Conditional logistic regression was employed to assess association between these two measures and presence of breast cancer, with adjustment for other imaging factors including mammographic breast density and MRI background parenchymal enhancement (BPE). The area under the receiver operating characteristic curve (AUC) was used to assess the ability of the kinetic measures to distinguish patients with cancer from controls.
When both kinetic measures were included in conditional logistic regression analysis, the odds ratio for breast cancer was 1.7 (95 % CI 1.1, 2.8; p = 0.017) for wash-in slope variance and 3.5 (95 % CI 1.2, 9.9; p = 0.019) for signal enhancement ratio volume, respectively. These odds ratios were similar on respective univariate analysis, and remained significant after adjustment for menopausal status, family history, and mammographic density. While percent BPE was associated with an odds ratio of 3.1 (95 % CI 1.2, 7.9; p = 0.018), in multivariable analysis of the three measures, percent BPE was non-significant (p = 0.897) and the two kinetics measures remained significant. For the differentiation of patients with cancer and controls, the unadjusted AUC was 0.71 using a combination of the two measures, which significantly (p = 0.005) outperformed either measure alone (AUC = 0.65 for wash-in slope variance and 0.63 for signal enhancement ratio volume).
Kinetic measures of wash-in slope and signal enhancement ratio quantified from normal parenchyma in DCE-MRI are jointly associated with presence of breast cancer, even after adjustment for mammographic density and BPE.
Unlike founding members of the Ras superfamily of small GTPases that are prominently known for oncogenic signaling, members of the Rab subfamily are key regulators of cellular membrane traffic. However, a number of Rabs have in recent years also been strongly implicated as tumorigenic or metastatic biomarkers. Rab23 is an emerging example whose differential expression in tumor cells and functional association with proliferation and invasiveness is attracting attention as a useful cancer marker and a potential therapeutic target. Rab23 is ubiquitously expressed but appears to be particularly enriched in the adult brain. It has important developmental functions in vertebrates and has been shown to modulate Sonic hedgehog (Shh) and Nodal signaling. Although its exact cellular role in membrane traffic regulation remains elusive, its known role in Shh signaling, in conjunction with several recent findings, has clearly implicated a role for Rab23 in transport processes to the primary cilium. In this review, we summarize what is currently known about Rab23 as a cancer marker and discuss possible mechanism by which this Rab GTPase may act as an oncogenic or metastatic driver, while exhibiting tumor suppressive activity in some cases.
This study investigated the interrelationship between alexithymia, defense style, emotional suppression, posttraumatic stress disorder (PTSD) following homicide and psychiatric co-morbidity. One hundred and fifty male homicide perpetrators and 156 male perpetrators of non-violent crime completed the Posttraumatic Stress Diagnostic Scale (except for non-violent perpetrators), the General Health Questionnaire-28, the Defense Styles Questionnaire, the Courtauld Emotional Control Scale and the Toronto Alexithymia Scale-20.
 The results showed that 44% of homicide perpetrators met the criteria for PTSD. No significant differences were found between groups in alexithymia, defense style and psychiatric co-morbidity. Homicide perpetrators suppressed depression significantly more than the non-violent group. PLS analyses showed that alexithymia was significantly correlated with defense style. Defense styles were significantly correlated with emotional suppression which, in turn, was associated with homicide-related PTSD and psychiatric co-morbidity. To conclude, perpetrators can experience PTSD reactions following the act of homicide. The severity of these reactions and other psychological problems were related to difficulty getting in touch with distressing emotions, the defenses they used to protect themselves psychologically and the way they suppressed their emotion.
The emergence of resistant power against different antimalarial agents particularly by Plasmodium falciparum is a challenge to combat malaria. Regular monitoring is essential not only to determine the efficacy and development of resistance by the parasite but also to detect early sign of regaining sensitivity to any anti-malarial agent that has been withdrawn for a long period. Studies on molecular markers associated with antimalarial drug resistance of prevailing Plasmodium population play an important role in this aspect. The present protocol was designed to study the polymorphisms in pfcrt and pfmdr-1 gene to determine any sign of regaining sensitivity to chloroquine among P. falciparum after five years of artemisinin combination therapy (ACT) implementation.
Clinical isolates were collected from P. falciparum positive patients attending the malaria clinic of Calcutta School of Tropical Medicine during December 2014 to December 2015. Genomic parasitic DNA was extracted and subjected to sequencing of pfcrt and pfmdr-1 gene directly from purified PCR products.
A total of 89 isolates were sequenced for pfcrt and 73 isolates for pfmdr-1 genes. In pfcrt gene mutant K76T was detected in all isolates and all were SVMNT haplotype. Out of three important polymorphisms in pfmdr-1 gene mutant Y184F was detected among all isolates. One synonymous G182G and one non-synonymous S232F/Y, mutation were detected in 99% isolates.
All isolates carrying mutant K76T in pfcrt gene, considered as hall mark for CQ resistance, indicate that there is no sign of regaining CQ sensitivity among the prevailing P. falciparum population of the study area after five years of ACT implementation.
Grapevine buds (Vitis vinifera L) enter endodormancy (ED) after perceiving the short-day (SD) photoperiod signal and undergo metabolic changes that allow them to survive the winter temperatures. In the present study, we observed an inverse relationship between the depth of ED and the respiration rate of grapevine buds. Moreover, the respiration of dormant and non-dormant buds differed in response to temperature and glucose, two stimuli that normally increase respiration in plant tissues. While respiration in non-dormant buds rose sharply in response to both stimuli, respiration in dormant buds was only slightly affected. This suggests that a metabolic inhibitor is present. Here, we propose that the plant hormone abscisic acid (ABA) could be this inhibitor. ABA inhibits respiration in non-dormant buds and represses the expression of respiratory genes, such as ALTERNATIVE NADH DEHYDROGENASE (VaND1, VvaND2), CYTOCHROME OXIDASE (VvCOX6) and CYTOCHROME C (VvCYTC), and induces the expression of VvSnRK1, a gene encoding a member of a highly conserved family of protein kinases that act as energy sensors and regulate gene expression in response to energy depletion. In addition to inducing ED the SD-photoperiod up-regulated the expression of VvNCED, a gene that encodes a key enzyme in ABA synthesis. Taken together, these results suggest that ABA through the mediation of VvSnRK1, could play a key role in the regulation of the metabolic changes accompanying the entry into ED of grapevine buds.
Purpose The purpose of this study is to examine the activity of collagenase from cultures of Vibrio alginolyticus as in vitro as in biological samples and to evaluate clinical perspectives of this product about the treatment of fibroproliferative diseases like Dupuytren's contracture. Methods The experimental part of the study has been divided in 2 stages. In the first stage, the collagenase has been produced in laboratory, assessing its purity, verifying the in vitro degradation of collagen by the enzyme and measuring the size of the fragments; in the second part, an experimental injection into samples of fibrous cord typical of Dupuytren's disease has been performed in vitro. For the injection we used only collagenase, or collagenase after having subjected them to 2 types of mechanical stress or a collagenase combined with ethylenediamine tetra-acetic acid. Considering that the human samples have been treated in vitro, our institution does not require a specific informed consent. Results It appeared evident that the collagenase obtained from Vibrio alginolyticus (nonpathogenic bacterium) is highly pure (>98%) and does not contain nonspecific protease. The collagenase from Vibrio alginolyticus therefore has an excellent degradative capacity against the collagen and this activity takes on a dose- and time-dependent behavior. The collagenase from Vibrio alginolyticus does not act negatively on cell survival and collagen peptides obtained may provide a better proliferative stimulus compared to controls. Conclusions The collagenase from Vibrio alginolyticus, given its obvious ability in vitro and biological samples, could be an option in the nonsurgical treatment of Dupuytren's disease. Level of evidence Level III, therapeutic.
The disturbances of β-hydroxybutyrate (β-HB) and pyruvate are linked with impaired brain energy utilization which involves in the psychopathology of schizophrenia. This study investigates the difference in levels of β-HB and pyruvate between patients with schizophrenia and healthy controls, and explores their relationship with metabolic profiles and disease characteristics. We recruited 54 physically-health schizophrenic patients and 54 age- and gender-matched healthy control subjects. Blood samples were gathered to determine the serum levels of β-HB and pyruvate and plasma levels of metabolic profiles, including fasting glucose, triglycerides, total cholesterol, high- and low-density lipoprotein-cholesterol and adiponectin. The disease characteristics and psychopathology of patients with schizophrenia were assessed by using the Positive and Negative Syndrome Scale. Of patients with schizophrenia, serum levels of β-HB were significantly correlated with fasting glucose (p=0.007) and triglycerides (p=0.021). Pyruvate was significantly correlated with fasting glucose (p=0.018), total cholesterol (p=0.005), triglycerides (p=0.014) and LDL-C (p=0.006). After controlling the metabolic profiles, β-HB was still significantly higher in schizophrenia patients than in controls (p<0.001), but no difference in pyruvate was observed. Neither β-HB nor pyruvate was significantly correlated with disease characteristics. However, pyruvate was higher in patients treated with olanzapine or clozapine than in those treated with other antipsychotics (p=0.048). Findings suggest that schizophrenic patients had significantly higher serum levels of β-HB than control subjects, possibly reflecting higher demands in energy utilization. Serum levels of β-HB, rather than pyruvate, may act as a potential indicator of energy utilization impairment for schizophrenia.
Electric fields (EF) of approx. 0.2 V/m have been shown to be sufficiently strong to both modulate neuronal activity in the cerebral cortex and have measurable effects on cognitive performance. We hypothesized that the EF caused by the electrical activity of extracranial muscles during natural chewing may reach similar strength in the cerebral cortex and hence might act as an endogenous modality of brain stimulation. Here, we present first steps toward validating this hypothesis.
Using a realistic volume conductor head model of an epilepsy patient having undergone intracranial electrode placement and utilizing simultaneous intracranial and extracranial electrical recordings during chewing, we derive predictions about the chewing-related cortical EF strength to be expected in healthy individuals.
We find that in the region of the temporal poles, the expected EF strength may reach amplitudes in the order of 0.1-1 V/m.
The cortical EF caused by natural chewing could be large enough to modulate ongoing neural activity in the cerebral cortex and influence cognitive performance.
The present study lends first support for the assumption that extracranial muscle activity might represent an endogenous source of electrical brain stimulation. This offers a new potential explanation for the puzzling effects of gum chewing on cognition, which have been repeatedly reported in the literature.
Most autoimmune diseases are associated with pathological pain development. Autoimmune diseases with pathological pain include complex regional pain syndrome, rheumatoid arthritis, and Guillian-Barré syndrome to name a few. The present Review explores research linking the immune system to the development of pathological pain in autoimmune diseases. Pathological pain has been linked to T-cell activation and the release of cytokines from activated microglia in the dorsal horn of the spinal cord. New research on the role of autoantibodies in autoimmunity has generated insights into potential mechanisms of pain associated with autoimmune disease. Autoantibodies may act through various mechanisms in autoimmune disorders. These include the alteration of neuronal excitability via specific antigens such as the voltage-gated
 potassium channel complexes or by mediating bone destruction in rheumatoid arthritis. Although more research must be done to understand better the role of autoantibodies in autoimmune disease related pain, this may be a promising area of research for new analgesic therapeutic targets. © 2016 Wiley Periodicals, Inc.
Inflammation act as a crucial role in carcinogenesis and tumor progression. In this study, we aim to investigate the prognostic significance of systemic inflammatory biomarkers in metastatic renal cell carcinoma (mRCC) and develop a survival predictive model. One hundred and sixty-one mRCC patients who had undergone cytoreductive nephrectomy were enrolled from January 2006 to December 2013. We created a systemic inflammation response index (SIRI) basing on pretreatment hemoglobin and lymphocyte to monocyte ratio (LMR), and evaluated its associations with overall survival (OS) and clinicopathological features. Pretreatment hemoglobin and LMR both remained as independent factors adjusted for other markers of systemic inflammation responses and conventional clinicopathological parameters. A high SIRI seems to be an independent prognosis predictor of worse OS and was significantly correlated with aggressive tumor behaviors. Inclusion of the SIRI into a prognostic model including Fuhrman grade, histology, tumor necrosis and targeted therapy established a nomogram, which accurately predicted 1-year survival for mRCC patients. The SIRI seems to be a prognostic biomarker in mRCC patients. The proposed nomogram can be applied to predict OS of patients with mRCC after nephrectomy.
Approximately 50% of a sample population will develop prolonged standing induced low back pain. The cause of this pain may be due to their lumbar spine posture. The purpose of this study was to investigate differences in lumbar posture between 17 participants categorized as a pain or non-pain developers during level ground standing. A secondary purpose was to evaluate the influence of two standing aids (an elevated surface to act as a foot rest and declined sloped surface) on lumbopelvic posture.
Four sagittal plane radiographs were taken: a normal standing position on level ground, when using an elevated foot rest, using a declined sloped surface, and maximum lumbar spine extension as a reference posture. Lumbosacral lordosis, total lumbar lordosis, and L1/L2 and L5/S1 intervertebral joint angles were measured on each radiograph.
There was a significant difference between the lumbosacral lordosis angle and L5/S1 angles in upright versus maximum extension; however, this was independent of pain group. The elevated surface was most effective at causing lumbosacral spine flexion.
Potentially successful postures for eliminating low back pain during prolonged standing mainly influence the lower lumbar lordosis. Future work should assess the influence of hip posture on low back pain development during standing.
T-cell factor/lymphoid enhancer-binding factor (TCF/LEF) proteins (TCFs) from the High Mobility Group (HMG) box family act as the main downstream effectors of the Wnt signaling pathway. The mammalian TCF/LEF family comprises four nuclear factors designated TCF7, LEF1, TCF7L1, and TCF7L2 (also known as TCF1, LEF1, TCF3, and TCF4, respectively). The proteins display common structural features and are often expressed in overlapping patterns implying their redundancy. Such redundancy was indeed observed in gene targeting studies; however, individual family members also exhibit unique features that are not recapitulated by the related proteins. In the present viewpoint, we summarized our current knowledge about the specific features of individual TCFs, namely structural-functional studies, posttranslational modifications, interacting partners, and phenotypes obtained upon gene targeting in the mouse. In addition, we employed several publicly available databases and web tools to evaluate the expression patterns and production of gene-specific isoforms of the TCF/LEF family members in human cells and tissues.
Bombus terrestris, commonly known as the buff-tailed bumblebee, is native to Europe, parts of Africa and Asia. It is commercially bred for use as a pollinator of greenhouse crops. Larvae pupate within a silken cocoon that they construct from proteins produced in modified salivary glands. The amino acid composition and protein structure of hand drawn B. terrestris, silk fibres was investigated through the use of micro-Raman spectroscopy. Spectra were obtained from single fibres drawn from the larvae salivary gland at a rate of 0.14 cm/s. Raman spectroscopy enabled the identification of poly(alanine), poly(alanine-glycine), phenylalanine, tryptophan, and methionine, which is consistent with the results of amino acid analysis. The dominant protein conformation was found to be coiled coil (73%) while the β-sheet content of 10% is, as expected, lower than those reported for hornets and ants. Polarized Raman spectra revealed that the coiled coils were highly aligned along the fibre axis while the β-sheet and random coil components had their peptide carbonyl groups roughly perpendicular to the fibre axis. The protein orientation distribution is compared to those of other natural and recombinant silks. A structural model for the B. terrestris silk fibre is proposed based on these results.
This study examined whether the conserved arginine cluster present within the 29-amino acid insert of the long form of the D₂ dopamine receptor (D2L-R) confers its predominant intracellular localization. We hypothesized that the conserved arginine cluster (RRR) located within the insert could act as an RXR-type endoplasmic reticulum (ER) retention signal. Arginine residues (R) within the cluster at positions 267, 268, and 269 were charge-reserved to glutamic acids (E), either individually or in clusters, thus generating single, double, and triple D2L-R mutants. Through analyses of cellular localization by confocal microscopy and enzyme-linked immunosorbent assay (ELISA), radioligand binding assay, bioluminescence resonance energy transfer (BRET²) β-arrestin 2 (βarr2) recruitment assay, and cAMP signaling, it was revealed that charge reversal of the R residues at all three positions within the motif impaired their colocalization with ER marker calnexin and led to significantly improved cell surface expression. Additionally, these data demonstrate that an R to glutamic acid (E) substitution at position 2 within the RXR motif is not functionally permissible. Furthermore, all generated D2L-R mutants preserved their functional integrity regarding ligand binding, agonist-induced βarr2 recruitment and Gαi-mediated signaling. In summary, our results show that the conserved arginine cluster within the 29-amino acid insert of third cytoplasmic loop (IC3) of the D2L-R appears to be the ER retention signal.
Peptide drug conjugates offer a novel strategy to achieve controlled drug release. This approach avoids the clinical obstacles of non-specific toxicity and overall drug resistance of conventional cytotoxic agents, such as paclitaxel. MMP2 plays important functions in tumour proliferation and metastasis. Herein, we conjugated the paclitaxel with a hexapeptide which is specific recognized by MMP2 protein. The conjugate is dissociated upon the MMP2 specific proteolysis at COOH terminal of hexapeptide, PVGLIG.The results clearly indicated that the PVGLIG-paclitaxel conjugate significantly enhanced the tumor specificity against HT-1080 and U87-MG tumour cells. Our finding suggested that the hexapeptide PVGLIG is capable to act as a controlled and sustained drug carrier of paclitaxel for the treatment against tumour proliferation and metastasis with high MMP2 expression.
T cell exhaustion is a state of T cell dysfunction that arises during many cancer. miRNAs are one of major gene regulators which result in translational inhibition and/or mRNA degradation. We hypothesized that miRNAs exist that can silence PD1 and act as a modulator in vitro to revert exhaustive status of T cells. We demonstrated that the exhausted T cells with inhibitory receptors (IRs) are significantly increased in the melanoma-bearing mice. Meanwhile, the differentiated miRNA profiles in PD1+ exhaustive T cells were identified using a miRNA array; 11 miRNAs were observed with significant altered levels in the exhausted T cells isolated from melanoma-bearing mice. Among those identified miRNA candidates, miR-28 was capable of binding to multiple IRs based on an in silico analysis and subsequently silencing PD1, as demonstrated by a dual luciferase assay. Moreover, the expression of PD1 was attenuated after transfection with miR-28 mimic. The ability of miR-28 in regulating T cell exhaustion was further evidenced by the fact that the expression of PD1, TIM3 and BTLA of exhausted T cells was increased by the inhibitor of miR28. On the other hand, miR-28 also regulated the PD1+ Foxp3+ and TIM3+ Foxp3+ exhaustive Treg cells in vitro. miR-28 regulating T cell exhaustion was also observed by its ability in reinstalling impaired secretion of cytokines IL-2 and TNF-α by exhausted T cells. This study is the first to discover the effect of miR-28 on T cell exhaustion, providing novel targets with potential use as therapeutic markers in cancer immunotherapy.
Influencing cancer metabolism by lifestyle changes is an attractive strategy as - if effective - exercise-induced problems may be less severe than those induced by classical anti-cancer therapies. Pursuing this idea, clinical trials evaluated the benefit of e.g. different diets such as the ketogenic diet, intermittent caloric restriction and physical exercise (PE) in the primary and secondary prevention of different cancer types. PE proved to be beneficial in the context of breast and colon cancer.Glioblastoma has a dismal prognosis, with an average overall survival
 of about one year despite maximal safe resection, concomitant radiochemotherapy with temozolomide followed by adjuvant temozolomide therapy. Here, we focused on the influence of PE as an isolated and adjuvant treatment in murine GB therapy.PE did not reduce toxic side effects of chemotherapy in mice administered in a dose escalating scheme as shown before for starvation. Although regular treadmill training on its own had no obvious beneficial effects, its combination with temozolomide was beneficial in the treatment of glioblastoma-bearing mice. As PE might partly act through the induction of reactive oxygen species, dihydroartemisinin - an approved anti-malarial drug which induces oxidative stress in glioma cells - was further evaluated in vitro and in vivo. Dihydroartemisinin showed anti-glioma activity by promoting autophagy, reduced the clonogenic survival and proliferation capacity of glioma cells, and prolonged the survival of tumor bearing mice. Using the reactive oxygen species scavenger n-acetyl-cysteine these effects were in part reversible, suggesting that dihydroartemisinin partly acts through the generation of reactive oxygen species.
Hypoxia inducible transcription factors (HIFs) are the main regulators of adaptive responses to hypoxia and are often activated in solid tumors, but their role in leukemia is less clear. In acute myeloid leukemia (AML), in particular, controversial new findings indicate that HIF-1α can act either as an oncogene or a tumor suppressor gene, and this may depend on the stage of leukemia development and/or the AML sub-type.In this study, we find that HIF-1α promotes leukemia progression in the acute monocytic leukemia sub-type of AML through activation of an invasive phenotype. By applying a list of validated HIF-1α-target genes to different AML sub-types, we identified a HIF-1α signature that typifies acute monocytic leukemia when compared with all other AML sub-types. We validated expression of this signature in cell lines and primary cells from AML patients. Interestingly, this signature is enriched for genes that control cell motility at different levels. As a consequence, inhibiting HIF-1α impaired leukemia cell migration, chemotaxis, invasion and transendothelial migration in vitro, and this resulted in impaired bone marrow homing and leukemia progression in vivo. Our data suggest that in acute monocytic leukemia an active HIF-1α-dependent pro-invasive pathway mediates the ability of leukemic cells to migrate and invade extramedullary sites and may be targeted to reduce leukemia dissemination.
After traumatic spinal cord injury, an acute phase triggered by trauma is followed by a subacute phase involving inflammatory processes. We previously demonstrated that peripheral serum cytokine expression changes depend on neurological outcome after spinal cord injury. In a subsequent intermediate phase, repair and remodeling takes place under the mediation of growth factors such as Insulin-like Growth Factor 1 (IGF-1). IGF-1 is a promising growth factor which is thought to act as a neuroprotective agent. Since previous findings were taken from animal studies, our aim was to investigate this hypothesis in humans based on peripheral blood serum. Forty-five patients after traumatic spinal cord injury were investigated over a period of three months after trauma. Blood samples were taken according to a fixed schema and IGF-1 levels were determined. Clinical data including AIS scores at admission to the hospital and at discharge were collected and compared with IGF-1 levels. In our study, we could observe distinct patterns in the expression of IGF-1 in peripheral blood serum after traumatic spinal cord injury regardless of the degree of plegia. All patients showed a marked increase of levels seven days after injury. IGF-1 serum levels were significantly different from initial measurements at four and nine hours and seven and 14 days after injury, as well as one, two and three months after injury. We did not detect a significant correlation between fracture and the IGF-1 serum level nor between the quantity of operations performed after trauma and the IGF-1 serum level. Patients with clinically documented neurological remission showed consistently higher IGF-1 levels than patients without neurological remission. This data could be the base for the establishment of animal models for further and much needed research in the field of spinal cord injury.
Polyadenylation is a critical 3'-end processing step during maturation of pre-mRNAs, and the length of the poly(A) tail affects mRNA stability, nuclear export and translation efficiency. The Arabidopsis thaliana genome encodes three canonical nuclear poly(A) polymerase (PAPS) isoforms fulfilling specialized functions, as reflected by their different mutant phenotypes. While PAPS1 affects several processes, such as the immune response, organ growth and male gametophyte development, the roles of PAPS2 and PAPS4 are largely unknown. Here we demonstrate that PAPS2 and PAPS4 promote flowering in a partially redundant manner. The enzymes act antagonistically to PAPS1, which delays the transition to flowering. The opposite flowering-time phenotypes in paps1 and paps2 paps4 mutants are at least partly due to decreased or increased FLC activity, respectively. In contrast to paps2 paps4 mutants, plants with increased PAPS4 activity flower earlier than the wild-type, concomitant with reduced FLC expression. Double mutant analyses suggest that PAPS2 and PAPS4 act independently of the autonomous pathway components FCA, FY and CstF64. The direct polyadenylation targets of the three PAPS isoforms that mediate their effects on flowering time do not include FLC sense mRNA and remain to be identified. Thus, our results uncover a role for canonical PAPS isoforms in flowering-time control, raising the possibility that modulating the balance of the isoform activities could be used to fine tune the transition to flowering.
Nature provides a wide range of inspiration for building mobile micromachines that can navigate through confined heterogenous environments and perform minimally invasive environmental and biomedical operations. For example, microstructures fabricated in the form of bacterial or eukaryotic flagella can act as artificial microswimmers. Due to limitations in their design and material properties, these simple micromachines lack multifunctionality, effective addressability and manoeuvrability in complex environments. Here we develop an origami-inspired rapid prototyping process for building self-folding, magnetically powered micromachines with complex body plans, reconfigurable shape and controllable motility. Selective reprogramming of the mechanical design and magnetic anisotropy of body parts dynamically modulates the swimming characteristics of the micromachines. We find that tail and body morphologies together determine swimming efficiency and, unlike for rigid swimmers, the choice of magnetic field can subtly change the motility of soft microswimmers.
Unbiased screening approaches are powerful tools enabling identification of novel players in biological processes. Chemical genetic screening refers to the technique of using a reporter response, such as expression of luciferase driven by a promoter of interest, to discover small molecules that affect a given process when applied to plants. These chemicals then act as tools for identification of regulatory components that could not otherwise be detected by forward genetic screens due to gene family redundancy or mutant lethality. This protocol describes a chemical genetic screen using Arabidopsis thaliana seedlings, which has led to recognition of novel players in the plant general stress response.
Neutrophils have a traditional role in inflammatory process and act as the first line of defense against infections. Although their contribution to tumorigenesis and progression is still controversial, accumulating evidence recently has demonstrated that tumor-associated neutrophils (TANs) play a key role in multiple aspects of cancer biology. Here, we detected that chemokine CXCL1 was dramatically elevated in serum from 3LL tumor-bearing mice. In vitro, 3LL cells constitutively expressed and secreted higher level of CXCL1. Furthermore, knocking down CXCL1 expression in 3LL cells significantly hindered tumor growth by inhibiting recruitment of neutrophils from peripheral blood into tumor tissues. Additionally, tumor-infiltrated neutrophils expressed higher levels of MPO and Fas/FasL, which may be involved in TAN-mediated inhibition of CD4(+) and CD8(+) T cells. These results demonstrate that tumor-derived CXCL1 contributes to TANs infiltration in lung cancer which promotes tumor growth.
Chromosome replication in Escherichia coli is initiated from a single origin, oriC. Initiation involves a number of DNA binding proteins, but only DnaA is essential and specific for the initiation process. DnaA is an AAA+ protein that binds both ATP and ADP with similar high affinities. DnaA associated with either ATP or ADP binds to a set of strong DnaA binding sites in oriC, whereas only DnaA(ATP) is capable of binding additional and weaker sites to promote initiation. Additional DNA binding proteins act to ensure that initiation occurs timely by affecting either the cellular mass at which DNA replication is initiated, or the time window in which all origins present in a single cell are initiated, i.e. initiation synchrony, or both. Overall, these DNA binding proteins modulate the initiation frequency from oriC by: (i) binding directly to oriC to affect DnaA binding, (ii) altering the DNA topology in or around oriC, (iii) altering the nucleotide bound status of DnaA by interacting with non-coding chromosomal sequences, distant from oriC, that are important for DnaA activity. Thus, although DnaA is the key protein
 for initiation of replication, other DNA-binding proteins act not only on oriC for modulation of its activity but also at additional regulatory sites to control the nucleotide bound status of DnaA. Here we review the contribution of key DNA binding proteins to the tight regulation of chromosome replication in E. coli cells.
The protein kinases ERK1 and ERK2 are the effector components of the prototypical ERK1/2 mitogen-activated protein (MAP) kinase pathway. This signaling pathway regulates cell proliferation, differentiation and survival, and is essential for embryonic development and cellular homeostasis. ERK1 and ERK2 homologs share similar biochemical properties but whether they exert specific physiological functions or act redundantly has been a matter of controversy. However, recent studies now provide compelling evidence in support of functionally redundant roles of ERK1 and ERK2 in embryonic development and physiology. In this review, we present a critical assessment of the evidence for the functional specificity or redundancy of MAP kinase isoforms. We focus on the ERK1/ERK2 pathway but also discuss the case of JNK and p38 isoforms.
Chlamydiales were recently proposed to have sheltered the future cyanobacterial ancestor of plastids in a common inclusion. The intracellular pathogens are thought to have donated those critical transporters that triggered the efflux of photosynthetic carbon and the consequent onset of symbiosis. Chlamydiales are also suspected to have encoded glycogen metabolism TTS (Type Three Secretion) effectors responsible for photosynthetic carbon assimilation in the eukaryotic cytosol. We now review the reasons underlying other chlamydial lateral gene transfers evidenced in the descendants of plastid endosymbiosis. In particular we show that half of the genes encoding enzymes of tryptophan synthesis in Archaeplastida are of chlamydial origin. Tryptophan concentration is an essential cue triggering two alternative modes of replication in Chlamydiales. In addition, sophisticated tryptophan starvation mechanisms are known to act as antibacterial defenses in animal hosts. We propose that Chlamydiales have donated their tryptophan operon to the emerging plastid to ensure increased synthesis of tryptophan by the plastid ancestor. This would have allowed massive expression of the tryptophan rich chlamydial transporters responsible for symbiosis. It would also have allowed possible export of this valuable amino-acid in the inclusion of the tryptophan hungry pathogens. Free-living single cell cyanobacteria are devoid of proteins able to transport this amino-acid. We therefore investigated the phylogeny of the Tyr/Trp transporters homologous to E. coli TyrP/Mre and found yet another LGT from Chlamydiales to Archaeplastida thereby considerably strengthening our proposal.
Efficient delivery of viruses, proteins and biological macromelecules into a micrometer-sized focal spot of an XFEL beam for coherent diffraction imaging inspired new development in touch-free particle injection methods in gaseous and vacuum environments. This paper lays out our ongoing effort in constructing an all-optical particle delivery approach that uses piconewton photophoretic and femtonewton light-pressure forces to control particle delivery into the XFEL beam. We combine a spatial light modulator (SLM) and an electrically tunable lens (ETL) to construct a variable-divergence vortex beam providing dynamic and stable positioning of levitated micrometer-size particles, under normal atmospheric pressure. A sensorless wavefront correction approach is used to reduce optical aberrations to generate a high quality vortex beam for particle manipulation. As a proof of concept, stable manipulation of optically-controlled axial motion of trapped particles is demonstrated with a response time of 100ms. In addition, modulation of trapping intensity provides a measure of the mass of a single, isolated particle. The driving signal of this oscillatory motion can potentially be phase-locked to an external timing signal enabling synchronization of particle delivery into the x-ray focus with XFEL pulse train.
Muscle invasive urinary bladder cancer is one of the most lethal cancers and its detection at the time of transurethral resection remains limited and diagnostic methods are urgently needed. We have developed a muscle invasive transitional cell carcinoma (TCC) model of the bladder using porcine bladder scaffold and the human bladder cancer cell line 5637. The progression of implanted cancer cells to muscle invasion can be monitored by measuring changes in the spectrum of endogenous fluorophores such as reduced nicotinamide dinucleotide (NADH) and flavins. We believe this could act as a useful tool for the study of fluorescence dynamics of developing muscle invasive bladder cancer in patients. Published by The Optical Society under the terms of the Creative Commons Attribution 4.0 License. Further distribution of this work must maintain attribution to the author(s) and the published article's title, journal citation, and DOI.
Maintenance of the individual patterns of gene expression in different cell types is required for the differentiation and development of multicellular organisms. Expression of many genes is controlled by Polycomb (PcG) and Trithorax (TrxG) group proteins that act through association with chromatin. PcG/TrxG are assembled on the DNA sequences termed PREs (Polycomb Response Elements), the activity of which can be modulated and switched from repression to activation. In this study, we analyzed the influence of transcriptional read-through on PRE activity switch mediated by the yeast activator GAL4. We show that a transcription terminator inserted between the promoter and PRE doesn't prevent switching of PRE activity from repression to activation. We demonstrate that, independently of PRE orientation, high levels of transcription fail to dislodge PcG/TrxG proteins from PRE in the absence of a terminator. Thus, transcription is not the main factor required for PRE activity switch.
Human metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) is a newly identified metastasis-associated long non-coding RNA. In a previous study, it was identified that plasma levels of MALAT1 were significantly increased in gastric cancer patients with metastasis compared with gastric cancer patients without metastasis and healthy control individuals. However, it is unclear whether plasma levels of MALAT1 may act as a biomarker for evaluating the development of metastasis in epithelial ovarian cancer (EOC). In the present study, groups that consisted of 47 patients with EOC and metastasis (EOC/DM), 47 patients with EOC without metastasis (EOC/NDM), and 47 healthy control (HC) individuals were established. Reverse transcription-quantitative polymerase chain reaction (RT-qPCR) was used to detect the level of plasma MALAT1 in these groups. The results showed that levels of plasma MALAT1 were significantly increased in the EOC/DM group compared with the EOC/NDM and HC groups (P<0.001). Receiver operating characteristic (ROC) analysis indicated that plasma MALAT1 yielded an area under the curve (AUC) of 0.820 [95% confidence interval (CI), 0.734-0.905; P<0.001], distinguishing between EOC/DM and EOC/NDM. ROC analysis also yielded an AUC of 0.884 (95% CI, 0.820-0.949; P<0.001), with 89.4% sensitivity and 72.3% specificity for distinguishing between EOC/DM and HC. Furthermore, multivariate analysis indicated that overexpression of MALAT1, differentiation (poor), tumor-node-metastasis stage (IV), lymph node metastasis (N3), peritoneal invasion (present) and higher serum carbohydrate antigen 125 levels were independent predictors of survival (hazard ratio, 3.322; P=0.028) in patients with EOC. Kaplan-Meier analysis revealed that patients with increased MALAT1 expression had a poorer disease-free survival time. In conclusion, the levels of plasma MALAT1 may act as a valuable biomarker for the diagnosis of metastasis.
Hypoxia-inducible factor-1α (HIF-1α) and toll-like receptor 4 (TLR4) are involved in numerous mechanisms of cancer biology, including cell proliferation and survival; however the interaction of the two factors under hypoxic conditions remains unclear. The present study investigated the in vitro mechanism that results in the suppression of tumor cell growth and cellular functions when HIF-1α is silenced. In the present study, the human hepatocellular carcinoma HepG2 cell line was transfected with short hairpin RNA (shRNA) against HIF-1α and cultured under hypoxic conditions (1% O2 for 24 h). The expression of HIF-1α and various growth factors, including epidermal growth factor (EGF), hepatocyte growth factor (HGF), vascular endothelial growth factor (VEGF) and fibroblast growth factor 2 (FGF2), were examined using quantitative polymerase chain reaction and immunoblotting. Tumor growth was measured using a Cell Counting Kit-8 assay and tumor activity was measured using tumor cell invasion and migration assays. Lipopolysaccharide and TAK-242 were used to activate and inhibit TLR4, respectively, to observe the role of TLR4 in the HIF-1α silenced tumor cells. The expression of TLR4 signaling pathway associates, including myeloid differentiation primary response gene 88 (MyD88), apoptosis signal-regulating kinase 1 (ASK1), p38 mitogen-activated protein kinases and HIF-1α, were analyzed by western blot assay. Under hypoxic conditions, silencing of HIF-1α expression suppressed tumor cell growth and regulated the expression of tumor growth-associated genes, including EGF, HGF, VEGF and FG2. Suppression of tumor cell invasion and migration was also observed in the HIF-1α silenced HepG2 cell line. In addition, TLR4 was identified to be involved in HIF-1α and MyD88 accumulation, and activation of ASK1 and p38 were demonstrated to be critical
 for TLR4-mediated HIF-1α pathway. In conclusion, silencing of HIF-1α expression may induce anti-tumor effects under hypoxic conditions in HepG2 cells via the TLR4 mediated pathway, suggesting that the HIF-1α/TLR4 signaling cohort may act as a novel therapeutic target for the treatment of hepatocellular cancer.
Cancer-associated genes serve a crucial role in carcinogenesis. The present study aimed to investigate the mRNA expression levels of microspherule protein 1 (MCRS1) and MCRS2 in colorectal cancer (CRC) and their association with clinical variables. The mRNA expression levels of MCRS1 and MCRS2 were assessed by semi-quantitative reverse transcription polymerase chain reaction in the tumor and corresponding non-tumor tissues of 54 newly-diagnosed CRC patients, as well as in the normal colonic mucosa tissue of 19 age/gender-matched healthy controls. Immunofluorescence was also employed to identify the expression of MCRS1 in CRC tissues, while the concentration of serum carcinoembryonic antigen (CEA) was determined by an enzyme-linked immunoassay. The results identified a negative correlation between MCRS1 and MCRS2 expression levels (r=-0.3018, P=0.0266). MCRS1 mRNA expression was significantly increased and MCRS2 mRNA expression was decreased in CRC tissues compared with the levels in the corresponding normal tissues (both P<0.001). An increase in MCRS1 expression and a decrease in MCRS2 expression was detected in advanced stage when compared with early stage CRC patients. Immunofluorescence analysis revealed increased expression of MCRS1 in CRC patients. Furthermore, the expression levels of MCRS1 displayed positive correlation, whilst those of MCRS2 displayed negative correlation, with the serum CEA level in patients with CRC. The results suggest that increased MCRS1 and decreased MCRS2 expression appeared to be involved in the pathogenesis of CRC. The present study provides evidence suggesting that MCRS1 and MCRS2 may identify CRC patients at a risk of disease relapse, and thus, may be potential tools for monitoring disease activity and act as novel diagnostic markers in the treatment of CRC.
As the first organ in plants to sense water-deficit in the soil, roots have important roles for improving crop adaption to water limited environments. Stem water soluble carbohydrates (WSC) are a major carbon source for grain filling under drought conditions. The contributions of root WSC during grain filling under drought has not been revealed. Wheat parental lines of Westonia, Kauz and their derived four double haploid (DH) lines, namely, DH 125, DH 139, DH 307, and DH 338 were used in a field drought experiment with four replications. Through measurements of the root and stem WSC components, and the associated enzyme activities during grain filling, we identified that the levels of root WSC and fructan were one third of the levels in stems. In particular, root glucose and 6-kestose levels were one third of the stem, while the root fructose and bifurcose level were almost half of the stem and sucrose level was two third of the stem. The accumulation and the degradation patterns of root fructan levels were similar to that in the stem, especially under drought. Correlations between root fructan levels and grain assimilation were highly significant, indicating that under terminal drought, root WSC represents a redistributed carbon source for grain filling rather than deep rooting. The significantly higher root sucrose levels under drought suggest that sucrose may act as a signal under drought stress. As compared with stem fructose levels, the earlier increased root fructose levels in DH 307, DH 139, and DH 338 provided agile response to drought stress. Our root results further confirmed that β-(2-6) linkages predominate in wheat with patterns of 6-kestose being closely correlated with overall fructan patterns. Further research will focus on the roles of 6-FEH during fructan remobilization in stems.
Transgenic plants with improved salt and drought stress tolerance have been developed with a large number of abiotic stress-related genes. Among these, the most extensively used genes are the glycine betaine biosynthetic codA, the DREB transcription factors, and vacuolar membrane Na(+)/H(+) antiporters. The use of codA, DREBs, and Na(+)/H(+) antiporters in transgenic plants has conferred stress tolerance and improved plant phenotype. However, the future deployment and commercialization of these plants depend on their safety to the environment. Addressing environmental risk assessment is challenging since mechanisms governing abiotic stress tolerance are much more complex than that of insect resistance and herbicide tolerance traits, which have been considered to date. Therefore, questions arise, whether abiotic stress tolerance genes need additional considerations and new measurements in risk assessment and, whether these genes would have effects on weediness and invasiveness potential of transgenic plants? While considering these concerns, the environmental risk assessment of abiotic stress tolerance genes would need to focus on the magnitude of stress tolerance, plant phenotype and characteristics of the potential receiving environment. In the present review, we discuss environmental concerns and likelihood of concerns associated with the use of abiotic stress tolerance genes. Based on our analysis, we conclude that the uses of these genes in domesticated crop plants are safe for the environment. Risk assessment, however, should be carefully conducted on biofeedstocks and perennial plants taking into account plant phenotype and the potential receiving environment.
Soil microbial communities are influenced by climate change drivers such as warming and altered precipitation. These changes create abiotic stresses, including desiccation and nutrient limitation, which act on microbes. However, our understanding of the responses of microbial communities to co-occurring climate change drivers is limited. We surveyed soil bacterial and fungal diversity and composition after a 1-year warming and altered precipitation manipulation in the Tibetan plateau alpine grassland. In isolation, warming and decreased precipitation treatments each had no significant effects on soil bacterial community structure; however, in combination of both treatments altered bacterial community structure (p = 0.03). The main effect of altered precipitation specifically impacted the relative abundances of Bacteroidetes and Gammaproteobacteria compared to the control, while the main effect of warming impacted the relative abundance of Betaproteobacteria. In contrast, the fungal community had no significant response to the treatments after 1-year. Using structural equation modeling (SEM), we found bacterial community composition was positively related to soil moisture. Our results indicate that short-term climate change could cause changes in soil bacterial community through taxonomic shifts. Our work provides new insights into immediate soil microbial responses to short-term stressors acting on an ecosystem that is particularly sensitive to global climate change.
The adrenal cortex has a molecular clock that generates circadian rhythms in glucocorticoid production, yet it is unclear how the clock responds to acute stress. We hypothesized that stress-induced ACTH provides a signal that phase shifts the adrenal clock. To assess whether acute stress phase shifts the adrenal clock in vivo in a phase-dependent manner, mPER2:LUC mice on a 12:12-h light:dark cycle underwent restraint stress for 15 min or no stress at zeitgeber time (ZT) 2 (early subjective day) or at ZT16 (early subjective night). Adrenal explants from mice stressed at ZT2 showed mPER2:LUC rhythms that were phase-advanced by ~2 h, whereas adrenals from mice stressed at ZT16 showed rhythms that were phase-delayed by ~2 h. The biphasic response was also observed in mice injected subcutaneously either with saline or with ACTH at ZT2 or ZT16. Blockade of the ACTH response with the glucocorticoid, dexamethasone, prevented restraint stress-induced phase shifts in the mPER2:LUC rhythm both at ZT2 and at ZT16. The finding that acute stress results in a phase-dependent shift in the adrenal mPER2:LUC rhythm that can be blocked by dexamethasone indicates that stress-induced effectors, including ACTH, act to phase shift the adrenal clock rhythm.
Glucocorticoids are a class of steroid hormones derived from cholesterol. Their actions are mediated by the glucocorticoid and mineralocorticoid receptors, members of the superfamily of nuclear receptors, which, once bound to their ligands, act as transcription factors that can directly modulate gene expression. Through protein-protein interactions with other transcription factors, they can also regulate the activity of many genes in a composite or tethering way. Rapid non-genomic signaling was also demonstrated since glucocorticoids can act through membrane receptors and activate signal transduction pathways, such as protein kinases cascades, to modulate other transcriptions factors and activate or repress various target genes. By all these different mechanisms, glucocorticoids regulate numerous important functions in a large variety of cells, not only in the peripheral organs but also in the central nervous system during development and adulthood. In general, glucocorticoids are considered anti-inflammatory and protective agents due to their ability to inhibit gene expression of pro-inflammatory mediators and other possible damaging molecules. Nonetheless, recent studies have uncovered situations in which these hormones can act as pro-inflammatory agents depending on the dose, chronicity of exposure, and the structure/organ analyzed. In this review, we will provide an overview of the conditions under which these phenomena occur, a discussion that will serve as a basis
 for exploring the mechanistic foundation of glucocorticoids pro-inflammatory gene regulation in the brain.
Recent studies indicate that anti-inflammatory drugs, act as a double-edged sword, not only exacerbating secondary brain injury but also contributing to neurological recovery after stroke. Our aim is to explore whether there is a beneficial role for neuroprotection and functional recovery using anti-inflammatory drug along with neurorehabilitation therapy using transcranial direct current stimulation (tDCS) and repetitive transcranial magnetic stimulation (rTMS), so as to improve functional recovery after ischemic stroke.
We develop a computational systems biology approach from preclinical data, using ordinary differential equations, to study the behavior of both phenotypes of microglia, such as M1 type (pro-inflammatory) vis-à-vis M2 type (anti-inflammatory) under anti-inflammatory drug action (minocycline). We explore whether pharmacological treatment along with cerebral stimulation using tDCS and rTMS is beneficial or not. We utilize the systems pathway analysis of minocycline in nuclear factor kappa beta (NF-κB) signaling and neurorehabilitation therapy using tDCS and rTMS that act through brain-derived neurotrophic factor (BDNF) and tropomyosin-related kinase B (TrkB) signaling pathways.
We demarcate the role of neuroinflammation and immunomodulation in post-stroke recovery, under minocycline activated-microglia and neuroprotection together with improved neurogenesis, synaptogenesis, and functional recovery under the action of rTMS or tDCS. We elucidate the feasibility of utilizing rTMS/tDCS to increase neuroprotection across the reperfusion stage during minocycline administration. We delineate that the signaling pathways of minocycline by modulation of inflammatory genes in NF-κB and proteins activated by tDCS and rTMS through BDNF, TrkB, and calmodulin kinase (CaMK) signaling. Utilizing systems biology approach, we show that the activation pathways for pharmacotherapy (minocycline) and neurorehabilitation (rTMS applied to ipsilesional cortex and tDCS) results into increased neuronal and synaptic activity that commonly occur through activation of N-methyl-d-aspartate receptors. We construe that considerable additive neuroprotection effect would be obtained and delayed reperfusion injury can be remedied, if one uses multimodal intervention of minocycline together with tDCS and rTMS.
Additive beneficial effect is, thus, noticed for pharmacotherapy along with neurorehabilitation therapy, by maneuvering the dynamics of immunomodulation using anti-inflammatory drug and cerebral stimulation for augmenting the functional recovery after stroke, which may engender clinical applicability for enhancing plasticity, rehabilitation, and neurorestoration.
While much has been written about the consequences of zero-sum (or fixed-pie) beliefs, their measurement has received almost no systematic attention. No researchers, to our awareness, have examined the question of whether the endorsement of a zero-sum-like proposition depends on how the proposition is formed. This paper focuses on this issue, which may also apply to the measurement of other attitudes. Zero-sum statements have a form such as "The more of resource X for consumer A, the less of resource Y for consumer B." X and Y may be the same resource (such as time), but they can be different (e.g., "The more people commute by bicycle, the less revenue for the city from car parking payments"). These statements have four permutations, and a strict zero-sum believer should regard these four statements as equally valid and therefore should endorse them equally. We find, however, that three asymmetric patterns routinely occur in people's endorsement levels, i.e., clear framing effects, whereby endorsement of one permutation substantially differs from endorsement of another. The patterns seem to arise from beliefs about asymmetric resource flows and power relations between rival consumers. We report three studies, with adult samples representative of populations in two Western and two non-Western cultures, demonstrating that most of the asymmetric belief patterns are consistent across these samples. We conclude with a discussion of the implications of this kind of "order-effect" for attitude measurement.
The catechol-O-methyltransferase (COMT) val158met polymorphism affects the breakdown of synaptic dopamine. Consequently, this polymorphism has been associated with a variety of neurophysiological and behavioral outcomes. Some of the effects have been found to be sex-specific and it appears estrogen may act to down-regulate the activity of the COMT enzyme. The dopaminergic system has been implicated in face recognition, a form of cognition for which a female advantage has typically been reported. This study aimed to investigate potential joint effects of sex and COMT genotype on face recognition. A sample of 142 university students was genotyped and assessed using the Faces I subtest of the Wechsler Memory Scale - Third Edition (WMS-III). A significant two-way interaction between sex and COMT genotype on face recognition performance was found. Of the male participants, COMT val homozygotes and heterozygotes had significantly lower scores than met homozygotes. Scores did not differ between genotypes for female participants. While male val homozygotes had significantly lower scores than female val homozygotes, no sex differences were observed in the heterozygotes and met homozygotes. This study contributes to the accumulating literature documenting sex-specific effects of the COMT polymorphism by demonstrating a COMT-sex interaction for face recognition, and is consistent with a role for dopamine in face recognition.
A common assumption in organizations is that information sharing improves situation awareness and ultimately organizational effectiveness. The sheer volume and rapid pace of information and communications received and readily accessible through computer networks, however, can overwhelm individuals, resulting in data overload from a combination of diverse data sources, multiple data formats, and large data volumes. The current conceptual framework of network enabled operations (NEO) posits that robust networking and information sharing act as a positive feedback loop resulting in greater situation awareness and mission effectiveness in military operations (Alberts and Garstka, 2004). We test this assumption in a large-scale, 2-week military training exercise. We conducted a social network analysis of email communications among the multi-echelon Mission Command staff (one Division and two sub-ordinate Brigades) and assessed the situational awareness of every individual. Results from our exponential random graph models challenge the aforementioned assumption, as increased email output was associated with lower individual situation awareness. It emerged that higher situation awareness was associated with a lower probability of out-ties, so that broadly sending many messages decreased the likelihood of attaining situation awareness. This challenges the hypothesis that increased information sharing improves situation awareness, at least for those doing the bulk of the sharing. In addition, we observed two trends that reflect a compartmentalizing of networked information sharing as email links were more commonly formed among members of the command staff with both similar functions and levels of situation awareness, than between two individuals with dissimilar functions and levels of situation awareness; both those findings can be interpreted to reflect effects of homophily. Our results have major implications that challenge the current conceptual framework of NEO. In addition, the information sharing network was largely imbalanced and dominated by a few key individuals so that most individuals in the network have very few email connections, but a small number of individuals have very many connections. These results highlight several major growing pains for networked organizations and military organizations in particular.
Mental illnesses are as prevalent among elite athletes as in the general population. Despite this, there is little research examining how to enhance mental health literacy or helping behaviors in elite sport environments. A Mental Health in Sport (MHS) workshop was therefore developed and its effects on mental health literacy and confidence studied in 166 coaches and support staff working with elite athletes and teams in Australia. Results indicated that participants increased their knowledge of the signs and symptoms of common mental illnesses and were more confident in helping someone who may be experiencing a mental health problem. We conclude that even a very brief intervention can be effective in improving the mental health literacy and confidence of key persons in elite sport environments, and may promote early intervention and timely referral of elite athletes with mental health concerns to appropriate professionals.
Large-conductance calcium-activated potassium (BK) channels are currently considered as vital players in a variety of renal physiological processes. In podocytes, BK channels become active in response to stimuli that increase local cytosolic Ca(2+), possibly secondary to activation of slit diaphragm TRPC6 channels by chemical or mechanical stimuli. Insulin increases filtration barrier permeability through mobilization of BK channels. In mesangial cells, BK channels co-expressed with β1 subunits act as a major component of the counteractive response to contraction in order to regulate glomerular filtration. This review aims to highlight recent discoveries on the localization, physiological and pathological roles of BK channels in glomerulus.
Over the years, animal studies have revealed a role for the endocannabinoid system in the
 regulation of multiple aspects of opiate addiction. The current review provides an overview of this literature in regards to opiate withdrawal. The opiate withdrawal syndrome, hypothesized to act as a negative reinforcer in mediating continued drug use, can be characterized by the emergence of spontaneous or precipitated aversive somatic and affective states following the termination of drug use. The behaviors measured to quantify somatic opiate withdrawal and the paradigms employed to assess affective opiate withdrawal (e.g., conditioned place aversion) in both acutely and chronically dependent animals are discussed in relation to the ability of the endocannabinoid system to modulate these behaviors. Additionally, the brain regions mediating somatic and affective opiate withdrawal are elucidated with respect to their modulation by the endocannabinoid system. Ultimately, a review of these findings reveals dissociations between the brain regions mediating somatic and affective opiate withdrawal, and the ability of cannabinoid type 1 (CB1) receptor agonism/antagonism to interfere with opiate withdrawal within different brain sub regions.
The issue of clusters as a form of organization of market entities has recently attracted an increasing attention of health care management theoreticians and practitioners. In our opinion the existing theoretical basis gives a foundation for considering clusters as a source of potential for increasing the effectiveness of health policy and health care organizations. It can be assumed that in case of health care clusters there is a possibility of interregional diffusion of innovation, based on ventures undertaken on the health care market, increasing not only the potential of the entities in the cluster, but also of its surroundings and subcontractors. It is possible to realize the idea of a flexible health care implemented regionally with the use of modern techniques of communication, knowledge transfer and high specialization. Nonetheless, in case of Poland the potential of clustrification remains untapped, being characterized by a limited actions of public and private bodies, marginal role of non-profit sector organizations and limited engagement of R&D sector. This is because a general distrust in the cluster formula, and the lack of relevant knowledge among local officials and health business leaders. For this reason the process of clustrification among health care entities requires external support through the increased efforts to create a system of legal and tax preferences for cluster initiatives and provision of organizational support in terms of know-how, targeted particularly at bodies and individuals, who may act as cluster leaders.
3D printing is a form of rapid prototyping technology, which has led to innovative new applications in biomedicine. It facilitates the production of highly accurate three dimensional objects from substrate materials. The inherent accuracy and other properties of 3D printing have allowed it to have exciting applications in anatomy education and surgery, with the specialty of neurosurgery having benefited particularly well. This article presents the findings of a literature review of the Pubmed and Web of Science databases investigating the applications of 3D printing in anatomy and surgical education, and neurosurgery. A number of applications within these fields were found, with many significantly improving the quality of anatomy and surgical education, and the practice of neurosurgery. They also offered advantages over existing approaches and practices. It is envisaged that the number of useful applications will rise in the coming years, particularly as the costs of this technology decrease and its uptake rises.
The concept of "expert patient" has been developed in the last two decades to define a patient who has a significant knowledge of his/her disease and treatment in addition to self-management skills. However, this concept has evolved over the last years, and these patients are now considered, not only to be more efficient in the management of their own condition and communicating effectively with health professionals, but to also act as educators for other patients and as resources for the last, provide feedback on care delivery, and be involved in the production and implementation of practice guidelines, as well as in the development and conduct of research initiatives. There are some barriers, however, to the integration of this new contributor to the health care team, and specific requirements need to be considered for an individual to be considered as an expert. This new player has, however, a potentially important role to improve current care, particularly in respiratory health.
Child sexual abuse is a global problem and a growing concern in Sub-Saharan Africa. It constitutes a profound violation of human rights. To address this problem, Kenya has established the Sexual Offences Act. In addition, Kenya has developed national guidelines on the management of sexual violence to grant minors access to health care. However, little is known about the experiences of sexually abused minors when they interact with the health and legal system. Accordingly, this study uses a triangulation of methods in the follow-up of two adolescent girls. Health records were reviewed, interactions between the girls and service providers were observed, in-depth interviews were conducted with the girls, and informal discussions were held with guardians and service providers. Findings indicated that the minors' rights to quality health care and protection were being violated. Protocols on postrape care delivery were unavailable. Furthermore, the health facility was ill equipped and poorly stocked. Health providers showed little regard for informed assent, confidentiality, and privacy while offering postrape care. Similarly, in the justice system, processing was met with delays and unresponsive law enforcement. Health providers and police officers are in grave need of training in sexual and gender-based violence, its consequences, comprehensive postrape care, and sexual and reproductive health rights to ensure the protection of minors' rights. Health administrators should ensure that facilities are equipped with skilled health providers, medical supplies, and equipment. Additionally, policies on the protection and care of sexually abused minors in Kenya require amendment.
Professional mononuclear phagocytes such as polymorphonuclear neutrophils (PMN), monocytes, and macrophages are considered as the first line of defence against invasive pathogens. The formation of extracellular traps (ETs) by activated mononuclear phagocytes is meanwhile well accepted as an effector mechanism of the early host innate immune response acting against microbial infections. Recent investigations showed evidence that ETosis is a widely spread effector mechanism in vertebrates and invertebrates being utilized to entrap and kill bacteria, fungi, viruses, and protozoan parasites. ETs are released in response to intact protozoan parasites or to parasite-specific antigens in a controlled cell death process. Released ETs consist of nuclear DNA as backbone adorned with histones, antimicrobial peptides, and phagocyte-specific granular enzymes thereby producing a sticky extracellular matrix capable of entrapping and killing pathogens. This review summarizes recent data on protozoa-induced ETosis. Special attention will be given to molecular mechanisms of protozoa-induced ETosis and on its consequences for the parasites successful reproduction and life cycle accomplishment.
This study aimed to understand the relationship between secure base phenomena and dating violence among couples. Within a relationship, a secure base can be defined as a balancing act of proximity-seeking and exploration at various times and contexts with the assurance of a caregiver's availability and responsiveness in emotionally distressing situations. Participants were 87 heterosexual couples. The Actor-Partner Interdependence Model was used to examine the relationship between each partner's scores on secure base representational knowledge and intimate partner violence. Findings demonstrated that women's secure base representational knowledge had a significant direct negative effect on the victimization of both men and women, while men's secure base representational knowledge did not have any significant partner or actor effects. Therefore, findings suggest that women with insecure attachments may be more vulnerable to being both the victims and the perpetrators of.
For insects, flexibility in the performance of terrestrial locomotion is a vital part of facing the challenges of their often unpredictable environment. Arthropods such as scorpions and crustaceans can switch readily from forward to backward locomotion, but in insects this behaviour seems to be less common and, therefore, is only poorly understood. Here we present an example of spontaneous and persistent backward walking in Cataglyphis desert ants that allows us to investigate rearward locomotion within a natural context. When ants find a food item that is too large to be lifted up and to be carried in a normal forward-faced orientation, they will drag the load walking backwards to their home nest. A detailed examination of this behaviour reveals a surprising flexibility of the locomotor output. Compared with forward walks with regular tripod coordination, no main coordination pattern can be assigned to rearward walks. However, we often observed leg-pair-specific stepping patterns. The front legs frequently step with small stride lengths, while the middle and the hind legs are characterized by less numerous but larger strides. But still, these specializations show no rigidly fixed leg coupling, nor are they strictly embedded within a temporal context; therefore,
 they do not result in a repetitive coordination pattern. The individual legs act as separate units, most likely to better maintain stability during backward dragging.
Pre-messenger RNA (pre-mRNA) splicing is carried out by the spliceosome, which undergoes an intricate assembly and activation process. Here, we report an atomic structure of an activated spliceosome (known as the B(act) complex) from Saccharomyces cerevisiae, determined by cryo-electron microscopy at an average resolution of 3.52 angstroms. The final refined model contains U2 and U5 small nuclear ribonucleoprotein particles (snRNPs), U6 small nuclear RNA (snRNA), nineteen complex (NTC), NTC-related (NTR) protein, and a 71-nucleotide pre-mRNA molecule, which amount to 13,505 amino acids from 38 proteins and a combined molecular mass of about 1.6 megadaltons. The 5' exon is anchored by loop I of U5 snRNA, whereas the 5' splice site (5'SS) and the branch-point sequence (BPS) of the intron are specifically recognized by U6 and U2 snRNA, respectively. Except for coordination of the catalytic metal ions, the RNA elements at the catalytic cavity of Prp8 are mostly primed for catalysis. The catalytic latency is maintained by the SF3b complex, which encircles the BPS, and the splicing factors Cwc24 and Prp11, which shield the 5' exon-5'SS junction. This structure, together with those determined earlier, outlines a molecular framework for the pre-mRNA splicing reaction.
A testing-based learning strategy is one that relies on the act of recalling (i.e., testing) information after exposure, and interleaving is a strategy in which the learning materials are presented in a serial order (e.g., texts 1, 2, 3, 1, 2, 3, 1, 2, 3) versus a blocked order (e.g., texts 1, 1, 1, 2, 2, 2, 3, 3, 3). Although both learning strategies have been thoroughly investigated, few studies have examined their additive effect with higher-order cognitive tasks such as the ability to identify themes across multiple texts, and none of those did so using physiology information. The purpose of the present study was to compare recall and thematic processing across five different physiology texts. Participants were randomly assigned to learn the texts using one of the following four learning strategies: 1) study-study-study (S-S-S) using a blocked order, 2) S-S-S using an interleaved order, 3) study-test-study (S-T-S) using a blocked order, and 4) S-T-S using an interleaved order. Over the course of the following week, the S-T-S groups had more stable recall of key text ideas compared with the S-S-S groups, and the S-T-S group had more stable recall of thematic information than the S-S-S group when interleaving was used as the presentation order.
Gold nanoparticles (GNPs) are widely used for biomedical applications due to unique optical properties, established synthesis methods, and biological compatibility. Despite important applications of plasmonic heating in thermal therapy, imaging, and diagnostics, the lack of quantification in heat generation leads to difficulties in comparing the heating capability for new plasmonic nanostructures and predicting the therapeutic and diagnostic outcome. This study quantifies GNP heat generation by experimental measurements and theoretical predictions for gold nanospheres (GNS) and nanorods (GNR). Interestingly, the results show a GNP-type dependent agreement between experiment and theory. The measured heat generation of GNS matches well with theory, while the measured heat generation of GNR is only 30% of that predicted theoretically at peak absorption. This then leads to a surprising finding that the polydispersity, the deviation of nanoparticle size and shape from nominal value, significantly influences GNR heat generation (>70% reduction), while having a limited effect for GNS (<10% change). This work demonstrates that polydispersity is an important metric in quantitatively predicting plasmonic heat generation and provides a validated framework to quantitatively compare the heating capabilities between gold and other plasmonic nanostructures.
Ligand-protein binding is a complex process that involves the formation of number of non-covalent interactions, e.g. H-bonds and hydrophobic interactions, between the ligand and the protein host. Upon binding, ligand functional groups can act synergistically (positive cooperativity) to improve the overall ligand binding affinity beyond what would be expected from their individual contributions. In this study, using thrombin as a protein model system, we evaluated the effect of the bioisosteric replacement of a carbonyl functionality with a sulphonyl functionality on positive cooperativity between their H-bonds with thrombin and hydrophobic binding in the adjacent S3 pocket. The positive cooperativity observed was greatly reduced when replacing the carbonyl group with a sulphonyl group. Evaluating how bioisosteric replacements affect cooperativity is important for making better informed ligand optimization SAR decisions.
As neural structures grow in size and increase metabolic demand, the CNS vasculature undergoes extensive growth, remodeling, and maturation. Signals from neural tissue act on endothelial cells to stimulate blood vessel ingression, vessel patterning, and acquisition of mature brain vascular traits, most notably the blood-brain barrier. Using mouse genetic and in vitro approaches, we identified retinoic acid (RA) as an important regulator of brain vascular development via non-cell-autonomous and cell-autonomous regulation of endothelial WNT signaling. Our analysis of globally RA-deficient embryos (Rdh10 mutants) points to an important, non-cell-autonomous function for RA in the development of the vasculature in the neocortex. We demonstrate that Rdh10 mutants have severe defects in cerebrovascular development and that this phenotype correlates with near absence of endothelial WNT signaling, specifically in the cerebrovasculature, and substantially elevated expression of WNT inhibitors in the neocortex. We show that RA can suppress the expression of WNT inhibitors in neocortical progenitors. Analysis of vasculature in non-neocortical brain regions suggested that RA may have a separate, cell-autonomous function in brain endothelial cells to inhibit WNT signaling. Using both gain and loss of RA signaling approaches, we show that RA signaling in brain endothelial cells can inhibit WNT-β-catenin transcriptional activity and that this is required to moderate the expression of WNT target Sox17. From this, a model emerges in which RA acts upstream of the WNT pathway via non-cell-autonomous and cell-autonomous mechanisms to ensure the formation of an adequate and stable brain vascular plexus.
Work presented here provides novel insight into important yet little understood aspects of brain vascular development, implicating for the first time a factor upstream of endothelial WNT signaling. We show that RA is permissive for cerebrovascular growth via suppression of WNT inhibitor expression in the neocortex. RA also functions cell-autonomously in brain endothelial cells to modulate WNT signaling and its downstream target, Sox17. The significance of this is although endothelial WNT signaling is required for neurovascular development, too much endothelial WNT signaling, as well as overexpression of its target Sox17, are detrimental. Therefore, RA may act as a "brake" on endothelial WNT signaling and Sox17 to ensure normal brain vascular development.
Two new europium (III) complexes have been synthesized with 1,3-[bis(4-methoxyphenyl)]propane-1,3-dionato (HBMPD) as main ligand and 2,2'-bipyridyl (bipy) or 1,10-phenanthroline (phen) as an auxiliary ligand. The main ligand HBMPD has been synthesized by ecofriendly microwave approach and complexes by solution precipitation method. The resulting materials are characterized by IR, (1)H-NMR, elemental analysis, X-ray diffraction, UV-visible and TG-DTG techniques. The photoluminescence (PL) spectroscopy depicts the detail analysis of photophysical properties of the complexes, their results show that the ligand interact with Eu (III) ion which act as antenna and transfers the absorbed energy to the central europium(III) ion via sensitization process efficiently. As a consequence of this interaction, these materials exhibit excellent luminescent intensity, long decay time (τ), high quantum efficiency (η) and Judd-Ofelt intensity parameter (Ω2). The CIE coordinates fall under the deep red region, matching well with the NTSC (National Television Standard Committee) standard. Hence, these highly efficient optical materials can be used as a red component in organic light emitting diodes (OLEDs) and full color flat panel displays.
How remote mutations can lead to changes in enzyme function at a molecular level is a central question in evolutionary biochemistry and biophysics. Here, we combine laboratory evolution with biochemical, structural, genetic, and computational analysis to dissect the molecular basis for the functional optimization of phosphotriesterase activity in a bacterial lactonase (AiiA) from the metallo-β-lactamase (MBL) superfamily. We show that a 1000-fold increase in phosphotriesterase activity is caused by a more favorable catalytic binding position of the paraoxon substrate in the evolved enzyme that resulted from conformational tinkering of the active site through peripheral mutations. A nonmutated active site residue, Phe68, was displaced by ∼3 Å through the indirect effects of two second-shell trajectory mutations, allowing molecular interactions between the residue and paraoxon. Comparative mutational scanning, i.e., examining the effects of alanine mutagenesis on different genetic backgrounds, revealed significant changes in the functional roles of Phe68 and other nonmutated active site residues caused by the indirect effects of trajectory mutations. Our
 work provides a quantitative measurement of the impact of second-shell mutations on the catalytic contributions of nonmutated residues and unveils the underlying intramolecular network of strong epistatic mutational relationships between active site residues and more remote residues. Defining these long-range conformational and functional epistatic relationships has allowed us to better understand the subtle, but cumulatively significant, role of second- and third-shell mutations in evolution.
Politicians' characteristics attract voters' attention and dominate impression formation. Thereby, social judgements are deduced from different information being available in a certain situation. The literature suggests that incidental bodily sensations can influence judgement processes. Here, two bodily treatments-the haptic sensation of weight and the act of hand cleansing-simultaneously contribute to judgements about politicians. This study expands previous works by (a) investigating potential interactions of two haptic information cues, (b) providing evidence for the significant role of conceptual closeness between embodied cues and judgement dimensions, (c) showing that hand cleansing leads to harsher moral judgements independently of whether a misconduct has been committed or not, and (d) showing that the familiarity of the target to be judged does not moderate the effect of embodied information. The results demonstrate that judgements can be modulated by basal sensorimotor experiences. We discuss implications and the important issue of result generalisation and replicability.
Breastfeeding is frequently described as a woman's decision, yet this choice is often illusionary owing to suboptimal social and structural supports. Despite passage of the Patient Protection and Affordable Care Act (2010) that requires all qualifying employers to provide mothers "reasonable" break time and a private, non-bathroom space to express breast milk, the majority of women in the United States still do not have access to both accommodations.
At least three issues may be influencing this suboptimal implementation at workplaces: 1) federal law does not address lactation space functionality and accessibility, 2) federal law only protects a subset of employees, and 3) enforcement of the federal law requires women to file a complaint with the United States Department of Labor.
To address each of these issues, we recommend the following modifications to current law: 1) additional requirements surrounding lactation space and functionality, 2) mandated coverage of exempt employees, and 3) requirement that employers develop company-specific lactation policies.
If the goal is to give women a real choice of whether to continue breastfeeding after returning to work, we must provide the proper social and structural supports that will allow for a truly personal decision. No mother should have to choose between breastfeeding her child and earning a paycheck.
To explore public health nurses' knowledge, perceptions, and practices under the Affordable Care Act (ACA).
A cross-sectional, web-based survey was completed by a sample of 1,143 public health nurses (PHNs) in the United States.
Descriptive statistics were analyzed for variables related to general knowledge and perception of the ACA and for the extent of involvement in activities related to the implementation of the ACA. Qualitative analysis was conducted on free text comments to two open-ended questions about current and future PHNs involvement in the ACA.
Approximately 45% of PHNs reported changes in their daily work due to the ACA. PHNs reported being very or somewhat involved in these activities of the ACA: integration of primary care and public health (62%), provision of clinical preventive services (60.3%), care coordination (55.4%), patient navigation (55.3%), establishment of private-public partnerships (55.3%), population health strategies (53.6%), population health data assessment and analysis (53.8%), community health assessments (49%), involvement in medical homes (37.8%), provision of maternal and child health home visiting services (32.1%), and involvement in Accountable Care Organizations (29.2%).
PHNs are making substantial contributions to implementation of the ACA.
This study investigated whether selenium species in wheat grains could be altered by exposure to different combinations of nitrogen (N) and sulphur (S) fertilisers in an agronomic biofortification experiment. Four Australian wheat cultivars (Mace, Janz, Emu Rock and Magenta) were grown in a glasshouse experiment and exposed to 3 mg Se kg(-1) soil as selenate (Se(VI)). Plants were also exposed to 60 mg N kg(-1) soil as urea and 20 mg S kg(-1) soil as gypsum in a factorial design (N + S + Se; N + Se; S + Se; Se only). Plants were grown to maturity with grain analysed for total Se concentrations via ICP-MS and Se species determined via HPLC-ICP-MS. Grain Se concentrations ranged from 22 to 70 µg Se g(-1) grain (dry mass). Selenomethionine (SeMet), Se-methylselenocystine (MeSeCys), selenohomolanthionine (SeHLan), plus a large concentration of uncharacterised Se species were found in the extracts from grains. SeMet was the major Se species identified accounting for between 9 and 24 µg Se g(-1) grain. Exposure to different N and S fertiliser combinations altered the SeMet content of Mace, Janz and Emu Rock grain, but not that of Magenta. MeSeCys and SeHLan were found in far lower concentrations (<4 µg Se g(-1) grain). A large component of the total grain Se was uncharacterisable (>30 % of total grain Se) in all samples. When N fertiliser was applied (with or without S), the proportion of uncharacterisable Se increased between 60 and 70 % of the total grain Se. The data presented here indicate that it is possible to alter the content of individual Se species in wheat grains via biofortification combined with manipulation of N and S fertiliser regimes. This has potential significance in alleviating or combating both Se deficiency and Se toxicity effects in humans.
It is well known that personal decision making in respect to organ donation is highly dependent on the balance of knowledge, trust, and fear. We wanted to explore the attitude of German medical students towards organ donation and investigate the relationship between knowledge, trust, and fear in this special subgroup.
We conducted an online survey utilizing (1) the snowball effect of using Facebook groups and advertisement as well as (2) mailing lists of medical faculties in Germany for distribution.
We surveyed 1370 medical students. 75.8 % (N = 988) of the participants stated to carry an organ donor card and allowed their organs to be donated. 1.8 % (N = 23) refused donation. 22.5 % (N = 293) did not carry an organ donor card. Analysis of the "decided" versus the "undecided" group revealed substantial differences regarding transplantation knowledge (mean knowledge score of 4.23 vs. 3.81; P < 0.001), trust in (mean trust score 4.11 vs. 3.39; P < 0.001), and fear of (mean fear score 1.63 vs. 2.22; P < 0.001) organ donation. 45.9 % of the undecided group (N = 134) opted for accessing additional information material. After reading the info material, 22.7 % (N = 29) stated their willingness to sign a donor card, whereas 76.6 % (N = 98) still could not reach a decision.
The willingness to potentially act as organ donor was related to the pre-existent knowledge, trust, and fear. Access to information material did promote the decision towards organ donation in a group of previously undecided medical students. This advocates initiating information campaigns even in population groups with strong medical background.
In Benin, artemisinin-based combination therapy (ACT) has been recommended as the first-line treatment for uncomplicated Plasmodium falciparum malaria since 2004. The emergence in Southeast Asia of parasites that are resistant to artemisinins poses a serious threat to global control of this disease. The presence of artemisinin resistance genotypes in parasite populations in Benin is currently unknown. The present study investigated the prevalence of relevant K13-propeller gene polymorphisms in parasite isolates from the north-western region of Benin.
Plasmodium falciparum isolates were collected from children with a confirmed diagnosis of malaria aged 6 months to 5 years in two towns, Cobly and Djougou, in the north-western part of Benin. The study was conducted during the rainy season from July to November 2014 in local health facilities. The K13-propeller gene was amplified in parasite isolates using nested PCR and subsequently sequenced.
A total of 108 children were recruited into the study. The efficiency of amplification reactions was 72% (78/108). The propeller domain of the K13 gene was successfully sequenced in 78 P. falciparum isolates; all of them were wild type with no polymorphisms detectable.
The absence of mutations in the K13 gene indicates that P. falciparum parasite populations in the study area are still fully susceptible to artemisinins.
Three new sets of mononuclear Ln(III) complexes of general formulas [LnL3 ]⋅CH3 OH [Ln(III) =Yb (1), Er (2), Dy (3), Gd (4), and Eu (5)], [LnL2 (tmh)(CH3 OH)]⋅n H2 O⋅m CH3 OH [Ln(III) =Yb (1 b), Er (2 b), Dy (3 b), Gd (4 b)], and [LnL2 (tta)(CH3 OH)]⋅CH3 OH [Ln(III) =Yb (1 c), Er (2 c), Dy (3 c), Gd (4 c)] were prepared by the reaction of Ln(CF3 SO3 )⋅n H2 O salts with the tridentate ligand 2-(tetrazol-5-yl)-1,10-phenanthroline (HL) and, for the last two sets, additionally with the β-diketonate ligands 2,2,6,6-tetramethylheptanoate (tmh) and 2-thenoyltrifluoroacetonate (tta), respectively. In the [LnL3 ]⋅CH3 OH complexes the Ln(III) ions are coordinated to three phenanthroline tetrazolate ligands with an LnN9 coordination sphere. Dynamic ac magnetic measurements on 1-3 reveal that these complexes only exhibit
 single-molecule magnet (SMM) behavior when an external dc magnetic field is applied, with Ueff values of 11.7 K (1), 16.0 K (2), and 20.2 K (3). When the tridentate phenanthroline tetrazolate ligand is replaced by one molecule of methanol and the β-diketonate ligand tmh (1 b-3 b) or tta (1 c-3 c), a significant increase in Ueff occurs and, in the case of the Dy(III) complexes 3 b and 3 c, out-of-phase χ'' signals below 15 and 10 K, respectively, are observed in zero dc magnetic field. CASSCF+RASSI ab initio calculations performed on the Dy(III) complexes support the experimental results. Thus, for 3 the ground Kramers' doublet is far from being axial and the first excited state is found to be very close in energy to the ground state, so the relaxation barrier in this case is almost negligible. Conversely, for 3 b and 3 c, the ground Kramers' doublet is axial with a small quantum tunneling of the magnetization, and the energy difference between the ground and first Kramers' doublets is much higher, which allows these compounds to behave as SMMs at zero field. Moreover, these calculations support the larger Ueff observed for 3 b compared to 3 c. Additionally, the solid-state photophysical properties of 1, 2, 4, and 5 show that the phenanthroline tetrazolate ligand can act as an effective antenna to sensitize the characteristic Yb(III) , Er(III) , and Eu(III) emissions through an energy-transfer process.

Objective: Our study aims to explore the correlation between fractional exhaled nitric oxide (FeNO) and inhaled corticosteroids (ICS) efficacy in childhood bronchial asthma (BA).
247 pediatric BA patients were selected and divided into 3 treatment groups based on drug therapy: treatment group 1 (seretide, n = 86), treatment group 2 (budesonide, n = 79), and treatment group 3 (salbutamol, n = 82). Another 90 healthy children were recruited as control group. FeNO, FEVl%pred, FEV1/FVC, MEF25%, MEF50% and PEF%, total serum IgE, EOS%, induced sputum EOS% and supernatant inflammatory indexes (ECP, IL-8, and TNF-α) of sputum, ECP, IL-8 and TNF-α were detected.
Compared with pretreatment, 6 months posttreatment, FeNO, induced sputum EOS%, supernatant inflammatory indexes decreased (all p < 0.05), but pulmonary function indexes and childhood asthma control test (C-ACT) increased in treatment groups (all p < 0.05). FeNO, induced sputum EOS%, and supernatant inflammatory indexes in treatment group 1 were lower than those in treatment group 2 and 3 (all p < 0.05); total serum IgE and peripheral blood EOS% in treatment group 1 and 2 were lower but pulmonary function indexes were higher than those in treatment group 3 (all p < 0.05); according to Pearson correlation analysis, in both ICS and non-ICS groups, FeNO was positively correlated to ECP but negatively to C-ACT.
ICS is effective in BA treatment, and FeNO associated with ICS efficacy is an indicator for BA intervention. FeNO combing with pulmonary function indexes had a predictive value in BA response.
Artificial spin ices are frustrated magnetic nanostructures where single domain nanobars act as macrosized spins. In connected kagome artificial spin ice arrays, reversal occurs along one-dimensional chains by propagation of ferromagnetic domain walls through Y-shaped vertices. Both the vertices and the walls are complex chiral objects with well-defined topological edge-charges. At room temperature, it is established that the topological edge-charges determine the exact switching reversal path taken. However, magnetic reversal at low temperatures has received much less attention and how these chiral objects interact at reduced temperature is unknown. In this study we use magnetic force microscopy to image the magnetic reversal process at low temperatures revealing the formation of quite remarkable high energy remanence states and a change in the dynamics of the reversal process. The implication is the breakdown of the artificial spin ice regime in these connected structures at low temperatures.
The treatment of glioma with bevacizumab results in decreased enhancement, making it challenging to diagnose tumor recurrence. Therefore, the primary aim of this retrospective study was to determine if the underlying biological processes occurring within regions of recurrent glioblastoma in patients undergoing bevacizumab therapy influence morphologic and diffusion-weighted magnetic resonance (MR) imaging characteristics.
In this Health Insurance Portability and Accountability Act-compliant and institutional review board-approved study, 26 patients treated with bevacizumab for high-grade glioma underwent lesion-wide apparent diffusion coefficient analysis before therapy and at the time of clinical/radiological progression, allowing for stratification by the presence or absence of reduced diffusion. Lesions with reduced diffusion were classified into "block" or "salt & pepper" phenotypes. Eight of the 26 patients underwent image-guided tissue sampling at the time of suspected disease recurrence allowing for direct biological correlation. Clinical, histologic, and MR imaging differences between diffusion groups were assessed using a two-sample Welch t test.
All patients had histologic evidence of recurrent disease with or without a background of treatment effect. Sixty-two percent of the cohort had developed reduced diffusion at clinical progression following bevacizumab. Image-guided tissue sampling demonstrated that treatment effect was not observed within regions of reduced diffusion. Recurrent tumor intermixed with treatment effect was more likely to be observed within the "salt & pepper" phenotype when compared to "block" phenotype.
Following bevacizumab therapy, recurrent glioblastoma can manifest as nonenhancing regions characterized by reduced diffusion. Histologically, these MR imaging characteristics correlate with aggressive biological features of disease recurrence.
Agricultural expansion and intensification are main drivers of land-use change in Brazil. Soybean is the major crop under expansion in the area. Soybean production involves large amounts of water and fertiliser that act as sources of contamination with potentially negative impacts on adjacent water bodies. These impacts might be intensified by projected climate change in tropical areas. A Water Footprint Assessment (WFA) serves as a tool to assess environmental impacts of water and fertiliser use. The aim of this study was to understand potential impacts on environmental sustainability of agricultural intensification close to a protected forest area of the Amazon under climate change. We carried out a WFA to calculate the water footprint (WF) related to soybean production, Glycine max, to understand the sustainability of the WF in the Tapajós river basin, a region in the Brazilian Amazon with large expansion and intensification of soybean. Based on global datasets, environmental hotspots - potentially unsustainable WF areas - were identified and spatially plotted in both baseline scenario (2010) and projection into 2050 through the use of a land-use change scenario that includes climate change effects. Results show green and grey WF values in 2050 increased by 304% and 268%, respectively. More than one-third of the watersheds doubled their grey WF in 2050. Soybean production in 2010 lies within sustainability limits. However, current soybean expansion and intensification trends lead to large impacts in relation to water pollution and water use, affecting protected areas. Areas not impacted in terms of water pollution dropped by 20.6% in 2050 for the whole catchment, while unsustainability increased 8.1%. Management practices such as water consumption regulations to stimulate efficient water use, reduction of crop water use and evapotranspiration, and optimal fertiliser application control could be key factors in achieving sustainability within a river basin.
Most of the Cultural Heritage built in NW Iberian Peninsula is made of granite which exposition to the environment leads to the formation of deposits and coatings, mainly two types: biological colonization and sulphated black crusts. Nowadays, another form of alteration derives from graffiti paints when these are applied as an act of vandalism. A deep revision needs to be addressed considering the severity of these deterioration forms on granite and the different cleaning effectiveness achieved by cleaning procedures used to remove them. The scientific literature about these topics on granite is scarcer than on sedimentary carbonate stones and marbles, but the importance of the granite in NW Iberian Peninsula Cultural Heritage claims this review centred on biological colonization, sulphated black crusts and graffiti on granite and their effectiveness of the common cleaning procedures. Furthermore, this paper carried out a review of the knowledge about those three alteration forms on granite, as well as bringing together all the major studies in the field of the granite cleaning with traditional procedures (chemical and mechanical) and with the recent developed technique based on the laser ablation. Findings concerning the effectiveness evaluation of these cleaning procedures, considering the coating extraction ability and the damage induced on the granite surface, are described. Finally, some futures research lines are pointed out.
In 2012, seized capsules containing white powder were analyzed to show the presence of unknown steroid-related compounds. Subsequent gas chromatography-mass spectrometry (GC-MS) and nuclear magnetic resonance (NMR) investigations identified a mixture of 3α- and 3β- isomers of the novel compound; 3-chloro-17α-methyl-5α-androstan-17β-ol. Synthesis of authentic reference materials followed by comparison of NMR, GC-MS and gas chromatography-tandem mass spectrometry (GC-MS/MS) data confirmed the finding of a new 'designer' steroid. Furthermore,
 in vitro androgen bioassays showed potent activity highlighting the potential for doping using this steroid. Due to the potential toxicity of the halogenated steroid, in vitro metabolic investigations of 3α-chloro-17α-methyl-5α-androstan-17β-ol using equine and human S9 liver fractions were performed. For equine, GC-MS/MS analysis identified the diagnostic 3α-chloro-17α-methyl-5α-androstane-16α,17β-diol metabolite. For human, the 17α-methyl-5α-androstane-3α,17β-diol metabolite was found. Results from these studies were used to verify the ability of GC-MS/MS precursor-ion scanning techniques to support untargeted detection strategies for designer steroids in anti-doping analyses. Copyright © 2015 John Wiley & Sons, Ltd.
Adolescent dating abuse (ADA) is an important public health problem, but existing measurement instruments have limitations. This study assessed the reliability and validity of the Dating Abuse Perpetration Acts Scale (DAPAS), a medium-length instrument (24 items) designed for use with adolescents aged 16 to 21 years. In Phase 1, 466 adolescent pediatric emergency department patients who reported perpetrating at least one act of physical ADA in the last year completed the DAPAS. In the second phase, 33 patients completed the DAPAS; two previously established dating violence measures, the Safe Dates Perpetration Act Scale and the revised Conflict Tactics Scales (CTS2); and a measure of violence, the Self-Report of Offending (SRO). Categorical confirmatory factor analyses indicated that a one-factor model of ADA perpetration best fit the data. Validity analyses showed moderate to high correlations between the DAPAS and both the Safe Dates measure and the CTS2 (r = .70 and .59) scores, and a small to moderate correlation between the DAPAS and SRO (r = .43). Sensitivity and specificity analysis of the DAPAS using 10 cut-points revealed an optimal cut-point, which correctly classified 85% of the respondents. The DAPAS showed concurrent validity with the Safe Dates measure and CTS2, as well as discriminant validity in its ability to differentiate perpetrators of violence in general from perpetrators of ADA. The DAPAS scale is a good alternative to the Safe Dates measure and should be considered for use in research studies of ADA.
Alcohol use disorder (AUD) is a classic multifactorial syndrome and it is critical to understand the diversity of the relevant risk factors and how they inter-relate over development.
We examined 21 risk factors for AUD in four developmental tiers reflecting (i) birth, (ii) childhood and early adolescence, (iii) late adolescence, and (iv) early adulthood in 47 414 Swedish men of whom 3907 (8.2%) were registered for AUD at or after age 25 with a mean length of follow-up of 33.9 (6.6) years. Structural equational model fitting was performed using Mplus.
The best-fitting model provided a good fit to the data and explained 23.4% of the variance in AUD. The five strongest predictors were: externalizing behaviors, criminal behavior, father's alcohol consumption, genetic risk, and low educational attainment. Two developmentally early familial/genetic risk factors had substantial direct paths to AUD: father's alcohol consumption and genetic liability. Other broad developmental pathways to risk for AUD were evident: externalizing, psychosocial and internalizing. Overall, the externalizing pathway to AUD was the strongest. However, these pathways were substantially interwoven over time such that risk factors from one domain were commonly predicted by and/or predicted risk factors from the other broad domains of risk.
AUD in men is an etiologically complex syndrome influenced by familial-genetic, psychosocial, internalizing, and especially externalizing risk factors that act and interact over development and have complicated mediational pathways.
E-mail may rule the world in other types of businesses, but for medical practices, the telephone remains the primary mode of communication with patients, specialists, and pharmacies. From making appointments to calling in prescriptions, telephones are essential to patient care. With technology changing very quickly and new capabilities coming into the medical practice, such as telemedicine and Skype, you need to know your options when choosing a new telephone system. The possibilities include on-site, cloud, and hybrid networked solutions. A wide variety of features and capabilities are available, from dozens of vendors. Of course, no matter what telephone solution you choose, you must meet regulatory compliance, particularly HIPAA, and Payment Card Industry Data Security Standard if you take credit cards. And it has to be affordable, reliable, and long lasting. This article explores what medical practices need to know when choosing a new business telephone system in order to find the right solutions for their businesses.
Medical practice management has never been more complex than it is today, with volumes of rapidly changing regulations, increasing cost pressures, and rising quality standards under the Affordable Care Act. These challenges have made it more critical for practices to assess their current position in order to determine how best to move the practice forward. A practice assessment begins with four simple steps: an evaluation of the long-term goals and motivation of the practice's owner; a review of key practice financials and how successfully the practice captures every dollar to which it is rightfully entitled; a measure of provider productivity and strategies to improve it; and an assessment of the talent and morale of the team of professionals at the practice.
A visible light photoredox-catalyzed aldehyde olefin cyclization is reported. The method represents a formal hydroacylation of alkenes and alkynes and provides chromanol derivatives in good yields. The protocol takes advantage of the double role played by trialkylamines (NR3) which act as (i) electron donors for reducing the catalyst and (ii) proton donors to activate the substrate via a proton-coupled electron transfer.
While the Affordable Care Act seeks to reduce emergency department visits for outpatient-treatable conditions, it remains unclear whether Medicaid patients or the uninsured have adequate access to follow-up care. The goal of this study was to determine the availability of follow-up orthopedic care by insurance status METHODS: Using simulated patient methodology, all 102 eligible general orthopedic practices in Dallas-Fort Worth, Texas were contacted twice by a caller requesting follow-up for an ankle fracture diagnosed in a local emergency department using a standardized script that differed by insurance status. Practices were randomly assigned to paired Private and Uninsured or Medicaid and Uninsured scenarios RESULTS: We completed 204 calls: 59 Private, 43 Medicaid, and 102 uninsured. Appointment success rate was 83.1% for privately insured (95% CI 73.2%-92.9%), 81.4% for uninsured (95% CI 73.7%-89.1%), and 14.0% for Medicaid callers (95% CI 3.2%-24.7%). Controlling for paired calls to the same practice, an uninsured caller had 5.7 times higher odds (95% CI 2.74-11.71) of receiving an appointment than a Medicaid caller (p<0.001), but the same odds as a privately insured caller (OR=1.0, 95% CI 0.19-5.37, p=1.0). Uninsured patients had to bring a median of $350 (IQR $250-$400) to their appointment to be seen, and only two uninsured patients were able to obtain an appointment for $100 or less up-front. In comparison, typical total payments collected for privately insured patients are $236 and for Medicaid patients $128. When asked where else they could go, 49 (48%) uninsured callers and one Medicaid caller (2%) were directed to local public hospital emergency departments as alternative sources of care. Of the practices that appeared on Medicaid's published list of orthopedic providers accepting new patients, 15 told callers they did not accept Medicaid, 11 did not treat ankles, 9 listed non-working phone numbers, and only 3 actually scheduled an appointment for the Medicaid caller CONCLUSIONS: Less than 1 in 7 Medicaid patients could obtain orthopedic follow-up after an ED visit for a fracture, and prices quoted to the uninsured were 30% higher than typical negotiated rates paid by the privately insured. High up-front costs for uninsured patients and low appointment availability for Medicaid patients may leave these patients with no other option than the emergency department for necessary care. This article is protected by copyright. All rights reserved.
Audio forgery is any act of tampering, illegal copy and fake quality in the audio in a criminal way. In the last decade, there has been increasing attention to the audio forgery detection due to a significant increase in the number of forge in different type of audio. There are a number of methods for forgery detection, which electric network frequency (ENF) is one of the powerful methods in this area for forgery detection in terms of accuracy. In spite of suitable accuracy of ENF in a majority of plug-in powered devices, the weak accuracy of ENF in audio forgery detection for battery-powered devices, especially in laptop and mobile phone, can be consider as one of the main obstacles of the ENF. To solve the ENF problem in terms of accuracy in battery-powered devices, a combination method of ENF and phase feature is proposed. From experiment conducted, ENF alone give 50% and 60% accuracy for forgery detection in mobile phone and laptop respectively, while the proposed method shows 88% and 92% accuracy respectively, for forgery detection in battery-powered devices. The results lead to higher accuracy for forgery detection with the combination of ENF and phase feature.
The interaction of amphiphilic and triphilic block copolymers with lipid monolayers has been studied. Amphiphilic triblock copolymer PGMA20-PPO34-PGMA20
 (GP) is composed of a hydrophobic poly(propylene oxide) (PPO) middle block that is flanked by two hydrophilic poly(glycerol monomethacrylate) (PGMA) side blocks. The attachment of a perfluoro-n-nonyl residue (F9) to either end of GP yields a triphilic polymer with the sequence F9-PGMA20-PPO34-PGMA20-F9 (F-GP). The F9 chains are fluorophilic, i.e., they have a tendency to demix in hydrophilic as well as in lipophilic environments. We investigated (i) the adsorption of both polymers to differently composed lipid monolayers and (ii) the compression behavior of mixed polymer/lipid monolayers. The lipid monolayers are composed of phospholipids with PC or PE headgroups and acyl chains of different length and saturation. Both polymers interact with lipid monolayers by inserting their hydrophobic moieties (PPO, F9). The interaction is markedly enhanced in the presence of F9 chains, which act as membrane anchors. GP inserts into lipid monolayers up to a surface pressure of 30 mN/m, whereas F-GP inserts into monolayers at up to 45 mN/m, suggesting that F-GP also inserts into lipid bilayer membranes. The adsorption of both polymers to lipid monolayers with short acyl chains is favored. Upon compression, a two-step squeeze-out of F-GP occurs, with PPO blocks being released into the aqueous subphase at 28 mN/m and the F9 chains being squeezed out at 48 mN/m. GP is squeezed out in one step at 28 mN/m because of the lack of F9 anchor groups. The liquid expanded (LE) to liquid condensed (LC) phase transition of DPPC and DMPE is maintained in the presence of the polymers, indicating that the polymers can be accommodated in LE- and LC-phase monolayers. These results show how fluorinated moieties can be included in the rational design of membrane-binding polymers.
To determine the pooled prevalence and review the influencing factors of methicillin-resistant Staphylococcus aureus (MRSA) nasal colonization in Chinese children.
Articles published between January 2005 and October 2015 that studied prevalence or influencing factors of MRSA nasal colonization in Chinese children were retrieved from Chinese Biomedical Literature database (CBM), China National Knowledge Infrastructure (CNKI) database, Chinese VIP database, Chinese Wanfang database, Medline database and Ovid database. Prevalence and influencing factors were analyzed by STATA 13.1.
Thirteen articles were included. The overall prevalence of MRSA nasal colonization was 4.4% (95% confidence interval [CI]: 0.027-0.062). With an MRSA prevalence of 3.9% (95% CI: 0.018-0.061) in healthy children and 5.8% (95% CI: 0.025-0.092) in children with underlying medical conditions. Children recruited in the hospitals presented MRSA prevalence of 6.4% (95% CI: 0.037-0.091), which was higher than those recruited in the communities [2.7% (95% CI: 0.012-0.043)]. A number of influencing factors for MRSA nasal colonization were noted in three eligible studies: gender (male vs female; OR: 0.67; 95% CI: 0.55-0.82), younger age (OR: 2.98; 95% CI: 1.31-6.96 and OR: 1.56; 95% CI: 1.21-2.00), attending day care centers (OR: 2.97; 95% CI: 1.28-6.76), having infectious diseases (OR: 2.31; 95% CI: 1.10-4.52), using antibiotics (OR: 2.77; 95% CI: 1.45-5.05), residing in northern Taiwan (OR: 1.41; 95% CI: 1.15-1.71), passive smoking (OR: 1.30; 95% CI: 1.02-1.63), and pneumococcal vaccination (OR: 1.22; 95% CI: 1.01-1.48).
Children could act as reservoirs of MRSA transmissions. Hospitals remained the most frequent microorganism-circulated settings. More MRSA infection control strategies are required to prevent the dissemination among children.
To examine the effect of the Affordable Care Act (ACA) on changes in premiums for subscribers of nongrandfathered, nongroup insurance plans that were "cancelled."
Retrospective multivariate analyses.
Changes in annual premiums post ACA were evaluated across subgroups of subscriber and health plan characteristics. Data was derived from databases containing information on premiums, plan benefit, and demographics for subscribers aged 18 to 64 years within Kaiser Permanente of the Mid-Atlantic States. A linear regression model was used to examine the independent association between subscriber and health plan characteristics on the relative change in premiums.
In 2013, 4169 nongroup subscribers were enrolled in plans that were cancelled as a result of the ACA. The median pre-ACA premium was $3240 (range = $780-$39,492), which increased by a median of 21.3% (range = -77.4% to 193.6%), or $685 (range = -$27,464 to $8676), post ACA in 2014. Premiums increased more for high-deductible plans (median = 63.7%) than standard-deductible plans (median = 8.4%). Due to shifts in the age curve, premiums decreased for more than half of women aged 18 to 44 years, but increased by 35.2% for women aged 55 to 64 years. Premiums fell by 15.5% for subscribers who did not pass standard medical underwriting due to preexisting conditions.
Changes in premiums in the nongroup market post ACA, varied substantially across subgroups, primarily due to differences in the amount of coverage, changes in rating criteria, shifts in the age curve, and anticipated differences in risk selection and composition of the risk pool. Given the extent of this variation, it would be incorrect to conclude the ACA as being uniformly beneficial or detrimental to subscribers of these cancelled plans.
Studies of transuranic organometallic complexes provide a particularly valuable insight into covalent contributions to the metal-ligand bonding, in which the subtle differences between the transuranium actinide ions and their lighter lanthanide counterparts are of fundamental importance for the effective remediation of nuclear waste. Unlike the organometallic chemistry of uranium, which has focused strongly on U(III) and has seen some spectacular advances, that of the transuranics is significantly technically more challenging and has remained dormant. In the case of neptunium, it is limited mainly to Np(IV). Here we report the synthesis of three new Np(III) organometallic compounds and the characterization of their molecular and electronic structures. These studies suggest that Np(III) complexes could act as single-molecule magnets, and that the lower oxidation state of Np(II) is chemically accessible. In comparison with lanthanide analogues, significant d- and f-electron contributions to key Np(III) orbitals are observed, which shows that fundamental neptunium organometallic chemistry can provide new insights into the behaviour of f-elements.
Apicoplasts are vestigial plastids in apicomplexan parasites like Plasmodium, the causative agent of malaria. Apicomplexan parasites are dependant on their apicoplasts for synthesis of various molecules that they are unable to scavenge in sufficient quantity from their host, which makes apicoplasts attractive drug targets. Proteins known as plastid phosphate translocators (pPTs) are embedded in the outer apicoplast membrane and are responsible for the import of carbon, energy and reducing power to drive anabolic synthesis in the organelle. We investigated how a pPT is targeted into the outer apicoplast membrane of the human malaria parasite P. falciparum. We showed that a transmembrane domain is likely to act as a recessed signal anchor to direct the protein into the endomembrane system, and that a tyrosine in the cytosolic N-terminus of the protein is essential for targeting, but one or more, as yet unidentified, factors are also essential to direct the protein into the outer apicoplast membrane.
Renal hypoplasia is a common cause of pediatric renal failure and several adult-onset diseases. Recent studies have associated a variant of the OSR1 gene with reduction of newborn kidney size and function in heterozygotes and neonatal lethality with kidney defects in homozygotes. How OSR1 regulates kidney development and nephron endowment is not well understood, however. In this study, by using the recently developed CRISPR genome editing technology, we genetically labeled the endogenous Osr1 protein and show that Osr1 interacts with Wt1 in the developing kidney. Whereas mice heterozygous for either an Osr1 or Wt1 null allele have normal kidneys at birth, most mice heterozygous for both Osr1 and Wt1 exhibit defects in metanephric kidney development, including unilateral or bilateral kidney agenesis or hypoplasia. The developmental defects in the Osr1+/-Wt1+/- mouse embryos were detected as early as E10.5, during specification of the metanephric mesenchyme, with the Osr1+/-Wt1+/- mouse embryos exhibiting significantly reduced Pax2-positive and Six2-positive nephron progenitor cells. Moreover, expression of Gdnf, the major nephrogenic signal for inducing ureteric bud outgrowth, was significantly reduced in the metanephric mesenchyme in Osr1+/-Wt1+/- embryos in comparison with the Osr1+/- or Wt1+/- littermates. By E11.5, as the ureteric buds invade the metanephric mesenchyme and initiate branching morphogenesis, kidney morphogenesis was significantly impaired in the Osr1+/-Wt1+/- embryos in comparison with the Osr1+/- or Wt1+/- embryos. These results indicate that Osr1 and Wt1 act synergistically to regulate nephron endowment by controlling metanephric mesenchyme specification during early nephrogenesis.
Epigenetic alterations in suppressor of cytokine signalling 3 (SOCS3) have been suggested as a potential biomarker in glioma.
To investigate whether SOCS3 methylation could act as a biomarker for glioma grading and prognosis.
Glioma samples were evaluated by pyrosequencing and quantitative reverse transcription-polymerase chain reaction (qRT-PCR).
SOCS3 promoter methylation was more frequent in the WHO III and (anaplastic) oligoastrocytomas group. SOCS3 methylation status was significantly inversely correlated with mRNA expression level. Mutant IDH1 caused marked increase in SOCS3 methylation.
SOCS3
 methylation is a potential biomarker for grading and prognosis in human glioma.
To explore the application of diffusion tensor imaging (DTI) for breast tissue and breast pathologies using a stimulated-echo acquisition mode (STEAM) with variable diffusion times.
In this Health Insurance Portability and Accountability Act-compliant study, approved by the local institutional review board, eight patients and six healthy volunteers underwent an MRI examination at 3 Tesla including STEAM-DTI with several diffusion times ranging from 68.5 to 902.5 ms. A DTI model was fitted to the data for each diffusion time, and parametric maps of mean diffusivity, fractional anisotropy, axial diffusivity, and radial diffusivity were computed for healthy fibroglandular tissue (FGT) and lesions. The median value of radial diffusivity for FGT was fitted to a linear decay to obtain an estimation of the surface-to-volume ratio, from which the radial diameter was calculated.
For healthy FGT, radial diffusivity presented a linear decay with the square root of the diffusion time resulting in a range of estimated radial diameters from 202 to 496 µm, while axial diffusivity presented a nearly time-independent diffusion. Residual fat signal was reduced at longer diffusion times due to the shorter T1 of fat. Residual fat signal to the overall signal in the healthy volunteers' FGT was found to range from 2.39% to 2.55% (shortest mixing time), and from 0.40% to 0.51% (longest mixing time) for the b500 images.
The use of variable diffusion times may provide an in vivo noninvasive tool to probe diffusion lengths in breast tissue and breast pathology, and might aid by improving fat suppression at longer diffusion times. J. Magn. Reson. Imaging 2016.
An important issue of regional air quality management is to allocate air quality management funds to maximize environmental and human health benefits. In this study, we use an innovative approach to tackle this air quality management issue. We develop an innovative resource allocation model that allows identification of air pollutant emission control strategies that maximize mortality avoidances subject to a resource constraint. We first present the development of the resource allocation model and then a case study to show how the model can be used to identify resource allocation strategies that maximize mortality avoidances for top five Metropolitan Statistical Areas (MSAs) (i.e., New York, Los Angeles, Chicago, Dallas-Fort Worth, and Philadelphia) in the continental United States collectively. Given budget constraints in the U.S. Environmental Protection Agency's (EPA) Clean Air Act assessment, the results of the case study suggest that controls of sulfur dioxide (SO2) and primary carbon (PC) emissions from EPA Regions 2, 3, 5, 6, and 9 would have significant health benefits for the five selected cities collectively. Around 30,800 air pollution-related mortalities could be avoided during the selected 2-week summertime episode for the five cities collectively if the budget could be allocated based on the results of the resource allocation model. Although only five U.S. cities during a 2-week episode are considered in the case study, the resource allocation model can be used by decision-makers to plan air pollution mitigation strategies to achieve the most significant health benefits for other seasons and more cities over a region or the continental U.S.
Effective allocations of air quality management resources are challenging and complicated, and it is desired to have a tool that can help decision-makers better allocate the funds to maximize health benefits of air pollution mitigation. An innovative resource allocation model developed in this study can help decision-makers identify the best resource allocation strategies for multiple cities collectively. The results of a case study suggest that controls of primary carbon and sulfur dioxides emissions would achieve the most significant health benefits for five selected cities collectively.
Copolymer-templated nitrogen-doped carbon (CTNC) films deposited on glassy carbon were used as electrodes to study electrochemically driven hydrogen evolution reaction (HER) in 0.5 M H2SO4. The activity of these materials was extremely enhanced when a platinum counter electrode was used instead of a graphite rod and reached the level of commercial Pt/C electrodes. Postreaction scanning electron microscopy (SEM) and X-ray photoelectron spectroscopy (XPS) measurements of electrode surfaces revealed that incorporation of even extremely low amounts of Pt resulted in this considerable gain of HER activity. High resolution XPS analysis and density functional theory (DFT) calculations confirmed that pyridinic nitrogen atoms act as active sites for Pt coordination and deposition. The Pt can be incorporated in both molecular (Pt(2+)) and metallic (Pt(0)) form. This study shows that great caution must be taken when designing "metal-free" HER catalysts based on N-doped carbons.
The number of data-based research articles focusing on patient sociodemographic profiling and experience with healthcare practices is still relatively small. One of the reasons for this relative lack of research is that categorizing patients into different demographic groups can lead to significant reductions in sample numbers for homogeneous subgroups. The aim of this article is to identify problems and issues when dealing with big data that contains information at two levels: patient experience of their general practice, and scores received by practices. The Practice Accreditation and Improvement Survey (PAIS) consisting of 27 five-point Likert items and 11 sociodemographic questions is a Royal Australian College of General Practitioners (RACGP)-endorsed instrument for seeking patient views as part of the accreditation of Australian general practices. The data were collected during the 3-year period May 2011-July 2014, during which time PAIS was completed for 3734 individual general practices throughout Australia involving 312,334 anonymous patients. This represents over 60% of practices in Australia, and ∼75% of practices that undergo voluntary accreditation. The sampling method for each general practice was convenience sampling. The results of our analysis show how sociodemographic profiles of Australian patients can affect their ratings of practices and also how the location of the practice (State/Territory, remote access area) can affect patient experience. These preliminary findings can act as an initial set of results against which future studies in patient experience trends can be developed and measured in Australia. Also, the methods used in this article provide a methodological framework for future patient experience researchers to use when dealing with data that contain information at two levels, such as the patient and practice. Finally, the outcomes demonstrate that different subgroups can experience healthcare provision differently, especially indigenous patients and young patients. The implications of these findings for healthcare policy and priorities will need to be further investigated.
Despite the variety of treatments available, including surgical procedures and antimicrobial therapy, bone infections is still a medical problem, because they are difficult to treat. Optimal treatment should stabilize the bone, promote the biological recovery of bone defects and destroy bacterial infection. Systemic antibiotics are part of the standard therapy after surgical treatment of infected bone, but their effectiveness is limited due to malnutrition and low absorption at the site of infection. Moreover, long-term treatment and higher doses are associated with serious side effects. In contrast, the antibiotic impregnated bone cements or fillers can act as a local anti-infective drug delivery system, which not only fills the dead space after debridement, but also provide high concentrations of antibiotics in a potential site of infection, no increase levels of antibiotics in serum. The review analyzed the use of antibiotic-impregnated cement as local delivery of antibiotics systems. Gentamycin impregnated polymethylmethacrylate (PMMA) beads, for the topical treatment of orthopedic infections clinically used for over 30 years. Application of antibiotic delivery systems using cement in the infected region is common method of treatment that continues to improve. On the downside of PMMA is that the material does not biodegradable requires subsequent invasive procedures necessary to remove the implant.
Cancer/testis-antigens (CTAs) are specifically expressed in human malignancies and testis tissue, but their molecular functions are poorly understood. CTAs serve as regulators of gene expression, cell cycle and spermatogenesis, as well as targets for immune-based therapies. The CTA PRAME is expressed in various cancers, antagonises retinoic acid signalling and is regulated by DNA methylation and histone acetylation.
We analysed the molecular function of the CTA PRAME in primordial germ cells (PGC) and testicular germ cell cancers (GCC). GCCs arise from a common precursor lesion termed germ cell neoplasia in situ (GCNIS), which itself is thought to originate from a defective PGC. GCNIS cells eventually develop into unipotent seminomas or totipotent embryonal carcinomas (ECs), which are capable of differentiation into teratomas, yolk-sac tumours and choriocarcinomas.
PRAME is, like the master regulator of PGCs SOX17 expressed in human PGCs, GCNIS and seminomas but absent in ECs. shRNA-mediated knockdown of PRAME in seminomatous TCam-2 cells left SOX17 levels unchanged, but resulted in downregulation of pluripotency- and PGC-related genes (LIN28, PRDM14, ZSCAN10), whereas somatic and germ cell differentiation markers were upregulated. So, PRAME seems to act downstream of SOX17 by mediating the regulation of the
 germ cell differentiation and pluripotency programme. Endoderm differentiation is triggered in somatic cells by SOX17, suggesting that in PGCs, PRAME represses this programme and modulates SOX17 to function as a PGC-master regulator. Surprisingly, knockdown of PRAME in TCam-2 cells did not render the cells sensitive towards retinoic acid, despite the fact that PRAME has been described to antagonise retinoic acid signalling. Finally, we demonstrate that in non-seminomas PRAME expression is silenced by DNA methylation, which can be activated by formation of euchromatin via histone-deacetylase-inhibitors.
We identified the CTA PRAME as a downstream factor of SOX17 and LIN28 in regulating pluripotency and suppressing somatic/germ cell differentiation in PGC, GCNIS and seminomas.
Traces collected on crime scene objects frequently result in challenging DNA mixtures from several contributors in different DNA proportions. Understanding how the relative proportion of DNA deposited by different persons who handled the same object evolves through time has important bearings. For instance, this information may help determine whether the major contributor in a mixed DNA profile is more likely to correspond to the object owner or to the person who may have stolen this object. In this perspective, a simulation-based protocol was designed where randomly paired participants were asked to act either as first (object owner) or second (last) users. The first user was asked to handle/wear 9 different plastic-, metal-, nitrile- and fabric-made objects, commonly found at burglary/robbery crime scenes, for a minimum of 20min during 8 or 10 consecutive days. The second user subsequently used them for 5, 30 or 120min in three distinct simulation sessions. The analysis of the relative DNA contribution on the resulting 234 mock DNA traces revealed a large variability in the contribution depending on the time, substrate and pairs of participants. Despite this, a progressive increase of the second user's DNA contribution, relative to the first user, was observed over time in 93% of the traces. The second user was shown to become the major contributor in approximately 15%, 33% and 55% of the traces recovered from objects used for 5, 30 and 120min, respectively. Single-source DNA profiles were shown to represent only 1% of the traces. In addition, the DNA profiles of 165 out of 234 (71%) simulated traces displayed extra alleles. Most of these occurred in the minor fraction of mixed DNA profiles and were interpreted as artefacts. Nevertheless, DNA profiles of known participants either involved or not in the simulations were observed in 9 cases (4%). This confirms that indirect DNA transfer should be taken into account when interpreting "touch" DNA evidence.
TMA&#39;s Medicare and CHIP Reauthorization Act (MACRA) Resource Center is poised to equip physicians for the paradigm shift in Medicare payment. One of the main goals of the MACRA Resource Center is to help physicians compare their options in the two payment tracks - each with its own requirements - and take advantage of continuing medical education opportunities, practice management services, and other tools to get started.
A mathematical model is presented to examine the propagation of bending waves on a plant stem that are induced by vibratory excitation from an attached insect. This idealized model represents the insect body as a mass and the legs as a linear spring along with a general time-varying force that is assumed to act in parallel with the spring. The spring connects the mass to a stem modeled as a beam having uniform geometric and material properties. The linearly elastic beam is assumed to undergo pure vibratory bending and to be infinitely long in each direction. The equations that govern the insect-induced, coupled motions of both the beam and the mass are solved for arbitrary time varying forces produced by the insect's legs. Solutions for the frequency response indicate that the response is dominated by frequency components near the natural resonant frequency of the attached insect while at higher frequencies the amplitude of the response is strongly influenced only by the properties of the stem.
The search for novel anticancer therapeutics with the ability to overcome multi-drug resistance (MDR) mechanisms is of high priority. A class of molecules that show potential in overcoming MDR are the N-alkylated isatins. In particular 5,7-dibromo-N-alkylisatins are potent microtubule destabilizing agents that act to depolymerize microtubules, induce apoptosis and inhibit primary tumor growth in vivo. In this study we evaluated the ability of four dibrominated N-alkylisatin derivatives and the parent compound, 5,7-dibromoisatin, to circumvent MDR. All of the isatin-based compounds examined retained potency against the MDR cell lines; U937VbR and MES-SA/Dx5 and displayed bioequivalent dose-dependent cytotoxicity to that of the parental control cell lines. We show that one mechanism by which the isatin-based compounds overcome MDR is by circumventing P-glycoprotein (P-gp) mediated drug efflux. Thus, as the isatin-based compounds are not susceptible to extrusion from P-gp overexpressing tumor cells, they represent a promising alternative strategy as a stand-alone or combination therapy for treating MDR cancer.
In a bundled payment system, a single payment covers all costs associated with a single episode of care. Spine surgery may be well suited for bundled payments because of clearly defined episodes of care, but the impact on current practice has not been studied. We sought to examine how a theoretical bundled payment strategy with financial disincentives to resource utilization would impact practice patterns.
A multiple-choice survey was administered to spine surgeons describing eight clinical scenarios. Respondents were asked about their current practice, and then their practice in a hypothetical bundled payment system. Respondents could choose from multiple types of implants, bone grafts, and other resources utilized at the surgeon's discretion.
Forty-three respondents completed the survey. Within each scenario, 24%-49% of respondents changed at least one aspect of management. The proportion of cases performed without implants was unchanged for four scenarios and increased in four by an average of 8%. Use of autologous iliac crest bone graft increased across all scenarios by an average of 18%. Use of neuromonitoring decreased in all scenarios by an average of 21%. Differences in costs were not statistically significant.
Financial disincentives to resource utilization may result in some changes to surgeons' practices but these appear limited to items with less clear benefits to patients. Choices of implants, which account for the majority of intra-operative costs, did not change meaningfully. A bundling strategy targeting peri-operative costs solely related to surgical practice may not yield substantive savings while rationing potentially beneficial treatments to patient care.
5.
N-Acetyl-p-Aminophenol (APAP), also known as acetaminophen, is the most commonly used over-the counter analgesic and antipyretic medication. However, its overdose leads to both liver and kidney damage. APAP-induced toxicity is considered as one of the primary causes of acute liver failure; numerous scientific reports have focused majorly on APAP hepatotoxicity. Alternatively, not many works approach APAP nephrotoxicity focusing on both its mechanisms of action and therapeutic exploration. Moringa oleifera (MO) is pervasive in nature, is reported to possess a surplus amount of nutrients, and is enriched with several bioactive candidates including trace elements that act as curatives for various clinical conditions. In this study, we evaluated the nephro-protective potential of MO leaf extract against APAP nephrotoxicity in male Balb/c mice. A single-dose acute oral toxicity design was implemented in this study. Group 2, 3, 4 and 5 received a toxic dose of APAP (400 mg/kg of bw, i.p) and after an hour, these groups were administered with saline (10 mL/kg), silymarin-positive control (100 mg/kg of bw, i.p), MO leaf extract (100 mg/kg of bw, i.p), and MO leaf extract (200 mg/kg bw, i.p) respectively. Group 1 was administered saline (10 mL/kg) during both the sessions. APAP-treated mice exhibited a significant elevation of serum creatinine, blood urea nitrogen, sodium, potassium and chloride levels. A remarkable depletion of antioxidant enzymes such as SOD, CAT and GSH-Px with elevated MDA levels has been observed in APAP treated kidney tissues. They also exhibited a significant rise in pro-inflammatory cytokines (TNF-α, IL-1β, IL-6) and decreased anti-inflammatory (IL-10) cytokine level in the kidney tissues. Disorganized glomerulus and dilated tubules with inflammatory cell infiltration were clearly observed in the histology of APAP treated mice kidneys. All these pathological changes were reversed in a dose-dependent manner after MO leaf extract treatment. Therefore, MO leaf extract has demonstrated some therapeutic effectiveness against APAP-induced nephrotoxicity through enhancement of the endogenous antioxidant system and a modulatory effect on specific inflammatory cytokines in kidney tissues.
To examine the association between patient race/ethnicity, insurance status, and their interaction with patient safety indicators among hospitalized patients.
Cross-sectional study was conducted. Data were extracted from the 2009 National Inpatient Sample. A total of 3,052,268 patient safety indicator-related discharges were identified. Dependent variables were 11 patient safety indicators (PSI) whereas independent variables included race/ethnicity and insurance status.
As compared with White patients, African American patients were more likely to experience pressure ulcer, post-operative hemorrhage or hematoma,
 and post-operative pulmonary embolism (PE) or deep vein thrombosis (DVE); Asian/Pacific Islander patients were more likely to experience pressure ulcer, post-operative PE or DVT, and two obstetric care PSIs; whereas Hispanic/Latino patients were more likely to experience post-operative physiometabolic derangement and accidental puncture/laceration. As compared with patients with private insurance, Medicaid patients were more likely to experience pressure ulcer, post-operative physiological metabolic derangement, post-operative PE or DVT, post-operative respiratory failure, post-operative wound dehiscence, and death among surgeries. However, both obstetric care PSIs showed that African Americans, Hispanics, and uninsured patients were less likely to incur them in comparison with their respective counterparts. Furthermore, strong interactive effects between African American and Medicaid on PSIs were detected.
Although mixed findings in disparities in PSIs were observed in our study, Asian/Pacific Islander patients and Medicaid patients seem to be the most vulnerable. Further, interactive effects between African American and Medicaid indicate that poverty may be a key factor related to disparities in health care. Future research is merited to identify underlying factors that are related to PSIs among Asian/Pacific Islander patients. Strategies are needed to improve PSIs among Medicaid patients, especially during the current Medicaid program expansion due to the implementation of the Affordable Care Act.
In order to contribute to evolutionary resilience and adaptive potential in highly modified landscapes, revegetated areas should ideally reflect levels of genetic diversity within and across natural stands. Landscape genomic analyses enable such diversity patterns to be characterized at genome and chromosomal levels. Landscape-wide patterns of genomic diversity were assessed in Eucalyptus microcarpa, a dominant tree species widely used in revegetation in Southeastern Australia. Trees from small and large patches within large remnants, small isolated remnants and revegetation sites were assessed across the now highly fragmented distribution of this species using the DArTseq genomic approach. Genomic diversity was similar within all three types of remnant patches analysed, although often significantly but only slightly lower in revegetation sites compared with natural remnants. Differences in diversity between stand types varied across chromosomes. Genomic differentiation was higher between small, isolated remnants, and among revegetated sites compared with natural stands. We conclude that small remnants and revegetated sites of our E. microcarpa samples largely but not completely capture patterns in genomic diversity across the landscape. Genomic approaches provide a powerful tool for assessing restoration efforts across the landscape.
Novel associations between plants and pathogens can have serious impacts on managed and natural ecosystems world-wide. The introduction of alien plants increases the potential for biogeographically novel plant-pathogen associations to arise when pathogens are transmitted from native to alien plant species and vice versa. We quantified biogeographically novel associations recorded in New Zealand over the last 150 yr between plant pathogens (fungi, oomycetes and plasmodiophorids) and vascular plants. We examined the extent to which taxonomic similarity, pathogen traits, contact opportunity and sampling effort could explain the number of novel associates for host and pathogen species. Novel associations were common; approximately one-third of surveyed plants and pathogens were recorded with at least one biogeographically novel associate. Native plants had more alien pathogens than vice versa. Taxonomic similarity between the native and alien flora and the total number of recorded associations (a measure of sampling effort) best explained the number of novel associates among species. The frequency of novel associations and the importance of sampling effort as an explanatory variable emphasize the need for effective monitoring and risk assessment tools to mitigate the potential environmental and economic impact of novel pathogen associations.
The United States health-care expenditure is rising precipitously. The Congressional Budget Office has estimated that, in 2025, at our current rate of increased spending, 25% of the gross domestic product will be allocated to health care. Our per-capita spending on health care also far exceeds that of any other industrialized country. Health-care costs must be addressed if our country is to remain competitive in the global marketplace and to maintain its financial solvency. If unchecked, the uncontrolled rise in health-care expenditures will not only affect our capacity to provide our patients with high-quality care but also threaten the ability of our nation to compete economically on the global stage. This is not hyperbole but fiscal reality.As physicians, we are becoming increasingly familiar with the economics impacting health-care policy. Thus, we are in a unique position to control the cost of health care. This includes an increased reliance on creating and adhering to evidence-based guidelines. We can do this and still continue to respect the primacy of patient welfare and the right of patients to act in their own self-interest. However, as evidenced by the use of high-volume centers of excellence, each strategy adapted to control costs must be vetted and must be monitored for its unintended ethical consequences.The solution to this complex problem must involve the input of all of the health-care stakeholders, including the patients, payers, and providers. Physicians ought to play a role in designing and executing a remedy. After all, we are the ones who best understand medicine and whose moral obligation is to the welfare of our patients.
A well-known physiological adaptation process of plants encountering drying soil is to achieve water balance by reducing shoot growth and maintaining or promoting root elongation, but little is known about the molecular basis of this process. This study investigated the role of a drought-up-regulated Triticum aestivum NAC69-1 (TaNAC69-1) in the modulation of root growth in wheat. TaNAC69-1 was predominantly expressed in wheat roots at the early vegetative stage. Overexpression of TaNAC69-1 in wheat roots using OsRSP3 (essentially root-specific) and OsPIP2;3 (root-predominant) promoters resulted in enhanced primary seminal root length and a marked increase in maturity root biomass. Competitive growth analysis under water-limited conditions showed that OsRSP3 promoter-driven TaNAC69-1 transgenic lines produced 32% and 35% more above-ground biomass and grains than wild-type plants, respectively. TaNAC69-1 overexpression in the roots down-regulated the expression of TaSHY2 and TaIAA7, which are from the auxin/IAA (Aux/IAA) transcriptional repressor gene family and are the homologs of negative root growth regulators SHY2/IAA3 and IAA7 in Arabidopsis. The expression of TaSHY2 and TaIAA7 in roots was down-regulated by drought stress and up-regulated by cytokinin treatment, which inhibited root growth. DNA binding and transient expression analyses revealed that TaNAC69-1 bound to the promoters of TaSHY2 and TaIAA7, acted as a transcriptional repressor and repressed the expression of reporter genes driven by the TaSHY2 or TaIAA7 promoter. These data suggest that TaNAC69-1 is a transcriptional repressor of TaSHY2 and TaIAA7 homologous to Arabidopsis negative root growth regulators and is likely to be involved in promoting root elongation in drying soil.
Crystalline Cu-based nanowire arrays (NWAs) including Cu(OH)2 , CuO, Cu2 O, and CuOx are facilely grown on Cu foil and are found to act as highly efficient, low-cost, and robust electrocatalysts for the oxygen evolution reaction (OER). Impressively, this noble-metal-free 3 D Cu(OH)2 -NWAs/Cu foil electrode shows the highest catalytic activity with a Tafel slope of 86 mV dec(-1) , an overpotential (η) of about 530 mV at ∼10 mA cm(-2) (controlled-potential electrolysis method without iR correction) and almost 100 % Faradic efficiency, paralleling the performance of the state-of-the-art RuO2 OER catalyst in 0.1 m NaOH solution (pH 12.8). To the best of our knowledge, this work represents one of the best results ever reported on Cu-based OER systems.
The Swedish Education Act (2011) mandated a new combination of services to boost students' physical health, their mental health and special education through interprofessional pupil health and well-being (PH) teams. For Swedish school nurses, providing these services presents new challenges.
To describe how Swedish school nurses experience their work and collaboration within the interprofessional PH teams.
Twenty-five school nurses (SNs) were interviewed in five focus groups. Content analysis was used to examine the data and to explore SNs' workplace characteristics by using the components of the sense of coherence (SOC) framework.
SNs' experiences of work and collaboration within PH teams can be described using three domains: the expectations of others regarding SNs' roles, SNs' contributions to pupils' health and well-being, and collaboration among SNs within PH teams. The results indicate a discrepancy between SNs' own experiences of their contribution and their experiences of other professionals' expectations regarding those contributions. Some duties were perceived as expected, comprehensible, manageable and meaningful, while other duties - though expected - were perceived as less meaningful, taking time away from school-related matters. Other duties that were not explicitly expected - promoting general health and creating safety zones for pupils, teachers and parents, for example - were nonetheless perceived as meaningful.
 Collaboration within PH teams was considered meaningful, comprehensible and manageable only if the objectives of the team meetings were clear, if other professionals were available and if professional roles on the team were clearly communicated.
The SNs reported a lack of clarity regarding their role in PH and its implementation in schools, indicating that professionals in PH teams need to discuss collaboration so as to find their niche given the new conditions. SOC theory emerged as a useful framework for discussing concrete work-related factors in the school environment.
An increasing number of studies demonstrate that individuals with a history of suicidality exhibit impaired executive functioning abilities. The current study examines whether these differences are linked to suicidal thoughts or suicidal acts-a crucial distinction given that most people who think about suicide will not act on their thoughts. A large online sample of U.S. participants with a history of suicide ideation (n = 197), suicide attempts (n = 166), and no suicidality (n = 180) completed self-report measures assessing executive functioning, suicide ideation and attempts; in addition, depression, self-efficacy, and history of drug abuse and brain injury were assessed as potential covariates. Individuals with recent suicide attempts reported significantly worse executive functioning than ideators. This difference was not accounted for by depression, self-efficacy, history of drug abuse or brain injury. Self-reported executive functioning may represent an important short-term risk factor for suicide attempts.
The goal of this study was to examine which motor learning options are applied by experienced physiotherapists in neurological rehabilitation, and how they choose between the different options.
A descriptive qualitative approach was used. A purposive sample of five expert physiotherapists from the neurological ward of a rehabilitation center participated. Data were collected using nine videotaped therapy situations. During retrospective think-aloud interviews, the physiotherapists were instructed to constantly "think aloud" while they were watching their own videos.
Five "operators" were identified: "act", "know", "observe", "assess" and "argue". The "act" operator consisted of 34 motor learning options, which were clustered into "instruction", "feedback" and "organization". The "know", "observe", "assess" and "argue" operators explained how therapists chose one of these options. The four operators seem to be interrelated and together lead to a decision to apply a particular motor learning option.
Results show that the participating physiotherapists used a great variety of motor learning options in their treatment sessions. Further, the decision-making process with regard to these motor learning options was identified. Results may support future intervention studies that match the content and process of therapy in daily practice. The study should be repeated with other physiotherapists. Implications for Rehabilitation The study provided insight into the way experienced therapist handle the great variety of possible motor learning options, including concrete ideas on how to operationalize these options in specific situations. Despite differences in patients' abilities, it seems that therapists use the same underlying clinical reasoning process when choosing a particular motor learning option. Participating physiotherapists used more than the in guidelines suggested motor learning options and considered more than the suggested factors, hence adding practice based options of motor learning to the recommended ones in the guidelines. A think-aloud approach can be considered for peer-to-peer and student coaching to enhance discussion on the motor learning options applied and the underlying choices and to encourage research by practicing clinicians.
Two-pore channels (TPC1-3) comprise a subfamily of the eukaryotic voltage-gated ion channels (VGICs) superfamily that are mainly expressed in acidic stores in plants and animals. TPCS are widespread across the animal kingdom, with primates, mice and rats lacking TPC3, and mainly act as Ca(+) and Na(+) channels, although it was also suggested that they could be permeable to other ions. Nowadays, TPCs have been related to the development of different diseases, including Parkinson´s disease, obesity or myocardial ischemia. Due to this, their study has raised the interest of the scientific community to try to understand their mechanism of action in order to be able to develop an efficient drug that could regulate TPCs activity. In this review, we will provide an updated view regarding TPCs structure, function and activation, as well as their role in different pathophysiological processes.
How healthcare providers distribute their time can impact on the quality and safety of care delivered, and this has been widely studied in hospitals providing care to adult patients. Children are different to adults and the workflow of healthcare providers in paediatric settings is largely unknown. The aim of this study was to quantify how clinical pharmacists working in a paediatric hospital spend their time. A direct observational time and motion study was conducted where two independent observers shadowed seven pharmacists covering eight wards for over 60 hours. Pharmacists spent the majority of time performing medication review (32.6%), followed by communication, non-clinical tasks, supply, medication discussion and in-transit. They were interrupted 3.5 times per hour and spent 4.4% of observed time multi-tasking. This is the first study to quantify how pharmacists in a paediatric hospital distribute their time. These results could act as useful baseline data against which to measure the impact of innovations, such as electronic medication management systems, on pharmacists' workflow.
There are significant challenges in addressing the mental health needs of college students. The current study tested an acceptance and commitment therapy (ACT), web-based self-help program to treat a broad range of psychological problems students struggle with. A sample of 79 college students was randomized to web-based ACT or a waitlist condition, with assessments at baseline and posttreatment. Results indicated adequate acceptability and program engagement for the ACT website. Relative to waitlist, participants receiving ACT improved on overall distress, general anxiety, social anxiety, depression, academic concerns, and positive mental health. There were no between-group effects on eating concerns, alcohol use, or hostility, or on some key ACT process of change measures. ACT participants improved more on mindful acceptance and obstruction to valued living, both of which mediated treatment outcomes. Results are discussed in the context of lessons learned with the website prototype, and areas for further research are presented.
Synaptojanin 2 Binding Protein (SYNJ2BP) is essential to cell proliferation. Previous studies show that SYNJ2BP participates in sprouting angiogenesis, which plays an important part in several abnormal conditions including cancer. However, the activity of SYNJ2BP in hepatocellular carcinoma (HCC) has not been elucidated yet.
Firstly, real-time PCR and western blotting (WB) were adopted to evaluate SYNJ2BP expressions in HCC tissues and HCC cell lines. Secondly, we did follow-up and prognostic study to explore the association of SYNJ2BP expression and HCC patients prognosis. Thirdly, we induced or silenced SYNJ2BP expression on selected HCC cell lines and explored the function of SYNJ2BP in vitro and in vivo. Lastly, we conducted Cignal Finder Cancer 10-Pathway Reporter Array in combination with loss- and gain-of-function assay to investigate potential mechanisms.
Through various techniques we found that SYNJ2BP was decreased in HCC tissues and HCC cell lines. The subsequent analysis showed that low expression of SYNJ2BP was associated with tumor size, tumor nodule number, vascular invasion, TNM stage and BCLC stage, and was an independent risk factor for survival of HCC. Later, the in vitro experiments demonstrated that SYNJ2BP inhibited HCC cells invasion, migration and proliferation, also the in vivo testing revealed that SYNJ2BP inhibited tumor growth and metastasis. Finally, we also uncovered that SYNJ2BP inhibited HCC growth and metastasis through activating DLL4-mediated Notch signaling pathway.
Collectively, our data provide evidence that SYNJ2BP may act as a tumor suppressor during HCC development and could serve as a potential therapeutic target.
The lack of a reliable in vitro system to assess reprotoxicity is an emerging problem in the context of European law for Registration, Evaluation, Authorization and Restriction of Chemicals (REACH, 2007), as it requires a reduction in animal utilization for testing. Furthermore, in vitro reprotoxicological tests would be more relevant and greatly improved by integrating both hepatic metabolism and the blood-testis barrier. Here, we took advantage of an integrated insert in a dynamic microfluidic platform (IIDMP) to co-cultivate hepatocytes in biochip and Sertoli cells in the bicameral chamber. This microfluidic tool has been previously demonstrated to be helpful in cell function and/or quality improvement. We demonstrate that permeability of the Sertoli barrier is reduced by dynamic coculture in our system. Exometabolomics analysis reveals that interactions between hepatocytes and Sertoli cells may have been mediated by the polyamines increase and/or mid-chain fatty acid decrease in the circulating medium. These metabolic changes may be involved in permeability reduction by contributing to modifying junction protein quantity and localization. The present study gives an example of IIDMP as an in vitro partitioning/transport model for cell culture and toxicological
 testing. Further, based on both our previous results using an intestinal-hepatic cell coculture and the present study, IIDMP seems to be well-suited for (i) assessing the dose-response effect of chemicals within the rodent or human male reproductive tract, and (ii) improving the quality of reprotoxicological assays by including hepatic metabolism. Copyright © 2016 John Wiley & Sons, Ltd.
The Improving Medicare Post-Acute Care Transformation (IMPACT) Act of 2014 stipulates that standardized functional status (self-care and mobility) and cognitive function data will be used for quality reporting in post-acute care settings. Thirty-day post-discharge unplanned rehospitalization is an established quality metric that has recently been extended to post-acute settings. The relationships between the functional domains in the IMPACT Act and 30-day unplanned rehospitalization are poorly understood.
To determine the degree to which discharge mobility, self-care, and cognitive function are associated with 30-day unplanned rehospitalization following discharge from post-acute care.
This was a retrospective cohort study.
Inpatient rehabilitation facilities submitting claims and assessment data to the Centers for Medicare and Medicaid Services in 2012-2013.
Medicare fee-for-service enrollees discharged from post-acute rehabilitation in 2012-2013. The sample included community-dwelling adults admitted for rehabilitation following an acute care stay who survived for 32 days following discharge (N = 252,406).
Not applicable.
Thirty-day unplanned rehospitalization following post-acute rehabilitation.
The unadjusted 30-day unplanned rehospitalization rate was 12.0 % (n = 30,179). Overall, patients dependent at discharge for mobility had a 50 % increased odds of rehospitalization (OR = 1.50, 95 % CI: 1.42-1.59), patients dependent for self-care a 36 % increased odds (OR = 1.36, 95 % CI: 1.27-1.47), and patients dependent for cognition a 19 % increased odds (OR = 1.19, 95 % CI: 1.09-1.29). Patients dependent for both self-care and mobility at discharge (n = 8312, 3.3 %) had a 16.1 % (95 % CI: 15.3-17.0 %) adjusted rehospitalization rate versus 8.5 % (95 % CI: 8.3-8.8 %) for those independent for both (n = 74,641; 29.6 %).
The functional domains identified in the IMPACT Act were associated with 30-day unplanned rehospitalization following post-acute care in this large national sample. Further research is needed to better understand and improve the functional measures, and to determine if their association with rehospitalizations varies across post-acute settings, patient populations, or episodes of care.
The knowledge and practices of health professionals have a recognized role in behaviors related to the health of their patients. During pregnancy, this influence can be even stronger because there is frequent contact between women and doctors/nurses at periodic antenatal visits. When trained, supported and motivated, these professionals can act as health promoters. This study aimed to evaluate the effect of a focused educational intervention on improving the knowledge and practices of health professionals concerning diet and physical activity during pregnancy.
A controlled, non-randomized study was performed to assess the effects of an educational intervention on the knowledge and practices of nurses and doctors who provide primary care to pregnant women. The intervention group, doctors and nurses (n = 22) from the family health units in a medium-sized city of São Paulo State, Brazil, received 16 h of training comprising an introductory course and three workshops, whereas the control group, doctors and nurses (n = 20) from traditional basic health units in Botucatu, did not. The professionals' knowledge was assessed at two time points, 1 month prior to and 1 year after the beginning of the intervention, using an ad hoc self-report questionnaire. The increases in the knowledge scores for walking and healthy eating of the intervention and control groups were calculated and compared using Student's t-test. To analyze the professionals' practice, women in the second trimester of pregnancy were asked whether they received guidance on healthy eating and leisure-time walking; 140 of these women were cared for by professionals in the intervention group, and 141 were cared for by professionals in the control group. The percentage of pregnant women in each group that received guidance was compared using the chi-square test and the Prevalence Ratio (PR), and the corresponding 95 % confidence intervals (CI) were calculated.
The intervention improved the professionals' knowledge regarding leisure-time walking (92 % increase in the score, p < 0.001). The women who were cared for by the intervention group were more likely to receive guidance regarding leisure-time walking (PR = 2.65; 95 % CI = 1.82-3.83) and healthy eating (PR = 1.76; 95 % CI = 1.34-2.31) when compared to the control group.
It is possible to improve the knowledge and practices of health professionals through the proposed intervention aimed at primary health care teams providing antenatal care.
International travel and infectious respiratory illnesses worldwide place health care workers (HCWs) at increasing risk of respiratory exposures. To ensure the highest quality safety initiatives, one health care system used a quality improvement model of Plan-Do-Study-Act and guidance from Occupational Safety and Health Administration's (OSHA) May 2015 Hospital Respiratory Protection Program (RPP) Toolkit to assess a current program. The toolkit aided in identification of opportunities for improvement within their well-designed RPP. One opportunity was requiring respirator use during aerosol-generating procedures for specific infectious illnesses. Observation data demonstrated opportunities to mitigate controllable risks including strap placement, user seal check, and reuse of disposable N95 filtering facepiece respirators. Subsequent interdisciplinary collaboration resulted in other ideas to decrease risks and increase protection from potentially infectious respiratory illnesses. The toolkit's comprehensive document to evaluate the program showed that while the OSHA standards have not changed, the addition of the toolkit can better protect HCWs.
The assembly of β-barrel proteins into membranes is mediated by an evolutionarily conserved machine. This process is poorly understood because no stable partially folded barrel substrates have been characterized. Here, we slowed the folding of the Escherichia coli β-barrel protein, LptD, with its lipoprotein plug, LptE. We identified a late-stage intermediate in which LptD is folded around LptE, and both components interact with the two essential β-barrel assembly machine (Bam) components, BamA and BamD. We propose a model in which BamA and BamD act in concert to catalyze folding, with the final step in the process involving closure of the ends of the barrel with release from the Bam components. Because BamD and LptE are both soluble proteins, the simplest model consistent with these findings is that barrel folding by the Bam complex begins in the periplasm at the membrane interface.
Although APOBEC3 cytidine deaminases A3G, A3F, A3D and A3H are packaged into virions and inhibit viral replication by inducing G-to-A hypermutation, it is not known whether they are copackaged and whether they can act additively or synergistically to inhibit HIV-1 replication. Here, we showed that APOBEC3 proteins can be copackaged by visualization of fluorescently-tagged APOBEC3 proteins using single-virion fluorescence microscopy. We further determined that viruses produced in the presence of A3G + A3F and A3G + A3H, exhibited extensive comutation of viral cDNA, as determined by the frequency of G-to-A mutations in the proviral genomes in the contexts of A3G (GG-to-AG) and A3D, A3F or A3H (GA-to-AA) edited sites. The copackaging of A3G + A3F and A3G + A3H resulted in an additive increase and a modest synergistic increase (1.8-fold) in the frequency of GA-to-AA mutations, respectively. We also identified distinct editing site trinucleotide sequence contexts for each APOBEC3 protein and used them to show that hypermutation of proviral DNAs from seven patients was induced by A3G, A3F (or A3H), A3D and A3G + A3F (or A3H). These results indicate that APOBEC3 proteins can be copackaged and can comutate the same genomes, and can cooperate to inhibit HIV replication.
Use of low resolution single cell DNA FISH and population based high resolution chromosome conformation capture techniques have highlighted the importance of pairwise chromatin interactions in gene regulation. However, it is unlikely that associations involving regulatory elements act in isolation of other interacting partners that also influence their impact. Indeed, the influence of multi-loci interactions remains something of an enigma as beyond low-resolution DNA FISH we do not have the appropriate tools to analyze these. Here we present a method that uses standard 4C-seq data to identify multi-loci interactions from the same cell. We demonstrate the feasibility of our method using 4C-seq data sets that identify known pairwise and novel tri-loci interactions involving the Tcrb and Igk antigen receptor enhancers. We further show that the three Igk enhancers, MiEκ, 3'Eκ and Edκ, interact simultaneously in this super-enhancer cluster, which add to our previous findings showing that loss of one element decreases interactions between all three elements as well as reducing their transcriptional output. These findings underscore the functional importance of simultaneous interactions and provide new insight into the relationship between enhancer elements. Our method opens the door for studying multi-loci interactions and their impact on gene regulation in other biological settings.
Two-component systems (TCS) and small
 regulatory RNAs (sRNAs) are both widespread regulators of gene expression in bacteria. TCS are in most cases transcriptional regulators. A large class of sRNAs act as post-transcriptional regulators of gene expression that modulate the translation and/or stability of target-mRNAs. Many connections have been recently unraveled between these two types of regulators, resulting in mixed regulatory circuits with poorly characterized properties. This study focuses on the negative feedback circuit that exists between the EnvZ-OmpR TCS and the OmrA/B sRNAs. We have shown that OmpR directly activates transcription from the omrA and omrB promoters, allowing production of OmrA/B sRNAs that target multiple mRNAs, including the ompR-envZ mRNA. This control of ompR-envZ by the Omr sRNAs does not affect the amount of phosphorylated OmpR, i.e. the presumably active form of the regulator. Accordingly, expression of robust OmpR targets, such as the ompC or ompF porin genes, is not affected by OmrA/B. However, we find that several OmpR targets, including OmrA/B themselves, are sensitive to changing total OmpR levels. As a result, OmrA/B limit their own synthesis. These findings unravel an additional layer of control in the expression of some OmpR targets and suggest the existence of differential regulation within the OmpR regulon.
An original step-by-step approach to synthesize and characterize a bifunctional heterogeneous catalyst consisting of isolated Ti(3+) centers and strong Lewis acid Al(3+) sites on the surface of a chlorinated alumina has been devised. A wide range of physicochemical and spectroscopic techniques were employed to demonstrate that the two sites, in close proximity, act in a concerted fashion to synergistically boost the conversion of ethylene into branched polyethylene, using ethylene as the only feed and without any activator. The coordinatively unsaturated Al(3+) ions promote ethylene oligomerization through a carbocationic mechanism and activate the Ti(3+) sites for the traditional ethylene coordination polymerization.
Drought negatively affects plant growth and development, thereby leading to loss of crop productivity. Several plant E3 ubiquitin ligases act as positive or negative regulators of abscisic acid (ABA) and thus play important roles in the drought stress response. Here, we show that the C3HC4-type RING finger E3 ligase, CaDTR1, regulates the drought stress response via ABA-mediated signalling. CaDTR1 contains an amino-terminal RING finger motif and two carboxyl-terminal hydrophobic regions; the RING finger motif functions during attachment of ubiquitins to the target proteins, and the carboxyl-terminal hydrophobic regions function during subcellular localisation. The expression of CaDTR1 was induced by ABA, drought, and NaCl treatments. CaDTR1 localised in the nucleus and displayed in vitro E3 ubiquitin ligase activity. CaDTR1-silenced pepper plants exhibited a drought-sensitive phenotype characterised by high levels of transpirational water loss. On the other hand, CaDTR1-overexpressing (OX) Arabidopsis plants exhibited an ABA-hypersensitive phenotype during the germinative and post-germinative growth stages. Moreover, in contrast to CaDTR1-silenced pepper plants, CaDTR1-OX plants exhibited a drought-tolerant phenotype characterised by low levels of transpirational water loss via increased stomatal closure and high leaf temperatures. Our data indicate that CaDTR1 functions as a positive regulator of the drought stress response via ABA-mediated signalling.
Iron is an important micronutrient, but it can also act as a dangerous element by interfering with glucose homeostasis and inflammation, two features that are already disturbed in obese subjects. In this work, we study the effects of systemic iron supplementation on metabolic and inflammatory responses in mice with hypoferremia induced by obesity to better characterize whether iron worsens the parameters that are already altered after 24 weeks of a high-fat diet (HFD). Mice were maintained on a control diet or a HFD for 24 weeks and received iron-III polymaltose (50 mg/kg/every 2 days) during the last two weeks. Glucose homeostasis (basal glucose and insulin test tolerance) and systemic and visceral adipose tissue (VAT) inflammation were assessed. Iron levels were measured in serum. The Prussian blue reaction was used in isolated macrophages to detect iron deposition. Iron supplementation resulted in an increased number of VAT macrophages that were positive for Prussian blue staining as well as increased serum iron levels. Systemic hepcidin, leptin, resistin, and monocyte chemoattractant protein-1 (MCP-1) levels were not altered by iron supplementation. Local adipose tissue inflammation was also not made worse by iron supplementation because the levels of hepcidin, MCP-1, leptin, and interleukin (IL)-6 were not altered. In contrast, iron supplementation resulted in an increased production of IL-10 by adipose tissue and VAT macrophages. Leukocytosis and VAT plasminogen activator inhibitor-1 (PAI-1) level were reduced, but insulin resistance was not altered after iron supplementation. In conclusion, systemic iron supplementation in mice with hypoferremia induced by obesity did not worsen inflammatory marker or adipose tissue inflammation or the metabolic status established by obesity. Iron deposition was observed in adipose tissue, mainly in macrophages, suggesting that these cells have mechanisms that promote iron incorporation without increasing the production of inflammatory mediators.
The Iowa Gambling Task (IGT) is commonly used to understand the processes involved in decision-making. Though the task was originally run without a computer, using a computerized version of the task has become typical. These computerized versions of the IGT are useful, because they can make the task more standardized across studies and allow for the task to be used in environments where a physical version of the task may be difficult or impossible to use (e.g., while collecting brain imaging data). Though these computerized versions of the IGT have been useful for experimentation, having multiple software implementations of the task could present reliability issues. We present an open-source software version of the Iowa Gambling Task (called IGT-Open) that allows for millisecond visual presentation accuracy and is freely available to be used and modified. This software has been used to collect data from human subjects and also has been used to run model-based simulations with computational process models developed to run in the ACT-R architecture.
Treatment services to patients with substance use disorders (SUDs), including those mandated to treatment, needs to be evaluated and evidence based. The Norwegian Municipal Health Care Act calls for mandated treatment for persons with "severe and life-threatening substance use disorder" if these individuals are not otherwise willing to be voluntarily treated and consequently risk their lives over drug use. This study aims to examine substance use-related outcomes at 6 months following inpatient treatment and to analyse factors associated with improved outcomes and abstinence.
This prospective study followed 202 hospitalized patients with SUD who were admitted voluntarily (VA; n = 137) or compulsorily (CA; n = 65). The European Addiction Severity Index was used at baseline and at follow-up to assess socio-demographic and substance use variables. Regression analysis was conducted to investigate factors associated with abstinence at 6 months of follow-up.
The frequency of use of a preferred substance showed marked improvement for both VA and CA patients (61 and 37 %, respectively) at follow-up. Seventy-five percent of VA patients using amphetamine reported improvement compared to 53 % of CA patients. At follow-up, the CA group continued to have a higher rate of injection use. The CA group had experienced higher rates of overdose in the past 6 months and lower abstinence rates (24 % versus 50 %) at follow-up. A lower severity of drug use at intake (non-injection drug use), voluntary treatment modality, and higher treatment involvement during follow-up all were significant factors associated with abstinence at 6 months after treatment.
Voluntary treatment for SUD generally yielded better outcomes; nevertheless, we also found improved outcomes for CA patients. It is important to keep in mind that in reality, the alternative to CA treatment is no treatment at all and instead a continuation of life-threatening drug use behaviours. Our observed outcomes for CA patients support the continuation of CA treatment.
Contents 1188 I. 1188 II. 1189 III. 1190 IV. 1191 V. 1192 1192 References 1192 SUMMARY: The amino- (N-) terminus (Nt) of a protein can undergo a diverse array of co- and posttranslational modifications. Many of these create degradation signals (N-degrons) that mediate protein destruction via the N-end rule pathway of ubiquitin-mediated proteolysis. In plants, the N-end rule pathway has emerged as a major system for regulated control of protein stability. Nt-arginylation-dependent degradation regulates multiple growth, development and stress responses, and recently identified functions of Nt-acetylation can also be linked to effects on the in vivo half-lives of Nt-acetylated proteins. There is also increasing evidence that N-termini could act as important protein stability determinants in plastids. Here we review recent advances in our understanding of the relationship between the nature of protein N-termini, Nt-processing events and proteolysis in plants.
Nutrients are of particular importance for bone health: they act as structural elements of bones, modulate the activity of osteoblasts and osteoclasts, and influence bone remodeling through various mediators. A bone protective diet can be characterised as a diet rich
 in fruits and vegetables, dairy products, seeds and nuts, whole grain and soy products and moderate amounts of fish, eggs and lean meat. This diet provides sufficient amounts of protein, calcium, magnesium and vitamins (e. g. K, C, folic acid, B6 and B12), which are important for bone development. For specific nutrients, the following bone-protective recommendations can be given: 1.0-1.3 g protein/kg body weight and day; 1000-1200 mg/day calcium, preferably as part of the normal diet. In case of insufficient calcium intake or on antiresorptive medication a supplementation of 200-500 mg or 500-1000 mg calcium/day, respectively, should be given. Furthermore, for prevention of bone fractures a cut off level of ≥ 75 nmol calcidiol/l is suggested.
According to the German Organ Transplantation Act, donor organs must be allocated with particular regard to chance of success and urgency. However, the objectives of these guiding criteria - the efficient use of available organs and meeting the most urgent need - are in conflict with each other, as success rate of transplantation (TX) ordinarily diminishes when urgency increases. Current allocation guidelines balance these criteria differently depending on the organ. This is only justified in part by medical reasons. Thus, further considerations are essential to develop consistent allocation rules. Therefore, a discussion on the stated trade-off considering the far-reaching consequences of such allocation decisions is indispensable. This also implies taking account of public preferences.
In this pilot study, preferences of 250 participants were assessed using a Discrete Choice Experiment. Choice-sets for the allocation of a donor organ included 2 patients, who were characterized by 3 success- and 2 urgency-based attributes. Data analysis was performed by Counting Analysis and Hierarchical Bayes estimation as well as Student's t-tests for subgroup analysis.
All attributes influenced allocation decisions significantly (p≤0.01). Both, patients with greater chance of success and higher urgency were preferred. As a whole, chance of success and urgency were equally important for the allocation of organs (53 and 47%, respectively). The importance of the success- and urgency-based criteria was quantified as follows: The post-TX 5-year probability of survival was weighted with 31%, the expected post-TX quality of life and the surgery survival rate with 11% each, the pre-TX 3-month mortality with 35% and the pre-TX quality of life with 12%. Subgroup analysis revealed significant differences.
The pilot study was successful in analyzing the balance of the guiding criteria chance of success and urgency without referring to a specific kind of organ. This type of results allows comparing current allocation rules and public preferences. These results could help decision makers to take into account public preferences developing organ-specific guidelines. A stronger involvement of citizens in decision making could gain confidence in transplantation medicine, increase the willingness to donate and potentially counteract the scarcity of organs and thereby the tragedy of the distributional conflict. Therefore the continuation of this project is advisable.
How combinations of gene-environment interactions collectively give rise to genotype-environment interactions is not fully understood. To shed light on this problem, we genetically dissected an environment-specific poor growth phenotype in a cross of two budding yeast strains. This phenotype is detectable when certain segregants are grown on ethanol at 37°C ('E37'), a condition that differs from the standard culturing environment in both its carbon source (ethanol as opposed to glucose) and temperature (37°C as opposed to 30°C). Using recurrent backcrossing with phenotypic selection, we identified 16 contributing loci. To examine how these loci interact with each other and the environment, we focused on a subset of four loci that together can lead to poor growth in E37. We measured the growth of all 16 haploid combinations of alleles at these loci in all four possible combinations of carbon source (ethanol or glucose) and temperature (30 or 37°C) in a nearly isogenic population. This revealed that the four loci act in an almost entirely additive manner in E37. However, we also found that these loci have weaker effects when only carbon source or temperature is altered, suggesting that their effect magnitudes depend on the severity of environmental perturbation. Consistent with such a possibility, cloning of three causal genes identified factors that have unrelated functions in stress response. Thus, our results indicate that polymorphisms in stress response can show effects that are intensified by environmental stress, thereby resulting in major genotype-environment interactions when multiple of these variants co-occur.
Advancing the health of the poor requires aligning a wide array of interests, all of which influence how health care is delivered. Global health professionals often face difficult decisions that can affect their working relationships with government officials, local colleagues, nongovernmental organizations (NGOs), and private sector interests. This article proposes a "compass-based" framework that urges global health professionals to act in a way that is both morally sound and pragmatically effective. Global health professionals must follow their "moral compass" and act in alignment with the interests of the communities they seek to serve while, at the same time, utilizing their "effectiveness compass" to navigate complex situations in ways that ensure achievement of practicable change that can motivate better health outcomes for those in need.
Parent-infant bonding has long-term consequences for the psychological wellbeing of the child. Considering the centrality of infant sleep patterns in infant-caregiver interactions in the first year of life, we propose that infant sleep patterns act as a catalyst or disruptor for mother-infant relationship, such that infant sleep patterns contribute to maternal mood, maternal sleep quality, perception of infant temperament, and her bonding experience. One hundred fifty-two Israeli mothers, of 5-8-month-old infants, responded to Internet-based questionnaires regarding their sleep, their mood, their infant's sleep, the infant's temperament, and their bonding experience. Eight percent of the mothers reported clinically significant depression, while 67 % reported significant sleep difficulties. Infant sleep difficulties correlated with maternal mood and sleep quality, infant fussiness, and bonding. Structural equation modeling demonstrated that maternal sleep partially mediated the relationship between infant sleep and maternal mood. Additionally, 22 % of the variance in bonding was explained by infant sleep problems and temperament. Notably, maternal depression moderated this effect such that infant sleep problems correlated with bonding only in those mothers who were depressed. The results suggest that infant sleep is a vector by which maternal cognitions and mood are transmitted to her child, with long-term implications for psychological development.
Two new tetradentate C2-symmetric pseudopeptidic ligands derived from Val and Phe containing two amino and two amido groups and a central o-substituted aromatic spacer have been prepared. Their complexes with Cu(2+), Zn(2+), and Ni(2+) have been studied by potentiometry, UV-vis spectrophotometry, FT-IR, and ESI-MS. The presence of the aromatic spacer provides Cu(2+) complexes with stability constants several orders of magnitude higher than those observed for related ligands containing aliphatic central spacers. Besides, the formation of [MH-2L] complex species is favored. Crystal structures for the corresponding Cu(2+) and Ni(2+) have been obtained, revealing the metal atom in an essentially square-planar geometry, although, in several instances, the oxygen atom of an amide carbonyl of a second complex species can act as a fifth coordination site. In the case of Zn(2+), the only crystal structure obtained displays a square-pyramidal arrangement of the metal center. Finally, preliminary experiments show the catalytic activity of some of these complexes, in particular, Zn(2+) complexes, for epoxide ring-opening with using aniline as the nucleophile in a ligand accelerated process.
Caffeine or ketorolac decrease the risk of retinopathy of prematurity and may act synergistically to improve beneficial effect. Combination of caffeine (Caff) and ketorolac (Keto) to prevent oxygen-induced retinopathy was studied.
Newborn rats exposed to room air (RA) or intermittent hypoxia (IH) consisting of 12% O2 during hyperoxia (50% O2) from birth (P0) had single daily IP injections of Caff from P0-P13 or saline; and/or ocular Keto (Acuvail, 0.45% ophthalmic solution) administered subcutaneously over the eyes from P5-P7. Pups were studied at P14 or placed in RA for recovery from IH (IHR) until P21. Eyes were examined for neovascularization, histopathology, growth factors, and VEGF-signaling genes.
Severe retinal damage noted during IHR in the untreated groups evidenced by hemorrhage, neovascularization, and oxygen-induced retinopathy (OIR) pathologies were prevented with Keto/Caff treatment. Keto and/or Caff treatment in IH also promoted retinal neural development evidenced by eye opening (92%, P < 0.001 vs. 31% in the placebo-treated IH group). No corneal pathologies were noted with Keto.
Caff or Keto given individually reduced retinal neovascularization, but the two drugs given together prevented severe OIR.
RIG-I (retinoic acid-inducible gene 1) is an archetypal member of the cytoplasmic DEAD-box dsRNA helicase family (RIG-I-like receptors or RLRs), the members of which play essential roles in the innate immune response of the metazoan cell. RIG-I functions as
 a pattern recognition receptor that detects nonself RNA as a pathogen-associated molecular pattern (PAMP). However, the exact molecular nature of the viral RNAs that act as a RIG-I ligand has remained a mystery and a matter of debate. In this article, we offer a critical review of the actual viral RNAs that act as PAMPs to activate RIG-I, as seen from the perspective of a virologist, including a recent report that the viral Leader-read-through transcript is a novel and effective RIG-I ligand.
Decreased antimicrobial efficiency has become a global public health issue. The paucity of new antibacterial drugs is evident, and the arsenal against infectious diseases needs to be improved urgently. The selection of plants as a source of prototype compounds is appropriate, since plant species naturally produce a wide range of secondary metabolites that act as a chemical line of defense against microorganisms in the environment. Although traditional approaches to combat microbial infections remain effective, targeting microbial virulence rather than survival seems to be an exciting strategy, since the modulation of virulence factors might lead to a milder evolutionary pressure for the development of resistance. Additionally, anti-infective chemotherapies may be successfully achieved by combining antivirulence and conventional antimicrobials, extending the lifespan of these drugs. This review presents an updated discussion of natural compounds isolated from plants with chemically characterized structures and activity against the major bacterial virulence factors: quorum sensing, bacterial biofilms, bacterial motility, bacterial toxins, bacterial pigments, bacterial enzymes, and bacterial surfactants. Moreover, a critical analysis of the most promising virulence factors is presented, highlighting their potential as targets to attenuate bacterial virulence. The ongoing progress in the field of antivirulence therapy may therefore help to translate this promising concept into real intervention strategies in clinical areas.
Lead halide perovskites have over the past few years attracted considerable interest as photo absorbers in PV applications with record efficiencies now reaching 22%. It has recently been found that not only the composition but also the precise stoichiometry is important for the device performance. Recent reports have, for example, demonstrated small amount of PbI2 in the perovskite films to be beneficial for the overall performance of both the standard perovskite, CH3NH3PbI3, as well as for the mixed perovskites (CH3NH3)x(CH(NH2)2)(1-x)PbBryI(3-y). In this work a broad range of characterization techniques including X-ray diffraction (XRD), scanning electron microscopy (SEM), transmission electron microscopy (TEM), photo electron spectroscopy (PES), transient absorption spectroscopy (TAS), UV-vis, electroluminescence (EL), photoluminescence (PL), and confocal PL mapping have been used to further understand the importance of remnant PbI2 in perovskite solar cells. Our best devices were over 18% efficient, and had in line with previous results a small amount of excess PbI2. For the PbI2-deficient samples, the photocurrent dropped, which could be attributed to accumulation of organic species at the grain boundaries, low charge carrier mobility, and decreased electron injection into the TiO2. The PbI2-deficient compositions did, however, also have advantages. The record Voc was as high as 1.20 V and was found in PbI2-deficient samples. This was correlated with high crystal quality, longer charge carrier lifetimes, and high PL yields and was rationalized as a consequence of the dynamics of the perovskite formation. We further found the ion migration to be obstructed in the PbI2-deficient samples, which decreased the JV hysteresis and increased the photostability. PbI2-deficient synthesis conditions can thus be used to deposit perovskites with excellent crystal quality but with the downside of grain boundaries enriched in organic species, which act as a barrier toward current transport. Exploring ways to tune the synthesis conditions to give the high crystal quality obtained under PbI2-poor condition while maintaining the favorable grain boundary characteristics obtained under PbI2-rich conditions would thus be a strategy toward more efficiency devices.
Extracellular vesicles (EVs) enable the exit of regulatory, mutant and oncogenic macromolecules (proteins, RNA and DNA) from their parental tumor cells and uptake of this material by unrelated cellular populations. Among the resulting biological effects of interest is the notion that cancer-derived EVs may mediate horizontal transformation of normal cells through transfer of mutant genes, including mutant ras. Here, we report that H-ras-mediated transformation of intestinal epithelial cells (IEC-18) results in the emission of exosome-like EVs containing genomic DNA, HRAS oncoprotein and transcript. However, EV-mediated horizontal transformation of non-transformed cells (epithelial, astrocytic, fibroblastic and endothelial) is transient, limited or absent due to barrier mechanisms that curtail the uptake, retention and function of oncogenic H-ras in recipient cells. Thus, epithelial cells and astrocytes are resistant to EV uptake, unless they undergo malignant transformation. In contrast, primary and immortalized fibroblasts are susceptible to the EV uptake, retention of H-ras DNA and phenotypic transformation, but these effects are transient and fail to produce a permanent tumorigenic conversion of these cells in vitro and in vivo, even after several months of observation. Increased exposure to EVs isolated from H-ras-transformed cancer cells, but not to those from their indolent counterparts, triggers demise of recipient fibroblasts. Uptake of H-ras-containing EVs stimulates but fails to transform primary endothelial cells. Thus, we suggest that intercellular transfer of oncogenes exerts regulatory rather than transforming influence on recipient cells, while cancer cells may often act as preferential EV recipients.
Li-rich layered materials have been considered as the most promising cathode materials for future high-energy-density lithium-ion batteries. However, they suffer from severe voltage decay upon cycling, which hinders their further commercialization. Here, we report a Li-rich layered material 0.5Li2MnO3·0.5LiNi0.8Co0.1Mn0.1O2 with high nickel content, which exhibits much slower voltage decay during long-term cycling compared to conventional Li-rich materials. The voltage decay after 200 cycles is 201 mV. Combining in situ X-ray diffraction (XRD), ex situ XRD, ex situ X-ray photoelectron spectroscopy, and scanning transmission electron microscopy, we demonstrate that nickel ions act as stabilizing ions to inhibit the Jahn-Teller effect of active Mn(3+) ions, improving d-p hybridization and supporting the layered structure as a pillar. In addition, nickel ions can migrate between the transition-metal layer and the interlayer, thus avoiding the formation of spinel-like structures and consequently mitigating the voltage decay. Our results provide a simple and effective avenue for developing Li-rich layered materials with mitigated voltage decay and a long lifespan, thereby promoting their further application in lithium-ion batteries with high energy density.
Disasters cause an acute deterioration in all stages of life. An area affected by the disaster in which the normal activities of life are disrupted is described as a "Field" in disaster terminology. Although it is not easy to define the borders of this zone, the area where there is normally functioning society is accepted as the boundary. Disaster management is the responsibility of the local government. However, in many large disaster responses many non-governmental and international organizations play a role. A Disaster Medical Team is a trained, mobile, self-contained, self-sufficient, multidisciplinary medical team that can act in the acute phase of a sudden-onset disaster (48 to 72 hours after its occurrence) to provide medical treatment in the affected area. The medical team can include physicians, nurses, paramedics and EMTS, technicians, personnel to manage logistics, security and others. Various models of Disaster Medical Teams can be observed around the world. There is paucity of evidence based literature regarding DMTs. There is a need for epidemiological studies with rigorous designs and sampling. In this section of the special edition of the journal, field organizations in health management during disasters will be summarized, with emphasis on preparedness and response phases, and disaster medical teams will be discussed.
Development of new methods for the diagnosis of point mutations is a pressing issue. We have developed a new approach to the design of graphene oxide-based test systems for the diagnosis of point mutations in native DNA. This new approach is based on the use of graphene oxide for the adsorption and quenching of fluorescently labeled primers in a post-amplification PCR mixture followed by detection of fluorescently labeled PCR products. It is possible to detect fluorescently labelled amplicons in the presence of an excess of primers in a PCR product solution due to the different affinities of single-stranded and double-stranded DNA molecules to graphene oxide, as well as the ability of graphene oxide to act as a quencher of the fluorophores adsorbed on its surface. The new approach was tested by designing a graphene oxide-based test system for the DNA diagnosis of the point mutation associated with the development of the 3M syndrome in Yakuts. The developed approach enables one to design graphene oxide-based test systems suitable for the diagnosis of any point mutations in native DNA.
The use of probiotics for human and animal health is continuously increasing. The probiotics
 used in humans commonly come from dairy foods, whereas the sources of probiotics used in animals are often the animals' own digestive tracts. Increasingly, probiotics from sources other than milk products are being selected for use in people who are lactose intolerant. These sources are non-dairy fermented foods and beverages, non-dairy and non-fermented foods such as fresh fruits and vegetables, feces of breast-fed infants and human breast milk. The probiotics that are used in both humans and animals are selected in stages; after the initial isolation of the appropriate culture medium, the probiotics must meet important qualifications, including being non-pathogenic acid and bile-tolerant strains that possess the ability to act against pathogens in the gastrointestinal tract and the safety-enhancing property of not being able to transfer any antibiotic resistance genes to other bacteria. The final stages of selection involve the accurate identification of the probiotic species.
The balance between immune effector cells such as T cells and natural killer cells, and immunosuppressive Treg cells, dendritic, myeloid and monocytic sub-populations in the tumor microenvironment acts to calibrate the immune response to malignant cells. Accumulating evidence is pointing to a role for B cells in modulating the immune response to both solid tumors and hematologic cancer. Evidence from murine autoimmune models has defined B regulatory cell (Breg) subsets that express cytokines such as IL-10, TGF-β, and/or express immune regulatory ligands such as PD-L1, which can suppress T cell and/or natural killer cell responses. Multiple murine tumor models exhibit decreased tumor growth in B cell deficient or B cell depleted mice. In several of these models, B cells inhibit T cell mediated tumor immunity and/or facilitate conversion of T cells to CD4(+)CD25(+)FoxP3(+) T regs, which act to attenuate the innate and/or adaptive antitumor immune response. Mechanisms of suppression include the acquisition of inhibitory ligand expression, and phosphorylation of Stat3, and induction of IL-10 and TGF-β, resulting in a Breg phenotype. Breg suppressive activity may affect diverse cell subtypes, including T effector cells, NK cells, myeloid derived suppressor cells (MDSC) and/or tumor associated macrophages. B cells may also directly promote tumorigenesis through recruitment of inflammatory cells, and upregulation of pro-angiogenic genes and pro-metastatic collagenases. Breg infiltration has now been identified in a variety of solid tumor malignancies including but not limited to ovarian, gastric, non-small cell lung cancer, pancreatic, esophageal, head and neck, and hepatocellular carcinomas. Increasing evidence suggests that recruitment of B cells and acquisition of suppressive activity within the tumor bed may be an important mechanism through which B cells may modulate innate and/or adaptive anti-tumor immunity. B cell depletion in the clinic using anti-CD20 antibodies and/or inhibitors of BTK and/or other signaling pathways, may be a useful strategy for augmenting the anti-tumor immune response.
Acute appendicitis (AA) is among the most common cause of acute abdominal pain. Diagnosis of AA is challenging; a variable combination of clinical signs and symptoms has been used together with laboratory findings in several scoring systems proposed for suggesting the probability of AA and the possible subsequent management pathway. The role of imaging in the diagnosis of AA is still debated, with variable use of US, CT and MRI in different settings worldwide. Up to date, comprehensive clinical guidelines for diagnosis and management of AA have never been issued. In July 2015, during the 3rd World Congress of the WSES, held in Jerusalem (Israel), a panel of experts including an Organizational Committee and Scientific Committee and Scientific Secretariat, participated to a Consensus Conference where eight panelists presented a number of statements developed for each of the eight main questions about diagnosis and management of AA. The statements were then voted, eventually modified and finally approved by the participants to The Consensus Conference and lately by the board of co-authors. The current paper is reporting the definitive Guidelines Statements on each of the following topics: 1) Diagnostic efficiency of clinical scoring systems, 2) Role of Imaging, 3) Non-operative treatment for uncomplicated appendicitis, 4) Timing of appendectomy and in-hospital delay, 5) Surgical treatment 6) Scoring systems for intra-operative grading of appendicitis and their clinical usefulness 7) Non-surgical treatment for complicated appendicitis: abscess or phlegmon 8) Pre-operative and post-operative antibiotics.
The aim of this study was to better understand the triggers of suicide, particularly among the ancient Greek and Persian soldiers and commanders.
'Herodotus:TheHistories' is a history of the rulers and soldiery who participated in the Greco-Persian wars (492-449 BCE). A new translation (2013) of this manuscript was studied. Accounts of suicide were collected and collated, with descriptions of circumstances, methods, and probable triggers.
Nine accounts of suicide were identified. Eight of these were named individuals (4 Greeks and 4 Persians); of whom, seven were male. Only one (not the female) appeared to act in response to a mental disorder. Other triggers of suicide included guilt, avoidance of dishonour/punishment and altruism. Cutting/ stabbing was the most common method; others included hanging, jumping, poison, and burning (the single female).
While soldiers at a time of war do not reflect the general community, they are nevertheless members of their society. Thus, this evidence demonstrates that suicide triggered by burdensome circumstances (in addition to mental disorder) was known to the Greek and Persian people more than two millennia ago.
This study evaluated the effects of three vehicles-ethanol (EtOH), isopropyl alcohol (IPA), and isopropyl myristate (IPM)-on stratum corneum (SC) absorption and diffusion of the [(14)C]-model compounds benzoic acid and butenafine hydrochloride to better understand the transport pathways of chemicals passing through and resident in SC. Following application of topical formulations to human dermatomed skin for 30 min, penetration flux was observed for 24 h post dosing, using an in vitro flow-through skin diffusion system. Skin absorption and penetration was compared to the chemical-SC (intact, delipidized, or SC lipid film) binding levels. A significant vehicle effect was observed for chemical skin penetration and SC absorption. IPA resulted in the greatest levels of intact SC/SC lipid absorption, skin penetration, and total skin absorption/penetration of benzoic acid, followed by IPM and EtOH, respectively. For intact SC absorption and total skin absorption/penetration of butenafine, the vehicle that demonstrated the highest level of sorption/penetration was EtOH, followed by IPA and IPM, respectively. The percent doses of butenafine that were absorbed in SC lipid film and penetrated through skin in 24 h were greatest for IPA, followed by EtOH and IPM, respectively. The vehicle effect was consistent between intact SC absorption and total chemical skin absorption and penetration, as well as SC lipid absorption and chemical penetration through skin, suggesting intercellular transport as a main pathway of skin penetration for model chemicals. These results suggest the potential to predict vehicle effects on skin permeability with simple SC absorption assays. As decontamination was applied 30 min after chemical exposure, significant vehicle effects on chemical SC partitioning and percutaneous penetration also suggest that skin decontamination efficiency is vehicle dependent, and an effective decontamination method should act on chemical solutes in the lipid domain.
Bt cotton was initially deployed in Australia in the mid-1990s to control the polyphagous pest Helicoverpa armigera (Hübner) which was intractably resistant to synthetic chemistries. A conservative strategy was enforced and resistance to first generation single toxin technology was managed. A decade later, shortly after the release of dual toxin cotton, high baseline frequencies of alleles conferring resistance to one of its components prompted a reassessment of the thinking behind the potential risks to this technology. Several reviews detail the characteristics of this resistance and the nuances of deploying first and second generation Bt cotton in Australia. Here we explore recent advances and future possibilities to estimate Bt resistance in Australian pest species and define what we see as the critical data for enabling effective pre-emptive strategies. We also foreshadow the imminent deployment of three toxin (Cry1Ac, Cry2Ab, Vip3A) Bollgard 3 cotton, and examine aspects of resistance to its novel component, Vip3A, that we believe may impact on its stewardship.
Floral scents act as long-distance signals to attract pollinators, but volatiles emitted from the vegetation and neighboring plant community may modify this mutualistic communication system. What impact does the olfactory background have on pollination systems and their evolution? We consider recent behavioral studies that address the context of when and where volatile backgrounds influence a pollinator's perception of floral blends. In parallel, we review neurophysiological studies that show the importance of blend composition and background in modifying the representation of floral blends in the pollinator brain, as well as experience-dependent plasticity in increasing the representation of a rewarding odor. Here, we suggest that the efficacy of the floral blend in different environments may be an important selective force shaping differences in pollinator olfactory receptor expression
 and underlying neural mechanisms that mediate flower visitation and plant reproductive isolation.
Although the nature of the genetic control of adaptive behaviours in insects is a major unresolved problem it is now understood that epigenetic mechanisms, bound by genetic constraints, are prime drivers of brain plasticity arising from both developmental and experience-dependent events. With the recent advancements in methylomics and emerging analyses of histones and non-protein-coding RNAs, insect epigenetics is well positioned to ask more direct questions and importantly, address them experimentally. To achieve rapid progress, insect epigenetics needs to focus on mechanistic explanations of epigenomic dynamics and move beyond low-depth genome-wide analyses to cell-type specific epigenomics. One topic of a high priority is the impact of sequence variants on generating differential methylation patterns and their contribution to behavioural plasticity.
Steered and equilibrium molecular dynamics simulations were employed to study the coalescence of a sI hydrate particle and a water droplet within a hydrocarbon mixture. The size of both the hydrate particle and the water droplet is comparable to that of the aqueous core in reverse micelles. The simulations were repeated in the presence of various quaternary ammonium chloride surfactants. We investigated the effects due to different groups on the quaternary head group (e.g. methyl vs. butyl groups), as well as different hydrophobic tail lengths (e.g. n-hexadecyl vs. n-dodecyl tails) on the surfactants' ability to prevent coalescence. Visual inspection of sequences of simulation snapshots indicates that when the water droplet is not covered by surfactants it is more likely to approach the hydrate particle, penetrate the protective surfactant film, reach the hydrate surface, and coalesce with the hydrate than when surfactants are present on both surfaces. Force-distance profiles obtained from steered molecular dynamics simulations and free energy profiles obtained from umbrella sampling suggest that surfactants with butyl tripods on the quaternary head group and hydrophobic tails with size similar to the solvent molecules can act as effective anti-agglomerants. These results qualitatively agree with macroscopic experimental observations. The simulation results provide additional insights, which could be useful in flow assurance applications: the butyl tripod provides adhesion between surfactants and hydrates; when the length of the surfactant tail is compatible with that of the hydrocarbon in the liquid phase a protective film can form on the hydrate; however, once a molecularly thin chain of water molecules forms through the anti-agglomerant film, connecting the water droplet and the hydrate, water flows to the hydrate and coalescence is inevitable.
The size of gene families associated with xenobiotic detoxification in insects may be associated with the complexity of their diets and their propensities to develop insecticide resistance. We test these hypotheses by collating the annotations of cytochrome P450, carboxyl/cholinesterase and glutathione S-transferase genes in 65 insect species with data on their host use and history of insecticide resistance. We find 2-4 fold variation across the species in the numbers of these genes and, in some orders, especially the Hymenoptera, there is a clear relationship between the numbers of genes and feeding preferences. However in other orders, in particular the Lepidoptera, no such relationship is apparent. The size of these three gene families also tend to correlate with insecticide resistance propensity but this may not be an independent effect because species with broader host ranges are more likely to be pests that are heavily sprayed with insecticides.
Our understanding on the phylogenetic relationships of insects has been revolutionised in the last decade by the proliferation of next generation sequencing technologies (NGS). NGS has allowed insect systematists to assemble very large molecular datasets that include both model and non-model organisms. Such datasets often include a large proportion of the total number of protein coding sequences available for phylogenetic comparison. We review some early entomological phylogenomic studies that employ a range of different data sampling protocols and analyses strategies, illustrating a fundamental renaissance in our understanding of insect evolution all driven by the genomic revolution. The analysis of phylogenomic datasets is challenging because of their size and complexity, and it is obvious that the increasing size alone does not ensure that phylogenetic signal overcomes systematic biases in the data. Biases can be due to various factors such as the method of data generation and assembly, or intrinsic biological feature of the data per se, such as similarities due to saturation or compositional heterogeneity. Such biases often cause violations in the underlying assumptions of phylogenetic models. We review some of the bioinformatics tools available and being developed to detect and minimise systematic biases in phylogenomic datasets. Phylogenomic-scale data coupled with sophisticated analyses will revolutionise our understanding of insect functional genomics. This will illuminate the relationship between the vast range of insect phenotypic diversity and underlying genetic diversity. In combination with rapidly developing methods to estimate divergence times, these analyses will also provide a compelling view of the rates and patterns of lineagenesis (birth of lineages) over the half billion years of insect evolution.
Stress interferes with instrumental learning. However, choice is also influenced by non-instrumental factors, most strikingly by biases arising from Pavlovian associations that facilitate action in pursuit of rewards and inaction in the face of punishment. Whether stress impacts on instrumental learning via these Pavlovian associations is unknown. Here, in a task where valence (reward or punishment) and action (go or no-go) were orthogonalised, we asked whether the impact of stress on learning was action or valence specific. We exposed 60 human participants either to stress (socially-evaluated cold pressor test) or a control condition (room temperature water). We contrasted two hypotheses: that stress would lead to a non-selective increase in the expression of Pavlovian biases; or that stress, as an aversive state, might specifically impact action production due to the Pavlovian linkage between inaction and aversive states. We found support for the second of these hypotheses. Stress specifically impaired learning to produce an action, irrespective of the valence of the outcome, an effect consistent with a Pavlovian linkage between punishment and inaction. This deficit in action-learning was also reflected in pupillary responses; stressed individuals showed attenuated pupillary responses to action, hinting at a noradrenergic contribution to impaired action-learning under stress.
Genetic decoding is not 'frozen' as was earlier thought, but dynamic. One facet of this is frameshifting that often results in synthesis of a C-terminal region encoded by a new frame. Ribosomal frameshifting is utilized for the synthesis of additional products, for regulatory purposes and for translational 'correction' of problem or 'savior' indels. Utilization for synthesis of additional products occurs prominently in the decoding of mobile chromosomal element and viral genomes. One class of regulatory frameshifting of stable chromosomal genes governs cellular polyamine levels from yeasts to humans. In many cases of productively utilized frameshifting, the proportion of ribosomes that frameshift at a shift-prone site is enhanced by specific nascent peptide or mRNA context features. Such mRNA signals, which can be 5' or 3' of the shift site or both, can act by pairing with ribosomal RNA or as stem loops or pseudoknots even with one component being 4 kb 3' from the shift site. Transcriptional realignment at slippage-prone sequences also generates productively utilized products encoded trans-frame with respect to the genomic sequence. This too can be enhanced by nucleic acid structure. Together with dynamic codon redefinition, frameshifting is one of the forms of recoding that enriches gene expression.
Oesophageal atresia (OA) with or without tracheoesophageal fistula (TOF) are rare anatomical congenital malformations whose cause is unknown in over 90% of patients. A genetic background is suggested, and among the reported genetic defects are copy number variations (CNVs). We hypothesized that CNVs contribute to OA/TOF development. Quantifying their prevalence could aid in genetic diagnosis and clinical care strategies. Therefore, we profiled 375 patients in a combined Dutch, American and German cohort via genomic microarray and compared the CNV profiles with their unaffected parents and published control cohorts. We identified 167 rare CNVs containing genes (frequency<0.0005 in our in-house cohort). Eight rare CNVs - in six patients - were de novo, including one CNV previously associated with oesophageal disease. (hg19 chr7:g.(143820444_143839360)_(159119486_159138663)del) 1.55% of isolated OA/TOF patients and 1.62% of patients with additional congenital anomalies had de novo CNVs. Furthermore, three (15q13.3, 16p13.3 and 22q11.2) susceptibility loci were identified based on their overlap with known OA/TOF-associated CNV syndromes and overlap with loci in published CNV association case-control studies in developmental delay. Our study suggests that CNVs contribute to OA/TOF development. In addition to the identified likely deleterious de novo CNVs, we detected 167 rare CNVs. Although not directly disease-causing, these CNVs might be of interest, as they can act as a modifier in a multiple hit
 model, or as the second hit in a recessive condition.
Pro-inflammatory cytokines can promote sleep and neuronal processes underlying memory formation. However, this has mainly been revealed in animal studies. In this double-blind, placebo-controlled within-subject designed study, we examined how changes in the balance between pro- and anti-inflammatory signalling affect sleep and sleep-associated memory consolidation in humans. After learning declarative memory tasks (word pairs, texts) and a procedural memory task (finger tapping) in the evening, 21 healthy young men orally received either 200 mg of the anti-inflammatory antibiotic minocycline or placebo shortly before nocturnal sleep. Sleep was allowed between 23:00 and 07:00 h and recorded polysomnographically. Retrieval of memories was tested two days later. Because of outliers or missing data, final sample size was reduced to n = 14-19. Our data suggest that rather than weakening sleep as expected based on animal studies, the anti-inflammatory agent promoted sleep and memory consolidation. Specifically, minocycline increased slow-wave activity (0.68-4.0 Hz) during non-rapid eye movement sleep stage 2 and selectively enhanced episodic aspects in memory (i.e. memory for the temporal order of events in the texts). In combination with previous results, our findings indicate that, in humans, reducing pro-inflammatory signalling can act towards deepening non-rapid eye movement sleep and enhancing its memory forming efficacy.
On page 1740, Xiao-Bo Chen and co-workers report an orthopedic implant material specifically designed for osteoporotic bone fractures. A newl strontium phosphate coating applied to a bone-mimicking low elastic titanium alloy with a comparative Young's modulus to that of natural bone results in upregulating the growth of osteoblasts and downregulating that of osteoclasts. Such a promising osteoanabolic effect reveals a suitability in particular for patients who suffer from low quality bone organism and slow fracture recovery.
Light-regulated drugs allow remotely photoswitching biological activity and enable plausible therapies based on small molecules. However, only freely diffusible photochromic ligands have been shown to work directly in endogenous receptors and methods for covalent attachment depend on genetic manipulation. Here we introduce a chemical strategy to covalently conjugate and photoswitch the activity of endogenous proteins and demonstrate its application to the kainate receptor channel GluK1. The approach is based on photoswitchable ligands containing a short-lived, highly reactive anchoring group that is targeted at the protein of interest by ligand affinity. These targeted covalent photoswitches (TCPs) constitute a new class of light-regulated drugs and act as prosthetic molecules that photocontrol the activity of GluK1-expressing neurons, and restore photoresponses in degenerated retina. The modularity of TCPs enables the application to different ligands and opens the way to new therapeutic opportunities.
Instabilities are common phenomena frequently observed in nature, sometimes leading to unexpected catastrophes and disasters in seemingly normal conditions. One prominent form of instability in a distributed system is its response to a harmonic modulation. Such instability has special names in various branches of physics and is generally known as modulation instability (MI). The MI leads to a growth-decay cycle of unstable waves and is therefore related to Fermi-Pasta-Ulam (FPU) recurrence since breather solutions of the nonlinear Schrödinger equation (NLSE) are known to accurately describe growth and decay of modulationally unstable waves in conservative systems. Here, we report theoretical, numerical and experimental evidence of the effect of dissipation on FPU cycles in a super wave tank, namely their shift in a determined order. In showing that ideal NLSE breather solutions can describe such dissipative nonlinear dynamics, our results may impact the interpretation of a wide range of new physics scenarios.
Water dispersible citrate-capped LaF3:Eu(5%) nanocrystals (NCs) have been partially surface-functionalized by 1,10-phenanthroline (phen) via a ligand exchange method to produce novel water dispersed citrate/phen-capped LaF3:Eu(5%) NCs in which citrate ligands preserve the water dispersibility of the NCs and phen ligands act as sensitizers of surface Eu(3+)-dopant sites. The partial ligand exchange and the formation of water dispersed NCs have been monitored by (1)H NMR spectroscopy, as well as luminescence measurements at different time intervals during the reaction. These NCs display a distinct phen-sensitized Eu(3+)-emission profile with enhanced intensity in water as compared to the emission profile and intensity obtained upon direct excitation. Time-resolved (or time-gated) emission spectroscopy (TRES) has been used to probe PL dynamics of Eu(3+)-sites of LaF3:Eu(5%) NCs by taking advantage of selectively sensitizing surface Eu(3+)-dopant sites by phen ligands as well as by exciting all the Eu(3+)-sites in the NCs upon direct excitation. TRES upon direct excitation of the citrate-capped LaF3:Eu(5%) NCs reveals that Eu(3+)-dopants occupy at least three different sites, each with a different emission profile and lifetime, and emission from purely interior Eu(3+)-sites has been resolved due to their long lifetime as compared to the lifetime of purely surface and near surface Eu(3+)-sites. In contrast, the phen-sensitized emission from citrate/phen-capped LaF3:Eu(5%) NCs displays similar emission profiles and lifetimes in TRES measurements, which reveal that phen truly sensitizes purely surface dopant sites of the NCs in water, all of which have nearly the same local environment. The phen-sensitized Eu(3+)-emission of the NCs in water remains stable even upon addition of various buffer solutions at physiological pH, as well as upon addition of water-miscible organic solvents. Furthermore, the two-photon excitation (λex. = 720 nm) of these water-soluble phen-capped NCs produces bright red Eu(3+) emission, which reveals that these NCs are promising for potential applications in biological imaging.
The Veterans Health Administration (VA) has undertaken a major initiative to transform care through implementation of Patient Aligned Care Teams (PACTs). Based on the patient-centered medical home (PCMH) concept, PACT aims to improve access, continuity, coordination, and comprehensiveness using team-based care that is patient-driven and patient-centered. However, how VA should adapt PACT to meet the needs of special populations, such as women Veterans (WVs), was not considered in initial implementation guidance. WVs' numerical minority in VA healthcare settings (approximately 7-8 % of users) creates logistical challenges to delivering gender-sensitive comprehensive care. The main goal of this study is to test an evidence-based quality improvement approach (EBQI) to tailoring PACT to meet the needs of WVs, incorporating comprehensive primary care services and gender-specific care in gender-sensitive environments, thereby accelerating achievement of PACT tenets for women (Women's Health (WH)-PACT).
EBQI is a systematic approach to developing a multilevel research-clinical partnership that engages senior organizational leaders and local quality improvement (QI) teams in adapting and implementing new care models in the context of prior evidence and local practice conditions, with researchers providing technical support, formative feedback, and practice facilitation. In a 12-site cluster randomized trial, we will evaluate WH-PACT model achievement using patient, provider, staff, and practice surveys, in addition to analyses of secondary administrative and chart-based data. We will explore impacts of receipt of WH-PACT care on quality of chronic disease care and prevention, health status, patient satisfaction and experience of care, provider experience, utilization, and costs. Using mixed methods, we will assess pre-post practice contexts; document EBQI activities undertaken in participating facilities and their relationship to provider/staff and team actions/attitudes; document WH-PACT implementation; and examine barriers/facilitators to EBQI-supported WH-PACT implementation through a combination of semi-structured interviews and monthly formative progress narratives and administrative data.
Lack of gender-sensitive comprehensive care has demonstrated consequences for the technical quality and ratings of care among WVs and may contribute to decisions to continue use or seek care elsewhere under the US Affordable Care Act. We hypothesize that tailoring PACT implementation through EBQI may improve the experience and quality of care at many levels.
ClinicalTrials.gov, NCT02039856.
We investigated the physiological responses of Lemna minor plants exposed to glyphosate. The deleterious effects of this herbicide on photosynthesis, respiration, and pigment concentrations were related to glyphosate-induced oxidative stress through hydrogen peroxide (H2O2) accumulation. By using photosynthetic and respiratory electron transport chain (ETC) inhibitors we located the primary site of reactive oxygen species (ROS) production in plants exposed to 500 mg glyphosate l(-1). Inhibition of mitochondrial ETC Complex I by rotenone reduced H2O2 concentrations in glyphosate-treated plants. Complex III activity was very sensitive to glyphosate which appears to act much like antimycin A (an inhibitor of mitochondrial ETC Complex III) by shunting electrons from semiquinone to oxygen, with resulting ROS formation. Confocal evaluations for ROS localization showed that ROS are initially produced outside of the chloroplasts upon initial glyphosate exposure. Our results indicate that in addition to interfering with the shikimate pathway, glyphosate can induce oxidative
 stress in plants through H2O2 formation by targeting the mitochondrial ETC, which would explain its observed effects on non-target organisms.
Toll-like receptors (TLRs) could recognize conserved molecular patterns and initiate a wide range of innate and adaptive immune responses against invading infectious agents. The aim of the this study is to assess the transcript profiling of mink TLRs (mTLRs) in mink peripheral blood mononuclear cells (PBMCs) and a range of tissues, and to explore the potential role of mTLRs in the antiviral immune response process. The results indicated that the mTLRs partial nucleotide sequences revealed a high degree of nucleotide identity with ferret sequences (95-98%). Phylogenetic analysis showed that mammallian TLRs grouped in to five TLR families with a closer relationship of the mTLRs to those of ferret than to the other mammalian sequences. Moreover, all the mTLRs were ubiquitously expressed in lymphoid organs (spleen and lymph nodes) and PBMCs. Interestingly, the mTLRs expression patterns in lung, uterus and heart showed a lot of similarity. Another remarkable observation was that the wide expression of mTLRs 1-3 mRNAs in all tissues. Among the analyzed tissues, skeletal muscle was revealed to being the lowest repertoire of mTLRs expression. Additionally, mink PBMCs exposed to the canine distemper virus (CDV) revealed significant up-regulation of mTLR2, mTLR4, mTLR7 and mTLR8 mRNAs, indicating that mTLRs act as a role in innate immunity in mink. Collectively, our results first establish the basic expression patterns of mTLRs and the relationship between mTLRs and virus, which contributes to better understanding of the evolution and the functions of mTLRs in the innate immune system in mink.
As part of a comprehensive plan to attempt to minimize the diversion of prescribed controlled substances, many professional organization and licensing boards are recommending the use of "pill counts." This study sought to evaluate acceptability of the use of cellular phone and computer pictures/video for "pill counts" by patients in buprenorphine maintenance treatment.
Patients prescribed buprenorphine/naloxone were asked a series of questions related to the type(s) of electronic communication to which they had access as well as their willingness to use these for the purpose of performing a "pill/film count."
Of the 80 patients, 4 (5 percent) did not have a phone at all. Only 28 (35 percent) had a "smart phone" with some sort of data plan and Internet access. Forty (50 percent) of the patients had a phone with no camera and 10 (12.5 percent) had a phone with a camera but no video capability. All patients said that they would be willing to periodically use the video or camera on their phone or computer to have buprenorphine/naloxone pills or film counted as long as the communication was protected from electronic tampering.
With the advent of applications for smart phones that allow for Health Insurance Portability and Accountability Act of 1996-compliant picture/video communication, a number of things can now be done that can enhance patient care as well as reduce the chances of misuse/diversion of prescribed medications. This could be used in settings where a larger proportion of controlled substances are prescribed including medication assisted therapy for opioid use disorders and pain management programs.
Cecropia pachystachya is a medicinal plant native to South and Central Americas used to treat asthma and diabetes.
In this study, we evaluated the genotoxic, mutagenic and antigenotoxic effects of crude aqueous extract of C. pachystachya (CAE-Cp) leaves.
CAE-Cp was analyzed by the Folin-Ciocalteu method to determine total phenolic and tannin contents. High performance liquid chromatography (HPLC) was used to identify major compounds. Distinct tissues from female and male adult mice were treated with 500-2000mg/kg of CAE-Cp by gavage for the comet assay and micronucleus test analyses. In addition, peripheral blood slides of the group treated with 2000mg/kg CAE-Cp were analyzed 3, 6, and 24h after treatment and were exposed to hydrogen peroxide (ex vivo) to evaluate the genotoxic effect using the comet assay. The Salmonella/microsome assay was carried out against to TA100, TA98, TA97a, TA102, and TA1535 strains in presence and absence of the S9 mix.
HPLC showed the presence of chlorogenic acid, isoorientin, orientin, and isovitexin as major compounds. Total phenolic and tannin contents were, respectively, 305.6±0.80 and 144.6±19.04mg of gallic acid equivalent/g of extract. Brain DNA damage was observed in all groups treated with CAE-Cp. The H2O2 challenge indicated genotoxic effect only 6h after the administration of the extract. No increase was detected in micronucleus frequency for any group treated with the extract. Mutagenic effects were detected by Salmonella/microsome assay only in TA102 strain without S9 mix at higher doses.
The results obtained indicate that CAE-Cp was genotoxic to brain tissue. This result is supported by other papers, showing that compounds present in this extract can cross the blood-brain barrier and act on central nervous system.
Asthma is the most prevalent chronic disease in adults. It affects their quality of life. Studies confirm that depression and anxiety occurs in asthma patients.
The study involved 96 patients with asthma divided into two groups: patients with controlled (n = 33) and uncontrolled asthma (n = 63). The analysis of asthma control was performed on the basis of the ACT (Asthma Control Test) results. The study used SF-36 (Short Form 36) questionnaire and HADS (Hospital and Depression Scale) Scale.
An analysis of the correlations between QoL (Quality of Life) and the level of depression revealed a decrease in QoL scores in MCS (Mental Component Score) domain in the group with controlled asthma (71.8 - patients without depression, 53.4 - patients with probable depression, and 51.4 - patients with depression; p = 0.032). A similar analysis of the correlations between QoL and the level of anxiety in this group of patients proved no correlations in PCS (Physical Component Score) and MCS domains. In the group of patients with uncontrolled asthma, anxiety and depression correlated negatively with the QoL in PCS and MCS domains. Anxiety and depression are found in asthma patients, with higher severity observed in patients with uncontrolled asthma. Female gender, the level of asthma control, asthma severity, smoking, as well as diagnoses of anxiety and depression are predictors of a significantly lower QoL in asthma.
Anxiety and depression are found in asthma patients, with higher severity observed in patients with uncontrolled asthma. Female gender, the level of asthma control, asthma severity, smoking, as well as diagnoses of anxiety and depression are predictors of a significantly lower quality of life in asthma.
Molybdenum disulfide (MoS2) has recently received much attention for nanoscale electronic and photonic applications. To explore the intrinsic properties and enhance the performance of MoS2-based field-effect transistors, thorough understanding of extrinsic effects such as environmental gas and contact resistance of the electrodes is required. Here, we report the effects of environmental gases on the transport properties of back-gated multilayered MoS2 field-effect transistors. Comparisons between different gases (oxygen, nitrogen, and air and nitrogen with varying relative humidities) revealed that water molecules acting as charge-trapping centers are the main cause of hysteresis in the transfer characteristics. While the hysteresis persisted even after pumping out the environmental gas for longer than 10 h at room temperature, it disappeared when the device was cooled to 240 K, suggesting a considerable increase in the time constant of the charge trapping/detrapping at these modestly low temperatures. The suppression of the hysteresis or instability in the easily attainable temperature range without surface passivation is highly advantageous for the device application of this system. The humidity dependence of the threshold voltages in the transfer curves indicates that the water molecules dominantly act as hole-trapping centers. A strong dependence of the on-state current on oxygen pressure was also observed.
This month, we have begun our discussion of the reasons why this is a very good time for hospitals to review and re-engineer their case management models and departments, including the Affordable Care Act and value-based purchasing, among others. Next time, we will discuss the elements you need to review when re-engineering your own case management department.
Gram-negative bacteria exhibit lipopolysaccharides (LPSs) on their outer membrane surface. LPS is considered one of the most potent bacterial virulence factors. Here we report the elucidation of the LPS O-chain structure isolated from Burkholderia fungorum, a bacterium isolated from the white-rot fungus Phanerochaete chrysosporium that can act as a pathogen for plants and domesticated animals. The structure was determined by the employment of detailed chemical and NMR spectroscopy analyses as the following.
This work was aimed at investigating the performance of the continuous-flow VUV photoreactor as a novel chemical-less advanced process for simultaneously oxidizing acetaminophen (ACT) as a model of pharmaceuticals and reducing nitrate in a single reactor. Solution pH was an important parameter affecting the performance of VUV; the highest ACT oxidation and nitrate reduction attained at solution pH between 6 and 8. The ACT was oxidized mainly by HO while the aqueous electrons were the main working agents in the reduction of nitrate. The performance of VUV photoreactor improved with the increase of hydraulic retention time (HRT); the complete degradation of ACT and ∼99% reduction
 of nitrate with 100% N2 selectivity achieved at HRT of 80min. The VUV effluent concentrations of nitrite and ammonium at HRT of 80min were below the drinking water standards. The real water sample contaminated with the ACT and nitrate was efficiently treated in the VUV photoreactor. Therefore, the VUV photoreactor is a chemical-less advanced process in which both advanced oxidation and advanced reduction reactions are accomplished. This unique feature possesses VUV photoreactor as a promising method of treating water contaminated with both pharmaceutical and nitrate.
The role of Wharton's jelly-derived human mesenchymal stem cells (WJ-MSCs) in inhibiting muscle cell death has been elucidated in this study. Apoptosis induced by serum deprivation in mouse skeletal myoblast cell lines (C2C12) was significantly reduced when the cell lines were cocultured with WJ-MSCs. Antibody arrays indicated high levels of chemokine (C motif) ligand (XCL1) secretion by cocultured WJ-MSCs and XCL1 protein treatment resulted in complete inhibition of apoptosis in serum-starved C2C12 cells. Apoptosis of C2C12 cells and loss of differentiated C2C12 myotubes induced by lovastatin, another muscle cell death inducer, was also inhibited by XCL1 treatment. However, XCL1 treatment did not inhibit apoptosis of cell lines other than C2C12. When XCL1-siRNA pretreated WJ-MSCs were cocultured with serum-starved C2C12 cells, apoptosis was not inhibited, thus confirming that XCL1 is a key factor in preventing C2C12 cell apoptosis. We demonstrated the therapeutic effect of XCL1 on the zebrafish myopathy model, generated by knock down of a causative gene ADSSL1. Furthermore, the treatment of XCL1 resulted in significant recovery of the zebrafish skeletal muscle defects. These results suggest that human WJ-MSCs and XCL1 protein may act as promising and novel therapeutic agents for treatment of myopathies and other skeletal muscle diseases.
Compared with other inorganic materials such as silica, metal oxides, noble metals and carbon, calcium silicate-based materials, especially nanostructured calcium silicate materials, have high biocompatibility, bioactivity and biodegradability, high specific surface area, nanoporous/hollow structure, high drug-loading capacity, pH-responsive drug release behavior and desirable drug release properties, and thus they are promising for the application in drug delivery. Calcium silicate-based drug delivery systems have a long drug-release time, which can significantly prolong the therapeutic effect of drugs. Another advantage of calcium silicate-based drug delivery systems is their pH-responsive drug release property, which can act as an ideal platform for targeted drug delivery.
In recent years, studies have been carried out on calcium silicate-based drug delivery systems, and important results and insights have been documented. This article is not intended to offer a comprehensive review on the research on calcium silicate-based drug delivery systems, but presents some examples reported in the literature, and includes new insights obtained by tracking the interactions between drug molecules and calcium silicate carriers on the molecular level using the synchrotron-based X-ray spectroscopy.
Finally, our opinions on calcium silicate-based drug delivery systems are provided, and several research directions for the future studies are proposed.
Pseudogymnoascus destructans, the causal agent of white-nose syndrome (WNS), is commonly found on bats captured both inside and outside caves during hibernation, a time when bats are most vulnerable to infection. It has not been documented in the southeast US on bats captured outside caves or on the landscape in summer. We collected 136 skin swabs from 10 species of bats captured at 20 sites on the Tennessee side of Great Smoky Mountains National Park, 12 May-16 August 2015. Three swabs were found positive for P. destructans, one from a male tricolored bat ( Perimyotis subflavus ) and two from male big brown bats ( Eptesicus fuscus ). This detection of P. destructans on free-flying male bats in the southeast US during summer has potential repercussions for the spread of the fungus to novel bat species and environments. Our finding emphasizes the need to maintain rigorous year-round decontamination of field clothing and equipment until more is understood about the viability of P. destructans found on bats captured outside hibernacula during summer, about the potential for males to act as reservoirs of the fungus, and the risk of fungal transmission and spread.
According to the attentional control theory (ACT) proposed by Eysenck and colleagues, anxiety interferes with cognitive processing by prioritizing bottom-up attentional processes over top-down attentional processes, leading to competition for access to limited resources in working memory, particularly the central executive (Eysenck, Derakshan, Santos, & Calvo, ). However, previous research using the n-back working memory task suggests that working memory load also reduces state anxiety. Assuming that similar mechanisms underlie the effect of anxiety on cognition, and the effect of cognition on anxiety, one possible implication of the ACT would suggest that the reduction of state anxiety with increasing working memory load is driven by activation of central executive attentional control processes. We tested this hypothesis using the Sternberg working memory paradigm, where maintenance processes can be isolated from central executive processes (Altamura et al., ; Sternberg, ). Consistent with the n-back results, subjects showed decreased state anxiety during the maintenance period of high-load trials relative to low-load trials, suggesting that maintenance processes alone are sufficient to achieve this state anxiety reduction. Given that the Sternberg task does not require central executive engagement, these results are not consistent with an implication of the ACT where the cognition/anxiety relationship and anxiety/cognition relationship are mediated by similar central executive mechanisms. Instead, we propose an extension of the ACT such that engaging working memory maintenance suppresses state anxiety in a load-dependent manner. Furthermore, we hypothesize that the efficacy of this effect may moderate the effect of trait anxiety on cognition.
Cancer immunotherapy has made much progress in recent years. Clinical trials evaluating a variety of immunotherapeutic approaches are underway in patients with malignant gliomas. Thanks to recent advancements in cell engineering technologies, infusion of ex vivo prepared immune cells have emerged as promising strategies of cancer immunotherapy.
Herein, the authors review recent and current studies using cellular immunotherapies for malignant gliomas. Specifically, they cover the following areas: a) cellular vaccine approaches using tumor cell-based or dendritic cell (DC)-based vaccines, and b) adoptive cell transfer (ACT) approaches, including lymphokine-activated killer (LAK) cells, γδ T cells, tumor-infiltrating lymphocytes (TIL), chimeric antigen receptor (CAR)-T cells and T-cell receptor (TCR) transduced T cells.
While some of the recent studies have shown promising results, the ultimate success of cellular immunotherapy in brain tumor patients would require improvements in the following areas: 1) feasibility in producing cellular therapeutics; 2) identification and characterization of targetable antigens given the paucity and heterogeneity of tumor specific antigens; 3) the development of strategies to promote effector T-cell trafficking; 4) overcoming local and systemic immune suppression, and 5) proper interpretation of imaging data for brain tumor patients receiving immunotherapy.
A rapid and straightforward synthesis of the new and highly reactive reagent N-methoxy-N-methylcyanoformamide from trimethylsilyl cyanide and N-methoxy-N-methylcarbamoylimidazole, is reported. This reagent enables the one-pot preparation of β-carbonyl Weinreb amides from lithium enolates, one-carbon homologated Weinreb amides, and unsymmetrical ketones in one-pot procedures from various organometallic species.
Series of polydimethylsiloxane (PDMS)-based polyurethane (PU)/polyhedral oligomeric silsesquioxane (POSS) composites are prepared using ether or polyether modified diol/polyol PDMS prepolymers, isophorone diisocyanate (IPDI) and either non-reactive or reactive POSS. The effect of POSS incorporated chemically or physically, number of ethylene oxide units and crosslinking on PDMS based PU is investigated in terms of thermal stability and ablation properties. The ablation property is measured using an oxyacetylene torch test, and the ablation rate is evaluated. The results show that POSS molecules make a considerable influence on the ablative resistance, because they act as protective silica forming precursors under oxyacetylene condition. POSS molecules, especially methyl POSS, in PU matrix leads to the formation of densely accumulated spherical silica layers on the top of the ablated surface, resulting in improved ablation resistance.
Adoptive cell therapy (ACT) using autologous cytokine-induced killer (CIK) cells is a promising treatment for metastatic carcinomas. In this study, we investigated the impact of RetroNectin on the proliferation, phenotype alternation, cytokine secretion, and cytotoxic activity of CIK cells from pancreatic cancer patients. Furthermore, we treated 13 patients with metastatic or locally advanced pancreatic cancer using autologous RetroNectin-activated CIK cells (R-CIK cells) alone or in combination with chemotherapy. Compared with only CD3 activated CIK cells (OKT-CIK cells), R-CIK cells showed stronger and faster proliferative ability, with a lower ratio of spontaneous apoptosis. Moreover, this ability continued after IL-2 was withdrawn from the culture system. R-CIK
 cells could also secrete higher levels of IL-2 and lower levels of IL-4 and IL-5 versus OKT-CIK cells. There was no difference between OKT-CIK and R-CIK cells in cytotoxic ability against lymphoma cell line K562. In patients who received auto-R-CIK cell infusion therapy, the overall objective response rate was 23.1%. Median survival time (mOS) after first R-CIK cell infusion was 10.57 months; the 1-year survival rate was 38.5%. No serious toxicity was associated with R-CIK cell infusion. In conclusion, RetroNectin may enhance antitumor activity of CIK cells: it is safe for use in treating pancreatic cancer.
Tuberculosis (TB) is one of the most important occupational risks for healthcare workers (HCWs) in South Korea. Many policies regarding the control and prevention of TB in healthcare settings recommend that HCWs are tested for latent tuberculosis infection (LTBI) in addition to active TB. Moreover, the Korean Tuberculosis Prevention Act also recommends that HCWs receive regular testing for LTBI. However, there are no specific or detailed guidelines for dealing with LTBI in HCWs. Herein, we discuss the diagnosis and treatment of LTBI in HCWs and focus particularly on the baseline screening of hired HCWs, routine follow-up, and contact investigation.
Early involvement of gut is observed in Parkinson's disease (PD) and symptoms such as constipation may precede motor symptoms. α-Synuclein pathology is extensively evident in the gut and appears to follow a rostrocaudal gradient. The gut may act as the starting point of PD pathology with spread toward the central nervous system. This spread of the synuclein pathology raises the possibility of prion-like propagation in PD pathogenesis. Recently, the role of gut microbiota in PD pathogenesis has received attention and some phenotypic correlation has also been shown. The extensive involvement of the gut in PD even in its early stages has led to the evaluation of enteric α-synuclein as a possible biomarker of early PD. The clinical manifestations of gastrointestinal dysfunction in PD include malnutrition, oral and dental disorders, sialorrhea, dysphagia, gastroparesis, constipation, and defecatory dysfunction. These conditions are quite distressing for the patients and require relevant investigations and adequate management. Treatment usually involves both pharmacological and non-pharmacological measures. One important aspect of gut dysfunction is its contribution to the clinical fluctuations in PD. Dysphagia and gastroparesis lead to inadequate absorption of oral anti-PD medications. These lead to response fluctuations, particularly delayed-on and no-on, and there is significant relationship between levodopa pharmacokinetics and gastric emptying in patients with PD. Therefore, in such cases, alternative routes of administration or drug delivery systems may be required.
The relationships of eggshell, air cell, and embryo cloacal temperatures in Ross × Ross 708 broiler hatching eggs were determined. Twenty eggs were weighed and set on each of 3 tray levels of a single incubator. Eggshell temperature (EST) of the eggs were recorded once in the morning (AM) and afternoon (PM) between 0 and 19 d of incubation (DOI) using an infrared thermometer (IRT). All eggs were candled and a transponder was implanted in the air cell of eggs containing live embryos (12 per tray level) at 12 DOI. At 19 DOI, transponders were implanted in the cloaca of live embryos from those same eggs. Air cell temperature (ACT) and EST readings were recorded once in the AM and PM between 12 and 19 DOI, and ACT and cloaca temperature (CLT) readings were recorded every 6 h between 19 and 21 DOI. The EST and ACT readings between 13 and 19 DOI were positively correlated. However, their respective mean temperatures between 13 and 19 DOI differed. The EST and ACT were not significantly influenced by tray level. Nevertheless, a main effect due to location (eggshell vs. air cell), and an interaction between DOI and time of day (AM and PM) in the 13 to 19 DOI interval were observed. Furthermore, an interaction was observed between location (air cell and cloaca) and the 6 h sequential time periods in the 19 to 21 DOI interval. However, across the entire 19 to 21 DOI interval, mean ACT and CLT were not significantly different, and were positively correlated. These data suggest that ACT readings are higher than those of EST during the last half of incubation, and that between 13 and 19 DOI, ACT readings may have the potential for use as a minimally invasive method by which to more accurately estimate the true core body temperature of broiler embryos. The effects of this method on hatchability and post-hatch performance need determination to better establish its practicality.
Intracellular signaling during oxidative stress is complex, with organelle-to-nucleus retrograde communication pathways ill-defined or incomplete. Here we identify the 3'-phosphoadenosine 5'-phosphate (PAP) phosphatase SAL1 as a previously unidentified and conserved oxidative stress sensor in plant chloroplasts. Arabidopsis thaliana SAL1 (AtSAL1) senses changes in photosynthetic redox poise, hydrogen peroxide, and superoxide concentrations in chloroplasts via redox regulatory mechanisms. AtSAL1 phosphatase activity is suppressed by dimerization, intramolecular disulfide formation, and glutathionylation, allowing accumulation of its substrate, PAP, a chloroplast stress retrograde signal that regulates expression of plastid redox associated nuclear genes (PRANGs). This redox regulation of SAL1 for activation of chloroplast signaling is conserved in the plant kingdom, and the plant protein has evolved enhanced redox sensitivity compared with its yeast ortholog. Our results indicate that in addition to sulfur metabolism, SAL1 orthologs have evolved secondary functions in oxidative stress sensing in the plant kingdom.
Phylogeography, and its extensions into comparative phylogeography, have their roots in the layering of gene trees across geography, a paradigm that was greatly facilitated by the nonrecombining, fast evolution provided by animal mtDNA. As phylogeography moves into the era of next-generation sequencing, the specter of reticulation at several levels-within loci and genomes in the form of recombination and across populations and species in the form of introgression-has raised its head with a prominence even greater than glimpsed during the nuclear gene PCR era. Here we explore the theme of reticulation in comparative phylogeography, speciation analysis, and phylogenomics, and ask how the centrality of gene trees has fared in the next-generation era. To frame these issues, we first provide a snapshot of multilocus phylogeographic studies across the Carpentarian Barrier, a prominent biogeographic barrier dividing faunas spanning the monsoon tropics in northern Australia. We find that divergence across this barrier is evident in most species, but is heterogeneous in time and demographic history, often reflecting the taxonomic distinctness of lineages spanning it. We then discuss a variety of forces generating reticulate patterns in phylogeography, including introgression, contact zones, and the potential selection-driven outliers on next-generation molecular markers. We emphasize the continued need for demographic models incorporating reticulation at the level of genomes and populations, and conclude that gene trees, whether explicit or implicit, should continue to play a role in the future of phylogeography.
Precise regulation of centrosome number is critical for accurate chromosome segregation and the maintenance of genomic integrity. In nontransformed cells, centrosome loss triggers a p53-dependent surveillance pathway that protects against genome instability by blocking cell growth. However, the mechanism by which p53 is activated in response to centrosome loss remains unknown. Here, we have used genome-wide CRISPR/Cas9 knockout screens to identify a USP28-53BP1-p53-p21 signaling axis at the core of the centrosome surveillance pathway. We show that USP28 and 53BP1 act to stabilize p53 after centrosome loss and demonstrate this function to be independent of their previously characterized role in the DNA damage response. Surprisingly, the USP28-53BP1-p53-p21 signaling pathway is also required to arrest cell growth after a prolonged prometaphase. We therefore propose that centrosome loss or a prolonged mitosis activate a common signaling pathway that acts to prevent the growth of cells that have an increased propensity for mitotic errors.
Death domain superfamily members typically act as adaptors mediating in the assembly of supramolecular complexes with critical apoptosis and inflammation functions. These modular proteins consist of death domains, death effector domains, caspase recruitment domains, and pyrin domains (PYD). Despite the high structural similarity among them, only homotypic interactions participate in complex formation, suggesting that subtle factors differentiate each interaction type. It is thus critical to identify these factors as an essential step toward the understanding of the molecular basis of apoptosis and inflammation. The proteins apoptosis-associated speck-like protein containing a CARD (ASC) and NLRP3 play key roles in the regulation of apoptosis and inflammation through self-association and protein-protein interactions mediated by their PYDs. To better understand the molecular basis of their function, we have characterized ASC and NLRP3 PYD self-association and their intermolecular interaction by solution NMR spectroscopy and analytical ultracentrifugation. We found that ASC self-associates and binds NLRP3 PYD through equivalent protein regions, with higher binding affinity for the latter. These regions are located at opposite sides of the protein allowing multimeric complex formation previously shown in ASC
 PYD fibril assemblies. We show that NLRP3 PYD coexists in solution as a monomer and highly populated large-order oligomerized species. Despite this, we determined its monomeric three-dimensional solution structure by NMR and characterized its binding to ASC PYD. Using our novel structural data, we propose molecular models of ASC·ASC and ASC·NLRP3 PYD early supramolecular complexes, providing new insights into the molecular mechanisms of inflammasome and apoptosis signaling.
Hydrogen peroxide (H2O2) can act as a signaling molecule that influences various aspects of plant growth and development, including stress signaling and cell death. To analyze molecular mechanisms that regulate the response to increased H2O2 levels in plant cells, we focused on the photorespiration-dependent peroxisomal H2O2 production in Arabidopsis thaliana mutants lacking CATALASE2 (CAT2) activity (cat2-2). By screening for second-site mutations that attenuate the PSII maximum efficiency (Fv'/Fm') decrease and lesion formation linked to the cat2-2 phenotype, we discovered that a mutation in SHORT-ROOT (SHR) rescued the cell death phenotype of cat2-2 plants under photorespiration-promoting conditions. SHR deficiency attenuated H2O2-dependent gene expression, oxidation of the glutathione pool, and ascorbate depletion in a cat2-2 genetic background upon exposure to photorespiratory stress. Decreased glycolate oxidase and catalase activities together with accumulation of glycolate further implied that SHR deficiency impacts the cellular redox homeostasis by limiting peroxisomal H2O2 production. The photorespiratory phenotype of cat2-2 mutants did not depend on the SHR functional interactor SCARECROW and the sugar signaling component ABSCISIC ACID INSENSITIVE4, despite the requirement for exogenous sucrose for cell death attenuation in cat2-2 shr-6 double mutants. Our findings reveal a link between SHR and photorespiratory H2O2 production that has implications for the integration of developmental and stress responses.
Lupus is a classical systemic autoimmune disease with genetics as one of the well known causative factors for the disease pathogenesis. Toll-like receptors are the major pattern recognition receptors associated with innate immunity and also act as an interface with the adaptive immunity. Genetic polymorphisms in genes encoding TLRs were implicated in the development of infections, malignancies and autoimmune diseases. TLR9 is a member of TLR family, and recognizes the CpG DNA motifs of pathogens. Though the incidence rate of lupus in Asians was reported to be low (30 - 50/100,000 population), poor disease prognosis due to higher incidence of renal complications and aggressive disease worsens the scenario. The ability of TLR9 to detect and elicit an immune response against double-stranded DNA makes TLR9 a relevant factor to be tested for its association with the clinical and serological phenotypes of lupus. However, lack of relevant genetic data on normative frequencies of the TLR9 (rs187084) polymorphism may serve as a constraint to derive the sample size to conduct case control association studies. Hence this study was conducted to establish the normative frequency of TLR9 (rs187084) polymorphism in Indian Tamils.
The TLR9 (rs187084) polymorphism was screened in South Indian Tamils (n = 208) by PCR-RFLP.
We observed a higher occurrence of the mutant allele (65%) in South Indian Tamils. No gender disparity with respect to the mutant allele frequency was observed. The higher incidence of mutant allele in both genders suggests that this population had undergone a genetic selection pressure as an evolutionary genetic measure to withstand the prevailing endemic infections like TB and malaria. Though the enhanced expression of TLR9 was protective against infections, it may also influence the development of autoimmune diseases.
The higher incidence of theTLR9 (rs187084) over-expression mutation in Indian Tamils is suggestive of a genetic adaptation or selection pressure to withstand the prevailing endemic infectious and parasitic diseases. However, this genetic adaptation poses a greater risk to develop autoimmune diseases like SLE etc through complex gene environment interactions. The normative frequency of the TLR9 (rs187084) polymorphism established in our population could now be used to define the sample size for future case control studies.
Intermittent seminal HIV-RNA detection can occur in MSM despite concomitant plasma virological control on combined ART (cART). We undertook the present study to determine if seminal HIV detection was associated with seminal cytomegalovirus (CMV) detection or detection of HIV-infected cells in semen.
Longitudinal semen samples from HIV-1-infected MSM on successful cART enrolled in the EVARIST ANRS EP 49 study were analysed. We first conducted a case-control analysis (ratio 1 : 3) to assess HIV-DNA detection in semen cells in the 20 patients with detectable HIV-RNA in seminal plasma (cases) matched with 60 participants with undetectable HIV-RNA (controls) based on total HIV-DNA load in blood cells. Second, we measured CMV-DNA in all seminal plasma samples.
HIV-1-DNA in semen cells was detected on at least one sample visit in 12/20 cases and 11/60 controls. Detection of HIV-RNA in seminal plasma was associated significantly with the detection of HIV-DNA in semen cells [OR, 7.6 (95% CI, 2.1-28.4); P = 0.002] when adjusted on total HIV-DNA in blood cells. CMV-DNA was detected in 107/273 seminal plasma samples with a median value of 3.62 log10 copies/mL (IQR, 2.83-4.38), yielding a prevalence of 39.2%. Seminal CMV-DNA shedding [OR, 1.5 (95% CI, 0.6-3.6); P = 0.343] was not associated with the risk of detection of HIV-RNA in seminal plasma.
The presence of HIV-DNA in semen cells was predictive of HIV-RNA detection, suggesting that viral particles arise through local HIV replication by infected semen cells. Despite virological control, compartmentalization of HIV in the genital tract might act in residual replication and transmission.
Acute coronary syndromes (ACS) are the most common cardiovascular diseases and are associated with a significant risk of mortality and morbidity. The Global Registry of Acute Coronary Events (GRACE) risk score postdischarge is a widely used ACS prediction model for risk of mortality (low, intermediate, and high); however, it has not yet been validated in patients from the Arabian Gulf. This prospective multicenter study (second Gulf Registry of Acute Coronary Events) provides detailed information of the GRACE risk score postdischarge in patients from the Arabian Gulf. Its prognostic utility was validated at 1-year follow-up in over 5000 patients with ACS from 65 hospitals in 6 Arabian Gulf countries (Bahrain, Saudi Arabia, Qatar, Oman, United Arab Emirates, and Yemen). Overall, the goodness of fit (Hosmer and Lemeshow statistic P value = .826), calibration, and discrimination (area under the receiver operating characteristic curve = 0.695; 95% confidence interval: 0.668-0.722) were good. The GRACE risk score postdischarge can be used to stratify 1 year mortality risk in the Arabian Gulf population; it does not require further calibration and has a good discriminatory ability.
Macrophages are major targets of human immunodeficiency virus (HIV) and can act as long term reservoirs of the virus. Chronic HIV 1 infection is associated with dysregulated inflammation. Recepteur d'origine nantais (RON) is expressed in tissue resident macrophages and functions to maintain inflammatory homeostasis. The present study aimed to compare the expression of RON on HIV-positive and -negative participants, and to investigate the mechanism by which HIV 1 influences the expression and function of RON in the JLTRG T cell line. The levels of RON and the RON ligand, macrophage stimulating protein (MSP), in the peripheral blood of HIV 1-positive patients that were receiving (n=22) or not receiving highly active anti retroviral therapy (HAART) (n=82) and 37 healthy control participants were determined by enzyme linked immunosorbent assay. Expression of RON and MSP in the JLTRG T cell line was assessed by western blotting and the subcellular location was analyzed by fluorescence microscopy. JLTRG cells were co cultured with a cell line that stably expresses HIV, H9/HTLV IIIB, and alterations in the levels of RON and nuclear factor κB (NF κB) in JLTRG cells were assessed by western blotting. The expression of RON and MSP were significantly different in the serum of HIV 1-positive patients that were receiving HAART compared with those not receiving HAART (P<0.05) and healthy control patients (P<0.01). RON was detected in JLTRG cells, and was shown to be downregulated by HIV 1 infection. HIV 1 infection of JLTRG cells also reduced NF κB phosphorylation. Thus, HIV 1 was shown to downregulate the expression and phosphorylation of RON by targeting the NF κB pathway.
Naringenin (NR), a flavonoid abundant in citrus fruits has been reported to possess anti-inflammatory properties. The present study aimed to investigate the protective of naringenin in rats after spinal cord injury (SCI) and the underlying mechanisms associated with neuroinflammation. Adult male Sprague-Dawley rats were subjected to laminectomy at T9-T11 and compression with a vascular clip. The spinal cords spanning the injury site about 0.8cm were collected for testing. There were five groups (n=7 in each group): (a) Control group; (b) sham group group; (c) SCI+saline; (d) SCI+NR (50mg/kg, p.o.) group and (e) SCI+NR (100mg/kg, p.o.) group. Different doses of NR (50mg/kg, p.o. and 100mg/kg, p.o.) or saline were administered once daily for 11 consecutive days, from 3days prior to surgery to 7days after surgery. The expression level of miR-223, NLRP3 and IL-1β were measured by RT- qPCR. The accumulation of neutrophils at the site of compression,
 as evaluated by measuring the tissue myeloperoxidase activity, significantly increased with time following the compression, peaking at 24h post compression. The expression of miR-223 was significant elevated in (b). However, spinal cord myeloperoxidase activity and the expression of miR-223 did not increase in sham-operated animals. NR significantly inhibited a SCI-induced activation of neutrophils through repressed miR-223 in group (d) and (e). There was a better effect in group (e) than group (d). miR-223 is thought to act as a fine-tuner of granulocyte production and the inflammatory response. Our findings suggested that repeated administration of naringenin (100mg/kg, p.o) may provide the protective effect of the spinal cord injury in rats, possibly through inhibiting neuroinflammation.
The civil rights and social legislation of the Great Society following the Civil Rights Act of 1964 was slow to provide relief for black in the South. Mississippi Senator James Eastland led an effort to defund Head Start, including his state's program, Child Development Group of Mississippi (CDGM), a program with a strong medical component. A senatorial committee, including Robert Kennedy, came to investigate CDGM in 1967. The unimaginable poverty, hunger, malnutrition and chronic disease found in black families was vehemently denied by Eastland. Visits of physician groups then corroborated the findings. The Mississippi delegation made sure that food relief never came and funding for CDGM ceased. Health services were lost to 6000 impoverished children. The epic television documentary, Hunger in America, soon premiered on network television. It triggered ongoing efforts to address health disparities, including implementation of the National Nutrition and Health Survey (NHANES). Similar physician leadership is needed to address the lasting health disparities in our country.
MicroRNAs (miRNAs) act as tumor promoters or tumor suppressors in different human malignancies. In the current study, using an Agilent miRNA microarray, miR 30a was found to be a significantly downregulated miRNA in castration resistant prostate cancer (CRPC) tissues, compared with androgen dependent prostate cancer tissues. Aberrant expression of cyclin E2 (CCNE2) has been reported in a variety of types of cancer including prostate cancer, and correlates with clinical outcome. The purpose of the current study was to determine the functions of miR 30a in CRPC cell lines and identify whether CCNE2 was regulated by miR 30a. To analyze the associations between miR 30a and CCNE2 expression levels, pathological specimens were collected, and reverse transcription quantitative polymerase chain reaction and immunohistochemical staining were conducted. The effect of miR 30a overexpression on CRPC cell lines and the predicted target gene, CCNE2, were evaluated by MTT assay, flow cytometry, tumor formation, luciferase reporter assay and western blotting. miR 30a overexpression resulted in a significant suppression of cell growth in vitro, and reduced tumorigenicity in vivo. miR 30a repressed the expression of CCNE2 through binding to its 3' untranslated region. CCNE2 was observed to be overexpressed in patients with CRCP and had an approximately inverse correlation with the level of miR 30a. The results suggest that miR 30a may function as a novel tumor suppressor in CRPC. Its anti oncogenic activity may occur by the reduced expression of a distinct cell cycle protein, CCNE2.
Three chelating-amino-functionalized lanthanide metal-organic frameworks, Y-DDQ, Dy-DDQ and Eu-DDQ, were synthesized with a flexible dicarboxylate ligand based on quinoxaline (H2DDQ = N, N'-dibenzoic acid-2,3-diaminoquinoxaline). The three-dimensional framework is constructed by the H2DDQ linkers connecting the zigzag ladders, showing a net of sra topology. In the structures, one kind of Ln(III) ions metal centers are six-coordinated and thus can potentially behave as open metal sites (OMSs), while the free chelating amino groups can act as free functional organic sites (FOSs). The N2 and Ar adsorption behaviors indicate that these Ln-DDQ exhibits stable microporous frameworks with high surface area after remove of the solvents. Owing to presence of OMSs and FOSs, these MOFs show good ability of CO2, dyes captures and Lewis acid catalyst for cyanosilylation reaction. In view of the existing FOSs in the framework, Pd NPs were immobilized onto the MOFs through graft interactions between free chelating amino groups and metal ions precursor using postsynthetic modification. The well dispersed Pd@Ln-DDQs exhibit efficient and recyclable catalytic reduction of 4-nitrophenol to 4-aminophenol, and they can also act as an excellent catalyst for Suzuki-Miyaura cross-coupling reactions with the exposed Pd NPs.
Thyroid hormone receptor β1 (TRβ1) is a ligand dependent transcription factor that belongs to the superfamily of nuclear receptors. TRβ1 has been found to act as a tumor suppressor in many solid tumors including breast cancer and hepatocellular carcinoma, but its role in the progression of human colorectal cancer (CRC) remains unclear. In this study, microarray data analysis revealed that TRβ1 mRNA was downregulated in CRC tumors compared with that in the normal counterparts in both The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) datasets. Using a CRC tissue microarray (TMA), we confirmed that the expression of TRβ1 was decreased in human CRC tumor tissues in contrast to normal colorectal mucosal tissues. Notably, the TRβ1 expression was strongly correlated with tumor size (p=0.045). Furthermore, we found that CRC cell proliferation and migration were significantly inhibited by TRβ1 overexpression in vitro. Mechanistic studies indicated that activated phosphorylated Akt was clearly suppressed by TRβ1 in the CRC tissues and cells. In conclusion, this study provides evidence that TRβ1 plays a critical role in the progression of CRC via the PI3K/Akt pathway, and the TRβ1 gene may represent a novel target for CRC therapeutics.
MicroRNAs (miRNAs) are a class of small endogenous non-coding RNAs that play important regulatory roles by targeting mRNAs for cleavage or translational repression. miRNAs act in diverse biological processes including development, cell growth, apoptosis, and hematopoiesis. The miRNA expression is associated with specific cytogenetic changes and can also be used to discriminate between the different subtypes of leukemia in acute lymphoblastic leukemia with common translocations, it is shown that the miRNAs have the potential to be used for clinical diagnosis and prognosis. We reviewed the roles of miRNA here with emphasis on their function in human leukemia and the mechanisms of the TEL/AML1, BCR/ABL, MLL/AF4 and TCF3/PBX1 oncoproteins on miRNAs expression in acute lymphoblastic leukemia.
The evolutionary transition to multicellularity probably began with the formation of simple undifferentiated cellular groups. Such groups evolve readily in diverse lineages of extant unicellular taxa, suggesting that there are few genetic barriers to this first key step. This may act as a double-edged sword: labile transitions between unicellular and multicellular states may facilitate the evolution of simple multicellularity, but reversion to a unicellular state may inhibit the evolution of increased complexity. In this paper, we examine how multicellular adaptations can act as evolutionary 'ratchets', limiting the potential for reversion to unicellularity. We consider a nascent multicellular lineage growing in an environment that varies between favouring multicellularity and favouring unicellularity. The first type of ratcheting mutations increase cell-level fitness in a multicellular context but are costly in a single-celled context, reducing the fitness of revertants. The second type of ratcheting mutations directly decrease the probability that a mutation will result in reversion (either as a pleiotropic consequence or via direct modification of switch rates). We show that both types of ratcheting mutations act to stabilize the multicellular state. We also identify synergistic effects between the two types of ratcheting mutations in which the presence of one creates the selective conditions favouring the other. Ratcheting mutations may play a key role in diverse evolutionary transitions in individuality, sustaining selection on the new higher-level organism by constraining evolutionary reversion.This article is part of the themed issue 'The major synthetic evolutionary transitions'.
Polyautoimmunity is defined as the presence of more than one well-defined autoimmune disease (AD) in a single patient. Polyautoimmunity is a frequent condition in Sjögren syndrome (SS) and follows a grouping pattern. The most frequent ADs observed in SS are autoimmune thyroid disease, rheumatoid arthritis, and systemic lupus erythematosus. Main factors associated with polyautoimmunity in SS are tobacco smoking and some genetic variants. The study of polyautoimmunity provides important clues for elucidating the common mechanisms of autoimmne diseases (ie, the autoimmune tautology).
Triazines are herbicides that are widely used worldwide, and we previously observed that the maternal exposure of mice to simazine (50 or 500μg/kg) resulted in smaller ovaries and uteri of their female offspring. Here, we investigated the underlying mechanism that may account for the reproductive dysfunction induced by simazine. We found that following maternal exposure, simazine is transmitted to the offspring, as evidenced by its presence in the offspring ovaries. Analyses of the simazine-exposed offspring revealed that the expression of the relaxin hormone receptor, relaxin-family peptide receptor 1 (RXFP1), prominently decreased in their ovaries and uteri. In addition, downstream target genes of the relaxin pathway including
 nitric oxide (NO) synthase 2 (Nos2), Nos3, matrix metallopeptidase 9 (Mmp9), and vascular endothelial growth factor (Vegf) were downregulated in their ovaries. Moreover, AKT and extracellular signal-regulated kinases (ERK) levels and their phosphorylated active forms decreased in simazine-exposed ovaries. In vitro exposure of the human ovarian granulosa cells (KGN) and uterine endometrium cells (Hec-1A) to very low concentrations (0.001 to 1nM) of triazines including atrazine, terbuthylazine, and propazine repressed NO production with a concurrent reduction in RXFP1, NOS2, and NOS3. The inhibitory action of triazines on NO release was dependent on RXFP1, phosphoinositol 3-kinase (PI3K)/AKT, and ERK. Radioligand-binding assay also confirmed that triazines competitively inhibited the binding of relaxin to its receptor. Therefore, the present study suggests that triazine herbicides act as endocrine disrupters by interfering with relaxin hormone signaling. Thus, further evaluation of their impact on human health is imperative.
Glucagon-like peptide-1 (7-36) amide (GLP-1) protects against stunning and cumulative left ventricular dysfunction in humans. The mechanism remains uncertain but GLP-1 may act by opening mitochondrial K-ATP channels in a similar fashion to ischemic conditioning. We investigated whether blockade of K-ATP channels with glibenclamide abrogated the protective effect of GLP-1 in humans.
Thirty-two non-diabetic patients awaiting stenting of the left anterior descending artery (LAD) were allocated into 4 groups (control, glibenclamide, GLP-1, and GLP-1 + glibenclamide). Glibenclamide was given orally prior to the procedure. A left ventricular conductance catheter recorded pressure-volume loops during a 1-min low-pressure balloon occlusion (BO1) of the LAD. GLP-1 or saline was then infused for 30-min followed by a further 1-min balloon occlusion (BO2). In a non-invasive study, 10 non-diabetic patients were randomized to receive two dobutamine stress echocardiograms (DSE) during GLP-1 infusion with or without oral glibenclamide pretreatment.
GLP-1 prevented stunning even with glibenclamide pretreatment; the Δ % dP/dtmax 30-min post-BO1 normalized to baseline after GLP-1: 0.3 ± 6.8 % (p = 0.02) and GLP-1 + glibenclamide: -0.8 ± 9.0 % (p = 0.04) compared to control: -11.5 ± 10.0 %. GLP-1 also reduced cumulative stunning after BO2: -12.8 ± 10.5 % (p = 0.02) as did GLP-1 + glibenclamide: -14.9 ± 9.2 % (p = 0.02) compared to control: -25.7 ± 9.6 %. Glibenclamide alone was no different to control. Glibenclamide pretreatment did not affect global or regional systolic function after GLP-1 at peak DSE stress (EF 74.6 ± 6.4 vs. 74.0 ± 8.0, p = 0.76) or recovery (EF 61.9 ± 5.7 vs. 61.4 ± 5.6, p = 0.74).
Glibenclamide pretreatment does not abrogate the protective effect of GLP-1 in human models of non-lethal myocardial ischemia. Trial registration Clinicaltrials.gov Unique Identifier: NCT02128022.
Burnout is a major issue among medical students. Its general characteristics are loss of interest in study and lack of motivation. A study of the phenomenon must extend beyond the university environment and personality factors to consider whether career choice has a role in the occurrence of burnout.
Quantitative, national survey (n = 733) among medical students, using a 12-item career motivation list compiled from published research results and a pilot study. We measured burnout by the validated Hungarian version of MBI-SS.
The most significant career choice factor was altruistic motivation, followed by extrinsic motivations: gaining a degree, finding a job, accessing career opportunities. Lack of altruism was found to be a major risk factor, in addition to the traditional risk factors, for cynicism and reduced academic efficacy. Our study confirmed the influence of gender differences on both career choice motivations and burnout.
The structure of career motivation is a major issue in the transformation of the medical profession. Since altruism is a prominent motivation for many women studying medicine, their entry into the profession in increasing numbers may reinforce its traditional character and act against the present trend of deprofessionalization.
We examine the phenomenon of variability in the kinetics of amyloid formation and detail methods for its simulation, identification and analysis. Simulated data, reflecting intrinsic variability, were produced using rate constants, randomly sampled from a pre-defined distribution, as parameters in an irreversible nucleation-growth kinetic model. Simulated kinetic traces were reduced in complexity through description in terms of three characteristic parameters. Practical methods for assessing convergence of the reduced parameter distributions were introduced and a bootstrap procedure was applied to determine convergence for different levels of intrinsic variation. Statistical methods for assessing the significance of shifts in parameter distributions, relating to either change in parameter mean or distribution shape, were tested. Robust methods for analyzing and interpreting kinetic data possessing significant intrinsic variance will allow greater scrutiny of the effects of anti-amyloid compounds in drug trials.
Currently, there are emerging multiple studies on human epididymis protein 4 (HE4) in ovarian cancer. HE4 possesses higher sensitivity and specificity than CA125 in the confirmative early diagnosis for ovarian cancer. Although much attention has been given to explore its clinical application, research of the basic mechanisms of HE4 in ovarian cancer are still unclear. In the present study, we provide fundamental data to identify full-scale differentially expressed genes (DEGs) in response to HE4 by use of human whole-genome microarrays in human epithelial ovarian cancer cell line ES-2 following overexpression and silencing of HE4. We found that a total of 717 genes were upregulated and 898 genes were downregulated in the HE4-overexpressing cells vs. the HE4-Mock cells, and 166 genes were upregulated and 285 were downregulated in the HE4-silenced cells vs. the HE4-Mock cells. An overlap of 16 genes consistently upregulated and 8 genes downregulated in response to HE4 were noted. These DEGs were involved in MAPK, steroid biosynthesis, cell cycle, the p53 hypoxia pathway, and focal adhesion pathways. Interaction network analysis predicted that the genes participated in the regulatory connection. Highly differential expression of the FOXA2, SERPIND1, BDKRD1 and IL1A genes was verified by quantitative real-time PCR in 4 cell line samples. Finally, SERPIND1 (HCII) was validated at the protein level by immunohistochemistry in 107 paraffin-embedded ovarian tissues. We found that SERPIND1 may act as a potential oncogene in the development of ovarian cancer. The present study displayed the most fundamental and full-scale data to show DEGs in response to HE4. These identified genes may provide a theoretical basis for investigations of the underlying molecular mechanism of HE4 in ovarian cancer.
The Affordable Care Act was modeled on the Massachusetts Health Reform of 2006, which reduced the number of uninsured largely through a Medicaid expansion and the provision of publicly subsidized insurance obtained through a Health Benefits Exchange.
We surveyed a convenience sample of 780 patients seeking care in a safety-net system who obtained Medicaid or publicly subsidized insurance after the Massachusetts reform, as well as a group of employed patients with private insurance.
We found that although most patients with Medicaid or publicly subsidized exchange-based plans were able to obtain assistance with applying for and choosing an insurance plan, substantial proportions of respondents experienced difficulties with the application process and with understanding coverage and cost features of plans.
Under the Affordable Care Act, efforts to simplify the application process and reduce the complexity of plans may be warranted, particularly for vulnerable patient populations cared for by the medical safety net.
In vitro and in vivo studies reported the anti-cancer potential of organosulfur compounds (OSCs) as they trigger biological effects leading to cell cycle arrest with accumulation of cells in G2/M, alteration of the microtubular network, modulation of Bcl-2 family protein expression patterns and changes of the redox status. Despite these well-described effects, no OSC derivative is yet undergoing clinical trials even though their chemistry is well understood as OSCs act as hydrogen sulfide (H2S) donors. H2S is a biological mediator, synthesized through cysteine degradation and modulates vasodilation, cytoprotection, inflammation and angiogenesis. It is well accepted that H2S plays a biphasic pharmacological role: the inhibition of endogenous synthesis of H2S and paradoxically also the use of H2S donors to increase H2S concentration, induce both anti-cancer effects leading therefore to controversial discussions. Altogether, the role of H2S in the anti-cancer action of OSCs remains poorly understood. In this review, we hypothesize that OSCs act through H2S signaling pathways in cancer cells, and that a clearer understanding of the mechanism of action of H2S in OSC-mediated anti-cancer activity is required for further application of these compounds in translational medicine.
The composition of the fatty acids of the roots and aerial parts of Aritolochia longa (Aristolacheae) and Bryonia dioïca (Cucurbutaceae) was analyzed by gas chromatography (GC-FID) and gas chromatography-mass spectrometry (GC-MS). The oils extracted from the aerial parts of both species were rich in polyunsaturated fatty acids with the essential linolenic and linoleic acids being the most prominent compounds. Oleic and linoleic acids were the majors fatty acids in the roots of both species. Whatever the plant
 part analyzed and the species, the saturated fatty acids were predominantly composed of palmitic and stearic acids. The antibacterial activity, minimum inhibitory concentration (MIC) and minimum bactericidal concentration (MBC) of the lipid extracts were determined against a panel of five bacterial strains. The results showed that the sensitivity to the lipid extracts was different for the test bacterial strains, and the susceptibility of gram positive bacteria was found to be greater than gram negative bacteria. The antibacterial activity of the root lipid extracts was particularly important against Enterococcus feacium (CMI value of 125 µg/mL; CMB values > 250 µg/mL) and Streptococcus agalactiae (CMI value of 125 µg/mL; CMB values 250 µg/mL for A. longa roots). These results indicate that A. longa and B. dioïca could be considered as good sources of essential fatty acids which can act as natural antibacterial agents.
Severe malaria has a case fatality rate of 10-20 %; however, few studies have addressed the quality of severe malaria case management. This study evaluated the diagnostic and treatment practices of malaria patients admitted to inpatient health facilities (HF) in Malawi.
In July-August 2012, a nationwide, cross-sectional survey of severe malaria management was conducted in 36 HFs selected with equal probability from all eligible public sector HFs in Malawi. Patient records from all admissions during October 2011 and April 2012 (low and high season, respectively) were screened for an admission diagnosis of malaria or prescription of any anti-malarial. Eligible records were stratified by age (< 5 or ≥ 5 years). A maximum of eight records was randomly selected within each age and month stratum. Severe malaria was defined by admission diagnosis or documentation of at least one sign or symptom of severe malaria. Treatment with intravenous (IV) quinine or artesunate was considered correct. Patients without documentation of severe malaria were analysed as uncomplicated malaria patients; treatment with an artemisinin-based combination therapy (ACT) or oral quinine based on malaria test results was considered correct. All analyses accounted for HF level clustering and sampling weights.
The analysis included 906 records from 35 HFs. Among these, 42 % (95 % confidence interval [CI] 35-49) had a severe malaria admission diagnosis and 50 % (95 % CI 44-57) had at least one severe malaria sign or symptom documented. Severe malaria patients defined by admission diagnosis (93, 95 % CI 86-99) were more likely to be treated correctly compared to patients defined by a severe sign (82, 95 % CI 75-89) (p < 0.0001). Among uncomplicated malaria patients, 26 % (95 % CI 18-35) were correctly treated and 53 % (95 % CI 42-64) were adequately treated with IV quinine alone or in combination with an ACT or oral quinine.
A majority of patients diagnosed with severe malaria received the recommended IV therapy in accordance with national treatment guidelines. However, the inconsistencies between diagnosis of severe malaria and documentation of severe signs and symptoms highlight the need to improve healthcare worker recognition and documentation of severe signs and symptoms.
The functional expression of recombinant α7 nicotinic acetylcholine receptors in human embryonic kidney (HEK) 293 cells has presented a challenge. Resistance to inhibitors of cholinesterase 3 (RIC 3) has been confirmed to act as a molecular chaperone of nicotinic acetylcholine receptors. The primary objectives of the present study were to investigate whether the co expression of human (h)RIC 3 with human α7 nicotinic acetylcholine receptor in HEK 293 cells facilitates functional expression of the α7 nicotinic acetylcholine receptor. Subsequent to transfection, western blotting and polymerase chain reaction were used to test the expression of α7 nicotinic acetylcholine receptor and RIC-3. The α7 nicotinic acetylcholine receptor was expressed alone or co expressed with hRIC 3 in the HEK 293 cells. Drug containing solution was then applied to the cells via a gravity driven perfusion system. Calcium influx in the cells was analyzed using calcium imaging. Nicotine did not induce calcium influx in the HEK 293 cells expressing human α7 nicotinic acetylcholine receptor only. However, in the cells co expressing human RIC 3 and α7 nicotinic acetylcholine receptor, nicotine induced calcium influx via the α7 nicotinic acetylcholine receptor in a concentration dependent manner (concentration required to elicit 50% of the maximal effect=29.21 µM). Taken together, the results of the present study suggested that the co expression of RIC 3 in HEK 293 cells facilitated the functional expression of the α7 nicotinic acetylcholine receptor.
Approximately 50% of paediatric weight management (WM) programme attendees do not complete their respective programmes. High attrition rates compromise both programme effectiveness and cost-efficiency. Past research has examined pre-intervention participant characteristics associated with programme (non-)completion, however study samples are often small and not representative of multiple demographics. Moreover, the association between programme characteristics and participant engagement is not well known. This study examined participant and programme characteristics associated with engagement in a large, government funded, paediatric WM programme. Engagement was defined as the family's level of participation in the WM programme.
Secondary data analysis of 2948 participants (Age: 10.44 ± 2.80 years, BMI: 25.99 ± 5.79 kg/m(2), Standardised BMI [BMI SDS]: 2.48 ± 0.87 units, White Ethnicity: 70.52%) was undertaken. Participants attended a MoreLife programme (nationwide WM provider) between 2009 and 2014. Participants were classified into one of five engagement groups: Initiators, Late Dropouts, Low- or High- Sporadic Attenders, or Completers. Five binary multivariable logistic regression models were performed to identify participant (n = 11) and programmatic (n = 6) characteristics associated with an engagement group. Programme completion was classified as ≥70% attendance.
Programme characteristics were stronger predictors of programme engagement than participant characteristics; particularly small group size, winter/autumn delivery periods and earlier programme years (proxy for scalability). Conversely, participant characteristics were weak predictors of programme engagement. Predictors varied between engagement groups (e.g. Completers, Initiators, Sporadic Attenders). 47.1% of participants completed the MoreLife programme (mean attendance: 59.4 ± 26.7%, mean BMI SDS change: -0.15 ± 0.22 units), and 21% of those who signed onto the programme did not attend a session.
As WM services scale up, the efficacy and fidelity of programmes may be reduced due to increased demand and lower financial resource. Further, limiting WM programme groups to no more than 20 participants could result in greater engagement. Baseline participant characteristics are poor and inconsistent predictors of programme engagement. Thus, future research should evaluate participant motives, expectations, and barriers to attending a WM programme to enhance our understanding of participant WM engagement. Finally, we suggest that session-by-session attendance is recorded as a minimum requirement to improve reporting transparency and enhance external validity of study findings.
B7-H4 is a co inhibitory molecule of the B7 family, which is expressed on antigen presenting cells (APCs) and is able to limit the T cell immune response. Macrophages act as professional APCs and are important for immunoregulation of the tumor microenvironment in breast cancer. In order to identify the association between the presence of B7 H4 on macrophages and infiltrating ductal carcinoma (IDC), the present study investigated the expression of B7 H4 on macrophages with different polarizations. The expression levels of B7 H4 in IDC tissues were determined using immunohistochemistry, and the expression of B7 H4 on macrophages in the breast IDC microenvironment were determined using western blot analysis and reverse transcription quantitative polymerase chain reaction (RT qPCR). The expression levels of interleukin (IL) 6 and IL 10 were detected in IDC tissues and the supernatants of polarized macrophages using an enzyme linked immunosorbent assay and RT qPCR. The present study demonstrated that B7 H4 was overexpressed in IDC tissues and macrophages. In vitro, M1 and M2 macrophages exhibited different expression levels of B7 H4. IL 6 and  10 exhibited higher expression in the IDC tissues compared with in distal pericarcinomatous tissues. In conclusion, B7 H4 exhibited overexpression in IDC tissues and cultured macrophage cells. Furthermore, M2 macrophages exhibited higher expression levels of B7 H4 compared with the M1 subtype. In addition, IL 6 and  10 may be associated with B7 H4 expression on macrophages of different polarizations in the IDC microenvironment.
Radial artery occlusion (RAO) may occur following transradial catheterization, precluding future use of the vessel for vascular access or as a coronary bypass graft. Recanalization of RAO may occur; however, long-term radial artery patency when revascularization is more likely to be required has not been investigated. Transradial catheterization is usually performed via 5-Fr or 6-Fr catheters. Insertion of 7-Fr sheaths into the radial artery enables complex coronary interventions but may increase the risk of RAO.
To assess the long-term radial artery patency following transradial catheterization via 7-Fr sheaths.
Antegrade radial artery blood flow was assessed by duplex ultrasound in 43 patients who had undergone transradial catheterization via a 7-Fr sheath.
All patients had received intravenous unfractionated heparin with a mean activated clotting time
 (ACT) of 247 ± 56 seconds. Twenty-four patients (56%) had received a glycoprotein IIbIIIa inhibitor and no vascular site complications had occurred. Mean time interval from catheterization to duplex ultrasound was 507 ± 317 days. Asymptomatic RAO was documented in 8 subjects (19%). Reduced body weight was the only significant univariate predictor of RAO (78 ± 11 vs. 89 ± 13 kg, P = 0.031). In a bivariate model using receiver operator characteristic (ROC) curves, the combination of lower weight and shorter ACT offered best prediction of RAO (area under the ROC curve 0.813).
Asymptomatic RAO was found at late follow-up in approximately 1 of 5 patients undergoing transradial catheterization via a 7-Fr sheath and was associated with lower body weight and shorter ACT.
Melanocytes are melanin-producing cells found in skin, hair follicles, eyes, inner ear, bones, heart and brain of humans. They arise from pluripotent neural crest cells and differentiate in response to a complex network of interacting regulatory pathways. Melanins are pigment molecules that are endogenously synthesized by melanocytes. The light absorption of melanin in skin and hair leads to photoreceptor shielding, thermoregulation, photoprotection, camouflage and display coloring. Melanins are also powerful cation chelators and may act as free radical sinks. Melanin formation is a product of complex biochemical events that starts from amino acid tyrosine and its metabolite, dopa. The types and amounts of melanin produced by melanocytes are determined genetically and are influenced by a variety of extrinsic and intrinsic factors such as hormonal changes, inflammation, age and exposure to UV light. These stimuli affect the different pathways in melanogenesis. In this review we will discuss the regulatory mechanisms involved in melanogenesis and explain how intrinsic and extrinsic factors regulate melanin production. We will also explain the regulatory roles of different proteins involved in melanogenesis.
This commentary outlines a protein engineering approach as an alternative to immobilisation developed in our laboratory. We use a recombinant silk protein into which metal active sites can be incorporated to produce solid-state metalloprotein materials. The silk protein directly coordinates to the metal centres providing control over their reactivity akin to that seen in naturally occurring metalloproteins. These solid-state materials are remarkably stable at a range of temperatures and different solvent conditions. I discuss the genesis of this approach and highlight areas where such solid-state materials could find application.
The presence of a highly conserved DNA binding domain in INO80 subfamily predicted that INO80 directly interacts with DNA and we demonstrated its DNA binding activity in vitro. Here we report the consensus motif recognized by the DBINO domain identified by SELEX method and demonstrate the specific interaction of INO80 with the consensus motif. We show that INO80 significantly down regulates the reporter gene expression through its binding motif, and the repression is dependent on the presence of INO80 but not YY1 in the cell. The interaction is lost if specific residues within the consensus motif are altered. We identify a large number of potential target sites of INO80 in the human genome through in silico analysis that can grouped into three classes; sites that contain the recognition sequence for INO80 and YY1, only YY1 and only INO80. We demonstrate the binding of INO80 to a representative set of sites in HEK cells and the correlated repressive histone modifications around the binding motif. In the light of the role of INO80 in homeotic gene regulation in Drosophila as an Enhancer of trithorax and polycomb protein (ETP) that can modify the effect of both repressive complexes like polycomb as well as the activating complex like trithorax, it remains to be seen if INO80 can act as a recruiter of chromatin modifying complexes.
The World Health Organisation recognizes confusing drug names as one of the most common causes of medication errors. Other factors include spelling, phonetic, or packaging similarities.
We presented a case report of an inadvertent administration of a non-ocular pharmaceutical product (Novasone lotion) into the eye of an octogenarian individual, and briefly reviewed the relevant literature.
We discussed prevention strategies to avoid similar ophthalmic medication errors.
As cells proceed along their developmental pathways they make a series of sequential cell fate decisions. Each of those decisions needs to be made in a robust manner so there is no ambiguity in the state of the cell as it proceeds to the next stage. Here we examine the decision made by the Drosophila R7 precursor cell to become a photoreceptor and ask how the robustness of that decision is achieved. The transcription factor Tramtrack (Ttk) inhibits photoreceptor assignment, and previous studies found that the RTK-induced degradation of Ttk was critically required for R7 specification. Here we find that the transcription factor Deadpan (Dpn) is also required; it is needed to silence ttk transcription, and only when Ttk protein degradation and transcriptional silencing occur together is the photoreceptor fate robustly achieved. Dpn expression needs to be tightly restricted to R7 precursors, and we describe the role played by Ttk in repressing dpn transcription. Thus, Dpn and Ttk act as mutually repressive transcription factors, with Dpn acting to ensure that Ttk is effectively removed from R7, and Ttk acting to prevent Dpn expression in other cells. Furthermore, we find that N activity is required to promote dpn transcription, and only in R7 precursors does the removal of Ttk coincide with high N activity, and only in this cell does Dpn expression result.
This study aims to identify enablers or facilitators of HIV testing among Latina immigrant women through qualitative interviews with five community health advocates (CHAs). CHAs act as cultural bridges between Latinos and service providers. We employed a single case-study design using the PEN-3 model as a conceptual framework for situating HIV testing behaviors within cultural and structural contexts of Latina immigrant women's lives. A cross-case analysis of themes revealed that intrinsic enablers of HIV testing included individual trust, confidentiality, intergenerational family participation, and peers. The extrinsic enablers were local community outreach, bicultural/bilingual testing staff, service location and mass media outlets. These results have implications for the cultural competency of health and social service providers, instituting and revising HIV testing outreach interventions, and the earlier identification of women who may have been infected. They offer important insights for promoting other health behaviors among the Latino communities.
The fragile X-related disorders result from expansion of a CGG/CCG microsatellite in the 5' UTR of the FMR1 gene. We have previously demonstrated that the MSH2/MSH3 complex, MutSβ, that is important for mismatch repair, is essential for almost all expansions in a mouse model of these disorders. Here we show that the MSH2/MSH6 complex, MutSα also contributes to the production of both germ line and somatic expansions as evidenced by the reduction in the number of expansions observed in Msh6-/- mice. This effect is not mediated via an indirect effect of the loss of MSH6 on the level of MSH3. However, since MutSβ is required for 98% of germ line expansions and almost all somatic ones, MutSα is apparently not able to efficiently substitute for MutSβ in the expansion process. Using purified human proteins we demonstrate that MutSα, like MutSβ, binds to substrates with loop-outs of the repeats and increases the thermal stability of the structures that they form. We also show that MutSα facilitates binding of MutSβ to these loop-outs. These data suggest possible models for the contribution of MutSα to repeat expansion. In addition, we show that unlike MutSβ, MutSα may also act to protect against repeat contractions in the Fmr1 gene.
Inhaled ultrafine particles (UFP) may induce greater adverse respiratory effects than larger particles occurring in the ambient atmosphere. Due to this potential of UFP to act as triggers for diverse lung injuries medical as well as physical research has been increasingly focused on the exact deposition behavior of the particles in lungs of various probands. Main purpose of the present study was the presentation of experimental and theoretical data of total, regional, and local UFP deposition in the lungs of men and women.
Both experiments and theoretical simulations were carried out by using particle sizes of 0.04, 0.06, 0.08, and 0.10 µm [number median diameters (NMD)]. Inhalation of UFP took place by application of predefined tidal volumes (500, 750, and 1,000 mL) and respiratory flow rates (150, 250, 375, and 500 mL·s(-1)). For male subjects a functional residual capacity (FRC) of 3,911±892 mL was measured, whereas female probands had a FRC of 3,314±547 mL. Theoretical predictions were based on (I) a stochastic model of the tracheobronchial tree; (II) particle transport computations according to a random walk algorithm; and (III) empirical formulae for the description of UFP deposition.
Total deposition fractions (TDF) are marked by a continuous diminution with increasing particle size. Whilst particles measuring 0.04 µm in size deposit in the respiratory tract by 40-70%, particles with a size of 0.10 µm exhibit deposition values ranging from 20% to 45%. Except for the largest particles studied here TDF of female probands are higher than those obtained for male probands. Differences between experimental and theoretical results are most significant for 0.10 µm particles, but never exceed 20%. Predictions of regional
 (extrathoracic, tracheobronchial, alveolar) UFP deposition show clearly that females tend to develop higher tracheobronchial and alveolar deposition fractions than males. This discrepancy is also confirmed by airway generation-specific deposition, which is permanently higher in women than in men.
From the experimental data and modeling predictions it can be concluded that females bear a slightly higher potential to develop lung insufficiencies after exposure to UFP than males. Besides higher deposition fractions occurring in female subjects, also total lung deposition dose is noticeably enhanced.
Circular RNAs (circRNAs) are a naturally occurring type of universal and diverse endogenous noncoding RNAs which unlike linear RNAs, have covalently linked ends. They are usually stable, abundant, conserved RNA molecules and often exhibit tissue/developmental-stage specific expression. Functional circRNAs have been identified to act as microRNA sponges and RNA-binding protein (RBP) sequestering agents as well as transcriptional regulators. These multiple functional roles elicit a great potential for circRNAs in biological applications. Emerging evidence shows that circRNAs play important roles in several diseases, particularly in cancer where they act through regulating protein expression of the pivotal genes that are critical for carcinogenesis. The presence of abundant circRNAs in saliva, exosomes and clinical standard blood samples will make them potential diagnostic or predictive biomarkers for diseases, particularly for cancer development, progression and prognosis. Here, we review the current literature and provide evidence for the impact of circRNAs in cancers and their potential significance in cancer prognosis and clinical treatment.
The role of microRNAs (miRNAs) in infectious diseases is becoming more and more apparent, and the use of miRNAs as a diagnostic tool and their therapeutic application has become the major focus of investigation. The aim of this study was to identify miRNAs involved in the immune signaling of macrophages in response to Arcobacter (A.) butzleri infection, an emerging foodborne pathogen causing gastroenteritis. Therefore, primary human macrophages were isolated and infected, and miRNA expression was studied by means of RNAseq. Analysis of the data revealed the expression of several miRNAs, which were previously associated with bacterial infections such as miR-155, miR-125, and miR-212. They were shown to play a key role in Toll-like receptor signaling where they act as fine-tuners to establish a balanced immune response. In addition, miRNAs which have yet not been identified during bacterial infections such as miR-3613, miR-2116, miR-671, miR-30d, and miR-629 were differentially regulated in A. butzleri-infected cells. Targets of these miRNAs accumulated in pathways such as apoptosis and endocytosis - processes that might be involved in A. butzleri pathogenesis. Our study contributes new findings about the interaction of A. butzleri with human innate immune cells helping to understand underlying regulatory mechanisms in macrophages during infection.
Nonnegative matrix factorization (NMF) is an advanced method for nonnegative feature extraction, with widespread applications. However, the NMF solution often entails to solve a global optimization problem with a nonconvex objective function and nonnegativity constraints. This paper presents a collective neurodynamic optimization (CNO) approach to this challenging problem. The proposed collective neurodynamic system consists of a population of recurrent neural networks (RNNs) at the lower level and a particle swarm optimization (PSO) algorithm with wavelet mutation at the upper level. The RNNs act as search agents carrying out precise local searches according to their neurodynamics and initial conditions. The PSO algorithm coordinates and guides the RNNs with updated initial states toward global optimal solution(s). A wavelet mutation operator is added to enhance PSO exploration diversity. Through iterative interaction and improvement of the locally best solutions of RNNs and global best positions of the whole population, the population-based neurodynamic systems are almost sure able to achieve the global optimality for the NMF problem. It is proved that the convergence of the group-best state to the global optimal solution with probability one. The experimental results substantiate the efficacy and superiority of the CNO approach to bound-constrained global optimization with several benchmark nonconvex functions and NMF-based clustering with benchmark data sets in comparison with the state-of-the-art algorithms.
Biochars have a high variability in chemical composition, which is influenced by pyrolysis conditions and type of biomass. Essential macronutrient P retained in biochar could be released and made available to plants, enhancing plant growth. This study was conducted in order to evaluate whether biochar, produced from agricultural residues, could release P in water, as well as study its potential effect on plant growth and P uptake. Biochar samples were prepared from rice husks, grape pomace and olive tree prunings by pyrolysis at 300 °C and 500 °C. These samples were used for P batch successive leaching experiments in order to determine P release in water. Subsequently, rice husk and grape pomace biochars, produced by pyrolysis at 300 °C, were applied to two temperate soils with highly different pH. A three-month cultivation period of ryegrass (Lolium perenne L.) was studied in threefold replication, while three harvests were accomplished. Treatments comprised control soils (without amendment) and soils amended only with biochar. Results of P leaching tests showed a continuous release of P from all biochars as compared to raw biomass samples, for which the highest P concentrations were detected during the first extraction. Grape pomace and rice husk biochars pyrolyzed at 500 °C showed higher levels of water-extractable P, as compared to their corresponding raw biomass. Biochars, at 500 °C, leached more P in all four extractions, compared to biochars at 300 °C, apart from olive tree prunings biochars, where both pyrolysis temperatures presented a similar trend. Concerning plant yield of ryegrass, rice husk and grape pomace biochars showed positive statistically significant effects on plant yield only in slightly acidic soil in second and third harvests. In terms of P uptake of ryegrass, grape pomace biochars depicted positive significant differences (P < 0.05) in third harvest, in slightly acidic soil, while in first and second harvests positive significant differences were observed in alkaline soil. These results suggest that biochars derived from agricultural residues may act as a source of P in agronomic applications and improve plant growth, although soil conditions may play a significant role.
There is a growing demand for a system in the field of sarcopenia and diabetes research that could be used to evaluate the effects of functional food ingredients that enhance muscle mass/contractile force or muscle glucose uptake. In this study, we developed a new type of in vitro muscle incubation system that systemizes an apparatus for muscle incubation, using an electrode, a transducer, an incubator, and a pulse generator in a compact design. The new system enables us to analyze the muscle force stimulated by the electric pulses and glucose uptake during contraction and it may thus be a useful tool for analyzing the metabolic changes that occur during muscle contraction. The system may also contribute to the assessments of new food ingredients that act directly on skeletal muscle in the treatment of sarcopenia and diabetes.
The immune response is the first defense against pathogens; however, it is very sensitive and can be impacted on by agrochemicals such as carbamate and organophosphate pesticides widely present in the environment. To understand how pesticides can affect immune cell function in vitro, this study investigated the effects of chlorpyrifos (CPF) and carbendazim (CBZ), the most commonly used pesticides worldwide, on murine immune cell (i.e. macrophage) functions, including lysosomal enzyme activity and pro-inflammatory cytokines (IL-1β and TNFα) and nitric oxide (NO) production by isolated mouse peritoneal macrophages. This study showed for the first time that CPF and CBZ dose-relatedly reduced macrophage lysosomal enzyme activity and LPS-induced production of IL-1β, TNFα and NO. In general, the effects caused by CPF appeared more pronounced than those by CBZ. Collectively, these results demonstrated that CPF and CBZ exhibited marked immunomodulatory effects and could act as potent immunosuppressive factors in vitro. This inhibition of macrophage pro-inflammatory function may be an integral part of the underlying mode of action related to pesticide-induced immunosuppression.
Shifts in biodiversity and ecological processes in stream ecosystems in response to rapid climate change will depend on how numerically and functionally dominant aquatic insect species respond to changes in stream temperature and hydrology. Across 253 minimally perturbed streams in eight ecoregions in the western USA, we modeled the distribution of 88 individual insect taxa in relation to existing combinations of maximum summer temperature, mean annual streamflow, and their interaction. We used a heat map approach along with downscaled general circulation model (GCM) projections of warming and streamflow change to estimate site-specific extirpation likelihood for each taxon, allowing estimation of whole-community change in streams across these ecoregions. Conservative climate change projections indicate a 30-40% loss of taxa in warmer, drier ecoregions and 10-20% loss in cooler, wetter ecoregions where taxa are relatively buffered from projected warming
 and hydrologic change. Differential vulnerability of taxa with key functional foraging roles in processing basal resources suggests that climate change has the potential to modify stream trophic structure and function (e.g., alter rates of detrital decomposition and algal consumption), particularly in warmer and drier ecoregions. We show that streamflow change is equally as important as warming in projected risk to stream community composition and that the relative threat posed by these two fundamental drivers varies across ecoregions according to projected gradients of temperature and hydrologic change. Results also suggest that direct human modification of streams through actions such as water abstraction is likely to further exacerbate loss of taxa and ecosystem alteration, especially in drying climates. Management actions to mitigate climate change impacts on stream ecosystems or to proactively adapt to them will require regional calibration, due to geographic variation in insect sensitivity and in exposure to projected thermal warming and hydrologic change.
Developing neural circuits are especially susceptible to environmental perturbation. Endocrine signaling systems such as steroids provide a mechanism to encode physiological changes and integrate function across various biological systems including the brain. 'Neurosteroids' are synthesized and act within the brain across development. There is a long history of steroids sculpting developing neural circuits; more recently, evidence has demonstrated how neurosteroids influence the early potential for neural circuits to organize and transmit precise information via non-canonical receptor types.
MicroRNAs (miRNAs) are a class of small noncoding RNAs that act as efficient post-transcriptional regulators of gene expression. In 2012, the first cross-kingdom miRNA-based interaction had been evidenced, demonstrating that exogenous miRNAs act in a manner of mammalian functional miRNAs. Starting from this evidence, we defined the concept of cross-kingdom functional homology between plant and mammalian miRNAs as a needful requirement for vegetal miRNA to explicit a regulation mechanism into the host mammalian cell, comparable to the endogenous one. Then, we proposed a new dedicated algorithm to compare plant and mammalian miRNAs, searching for functional sequence homologies between them, and we developed a web software called MirCompare. We also predicted human genes regulated by the selected plant miRNAs, and we determined the role of exogenous miRNAs in the perturbation of intracellular interaction networks. Finally, as already performed by Pirrò and coworkers, the ability of MirCompare to select plant miRNAs with functional homologies with mammalian ones has been experimentally confirmed by evaluating the ability of mol-miR168a to downregulate the protein expression of SIRT1, when its mimic is transfected into human hepatoma cell line G2 (HEPG2) cells. This tool is implemented into a user-friendly web interface, and the access is free to public through the website http://160.80.35.140/MirCompare.
RNA capping and decapping are thought to be distinctive features of eukaryotes. The redox cofactor NAD was recently discovered to be attached to small regulatory RNAs in bacteria in a cap-like manner, and Nudix hydrolase NudC was found to act as a NAD-decapping enzyme in vitro and in vivo. Here, crystal structures of Escherichia coli NudC in complex with substrate NAD and with cleavage product NMN reveal the catalytic residues lining the binding pocket and principles underlying molecular recognition of substrate and product. Biochemical mutation analysis identifies the conserved Nudix motif as the catalytic center of the enzyme, which needs to be homodimeric, as the catalytic pocket is composed of amino acids from both monomers. NudC is single-strand specific and has a purine preference for the 5'-terminal nucleotide. The enzyme strongly prefers NAD-linked RNA (NAD-RNA) over NAD and binds to a diverse set of cellular RNAs in an unspecific manner.
The Hippo signaling pathway regulates cellular proliferation and survival, thus exerting profound effects on normal cell fate and tumorigenesis. The pivotal effector of this pathway is YAP1, a transcriptional co-activator amplified in mouse and human cancers where it promotes epithelial-to-mesenchymal transition (EMT) and malignant transformation. The Hippo tumor suppressor pathway has been suggested to inhibit the YAP1 function through serine phosphorylation-induced cytoplasmic retention and degradation. Here we report that the tyrosine188 (Y188) site of YAP1 isoform with 2 WW domains (known as YAP1-2) plays an important role in YAP1-induced cellular transformation. IP-Mass Spectrometry analysis of YAP1 identified the phosphorylation of Y188 but not other tyrosine residues. In contrast to the aberrant 3D acinus formation observed in YAP1-WT transduced cells, overexpression of YAP1-Y188F (non-phosphorylated mimic) displayed normal 3D structures. In addition, knockdown of the endogenous YAP1 in MDA-MB231 breast cancer cells inhibited cell proliferation and migration, which were then successfully rescued by the exogenous YAP1-WT and YAP1-Y188E but not Y188F. Mechanistically, we also demonstrated that YAP1-Y188F had a higher affinity to the upstream negative regulator PTPN14 and was extensively localized in the cytoplasm. Since the Y188 is located in the conserved aromatic core of the WW domain of YAP1, our finding has a wide implication for WW domain signaling in general, where Y phosphorylation may act as a common positive regulator of the complex formation via WW domains. In summary, our results indicate that tyrosine 188 plays an important role in the YAP1-induced cellular transformation and its phosphorylation may intriguingly serve as a positive indicator of YAP1 activation.
there is a lack of public understanding about fetal alcohol spectrum disorders (FASD), and many countries lack policies to deal with FASD concerns. Given the role of news media in disseminating a range of health information, the aim of the current study was to explore the media coverage on alcohol use during pregnancy and FASD, and to identify ways to improve associated health messages.
the current study uses a framing analysis of news media reports about FASD over a 1-year period. Framing analysis seeks to better understand how media messages serve to shape the thoughts, feelings, and decisions of readers.
two frames dominated the media coverage of FASD: a frame of sympathy, and a frame of shame. Some news media encouraged feelings of sympathy for children with FASD, while others encouraged sympathy towards mothers of these children. At the same time, mothers were also portrayed as deserving of shame.
the interrelated frames of sympathy and shame may confuse readers, as they inconsistently hold different parties responsible for the impact of FASD. Media portrayals that encourage women to refrain from alcohol consumption during pregnancy might be more useful than stigmatising and isolating those who do.
practitioners should be aware that conflicting messages about alcohol consumption during pregnancy might lead to shame and confusion, and should encourage openness with mothers to challenge stigma. Guidelines for media reporting should discourage stigmatising frames, and media articles should also consider the role that government, non-government organisations, and the alcohol industry could play for improving FASD shame.
Somali-born women constitute one of the largest groups of childbearing refugee women in Sweden after more than two decades of political violence in Somalia. In Sweden, these women encounter antenatal care that includes routine questions about violence being asked. The aim of the study was to explore how Somali-born women understand and relate to violence and wellbeing during their migration transition and their views on being approached with questions about violence in Swedish antenatal care.
Qualitative interviews (22) with Somali-born women (17) living in Sweden were conducted and analysed using thematic analysis.
A balancing act between keeping private life private and the new welfare system was identified, where the midwife's questions about violence were met with hesitance. The midwife was, however, considered a resource for access to support services in the new society. A focus on pragmatic strategies to move on in life, rather than dwelling on potential experiences of violence and related traumas, was prominent. Social networks, spiritual faith and motherhood were crucial for regaining coherence in the aftermath of war. Dialogue and mutual adjustments were identified as strategies used to overcome power tensions in intimate relationships undergoing transition.
If confidentiality and links between violence and health are explained and clarified during the care encounter, screening for violence can be more beneficial in relation to Somali-born women. The focus on "moving on" and rationality indicates strength and access to alternative resources, but needs to be balanced against risks for hidden needs in care encounters. A care environment with continuity of care and trustful relationships enhances possibilities for the midwife to balance these dual perspectives and identify potential needs. Collaborations between Somali communities, maternity care and social service providers can contribute with support to families in transition and bridge gaps to formal social and care services.
Iron oxide nanowires produced by bacteria (Mariprofundus ferrooxydans) are demonstrated as new multifunctional drug carriers for triggered therapeutics release and cancer hyperthmia applications. Iron oxide nanowires are obtained from biofilm waste in the bore system used to pump saline groundwater into the River Murray, South Australia (Australia) and processed
 into individual nanowires with extensive magnetic properties. The drug carrier capabilities of these iron oxide nanowires (Bac-FeOxNWs) are assessed by loading anticancer drug (doxorubicin, Dox) followed by measuring its elution under sustained and triggered release conditions using alternating magnetic field (AMF). The cytotoxicity of Bac-FeOxNWs assessed in 2D (96 well plate) and 3D (Matrigel) cell cultures using MDA-MB231-TXSA human breast cancer cells and mouse RAW 264.7 macrophage cells shows that these Bac-FeOxNWs are biocompatible even at concentrations as high as 250 μg/mL after 24 h of incubation. Finally, we demonstrate the capabilities of Bac-FeOxNWs as potential hyperthermia agent in 3D culture setup. Application of AMF increased the local temperature by 14 °C resulting in approximately 34% decrease in cell viability. Our results demonstrate that these naturally produced nanowires in the form of biofilm can efficiently act as drug carriers with triggered payload release and magnetothermal heating features for potential anticancer therapeutics applications.
Anodic aluminum oxide (AAO), with a self-ordered hexagonal array, is important for various applications in nanofabrication including as the fabrication of nanotemplates and other nanostructures. With the consideration, there have been many efforts to control the characteristic parameters of porous anodic alumina by adjustment of the anodizing conditions such as the electrolyte, temperature, applied potential, and Al purity. In particular, impurities in Al are changing the morphology of an alumina film; however, the formation mechanism has not yet been explained. In this work, we anodized a high purity (99.999%, Al(high)) and low purity (99.8%, Al(low)) aluminum foil by a two-step anodization process in an oxalic acid solution or phosphoric acid. It was found that the purity of aluminum foil has influenced the morphology of the alumina film resulting in branched and meshed pores. Also, electrochemical analysis indicated that the branched and meshed pores in the low-purity Al foil formed by the presence of impurities. Impurities act as defects and change the general growth mechanism for pore formation by inducing an electric field imbalance during anodization. This work contributes to the research field of topographical chemistry and applied fields including nanofabrication.
The recycling of e-waste has attracted significant attention due to emissions of polychlorinated biphenyls (PCBs) and other contaminants into the environment. We measured PCB concentrations in surface soils, air equilibrated with the soil, and air at 1.5-m height using a fugacity sampler in an abandoned electronic waste (e-waste) recycling site in South China. The total concentrations of PCBs in the soils were 39.8-940 ng/g, whereas the concentrations in air equilibrated with the soil and air at 1.5 m height were 487-8280 pg/m(3) and 287-7380 pg/m(3), respectively. The PCB concentrations displayed seasonal variation; they were higher in winter in the soils and higher in summer in the air, indicating that the emission of PCBs from the soil was enhanced during hot seasons for the relatively high temperature or additional sources, especially for low-chlorinated PCBs. We compared two methods (traditional fugacity model and fugacity sampler) for assessing the soil-air partition coefficients (Ksa) and the fugacity fractions of PCBs. The results suggested that the fugacity sampler provided more instructive and practical estimation on Ksa values and trends in air-soil exchange, especially for low-chlorinated PCBs. The abandoned e-waste burning site still acted as a significant source of PCBs many years after the prohibition on open burning.
Cysteine cathepsins are lysosomal proteases involved in regulation of both normal cellular processes and disease. Biochemical studies with peptide substrates indicate that cathepsins have optimal activity at acidic pH and highly attenuated activity at neutral pH. In contrast, there is mounting evidence that cathepsins have biological roles in environments that have non-acidic pH. To further define the specific pH environments where cathepsins act, we designed bifunctional activity-based probes (ABPs) that allow simultaneous analysis of cathepsin protease activity and pH. We use these probes to analyze the steady-state environment of cathepsin activity in macrophages and to measure dynamic changes in activity and pH upon stimulation. We show that Salmonella typhimurium induces a change in lysosomal pH that ultimately impairs cathepsin activity in both infected cells and a fraction of bystander cells, highlighting a mechanism by which Salmonella can simultaneously flourish within host cells and alter the behavior of nearby uninfected cells.
We developed the transcription factor (TF)-target gene database and the Systems Genetics Network Analysis (SYGNAL) pipeline to decipher transcriptional regulatory networks from multi-omic and clinical patient data, and we applied these tools to 422 patients with glioblastoma multiforme (GBM). The resulting gbmSYGNAL network predicted 112 somatically mutated genes or pathways that act through 74 TFs and 37 microRNAs (miRNAs) (67 not previously associated with GBM) to dysregulate 237 distinct co-regulated gene modules associated with patient survival or oncogenic processes. The regulatory predictions were associated to cancer phenotypes using CRISPR-Cas9 and small RNA perturbation studies and also demonstrated GBM specificity. Two pairwise combinations (ETV6-NFKB1 and romidepsin-miR-486-3p) predicted by the gbmSYGNAL network had synergistic anti-proliferative effects. Finally, the network revealed that mutations in NF1 and PIK3CA modulate IRF1-mediated regulation of MHC class I antigen processing and presentation genes to increase tumor lymphocyte infiltration and worsen prognosis. Importantly, SYGNAL is widely applicable for integrating genomic and transcriptomic measurements from other human cohorts.
The description of the cell life needs not only the knowledge of its genome and proteome, but also of the location of the metal ions and their different complex species in the subcellular compartments, that is of metallome. The cross-talk among these players of the omics' world secures the cellular homeostasis by means of a complex network, the alteration of which may give rise to many diseases. Copper and zinc ions levels regulate protein expression and metal-responsive transcription factors and in many pathologies metal dyshomeostasis induces to aberrant expression of different factors. microRNAs, a class of a small non-coding RNA molecules, act as RNA silencing and post-transcriptional regulators of gene expression contributing also to metal regulatory activity. The aim of the present review is to present how metals dyshomeostasis can be cause of diseases, involving different and specific metal chaperones, metal transporters, metalloproteins, small molecules and metal-sensing transcription factors. Two distinct classes of pathologies, cancer and osteoarthritis, are discussed starting from the metallostasis (metal homeostasis) and turning up to miRNAs regulation. The understanding of post-translational regulation, driven by metal ions sensing, may help to identify more specific targets and drugs to pathologies in which metal ions are involved.
Osteogenesis is a complex process which relies on the coordination of signals and transcription factors. BMP-2/Smad5 signal transduction pathway plays an important role in the process. Recent evidence indicates that microRNAs (miRNAs) act as important post-transcriptional regulators in a large number of biological processes including osteoblast differentiation. In this study, we investigated the effect of miR-106b-5p and miR-17-5p on osteogenic differentiation. We observed an obvious decreasement in miR-106b-5p and miR-17-5p levels during osteogenic differentiation. By using gain- and loss-of function experiments, we noticed that miR-106b-5p and miR-17-5p could suppress the osteogenic differentiation of C2C12 and MC3T3-E1 cells. In addition, we performed bioinformatic analysis, western blot and luciferase reporter assay to confirm that miR-106b-5p and miR-17-5p could regulate Smad5 expression negatively. When we inhibited Smad5 expression by siRNA, the effects of miR-106b-5p and miR-17-5p inhibition on osteogenesis of C2C12 cells could be significantly reversed by Smad5 RNA interference. Furthermore, silencing of miR-106b-5p and miR-17-5p in sham and ovariectomized (OVX) mice increased bone formation and bone mass, resulting in an improvement of trabecular microarchitecture. Taken together, these data showed that miR-106b-5p and miR-17-5p are novel Smad5 regulators, and they have a crucially physiological function in bone formation and osteoblast differentiation.
In folklore medicine Ananas comosus (pineapple) is reputed to act as an abortifacient and in expectant women as a means of inducing labor. Several reports have claimed abortifacient property of A. comosus fruit (ripe or unripe). Ripe fruit has been used orally as traditional medicine in inducing abortion in Kerala state of India while the juice of unripe fruit was used for abortion in Bangladesh. However, scientific evidence supporting the efficacy of pineapple extracts in inducing uterine contractions is clearly lacking.
This study investigated the pharmacological effects of different fractions of pineapple extract with a range of maturities to identify the most potent uterotonic fraction.
The ethanolic crude extracts of pineapple (edible part) were prepared and fractionated through a series of liquid-liquid partitions. Fractions were separately tested on isolated uterine muscle from pregnant SD rats and human pregnant myometrium, which were cut into strips along the longitudinal axis of uterus. The strips were mounted
 vertically in organ baths (37°C) and exposed to cumulative addition of fractions (0.1-10mgml(-1)), serotonin (0.05-5µM) and different inhibitors to delineate the mechanism of action of the active ingredients of the extract.
Aqueous fraction (F4) possesses uterine stimulant property which was blocked by verapamil but unaffected by indomethacin, prazosin and atosiban. Notably, ketanserin (10µM) diminished the maximal contractile response induced by both F4 and 5HT by 74.3% and 92.1% respectively.
These results may indicate the presence of 5HT or 5HT-like compound(s) and serotonergic pathways may contribute to the uterotonic activity of pineapple extract.
Abnormal development or disturbed functioning of the enteric nervous system (ENS), the intrinsic innervation of the gastrointestinal tract, is associated with the development of neuropathic gastrointestinal motility disorders. Here, we review the underlying molecular basis of these disorders and hypothesize that many of them have a common defective biological mechanism. Genetic burden and environmental components affecting this common mechanism are ultimately responsible for disease severity and symptom heterogeneity. We believe that they act together as the fulcrum in a seesaw balanced with harmful and protective factors, and are responsible for a continuum of symptoms ranging from neuronal hyperplasia to absence of neurons.
In the last 10 years, there has been a major change in the treatment of lung cancer (LC). The discovery of activating mutations in the epidermal growth factor receptor (EGFR) in some histological subtypes of LC and its sensitivity to tyrosine kinase inhibitors (TKI) has represented a substantial advance in the treatment of this entity. Until then, the only available option to treat this type of tumour was based on chemotherapy, with a small but significant benefit in terms of survival and quality of life. The arrival of new agents that act against activating EGFR mutations gave rise to the era of precision medicine with targeted therapies able to act on the origin of the tumour, thus providing a therapeutic benefit while minimizing adverse effects and delaying administration of chemotherapy. In addition, this has produced a change in the diagnostic paradigm of lung cancer (as well as in that of all tumours), with a shift from a purely histological diagnosis to a classification of tumours based on their mutational characteristics. This shift has been made possible by the development of technologies allowing complex DNA analysis. Together with the efforts of researchers from all over the world, these techniques allow continued discovery of genetic alterations that could be the target of new drugs as well as definition of the mechanisms of activity and resistance to treatments. This extraordinary development of targeted therapies cannot change the fact that metastatic lung cancer continues to be an incurable disease and, at the present time, only a few patients will benefit from targeted therapies. Ongoing research will shed new light on the molecular alterations that give rise to LC and will provide new treatment alternatives for this disease.
The indole alkaloid ibogaine, present in the root bark of the West African rain forest shrub Tabernanthe iboga, has been adopted in the West as a treatment for drug dependence. Treatment of patients requires large doses of the alkaloid to cause hallucinations, an alleged integral part of the patient's treatment regime. However, case reports and case series continue to describe evidences of ataxia, gastrointestinal distress, ventricular arrhythmias and sudden and unexplained deaths of patients undergoing treatment for drug dependence. High doses of ibogaine act on several classes of neurological receptors and transporters to achieve pharmacological responses associated with drug aversion; limited toxicology research suggests that intraperitoneal doses used to successfully treat rodents, for example, have also been shown to cause neuronal injury (purkinje cells) in the rat cerebellum. Limited research suggests lethality in rodents by the oral route can be achieved at approximately 263mg/kg body weight. To consider an appropriate and safe initial dose for humans, necessary safety factors need to be applied to the animal data; these would include factors such as intra- and inter-species variability and for susceptible people in a population (such as drug users). A calculated initial dose to treat patients could be approximated at 0.87mg/kg body weight, substantially lower than those presently being administered to treat drug users. Morbidities and mortalities will continue to occur unless practitioners reconsider doses being administered to their susceptible patients.
Docosahexaenoic acid (DHA, C22:6, ω-3) is a highly polyunsaturated omega-3 fatty acid. It is concentrated in neuronal brain membranes, for which reason it is also referred to as a "brain food". DHA is essential for brain development and function. It plays an important role in improving antioxidant and cognitive activities of the brain. DHA deficiency occurs during aging and dementia, impairs memory and learning, and promotes age-related neurodegenerative diseases, including Alzheimer's disease (AD). For about two decades, we have reported that oral administration of DHA increases spatial memory acquisition, stimulates neurogenesis, and protects against and reverses memory impairment in amyloid β peptide-infused AD rat models by decreasing amyloidogenesis and protects against age-related cognitive decline in the elderly. These results demonstrate a robust link between DHA and cognitive health. Rodents that were fed a diet low in ω-3 polyunsaturated fatty acids, particularly those that were DHA-deficient, frequently suffered from anxiety, depression and memory impairment. Although the exact mechanisms of action of DHA in brain functions are still elusive, a host of mechanisms have been proposed. For example, DHA, which inherently has a characteristic three-dimensional structure, increases membrane fluidity, strengthens antioxidant activity and enhances the expression of several proteins that act as substrates for improving memory functions. It reduces the brain amyloid burden and inhibits in vitro fibrillation and amyloid-induced neurotoxicity in cell-culture model. In this review, we discuss how DHA acts as a molecule with diverse functions.
Alzheimer's disease (AD) is a chronic neurodegenerative disorder characterized by the pathological accumulation of amyloid beta (Aβ) peptides and neurofibrillary tangles containing hyperphosphorylated neuronal tau protein. AD pathology is also characterized by chronic brain inflammation, which promotes disease pathogenesis. In this context, the blood-brain barrier (BBB), a highly specialized endothelial cell membrane that lines cerebral microvessels, represents the interface between neural cells and circulating cells of the immune system. The BBB thus plays a key role in the generation and maintenance of chronic inflammation during AD. The BBB operates within the neurovascular unit (NVU), which includes clusters of glial cells, neurons and pericytes. The NVU becomes dysfunctional during AD, and each of its components may undergo functional changes that contribute to neuronal injury and cognitive deficit. In transgenic animals with AD-like pathology, recent studies have shown that circulating leukocytes migrate through the activated brain endothelium when certain adhesion molecules are expressed, penetrating into the brain parenchyma, interacting with the NVU components and potentially affecting their structural integrity and functionality. Therefore, migrating immune system cells in cerebral vessels act in concert with the modified BBB and may be integrated into the dysfunctional NVU. Notably, blocking the adhesion mechanisms controlling leukocyte-endothelial interactions inhibits both Aβ deposition and tau hyperphosphorylation, and reduces memory loss in AD models. The characterization of molecular mechanisms controlling vascular inflammation and leukocyte trafficking could therefore help to determine the basis of BBB dysfunction during AD and may lead to the development of new therapeutic approaches.
Invasion of hepatocytes by sporozoites is essential for Plasmodium to initiate infection of the mammalian host. The parasite's subsequent intracellular differentiation in the liver is the first developmental step of its mammalian cycle. Despite their biological significance, surprisingly little is known of the signalling pathways required for sporozoite invasion. We report that sporozoite invasion of hepatocytes requires signalling through two second-messengers - cGMP mediated by the parasite's cGMP-dependent protein kinase (PKG), and Ca(2+) , mediated by the parasite's calcium-dependent protein kinase 4 (CDPK4). Sporozoites expressing a mutated form of Plasmodium berghei PKG or carrying a deletion of the CDPK4 gene are defective in invasion of hepatocytes. Using specific and potent inhibitors of Plasmodium PKG and CDPK4, we demonstrate that PKG and CDPK4 are required for sporozoite motility, and that PKG regulates the secretion of TRAP, an adhesin that is essential for motility. Chemical inhibition of PKG decreases parasite egress from hepatocytes by inhibiting either the formation or release of merosomes. In contrast, genetic inhibition of CDPK4 does not significantly decrease the number of merosomes. By revealing the requirement for PKG and CDPK4 in Plasmodium sporozoite invasion, our work enables a better understanding of kinase pathways that act in different Plasmodium stages.
Some neurons have the ability to enhance output voltage to input current with a preferred frequency, which is called resonance. Resonance is thought to be a basis for membrane potential oscillation. Although ion channels responsible
 for resonance have been reported, the precise mechanisms by which these channels work remain poorly understood. We have found that resonance is reduced but clearly present in the inferior olivary neurons of Cav3.1 T-type voltage-dependent Ca(2+) channel knockout (KO) mice. The activation of Cav3.1 channels is strongly membrane potential dependent, but less frequency dependent. Residual resonance in Cav3.1 KO mice is abolished by a hyper-polarization-activated cyclic nucleotide-gated (HCN) channel blocker, ZD7288, and is partially suppressed by voltage-dependent K(+) channel blockers. Resonance is inhibited by ZD7288 in wild-type mice and impaired in HCN1 KO mice, suggesting that the HCN1 channel is essential for resonance. The ZD7288-sensitive current is nearly sinusoidal and strongly frequency dependent. These results suggest that Cav3.1 and HCN1 channels act as amplifying and resonating conductances, respectively.
Leucine-rich repeat kinase 2 (LRRK2) has been linked to several clinical disorders including Parkinson's disease (PD), Crohn's disease, and leprosy. Furthermore in rodents, LRRK2 deficiency or inhibition leads to lysosomal pathology in kidney and lung. Here we provide evidence that LRRK2 functions together with a second PD-associated gene, RAB7L1, within an evolutionarily conserved genetic module in diverse cellular contexts. In C. elegans neurons, orthologues of LRRK2 and RAB7L1 act coordinately in an ordered genetic pathway to regulate axonal elongation. Further genetic studies implicated the AP-3 complex, which is a known regulator of axonal morphology as well as of intracellular protein trafficking to the lysosome compartment, as a physiological downstream effector of LRRK2 and RAB7L1. Additional cell-based studies implicated LRRK2 in the AP-3 complex-related intracellular trafficking of lysosomal membrane proteins. In mice, deficiency of either RAB7L1 or LRRK2 leads to prominent age-associated lysosomal defects in kidney proximal tubule cells, in the absence of frank CNS pathology. We hypothesize that defects in this evolutionarily conserved genetic pathway underlie the diverse pathologies associated with LRRK2 in humans and in animal models.
In the psychological therapies, patient outcomes are not always positive. Some patients leave therapy prematurely (dropout), while others experience deterioration in their psychological well-being.
The sample for dropout comprised patients (n = 10 521) seen by 85 therapists, who attended at least the initial session of one-to-one therapy and completed a Clinical Outcomes in Routine Evaluation-Outcome Measure (CORE-OM) at pre-treatment. The subsample for patient deterioration comprised patients (n = 6405) seen by the same 85 therapists but who attended two or more sessions, completed therapy and returned a CORE-OM at pre-treatment and post-treatment. Multilevel modelling was used to estimate the extent of therapist effects for both outcomes after controlling for patient characteristics.
Therapist effects accounted for 12.6% of dropout variance and 10.1% of deterioration variance. Dropout rates for therapists ranged from 1.2% to 73.2%, while rates of deterioration ranged from 0% to 15.4%. There was no significant correlation between therapist dropout rate and deterioration rate (Spearman's rho = 0.07, p = 0.52).
The methods provide a reliable means for identifying therapists who return consistently poorer rates of patient dropout and deterioration compared with their peers. The variability between therapists and the identification of patient risk factors as significant predictors has implications for the delivery of safe psychological therapy services. Copyright © 2016 John Wiley & Sons, Ltd.
Therapists play an important role in contributing to patient dropout and deterioration, irrespective of case mix. Therapist effects on patient dropout and deterioration appear to act independently. Being unemployed as a patient was the strongest predictor of both dropout and deterioration. Patient risk to self or others was also an important predictor.
Mutations in the isocitrate dehydrogenase-1 gene (IDH1) are common drivers of acute myeloid leukemia (AML) but their mechanism is not fully understood. It is thought that IDH1 mutants act by inhibiting TET2 to alter DNA methylation, but there are significant unexplained clinical differences between IDH1- and TET2-mutant diseases. We have discovered that mice expressing endogenous mutant IDH1 have reduced numbers of hematopoietic stem cells (HSCs), in contrast to Tet2 knockout (TET2-KO) mice. Mutant IDH1 downregulates the DNA damage (DD) sensor ATM by altering histone methylation, leading to impaired DNA repair, increased sensitivity to DD, and reduced HSC self-renewal, independent of TET2. ATM expression is also decreased in human IDH1-mutated AML. These findings may have implications for treatment of IDH-mutant leukemia.
Reactive oxygen species (ROS) have been shown to be toxic but also function as signaling molecules in a process called redox signaling. In seeds, ROS are produced at different developmental stages including dormancy release and germination. Main targets of oxidation events by ROS in cell are lipids, nucleic acids, and proteins. Protein oxidation has various effects on their function, stability, location, and degradation. Carbonylation represents an irreversible and unrepairable modification that can lead to protein degradation through the action of the 20S proteasome. Here, we present techniques which allow the quantification of protein carbonyls in complex protein samples after derivatization by 2,4-dinitrophenylhydrazine (DNPH) and the determination proteasome activity by an activity-based protein profiling (ABPP) using the probe MV151. These techniques, routinely easy to handle, allow the rapid assessment of protein carbonyls and proteasome activity in seeds in various physiological conditions where ROS may act as signaling or toxic elements.
To compare the cost-effectiveness between actinomycin D (Act-D) and methotrexate-folinic acid (MTX-FA) in the treatment of low-risk gestational trophoblastic neoplasia (GTN) in the Thai population.
A comparative cost-effectiveness analysis was performed from a societal perspective. A decision tree model was developed comparing 2 alternative treatment options: initial 5-day Act-D and 8-day MTX-FA. Treatment would be switched to another regimen in case of resistance. The outcome of interest is number of days to remission. Clinical data was obtained from our previous study in which Act-D demonstrated 100% remission rates as compared to 73.6% for MTX-FA. Cost of treatment data, which includes chemotherapeutics, accessory medications, laboratory tests, and hospital fees, was obtained from a university hospital. Patient-related travel cost and opportunity cost due to absence from work were also included. All costs were calculated to 2015 base year.
Costs per treatment cycle were $308.01 and $227.20 US dollars (USD) for 5-day Act-D and 8-day MTX-FA, respectively. Expected time toward treatment completion for Act-D was 12.6 days shorter than for MTX-FA. Expected costs toward remission for initial treatment with Act-D and MTX-FA were $1,078.04 and $1,064.56 USD, respectively, i.e., an incremental cost effectiveness ratio (ICER) of $1.07 USD/day of earlier treatment completion. After sensitivity analysis, remission rate of lower than 72% would make initial treatment with MTX-FA more expensive than with Act-D.
Treatment costs of low-risk GTN are almost equal between the 2 treatment options with different time to remission. Initial treatment with MTX-FA is slightly less expensive, but there is longer time to remission. The ICER of initial treatment with Act-D over MTX-FA is $1.07 USD/day of earlier treatment completion.
A simple one-step method for the extraction of gold from wastes as nanoparticles stabilized by phospholipids is demonstrated. This is achieved by applying an AC voltage for 5s to the gold-containing wastes, which act as the electrodes in a buffer solution containing a dispersed phospholipid (1,2-dioleoyl-sn-glycero-3-phosphocholine, DOPC). This is an environmentally friendly and rapid method for recovering gold from wastes. The extracted gold nanoparticles have significant potential as a catalyst or biomedical material.
Adrenal tumors are quite rare in infancy and childhood with the exception of neuroblastoma. In fact, adrenocortical tumors (ACT) account for only 0.2% of all malignant cancers in children and adolescents. According to a multicenter registry investigation, the median interval between first endocrine symptoms and the diagnosis of ACT is 5months, and death is seen in 38% of patients, who suffer from tumor progression following the diagnosis in about 2½years. The prognosis of pediatric ACC is poor with a 5-year event-free survival of 54%. To face this dreadful scenario, a few decades ago the International Pediatric Adrenocortical Tumor Registry (IPACTR) was established. Moreover, Children's Oncology Group (COG) and National Cancer Institute (NCI) have approved several clinical trials designed to investigate new treatment options in pediatric ACT. In this systematic review, we summarize the diagnostic histopathologic criteria, bio-markers, and clinical trials of this challenging diagnosis. Eleven pediatric ACT trials were reviewed in our investigation. Two out of 11 studies were conducted in Brazil showing apparently an increased rate of germline mutation-related pediatric ACT. A heterogeneous methodology was evident with four non-randomized clinical trials, three prospective cohort studies, and four retrospective case-control studies limiting higher statistical approach. Tumor histology remains the backbone to diagnose ACT creating a common investigative platform and potentially supporting studies aiming to increase international collaborative research,
 which is crucial for this challenging disease.
Facilitation is a powerful approach to support practice change. The purpose of this study is to better understand the facilitation roles exercised by both external facilitators and interprofessional facilitation teams to foster the implementation of change. Building on Dogherty et al.'s taxonomy of facilitation activities, this study uses an organizational development lens to identify and analyze facilitation roles. It includes a concise definition of what interprofessional facilitation teams actually do, thus expanding our limited knowledge of teams that act as change agents. We also investigate the facilitation dynamics between change actors.
We carried out a qualitative analysis of a 1-year process of practice change implementation. We studied four family medicine groups, in which we constituted interprofessional facilitation teams. Each team was supported by one external facilitator and included at least one family physician, one case manager nurse, and health professionals located on or off the family medicine group's site (one pharmacist, plus at least one nutritionist, kinesiologist, or psychologist). We collected our data through focus group interviews with the four teams, individual interviews with the two external facilitators, and case audit documentation. We analyzed both predetermined (as per Dogherty et al., 2012) and emerging facilitation roles, as well as facilitation dynamics.
A non-linear framework of facilitation roles emerged from our data, based on four fields of expertise: change management, project management, meeting management, and group/interpersonal dynamics. We identified 72 facilitation roles, grouped into two categories: "implementation-oriented" and "support-oriented." Each category was subdivided into themes (n = 6; n = 5) for clearer understanding (e.g., legitimation of change/project, management of effective meetings). Finally, an examination of facilitation dynamics revealed eight relational ties occurring within and/or between groups of actors.
Facilitation is an approach used by appointed individuals, which teams can also foster, to build capacity and support practice change. Increased understanding of facilitation roles constitutes an asset in training practitioners such as organizational development experts, consultants, facilitators, and facilitation teams. It also helps decision makers become aware of the multiple roles and dynamics involved and the key competencies needed to recruit facilitators and members of interprofessional facilitation teams.
Many studies have shown that cytotoxic T lymphocyte antigen-4 (CTLA-4) gene variants are associated with several autoimmune diseases particularly type 1 diabetes. Due to the lack of consistent data for this association with type 2 diabetes (T2D), this study explored the possible influence of CTLA-4 gene polymorphisms at -1722 (T/C), -318 (C/T), and +49 (G/A) positions for susceptibility to T2D in relation with neuropathy. One hundred and eleven unrelated patients with T2D [49 patients with diabetic peripheral neuropathy (DPN) and 62 patients without PDN] and 100 healthy ethnic- and gender-matched controls were included in this study. The dimorphisms at -1722 (C/T), -318 (C/T) and +49 (A/G) for CTLA-4 gene were determined using ARMS-PCR. The CTLA-4 (+49 G/G) and (+49 A/A) genotypes were found to be positively and negatively associated with T2D, respectively (p=0.03). The -318 C/T and T/T genotypes were more frequent in patients than controls and -318 C/C genotype was shown to be protective for T2D (p=0.003). ACT and GTT Haplotypes were less and more frequent in controls and patients, respectively (p=3.86×10-7 and p=2.29×10-5). Genotypes distribution among T2D patients with and without DPN compared to healthy controls showed significantly lower frequencies for -318 C/C and +49 A/A genotypes and significantly higher frequencies for -318 C/T and T/T genotypes as well. Our findings indicate that CTLA-4 (+49 A/G) and (-318 C/T) genotypes could be considered as genetic risk factors associated with susceptibility or protection for T2D.
Sialic acids (Sia) are key monosaccharide constituents of sialylated glycoproteins (Sia-GP), human sialylated milk oligosaccharide (Sia-MOS), and gangliosides. Human milk sialylated glycoconjugates (Sia-GC) are bioactive compounds known to act as prebiotics and promote neurodevelopment, immune function, and gut maturation in newborns. Only limited data are available on the Sia content of porcine milk. The objective of this study was to quantitatively determine the total level of Sia N-acetylneuraminic acid (Neu5Ac), N-glycolylneuraminic acid (Neu5Gc), and ketodeoxynonulosonic acid (KDN) in porcine milk and to compare these levels in gilt and sow milk during lactation. Milk from 8 gilts and 22 sows was collected at 3 stages of lactation (colostrum, transition, and mature milk). Standard and experimental samples were derivatized using 1,2-diamino-4,5-methylenedioxy-benzene and analyzed by ultra-high-performance liquid chromatography using a fluorescence detector. The following new findings are reported: (1) Gilt and sow milk contained significant levels of total Sia, with the highest concentration in colostrum (1,238.5 mg/L), followed by transition milk (778.3 mg/L) and mature milk (347.2 mg/L); (2) during lactation, the majority of Sia was conjugated to Sia-GP (41-46%), followed by Sia-MOS (31-42%) and a smaller proportion in gangliosides (12-28%); (3) Neu5Ac was the major form of Sia (93-96%), followed by Neu5Gc (3-6%) and then KDN (1-2%), irrespective of milk fraction or stage of lactation; (4) the concentration of Sia in Sia-GP and Sia-MOS showed a significant decline during lactation, but the level of ganglioside Sia remained relatively constant; (5) mature gilt milk contained a significantly higher concentration of Sia-GP than sow milk. The high concentration of total Sia in porcine milk suggests that Sia-GC are important nutrients that contribute to the optimization of neurodevelopment, immune function, and growth and development in piglets. These findings provide an important rationale for the inclusion of Sia-GC in pig milk replacers to mimic porcine milk composition for the optimal growth and development of piglets.
Humans and other animals are exposed to a wide array of man-made toxicants, many of which act as endocrine disruptors that exhibit differential effects across the lifespan. In humans, while the impact of adult exposure is known for some compounds, the potential consequences of developmental exposure to endocrine disrupting chemicals (EDCs) is more difficult to ascertain. Animal studies have revealed that exposure to EDCs prior to puberty can lead to adult reproductive disease and dysfunction. Specifically, in adult female mice with an early life exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), we demonstrated a transgenerational occurrence of several reproductive diseases that have been linked to endometriosis in women. Herein, we review the evidence for TCDD-associated development of adult reproductive disease as well as known epigenetic alterations associated with TCDD and/or endometriosis. We will also introduce new "Organ-on-Chip" models which, combined with our established murine model, are expected to further enhance our ability to examine alterations in gene-environment interactions that lead to heritable disease.
The NAD(+)-dependent deacetylase SIRT1 plays key roles in numerous cellular processes including DNA repair, gene transcription, cell differentiation, and metabolism. Overexpression of SIRT1 protects against a number of age-related diseases including diabetes, cancer, and Alzheimer's disease. Moreover, overexpression of SIRT1 in the murine brain extends lifespan. A number of small-molecule sirtuin-activating compounds (STACs) that increase SIRT1 activity in vitro and in cells have been developed. While the mechanism for how these compounds act on SIRT1 was once controversial, it is becoming increasingly clear that they directly interact with SIRT1 and enhance its activity through an allosteric mechanism. Here, we present detailed chemical syntheses for four STACs, each from a distinct structural class. Also, we provide a general protocol for purifying active SIRT1 enzyme and outline two complementary enzymatic assays for characterizing the effects of STACs and similar compounds on SIRT1 activity.
User testing evaluates written medicine information (WMI) usability by examining participants' ability to find and understand information. It can also be an effective method to determine how consumers say they will act on information on an over-the-counter (OTC) label.
To examine consumers' proposed behaviors regarding dosage and storage as a measure of a medicine label's usability and consumers' functional health literacy.
User testing of 5 diclofenac OTC labels (by 50 subjects; 10 per label) measured consumers' ability to find and understand key points of information using a 13-item questionnaire. Consumers were required to elaborate on their behavior in regard to 2 additional questions: 1) when they would take diclofenac if they had constant back pain from 8 am (dosage-related) and; 2) where they would store it in their home (storage-related). Responses were transcribed verbatim, and coded by 2 pharmacists.
Appropriate dosing for constant back pain was reported by 29 consumers. However, dosing intervals shorter than the specified 8 h were often reported (n = 19), due to adjusting intervals to accommodate up to the maximum of 8 tablets in 24 h, desire for pain relief, and/or pragmatic dosing (e.g. around bedtime). Only 29 consumers stated completely appropriate storage location examples (e.g. medicine cabinet).
Consumers may act inappropriately on OTC label information about dosage and/or storage, which could potentially
 adversely impact medication use. User testing can contribute to the development of high quality WMI and help identify where label wordings are inappropriate for the health literacy levels of consumers.
This study investigated a novel approach for the synthesis of an integrated ternary nanocomposite which could act as a good photo-catalyst under visible light irradiation for the removal of organic pollutants from aqueous environments. The photo-catalyst included nickel oxide (NiO) as a dopant, and reduced graphene oxide (RGO) as a good carbon basal support for enhancement of the photo-catalytic activity of TiO2. Under irradiation with visible light, the ternary nanocomposite (TiO2/NiO-RGO) system generates e(-)/h(+) pairs, and then reacts with H2O and O2(-) molecules to produce oxy-radicals which can be used for the mineralization of o-chlorophenol from aqueous solution. The characteristic of all photo-catalysts were investigated by UV-Vis analysis, with surface area and pore size measurements by Brunauer-Emmett-Teller (BET), crystallinity by X-ray diffraction (XRD), elemental composition by X-ray photoelectron spectroscopy (XPS), and morphology by scanning electron microscopy with energy dispersive X-ray spectroscopy (SEM/EDX). The functional groups were measured by Fourier transform infrared (FT-IR) spectroscopy before and after o-chlorophenol degradation. TiO2/NiO-RGO was capable of achieving 88.4% photo-degradation of 100 mg/L o-chlorophenol (100 mL) within 8 h with addition of 0.01% H2O2 under visible light irradiation at pH 6.5. The photo-degradation followed a pseudo-first-order reaction. The TiO2/NiO-RGO nanocomposite retained its high removal efficiency, even after four photo-catalytic cycles.
The sulfonamide class of antibiotics has been in continuous use for over 70years. They are thought to act by directly inhibiting dihydropteroate synthase (DHPS), and also acting as prodrugs that sequester pterin pools by forming dead end pterin-sulfonamide conjugates. In this study, eight pterin-sulfonamide conjugates were synthesized using a novel synthetic strategy and their biochemical and microbiological properties were investigated. The conjugates were shown to competitively inhibit DHPS, and inhibition was enhanced by the presence of pyrophosphate that is crucial to catalysis and is known to promote an ordering of the DHPS active site. The co-crystal structure of Yersinia pestis DHPS bound to one of the more potent conjugates revealed a mode of binding that is similar to that of the enzymatic product analog pteroic acid. The antimicrobial activities of the pterin-sulfonamide conjugates were measured against Escherichia coli in the presence and absence of folate precursors and dependent metabolites. These results show that the conjugates have appreciable antibacterial activity and act by an on target, anti-folate pathway mechanism rather than as simple dead end products.
Despite the impact of mental health problems on sickness absence, only few occupational health guidelines addressing these problems are available. Moreover, adherence has found to be suboptimal. To improve adherence to the Dutch guideline on mental health problems a training was developed for Dutch occupational physicians (OPs) focusing on identifying barriers and addressing them. The aim of this study was to provide an overview of the barriers that OPs perceived in adhering to the Dutch guideline on mental health problems as well as their solutions to overcome them.
A qualitative study was conducted using data from the peer group training. Thirty-two (6 groups of 4 to 6) OPs received a multiple-session interactive training over the course of a year, focusing on identifying and addressing barriers, using a Plan-Do-Check-Act approach. Sessions were audio-taped and transcribed verbatim. Thematic content analysis was performed by two researchers with a selection of 50 % (21 out of 42) of the transcripts to identify the perceived barriers and the suggested solutions, using AtlasTi 7.0.
Knowledge-related barriers were perceived regarding the content of all parts of the guideline. Commonly perceived attitude-related barriers were a lack of self-efficacy to perform certain guideline recommendations and difficulties with changing habits and routines. External barriers that were commonly perceived were work-contextual barriers, such as a lack of time/work pressure, tight contracts between occupational health services (OHSs) and employers, and conflicting policy of and a lack of collaboration with other parties (e.g. employer, other healthcare providers). The most often tested solutions by OPs during the training were sharing information, experiences, tips and tricks and referring to existing tools, or developing new tools to facilitate guideline usage.
Dutch OPs perceive a range of knowledge-related, attitude-related and external barriers in adhering to the guideline on mental health problems. The tested solutions during the training particularly seemed to focus on knowledge and attitude-related barriers. To optimally implement this or similar mental health guidelines, it may be important to complement guideline training and education of individual or groups of OPs, with interventions that address external barriers such as changing tight contracts, or improving communication and collaboration with other parties.
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The Medicare Access and CHIP Reauthorization Act (MACRA) replaces the sustainable growth rate with a payment system based on the Merit-Based Incentive Payment System and incentives for alternative payment model participation. It is important that radiologists understand the statutory requirements of MACRA. This includes the nature of the Merit-Based Incentive Payment System composite performance score and its impact on payments. The timeline for MACRA implementation is fairly aggressive and includes a robust effort to define episode groups, which include radiologic services. A number of organizations, including the ACR, are commenting on the structure of MACRA-directed initiatives.
The passage of the Medicare Access and CHIP Reauthorization Act (MACRA) replaces the sustainable growth rate with a payment system based on quality and alternative payment model participation. The general structure of payment under MACRA is included in the statute, but the rules and regulations defining its implementation are yet to be formalized. It is imperative that the radiology profession inform policymakers on their role in health care under MACRA. This will require a detailed understanding of prior legislative and nonlegislative actions that helped shape MACRA. To that end, the authors provide a detailed historical context for payment reform, focusing on the payment quality initiatives and alternative payment model demonstrations that helped provide the foundation of future MACRA-driven payment reform.
GsMTx4 is a selective inhibitor of cationic mechanosensitive ion channels (MSCs) and has helped establish the role of MSCs in cardiac physiology. Inhomogeneous local mechanical stresses due to hypercontracture and swelling during ischemic reperfusion injury (IRI) likely induce elevated MSC activity that can contribute to cation imbalance. The aim of this study was to determine if the D enantiomer of GsMTx4 can act as a cardioprotectant in a mouse IRI model. Ischemia and reperfusion involved ligating a coronary artery followed by release of the ligature. GsMTx4-D was tested by either acute intravenous injection during the ischemic event or by two day pretreatment by intraperitoneal injection, both methods achieving similar results. Based on pharmacokinetic studies, GsMTx4-D dosage was set to achieve expected plasma concentrations between 50 and 5000nM and heart tissue concentrations between 1 and 200nM by intravenous injection. Relative to vehicle injected animals, GsMTx4-D reduced infarct area by ~40% for acute and pretreated animals for both 20 and 45min ischemic challenges. Many indicators of cardiac output were indistinguishable from sham-treated control hearts after GsMTx4-D treatment showing improvement at both 4 and 48h post ischemia, and premature ventricular beats immediately following reperfusion were also significantly reduced. To determine if GsMTx4-D cardioprotection could act directly at the level of cardiomyocytes, we tested its effects in vitro on indicators of IRI damage like cation influx and activation of inflammatory kinases in isolated myocytes cultured under hypoxic conditions. Hypoxia challenged cardiomyocytes treated with 10μM GsMTx4-D showed improved contractility and near normal contraction-related Ca(2+) influx. GsMTx4-D inhibited indicators of ischemic damage such as the apoptotic signaling system JNK/c-Jun, but also inhibited the energy response signaling system Akt kinase. We conclude that GsMTx4-D is a potent cardioprotectant in vivo that may act directly on cardiomyocytes and potentially be useful in multidrug strategies to treat IRI.
Purpose In recognition of the importance of performance measurement and MCH epidemiology leadership to quality improvement (QI) efforts, a plenary session dedicated to this topic was presented at the 2014 CityMatCH Leadership and MCH Epidemiology Conference. This paper summarizes the session and provides two applications of performance measurement to QI in MCH. Description Performance measures addressing processes of care are ubiquitous in the current health system landscape and the MCH community is increasingly applying QI processes, such as Plan-Do-Study-Act (PDSA) cycles,
 to improve the effectiveness and efficiency of systems impacting MCH populations. QI is maximally effective when well-defined performance measures are used to monitor change. Assessment MCH epidemiologists provide leadership to QI initiatives by identifying population-based outcomes that would benefit from QI, defining and implementing performance measures, assessing and improving data quality and timeliness, reporting variability in measures throughout PDSA cycles, evaluating QI initiative impact, and translating findings to stakeholders. MCH epidemiologists can also ensure that QI initiatives are aligned with MCH priorities at the local, state and federal levels. Two examples of this work, one highlighting use of a contraceptive service performance measure and another describing QI for peripartum hemorrhage prevention, demonstrate MCH epidemiologists' contributions throughout. Challenges remain in applying QI to complex community and systems-level interventions, including those aimed at improving access to quality care. Conclusion MCH epidemiologists provide leadership to QI initiatives by ensuring they are data-informed and supportive of a common MCH agenda, thereby optimizing the potential to improve MCH outcomes.
Respiratory syncytial virus (RSV) is a common cause of lower respiratory tract infections. Immunity to RSV is initiated upon detection of the virus by pattern recognition receptors, such as RIG-I-like receptors. RIG-I-like receptors signal via MAVS to induce the synthesis of proinflammatory mediators, including type I interferons (IFNs), which trigger and shape antiviral responses and protect cells from infection. Alveolar macrophages (AMs) are amongst the first cells to encounter invading viruses and the ones producing type I IFNs. However, it is unclear whether IFNs act to prevent AMs from serving as vehicles for viral replication. In this study, primary AMs from MAVS (Mavs-/-)- or type I IFN receptor (Ifnar1-/-)-deficient mice were exposed to RSV ex vivo. Wild-type (wt) AMs but not Mavs-/- and Ifnar1-/- AMs produced inflammatory mediators in response to RSV. Furthermore, Mavs-/- and Ifnar1-/- AMs accumulated more RSV proteins than wt AMs, but the infection was abortive. Thus, RIG-I-like receptor-MAVS and IFNAR signalling are important for the induction of proinflammatory mediators from AMs upon RSV infection, but this signalling is not central for controlling viral replication. The ability to restrict viral replication makes AMs ideal sensors of RSV infection and important initiators of immune responses in the lung.
Rigorous evaluations of cognitive behavioral self-help books for anxiety in pure self-help contexts are lacking. The present study evaluated the effectiveness of an Acceptance and Commitment Therapy (ACT) self-help workbook for anxiety-related concerns, with no therapist contact, in an international sample. Participants (N=503; 94% mental health diagnosis) were randomized to an immediate workbook (n=256) or wait-list condition (n=247). Assessments at pretreatment, 12weeks, 6months, and 9months evaluated anxiety and related symptoms, quality of life, and ACT treatment processes (e.g., psychological flexibility). Participants in the wait-list arm crossed over to the workbook following the 12-week assessment. The workbook condition yielded significant improvements on all assessments from pre- to posttreatment relative to wait-list, and these gains were maintained at follow-ups. The pattern observed in the wait-list condition was virtually identical to the active treatment arm after receiving the workbook, but not before. Attrition was notable, but supplemental analyses suggested dropout did not influence treatment effects for all but one measure. Overall, findings provide preliminary support for the effectiveness of this self-help workbook and suggest ACT-based self-help bibliotherapy might be a promising low-cost intervention for people experiencing significant anxiety-related concerns.
Living cells respond to their environment using networks of signaling molecules that act as sensors, information processors, and actuators. These signaling systems are highly modular at both the molecular and network scales, and much evidence suggests that evolution has harnessed this modularity to rewire and generate new physiological behaviors. Conversely, we are now finding that, following nature's example, signaling modules can be recombined to form synthetic tools for monitoring, interrogating, and controlling the behavior of cells. Here we highlight recent progress in the modular design of synthetic receptors, optogenetic switches, and phospho-regulated proteins and circuits, and discuss the expanding role of combinatorial design in the engineering of cellular signaling proteins and networks.
Adult Congenital Heart Disease (ACHD) complicating pregnancy remains a relatively new and evolving field. An acceptance by paediatric cardiologists of the importance of working alongside their colleagues dealing with adult care as their patients get older is vital to ensure that these patients are provided with seamless continuity of care. One might have expected that as ACHD cardiologists increasingly forge ties with obstetricians who manage high risk pregnancy so that together they provide care for their mutual patients, we would see the mortality and morbidity of pregnancy in women with heart disease decline. Sadly this is yet to be the case and cardiac disease remains the leading single indirect cause of maternal death in the developed world. These disappointing figures should act as wake up call not only to the profession but also to those involved in commissioning and funding such services. Some progress has been made improving the outlook for many women with complex congenital heart disease as they consider embarking upon pregnancy. However, concerns still exist in relation to young patients being lost to follow-up and presenting pregnant without appropriate counselling and optimization of their cardiac condition. Furthermore it is unclear whether there is currently adequate workforce planning to deliver enough trained specialists who have the expertise to work in this area in the future. We submit herewith that further investment is essential if we wish to see improvements in the care of women with heart disease in relation to pregnancy.
This article explores expositions of subjectivity in accounts of postnatal depression (PND). It examines the public narratives of 19 Australian women contributing to a health information website (healthtalkaustralia.org), collected across two Australian qualitative research studies conducted between 2011 and 2014. For the first part of the paper we analysed narrative data using a combination of phenomenological and psychoanalytic techniques. We found that postnatal distress was described in embodied, relational terms and that women depicted their distress as a pre-verbal intrusion into 'known' selves. We interpreted this intrusion as a doubly relational phenomenon - informed at once by a woman's encounter with her infant and her 'body memory' of earlier relational experiences. For the second part we examined how and why women classified this relational distress as PND. We drew on illness narrative literature and recent work on narrative identity to explore why women would want to 'narrate PND' - an apparently antithetical act in an environment where there is a duty to be a good (healthy) mother. We highlight the dual purpose of the public PND narration - as a means of re-establishing a socially sanctioned known self and as a relational act prompted by the heightened relationality of early maternity. Our focus on the salutary aspects of narrating PND, and its links to relational maternal subjectivities, offers a novel contribution to the current literature and a timely analysis of a largely uninterrogated sociocultural phenomenon.
The April 2015 passage of the Medicare Access and Children's Health Insurance Program Reauthorization Act is accelerating the move of the US health care industry from traditional fee-for-service provider payments to alternative payment methods that are focused on value rather than volume of services. Medicaid, private employers, and consumer groups are also developing similar payment models. Learning from the experience of the 27 early accountable care organizations in North Carolina, such as Cornerstone Health Care, will help to accelerate the transformation that will be necessary across the health care delivery ecosystem in our state.
The Patient Protection and Affordable Care Act and the Triple Aim are driving a shift toward value-based care. Significant financial risk is being transferred from commercial insurers and government payers to hospital systems and independent physician groups. Medicare has developed bundled payment programs, but legislative barriers still impede the implementation of value-based health care.
G-quadruplex (G4) with stacked G-tetrads structure is able to bind hemin (iron (III)-protoporphyrin IX) to form a unique type of DNAzyme/RNAzyme with peroxidase-mimicking activity, which has been widely employed in multidisciplinary fields. However, its further applications are hampered by its relatively weak activity compared with protein enzymes. Herein, we report a unique intramolecular enhancement effect of the adjacent adenine (EnEAA) at 3' end of G4 core sequences that significantly improves the activity of G4 DNAzymes. Through detailed investigations of the EnEAA, the added 3' adenine was proved to accelerate the compound I formation in catalytic cycle and thus improve the G4 DNAzyme activity. EnEAA was found to be highly dependent on the unprotonated state of the N1 of adenine, substantiating that adenine might function as a general acid-base catalyst. Further adenine analogs analysis supported that both N1 and exocyclic
 6-amino groups in adenine played key role in the catalysis. Moreover, we proved that EnEAA was generally applicable for various parallel G-quadruplex structures and even G4 RNAzyme. Our studies implied that adenine might act analogously as the distal histidine in protein peroxidases, which shed light on the fundamental understanding and rational design of G4 DNAzyme/RNAzyme catalysts with enhanced functions.
Chronic cold urticaria results in significant morbidity, yet information on its natural history is limited.
We examined the natural history of chronic cold urticaria and its impact on quality of life.
We analysed the characteristics of patients diagnosed with cold urticaria at a community-based specialist allergy practice in the Australian Capital Territory (ACT) between 1995 and 2015. Follow-up data were obtained using a mailed questionnaire. Possible predictive factors of disease severity and symptom duration were evaluated.
A total of 99 patients were assessed with a median age of 42 (range 5-81 years); 63% were female and the median age of onset of symptoms was 22 years. Of 41 questionnaire responders (14 ± 10.9 years follow-up; median 12 years), 5- and 10-year resolution rates were 17.9% ± 6.2% and 24.5% ± 7.2%, respectively. Whereas 22% reported resolution and 23% described improvement, the remaining 55% reported stable or worsening disease. Most individuals relied on lifestyle modification to ameliorate symptoms rather than medication. Risk factors for persistent disease were intercurrent atopic disease (P = 0.025) and those with longer duration of symptoms at the time of initial assessment (P < 0.001). Secondary causes of cold urticaria were identified in only two patients, both with B-cell malignancy.
In a subset of patients, cold urticaria has low rates of spontaneous resolution and results in lifestyle changes and impaired quality of life.
Sewage spills can release antibiotic-resistant bacteria into surface waters, contributing to environmental reservoirs and potentially impacting human health. Vancomycin-resistant enterococci (VRE) are nosocomial pathogens that have been detected in environmental habitats, including soil, water, and beach sands, as well as wildlife feces. However, VRE harboring vanA genes that confer high-level resistance have infrequently been found outside clinical settings in the United States. This study found culturable Enterococcus faecium harboring the vanA gene in water and sediment for up to 3 days after a sewage spill, and the quantitative PCR (qPCR) signal for vanA persisted for an additional week. Culturable levels of enterococci in water exceeded recreational water guidelines for 2 weeks following the spill, declining about five orders of magnitude in sediments and two orders of magnitude in the water column over 6 weeks. Analysis of bacterial taxa via 16S rRNA gene sequencing showed changes in community structure through time following the sewage spill in sediment and water. The spread of opportunistic pathogens harboring high-level vancomycin resistance genes beyond hospitals and into the broader community and associated habitats is a potential threat to public health, requiring further studies that examine the persistence, occurrence, and survival of VRE in different environmental matrices.
Vancomycin-resistant enterococci (VRE) are harmful bacteria that are resistant to the powerful antibiotic vancomycin, which is used as a last resort against many infections. This study followed the release of VRE in a major sewage spill and their persistence over time. Such events can act as a means of spreading vancomycin-resistant bacteria in the environment, which can eventually impact human health.
Pathological proliferation of human airway smooth muscle cells (HASMCs) causes hyperplasia in chronic lung diseases. Signaling pathways that link airway inflammation to HASMC proliferation might provide therapeutic targets for the prevention of airway remodeling and chronic lung diseases. Endothelin-1 (ET-1) signals via endothelin-A- and B-receptors (ETAR, ETBR) to perpetuate HASMC-associated and TNFα-dependent inflammatory processes.
endothelin receptor antagonists (ERAs) suppress HASMC proliferation induced by inflammatory cytokines. HASMCs were stimulated ex vivo with cytokines in the presence or absence of ERAs (ETAR-specific/selective: BQ123, ambrisentan; ETBR-specific: BQ788; non-selective: bosentan, macitentan, ACT-132577) or cytokine-blocking antibodies. Cell counts, DNA-synthesis (BrdU-incorporation assay), cytokine production (ELISA) and ETBR expression (whole-genome microarray data, western blot) were analyzed. ET-1-induced HASMC proliferation and DNA-synthesis were reduced by protein kinase inhibitors and ETAR-specific/selective ERAs but not by BQ788. TNFα-induced HASMC proliferation and DNA-synthesis were reduced by all ERAs. TNFα induced ET-1 and ETBR expression. TNFα- and ET-1-induced GM-CSF releases were both reduced by BQ123 and BQ788. TNFα- and ET-1-induced IL-6 releases were both reduced by BQ123 but not by BQ788. Combined but not single blockade of GM-CSF-receptor-α-chain and IL-6 reduced TNFα- and ET-1-induced HASMC proliferation and DNA-synthesis. Combined but not single treatment with GM-CSF and IL-6 induced HASMC proliferation and DNA-synthesis in the presence of ET-1. In conclusion, TNFα induces HASMC proliferation via ET-1/GM-CSF/IL-6. ETBR requires up-regulation by TNFα to mediate ET-1 effects on HASMC proliferation. This signaling cascade links airway inflammation to HASMC-associated remodeling processes and is sensitive to ERAs. Therefore, ERAs could prevent inflammation-induced airway smooth muscle hyperplasia.
An extensive body of literature provides evidence supporting the effectiveness of assertive community treatment (ACT) with regard to non-forensic outcome measures, such as number of hospital admissions and length of stay. However, research findings on the effectiveness of ACT for forensic outcome measures, such as rearrests or detentions, is much less clear. The present review, therefore, focuses on the application of ACT in forensic populations, combining key elements of ACT with elements of forensic rehabilitation models. Specifically, a review of the literature was conducted using a systematic methodology in an attempt to combine evidence-based elements of 40 years of research on regular ACT with elements of forensic rehabilitation models. Results reveal limited yet promising evidence in support of the effectiveness of forensic ACT for forensic outcome measures. Implications for future research and clinical practice are discussed.
MicroRNAs (miRNAs) play significant roles in multiple diseases by regulating the expression of their target genes. Type 2 diabetes mellitus (T2DM) is a chronic endocrine and metabolic disease with complex mechanisms. T2DM can result in diabetic osteoporosis (DO), which is characterized by bone loss, decreased bone mineral density and increased bone fractures. The promotion of osteogenic differentiation of osteoblasts is an effective way to treat osteoporosis. In the present study, high glucose (HG) and free fatty acids (FFA) were employed to mimic T2DM in MC3T3-E1 cells. To induce osteogenic differentiation, MC3T3-E1 cells were cultured in osteogenic medium. The results showed that osteogenic differentiation was significantly suppressed by HG and FFA. We found that miR-132 expression was significantly upregulated and much higher in HG-FFA-induced cells than other selected miRNAs, indicating that miR-132 might play an important role in DO. Furthermore, overexpression of miR-132 markedly inhibited the expression of key markers of osteogenic differentiation and alkaline phosphatase (ALP) activity. Reciprocally, inhibition of miR-132 restored osteogenic differentiation, even under treatment with HG-FFA. We also showed that Sirtuin 1 (Sirt1) was one of the target genes of miR-132, whose expression was controlled by miR-132. Ectopic expression of Sirt1 reversed the decrease in osteogenic differentiation caused by miR-132 and HG-FFA. These results demonstrated the direct role of miR-132 in suppressing osteogenic differentiation through downregulating Sirt1. Moreover, we demonstrated that peroxisome proliferator-activated receptor β/δ (PPARβ/δ) was a downstream molecule of Sirt1, and its knockout by PPARβ/δ siRNA significantly abolished the promotive effects of Sirt1 on osteogenic differentiation, indicating that Sirt1 functioned in a PPARβ/δ-dependent manner. Taken together, we provide crucial evidence that miR-132 plays a key role in regulating osteogenic differentiation through Sirt1 in a PPARβ/δ-dependent manner, indicating that miR-132 and Sirt1-PPARβ/δ may act as potential therapeutic targets for T2DM-induced osteoporosis.
Regulation of pH by ameloblasts during amelogenesis is critical for enamel mineralization. We examined the effects of reduced bicarbonate secretion and the presence or absence of amelogenins on ameloblast modulation and enamel mineralization. To that end, the composition of fluorotic and non-fluorotic enamel of several different mouse mutants, including enamel of cystic fibrosis transmembrane conductance regulator-deficient (Cftr null), anion exchanger-2-deficient (Ae2a,b null), and amelogenin-deficient (Amelx null) mice, was determined by quantitative X-ray microanalysis. Correlation analysis was carried out to compare the effects of changes in the levels of sulfated-matrix (S) and chlorine (Cl; for bicarbonate secretion) on mineralization and modulation. The chloride (Cl(-) ) levels in forming enamel determined the ability of ameloblasts to modulate, remove matrix, and mineralize enamel. In general, the lower the Cl(-) content, the stronger the negative effects. In Amelx-null mice, modulation was essentially normal and the calcium content was reduced least. Retention of amelogenins in enamel of
 kallikrein-4-deficient (Klk4-null) mice resulted in decreased mineralization and reduced the length of the first acid modulation band without changing the total length of all acidic bands. These data suggest that buffering by bicarbonates is critical for modulation, matrix removal and enamel mineralization. Amelogenins also act as a buffer but are not critical for modulation.
A portion of patients with diabetes are repeatedly hospitalized for diabetic ketoacidosis (DKA), termed recurrent DKA, which is associated with poorer clinical outcomes. This study evaluated recurrent DKA, fragmentation of care, and mortality throughout six institutions in the Chicago area.
A deidentified Health Insurance Portability and Accountability Act-compliant data set from six institutions (HealthLNK) was used to identify 3,615 patients with DKA (ICD-9 250.1x) from 2006 to 2012, representing 5,591 inpatient admissions for DKA. Demographic and clinical data were queried. Recurrence was defined as more than one DKA episode, and fragmentation of health care was defined as admission at more than one site.
Of the 3,615 patients, 780 (21.6%) had recurrent DKA. Patients with four or more DKAs (n = 211) represented 5.8% of the total DKA group but accounted for 26.3% (n = 1,470) of the encounters. Of the 780 recurrent patients, 125 (16%) were hospitalized at more than one hospital. These patients were more likely to recur (odds ratio [OR] 2.96; 95% CI 1.99, 4.39; P < 0.0001) and had an average of 1.88-times the encounters than nonfragmented patients. Although only 13.6% of patients died of any cause during the study period, odds of death increased with age (OR 1.06; 95% CI 1.05, 1.07; P < 0.001) and number of DKA encounters (OR 1.28; 95% CI 1.04, 1.58; P = 0.02) after adjustment for age, sex, insurance, race, fragmentation, and DKA visit count. This study was limited by lack of medical record-level data, including comorbidities without ICD-9 codes.
Recurrent DKA was common and associated with increased fragmentation of health care and increased mortality. Further research is needed on potential interventions in this unique population.
Biological invasions are widely acknowledged as a major threat to global biodiversity. Species from all major taxonomic groups have become invasive. The range of impacts of invasive taxa and the overall magnitude of the threat is increasing. Plants comprise the biggest and best-studied group of invasive species. There is a growing debate; however, regarding the nature of the alien plant threat-in particular whether the outcome is likely to be the widespread extinction of native plant species. The debate has raised questions on whether the threat posed by invasive plants to native plants has been overstated. We provide a conceptual framework to guide discussion on this topic, in which the threat posed by invasive plants is considered in the context of a progression from no impact through to extinction. We define six thresholds along the 'extinction trajectory', global extinction being the final threshold. Although there are no documented examples of either 'in the wild' (Threshold 5) or global extinctions (Threshold 6) of native plants that are attributable solely to plant invasions, there is evidence that native plants have crossed or breached other thresholds along the extinction trajectory due to the impacts associated with plant invasions. Several factors may be masking where native species are on the trajectory; these include a lack of appropriate data to accurately map the position of species on the trajectory, the timeframe required to definitively state that extinctions have occurred and management interventions. Such interventions, focussing mainly on Thresholds 1-3 (a declining population through to the local extinction of a population), are likely to alter the extinction trajectory of some species. The critical issue for conservation managers is the trend, because interventions must be implemented before extinctions occur. Thus the lack of evidence for extinctions attributable to plant invasions does not mean we should disregard the broader threat.
Geminin exerts two distinct molecular roles. Geminin negatively regulates DNA replication licensing through the direct interaction with Cdt1 to prevent re-replication in proliferating cells. Geminin also regulates chromatin remodeling through the direct interaction with Brahma/Brg1 to maintain undifferentiated states of stem cells. We previously uncovered that Polycomb-group complex 1 and Hoxb4/Hoxa9, well-known intrinsic factors that are essential for maintaining the hematopoietic stem cell (HSC) activity, alternatively act as ubiquitin-proteasome systems for Geminin protein to reduce the protein expression level, and sustain the HSC activity. Thus, Geminin is presumed to play an important role in determining cell fate, i.e., turning on and off cellular quiescence and proliferation/differentiation, in HSCs. We recently generated recombinant cell-penetrating Geminin (CP-Geminin), enabling rapid incorporation and withdraw of Geminin protein in cells. CP-Geminin may be useful in regulating the cell cycle and chromatin configuration. In this article, we summarize current information on the molecular functions of Geminin and the regulatory system for Geminin protein expression, and argue for the molecular role of Geminin in cell fate determination of HSCs, and future perspective of a new technology for manipulating the activities of HSCs and cancer stem cells (CSCs).
Neural α7 nicotinic acetylcholine receptors (α7 nAChRs) emerged as a potential pharmacologic target for treating cognitive deficits in schizophrenia and Alzheimer's disease. Experiments modeling these dysfunctions, as well as clinical evidence, demonstrate the relatively consistent procognitive effects of α7 nAChR agonists. One preclinical observation supporting the procognitive role of α7 nAChRs is their ability to modulate neuronal network oscillations closely associated with learning and memory, especially hippocampal oscillations. Due to the high degree of structural similarity between α7 nACh and 5-HT receptors, the majority of α7 nAChR agonists to date also act as 5-HT3 antagonists. To address this confounding property and determine the relevance of α7 nAChR agonist binding to 5-HT3 receptors in modulating hippocampal activity, we tested two well-described α7 nAChR agonists, PNU-282987 and FRM-17874, in mice lacking α7 nAChRs (α7 knock-out, α7KO) using the brainstem simulation-elicited hippocampal theta oscillation assay. Under urethane anesthesia both agonists at equivalent doses demonstrated efficacy in wild-type (WT) mice, significantly enhancing theta power and theta phase-gamma amplitude coupling as compared to saline treated control mice. These effects are comparable to those seen with drugs clinically used to treat Alzheimer's disease. Although α7KO mice showed no alterations in elicited hippocampal oscillations, both α7 nAChR agonists failed to enhance theta power or theta phase - gamma amplitude coupling in these mice. Our findings demonstrate that selective activation of α7 nAChRs can modulate hippocampal oscillation, and these receptors are the primary targets of the tested agonists, PNU-282987 and FRM-17874 and likely underlies their observed procognitive activity.
The genome of Bacillus subtilis encodes homologues of the Cid/Lrg network. In other bacterial species, this network consists of holin- and antiholin-like proteins that regulate cell death by controlling murein hydrolase activity. The YsbA protein of B. subtilis is currently annotated as a putative antiholin-like protein that possibly impedes cell death, whereas YwbH is thought to act as holin-like protein. However, the actual functions of YsbA and YwbH in B. subtilis have never been characterized. Therefore, we examined the impact of these proteins on growth and cell death in B. subtilis. We did not find a connection to the regulation of programmed cell death, but instead, our experiments reveal that YsbA and its two-component regulator LytST are essential for growth on pyruvate. Moreover, deletion of ysbA and lytS significantly reduces pyruvate consumption. Our findings suggest that LytST induces ysbA transcription in the presence of pyruvate, and that YsbA is involved in pyruvate utilization presumably by functioning as pyruvate uptake system. We show that B. subtilis excretes pyruvate as overflow metabolite in rich medium, indicating that pyruvate could be a common nutrient in the environment. Hence, YsbA and LytST might play a major role in environmental growth of B. subtilis.
Reprogramming of antigen-specific T lymphocytes into induced pluripotent stem cells (iPSCs) and their subsequent re-differentiation has enabled expansion of functional T lymphocytes in vitro, thus opening up new approaches for immunotherapy of cancer and other diseases. In this study, we have established a robust protocol to reprogram human invariant NKT (Vα24(+) iNKT) cells, which have been shown to act as cellular adjuvants and thus exert anti-tumor activity in mice and humans, and to re-differentiate the iNKT cell-derived iPSCs into functional iNKT cells. These iPSC-derived iNKT cells (iPS-Vα24(+) iNKT cells) can be activated by ligand-pulsed dendritic cells (DCs) and produce a large amount of interferon-γ upon activation, as much as parental Vα24(+) iNKT cells, but exhibit even better cytotoxic activity against various tumor cell lines. The iPS-Vα24(+) iNKT cells possess significant anti-tumor activity in tumor-bearing mice and can activate autologous NK cells upon activation by ligand-pulsed DCs in the NOG mouse model in vivo, further extending their therapeutic potential. This study thus provides a first proof of concept for the clinical application of human iPS-Vα24(+) iNKT cells for cancer immunotherapy. Stem Cells 2016;34:2852-2860.
Few
 studies have examined modifiable psychosocial risk factors for mental disorders among university students, and of these, none have employed measures that correspond to clinical diagnostic criteria. The aim of this study was to examine psychosocial and demographic risk factors for major depression and generalised anxiety disorder (GAD) in a sample of Australian university students.
An anonymous web-based survey was distributed to undergraduate and postgraduate students at a mid-sized Australian university. A range of psychosocial and demographic risk factors were measured, and logistic regression models were used to examine significant predictors of major depression and GAD.
A total of 611 students completed the survey. The prevalence of major depression and GAD in the sample was 7.9 and 17.5 %, respectively. In terms of demographic factors, the risk of depression was higher for students in their first year of undergraduate study, and the risk of GAD was higher for female students, those who moved to attend university, and students experiencing financial stress. In terms of psychosocial factors, students with experience of body image issues and lack of confidence were at significantly greater risk of major depression, and feeling too much pressure to succeed, lack of confidence, and difficulty coping with study was significantly associated with risk of GAD.
University students experience a range of unique psychosocial stressors that increase their risk of major depression and GAD, in addition to sociodemographic risk factors. It is important to examine psychosocial factors, as these are potentially modifiable and could be the focus of university-specific mental health interventions.
Perivascular stromal cells (PSCs) are a recently identified cell type that comprises a small percentage of the platelet derived growth factor receptor-β+ cells within the CNS perivascular space. PSCs are activated following injury to the brain or spinal cord, expand in number and contribute to fibrotic scar formation within the injury site. Beyond fibrosis, their high density in the lesion core makes them a potential significant source of signals that act on neural cells adjacent to the lesion site.
Our developmental analysis of PSCs, defined by expression of Collagen1a1 in the maturing brain, revealed that PSCs first appear postnatally and may originate from the meninges. PSCs express many of the same markers as meningeal fibroblasts, including expression of the retinoic acid (RA) synthesis proteins Raldh1 and Raldh2. Using a focal brain ischemia injury model to induce PSC activation and expansion, we show a substantial increase in Raldh1+/Raldh2+ PSCs and Raldh1+ activated macrophages in the lesion core. We find that RA levels are significantly elevated in the ischemic hemisphere and induce signaling in astrocytes and neurons in the peri-infarct region.
This study highlights a dual role for activated, non-neural cells where PSCs deposit fibrotic ECM proteins and, along with macrophages, act as a potentially important source of RA, a potent signaling molecule that could influence recovery events in a neuroprotective fashion following brain injury.
The colloidal stability of a protein solution during downstream processing, formulation, and storage is a key issue for the biopharmaceutical production process. Thus, knowledge about colloidal solution characteristics, such as the tendency to form aggregates or high viscosity, at various processing conditions is of interest. This work correlates changes in the apparent diffusion coefficient as a parameter of protein interactions with observed protein aggregation and dynamic viscosity of the respective protein samples. For this purpose, the diffusion coefficient, the protein phase behavior, and the dynamic viscosity in various systems containing the model proteins α-lactalbumin, lysozyme, and glucose oxidase were studied. Each of these experiments revealed a wide range of variations in protein interactions depending on protein type, protein concentration, pH, and the NaCl concentration. All these variations showed to be mirrored by changes in the apparent diffusion coefficient in the respective samples. Whereas stable samples with relatively low viscosity showed an almost linear dependence, the deviation from the concentration-dependent linearity indicated both an increase in the sample viscosity and probability of protein aggregation. This deviation of the apparent diffusion coefficient from concentration-dependent linearity was independent of protein type and solution properties for this study. Thus, this single parameter shows the potential to act as a prognostic tool for colloidal stability of protein solutions.
Synthetic cannabinoids are new psychoactive substances (NPS) acting as agonists at the cannabinoid receptors. The aminoalkylindole-type synthetic cannabinoid naphthalen-1-yl-(1-pentylindol-3-yl)methanone (JWH-018) was among the first to appear on the illicit drug market and its metabolism has been extensively investigated. The N-pentyl side chain is a major site of human cytochrome P450 (CYP)-mediated oxidative metabolism, and the ω-carboxylic acid metabolite appears to be a major in vivo human urinary metabolite. This metabolite is, however, not formed to any significant extent in human liver microsomal (HLM) incubations raising the possibility that the discrepancy is due to involvement of cytosolic enzymes. Here we demonstrate in incubations with human liver cytosol (HLC), that JWH-018 ω-OH, but not the JWH-018 parent compound, is a substrate for nicotinamide adenine dinucleotide (NAD(+))-dependent alcohol dehydrogenase (ADH) and aldehyde dehydrogenase (ALDH) enzymes. The sole end-product identified in HLC was the JWH-018 ω-COOH metabolite, while trapping tests with methoxyamine proved the presence of the aldehyde intermediate. ADH/ALDH and UDP-glucuronosyl-transferases (UGT) enzymes may therefore both act on the JWH-018 ω-OH substrate. Finally, we note that for [1-(5-fluoropentyl)indol-3-yl]-naphthalen-1-yl-methanone (AM-2201), the ω-fluorinated analog of JWH-018, a high amount of JWH-018 ω-OH was formed in HLM incubated without NADPH, suggesting that the oxidative defluorination is efficiently catalyzed by non-CYP enzyme(s). The pathway presented here may therefore be especially important for N-(5-fluoropentyl) substituted synthetic cannabinoids, because the oxidative defluorination can occur even if the CYP-mediated metabolism preferentially takes place on other parts of the molecule than the N-alkyl side chain. Controlled clinical studies in humans are ultimately required to demonstrate the in vivo importance of the oxidation pathway presented here.
Ecological models are currently the most used approaches to classify and conceptualise determinants of sedentary behaviour, but these approaches are limited in their ability to capture the complexity of and interplay between determinants. The aim of the project described here was to develop a transdisciplinary dynamic framework, grounded in a system-based approach, for research on determinants of sedentary behaviour across the life span and intervention and policy planning and evaluation.
A comprehensive concept mapping approach was used to develop the Systems Of Sedentary behaviours (SOS) framework, involving four main phases: (1) preparation, (2) generation of statements, (3) structuring (sorting and ranking), and (4) analysis and interpretation. The first two phases were undertaken between December 2013 and February 2015 by the DEDIPAC KH team (DEterminants of DIet and Physical Activity Knowledge Hub). The last two phases were completed during a two-day consensus meeting in June 2015.
During the first phase, 550 factors regarding sedentary behaviour were listed across three age groups (i.e., youths, adults and older adults), which were reduced to a final list of 190 life course factors in phase 2 used during the consensus meeting. In total, 69 international delegates, seven invited experts and one concept mapping consultant attended the consensus meeting. The final framework obtained during that meeting consisted of six clusters of determinants: Physical Health and Wellbeing (71% consensus), Social and Cultural Context (59% consensus), Built and Natural Environment (65% consensus), Psychology and Behaviour (80% consensus), Politics and Economics (78% consensus), and Institutional and Home Settings (78% consensus). Conducting studies on Institutional Settings was ranked as the first research priority. The view that this framework captures a system-based map of determinants of sedentary behaviour was expressed by 89% of the participants.
Through an international transdisciplinary consensus process, the SOS framework was developed for the determinants of sedentary behaviour through the life course. Investigating the influence of Institutional and Home Settings was deemed to be the most important area of research to focus on at present and potentially the most modifiable. The SOS framework can be used as an important tool to prioritise future research and to develop policies to reduce sedentary time.
Falciparum malaria persists in hard-to-reach areas or demographic groups that are missed by conventional healthcare systems but could be reached by trained community members in a malaria post (MP). The main focus of a MP is to provide uninterrupted and rapid access to rapid diagnostic tests (RDTs) and artemisinin-based combination therapy (ACT) too all inhabitants of a village. RDTs allow trained community members to perform malaria diagnosis accurately and prescribe appropriate treatment, reducing as much as possible any delay between the onset of fever and treatment. Early treatment with ACT and with a low-dose of primaquine prevents further transmission from human to mosquito. A functioning MP represents an essential component of
 any malaria elimination strategy. Implementing large-scale, high-coverage, community-based early diagnosis and treatment through MPs requires few technological innovations but relies on a very well structured organization able to train, supervise and supply MPs, to monitor activity and to perform strict malaria surveillance.
Physical Activity (PA) occurs in several behavioral domains (e.g., sports, active transport), and is affected by distinct environmental factors. By filtering objective PA using children's school schedules, daily PA can be separated into more conceptually meaningful domains. We used an ecological design to investigate associations between "playability" of 21 school-environments and children's objectively measured after-school PA. We also examined to what extent distinct time-periods after-school and the distance from children's residence to their school influenced this association.
PA was measured in 587 8-11 year-old children by accelerometers, and separated in four two-hour time-periods after-school. For each school-environment, standardized playability-scores were calculated based on standardized audits within 800 m network buffers around each school. Schools and children's residences were geocoded, and we classified each child to be residing in 400, 800, 1600, or >1600 m crow-fly buffers from their school. The influence of network-distance buffers was also examined using the same approach.
Playability was associated with light PA and moderate-to-vigorous PA after-school, especially in the time-period directly after-school and among children who lived within 800 m from their school. Playability explained approximately 30% of the after-school PA variance between schools. Greater distance from children's residence to their school weakened the association between playability of the school-environments and after-school PA.
This study demonstrated that relationships between the conceptually matched physical environment and PA can be revealed and made plausible with increasing specificity in time and distance.
The full potential for research to improve Aboriginal health has not yet been realised. This paper describes an established long-term action partnership between Aboriginal Community Controlled Health Services (ACCHSs), the Aboriginal Health and Medical Research Council of New South Wales (AH&MRC), researchers and the Sax Institute, which is committed to using high-quality data to bring about health improvements through better services, policies and programs. The ACCHSs, in particular, have ensured that the driving purpose of the research conducted is to stimulate action to improve health for urban Aboriginal children and their families. This partnership established a cohort study of 1600 urban Aboriginal children and their caregivers, known as SEARCH (the Study of Environment on Aboriginal Resilience and Child Health), which is now having significant impacts on health, services and programs for urban Aboriginal children and their families. This paper describes some examples of the impacts of SEARCH, and reflects on the ways of working that have enabled these changes to occur, such as strong governance, a focus on improved health, AH&MRC and ACCHS leadership, and strategies to support the ACCHS use of data and to build Aboriginal capacity.
Indole and indazole synthetic cannabinoids (SCs) featuring l-valinate or l-tert-leucinate pendant group have recently emerged as prevalent recreational drugs, and their use has been associated with serious adverse health effects. Due to the limited pharmacological data available for these compounds, 5F-AMBICA, 5F-AMB, 5F-ADB, AMB-FUBINACA, MDMB-FUBINACA, MDMB-CHMICA, and their analogues were synthesized and assessed for cannabimimetic activity in vitro and in vivo. All SCs acted as potent, highly efficacious agonists at CB1 (EC50 = 0.45-36 nM) and CB2 (EC50 = 4.6-128 nM) receptors in a fluorometric assay of membrane potential, with a general preference for CB1 activation. The cannabimimetic properties of two prevalent compounds with confirmed toxicity in humans, 5F-AMB and MDMB-FUBINACA, were demonstrated in vivo using biotelemetry in rats. Bradycardia and hypothermia were induced by 5F-AMB and MDMB-FUBINACA doses of 0.1-1 mg/kg (and 3 mg/kg for 5F-AMB), with MDMB-FUBINACA showing the most dramatic hypothermic response recorded in our laboratory for any SC (>3 °C at 0.3 mg/kg). Reversal of hypothermia by pretreatment with a CB1, but not CB2, antagonist was demonstrated for 5F-AMB and MDMB-FUBINACA, consistent with CB1-mediated effects in vivo. The in vitro and in vivo data indicate that these SCs act as highly efficacious CB receptor agonists with greater potency than Δ(9)-THC and earlier generations of SCs.
This study aims to identify significant pathways in hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC) based on the pathway network strategy. We proposed a pathway network where a protein-protein interaction (PPI) network was integrated with the crosstalk of pathways. Pathway data were first obtained from background PPI network, Reactome pathway database, and common genes between mRNA differentially expressed genes (DEGs), and miRNA target genes of HBV-related HCC. Pathway interactions were subsequently randomly extracted based on gene-gene interactions, and a weight value was assigned to each crosstalk using the Spearman correlation coefficient. Finally, pathways and crosstalk were visualized via Cytoscape to construct the final pathway network. A total of 9 common genes were identified between 396 mRNA DEGs and 400 miRNA target genes, and 17 pathways were identified based on background pathways and common genes. In addition, we constructed a pathway network that included 136 interactions and 17 pathways. The weight value of netrin-1 signaling and regulation of Frizzled proteins (FZD) by ubiquitination was the largest, at 0.228. In conclusion, we identified 17 significant pathways that might act as potential biomarkers of HBV-related HCC. This information may offer some insight into treatment and detection of HBV-related HCC.
Cytochrome P450 monooxygenases (P450s) are some of nature's most ubiquitous and versatile enzymes for performing oxidative metabolic transformations. Their unmatched ability to selectively functionalize inert C-H bonds has led to their increasing employment in academic and industrial settings for the production of fine and commodity chemicals. Many of the most interesting and potentially biocatalytically useful P450s come from microorganisms, where they catalyze key tailoring reactions in natural product biosynthetic pathways. While most of these enzymes act on structurally complex pathway intermediates with high selectivity, they often exhibit narrow substrate scope, thus limiting their broader application. In the present study, we investigated the reactivity of the P450 MycCI from the mycinamicin biosynthetic pathway toward a variety of macrocyclic compounds and discovered that the enzyme exhibits appreciable activity on several 16-membered ring macrolactones independent of their glycosylation state. These results were corroborated by performing equilibrium substrate binding experiments, steady-state kinetics studies, and X-ray crystallographic analysis of MycCI bound to its native substrate mycinamicin VIII. We also characterized TylHI, a homologous P450 from the tylosin pathway, and showed that its substrate scope is severely restricted compared to MycCI. Thus, the ability of the latter to hydroxylate both macrocyclic aglycones and macrolides sets it apart from related biosynthetic P450s and highlights its potential for developing novel P450 biocatalysts with broad substrate scope and high regioselectivity.
Epidemiological studies have demonstrated that the human immunodeficiency virus (HIV)-1 drug-resistant rate among injecting drug users is higher than that in other HIV-1-positive populations, which is generally believed to be largely due to clinical nonadherence. Little is known, however, about whether heroin abuse has a direct impact on the generation of HIV-1 drug-resistant mutations. In this study, we investigated the impacts of morphine, the active metabolite of heroin, on HIV-1 infection/replication and HIV-1 drug-resistant mutations through an in vitro HIV-1-CD4(+) T cell system under selective pressure from two typical antiviral drugs, Lamivudine and Nevirapine. We found that morphine treatment of MT4 cells (a CD4(+) T-cell line) significantly increased HIV-1 III B (a T-tropic viral strain) infection and replication in MT4 cells, and the effect of morphine on HIV-1 was mediated through an opioid receptor. More importantly, our results showed that morphine treatment not only induced more drug-resistant mutations under selective pressure from antiretroviral drugs but also shortened the mutations' generation time, compared with the control groups that were treated with antiretroviral drugs alone. Although the in vivo relevance remains to be determined, these findings provide direct in vitro evidence to support the possibility that heroin abuse itself can act as an independent factor contributing to the generation of HIV-1 drug resistance during clinical antiretroviral therapy. Therapeutic guidelines should consider this issue for heroin users with HIV infection.
Neuroinflammation mediated by microglia cells plays a critical role in the development of Alzheimer's disease. To identify novel natural neuroinflammation inhibitors, a bioactivity-guided phytochemical research was performed on the traditional Chinese medicine "Awei", that exhibited a significant inhibitory effect on nitric oxide production in over-activated microglia cells. The research identified sixteen bioactive sesquiterpene coumarins (two new and fourteen known ones) in the effective extract of Ferula sinkiangensis. Further, the anti-neuroinflammatory
 activities in BV-2 microglial cells were evaluated by monitoring LPS-induced nitric oxide production. In conclusion, the major constituent, (3'S, 5'S, 8'R, 9'S, 10'R)-kellerin (1.5 %, w/w), should be responsible for the anti-neuroinflammatory effect exhibited by Awei. Furthermore, it might be a potential natural therapeutic agent for Alzheimer's disease. The research indicated moreover, that its primary mechanism is the inhibition of mRNA expression of the inflammatory cytokines nitric oxide, tumor necrosis factor-α, cyclooxygenase-2, interleukin-6 and interleukin-1β.
A new impedimetric immunosensor for the fast determination of ochratoxin A (OTA) in food samples was developed based on the instant catalyst as enhancer. Initially, the signal tags were prepared via co-immobilization of anti-OTA antibody and amine-terminated dendrimer (PAMAM) on the graphene oxide nanosheets through the covalent interaction, which were utilized as a good platform for combining manganese ion (anti-OTA-GO-PAMAM-Mn(2+)). Upon target OTA introduction, a competitive-type immunoreaction was implemented between the analyte and the immobilized OTA-BSA on the electrode for the anti-OTA antibody on the graphene oxide nanosheets labels. After a competitive immunoassay format, the anti-OTA-GO-PAMAM-Mn(2+) were captured onto the electrode surface, which could induce the in situ formation of MnO2via classical redox reaction between Mn(2+) and KMnO4 on the immunesensing platform. Moreover, the generated MnO2 nanoparticles act as efficient catalyst could catalyze the 4-chloro-1-naphthol (4-CN) oxidation without H2O2 to generate an insoluble precipitation on the platform. Under the optimal conditions, the instant catalyst based impedimetric immunosensor displayed a wide dynamic working range between 0.1pgmL(-1) and 30ngmL(-1). The detection limit (LOD) of the assay was 0.055pgmL(-1). The developed method exhibited high selectivity and can be used for the determination of OTA in real red wine samples.
Brassinosteroids (BRs) are a group of steroid molecules perceived at the cell surface and that act as plant hormones. Since their discovery as crucial growth substances, BRs were mainly studied for their action in above ground organs and the BR signaling pathway was largely uncovered in the context of hypocotyl elongation. However, for the past two years, most of the exciting findings on BR signaling have been made using roots as a model. The Arabidopsis root is a system of choice for cell biology and allowed detailed characterization of BR perception at the cell membrane. In addition, a series of elegant articles dissected how BRs act in tissue specific manners to control root growth and development.
Adenylate kinases (ADK) are key enzymes that maintain the energetic balance in cellular compartments by catalyzing the reaction: AMP + ATP↔2 ADP. Here, we analyzed the chloroplast ADK 3 from the green alga, Chlamydomonas reinhardtii for the first time. This enzyme bears a C-terminal extension that is highly similar to the C-terminal end of the intrinsically disordered protein CP12 that plays a major role in the redox regulation of key enzymes of the Calvin-Benson cycle like glyceraldehyde 3-phosphate dehydrogenase (GAPDH) and phosphoribulokinase. The only other known example of a CP12-like extension is found in the GapB isoform of GAPDH, where it is responsible for the autonomous redox regulation of the higher plant A2 B2 GAPDH. In this study, we show that the CP12-like tail is not involved in the redox regulation of ADK 3, but contributes greatly to its stability, and is essential for the post-translational modification of the Cys221 residue by glutathione. This report highlights the fact that the C-terminal part of the CP12 protein can act as a moonlighting, intrinsically disordered module conferring additional capabilities to the proteins to which it is added.
Adenylate kinase (ADK, EC 2.7.4.3) and glyceraldehyde 3-phosphate dehydrogenase (GAPDH, EC 1.2.1.13).
ASBTRACT Increased rates of cholesterol and lipid synthesis have long been recognized as important aspects of the metabolic rewiring that occurs during cancerous transformation. Many genes encoding enzymes involved in cholesterol and fatty acid biogenesis are transcriptional targets of the sterol regulatory element-binding proteins (SREBPs). The SREBPs act as a hub for metabolic and proliferation-related signals; their activity is the focus of a tug-of-war between tumor suppressors, who generally inhibit SREBP function, and oncogenes, who often promote, and rely on, SREBP activity. The Hippo pathway plays a central role in coordinating cell proliferation and organ size, whereas p53 is a crucial tumor suppressor that maintains metabolic homeostasis and orchestrates cellular stress responses. Together, the Hippo and p53 signaling pathways cooperate on multiple levels to fine-tune SREPB activity and regulate cholesterol/lipid levels. Cholesterol biosynthesis inhibitors such as statins are appealing conceptually, but have yet to show an indisputable effect on cancer development. Fortunately, the complex regulation surrounding the Hippo-p53-SREBP network potentially provides a broad interface for additional novel cancer-targeting interventions.
The issue of home care for older people is concerned with availability of information.
To compare delivery of electronic health record (EHR) in home care for older people.
An applied-comparative library study was conducted in 2015. The study population included Canada, Australia, England, Denmark and Taiwan. Data were extracted from literature related to EHR on home care and older people.
The main functions included collection, documentation of lab and imaging results. Common data elements were demographic information, prescriptions and nursing observations. Security needs were identified according to the Personal Information Protection and Electronic Document Act, enacted in Canada and the Privacy Act 1988 in Australia.
The basic functions of EHR are determined as collection, documentation and retrieval of information. It is recommended that legislation protects access to information on personal health and implementation of a national unique identifier applicable to shared data.
Perhydroquinoline 4, the product of a Raney-cobalt mediated reductive cyclization reaction, was readily converted into the cis-ring-fused perhydroquinoline 15 that could be epimerized to its trans-fused counterpart 2 on sequential treatment with iodosylbenzene then sodium borohydride. Tetracycle 2 is an advanced intermediate associated with a recently reported total synthesis of the alkaloid kopsihainanine A (1).
Astragalus membranaceus BUNGE (AM; huáng qí) has been widely used as a medicinal herb for different kinds of diseases. AM treatment in vitro enhance sperm motility and ameliorates testicular toxicity, it has demonstrated the ability as a potential treatment for male infertility. In order to gain further insights on the molecular understanding of how AM enhances spermatogenesis, this study investigated whether AM has an affect on sperm parameters associated with cAMP response element modulator (CREM) and activator of CREM in testis (ACT) expression. Five-week-old male ICR mice were divided into four groups; control group and three different concentrations of AM treated groups. Each group was treated for 5 days a week for 5 weeks. Testis samples were collected for real time quantitative PCR and western blot analysis. Epididymis was taken out and used for sperm analysis using the computer assisted semen analysis (CASA) system. To facilitate expression of genes required for spermatogenesis, it is controlled by fine-tuning of CREM and its coactivator, ACT. AM treatment promotes CREM and ACT mRNA expression and also protein expression compared to control. AM enhances sperm values such as sperm count and motility compared to control. Overall, the study highlights, the ability of AM to increases CREM and ACT expression to facilitate sperm development and semen quality.
Physical inactivity is the third leading cause of the burden of disease for Australian Aboriginal adults. The neighborhood environment and social support are known to influence physical activity (PA) participation. This study examined these factors in relation to achieving PA recommendations in Aboriginal and non-Aboriginal Australians. Cross-sectional data from the 2010 Social, Economic, and Environmental Factor (SEEF) Study in New South Wales, Australia were used to estimate adjusted odds ratios (OR) for Aboriginal versus non-Aboriginal participants for PA-related attributes, including achieving PA recommendations. ORs for achieving PA recommendations were estimated in both groups. Overall, 63.1% of Aboriginal (n = 314) and 65.4% of non-Aboriginal (n = 59,175) participants met PA recommendations. Odds of healthy sleep duration were lower, and receiving GP advice to be active was higher, among Aboriginal versus non-Aboriginal participants. Aboriginal respondents had higher odds of reporting that the crime rate made it unsafe to walk and that local public transport was inaccessible. They had higher odds of disagreeing they have local shops, footpaths or free/low cost recreation facilities. PA correlates were similar in both groups. The factors relating to PA were similar in Aboriginal and non-Aboriginal people. Neighborhood and social features were less PA-favorable for Aboriginal participants suggesting multiple possible avenues for increasing PA in this older population group.
Bauxite mining is not known to most Malaysian except recently due to environmental pollution issues in Kuantan, Pahang. Potential impacts are expected to go beyond physical environment and physical illness if the situation is not controlled. Loss of economic potentials, and the presence of unpleasant red dust causing mental distress, anger and
 community outrage. More studies are needed to associate it with chronic physical illness. While evidences are vital for action, merely waiting for a disease to occur is a sign of failure in prevention. All responsible agencies should focus on a wider aspect of health determinants rather than merely on the occurrence of diseases to act and the need to emphasize on sustainable mining to ensure health of people is not compromised.
To develop the capacity for rapid-cycle improvement at the unit level, a large freestanding children's hospital designated 2 inpatient units with normal patient loads and workforce as pilot "Innovation Units" where frontline staff was trained to lead rigorous improvement portfolios.
Frontline staff received improvement training, and interdisciplinary teams brainstormed ideas for tests of change. Ideas were prioritized using an impact-effort evaluation and an assessment of how they aligned with high-level goals. A template for each test summarized the following: the opportunity for improvement, the test being conducted, dates for the tests, driver diagrams, metrics to measure effects, baseline data, results, findings, and next steps. Successful interventions were implemented and disseminated to other units.
Multidisciplinary staff generated 150 improvement ideas and Innovation Units collectively ran >40 plan-do-study-act cycles. Of the 10 distinct improvement projects, elements of all 10 were deemed "successful" and fully implemented on the unit, and elements from 8 were spread to other units. More than 3 years later, elements of all of the successful improvements are still in practice in some form on the units, and each unit has tested >20 additional improvement ideas, using multiple plan-do-study-act cycles to refine them.
The Innovation Unit model successfully engaged frontline staff in improvement work and established a sustainable system and framework for managing rigorous improvement portfolios at the unit level. Other hospitals and health care delivery settings may find our quality improvement approach helpful, especially because it is rooted in the microsystem of care delivery.
Declarative memories are our so-called daily language memories, which we are able to describe or explicitly experience through the act of remembering. This conscious recollection makes it possible for us to think about the future based on our previous experience (episodic memory) and knowledge (semantic memory). This cognitive function is substantiated by the medial temporal lobe (MTL), a hierarchically organized complex in which the perirhinal cortex and parahippocampal cortex provide item and context information to the hippocampus via the entorhinal cortex, and the hippocampus plays the main role in association and recollection. This conventional view provides an easily understood structure to the declarative memory system. However, neurophysiological studies reporting the activities of single neurons bring a more complicated view. In this article, I review single-unit studies, particularly those focused on the perirhinal cortex and hippocampus, and suggest that association processes for declarative memory are more distributed over the MTL areas. The perirhinal cortex represents both between-domain associations (e.g., item-reward, item-place and item-time) and within-domain associations (e.g., item-item) and contributes to both subcategories of declarative memory (i.e., episodic and semantic memory) in a way that is complementary with the hippocampus.
The year 1965 was critical for US health care policy. In that year, Medicare was created as part of the Social Security Act under President Lyndon B. Johnson after several earlier attempts by Presidents Franklin Roosevelt and Harry Truman. In 1966, the American Medical Association first published a set of standard terms and descriptors to document medical procedures, known as Current Procedural Terminology, or CPT. Fifty years later, though providers have certainly heard the term "CPT code," most would benefit from an enhanced understanding of the historical basis, current structure, and relationship to valuation of Current Procedural Terminology. This article will highlight this evolution, particularly as it relates to neuroradiology.
Defective FUS metabolism is strongly associated with amyotrophic lateral sclerosis and frontotemporal dementia (ALS/FTD), but the mechanisms linking FUS to disease are not properly understood. However, many of the functions disrupted in ALS/FTD are regulated by signalling between the endoplasmic reticulum (ER) and mitochondria. This signalling is facilitated by close physical associations between the two organelles that are mediated by binding of the integral ER protein VAPB to the outer mitochondrial membrane protein PTPIP51, which act as molecular scaffolds to tether the two organelles. Here, we show that FUS disrupts the VAPB-PTPIP51 interaction and ER-mitochondria associations. These disruptions are accompanied by perturbation of Ca(2+) uptake by mitochondria following its release from ER stores, which is a physiological read-out of ER-mitochondria contacts. We also demonstrate that mitochondrial ATP production is impaired in FUS-expressing cells; mitochondrial ATP production is linked to Ca(2+) levels. Finally, we demonstrate that the FUS-induced reductions to ER-mitochondria associations and are linked to activation of glycogen synthase kinase-3β (GSK-3β), a kinase already strongly associated with ALS/FTD.
The notion of "context" has played an important but complicated role in animal learning theory. Some studies have found that contextual stimuli (e.g., conditioning chamber) act much like punctate stimuli, entering into competition with other cues as would be predicted by standard associative learning theories. Other studies have found that contextual stimuli act more like "occasion setters," modulating the associative strength of punctate stimuli without themselves acquiring associative strength. Yet other studies have found that context is often largely ignored, resulting in transfer of performance across context changes. This article argues that these diverse functions of context arise in part from different causal interpretations of the environment. A Bayesian theory is presented that infers which causal interpretation best explains an animal's training history, and hence which function of context is appropriate. The theory coherently accounts for a number of disparate experimental results, and quantitatively predicts the results of a new experiment designed to directly test the theory.
Solvothermal reactions of Cd(OAc)2/Zn(OAc)2 with a new ligand, (pyridin-3-yl)methyl 4-(2-(4-((pyridin-3-yl)methoxy)phenyl)diazenyl)benzoate (L1), under different templates via an in situ ligand transformation reaction produced five coordination polymers, [CdL2(H2O)]n (1), [Cd1.5L3]n (2), [Cd2L4]n (3), [(ZnL2)·H2O]n (4) and {[Zn(1,3-BDC)(L1)]·MeCN·0.5H2O}n (5), where HL = 4-(2-(4-((pyridin-3-yl)methoxy)phenyl)diazenyl)benzoic acid, 1,3-H2BDC = 1,3-benzenedicarboxylic acid. Compound 1 is a three-dimensional (3D) wave-like structure constructed from 4-connected Cd(ii) nodes and L(-) linkers. Compounds 2 and 3 bear similar 2D networks built from metallocyclic [Cd4L4] units. Compound 4 features a wrinkled 2D layer based on metallocyclic [Zn4L4] units. Compound 5 has a novel 1D single-wall metal-organic nanotube (SWMONT) in which the 1,3-BDC ligands act as linkers to connect the [Zn2(L1)2] rings. The results reveal that the different templates have a significant effect on the final structures. Compounds 1-5 exhibited relatively high photocatalytic activity towards the degradation of methylene blue (MB) in aqueous solution under UV-Vis irradiation. The kinetics of the catalytic photodegradation reactions and the stabilities of photocatalysts were also investigated.
Infection by parasites can alter the feeding behaviour of hosts. Some animals seek out substances that can therapeutically clear infections (self-medication), some may seek out resources to recoup resources lost while fighting off infection (compensatory feeding) and others may be manipulated to ingest substances that benefit parasite fitness (parasite manipulation of host). Recent studies have indicated that pathogen-challenged insects can self-medicate by increasing their protein intake relative to carbohydrate, which is thought to act by boosting the insect's immune response. However, increased protein intake could also be due to compensatory feeding or pathogen manipulation of the host, and a rigorous examination of all four of the testable predictions, which is necessary for verifying self-medication behaviour, has not been conducted. The therapeutic behaviour must (1) only be employed by infected individuals and (2) alleviate the potential fitness loss of the infected individual. (3) If an uninfected individual engages in the behaviour, they suffer a decrease in fitness, and lastly, (4) the parasite cannot benefit from the behaviour. In response to baculovirus-challenge (AcMNPV) at 24°C, the cabbage looper, Trichoplusia ni, increased proportional protein intake, by increasing protein intake rather than decreasing carbohydrate intake. Increased protein intake did not benefit virus fitness, but it also did not increase the probability of host survival. Increased proportional protein intake did not occur in response to TnSNPV-challenge at 24°C or in response to AcMNPV-challenge at a higher temperature (32°C), indicating that the virus-induced change in nutrient intake depends on virus identity and temperature. Since virus-challenged T. ni did not show the typical costs associated with infection, the altered nutrient intake is likely to be a compensatory response. Understanding the motivation behind pathogen-induced changes in feeding behaviour could have significant implications
 for determining its importance for species interactions at multiple trophic levels.
Impulsivity and compulsivity have emerged as important dimensional constructs that challenge traditional psychiatric classification systems. Both are present in normal healthy populations where the need to act quickly and repeatedly without hesitation can be highly advantageous. However, when excessively expressed, impulsive and compulsive behavior can lead to adverse consequences and spectrum disorders exemplified by attention-deficit/hyperactivity disorder (ADHD), obsessive compulsive disorder (OCD), autism, and drug addiction. Impulsive individuals have difficulty in deferring gratification and are inclined to 'jump the gun' and respond prematurely before sufficient information is gathered. Compulsivity involves repetitive behavior often motivated by the need to reduce or prevent anxiety, thus leading to the maladaptive perseveration of behavior. Defined in this way, impulsivity and compulsivity could be viewed as separate entities or 'traits' but overwhelming evidence indicates that both may be present in the same disorder, either concurrently or even separately at different time points. Herein we discuss the neural and cognitive heterogeneity of impulsive and compulsive endophenotypes. These constructs map onto distinct fronto-striatal neural and neurochemical structures interacting both at nodal convergent points and as opponent processes highlighting both the heterogeneity and the commonalities of function. We focus on discoveries made using both translational research methodologies and studies exclusively in humans, and implications for treatment intervention in disorders in which impulsive and compulsive symptoms prevail. We emphasize the relevance of these constructs for understanding dimensional psychiatry.
The Wilms' tumor suppressor gene 1 (Wt1) is critically involved in a number of developmental processes in vertebrates, including cell differentiation, control of the epithelial/mesenchymal phenotype, proliferation, and apoptosis. Wt1 proteins act as transcriptional and post-transcriptional regulators, in mRNA splicing and in protein-protein interactions. Furthermore, Wt1 is involved in adult tissue homeostasis, kidney function, and cancer. For these reasons, Wt1 function has been extensively studied in a number of animal models to establish its spatiotemporal expression pattern and the developmental fate of the cells expressing this gene. In this chapter, we review the developmental anatomy of Wt1, collecting information about its dynamic expression in mesothelium, kidney, gonads, cardiovascular system, spleen, nervous system, lung, and liver. We also describe the adult expression of Wt1 in kidney podocytes, gonads, mesothelia, visceral adipose tissue, and a small fraction of bone marrow cells. We have reviewed the available animal models for Wt1-expressing cell lineage analysis, including direct Wt1 expression reporters and systems for permanent Wt1 lineage tracing, based on constitutive or inducible Cre recombinase expression under control of a Wt1 promoter. Finally we provide a number of laboratory protocols to be used with these animal models in order to assess reporter expression.
The Diels-Alder reaction is a quintessential type of [4+2] cycloaddition that remains one of the most intriguing transformations in synthetic chemistry. This reaction has long been envisaged to participate in the biosynthesis of a number of cyclohexene-containing natural products, although the question of whether a bona fide Diels-Alderase exists remains unsolved. In nature, there are remarkably few enzymes known to have the activity of [4+2] cycloaddition. These enzymes are phylogenetically distinct and are often classified according to the specific chemical structures. The variation of protein ancestors and in many cases the instability/complexity of the substrates and products pose a significant challenge in identification of the [4+2] cycloaddition catalysts using general homology-based mining approaches. We here provide the detailed description of the multiple comparison-based strategy and methods for the characterization of two distinct types of dedicated [4+2] cyclases (eg, PyrE3 and PyrI4) in the biosynthesis of spirotetramates and spirotetronates, where they act in tandem for coordinated cross-bridging of a linear polyene intermediate into a enantiomerically pure pentacyclic core. The search of new protein scaffolds with the [4+2] cycloaddition activity could enrich the pool of the candidates for mechanistic examination of a true enzymatic Diels-Alder reaction. The protocols presented in this study would also be applicable to the study of other functionally similar but phylogenetically different proteins, eg, the spiroketal cyclases.
To assess the effect of poor sleep quality on Overweight/Obesity (Ow/Ob) in young subjects, and explore if this association is independent of sleep duration.
Pubmed, EMBASE, and MEDLINE databases were searched for papers on sleep quality and overweight/obesity, focusing on children, adolescents, and young adults. Studies based on subjects with medical/psychological problems or published in languages other than English were excluded. Quality effects model was used to pool studies for meta-analysis.
Findings from the systematic review suggest a link between poor sleep quality and Ow/Ob in young subjects. Pooled estimate (from 26,553 subjects) suggest a role of inadequate sleep (including both short duration and poor quality) in Ow/Ob (OR: 1.27 95% CI: 1.05-1.53). Sub-group-analyses suggest considerably higher odds of Ow/Ob (OR = 1.46, 95% CI: 1.24-1.72) in young subjects with poor sleep quality (independent of duration).
Poor sleep quality seems to be associated with Ow/Ob, and some studies indicate this association to be independent of duration. Therefore, considering only sleep duration might not help in disentangling sleep-obesity association. However, this review is mostly composed of cross-sectional studies. Therefore, a causal link or the stability of the sleep quality and Ow/Ob association could not be established.
MicroRNA-154 (miR-154) was previously reported to be downregulated in several types of human cancers and may act as a tumour suppressor. This study aimed to measure miR-154 levels and determine its clinical significance in human glioma.
This retrospective study analysed fresh human glioma specimens and non-neoplastic brain tissues using real-time quantitative reverse transcription-polymerase chain reaction to determine the relative levels of miR-154. The association between miR-154 levels and various clinicopathological characteristics and survival was analysed.
A total of 115 patients with gliomas and 115 non-neoplastic brain tissues were examined. MiR-154 levels were significantly downregulated in gliomas compared with non-neoplastic brain tissues. Low levels of miR-154 were associated with high World Health Organization grade, large tumour size (≥ 5 cm), a low Karnofsky performance status score (< 80), and a shorter overall survival. Multivariate analyses using the Cox proportional hazards regression model confirmed that decreased miR-154 level was an independent predictor of a poor prognosis.
These results suggest that miR-154 downregulation may be involved in glioma formation and progression, and that miR-154 might serve as a potential prognostic biomarker for patients with this disease.
In June 2010, Rosie, a descendant of the chimpanzees sent into space, and thirteen others were shipped from New Mexico to a laboratory in Texas for possible use in hepatitis research. They were to be the first group of approximately two hundred chimpanzees to be reintroduced to invasive research. These chimpanzees had been in semiretirement for a decade after being removed from an enormous laboratory that was in egregious violation of the Animal Welfare Act. I, along with many bioethicists, scientists, primatologists, and others, have long been arguing against the use of chimpanzees in invasive research on ethical grounds. The United States is now poised to join the rest of the world in ending invasive research on our closest primate relatives.
Sulfur chemistry is of great interest to the atmospheric chemistry of several planets. In the presence of water, oxidized sulfur can lead to new particle formation, influencing climate in significant ways. Observations of sulfur compounds in planetary atmospheres when compared with model results suggest that there are missing chemical mechanisms. Here we propose a novel mechanism for the formation of sulfurous acid, which may act as a seed for new particle formation. In this proposed mechanism, the lowest triplet state of SO2 ((3)B1), which may be accessed by near-UV solar excitation of SO2 to its excited (1)B1 state followed by rapid intersystem crossing, reacts directly with water to form H2SO3 in the gas phase. For ground state SO2, this reaction is endothermic and has a very high activation barrier; our quantum chemical calculations point to a facile reaction being possible in the triplet state of SO2. This hygroscopic H2SO3 molecule may act as a condensation nucleus for water, giving rise to facile new particle formation (NPF).
Among the two leading causes of death in the United States, each responsible for one in every four deaths, heart disease costs Americans $300 billion, while cancer costs Americans $216 billion per year. They also rank among the top three causes of death in Europe and Asia. In 2012 the University of Michigan Center for Public Health and Community Genomics and Genetic Alliance, with the support of the Centers for Disease Control and Prevention Office of Public Health Genomics, hosted a conference in Atlanta, Georgia to consider related action strategies based on public health genomics. The aim of the conference was consensus
 building on recommendations to implement genetic screening for three major heritable contributors to these mortality and cost figures: hereditary breast and ovarian cancer (HBOC), familial hypercholesterolemia (FH), and Lynch syndrome (LS). Genetic applications for these three conditions are labeled with a "Tier 1" designation by the U.S. Centers for Disease Control and Prevention because they have been fully validated and clinical practice guidelines based on systematic review support them.
The conference followed a deliberative sequence starting with nationally recognized clinical and public health presenters for each condition, followed by a Patient and Community Perspectives Panel, working group sessions for each of the conditions, and a final plenary session. The 74 conference participants represented disease research and advocacy, public health, medicine and nursing, genetics, governmental health agencies, and industry. Participants drew on a public health framework interconnecting policy, clinical intervention, surveillance, and educational functions for their deliberations.
Participants emphasized the importance of collaboration between clinical, public health, and advocacy groups in implementing Tier 1 genetic screening. Advocacy groups could help with individual and institutional buy-in of Tier 1 programs. Groups differed on funding strategies, with alternative options such as large-scale federal funding and smaller scale, incremental funding solutions proposed. Piggybacking on existing federal breast and colorectal cancer control programs was suggested. Public health departments need to assess what information is now being collected by their state cancer registries. The groups advised that information on cascade screening of relatives be included in toolkits for use by states. Participants stressed incorporation of family history into health department breast cancer screening programs, and clinical HBOC data into state surveillance systems. The carrying out of universal LS screening of tumors in those with colorectal cancer was reviewed. Expansion of universal screening to include endometrial tumors was discussed, as was the application of guidelines recommending cholesterol screening of children 9-11 years old. States more advanced in terms of Tier 1 testing could serve as models and partners with other states launching screening and surveillance programs. A multidisciplinary team of screening program champions was suggested as a means of raising awareness among the consumer and health care communities. Participants offered multiple recommendations regarding use of electronic health records, including flagging of at-risk family members and utilization of state-level health information exchanges. The paper contains an update of policy developments and happenings for all three Tier 1 conditions, as well as identified gaps.
Implementation of cascade screening of family members for HBOC and FH, and universal screening for LS in CRC tumors has reached a point of readiness within the U.S., with creative solutions at hand. Facilitating factors such as screening coverage through the Patient Protection and Affordable Care Act, and state health information exchanges can be tapped. Collaboration is needed between public health departments, health care systems, disease advocacy groups, and industry to fully realize Tier 1 genetic screening. State health department and disease networks currently engaged in Tier 1 screening can serve as models for the launch of new initiatives.
Wild ungulates may act as reservoirs of various vector borne pathogens that can infect humans and domestic animals. In the present study, blood samples from 196 red deer (Cervus elaphus) from Western Austria (Vorarlberg, Tyrol and Salzburg) were collected on filter paper and tested for Anaplasmataceae, Piroplasmida, Rickettsia and filarioid helminths using molecular tools. Babesia divergens was detected in ten (5.1%) and Anaplasma phagocytophilum in three (1.5%) of the 196 samples. Filarioid helminths, Rickettsia spp. and Theileria spp. were not detected. These findings indicate that red deer may serve as reservoirs of Babesia divergens and Anaplasma phagocytophilum in Western Austria. Further investigations are needed to assess the presence of these pathogens in ticks in this geographical region, and the significance of these pathogens in both animals and humans.
Traditional ecological theory predicts that specialisation can promote speciation; hence, recently derived species are specialists. However, an alternative view is that new species have broad niches, which become narrower and specialised over time. Here, we test these hypotheses using avian brood parasites and three different measures of host specialisation. Brood parasites provide an ideal system in which to investigate the evolution of specialisation, because some exploit more than 40 host species and others specialise on only one. We find that young brood parasite species are smaller and specialise on a narrower range of host sizes, as expected, if specialisation is linked with the generation of new species. Moreover, we show that highly virulent parasites are more specialised, supporting findings in other host-parasite systems. Finally, we demonstrate that different measures of specialisation can lead to different conclusions, and specialisation indices should be designed taking into account the biology of each system.
To examine occupational differences in workplace exposure to secondhand smoke (SHS) among young adults in California.
Data are taken from the 2014 Bay Area Young Adult Health Survey, a probabilistic multimode cross-sectional household survey of young adults, aged 18-26, in Alameda and San Francisco Counties. Respondents were asked whether they had been exposed to SHS 'indoors' or 'outdoors' at their workplace in the previous 7 days and also reported their current employment status, industry and occupation. Sociodemographic characteristics and measures of health perception and behaviour were included in the final model.
Young adults employed in service (p<0.001), construction and maintenance (p<0.01), and transportation and material moving (p<0.05) sectors were more likely to report workplace SHS exposure while those reporting very good or excellent self-rated health were less likely (p<0.001).
Despite California's clean indoor air policy, 33% of young adults in the San Francisco Bay Area still reported workplace SHS exposure in the past week, with those in lower income occupations and working in non-office environments experiencing the greatest exposure. Closing the gaps that exempt certain types of workplaces from the Smoke-Free Workplace Act may be especially beneficial for young adults.
Amyloid light-chain (LC) amyloidosis (AL amyloidosis) is a rare and fatal disease for which there are no approved therapies. In patients with AL amyloidosis, LC aggregates progressively accumulate in organs, resulting in organ failure that is particularly lethal when the heart is involved. A significant obstacle in the development of treatments for patients with AL amyloidosis, as well as for those with any disease that is rare, severe and heterogeneous, has been satisfying traditional clinical trial end points (for example, overall survival or progression-free survival). It is for this reason that many organizations, including the United States Food and Drug Administration through its Safety and Innovation Act Accelerated Approval pathway, have recognized the need for biomarkers as surrogate end points. The international AL amyloidosis expert community is in agreement that the N-terminal fragment of the pro-brain natriuretic peptide (NT-proBNP) is analytically validated and clinically qualified as a biomarker for use as a surrogate end point for survival in patients with AL amyloidosis. Underlying this consensus is the demonstration that NT-proBNP is an indicator of cardiac response in all interventional studies in which it has been assessed, despite differences in patient population, treatment type and treatment schedule. Furthermore, NT-proBNP expression is directly modulated by amyloidogenic LC-elicited signal transduction pathways in cardiomyocytes. The use of NT-proBNP will greatly facilitate the development of targeted therapies for AL amyloidosis. Here, we review the data supporting the use of NT-proBNP, a biomarker that is analytically validated, clinically qualified, directly modulated by LC and universally accepted by AL amyloidosis specialists, as a surrogate end point for survival.
Deprescribing is the term used to describe the process of withdrawal of an inappropriate medication supervised by a clinician. This article presents a discussion of how the Four Principles of biomedical ethics (beneficence, non-maleficence, autonomy, and justice) that may guide medical practitioners' prescribing practices apply to deprescribing medications in older adults. The view of deprescribing as an act creates stronger moral duties than if viewed as an omission. This may explain the fear of negative outcomes which has been reported by prescribers as a barrier to deprescribing. Respecting the autonomy of older adults is complex as they may not wish to be active in the decision-making process; they may also have reduced cognitive function and family members may therefore have to step in as surrogate decision-makers. Informed consent is intended as a process of information giving and reflection, where consent can be withdrawn at any time. However, people are rarely updated on the altered risks and benefits of their long-term medications as they age. Cessation of inappropriate medication use has a large financial benefit to the individual and the community. However, the principle of justice also dictates equal rights to treatment regardless of age.
To incentivize hospitals to provide
 better quality care at a lower cost, the Affordable Care Act of 2010 included the Hospital Readmissions Reduction Program (HRRP), which reduces payments to hospitals with excess 30-day readmissions for Medicare patients treated for certain conditions. We use triple difference estimation to identify the HRRP's effects in Virginia hospitals; this method estimates the difference in changes in readmission over time between patients targeted by the policy and a comparison group of patients and then compares those difference-in-differences estimates in patients treated at hospitals with readmission rates above the national average (i.e., those at risk for penalties) and patients treated at hospitals with readmission rates below or equal to the national average (those not at risk). We find that the HRRP significantly reduced readmission for Medicare patients treated for acute myocardial infarction (AMI). We find no evidence that hospitals delay readmissions, treat patients with greater intensity, or alter discharge status in response to the HRRP, nor do we find changes in the age, race/ethnicity, health status, and socioeconomic status of patients admitted for AMI. Future research on the specific mechanisms behind reduced AMI readmissions should focus on actions by healthcare providers once the patient has left the hospital. Copyright © 2016 John Wiley & Sons, Ltd.
Arctic ecosystems are characterized by a wide range of soil moisture conditions and thermal regimes and contribute differently to the net methane (CH4 ) budget. Yet, it is unclear how climate change will affect the capacity of those systems to act as a net source or sink of CH4 . Here, we present results of in situ CH4 flux measurements made during the growing season 2014 on Disko Island (west Greenland) and quantify the contribution of contrasting soil and landscape types to the net CH4 budget and responses to summer warming. We compared gas flux measurements from a bare soil and a dry heath, at ambient conditions and increased air temperature, using open-top chambers (OTCs). Throughout the growing season, bare soil consumed 0.22 ± 0.03 g CH4 -C m(-2) (8.1 ± 1.2 g CO2 -eq m(-2) ) at ambient conditions, while the dry heath consumed 0.10 ± 0.02 g CH4 -C m(-2) (3.9 ± 0.6 g CO2 -eq m(-2) ). These uptake rates were subsequently scaled to the entire study area of 0.15 km(2) , a landscape also consisting of wetlands with a seasonally integrated methane release of 0.10 ± 0.01 g CH4 -C m(-2) (3.7 ± 1.2 g CO2 -eq m(-2) ). The result was a net landscape sink of 12.71 kg CH4 -C (0.48 tonne CO2 -eq) during the growing season. A nonsignificant trend was noticed in seasonal CH4 uptake rates with experimental warming, corresponding to a 2% reduction at the bare soil, and 33% increase at the dry heath. This was due to the indirect effect of OTCs on soil moisture, which exerted the main control on CH4 fluxes. Overall, the net landscape sink of CH4 tended to increase by 20% with OTCs. Bare and dry tundra ecosystems should be considered in the net CH4 budget of the Arctic due to their potential role in counterbalancing CH4 emissions from wetlands - not the least when taking the future climatic scenarios of the Arctic into account.
In this work, 84 isolates of aeromonads were isolated from water and clinical samples, identified, and characterized. Identification was based on routine phenotyping combined with multiplex PCR. In this study, multiplex PCR was retested and reevaluated and its identification key was enhanced by 17 newly described species and five subspecies. Identification score increased from 36 % (only phenotyping) to 90 % when supported with multiplex PCR. Further description of isolates included detection of eight virulence genes. These genes were overall present in 46 % (act), 2.4 % (ast), 80 % (alt), 40 % (ahh1), 20 % (asa1), 69 % (pla/lip/lipH3/alp-1), 69 % (ser), and 81 % (fla), and no significant differences between water and clinical isolates were found. Results of this work show that the proper combination of different approaches is necessary for final identification of Aeromonas spp. at the species level. Multiplex PCR was shown to have limits in final identification, specifically inability to distinguish four species pairs and one triplet as their gene profiles are identical. However, it seems to be rapid and easy to do method able to support routine biochemical identification in laboratories. Moreover, our results supported previous proposal of reclassification of "Aeromonas hydrophila subsp. dhakensis" and "Aeromonas aquariorum" as identical species.
Aberrant expression of BORIS/CTCFL (Brother of the Regulator of Imprinted Sites/CTCF-like protein) is reported in different malignancies. In this study, we characterized the entire promoter region of BORIS/CTCFL, including the CpG islands, to assess the relationship between BORIS expression and lung cancer. To simplify the construction of luciferase reporter cassettes with various-sized portions of the upstream region, genomic copies of BORIS were isolated using TAR cloning technology. We analyzed three promoter blocks: the GATA/CCAAT box, the CpG islands and the minisatellite region BORIS-MS2. Polymorphic minisatellite sequences were isolated from genomic DNA prepared from the blood of controls and cases. Of the three promoter blocks, the GATA/CCAAT box was determined to be a critical element of the core promoter, while the CpG islands and the BORIS-MS2 minisatellite region were found to act as regulators. Interestingly, the polymorphic minisatellite region BORIS-MS2 was identified as a negative regulator that repressed the expression levels of luciferase reporter cassettes less effectively in cancer cells compared with normal cells. We also examined the association between the size of BORIS-MS2 and lung cancer in a case-control study with 590 controls and 206 lung cancer cases. Rare alleles of BORIS-MS2 were associated with a statistically significantly increased risk of lung cancer (odds ratio, 2.04; 95% confidence interval, 1.02-4.08; and P=0.039). To conclude, our data provide information on the organization of the BORIS promoter region and gene regulation in normal and cancer cells. In addition, we propose that specific alleles of the BORIS-MS2 region could be used to identify the risk for lung cancer.
One of the priorities of the military health care is to improve the system of rationing medical equipment for the hospital unit of the medical service of the Armed Forces in wartime. This is determined the fact that the effectiveness of measures to provide military field hospitals with medical supplies depends on the quality of medical care for the wounded and sick, as well as the level of their return to duty. The article presents the characteristics of modern standards medical supplies procurement of military field hospitals included in the new regulatory legal act of the Russian Federation Ministry of Defence--"Standards of supplies medical supplies medical and pharmaceutical organizations (units) of the Russian Federation on the wartime armed forces", approved and put into effect in 2015 by order of the Minister of Defence of the Russian Federation.
Since 2014, when the Health Insurance Marketplaces (HIMs) authorized by the Patient Protection and Affordable Care Act (ACA) were implemented, considerable premium changes have been observed in the marketplaces across the 50 states and the District of Columbia. This policy brief assesses the changes in average HIM plan premiums from 2014 to 2016, before accounting for subsidies, with an emphasis on the widening variation across rural and urban places. Since this brief focuses on premiums without accounting for subsidies, this is not intended to be an analysis of the "affordability" of ACA premiums, as that would require assessment of premiums, cost-sharing adjustments, and other factors.
In late 2015, California passed the End of Life Option Act (AB 15), which allows residents at the terminal stage of an illness to request a prescription for medications meant to hasten death. As California seeks to implement the law in June 2016, findings from other states that practice aid in dying (AID) may guide implementation. This policy brief provides an overview of the use of AID, outlines outstanding questions about practice and ethics, and recommends steps for improving California's implementation of AB 15. Specifically, the implementation of AB 15 would be improved by adjusting surveillance data-collection requirements and encouraging additional research investment, using the legalization of AID to improve knowledge of and practices for end-of-life care generally, and creating ongoing educational opportunities for providers and the general public.
Clostridium difficile is a global health burden and the leading cause of antibiotic-associated diarrhoea worldwide, causing severe gastrointestinal disease and death. Three well characterised toxins are encoded by this bacterium in two genetic loci, specifically, TcdB (toxin B) and TcdA (toxin A) in the Pathogenicity Locus (PaLoc) and binary toxin (CDT) in the genomically distinct CDT locus (CdtLoc). Toxin production is controlled by regulators specific to each locus. The orphan response regulator, CdtR, encoded within the CdtLoc, up-regulates CDT production. Until now there has been no suggestion that CdtR influences TcdA and TcdB production since it is not carried by all PaLoc-containing strains and CdtLoc is not linked genetically to PaLoc. Here we show that, in addition to CDT, CdtR regulates TcdA and TcdB production but that this effect is strain dependent. Of clinical relevance, CdtR increased the production of TcdA, TcdB and CDT in two epidemic ribotype 027 human strains, modulating their virulence in a mouse infection model. Strains traditionally from animal lineages, notably ribotype 078 strains, are increasingly
 being isolated from humans and their genetic and phenotypic analysis is critical for future studies on this important pathogen. Here we show that CdtR-mediated toxin regulation did not occur in other strain backgrounds, including a ribotype 078 animal strain. The finding that toxin gene regulation is strain dependent highlights the regulatory diversity between C. difficile isolates and the importance of studying virulence regulation in diverse lineages and clinically relevant strains. Our work provides the first evidence that TcdA, TcdB and CDT production is linked by a common regulatory mechanism and that CdtR may act as a global regulator of virulence in epidemic 027 strains.
2,3-Di-O-acetyl-triterpenoic acid derived amides possessing a (2β, 3β) configuration in ring A and two acetyl groups were previously shown to possess high cytotoxicity for human tumor cell lines but to exhibit low cytotoxicity for non-malignant mouse fibroblasts. In this study, augustic acid (1) and 2-epi-corosolic acid (2) were chosen as starting points for the synthesis of analogs. While augustic acid derived 3-quinolinyl amide 9 gave low EC50 values in SRB assays but was cytotoxic for all lines, the isomeric 4-isoquinolinyl amide 21 was very cytotoxic for the tumor cell lines but significantly less cytotoxic for the mouse fibroblasts NIH 3T3. In addition, a triacetylated 4-isoquinolinyl derivative of asiatic acid (28) gave EC50 = 80 nM (for A2780 ovarian cancer cells). As shown by additional experiments (acridine orange/propidium iodide staining, fluorescence spectroscopy and cell cycle investigations) these compounds act mainly by apoptosis.
The synthesis, structural characterization, luminescence properties, and proton conduction performance of a new family of isostructural cationic 2D layered compounds are reported. These have the general formula [Ln(H4NMP)(H2O)2]Cl·2H2O [Ln = La(3+), Pr(3+), Sm(3+), Eu(3+), Gd(3+), Tb(3+), Dy(3+), Ho(3+), H6NMP = nitrilotris(methylphosphonic acid)], and contain Cl(-) as the counterion. In the case of Ce(3+), a 1D derivative, [Ce2(H3NMP)2(H2O)4]·4.5H2O, isostructural with the known lanthanum compound has been isolated by simply crystallization at room temperature. The octa-coordinated environment of Ln(3+) in 2D compounds is composed by six oxygen atoms from three different ligands and two oxygens from each bound water. Two of the three phosphonate groups act as both chelating and bridging linkers, while the third phosphonate group acts solely as a bridging moiety. The materials are stable at low relative humidity at less at 170 °C. However, at high relative humidity transform to other chloride-free phases, including the 1D structure. The proton conductivity of the 1D materials varies in a wide range, the highest values corresponding to the La derivative (σ ≈ 2 × 10(-3) S·cm(-1) at RH 95% and 80 °C). A lower proton conductivity, 3 × 10(-4) S·cm(-1), was measured for [Gd(H4NMP)(H2O)2]Cl·2H2O at 80 °C, which remains stable under the work conditions used. Absorption and luminescence spectra were recorded for selected [Ln(H4NMP)(H2O)2]Cl·2H2O compounds. In all of them, the observed transitions are attributed solely to f-f transitions of the lanthanide ions present, as the H4NMP(2-) organic group has no measurable absorption or luminescence properties.
We analyze ultrasensitivity in a model of Vibrio harveyi quorum sensing. We consider a feedforward model consisting of two biochemical networks per cell. The first represents the interchange of a signaling molecule (autoinducer) between the cell cytoplasm and an extracellular domain and the binding of intracellular autoinducer to cognate receptors. The unbound and bound receptors within each cell act as kinases and phosphotases, respectively, which then drive a second biochemical network consisting of a phosphorylation-dephosphorylation cycle. We ignore subsequent signaling pathways associated with gene regulation and the possible modification in the production rate of an autoinducer (positive feedback). We show how the resulting quorum sensing system exhibits ultrasensitivity with respect to changes in cell density. We also demonstrate how quorum sensing can protect against the noise amplification of fast environmental fluctuations in comparison to a single isolated cell.
An integrable model possessing inhomogeneous ground states is proposed as an effective model of nonuniform quantum condensates such as supersolids and Fulde-Ferrell-Larkin-Ovchinnikov superfluids. The model is a higher-order analog of the nonlinear Schrödinger equation. We derive an n-soliton solution via the inverse scattering theory with elliptic-functional background and reveal various kinds of soliton dynamics such as dark soliton billiards, dislocations, gray solitons, and envelope solitons. We also provide the exact bosonic and fermionic quasiparticle eigenstates and show their tunneling phenomena. The solutions are expressed by a determinant of theta functions.
Terahertz time-domain spectroscopy (THz-TDS) has emerged as a powerful tool for materials characterization and imaging. A trend toward size reduction, higher component integration, and performance improvement for advanced THz-TDS systems is of increasing interest. The use of single semiconducting nanowires for terahertz (THz) detection is a nascent field that has great potential to realize future highly integrated THz systems. In order to develop such components, optimized material optoelectronic properties and careful device design are necessary. Here, we present antenna-optimized photoconductive detectors based on single InP nanowires with superior properties of high carrier mobility (∼1260 cm(2) V(-1) s(-1)) and low dark current (∼10 pA), which exhibit excellent sensitivity and broadband performance. We demonstrate that these nanowire THz detectors can provide high quality time-domain spectra for materials characterization in a THz-TDS system, a critical step toward future application in advanced THz-TDS system with high spectral and spatial resolution.
Crizotinib is an oral inhibitor of anaplastic lymphoma kinase (ALK) with remarkable clinical activity in patients suffering from ALK-rearranged non-small cell lung cancer (NSCLC), accounting to its superiority compared to chemotherapy. Unfortunately, virtually all ALK-rearranged tumors acquire resistance to crizotinib, frequently within one year since the treatment initiation. To date, therapeutic strategies to overcome crizotinib resistance have focused on the use of more potent and structurally different compounds. Second-generation ALK inhibitors such as ceritinib (LDK378), alectinib (CH5424802/RO5424802) and brigatinib (AP26113) have shown relevant clinical activity, consequently fostering their rapid clinical development and their approval by health agencies. The third-generation inhibitor lorlatinib (PF-06463922), selectively active against ALK and ROS1, harbors impressive biological potency; its efficacy in reversing resistance to crizotinib and to other ALK inhibitors is being proven by early clinical trials. The NTRK1-3 and ROS1 inhibitor entrectinib (RXDX-101) has been reported to act against NSCLC harboring ALK fusion proteins too. Despite the quick development of these novel agents, several issues remain to be discussed in the treatment of patients suffering from ALK-rearranged NSCLC. This position paper will discuss the development, the current evidence and approvals, as long as the future perspectives of new ALK inhibitors beyond crizotinib. Clinical behaviors of ALK-rearranged NSCLC vary significantly among patients and differential molecular events responsible of crizotinib resistance account for the most important quote of this heterogeneity. The precious availability of a wide range of active anti-ALK compounds should be approached in a critical and careful perspective, in order to develop treatment strategies tailored on the disease evolution of every single patient.
Senile cataract is a clouding of the lens in the aging eye leading to a decrease in vision. Symptoms may include faded colors, blurry vision, halos around light, trouble with bright lights, and trouble seeing at night. This may result in trouble driving, reading, or recognizing faces. Cataracts are the cause of half of blindness and 33% of visual impairment worldwide. Cataracts result from the deposition of aggregated proteins in the eye lens and lens fiber cells plasma membrane damage which causes clouding of the lens, light scattering, and obstruction of vision. ROS induced damage in the lens cell may consist of oxidation of proteins, DNA damage and/or lipid peroxidation, all of which have been implicated in cataractogenesis. The inner eye pressure (also called intraocular pressure or IOP) rises because the correct amount of fluid can't drain out of the eye. With primary open-angle glaucoma, the entrances to the drainage canals are clear and should be working correctly. The clogging problem occurs further inside the drainage canals, similar to a clogged pipe below the drain in a sink. The excessive oxidative damage is a major factor of the ocular diseases because the mitochondrial respiratory chain in mitochondria of the vital cells is a significant source of the damaging reactive oxygen species superoxide and hydrogen peroxide. However, despite the clinical importance of mitochondrial oxidative damage, antioxidants have been of limited therapeutic success. This may be because the antioxidants are not selectively taken up by mitochondria, but instead are dispersed throughout the body, ocular tissues and fluids' moieties. This work is an attempt to integrate how mitochondrial reactive oxygen species (ROS) are altered in the aging eye, along with those protective and repair therapeutic systems believed to regulate ROS levels in ocular tissues and how damage to these systems contributes to
 age-onset eye disease and cataract formation. Mitochondria-targeted antioxidants might be used to effectively prevent ROS-induced oxidation of lipids and proteins in the inner mitochondrial membrane in vivo. The authors developed and patented the new ophthalmic compositions including N-acetylcarnosine acting as a prodrug of naturally targeted to mitochondria l-carnosine endowed with pluripotent antioxidant activities, combined with mitochondria-targeted rechargeable antioxidant (either MitoVit E, Mito Q or SkQs) as a potent medicine to treat ocular diseases. Such specificity is explained by the fact that developed compositions might be used to effectively prevent ROS-induced oxidation of lipids and proteins in the inner mitochondrial membrane in vivo and outside mitochondria in the cellular and tissue structures of the lens and eye compartments. Mitochondrial targeting of compounds with universal types of antioxidant activity represents a promising approach for treating a number of ROS-related ocular diseases of the aging eye and can be implicated in the management of cataracts and primary open-angle glaucoma.
•This work considers mitochondrial reactive oxygen species (ROS) effects in the aging eye•The excessive oxidative damage is a major factor of the eye diseases (cataract, primary open-angle glaucoma)•The conventional antioxidants are not selectively taken up by mitochondria of the cells•The author developed the new ophthalmic compositions of mitochondria-targeted antioxidants•The formulation comprises N-acetylcarnosine combined with mitochondria-targeted rechargeable antioxidant•Mitochondrial targeting of antioxidants represents a promising therapeutic approach•A number of ROS-related ocular diseases of the aging eye can be treated.
Nefopam has been known as an inhibitor of the reuptake of monoamines, and the noradrenergic and/or serotonergic system has been focused on as a mechanism of its analgesic action. Here we investigated the role of the spinal dopaminergic neurotransmission in the antinociceptive effect of nefopam administered intravenously or intrathecally.
The effects of intravenously and intrathecally administered nefopam were examined using the rat formalin test. Then we performed a microdialysis study to confirm the change of extracellular dopamine concentration in the spinal dorsal horn by nefopam. To determine whether the changes of dopamine level are associated with the nefopam analgesia, its mechanism was investigated pharmacologically via pretreatment with sulpiride, a dopaminergic D2 receptor antagonist.
When nefopam was administered intravenously the flinching responses in phase I of the formalin test were decreased, but not those in phase II of the formalin test were decreased. Intrathecally injected nefopam reduced the flinching responses in both phases of the formalin test in a dose dependent manner. Microdialysis study revealed a significant increase of the level of dopamine in the spinal cord by intrathecally administered nefopam (about 3.8 fold the baseline value) but not by that administered intravenously. The analgesic effects of intrathecally injected nefopam were not affected by pretreatment with sulpiride, and neither were those of the intravenous nefopam.
Both the intravenously and intrathecally administered nefopam effectively relieved inflammatory pain in rats. Nefopam may act as an inhibitor of dopamine reuptake when delivered into the spinal cord. However, the analgesic mechanism of nefopam may not involve the dopaminergic transmission at the spinal level.
Identifying dietary alternatives for artificial antioxidants capable of boosting antihemolytic and antioxidative defense has been an important endeavor in improving human health. In the present study, we studied antihemolytic and antioxidative effects of germosprout (i.e., the germ part along with sprouted stems plus roots) extract prepared from the pregerminated rice. The extract contained considerable amounts of antioxidant β-carotene (414 ± 12 ng/g of extract) and phytochemicals such as total polyphenols (12.0 ± 1.1 mg gallic acid equivalent/g of extract) and flavonoids (11.0 ± 1.4 mg catechin equivalent/g of extract). The antioxidant potential of the extract was assessed by its DPPH- (2,2-diphenyl-1-picrylhydrazyl-) free radical scavenging activity where we observed that germosprout extract had considerable antioxidative potentials. To evaluate antihemolytic effect of the extract, freshly prepared erythrocytes were incubated with either peroxynitrite or Fenton's reagent in the absence or presence of the extract. We observed that erythrocytes pretreated with the extract exhibited reduced degree of in vitro hemolysis. To support the proposition that germosprout extract could act as a good antioxidative agent, we also induced in vitro oxidative stress in erythrocyte membranes and in the aorta, brain, heart, and liver tissue homogenates in the presence of the extract. As expected, germosprout extract decreased oxidative stress almost to the same extent as that of vitamin E, as measured by lipid peroxide levels, in all the mentioned tissues. We conclude that rice germosprout extract could be a good natural source of antioxidants to reduce oxidative stress-induced hemolysis and damage of blood vessels and other tissues.
Background. Mycoplasmas are known to cause various infections in humans, mainly in the respiratory and urogenital tracts. The different species are usually host-specific and cause diseases in well-defined sites. New species have been isolated, including those from HIV-infected persons. Summary. Its in vitro properties, combined with clinical findings, have led to the hypothesis that these microorganisms may act as cofactors of HIV in AIDS development. Even today this point of view is quite polemic among infectious disease specialists and many aspects remain to be clarified, in contrast to what happens, for instance, with HIV/Mycobacterium tuberculosis coinfection. Dozens of papers have been published covering aspects of Mollicutes/HIV coinfection, but they add little to no information about the putative contribution of Mollicutes to the evolution of AIDS. Very few researchers have devoted their efforts to trying to answer this question, which remains open. In this review, we discuss the evidences that may support this statement in the light of current knowledge in the field of mycoplasmology.
Emergency contraception (EC) is use of drug or device to prevent pregnancy after unprotected sexual intercourse. Unlike other regular methods of contraception which are taken prior to the sexual act, EC is used after the unprotected sex.
To assess the knowledge and attitude toward use of emergency contraceptives among medical students.
A cross-sectional questionnaire based study was conducted among all the medical students in the Government Medical College in North-West India.
A questionnaire seeking information on knowledge and attitude of undergraduate medical students was administered over a period of 4 weeks in the month of February and March 2014.
The data were entered in MS excel and expressed using percentages. Chi-square test was used as a test of statistical significance.
About 61.6% (247/401) of the participants were aware about the timing of use of EC. Audio visual media (76.6%; 307/401) was the most common source of information for of these medical students.
The lack of appropriate in-depth knowledge of EC among future health care professional should alarm the medical teaching system as EC is the only method that can be used to prevent pregnancy after unprotected sex or contraceptive accident.
Aim of this work was to design and identify some S-adenosyl-L-homocysteine (SAH) analogs as inhibitors of S-adenosyl-L-methionine-dependent methyltransferase (MTase) protein using computational approaches.
According to the current scenario the dengue has been a global burden. The people are being killed by dengue virus in an abundant number. Despite of lot of research being going on dengue worldwide, there is no single drug which can kill its virus. This creates an urge for new drug target identification and designing. MTase has been reported as an effective target against dengue virus as it catalyzes an essential step in methylation and capping of viral RNA for viral replication.
The crystal structure of MTase in complex with SAH was used for designing new analogs of SAH. SAH analogs designed were analyzed on the basis of docking, ADMET, and toxicity analysis done using Discovery Studio 3.5.
Seventeen analogs found noncarcinogenic, nonmutagenic, as well as good ADMET properties and good drug-like profile.
These SAH analogs, inhibitors of MTase may act as drugs against dengue virus. Further synthesis and biological testing against dengue virus is under observation.
Leishmaniasis is a major infectious disease caused by protozoan parasites of the genus Leishmania. Despite of many efforts toward vaccine against Leishmania no effective vaccine has been approved yet. DNA vaccines can generate more powerful and broad immune responses than conventional vaccines. In order to increase immunity, the DNA vaccine has been supplemented with adjuvant. In this study a new nano-vaccine containing TSA recombinant plasmid and poly(methylmethacrylate) nanoparticles (act as adjuvant) was designed and its immunogenicity tested on BALB/c mouse. After three intramuscular injection of nano-vaccine (100 μg), the recombinant TSA protein (20 μg) was injected subcutaneously. Finally as a challenge animals were infected by Leishmania major. After the last injection of nano-vaccine, after protein booster injection, and also after challenge, cellular immune and antibody responses were evaluated by ELISA method. The findings of this study showed the new nano-vaccine was capable of induction both cytokines secretion and specific antibody responses,
 but predominant Th1 immune response characterized by IFN-γ production compared to control groups. Moreover, results revealed that nano-vaccine was effective in reducing parasite burden in the spleen of Leishmania major-infected BALB/c mice. Base on results, current candidate vaccine has potency for further studies.
Human fibroblast-like synoviocytes play a vital role in joint synovial inflammation in rheumatoid arthritis (RA). Proinflammatory cytokines induce fibroblast-like synoviocyte activation and dysfunction. The inflammatory mediator Krüppel-like factor 4 is upregulated during inflammation and plays an important role in endothelial and macrophage activation during inflammation. However, the role of Krüppel-like factor 4 in fibroblast-like synoviocyte activation and RA inflammation remains to be defined. In this study, we identify the notion that Krüppel-like factor 4 is higher expressed in synovial tissues and fibroblast-like synoviocytes from RA patients than those from osteoarthritis patients. In vitro, the expression of Krüppel-like factor 4 in RA fibroblast-like synoviocytes is induced by proinflammatory cytokine tumor necrosis factor-α. Overexpression of Krüppel-like factor 4 in RA fibroblast-like synoviocytes robustly induced interleukin-6 production in the presence or absence of tumor necrosis factor-α. Conversely, knockdown of Krüppel-like factor 4 markedly attenuated interleukin-6 production in the presence or absence of tumor necrosis factor-α. Krüppel-like factor 4 not only can bind to and activate the interleukin-6 promoter, but also may interact directly with nuclear factor-kappa B. These results suggest that Krüppel-like factor 4 may act as a transcription factor mediating the activation of fibroblast-like synoviocytes in RA by inducing interleukin-6 expression in response to tumor necrosis factor-α.
Calreticulin is a lectin chaperone of the endoplasmic reticulum that interacts with newly synthesized glycoproteins by binding to Glc1Man9GlcNAc2 oligosaccharides as well as to the polypeptide chain. In vitro, the latter interaction potently suppresses the aggregation of various non-glycosylated proteins. Although the lectin-oligosaccharide association is well understood, the polypeptide-based interaction is more controversial because the binding site on calreticulin has not been identified, and its significance in the biogenesis of glycoproteins in cells remains unknown. In this study, we identified the polypeptide binding site responsible for the in vitro aggregation suppression function by mutating four candidate hydrophobic surface patches. Mutations in only one patch, P19K/I21E and Y22K/F84E, impaired the ability of calreticulin to suppress the thermally induced aggregation of non-glycosylated firefly luciferase. These mutants also failed to bind several hydrophobic peptides that act as substrate mimetics and compete in the luciferase aggregation suppression assay. To assess the relative contributions of the glycan-dependent and -independent interactions in living cells, we expressed lectin-deficient, polypeptide binding-deficient, and doubly deficient calreticulin constructs in calreticulin-negative cells and monitored the effects on the biogenesis of MHC class I molecules, the solubility of mutant forms of α1-antitrypsin, and interactions with newly synthesized glycoproteins. In all cases, we observed a profound impairment in calreticulin function when its lectin site was inactivated. Remarkably, inactivation of the polypeptide binding site had little impact. These findings indicate that the lectin-based mode of client interaction is the predominant contributor to the chaperone functions of calreticulin within the endoplasmic reticulum.
Visual attention, which improves perception of attended locations or objects, has long been known to affect many aspects of the responses of neuronal populations in visual cortex. There are two nonmutually exclusive hypotheses concerning the neuronal mechanisms that underlie these perceptual improvements. The first hypothesis, that attention improves the information encoded by a population of neurons in a particular cortical area, has considerable physiological support. The second hypothesis is that attention improves perception by selectively communicating relevant visual information. This idea has been tested primarily by measuring interactions between neurons on very short timescales, which are mathematically nearly independent of neuronal interactions on longer timescales. We tested the hypothesis that attention changes the way visual information is communicated between cortical areas on longer timescales by recording simultaneously from neurons in primary visual cortex (V1) and the middle temporal area (MT) in rhesus monkeys. We used two independent and complementary approaches. Our correlative experiment showed that attention increases the trial-to-trial response variability that is shared between the two areas. In our causal experiment, we electrically microstimulated V1 and found that attention increased the effect of stimulation on MT responses. Together, our results suggest that attention affects both the way visual stimuli are encoded within a cortical area and the extent to which visual information is communicated between areas on behaviorally relevant timescales.
Visual attention dramatically improves the perception of attended stimuli. Attention has long been thought to act by selecting relevant visual information for further processing. It has been hypothesized that this selection is accomplished by increasing communication between neurons that encode attended information in different cortical areas. We recorded simultaneously from neurons in primary visual cortex and the middle temporal area while rhesus monkeys performed an attention task. We found that attention increased shared variability between neurons in the two areas and that attention increased the effect of microstimulation in V1 on the firing rates of MT neurons. Our results provide support for the hypothesis that attention increases communication between neurons in different brain areas on behaviorally relevant timescales.
Select adhesion proteins control the development of synapses and modulate their structural and functional properties. Despite these important roles, the extent to which different synapse-organizing mechanisms act across brain regions to establish connectivity and regulate network properties is incompletely understood. Further, their functional roles in different neuronal populations remain to be defined. Here, we applied diffusion tensor imaging (DTI), a modality of magnetic resonance imaging (MRI), to map connectivity changes in knock-out (KO) mice lacking the synaptogenic cell adhesion protein SynCAM 1. This identified reduced fractional anisotropy in the hippocampal CA3 area in absence of SynCAM 1. In agreement, mossy fiber refinement in CA3 was impaired in SynCAM 1 KO mice. Mossy fibers make excitatory inputs onto postsynaptic specializations of CA3 pyramidal neurons termed thorny excrescences and these structures were smaller in the absence of SynCAM 1. However, the most prevalent targets of mossy fibers are GABAergic interneurons and SynCAM 1 loss unexpectedly reduced the number of excitatory terminals onto parvalbumin (PV)-positive interneurons in CA3. SynCAM 1 KO mice additionally exhibited lower postsynaptic GluA1 expression in these PV-positive interneurons. These synaptic imbalances in SynCAM 1 KO mice resulted in CA3 disinhibition, in agreement with reduced feedforward inhibition in this network in the absence of SynCAM 1-dependent excitatory drive onto interneurons. In turn, mice lacking SynCAM 1 were impaired in memory tasks involving CA3. Our results support that SynCAM 1 modulates excitatory mossy fiber inputs onto both interneurons and principal neurons in the hippocampal CA3 area to balance network excitability.
This study advances our understanding of synapse-organizing mechanisms on two levels. First, the data support that synaptogenic proteins guide connectivity and can function in distinct brain regions even if they are expressed broadly. Second, the results demonstrate that a synaptogenic process that controls excitatory inputs to both pyramidal neurons and interneurons can balance excitation and inhibition. Specifically, the study reveals that hippocampal CA3 connectivity is modulated by the synapse-organizing adhesion protein SynCAM 1 and identifies a novel, SynCAM 1-dependent mechanism that controls excitatory inputs onto parvalbumin-positive interneurons. This enables SynCAM 1 to regulate feedforward inhibition and set network excitability. Further, we show that diffusion tensor imaging is sensitive to these cellular refinements affecting neuronal connectivity.
An exploratory examination of rural hospital staff experiences to determine whether the physical state of rural healthcare facilities influence the healthcare experience and perception of care quality.
Rural hospitals have served as the backbone of rural communities in the United States. Over time, these facilities have witnessed enhanced expectations, expanding their scope of operations from acute care to diversified services through linked provider networks and disaster management. Simultaneously, financial challenges, increasing emphasis on safety and quality, and the Affordable Care Act have introduced new challenges for rural hospitals. Currently, there is little empirical knowledge in this domain from a facility perspective.
An exploratory qualitative study was conducted, involving semistructured interviews of upper and mid-level administrators in four rural hospitals located in West Texas. All questions attempted to obtain the subject's knowledge, ideas, and opinions concerning the physical design of the hospitals and the hospital experience.
According to data on staff
 experiences, two classes of factors surfaced as potential influencers of hospital experience and care quality: (1) care configuration and (2) outdated building. Care configuration pertains to positioning facilities designed with inpatient care focus to a market expanding in outpatient services. Outdated buildings affect several issue including perceived provider quality and spatial accommodations for safe/efficient care and thereby also affecting the healthcare experience.
Physical infrastructure of rural hospitals may have important and meaningful implications for population health performance in rural America.
Objective To investigate the effect of Shengqifuzheng Injection (SQFZ) on the number recovery of B cells in gut-associated lymphoid tissues (GALTs) of mice receiving cyclophosphamide-based chemotherapy. Methods BALB/c mice were randomly divided into control group, cyclophosphamide (Cy) group and SQFZ group. Mice in Cy group and SQFZ group were injected intraperitoneally with Cy (100 mg/kg), while the control mice were injected with an equal volume of normal saline. Twenty-four hours later, mice in SQFZ group were administrated intragastricly with 1 mL SQFZ once daily for 10 consecutive days, and mice in the other groups were given the same volume of normal saline. Body mass of all the mice was measured every day. Mice were killed on day 10, and the indexes of spleen and thymus were measured. Cell cycles of bone marrow cells and the percentage of B cells in lymphocytes in mesenteric lymph node (MLN) and Peyer's patch (PP) were detected by flow cytometry. In vitro, after being treated with SQFZ, activity of lymphocytes was evaluzed by MTT assay; expression of CD86 on B cell surface was analyzed by flow cytometry; and B cell proliferation was tested by carboxyfluorescein succinimidyl ester (CFSE)-based lymphocyte proliferation assay. Results SQFZ alleviated the loss of body mass caused by Cy and promoted the recovery of thymus indexes, spleen indexes and B cell number in MLN and PP. But it did not alleviate the bone marrow suppression of mice in this condition. In vitro, SQFZ enhanced lymphocyte activity, and improved the activation and proliferation of B cells. Conclusion SQFZ could accelerate the recovery of B cells in GALTs of mice receiving chemotherapy and it might act by promoting B cell proliferation.
Objective To observe the effect of selective activation of melanocortin 4 receptor (MC4R) on the rats with sepsis-induced acute liver injury. Methods Sixty-four male SD rats were randomly grouped into sham operation group (PBS treatment after sham operation), cecal ligation and puncture (CLP) group (sepsis model was established by CLP), Ro27-3225 treatment group (Ro27-3225 treatment after CLP), and Ro27-3225 sham operation control group (Ro27-3225 treatment after sham operation), 16 rats for each group (ten rats were used to observe general condition and 72-hour survival after operation. Then, six rats were used to collect blood and liver samples). These groups were intraperitoneally injected with PBS or Ro27-3225 (180 μg/kg) 30 minutes after operation. Heart rate (HR), mean arterial pressure (MAP), aspartate transaminase (AST) and alanine transaminase (ALT) were measured 24 hours after operation. After execution of the rats, pathological changes of liver tissues were observed by HE staining. The levels of Toll-like receptor 4 (TLR4), high mobility group box 1 (HMGB1) and caspase-3 mRNA in liver tissues were analyzed by reverse transcription PCR. The expression of nuclear factor-κB (NF-κB) p65 in hepatocytes was detected by immunohistochemical staining, which was followed by analysis of nuclear positive rate of NF-κB p65. Results Compared with the sham operation group, CLP group showed decreased 72-hour survival and MAP, significantly increased levels of AST and ALT, hepatic cords disorder, hepatocyte swelling, and diffuse inflammatory cell infiltration; the levels of TLR4, HMGB1 and caspase-3 mRNA in liver tissues remarkably increased, and the positive rate of NF-κB p65 in hepatocytes went up as well. However, compared with the CLP group, the Ro27-3225 treatment group was found with obviously increased 72-hour survival and MAP, inhibited levels of AST and ALT, attenuated damage of liver tissues, decreased levels of TLR4, HMGB1 and caspase-3 mRNA in liver tissues, and significantly downregulated positive rate of NF-κB p65 in hepatocytes. Conclusion Sepsis causes liver injury. Selectively activating MC4R can reduce sepsis-induced acute liver injury in rats, which may act via inhibiting HMGB1/TLR4/NF-κB signaling pathway to relieve inflammation response.
Nitric oxide (NO) plays important, but incompletely defined roles in skeletal muscle. NO exerts its regulatory effects partly though S-nitrosylation, which is balanced by denitrosylation by enzymes such as S-nitrosoglutathione reductase (GSNOR), whose functions in skeletal muscle remain to be fully deciphered.
GSNOR null (GSNOR(-/-)) tibialis anterior (TA) muscles showed normal growth and were stronger and more fatigue resistant than controls in situ. However, GSNOR(-/-) lumbrical muscles showed normal contractility and Ca(2+) handling in vitro, suggesting important differences in GSNOR function between muscles or between in vitro and in situ environments. GSNOR(-/-) TA muscles exhibited normal mitochondrial content, and capillary densities, but reduced type IIA fiber content. GSNOR inhibition did not impact mitochondrial respiratory complex I, III, or IV activities. These findings argue that enhanced GSNOR(-/-) TA contractility is not driven by changes in mitochondrial content or activity, fiber type, or blood vessel density. However, loss of GSNOR led to RyR1 hypernitrosylation, which is believed to increase muscle force output under physiological conditions. cGMP synthesis by soluble guanylate cyclase (sGC) was decreased in resting GSNOR(-/-) muscle and was more responsive to agonist (DETANO, BAY 41, and BAY 58) stimulation, suggesting that GSNOR modulates cGMP production in skeletal muscle.
GSNOR may act as a "brake" on skeletal muscle contractile performance under physiological conditions by modulating nitrosylation/denitrosylation balance.
GSNOR may play important roles in skeletal muscle contractility, RyR1 S-nitrosylation, fiber type specification, and sGC activity. Antioxid. Redox Signal. 00, 000-000.
The human papillomavirus (HPV) life cycle is tightly linked to differentiation of the infected epithelium. This means that viral proteins must exert control over epithelial gene expression in order to optimize viral production. The HPV E2 protein controls replication, transcription, and viral genome partitioning during the viral infectious life cycle. It consists of a nucleic acid-binding domain and a protein-protein interaction domain separated by a flexible serine and arginine-rich hinge region. Over the last few years, mounting evidence has uncovered an important new role for E2 in viral and cellular RNA processing. This Gem discusses the role of E2 in controlling the epithelial cellular environment and how E2 might act to coordinate late events in the viral replication cycle.
The purpose of this article was to examine the potential impact of child welfare services on the risk for fatal child maltreatment. This was conducted using a subsample of children who were identified as "prior victims" in the National Child Abuse and Neglect Data System from 2008 to 2012. At the multivariate level, the analyses show that case management services act to protect children from death as do family support services, family preservation services, and foster care, but that the results vary by type of maltreatment experienced. The author recommends that before strong conclusions are drawn, additional research in this area is warranted.
Parental feeding practices are thought to play a causal role in shaping a child's fussiness; however, a child-responsive model suggests that feeding practices may develop in response to a child's emerging appetitive characteristics. We used a novel twin study design to test the hypothesis that mothers vary their feeding practices for twin children who differ in their 'food fussiness', in support of a child-responsive model.
Participants were mothers and their 16 month old twin children (n = 2026) from Gemini, a British twin birth cohort of children born in 2007. Standardized psychometric measures of maternal 'pressure to eat', 'restriction' and 'instrumental feeding', as well as child 'food fussiness', were completed by mothers. Within-family analyses examined if twin-pair differences in 'food fussiness' were associated with differences in feeding practices using linear regression models. In a subset of twins (n = 247 pairs) who were the most discordant (highest quartile) on 'food fussiness' (difference score ≥ .50), Paired Samples T-test were used to explore the magnitude of differences in feeding practices between twins. Between-family analyses used Complex Samples General Linear Models to examine associations between feeding practices and 'food fussiness'.
Within-pair differences in 'food fussiness' were associated with differential 'pressure to eat' and 'instrumental feeding' (ps < .001), but not with 'restriction'. In the subset of twins most discordant on 'food fussiness', mothers used more pressure (p < .001) and food rewards (p < .05) with the fussier twin. Between-family analyses indicated that 'pressure to eat' and 'instrumental feeding' were positively associated with 'food fussiness', while 'restriction' was negatively associated with 'food fussiness' (ps < .001).
Mothers appear to subtly adjust their feeding practices according to their perceptions of their toddler's emerging fussy eating behavior. Specifically, the fussier toddler is pressured more than their less fussy co-twin, and is more likely to be offered food rewards.
 Guiding parents on how to respond to fussy eating may be an important aspect of promoting feeding practices that encourage food acceptance.
There is great interest in the development of Ab-inducing subunit vaccines targeting infections, including HIV, malaria, and Ebola. We previously reported that adenovirus vectored vaccines are potent in priming Ab responses, but uncertainty remains regarding the optimal approach for induction of humoral immune responses. In this study, using OVA as a model Ag, we assessed the magnitude of the primary and anamnestic Ag-specific IgG responses of mice to four clinically relevant vaccine formulations: replication-deficient adenovirus; modified vaccinia Ankara (a poxvirus); protein with alum; and protein in the squalene oil-in-water adjuvant Addavax. We then used flow cytometric assays capable of measuring total and Ag-specific germinal center (GC) B cell and follicular Th cell responses to compare the induction of these responses by the different formulations. We report that adenovirus vectored vaccines induce Ag insert-specific GC B cell and Ab responses of a magnitude comparable to those induced by a potent protein/squalene oil-in-water formulation whereas-despite a robust overall GC response-the insert-specific GC B cell and Ab responses induced by modified vaccinia Ankara were extremely weak. Ag-specific follicular Th cell responses to adenovirus vectored vaccines exceeded those induced by other platforms at day 7 after immunization. We found little evidence that innate immune activation by adenovirus may act as an adjuvant in such a manner that the humoral response to a recombinant protein may be enhanced by coadministering with an adenovirus lacking a transgene of interest. Overall, these studies provide further support for the use of replication-deficient adenoviruses to induce humoral responses.
Advanced glycation end products (AGEs) are formed both during the endogenous and exogenous reactions and are implicated in the process of ageing, pathogenesis of diabetes, atherosclerosis, female fertility, and cancers. Food and smoking are the most important sources of exogenous AGEs in daily life. The biochemical composition of meal, cooking methods, time and temperature of food preparation may impact AGEs formation, therefore Western-type diet, rich in animal-derived products as well as in fast foods seems to be the main source of AGEs. Both, endogenous and exogenous AGEs can act intracellularly or during serum interaction with cell surface receptors called RAGE influencing variety of molecular pathways. Polycystic ovary syndrome (PCOS) is the most common endocrinopathy in women of reproductive age. The aetiology of this disorder remains unclear, however the environmental and genetic factors may play an important role in its pathogenesis. Nevertheless, PCOS women have increased factors for reproductive and cardiometabolic comorbidities. AGEs can contribute to the pathogenesis of PCOS as well as its consequences. It has been shown that chronic inflammation and increased oxidative stress may be a link between the mechanisms of AGEs action and the metabolic and reproductive consequences of PCOS. This review highlights that high dietary AGEs intake promotes deteriorating biological effects in women with PCOS, whereas AGEs restriction seems to have beneficial impact on women health. Better understanding AGEs formation and biochemistry as well as AGE-mediated pathophysiological mechanisms may open new therapeutic avenues converging to the achievement of the complete treatment of PCOS and its consequences.
Due to increasing antibiotic resistance, the use of silver coated single walled carbon nanotubes (SWCNTs-Ag) and antimicrobial peptides (APs) is becoming popular due to their antimicrobial properties against a wide range of pathogens. However, stability against various conditions and toxicity in human cells are some of the major drawbacks of APs and SWCNTs-Ag, respectively. Therefore, we hypothesized that APs-functionalized SWCNTs-Ag could act synergistically. Various covalent functionalization protocols described previously involve harsh treatment of carbon nanotubes for carboxylation (first step in covalent functionalization) and the non-covalently functionalized SWCNTs are not satisfactory.
The present study is the first report wherein SWCNTs-Ag were first carboxylated using Tri sodium citrate (TSC) at 37 °C and then subsequently functionalized covalently with an effective antimicrobial peptide from Therapeutic Inc., TP359 (FSWCNTs-Ag). SWCNTs-Ag were also non covalently functionalized with TP359 by simple mixing (SWCNTs-Ag-M) and both, the FSWCNTs-Ag (covalent) and SWCNTs-Ag-M (non-covalent), were characterized by Fourier transform infrared spectroscopy (FT-IR), Ultraviolet visualization (UV-VIS) and transmission electron microscopy (TEM). Further the antibacterial activity of both and TP359 were investigated against two gram positive (Staphylococcus aureus and Streptococcus pyogenes) and two gram negative (Salmonella enterica serovar Typhimurium and Escherichia coli) pathogens and the cellular toxicity of TP359 and FSWCNTs-Ag was compared with plain SWCNTs-Ag using murine macrophages and lung carcinoma cells.
FT-IR analysis revealed that treatment with TSC successfully resulted in carboxylation of SWCNTs-Ag and the peptide was indeed attached to the SWCNTs-Ag evidenced by TEM images. More importantly, the present study results further showed that the minimum inhibitory concentration (MIC) of FSWCNTs-Ag were much lower (~7.8-3.9 µg/ml with IC50: ~4-5 µg/ml) compared to SWCNTs-Ag-M and plain SWCNTs-Ag (both 62.6 µg/ml, IC50: ~31-35 µg/ml), suggesting that the covalent conjugation of TP359 with SWCNTs-Ag was very effective on their counterparts. Additionally, FSWCNTs-Ag are non-toxic to the eukaryotic cells at their MIC concentrations (5-2.5 µg/ml) compared to SWCNTs-Ag (62.5 µg/ml).
In conclusion, we demonstrated that covalent functionalization of SWCNTs-Ag and TP359 exhibited an additive antibacterial activity. This study described a novel approach to prepare SWCNT-Ag bio-conjugates without loss of antimicrobial activity and reduced toxicity, and this strategy will aid in the development of novel and biologically important nanomaterials.
Amelogenesis imperfecta (AI) is a heterogeneous group of genetic conditions that result in defective dental enamel formation. Amelotin (AMTN) is a secreted protein thought to act as a promoter of matrix mineralization in the final stage of enamel development, and is strongly expressed, almost exclusively, in maturation stage ameloblasts. Amtn overexpression and Amtn knockout mouse models have defective enamel with no other associated phenotypes, highlighting AMTN as an excellent candidate gene for human AI. However, no AMTN mutations have yet been associated with human AI. Using whole exome sequencing, we identified an 8,678 bp heterozygous genomic deletion encompassing exons 3-6 of AMTN in a Costa Rican family segregating dominant hypomineralised AI. The deletion corresponds to an in-frame deletion of 92 amino acids, shortening the protein from 209 to 117 residues. Exfoliated primary teeth from an affected family member had enamel that was of a lower mineral density compared to control enamel and exhibited structural defects at least some of which appeared to be associated with organic material as evidenced using elemental analysis. This study demonstrates for the first time that AMTN mutations cause non-syndromic human AI and explores the human phenotype, comparing it with that of mice with disrupted Amtn function.
Complex interactions between plants and soil microorganisms drive key ecosystem and community properties such as productivity and diversity. In nutrient-poor systems such as sand dunes, plant traits and fungal symbioses related to nutrient acquisition can strongly influence vegetation dynamics. We investigated plant and fungal communities in a relic foredune plain located on an archipelago in Québec, Canada. We detected distinct communities across the edaphic and successional gradient. Our results showed a clear increase in plant species richness, as well as in the diversity of nutrient-acquisition strategies. We also found a strong correlation between aboveground vegetation and soil fungal communities, and both responded similarly to soil physicochemical properties. Soil pH influenced the composition of plant and fungal communities, and could act as an important environmental filter along this relic foredune plain. The increasing functional diversity in plant nutrient-acquisition strategies across the gradient might favor resource partitioning and facilitation among co-occurring plant species. The coordinated changes in soil microbial and plant communities highlight the importance of aboveground-belowground linkages and positive biotic interactions during ecological succession in nutrient-poor environments.
Adjuvants enhance immunogenicity and sustain long-term immune responses. As vital components of vaccines, efficient adjuvants are highly desirable. Recent evidence regarding the potential of carbon nanotubes (CNTs) to act as a support material has suggested that certain properties, such as their unique hollow structure, high specific surface area, and chemical stability, make CNTs desirable for a variety of antigen-delivery applications. Lentinan, a β-1,3-glucohexaose with β-1,6-branches that is extracted from the mushroom Lentinus edodes, is an effective immunostimulatory drug that has been clinically used in Japan and China, and recent studies have proved that specific beta-glucans can bind to various immune receptors. In this research, we covalently attached lentinan to multiwalled carbon nanotubes (MWCNTs) and tested their ability to enhance immune responses as a vaccine delivery system. In vitro study results showed that
 the nanotube constructs could rapidly enter dendritic cells and carry large amounts of antigen. Moreover, maturation markers were significantly upregulated versus the control. Thus, lentinan-modified multiwalled carbon nanotubes (L-MWCNTs) were regarded as an effective intracellular antigen depot and a catalyzer that could induce phenotypic and functional maturation of dendritic cells. Furthermore, compared with L-MWCNTs (35 μg/mL), a corresponding concentration of carboxylic carbon nanotubes (C-MWCNTs, 31.8 μg/mL) and an equivalent concentration of lentinan (3.2 μg/mL) did not remarkably influence the immune reaction in vitro or in vivo. Hence, we can hypothesize that the capability of L-MWCNTs was a consequence of the increased intracellular quantity of lentinan grafted onto the nanotubes. Overall, our studies demonstrated that L-MWCNTs significantly increased antigen accumulation in the cells and potentiated cellular and humoral immunity. In conclusion, L-MWCNTs constitute a potential vaccine delivery system to enhance immunogenicity for therapeutic purposes.
To discuss Ethiopian food taboos during pregnancy and their relation to maternal nutritional status and pregnancy outcomes.
Recent waves of migration have seen large groups of Ethiopian refugees moving to countries around the globe. This is of concern as Ethiopian women are at risk of a number of medical and pregnancy complications. Health is further compromised by poor diet and adherence to cultural food beliefs and taboos. In refugee women, many of these factors correspond with significantly higher rates of pregnancy complications and poor birth outcomes.
This is a discussion paper informed by a literature review.
A search of the Scopus, PubMed, Web of Science and Academic Search Premier databases for the keywords Ethiopian, pregnancy, food and taboos was conducted in the research literature published from 1998-2015. This time is contingent with Ethiopian migration trends.
Ethiopian migrant women are at risk of inadequate nutrition during pregnancy. Risks include cultural factors associated with food taboos as well as issues associated with low socioeconomic status. Consequently, Ethiopian women are more likely to have nutritional deficiencies such as anaemia which have been associated with a range of pregnancy complications.
There are many serious consequences of poor diet during pregnancy; however, most of these can be avoided by greater awareness about the role of nutrition during pregnancy and by adopting a balanced diet.
There is an urgent unmet need for nutrition education among Ethiopian women. Research indicates that Ethiopian women are receptive to nutritional advice during pregnancy and also that pregnant women are generally motivated to act in the baby's interest. These factors suggest that this high-risk group would be amenable to culturally appropriate nutrition education, which would provide much-needed meaningful support in pregnancy.
There has been renewed global interest in both genetic and management strategies to improve root system function in order to improve agricultural productivity and minimize environmental damage. Improving root system capture of water and nutrients is an obvious strategy, yet few studies consider the important interactions between the genetic improvements proposed, and crop management at a system scale that will influence likely success.
To exemplify these interactions, the contrasting cereal-based farming systems of Denmark and Australia were used, where the improved uptake of water and nitrogen from deeper soil layers has been proposed to improve productivity and environmental outcomes in both systems. The analysis showed that water and nitrogen availability, especially in deeper layers (>1 m), was significantly affected by the preceding crops and management, and likely to interact strongly with deeper rooting as a specific trait of interest.
In the semi-arid Australian environment, grain yield impacts from storage and uptake of water from depth (>1 m) could be influenced to a stronger degree by preceding crop choice (0·42 t ha(-1)), pre-crop fallow management (0·65 t ha(-1)) and sowing date (0·63 t ha(-1)) than by current genetic differences in rooting depth (0·36 t ha(-1)). Matching of deep-rooted genotypes to management provided the greatest improvements related to deep water capture. In the wetter environment of Denmark, reduced leaching of N was the focus. Here the amount of N moving below the root zone was also influenced by previous crop choice or cover crop management (effects up to 85 kg N ha(-1)) and wheat crop sowing date (up to 45 kg ha(-1)), effects which over-ride the effects of differences in rooting depth among genotypes. These examples highlight the need to understand the farming system context and important G × E × M interactions in studies on proposed genetic improvements to root systems for improved productivity or environmental outcomes.
The ATP analog ATPγS inhibits pre-mRNA splicing in vitro, but there have been conflicting reports as to which step of splicing is inhibited by this small molecule and its inhibitory mechanism remains unclear. Here we have dissected the effect of ATPγS on pre-mRNA splicing in vitro. Addition of ATPγS to splicing extracts depleted of ATP inhibited both catalytic steps of splicing. At ATPγS concentrations ≥0.5 mM, precatalytic B complexes accumulate, demonstrating a block prior to or during the spliceosome activation stage. Affinity purification of the ATPγS-stalled B complexes (B(ATPγS)) and subsequent characterization of their abundant protein components by 2D gel electrophoresis revealed that B(ATPγS) complexes are compositionally more homogeneous than B complexes previously isolated in the presence of ATP. In particular, they contain little or no Prp19/CDC5L complex proteins, indicating that these proteins are recruited after assembly of the precatalytic spliceosome. Under the electron microscope, B(ATPγS) complexes exhibit a morphology highly similar to B complexes, indicating that the ATPγS-induced block in the transformation of the B to B(act) complex is not due to a major structural defect. Likely mechanisms whereby ATPγS blocks spliceosome assembly at the activation stage, including inhibition of the RNA helicase Brr2, are discussed. Given their more homogeneous composition, B complexes stalled by ATPγS may prove highly useful for both functional and structural analyses of the precatalytic spliceosome and its conversion into an activated B(act) spliceosomal complex.
Mycobacteriophages produce lysins that break down the host cell wall at the end of lytic cycle to release their progenies. The ability to lyse mycobacterial cells makes the lysins significant. Mycobacteriophage Che12 is the first reported temperate phage capable of infecting and lysogenising Mycobacterium tuberculosis. Gp11 of Che12 was found to have Chitinase domain that serves as endolysin (lysin A) for Che12. Structure of gp11 was modeled and evaluated using Ramachandran plot in which 98 % of the residues are in the favored and allowed regions. Che12 lysin A was predicted to act on NAG-NAM-NAG molecules in the peptidoglycan of cell wall. The tautomers of NAG-NAM-NAG molecule were generated and docked with lysin A. The stability and binding affinity of lysin A - NAG-NAM-NAG tautomers were studied using molecular dynamics simulations.
The Affordable Care Act (ACA) was instated on 23 March 2010 to improve healthcare quality, reduce costs, and increase access. The Pretty in Pink Foundation (PIPF), a non-profit 501(C)(3) organization in North Carolina, provides financial assistance and in-kind support to individuals seeking help with breast cancer care. The objective of this study was to determine whether sociodemographic variables and treatment services varied among PIPF recipients since enactment of the ACA.
North Carolinians who received financial assistance from the PIPF between 1 January 2013 and 31 December 2014 were included in the study, and the cohort was divided into two groups based on receipt of assistance before or after the enactment of the ACA. Descriptive statistics were tabulated as frequencies. Comparative univariate analysis between both groups was conducted using the χ (2) and Mann-Whitney U tests. All tests were two-sided and a p value <0.05 was considered statistically significant. All analyses were conducted using Stata.
Overall, 1016 individuals fulfilled the inclusion criteria, and the median age of the cohort was 49 years (interquartile range 45-55). The ACA groups did not differ significantly by age, race, and sex; however, the groups varied with respect to income, employment, and clinical stage. In addition, the groups differed on the types of services for which they received financial assistance, but no difference was observed between groups with respect to insurance status.
Since the enactment of the health insurance market component of the ACA, there has been a reduction in subjects receiving assistance from the PIPF; however, no change in their insurance status has been observed.
Chief emergency physicians are regarded as an important element in the care of the injured and sick following mass casualty accidents. Their education is very theoretical; practical content in contrast often falls short. Limitations are usually the very high costs of realistic (large-scale) exercises, poor reproducibility of the scenarios, and poor corresponding results.
To substantially improve the educational level because of the complexity of mass casualty accidents, modified training concepts are required that teach the not only the theoretical but above all the practical skills considerably more intensively than at present. Modern training concepts should make it possible for the learner to realistically simulate decision processes. This article examines how interactive virtual
 environments are applicable for the education of emergency personnel and how they could be designed.
Virtual simulation and training environments offer the possibility of simulating complex situations in an adequately realistic manner. The so-called virtual reality (VR) used in this context is an interface technology that enables free interaction in addition to a stereoscopic and spatial representation of virtual large-scale emergencies in a virtual environment. Variables in scenarios such as the weather, the number wounded, and the availability of resources, can be changed at any time. The trainees are able to practice the procedures in many virtual accident scenes and act them out repeatedly, thereby testing the different variants.
With the aid of the "InSitu" project, it is possible to train in a virtual reality with realistically reproduced accident situations. These integrated, interactive training environments can depict very complex situations on a scale of 1:1. Because of the highly developed interactivity, the trainees can feel as if they are a direct part of the accident scene and therefore identify much more with the virtual world than is possible with desktop systems.
Interactive, identifiable, and realistic training environments based on projector systems could in future enable a repetitive exercise with changes within a decision tree, in reproducibility, and within different occupational groups. With a hard- and software environment numerous accident situations can be depicted and practiced. The main expense is the creation of the virtual accident scenes. As the appropriate city models and other three-dimensional geographical data are already available, this expenditure is very low compared with the planning costs of a large-scale exercise.
Aberrant expression of ten-eleven translocation 1 (TET1) plays a critical role in tumor development and progression. We systematically summarized the latest research progress on the role and mechanisms of TET1 in cancer biology.
Relevant articles published in English from 1980 to April 2016 were selected from the PubMed database. The terms "ten-eleven translocation 1," "5mC," "5hmC," "microRNA," "hypoxia," and "embryonic stem cell" were used for the search.
Articles focusing on the role and mechanism of TET1 in tumor were reviewed, including clinical and basic research articles.
TET proteins, the key enzymes converting 5-methylcytosine to 5-hydroxymethylcytosine, play vital roles in DNA demethylation regulation. Recent studies have shown that loss of TET1 is associated with tumorigenesis and can be used as a potential biomarker for cancer therapy, which indicates that TET1 serves as tumor suppressor gene. Moreover, besides its dioxygenase activity, TET1 could induce epithelial-mesenchymal transition and act as a coactivator to regulate gene transcription, such as developmental regulator in embryonic stem cells (ESCs) and hypoxia-responsive gene in cancer. The regulation of TET1 is also correlated with microRNA in a posttranscriptional modification process. Hence, it is complex but critical to comprehend the mechanisms of TET1 in the biology of ESCs and cancer.
TET1 not only serves as a demethylation enzyme but also plays multiple roles during tumorigenesis and progression. More studies should be carried out to elucidate the exact mechanisms of TET1 and its associations with cancer before considering it as a therapeutic tool.
Because it plays an essential role in nitrogen (N) assimilation and photorespiration, the glutamine synthetase (GS)/glutamate synthase (GOGAT) system is widely accepted as occupying a central position in leaf N metabolism. However, the regulation of GOGAT at the post-transcriptional level is poorly understood. Here, we show that ACR11, an ACT (acronym for aspartate kinase, chorismate mutase, and TyrA) domain-containing family protein, interacts with Glu1-encoded ferredoxin (Fd)-GOGAT in Arabidopsis chloroplasts. In addition, Arabidopsis acr11 mutants have lost the capability to control Fd-GOGAT levels in response to light/dark diurnal cycles, nitrogen inputs, and changes in photorespiratory activity. Considering that ACR11 has putative glutamine-binding domains, our results indicate that ACR11 is necessary for post-transcriptional control of leaf Glu1-encoded Fd-GOGAT. This regulation takes place through direct interaction of ACR11 and Fd-GOGAT, possibly in an allosteric manner.
New infection treatments are urgently needed to combat the rising threat of multi-drug resistant bacteria. Despite early clinical set-backs attention has re-focused on host defense proteins (HDPs), as potential sources for new and effective antimicrobial treatments. HDPs appear to act at multiple targets and their repertoire includes disruptive membrane and intracellular activities against numerous types of pathogens as well as immune modulatory functions in the host. Importantly, these novel activities are associated with a low potential for emergence of resistance and little cross-resistance with other antimicrobial agents. Based on these properties, HDPs appear to be ideal candidates for new antibiotics; however, their development has been plagued by the many therapeutic limitations associated with natural peptidic agents. This review focuses on HDP mimetic approaches aimed to improve metabolic stability, pharmacokinetics, safety and manufacturing processes. Early efforts with β-peptide or peptoid analogs focused on recreating stable facially amphiphilic structures but demonstrated that antimicrobial activity was modulated by more, complex structural properties. Several approaches have used lipidation to increase the hydrophobicity and membrane activity. One lead compound, LTX-109, has entered clinical study as a topical agent to treat impetigo and nasal decolonization. In a more significant departure from the amino acid like peptidomimetics, considerable effort has been directed at developing amphiphilic compounds that recapitulate the structural and biological properties of HDPs on small abiotic scaffolds. The lead compound from this approach, brilacidin, has completed two phase 2 studies as an intravenous agent for skin infections.
Nanomaterials have ignited new interest due to their distinctive electronic, mechanical, and optical properties. Zinc oxide nanostructures are fabricated into thin film and then inserted between two fiber ferrules to act as a saturable absorber (SA). The modulation depth and insertion loss of the SA are 5% and 3.5 dB, respectively. When the ZnO-SA is incorporated into the laser cavity, a stable Q-switched pulse tunable from 1536 to 1586 nm (50 nm range) with pulse energy up to 46 nJ was observed. Our result suggests that ZnO is a promising broadband SA to generate passively Q-switched fiber lasers.
The timing, location, and level of WNT signaling are highly regulated during embryonic development and for the maintenance of adult tissues. Consequently the ability to provide a defined and directed source of WNT proteins is crucial to fully understand its role in tissue development and to mimic its activity in vitro. Here we describe a one-step immobilization technique to covalently bind WNT3A proteins as a basal surface with easy storage and long-lasting activity. We show that this platform is able to maintain adult and embryonic stem cells while also being adaptable for 3D systems. Therefore, this platform could be used for recapitulating specific stem cell niches with the goal of improving tissue engineering.
A series of samples with varying growth pressure are grown and their optical and structural properties are investigated. It is found that the residual carbon concentration decreases when the reactor pressure increases from 80 to 450 Torr during the InGaN/GaN multiple quantum well growth. It results in an enhanced peak intensity of electroluminescence because carbon impurities can induce deep energy levels and act as non-radiative recombination centers in InGaN layers.
B-type cyclin-dependent kinase activity must be turned off for mitotic exit and G1 stabilization. B-type cyclin degradation is mediated by the anaphase-promoting complex/cyclosome (APC/C); during and after mitotic exit, APC/C is dependent on Cdh1. Cdh1 is in turn phosphorylated and inactivated by cyclin-CDK at the Start transition of the new cell cycle. We developed a biosensor to assess the cell cycle dynamics of APC/C-Cdh1. Nuclear exit of the G1 transcriptional repressor Whi5 is a known marker of Start; APC/C-Cdh1 is inactivated 12 min after Whi5 nuclear exit with little measurable cell-to-cell timing variability. Multiple phosphorylation sites on Cdh1 act in a redundant manner to repress its activity. Reducing the number of phosphorylation sites on Cdh1 can to some extent be tolerated for cell viability, but it increases variability in timing of APC/C-Cdh1 inactivation. Mutants with minimal subsets of phosphorylation sites required for viability exhibit striking stochasticity in multiple responses including budding, nuclear division, and APC/C-Cdh1 activity itself. Multiple cyclin-CDK complexes, as well as the stoichiometric inhibitor Acm1, contribute to APC/C-Cdh1 inactivation; this redundant control is likely to promote rapid and reliable APC/C-Cdh1 inactivation immediately following the Start transition.
This study aims to investigate the effects of lighting color temperatures on elementary students' performance, and thereby propose a dynamic lighting system for a smart learning environment. Three empirical studies were conducted: First, physiological responses were measured as a potential mediator of performance. Second, cognitive and behavioral responses were observed during academic and recess activities. Lastly, the experiment was carried out in a real-life setting with prolonged exposure. With a comprehensive analysis of the three studies, three lighting
 presets-3500 K, 5000 K, and 6500 K-are suggested for easy, standard, and intensive activity, respectively. The study is expected to act as a good stepping stone for developing dynamic lighting systems to support students' performance in learning environments.
We herein report an investigation of the device performance capabilities and impedance characteristics of solution-processed organic light-emitting devices (OLEDs) with all-water-processable triple-stacked hole-selective layers (HSLs) on an indium-tin-oxide (ITO) anode, fabricated using a simple coating technique. Highly smooth and homogeneous triple-stacked layers were deposited via horizontal-dip- (H-dip-) coating using aqueous dispersions of graphene oxide (GO), molybdenum oxide (MoO<sub>3</sub>), and poly(ethylenedioxy thiophene):poly(styrene sulfonate) (
PSS). From the triple-stacked GO/MoO<sub>3</sub>/
PSS HSLs used as hole-injection layers (HILs) in the OLEDs, which outperform a conventional single HIL of
PSS, it was found that OLEDs with triple-stacked HILs exhibited characteristic impedance properties, including low parallel resistance with trap-free space-charge-limited conductivity. Furthermore, it was shown that the relaxation frequency of a sample OLED with triple-stacked GO/MoO<sub>3</sub>/
PSS HILs was much higher than that of a reference device with a single
PSS HIL. These impedance behaviors indicate that carrier (hole) injection in the sample OLED is more efficient than that in any of the other devices tested here. The results presented here clarify that the triple-stacked GO/MoO<sub>3</sub>/
PSS layers can act as efficient HILs on an ITO anode, representing a remarkable advance in relation to the mass production of high-performance solution-processable OLEDs.
Gingival recession has direct causes and predisposing factors. Orthodontic treatment is able to prevent recession and even contribute to its treatment, with or without periodontal approach, depending on the type and severity of gingival tissue damage. There is no evidence on the fact that orthodontic treatment alone might induce gingival recession, although it might lead the affected teeth (usually mandibular incisors or maxillary canines) to be involved in situations that act as predisposing factors, allowing direct causes to act and, therefore, trigger recession, especially when the buccal bone plate is very thin or presents with dehiscence. Several aspects regarding the relationship between orthodontic treatment and gingival recession have been addressed, and so has the importance of the periosteum to the mechanism of gingival recession formation. Clinical as well as experimental trials on the subject would help to clarify this matter, of which understanding is not very deep in the related literature.
This follow-up paper completes the author's investigations to explore the in-solution structural preferences and relative free energies of all OH-substituted oxazole, thiazole, isoxazole, and isothiazole systems. The polarizable continuum dielectric solvent method calculations in the integral-equation formalism (IEF-PCM) were performed at the DFT/B97D/aug-cc-pv(q+(d))z level for the stable neutral tautomers with geometries optimized in dichloromethane and aqueous solution. With the exception of the predictions for the predominant tautomers of the 3OH isoxazole and isothiazole, the results of the IEF-PCM calculations for identifying the most stable tautomer of the given species in the two selected solvents agreed with those from experimental investigations. The calculations predict that the hydroxy proton, with the exception for the 4OH isoxazole and 4OH isothiazole, moves preferentially to the ring nitrogen or to a ring carbon atom in parallel with the development of a C=O group. The remaining, low-fraction OH tautomers will not be observable in the equilibrium compositions. Relative solvation free energies obtained by the free energy perturbation method implemented in Monte Carlo simulations are in moderate accord with the IEF-PCM results, but consideration of the ΔGsolv/MC values in calculating ΔG(s)tot maintains the tautomeric preferences. It was revealed from the Monte Carlo solution structure analyses that the S atom is not a hydrogen-bond acceptor in any OH-substituted thiazole or isothiazole, and the OH-substituted isoxazole and oxazole ring oxygens may act as a weak hydrogen-bond acceptor at most. The molecules form 1.0-3.4 solute-water hydrogen bonds in generally unexplored numbers at some specific solute sites. Nonetheless, hydrogen-bond formation is favorable with the NH, C=O and OH groups.
A small series of tetrahydroindazoles was prepared, starting from 2-acetylcyclohexanone and different hydrazines using reflux and a focused microwave reactor. Microwave irradiation (MW) favored the formation of the desired products with improved yields and shortened reaction times. This is a simple and green method for the synthesis of substituted tetrahydroindazole derivatives. The in vitro antioxidant activity was evaluated using the DPPH and ABTS methods. In these assays, 2-(4-fluorophenyl)-3-methyl-4,5,6,7-tetrahydro-2H-indazole (3f) showed moderate DPPH decoloring activity, while 3-methyl-4,5,6,7-tetrahydro-1H-indazole (3a), 3-methyl-2-phenyl-4,5,6,7-tetrahydro-2H-indazole (3b) and 2-(4-fluorophenyl)-3-methyl-4,5,6,7-tetrahydro-2H-indazole (3f) were the most active in the ABTS assay. All compounds were well characterized by IR, ¹H-, (13)C-NMR and GC-MS spectroscopy and physical data, while the structure of 4-(3-methyl-4,5,6,7-tetrahydro-2H-indazol-2-yl)benzoic acid (3e) was also determined by single crystal X-ray analysis.
Subcellular compartmentation of the ubiquitous second messenger cAMP has been widely proposed as a mechanism to explain unique receptor-dependent functional responses. How exactly compartmentation is achieved, however, has remained a mystery for more than 40 years. In this study, we developed computational and mathematical models to represent a subcellular sarcomeric space in a cardiac myocyte with varying detail. We then used these models to predict the contributions of various mechanisms that establish subcellular cAMP microdomains. We used the models to test the hypothesis that phosphodiesterases act as functional barriers to diffusion, creating discrete cAMP signaling domains. We also used the models to predict the effect of a range of experimentally measured diffusion rates on cAMP compartmentation. Finally, we modeled the anatomical structures in a cardiac myocyte diad, to predict the effects of anatomical diffusion barriers on cAMP compartmentation. When we incorporated experimentally informed model parameters to reconstruct an in silico subcellular sarcomeric space with spatially distinct cAMP production sites linked to caveloar domains, the models predict that under realistic conditions phosphodiesterases alone were insufficient to generate significant cAMP gradients. This prediction persisted even when combined with slow cAMP diffusion. When we additionally considered the effects of anatomic barriers to diffusion that are expected in the cardiac myocyte dyadic space, cAMP compartmentation did occur, but only when diffusion was slow. Our model simulations suggest that additional mechanisms likely contribute to cAMP gradients occurring in submicroscopic domains. The difference between the physiological and pathological effects resulting from the production of cAMP may be a function of appropriate compartmentation of cAMP signaling. Therefore, understanding the contribution of factors that are responsible for coordinating the spatial and temporal distribution of cAMP at the subcellular level could be important for developing new strategies for the prevention or treatment of unfavorable responses associated with different disease states.
The synergistic Ag(+) /X2 system (X=Cl, Br, I) is a very strong, but ill-defined oxidant-more powerful than X2 or Ag(+) alone. Intermediates for its action may include [Agm (X2 )n ](m+) complexes. Here, we report on an unexpectedly variable coordination chemistry of diiodine towards this direction: (A)Ag-I2 -Ag(A), [Ag2 (I2 )4 ](2+) (A(-) )2 and [Ag2 (I2 )6 ](2+) (A(-) )2 ⋅(I2 )x≈0.65 form by reaction of Ag(A) (A=Al(OR(F) )4 ; R(F) =C(CF3 )3 ) with diiodine (single crystal/powder XRD, Raman spectra and quantum-mechanical calculations). The molecular (A)Ag-I2 -Ag(A) is ideally set up to act as a 2 e(-) oxidant with stoichiometric formation of 2 AgI and 2 A(-) . Preliminary reactivity tests proved this (A)Ag-I2 -Ag(A) starting material to oxidize n-C5 H12 , C3 H8 , CH2 Cl2 , P4 or S8 at room temperature. A rough estimate of its electron affinity places it amongst very strong oxidizers like MF6 (M=4d metals). This suggests that (A)Ag-I2 -Ag(A) will serve as an easily in bulk accessible, well-defined, and very potent oxidant with multiple applications.
Nanoscale stress-sensing can be used across fields ranging from detection of incipient cracks in structural mechanics to monitoring forces in biological tissues. We demonstrate how tetrapod quantum dots (tQDs) embedded in block copolymers act as sensors of tensile/compressive stress. Remarkably, tQDs can detect their own composite dispersion and mechanical properties with a switch in optomechanical response when tQDs are in direct contact. Using experimental characterizations, atomistic simulations and finite-element analyses, we show that under tensile stress, densely packed tQDs exhibit a photoluminescence peak shifted to higher energies ("blue-shift") due to volumetric compressive stress in their core; loosely packed tQDs exhibit a peak shifted to lower energies ("red-shift") from tensile stress in the core. The stress shifts result from the tQD's unique branched morphology in which the CdS arms act as antennas that amplify the stress in the CdSe core. Our nanocomposites exhibit
 excellent cyclability and scalability with no degraded properties of the host polymer. Colloidal tQDs allow sensing in many materials to potentially enable autoresponsive, smart structural nanocomposites that self-predict impending fracture.
Road safety education for children is one of the most important means for raising awareness of road safety and for educating children to behave safely as pedestrians, bicycle riders, and vehicle passengers. The current research presents a novel attempt to examine the effect of a unique road safety educational program for kindergarten children on a secondary target group-the parents. The program, named the "Zahav Bagan" program (ZBP), is presented at kindergartens once a week during the entire academic year. It is conducted by senior citizen volunteers and is part of the formal education of the children. The main purpose of the current study was to compare the behavior, awareness, and knowledge about child road safety, of two groups of parents-those whose children participated in the ZBP group, and those whose children did not; this latter group was the control group. A telephone-based survey was conducted using a sample of 76 ZBP parents and 59 control group parents. Results of the survey showed no effect of ZBP on parents' knowledge of child road safety law and recommendations, but more importantly, the results did show a significant effect in terms of parents' observance of safe behavior and in their awareness of road safety in everyday life. These results confirm the importance of educational programs on road safety, especially as triggers and reminders to children and to their parents, to act as cautious road users.
Many oxygenated hydrocarbon species formed during combustion, such as furans, are highly toxic and detrimental to human health and the environment. These species may also increase the hygroscopicity of soot and strongly influence the effects of soot on regional and global climate. However, large furans and associated oxygenated species have not previously been observed in flames, and their formation mechanism and interplay with polycyclic aromatic hydrocarbons (PAHs) are poorly understood. We report on a synergistic computational and experimental effort that elucidates the formation of oxygen-embedded compounds, such as furans and other oxygenated hydrocarbons, during the combustion of hydrocarbon fuels. We used ab initio and probabilistic computational techniques to identify low-barrier reaction mechanisms for the formation of large furans and other oxygenated hydrocarbons. We used vacuum-UV photoionization aerosol mass spectrometry and X-ray photoelectron spectroscopy to confirm these predictions. We show that furans are produced in the high-temperature regions of hydrocarbon flames, where they remarkably survive and become the main functional group of oxygenates that incorporate into incipient soot. In controlled flame studies, we discovered ∼100 oxygenated species previously unaccounted for. We found that large alcohols and enols act as precursors to furans, leading to incorporation of oxygen into the carbon skeletons of PAHs. Our results depart dramatically from the crude chemistry of carbon- and oxygen-containing molecules previously considered in hydrocarbon formation and oxidation models and spearhead the emerging understanding of the oxidation chemistry that is critical, for example, to control emissions of toxic and carcinogenic combustion by-products, which also greatly affect global warming.
It has been generally assumed that partner's erectile dysfunction, premature, and delayed ejaculation play a significant role in determining female sexual dysfunction (FSD). This study aimed to evaluate the role of the male partner's sexual function, as perceived by women, in determining FSD. A consecutive series of 156 heterosexual women consulting our clinic for FSD was retrospectively studied. All patients underwent a structured interview and completed the Female Sexual Function Index (FSFI). FSFI total score decreased as a function of partner's age, conflicts within the couple, relationship without cohabitation and the habit of engaging in intercourse to please the partner; FSFI total score increased as a function of frequency of intercourse, attempts to conceive and fertility-focused intercourse. FSFI total score showed a negative, stepwise correlation with partner's perceived hypoactive sexual desire (HSD) (r = -0.327; p < 0.0001), whereas no significant correlation was found between FSFI and erectile dysfunction, premature and delayed ejaculation. In an age-adjusted model, partner's HSD was negatively related to FSFI total score (Wald = 9.196, p = 0.002), arousal (Wald = 7.893, p = 0.005), lubrication (Wald = 5.042, p = 0.025), orgasm (Wald = 9.293, p = 0.002), satisfaction (Wald = 12.764, p < 0.0001), and pain (Wald = 6.492, p = 0.011) domains. Partner's HSD was also significantly associated with somatized anxiety, low frequency of intercourse, low partner's care for the patient's sexual pleasure, and with a higher frequency of masturbation, even after adjusting for age. In patients not reporting any reduction in libido, FSFI total score was significantly lower when their partner's libido was low (p = 0.041); the correlation disappeared if the patient also experienced HSD. In conclusion, the presence of erectile dysfunction, premature, and delayed ejaculation of the partner may not act as a primary contributing factor to FSD, as determined by FSFI scores; conversely, women's sexuality seems to be mostly impaired by the perceived reduction in their partner's sexual interest.
In females, ovarian estradiol modulates kisspeptin (Kiss-1) synthesis to act as an obligatory regulator of downstream gonadotropin release in vivo, via stimulation of GnRH neurons. Changes in the ovarian condition are relayed to the neuroendocrine hypothalamus via two sexually dimorphic Kiss-1 populations, located in the anteroventral periventricular (AVPV) and arcuate nuclei, conveying estradiol-positive and -negative feedback, respectively. To elucidate how differential responsiveness to estradiol is mediated in these populations, we generated two kisspeptin-secreting cell lines from an adult kiss1-green fluorescent protein (GFP) female mouse. These lines recapitulate in vivo responsiveness to estradiol, with KTaV-3 (AVPV) cells demonstrating significantly increased kiss1 expression under high physiological estradiol exposure, whereas KTaR-1 (arcuate) cells exhibit kiss1 suppression after lower estradiol exposure. Baseline expression of estrogen receptor-α (esr1) differs significantly between KTaV-3 and KTaR-1 cells, with KTaR-1 cells demonstrating higher basal expression of esr1. Estradiol stimulation of kiss1 expression in KTaV-3 cells is modulated in a dose-dependent manner up to 25.0 pM, with less responsiveness observed at higher doses (>50.0 pM). In contrast, KTaR-1 kiss1 attenuates at lower estradiol doses (2.0-5.0 pM), returning to baseline levels at 25.0 pM and greater. Furthermore, the expression of the core clock genes bmal1 and per2 show normal rhythms in KTaV-3 cells, regardless of estradiol treatment. Conversely, KTaR-1 antiphasic transcription of bmal1 and per2 is phase delayed by low estradiol treatment. Strikingly, estradiol induces circadian rhythms of kiss1 expression only in KTaV-3 cells. Further exploration into estradiol responsiveness will reveal mechanisms responsible for the differential expression pattern demonstrated in vivo between these cell types.
Colon cancer (CC) likes many epithelial-derived cancers, resulting from a complex tumorigenic process. However, the exactly mechanisms of development and progression of CC are still unknown. In this study, integrated analysis in the GSE33113 and Fudan University Shanghai Cancer Center Hospital datasets revealed that WISP1 expression was significantly increased in CC cases, positivity correlated with the advanced pathologic stage and a poor prognosis was more likely in CC patients with higher levels of WISP1. Downregulation of WISP1 inhibited cell proliferation and invasion through increasing apoptosis and blocking cell cycle at G1 phase in CC LOVO and RKO cells. Besides, Gene set enrichment analysis (GSEA) revealed that relative genes involved in the Cell adhesion molecules and Cytokine-cytokine receptor interaction pathways were enriched in WISP1-higher expression patients. Western blot analysis showed that Cell adhesion molecules pathway associated genes (ICAM- 1, VCAM-1, SDC2 and CDH2) and Cytokine-cytokine receptor interaction pathway associated genes (VEGFC, CCL18, CXCR4 and TGFBR1) were also modulated by WISP1 downregulation. Then, we found that the protein β-catenin was identified as a binding partner of WISP1 and mediated the functions of WISP1 through promoting cell proliferation and invasion in LOVO and RKO cells. Further in vivo tumor formation study in nude mice indicated that inhibition of WISP1 delayed the progress of tumor formation and inhibited PCNA expression. These results indicate that WISP1 could act as an oncogene and may serve as a promising therapeutic strategy for colon cancer.
Asthma is the most commonly encountered chronic disease in children. Periodic assessment of asthma severity and control is an integral part of asthma management, but patients with uncontrolled asthma don't always schedule routine asthma care visits. The aim of this project was to improve asthma control and severity screening in a primary care setting by using a validated tool for all visits for patients with a diagnosis of asthma aged 4-21 years. Our QI team developed a protocol to administer the Asthma Control Test (TM), a validated questionnaire to assess asthma control. The stakeholders involved were the physicians, nursing staff, and the Health Information Team (HIT). All patients who had a prior diagnosis
 of asthma or with an asthma medication in their chart, who presented for any clinical visit including asthma were administered ACT. The staff scored the ACT and included the form in the encounter sheet so that the physicians can review the scores, address the asthma control, severity, and document in the chart. The number of patients whose asthma control was assessed improved from 10% per year to 85% after the three PDSA cycles. Administration of the tool did not impact the flow of the patients in a busy primary care practice. Screening asthma severity and control for patients diagnosed with asthma with a validated questionnaire when presenting for any chief complaint including asthma will help the provider address the severity and control of asthma symptoms in a timely manner and would potentially help prevent unwanted emergency department or urgent care usage.
Acute graft-versus-host disease (aGvHD) continues to be a major obstacle to allogeneic haematopoietic stem cell transplantation. Thymic damage secondary to aGvHD along with corticosteroids and other non-selective T lymphocyte-suppressive agents used in the treatment of aGvHD concurrently impair thymopoiesis and negatively impact on immunoreconstitution of the adaptive immune compartment and ultimately adversely affect clinical outcome. Extracorporeal photopheresis (ECP) is an alternative therapeutic strategy that appears to act in an immunomodulatory fashion, potentially involving regulatory T lymphocytes and dendritic cells. By promoting immune tolerance and simultaneously avoiding systemic immunosuppression, ECP could reduce aGvHD and enable a reduction in other immunosuppression, allowing thymic recovery, restoration of normal T lymphopoiesis, and complete immunoreconstitution with improved clinical outcome. Although the safety and efficacy of ECP has been demonstrated, further randomised controlled studies are needed as well as elucidation of the underlying mechanisms responsible and the effect of ECP on thymic recovery.
Klebsiella pneumoniae subsp. pneumoniae KP617 is a pathogenic strain that coproduces OXA-232 and NDM-1 carbapenemases. We sequenced the genome of KP617, which was isolated from the wound of a Korean burn patient, and performed a comparative genomic analysis with three additional strains: PittNDM01, NUHL24835 and ATCC BAA-2146.
The complete genome of KP617 was obtained via multi-platform whole-genome sequencing. Phylogenetic analysis along with whole genome and multi-locus sequence typing of genes of the Klebsiella pneumoniae species showed that KP617 belongs to the WGLW2 group, which includes PittNDM01 and NUHL24835. Comparison of annotated genes showed that KP617 shares 98.3 % of its genes with PittNDM01. Nineteen antibiotic resistance genes were identified in the KP617 genome: bla OXA-1 and bla SHV-28 in the chromosome, bla NDM-1 in plasmid 1, and bla OXA-232 in plasmid 2 conferred resistance to beta-lactams; however, colistin- and tetracycline-resistance genes were not found. We identified 117 virulence factors in the KP617 genome, and discovered that the genes encoding these factors were also harbored by the reference strains; eight genes were lipopolysaccharide-related and four were capsular polysaccharide-related. A comparative analysis of phage-associated regions indicated that two phage regions are specific to the KP617 genome and that prophages did not act as a vehicle for transfer of antimicrobial resistance genes in this strain.
Whole-genome sequencing and bioinformatics analysis revealed similarity in the genome sequences and content, and differences in phage-related genes, plasmids and antimicrobial resistance genes between KP617 and the references. In order to elucidate the precise role of these factors in the pathogenicity of KP617, further studies are required.
Carbonic anhydrases (CAs, EC 4.2.1.1) catalyse the interconversion between CO2 and bicarbonate as well as other hydrolytic reactions. Among the six genetic families known to date, the α-, β-, γ-, δ-, ζ- and η-CAs, detailed kinetic and X-ray crystallographic studies have allowed a deep understanding of the structure-function relationship in this superfamily of proteins. A metal hydroxide nucleophilic species of the enzyme, and a unique active site architecture, with half of it hydrophilic and the opposing part hydrophobic, allow these enzymes to act as some of the most effective catalysts known in Nature. The CA activation and inhibition mechanisms are also known in detail, with a large number of new inhibitor classes being described in the last years. Apart from the zinc binders, some classes of inhibitors anchor to the metal ion coordinated nucleophile, others occlude the entrance of the active site cavity and more recently, compounds binding outside the active site were described. CA inhibition has therapeutic applications for drugs acting as diuretics, antiepileptics, antiglaucoma, antiobesity and antitumour agents. Targeting such enzymes from pathogens may lead to novel anti-infectives. Successful structure-based drug design campaigns allowed the discovery of highly isoform selective CA inhibitors (CAIs), which may lead to a new generation of drugs targeting these widespread enzymes. The use of CAs in CO2 capture processes for mitigating the global temperature rise has also been investigated more recently.
DNA damage tolerance facilitates the progression of replication forks that have encountered obstacles on the template strands. It involves either translesion DNA synthesis initiated by proliferating cell nuclear antigen monoubiquitination or less well-characterized fork reversal and template switch mechanisms. Herein, we characterize a novel tolerance pathway requiring the tumor suppressor p53, the translesion polymerase ι (POLι), the ubiquitin ligase Rad5-related helicase-like transcription factor (HLTF), and the SWI/SNF catalytic subunit (SNF2) translocase zinc finger ran-binding domain containing 3 (ZRANB3). This novel p53 activity is lost in the exonuclease-deficient but transcriptionally active p53(H115N) mutant. Wild-type p53, but not p53(H115N), associates with POLι in vivo. Strikingly, the concerted action of p53 and POLι decelerates nascent DNA elongation and promotes HLTF/ZRANB3-dependent recombination during unperturbed DNA replication. Particularly after cross-linker-induced replication stress, p53 and POLι also act together to promote meiotic recombination enzyme 11 (MRE11)-dependent accumulation of (phospho-)replication protein A (RPA)-coated ssDNA. These results implicate a direct role of p53 in the processing of replication forks encountering obstacles on the template strand. Our findings define an unprecedented function of p53 and POLι in the DNA damage response to endogenous or exogenous replication stress.
Highly efficient subtractive tri-color filters of cyan, magenta, and yellow with enhanced color purity and robustness have been proposed and realized, by exploiting a silicon-aluminum (Si-Al) hybrid-nanodisk (ND) metasurface atop a Si substrate. The aspect ratio of the Si-Al hybrid ND is much lower than that of the conventional Si nanowire, which is disadvantageous due to its fragility and low color purity. In response to incident light impinging upon the metasurface, the hybrid-NDs individually play the role in exciting a magnetic dipole (MD) resonance through the mediation of Mie-scattering between the hybrid ND and air. The light stored in the resonance is coupled to the substrate, giving rise to a suppressed reflection. By virtue of the top Al ND, the excited MD resonance is strongly confined by the Si ND. As a consequence, a near-zero resonant dip that exhibits high off-resonance reflection and narrow bandwidth is produced for embodying highly efficient tri-color filters with enhanced color purity. The spectral position can be tuned by a simple adjustment of the hybrid-ND diameter. A full-color palette was successfully created with a high color purity and large color gamut. The proposed devices may be applied for photorealistic high-resolution color printing and holographic displays.
The preparation of novel one-dimensional core-shell Fe/Fe2 O3 nanowires as anodes for high-performance lithium-ion batteries (LIBs) is reported. The nanowires are prepared in a facile synthetic process in aqueous solution under ambient conditions with subsequent annealing treatment that could tune the capacity for lithium storage. When this hybrid is used as an anode material for LIBs, the outer Fe2 O3 shell can act as an electrochemically active material to store and release lithium ions, whereas the highly conductive and inactive Fe core functions as nothing more than an efficient electrical conducting pathway and a remarkable buffer to tolerate volume changes of the electrode materials during the insertion and extraction of lithium ions. The core-shell Fe/Fe2 O3 nanowire maintains an excellent reversible capacity of over 767 mA h g(-1) at 500 mA g(-1) after 200 cycles with a high average Coulombic efficiency of 98.6 %. Even at 2000 mA g(-1) , a stable capacity as high as 538 mA h g(-1) could be obtained. The unique composition and nanostructure of this electrode material contribute to this enhanced electrochemical performance. Due to the ease of large-scale fabrication and superior electrochemical performance, these hybrid nanowires are promising anode materials for the next generation of high-performance LIBs.
Peroxidases (POXs) make up a large superfamily of enzymes that act in a wide range of biological mechanisms, including maintaining appropriate redox balances within cells, among other actions. In this study, we cloned a sequence that encodes a POX protein, SaPOX, from wheat aphids, Sitobion avenae. Amino acid sequence alignment showed the SaPOX sequence was conserved with POXs from other insect species. SaPOX mRNA accumulations were present
 in all nymphal and adult stages, at higher levels during the first and second instar, and lower during later stages in the life cycle. Ingestion of dsRNA specific to POX led to reduced SaPOX mRNA accumulation. Sitobion avenae nymphs continuously exposed to dietary dsPOX via an artificial diet led to reduced survival rate and ecdysis index. We infer that POX is important to maintain the growth and development of S. avenae.
Adaptive Speech Reception Threshold in noise (SRTn) measurements are often used to make comparisons between alternative hearing aid (HA) systems. Such measurements usually do not constrain the signal-to-noise ratio (SNR) at which testing takes place. Meanwhile, HA systems increasingly include nonlinear features that operate differently in different SNRs, and listeners differ in their inherent SNR requirements.
To show that SRTn measurements, as commonly used in comparisons of alternative HA systems, suffer from threats to their validity, to illustrate these threats with examples of potentially invalid conclusions in the research literature, and to propose ways to tackle these threats.
An examination of the nature of SRTn measurements in the context of test theory, modern nonlinear HAs, and listener diversity.
Examples from the audiological research literature were used to estimate typical interparticipant variation in SRTn and to illustrate cases where validity may have been compromised.
There can be no doubt that SRTn measurements, when used to compare nonlinear HA systems, in principle, suffer from threats to their internal and external/ecological validity. Interactions between HA nonlinearities and SNR, and interparticipant differences in inherent SNR requirements, can act to generate misleading results. In addition, SRTn may lie at an SNR outside the range for which the HA system is designed or expected to operate in. Although the extent of invalid conclusions in the literature is difficult to evaluate, examples of studies were nevertheless identified where the risk of each form of invalidity is significant. Reliable data on ecological SNRs is becoming available, so that ecological validity can be assessed. Methodological developments that can reduce the risk of invalid conclusions include variations on the SRTn measurement procedure itself, manipulations of stimulus or scoring conditions to place SRTn in an ecologically relevant range, and design and analysis approaches that take account of interparticipant differences.
COL2A1 mutations causing haploinsufficiency of type II collagen cause type 1 Stickler syndrome that has a high risk of retinal detachment and failure of the vitreous to develop normally. Exon 2 of COL2A1 is alternatively spliced, expressed in the eye but not in mature cartilage and encodes a region that binds growth factors TGFβ1 and BMP-2. We investigated how both an apparently de novo variant and a polymorphism in intron 2 altered the efficiency of COL2A1 exon 2 splicing and how the latter may act as a predisposing risk factor for the occurrence of posterior vitreous detachment (PVD)-associated rhegmatogenous retinal detachment (RRD) in the general population. Using amplification of illegitimate transcripts and allele-specific minigenes expressed in cultured cells, we demonstrate variability in exon 2 inclusion not only between different control individuals, but also between different COL2A1 alleles. We identify transacting factors that bind to allele-specific RNA sequences, and investigate the effect of knockdown and overexpression of these factors on exon 2 splicing efficiency. Finally, using a specific cohort of patients with PVD-associated RRD and a control population, we demonstrate a significant difference in the frequency of the COL2A1 intronic variant rs1635532 between the two groups.
Prions are infectious protein particles that replicate by templating their aggregated state onto soluble protein of the same type. Originally identified as the causative agent of transmissible spongiform encephalopathies, prions in yeast (Saccharomyces cerevisiae) are epigenetic elements of inheritance that induce phenotypic changes of their host cells. The prototype yeast prion is the translation termination factor Sup35. Prions composed of Sup35 or its modular prion domain NM are heritable and are transmitted vertically to progeny or horizontally during mating. Interestingly, in mammalian cells, protein aggregates derived from yeast Sup35 NM behave as true infectious entities that employ dissemination strategies similar to those of mammalian prions. While transmission is most efficient when cells are in direct contact, we demonstrate here that cytosolic Sup35 NM prions are also released into the extracellular space in association with nanometer-sized membrane vesicles. Importantly, extracellular vesicles are biologically active and are taken up by recipient cells, where they induce self-sustained Sup35 NM protein aggregation. Thus, in mammalian cells, extracellular vesicles can serve as dissemination vehicles for protein-based epigenetic information transfer.
Prions are proteinaceous infectious particles that propagate by templating their quaternary structure onto nascent proteins of the same kind. Prions in yeast act as heritable epigenetic elements that can alter the phenotype when transmitted to daughter cells or during mating. Prion activity is conferred by so-called prion domains often enriched in glutamine and asparagine residues. Interestingly, many mammalian proteins also contain domains with compositional similarity to yeast prion domains. We have recently provided a proof-of-principle demonstration that a yeast prion domain also retains its prion activity in mammalian cells. We demonstrate here that cytosolic prions composed of a yeast prion domain are also packaged into extracellular vesicles that transmit the prion phenotype to bystander cells. Thus, proteins with prion-like domains can behave as proteinaceous information molecules that exploit the cellular vesicle trafficking machinery for intercellular long-distance dissemination.
Small mammals provide ecosystem services, acting, for example, as pollinators and seed dispersers. In addition, they are also disease reservoirs that can be detrimental to human health and they can also act as crop pests. Knowledge of their dispersal preferences is therefore useful for population management and landscape planning. Genetic data were used alongside landscape data to examine the influence of the landscape on the demographic connectedness of the Natal multimammate mouse (Mastomys natalensis) and to identify landscape characteristics that influence the genetic structure of this species across a spatially and temporally varying environment. The most significant landscape features shaping gene flow were aspect, vegetation cover, topographic complexity (TC) and rivers, with western facing slopes, topographic complexity and rivers restricting gene flow. In general, thicket vegetation was correlated with increased gene flow. Identifying features of the landscape that facilitate movement/dispersal in M. natalensis potentially has application for other small mammals in similar ecosystems. As the primary reservoir host of the zoonotic Lassa virus, a landscape genetics approach may have applications in determining areas of high disease risk to humans. Identifying these landscape features may also be important in crop management due to damage by rodent pests.
The increased use of silver nanoparticles (AgNP) in industrial and consumer products worldwide has resulted in their release to aquatic environments. Previous studies have mainly focused on the effects of AgNP on pelagic species, whereas few studies have assessed the risks to benthic invertebrates despite the fact that the sediments act as a large potential sink for NPs. In this study, the toxicity of sediment-associated AgNP was evaluated using the standard sediment toxicity test for chemicals provided by the Organization of Economic Cooperation and Development. The freshwater benthic oligochaete worm Lumbriculus variegatus was exposed to sediment-associated AgNP in artificial and natural sediments at concentrations ranging from 91 to 1098 mg Ag/kg sediment dry weight. Silver nitrate (AgNO3) was used as a reference compound for Ag toxicity. The measured end points of toxicity were mortality, reproduction, and total biomass. In addition, the impact of sediment-associated AgNP on the feeding rate of L. variegatus was studied in a similar test set-up as mentioned previously. The addition of AgNP into the sediment significantly affected the feeding rate and reproduction of the test species only at the highest concentration (1098 mg/kg) of Ag in the natural sediment with the lowest pH. In comparison, the addition of AgNO3 resulted in reproductive toxicity in every tested sediment, and Ag was more toxic when spiked as AgNO3 than AgNP. In general, sediments were observed to have a high capacity to eliminate the AgNP-derived toxicity. However, the capacity of sediments to eliminate the toxicity of Ag follows a different pattern when spiked as AgNP than AgNO3. The results of this study emphasize the importance of sediment-toxicity testing and the role of sediment properties when evaluating the environmental effects and behavior of AgNP in sediments.
In June 2008, a surveillance study for metals in honeybees was performed in the Netherlands. Randomly, 150 apiaries were selected. In each apiary, five colonies were sampled. Per apiary, the hive samples were pooled. The apiary sample was analysed for Al, As, Ba, Cd, Co, Cr, Cu, Li, Mn, Mo, Ni, Sb, Se, Sn, Sr, Ti, V and Zn. All metals could be detected in all apiaries. As, Li, Sb, Sn and V were detected in part of the apiaries. The overall picture showed a regional pattern. In apiaries in the east of the Netherlands, Al, Ba, Cr, Mn, Mo, Ni, Se and
 Ti are found in higher concentrations compared to the west. In-region variation was demonstrated, indicating local effects. The vicinity of the apiaries was mapped afterwards and characterised as land uses of >50 % agricultural area, >50 % wooded area, >50 % urban area and mixed land use within a circle of 28 km(2) around the apiary. The results indicated that in apiaries located in >50 % wooded areas, significantly higher concentrations of Al, Ba, Cd, Cr, Cu, Li, Mn, Mo, Ni, Sb, Sr, Ti and Zn were found compared to agricultural, urban and mixed land use areas. We conclude that (1) the ratio between metal concentrations varies per region, demonstrating spatial differences, and (2) there is in-region local variation per metal. The results indicate the impact of land use on metal concentrations in honeybees. For qualitative bioindication studies, regional, local and land use effects should be taken into account.
Staphylococcus aureus (S. aureus) is a formidable foe equipped with an armamentarium of virulence factors to thwart host defenses and establish a successful infection. Among these virulence factors, S. aureus produces several potent secreted proteins that act as cytotoxins, predominant among them the beta-barrel pore-forming toxins. These toxins play several roles in pathogenesis, including disruption of cellular adherens junctions at epithelial barriers, alteration of intracellular signaling events, modulation of host immune responses, and killing of eukaryotic immune and non-immune cells. This chapter provides an updated overview on the S. aureus beta-barrel pore-forming cytotoxins, the identification of toxin receptors on host cells, and their roles in pathogenesis.
Although anti-malarial medicines are free in Kenyan public health facilities, patients often seek treatment from private sector retail drug outlets. In mid-2010, the Affordable Medicines Facility-malaria (AMFm) was introduced to make quality-assured artemisinin-based combination therapy (ACT) accessible and affordable in private and public sectors.
Private sector retail drug outlets stocking anti-malarial medications within a surveillance area of approximately 220,000 people in a malaria perennial high-transmission area in rural western Kenya were identified via a census in September 2013. A cross-sectional study was conducted in September-October 2013 to determine availability and price of anti-malarial medicines and malaria rapid diagnostic tests (RDTs) in drug outlets. A standardized questionnaire was administered to collect drug outlet and personnel characteristics and availability and price of anti-malarials and RDTs.
Of 181 drug outlets identified, 179 (99 %) participated in the survey. Thirteen percent were registered pharmacies, 25 % informal drug shops, 46 % general shops, 13 % homesteads and 2 % other. One hundred sixty-five (92 %) had at least one ACT type: 162 (91 %) had recommended first-line artemether-lumefantrine (AL), 22 (12 %) had recommended second-line dihydroartemisinin-piperaquine (DHA-PPQ), 85 (48 %) had sulfadoxine-pyrimethamine (SP), 60 (34 %) had any quinine (QN) formulation, and 14 (8 %) had amodiaquine (AQ) monotherapy. The mean price (range) of an adult treatment course for AL was $1.01 ($0.35-4.71); DHA-PPQ was $4.39 ($0.71-7.06); QN tablets were $2.24 ($0.12-4.71); SP was $0.62 ($0.24-2.35); AQ monotherapy was $0.42 ($0.24-1.06). The mean AL price with or without the AMFm logo did not differ significantly ($1.01 and 1.07, respectively; p = 0.45). Only 17 (10 %) drug outlets had RDTs; 149 (84 %) never stocked RDTs. The mean RDT price was $0.92 ($0.24-2.35).
Most outlets never stocked RDTs; therefore, testing prior to treatment was unlikely for customers seeking treatment in the private retail sector. The recommended first-line treatment, AL, was widely available. Although SP and AQ monotherapy are not recommended for treatment, both were less expensive than AL, which might have caused preferential use by customers. Interventions that create community demand for malaria diagnostic testing prior to treatment and that increase RDT availability should be encouraged.
A combination of dietary guild analysis and nitrogen (δ(15) N) and carbon (δ(13) C) stable-isotope analysis was used to assess the trophic structure of the fish community in Rhode Island and Block Island Sounds, an area off southern New England identified for offshore wind energy development. In the autumn of 2009, 2010 and 2011, stomach and tissue samples were taken from 20 fish and invertebrate species for analysis of diet composition and δ(15) N and δ(13) C signatures. The food chain in Rhode Island and Block Island Sounds comprises approximately four trophic levels within which the fish community is divided into distinct dietary guilds, including planktivores, benthivores, crustacivores and piscivores. Within these guilds, inter-species isotopic and dietary overlap is high, suggesting that resource partitioning or competitive interactions play a major role in structuring the fish community. Carbon isotopes indicate that most fishes are supported by pelagic phytoplankton, although there is evidence that benthic production also plays a role, particularly for obligate benthivores such as skates Leucoraja spp. This type of analysis is useful for developing an ecosystem-based approach to management, as it identifies species that act as direct links to basal resources as well as species groups that share trophic roles.
A novel approach to potentially improve pig growth and welfare is to supplement environments with biologically meaningful odors that are deficient. The post-weaning environment lacks maternal odors that may contribute to the often-observed post-weaning lag in growth and health challenges. A recently reported rabbit maternal pheromone (2-methyl-2-butenal (2M2B)) may act as an interomone in the pig. The objective of this study was to determine if providing a maternal pheromone/interomone during transport and the post-weaning environment may enhance pig performance. A total of 40 replicated pens were used in a factorial arrangement of two transport olfactory experiences (Control v. 2M2B), two nursery olfactory experiences (Control v. 2M2B) and two sexes (barrow v. gilt). Pig body weight, average daily gain (ADG), average daily feed intake (ADFI) and gain : feed ratio (G : F) were measured and calculated over a 28-day post-weaning period. Pig sex and application of 2M2B during transport had no effect on pig performance. However, pigs that had 2M2B applied to their feeder at weaning had 15% greater feed intake (0.74 v. 0.64±0.03 kg/day, P<0.01) and 12% greater ADG (0.27 v. 0.24 kg/day, P<0.05) than control pigs. G : F ratio was not different between treatments. The interomone 2M2B is a novel, safe molecule that can improve pig post-weaning performance. This report highlights a new area of study and a natural class of compounds that can improve pig performance and potentially improve pig welfare.
Among the Karo of Indonesia, the frequency of matrilateral cross-cousin (impal) marriage has declined in recent decades. We conducted a vignette experiment to assess the contributions of a handful of factors in shaping this pattern. Surprisingly, we found that cosocialization of a hypothetical woman with her impal led to increased judgments of marriage likelihood and decreased feelings of disgust in male and female respondents (n = 154). We also found that females, more than males, judged impal marriage more likely when there were practical advantages. Finally, we found that younger men expressed more disgust in response to impal marriages than did older men, while women displayed an opposite but weaker reaction. This suggests the existence of gender-specific changes in attitudes toward the practice, indicating that a full understanding may require the application of sexual conflict theory. Our study illustrates the potential utility-and limitations-of vignette experiments for studying social change.
The nonstructural protein 1 (NS1) of influenza A viruses can act as a viral replication enhancer by antagonizing type I interferon (IFN) induction and response in infected cells. We previously reported that A/Puerto Rico/8/1934 (H1N1) (PR8) containing the NS1 gene derived from A/swine/IA/15/1930 (H1N1) (IA30) replicated more efficiently than the wild type virus. Here, we identified amino acids in NS1 critical for enhancing viral replication.
To identify a key amino acid in NS1 which can increase the virus replication, growth kinetics of PR8 viruses encoding single mutation in NS1 were compared in A549 cells. NS1 mutant functions were studied using dsRNA-protein pull down, RIG-I mediated IFNβ-promoter activity assays and growth curve analysis in murine lung epithelial type I (Let1) cells.
The G45R mutation in the NS1 of PR8 (G45R/NS1) virus is critical for the enhanced viral replication in A549 cells. G45R/NS1 slightly decreased NS1 binding to dsRNA but did not interfere with its suppression of RIG-I-mediated type I IFN production. Likewise, replication of G45R/NS1 virus was increased in comparison to wild type virus in both wild type and type I interferon receptor null Let1 cells.
The non-conserved amino acid, R45, enhances viral replication which is apparently independent of dsRNA binding and suppression of type I IFN, suggesting a non-characterized function of NS1 for the enhanced viral replication. As G45R/NS1 virus induced the type I IFN induction and response in infected A549 cells, it is also interesting to investigate virus virulence for further studies.
Maternal hyperoxygenation has been reported to increase foetal oxygen saturation, and is frequently employed during intra-partum episodes of foetal compromise as a component of in utero resuscitation. However, there has been little investigation of its influence on foetal haemodynamics, particularly in
 appropriately grown foetuses.
This cohort study was undertaken between July 2013 and November 2013. All participants underwent an ultrasound scan prior to active labour (<4 cm dilated), during which foetal biometry, umbilical and middle cerebral artery Dopplers were recorded. Doppler measurements were then repeated after a 20-min period (to act as a control for subsequent measurements after oxygen therapy). Women were then asked to breathe 60% oxygen through Venturi valve masks for 20 min, after which the Doppler measurements were repeated.
Twenty women were recruited to the study. No significant change in the foetal cerebro-umbilical (CU) ratio was observed following maternal oxygen therapy. The degree of change in Doppler parameters after oxygen therapy was not related to the baseline value of the Doppler parameter.
Maternal hyperoxygenation using 60% oxygen concentration over a 20-min period does not influence foetal umbilical or middle cerebral artery Doppler in appropriately grown foetuses. No adverse effects of maternal oxygen therapy were observed.
Sexual behaviour is a core determinant of the HIV and sexually transmitted infection (STI) epidemics in women living in rural South Africa. Knowledge of sexual behaviour in these areas is limited, but constitutes essential information for a combination prevention approach of behavioural change and biomedical interventions.
This descriptive study was conducted in rural Mopani District, South Africa, as part of a larger study on STI. Women of reproductive age (18-49 years) who reported sexual activity were included regardless of the reason for visiting the facility. Questionnaires were administered to 570 women. We report sexual behaviour by age group, ethnic group and self-reported HIV status.
Young women (<25 years) were more likely to visit bars, practice fellatio, have concurrent sexual partners and report a circumcised partner than older women (>34 years); there was no difference for condom use during last sex act (36 % overall). Sotho women were more likely to report concurrent sexual partners whereas Shangaan women reported more frequent intravaginal cleansing and vaginal scarring practice in our analysis. HIV-infected women were older, had a higher number of lifetime sexual partners, reported more frequent condom use during the last sex act and were more likely to have a known HIV-infected partner than women without HIV infection; hormonal contraceptive use, fellatio, and a circumcised partner were less often reported.
This study provides insight into women's sexual behaviour in a rural South African region. There are important differences in sexual behaviour by age group and ethnicity and HIV status; these should be taken into account when designing tailor-made prevention packages.
Helicobacter pylori infection is the main risk factor for developing gastric cancer, with the influence of genetic, toxic and dietary factors. It is the fourth most common cancer and the second most deadly worldwide, so its prevention is important specially focusing on dietary habits, to be approached from the primary care setting.
Evaluate the influence of diet on the primary prevention of gastric cancer in patients with Helicobacter pylori infection.
Systematic review, the keywords "Helicobacter pylori", "diet" and "stomach neoplasms" were previously selected from the DeCS and MeSH structured vocabulary. Sources of primary and secondary databases were consulted, limits were established.
H. pylori infection and dietary factors may act synergistically in the development of gastric cancer and some cooking practices. Dietary factors may increase the risk of gastric cancer like the high consumption of salt, salty foods, saturated fat, red and processed meats, while fruits and vegetables may be considered as a protective factor, especially the high consumption of Allium and the cruciferous family.
The lifestyle and dietary habits may influence the development of gastric cancer, especially in patients with H. pylori infection. Decreasing consumption of salty, processed, smoked or pickled foods, red meat and saturated fat, avoiding toxins, and carrying out a diet rich in fruits and vegetables, in addition to eradicating the bacteria, can be considered the most effective preventive strategy against the risk of developing gastric cancer.
The reduction of DNA damage repair capacity in terminally differentiated cells may be involved in sensitivity to cancer chemotherapy drugs; however, the underlying molecular mechanism is still not fully understood. Herein, we evaluated the role of miR-638 in the regulation of DNA damage repair in terminally differentiated cells. Our results show that miR-638 expression was up-regulated during cellular terminal differentiation and involved in mediating DNA damage repair processes. Results from a luciferase reporting experiment show that structural maintenance of chromosomes (SMC)1A was a potential target of miR-638; this was verified by western blot assays during cell differentiation and DNA damage induction. Overexpression of miR-638 enhanced the sensitivity of cancer cells to cisplatin, thus reducing cell viability in response to chemotherapy drug treatment. Furthermore, miR-638 overexpression affected DNA damage repair processes by interfering with the recruitment of the DNA damage repair-related protein, γH2AX, to DNA break sites. These findings indicate that miR-638 might act as a sensitizer in cancer chemotherapy and accompany chemotherapy drugs to enhance chemotherapeutic efficacy and to improve the chance of recovery from cancer.
There is an urgent need to develop a puissant and environmentally benign antibacterial composite that act via multiple mechanisms to make response to the potentially daunting complexity of the microbial population and microbial antibiotic resistance. In this work, a facile and green approach, layer-by-layer self-assembly technology was applied to assemble polycation quaternized chitosan (QAC) and polyanion sodium alga acid onto magnetic nanoparticles (MNPs). Then silver nanoparticles (AgNPs) with stable and narrow-sized distribution in the range of 25-35 nm were immobilized on the surface of MNPs with L-ascorbic acid as reducing agent and organic multilayers as stabilizer. Through above modification on MNPs, we expected to achieve a green dual antibacterial and recyclable composite via the combined antibacterial action of QAC and AgNPs. Fourier transform infrared spectroscopy, X-ray diffraction, thermogravimetric analysis, transmission electron microscopy, zeta potentials, and dynamic light scattering were employed to confirm the success of the surface functionalization. Silver ion release process was detected by inductively coupled plasma mass spectrometry. Furthermore, the antibacterial properties of the biomaterials against Gram-negative Escherichia coli and Gram-positive Staphylococcus aureus were studied. The modified MNPs exhibited rapid, efficient, and long-lasting biocidal abilities against E. coli and S. aureus. The magnetic antibacterial composite still showed excellent antibacterial efficiency during five exposure/collection/recycle procedures.
Persons who inject drugs (PWID) may have less access to, and utilization of, health-care services, and African American PWID may be less likely than other racial groups to utilize health care in the United States. The present study evaluated the prevalence of health-care utilization (HCU) among a cohort of African American PWID in Baltimore. Data were from the 2012 Baltimore National HIV Behavioral Surveillance study. Participants were adult PWID and recruited using respondent-driven sampling (RDS). They completed a comprehensive sociobehavioral survey and voluntary HIV test with trained study interviewers. Analyses included descriptive and bivariate statistics to examine the prevalence of HCU, defined as seeing a health-care provider in the past year. Poisson regression assessed correlates of HCU. Participants were 61% male; 23% self-reported HIV seropositivity. Nearly 90% reported unemployment and/or disability; HCU prevalence was 85%. Significant negative correlates of HCU included age and higher injection frequency; positive correlates included previous incarceration and moderate financial stability. Interaction analyses showed unemployed publicly insured individuals had 30% higher HCU than unemployed and uninsured individuals (χ(2) = 2.52; p < .05). There is a need to improve health-care utilization among PWID. High prevalence of disability was still found, despite insurance coverage and access to care in this population. While the recent Affordable Care Act has increased health-care coverage and access, our results suggest that is only a first step to improving health outcomes among PWID; targeted intervention to integrate these individuals is still needed.
Cutaneous somatosensory nerves function to detect diverse stimuli that act upon the skin. In addition to their established sensory roles, recent studies have suggested that nerves may also modulate skin disorders including atopic dermatitis, psoriasis and cancer. Here, we describe protocols for testing the requirement for nerves in maintaining a cutaneous mechanosensory organ, the touch dome (TD). Specifically, we discuss methods for genetically labeling, harvesting and visualizing TDs by whole-mount staining, and for performing unilateral surgical denervation on mouse dorsal back skin. Together, these approaches can be used to directly compare TD morphology and gene expression in denervated as well as sham-operated skin from the same animal. These methods can also be readily adapted to examine the requirement for nerves in mouse models of skin pathology. Finally, the ability to repeatedly sample the skin provides an opportunity to monitor disease progression at different stages and times after initiation.
Zwitterion-functionalized
 polycations are ideal gene carriers with long circulation, high cellular uptaking and low cell viability. However, the trade-off between the DNA condensation efficiency and the cell viability must be addressed. The purpose of this study is to provide a microscopic insight into the DNA condensation process and to explore the effect of a zwitterionic block of zwitterion-functionalized polycation, which is of great significance in designing novel gene delivery systems. Poly[2-(dimethylamino)ethyl methacrylate-b-(sulfobetaine methacrylate)] (PDMAEMA-b-PSBMA) copolymers were synthesized and used as the model systems. Different from the conventional concept that the PSBMA zwitterionic block act only as the "stealthy" groups, the subtle differences in physical and colloidal characteristics between the polycation/DNA polyplexes show that the PSBMA segment is capable of wrapping DNA attributed to the quaternary ammonium cations, without compromising the DNA condensation capability. On the other hand, the incorporation of PSBMA block reduces the surface charge of the polyplexes, which substantially result in the inefficient transfection and the reduced cytotoxicity.
During motor behaviour, humans interact with the environment by for example manipulating objects and this is only possible because sensory feedback is constantly integrated into the central nervous system and these sensory inputs need to be weighted in order meet the task specific goals. Additional feedback presented as augmented feedback was shown to have an impact on motor control and motor learning. A number of studies investigated whether force or position feedback has an influence on motor control and neural activation. However, as in the previous studies the presentation of the force and position feedback was always identical, a recent study assessed whether not only the content but also the interpretation of the feedback has an influence on the time to fatigue of a sustained submaximal contraction and the (inhibitory) activity of the primary motor cortex using subthreshold transcranial magnetic stimulation. This paper describes one possible way to investigate the influence of the interpretation of feedback on motor behaviour by investigating the time to fatigue of submaximal sustained contractions together with the neuromuscular adaptations that can be investigated using surface EMG. Furthermore, the current protocol also describes how motor cortical (inhibitory) activity can be investigated using subthreshold TMS, a method known to act solely on the cortical level. The results show that when participants interpret the feedback as position feedback, they display a significantly shorter time to fatigue of a submaximal sustained contraction. Furthermore, subjects also displayed an increased inhibitory activity of the primary cortex when they believed to receive position feedback compared when they believed to receive force feedback. Accordingly, the results show that interpretation of feedback results in differences on a behavioural level (time to fatigue) that is also reflected in interpretation-specific differences in the amount of inhibitory M1 activity.
Reliable measures of muscle strength and functional capacity in older adults are essential. The aim of this study was to determine whether coefficients of variation (CVs) of individuals obtained at the first session can infer repeatability of performance in a subsequent session. Forty-eight healthy older adults (mean age 68.6 ± 6.1 years; age range 60 - 80 years) completed two assessment sessions, and on each occasion undertook: Dynamometry for isometric and isokinetic quadriceps strength, 6 metre fast walk (6mFWT), timed up and go (TUG), stair climb and descent, and vertical jump. Significant linear relationships were observed between CVs in session 1 and the percentage difference between sessions 1 and 2 for torque at 60, 120, 240 and 360º/s, 6mFWT, TUG, stair climb and stair descent. The results of this study could be used to establish criteria for determining an acceptably reliable performance in strength and functional tests.
Studies have examined the independent and additive effects of health behaviors (e.g., physical activity, diet, sleep, and smoking) on systemic inflammation, but we know little about whether different pairs of these behaviors differentially influence inflammation, which was the purpose of this study.
Cross-sectional.
The National Health and Nutrition Examination Survey (NHANES) 2005-2006.
A total of 2051 adults (≥20 years).
A questionnaire/interview was used to assess sleep and dietary behavior; physical activity was assessed via accelerometry; smoking was assessed via cotinine levels; and a blood sample was taken to assess systemic inflammation (C-reactive protein; [CRP]).
Multivariable linear regression analysis.
Six health behavior pairs were evaluated: (1) active and healthy diet, (2) active and adequate sleep, (3) active and nonsmoker, (4) healthy diet and adequate sleep, (5) healthy diet and nonsmoker, and (6) adequate sleep and nonsmoker. After adjusting for age, gender, race-ethnicity, poverty level, and chronic disease, only active and nonsmoker (β = -.15) and healthy diet and adequate sleep (β = -.16) were associated with CRP.
Regular physical activity and smoking avoidance and healthy eating and adequate sleep were the two health behavior pairs associated with less inflammation. This suggests that certain health behaviors may act synergistically on reducing systemic inflammation, whereas other health behavior combinations may not. Such knowledge may help to develop and implement tailored health behavior interventions.
Matrix metalloproteinase-3 is invariably upregulated in cancerous condition. So we aimed to determine serum level of MMP-3 in canine mammary tumors. The gene was expressed in E. coli system as ~43kDa recombinant protein, which was refolded, purified, and confirmed. Hyperimmune serum was raised against the expressed protein in rabbits and mice to standardize sandwich ELISA. ROC analysis revealed largest area under the curve of 0.998 with sensitivity (100%) and specificity (95%) for a cut-off value of 0.363 with respect to histopathological staining. The finding of the present study indicates that MMP-3 can act as a potential molecular marker for serodiagnosis of canine mammary carcinomas.
Here we describe an in vitro primary culture system for Caenorhabditis elegans germline stem cells. This culture system was used to identify a bacterial folate as a positive regulator of germ cell proliferation. Folates are a family of B-complex vitamins that function in one-carbon metabolism to allow the de novo synthesis of amino acids and nucleosides. We show that germ cell proliferation is stimulated by the folate 10-formyl-tetrahydrofolate-Glun both in vitro and in animals. Other folates that can act as vitamins to rescue folate deficiency lack this germ cell stimulatory activity. The bacterial folate precursor dihydropteroate also promotes germ cell proliferation in vitro and in vivo, despite its inability to promote one-carbon metabolism. The folate receptor homolog FOLR-1 is required for the stimulation of germ cells by 10-formyl-tetrahydrofolate-Glun and dihydropteroate. This work defines a folate and folate-related compound as exogenous signals to modulate germ cell proliferation.
In this issue of Developmental Cell, Chaudhari and colleagues (2016) use a novel method to create an in vitro proliferative cell line from tumorous C. elegans germ cells, and in the process discover that bacterial folates act as signals for proliferation, independent of their roles as vitamins.
How do plants make species-specific leaves and flowers with stereotypical size and shape? A new study in Developmental Cell finds that local spatiotemporal variability in cell growth rate is essential for robustness in organ geometry control, and reactive oxygen species act to suppress this local heterogeneity during organ maturation.
Benzo[a]pyrene (BaP) is a human carcinogen that covalently binds to DNA after activation by cytochrome P450 (P450). Here, we investigated whether NADH:cytochrome b5 reductase (CBR) in the presence of cytochrome b5 can act as sole electron donor to human P450 1A1 during BaP oxidation and replace the canonical NADPH:cytochrome P450 reductase (POR) system. We also studied the efficiencies of the coenzymes of these reductases, NADPH as a coenzyme of POR, and NADH as a coenzyme of CBR, to mediate BaP oxidation. Two systems containing human P450 1A1 were utilized: human recombinant P450 1A1 expressed with POR, CBR, epoxide hydrolase, and cytochrome b5 in Supersomes and human recombinant P450 1A1 reconstituted with POR and/or with CBR and cytochrome b5 in liposomes. BaP-9,10-dihydrodiol, BaP-7,8-dihydrodiol, BaP-1,6-dione, BaP-3,6-dione, BaP-9-ol, BaP-3-ol, a metabolite of unknown structure, and two BaP-DNA adducts were generated by the P450 1A1-Supersomes system, both in the presence of NADPH and in the presence of NADH. The major BaP-DNA adduct detected by (32)P-postlabeling was characterized as 10-(deoxyguanosin-N(2)-yl)-7,8,9-trihydroxy-7,8,9,10-tetrahydro-BaP (assigned adduct 1), while the minor adduct is probably a guanine adduct derived from 9-hydroxy-BaP-4,5-epoxide (assigned adduct 2). BaP-3-ol as the major metabolite, BaP-9-ol, BaP-1,6-dione, BaP-3,6-dione, an unknown metabolite, and adduct 2 were observed in the system using P450 1A1 reconstituted with POR plus NADPH. When P450 1A1 was reconstituted with CBR and cytochrome b5 plus NADH, BaP-3-ol was the predominant metabolite too, and an adduct 2 was also generated. Our results demonstrate that the NADH/cytochrome b5/CBR system can act as the sole electron donor both for the first and second reduction of P450 1A1 during the oxidation of BaP in vitro. They suggest that NADH-dependent CBR can replace NADPH-dependent
 POR in the P450 1A1-catalyzed metabolism of BaP.
Multiple meiosis-specific cohesion proteins act to facilitate homolog segregation at the first meiotic division. A recent paper demonstrates that meiotic cohesins can be separated into two complexes, one that establishes and maintains intersister cohesion and one that promotes interhomolog adhesion by regulating synaptonemal complex assembly.
The Ayurvedic Pharmacopoeia of India (API) is a unique book of standards describing the quality, purity and strength of selected drugs that are manufactured, distributed, and sold by the licensed manufacturers in pan India. It is developed in two parts; the part one comprises of mono-monographs of medicinal substances of natural origin and part two includes selected compound formulations sourced from the schedule - I books under the Drugs and Cosmetics Act, 1940 comprising of popular Ayurvedic classics of different period of times. The first part of the Ayurvedic Formulary of India was published in 1978 and thereafter, the Ayurvedic Pharmacopoeia of India (mono-monograph) Part-I, Vol. I was published in the year 1989 and subsequently, the other volumes were published with their legalized status under Drugs and Cosmetics Act, 1940.
The study was aimed to bring out the existing knowledge on the Ayurvedic pharmacopoeia with its chronological development reviewed from the ancient Vedic Compendia with its continuum in Ayurvedic classics of different period of time till recent past.
A literary search based on the ancient origin of Ayurveda was carried out. The drug making from the natural resources and utility of the knowledge exist in classical Ayurvedic works of different period of time till composition of the Ayurvedic Pharmacopoeia of India and its importance as official documents of Govt. of India for Standards of Ayurvedic Drugs and its perspectives have been discussed.
The present paper reviews on the systemic development and different aspects of drug-making (Pharmacopoeia) with evidence lying in the 5000 years old work of India. During the systematic review of the various works of different period of times (ancient, medieval and modern), it was found that the Ayurvedic Pharmacopoeia of India has its development during 20th Century as an official document of Govt. of India comprising of single drugs monograph and compound formulations.
In India, the development of the Indian Pharmacopoeia started in 20th Century on the recommendation of the Col. R.N. Chopra Committee and in 1978 the first part of the Ayurvedic formulary of India was published. Subsequently, the amendment in the drugs and cosmetics Act 1940 was brought in 1964 for regulation of the drugs in Indian Systems of Medicine (Ayurveda, Unani and Siddha). Later on the Ayurvedic Pharmacopoeia of India (Mono-Monograph) Part-I, Volume I, was published in the year 1989 and the other volumes were published subsequently in different years.
The potassium channel Kv 1.3 plays a vital part in the activation of T lymphocytes and is an attractive pharmacological target for autoimmune diseases. BmP02, a 28-residue peptide isolated from Chinese scorpion (Buthus martensi Karsch) venom, is a potent and selective Kv1.3 channel blocker. However, the mechanism through which BmP02 recognizes and inhibits the Kv1.3 channel is still unclear. In the present study, a complex molecular model of Kv1.3-BmP02 was developed by docking analysis and molecular dynamics simulations. From these simulations, it appears the large β-turn (residues 10-16) of BmP02 might be the binding interface with Kv 1.3. These results were confirmed by scanning alanine mutagenesis of BmP02, which identified His9, Lys11 and Lys13, which lie within BmP02's β-turn, as key residues for interacting with Kv1.3. Based on these results and molecular modeling, two negatively charged residues of Kv1.3, D421 and D422, located in turret region, were predicted to act as the binding site for BmP02. Mutation of these residues reduced sensitivity of Kv 1.3 to BmP02 inhibition, suggesting that electrostatic interactions play a crucial role in Kv1.3-BmP02 interaction. This study revealed the molecular basis of Kv 1.3 recognition by BmP02 venom, and provides a novel interaction model for Kv channel-specific blocker complex, which may help guide future drug-design for Kv1.3-related channelopathies.
Acylcarnitines are intermediates of fatty acid oxidation and accumulate as a consequence of the metabolic dysfunction resulting from the insufficient integration between β-oxidation and the tricarboxylic acid (TCA) cycle. The aim of this study was to investigate whether acylcarnitines accumulate in prostate cancer tissue, and whether their biological actions could be similar to those of dihydrotestosterone (DHT), a structurally related compound associated with cancer development.
Levels of palmitoylcarnitine (palcar), a C16:00 acylcarnitine, were measured in prostate tissue using LC-MS/MS. The effect of palcar on inflammatory cytokines and calcium (Ca(2+) ) influx was investigated in in vitro models of prostate cancer.
We observed a significantly higher level of palcar in prostate cancerous tissue compared to benign tissue. High levels of palcar have been associated with increased gene expression and secretion of the pro-inflammatory cytokine IL-6 in cancerous PC3 cells, compared to normal PNT1A cells. Furthermore, we found that high levels of palcar induced a rapid Ca(2+) influx in PC3 cells, but not in DU145, BPH-1, or PNT1A cells. This pattern of Ca(2+) influx was also observed in response to DHT. Through the use of whole genome arrays we demonstrated that PNT1A cells exposed to palcar or DHT have a similar biological response.
This study suggests that palcar might act as a potential mediator for prostate cancer progression through its effect on (i) pro-inflammatory pathways, (ii) Ca(2+) influx, and (iii) DHT-like effects. Further studies need to be undertaken to explore whether this class of compounds has different biological functions at physiological and pathological levels. Prostate 76:1326-1337, 2016. © 2016 The Authors. The Prostate published by Wiley Periodicals, Inc.
As global warming and climate-change proceeds ever more rapidly, organisms depending on seasonal cues to synchronize reproduction face an unclear future. Reproduction in Diadema setosum in the Gulf of Aqaba (Red Sea) is seasonal, with mature individuals occurring from July to October. Gonad indexes (GI), in contrast, indicate that spawning occurs from August through December and suggests two main spawning events. Histological analysis, however, indicate that the second peak of GI values cannot be related to spawning, but rather correspond to recovering individuals. In Diadema, examination of GI values alone may thus lead to erroneous conclusions. GI was moderately-strong positively correlated with sea-surface temperatures, but not with chlorophyll-a concentrations or photoperiod. Spawning coincides with the onset of the annual chlorophyll-a increase, however, which might be advantageous for nutrition of the developing larvae. First significant GI increase coincides with the shortening of day-length, which may act as a cue for D. setosum gametogenesis. Gametogenesis is highly synchronised between sexes, although the mature phase of females exceeds that of males. The non-complete overlap may represent sampling bias or represent an adaptive strategy for enhancing fertilisation success. Skewed sex ratios (♀:♂ 1:0.59, n = 360) in the Gulf of Aqaba may be related to pollution.
African American young adults ages 18-25 smoke less than their Caucasian peers, yet the burden of tobacco-related illness is significantly higher in African Americans than in Caucasians across the lifespan. Little is known about how clean indoor air laws affect tobacco smoking among African American young adults. We conducted a systematic observation of bars and clubs with events targeted to African American adults 18-25 in Baltimore City at two timepoints (October and November of 2008 and 2010) after enforcement of the Maryland Clean Indoor Air Act (CIAA). Twenty venues-selected on the basis of youth reports of popular venues-were rated during peak hours. All surveillance checklist items were restricted to what was observable in the public domain. There was a significant decrease in observed indoor smoking after CIAA enforcement. Observed outdoor smoking also decreased, but this change was not significant. Facilities for smoking outdoors increased significantly. The statewide smoking ban became effective February 1, 2008, yet measurable changes in smoking behavior in bars were not evident until the City engaged in stringent enforcement of the ban several months later.
There are many reasons why a woman's pregnancy can put her at risk for orthopedic pain and injury. Given the high percentage of pregnant patients experiencing some degree of musculoskeletal pain, it is surprising that this is not an area of wider study. This chapter takes an evidence based approach to help the reader understand the implications of the numerous anatomic and physiologic changes associated with the gravid state, and how they act to promote both discomfort and injury. One-third of pregnant women in America are obese, further increasing risk. Exercise in most pregnancies is recommended and regarded as safe and thus obstetric care providers need to understand risk, diagnostic techniques and treatments.
Medical error stems from inadequate professional conduct that is capable of producing harm to life or exacerbating the health of another, whether through act or omission. This situation has become increasingly common in Brazil and worldwide. In this study, the aim was to understand what being the victim of medical error is like and to investigate the circumstances imposed on this condition of victims in Brazil. A semi-structured
 interview was conducted with twelve people who had gone through situations of medical error in their lives, creating a space for narratives of their experiences and deep reflection on the phenomenon. The concept of medical error has a negative connotation, often being associated with the incompetence of a medical professional. Medical error in Brazil is demonstrated by low-quality professional performance and represents the current reality of the country because of the common lack of respect and consideration for patients. Victims often remark on their loss of identity, as their social functions have been interrupted and they do not expect to regain such. It was found, however, little assumption of error in the involved doctors' discourses and attitudes, which felt a need to judge the medical conduct in an attempt to assert their rights. Medical error in Brazil presents a punitive character and is little discussed in medical and scientific circles. The stigma of medical error is closely connected to the value and cultural judgments of the country, making it difficult to accept, both by victims and professionals.
Does fertility-related quality of life (FertiQOL) differ by infertility diagnosis between women with polycystic ovary syndrome (PCOS) and their partners, compared with couples with unexplained infertility (UI)?
Women with PCOS report lower QOL than those with UI, whereas males with UI report lower QOL than males with PCOS partners.
The fertility-specific QOL survey, FertiQOL, has been used to examine fertility-related QOL in a number of worldwide cohorts. Few data have addressed fertility-related QOL as a function of infertility diagnosis. Overall, men report better QOL than women with infertility, and there is variation in FertiQOL scores across different samples from different countries.
This was a prospective, cohort study derived from two concurrent, randomized clinical trials, and designed to examine QOL in infertile females with PCOS and UI at the time of enrollment compared with each other and their male partners; to compare concordance FertiQOL scores in this study across other worldwide cohorts; and to determine if baseline FertiQOL was associated with pregnancy outcome.
Women with PCOS and their partners (n = 733 and n = 641, respectively), and couples with UI (n = 865 women and 849 men) completed a validated fertility-specific QOL survey (FertiQOL) at the time of the study screening visit. PCOS women were randomized to either clomiphene citrate or letrozole treatment; couples with UI were randomized to clomiphene citrate, letrozole or gonadotrophin plus IUI. FertiQOL results were compiled by diagnosis (PCOS or UI) and compared by diagnosis and sex using Wilcoxon Rank-Sum testing. Relationships between baseline FertiQOL and pregnancy outcomes were examined using logistic regression. Multivariable models were performed to assess the association between FertiQOL scores and key participant characteristics.
Women with PCOS had lower total FertiQOL scores (72.3 ± 14.8) than those with UI (77.1 ± 12.8; P < 0.001); this was true for each domain (except Relational). These differences were largely explained by variation in BMI, hirsutism, household income and age. Women had lower overall FertiQOL scores than their male partners. Males with PCOS partners had higher scores than males with UI (84.9 ± 10.2 versus 83.3 ± 10.8; P = 0.003). Scores were not consistently associated with conception or pregnancy outcome.
The use of multiple tests of association may have resulted in spurious statistically significant findings. Inherent sociodemographic differences between women with PCOS and those with UI largely account for the lower QOL in women with PCOS. Our study was unable to assess if changes in QOL affected pregnancy outcome as FertiQOL data were collected prior to treatment. Finally, the participants for both studies represent their local communities, but are not a population-based sample and thus firm conclusions about how representative these couples are to the general population must be made with caution.
Women with PCOS with elevated BMI and hirsutism scores and with lower socioeconomic status may require more, targeted psychosocial support than those with other diagnoses. Possible attribution of infertility to the male partner appears to result in a lower QOL. There appears to be substantial national variation in FertiQOL scores, with US-based cohorts reporting overall higher QOL.
This work was supported by National Institutes of Health (NIH)/Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) Grants U10 HD39005 (to M.D.), U10 HD38992 (to R.S.L.), (to C.C.), U10 HD38998 (to R.A.), U10 HD055942 (to R.D.R.), HD055944 (to P.C.), U10 HD055936 (to G.C.), U10HD055925 (to H.Z.); and U10 U54-HD29834 (to the University of Virginia Center for Research in Reproduction Ligand Assay and Analysis Core of the Specialized Cooperative Centers Program in Reproduction and Infertility Research). Most importantly, this research was made possible by the funding by American Recovery and Reinvestment Act. N.S., E.E., J.C.T., C.G., H.H., R.A., P.C., G.C., C.C., M.D., S.J., W.D.S. and H.Z. report no conflicts of interests/disclosures. L.B.C. reports research support from Ferring Pharmaceuticals and Roche Diagnostics; R.S.L. reports receipt of consulting fees from AstraZeneca, Euroscreen, Sprout Pharmaceuticals, Taken, Kindex, Clarus and Bayer, Inc., and research support from AstraZeneca and Ferring Pharmaceuticals. R.D.R. reports research support from AbbVie.
Pregnancy in Polycystic Ovary Syndrome II (PPCOS II), NCT00719186; Assessment of Multiple Intrauterine Gestations in Ovulation Stimulation (AMIGOS) NCT01044862, clinicaltrials.gov.
PPCOS II 17 July 2008; AMIGOS 7 January 2010.
PPCOS II 19 February 2009; AMIGOS 2 August 2010.
The RNA exosome is a conserved complex for RNA degradation with two ribonucleolytic subunits, Dis3 and Rrp6. Rrp6 is a 3'-5' exonuclease, but it also has a structural role in helping target RNAs to the Dis3 activity. The relative importance of the exonuclease activity and the targeting activity probably differs between different RNA substrates, but this is poorly understood. To understand the relative contributions of the exonuclease and the targeting activities to the degradation of individual RNA substrates in Schizosaccharomyces pombe, we compared RNA levels in an rrp6 null mutant to those in an rrp6 point mutant specifically defective in exonuclease activity. A wide range of effects was found, with some RNAs dependent mainly on the structural role of Rrp6 ("protein-dependent" targets), other RNAs dependent mainly on the catalytic role ("activity-dependent" targets), and some RNAs dependent on both. Some protein-dependent RNAs contained motifs targeted via the RNA-binding protein Mmi1, while others contained a motif possibly involved in response to iron. In these and other cases Rrp6 may act as a structural adapter to target specific RNAs to the exosome by interacting with sequence-specific RNA-binding proteins.
Phenotypic plasticity involves a process in which cells transiently acquire phenotypic traits of another lineage. Two commonly studied types of phenotypic plasticity are epithelial-mesenchymal transition (EMT) and mesenchymal-epithelial transition (MET). In carcinomas, EMT drives invasion and metastatic dissemination, while MET is proposed to play a role in metastatic colonization. Phenotypic plasticity in sarcomas is not well studied; however, there is evidence that a subset of sarcomas undergo an MET-like phenomenon. While the exact mechanisms by which these transitions occur remain largely unknown, it is likely that some of the same master regulators that drive EMT and MET in carcinomas also act in sarcomas. In this study, we combined mathematical models with bench experiments to identify a core regulatory circuit that controls MET in sarcomas. This circuit comprises the microRNA 200 (miR-200) family, ZEB1, and GRHL2. Interestingly, combined expression of miR-200s and GRHL2 further upregulates epithelial genes to induce MET. This effect is phenocopied by downregulation of either ZEB1 or the ZEB1 cofactor, BRG1. In addition, an MET gene expression signature is prognostic for improved overall survival in sarcoma patients. Together, our results suggest that a miR-200, ZEB1, GRHL2 gene regulatory network may drive sarcoma cells to a more epithelial-like state and that this likely has prognostic relevance.
Worldwide, inequalities in health are increasing, even in well-developed welfare states such as Norway, which in 2012, saw a new public health act take effect that enshrined equity in health as national policy and devolved to municipalities' responsibility to act on the social determinants of health. The act deems governance structures and "Health in All Policies" approaches as important steering mechanisms for local health promotion. The aim of this study is to investigate whether Norway's municipalities address living conditions - economic circumstances, housing, employment and educational factors - in local health promotion, and what factors are associated with doing so. All Norway's municipalities (n= 428) were included in this cross-sectional study, and both register and survey data were used and were subjected to descriptive and bi- and multivariate regression analyses. Eighty-two percent of the municipalities reported that they were capable of reducing inequalities in health. Forty percent of the municipalities defined living conditions as a main challenge in their local public health promotion, while 48% cited it as a main health promotion priority. Our study shows that defining living conditions as a main challenge is positively associated with size of municipality, and also its assessment of its own capability in reducing inequalities in health.
 The latter factor was also associated with actually prioritizing living conditions in health promotion, as was having established cross-sectorial working groups or inter-municipal collaboration related to local health promotion. This study underlines the importance of inter-sectoral collaboration to promote health and well-being.
The purpose of this study was to determine the strength of the relationship between forced expiratory spirometric tests and physical activity levels in older women divided into two groups based on whether they met or did not meet guidelines for weekly physical activity according to the Global Recommendations on Physical Activity for Health (WHO, 2011). Research included 61 healthy, nonsmoker female seniors (Mage =66 years, SDage =4.4 years). Weekly physical activity was assessed using an ActiGraph Gt3X triaxial accelerometer. In order to evaluate pulmonary function, forced spirometry tests were performed. The women who met criteria of physical activity for health achieved significantly higher values for forced vital capacity (FVC), t(59) = -1.58, p < .001, and forced expiratory volume in one second (FEV1), t(59) = -3.33, p = 0.002. Meeting criteria of Global Recommendations on Physical Activity for Health is associated with better FVC and FEV1 parameters in healthy older women.
The purpose of this investigation is to examine differences in rest-activity patterns and sleep characteristics in older adults with HF and healthy older adults. The sample included older adults with HF (n = 20) and a reference group of healthy older adults (n = 20). Traditional cosinor analysis was used to assess three parameters of rest-activity from wrist actigraphy data: amplitude (range of activity), mesor (mean activity), and acrophase (time of peak activity). Traditional sleep characteristics were also determined from actigraphy data: Total Sleep Time, Sleep Latency, Sleep efficiency, and Wake after Sleep Onset. The HF group demonstrated significantly lower mesor and amplitude than the reference group (p < 0.01). The HF group had significantly greater TST (p < 0.01), but the groups had similar SE, SL, and WASO. Despite similar sleep characteristics to healthy older adults, overall rest-activity patterns were significantly dampened in those with HF.
The ill-health effects of sedentary behavior are becoming well-documented, yet older adults spend 70-80% of waking hours sedentary.
To determine if a portable elliptical device increases energy expenditure (EE) while performing popular seated activities.
Twenty older adults (68.1±1.4 years) participated to compare the measured EE between seated rest and three randomized seated pedaling activities: computer use, reading, TV viewing. Each pedaling activity included 5-minutes of self-selected paced/no resistance (SSP) and externally paced/added resistance pedaling (Paced).
A significant increase in EE existed during SSP (+1.44 ± 0.12 kcal/min) and Paced (+2.19 ± 0.09 kcal/min) pedaling relative to Seated Rest (p<0.001). EE during the Paced activities was significantly greater than all SSP activities (p<0.01).
Extrapolating these results, pedaling at a SSP for an hour while performing seated activities is equivalent to the net EE of walking 1.6 miles. Future home-based effectiveness and feasibility should be explored.
To investigate the short and long time effects of concurrent strength and high intensity interval training (HIIT) on octogenarian COPD patients, nine males (age=84.2 ± 2.8 yrs, BMI=29.3 ± 2.3), with low to severe COPD level (2.1 ± 1.5 BODE index), underwent a supervised 9-week strength and HIIT exercise program. Training had a significant (P<0.05) impact on senior fitness test scores (23-45%), 30m walking speed (from 1.29 ± 0.29 to 1.62 ± 0.33 m/s), leg and chest press 1RM (38 and 45% respectively), maximal isometric strength (30-35%), and 6-minute walking test (from 286.1 ± 107.2 to 396.2 ± 106.5 m) and tended to increase predicted forced vital capacity by 14% (P=0.07). One year after the intervention all training-induced gains returned to their pre-intervention values except for the chest press 1RM (P<0.05). Short-term concurrent strength and HIIT training increases physical fitness in the oldest old COPD patients, and has potential long-term benefits.
We aim to explore the phenomenon of suicide by driving one vehicle into another, and draw attention to the cost to occupants of targeted vehicles.
We examined academic literature, court and newspaper reports, and online sources.
Driver suicide may be achieved by colliding with a fixed object or another vehicle. When a second vehicle is targeted, the occupants of that vehicle experience property loss, and potentially physical and psychiatric injury, or death. Driver suicides are associated with death of another person, in 11.3% of cases. Some suicidal individuals are able to act with great consideration for the consequences of their actions.
Every effort must be made to help suicidal people with mental disorders or other predicaments. There is a need for public discussion of suicide by targeting an oncoming vehicle. It is less likely that suicide drivers who target other vehicles are unable to choose and more likely they have not considered the consequences of their actions.
The objective of this study was to examine the association between cognitive ability and gait initiation performance in older adults. Global and specific cognitive functions and spatiotemporal gait parameters during gait initiation were assessed in 60 older adults. Multivariate linear regression was conducted to determine the association between cognitive functions and gait initiation parameters. Results showed that global cognitive function was not associated with any of the spatiotemporal parameters. Poorer performance on measures of executive function and language ability were associated with shorter step length, narrower step width, and longer step time. In addition, poorer performance on test of visuospatial ability was associated with longer step time. In conclusion, specific but not global cognitive functions were associated with gait initiation performance. Clinical gait examination should incorporate gait initiation and cognitive assessments. Rehabilitation strategies aimed at improving cognition and gait initiation performance may be beneficial for preventing falls.
The human genome contains millions of fragments from retrotransposons-highly repetitive DNA sequences that were once able to "copy and paste" themselves to other regions in the genome. However, the majority of retrotransposons have lost this capacity through acquisition of mutations or through endogenous silencing mechanisms. Without this imminent threat of transposition, retrotransposons have the potential to act as a major source of genomic innovation. Indeed, large numbers of retrotransposons have been found to be active in specific contexts: as gene regulatory elements and promoters for protein-coding genes or long noncoding RNAs, among others. In this review, we summarise recent findings about retrotransposons, with implications in gene expression regulation, the expansion of gene isoform diversity and the generation of long noncoding RNAs. We highlight key examples that demonstrate their role in cellular identity and their versatility as markers of cell states, and we discuss how their dysregulation may contribute to the formation of and possibly therapeutic response in human cancers.
People often discuss events they have seen and these discussions can influence later recollections. We investigated the effects of factual, emotional, and free retelling discussion on memory recollections of individuals who have witnessed an event. Participants were shown a video, made an initial individual recall, participated in one of the three retelling conditions (emotional versus factual versus free) or a control condition, and then recalled the event individually again. Participants in the factual and free retelling conditions reported more items not previously recalled than participants in the control condition did, while the emotional condition did not show the same advantage. Participants in all three retelling conditions failed to report more previously recalled items as compared with the control condition. Finally, a memory conformity effect was observed for all three retelling conditions. These findings suggest that eyewitnesses' discussions may influence the accuracy of subsequent memory reports, especially when these discussions are focused on emotional details and thoughts.
Color vision in birds is mediated by four types of cone photoreceptors whose maximal sensitivities (λmax) are evenly spaced across the light spectrum. In the course of avian evolution, the λmax of the most shortwave-sensitive cone, SWS1, has switched between violet (λmax > 400 nm) and ultraviolet (λmax < 380 nm) multiple times. This shift of the SWS1 opsin is accompanied by a corresponding short-wavelength shift in the spectrally adjacent SWS2 cone. Here, we show that SWS2 cone spectral tuning is mediated by modulating the ratio of two apocarotenoids, galloxanthin and 11’,12’-dihydrogalloxanthin, which act as intracellular spectral filters in this cell type. We propose an enzymatic pathway that mediates the differential production of these apocarotenoids in the avian retina, and we use color vision modeling to demonstrate how correlated evolution of spectral tuning is necessary to achieve even sampling of the light spectrum and thereby maintain near-optimal color discrimination.
Stems cells of the colon crypt are the origin of colon mature cells. Colorectal cancer cells are also suggested to originate from crypt stem cells undergoing a series of epigenetic and genetic alterations. Aberrant methylation plays important roles in early carcinogenesis and lead to altered gene expression and regulation,
 resulting in accumulation of damages to cell function and ultimately, malignant transformation. Aberrances in hypermethylation and hypomethylation act in different mechanism through the regulation of various genes during CSC carcinogenesis, and both of them play crucial roles in stem cell differentiation towards cancer cells. A large majority of epigenetic and genetic abnormalities that work coordinately in colorectal carcinogenesis are related to cell growth and division, indicating that the intrinsic abnormalities of CRC lie in dysregulation of basic cellular processes. Detection of abnormal methylation can be used in cancer screening and early detection, while reversal of aberrant methylation using drugs may have potential in cancer therapy. This review will provide an overview on the roles of aberrant methylation and a summary of genes that are affected during CRC carcinogenesis.
Neurogenic agents emerge as innovative drugs for the treatment of Alzheimer's disease (AD), whose pathological complexity suggests strengthening research in the multi-target directed ligands strategy.
By combining the lipoic acid structure with N-benzylpiperidine or N,N-dibenzyl(N-methyl)amine fragments, new multi-target directed ligands were obtained that act at three relevant targets in AD: σ-1 receptor (σ1R), β-secretase-1 (BACE1) and acetylcholinesterase (AChE). Moreover, they show potent neurogenic properties, good antioxidant capacity and favorable CNS permeability. Molecular modeling studies on AChE, σ1R and BACE1 highlight relevant drug-protein interactions that may contribute to the development of new disease-modifying drugs.
New lipoic-based σ1 agonists endowed with neurogenic, antioxidant, cholinergic and amyloid β-peptide-reducing properties have been discovered for the potential treatment of AD.
Various circular RNAs (circRNAs) are newly identified in animals and plants through high-throughput deep sequencing which play important roles in miRNA function and transcriptional controlling. However, little is known regarding circRNAs in tomato fruit. In this study, we systematically parse the circRNAs in the whole genome using the combination methods of deep sequencing and bioinformatics. In all, 854 circRNAs were identified in our results, among them, 163 circRNAs exhibit chilling responsive expression. Intriguingly, several circRNAs were predicted to involved in chilling responsive process, such as redox reaction, cell wall degradation, Arginine and polyamine metabolism, heat and cold shock protein, energy metabolism, Jasmonic acid and abscisic acid metabolism, low temperature and salt responsive protein and low temperature-induced transcription factors(CBF and WRKY). Furthermore, 102 circRNAs were found to act as the corresponding 24 miRNAs sponges in tomato. These discoveries deciphered the unexpected complexity of the regulatory circRNAs and may open a window for understanding the functions of circRNAs in plants.
Acetabular cartilage lesions are frequently seen in young patients with hip pain and have been identified as an important prognostic factor. New therapies have complemented abrasion and microfracture procedures. The aim of the study is to evaluate the early outcome of patients with arthroscopic injectable autologous chondrocyte transplantations (ACT) for full thickness acetabular cartilage defects.
A two-step procedure ACT was performed in patients with full thickness acetabular cartilage defects measuring ≥2 cm(2). The patients were closely followed with clinical examination, pre- and postoperative scores until the latest available follow-up of 3, 6, 12, and 24 months.
20 consecutive cases (4 female, 16 male, mean age 33 years) were included. No patients were lost at final follow-up. The average defect size was 5.05 (range 2-6) cm(2). The average follow-up was 12.05 (range 6-24) months. Three months postoperatively the preoperative scores improved significantly from a mean mHHS of 63-81 points (p = 0.009), iHOT33 of 44-66 % (p = 0.028) and subjective hip assessment (Subjective Hip Value, SHV) of 60-87 % (p = 0.007). After 12 months the results improved significantly to a mean mHHS of 93 points (p = 0.017), an iHOT33 of 79 % (p = 0.007) and an SHV of 82 % (p = 0.048) compared with the preoperative scores.
The injectable matrix associated ACT is a reliable procedure, yielding promising early results with a significant increase of all scores evaluated in patients with full thickness acetabular cartilage defects.
Aquaporins (Aqps) are expressed within key osmoregulatory tissues where they mediate the movement of water and selected solutes across cell membranes. We leveraged the functional plasticity of Mozambique tilapia (Oreochromis mossambicus) gill epithelium to examine how Aqp3, an aquaglyceroporin, is regulated in response to osmoregulatory demands. Particular attention was paid to the actions of critical osmoregulatory hormones, namely, prolactin (Prl), growth hormone and cortisol. Branchial aqp3 mRNA levels were modulated following changes in environmental salinity, with enhanced aqp3 mRNA expression upon transfer from seawater to freshwater (FW). Accordingly, extensive Aqp3 immunoreactivity was localized to cell membranes of branchial epithelium in FW-acclimated animals. Upon transferring hypophysectomized tilapia to FW, we identified that a pituitary factor(s) is required for Aqp3 expression in FW. Replacement with ovine Prl (oPrl) was sufficient to stimulate Aqp3 expression in hypophysectomized animals held in FW, an effect blocked by coinjection with cortisol. Both oPrl and native tilapia Prls (tPrl177 and tPrl188) stimulated aqp3 in incubated gill filaments in a concentration-related manner. Consistent with in vivo responses, coincubation with cortisol blocked oPrl-stimulated aqp3 expression in vitro Our data indicate that Prl and cortisol act directly upon branchial epithelium to regulate Aqp3 in tilapia. Thus, within the context of the diverse actions of Prl on hydromineral balance in vertebrates, we define a new role for Prl as a regulator of Aqp expression.
Human papillomavirus and Chlamydia trachomatis share the same route of sexual transmission and possess similar risk factors, indicating that coinfection may act synergistically in the induction of epithelial cell abnormalities.
This study aimed to determine the prevalence of human papillomavirus and Chlamydia trachomatis in adolescents and young women and identify factors associated with coinfection.
This cross-sectional study included 276 female participants, aged 15-24 years, who were sexually active. Interviews were conducted and cervical specimens were collected for cervical smears and molecular tests. All cervical specimens were tested for 27 human papillomavirus genotypes by polymerase chain reaction amplification and hybridization to a human papillomavirus linear array. Detection of Chlamydia trachomatis was performed by polymerase chain reaction using primers directed to the region encoding the cryptic plasmid. Bivariate and multivariate analyses were performed to evaluate the factors associated with coinfection with human papillomavirus and Chlamydia trachomatis. The odds ratio, the adjusted odds ratio, and the 95% confidence interval were calculated.
The prevalence of infection by Chlamydia trachomatis and human papillomavirus was 9.1% (95% confidence interval, 5.61-12.4) and 47.1% (95% confidence interval, 41.0-53.2), respectively. The prevalence of coinfection with human papillomavirus and Chlamydia trachomatis was 5.8% (95% confidence interval, 3.3-9.2); coinfection with 1 human papillomavirus type was 3.3% (95% confidence interval, 1.5-6.1) and with multiple types was 2.5% (95% confidence interval, 1.0-5.2). The prevalence of cytological abnormalities was 12.3% (95% confidence interval, 8.6-16.79). Human papillomavirus infections of high oncogenic risk were more prevalent (85.4%). Factors independently associated with coinfection of human papillomavirus/Chlamydia trachomatis obtained by multivariate analysis were the initiation of sexual activity under 16 years of age with an an odds ratio of 4.9 (95% confidence interval, 1.0-23.63; P = .05) and cytological abnormalities with an odds ratio of 10.7 (95% confidence interval, 1.9-59.5; P = .01), which indicates there is risk for the detection of cytological abnormalities in adolescents and young women coinfected with human papillomavirus/Chlamydia trachomatis.
The prevalence of coinfection among our study population was of a magnitude that warrants attention by public health services. Adolescents and young women should be monitored for Chlamydia trachomatis infection and vaccinated against human papillomavirus. The association between cytological abnormalities and coinfection with human papillomavirus and Chlamydia trachomatis indicates the potential synergistic role of these infections in carcinogenesis of the cervix.
Sulphiting agents, such as sodium metabisulphite (SM), are used in food as bleaching agents and to prevent browning reactions. A 1972 repeat dose study in rats found that dietary sulphites caused irritation of the stomach with inflammation, hyperplasia and bleeding. We conducted a 7-day dietary study in rats to confirm that stomach lesions were the most sensitive toxicological endpoint. Rat feed was prepared daily with 0%, 0.25%, 0.5%, 1% or 4% (w/w) SM. Parameters included clinical signs, feed and water intake, bodyweight gain, haematology, serum protein chemistry, necropsy findings and gastrointestinal histopathology. There were no treatment-related clinical signs or gastrointestinal lesions. Mean bodyweight gain was markedly decreased in the 4% (w/w) SM group although feed consumption was marginally depressed. Slightly lower mean values for RBC, Hb, Hct, total WBC and lymphocyte count were observed in the 4% SM group with no evidence of compensatory haematopoiesis.
 The gastric lesions in rats observed in a 1972 study of dietary SM for 10-56 days could not be replicated. These findings create uncertainty around the most relevant toxicological endpoint to establish a suitable health based guidance value, which can only be overcome if a robust long-term dietary study is undertaken.
Renin-angiotensin system (RAS) activity increases under hyperglycemic states, and is thought to be involved in diabetic complications. We previously demonstrated that angiotensin (Ang) II, a main bioactive component of the RAS, might act as a neurotransmitter and/or neuromodulator in the transmission of nociceptive information in the spinal cord. Here, we examined whether the spinal Ang II system is responsible for diabetic neuropathic pain induced by streptozotocin (STZ). Tactile allodynia was observed concurrently with an increase in blood glucose levels the day after mice received STZ (200 mg/kg, i.v.) injections. Tactile allodynia on day 14 was dose-dependently inhibited by intrathecal administration of losartan, an Ang II type 1 (AT1) receptor antagonist, but not by PD123319, an AT2 receptor antagonist. In the lumbar dorsal spinal cord, the expression of Ang II, Ang converting enzyme (ACE), and phospho-p38 mitogen-activated protein kinase (MAPK) were all significantly increased on day 14 after STZ injection compared with vehicle-treated controls, whereas no differences were observed among AT1 receptors or angiotensinogen levels. Moreover, the increase in phospho-p38 MAPK was significantly inhibited by intrathecal administration of losartan. These results indicate that the expression of spinal ACE increased in STZ-induced diabetic mice, which in turn led to an increase in Ang II levels and tactile allodynia. This increase in spinal Ang II was accompanied by the phosphorylation of p38 MAPK, which was shown to be mediated by AT1 receptors.
There is good evidence that natural selection drives the evolution of locomotor performance, but the processes that generate the among-individual variation for selection to act on are relatively poorly understood. We measured prolonged swimming performance, Ucrit, and morphology in a large cohort (n=461) of wild-type zebrafish (Danio rerio) at ∼6 months and again at ∼9 months. Using mixed-model analyses to estimate repeatability as the intraclass correlation coefficient, we determined that Ucrit was significantly repeatable (r=0.55; 95% CI: 0.45-0.64). Performance differences between the sexes (males 12% faster than females) and changes with age (decreasing 0.07% per day) both contributed to variation in Ucrit and, therefore, the repeatability estimate. Accounting for mean differences between sexes within the model decreased the estimate of Ucrit repeatability to 21% below the naïve estimate, while fitting age in the models increased the estimate to 14% above the naïve estimate. Greater consideration of factors such as age and sex is therefore necessary for the interpretation of performance repeatability in wild populations. Body shape significantly predicted Ucrit in both sexes in both assays, with the morphology-performance relationship significantly repeatable at the population level. However, morphology was more strongly predicative of performance in older fish, suggesting a change in the contribution of morphology relative to other factors such as physiology and behaviour. The morphology-performance relationship changed with age to a greater extent in males than females.
Chromosomal rearrangements can shape the structure of genetic variation in the genome directly through alteration of genes at breakpoints or indirectly by holding combinations of genetic variants together due to reduced recombination. The third chromosome of Drosophila pseudoobscura is a model system to test hypotheses about how rearrangements are established in populations because its third chromosome is polymorphic for >30 gene arrangements that were generated by a series of overlapping inversion mutations. Circumstantial evidence has suggested that these gene arrangements are selected. Despite the expected homogenizing effects of extensive gene flow, the frequencies of arrangements form gradients or clines in nature, which have been stable since the system was first described >80 years ago. Furthermore, multiple arrangements exist at appreciable frequencies across several ecological niches providing the opportunity for heterokaryotypes to form. In this study, we tested whether genes are differentially expressed among chromosome arrangements in first instar larvae, adult females and males. In addition, we asked whether transcriptional patterns in heterokaryotypes are dominant, semidominant, overdominant, or underdominant. We find evidence for a significant abundance of differentially expressed genes across the inverted regions of the third chromosome, including an enrichment of genes involved in sensory perception for males. We find the majority of loci show additivity in heterokaryotypes. Our results suggest that multiple genes have expression differences among arrangements that were either captured by the original inversion mutation or accumulated after it reached polymorphic frequencies, providing a potential source of genetic variation for selection to act upon. These data suggest that the inversions are favored because of their indirect effect of recombination suppression that has held different combinations of differentially expressed genes together in the various gene arrangement backgrounds.
Many previous studies conclude that pre-zygotic barriers such as mechanical isolation account for most reproductive isolation between pairs of taxa. However, the inheritance and persistence of barriers such as these after the first generation of hybridization is rarely quantified, even though it is a vital consideration in understanding gene flow potential. There is an asymmetrical pre-zygotic mechanical barrier to hybridization between Eucalyptus nitens and Eucalyptus globulus, which completely prevents small-flowered E. nitens pollen from mating with large E. globulus flowers, while the reverse cross is possible. We aimed to determine the relative importance of pre- and post-zygotic barriers in preventing gene flow following secondary contact between E. nitens and E. globulus, including the inheritance of barriers in advanced-generation hybrids.
Experimental crossing was used to produce outcrossed E. nitens, E. globulus and their F1, F2, BCg and BCn hybrids. The strength and inheritance of a suite of pre- and post-zygotic barriers were assessed, including 20-year survival, growth and reproductive capacity.
The mechanical barrier to hybridization was lost or greatly reduced in the F1 hybrid. In contrast, intrinsic post-zygotic barriers were strong and persistent. Line-cross analysis indicated that the outbreeding depression in the hybrids was best explained by epistatic loss.
The removal of strong mechanical barriers between E. nitens and E. globulus allows F1 hybrids to act as a bridge for bi-directional gene flow between these species. However, strong and persistent post-zygotic barriers exist, meaning that wherever F1 hybridization does occur, intrinsic post-zygotic barriers will be responsible for most reproductive isolation in this system. This potential transient nature of mechanical barriers to zygote formation due to additive inheritance in hybrids appears under-appreciated, and highlights the often important role that intrinsic post-mating barriers play in maintaining species boundaries at zones of secondary contact.
In the development of osteoarthritis, aggrecan degrades prior to cartilage destruction. Aggrecanase-1 (ADAMTS-4) is considered to be the major enzyme responsible for cleaving the Glu373-Ala374 bond in the interglobular domain of aggrecan in humans. Therefore, inhibitors of ADAMTS-4 have therapeutic potential in the treatment of osteoarthritis. In the present work, we developed a chemical feature based pharmacophore model of ADAMTS-4 inhibitors using the HipHop module within the Catalyst program package in order to elucidate the structure-activity relationship and to carry out in-silico screening. The Maybridge database was screened using Hypo1 as a 3D query, and the best-fit hits that followed Lipinski's rule of five were subsequently screened to select the compounds. The hit compounds were then docked into the active site of ADAMTS-4, and interactions were visualized to determine the potential lead molecules. After subjecting all of the hits to various screening and filtering processes, 13 compounds were finally evaluated for their in vitro inhibitory activities. This study resulted in the identification of two lead compounds with potent inhibitory effects on ADAMTS-4 activity, with IC50 values of 0.042 μM and 0.028 μM, respectively. These results provide insight into the pharmacophoric requirements for the development of more potent ADAMTS-4 inhibitors. Graphical Abstract The aggrecan-degrading metalloprotease ADAMTS-4 has been identified as a novel therapeutic target for osteoarthritis. In this work, we used HipHop-based pharmacophore modeling and virtual screening of the Maybridge database to identify novel ADAMTS-4 inhibitors. These novel lead compounds act as potent and specific inhibitors for the ADAMTS-4 enzyme and could have therapeutic potential in the treatment of OA.
Blood clots (haematomas) that form immediately following a bone fracture have been shown to be vital for the subsequent healing process. During the clotting process, a number of factors can influence the fibrin clot structure, such as fibrin polymerization, growth factor binding, cellular infiltration (including platelet retraction), protein concentrations and cytokines. The modulation of the fibrin clot structure within the fracture site has important clinical implications and could result in
 the development of multifunctional scaffolds that mimic the natural structure of a haematoma. Artificial haematoma structures such as these can be created from the patient's own blood and can therefore act as an ideal bone defect filling material for potential clinical application to accelerate bone regeneration. Copyright © 2016 John Wiley & Sons, Ltd.
Mycotoxins are toxic secondary metabolites formed by various fungal species that are found as natural contaminants in food. This very heterogeneous group of compounds triggers multiple toxic mechanisms, including endocrine disruptive potential. Current risk assessment of mycotoxins, as for most chemical substances, is based on the effects of single compounds. However, concern on a potential enhancement of risks by interactions of single substances in naturally occurring mixtures has greatly increased recently. In this study, the combinatory effects of three mycoestrogens were investigated in detail. This includes the endocrine disruptors zearalenone (ZEN) and α-zearalenol (α-ZEL) produced by Fusarium fungi and alternariol (AOH), a cytotoxic and estrogenic mycotoxin formed by Alternaria species. For evaluation of effects, estrogen-dependent activation of alkaline phosphatase (AlP) and cell proliferation were tested in the adenocarcinoma cell line Ishikawa. The estrogenic potential varied among the single substances. Half maximum effect concentrations (EC50) for AlP activation were evaluated for α-ZEL, ZEN and AOH as 37 pM, 562 pM and 995 nM, respectively. All three mycotoxins were found to act as partial agonists. The majority of binary combinations, even at very low concentrations in the case of α-ZEL, showed strong synergism in the AlP assay. These potentiating phenomena of mycotoxin mixtures highlight the urgent need to incorporate combinatory effects into future risk assessment, especially when endocrine disruptors are involved. To the best of our knowledge, this study presents the first investigation on synergistic effects of mycoestrogens.
This qualitative study assessed the experiences of assertive community treatment (ACT) team members regarding the integration of physical and mental health self-management for persons with serious mental illness. Three focus groups elicited information from participants concerning barriers, strategies, and recommendations. Findings from inductive analyses revealed six overarching themes: (1) collaboration with primary care, (2) improvements in engagement, (3) team-focused roles, (4) education and training, (5) recommendations for system level barriers, and (6) systems collaboration. Participant recommendations suggest that ACT teams are well positioned to integrate mental and physical health treatment, but further research is needed to support integrated care.
Evidence from the US Truth campaign suggests that interventions focusing on tobacco industry tactics can be effective in preventing smoking uptake by children. Operation Smoke Storm is the first school-based intervention based on this premise and comprises three classroom sessions in which students act as secret agents uncovering tobacco industry tactics through videos, quizzes, discussions, and presentations. We report a qualitative evaluation of its acceptability.
We conducted eight focus groups with 79 students aged 11-12 who participated in Operation Smoke Storm at two UK schools in Autumn 2013, and 20 interviews with teachers who delivered the intervention. These were digitally audio-recorded, transcribed verbatim and analysed using the framework method.
Students enjoyed the secret agent scenario and reported acquiring new knowledge about smoking and the tobacco industry, which seemed to strengthen their aversion to smoking. Teachers felt confident delivering the 'off the shelf' resource, although they would have welcomed more background information about the topic and guidance on steering discussions. Teachers highlighted a need for the resource to be flexible and not dependent on lesson length, teacher confidence, or expertise. Students and teachers endorsed the idea of developing a booster component for older students and supported the development of printed information complementing the resource to encourage parents to support their child not to smoke.
These findings demonstrate that Operation Smoke Storm can be delivered by teachers to raise awareness about smoking-related issues. The ideas and issues raised are now being used to improve and extend the resource for further evaluation.
Bone tissue engineering and the research surrounding peptides has expanded significantly over the last few decades. Several peptides have been shown to support and stimulate the bone healing response and have been proposed as therapeutic vehicles for clinical use. The aim of this comprehensive review is to present the clinical and experimental studies analysing the potential role of peptides for bone healing and bone regeneration.
A systematic review according to PRISMA guidelines was conducted. Articles presenting peptides capable of exerting an upregulatory effect on osteoprogenitor cells and bone healing were included in the study.
Based on the available literature, a significant amount of experimental in vitro and in vivo evidence exists. Several peptides were found to upregulate the bone healing response in experimental models and could act as potential candidates for future clinical applications. However, from the available peptides that reached the level of clinical trials, the presented results are limited.
Further research is desirable to shed more light into the processes governing the osteoprogenitor cellular responses. With further advances in the field of biomimetic materials and scaffolds, new treatment modalities for bone repair will emerge.
The antipsychotic clozapine is uniquely effective in the management of schizophrenia; however, its use is limited by its potential to induce agranulocytosis. The causes of this, and of its precursor neutropenia, are largely unknown, although genetic factors have an important role. We sought risk alleles for clozapine-associated neutropenia in a sample of 66 cases and 5583 clozapine-treated controls, through a genome-wide association study (GWAS), imputed human leukocyte antigen (HLA) alleles, exome array and copy-number variation (CNV) analyses. We then combined associated variants in a meta-analysis with data from the Clozapine-Induced Agranulocytosis Consortium (up to 163 cases and 7970 controls). In the largest combined sample to date, we identified a novel association with rs149104283 (odds ratio (OR)=4.32, P=1.79 × 10(-8)), intronic to transcripts of SLCO1B3 and SLCO1B7, members of a family of hepatic transporter genes previously implicated in adverse drug reactions including simvastatin-induced myopathy and docetaxel-induced neutropenia. Exome array analysis identified gene-wide associations of uncommon non-synonymous variants within UBAP2 and STARD9. We additionally provide independent replication of a previously identified variant in HLA-DQB1 (OR=15.6, P=0.015, positive predictive value=35.1%). These results implicate biological pathways through which clozapine may act to cause this serious adverse effect.Molecular Psychiatry advance online publication, 12 July 2016; doi:10.1038/mp.2016.97.
The objective was to describe and analyze national network television news framing of contraception, recognizing that onscreen news can influence the public's knowledge and beliefs.
We used the Vanderbilt Television News Archives and LexisNexis Database to obtain video and print transcripts of all relevant national network television news segments covering contraception from January 2010 to June 2014. We conducted a content analysis of 116 TV news segments covering contraception during the rollout of the Affordable Care Act. Segments were quantitatively coded for contraceptive methods covered, story sources used, and inclusion of medical and nonmedical content (intercoder reliability using Krippendorf's alpha ranged 0.6-1 for coded categories).
Most (55%) news stories focused on contraception in general rather than specific methods. The most effective contraceptive methods were rarely discussed (implant, 1%; intrauterine device, 4%). The most frequently used sources were political figures (40%), advocates (25%), the general public (25%) and Catholic Church leaders (16%); medical professionals (11%) and health researchers (4%) appeared in a minority of stories. A minority of stories (31%) featured medical content.
National network news coverage of contraception frequently focuses on contraception in political and social terms and uses nonmedical figures such as politicians and church leaders as sources. This focus deemphasizes the public health aspect of contraception, leading medical professionals and health content to be rarely featured.
Media coverage of contraception may influence patients' views about contraception. Understanding the content, sources and medical accuracy of current media portrayals of contraception may enable health care professionals to dispel popular misperceptions.
The most prominent character of a new type of antibacterial urological catheters is the zebra-stripe pattern of a silver film, which is plated electroless on their interior wall and capped by a very thin semipermeable layer of parylene. This design effectively controls the release rate of Ag(+) ions in artificial urine, which has been measured as function of time with optical emission spectroscopy. By evaluating the minimum inhibitory concentration against certain strains of bacteria with solutions of AgNO3 of known concentration with the method of optical density and applying this analysis to the silver-eluting catheters, it was shown that this moderation prolongs the period of their application significantly. But to act as antibacterial agent
 in chlorine-containing solutions, as in urine, the presence of urea is required to avoid precipitation of AgCl and to meet or even exceed the minimum inhibitory concentration of Ag(+). The quality of the silver depot layer was further determined by the deposition rate and its morphology, which revealed that the film consisted of grains with a mean size of 150 nm.
Tendon injuries are one of the most common musculoskeletal conditions in active patients. Platelet-rich plasma (PRP) has shown some promise in the treatment of tendon disorders, but little is known as to the mechanisms by which PRP can improve tendon regeneration. PRP contains numerous different growth factors and cytokines that activate various cellular signaling cascades, but it has been difficult to determine precisely which signaling pathways and cellular responses are activated after PRP treatment. Additionally, macrophages play an important role in modulating tendon regeneration, but the influence of PRP on determining whether macrophages assume a proinflammatory or anti-inflammatory phenotype remains unknown.
To use genome-wide expression profiling, bioinformatics, and protein analysis to determine the cellular pathways activated in fibroblasts treated with PRP. The effect of PRP on macrophage polarization was also evaluated.
Controlled laboratory study.
Tendon fibroblasts or macrophages from rats were cultured and treated with either platelet-poor plasma (PPP) or PRP. RNA or protein was isolated from cells and analyzed using microarrays, quantitative polymerase chain reaction, immunoblotting, or bioinformatics techniques.
Pathway analysis determined that the most highly induced signaling pathways in PRP-treated tendon fibroblasts were TNFα and NFκB pathways. PRP also downregulated the expression of extracellular matrix genes and induced the expression of autophagy-related genes and reactive oxygen species (ROS) genes and protein markers in tendon fibroblasts. PRP failed to have a major effect on markers of macrophage polarization.
PRP induces an inflammatory response in tendon fibroblasts, which leads to the formation of ROS and the activation of oxidative stress pathways. PRP does not appear to significantly modulate macrophage polarization.
PRP might act by inducing a transient inflammatory event, which could then trigger a tissue regeneration response.
For people with low and moderate incomes, the Affordable Care Act's tax credits have made premium costs roughly comparable to those paid by people with job-based health insurance. For those with higher incomes, the tax credits phase out, meaning that adults in marketplace plans on average have higher premium costs than those in employer plans. The law's cost-sharing reductions are reducing deductibles. Lower-income adults in marketplace plans were less likely than higher-income adults to report having deductibles of $1,000 or more. Majorities of new marketplace enrollees and those who have changed plans since they initially obtained marketplace coverage are satisfied with the doctors participating in their plans. Overall, the majority of marketplace enrollees expressed confidence in their ability to afford care if they were to become seriously ill. This issue brief explores these and other findings from the Commonwealth Fund Affordable Care Act Tracking Survey, February--April 2016.
This final rule increases access to medication-assisted treatment (MAT) with buprenorphine and the combination buprenorphine/naloxone (hereinafter referred to as buprenorphine) in the office-based setting as authorized under the United States Code. Section 303(g)(2) of the Controlled Substances Act (CSA) allows individual practitioners to dispense or prescribe Schedule III, IV, or V controlled substances that have been approved by the Food and Drug Administration (FDA). Section 303(g)(2)(B)(iii) of the CSA allows qualified practitioners who file an initial notification of intent (NOI) to treat a maximum of 30 patients at a time. After 1 year, the practitioner may file a second NOI indicating his/her intent to treat up to 100 patients at a time. This final rule will expand access to MAT by allowing eligible practitioners to request approval to treat up to 275 patients under section 303(g)(2) of the CSA. The final rule also includes requirements to ensure that patients receive the full array of services that comprise evidence-based MAT and minimize the risk that the medications provided for treatment are misused or diverted.
This final rule implements requirements under Section 105 of the Medicare Access and CHIP Reauthorization Act of 2015 that expand how qualified entities may use and disclose data under the qualified entity program to the extent consistent with applicable program requirements and other applicable laws, including information, privacy, security and disclosure laws. This rule also explains how qualified entities may create non-public analyses and provide or sell such analyses to authorized users, as well as how qualified entities may provide or sell combined data, or provide Medicare claims data alone at no cost, to certain authorized users. In addition, this rule implements certain privacy and security requirements, and imposes assessments on qualified entities if the qualified entity or the authorized user violates the terms of a data use agreement required by the qualified entity program.
We report the design of hydrogels that can act as "smart" valves or membranes. Each hydrogel is engineered with a pore (about 1 cm long and <1 mm thick) that remains closed under ambient conditions but opens under specific conditions. Our design is inspired by the stomatal valves in plant leaves, which regulate the movement of water and gases in and out of the leaves. The design features two different gels, active and passive, which are attached concentrically to form a disc-shaped hybrid film. The pore is created in the central active gel, and the conditions for opening the pore can be tuned based on the chemistry of this gel. For example, if the active gel is made from N-isopropylacrylamide (NIPA), the actuation of the pore depends on the temperature of water relative to 32 °C, which is the lower-critical solution temperature (LCST) of NIPA. The concentric design of our hybrid provides directionality to the volumetric transition of the active gel, i.e., it ensures that the pore opens as the active gel shrinks. In turn, contact with hot water (T > 32 °C) opens the pore and allows the water to pass through the gel. Conversely, the pore remains closed when the water is cold (T < 32 °C). The gel thereby acts as a "smart" valve that is able to regulate the flow of solvent depending on its properties. We have extended the concept to other stimuli that can cause gel-swelling transitions including solvent composition, pH, and light. Additionally, when two different gel-based valves are arranged in series, the assembly acts as a logical "AND" gate, i.e., water flows through the valve-combination only if it simultaneously satisfies two distinct conditions (such as its pH being below a critical value and its temperature being above a critical value).
The Affordable Care Act is the most important health care legislation enacted in the United States since the creation of Medicare and Medicaid in 1965. The law implemented comprehensive reforms designed to improve the accessibility, affordability, and quality of health care.
To review the factors influencing the decision to pursue health reform, summarize evidence on the effects of the law to date, recommend actions that could improve the health care system, and identify general lessons for public policy from the Affordable Care Act.
Analysis of publicly available data, data obtained from government agencies, and published research findings. The period examined extends from 1963 to early 2016.
The Affordable Care Act has made significant progress toward solving long-standing challenges facing the US health care system related to access, affordability, and quality of care. Since the Affordable Care Act became law, the uninsured rate has declined by 43%, from 16.0% in 2010 to 9.1% in 2015, primarily because of the law's reforms. Research has documented accompanying improvements in access to care (for example, an estimated reduction in the share of nonelderly adults unable to afford care of 5.5 percentage points), financial security (for example, an estimated reduction in debts sent to collection of $600-$1000 per person gaining Medicaid coverage), and health (for example, an estimated reduction in the share of nonelderly adults reporting fair or poor health of 3.4 percentage points). The law has also begun the process of transforming health care payment systems, with an estimated 30% of traditional Medicare payments now flowing through alternative payment models like bundled payments or accountable care organizations. These and related reforms have contributed to a sustained period of slow growth in per-enrollee health care spending and improvements in health care quality. Despite this progress, major opportunities to improve the health care system remain.
Policy makers should build on progress made by the Affordable Care Act by continuing to implement the Health Insurance Marketplaces and delivery system reform, increasing federal financial assistance for Marketplace enrollees, introducing a public plan option in areas lacking individual market competition, and taking actions to reduce prescription drug costs. Although partisanship and special interest opposition remain, experience with the Affordable Care Act demonstrates that positive change is achievable on some of the nation's most complex challenges.
The late effects of traumatic brain injury (TBI) are of great interest, but studies characterizing these effects are limited.
To determine whether TBI with loss of consciousness
 (LOC) is associated with an increased risk for clinical and neuropathologic findings of Alzheimer disease (AD), Parkinson disease (PD), and other dementias.
This study analyzed data from the Religious Orders Study (ROS), Memory and Aging Project (MAP), and Adult Changes in Thought study (ACT). All ROS and MAP participants and a subset of ACT participants consent to autopsy. Studies performed annual (ROS and MAP) or biennial (ACT) cognitive and clinical testing to identify incident cases of dementia and AD. The 7130 participants included members of a Seattle-area health care delivery system (ACT), priests and nuns living in orders across the United States (ROS), and Chicago-area adults in retirement communities (MAP). Of these, 1589 underwent autopsy. Primary hypothesis was that TBI with LOC would be associated with increased risk for AD and neurofibrillary tangles. Data were accrued from 1994 to April 1, 2014.
Self-reported TBI when the participant was free of dementia, categorized as no more than 1 vs more than 1 hour of LOC.
Clinical outcomes included incident all-cause dementia, AD, and PD in all studies and incident mild cognitive impairment and progression of parkinsonian signs in ROS and MAP. Neuropathologic outcomes included neurofibrillary tangles, neuritic plaques, microinfarcts, cystic infarcts, Lewy bodies, and hippocampal sclerosis in all studies.
Of 7130 participants (2879 [40.4%] men; overall mean [SD] age, 79.9 [6.9] years), 865 reported a history of TBI with LOC. In 45 190 person-years of follow-up, 1537 incident cases of dementia and 117 of PD were identified. No association was found between TBI with LOC and incident dementia (ACT: HR for TBI with LOC ≤1 hour, 1.03; 95% CI, 0.83-1.27; HR for TBI with LOC >1 hour, 1.18; 95% CI, 0.77-1.78; ROS and MAP: HR for TBI with LOC ≤1 hour, 0.87; 95% CI, 0.58-1.29; HR for TBI with LOC >1 hour, 0.84; 95% CI, 0.44-1.57) or AD (findings similar to those for dementia). Associations were found for TBI with LOC and incident PD in ACT (HR for TBI with LOC >1 hour, 3.56; 95% CI, 1.52-8.28) and progression of parkinsonian signs in ROS and MAP (odds ratio [OR] for TBI with LOC ≤1 hour, 1.65; 95% CI, 1.23-2.21; OR for TBI with LOC >1 hour, 2.23; 95% CI, 1.16-4.29). Traumatic brain injury with LOC was associated with Lewy bodies (any Lewy body in ACT: RR for TBI with LOC >1 hour, 2.64; 95% CI, 1.40-4.99; Lewy bodies in substantia nigra and/or locus ceruleus in ACT: RR for TBI with LOC >1 hour, 3.30; 95% CI, 1.71-6.38; Lewy bodies in frontal or temporal cortex in ACT: RR for TBI with LOC >1 hour, 5.73; 95% CI, 2.18-15.0; ROS and MAP: RR for TBI with LOC ≤1 hour, 1.64; 95% CI, 1.00-2.70; pooled RR for TBI with LOC ≤1 hour, 1.59; 95% CI, 1.06-2.39) and microinfarcts (any cortical microinfarct in ROS and MAP: RR for TBI with LOC >1 hour, 2.12; 95% CI, 1.12-4.01; pooled RR for TBI with LOC >1 hour, 1.58; 95% CI, 1.06-2.35).
Pooled clinical and neuropathologic data from 3 prospective cohort studies indicate that TBI with LOC is associated with risk for Lewy body accumulation, progression of parkinsonism, and PD, but not dementia, AD, neuritic plaques, or neurofibrillary tangles.
In recent years, a variety of new synthetic methodologies and concepts have been proposed in the search for new pharmaceutical lead structures and optimization. Notably, the Cu(I)-catalyzed azide-alkyne cycloaddition (CuAAC) click chemistry approach has drawn great attention and has become a powerful tool for the generation of privileged medicinal skeletons in the discovery of anti-HIV agents. This is due to the high degree of reliability, complete specificity (chemoselectivity and regioselectivity), mild conditions, and the biocompatibility of the reactants.
Herein, the authors describe the progress thus far on the discovery of novel anti-HIV agents via the CuAAC click chemistry-based approach.
CuAAC click chemistry is a proven protocol for synthesizing triazole products which could serve as basic pharmacophores, act as replacements of traditional scaffold or substituent modification, be a linker of dual-target or dual-site inhibitors and more for the discovery of novel anti-HIV agents. What's more, it also provides convenience and feasibility for dynamic combinatorial chemistry and in situ screening. It is envisioned that click chemistry will draw more attention and make more contributions in anti-HIV drug discovery in the future.
The racemic form of the title natural product 1 has been synthesized by engaging, as a key step, the iodoarene-tethered cyclohexene 22 in an intramolecular Heck reaction to give compound 23. This angularly substituted tetrahydrodibenzo[b,d]furan was elaborated over a further five steps into target (±)-1.
Health care stakeholders are concerned about the growing risk of protecting sensitive patient health information from breaches. The Federal Emergency Management Agency (FEMA) has identified cyber attacks as an emerging concern, and regulations such as the Health Insurance Portability and Accountability Act (HIPAA) and the Health Information Technology for Economic and Clinical Health Act (HITECH) have increased security requirements and are enforcing compliance through stiff financial penalties.
The purpose of this study is to describe health care breaches of protected information, analyze the hazards and vulnerabilities of reported breach cases, and prescribe best practices of managing risk through security controls and countermeasures. Prescriptive findings were used to construct a checklist tool to assess and monitor common risks.
This research uses a case methodology to describe specific examples of the 3 major types of cyber breach hazards: portable device, insider, and physical breaches. We utilize a risk management framework to prescribe preventative actions that organizations can take to assess, analyze, and mitigate these risks.
The health care sector has the largest number of reported breaches, with 3 major types: portable device, insider, and physical breaches. Analysis of actual cases indicates security gaps requiring prescriptive fixes based on "best practices."
Our research culminates in a 25-item checklist that organizations can use to assess existing practices and identify security gaps requiring improvement.
Studies have shown that irrigation water can be a vector for pathogenic bacteria. Due to this, the Food Safety Modernization Act's (FSMA) produce safety rule requires that agricultural water directly applied to produce be safe and of adequate sanitary quality for use, which may pose a challenge for some farmers. The purpose of this research was to assess the presence and concentration of Salmonella and generic Escherichia coli in irrigation water from distribution systems in a mixed produce production region of southern Georgia. Water samples were collected during three growing seasons at three farms irrigating crops with surface water (Pond 1, Pond 2) or groundwater (Well) during 2012-2013. Salmonella and generic E. coli populations were monitored by culture and Most Probable Number (MPN). Confirmed isolates were characterized by pulsed-field gel electrophoresis and serotyping. In Pond 1, Salmonella was detected in 2/21 surface, 5/26 subsurface, 10/50 center pivot, and 0/16 solid set sprinkler head water samples. In Pond 2, Salmonella was detected in 2/18 surface, 1/18 subsurface, 6/36 drip line start, and 8/36 drip line end water samples. Twenty-six well pumps and 64 associated drip line water samples were negative. The overall mean Salmonella concentration for positive water samples was 0.03 MPN/100 mL (range <0.0011-1.8 MPN/100 mL). Nine Salmonella serovars comprising 22 pulsotypes were identified. Identical serovars and subtypes were found three times on the same day and location: Pond 1-Pivot-Cantaloupe (serovar Rubislaw), Pond 1-Pivot-Peanut (serovar Saintpaul), and Pond 2-Drip Line Start-Drip Line End-Yellow Squash (serovar III_16z10:e,n,x,z15). Generic E. coli was detected in water from both farm ponds and irrigation distribution systems, but the concentrations met FSMA microbial water quality criteria. The results from this study will allow producers in southern Georgia to better understand how potential pathogens move through irrigation distribution systems.
Multicopy small RNAs (sRNAs) have gained recognition as an important feature of bacterial gene regulation. In the human pathogen Listeria monocytogenes, 5 homologous sRNAs, called LhrC1-5, control gene expression by base pairing to target mRNAs though 3 conserved UCCC motifs common to all 5 LhrCs. We show here that the sRNAs Rli22 and Rli33-1 are structurally and functionally related to LhrC1-5, expanding the LhrC family to 7 members, which makes it the largest multicopy sRNA family reported so far. Rli22 and Rli33-1 both contain 2 UCCC motifs important for post-transcriptional repression of 3 LhrC target genes. One such target, oppA, encodes a virulence-associated oligo-peptide binding protein. Like LhrC1-5, Rli22 and Rli33-1 employ their UCCC motifs to recognize the Shine-Dalgarno region of oppA mRNA and prevent formation of the ribosomal complex, demonstrating that the 7 sRNAs act in a functionally redundant manner. However, differential expression profiles of the sRNAs under infection-relevant conditions suggest that they might also possess non-overlapping functions. Collectively, this makes the LhrC family a unique case for studying the purpose of sRNA multiplicity in the context of bacterial virulence.
Since abortion became legal nationwide, federal and state "conscience clauses" have been established to define the context in which health professionals may decline to participate in contested services. Patients and health care providers may act according to conscience in making health care decisions and in deciding whether to abstain from or to participate in contested services.
 Historically, however, conscience clauses largely have equated conscience in health care with provider abstinence from such services. We propose a framework to analyze the ethical implications of conscience laws. There is a rich literature on the exercise of conscience in the clinical encounter. This essay addresses the need to ensure that policy, too, is grounded in an ethical framework. We argue that the ideal law meets three standards: it protects patients' exercise of conscience, it safeguards health care providers' rights of conscience, and it does not contradict standards of ethical conduct established by professional societies. We have chosen Illinois as a test of our framework because it has one of the nation's broadest conscience clauses and because an amendment to ensure that women receive consistent access to contested services has just passed in the state legislature. Without such an amendment, Illinois law fails all three standards of our framework. If signed by the governor, the amended law will provide protections for patients' positive claims of conscience. We recommend further protections for providers' positive claims as well. Enacting such changes would offer a model for how ethics-based analysis could be applied to similar policies nationwide.
Asthma is a common respiratory disorder, since about 10% of the population suffer from this disease, and up to 10% have a severe form. Recent findings have allowed a greater and deeper understanding of the pathophysiological mechanisms, distinguishing two groups of patients according to the prevalent cellular population that drives the inflammatory process, and consequentially, to intervene on different cellular targets.
Currently, several biological drugs directly interfering with these pathophysiological mechanisms (namely IgE, IL-4, IL-5, IL-13, and IL-17) are under investigation. Expert commentary: With the elucidation of mechanisms, new-targeted drugs have been developed. Asthma therapy is changing from a 'one size fits all' therapy to a 'precision medicine' model, where we may prescribe the most appropriate treatment for each patient. Moreover, in the near future, the possibility to act a 'sequential bio-combination therapy' can be envisaged, using different biological drugs in the same patient to act on different pathophysiological mechanisms.
Extracellular electron transfer (EET) is a mechanism that enables microbes to respire solid-phase electron acceptors. These EET reactions most often occur in the absence of oxygen, since oxygen can act as a competitive electron acceptor for many facultative microbes. However, for Shewanella oneidensis MR-1, oxygen may increase biomass development, which could result in an overall increase in EET activity. Here, we studied the effect of oxygen on S. oneidensis MR-1 EET rates using bioelectrochemical systems (BESs). We utilized optically accessible BESs to monitor real-time biomass growth, and studied the per-cell EET rate as a function of oxygen and riboflavin concentrations in BESs of different design and operational conditions. Our results show that oxygen exposure promotes biomass development on the electrode, but significantly impairs per-cell EET rates even though current production does not always decrease with oxygen exposure. Additionally, our results indicated that oxygen can affect the role of riboflavin in EET. Under anaerobic conditions, both current density and per-cell EET rate increase with the riboflavin concentration. However, as the dissolved oxygen (DO) value increased to 0.42 mg/L, riboflavin showed very limited enhancement on per-cell EET rate and current generation. Since it is known that oxygen can promote flavins secretion in S. oneidensis, the role of riboflavin may change under anaerobic and aerobic conditions. Biotechnol. Bioeng. 2017;114: 96-105. © 2016 The Authors. Biotechnology and Bioengineering Published by Wiley Periodicals, Inc.
The 2 structurally and functionally related peptides, neuropeptide B (NPB) and neuropeptide W (NPW), together with their receptor(s) (NPBWR1/NPBWR2) constitute the NPB/NPW system, which acts mainly on the central nervous system to regulate many physiological processes in mammals. However, little is known about this NPB/NPW system in nonmammalian vertebrates. In this study, the functionality and expression of this NPB/NPW system and its actions on the pituitary were investigated in chickens. The results showed that: 1) chicken NPB/NPW system comprises an NPB peptide of 28 amino acids (cNPB28), an NPW peptide of 23 or 30 amino acids (cNPW23/cNPW30), and their 2 receptors (cNPBWR1 and cNPBWR2), which are highly homologous to their human counterparts. 2) Using a pGL3-CRE-luciferase reporter system, we demonstrated that cNPBWR2 expressed in Chinese hamster ovary cells can be potently activated by cNPW23 (not cNPB28), and its activation inhibits the intracellular cAMP signaling pathway, whereas cNPBWR1 shows no response to peptide treatment, suggesting a crucial role of cNPBWR2 in mediating cNPW/cNPB actions. 3) Quantitative real-time PCR revealed that cNPW and cNPB are widely expressed in chicken tissues, including hypothalamus, whereas cNPBWR1 and cNPBWR2 are mainly expressed in brain or pituitary. 4) In accordance with abundant cNPBWR2 expression in pituitary, cNPW23 could dose dependently inhibit GH and prolactin secretion induced by GHRH and vasoactive intestinal polypeptide, respectively, in cultured chick pituitary cells, as monitored by Western blotting. Collectively, our data reveal a functional NPB/NPW system in birds and offer the first proof that NPW can act directly on pituitary to inhibit GH/prolactin secretion in vertebrates.
Ab initio MP2/aug'-cc-pVTZ calculations have been carried out on B4H4 and B4(CH3)4 to investigate the base properties of these molecules with Td symmetry. Each face of the tetrahedral structure of B4H4 and B4(CH3)4 is stabilized by a two-electron, three-center B-B-B bond. The face uses these two electrons to act uniquely as an electron-pair donor for the formation of stable hydrogen-bonded and halogen-bonded complexes with C3v symmetry. The hydrogen-bonded complexes are B4H4:HY and B4(CH3)4:HY, with HY = HNC, HF, HCl, HCN, and HCCH; the halogen-bonded complexes are B4H4:ClY and B4(CH3)4:ClY, with ClY = ClF, ClCl, ClNC, ClCN, ClCCH, and ClH. The absolute values of the binding energies of the hydrogen-bonded complexes B4(CH3)4:HY and of the halogen-bonded complexes B4(CH3)4:ClY are significantly greater than the binding energies of the corresponding complexes with B4H4. The binding energies of each series correlate with the distance from the hydrogen-bonded H atom or halogen-bonded Cl atom to the centroid of the interacting face. Charge transfer stabilizes all complexes and occurs from the B2-B3-B4 orbital of the face to the antibonding H-X orbital of HY in hydrogen-bonded complexes and to the antibonding Cl-X orbital of ClY in halogen-bonded complexes, with X being the atom of Y that is directly bonded to either H or Cl. For fixed HY, EOM-CCSD spin-spin coupling constants J(X-B1) are greater than J(X-Bn) for complexes B4H4:HY, even though the X-B1 distances are longer. B1 and Bn are the atoms at the apex and in the interacting face, respectively. Similarly, for complexes B4H4:ClY, J(Cl-B1) is greater than J(Cl-Bn). In the halogen-bonded complexes, both coupling constants correlate with the corresponding distances.
Here we report the identification of a novel tryptophyllin-3 peptide with arterial smooth muscle relaxation activity from the skin secretion of the purple-sided leaf frog, Phyllomedusa baltea. This new peptide was named baltikinin and had the following primary structure, pGluDKPFGPPPIYPV, as determined by tandem mass spectrometry (MS/MS) fragmentation sequencing and from cloned skin precursor-encoding cDNA. A synthetic replicate of baltikinin was found to have a similar potency to bradykinin in relaxing arterial smooth muscle (half maximal effective concentration (EC50) is 7.2 nM). These data illustrate how amphibian skin secretions can continue to provide novel potent peptides that act through functional targets in mammalian tissues.
The Gram-positive anaerobic bacterium Clostridium perfringens is widely distributed in nature, especially in soil and the gastrointestinal tracts of humans and animals. C. perfringens causes gas gangrene and food poisoning, and it produces extracellular enzymes and toxins that are thought to act synergistically and contribute to its pathogenesis. A complicated regulatory network of toxin genes has been reported that includes a two-component system for regulatory RNA and cell-cell communication. It is necessary to clarify the global regulatory system of these genes in order to understand and treat the virulence of C. perfringens. We summarize the existing knowledge about the regulatory mechanisms here.
The province of Ontario has shown great commitment towards the development of renewable energy and, specifically, wind power. Fuelled by the Green Energy Act (GEA) of 2009, the Province has emerged as Canada's leader in wind energy development (WED). Nonetheless, Ontario's WED trajectory is characterized by social conflicts, particularly around environmental health. Utilizing the Social Amplification of Risk Framework, this paper presents an eight-year longitudinal media content analysis conducted to understand the role Ontario's media may be playing in both reflecting and shaping public perceptions of wind turbine health risks. We find that before and after the GEA, instances of health risk amplification were far greater than attenuations in both quantity and quality. Discourses that amplified turbine health risks often simultaneously highlighted injustices in the WED process, especially after the GEA. Based on these findings, we suggest that Ontario's media may be amplifying perceptions
 of wind turbine health risks within the public domain. We conclude with policy recommendations around public engagement for more just WED.
Offshore design and construction is much more difficult than land-based design and construction, particularly due to hoisting operations. Real-time monitoring of the orientation and movement of a hoisted structure is thus required for operators' safety. In recent years, rapid development of the smart-phone commercial market has offered the possibility that everyone can carry a mini personal computer that is integrated with sensors, an operating system and communication system that can act as an effective aid for cyber-physical systems (CPS) research. In this paper, a CPS for hoisting monitoring using smartphones was proposed, including a phone collector, a controller and a server. This system uses smartphones equipped with internal sensors to obtain girder movement information, which will be uploaded to a server, then returned to controller users. An alarming system will be provided on the controller phone once the returned data exceeds a threshold. The proposed monitoring system is used to monitor the movement and orientation of a girder during hoisting on a cross-sea bridge in real time. The results show the convenience and feasibility of the proposed system.
We consider flow systems that have been utilized for small-scale biomolecular computing and digital signal processing in binary-operating biosensors. Signal measurement is optimized by designing a flow-reversal cuvette and analyzing the experimental data to theoretically extract the pulse shape, as well as reveal the level of noise it possesses. Noise reduction is then carried out numerically. We conclude that this can be accomplished physically via the addition of properly designed well-mixing flow-reversal cell(s) as an integral part of the flow system. This approach should enable improved networking capabilities and potentially not only digital but analog signal-processing in such systems. Possible applications in complex biocomputing networks and various sense-and-act systems are discussed.
Within medicinal chemistry nowadays, the so-called pharmaco-dynamics seeks for qualitative (for understanding) and quantitative (for predicting) mechanisms/models by which given chemical structure or series of congeners actively act on biological sites either by focused interaction/therapy or by diffuse/hazardous influence. To this aim, the present review exposes three of the fertile directions in approaching the biological activity by chemical structural causes: the special computing trace of the algebraic structure-activity relationship (SPECTRAL-SAR) offering the full analytical counterpart for multi-variate computational regression, the minimal topological difference (MTD) as the revived precursor for comparative molecular field analyses (CoMFA) and comparative molecular similarity indices analysis (CoMSIA); all of these methods and algorithms were presented, discussed and exemplified on relevant chemical medicinal systems as proton pump inhibitors belonging to the 4-indolyl,2-guanidinothiazole class of derivatives blocking the acid secretion from parietal cells in the stomach, the 1-[(2-hydroxyethoxy)-methyl]-6-(phenylthio)thymine congeners' (HEPT ligands) antiviral activity against Human Immunodeficiency Virus of first type (HIV-1) and new pharmacophores in treating severe genetic disorders (like depression and psychosis), respectively, all involving 3D pharmacophore interactions.
(1) BACKGROUND: Several triterpenoids were found to act synergistically with classes of antibiotic, indicating that plant-derived chemicals have potential to be used as therapeutics to enhance the activity of antibiotics against multidrug-resistant pathogens. However, the mode of action of triterpenoids against bacterial pathogens remains unclear. The objective of this study is to evaluate the interaction between ursolic acid against methicillin-resistant Staphylococcus aureus (MRSA); (2) METHODS: The ability of ursolic acid to damage mammalian and bacterial membranes was examined. The proteomic response of methicillin-resistant S. aureus in ursolic acid treatment was investigated using two-dimensional (2D) proteomic analysis; (3) RESULTS: Ursolic acid caused the loss of staphylococcal membrane integrity without hemolytic activity. The comparison of the protein pattern of ursolic acid-treated and normal MRSA cells revealed that ursolic acid affected a variety of proteins involved in the translation process with translational accuracy, ribonuclease and chaperon subunits, glycolysis and oxidative responses; (4) CONCLUSION: The mode of action of ursolic acid appears to be the influence on the integrity of the bacterial membrane initially, followed by inhibition of protein synthesis and the metabolic pathway. These findings reflect that the pleiotropic effects of ursolic acid against MRSA make it a promising antibacterial agent in pharmaceutical research.
Vascular imaging is essential to safe planning of stereotactic trajectories. This is particularly true for Stereo electroencephalographic (EEG) trajectory planning, in which nonuniform trajectories are utilized to interrogate deep structures or optimize recordings for a particular hypothesis test. Rotational angiography with 3-dimensional computed tomographic (CT) reconstruction enables visualization of small vessels for optimization of trajectory planning.
A total of 25 patients underwent selective angiography before Stereo EEG planning. Syngo DynaCT"! (Siemens, Munich, Germany) was used to create angiographic CT (ACT). Arterial contrast bolus of 22 mL was delivered with automated power injector at 1 mL/s over 22 seconds with 0.2 seconds delay, and imaging acquired over 20 seconds of acquisition through 220° of rotation. Trajectory planning was performed with merged T1-weighted, gadolinium enhanced (T1-Gd) MRI and ACT on WayPoint Navigator"! planning software (FHC Inc., Bowdoin, Maine).
Small-caliber vessels in both superficial and deep locations were routinely identified on ACT but not on T1-Gd MRI, resulting in alteration of planned trajectory. Skull thickness identified on ACT also altered trajectory entry points, particularly in thinned areas of squamous temporal bone and adjacent to prior craniotomies.
Three-dimensional ACT improves the resolution of small-caliber vessels due to image acquisition throughout the late arterial to early venous phase. This is particularly important during the planning of complex Stereo EEG trajectories.
Through a single-institution sport-related concussion (SRC) registry, we sought to: (1) provide a descriptive analysis of mechanisms of SRC in football, basketball, and soccer and (2) determine if mechanism of injury was associated with symptom duration.
A retrospective cohort study was conducted through in-depth patient interviews. Complete data were collected for 295 patients. Mechanisms were stratified into 3 components: a contact mechanism, a player mechanism, and an awareness mechanism. For each sport, each mechanism was compared via 1-way χ analyses. Symptom duration data were represented with Kaplan-Meier survival plots and Cox proportional hazards models to estimate the relationship between the exposure (concussion mechanism) to the time variable outcome (days of symptom duration).
The majority of athletes were male (70%) with an average age of 15.9 (±2.0) years. Football was the most represented sport (51%). The most common contact mechanisms were helmet-to-helmet contact in football (74%), ground/equipment in basketball (40%), and player to head in soccer (33%). Helmet-to-helmet contact was significantly overrepresented in football (χ = 69.267, df = 2, P < .001). Within the player mechanism, tackling (33%) and blocking (32%) predominated in football, rebounding (45%) and defense/loose-ball (33%) were most common in basketball, and challenging a player (44%) along with the act of heading (40%) were most commonly reported in soccer. Within the awareness mechanism, basketball (χ = 8.805, df = 1, P = .003) and soccer (χ = 11.255, df = 1, P = .001) players were more likely to be unaware of the oncoming collision. For soccer, being unaware of the oncoming collision was associated with a 2.54 (95% confidence interval, 1.14-5.69) times increased risk of not achieving asymptomatic status.
The current study analyzed mechanisms of SRC via a regional sports concussion outcomes registry. In middle school, high school, and collegiate athletes: (1) a helmet-to-helmet collision was most common football mechanism; (2) ground and surrounding equipment and player elbows predominated in basketball; (3) challenging a player and heading were the most common mechanisms of SRC in soccer; and (4) "awareness" of an oncoming collision in soccer was the only mechanism associated with a decreased the risk of prolonged symptom recovery.
Precise control of stem cells, such as human bone marrow-derived mesenchymal stem cells (hMSCs), is critical for the development of effective cellular therapies for tissue engineering and regeneration medicine. Emerging evidence suggests that several miRNAs act as key regulators of diverse biological processes, including differentiation of various stem cells. In this study, we have described a delivery system for miR-29b using PEI-capped gold nanoparticles (AuNPs) to synergistically promote osteoblastic differentiation. The cell proliferation assay revealed that AuNPs and AuNPs/miR-29b exert negligible cytotoxicity to hMSCs and MC3T3-E1 cells. With the assistance of AuNPs as a delivery vector, miR-29b could efficiently enter the cytoplasm and regulate osteogenesis. AuNPs/miR-29b more effectively promoted osteoblast differentiation and mineralization through induced the expression of osteogenesis genes (RUNX2, OPN, OCN, ALP) for the long-term, compared
 to the widely used commercial transfection reagent, Lipofectamine. With no obvious cytotoxicity, PEI-capped AuNPs showed great potential as an adequate miRNA vector for osteogenesis differentiation. Interestingly, we observed loading of AuNPs as well as AuNPs/miR-29b into the lumen of the endoplasmic reticulum (ER). Our findings collectively suggest that AuNPs, together with miR-29b, exert a synergistic promotory effect on osteogenic differentiation of hMSCs and MC3T3-E1 cells.
Stigmasterol is a phytosterol contained in Kraft mill effluent that is able to increase over 100% after aerobic biological treatment. This compound can act as an endocrine disrupter as its structure is similar to that of cholesterol. The aim of this study was to evaluate the removal of stigmasterol from Kraft mill effluents treated by a moving bed biofilm reactor (MBBR) with steroidal metabolite detection. The MBBR was operated for 145 days, with a hydraulic retention time of 2 days. Stigmasterol and steroidal metabolites were detected by gas chromatography with a flame ionization detector during MBBR operation. The results show that the MBBR removed 87.4% of biological oxygen demand (BOD5), 61.5% of chemical oxygen demand (COD), 24.5% of phenol and 31.5% of lignin, expressed in average values. The MBBR system successfully removed 100% of the stigmasterol contained in the influent (33 µg L(-1)) after 5 weeks of operation. In that case, the organic load rate was 0.343 kg COD m(-3) d(-1). Furthermore, different steroidal compounds (e.g., testosterone propionate, stigmast-4-en-3-one, 5α-pregnan-12-one-20α-hydroxy, 5α-pregnane-3,11,20-trione and 3α-hydroxy-5α-androstane-11,17-dione were detected in the Kraft mill effluent as potential products of phytosterol biotransformation.
The field of small self-cleaving nucleolytic ribozymes has been invigorated by the recent discovery of the twister, twister-sister, pistol and hatchet ribozymes. We report the crystal structure of a pistol ribozyme termed env25, which adopts a compact tertiary architecture stabilized by an embedded pseudoknot fold. The G-U cleavage site adopts a splayed-apart conformation with in-line alignment of the modeled 2'-O of G for attack on the adjacent to-be-cleaved P-O5' bond. Highly conserved residues G40 (N1 position) and A32 (N3 and 2'-OH positions) are aligned to act as a general base and a general acid, respectively, to accelerate cleavage chemistry, with their roles confirmed by cleavage assays on variants, and an increased pKa of 4.7 for A32. Our structure of the pistol ribozyme defined how the overall and local topologies dictate the in-line alignment at the G-U cleavage site, with cleavage assays on variants revealing key residues that participate in acid-base-catalyzed cleavage chemistry.
Although hyperhomocysteinemia (HHcy) is an independent risk factor for cardiovascular diseases (CVD), there is a debate on whether HHcy is a risk factor or just a biomarker. Interestingly, homocysteine lowering strategies in humans had very little effect on reducing the cardiovascular risk, as compared with animals; this may suggest heterogeneity in human population and epigenetic alterations. Moreover, there are only few studies that suggest the idea that HHcy contributes to CVD in the presence of other risk factors such as inflammation, a known risk factor for CVD. Elevated levels of homocysteine have been shown to contribute to inflammation. Here, we highlight possible relationships between homocysteine, T cell immunity, and hypertension, and summarize the evidence that suggested these factors act together in increasing the risk for CVD. In light of this new evidence, we further propose that there is a need for evaluation of the causes of HHcy, defective remethylation or defective transsulfuration, which may differentially modulate hypertension progression, not just the homocysteine levels.
Cationic ordered layered tetragonal perovskite phase LaBaCo₂O₆ (LBCO) nanomaterials with irregular shape, and an average diameter of about 100 nm were successfully prepared. A precursor material was annealed in an argon atmosphere at 1100 °C for 48 hours, and then heat treated in an oxygen atmosphere pressure at 800 °C for 12 hours. The resulting LBCO nanomaterials show ferromagnetic transition at about 175 K without any structural changes. They show metallic behavior at below 140 K, and adopt the behavior of soft ferromagnetic materials at 80 K. Cationic ordered LBCO nanomaterials display photocatalytic activities, as they successfully degrade MB solutions under both UV irradiation and visible light. The B-site cations act as the active center, and are located in the centre of BO₆ octahedron units. The various valence states of Co ions in LBCO could contribute to the enhancement of photocatalytic activies.
An energy transfer cassette was reported with energy donor and acceptor incorporated in one molecular. The two units (naphthalene and bisindolylmaleimide) were connected by covalent single bond. The intramolecular repulsion twisted the molecular conformation, thereby forcing the two units act as independent chromophores. Upon photoexcitation (λ = 280 nm), bright emission peak was observed around 583 nm. The intramolecular cascade energy transfer from the naphthalene moiety to the bisindolylmaleimide framework is efficient and the efficiency is estimated to be 86%, providing large pseudo-Stoke's shift (303 nm). At such a short separation, the orbital overlap interaction was completely isolated between chromophoric units. Computational study was carried out based on DFT. Further analysis of optimized structure and FMOs supports the efficient energy transfer in NBM. Favorable photophysical properties, such as efficient energy transfer, strong emission, and large Stoke's shift make it an attractive functional dye.
Recently, several new atypical antipsychotic agents have been introduced in Ontario, and regulatory warnings have been issued regarding use of atypical antipsychotics in older adults. We sought to establish the impact of newer atypical antipsychotics on prescribing rates and costs.
We performed a population-based cross-sectional study of Ontario adults aged 65 years or more using atypical antipsychotics from Jan. 1, 2007, to Mar. 31, 2013. These people have universal access to publicly funded drugs through the Ontario Health Insurance Plan and the Ontario Drug Benefit. We conducted time-series analysis to assess the impact of the introduction of new atypical antipsychotics on rates of use of atypical antipsychotics and associated expenditures.
Rates of atypical antipsychotic use increased following the introduction of new agents in 2009, from 27.6 users per 1000 older adults in the third quarter of 2009 to 29.1 users per 1000 older adults at the end of the study period (p = 0.04). Although prescribing rates for the newer atypical agents (paliperidone, ziprasidone and aripiprazole) remained low relative to their older counterparts (risperidone, olanzapine and quetiapine), rates of aripiprazole use rose to 1.0 user per 1000 older adults by the end of the study period. The proportion of prescriptions that were for brand-name agents fell from 57.5% in the second quarter of 2007 to 6.1% in the second quarter of 2009, and then rose to 11.7% by the end of the study period. By the first quarter of 2013, newer atypical antipsychotic agents were used by 4.4% of atypical antipsychotic users but accounted for 14.1% ($1.2 million of $8.5 million) of atypical antipsychotic expenditures.
Although the overall prevalence of use of new atypical antipsychotic agents remains low, their introduction has led to increased prescribing of this class of drugs in older adults. Given the potential cost implications, further study of these trends would be prudent.
Endometrial cancer (ECa) is one of the serious healthy burden for female worldwide. The treatments of ECa focus on the application of endocrine therapy and aberrant signaling proteins expression recently years. Medroxyprogesterone acrtate (MPA) plays crucial role in the endocrine therapy for ECa patients. However, the outcomes are still not ideal in the advanced stage tumor, especially in the progesterone-resistant ECa. Thioridazine (THIO) is an anti-psychotic agent, which has been reported to suppress the development of several human cancers. In this study, we aimed at to explore the clinical significant of THIO in the treatment of ECa.
Two ECa cell lines (ISK and KLE) were enrolled in this study, and were grouped into fore groups based on the treatment with different agents. Methylthiazolyldiphenyl-tetrazolium bromide (MTT) assay was used to analyze the viability of ECa cell lines. The apoptosis of ECa cells was examined by using the flow cytometer. To investigate the expression of important proteins, we applied the quantitative real-time RT-PCR (qRT-PCR) method and western blot analysis.
The viability of ECa cells was downregulated, and the apoptosis of ECa cells was upregulated after treating with the THIO plus MPA. The expression of progesterone receptor B (PRB) and dopamine receptor D2 (DRD2) were increased, and epidermal growth factor receptor (EGFR) and p-AKT were decreased in the THIO+MPA group. All these results suggested that the THIO could promote MPA to inhibit the growth of cells in ECa, especially in the progesterone-resistant ECa.
Taken together, all the data in the present study suggested that the THIO plus MPA might act as the suppressor of tumor growth in ECa by inhibiting the PI3K/AKT signal transduction pathway, which was mediated by PRB, DRD2 and EGFR.
Increasing evidences have demonstrated that microRNAs (miRNAs) act an essential role in regulating tumor progression and metastasis. Previous miRNAs microarray data showed that hsa-miR-599 is lower expressed in hepatocellular carcinoma (HCC); however, the function and molecular mechanism
 of hsa-miR-599 on HCC has not been well illustrated. Here, we first analyzed the expression level of hsa-miR-599 in HCC tissues and cell lines by real-time reverse-transcription PCR (qRT-PCR). Interestingly, we found that hsa-miR-599 was significantly down-regulated in the examined HCC tissues and cell lines. Then cells proliferation, migration and invasion were assessed by MTT, wound-healing and trans-well assay respectively. The results showed that over-expression of hsa-miR-599 resulted in inhibited HCC cells proliferation, migration and invasion in vitro. In addition, dual-luciferase reporter assay, qRT-PCR and Western blot analyzes were used to confirm MYC (v-myc avian myelocytomatosis viral oncogene homolog) as a target gene of hsa-miR-599. MYC expression was up-regulated in HCC tissues and cell lines, and restoration of hsa-miR-599 could remarkably decreased the mRNA and protein levels of MYC. Moreover, over-expression of MYC partly reversed hsa-miR-599-mediated inhibition of HCC cells proliferation, migration and invasion in vitro. Taken together, our data demonstrate that hsa-miR-599 acts as a tumor suppressor and inhibits HCC cells proliferation, migration and invasion by partly targeting oncogenic MYC, which hints that hsa-miR-599 can be a diagnostic and therapeutic biomarker in HCC.
Inflammatory bowel disease (IBD) is a chronic nonspecific intestinal inflammatory disease, including ulcerative colitis (UC) and Crohn's disease (CD). Its pathogenesis remains not yet clear. Current researchers believe that after environmental factors act on individuals with genetic susceptibility, an abnormal intestinal immune response is launched under stimulation of intestinal flora. However, previous studies only focused on adaptive immunity in the pathogenesis of IBD. Currently, roles of innate immune response in the pathogenesis of intestinal inflammation have also drawn much attention. In this study, IBD related innate immunity and adaptive immunity were explained, especially the immune mechanisms in the pathogenesis of IBD.
The distinction between proactive and reactive functions of aggression is one of the most common divisions when investigating aggression among children and adolescents. To date, self-report is the least used measurement, despite existing literature supporting the view that the best informant regarding internal processes and motives are children themselves. The main aim of this study was to examine the construct and concurrent validity of a new self-report questionnaire, which aims to disentangle acts of reactive vs. proactive aggression that are most common within the daily lives of children. We examined the self-report measure among 578 children (313 girls, 265 boys, mean age 11 years, range 9-13 years). Most children (90% boys; 85% girls) reported at least one act of aggression over the last four weeks. Furthermore, the outcomes support the two-factor structure (reactive and proactive aggression) and the questionnaire showed good concurrent and discriminant validity with measures for emotional and social functioning. This study validates the use of the self-report instrument for reactive and proactive aggression and demonstrates that children can successfully distinguish between their own motives for reactive and proactive forms of aggressive behaviours.
Third (infective)-stage Gnathostoma spinigerum larvae (L3) mainly cause human gnathostomiasis. G. spinigerum L3 migrate throughout the subcutaneous tissues, vital organs, and central nervous system and can cause various pathogenesis including sudden death. Interestingly, G. spinigerum L3 can survive and evade host cellular immunity for months or years. The effects of G. spinigerum excretory-secretory (ES) products involved in larval migration and immune-evasive strategies are unknown. Monocytes are innate immune cells that act as phagocytic and antigen-presenting cells and also play roles against helminthic infections via a complex interplay between other immune cells. Fc gamma receptor I (FcγRI) is a high-affinity receptor that is particularly expressed on monocytes, macrophages, and dendritic cells. The cross-linking of FcγRI and antigen-antibody complex initiates signal transduction cascades in phagocytosis, cytokine production, and antibody-dependent cell-mediated cytotoxicity (ADCC). This study investigated whether ES antigen (ESA) from G. spinigerum L3 affects monocyte functions.
Cultures of normal peripheral blood mononuclear cells (PBMC) separated from healthy buffy coats were used as a human immune cell model. ESA was prepared from G. spinigerum L3 culture. Using Real-Time quantitative reverse transcription-polymerase chain reaction (qRT-PCR), the effect of ESA to down-regulate FcγRI mRNA expression in monocytes during 90 min of observation was not well delineated. Flow cytometry analysis revealed a significant phenotypic-decreased FcγRI expression on the monocyte surface at 12 hours (h) of cultivation with the ESA (p = 0.033). Significantly reduced monocyte-mediated phagocytosis capacity was consistently observed after 12 h of ESA pretreatment (p = 0.001).
Our results suggest that G. spinigerum ESA modulates monocyte function via depletion of FcγRI expression. This study provides preliminary information for future in-depth studies to elucidate mechanisms of the immune-evasive strategy of G. spinigerum larvae.
A putative new limpet species (Patellogastropoda) from the Sea of Japan is revealed by molecular genetic analyses using the mitochondrial markers 16S rRNA and cytochrome c oxidase subunit I (CO1), as well as the DNA marker 18S rRNA. Our data indicate that the limpet, collected in the Peter the Great Bay (Russian Federation), is not, as its morphology suggests, the Japanese species Lottia kogamogai Sasaki and Okutani, 1994, and might also hint towards another putative species complex in the Sea of Japan. The different currents between the Far East Asian mainland (cold, subpolar jet running southwards) and the Japanese archipelago (warm, subtropical jet running northwards) are likely to act as a barrier that has a substantial influence on species distribution in these waters. Accordingly, our results indicate that it is about time for a revision of patellogastropod species with a reported distribution in Japanese and Far Eastern Russian waters by an integrative approach using molecular genetic and morphological characters. The species investigated herein is referred to as Lottia cf. kogamogai until it is morphologically re-examined and compared with primary type specimens of known species.
Acceptance and commitment therapy (ACT) for chronic pain aims to improve patient functioning by fostering greater psychological flexibility. While promising, ACT treatment process research in the context of chronic pain so far has only focused on a few of the processes of psychological flexibility. Therefore, this study aimed to more comprehensively examine changes in processes of psychological flexibility following an ACT-based treatment for chronic pain, and to examine change in these processes in relation to improvements in patient functioning. Individuals with chronic pain attending an interdisciplinary ACT-based rehabilitation program completed measures of pain, functioning, depression, pain acceptance, cognitive fusion, decentering, and committed action at pre- and post-treatment and during a nine-month follow-up. Significant improvements were observed from pre- to post-treatment and pre-treatment to follow-up on each of the treatment outcome and process variables. Regression analyses indicated that change in psychological flexibility processes cumulatively explained 6-27 % of the variance in changes in functioning and depression over both assessment periods, even after controlling for changes in pain intensity. Further research is needed to maximize the effectiveness of ACT for chronic pain, and to determine whether larger improvements in the processes of psychological flexibility under study will produce better patient outcomes, as predicted by the psychological flexibility model.
The ability to design agonists that target peptide signaling is a strategy to delineate underlying mechanisms and influence biology. A sequence that uniquely characterizes a peptide provides a distinct site to generate novel agonists. Drosophila melanogaster sulfakinin encodes non-sulfated drosulfakinin I (nsDSK I; FDDYGHMRF-NH2) and nsDSK II (GGDDQFDDYGHMRF-NH2). Drosulfakinin is typical of sulfakinin precursors, which are conserved throughout invertebrates. Non-sulfated DSK II is structurally related to DSK I, however, it contains a unique 5-residue N-terminal extension; drosulfakinins signal through G-protein coupled receptors, DSK-R1 and DSK-R2. Drosulfakinin II distinctly influences adult and larval gut motility and larval locomotion; yet, its structure-activity relationship was unreported. We hypothesized substitution of an N-terminal extension residue may alter nsDSK II activity. By targeting the extension we identified, not unexpectedly, analogs mimicking nsDSK II, yet, surprisingly, we also discovered novel agonists with increased (super) and opposite (protean) effects. We determined [A3] nsDSK II increased larval gut contractility rather than, like nsDSK II, decrease it. [N4] nsDSK II impacted larval locomotion, although nsDSK II was inactive. In adult gut, [A1] nsDSK II, [A2] nsDSKII, and [A3] nsDSK II mimicked nsDSK II, and [A4] nsDSK II and [A5] nsDSK II were more potent; [N3] nsDSK II and [N4] nsDSK II mimicked nsDSK II. This study reports nsDSK II signals through DSK-R2 to influence gut motility and locomotion, identifying a novel role for the N-terminal extension in sulfakinin biology and receptor activation; it also led to the discovery of nsDSK II structural analogs that act as super and protean agonists.
Mesenchymal stromal cells (MSCs) have
 shown great potential for treating inflammatory bowel disease, which is ameliorated through paracrine cross talk between MSCs and T-cells. Members of the insulin-like growth factor binding protein (IGFBP) family have important immunomodulatory functions in MSCs, but the underlying mechanisms behind these functions have not yet been clearly elucidated. In this study, we investigate whether MSC-produced IGFBP7 is involved in immune modulation using a mouse experimental colitis model. Gene expression profiling revealed that IGFBP7 was highly expressed in MSCs. Consistent with this findings, IGFBP7 knockdown in MSCs significantly decreased their immunomodulatory properties, decreasing the antiproliferative functions of MSCs against T-cells, while also having an effect on the proinflammatory cytokine production of the T-cells. Furthermore, in the mouse experimental colitis model, MSC-derived IGFBP7 ameliorated the clinical and histopathological severity of induced colonic inflammation and also restored the injured gastrointestinal mucosal tissues. In conclusion, IGFBP7 contributes significantly to MSC-mediated immune modulation, as is shown by the ability of IGFBP7 knockdown in MSCs to restore proliferation and cytokine production in T-cells. These results suggest that IGFBP7 may act as a novel MSC-secreted immunomodulatory factor.
This article explores an apparent paradox of stability and change in patient safety thinking and practice. The dominant approach to patient safety has largely been focused on closing 'safety gaps' through standardisation in seemingly stable healthcare systems. However, the presupposition of system stability and predictability is presently being challenged by critics who insist that healthcare systems are complex and changing entities, thereby shifting focus towards the healthcare organisation's resilient and adaptive capacities. Based on a close reading of predominant patient safety literature, the article analyses how a separation between stability and change is articulated in ontological, historical, and situated terms, and it suggests the way in which predetermining healthcare settings as either stable or unstable paves the way for a system engineering approach to patient safety that pre-empts certain types of safety solutions. Drawing on John Dewey's influential ideas about the interconnectedness of stability and change, this prescriptive perspective is discussed and challenged. It is suggested that only by rethinking the relationship between change and stability can patient safety efforts begin to address the uncertainty of medical practice as well as the necessary competences of healthcare professionals to act with 'safety dispositions' as a precondition for delivering safe care.
Class A plexins (PlxnAs) act as semaphorin receptors and control diverse aspects of nervous system development and plasticity, ranging from axon guidance and neuron migration to synaptic organization. PlxnA signaling requires cytoplasmic domain dimerization, but extracellular regulation and activation mechanisms remain unclear. Here we present crystal structures of PlxnA (PlxnA1, PlxnA2, and PlxnA4) full ectodomains. Domains 1-9 form a ring-like conformation from which the C-terminal domain 10 points away. All our PlxnA ectodomain structures show autoinhibitory, intermolecular "head-to-stalk" (domain 1 to domain 4-5) interactions, which are confirmed by biophysical assays, live cell fluorescence microscopy, and cell-based and neuronal growth cone collapse assays. This work reveals a 2-fold role of the PlxnA ectodomains: imposing a pre-signaling autoinhibitory separation for the cytoplasmic domains via intermolecular head-to-stalk interactions and supporting dimerization-based PlxnA activation upon ligand binding. More generally, our data identify a novel molecular mechanism for preventing premature activation of axon guidance receptors.
Several receptor mediated pathways have been shown to modulate the murine head twitch response (HTR). However, the role of sigma receptors in the murine (±)-2,5-dimethoxy-4-iodoamphetamine (DOI)-induced HTR has not been previously investigated. We examined the ability of LS-1-137, a novel sigma-1 vs. sigma-2 receptor selective phenylacetamide, to modulate the DOI-induced HTR in DBA/2J mice. We also assessed the in vivo efficacy of reference sigma-1 receptor antagonists and agonists PRE-084 and PPCC. The effect of the sigma-2 receptor selective antagonist RHM-1-86 was also examined. Rotarod analysis was performed to monitor motor coordination after LS-1-137 administration. Radioligand binding techniques were used to determine the affinity of LS-1-137 at 5-HT2A and 5-HT2C receptors. LS-1-137 and the sigma-1 receptor antagonists haloperidol and BD 1047 were able to attenuate a DOI-induced HTR, indicating that LS-1-137 was acting in vivo as a sigma-1 receptor antagonist. LS-1-137 did not compromise rotarod performance within a dose range capable of attenuating the effects of DOI. Radioligand binding studies indicate that LS-1-137 exhibits low affinity binding at both 5-HT2A and 5-HT2C receptors. Based upon the results from these and our previous studies, LS-1-137 is a neuroprotective agent that attenuates the murine DOI-induced HTR independent of activity at 5-HT2 receptor subtypes, D2-like dopamine receptors, sigma-2 receptors and NMDA receptors. LS-1-137 appears to act as a sigma-1 receptor antagonist to inhibit the DOI-induced HTR. Therefore, the DOI-induced HTR can be used to assess the in vivo efficacy of sigma-1 receptor selective compounds.
Savlon (0.5% cetrimide/0.05% chlorhexidine) is used as a scolicidal during surgery of hydatid cysts. It is considered a safe and effective agent. However, there are no recommendations for the appropriate concentration or dosage of these agents. Previously reported to cause severe metabolic acidosis, its effects on the pulmonary system have not been explored. We present a case of acute lung injury and respiratory distress along with acute cardiopulmonary distress, severe metabolic acidosis, and renal failure following its use during surgical removal of pulmonary hydatid cyst. The agent may act as a chemical sclerosant causing pulmonary parenchymal damage through bronchial openings present in the pericyst. Till safe dose limits are known, use of this agent should be limited, especially in large or multiple cyst surgery.
Assess the added value of nonenhanced computed tomography (NECT) to contrast-enhanced CT (CECT) of the abdomen for characterization of hypervascular liver metastases and incidental findings. Institutional review board approved, Health Insurance Probability and Accountability Act compliant, retrospective study of patients with melanoma, neuroendocrine tumor, or thyroid cancer. First available triphasic abdomen CT after initial diagnosis was reviewed by 3 radiologists. The 3 most suspicious lesions were characterized on the CECT as benign or malignant and then recharacterized after reviewing the NECT with CECT. Incidental renal and adrenal lesions were characterized similarly. Diagnostic performance of CECT vs its combination with NECT was assessed. Statistical significance level was set at P < 0.05. A total of 81 patients were included (mean age = 55 years; 52% male; 64% with liver lesions; 27% and 11% with incidental renal and adrenal lesions, respectively). Percentage area under the curve and 95% CI of CECT vs combination with NECT for characterization of liver metastases was 98(94-100) vs 99(96-100) for reviewer 1 (P = 0.35), 93(86-100) vs 94(87-100) for reviewer 2 (P = 0.23), and 96(90-100) vs 99(97-100) for reviewer 3 (P = 0.32). Mean difference in area under the curve and 95% CI between 2 protocols for characterization of liver, renal, and adrenal lesions were -0.007(-0.05 to 0.04) (P = 0.63), -0.09(-0.25 to 0.07) (P = 0.22), and -0.01(-0.05 to 0.02) (P = 0.27), respectively. After addition of NECT, confidence level for lesion characterization increased 4%-15% for liver metastases, 18%-59% and 33%-67% for renal and adrenal lesions, respectively. In conclusion, while addition of NECT to CECT improved radiologist' confidence, there was no statistically significant change in characterization of hypervascular liver metastases or incidental renal and adrenal lesions.
Human postural control is dependent on the central integration of vestibular, visual and proprioceptive inputs. Psychological states can affect balance control: anxiety, in particular, has been shown to influence balance mediated by visual stimuli. We hypothesized that patients with eating disorders would show postural destabilization when exposed to their image in a mirror and to the image of a fashion model representing their body ideal in comparison to body neutral stimuli. Seventeen females patients attending a day centre for the treatment of eating disorders were administered psychometric measures of body dissatisfaction, anxiety, depression and underwent posturographic measures with their eyes closed, open, watching a neutral stimulus, while exposed to a full length mirror and to an image of a fashion model corresponding to their body image. Results were compared to those obtained by eighteen healthy subjects. Eating disordered patients showed higher levels of body dissatisfaction and higher postural destabilization than controls, but this was limited to the conditions in which they were exposed to their mirror image or a fashion model image. Postural destabilization under these conditions correlated with measures of body dissatisfaction. In eating disordered patients, body related stimuli seem to act as phobic stimuli in the posturographic paradigm used. If confirmed, this has the potential to be developed for diagnostic and therapeutic purposes.
It is well established that lncRNAs are aberrantly expressed in cancer where they have been shown to act as
 oncogenes or tumor suppressors. RNA profiling of 314 colorectal adenomas/adenocarcinomas and 292 adjacent normal colon mucosa samples using RNA-sequencing demonstrated that the snoRNA host gene 16 (SNHG16) is significantly up-regulated in adenomas and all stages of CRC. SNHG16 expression was positively correlated to the expression of Wnt-regulated transcription factors, including ASCL2, ETS2, and c-Myc. In vitro abrogation of Wnt signaling in CRC cells reduced the expression of SNHG16 indicating that SNHG16 is regulated by the Wnt pathway. Silencing of SNHG16 resulted in reduced viability, increased apoptotic cell death and impaired cell migration. The SNHG16 silencing particularly affected expression of genes involved in lipid metabolism. A connection between SNHG16 and genes involved in lipid metabolism was also observed in clinical tumors. Argonaute CrossLinking and ImmunoPrecipitation (AGO-CLIP) demonstrated that SNHG16 heavily binds AGO and has 27 AGO/miRNA target sites along its length, indicating that SNHG16 may act as a competing endogenous RNA (ceRNA) "sponging" miRNAs off their cognate targets. Most interestingly, half of the miRNA families with high confidence targets on SNHG16 also target the 3'UTR of Stearoyl-CoA Desaturase (SCD). SCD is involved in lipid metabolism and is down-regulated upon SNHG16 silencing. In conclusion, up-regulation of SNHG16 is a frequent event in CRC, likely caused by deregulated Wnt signaling. In vitro analyses demonstrate that SNHG16 may play an oncogenic role in CRC and that it affects genes involved in lipid metabolism, possible through ceRNA related mechanisms.
Mesoporous silica-coated gold nanorods (AuNR@MS) act as a colloidally stable Raman sensing platform with a built-in analyte size cutoff. Herein, these core-shell plasmonic nanostructures were presented with a range of thiolated Raman-active molecules to probe the limits of this platform for SERS sensing. The experimental results show generally, that the transport of molecules through the mesopores is highly dependent on the size of the molecule and specifically, that AuNR@MS with pores of ∼4 nm diameter are able to sense analytes with molecular dimensions smaller than 1.5 nm. This sensing platform will likely find broad use, performing well even in complex media based on the high colloidal stability imbued by the mesoporous silica shell.
This study aimed to determine whether uterine leiomyoma can be distinguished from uterine leiomyosarcoma on ultrasound (US), computed tomography (CT), and/or magnetic resonance imaging (MRI) without diffusion-weighted imaging.
Institutional review board approval was obtained and informed consent was waived for this Health Insurance Portability and Accountability Act-compliant retrospective case-control diagnostic accuracy study. All subjects with resected uterine leiomyosarcoma diagnosed over a 17-year period (1998-2014) at a single institution for whom pre-resection US (n = 10), CT (n = 11), or MRI (n = 7) was available were matched by tumor size and imaging modality with 28 subjects with resected uterine leiomyoma. Six blinded radiologists (three attendings, three residents) assigned 5-point Likert scores for the following features: (1) margins, (2) necrosis, (3) hemorrhage, (4) vascularity, (5) calcifications, (6) heterogeneity, and (7) likelihood of malignancy (primary end point). Mean suspicion scores were calculated and receiver operating characteristic curves were generated. The ability of individual morphologic features to predict malignancy was assessed with logistic regression.
Mean suspicion scores were 2.5 ± 1.2 (attendings) and 2.4 ± 1.3 (residents) for leiomyoma, and 2.7 ± 1.3 (attendings) and 2.7 ± 1.4 (residents) for leiomyosarcoma. The areas under the receiver operating characteristic curves (range: 0.330-0.685) were not significantly different from chance, either overall (P = .36-.88) or by any modality (P = .28-.96), for any reader. Reader experience had no effect on diagnostic accuracy. No morphologic parameter was significantly predictive of malignancy (P = .10-.97).
Uterine leiomyoma cannot be differentiated accurately from leiomyosarcoma on US, CT, or MRI without diffusion-weighted imaging.
MicroRNA (miRNA) is a class of small non-coding RNAs which mediate post-transcriptional gene silencing (PTGS) by sequence-specific inhibition of target mRNAs translation and/or lowering their half-lives in the cytoplasm. Together with their binding partners, Argonaute (AGO) proteins, miRNAs form cores of RNA-induced silencing complexes (RISC). Despite a substantial progress in understanding RISC structure, until recently little was known about its localization in the cell. This review is aimed to provide an overview of the emerging picture of miRNA and RISC localization and function both in the intracellular space and outside of the cell. In contrast to the common assumption that PTGS occurs in the cytoplasm, it was found to operate mainly on the membranes of the endoplasmic reticulum (ER). Besides ER membranes miRNAs were found in all main cellular compartments including nucleus, nucleolus and mitochondria where they regulate various processes including transcription, translation, alternative splicing and DNA repair. Moreover, a certain pool of miRNAs may not be associated with RISC and carry completely different functions. Finally, the discovery of cell-free miRNAs in all biological fluids suggests that miRNAs might also act as signaling molecules outside the cell, and may be utilized as biomarkers for a variety of diseases. In this review we discuss miRNA secretion mechanisms and possible pathways of cell-cell communication via miRNA-containing exosomes in vivo.
In order to explore the potential of nanocomposites comprising semiconductor quantum dots (QDs) and metal nanoclusters (NCs) in photovoltaic and catalytic applications, the interaction between CdTe QDs and gold NCs, Au10 and Au25, stabilized by histidine, bovine serum albumin (BSA) and glutathione, is studied by an ultrafast transient absorption (TA) technique. Temporal and spectral studies of the transients reveal photoinduced 2-way electron transfer between the two constituents of the nanocomposites, where Au NCs, which generally act as electron donors when used as photosensitizers, perform the role of the efficient electron acceptor. Interestingly, it is found that the electron transfer dynamics in these composites is governed not by the distance of separation of the constituents but by the nature of the surface capping ligands. Despite a large separation between the QDs and NCs in a giant BSA-capped system, a higher electron transfer rate in this composite suggests that unlike other smaller capping agents, which act more like insulators, BSA allows much better electron conduction, as indicated previously.
Each year, two or three species that had been considered to be extinct are rediscovered. Uncertainty about whether or not a species is extinct is common, because rare and highly threatened species are difficult to detect. Biological traits such as body size and range size are expected to be associated with extinction. However, these traits, together with the intensity of search effort, might influence the probability of detection and extinction differently. This makes statistical analysis of extinction and rediscovery challenging. Here, we use a variant of survival analysis known as cure rate modelling to differentiate factors that influence rediscovery from those that influence extinction. We analyse a global data set of 99 mammals that have been categorized as extinct or possibly extinct. We estimate the probability that each of these mammals is still extant and thus estimate the proportion of missing (presumed extinct) mammals that are incorrectly assigned extinction. We find that body mass and population density are predictors of extinction, and body mass and search effort predict rediscovery. In mammals, extinction rate increases with body mass and population density, and these traits act synergistically to greatly elevate extinction rate in large species that also occurred in formerly dense populations. However, when they remain extant, larger-bodied missing species are rediscovered sooner than smaller species. Greater search effort increases the probability of rediscovery in larger species of missing mammals, but has a minimal effect on small species, which take longer to be rediscovered, if extant. By separating the effects of species characteristics on extinction and detection, and using models with the assumption that a proportion of missing species will never be rediscovered, our new approach provides estimates of extinction probability in species with few observation records and scant ecological information.
Exploiting metal-free catalysts for the oxygen reduction reaction (ORR) and understanding their catalytic mechanisms are vital for the development of fuel cells (FCs). Our study has demonstrated that in-plane heterostructures of graphene and boron nitride (G/BN) can serve as an efficient metal-free catalyst for the ORR, in which the C-N interfaces of G/BN heterostructures act as reactive sites. The formation of water at the heterointerface is both energetically and kinetically favorable via a four-electron pathway. Moreover, the water formed can be easily released from the heterointerface, and the catalytically active sites can be regenerated for the next cycle. Since G/BN heterostructures with controlled domain sizes have been successfully synthesized in recent reports (e.g. Nat. Nanotechnol., 2013, 8, 119), our results highlight the great potential of such heterostructures as a promising metal-free catalyst for the ORR in FCs.
G protein-coupled receptor 56 (GPR56) is an atypical G protein-coupled receptor, with the long extracellular N-terminus. GPR56 can trigger various downstream signaling
 responsible for cell survival, proliferation, adhesion, and migration. Expression of GPR56 is associated with cell malignant transformation and tumor cell metastasis in several carcinomas such as melanoma and glioma. Osteosarcoma is the most common malignant bone tumor in adolescents and young adults with high metastasis tendency. The overall survival of osteosarcoma is unsatisfied, partially due to the lacking of predictive markers for metastasis and overall prognosis. This study aimed at figuring out whether expression of the GPR56 was associated with clinicopathological features of osteosarcoma. Eighty-nine patients who received osteosarcoma operation between March 2004 and February 2011 in Linyi People's Hospital were recruited. Immunohistochemical staining (IHC) was carried out to identify the expression of GPR56 in those osteosarcoma tissues, and our cohort was divided into higher-expression group and lower-expression group according to the cut-off of IHC score. Expression of GPR56 in osteosarcoma tissues was correlated with the TNM stage and overall survival. Univariate and multivariate analysis showed that GPR56 could act as an independent prognosis factor for osteosarcoma. Western blot results demonstrated that GPR56-siRNA down-regulated the expression of GTP-RhoA and Ki67. GTP-RhoA participates in the cell migration process, while Ki67 plays important roles in cell proliferation, indicating GPR56 may function in tumor development. Correspondingly, we show that GPR56 regulates the proliferation and invasion capacity of osteosarcoma cells. Our study has revealed the prognostic value of GPR56 expression in osteosarcoma.
Ras proteins are small GTPases, cycling between inactive GDP-bound and active GTP-bound states. Through these switches they regulate signaling that controls cell growth and proliferation. Activating Ras mutations are associated with approximately 30% of human cancers, which are frequently resistant to standard therapies. Over the past few years, structural biology and in silico drug design, coupled with improved screening technology, led to a handful of promising inhibitors, raising the possibility of drugging Ras proteins. At the same time, the invariable emergence of drug resistance argues for the critical importance of additionally honing in on signaling pathways which are likely to be involved. Here we overview current advances in Ras structural knowledge, including the conformational dynamic of full-length Ras in solution and at the membrane, therapeutic inhibition of Ras activity by targeting its active site, allosteric sites, and Ras-effector protein-protein interfaces, Ras dimers, the K-Ras4B/calmodulin/PI3Kα trimer, and targeting Ras with siRNA. To mitigate drug resistance, we propose signaling pathways that can be co-targeted along with Ras and explain why. These include pathways leading to the expression (or activation) of YAP1 and c-Myc. We postulate that these and Ras signaling pathways, MAPK/ERK and PI3K/Akt/mTOR, act independently and in corresponding ways in cell cycle control. The structural data are instrumental in the discovery and development of Ras inhibitors for treating RAS-driven cancers. Together with the signaling blueprints through which drug resistance can evolve, this review provides a comprehensive and innovative master plan for tackling mutant Ras proteins.
The goal of the International Journal of Behavioral Nutrition and Physical Activity (IJBNPA) is to be the leading diet and physical activity journal. To achieve this aim we embrace and publish a number of different research designs from small, but in depth, qualitative studies to large scale cohort studies. IJBNPA prioritises research based on randomised controlled trials (RCTs), systematic reviews (with or without meta-analyses, as appropriate), and well conducted observational studies that expand knowledge and understanding of the area. IJBNPA will also consider and publish other study designs that are of sufficient quality such as strong or ground-breaking methodological papers, rigorous qualitative studies, debate papers and commentaries. However, due to the demands on the journal, we publish pilot studies only in exceptional circumstances and we do not publish protocol papers or letters to the editors. The goal of this editorial is to highlight to our readers and authors the process by which we identify which papers to review and publish along with our editorial priorities.
Herpes simplex is a disease that is widely distributed throughout the world. It is caused by herpes simplex virus type 1 (HSV-1) and simplex virus type 2 (HSV-2). The drugs of choice for treatment are acyclovir (ACV), Penciclovir (PCV) and other guanine analogues, which have the same mechanism of action. However, due to the constant increase of ACV-resistant strains in immunocompromised patients, it is necessary to find new treatment alternatives. It has been shown that natural products are a good alternative for the treatment of these diseases as well as being an excellent source of compounds with anti-herpetic activity, which may be useful for the development of new drugs and act through a mechanism of action different from ACV and PCV. This paper compiles reports on extracts and compounds isolated from plants that have anti-herpetic activity. We present an analysis of the solvents most widely used for extraction from plants as well as cells and commonly used methods for evaluating cytotoxic and anti-herpetic activity. Families that have a higher number of plants with anti-herpetic activity are evaluated, and we also highlight the importance of studies of mechanisms of action of extracts and compounds with anti-herpetic activity.
Following recent molecular studies on avocado thrips, a new species is described from Costa Rica, Ecuador, and Colombia from the young leaves of avocado, Persea americana. Scirtothrips hansoni sp.n. is closely related to the Californian pest, S. perseae, and also to S. astrictus from Costa Rica that remains known from a single female. An illustrated key to these three species is provided.
Based on near-topotypic specimens of Dixonius vietnamensis from Khanh Hoa Province in southern Vietnam genetic analyses showed that the recently described D. taoi is sister to D. vietnamensis and several separate forms exist which previously have been misidentified as D. vietnamensis and D. siamensis. The Dixonius population from Vinh Cuu Nature Reserve, Dong Nai Province, Vietnam, represents an undescribed species. Dixonius minhlei sp. nov. can be distinguished from its congeners based on the following diagnostic characters: small size (up to 47.5 mm SVL); 7-9 supralabials; 14-15 rows of keeled tubercles on dorsum; 20-23 ventral scale rows; 7 or 8 precloacal pores in males; a canthal stripe running from rostrum through the eye and terminating at back of head; lateral second pair of postmentals maximum one quarter the size of first pair; dorsum olive gray with more or less discernible brownish olive blotches. This is the sixth species of Dixonius known to occur in Vietnam.
Six species in Goodangarkia are described. Information on the distribution. ecology and cytology of species is presented. An unusual characteristic of cranial stridulation of one species is noted. Cytological evidence suggests the chromosome complement of species are more basal than those from Africa for example.
From the north of Australia's Northern Territory, far northeastern Queensland and Torres Strait Islands, six new species of microcaddisfly are described: Hydroptila roperi sp. nov., Hellyethira khukri sp. nov., Oxyethira (Trichoglene) bamaga sp. nov., Oxyethira (Dampfitrichia) torresiana sp. nov., Orthotrichia pethericki sp. nov., and Orthotrichia becca sp. nov. Oxyethira torresiana is recorded from the northwest of York Peninsula and Badu Island in the Torres Strait as well as from Papua New Guinea. Northern Australian records are given for Orthotrichia veikaba Wells and Orthotrichia ensiformis Wells, previously known only from Papua New Guinea. Northern Australian distributions are extended eastwards for  Tricholeiochiton jabirella Wells and westwards for Oxyethira (Trichoglene) triangulata Wells, until now recorded only from the Northern Territory and northeastern Australia, respectively. Brief notes are given on collecting methods and sites.
This paper reviews 47 names that have been used at the levels of Family, Subfamily and Tribe, for mites in the suborder Uropodina. Complete bibliographic references are provided for all of these names and the names of their type genera. The spelling and authorship of taxon names is corrected where necessary. Fifteen of these family-group names are unavailable, because they do not satisfy the requirements of the International Code of Zoological Nomenclature. However, some of these names represent taxonomic concepts that may be useful in future revisions of the group.
The genus Elseya has had a checkered taxonomic history, but is now restricted to species characterized by an alveolar ridge on the triturating surfaces of the jaw. The Australian forms were once regarded as a single widespread species extending from the Mary River of south-eastern Queensland to the Fitzroy River of north Western Australia, but a number of Australian species have now been identified based on a combination of molecular and morphological data-Elseya dentata, E. irwini, E. lavarackorum and E. albagula. The genus is represented in New Guinea by E. branderhorsti, E. novaeguineae, E. schultzii, and E. rhodini. One additional Australian taxon first identified in 1981 and subsequently established as a distinct taxon by molecular studies, is described here. It is a large chelid turtle that can be distinguished from all other Australian members of the genus Elseya by the distinctive cream or yellow plastron, free of the dark streaking,
 blotches or suffusing present in other species; an extensive bridge with little or no abrupt angle between the bridge and the ventral surface of the plastron; a head shield broken into a series of small plates rather than a single unit; flat uncornified temporal scales; and a narrower, less robust skull. Osteologically, it can be distinguished from Elseya dentata by the contact of the vomer and the pterygoids. The carapace is typically a light to medium brown in color whereas the carapace of Elseya dentata is typically dark brown to almost black in color. Distribution is the Mary, South Alligator, East Alligator, Goyder and Mann River drainages of the north east of the Northern Territory, Australia. It does not appear to be in sympatry with any other member of Elseya. It is, however, in sympatry with three species of Chelodina, at least two species of Emydura, Myuchelys latisternum and Carettochelys insculpta.
Our aim was to illustrate the effect of higher activated clotting time (ACT) values versus lower ACT values on thrombotic or hemorrhagic events in coronary atherosclerotic heart disease (CHD) patients undergoing percutaneous coronary intervention (PCI). PubMed, Embase, Web of Science, and Cochrane Library were searched. Observational studies assessing ACT related major adverse cardiac event (MACE) and major bleeding were included. Studies were allocated into three groups. Group 1 included studies with low percentage of participants prescribed with glycoprotein IIb/IIIa inhibitors ([GPI] ≤30%), Group 2 with high percentage of participants prescribed with GPI (>30%), and Group 3 with routine direct thrombin inhibitors (DTI) prescription. The cutoff is designed as 300s (290-310s) for Group 1, and 250s (240-260s) for Group 2. With regard to MACE and major bleeding in Group 1, there was no significant difference between higher ACT values and lower ACT values (risk ratio [RR] for MACE, 1.16, 95% confidence interval [CI], 0.65-2.05, p=0.62, I(2)=94%, RR for major bleeding, 0.96, 95% CI, 0.66-1.40, p=0.83, I(2)=0%). Likewise, no significant difference was found in Group 2 between higher ACT values and lower ACT values (RR for MACE, 1.15, 95% CI, 0.97-1.35, p=0.10, I(2)=0%, RR for major bleeding, 0.85, 95% CI, 0.45-1.60, p=0.61, I(2)=83%). In conclusion, ACT may not have a substantial effect on thrombotic or hemorrhagic complications. Under current clinical practice, target ACT may be higher than what is necessary to prevent thrombotic events. We may achieve a relative low ACT level to preserve efficacy and enhance safety.
Dietary patterns influence various cardiometabolic risk factors, including body weight, lipoprotein concentrations, and function, blood pressure, glucose-insulin homeostasis, oxidative stress, inflammation, and endothelial health. The Mediterranean diet can be described as a dietary pattern characterized by the high consumption of plant-based foods, olive oil as the main source of fat, low-to-moderate consumption of fish, dairy products and poultry, low consumption of red and processed meat, and low-to-moderate consumption of wine with meals. The American Diabetes Association and the American Heart Association recommend Mediterranean diet for improving glycemic control and cardiovascular risk factors in type 2 diabetes. Prospective studies show that higher adherence to the Mediterranean diet is associated with a 20-23 % reduced risk of developing type 2 diabetes, while the results of randomized controlled trials show that Mediterranean diet reduces glycosylated hemoglobin levels by 0.30-0.47 %, and is also associated with a 28-30 % reduced risk for cardiovascular events. The mechanisms by which Mediterranean diet produces its cardiometabolic benefits in type 2 diabetes are, for the most, anti-inflammatory and antioxidative: increased consumption of high-quality foods may cool down the activation of the innate immune system, by reducing the production of proinflammatory cytokines while increasing that of anti-inflammatory cytokines. This may favor the generation of an anti-inflammatory milieu, which in turn may improve insulin sensitivity in the peripheral tissues and endothelial function at the vascular level and ultimately act as a barrier to the metabolic syndrome, type 2 diabetes and development of atherosclerosis.
A number of Australian species have been placed in the wrong, often non-Australian, genera. Some of these problems have been corrected here, by transfer or establishment of new genera. Several new species discovered during the course of the work are also described. Marptusa jovialis L. Koch, 1879 and Marptusa bracteata L. Koch, 1879 are transferred to Apricia gen. nov. Apricia longipalpis sp. nov. is also described from Australia. The study of the Australian species presently included in Trite Simon 1885 showed that this genus does not occur in mainland Australia. Hence, Marptusa vulpecula Thorell, 1881 is transferred to Capeyorkia gen. nov., while Marptusa longula Thorell, 1881 is transferred to Evarcha Simon, 1902. The only previously described 'Australian' species to remain in Trite is Trite concinna Rainbow, 1920, from Lord Howe Island and Norfolk Island in the Pacific, while Trite grayi sp. nov., also from Lord Howe Island, is described here. Trite concinna Rainbow 1920 is redescribed. Most specimens previous listed as this species from Lord Howe Island (including most of the syntype series) belong in Ancepitilobus howensis gen. nov. et sp. nov. Clynotis severus (L. Koch, 1879) is the solitary species that remains in Clynotis Simon, 1901, with the remainder of the mainland species being transferred to Pungalina Richardson, 2013: P. albobarbata (L. Koch, 1879) comb. nov., P. semiatra (L. Koch, 1879) comb. nov. and P. semiferruginea (L. Koch, 1879) comb. nov. Pungalina plurilineata sp. nov. and Pungalina waldockae sp. nov. are also described from Australia. Clynotis gratiosa from Lord Howe Island is formally transferred to Tara Peckham & Peckham, 1886, as suggested previously. Tara gratiosa (Rainbow, 1920) is redescribed. Finally, three names, Gangus longulus Simon, 1902, Trite ornata Rainbow, 1915 and Plexippus albopilosus Keyserling, 1883, are considered species inquirendae, due to the state or loss of type material.
Until recently, mites in the families Ascidae, Blattisociidae and Melicharidae together constituted what was considered to be a single family, the Ascidae (sensu lato). We include all three families in this catalogue because of their many morphological similarities, as well as for historic and ecological reasons. Together with most Phytoseiidae and some Ameroseiidae, these are the only mesostigmatid mites commonly found on plants. In this publication we initially provide a historic overview of these groups, summarising the changes in the taxonomic concepts of the genera and other subfamilial taxa. This is followed by a thorough characterisation of each family and genus. A dichotomous key for the separation of families and genera is included. We then list the species considered to belong to these families, with details of the literature concerning the taxonomy of each species, and information about their type specimens and type localities wherever possible. The numbers of taxa considered as valid in this publication are: 372 species in 17 genera of Ascidae, 367 species in 14 genera of Blattisociidae, and 206 species in 11 genera of Melicharidae. We attempt to place each species in the most appropriate genus. In doing so, we propose 30 new combinations, including a species here transferred from Ascidae sensu stricto to Rhodacaridae. We propose five new names to replace junior homonyms, one new generic synonymy, and one new specific synonymy. Some species are insufficiently known and could not be reliably placed in any genus; these are listed as species incertae sedis. We also provide a list of species and genera that have been placed in these families at some time, but which have been transferred to other groups.
In the present study, konjac glucomannan (KGM) was degraded by H2O2, and then used trisulfonated sodium amine and HCl, individually, to obtain two kinds of derivatives: oxidized konjac glucomannan sulfates (OKGMS) and acidolysis-oxidized konjac glucomannan (A-OKGM). The effects of two OKGM modified products on the immune parameters and expressions of toll-like receptor 22 (TLR22), myeloid differentiation factor 88 (MyD88) and interferon regulatory factors 7 (IRF7) genes in Schizothorax prenanti were determined. The alternative haemolytic complement (ACH50) activity was found to be significantly increased by the OKGMS diets. The immunoglobulin M (IgM) level was significantly enhanced by the OKGMS diets. The lysozyme activity was significantly increased by both OKGMS and A-OKGM diets. The superoxide dismutase (T-SOD) activity in fish fed with all doses of OKGMS diets was significantly higher than that in fish fed with basal diet. The glutathione peroxidase (GSH-PX) activity in fish fed with 0.8% and 1.6% A-OKGM diets was significantly higher than control group. The malondialdehyde (MDA) level was significantly decreased by both OKGMS and A-OKGM diets. The 0.8% A-OKGM diet significantly up-regulated TLR22 gene expression in the head kidney and spleen. TLR22 gene expression was significantly promoted by all OKGMS diets in the mesonephros and liver. The MyD88 mRNA level in 1.6% A-OKGM group significantly increased in the head kidney. The low dose of OKGMS significantly induced the MyD88 gene expression in the mesonephros, gut and liver, while 0.8% A-OKGM group also showed a significantly enhanced MyD88 mRNA expression in the gut. High dose of OKGMS significantly increased the IRF7 mRNA expression in the mesonephros and spleen. Fish fed with low dose of A-OKGM showed significantly higher expression of IRF7 in the gut and liver. Present study suggested that OKGMS
 and A-OKGM can act as immunostimulant to improve the immune indexes and up-regulate the immune-related gene expressions.
Character states used in distinguishing taxa within the Thripidae subfamily Dendrothripinae are discussed, and a key presented to the 11 genera recognized worldwide. Comments on each of these genera are provided, together with keys to the species from Australia of Dendrothrips, Ensiferothrips and Pseudodendrothrips. From Australia are described, four new species of Dendrothrips, one of Pseudodendrothrips, and a remarkable new species of Ensiferothrips that has required a re-diagnosis of that genus. Another new species of Ensiferothrips is described from Sulawesi, thus greatly extending the known geographical range of this previously Australian genus.
Ongoing fieldwork and molecular research continues to reveal that the monsoonal tropics of northern Australia contain more vertebrate species than currently recognised. Here we focus on two morphologically distinctive, yet unrecognised forms in the genus Gehyra from the southern Kimberley region and surrounding deserts. We base our descriptions on a combination of unpublished genetic data and a morphological examination of voucher specimens. We recognise and redescribe G. kimberleyi, a species with a broad distribution extending over most of the south-west Kimberley, across the Great Sandy Desert and into the far northern Pilbara. This species has been previously assigned to G. pilbara owing to its frequent occurrence on termite mounds and short snout, but can be distinguished from G. pilbara and other regionally sympatric Gehyra by its moderate body size, moderate number of pre-cloacal pores in males (12-17) and aspects of dorsal colouration. We also describe G. girloorloo sp. nov., a small rock-dwelling species with a short snout, low number of pre-cloacal pores in males (8-11) and pinkish-grey dorsal colouration with alternating series of indistinct pale spots and irregular transversely-aligned dark blotches. The new species appears to be restricted to a relatively small region of exposed limestone karst in the south-west Kimberley and is entirely circumscribed by morphologically similar congeners.
The 28 known species of Metapone are monographed and illustrated. Twelve are described as new: M. africana, Gabon; M. balinensis, Bali, Indonesia; M. enigmatica, northeast New Guinea; M. hoelldobleri, northeast Queensland, Australia; M. javana, Java, Indonesia; M. manni, Viti Levu, Fiji; M. mathinnae, Flinders Island, Tasmania, Australia; M. philwardi, northeast New Guinea; M. salomonis, Guadalcanal, Solomon Islands; M. tecklini, northeast Queensland; M. titan, New Ireland, Papua New Guinea; M. wallaceana, Lombok, Indonesia; spp.n. New synonymies include M. greeni Forel = M. johni Karavaiev (Sri Lanka) syn.n, and M. jacobsoni Crawley (Sumatra) = M. nicobarensis Tiwari & Jonathan (Great Nicobar Island) syn.n.
Straight-chained lepidopteran pheromones are now regulated under a group standard in New Zealand, which is generic for moth pheromone products of similar low risk, under the Hazardous Substances and New Organisms Act (1996). This means that compliant new pheromone products can be developed and commercialized with low regulatory requirements. This encourages innovation and supports fruit industries interested in meeting export phytosanitary standards, while targeting low or nil residues of pesticides. Changes to pheromone blends for reasons such as technical improvements or variations in pest species composition in different crops can be made with minimal regulatory involvement. We illustrate how this system now operates with a four species mating disruption product commercialized in 2012. The odors involved in "4-Play™" consist of a range of components used by codling moth (Cydia pomonella), lightbrown apple moth (Epiphyas postvittana), green-headed leafroller (Planotortrix octo), and brown-headed leafroller (Ctenopseustis obliquana). The development of 4-Play™ illustrates how mating disruption of insects can support industry goals.
To explore the microstructural integrity of the optic nerve and its role as a cognitive predictor in patients with de novo Parkinson's disease (PD) using diffusion tensor image-based magnetic resonance scans.
We enrolled 82 patients with de novo PD, 36 patients with drug-induced parkinsonism (DIP), and 36 controls. Fractional anisotropy (FA) and apparent diffusion coefficient (ADC) were measured on the mid-portion of the intraorbital optic nerve. Using a multivariate analysis of variance with repeated measures, longitudinal changes in cognitive subscores of a comprehensive neuropsychological test were evaluated in PD patients according to optic nerve integrity.
The mean FA value in PD was significantly lower (0.552 ± 0.103, p < 0.001) than that in DIP (0.645 ± 0.099) or the controls (0.689 ± 0.089), whereas the mean ADC value was significantly higher in the PD group compared to the DIP or control group (p < 0.001). Optic nerve integrity was not associated with parkinsonian motor severity, striatal dopamine transporter activity, olfaction, or baseline cognitive performance in PD patents. In a longitudinal assessment of cognition in PD, the lower FA group showed significant decline in the performance of Clock Drawing Test (F = 3.39, p = 0.038), but no significant differences in the other cognitive subsets.
This study demonstrated that microstructural integrity in the optic nerve was distorted in PD patients, and that this nerve integrity might act as a cognitive predictor of visuospatial dysfunction.
Avibactam restored the in-vitro antibacterial activity of ceftazidime, ceftaroline, and aztreonam against isogenic Escherichia coli expressing class A, class C, and class D β-lactamases. The enzymes included TEM and CTX-M extended spectrum β-lactamases, ACT, CMY and FOX AmpC-type enzymes, and carbapenemases including rarer KPC variants and OXA-139.
We describe a new species of small terrestrial gecko in the genus Diplodactylus from inland regions of western Queensland and New South Wales, Australia. Diplodactylus ameyi sp. nov. can be distinguished from its congeners in the Diplodactylus conspicillatus species-group by its relatively large size, bulbous tail which lacks an acute attenuated extension at tip, small first labial scale and comparatively robust head morphology (which includes a broadly rounded snout and no well-defined canthus rostralis). Related populations from eastern and central Queensland currently referred to D. platyurus include further deeply divergent lineages but additional material is required to resolve systematic boundaries in this region.
Sun moths (Castniidae) constitute a family of day-flying moths that due to their slim bodies, broad and often richly coloured wings and clubbed antennae closely resemble butterflies. However, despite this superficial similarity, sun moths are not related to butterflies but belong to the diverse cossoid assemblage of lepidopterous families (Edwards et al. 1998). Until recently, Castniidae were assigned to the superfamily Sesioidea (Minet 1991). A molecular study by Mutanen et al. (2010), however, failed to find support for a close relationship of Sesiidae and Castniidae, resulting in the inclusion of both families in a larger concept of Cossoidea (Nieukerken et al. 2011). In contrast, Heikkil et al. (2015) who added considerable morphological data to DNA, recovered Sesioidea as monophyletic, with Sesiidae, Castniidae and Brachodidae as constituent families, yet with low support values. Thus, although the monophyly of Castniidae is well supported, the systematic position of this family is unresolved.
Leucine-rich repeat kinase 2 (LRRK2) has been implicated in oxidative stress (OS) and neurodegeneration in Parkinson's disease (PD). However, the pathophysiological mechanism of the LRRK2 kinase in neurons under stress stimuli is not yet understood. We demonstrate that rotenone (ROT), a mitochondria complex I inhibitor frequently used to generate in vitro and in vivo experimental models of PD, induces LRRK2 phosphorylation at serine 935 p-(S935) concomitant with cell death in nerve-like differentiated cells (NLCs). Indeed, ROT (50 µM) at 6 h exposure significantly increased reactive oxygen species (ROS) (~100 %), p-(S935)-LRRK2 kinase [~2 f(old)-(i)ncrease] level, induced nuclei condensation/fragmentation (16 %), increased the expression of NF-κB (5.6 f-i), p53 (5.3 f-i), c-Jun (5.4 f-i) transcription factors, activated caspase-3 (8.0 f-i) and AIF (6.8 f-i) proteins; but significantly decreased mitochondrial membrane potential (∆Ψm, ~21 %), indicative of apoptosis -a type of regulated cell death process- compared to untreated cells. Strikingly, the LRRK2 kinase inhibitor PF-06447475 (PF-475, 1 µM) protects NLCs against ROT induced noxious effect. The inhibitor not only blocked the p-(S935)-LRRK2 kinase phosphorylation but also completely abolished ROS, and significantly reversed all ROT-induced apoptosis signaling and OS associated markers to comparable control values. We conclude that wild-type LRRK2 may act as a pro-apoptotic factor under OS stimuli. Our findings suggest an association between OS and LRRK2 phosphorylation in the NLCs death process, as PD model. Therefore, the pharmacological inhibition of LRRK2 might help to understand the OS-mediated kinase activation in PD neurodegenerative disorder.
Synthetic quinoline derivatives continue to be considered as candidates for new drug discovery if they act against CQ-resistant strains of malaria even after the widespread emergence of resistance to CQ. In this study, we explored the activities of two series of new 4-aminoquinoline derivatives and found them to be effective against Plasmodium falciparum under in vitro conditions. Further, we selected four most active derivatives 1m, 1o, 2c and 2j and evaluated their antimalarial
 potential against Plasmodium berghei in vivo. These 4-aminoquinolines cured BALB/c mice infected with P. berghei. The ED50 values were calculated to be 2.062, 2.231, 1.431, 1.623 and 1.18 mg/kg of body weight for each of the compounds 1m, 1o, 2c, 2j and amodiaquine, respectively. Total doses of 500 mg/kg of body weight were well received. The study suggests that these new 4-aminoquinolines should be used for structure activity relationship to find lead molecules for treating multidrug-resistant Plasmodium falciparum and Plasmodium vivax.
Lizards restricted to rocky habitats often comprise numerous deeply divergent lineages, reflecting the disjunct nature of their preferred habitat and the capacity of rocky habitats to function as evolutionary refugia. Here we review the systematics and diversity of the predominantly saxicoline Australian marbled velvet geckos (genus Oedura) in the Australian arid and semi-arid zones using newly-gathered morphological data and previously published genetic data. Earlier work showed that four largely allopatric and genetically divergent lineages are present: Western (Pilbara and Gascoyne regions), Gulf (west and south of the Gulf of Carpentaria), Central (central ranges) and Eastern (Cooper and Darling Basins). None of these four populations are conspecific with true O. marmorata, a seperate species complex that is restricted to the Top End region of the Northern Territory. Top End forms share a short, bulbous tail whereas the other four lineages treated here possess a long, tapering tail. Morphological differences among the arid and semi-arid lineages include smaller body size, tapering lamellae and a shorter tail for the Gulf population, and a partially divided rostral scale in the Western population compared to the Central and Eastern populations. Accordingly, we resurrect O. cincta de Vis from synonymy for the Central and Eastern lineages, and regard this species as being comprised of two evolutionary significant units. We also describe the Gulf and Western lineages as new species: Oedura bella sp. nov. and O. fimbria sp. nov., respectively. We note that a predominantly arboreal lineage (the Eastern lineage of O. cincta) is more widely distributed than the other lineages and is phylogenetically nested within a saxicoline clade, but tends to have a deeper head and shorter limbs, consistent with morphological variation observed in other lizard radiations including both saxicoline and arboreal taxa.
The survey of Thysanoptera in peninsular Malaysia has been concentrated largely in areas growing crops and flowers around Kuala Lumpur, and the Cameron Highlands, and there are few records of these insects from native forests particularly in the northern part of the country. The two species described here were collected during a recent visit to Belum-Temengor Forest Complex, in Perak State, part of the second largest forested area on the peninsular, and connected to the Bang Lang National Park, in Yala Province, Thailand. This forest has been well known as home to a number of endangered animals, including Malayan tigers and Asian elephants, as well as remarkable plant species such as Rafflesia with the world's largest flowers (Abdullah et al. 2011). Despite this, forest areas are facing a major challenge from the insatiable demand for timber, palm oil and minerals, with an 80% increase in deforestation rate in Malaysia between 1990 and 2005 (FAO 2010). Forested land in peninsular Malaysia has been estimated at 5.88 million-ha or 44% of total area, but the coverage of reserved virgin forest is about 0.40 % or 23,002-ha (Dahlan 2008).
Recombinant protein technology has revolutionized the world of biology and medicine. Following this progress, fusion protein technology, as a novel innovation, has opened new horizons for the development of proteins that do not naturally exist. Fusion proteins are generated via genetically fusing two or more genes coding for separate proteins, thus the product is a single protein having functional properties of both proteins. As an indispensable element in fusion protein construction, linkers are used to separate the functional domains in order to improve their expression, folding and stability.
We computationally fused an antigen and an adjuvant together using different linkers to obtain a two-domain fusion construct which can potentially act as an oral vaccine candidate against malaria. We then predicted the structures computationally to find out the probable folding of each domain in the designed construct.
One of the fusion constructs was selected based on the highest value for C-score. Ramchandran Plot analysis represented that most residues were fallen in favorable regions.
Our in silico analysis showed that (GGGGS)3 linker confers the best structure and stability for our target fusion protein.
To investigate the correlation of arachidonic acid (ARA) metabolites and prognosis in ACS patients.
This is a mono-center retrospective nested case-control study. We followed up 470 ACS patients, of whom 39 patients had MACE in a mean follow up time of 1037days (identified as MACE group). Another 39 clinically matched patients without MACE were selected from the 470 ACS patients (Non-MACE group). Thirty-nine subjects without Coronary Heart Disease were enrolled as Control group. Metabolites of ARA were determined by LC-MS/MS. We found that plasma levels of LTB4, 8-HETE, 11-HETE, 12-HETE, and 15-HETE were significantly increased in MACE and Non-MACE groups, 5-HETE and 9-HETE were significantly increased in MACE group comparing with Control group (P<0.05). Importantly, plasma level of 19-HETE in MACE group was significantly lower than Non-MACE and Control groups. 19-HETE significantly correlated with the prognosis of ACS after adjustment for clinical characteristics (HR=0.103, 95% C.I.: 0.014-0.766). The AUC for ROC curve of 19-HETE in predicting MACE was 0.637 (P<0.05). Survival analysis showed that ACS patients with 19-HETE levels higher than 0.13ng/ml tend to have better prognosis than those lower than 0.13ng/ml (P<0.05). GRACE score and serum Fib levels were also significantly correlated with MACE. 20-HETE level was found significantly higher in STEMI group comparing with NSTE-ACS group (P<0.05).
Plasma arachidonic acid metabolites may act as prognostic markers for ACS patients.
Salinization of freshwater ecosystems as a result of human activities represents a global threat for ecosystems' integrity. Whether different sources of salinity with their differing ionic compositions lead to variable effects in ecosystem functioning is unknown. Therefore, the present study assessed the impact of dryland- (50μS/cm to 11,000μS/cm) and coalmine-induced (100μS/cm to 2400μS/cm) salinization on the leaf litter breakdown, with focus on microorganisms as main decomposer, in two catchments in New South Wales, Australia. The breakdown of Eucalyptus camaldulensis leaves decreased with increasing salinity by up to a factor of three. Coalmine salinity, which is characterised by a higher share of bicarbonates, had a slightly but consistently higher breakdown rate at a given salinity relative to dryland salinity, which is characterised by ionic proportions similar to sea water. Complementary laboratory experiments supported the stimulatory impact of sodium bicarbonates on leaf breakdown when compared to sodium chloride or artificial sea salt. Furthermore, microbial inoculum from a high salinity site (11,000μS/cm) yielded lower leaf breakdown at lower salinity relative to inoculum from a low salinity site (50μS/cm). Conversely, inoculum from the high salinity site was less sensitive towards increasing salinity levels relative to inoculum from the low salinity site. The effects of the different inoculum were the same regardless of salt source (sodium bicarbonate, sodium chloride and artificial sea salt). Finally, the microorganism-mediated leaf litter breakdown was most efficient at intermediate salinity levels (≈500μS/cm). The present study thus points to severe implications of increasing salinity intensities on the ecosystem function of leaf litter breakdown, while the underlying processes need further scrutiny.
Discovering cryptic species in well-studied areas and taxonomic groups can have profound implications in understanding eco-evolutionary processes and in nature conservation because such groups often involve research models and act as flagship taxa for nature management. In this study, we use an array of techniques to study the butterflies in the Spialia sertorius species group (Lepidoptera, Hesperiidae). The integration of genetic, chemical, cytogenetic, morphological, ecological and microbiological data indicates that the sertorius species complex includes at least five species that differentiated during the last three million years. As a result, we propose the restitution of the species status for two taxa often treated as subspecies, Spialia ali (Oberthür, 1881) stat. rest. and Spialia therapne (Rambur, 1832) stat. rest., and describe a new cryptic species Spialia rosae Hernández-Roldán, Dapporto, Dincă, Vicente & Vila sp. nov. Spialia sertorius (Hoffmannsegg, 1804) and S. rosae are sympatric and synmorphic, but show constant differences in mitochondrial DNA, chemical profiles and ecology, suggesting that S. rosae represents a case of ecological speciation involving larval host plant and altitudinal shift, and apparently associated with Wolbachia infection. This study exemplifies how a multidisciplinary approach can reveal elusive cases of hidden diversity.
Prisons can act as reservoirs of tuberculous infection. Previous studies have shown that the prevalence of latent tuberculous infection (LTBI) is high in prisons.
To investigate the prevalence and incidence rates of LTBI and contributing factors in a prison population in Iran.
In March 2013, inmates at the Hamadan Central
 Prison were invited to participate in a voluntary two-stage screening programme using the tuberculin skin test (TST). In the first stage, the standard TST was administered and read, and was repeated in negative cases to identify cases with delayed TST reactivity and boosted reaction. In the second stage, inmates with a true-negative TST underwent repeat screening 6 months later to identify incident LTBI. Information about risk factors was obtained using structured interviews.
Among 1208 screened inmates, TST positivity was recorded in 756 cases (prevalence 62.6%). HIV-positive inmates and cigarette smokers were also more likely to have LTBI. In 380 inmates returning for a follow-up visit, the 6-month incidence rate was 7.6%. Two cases of pulmonary tuberculosis were identified during the period of study.
LTBI prevalence and incidence rates among Iranian prisoners are high. Comprehensive plans are needed to for effective TB control among prisoners.
Carbohydrates comprise a large fraction of the typical diet, yet humans are only able to directly process some types of starch and simple sugars. The remainder transits the large intestine where it becomes food for the commensal bacterial community. This is an environment of not only intense competition but also impressive cooperation for available glycans, as these bacteria work to maximize their energy harvest from these carbohydrates during their limited transit time through the gut. The species within the gut microbiota use a variety of strategies to process and scavenge both dietary and host-produced glycans such as mucins. Some act as generalists that are able to degrade a wide range of polysaccharides, while others are specialists that are only able to target a few select glycans. All are members of a metabolic network where substantial cross-feeding takes place, as by-products of one organism serve as important resources for another. Much of this metabolic activity influences host physiology, as secondary metabolites and fermentation end products are absorbed either by the epithelial layer or by transit via the portal vein to the liver where they can have additional effects. These microbially derived compounds influence cell proliferation and apoptosis, modulate the immune response, and can alter host metabolism. This review summarizes the molecular underpinnings of these polysaccharide degradation processes, their impact on human health, and how we can manipulate them through the use of prebiotics.
Public perception research evaluating awareness and attitudes towards marine protection is limited in the United Kingdom (UK) and worldwide. Given public opinion can help drive policy and affect its successful delivery we conducted nationwide surveys in 2005, 2010 and 2015 to assess public knowledge of UK (England, Scotland and Wales) sea 'health' and management. Respondents from all three surveys were relatively pessimistic about sea 'health', perceiving this as poor-fair and largely in decline. Enthusiasm for marine conservation was high with almost two-thirds of respondents in each survey wanting >40% of UK seas highly protected from fishing and damaging activities. In 2015 there was considerable dissatisfaction with the rate of progress in Marine Conservation Zone designation and over three-quarters of respondents considered dredging and trawling to be inappropriate in protected areas, contrary to management. The UK government and devolved administrations need to better align future conservation and management with public expectations.
Nipah virus (NiV) is a member of the genus Henipavirus of the family Paramyxoviridae, characterized by high pathogenicity and endemic in South Asia. It is classified as a Biosafety Level-4 (BSL-4) agent. The case-fatality varies from 40% to 70% depending on the severity of the disease and on the availability of adequate healthcare facilities. At present no antiviral drugs are available for NiV disease and the treatment is just supportive. Phylogenetic and evolutionary analyses can be used to help in understanding the epidemiology and the temporal origin of this virus. This review provides an overview of evolutionary studies performed on Nipah viruses circulating in different countries. Thirty phylogenetic studies have been published from 2000 to 2015 years, searching on pub-med using the key words 'Nipah virus AND phylogeny' and twenty-eight molecular epidemiological studies from 2006 to 2015 have been performed, typing the key words 'Nipah virus AND molecular epidemiology'. Overall data from the published study demonstrated as phylogenetic and evolutionary analysis represent promising tools to evidence NiV epidemics, to study their origin and evolution and finally to act with effective preventive measure.
Amyloid-β (Aβ) peptides generated by the amyloidogenic pathway of amyloid-β protein precursor processing contribute significantly to neurodegeneration characteristic of Alzheimer's disease (AD). The involvement of Aβ peptides in the etiology of AD remains a subject of debate. Data published in the last 6 years by three different groups have added a new twist by revealing that Aβ peptides could act as antimicrobial peptides (AMP) in in vitro assays against some common and clinically relevant microorganisms, inhibit replication of seasonal and pandemic strains of influenza A and HSV-1 virus. These observations are of significance with respect to the notion that pathogens may be important contributors to the development of AD, particularly in the case of herpes simplex virus (HSV) infection, which often resides in the same cerebral sites where AD arises. Here, we review the data that support the interpretation that Aβ peptides behave as AMP, with an emphasis on studies concerning HSV-1 and a putative molecular mechanism that suggests that interactions between Aβ peptides and the HSV-1 fusogenic protein gB lead to impairment of HSV-1 infectivity by preventing the virus from fusing with the plasma membrane. A number of avenues for future research are suggested.
A green version of the "Fe" impurity-induced peroxidase mimicry exhibited by simple and cheap substrate "nanoclay (NC)" along with the highly sensitive amperometric and spectrophotometric determination of cholesterol is demonstrated. The "Fe" impurity can act as the catalyst center for hydrogen peroxide reduction similar to the horseradish peroxidase (HRP)-catalyzed reaction. The Michaelis-Menten constant for the NC-catalyzed reaction is found to be lower than that of the HRP-catalyzed reaction indicating high affinity for the substrate. The NC-modulated peroxidase-like catalytic activity originates from the electron transfer between the reducing substrate in the catalyst center and H2O2 with the intermediate generation of hydroxyl radicals. The peroxidase mimicry is successfully applied for the low-potential electrochemical detection of H2O2 (linear detection range 1.96-10.71 mM, R (2) = 0.97). The H2O2 sensing platform is further modified with cholesterol oxidase (CHOx) for the spectrophotometric (linear detection range 50-244 μM, R (2) = 0.99) and amperometric detection of cholesterol (linear detection range 0.099-1.73 mM, R (2) = 0.998). Graphical abstract Peroxidase mimicry of nanoclay for the determination of cholesterol.
The aim of this study was to identify factors associated with comfort and confidence in providing care to patients at risk of suicide, in a sample of Australian medical students.
An online cross-sectional survey was completed by 116 current medical students (42 % male) aged between 20 and 41 years (M = 25, SD = 3.8).
Greater personal experience of suicide and previous contact with patients with psychiatric problems were significantly associated with both increased perceived comfort and increased confidence in providing care for individuals with suicidal thoughts or behaviors, based on self-report. However, these effects may not reflect objective measures of competency and additional research is needed to assess generalizability of the findings due to the sampling method.
Increasing medical student contact with patients at risk of suicide through the implementation of psychiatry placements, gateway programs, and early year exposure to patients with psychiatric problems may increase perceived confidence and comfort in providing care to individuals at risk of suicide. Further research should evaluate the impact of such programs on behavioral indices of clinical competency.
Estrogens play a key role in regulating reproductive and neuroendocrine function by activating classical nuclear steroid receptors that act as ligand gated transcription factors. However evidence is growing that estrogens also promote rapid non-genomic responses via activation of membrane-associated estrogen receptors. The G protein-coupled estrogen receptor (GPER1; also known as GPR30) has been identified as one of the main estrogen-sensitive receptors responsible for the rapid non-genomic actions of estrogen. In recent years, our understanding of the CNS actions of GPER1s has significantly increased following the development of selective pharmacological tools and via the use of transgenic technologies to knockout GPER1 in mice. Here we review recent advances that have been made to uncover the role of GPER1s in the CNS.
Compartment boundaries are an essential developmental mechanism throughout evolution, designated to act as organizing centers and to regulate and localize differently fated cells. The hindbrain serves as a fascinating example for this phenomenon as its early development is devoted to the formation of repetitive rhombomeres and their well-defined boundaries in all vertebrates. Yet, the actual role of hindbrain boundaries remains unresolved, especially in amniotes.
Here, we report that hindbrain boundaries in the chick embryo consist of a subset of cells expressing the key
 neural stem cell (NSC) gene Sox2. These cells co-express other neural progenitor markers such as Transitin (the avian Nestin), GFAP, Pax6 and chondroitin sulfate proteoglycan. The majority of the Sox2(+) cells that reside within the boundary core are slow-dividing, whereas nearer to and within rhombomeres Sox2(+) cells are largely proliferating. In vivo analyses and cell tracing experiments revealed the contribution of boundary Sox2(+) cells to neurons in a ventricular-to-mantle manner within the boundaries, as well as their lateral contribution to proliferating Sox2(+) cells in rhombomeres. The generation of boundary-derived neurospheres from hindbrain cultures confirmed the typical NSC behavior of boundary cells as a multipotent and self-renewing Sox2(+) cell population. Inhibition of Sox2 in boundaries led to enhanced and aberrant neural differentiation together with inhibition in cell-proliferation, whereas Sox2 mis-expression attenuated neurogenesis, confirming its significant function in hindbrain neuronal organization.
Data obtained in this study deciphers a novel role of hindbrain boundaries as repetitive pools of neural stem/progenitor cells, which provide proliferating progenitors and differentiating neurons in a Sox2-dependent regulation.
The US Orphan Drug Act, passed in 1982, was the first orphan drug legislation in the world. It is a law based on economic incentives making it financially possible for pharmaceutical firms to develop products for small patient populations. Since passage, many additional countries have developed orphan drug programs and many pharmaceutical firms have developed around the orphan program. Today, more than 500 drugs for rare diseases have been developed in the United States.
To validate the activPAL3 algorithm for predicting metabolic equivalents (TAMETs) and classifying MVPA in 5- to 12-year-old children.
Fifty-seven children (9.2 ± 2.3y, 49.1% boys) completed 14 activities including sedentary behaviors (SB), light (LPA) and moderate-to-vigorous physical activities (MVPA). Indirect calorimetry (IC) was used as the criterion measure. Analyses included equivalence testing, Bland-Altman procedures and area under the receiver operating curve (ROC-AUC).
At the group level, TAMETs were significantly equivalent to IC for handheld e-game, writing/coloring, and standing class activity (P < .05). Overall, TAMETs were overestimated for SB (7.9 ± 6.7%) and LPA (1.9 ± 20.2%) and underestimated for MVPA (27.7 ± 26.6%); however, classification accuracy of MVPA was good (ROC-AUC = 0.86). Limits of agreement were wide for all activities, indicating large individual error (SB: -27.6% to 44.7%; LPA: -47.1% to 51.0%; MVPA: -88.8% to 33.9%).
TAMETs were accurate for some SB and standing, but were overestimated for overall SB and LPA, and underestimated for MVPA. Accuracy for classifying MVPA was, however, acceptable.
To improve the scope of the Youth Compendium of Energy Expenditures, a range of everyday activities of varying intensity should be measured. This study measures the energy cost of children undertaking common household chores, rollerblading and riding a foot-propelled scooter.
Participants were 9- to 14-year-old children. A metabolic cart was used to measure oxygen cost (VO2) of a variety of household chores. A Cosmed K4b2 portable oxygen analyzer was used to measure VO2 during rollerblading and riding a scooter at self-selected speeds. Energy costs for each participant were calculated as child METs.
Mean child MET costs for the household chores ranged from 1.3 to 3.6 METs. Rollerblading and riding a scooter yielded mean child MET costs of 6.5 and 6.3 METs respectively.
Household chores were found to be of light to moderate intensity, while rollerblading and riding a scooter were vigorous activities.
This study sought to ascertain the energy expenditure (EE) associated with different sedentary and physically active free-play activities in primary school-aged children.
Twenty-eight children (13 boys; 11.4 ± 0.3 years; 1.45 ± 0.09 m; 20.0 ± 4.7 kg∙m-2) from 1 primary school in Northwest England engaged in 6 activities representative of children's play for 10 minutes (drawing, watching a DVD, playground games and free-choice) and 5 minutes (self-paced walking and jogging), with 5 minutes rest between each activity. Gas exchange variables were measured throughout. Resting energy expenditure was measured during 15 minutes of supine rest.
Child (Schofield-predicted) MET values for watching a DVD, self-paced jogging and playing reaction ball were significantly higher for girls (P < .05).
Utilizing a field-based protocol to examine children's free-living behaviors, these data contribute to the scarcity of information concerning children's EE during play to update the Compendium of Energy Expenditures for Youth.
This study reports energy expenditure (EE) data for lifestyle and ambulatory activities in young children.
Eleven children aged 3 to 6 years (mean age = 4.8 ± 0.9; 55% boys) completed 12 semistructured activities including sedentary behaviors (SB), light (LPA), and moderate-to-vigorous physical activities (MVPA) over 2 laboratory visits while wearing a portable metabolic system to measure EE.
Mean EE values for SB (TV, reading, tablet and toy play) were between 0.9 to 1.1 kcal/min. Standing art had an energy cost that was 1.5 times that of SB (mean = 1.4 kcal/min), whereas bike riding (mean = 2.5 kcal/min) was similar to LPA (cleaning-up, treasure hunt and walking) (mean = 2.3 to 2.5 kcal/min), which had EE that were 2.5 times SB. EE for MVPA (running, active games and obstacle course) was 4.2 times SB (mean = 3.8 to 3.9 kcal/min).
EE values reported in this study can contribute to the limited available data on the energy cost of lifestyle and ambulatory activities in young children.
The assessment of physical activity (PA) and energy expenditure (EE) in youth is complicated by inherent variability in growth and maturation during childhood and adolescence. This study provides descriptive summaries of the EE of a diverse range of activities in children ages 7 to 13.
A sample of 105 7- to 13-year-old children (boys: 57%, girls: 43%, and Age: 9.9 ± 1.9) performed a series of 12 activities from a pool of 24 activities while being monitored with an indirect calorimetry system.
Across physical activities, averages of VO2 ml·kg·min-1, VO2 L·min-1, EE, and METs ranged from 3.3 to 53.7 ml·kg·min-1, from 0.15 to 3.2 L·min-1, from 0.7 to 15.9 kcal·min-1, 1.5 MET to 7.8 MET, respectively.
The energy costs of the activities varied by age, sex, and BMI status reinforcing the need to consider adjustments when examining the relative intensity of PA in youth.
The aim of this study is to establish the energy expenditure (EE) of a range of child-relevant activities and to compare different methods of estimating activity MET.
27 children (17 boys) aged 9 to 11 years participated. Participants were randomly assigned to 1 of 2 routines of 6 activities ranging from sedentary to vigorous intensity. Indirect calorimetry was used to estimate resting and physical activity EE. Activity metabolic equivalent (MET) was determined using individual resting metabolic rate (RMR), the Harrell-MET and the Schofield equation.
Activity EE ranges from 123.7± 35.7 J/min/Kg (playing cards) to 823.1 ± 177.8 J/min/kg (basketball). Individual RMR, the Harrell-MET and the Schofield equation MET prediction were relatively similar at light and moderate but not at vigorous intensity. Schofield equation provided a better comparison with the Compendium of Energy Expenditure for Youth.
This information might be advantageous to support the development of a new Compendium of Energy Expenditure for Youth.
There is limited data regarding objectively measured energy cost and intensity of classroom instruction. Therefore, the purpose of current study was to objectively measure energy cost and subsequently calculate MET values using a portable indirect calorimeter (IC) for both normal classroom instruction (NCI) and active classroom instruction (ACI).
We assessed energy expenditure (EE) and intensity levels (METs) in elementary school children (17 boys and 15 girls) using an IC (COSMED K4b2). Independent t-tests were used to evaluate potential sex and grade level differences for age, BMI, VO2, EE, and METs.
The average EE for NCI and ACI were 1.8 ± 0.4 and 3.9 ± 1.0, respectively. The average intensity level for NCI and ACI were 1.9 ± 0.4 and 4.2 ± 0.9 METs, respectively.
PA delivered through ACI can elicit EE at a moderate intensity level. These results provide evidence for ACI as a convenient/feasible avenue for increasing PA in youth without decreasing instruction time.
This study determined the metabolic equivalents (METs) of several activities typically performed by Chinese youth.
Thirty youth (12 years) performed 7 activities that reflected their daily activities while Energy Expenditure (EE) was measured in a metabolic chamber.
METs were calculated as activity EE divided by participant's measured resting metabolic rate. A MET value ranging from 0.8 to 1.2 was obtained for sleeping, watching TV, playing computer games, reading and doing homework. Performing radio gymnastics had a MET value of 2.9. Jumping rope at low effort required 3.1 METs. Except for watching TV, METs for other activities in this study were lower than Youth Compendium values.
The results provide empirical evidence for more accurately assessing EE of activities commonly performed by Chinese youth. This is the first study to determine METs for radio gymnastics and jump rope in Chinese youth.
Limited data are available on energy cost of common children's games using measured oxygen consumption.
Children (10.6 ± 2.9 years; N = 37; 26 male, 9 female) performed a selection of structured (bowling, juggling, obstacle course, relays, active kickball) and unstructured (basketball,
 catch, tennis, clothespin tag, soccer) activities for 5 to 30 minutes. Resting metabolic rate (RMR) was calculated using Schofield's age- and sex-specific equation. Children wore a portable metabolic unit, which measured expired gases to obtain oxygen consumption (VO2), youth METs (relative VO2/child's calculated RMR), and activity energy expenditure (kcal/kg/min). Descriptive statistics were used to summarize data.
Relative VO2 ranged from 16.8 ± 4.6 ml/kg/min (bowling) to 32.2 ± 6.8 ml/kg/min (obstacle course). Obstacle course, relays, active kickball, soccer, and clothespin tag elicited vigorous intensity (>6 METs), the remainder elicited moderate intensity (3-6 METs).
This article contributes energy expenditure data for the update and expansion of the youth compendium.
Replacing sedentary time with physical activity through new generation exergames (eg, XBOX Kinect) is a potential intervention strategy. The study's purpose was to compare youth energy expenditure while playing different exergames in single- vs. multiplayer mode.
Participants (26 male, 14 female) were 10 to 13 years old. They wore a portable metabolic analyzer while playing 4 XBOX Kinect games for 15 minutes each (2 single-, 2 multiplayer). Repeated-measures ANOVA (with Bonferroni correction) was used to examine player mode differences, controlling for age group, sex, weight status, and game.
There was a significant difference in energy expenditure between single player (mean = 15.4 ml/kg/min, SD = 4.5) and multiplayer mode (mean = 16.8 ml/kg/min, SD = 4.7). Overweight and obese participants (mean = 13.7 ml/kg/min, SD = 4.2) expended less energy than normal weight (mean = 17.8 ml/kg/min, SD = 4.5) during multiplayer mode (d = 0.93).
Player mode, along with personal factors such as weight status, may be important to consider in energy expenditure during exergames.
Published energy cost data for children and adolescents are lacking. The purpose of this study was to measure and describe developmental trends in the energy cost of 12 physical activities commonly performed by youth.
A mixed age cohort of 209 participants completed 12 standardized activity trials on 4 occasions over a 3-year period (baseline, 12-months, 24-months, and 36-months) while wearing a portable indirect calorimeter. Bayesian hierarchical regression was used to link growth curves from each age cohort into a single curve describing developmental trends in energy cost from age 6 to 18 years.
For sedentary and light-intensity household chores, YOUTH METs (METy) remained stable or declined with age. In contrast, METy values associated with brisk walking, running, basketball, and dance increased with age.
The reported energy costs for specific activities will contribute to efforts to update and expand the youth compendium.
There has been a call for updating the Youth Compendium of Energy Expenditure (YCEE) by including energy expenditure (EE) data of young children (ie, < 6-year-old children). Therefore, this study examined the activity EE in 3 to 6 year old children using indirect calorimetry.
Using Oxycon Mobile portable indirect calorimetry, both the oxygen consumption (VO2) and the EE of 28 children (Girls: 46%, Age: 4.8 ± 1.0, BMI: 16.4 ± 1.6) were measured while they performed various daily living activities (eg, watching TV, playing with toys, shooting baskets, soccer).
Across physical activities, averages of VO2 (ml·kg·min-1), VO2 (L·min-1), and EE ranged from 8.9 ± 1.5 to 33.3 ± 4.8 ml·kg·min-1, from 0.17 ± 0.04 to 0.64 ± 0.16 L·min-1, and from 0.8 ± 0.2 to 3.2 ± 0.7 kcal·min-1, respectively.
These findings will contribute to the upcoming YCEE update.
Energy expenditure (EE) estimates for a broad age range of youth performing a variety of activities are needed.
106 participants (6-18 years) completed 6 free-living activities (seated rest, movie watching, coloring, stair climbing, basketball dribbling, jumping jacks) and up to 9 treadmill walking bouts (13.4 to 120.7 m/min; 13.4 m/min increments). Breath-by-breath oxygen uptake (VO2) was measured using the COSMED K4b2 and EE was quantified as youth metabolic equivalents (METy1:VO2/measured resting VO2, METy2:VO2/estimated resting VO2). Age trends were evaluated with ANOVA.
Seated movie watching produced the lowest mean METy1 (6- to 9-year-olds: 0.94 ± 0.13) and METy2 values (13- to 15-year-olds: 1.10 ± 0.19), and jumping jacks produced the highest mean METy1 (13- to 15-year-olds: 6.89 ± 1.47) and METy2 values (16- to 18-year-olds: 8.61 ± 2.03). Significant age-related variability in METy1 and METy2 were noted for 8 and 2 of the 15 evaluated activities, respectively.
Descriptive EE data presented herein will augment the Youth Compendium of Physical Activities.
Thirty-five percent of the activities assigned MET values in the Compendium of Energy Expenditures for Youth were obtained from direct measurement of energy expenditure (EE). The aim of this study was to provide directly measured EE for several different activities in youth.
Resting metabolic rate (RMR) of 178 youths (80 females, 98 males) was first measured. Participants then performed structured activity bouts while wearing a portable metabolic system to directly measure EE. Steady-state oxygen consumption data were used to compute activity METstandard (activity VO2/3.5) and METmeasured (activity VO2/measured RMR) for the different activities.
Rates of EE were measured for 70 different activities and ranged from 1.9 to 12.0 METstandard and 1.5 to 10.0 METmeasured.
This study provides directly measured energy cost values for 70 activities in children and adolescents. It contributes empirical data to support the expansion of the Compendium of Energy Expenditures for Youth.
Researchers have investigated the energy expenditure of tennis practice and match play in adults but not youth.
VO2 was recorded for 36 youth, ages 9 to 18, during 10-minute bouts of tennis practice and match play. A GLM was used to compare VO2 between practice and match play and among age groups (9-12 years, 13-15 years, and 16-18 years); also to compare the difference in adult and child-derived MET values (ΔMET).
VO2 was higher for tennis match play vs. practice (P < .05) and there was a trend for 16 to 18 year olds having lower VO2 than 9 to 12 year olds (P = .055). ΔMET did not differ between settings but varied by age group (P = .004); it was highest in 9- to 12-year-olds and lowest in 16- to 18-year-olds.
Youth expend more energy while playing a tennis match than practice, regardless of age. Child-derived MET values equaled those of adults once youth reached ages 16 to 18.
Standardized measures of energy expenditure (EE) for sedentary activities in youth are needed. The goal was to determine EE of common contemporary and computer-related sedentary activities in youth.
We measured EE for sedentary tasks in 10- to 17-year-old youths (n = 24) during ~24 hours in a whole-room indirect calorimeter. Directly monitored tasks were performed for ~10-min. EE was calculated from oxygen consumed and carbon dioxide produced, converted to metabolic equivalents (MET) by normalization to an individual's measured resting EE, and compared with the Compendium of Energy Expenditures for Youth.
Compared with the youth compendium, measured METs were lower for internet surfing (1.3), computer keyboard typing (1.3), and sorting beads/crafts (1.5) (all P < .002), and similar for handwriting (1.4), playing cards (1.6), video-gaming (1.6), and telephoning (1.5).
Current youth compendium MET estimates should be used with caution when predicting EE of common contemporary and computer-related sedentary activities in youth.
The absolute energy cost of activities in children increase with age due to greater muscle mass and physical capability associated with growth and developmental maturation; however, there is a paucity of data in preschool-aged children. Study aims were 1) to describe absolute and relative energy cost of common activities of preschool-aged children in terms of VO2, energy expenditure (kilocalories per minute) and child-specific metabolic equivalents (METs) measured by room calorimetry for use in the Youth Compendium of Physical Activity, and 2) to predict METs from age, sex and heart rate (HR).
Energy expenditure (EE), oxygen consumption (VO2), HR, and child-METs of 13 structured activities were measured by room respiration calorimetry in 119 healthy children, ages 3 to 5 years.
EE, VO2, HR, and child-METs are presented for 13 structured activities ranging from sleeping, sedentary, low-, moderate- to high-active. A significant curvilinear relationship was observed between child-METs and HR (r2 = .85; P = .001).
Age-specific child METs for 13 structured activities in preschool-aged children will be useful to extend the Youth Compendium of Physical Activity for research purposes and practical applications. HR may serve as an objective measure of MET intensity in preschool-aged children.
No abstract available for this article.
Recent evidence shows that warm semi-arid ecosystems are playing a disproportionate role in the interannual variability and greening trend of the global carbon cycle given their mean lower productivity when compared with other biomes (Ahlström et al. 2015 Science, 348, 895). Using multiple observations (land-atmosphere fluxes, biomass, streamflow and remotely sensed vegetation cover) and two state-of-the-art biospheric models, we show that climate variability and extremes lead to positive or negative responses in the biosphere, depending on vegetation type. We find Australia to be a global hot spot for variability, with semi-arid ecosystems in that country exhibiting increased carbon uptake due to both asymmetry in the interannual distribution of rainfall (extrinsic forcing), and asymmetry in the response of gross primary production (GPP) to rainfall change (intrinsic response). The latter
 is attributable to the pulse-response behaviour of the drought-adapted biota of these systems, a response that is estimated to be as much as half of that from the CO2 fertilization effect during 1990-2013. Mesic ecosystems, lacking drought-adapted species, did not show an intrinsic asymmetric response. Our findings suggest that a future more variable climate will induce large but contrasting ecosystem responses, differing among biomes globally, independent of changes in mean precipitation alone. The most significant changes are occurring in the extensive arid and semi-arid regions, and we suggest that the reported increased carbon uptake in response to asymmetric responses might be contributing to the observed greening trends there.
This study investigated bacteria from soil samples to (i) determine the main bacterial genera and species having resistance to carbapenem and other β-lactams and (ii) establish if the mechanism of resistance was due to the production of metallo-β-lactamases. The isolates were characterized by PCR for metallo-β-lactamases and integrons, by antimicrobial susceptibility testing, and by sequencing. The antimicrobial profile of 40 imipenem-resistant Gram-positive soil isolates from all Brazilian regions demonstrated that 31 (77.5%) of them were multidrug resistant. Among the 40 isolates, 19 presented the blaVIM gene and class 1 integrons by PCR. Six of the 19 isolates were identified as Paenibacillus sp., 12 as Bacillus sp., and just 1 was classified as Staphylococcus sp., by sequencing of the 16S rRNA gene. These results suggest that bacteria from soil can act as a source of blaVIM-1 genes, representing a threat to public health.
The ability of a drug to cross the intestine-blood barrier is a key quantity for drug design and employment and is normally quantified by the permeability coefficient P, often evaluated in the so-called Caco-2 assay. This assay is based on measuring the initial growth rate of the concentration of the drug beyond the cellular barrier but not its steady-state flux through the membrane. This might lead to confusion since, in the case of lipophilic drugs, the initial slope is strongly affected by the retention of the drug in the membrane. This effect is well known but seldom considered in the assay. Here, we exploit all-atoms molecular dynamics and bias exchange metadynamics to calculate the concentration of two lipophilic drugs across a model membrane as a function of time. This allows estimating both the steady-state flux and the initial slope of the concentration growth and comparing Caco-2 and steady-state estimates of P. We show that our computational procedure is able to reproduce the experimental values, although these may differ from the permeability coefficients by orders of magnitude. Our findings are generalized by a simplified one-dimensional model of the permeation process that may act as a roadmap to assess which measure of membrane permeability would be more appropriate and, consequently, whether retention corrections should be included in estimates based on Caco-2 assays.
An ultrasensitive electrochemical biosensor for microRNA (miRNA) is developed based on tungsten oxide-graphene composites coupling with catalyzed hairpin assembly target recycling and enzyme signal amplification. WO3-Gr is prepared by a simple hydrothermal method and then coupled with gold nanoparticles to act as a sensing platform. The thiol-terminated capture probe H1 is immobilized on electrode through Au-S interaction. In the presence of target miRNA, H1 opens its hairpin structure by hybridization with target miRNA. This hybridization can be displaced from the structure by another stable biotinylated hairpin DNA (H2), and target miRNA is released back to the sample solution for next cycle. Thus, a large amount of H1-H2 duplex is produced after the cyclic process. At this point, a lot of signal indicators streptavidin-conjugated alkaline phosphatase (SA-ALP) are immobilized on the electrode by the specific binding of avidin-biotin. Then, thousands of ascorbic acid, which is the enzymatic product of ALP, induces the electrochemical-chemical-chemical redox cycling to produce a strongly electrochemical response in the presence of ferrocene methanol and tris (2-carboxyethyl) phosphine. Under the optimal experimental conditions, the established biosensor can detect target miRNA down to 0.05fM (S/N=3) with a linear range from 0.1fM to 100pM, and discriminate target miRNA from mismatched miRNA with a high selectivity.
Co-receptors, being either co-stimulatory or co-inhibitory, play a pivotal role in T-cell immunity. Several studies have indicated that CD43, one of the abundant T-cell surface glycoproteins, acts not only as a potent co-receptor but also as a negative regulator for T-cell activation. Here we demonstrate that co-stimulation of human peripheral blood (PB) T cells through two distinct CD43 epitopes recognized by monoclonal antibodies (mAb) CD43-6E5 (T6E5-act ) and CD43-10G7 (T10G7-act ) potently induced T-cell proliferation. However, T-cell co-stimulation through two CD43 epitopes differentially regulated activation of nuclear factor of activated T cells (NFAT) and nuclear factor-κB (NF-κB) transcription factors, T-cell cytokine production and effector function. T6E5-act produced high levels of interleukin-22 (IL-22) and interferon-γ (IFN-γ) similar to T cells activated via CD28 (TCD28-act ), whereas T10G7-act produced low levels of inflammatory cytokines but higher levels of regulatory cytokines transforming growth factor-β (TGF-β) and interleukin-35 (IL-35). Compared with T6E5-act or to TCD28-act , T10G7-act performed poorly in response to re-stimulation and further acquired a T-cell suppressive function. T10G7-act did not directly inhibit proliferation of responder T cells, but formed stable heterotypic clusters with dendritic cells (DC) via CD2 to constrain activation of responder T cells. Together, our data demonstrate that CD43 is a unique and polarizing regulator of T-cell function.
Attack of plants by herbivorous arthropods may result in considerable changes to the plant's chemical phenotype with respect to emission of herbivore-induced plant volatiles (HIPVs). These HIPVs have been shown to act as repellents to the attacking insects as well as attractants for the insects antagonistic to these herbivores. Plants can also respond to HIPV signals from other plants that warn them of impending attack. Recent investigations have shown that certain maize varieties are able to emit volatiles following stemborer egg deposition. These volatiles attract the herbivore's parasitoids and directly deter further oviposition. However, it was not known whether these oviposition-induced maize (Zea mays, L.) volatiles can mediate chemical phenotypic changes in neighbouring unattacked maize plants. Therefore, this study sought to investigate the effect of oviposition-induced maize volatiles on intact neighbouring maize plants in 'Nyamula', a landrace known to respond to oviposition, and a standard commercial hybrid, HB515, that did not. Headspace volatile samples were collected from maize plants exposed to Chilo partellus (Swinhoe) (Lepidoptera: Crambidae) egg deposition and unoviposited neighbouring plants as well as from control plants kept away from the volatile emitting ones. Behavioural bioassays were carried out in a four-arm olfactometer using egg (Trichogramma bournieri Pintureau & Babault (Hymenoptera: Trichogrammatidae)) and larval (Cotesia sesamiae Cameron (Hymenoptera: Braconidae)) parasitoids. Coupled Gas Chromatography-Mass Spectrometry (GC-MS) was used for volatile analysis. For the 'Nyamula' landrace, GC-MS analysis revealed HIPV production not only in the oviposited plants but also in neighbouring plants not exposed to insect eggs. Higher amounts of EAG-active biogenic volatiles such as (E)-4,8-dimethyl-1,3,7-nonatriene were emitted from these plants compared to control plants. Subsequent behavioural assays with female T. bournieri and C. sesamiae parasitic wasps indicated that these parasitoids preferred volatiles from oviposited and neighbouring landrace plants compared to those from the control plants. This effect was absent in the standard commercial hybrid we tested. There was no HIPV induction and no difference in parasitoid attraction in neighbouring and control hybrid maize plants. These results show plant-plant signalling: 'Nyamula' maize plants emitting oviposition-induced volatiles attractive to the herbivore's natural enemies can induce this indirect defence trait in conspecific neighbouring undamaged maize plants. Maize plants growing in a field may thus benefit from this indirect defence through airborne signalling which may enhance the fitness of the volatile-emitting plant by increasing predation pressure on herbivores.
Reverse transcription quantitative real-time polymerase chain reaction (RT-qPCR) is the sensitive method to quantify the expression levels of target genes on the basis of endogenous control. An appropriate reference gene set for normalization is essential for reliable results. The ghost moth, Thitarodes armoricanus, a host species of a medicinal fungus, Ophiocordyceps sinensis, is an economically important member of the Lepidoptera. Recent studies have focused on the mechanism of adaptation of this species to its high-altitude environment and host immune response to O. sinensis infection and RT-qPCR is commonly used in these studies to decipher the genetic basis of physiological functions. However, a thorough assessment of candidate reference genes in the genus Thitarodes is lacking. Here, the expression levels of eight candidate reference genes (ACT, EF, EIF4A, GAPDH, G6PDH, RPL13A, TUB and 18S) in T. armoricanus at different developmental stages and in different body parts of the seventh instar larvae were analyzed, along with larvae
 kept under low temperatures, larvae exposed to two fungal infections and larvae fed different diets. Three established software programs-Bestkeeper, geNorm and NormFinder-were employed to calculate variation among the treatments. The results revealed that the best-suited reference genes differed across the treatments, with EF, EIF4A and GAPDH found to be the best suited for the different developmental stages and larvae body parts; EF, EIF4A and RPL13A found to be the best suited for low-temperature challenge; and EF, EIF4A and TUB found to be the best suited for the fungal infections and dietary treatments. This study thus further contributes to the establishment of an accurate method for normalizing RT-qPCR results for T. armoricanus and serves as a reference for gene expression studies of related insect species.
Around the world, various interventions have been developed to encourage the adoption of healthy lifestyles, particularly nutrition and physical activity. Physical, political, economic and socio-cultural environments have a major influence on individual attitudes in relation to healthy lifestyle. However, stakeholders with the greatest impact on improving these environments are not always well informed about the theory and their roles on the creation of environments favourable to healthy lifestyles. Various stakeholders from the province of Quebec were therefore invited to attend training sessions in order to prepare them to act on these four environments.
1) To describe the perceptions of the stakeholders who attended these sessions concerning the content and teaching methods and 2) to identify stakeholders’ changes of perceptions and practices following the training session.
Twelve (12) focus groups and 52 individual interviews were conducted across Quebec with stakeholders who attended a training session.
Our results indicate increased awareness of stakeholders on the importance of their role but also the need to more precisely target those aspects requiring increased awareness. A content better suited to the level of expertise is therefore proposed to maximize the benefits of these training sessions.
Training sessions must be addressed to influential stakeholders with a limited knowledge on the subject, which is often the case for municipal decision-makers known to play a major role in promoting environments favourable to healthy eating and physical activity.
The catalytic activities of covalent and ATP-dependent chromatin remodeling are central to regulating the conformational state of chromatin and the resultant transcriptional output. The enzymes that catalyze these activities are often contained within multiprotein complexes in nature. Two such multiprotein complexes, the polycomb repressive complex 2 (PRC2) methyltransferase and the SWItch/Sucrose Non-Fermentable (SWI/SNF) chromatin remodeler have been reported to act in opposition to each other during development and homeostasis. An imbalance in their activities induced by mutations/deletions in complex members (e.g. SMARCB1) has been suggested to be a pathogenic mechanism in certain human cancers. Here we show that preclinical models of synovial sarcoma-a cancer characterized by functional SMARCB1 loss via its displacement from the SWI/SNF complex through the pathognomonic SS18-SSX fusion protein-display sensitivity to pharmacologic inhibition of EZH2, the catalytic subunit of PRC2. Treatment with tazemetostat, a clinical-stage, selective and orally bioavailable small-molecule inhibitor of EZH2 enzymatic activity reverses a subset of synovial sarcoma gene expression and results in concentration-dependent cell growth inhibition and cell death specifically in SS18-SSX fusion-positive cells in vitro. Treatment of mice bearing either a cell line or two patient-derived xenograft models of synovial sarcoma leads to dose-dependent tumor growth inhibition with correlative inhibition of trimethylation levels of the EZH2-specific substrate, lysine 27 on histone H3. These data demonstrate a dependency of SS18-SSX-positive, SMARCB1-deficient synovial sarcomas on EZH2 enzymatic activity and suggests the potential utility of EZH2-targeted drugs in these genetically defined cancers.
To date germanene has only been synthesized on metallic substrates. A metallic substrate is usually detrimental for the two-dimensional Dirac nature of germanene because the important electronic states near the Fermi level of germanene can hybridize with the electronic states of the metallic substrate. Here we report the successful synthesis of germanene on molybdenum disulfide (MoS_{2}), a band gap material. Preexisting defects in the MoS_{2} surface act as preferential nucleation sites for the germanene islands. The lattice constant of the germanene layer (3.8±0.2  Å) is about 20% larger than the lattice constant of the MoS_{2} substrate (3.16 Å). Scanning tunneling spectroscopy measurements and density functional theory calculations reveal that there are, besides the linearly dispersing bands at the K points, two parabolic bands that cross the Fermi level at the Γ point.
Intrinsically disordered regions (IDRs) are peculiar stretches of amino acids that lack stable conformations in solution. Intrinsic Disorder containing Proteins (IDP) are defined by the presence of at least one large IDR and have been linked to multiple cellular processes including cell signaling, DNA binding and cancer. Here we used computational analyses and publicly available databases to deepen insight into the prevalence and function of IDRs specifically in transmembrane proteins, which are somewhat neglected in most studies. We found that 50% of transmembrane proteins have at least one IDR of 30 amino acids or more. Interestingly, these domains preferentially localize to the cytoplasmic side especially of multi-pass transmembrane proteins, suggesting that disorder prediction could increase the confidence of topology prediction algorithms. This was supported by the successful prediction of the topology of the uncharacterized multi-pass transmembrane protein TMEM117, as confirmed experimentally. Pathway analysis indicated that IDPs are enriched in cell projection and axons and appear to play an important role in cell adhesion, signaling and ion binding. In addition, we found that IDP are enriched in phosphorylation sites, a crucial post translational modification in signal transduction, when compared to fully ordered proteins and to be implicated in more protein-protein interaction events. Accordingly, IDPs were highly enriched in short protein binding regions called Molecular Recognition Features (MoRFs). Altogether our analyses strongly support the notion that the transmembrane IDPs act as hubs in cellular signal events.
Integrate-and-express models of synaptic plasticity propose that synapses may act as low-pass filters, integrating synaptic plasticity induction signals in order to discern trends before expressing synaptic plasticity. We have previously shown that synaptic filtering strongly controls destabilizing fluctuations in developmental models. When applied to palimpsest memory systems that learn new memories by forgetting old ones, we have also shown that with binary-strength synapses, integrative synapses lead to an initial memory signal rise before its fall back to equilibrium. Such an initial rise is in dramatic contrast to nonintegrative synapses, in which the memory signal falls monotonically. We now extend our earlier analysis of palimpsest memories with synaptic filters to consider the more general case of discrete state, multilevel synapses. We derive exact results for the memory signal dynamics and then consider various simplifying approximations. We show that multilevel synapses enhance the initial rise in the memory signal and then delay its subsequent fall by inducing a plateau-like region in the memory signal. Such dynamics significantly increase memory lifetimes, defined by a signal-to-noise ratio (SNR). We derive expressions for optimal choices of synaptic parameters (filter size, number of strength states, number of synapses) that maximize SNR memory lifetimes. However, we find that with memory lifetimes defined via mean-first-passage times, such optimality conditions do not exist, suggesting that optimality may be an artifact of SNRs.
The purpose of this study was to explore the barriers and facilitators healthcare professionals experience when managing type 2 diabetes in people with severe mental illness (SMI).
A qualitative semi-structured interview approach was employed. Questions were structured according to the Theoretical Domains Framework (TDF), which outlines 14 domains that can act as barriers and facilitators to changing behaviour. Interviews were audio-recorded and transcribed verbatim. The data were coded according to the 14 domains of the TDF, belief statements were created within each domain and the most relevant belief statements within each domain identified through a consensus approach. Analyses were conducted by two researchers, and discrepancies agreed with a third researcher.
Sixteen healthcare professionals, from a range of services, involved in the care of people with type 2 diabetes and SMI took part in an interview. Inter-rater reliability for each of the domains varied (25 %-74 %). All fourteen domains were deemed relevant, with 42 specific beliefs identified as important to the target behaviour. Participants identified having relevant knowledge and skills for diabetes management, prioritising this area of health, and reviewing health behaviours to develop action plans, as particularly important. At an organisational level, integrated care provision and shared information technology (IT) services between mental health and physical services, and clearly defined roles and responsibilities for the different professions, with designated time to undertake
 the work were identified as crucial.
The findings highlight that healthcare professionals' experience a range of barriers and enablers when attempting to manage type 2 diabetes in people with SMI. These include organisational factors and individual beliefs, suggesting that interventions need to be targeted at both an organisation and individual level in order to change behaviour. Further work is needed to model these relationships in a larger sample of participants in line with the MRC guidance for developing complex interventions.
Very low birth-weight (<1500 g) infants are vulnerable to their environment during the first hour after birth. We designed an evidence-based golden hour protocol (GHP) with a goal to stabilize and perform admission procedures within 1 hour of birth at a level IIIB neonatal intensive care unit (NICU).
The aim of this quality improvement project was to ascertain whether an evidence-based GHP would improve care efficiency and short-term outcomes.
Rapid cycles of change using Plan Do Study Act were utilized to document progress and gain knowledge during the quality improvement project. Measures were plotted with statistical process control methods (SPC), which analyzed improvement over time.
Both admission temperature and glucose-level means were within reference range throughout the project and predicted a stable process. We observed significantly decreased time to initiation of intravenous fluids and antibiotics. An upward trend of surfactant administration within the first 2 hours of life was also observed.
The use of a GHP provided an organized approach to admission procedures and care. By using a checklist and recording intervention times, NICU caregivers were more aware of time management for each intervention and were able to decrease time to initiation of intravenous fluids and antibiotics.
Future research should focus on establishing normal blood pressure ranges and safe pain management during the "golden hour" and beyond. Future quality improvement should focus on improving subsequent temperature and blood glucose levels after admission umbilical artery and venous catheter placement.
CircRNAs are a class of endogenous RNA that regulates gene expression at the post-transcriptional or transcriptionallevel through interacting with other molecules or microRNAs. Increasing studies have demonstrated that circRNAs play a crucial role in biology processes. CircRNAs are proved as potentialbiomarkers in many diseases including cancers. However, the role of Cdr1as in Hepatocellular carcinoma (HCC) remains to be elucidated. We demonstrated that Cdr1as expression was upregulated in HCC tissues compared with the adjacent non-tumor tissues. In addtion, miR-7 expression was downregulated in HCC tissues compared with the adjacent non-tumor tissues. Moreover, the expression level of miR-7 was inversely correlated with that in HCC tissues. Knockdown of Cdr1as suppressed the HCC cell proliferation and invasion. Overexpression of miR-7 inhibited the HCC cell proliferation and invasion. Overexpression of miR-7 could suppress the direct target gene CCNE1 and PIK3CD expression. Knockdown of Cdr1as suppressed the expression of miR-7 and also inhibited the CCNE1 and PIK3CD expression. Furthermore, knockdown of Cdr1as suppressed the HCC cell proliferation and invasion through targeting miR-7. These data suggested that Cdr1as acted as an oncogene partly through targeting miR-7 in HCC.
RNA polymerase I (Pol I)-mediated transcription of the ribosomal RNA genes (rDNA) is confined to the nucleolus and is a rate-limiting step for cell growth and proliferation. Inhibition of Pol I by CX-5461 can selectively induce p53-mediated apoptosis of tumour cells in vivo. Currently, CX-5461 is in clinical trial for patients with advanced haematological malignancies (Peter Mac, Melbourne).Here we demonstrate that CX-5461 also induces p53-independent cell cycle checkpoints mediated by ATM/ATR signaling in the absence of DNA damage. Further, our data demonstrate that the combination of drugs targeting ATM/ATR signaling and CX-5461 leads to enhanced therapeutic benefit in treating p53-null tumours in vivo, which are normally refractory to each drug alone. Mechanistically, we show that CX-5461 induces an unusual chromatin structure in which transcriptionally competent relaxed rDNA repeats are devoid of transcribing Pol I leading to activation of ATM signaling within the nucleoli. Thus, we propose that acute inhibition of Pol transcription initiation by CX-5461 induces a novel nucleolar stress response that can be targeted to improve therapeutic efficacy.
The etiology of rheumatoid arthritis (RA) is poorly understood, and 30% of patients are unresponsive to established treatments targeting tumor necrosis factor α (TNFα). Akt kinase is implicated in TNFα signaling and may act as a barometer of patient responses to biologic therapies. Fluorescent peptide sensors and chemical cytometry were employed to directly measure Akt activity as well as proteolytic activity in individual fibroblast-like synoviocytes (FLS) from RA and normal subjects. The specificity of the peptide reporter was evaluated and shown to be a valid measure of Akt activity in single cells. The effect of TNFα treatment on Akt activity was highly heterogeneous between normal and RA subjects, which was not observable in bulk analyses. In 2 RA subjects, a bimodal distribution of Akt activity was observed, primarily due to a subpopulation (21.7%: RA Subject 5; 23.8%: RA Subject 6) of cells in which >60% of the reporter was phosphorylated. These subjects also possessed statistically elevated proteolytic cleavage of the reporter relative to normal subjects, suggesting heterogeneity in Akt and protease activity that may play a role in the RA-affected joint. We expect that chemical cytometry studies pairing peptide reporters with capillary electrophoresis will provide valuable data regarding aberrant kinase activity from small samples of clinical interest.
Colorectal cancer (CRC) remains one of the most common cancers worldwide. Increasing evidence indicates that SPRY4 intronic transcript 1 (SPRY4-IT1) regulate cell growth, differentiation, apoptosis, and cancer progression. However, the expression and function of SPRY4-IT1 in the progression of CRC remains largely unknown. Here, we reported that SPRY4-IT1 was upregulated in CRC. Increased SPRY4-IT1 expression in CRC was associated with larger tumor size and higher clinical stage. In vitro experiments revealed that SPRY4-IT1 knockdown significantly inhibited CRC cell proliferation by causing G1 arrest and promoting apoptosis, whereas SPRY4-IT1 overexpression promoted cell proliferation. Further functional assays indicated that SPRY4-IT1 overexpression significantly promoted cell migration and invasion by regulate the epithelial-mesenchymal transition (EMT). Taken together, our study demonstrates that SPRY4-IT1 could act as a functional oncogene in CRC, as well as a potential therapeutic target to inhibit CRC metastasis.
This review discusses the evidence linking industrial chemicals to a variety of health and reproductive outcomes. Industrial chemical production has increased over the past 30 to 40 years. Basic science, animal models, and epidemiologic data suggest that certain chemicals may act as endocrine disruptors (substances that interfere with normal hormonal action) and may play an etiologic role in a number of conditions whose incidence has also increased during this same period. These include low birth weight, gestational diabetes, obesity, certain cancers, certain birth defects, and neurodevelopmental disorders such as attention deficit disorder and autism. In addition, some environmental chemicals may have epigenetic effects, resulting in transgenerational health impacts. The epidemiologic and experimental evidence that links chemicals such as plasticizers (eg, phthalates and phenols), flame retardants, perfluorinated compounds, and pesticides with adverse reproductive health outcomes is reviewed. Women's health care providers are the liaison between scientific research and their patients; they should educate themselves on the significance of environmental toxins to health. They are ideally positioned, not only to counsel and reassure pregnant women, but also to suggest practicable changes in dietary and lifestyle habits to improve their health. Furthermore, women's health care providers should advocate for regulatory changes that protect women and their families from the health effects of environmental toxins.
Novel pro-inflammatory and anti-inflammatory derivatives from adipose tissue, known as adipokines, act as metabolic factors. The aim of this study was to analyse the secreted expression of different adipo/cytokines in secretomes of unstable carotid atherosclerotic plaque versus non-atherosclerotic mammary artery.
We evaluated the secretion levels of adiponectin, visfatin, lipocalin-2, resistin, IL-6 and TNFR2 by ELISA in human secretomes from cultured unstable carotid atherosclerotic plaque (n = 18) and non-atherosclerotic mammary artery (n = 13). We also measured visfatin serum levels in patients suffering from atherosclerosis and in a serum cohort of healthy subjects (n = 16).
We found that visfatin levels were significantly increased in unstable carotid atherosclerotic plaque secretome than in non-atherosclerotic mammary artery secretome. No differences were found with regard the other adipo/cytokines studied. Regarding visfatin circulating levels, there were no differences between unstable carotid atherosclerotic plaque and non-atherosclerotic mammary artery group. However, these visfatin levels were increased in comparison to serum cohort of healthy subjects.
Of all the adipo/cytokines analysed, only visfatin showed increased levels in secretomes of unstable carotid atherosclerotic plaque. Additional
 human studies are needed to clarify the possible role of visfatin as prognostic factor of unstable carotid atherosclerotic plaque.
Enterocytozoon bieneusi is a common opportunistic pathogen that is widely detected in humans, domestic animals and wildlife, and poses a challenge to public health. The present study was performed to evaluate the prevalence, genotypic diversity and zoonotic potential of E. bieneusi among wildlife at Chengdu and Bifengxia zoological gardens in Sichuan Province, China.
Of the 272 fresh fecal samples harvested from 70 captive wildlife species at Chengdu Zoo (n = 198) and Bifengxia Zoo (n = 74), 21 (10.6 %) and 22 (29.7 %) tested positive for E. bieneusi by internal transcribed spacer (ITS) sequencing analysis, respectively. Specifically, genotypes D, Peru 6, CHB1, BEB6, CHS9, SC02 and SC03, and genotypes D, CHB1, SC01 and SC02 were detected in the Chengdu and Bifengxia Zoo samples, respectively. Five known genotypes (D, Peru 6, BEB6, CHS9 and CHB1) and three novel genotypes (SC01, SC02 and SC03) were clustered into the zoonotic group (group 1) and host-adapted group (group 2). Multilocus sequence typing (MLST) analysis targeting three microsatellites (MS1, MS3 and MS7) and one minisatellite (MS4) were successfully sequenced for 37, 33, 35 and 37 specimens, generating 8, 3, 11 and 15 distinct locus types, respectively. Altogether, we identified 27 multilocus genotypes (MLGs) among the E. bieneusi isolates by MLST. These data highlight the high genetic diversity of E. bieneusi among zoo wildlife.
To our knowledge, this is the first report on the prevalence and genotypic diversity of E. bieneusi infections among captive wildlife in zoos in southwest China. Notably, we identified three novel E. bieneusi genotypes, as well as six new mammalian hosts (Asian golden cats, Tibetian blue bears, blackbucks, hog deer, Malayan sun bears and brown bears) for this organism. Moreover, the occurrence of zoonotic genotypes suggests that wildlife may act as reservoirs of E. bieneusi that can serve as a source of human microsporidiosis. The findings presented here should contribute to the control of zoonotic disease in China.
Human embryonic stem cell (hESC)-derived endodermal cells are of interest for the development of cellular therapies to treat disorders such as liver failure. The soluble form of activin A (Act) has been widely used as an in vitro inducer of definitive endoderm (DE). In this study, we have developed a nanofibrous poly (ɛ-caprolactone) substrate, biofunctionalized with Act, for directed differentiation of hESCs into DE. Bioconjugation of Act on nanofibrous meshes was confirmed by enzyme-linked immunosorbent assay (ELISA) and immunostaining. In order to investigate the bioactivity of immobilized Act (iAct), hESCs were cultivated on the Act-conjugated nanofibers for five days. The nanofibers with covalent iAct significantly increased expression levels of the endodermal markers SOX17, FOXA2, and CXCR4, compared with physically adsorbed Act (aAct) or without Act (noAct). In addition, iAct retained its bioactivity after storage for five days in the absence of cell seeding. The capability of cultivated cells to generate the DE-derived lineage was evaluated through further differentiation of seeded cells into hepatocyte-like cells (HLCs). Interestingly, the iAct sample showed a higher level of hepatic markers compared to the aAct sample. We also demonstrated that iAct in the presence of soluble Act (sAct) could improve the conventional protocol to generate HLCs from hESCs. © 2016 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 104A: 2861-2872, 2016.
Randomized controlled trials reported that pre-exposure prophylaxis (PrEP) with tenofovir and emtricitabine rarely selects for drug resistance. However, drug resistance due to PrEP is not completely understood. In daily practice, PrEP will not be used under the well-controlled conditions available in the trials, suggesting that widespread use of PrEP can result in increased drug resistance.
We surveyed expert virologists with questions about biological assumptions regarding drug resistance due to PrEP use. The influence of these assumptions on the prevalence of drug resistance and the fraction of HIV transmitted resistance was studied with a mathematical model. For comparability, 50% PrEP-coverage of and 90% per-act efficacy of PrEP in preventing HIV acquisition are assumed in all simulations.
Virologists disagreed on the following: the time until resistance emergence (range: 20-180 days) in infected PrEP users with breakthrough HIV infections; the efficacy of PrEP against drug-resistant HIV (25%-90%); and the likelihood of resistance acquisition upon transmission (10%-75%). These differences translate into projections of 0.6%- 1% and 3.5%-6% infected individuals with detectable resistance 10 years after introducing PrEP, assuming 100% and 50% adherence, respectively. The rate of resistance emergence following breakthrough HIV infection and the rate of resistance reversion after PrEP use is discontinued, were the factors identified as most influential on the expected resistance associated with PrEP. Importantly, 17-23% infected individuals could virologically fail treatment as a result of past PrEP use or transmitted resistance to PrEP with moderate adherence.
There is no broad consensus on quantification of key biological processes that underpin the emergence of PrEP-associated drug resistance. Despite this, the contribution of PrEP use to the prevalence of the detectable drug resistance is expected to be small. However, individuals who become infected despite the use of PrEP should be closely monitored due to higher risk of virological failure when initiating antiretroviral treatment in the future.
Over the past decades, both health inequalities and income inequalities have been increasing in many European countries, but it is unknown whether and how these trends are related. We test the hypothesis that trends in health inequalities and trends in income inequalities are related, i.e. that countries with a stronger increase in income inequalities have also experienced a stronger increase in health inequalities.
We collected trend data on all-cause and cause-specific mortality, as well as on the household income of people aged 35-79, for Belgium, Denmark, England & Wales, France, Slovenia, and Switzerland. We calculated absolute and relative differences in mortality and income between low- and high-educated people for several time points in the 1990s and 2000s. We used fixed-effects panel regression models to see if changes in income inequality predicted changes in mortality inequality.
The general trend in income inequality between high- and low-educated people in the six countries is increasing, while the mortality differences between educational groups show diverse trends, with absolute differences mostly decreasing and relative differences increasing in some countries but not in others. We found no association between trends in income inequalities and trends in inequalities in all-cause mortality, and trends in mortality inequalities did not improve when adjusted for rising income inequalities. This result held for absolute as well as for relative inequalities. A cause-specific analysis revealed some association between income inequality and mortality inequality for deaths from external causes, and to some extent also from cardiovascular diseases, but without statistical significance.
We find no support for the hypothesis that increasing income inequality explains increasing health inequalities. Possible explanations are that other factors are more important mediators of the effect of education on health, or more simply that income is not an important determinant of mortality in this European context of high-income countries. This study contributes to the discussion on income inequality as entry point to tackle health inequalities. More research is needed to test the common and plausible assumption that increasing income inequality leads to more health inequality, and that one needs to act against the former to avoid the latter.
A major debate in medical ethics is the request for futile treatment. The topic of medical futility requires discrete assessment in Iran for at least two reasons. First, the common principles and foundations of medical ethics have taken shape in the context of Western culture and secularism. Accordingly, the implementation of the same guidelines and codes of medical ethics as Western societies in Muslim communities does not seem rational. Second, the challenges arising in health service settings are divergent across different countries. The Quranic concept of idle (laghw) and its derivatives are used in 11 honorable verses of the Holy Quran. Among these verses, the 3rd verse of the blessed Al-Muminūn Surah was selected for its closer connection to the concept under examination. The selected verse was researched in the context of all dictionaries presented in Noor Jami` al-Tafasir 2 (The Noor Collection of Interpretations 2) software. "Idle" is known as any insignificant speech, act, or thing that is not beneficial; an action from which no benefit is gained; any falsehood (that is not stable or realized); an entertaining act; any foul, futile talk and action unworthy of attention; loss of hope; and something that is not derived from method and thought. The word has also been used to refer to anything insignificant. The notes and derived interpretations were placed in the following categories: A) Having no significant benefit (When medical care does not benefit the patient (his body and/or soul and his life in this world and/or the Hereafter), it is wrong to proceed with that medical modality; B) Falsehood (Actions that fail to provide, maintain, and improve health are clearly futile); C) Unworthy of attention (An action
 that neither improves health nor threatens it is wrong and impermissible).
To examine whether serum adiponectin or leptin level has the ability to differentiate clear cell renal cell carcinoma (ccRCC) from other subtypes of renal cell carcinoma (RCC) in a Chinese population.
We recruited 198 consecutive patients who were treated with radical or partial nephrectomy in our department from September 2011 to June 2013. Their histological types were all malignant, including clear cell, papillary, chromophobe and unclassified RCC. We also enrolled 86 people with no cancer or cancer-related diseases as normal controls. We measured patients' preoperative blood samples for plasma adiponectin and leptin concentrations using an enzyme-linked immunosorbent assay method. Statistical methods were used to analyze ccRCC and other subtypes as they relate to serum adiponectin/leptin level and other factors such as body mass index or visceral fat area.
In our database, normal controls had significantly higher circulating adiponectin (p < 0.001) and leptin levels (p < 0.001) than patients with RCC. Among the 198 RCC patients, 156 patients had ccRCC while 42 patients had other histological types. Serum adiponectin levels were lower in ccRCC patients than in non-clear-cell RCC patients (p = 0.004). However, the plasma leptin level was not differently distributed between ccRCC and non-ccRCC patients (p = 0.940). In multivariate analysis, we found that serum adiponectin level may be an independent predictor for discriminating ccRCC patients from others (p = 0.004). Furthermore, in the ccRCC subgroup, we observed that men with ccRCC had lower leptin (p < 0.001) and adiponectin (p = 0.002) levels, and diabetic patients had lower plasma adiponectin levels (p = 0.001).
Lower plasma adiponectin concentration was related to an increased incidence of ccRCC and may act as an independent predictor for ccRCC. Our study may help define the process from obesity to adipose tissue, to cytokines and finally to ccRCC.
Our previous studies demonstrated that depletion of tubulin polymerization promoting protein family member 3 (TPPP3) inhibits proliferation and induces apoptosis of HeLa cells. However, the expression and roles of TPPP3 in cancers remain largely unknown. In this study, we investigated the expression of TPPP3 in clinicopathological correlations in non-small-cell lung cancer (NSCLC) samples by immunohistochemistry. TPPP3 expression was significantly upregulated in NSCLC tissues, and high TPPP3 expression was positively associated with tumor size, lymph node metastasis, clinical stage, and poor survival. Furthermore, knockdown of TPPP3 by shRNA significantly inhibited cell proliferation and induced cell apoptosis and cell cycle arrest in vitro. In addition, depletion of TPPP3 inhibited lung cancer growth in vivo in the xenografts of H1299 cells; this effect was accompanied by the suppression of Ki67 expression. Our data suggested that TPPP3 might act as an oncogene in NSCLC. TPPP3 warrants consideration as a therapeutic candidate with anti-tumor potential.
The human SLC30A8 gene encodes the secretory granule-localised zinc transporter ZnT8 whose expression is chiefly restricted to the endocrine pancreas. Single nucleotide polymorphisms (SNPs) in the human SLC30A8 gene have been associated, through genome-wide studies, with altered type 2 diabetes risk. In addition to a role in the control of insulin release, recent studies involving targeted gene ablation from the pancreatic α cell (Solomou et al., J Biol Chem 290(35):21432-42) have also implicated ZnT8 in the control of glucagon release. Up to now, however, the possibility that increased levels of the transporter in these cells may impact glucagon secretion has not been explored.
Here, we use a recently-developed reverse tetracyline transactivator promoter-regulated ZnT8 transgene to drive the over-expression of human ZnT8 selectively in the α cell in adult mice. Glucose homeostasis and glucagon secretion were subsequently assessed both in vivo during hypoglycemic clamps and from isolated islets in vitro.
Doxyclin-dependent human ZnT8 mRNA expression was apparent in both isolated islets and in fluorescence-activated cell sorting- (FACS) purified α cells. Examined at 12 weeks of age, intraperitoneal glucose (1 g/kg) tolerance was unchanged in transgenic mice versus wild-type littermates (n = 8-10 mice/genotype, p > 0.05) and sensitivity to intraperitoneal insulin (0.75U/kg) was similarly unaltered in transgenic animals. In contrast, under hyperinsulinemic-hypoglycemic clamp, a ~45 % (p < 0.001) reduction in glucose infusion rate was apparent, and glucagon release was significantly (~40 %, p < 0.01) impaired, in transgenic mice. Correspondingly, examined in vitro, glucagon secretion was significantly reduced (~30 %, p < 0.05) from transgenic versus control islets at low, stimulatory glucose concentrations (1 mM, p < 0.05) but not at high glucose (17 mM) glucose (p > 0.05). Over-expression of ZnT8 in glucagonoma-derived αTC1-9 cells increased granule free Zn(2+) concentrations consistent with a role for Zn(2+) in this compartment in the action of ZnT8 on glucagon secretion.
Increased ZnT8 expression, and a likely increase in intragranular free Zn(2+) concentration, is deleterious in pancreatic α cells for stimulated glucagon release. These data provide further evidence that type 2 diabetes-associated polymorphisms in the SLC30A8/ZnT8 gene may act in part via alterations in glucagon release and suggest that ZnT8 activation may restrict glucagon release in some settings.
Ionic liquids can both act as a solvent and mediate esterification to valorize low-titer volatile fatty acids and generate organic solvents from renewable carbon sources including biowaste and CO2 . In this study, four phosphonium ionic liquids were tested for single-stage extraction of acetic acid from a dilute stream and esterification to ethyl acetate with added ethanol and heat. The esterification proceeded with a maximum conversion of 85.9±1.3 % after 30 min at 75 °C at a 1:1 stoichiometric ratio of reactants. Extraction and esterification can be tailored using mixed-anion ionic liquids; this is demonstrated herein using a common trihexyl(tetradecyl)phosphonium cation and a mixed chloride and bis(trifluoromethylsulfonyl)imide anion ionic liquid. As a further proof-of-concept, ethyl acetate was generated from an ionic liquid-driven esterification of an acetic acid extractant generated using CO2 as the only carbon source by microbial electrosynthesis.
Histamine-2 receptor (H2) blockers are often used in very low birth weight infants despite lack of population specific efficacy and safety data.
We sought to describe safety and temporal trends in histamine-2 receptor (H2) blocker use in hospitalized very low birth weight (VLBW) infants.
We conducted a retrospective cohort study using a clinical database populated by an electronic health record shared by 348 neonatal intensive care units in the United States.
We included all VLBW infants without major congenital anomalies.
We used multivariable logistic regression with generalizing estimating equations to evaluate the association between days of H2 blocker exposure and risk of: 1) death or necrotizing enterocolitis (NEC); 2) death or sepsis; and 3) death, NEC, or sepsis.
Of 127,707 infants, 20,288 (16%) were exposed to H2 blockers for a total of 6,422,352days. Median gestational age for infants exposed to H2 blockers was 27weeks (25th 75th percentile 26, 29). H2 blocker use decreased from 18% of infants in 1997 to 8% in 2012 (p<0.001). On multivariable analysis, infants were at increased risk of the combined outcome of death, NEC, or sepsis on days exposed to H2 blockers (odds ratio=1.14) (95% confidence interval 1.08, 1.19).
H2 blocker use is associated with increased risk of the combined outcome of death, NEC, or sepsis in hospitalized VLBW infants.
Objectives To assess the content and readability of online patient information resources against the current understanding of gout. Methods An online survey was undertaken using Google UK, USA, Australia and Canada. Information was assessed for content and accuracy on nineteen key points regarded core content for gout patient information resource. Readability was assessed using Flesch-Kincaid Reading Ease score. Fifteen randomly selected websites were reviewed by a blinded second observer. Results Eighty-five websites were selected. More than 50% of websites provided no information or had inaccuracies regarding the pathogenesis of gout. Most websites contained infomraiton on dietary and lifestyle modifications for treating gout and did not emphasise urate lowering therapy (ULT) and its potential for "cure". Over 75% websites had no/inaccurate information on the role of ULT or prophylaxis for preventing gout attacks on starting ULT. The majority of websites were difficult to read, with information in 68% websites rated at least fairly difficult. Conclusion Only few web-based patient information resources provide accurate and easy to read information on gout. This study will help physicians direct patients to currently reliable resources, but there is a need to improve many web-based patient information resources which at present act as barriers to care. This article is protected by copyright. All rights reserved.
Ticks are important vectors of pathogens and secreted neurotoxins with approximately 69 out of 692 tick species having the ability to induce severe toxicoses in their hosts. The Australian paralysis tick (Ixodes holocyclus) is known to be one of the most virulent tick species producing a flaccid paralysis and fatalities caused by a family of neurotoxins known as holocyclotoxins (HTs). The paralysis mechanism of these toxins is temperature dependent and is thought to involve inhibition of acetylcholine levels at the neuromuscular
 junction. However, the target and mechanism of this inhibition remain uncharacterised. Here, we report that three members of the holocyclotoxin family; HT-1 (GenBank AY766147), HT-3 (GenBank KP096303) and HT-12 (GenBank KP963967) induce muscle paralysis by inhibiting the dependence of transmitter release on extracellular calcium. Previous study was conducted using extracts from tick salivary glands, while the present study is the first to use pure toxins from I. holocyclus. Our findings provide greater insight into the mechanisms by which these toxins act to induce paralysis.
We examined whether variations in photosynthetic capacity are linked to variations in the environment and/or associated leaf traits for tropical moist forests (TMFs) in the Andes/western Amazon regions of Peru. We compared photosynthetic capacity (maximal rate of carboxylation of Rubisco (Vcmax ), and the maximum rate of electron transport (Jmax )), leaf mass, nitrogen (N) and phosphorus (P) per unit leaf area (Ma , Na and Pa , respectively), and chlorophyll from 210 species at 18 field sites along a 3300-m elevation gradient. Western blots were used to quantify the abundance of the CO2 -fixing enzyme Rubisco. Area- and N-based rates of photosynthetic capacity at 25°C were higher in upland than lowland TMFs, underpinned by greater investment of N in photosynthesis in high-elevation trees. Soil [P] and leaf Pa were key explanatory factors for models of area-based Vcmax and Jmax but did not account for variations in photosynthetic N-use efficiency. At any given Na and Pa , the fraction of N allocated to photosynthesis was higher in upland than lowland species. For a small subset of lowland TMF trees examined, a substantial fraction of Rubisco was inactive. These results highlight the importance of soil- and leaf-P in defining the photosynthetic capacity of TMFs, with variations in N allocation and Rubisco activation state further influencing photosynthetic rates and N-use efficiency of these critically important forests.
Modulation of diet is the primary lifestyle approach for reducing cardiovascular disease (CVD) risk, with a major focus of current guidelines being to lower LDL cholesterol by reducing intake of saturated fatty acids. However, dietary effects on lipid-related CVD risk factors extend beyond LDL cholesterol, with growing emphasis on the prevention and management of atherogenic dyslipidemia, which includes elevated triglyceride, small dense LDL, and reduced HDL cholesterol, and which is associated with excess adiposity and insulin resistance. We here review recent studies of dietary macronutrient effects on CVD risk that may act through effects on plasma lipid and lipoprotein metabolism.
Effects of reducing saturated fatty acids on CVD risk have been evaluated both in terms of the replacement macronutrient(s) and the food and dietary context in which the macronutrients are consumed. Although weight loss remains the most important goal for reducing cardiometabolic risk among overweight and obese individuals, a variety of lines of evidence support limitation of added sugars and processed starches for improving features of atherogenic dyslipidemia.
Increasing understanding of the complexity of nutrient-disease relationships has shifted the framework for CVD prevention from a focus on macronutrient content of diets to foods and dietary patterns.
Transition from laying to incubation behavior in chicken is an interesting topic in reproductive biology. The decline of incubation behavior in chicken population has led to considerable phenotypic differences in reproductive traits between breeds. However, the exact genetic mechanism of the reproductive phase transition still largely unknown and little is known about the gene expression changes that contribute to the phenotypic differences. We performed mRNA sequencing to investigate the molecular mechanism underlying the transition from laying to brooding and to detect difference in gene regulation underlying the phenotypic diversification using two chicken breeds. The majority of gene expression changes during phase transition were steroidogenesis and hormone-releasing genes. Brooding chickens shared a conservative pattern of greatly inhibited steroidogenic enzyme genes in the pituitary gland, therefore, low levels of steroidogenic enzymes might result in reproductive defects such as ovary regression and brooding onset. The conserved network responsible for brooding behavior was maintained by steroid biosynthesis and hormonal interactions. Interestingly, three transcription factors, SREBF2, NR5A1 and PGR, act as central signal modulators of steroid biosynthesis and hormonal interactions during the transition from laying to brooding modes at the molecular level. Furthermore, Genes correlated with protein synthesis and accumulation showed expression variation between breeds, which might result in different concentrations of and sensitivities to reproduction-related hormones. This study provided a new insight in neuroendocrine system at the molecular level, and helps to understand the genetic and hormonal responses that ultimately translate into behavior in chicken.
Mediator is a multiprotein complex that acts as a versatile transcription coactivator in eukaryotes. CDK8 kinase complex is a 4-protein subunit of the mediator complex that can act as a transcriptional repressor or coactivator, depending on the specific pathways involved. Although the role of MED12 exon 2 mutations is documented in the pathogenesis of uterine leiomyomas, its role in extrauterine smooth muscle tumorigenesis is less clear. Similarly, there is a paucity of data on the role of CDK8 in extrauterine smooth muscle tumorigenesis and progression. Our study correlates immunohistochemical expression of CDK8 and MED12 with clinical and pathologic parameters in extrauterine leiomyosarcomas. Immunohistochemical expression of CDK8 and MED12 in leiomyosarcomas was correlated with the tumor grade, stage, and the presence of local recurrence or metastasis. MED12 was expressed in the majority of leiomyosarcomas regardless of their stage or grade. CDK8 expression was lost in 1 of 6 pT1 tumors, compared with 9 of 10 pT2 tumors (P=0.0076). When the second group was expanded to include those tumors that did not have a recorded pathologic stage but had local recurrence and distant metastases, the difference in CDK8 expression was also statistically significant. Loss of CDK8 expression by immunohistochemistry is more prevalent in somatic leiomyosarcomas presenting at a higher histopathologic stage, as well as with local and distant recurrence, and can be used to enhance the current predictive parameters.
Magnetic paleoclimatic records often represent mixed environmental signals. Unmixing these signals may improve our understanding of the paleoenvironmental information contained within these records, but such a task is challenging. Here we report an example of numerical unmixing of magnetic hysteresis data obtained from Chinese loess and red clay sequences. We find that the mixed magnetic assemblages of the loess and red clay sediments both contain a component characterized by a narrow hysteresis loop, the abundance of which is positively correlated with magnetic susceptibility. This component has grain sizes close to the superparamagnetic/stable single domain boundary and is attributed to pedogenic activity. Furthermore, a wasp-waisted component is found in both the loess and red clay, however, the wasp-waisted form is more constricted in the red clay. We attribute this component to a mixture of detrital ferrimagnetic grains with pedogenic hematite. The abundance of this component decreases from the base to the top of the red clay, a pattern we attribute to decreased hematite production over the Chinese Loess Plateau (CLP) due to long-term climate cooling. This work demonstrates the potential of hysteresis loop unmixing to recover quantitative paleoclimatic information carried by both low and high coercivity magnetic minerals.
Patients suffering from sepsis experience organ failure and metabolic derangements, with a negative impact on their prognosis and survival. Objective markers for dismal prognosis in this group of patients are sought.
To assess the potential role of corrected QT interval anomalies as surrogates for metabolic derangements leading to increased short and medium-term mortality in patients suffering from sepsis.
This study utilised a historic-cohort analysis of 257 septic patients admitted to internal medicine departments. Personal data, vital signs, laboratory results and electrocardiograms were collected. Patients were grouped according to QTc duration, weather mid-range (395-490 ms) or non-mid-range, and further defined as shorter (<395 ms) or longer (>490 ms).
Mortality rates differed significantly between the mid-range QTc group and the non-mid-range groups at 14 days (23.7 vs 38.2%, respectively; P = 0.014) and at 3 months (38.5 vs 59.6%, respectively; P = 0.001). In a three-group analysis, the 14-day mortality was the highest in the longer QTc group and the lowest in the mid-range group compared with the shorter QTc group (44.4, 23.7 and 35.5%, respectively; P = 0.034), and this difference also remained at 3 months (74.1, 38.5 and 53.2%, respectively; P = 0.001). All differences remained statistically significant in a multivariate Cox regression analysis.
QTc duration anomalies are associated with worse short- and medium-term prognosis and may act as a marker for more severe clinical sequelae.
During atrial fibrillation ablation, heparin is required and is guided by the activated clotting time (ACT). Differences in the ACT before ablation and adequate initial heparin dosing in patients receiving non-vitamin K antagonist oral anticoagulants (NOACs) were examined.
Patients who received warfarin (control, N = 90), dabigatran
 etexilate (N = 90), rivaroxaban (N = 90) and apixaban (N = 90) were studied. A 100 U/kg dose of heparin was administered as a reliable control dose for warfarin, and the remaining patients were randomly administered 110, 120 or 130 U/kg of heparin in each NOAC group, followed by a continuous heparin infusion.
Periprocedural thromboembolic and major bleeding were not observed. Minor bleeding occurred rarely without significant differences among the groups examined. Baseline ACTs were longer in the warfarin (152 ± 16 s) and dabigatran (153 ± 13 s) groups than in the rivaroxaban (134 ± 13 s) and apixaban (133 ± 20 s) groups. The initial bolus heparin dosages required to produce an ACT 15 min after the initial bolus that was identical to the control (333 ± 32 s) were 120 U/kg (318 ± 29 s) and 130 U/kg (339 ± 43 s) for dabigatran, 130 U/kg (314 ± 31 s) for rivaroxaban and 130 U/kg (317 ± 39 s) for apixaban. The NOAC groups required significantly larger doses of total heparin than the warfarin group.
The baseline ACTs differed among the three NOAC groups. The results of the comparison with warfarin (the control) indicated that dosages of 120 or 130 U/kg for dabigatran, and 130 U/kg for rivaroxaban and apixaban, were adequate initial heparin dosages.
We use density functional theory to describe a novel way for metal free catalytic reduction of nitric oxide NO utilizing borondopedgraphene. The present study is based on the observation that borondopedgraphene and O-N=N-O(-) act as Lewis acid-base pair allowing the graphene surface to act as a catalyst. The process implies electron assisted N=N bond formation prior to N-O dissociation. Two N2 + O2 product channels, one of which favoring N2O formation, are envisaged as outcome of the catalytic process. Besides, we show also that the N2 + O2formation pathways are contrasted by a side reaction that brings to N3O3 (-)formation and decomposition into N2O + NO2 (-).
Tyrosine sulfation is a post-translational modification that facilitates protein-protein interaction. Two sulfated tyrosines (Tys173 and Tys177) were recently identified within the second variable (V2) loop of the major HIV-1 envelope glycoprotein, gp120, and shown to contribute to stabilizing the intramolecular interaction between V2 and the third variable (V3) loop. Here, we report that tyrosine-sulfated peptides derived from V2 act as structural and functional mimics of the CCR5 N-terminus and potently block HIV-1 infection. Nuclear magnetic and surface plasmon resonance analyses indicate that a tyrosine-sulfated V2 peptide (pV2α-Tys) adopts a CCR5-like helical conformation and directly interacts with gp120 in a CD4-dependent fashion, competing with a CCR5 N-terminal peptide. Sulfated V2 mimics, but not their non-sulfated counterparts, inhibit HIV-1 entry and fusion by preventing coreceptor utilization, with the highly conserved C-terminal sulfotyrosine, Tys177, playing a dominant role. Unlike CCR5 N-terminal peptides, V2 mimics inhibit a broad range of HIV-1 strains irrespective of their coreceptor tropism, highlighting the overall structural conservation of the coreceptor-binding site in gp120. These results document the use of receptor mimicry by a retrovirus to occlude a key neutralization target site and provide leads for the design of therapeutic strategies against HIV-1.
Adenotonsillar hyperplasia (ATH) and allergic rhinitis (AR) are the most common causes of upper airway obstruction in children. Such diseases, by affecting the upper airways, can cause chronic alveolar hypoventilation, pulmonary vasoconstriction and pulmonary hypertension, which in some cases, are irreversible.
This cross-sectional study aimed to evaluate the prevalence of pulmonary hypertension in two groups of mouth-breathing (MB) 2-12 year old children with ATH and isolated allergic rhinitis, through Doppler echocardiography.
54 patients with ATH and indications for adenoidectomy and/or tonsillectomy and 24 patients with persistent allergic rhinitis were selected and submitted to Doppler echocardiography. The Systolic Pulmonary Artery Pressure (SPAP) was determined by tricuspid regurgitation and the Mean Pulmonary Artery Pressure (MPAP) was calculated from the SPAP. Similar measurements were carried out in 25 nasal breathing (NB) individuals.
The mean MPAP and SPAP were higher in the MB than in the NB group (17.62±2.06 [ATH] and 17.45±1.25 [AR] vs. 15.20±2.36 [NB] mmHg, p<0.005, and 25.61±3.38 [ATH] and 25.33±2.06 [AR] vs. 21.64±3.87 [NB] mmHg, p<0.005, respectively) and the mean acceleration time of pulmonary flow trace (Act) was higher in the NB than in the MB group (127.24±12.81 [RN] vs. 114.06±10.63ms [ATH] and 117.96±10.28 [AR] MS [AR]; p<0.0001).
None of the MB children (ATH and AR) met the PH criteria, although individuals with both ATH and isolated AR showed significant evidence of increased pulmonary artery pressure by Doppler echocardiography in relation to NB individuals. No differences were observed between the ATH and AR groups.
To compare ultrasound (US) versus computed tomography (CT) for primary guidance during needle biopsy of chest lesions.
Institutional Review Board approval was obtained for this Health Insurance Portability and Accountability Act-compliant retrospective study, and the need for informed consent was waived. All US- and CT-guided chest biopsy procedures performed between January 1, 2012, and October 15, 2014, at our institution were reviewed, and all procedures targeting peripheral intrathoracic and chest wall lesions were included. Axillary lesions, lung lesions without peripheral pleural contact, and mediastinal lesions without a transcutaneous US window were excluded. Radiologic, pathologic, and clinical records were reviewed.
Fifty-five procedures with primary US guidance (23 lung, 6 pleural, 2 mediastinal, and 24 chest wall) and 130 CT procedures (88 lung, 10 pleural, 7 mediastinal, and 25 chest wall) were performed. Diagnostic samples were obtained in 98% (54 of 55) of US procedures and 87% (113 of 130) of CT procedures (P = .02). Pneumothorax requiring treatment occurred in 2% (1 of 55) of US procedures and 5% (7 of 130) of CT procedures (P = .25). Computed tomographic localization was used in 29% (16 of 55) of US procedures. Nevertheless, the average patient radiation dose was significantly less in US procedures (182 mGy-cm) versus CT procedures (718 mGy-cm; P< .01). The average procedure time was 40 minutes for US and 38 minutes for CT (P = .39). The average lesion size was 4.5 cm for US and 4.9 cm for CT (P = .14).
During biopsy of peripheral intrathoracic lesions and chest wall lesions, primary US guidance resulted in a higher likelihood of a diagnostic sample and a decreased patient radiation dose compared with CT guidance.
TiO2 and Ag NPs are widely used as antibacterial agents against many bacterial pathogens. Chitosan (polymer) itself acts as a strong antibacterial agent. Hence, chitosan/TiO2/Ag NPs incorporated nanocomposite film was prepared against packed drinking water bacterial strains. A concentration-dependent increase in the reduction of cell viability was observed in all the isolates under UV-C and dark exposure conditions. The bacteria consortium showed greater resistance against antibacterial effects of chitosan/TiO2/Ag nanocomposite as compared to single isolates. Glycocalyx test and mass assessment conclude the effective antibacterial activity by inhibiting bacterial adhesion on the film surface. The release of LDH and generation of ROS act as the predominant antibacterial mechanism induced by TiO2/Ag NPs. Surface characterization of chitosan/TiO2/Ag nanocomposite was studied by FTIR and XRD analyses and SEM analysis after interaction with the bacteria.
Phenomenon: This paper concerns itself with the value system that informs and motivates medical students of the twenty-first century as distinct from earlier cohorts. It notes a shift from an era of altruism within which the medical professional was a 'pillar of society' always 'on duty' and always concerned foremost for the patient to an era in which he/she is just another member of the work force, subject to public scrutiny and criticism, to patient autonomy and to a self-serving ethos which characterizes the present age. Whilst concerns have been raised for a continuing and separate morality of medicine, young professionals in other studies have cited a range of characteristics including honesty, trustworthiness and respect alongside competence and medical skill. However, the notion of 'performance' has made a strong thrust into the literature, with students citing the putting on and taking off of dual personae as part of their complex identity in this present time. They are entitled to their own lives, to drop the act and just be themselves when off duty, picking it back up again with the duty call.
The present study then investigated the views on this subject of two groups of medical students in Trinidad & Tobago in the Caribbean, one made up entirely of nationals and one including students from other parts of the Caribbean and the USA. They discussed the topic in focus groups of eight; their responses were then analysed thematically and subject to discourse analysis.
The study revealed diverse attitudes with some embracing the ethical standards of a high calling that whilst others were concerned that too much was expected, that they had a right to break free and be themselves as long as they did not transgress too far from their expected roles. There were two distinct groups both concerned with 'how' they 'carried themselves about' but this meant different things to each dependent on which of the two perspectives they embraced. As a whole, the study revealed an ongoing conflict of value systems with concern for patient welfare just remaining uppermost. Insights: As The University of the West Indies has now stepped into
 the field of medical professionalism actively it would hope to support students in resolving their conflicts more consciously in response to the range of philosophical stances which currently present themselves.
Members of the NAC transcription factor family have been implicated in the regulation of different processes of plant development including senescence. In this study, the role of ANAC032 is analyzed in Arabidopsis thaliana (Col-0). ANAC032 is shown to act as a transcriptional activator and its expression is induced in senescing leaves as well as in dark-treated detached leaves. Analysis of transgenic overexpressors (OXs) and chimeric repressors (SRDXs) of ANAC032 indicates that ANAC032 positively regulates age-dependent and dark-induced leaf senescence. Quantitative real-time PCR analysis showed that ANAC032 regulates leaf senescence mainly through the modulation of expression of the senescence-associated genes AtNYE1, SAG113 and SAUR36/SAG201, which are involved in Chl degradation, and ABA and auxin promotion of senescence, respectively. In addition, ANAC032 expression is induced by a range of oxidative and abiotic stresses. As a result, ANAC032 overexpression lines exhibited enhanced leaf senescence when challenged with different oxidative (3-aminotriazole, fumonisin B1 and high light) and abiotic stress (osmotic and salinity) conditions compared with the wild type. In contrast, ANAC032 SRDX lines displayed the opposite phenotype. ANAC032 transgenic lines showed altered 2,4-D-mediated root tip swelling and root inhibition responses when compared with the wild type. The altered response to auxin, oxidative and abiotic stress treatments in ANAC032 transgenic lines involves differential accumulation of H2O2 compared with the wild type. Taken together, these results indicate that ANAC032 is an important transcription factor that positively regulates age-dependent and stress-induced senescence in A. thaliana by modulating reactive oxygen species production.
Anticoagulant rodenticides (ARs) are highly toxic compounds that are exclusively used for the control of rodent pests. Despite their defined use, they are nonetheless found in a large number of non-target species indicating widespread penetration of wildlife. Attempts to quantify the scale of problem are complicated by non-random sampling of individuals tested for AR contamination. The American mink (Neovison vison) is a wide ranging, non-native, generalist predator that is subject to wide scale control efforts in the UK. Exposure to eight ARs was determined in 99 mink trapped in NE Scotland, most of which were of known age. A high percentage (79%) of the animals had detectable residues of at least one AR, and more than 50% of the positive animals had two or more ARs. The most frequently detected compound was bromadiolone (75% of all animals tested), followed by difenacoum (53% of all mink), coumatetralyl (22%) and brodifacoum (9%). The probability of mink exposure to ARs increased by 4.5% per month of life, and was 1.7 times higher for mink caught in areas with a high, as opposed to a low, density of farms. The number of AR compounds acquired also increased with age and with farm density. No evidence was found for sexual differences in the concentration and number of ARs. The wide niche and dietary overlap of mink with several native carnivore species, and the fact that American mink are culled for conservation throughout Europe, suggest that this species may act as a sentinel species, and the application of these data to other native carnivores is discussed.
An increasing number of studies have highlighted the potential link between EXO1 polymorphisms and cancer risk, although no consensus has yet been obtained. Thus, we aimed to obtain a thorough and current assessment of EXO1 polymorphisms and cancer susceptibility by performing a meta-analysis. A comprehensive literature retrieval was performed on PubMed, EMbase, Web of Science and Wanfang databases. The odds ratio (OR) and 95% confidence interval (CI) were applied to assess the results. Finally, 39 case-control studies of the nine EXO1 polymorphisms that involved 21,651 cases and 21,348 controls met our inclusion criteria. The pooled analysis indicated that the rs1047840 polymorphism conferred a significantly increased susceptibility to cancer in an allelic model. Similarly, the rs3754093, rs1776177, rs9350, rs10802996, rs1635498, rs1776148 and rs851797 polymorphisms were also associated with an increased susceptibility to cancer in an allelic model, respectively, while no significant association was identified for rs1635517 polymorphism. For the rs1047840 polymorphism, in an ethnicity subgroup analysis, a significantly increased susceptibility to cancer for Asians was identified in all the genetic models, and for Caucasians in an allelic model. Our findings provide the evidence that the rs1047840, rs9350, rs10802996, rs1635498, rs1776148, rs1776177, rs3754093 and rs851797 polymorphisms may act as risk factors for cancer.
Inflammation secondary to autoantibody-mediated effects occurring in multiple organs is a hallmark of systemic lupus erythematosus (SLE). The inflammatory response to SLE-mediated damage in brain parenchyma has been postulated in both normal and cognitively impaired individuals. Our goal is to use molecular imaging to investigate the distribution within the brain of the mitochondrial translocator protein (TSPO) that is upregulated during glial cell activation, and is considered as a marker of brain injury and repair.
We sought to characterize TSPO distribution in the brain of SLE patients using positron emission tomography (PET) and [(11)C]DPA-713 (DPA), a radiopharmaceutical that targets TSPO. We imaged 11 healthy controls and 10 patients with SLE (years of diagnosis: 13.0 ± 7.7), all between the ages of 22 and 52.
Among the nine brain regions studied, no statistically significant increases in DPA binding were observed in SLE. Instead, there was a significant decrease in TSPO distribution in the cerebellum and hippocampus of SLE patients, as compared to healthy controls. Such decreases were most significant in cognitively normal SLE subjects, but showed pseudo-normalization in those with cognitive impairment, due to higher cerebellar and hippocampal DPA binding in the cognitively impaired (versus normal) SLE brain.
Results from this pilot study suggest a link between diminished regional TSPO expression in the brain of patients with SLE, as well as possible glial cell activation within the cerebellum and hippocampus of cognitively impaired individuals with SLE. Further studies are needed to elucidate how mitochondrial dysfunction and glial cell activation may act together in SLE and SLE-mediated neurocognitive deficits.
To determine the impact of the introduction of artemisinin-based combination therapy (ACT) on parasite susceptibility, a molecular surveillance for antimalarial drug resistance was conducted on local isolates from the Hôpital Principal de Dakar between November 2013 and January 2014 and between August 2014 and December 2014.
The prevalence of genetic polymorphisms in antimalarial resistance genes (pfcrt, pfmdr1, pfdhfr and pfdhps) was evaluated in 103 isolates.
The chloroquine-resistant haplotypes CVIET and CVMET were identified in 31.4 and 3.9 % of the isolates, respectively. The frequency of the pfcrt K76T mutation was increased from 29.3 % in 2013-2014 to 43.2 % in 2014. The pfmdr1 N86Y and Y184F mutations were identified in 6.1 and 53.5 % of the isolates, respectively. The pfdhfr triple mutant (S108N, N51I and C59R) was detected in the majority of the isolates (82.3 %). The prevalence of quadruple mutants (pfdhfr S108N, N51I, C59R and pfdhps A437G) was 40.4 %. One isolate (1.1 %) harboured the pfdhps mutations A437G and K540E and the pfdhfr mutations S108N, N51I and C59R.
Despite a decline in the prevalence of chloroquine resistance due to the official withdrawal of the drug and to the introduction of ACT, the spread of resistance to chloroquine has continued. Furthermore, susceptibility to amodiaquine may be decreased as a result of cross-resistance. The frequency of the pfmdr1 mutation N86Y declined while the Y184F mutation increased in prevalence, suggesting that selective pressure is acting on pfmdr1, leading to a high prevalence of mutations in these isolates and the lack of specific mutations. The 50.5 % prevalence of the pfmdr1 polymorphisms N86Y and Y184F suggests a decrease in lumefantrine susceptibility. Based on these results, intensive surveillance of ACT partner drugs must be conducted regularly in Senegal.
CdS-polyaniline-Pt and ZnS-polyaniline-Pt micromotors have been synthesized and characterized. The nanocrystals are generated "in situ" during the template electrosynthesis of the micromotors while being simultaneously trapped in the polymeric network, generating a hybrid structure. The presence of nanocrystal "edges" in the inner polyaniline layer result in a rough Pt catalytic surface and enhanced electron transfer for highly efficient bubble propulsion at remarkable speeds of over 2500 μm/s. The incorporation of CdS and ZnS nanocrystals impart several attractive functions, including cation-exchange based chemical transformation capabilities and enhanced photocatalytic performance. The remarkable ion-exchange properties of ZnS-polyaniline (PANI)-Pt micromotors are illustrated for the cation exchange of heavy metals cations. The superior photocatalytic performance of CdS-PANI-Pt micromotors is used for the enhanced photocatalytic oxidation of bisphenol A. Such self-propelled micromotors act as highly efficient dynamic platforms that offer significantly shorter and more efficient processes as compared with common static operations. The attractive properties of these micromotors will pave the way for diverse sensing, decontamination, energy generation,
 or electronic applications.
Fire-eater's pneumonia is an exogenous chemical pneumonitis after accidental aspiration of hydrocarbon fluids during the act of fire-eating. There have been few case reports in the literature regarding complications after fire-eating but so far none, to the best of our knowledge, have described such drastic and life-threatening pulmonary complications as in this case while only having swallowed a small amount of fluid.
We present a case of fire-eater's pneumonia in a 28-year-old white man with severe pulmonary complications. He presented with pneumonitis and partial respiratory insufficiency. He was diagnosed with acute respiratory distress syndrome and was treated with antibiosis, oxygen therapy, and required non-invasive ventilation. He had a good recovery.
Accidental aspiration of even small amounts of lamp oil can lead to serious life-threatening pulmonary complications. Although fire-eaters are a comparatively small occupational group, the severity of possible complications illustrates that awareness of these consequences should be raised in teenagers and young adults who might be tempted into trying it. This case in a Western country shows that the dangers of fire-eating are not to be underestimated and are not limited to Eastern European countries where the majority of cases have been reported.
Adolescent girls have been targeted as a priority group for promoting physical activity levels however it is unclear how this can be achieved. There is some evidence to suggest that social support could impact the physical activity levels of adolescent girls, although the relationship is complex and not well understood. We aimed to systematically review and meta-analyse the relationship between social support and physical activity in adolescent girls, exploring how different types and providers of social support might influence the relationship. Articles were identified through a systematic search of the literature using 14 electronic databases, personal resources, grey literature, and reference lists of included studies and previous reviews. Search terms representing social support, physical activity and adolescent girls were identified and used in various combinations to form a search strategy which was adapted for different databases. Cross-sectional or longitudinal articles published in English that reported an association between social support and physical activity in adolescent girls between the ages of 10 to 19 years were included. Studies that focused only on clinical or overweight populations were excluded. Data extraction was carried out by one reviewer using an electronic extraction form. A random 25 % of included articles were selected for data extraction by a second reviewer to check fidelity. Risk of bias was assessed using a custom tool informed by the Critical Appraisal Skills Programme Cohort Study Checklist in conjunction with data extraction. Cross-sectional results were meta-analysed and longitudinal results were presented narratively. Small but significant associations between all available providers of total social support (except teachers) and physical activity were found (r = .14-.24). Small but significant associations were also identified for emotional, instrumental and modelling support for some providers of support (r = .10-.21). Longitudinal research supported the cross-sectional analyses. Many of the meta-analysis results suggested high heterogeneity and there was some evidence of publication bias, therefore, the meta-analysis results should be interpreted with caution. In conclusion, the meta-analysis results suggest that social support is not a strong predictor of physical activity in adolescent girls though parents and friends may have a role in enhancing PA.
PROSPERO 2014: CRD42014006738.
Homing endonucleases are sequence-tolerant DNA endonucleases that act as mobile genetic elements. The ability of homing endonucleases to cleave substrates with multiple nucleotide substitutions suggests a high degree of adaptability in that changing or modulating cleavage preference would require relatively few amino acid substitutions. Here, using directed evolution experiments with the GIY-YIG homing endonuclease I-TevI that targets the thymidylate synthase gene of phage T4, we readily isolated variants that dramatically broadened I-TevI cleavage preference, as well as variants that fine-tuned cleavage preference. By combining substitutions, we observed an ∼10 000-fold improvement in cleavage on some substrates not cleaved by the wild-type enzyme, correlating with a decrease in readout of information content at the cleavage site. Strikingly, we were able to change the cleavage preference of I-TevI to that of the isoschizomer I-BmoI which targets a different cleavage site in the thymidylate synthase gene, recapitulating the evolution of cleavage preference in this family of homing endonucleases. Our results define a strategy to isolate GIY-YIG nuclease domains with distinct cleavage preferences, and provide insight into how homing endonucleases may escape a dead-end life cycle in a population of saturated target sites by promoting transposition to different target sites.
Promoting active travel is an important part of increasing population physical activity, which has both physical and mental health benefits. A key benefit described by the then Scottish Government of the five-mile M74 motorway extension, which opened during June 2011 in the south of Glasgow, was that the forecast reduction in motor traffic on local streets would make these streets safer for walking and cycling, thus increasing active travel by the local population. The aim of the study was to evaluate the impact of new motorway infrastructure on the proportion of journey stages made actively (cycling or on foot) by individuals travelling in and out of the local area.
Data for the periods 2009-10 and 2012-13 were extracted from the Scottish Household Survey (SHS) travel diaries, which record each journey stage made during the previous day by a representative sample of the Scottish population aged 16 and over. Each individual journey stage was assigned to one of the following study areas surrounding existing and new transport infrastructure: (1) an area surrounding the new M74 motorway extension (n = 435 (2009-10), 543 (2012-13)), (2) a comparator area surrounding an existing motorway (n = 477 (2009-10), 560 (2012-13)), and (3) a control area containing no comparable motorway infrastructure (n = 541 (2009-10), 593 (2012-13)). Multivariable, multi-level regression analysis was performed to determine any between-area differences in change in active travel over time, which might indicate an intervention effect. Reference populations were defined using two alternative definitions, (1) Glasgow City and (2) Glasgow and surrounding local authorities.
The results showed an increase in the proportion of journey stages using active travel in all study areas compared to both reference populations. However, there were no significant between-area differences to suggest an effect attributable the M74 motorway extension.
There was no clear evidence that the M74 motorway extension either increased or decreased active travel in the local area. The anticipation by policy makers that reduced motorised traffic on local streets might increase journeys walked or cycled appears to have been unfounded.
Computational models of cognition provide an interface to connect advanced mathematical tools and methods to empirically supported theories of behavior in psychology, cognitive science, and neuroscience. In this article, we consider a computational model of instance-based learning, implemented in the ACT-R cognitive architecture. We propose an approach for obtaining mathematical reformulations of such cognitive models that improve their computational tractability. For the well-established Sugar Factory dynamic decision making task, we conduct a simulation study to analyze central model parameters. We show how mathematical optimization techniques can be applied to efficiently identify optimal parameter values with respect to different optimization goals. Beyond these methodological contributions, our analysis reveals the sensitivity of this particular task with respect to initial settings and yields new insights into how average human performance deviates from potential optimal performance. We conclude by discussing possible extensions of our approach as well as future steps towards applying more powerful derivative-based optimization methods.
Pulmonary adverse effects of interferon (IFN) therapies are rare but can be life threatening. This article proposes to review clinical and experimental data suggesting a causal link between interferon exposure and pulmonary arterial hypertension (PAH).
Interferon has recently been added to the list of possible risk factors for PAH. This was justified by the reporting of many cases of pulmonary hypertension potentially associated with IFN-α or IFN-β exposure. Some of them were reversible after cessation of interferon exposure, especially in patients without concomitant risk factors for pulmonary hypertension. In contrast, it remains a challenge to definitively confirm the causal role of IFN-α in patients treated for hepatitis C viral infection because of frequent concomitant PAH risk factors such as portal hypertension and/or HIV infection. In these patients, temporal and clinical arguments suggest that interferon may potentially act as an additional trigger for PAH. Moreover, the information obtained from clinical experience with interferon therapy has been enriched by basic science research on this topic suggesting that interferon is involved in both human and experimental pulmonary hypertension.
Many clinical and experimental data corroborate the link between interferon exposure and the
 risk to develop PAH.
Few studies have investigated the accuracy of the ActiGraph (AG) GTX3 accelerometer for assessing children's sitting and standing time. The activPAL (aP) has an inclinometer function that enables it to distinguish between sitting/lying and standing; however, its accuracy for assessing sitting and standing in older children is unknown. This study validated the accuracy of these devices for estimating sitting and standing time in a school classroom against a criterion measure of direct observation (DO).
Forty children in grades 5-7 wore both devices while being video recorded during two school lessons. AG and aP data were simultaneously collected in 15-s epochs. Individual participant DO and aP data were recorded as total time spent sitting/lying, standing and stepping. AG data were converted into time spent sitting and standing using previously established cut-points. Compared with DO, the aP underestimated sitting time (mean bias = -1.9 min, 95 % LoA = -8.9 to 5.2 min) and overestimated standing time (mean bias = 1.8 min, 95% LoA = -9.6 to 13.3 min). The best-performing AG cut-point across both sitting and standing (<75 counts/15 s) was more accurate than the aP, underestimating sitting time (mean bias = -0.8 min, 95 % LoA = -10.5 to 9.9 min) and standing time (mean bias = -0.4 min, 95% LoA = -9.8 to 9.1 min), but was less precise as evidenced by wider LoAs and poorer correlations with DO (sitting r = 0.86 aP vs 0.80 AG; standing r = 0.78 aP vs 0.60 AG).
The aP demonstrated good accuracy and precision for assessing free-living sitting and standing time in classroom settings. The AG was most accurate using a cut-point of < 75 counts/15 s. Further studies should validate the monitors in settings with greater inter- and intra-individual variation in movement patterns.
Biological applications of nanoparticles are rapidly increasing, which introduces new possibilities to improve the efficacy of radiotherapy. Here, we synthesized titanium peroxide nanoparticles (TiOxNPs) and investigated their efficacy as novel agents that can potently enhance the effects of radiation in the treatment of pancreatic cancer.
TiOxNPs and polyacrylic acid-modified TiOxNPs (PAA-TiOxNPs) were synthesized from anatase-type titanium dioxide nanoparticles (TiO2NPs). The size and morphology of the PAA-TiOxNPs was evaluated using transmission electron microscopy and dynamic light scattering. The crystalline structures of the TiO2NPs and PAA-TiOxNPs with and without X-ray irradiation were analyzed using X-ray absorption. The ability of TiOxNPs and PAA-TiOxNPs to produce reactive oxygen species in response to X-ray irradiation was evaluated in a cell-free system and confirmed by flow cytometric analysis in vitro. DNA damage after X-ray exposure with or without PAA-TiOxNPs was assessed by immunohistochemical analysis of γ-H2AX foci formation in vitro and in vivo. Cytotoxicity was evaluated by a colony forming assay in vitro. Xenografts were prepared using human pancreatic cancer MIAPaCa-2 cells and used to evaluate the inhibition of tumor growth caused by X-ray exposure, PAA-TiOxNPs, and the combination of the two.
The core structures of the PAA-TiOxNPs were found to be of the anatase type. The TiOxNPs and PAA-TiOxNPs showed a distinct ability to produce hydroxyl radicals in response to X-ray irradiation in a dose- and concentration-dependent manner, whereas the TiO2NPs did not. At the highest concentration of TiOxNPs, the amount of hydroxyl radicals increased by >8.5-fold following treatment with 30 Gy of radiation. The absorption of PAA-TiOxNPs enhanced DNA damage and resulted in higher cytotoxicity in response to X-ray irradiation in vitro. The combination of the PAA-TiOxNPs and X-ray irradiation induced significantly stronger tumor growth inhibition compared to treatment with either PAA-TiOxNPs or X-ray alone (p < 0.05). No apparent toxicity or weight loss was observed for 43 days after irradiation.
TiOxNPs are potential agents for enhancing the effects of radiation on pancreatic cancer and act via hydroxyl radical production; owing to this ability, they can be used for pancreatic cancer therapy in the future.
Physical activity may reduce the risk of adverse pregnancy outcomes; however, compared to non-pregnant women, a lower proportion of pregnant women meet the physical activity guidelines. Our objectives were to explore overall changes and ethnic differences in objectively recorded moderate-to-vigorous intensity physical activity (MVPA) during pregnancy and postpartum and to investigate the associations with objective and perceived access to recreational areas.
We analysed 1,467 person-observations from 709 women in a multi-ethnic population-based cohort, with MVPA data recorded with the SenseWear™ Pro(3) Armband in early pregnancy (mean gestational week (GW) 15), mid-pregnancy (mean GW 28) and postpartum (mean postpartum week 14). MVPA was limited to bouts ≥10 min. Women were nested within 56 neighbourhoods defined by postal code area. We derived neighbourhood-level objective access to recreational areas (good vs limited) by geographic information systems. We collected information about perceived access (high vs low perception) to recreational areas in early pregnancy. We treated ethnicity, objective and perceived access as explanatory variables in separate models based on linear mixed effects regression analyses.
Overall, MVPA dropped between early and mid-pregnancy, followed by an increase postpartum. Western women performed more MVPA than women in other ethnic groups across time points, but the differences increased postpartum. Women residing in neighbourhoods with good objective access to recreational areas accumulated on average nine additional MVPA minutes/day (p < 0.01) compared with women in neighbourhoods with limited access. Women with perceptions of high access to recreational areas accumulated on average five additional MVPA minutes/day (p < 0.01) compared with women with perceptions of low access. After mutual adjustments, perceived and objective access to recreational areas remained significantly associated with MVPA. The association between MVPA and access to recreational areas did not differ by time point, ethnic group or socio-economic position.
In all ethnic groups, we observed a decline in MVPA between early and mid-pregnancy. However, at both time points during pregnancy, and especially three months postpartum, Western women were more physically active than ethnic minority women. In all ethnic groups, and at all three time points, both objective and perceived access to recreational areas were positively associated with MVPA levels.
The functional role of progesterone receptor (PR) and its impact on estrogen signaling in breast cancer remain controversial. In primary ER(+) (estrogen receptor-positive)/PR(+) human tumors, we report that PR reprograms estrogen signaling as a genomic agonist and a phenotypic antagonist. In isolation, estrogen and progestin act as genomic agonists by regulating the expression of common target genes in similar directions, but at different levels. Similarly, in isolation, progestin is also a weak phenotypic agonist of estrogen action. However, in the presence of both hormones, progestin behaves as a phenotypic estrogen antagonist. PR remodels nucleosomes to noncompetitively redirect ER genomic binding to distal enhancers enriched for BRCA1 binding motifs and sites that link PR and ER/PR complexes. When both hormones are present, progestin modulates estrogen action, such that responsive transcriptomes, cellular processes, and ER/PR recruitment to genomic sites correlate with those observed with PR alone, but not ER alone. Despite this overall correlation, the transcriptome patterns modulated by dual treatment are sufficiently different from individual treatments, such that antagonism of oncogenic processes is both predicted and observed. Combination therapies using the selective PR modulator/antagonist (SPRM) CDB4124 in combination with tamoxifen elicited 70% cytotoxic tumor regression of T47D tumor xenografts, whereas individual therapies inhibited tumor growth without net regression. Our findings demonstrate that PR redirects ER chromatin binding to antagonize estrogen signaling and that SPRMs can potentiate responses to antiestrogens, suggesting that cotargeting of ER and PR in ER(+)/PR(+) breast cancers should be explored.
This study explains the history, current problems, and future possibilities of Islamic insurance (takaful) in Bangladesh. To articulate these issues, the researcher has adopted the qualitative method, and data has been collected through secondary sources i.e. articles, books, and online resources. The study reveals that Islamic insurance in Bangladesh is regulated by the Insurance Act 2010 which is contradictory with Islamic insurance causing numerous problems for Islamic insurance. This study also points out that Islamic insurance is a fast growing industry with huge prospects in Bangladesh. The government should introduce separate regulations for both Islamic and conventional insurance. The research concludes with suggestions for the further development of Islamic insurance in Bangladesh.
Cancer cachexia is a major cause of morbidity and mortality with no widely approved treatment.
The ACT-ONE trial is a randomized, double-blind, parallel group, placebo-controlled, phase II multicentre trial in patients (25-80 years) with stages III or IV colorectal cancer or non-small cell lung cancer-related cachexia that tested two doses of espindolol (a novel non-selective β blocker with central 5-HT1a and partial β2 receptor agonist effects). The primary endpoint was the difference in the rate of weight change over 16 weeks (linear mixed-effect model for repeated measures) between high-dose espindolol and placebo.
Eighty-seven patients were randomized centrally
 in blocks in a ratio 3:2:1 [42 high dose, 10 mg twice daily (bd):31 placebo:14 low dose, 2.5 mg bd]. High-dose espindolol produced a statistically and clinically significant weight gain (+0.54 kg/4 weeks, 95% CI 0.38-0.70) compared with a weight loss on placebo (-0.21 kg/4 weeks, 95% CI -0.37-0.05); P < 0.0001. High-dose espindolol produced a statistically significant increase in lean body mass, whilst changes in fat mass were neutral. Hand grip strength significantly (high dose -1.15 ± 0.7 kg, placebo -3.51 ± 0.8 kg change per 4 weeks; P = 0.0134), stair climbing power, and 6-min walk test non-significantly were all directionally in favour of high-dose espindolol. There were no clinically significant differences in safety signals or survival between treatment groups, although a numerical excess of dyspnoea was seen with high-dose espindolol (19.1%) compared with placebo (3.2%).
This positive trial showed that espindolol 10 mg bd significantly reversed weight loss, improved fat free mass, and maintained fat mass in advanced colorectal cancer and non-small cell lung cancer-related cachexia. This was associated with a significant improvement in handgrip strength, supporting the further investigation of 10 mg bd espindolol for the treatment of cancer cachexia. Although not powered to look at dose response, most treatment effects for low dose lay between high dose and placebo, suggesting that there may be a dose response in the effects of espindolol.
In 2012, more than 400,000 urinary bladder cancer cases occurred worldwide, making it the 7(th) most common type of cancer. Although many previous studies focused on the relationship between diet and bladder cancer, the evidence related to specific food items or nutrients that could be involved in the development of bladder cancer remains inconclusive. Dietary components can either be, or be activated into, potential carcinogens through metabolism, or act to prevent carcinogen damage.
The BLadder cancer, Epidemiology and Nutritional Determinants (BLEND) study was set up with the purpose of collecting individual patient data from observational studies on diet and bladder cancer. In total, data from 11,261 bladder cancer cases and 675,532 non-cases from 18 case-control and 6 cohort studies from all over the world were included with the aim to investigate the association between individual food items, nutrients and dietary patterns and risk of developing bladder cancer.
The substantial number of cases included in this study will enable us to provide evidence with large statistical power, for dietary recommendations on the prevention of bladder cancer.
Konzo is an irreversible paralysis of the legs that occurs mainly in children and young women associated with large cyanide intake from bitter cassava coupled with malnutrition. In East Africa outbreaks occur during drought, when cassava plants produce much more cyanogens than normal. A wetting method that removes cyanogens from cassava flour was taught to the women of three konzo villages in Mozambique, to prevent sporadic konzo and konzo outbreaks in the next drought. The intervention was in three villages with 72 konzo cases and mean konzo prevalence of 1.2%. The percentage of children with high (>350 μmol/L) urinary thiocyanate content and at risk of contracting konzo in Cava, Acordos de Lusaka, and Mujocojo reduced from 52, 10, and 6 at baseline to 17, 0, and 4 at conclusion of the intervention. Cassava flour showed large reductions in total cyanide over the intervention. The percentage of households using the wetting method was 30-40% in Acordos de Lusaka and Mujocojo and less in Cava. If the wetting method is used extensively by households during drought it should prevent konzo outbreaks and chronic cyanide intoxication. We recommend that the wetting method be taught in all konzo areas in East Africa.
Adjuvant chemotherapy (ACT) can reduce the risk of recurrence and improve survival after surgical resection in non-small cell lung cancer (NSCLC) patients. We explore the optimal time from surgery to initiation of ACT in Chinese patients with stage IIIA NSCLC.
Patients pathologically diagnosed with IIIA NSCLC who underwent radical surgery were included in this study. The cut-off point of time to initiation of adjuvant chemotherapy (TTAC) was determined by maximally selected log-rank statistics. Patients were divided into two groups according to the TTAC cut-off point. Propensity score matching (PSM) was used to eliminate confounding variables, and Kaplan-Meier analysis was used to analyze the impact of TTAC on disease-free survival (DFS).
The cut-off time was 46 days from surgery to the first ACT. Prior to PSM, baseline characteristic variables were balanced with no statistical difference between the groups, except for pathologic subtype and smoking history. No difference in DFS was found between the two groups prior to PSM (P = 0.529); after PSM, the median DFS was consistent between the two (P = 0.822). N2 lymph node station involvement was an independent factor associated with poor survival compared with patients with N0 lymph node involvement. Moderate differentiation and postoperative radiotherapy could improve survival; however, TTAC was not significantly correlated with DFS. Subgroup analyses showed no significant correlation between DFS and different TTAC programs.
No survival difference was obtained as to when ACT was initiated for patients with stage IIIA NSCLC.
Mentally ill prisoners, when requiring admission in a psychiatric facility, have to be admitted only by a reception order of a judicial magistrate and convicts by warrants issued by the Government to jail superintendents and the superintendent of the hospital. Both can be only under Section 27 of The Mental Health Act, 1987.
A study of the contents of reception order and warrants regarding the acts and section under which they were issued over 1 year period for the admission of the patients in the criminal ward of the Institute of Mental Health was carried out.
Only three reception orders quoted Section 27 out of 54 patients admitted under a reception order. Nineteen patients were admitted by the jail superintendents.
Various issues that were found in the reception order and their consequences are discussed, and a possible response to these issues is mooted.
Almost none of the reception orders were found to be proper. This deficit needs to be rectified by sensitizing the various authorities.
Do changes in the expression of bone morphogenetic proteins (BMPs) 2 and 4, and their antagonists Gremlin1 (GREM1) and Gremlin2 (GREM2) during human fetal ovarian development impact on BMP pathway activity and lead to changes in gene expression that may influence the fate and/or function of ovarian somatic cells?
BMPs 2 and 4 differentially regulate gene expression in cultured human fetal ovarian somatic cells. Expression of some, but not all BMP target genes is antagonised by GREM1 and GREM2, indicating the existence of a mechanism to fine-tune BMP signal intensity in the ovary. Leucine-rich repeat-containing G-protein coupled receptor 5 (LGR5), a marker of immature ovarian somatic cells, is identified as a novel transcriptional target of BMP4.
Extensive re-organisation of the germ and somatic cell populations in the feto-neonatal ovary culminates in the formation of primordial follicles, which provide the basis for a female's future fertility. BMP growth factors play important roles at many stages of ovarian development and function. GREM1, an extracellular antagonist of BMP signalling, regulates the timing of primordial follicle formation in the mouse ovary, and mRNA levels of BMP4 decrease while those of BMP2 increase prior to follicle formation in the human fetal ovary.
Expression of genes encoding BMP pathway components, BMP antagonists and markers of ovarian somatic cells were determined by quantitative (q)RT-PCR in human fetal ovaries (from 8 to 21 weeks gestation) and fetal ovary-derived somatic cell cultures. Ovarian expression of GREM1 protein was confirmed by immunoblotting. Primary human fetal ovarian somatic cell cultures were derived from disaggregated ovaries by differential adhesion and cultured in the presence of recombinant human BMP2 or BMP4, with or without the addition of GREM1 or GREM2.
We demonstrate that the expression of BMP antagonists GREM1, GREM2 and CHRD  increases in the lead-up to primordial follicle formation in the human fetal ovary, and that the BMP pathway is active in cultured ovarian somatic cells. This leads to differential changes in the expression of a number of genes, some of which are further modulated by GREM1 and/or GREM2. The positive transcriptional regulation of LGR5 (a marker of less differentiated somatic cells) by BMP4 in vitro suggests that increasing levels of GREM1 and reduced levels of BMP4 as the ovary develops in vivo may act to reduce LGR5 levels and allow pre-granulosa cell differentiation.
While we have demonstrated that markers of different somatic cell types are expressed in the cultured ovarian somatic cells, their proportions may not represent the same cells in the intact ovary which also contains germ cells.
This study extends previous work identifying germ cells as targets of ovarian BMP signalling, and suggests BMPs may regulate the development of both germ and somatic cells in the developing ovary around the time of follicle formation.
Not applicable.
This work was supported by The UK Medical Research Council (Grant No.: G1100357 to RAA), and Medical Research Scotland (Grant No. 345FRG to AJC). The authors have no competing interests to declare.
Microfluidics technology offers us an opportunity to model the biophysical and biochemical environments encountered by sperm moving through the female reproductive tract and, at the same time, to study sperm swimming dynamics at a quantitative level. In humans,
 coitus results in the deposition of sperm in the vagina at the entrance to the cervix. Consequently, sperm must swim or be drawn through the cervix, uterus, uterotubal junction and oviductal isthmus to reach the oocyte in the oviductal ampulla. Only a very small percentage of inseminated sperm reach the ampulla in the periovulatory period, indicating that strong selection pressures act on sperm during migration. A better understanding of how sperm interact with the female tract would inspire improvements in diagnosis of fertility problems and development of novel-assisted reproductive technologies that minimize damage to sperm and mimic natural selection pressures on sperm.
The short chain fatty acid receptor FFA2 is able to stimulate signaling via both Gi- and Gq/G11-promoted pathways. These pathways are believed to control distinct physiological end points but FFA2 receptor ligands appropriate to test this hypothesis have been lacking. Herein, we characterize AZ1729, a novel FFA2 regulator that acts as a direct allosteric agonist and as a positive allosteric modulator, increasing the activity of the endogenously produced short chain fatty acid propionate in Gi-mediated pathways, but not at those transduced by Gq/G11 Using AZ1729 in combination with direct inhibitors of Gi and Gq/G11 family G proteins demonstrated that although both arms contribute to propionate-mediated regulation of phospho-ERK1/2 MAP kinase signaling in FFA2-expressing 293 cells, the Gq/G11-mediated pathway is predominant. We extend these studies by employing AZ1729 to dissect physiological FFA2 signaling pathways. The capacity of AZ1729 to act at FFA2 receptors to inhibit β-adrenoreceptor agonist-promoted lipolysis in primary mouse adipocytes and to promote chemotaxis of isolated human neutrophils confirmed these as FFA2 processes mediated by Gi signaling, whereas, in concert with blockade by the Gq/G11 inhibitor FR900359, the inability of AZ1729 to mimic or regulate propionate-mediated release of GLP-1 from mouse colonic preparations defined this physiological response as an end point transduced via activation of Gq/G11.
There are many reports on long persistent phosphors (LPPs) applied in bioimaging. However, there are few reports on LPPs applied in photothermal therapy (PTT), and an integrated system with multiple functions of diagnosis and therapy. In this work, we fabricate effective multifunctional phosphors Zn3 Ga2 SnO8 : Cr(3+) , Nd(3+) , Gd(3+) with NIR persistent phosphorescence, photothermal response and magnetism. Such featured materials can act as NIR optical biolabels and magnetic resonance imaging (MRI) contrast agents for tracking the early cancer cells, but also as photothermal therapeutic agent for killing the cancer cells. This new multifunctional biomaterial is expected to open a new possibility of setting up an advanced imaging-guided therapy system featuring a high resolution for bioimaging and low side effects for the photothermal ablation of tumors.
Given their association with cardiovascular disease protection, there has been intense interest in understanding the biology of high density lipoproteins (HDL). HDL is actually a family of diverse particle types, each made up of discrete - but as yet undetermined - combinations of proteins drawn from up to 95 lipophilic plasma proteins. The abundant apolipoproteins (apo) of the A class (apoA-I, apoA-II and apoA-IV) have been proposed to act as organizing platforms for auxiliary proteins, but this concept has not been systematically evaluated. We assessed the impact of genetic knock down of each platform protein on the particle size distribution of auxiliary HDL proteins. Loss of apoA-I or apoA-II massively reduced HDL lipids and changed the plasma size pattern and/or abundance of several plasma proteins. Surprisingly though, many HDL proteins were not affected, suggesting they assemble on lipid particles in the absence of apoA-I or apoA-II. In contrast, apoA-IV ablation had minor effects on plasma lipids and proteins, suggesting that it forms particles that largely exclude other apolipoproteins. Overall, the data indicate that distinct HDL subpopulations exist that do not contain, nor depend on, apoA-I, apoA-II or apoA-IV and these contribute substantially to the proteomic diversity of HDL.
Plasma levels of high density lipoproteins (HDL) are inversely correlated with cardiovascular disease. These particles are becoming known as highly heterogeneous entities that have diverse compositions and functions that may impact disease. Unfortunately, we know little about the forces that maintain the composition of each particle in plasma. It has been suggested that certain 'scaffold' proteins, such as apolipoprotein (apo) A-I, apoA-II and apoA-IV, may act as organizing centers for the docking of myriad accessory proteins. To test this hypothesis, we took advantage of the genetic tractability of the mouse model and ablated these three proteins individually. We then tracked the abundance and size profile of the remaining HDL proteins by gel filtration chromatography combined with mass spectrometry. The results clearly show that certain cohorts of proteins depend on each scaffold molecule to assemble normal sized HDL particles under wild-type conditions. This work forms the basis for more detailed studies that will define the specific compositions of HDL subspecies with the possibility of connecting them to specific functions or roles in disease.
The measurement of intracellular ion concentrations, and the screening of chemical agents to identify molecules targeting ion transport, has traditionally involved low-throughput techniques. Here we present a novel HPLC method that allows the rapid, high-sensitivity measurement of cell Na(+) and K(+) content, demonstrating its utility by monitoring the ionic changes induced in the intracellular malaria parasite by the new spiroindolone antimalarial KAE609.
Numerous compounds containing urea bridge and biurea moieties are used in a variety of fields, especially as drugs and pesticides. To search for novel, environmentally benign and ecologically safe pesticides with unique modes of action, four series of novel triazone analogues containing urea, thiourea, biurea, and thiobiurea bridge, respectively, were designed and synthesized, according to various calcium ion channel inhibitors which act on transient receptor potential protein. Their structures were characterized by [Formula: see text] NMR, [Formula: see text] NMR, and HRMS. The insecticidal activities of the new compounds were obtained. The bioassay results indicated that compounds containing a thiourea bridge and a thiobiurea bridge exhibited excellent insecticidal activities against bean aphid. Specifically, compounds [Formula: see text], [Formula: see text], and [Formula: see text] exhibited 85, 90, and 95 % activities, respectively, at 10 mg/kg. Compounds [Formula: see text] (30 %), [Formula: see text] (35 %), [Formula: see text] (30 %), and [Formula: see text] (40 %) exhibited the approximate aphicidal activity of pymetrozine (30 %) at 5 mg/kg. In addition, some target compounds exhibited insecticidal activities against lepidopteran pests. From a molecular design standpoint, the information obtained in this study could help in the further design of new derivatives with improved insecticidal activities.
To account for tobacco users' excess health care costs and encourage cessation, the Affordable Care Act (ACA) allowed insurers to impose a surcharge on tobacco users' premiums for plans offered on the health insurance exchanges, or Marketplaces. Low-income tax credits for Marketplace coverage were based on premiums for non-tobacco users, which means that these credits did not offset any surcharge costs. Thus, this policy greatly increased out-of-pocket premiums for many tobacco users. Using data for 2011-14 from the Behavioral Risk Factor Surveillance System, we examined the effect of tobacco surcharges on insurance status and smoking cessation in the first year of the exchanges' implementation, among adults most likely to purchase insurance from them. Relative to smokers who faced no surcharges, smokers facing medium or high surcharges had significantly reduced coverage (reductions of 4.3 percentage points and 11.6 percentage points, respectively), but no significant differences in smoking cessation. In contrast, those facing low surcharges showed significantly less smoking cessation. Taken together, these findings suggest that tobacco surcharges conflicted with a major goal of the ACA-increased financial protection-without increasing smoking cessation. States should consider these potential effects when deciding whether to limit surcharges to less than the federal maximum.
Under the Affordable Care Act, if one family member has an employer offer of single coverage deemed to be affordable-that is, costing less than 9.66 percent of family income in 2016-then all family members are ineligible for tax credits for Marketplace coverage, even if the cost of providing coverage to the whole family is greater than 9.66 percent of income. More than six million people live in such families and as a result are ineligible for premium tax credits. These families face premiums that can amount to 15.8 percent of income, or 12.0 percent after the tax advantages of employer-sponsored health coverage are factored in. We modeled the potential impact of changing the affordability test to take into account the cost of family coverage. Doing so would reduce spending on premiums from 12.0 percent to 6.3 percent of income, significantly alleviating financial burdens, but would generate little additional coverage. We estimated the additional costs to the federal government for premium tax credits and cost-sharing reductions to be between $3.7 billion and $6.5 billion in 2016.
The adequacy of provider networks
 for plans sold through insurance Marketplaces established under the Affordable Care Act has received much scrutiny recently. Various studies have established that networks are generally narrow. To learn more about network adequacy and access to care, we investigated two questions. First, no matter the nominal size of a network, can patients gain access to primary care services from providers of their choice in a timely manner? Second, how does access compare to plans sold outside insurance Marketplaces? We conducted a "secret shopper" survey of 743 primary care providers from five of California's nineteen insurance Marketplace pricing regions in the summer of 2015. Our findings indicate that obtaining access to primary care providers was generally equally challenging both inside and outside insurance Marketplaces. In less than 30 percent of cases were consumers able to schedule an appointment with an initially selected physician provider. Information about provider networks was often inaccurate. Problems accessing services for patients with acute conditions were particularly troubling. Effectively addressing issues of network adequacy requires more accurate provider information.
Dysregulation of RNA polymerase I (Pol I)-dependent ribosomal DNA (rDNA) transcription is a consistent feature of malignant transformation that can be targeted to treat cancer. Understanding how rDNA transcription is coupled to the availability of growth factors and nutrients will provide insight into how ribosome biogenesis is maintained in a tumour environment characterised by limiting nutrients. We demonstrate that modulation of rDNA transcription initiation, elongation and rRNA processing is an immediate, co-regulated response to altered amino acid abundance, dependent on both mTORC1 activation of S6K1 and MYC activity. Growth factors regulate rDNA transcription initiation while amino acids modulate growth factor-dependent rDNA transcription by primarily regulating S6K1-dependent rDNA transcription elongation and processing. Thus, we show for the first time amino acids regulate rRNA synthesis by a distinct, post-initiation mechanism, providing a novel model for integrated control of ribosome biogenesis that has implications for understanding how this process is dysregulated in cancer.
Different from so far reported oxacalix[4]crown-based host-guest motifs in which oxacalix[4]crowns act only as hydrogen bond acceptors, a [2]pseudorotaxane-type tetranitro-oxacalix[4]crown/urea host-guest recognition motif was developed in which tetranitro-oxacalix[4]crown played a role as both a hydrogen bond donor and an acceptor to stabilize the resulting supramolecular complex. Furthermore, on the basis of a [2]pseudorotaxane complex formed from a tetranitro-oxacalix[4]crown and an axle containing a secondary ammonium ion and a urea group, a [2]rotaxane-based molecular switch was created, in which the oxacalix[4]crown wheel was able to reversibly translocate between the secondary ammonium binding site and the urea binding site of the axle under acid-base stimulation.
HIV-1 maturation inhibitors are a novel class of antiretroviral compounds that consist of two structurally distinct chemical classes: betulinic acid derivatives and the pyridone-based compound PF-46396. It is currently believed that both classes act by similar modes of action to generate aberrant noninfectious particles via inhibition of CA-SP1 cleavage during Gag proteolytic processing. In this study, we utilized a series of novel analogues with decreasing similarity to PF-46396 to determine the chemical groups within PF-46396 that contribute to antiviral activity, Gag binding, and the relationship between these essential properties. A spectrum of antiviral activity (active, intermediate, and inactive) was observed across the analogue series with respect to CA-SP1 cleavage and HIV-1 (NL4-3) replication kinetics in Jurkat T cells. We demonstrate that selected inactive analogues are incorporated into wild-type (WT) immature particles and that one inactive analogue is capable of interfering with PF-46396 inhibition of CA-SP1 cleavage. Mutations that confer PF-46396 resistance can impose a defective phenotype on HIV-1 that can be rescued in a compound-dependent manner. Some inactive analogues retained the capacity to rescue PF-46396-dependent mutants (SP1-A3V, SP1-A3T, and CA-P157S), implying that they can also interact with mutant Gag. The structure-activity relationships observed in this study demonstrate that (i) the tert-butyl group is essential for antiviral activity but is not an absolute requirement for Gag binding, (ii) the trifluoromethyl group is optimal but not essential for antiviral activity, and (iii) the 2-aminoindan group is important for antiviral activity and Gag binding but is not essential, as its replacement is tolerated.
Combinations of antiretroviral drugs successfully treat HIV/AIDS patients; however, drug resistance problems make the development of new mechanistic drug classes an ongoing priority. HIV-1 maturation inhibitors are novel as they target the Gag protein, specifically by inhibiting CA-SP1 proteolytic cleavage. The lack of high-resolution structural information of the CA-SP1 target in Gag has hindered our understanding of the inhibitor-binding pocket and maturation inhibitor mode of action. Therefore, we utilized analogues of the maturation inhibitor PF-46396 as chemical tools to determine the chemical components of PF-46396 that contribute to antiviral activity and Gag binding and the relationship between these essential properties. This is the first study to report structure-activity relationships of the maturation inhibitor PF-46396. PF-46396 is chemically distinct from betulinic acid-derived maturation inhibitors; therefore, our data provide a foundation of knowledge that will aid our understanding of how structurally distinct maturation inhibitors act by similar modes of action.
The presence of nitrogen inhibits legume nodule formation, but the mechanism of this inhibition is poorly understood. We found that 2.5 mM nitrate and above significantly inhibited nodule initiation but not root hair curling in Medicago trunatula. We analyzed protein abundance in M. truncatula roots after treatment with either 0 or 2.5 mM nitrate in the presence or absence of its symbiont Sinorhizobium meliloti after 1, 2 and 5 days following inoculation. Two-dimensional gel electrophoresis combined with mass spectrometry was used to identify 106 differentially accumulated proteins responding to nitrate addition, inoculation or time point. While flavonoid-related proteins were less abundant in the presence of nitrate, addition of Nod gene-inducing flavonoids to the Sinorhizobium culture did not rescue nodulation. Accumulation of auxin in response to rhizobia, which is also controlled by flavonoids, still occurred in the presence of nitrate, but did not localize to a nodule initiation site. Several of the changes included defense- and redox-related proteins, and visualization of reactive oxygen species indicated that their induction in root hairs following Sinorhizobium inoculation was inhibited by nitrate. In summary, the presence of nitrate appears to inhibit nodulation via multiple pathways, including changes to flavonoid metabolism, defense responses and redox changes.
Recent evidence suggest that a β-glucan derived from mushroom Schizophyllan(SPG) complexed with a humanized TLR9 agonistic CpG DNA, K3 (K3-SPG) is a promising vaccine adjuvant that induces robust CD8 T cell responses to co-administered antigen. However, it has not been investigated whether K3-SPG alone can act as an anti-cancer immunotherapeutic agent or not. Here, we demonstrate that intravenous injection of K3-SPG, but not CpG alone, is accumulated in the tumor microenvironment and triggered immunogenic cell death (ICD) of tumor cells by local induction of type-I interferon (IFN) as well as IL-12. Resultant innate immune activation as well as subsequent tumor-specific CD8 T cell responses were contributed the tumor growth suppression. This anti-tumor effect of K3-SPG monotherapy was also confirmed by using various tumor models including pancreatic cancer peritoneal dissemination model. Taken together, nano-particulate TLR9 agonist injected intravenously can scout out tumor microenvironment to provoke local innate immune activation and release dead tumor cells into circulation that may induce broader and protective tumor antigen-specific CD8 T cells.
Purkinje cell protein (PCP) 4/peptide (PEP) 19 is expressed in Purkinje cells where it has a calmodulin-binding, anti-apoptotic function. We recently demonstrated that PCP4/PEP19 is expressed and inhibit apoptosis in human breast cancer cell lines. In the present study we investigated the role of PCP4/PEP19 in cell morphology, adhesion, migration, and invasion in MCF-7 and T47D human breast cancer cell lines. Knockdown of PCP4/PEP19 reduced the formation of filopodia-like cytoplasmic structures and vinculin expression, and enhanced E-cadherin expression. Activities of migration, invasion, and cell adhesion were also decreased after the knockdown of PCP4/PEP19 in MCF-7 and T47D cells. These results suggested that PCP4/PEP19 promotes cancer cell adhesion, migration, and invasion and that PCP4/PEP19 may be a potential target for therapeutic agents in breast cancer treatment which act by inhibiting epithelial-mesenchymal transition and enhancing apoptotic cell death.
We report a very simple method for the self-assembly of spherical gold nanoparticles (AuNPs), coated with poly(ethylene glycol) (PEG), through a slow evaporation process at room temperature. Clusters of particles forming satellite structures may act as seeds for the self-assembly in a crystallization-like process. Based on the transmission electron microscopy (TEM) images obtained a mechanism for the
 self-assembly was suggested.
Initially considered as mere side effects of antipsychotic medication, there is now evidence that motor and somatosensory disturbances precede the onset of the illness and can be found in drug-naive patients. However, research on the topic is scarce. Here, we were interested in assessing the accuracy of the neural signal in detecting parametric variations of force linked to a voluntary motor act and a received tactile sensation, either self-generated or externally generated. Patients with a diagnosis of schizophrenia and healthy controls underwent functional magnetic resonance imaging while asked to press, or abstain from pressing, a lever in order to match a visual target force. Forces, exerted and received, varied on 10 levels from 0.5 N to 5 N in 0.5 N increments. Healthy participants revealed a positive correlation between force and activity in contralateral primary somatosensory area (S1) when performing a movement as well as when receiving a tactile sensation but only when this was externally, and not self-, generated. Patients showed evidence of altered force signaling in both motor and tactile conditions, as well as increased correlation with force when tactile sensation was self-generated. Findings are interpreted in line with accounts of predictive and sensory integration mechanisms and point toward alterations in the encoding of parametric forces in the motor and somatosensory domain in patients affected by schizophrenia.
Three-dimensional organic-inorganic perovskites have emerged as one of the most promising thin-film solar cell materials owing to their remarkable photophysical properties, which have led to power conversion efficiencies exceeding 20 per cent, with the prospect of further improvements towards the Shockley-Queisser limit for a single‐junction solar cell (33.5 per cent). Besides efficiency, another critical factor for photovoltaics and other optoelectronic applications is environmental stability and photostability under operating conditions. In contrast to their three-dimensional counterparts, Ruddlesden-Popper phases--layered two-dimensional perovskite films--have shown promising stability, but poor efficiency at only 4.73 per cent. This relatively poor efficiency is attributed to the inhibition of out-of-plane charge transport by the organic cations, which act like insulating spacing layers between the conducting inorganic slabs. Here we overcome this issue in layered perovskites by producing thin films of near-single-crystalline quality, in which the crystallographic planes of the inorganic perovskite component have a strongly preferential out-of-plane alignment with respect to the contacts in planar solar cells to facilitate efficient charge transport. We report a photovoltaic efficiency of 12.52 per cent with no hysteresis, and the devices exhibit greatly improved stability in comparison to their three-dimensional counterparts when subjected to light, humidity and heat stress tests. Unencapsulated two-dimensional perovskite devices retain over 60 per cent of their efficiency for over 2,250 hours under constant, standard (AM1.5G) illumination, and exhibit greater tolerance to 65 per cent relative humidity than do three-dimensional equivalents. When the devices are encapsulated, the layered devices do not show any degradation under constant AM1.5G illumination or humidity. We anticipate that these results will lead to the growth of single-crystalline, solution-processed, layered, hybrid, perovskite thin films, which are essential for high-performance opto-electronic devices with technologically relevant long-term stability.
Environmental rhythms potently drive predictive resource allocation in time, typically leading to perceptual and motor benefits for on-beat, relative to off-beat, times, even if the rhythmic stream is not intentionally used. In two human EEG experiments, we investigated the behavioral and electrophysiological expressions of using rhythms to direct resources away from on-beat times. This allowed us to distinguish goal-directed attention from the automatic capture of attention by rhythms. The following three conditions were compared: (1) a rhythmic stream with targets appearing frequently at a fixed off-beat position; (2) a rhythmic stream with targets appearing frequently at on-beat times; and (3) a nonrhythmic stream with matched target intervals. Shifting resources away from on-beat times was expressed in the slowing of responses to on-beat targets, but not in the facilitation of off-beat targets. The shifting of resources was accompanied by anticipatory adjustment of the contingent negative variation (CNV) buildup toward the expected off-beat time. In the second experiment, off-beat times were jittered, resulting in a similar CNV adjustment and also in preparatory amplitude reduction of beta-band activity. Thus, the CNV and beta activity track the relevance of time points and not the rhythm, given sufficient incentive. Furthermore, the effects of task relevance (appearing in a task-relevant vs irrelevant time) and rhythm (appearing on beat vs off beat) had additive behavioral effects and also dissociable neural manifestations in target-evoked activity: rhythm affected the target response as early as the P1 component, while relevance affected only the later N2 and P3. Thus, these two factors operate by distinct mechanisms.
Rhythmic streams are widespread in our environment, and are typically conceptualized as automatic, bottom-up resource attractors to on-beat times-preparatory neural activity peaks at rhythm-on-beat times and behavioral benefits are seen to on-beat compared with off-beat targets. We show that this behavioral benefit is reversed when targets are more frequent at off-beat compared with on-beat times, and that preparatory neural activity, previously thought to be driven by the rhythm to on-beat times, is adjusted toward off-beat times. Furthermore, the effect of this relevance-based shifting on target-evoked brain activity was dissociable from the automatic effect of rhythms. Thus, rhythms can act as cues for flexible resource allocation according to the goal relevance of each time point, instead of being obligatory resource attractors.
The aim of this article is to show current knowledge concerning valuable substances biologically active present in hen eggs and underline important nutritive role of hen eggs. Hen egg is a good source of nutrients such as proteins, vitamins (A, B2, B6, B12, D, E, K), minerals and lipids. The significant part of lipids is a group of unsaturated phospholipids, which are components of cell membranes, act protectively on the cardiovascular system and contribute to a decrease of cholesterol level and blood pressure. Therefore, the consumption of unsaturated phospholipids is recommended especially in patients suffering from diseases of the cardiovascular system. Another important substance is egg cystatin, which has a wide spectrum of biological functions, for example the ability to stimulate cell growth, inhibit inflammatory processes and has antibacterial and antiviral properties. Other substance presented in the egg white which helps fight bacteria is lysozyme. It is used in medicine as an aid in antibiotic therapy and analgesic in the course of infection, as well as in tumor malignancies. Among the components contained in the egg yolk there is also immunoglobulin Y which due to its therapeutic importance deserves special attention. Its use offers the possibility of replacing chemotherapeutic agents in the treatment of bacterial infections of digestive system, as well as an opportunity for the development of medicine associated with passive immunization of patients. The egg is a rich source of retinol which gradual depletion in the organism causes many eye pathologies. A very important and useful part of the egg, used in medicine is a shell and its membranes, due to the high collagen content relevant in the treatment of connective tissue diseases.
To explore the association between workplace bullying and workplace environment factors among nurses in Japan.
Workplace bullying among nurses is increasing globally and occurs more frequently than among other professions. However, there is little information on the impact of workplace environment factors on nurse bullying in Japan.
A cross-sectional survey using a self-administered questionnaire.
Participants were 1152 nurses recruited at seminars or training courses outside of their workplaces in Tokyo. Workplace bullying was measured using the Negative Acts Questionnaire-Revised. Participants were considered to have been 'bullied' if they reported experiencing at least one negative act on a daily or weekly basis. Workplace environment factors were measured using the Practice Environment Scale of the Nursing Work Index, which comprises five domains: nurse participation in hospital affairs; nursing foundations for quality of care; nurse manager ability, leadership and support of nurses; staffing and resource adequacy; and collegial nurse-physician relationships.
A total of 898 (78·0%) questionnaires were returned, of which 825 (71·6%) were analysed. Altogether, 153 (18·5%) nurses were considered 'bullied.' The three most frequent negative acts reported as occurring on a weekly or daily basis were 'someone withholding information which affects your performance' (6·7%), 'being exposed to an unmanageable workload' (4·4%) and 'being shouted at or being the target of spontaneous anger (or rage)' (3·6%). Logistic regression analysis indicated that 'bullied' were associated with low scores on two work environment domains: nurse manager ability, leadership and support of nurses and staffing and resource adequacy.
Effective nurse manager leadership and support as well as appropriate staffing management may positively influence workplace bullying among nurses
 in Japan. Authentic leadership styles and allowing nurses to easily request days off might also be important.
Nurse managers' leadership may influence nurses' workplace bullying.
To compare the impact of malaria rapid diagnostic tests (mRDTs), used by community health workers (CHWs), on the proportion of children <5 years of age receiving appropriately targeted treatment with artemisinin-based combination therapy (ACT), vs. presumptive treatment.
Cluster-randomized trials were conducted in two contrasting areas of moderate-to-high and low malaria transmission in rural Uganda. Each trial examined the effectiveness of mRDTs in the management of malaria and targeting of ACTs by CHWs comparing two diagnostic approaches: (i) presumptive clinical diagnosis of malaria [control arm] and (ii) confirmatory diagnosis with mRDTs followed by ACT treatment for positive patients [intervention arm], with village as the unit of randomisation. Treatment decisions by CHWs were validated by microscopy on a reference blood slide collected at the time of consultation, to compare the proportion of children <5 years receiving appropriately targeted ACT treatment, defined as patients with microscopically-confirmed presence of parasites in a peripheral blood smear receiving artemether-lumefantrine or rectal artesunate, and patients with no malaria parasites not given ACT.
In the moderate-to-high transmission area, ACT treatment was appropriately targeted in 79.3% (520/656) of children seen by CHWs using mRDTs to diagnose malaria, vs. 30.8% (215/699) of children seen by CHWs using presumptive diagnosis (P < 0.001). In the low transmission area, 90.1% (363/403) children seen by CHWs using mRDTs received appropriately targeted ACT treatment vs. 7.8% (64/817) seen by CHWs using presumptive diagnosis (P < 0.001). Low mRDT sensitivity in children with low-density parasitaemia (<200 parasites/μl) was identified as a potential concern.
When equipped with mRDTs, ACT treatments delivered by CHWs are more accurately targeted to children with malaria parasites. mRDT use could play an important role in reducing overdiagnosis of malaria and improving fever case management within iCCM, in both moderate-to-high and low transmission areas. Nonetheless, missed treatments due to the low sensitivity of current mRDTs in patients with low parasite density are a concern. For community-based treatment in areas of low transmission and/or non-immune populations, presumptive treatment of all fevers as malaria may be advisable, until more sensitive diagnostic assays, suitable for routine use by CHWs in remote settings, become available.
A direct observation and an in-depth characterization of the steps by which bone mineral nucleates and grows in the extracellular matrix during the earliest stages of maturation, using relevant biomineralization models as they grow into mature bone mineral, is an important research goal. To better understand the process of bone mineralization in the extracellular matrix, we used nanoanalytical electron microscopy techniques to examine an in vitro model of bone formation. This study demonstrates the presence of three dominant CaP structures in the mineralizing osteoblast cultures: <80 nm dense granules with a low calcium to phosphate ratio (Ca/P) and crystalline domains; calcium phosphate needles emanating from a focus: "needle-like globules" (100-300 nm in diameter) and mature mineral, both with statistically higher Ca/P compared to that of the dense granules. Many of the submicron granules and globules were interspersed around fibrillar structures containing nitrogen, which are most likely the signature of the organic phase. With high spatial resolution electron energy loss spectroscopy (EELS) mapping, spatially resolved maps were acquired showing the distribution of carbonate within each mineral structure. The carbonate was located in the middle of the granules, which suggested the nucleation of the younger mineral starts with a carbonate-containing precursor and that this precursor may act as seed for growth into larger, submicron-sized, needle-like globules of hydroxyapatite with a different stoichiometry. Application of analytical electron microscopy has important implications in deciphering both how normal bone forms and in understanding pathological mineralization.
Several strategies have been adopted to design an artificial light-harvesting system in which light energy is captured by peripheral chromophores and it is subsequently transferred to the core via energy transfer. A composite of carbon dots and dye-encapsulated BSA-protein-capped gold nanoclusters (AuNCs) has been developed for efficient light harvesting and white light generation. Carbon dots (C-dots) act as donor and AuNCs capped with BSA protein act as acceptor. Analysis reveals that energy transfer increases from 63 % to 83 % in presence of coumarin dye (C153), which enhances the cascade energy transfer from carbon dots to AuNCs. Bright white light emission with a quantum yield of 19 % under the 375 nm excitation wavelength is achieved by changing the ratio of components. Interesting findings reveal that the efficient energy transfer in carbon-dot-metal-cluster nanocomposites may open up new possibilities in designing artificial light harvesting systems for future applications.
Cation/proton antiporter 1 (CPA1) genes encode cellular Na(+) /H(+) exchanger proteins, which act to adjust ionic balance. Overexpression of CPA1s can improve plant performance under salt stress. However, the diversified roles of the CPA1 family and the various parameters used in evaluating transgenic plants over-expressing CPA1s make it challenging to assess the complex functions of CPA1s and their physiological mechanisms in salt tolerance. Using meta-analysis, we determined how overexpression of CPA1s has influenced several plant characteristics involved in response and resilience to NaCl stress. We also evaluated experimental variables that favour or reduce CPA1 effects in transgenic plants. Viewed across studies, overexpression of CPA1s has increased the magnitude of 10 of the 19 plant characteristics examined, by 25% or more. Among the ten moderating variables, several had substantial impacts on the extent of CPA1 influence: type of culture media, donor and recipient type and genus, and gene family. Genes from monocotyledonous plants stimulated root K(+) , root K(+) /Na(+) , total chlorophyll, total dry weight and root length much more than genes from dicotyledonous species. Genes transformed to or from Arabidopsis have led to smaller CPA1-induced increases in plant characteristics than genes transferred to or from other genera. Heterogeneous expression of CPA1s led to greater increases in leaf chlorophyll and root length than homologous expression. These findings should help guide future investigations into the function of CPA1s in plant salt tolerance and the use of genetic engineering for breeding of resistance.
Nickel allergy is the most frequent contact allergy in the industrialized country. In allergic contact dermatitis after the presentation of haptenated peptides by resident or newly recruited skin cells, activated CD8+ T cells release IFN-γ and TNF-α, these cytokines are potent activator of keratinocytes. The role of specific cytokines in nickel allergy is not yet fully elucidated. The adenine nucleotide at position -308 in the promoter region of the TNFA gene is associated with an increased production of TNF-α, that is a potent activator of keratinocytes.
To evaluate the expression of TNF-α polymorphism in patients with allergic contact dermatitis and in healthy people, 41 patients with allergic contact dermatitis to nickel and 40 healthy controls were enrolled. A total of 81 subjects (41 cases and 40 controls) underwent genotyping for the 308 genetic polymorphism in the TNFA gene.
The distribution of TNF genotypes TNF-α 308 G/A polymorphism in cases didn't differ significantly in the controls group. The genotype GA was present in the 75% of the patients with polysensitization. In one patient was observed the rare genotype A/A.
The carriage of the TNFA-308 A/A and GA genotype may act as a marker of enhanced susceptibility to contact polysensitization, indicating that TNF-α is a key regulator of the initiation of delayed-type hypersensitivity reactions, the polymorphism seems to be not enough for the development of nickel monosensitization.
Mammary epithelium is comprised of an inner layer of luminal epithelial cells and an outer layer of contractile myoepithelial cells with mesenchymal properties. These two compartments interact throughout mammary morphogenesis to form branching ducts during puberty and terminate in secretory alveoli during lactation. It is not known how the myoepithelial cell lineage is specified, nor how signals in myoepithelial cells contribute to lactogenesis. Here, we show that Numb and Numbl are enriched in mammary myoepithelial cells, with their expression peaking during pregnancy. We use conditional Numb- and Numbl-knockout mouse models to demonstrate that loss of Numb/Numbl compromised the myoepithelial layer and expanded the luminal layer, led epithelial cells to undergo epithelial-to-mesenchymal transition, and resulted in lactation failure as a result of abnormal alveolar formation during pregnancy. Numb and Numbl function via repression of the Notch signaling pathway and of the p53-p21 axis during mammary gland development. These findings highlight the importance of Numb and Numbl in the control of myoepithelial cell fate determination, epithelial identity, and lactogenesis.-Zhang Y., Li, F., Song, Y., Sheng, X., Ren, F., Xiong, K., Chen, L., Zhang, H., Liu, D., Lengner, C. J., Xue, L., Yu, Z. Numb and Numbl act to determine mammary myoepithelial cell fate, maintain epithelial identity, and support lactogenesis.
Whether infertile women exhibit
 accelerated ovarian aging and whether a low ovarian reserve is overrepresented in infertility populations is not known.
To compare the age-related decline in antral follicle count (AFC), a biomarker of the ovarian reserve, in fertile and infertile women.
Cross-sectional data from a large prospective cohort study conducted from January 2013 to December 2014.
Thirteen fertility centers across Spain.
Consecutive women aged 18 to 45 years of age attending the fertility centers either seeking fertility treatment or as fertile women wishing to act as potential oocyte donors.
Standardized AFC assessment on day 2 to 4 of the cycle.
Age-related decline of AFC for both fertile and infertile women.
A total of 15 500 women, of whom 5722 were potential donors and 9778 were patients seeking fertility treatment, participated in the study. Average AFC was greater in potential oocyte donors than in infertile women (20 [interquartile range, 16-24] vs 10 [interquartile range, 6-15], respectively; P < .001), a difference that was maintained after adjustment for age (P < .001) in a model predicting log(AFC) from donor vs infertility, adjusting for 2-year age bands. The age-related decline in AFC was much steeper in infertile women compared with that of potential oocyte donors, with an increased prevalence of a low ovarian reserve (AFC < 5) at all ages in infertile women.
The age-related decline in AFC was substantially greater in infertility patients than potential oocyte donors. Overrepresentation in infertility populations of women with low ovarian reserve may be an additional functional cause of infertility.
The molecular structures of a number of solvates of the [2 + 2] Schiff-base macrocycles {[2-(OH)-5-(R)-C6H2-1,3-(CH)2][O(2-C6H4N)2]}2 (R = Me L(1)H2, tBu L(2)H2, Cl L(3)H2), formed by reacting 2,6-dicarboxy-4-R-phenol with 2,2'-oxydianiline (2-aminophenylether), (2-NH2C6H4)2O, have been determined. Reaction of L(n)H2 with two equivalents of AlR'3 (R' = Me, Et) afforded dinuclear alkylaluminium complexes [(AlR'2)2L(1-3)] (R = R' = Me (1), R = tBu, R' = Me (2), R = Cl, R' = Me (3), R = Me, R' = Et (4), R = tBu, R' = Et (5), R = Cl, R' = Et (6)). For comparative studies, reactions of two equivalents of AlR'3 (R' = Me, Et) with the macrocycle derived from 2,2'-ethylenedianiline and 2,6-dicarboxy-R-phenols (R = Me L(4)H2, tBu L(5)H2) were conducted; the complexes [(AlMe)(AlMe2)L(5)]·2¼MeCN (7·2¼MeCN) and [(AlEt2)2L(4)] (8) were isolated. Use of limited AlEt3 with L(3)H2 or L(5)H2 afforded mononuclear bis(macrocyclic) complexes [Al(L(3))(L(3)H)]·4toluene (9·4toluene) and [Al(L(5))(L(5)H)]·5MeCN (10·5MeCN), respectively. Use of four equivalents of AlR'3 led to transfer of alkyl groups and isolation of the complexes [(AlR'2)4L(1'-3')] (R = L(2'), R' = Me (11); L(3'), R' = Me (12); L(1'), R' = Et (13); L(2'), R' = Et (14); L(3'), R' = Et (15)), where L(1'-3') is the macrocycle resulting from double alkyl transfer to imine, namely {[2-(O)-5-(R)C6H2-1-(CH)-3-C(R')H][(O)(2-(N)-2'-C6H4N)2]}2. Molecular structures of complexes 7·2¼MeCN, 8, 9·4toluene, 10·5MeCN and 11·1¾toluene·1¼hexane are reported. These complexes act as catalysts for the ring opening polymerisation (ROP) of ε-caprolactone and rac-lactide; high conversions were achieved over 30 min at 80 °C for ε-caprolactone, and 110 °C over 12 h for rac-lactide.
It has been reported that the fragmented QRS (fQRS) is related to left ventricular systolic dysfunction and diastolic dysfunction. The aim of this study was to determine the frequency of fragmented QRS (fQRS) in patients with decompensated cirrhosis and to evaluate the relationship between the presence of fQRS and systolic and diastolic dysfunction.
PThe study included consecutive 189 patients with decompensated cirrhosis. fQRS pattern was described as presence of RSR' manifested as existence of additional R wave and notching in either R or S waves in ECG recordings. Conventional echocardiography and tissue doppler echocardiography were performed in all patients.
The prevalence of fQRS was 31% (59/189) in patients with decompensated cirrhosis. The patients with fQRS had worse diastolic and systolic functions in comparison to the patients without fQRS. In addition, multivariate analysis revealed that the presence of an fQRS, Na levels < 125 mEq/L, the Child-Pugh score and the MELD score were independent predictive factors for mortality (respectively, p < 0.001, p < 0.001, p < 0.001 and p < 0.001).
In conclusion,this study showed a relationship between the presence of an fQRS and cardiac dysfunction. In addition, the fQRS appeared to act as an independent predictor of mortality in patients with decompensated cirrhosis. These data suggest that the fQRS may represent a novel noninvasive marker for cardiac involvement and for predicting mortality in patients with decompensated cirrhosis.
Measuring non-invasive blood pressure (NIBP) in less than one minute intervals (STAT NIBP measurements) is not always feasible. Therefore, large number of undetectable hypotension episodes can only be recognized with continuous beat to beat monitoring of blood pressure, for example, by continuous non-invasive arterial pressure monitor (CNAP).
The purpose of the current study was to investigate whether CNAP correlates well with conventional intermittent oscillometric NIBP during elective cesarean sections under subarachnoid blockade (SAB) and whether CNAP based patient management results in improved immediate maternal vasopressor requirements and improved immediate fetal/neonatal outcomes compared with NIBP based patient management.
The CNAP finger cuff together with the CNAP arm cuff were placed on the same arm which also had the peripheral intravenous access.. On the contralateral arm the conventional NIBP arm cuff was placed. Study Group: The patients were managed by the anesthesia provider based on the CNAP monitor readings. Control Group: The patients were managed by the anesthesia provider based on the NIBP monitor readings. Results: The CNAP-based treatment (study) group had a statistically significant lower use of oxytocin and lower estimated blood loss than the NIBP-based treatment (control) group. The differences in incidences of vasopressors use and peri-operative nausea vomiting between study group and control group did not reach statistical significance. CNAP readings were more likely to be in systolic hypotensive phases (<l00mmHg) and diastolic hypertensive phases (>80mmHg) as compared to NIBP readings.
Continuous non-invasive arterial pressure (CNAP) device may ONLY act as an adjunct to recognize fluctuating blood pressures during elective cesarean section under subarachnoid blockade (SAB).
Since the mid-twentieth century, many species, very different from each other and located in all areas and comers of the planet, began presenting various alterations, many of which suggested to be related to endocrine disorders. Research has shown that such alterations were caused by exposure to various chemical contaminants that could affect the health and cause serious illnesses. Among them stands a diverse and large group of compounds, with very different chemical structures, capable of altering the hormonal balance, act at very low doses and with different mechanisms of action, that are called "endocrine disrupting chemicals". When released into the environment or as part of objects, food or medicines, constitute a major risk to animals and humans, which produces not only endocrine dysfunctions but also different cancers, which include the most common types. Despite the importance and significance of the impact of these compounds, they are not sufficiently known or understood, so the aim of this review is to show their origin and impact in the field of human health, highlighting their role as inducers of cancer, which has led to multiple clinical and biological investigations.
Respirometry is frequently used to estimate metabolic rates and examine organismal responses to environmental change. Although a range of methodologies exists, it remains unclear whether differences in chamber design and exercise (type and duration) produce comparable results within individuals and whether the most appropriate method differs across taxa. We used a repeated-measures design to compare estimates of maximal and standard metabolic rates (MMR and SMR) in four coral reef fish species using the following three methods: (i) prolonged swimming in a traditional swimming respirometer; (ii) short-duration exhaustive chase with air exposure followed by resting respirometry; and (iii) short-duration exhaustive swimming in a circular chamber. We chose species that are steady/prolonged swimmers, using either a body-caudal fin or a median-paired fin swimming mode during routine swimming. Individual MMR estimates differed significantly depending on the method used. Swimming respirometry consistently provided the best (i.e. highest) estimate of MMR in all four species irrespective of swimming mode. Both short-duration protocols (exhaustive chase and swimming in a circular chamber) produced similar MMR estimates, which were up to 38% lower than those obtained during prolonged swimming. Furthermore, underestimates were not consistent across swimming modes or species, indicating that a general correction factor cannot be used. However, SMR estimates (upon recovery from both of the exhausting swimming methods) were consistent across both short-duration methods. Given the increasing use of metabolic data to assess organismal responses to environmental stressors, we recommend carefully considering respirometry protocols before experimentation. Specifically, results should not readily be compared across methods; discrepancies could result in misinterpretation of MMR and aerobic scope.
The incidence of serotonin syndrome is increasing due to the widening use of serotonergic drugs. Identification
 of serotonin syndrome is challenging as the manifestations are diverse. Misdiagnosis can lead to delay in care and inappropriate treatment.
The objectives of this study were to determine if staff of community pharmacies in Australia could identify the symptoms of serotonin syndrome in simulated patients and recommend an appropriate course of action.
Agents acting on behalf of a simulated patient were trained on a patient scenario that reflected possible serotonin syndrome due to an interaction between duloxetine and recently prescribed tramadol. They entered 148 community pharmacies in Australia to ask for advice about a 60 year old male simulated patient who was 'not feeling well'. The interaction was audio recorded and analysed for degree of access to the pharmacist, information gathered by pharmacy staff, management advice given and pharmacotherapy recommended.
The simulated patient's agent was consulted by a pharmacist in 94.0% (139/148) of cases. The potential for serotonin syndrome was identified by 35.1% (52/148) of pharmacies. Other suggested causes of the simulated patient's symptoms were viral (16.9%; 25/148) and cardiac (15.5%; 23/148). A total of 33.8% (50/148) of pharmacies recommended that the simulated patient should cease taking tramadol. This advice always came from the pharmacist. Immediate cessation of tramadol was advised by 94.2% (49/52) of pharmacists correctly identifying serotonin syndrome. The simulated patient was advised to seek urgent medical care in 14.2% (21/148) of cases and follow up with a doctor when possible in 68.2% (101/148) of cases. The majority of pharmacies (87.8%; 130/148) did not recommend non-prescription medicines.
While not identifying the cause of the simulated patient's symptoms in the majority of cases, community pharmacies recommended appropriate action to minimise the health impact of serotonin syndrome by advising to cease tramadol and/or referring to a doctor and not recommending non-prescription medicines to treat symptoms. Raising pharmacists' awareness of the signs and symptoms of serotonin syndrome, and the importance of taking a comprehensive medication history when assessing a set of symptoms, may help community pharmacies further reduce serotonin syndrome toxicity.
Normal human breast tissue consists of epithelial and nonepithelial cells with different molecular profiles and differentiation grades. This molecular heterogeneity is known to yield abnormal clones that may contribute to the development of breast carcinomas. Stem cells that are found in developing and mature breast tissue are either positive or negative for cytokeratin 19 depending on their subtype. These cells are able to generate carcinogenesis along with mature cells. However, scientific data remains controversial regarding the monoclonal or polyclonal origin of breast carcinomas. The majority of breast carcinomas originate from epithelial cells that normally express BRCA1. The consecutive loss of the BRCA1 gene leads to various abnormalities in epithelial cells. Normal breast epithelial cells also express hypoxia inducible factor (HIF) 1α and HIF-2α that are associated with a high metastatic rate and a poor prognosis for malignant lesions. The nuclear expression of estrogen receptor (ER) and progesterone receptor (PR) in normal human breast tissue is maintained in malignant tissue as well. Several controversies regarding the ability of ER and PR status to predict breast cancer outcome remain. Both ER and PR act as modulators of cell activity in normal human breast tissue. Ki-67 positivity is strongly correlated with tumor grade although its specific role in applied therapy requires further studies. Human epidermal growth factor receptor 2 (HER2) oncoprotein is less expressed in normal human breast specimens but is highly expressed in certain malignant lesions of the breast. Unlike HER2, epidermal growth factor receptor expression is similar in both normal and malignant tissues. Molecular heterogeneity is not only found in breast carcinomas but also in normal breast tissue. Therefore, the molecular mapping of normal human breast tissue might represent a key research area to fully elucidate the mechanisms of breast carcinogenesis.
The Home Independence Program (HIP), an Australian restorative home care/reablement service for older adults, has been shown to be effective in reducing functional dependency and increasing functional mobility, confidence in everyday activities, and quality of life. These gains were found to translate into a reduced need for ongoing care services and reduced health and aged care costs over time. Despite these positive outcomes, few Australian home care agencies have adopted the service model - a key reason being that few Australian providers employ health professionals, who act as care managers under the HIP service model. A call for proposals from Health Workforce Australia for projects to expand the scope of practice of health/aged care staff then provided the opportunity to develop, implement, and evaluate a service delivery model, in which nonprofessionals replaced the health professionals as Care Managers in the HIP service. Seventy older people who received the HIP Coordinator (HIPC) service participated in the outcomes evaluation. On a range of personal outcome measures, the group showed statistically significant improvement at 3 and 12 months compared to baseline. On each outcome, the improvement observed was larger than that observed in a previous trial in which the service was delivered by health professionals. However, differences in the timing of data collection between the two studies mean that a direct comparison cannot be made. Clients in both studies showed a similarly reduced need for ongoing home care services at both follow-up points. The outcomes achieved by HIPC, with non-health professionals as Care Managers, were positive and can be considered to compare favorably with the outcomes achieved in HIP when health professionals take the Care Manager role. These findings will be of interest to managers of home care services and to policy makers interested in reducing the long-term care needs of older community dwelling individuals.
Heavy metal pollution is a global public health challenge due to its stable and persistent environmental contamination. Of these lead is considered to be one of the most common ubiquitous and industrial pollutants and at low concentration it exerts extensive damages to the tissues. Daily feeding of lead acetate solution (Dose: 10 mg/kg/day) to normal rats for a month adversely altered the parameters of blood, serum and tissues, viz; RBC, WBC, Hb, ɗ- ALAD (Delta amino levulinic acid dehydratase), Pb content, lipids, oxidized lipids (TBARS), vitamins C and E and GSH levels and activities of AST, ALT and antioxidant enzymes viz; catalase, GR, Gpx and SOD. In order to study whether antioxidants have any effect to counteract the toxicity of lead we have selected comparatively better active allium fractions for the study viz: polar fraction of garlic (PFG) and polar fraction of onion (PFO). On feeding of these active fractions of garlic and onion oils i.e. their polar fractions and vitamin E (Dose 100 mg/kg/day) separately for a month along with or without lead acetate to rats each nutraceutical and vitamin E counteracted the adverse effects of Pb significantly (p ≤ 0.05). Their effects are in the order of PFG > PFO > Vitamin E. All these results point out that garlic and onion oils contain natural disulfoxide compounds which act as antioxidant and anti toxic to lead compounds. Their comparative differences in action may be due to the presence and position of double bonds and disulfide oxide bonds in their molecules. i.e., in PFG the allyl disulfide oxide group is present and in PFO saturated methyl and propyl groups and unsaturated propenyl group are present in place of allyl groups. The former group confers a better antioxidant activity on PFG, while the latter groups confer a lesser activity on PFO.
Transcription factors dynamically bind to chromatin and are essential for the regulation of genes. Although a large percentage of these proteins appear to self-associate to form dimers or higher order oligomers, the stoichiometry of DNA-bound transcription factors has been poorly characterized in vivo. The glucocorticoid receptor (GR) is a ligand-regulated transcription factor widely believed to act as a dimer or a monomer. Using a unique set of imaging techniques coupled with a cell line containing an array of DNA binding elements, we show that GR is predominantly a tetramer when bound to its target DNA. We find that DNA binding triggers an interdomain allosteric regulation within the GR, leading to tetramerization. We therefore propose that dynamic changes in GR stoichiometry represent a previously unidentified level of regulation in steroid receptor activation. Quaternary structure analysis of other members of the steroid receptor family (estrogen, androgen, and progesterone receptors) reveals variation in oligomerization states among this family of transcription factors. Because GR's oligomerization state has been implicated in therapy outcome, our findings open new doors to the rational design of novel GR ligands and redefine the quaternary structure of steroid receptors.
Complex organic molecules such as sugars and amides are ubiquitous in star- and planet-forming regions, but their formation mechanisms have remained largely elusive until now. Here we show in a combined experimental, computational, and astrochemical modeling study that interstellar aldehydes and enols like acetaldehyde (CH3CHO) and vinyl alcohol (C2H3OH) act as key tracers of a cosmic-ray-driven nonequilibrium chemistry leading to complex organics even deep within low-temperature interstellar ices at 10 K. Our findings challenge conventional wisdom and
 define a hitherto poorly characterized reaction class forming complex organic molecules inside interstellar ices before their sublimation in star-forming regions such as SgrB2(N). These processes are of vital importance in initiating a chain of chemical reactions leading eventually to the molecular precursors of biorelevant molecules as planets form in their interstellar nurseries.
The chemistry of hydrogen cyanide (HCN) is believed to be central to the origin of life question. Contradictions between Cassini-Huygens mission measurements of the atmosphere and the surface of Saturn's moon Titan suggest that HCN-based polymers may have formed on the surface from products of atmospheric chemistry. This makes Titan a valuable "natural laboratory" for exploring potential nonterrestrial forms of prebiotic chemistry. We have used theoretical calculations to investigate the chain conformations of polyimine (pI), a polymer identified as one major component of polymerized HCN in laboratory experiments. Thanks to its flexible backbone, the polymer can exist in several different polymorphs, which are relatively close in energy. The electronic and structural variability among them is extraordinary. The band gap changes over a 3-eV range when moving from a planar sheet-like structure to increasingly coiled conformations. The primary photon absorption is predicted to occur in a window of relative transparency in Titan's atmosphere, indicating that pI could be photochemically active and drive chemistry on the surface. The thermodynamics for adding and removing HCN from pI under Titan conditions suggests that such dynamics is plausible, provided that catalysis or photochemistry is available to sufficiently lower reaction barriers. We speculate that the directionality of pI's intermolecular and intramolecular =N-H(…)N hydrogen bonds may drive the formation of partially ordered structures, some of which may synergize with photon absorption and act catalytically. Future detailed studies on proposed mechanisms and the solubility and density of the polymers will aid in the design of future missions to Titan.
Plant responses to drought stress require the regulation of transcriptional networks via drought-responsive transcription factors, which mediate a range of morphological and physiological changes. AP2/ERF transcription factors are known to act as key regulators of drought resistance transcriptional networks; however, little is known about the associated molecular mechanisms that give rise to specific morphological and physiological adaptations. In this study, we functionally characterized the rice (Oryza sativa) drought-responsive AP2/ERF transcription factor OsERF71, which is expressed predominantly in the root meristem, pericycle, and endodermis. Overexpression of OsERF71, either throughout the entire plant or specifically in roots, resulted in a drought resistance phenotype at the vegetative growth stage, indicating that overexpression in roots was sufficient to confer drought resistance. The root-specific overexpression was more effective in conferring drought resistance at the reproductive stage, such that grain yield was increased by 23% to 42% over wild-type plants or whole-body overexpressing transgenic lines under drought conditions. OsERF71 overexpression in roots elevated the expression levels of genes related to cell wall loosening and lignin biosynthetic genes, which correlated with changes in root structure, the formation of enlarged aerenchyma, and high lignification levels. Furthermore, OsERF71 was found to directly bind to the promoter of OsCINNAMOYL-COENZYME A REDUCTASE1, a key gene in lignin biosynthesis. These results indicate that the OsERF71-mediated drought resistance pathway recruits factors involved in cell wall modification to enable root morphological adaptations, thereby providing a mechanism for enhancing drought resistance.
Secreted cysteine-rich peptides (CRPs) represent one of the main classes of signalling peptides in plants. Whereas post-translationally modified small non-CRP peptides (psNCRPs) are mostly involved in signalling events during vegetative development and interactions with the environment, CRPs are overrepresented in reproductive processes including pollen germination and growth, self-incompatibility, gamete activation and fusion as well as seed development. In this opinion paper we compare the involvement of both types of peptides in vegetative and reproductive phases of the plant lifecycle. Besides their conserved cysteine pattern defining structural features, CRPs exhibit hypervariable primary sequences and a rapid evolution rate. As a result, CRPs represent a pool of highly polymorphic signalling peptides involved in species-specific functions during reproduction and thus likely represent key players to trigger speciation in plants by supporting reproductive isolation. In contrast, precursers of psNCRPs are proteolytically processed into small functional domains with high sequence conservation and act in more general processes. We discuss parallels in downstream processes of CRP signalling in both reproduction and defence against pathogenic fungi and alien pollen tubes, with special emphasis on the role of ROS and ion channels. In conclusion we suggest that CRP signalling during reproduction in plants has evolved from ancient defence mechanisms.
Topological insulators (TIs), are novel two-dimension materials, which can act as effective saturable absorbers (SAs) in a fiber laser. Moreover, based on the evanescent wave interaction, deposition of the TI on microfiber would create an effective SA, which has combined advantages from the strong nonlinear optical response in TI material together with the sufficiently-long-range interaction length in fiber taper. By using this type of TI SA, various scalar solitons have been obtained in fiber lasers. However, a single mode fiber always exhibits birefringence, and hence can support two orthogonal degenerate modes. Here we investigate experimentally the vector characters of a TI SA fiber laser. Using the saturated absorption and the high nonlinearity of the TI SA, a rich variety of dynamic states, including polarization-locked dark pulses and their harmonic mode locked counterparts, polarization-locked noise-like pulses and their harmonic mode locked counterparts, incoherently coupled polarization domain wall pulses, including bright square pulses, bright-dark pulse pairs, dark pulses and bright square pulse-dark pulse pairs are all observed with different pump powers and polarization states.
Multiple placement changes disrupt continuity in caregiving and undermine well-being in children in child welfare. This study conducted secondary data analysis of a randomized controlled trial to examine whether a relationship-based intervention, Promoting First Relationships(©) (PFR), reduced risk for a maladaptive cascade from placement instability to less secure attachment to elevated externalizing problems. Participants included caregivers (birth or foster/kin) of toddlers (10-24 months) recently transitioned to their care because of child welfare placement decisions. Although main effects of PFR on security and externalizing problems were not previously observed, this study's results revealed that PFR attenuated the association between multiple placement changes (baseline) and less security (postintervention) and that the indirect effect of placement instability on greater externalizing problems (6-month follow-up) via less security was evident only in toddlers in the comparison condition. These findings shed light on how a history of multiple caregiver changes may influence toddlers' risk for poor adjustment in subsequent placements, and the promise of supporting caregivers through a parenting intervention to prevent such risk.
To report implantation of an iliac branch device (IBD) for preserving antegrade blood flow to a sole internal iliac artery (IIA) via an ipsilateral approach during endovascular repair to reline an aortobi-iliac allograft.
The technique is described in a 55-year-old man with an enteric fistula involving an aortobi-iliac Y-prosthesis. After complete excision, the prosthesis was replaced by an allograft. Due to rebleeding and resuturing of the graft, total stent-graft relining of the allograft was planned with preservation of the sole left IIA using an iliac side branch (ZBIS). During introduction of a 12-F sheath over the allograft's neobifurcation to establish a femorofemoral through-and-through approach, the allograft ruptured. A compliant balloon was inflated to control the hemorrhage. The IBD was first fully deployed, followed by stent-graft relining. Consequently, stent-graft implantation in the left IIA using a crossover maneuver was no longer feasible, so a 0.035-inch super stiff wire was introduced through the IBD's 20-F sheath. A 12-mm semi-compliant balloon was inflated in the common iliac artery above the iliac branch to act as an abutment for a 7-F sheath to run over the stiff wire into the IIA for delivery/deployment of a stent-graft.
It is feasible to use a complete ipsilateral femoral approach for IBD implantation after aortic stent-graft placement.
Corynebacterium diphtheriae utilizes heme and hemoglobin (Hb) as iron sources for growth in low-iron environments. In C. diphtheriae, the two-component signal transduction systems (TCSs) ChrSA and HrrSA are responsive to Hb levels and regulate the transcription of promoters for hmuO, hrtAB, and hemA ChrSA and HrrSA activate transcription at the hmuO promoter and repress transcription at hemA in an Hb-dependent manner. In this study, we show that HrrSA is the predominant repressor at hemA and that its activity results in transcriptional repression in the presence and absence of Hb, whereas repression of hemA by ChrSA is primarily responsive to Hb. DNA binding studies
 showed that both ChrA and HrrA bind to the hemA promoter region at virtually identical sequences. ChrA binding was enhanced by phosphorylation, while binding to DNA by HrrA was independent of its phosphorylation state. ChrA and HrrA are phosphorylated in vitro by the sensor kinase ChrS, whereas no kinase activity was observed with HrrS in vitro Phosphorylated ChrA was not observed in vivo, even in the presence of Hb, which is likely due to the instability of the phosphate moiety on ChrA. However, phosphorylation of HrrA was observed in vivo regardless of the presence of the Hb inducer, and genetic analysis indicates that ChrS is responsible for most of the phosphorylation of HrrA in vivo Phosphorylation studies strongly suggest that HrrS functions primarily as a phosphatase and has only minimal kinase activity. These findings collectively show a complex mechanism of regulation at the hemA promoter, where both two-component systems act in concert to optimize expression of heme biosynthetic enzymes.
Understanding the mechanism by which two-component signal transduction systems function to respond to environmental stimuli is critical to the study of bacterial pathogenesis. The current study expands on the previous analyses of the ChrSA and HrrSA TCSs in the human pathogen C. diphtheriae The findings here underscore the complex interactions between the ChrSA and HrrSA systems in the regulation of the hemA promoter and demonstrate how the two systems complement one another to refine and control transcription in the presence and absence of Hb.
Many pathogens use homologous recombination to vary surface antigens in order to avoid immune surveillance. Neisseria gonorrhoeae, the bacterium responsible for the sexually transmitted infection gonorrhea, achieves this in part by changing the sequence of the major subunit of the type IV pilus in a process termed pilin antigenic variation (Av). The N. gonorrhoeae chromosome contains one expression locus (pilE) and many promoterless, partial-coding silent copies (pilS) that act as reservoirs for variant pilin information. Pilin Av occurs by high-frequency gene conversion reactions, which transfer pilS sequences into the pilE locus. We have developed a 454 sequencing-based assay to analyze the frequency and characteristics of pilin Av that allows a more robust analysis of pilin Av than previous assays. We used this assay to analyze mutations and conditions previously shown to affect pilin Av, confirming many but not all of the previously reported phenotypes. We show that mutations or conditions that cause growth defects can result in Av phenotypes when analyzed by phase variation-based assays. Adapting the 454 sequencing to analyze pilin Av demonstrates the utility of this technology to analyze any diversity generation system that uses recombination to develop biological diversity.
Measuring and analyzing complex recombination-based systems constitute a major barrier to understanding the mechanisms used to generate diversity. We have analyzed the contributions of many gonococcal mutations or conditions to the process of pilin antigenic variation.
New advances in crop genetic engineering can significantly pace up the development of genetically improved varieties with enhanced yield, nutrition and tolerance to biotic and abiotic stresses. Genetically modified (GM) crops can act as powerful complement to the crops produced by laborious and time consuming conventional breeding methods to meet the worldwide demand for quality foods. GM crops can help fight malnutrition due to enhanced yield, nutritional quality and increased resistance to various biotic and abiotic stresses. However, several biosafety issues and public concerns are associated with cultivation of GM crops developed by transgenesis, i.e., introduction of genes from distantly related organism. To meet these concerns, researchers have developed alternative concepts of cisgenesis and intragenesis which involve transformation of plants with genetic material derived from the species itself or from closely related species capable of sexual hybridization, respectively. Recombinase technology aimed at site-specific integration of transgene can help to overcome limitations of traditional genetic engineering methods based on random integration of multiple copy of transgene into plant genome leading to gene silencing and unpredictable expression pattern. Besides, recently developed technology of genome editing using engineered nucleases, permit the modification or mutation of genes of interest without involving foreign DNA, and as a result, plants developed with this technology might be considered as non-transgenic genetically altered plants. This would open the doors for the development and commercialization of transgenic plants with superior phenotypes even in countries where GM crops are poorly accepted. This review is an attempt to summarize various past achievements of GM technology in crop improvement, recent progress and new advances in the field to develop improved varieties aimed for better consumer acceptance.
The psychiatrist Herman Wedel Major planned Gaustad asylum in collaboration with his brother-in-law, the architect Heinrich Ernst Schirmer. The planning of Gaustad took place in parallel with the preparation of the first Norwegian Mental Health Act, adopted by the Storting on 30 July 1848, and Gaustad's architecture provides a good illustration of the ideals behind the mental health reform of the 19th century. In particular, Major's and Schirmer's Gaustad represents a break with Frederik Holst's ideal of the panoptic institution. Whereas Holst and his architect Christian Heinrich Grosch promoted a radial plan institution based on the type used for penitentiaries, Schirmer and Major designed a modern, pavilion-style hospital with wards placed independently in the landscape.
Palmitic acid (C16:0) already makes up approximately 25% of the total fatty acids in the conventional cotton seed oil. However, further enhancements in palmitic acid content at the expense of the predominant unsaturated fatty acids would provide increased oxidative stability of cotton seed oil and also impart the high melting point required for making margarine, shortening and confectionary products free of trans fatty acids. Seed-specific RNAi-mediated down-regulation of β-ketoacyl-ACP synthase II (KASII) catalysing the elongation of palmitoyl-ACP to stearoyl-ACP has succeeded in dramatically increasing the C16 fatty acid content of cotton seed oil to well beyond its natural limits, reaching up to 65% of total fatty acids. The elevated C16 levels were comprised of predominantly palmitic acid (C16:0, 51%) and to a lesser extent palmitoleic acid (C16:1, 11%) and hexadecadienoic acid (C16:2, 3%), and were stably inherited. Despite of the dramatic alteration of fatty acid composition and a slight yet significant reduction in oil content in these high-palmitic (HP) lines, seed germination remained unaffected. Regiochemical analysis of triacylglycerols (TAG) showed that the increased levels of palmitic acid mainly occurred at the outer positions, while C16:1 and C16:2 were predominantly found in the sn-2 position in both TAG and phosphatidylcholine. Crossing the HP line with previously created high-oleic (HO) and high-stearic (HS) genotypes demonstrated that HP and HO traits could be achieved simultaneously; however, elevation of stearic acid was hindered in the presence of high level of palmitic acid.
The indole ascarosides (icas) represent a highly potent class of nematode-derived modular signalling components that integrate structural inputs from amino acid, carbohydrate, and fatty acid metabolism. Comparative analysis of the crude exo-metabolome of hermaphroditic Caenorhabditis briggsae using a highly sensitive mass spectrometric screen reveals an indole ascaroside blend dominated by two new components. The structures of isolated icas#2 and icas#6.2 were determined by NMR spectroscopy and confirmed by total synthesis and chemical correlation. Low atto- to femtomolar amounts of icas#2 and icas#6.2 act in synergism to attract males indicating a function as sex pheromone. Comparative analysis of 14 Caenorhabditis species further demonstrates that species-specific indole ascaroside biosynthesis is highly conserved in the Elegans group. Functional characterization of the dominating indole ascarosides icas#2, icas#3, and icas#9 reveals a high degree of species-specificity and considerable variability with respect to gender-specificity, thus, confirming that indole ascarosides modulate different biological functions within the Elegans group. Although the nematode response was usually most pronounced towards conspecific signals, Caenorhabditis brenneri, the only species of the Elegans group that does not produce any indole ascarosides, exhibits a robust response to icas#2 suggesting the potential for interspecies interactions.
To propose a functional in vitro fertilization (IVF) prediction model to assist clinicians in tailoring personalized treatment of subfertile couples and improve assisted reproduction outcome.
Construction and evaluation of an enhanced web-based system with a novel Artificial Neural Network (ANN) architecture and conformed input and output parameters according to the clinical and bibliographical standards, driven by a complete data set and "trained" by a network expert in an IVF setting.
The system is capable to act as a routine information technology platform for the IVF unit and is capable of recalling and evaluating a vast amount of information in a rapid and automated manner to provide an objective indication on the outcome of an artificial reproductive cycle.
ANNs are an exceptional candidate in providing the fertility specialist with numerical estimates to promote personalization of healthcare and adaptation of the course of treatment
 according to the indications.
This paper reviews the evidence of youth mental ill health and its impact on secondary school educational attainment.
This narrative review presents the current research related to the mental ill health of young people in urban and rural Australia, their educational attainment and the effectiveness of mental health strategies implemented in secondary schools.
The prevalence of mental ill health is high for Australian young people and the onset of depression, anxiety, substance-use disorders and first episode psychosis (FEP) commonly occurs when the individual is at school. The prevalence is reported to be higher for rural young people and barriers to treatment exist. Current evidence suggests that 40% of young people experiencing depression or anxiety disorders are not completing secondary school. Further evidence shows that over 50% of individuals who experience FEP do not finish secondary school. Current mental health promotion strategies employed in secondary schools have not been shown to reduce rates of depression or anxiety in adolescence nor identify prodromal or acute FEP. These strategies have not led to interventions that assist young people with mental ill health to finish school.
Not completing secondary school can limit employment options, lead to severe levels of disadvantage and increased burden on welfare and healthcare systems. All young people, including those in rural areas, have the right to education and should not be disadvantaged in their educational aspirations because they have an emerging or current mental illness.
Serotonergic system participates in various developmental processes and modulation of behaviour. Autism Spectrum Disorder (ASD) is characterized by a range of behavioral symptoms scaling from mild to severe. Abnormal 5-HT synthesis and signalling, platelet hyperserotonemia and amelioration of repetitive behaviours by SSRI are some of the key findings, which reinforced the hypothesis that serotonergic genes might act as ASD susceptible genes. Therefore, genes encoding monoamine oxidases A/B (MAOA/MAOB) received special attention as these genes are located on the X-chromosome and the gene products are responsible for 5-HT degradation. In the present study, we conducted population-based association analysis of eight markers of MAOB with ASD in a study cohort of 203 cases and 236 controls form India and examined its effect on platelet 5-HT content and behaviour. Gender-specific changes were observed for the contrasting LD between pair of markers among cases and controls. Case-control analysis demonstrated over-distribution of major C allele of rs2283728 and rs2283727 in male and female ASD cases respectively. Haplotypic distribution and interaction among markers showed more robust effect in male cases. Interestingly, male ASD cases displayed higher platelet 5-HT content in comparison to the respective controls. Quantitative trait analysis revealed significant correlation of genetic variants and haplotypes of MAOB markers, rs1799836 and rs6324 with increased platelet 5-HT level and CARS scores for specific behavioral symptoms respectively in males. This study suggests that MAOB increases ASD risk in males, possibly through its sex-specific regulatory effect on 5-HT metabolism and behavior.
Epacs (exchange proteins directly activated by cyclic AMP [cAMP]) act as downstream effectors of cAMP and play important roles in energy balance and glucose homeostasis. While global deletion of Epac1 in mice leads to heightened leptin sensitivity in the hypothalamus and partial protection against high-fat diet (HFD)-induced obesity, the physiological functions of Epac1 in white adipose tissue (WAT) has not been explored. Here, we report that adipose tissue-specific Epac1 knockout (AEKO) mice are more prone to HFD-induced obesity, with increased food intake, reduced energy expenditure, and impaired glucose tolerance. Despite the fact that AEKO mice on HFD display increased body weight, these mice have decreased circulating leptin levels compared to their wild-type littermates. In vivo and in vitro analyses further reveal that suppression of Epac1 in WAT decreases leptin mRNA expression and secretion by inhibiting cAMP response element binding (CREB) protein and AKT phosphorylation, respectively. Taken together, our results demonstrate that Epac1 plays an important role in regulating energy balance and glucose homeostasis by promoting leptin expression and secretion in WAT.
Anaphylatoxin C5a, a potent pro-inflammatory peptide produced in the process of complement activation, was proved to have a vital role in tumor initiation and progession by previous investigations. However whether it could act as a prognostic marker remains unknown. Here we retrospectively enrolled 272 ccRCC patients undergoing nephrectomy in Zhongshan Hospital, Shanghai between 2005 and 2007. C5a level was assessed by immunohistochemistry and its association with clinicopathologic features and prognosis were evaluated. Our results indicated that high tumoral C5a level was associated with poor overall survival (OS) (hazard ratio = 1.753, 95% CI 1.068-2.878, P = 0.026). In addition, tumoral C5a could significantly stratify patients' prognosis both in advanced stage (TNM III + IV) and intermediate/high risk group (SSIGN score ≥4) (P < 0.001 and = 0.008, respectively). Furthermore, incorporating tumoral C5a with other parameters could improve the predicting accuracy, compared with TNM and SSIGN system (c-index = 0.789, 0.713 and 0.727, respectively). In conclusion, tumoral C5a is an independent adverse prognostic biomarker for clinical outcome of ccRCC patients after nephectomy.
Antiviral drugs are important in preventing and controlling influenza, particularly when vaccines are ineffective or unavailable. A single class of antiviral drugs, the neuraminidase inhibitors (NAIs), is recommended for treating influenza. The limited therapeutic options and the potential risk of antiviral resistance are driving the search for additional small-molecule inhibitors that act on influenza virus proteins. The acid polymerase (PA) of influenza viruses is a promising target for new antivirals because of its essential role in initiating virus transcription. Here, we characterized a novel compound, RO-7, identified as a putative PA endonuclease inhibitor. RO-7 was effective when added before the cessation of genome replication, reduced polymerase activity in cell-free systems, and decreased relative amounts of viral mRNA and genomic RNA during influenza virus infection. RO-7 specifically inhibited the ability of the PA endonuclease domain to cleave a nucleic acid substrate. RO-7 also inhibited influenza A viruses (seasonal and 2009 pandemic H1N1 and seasonal H3N2) and B viruses (Yamagata and Victoria lineages), zoonotic viruses (H5N1, H7N9, and H9N2), and NAI-resistant variants in plaque reduction, yield reduction, and cell viability assays in Madin-Darby canine kidney (MDCK) cells with nanomolar to submicromolar 50% effective concentrations (EC50s), low toxicity, and favorable selective indices. RO-7 also inhibited influenza virus replication in primary normal human bronchial epithelial cells. Overall, RO-7 exhibits broad-spectrum activity against influenza A and B viruses in multiple in vitro assays, supporting its further characterization and development as a potential antiviral agent for treating influenza.
Gene expression regulation is a critical question in host-pathogen interactions, and RNAs act as key players in this process. In this review, we focus on the mammalian RNA response to bacterial infection, with a special interest on microRNAs and long non-coding RNAs. We discuss the role of cellular miRNAs in immunity, the implication of circulating miRNAs as well as the influence of the microbiome on the miRNA response. We also review how pathogens counteract the host miRNA expression. Interestingly, bacterial non-coding RNAs regulate host gene expression and conversely eukaryotic miRNAs may regulate bacterial gene expression. Overall, the characterization of RNA regulatory networks represents an emerging theme in the field of host pathogen interactions.
With the development of microfluidics, electro-osmotic (EO) driven flow has gained intense research interest as a result of its unique flow profile and the corresponding benefits in its application in the transportation of sensitive samples. Sensitive samples, such as DNA, are incapable of enduring strong flow shear induced by conventional hydrodynamic driven methods. EO driven flow is thus a niche area. However, even though there are a few research studies focusing on bio-fluidic samples related to EO driven flow, the majority of them are merely theoretical modeling without solid evidence from experiments due to the inherent complex rheological behavior of the bio-fluids. Challenges occur when the EO driven mechanism meets with complex rheology; vital questions such as can the zeta potential still be assumed to be constant when dealing with fluids with complex rheology? and "Does the shear thinning effect enhance electro-osmotic driven flow?" need to be answered. We conducted experiments using current monitoring and microscopy fluorescence methods, and developed a theoretical model by coupling a generalized Smoluchowski approach with the power-law constitutive model. We calculated the zeta potential and compared the experimental results with modeling to answer the questions. The results show a reduction of zeta potential in the presence of PEO aqueous solutions. A constant zeta potential is also indicated by varying the PEO concentration and the electric field strength.The shear thinning effect is also addressed via experimental data and theoretical calculations. The results show a promising enhancement of the EO driven velocity due to the shear thinning effect.
The
 protocadherins Fat4 and Dchs1 act as a receptor-ligand pair to regulate many developmental processes in mice and humans, including development of the vertebrae. Based on conservation of function between Drosophila and mammals, Fat4-Dchs1 signalling has been proposed to regulate planar cell polarity (PCP) and activity of the Hippo effectors Yap and Taz, which regulate cell proliferation, survival and differentiation. There is strong evidence for Fat regulation of PCP in mammals but the link with the Hippo pathway is unclear. In Fat4(-/-) and Dchs1(-/-) mice, many vertebrae are split along the midline and fused across the anterior-posterior axis, suggesting that these defects might arise due to altered cell polarity and/or changes in cell proliferation/differentiation. We show that the somite and sclerotome are specified appropriately, the transcriptional network that drives early chondrogenesis is intact, and that cell polarity within the sclerotome is unperturbed. We find that the key defect in Fat4 and Dchs1 mutant mice is decreased proliferation in the early sclerotome. This results in fewer chondrogenic cells within the developing vertebral body, which fail to condense appropriately along the midline. Analysis of Fat4;Yap and Fat4;Taz double mutants, and expression of their transcriptional target Ctgf, indicates that Fat4-Dchs1 regulates vertebral development independently of Yap and Taz. Thus, we have identified a new pathway crucial for the development of the vertebrae and our data indicate that novel mechanisms of Fat4-Dchs1 signalling have evolved to control cell proliferation within the developing vertebrae.
Enhancers, not promoters, are the most dynamic in their DNA methylation status throughout development and differentiation. Generally speaking, enhancers that are primed to or actually drive gene expression are characterized by relatively low levels of DNA methylation (hypo-methylation), while inactive enhancers display hyper-methylation of the underlying DNA. The direct functional significance of the DNA methylation state of enhancers is, however, unclear for most loci.
In contrast to conventional epigenetic interactions at enhancers, we find that DNA methylation status and enhancer activity during early zebrafish development display very unusual correlation characteristics: hypo-methylation is a unique feature of primed enhancers whereas active enhancers are generally hyper-methylated. The hypo-methylated enhancers that we identify (hypo-enhancers) are enriched close to important transcription factors that act later in development. Interestingly, hypo-enhancers are de-methylated shortly before the midblastula transition and reside in a unique epigenetic environment. Finally, we demonstrate that hypo-enhancers do become active at later developmental stages and that they are physically associated with the transcriptional start site of target genes, irrespective of target gene activity.
We demonstrate that early development in zebrafish embodies a time window characterized by non-canonical DNA methylation-enhancer relationships, including global DNA hypo-methylation of inactive enhancers and DNA hyper-methylation of active enhancers.
Although the heart rate variability (HRV) response to hypoxia has been studied, little is known about the dynamics of HRV after hypoxia exposure. The purpose of this study was to assess the HRV and oxygen saturation (SpO2 ) responses to normobaric hypoxia (FiO2  = 9·6%) comparing 1 min segments to baseline (normoxia). Electrocardiogram and SpO2 were recorded during a 10-min hypoxia exposure in 29 healthy male subjects aged 26·0 ± 4·9 years. Baseline HRV values were obtained from a 5-min recording period prior to hypoxia. The hypoxia period was split into 10 non-overlapping 1-min segments and time domain HRV indexes (RMSSD and SDNN) were calculated for each segment. Differences (Δ) from baseline values were calculated and transformed using natural logarithm (Ln). This study revealed that the decrease in ΔSpO2 became significant (P<0·001) in the first minute of hypoxia, the decrease in ΔLn RMSSD became significant (P = 0·002) in the second minute, and the decrease in ΔLn SDNN became significant (P = 0·001) in the third minute. Between the second and fifth minute of hypoxia, ΔSpO2 correlated with ΔLn RMSSD (r = 0·57, P<0·001) and ΔLn SDNN (r = 0·44, P<0·001). Five min after the onset of hypoxia, ΔSpO2 was significantly (P = 0·002) decreased but changes in ΔLn RMSSD (P = 0·344) and ΔLn SDNN (P = 0·558) were not significant. In conclusion, the decrease in HRV was proportional to desaturation but only during the first 5 min of hypoxia.
The Tobacco Products Control Act, No. 83 of 1993 was introduced in South Africa in 1993. Due to the shortfalls of the 1993 Act, the Tobacco Products Control Amendment Act, No. 12 of 1999 was passed in 1999. The regulation relating to smoking of tobacco products in public places was gazetted in 2000 and implemented in 2001.
The setting for the study was all selected registered licensed bar-lounges including restaurants within the municipality.
To examine compliance levels with the current smoke-free regulation at bar-lounges and restaurants in Thulamela Municipality.
To observe whether structural alterations had been effected to accommodate smoking patrons. To observe whether tobacco-related litter was present in nonsmoking areas and in the outdoor areas within 5 meters of windows and entry ways. To observe whether individuals or groups engaged in smoking in non-smoking areas.
An observational survey was conducted to measure the level of compliance by lounges and restaurants in Thulamela Municipality. A convenience sampling method was used to sample 56 bar-lounges, including restaurants. Data were collected using an observation log. Collected data were analysed using SPSS 20.0.
The study findings noted low compliance with the legislation with only one establishment (1.8%) complying with the requirements of the legislation.
The level of compliance with the legislation is in a very low state in Thulamela Municipality. Further research is needed to explore factors influencing non-compliance with the regulation.
The indigenous health system was perceived to be a threat to the allopathic health system. It was associated with 'witchcraft', and actively discouraged, and repressed through prohibition laws. The introduction of the Traditional Health Practitioners Act No 22 of 2007 brought hope that those centuries of disrespect for traditional health systems would change. The study examined the perceptions and experiences of allopathic health practitioners on collaboration with traditional health practitioners in post-apartheid South Africa.
Qualitative descriptive research methodology was used to collect data from allopathic health practitioners employed by Limpopo's Department of Health. In-depth focus group discussions and meetings were conducted between January and August 2014. Perceptions and experiences of working with traditional health practitioners were explored. Ethical clearance was obtained from the University of Pretoria and approval from the Department's Research Committee.
Dominant views were that the two health systems were not compatible with respect to the science involved and the source of knowledge. Overall, quality of health care will be compromised if traditional health practitioners are allowed to work in public health facilities.
Allopathic health practitioners do not appear ready to work with traditional health practitioners, citing challenges of quality of health care, differences regarding concept of sciences and source of knowledge; and lack of policy on collaboration. Lack of exposure to traditional medicine seems to impede opportunities to accept and work with traditional healers. Exposure and training at undergraduate level regarding the traditional health system is recommended. Policy guidelines on collaborations are urgently required.
Professional midwives have an important role to play in midwifery training to produce a competent midwife. According to the social learning theory, professional midwives act as role models for students. When allocated for clinical learning experiences in the training hospitals, students will have the opportunity to observe the well-trained, skilled, and experienced professional midwives. The whole process will enable students to integrate theory with practice and they will become competent.
The aim of this study was to determine the factors affecting integration of midwifery nursing science theory with clinical practice as perceived by midwives.
The study was conducted at the training hospitals in Vhembe district of the Limpopo Province, South Africa. These hospitals were: Donald Fraser, Siloam, and Tshidzini.
A qualitative explorative, descriptive and contextual design was used. A Nonprobability, convenient sampling method was used to select 11 midwives from the following hospitals: Donald Fraser, Siloam, and Tshidzini, in Vhembe district. In-depth individual interviews were conducted. Data were analysed through open coding method.
One theme and five sub-themes emerged from the analysed data, namely: shortage of midwives, attitudes towards student midwives, reluctance to perform teaching functions, language barriers, and declining midwifery practice standards.
Shortage of midwives in the clinical areas led to fewer numbers of mentors whom the students could observe and imitate to acquire clinical skills. Some of the midwives were reluctant to teach students. Recommendations were made for both training institutions and hospitals to employ preceptors for students in the clinical practical.
Like many nations, population ageing is challenging Australia's economic future; increasing the workforce participation of mothers and mature-aged adults are two policy strategies to address it. Drawing on a
 Health in All Policies (HiAPs) framework, our study aims to supply longitudinal evidence on connections between this policy strategy and health. Considering physical inactivity, poor mental health, overweight and obesity we estimate associations with the level of participation (not employed compared with part- or full-time employed). Using eight waves of data from the Household, Income and Labour Dynamics in Australia survey, a series of random intercept logistic models estimate the odds for mothers (n = 2105) and Australians aged 55-64 years (n = 3201) on each health outcome. We find that there are health benefits as well as risks linked to level of participation. Mothers who worked >20 h/wk had higher odds of physical inactivity, as did mature-aged Australians working either part - or full-time. Working part- or full-time was unrelated to overweight or obesity over the span of our study. Level of participation was unrelated to mental health among mature-age Australians, although part-time (but not full-time) work benefited mothers'. In terms of health, working more may offer mixed blessings to these two target populations; part-time work appears to be optimal. By using health as a metric, our study adds to the case for a HiAPs approach.
For some decades now, nanotechnology has been touted as the 'next big thing' with potential impact comparable to the steam, electricity or Internet revolutions - but has it lived up to these expectations? While advances in top-down nanolithography, now reaching 10-nm resolution, have resulted in devices that are rapidly approaching mass production, attempts to produce nanoscale devices using bottom-up approaches have met with only limited success. We have been inundated with nanoparticles of almost any shape, material and composition, but their societal impact has been far from revolutionary, with growing concerns over their toxicity. Despite nebulous hopes that making hierarchical nanomaterials will lead to new, emergent properties, no breakthrough applications seem imminent. In this Perspective, we argue that the time is ripe to look beyond individual nano-objects and their static assemblies, and instead focus on systems comprising different types of 'nanoparts' interacting and/or communicating with one another to perform desired functions. Such systems are interesting for a variety of reasons: they can act autonomously without external electrical or optical connections, can be dynamic and reconfigurable, and can act as 'nanomachines' by directing the flow of mass, energy or information . In thinking how this systems nanoscience approach could be implemented to design useful - as opposed to toy-model - nanosystems, our choice of applications and our nanoengineering should be inspired by living matter.
Biosurfactants are promising additives for surfactant enhanced remediation (SER) technologies due to their low toxicity and high biodegradability. To develop green and efficient additives for SER, the aqueous solubility enhancements of polycyclic aromatic hydrocarbons (PAHs; naphthalene, phenanthrene, and pyrene) by rhamnolipid (RL) and sophorolipid (SL) biosurfactants were investigated in single and binary mixed systems. The solubilization capacities were quantified in terms of the solubility enhancement factor, molar solubilization ratio (MSR), and micelle-water partition coefficient (). Rughbin's model was applied to evaluate the interaction parameters (β) in the mixed RL-SL micelles. The solubility of the PAHs increased linearly with the glycolipid concentration above the critical micelle concentration (CMC) in both single and mixed systems. Binary RL-SL mixtures exhibited greater solubilization than individual glycolipids. At a SL molar fraction of 0.7 to 0.8, the solubilization capacity was the greatest, and the MSR and reached their maximum values, and β values became positive. These results suggest that the two biosurfactants act synergistically to increase the solubility of the PAHs. The solubilization capacity of the RL-SL mixtures increased with increasing temperature and decreased with increasing salinity. The aqueous solubility of phenanthrene reached a maximum value at pH of 5.5. Moreover, the mixed RL-SL systems exhibited a strong ability to solubilize PAHs, even in the presence of heavy metal ions. These mixed biosurfactant systems have the potential to improve the performance of SER technologies using biosurfactants to solubilize hydrophobic organic contaminants by decreasing the applied biosurfactant concentration, which reduces the costs of remediation.
The effects of both continuous and alternate exposure to 2mgL(-1) of enrofloxacin (EFX) on survival, growth and reproduction were evaluated over four generations of Daphnia magna. Mortality increased, reaching 100% in most groups by the end of the third generation. Growth inhibition was detected in only one group of the fourth generation. Reproduction inhibition was >50% in all groups and, in second and third generations, groups transferred to pure medium showed a greater inhibition of reproduction than those exposed to EFX. To verify whether the effects observed in these groups could be explained by the perinatal exposure to the antibacterial, a reproduction test with daphnids obtained from in vitro exposed D. magna embryos was also carried out. Perinatal exposure to EFX seemed to act as an 'all-or-nothing' toxicity effect as 31.4% of embryos died, but the surviving daphnids did not show any inhibition of reproduction activity. However, the embryonic mortality may at least partially justify the inhibition of reproduction observed in exposed groups along the multigenerational test. Concluding, the multigenerational test with D. magna did show disruption to a population that cannot be evidenced by the official tests. The increasing deterioration across generations might be inferred as the consequence of heritable alterations. Whilst the concentration tested was higher than those usually detected in the natural environment, the increasing toxicity of EFX across generations and the possible additive toxicity of fluoroquinolone mixtures, prevent harm to crustacean populations by effects in the real context from being completely ruled out.
Controversy remains exist for the effect of adjuvant chemotherapy (ACT) among stage IB lung adenocarcinoma patients. This study aimed to investigate the predictive value of the current lung adenocarcinoma classification system on benefit of ACT among patients with stage IB lung adenocarcinoma.
A total of 928 pathological stage IB invasive adenocarcinoma patients with R0 resection were included in this study. Based on the predominant growth pattern present in the tumor, invasive adenocarcinomas with mixed histologic components were classified into five subtypes: lepidic (LEP), acinar (ACN), papillary (PAP), micropapillary (MIP) and solid (SOL). These five histologic subtypes were collapsed into three groups (LEP, ACN/PAP and SOL/MIP). Disease-free survival (DFS) and overall survival (OS) were analyzed to evaluate benefit from ACT in patients with different histologic patterns using the Kaplan-Meier approach and multivariable Cox models.
For all stage IB invasive adenocarcinoma patients, SOL/MIP subgroup presented the worst prognosis, and LEP subgroup showed approximately 100 % 5-year survival. ACT was associated with a better DFS (HR, 0.70; 95 % CI 0.51-0.96, p = .026) for all stage IB patients. In SOL/MIP subgroup, patients could benefit from ACT for a significant improved DFS (HR, 0.81; 95 % CI 0.49-1.35; p = .030), but not for OS (HR, 0.39; 95 % CI 0.12-1.30, p = .111). In ACN/PAP subgroup, there was no significant benefit from ACT for both DFS (HR, 0.76; 95 % CI 0.54-1.08, p = .125) and OS (HR, 0.81; 95 % CI 0.49-1.35, p = .421).
SOL/MIP predominant pattern was predictive for ACT benefit for DFS among invasive lung adenocarcinoma patients in stage IB.
The activity of the digestive system is dynamically regulated by external factors, including body nutritional and activity states, emotions and the contents of the digestive tube. The gut must adjust its activity to assimilate a hugely variable mixture that is ingested, particularly in an omnivore such as human for which a wide range of food choices exist. It must also guard against toxins and pathogens. These nutritive and non-nutritive components of the gut contents interact with the largest and most vulnerable surface in the body, the lining of the gastrointestinal tract. This requires a gut sensory system that can detect many classes of nutrients, non-nutrient components of food, physicochemical conditions, toxins, pathogens and symbionts (Furness et al., Nat Rev Gastroenterol Hepatol 10:729-740, 2013). The gut sensors are in turn coupled to effector systems that can respond to the sensory information. The responses are exerted through enteroendocrine cells (EEC), the enteric nervous system (ENS), the central nervous system (CNS) and the gut immune and tissue defence systems. It is apparent that the control of the digestive organs is an integrated function of these effectors. The peripheral components of the EEC, ENS and CNS triumvirate are extensive. EEC cells have traditionally been classified into about 12 types (disputed in this review), releasing about 20 hormones, together making the gut endocrine system the largest endocrine organ in the body. Likewise, in human the ENS contains about 500 million neurons, far more than the number of neurons in the remainder of the peripheral autonomic nervous system. Together gut hormones, the ENS and the CNS control or influence functions including satiety, mixing and propulsive activity, release of digestive enzymes, induction of nutrient transporters, fluid transport, local blood flow, gastric acid secretion, evacuation and immune responses. Gut content receptors, including taste, free
 fatty acid, peptide and phytochemical receptors, are primarily located on EEC. Hormones released by EEC act via both the ENS and CNS to optimise digestion. Toxic chemicals and pathogens are sensed and then avoided, expelled or metabolised. These defensive activities also involve the EEC and signalling from EEC to the ENS and the CNS. A major challenge is to develop a comprehensive understanding of the integrated responses of the gut, via its effector systems, the ENS, extrinsic innervation, EEC and the gut immune system, to the sensory information it receives.
Rett syndrome (RTT) is a postnatal neurodevelopmental disorder that primarily affects girls. Mutations in the methyl-CpG-binding protein 2 (MECP2) gene account for approximately 95 % of all RTT cases. To model RTT in vitro, we generated induced pluripotent stem cells (iPSCs) from fibroblasts of two RTT patients with different mutations (MECP2 (R306C) and MECP2 (1155Δ32)) in their MECP2 gene. We found that these iPSCs were capable of differentiating into functional neurons. Compared to control neurons, the RTT iPSC-derived cells had reduced soma size and a decreased amount of synaptic input, evident both as fewer Synapsin 1-positive puncta and a lower frequency of spontaneous excitatory postsynaptic currents. Supplementation of the culture media with choline rescued all of these defects. Choline supplementation may act through changes in the expression of choline acetyltransferase, an important enzyme in cholinergic signaling, and also through alterations in the lipid metabolite profiles of the RTT neurons. Our study elucidates the possible mechanistic pathways for the effect of choline on human RTT cell models, thereby illustrating the potential for using choline as a nutraceutical to treat RTT.
Nanomaterials are proving useful for regenerative medicine in combination with stem cell therapy. Nanoparticles (NPs) can be administrated and targeted to desired tissues or organs and subsequently be used in non-invasive real-time visualization and tracking of cells by means of different imaging techniques, can act as therapeutic agent nanocarriers, and can also serve as scaffolds to guide the growth of new tissue. NPs can be of different chemical nature, such as gold, iron oxide, cadmium selenide, and carbon, and have the potential to be used in regenerative medicine. However, there are still many issues to be solved, such as toxicity, stability, and resident time. Upconversion NPs have relevant properties such as (i) low toxicity, (ii) capability to absorb light in an optical region where absorption in tissues is minimal and penetration is optimal (note they can also be designed to emit in the near-infrared region), and (iii) they can be used in multiplexing and multimodal imaging. An overview on the potentiality of upconversion materials in regenerative medicine is given.
It has been suggested that pediatric acute respiratory distress syndrome (PARDS) may be a different entity, vis-à-vis adult acute respiratory distress syndrome (ARDS), based on its epidemiology and outcomes. A more pediatric-specific definition of PARDS to include the subgroup of patients with underlying lung (and heart) disease has been proposed. Epidemiological data suggest that up to 13% of the children with ARDS have a history of prematurity and/or underlying chronic lung disease. However, the specific contribution of bronchopulmonary dysplasia (BPD), the most common chronic lung disease in infants, to the development of PARDS is not known. BPD leads to damaged lungs with long-term consequences secondary to disordered growth and immune function. These damaged lungs could potentially act as a substrate, which given the appropriate noxious stimuli, can predispose a child to PARDS. Interestingly, similar biomarkers [KL-6, interleukin (IL)-6, IL-8, sICAM-1, angiopoietin-2, and matrix metalloproteinase-8 and -9] of pulmonary injury have been associated both with BPD and ARDS. Recognition of a unique pattern of clinical symptomatology and/or outcomes of PARDS, if present, could potentially be useful for investigating targeted therapeutic interventions.
While endocrine therapy is the mainstay of ER+ breast cancer, the clinical effectiveness of these agents is limited by the phenomenon of acquired resistance that is associated with disease relapse and poor prognosis. Our previous studies revealed that acquired resistance is accompanied by a gain in cellular invasion and migration and also that CD44 family proteins are overexpressed in the resistant phenotype. Given the association of CD44 with tumor progression, we hypothesized that its overexpression may act to promote the aggressive behavior of endocrine-resistant breast cancers. Here, we have investigated further the role of two specific CD44 isoforms, CD44v3 and CD44v6, in the endocrine-resistant phenotype. Our data revealed that overexpression of CD44v6, but not CD44v3, in endocrine-sensitive MCF-7 cells resulted in a gain in EGFR signaling, enhanced their endogenous invasive capacity, and attenuated their response to endocrine treatment. Suppression of CD44v6 in endocrine-resistant cell models was associated with a reduction in their invasive capacity. Our data suggest that upregulation of CD44v6 in acquired resistant breast cancer may contribute to a gain in the aggressive phenotype of these cells and loss of endocrine response through transactivation of the EGFR pathway. Future therapeutic targeting of CD44v6 may prove to be an effective strategy alongside EGFR-targeted agents in delaying/preventing acquired resistance in breast cancer.
Polyamines are small basic compounds present in all living organisms and act in a variety of biological processes. However, the mechanism of polyamine sensing, signaling and response in relation to other metabolic pathways remains to be fully addressed in plant cells. As one approach, we isolated Arabidopsis mutants that show increased resistance to spermine in terms of chlorosis. We show here that two of the mutants have a point mutation in a nitrate transporter gene of the NRT1/PTR family (NPF), NRT1.3 (AtNPF6.4). These mutants also exhibit increased resistance to putrescine and spermidine while loss-of-function mutants of the two closest homologs of NRT1.3, root-specific NRT1.1 (AtNPF6.3) and petiole-specific NRT1.4 (AtNPF6.2), were shown to have a normal sensitivity to polyamines. When the GUS reporter gene was expressed under the control of the NRT1.3 promoter, GUS staining was observed in leaf mesophyll cells and stem cortex cells but not in the epidermis, suggesting that NRT1.3 specifically functions in parenchymal tissues. We further found that the aerial part of the mutant seedling has normal levels of polyamines but shows reduced uptake of norspermidine compared with the wild type. These results suggest that polyamine transport or metabolism is associated with nitrate transport in the parenchymal tissue of the shoot.
Plants being sessile in nature are often challenged to various abiotic stresses including temperature fluctuations, water supply, salinity, and nutrient availability. Exposure of plants to such environmental perturbations result in the formation of reactive oxygen species (ROS) in cells. To scavenge ROS, enzymatic and molecular antioxidants are produced at a cellular level. ROS act as a signaling entity at lower concentrations maintaining normal growth and development, but if their levels increase beyond certain threshold, they produce toxic effects in plants. Some developmental stages, such as development of reproductive organs are more sensitive to abiotic stress than other stages of growth. As success of plant reproductive development is directly correlated with grain yield, stresses coinciding with reproductive phase results in the higher yield losses. In this article, we summarize the redox control of plant reproductive development, and elaborate how redox homeostasis is compromised during abiotic stress exposure. We highlight why more emphasis should be given to understand redox control of plant reproductive organ development during abiotic stress exposure96to engineer crops with better crop yield. We specifically discuss the role of ROS as a signaling molecule and its cross-talk with other signaling molecules such as hormones and sugars.
Cell-cell communications, known as quorum sensing (QS) in bacteria, involve the signal molecules as chemical languages and the corresponding receptors as transcriptional regulators. In Gram-negative bacteria, orphan LuxR receptors recognize signals more than just acylhomoserine lactones, and modulate interspecies and interkingdom communications. Whereas, in the Gram-positive Streptomyces, pseudo gamma-butyrolactones (GBLs) receptors bind antibiotics other than GBL signals, and coordinate antibiotics biosynthesis. By interacting with structurally diverse molecules like antibiotics, the TetR family receptors regulate multidrug resistance (MDR) by controlling efflux pumps. Antibiotics at subinhibitory concentration may act as signal molecules; while QS signals also have antimicrobial activity at high concentration. Moreover, the QS and MDR systems may share the same exporters to transport molecules. Among these orphan LuxR, pseudo GBL receptors, and MDR regulators, although only with low sequence homology, they have some structure similarity and function correlation. Therefore, perhaps there might be evolutionary relationship and biological relevance between the regulatory systems of QS and MDR. Since the QS systems become new targets for antimicrobial strategy, it would expand our understanding about the evolutionary history of these regulatory systems.
Objective. To observe the effects of empirical prescriptions of traditional Chinese medicine (TCM) on inflammatory mediators in pediatric asthma and to explore the underlying molecular mechanism in
 the treatment of asthma. Methods. A total of 182 children with asthma were randomly placed into either the TCM group (n = 97) or the salbutamol and montelukast (SM) group (n = 85). Patients in the TCM group were treated with a series of empirical prescriptions of TCM, while those in the SM group received salbutamol and montelukast. Both groups received their respective treatment for 12 weeks. There were 35 patients in TCM group and 34 patients in SM group providing venous blood. Real-time PCR was used to determine the mRNA expression levels of interleukin- (IL-) 10, IL-17, matrix metalloproteinase-9 (MMP-9), and transforming growth factor β1 (TGF-β1) in peripheral blood mononuclear cells before and after treatment. Enzyme-linked immunosorbent assay was used to measure the levels of IL-10, IL-17, MMP-9, and TGF-β1 in peripheral blood before and after treatment. Results. The mRNA expression of TGF-β1 in the SM group was downregulated (P = 0.00) after treatment. No significant differences were found between the TCM group and the SM group after treatment (P > 0.05). In the TCM group, the levels of IL-10, IL-17, and MMP-9 significantly decreased after treatment (P = 0.01, 0.04, and 0.03, resp.). In the SM group, IL-17, MMP-9, and TGF-β1 levels significantly decreased after treatment (P = 0.00, 0.03, and 0.00, resp.). There was no significant difference between the two groups regarding the levels of IL-10, IL-17, TGF-β1, and MMP-9 (P > 0.05). The difference of the level of IL-17 was negatively correlated with the change of C-ACT score in TCM group and SM group. Conclusion. TCM has a regulatory effect on the balance of some inflammatory mediators in pediatric asthma.
The objective of this Perspective was to provide guidance to hospitalists and hospital clinical leadership on how to implement the Caregiver Advise Record and Enable (CARE) Act, which has been passed into law in 30 US states and territories. Specifically, the objective is 3-fold: (1) increase awareness among hospitalists and encourage them to begin to prepare for implementation, (2) explore the impetus for this legislation, and (3) provide a list of suggested resources geared to both family caregivers and healthcare professionals that may be helpful in preparation for implementing the CARE Act. Journal of Hospital Medicine 2015;11:883-885. © 2015 Society of Hospital Medicine.
Cell lineages of the early human gonad commit to one of the two mutually antagonistic organogenetic fates, the testis or the ovary. Some individuals with a 46,XX karyotype develop testes or ovotestes (testicular or ovotesticular disorder of sex development; TDSD/OTDSD), due to the presence of the testis-determining gene, SRY Other rare complex syndromic forms of TDSD/OTDSD are associated with mutations in pro-ovarian genes that repress testis development (e.g. WNT4); however, the genetic cause of the more common non-syndromic forms is unknown. Steroidogenic factor-1 (known as NR5A1) is a key regulator of reproductive development and function. Loss-of-function changes in NR5A1 in 46,XY individuals are associated with a spectrum of phenotypes in humans ranging from a lack of testis formation to male infertility. Mutations in NR5A1 in 46,XX women are associated with primary ovarian insufficiency, which includes a lack of ovary formation, primary and secondary amenorrhoea as well as early menopause. Here, we show that a specific recurrent heterozygous missense mutation (p.Arg92Trp) in the accessory DNA-binding region of NR5A1 is associated with variable degree of testis development in 46,XX children and adults from four unrelated families. Remarkably, in one family a sibling raised as a girl and carrying this NR5A1 mutation was found to have a 46,XY karyotype with partial testicular dysgenesis. These unique findings highlight how a specific variant in a developmental transcription factor can switch organ fate from the ovary to testis in mammals and represents the first missense mutation causing isolated, non-syndromic 46,XX testicular/ovotesticular DSD in humans.
Humans are adept at performing an extraordinary breadth of voluntary motor actions that allow us to rapidly move around and interact with the environment. While voluntary motor actions necessarily include top-down intention to generate a motor act, a key to voluntary control is the selective use of bottom-up sensory feedback to select and guide motor actions. This review classifies the many ways in which sensory feedback is used by the motor system and highlights regularities in the timing of each class of motor responses to sensory stimuli, revealing a functional hierarchical organization of motor control. The highly automatic way in which feedback is typically used in goal-directed action blurs the distinction between reflexes and voluntary control.
Matrix assisted laser desorption/ionization mass spectrometry (MALDI-MS) is widely used for the detection and analysis of ionizable compounds. However, the method has less potential for the analysis of neutral compounds, such as polyphenols, owing to their lack of favorable proton-attachment or -removal groups. In this study, we reported for the first time that nifedipine (2,6-dimethyl-3,5-dicarbomethoxy-4-(2-nitrophenyl)-1,4-dihydropyridine), which is a strong photobase generator commonly used in polymerization, can abstract protons from neutral compounds in negative mode-MALDI experiments. When nifedipine (5 mg/ml) was used as a matrix reagent, the limit of detection (LOD) for epigallocatechin-3-O-gallate (EGCG) was determined to be 100 fmol/spot, which constitutes >50-fold improvement compared to the LOD obtained when trans-3-indoleacrylic acid, a matrix reagent previously reported for polyphenol detection, was used. Of the dihydropyridines investigated, only nifedipine facilitated the detection of EGCG, suggesting that the nitrosophenyl pyridine derivative of nifedipine formed by photoreduction under laser irradiation at 355 nm plays a crucial role in detecting polyphenols in negative mode. Reduced MS detection of 5-O-methylnaringenin indicated that nifedipine may preferably remove a proton from the 5-position OH group in the A ring of the flavonoid skeleton. The significant MS detection by nifedipine was extensively observed for polyphenols including flavones, flavonones, chalcones, stilbenoids and phenolic acids. In conclusion, nifedipine can act as a novel matrix for improving polyphenol detection by MALDI-MS in negative mode. Copyright © 2016 John Wiley & Sons, Ltd.
This study was conducted to clone and functionally characterize a full-length cDNA encoding arachidonate 5-lipoxygenase (Alox5) from large yellow croaker (Larmichthys crocea) and investigate its gene expression in response to graded dietary ratio of linolenic acid (ALA) to linoleic acid (LNA) (0.03, 0.06, 0.45, 0.90 and 1.51). An isolated 2372bp cDNA clone of Alox5 contained an open reading frame spanning 2025bp encoding a protein with the ability to modify arachidonate acid (AA) to 5-hydroxyeicosatetraenoic (5-HETE). In the liver, the Alox5 mRNA expression levels significantly increased to the maximum when the dietary ALA/LNA increased from 0.03 to 0.06, and then significantly decreased with dietary ALA/LNA increased to 1.51 (P<0.05). In the kidney, the expression levels of Alox5 of fish fed diets with low dietary ALA/LNA (0.03-0.06) were significantly higher than those of fish fed diets with high dietary ALA/LNA (0.45-1.51) (P<0.05). The dual-luciferase reporter assays showed that the nuclear factor kappa B (NF-κB) could act on cognate cis-acting elements in the promoter of Alox5 and increased the transcription of Alox5. Results of the present study suggested that the expression of Alox5 is higher in croakers fed high concentrations of LNA compared to those fed high concentrations of ALA, which might be regulated by NF-κB and contribute to the inflammation process by catalyzing the dioxygenation of AA.
Until recently, the mechanism of adaptive thermogenesis was ascribed to the expression of uncoupling protein 1 (UCP1) in brown and beige adipocytes. UCP1 is known to catalyze a proton leak of the inner mitochondrial membrane, resulting in uncoupled oxidative metabolism with no production of adenosine triphosphate and increased energy expenditure. Thus increasing brown and beige adipose tissue with augmented UCP1 expression is a viable target for obesity-related disorders. Recent work demonstrates an UCP1-independent pathway to uncouple mitochondrial respiration. A secreted enzyme, PM20D1, enriched in UCP1+ adipocytes, exhibits catalytic and hydrolytic activity to reversibly form N-acyl amino acids. N-acyl amino acids act as endogenous uncouplers of mitochondrial respiration at physiological concentrations. Administration of PM20D1 or its products, N-acyl amino acids, to diet-induced obese mice improves glucose tolerance by increasing energy expenditure. In short-term studies, treated animals exhibit no toxicity while experiencing 10% weight loss primarily of adipose tissue. Further study of this metabolic pathway may identify novel therapies for diabesity, the disease state associated with diabetes and obesity.
PR1 is an HLA-A2 restricted leukemia-associated antigen derived from neutrophil elastase and proteinase 3, both of which are normally stored in the azurophil granules of myeloid cells but overexpressed in myeloid leukemic cells. PR1-specific cytotoxic lymphocytes (PR1-CTLs) have activity against primary myeloid leukemia in vitro and in vivo and thus could have great potential in the setting of adoptive cellular therapy (ACT). Adult peripheral blood-derived PR1-CTLs are infrequent but preferentially lyse myeloid leukemia cells. We sought to examine PR1-CTLs in umbilical cord blood (UCB) because UCB units provide a rapidly available cell source and a lower risk of graft-versus-host disease, even in the setting
 of mismatched human leukocyte antigen (HLA) loci.
We first determined the frequency of PR1-CTLs in HLA-A2(+) UCB units and then successfully expanded them ex vivo using repeated stimulation with PR1 peptide-pulsed antigen-presenting cells (APCs). After expansion, we assessed the PR1-CTL phenotype (naive, effector, memory) and function against PR1-expressing target cells.
PR1-CTLs are detected at an average frequency of 0.14% within the CD8(+) population of fresh UCB units, which is 45 times higher than in healthy adult peripheral blood. UCB PR1-CTLs are phenotypically naive, consistent with the UCB CD8(+) population as a whole. In addition, the cells can be expanded by stimulation with PR1 peptide-pulsed APCs. Expansion results in an increased frequency of PR1-CTLs, up to 4.56%, with an average 20-fold increase in total number. After expansion, UCB PR1-CTLs express markers consistent with effector memory T cells. Expanded UCB PR1-CTLs are functional in vitro as they are able to produce cytokines and lyse PR1-expressing leukemia cell lines.
This study is the first report to show that T cells specific for a leukemia-associated antigen are found at a significantly higher frequency in UCB than adult blood. Our results also demonstrate specific cytotoxicity of expanded UCB-derived PR1-CTLs against PR1-expressing targets. Together, our data suggest that UCB PR1-CTLs could be useful to prevent or treat leukemia relapse in myeloid leukemia patients.
So far >180 mutations have been identified within the 153-residue human SOD1 to cause familial amyotrophic lateral sclerosis (FALS), while wild-type (WT) SOD1 was intriguingly implicated in sporadic ALS (SALS). SOD1 mutations lead to ALS by a dominant gain of cytotoxicity but its mechanism still remains elusive. Previously functional studies have revealed that SOD1 mutants became unexpectedly associated with organelle membranes. Indeed we decoded that the ALS-causing truncation mutant L126Z-SOD1 with an elevated toxicity completely loses the ability to fold into the native β-barrel structure but acquire a novel capacity to interact with membranes by forming helices over hydrophobic/amphiphilic segments. Very recently, the abnormal insertion of SOD1 mutants into ER membrane has been functionally characterized to trigger ER stress, an initial event of a cascade of cell-specific damages in ALS pathogenesis. Here we attempted to understand the mechanism for gain of cytotoxicity of the WT SOD1. We obtained atomic-resolution evidence that the nascent WT SOD1 without metalation and disulfide bridge is also highly disordered as L126Z. Most importantly, it owns the same capacity in interacting with membranes by forming very similar helices over the first 125 residues identical to L126Z-SOD1, plus an additional hydrophobic helix over Leu144-Ala152. Our study thus implies that the WT and mutant SOD1 indeed converge on a common mechanism for gain of cytotoxicity by abnormally interacting with membranes. Moreover, any genetic/environmental factors which can delay or impair its maturation might act to transform SOD1 into cytotoxic forms with the acquired capacity to abnormally interact with membranes.
Individual sensory liking appears to be an important determinant of dietary intake and may consequently influence weight status. Cross-sectional studies have shown positive association between fat liking and weight status and equivocal results regarding salt and sweet liking. Moreover, the contribution of dietary intake to explain this relationship has not been studied yet. We investigated the prospective association between sensory liking for fat, sweet or salt and the onset of obesity over 5 years in adults, and the mediating effect of dietary intake.
We prospectively examine the risk of obesity among 24,776 French adults participating in the NutriNet-Santé cohort study. Liking scores and dietary data were assessed at baseline using a validated web-based questionnaire and 24 h records, respectively. Self-reported anthropometric data were collected using web-based questionnaire, each year during 5 years. Associations between quartiles of liking for fat, sweet or salt and obesity risk, and the mediating effect of diet were assessed by multivariate Cox proportional hazards models stratified by gender, adjusted for sociodemographic and lifestyle factors.
In both genders, sensory liking for fat was associated with an increased risk of obesity (hazard ratios for quartile 4 compared to quartile 1, men: HR(Q4vs.Q1) = 2.39 (95% CI 1.39,4.11) P-trend = 0.0005, women: HR(Q4vs.Q1) = 2.02 (1.51,2.71) P-trend = <0.0001). Dietary intake explained 32% in men and 52% in women of the overall variation of liking for fat in obesity. Sensory liking for sweet was associated with a decreased risk of obesity (men: HR(Q4vs.Q1) = 0.51 (0.31,0.83) P-trend = 0.01, women: HR(Q4vs.Q1) = 0.72 (0.54,0.96) P-trend = 0.035). No significant association between salt liking and the risk of obesity was found.
Unlike sweet and salt liking, higher liking for fat appears to be a major risk factor of obesity, largely explained by dietary intake. Our findings emphasize the need to centrally position sensory liking in obesity prevention.
The neighbourhood environment such as the availability of parks are a key, but under-researched, influence on adolescents' physical activity. In addition to overall physical activity levels, park-based physical activity and park visitation is low in this age group. Thus, it is critical to identify park features that may encourage or discourage adolescents from visiting parks. This study used a novel methodology to identify key physical characteristics of parks that are perceived to be important for park visitation and park-based physical activity among adolescents.
Four secondary schools located in low, mid and high socio-economic status areas of Victoria, Australia were recruited. Using a purpose-built computer application, students in years 8-10 were presented with 44 original photographic images of park features. Participants rated each image (range 1-10) on how likely the feature would be to encourage them to visit a park and to engage in park-based physical activity, and placed symbols ('thumbs up'/'thumbs down') on aspects of the image that had a positive or negative influence on their ratings.
Participants (n = 99) had a mean age of 13.3 years (SD = 0.87) and 53% were female. Overall, the top three rated images prompting park visitation by adolescents were: a long steep slide, a flying fox and a table tennis table. These first two features were also reported as being likely to promote physical activity in the park. Differences in ratings were observed for boys and girls. The images that received the greatest number of "thumbs-up" symbols included large swings and slides, table tennis tables, no-smoking signs, flying foxes and BMX tracks. The images that received the greatest number of "thumbs-down" symbols included signage about rules, graffiti, toilets, concrete steps, and skate bowls.
Physically challenging play equipment is likely to encourage adolescents to visit and be active in parks. Rules, graffiti, toilets and skate bowls may discourage visitation. It is important for park designers, planners and policy makers to consider adolescents' views of what park design features are important so that parks are created that support and encourage visitation and optimise levels of physical activity when in the park.
Homeostatic biological systems resist external disturbances, allowing cells and organisms to maintain a constant internal state despite perturbations from their surroundings. Many biological regulatory networks are known to act homeostatically, with examples including thermal adaptation, osmoregulation, and chemotaxis. Understanding the network topologies (sets of regulatory interactions) and biological parameter regimes that can yield homeostasis in a biological system is of interest both for the study of natural biological system, and in the context of designing new biological control schemes for use in synthetic biology. Here, we examine the mathematical properties of a function that maps a biological system's inputs to its outputs, we have formulated a novel criterion (the "cofactor condition") that compactly describes the conditions for homeostasis. We further analyze the problem of robust homeostasis, wherein the system is required to maintain homeostatic behavior when its parameter values are slightly altered. We use the cofactor condition to examine previously reported examples of robust homeostasis, showing that it is a useful way to unify a number of seemingly different analyses into a single framework. Based on the observation that all previous robustly homeostatic examples fall into one of three classes, we propose a "strong cofactor condition" and use it to provide an algorithm for designing new robustly homeostatic biological networks, giving both their topologies and constraints on their parameter values. Applying the design algorithm to a three-node biological network, we construct several robustly homeostatic genetic networks, uncovering network topologies not previously identified as candidates for exhibiting robust homeostasis.
To investigate the factors eligible applicants consider in electing for a rural pathway into specialty training.
Cohort study.
Australia.
Applicants to the Australian General Practice Training program.
Applicants' initial preference of either a general or rural pathway to undertake specialty training.
Of the 2,221 applicants, 45% were Australian Medical Graduates (AMGs), 27% Foreign Graduates of Accredited Medical Schools (FGAMS) and 29% International Medical Graduates (IMGs). Through government regulation, two thirds (70%) were eligible to train on both general and rural pathways and a third (30%) were required to train rurally. For applicants
 eligible for general pathway (n = 1552), those with rural background [Odds Ratio (OR) = 3.7, 95% CI 2.7-5.2] and rural clinical school experience (OR = 2.0, 95% CI 1.5-2.8) were more likely to choose the rural pathway. In addition, FGAMS who were eligible for the general pathway were less likely to choose a rural pathway when compared with IMGs (OR = 0.33, 95%CI 0.1 = 0.7). In applicants who changed their training pathway from their initial to revised preference, lower Multiple-Mini-Interview (OR = 0.54, 95% CI 0.43-0.66) and Situational Judgement Test z-scores (OR = 0.68, 95% CI 0.56-0.83) were associated with a higher probability of changing from a general to rural pathway preference.
For those eligible for a general or rural pathway, rural background and rural clinical school experience are associated with the decision to elect for rural training. Targeted support for international and foreign graduates of Australia/New Zealand schools may influence them to train rurally.
To determine the incidence of acute kidney injury (AKI), need for emergent dialysis, and renal graft loss in patients with kidney transplants, who underwent CT examinations with low-osmolality iodine-based contrast material (IBCM).
Our institutional review board approved this retrospective Health Insurance Portability and Accountability Act compliant study. From January 2005 to April 2015, a total of 224 CT examinations were performed using low-osmolality IBCM in patients with kidney transplants. Six patients who had septic or cardiogenic shock and 30 patients with documented, failed transplants were excluded from our analysis, yielding a total of 188 examinations. Of these, pre- and post-CT serum creatinine (SCr) values were available for 104 examinations, to allow evaluation of AKI. The mean baseline SCr and estimated glomerular filtration rate (eGFR) in this subgroup were 1.37 mg/dL (median 1.18, range 0.5-6.05) and 65.8 mL/min/1.73 m(2), respectively (median 65, range 9-114). AKI was defined as a rise in SCr of either (a) ≥0.3 mg/dL or (b) ≥0.5 mg/dL in the 24- to 72-h period following IBCM administration. For all patients undergoing the 188 examinations, need for dialysis and graft loss 30 days after contrast administration were evaluated.
In patients with pre- and post-CT SCr values, the incidence of AKI was 7% (7/104) based on a rise of ≥0.3 mg/dL and 3% (3/104) based on a rise of ≥0.5 mg/dL. All three patients with the more strict definition (≥0.5 mg/dL) had a pre-CT eGFR <60 mL/min/1.73 m(2). No patient required dialysis or had renal graft loss 30 days after contrast administration.
The incidence of AKI after administration of low-osmolality IBCM administration in renal transplant recipients is low, with no instances of emergent dialysis or graft loss at 30 days post contrast.
There is long-term (trophic) purinergic signalling involving cell proliferation, differentiation, motility and death in the development and regeneration of most systems of the body, in addition to fast purinergic signalling in neurotransmission, neuromodulation and secretion. It is not always easy to distinguish between short- and long-term signalling. For example, adenosine triphosphate (ATP) can sometimes act as a short-term trigger for long-term trophic events that become evident days or even weeks after the original challenge. Examples of short-term purinergic signalling during sympathetic, parasympathetic and enteric neuromuscular transmission and in synaptic transmission in ganglia and in the central nervous system are described, as well as in neuromodulation and secretion. Long-term trophic signalling is described in the immune/defence system, stratified epithelia in visceral organs and skin, embryological development, bone formation and resorption and in cancer. It is likely that the increase in intracellular Ca(2+) in response to both P2X and P2Y purinoceptor activation participates in many short- and long-term physiological effects.This article is part of the themed issue 'Evolution brings Ca(2+) and ATP together to control life and death'.
Vitamin D is a hormone that maintains healthy cells. It functions by regulating the low resting levels of cell signalling components such as Ca(2+) and reactive oxygen species (ROS). Its role in maintaining phenotypic stability of these signalling pathways depends on the ability of vitamin D to control the expression of those components that act to reduce the levels of both Ca(2+) and ROS. This regulatory role of vitamin D is supported by both Klotho and Nrf2. A decline in the vitamin D/Klotho/Nrf2 regulatory network may enhance the ageing process, and this is well illustrated by the age-related decline in cognition in rats that can be reversed by administering vitamin D. A deficiency in vitamin D has also been linked to two of the major diseases in man: heart disease and Alzheimer's disease (AD). In cardiac cells, this deficiency alters the Ca(2+) transients to activate the gene transcriptional events leading to cardiac hypertrophy and the failing heart. In the case of AD, it is argued that vitamin D deficiency results in the Ca(2+) landscape that initiates amyloid formation, which then elevates the resting level of Ca(2+) to drive the memory loss that progresses to neuronal cell death and dementia.This article is part of the themed issue 'Evolution brings Ca(2+) and ATP together to control life and death'.
In the central nervous system (CNS), during both brain and spinal cord development, purinergic and pyrimidinergic signalling molecules (ATP, UTP and adenosine) act synergistically with peptidic growth factors in regulating the synchronized proliferation and final specification of multipotent neural stem cells (NSCs) to neurons, astrocytes or oligodendrocytes, the myelin-forming cells. Some NSCs still persist throughout adulthood in both specific 'neurogenic' areas and in brain and spinal cord parenchyma, retaining the potentiality to generate all the three main types of adult CNS cells. Once CNS anatomical structures are defined, purinergic molecules participate in calcium-dependent neuron-to-glia communication and also control the behaviour of adult NSCs. After development, some purinergic mechanisms are silenced, but can be resumed after injury, suggesting a role for purinergic signalling in regeneration and self-repair also via the reactivation of adult NSCs. In this respect, at least three different types of adult NSCs participate in the response of the adult brain and spinal cord to insults: stem-like cells residing in classical neurogenic niches, in particular, in the ventricular-subventricular zone (V-SVZ), parenchymal oligodendrocyte precursor cells (OPCs, also known as NG2-glia) and parenchymal injury-activated astrocytes (reactive astrocytes). Here, we shall review and discuss the purinergic regulation of these three main adult NSCs, with particular focus on how and to what extent modulation of intracellular calcium levels by purinoceptors is mandatory to determine their survival, proliferation and final fate.This article is part of the themed issue 'Evolution brings Ca(2+) and ATP together to control life and death'.
KATP channels act as key regulators of electrical excitability by coupling metabolic cues-mainly intracellular adenine nucleotide concentrations-to cellular potassium ion efflux. However, their study has been hindered by their rapid loss of activity in excised membrane patches (rundown), and by a second phenomenon, the decline of activation by Mg-nucleotides (DAMN). Degradation of PI(4,5)P2 and other phosphoinositides is the strongest candidate for the molecular cause of rundown. Broad evidence indicates that most other determinants of rundown (e.g. phosphorylation, intracellular calcium, channel mutations that affect rundown) also act by influencing KATP channel regulation by phosphoinositides. Unfortunately, experimental conditions that reproducibly prevent rundown have remained elusive, necessitating post hoc data compensation. Rundown is clearly distinct from DAMN. While the former is associated with pore-forming Kir6.2 subunits, DAMN is generally a slower process involving the regulatory sulfonylurea receptor (SUR) subunits. We speculate that it arises when SUR subunits enter non-physiological conformational states associated with the loss of SUR nucleotide-binding domain dimerization following prolonged exposure to nucleotide-free conditions. This review presents new information on both rundown and DAMN, summarizes our current understanding of these processes and considers their physiological roles.This article is part of the themed issue 'Evolution brings Ca(2+) and ATP together to control life and death'.
Nitric oxide (NO) is an essential endogenous mediator with a physiological role in the central nervous system as neurotransmitter and neuromodulator. A growing number of studies have demonstrated that abnormal nitrergic signaling is a crucial event in the development of neurodegeneration. In particular, the uncontrolled production of NO by neuronal nitric oxide synthase (nNOS) is observed in several neurodegenerative diseases. Moreover, it is well recognized that specific isoforms of human carbonic anhydrase (hCA) physiologically modulate crucial pathways of signal processing and that low expression of CA affects cognition, leading to mental retardation, Alzheimer's disease, and aging-related cognitive impairments. In light of this, dual agents that are able to target both NOS (inhibition) and CA (activation) could be useful drug candidates for the treatment of Alzheimer's disease, aging, and other neurodegenerative diseases. In the present work, we show the design, synthesis, and in vitro biological evaluation of new nitrogen-based heterocyclic compounds. Among the tested molecules, 2-amino-3-(4-hydroxyphenyl)-N-(1H-indazol-5-yl)propanamide hydrochloride (10 b) was revealed to
 be a potent dual agent, able to act as a selective nNOS inhibitor and activator of the hCA I isoform.
This study provides high-quality variation data of diverse radish genotypes. Genome-wide SNP comparison along with RNA-seq analysis identified candidate genes related to domestication that have potential as trait-related markers for genetics and breeding of radish. Radish (Raphanus sativus L.) is an annual root vegetable crop that also encompasses diverse wild species. Radish has a long history of domestication, but the origins and selective sweep of cultivated radishes remain controversial. Here, we present comprehensive whole-genome resequencing analysis of radish to explore genomic variation between the radish genotypes and to identify genetic bottlenecks due to domestication in Asian cultivars. High-depth resequencing and multi-sample genotyping analysis of ten cultivated and seven wild accessions obtained 4.0 million high-quality homozygous single-nucleotide polymorphisms (SNPs)/insertions or deletions. Variation analysis revealed that Asian cultivated radish types are closely related to wild Asian accessions, but are distinct from European/American cultivated radishes, supporting the notion that Asian cultivars were domesticated from wild Asian genotypes. SNP comparison between Asian genotypes identified 153 candidate domestication regions (CDRs) containing 512 genes. Network analysis of the genes in CDRs functioning in plant signaling pathways and biochemical processes identified group of genes related to root architecture, cell wall, sugar metabolism, and glucosinolate biosynthesis. Expression profiling of the genes during root development suggested that domestication-related selective advantages included a main taproot with few branched lateral roots, reduced cell wall rigidity and favorable taste. Overall, this study provides evolutionary insights into domestication-related genetic selection in radish as well as identification of gene candidates with the potential to act as trait-related markers for background selection of elite lines in molecular breeding.
Efficacy of pre-trauma prevention for post-traumatic stress disorder (PTSD) has not yet been established in a randomized controlled trial. Attention bias modification training (ABMT), a computerized intervention, is thought to mitigate stress-related symptoms by targeting disruptions in threat monitoring. We examined the efficacy of ABMT delivered before combat in mitigating risk for PTSD following combat.
We conducted a double-blind, four-arm randomized controlled trial of 719 infantry soldiers to compare the efficacy of eight sessions of ABMT (n = 179), four sessions of ABMT (n = 184), four sessions of attention control training (ACT; n = 180), or no-training control (n = 176). Outcome symptoms were measured at baseline, 6-month follow-up, 10 days following combat exposure, and 4 months following combat. Primary outcome was PTSD prevalence 4 months post-combat determined in a clinical interview using the Clinician-Administered PTSD Scale. Secondary outcomes were self-reported PTSD and depression symptoms, collected at all four assessments.
PTSD prevalence 4 months post-combat was 7.8% in the no-training control group, 6.7% with eight-session ABMT, 2.6% with four-session ABMT, and 5% with ACT. Four sessions of ABMT reduced risk for PTSD relative to the no-training condition (odds ratio 3.13, 95% confidence interval 1.01-9.22, p < 0.05, number needed to treat = 19.2). No other between-group differences were found. The results were consistent across a variety of analytic techniques and data imputation approaches.
Four sessions of ABMT, delivered prior to combat deployment, mitigated PTSD risk following combat exposure. Given its low cost and high scalability potential, and observed number needed to treat, research into larger-scale applications is warranted. The ClinicalTrials.gov identifier is NCT01723215.
The filamentous fungus Hypocrea jecorina produces a number of cellulases and hemicellulases that act in a concerted fashion on biomass and degrade it into monomeric or oligomeric sugars. β-Glucosidases are involved in the last step of the degradation of cellulosic biomass and hydrolyse the β-glycosidic linkage between two adjacent molecules in dimers and oligomers of glucose. In this study, it is shown that substituting the β-glucosidase from H. jecorina (HjCel3A) with the β-glucosidase Cel3A from the thermophilic fungus Rasamsonia emersonii (ReCel3A) in enzyme mixtures results in increased efficiency in the saccharification of lignocellulosic materials. Biochemical characterization of ReCel3A, heterologously produced in H. jecorina, reveals a preference for disaccharide substrates over longer gluco-oligosaccharides. Crystallographic studies of ReCel3A revealed a highly N-glycosylated three-domain dimeric protein, as has been observed previously for glycoside hydrolase family 3 β-glucosidases. The increased thermal stability and saccharification yield and the superior biochemical characteristics of ReCel3A compared with HjCel3A and mixtures containing HjCel3A make ReCel3A an excellent candidate for addition to enzyme mixtures designed to operate at higher temperatures.
Metal-organic frameworks (MOFs) based on multidentate N-heterocyclic ligands involving imidazole, triazole, tetrazole, benzimidazole, benzotriazole or pyridine present intriguing molecular topologies and have potential applications in ion exchange, magnetism, gas sorption and storage, catalysis, optics and biomedicine. The 2-[(1H-1,2,4-triazol-1-yl)methyl]-1H-benzimidazole (tmb) ligand has four potential N-atom donors and can act in monodentate, chelating, bridging and tridentate coordination modes in the construction of complexes, and can also act as both a hydrogen-bond donor and acceptor. In addition, the tmb ligand can adopt different coordination conformations, resulting in complexes with helical structures due to the presence of the flexible methylene spacer. A new three-dimensional coordination polymer, poly[[bis(μ2-benzene-1,4-dicarboxylato)-κ(4)O(1),O(1'):O(4),O(4');κ(2)O(1):O(4)-bis{μ2-2-[(1H-1,2,4-triazol-1-yl)methyl-κN(4)]-1H-benzimidazole-κN(3)}dizinc(II)] trihydrate], {[Zn(C8H4O4)(C10H9N5)]·1.5H2O}n, has been synthesized by the reaction of ZnCl2 with tmb and benzene-1,4-dicarboxylic acid (H2bdic) under solvothermal conditions. There are two crystallographically distinct bdic(2-) ligands [bdic(2-)(A) and bdic(2-)(B)] in the structure which adopt different coordination modes. The Zn(II) ions are bridged by tmb ligands, leading to one-dimensional helical chains with different handedness, and adjacent helices are linked by bdic(2-)(A) ligands, forming a two-dimensional network structure. The two-dimensional layers are further connected by bdic(2-)(B) ligands, resulting in a three-dimensional framework with the topological notation 6(6). The IR spectra and thermogravimetric curves are consistent with the results of the X-ray crystal structure analysis and the title polymer exhibits good fluorescence in the solid state at room temperature.
The challenge in efficient electrochemical detection of trace heavy metal ions (HMI) for early warning is to construct an electrode with a nano-patterned architecture. In this study, a range of carbon electrodes with ordered structures were fabricated using colloidal hollow carbon nanospheres (HCSs) as sensing materials for trace HMI (represented by Pb(ii)) detection by square wave anodic stripping voltammetry. The regular geometrical characteristics of the carbon electrode allow it to act as a model system for the estimation of electron transfer pathways by calculating contact points between HCSs and a glassy carbon electrode. A clear correlation between the contact points and the electron transfer resistance has been established, which fits well with the quadratic function model and is dependent on the size of HCSs. To our knowledge, this is the first clear function that expresses the structure-sensing activity relationship of carbon-based electrodes. The prepared carbon electrode is capable of sensing Pb(ii) with a sensitivity of 0.160 μA nM(-1), which is much higher than those of other electrodes reported in the literature. Its detection limit of 0.6 nM is far below the guideline value (72 nM) given by the US Environmental Protection Agency. In addition, the carbon electrode could be a robust alternative to various heavy metal sensors.
Four coordination compounds of formulae [Cu(II)2(H2L(1))(HL(1))](ClO4)3·H2O (1), [Cu(II)2(H2L(2))(CH3OH)2](ClO4)2·2CH3OH (2), [Co(II)2(H2L(1))2](ClO4)4 (3) and [Co(II)2(H2L(2))2]·2H2O (4) were synthesized via self-assembly of succinohydrazone derived ligands (H2L(1) = N',N'-4-bis(2-pyridyl)succinohydrazide, H4L(2) = N',N'-4-bis(2-hydroxybenzylidene)succinohydrazide) and Cu(2+) and Co(2+) ions, respectively. The compounds were characterized by crystal structure determination, magnetic measurements and biological activities. Compounds 1, 3 and 4 have discrete double helicate structures, whereas compound 2 is a one-dimensional chain. Magnetic studies show antiferromagnetic exchange interactions in 2 with a J value of -67.1 cm(-1) and antiferromagnetic spin-canting in compound 3 originates through supramolecular H-bonding. For compound 3, a clear bifurcation was observed in zero field cooled (ZFC) and field cooled (FC) measurement at a temperature of 3.5 K and field of 0.1 T, implying long range magnetic ordering below this temperature. Interestingly, all of compounds 1-4 show significant changes in their absorption (hypo- and hyperchromism) in the presence of SS-DNA, inferring interaction between the compounds and DNA. In addition, compounds 1-4 significantly exhibited nuclease activities on both RNA and pUC19 plasmid DNA. Moreover, the nuclease activity was further enhanced in the presence of oxidant (H2O2)
 and suggests the possible role of reactive oxygen species in DNA nicking ability of compounds 1-4. Furthermore, compounds 1, 2 and 4 exhibited significant cytotoxicity against mammalian cancer cell lines (HeLa, A549 and MDAMB-231). In addition, our results from Annexin/PI staining and DNA fragmentation assays revealed that these compounds are capable of inducing apoptosis and have potential to act as anticancer drugs.
To understand the effects of tellurium (Te) inclusions on the device performance of CdZnTe radiation detectors, the perturbation of the electrical field in and around Te inclusions was studied in CdZnTe single crystals via Kelvin probe force microscopy (KPFM). Te inclusions were proved to act as lower potential centers with respect to surrounding CdZnTe matrix. Based on the KPFM results, the energy band diagram at the Te/CdZnTe interface was established, and the bias-dependent effects of Te inclusion on carrier transportation is discussed.
Psoriasis commonly responds beneficially to UV radiation from natural sunlight or artificial sources. Therapeutic mechanisms include the proapoptotic and immunomodulating effects of UV, affecting many cells and involving a variety of pro- and anti-inflammatory cytokines, downregulating the Th17/IL-23 response with simultaneous induction of regulatory immune cells. However, exposure to UV radiation in a subset of psoriasis patients leads to exacerbation of the disease. We herein shed light on the predisposing factors of photosensitive psoriasis, including genetics (such as HLA-Cw*0602 or CARD14), gender and coexisting photodermatoses such as polymorphic light eruption (PLE) in the context of potential molecular mechanisms behind therapeutic photoresponsiveness or photoaggravation. UV-induced damage/pathogen-associated molecular patterns, damage to self-coding RNA (signalling through Toll-like receptors), certain antimicrobial peptides and/or inflammasome activation may induce innate immunity, leading to psoriasis at the site of UV exposure when there is concomitant, predisposing resistance against UV-induced suppression of the adaptive immune response (like in PLE) that otherwise would act to reduce psoriasis.
Medicaid reimburses healthcare providers for services at a lower rate than any other type of insurance coverage. To account for the burden of treating Medicaid patients, providers claim that they must cost-shift by raising the rates of individuals covered by private insurance. Previous investigations of cost-shifting has produced mixed results. In this paper, I exploit a disabled Medicaid expansion where crowd-out was complete to investigate cost-shifting. I find that hospitals reduce the charge rates of the privately insured. Given that Medicaid is expanding in several states under the Affordable Care Act, these results may alleviate cost-shifting concerns of the reform.
Perfluoroaryl-substituted tellurophenes act as anion receptors through noncovalent chalcogen bonding interactions. Linking two tellurophenes through an ethynylene group results in a significant level of chelate cooperativity, thus demonstrating that chalcogen bonding can be used to achieve multidentate anion recognition.
Psoriasis is a common chronic inflammatory disease with an incidence of about 0.5-3 %. Previously psoriasis was not primarily regarded to be associated with pruritus; however, this perception has changed in recent years. Meanwhile data conclusively show that between 64 and 97 % of patients report about pruritus that can be severe in a number of cases. Apart from suffering from psoriasis, the presence of pruritus causes additional stress and leads to a significant impairment of health-related quality of life. Neurogenic inflammation at least in part contributes to the development of pruritus in psoriasis skin lesions. A number of neuropeptides including substance P and calcitonin gene related peptide can act as pro-inflammatory mediators. There is evidence for a dysbalance between κ  and µ opioid receptors in lesional skin favoring inflammation and pruritus. After clearing of psoriasis lesions, pruritus is relieved as well. Therefore, specific treatment of pruritus is not necessary in general. In cases where severe pruritus is a prominent symptom, targeted therapy with mirtazapin or doxepin or neuroleptic compounds such as pregabalin or gabapentin or drugs affecting the κ  und µ opioid receptor balance can be administered. Today the importance of pruritus as a prominent symptom of psoriasis lesions has been widely accepted. In recent and running clinical trials with new drugs, pruritus at baseline and the effect of these drugs on pruritus is always assessed. This awareness also fuels basic research about pruritus in psoriasis.
p53 is one of the most important tumor suppressors and is known to play critical roles in the process of tumor development. Similarly, as an important proto-oncogenes, c-Myc is activated in over half of human cancers. Both p53 and c-Myc participate in almost every crucial decision of almost every cell. Therefore, it is utmost important to gain a better understanding of how they affect multiple cellular processes. The physiological and pathologic patterns of p53 and c-Myc regulations are modulated by a large number of cis-elements and transfactors (RNAs and proteins). These elements and factors are composed of a complicated network of intracellular and extracellular pathways. How the noncoding RNAs are involved in their regulations has not been comprehensively reviewed. In this chapter, we will list and describe recently published important noncoding RNAs including microRNAs and long noncoding RNAs, which act as effectors and regulators for both p53 and c-Myc regulation. The purpose of this chapter is to provide a recent progress of noncoding RNA in the regulation of p53 and c-Myc on network of cellular signaling and its potential implications in both basic science and clinical application.
The cellular signaling network plays a fundamental role during development and disease, especially cancer progression. By deregulating signaling pathways, cancer cells acquire hallmarks of the disease including uncontrolled proliferation, evasion from cell death, activation of angiogenesis, invasion, and metastasis. Noncoding RNAs make substantial contributions to regulating signal transduction in cancer, thereby promoting or suppressing different biological processes during tumorigenesis. This chapter provides an overview on the regulatory functions of noncoding RNAs in the signaling network in cancer cells. It summarizes examples of noncoding RNAs that act as oncogenes or tumor-suppressing genes involved in key signal pathways as well as signal crosstalk in cancer cells.
Epigenetic alterations, including aberrant DNA methylation and histone modification, play key roles in the dysregulation of tumor-related genes, thereby affecting numerous cellular processes, including cell proliferation, cell adhesion, apoptosis, and metastasis. In recent years, studies have demonstrated that short and long noncoding RNAs (ncRNAs) are key players in the initiation and progression of cancer, and epigenetic mechanisms are deeply involved in their dysregulation. Indeed, the growing list of microRNA (miRNA) genes aberrantly methylated in cancer suggests that a large number of miRNAs act as tumor suppressors or oncogenes. In addition, emerging evidence suggests that dysregulation of long ncRNAs (lncRNAs) plays critical roles in tumorigenesis. And because ncRNAs are involved in regulating gene expression through interaction with epigenetic modifiers, their dysregulation appears causally related to epigenetic alterations in cancer. Dissection of the interrelationships between ncRNAs and epigenetic alterations has the potential to reveal novel approaches to the diagnosis and treatment of cancer.
The world of noncoding RNAs (ncRNAs) has gained widespread attention in recent years due to their novel and crucial potency of biological regulation. Noncoding RNAs play essential regulatory roles in a broad range of developmental processes and diseases, notably human cancers. Regulatory ncRNAs represent multiple levels of structurally and functionally distinct RNAs, including the best-known microRNAs (miRNAs), the complicated long ncRNAs (lncRNAs), and the newly identified circular RNAs (circRNAs). However, the mechanisms by which they act remain elusive. In this chapter, we will review the current knowledge of the ncRNA field, discussing the genomic context, biological functions, and mechanisms of action of miRNAs, lncRNAs, and circRNAs. We also highlight the implications of the biogenesis and gene expression dysregulation of different ncRNA subtypes in the initiation and development of human malignancies.
During T cell development, multipotent progenitors relinquish competence for other fates and commit to the T cell lineage by turning on Bcl11b, which encodes a transcription factor. To clarify lineage commitment mechanisms, we followed developing T cells at the single-cell level using Bcl11b knock-in fluorescent reporter mice. Notch signaling and Notch-activated transcription factors collaborate to activate Bcl11b expression irrespectively of Notch-dependent proliferation. These inputs work via three distinct, asynchronous mechanisms: an early locus 'poising' function dependent on TCF-1 and GATA-3, a stochastic-permissivity function dependent on Notch signaling, and a separate amplitude-control function dependent on Runx1, a factor already present in multipotent progenitors. Despite their necessity for Bcl11b expression, these inputs act in a stage-specific manner, providing a multitiered mechanism for developmental gene regulation.
Many genes determining cell identity are regulated by clusters of Mediator-bound enhancer elements collectively referred to as super-enhancers. These super-enhancers
 have been proposed to manifest higher-order properties important in development and disease. Here we report a comprehensive functional dissection of one of the strongest putative super-enhancers in erythroid cells. By generating a series of mouse models, deleting each of the five regulatory elements of the α-globin super-enhancer individually and in informative combinations, we demonstrate that each constituent enhancer seems to act independently and in an additive fashion with respect to hematological phenotype, gene expression, chromatin structure and chromosome conformation, without clear evidence of synergistic or higher-order effects. Our study highlights the importance of functional genetic analyses for the identification of new concepts in transcriptional regulation.
The accumulation of macrophages (MΦ) at the sensor-tissue interface is thought to be a major player in controlling tissue reactions and sensor performance in vivo. Nevertheless until recently no direct demonstration of the causal relationship between MΦ aggregation and loss of sensor function existed. Using a Continuous Glucose Monitoring (CGM) murine model we previously demonstrated that genetic deficiencies of MΦ or depletion of MΦ decreased MΦ accumulation at sensor implantation sites, which led to significantly enhanced CGM performance, when compared to normal mice. Additional studies in our laboratories have also demonstrated that MΦ can act as "metabolic sinks" by depleting glucose levels at the implanted sensors in vitro and in vivo. In the present study we extended these observations by demonstrating that MΦ chemokine (CCL2) and receptor (CCR2) knockout mice displayed a decrease in inflammation and MΦ recruitment at sensor implantation sites, when compared to normal mice. This decreased MΦ recruitment significantly enhanced CGM performance when compared to control mice. These studies demonstrated the importance of the CCL2 family of chemokines and related receptors in MΦ recruitment and sensor performance and suggest chemokine targets for enhancing CGM in vivo.
Pseudomonas aeruginosa is an opportunistic pathogen responsible for many diseases such as chronic lung colonization in cystic fibrosis patients and acute infections in hospitals. The capacity of P. aeruginosa to be pathogenic toward several hosts is notably due to different secretion systems. Amongst them, P. aeruginosa encodes three Type Six Secretion Systems (T6SS), named H1- to H3-T6SS, that act against either prokaryotes and/or eukaryotic cells. They are independent from each other and inject diverse toxins that interact with different components in the host cell. Here we summarize the roles of these T6SSs in the PAO1 strain, as well as the toxins injected and their targets. While H1-T6SS is only involved in antiprokaryotic activity through at least seven different toxins, H2-T6SS and H3-T6SS are also able to target prokaryotic as well as eukaryotic cells. Moreover, recent studies proposed that H2- and H3-T6SS have a role in epithelial cells invasion by injecting at least three different toxins. The diversity of T6SS effectors is astounding and other effectors still remain to be discovered. In this review, we present a table with other putative P. aeruginosa strain PAO1 T6SS-dependent effectors. Altogether, the T6SSs of P. aeruginosa are important systems that help fight other bacteria for their ecological niche, and are important in the pathogenicity process.
Psychological inflexibility is a core concept in the acceptance and commitment therapy (ACT) model. The current study hypothesized and tested two models in which psychological inflexibility was linked with higher levels of depressive symptoms and sleep difficulty.
To attain data, Japanese university students (N = 633) completed questionnaires related to psychological inflexibility, depressive symptoms, and sleep difficulty. Psychological inflexibility was significantly correlated with higher levels of both depressive symptoms (r = 0.61) and sleep difficulty (r = 0.39). Structural equation modeling showed that psychological inflexibility was associated with higher levels of depressive symptoms after controlling for the effect of sleep difficulty. Additionally, psychological inflexibility was correlated with higher levels of sleep difficulty after controlling for the effect of depressive symptoms. These findings might assist with motivating clinicians to use ACT for insomnia.
The current study found that greater psychological inflexibility was linked with high levels of depressive symptoms and sleep difficulties. These findings might assist with motivating clinicians to use ACT for insomnia.
Several chemo-drugs act as the biocompatible fluorophores. Here, the laser induced fluorescence (LIF) properties of doxorubicin, paclitaxel and bleomycin are investigated. The absorption lines mostly lie over UV range according to the UV-VIS spectra. Therefore, a single XeCl laser provokes the desired transitions of the chemo-drugs of interest at 308 nm. It is shown that LIF spectra are strongly dependent on the fluorophore concentration giving rise to the sensible red shift. This happens when large overlapping area appears between absorption and emission spectra accordingly. The red shift is taken into account as a characteristic parameter of a certain chemo-drug. The fluorescence extinction (α) and self-quenching (k) coefficients are determined based on the best fitting of the adopted Lambert-Beer equation over experimental data. The quantum yield of each chemo-drug is also measured using the linearity of the absorption and emission rates.
Optically controlled release of a DNA strand based on a nonradiative relaxation process of black hole quenchers (BHQs), which are a sort of dark quenchers, is presented. BHQs act as efficient energy sources because they relax completely via a nonradiative process, i.e., without fluorescent emission-based energy losses. A DNA strand is modified with BHQs and the release of its complementary strand is controlled by excitation of the BHQs. Experimental results showed that up to 50% of the target strands were released, and these strands were capable of inducing subsequent reactions. The controlled release was localized on a substrate within an area of no more than 5 micrometers in diameter.
In the crystal of the title compound, C16H9BrN2O4·0.5C6H6, the mol-ecules stack in a centrosymmetric unit cell in a 2:1 stoichiometry with co-crystallized benzene solvent mol-ecules and inter-act via various weak inter-actions. This induces a geometry different from that predicted by theory, and is unique among the hemibi-quinones heretofore reported.
The asymmetric unit of the title compound, 4C4H4FN3O·C3H6N6, comprises of two independent 5-fluoro-cytosine (5FC) mol-ecules (A and B) and one half-mol-ecule of melamine (M). The other half of the melamine mol-ecule is generated by a twofold axis. 5FC mol-ecules A and B are linked through two different homosynthons [R 2 (2)(8) ring motif]; one is formed via a pair of N-H⋯O hydrogen bonds and the second via a pair of N-H⋯N hydrogen bonds. In addition to this pairing, the O atoms of 5FC mol-ecules A and B inter-act with the N2 amino group on both sides of the melamine mol-ecule, forming a DDAA array of quadruple hydrogen bonds and generating a supra-molecular pattern. The 5FC (mol-ecules A and B) and two melamine mol-ecules inter-act via N-H⋯O, N-H⋯N and N-H⋯O, N-H⋯N, C-H⋯F hydrogen bonds forming R 6 (6)(24) and R 4 (4)(15) ring motifs. The crystal structure is further strengthened by C-H⋯F, C-F⋯π and π-π stacking inter-actions.
The title salts, C4H7N2 (+)·NO3 (-)·C4H6N2, (I), and C4H7N2 (+)·NO3 (-), (II), were obtained from solutions containing 2-methyl-imidazole and nitric acid in different concentrations. In the crystal structure of salt (I), one of the -NH H atoms of the imidazole ring shows half-occupancy, hence only every second mol-ecule is in its cationic form. The nitrate anion in this structure lies on a twofold rotation axis. The neutral 2-methyl-imidazole mol-ecule and the 2-methyl-1H-imidazol-3-ium cation inter-act through N-H⋯N hydrogen bonds to form [(C4H6N2)⋯(C4H7N2)(+)] pairs. These pairs are linked with two nitrate anions on both sides through bifurcated N-H⋯(O,O) hydrogen bonds into chains running parallel to [001]. In the crystal structure of salt (II), the C4H7N2 (+) cation and the NO3 (-) anion are both located on a mirror plane, leading to a statistical disorder of the methyl H atoms. The cations and anions again inter-act through bifurcated N-H⋯(O,O) hydrogen bonds, giving rise to the formation of chains consisting of alternating anions and cations parallel to [100].
Polymicrobial biofilms are abundant in clinical disease, particularly within the oral cavity. Creating complex biofilm models that recapitulate the polymicrobiality of oral disease are important in the development of new chemotherapeutic agents. In order to do this accurately we require the ability to undertake compositional analysis, in addition to determine individual cell viability, which is difficult using conventional microbiology. The aim of this study was to develop a defined multispecies denture biofilm model in vitro, and to assess viable compositional analysis following defined oral hygiene regimens.
An in vitro multispecies denture biofilm containing various oral commensal and pathogenic bacteria and yeast was created on poly (methyl methacrylate) (PMMA). Denture hygiene regimens tested against the biofilm model included brushing only, denture cleansing only and combinational brushing and denture cleansing. Biofilm composition and viability were assessed by culture (CFU) and molecular (qPCR) methodologies. Scanning electron microscopy and confocal laser scanning microscopy were also employed to visualize changes in denture biofilms following treatment.
Combinational treatment
 of brushing and denture cleansing had the greatest impact on multispecies denture biofilms, reducing the number of live cells by more than 2 logs, and altering the overall composition in favor of streptococci. This was even more evident during the sequential testing, whereby daily sequential treatment reduced the total and live number of bacteria and yeast more than those treated intermittently. Bacteria and yeast remaining following treatment tended to aggregate in the pores of the PMMA, proving more difficult to fully eradicate the biofilm.
Overall, we are the first to develop a method to enable viable compositional analysis of an 11 species denture biofilm following chemotherapeutic challenge. We were able to demonstrate viable cell reduction and changes in population dynamics following evaluation of various denture cleansing regimens. Specifically, it was demonstrated that daily combinational treatment of brushing and cleansing proved to be the most advantageous denture hygiene regimen, however, residual organisms still remained within the pores of PMMA surface, which could act as a reservoir for further biofilm regrowth. We have identified an industry need for denture cleansing agents with the capacity to penetrate these pores and disaggregate these complex biofilm consortia.
tRNAs are charged with cognate amino acids by aminoacyl-tRNA synthetases (aaRSs) and subsequently delivered to the ribosome to be used as substrates for gene translation. Whether aminoacyl-tRNAs are channeled to the ribosome by transit within translational complexes that avoid their diffusion in the cytoplasm is a matter of intense investigation in organisms of the three domains of life. In the cyanobacterium Anabaena sp. PCC 7120, the valyl-tRNA synthetase (ValRS) is anchored to thylakoid membranes by means of the CAAD domain. We have investigated whether in this organism ValRS could act as a hub for the nucleation of a translational complex by attracting other aaRSs to the membranes. Out of the 20 aaRSs, only ValRS was found to localize in thylakoid membranes whereas the other enzymes occupied the soluble portion of the cytoplasm. To investigate the basis for this asymmetric distribution of aaRSs, a global search for proteins interacting with the 20 aaRSs was conducted. The interaction between ValRS and the FoF1 ATP synthase complex here reported is of utmost interest and suggests a functional link between elements of the gene translation and energy production machineries.
In two experiments (n = 35, n = 34), we used a modified fear-conditioning paradigm to investigate the role of aversive learning in retaliatory behavior in social context. Participants first completed an initial aversive learning phase in which the pairing of a neutral conditioned stimulus (CS; i.e., neutral face) with a naturally aversive unconditioned stimulus (US; electric shock) was learned. Then they were given an opportunity to interact (i.e., administer 0-2 shocks) with the same faces again, during a Test phase. In Experiment 2, we used the same paradigm with the addition of online trial-by-trial ratings (e.g., US expectancy and anger) to examine the role of aversive learning, anger, and the learned expectancy of receiving punishment more closely. Our results indicate that learned aversions influenced future retaliation in a social context. In both experiments, participants showed largest skin conductance responses (SCRs) to the faces paired with one or two shocks, demonstrating successful aversive learning. Importantly, participants administered more shocks to the faces paired with the most number of shocks when the opportunity was given during test. Also, our results revealed that aggressive traits (Buss and Perry Aggression scale) were associated with retaliation only toward CSs associated with aversive experiences. These two experiments show that aggressive traits, when paired with aversive learning experiences enhance the likelihood to act anti-socially toward others.
HIGHLIGHTS Many CNS targets are being explored for multi-target drug designNew databases and cheminformatic methods enable prediction of primary pharmaceutical target and off-targets of compoundsQSAR, virtual screening and docking methods increase the potential of rational drug design The diverse cerebral mechanisms implicated in Central Nervous System (CNS) diseases together with the heterogeneous and overlapping nature of phenotypes indicated that multitarget strategies may be appropriate for the improved treatment of complex brain diseases. Understanding how the neurotransmitter systems interact is also important in optimizing therapeutic strategies. Pharmacological intervention on one target will often influence another one, such as the well-established serotonin-dopamine interaction or the dopamine-glutamate interaction. It is now accepted that drug action can involve plural targets and that polypharmacological interaction with multiple targets, to address disease in more subtle and effective ways, is a key concept for development of novel drug candidates against complex CNS diseases. A multi-target therapeutic strategy for Alzheimer's disease resulted in the development of very effective Multi-Target Designed Ligands (MTDL) that act on both the cholinergic and monoaminergic systems, and also retard the progression of neurodegeneration by inhibiting amyloid aggregation. Many compounds already in databases have been investigated as ligands for multiple targets in drug-discovery programs. A probabilistic method, the Parzen-Rosenblatt Window approach, was used to build a "predictor" model using data collected from the ChEMBL database. The model can be used to predict both the primary pharmaceutical target and off-targets of a compound based on its structure. Several multi-target ligands were selected for further study, as compounds with possible additional beneficial pharmacological activities. Based on all these findings, it is concluded that multipotent ligands targeting AChE/MAO-A/MAO-B and also D1-R/D2-R/5-HT2A -R/H3-R are promising novel drug candidates with improved efficacy and beneficial neuroleptic and procognitive activities in treatment of Alzheimer's and related neurodegenerative diseases. Structural information for drug targets permits docking and virtual screening and exploration of the molecular determinants of binding, hence facilitating the design of multi-targeted drugs. The crystal structures and models of enzymes of the monoaminergic and cholinergic systems have been used to investigate the structural origins of target selectivity and to identify molecular determinants, in order to design MTDLs.
To examine the predictions of alternative models for the stochastic shut-off of activated rhodopsin (R*) and their implications for the interpretation of experimentally recorded single-photon responses (SPRs) in mammalian rods.
We analyze the transitions that an activated R* molecule undergoes as a result of successive phosphorylation steps and arrestin binding. We consider certain simplifying cases for the relative magnitudes of the reaction rate constants and derive the probability distributions for the time to arrestin binding. In addition to the conventional model in which R* catalytic activity declines in a graded manner with successive phosphorylations, we analyze two cases in which the activity is assumed to occur not via multiple small steps upon each phosphorylation but via a single large step. We refer to these latter two cases as the binary R* shut-off and three-state R* shut-off models.
We simulate R*'s stochastic reactions numerically for the three models. In the simplifying cases for the ratio of rate constants in the binary and three-state models, we show that the probability distribution of the time to arrestin binding is accurately predicted. To simulate SPRs, we then integrate the differential equations for the downstream reactions using a standard model of the rod outer segment that includes longitudinal diffusion of cGMP and Ca(2+).
Our simulations of SPRs in the conventional model of graded shut-off of R* conform closely to the simulations in a recent study. However, the gain factor required to account for the observed mean SPR amplitude is higher than can be accounted for from biochemical experiments. In addition, a substantial minority of the simulated SPRs exhibit features that have not been reported in published experiments. Our simulations of SPRs using the model of binary R* shut-off appear to conform closely to experimental results for wild type (WT) mouse rods, and the required gain factor conforms to biochemical expectations. However, for the arrestin knockout (Arr(-/-)) phenotype, the predictions deviated from experimental findings and led us to invoke a low-activity state that R* enters before arrestin binding. Our simulations of this three-state R* shut-off model are very similar to those of the binary model in the WT case but are preferred because they appear to accurately predict the mean SPRs for four mutant phenotypes, Arr(+/-), Arr(-/-), GRK1(+/-), and GRK1(-/-), in addition to the WT phenotype. When we additionally treated the formation and shut-off of activated phosphodiesterase (E*) as stochastic, the simulated SPRs appeared even more similar to real SPRs, and there was very little change in the ensemble mean and standard deviation or in the amplitude distribution.
We conclude that the conventional model of graded reduction in R* activity through successive phosphorylation steps appears to be inconsistent with experimental results. Instead, we find that two variants of a model in which R* activity initially remains high and then declines abruptly after several phosphorylation steps appears capable of providing a better description of experimentally measured SPRs.
Alcohol is a well-established teratogen that can cause variable physical and
 behavioral effects on the fetus. The most severe condition in this spectrum of diseases is known as fetal alcohol syndrome (FAS). The differences in maternal and fetal enzymes, in terms of abundance and efficiency, in addition to reduced elimination, allow for alcohol to have a prolonged effect on the fetus. This can act as a teratogen through numerous methods including reactive oxygen species (generated as by products of CYP2E1), decreased endogenous antioxidant levels, mitochondrial damage, lipid peroxidation, disrupted neuronal cell-cell adhesion, placental vasoconstriction, and inhibition of cofactors required for fetal growth and development. More recently, alcohol has also been shown to have epigenetic effects. Increased fetal exposure to alcohol and sustained alcohol intake during any trimester of pregnancy is associated with an increased risk of FAS. Other risk factors include genetic influences, maternal characteristics, for example, lower socioeconomic statuses and smoking, and paternal chronic alcohol use. The treatment options for FAS have recently started to be explored although none are currently approved clinically. These include prenatal antioxidant administration food supplements, folic acid, choline, neuroactive peptides, and neurotrophic growth factors. Tackling the wider impacts of FAS, such as comorbidities, and the family system have been shown to improve the quality of life of FAS patients. This review aimed to focus on the pathogenesis, especially mechanisms of alcohol teratogenicity, and risks of developing FAS. Recent developments in potential management strategies, including prenatal interventions, are discussed.
[Pd(PPh3 )4 ] catalyzes a Suzuki-Miyaura-like twofold cross-coupling sequence between underivatized propargylic diols and either aryl or alkenyl boronic acids to furnish highly substituted 1,3-dienes. Thus, 2,3-diaryl-1,3-butadienes and their dialkenic congeners ([4]dendralenes) are delivered in a (pseudo)halogen-free, single-step synthesis which supersedes existing methods. Allenols are also readily formed. Treatment of these single- and twofold cross-coupled products with acid leads to remarkably short syntheses of highly-substituted benzofulvenes and aryl indenes, respectively.
Directional evolution is one of the most compelling evolutionary patterns observed in macroevolution. Yet, despite its importance, detecting such trends in multivariate data remains a challenge. In this study, we evaluate multivariate evolution of shell shape in 93 bivalved scallop species, combining geometric morphometrics and phylogenetic comparative methods. Phylomorphospace visualization described the history of morphological diversification in the group; revealing that taxa with a recessing life habit were the most distinctive in shell shape, and appeared to display a directional trend. To evaluate this hypothesis empirically, we extended existing methods by characterizing the mean directional evolution in phylomorphospace for recessing scallops. We then compared this pattern to what was expected under several alternative evolutionary scenarios using phylogenetic simulations. The observed pattern did not fall within the distribution obtained under multivariate Brownian motion, enabling us to reject this evolutionary scenario. By contrast, the observed pattern was more similar to, and fell within, the distribution obtained from simulations using Brownian motion combined with a directional trend. Thus, the observed data are consistent with a pattern of directional evolution for this lineage of recessing scallops. We discuss this putative directional evolutionary trend in terms of its potential adaptive role in exploiting novel habitats.
The hallmark of pancreatic ductal adenocarcinoma (PDAC) is abundant desmoplasia, which is orchestrated by pancreatic stellate cells (PSCs) and accounts for the majority of the stroma surrounding the tumour. Healthy PSCs are quiescent, but upon activation during disease progression, they adopt a myofibroblast-contractile phenotype and secrete and concomitantly reorganise the stiff extracellular matrix (ECM). Transforming growth factor β (TGF-β) is a potent activator of PSCs, and its activation requires spatiotemporal organisation of cellular and extracellular cues to liberate it from an inactive complex with latent TGF-β binding protein (LTBP). Here we study the mechanical activation of TGF-β by PSCs in vitro by investigating LTBP-1 organisation with fibrillar fibronectin and show that all trans-retinoic acid (ATRA), which induces PSC quiescence, down-regulates the ability of PSCs to mechanically organise LTBP-1 and activate TGF-β through a mechanism involving myosin II dependent contractility. Therefore, ATRA inhibits the ability of PSCs to mechanically release active TGF-β, which might otherwise act in an autocrine manner to sustain PSCs in an active state and a tumour-favouring stiff microenvironment.
A 2,7-disubstituted phosphodiester-linked phenanthrene trimer forms tubular structures in aqueous media. Chromophores are arranged in H-aggregates. Incorporation of small quantities of pyrene results in the development of light-harvesting nanotubes in which phenanthrenes act as antenna chromophores and pyrenes as energy acceptors. Energy collection is most efficient after excitation at the phenanthrene H-band. Fluorescence quantum yields up to 23 % are reached in pyrene doped, supramolecular nanotubes.
Extracellular vesicles (EVs) appear as important actors in cell-to-cell communication. EV content is characterized by proteins and RNA species that dynamically reflect cell and tissue state. Urinary EVs in particular may act in inter-nephron communication with possible beneficial or detrimental effects. Increasing interest is addressed to the pharmacological properties of EVs as a cell-free therapy, since several of the effects crAQ/tgqcedited to stem cells have been recapitulated by administration of their EVs. Preclinical data in models of renal damage indicate a general regenerative potential of EVs derived from mesenchymal stromal cells of different sources, including bone marrow, fetal tissues, urine and kidney. In this review we will discuss the results on the effect of EVs in repair of acute and chronic renal injury, and the mechanisms involved. In addition, we will analyse the strategies for EV pharmacological applications in renal regenerative medicine and limits and benefits involved.
The transdifferentiation of epithelial cells toward a mesenchymal condition (EMT) is a complex process that allows tumor cells to migrate to ectopic sites. Cadherins are not just structural proteins, but they act as sensors of the surrounding microenvironment and as signaling centers for cellular pathways. However, the molecular mechanisms underlying these signaling functions remain poorly characterized. Cadherin-6 (CDH6) is a type 2 cadherin, which drives EMT during embryonic development and it is aberrantly re-activated in cancer. We recently showed that CDH6 is a TGFβ target and an EMT marker in thyroid cancer, suggesting a role for this protein in the progression of this type of tumor. Papillary thyroid carcinomas (PTCs) are usually indolent lesions. However, metastatic spreading occurs in about 5% of the cases. The identification of molecular markers that could early predict the metastatic potential of these lesions would be strategic to design more tailored approaches and reduce patients overtreatment. In this work, we assessed the role of CDH6 in the metastatic progression of thyroid cancer. We showed that loss of CDH6 expression profoundly changes cellular architecture, alters the inter-cellular interaction modalities and attenuates EMT features in thyroid cancer cells. Using a yeast two-hybrid screening approach, based on a thyroid cancer patients library, we showed that CDH6 directly interacts with GABARAP, BNIP3 and BNIP3L, and that through these interactions CDH6 restrains autophagy and promotes re-organization of mitochondrial network through a DRP1-mediated mechanism. Analysis of the LIR domains suggests that the interaction with the autophagic machinery may be a common feature of many cadherin family members. Finally, the analysis of CDH6 expression in a unique cohort of human PTCs showed that CDH6 expression marks specifically EMT cells. and it is strongly associated with metastatic behavior and worse outcome of PTCs.Oncogene advance online publication, 4 July 2016; doi:10.1038/onc.2016.237.
Ewing sarcoma is characterized by chromosomal translocations fusing the EWS gene with various members of the ETS family of transcription factors, most commonly FLI1. EWS-FLI1 is an aberrant transcription factor driving Ewing sarcoma tumorigenesis by either transcriptionally inducing or repressing specific target genes. Herein, we showed that Sprouty 1 (SPRY1), which is a physiological negative feedback inhibitor downstream of fibroblast growth factor (FGF) receptors (FGFRs) and other RAS-activating receptors, is an EWS-FLI1 repressed gene. EWS-FLI1 knockdown specifically increased the expression of SPRY1, while other Sprouty family members remained unaffected. Analysis of SPRY1 expression in a panel of Ewing sarcoma cells showed that SPRY1 was not expressed in Ewing sarcoma cell lines, suggesting that it could act as a tumor suppressor gene in these cells. In agreement, induction of SPRY1 in three different Ewing sarcoma cell lines functionally impaired proliferation, clonogenic growth and migration. In addition, SPRY1 expression inhibited extracellular signal-related kinase/mitogen-activated protein kinase (MAPK) signaling induced by serum and basic FGF (bFGF). Moreover, treatment of Ewing sarcoma cells with the potent FGFR inhibitor PD-173074 reduced bFGF-induced proliferation, colony formation and in vivo tumor growth in a dose-dependent manner, thus mimicking SPRY1 activity
 in Ewing sarcoma cells. Although the expression of SPRY1 was low when compared with other tumors, SPRY1 was variably expressed in primary Ewing sarcoma tumors and higher expression levels were significantly associated with improved outcome in a large patient cohort. Taken together, our data indicate that EWS-FLI1-mediated repression of SPRY1 leads to unrestrained bFGF-induced cell proliferation, suggesting that targeting the FGFR/MAPK pathway can constitute a promising therapeutic approach for this devastating disease.Oncogene advance online publication, 4 July 2016; doi:10.1038/onc.2016.244.
The topical application of drugs allows for a local application in skin disease and can reduce side effects. Here we present biodegradable core-multishell (CMS) nanocarriers which are composed of a hyperbranched polyglycerol core functionalized with diblock copolymers consisting of polycaprolactone (PCL) and poly(ethylene glycol) (mPEG) as the outer shell. The anti-inflammatory drug Dexamethasone (Dexa) was loaded into these CMS nanocarriers. DLS results suggested that Dexa loaded nanoparticles mostly act as a unimolecular carrier system. With longer PCL segments, a better transport capacity is observed. In vitro skin permeation studies showed that CMS nanocarriers could improve the Nile red penetration through the skin by up to 7 times, compared to a conventional cream formulation. Interestingly, covalently FITC-labeled CMS nanocarriers remain in the stratum corneum layer. This suggests the enhancement is due to the release of cargo after being transported into the stratum corneum by the CMS nanocarriers. In addition, the hPG-PCL-mPEG CMS nanocarriers exhibited good stability, low cytotoxicity, and their production can easily be scaled up, which makes them promising nanocarriers for topical drug delivery.
Humans are exposed to organic arsenic species through their diet and therefore, are susceptible to arsenic toxicity. Investigating the transformations occurring in the gastrointestinal tract will influence which arsenic species to focus on when studying metabolism in cells. Using a physiologically based extraction test, the bioaccessibility of arsenic species was determined after the simulated gastrointestinal digestion of rice, seaweed and fish. Pure standards of the major arsenic species present in these foodstuffs (arsenic glutathione complexes, arsenosugars and short chain fatty acids) were also evaluated to assess the effect of the food matrix on bioaccessibility and transformation. Approximately 80% of arsenic is released from these foodstuffs, potentially becoming available. Hydrolysis and demethylation of arsenic glutathione complexes and arsenosugars standards was observed, but no transformations occurred to arsenosugars present in seaweed. Demethylation of MA and DMA from rice occurs increasing the amount of inorganic arsenic species available for metabolism.
To explore two transcript variants expression of long noncoding RNA C6orf176 in non-small cell lung cancer (NSCLC) and the clinical pathological significance. 

The expressions of transcript variant 1 (TV1) and transcript variant 2 (TV2) of long noncoding RNA C6orf176 in 57 NSCLC and adjacent cancerous tissues were examined by qPCR with β-actin as internal control.

Based on the results of qPCR, for C6orf176-TV1, 42 cases were down-regulated and 15 cases were up-regulated. The C6orf176-TV1 level was correlated to the grade of differentiation (P<0.05) but it was not correlated with gender, age, smoking history, tumor type and TNM stage. The expression of C6orf176-TV1 had a potential value in diagnosis of NSCLC by receiver operator characteristic (ROC) curve. Area under curve (AUC) of ROC curve was 0.708 (95% CI 0.615 to 0. 802). The sensitivity and specificity were 51% and 88%, respectively. For C6orf176-TV2, 39 cases were down-regulated and 18 cases were up-regulated. The C6orf176-TV2 level was correlated with the grade of differentiation (P<0.05) but it was not correlated with gender, age, tumor size, smoking history and TNM stage. C6orf176-TV2 level had value in diagnosis of NSCLC by ROC curve. AUC of ROC curve was 0.64 (95% CI 0.531 to 0.749). The sensitivity and specificity were 49% and 75%, respectively. Of the 57 specimens, 53 cases were simultaneous up or down-regulation of C6orf176-TV1 and C6orf176-TV2. The correlation coefficient was 0.99.

The expression of C6orf176-TV1 or C6orf176-TV2 is down-regulated in NSCLC and it is correlated with the grade of differentiation. It may act as a diagnosis indicator for NSCLC patients.
目的：探讨长链非编码RNA C6orf176两个转录本C6orf176-TV1和C6orf176-TV2在非小细胞肺癌(non-small cell lung cancer，NSCLC)中的表达及临床意义。方法：采用实时荧光定量PCR技术检测57例NSCLC组织及配对癌旁组织中C6orf176-TV1与C6orf176-TV2的表达水平，并分析其与临床病理特征的关系。结果：NSCLC组织中C6orf176-TV1表达下调42例，表达上调15例，其表达与肿瘤分化程度有关(P<0.05)，与性别、年龄、吸烟史、病理类型、TNM分期均无关。C6orf176-TV1表达诊断癌组织与癌旁组织的受试者工作特征(receiver operator characteristic，ROC)曲线下面积(area under curve，AUC)为0.708(95% CI：0.615~0.802)，灵敏度和特异度分别为51%和88%。NSCLC组织中C6orf176-TV2表达下调39例，表达上调的18例，其表达与肿瘤分化程度有关(P<0.05)，与性别、年龄、吸烟史、病理类型、TNM分期均无关。C6orf176-TV2表达诊断癌组织与配对癌旁组织的ROC的AUC为0.64(95% CI: 0.531~0.749)，灵敏度和特异度分别为49%和75%。57例标本中C6orf176-TV1与C6orf176-TV2同时上调或下调的标本有53对，其相关系数为0.99。结论：C6orf176-TV1与 C6orf176-TV2在NSCLC组织中均表达下调，其与肺癌肿瘤细胞分化程度相关，可作为NSCLC的诊断指标。.
Degradation of Gram-positive bacterial cell wall peptidoglycan in macrophage and dendritic cell phagosomes leads to activation of the NLRP3 inflammasome, a cytosolic complex that regulates processing and secretion of interleukin (IL)-1β and IL-18. While many inflammatory responses to peptidoglycan are mediated by detection of its muramyl dipeptide component in the cytosol by NOD2, we report here that NLRP3 inflammasome activation is caused by release of N-acetylglucosamine that is detected in the cytosol by the glycolytic enzyme hexokinase. Inhibition of hexokinase by N-acetylglucosamine causes its dissociation from mitochondria outer membranes, and we found that this is sufficient to activate the NLRP3 inflammasome. In addition, we observed that glycolytic inhibitors and metabolic conditions affecting hexokinase function and localization induce inflammasome activation. While previous studies have demonstrated that signaling by pattern recognition receptors can regulate metabolic processes, this study shows that a metabolic enzyme can act as a pattern recognition receptor. PAPERCLIP.
Translation elongation efficiency is largely thought of as the sum of decoding efficiencies for individual codons. Here, we find that adjacent codon pairs modulate translation efficiency. Deploying an approach in Saccharomyces cerevisiae that scored the expression of over 35,000 GFP variants in which three adjacent codons were randomized, we have identified 17 pairs of adjacent codons associated with reduced expression. For many pairs, codon order is obligatory for inhibition, implying a more complex interaction than a simple additive effect. Inhibition mediated by adjacent codons occurs during translation itself as GFP expression is restored by increased tRNA levels or by non-native tRNAs with exact-matching anticodons. Inhibition operates in endogenous genes, based on analysis of ribosome profiling data. Our findings suggest translation efficiency is modulated by an interplay between tRNAs at adjacent sites in the ribosome and that this concerted effect needs to be considered in predicting the functional consequences of codon choice.
Immunotherapies are highly promising cancer treatments, but understanding the factors mediating their resistance remains critical. Successes in randomized clinical testing have supported the growing appreciation that oncolytic virotherapies primarily act as immunotherapies. Here we identified prostaglandin E2 (PGE2) in the tumor as a key mediator of resistance to immunotherapies, including oncolytic vaccinia virotherapy. Elevated levels of PGE2 coupled to suppressive chemokine profiles and high levels of granulocytic myeloid-derived suppressor cells resulted in loss of immunotherapeutic potential. Viral vectors engineered to target PGE2 were capable of overcoming localized immunosuppression leading to profound changes in the tumor's immune status. This allowed the viral vectors to raise robust anti-tumor adaptive immune responses and sensitized established and previously resistant tumors to immunotherapies.
Exposure to severe and prolonged stress has detrimental effects on the hippocampus. However, relatively little is known about the gradual changes in hippocampal structure, and its behavioral consequences, over the course of repeated stress. Behavioral analyses during 10 days of chronic stress pointed to a delayed decline in spatial memory, the full impact of which is evident only after the end of stress. In contrast, concurrent volumetric measurements in the same animals revealed significant reduction in hippocampal volumes in stressed animals relative to their unstressed counterparts, as early as the third day of stress. Notably, animals that were behaviorally the worst affected at the end of chronic stress suffered the most pronounced early loss in hippocampal volume. Together, these findings support the view that not only is smaller hippocampal volume linked to stress-induced memory deficits, but it may also act as an early risk factor for the eventual development of cognitive impairments seen in stress-related psychiatric disorders.
We present a cost-effective metabarcoding approach, aMPlex Torrent, which relies on an improved multiplex PCR adapted to highly degraded DNA, combining barcoding and next-generation sequencing to simultaneously analyse many heterogeneous samples. We demonstrate the strength of these improvements by generating a phylochronology through the genotyping of ancient rodent remains from a Moroccan cave whose stratigraphy covers the last 120 000 years. Rodents are important for epidemiology, agronomy
 and ecological investigations and can act as bioindicators for human- and/or climate-induced environmental changes. Efficient and reliable genotyping of ancient rodent remains has the potential to deliver valuable phylogenetic and paleoecological information. The analysis of multiple ancient skeletal remains of very small size with poor DNA preservation, however, requires a sensitive high-throughput method to generate sufficient data. We show this approach to be particularly adapted at accessing this otherwise difficult taxonomic and genetic resource. As a highly scalable, lower cost and less labour-intensive alternative to targeted sequence capture approaches, we propose the aMPlex Torrent strategy to be a useful tool for the genetic analysis of multiple degraded samples in studies involving ecology, archaeology, conservation and evolutionary biology.
Electrochemistry-based nucleic acid sensors have long been plagued by the limited accessibility of target molecules to the capture probes immobilized on heterogeneous surfaces, which largely hinders their practical application. In this work, we find that dual-thiolated hairpin DNA immobilized on an electrode surface as the capture probe cannot only efficiently bind with target molecule as well as the signal probe but also process impressive protein-repelling ability, which allows us to directly detect as few as attomolar targets (∼300 copies in 100 μL sample) with single-base discrimination ability. Meanwhile, the preparation of functional electrode surface becomes simple (one step), fast (30 min), and homogeneous (just one probe modified surface without small molecules coassembled). These advantages are attributed to the unique probe design, where the stem of the capture probe can act as rigid scaffold to keep it upright, and the loop of the capture probe may provide an enclosed platform for target and signal probe binding. More importantly, through tuning the distance between enzyme and the electrode surface (from 8.5 to 13.6 nm), we find that the performance of the sensor can be favorably controlled. Furthermore, taking advantage of this new binding model, different complex samples including polymerase chain reaction (PCR) product, mRNA, and micro RNA can be conveniently analyzed, which may hold great potential for real application.
Adult mammalian brain contains a number of specialized neurovascular structures termed "niches" that act as sources of neuronal cells throughout the individual's life. Some of the niches generate neurons to satisfy the need for 'replacement' neurons within the same or closely located brain structures, whereas the other can provide such cells for more distant destinations in the brain. A common characteristic of known neurovascular niches is the presence of a complex 3-dimensional network of basal lamina processes, called fractones. It apparently plays a major role in communication between the various niche-populating cell types as well as in niche activity and output. We hypothesized that similar niches may form ad hoc after a mechanical brain trauma, and tested this possibility in a rat model of surgical brain injury. Four days after removing a small fragment of sensorimotor cortex, the peri-wound region showed numerous symptoms of active repair and remodeling of brain parenchyma, including the presence of multiple cell types of immature phenotypes. The latter, as shown by a variety of light and electron microscopy techniques, included endothelial cell precursors as well as nestin-positive immature neural cells of astrocytic or non-glial characteristics. However, there was no evidence of in situ neurogenesis or a considerable migration of cells from SVZ. The centers of the said repair processes were capillary blood vessels connected with basal lamina-formed fractones. These results indicate that surgical brain trauma causes the formation of a vascular niche with no apparent neurogenic potential.
Bacteriocin, which is produced by lactic acid bacteria (LAB), has the potential to act as natural preservatives in the food industry. To develop strategies to overproduce such peptides, plantaricin NC8, a class IIb LAB bacteriocin that consists of two peptides, PLNC8α and PLNC8β, was successfully heterologously expressed in Escherichia coli BL21 (DE3). PLNC8α and PLNC8β peptides were expressed as His6-tag fusion proteins and were separated by Ni(2+) chelating affinity chromatography. To get the PLNC8α and PLNC8β peptides without extra amino acids in the N-terminus, the fusion proteins were cleaved by enterokinase and further purified using the Ni-NTA Sefinose™ Resin Kit. The molecular masses of peptides were checked using Tricine-SDS-PAGE and MALDI-TOF-MS. The yield of purified PLNC8α was around 2-2.5 mg/L, and the yield of PLNC8β was around 1.5-2 mg/L. The antimicrobial spectrum of cleaved peptides was detected and the synergistic action of PLNC8α and PLNC8β was preliminarily confirmed. It was found that E. coli was a suitable host for heterologous expression of plantaricin NC8 with a significant yield. Importantly, the bacteriocin appeared to be very active for controlling and inhibiting the food-borne pathogenic Gram-negative bacteria Salmonella spp., and might be useful as a natural preservative candidate.
Prezygotic isolating mechanisms act to limit hybridization and maintain the genetic identity of closely-related species. While synchronous intraspecific spawning is a common phenomenon amongst marine organisms and plays an important role in reproductive success, asynchronous spawning between potentially hybridizing lineages may also be important in maintaining species boundaries. We tested this hypothesis by comparing reproductive synchrony over daily to hourly timescales in a sympatric assemblage of intertidal fucoid algae containing selfing hermaphroditic (Fucus spiralis and Fucus guiryi) and dioecious (Fucus vesiculosus and Fucus serratus) species. Our results confirm that gametes are released on semi-lunar cycles in all species. However, sister species with different mating systems showed asynchronous spawning at finer circadian timescales, thus providing evidence for a partial reproductive barrier between hermaphroditic and dioecious species. Finally, our data also emphasize the ecological, developmental, and/or physiological constraints that operate to restrict reproduction to narrow temporal windows of opportunity in the intertidal zone and more generally the role of ecological factors in marine speciation.
Openness and transparency are important considerations for medicines regulators, where public health is of paramount concern. As part of their commitment to transparency, the European Medicines Agency (EMA) and Therapeutic Goods Administration (TGA) in Australia publish information relating to their evaluation of medicines via public assessment reports. European Public Assessment Reports (EPARs) and Australian Public Assessment Reports (AusPARs) provide information about the considerations that led the regulator to approve or refuse the application. The reports summarise assessments by each regulator of the information provided on the quality, safety, and efficacy of the medicine under evaluation. Here, we describe the experiences of two established medicines regulators in publishing public assessment reports, and reflect on their future role in communicating medicines information.
Intensive research in past two decades has uncovered the presence and importance of noncoding RNAs (ncRNAs), which includes microRNAs (miRs) and long ncRNAs (lncRNAs). These two classes of ncRNAs interact to a certain extent, as some lncRNAs bind to miRs to sequester them. Such lncRNAs are collectively called 'competing endogenous RNAs' or 'miRNA sponges'. In this study, we screened for lncRNAs that may act as miRNA sponges using the publicly available data sets and databases. To uncover the roles of miRNA sponges, loss-of-function experiments were conducted, which revealed the biological roles as miRNA sponges. LINC00324 is important for the cell survival by binding to miR-615-5p leading to the de-repression of its target BTG2 LOC400043 controls several biological functions via sequestering miR-28-3p and miR-96-5p, thereby changing the expressions of transcriptional regulators. Finally, we also screened for circular RNAs (circRNAs) that may function as miRNA sponges. The results were negative at least for the selected circRNAs in this study. In conclusion, miRNA sponges can be identified by applying a series of bioinformatics techniques and validated with biological experiments.
Organs-on-a-chip has emerged as a powerful tool for pharmacological and physiological studies. A key part in the construction of such a model is the ability to pattern or culture cells in a biomimetic fashion. Most of the reported cells-on-a-chip models integrate cells on a flat surface, which does not accurately represent the extracellular matrix that they experience in vivo. Electrospinning, a technique used to generate sub-micron diameter polymer fibers, has been used as an in vitro cell culture substrate and for tissue engineering applications. Electrospinning of fibers directly into a fully sealed fluidic channel using a conventional setup has not been possible due to issues of confining the fibers into a discrete network. In this work, a dynamic focusing method was developed, with this approach enabling direct deposition of electrospun fibers into a fully sealed fluidic channel, to act as a matrix for cell culture and subsequent studies under continuous flowing conditions. Scanning electron microscopy of electrospun polycaprolactone fibers shows that this method enables the formation of fibrous layers on the inner wall of a 3D-printed fluidic device (mean fiber size = 1.6 ± 0.6 μm and average pore size = 113 ± 19 μm(2)). Cells were able to be cultured in this 3D scaffold
 without the addition of adhesion proteins. Media was pumped through the channel at high flow rates (up to 400 μL min(-1)) during a dynamic cell culture process and both the fibers and the cells were found to be strongly adherent. A PDMS fluidic device was also prepared (from a 3D printed mold) and coated with polycaprolactone fibers. The PDMS device enables optical detection and confocal imaging of cultured cells on the fibers. Finally, macrophages were cultured in the devices to study how the fibrous scaffold can affect cell behavior. It was found that under lipopolysaccharide stimulation, macrophages cultured on PCL fibers inside of a channel secreted significantly more cytokines than those cultured on a thin layer of PCL in a channel or directly on the inner channel wall. Overall, this study represents a new approach for in vitro cell studies, where electrospinning can be used to easily and quickly create 3D scaffolds that can improve the culture conditions in microfluidic devices.
The search for new drugs that could treat tropical protozoan diseases, such as malaria or neglected tropical diseases (NTDs), motivates many medicinal chemists. New classes of antiprotozoal drugs that act through a novel mechanism of action must be developed. This review presents our efforts toward finding new candidate treatments for malaria, American trypanosomiasis, human African trypanosomiasis and leishmaniasis based on π-delocalized lipophilic cations (DLCs). DLCs, such as rhodacyanines, azarhodacyanines, β-carbolinium salts, and phenoxazinium salts, displayed strong antiprotozoal activities with highly selective indices. Several DLCs displayed moderate to excellent in vivo efficacies against Plasmodium berghei when administered intraperitoneally or orally. This review also discusses chemical biology approaches to understanding the mechanism of action underlying the antimalarial rhodacyanines.
Alcohol consumption is often a comorbid condition in other chronic liver diseases. It has been shown to act in synergy to increase liver injury in viral hepatitis, hereditary hemochromatosis, and nonalcoholic fatty liver disease (NAFLD), leading to an increased risk of cirrhosis, hepatocellular carcinoma, and liver-related mortality. Data suggest that modest alcohol consumption may be inversely related to the risk of developing NAFLD and lower rates of progression of NAFLD to nonalcoholic steatohepatitis (NASH). This article reviews data on the relationship between alcohol consumption and other chronic liver diseases.
Symbiosis between legumes and rhizobia leads to the formation of N2-fixing root nodules. In soybean, several host genes, referred to as Rj genes, control nodulation. Soybean cultivars carrying the Rj4 gene restrict nodulation by specific rhizobia such as Bradyrhizobium elkanii We previously reported that the restriction of nodulation was caused by B. elkanii possessing a functional type III secretion system (T3SS), which is known for its delivery of virulence factors by pathogenic bacteria. In the present study, we investigated the molecular basis for the T3SS-dependent nodulation restriction in Rj4 soybean. Inoculation tests revealed that soybean cultivar BARC-2 (Rj4/Rj4) restricted nodulation by B. elkanii USDA61, whereas its nearly isogenic line BARC-3 (rj4/rj4) formed nitrogen-fixing nodules with the same strain. Root-hair curling and infection threads were not observed in the roots of BARC-2 inoculated with USDA61, indicating that Rj4 blocked B. elkanii infection in the early stages. Accumulation of H2O2 and salicylic acid (SA) was observed in the roots of BARC-2 inoculated with USDA61. Transcriptome analyses revealed that inoculation of USDA61, but not its T3SS mutant in BARC-2, induced defense-related genes, including those coding for hypersensitive-induced responsive protein, which act in effector-triggered immunity (ETI) in Arabidopsis. These findings suggest that B. elkanii T3SS triggers the SA-mediated ETI-type response in Rj4 soybean, which consequently blocks symbiotic interactions. This study revealed a common molecular mechanism underlying both plant-pathogen and plant-symbiont interactions, and suggests that establishment of a root nodule symbiosis requires the evasion or suppression of plant immune responses triggered by rhizobial effectors.
Gastric cancer (GC) is the third leading cause of global cancer mortality. Adenosine-to-inosine RNA editing is a recently described novel epigenetic mechanism involving sequence alterations at the RNA but not DNA level, primarily mediated by ADAR (adenosine deaminase that act on RNA) enzymes. Emerging evidence suggests a role for RNA editing and ADARs in cancer, however, the relationship between RNA editing and GC development and progression remains unknown.
In this study, we leveraged on the next-generation sequencing transcriptomics to demarcate the GC RNA editing landscape and the role of ADARs in this deadly malignancy.
Relative to normal gastric tissues, almost all GCs displayed a clear RNA misediting phenotype with ADAR1/2 dysregulation arising from the genomic gain and loss of the ADAR1 and ADAR2 gene in primary GCs, respectively. Clinically, patients with GCs exhibiting ADAR1/2 imbalance demonstrated extremely poor prognoses in multiple independent cohorts. Functionally, we demonstrate in vitro and in vivo that ADAR-mediated RNA misediting is closely associated with GC pathogenesis, with ADAR1 and ADAR2 playing reciprocal oncogenic and tumor suppressive roles through their catalytic deaminase domains, respectively. Using an exemplary target gene PODXL (podocalyxin-like), we demonstrate that the ADAR2-regulated recoding editing at codon 241 (His to Arg) confers a loss-of-function phenotype that neutralizes the tumorigenic ability of the unedited PODXL.
Our study highlights a major role for RNA editing in GC disease and progression, an observation potentially missed by previous next-generation sequencing analyses of GC focused on DNA alterations alone. Our findings also suggest new GC therapeutic opportunities through ADAR1 enzymatic inhibition or the potential restoration of ADAR2 activity.
Adenosine deaminases that act on RNA (ADARs) convert adenosine residues to inosine in double-stranded RNA. In vivo, ADAR1 is essential for the maintenance of hematopoietic stem/progenitors. Whether other hematopoietic cell types also require ADAR1 has not been assessed. Using erythroid- and myeloid-restricted deletion of Adar1, we demonstrate that ADAR1 is dispensable for myelopoiesis but is essential for normal erythropoiesis. Adar1-deficient erythroid cells display a profound activation of innate immune signaling and high levels of cell death. No changes in microRNA levels were found in ADAR1-deficient erythroid cells. Using an editing-deficient allele, we demonstrate that RNA editing is the essential function of ADAR1 during erythropoiesis. Mapping of adenosine-to-inosine editing in purified erythroid cells identified clusters of hyperedited adenosines located in long 3'-untranslated regions of erythroid-specific transcripts and these are ADAR1-specific editing events. ADAR1-mediated RNA editing is essential for normal erythropoiesis.
During droughts, leaves are predicted to act as 'hydraulic fuses' by shedding when plants reach critically low water potential (Ψplant ), thereby slowing water loss, stabilizing Ψplant and protecting against cavitation-induced loss of stem hydraulic conductivity (Ks ). We tested these predictions among trees in seasonally dry tropical forests, where leaf shedding is common, yet variable, among species. We tracked leaf phenology, Ψplant and Ks in saplings of six tree species distributed across two forests. Species differed in their timing and extent of leaf shedding, yet converged in shedding leaves as they approached the Ψplant value associated with a 50% loss of Ks and at which their model-estimated maximum sustainable transpiration rate approached zero. However, after shedding all leaves, the Ψplant value of one species, Genipa americana, continued to decline, indicating that water loss continued after leaf shedding. Ks was highly variable among saplings within species and seasons, suggesting a minimal influence of seasonal drought on Ks . Hydraulic limits appear to drive diverse patterns of leaf shedding among tropical trees, supporting the hydraulic fuse hypothesis. However, leaf shedding is not universally effective at stabilizing Ψplant , suggesting that the main function of drought deciduousness may vary among species.
Colorectal cancer is one of the most common cancers worldwide. Previous studies suggest that chemoradiotherapy is more effective for the treatment of colorectal cancer than is radiotherapy or chemotherapy alone. To enhance the radiosensitivity of tumor cells, several investigators have used targeted therapeutic agents that act as radiosensitizers. In the present study, we provide a scientific rationale for the clinical application of SU5416, an inhibitor of vascular endothelial growth factor receptor-2, as a radiosensitizer for colorectal cancer. Two human colorectal adenocarcinoma cell lines, HCT116 and HT-29, were treated with SU5416 and radiation alone or radiation followed by SU5416. In vitro tests were performed using colony forming assays, flow cytometric analysis, immunohistochemistry, senescence-associated β-galactosidase, tumor cell motility and invasion assays. The combination of radiation and SU5416 synergistically inhibited cell survival and induced apoptosis through reactive oxygen species, enhanced IR-induced premature senescence, and inhibited DNA repair activity, cell migration and invasion. Collectively, our results favor the use of SU5416 and radiotherapy as a combination therapy for the treatment of colon cancer and it can be combined successfully with a radiation regimen to potentiate its antitumor and
 antimetastatic activities for future clinical trials.
Chlorophyll (Chl) degradation is an integral process of leaf senescence, and NYE1/SGR1 has been demonstrated as a key regulator of Chl catabolism in diverse plant species. In this study, using yeast one-hybrid screening, we identified three abscisic acid (ABA)-responsive element (ABRE)-binding transcription factors, ABF2 (AREB1), ABF3, and ABF4 (AREB2), as the putative binding proteins of the NYE1 promoter. Through the transactivation analysis, electrophoretic mobility shift assay, and chromatin immunoprecipitation, we demonstrated that ABF2, ABF3, and ABF4 directly bound to and activated the NYE1 promoter in vitro and in vivo. ABA is a positive regulator of leaf senescence, and exogenously applied ABA can accelerate Chl degradation. The triple mutant of the ABFs, abf2abf3abf4, as well as two ABA-insensitive mutants, abi1-1 and snrk2.2/2.3/2.6, exhibited stay-green phenotypes after ABA treatment, along with decreased induction of NYE1 and NYE2 expression. In contrast, overexpression of ABF4 accelerated Chl degradation upon ABA treatment. Interestingly, ABF2/3/4 could also activate the expression of two Chl catabolic enzyme genes, PAO and NYC1, by directly binding to their promoters. In addition, abf2abf3abf4 exhibited a functional stay-green phenotype, and senescence-associated genes (SAGs), such as SAG29 (SWEET15), might be directly regulated by the ABFs. Taken together, our results suggest that ABF2, ABF3, and ABF4 likely act as key regulators in mediating ABA-triggered Chl degradation and leaf senescence in general in Arabidopsis.
In Drosophila melanogaster, the mini-w(+) transgene in Pci is normally expressed throughout the adult eye; however, when other P or KP elements are present, a variegated-eye phenotype results, indicating random w(+) silencing during development called P-element-dependent silencing (PDS). Mutant Su(var)205 and Su(var)3-7 alleles act as haplo-suppressors/triplo-enhancers of this variegated phenotype, indicating that these heterochromatic modifiers act dose dependently in PDS. Previously, we recovered a spontaneous mutation of P{lacW}ci(Dplac) called P{lacW}ci(DplacE1) (E1) that variegated in the absence of P elements, presumably due to the insertion of an adjacent gypsy element. From a screen for genetic modifiers of E1 variegation, we describe here the isolation of five mutations in ash1 and three in trx that enhance the E1 variegated phenotype in a dose-dependent and cumulative manner. These mutant alleles enhance PDS at E1, and in E1/P{lacW}ci(Dplac), but suppress position effect variegation (PEV) at In(1)w(m)(4). This opposite action is consistent with a model where ASH1 and TRX mark transcriptionally active chromatin domains. If ASH1 or TRX function is lost or reduced, heterochromatin can spread into these domains creating a sink that diverts heterochromatic proteins from other variegating locations, which then may express a suppressed phenotype.
We are revising the criteria in the Listing of Impairments (listings) that we use to evaluate disability claims involving neurological disorders in adults and children under titles II and XVI of the Social Security Act (Act). These revisions reflect our program experience; advances in medical knowledge, treatment, and methods of evaluating neurological disorders; comments we received from medical experts and the public at an outreach policy conference; responses to an advance notice of proposed rulemaking (ANPRM); and public comments we received in response to a Notice of Proposed Rulemaking (NPRM) and a Federal Register notice that reopened the NPRM comment period.
In accordance with the Federal Civil Penalties Inflation Adjustment Act of 1990, as amended by the Debt Collection Improvement Act of 1996, and further amended by the Bipartisan Budget Act of 2015, section 701: Federal Civil Penalties Inflation Adjustment Act Improvements Act of 2015, this interim final rule incorporates the penalty inflation adjustments for the civil money penalties contained in the Social Security Act
This final rule implements requirements of section 216 of the Protecting Access to Medicare Act of 2014 (PAMA), which significantly revises the Medicare payment system for clinical diagnostic laboratory tests. This final rule also announces an implementation date of January 1, 2018 for the private payor rate-based fee schedule required by PAMA.
This document contains final regulations that provide guidance to Blue Cross and Blue Shield organizations, and certain other organizations, on computing and applying the medical loss ratio and the consequences for not meeting the medical loss ratio threshold. The final regulations reflect the enactment of a technical correction to section 833(c)(5) of the Internal Revenue Code by the Consolidated and Further Continuing Appropriations Act of 2015. The final regulations affect Blue Cross and Blue Shield organizations, and certain other organizations involved in providing health insurance.
Lysine acetylation is long known as a regulatory posttranslational modification of histone proteins and is emerging as a ubiquitous intracellular protein modification. Additional lysine acylations such as succinylation and glutarylation have also been found on histones and other proteins. Acylations are reversibly attached through nonenzymatic acylation mechanisms and the action of protein acyl transferases and protein deacylases (PDACs). Sirtuins are an evolutionary defined class of PDACs and act as metabolic sensors by catalyzing a unique deacylation reaction that requires the cosubstrate NAD(+). Sirtuins are found in all domains of life, and the mammalian sirtuin family comprises seven isoforms in different cellular compartments. They regulate a wide range of cellular targets and functions, such as energy metabolism and stress responses, and they have been implicated in aging processes and aging-related diseases. A large body of functional, biochemical, biophysical, and structural work on isolated sirtuins has provided many important insights that complement the many physiological studies on this enzyme family. They enabled the comprehensive structural and biochemical analysis of sirtuin catalysis, substrate selectivity, and regulation. Here, we describe the recombinant production of sirtuin proteins, with an emphasis on the mammalian isoforms. We then describe their application in activity and binding assays and for crystal structure analysis. We provide protocols for these procedures, and we discuss typical pitfalls in studying this enzyme family and how to avoid them. This information will support further molecular studies on sirtuin mechanisms and functions.
A new type of cell-penetrating ratiometric fluorescence oxygen sensing nanoparticle was prepared through a facile co-precipitation method. Amphiphilic polymer poly (styrene-co-maleic anhydride) (PSMA) was firstly cooperated with polystyrene (PS) to envelop the highly photostable phosphorescent oxygen indicator, platinum(II)-tetrakis(pentafluorophenyl)porphyrin (PtTFPP, emission at 648nm), and the reference fluorophore, poly(9, 9-dioctylfluorene) (PFO, emission at 440nm ), via hydrophobic interaction in aqueous solution. To improve the sensor biocompatibility, the biomacromolecule poly-l-lysine (PLL) was selected to act as a shell via electrostatic forces. The as-prepared PtTFPP doped core-shell nanoparticles (called PPMA/PLL NPs) exhibited an excellent ratiometric luminescence response to O2 content with high quenching efficiency and full reversibility in the oxygen sensing. More importantly, these oxygen nanosensors passed across the cell membrane after co-incubation without external force. Labeled cells exhibited high brightness in the matching blue and red channels of a digital camera. And most nanosensors were found locating in cytoplasm rather than being trapped in endosomes.
This systematic review aimed to synthesise the evidence relating to pre-treatment predictors of gambling outcomes following psychological treatment for disordered gambling across multiple time-points (i.e., post-treatment, short-term, medium-term, and long-term). A systematic search from 1990 to 2016 identified 50 articles, from which 11 socio-demographic, 16 gambling-related, 21 psychological/psychosocial, 12 treatment, and no therapist-related variables, were identified. Male gender and low depression levels were the most consistent predictors of successful treatment outcomes across multiple time-points. Likely predictors of successful treatment outcomes also included older age, lower gambling symptom severity, lower levels of gambling behaviours and alcohol use, and higher treatment session attendance. Significant associations, at a minimum of one time-point, were identified between successful treatment outcomes and being employed, ethnicity, no gambling debt, personality traits and being in the action stage of change. Mixed results were identified for treatment goal, while education, income, preferred gambling activity, problem gambling duration, anxiety, any psychiatric comorbidity, psychological distress, substance use, prior gambling treatment and medication use were not significantly associated with treatment outcomes at any time-point. Further research involving consistent treatment outcome frameworks, examination of treatment and therapist predictor variables, and evaluation of predictors across long-term follow-ups is warranted to advance this developing field of research.
Specifically deuterated 4-((propylamino)methyl)benzoic acid-grafted silica (PAMBA-silica) was prepared by benzylation of propylamino-grafted silica (PA-silica) by either in situ reduction by sodium cyanoborodeuteride (NaCNBD3) of the Schiff base, formed by the reaction between PA-silica and 4-formylbenzoic acid, or by NaCNBD3 reduction of the isolated Schiff base. The
 PAMBA-silicas, which contain amine and carboxylic acid functionalities, were characterized by elemental analysis, (13)C, (29)Si, and (2)H solid state NMR, and HPLC. Solid state (13)C NMR revealed that PAMBA-silica prepared by the in situ method consists of di-benzylated, mono-benzylated, and unreacted amino-groups while PAMBA-silica prepared by the two-step synthesis consists of only mono-benzylated and unreacted amino-groups. (29)Si solid-state NMR spectra indicated that no significant loss of propylamine groups had occurred during benzylation. Nearly ideal uniaxial rigid-limit (2)H NMR spectra of grafted 4-PAMBA ligands indicates that they form a rigid structure, which provides effective electrostatic screening of inner positive charges when the ligands are in zwitterionic form. HPLC columns packed with PAMBA-silica and PA-silica were evaluated for ionic solutes at different pH of the mobile phase. Retention times increased for cations and decreased for anions at increasing pH. These trends show that PAMBA-silicas act as cation and anion exchangers at high and low pH, respectively. The pKa values of grafted carboxylic acid, determined from HPLC of weakly retaining solutes, are close to pKa of the solution PAMBA.
To determine cortical grey matter (GM) changes and their clinical and biochemical correlates in patients with Wilson's disease using voxel based morphometry (VBM).
Clinical and imaging data of 10 patients (all male, mean age 16.0 ± 6.3years) with Wilson's Disease were analyzed. T1W volumetric MRI data of patients without obvious cortical atrophy or signal changes on conventional MRI was compared with MRI of 11 matched control subjects using VBM analysis with Statistical Parametric Mapping 8. Results were expressed at statistical threshold of p < 0.05 (FWE corrected) and p < 0.001 (uncorrected). Multiple regression analysis was done to analyze possible relation between GM atrophy, duration of disease and biochemical abnormalities.
Compared to controls, patients showed scattered areas of reduced GM volume in bilateral caudate head, medial part of right globus pallidus and body of right caudate (FWE corrected p < 0.05). At p < 0.001(uncorrected) widespread areas of cortical atrophy were also noted involving the frontal and temporal lobes, lentiform nuclei, cerebellum and thalamus. Significant positive correlation (uncorrected p < 0.001) were noted between (i) duration of disease and cortical GM volume of frontal, parietal and temporal lobes and cerebellum (ii) serum copper levels and GM volume of right medial frontal gyrus and paracentral lobule.
To the best of our knowledge, this is the first VBM study in patients with Wilson's disease. In spite of apparently normal cortex on visual inspection of MRI, decreased cortical GM volume was detected using VBM. In addition, serum copper may act as surrogate marker of cortical abnormalities in Wilson's disease.
While the majority of the photochemical states and pathways related to the biological capture of solar energy are now well understood and provide paradigms for artificial device design, additional low-energy states have been discovered in many systems with obscure origins and significance. However, as low-energy states are naively expected to be critical to function, these observations pose important challenges. A review of known properties of low energy states covering eight photochemical systems, and options for their interpretation, are presented. A concerted experimental and theoretical research strategy is suggested and outlined, this being aimed at providing a fully comprehensive understanding.
Induced pluripotent stem cells (iPSCs) derived from controls and patients can act as a starting point for in vitro differentiation into human brain cells for discovery of novel targets and treatments for human disease without the same ethical limitations posed by embryonic stem cells. Numerous groups have successfully produced and characterized Huntington's disease (HD) iPSCs with different CAG repeat lengths, including cells from patients with one or two HD alleles. HD iPSCs and the neural cell types derived from them recapitulate some disease phenotypes found in both human patients and animal models. Although these discoveries are encouraging, the use of iPSCs for cutting edge and reproducible research has been limited due to some of the inherent problems with cell lines and the technological differences in the way laboratories use them. The goal of this review is to summarize the current state of the HD iPSC field, and to highlight some of the issues that need to be addressed to maximize their potential as research tools.
There is interest in understanding how farmers' behaviour influences their management of livestock. We extend the theory of planned behaviour with farmers attitudes, beliefs, emotions and personality to investigate how these are associated with management of livestock disease using the example of footrot (FR) in sheep. In May 2013 a one-year retrospective questionnaire was sent to 4000 sheep farmers in England, requesting data on lameness prevalence, management of footrot, farm/flock descriptors, and farmer-orientated themes: barriers to treating footrot, opinions and knowledge of footrot, relating to other people and personality. Principal component analysis (PCA) was used to make composite variables from explanatory variables and latent class (LC) analysis was used to subgroup farmers, based on nine managements of FR. Associations between LC and composite variables were investigated using multinomial logistic regression. Negative binomial regression was used to investigate associations between the proportion of lame sheep and composite and personality variables. The useable response rate was 32% and 97% of farmers reported having lame sheep; the geometric mean prevalence of lameness (GMPL) was 3.7% (95% CI 3.51%-3.86%). Participants grouped into three latent classes; LC1 (best practice-treat FR within 3days of sheep becoming lame; use injectable and topical antibiotics; avoid foot trimming), 11% farmers), LC2 (slow to act, 57%) and LC3 (slow to act, delayed culling, 32%), with GMPL 2.95%, 3.60% and 4.10% respectively. Farmers who reported the production cycle as a barrier to treating sheep with FR were more likely to be in LC2 (RRR 1.36) than LC1. Negative emotions towards FR were associated with higher risk of being in LC2 (RRR 1.39) than LC1. Knowledge of preventing FR spread was associated with a lower risk of being in LC2 (RRR 0.46) or LC3 (RRR 0.34) than LC1. Knowledge about FR transmission was associated with a lower risk of being in LC3 (RRR 0.64) than LC1. An increased risk of lameness was associated with the production cycle being a barrier to treating sheep with FR (IRR 1.13), negative emotions towards FR (IRR 1.13) and feelings of hopelessness towards FR (IRR 1.20). Conscientiousness (IRR 0.95) and understanding the importance of active control of lameness (IRR 0.76) were associated with reduced risk of lameness. We conclude that emotions and personality are associated with differences in farmer management of FR and prevalence of lameness. Further understanding how personality and emotions influence change in behaviour is key to increasing uptake of new information.
Determining muscle contractile properties following exercise is critical in understanding neuromuscular function. Following high intensity training, individuals often experience exercise induced muscle damage (EIMD). The purpose of this investigation was to determine the effect of whole-body vibration (WBV) on muscle contractile properties following EIMD. Twenty-seven females volunteered for 7 sessions and were randomly assigned to a treatment or control group. Muscle contractile properties were assessed via voluntary torque (VT), peak twitch torque (TT), time to reach peak torque, half relaxation time of twitch torque, percent activation (%ACT), rate of rise (RR), rate of decline (RD), mean and peak electromyography during maximum voluntary isometric contraction. Two testing sets were collected each day, consisting of pre measures followed by WBV or control and post measures. A mixed factor analysis of variance was conducted for each variable. %ACT measures found baseline being less than day 1 in both measures in the control group. TT was found to be greater in the control group compared to WBV group. TT and VT baseline measures were greater than all other time points. RR showed control group had higher values than WBV group. These results indicate that WBV following EIMD had some positive effects on muscle contractile properties.
Poly(vinyl alcohol) (PVA) is reinforced with TiO2 nanoparticles in order to enhance thermo-mechanical stabilities, surface characteristics and osteoblastic cell adhesion. PVA-TiO2 nanocomposite films with desirable mechanical, thermal and biocompatible properties are fabricated through solution casting method followed by de-hydrothermal cross-linking treatment. The composition of TiO2 nanoparticles was standardized to achieve mechanically stable nanocomposite films, based on tensile strength measurements composition of TiO2 is determined as optimal at 3wt%. PVA-TiO2 nanocomposite films were characterized by Scanning electron microscopy, Energy dispersive spectroscopy, Atomic force microscopy, Ultra violet and Fourier transform infrared spectroscopic techniques. Elemental mapping studies substantiate incorporation of TiO2 nanoparticles within the PVA matrix. Dimensional stability evaluated by soaking films in SBF for 24h insinuates the role of TiO2 in the direction of controlling degree of swelling. In-vitro bioactivity test and cell adhesion results also predict that presence of TiO2 is advantageous to enhance apatite growth and promote cell-substrate interaction. SEM studies illustrate improved surface morphology of PVA-TiO2 nanocomposite
 film with homogenously distributed TiO2 nanoparticles, which help to enhance thermo-mechanical behavior. TiO2 nanoparticles construct cell-adhesive hydrophilic nano-domains that act as potential cell adhesion sites and promotes osteointegration. Bio compatibility studies proved that thermally cross-linked PVA is non-toxic in relation to PVA cross-linked with glutaraldehyde. Cytotoxicity and cell adhesion of nanocomposite films evaluated through cell viability (MMT) assay and crystal violet staining revealed that PVA-3wt% TiO2nanocomposite could act as an excellent composite and hence suitable to be used in bone implant applications.
The p53 protein is essential for the implementation of the cellular response to challenging environmental conditions. Reacting to stochastic nutrient stress, p53 integrates the activity of key metabolite-sensing pathways to coordinate an appropriate cell response. During starvation, p53 activity augments cell survival pathways, inhibits unnecessary growth, and promotes efficient nutrient generation, utilization, and conservation. Similarly, during oxygen stress, p53 facilitates redirection of cellular metabolism toward energy generation through nonoxidative means, the suppression of reactive oxygen species (ROS) generation, and ROS detoxification-promoting cell survival. However, if adverse conditions are too acute or persistent, p53 can switch roles to implement canonical cell killing. The ability of p53 to regulate metabolism is a powerful feature of p53 biology that can both promote cell survival and act as a check on the inappropriate proliferation of cancer cells.
Ghana has developed two main community-based strategies that aim to increase access to quality treatment for malaria, diarrhoea and pneumonia: the Home-based Care (HBC) and the Community-based Health Planning and Services (CHPS). The objective was to assess the effectiveness of HBC and CHPS on utilization, appropriate treatment given and users' satisfaction for the treatment of malaria, diarrhoea and pneumonia.
A household survey was conducted 2 and 8 years after implementation of HBC in the Volta and Northern Regions of Ghana, respectively. The study population was carers of children under-five who had fever, diarrhoea and/or cough in the last 2 weeks prior to the interview. HBC and CHPS utilization were assessed based on treatment-seeking behaviour when the child was sick. Appropriate treatment was based on adherence to national guidelines and satisfaction was based on the perceptions of the carers after the treatment-seeking visit.
HBC utilization was 17.3 and 1.0 % in the Volta and Northern Regions respectively, while CHPS utilization in the same regions was 11.8 and 31.3 %, with large variation among districts. Regarding appropriate treatment of uncomplicated malaria, 36.7 % (n = 17) and 19.4 % (n = 1) of malaria cases were treated with ACT under the HBC in the Volta and Northern Regions respectively, and 14.7 % (n = 7) and 7.4 % (n = 26) under the CHPS in the Volta and Northern Regions. Regarding diarrhoea, 7.6 % (n = 4) of the children diagnosed with diarrhoea received oral rehydration salts (ORS) or were referred under the HBC in the Volta Region and 22.1 % (n = 6) and 5.6 % (n = 8) under the CHPS in the Volta and Northern Regions. Regarding suspected pneumonia, CHPS in the Northern Region gave the most appropriate treatment with 33.0 % (n = 4) of suspected cases receiving amoxicillin. Users of CHPS in the Volta Region were the most satisfied (97.7 % were satisfied or very satisfied) when compared with those of the HBC and of the Northern Region.
HBC showed greater utilization by children under-five years of age in the Volta Region while CHPS was more utilized in the Northern Region. Utilization of HBC contributed to prompt treatment of fever in the Volta Region. Appropriate treatment for the three diseases was low in the HBC and CHPS, in both regions. Users were generally satisfied with the CHPS and HBC services.
Cattle are the main reservoir of verocytotoxigenic Escherichia coli (VTEC), food-borne pathogens that express verocytotoxins (vtx) encoded by temperate bacteriophage. Bovine faeces and unturned manure heaps can support the survival of VTEC and may propagate and transmit VTEC. This study investigated the survival of a vtx2 bacteriophage, φ24B ::Kan, in bovine faeces and slurry. The survival of an anti-Escherichia coli O157:H7 lytic bacteriophage, e11/2, was examined in the same matrices, as a possible bio-control option for VTEC.
Samples were inoculated with φ24B ::Kan and/or e11/2 bacteriophage at a concentration of 7-8 log10  PFU g(-1)  (faeces) or ml(-1) (slurry), stored at 4 and 14°C and examined every 2 days for 36 days. The ability of φ24B ::Kan to transduce E. coli cells was examined. Moreover, E. coli concentrations in the faeces and slurry were monitored throughout the experiment as were the pH and aw (faeces only). Both bacteriophages survived well in faeces and slurry. In addition, φ24B ::Kan was able to form lysogens.
φ24B ::Kan and e11/2 phage can survive and remain infective in bovine faeces and slurry for at least 30 days under representative Irish temperatures.
Bovine faeces and slurry may act as a reservoir for vtx bacteriophages. The survival of the anti-O157 phage suggests it may be a suitable bio-control option in these matrices.
Alzheimer's disease (AD) is a neurodegenerative disorder causing progressive memory loss and cognitive dysfunction. Anti-AD strategies targeting cell receptors consider them as isolated units. However, many cell surface receptors cooperate and physically contact each other forming complexes having different biochemical properties than individual receptors. We here report the discovery of dopamine D1, histamine H3, and N-methyl-D-aspartate (NMDA) glutamate receptor heteromers in heterologous systems and in rodent brain cortex. Heteromers were detected by co-immunoprecipitation and in situ proximity ligation assays (PLA) in the rat cortex where H3 receptor agonists, via negative cross-talk, and H3 receptor antagonists, via cross-antagonism, decreased D1 receptor agonist signaling determined by ERK1/2 or Akt phosphorylation, and counteracted D1 receptor-mediated excitotoxic cell death. Both D1 and H3 receptor antagonists also counteracted NMDA toxicity suggesting a complex interaction between NMDA receptors and D1-H3 receptor heteromer function. Likely due to heteromerization, H3 receptors act as allosteric regulator for D1 and NMDA receptors. By bioluminescence resonance energy transfer (BRET), we demonstrated that D1 or H3 receptors form heteromers with NR1A/NR2B NMDA receptor subunits. D1-H3-NMDA receptor complexes were confirmed by BRET combined with fluorescence complementation. The endogenous expression of complexes in mouse cortex was determined by PLA and similar expression was observed in wild-type and APP/PS1 mice. Consistent with allosteric receptor-receptor interactions within the complex, H3 receptor antagonists reduced NMDA or D1 receptor-mediated excitotoxic cell death in cortical organotypic cultures. Moreover, H3 receptor antagonists reverted the toxicity induced by ß1-42-amyloid peptide. Thus, histamine H3 receptors in D1-H3-NMDA heteroreceptor complexes arise as promising targets to prevent neurodegeneration.
A developed alternating current calorimeter for measuring the absolute value of specific heat C of a very small sample under a pressure up to 10 GPa and low temperature below 10 K is described. A Bridgman anvil cell made of tungsten carbide with a top diameter of 3 mm is used. A hollow at the top prevents expansion of the sample space over the anvil top. Two chip resistors, which act as a thermometer and a heater, are mounted on the outer part of a copper-beryllium gasket with a frying pan-like shape. Thus, the thermometer is not pressurized. In order to isolate the gasket from the anvil thermally, diamond powder with a grain size of 0.25 μm is placed on the anvil top. Two jumps of C at the superconducting transitions of Pb (3.3 mg) and In (5.0 mg) are observed under various pressures up to 9 GPa, as clearly as those at the ambient pressure.
With the recent detection of gravitational waves, non-classical light sources are likely to become an essential element of future detectors engaged in gravitational wave astronomy and cosmology. Operating a squeezed light source under high vacuum has the advantages of reducing optical losses and phase noise compared to techniques where the squeezed light is introduced from outside the vacuum. This will ultimately provide enhanced sensitivity for modern interferometric gravitational wave detectors that will soon become limited by quantum noise across much of the detection bandwidth. Here we describe the optomechanical design choices and construction techniques of a near monolithic glass optical parametric oscillator that has been operated under a vacuum of 10(-6) mbar. The optical parametric oscillator described here has been shown to produce 8.6 dB of quadrature squeezed light in the audio frequency band down to 10 Hz. This performance has been maintained for periods of around an hour and the system has been under vacuum continuously for several months without a degradation of this performance.
The ShARe/CLEF eHealth challenge lab aims to stimulate development of natural language processing and information retrieval technologies to aid patients in understanding their clinical reports. In clinical text, acronyms and abbreviations, also referenced as short forms, can be difficult for patients to understand. For one of three shared tasks in 2013 (Task 2), we generated a reference standard of clinical short forms normalized to the Unified Medical Language System. This reference standard can be used to improve patient understanding by linking to web sources with lay descriptions of annotated short forms
 or by substituting short forms with a more simplified, lay term.
In this study, we evaluate 1) accuracy of participating systems' normalizing short forms compared to a majority sense baseline approach, 2) performance of participants' systems for short forms with variable majority sense distributions, and 3) report the accuracy of participating systems' normalizing shared normalized concepts between the test set and the Consumer Health Vocabulary, a vocabulary of lay medical terms.
The best systems submitted by the five participating teams performed with accuracies ranging from 43 to 72 %. A majority sense baseline approach achieved the second best performance. The performance of participating systems for normalizing short forms with two or more senses with low ambiguity (majority sense greater than 80 %) ranged from 52 to 78 % accuracy, with two or more senses with moderate ambiguity (majority sense between 50 and 80 %) ranged from 23 to 57 % accuracy, and with two or more senses with high ambiguity (majority sense less than 50 %) ranged from 2 to 45 % accuracy. With respect to the ShARe test set, 69 % of short form annotations contained common concept unique identifiers with the Consumer Health Vocabulary. For these 2594 possible annotations, the performance of participating systems ranged from 50 to 75 % accuracy.
Short form normalization continues to be a challenging problem. Short form normalization systems perform with moderate to reasonable accuracies. The Consumer Health Vocabulary could enrich its knowledge base with missed concept unique identifiers from the ShARe test set to further support patient understanding of unfamiliar medical terms.
Atorvastatin and metformin are known energy restricting mimetic agents that act synergistically to produce molecular and metabolic changes in advanced prostate cancer (PCa). This trial seeks to determine whether these drugs favourably alter selected parameters in men with clinically-localized, aggressive PCa.
This prospective phase II randomized, controlled window trial is recruiting men with clinically significant PCa, confirmed by biopsy following multiparametric MRI and intending to undergo radical prostatectomy. Ethical approval was granted by the Royal Brisbane and Women's Hospital Human and The University of Queensland Medical Research Ethics Committees. Participants are being randomized into four groups: metformin with placebo; atorvastatin with placebo; metformin with atorvastatin; or placebo alone. Capsules are consumed for 8weeks, a duration selected as the most appropriate period in which histological and biochemical changes may be observed while allowing prompt treatment with curative intent of clinically significant PCa. At recruitment and prior to RP, participants provide blood, urine and seminal fluid. A subset of participants will undergo 7Tesla magnetic resonance spectroscopy to compare metabolites in-vivo with those in seminal fluid and biopsied tissue. The primary end point is biochemical evolution, defined using biomarkers (serum prostate specific antigen; PCA3 and citrate in seminal fluid and prostatic tissue). Standard pathological assessment will be undertaken.
This study is designed to assess the potential synergistic action of metformin and atorvastatin on PCa tumour biology. The results may determine simple methods of tumour modulation to reduce disease progression.
Clinical trials oversight by a Trial Steering Committee (TSC) is mandated by Good Clinical Practice. This study used qualitative methods to explore the role and valued attributes of the TSC to inform planned updates of Medical Research Council guidance and TSC terms of reference.
An ethnographic study was conducted during 2013-2014. TSC and Trial Management Group meetings from eight trials were observed and audio-recorded, and semi-structured interviews conducted with purposively sampled key informants: independent and non-independent TSC members, trial sponsor representatives, funder representatives and chief investigators. The selected trials were currently recruiting and dealing with challenging scenarios. Data were analysed thematically and findings triangulated and integrated to give a multi-perspective account of the role and valued attributes of a TSC.
Eight TSC meetings and six Trial Management Group meetings were observed. Sixty-five interviews were conducted with 51 informants. The two main roles played by the TSC were quality assurance and patient advocacy. Quality assurance involved being a 'critical friend' or a provider of 'tough love'. Factors influencing the ability of the TSC to fulfil this role included the TSC Chair, other independent TSC members and the model of the TSC and its fit with the trial subject. The role of the TSC as an advocate for patient well-being was perceived as paramount. Two attributes of TSC members emerged as critical: experience (of running a trial, trial oversight or in a clinical/methodological area) and independence. While independence was valued for giving impartiality, the lack of consensus about its definition and strict requirements of some funders made it difficult to operationalise.
We found tensions and ambiguities in the roles expected of TSCs and the attributes valued of TSC members. In particular, the requirements of independence and experience could conflict, impacting the TSCs' quality assurance role. Concerns were raised regarding whose interests are served by funders' criteria of independence; in particular, funders' selection of TSC members was thought to potentially inhibit TSCs' ability to fulfil their patient advocacy role. These findings should be incorporated in revising guidance and terms of reference for TSCs.
RFamide-related peptides (RFRPs) have been heavily implicated in the control of reproductive function subsequent to their discovery more than 16 years ago. However, recent studies using genetic and pharmacological tools have challenged their importance in regulating the hypothalamic-pituitary-gonadal axis. It is generally accepted that RFRPs act as part of a wider RFamide system, which involves two receptors, called the neuropeptide FF receptors (NPFFR1 and R2), and includes the closely-related neuropeptide NPFF. NPFF has been studied ever since the 1980s and many of the functions of NPFF are also shared by RFRPs. The current review questions whether these functions of NPFF are indeed specific to just NPFF alone and presents evidence from both neuroendocrine and pharmacological perspectives. Furthermore, recently emerging new functions of RFRPs are discussed with the overall goal of clarifying the functions of RFRPs beyond the hypothalamic-pituitary-gonadal axis.
NHS England, in partnership with other agencies, has developed a toolkit to address changes to the way health and social care organisations must work together to identify, assess and support carers as well as their families. The toolkit covers new duties required of NHS organisations, brought about by the Care Act 2014, and the Children and Families Act 2014, and includes many examples of best practice. The resource helps promote the development of an integrated approach to supporting carers of all ages, between adult social care services, NHS commissioners and providers and the third sector.
We aimed to compare Theory of Mind (ToM) functions and investigate the relationship between ToM functions and verbal working memory (VWM) in first degree relatives of bipolar disorder and schizophrenia patients.
The sample consisted of first degree relatives of patients with bipolar disorder (n=22), schizophrenia (n=28), and age, gender, education and total IQ matched healthy volunteers (n=27) without a family history of schizophrenia or bipolar disorder. We administered Auditory Consonants Test (ACT) to evaluate VWM, first and second order false belief tests (ToM-1, ToM-2), Faux Pas Test (FPT), Hinting Test (HT) to evaluate different domains of ToM functions.
Both relative groups performed significantly lower in all components of ToM and VWM tests compared to the control group. When VWM scores were employed as covariate in the analyses, the FPT difference between the groups remained significant, HT difference regressed to a marginal level, and the difference between ToM-1 and ToM-2 disappeared.
To our knowledge, this is the first study indicating the presence of ToM impairment among first degree relatives of bipolar disorder patients similar to relatives of schizophrenia patients. VWM performance seems to affect first and second order ToM functions in relatives of patients with schizophrenia and bipolar disorder. On the other hand, FPT and HT domains seem to be independent of VWM performances in these groups. FPT and HT impairments may be familial vulnerability markers that are independent from neurocognitive impairment.
Integrase strand transfer inhibitors (INSTIs) are highly effective against HIV infections. Co-crystal structures of the prototype foamy virus intasome have shown that all three FDA-approved drugs, raltegravir (RAL), elvitegravir and dolutegravir (DTG), act as interfacial inhibitors during the strand transfer (ST) integration step. However, these structures give only a partial sense for the limited inhibition of the 3'-processing reaction by INSTIs and how INSTIs can be modified to overcome drug resistance, notably against the G140S-Q148H double mutation. Based on biochemical experiments with modified oligonucleotides, we demonstrate that both the viral DNA +1 and -1 bases, which flank the 3'-processing site, play a critical role for 3'-processing efficiency and inhibition by RAL and DTG. In addition, the G140S-Q148H (SH) mutant integrase, which has a reduced 3'-processing activity, becomes more active and more resistant to inhibition of 3'-processing by RAL and DTG in the absence of the -1 and +1 bases. Molecular modeling of HIV-1 integrase,
 together with biochemical data, indicate that the conserved residue Q146 in the flexible loop of HIV-1 integrase is critical for productive viral DNA binding through specific contacts with the virus DNA ends in the 3'-processing and ST reactions. The potency of integrase inhibitors against 3'-processing and their ability to overcome resistance is discussed.
We examined the regulation of Yes-associated protein (YAP) localization, phosphorylation, and transcriptional activity in intestinal epithelial cells. Our results show that stimulation of intestinal epithelial IEC-18 cells with the G protein-coupled receptor (GPCR) agonist angiotensin II, a potent mitogen for these cells, induced rapid translocation of YAP from the nucleus to the cytoplasm (within 15 min) and a concomitant increase in YAP phosphorylation at Ser(127) and Ser(397) Angiotensin II elicited YAP phosphorylation and cytoplasmic accumulation in a dose-dependent manner (ED50 = 0.3 nm). Similar YAP responses were provoked by stimulation with vasopressin or serum. Treatment of the cells with the protein kinase D (PKD) family inhibitors CRT0066101 and kb NB 142-70 prevented the increase in YAP phosphorylation on Ser(127) and Ser(397) via Lats2, YAP cytoplasmic accumulation, and increase in the mRNA levels of YAP/TEAD-regulated genes (Ctgf and Areg). Furthermore, siRNA-mediated knockdown of PKD1, PKD2, and PKD3 markedly attenuated YAP nuclear-cytoplasmic shuttling, phosphorylation at Ser(127), and induction of Ctgf and Areg expression in response to GPCR activation. These results identify a novel role for the PKD family in the control of biphasic localization, phosphorylation, and transcriptional activity of YAP in intestinal epithelial cells. In turn, YAP and TAZ are necessary for the stimulation of the proliferative response of intestinal epithelial cells to GPCR agonists that act via PKD. The discovery of interaction between YAP and PKD pathways identifies a novel cross-talk in signal transduction and demonstrates, for the first time, that the PKDs feed into the YAP pathway.
Ca(2+)/calmodulin-dependent protein kinase phosphatase (CaMKP/PPM1F) is a Ser/Thr phosphatase that belongs to the PPM family. Growing evidence suggests that PPM phosphatases including CaMKP act as a complex with other proteins to regulate cellular functions. In this study, using the two-dimensional far-western blotting technique with digoxigenin-labeled CaMKP as a probe, in conjunction with peptide mass fingerprinting analysis, we identified neurofilament L (NFL) as a CaMKP-binding protein in a Triton-insoluble fraction of rat brain. We confirmed binding of fluorescein-labeled CaMKP (F-CaMKP) to NFL in solution by fluorescence polarization. The analysis showed that the dissociation constant of F-CaMKP for NFL is 73 ± 17 nM (n = 3). Co-immunoprecipitation assay using a cytosolic fraction of NGF-differentiated PC12 cells showed that endogenous CaMKP and NFL form a complex in cells. Furthermore, the effect of CaMKP on self-assembly of NFL was examined. Electron microscopy revealed that CaMKP markedly prevented NFL from forming large filamentous aggregates, suggesting that CaMKP-binding to NFL inhibits its filament association. These findings may provide new insights into a novel mechanism for regulating network formation of neurofilaments during neuronal differentiation.
The present study focuses on the development of an effective topical nanogel formulation of two anti-psoriatic drugs; Acitretin (Act) and Aloe-emodin (AE) using natural polymer chitin. Simple regeneration chemistry was used to prepare Chitin Nanogel Systems (CNGs). The developed control chitin (CNGs) nanogels, acitretin loaded chitin nanogels (ActCNGs) and aloe-emodin loaded chitin nanogels (AECNGs) were characterized by DLS, SEM, FTIR, XRD and TG-DTA. The systems were found to be spherical in shape with a size range of 98±10, 138±8 and 238±6nm having zeta potential values of +28±3, +27±3 and +25±6mV for CNGs, ActCNGs and AECNGs respectively. The in vitro haemolysis assay revealed that all the nanogel systems are blood compatible. The systems exhibited higher swelling and release at acidic pH. The ex vivo skin permeation studies using porcine skin confirmed the higher deposition of the systems at epidermal and dermal layers, which was confirmed further by fluorescent imaging. The in vivo anti-psoriatic activity study using Perry's mouse tail model and skin safety studies confirmed the potential benefit of the system for topical delivery of acitretin and aloe-emodin in psoriasis.
Type 2 diabetes mellitus is characterized by chronic hyperglycemia and associated with oxidative stress resulting from accumulation of free radicals in body's tissues, which especially affects beta cells in pancreas and is an important factor in the development of diabetes and its complications. Glutathione S-transferases (GSTs) are a family of antioxidant enzymes that play important roles in decreasing ROS species and act as a kind of antioxidant defense. In a case-control study, we investigated the role of GSTP1 Ile105Val polymorphism in predisposition to T2DM in patients from Tarabah province, Saudi Arabia. The polymorphism was screened by PCR-RFLP in 90 T2DM patients and 87 healthy controls. The genotypes and alleles frequencies in cases and controls were assessed using Cochran-Armitage trend test and odds ratios (ORs), and 95 % confidence intervals (CIs) in different genetic models of inheritance were calculated. Our data indicate that G allele (Val) is associated with an increased risk for T2DM in this population in any combination (OR 4.101, 95 % CI 1.986-8.469, P = 0.00008). This indicates that individuals who are carriers for the mutant allele, either in homozygous (GG) or heterozygous (AG) state, are at fourfold higher risk for development of T2DM than other subjects in this population.
Laughter is a simple, stereotyped, innate, human play vocalization that is ideal for the study of vocal evolution. The basic approach of describing the act of laughter and when we do it has revealed a variety of phenomena of social, linguistic, and neurological significance. Findings include the acoustic structure of laughter, the minimal voluntary control of laughter, the punctuation effect (which describes the placement of laughter in conversation and indicates the dominance of speech over laughter), and the role of laughter in human matching and mating. Especially notable is the use of laughter to discover why humans can speak and other apes cannot. Quadrupeds, including our primate ancestors, have a 1:1 relation between breathing and stride because their thorax must absorb forelimb impacts during running. The direct link between breathing and locomotion limits vocalizations to short, simple utterances, such as the characteristic panting chimpanzee laugh (one sound per inward or outward breath). The evolution of bipedal locomotion freed the respiration system of its support function during running, permitting greater breath control and the selection for human-type laughter (a parsed exhalation), and subsequently the virtuosic, sustained, expiratory vocalization of speech. This is the basis of the bipedal theory of speech evolution.
Studies of odour-driven foraging by mammals focus on attractant cues emitted by flowers, fruits, and fungi. Yet, the leaves of many plant species worldwide produce odour, which could act as a cue for foraging mammalian herbivores. Leaf odour may thus improve foraging efficiency for such herbivores in many ecosystems by reducing search time, particularly but not only, for plants that are visually obscured. We tested the use of leaf odour by a free-ranging mammalian browser, the swamp wallaby (Wallabia bicolor) to find and browse palatable tree seedlings (Eucalyptus pilularis). Wallabies visited patches non-randomly with respect to the presence of seedlings. In the absence of visual plant cues, they used leaf odour (cut seedlings in vials) to find patches earlier, and visited and investigated them more often than control patches (empty vials), supporting the hypothesis that wallabies used seedling odour to enhance search efficiency. In contrast, the grey kangaroo (Macropus giganteus), a grazer, showed no response to seedling odour. When the availability of seedling visual and olfactory cues was manipulated, wallabies browsed seedlings equally quickly in all treatments: upright (normal cues), pinned to the ground (reduced visual cues), and upright plus pinned seedlings (double olfactory cues). Odour cues play a critical role in food-finding by swamp wallabies, and these animals are finely tuned to detecting these cues with their threshold for detection reached by odours from only a single plant. The global significance of leaf odour in foraging by mammalian herbivores consuming conifers, eucalypts, and other odour-rich species requires greater attention.
Lipidomics has been proving that membrane lipids play a crucial role in several cell functions and are involved in several pathologies, including cancer. In fact, beyond a scaffold where proteins and other components are embedded, the cell membrane can also act as a barrier or a target for anticancer drugs. From this point of view, the development of new chemotherapeutic agents should also take into account the role of the membrane in their activity. This Review aims to highlight the importance of anticancer drug-membrane interactions as a powerful strategy to improve cancer therapy. Biophysical techniques emerge, therefore, as essential tools to unveil such interactions.
We have elucidated the spatial arrangement of proteins and snRNP subunits within the purified spliceosomal B(act) complex from Saccharomyces cerevisiae, using negative-stain immunoelectron microscopy. The B(act) spliceosome exhibits a mushroom-like shape with a main body connected to a foot and a steep and
 a shallow slope. The U5 core components, including proteins Snu114 and Prp8, are located in the main body and foot, while Brr2 is on the shallow slope. U2 snRNP components and the RNA helicase Prp2 were predominantly located in the upper regions of both slopes. While several proteins of the "nineteen complex" are located on the steep slope, Prp19, Cef1, and the U6 snRNA-binding protein Cwc2 are on the main body. Our results also indicate that the catalytic core RNP of the spliceosome resides in its main body. We thus assign distinct domains of the B(act) complex to its snRNP and protein components, and we provide first structural insights into the remodeling events at the spliceosome during its transformation from the B to the B(act) complex.
Artemisinin-based combination therapy (ACT) has been adopted by the World Health Organization as a first-line treatment for uncomplicated Plasmodium falciparum malaria. In endemic regions, it has proven more effective in treating the disease, and even in reducing its transmission. Nonetheless, there is a scarcity of studies carried out in non-endemic areas on imported uncomplicated malaria.
This is a retrospective, observational study performed on patients diagnosed and admitted with uncomplicated P. falciparum malaria between 2004 and 2015. The objective was to compare the parasite clearance period and the average hospital length of stay for patients treated with ACT vs those receiving other treatment regimens.
Eighty-five patients were included in the study. Fifty-one received ACT treatment (dihydroartemisinin-piperaquine) and thirty-four patients were treated with quinine sulfate+doxycycline or atovaquone/proguanil. The parasite clearance period was shorter in the group of patients treated with ACT compared to those receiving other treatment types: 24 h (IQR 24) vs 48 h (IQR 48), p < 0.01. The average hospital stay was also shorter in the ACT group with respect to the second group: 2.67 days (IQR 1.08) vs 3.96 days (IQR 2.87), p < 0.001. A mild case of hepatitis was registered in the group treated with ACT.
ACT treatment of admitted hospital patients with imported uncomplicated malaria from P. falciparum reduced the days spent hospitalized as well as producing a more rapid parasite clearance compared to classic treatment. In spite of being treated with safe medications, one has to be alert to possible adverse effects such as hepatitis and delayed haemolytic anaemia.
Plant MYB transcription factors control diverse biological processes, such as differentiation, development and abiotic stress responses. In this study, we characterized BplMYB46, an MYB gene from Betula platyphylla (birch) that is involved in both abiotic stress tolerance and secondary wall biosynthesis. BplMYB46 can act as a transcriptional activator in yeast and tobacco. We generated transgenic birch plants with overexpressing or silencing of BplMYB46 and subjected them to gain- or loss-of-function analysis. The results suggest that BplMYB46 improves salt and osmotic tolerance by affecting the expression of genes including SOD, POD and P5CS to increase both reactive oxygen species scavenging and proline levels. In addition, BplMYB46 appears to be involved in controlling stomatal aperture to reduce water loss. Overexpression of BplMYB46 increases lignin deposition, secondary cell wall thickness and the expression of genes in secondary cell wall formation. Further analysis indicated that BplMYB46 binds to MYBCORE and AC-box motifs and may directly activate the expression of genes involved in abiotic stress responses and secondary cell wall biosynthesis whose promoters contain these motifs. The transgenic BplMYB46-overexpressing birch plants, which have improved salt and osmotic stress tolerance, higher lignin and cellulose content and lower hemicellulose content than the control, have potential applications in the forestry industry.
Semiochemicals are of paramount importance in sexually deceptive plants. These plants sexually lure specific male insects as pollinators by chemical and physical mimicry of the female of the pollinator. The strategy has evolved repeatedly in orchids, with a wide diversity of insect groups exploited. Chemical communication systems confirmed by field bioassays include: alkenes and alkanes in bee pollinated Ophrys species, keto-acid and hydroxy-acids in scoliid wasp pollinated O. speculum, and cyclohexanediones and pyrazines in thynnine wasp pollinated Chiloglottis and Drakaea orchids, respectively. In Ophrys, stearoyl-acyl carrier protein desaturase (SAD) enzymes have been confirmed to control species level variation in alkene double bond position. The production of cyclohexanediones in Chiloglottis unexpectedly depends on UVB light, a phenomenon unknown for other plant specialised metabolites. Potential biosynthetic pathways for other systems are explored, and alternative approaches to further accelerate chemical discovery in sexually deceptive plants are proposed.
Monk parakeets, Myiopsitta monachus Boddaert, are native to South America but have established populations in North America, Europe, Africa and Asia. They are claimed to act as agricultural pests in their native range, and their communal stick nests may damage human infrastructure. Although several monk parakeet populations are present in the Mediterranean Basin and temperate Europe, little empirical data are available on their population size and growth, distribution and potential impact. We investigated the temporal and spatial dynamics of monk parakeets in Israel to assess their invasion success and potential impact on agriculture.
Monk parakeet populations are growing exponentially at a higher rate than that reported elsewhere. The current Israeli population of monk parakeets comprises approximately 1500 individuals. The distribution of the species has increased and shifted from predominantly urban areas to agricultural landscapes.
In Israel, monk parakeet populations are growing fast and have dispersed rapidly from cities to agricultural areas. At present, reports of agricultural damage are scarce. A complete assessment of possible management strategies is urgently needed before the population becomes too large and widespread to allow for cost-effective mitigation campaigns to be implemented. © 2016 Society of Chemical Industry.
The literature on neoliberal health governance explores how macro-economic neoliberal policies as well as individual attitudes and behaviors reflect an increasingly individualized construction of health and citizens' responsibility over it. This study contributes to this literature and expands it in important ways. Drawing on qualitative interviews from 22 midwives and birth workers (doulas, childbirth educators, lactation consultants) practicing in the US, this study explores how midwives and birth workers act as "experts of conduct" who promote certain neoliberal values in their logics of care and interactions with clientele. The findings reveal that midwives and birth workers promote a form of maternal neoliberal health governance by: 1) making distinctions between their clientele that signal differences in health competence and resources, 2) encouraging autonomy and responsibility over birth experiences, and 3) promoting an empowerment discourse that hinges implicitly on an exclusionary consumer choice rhetoric. Midwives and birth workers are crucially implicated in shaping maternal subjectivities through pedagogical interactions I refer to as "mothercraft." This study illustrates how the promotion of certain health identities by experts further stratifies patient populations, exacerbating differences between women based on their socioeconomic status, racial-ethnic, and cultural positions.
The consequences of heavy alcohol use remain a serious public health problem. Consistent evidence has demonstrated that both genetic and social influences contribute to alcohol use. Research on gene-environment interaction (GxE) has also demonstrated that these social and genetic influences do not act independently. Instead, certain environmental contexts may limit or exacerbate an underlying genetic predisposition. However, much of the work on GxE and alcohol use has focused on adolescence and less is known about the important environmental contexts in young adulthood. Using data from the young adult wave of the Finnish Twin Study, FinnTwin12 (N = 3402), we used biometric twin modeling to test whether education moderated genetic risk for alcohol use as assessed by drinking frequency and intoxication frequency. Education is important because it offers greater access to personal resources and helps determine one's position in the broader stratification system. Results from the twin models show that education did not moderate genetic variance components and that genetic risk was constant across levels of education. Instead, education moderated environmental variance so that under conditions of low education, environmental influences explained more of the variation in alcohol use outcomes. The implications and limitations of these results are discussed.
Veterans of the wars in Iraq and Afghanistan who receive care in the Veterans Health Administration (VA) have high disease burden. Distinct comorbidity patterns have been shown to be differentially associated with adverse outcomes, including death. This study determined correlates of 5-year mortality.
VA demographic, military, homelessness, and clinical measures informed this retrospective analysis. Previously constructed comorbidity classifications over 3 years of care were entered into a Cox proportional hazards model of death.
There were 164,933 veterans in the cohort, including African Americans (16%), Hispanics (11%), and whites (65%). Most were in their 20s at baseline (60%); 12% were women; 4% had attempted suicide; 4% had been homeless. Having clustered
 disorders of pain, posttraumatic stress disorder, and traumatic brain injury was associated with death [hazard ratio (HR)=2.0]. Mental disorders including substance abuse were similarly associated (HR=2.1). Prior suicide attempt (HR=2.2) or drug overdose (HR=3.0) considerably increased risk of death over 5 years.
As congressional actions such as Veterans Choice Act offer more avenues to seek care outside of VA, coordination of care, and suicide prevention outreach for recent veterans may require innovative approaches to preserve life.
The 2010 Dependent Coverage Provision (DCP) of the Affordable Care Act allowed young adults to remain on their parents' health insurance plans until age 26 years. Although the provision improved coverage and survey-reported access to care, little is known regarding its impact on timely access for acute conditions. This study aims to assess changes in insurance coverage and perforation rates among young adults with acute appendicitis-an established metric for population-level health care access-after the DCP.
The National Inpatient Sample and difference-in-differences linear regression were used to assess prepolicy/postpolicy changes for policy-eligible young adults (aged 19-25 y) compared with a slightly older, policy-ineligible comparator group (aged 26-34 y).
After adjustment for covariates, 19-25 year olds experienced a 3.6-percentage point decline in the uninsured rate after the DCP (baseline 22.5%), compared with 26-34 year olds (P<0.001). This coincided with a 1.4-percentage point relative decline in perforated appendix rate for 19-25 year olds (baseline 17.5%), compared with 26-34 year olds (P=0.023). All subgroups showed significant reductions in uninsured rates; however, statistically significant reductions in perforation rates were limited to racial/ethnic minorities, patients from lower-income communities, and patients presenting to urban teaching hospitals.
Reductions in uninsured rates among young adults after the DCP were associated with significant reductions in perforated appendix rates relative to a comparator group, suggesting that insurance expansion could lead to fewer delays in seeking and accessing care for acute conditions. Greater relative declines in perforation rates among the most at-risk subpopulations hold important implications for the use of coverage expansion to mitigate existing disparities in access to care.
Transitory phenotypic changes such as the epithelial-mesenchymal transition (EMT) help embryonic cells to generate migratory descendants that populate new sites and establish the distinct tissues in the developing embryo. The mesenchymal descendants of diverse epithelia also participate in the wound healing response of adult tissues, and facilitate the progression of cancer. EMT can be induced by several extracellular cues in the microenvironment of a given epithelial tissue. One such cue, transforming growth factor β (TGFβ), prominently induces EMT via a group of specific transcription factors. The potency of TGFβ is partly based on its ability to perform two parallel molecular functions, i.e. to induce the expression of growth factors, cytokines and chemokines, which sequentially and in a complementary manner help to establish and maintain the EMT, and to mediate signaling crosstalk with other developmental signaling pathways, thus promoting changes in cell differentiation. The molecules that are activated by TGFβ signaling or act as cooperating partners of this pathway are impossible to exhaust within a single coherent and contemporary report. Here, we present selected examples to illustrate the key principles of the circuits that control EMT under the influence of TGFβ.
Malaria is a parasitic tropical disease that kills around 600,000 patients every year. The emergence of resistant Plasmodium falciparum parasites to artemisinin-based combination therapies (ACTs) represents a significant public health threat, indicating the urgent need for new effective compounds to reverse ACT resistance and cure the disease. For this, extensive curation and homogenization of experimental anti-Plasmodium screening data from both in-house and ChEMBL sources were conducted. As a result, a coherent strategy was established that allowed compiling coherent training sets that associate compound structures to the respective antimalarial activity measurements. Seventeen of these training sets led to the successful generation of classification models discriminating whether a compound has a significant probability to be active under the specific conditions of the antimalarial test associated with each set. These models were used in consensus prediction of the most likely active from a series of curcuminoids available in-house. Positive predictions together with a few predicted as inactive were then submitted to experimental in vitro antimalarial testing. A large majority from predicted compounds showed antimalarial activity, but not those predicted as inactive, thus experimentally validating the in silico screening approach. The herein proposed consensus machine learning approach showed its potential to reduce the cost and duration of antimalarial drug discovery.
The sessile plants have evolved diverse intrinsic mechanisms to control their proper development under variable environments. In contrast to plastic vegetative development, reproductive traits like floral identity often show phenotypic robustness against environmental variations. However, it remains obscure about the molecular basis of this phenotypic robustness. In this study, we found that eg1 (extra glume1) mutants of rice (Oryza savita L.) showed floral phenotypic variations in different growth locations resulting in a breakdown of floral identity robustness. Physiological and biochemical analyses showed that EG1 encodes a predominantly mitochondria-localized functional lipase and functions in a high temperature-dependent manner. Furthermore, we found that numerous environmentally responsive genes including many floral identity genes are transcriptionally repressed in eg1 mutants and OsMADS1, OsMADS6 and OsG1 genetically act downstream of EG1 to maintain floral robustness. Collectively, our results demonstrate that EG1 promotes floral robustness against temperature fluctuation by safeguarding the expression of floral identify genes through a high temperature-dependent mitochondrial lipid pathway and uncovers a novel mechanistic insight into floral developmental control.
This study determined if combined treatment with the muscarinic receptor (MR) antagonist solifenacin and the β3 -adrenergic receptor (AR) agonist mirabegron could inhibit detrusor overactivity induced by cold stress in spontaneously hypertensive rats (SHRs).
Thirty-two female 10-week-old SHRs were fed an 8% NaCl-supplemented diet for 4 weeks. Cystometric measurements of the unanesthetized, unrestricted rats were performed at room temperature (RT, 27 ± 2°C) for 20 min. The rats were then intravenously administered vehicle, 0.1 mg/kg solifenacin alone, 0.1 mg/kg mirabegron alone, or the combination of 0.1 mg/kg mirabegron and 0.1 mg/kg solifenacin (n = 8 each group). Five minutes later, the treated rats were exposed to low temperature (LT, 4 ± 2°C) for 40 min. Finally, the rats were returned to RT. After the cystometric investigations, the β3 -ARs and M3 -MRs expressed within the urinary bladders were analyzed.
Just after transfer from RT to LT, vehicle-, solifenacin-, and mirabegron-treated SHRs exhibited detrusor overactivity that significantly decreased voiding interval and bladder capacity. However, treatment with the combination of solifenacin and mirabegron partially inhibited the cold stress-induced detrusor overactivity patterns. The decreases of voiding interval and bladder capacity in the combination-treated rats were significantly inhibited compared to other groups. Within the urinary bladders, there were no differences between expression levels of M3 -MR and β3 -AR mRNA. The tissue distribution of M3 -MRs was similar to that of the β3 -ARs.
This study suggested that the combination of solifenacin and mirabegron act synergistically to inhibit the cold stress-induced detrusor overactivity in SHRs. Neurourol. Urodynam. © 2016 The Authors. Neurourology and Urodynamics Published by Wiley Periodicals, Inc.
Guanidine compounds act as ion channel modulators. In the case of Cys-loop receptors, the guanidine compound amiloride antagonized the heteromeric GABA-A, glycine, and nicotinic acetylcholine receptors. However, amiloride exhibits characteristics consistent with a positive allosteric modulator for the human GABA-A (hGABA-A) ρ1 receptor. Site-directed mutagenesis revealed that the positive allosteric modulation was influenced by the GABA-A ρ1 second transmembrane domain 15' position, a site implicated in ligand allosteric modulation of Cys-loop receptors. There are a variety of amiloride derivatives that provide opportunities to assess the significance of amiloride functional groups (e.g., the guanidine group, the pyrazine ring, etc.) in the modulation of the GABA-A ρ1 receptor activity. We utilized 3 amiloride derivatives (benzamil, phenamil, and 5-(N, N-Hexamethylene) amiloride) to assess the contribution of these groups toward the potentiation of the GABA-A ρ1 receptor. Benzamil and phenamil failed to potentiate on the wild type GABA-A ρ1 GABA-mediated current while HMA demonstrated efficacy only at the highest concentration studied. The hGABA-A ρ1 (I15'N) mutant receptor activity was potentiated by lower HMA concentrations compared to the wild type receptor. Our findings suggest that an exposed guanidine group on amiloride and amiloride derivatives is critical for modulating the GABA-A ρ1 receptor. The present study provides a conceptual framework for predicting which amiloride derivatives will demonstrate positive allosteric modulation
 of the GABA-A ρ1 receptor.
Adjuvant chemotherapy (ACT) after radical surgery is known to improve the survival of patients with non-small cell lung cancer (NSCLC). However, there are few studies reporting the impact of age on the efficacy of ACT in NSCLC patients. All patients who received postoperative ACT in the Cancer Hospital, the Chinese Academy of Medical Sciences, between 2001 and 2013 with complete records in the database of the hospital and met the inclusion criteria were enrolled in this study for analysis. The primary end point was disease-free survival (DFS) in terms of age. Survival analysis was performed using Kaplan-Meier estimates, log-rank tests, and Cox's proportional hazards regression analysis. Propensity score matching (PSM) was used, survival analysis and subgroup analysis of the match data were carried out. Of 1095 patients with stage IB to stage IIIA NSCLC who underwent radical resection, 865 cases who met the inclusion criteria were analyzed. Of them, 156 (18.0%) patients were 65 years old or older, and the remaining 709 (82.0%) patients were younger than 65. The DFS between the younger group and the elderly group was not significantly different neither before PSM (100.714 weeks [95% CI: 84.421, 117.007] vs. 99.571 weeks [95% CI: 82.621, 116.522]; P = 0.555) nor after PSM (104.857 weeks [95% CI: 81.495, 128.220] vs. 97.429 weeks [95% CI: 81.743, 113.114]; P = 0.328) using the Kaplan-Meier method.The results suggest that the benefit on DFS was similar regardless of age of NSCLC patients. ACT should not be withheld from elderly patients. However, these conclusions are limited by the nature of this retrospective study, and therefore prospective trials are required for further verification.
We provide evidence that spin ferroquadrupolar (FQ) order is the likely ground state in the nonmagnetic nematic phase of stoichiometric FeSe. By studying the variational mean-field phase diagram of a bilinear-biquadratic Heisenberg model up to the 2nd nearest neighbor, we find the FQ phase in close proximity to the columnar antiferromagnet commonly realized in iron-based superconductors; the stability of the FQ phase is further verified by the density matrix renormalization group. The dynamical spin structure factor in the FQ state is calculated with flavor-wave theory, which yields a qualitatively consistent result with inelastic neutron scattering experiments on FeSe at both low and high energies. We verify that FQ can coexist with C_{4} breaking environments in the mean-field calculation, and further discuss the possibility that quantum fluctuations in FQ act as a source of nematicity.
Magnetic resonance (MR) contrast agents have been widely used over the last 3 decades in routine clinical practice. Paul Lauterbur recognized the presence of these contrast agents, which act as paramagnetic catalysts that accelerate the T1 relaxation process. The first MR contrast agent to be approved for clinical use was in 1988, and since then, it is estimated that 200 million doses have been administered worldwide. These contrast agents have diverse clinical as well as research applications, involving almost all the body organs. This review will cover some existing as well as many new applications that have emerged over the last few decades. MR imaging now has the potential of being used to monitor enzymatic activity, gene expression, metal ion homeostasis, and cell death in vivo. In future, newer contrast agents will develop and become commercially available, expanding the current clinical applications of MR contrast media.
Acquired brain injury (ABI) is a leading cause of permanent disability, currently affecting 20,000 Australian children. Community participation is essential for childhood development and enjoyment, yet children with ABI can often experience barriers to participation. The factors which act as barriers and facilitators to community participation for children with an ABI are not well understood.
To identify the viewpoints of parents of children with an ABI, regarding the barriers and facilitators most pertinent to community participation for their child.
Using Q-method, 41 parents of children with moderate/severe ABI sorted 37 statements regarding barriers and facilitators to community participation. Factor analysis identified three viewpoints.
This study identified three distinct viewpoints, with the perceived ability to participate decreasing with a stepwise trend from parents who felt their child and family "can" participate in viewpoint one, to "want" in viewpoint two and "try" in viewpoint three.
Findings indicated good participation outcomes for most children and families, however some families who were motivated to participate experienced significant barriers. The most significant facilitators included child motivation, supportive relationships from immediate family and friends, and supportive community attitudes. The lack of supportive relationships and attitudes was perceived as a fundamental barrier to community participation.
This research begins to address the paucity of information regarding those factors that impact upon the participation of children with an ABI in Australia. Findings have implications for therapists, service providers and community organisations.
The hepatitis C viral proteins NS3/4A protease, NS5B polymerase, and NS5A are clinically validated targets for direct-acting antiviral therapies. The NS5B polymerase may be inhibited directly through the action of nucleosides or nucleotide analogues or allosterically at a number of well-defined sites. Herein we describe the further development of a series of thiophene carboxylate allosteric inhibitors of NS5B polymerase that act at the thumb pocket 2 site. Lomibuvir (1) is an allosteric HCV NS5B inhibitor that has demonstrated excellent antiviral activity and potential clinical utility in combination with other direct acting antiviral agents. Efforts to further explore and develop this series led to compound 23, a compound with comparable potency and improved physicochemical properties.
The US Affordable Care Act mandates that private insurers cover a list of preventive services without cost sharing. The list is determined by 4 expert committees that evaluate the overall health effect of preventive services. We analyzed the process by which the expert committees develop their recommendations. Each committee uses different criteria to evaluate preventive services and none of the committees consider cost systematically. We propose that the existing committees adopt consistent evidence review methodologies and expand the scope of preventive services reviewed and that a separate advisory committee be established to integrate economic considerations into the final selection of free preventive services. The comprehensive framework and associated criteria are intended to help policy makers in the future develop a more evidence-based, consistent, and ethically sound approach.
Background. State-level 'age 21' drinking laws conform generally with the United States National Minimum Drinking Age Act of 1984 (US), and are thought to protect young people from adverse drinking experiences such as heavy episodic drinking (HED, sometimes called 'binge drinking'). We shed light on this hypothesis while estimating the age-specific risk of transitioning from 1st full drink to 1st HED among 12-to-23-year-old newly incident drinkers, with challenge to a "gender gap" hypothesis and male excess described in HED prevalence reports. Methods. The study population consisted of non-institutionalized civilians in the United States, with nine independently drawn nationally representative samples of more than 40,000 12-to-23-year-olds (2006-2014). Standardized audio computer-assisted self-interviews identified 43,000 newly incident drinkers (all with 1st HED evaluated within 12 months of drinking onset). Estimated age-specific HED risk soon after first full drink is evaluated for males and females. Results. Among 12-to-23-year-old newly incident drinkers, an estimated 20-30% of females and 35-45% of males experienced their 1st HED within 12 months after drinking onset. Before mid-adolescence, there is no male excess in such HED risk. Those who postponed drinking to age 21 are not spared (27% for 'postponer' females; 95% CI [24-30]; 42% for 'postponer' males; 95% CI [38-45]). An estimated 10-18% females and 10-28% males experienced their 1st HED in the same month of their 1st drink; peak HED risk estimates are 18% for 'postponer' females (95% CI [15-21]) and 28% for 'postponer' males (95% CI [24-31]). Conclusions. In the US, one in three young new drinkers transition into HED within 12 months after first drink. Those who postpone the 1st full drink until age 21 are not protected. Furthermore, 'postponers' have substantial risk for very rapid transition to HED. A male excess in this transition to HED is not observed until after age 14.
MicroRNAs (miRNAs) are short nucleotide sequences that form a typical hairpin structure which is recognized by a complex enzyme machinery. It ultimately leads to the incorporation of 18-24 nt long mature miRNAs into RISC where they act as recognition keys to aid in regulation of target mRNAs. It is involved to determine miRNAs experimentally and, therefore, machine learning is used to complement such endeavors. The success of machine learning mostly depends on proper input data and appropriate features for parameterization of the data. Although, in general, two-class classification (TCC) is used in the field; because negative examples are hard to come by, one-class classification (OCC) has been tried for pre-miRNA detection. Since both positive and negative examples are currently somewhat limited, feature selection can prove to be vital for furthering the field of pre-miRNA detection. In this study, we compare the performance of
 OCC and TCC using eight feature selection methods and seven different plant species providing positive pre-miRNA examples. Feature selection was very successful for OCC where the best feature selection method achieved an average accuracy of 95.6%, thereby being ∼29% better than the worst method which achieved 66.9% accuracy. While the performance is comparable to TCC, which performs up to 3% better than OCC, TCC is much less affected by feature selection and its largest performance gap is ∼13% which only occurs for two of the feature selection methodologies. We conclude that feature selection is crucially important for OCC and that it can perform on par with TCC given the proper set of features.
The ability to conceptualize 3D shapes is central to understanding biological processes. The concept that the structure of a biological molecule leads to function is a core principle of the biochemical field. Visualisation of biological molecules often involves vocal explanations or the use of two dimensional slides and video presentations. A deeper understanding of these molecules can however be obtained by the handling of objects. 3D printed biological molecules can be used as active learning tools to stimulate engagement in large group lectures. These models can be used to build upon initial core knowledge which can be delivered in either a flipped form or a more didactic manner. Within the teaching session the students are able to learn by handling, rotating and viewing the objects to gain an appreciation, for example, of an enzyme's active site or the difference between the major and minor groove of DNA. Models and other artefacts can be handled in small groups within a lecture theatre and act as a focal point to generate conversation. Through the approach presented here core knowledge is first established and then supplemented with high level problem solving through a "Think-Pair-Share" cooperative learning strategy. The teaching delivery was adjusted based around experiential learning activities by moving the object from mental cognition and into the physical environment. This approach led to students being able to better visualise biological molecules and a positive engagement in the lecture. The use of objects in teaching allows the lecturer to create interactive sessions that both challenge and enable the student.
Chronic myeloid leukemia (CML) is a myeloproliferative disorder characterized by overproduction of immature and matured myeloid cells in the peripheral blood, bone marrow and spleen.
A hallmark of CML is the presence of (9; 22) (q34; q11) reciprocal translocation, which is cytogenetically visible as Philadelphia chromosome (Ph) and results in the formation of BCR-ABL1 fusion protein. This fusion protein is a constitutively active tyrosine kinase which is necessary and sufficient for malignant transformation. The introduction of imatinib, a BCR-ABL1- targeting tyrosine kinase inhibitor (TKI) has revolutionized CML therapy. Subsequently, two other TKIs with increased activity against BCR-ABL1, dasatinib and nilotinib, were developed and approved for CML patients. Nevertheless, CML therapy faces major challenges.
The first is the development of resistance to BCR-ABL1 inhibitors in some patients, which can be due to BCR-ABL1 overexpression, differences in cellular drug influx and efflux, activation of alternative signaling pathways, or emergence of BCR-ABL1 kinase domain mutations during TKI treatment. The second is the limited efficiency of BCR-ABL1-TKIs in blast crisis (BC) CML. The third is the insensitivity of CML stem cells to BCR-ABL1 inhibitors. Conventional chemotherapeutics and BCR-ABL1 inhibitors which act by inhibiting cell proliferation and inducing apoptosis, are ineffective against quiescent CML stem cells.
A better understanding of the mechanisms that underlie TKI resistance, progression to BC, genomic instability and stem cell quiescence is essential to develop curative strategies for patients with CML.
Beclin1 is an important, primary molecule for autophagy.
It is suggested that the control of the autophagy path increases the sensitivity of tumor cells to VSV.
In this study, the degree of Beclin1 gene expression in two cell lines, HeLa and A549, has been examined and the percentage of living cells subsequent infection with virus has been evaluated by MTT assay method.
The results showed that the degree of Beclin1 gene expression in HeLa cells in comparison with A549 cells has reduced, and the sensitivity of these cells to vesicular stomatits virus (VSV) oncolysis is more than A549.
It seems that by using some methods for reducing autophagy, it is possible to make tumor cells more sensitive to virotherapy and even other treatments.
Glycoside hydrolases (GH) targeting cellulose, xylan, and chitin are common in the bacterial genomes that have been sequenced. Little is known, however, about the architecture of multi-domain and multi-activity glycoside hydrolases. In these enzymes, combined catalytic domains act synergistically and thus display overall improved catalytic efficiency, making these proteins of high interest for the biofuel technology industry.
Here, we identify the domain organization in 40,946 proteins targeting cellulose, xylan, and chitin derived from 11,953 sequenced bacterial genomes. These bacteria are known to be capable, or to have the potential, to degrade polysaccharides, or are newly identified potential degraders (e.g., Actinospica, Hamadaea, Cystobacter, and Microbispora). Most of the proteins we identified contain a single catalytic domain that is frequently associated with an accessory non-catalytic domain. Regarding multi-domain proteins, we found that many bacterial strains have unique GH protein architectures and that the overall protein organization is not conserved across most genera. We identified 217 multi-activity proteins with at least two GH domains for cellulose, xylan, and chitin. Of these proteins, 211 have GH domains targeting similar or associated substrates (i.e., cellulose and xylan), whereas only six proteins target both cellulose and chitin. Fifty-two percent of multi-activity GHs are hetero-GHs. Finally, GH6, -10, -44 and -48 domains were mostly C-terminal; GH9, -11, -12, and -18 were mostly N-terminal; and GH5 domains were either N- or C-terminal.
We identified 40,946 multi-domain/multi-activity proteins targeting cellulase, chitinase, and xylanase in bacterial genomes and proposed new candidate lineages and protein architectures for carbohydrate processing that may play a role in biofuel production.
Background. Direct disk diffusion susceptibility testing provides faster results than standard microtitre susceptibility. The direct result may impact patient outcome in sepsis if it is accurate and if physicians use the information to promptly and appropriately change antibiotic treatment. Objective. To compare the performance of direct disk diffusion with standard susceptibility and to consider physician decisions in response to these early results, for community acquired bacteremia with Gram-negative Bacilli. Methods. Retrospective observational study of all positive blood cultures with Gram-negative Bacilli, collected over one year. Physician antibiotic treatment decisions were assessed by an infectious diseases physician based on information available to the physician at the time of the decision. Results. 89 bottles growing Gram-negative Bacilli were included in the analysis. Direct disk diffusion agreement with standard susceptibility varied widely. In 47 cases (52.8%), the physician should have changed to a narrower spectrum but did not, in 18 cases (20.2%), the physician correctly narrowed from appropriate broad coverage, and in 8 cases (9.0%), the empiric therapy was correct. Discussion. Because inoculum is not standardized, direct susceptibility results do not agree with standard susceptibility results for all drugs. Physicians do not act on direct susceptibility results. Conclusion. Direct susceptibility should be discontinued in clinical microbiology laboratories.
Tendon-to-bone healing after rotator cuff repair surgery has a failure rate of 20%-94%. There has been a recent interest to determine the factors that act as determinants between successful and unsuccessful rotator cuff repair. Vitamin D level in patients is one of the factors that have been linked to bone and muscle proliferation and healing, and it may have an effect on tendon-to-bone healing. The purpose of this article is to critically review relevant published research that relates to the effect of vitamin D on rotator cuff tears and subsequent healing. A review of the literature was conducted to identify all studies that investigate the relationship between vitamin D and tendon healing, in addition to its mechanism of action. The data were then analyzed in order to summarize what is currently known about vitamin D, rotator cuff pathology, and tendon-to-bone healing. The activated metabolite of vitamin D, 1α,25-dihydroxyvitamin D3, affects osteoblast proliferation and differentiation. Likewise, vitamin D plays a significant role in the tendon-to-bone healing process by increasing the bone mineral density and strengthening the skeletal muscles. The 1α,25-dihydroxyvitamin D3 binds to vitamin D receptors on myocytes to stimulate growth and proliferation. The form of vitamin D produced by the liver, calcifediol, is a key initiator of the myocyte healing process by moving phosphate into myocytes, which improves function and metabolism. Investigation into the effect of vitamin D on tendons has been sparse, but limited studies have been promising. Matrix metalloproteinases play an active role in remodeling the extracellular matrix (ECM) of tendons, particularly deleterious remodeling of the collagen fibers. Also, the levels of transforming growth factor-β3 positively influence
 the success of the surgery for rotator cuff repair. In the tendon-to-bone healing process, vitamin D has been shown to successfully influence bone and muscle healing, but more research is needed to delve into the mechanisms of vitamin D as a factor in skeletal tendon health and healing.
Cancer survivors with certain comorbidities had lower quality of life (QOL). This study was performed to investigate the prevalence of comorbidities and the association between comorbidities and the QOL among Chinese colorectal cancer survivors (CCS).
A cross-sectional study was conducted among 1,398 CCS between April and July 2013 in Shanghai, People's Republic of China. All the participants were asked to complete a simplified Chinese version of the European Organization for Research and Treatment quality of life version 3 questionnaire and questions on sociodemographic characteristics and comorbidities. In order to mitigate the bias caused by confounding factors, multiple linear regression models were employed to calculate the adjusted means of QOL scores.
The proportion of participants without any comorbidity was only 20.2%. The CCS with comorbidities except hypertension scored significantly lower on the European Organization for Research and Treatment quality of life version 3 questionnaire global health and functioning scales and Functional Assessment of Cancer Therapy-General scales but higher on the European Organization for Research and Treatment quality of life version 3 questionnaire symptom scores, indicating that they had poorer QOL, particularly for cardiovascular, respiratory, digestive, and musculoskeletal diseases.
There exists a significant association between comorbidities and QOL among Chinese CCS, and participants with comorbidities generally reported lower QOL scores. These findings suggested comprehensive care for CCS.
Education has been known to essential for management of chronic airway diseases. However the real benefits remain unclear. We evaluated the effectiveness of an organized educational intervention for chronic airway diseases directed at primary care physicians and patients. The intervention was a 1-month education program of three visits, during which subjects were taught about their disease, an action plan in acute exacerbation and inhaler technique. Asthma control tests (ACT) for asthma and, chronic obstructive pulmonary disease (COPD) assessment tests (CAT) for COPD subjects were compared before and after education as an index of quality of life. Educational effectiveness was also measured associated with improvement of their knowledge for chronic airway disease itself, proper use of inhaler technique, and satisfaction of the subjects and clinicians before and after education. Among the 285 participants, 60.7% (n = 173) were men and the mean age was 62.2 ± 14.7. ACT for asthma and CAT in COPD patients were significantly improved by 49.7% (n = 79) and 51.2% (n = 65) more than MCID respectively after education (P < 0.05). In all individual items, knowledge about their disease, inhaler use and satisfaction of the patients and clinicians were also improved after education (P < 0.05). This study demonstrates the well-organized education program for primary care physicians and patients is a crucial process for management of chronic airway diseases.
Plants have been an important source for discovery of anticancer compounds. With the current decline in the number of new molecular entities from the pharmaceutical industry, novel anticancer agents are being sought from traditional medicines; therefore the anticancer efficacy of many plants that are used in traditional medicine is yet to be verified. The objective of the study was to evaluate the cytotoxic potential of ethanolic leaf gall extract of Terminalia chebula are evaluated against buffalo rat liver 3A, MCF-7 (Human mammary gland adenocarcinoma) and A-549 (Human lung cancer) cell lines. The cytotoxic effect of the ethanolic extract was evaluated by MTT assay. The extract was potent and effective in inducing cytotoxic effects in all the cell lines with an IC50 value of 305.18 ± 1.7 μg/mL, 643.13 ± 4.2 μg/mL, and 208.16 ± 3.7 μ/mL, respectively. The extract was more effective against A549 cell lines when compared to others. The presences of phenolics, triterpenoids, and flavonoids were identified in the extract. The extract showed total phenolic and flavonoid content of 478 ± 2.2 mg of gallic acid equivalent/g d.w and 538 ± 1.4 mg of quercetinequivalent/g d.w, respectively. This higher content of total phenolics and flavonoids found in the ethanolic extract was directly associated to higher cytotoxicity activity.
The ethanolic leaf gall extract of T. chebula showed effective cytotoxic activities; which might be attributed to the phenolics/flavonoids present in higher concentration. Future work will be interesting to know the chemical composition of the extract and also better understand the mechanism of action of the constituents present in the extract to develop it as drug for therapeutic application.
The present investigation establishes the anticancer activities of T. chebula leaf gall extracts on BRL3A, MCF-7, and A-549 cells. Presumably, these activities could be attributed in part to the phenolics/flavanoids features of the extract that has been demonstrated to act as cytotoxic agents. The experimental evidence obtained in the laboratory model could provide a rationale for the traditional use of plant as a source of easily available effective anticancer agents to the people, particularly in developing countries.
Based on chemotaxonomy, we decided to investigate the possible antidiarrheal activity in mice of a crude ethanolic extract obtained from aerial parts of Croton grewioides (CG-EtOH). We tested for any possible toxicity in rat erythrocytes and acute toxicity in mice. Antidiarrheal activity was assessed by determining the effect of CG-EtOH on defecation frequency, liquid stool, intestinal motility and intestinal fluid accumulation. CG-EtOH showed no in vitro cytotoxicity and was not orally lethal. In contrast, the extract given intraperitoneally (at 2000 mg/kg) was lethal, but only in females. CG-EtOH produced a significant and equipotent antidiarrheal activity, both in defecation frequency (ED50 = 106.0 ± 8.1 mg/kg) and liquid stools (ED50 = 105.0 ± 9.2 mg/kg). However, CG-EtOH (125 mg/kg) decreased intestinal motility by only 22.7% ± 4.4%. Moreover, extract markedly inhibited the castor oil-induced intestinal contents (ED50 = 34.6 ± 5.4 mg/kg). We thus conclude that CG-EtOH is not orally lethal and contains active principles with antidiarrheal activity, and this effect seems to involve mostly changes in intestinal secretion.
CG-EtOH showed no in vitro cytotoxicity and was not orally lethal. In contrast, the extract given intraperitoneally (at 2000 mg/kg) was lethal, but only in females.CG-EtOH probably contains active metabolites with antidiarrheal activity.CG-EtOH reduced the frequency and number of liquid stools.Metabolites presents in the CG-EtOH act mainly by reducing intestinal fluid and, to a lesser extent, reducing intestinal motility. Abbreviations Used: CG-EtOH: crude ethanolic extract obtained from the aerial parts of C. grewioides; WHO: World Health Organization; ED50: dose of a drug that produces 50% of its maximum effect; Emax: maximum effect.
This cross-sectional retrospective study was designed to assess the relationships among breastfeeding duration, nonnutritive sucking habits, convex facial profile, nonspaced dentition, and distoclusion in the deciduous dentition.
A sample of 415 children (228 males, 187 females) aged 4 to 6 years from a mixed Indian population was clinically examined by two orthodontists. Information about breastfeeding duration and nonnutritive sucking habits was obtained by written questionnaire which was answered by the parents.
Chi-square test did not indicate any significant association among breastfeeding duration, convex facial profile, and distoclusion. Statistically significant association was observed between breastfeeding duration and nonspaced dentition and also between breastfeeding duration and nonnutritive sucking habits. Nonnutritive sucking habits had a statistically significant association with distoclusion and convex facial profile (odds ratio 7.04 and 4.03 respectively). Nonnutritive sucking habits did not have a statistically significant association with nonspaced dentition.
The children breastfed < 6 months had almost twofold increased probability for developing sucking habits and nonspaced dentition, respectively, than the children who had breastfeeding > 6 months duration. It can also be hypothesized that nonnutritive sucking habits may act as a dominant variable in the relationship between breastfeeding duration and occurrence of convex facial profile and distoclusion in deciduous dentition. How to cite this article: Agarwal SS, Sharma M, Nehra K, Jayan B, Poonia A, Bhattal H. Validation of Association between Breastfeeding Duration, Facial Profile, Occlusion, and Spacing: A Cross-sectional Study. Int J Clin Pediatr Dent 2016;9(2):162-166.
Diffuse large B-cell lymphoma is the most common type of non-Hodgkin lymphoma. MicroRNAs (miRNAs) are endogenous small RNA, which can regulate gene expression at the post-transcriptional level. MiRNA profiling has shown a great potential as novel diagnostic and prognostic biomarkers. The present study was performed at the Nemazee Teaching Hospital (Shiraz, Iran) from 2011 to 2013. The aim of this study was to assess the deregulation of miRNAs profiles in DLBL against hyperplasic reactive lymph node as a normal. This could serve as a biomarker for DLBL. The miRCURY LNA™ microarray was used on the total RNA, which was extracted from formalin-fixed paraffin-embedded tissue of 24 de novo diffuse large B-cell lymphoma patients and 14 normal lymph
 nodes. The greatest changes were detected in miR-4284 and miR-4484 level in patient's lymphoma samples. These miRNAs can act as a diagnostic biomarker for DLBL.
Introduction: Patients receiving fertility treatment in Germany appear to be disadvantaged in comparison to those in other countries due to the restrictive Embryo Protection Act ("Embryonenschutzgesetz, ESchG"), which prohibits the selection of a "top" embryo. The so-called German Middleway ("Deutscher Mittelweg, DMW") now provides for a liberal interpretation of the ESchG by allowing the culture of numerous pronuclear stages (2PN stage). Materials and Methods: Retrospective cohort study of 2 assisted reproduction treatment cycles in n = 400 patients between the ages of 21 and 45 years, either treated 2× conservatively or 1× conservatively and 1× liberally according to DMW. Results: Pregnancy was achieved in 35 % of patients in the DMW group and 31 % of controls. The birth rate among controls was 28.5 % and 30.5 % in the DMW group. Most pregnancies resulted from the culture of 4 × 2PN stages. Conclusion: Patients in the DMW group had significantly higher pregnancy and birth rates compared to their previous cycles despite significantly increased age and significantly fewer transferred embryos. Key factors were the number of 2PNs generated and the quality of embryos transferred. Thus it can be assumed that particularly older patients with adequate ovarian reserves will benefit from DMW, i.e. the transfer of fewer embryos of the best possible quality.
Einleitung: Deutsche Kinderwunschpatienten erscheinen im internationalen Vergleich aufgrund der restriktiven Vorgaben des Embryonenschutzgesetzes (ESchG) und des Verbots der Auswahl eines „Top-Embryos“ benachteiligt. Die Durchführung des Deutschen Mittelwegs (DMW) erlaubt nun eine liberale Interpretation des ESchG im Sinne der Kultur mehrerer Vorkernstadien (2PN-Stadien). Material und Methoden: Retrospektive Kohortenstudie mit 2 Behandlungszyklen im Rahmen einer assistierten Reproduktion mit n = 400 Patientinnen im Alter zwischen 21 und 45 Jahren, die entweder 2 × konservativ oder 1 × konservativ und 1 × liberal nach DMW behandelt wurden. Ergebnisse: Eine Schwangerschaft konnte in der DMW-Gruppe in 35 % der Fälle, in der Kontrollgruppe in 31 % erzielt werden. Die Geburtenrate lag in der Kontrollgruppe bei 28,5 % und in der DMW-Gruppe bei 30,5 %. Die meisten Schwangerschaften resultierten aus der Kultur von 4 × 2PN-Stadien. Schlussfolgerung: Im Vergleich zum Vorzyklus einer Patientin der DMW-Gruppe kam es zu signifikant höheren Schwangerschafts- und Geburtenraten bei gleichzeitig signifikant gestiegenem Alter und signifikant weniger transferierten Embryonen. Entscheidende Einflussfaktoren waren die Anzahl der generierten 2PN-Stadien und die Qualität der transferierten Embryonen. Somit ist davon auszugehen, dass gerade ältere Patientinnen mit einer ausreichenden ovariellen Reserve vom DMW bzw. vom Transfer von weniger Embryonen mit möglichst hoher Qualität profitieren.
Numerous studies have shown that breast cancer and epigenetic mechanisms have a very powerful interactive relation. The MCF7 cell line, representative of luminal subtype and the MDA-MB 231 cell line representative of mesenchymal-like subtype were treated respectively with a Histone Methyl Transferase Inhibitors (HMTi), 3-Deazaneplanocin hydrochloride (DZNep), two histone deacetylase inhibitors (HDACi), sodium butyrate (NaBu), and suberoylanilide hydroxamic acid (SAHA) for 48 h.
Chromatin immunoprecipitation (ChIP) was used to observe HDACis (SAHA and NaBu) and HMTi (DZNep) impact on histones and more specifically on H3K27me3, H3K9ac and H3K4ac marks with Q-PCR analysis of BRCA1, SRC3 and P300 genes. Furthermore, the HDACi and HMTi effects on mRNA and protein expression of BRCA1, SRC3 and P300 genes were checked. In addition, statistical analyses were used.
In the MCF7 luminal subtype with positive ER, H3k4ac was significantly increased on BRCA1 with SAHA. On the contrary, in the MDA-MB 231 breast cancer cell line, representative of mesenchymal-like subtype with negative estrogen receptor, HDACis had no effect. Also, DZNEP decreased significantly H3K27me3 on BRCA1 in MDA-MB 231. Besides, on SRC3, a significant increase for H3K4ac was obtained in MCF7 treated with SAHA. And DZNEP had no effect in MCF7. Also, in MDA-MB 231 treated with DZNEP, H3K27me3 significantly decreased on SRC3 while H3K4ac was significantly increased in MDA-MB-231 treated with SAHA or NaBu for P300.
Luminal and mesenchymal-like breast cancer subtype cell lines seemed to act differently to HDACis (SAHA and NaBu) or HMTi (DZNEP) treatments.
Asthma is a chronic airway inflammatory disorder with characteristic symptoms of dyspnea, wheeze, chest tightness and cough, and physiological abnormalities of variable airway obstruction, airway hyperresponsiveness, and in some patients with chronic long standing disease reduced lung function. The physiological abnormalities are due to chronic airway inflammation and underlying structural changes to the airway wall. The interaction between the airway epithelium and the environment is crucial to the pathobiology of asthma. Several recent discoveries have highlighted a crucial role of airway epithelial derived cytokines such as interleukin (IL)-25, IL-33 and thymic stromal lymphopoietin (TSLP). These cytokines are collectively known as epithelial "alarmins", which act solely or in concert to activate and potentiate the innate and humoral arms of the immune system in the presence of actual or perceive damage. Understanding the role of alarmins and how they are activated and released may allow the development of novel new therapeutics to treat asthma. This review describes the interactions between inhaled air, the pulmonary microbiome, airway epithelial cell layer and the alarmins, IL-25, IL-33 and TSLP. There is already compelling evidence for a role of TSLP in the airway responses to environmental allergens in allergic asthmatics, as well as in maintaining airway eosinophilic inflammation in these subjects. Further work is required to develop human monoclonal antibodies (hMabs) directed against IL-25 and IL-33 or their receptors, to help understand their role in the initiation and/or persistence of asthma.
While the genetic origin of Fabry disease (FD) is well known, it is still unclear why the disease presents a wide heterogeneity of clinical presentation and progression, even within the same family. Emerging observations reveal that mitochondrial impairment and oxidative stress may be implicated in the pathogenesis of FD. To investigate if specific genetic polymorphisms within the mitochondrial genome (mtDNA) could act as susceptibility factors and contribute to the clinical expression of FD, we have genotyped European mtDNA haplogroups in 77 Italian FD patients and 151 healthy controls. Haplogroups H and I, and haplogroup cluster HV were significantly more frequent in patients than controls. However, no correlation with gender, age of onset, organ involvement was observed. Our study seems to provide some evidence of a contribution of mitochondrial variation in FD pathogenesis, at least in Italy.
Cancer cell behavior is not only governed by tumor cell-autonomous properties but also by the surrounding tumor stroma. Cancer-associated fibroblasts, blood vessels, immune cells and the extracellular matrix of the tumor microenvironment have a profound influence on tumor progression. Proteoglycans control various normal and pathological processes, modulating cell proliferation and motility, cell-matrix interactions, immune cell recruitment and angiogenesis. They are major mediators of cancer cell behavior though a dynamic interplay with extracellular matrix components. During cancer progression, their altered expression can promote the activation of several signaling cascades regulating crucial functional properties of cancer cells. Notably, the function of cell surface proteoglycans can be altered by ectodomain shedding, which converts membrane-bound coreceptors into soluble paracrine effector molecules. In this review, we highlight the importance of proteoglycans and their soluble counterparts in cancer progression and the consequences of their interactions with the adjacent stroma. The dynamic interplay among shed proteoglycans and proteolytic enzymes has a significant impact both on tumor cells and their surrounding stroma, with important implications for the diagnosis of this disease and for novel therapeutic approaches. Graphical Abstract Syndecan shedding. The mechanism of shedding involves the proteolytic cleavage of their ectodomain near the plasma membrane by metzincin enzymes, such as metalloproteinases. N-acetylglucosamine-alpha-L-iduronic acid/beta-D-glucuronic acid (HS) chains can be additionally cleaved by heparanase. Syndecan core protein can be further processed by intramembrane enzymatic cleavage. Syndecans are in a dynamic interplay with the extracellular matrix and several receptor-tyrosine-kinases (RTKs) and various growth factors, for which they act as co-receptors, thus mediating numerous signaling pathways.
The concept of physical literacy has stimulated increased research attention in recent years-being deployed in physical education, sport participation, and the promotion of physical activity. Independent research groups currently operationalize the construct differently.
The purpose of this systematic review was to conduct a systematic review of the physical literacy construct, as reflected in contemporary research literature.
Five databases were searched using the preferred reporting items for systematic reviews and meta-analyses (PRISMA) guidelines for systematic reviews. Inclusion criteria were English language, peer reviewed, published by March 2016, and seeking to conceptualize physical literacy. Articles that met these
 criteria were analyzed in relation to three core areas: properties/attributes, philosophical foundations and theoretical associations with other constructs. A total of 50 published articles met the inclusion criteria and were analyzed qualitatively using inductive thematic analysis.
The thematic analysis addressed the three core areas. Under definitions, core attributes that define physical literacy were identified, as well as areas of conflict between different approaches currently being adopted. One relatively clear philosophical approach was prominent in approximately half of the papers, based on a monist/holistic ontology and phenomenological epistemology. Finally, the analysis identified a number of theoretical associations, including health, physical activity and academic performance.
Current literature contains different representations of the physical literacy construct. The costs and benefits of adopting an exclusive approach versus pluralism are considered. Recommendations for both researchers and practitioners focus on identifying and clearly articulating the definitions, philosophical assumptions and expected outcomes prior to evaluating the effectiveness of this emerging concept.
Many Pacific Island countries (PICs) are recipients of funding support from the Global Fund to Fight AIDS, Tuberculosis and Malaria (Global Fund). However, most of these countries cannot be expected to meet Global Fund and World Health Organization (WHO) minimum requirements for a functioning pharmacovigilance (PV) system. We argue that a different approach is required to move PV forward in such countries. Although the long-term aim is to build adequate national PV capacity, we propose an approach in which resources are focused initially towards ensuring a proper system for the reporting of "problems with medicines" such as substandard and counterfeit products. The limited health system resources in these countries require that PV will be supported by some of the organizations also giving funding aid for the supply of medicines.
Steroid hormone receptors (SHRs) act in cell type- and gene-specific manner through interactions with coregulatory proteins to regulate numerous physiological and pathological processes at the level of gene regulation. Binding of steroid receptor modulator (SRM) ligand leads to allosteric changes in SHR to exert positive or negative effects on the expression of target genes. Due, in part, to the fact that current SRMs generally target ligand binding domain (LBD)/AF2 and neglect intrinsically disordered (ID) N-terminal domain (NTD)/AF1, clinically relevant SRMs lack selectivity and are also prone to the development of resistance over time. Therefore, to maximize the efficacy of SHR-based therapeutics, the possibility of developing unique modulators that act to control AF1 activity must be considered. Recent studies targeting androgen receptor's (AR's) ID AF1 domain for the castration-resistant prostate cancer has provided the possibility of therapeutically targeting ID NTD/AF1 surfaces by allosteric modulations to achieve desired effects. In this review article, we discuss how inter- and intra- molecular allosteric regulations controlled by AR's structural flexibility and dynamics particularly the ID NTD/AF1 is an emerging area of investigation, which could be exploited for drug development and therapeutic targeting of prostate cancer.
Asexual development (conidiation) in the filamentous fungus Aspergillus nidulans is governed by orchestrated gene expression. The three key negative regulators of conidiation SfgA, VosA, and NsdD act at different control point in the developmental genetic cascade. Here, we have revealed that NsdD is a key repressor affecting the quantity of asexual spores in Aspergillus. Moreover, nullifying both nsdD and vosA results in abundant formation of the development specific structure conidiophores even at 12 h of liquid culture, and near constitutive activation of conidiation, indicating that acquisition of developmental competence involves the removal of negative regulation exerted by both NsdD and VosA. NsdD's role in repressing conidiation is conserved in other aspergilli, as deleting nsdD causes enhanced and precocious activation of conidiation in Aspergillus fumigatus or Aspergillus flavus. In vivo NsdD-DNA interaction analyses identify three NsdD binding regions in the promoter of the essential activator of conidiation brlA, indicating a direct repressive role of NsdD in conidiation. Importantly, loss of flbC or flbD encoding upstream activators of brlA in the absence of nsdD results in delayed activation of brlA, suggesting distinct positive roles of FlbC and FlbD in conidiation. A genetic model depicting regulation of conidiation in A. nidulans is presented.
Bilirubin is a potent antioxidant that is produced from the reduction of the heme degradation product biliverdin. In mammalian cells and Cyanobacteria, NADH/NADPH-dependent biliverdin reductases (BVRs) of the Rossmann-fold have been shown to catalyze this reaction. Here, we describe the characterization of Rv2074 from Mycobacterium tuberculosis, which belongs to a structurally and mechanistically distinct family of F420 H2 -dependent BVRs (F-BVRs) that are exclusively found in Actinobacteria. We have solved the crystal structure of Rv2074 bound to its cofactor, F420 , and used this alongside molecular dynamics simulations, site-directed mutagenesis and NMR spectroscopy to elucidate its catalytic mechanism. The production of bilirubin by Rv2074 could exploit the anti-oxidative properties of bilirubin and contribute to the range of immuno-evasive mechanisms that have evolved in M. tuberculosis to allow persistent infection.
Infants with abdominal wall defects (AWD) are at risk of poor outcomes including prolonged hospitalization, infections and mortality. Our objective was to describe and compare the outcomes of infants admitted with gastroschisis and omphalocele over 18years.
Population-based study of clinical data and outcomes of live-born infants with AWD admitted to all tertiary-level neonatal intensive care units in New South Wales and Australian Capital Territory from 1992 to 2009.
There were 502 infants with AWD - 336 gastroschisis, 166 omphalocele. Infants with gastroschisis required a longer duration of total parenteral nutrition (19 vs 4days, p<0.05), longer hospitalization (28 vs 15days, p<0.05) and had a higher rate of systemic infection [23.5% vs 13.3%, OR 1.77 (1.15-2.74), p<0.05] compared to infants with omphalocele. Overall, omphalocele infants had higher mortality rate compared to gastroschisis infants [OR 2.77 (1.53, 5.04), p<0.05]. Gastroschisis mortality rates increased from epoch 1 to epoch 3 (4.2% to 8.8%).
Compared to infants with omphalocele, infants with gastroschisis required significantly longer hospitalization and parenteral nutrition with higher rates of infection. Infants with omphalocele had higher overall mortality rates. However, there has been an increase in the gastroschisis mortality rates but the cause for this is unclear.
By means of density functional theory (DFT) computations, we investigated the electronic and optical properties of B,F-monodoped and B/F-codoped graphitic carbon nitride (g-C3N4) to explore the doping effects on the photocatalytic performance of g-C3N4. It is found that F atom addition plays a key role in stabilizing the surface of g-C3N4 and facilitating B atom substitution into g-C3N4. Among the different doping strategies, only B/F-codoping does not have localized states in the midgap, which act as recombination centers for the photogenerated electron-hole pairs. All the doping strategies in this study can improve the utilization ratio of visible light for the g-C3N4 photocatalyst. Considering the relationship of overpotential of water redox reaction over g-C3N4 and band edge positions with respect to the water redox potentials, only the F-doped and B/F-codoped g-C3N4 satisfy the criterion for overall water splitting. In other words, the B/F-codoping strategy not only meets the demands of no recombination centers and enhances the visible light utilization ratio, but also satisfies the need of overpotential. Thus, B/F-codoped g-C3N4 is expected to be a promising photocatalyst for overall water splitting under visible light.
Inositol pyrophosphates such as 5-diphosphoinositol pentakisphosphate (5-IP7) are highly energetic inositol metabolites containing phosphoanhydride bonds. Although inositol pyrophosphates are known to regulate various biological events, including growth, survival, and metabolism, the molecular sites of 5-IP7 action in vesicle trafficking have remained largely elusive. We report here that elevated 5-IP7 levels, caused by overexpression of inositol hexakisphosphate (IP6) kinase 1 (IP6K1), suppressed depolarization-induced neurotransmitter release from PC12 cells. Conversely, IP6K1 depletion decreased intracellular 5-IP7 concentrations, leading to increased neurotransmitter release. Consistently, knockdown of IP6K1 in cultured hippocampal neurons augmented action potential-driven synaptic vesicle exocytosis at synapses. Using a FRET-based in vitro vesicle fusion assay, we found that 5-IP7, but not 1-IP7, exhibited significantly higher inhibitory activity toward synaptic vesicle exocytosis than IP6 Synaptotagmin 1 (Syt1), a Ca(2+) sensor essential for synaptic membrane fusion, was identified as a molecular target of 5-IP7 Notably, 5-IP7 showed a 45-fold higher binding affinity for Syt1 compared with IP6 In addition, 5-IP7-dependent inhibition of synaptic vesicle fusion was abolished by increasing Ca(2+) levels. Thus, 5-IP7 appears to act through Syt1 binding to interfere with the fusogenic activity of Ca(2+) These findings reveal a role of 5-IP7 as a potent inhibitor of Syt1 in controlling the synaptic exocytotic pathway and expand our understanding
 of the signaling mechanisms of inositol pyrophosphates.
Silk fibroin (SF) has anti-inflammatory properties and promotes wound healing. Moreover, SF particles act as carriers of active drugs against intestinal inflammation due to their capacity to deliver the compound to the damaged colonic tissue. The present work assesses the effect of SF in the trinitrobenzenesulfonic acid model of rat colitis that resembles human intestinal inflammation. SF (8mg/kg) was administered in aqueous solution orally and in two particulate formats by intrarectal route, following two technologies: spray drying to make microparticles and desolvation in organic solvent to produce nanoparticles. SF treatments ameliorated the colonic damage, reduced neutrophil infiltration and improved the compromised oxidative status of the colon. They also reduced the gene expression of pro-inflammatory cytokines like IL-1β and the anti-inflammatory cytokine IL-10. Moreover, they improved the intestinal wall integrity by increasing the gene expression of some of its markers (villin, trefoil factor-3 and mucins), thus accelerating the healing. The immunomodulatory properties of SF particles were also tested in vitro in macrophages: they activated the immune response in basal conditions without increasing it after a pro-inflammatory insult. In conclusion, SF particles could be useful as carriers to deliver active drugs to the damaged intestinal colon with additional anti-inflammatory and healing properties.
Most agronomical traits of crop species are complex traits controlled by multiple genes and affected by environmental factors. While considerable efforts have been made to fine-map and clone major quantitative trait loci (QTLs) for yield-related traits in rice, it is not until recently that the attention has been paid to minor QTLs. Following previous dissection of QTLs for grain weight and grain size in a 12-Mb interval on the long arm of chromosome 1 in rice, this study targeted at one putative QTL region for a more precise mapping and for analyzing the genotype-by-environment interaction of minor QTLs.
Four BC2F10 plants of the indica rice cross ZS97///ZS97//ZS97/MY46 were selected. They carried overlapped heterozygous segments that jointly covered the entire putative region for qTGW1.1 detected previously. Four sets of near isogenic lines (NILs) were developed from selfing progenies of the four plants. Each NIL set consisted of 32 ZS97 homozygous lines and 32 MY46 homozygous lines that differed in the corresponding heterozygous region. They were grown in two locations having distinct ecological conditions and measured for 1000-grain weight, grain length and grain width. Two QTLs were separated in an 835.2-kb interval flanked by DNA markers Wn28447 and RM11569. They both showed consistent effects across the two environments. The qTGW1.1a located within the 120.4-kb interval Wn28447 - RM11543 significantly affect all the three traits with the enhancing allele derived from ZS97, showing a stronger influence on grain weight than on grain length and width. The qTGW1.1b located in the 521.8-kb interval RM11554 - RM11569 significantly affect grain weight and length with the enhancing allele derived from MY46, having a stronger influence on grain length than on grain weight. Consistent performance of the two QTLs was confirmed in a validation experiment using five NIL-F2 populations segregated for either qTGW1.1a or qTGW1.1b.
Separation of closely-linked QTLs having small effects is achievable in the absence of major-QTL segregation. Minor QTLs for complex traits could act consistently in diverse environments, offering the potential of pyramiding beneficial alleles of multiple minor QTLs through marker-assisted selection.
Ketamine is emerging as a new hope against depression, but ketamine-associated psychotomimetic effects limit its clinical use. An adjunct therapy along with ketamine to alleviate its adverse effects and even potentiate the antidepressant effects might be an alternative strategy. Betaine, a methyl derivative of glycine and a dietary supplement, has been shown to have antidepressant-like effects and to act like a partial agonist at the glycine site of N-methyl-D-aspartate receptors (NMDARs). Accordingly, betaine might have potential to be an adjunct to ketamine treatment for depression. The antidepressant-like effects of ketamine and betaine were evaluated by forced swimming test and novelty suppressed feeding test in mice. Both betaine and ketamine produced antidepressant-like effects. Furthermore, we determined the effects of betaine on ketamine-induced antidepressant-like and psychotomimetic behaviors, motor incoordination, hyperlocomotor activity, and anesthesia. The antidepressant-like responses to betaine combined with ketamine were stronger than their individual effects. In contrast, ketamine-induced impairments in prepulse inhibition, novel object recognition test, social interaction, and rotarod test were remarkably attenuated, whereas ketamine-induced hyperlocomotion and loss of righting reflex were not affected by betaine. These findings revealed that betaine could enhance the antidepressant-like effects, yet block the psychotomimetic effects of ketamine, suggesting that betaine can be considered as an add-on therapy to ketamine for treatment-resistant depression and suitable for the treatment of depressive symptoms in patients with schizophrenia.
Little is known about how comorbidities affect difficult asthma patients across different domains of asthma outcomes. We hypothesized that comorbidities in difficult asthma significantly influence asthma outcomes.
We analysed 90 consecutive patients who underwent systematic assessment at our hospital's difficult asthma clinic. Eight comorbidities were assessed in all patients. They were allergic rhinitis, chronic rhinosinusitis (CRS), gastroesophageal reflux disease, obesity, obstructive sleep apnoea, anxiety or depression, dysfunctional breathing (DB) and vocal cord dysfunction (VCD). Asthma outcomes examined were exacerbation frequency (≥3/year vs <3/year), asthma control using the Asthma Control Test (ACT) and quality of life using the Asthma Quality of Life Questionnaire (AQLQ). Multivariate logistic regression was performed for dichotomous outcomes and linear regression for continuous outcomes. Analyses were adjusted for lung function and absolute blood eosinophils.
Increasing BMI was an independent risk factor for exacerbations (OR: 1.1, 95% CI: 1-1.1, P = 0.042), lower ACT score (β coefficient: -0.25, 95% CI: -0.37 to -0.12, P < 0.001) and poorer AQLQ (β coefficient: -0.05, 95% CI: -0.09 to -0.02, P = 0.006). DB predicted lower ACT (β coefficient: -2.85, 95% CI: -5 to -0.7, P = 0.01) and AQLQ scores (β coefficient: -0.73, 95% CI: -1.34 to -0.12, P = 0.02). Patients with CRS had more exacerbations (OR: 4, 95% CI: 1.5-10.9, P = 0.006). Patients with VCD had lower AQLQ scores (β coefficient: -0.78, 95% CI: -1.38 to -0.18, P = 0.012).
Comorbidities independently impact a broad spectrum of outcomes in difficult asthma. Systematic evaluation of these conditions is essential in difficult asthma.
There are currently no national measures in England reporting the experiences of people who have been involved with adult safeguarding services following concerns that they may be at risk of abuse or neglect. The Health and Social Care Information Centre (HSCIC) aimed to develop a new adult safeguarding outcome measure (survey) for local authorities (LAs) that could be added to the Adult Social Care Outcomes Framework (ASCOF). The ASCOF is a national collection of social care outcomes performance indicators collected from the perspective of people receiving partial or total funding from a LA for care services.
An outcome measure (a face-to-face interview based survey consisting of 7 questions) was piloted in 40 LAs with 382 adults at risk (or their representative) who had been the subject of a safeguarding investigation. The aim was to investigate the feasibility of the survey in three domains: i) if a statistically representative sample of adults at risk (or their family, friend, carer or advocate) could be recruited; ii) analysis of survey responses and its acceptability to participants iii) feedback from LAs about the survey's administration.
Overall the survey results met statistical confidence; however the individual results for adults at risk did not, due to the high proportion of representatives who responded because adults at risk were unable. Responses to the survey were generally positive; 72 % of participants felt that the help received during the safeguarding investigation had made them or the adult at risk (if reporting as a proxy) feel 'quite a bit' or 'a lot safer'. These results are the most robust data collected in England on the perspectives of adults at risk and their representatives on safeguarding services. Participants reported they appreciated being asked for feedback. LAs suggested survey administration improvements.
This survey is one way LAs can meet their new legal requirement under the Care Act 2014 to 'seek feedback' from adults at risk about adult safeguarding services. The survey findings provide the first robust evidence that safeguarding services in the main meet their goals of promoting feelings of safety among adults at risk.
Intrauterine growth restriction (IUGR) is a pathology of pregnancy that results in failure of the fetus to reach its genetically determined growth potential. In developed nations the most common cause of IUGR is impaired placentation resulting from poor trophoblast function, which reduces blood flow to the fetoplacental unit, promotes hypoxia and enhances production of bioactive lipids (TXA2 and isoprostanes) which act through the thromboxane receptor (TP). TP activation has been implicated as a pathogenic factor in pregnancy complications,
 including IUGR; however, the role of TP isoforms during pregnancy is poorly defined. We have determined that expression of the human-specific isoform of TP (TPβ) is increased in placentae from IUGR pregnancies, compared to healthy pregnancies. Overexpression of TPα enhanced trophoblast proliferation and syncytialisation. Conversely, TPβ attenuated these functions and inhibited migration. Expression of the TPβ transgene in mice resulted in growth restricted pups and placentae with poor syncytialisation and diminished growth characteristics. Together our data indicate that expression of TPα mediates normal placentation; however, TPβ impairs placentation, and promotes the development of IUGR, and represents an underappreciated pathogenic factor in humans.
Joan Mary Anderson, known to most people as Jan, was born on May 12, 1932 in Dunedin, New Zealand. She died on August 28, 2015 in Canberra, Australia. To celebrate her life, we present here a brief biography, some comments on her discoveries in photosynthesis during a career spanning more than half a century, and reminiscences from family and friends. We remember this wonderful person who had an unflagging curiosity, creative ability to think laterally, enthusiasm, passion, generosity and love of color and culture.
The modulatory actions of glutamate, the main excitatory neurotransmitter in the central nervous system (CNS), are exerted through the activation of metabotropic glutamate receptors (mGluRs). Of the eight known mGluRs (mGluR1-8), group III mGluRs (mGluR4, mGluR6, mGluR7, and mGluR8) are less understood because of the lack of selective ligands. Except for mGluR6, group III mGluRs are widely distributed throughout the CNS. They are mainly located on presynaptic terminals where they inhibit neurotransmitter release at glutamatergic and γ-aminobutyric (GABA)ergic synapses. Their location at certain synapses is considered critical for normal CNS function, which makes them potential targets in neurological and psychiatric treatments. Novel ligands that are selective for group III mGluR subtypes have recently been developed. These compounds, which mainly target allosteric sites and act as positive or negative allosteric modulators (PAMs or NAMs) of glutamate transmission, are contributing to the understanding of the functional roles of group III mGluRs in a number of pathological conditions, such as epilepsy, anxiety, neurodegenerative diseases, and chronic pain. Moreover, the presence of group III mGluRs throughout the entire pain neuraxis and particularly in the descending system suggests that these analgesic endogenous substrates that extend from the cortex to the first spinal synapse are candidates for pain control. Recent data on chronic pain alleviation by group III mGluR ligands encourage further studies as pathological pain is one of the most troublesome diseases because of the current lack of satisfactory therapy. This review summarizes recent findings on studies of group III mGluRs in animal models of chronic pain, such as the opposite modulation of mGluR7 and mGluR8 on pain responses and only pathological pain. This article is protected by copyright. All rights reserved.
Despite remarkable advances in the development of organic field-effect transistor (OFET) memories over recent years, the charge trapping elements remain confined to the critical electrets of polymers, nanoparticles, or ferroelectrics. Nevertheless, rare reports are available on the complementary advantages of different types of trapping elements integrated in one single OFET memory. To address this issue, we fabricated two kinds of pentacene-based OFET memories with solution-processed amorphous and β-phase poly(9,9-dioctylfluorene) (PFO) films as charge trapping layers, respectively. Compared to the amorphous film, the β-PFO film has self-doped nanostructures (20-120 nm) and could act as natural charge trapping elements, demonstrating the synergistic effects of combining both merits of polymer and nanoparticles into one electret. Consequently, the OFET memory with β-PFO showed nearly 26% increment in the storage capacity and a pronounced memory window of ∼45 V in 20 ms programming time. Besides, the retention time of β-PFO device extended 2 times to maintain an ON/OFF current ratio of 10(3), indicating high bias-stress reliability. Furthermore, the β-PFO device demonstrated good photosensitivity in the 430-700 nm range, which was attributed to the additive effect of smaller bandgap and self-doped nanostructures of β-phase. In this regard, the tuning of molecular conformation and aggregation in a polymer electret is an effective strategy to obtain a high performance OFET memory.
Objective To oberseve the expressions of B cell lymphoma 6 (Bcl-6) and B lymphocyte-induced maturation protein 1 (Blimp-1) in the decidua of patients with unexplained recurrent spontaneous abortion (URSA), and investigate the roles that Bcl-6 and Blimp-1 act in URSA. Methods Decidual tissues were collected from patients with URSA (URSA group) and normal pregnant women (control group). Then, we detected the expressions of Bcl-6 and Blimp-1 in the deciduas of the two groups using real-time fluorescent quantitative PCR and immunohistochemistry. The relationship between Blimp-1 and Bcl-6 was estimated by Pearson's correlation analysis. Results Compared with the control group, the levels of Blimp-1 mRNA and protein, Bcl-6 mRNA significantly increased in the URSA group. However, Bcl-6 protein was raised insignificantly in URSA group. Furthermore, there was a positive correlation between Bcl-6 and Blimp-1 at the level of mRNA. Conclusion The expressions of Bcl-6 and Blimp-1 are enhanced in the deciduas of URSA patients.
The Affordable Care Act created new conditions of federal tax exemption for nonprofit hospitals, including a requirement that hospitals conduct a community health needs assessment (CHNA) every three years to identify significant health needs in their communities and then develop and implement a strategy responding to those needs. As a result, hospitals must now do more than provide charity care to their patients in exchange for the benefits of tax exemption. The CHNA requirement has the potential both to prompt a radical change in hospitals' relationship to their communities and to enlist hospitals as meaningful contributors to community health improvement initiatives. Final regulations issued in December 2014 clarify hospitals' obligations under the CHNA requirement, but could do more to facilitate hospitals' engagement in collaborative community health projects. The Internal Revenue Service (IRS) has a rich opportunity, while hospitals are still learning to conduct CHNAs, to develop guidance establishing clear but flexible expectations for how providers should assess and address community needs. This Article urges the IRS to seize that opportunity by refining its regulatory framework for the CHNA requirement. Specifically, the IRS should more robustly promote transparency, accountability, community engagement, and collaboration while simultaneously leaving hospitals a good degree of flexibility. By promoting alignment between hospitals' regulatory compliance activities and broader community health improvement initiatives, the IRS could play a meaningful role in efforts to reorient our system towards promoting health and not simply treating illness.
During the last decades of the 13th century, in the midst of the shaping and medicalization of the new Kingdom of Valencia, the authorities and citizens envisaged the role that physicians could have in clarifying violent deaths. The first circumstance that compelled judges to resort to physicians was the possible poisoning of an individual, given that they could contribute to elucidating the truth with their expert knowledge. They were even requested to use post-mortem dissection if necessary for this purpose. In reality, physicians were conscious of their limitations in this field and the need for them to act with caution.
Epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) show a clinical benefit when used to treat patients with EGFR-mutated non-small-cell lung cancer (NSCLC), but this treatment unfortunately fails in patients with TKI-resistant tumors. We here provide evidence that TC-N19 (N19), a novel dual inhibitor of EGFR and cMET, efficiently overcomes the EGFR-TKI resistance in EGFR-mutated NSCLC cells via simultaneous degradation of both proteins by ubiquitin proteasomes. Comparison with HSP90 inhibitor treatment and knockdown of EGFR and cMET by small hairpin RNAs reveal that the reduction of EGFR and cMET expression by N19 is responsible for overcoming the intrinsic TKI resistance mediated by paxillin (PXN) in high PXN-expressing cells, PXN-overexpressing PC9 cells (PC9-PXN), the EGFR-T790M-mediated TKI resistance in H1975 and CL97 cells, and the acquired resistance to gefitinib in gefitinib-resistant PC9 cells (PC9GR). Annexin V-PI staining assay showed that the induction of apoptosis in NSCLC cells by N19 depended on the reduction in levels of both proteins. Xenograft tumor formation in nude mice induced by a PC9-PXN-stable clone and by PC9GR cells was nearly completely suppressed by N19 treatment, with no changes in animal body weight. MTT assays of normal lung cells and reticulocytes showed no cytotoxicity responses to N19. In summary, N19 may act as a novel dual inhibitor of EGFR and cMET that induces apoptosis in TKI-resistant EGFR-mutated NSCLC cells and suppresses xenograft tumor formation. We suggest that N19 may be a potential new-generation TKI or HSP90 inhibitor used for treatment of NSCLC patients who show resistance to current TKI-targeting therapies.
The Pierre Robin Sequence (PRS), consisting of cleft palate, glossoptosis and micrognathia, is a common human birth defect. However, how this abnormality occurs
 remains largely unknown. Here we report that neural crest cell (NCC)-specific knockout of transferrin receptor (Tfrc), a well known transferrin transporter protein, caused micrognathia, cleft palate, severe respiratory distress and inability to suckle in mice, which highly resemble human PRS. Histological and anatomical analysis revealed that the cleft palate is due to the failure of palatal shelves elevation that resulted from a retarded extension of Meckel's cartilage. Interestingly, Tfrc deletion dramatically suppressed both transforming growth factor-β (TGF-β) and bone morphogenetic protein (BMP) signaling in cranial NCCs-derived mandibular tissues, suggesting that Tfrc may act as a facilitator of these two signaling pathways during craniofacial morphogenesis. Together, our study uncovers an unknown function of Tfrc in craniofacial development and provides novel insight into the etiology of PRS.
The purpose was to characterize energy expenditure (EE) during academic subjects and activities during an elementary school day.
Children in 2nd to 4th grades (N = 33) wore the SenseWear Armband (SWA) for 5 school days to measure EE. Teachers' logs were compared with SWA data to extract information about EE throughout the day. Energy expenditure was also compared among grades.
After controlling for body mass, grade level was not a significant predictor of average daily caloric expenditure, F (2, 17.58) = .29, P = .75, ω(2) = .05. When comparing activities throughout the day, relative rates of EE differed significantly, Wilks' F (7, 23) = 52.2, P = .00, ηp(2) = .94, with PE and recess having higher EE. When academic subjects were compared (math, science, language arts), relative rate of EE was also significantly different, Wilks' F (2, 30) = 4.31, P = .02, ηp(2) = .22. For the full sample, relative rate EE was higher in science than in language arts.
The school day provides opportunity for EE for children. These data support the potential benefit of active instruction in language arts as a method to increase school day EE.
To examine the factors associated with psychological distress in parents and carers of Aboriginal children living in urban communities in New South Wales.
Cross-sectional survey (phase one of the Study of Environment on Aboriginal Resilience and Child Health [SEARCH], November 2007 - December 2011).
Primary care; 589 parents and carers of Aboriginal children were recruited when attending one of the four Aboriginal Community Controlled Health Services (ACCHSs) in urban NSW that participated in SEARCH.
Kessler Psychological Distress Scale (K10) scores; a score of 22 or higher was deemed to indicate high levels of psychological distress.
High levels of psychological distress were identified in 18% of our sample. The factors most strongly associated with this distress were functional limitations (v those with K10 scores under 22: adjusted odds ratio [aOR], 4.2; 95% CI, 1.3-13.5), previous hospitalisation (aOR, 5.5; 95% CI, 1.5-19.4) or other treatment for social and emotional wellbeing (aOR, 3.3; 95% CI, 1.3-8.4), low satisfaction with feeling part of the community (aOR, 0.83; 95% CI, 0.70-0.98) and low involvement in clubs and groups (aOR, 2.9; 95% CI, 1.2-7.3).
Clinicians should note that those with functional limitations or a history of treatment for mental health problems are at higher risk of psychological distress and may require additional support. Increased funding that allows ACCHSs to provide mental health services, and funding and promoting programs and activities that increase social connectedness should remain focuses for ACCHSs and policy makers.
This paper complements previous estimations regarding socioeconomic inequalities in obesity for Spanish adults, and provides new evidence about the mechanisms through which socioeconomic status (SES) affects obesity. Microdata from the Spanish National Health Survey (SNHS) 2011-2012 are analysed. Corrected concentration indices (CCI) are calculated to measure inequality. Path analysis is employed to disentangle direct and indirect effects of SES on obesity, where dietary patterns, physical activity and sleep habits act as mediator variables. Multivariate logistic models are used to select those exogenous variables to be included in the path diagram. Men and women are analysed separately. Our results show significant pro-rich inequality in the distribution of obesity (the poorer the more obese), particularly for women (CCI=-0.070 for men, CCI=-0.079 for women). The indirect effects of SES on obesity (those transmitted via mediator variables) are quite modest (3.3% for males, 2.4% for females) due to three reasons. Firstly, dietary habits do not show a significant mediating effect. Secondly, the mediating effect of physical activity in leisure time, although significant (14% for males, 11.1% for females), is offset by that related to main activity. Finally, sleep habits contribution to total effect of SES on obesity is statistically significant but small (roughly 1%). Our results indicate that promoting physical activity in leisure time for those with a low SES, particularly for men, would contribute to prevent obesity and to reduce health inequalities. Promotion of adequate sleep habits for women with a low SES might have a similar effect. However, interventions aimed to reduce sedentarism related to main activity, although useful to prevent obesity, would amplify the obesity socioeconomic gradient. Since effects of SES are different for men and women, socioeconomic health inequalities should be addressed also from a gender perspective.
Cell surface carbohydrates play significant roles in many physiological processes and act as primary markers to indicate various cellular physiological states. The functions of carbohydrates are always associated with their expression and distribution on cell membranes. Based on our previous work, we found that carbohydrates tend to form clusters; however, the underlying mechanism of these clusters remains unknown. Through the direct stochastic optical reconstruction microscopy (dSTORM) strategy, we found that with the contributions of lipid raft as a stable factor and actin cytoskeleton as a restrictive factor, carbohydrate clusters can stably exist with restricted size. Additionally, we revealed that the formation of most carbohydrate clusters (Gal and GlcANc clusters) depended on the carbohydrate-binding proteins (i.e., galectins) cross-linking their specific carbohydrate ligands. Our results clarify the organizational mechanism of carbohydrates on cell surfaces from their formation, stable existence and size-restriction, which promotes a better understanding of the relationship between the function and distribution of carbohydrates, as well as the structure of cell membranes.
Phenol and its derivatives are common pollutants that are present in industrial discharge and are major xenobiotics that lead to water pollution. To monitor as well as improve water quality, attempts have been made in the past to engineer bacterial in vivo biosensors. However, due to the paucity of structural information, there is insufficiency in gauging the factors that lead to high sensitivity and selectivity, thereby impeding development. Here, we present the crystal structure of the sensor domain of MopR (MopR(AB)) from Acinetobacter calcoaceticus in complex with phenol and its derivatives to a maximum resolution of 2.5 Å. The structure reveals that the N-terminal residues 21-47 possess a unique fold, which are involved in stabilization of the biological dimer, and the central ligand binding domain belongs to the "nitric oxide signaling and golgi transport" fold, commonly present in eukaryotic proteins that bind long-chain fatty acids. In addition, MopR(AB) nests a zinc atom within a novel zinc binding motif, crucial for maintaining structural integrity. We propose that this motif is crucial for orchestrated motions associated with the formation of the effector binding pocket. Our studies reveal that residues W134 and H106 play an important role in ligand binding and are the key selectivity determinants. Furthermore, comparative analysis of MopR with XylR and DmpR sensor domains enabled the design of a MopR binding pocket that is competent in binding DmpR-specific ligands. Collectively, these findings pave way towards development of specific/broad based biosensors, which can act as useful tools for detection of this class of pollutants.
A three-domain pressure-volume relationship (PV curve) was studied in relation to leaf anatomical structure during dehydration in the grey mangrove, Avicennia marina. In domain 1, relative water content (RWC) declined 13% with 0.85 MPa decrease in leaf water potential, reflecting a decrease in extracellular water stored primarily in trichomes and petiolar cisternae. In domain 2, RWC decreased by another 12% with a further reduction in leaf water potential to -5.1 MPa, the turgor loss point. Given the osmotic potential at full turgor (-4.2 MPa) and the effective modulus of elasticity (~40 MPa), domain 2 emphasized the role of cell wall elasticity in conserving cellular hydration during leaf water loss. Domain 3 was dominated by osmotic effects and characterized by plasmolysis in most tissues and cell types without cell wall collapse. Extracellular and cellular water storage could support an evaporation rate of 1 mmol m(-2) s(-1) for up to 54 and 50 min, respectively, before turgor loss was reached. This study emphasized the importance of leaf anatomy for the interpretation of PV curves, and identified extracellular water storage sites that enable transient water use without substantive turgor loss when other factors, such as high soil salinity, constrain rates of water transport.
Bisphenol AF (BPAF) is an analog of Bisphenol A (BPA) and is widely used as a raw material in the plastics industry. However,
 an understanding of the potential risks posed by BPAF in the aquatic environment is lacking. The bioconcentration factor (BCF) is a measure used to assess the secondary poisoning potential as well as risks to human health. In this work we measured the accumulation and elimination of BPAF in the whole-body and in liver, muscle and gonad tissues of zebrafish. BPAF uptake was relatively rapid with equilibrium concentrations reached after 24-72h of exposure. We observed gender differences both in whole-body and in tissue accumulation. Muscle was the primary BPAF storage tissue during the uptake phase in this study. In the elimination phase, BPAF concentrations declined rapidly during depuration, especially during the initial 2h, and the rate of elimination in males was faster than females from the whole-body and from tissues. The appearance of BPAF glucuronide (BPAF-G) at the start of the uptake phase indicated the rapid biotransformation of BPAF to BPAF-G in vivo. The high lipid content of female gonad could act to delay the diffusion of the xenobiotic within the body in a contaminated environment, but it also acts to delay xenobiotic elimination from the body.
We study how zwitterionic and anionic biomembrane models interact with neurotransmitters (NTs) and anesthetics (ATs) in the presence of Ca(2+) and different pH conditions. As NTs we used acetylcholine (ACh), γ-aminobutyric acid (GABA), and l-glutamic acid (LGlu). As ATs, tetracaine (TC), and pentobarbital (PB) were employed. By using differential scanning calorimetry (DSC), we analyzed the changes such molecules produce in the thermal properties of the membranes. We found that calcium and pH play important roles in the interactions of NTs and ATs with the anionic lipid membranes. Changes in pH promote deprotonation of the phosphate groups in anionic phospholipids inducing electrostatic interactions between them and NTs; but if Ca(2+) ions are in the system, these act as bridges. Such interactions impact the physical properties of the membranes in a similar manner that anesthetics do. Beyond the usual biochemical approach, we claim that these effects should be taken into account to understand the excitatory-inhibitory orchestrated balance in the nervous system.
Apathy is common in neurocognitive disorders (NCDs) such as Alzheimer's disease and mild cognitive impairment. Although the definition of apathy is inconsistent in the literature, apathy is primarily defined as a loss of motivation and decreased interest in daily activities.
The Alzheimer's Association International Society to Advance Alzheimer's Research and Treatment (ISTAART) Neuropsychiatric Syndromes Professional Interest Area (NPS-PIA) Apathy workgroup reviewed the latest research regarding apathy in NCDs.
Progress has recently been made in three areas relevant to apathy: (1) phenomenology, including the use of diagnostic criteria and novel instruments for measurement, (2) neurobiology, including neuroimaging, neuropathological and biomarker correlates, and (3) interventions, including pharmacologic, nonpharmacologic, and noninvasive neuromodulatory approaches.
Recent progress confirms that apathy has a significant impact on those with major NCD and those with mild NCDs. As such, it is an important target for research and intervention.
Differences in phenological responses to climate change among species can desynchronise ecological interactions and thereby threaten ecosystem function. To assess these threats, we must quantify the relative impact of climate change on species at different trophic levels. Here, we apply a Climate Sensitivity Profile approach to 10,003 terrestrial and aquatic phenological data sets, spatially matched to temperature and precipitation data, to quantify variation in climate sensitivity. The direction, magnitude and timing of climate sensitivity varied markedly among organisms within taxonomic and trophic groups. Despite this variability, we detected systematic variation in the direction and magnitude of phenological climate sensitivity. Secondary consumers showed consistently lower climate sensitivity than other groups. We used mid-century climate change projections to estimate that the timing of phenological events could change more for primary consumers than for species in other trophic levels (6.2 versus 2.5-2.9 days earlier on average), with substantial taxonomic variation (1.1-14.8 days earlier on average).
The H-NS (heat-stable nucleoid structuring) protein affects both nucleoid compaction and global gene regulation. H-NS appears to act primarily as a silencer of AT-rich genetic material acquired by horizontal gene transfer. As such, it is key in the regulation of most genes involved in virulence and in adaptation to new environmental niches. Here we review recent progress in understanding the biochemistry of H-NS and how xenogeneic silencing affects bacterial evolution. We highlight the strengths and weaknesses of some of the models proposed in H-NS-mediated nucleoprotein complex formation. Based on recent single-molecule studies, we also propose a novel mode of DNA compaction by H-NS termed intrabridging to explain over two decades of observations of the H-NS molecule.
Conclusions of epidemiological studies examining the effects of alcoholic beverages on human health may be unclear and limited if they do not take into account drinking pattern parameters such as beverage type, regular moderate versus binge drinking and drinking with or without meals. This review considers different aspects of drinking patterns and effects on human health with special attention to wine. We particularly discuss the potential underlying mechanisms for epidemiological evidence that the beneficial effects of wine are more evident if consumed with food. In this context, we address the effects of food on blood alcohol concentration and acetaldehyde production in the gastrointestinal tract, the role of wine components and uric acid in counteracting the detrimental effects of postprandial oxidative stress, as well as wine's antimicrobial properties and its potential to act as a digestive aid. In addition to its biological correlates, drinking patterns with regard to different socio-cultural circumstances in different populations are also considered. In order to avoid confusion and misconceptions in the general population because of the hormetic associations of wine with human health, it is important that all medical and scientific information concerning the effect of wine consumption on human health are evidence-based and communicated in a competent, credible and unbiased manner. In conclusion, we propose several practical recommendations concerning wine consumption and consumer information to minimize the risks of alcohol-related harm and to encourage individual responsibility and a healthy lifestyle.
BRUTUS (BTS) is a hemerythrin (HHE) domain containing E3 ligase that facilitates the degradation of POPEYE-like (PYEL) proteins in a proteasomal-dependent manner. Deletion of BTS HHE domains enhances BTS stability in the presence of iron and also complements loss of BTS function, suggesting that the HHE domains are critical for protein stability but not for enzymatic function. The RING E3 domain plays an essential role in BTS' capacity to both interact with PYEL proteins and to act as an E3 ligase. Here we show that removal of the RING domain does not complement loss of BTS function. We conclude that enzymatic activity of BTS via the RING domain is essential for response to iron deficiency in plants. Further, we analyze possible BTS domain structure evolution and predict that the combination of domains found in BTS is specific to photosynthetic organisms, potentially indicative of a role for BTS and its orthologs in mitigating the iron-related challenges presented by photosynthesis.
The development of low material-consuming adhesion techniques for different kinds of materials such as polymers and metals is important for the realization of sustainable societies. This study demonstrates that coating layers, expected to be formed as self-assembled monolayers, of silane coupling agents can act as adhesion layers at the polymer film-metal plate interfaces. Polyimide films were alkaline hydrolyzed to generate carboxy groups on their surfaces, whereas titanium plate surfaces were treated with the aminosilanes to form their coating layers thereon. These modified surfaces were placed in contact with each other and then hot pressed, which resulted in adhesion between them. An examination of the adhesion strength using lap shear tests and surface characterization of the prepared surfaces using X-ray photoelectron spectroscopy and other techniques indicated the formation of ionic bonds and/or amide bonds between the carboxy groups of the PI film surfaces and the amino groups immobilized on the titanium plate surfaces. The activation of the carboxy groups using N-hydroxysuccinimide resulted in adhesion obtaining a water-resistant property, which supported the increase in amide bond formation. On the basis of the results, the adhesion mechanism and the possible breaking points upon the breaking of adhesions are proposed.
Saliva as major human body fluid may act as an indicator of oral disease status. Oral mucositis is a common and often treatment-limiting side effect of radiotherapy for head and neck cancer patients. In this dataset, we provide the complete proteome dataset (raw and search files) of the patients at baseline of radiotherapy treatment in patients undergoing radiotherapy analyzed by nano liquid chromatography coupled to mass spectrometry (LC-MS/MS). In the data set, 5323 tryptic peptides were identified which can be assigned to 487 distinct proteins (≥2 peptides). The MS data have been deposited to the ProteomeXchange ("ProteomeXchange provides globally coordinated proteomics data submission
 and dissemination" [1]) via the PRIDE partner repository with the dataset identifier PRIDE: PXD003230. The data are associated with the previously published work, "Differences in the whole saliva baseline proteome profile associated with development of oral mucositis in head and neck cancer patients undergoing radiotherapy" [2].
Recombinant human interleukin-3 (rhIL-3) is a multiple hematopoietic growth factor, which enhances stem cell expansion and hematopoiesis regeneration in vitro and in vivo, when administrated in combination with other cytokines. However, the structure-function study of rhIL-3 remains rarely studied, so far. The purpose of this study was to recognize the short peptide with similar function as rhIL-3, and assess the hematopoietic efficacy in umbilical cord blood (UCB) stem cell culture as well.
Two novel monoclonal antibodies (mAb) (C1 and E1) were generated against rhIL-3 using hybridoma technique. Eleven short peptides were depicted and synthesized to overlap covering the full length sequence of rhIL-3. ELISA was employed to distinguish the antibody-binding peptide from the negative peptides. In addition, the multi-potential hematopoiesis capabilities of the positive peptides were evaluated by adding 25 ng/mL of each peptide to the culture medium of hematopoietic stem cells (HSCs) derived from UCB. Total nucleated cell number and the CD34(+) cell number from each individual treatment group were calculated on day 7. Correlated antibodies at 0.5 or 2 molar fold to each peptide were also tested in the stem cell expansion experiment, to further confirm the bioactivity of the peptides.
Two peptides were recognized by the novel generated antibodies, using ELISA. Peptide 3 and 8 exhibited comparable hematopoiesis potentials, with 25.01±0.14 fold, and 19.89±0.12 fold increase of total nucleated cell number on day 7, respectively, compared with the basal medium control (4.93±0.55 fold). These biological effects were neutralized by adding the corresponding mAb at a dose dependent manner.
Our results identified two specific regions of rhIL-3 responsible for HSC proliferation and differentiation, which were located from 28 to 49 amino acids (P3), and 107 to 127 amino acids (P8), respectively. The short peptide 3 and 8 might act synergistically, which could serve as an economic substitute to rhIL-3 in research laboratory.
Non-injectable delivery of peptide and protein drugs is hampered by their labile nature, hydrophilicity, and large molecular size; thus limiting their permeation across mucosae, which represent major biochemical and physical barriers to drugs administered via e.g. the oral, nasal, and pulmonary routes. However, in recent years cell-penetrating peptides (CPP) have emerged as promising tools to enhance mucosal delivery of co-administered or conjugated peptide and protein cargo and more advanced CPP-cargo formulations are emerging. CPPs act as transepithelial delivery vectors, but the mechanism(s) by which CPPs mediate cargo translocation across an epithelium is so far poorly understood; both due to the fact that multiple factors influence the resulting uptake and trafficking mechanisms as well as to the complicated nature of sensitive studies of this. In addition to a proper mechanistic understanding, documentation of CPP-mediated delivery in higher animal species than rodent as well as extensive toxicological studies are necessary for CPP-containing non-injectable DDSs to reach the clinic.
Decision makers often assume they know the public's standpoints and see themselves as capable of representing them. The aim of this study is to assess the level of acquaintance that senior decision-makers in the Israeli health system have concerning the priorities of the public in whose name they act.
A phone survey was conducted with a representative population sample and face-to-face interviews were conducted with senior decision-makers.
The decision-makers did predict correctly the public's desired level of government involvement in health care; but only some of them correctly predicted the public's preferences on allocation of funds-to health versus other areas. They had difficulty foreseeing public priorities for allocating additional monies to health, and even greater difficulty ascertaining preferences of the public for their own health insurance.
Government decision-making processes should include evidence about public preferences. The findings of this study indicate that decision makers need to be provided with reliable, systematic information on public preferences.
Coronary artery diseases including atherosclerosis is considered as commonest problem worldwide. Ergosterols are the main components of vegetable oils and nuts. The objective of this study was to evaluate the potential hypoplipidemic and hypocholesterolemic effects of ergosterol in combination with niacin in rats fed high fat diet (HFD).
Eighty male albino rats were included in this study divided into two main groups: Group I: Normal rats fed standard diet treated with either niacin (8.5 mg /kg b.w) or ergosterol (100 mg/Kg b.w) or both. Group II; rats fed HFD treated with either niacin (8.5 mg /kg b.w) or ergosterol (100 mg/Kg b.w) or both The feeding and treatment lasted for 8 weeks.
A significant elevation in the levels of total cholesterol, triacylglycerol, VLDL-c, LDL-c and atherogenic factor (p<0.001) in rats fed on HFD compared with normal control while HDL-c was significantly reduced in HFD rats compared with control group. Supplementation of diet with niacin or ergosterol or combined exerts improvement in the studied parameters by lowering triacylglycerol, total cholesterol, LDL-c and atherogenic factor and elevate HDL-c near to the value of control. Niacin combined with ergosterol were effective in the reduction of hydroxy methyl glutaryl-CoA reducatase (HMGCoA) compared with control (p<0.001). The combined effect was more potent than individual alone.
Utilization of niacin and ergosterol may prevent the hypercholesterolemia and incidence of coronary heart diseases. These functional foods act as nutriceutical as dyslipidemics.
Hydrogen peroxide (H2O2) functions as an early damage signal contributing to the oxidative stress response and can act as a trigger in smart oxidation-responsive drug delivery systems that are currently in development. Current H2O2-triggered oxidation-responsive polymeric systems are usually derived from chemical synthesis and rarely include natural polymers. Herein, we report two series of nanoparticle (NP) complexes prepared with the biopolymer chitosan (CS) and four different metal ions (Cu(2+), Ca(2+), Zn(2+), and Fe(3+)), defined as CSNPs-metal complexes (Series 1) and CS-metal complexes NPs (Series 2), which responded to oxidation by dissolving upon H2O2 exposure. Experiments examining Nile red release and H2O2-triggered degradation confirmed that both series of complexes showed better sensitivity to oxidation than the CSNPs alone. Furthermore, preliminary cytotoxicity and histological observations indicated that the two series exhibited little or no cytotoxicity and generated a mild inflammatory response. Our work provides a novel and promising strategy for developing NPs for use as intelligent oxidation-responsive systems.
Tobacco consumption epidemic is one of the biggest public health threats that the world is facing and attracts the attention of researchers to identify the cause for the same in specific groups. Medical students act as mentors to fight against tobacco use, but several reports suggest that a good number of medical undergraduates are themselves addicted to tobacco use. Thus, the objective of the study was to determine the prevalence of tobacco consumption and its association with various factors among undergraduate medical students.
A cross-sectional study was conducted on 372 undergraduate medical students from first to fourth year during November 2013 to January 2015. A pre-designed, pre-tested, structured and self-administered questionnaire was used. Statistical analysis was done using SPSS software version 16. Data was analyzed for percentage, Chi-square test and regression analysis to find association between tobacco use and various independent variables.
The mean age of the participants was 21.2 (SD=2.28) years with a male-female ratio of 1.92:1. The prevalence of tobacco use was 27.1% (n=101). The overall prevalence of smoking and smokeless tobacco use was 22.6% (n=84) and 7.8% (n=29) respectively. The prevalence of current tobacco use was 24.2% (n=90). Among the ever tobacco users, about 3% (n=11) had quit using tobacco. Tobacco consumption was observed to be significantly associated with male gender (p<.001), increasing age (p<0.01), residing in hostels (p<.001) and with a parental history of using tobacco (p<.001).
The prevalence of tobacco use in smoking and smokeless form among undergraduate medical students was high.This has important implications in the strict implementation and monitoring of smoking-related rules in hostels of medical colleges, especially those related to peer-support.
Endocannabinoids act on G protein-coupled receptors that are considered potential targets for a variety of diseases. There are two different cannabinoid receptor types: ligands for cannabinoid type 2 receptors (CB2Rs) show more promise than those for cannabinoid type 1 receptors (CB1Rs) because they lack psychotropic actions. However, the complex pharmacology of these receptors, coupled with the lipophilic nature of ligands, is delaying the translational success of medications targeting the endocannabinoid system. We here report the discovery and synthesis of a fluorophore-conjugated CB2R-selective compound, CM-157 (3-[[4-[2-tert-butyl-1-(tetrahydropyran-4-ylmethyl)benzimidazol-5-yl]sulfonyl-2-pyridyl]oxy]propan-1-amine), which was useful for pharmacological characterization
 of CB2R by using a time-resolved fluorescence resonance energy transfer assay. This methodology does not require radiolabeled compounds and may be undertaken in homogeneous conditions and in living cells (i.e., without the need to isolate receptor-containing membranes). The affinity of the labeled compound was similar to that of the unlabeled molecule. Time-resolved fluorescence resonance energy transfer assays disclosed a previously unreported second affinity site and showed conformational changes in CB2R forming receptor heteromers with G protein-coupled receptor GPR55, a receptor for l-α-lysophosphatidylinositol. The populations displaying subnanomolar and nanomolar affinities were undisclosed in competitive assays using a well known cannabinoid receptor ligand, AM630 (1-[2-(morpholin-4-yl)ethyl]-2-methyl-3-(4-methoxybenzoyl)-6-iodoindole), and TH-chrysenediol, not previously tested on binding to cannabinoid receptors. Variations in binding parameters upon formation of dimers with GPR55 may reflect decreases in binding sites or alterations of the quaternary structure of the macromolecular G protein-coupled receptor complexes. In summary, the homogeneous binding assay described here may serve to better characterize agonist binding to CB2R and to identify specific properties of CB2R on living cells.
Heme nitric oxide/oxygen (H-NOX)-binding proteins act as nitric oxide (NO) sensors among various bacterial species. In several cases, they act to mediate communal behavior such as biofilm formation, quorum sensing, and motility by influencing the activity of downstream signaling proteins such as histidine kinases (HisKa) in a NO-dependent manner. An H-NOX/HisKa regulatory circuit was recently identified in Vibrio cholerae, and the H-NOX protein has been spectroscopically characterized. However, the influence of the H-NOX protein on HisKa autophosphorylation has not been evaluated. This process may be important for persistence and pathogenicity in this organism. Here, we have expressed and purified the V. cholerae HisKa (HnoK) and H-NOX in its heme-bound (holo) and heme-free (apo) forms. Autophosphorylation assays of HnoK in the presence of H-NOX show that the holoprotein in the Fe(II)-NO and Fe(III) forms is a potent inhibitor of HnoK. Activity of the Fe(III) form and aerobic instability of the Fe(II) form suggested that Vibrio cholerae H-NOX may act as a sensor of the redox state as well as NO. Remarkably, the apoprotein also showed robust HnoK inhibition that was dependent on the oxidation of cysteine residues to form disulfide bonds at a highly conserved zinc site. The importance of cysteine in this process was confirmed by mutagenesis, which also showed that holo Fe(III), but not Fe(II)-NO, H-NOX relied heavily upon cysteine for activation. These results highlight a heme-independent mechanism for activation of V. cholerae H-NOX that implicates this protein as a dual redox/NO sensor.
We investigated whether interictal thalamic dysfunction in migraine without aura (MO) patients is a primary determinant or the expression of its functional disconnection from proximal or distal areas along the somatosensory pathway.
Twenty MO patients and twenty healthy volunteers (HVs) underwent an electroencephalographic (EEG) recording during electrical stimulation of the median nerve at the wrist. We used the functional source separation algorithm to extract four functionally constrained nodes (brainstem, thalamus, primary sensory radial, and primary sensory motor tangential parietal sources) along the somatosensory pathway. Two digital filters (1-400 Hz and 450-750 Hz) were applied in order to extract low- (LFO) and high- frequency (HFO) oscillatory activity from the broadband signal.
Compared to HVs, patients presented significantly lower brainstem (BS) and thalamic (Th) HFO activation bilaterally. No difference between the two cortical HFO as well as in LFO peak activations between the two groups was seen. The age of onset of the headache was positively correlated with HFO power in the right brainstem and thalamus.
This study provides evidence for complex dysfunction of brainstem and thalamocortical networks under the control of genetic factors that might act by modulating the severity of migraine phenotype.
N-Benzylpiperazine (BZP) and 1-(3-trifluoromethylphenyl)piperazine (TFMPP) are two synthetic phenylpiperazine analogues that have been frequently commercialized in combination as an alternative to ecstasy ('Legal X'). Despite reports of several clinical complications following the use of these drugs in association, few studies have been conducted so far to elucidate their combined toxicity. The present study was aimed at clarifying the cytotoxic effects of mixtures of BZP and TFMPP in vitro. Human-derived HepaRG cells and primary rat hepatocytes were exposed to the drugs, individually or combined at different mixture ratios, and cytotoxicity was assessed by the MTT assay. Mixture additivity expectations were calculated by the independent action and the concentration addition (CA) models and compared with the experimental outcomes. To delineate the mechanisms underlying the elicited effects, a range of stress endpoints was evaluated, including oxidative stress, energetic imbalance, and metabolic interactions. It was observed that primary rat hepatocytes are more sensitive than HepaRG cells to the toxicity of BZP (EC50 2.20 and 6.60 mM, respectively) and TFMPP (EC50 0.14 and 0.45 mM, respectively). For all BZP-TFMPP combinations tested, CA was the most appropriate model to predict the mixture effects. TFMPP proved to act additively with BZP to produce significant hepatotoxicity (p < 0.01). Remarkably, substantial mixture effects were observed even when each drug was present at concentrations that were harmless individually. In primary hepatocytes, a small deviation from additivity (antagonism) was observed toward the upper range of the concentration-response curve. GC/MS data suggest that a metabolic interaction may be at a play, as the mixture favors the metabolism of both substances, to a significant extent in the case of BZP (p < 0.05). Also, our results demonstrate the influence of oxidative stress and energetic imbalance on these effects (increase in RNS and ROS production, decrease in intracellular GSH/GSSG, ATP depletion and mitochondrial Δψm disruption). The present work clearly demonstrates that potentially harmful interactions among BZP and TFMPP are expected when these drugs are taken concomitantly.
Accumulative evidences have underpinned the nature candidates from Chinese medicine (CM), particularly CM served as blood activating and stasis resolving (BASR, Huoxue Huayu in Chinese) by targeting tumor-associated angiogenesis. However, recent experiment research on the therapeutic angiogenesis by BASR-CM attracts wide attention and discussion. This opinion review focused on the underlying link between two indications and anticipated that (1) BASR-CM might emphasize on a balanced multi-cytokines network interaction; (2) BASR-CM might address on the nature of diseases prior to differently affecting physiological and pathological angiogenesis; (3) BASR-CM might mainly act on perivascular cells, either promotes arteriogenesis by increasing arteriogenic factors in ischemic diseases, or simultaneously keep a quiescent vasculature to impede angiogenesis in tumor context.
Nonalcoholic fatty liver disease (NAFLD) is a burgeoning health problem worldwide and an important risk factor for both hepatic and cardiometabolic mortality. The rapidly increasing prevalence of this disease and of its aggressive form nonalcoholic steatohepatitis (NASH) will require novel therapeutic approaches to prevent disease progression to advanced fibrosis or cirrhosis and cancer. In recent years, bile acids have emerged as relevant signaling molecules that act at both hepatic and extrahepatic tissues to regulate lipid and carbohydrate metabolic pathways as well as energy homeostasis. Activation or modulation of bile acid receptors, such as the farnesoid X receptor and TGR5, and transporters, such as the ileal apical sodium-dependent bile acid transporter, appear to affect both insulin sensitivity and NAFLD/NASH pathogenesis at multiple levels, and these approaches hold promise as novel therapies. In the present review, we summarize current available data on the relationships of bile acids to NAFLD and the potential for therapeutically targeting bile-acid-related pathways to address this growing world-wide disease. (Hepatology 2016).
Myofascial pain syndrome (MPS) is characterized by chronic pain in multiple myofascial trigger points and fascial constrictions. In recent years, the scientific literature has recognized the need to include the patient with MPS in a multidimensional rehabilitation project. At the moment, the most widely recognized therapeutic methods for the treatment of myofascial syndrome include the stretch and spray pressure massage. Microcurrent electric neuromuscular stimulation was proposed in pain management for its effects on normalizing bioelectricity of cells and for its sub-sensory application. In this study, we tested the efficacy of low-intensity pulsed electric neuromuscular stimulus (PENS) on pain in patients with MPS of cervical spine muscles. We carried out a prospective-analytic longitudinal study at an outpatient clinic during two weeks. Forty subjects (mean age 42±13 years) were divided into two groups: treatment (TrGr, n=20) and control group (CtrlGr, n=20). Visual-analog scale (VAS) values, concerning the spontaneous and movement-related pain in the cervical-dorsal region at baseline (T0) and at the end of the study (T1), showed a reduction from 7 to 3.81 (p < 0.001) in TrGr. In the CtrlGr, VAS was reduced from 8.2 to 7.2 (n.s.). Moreover, the pressure pain threshold at T0 was 2.1 vs 4.2 at T1 (p < 0.001) in TrG.
 In the CtrlGR we observed no significant changes. Modulated low-intensity PENS is an innovative therapy permitting to act on the transmission of pain and on the restoration of tissue homeostasis. It seems to affect the transmission of pain through the stimulation of A-beta fibers. The above results show that low-intensity PENS can be considered as an effective treatment to reduce pain and disability in patients with MPS.
High-mobility group box 1 (HMGB1) is a nuclear protein released extracellularly in response to infection or injury, where it activates immune responses and contributes to the pathogenesis of kidney dysfunction in sepsis and sterile inflammatory disorders. Recently, we demonstrated that HMGB1 inhibits HCO3 (-) absorption in perfused rat medullary thick ascending limbs (MTAL) through a basolateral receptor for advanced glycation end products (RAGE)-dependent pathway that is additive to Toll-like receptor 4 (TLR4)-ERK-mediated inhibition by LPS (Good DW, George T, Watts BA III. Am J Physiol Renal Physiol 309: F720-F730, 2015). Here, we examined signaling and transport mechanisms that mediate inhibition by HMGB1. Inhibition of HCO3 (-) absorption by HMGB1 was eliminated by the Rho-associated kinase (ROCK) inhibitor Y27632 and by a specific inhibitor of Rho, the major upstream activator of ROCK. HMGB1 increased RhoA and ROCK1 activity. HMGB1-induced ROCK1 activation was eliminated by the RAGE antagonist FPS-ZM1 and by inhibition of Rho. The Rho and ROCK inhibitors had no effect on inhibition of HCO3 (-) absorption by bath LPS. Inhibition of HCO3 (-) absorption by HMGB1 was eliminated by bath amiloride, 0 Na(+) bath, and the F-actin stabilizer jasplakinolide, three conditions that selectively prevent inhibition of MTAL HCO3 (-) absorption mediated through NHE1. HMGB1 decreased basolateral Na(+)/H(+) exchange activity through activation of ROCK. We conclude that HMGB1 inhibits HCO3 (-) absorption in the MTAL through a RAGE-RhoA-ROCK1 signaling pathway coupled to inhibition of NHE1. The HMGB1-RAGE-RhoA-ROCK1 pathway thus represents a potential target to attenuate MTAL dysfunction during sepsis and other inflammatory disorders. HMGB1 and LPS inhibit HCO3 (-) absorption through different receptor signaling and transport mechanisms, which enables these pathogenic mediators to act directly and independently to impair MTAL function.
Sarafotoxin-i3 from Atractaspis irregularis is a long sarafotoxin with an extended C terminus extension. Sarafotoxin-b from Atractaspis engaddensis is shorter by four amino acids. These peptides belong to the endothelin-like peptide family with a high sequence homology and similar three-dimensional structure. They act on endothelin receptors situated on the membrane of endothelial and smooth muscle cells. However, SRTX-i 3, despite a high toxicity, has a very low affinity for endothelin receptors compared to SRTX-b. The present work was carried out in order to compare the precise in vivo cardiovascular effect of SRTX-b and SRTX-i3. Male Wistar rats were anesthetized and mechanically ventilated. Doppler echocardiography was performed to measure left and right ventricular functions. The rats were divided into three groups that received intravenous injections of: saline, SRTX-b or SRTX-i3. All measurements were taken at baseline, at 1 min and at 6 min after injection. Both toxins impaired cardiac output. SRTX-b impaired left ventricular function, while SRTX-i3 increased airway pressures and led to acute right ventricular dilatation associated with a decreased tricuspid annulus peak systolic velocity. SRTX-b and SRTX-i3 appear to exert toxic effects via different mechanisms, SRTX-b impairs left ventricular function, while SRTX-i3 increases airway pressures and impairs right ventricular function.
The environmental pollutant 2,3,7,8-tetrachlorodibenzo-ρ-dioxin (TCDD) is the prototype of a large number of non-genotoxic carcinogens, dietary phytochemicals and endogenous metabolites that act via binding the aryl hydrocarbon receptor (AHR). The TCDD-liganded AHR massively upregulates CYP1A1, CYP1A2 and CYP1B1 in many mammalian organs. We demonstrated that TCDD treatment markedly increases the levels of several epoxides and diol metabolites of the epoxides of both ω-6 and ω-3 polyunsaturated fatty acids (PUFA) in the liver and lungs of mice, in an aryl hydrocarbon receptor-dependent fashion, and most likely via the activities of the CYP1 family members. ω-6 Epoxides are known to stimulate tumor growth, angiogenesis, and metastasis in mice. Interestingly, ω-3 epoxides have the opposite effect on these parameters. TCDD and other AHR agonists may, therefore, impact angiogenesis, growth and metastasis of tumors in either a positive or negative way, depending on the relative levels of ω -6 epoxides and ω-3 epoxides generated in the host and/or tumor cells. This is of potential relevance to carcinogenesis by AHR agonists in the human, since the human population is exposed to widely varying ω-6: ω-3 PUFA ratios in the diet.
Thiol isomerases are multifunctional enzymes that influence protein structure via their oxidoreductase, isomerase, and chaperone activities. These enzymes localize at high concentrations in the endoplasmic reticulum of all eukaryotic cells where they serve an essential function in folding nascent proteins. However, thiol isomerases can escape endoplasmic retention and be secreted and localized on plasma membranes. Several thiol isomerases including protein disulfide isomerase, ERp57, and ERp5 are secreted by and localize to the membranes of platelets and endothelial cells. These vascular thiol isomerases are released following vessel injury and participate in thrombus formation. Although most of the activities of vascular thiol isomerases that contribute to thrombus formation are yet to be defined at the molecular level, allosteric disulfide bonds that are modified by thiol isomerases have been described in substrates such as αIIbβ3, αvβ3, GPIbα, tissue factor, and thrombospondin. Vascular thiol isomerases also act as redox sensors. They respond to the local redox environment and influence S-nitrosylation of surface proteins on platelets and endothelial cells. Despite our rudimentary understanding of the mechanisms by which thiol isomerases control vascular function, the clinical utility of targeting them in thrombotic disorders is already being explored in clinical trials.
Our understanding of how the endoplasmic reticulum (ER)-associated protein degradation (ERAD) machinery efficiently targets terminally misfolded proteins while avoiding the misidentification of nascent polypeptides and correctly folded proteins is limited. For luminal N-glycoproteins, demannosylation of their N-glycan to expose a terminal α1,6-linked mannose is necessary for their degradation via ERAD, but whether this modification is specific to misfolded proteins is unknown. Here we report that the complex of the mannosidase Htm1p and the protein disulfide isomerase Pdi1p (Htm1p-Pdi1p) acts as a folding-sensitive mannosidase for catalyzing this first committed step in Saccharomyces cerevisiae We reconstitute this step in vitro with Htm1p-Pdi1p and model glycoprotein substrates whose structural states we can manipulate. We find that Htm1p-Pdi1p is a glycoprotein-specific mannosidase that preferentially targets nonnative glycoproteins trapped in partially structured states. As such, Htm1p-Pdi1p is suited to act as a licensing factor that monitors folding in the ER lumen and preferentially commits glycoproteins trapped in partially structured states for degradation.
High grade gliomas (HGGs) are primary CNS cancers with more than 95% of patients experiencing tumor recurrence following radiation therapy, chemotherapy, and/or an anti-angiogenic therapy. Populations of glioma 'stem-like' cells (GSCs) exist in both proliferative and non-proliferative states and are capable of tumor regrowth. These GSCs survive within hypoxic tumor regions and avascular tumor margins, while retaining the capability to regenerate. Successful treatment of HGGs depends on therapeutic targeting of GSCs to avert tumor regeneration. Here, we review novel intracellular mechanisms by which 3-amino-5-arylamino-6-chloro-N-(diaminomethylene) pyrazine-2-carboximide (UCD38B) and the much more potent 5'-substituted arylamino compounds (cmpd 10357) irreversibly kill GSCs utilizing caspase-independent, programmed necrotic cell death. Drug-induced relocation of a subset of endosomes to perinuclear mitochondria triggers the mitochondrial release and nuclear translocation of apoptosis inducible factor (AIF) that is followed by nuclear condensation and cancer cell demise. This drug-induced endosomal 'mis-trafficking' affects a subset of endosomes containing proteins belonging to the urokinase plasminogen activator system (uPAS) and guided by lipoprotein receptor protein type 1 (LRP-1). UCD38B and congeners act intracellularly and bind to intracellular urokinase plasminogen activator (uPA) to disrupt uPA binding to PAI-1 and the endosomal LRP-1 guidance protein. These small molecules are cytotoxic to persistently hypoxic and acidotic HGG cell lines and to high grade gliomas from patient derived xenografts (PDX). Immunodeficient mice with intracerebral PDX glial tumors demonstrate drug-specific, AIF- mediated necrosis after 24h of treatment. The propensity of these small molecules to kill non-proliferating and proliferating hypoxic GSCs, suggests a potential synergistic therapeutic role with radiotherapy, anti-mitotic and anti-angiogenic therapies.
The physician and psychologist Dr. Fredy Quadfasel, born in East Prussia, was trained in neuropsychiatry by Kurt Goldstein in Frankfurt/Main and by Karl Bonhoeffer at the Charité in Berlin. After he was detained by the Gestapo due to political opposition, he was probably denounced for offending the so-called
 Malicious Practices Act (Heimtückegesetz) from March 1933, and imprisoned for 2-3 months. In 1934/35 he emigrated to the USA via England and Canada, where he initially ran a neuropsychiatry office in New York. Very soon he was able to take on an academic post and became an instructor in neurology. After medical military service in 1944-1947 at the Cushing General Hospital in Framingham near Boston, he was appointed head of the neurological department. Later he moved on to the Boston Veterans Administration Hospital. His academic positions included being an instructor in neurology at Harvard Medical School and associate professor at the Boston University School of Medicine. He had a considerable impact on neurology, especially on the locally emerging discipline of neuropsychology represented by Harold Goodglass and Norman Geschwind. Despite a lack of personal records of Quadfasel, a chequered reconstruction of his life and work was possible due to many archival documents with which it was possible to trace the career of a highly esteemed neurologist in Germany and the USA.
The purpose of this study was to gain an understanding of first-generation Somali families' experiences of parenting in the United States to discover potential barriers to effective parenting with the goal to design supportive interventions. Using descriptive phenomenological design, 20 Somali families in Seattle, Washington, were interviewed. Interview transcripts were then analyzed using steps outlined by Colaizzi. The overarching theme that emerged was "Parenting: A Balancing Act," which represents Somali parents trying to balance traditional cultural values and parenting traditions with dominant cultural expectations. Participants expressed fear of losing their children to American lifestyle choices, such as drugs or gangs, and misuse of the American system to turn on their parents. Parents also acknowledged the benefits of access to education and health care for children. To cope with the stressors of their new life, participants sought to preserve traditional cultural and religious values, thus strengthening their Somali community.
Continuous deep sedation at the end of life is a practice that has been the topic of considerable ethical debate, for example surrounding its perceived similarity or dissimilarity with physician-assisted dying. The practice is generally considered to be legal as a form of symptom control, although this is mostly only assumed. France has passed an amendment to the Public Health Act that would grant certain terminally ill patients an explicit right to continuous deep sedation until they pass away. Such a framework would be unique in the world.
In this paper we will highlight and reflect on four relevant aspects and shortcomings of the proposed bill. First, that the bill suggests that continuous deeps sedation should be considered as a sui generis practice. Second, that it requires that sedation should always be accompanied by the withholding of all artificial nutrition and hydration. In the most recently amended version of the legal proposal it is stated that life sustaining treatments are withheld unless the patient objects. Third, that the French bill would not require that the suffering for which continuous deep sedation is initiated is unbearable. Fourth, the question as to whether the proposal should be considered as a way to avoid having to decriminalise euthanasia and/or PAS or, on the contrary, as a veiled way to decriminalise these practices. The French proposal to amend the Public Health Act to include a right to continuous deep sedation for some patients is a unique opportunity to clarify the legality of continuous deep sedation as an end-of-life practice. Moreover, it would recognize that the practice of continuous deep sedation raises ethical and legal issues that are different from those raised by symptom control on the one hand and assisted dying on the other hand. Nevertheless, there are still various issues of significant ethical concern in the French legislative proposal.
Bats are reservoirs for viruses with zoonotic potential in the Americas, and scattered evidence exists suggesting that bats may act as reservoirs for dengue virus (DENV). To explore further the role of bats as part of DENV sylvatic cycles, 240 bats of 18 species were captured in 2 states of Mexico with contrasting ecological characteristics but concurrent DENV activity in humans. RT-PCR analysis of RNA extracted from liver or spleen tissue from de bats failed to show evidence for the presence of DENV nucleic acids in these organs. In addition, plasma assayed by plaque reduction neutralization test showed no evidence of neutralizing anti-DENV antibodies. These results suggest that American bats may not be reservoirs or amplification host for DENV infection.
The exposure of farm animals to antimicrobials for treatment, prophylaxis, or growth promotion can select for resistant bacteria that can be transmitted to humans, and Salmonella as an important zoonotic pathogen can act as a potential reservoir of antimicrobial resistance determinants. We assessed the antibiogram profiles of Salmonella species isolated from pig herds in two commercial farms in South Africa. Two hundred fifty-eight presumptive Salmonella isolates were recovered from the fecal samples of 500 adult pigs. Specific primers targeting Salmonella serogroups A, B, C1, C2, and D were used to determine the prevalence of different serogroups. Only serogroup A (n = 48) was detected, while others were not. Antimicrobial susceptibility of the confirmed Salmonella serogroup A isolates was performed by using the disk diffusion method against a panel of 18 antibiotics. All the 48 isolates were resistant to tetracycline and oxytetracycline, while 75% were resistant to ampicillin, sulphamethoxazole-trimethoprim, nalidixic acid, and streptomycin. All the isolates exhibited multidrug resistance, with the predominant phenotype being against 11 antibiotics, and multiple antibiotic resistance index ranged between 0.3 and 0.6. The incidence of genes encoding resistance against ampicillin (ampC), tetracycline (tetA), and streptomycin (strA) were 54, 61, and 44%, respectively. We conclude that healthy pigs are potential reservoirs of multidrug-resistant Salmonella that could be transmitted to humans through the food chain and, hence, a significant public health threat.
New fat cells originate from a preexisting population of undifferentiated progenitor cells named preadipocytes. The process in which preadipocytes proliferate and differentiate into mature adipocytes under certain circumstances is called adipogenesis. In the past decade, many epigenetic factors have been shown to be pivotal for the appropriate timing of adipogenesis. A large number of coregulators at critical gene promoters set up specific patterns of DNA methylation, histone methylation and RNA methylation, which act as an epigenetic code to modulate the correct progress of adipocyte differentiation and adipogenesis. In this review, we focus on the functions and roles of epigenetic processes in preadipocyte differentiation and adipogenesis.
Interleukin-1 (IL-1), a proinflammatory cytokine synthesized and released by activated microglia, can cause dopaminergic neurodegeneration leading to Parkinson's disease (PD). However, it is uncertain whether IL-1 can act directly, or by exacerbating the harmful actions of other brain insults. To ascertain the role of the IL-1 pathway on dopaminergic neurodegeneration and motor skills during aging, we compared mice with impaired [caspase-1 knockout (casp1(-/-))] or overactivated IL-1 activity [IL-1 receptor antagonist knockout (IL-1ra(-/-))] to wild-type (wt) mice at young and middle age. Their motor skills were evaluated by the open-field and rotarod tests, and quantification of their dopamine neurons and activated microglia within the substantia nigra were performed by immunohistochemistry. IL-1ra(-/-) mice showed an age-related decline in motor skills, a reduced number of dopamine neurons, and an increase in activated microglia when compared to wt or casp1(-/-) mice. Casp1(-/-) mice had similar changes in motor skills and dopamine neurons, but fewer activated microglia cells than wt mice. Our results suggest that the overactivated IL-1 pathway occurring in IL-1ra(-/-) mice in the absence of inflammatory interventions (e.g., intracerebral injections performed in animal models of PD) increased activated microglia, decreased the number of dopaminergic neurons, and reduced their motor skills. Decreased IL-1 activity in casp1(-/-) mice did not yield clear protective effects when compared with wt mice. In summary, in the absence of overt brain insults, chronic activation of the IL-1 pathway may promote pathological aspects of PD per se, but its impairment does not appear to yield advantages over wt mice.
Recognizing cancer patients' preferences to obtain health information can help improve and reform the methods of communicating and providing proper services and consequently lead to effective patient education. The present cross-sectional study to prioritize the preferences of cancer patients regarding the acquisition of health informationwas conducted on cancer patients referred to hospitals affiliated to Semnan University of Medical Sciences in 2015. An anonymous self-administered questionnaire was developed. In the field of side effects of medications, 50 (46.7%) reported knowing about weight change, in the area of achieving relative health, 62(57.9%) announced awareness about diet, and 45 (42.1%) reported physical complications as a first regarding information needs. In the area of obtaining information, 50 (46.7%) tended to take their information through means outside of the hospital setting. These results can help with design of clinical information systems, as they inform the most
 relevant and useful coverage designed for cancer patients. Providing useful information through healthcare providers, the media and clinical information systems can act as a major source of social support for cancer patients.
The abnormal expression of microRNAs (miRs) as oncogenes or tumor suppressor genes has been widely investigated in various tumor types. However, the roles of miR 335 in bladder cancer cells have remained elusive. The aim of the present study was to assess the expression of miR 335 in bladder cancer as well as the effects of miR 335 on bladder cancer cell proliferation, metastasis and apoptosis. PCR and western blot analyses revealed that miR 335 was significantly downregulated in bladder cancer tissues, and low levels of miR 335 were associated with more aggressive phenotypes of bladder cancer. Overexpression of miR 335 in T24 cells inhibited cell proliferation and induced apoptosis as indicated by an MTT assay and flow cytometric analysis, respectively. Furthermore, overexpression of miR 335 significantly suppressed cell migration, as indicated by a Transwell assay. The expression of mitogen activated protein kinase (MAPK)1 was decreased after overexpression of miR 335, indicating that MAPK1 may be a target gene of miR 335. In addition, silencing of MAPK1 inhibited the proliferation and migration of bladder cancer cells. In conclusion, the results of the present study demonstrated that miR 335 was significantly downregulated in bladder cancer, and may act as a tumor suppressor through repression of MAPK1.
Several works have demonstrated the existence of a link between Mycobacterium avium subsp. paratuberculosis (MAP) and MS in Italy. In this study, we analyzed the serology of MAP in a Japanese population while looking at several markers of MAP. Fifty MS patients, 12 clinically isolated syndrome (CIS) patients, 30 other neurological disorders (OND) patients, and 50 healthy controls (HCs) were tested using ELISA for the presence of IgG antibodies toward immunodominant epitopes MAP_0106c121-132, homologues MBP85-98, homologues IRF5424-432, MAP_402718-32, and MAP_2694295-303. MAP-positive patients were also analyzed in relation to their clinical/demographic characteristics. Amongst all peptides, only antibodies against MAP_2694295-303 were more prevalent in MS patients (30%), as compared to OND patients (3%) (p = 0.009; area under roc curve (AUC) = 0.61) and HCs (2%) (p = 0.0004; AUC = 0.65) and in CIS patients (25%) compared to HCs (p = 0.023; AUC = 0.55). Logistic regression analysis showed a higher frequency of anti-MAP_2694295-303 antibodies in the sera of oligoclonal bands positive MS patients (p = 0.2; OR = 2, 95%CI: 0.55-7.7). These findings support the view that MAP could act as a risk factor or a triggering agent of MS in some Japanese patients with a genetic susceptibility to the mycobacterium.
Polyphenols are probably the most known and investigated molecules of nutritional interest as micronutrients present in abundance in our diet. Some of the most important food sources of polyphenols in the Mediterranean diet are olives and olive oil. A growing body of evidence from animal models to clinical studies indicates that polyphenol compounds may have neuroprotective effects in several pathologies of the nervous system through the control of oxidative stress, inflammation, apoptosis and mitochondrial dysfunction.
Based on the most recent scientific literature, dietary intake of polyphenols attenuates oxidative stress and reduces risk for related neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, stroke, multiple sclerosis and Huntington's disease. Also at the peripheral level, they act as antioxidant, defending tissues against oxidative damage and scavenging free radicals.
Recent findings in animal models and humans show that polyphenols may have a role in regulating neurotrophins levels, in particular nerve growth factor (NGF) and brainderived neurotrophic factor (BDNF), suggesting that polyphenols may also induce their protective effects through the potentiation of neurotrophins action. NGF and BDNF, primarily known as biological mediators stimulating neuron growth, proliferation, survival and differentiation are recently studied also as metabotrophic factors, acting on glucose and energy metabolism, pancreatic beta cells and cardiovascular homeostasis.
In this context, a better understanding of the effects of polyphenols on neurotrophins and their receptors (TrkA, TrkB, p75NTR) could certainly generate interest for drug discovery and also for the potential dietary prevention of several neurological and cardiometabolic diseases.
Skin cancer in humans represents about 30% of all new cancers and by far the most common malignancy in Caucasian population. Exposure to radiations especially ultraviolet-B (UV-B) radiation is the major cause for development of skin cancers along with other chemical or biological factors. The growing incidence rates of skin cancer around the world, demanded the need for new treatment options. Understanding the etiology and pathogenesis of skin cancer is therefore crucial for developing an effective drug against this prevailing disease. Medicinal plants are rich with numerous secondary metabolites such as flavonoids, which are now known to treat various chronic diseases, including inflammations and cancers. Flavonoids are sub-classified in to flavones, flavonols, iosflavones, flavanones, flavanols and anthocyanidins. They act by different targets including scavenging reactive oxygen species (ROS), regulation of cell cycle, and initiation of DNA repair mechanisms, apoptotic induction and inhibition of metastasis. Innumerable evidence suggested that an increased consumption of flavonoid-rich fruits and vegetables rendered DNA protection to normal skin exposed to carcinogens such as UV-B radiations. Flavonoids also showed the potential to induce cell death mechanisms in melanoma, the most dreadful form of skin cancer. This comprehensive review presents flavonoids and their mechanism of action in relation to inflammation and skin cancer management.
Cu3 V2 O8 nanoparticles with particle sizes of 40-50 nm have been prepared by the co-precipitation method. The Cu3 V2 O8 electrode delivers a discharge capacity of 462 mA h g(-1) for the first 10 cycles and then the specific capacity, surprisingly, increases to 773 mA h g(-1) after 50 cycles, possibly as a result of extra lithium interfacial storage through the reversible formation/decomposition of a solid electrolyte interface (SEI) film. In addition, the electrode shows good rate capability with discharge capacities of 218 mA h g(-1) under current densities of 1000 mA g(-1) . Moreover, the lithium storage mechanism for Cu3 V2 O8 nanoparticles is explained on the basis of ex situ X-ray diffraction data and high-resolution transmission electron microscopy analyses at different charge/discharge depths. It was evidenced that Cu3 V2 O8 decomposes into copper metal and Li3 VO4 on being initially discharged to 0.01 V, and the Li3 VO4 is then likely to act as the host for lithium ions in subsequent cycles by means of the intercalation mechanism. Such an "in situ" compositing phenomenon during the electrochemical processes is novel and provides a very useful insight into the design of new anode materials for application in lithium-ion batteries.
To predict the genes that affect endometrial receptivity through the differential expression of microRNA (miRNA) in eutopic endometrial tissues during implantation window in patients with endometriosis infertility.
Among infertile patients that received treatments at the Center for Reproductive Medicine, Peking University Third Hospital between May and December 2013, patients with endometriosis infertility were selected as endometriosis group (among the selected 17 cases, there were 6 cases with follicular phase endometrium and 11 cases with implantation window phase endometrium), and patients with tubal factor infertility were selected as control group (among the selected 19 cases, there were 7 cases with follicular phase endometrium and 12 cases with implantation window phase endometrium). (1)Implantation window phase endometrium was selected from 3 cases in each group. Using miRNA and mRNA joint gene sequencing and database for forecast results, as well as using the negative regulatory relationship between miRNA and mRNA, the intersection of target gene that negatively correlates with miRNA expression were obtained. The co-expression network of miRNA-mRNA wae constructed. Combined with the genes associated with endometrial receptivity found through bioinformatics method, the miRNA with core regulatory functionwas found. (2) Expand sample size to 14 cases for endometriosis group and 16 cases for control group.Reverse transcription (RT)-PCR technique was utilized to detect the expression of miR- 142- 5p, miR- 146a- 5p and miR- 543 in endometrial tissues, and verify miRNA microarray results.
(1) miRNA and mRNA microarray screening results showed that, among the endometrial tissues of patients with endometriosis infertility and with implantation window phase, 6 differentially expressed miRNA were indentified, among which miR-142-5p, miR-146a-5p, miR-1281, miR-940, miR-4634 showed significantly enhanced expression and miR- 543 showed significantly inhibited expression. Sixty- three differentially expressed mRNA were indentified, among which 58 mRNA such as CADM1, IL-10RA, ITGAL and LPAR5 had significantly enhanced expression. Five mRNA such as HLA- DRB1,3,4,5 and SOHLH2 showed significantly inhibited expression. Thirty- six taget genes were found in consideration of negatively correlated miRNA expression with the genes, miRNA-mRNA co-expression network were constructed. The miR-543 was found at the core of the network. Targetscan and other database predicted that
 miR-142-5p, miR- 146a- 5p and miR- 543 could act on various types of endometrial receptivity molecular corresponding marker genes such as HOX10, ITGAV, ITGB3, OPN, LIF, ESR, PGR, CDH1 and MMP. (2) RT- PCR test showed that the average levels of expression of miR-142-5p and miR-146a-5p in implantation window phase endometrium in endometriosis group were 8.3±10.6 and 1.9±0.8 respectively; the average levels of that in control group were 1.1±0.6 and 0.9±0.4, respectively. The difference was statistically significant (P=0.027, P=0.015), and was consistent with results from miRNA microarray test. The expression of miR-543 in tissues of follicular phase endometrium in endometriosis group (2.3±1.0) was significantly higher than that in control group (1.0 ± 0.4), and the difference was statistically significant (P=0.008). However, when comparing the expression of miR-543 implantation window phase endometrium in endometriosis group (1.2±0.6) with that in control group (1.5±1.0), the difference was not statistical significant (P=0.890).
There are multiple differential expressions of miRNA in the implantation window phase endometrium tissues of endometriosis infertility patients, among which miR-142-5p and miR-146a-5p show significantly enhanced expression and may affect embryo implantation by acting on a variety of endometrial receptivity marker molecules. The expression of miR- 543 in implantation window phase endometrium of endometriosis infertility patients is lower than that in the follicular phase, forewarned changes in the pattern of cyclic variation of miR-543, and may be the reason for affecting endometrial receptivity.
In the practice of modern emergency medicine (EM), transitions of care (TOC) have taken a prominent role, and during this time of healthcare reform, TOC has become a focal point of improvement initiatives across the continuum of care. This review includes a comprehensive examination of various regulatory, accreditation, and policy-based elements with which EM physicians interact in their daily practice. The content is organized into five domains: Accreditation Council for Graduate Medical Education (ACGME), The Joint Commission, Affordable Care Act, National Quality Forum (NQF), and accountable care organizations. This review is meant to be a synthesis of TOC material, tailored for EM physicians and the teams that make these departments run. We include (1) relevant current regulations and standards from various entities that are most likely to affect the day-to-day practice of EM; (2) examination of the consequences of these regulations and standards and how they can be used to shape EM practice and clinical decision making; and (3) comparison of interventions aimed at improving TOC, including evidence from current literature, practical examples, and proposals. Emergency departments must develop, implement, and monitor TOC programs and processes that can facilitate seamless and efficient care as patients transfer between settings. This report provides a framework for that effort and is designed to help EM physicians continue to take the lead in improving TOC to help shape the future of modern practice.
The 2004 Act on bioethics has amended the 1994 Act regarding the donation and the use of elements and products of the human body, medically assisted procreation and prenatal diagnosis. The very purpose of these laws led the legislature not to attempt the summa divisio order distinguishing the object to the person. The analysis of bioethical laws reveals the consecration of the non-commercialization of the human body at the expense of its unavailability. Bioethical laws appear to be catalysts of biological scientific advances releasing the status of the components and the products of the human body while framing it. By limiting scientific opportunities, they prevent human beings from trying to play the sorcerer's apprentice.
A 3D metal-organic framework (MOF) having single-molecule magnet (SMM) linkers was prepared in crystalline form by using a tetrairon(III) complex functionalised with two divergent pyridyl groups, namely [Fe4 (pPy)2 (dpm)6 ] (1; H3 pPy=2-(hydroxymethyl)-2-(pyridin-4-yl)propane-1,3-diol, Hdpm=dipivaloylmethane). Reaction of 1 with silver(I) perchlorate afforded {[Fe4 (pPy)2 (dpm)6 ]2 Ag}ClO4 (2), which crystallises in a cubic face-centred lattice and exhibits two interlocked diamondoid networks. In 2, the SMMs act as linear ditopic synthons, and silver(I) ions as tetrahedral nodes coordinated by four pyridyl nitrogen atoms. The magnetic properties of 1 (S=5 and D≈-0.4 cm(-1) in the ground spin state) are largely preserved in 2, which shows slow magnetic relaxation with an anisotropy barrier of Ueff /kB =11.46(10) K in zero field and 14.25(8) K in an applied field of 1 kOe. However, crystal symmetry triggers highly noncollinear magnetic anisotropy contributions oriented at 109.47° from each other along the threefold axes of AgN4 tetrahedra, a unique scenario fully confirmed by a single-crystal cantilever torque magnetometry investigation. Magnetisation curves down to 0.03 K demonstrated the occurrence of a wide hysteresis loop when the magnetic field was swept along one of the four Ag-N bonds. By symmetry, the crystalline compound can then be persistently magnetised parallel or antiparallel to the four main diagonals of the unit cell, although the crystals have no overall second-order anisotropy.
Discovery of glycan-competitive galectin-3-binding compounds that attenuate lung fibrosis in a murine model and that block intracellular galectin-3 accumulation at damaged vesicles, hence revealing galectin-3-glycan interactions involved in fibrosis progression and in intracellular galectin-3 activities, is reported. 3,3'-Bis-(4-aryltriazol-1-yl)thiodigalactosides were synthesized and evaluated as antagonists of galectin-1, -2, -3, and -4 N-terminal, -4 C-terminal, -7 and -8 N-terminal, -9 N-terminal, and -9 C-terminal domains. Compounds displaying low-nanomolar affinities for galectins-1 and -3 were identified in a competitive fluorescence anisotropy assay. X-ray structural analysis of selected compounds in complex with galectin-3, together with galectin-3 mutant binding experiments, revealed that both the aryltriazolyl moieties and fluoro substituents on the compounds are involved in key interactions responsible for exceptional affinities towards galectin-3. The most potent galectin-3 antagonist was demonstrated to act in an assay monitoring galectin-3 accumulation upon amitriptyline-induced vesicle damage, visualizing a biochemically/medically relevant intracellular lectin-carbohydrate binding event and that it can be blocked by a small molecule. The same antagonist administered intratracheally attenuated bleomycin-induced pulmonary fibrosis in a mouse model with a dose/response profile comparing favorably with that of oral administration of the marketed antifibrotic compound pirfenidone.
Self-assembled peptides have shown outstanding characteristics for vaccine delivery and drug targeting. Peptide molecules can be rationally designed to self-assemble into specific nanoarchitectures in response to changes in their assembly environment including: pH, temperature, ionic strength, and interactions between host (drug) and guest molecules. The resulting supramolecular nanostructures include nanovesicles, nanofibers, nanotubes, nanoribbons, and hydrogels and have a diverse range of mechanical and physicochemical properties. These molecules can be designed for cell-specific targeting by including adhesion ligands, receptor recognition ligands, or peptide-based antigens in their design, often in a multivalent display. Depending on their design, self-assembled peptide nanostructures have advantages in biocompatibility, stability against enzymatic degradation, encapsulation of hydrophobic drugs, sustained drug release, shear-thinning viscoelastic properties, and/or adjuvanting properties. These molecules can also act as intracellular transporters and respond to changes in the physiological environment. Furthermore, this class of materials has shown sequence- and structure-dependent impacts on the immune system that can be tailored to non-immunogenic for drug targeting, and immunogenic for vaccine delivery. This review explores self-assembled peptide nanostructures (beta sheets, alpha helices, peptide amphiphiles, amino acid pairing, elastin like polypeptides, cyclic peptides, short peptides, Fmoc peptides, and peptide hydrogels) and their application in vaccine delivery and drug targeting.
Problematic alcohol use is common among university students and personality might account for individual differences in developing this maladaptive behavior. Two personality dispositions implicated in problematic alcohol use are negative urgency and neuroticism. However, the relationship of these traits to problematic alcohol use is unclear. In college students high neuroticism is not directly linked to problematic alcohol use. On the other hand, the experience of emotional distress in people high in neuroticism could impair the capacity for impulse control. Loss of impulse control under conditions of negative affect could trigger impulsive drinking and problematic alcohol use in the long run.
We investigated this idea by testing whether negative urgency mediates the relationship of neuroticism to problematic alcohol use.
Participants were 60 undergraduate university students who completed the Urgency subscale of the Urgency, (lack of) Premeditation, (lack of) Perseverance, Sensation Seeking, and Positive Urgency Impulsive Behaviour scale (UPPS-P), the Alcohol Use Disorders Identification Test (AUDIT), and the Neuroticism subscale of the Eysenck Personality Questionnaire Revised short form (EPQ-RSS).
The results confirmed our hypothesis as we found an indirect effect of negative urgency on the relationship between
 neuroticism and problematic alcohol use.
It appears that it is not distress but the tendency to act rashly when distressed that is important in developing problematic alcohol drinking in university students.
The publication of the US Physician Payments Sunshine Act provides insight into the financial relationship between physicians and the pharmaceutical industry. This added transparency creates new opportunities of using objective data to better understand prior research that implicates pharmaceutical promotions as an important factor in a physician's decision-making process.
To assess the association between reported industry payments and physician-prescribing habits by comparing the use of anti-vascular endothelial growth factor (VEGF) intravitreal injections by US ophthalmologists to the industry payments these same physicians received.
This study reviews data from the Centers for Medicare & Medicaid Services (CMS) 2013 Medicare Provider Utilization and Payment Data: Physician and Other Supplier Public Use File and the CMS-sponsored August through December 2013 Open Payments program (Physician Payments Sunshine Act). Ophthalmologists who prescribe anti-VEGF injections for all indications were analyzed.
Association between industry payments reportedly received and the number and type of anti-VEGF injections administered.
A total of 3011 US ophthalmologists were reimbursed by CMS for 2.2 million anti-VEGF injections in 2013. Of these physicians, 38.0% reportedly received $1.3 million in industry payments for ranibizumab and aflibercept. Analysis revealed positive associations between increasing numbers of reported industry payments and total injection use (r = 0.24; 95% CI, 0.22-0.26; P < .001), aflibercept and ranibizumab injection use (r = 0.32; 95% CI, 0.29-0.34; P < .001), and percentage of injections per physician that were aflibercept or ranibizumab (r = 0.27; 95% CI, 0.25-0.29; P < .001). A smaller association was noted between greater number of industry payments and bevacizumab injection use (r = 0.07; 95% CI, 0.04-0.09; P < .001). Similar associations were found between the total dollars of reported industry payments received to injection use. Subgroup analysis further revealed that physicians receiving $1 to $25 in reported industry benefits were more likely than those not receiving industry payments to perform a greater percentage of their injections with aflibercept and ranibizumab.
Among ophthalmologists who prescribe anti-VEGF medications, there is a positive association between reported pharmaceutical payments and increased use of aflibercept and ranibizumab injections. As is inherent to the design of correlation studies, this analysis cannot determine whether the payments reported caused the increased use, are a result of the increased use, or are merely associated with some other factor that causes the increased use.
With insurance enrollment greater than expected under the Affordable Care Act, uncertainty about the availability and timeliness of healthcare services for newly insured individuals has increased. We examined primary care appointment availability and wait times for new Medicaid and privately insured patients before and after Medicaid expansion in Michigan.
Simulated patient ("secret shopper") study.
Extended follow-up of a previously reported simulated patient ("secret shopper") study assessing accessibility of routine new patient appointments in a stratified proportionate random sample of Michigan primary care practices before versus 4, 8, and 12 months after Medicaid expansion.
During the study period, approximately 600,000 adults enrolled in Michigan's Medicaid expansion program, representing 57% of the previously uninsured nonelderly adult population. One year after expansion, we found that appointment availability remained increased by 6 percentage points for new Medicaid patients (95% CI, 1.6-11.1) and decreased by 2 percentage points for new privately insured patients (95% CI, -0.5 to -3.8). Over the same period, the proportion of appointments scheduled with nonphysician providers (nurse practitioners or physician assistants) increased from 8% to 21% of Medicaid appointments (95% CI, 5.6-20.2) and from 11% to 19% of private-insurance appointments (95% CI, 1.3-14.1). Median wait times remained stable for new Medicaid patients and increased slightly for new privately insured patients, both remaining within 2 weeks.
During the first year following Medicaid expansion in Michigan, appointment availability for new Medicaid patients increased, a greater proportion of appointments could be obtained with nonphysician providers, and wait times remained within 2 weeks.
The Patient Protection and Affordable Care Act (ACA) was implemented to guarantee financial coverage for health care for all Americans. The implementation of ACA is likely to influence the insurance status of Americans and reimbursement rates of trauma centers. The aim of this study was to assess the impact of ACA on the patient insurance status, hospital reimbursements, and clinical outcomes at a Level I trauma center. We hypothesized that there would be a significant decrease in the proportion of uninsured trauma patients visiting our Level I trauma center following the ACA, and this is associated with improved reimbursement.
We performed a retrospective analysis of the trauma registry and financial database at our Level I trauma center for a 27-month (July 2012 to September 2014) period by quarters. Our outcome measures were change in insurance status, hospital reimbursement rates (total payments/expected payments), and clinical outcomes before and after ACA (March 31, 2014). Trend analysis was performed to assess trends in outcomes over each quarter (3 months).
A total of 9,892 patients were included in the study. The overall uninsured rate during the study period was 20.3%. Post-ACA period was associated with significantly lower uninsured rate (p < 0.001). During the same time, there was as a significant increase in the Medicaid patients (p = 0.009). This was associated with significantly improved hospital reimbursements (p < 0.001).On assessing clinical outcomes, there was no change in hospitalization (p = 0.07), operating room procedures (p = 0.99), mortality (p = 0.88), or complications (p = 0.20). Post-ACA period was also not associated with any change in the hospital (p = 0.28) or length of stay at intensive care unit (p = 0.66).
The implementation of ACA has led to a decrease in the number of uninsured trauma patients. There was a significant increase in Medicaid trauma patients. This was associated with an increase in hospital reimbursements that substantially improved the financial revenues. Despite the controversies, implementation of ACA has the potential to substantially improve the financial outcomes of trauma centers through Medicaid expansion.
Economic and value-based evaluation, level III.
Low field magnetoresistance is experimentally studied in a two-dimensional topological insulator (TI) in both diffusive and quasiballistic samples fabricated on top of a wide (14 nm) HgTe quantum well. In all cases a pronounced quasi-linear positive magnetoresistance is observed similar to that found previously in diffusive samples based on a narrow (8 nm) HgTe well. The experimental results are compared with the main existing theoretical models based on different types of disorder: sample edge roughness, nonmagnetic disorder in an otherwise coherent TI and metallic puddles due to locally trapped charges that act like local gate on the sample. The quasiballistic samples with resistance close to the expected quantized values also show a positive low-field magnetoresistance but with a pronounced admixture of mesoscopic effects.
The integrity of the pharmaceutical supply chain is threatened by medication counterfeiting, importation of unapproved and substandard drugs, and grey markets - all of which have the potential to distribute drug products with the potential for serious harm. On November 27, 2013, President Obama signed into law Title II of the Drug Quality and Security Act, now known as the Drug Supply Chain Security Act (DSCSA). Over the next 10 years, the DSCSA will require the pharmaceutical supply chain to implement medication tracking and tracing; serialization, verification, and detection of suspicious products; and strict guidelines for wholesaler licensing and reporting. This article reviews the important aspects of the DSCSA and outlines the role of health-system pharmacy leaders in ensuring compliance to the DSCSA. By verifying that medication supplies are free from adulteration and tampering, the DSCSA serves as a foundational law to ensure quality in providing patient-centered pharmacy services.
Three species of cactus whose spines act as dew harvesters were chosen for this study: Copiapoa cinerea var. haseltoniana, Mammillaria columbiana subsp. yucatanensis and Parodia mammulosa and compared with Ferocactus wislizenii whose spines do not perform as dew harvesters. Time-lapse snapshots of C. cinerea showed movement of dew droplets from spine tips to their base, even against gravity. Spines emanating from one of the areoles of C. cinerea were submerged in water laced with fluorescent nanoparticles and this particular areole with its spines and a small area of stem was removed and imaged. These images clearly showed that fluorescent water had moved into the stem of the plant. Lines of vascular bundles radiating inwards from the surface areoles (from where the spines emanate) to the core of the stem were detected using magnetic resonance imaging, with the exception of F. wislizenii that does not harvest dew on its spines. Spine microstructures were examined using SEM images and surface roughness measurements (Ra and Rz) taken of the spines of C. cinerea It was found that a roughness gradient created by
 tapered microgrooves existed that could potentially direct surface water from a spine tip to its base.This article is part of the themed issue 'Bioinspired hierarchically structured surfaces for green science'.
β-adrenergic receptors (βARs) are critical regulators of acute cardiovascular physiology. In response to elevated catecholamine stimulation during development of congestive heart failure (CHF), chronic activation of Gs-dependent β1AR and Gi-dependent β2AR pathways leads to enhanced cardiomyocyte death, reduced β1AR expression, and decreased inotropic reserve. β-blockers act to block excessive catecholamine stimulation of βARs to decrease cellular apoptotic signaling and normalize β1AR expression and inotropy. Whereas these actions reduce cardiac remodeling and mortality outcomes, the effects are not sustained. Converse to G-protein-dependent signaling, β-arrestin-dependent signaling promotes cardiomyocyte survival. Given that β2AR expression is unaltered in CHF, a β-arrestin-biased agonist that operates through the β2AR represents a potentially useful therapeutic approach. Carvedilol, a currently prescribed nonselective β-blocker, has been classified as a β-arrestin-biased agonist that can inhibit basal signaling from βARs and also stimulate cell survival signaling pathways. To understand the relative contribution of β-arrestin bias to the efficacy of select β-blockers, a specific β-arrestin-biased pepducin for the β2AR, intracellular loop (ICL)1-9, was used to decouple β-arrestin-biased signaling from occupation of the orthosteric ligand-binding pocket. With similar efficacy to carvedilol, ICL1-9 was able to promote β2AR phosphorylation, β-arrestin recruitment, β2AR internalization, and β-arrestin-biased signaling. Interestingly, ICL1-9 was also able to induce β2AR- and β-arrestin-dependent and Ca(2+)-independent contractility in primary adult murine cardiomyocytes, whereas carvedilol had no efficacy. Thus, ICL1-9 is an effective tool to access a pharmacological profile stimulating cardioprotective signaling and inotropic effects through the β2AR and serves as a model for the next generation of cardiovascular drug development.
Early eukaryotic ribosome biogenesis involves large multi-protein complexes, which co-transcriptionally associate with pre-ribosomal RNA to form the small subunit processome. The precise mechanisms by which two of the largest multi-protein complexes-UtpA and UtpB-interact with nascent pre-ribosomal RNA are poorly understood. Here, we combined biochemical and structural biology approaches with ensembles of RNA-protein cross-linking data to elucidate the essential functions of both complexes. We show that UtpA contains a large composite RNA-binding site and captures the 5' end of pre-ribosomal RNA. UtpB forms an extended structure that binds early pre-ribosomal intermediates in close proximity to architectural sites such as an RNA duplex formed by the 5' ETS and U3 snoRNA as well as the 3' boundary of the 18S rRNA. Both complexes therefore act as vital RNA chaperones to initiate eukaryotic ribosome assembly.
Verticillium dahliae, a destructive and soil-borne fungal pathogen, causes massive losses in cotton yields. However, the resistance mechanism to V. dahilae in cotton is still poorly understood. Accumulating evidence indicates that chitinases are crucial hydrolytic enzymes, which attack fungal pathogens by catalyzing the fungal cell wall degradation. As a large gene family, to date, the chitinase genes (Chis) have not been systematically analyzed and effectively utilized in cotton. Here, we identified 47, 49, 92, and 116 Chis from four sequenced cotton species, diploid Gossypium raimondii (D5), G. arboreum (A2), tetraploid G. hirsutum acc. TM-1 (AD1), and G. barbadense acc. 3-79 (AD2), respectively. The orthologous genes were not one-to-one correspondence in the diploid and tetraploid cotton species, implying changes in the number of Chis in different cotton species during the evolution of Gossypium. Phylogenetic classification indicated that these Chis could be classified into six groups, with distinguishable structural characteristics. The expression patterns of Chis indicated their various expressions in different organs and tissues, and in the V. dahliae response. Silencing of Chi23, Chi32, or Chi47 in cotton significantly impaired the resistance to V. dahliae, suggesting these genes might act as positive regulators in disease resistance to V. dahliae.
Although marine reserves represent one of the most effective management responses to human impacts, their capacity to sustain the same diversity of species, functional roles and biomass of reef fishes as wilderness areas remains questionable, in particular in regions with deep and long-lasting human footprints. Here we show that fish functional diversity and biomass of top predators are significantly higher on coral reefs located at more than 20 h travel time from the main market compared with even the oldest (38 years old), largest (17,500 ha) and most restrictive (no entry) marine reserve in New Caledonia (South-Western Pacific). We further demonstrate that wilderness areas support unique ecological values with no equivalency as one gets closer to humans, even in large and well-managed marine reserves. Wilderness areas may therefore serve as benchmarks for management effectiveness and act as the last refuges for the most vulnerable functional roles.
Plants produce a variety of secondary metabolites to defend themselves from pathogen attack, while pathogens have evolved to overcome plant defences by producing enzymes that degrade or modify these defence compounds. However, many compounds targeted by pathogen enzymes currently remain enigmatic. Identifying host compounds targeted by pathogen enzymes would enable us to understand the potential importance of such compounds in plant defence and modify them to make them insensitive to pathogen enzymes. Here, a proof of concept metabolomics-based method was developed to discover plant defence compounds modified by pathogens using two pathogen enzymes with known targets in wheat and tomato. Plant extracts treated with purified pathogen enzymes were subjected to LC-MS, and the relative abundance of metabolites before and after treatment were comparatively analysed. Using two enzymes from different pathogens the in planta targets could be found by combining relatively simple enzymology with the power of untargeted metabolomics. Key to the method is dataset simplification based on natural isotope occurrence and statistical filtering, which can be scripted. The method presented here will aid in our understanding of plant-pathogen interactions and may lead to the development of new plant protection strategies.
We compared methane (CH4) and carbon dioxide (CO2) fluxes in samples collected from the aboveground parts of wood ant nests and in the organic and mineral layer of the surrounding forest floor. Gas fluxes were measured during a laboratory incubation, and microbial properties (abundance of fungi, bacteria and methanotrophic bacteria) and nutrient contents (total and available carbon and nitrogen) were also determined. Both CO2 and CH4 were produced from ant nest samples, indicating that the aboveground parts of wood ant nests act as sources of both gases; in comparison, the forest floor produced about four times less CO2 and consumed rather than produced CH4 Fluxes of CH4 and CO2 were positively correlated with contents of available carbon and nitrogen. The methanotrophic community was represented by type II methanotrophic bacteria, but their abundance did not explain CH4 flux. Fungal abundance was greater in ant nest samples than in forest floor samples, but bacterial abundance was similar in both kinds of samples, suggesting that the organic materials in the nests may have been too recalcitrant for bacteria to decompose. The results indicate that the aboveground parts of wood ant nests are hot spots of CO2 and CH4 production in the forest floor.
MicroRNAs (miRNAs) control cellular gene expression via primarily binding to 3' or 5' untranslated region of the target transcript leading to translational repression or mRNA degradation. In most cases, miRNAs have been observed to fine-tune the cellular responses and, therefore, act as a rheostat rather than an on/off switch. Transcription factor PU.1 is a master switch that controls monocyte/macrophage development from hematopoietic stem cells. Recent Advances: PU.1 induces a specific set of miRNAs while suppressing the miR17-92 cluster to regulate monocyte/macrophage development. In addition to development, miRNAs tightly control the macrophage polarization continuum from proinflammatory M1 or proreparative M2 by regulating expression of key transcription factors involved in the process of polarization.
miRNAs are intricately involved with fine-tuning fundamental macrophage functions such as phagocytosis, efferocytosis, inflammation, tissue repair, and tumor promotion. Macrophages are secretory cells that participate in intercellular communication by releasing regulatory molecules and microvesicles (MVs). MVs are bilayered lipid membranes packaging a hydrophilic cargo, including proteins and nucleic acids. Macrophage-derived MVs carry functionally active miRNAs that suppress gene expression in target cells via post-transcriptional gene silencing, thus regulating cell function. In summary, miRNAs fine-tune several major facets of macrophage development and function. Such fine-tuning is critical in preventing exaggerated macrophage response to endogenous or exogenous stimuli.
A critical role of miRNAs in the regulation of innate immune response and macrophage biology, including development, differentiation, and activation, has emerged. A clear understanding of such regulation on macrophage function remains to be elucidated. Antioxid. Redox
 Signal. 25, 795-804.
To undertake a comprehensive prospective national study of the outcomes of retroperitoneal lymph node dissection (RPLND) for testis cancer over a 1-year period in the UK.
Data were submitted online using the British Association of Urological Surgeons Section of Oncology Data and Audit System. All new patients undergoing RPLND for testis cancer between March 2012 and February 2013 were studied prospectively. Data were analysed using Tableau software and case ascertainment compared with Hospital Episode Statistics data.
In all, 162 men underwent RPLND by 20 surgeons in 17 centres. The mean (range) case volume per centre was 9 (2-32) and the median (range) case volume per surgeon was 6 (1-30). Indications included: residual mass after chemotherapy (73%), primary treatment (6%), relapse (14%), and salvage (7%). The median time to surgery after chemotherapy was 8-12 weeks (<4 - >12 weeks) and 91% of procedures utilised open surgery. The median operating time was 3-4 h (<1.5 - >6 h). Nerve sparing was performed in 67% of patients (19% bilateral, 48% unilateral). The dissection was template in 81% and lumpectomy in 16%; 25% required additional intraoperative procedures including 11% synchronous planned nephrectomy. In all, 157/160 (98%) of recorded RPLND operations were completed. One was terminated due to bleeding and in two the mass could not be removed. There were no deaths within 30 days of surgery. In all, 75% of the men did not require a blood transfusion, 15% required 1-2 units and 10% received >2 units. There were postoperative complications in 10% of the men (Clavien-Dindo Grade I, seven men; Grade II, seven; and Grade III, one). The mean (range) length of stay was 5.5 (1-59) days. Histology showed necrosis in 22%; teratoma differentiated in 42%; and residual cancer in 36%.
This prospective collaborative national study describes for the first time the surgical outcomes after RPLND across the UK. The quality of RPLND in the UK appears high. The study can act as a benchmark for this type of surgery across the world.
Wildfires are complex adaptive systems, and have been hypothesized to exhibit scale-dependent transitions in the drivers of fire spread. Among other things, this makes the prediction of final fire size from conditions at the ignition difficult. We test this hypothesis by conducting a multi-scale statistical modelling of the factors determining whether fires reached 10 ha, then 100 ha then 1000 ha and the final size of fires >1000 ha. At each stage, the predictors were measures of weather, fuels, topography and fire suppression. The objectives were to identify differences among the models indicative of scale transitions, assess the accuracy of the multi-step method for predicting fire size (compared to predicting final size from initial conditions) and to quantify the importance of the predictors. The data were 1116 fires that occurred in the eucalypt forests of New South Wales between 1985 and 2010. The models were similar at the different scales, though there were subtle differences. For example, the presence of roads affected whether fires reached 10 ha but not larger scales. Weather was the most important predictor overall, though fuel load, topography and ease of suppression all showed effects. Overall, there was no evidence that fires have scale-dependent transitions in behaviour. The models had a predictive accuracy of 73%, 66%, 72% and 53% accuracy at 10 ha, 100 ha, 1000 ha and final size scales. When these steps were combined, the overall accuracy for predicting the size of fires was 62%, while the accuracy of the one step model was only 20%. Thus, the multi-scale approach was an improvement on the single scale approach, even though the predictive accuracy was probably insufficient for use as an operational tool. The analysis has also provided further evidence of the important role of weather, compared to fuel, suppression and topography in driving fire behaviour.
The adaptor molecule Cbl-interacting protein of 85 kD (CIN85) regulates signaling from a number of cell surface receptors, such as growth factor receptors and antigen receptors on lymphocytes. Because of its multidomain structure, CIN85 is thought to act as a classical adaptor protein that connects functionally distinct components of a given signaling pathway through diverse protein domains. However, we found that in B lymphocytes, CIN85 functions to oligomerize SLP-65, which is the central effector protein of the B cell receptor (BCR). Therefore, CIN85 trimerizes through a carboxyl-terminal, coiled-coil domain. The multiple Src homology 3 (SH3) domains of trimeric CIN85 molecules associated with multiple SLP-65 molecules, which recruited further CIN85 trimers, thereby perpetuating the oligomerization process. Formation of this oligomeric signaling complex in resting B cells rendered the cells poised for the efficient initiation of intracellular signaling upon BCR stimulation. Our data suggest that the functionality of signaling cascades does not rely solely on the qualitative linkage of their various components but requires a critical number of effectors to become concentrated in signaling complexes.
The effects of serotonin (5-HT) on anxiety and depression are mediated by a number of 5-HT receptors, including autoreceptors that act to inhibit 5-HT release. While the majority of anxiety and depression-related research has focused on the 5-HT1A receptor, the 5-HT1B receptor has a lesser known role in modulating emotional behavior. 5-HT1B receptors are inhibitory GPCRs located on the presynaptic terminal of both serotonin and non-serotonin neurons, where they act to inhibit neurotransmitter release. The autoreceptor population located on the axon terminals of 5-HT neurons is a difficult population to study due to their diffuse localization throughout the brain that overlaps with 5-HT1B heteroreceptors (receptors located on non-serotonergic neurons). In order to study the contribution of 5-HT1B autoreceptors to anxiety and depression-related behaviors, we developed a genetic mouse model that allows for selective ablation of 5-HT1B autoreceptors. Mice lacking 5-HT1B autoreceptors displayed the expected increases in extracellular serotonin levels in the ventral hippocampus following administration of a selective serotonin reuptake inhibitor. In behavioral studies, they displayed decreased anxiety-like behavior in the open field and antidepressant-like effects in the forced swim and sucrose preference tests. These results suggest that strategies aimed at blocking 5-HT1B autoreceptors may be useful for the treatment of anxiety and depression.
To investigate the extent of objective 'non-beneficial treatments (NBTs)' (too much) anytime in the last 6 months of life in routine hospital care.
English language publications in Medline, EMBASE, PubMed, Cochrane library, and the grey literature (January 1995-April 2015).
All study types assessing objective dimensions of non-beneficial medical or surgical diagnostic, therapeutic or non-palliative procedures administered to older adults at the end of life (EOL).
A 13-item quality score estimated independently by two authors.
Evidence from 38 studies indicates that on average 33-38% of patients near the EOL received NBTs. Mean prevalence of resuscitation attempts for advanced stage patients was 28% (range 11-90%). Mean death in intensive care unit (ICU) was 42% (range 11-90%); and mean death rate in a hospital ward was 44.5% (range 29-60%). Mean prevalence of active measures including dialysis, radiotherapy, transfusions and life support treatment to terminal patient was 7-77% (mean 30%). Non-beneficial administration of antibiotics, cardiovascular, digestive and endocrine treatments to dying patients occurred in 11-75% (mean 38%). Non-beneficial tests were performed on 33-50% of patients with do-not-resuscitate orders. From meta-analyses, the pooled prevalence of non-beneficial ICU admission was 10% (95% CI 0-33%); for chemotherapy in the last six weeks of life was 33% (95% CI 24-41%).
This review has confirmed widespread use of NBTs at the EOL in acute hospitals. While a certain level of NBT is inevitable, its extent, variation and justification need further scrutiny.
The Physician Payment Sunshine Act was implemented to provide transparency to financial transactions between industry and physicians. Under this law, the Open Payments Program (OPP) was created to publicly disclose all transactions and inform patients of potential conflicts of interest. Collaboration between industry and cardiothoracic surgeon-scientists is essential in developing new approaches to treating patients with cardiac disease. The objective of this study is to characterize industry payments to cardiothoracic surgeons as reported by the OPP.
We used the first wave of Physician Payment Sunshine Act data (August 2013 to December 2013) to assess industry payments made to cardiothoracic surgeons.
Cardiothoracic surgeons (n = 2,495) received a total of $4,417,545 during a 5-month period. Cardiothoracic surgeons comprised 0.5% of all persons in the OPP and received 0.9% of total disclosed industry funding. Among cardiothoracic surgeons receiving funding, 34% received payments less than $100, 43% received payments of $100 to $999, 19% received payments of $1,000 to $9,999, 4% received payments of $10,000 to $99,999, and 0.2% received payments of more than $100,000. The median was $181 (interquartile range [IQR]: $60 to $843) and the mean ± standard deviation was $1,771 ± $7,664. The largest payment to an individual surgeon was $159,444. The three largest median payments made to cardiothoracic surgeons by expense category were royalty fees $8,398 (IQR: $536 to $12,316), speaker fees $3,600 (IQR: $1,500 to $8,000), and honoraria $3,344 (IQR: $1,563 to $7,350).
Among cardiothoracic surgeons who are listed as recipients
 of nonresearch industry payments, 50% of cardiothoracic surgeons received less than $181. Awareness of the OPP data is critical for cardiothoracic surgeons, as it provides a means to prevent potential public misconceptions about industry payments within the specialty that may affect patient trust.
Bacillus thuringiensis and Bacillus endophyticus both act as the companion bacteria, which cooperate with Ketogulonigenium vulgare in vitamin C two-step fermentation. Two Bacillus species have different morphologies, swarming motility and 2-keto-L-gulonic acid productivities when they co-culture with K. vulgare. Here, we report the complete genome sequencing of B. thuringiensis Bc601 and eight plasmids of B. endophyticus Hbe603, and carry out the comparative genomics analysis. Consequently, B. thuringiensis Bc601, with greater ability of response to the external environment, has been found more two-component system, sporulation coat and peptidoglycan biosynthesis related proteins than B. endophyticus Hbe603, and B. endophyticus Hbe603, with greater ability of nutrients biosynthesis, has been found more alpha-galactosidase, propanoate, glutathione and inositol phosphate metabolism, and amino acid degradation related proteins than B. thuringiensis Bc601. Different ability of swarming motility, response to the external environment and nutrients biosynthesis may reflect different companion mechanisms of two Bacillus species. Comparative genomic analysis of B. endophyticus and B. thuringiensis enables us to further understand the cooperative mechanism with K. vulgare, and facilitate the optimization of bacterial consortium.
Novel molecular analytes are needed in small bowel neuroendocrine tumours (SBNETs) to better determine disease aggressiveness and predict treatment response. In this study, we aimed to profile the global miRNome of SBNETs, and identify microRNAs (miRNAs) involved in tumour progression for use as potential biomarkers. Two independent miRNA profiling experiments were performed (n=90), including primary SBNETs (n=28), adjacent normal small bowel (NSB; n=14), matched lymph node (LN) metastases (n=24), normal LNs (n=7), normal liver (n=2) and liver metastases (n=15). We then evaluated potentially targeted genes by performing integrated computational analyses. We discovered 39 miRNAs significantly deregulated in SBNETs compared with adjacent NSB. The most upregulated (miR-204-5p, miR-7-5p and miR-375) were confirmed by qRT-PCR. Two miRNAs (miR-1 and miR-143-3p) were significantly downregulated in LN and liver metastases compared with primary tumours. Furthermore, we identified upregulated gene targets for miR-1 and miR-143-3p in an existing SBNET dataset, which could contribute to disease progression, and show that these miRNAs directly regulate FOSB and NUAK2 oncogenes. Our study represents the largest global miRNA profiling of SBNETs using matched primary tumour and metastatic samples. We revealed novel miRNAs deregulated during SBNET disease progression, and important miRNA-mRNA interactions. These miRNAs have the potential to act as biomarkers for patient stratification and may also be able to guide treatment decisions. Further experiments to define molecular mechanisms and validate these miRNAs in larger tissue cohorts and in biofluids are now warranted.
Two thermally activated ruthenium(ii) polypyridyl complexes, cis-Ru(bpy)2Cl2 and trans-Ru(qpy)Cl2 were investigated to determine the impact of the geometric arrangement of the exchangable ligands on the potential of the compounds to act as chemotherapeutics. In contrast to the geometry requirements for cisplatin, trans-Ru(qpy)Cl2 was 7.1-9.5× more cytotoxic than cis-Ru(bpy)2Cl2. This discovery could open up a new area of metal-based chemotherapeutic research.
: Mesenchymal stem cells (MSCs) usually promote tumor growth and metastasis. By using a breast tumor 4T1 cell-based animal model, this study determined that coinjection and distant injection of allogeneic bone marrow-derived MSCs with tumor cells could exert different effects on tumor growth. Whereas the coinjection of MSCs with 4T1 cells promoted tumor growth, surprisingly, the injection of MSCs at a site distant from the 4T1 cell inoculation site suppressed tumor growth. We further observed that, in the distant injection model, MSCs decreased the accumulation of myeloid-derived suppressor cells and regulatory T cells in tumor tissues by enhancing proinflammatory factors such as interferon-γ, tumor necrosis factor-α, Toll-like receptor (TLR)-3, and TLR-4, promoting host antitumor immunity and inhibiting tumor growth. Unlike previous reports, this is the first study reporting that MSCs may exert opposite roles on tumor growth in the same animal model by modulating the host immune system, which may shed light on the potential application of MSCs as vehicles for tumor therapy and other clinical applications.
Mesenchymal stem cells (MSCs) have been widely investigated for their potential roles in tissue engineering, autoimmune diseases, and tumor therapeutics. This study explored the impact of coinjection and distant injection of allogeneic bone marrow-derived MSCs on mouse 4T1 breast cancer cells. The results showed that the coinjection of MSCs and 4T1 cells promoted tumor growth. MSCs might act as the tumor stromal precursors and cause immunosuppression to protect tumor cells from immunosurveillance, which subsequently facilitated tumor metastasis. Interestingly, the distant injection of MSCs and 4T1 cells suppressed tumor growth. Together, the results of this study revealed the dual functions of MSCs in immunoregulation.
Rosa canina fruits have been used traditionally for the treatment of diabetes mellitus and its complications. The aim of current study was to evaluate the in vitro mechanism of action of R canina in managing diabetes mellitus. Cell proliferation and cytotoxicity assay were performed on pancreatic β-cells, βTC6. The protective activity of the extract on streptozotocin-induced death in βTC6 cells was studied. The effect of R canina on the metabolism of glucose in HepG2, a hepatocellular carcinoma cell line, was evaluated. The effect of the extract on glucose diffusion across the dialysis membrane, which is a comfortable model for assessing cellular glucose absorption, was evaluated. The results obtained from current study confirmed that R canina extract can act as a growth factor for pancreatic β-cell line providing a novel mechanism for the observed antidiabetic effect of this natural agent. Further preclinical studies are necessary to evaluate the perfect mechanism of action of R canina in diabetes mellitus.
In this paper, one kind of helix-like chiral metamaterial which can be realized by multiple conventional lithography or electron beam lithographic techniques is proposed to have a broadband bianisotropic optical response analogous to helical metamaterials. On the basis of twisted metamaterials, via tailoring the relative orientation within the lattice, the anisotropy of arcs is converted into magneto-electric coupling of closely spaced arc pairs, which leads to a broad bianisotropic optical response. By connecting the adjacent upper and lower arcs, the coupling of metasurface pairs is transformed into the coupling of the three-dimensional inclusions, and provides a much broader and higher bianisotropic optical response. For only a four-layer helix-like metamaterial, the maximum extinction ratio can reach 19.7. The operation band is in the wavelength range of 4.69 μm to 8.98 μm with an average extinction ratio of 6.9. And the transmittance for selective polarization is above 0.8 in the entire operation band. Such a structure is a promising candidate for integratable and scalable broadband circular polarizers, especially it has great potential to act as a broadband circular micropolarizer in the field of the full-Stokes division of focal plane polarimeters.
Homologous recombination (HR) of nuclear DNA occurs within the context of a highly complex chromatin structure. Despite extensive studies of HR in diverse organisms, mechanisms regulating HR within the chromatin context remain poorly elucidated. Here we investigate the role and interplay of the histone chaperones NUCLEOSOME ASSEMBLY PROTEIN1 (NAP1) and NAP1-RELATED PROTEIN (NRP) and the ATP-dependent chromatin-remodeling factor INOSITOL AUXOTROPHY80 (INO80) in regulating somatic HR in Arabidopsis thaliana. We show that simultaneous knockout of the four AtNAP1 genes and the two NRP genes in the sextuple mutant m123456-1 barely affects normal plant growth and development. Interestingly, compared with the respective AtNAP1 (m123-1 and m1234-1) or NRP (m56-1) loss-of-function mutants, the sextuple mutant m123456-1 displays an enhanced plant hypersensitivity to UV or bleomycin treatments. Using HR reporter constructs, we show that AtNAP1 and NRP act in parallel to synergistically promote somatic HR. Distinctively, the AtINO80 loss-of-function mutation (atino80-5) is epistatic to m56-1 in plant phenotype and telomere length but hypostatic to m56-1 in HR determinacy. Further analyses show that expression of HR machinery genes and phosphorylation of H2A.X (γ-H2A.X) are not impaired in the mutants. Collectively, our study indicates that NRP and AtNAP1 synergistically promote HR upstream of AtINO80-mediated chromatin remodeling after the formation of γ-H2A.X foci during DNA damage repair.
The p53 protein plays a passive and an active role in stem cells. The transcriptional activities of p53 for cell-cycle arrest and DNA repair are largely turned off in stem cells, but there is some indication that long-term stem-cell viability may require other p53-regulated functions. When p53 is activated in stem cells, it stops cell division and promotes the commitment to a differentiation pathway and the formation of progenitor cells. In the absence
 of any p53 activity, stem-cell replication continues and mistakes in the normal epigenetic pathway occur at a higher probability. In the presence of a functionally active p53 protein, epigenetic stability is enforced and stem-cell replication is regulated by commitment to differentiation. Over a lifetime of an organism, stem-cell clones compete in a tissue niche for Darwinian replicative advantages and in doing so accumulate mutations that permit stem-cell replication. Mutations in the p53 gene give stem cells this advantage, increase the clonal stem-cell population, and lower the age at which cancers can occur. Li-Fraumeni patients that inherit p53 mutations develop tumors in a tissue-type-specific fashion at younger ages. Throughout the life of a Li-Fraumeni patient, the tumor types that arise occur in tissues where stem cells are active and cell division is most rapid. Thus, p53 mutations that are inherited or occur during developmental life act in stem cells of the mesenchymal and epithelial lineages, whereas p53 mutations that occur in progenitor or differentiated (somatic) cells later in life function in tissues of endodermal origins, indicating that p53 may function differently in different developmental lineages.
Working to establish analytic contact (Waska, 2007) with a patient involves the verbal act of interpretation. But, how one interprets and what we try to hold in words is not the same with each patient. Each patient requires, invites, provokes and responds to a unique mixture of interpretive elements or approaches. The projective identification process that is so often the bedrock of the transference, and therefore the catalyst of the counter-transference, forms the psychological climate between patient and analyst. Case material is used to explore a Modern Kleinian interpretive approach with both a very entrenched depressive position (Klein, 1935, 1940) patient and a very primitive paranoid-schizoid (Klein, 1946) patient. Both these individuals desired relief from their symptoms of anxiety, anger, emptiness, and guilt. But, their unbearable unconscious phantasies offered pathological security that they were familiar with and therefore they preferred the known internal trauma and chaos to facing the unknown and undefined reality of self and other that change, grief, and growth would bring.
Asthma manifests as a heterogeneous syndrome characterized by airway obstruction, inflammation and hyperresponsiveness (AHR). Although the molecular mechanisms remain unclear, activation of specific PI3K isoforms mediate inflammation and AHR. We aimed to determine whether inhibition of PI3Kδ evokes dilation of airways and to elucidate potential mechanisms.
Human precision cut lung slices from non-asthma donors and primary human airway smooth muscle (HASM) cells from both non-asthma and asthma donors were utilized. Phosphorylation of Akt, myosin phosphatase target subunit 1 (MYPT1) and myosin light chain (MLC) were assessed in HASM cells following either PI3K inhibitor or siRNA treatment. HASM relaxation was assessed by micro-pattern deformation. Reversal of constriction of airways was assessed following stimulation with PI3K or ROCK inhibitors.
Soluble inhibitors or PI3Kδ knockdown reversed carbachol-induced constriction of human airways, relaxed agonist-contracted HASM and inhibited pAkt, pMYPT1 and pMLC in HASM. Similarly, inhibition of Rho kinase also dilated human PCLS airways and suppressed pMYPT1 and pMLC. Baseline pMYPT1 was significantly elevated in HASM cells derived from asthma donors in comparison with non-asthma donors. After desensitization of the β2 -adrenoceptors, a PI3Kδ inhibitor remained an effective dilator. In the presence of IL-13, dilation by a β agonist, but not PI3K inhibitor, was attenuated.
PI3Kδ inhibitors act as dilators of human small airways. Taken together, these findings provide alternative approaches to the clinical management of airway obstruction in asthma.
In the UK, as in most other countries in the world, levels of obesity are increasing. According to the Kinsey report, obesity has the second largest public health impact after smoking, and it is inextricably linked to physical inactivity. Since the UK Health and Social Care Act reforms of 2012, there has been a significant restructuring of the National Health Service (NHS). As a consequence, NHS England and the Department of Health have issued new policy guidelines regarding the commissioning of obesity treatment. A 4-tier model of care is now widely accepted and ranges from primary activity, through community weight management and specialist weight management for severe and complex obesity, to bariatric surgery. However, although there are clear care pathways and clinical guidelines for evidence-based practice, there remains no single stakeholder willing to take overall responsibility for obesity care. There is a lack of provision of adequate services characterised by a noticeable 'postcode lottery', and little political will to change the obesogenic environment.
We design spin filters for particles with potentially arbitrary spin [Formula: see text] using a one-dimensional periodic chain of magnetic atoms as a quantum device. Describing the system within a tight-binding formalism we present an analytical method to unravel the analogy between a one-dimensional magnetic chain and a multi-strand ladder network. This analogy is crucial, and is subsequently exploited to engineer gaps in the energy spectrum by an appropriate choice of the magnetic substrate. We obtain an exact correlation between the magnitude of the spin of the incoming beam of particles and the magnetic moment of the substrate atoms in the chain desired for opening up of a spectral gap. Results of spin polarized transport, calculated within a transfer matrix formalism, are presented for particles having half-integer as well as higher spin states. We find that the chain can be made to act as a quantum device which opens a transmission window only for selected spin components over certain ranges of the Fermi energy, blocking them in the remaining part of the spectrum. The results appear to be robust even when the choice of the substrate atoms deviates substantially from the ideal situation, as verified by extending the ideas to the case of a 'spin spiral'. Interestingly, the spin spiral geometry, apart from exhibiting the filtering effect, is also seen to act as a device flipping spins-an effect that can be monitored by an interplay of the system size and the period of the spiral. Our scheme is applicable to ultracold quantum gases, and might inspire future experiments in this direction.
Nanomaterials that can restrain or reduce the production of excessive reactive oxygen species such as H2O2 to defend and treat against Alzheimer's disease (AD) have attracted much attention. In this paper, we adopt the strategy of layer-by-layer deposition; namely, first synthesizing available gadolinium-doped ytterbia nanoparticles (Yb2O3:Gd NPs) as cores, and then coating them with silica via the classical Stöber method to prevent leakage and act as a carrier for subsequent ceria deposition and PEGylation, and finally obtain the expected core@shell-structured nanocomposite of PEGylated Yb2O3:Gd@SiO2@CeO2 islands. The nanomaterial has proved not only to be a high-performance dual-modal contrast agent for use in MRI and CT, but also to exhibit excellent catalase mimetic activity, which may help the prognosis, diagnosis and treatment of AD in the future. In addition, scanning electron microscopy (SEM), transmission electron microscopy (TEM), energy dispersive spectroscopy (EDS), X-ray diffraction (XRD), X-ray photoelectron spectroscopy (XPS), and Fourier transform infrared (FTIR) spectroscopy characterization have revealed the successful design and synthesis of the cores with remarkable size uniformity, with well-distributed CeO2 islands decorated on the surface of SiO2 shells, and tightly immobilized PEG.
IgA nephropathy is one of the leading causes of primary glomerulonephritis worldwide and an important etiology of renal disease in young adults. IgA nephropathy is considered an immune complex-mediated disease.
This review article summarizes recent evidence on the pathophysiology of IgA nephropathy.
Current studies indicate an ordered sequence of multi-hits as fundamental to disease occurrence. Altered glycan structures in the hinge region of the heavy chains of IgA1 molecules act as auto-antigens, potentially triggering the production of glycan-specific autoantibodies. Recognition of novel epitopes by IgA and IgG antibodies leads to the formation of immune complexes galactose deficient-IgA1/anti-glycan IgG or IgA. Immune complexes of IgA combined with FcαRI/CD89 have also been implicated in disease exacerbation. These nephritogenic immune complexes are formed in the circulation and deposited in renal mesangium. Deposited immune complexes ultimately induce glomerular injury, through the release of pro-inflammatory cytokines, secretion of chemokines and the resultant migration of macrophages into the kidney. The TfR1/CD71 receptor has a pivotal role in mesangial cells. New signaling intracellular mechanisms have also been described.
The knowledge of the whole pathophysiology of this disease could provide the rational bases for developing novel approaches for diagnosis, for monitoring disease activity, and for disease-specific treatment.
Sophoraflavanone G (SG), a prenylated flavonoid from Sophora alopecuroides, has been reported to have many pharmacological activities including anti-inflammation. However, the molecular mechanisms of its anti-inflammatory activity remain largely unclear. In this study we investigated the effects and the underlying molecular mechanisms of SG on lipopolysaccharide (LPS)-induced inflammation in RAW264.7 cells. Pretreatment with SG inhibited LPS-induced
 production of nitric oxide (NO) and prostaglandin E2 (PGE2) through reducing the expressions of inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2). SG also decreased the expressions of pro-inflammatory cytokines, tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6) and interleukin-1β (IL-1β), both in the protein and gene levels. Further experiments demonstrated that SG downregulated the LPS-induced upregulation of phosphorylated phosphoinositide-3-kinase and Akt (PI3K/Akt). SG also attenuated the expression of phosphorylated Janus kinase signal transducer and activator of transcription (JAK/STAT). In addition, SG upregulated heme oxygenase-1 (HO-1) expression via nuclear translocation of nuclear factor E2-related factor 2 (Nrf2). Taken together, SG may act as a natural agent to treat some inflammatory diseases by targeting PI3K/Akt, JAK/STAT and Nrf2/HO-1 pathways.
Objective: The extent to which childrens's welfare is compromised when they do not attend compulsory prevention medical check-ups is yet to be determined. Together with the Hessen Prevention Center for Children (Hessisches Kindervorsorgezentrum), the Child Protection Services in the Main-Taunus district have conducted a study to investigate failure to attend child preventive examinations as a possible indication of risk to the welfare of such children. Method: 605 notifications of child preventive examinations that were not carried out, sent in 2012 to the Child Protection Services by the Hessen Prevention Center for Children, were analyzed retrospectively. Each case was recorded using a standardized questionnaire and, cases that were passed on to General Social Services within Child Protection Services were investigated with an additional interview with the employee responsible. Results: In 60 (10%) cases there was no certificate to show that the check-up had been conducted, while in 165 (27%) cases the check-up was conducted late, i. e. only after being contacted by the Child Protection Services. In 9 of the 605 cases (1.5%), the families involved were already known to Child Protection Services due to previous proceedings against them under endangering children's welfare act (known as § 8a cases). No new case of a risk to children's welfare was detected. In 58 cases, families gave reasons for the missed or late check-up. Reasons included being abroad and moving house (20 cases), forgetting (14 cases) and illness (11 cases), as well as lack of knowledge of the law (6 cases), lack of health insurance (4 cases), lack of language skills (2 cases) and objection to the law in principle (1 case). It was notable that, in 57% of the cases notified, documentary evidence could be provided by the end of the case work that the check-up had taken place within the recommended period (including additional discretionary period). The majority of these notifications of failure to attend can be prevented by an upstream clearing procedure.
Reactions of bis(phosphinimino)amines LH and L'H with Me2 S⋅BH2 Cl afforded chloroborane complexes LBHCl (1) and L'BHCl (2), and the reaction of L'H with BH3 ⋅Me2 S gave a dihydridoborane complex L'BH2 (3) (LH=[{(2,4,6-Me3 C6 H2 N)P(Ph2 )}2 N]H and L'H=[{(2,6-iPr2 C6 H3 N)P(Ph2 )}2 N]H). Furthermore, abstraction of a hydride ion from L'BH2 (3) and LBH2 (4) mediated by Lewis acid B(C6 F5 )3 or the weakly coordinating ion pair [Ph3 C][B(C6 F5 )4 ] smoothly yielded a series of borenium hydride cations: [L'BH](+) [HB(C6 F5 )3 ](-) (5), [L'BH](+) [B(C6 F5 )4 ](-) (6), [LBH](+) [HB(C6 F5 )3 ](-) (7), and [LBH](+) [B(C6 F5 )4 ](-) (8). Synthesis of a chloroborenium species [LBCl](+) [BCl4 ](-) (9) without involvement of a weakly coordinating anion was also demonstrated from a reaction of LBH2 (4) with three equivalents of BCl3 . It is clear from this study that the sterically bulky strong donor bis(phosphinimino)amide ligand plays a crucial role in facilitating the synthesis and stabilization of these three-coordinated cationic species of boron. Therefore, the present synthetic approach is not dependent on the requirement of weakly coordinating anions; even simple BCl4 (-) can act as a counteranion with borenium cations. The high Lewis acidity of the boron atom in complex 8 enables the formation of an adduct with 4-dimethylaminopyridine (DMAP), [LBH⋅(DMAP)](+) [B(C6 F5 )4 ](-) (10). The solid-state structures of complexes 1, 5, and 9 were investigated by means of single-crystal X-ray structural analysis.
Rare earth elements and yttrium (REY) are raw materials of increasing importance for modern technologies, and finding new sources has become a pressing need. Acid mine drainage (AMD) is commonly considered an environmental pollution issue. However, REY concentrations in AMD can be several orders of magnitude higher than in naturally occurring water bodies. With respect to shale standards, the REY distribution pattern in AMD is enriched in intermediate and valuable REY, such as Tb and Dy. The objective of the present work is to study the behavior of REY in AMD passive-remediation systems. Traditional AMD passive remediation systems are based on the reaction of AMD with calcite-based permeable substrates followed by decantation ponds. Experiments with two columns simulating AMD treatment demonstrate that schwertmannite does not accumulate REY, which, instead, are retained in the basaluminite residue. The same observation is made in two field-scale treatments from the Iberian Pyrite Belt (IPB, southwest Spain). On the basis of the amplitude of this process and on the extent of the IPB, our findings suggest that the proposed AMD remediation process can represent a modest but suitable REY source. In this sense, the IPB could function as a giant heap-leaching process of regional scale in which rain and oxygen act as natural driving forces with no energy investment. In addition to having environmental benefits of its treatment, AMD is expected to last for hundreds of years, and therefore, the total reserves are practically unlimited.
The nonenzymatic replication of RNA is a potential transitional stage between the prebiotic chemistry of nucleotide synthesis and the canonical RNA world in which RNA enzymes (ribozymes) catalyze replication of the RNA genomes of primordial cells. However, the plausibility of nonenzymatic RNA replication is undercut by the lack of a protocell-compatible chemical system capable of copying RNA templates containing all four nucleotides. We show that short 5'-activated oligonucleotides act as catalysts that accelerate primer extension, and allow for the one-pot copying of mixed sequence RNA templates. The fidelity of the primer extension products resulting from the sequential addition of activated monomers, when catalyzed by activated oligomers, is sufficient to sustain a genome long enough to encode active ribozymes. Finally, by immobilizing the primer and template on a bead and adding individual monomers in sequence, we synthesize a significant part of an active hammerhead ribozyme, forging a link between nonenzymatic polymerization and the RNA world.
The Government of India has taken various initiatives for tobacco control by enacting comprehensive tobacco control legislation (Cigarette and Other Tobacco Products Act [COTPA], 2003).
The aim of this study was to assess the level of compliance of Sections 4, 5, 6-a, and 6-b, and 7, 8, and 9 of COTPA with respect to public places, educational institutes, point of sale (PoS), and warning on packaging (COTPA) in public places of Alwar District of Rajasthan.
A cross-sectional observational study was conducted in 2014 in Alwar city and four blocks of the district. The study was done around 365 public places for observing the compliance of Section 4 of COTPA, 357 educational institutions for observing the compliance of Section 6-b of COTPA, and 357 tobacco retailers for observing the compliance of Sections 5 and 6-a of COTPA.
The criteria for the evaluation (the core indicators) and decision criteria for a district to qualify for the "Smoke free" status include six parameters. From the total of 365 places visited, 90% places displayed the "No-smoking" signage and out of total 328 places, 99% were as per the COTPA specification. Alwar city, Ramgarh, Thanagaji, and Alwar rural block followed the compliance of Section 4. The PoS visited Alwar district displayed 93% (332) signage and all the displayed signage followed the COTPA compliance. In Alwar city, Thanagaji, Ramgarh, and Alwar rural block, the compliance of Section 6-a was above 90%. The compliance of Section 6-b was above 90% in Alwar city, Ramgarh, Thanagaji, and Alwar rural block. Ninety-three percent (332) of the PoS did not display tobacco advertisement in Alwar district, which is a positive sign of COTPA compliance.
This finding suggest a high level of compliance of Section 4, Section 5, Section 6-a, and Section 6-b of COTPA at Alwar district.
Aptamers are single-stranded nucleic acids or peptides identified from a randomized combinatorial library through specific interaction with the target of interest. Targets can be of any size, from small molecules to whole cells, attesting to the versatility of aptamers for binding a wide range of targets. Aptamers show drug properties that are analogous to antibodies, with high specificity and affinity to their target molecules. Aptamers can penetrate disease-causing microbial and mammalian cells. Generated aptamers that target surface biomarkers act as cell-targeting agents and intracellular delivery vehicles. Within this context, the "cell-internalizing aptamers" are widely investigated via the process of cell uptake with selective binding during in vivo systematic evolution of ligands by exponential enrichment (SELEX) or by cell-internalization SELEX, which targets cell surface antigens to be receptors. These internalizing aptamers are highly preferable for
 the localization and functional analyses of multiple targets. In this overview, we discuss the ways by which internalizing aptamers are generated and their successful applications. Furthermore, theranostic approaches featuring cell-internalized aptamers are discussed with the purpose of analyzing and diagnosing disease-causing pathogens.
An analysis of the risk factors and seasonal and spatial distribution of individuals with subclinical malaria in hypoendemic Bangladesh was performed.
From 2009 to 2012, active malaria surveillance without regard to symptoms was conducted on a random sample (n=3971) and pregnant women (n=589) during a cohort malaria study in a population of 24000.
The overall subclinical Plasmodium falciparum malaria point prevalence was 1.0% (n=35), but was 3.2% (n=18) for pregnant women. The estimated incidence was 39.9 per 1000 person-years for the overall population. Unlike symptomatic malaria, with a marked seasonal pattern, subclinical infections did not show a seasonal increase during the rainy season. Sixty-nine percent of those with subclinical P. falciparum infections reported symptoms commonly associated with malaria compared to 18% without infection. Males, pregnant women, jhum cultivators, and those living closer to forests and at higher elevations had a higher prevalence of subclinical infection.
Hypoendemic subclinical malaria infections were associated with a number of household and demographic factors, similar to symptomatic cases. Unlike clinical symptomatic malaria, which is highly seasonal, these actively detected infections were present year-round, made up the vast majority of infections at any given time, and likely acted as reservoirs for continued transmission.
Homelessness is present in most societies and represents a situation in which the basic needs for survival including food are often limited. It is logical to surmise that the homeless person's diet is likely to be nutritionally deficient and yet there is a relative paucity in research regarding this issue with studies varying in both their methodology and homeless population. Despite these differences, diets of the homeless are frequently characterised as high in saturated fat and deficient in fibre and certain micronutrients, all of which can have negative implications for the homeless individual's health and/or mental state. The conclusion from intervention studies is that there is no consensus as to the most effective method for assessing dietary intake. In order to address this, the present review aims to provide a greater understanding of the existing literature surrounding nutrition and the homeless and to act as a foundation from which further research can be conducted. An evaluation of the main findings and challenges surrounding the assessment of the nutritional status of the homeless will be provided followed by a review of the physical and mental consequences of the homeless diet. Current and potential interventions aimed at increasing the nutritional quality of food consumed by the homeless will be addressed with a focus on the role of the nutritional science community in assisting in this endeavour.
In Saccharomyces cerevisiae, proline is a stress protectant interacting with other substrate uptake systems against oxidative stress under low pH conditions. In this study, we performed metabolomics analysis to investigate the response associated with an increase in cell growth rates and maximum densities when cells were treated with proline under normal and acid stress conditions. Metabolome data show that concentrations of components of central metabolism are increased in proline-treated S. cerevisiae. No consumption of proline was observed, suggesting that proline does not act as a nutrient but regulates metabolic state and growth of cells. Treatment of lactic acid-producing yeast with proline during lactic acid bio-production improved growth rate and increased the final concentration of lactic acid.
Physical inactivity is a well-known public health risk that should be monitored at the population level. Physical activity levels are often surveyed across Europe. This systematic literature review aims to provide an overview of all existing cross-European studies that assess physical activity in European adults, describe the variation in population levels according to these studies, and discuss the impact of the assessment methods.
Six literature databases (PubMed, EMBASE, CINAHL, PsycINFO, SportDiscus and OpenGrey) were searched, supplemented with backward- and forward tracking and searching authors' and experts' literature databases. Articles were included if they reported on observational studies measuring total physical activity and/or physical activity in leisure time in the general population in two or more European countries. Each record was reviewed, extracted and assessed by two independent researchers and disagreements were resolved by a third researcher. The review protocol of this review is registered in the PROSPERO database under registration number CRD42014010334.
Of the 9,756 unique identified articles, twenty-five were included in this review, reporting on sixteen different studies, including 2 to 35 countries and 321 to 274,740 participants. All but two of the studies used questionnaires to assess physical activity, with the majority of studies using the IPAQ-short questionnaire. The remaining studies used accelerometers. The percentage of participants who either were or were not meeting the physical activity recommendations was the most commonly reported outcome variable, with the percentage of participants meeting the recommendations ranging from 7% to 96% across studies and countries.
The included studies showed substantial variation in the assessment methods, reported outcome variables and, consequently, the presented physical activity levels. Because of this, absolute population levels of physical activity in European adults are currently unknown. However, when ranking countries, Ireland, Italy, Malta, Portugal, and Spain generally appear to be among the less active countries. Objective data of adults across Europe is currently limited. These findings highlight the need for standardisation of the measurement methods, as well as cross-European monitoring of physical activity levels.
The built-in piezoelectric fields in group III-nitrides can act as road blocks on the way to maximizing the efficiency of opto-electronic devices. In order to overcome this limitation, a proper characterization of these fields is necessary. In this work nano-beam electron diffraction in scanning transmission electron microscopy mode has been used to simultaneously measure the strain state and the induced piezoelectric fields in a GaN/AlN multiple quantum well system.
Sedentary behaviour is increasingly recognized as a public health risk that needs to be monitored at the population level. Across Europe, there is increasing interest in assessing population levels of sedentary time. This systematic literature review aims to provide an overview of all existing cross-European studies that measure sedentary time in adults, to describe the variation in population levels across these studies and to discuss the impact of assessment methods.
Six literature databases (PubMed, EMBASE, CINAHL, PsycINFO, SportDiscus and OpenGrey) were searched, supplemented with backward- and forward tracking and searching authors' and experts' literature databases. Articles were included if they reported on observational studies measuring any form of sedentary time in the general population in two or more European countries. Each record was reviewed, extracted and assessed by two independent researchers, and disagreements were resolved by a third researcher. The review protocol of this review is registered in the PROSPERO database under registration number CRD42014010335.
Of the 9,756 unique articles that were identified in the search, twelve articles were eligible for inclusion in this review, reporting on six individual studies and three Eurobarometer surveys. These studies represented 2 to 29 countries, and 321 to 65,790 participants. Eleven studies focused on total sedentary time, while one studied screen time. The majority of studies used questionnaires to assess sedentary time, while two studies used accelerometers. Total sedentary time was reported most frequently and varied from 150 (median) to 620 (mean) minutes per day across studies and countries.
One third of European countries were not included in any of the studies. Objective measures of European adults are currently limited, and most studies used single-item self-reported questions without assessing sedentary behaviour types or domains. Findings varied substantially between studies, meaning that population levels of sedentary time in European adults are currently unknown. In general, people living in northern Europe countries appear to report more sedentary time than southern Europeans. The findings of this review highlight the need for standardisation of the measurement methods and the added value of cross-European surveillance of sedentary behaviour.
There are different genetic patterns for cardio-metabolic parameters among different populations. Additionally, it has been found that ancestral genetic components (the proportion of Amerindian, European and African) in admixed Latin American populations influence an individual's susceptibility to cardio-metabolic disorders. The aim of this study was to evaluate the effect of ancestral genetic composition on a series of cardio-metabolic risk factors in a young admixed population from Colombia.
In a sample of 853 Colombian youth, 10 to 18 years old, the mean European contribution was 66.6 % (range: 41-82 %), the mean African contribution was 14 % (range: 4-48 %), and the mean Amerindian contribution was 19.4 % (range: 10-35 %)
 using a panel of 40 autosomal ancestry-informative markers (AIMs). We assessed the degree of association between ancestral African, Amerindian and European genetic components and measures of body mass index, waist circumference, fasting glucose, fasting insulin, insulin resistance, triglycerides, high-density lipoprotein, and systolic and diastolic blood pressure. Two of the nine measures assessed presented a nominal significant association with ancestral components after adjusting for confounding variables: triglyceride levels were associated with the Amerindian component (OR = 1.06, 98.3 % CI = 1.01-1.11, P = 0.002) and systolic blood pressure was associated with the European component (OR = 0.93, 98.3 % CI = 0.87 to 0.99, P = 0.008) and the African component (OR = 1.07, CI = 1.01-1.14 P = 0.008), although it was not significant following a global Bonferroni correction. Additionally, insulin levels and insulin resistance showed associations with the African component.
Our findings support the idea that an Amerindian ancestral component may act as a risk factor for high triglyceride levels. In addition, an African ancestral component confers a risk for high systolic blood pressure, and a European ancestry serves as a protective factor for this condition in a young admixed population from Colombia. However, these results should be confirmed in a larger population.
Regular physical activity is associated with physical, social and mental health benefits, whilst insufficient physical activity is associated with several negative health outcomes (e.g. metabolic problems). Population monitoring of physical activity is important to gain insight into prevalence of compliance to physical activity recommendations, groups at risk and changes in physical activity patterns. This review aims to provide an overview of all existing studies that measure physical activity in youth, in cross-European studies, to describe the variation in population levels of physical activity and to describe and define challenges regarding assessment methods that are used.
A systematic search was performed on six databases (PubMed, EMBASE, CINAHL, PsycINFO, SportDiscus and OpenGrey), supplemental forward- and backward tracking was done and authors' and experts' literature databases were searched to identify relevant articles. Journal articles or reports that reported levels of physical activity in the general population of youth from cross-European studies were included. Data were reviewed, extracted and assessed by two researchers, with disagreements being resolved by a third researcher. The review protocol of this review is published under registration number CRD42014010684 in the PROSPERO database.
The search resulted in 9756 identified records of which 30 articles were included in the current review. This review revealed large differences between countries in prevalence of compliance to physical activity recommendations (i.e. 60 min of daily moderate- to vigorous-intensity physical activity (MVPA)) measured subjectively (5-47%) and accelerometer measured minutes of MVPA (23-200 min). Overall boys and children were more active than girls and adolescents. Different measurement methods (subjective n = 12, objective n = 18) and reported outcome variables (n = 17) were used in the included articles. Different accelerometer intensity thresholds used to define MVPA resulted in substantial differences in MVPA between studies conducted in the same countries when assessed objectively.
Reported levels of physical activity and prevalence of compliance to physical activity recommendations in youth showed large variation across European countries. This may reflect true variation in physical activity as well as variation in assessment methods and reported outcome variables. Standardization across Europe, of methods to assess physical activity in youth and reported outcome variables is warranted, preferably moving towards a pan-European surveillance system combining objective and self-report methods.
Arrestins desensitize G protein-coupled receptors (GPCRs) and act as mediators of signalling. Here we investigated the interactions of arrestin-1 with two functionally distinct forms of the dim-light photoreceptor rhodopsin. Using unbiased scanning mutagenesis we probed the individual contribution of each arrestin residue to the interaction with the phosphorylated apo-receptor (Ops-P) and the agonist-bound form (Meta II-P). Disruption of the polar core or displacement of the C-tail strengthened binding to both receptor forms. In contrast, mutations of phosphate-binding residues (phosphosensors) suggest the phosphorylated receptor C-terminus binds arrestin differently for Meta II-P and Ops-P. Likewise, mutations within the inter-domain interface, variations in the receptor-binding loops and the C-edge of arrestin reveal different binding modes. In summary, our results indicate that arrestin-1 binding to Meta II-P and Ops-P is similarly dependent on arrestin activation, although the complexes formed with these two receptor forms are structurally distinct.
A high amount of sedentary time has been proposed as a risk factor for various health outcomes in adults. While the evidence is less clear in children and adolescents, monitoring sedentary time is important to understand the prevalence rates and how this behaviour varies over time and by place. This systematic literature review aims to provide an overview of existing cross-European studies on sedentary time in children (0-12y) and adolescents (13-18y), to describe the variation in population levels of sedentary time, and to discuss the impact of assessment methods.
Six literature databases were searched (PubMed, EMBASE, CINAHL, PsycINFO, SportDiscus and OpenGrey), followed by backward- and forward tracking and searching authors' and experts' literature databases. Included articles were observational studies reporting on levels of sedentary time in the general population of children and/or adolescents in at least two European countries. Population levels were reported separately for children and adolescents. Data were reviewed, extracted and assessed by two researchers, with disagreements being resolved by a third researcher. The review protocol is published under registration number CRD42014013379 in the PROSPERO database.
Forty-two eligible articles were identified, most were cross-sectional (n = 38). The number of included European countries per article ranged from 2 to 36. Levels of sedentary time were observed to be higher in East-European countries compared to the rest of Europe. There was a large variation in assessment methods and reported outcome variables. The majority of articles used a child-specific questionnaire (60%). Other methods included accelerometers, parental questionnaires or interviews and ecological momentary assessment tools. Television time was reported as outcome variable in 57% of included articles (ranging from a mean value of 1 h to 2.7 h in children and 1.3 h to 4.4 h in adolescents), total sedentary time in 24 % (ranging from a mean value of 192 min to 552 min in children and from 268 min to 506 min in adolescents).
A substantial number of published studies report on levels of sedentary time in children and adolescents across European countries, but there was a large variation in assessment methods. Questionnaires (child specific) were used most often, but they mostly measured specific screen-based activities and did not assess total sedentary time. There is a need for harmonisation and standardisation of objective and subjective methods to assess sedentary time in children and adolescents to enable comparison across countries.
Despite widespread use of transjugular intrahepatic portosystemic shunt (TIPS) for treatment of portal hypertension, a paucity of nationwide data exists on predictors of the economic impact related to TIPS.
Using the National Inpatient Sample (NIS) database from 2001 to 2012, we aimed to evaluate factors contributing to hospital cost of patients admitted to US hospitals for TIPS.
Using the NIS, we identified a discharge-weighted national estimate of 61,004 TIPS procedures from 2001 to 2012. Through independent sample analysis, we determined profile factors related to increases in hospital costs.
Of all TIPS cases, the mean charge adjusted for inflation to the year 2012 is $125,044 ± $160,115. The mean hospital cost adjusted for inflation is $44,901 ± $54,565. Comparing pre- and post-2005, mean charges and cost have increased considerably ($98,154 vs. $142,652, p < 0.001 and $41,656 vs. $46,453, p < 0.001, respectively). Patients transferred from a different hospital, weekend admissions, Asian/Pacific Islander patients, and hospitals in the Northeastern and Western region had higher cost. Number of diagnoses and number of procedures show positive correlations with hospital cost, with number of procedures exhibiting stronger relationships (Pearson 0.613). Comorbidity measures with highest increases in cost were pulmonary circulation disorders ($32,157 increase, p < 0.001).
The cost of the TIPS procedure is gradually rising for hospitals. Alongside recent healthcare reform through the Affordable Care Act, measures to reduce the economic burden of TIPS are of increasing importance. Data from this study are intended to aid physicians and hospitals in identifying improvements that could reduce hospital costs.
Adipogenesis is a physiological process required for fat-tissue development, mainly involved in regulating the organism energetic-state. Abnormal distribution-changes and dysfunctions in such tissue are associated to different pathologies. Adipocytes are generated from progenitor cells, via a complex differentiating process not yet well understood. Therefore, we investigated differential mRNA and miRNA expression patterns of human mesenchymal stromal-cells (MSC)
 induced and not induced to differentiate into adipocytes by next (second)-generation sequencing. A total of 2,866 differentially expressed genes (101 encoding miRNA) were identified, with 705 (46 encoding miRNA) being upregulated in adipogenesis. They were related to different pathways, including PPARG, lipid, carbohydrate and energy metabolism, redox, membrane-organelle biosynthesis, and endocrine system. Downregulated genes were related to extracellular matrix and cell migration, proliferation, and differentiation. Analyses of mRNA-miRNA interaction showed that repressed miRNA-encoding genes can act downregulating PPARG-related genes; mostly the PPARG activator (PPARGC1A). Induced miRNA-encoding genes regulate downregulated genes related to TGFB1. These results shed new light to understand adipose-tissue differentiation and physiology, increasing our knowledge about pathologies like obesity, type-2 diabetes and osteoporosis. J. Cell. Physiol. 9999: 1-14, 2016. © 2016 Wiley Periodicals, Inc.
Maintaining reactive oxygen species (ROS) homeostasis plays a central role in plants, and is also critical for plant root development. Threshold levels of ROS act as signals for elongation and differentiation of root cells. The protein phosphatase LIKE SEX FOUR2 (LSF2) has been reported to regulate starch metabolism in Arabidopsis, but little is known about the mechanism how LSF2 affect ROS homeostasis. Here, we identified that LSF2 function as a component modulating ROS homeostasis in response to oxidative stress and, thus regulate root development. Compared with wild type Arabidopsis, lsf2-1 mutant exhibited reduced rates of superoxide generation and higher levels of hydrogen peroxide upon oxidative stress treatments. The activities of several antioxidant enzymes, including superoxide dismutase, catalase, and ascorbate peroxidase, were also affected in lsf2-1 mutant under these oxidative stress conditions. Consequently, lsf2-1 mutant exhibited the reduced root growth but less inhibition of root hair formation compared to wild type Arabidopsis plants. Importantly, protein phosphatase LSF2 interacted with mitogen-activated protein kinase 8 (MPK8), a known component of ROS homeostasis pathways in the cytoplasm. These findings indicated the novel function of LSF2 that controls ROS homeostasis to regulate root development.
Graphene has unique physical and chemical properties, making it appealing for a number of applications in optoelectronics, sensing, photonics, composites, and smart coatings, just to cite a few. These require the development of production processes that are inexpensive and up-scalable. These criteria are met in liquid-phase exfoliation (LPE), a technique that can be enhanced when specific organic molecules are used. Here we report the exfoliation of graphite in N-methyl-2-pyrrolidinone, in the presence of heneicosane linear alkanes terminated with different head groups. These molecules act as stabilizing agents during exfoliation. The efficiency of the exfoliation in terms of the concentration of exfoliated single- and few-layer graphene flakes depends on the functional head group determining the strength of the molecular dimerization through dipole-dipole interactions. A thermodynamic analysis is carried out to interpret the impact of the termination group of the alkyl chain on the exfoliation yield. This combines molecular dynamics and molecular mechanics to rationalize the role of functionalized alkanes in the dispersion and stabilization process, which is ultimately attributed to a synergistic effect of the interactions between the molecules, graphene, and the solvent.
Food supply and consumption are critical for sustaining urban system functions, and are key determinants of the quantity and pathways of nutrient flow in cities. Nutrient elements from urban food consumption are becoming major pollutant sources in urban environments. Therefore, understanding flow magnitude and pathways, the role of a growing population, and changing dietary structure and technology in future nutrient metabolism are essential to understand cities as ecosystems and urban environmental management. Taking the city of Xiamen, a rapid urbanizing area of Southeast China as a case study, we simulated urban metabolism of three major food-sourced nutrient elements (carbon, nitrogen, and phosphorus or CNP) over 1991-2010 and environmental emissions. Impacts of future population growth, dietary habit change, and waste treatment improvement on various environments were forecast by scenario analysis. A sensitivity analysis was conducted to test how different waste treatment technologies affect environmental emissions from food-sourced nutrients. Our results show that the food-sourced CNP had various metabolic fluxes through urban systems, with carbon mostly emitted into the air and nitrogen and phosphorus mostly discharged into landfills and water. Population growth and dietary structure change will accelerate increases of nutrient emissions to the environment, whereas enhancing current waste treatment technology can just alter emissions to different environments. Based on the results, we discuss how food-sourced nutrient metabolism can be better managed, to enhance connectivity between cities and their hinterlands and maintain environmental emissions within the carrying capacity of the cities.
Behavioral learning has been shown to involve changes in the function and structure of synaptic connections of the central nervous system (CNS). On the other hand, the neuronal circuitry in the mature brain is characterized by a high degree of stability possibly providing a correlate for long-term storage of information. This observation indicates the requirement for a set of molecules inhibiting plasticity and promoting stability thereby providing temporal and spatial specificity to plastic processes. Indeed, signaling of Nogo-A via its receptors has been shown to play a crucial role in restricting activity-dependent functional and structural plasticity in the adult CNS. However, whether Nogo-A controls learning and memory formation and what are the cellular and molecular mechanisms underlying this function is still unclear. Here we show that Nogo-A signaling controls spatial learning and reference memory formation upon training in the Morris water maze and negatively modulates structural changes at spines in the mouse hippocampus. Learning processes and the correlated structural plasticity have been shown to involve changes in excitatory as well as in inhibitory neuronal connections. We show here that Nogo-A is highly expressed not only in excitatory, but also in inhibitory, Parvalbumin positive neurons in the adult hippocampus. By this means our current and previous data indicate that Nogo-A loss-of-function positively influences spatial learning by priming the neuronal structure to a higher plasticity level. Taken together our results link the role of Nogo-A in negatively regulating plastic processes to a physiological function in controlling learning and memory processes in the mature hippocampus and open the interesting possibility that it might mainly act by controlling the function of the hippocampal inhibitory circuitry.
Hydroxypropyl cellulose (HPC) and ethyl cellulose (EC) can be used for extended release coatings, where the water-soluble HPC may act as a pore former. The aim was to investigate the effect of the molecular weight of HPC on the microstructure and mass transport in phase-separated freestanding EC/HPC films with 30% w/w HPC. Four different HPC grades were used, with weight averaged molecular weights (Mw) of 30.0 (SSL), 55.0 (SL), 83.5 (L) and 365 (M) kg/mol. Results showed that the phase-separated structure changed from HPC-discontinuous to bicontinuous with increasing Mw of HPC. The film with the lowest Mw HPC (SSL) had unconnected oval-shaped HPC-rich domains, leaked almost no HPC and had the lowest water permeability. The remaining higher Mw films had connected complex-shaped pores, which resulted in higher permeabilities. The highest Mw film (M) had the smallest pores and very slow HPC leakage, which led to a slow increase in permeability. Films with grade L and SL released most of their HPC, yet the permeability of the L film was three times higher due to greater pore connectivity. It was concluded that the phase-separated microstructure, the level of pore percolation and the leakage rate of HPC will be affected by the choice of HPC Mw grade used in the film and this will in turn have strong impact on the film permeability.
Endocrine disruptors (EDs) are pollutants that alter the endocrine system and are involved in carcinogenesis. EDs have multiple and complex levels of action. They can affect the synthesis, release and transport of natural hormones. In target tissues, EDs can reduce or increase the effects of natural hormones on their receptors and change signaling cascades. When ED exposure happens at critical periods of life, from embryo to puberty, they can act at doses considered safe for an adult. Furthermore, their epigenetic effects can also influence the cancer risk of future generations. The cancer mechanisms of known EDs are hereby reviewed, There are thousands of newly introduced substances whose potential endocrine-disrupting and cancer effects are completely unknown. Although there are still gaps in our knowledge, these data support the urgent need for health and environmental policies aimed at protecting the public and in particular, the developing fetus and women of reproductive age.
Microglia and peripheral monocytes contribute to hypersensitivity in rodent models of neuropathic pain. However, the precise respective function of microglia and peripheral monocytes has not been investigated in these models. To address this question, here we combined transgenic mice and pharmacological tools to specifically
 and temporally control the depletion of microglia and monocytes in a mouse model of spinal nerve transection (SNT). We found that although microglia and monocytes are required during the initiation of mechanical allodynia or thermal hyperalgesia, these cells may not be as important for the maintenance of hypersensitivity. Moreover, we demonstrated that either resident microglia or peripheral monocytes are sufficient in gating neuropathic pain after SNT. We propose that resident microglia and peripheral monocytes act synergistically to initiate hypersensitivity and promote the transition from acute to chronic pain after peripheral nerve injury.
Shigella spp. are the primary causative agents of bacillary dysentery. Since its emergence in the late 1980s, the S. flexneri serotype 1c remains poorly understood, particularly with regard to its origin and genetic evolution. This article provides a molecular insight into this novel serotype and the gtrIC gene cluster that determines its unique immune recognition.
A PCR of the gtrIC cluster showed that serotype 1c isolates from different geographical origins were genetically conserved. An analysis of sequences flanking the gtrIC cluster revealed remnants of a prophage genome, in particular integrase and tRNA(Pro) genes. Meanwhile, Southern blot analyses on serotype 1c, 1a and 1b strains indicated that all the tested serotype 1c strains may have had a common origin that has since remained distinct from the closely related 1a and 1b serotypes. The identification of prophage genes upstream of the gtrIC cluster is consistent with the notion of bacteriophage-mediated integration of the gtrIC cluster into a pre-existing serotype.
This is the first study to show that serotype 1c isolates from different geographical origins share an identical pattern of genetic arrangement, suggesting that serotype 1c strains may have originated from a single parental strain. Analysis of the sequence around the gtrIC cluster revealed a new site for the integration of the serotype converting phages of S. flexneri. Understanding the origin of new pathogenic serotypes and the molecular basis of serotype conversion in S. flexneri would provide information for developing cross-reactive Shigella vaccines.
External ventricular drains (EVD) are crucial for the emergency management of hydrocephalus and raised intracranial pressure. Infection is the most morbid and costly cause of EVD malfunction and can cost up to $50,000 US to treat per case. In 2007, Canberra Hospital changed EVD management protocols requiring set-up of EVD transducer systems in theatre, cessation of prophylactic antibiotics after 24hours, cerebrospinal fluid (CSF) samples second or third daily and discontinuation of elective EVD changes. The current study aimed to retrospectively audit EVD inserted between 2006 and 2010 in order to determine the impact of these changes. There was a non-significant downward trend in infection rates from 20.93% to 11.50% (p=0.343) after the protocol changes. Patient age (OR=1.032, p=0.064, confidence interval (CI): 0.998-1.067) and sex (OR=1.405, p=0.595, CI: 0.401-4.917) were not significantly associated with infection. However, multiple drains were associated with a significant increase in infections rates (OR=21.96, p=0.001, CI: 6.103-79.023) and systemic perioperative antibiotic prophylaxis was associated with decreased rates of infections (OR=0.269, p=0.044, CI: 0.075-0.964). Our study showed a non-significant downwards trend in infections with introduction of changes to hospital protocol and illustrated some risk factors for infection in the Australian setting.
Smart drug delivery systems (DDSs) have attracted the attention of many scientists, as carriers that can be stimulated by changes in environmental parameters such as temperature, pH, light, electromagnetic fields, mechanical forces, etc. These smart nanocarriers can release their cargo on demand when their target is reached and the stimulus is applied. Using the techniques of nanotechnology, these nanocarriers can be tailored to be target-specific, and exhibit delayed or controlled release of drugs. Temperature-responsive nanocarriers are one of most important groups of smart nanoparticles (NPs) that have been investigated during the past decades. Temperature can either act as an external stimulus when heat is applied from the outside, or can be internal when pathological lesions have a naturally elevated termperature. A low critical solution temperature (LCST) is a special feature of some polymeric materials, and most of the temperature-responsive nanocarriers have been designed based on this feature. In this review, we attempt to summarize recent efforts to prepare innovative temperature-responsive nanocarriers and discuss their novel applications.
A significant amount of experimental evidence suggests that G-protein coupled receptors (GPCRs) do not act exclusively as monomers but also form biologically relevant dimers and oligomers. However, the structural determinants, stoichiometry and functional importance of GPCR oligomerization remain topics of intense speculation. In this study we attempted to evaluate the nature and dynamics of GPCR oligomeric interactions. A representative set of GPCR homodimers were studied through Coarse-Grained Molecular Dynamics simulations, combined with interface analysis and concepts from network theory for the construction and analysis of dynamic structural networks. Our results highlight important structural determinants that seem to govern receptor dimer interactions. A conserved dynamic behavior was observed among different GPCRs, including receptors belonging in different GPCR classes. Specific GPCR regions were highlighted as the core of the interfaces. Finally, correlations of motion were observed between parts of the dimer interface and GPCR segments participating in ligand binding and receptor activation, suggesting the existence of mechanisms through which dimer formation may affect GPCR function. The results of this study can be used to drive experiments aimed at exploring GPCR oligomerization, as well as in the study of transmembrane protein-protein interactions in general.
One hypothesis to explain the blue-green colour of the eggs of many bird species is that it is a sexually-selected signal of the laying female's quality, which males use to determine their investment. This hypothesis requires that eggshell pigmentation carries a cost or is otherwise linked to female quality. One potential cost is that biliverdin, a haem derivative and the pigment responsible for eggshell colouration, is limiting. To assess this potential cost, we attempted to manipulate haematocrit and haemoglobin in free-living European starlings (Sturnus vulgaris Linnaeus). Upon collecting unmanipulated first clutches, we treated females with phenylhydrazine (PHZ), a haemolytic agent, and measured the blue-green chroma and reproductive performance of replacement clutches. We also investigated whether eggshell colour was associated with haematocrit or haemoglobin levels in unmanipulated first clutches. To test whether eggshell colour might act as a sexual signal, we examined associations between eggshell colour and reproductive performance, as well as the provisioning rate of the male.
PHZ-treatment did not affect eggshell colour in replacement clutches. In unmanipulated first clutches, eggshell colour was not correlated with haematocrit or haemoglobin levels. Eggshell colour was correlated with female mass in unmanipulated first clutches but not replacement clutches. Chicks from eggs with higher eggshell colour had higher haemoglobin levels and longer tarsi just prior to fledging, suggesting that eggshell colour could reflect brood quality. However, eggshell colour was not correlated with the provisioning rate of the male or any other measure of reproductive performance.
We found no evidence to support the hypothesis that the availability of resources required for the synthesis of pigment limits eggshell colour in European starlings, or that eggshell colour is used by males to determine their level of reproductive investment. We found little evidence that eggshell colour is correlated with female or offspring quality in this species.
We demonstrated previously that phosphocholine and phosphocholine-modified macromolecules efficiently inhibit ATP-dependent release of interleukin-1β from human and murine monocytes by a mechanism involving nicotinic acetylcholine receptors (nAChR). Interleukin-1β is a potent pro-inflammatory cytokine of innate immunity that plays pivotal roles in host defence. Control of interleukin-1β release is vital as excessively high systemic levels cause life threatening inflammatory diseases. In spite of its structural similarity to acetylcholine, there are no other reports on interactions of phosphocholine with nAChR. In this study, we demonstrate that phosphocholine inhibits ion-channel function of ATP receptor P2X7 in monocytic cells via nAChR containing α9 and α10 subunits. In stark contrast to choline, phosphocholine does not evoke ion current responses in Xenopus laevis oocytes, which heterologously express functional homomeric nAChR composed of α9 subunits or heteromeric receptors containing α9 and α10 subunits. Preincubation of these oocytes with phosphocholine, however, attenuated choline-induced ion current changes, suggesting that phosphocholine may act as a silent agonist. We conclude that phophocholine activates immuno-modulatory nAChR expressed by monocytes but does not stimulate canonical ionotropic receptor functions.
We previously reported that passage of the 2013 Psychoactive Substances Act (PSA), which limited retail availability of synthetic cannabinoids (SCs), was followed by reduced numbers of presentations to one psychiatric emergency service. This analysis examined national trends
 in hospital presentations associated with use of SCs, and how these changed after passage of laws in 2011, 2013 and 2014, that altered SC availability.
Analysis of 2011-2015 Ministry of Health dataset of patients presenting to hospital associated with use of SCs. The relationship between changes in hospital presentations and the 3 legislative changes was evaluated using time series models.
Monthly hospital presentations peaked in mid-2011, 2013 and 2014. Steep declines in numbers of presentations occurred after law changes between August and September 2011 (current SCs removed from sale), July and August 2013 (reduced number of SC retail outlets), and May and June 2014 (all SCs banned). The 2013 reduction in supply was associated with mean monthly presentations decreasing by 10.6 (95% CI 1.5, 19.7; p=0.023). Patients were predominantly young males, and presented with a range of emotional, psychotic and behavioural symptoms.
Law changes that reduced SC availability were associated with reduced harms (hospitalisation) associated with use of SCs.
Non-alcoholic fatty liver disease (NAFLD) is considered the most common manifestation of metabolic syndrome. One of its most important features is the accumulation of triglycerides in the hepatocyte cells. Thiazolidinediones (TZDs) act as insulin sensitizers and are used to treat patients with type 2 diabetes and other conditions that are resistant to insulin, such as hepatic steatosis. Controversially, TZDs are also associated with the development of cardiovascular events and liver problems. For this reason, new therapeutic strategies are necessary to improve liver function in patients with chronic liver diseases. The aim of the present study was to evaluate the effects of LPSF/GQ-02 on the liver lipid metabolism in a murine model of NAFLD. Eighty male LDLR-/- mice were divided into 3 groups: 1-fed with a high-fat diet (HFD); 2-HFD+Pioglitazone (20mg/kg/day); 3-HFD+LPSF/GQ-02 (30mg/kg/day). The experiments lasted 12 weeks and drugs were administered daily by gavage in the final four weeks. The liver was processed for optical microscopy, Oil Red O, immunohistochemistry, immunofluorescence and western blot analysis. LPSF/GQ-02 effectively decreased fat accumulation, increased the hepatic levels of p-AMPK, FoxO1, ATGL, p-ACC and PPARα, and reduced the expression of LXRα, SREBP-1c and ACC. These results suggest that LPSF/GQ-02 acts directly on the hepatic lipid metabolism through the activation of the PPAR-α/AMPK/FoxO1/ATGL lipolytic pathway, and the inhibition of the AMPK/LXR/SREBP-1c/ACC/FAS lipogenic pathway.
The Dutch Euthanasia Act seems to be set in stone. Since it took effect in 2002, it has not seen any significant amendments. Recent developments, however, indicate that a major component of the act-the review procedure-is due for revision. The review practice of the regional euthanasia review committees-responsible for applying and interpreting the law-now also extends to instances of euthanasia and assisted suicide for special categories of patients: psychiatric patients, patients with early-stage dementia, and patients whose suffering is derived from a combination of medical and existential causes. In this article, it is argued that a reconsideration of the review practice for these new cases is necessary primarily because review committees lack the legitimacy needed for the development of policies with such a large impact on society.
In 2011, Frank Van Den Bleeken became the first detainee to request euthanasia under Belgium's Euthanasia Act of 2002. This article investigates whether it would be lawful and morally permissible for a doctor to accede to this request. Though Van Den Bleeken has not been held accountable for the crimes he committed, he has been detained in an ordinary prison, without appropriate psychiatric care, for more than 30 years. It is first established that Van Den Bleeken's euthanasia request plausibly meets the relevant conditions of the Euthanasia Act and that, consequently, a doctor could lawfully fulfill it. Next, it is argued that autonomy-based reasons for euthanizing him outweigh complicity-based reasons against doing so, and that, therefore, it is also morally permissible for a doctor to carry out the euthanasia request.
For several years after the reinstitution of a pharmaceutical patent regime in India, most innovator pharmaceutical companies have faced a string of high-profile defeats during litigation in India. In the last 2 years, however, the fortunes of pharmaceutical patentees have changed dramatically. Not only have Indian courts enforced pharmaceutical patents and issued injunctions restraining Indian generic companies from infringing valid patents, but they have also refused to invoke 'public interest' arguments to delay the enforcement of patents. This string of victories for pharmaceutical patents indicates a new era for the innovator industry in India. These victories for the innovator industry demonstrate the objectivity of the Indian judiciary. Even on the issue of compulsory licensing, the Patent Office, which functions as a part of the central government, has been restrained - granting only one compulsory license for a drug owned by Bayer but declining two other similar requests. Similarly, even the Indian judiciary while enforcing patents has also remained sensitive to the flexibilities in the Patents Act, such as the 'Bolar-type' provisions and compulsory licensing provisions.
Mucosal HIV-1 transmission is inefficient. However, certain viral and host characteristics may play a role in facilitating HIV acquisition and systemic expansion. Cells expressing high levels of integrin α4β7 have been implicated in favoring the transmission process and the infusion of an anti-α4β7 mAb (RM-Act-1) prior to, and during a repeated low-dose vaginal challenge (RLDC) regimen with SIVmac251 reduced SIV acquisition and protected the gut-associated lymphoid tissues (GALT) in the macaques that acquired SIV. α4β7 expression is required for lymphocyte trafficking to the gut lamina propria and gut inductive sites. Several therapeutic strategies that target α4β7 have been shown to be effective in treating inflammatory conditions of the intestine, such as inflammatory bowel disease (IBD). To determine if blocking α4β7 with ELN, an orally available anti-α4 small molecule, would inhibit SHIV-SF162P3 acquisition, we tested its ability to block MAdCAM-1 (α4β7 natural ligand) and HIV-gp120 binding in vitro. We studied the pharmacokinetic profile of ELN after oral and vaginal delivery in macaques. Twenty-six macaques were divided into 3 groups: 9 animals were treated with ELN orally, 9 orally and vaginally and 8 were used as controls. All animals were challenged intra-vaginally with SHIV-SF162P3 using the RLDC regimen. We found that ELN did not protect macaques from SHIV acquisition although it reduced the SHIV-induced inflammatory status during the acute phase of infection. Notably, integrins can exist in different activation states and, comparing the effect of ELN and the anti-α4β7 mAb RM-Act-1 that reduced susceptibility to SIV infection, we determined that ELN induces the active conformation of α4β7, while RM-Act-1 inhibits its activation through an allosteric mechanism. These results suggest that inhibition of α4β7 activation may be necessary to reduce susceptibility to SIV/SHIV infection and highlight the complexity of anti-integrins therapeutic approach in HIV as well as in IBD and other autoimmune diseases.
We demonstrate the preparation of surface-bound cucurbit[8]uril (CB[8]) catenanes on silica nanoparticles (NPs), where CB[8] was employed as a tethered supramolecular "handcuff" to selectively capture target guest molecules. In this catenane, CB[8] was threaded onto a methyl viologen (MV(2+) ) axle and immobilized onto silica NPs. The formation of CB[8] catenanes on NPs were confirmed by UV/Vis titration experiments and lithographic characterization, demonstrating a high density of CB[8] on the silica NPs surface, 0.56 nm(-2) . This CB[8] catenane system exhibits specific molecular recognition towards certain aromatic molecules such as perylene bis(diimide), naphthol and aromatic amino acids, and thus it can act as a nanoscale molecular receptor for target guests. Furthermore, we also demonstrate its use as an efficient and recyclable nano-platform for peptide separation. By embedding magnetic NPs inside silica NPs, separation could be achieved by simply applying an external magnetic field. Moreover, the peptides captured by the catenanes could be released by reversible single-electron reduction of MV(2+) . The entire process demonstrated high recoverability.
The objective was to assess self-care knowledge changes with dually eligible Medicare and Medicaid patients diagnosed with congestive heart failure (CHF), who received a telecoaching protocol integrating symptom monitoring with face-to-face video chat with a social worker. We recruited 45 patients with CHF from a regional managed care organization. Sessions via a Health Insurance Portability and Accountability Act-compliant tablet-based platform focused on educational information designed to improve patient self-care. Social workers administered the 13-item Member Confidence Measure (MCM) at baseline and at a 30-day follow-up period. Scores were recorded to measure differences in patients' understanding of CHF and related symptoms, their knowledge of the disease, and the behaviors necessary to prevent their symptoms from getting worse. Over the 30-day period, scores significantly (p < .01) increased on the total scale score and specific confidence measure subscales (symptom recognition, medication adherence, medical attention, healthy choices, and safety). Gender, race, and age were unrelated to these improvements. In addition, effect sizes for the sub-scales ranged from .54 to 1.08;
 the effect size of the intervention as expressed by the total scale score was 1.12. Overall, patients increased knowledge over a 30-day period. Tele-coaching by social workers holds promise as a feasible model for health education for high-risk populations.
The iIFN1a (intracellular IFN-a1), that is one of the IFN-a1 variants, was shown to be functional intracellularly and act as a novel defense against an infectious hematopoietic necrosis virus (IHNV). To determine its antiviral properties, a recombinant iIFN1a was generated in Escherichia coli. Its antiviral activity against IHNV was 1.69×10(7)U/mg in CHSE-214 cells. Additionally, iIFN1a was capable of inducing comparable levels of IRF-1, IRF-2, IFN-I, IFN-γ and Mx transcription in head kidney, spleen and liver tissues at an early time point (6h), that was followed by a rapid decline 24h after induction. The recombinant protein also elicited protection against IHNV in vivo. At 6 and 24h after induction there was 100% protection against the virus, however, at 48 and 72h the protection decreased to 57 and 40%, respectively. The in vivo protection kinetics correlated with the kinetics of gene expression. The results of this study provide details of the antiviral state that was induced by iIFN1a in vivo for the first time. Additionally, this information will facilitate the development of this recombinant protein as a potential anti-viral treatment and/or adjuvant.
As human health concerns over disinfection byproducts (DBP) in drinking water increase, so does the need to develop new materials that remove them rapidly and at high capacity. Ion exchange (IEX) is an effective method for the removal of natural organic matter (NOM), especially anion exchange resins (AERs) with quaternary ammonium functional groups. However, capacity is limited in existing commercial resin materials because adsorbates can only interact with the outermost surface area, which makes these products inefficient on a mass basis. We have synthesized a novel "NanoResin" exploiting the enhanced NOM removal of the quaternary ammonium resin while utilizing the vast surface area of SWCNTs, which act as scaffolding for the resin. Our nanomaterials show increased adsorption capacity compared to commercially available adsorbents, in a fraction of the time. This NanoResin requires only about 10 s to reach ion-exchange equilibrium. Comparatively, commercial AERs only achieved partial removal after more than 30 min. High capacity adsorption of a low molecular weight (MW) surrogate has been measured. NOM removal was demonstrated in solutions of both low and high specific UV absorbance (SUVA) composition with these nanomaterials. Additionally, the NanoResin showed enhanced removal of a NOM concentrate sample taken from Myrtle Beach, SC, demonstrating NanoResin is an effective method of removal for refractory NOM in a natural aqueous environment. Synthesis and characterization of the polymers and nanomaterials are presented below. Adsorption capacity, adsorption kinetics, and the regeneration and reusability of these new materials for NOM removal are described. The open matrix microstructure precludes any intraparticle diffusion of adsorbates; thus, these nanomaterials act as a "contact resin".
Pesticide presence in streams is a potential threat to Endangered Species Act listed salmonids in the Hood River basin, Oregon, a primarily forested and agricultural basin. Two types of passive samplers, polar organic chemical integrative samplers (POCIS) and semipermeable membrane devices (SPMDs), were simultaneously deployed at four sites in the basin during Mar. 2011-Mar. 2012 to measure the presence of pesticides, polybrominated diphenyl ethers (PBDEs), and polychlorinated biphenyls (PCBs). The year-round use of passive samplers is a novel approach and offers several new insights. Currently used pesticides and legacy contaminants, including many chlorinated pesticides and PBDEs, were present throughout the year in the basin's streams. PCBs were not detected. Time-weighted average water concentrations for the 2-month deployment periods were estimated from concentrations of chemicals measured in the passive samplers. Currently used pesticide concentrations peaked during spring and were detected beyond their seasons of expected use. Summed concentrations of legacy contaminants in Neal Creek were highest during July-Sept., the period with the lowest streamflows. Endosulfan was the only pesticide detected in passive samplers at concentrations exceeding Oregon or U.S. Environmental Protection Agency water-quality thresholds. A Sensitive Pesticide Toxicity Index (SPTI) was used to estimate the relative acute potential toxicity among sample mixtures. The acute potential toxicity of the detected mixtures was likely greater for invertebrates than for fish and for all samples in Neal Creek compared to Rogers Creek, but the indices appear to be low overall (<0.1). Endosulfans and pyrethroid insecticides were the largest contributors to the SPTIs for both sites. SPTIs of some discrete (grab) samples from the basin that were used for comparison exceeded 0.1 when some insecticides (azinphos methyl, chlorpyrifos, malathion) were detected at concentrations near or exceeding acute water-quality thresholds. Early life stages and adults of several sensitive fish species, including salmonids, are present in surface waters of the basin throughout the year, including during periods of peak estimated potential toxicity. Based on these data, direct toxicity to salmonids from in-stream pesticide exposure is unlikely, but indirect impacts (reduced fitness due to cumulative exposures or negative impacts to invertebrate prey populations) are unknown.
Given the growing aging population in Finland, retaining health staff to care for them is important. In an exploration of predictors of quitting before the typical retirement age, which ranges from 63 to 68 years in Finland, we examined whether organizational justice moderated the association between job involvement and retirement intentions among nurses 50 years and over. The sample was 446 nurses (70% practical nurses) working in 134 assisted living facilities providing 24-hour care for older residents in Finland. Job involvement was measured with the Job Involvement Questionnaire, and organizational justice with a scale that tapped its three dimensions: distributive justice, procedural justice, and interactional justice. In covariance analyses, low organizational justice and low job involvement were associated with a higher likelihood of retirement intention. Both interactional justice and procedural justice moderated the association of job involvement with retirement intentions. Among nurses with low job involvement, those who experienced unjust treatment, that is, low interactional justice, and evaluated organizational procedures as unjust had significantly stronger retirement intentions than nurses with high levels of interactional and procedural justice. Distributive justice was associated with retirement intentions in both high and low job-involved respondents. Organizational justice may act as a buffer against retirement intention as one consequence of nurses' low job involvement. © 2016 Wiley Periodicals, Inc.
Diabetic retinopathy (DR) is the leading cause of blindness among working-age adults. DR often leads to diabetic macular edema (DME), which often goes unnoticed until a patient presents with vision loss. However, treatment options and data for DME are continually improving. We know that vascular endothelial growth factor (VEGF) plays a key role in DME progression; therapies that act by inhibiting VEGF production seem to improve visual acuity in patients with DME. Of the anti-VEGF therapies available, two have been approved by the U.S. Food and Drug Administration to treat DME: ranibizumab (Lucentis; Genentech, South San Francisco, CA) and aflibercept (Eylea; Regeneron, Tarrytown, NY). Bevacizumab (Avastin; Genentech, South San Francisco, CA), which is approved for the treatment of certain types of cancer, is occasionally used off-label to treat DME. Anti-VEGF therapy can stop vision loss and even improve visual acuity. Other treatments remain effective, and these various treatment options fuel a need for new data and discussion. This roundtable discussion, which took place during the 2015 annual meeting of the American Academy of Ophthalmology, outlines the current protocols used to treat DME and provides clinical opinions about selecting and treating with an appropriate anti-VEGF therapy. [Ophthalmic Surg Lasers Imaging Retina. 2016;47:S5-14.].
Pathogen-associated molecular pattern-triggered immunity (PTI) builds one of the first layers of plant disease resistance. In susceptible plants, PTI is overcome by adapted pathogens. This can be achieved by suppression of PTI with the help of pathogen virulence effectors. However, effectors may also contribute to modification of host metabolism or cell architecture to ensure successful pathogenesis. Barley responds to treatment with the pathogen-associated molecular patterns flg22 or chitin with phosphorylation of mitogen-activated protein kinases and an oxidative burst. RAC/ROP GTPases can act as positive or negative modulators of these plant immune responses. The RAC/ROP GTPase RACB is a powdery mildew susceptibility factor of barley. However, RACB apparently does not negatively control early PTI responses but functions in polar cell development during invasion of the pathogen into living host epidermal cells. Here, we further discuss the incomplete picture of PTI in Triticeae.
The effect of gender (entire male, female and castrate), ageing period (2 or 7days) and endpoint temperature (70 or 75°C) on consumer perceptions of cuts from the loin (Musculuslongissimus thoracis et lumborum), silverside (Musculus biceps femoris) and shoulder
 (Musculus triceps brachii (roast) and Musculus supraspinatus (stir fry)) when roasted or stir fried (all primals) or grilled as steaks (loin only) was investigated. Higher scores for juiciness (P=0.035), flavour (P=0.017), overall liking (P=0.018), quality grade (P=0.026) were obtained from castrates than entire males, with females intermediate. Neither ageing period nor endpoint temperature, as main effects, influenced sensory scores. Loin steaks and silverside roasts obtained lower (P<0.001) scores for all sensory traits except aroma; scores for shoulder cuts were highest (P<0.001). Cooking to 70°C improved (P<0.05) juiciness, flavor and overall liking scores of loin steaks compared with 75°C. Different pathway interventions are required to optimize eating quality of different pork cuts and the cooking methods used to prepare them.
Medication therapy management (MTM) programs were first introduced as a result of the 2003 Medicare Prescription Drug Improvement and Modernization Act. Since then, the Centers for Medicare & Medicaid Services (CMS) have established minimum requirements for health plans to follow in establishing patient eligibility for enrollment in these programs. The eligibility criteria are based on projected annual Part D medication costs, number of chronic disease states, and number of chronic Part D covered medications. Patients meeting these criteria are automatically enrolled in an MTM program so must ask to be disenrolled from the program if they wish to not participate (opt-out). CMS rates the quality of health plans using the Five-Star Quality Rating System. Star ratings for various metrics are given to health plans based on a scale of 1 to 5 stars, with 5 stars being the highest quality rating that health plans can achieve. The "Medication Therapy Management Program Completion Rate for Comprehensive Medication Reviews (Part D)" was a display measure and is now a performance measure as of 2016. Consumers can view the star ratings and display measures for their health plans during the enrollment period, so these ratings can affect patient enrollments. Additionally, star ratings may also determine bonus payments awarded to health plans. To address the comprehensive medication review (CMR) measure, different outreach models are used by health plans and vendors to complete CMRs. Comparison of the effectiveness of these outreach models has not been sufficiently studied.
To compare the completion rate of CMRs by the University of Florida Medication Therapy Management Communication and Care Center (MTMCCC) for 3 models of patient outreach (cold calling, the initial offer and acceptance of a CMR from the health plan before contact by the MTMCCC, and scheduling of a CMR after mailing a welcome letter from the health plan) used for 3 different health plans.
This study is a retrospective chart analysis using data obtained from completed CMRs at the MTMCCC for health insurance beneficiaries enrolled in 3 different health plans. The CMR completion rate for 3 models of patient outreach used for 3 different health plans over the service period was compared. The CMR completion rate for this study was calculated using the number of completed CMRs and the total number of beneficiaries who were contacted at least once for the provision of a CMR for each respective model by the MTMCCC. The CMR completion rate calculated for this study is modified slightly from the CMS definition because of limitations in patient population assignment to the MTMCCC.
The model in which patients were previously offered and subsequently completed a CMR from their health plans before contact by the MTMCCC had the highest CMR completion rate at 49.8%, compared with 40.5% and 23.8% for the other 2 outreach models.
Offering patients a CMR, and subsequent completion, before provision of MTM services may increase CMR completion rate for health plans.
No outside funding supported this research. The University of Florida (UF) Medication Therapy Management Communication and Care Center (MTMCCC) receives grant funding from the Agency for Health Care Administration (AHCA) for services. Roane and Hardin are currently employed by UF as faculty with their practice sites at the UF MTMCCC. Salo is currently employed at UF as a clinical pharmacist with her practice site at the UF MTMCCC. Miller is currently employed as a transition of care clinical pharmacist at St. Joseph's Hospital in Tampa, Florida. The authors declare no potential conflicts of interest with respect to the research, authorship, and/or publication of this article. Miller and Roane were primary contributors to study concept and design, along with Salo and Hardin. Miller and Roane took the lead in data collection, assisted by Salo and Hardin, and data interpretation was performed by all the authors. The manuscript was written by all the authors and revised primarily by Roane and Miller, along with Salo and Hardin.
We herein report a thermocontrolled strategy for realizing in situ conformational transition of polymer-peptide conjugates at cell surfaces to manipulate and monitor HER2 receptor clustering, which finally result in effective breast cancer cell proliferation inhibition. Functional paring motifs (HBP) are covalently linked to a synthetic thermoresponsive polymer PNIPAAm to incorporate temperature control properties to HER2 targeting peptide. At 40 °C, the PNIPAAm polymers collapse and act as a "shield" to block the aggregation of HBP. Upon cooling to 35 °C, polymers are in their extended state and HBP are expose in aqueous and aggregate subsequently with enhanced fluorescence, allowing for promoting and in situ monitoring of receptor clustering. Ultimately, HER2 receptor clustering leads to cytoplasmic domain phosphorylation, which further results in effective cancer cell proliferation inhibition. We envision that this useful approach has the potential to be applied for molecule-targeted tumor therapy.
The great hunt for florigen, the universal, long distance flowering regulator proposed by Chailakhan in the 1930s, resulted in the discovery a decade ago that FT-like proteins fulfilled the predictions for florigen. They are small (∼175 amino acids), globular, phosphatidylethanolamine-binding (PEBP) proteins, phloem-expressed, graft-transmissible and able to move to the shoot apex to act as potent stimulators of flowering in many plants. Genes that regulate Arabidopsis FT protein movement and some features of Arabidopsis FT protein that make it an effective florigen have recently been identified. Although floral promotion via graft transmission of FT has not been demonstrated in trees, FT-like genes have been successfully applied to reducing the long juvenile (pre-flowering) phase of many trees enabling fast track breeding.
Over 40% of patients with pre-eclampsia are nonresponsive to antihypertensive therapy, but the underlying mechanisms are unknown. We examined the effects of plasma from nonresponsive and responsive patients on endothelial gene expression.
PCR array was performed in human umbilical vein endothelial cells (HUVEC) incubated with plasma from nonresponsive (n = 4) and responsive (n = 4) patients. Gene networks and interactions with antihypertensive drugs used in pre-eclampsia were identified by Ingenuity Pathway Analysis.
Nifedipine and hydralazine act by upregulate or downregulate genes found to be downregulated or upregulated in HUVEC incubated with plasma from nonresponsive patients.
Our novel findings suggest that plasma from nonresponsive and responsive patients evoke different responses in HUVEC, and might advance the pharmacogenomics research in pre-eclampsia.
Amino-acid-based chiral surfactants with polymerizable moieties are synthesized, and a versatile approach to prepare particles thereof with a chiral surface functionality is presented. As an example of an application, the synthesized particles are tested for their ability as nucleating agents in the enantioselective crystallization of amino acid conglomerate systems, taking rac-asparagine as a model system. Particles resulting from chiral surfactants with different tail groups are compared and the results demonstrate that only the chiral nanoparticles made of the polymerizable surfactant are able to act efficiently as nucleation agent in enantioselective crystallization.
Copper (Cu(2+)) is physiologically essential, but excessive Cu(2+) may cause potential risk to plants and animals due to the bioaccumulative properties. Hence, sensitive recognition is crucial to avoid overintake of Cu(2+), and visual recognition is more favored for practical application. In this work, a dual-emission ratiometric fluorescent nanoprobe was developed possessing the required intensity ratio, which can facilitate the sensitive identification of Cu(2+) by the naked eye. The probe hybridizes two fluorescence nanodots (quantum dots (QDs) and carbon dots (CDs)). Although both of them can be viable fluorescence probes for metal ion detection, rarely research has coupled this two different kinds of fluorescence material in one nanosensor to fabricate a selectively ratiometric fluorescence probe for intracellular imaging. The red emitting CdTe/CdS QDs were capped around the silica microsphere to serve as the response signal label, and the blue-emitting CDs, which is insensitive to the analyte, were covalently attached to the QDs surface to act as the reference signal. This core-satellite hybrid sphere not only improves the stability and brightness of QDs significantly but also decreases the cytotoxicity toward HeLa cells tremendously. Moreover, the Cu(2+) could quench the QDs emission effectively but have no ability for reduction of the CDs emission. Accordingly, a simple, efficient, and precise method for tracing Cu(2+) was proposed. The increase of Cu(2+) concentration in the series of 0-3 × 10(-6) M was in accordance
 with linearly decrease of the F650/F425 ratio. As for practical application, this nanosensor was utilized to the ratiometric fluorescence imaging of copper ions in HeLa cells.
Diagnostic errors pose a significant threat to patient safety but little is known about public perceptions of diagnostic errors. A study published in BMJ Quality & Safety in 2014 estimated that diagnostic errors affect at least 5% of US adults (or 12 million) per year. We sought to explore online public reactions to media reports on the reported frequency of diagnostic errors in the US adult population.
We searched the World Wide Web for any news article reporting findings from the study. We then gathered all the online comments made in response to the news articles to evaluate public reaction to the newly reported diagnostic error frequency (n=241). Two coders conducted content analyses of the comments and an experienced qualitative researcher resolved differences.
Overall, there were few comments made regarding the frequency of diagnostic errors. However, in response to the media coverage, 44 commenters shared personal experiences of diagnostic errors. Additionally, commentary centered on diagnosis-related quality of care as affected by two emergent categories: (1) US health care providers (n=79; 63 commenters) and (2) US health care reform-related policies, most commonly the Affordable Care Act (ACA) and insurance/reimbursement issues (n=62; 47 commenters).
The public appears to have substantial concerns about the impact of the ACA and other reform initiatives on the diagnosis-related quality of care. However, policy discussions on diagnostic errors are largely absent from the current national conversation on improving quality and safety. Because outpatient diagnostic errors have emerged as a major safety concern, researchers and policymakers should consider evaluating the effects of policy and practice changes on diagnostic accuracy.
Literature related to primary care and behavioral health integration initiatives is becoming abundant. The United States' 2010 Patient Protection and Affordable Care Act included provisions encouraging increased collaboration of care for individuals with behavioral and physical health service needs in the public sector. There is relatively little known of Advanced Practice Registered Nurses' (APRNs) roles with integrating primary and behavioral healthcare. The goal of this review article is to: (a) define integration of physical and behavioral healthcare and potential models; (b) answer the question as to what are effective evidence based models/strategies for integrating behavioral health and primary care; (c) explore the future role and innovations of APRNs in the integration of physical and behavioral healthcare.
The evidence- based literature is limited to three systematic reviews and six randomized controlled trials. It was difficult to generalize the data and the effective integration strategies varied from such interventions as care management to use of sertraline to depression management and to access. There were, though, implications for the integrated care advanced practice nurse to have roles inclusive of competencies, leadership, engagement, collaboration and advocacy.
Endometrial cancer is the most common invasive gynaecological malignancy. While endocrine, genetic and inflammatory factors are thought to contribute to its pathogenesis, its precise etiology and molecular regulators remain poorly understood. Fibulin-5 is an extracellular matrix (ECM) protein that inhibits cell growth and invasion in several cancer cell types and is downregulated in a number of types of human cancer. However, it is unknown whether fibulin-5 plays a role in endometrial tumourigenesis. In the current report, the expression and localisation of fibulin-5 in type I endometrioid human endometrial cancers of grades (G) 1-3 was investigated using reverse transcription-quantitative polymerase chain reaction and immunohistochemistry. Fibulin-5 mRNA was found to be significantly reduced in whole tumour tissues from women across G1-3 compared with benign endometrium (P<0.0001). Consistently, fibulin-5 protein was also reduced in the tumour epithelial compartment across increasing tumour grades. By contrast, increased protein localisation to the tumour stroma was observed with increasing grade. Knockdown by small interfering RNA in Ishikawa endometrial epithelial cancer cells expressing fibulin-5 stimulated cell adhesion and proliferation in vitro. Fibulin-5 mRNA expression in Ishikawa cells was induced by transforming growth factor-β and fibulin-5 in turn activated extracellular signal-regulated kinases (ERK1/2), suggesting that it may act via the mitogen-activated protein kinase pathway. In summary, the present study identified fibulin-5 as a downregulated ECM gene in human endometrial cancer and observed a shift from epithelial to stromal protein localisation with increasing tumour grade in women. These data suggest that loss of fibulin-5 function may promote endometrial cancer progression by enhancing epithelial cell adhesion and proliferation.
The identification of a specific molecular marker for aggressiveness of nonfunctioning pituitary adenomas (NFPAs) is urgently required in order to guide the clinical diagnosis and treatment of NFPAs. In the present study, low expression of secreted frizzled-related protein 2 (sFRP2) in NFPAs was demonstrated by reverse transcription-quantitative polymerase chain reaction, western blot and immunohistochemical analyses. The results confirmed an abnormal accumulation of free β-catenin in the nuclei of NFPAs, which is the core step for the activation of the Wnt canonical signaling pathway. Furthermore, cyclin D1 and c-Myc, the downstream proteins of the Wnt canonical signaling pathway, were overexpressed in aggressive NFPAs. These findings demonstrated the activation of the Wnt canonical signaling pathway in aggressive NFPAs. In addition, sFRP2 expression was observed to be inversely correlated to the aggressiveness of NFPAs. Therefore, sFRP2 may act as a tumor suppressor through modulation of the cellular cytosolic pool of β-catenin in NFPAs. Furthermore, the expression of sFRP2 may serve as a biomarker for NFPAs aggressiveness and prognosis.
Tandem uncaging systems in which a two-photon absorbing module and a cage moiety, linked via a phosphorous clip, that act together by Förster resonance energy transfer (FRET) have been developed. A library of these compounds, using different linkers and cages (7-nitroindolinyl or nitroveratryl) has been synthesized. The investigation of their uncaging and two-photon absorption properties demonstrates the scope and versatility of the engineering strategy towards efficient two-photon cages and reveals surprising cooperative and topological effects. The interactions between the 2PA module and the caging moiety are found to promote cooperative effects on the 2PA response while additional processes that enhance the uncaging efficiency are operative in well-oriented nitroindoline-derived dyads. These synergic effects combine to lead to record two-photon uncaging cross-section values (i.e., up to 20 GM) for uncaging of carboxylic acids.
We synthesized two novel lanthanide doped spindle-like mesocrystals, YF3:Ce,Eu,Gd and YF3:Ce,Tb,Gd (abbreviated as YEG and YTG mesospindles, respectively). Both of them possess paramagnetic and fluorescent properties, and their excellent cyto-compatibility and low haemolysis are further confirmed. Therefore, they could act as dual mode contrast agents for magnetic resonance imaging (MRI) and fluorescence imaging. Furthermore, YEG and YTG mesospindles induce dose and time dependent autophagy by activating the PI3K signaling pathway. The autophagy induced by YEG and YTG mesocrystals is confirmed by enhanced autophagosome formation, normal cargo degradation, and no disruption of lysosomal function. This work is important to illustrate how rare-earth mesocrystals affect the autophagic pathway, indicating the potential of the YEG and YTG mesospindles in diagnosis and therapy.
With the implementation of the Affordable Care Act (ACA) in 2014, many safety net resources, including state AIDS Drug Assistance Programs (ADAPs), incorporated ACA Qualified Health Plans (QHPs) into their healthcare delivery model. This article highlights the benefits of the ACA for persons living with HIV. It also describes the range of strategies employed by state ADAPs to enroll patients in QHPs. The Virginia ADAP ACA implementation experience is described to illustrate one ADAP's shift to purchasing QHPs in addition to providing direct medications. Virginia ADAP is in a Medicaid nonexpansion state and funds the full costs of the QHP premiums, deductibles, and medication copayments. Virginia's experience is applicable to other Medicaid nonexpansion states and to state ADAPs in Medicaid expansion states, who are looking for options for their Medicaid ineligible clients. This article provides practical details of Virginia ADAP's ACA implementation as well as insights and best practices at both the state and clinic level.
Sport supplements containing steroids never approved for therapeutic use have the potential for abuse by athletes. Most are marketed online and may contain undisclosed steroids yet are readily available despite lacking toxicological or pharmacological evaluation. In this study, 18 supplements purchased online underwent organic solvent extraction to isolate any steroids they contained. From the 18 supplements, 19 steroids were identified and for each, its intrinsic androgenic potency was determined by a yeast cell (Saccharomyces cerevisiae) androgen bioassay and its potential androgenic potency was determined by a liver (HuH7) cell androgen bioassay. The yeast bioassay showed that of the 19 steroids tested, 6 demonstrated strong intrinsic
 bioactivity, with 4 metabolically activated to even stronger androgens. Moreover, 4 steroids with moderate and 1 with intrinsically weak androgenic bioactivity were activated to more potent androgens. Finally, 8 steroids were metabolically inactivated or deactivated into weaker androgens. Our results show that Internet-sourced sport supplements may contain intrinsically strong androgens, or precursors that can be metabolized to them. These potentially potent pharmacologically active steroids are being used without regulatory control or consumer awareness of their potential adverse effects. Copyright © 2016 John Wiley & Sons, Ltd.
In this study human serum albumin (HSA), the most abundant protein of blood plasma, was modified with varying concentrations of peroxynitrite. The peroxynitrite induced changes in HSA was monitored by spectroscopy, SDS-PAGE, 1-anilinonaphthalene-8-sulfonic acid (ANS), thermal denaturation studies and matrix assisted laser desorption / inonization-time of flight mass spectrometry (MALDI-TOF MS). Aggregate formation was studied by thioflavin T binding and scanning electron microscopy (SEM). The results indicated formation of 3-nitrotyrosine, 6-nitrotryptophan, dityrosine and carbonyls in modified samples and showed retarded mobility in SDS-polyacrylamide gel. Reduction in α-helicity and surface protein hydrophobicity confirmed the secondary and tertiary structure alterations in peroxynitrite-modified-HSA. Also, attachment of nitro group and increase in melting temperature was observed in modified sample. Furthermore, significant enhancement in the fluorescence intensity of ThT upon binding with peroxynitrite-modified-HSA and images under scanning electron microscope are suggestive of protein aggregation. It is, therefore, speculated that HSA modified by endogenously formed peroxynitrite might act as a trigger for nitration / aggregation and suggested the role of peroxynitrite-modified-HSA in SLE.
Details of data quality and how quality issues were solved have not been reported in published comparative effectiveness studies using electronic health record data.
We developed a conceptual framework of data quality assessment and preprocessing and apply it to a study comparing angiotensin-converting enzyme inhibitors with angiotensin receptor blockerss on renal function decline in diabetes patients.
The framework establishes a line of thought to identify and act on data issues. The core concept is to evaluate whether data are fit-for-use for research tasks. Possible quality problems are listed through specific signal detections, and verified whether they are true problems. Optimal solutions are selected for the identified problems.
This framework can be used in observational studies to improve validity of results.
The molecular mechanisms underlying the regulation of pluripotency by cellular metabolism in human embryonic stem cells (hESCs) are not fully understood. We found that high levels of glutamine metabolism are essential to prevent degradation of OCT4, a key transcription factor regulating hESC pluripotency. Glutamine withdrawal depletes the endogenous antioxidant glutathione (GSH), which results in the oxidation of OCT4 cysteine residues required for its DNA binding and enhanced OCT4 degradation. The emergence of the OCT4(lo) cell population following glutamine withdrawal did not result in greater propensity for cell death. Instead, glutamine withdrawal during vascular differentiation of hESCs generated cells with greater angiogenic capacity, thus indicating that modulating glutamine metabolism enhances the differentiation and functional maturation of cells. These findings demonstrate that the pluripotency transcription factor OCT4 can serve as a metabolic-redox sensor in hESCs and that metabolic cues can act in concert with growth factor signaling to orchestrate stem cell differentiation.
Species extinctions are accelerating globally, yet the mechanisms that maintain local biodiversity remain poorly understood. The extinction of species that feed on or are fed on by many others (i.e. 'hubs') has traditionally been thought to cause the greatest threat of further biodiversity loss. Very little attention has been paid to the strength of those feeding links (i.e. link weight) and the prevalence of indirect interactions. Here, we used a dynamical model based on empirical energy budget data to assess changes in ecosystem stability after simulating the loss of species according to various extinction scenarios. Link weight and/or indirect effects had stronger effects on food-web stability than the simple removal of 'hubs', demonstrating that both quantitative fluxes and species dissipating their effects across many links should be of great concern in biodiversity conservation, and the potential for 'hubs' to act as keystone species may have been exaggerated to date.
Dehydroepiandrosterone(DHEA), an adrenal androgen, has attracted much attention as an anti-aging hormone as well as a marker for senescence because of its unique change along with aging. DHEA is reported to have beneficial effects such as anti-diabetes, anti-obesity, and anti-atherosclerosis. It is also shown that DHEA has anti-osteoporosis effects to increase bone mineral density in randomized controlled trials(RCTs). As osteoblasts express aromatase which will convert androgen to estrogen, DHEA may act protectively against osteoporosis through its metabolites. Because there is no report on fracture risk by DHEA administration, further studies are required to clarify DHEA effects on human bone metabolism.
There is limited and contradictory information regarding the role of serum ischemia-modified albumin (IMA) in obstructive sleep apnea (OSA). In this study we examine the effects of OSA and obesity on IMA and interleukin-6 (IL-6), and detect whether IMA and IL-6 may be potential biomarkers in OSA.
Fifty-one males who underwent all night polysomnography test were included into the study. Body-mass index (BMI) and apnea-hypopnea index (AHI) of all patients were determined. Serum IMA and IL-6 levels, erythrocyte sedimentation rate (ESR), complete blood count, routine blood biochemistry and thyroid function tests were performed.
Mean IMA [0.36 (± 0.04) U/ml, 0.89 (± 0.15) U/ml], mean IL-6 [1.01 (± 0.19) pg/ml, 2.02 (± 1.19) pg/ml] and mean ESR [4.14 (± 2.5) mm/h, 14.35 (± 13.7) mm/h] levels showed significant difference between non-OSA and OSA groups (P = 0.005, P < 0.001, P < 0.001, respectively). Sensitivity of IMA in distinction of non-OSA/OSA was equal to IL-6 and higher than ESR. IMA was also a stronger predictive factor than IL-6 and ESR in the evaluation of OSA groups (severe/mild/moderate OSA and non-OSA). IMA was the sole distinctive biomarker in assessment of obese and non-obese cases. IMA correlated with IL-6, AHI and ESR.
Serum IMA may be a valuable oxidative stress indicator for OSA and could act as a better biomarker than IL-6 for reflecting the presence and the severity of OSA.
Novel Fe10 and Fe14 clusters [Rb9 Cs4 H37 Fe10 O34 (A-α-PW9 O31 )3 (OH)3 ]⋅36 H2 O (1) and [H3 Rb3 Fe14 (OH)12 (PO4 )6 (B-α-PW9 O34 )2 ]⋅21 H2 O (2) were synthesized and characterized in the solid state by single-crystal X-ray diffraction, IR spectroscopy, thermogravimetric analysis (TGA), and magnetic studies, and in solution by electrochemistry. Cluster 1 is a decameric Fe(III) polyanionic cluster encapsulating a cesium atom in the center. Cluster 2 is a unique tetradecanuclear Fe(III) sandwich structure with phosphate-linked units featuring two quasicubic Fe4 O4 moieties. Apparently, 2 has the highest nuclearity of all known Fe(III) sandwich-type polyoxometalate clusters. Clusters 1 and 2 also act as photocatalysts with platinum as cocatalyst for H2 evolution from light-driven water splitting. Changes in the cyclovoltammetric patterns with variations in pH were observed for 1 and 2, most likely due to intermolecular interactions among the high-nuclearity Fe(III) cluster cores and subsequent changes in the acid-base properties of the two reduced POMs. Magnetic studies provide evidence of antiferromagnetic interactions in 1 and 2. TGA showed that complexes 1 and 2 decompose between 580 and 590 °C.
The dietary components, flavonoids, are important for their anti-oxidant properties and the ability to act as metal ion chelators. The characterization of the morin-Cu(ii) complex is executed using elemental analysis, FTIR and mass spectroscopy. DNA cleaving and cell cytotoxicity properties followed by serum albumin binding have been investigated in this report. The morin-Cu(ii) complex was found to cleave plasmid pBR322 DNA via an oxidative pathway as revealed by agarose gel based assay performed in the presence of some scavengers and reactive oxygen species. The breaking of the deoxyribose ring of calf thymus DNA (ct-DNA) was also confirmed by the formation of thiobarbituric acid reacting species (TBARS) between thiobarbituric acid and malonaldehyde. The morin-Cu(ii) complex is able to inhibit the growth of human HeLa cells. Fluorescence studies revealed that the morin-Cu(ii) complex can quench the intrinsic fluorescence of serum albumins (SAs) via a static quenching method. The binding constants were found to be in the order of 10(5) M(-1) and observed to increase with temperature. Both ΔH° and ΔS° are positive for the binding of the morin-Cu(ii) complex with serum albumins which indicated the presence of hydrophobic forces. Site-selectivity studies reveal that the morin-Cu(ii) complex binds to both site 1 (subdomain IIA) and site 2 (subdomain IIIA) of human serum albumin (HSA) and bovine serum albumin (BSA). Circular dichroism (CD) studies showed the structural perturbation of SAs during binding with the morin-Cu(ii) complex. The results from binding studies confirmed that after complexation with the Cu(ii) ion, morin alters its mode of interaction
 with SAs which could have differential implications on its other biological and pharmaceutical properties.
Among protists, pheromones have been identified in a great variety of algal species for their activity in driving gamete-gamete interactions for fertilization. Analogously in ciliates, pheromones have been identified for their activity in inducing the sexual phenomenon of conjugation. Although this identification was pioneered by Kimball more than fifty years ago, an effective isolation and chemical characterization of ciliate pheromones has remained confined to species of Blepharisma, Dileptus and Euplotes. In Euplotes species, in which the molecular structures have been determined, pheromones form species-specific families of structurally homologous helical, cysteine-rich, highly-stable proteins. Being structurally homologous, they can bind cells in competition with one another, raising interesting functional analogies with the families of growth factors and cytokines that regulate cell differentiation and development in higher organisms. In addition to inducing conjugation by binding cells in heterologous fashion, Euplotes pheromones act also as autocrine growth factors by binding to, and promoting the vegetative reproduction of the same cells from which they originate. This autocrine activity is most likely primary, providing a concrete example of how the original function of a molecule can be obscured during evolution by the acquisition of a new one.
MicroRNAs (miRNAs) may act as carcinogen or tumor suppressor genes by targeting various biological molecules. Therefore, it is important to identify significant markers for prognosis, diagnosis treatment strategies of cancers.
To evaluate the clinical importance and prognostic value of miR-9 and miR-145 in cervical cancer.
miRNAs expression was detected using quantitative real-time polymerase chain reaction in cervical cancer specimens and adjacent normal tissues.
MiR-9 up-regulated in cervical cancer specimens than adjacent normal tissues (9.743 ± 2.172 vs. 2.131 ± 1.083; P < 0.05). MiR-145 was decreased in cervical cancer specimens compared to corresponding normal tissues (2.189 ± 0. 724 vs. 7.173 ± 1.558 P < 0.05). In addition, increased expression of miR-9 was strongly linked to lymph node metastasis (P = 0.017) and vascular invasion (P = 0.011). On the other hand, the low expression of miR-145 was related to advanced FIGO stage (P = 0.007), lymph node metastasis (P = 0.02) and vascular invasion (0.026). Kaplan-Meier survival and log-rank analysis suggested that patients with high expression of miR-9 had shorter overall survival compared with those with low expression (log-rank test P = 0.028; P < 0.001). In addition, shorter overall survival time was remarkably linked to decreased expression of miR-145 (log-rank test P < 0.001). Multivariate Cox proportional hazards model analysis of miR-9 and miR-145 showed that FIGO stage (P = 0.011) high expression of miR-9 and low expression of miR-145 (P = 0.023; P = 0.031) were independent prognostic factors for overall survival of patients.
miRNA-145 and 9 may be as potential prognostic marker in patients suffering from cervical cancer.
The epidermal growth factor receptor (EGFR) is a clinically validated target in head and neck squamous cell carcinoma (HNSCC), where EGFR-blocking antibodies are approved for first-line treatment. However, as with other targeted therapies, intrinsic/acquired resistance mechanisms limit efficacy. In the FaDu HNSCC xenograft model, we show that combined blockade of EGFR and ERBB3 promotes rapid tumor regression, followed by the eventual outgrowth of resistant cells. RNA sequencing revealed that resistant cells express FGFR3-TACC3 fusion proteins, which were validated as drivers of the resistant phenotype by several approaches, including CRISPR-mediated inactivation of FGFR3-TACC3 fusion genes. Interestingly, analysis of signaling in resistant cell lines demonstrated that FGFR3-TACC3 fusion proteins promote resistance by preferentially substituting for EGFR/RAS/ERK signaling rather than ERBB3/PI3K/AKT signaling. Furthermore, although FGFR3-TACC3 fusion proteins promote resistance of additional EGFR-dependent HNSCC and lung cancer cell lines to EGFR blockade, they are unable to compensate for inhibition of PI3K signaling in PIK3CA-mutant HNSCC cell lines. Validation of FGFR3-TACC3 fusion proteins as endogenous drivers of resistance in our screen provides strong evidence that these fusions are capable of substituting for EGFR signaling. Thus, FGFR3-TACC3 fusion proteins may represent a novel mechanism of acquired resistance in EGFR-dependent cancers of multiple cell lineages.Oncogene advance online publication, 27 June 2016 ; doi:10.1038/onc.2016.216.
Adrenomedullin (AM) and proadrenomedullin N-terminal 20 peptide (PAMP) are 2 biologically active peptides produced by the same gene, ADM, with ubiquitous distribution and many physiological functions. Adrenomedullin is composed of 52 amino acids, has an internal molecular ring composed by 6 amino acids and a disulfide bond, and shares structural similarities with calcitonin gene-related peptide, amylin, and intermedin. The AM receptor consists of a 7-transmembrane domain protein called calcitonin receptor-like receptor in combination with a single transmembrane domain protein known as receptor activity-modifying protein. Using morphologic techniques, it has been shown that AM and PAMP are expressed throughout the gastrointestinal tract, being specially abundant in the neuroendocrine cells of the gastrointestinal mucosa; in the enterochromaffin-like and chief cells of the gastric fundus; and in the submucosa of the duodenum, ileum, and colon. This wide distribution in the gastrointestinal tract suggests that AM and PAMP may act as gut hormones regulating many physiological and pathologic conditions. To date, it has been proven that AM and PAMP act as autocrine/paracrine growth factors in the gastrointestinal epithelium, play key roles in the protection of gastric mucosa from various kinds of injury, and accelerate healing in diseases such as gastric ulcer and inflammatory bowel diseases. In addition, both peptides are potent inhibitors of gastric acid secretion and gastric emptying; they regulate the active transport of sugars in the intestine, regulate water and ion transport in the colon, modulate colonic bowel movements and small-intestine motility, improve endothelial barrier function, and stabilize circulatory function during gastrointestinal inflammation. Furthermore, AM and PAMP are antimicrobial peptides, and they contribute to the mucosal host defense system by regulating gut microbiota. To get a formal demonstration of the effects that endogenous AM and PAMP may have in gut microbiota, we developed an inducible knockout of the ADM gene. Using this model, we have shown, for the first time, that lack of AM/PAMP leads to changes in gut microbiota composition in mice. Further studies are needed to investigate whether this lack of AM/PAMP may have an impact in the development and/or progression of intestinal diseases through their effect on microbiota composition.
The high metabolic priority of the mammary gland for milk production, accompanied by limited feed intake around parturition results in a high propensity to mobilize body fat reserves. Under these conditions, fuel selection of many peripheral organs is switched, for example, from carbohydrate to fat utilization to spare glucose for milk production and to ensure partitioning of tissue- and dietary-derived nutrients toward the mammary gland. For example, muscle tissue uses nonesterified fatty acids (NEFA) but releases lactate and amino acids in a coordinated order, thereby providing precursors for milk synthesis or hepatic gluconeogenesis. Tissue metabolism and in concert, nutrient partitioning are controlled by the endocrine system involving a reduction in insulin secretion and systemic insulin sensitivity and orchestrated changes in plasma hormones such as insulin, adiponectin, insulin growth factor-I, growth hormone, glucagon, leptin, glucocorticoids, and catecholamines. However, the endocrine system is highly sensitive and responsive to an overload of fatty acids no matter if excessive NEFA supply originates from exogenous or endogenous sources. Feeding a diet containing rumen-protected fat from late lactation to calving and beyond exerts similar negative effects on energy intake, glucose and insulin concentrations as does a high extent of body fat mobilization around parturition in regard to the risk for ketosis and fatty liver development. High plasma NEFA concentrations are thought not to act directly at the brain level, but they increase the energy charge of the liver which is, signaled to the brain to diminish feed intake. Cows differing in fat mobilization during the transition phase differ in their hepatic energy charge, whole body fat oxidation, glucose metabolism, plasma ghrelin, and leptin concentrations and in feed intake several week before parturition. Hence, a high lipid load, no matter if stored, mobilized or fed, affects the endocrine system, metabolism, and feed intake, and increases the risk for metabolic disorders. Future research should focus on a timely parallel increase in feed intake and milk yield during early lactation to reduce the impact of body fat on feed intake, metabolic health, and negative energy balance.
There is a strong inter-relationship between activation of the hypothalamo-pituitary-adrenal axis and energy homeostasis. Patients with abdominal obesity have elevated cortisol levels. Furthermore, stress and glucocorticoids act to control both food intake and energy expenditure. In particular, glucocorticoids are known to increase the consumption of foods enriched in fat and sugar. It is well-known that, in all species, the cortisol response
 to stress or adrenocorticotropin is highly variable. It has now emerged that cortisol responsiveness is an important determinant in the metabolic sequelae to stress. Sheep that are characterized as high-cortisol responders (HRs) have greater propensity to weight gain and obesity than low-cortisol responders (LRs). This difference in susceptibility to become obese is associated with a distinct metabolic, neuroendocrine, and behavioral phenotype. In women and ewes, HR individuals eat more in response to stress than LR. Furthermore, HR sheep have impaired melanocortin signaling and reduced skeletal muscle thermogenesis. High-cortisol responder sheep exhibit reactive coping strategies, whereas LRs exhibit proactive coping strategies. This complex set of traits leads to increased food intake and reduced energy expenditure in HR and thus, predisposition to obesity. We predict that cortisol responsiveness may be used as a marker to identify individuals who are at risk of weight gain and subsequent obesity.
Maintenance of electric potential and synaptic transmission are energetically demanding tasks that neuronal metabolism must continually satisfy. Inability to fulfil these energy requirements leads to the development of neurodegenerative disorders, including Alzheimer's disease. A prominent feature of Alzheimer's disease is in fact neuronal glucose hypometabolism. Thus understanding the fine control of energetic metabolism might help to understand neurodegenerative disorders. Recent research has indicated that a novel class of signalling molecules, the inositol pyrophosphates, act as energy sensors. They are able to alter the balance between mitochondrial oxidative phosphorylation and glycolytic flux, ultimately affecting the cellular level of ATP. The neuronal inositol pyrophosphate synthesis relies on the activity of the neuron enriched inositol hexakisphosphate kinase 3 (IP6K3) enzyme. To verify an involvement of inositol pyrophosphate signalling in neurodegenerative disorders, we performed tagging single nucleotide polymorphism (SNP) analysis of the IP6K3 gene in patients with familial and sporadic late onset Alzheimer's disease (LOAD). Two SNPs in the 5'-flanking promoter region of the IP6K3 gene were found to be associated with sporadic LOAD. Characterizing the functionality of the two polymorphisms by luciferase assay revealed that one of them (rs28607030) affects IP6K3 promoter activity, with the G allele showing an increased activity. As the same allele has a beneficial effect on disease risk, this may be related to upregulation of IP6K3 expression, with a consequent increase in inositol pyrophosphate synthesis. In conclusion, we provide the first evidence for a contribution of genetic variability in the IP6K3 gene to LOAD pathogenesis.
The development of post-transplantation antibodies against non-HLA autoantigens is associated with rejection and decreased long-term graft survival. Although our knowledge of non-HLA antibodies is incomplete, compelling experimental and clinical findings demonstrate that antibodies directed against autoantigens such as angiotensin type 1 receptor, perlecan and collagen, contribute to the process of antibody-mediated acute and chronic rejection. The mechanisms that underlie the production of autoantibodies in the setting of organ transplantation is an important area of ongoing investigation. Ischaemia-reperfusion injury, surgical trauma and/or alloimmune responses can result in the release of organ-derived autoantigens (such as soluble antigens, extracellular vesicles or apoptotic bodies) that are presented to B cells in the context of the transplant recipient's antigen presenting cells and stimulate autoantibody production. Type 17 T helper cells orchestrate autoantibody production by supporting the proliferation and maturation of autoreactive B cells within ectopic tertiary lymphoid tissue. Conversely, autoantibody-mediated graft damage can trigger alloimmunity and the development of donor-specific HLA antibodies that can act in synergy to promote allograft rejection. Identification of the immunologic phenotypes of transplant recipients at risk of non-HLA antibody-mediated rejection, and the development of targeted therapies to treat such rejection, are sorely needed to improve both graft and patient survival.
Medical pluralism flourished in the 18th century in the Dutch colony of Suriname. White physicians and surgeons, trained in European medicine, existed along with Indigenous priest/healers and herbalists, slave priest/diviners, and healers of African origin, their diverse practices played out on the plantation itself. While decrying the "superstition" of slave healers, physicians began to take note of their plant remedies, such as the local bark used to reduce fever discovered by the celebrated diviner Quassie. Some slave healers were trained in European surgical practices. The Suriname government acted against the slave "poisoners," who were feared by slaves as well, but they did not act against other non-European healers.
Diagnosis of cancer and photothermal therapy using optoelectronic properties of noble metal nanoparticles (NPs) has established a new therapeutic approach for treating cancer. Here we address the intrinsic properties of noble metal NPs (gold and silver) as well as the mechanism of their potential antitumor activity. For this, the study addresses the functional characterization of tumor associated macrophages (TAMs) isolated from murine fibrosarcoma induced by a chemical carcinogen, 3-methylcholanthrene (MCA). We have previously shown antitumor activity of both gold nanoparticles (AuNPs) and silver nanoparticle (AgNPs) in vivo in a murine fibrosarcoma model. In the present study, it has been seen that AuNPs and AgNPs modulate the reactive oxygen species (ROS) and reactive nitrogen species (RNS) production, suppressing the antioxidant system of cells (TAMs). Moreover, the antioxidant-mimetic action of these NPs maintain the ROS and RNS levels in TAMs which act as second messengers to activate the proinflammatory signaling cascades. Thus, while there is a downregulation of tumor necrosis factor-α (TNF-α) and Interleukin-10 (IL-10) in the TAMs, the proinflammatory cytokine Interleukin-12 (IL-12) is upregulated resulting in a polarization of TAMs from M2 (anti-inflammatory) to M1 (pro-inflammatory) nature.
Novel copper complexes of Schiff base ligands of 2-aminobenzothiazole derivatives were synthesized by the condensation of Knoevenagel condensate of acetoacetanilide (obtained from substituted benzaldehydes and acetoacetanilide) and 2-aminobenzothiazole. They were characterized by elemental analysis, IR, (1)H NMR, UV-Vis., molar conductance, magnetic susceptibility measurements and electrochemical studies. Based on the magnetic moment and electronic spectral data, square planar geometry has been suggested for all the complexes. Antibacterial and antifungal screening of the ligands and their complexes reveal that all the complexes show higher activities than the ligands. The binding behaviour of the complexes with calf thymus DNA has been investigated by electronic absorption spectra, viscosity measurements and cyclic voltammetry. The DNA binding constants reveal that all these complexes interact with DNA through intercalation binding mode. Superoxide dismutase and antioxidant activities of the copper complexes have also been studied. The antioxidant activities of the complexes showed higher activities. Thermal denaturation studies suggested the nature binding affinity of copper complexes with CT-DNA. All complexes exhibit suitable Cu(II)/Cu(I) redox potential to act as antioxidant enzymes mimic. Further, the copper complexes also showed catalase activity. It is hope that copper complexes were capable of decrease ROS levels or reduce oxidative stress in Alzheimer's patients.
In plants, carotenoids are essential for photosynthesis and photoprotection. However, carotenoids are not the end products of the pathway; apocarotenoids are produced by carotenoid cleavage dioxygenases (CCDs) or non-enzymatic processes. Apocarotenoids are more soluble or volatile than carotenoids but they are not simply breakdown products, as there can be modifications post-cleavage and their functions include hormones, volatiles, and signals. Evidence is emerging for a class of apocarotenoids, here referred to as apocarotenoid signals (ACSs), that have regulatory roles throughout plant development beyond those ascribed to abscisic acid (ABA) and strigolactone (SL). In this context we review studies of carotenoid feedback regulation, chloroplast biogenesis, stress signaling, and leaf and root development providing evidence that apocarotenoids may fine-tune plant development and responses to environmental stimuli.
Approximately 50% of buffalo herds in Brazil are located in Pará state in northern Brazil. There are several properties where cattle and buffalo live and graze together, and thus, buffalo pathogens may threaten the health of cattle and vice versa. Therefore, knowledge of infectious agents of buffalo is essential for maintaining healthy livestock. Clinical disease caused by Theileria and Babesia parasites in the Asian water buffalo is not common, although these animals may act as reservoir hosts, and the detection of these hemoparasites in buffaloes is as important as it is in cattle. Studies of the infection of buffaloes by hemoparasites in Brazil are scarce. The objective of the present study was to investigate the occurrence of Piroplasmida parasites in Asian water buffaloes in the state of Pará in the Amazon region of Brazil using nested PCR assays and phylogenetic analysis. The 18S rRNA gene and ITS complete region were amplified from DNA extracted from blood samples collected from 308 apparently healthy buffaloes bred on six properties in the state of Pará, Brazil. The
 prevalence of positive buffalo samples was 4.2% (13/308) for Theileria spp., 3.6% (11/308) for Babesia bovis and 1% (3/308) for Babesia bigemina. Animals infected with Theileria were detected in 50% (3/6) of the assessed properties. Phylogenetic analyses indicated that the Theileria species detected in this study were closely related to Theileria buffeli, Theileria orientalis and Theileria sinensis. To our knowledge, this is the first report of Theileria in Asian water buffaloes in the Americas. The majority of Theileria-positive buffaloes (11/13) belong to a property that has a history of animals presenting lymphoproliferative disease of unknown etiology. Therefore, the present research suggests that this disorder can be associated with Theileria infection in this property. Our results provide new insights on the distribution and biological aspects of hemoparasites transmissible from buffaloes to cattle.
Metformin (dimethylbiguanide) has been found to be effective for the treatment of a wide range of cancer. Herein, a novel lipid (1,2-di-(9Z-octadecenoyl)-3-biguanide-propane (DOBP)) was elaborately designed by utilizing biguanide as the cationic head group. This novel cationic lipid was intended to act as a gene carrier with intrinsic antitumor activity. When compared with 1,2-di-(9Z-octadecenoyl)-3-trimethylammonium-propane (DOTAP), a commercially available cationic lipid with a similar structure, the blank liposomes consisting of DOBP showed much more potent antitumor effects than DOTAP in human lung tumor xenografts, following an antitumor mechanism similar to metformin. Given its cationic head group, biguanide, DOBP could encapsulate TNF-related apoptosis-inducing ligand (TRAIL) plasmids into Lipid-Protamine-DNA (LPD) nanoparticles (NPs) for systemic gene delivery. DOBP-LPD-TRAIL NPs demonstrated distinct superiority in delaying tumor progression over DOTAP-LPD-TRAIL NPs, due to the intrinsic antitumor activity combined with TRAIL-induced apoptosis in the tumor. These results indicate that DOBP could be used as a versatile and promising cationic lipid for improving the therapeutic index of gene therapy in cancer treatment.
An emerging body of research has documented an association between problem gambling and domestic violence in a range of study populations and locations. Yet little research has analysed this relationship at ecological scales. This study investigates the proposition that gambling accessibility and the incidence of domestic violence might be linked. The association between police-recorded domestic violence and electronic gaming machine accessibility is described at the postcode level. Police recorded family incidents per 10,000 and domestic-violence related physical assault offenses per 10,000 were used as outcome variables. Electronic gaming machine accessibility was measured as electronic gaming machines per 10,000 and gambling venues per 100,000. Bayesian spatio-temporal mixed-effects models were used to estimate the associations between gambling accessibility and domestic violence, using annual postcode-level data in Victoria, Australia between 2005 and 2014, adjusting for a range of covariates. Significant associations of policy-relevant magnitudes were found between all domestic violence and EGM accessibility variables. Postcodes with no electronic gaming machines were associated with 20% (95% credibility interval [C.I.]: 15%, 24%) fewer family incidents per 10,000 and 30% (95% C.I.: 24%, 35%) fewer domestic-violence assaults per 10,000, when compared with postcodes with 75 electronic gaming machine per 10,000. The causal relations underlying these associations are unclear. Quasi-experimental research is required to determine if reducing gambling accessibility is likely to reduce the incidence of domestic violence.
Despite substantial focus on sustainability issues in both science and politics, humanity remains on largely unsustainable development trajectories. Partly, this is due to the failure of sustainability science to engage with the root causes of unsustainability. Drawing on ideas by Donella Meadows, we argue that many sustainability interventions target highly tangible, but essentially weak, leverage points (i.e. using interventions that are easy, but have limited potential for transformational change). Thus, there is an urgent need to focus on less obvious but potentially far more powerful areas of intervention. We propose a research agenda inspired by systems thinking that focuses on transformational 'sustainability interventions', centred on three realms of leverage: reconnecting people to nature, restructuring institutions and rethinking how knowledge is created and used in pursuit of sustainability. The notion of leverage points has the potential to act as a boundary object for genuinely transformational sustainability science.
Tissue mechanics provides an appropriate niche for cell growth and functions. Integrin proteins play a pivotal role in mechanosensing associated with both extracellular matrix and intracellular cytoskeleton proteins. Endocytosis of integrin β1 of BMMSCs on collagen I-coated soft substrates promotes cell differentiation, providing a mechanism that cell senses elasticity through integrin. To determine whether other integrin subunits act the same way in BMMSCs, we carried on immunocytochemical staining and biotin labeling experiments to assay their subcellular distribution on stiff and soft hydrogels. Our results indicate that, consistent with our previous studies conducted on β1 integrin, more integrin α1 and α2 were internalized on collagen I-coated soft substrates compared with stiff substrate counterparts. This internalization is mainly mediated by caveolin-dependent endocytosis and would involve in soft matrix-promoted neurogentic lineage commitment. Cells on hydrogels coated by fibronectin and laminin, respective ligands of integrin α5 and α6, demonstrated no apparent soft substrate inducing endocytosis of these two subunits. These findings suggest that integrin-mediated mechanosensing is coupling with ECM ligands.
The misuse of over-the-counter (OTC) drugs became a global public health concern. Although abuse with dextrometorphan (DXM), pseudoefedrine (PSD), codeine (COD) or benzydamine (BND) may lead even to psychosis, drugs containing these substances are relatively cheap and freely available. In Poland the Act on Counteracting Drug Addiction was amended in 2015, however it seems that there are still some points which could be improved.
Study was conducted between October 2014 and June 2015 using a specially designed questionnaire delivered to pharmacists from the Greater Poland region. Questionnaire consisting of 11 closed questions was distributed by direct contact and via the Internet. From over 2500 distributed questionnaires, we received 761 sheets and 680 were included.
The misuse of OTC drugs is increasing in Poland from pharmacists point of view. The most popular substance was PSD followed by COD and DXM. The main reason of misuse of these drugs could be related to the use of Internet and free access to these medications. In respondents (58.2%) opinion OTC drugs containing analyzed substances should be moved into the prescription status.
The misuse of OTC drugs should be considered as a very dangerous phenomenon. Although the Act on Counteracting Drug Addiction was amended in Poland in 2015, there are some facets requiring improvement. Social education may play a key role in the limitation of misuse of OTC drugs.
Lymphopenia is strongly associated with autoimmune diseases. The molecular mechanisms that link both phenomena are still unclear, but certain key pathways have been described. Central tolerance is as important as peripheral. In the earlier, epithelial and dendritic cells play a crucial role in the selection of clones. In the latter, regulatory T cells (Tregs) rise as inductors of anergy in order to prevent the development of autoimmune pathology. In lymphopenic conditions, T cells develop the process of lymphopenia-induced proliferation (LIP). A complex interaction between the major histocompatibility complex (MHC) and the T cell receptor (TCR) makes this process possible. Furthermore, IL-7 can act synergistically or in an independent manner to promote LIP. A lack of Transforming Growth Factor-β (TGF-β) was recently described as the second hit needed to develop autoimmunity in a lymphopenic microenvironment, given its actions in Tregs and its interaction with CTLA-4. Regarding autoimmune clinical scenarios, lymphopenia is related to both, systemic and organ-specific diseases. Thus, the molecular study of such patients has been limited and needs to be widened to the pathways shown here to be involved in the development of lymphopenia and autoimmunity.
Active sampling of olfactory environment consists of sniffing in rodents. The importance of sniffing dynamics is well established at the neuronal and behavioral levels. Patterns of sniffing have been shown to be modulated by the physicochemical properties of odorants, particularly concentration and sorption. Sniffing is also heavily impacted by higher processing related to the behavioral context, emotion and attentional demand. However, how the pattern of sniffing evolves over the course of learning of an experimental olfactory conditioning is still poorly understood. We tested this question by monitoring sniffing activity, using a whole-body plethysmograph, on rats performing a two-alternative choice odor discrimination task. We followed sniff variations at different learning stages (naïve, well-trained, expert). We found that during the acquisition of an odor discrimination task, rats acquired a global sniffing pattern, independent of the odor pair used. This pattern consists of a longer sampling duration, a higher sniffing frequency, and a larger amplitude. In parallel, subtle
 differences of sniffing between the two odors of a pair were also observed. This sniffing behavior was not only associated with a better and faster acquisition of the discrimination task but was also transferred to other odor sets and refined after a long-term pause so as to reduce the sampling duration and maintain a specific sniffing frequency. Our results provide additional arguments that sniffing is a complex sensorimotor act that is strongly affected by olfactory learning.
Drought is today, and perhaps even more in the future, the main challenge for grain crops, resulting in a drastic yield reduction. Thus, it is of great interest to obtain soybean genotypes tolerant to water deficit. The drought tolerance trait is difficult to obtain through classical breeding due to its polygenic basis. In this context, genetic engineering is presented as a way to achieve this attribute. The ability to modulate the expression of many genes placed the transcription factors as promising biotechnological targets to develop stress tolerant cultivars. The WRKY proteins form a large family of transcription factors that are involved in important physiological and biochemical processes in plants, including the response to water deficit. In this study, the expression pattern determined by qPCR showed that, GmWRKY6, GmWRKY46, GmWRKY56, GmWRKY106 and GmWRKY149 genes are differentially expressed between a drought tolerant and a susceptible soybean genotype in water stress conditions. The in silico promoter and coexpression analysis indicate that these genes act in a stress physiological background.
In this work, we sought to generate sustained-release injectable microspheres loaded with the GLP-1 analogue liraglutide. Using water-in-oil-in-water double emulsion methods, poly(lactic-co-glycolic acid) (PLGA) microspheres loaded with liraglutide were prepared. The microspheres gave sustained drug release over 30days, with cumulative release of up to 90% reached in vitro. The microspheres were further studied in a rat model of diabetes, and their performance compared with a group given daily liraglutide injections. Reduced blood sugar levels were seen in the microsphere treatment groups, with the results being similar to those obtained with conventional injections between 10 and 25days after the commencement of treatment. After 5 and 30days of treatment, the microspheres seem a little slower to act than the injections. The pathology of the rats' spleen, heart, kidney and lungs was probed after the 30-day treatment period, and the results indicated that the microspheres were safe and had beneficial effects on the liver, reducing the occurrence of fatty deposits seen in untreated diabetic rats. Moreover, in terms of liver, renal and cardiac functions, and blood lipid and antioxidant levels, the microspheres were as effective as the injections. The expression of several proteases linked to the metabolism of aliphatic acids and homocysteine was promoted by the microsphere formulations. Inflammatory markers in the microsphere treatment groups were somewhat higher than the injection group, however. The liraglutide/PLGA microspheres prepared in this work are overall shown to be efficacious in a rat model of diabetes, and we thus believe they have strong potential for clinical use.
Dingoes (genus Canis) produce a stereotyped bark-howl vocalisation, which is a unimodal complex signal formed by the concatenation of two call types (a bark and a howl). Bark-howls may function as alarm signals, although there has been no empirical investigation of this vocalisation's structure or function. We quantified the content and efficacy of the bark and howl segments separately and when combined, using 140 calls from 10 individuals. We found that both segments are individually distinctive, although howl segments are more accurately classified, suggesting a higher level of individuality. Furthermore, howls convey signature characteristics that are conserved across different contexts of production, and thus may act as 'identity signals'. The individual distinctiveness of full bark-howls increases above that of isolated segments, which may be a result of selection on improved signal discriminability. Propagation tests revealed that bark-howls are best described as medium-range signals, with both segments potentially allowing for individual discrimination up to 200m regardless of environmental conditions. We discuss our findings regarding the fitness benefits of encoding identity cues in a potential alarm call and propose additional hypotheses for the function(s) of bark and howl segments.
Herbivory and nutrient limitation can increase the resistance of temperature-limited systems to invasions under climate warming. We imported seeds of lowland species to tundra under factorial treatments of warming, fertilization, herbivore exclusion and biomass removal. We show that warming alone had little impact on lowland species, while exclusion of native herbivores and relaxation of nutrient limitation greatly benefitted them. In contrast, warming alone benefitted resident tundra species and increased species richness; however, these were canceled by negative effects of herbivore exclusion and fertilization. Dominance of lowland species was associated with low cover of tundra species and resulted in decreased species richness. Our results highlight the critical role of biotic and abiotic filters unrelated to temperature in protecting tundra under warmer climate. While scarcity of soil nutrients and native herbivores act as important agents of resistance to invasions by lowland species, they concurrently promote overall species coexistence. However, when these biotic and abiotic resistances are relaxed, invasion of lowland species can lead to decreased abundance of resident tundra species and diminished diversity.
Irradiation of plants and animals can result in disruption of ecological relationships between the components of ecosystems. Such effects may act as triggers of perturbation and lead to consequences that may differ essentially from expected ones based on effects observed at the organismal level. Considerable differences in ecology and niches occupied by different species lead to substantial differences in doses of ionizing radiation absorbed by species, even when they all are present in the same environment at the same time. This is especially evident for contamination with α-emitting radionuclides. Radioactive contamination can be considered an ecological factor that is able to modify the resistance in natural populations. However, there are radioecological situations when elevated radioresistance does not evolve or persist. The complexity and non-linearity of the structure and functioning of ecosystems can lead to unexpected consequences of stress effects, which would appear harmless if they were assessed within the narrower context of organism-based traditional radioecology. Therefore, the use of ecological knowledge is essential for understanding responses of populations and ecosystems to radiation exposure. Integration of basic ecological principles in the design and implementation of radioecological research is essential for predicting radiation effects under rapidly changing environmental conditions.
Deep venous thrombosis (DVT) is a manifestation of venous thromboembolism (VTE). It has been estimated that there are 900,000 cases of pulmonary emboli (PE) and DVT per year resulting in 60,000 to 300,000 deaths. About two-thirds of VTE cases are associated with prolonged hospitalizations, emphasizing the importance of major surgery or immobilization as risk factors.
Retrospective study conducted in a Metropolitan Hospital. A total of 46 records were obtained from the hospital database following the established inclusion and exclusion criteria. For the control group a total of 42 records were selected. Patients included in this study were admitted with the diagnosis of deep venous thrombosis identified either by lower leg Doppler.
Monocytosis with DVT, p-value was <0.001, with an Odd Ratio (OR) 9.35 and Interval Confidence (IC) 95% (3.2-27.3). The p-value for eosinophilia with DVT was 0.092, for males with DVT the p-value was 0.35 and age related groups with DVT value was 0.720. Sensitivity of monocytosis was 67.3%, specificity 80%, positive predictive value (PPV) 79.49% and negative predictive value (NPV) 63.9%.
This study revealed the association between monocytosis and DVT, thus patients with monocytosis are more likely to develop DVT. This evidence is consistent with previous studies establishing that monocytes could have an important role with the coagulation cascade activation and the formation of DVT. The association of monocyte count and DVT can be used in the future as a significant tool in those patients with suspected DVT to increase diagnostic yield.
Cadherins have been identified as receptors of Bacillus thuringiensis (Bt) Cry1A toxins in several lepidopteran insects including the cotton bollworm, Helicoverpa armigera. Disruption of the cadherin gene HaCad has been genetically linked to resistance to Bt toxin Cry1Ac in H. armigera. By using the CRISPR/Cas9 genome editing system (Clustered Regularly Interspaced Short Palindromic Repeats/CRISPR-associated protein 9), HaCad from the Cry1Ac-susceptible SCD strain of H. armigera was successfully knocked out. A single positive CRISPR event with a frame shift deletion of 4 nucleotides was identified and made homozygous to create a knockout line named SCD-Cad. Western blotting confirmed that HaCad was no longer expressed in the SCD-Cad line while an intact HaCad of 210 kDa was present in the parental SCD strain. Insecticide bioassays were used to show that SCD-Cad exhibited 549-fold resistance to Cry1Ac compared with SCD, but no significant change in susceptibility to Cry2Ab. Our results not only provide strong
 reverse genetics evidence for HaCad as a functional receptor of Cry1Ac, but also demonstrate that the CRISPR/Cas9 technique can act as a powerful and efficient genome editing tool to study gene function in a global agricultural pest, H. armigera.
For the individual, it is vital to promptly detect and recognize a danger that threatens the integrity of the body. Pattern recognition receptors (PRRs) are several classes of protein families originally classified as receptors detecting exogenous pathogens. PRRs are also capable of recognizing molecules released from damaged tissues (damage-associated molecular pattern molecules; DAMPs) and thereby contribute to danger recognition. Importantly, it is now evident that PRRs, such as toll-like receptors (TLRs) and receptors for advanced glycation end products (RAGE), are not only expressed in peripheral immune cells but also present in neurons and glial cells in the nervous system. These PRR-expressing cells work in concert, enabling highly sensitive danger recognition. However, this sensitiveness can act as a double-edged sword. Accumulated evidence has led to the hypothesis that aberrant activation of PRRs may play a crucial role in the pathogenesis of pathological pain. Indeed, numerous studies employing gene deletion or pharmacological inhibition of PRRs successfully reversed or prevented pathological pain in experimental animal models. Furthermore, a number of preclinical studies have shown the therapeutic potential of targeting PRRs for chronic pain. Here, we review the current knowledge regarding the role of PRRs in chronic pain and discuss the promise and challenges of targeting PRRs as a novel therapeutic approach for chronic pain.
The conjugation of therapeutic proteins to polyethylene glycol (PEG) is known as PEGylation. It improves their retention in the body and reduces the frequency of injections. Development of noninvasive delivery systems for biopharmaceuticals can improve the patients' quality of life. The present study aimed to evaluate the cell-penetrating peptides (CPPs), which act as bioenhancers, for the nasal delivery of protein drug interferon beta (IFN-β) and its PEGylated form (PEG-IFN-β). The ability of CPPs to enhance the nasal mucosal absorption of unmodified IFN-β was assessed in rats. It was shown that only d-amino acid forms of amphipathic CPPs, penetratin and PenetraMax significantly enhanced the nasal absorption of IFN-β. Especially, D-penetratin (up to 2mM) enhanced the absorption of INF-β in a dose-dependent manner. The maximum absolute bioavailability reached 8.26% following in situ nasal coadministration of IFN-β with d-penetratin (2mM). Furthermore, it was found that the coadministration of d-penetratin also facilitated the nasal absorption of PEG-IFN-β, which remained in the circulation for more than 6h. Moreover, the toxicity assessments showed no damage to the epithelial membranes after nasal administration of CPPs including penetratin and PenetraMax. Altogether, this study provides the first evidence that the noncovalent coadministration of PEGylated proteins with CPPs could be a potent strategy for the noninvasive and sustained nasal delivery of therapeutic proteins.
Methylphenidate (MPH) is a neural stimulant with unclear neurochemical and behavioral effects. Lithium is a neuroprotective agent in use clinically for the management of manic-depressive and other neurodegenerative disorders. This study investigated the protective effect of lithium on MPH-induced oxidative stress, anxiety, depression and cognition impairment. Forty-eight adult male rats were divided randomly and equally into 6 groups. Treatment groups were received MPH (10mg/kg) and various doses of lithium (75, 150 and 300mg/kg) simultaneously and also lithium (150mg/kg) alone for 21 days. Elevated Plus Maze and Forced Swim Test were used to determine the level of anxiety and depression in animals. Morris Water Maze was used to evaluate spatial learning and memory. The hippocampi of rats were isolated and the level and activity of oxidative, anti-oxidant and inflammatory factors were measured. Also brain derived neurotropic factor expression level was measured by RT-PCR and western blotting. MPH (10mg/kg) caused behaviors indicative of anxiety and depression-like phenotypes in EPM and FST and cognition impairment in MWM. While lithium in all mentioned doses inhibited these effects. Treatment with MPH significantly increased lipid peroxidation, mitochondrial GSH content and IL-1β and TNF-α levels in isolated hippocampal cells. Moreover superoxide dismutase and glutathione peroxidase activities and BDNF expression remarkably decreased. Various doses of lithium attenuated these effects and significantly mitigated MPH-induced oxidative damage, inflammation and increased BDNF expression level. Lithium has the potential to act as a neuroprotective agent against MPH induced toxicity in rat brain and this might be mediated by BDNF expression in hippocampus of rats.
Atrial natriuretic peptide (ANP)-mediated natriuretic response is a well-established cardiac endocrine function. Corin is a transmembrane protease that activates ANP in the heart. Corin expression has been detected in non-cardiac tissues including the kidney. Here we examined corin, pro-ANP/ANP and natriuretic peptide receptor-A (NPR-A) expression in human renal segments. By immunostaining and in situ hybridization, we found similar corin, pro-ANP/ANP and NPR-A protein and mRNA expression in human renal segments. The expression was most abundant in the proximal convoluted tubules and the medullary connecting ducts. In the proximal tubules, corin protein was present in the apical membrane region underneath the brush border where the ANP-degrading protease neprilysin was abundant. These results suggest that corin-mediated pro-ANP activation may occur in renal segments and that locally produced ANP may act in an autocrine manner to regulate sodium and water reabsorption in situ Our results also point to the proximal convoluted tubules as a major site for local ANP action. Such a renal corin/ANP autocrine mechanism may differ from the cardiac corin/ANP endocrine mechanism in regulating sodium homoeostasis under physiological and pathological conditions.
Prenatal infection and traumatizing experiences have both been linked with schizophrenia, but none of these factors seem sufficient to cause the disorder. However, recent evidence suggests that these environmental insults act in synergy to increase schizophrenia risk.
To estimate the independent and joint effects of exposure to prenatal infection and peripubertal psychological trauma on the risk of schizophrenia.
Danish nationwide registers were linked in this prospective cohort study. We used survival analysis to report incidence rate ratios (IRRs) and corresponding 95% confidence intervals (95% CIs). Analyses were adjusted for age and calendar period and stratified by sex.
A total of 979701 persons born between 1980 and 1998 were followed up from January 1, 1995 through December 31, 2013, with 9656 having a hospital contact for schizophrenia.
Females exposed to prenatal infection had a significantly increased risk of schizophrenia (IRR: 1.61, 95% CI: 1.30-2.00), but not males (IRR: 0.99, 95% CI: 0.77-1.28). Peripubertal trauma was associated with increased risk in both sexes. Males, however, had a significantly higher risk of schizophrenia after exposure to both prenatal infection and peripubertal psychological trauma (IRR: 2.85, 95% CI: 2.32-3.51), with significant interaction between infection and peripubertal trauma on the multiplicative scale (P = .007).
Our study demonstrated for the first time that prenatal infection and psychological trauma in peripubertal life can act in synergy to increase the risk of schizophrenia, with a potentially stronger susceptibility in males.
To seek differences of Achilles tendon hardness between insertional tendinopathy (IT) and asymptomatic controls by using computer-assisted quantification on axial-strain sonoelastography (ASE).
The study consisted of 37 non-athletic patients presenting with Achilles tendon pain in one or two tendons. Both tendons were examined clinically. Among the 74 tendons, 16 were diagnosed and categorized into an IT group and 29 into an asymptomatic group. The remaining 29 tendons were excluded due to non-insertional tendinopathy, ruptures, previous surgery or mixed disorders. The tendons in the IT and asymptomatic groups were examined with both ASE and conventional ultrasound. Computer-assisted quantification on ASE was conducted to extract parameters of tendon hardness, including the 20th percentile (H20), median (H50) and skewness (Hsk) of the hardness within tendon, as well as the ratio of the mean hardness within tendon to that outside tendon (Hratio).
The H20 (p = 0.003), H50 (p = 0.004) and Hratio (p = 0.002) were larger and Hsk (p = 0.001) was smaller at distal thirds of IT tendons than those of asymptomatic tendons. For differentiation between two groups, the Hsk achieved the best value (0.815) of area under the receiver operating characteristic curve, with a sensitivity of 81.3 %, a specificity of 86.2 % and an accuracy of 84.4 %.
Computer-assisted quantification on ASE shows that IT tendons are harder than asymptomatic tendons. It might act as a potentially useful technique for identification and risk stratification of IT patients and thus be valuable in day-by-day clinical practice for monitoring IT progression and for evaluating therapeutic effects.
III.
This study reports the presence of hospital-associated high-risk lineages of OXA-23-producing ST79 Acinetobacter baumannii and SPM-1-producing ST277 Pseudomonas aeruginosa in urban rivers in Brazil. These findings indicate that urban rivers can act as reservoirs of clinically important multidrug-resistant bacteria, which constitute a potential
 risk to human and animal health.
Nitrogen mustard (NM), a bifunctional alkylating agent (BAA), contains two alkyl arms and can act as a cross-linking bridge between DNA and protein to form a DNA-protein cross-link (DPC). O(6)-methylguanine-DNA methyltransferase (MGMT), a DNA repair enzyme for alkyl adducts removal, is found to enhance cell sensitivity to BAAs and to promote damage, possibly due to its stable covalent cross-linking with DNA mediated by BAAs. To investigate MGMT-DNA cross-link (mDPC) formation and its possible dual roles in NM exposure, human bronchial epithelial cell line 16HBE was subjected to different concentrations of HN2, a kind of NM, and we found mDPC was induced by HN2 in a concentration-dependent manner, but the mRNA and total protein of MGMT were suppressed. As early as 1h after HN2 treatment, high mDPC was achieved and the level maintained for up to 24h. Quick total DPC (tDPC) and γ-H2AX accumulation were observed. To evaluate the effect of newly predicted protease DVC1 on DPC cleavage, we applied siRNA of MGMT and DVC1, MG132 (proteasome inhibitor), and NMS-873 (p97 inhibitor) and found that proteolysis plays a role. DVC1 was proven to be more important in the cleavage of mDPC than tDPC in a p97-dependent manner. HN2 exposure induced DVC1 upregulation, which was at least partially contributed to MGMT cleavage by proteolysis because HN2-induced mDPC level and DNA damage was closely related with DVC1 expression. Homologous recombination (HR) was also activated. Our findings demonstrated that MGMT might turn into a DNA damage promoter by forming DPC when exposed to HN2. Proteolysis, especially DVC1, plays a crucial role in mDPC repair.
Escherichia coli is the most commonly used indicator for fecal contamination in drinking water distribution systems (WDS). The assumption is that E. coli bacteria are of enteric origin and cannot persist for long outside their host and therefore act as indicators of recent contamination events. This study investigates the fate of E. coli in drinking water, specifically addressing survival, biofilm formation under shear stress, and regrowth in a series of laboratory-controlled experiments. We show the extended persistence of three E. coli strains (two enteric isolates and one soil isolate) in sterile and nonsterile drinking water microcosms at 8 and 17°C, with T90 (time taken for a reduction in cell number of 1 log10 unit) values ranging from 17.4 ± 1.8 to 149 ± 67.7 days, using standard plate counts and a series of (reverse transcription-)quantitative PCR [(RT-)Q-PCR] assays targeting 16S rRNA, tuf, uidA, and rodA genes and transcripts. Furthermore, each strain was capable of attaching to a surface and replicating to form biofilm in the presence of nutrients under a range of shear stress values (0.6, 2.0, and 4.4 dynes [dyn] cm(-2); BioFlux system; Fluxion); however, cell numbers did not increase when drinking water flowed over the biofilm (P > 0.05 by t test). Finally, E. coli regrowth within drinking water microcosms containing polyethylene PE-100 pipe wall material was not observed in the biofilm or water phase using a combination of culturing and Q-PCR methods for E. coli The results of this work highlight that when E. coli enters drinking water it has the potential to survive and attach to surfaces but that regrowth within drinking water or biofilm is unlikely.
The provision of clean, safe drinking water is fundamental to society. WDS deliver water to consumers via a vast network of pipes. E. coli is used as an indicator organism for recent contamination events based on the premise that it cannot survive for long outside its host. A key public health concern therefore arises around the fate of E. coli on entering a WDS; its survival, ability to form a biofilm, and potential for regrowth. In particular, if E. coli bacteria have the ability to incorporate and regrow within the pipe wall biofilm of a WDS, they could reinoculate the water at a later stage. This study sheds light on the fate of environmental and enteric strains of E. coli in drinking water showing extended survival, the potential for biofilm formation under shear stress, and importantly, that regrowth in the presence of an indigenous microbial community is unlikely.
4-n-Butylresorcinol (BR) is considered the most potent inhibitor of tyrosinase, which is why it is used in cosmetics as a depigmenting agent. However, this work demonstrates that BR is a substrate of this enzyme. The Em (met-tyrosinase) form is not active on BR, but Eox (oxy-tyrosinase) can act on this molecule, hydroxylating it to o-diphenol. In turn, this is oxidized to an o-quinone, which isomerizes to a red p-quinone. Thus, for tyrosinase to act on this compound, a mechanism to generate Eox in the medium is required, which can be achieved by means of hydrogen peroxide or ascorbic acid. A kinetic analysis of the proposed mechanism allows its kinetic characterization: catalytic constant kcatBR (8.49 ± 0.20 s(-1) ) and Michaelis-constant KMBR (60.26 ± 8.76 μM). These findings are compared with those for other monophenolic substrates of tyrosinase. Studies of BR docking to the Em form of the enzyme show that the hydroxyl group in C-1 position is oriented toward the copper atom A (CuA), as in it is L-tyrosine. As regards Eox , BR is oriented with the carbon in C-6 position ready to be hydroxylated. The reaction of BR originates o-quinones, which isomerize to p-quinones, which in turn, could react with thiol compounds, a finding that could have important implications for pharmacology and the cosmetic industry. © 2016 IUBMB Life, 68(8):663-672, 2016.
The threat to global food security of stagnating yields and population growth makes increasing crop productivity a critical goal over the coming decades. One key target for improving crop productivity and yields is increasing the efficiency of photosynthesis. Central to photosynthesis is Rubisco, which is a critical but often rate-limiting component. Here, we present full Rubisco catalytic properties measured at three temperatures for 75 plants species representing both crops and undomesticated plants from diverse climates. Some newly characterized Rubiscos were naturally "better" compared to crop enzymes and have the potential to improve crop photosynthetic efficiency. The temperature response of the various catalytic parameters was largely consistent across the diverse range of species, though absolute values showed significant variation in Rubisco catalysis, even between closely related species. An analysis of residue differences among the species characterized identified a number of candidate amino acid substitutions that will aid in advancing engineering of improved Rubisco in crop systems. This study provides new insights on the range of Rubisco catalysis and temperature response present in nature, and provides new information to include in models from leaf to canopy and ecosystem scale.
C-TERMINALLY ENCODED PEPTIDEs (CEPs) control root system architecture in a non-cell-autonomous manner. In Medicago truncatula, MtCEP1 affects root development by increasing nodule formation and inhibiting lateral root emergence by unknown pathways. Here, we show that the MtCEP1 peptide-dependent increase in nodulation requires the symbiotic signaling pathway and ETHYLENE INSENSITIVE2 (EIN2)/SICKLE (SKL), but acts independently of SUPER NUMERIC NODULES. MtCEP1-dependent inhibition of lateral root development acts through an EIN2-independent mechanism. MtCEP1 increases nodulation by promoting rhizobial infections, the developmental competency of roots for nodulation, the formation of fused nodules, and an increase in frequency of nodule development that initiates at proto-phloem poles. These phenotypes are similar to those of the ein2/skl mutant and support that MtCEP1 modulates EIN2-dependent symbiotic responses. Accordingly, MtCEP1 counteracts the reduction in nodulation induced by increasing ethylene precursor concentrations, and an ethylene synthesis inhibitor treatment antagonizes MtCEP1 root phenotypes. MtCEP1 also inhibits the development of EIN2-dependent pseudonodule formation. Finally, mutants affecting the COMPACT ROOT ARCHITECTURE2 (CRA2) receptor, which is closely related to the Arabidopsis CEP Receptor1, are unresponsive to MtCEP1 effects on lateral root and nodule formation, suggesting that CRA2 is a CEP peptide receptor mediating both organogenesis programs. In addition, an ethylene inhibitor treatment counteracts the cra2 nodulation phenotype. These results indicate that MtCEP1 and its likely receptor, CRA2, mediate nodulation and lateral root development through different pathways.
Ribosomal RNA (rRNA) modifications are essential for ribosome function in all cellular organisms. Box C/D small (nucleolar) ribonucleoproteins [s(no)RNPs] catalyze 2'-O-methylation, one rRNA modification type in Eukarya and Archaea. Negatively stained electron microscopy (EM) models of archaeal box C/D sRNPs have demonstrated the dimeric sRNP (di-sRNP) architecture, which has been corroborated by nuclear magnetic resonance (NMR) studies. Due to limitations of the structural techniques, the orientation of the box C/D sRNAs has remained unclear. Here, we have used cryo-EM to elucidate the sRNA orientation in a M. jannaschii box C/D di-sRNP. The cryo-EM reconstruction suggests a parallel orientation of the two sRNAs. Biochemical and structural analyses of sRNPs assembled with mutant sRNAs indicate a potential interaction between the sRNA stem ends. Our results suggest that the parallel arrangement of the sRNAs juxtaposes their stem ends into close proximity to allow for a stabilizing interaction that helps maintain the di-sRNP architecture.
The essential mycobacterial transcriptional regulators RbpA and CarD act to modulate transcription by associating to the initiation complex and increasing the flux of
 transcript production. Each of these factors interacts directly with the promoter DNA template and with RNA polymerase (RNAP) holoenzyme. We recently reported on the energetics of CarD-mediated open complex stabilization on the Mycobacterium tuberculosis rrnAP3 ribosomal promoter using a stopped-flow fluorescence assay. Here, we apply this approach to RbpA and show that RbpA stabilizes RNAP-promoter open complexes (RPo) via a distinct mechanism from that of CarD. Furthermore, concentration-dependent stopped-flow experiments with both factors reveal positive linkage (cooperativity) between RbpA and CarD with regard to their ability to stabilize RPo The observation of positive linkage between RbpA and CarD demonstrates that the two factors can act on the same transcription initiation complex simultaneously. Lastly, with both factors present, the kinetics of open complex formation is significantly faster than in the presence of either factor alone and approaches that of E. coli RNAP on the same promoter. This work provides a quantitative framework for the molecular mechanisms of these two essential transcription factors and the critical roles they play in the biology and pathology of mycobacteria.
Cardiac Troponin I and Troponin T are both very sensitive and specific, with the troponin pathology test recommended for the diagnosis of myocardial infarction. The diagnosis of myocardial infarction, in conjunction with electrocardiogram myocardial infarction, is based on a rise or fall of troponin with at least one value above the 99th percentile for the population. Troponin levels are regularly ordered within hospitals, especially in emergency medicine. It has been suggested that much of this testing is ordered despite the absence of clinical suspicion for acute coronary syndrome.
This study examined the appropriateness of troponin testing within one Australian teaching hospital.
A retrospective chart review was conducted of 111 randomly selected patients who received a troponin assay within the hospital's Emergency Department. To determine appropriateness, the troponin test needed to reflect Australian clinical guidelines, and inform the ongoing management of the patient.
Results demonstrate that the majority (76.6 %) of troponin testing was appropriate, with the remainder (23.4 %) deemed inappropriate due to not altering the ongoing patient management (n = 26), and not being informed by clinical guidelines (n = 26).
Troponin testing is important in the diagnosis of myocardial infarction, although should not be ordered routinely, or unnecessary. This study has determined that using clinical guidelines can promote rational ordering, and that testing should ultimately benefit patient management. Reducing inappropriate pathology test ordering is important to maximize productive clinical time, reduce false positives, maximize patient care, and to reduce financial waste.
Head and neck squamous cell carcinoma is the sixth leading cause of cancer worldwide. The most common risk factors are carcinogens (tobacco, alcohol), and infection of the human papilloma virus. Surgery is still considered as the treatment of choice in case of head and neck cancer, followed by a reconstructive surgery to enhance the quality of life in the patients. However, the widespread use of artificial implants does not provide appropriate physiological activities and often cannot act as a long-term solution for the patients. Here we review the applicability of multiple stem cell types for tissue engineering of cartilage, trachea, vocal folds and nerves for head and neck injuries. The ability of the cells to self-renew and maintain their pluripotency state makes them an attractive tool in tissue engineering.
OBJECTIVE The emphasis on health-related quality of life (HRQOL) outcomes is increasing, along with an emphasis on evidence-based medicine. However, there is a notable paucity of validated HRQOL instruments for the pediatric population. Furthermore, no standardization or consensus currently exists concerning which HRQOL outcome measures ought to be used in pediatric neurosurgery. The authors wished to identify HRQOL outcomes used in pediatric neurosurgery research over the past 10 years, their frequency, and usage trends. METHODS Three top pediatric neurosurgical journals were reviewed for the decade from 2005 to 2014 for clinical studies of pediatric neurosurgical procedures that report HRQOL outcomes. Similar studies in the peer-reviewed journal Pediatrics were also used as a benchmark. Publication year, level of evidence, and HRQOL outcomes were collected for each article. RESULTS A total of 31 HRQOL studies were published in the pediatric neurosurgical literature over the study period. By comparison, there were 55 such articles in Pediatrics. The number of publications using HRQOL instruments showed a significant positive trend over time for Pediatrics (B = 0.62, p = 0.02) but did not increase significantly over time for the 3 neurosurgical journals (B = 0.12, p = 0.5). The authors identified a total of 46 different HRQOL instruments used across all journals. Within the neurosurgical journals, the Hydrocephalus Outcome Questionnaire (HOQ) (24%) was the most frequently used, followed by the Health Utilities Index (HUI) (16%), the Pediatric Quality of Life Inventory (PedsQL) (12%), and the 36-Item Short Form Health Survey (SF-36) (12%). Of the 55 articles identified in Pediatrics, 22 (40%) used a version of the PedsQL. No neurosurgical study reached above Level 4 on the Oxford Centre for Evidence-Based Medicine (OCEBM) system. However, multiple studies from Pediatrics achieved OCEBM Level 3, several were categorized as Level 2, and one reached Level 1. CONCLUSIONS The frequency of studies using HRQOL outcomes in pediatric neurosurgical research has not increased over the past 10 years. Within pediatric neurosurgery, high-quality studies and standardization are lacking, as compared with contemporary studies in Pediatrics. In general, although the HOQ, HUI, PedsQL, and SF-36 instruments are emerging as standards in pediatric neurosurgery, even greater standardization across the specialty is needed, along with the design and implementation of more rigorous studies.
Multifunctional nanomaterials have shown excellent and promising properties for cancer diagnosis and treatment. Herein, we have developed iron doped copper sulfide (Cu5FeS4) nanoparticles with a non-covalent polyethylene glycol (PEG) coating (Cu5FeS4-PEG) for tumor dual-modal imaging and photothermal therapy (PTT). The obtained Cu5FeS4-PEG nanoparticles with high near-infrared absorbance could be used for phototoacoustic (PA) imaging and PTT, whereas Fe(3+) doping offer the nanoparticles the additional property for magnetic resonance (MR) imaging. As shown by PA imaging, Cu5FeS4-PEG exhibit a high tumor uptake (∼10% ID g(-1)) after intravenous injection. In vitro and in vivo cancer treatment further confirm that Cu5FeS4-PEG could act as a novel therapeutic agent for PTT of cancer cells. Our study further promotes the potential applications of multifunctional nanomaterials in a range of tumor diagnoses and treatments.
Understanding the trajectories of youths within Child and Adolescents Mental Health Service (CAMHS) is of primary importance. Our objective is to assess the usefulness of the Health of the Nation Outcome Scales for Children and Adolescents (HoNOSCA) to predict inpatient (IP) stay for youths followed by assertive community treatment (ACT) teams. 82 youths followed exclusively by ACT and 42 who needed IP were assessed with the HoNOSCA at admission to the program. The HoNOSCA allowed the computing of three scores: a total score, an externalizing symptoms (Ext) score and an emotional problems (Emo) score. Logistic regressions revealed that the three HoNOSCA scores at admission of ACT predicted later need for hospitalization. Using ROC curve analyses, we set up cut off scores with appropriate sensitivity and specificity for the HoNOSCA Total and Ext to optimally predict the need for hospitalization. This study revealed that the HoNOSCA may be a useful tool to predict the need for later IP during ACT. Such knowledge is important to set up the best therapeutic strategies.
We experimentally study a driven-dissipative Josephson junction array, realized with a weakly interacting Bose-Einstein condensate residing in a one-dimensional optical lattice. Engineered losses on one site act as a local dissipative process, while tunneling from the neighboring sites constitutes the driving force. We characterize the emerging steady states of this atomtronic device. With increasing dissipation strength γ the system crosses from a superfluid state, characterized by a coherent Josephson current into the lossy site, to a resistive state, characterized by an incoherent hopping transport. For intermediate values of γ, the system exhibits bistability, where a superfluid and an incoherent branch coexist. We also study the relaxation dynamics towards the steady state, where we find a critical slowing down, indicating the presence of a nonequilibrium phase transition.
CRISPR/Cas9 technology is currently considered the most advanced tool for targeted genome engineering. Its sequence-dependent specificity has been explored for locus-directed transcriptional modulation. Such modulation, in particular transcriptional activation, has been proposed as key approach to overcome silencing of dormant HIV provirus in latently infected cellular reservoirs. Currently available agents for provirus activation, so-called latency reversing agents (LRAs), act indirectly through cellular pathways to induce viral transcription. However, their clinical performance remains suboptimal, possibly because reservoirs have diverse cellular identities and/or proviral DNA is intractable to the induced pathways. We have explored two CRISPR/Cas9-derived
 activator systems as targeted approaches to induce dormant HIV-1 proviral DNA. These systems recruit multiple transcriptional activation domains to the HIV 5' long terminal repeat (LTR), for which we have identified an optimal target region within the LTR U3 sequence. Using this target region, we demonstrate transcriptional activation of proviral genomes via the synergistic activation mediator complex in various in culture model systems for HIV latency. Observed levels of induction are comparable or indeed higher than treatment with established LRAs. Importantly, activation is complete, leading to production of infective viral particles. Our data demonstrate that CRISPR/Cas9-derived technologies can be applied to counteract HIV latency and may therefore represent promising novel approaches in the quest for HIV elimination.
Multiple myeloma (MM) is still an incurable hematological malignancy. Despite recent progress due to new anti-myeloma agents, the pathology is characterized by a high frequency of de novo or acquired resistance. Delineating the mechanisms of MM resistance is essential for therapeutic advances. We previously showed that long-term genotoxic stress induces the establishment of a senescence-associated secretory phenotype, a pro-inflammatory response that favors the emergence of cells with cancer stem-like properties. Here, we studied the short-term response of MM cells following treatment with various DNA damaging agents such as the energetic C-ion irradiation. MM cells are highly resistant to all treatments and do not enter apoptosis after they arrest cycling at the G2 phase. Although the DNA damage response pathway was activated, DNA breaks remained chronically in damaged MM cells. We found, using a transcriptomic approach that RAD50, a major DNA repair gene was downregulated early after genotoxic stress. In two gerosuppression situations: induction of hypoxia and inhibition of the mammalian target of rapamycin (mTOR) pathway, we observed, after the treatment with a DNA damaging agent, a normalization of RAD50 expression concomitant with the absence of cell cycle arrest. We propose that combining inhibitors of mTOR with genotoxic agents could avoid MM cells to senesce and secrete pro-inflammatory factors responsible for cancer stem-like cell emergence and, in turn, relapse of MM patients.
Pancreatic resection is the only effective treatment with prolonged survival in operable pancreatic cancer and peri-ampullary cancer; it is also a procedure of significant morbidity and complications. Vascular injury is one of the most serious intraoperative complications.
We report here a case of common hepatic artery injury during pancreaticodudenectomy followed by complete thrombosis after its repair. As common hepatic artery is the only arterial blood supply of the liver, acute liver failure and necrosis were the usual course. Surprisingly liver enzymes and bilirubin start to improve in post operatively due to small hardly detected accessory left and middle hepatic artery.
Although hepatic artery is the only arterial supply of the liver, occasionally small accessory arteries may give significant arterial blood supply. In such a situation liver enzymes act as surrogate markers to assess the sufficiency of this flow to the liver.
We previously demonstrated that cancer-associated fibroblasts (CAFs) accumulate at tumor sites through the interaction between a chemokine, CCL3, and its receptor, CCR5, in the late phase of colitis-associated colon carcinogenesis. Here we examined the effect of a CCR5 antagonist, maraviroc, on tumor growth arising from the orthotopic injection of mouse or human colon cancer cell lines into the cecal wall by focusing on CAFs. Orthotopic injection of either cell line caused tumor formation together with leukocyte infiltration and fibroblast accumulation. Concomitant oral administration of maraviroc reduced tumor formation with few effects on leukocyte infiltration. In contrast, maraviroc reduced the intratumor number of α-smooth muscle actin-positive fibroblasts, which express epidermal growth factor, a crucial growth factor for colon cancer cell growth. These observations suggest that maraviroc or other CCR5 antagonists might act as novel anti-CRC drugs to dampen CAFs, an essential cell component for tumor progression.
Dialysis patients present a cardiovascular risk substantially higher than general population, due to both traditional and non-traditional risk factors. Hemorheologic alterations have been extensively described in hemodialysis patients (HD), while little data on hemorheology exist about peritoneal dialysis patients (PD). Aim of our study is to characterize the hemorheological profile of 49 PD, and to compare these data with HD and healthy volunteers. PD showed an improvement of parameters related to macro-circulation (plasma viscosity, whole blood viscosity at 1-Hz, erythrocyte aggregation index and yield stress) when compared to HD, while microcirculatory function resulted severely impaired, as expressed by high values for whole blood viscosity 200-Hz shear rate and lower erythrocyte deformability (ED). In conclusion, we found hemorheologic alterations in PD, with substantial differences with respect to HD; in particular, PD showed profound dysfunction in microcirculatory flow with impaired ED. This alterations may act as a risk factor for accelerated atherosclerosis and precipitate cardiovascular events, and it may have a detrimental effect in the peritoneal microcirculation promoting endothelial activation with subsequent fibrosis, leading to peritoneal membrane malfunctioning.
Workplace violence (WPV) is becoming an issue that needs immediate attention in the United States, especially during this period as more states are adopting the "stand your ground laws to promote worker protection." This study was conducted to investigate how WPV has contributed to an unsafe environment for nurses and nursing assistants who work in long-term medical care facilities.
A structure questionnaire was used to collect data for the study. Three facilities were sampled and 80 nurses and certified nursing assistants participated in the study. Ninety-two percent (n = 74) were female and 8% (n = 6) were male. Approximately 62% were black or African American, approximately 33% were Caucasians, and only 2% were from other ethnicities.
We found that 65% of the participants had experienced WPV while 41% believed that management shows little or no concern for their safety. Approximately 23% of respondents believed that reporting supervisor's WPV act is an unsafe action. In addition, 22% of those who reported that they have experienced WPV believed that the work environment is not safe to perform their duties. This significant difference in perception of workplace safety between those who had experienced WPV and those who had not was significant (t = 3.95, df = 158, p < 0.0001).
WPV is an epidemic problem that affects all health-care professionals. The findings of this study could help long-term medical care facilities' management identify the areas to focus on mitigating, controlling, and/or eliminating incidents of WPV.
Bacteria, which prey on other microorganisms, are commonly found in the environment. While some of these organisms act as solitary hunters, others band together in large consortia before they attack their prey. Anecdotal reports suggest that bacteria practicing such a wolfpack strategy utilize antibiotics as predatory weapons. Consistent with this hypothesis, genome sequencing revealed that these micropredators possess impressive capacities for natural product biosynthesis. Here, we will present the results from recent chemical investigations of this bacterial group, compare the biosynthetic potential with that of non-predatory bacteria and discuss the link between predation and secondary metabolism.
Acute inflammation is a host-protective response that is mounted in response to tissue injury and infection. Initiated and perpetuated by exogenous and endogenous mediators, acute inflammation must be resolved for tissue repair to proceed and for homeostasis to be restored. Resolution of inflammation is an actively regulated process governed by an array of mediators as diverse as those that initiate inflammation. Among these, resolvins have emerged as a genus of evolutionarily conserved proresolving mediators that act on specific cellular receptors to regulate leukocyte trafficking and blunt production of inflammatory mediators, while also promoting clearance of dead cells and tissue repair. Given that chronic unresolved inflammation is emerging as a central causative factor in the development of cardiovascular diseases, an understanding of the endogenous processes that govern normal resolution of acute inflammation is critical for determining why sterile maladaptive cardiovascular inflammation perpetuates. Here, we provide an overview of the process of resolution with a focus on the enzymatic biosynthesis and receptor-dependent actions of resolvins and related proresolving mediators in immunity, thrombosis, and vascular biology. We discuss how nutritional and current therapeutic approaches modulate resolution and propose that harnessing resolution concepts could potentially lead to the development of new approaches for treating chronic cardiovascular inflammation in a manner that is not host disruptive.
Anne Barnhill and Franklin Miller dispute my claim that the prescriptions of placebo treatments to patients are not typically deceptive, and do not typically violate the patients' informed consent. However, Barnhill and Miller seriously mischaracterise my position in two ways, as well as failing to show that the procedure I discuss requires a physician to act wrongfully in deceiving her patient. Accordingly, I find their argument unpersuasive.
Studies into the function of structures
 are crucial for making connections between morphology and behaviour of organisms, but are still rare for the terrestrial Testudinidae. We investigated the kinematics of shoulder girdle and forelimb motion in Hermann's tortoise Testudo hermanni using biplanar X-ray fluoroscopy with a twofold aim: firstly, to understand how the derived shapes of shoulder girdle and carapace together influence rotation of the girdle; and, secondly, to understand how girdle rotation affects forelimb excursion. The total degree of shoulder rotation in the horizontal plane is similar to a species with a less domed shell, but because of the long and nearly vertically oriented scapular prong, shoulder girdle rotation contributes more than 30% to the horizontal arc of the humerus and nearly 40% to the rotational component of step length. The antebrachium and manus, which act as a functional unit, contribute roughly 50% to this component of the step length because of their large excursion almost parallel to the mid-sagittal plane. This large excursion is the result of the complex interplay between humerus long-axis rotation, counter-rotation of the antebrachium, and elbow flexion and extension. A significant proportion of forelimb step length results from body translation that is due to the propulsive effect of the other limbs during their stance phases. Traits that are similar to other tortoises and terrestrial or semi-aquatic turtles are the overall slow walk because of a low stride frequency, and the lateral-sequence, diagonally coupled footfall pattern with high duty factors. Intraspecific variation of carapace shape and shoulder girdle dimensions has a corresponding effect on forelimb kinematics.
Dental plaque is a biofilm that forms naturally on the surfaces of exposed teeth and other areas of the oral cavity. It is the primary etiological factor for the most frequently occurring oral diseases, such as dental caries and periodontal diseases. Specific, nonspecific, and ecologic plaque hypothesis explains the causation of dental and associated diseases. Adequate control of biofilm accumulation on teeth has been the cornerstone of prevention of periodontitis and dental caries. Mechanical plaque control is the mainstay for prevention of oral diseases, but it requires patient cooperation and motivation; therefore, chemical plaque control agents act as useful adjuvants for achieving the desired results. Hence, it is imperative for the clinicians to update their knowledge in chemical antiplaque agents and other developments for the effective management of plaque biofilm-associated diseases. This article explores the critical analysis of various chemical plaque control strategies and the current trends in the control and prevention of dental plaque biofilm.
Our understanding of the functions of cardiac fibroblasts has moved beyond their roles in heart structure and extracellular matrix generation and now includes their contributions to paracrine, mechanical and electrical signalling during ontogenesis and normal cardiac activity. Fibroblasts also have central roles in pathogenic remodelling during myocardial ischaemia, hypertension and heart failure. As key contributors to scar formation, they are crucial for tissue repair after interventions including surgery and ablation. Novel experimental approaches targeting cardiac fibroblasts are promising potential therapies for heart disease. Indeed, several existing drugs act, at least partially, through effects on cardiac connective tissue. This Review outlines the origins and roles of fibroblasts in cardiac development, homeostasis and disease; illustrates the involvement of fibroblasts in current and emerging clinical interventions; and identifies future targets for research and development.
There is an increasing interest for combined nutraceuticals that can act on several points of lipid and glucose metabolism with preventive purposes. However, the simple assemblage of nutraceuticals with potentially additive mechanism of action need to be clinically tested.
To assess the effects of a combination of nutraceuticals based on artichoke, red yeast rice, banaba, and coenzyme Q10, we performed a double bind, cross-over designed trial versus placebo in 30 adults with LDL cholesterol suboptimal in primary prevention of cardiovascular disease. After a period of 3 weeks of dietary habits correction, patients began a period of 6 weeks of treatment with nutraceutical or placebo, followed by 2 weeks of washout and finally 6 weeks in cross-over. Data related to lipid pattern, insulin resistance, renal function, liver and CPK have been obtained at each visit.
In particular, the after the nutraceutical treatment the enrolled patients experienced a significant improvement in total cholesterol (-13.6 %), LDL-C (-18.2 %), non-HDL-C (-15 %), glutamic oxaloacetic transaminase (-10 %), glutamate-pyruvate transaminase (-30.9 %), and hs-CRP (-18.2 %) versus placebo. No changes have been observed in the other investigated parameters in both groups.
The tested combination of nutraceuticals has shown clinical efficacy in the reduction of total cholesterol, non-HDL, LDL and triglycerides, while improving the level of liver transaminases and high sensitivity C-reactive protein. Further confirmation are needed to verify these observations on the middle and long term with a larger number of subjects.
Metastases are the most common reason of cancer death in patients with solid tumors. Lymph nodes, once invaded by tumor cells, act as reservoirs before cancer cells spread to distant organs. To address the limited access of intravenously infused chemotherapeutics to the lymph nodes, we have developed PEGylated polyglutamic acid nanocapsules (PGA-PEG NCs), which have shown ability to reach and to accumulate in the lymphatic nodes and could therefore act as nanotransporters. Once in the lymphatics, the idea is that these nanocapsules would selectively interact with cancer cells, while avoiding non-specific interactions with immune cells and the appearance of subsequent immunotoxicity.
The potential of the PGA-PEG NCs, with a mean size of 100 nm and a negative zeta potential, to selectively reach metastatic cancer cells, has been explored in a novel 3D model that mimics an infiltrated lymph node. Our 3D model, a co-culture of cancer cells and lymphocytes, allows performing experiments under dynamic conditions that simulate the lymphatic flow. After perfusion of the nanocarriers, we observe a selective interaction with the tumor cells. Efficacy studies manifest the need to develop specific therapies addressed to treat metastatic cells that can be in a dormant state.
We provide evidence of the ability of PGA-PEG NCs to selectively interact with the tumor cells in presence of lymphocytes, highlighting their potential in cancer therapeutics. We also state the importance of designing precise in vitro models that allow performing mechanistic assays, to efficiently develop and evaluate specific therapies to confront the formation of metastasis.
Long non-coding RNAs (lncRNAs) are a group greater than 200 nucleotides in length. An increasing number of studies has shown that lncRNAs play important roles in diverse cellular processes, including proliferation, differentiation, apoptosis, invasion and chromatin remodelling. In this regard, deregulation of lncRNAs has been documented in human cancers. TUG1 is a recently identified oncogenic lncRNA whose aberrant upregulation has been detected in different types of cancer, including B-cell malignancies, oesophageal squamous cell carcinoma, bladder cancer, hepatocellular carcinoma and osteosarcoma. In these malignancies, knock-down of TUG1 has been shown to suppress cell proliferation, invasion and/or colony formation. Interestingly, TUG1 has been found to be downregulated in non-small cell lung carcinoma, indicative of its tissue-specific function in tumourigenesis. Pertinent to clinical practice, TUG1 may act as a prognostic biomarker for tumours. In this review, we summarize current knowledge concerning the role of TUG1 in tumour progression and discuss mechanisms associated with it.
Sphingolipids are a series of cell membrane-derived lipids which act as signaling molecules and play a critical role in cell death and survival, proliferation, recognition, and migration. Sphingosine-1-phosphate acts as a key signaling molecule and regulates lymphocyte trafficking, glial cell activation, vasoconstriction, endothelial barrier function, and neuronal death pathways which plays a critical role in numerous neurological conditions. Stroke is a second leading cause of death all over the world and effective therapies are still in great demand, including ischemic stroke and hemorrhagic stroke as well as poststroke repair. Significantly, sphingolipid activities change after stroke and correlate with stroke outcome, which has promoted efforts to testify whether the sphingolipid pathway could be a novel therapeutic target in stroke. The sphingolipid metabolic pathway, the connection between the pathway and stroke, as well as therapeutic interventions to manipulate the pathway to reduce stroke-induced brain injury are discussed in this review.
The nephrons of the kidney are independent functional units harboring cells of a low turnover during homeostasis. As such, physiological renal cell death is a rather rare event and dead cells are flushed away rapidly with the urinary flow. Renal cell necrosis occurs in acute kidney injuries such as thrombotic microangiopathies, necrotizing glomerulonephritis, or tubular necrosis. All of these are associated with intense intrarenal inflammation, which contributes to further renal cell loss, an autoamplifying process referred to as necroinflammation. But how does renal cell necrosis trigger inflammation? Here, we discuss the role of danger-associated molecular patterns (DAMPs),
 mitochondrial (mito)-DAMPs, and alarmins, as well as their respective pattern recognition receptors. The capacity of DAMPs and alarmins to trigger cytokine and chemokine release initiates the recruitment of leukocytes into the kidney that further amplify necroinflammation. Infiltrating neutrophils often undergo neutrophil extracellular trap formation associated with neutrophil death or necroptosis, which implies a release of histones, which act not only as DAMPs but also elicit direct cytotoxic effects on renal cells, namely endothelial cells. Proinflammatory macrophages and eventually cytotoxic T cells further drive kidney cell death and inflammation. Dissecting the molecular mechanisms of necroinflammation may help to identify the best therapeutic targets to limit nephron loss in kidney injury.
Teachers are thought to play an important role in fostering youth civic engagement; however, the current literature is limited with regard to providing concrete suggestions as to what teachers can do to promote youth civic engagement and why teachers have an impact on youth. To address these limitations, we simultaneously tested three alternative explanations to identify the critical way(s) in which perceived teachers' behaviors might contribute to youth civic engagement in school. We also investigated the underlying processes that may explain why youth's perceptions of teachers' behaviors matter, by focusing on the mediating roles of young people's feelings about politics and their political efficacy beliefs. The sample included 7th (n = 876, M age  = 13.42, SD = .71; 51 % girls) and 10th grade students (n = 857, M age  = 16.62, SD = .71; 51 % girls) residing in Sweden. Among the different aspects of perceived teacher behaviors, only an engaged and inspiring teaching style fostered youth's initiations of civic and political discussions in class over time among both early and late adolescents. Moreover, youth's feelings about politics significantly mediated the effect of perceived teachers' behaviors on youth civic engagement in class. Contrary to our expectation, youth's political efficacy did not act as a mediator. The present study sheds light on what teachers can do to promote youth civic and political engagement in a school setting.
The metal molybdenum (Mo) thin films deposited on flexible substrates can act as the contact electrode of flexible Cu(In,Ga)Se2 or Cu2ZnSn(S,Se)4 solar cells. In this work, in order to enhance the structural and electrical characteristics of flexible Mo thin films, a negative substrate bias was applied during the direct current sputtering of Mo thin films. The flexible substrates used for growing the Mo films were stainless steel foils and polyimides. The characteristics of Mo thin films were studied by x-ray diffraction and sheet resistance measurements. The measured results reveal that an optimal value of negative substrate bias can be found for improving the electrical and structural characteristics of Mo thin films on flexible substrates. The minimum sheet resistances of Mo thin films are 2.50 Ω/sq and 2.73 Ω/sq for the stainless steel foil and polyimide substrates, respectively.
Hypervirulent Clostridium difficile strains, which are associated with increased morbidity and mortality, produce the actin-ADP ribosylating toxin Clostridium difficile transferase (CDT). CDT depolymerizes actin, causes formation of microtubule-based protrusions, and increases pathogen adherence. Here, we show that septins (SEPT) are essential for CDT-induced protrusion formation. SEPT2, -6, -7, and -9 accumulate at predetermined protrusion sites and form collar-like structures at the base of protrusions. The septin inhibitor forchlorfenuron or knockdown of septins inhibits protrusion formation. At protrusion sites, septins colocalize with the GTPase Cdc42 (cell division control protein 42) and its effector Borg (binder of Rho GTPases), which act as up-stream regulators of septin polymerization. Precipitation and surface plasmon resonance studies revealed high-affinity binding of septins to the microtubule plus-end tracking protein EB1, thereby guiding incoming microtubules. The data suggest that CDT usurps conserved regulatory principles involved in microtubule-membrane interaction, depending on septins, Cdc42, Borgs, and restructuring of the actin cytoskeleton.
Intracellular NLR (Nucleotide-binding domain and Leucine-rich Repeat-containing) receptors are sensitive monitors that detect pathogen invasion of both plant and animal cells. NLRs confer recognition of diverse molecules associated with pathogen invasion. NLRs must exhibit strict intramolecular controls to avoid harmful ectopic activation in the absence of pathogens. Recent discoveries have elucidated the assembly and structure of oligomeric NLR signalling complexes in animals, and provided insights into how these complexes act as scaffolds for signal transduction. In plants, recent advances have provided novel insights into signalling-competent NLRs, and into the myriad strategies that diverse plant NLRs use to recognise pathogens. Here, we review recent insights into the NLR biology of both animals and plants. By assessing commonalities and differences between kingdoms, we are able to develop a more complete understanding of NLR function.
Topography can create substantial environmental variation at fine spatial scales. Shaped by slope, aspect, hill-position and elevation, topoclimate heterogeneity may increase ecological diversity, and act as a spatial buffer for vegetation responding to climate change. Strong links have been observed between climate heterogeneity and species diversity at broader scales, but the importance of topoclimate for woody vegetation across small spatial extents merits closer examination. We established woody vegetation monitoring plots in mixed evergreen-deciduous woodlands that spanned topoclimate gradients of a topographically heterogeneous landscape in northern California. We investigated the association between the structure of adult and regenerating size classes of woody vegetation and multidimensional topoclimate at a fine scale. We found a significant effect of topoclimate on both single-species distributions and community composition. Effects of topoclimate were evident in the regenerating size class for all dominant species (four Quercus spp., Umbellularia californica and Pseudotsuga menziesii) but only in two dominant species (Quercus agrifolia and Quercus garryana) for the adult size class. Adult abundance was correlated with water balance parameters (e.g. climatic water deficit) and recruit abundance was correlated with an interaction between the topoclimate parameters and conspecific adult abundance (likely reflecting local seed dispersal). However, in all cases, the topoclimate signal was weak. The magnitude of environmental variation across our study site may be small relative to the tolerance of long-lived woody species. Dispersal limitations, management practices and patchy disturbance regimes also may interact with topoclimate, weakening its influence on woody vegetation distributions. Our study supports the biological relevance of multidimensional topoclimate for mixed woodland communities, but highlights that this relationship might be mediated by interacting factors at local scales.
Receptor activator of nuclear factor kappa beta-ligand (RANKL) is thought to promote vascular calcification (VC) by inducing osteoblastic behaviour in vascular smooth muscle cells (VSMC) in an ill-defined process. The present study assessed whether RANKL affects pro-osteoblastic paracrine signalling between human aortic endothelial cells (HAEC) and human aortic smooth muscle cells (HASMC) using both conditioned media transfer and cell co-culture experimental approaches.
For initial experiments (6-well format), HAEC-conditioned media was harvested following 72h exposure to RANKL, and transferred to reporter HASMCs with/without noggin, an inhibitor of pro-osteoblastic bone morphogenetic protein (BMP) paracrine signalling. In further experiments, HAECs and HASMCs were co-cultured within the CellMax(®) Duo, a perfusing bioreactor unit that mimics the flow-mediated co-interaction of these cells within the arterial wall, and RANKL was added to the perfusing media for 72h. At the conclusion of each experiment markers of osteoblastic activity were measured in HASMCs, including alkaline phosphatase (ALP) activity, mRNA levels of ALP and Runx2, as well as BMP-2 and BMP-4 concentrations. RANKL increased BMP-2 release from HAECs, while exposure of HASMCs to RANKL-treated HAEC-conditioned media induced osteoblastic behaviour in HASMCs, an effect prevented by noggin. Within the CellMax(®) Duo bioreactor, the addition of RANKL to the intraluminal HAECs also produced an increase in BMP-2 and increased osteoblastic behaviour within the co-cultured HASMC population.
RANKL promotes VC by inducing BMP-2 release from HAECs, which in turn appears to act in a paracrine fashion on the adjacent HASMC population to increase osteoblastic activity.
Activating mutations of the G protein-coupled receptor, calcium-sensing receptor (CaSR), cause autosomal dominant hypocalcemia and Bartter syndrome type 5. These mutations lower the set-point for extracellular calcium sensing, thereby causing decreased parathyroid hormone secretion and disturbed renal calcium handling with hypercalciuria. Available therapies increase serum calcium levels but raise the risk of complications in affected patients. Symptom relief and the prevention of adverse outcome is currently very difficult to achieve. Calcilytics act as CaSR antagonists that attenuate its activity, thereby correcting the molecular defect of activating CaSR proteins in vitro and elevating serum calcium in mice and humans in vivo, and have emerged as the most promising therapeutics for the treatment of these
 rare and difficult to treat diseases.
Ubiquitination regulates a broad array of cellular processes, and defective ubiquitination is implicated in several neurological disorders. Loss of the E3 ubiquitin-protein ligase UBE3A causes Angelman syndrome. Despite its clinical importance, the normal role of UBE3A in neurons is still unclear. As a step toward deciphering its possible functions, we performed high-resolution light and electron microscopic immunocytochemistry. We report a broad distribution of UBE3A in neurons, highlighted by concentrations in axon terminals and euchromatin-rich nuclear domains. Our findings suggest that UBE3A may act locally to regulate individual synapses while also mediating global, neuronwide influences through the regulation of gene transcription. J. Comp. Neurol. 525:233-251, 2017. © 2016 Wiley Periodicals, Inc.
Nuclear pore complexes in the nuclear membrane act as the sole gateway of transport of molecules from the cytoplasm to the nucleus and vice versa. Studies on biomolecular transport through nuclear membranes provide vital data on the nuclear pore complexes. In this work, we use fluorescein isothiocyanate-labeled dextran molecules as a model system and study the passive nuclear import of biomolecules through nuclear pore complexes in digitonin-permeabilized HeLa cells. Experiments are carried out under transient conditions in the time lapse imaging scheme using an in-house constructed confocal laser scanning microscope. Transport rates of dextran molecules having molecular weights of 4-70 kDa corresponding to Stokes radius of 1.4-6 nm are determined. Analyzing the permeability of the nuclear membrane for different sizes the effective pore radius of HeLa cell nuclear membrane is determined to be 5.3 nm, much larger than the value reported earlier using proteins as probe molecules. The range of values reported for the nuclear pore radius suggest that they may not be rigid structures and it is quite probable that the effective pore size of nuclear pore complexes is critically dependent on the probe molecules and on the environmental factors.
Migraine is a common episodic neurovascular brain disorder associated with increased risk of cardio- and cerebrovascular ischemia. Migraine headache is likely caused by activation of the trigeminovascular system and release of calcitonin gene-related peptide (CGRP). Monoclonal antibodies against CGRP or its receptor are currently being evaluated for the prevention of migraine attacks. Preliminary efficacy data are promising. However, because CGRP may act as a vasodilatory safeguard during cerebral and cardiac ischemia, CGRP blockade could transform transient mild ischemic events into full-blown infarcts. Here, we review the cerebro- and cardiovascular risks that might be associated with CGRP blockade and which clinical and preclinical studies should be conducted to better assess the potential safety issues of this new promising class of drug.
A new generation of nano-additives for robust high performance nanodielectrics is proposed. It is demonstrated for the first time that mesoporous material could act as "degradation inhibitor" for polymer dielectrics to sequestrate the electrical degradation products then restrain the electrical aging process especially under high temperature conditions, which is superior to the existing additives of nanodielectrics except further increasing the dielectric strength. Polyethylenimine (PEI) loaded nano-scaled mesoporous silica MCM-41 (nano-MS) is doped into the dielectric matrix to prepare the PP/MCM-41-PEI nanocomposites. PEI provides the amines to capture the electrical degradation products while the MCM-41 brackets afford large adsorption surface, bring down the activating temperature of the absorbent then enhance the absorptive capacity. The electrical aging tests confirm the contribution of the mesoporous structure to electrical aging resistance and FT-IR analysis of the electrical degraded regions demonstrates the chemical absorption especially under high temperature conditions. Take the experimental data as examples, extending the aging durability and dielectric strength of polymer dielectrics by 5 times and 16%, respectively, can have substantial commercial significance in energy storage, power electronics and power transmission areas.
The HIPAA Privacy Rule is notoriously weak because of its incomplete coverage, numerous exclusions and exemptions, and limited rights for individuals. The three areas in which it provides the most protection are fundraising, marketing, and research. Provisions of the 21st Century Cures Act, pending in Congress, and the Notice of Proposed Rulemaking to amend the federal research regulations (Common Rule), awaiting final regulatory action, would weaken the privacy protections for research. If these measures are adopted, the HIPAA Privacy Rule would have so little value that it might not be worth the aggravation and burden.
Humans and animals are continuously exposed to a number of environmental substances that act as endocrine disruptors (EDs). While a growing body of evidence is available to prove their adverse health effects, very little is known about the consequences of simultaneous exposure to a combination of such chemicals;
Here, we used an in vitro model to demonstrate how exposure to bisphenol A, zearalenone, arsenic, and 4-methylbenzylidene camphor, alone or in combination, affect estrogen receptor β (ERβ) mRNA expression in primary cerebellar cell cultures. Additionally, we also show the modulatory role of intrinsic biological factors, such as estradiol (E2), triiodo-thyronine (T3), and glial cells, as potential effect modulators;
RESULTS show a wide diversity in ED effects on ERβ mRNA expression, and that the magnitude of these ED effects highly depends on the presence or absence of E2, T3, and glial cells;
The observed potency of the EDs to influence ERβ mRNA expression, and the modulatory role of E2, T3, and the glia suggests that environmental ED effects may be masked as long as the hormonal milieu is physiological, but may tend to turn additive or superadditive in case of hormone deficiency.
Diarrhea and malnutrition represent leading causes of death for children in Mali. Understanding a community's needs and ideas are critical to ensure the success of prevention and treatment interventions for diarrheal disease, as well as to improve food security to help reduce malnutrition. The objective of this study was to incorporate the Community Readiness Model (CRM) for the issues of childhood diarrheal disease and food security in Mali to measure baseline community readiness prior to any program implementation. Thirteen key respondents residing in Dioro, Mali were selected based on varied social roles and demographics and completed two questionnaires on these public health issues. The overall readiness score to reduce childhood diarrheal disease was 5.75 ± 1.0 standard deviation (preparation stage). The overall readiness score to improve food security was 5.5 ± 0.5 standard deviation (preparation stage). The preparation stage indicates that at least some of the community have basic knowledge regarding these issues, and want to act locally to reduce childhood diarrhea and improve food security and nutrition. Proposed activities to increase community readiness on these issues are provided and are broad enough to allow opportunities to implement community- and culturally-specific activities by the Dioro community.
Mycosporine-like amino acids (MAAs) are secondary metabolites, produced by a large variety of microorganisms including algae, cyanobacteria, lichen and fungi. MAAs act as UV-absorbers and photo-protectants. MAAs are suggested to exert pharmaceutical relevant bioactivities in the human system. We particularly focused on their effect on defence and regulatory pathways that are active in inflamed environments. The MAAs shinorine and porphyra-334 were isolated and purified from the red algae Porphyra sp. using chromatographic methods. The effect of MAAs on central signaling cascades, such as transcription factor nuclear factor kappa b (NF-κB) activation, as well as tryptophan metabolism, was investigated in human myelomonocytic THP-1 and THP-1-Blue cells. Cells were exposed to the MAAs in the presence or absence of lipopolysaccharide (LPS). NF-κB activity and the activity of tryptophan degrading enzyme indoleamine 2,3-dioxygenase (IDO-1) were used as readout. Compounds were tested in the concentration range from 12.5 to 200 µg/mL. Both MAAs were able to induce NF-κB activity in unstimulated THP-1-Blue cells, whereby the increase was dose-dependent and more pronounced with shinorine treatment. While shinorine also slightly superinduced NF-κB in LPS-stimulated cells, porphyra-334 reduced NF-κB activity in this inflammatory background. Modulation of tryptophan metabolism was moderate, suppressive in stimulated cells with the lower treatment concentration of both MAAs and with the unstimulated cells upon porphyra-334 treatment. Inflammatory pathways are affected by MAAs, but despite the structural similarity, diverse effects were observed.
MicroRNAs act by post-transcriptionally regulating the gene expression of 30%-60% of mammalian genomes. MicroRNAs are key regulators in all cellular processes, though the mechanism by which the cell activates or represses microRNA-mediated translational regulation is poorly understood. In this review, we discuss the RNA binding protein Fragile X Mental Retardation Protein (FMRP) and its role in microRNA-mediated translational regulation. Historically, FMRP is known to function as a translational suppressor. However, emerging data suggests that FMRP has both an agonistic and antagonistic role in regulating microRNA-mediated translational suppression. This bi-functional role is dependent on FMRP's interaction with the RNA helicase
 Moloney leukemia virus 10 (MOV10), which modifies the structural landscape of bound mRNA, therefore facilitating or inhibiting its association with the RNA-Induced Silencing Complex.
The chemical composition of volatile oils from 22 genotypes of Citrus and related genera was poorly differentiated, but chemometric techniques have clarified the relationships between the 22 genotypes, and allowed us to understand their resistance to D. citri. The most convincing similarities include the synthesis of (Z)-β-ocimene and (E)-caryophyllene for all 11 genotypes of group A. Genotypes of group B are not uniformly characterized by essential oil compounds. When stimulated with odor sources of 22 genotypes in a Y-tube olfactometer D. citri preferentially entered the arm containing the volatile oils of Murraya paniculata, confirming orange jasmine as its best host. C. reticulata × C. sinensis was the least preferred genotype, and is characterized by the presence of phytol, (Z)-β-ocimene, and β-elemene, which were not found in the most preferred genotype. We speculate that these three compounds may act as a repellent, making these oils less attractive to D. citri.
We show the influence of species present in precursor solution during formation of lead halide perovskite materials on the structural defects of the films. The coordination of lead by competing solvent molecules and iodide ions dictate the type of complexes present in the films. Depending on the processing conditions all PbIS5 (+) , PbI2 S4, PbI3 S3 (-) , PbI4 S2 (2-) , PbI5 S2 (3-) , PbI6 (4-) and 1D (Pb2 I4 )n chains are observed by absorption measurements. Different parameters are studied such as polarity of the solvent, concentration of iodide ions, concentration of solvent molecules and temperature. It is concluded that strongly coordinating solvents will preferentially form species with a low number of iodide ions and less coordinative solvents generate high concentration of PbI6 (-) . We furthermore propose that all these plumbate ions may act as structural defects determining electronic properties of the photovoltaic films.
Moorella thermoacetica is one of the model acetogenic bacteria for the resolution of the Wood-Ljungdahl (acetyl-CoA) pathway in which CO2 is autotrophically assimilated yielding acetyl-CoA as central intermediate. Its further conversion into acetate relies on subsequent phosphotransacetylase (PTA) and acetate kinase reactions. However, the genome of M. thermoacetica contains no pta homologous gene. It has been speculated that the moth_0864 and moth_1181 gene products sharing similarities with an evolutionarily distinct phosphotransacylase involved in 1,2-propanediol utilization (PDUL) of Salmonella enterica act as PTAs in M. thermoacetica. Here, we demonstrate specific PTA activities with acetyl-CoA as substrate of 9.05 and 2.03 U/mg for the recombinant enzymes PDUL1 (Moth_1181) and PDUL2 (Moth_0864), respectively. Both showed maximal activity at 65 °C and pH 7.6. Native proteins (90 kDa) are homotetramers composed of four subunits with apparent molecular masses of about 23 kDa. Thus, one or both PDULs of M. thermoacetica might act as PTAs in vivo catalyzing the penultimate step of the Wood-Ljungdahl pathway toward the formation of acetate. In silico analysis underlined that up to now beside of M. thermoacetica, only Sporomusa ovata contains only PDUL like class(III)-PTAs but no other phosphotransacetylases or phosphotransbutyrylases (PTBs).
Superoxide dismutases (SOD), antioxidant metallo-enzymes, are a part of the first line of defense in the trematode parasites which act as the chief scavengers for reactive oxygen species (ROS). A recombinant Fasciola gigantica cytosolic SOD (FgSOD) was expressed in Escherichia coli BL21 (DE3) and used for immunizing rabbits to obtain polyclonal antibodies (anti-rFgSOD). This rabbit anti-rFgSOD reacted with the native FgSOD at a molecular weight of 17.5kDa. The FgSOD protein was expressed at high level in parenchyma, caecal epithelium and egg of the parasite. The rFgSOD reacted with antisera from rabbits infected with F. gigantica metacercariae collected at 2, 5, and 7 weeks after infection, and reacted with sera of infected mice. Anti-rFgSOD exhibited cross reactivity with the other parasites' antigens, including Eurytrema pancreaticum, Cotylophoron cotylophorum, Fischoederius cobboldi, Gastrothylax crumenifer, Paramphistomum cervi, and Setaria labiato papillosa. A vaccination was performed in imprinting control region (ICR) mice by subcutaneous injection with 50μg of rFgSOD combined with Freund's adjuvant. At 2 weeks after the second boost, mice were infected with 15 metacercariae by oral route. IgG1 and IgG2a in the immune sera were determined to indicate Th2 and Th1 immune responses. It was found that the parasite burden was reduced by 45%, and both IgG1 and IgG2a levels showed correlation with the numbers of worm recoveries.
To study the actions of c-Myc gene fragments in restenosis after coronary artery bypass grafting (CABG).
A total of 25 healthy pure breeds New Zealand white rabbits were randomly divided into 5 groups according to weight, 5 in each group. The external jugular vein is placed at ipsilateral common carotid artery and sampling at 6h, 2d, 7d, 14d and 28d. The expression of the c-Myc positive cell population was observed in different time using immunohistochemistry and morphological analysis. The thickness and ratio of luminal intima and media were measured by the computer image analytical method.
The luminal intima and media thickness at day 7 is significantly thickening (p <0.01) from 6h while it has not changed (p >0.05) at day 14 and 28 compared to day 7. C-Myc proteins are gradually increased from 6h to day 7, reached a peak (p <0.01) at day 7; started declining from day 14-28. The difference has statistical significance (p <0.01) compared to day 7.
C-Myc positive cell population has reached a peak after transplantation, which is identical with the peak of fast intimal proliferation. It indicates that c-Myc protein expression is closely associated to intimal proliferation. It can act as an indicator for intimal proliferation after vascular injuries in the early stage of reactions.
Maintaining regular physical activity (PA) can be challenging for persons with late effects of polio. This qualitative study of ambulatory persons with late effects of polio explored their perceptions of PA, and facilitators of and barriers to PA. Semistructured interviews were conducted with 15 persons and analyzed with content analysis using the International Classification of Functioning, Disability and Health (ICF) as framework. The participants described positive perceptions of PA and its health benefits. PA was used to prevent further decline in functioning, and the type and frequency of activities had changed over time. Past experiences and personal characteristics impacted on PA. Support from close relatives, knowledgeable health care professionals, mobility devices and accessible environments facilitated PA, whereas impairments, inaccessible environments and cold weather were the main barriers. To perform PA regularly, persons with late effects of polio may benefit from individualized advice based on their disability, personal and environmental factors.
Dementia cases are on the rise and researchers seek innovative ways to prevent or ameliorate cognitive impairment in later life. Some research has reported that combining mental and physical exercise may benefit cognition more than either alone. This randomized pilot trial examined the feasibility and cognitive benefit for older adults (n = 30) of a single bout of neuro-exergaming (physical activity with cognitive training), using an interactive physical and cognitive exercise system (iPACES™), compared to that of exergaming or neurogaming alone. Intent-to-treat and sensitivity analyses were conducted using repeated measures ANOVA, controlling for age, sex, and education. A significant interaction effect was found for executive function (Color Trails 2), with a significant improvement in the neuro-exergaming condition. Results demonstrate feasibility for older adults to use a novel and theoretically-derived neuro-exergame, and also provide promising new evidence that neuro-exergaming can yield greater cognitive benefit than either of its component parts.
The ability to act jointly with another person is a fundamental requirement for participation in social life. The current study examines the development of action planning in a joint action context. In 4 experiments, 3-, 5-, and 7-year-old children as well as a group of adults (n = 196) interacted with another person to operate a novel apparatus. Their task was to hand the experimenter a tool with which she could activate 1 of 2 different effects on the apparatus. The elicitation of each effect required participants to grasp and insert the tool in a particular orientation. We assessed whether participants planned their grasping and reaching action in such a way that it enabled the partner to efficiently handle the tool, that is, anticipating the final end state of the joint activity. We found that 3-year-old children did not adjust their behavior to accommodate the other's action and that they did not increase their performance over multiple trials. Five- and 7-year-old children initially showed a tendency to plan their action in an egocentric manner (i.e., showed a form of egocentrism), but improved their joint action performance over time. Adult participants demonstrated joint action planning from the beginning. Interestingly, 3- and 5-year-old children were able to plan their grasp efficiently when acting alone on the apparatus. Yet, having first-hand experience with the task before acting with a partner did not facilitate performance in the joint action task for younger children. Overall, the
 study informs current approaches on the psychological basis and ontogenetic origins of joint action in childhood. (PsycINFO Database Record
It has been argued that children who possess an advanced theory of mind (ToM) are more likely to act prosocially, yet the empirical findings are mixed. To address this issue definitively, a meta-analytic integration of all prior literature that met appropriate inclusion criteria was conducted. In total, 76 studies including 6,432 children between 2 and 12 years of age contributed to these analyses. Collapsed across all studies, a significant association emerged (r = .19), indicating that children with higher ToM scores also received higher scores on concurrent measures of prosocial behavior. The magnitude of this effect was similar across ToM assessments requiring identification of others' cognitions versus emotions, and it existed irrespective of whether the ToM measure imposed demands on false belief reasoning or not. The association with ToM was also evident for different subtypes of prosocial behavior (helping, cooperating, comforting). ToM had a similar effect for boys and girls, but was slightly stronger in children aged 6 years or older, relative to their younger peers. Taken together, these findings provide the strongest evidence to date that being able to explicitly consider what other people are thinking and feeling is related to children's tendencies to act prosocially, although the magnitude of the association is relatively weak. (PsycINFO Database Record
The resemblance between invasive behavior of cancer cells and placental trophoblasts and the role of aberrant epigenetic regulation in cancer development is well known.
We analyzed the role of promoter region CpG-methylation and H3K9/27me3 of tumor suppressor genes in normal and pathological pregnancies and utilized their CpG-methylation data to search for fetal DNA epigenetic marker in maternal blood.
CpG and H3K9/27-methylation associated decreased expression of RASSF1A and APC and increased expression of P16, RB1 and PRKCDBP was observed with advancing normal gestation. Gestational trophoblastic diseases and preeclampsia revealed gene-specific epigenetic deregulation of candidate tumor suppressor genes. Furthermore, APC and PRKCDBP showed the potential to act as fetal DNA epigenetic markers, similar to RASSF1A.
Deregulation of methylation of tumor suppressor genes contributes to the development of preeclampsia and gestational trophoblastic diseases. APC and PRKCDBP may act as fetal DNA epigenetic markers for prenatal diagnosis.
For more than five decades, Southeast Asia (SEA) has been fertile ground for the emergence of drug-resistant Plasmodium falciparum malaria. After generating parasites resistant to chloroquine, sulfadoxine, pyrimethamine, quinine, and mefloquine, this region has now spawned parasites resistant to artemisinins, the world's most potent antimalarial drugs. In areas where artemisinin resistance is prevalent, artemisinin combination therapies (ACTs)-the first-line treatments for malaria-are failing fast. This worrisome development threatens to make malaria practically untreatable in SEA, and threatens to compromise global endeavors to eliminate this disease. A recent series of clinical, in vitro, genomics, and transcriptomics studies in SEA have defined in vivo and in vitro phenotypes of artemisinin resistance, identified its causal genetic determinant, explored its molecular mechanism, and assessed its clinical impact. Specifically, these studies have established that artemisinin resistance manifests as slow parasite clearance in patients and increased survival of early-ring-stage parasites in vitro; is caused by single nucleotide polymorphisms in the parasite's K13 gene, is associated with an upregulated "unfolded protein response" pathway that may antagonize the pro-oxidant activity of artemisinins, and selects for partner drug resistance that rapidly leads to ACT failures. In SEA, clinical studies are urgently needed to monitor ACT efficacy where K13 mutations are prevalent, test whether new combinations of currently available drugs cure ACT failures, and advance new antimalarial compounds through preclinical pipelines and into clinical trials. Intensifying these efforts should help to forestall the spread of artemisinin and partner drug resistance from SEA to sub-Saharan Africa, where the world's malaria transmission, morbidity, and mortality rates are highest.
Rice (Oryza sativa) produces a variety of labdane-related diterpenoids as phytoalexins and allelochemicals. The production of these important natural products has been partially elucidated. However, the oxidases responsible for production of the keto groups found in many of these diterpenoids have largely remained unknown. Only one short-chain alcohol dehydrogenase/reductases (SDRs), which has been proposed to catalyze the last step in such a pathway, has been characterized to date. While rice contains >220 SDRs, only the transcription of five has been shown to be induced by the fungal cell wall elicitor chitin. This includes the momilactone A synthase (OsMAS/SDR110C-MS1), with the other four all falling in the same SDR110C family, further suggesting roles in diterpenoid biosynthesis. Here, biochemical characterization with simplified substrate analogs was first used to indicate potential functions, which were then supported by further analyses with key biosynthetic intermediates. Kinetic studies were then employed to further clarify these roles. Surprisingly, OsSDR110C-MS2 more efficiently catalyzes the final oxidation to produce momilactone A that was previously assigned to OsMAS/SDR110C-MS1, and we speculate that this latter SDR may have an alternative function instead. Conversely, two of these SDRs clearly appear to act in oryzalexin biosynthesis, with OsSDR110C-MI3 readily oxidizing the 3α-hydroxyl of oryzalexin D, while OsSDR110C-MS3 can also oxidize the accompanying 7β-hydroxyl. Together, these SDRs then serve to produce oryzalexins A-C from oryzalexin D, essentially completing elucidation of the biosynthesis of this family of rice phytoalexins.
While the oxygen-dependent reversal of lysine N(ɛ)-methylation is well established, the existence of bona fide N(ω)-methylarginine demethylases (RDMs) is controversial. Lysine demethylation, as catalysed by two families of lysine demethylases (the flavin-dependent KDM1 enzymes and the 2-oxoglutarate- and oxygen-dependent JmjC KDMs, respectively), proceeds via oxidation of the N-methyl group, resulting in the release of formaldehyde. Here we report detailed biochemical studies clearly demonstrating that, in purified form, a subset of JmjC KDMs can also act as RDMs, both on histone and non-histone fragments, resulting in formaldehyde release. RDM catalysis is studied using peptides of wild-type sequences known to be arginine-methylated and sequences in which the KDM's methylated target lysine is substituted for a methylated arginine. Notably, the preferred sequence requirements for KDM and RDM activity vary even with the same JmjC enzymes. The demonstration of RDM activity by isolated JmjC enzymes will stimulate efforts to detect biologically relevant RDM activity.
The Na+/Cl- dependent glycine transporters GlyT1 and GlyT2 regulate synaptic glycine concentrations. Glycine transport by GlyT2 is coupled to the co-transport of three Na+ ions, whereas transport by GlyT1 is coupled to the co-transport of only two Na+ ions. These differences in ion-flux coupling determine their respective concentrating capacities and have a direct bearing on their functional roles in synaptic transmission. The crystal structures of the closely related bacterial Na+-dependent leucine transporter, LeuTAa, and the Drosophila dopamine transporter, dDAT, have allowed prediction of two Na+ binding sites in GlyT2, but the physical location of the third Na+ site in GlyT2 is unknown. A bacterial betaine transporter, BetP, has also been crystallized and shows structural similarity to LeuTAa. Although betaine transport by BetP is coupled to the co-transport of two Na+ ions, the first Na+ site is not conserved between BetP and LeuTAa, the so called Na1' site. We hypothesized that the third Na+ binding site (Na3 site) of GlyT2 corresponds to the BetP Na1' binding site. To identify the Na3 binding site of GlyT2, we performed molecular dynamics (MD) simulations. Surprisingly, a Na+ placed at the location consistent with the Na1' site of BetP spontaneously dissociated from its initial location and bound instead to a novel Na3 site. Using a combination of MD simulations of a comparative model of GlyT2 together with an analysis of the functional properties of wild type and mutant GlyTs we have identified an electrostatically favorable novel third Na+ binding site in GlyT2 formed by Trp263 and Met276 in TM3, Ala481 in TM6 and Glu648 in TM10.
Experts disagree about the pending legislation intended to remove treatment barriers.
Diagnostic assays that incorporate a signal amplification mechanism permit the detection of analytes with enhanced selectivity. Herein, we report a gold nanoparticle-based chemical system able to differentiate ATP from ADP by means of catalytic signal amplification. The discrimination between ATP and ADP is of relevance for the development of universal assays for the detection of enzymes which consume ATP. For example, protein kinases are a class of enzymes critical for the regulation of cellular functions, and act to modulate the activity of other proteins by transphosphorylation, transferring a phosphate group from ATP to give ADP as a byproduct. The system described here exploits the ability of cooperative catalytic head groups on gold nanoparticles to very efficiently catalyze chromogenic reactions such as the transphosphorylation of 2-hydroxypropyl-4-nitrophenyl phosphate (HPNPP). A series of chromogenic
 substrates have been synthesized and evaluated by means of Michaelis-Menten kinetics (compounds 2, 4-6). 2-Hydroxypropyl-(3-trifluoromethyl-4-nitro)phenyl phosphate (5) was found to display higher reactivity (kcat) and higher binding affinity (KM) when compared to HPNPP. This higher binding affinity allows phosphate 5 to compete with ATP and ADP to different extents for binding on the monolayer surface, thus enabling a catalytically amplified signal only when ATP is absent. Overall, this represents a viable new approach for monitoring the conversion of ATP into ADP with high sensitivity.
A series of non-heme (μ-oxo)bis(μ-dicarboxylato)-bridged diiron(iii) complexes, [Fe2(O)(OOCH)2(L)2](2+)1, [Fe2(O)(OAc)2(L)2](2+)2, [Fe2(O)(Me3AcO)2(L)2](2+)3, [Fe2(O)(OBz)2(L)2](2+)4, [Fe2(O)(Ph2AcO)2(L)2](2+)5 and [Fe2(O)(Ph3AcO)3(L)2](2+)6, where L = N,N-dimethyl-N'-(pyrid-2-ylmethyl)ethylenediamine, OAc(-) = acetate, Me3AcO(-) = trimethylacetate, OBz(-) = benzoate, Ph2AcO(-) = diphenylacetate and Ph3AcO(-) = triphenylacetate, have been isolated and characterized using elemental analysis and spectral and electrochemical techniques. They have been studied as catalysts for the selective oxidation of alkanes using m-chloroperbenzoic acid (m-CPBA) as the oxidant. Complexes 2, 3, and 4 possess a distorted bioctahedral geometry in which each iron atom is coordinated to an oxygen atom of the μ-oxo bridge, two oxygen atoms of the μ-carboxylate bridge and three nitrogen atoms of the 3N ligand. In an acetonitrile/dichloromethane solvent mixture all the complexes display a d-d band characteristic of the triply bridged diiron(iii) core, revealing that they retain their identity in solution. Upon replacing electron-donating substituents on the bridging carboxylates by electron-withdrawing ones the E1/2 value of the one-electron Fe(III)Fe(III)→ Fe(III)Fe(II) reduction becomes less negative. On adding one equivalent of Et3N to a mixture of one equivalent of the complex and an excess of m-CPBA in the acetonitrile/dichloromethane solvent mixture an intense absorption band (λmax, 680-720 nm) appears, which corresponds to the formation of a mixture of complex species. All the complexes act as efficient catalysts for the hydroxylation of cyclohexane with 380-500 total turnover numbers and good alcohol selectivity (A/K, 6.0-10.1). Adamantane is selectively oxidized to 1-adamantanol and 2-adamantanol (3°/2°, 12.9-17.1) along with a small amount of 2-adamantanone (total TON, 381-476), and interestingly, the sterically demanding trimethylacetate bridge around the diiron(iii) centre leads to high 3°/2° bond selectivity; on the other hand, the sterically demanding triphenylacetate bridge gives a lower 3°/2° bond selectivity. A remarkable linear correlation between the pKa of the bridging carboxylate and TON for both cyclohexane and adamantane oxidation is observed, illustrating the highest catalytic activity for 3 with strongly electron-releasing trimethylacetate bridges.
It is well accepted that junctophilin (JPHs) isoforms act as a physical bridge linking plasma membrane and endoplasmic reticulum (ER) for channel crosstalk in excitable cells. Our purpose is to investigate whether JPHs are involved in the proper communication between Ca(2+) influx and subsequent Ca(2+) amplification in pancreatic beta cells, thereby participating in regulating insulin secretion. The expression of JPH isoforms was examined in human and mouse pancreatic tissues, and JPH3 expression was found in both the beta cells. In mice, knockdown of Jph3 (si-Jph3) in islets decreased glucose-stimulated insulin secretion (GSIS) accompanied by mitochondrial function impairment. Si-Jph3 lowered the insulin secretory response to Ca(2+) signaling in the presence of glucose, and reduced [Ca(2+)]c transient amplitude triggered by caffeine. Si-Jph3 also attenuated mitofusin 2 expression, thereby disturbing the spatial organization of ER-mitochondria contact in islets. These results suggest that the regulation of GSIS by the KATP channel-independent pathways is partly impaired due to decrease of JPH3 expression in mouse islets. JPH3 also binds to type 2 ryanodine receptors (RyR2) in mouse and human pancreatic tissues, which might contribute to Ca(2+) release amplification in GSIS. This study demonstrates some previously unrecognized findings in pancreatic tissues: (1) JPH3 expresses in mouse and human beta cells; (2) si-Jph3 in mouse primary islets impairs GSIS in vitro; (3) impairment in GSIS in si-Jph3 islets is due to changes in RyR2-[Ca(2+)]c transient amplitude and ER-mitochondria contact.
Partial pancreatic duct ligation (PDL) of mouse pancreas induces a doubling of the β-cell mass mainly through proliferation of pre-existing and newly formed β-cells. The molecular mechanism governing this process is still largely unknown. Given the inflammatory nature of PDL and inflammation-induced signaling via the signal transducer and activator of transcription 3 (STAT3), the activation and the role of STAT3 in PDL-induced β-cell proliferation were investigated. Duct ligation stimulates the expression of several cytokines that can act as ligands inducing STAT3 signaling and phosphorylation in β-cells. β-Cell cycling increased by conditional β-cell-specific Stat3 knockout and decreased by STAT3 activation through administration of interleukin-6. In addition, the level of DNA damage in β-cells of PDL pancreas increased after deletion of Stat3. These data indicate a role for STAT3 in maintaining a steady state in the β-cell, by modulating its cell cycle and protection from DNA damage.
[This corrects the article DOI: 10.1371/journal.pgen.1005995.].
Improving self-esteem, dietary habits, and physical activity is essential for long-term success in childhood obesity prevention. The aim is to evaluate the effects of a healthy living promotion program, Healthy Kids-Houston, on BMI, dietary habits, self-esteem, and physical activity among minority children.
The after-school program was implemented at community centers in low-income neighborhoods with close proximity to public schools. The program consisted of 3 6-week sessions. Each week, children attended 2 2-hour sessions. Each 2-hour session in the intervention included 90 minutes of structured physical activities and 30 minutes of nutrition and healthy habit lessons. The control group received typical enrichment programs. Outcomes were measured before the intervention and at the end of each 6-week session.
We enrolled 877 children (age 10.2 ± 0.1 years (mean ± SE); body mass index z score: 1.49 ± 0.1; 52.0% boys; 72.6% Hispanic) in the program with 524 children received the intervention at 14 community centers and 353 children served as control at 10 community centers. The intervention led to no improvements in BMI z score (P = 0.78) and dietary habits (P = 0.46). Significant improvements (P ≤ 0.02) were detected in the amount of exercise that a child perceived to be required to offset a large meal and in several key self-esteem scores. No improvements were detected in physical activities (P ≥ 0.21).
The improvement in some key self-esteem scores and nutrition knowledge may act as a mediator to motivate these children to adopt a healthier lifestyle in the future.
Maturation of tRNA depends on a single endonuclease, ribonuclease P (RNase P), to remove highly variable 5' leader sequences from precursor tRNA transcripts. Here, we use high-throughput enzymology to report multiple-turnover and single-turnover kinetics for Escherichia coli RNase P processing of all possible 5' leader sequences, including nucleotides contacting both the RNA and protein subunits of RNase P. The results reveal that the identity of N(-2) and N(-3) relative to the cleavage site at N(1) primarily control alternative substrate selection and act at the level of association not the cleavage step. As a consequence, the specificity for N(-1), which contacts the active site and contributes to catalysis, is suppressed. This study demonstrates high-throughput RNA enzymology as a means to globally determine RNA specificity landscapes and reveals the mechanism of substrate discrimination by a widespread and essential RNA-processing enzyme.
This work demonstrates that chiral imprinted CdSe quantum dots (QDs) can act as spin selective filters for charge transport. The spin filtering properties of chiral nanoparticles were investigated by magnetic conductive-probe atomic force microscopy (mCP-AFM) measurements and magnetoresistance measurements. The mCP-AFM measurements show that the chirality of the quantum dots and the magnetic orientation of the tip affect the current-voltage curves. Similarly, magnetoresistance measurements demonstrate that the electrical transport through films of chiral quantum dots correlates with the chiroptical properties of the QD. The spin filtering properties of chiral quantum dots may prove useful in future applications, for example, photovoltaics, spintronics, and other spin-driven devices.
Adults with serious mental illness (SMI) often experience gaps in access to needed health care compared with other populations. Such disparities may be even more pronounced between certain groups of patients with SMI, differing by race, ethnicity, gender, economic disadvantage (including housing stability) and socioeconomic status, and geographic location (chiefly, rural versus urban residence); disparities arise as well for individuals identifying as lesbian, gay, bisexual, and transgender (LGBT) and those who have difficulty communicating in English (because it is a second language).
The primary goal of this Technical Brief is to describe and review the effectiveness of interventions that address disparities among adult patients with SMI in these important groups.
We reviewed the published and gray literature and interviewed Key Informants (KIs) to address four Guiding Questions
 (GQs). The four refined GQs for this Technical Brief focus on the critical areas of concern in relation to mental health treatment disparities—access to health insurance with appropriate coverage for these SMI conditions, accurate diagnostic evaluations, receipt of necessary and appropriate therapeutic services, quality of the health services, adherence to treatment over the long term, and various outcomes of care. The principal focus for the first three GQs is a description of the interventions (GQ 1), the context in which they are implemented (GQ 2), and a description of the evidence about the effectiveness of the interventions (GQ 3); GQ 4 presents conclusions, examines the gaps in the knowledge base, and identifies high-priority needs for future research. We include interventions addressing diagnosis, access to, and quality of treatment and support services among disparity groups of adults with SMI.
We identified 42 descriptive articles meeting inclusion criteria for GQs 1, 2, and 4, plus 37 articles measuring intervention effectiveness reporting on 26 unique studies (GQ 3). For GQ 1, the goals of each intervention were related to the specific diagnosis and disparity group that the intervention was targeting. Increased service use and treatment adherence were the most common intervention goals. For GQ 2, settings involved primarily mental health specialists being colocated in nonpsychiatric locations. These were usually primary care, but sometimes they were obstetrics-gynecology clinics, perinatal health care settings, and community mental health entities. For GQ 3, most interventions tested adding enhanced services to usual available care, including culturally adapted collaborative care or other therapies, integrated services, case management and telemedicine. We found no studies of interventions for individuals identifying as LGBT or focusing only on English as a second language, addressing access to health care coverage, or addressing diagnostic accuracy. We found one study of the elderly, a group that can be predicted to have a larger number of physical comorbidities and difficulties obtaining necessary care because of their SMI.
Future research should identify interventions that are effective in reducing disparities all along the health care continuum and determine whether such interventions are equally effective for particular groups within the SMI population. Many promising interventions focused on disadvantaged individuals, including homeless individuals and racial or ethnic minority disparity groups. Future research can include comparative findings between minority and majority group patients and subgroup analyses to evaluate effectiveness among different disparity groups. Most interventions targeted depressive and psychotic disorders. The use of collaborative care, intensive case management approaches, such as the Critical Time Intervention (CTI) and Assertive Community Treatment (ACT), and specific culturally adapted therapies, including those involving families of individuals with SMI, were the most noticeable modifications to interventions, but were not widely applied across groups. Gaps persist both in terms of the diversity of disparity groups included in studies (particularly individuals who identify as LGBT and the elderly) and approaches considered.
The adoption of the Patient Protection and Affordable Care Act (ACA) 2010 was a turning point in the history of behavioral health for children and adolescents in the United States. The ACA requires most health insurance plans to conduct behavioral health assessments for children, as well as depression screening for adults. Looking ahead, however, questions have been raised about how to promote children's behavioral health, how to make use of innovations, and how to sustain funding over time. To respond to these questions, the Forum on Promoting Children's Cognitive, Affective, and Behavioral Health of the National Academies of Sciences, Engineering, and Medicine held a workshop in Washington, D.C., on April 1-2, 2015. The workshop focused on how recent reforms in health care provide new opportunities to promote children's cognitive, affective, and behavioral health. It also assessed behavioral health needs of all children, including those with special physical or behavioral health conditions, and programs that support families.This report summarizes the presentations and discussion of the workshop.
Intervention strategies in adolescents at ultra high-risk (UHR) for psychosis are promising for reducing conversion to overt illness, but have only limited impact on functional outcome. Recent studies suggest that cognition does not further decline during the UHR stage. As social and cognitive impairments typically develop before the first psychotic episode and even years before the UHR stage, prevention should also start much earlier in the groups at risk for schizophrenia and other psychiatric disorders. Early intervention strategies could aim to improve stress resilience, optimize brain maturation, and prevent or alleviate adverse environmental circumstances. These strategies should urgently be tested for efficacy: the prevalence of ~1% implies that yearly ~22 in every 100,000 people develop overt symptoms of this illness, despite the fact that for many of them-e.g., children with an affected first-degree family member or carriers of specific genetic variants-increased risk was already identifiable early in life. Our current ability to recognize several risk groups at an early age not only provides an opportunity, but also implies a clinical imperative to act. Time is pressing to investigate preventive interventions in high-risk children to mitigate or prevent the development of schizophrenia and related psychiatric disorders.
During the past five years, it has been shown that carbon nanotubes act as an exceptional reinforcement for composites. For this reason, a large number of investigations have been devoted to analysis of fundamental, structural behavior of solid structures made of carbon-nanotube-reinforced composites (CNTRC). The present research, as an extension of the available works on the vibration analysis of CNTRC structures, examines the free vibration characteristics of plates containing a cutout that are reinforced with uniform or nonuniform distribution of carbon nanotubes. The first-order shear deformation plate theory is used to estimate the kinematics of the plate. The solution method is based on the Ritz method with Chebyshev basis polynomials. Such a solution method is suitable for arbitrary in-plane and out-of-plane boundary conditions of the plate. It is shown that through a functionally graded distribution of carbon nanotubes across the thickness of the plate, the fundamental frequency of a rectangular plate with or without a cutout may be enhanced. Furthermore, the frequencies are highly dependent on the volume fraction of carbon nanotubes and may be increased upon using more carbon nanotubes as reinforcement.
Photothermal excitation is a cantilever excitation method that enables stable and accurate operation for dynamic-mode AFM measurements. However, the low excitation efficiency of the method has often limited its application in practical studies. In this study, we propose a method for improving the photothermal excitation efficiency by coating cantilever backside surface near its fixed end with colloidal graphite as a photothermal conversion (PTC) layer. The excitation efficiency for a standard cantilever of PPP-NCHAuD with a spring constant of ≈40 N/m and a relatively stiff cantilever of AC55 with a spring constant of ≈140 N/m were improved by 6.1 times and 2.5 times, respectively, by coating with a PTC layer. We experimentally demonstrate high stability of the PTC layer in liquid by AFM imaging of a mica surface with atomic resolution in phosphate buffer saline solution for more than 2 h without any indication of possible contamination from the coating. The proposed method, using a PTC layer made of colloidal graphite, greatly enhances photothermal excitation efficiency even for a relatively stiff cantilever in liquid.
Physisorbed water originating from exposure to the ambient can have a strong impact on the structure and chemistry of oxide nanomaterials. The effect can be particularly pronounced when these oxides are in physical contact with a solid substrate such as the ones used for immobilization to perform electron or ion microscopy imaging. We used helium ion microscopy (HIM) and investigated morphological changes of vapor-phase-grown MgO cubes after vacuum annealing and pressing into foils of soft and high purity indium. The indium foils were either used as obtained or, for reference, subjected to vacuum drying. After four days of storage in the vacuum chamber of the microscope and at a base pressure of p < 10(-7) mbar, we observed on these cubic particles the attack of residual physisorbed water molecules from the indium substrate. As a result, thin magnesium hydroxide layers spontaneously grew, giving rise to characteristic volume expansion effects, which depended on the size of the particles. Rounding of the originally sharp cube edges leads to a significant loss of the morphological definition specific to the MgO cubes. Comparison of different regions within one sample before and after exposure to liquid water reveals different transformation processes, such as the formation of Mg(OH)2 shells that act as diffusion barriers for MgO dissolution or the evolution of brucite nanosheets organized in characteristic flower-like microstructures. The findings underline the significant metastability of nanomaterials under both ambient and high-vacuum conditions and show the dramatic effect of ubiquitous water films during storage and characterization of oxide nanomaterials.
Hyperprolactinemia is a common adverse effect
 of antipsychotic medication. Switching over to aripiprazole or adjunctive aripiprazole has been advocated for optimal management of antipsychotic-induced hyperprolactinemia. Adjunctive treatment with aripiprazole has been shown to normalize prolactin levels without affecting already achieved improvements in psychotic symptoms. However, here, we present the case of a 36 year old female with delusional disorder who developed symptomatic hyperprolactinemia while on aripiprazole treatment. Dopamine acts as a tonic inhibitor of prolactin secretion through the tubero-infundibular dopaminergic system. Aripiprazole being a partial agonist has a lower intrinsic activity at the D2 receptor than dopamine, allowing it to act as both, a functional agonist and antagonist, depending on the surrounding levels of dopamine. Hence, in the absence of a competing D2 antagonist and the presence of dopamine (the natural agonist), aripiprazole could act as a functional antagonist and thus elevate prolactin levels.
Parainfluenza virus 5 (PIV5) is an enveloped, single-stranded, negative-sense RNA virus of the Paramyxoviridae family. PIV5 fusion and entry are mediated by the coordinated action of the receptor-binding protein, hemagglutinin-neuraminidase (HN), and the fusion protein (F). Upon triggering by HN, F undergoes an irreversible ATP- and pH-independent conformational change, going down an energy gradient from a metastable prefusion state to a highly stable postfusion state. Previous studies have highlighted key conformational changes in the F-protein refolding pathway, but a detailed understanding of prefusion F-protein metastability remains elusive. Here, using two previously described F-protein mutations (S443D or P22L), we examine the capacity to modulate PIV5 F stability and the mechanisms by which these point mutants act. The S443D mutation destabilizes prefusion F proteins by disrupting a hydrogen bond network at the base of the F-protein globular head. The introduction of a P22L mutation robustly rescues destabilized F proteins through a local hydrophobic interaction between the N-terminal helix and a hydrophobic pocket. Prefusion stabilization conferred by a P22L-homologous mutation is demonstrated in the F protein of Newcastle disease virus, a paramyxovirus of a different genus, suggesting a conserved stabilizing structural element within the paramyxovirus family. Taken together, the available data suggest that movement of the N-terminal helix is a necessary early step for paramyxovirus F-protein refolding and presents a novel target for structure-based drug design.
Accurate spindle positioning is essential for error-free cell division. The one-cell Caenorhabditis elegans embryo has proven instrumental for dissecting mechanisms governing spindle positioning. Despite important progress, how the cortical forces that act on astral microtubules to properly position the spindle are modulated is incompletely understood. Here, we report that the PP6 phosphatase PPH-6 and its associated subunit SAPS-1, which positively regulate pulling forces acting on spindle poles, associate with the Aurora A kinase AIR-1 in C. elegans embryos. We show that acute inactivation of AIR-1 during mitosis results in excess pulling forces on astral microtubules. Furthermore, we uncover that AIR-1 acts downstream of PPH-6-SAPS-1 in modulating spindle positioning, and that PPH-6-SAPS-1 negatively regulates AIR-1 localization at the cell cortex. Moreover, we show that Aurora A and the PP6 phosphatase subunit PPP6C are also necessary for spindle positioning in human cells. There, Aurora A is needed for the cortical localization of NuMA and dynein during mitosis. Overall, our work demonstrates that Aurora A kinases and PP6 phosphatases have an ancient function in modulating spindle positioning, thus contributing to faithful cell division.
Inner-city, minority children with asthma have the highest rates of morbidity and death from asthma and the lowest rates of asthma controller medication adherence. Some recent electronic medication monitoring interventions demonstrated dramatic improvements in adherence in lower-risk populations. The feasibility and acceptability of such an intervention in the highest-risk children with asthma has not been studied.
Our objective was to assess the feasibility and acceptability of a community health worker-delivered electronic adherence monitoring intervention among the highest utilizers of acute asthma care in an inner-city practice.
This was a prospective cohort pilot study targeting children with the highest frequency of asthma-related emergency department and hospital care within a local managed care Medicaid plan. The 3-month intervention included motivational interviewing, electronic monitoring of controller and rescue inhaler use, and outreach by a community health worker for predefined medication alerts. We measured acceptability by using a modified technology acceptability model and changes in asthma control using the Asthma Control Test (ACT). Given prominent feasibility issues, we describe qualitative patterns of medication use at baseline only.
We enrolled 14 non-Hispanic black children with a median age of 3.5 years. Participants averaged 7.8 emergency or hospital visits in the year preceding enrollment. We observed three distinct patterns of baseline controller use: 4 patients demonstrated sustained use, 5 patients had periodic use, and 5 patients lapsed within 2 weeks. All participants initiated use of the electronic devices; however, no modem signal was transmitted for 5 or the 14 participants after a mean of 45 days. Of the 9 (64% of total) caregivers who completed the final study visit, all viewed the electronic monitoring device favorably and would recommend it to friends, and 5 (56%) believed that the device helped to improve asthma control. ACT scores improved by a mean of 2.7 points (P=.05) over the 3-month intervention.
High-utilizer, minority families who completed a community health worker-delivered electronic adherence intervention found it generally acceptable. Prominent feasibility concerns, however, such as recruitment, data transmission failure, and lost devices, should be carefully considered when designing interventions in this setting.
JASMONATE ZIM-domain (JAZ) proteins act as transcriptional repressors of jasmonic acid (JA) responses and play a crucial role in the regulation of host immunity in plants. Here, we report that OsMYC2, a JAZ-interacting transcription factor in rice (Oryza sativa L.), plays an important role in the resistance response against rice bacterial blight, which is one of the most serious diseases in rice, caused by Xanthomonas oryzae pv. oryzae (Xoo). The results showed that OsMYC2 interacted with some OsJAZ proteins in a JAZ-interacting domain (JID)-dependent manner. The up-regulation of OsMYC2 in response to JA was regulated by OsJAZ8. Transgenic rice plants overexpressing OsMYC2 exhibited a JA-hypersensitive phenotype and were more resistant to Xoo. A large-scale microarray analysis revealed that OsMYC2 up-regulated OsJAZ10 as well as many other defense-related genes. OsMYC2 selectively bound to the G-box-like motif of the OsJAZ10 promoter in vivo and regulated the expression of early JA-responsive genes, but not of late JA-responsive genes. The nuclear localization of OsMYC2 depended on a nuclear localization signal within JID. Overall, we conclude that OsMYC2 acts as a positive regulator of early JA signals in the JA-induced resistance against Xoo in rice.
Besides its widely described function in the innate immune response, no other clear physiological function has been attributed so far to the Liver-Expressed-Antimicrobial-Peptide 2 (LEAP2). We used the Xenopus embryo model to investigate potentially new functions for this peptide. We identified the amphibian leap2 gene which is highly related to its mammalian orthologues at both structural and sequence levels. The gene is expressed in the embryo mostly in the endoderm-derived tissues. Accordingly it is induced in pluripotent animal cap cells by FGF, activin or a combination of vegT/β-catenin. Modulating leap2 expression level by gain-of-function strategy impaired normal embryonic development. When overexpressed in pluripotent embryonic cells derived from blastula animal cap explant, leap2 stimulated FGF while it reduced the activin response. Finally, we demonstrate that LEAP2 blocks FGF-induced migration of HUman Vascular Endothelial Cells (HUVEC). Altogether these findings suggest a model in which LEAP2 could act at the extracellular level as a modulator of FGF and activin signals, thus opening new avenues to explore it in relation with cellular processes such as cell differentiation and migration.
To describe the perceived experiences of stigma and discrimination among people living with severe and persistent mental illness in assertive community treatment (ACT teams) settings in New South Wales (NSW), Australia.
The Discrimination and Stigma Scale (DISC) was used in this cross-sectional study with people living with severe and persistent mental illness. The DISC is a reliable and valid, quantitative and qualitative instrument used to explore and measure levels of negative, anticipated and positive discrimination. Relevant clinical history and socio-demographic information were also collected.
A total of 50 clients participated, with 40 (80%) reporting experienced negative discrimination in at least one life area. Negative discrimination was most commonly experienced in being avoided or shunned (n=25, 50%), by neighbours (n=24, 48%) and family (n=23, 46%). Anticipated discrimination was common, with half of participants (n=25, 50%) feeling the need to conceal their mental health diagnosis.
Discrimination was highly prevalent in everyday aspects of life. While healthcare professionals often tend to increase perceived
 stigma and discrimination, this was only experienced in interactions with general health professionals, while interactions with ACT team members decreased perceived stigma and increased positive discrimination. This indicates that healthcare professionals potentially have a significant role in reducing stigma and discrimination in mental health and that such an effect may be optimised in an ACT team setting.
The feeding behavior in humans is complex, with psychological, social, and cultural factors. This pathology consists of the desire to eat (reinforcement/reward) and the control of the act of eating (inhibitory control). It is well known that blocking post-synaptic D2 receptors in the nucleus accumbens induces a decrease of craving behavior. Due to this, to test hypothesis we measured the expression of the DRD2 gene and the expression of the type of feeding factor in a group of Mexican twins.
In the study were included 18 pairs of twins (n = 36), reared together (at least up to 18 years old); native to Mexico City; to whom we applied the three factors of food instrument.
We observed a significant correlation between the "uncontrolled" factor and expression of the DRD2 gene (p < 0.03).
Therefore, we propose that the expression of the DRD2 gene in subjects is a linkage to the type of feeding factor.
Macroautophagy (hereafter called autophagy) is a vacuolar lysosomal pathway for degradation of intracellular material in eukaryotic cells. Autophagy plays crucial roles in tissue homeostasis, in adaptation to stress situations, and in immune and inflammatory responses. Alteration of autophagy is associated with cancer, diabetes and obesity, cardiovascular disease, neurodegenerative disease, autoimmune disease, infection, and chronic inflammatory disease. Autophagy is controlled by autophagy-related (ATG) proteins that act in a coordinated manner to build up the initial autophagic vacuole named the autophagosome. It is now known that the activities of ATG proteins are modulated by posttranslational modifications such as phosphorylation, ubiquitination, and acetylation. Moreover, transcriptional and epigenetic controls are involved in the regulation of autophagy in stress situations. Here we summarize and discuss how posttranslational modifications and transcriptional and epigenetic controls regulate the involvement of autophagy in the proteostasis network.
Retinoic acid, the bioreactive metabolite of beta-carotene or vitamin A, plays a pleiotropic, multifunctional role in vertebrate development. Studies in rodents revealed that a diet deficient in vitamin A results in a complex neonatal syndrome (the VAD syndrome), manifested in many organs. In humans, the function of retinoic acid (RA) extends into adulthood, where it has important roles in fertility, vision, and suppression of neoplastic growth. In recent years, it has also been suggested that retinoic acid might potentially act as a therapeutically relevant drug in attenuating or even preventing neurodegenerative diseases such as Alzheimer's disease (AD). Here, we report that VAD leads to an increase in A-beta peptide levels while only minor effects were observed on expression levels of the amyloid precursor protein (APP) processing proteinases in wild type mice. In line with these findings, rescue of hypovitaminosis reduced A-beta amount to baseline and induced sApp-alpha secretion in combination with an increase of alpha-secretase Adam10. By comparing retinoic acid treatment starting from a full nutrition status and a "VAD" situation in human neuroblastoma cells, we show that while intensities of differential gene expression were higher in replenished cells, a large overlap in AD-related, regulated genes was observed. Our data suggest that hypovitaminosis A can contribute to onset or progression of AD by increasing synthesis of A-beta peptides and that several AD-related genes such as ADAM10 or BDNF are regulated by retinoic acid. We suggest that dietary supplementation with retinoic acid derivatives is likely to have a beneficial effect on AD-pathology in both, individuals with hypovitaminosis and patients with normal vitamin A status.
Copper is an essential trace metal required by organisms to perform a number of important biological processes. Copper readily cycles between its reduced Cu(i) and oxidised Cu(ii) states, which makes it redox active in biological systems. This redox-cycling propensity is vital for copper to act as a catalytic co-factor in enzymes. While copper is essential for normal physiology, enhanced copper levels in tumours leads to cancer progression. In particular, the stimulatory effect of copper on angiogenesis has been established in the last several decades. Additionally, it has been demonstrated that copper affects tumour growth and promotes metastasis. Based on the effects of copper on cancer progression, chelators that bind copper have been developed as anti-cancer agents. In fact, a novel class of thiosemicarbazone compounds, namely the di-2-pyridylketone thiosemicarbazones that bind copper, have shown great promise in terms of their anti-cancer activity. These agents have a unique mechanism of action, in which they form redox-active complexes with copper in the lysosomes of cancer cells. Furthermore, these agents are able to overcome P-glycoprotein (P-gp) mediated multi-drug resistance (MDR) and act as potent anti-oncogenic agents through their ability to up-regulate the metastasis suppressor protein, N-myc downstream regulated gene-1 (NDRG1). This review provides an overview of the metabolism and regulation of copper in normal physiology, followed by a discussion of the dysregulation of copper homeostasis in cancer and the effects of copper on cancer progression. Finally, recent advances in our understanding of the mechanisms of action of anti-cancer agents targeting copper are discussed.
Since 2005, the Togo National Malaria Control Programme has recommended two different formulations of artemisinin-based combination therapy (ACT), artesunate-amodiaquine (ASAQ) and artemether-lumefantrine (AL), for the treatment of uncomplicated malaria. Regular efficacy monitoring of these two combinations is conducted every 2 or 3 years. This paper reports the latest efficacy assessment results and the investigation of mutations in the k13 propeller domain.
The study was conducted in 2012-2013 on three sentinel sites of Togo (Lomé, Sokodé and Niamtougou). Children aged 6-59 months, who were symptomatically infected with Plasmodium falciparum, were treated with either AL (Coartem(®), Novartis Pharma, Switzerland) or ASAQ (Co-Arsucam(®), Sanofi Aventis, France). The WHO standard protocol for anti-malarial treatment evaluation was used. The primary end-point was 28-day adequate clinical and parasitological response (ACPR), corrected to exclude reinfection using polymerase-chain reaction (PCR) genotyping.
A total of 523 children were included in the study. PCR-corrected ACPR was 96.3-100 % for ASAQ and 97-100 % for AL across the three study sites. Adverse events were negligible: 0-4.8 % across all sites, for both artemisinin-based combinations. Upon investigation of mutations in the k13 propeller domain, only 9 (1.8 %) mutations were reported, three in each site. All mutant parasites were cleared before day 3. All day 3 positive patients were infected with k13 wild type parasites.
The efficacy of AL and ASAQ remains high in Togo, and both drugs are well tolerated. ASAQ and AL would be recommended for the treatment of uncomplicated malaria in Togo.
Microbialites, bioaccretionary structures formed during the growth and metabolism of microorganisms (principally cyanobacteria) were the dominant lifeform in shallow late-Archean and Proterozoic oceans. During the Cambrian radiation of metazoan life, which began ~540 Mya, microbialite abundance and diversity further declined following a peak in the Mesoproterozoic. Notwithstanding contention, grazing and bioturbation effects of metazoans have been hypothesized as the dominant driver of modern microbialite scarcity. However, this metazoan-microbialite exclusion has not been fully explored in the few extant microbialites. Here we provide further evidence showing that living marine layered microbialites (stromatolites) coexist with a persistent assemblage of benthic macro-invertebrates, as has previously been demonstrated in some thrombolitic (clotted) microbialites. Surprisingly, these metazoans have active habits, such as burrowing, which should be expected to disrupt the layered matrix. As other studies have shown, through a network of burrows, metazoans can exploit local diurnal oxygen refugia within microbialites as well as escape predation. Our results, therefore, add novel evidence in support of the hypotheses that geologically, metazoans are not always incompatible with stromatolites, while ecologically, microbialites may act as micro-refugia for modern metazoans and historically have performed a similar inferred role in past ecosystems.
This population-based study determined the delivery room management and outcomes of extremely preterm infants born with Apgar scores of 0.
We linked birth, neonatal intensive care unit (NICU) and death records for babies who were born between 22 + 0 and 27 + 6 weeks of gestation with a one-minute Apgar score of 0, in New South Wales, Australia, between 1998 and 2011.
We classified 2173/2262 (96%) of infants with a one-minute Apgar score of 0 as stillborn. Resuscitation was provided for 48/89 (54%) live births and 40/2173 (2%) stillbirths. Cardiac massage was given to 44 infants, including three 22-week stillborn babies. Of the 13 live births admitted to an NICU, 11 survived to hospital discharge. Most (98%) of the 2212 deaths occurred on the first day of life. One baby who was classified as stillborn lived for 51 days. Resuscitation increased the mean (95% confidence
 interval) duration of survival from 1 (0-2) to 45 (0-104) hours (p < 0.001). No infant with a five-minute Apgar score of 0 survived.
Clinicians resuscitated extremely preterm infants without a detectable heartbeat, even at 22 weeks of gestation. No infant survived without resuscitation or if their heartbeat was not regained by five minutes.
Mary Gordon's short story, Mrs. Cassidy's Last Year, is about a family trying to cope, not only with Mrs. Cassidy, who has dementia and is physically and verbally abusive, but also with her elderly husband's difficulties caring for her at home. Mr. Cassidy's dilemma, expressed through the dissonance between his private "inner talk" of emotions and desires that he feels are forbidden and shameful, and his insistence to his son and daughter-in-law that his wife is still the woman he married and her care is not too much for him. This article attempts to open up conceptual space on such questions of caregiver perceptions of the personhood (who they are now), and "personness"-the motivations and intentions-of the person with dementia; caregiver and family motivations and feeling states; and the ways that cultural narratives of obligation in family caregiving affect a caregiver's sense of self and moral certitude. In addition, the story helps us to consider the implications of a bifurcation between a caregiver's inner feelings, and what he or she understands to be the way he or she should feel and act publically. The article attempts to illustrate the interplay and tensions between narratives-master narratives from the culture, those from more immediate ideological environments, auto- and biographical stories, memories, and the stories we tell ourselves about who we are-and how these come into stark relief in the context of a radically altered intimate relationship.
Relatively few studies have investigated whether relatives of patients with bipolar disorder show brain functional changes, and these have focused on activation changes. Failure of de-activation during cognitive task performance is also seen in the disorder and may have trait-like characteristics since it has been found in euthymia.
A total of 20 euthymic patients with bipolar disorder, 20 of their unaffected siblings and 40 healthy controls underwent functional magnetic resonance imaging during performance of the n-back working memory task. An analysis of variance (ANOVA) was fitted to individual whole-brain maps from each set of patient-relative-matched pair of controls. Clusters of significant difference among the groups were used as regions of interest to compare mean activations/de-activations between them.
A single cluster of significant difference among the three groups was found in the whole-brain ANOVA. This was located in the medial prefrontal cortex, a region of task-related de-activation in the healthy controls. Both the patients and their siblings showed significantly reduced de-activation compared with the healthy controls in this region, but the failure was less marked in the relatives.
Failure to de-activate the medial prefrontal cortex in both euthymic bipolar patients and their unaffected siblings adds to evidence for default mode network dysfunction in the disorder, and suggests that it may act as a trait marker.
Agents acting via cannabinoid receptors have been widely developed; starting from the chemical structure of phytocannabinoids isolated from cannabis sativa plant, specific and selective compounds of these receptors have been produced ranging from partial to full agonists and /or antagonists endowed with different potency. The enhanced interest on developing such classes of drugs is due to the beneficial properties widely reported by both anecdotal reports and scientific studies describing the potential medicinal use of cannabinoids and their derivatives in numerous pathological conditions in both in vitro and in vivo models. The use of these drugs has been found to be of benefit in a wide number of neurological and neuropsychiatric disorders, and in many other diseases ranging from cancer, atherosclerosis, stroke, hypertension, inflammatory related disorders, and autoimmune diseases, just to mention some. In particular, being the cannabinoid CB1 receptor a central receptor expressed by neurons of the central nervous system, the attention for the treatment of neurological diseases has been mainly focused on compounds acting via this receptor, however some of these compounds has been showed to act by alternative pathways in some cases unrelated to CB1 receptors. Nonetheless, endocannabinoids are potent regulators of the synaptic function in the central nervous system and their levels are modulated in neurological diseases. In this study, we focused on endocannabinoid mechanism of action in neuronal signaling and on cannabimimetic drug potential application in neurological disorders. Finally, novel patents on cannabis-based drugs with applicability in central nervous system disorders are highlighted, to suggest future potential therapeutic utility of derivatives of this ancient plant.
There are nutritional differences between the sexes: eating behavior in men is often rated as "unhealthy" compared with that in women. Nutrition in men and women is rather more of an expression of social gender roles and expectations than biologically determined. Meat and alcohol, for instance, are regarded as "powerful" foods and thus have masculine connotations. Fruit and vegetables, on the other hand, are considered "weak" and therefore feminine foods. This overlooks the fact that a "typically" female diet is often oriented toward attractiveness and is associated with restricted eating behavior. The so-called "healthier" nutrition of women is also accompanied by greater nutritional knowledge and competence. However, it needs to be questioned whether male family or household members are absolved from responsibility for their own health or whether they are happy to leave this to women because of the socially perceived feminine responsibility for all aspects of nutrition, sustenance and care-giving. The advanced knowledge and competence of women in questions of healthy eating and food preparation compared with men often act as an obstacle to men engaging and actively participating in nutritional issues.Emphasizing the observed gender differences is not expedient in terms of effective communication on nutrition and health and can run the risk of reproducing gender stereotypes and neglecting other more powerful social categories. Alternative strategies consist of focusing more on the "eating person" and following a gender-neutral communication and counseling strategy.
With the emergence of large-scale Cap Analysis of Gene Expression (CAGE) datasets from individual labs and the FANTOM consortium, one can now analyze the cis-regulatory regions associated with gene transcription at an unprecedented level of refinement. By coupling transcription factor binding site (TFBS) enrichment analysis with CAGE-derived genomic regions, CAGEd-oPOSSUM can identify TFs that act as key regulators of genes involved in specific mammalian cell and tissue types. The webtool allows for the analysis of CAGE-derived transcription start sites (TSSs) either provided by the user or selected from ∼1300 mammalian samples from the FANTOM5 project with pre-computed TFBS predicted with JASPAR TF binding profiles. The tool helps power insights into the regulation of genes through the study of the specific usage of TSSs within specific cell types and/or under specific conditions.
The CAGEd-oPOSUM web tool is implemented in Perl, MySQL and Apache and is available at http://cagedop.cmmt.ubc.ca/CAGEd_oPOSSUM CONTACTS: anthony.mathelier@ncmm.uio.no or wyeth@cmmt.ubc.ca
Supplementary data are available at Bioinformatics online.
Few studies have examined young children's leisure- and school-based energy expenditure (EE) and moderateto-vigorous physical activity (MVPA). The purpose of this study was to explore children's estimated EE rates and time spent in MVPA in 3 time segments: at-school, after-school, and weekends.
A total of 187 second and third grade children from 2 elementary schools participated in the study. Accelerometers were used to assess children's 5-day EE and MVPA. Multiple 2 (Grade) × 2 (Gender) ANOVAs with repeated measures (Time) were conducted to examine the differences in the outcome variables.
Significant time effects on EE and MVPA were revealed. Children's EE rate and minutes in MVPA per day were higher during after school and weekends than at school.
Although children were more active outside of school, their MVPA during weekdays and weekends still fell far short of the recommended level of 60 minutes/day.
Modern biomedical research depends critically on access to databases that house and disseminate genetic, genomic, molecular, and cell biological knowledge. Even as the explosion of available genome sequences and associated genome-scale data continues apace, the sustainability of professionally maintained biological databases is under threat due to policy changes by major funding agencies. Here, we focus on model organism databases to demonstrate the myriad ways in which biological databases not only act as repositories but actively facilitate advances in research. We present data that show that reducing financial support to model organism databases could prove to be not just scientifically, but also economically, unsound.
Nucleic acid (NA) is continuously degraded in lysosomes, cytoplasm, and nucleus. NA degradation has a key role in preventing hazardous activation of NA sensors. DNA degradation by lysosomal and cytoplasmic DNases prevents homeostatic activation of cytoplasmic DNA sensing pathways. Crude NA, however, is not sufficient for stimulating NA sensors. mRNAs and rRNAs need to be processed by inositol-requiring enzyme 1
 (IRE-1) or RNase L before stimulating cytoplasmic RNA sensors. Activation of cytoplasmic RNA sensors by processed RNAs is tightly controlled by their degradation through the machineries, such as RNA editing, by adenosine (A) deaminases that act on RNA 1 (ADAR1) and the RNA exosome. Impaired degradation of processed RNAs in humans causes activation of cytoplasmic RNA sensors, leading to Aicardi-Goutières syndrome or trichohepatoenteric syndrome. Lysosomal TLRs are also dependent on NA processing in lysosomes. Digestion of dsDNA by DNase II is required for TLR9 response to ssDNA. TLR7 and TLR8 respond to ribonucleosides and oligoribonucleotides, instead of ssRNA itself, indicating requirement for RNA processing. NA-sensing TLRs themselves need to be processed by lysosomal proteases. Without processing, TLR8 and TLR9 fail to form dimers. In addition to NA degradation, the processing of NAs and TLRs by a variety of enzymes is an emerging concept on the control of innate immune responses to NAs.
To achieve tumor-specific delivery of doxorubicin, TiO2@Fe3O4/PEI/delivery of doxorubicin conjugates were designed and synthesized. Fe3O4 could act as magnetically responsive carriers and enhance the visible light photodynamic activities of TiO2 Delivery of doxorubicin was conjugated via coordination bond. The drug release rate at pH 5.2 was much faster than that at pH 7.4, due to pH-sensitive coordination bond. Besides, TiO2@Fe3O4/PEI/delivery of doxorubicin showed high antitumor efficacy combining with phototherapy, good bio-safety, higher cellular uptake with an external magnetic field, and less toxicity in vitro and in vivo. These results suggested that TiO2@Fe3O4/PEI/delivery of doxorubicin may be promising for high tumor treatment efficacy with minimal side effects in future.
- The central theme of the guideline 'Post-mortem examination for attending doctors' is that the primary aim of the post-mortem examination is not to ascertain death as such, but to investigate whether the person died of natural or unnatural causes.- The guideline gives indications for the content of the post-mortem in order to make this differentiation reliable.- Only in cases of natural death is the attending doctor permitted to fill in a death certificate. - In cases of possible unnatural death where a crime or an imputable act may have been committed, a municipal coroner should be called in. - Post-mortem should be carried out as quickly as possible after notification, with the exception of nocturnal deaths in nursing homes, or comparable care institutions, when this decease is expected.
PC3/Tis21 is a transcriptional cofactor that inhibits proliferation in several cell types, including neural progenitors. Here we report that PC3/Tis21 associates with HDAC1, HDAC4 and HDAC9 in vivo, in fibroblast cells. Furthermore, when HDAC1, HDAC4 or HDAC9 are silenced in fibroblasts or in a line of cerebellar progenitor cells, the ability of PC3/Tis21 to inhibit proliferation is significantly reduced. Overexpression of HDAC1, HDAC4 or HDAC9 in fibroblasts and in cerebellar precursor cells synergizes with PC3/Tis21 in inhibiting the expression of cyclin D1, a cyclin selectively inhibited by PC3/Tis21. Conversely, the depletion of HDAC1 or HDAC4 (but not HDAC9) in fibroblasts and in cerebellar precursor cells significantly impairs the ability of PC3/Tis21 to inhibit cyclin D1 expression. An analysis of HDAC4 deletion mutants shows that both the amino- terminal moiety and the catalytic domain of HDAC4 associate to PC3/Tis21, but neither alone is sufficient to potentiate the inhibition of cyclin D1 by PC3/Tis21. As a whole, our findings indicate that PC3/Tis21 inhibits cell proliferation in a way dependent on the presence of HDACs, in fibroblasts as well as in neural cells. Considering that several reports have demonstrated that HDACs can act as transcriptional corepressors on the cyclin D1 promoter, our data suggest that the association of PC3/Tis21 to HDACs is functional to recruit them to target genes, such as cyclin D1, for repression of their expression. This article is protected by copyright. All rights reserved.
Commensal bacteria are microorganisms that occur among others in the gastrointestinal, respiratory and urogenital tract not exhibit the characteristics of pathogenicity, and act on the immune system and the metabolism of macroorganism and "create" protective barrier against pathogenic bacteria. Currently, it is estimated that the number of commensal bacteria inhabiting in and on human, are more than ten times the number of cells that build the body. The composition of these microorganisms depends on health and physiological status of macroorganism, including its immune status, but also largely on environmental factors (living and diet). These bacteria affecting the immune system in the gastrointestinal, respiratory and urogenital tract, stimulate the synthesis of a number of immunological substances that interact multiphase, for example: blocking the adhesion of pathogenic microorganisms and to reduce or entirely eliminate their influence on the contact and macroorganism.
Endocannabinoids exert their effect on the regulation of energy homeostasis via activation of specific receptors. They control food intake, secretion of insulin, lipids and glucose metabolism, lipid storage. Long chain fatty acids are the main myocardial energy substrate. However, the heart exerts enormous metabolic flexibility emphasized by its ability to utilzation not only fatty acids, but also glucose, lactate and ketone bodies. Endocannabinoids can directly act on the cardiomyocytes through the CB1 and CB2 receptors present in cardiomyocytes. It appears that direct activation of CB1 receptors promotes increased lipogenesis, pericardial steatosis and bioelectrical dysfunction of the heart. In contrast, stimulation of CB2 receptors exhibits cardioprotective properties, helping to maintain appropriate amount of ATP in cardiomyocytes. Furthermore, the effects of endocannabinoids at both the central nervous system and peripheral tissues, such as liver, pancreas, or adipose tissue, resulting indirectly in plasma availability of energy substrates and affects myocardial metabolism. To date, there is little evidence that describes effects of activation of the endocannabinoid system in the cardiovascular system under physiological conditions. In the present paper the impact of metabolic diseases, i. e. obesity and diabetes, as well as the cardiovascular diseases - hypertension, myocardial ischemia and myocardial infarction on the deregulation of the endocannabinoid system and its effect on the metabolism are described.
The passage of the 2009 Family Smoking Prevention and Tobacco Control Act has necessitated the execution of timely, innovative, and policy-relevant tobacco control research to inform Food and Drug Administration (FDA) regulatory and messaging efforts. With recent dramatic changes to tobacco product availability and patterns of use, nationally representative data on tobacco-related perceptions and behaviors are vital, especially for vulnerable populations.
The UNC Center for Regulatory Research on Tobacco Communication conducted a telephone survey with a national sample of adults ages 18 and older living in the United States (U.S.). The survey assessed regulatory relevant factors such as tobacco product use, tobacco constituent perceptions, and tobacco regulatory agency credibility. The study oversampled high smoking/low income areas as well as cell phone numbers to ensure adequate representation among smokers and young adults, respectively. Coverage extended to approximately 98 % of U.S. households.
The final dataset (N = 5,014) generated weighted estimates that were largely comparable to other national demographic and tobacco use estimates. Results revealed that over one quarter of U.S. adults, and over one third of smokers, reported having looked for information about tobacco constituents in cigarette smoke; however, the vast majority was unaware of what constituents might actually be present. Although only a minority of people reported trust in the federal government, two thirds felt that the FDA can effectively regulate tobacco products.
As the FDA continues their regulatory and messaging activities, they should expand both the breadth and availability of constituent-related information, targeting these efforts to reach all segments of the U.S. population, especially those disproportionately vulnerable to tobacco product use and its associated negative health outcomes.
Dextromethorphan is a safe, effective cough suppressant, available without a prescription in the United States since 1958. Due to a perceived prevalence of abuse of dextromethorphan by teens, in 2007 the Drug Enforcement Administration requested the Food and Drug Administration evaluate whether dextromethorphan should be recommended for scheduling under the Controlled Substances Act. The Food and Drug Administration held an Advisory Committee meeting in 2010 to provide a scientific and medical evaluation of dextromethorphan and its abuse potential.
To address reports of abuse, particularly by teens in the United States, the Consumer Healthcare Products Association initiated an abuse mitigation plan in 2010 with specific goals related to awareness of the behavior, perception of risk, social disapproval, and access to the products. In identifying abuse interventions, experts acknowledge that substance abuse among teens is a highly complex behavior and indicate that the best course of action is to address prevention by focusing on the factors that impact teen behavior.
It is noteworthy that the annual prevalence of over-the-counter cough medicine abuse has sharply decreased since 2010. While a true cause-and-effect relationship cannot be assured, the Consumer Healthcare Products Association and its member
 companies believe that the increased awareness of the issue since the 2010 Food and Drug Administration Advisory Committee meeting, and the subsequent implementation of a well-delivered and targeted abuse mitigation plan that addressed the levers influencing teen decisions is contributing to the observed reduction in abuse. During the period of 2010-2015, reported abuse of dextromethorphan by 8(th), 10(th), and 12(th) graders decreased 35 %. The authors believe this reduction supports the view of the Consumer Healthcare Products Association at the outset of the abuse mitigation plan effort and today: Controlled substance scheduling or prescription requirements would result in a reduction in the legitimate use of this medicine that has benefits that far outweigh its risks. Instead, there are more targeted, more effective, and less disruptive interventions to address dextromethorphan abuse.
Artemisinin-based combination therapy (ACT) is a key strategy for global malaria elimination efforts. However, the development of artemisinin-resistant malaria parasites threatens progress and continued usage of oral artemisinin monotherapies (AMT) predisposes the selection of drug resistant strains. This is particularly a problem along the Myanmar/Thailand border. The artemisinin monotherapy replacement programme (AMTR) was established in 2012 to remove oral AMT from stocks in Myanmar, specifically by replacing oral AMT with quality-assured ACT and conducting behavioural change communication activities to the outlets dispensing anti-malarial medications. This study attempts to quantify the characteristics of outlet providers who continue to stock oral AMT despite these concerted efforts.
A cross-sectional survey of all types of private sector outlets that were stocking anti-malarial drugs in 13 townships of Eastern Myanmar was implemented from July to August 2014. A total of 573 outlets were included. Bivariate and multivariable logistic regressions were conducted to assess outlet and provider-level characteristics associated with stocking oral AMT.
In total, 2939 outlets in Eastern Myanmar were screened for presence of any anti-malarial drugs in August 2014. The study found that 573 (19.5 %) had some kind of oral anti-malarial drug in stock at the time of survey and among them, 96 (16.8 %) stocked oral AMT. In bivariate analyses, compared to health care facilities, itinerant drug vendors, retailers and health workers were less likely to stock oral AMT (33.3 vs 12.9, 10.0, 8.1 %, OR = 0.30, 0.22, 0.18, respectively). Providers who cut blister pack or sell partial courses (40.6 vs 11.7 %, OR 5.18, CI 3.18-8.44) and those who based their stock decision on consumer demand (32.8 vs 12.1 %, OR 3.54, CI 2.21-5.63) were more likely to stock oAMT. Multivariate logistic regressions produced similar significant associations.
Private healthcare facilities and drug shops and providers who prioritize consumers' demand instead of recommended practices were more likely to stock oral AMT. Malaria elimination strategies should include targeted interventions to effectively reach those outlets.
Medical Devices Law is a relatively new legal system, which has replaced the Medical Devices Regulations still well-known in Germany. German Medical Devices Law is based on European directives, which are, in turn, incorporated into national law by the Medical Devices Act. The Medical Devices Act is a framework law and covers a number of regulations that address specific topics within Medical Devices Law. In turn, in individual regulations, reference is made to guidelines, recommendations, etc. from other sources that provide detailed technical information on specific topics. Medical Devices Law is a very complex legal system, which needs to be permanently observed due to constant updating and adjustment. In the current article, the design and the structure of the system will be described, but special emphasis will be laid on important problem areas that need to be considered when applying and operating medical products, in this case by pain therapists in particular.
The authors describe a case of a recurrent World Health Organization grade III extradural, sinonasal meningioma that presented with epiphoria. Primary extradural meningiomas are rare, comprising only 1% to 2% of all meningiomas. These tumors are diagnosed and graded histologically according to the World Health Organization criteria. Grade III tumors are very malignant with high recurrence and death rates. This case highlights the rarity of sinonasal tract meningiomas involving the orbit. In addition, it shows the poor prognosis of such malignant disease and the need for a multidisciplinary approach. Collection and evaluation of protected patient health information for this report was in compliance with the Health Insurance Portability and Accountability Act and approved by the Institutional Review Board of Northwestern University Feinberg School of Medicine. Research adhered to the tenets of the Declaration of Helsinki.
The Food and Drug Administration Modernization Act (FDAMA) of 1997 included Section 114 as a regulatory safe harbor with the goal of increasing the dissemination of health care economic information (HCEI) to those responsible for formulary decision making. HCEI is typically not included within FDA-approved labeling. Although it has been nearly 20 years since passage and enactment of Section 114, proactive distribution of HCEI has been underutilized by biopharmaceutical companies partly because of (a) vague wording in the statute and (b) the absence of FDA-implementing regulations. Consequently, companies and health care decisions makers have had to speculate about the scope of the provisions. As a result, the biopharmaceutical industry has significant concerns about stepping over the line when using the safe harbor. Also, payers and other "payer-like" decision makers (e.g., self-funded corporate insurers) who are trying to make appropriate coverage and utilization decisions are demanding this information but are not receiving it because of the uncertainties in the statute. Considering this renewed interest by multiple stakeholders regarding the need for revisions and/or guidance pertaining to Section 114, the Academy of Managed Care Pharmacy held a partnership forum on March 1-2, 2016, with a diverse group of health care stakeholders to provide the FDA with considerations for disseminating a guidance document on current thinking for the sharing of HCEI with health care decision makers. Forum participants represented the managed care industry, biopharmaceutical industry, health care providers, pharmacoeconomic experts, policy experts, and patient advocacy groups with specific expertise in the development, use, and dissemination of HCEI. The multistakeholder group represented the key professionals and entities affected by the provisions of Section 114 and present the collective credibility necessary for Congress and the FDA to modernize and operationalize the safe harbor by using the consensus recommendations developed during the forum. Speakers, panelists, and attendees focused on 4 terms in Section 114 that remain open to interpretation by companies and enforcement bodies: (1) the scope of HCEI, (2) the scope of "formulary committee or similar entity," (3) the definition of "competent and reliable scientific evidence (CRSE)," and (4) the parameters of how information "directly relates to an approved indication." Based on the forum results, it was recommended that the safe harbor for companies' proactive dissemination of information under Section 114 should include health care decision makers beyond health plan formulary committees, including organizations, or individuals in their role in an organization, who make health care decisions for patient populations. Recommendations also suggested expansion to organizations that evaluate HCEI or develop value frameworks and compendia and individuals in such organizations. Forum participants also recommended that HCEI be truthful, and not misleading, and be based on the expertise of professionals in the relevant area. HCEI must also be developed and disclosed in a transparent, reproducible, and accurate manner. Forum participants also discussed and agreed on the types of information, format, and processes by which managed care pharmacy and other health care decision makers seek to receive HCEI from biopharmaceutical companies. Finally, participants encouraged the FDA, Congress, and other stakeholders to find ways to ensure that patients or their representative organizations have appropriate access to a full range of information about their medications and that information related to the medication pipeline is communicated to appropriate stakeholders in a timely manner.
The AMCP Partnership Forum on FDAMA Section 114-Improving the Exchange of Pharmacoeconomic Data and the development of this proceedings document were supported by AbbVie, Amgen, Boehringer Ingelheim Pharmaceuticals, Merck & Co., National Pharmaceutical Council, Pharmaceutical Research and Manufacturers of America, Precision for Value, Pfizer, Takeda Pharmaceuticals, U.S.A., and Xcenda. All sponsors participated in the forum and participated in revising and approving the manuscript.
Direct C-H bond activation is an important reaction in synthetic organic chemistry. This methodology has the potential to simplify reactions by avoiding the use of prefunctionalized reagents. However, selectivity, especially site selectivity, remains challenging. Sequential reactions, in which different molecules or groups are combined in an ordered sequence, represent a powerful tool for the construction of complex molecules in a single operation. We have discovered and developed a synthetic methodology that combines selective C-H bond activation with sequential reactions. This procedure, which
 is now known as the "Catellani reaction", enables the selective functionalization of both the ortho and ipso positions of aryl halides. The desired molecules are obtained with high selectivity from a pool of simple precursors. These molecules are assembled under the control of a palladacycle, which is formed through the joint action of a metal (Pd) and an olefin such as norbornene. These two species act cooperatively with an aryl halide to construct the palladacycle, which is formed through ortho-C-H activation of the original aryl halide. The resulting complex acts as a scaffold to direct the reaction (via Pd(IV)) of other species, such as alkyl or aryl halides and amination or acylation agents, toward the sp(2) C-Pd bond. At the end of this process, because of steric hindrance, the scaffold is dismantled by norbornene extrusion. Pd(0) is cleaved from the organic product through C-C, C-H, C-N, C-O, or C-B coupling, in agreement with the well-known reactivity of aryl-Pd complexes. The cycle involves Pd(0), Pd(II), and Pd(IV) species. In particular, our discovery relates to alkylation and arylation reactions. Recently, remarkable progress has been made in the following areas: (a) the installation of an amino or an acyl group at the ortho position of aryl halides, (b) the formation of a C-B bond at the ipso position, (c) the achievement of meta-C-H bond activation of aryl rings bearing a chelating directing group by Pd(II)/Pd(IV)/norbornene catalysis, and (d) the activation of N-H and C-H bonds in sequence for indole 2-alkylation. In this Account, we explain the main features of this methodology, describe its synthetic potential, and illustrate some remarkable progress that has been made, emphasizing the most recent developments and applications in total synthesis.
At term, the signals of fetal maturity and feto-placental tissue aging prompt uterine readiness for delivery by transitioning quiescent myometrium to an active stage. It is still unclear how the signals reach the distant myometrium. Exosomes are a specific type of extracellular vesicle (EVs) that transport molecular signals between cells, and are released from a wide range of cells, including the maternal and fetal cells. In this study, we hypothesize that i) exosomes act as carriers of signals in utero-placental compartments and ii) exosomes reflect the physiologic status of the origin cells. The primary aims of this study were to determine exosomal contents in exosomes derived from primary amnion epithelial cells (AEC). We also determined the effect of oxidative stress on AEC derived exosomal cargo contents. AEC were isolated from amniotic membrane obtained from normal, term, not in labor placentae at delivery, and culture under standard conditions. Oxidative stress was induced using cigarette smoke extract for 48 hours. AEC-conditioned media were collected and exosomes isolated by differential centrifugations. Both growth conditions (normal and oxidative stress induced) produced cup shaped exosomes of around 50 nm, expressed exosomes enriched markers, such as CD9, CD63, CD81 and HSC70, embryonic stem cell marker Nanog, and contained similar amounts of cell free AEC DNA. Using confocal microscopy, the colocalization of histone (H) 3, heat shock protein (HSP) 70 and activated form of pro-senescence and term parturition associated marker p38 mitogen activated protein kinase (MAPK) (P-p38 MAPK) co-localized with exosome enrich marker CD9. HSP70 and P-p38 MAPK were significantly higher in exosomes from AEC grown under oxidative stress conditions than standard conditions (p<0.05). Finally, mass spectrometry and bioinformatics analysis identified 221 different proteins involved in immunomodulatory response and cell-to-cell communication. This study determined AEC exosome characteristics and their cargo reflected the physiologic status of the cell of origin and suggests that AEC-derived exosomal p38 MAPK plays a major role in determining the fate of pregnancy. Understanding the propagation of fetal signals and their mechanisms in normal term pregnancies can provide insights into pathologic activation of such signals associated with spontaneous preterm parturitions.
Cannabinoids, such as Δ9-THC, act through an endogenous signaling system in the vertebrate eye that reduces IOP via CB1 receptors. Endogenous cannabinoid (eCB) ligand, 2-arachidonoyl glycerol (2-AG), likewise activates CB1 and is metabolized by monoacylglycerol lipase (MAGL). We investigated ocular 2-AG and its regulation by MAGL and the therapeutic potential of harnessing eCBs to lower IOP.
We tested the effect of topical application of 2-AG and MAGL blockers in normotensive mice and examined changes in eCB-related lipid species in the eyes and spinal cord of MAGL knockout (MAGL-/-) mice using high performance liquid chromatography/tandem mass spectrometry (HPLC/MS/MS). We also examined the protein distribution of MAGL in the mouse anterior chamber.
2-Arachidonoyl glycerol reliably lowered IOP in a CB1- and concentration-dependent manner. Monoacylglycerol lipase is expressed prominently in nonpigmented ciliary epithelium. The MAGL blocker KML29, but not JZL184, lowered IOP. The ability of CB1 to lower IOP is not desensitized in MAGL-/- mice. Ocular monoacylglycerols, including 2-AG, are elevated in MAGL-/- mice but, in contrast to the spinal cord, arachidonic acid and prostaglandins are not changed.
Our data confirm a central role for MAGL in metabolism of ocular 2-AG and related lipid species, and that endogenous 2-AG can be harnessed to reduce IOP. The MAGL blocker KML29 has promise as a therapeutic agent, while JZL184 may have difficulty crossing the cornea. These data, combined with the relative specificity of MAGL for ocular monoacylglycerols and the lack of desensitization in MAGL-/- mice, suggest that the development of an optimized MAGL blocker offers therapeutic potential for treatment of elevated IOP.
This work describes the gelation behaviors of a biological amphiphile, deoxycholate (DC(-)), in aqueous solution by adding inorganic salts and modulating pH. Electrostatic interaction and hydrogen bonding can separately act as the controlling interaction for the hydrogel formation. The hydrogels formed at higher pH (about 8.5) through introducing monovalent inorganic cations (Na(+)) are mainly driven by electrostatic interaction between deoxycholate species and Na(+) ions. When pH is decreased, with the formation of DCA molecules, hydrogen bonding between DC(-) and DCA come into being another leading role to construct the hydrogels, which can induce the gels within an appropriate pH region (6.7-7.3) without inorganic cations. Gels constructed through the self-assembly of deoxycholate present diverse properties according to the difference in the main driving force. Moreover, the combination of the two important interactions can significantly enhance the gelation ability.
Thyroid disease can be subtle in its presentation, and TSH reference intervals may be artefactually increased by including persons with subclinical thyroid disease. We have therefore used a thyroid disease-free population to determine TSH and fT4 reference intervals.
Apparently healthy subjects were assessed by health questionnaire, drug history, clinical assessment and measurement of thyroid antibodies.
Healthy subjects in a community setting.
TSH, free T4, antithyroglobulin and anti-TPO were measured on the Abbott Architect analyser. Subjects with clinical abnormalities, consumption of thyroid-active medications or with thyroid antibodies above the manufacturer-quoted reference intervals were excluded. TSH and fT4 data were log-transformed, and the central 95% was used to calculate reference intervals. We assessed whether these data were normally distributed. We compared samples spanning the reference intervals for both TSH and fT4 between different assays looking at biases.
From a population of 1,606 subjects, 140 males (18%) and 284 females (34%) were excluded. The central population 95% for TSH was 0·43-3·28 mU/l and for fT4 10·8-16·8 pmol/l. There were no age- or sex-related differences. For both analytes, the distribution was not significantly different to a Gaussian distribution (P > 0·05). For 5 commonly used assays for TSH, the maximum difference in the upper limit of the TSH reference interval was 0·48 mU/l and for fT4 the maximum difference for the upper reference limit was 4·1 pmol/l.
A substantial proportion of apparently healthy persons have subclinical thyroid disease. These subjects must be excluded for any thyroid hormone reference interval studies.
Bacteria in humans play an important role in health and disease. Considerable emphasis has been placed in understanding the role of bacteria in host-microbiome interkingdom communication. Here we show that serotonin, responsible for mood in the brain and motility in the gut, can also act as a bacterial signaling molecule for pathogenic bacteria. Specifically, we found that serotonin acts as an interkingdom signaling molecule via quorum sensing and that it stimulates the production of bacterial virulence factors and increases biofilm formation in vitro and in vivo in a novel mouse infection model. This discovery points out at roles of serotonin both in bacteria and humans, and at phenotypic implications not only manifested in mood behavior but also in infection processes in the host. Thus, regulating serotonin concentrations in the gut may provide with paradigm shifting therapeutic approaches.
This article demonstrates the synthesis of lactic acid oligomer-grafted-chitosan (OLLA-g-CH), a nanoamphiphilic molecule, by in situ condensation polymerization and its effective use as a nanofiller for improvement in multiple properties of poly(lactic acid) (PLA) films, essential for stringent food packaging applications. Fourier transform infrared spectroscopy (FTIR) analysis
 shows the presence of amide-ester bond at 1539 cm(-1), which confirms the structural grafting of OLLA chains with chitosan molecules. This nanoamphiphilic OLLA-g-CH molecule act as surfactant containing hydrophilic chitosan head and hydrophobic OLLA tails with average size in the range of ∼2-4 nm. Prepared PLA/OLLA-g-CH bionanocomposite films appear with uniform dispersion of nanoamphiphilic OLLA-g-CH molecules with self-assembled micelles having size as low as ∼20 nm and as high as ∼150 nm with core-shell morphology in PLA matrix. This nanofiller is found very effective toward significant reduction in oxygen permeability (OP) by ∼10-fold due to the reduction in solubility of oxygen molecules and improvement in crystal nucleation density due to availability of nanonucleating sites. Ultimate tensile strength (UTS) of PLA/OLLA-g-CH bionanocomposite films are relatively comparable to that of PLA, however, elongation at break is improved significantly. The onset of thermal degradation of PLA/(OLLA-g-CH) films is also found comparable to that of PLA film. The glass transition temperature (Tg) of bionanocomposites is decreased by more than 18 °C with increase in OLLA-g-CH loading, which indicates the improved plasticization characteristics of PLA matrix. The crystallization kinetics suggest nonthree dimensional truncated spherical structures, which is controlled by the combination of thermal and athermal instantaneous nucleations. POM analysis suggested that the spherulite growth of PLA is improved significantly with the addition of OLLA-g-CH. The reduction in Tg of PLA with improvement in elongation at break and multifold reduction in oxygen permeability offers this bionanocomposite films, a promising candidate for stringent food packaging applications.
Sudden cardiac death among children and young adults is a devastating event. We performed a prospective, population-based, clinical and genetic study of sudden cardiac death among children and young adults.
We prospectively collected clinical, demographic, and autopsy information on all cases of sudden cardiac death among children and young adults 1 to 35 years of age in Australia and New Zealand from 2010 through 2012. In cases that had no cause identified after a comprehensive autopsy that included toxicologic and histologic studies (unexplained sudden cardiac death), at least 59 cardiac genes were analyzed for a clinically relevant cardiac gene mutation.
A total of 490 cases of sudden cardiac death were identified. The annual incidence was 1.3 cases per 100,000 persons 1 to 35 years of age; 72% of the cases involved boys or young men. Persons 31 to 35 years of age had the highest incidence of sudden cardiac death (3.2 cases per 100,000 persons per year), and persons 16 to 20 years of age had the highest incidence of unexplained sudden cardiac death (0.8 cases per 100,000 persons per year). The most common explained causes of sudden cardiac death were coronary artery disease (24% of cases) and inherited cardiomyopathies (16% of cases). Unexplained sudden cardiac death (40% of cases) was the predominant finding among persons in all age groups, except for those 31 to 35 years of age, for whom coronary artery disease was the most common finding. Younger age and death at night were independently associated with unexplained sudden cardiac death as compared with explained sudden cardiac death. A clinically relevant cardiac gene mutation was identified in 31 of 113 cases (27%) of unexplained sudden cardiac death in which genetic testing was performed. During follow-up, a clinical diagnosis of an inherited cardiovascular disease was identified in 13% of the families in which an unexplained sudden cardiac death occurred.
The addition of genetic testing to autopsy investigation substantially increased the identification of a possible cause of sudden cardiac death among children and young adults. (Funded by the National Health and Medical Research Council of Australia and others.).
The incidence of food allergies in western countries has increased dramatically in recent decades. Tolerance to food antigens relies on mucosal CD103(+) dendritic cells (DCs), which promote differentiation of regulatory T (Treg) cells. We show that high-fiber feeding in mice improved oral tolerance and protected from food allergy. High-fiber feeding reshaped gut microbial ecology and increased the release of short-chain fatty acids (SCFAs), particularly acetate and butyrate. High-fiber feeding enhanced oral tolerance and protected against food allergy by enhancing retinal dehydrogenase activity in CD103(+) DC. This protection depended on vitamin A in the diet. This feeding regimen also boosted IgA production and enhanced T follicular helper and mucosal germinal center responses. Mice lacking GPR43 or GPR109A, receptors for SCFAs, showed exacerbated food allergy and fewer CD103(+) DCs. Dietary elements, including fiber and vitamin A, therefore regulate numerous protective pathways in the gastrointestinal tract, necessary for immune non-responsiveness to food antigens.
This article explores barriers to end-of-life (EOL) care (including development of a death denying culture, ongoing perceptions about EOL care, poor communication, delayed access, and benefit restrictions) through the theoretical lens of symbolic interactionism (SI), and applies general systems theory (GST) to a promising practice model appropriate for addressing these barriers. The Compassionate Care program is a practice model designed to bridge gaps in care for the dying and is one example of a program offering concurrent care, a recent focus of evaluation though the Affordable Care Act. Concurrent care involves offering curative care alongside palliative or hospice care. Additionally, the program offers comprehensive case management and online resources to enrollees in a national health plan (Spettell et al., 2009).SI and GST are compatible and interrelated theories that provide a relevant picture of barriers to end-of-life care and a practice model that might evoke change among multiple levels of systems. These theories promote insight into current challenges in EOL care, as well as point to areas of needed research and interventions to address them. The article concludes with implications for policy and practice, and discusses the important role of social work in impacting change within EOL care.
Tele-technology in the health care system is prognosed to be able to produce better health, better care at lower cost (Triple aim). This paper will discuss the validity of this prognosis, which in many ways is considered as some sort of diagnosis of the conditions concerning triple aim in relation to Tele-technology. Tele-technology in the health care system covers three different types of technological settings: telecare, telehealth and telemedicine. This paper will disclose the different meanings of telecare, telehealth and telemedicine and discusses how nursing informatics can accomplish and gain from this disclosure. Theoretically and methodologically the paper is based on post-phenomenological readings and reflections, where use, practice, users, participants, values and knowledge systems are addressed on an equal level in order to understand technology and how we act appropriately through and with technology.
Leveraging the experience of the European project MobiGuide, this paper elaborates on the nurses' role in developing, delivering and evaluating e-health based services. We focus on the home monitoring of atrial fibrillation. Patients enrolled in our study are provided with a smartphone and an ECG sensor, and receive recommendations, reminders and alerts concerning medications and measurements that they should perform through a mobile decision support system that is constantly updated by a backend system. Patients' data are sent to health care personnel that may visualize them, and act accordingly. Nurses play a central role in such setting. After being involved in the design of the caregiver interface, they are responsible for the patients' enrollment phase (which includes patients' training), for the daily checking of incoming data, for the triage of patients' complaints, and for the final phase of the study where patients are interviewed about their experience with the system.
Cells that mutate or commit to a specialized function (differentiate) often undergo conversions that are effectively irreversible. Slowed growth of converted cells can act as a form of selection, balancing unidirectional conversion to maintain both cell types at a steady-state ratio. However, when one-way conversion is insufficiently counterbalanced by selection, the original cell type will ultimately be lost, often with negative impacts on the population's overall fitness. The critical balance between selection and conversion needed for preservation of unconverted cells and the steady-state ratio between cell types depends on the spatial circumstances under which cells proliferate. We present experimental data on a yeast strain engineered to undergo irreversible conversion: this synthetic system permits cell-type-specific fluorescent labeling and exogenous variation of the relative growth and conversion rates. We find that populations confined to grow on a flat agar surface are more susceptible than their well-mixed counterparts to fitness loss via a conversion-induced "meltdown." We then present analytical predictions for growth in several biologically relevant geometries-well-mixed liquid media, radially expanding two-dimensional colonies, and linear fronts in two dimensions-by employing analogies to the directed-percolation transition from nonequilibrium statistical physics. These simplified theories are consistent with the experimental results.
Cells are dynamic systems that generate and respond to forces over a range of spatial and temporal scales,
 spanning from single molecules to tissues. Substantial progress has been made in recent years in identifying the molecules and pathways responsible for sensing and transducing mechanical signals to short-term cellular responses and longer-term changes in gene expression, cell identity, and tissue development. In this perspective article, we focus on myosin motors, as they not only function as the primary force generators in well-studied mechanobiological processes, but also act as key mechanosensors in diverse functions including intracellular transport, signaling, cell migration, muscle contraction, and sensory perception. We discuss how the biochemical and mechanical properties of different myosin isoforms are tuned to fulfill these roles in an array of cellular processes, and we highlight the underappreciated diversity of mechanosensing properties within the myosin superfamily. In particular, we use modeling and simulations to make predictions regarding how diversity in force sensing affects the lifetime of the actomyosin bond, the myosin power output, and the ability of myosin to respond to a perturbation in force for several nonprocessive myosin isoforms.
The search for more efficient therapeutic strategies and diagnosis tools is a continuous challenge. Advances in understanding the biological mechanisms behind diseases and tissues regeneration have widened the field of applications of particulate systems. Particles are no more just protective systems for the encapsulated drugs, but they play an active role in the success of the therapy. Moreover, particles have been explored for innovative purposes as templates for cells growth and as diagnostic tools. Until few years ago the most relevant parameters in particles formulation were the chemistry and the size. Currently, it is known that other physical characteristics can remarkably affect the performance of particulate systems. Particles with non-conventional shapes exhibit advantages due to the increasing circulation time in blood stream, less clearance by the immune system and more efficient cell internalization and trafficking. Creation of compartments has been found useful to control drug release, to tune the transport of substances across biological barriers, to supply the target with more than one bioactive agent or even to act as theranostic systems. It is expected that such complex shaped and compartmentalized systems improve the therapeutic outcomes and also the patient's compliance, acting as advanced devices that serve for simultaneous diagnosis and treatment of the disease, combining agents of very different features, at the same time. In this review, we overview and analyse the most recent advances in particle shape and compartmentalization and applications of newly designed particulate systems in the biomedical field.
The aberrant activity of Wnt signaling is an early step in the transformation of normal intestinal cells to malignant tissue, leading to more aggressive tumors, and eventually metastases. In colorectal cancer (CRC), metastasis accounts for about 90% of patient deaths, representing the most lethal event during the course of the disease and is directly linked to patient survival, critically limiting successful therapy. This review focuses on our studies of the metastasis-inducing gene S100A4, which we identified as transcriptional target of β-catenin. S100A4 increased migration and invasion in vitro and metastasis in mice. In patient CRC samples, high S100A4 levels predict metastasis and reduced patient survival. Our results link pathways important for tumor progression and metastasis: the Wnt signaling pathway and S100A4, which regulates motility and invasiveness. S100A4 suppression by interdicting Wnt signaling has potential for therapeutic intervention. As proof of principle, we applied S100A4 shRNA systemically and prevented metastasis in mice. Furthermore, we identified small molecule inhibitors from high-throughput screens of pharmacologically active compounds employing an S100A4 promoter-driven reporter. Best hits act, as least in part, via intervening in the Wnt pathway and restricted metastasis in mouse models. We currently translate our findings on restricting S100A4-driven metastasis into clinical practice. The repositioned FDA-approved drug niclosamide, targeting Wnt signaling, is being tested in a prospective phase II clinical trial for treatment of CRC patients. Our assay for circulating S100A4 transcripts in patient blood is used to monitor treatment success.
The synchronization of native state motions as they transition between microstates influences catalysis kinetics, mediates allosteric interactions, and reduces the conformational entropy of proteins. However, it has proven difficult to describe native microstates because they are usually minimally frustrated and may interconvert on the micro- to millisecond time scale. Direct observation of concerted equilibrium fluctuations would therefore be an important tool for describing protein native states. Here we propose a strategy that relates NMR cross-correlated relaxation (CCR) rates between dipolar interactions to residual dipolar couplings (RDCs) of individual consecutive H(N)-N and H(α)-C(α) bonds, which act as a proxy for the peptide planes and the side chains, respectively. Using Xplor-NIH ensemble structure calculations restrained with the RDC and CCR data, we observe collective motions on time scales slower than nanoseconds in the backbone for GB3. To directly access the correlations from CCR, we develop a structure-free data analysis. The resulting dynamic correlation map is consistent with the ensemble-restrained simulations and reveals a complex network. In general, we find that the bond motions are on average slightly correlated and that the local environment dominates many observations. Despite this, some patterns are typical over entire secondary structure elements. In the β-sheet, nearly all bonds are weakly correlated, and there is an approximately binary alternation in correlation intensity corresponding to the solvent exposure/shielding alternation of the side chains. For α-helices, there is also a weak correlation in the H(N)-N bonds. The degree of correlation involving H(α)-C(α) bonds is directly affected by side-chain fluctuations, whereas loops show complex and nonuniform behavior.
The Emergency Medical Treatment and Labor Act (EMTALA) of 1986 was enacted to prevent hospitals from "dumping" or refusing service to patients for financial reasons. The statute prohibits discrimination of emergency department (ED) patients for any reason. The Office of the Inspector General (OIG) of the Department of Health and Human Services enforces the statute. The objective of this study is to determine the scope, cost, frequency and most common allegations leading to monetary settlement against hospitals and physicians for patient dumping.
Review of OIG investigation archives in May 2015, including cases settled from 2002-2015 ( https://oig.hhs.gov/fraud/enforcement/cmp/patient_dumping.asp ).
There were 192 settlements (14 per year average for 4000+ hospitals in the USA). Fines against hospitals and physicians totaled $6,357,000 (averages $33,435 and $25,625 respectively); 184/192 (95.8%, $6,152,000) settlements were against hospitals and eight against physicians ($205,000). Most common settlements were for failing to screen 144/192 (75%) and stabilize 82/192 (42.7%) for emergency medical conditions (EMC). There were 22 (11.5%) cases of inappropriate transfer and 22 (11.5%) more where the hospital failed to transfer. Hospitals failed to accept an appropriate transfer in 25 (13.0%) cases. Patients were turned away from hospitals for insurance/financial status in 30 (15.6%) cases. There were 13 (6.8%) violations for patients in active labor. In 12 (6.3%) cases, the on-call physician refused to see the patient, and in 28 (14.6%) cases the patient was inappropriately discharged. Although loss of Medicare/Medicaid funding is an additional possible penalty, there were no disclosures of exclusion of hospitals from federal funding. There were 6,035 CMS investigations during this time period, with 2,436 found to have merit as EMTALA violations (40.4%). However, only 192/6,035 (3.2%) actually resulted in OIG settlements. The proportion of CMS-certified EMTALA violations that resulted in OIG settlements was 7.9% (192/2,436).
Of 192 hospital and physician settlements with the OIG from 2002-15, most were for failing to provide screening (75%) and stabilization (42%) to patients with EMCs. The reason for patient "dumping" was due to insurance or financial status in 15.6% of settlements. The vast majority of penalties were to hospitals (95% of cases and 97% of payments). Forty percent of investigations found EMTALA violations, but only 3% of investigations triggered fines.
Human primary cells originating from different locations within the body could differ greatly in their metabolic phenotypes, influencing both how they act during physiological/pathological processes and how susceptible/resistant they are to a variety of disease risk factors. A novel way to monitor cellular metabolism is through cell energetics assays, so we explored this approach with human primary cell types, as models of sclerotic disorders.
In order to better understand pathophysiological processes at the cellular level, our goals were to measure metabolic pathway activities of endothelial cells and fibroblasts, and determine their metabolic phenotype profiles.
Biolog Phenotype MicroArray™ technology was used for the first time to characterize metabolic phenotypes of diverse primary cells. These colorimetric assays enable detection of utilization of 367 specific biochemical substrates by human endothelial cells from the coronary artery (HCAEC), umbilical vein (HUVEC) and normal, healthy lung fibroblasts
 (NHLF).
Adenosine, inosine, d-mannose and dextrin were strongly utilized by all three cell types, comparable to glucose. Substrates metabolized solely by HCAEC were mannan, pectin, gelatin and prevalently tricarballylic acid. HUVEC did not show any uniquely metabolized substrates whereas NHLF exhibited strong utilization of sugars and carboxylic acids along with amino acids and peptides.
Taken together, we show for the first time that this simple energetics assay platform enables metabolic characterization of primary cells and that each of the three human cell types examined gives a unique and distinguishable profile.
The field of nanotechnology mainly encompasses with biology, physics, chemistry and material sciences and it develops novel therapeutic nanosized materials for biomedical and pharmaceutical applications. The biological syntheses of nanoparticles are being carried out by different macro-microscopic organisms such as plant, bacteria, fungi, seaweeds and microalgae. The biosynthesized nanomaterials have been effectively controlling the various endemic diseases with less adverse effect. Plant contains abundant natural compounds such as alkaloids, flavonoids, saponins, steroids, tannins and other nutritional compounds. These natural products are derived from various parts of plant such as leaves, stems, roots shoots, flowers, barks, and seeds. Recently, many studies have proved that the plant extracts act as a potential precursor for the synthesis of nanomaterial in non-hazardous ways. Since the plant extract contains various secondary metabolites, it acts as reducing and stabilizing agents for the bioreduction reaction to synthesized novel metallic nanoparticles. The non-biological methods (chemical and physical) are used in the synthesis of nanoparticles, which has a serious hazardous and high toxicity for living organisms. In addition, the biological synthesis of metallic nanoparticles is inexpensive, single step and eco-friendly methods. The plants are used successfully in the synthesis of various greener nanoparticles such as cobalt, copper, silver, gold, palladium, platinum, zinc oxide and magnetite. Also, the plant mediated nanoparticles are potential remedy for various diseases such as malaria, cancer, HIV, hepatitis and other acute diseases.
Head and neck squamous cell carcinoma (HNSCC) is the sixth most frequent cancer type, with an annual incidence of approximately half a million people worldwide. It has a high recurrence rate and an extremely low survival rate. This is due to limited availability of effective therapies to reduce the rate of recurrence, resulting in high morbidity and mortality of patients with advanced stages of the disease. HNSCC often develops resistance to chemotherapy and targeted drug therapy. Thus, to overcome the problem of drug resistance, there is a need to explore novel drug targets. Sphingosine-1-phosphate (S1P) is a bioactive sphingolipid involved in inflammation, tumor progression, and angiogenesis. S1P is synthesized intracellularly by two sphingosine kinases (SphKs). It can be exported to the extracellular space, where it can activate a family of G-protein-coupled receptors. Alternatively, S1P can act as an intracellular second messenger. SphK1 regulates tumor progression, invasion, metastasis, and chemoresistance in HNSCC. SphK1 expression is highly elevated in advanced stage HNSCC tumors and correlates with poor survival. In this article, we review current knowledge regarding the role of S1P receptors and enzymes of S1P metabolism in HNSCC carcinogenesis. Furthermore, we summarize the current perspectives on therapeutic approaches for targeting S1P pathway for treating HNSCC.
Lutzomyia wellcomei (Fraiha, Shaw & Lainson) (Diptera: Psychodidae) can act as an important vector of Leishmania (Viannia) braziliensis This study presents the results of collections carried out in a fragment of Atlantic Forest in a Conservation Unit of Rio Grande do Norte state. Collections occurred over 12 consecutive months using Shannon and CDC traps. A total of 777 sand flies from eight species were collected: Lutzomyia walkeri (Newstead), Lutzomyia evandroi (Costa Lima & Antunes), Lutzomyia wellcomei (Fraiha, Shaw & Lainson), Lutzomyia sordellii (Shannon & Del Ponte), Lutzomyia brasiliensis (Costa Lima), Lutzomyia lenti (Mangabeira), Lutzomyia longipalpis (Lutz & Neiva), and Lutzomyia abonnenci (Floch & Chassignet). Lutzomyia wellcomei was the most abundant species using the Shannon trap (97%) and L. walkeri in the CDC trap (81%). It is important to note the abundance of L. wellcomei in Shannon trap collections, which favors the capture of anthropophilic species. Lutzomyia wellcomei was only present in months where rainfall was above 100 mm, confirming it as a species adapted to wetter months.
Lipids encompass a wide variety of molecules such as fatty acids, sterols, phospholipids, and triglycerides. These molecules represent a highly efficient energy resource and can act as structural elements of membranes or as signaling molecules that regulate metabolic homeostasis through many mechanisms. Cells possess an integrated set of response systems to adapt to stresses such as those imposed by nutrient fluctuations during feeding-fasting cycles. While lipids are pivotal for these homeostatic processes, they can also contribute to detrimental metabolic outcomes. When metabolic stress becomes chronic and adaptive mechanisms are overwhelmed, as occurs during prolonged nutrient excess or obesity, lipid influx can exceed the adipose tissue storage capacity and result in accumulation of harmful lipid species at ectopic sites such as liver and muscle. As lipid metabolism and immune responses are highly integrated, accumulation of harmful lipids or generation of signaling intermediates can interfere with immune regulation in multiple tissues, causing a vicious cycle of immune-metabolic dysregulation. In this review, we summarize the role of lipotoxicity in metaflammation at the molecular and tissue level, describe the significance of anti-inflammatory lipids in metabolic homeostasis, and discuss the potential of therapeutic approaches targeting pathways at the intersection of lipid metabolism and immune function.
Various recent studies revealed that the proteins of the Shank family act as major scaffold organizing elements in the post-synaptic density of excitatory synapses and that their expression level is able to influence synapse formation, maturation and ultimately brain plasticity. An imbalance in Shank3 protein levels has been associated with a variety of neuropsychological and neurodegenerative disorders including autism spectrum disorders and Phelan-McDermid syndrome. Given that sleep disorders and low melatonin levels are frequently observed in autism spectrum disorders, and that circadian rhythms may be able to modulate Shank3 signaling and thereby synaptic function, here, we performed in vivo studies on CBA mice using protein biochemistry to investigate the synaptic expression levels of Shank3α during the day in different brain regions. Our results show that synaptic Shank3 protein concentrations exhibit minor oscillations during the day in hippocampal and striatal brain regions that correlate with changes in serum melatonin levels. Furthermore, as circadian rhythms are tightly connected to activity levels in mice, we increased physical activity using running wheels. The expression of Shank3α increases rapidly by induced activity in thalamus and cortex, but decreases in striatum, superimposing the circadian rhythms of different brain regions. We conclude that synaptic Shank3 proteins build highly dynamic platforms that are modulated by the light:dark cycles but even more so driven by activity. Using wild-type CBA mice, we show that Shank3 is a highly dynamic and activity-regulated protein at synapses. In the hippocampus, changes in synaptic Shank3 levels are influenced by circadian rhythm/melatonin concentration, while running activity increases and decreases levels of Shank3 in the cortex and striatum respectively.
The optimal allocation of resources to sexual signals and other life history traits is usually dependent on an individual's condition, while variation in the expression of sexual traits across environments depends on the combined effects of local adaptation, mean condition, and phenotypic responses to environment-specific cues that affect resource allocation. A clear contrast can often be drawn between natural habitats and novel habitats, such as forest plantations and urban areas. In some species, males seem to change their sexual signals in these novel environments, but why this occurs and how it affects signal reliability is still poorly understood.
The relative size of sexual traits and level of immune responses were significantly lower for male palmate newts Lissotriton helveticus caught in pine and eucalyptus plantations compared to those caught in native forests, but there was no habitat-dependent difference in body condition (n = 18 sites, 382 males). The reliability with which sexual traits signalled body condition and immune responses was the same in all three habitats. Finally, we conducted a mesocosm experiment in which males were maintained in pine, eucalypt or oak infused water for 21 days. Males in plantation-like water (pine or eucalypt) showed significantly lower immune responses but no change in body condition. This matches the pattern seen for field-caught males. Unlike field-caught males, however, there was no relationship between water type and relative sexual trait size.
Pine and eucalyptus plantations are likely to be detrimental to male palmate newt because they are associated with reduced immune function and smaller sexual traits. This could be because ecological aspects of these novel habitats, such as high water turbidity or changes in male-male
 competition, drive selection for reduced investment into sexual traits. However, it is more probable that there are differences in the ease of acquisition, hence optimal allocation, of resources among habitats. Our mesocosm experiment also provides some evidence that water toxicity is a causal factor. Our findings offer insights into how plantations affect amphibian life histories, and how novel habitats might generate long-term selection for new resource allocation strategies in native species.
The understanding of the mechanisms and interactions that occur when nanomaterials enter biological systems is important to improve their future use. The adsorption of proteins from biological fluids in a physiological environment to form a corona on the surface of nanoparticles represents a key step that influences nanoparticle behaviour. In this study, the quantitative description of the composition of the protein corona was used to study the effect on cell association induced by 84 surface-modified gold nanoparticles of different sizes. Quantitative relationships between the protein corona and the activity of the gold nanoparticles were modelled by using several machine learning-based linear and non-linear approaches. Models based on a selection of only six serum proteins had robust and predictive results. The Projection Pursuit Regression method had the best performances (r(2) = 0.91; Q(2)loo = 0.81; r(2)ext = 0.79). The present study confirmed the utility of protein corona composition to predict the bioactivity of gold nanoparticles and identified the main proteins that act as promoters or inhibitors of cell association. In addition, the comparison of several techniques showed which strategies offer the best results in prediction and could be used to support new toxicological studies on gold-based nanomaterials.
Wrinkles are just one indicator of facial aging, but an indicator that is of prime importance in our world of facial aesthetics. Wrinkles occur where fault lines develop in aging skin. Those fault lines may be due to skin distortion resulting from facial expression or may be due to skin distortion from mechanical compression during sleep. Expression wrinkles and sleep wrinkles differ in etiology, location, and anatomical pattern. Compression, shear, and stress forces act on the face in lateral or prone sleep positions. We review the literature relating to the development of wrinkles and the biomechanical changes that occur in response to intrinsic and extrinsic influences. We explore the possibility that compression during sleep not only results in wrinkles but may also contribute to facial skin expansion.
Polycaprolactone (PCL) is used as a material of choice for surgical sutures, wound dressings, contraceptives, fixation devices and dentistry in paramedical sciences. In addition, adipose-derived stem cells (ASCs) have been shown to be effective in the treatment of acute and chronic wounds. This study aimed to evaluate the effect of electrospun PCL fibers on keratinocyte differentiation of ASCs and wound healing. PCL solution was electrospun and characterized. Isolated and characterized ASCs were differentiated into keratinocyte-like cells on a tissue culture plate (TCP) and PCL matrices and compared. PCL nano-/microfibers cultured with ASCs (test group) or alone (control) were implanted as a dermal substitute for wound healing. There were significant increases in the proliferation rate and expression level of cytokeratin 14, filaggrin and involucrin in cells cultured on PCL matrices compared to TCP (p < 0.05). After histological and immunological evaluation of the reconstituted skin, a thick epidermal layer with several skin appendages was evidently observed in the ASC/PCL group, whereas no real and mature epidermis was formed, especially in the central area of the healing wound in the pure PCL group on day 14. Pure PCL, if possessing suitable properties including good adhesiveness, high proliferative capability, inductive elasticity and stiffness for migration and differentiation, could drive the keratinocyte differentiation of ASCs and act as an efficient dermal equivalent to promote wound healing.
This paper aims to describe the prevalence, assessment and management of affective disorders as well as functional (non-epileptic) seizures in people with epilepsy.
This paper comprises a selective review of the literature of the common affective manifestations of epilepsy.
Affective disorders are the most common psychiatric comorbidity seen in people with epilepsy and assessment and management parallels that of the general population. Additionally, people with epilepsy may experience higher rates of mood instability, irritability and euphoria, classified together as a group, interictal dysphoric disorder and resembling an unstable bipolar Type II disorder. Functional seizures present unique challenges in terms of identification of the disorder and a lack of specific management.
Given their high prevalence, it is important to be able to recognise affective disorders in people with epilepsy. Management principles parallel those in the general population with specific caution exercised regarding the potential interactions between antidepressant medications and antiepileptic drugs. Functional seizures are more complex and require a coordinated approach involving neurologists, psychiatrists, general practitioners, nursing and allied health. There is very limited evidence to guide psychological and behavioural interventions for neurotic disorders in epilepsy and much more research is needed.
This clinical update review focuses on treatment approaches of neuropsychiatric manifestations in Parkinson's disease.
We conducted a systematic search of the literature using Pubmed and selected recent and relevant papers for this review.
Neuropsychiatric symptoms in Parkinson's disease usually require optimization of levodopa therapy as a first step. Most psychotropic drugs can be used in Parkinson's disease, however there is still lack of an evidence base due to limited studies and difficulties in diagnosis of neuropsychiatric disorders. Non-pharmacological treatments have also proved effective in Parkinson's disease. Cognitive impairment requires special consideration.
Management of neuropsychiatric manifestations in Parkinson's disease is complicated by the lack of evidence. Treatment should be individualized and benefits and risks must be balanced.
Recent studies of Enterovirus (EV) in nonhuman primates (NHPs), which could act as a source of future emerging human viral diseases, have boosted interest in the search for novel EVs. Here, a highly divergent strain of EV, tentatively named SEV-gx, was identified by viral metagenomic analysis from stool samples of rhesus macaques in China. In total, 27 of 280 (9.6%) faecal samples from rhesus macaques were positive for SEV-gx. Its complete genomic sequence is 7,367 nucleotide (nt). Genomic analyses showed that it has a standard genomic organisation for EVs, being more closely related to EV-J strains (approximately 54.0%, 43.0-44.1%, 52.3-55.2%, 61.1-62.7% and 64.0% amino acids identity in polyprotein, P1, P2 and P3 and combined 2C/3CD regions, respectively). It was also shown to have genome characteristics typical of EVs. Phylogenetic analysis of P1, 2C and 3CD aa indicated that SEV-gx can be classified as a distinct cluster in the EVs. All of this evidence demonstrates SEV-gx is a novel species (tentatively named EV-K) in the EV genus, which contributes to our understanding of the genetic diversity and evolution of EVs. Further studies are needed to investigate the potential pathogenicity of SEV-gx in NHPs and humans.
Evaluate the effect of a pay-for-performance intervention on the quality of hypertension care provided to black patients and determine whether it produced risk selection.
Primary data collected between 2007 and 2009 from Veterans Affairs physicians and their primary care panels.
Nested study within a cluster randomized controlled trial of three types of financial incentives and no incentives (control). We compared the proportion of physicians' black patients meeting hypertension performance measures for baseline and final performance periods. We measured risk selection by comparing the proportion of patients who switched providers, patient visit frequency, and panel turnover. Due to limited power, we prespecified in the analysis plan combining the three incentive groups and oversampling black patients.
Data collected electronically and by chart review.
The proportion of black patients who achieved blood pressure control or received an appropriate response to uncontrolled blood pressure in the final period was 6.3 percent (95 percent confidence interval, 0.8-11.7 percent) greater for physicians who received an incentive than for controls. There was no difference between intervention and controls in the proportion of patients who switched providers, visit frequency, or panel turnover.
A pay-for-performance intervention improved blood pressure control or appropriate response to uncontrolled blood pressure in black patients and did not produce risk selection.
MicroRNA-19a (miR-19a) is upregulated in different types of cancers, including gliomas, but its specific role and function in gliomas have yet to be fully elucidated. In this study, we found that miR-19a was significantly upregulated in human glioma tissues and cell lines. Overexpression of miR-19a by a miR-19a mimic promoted glioma cell proliferation and invasion. In contrast, miR-19a inhibitor suppressed cell proliferation and invasion. Furthermore, by a dual-luciferase reporter assay and expression analysis, we determined that Ras homolog family member B was a direct target of miR-19a. Knockdown of Ras homolog family member B could block cell proliferation and invasion induced by the miR-19a mimic. In conclusion,
 our study demonstrated that miR-19a upregulation is common in gliomas and that suppression of miR-19a expression inhibits cell proliferation and invasion, which indicates that miR-19a may act as an oncogene in gliomas.
Though QSAR was originally developed in the context of physical organic chemistry, it has been applied very extensively to chemicals (drugs) which act on biological systems, in this idea one of the most important QSAR methods is the 3D QSAR model. However, due to the complexity of understanding the results it is necessary to postulate new methodologies to highlight their physical-chemical meaning. In this sense, this work postulates new insights to understand the CoMFA results using molecular quantum similarity and chemical reactivity descriptors within the framework of density functional theory. To obtain these insights a simple theoretical scheme involving quantum similarity (overlap, coulomb operators, their euclidean distances) and chemical reactivity descriptors such as chemical potential (μ), hardness (ɳ), softness (S), electrophilicity (ω), and the Fukui functions, was used to understand the substitution effect. In this sense, this methodology can be applied to analyze the biological activity and the stabilization process in the non-covalent interactions on a particular molecular set taking a reference compound.
Reactive oxygen species (ROS) regulate testicular function in health and disease. We previously described a prostaglandin D2 (PGD2) system in Sertoli cells. Now, we found that PGD2 increases ROS and hydrogen peroxide (H2O2) generation in murine TM4 Sertoli cells, and also induces antioxidant enzymes expression suggesting that defense systems are triggered as an adaptive stress mechanism that guarantees cell survival. ROS and specially H2O2 may act as second messengers regulating signal transduction pathways and gene expression. We describe a stimulatory effect of PGD2 on lactate dehydrogenase (LDH) expression via DP1/DP2 receptors, which is prevented by the antioxidant N-acetyl-L-cysteine and the PI3K/Akt pathway inhibitor LY 294002. PGD2 also enhances Akt and CREB/ATF-1 phosphorylation. Our results provide evidence for a role of PGD2 in the regulation of the oxidant/antioxidant status in Sertoli cells and, more importantly, in the modulation of LDH expression which takes place through ROS generation and the Akt-CREB/ATF-1 pathway.
Congenital stationary night-blindness (CSNB) is a recessive autosomal defect in low-light vision in Appaloosa and other horse breeds. This condition has been mapped by linkage analysis to a gene coding for the Transient Receptor Potential cation channel Member 1 (TRPM1). TRPM1 is normally expressed in the ON-bipolar cells of the inner nuclear layer of the retina. Down-regulation of TRPM1 expression in CSNB results from a transposon-like insertion in intron 1 of the TRPM1 gene. Stop transcription signals in this transposon significantly reduce TRPM1 primary transcript levels in CSNB horses. This study describes additional contributions by a second mutation of the TRPM1 gene, the ECA1 108,249,293 C > T SNP, to down-regulation of transcription of the TRPM1 gene in night-blind horses. This TRPM1 SNP introduces a consensus binding site for neuro-oncological ventral antigen 1 (Nova-1) protein in the primary transcript. Nova-1 binding disrupts normal splicing signals, producing unstable, non-functional mRNA transcripts.
Retinal bipolar cells express both TRPM1 and Nova-1 proteins. In vitro addition of Nova-1 protein retards electrophoretic migration of TRPM1 RNA containing the ECA1 108,249,293 C > T SNP. Up-regulating Nova-1 expression in primary cultures of choroidal melanocytes carrying the intron 11 SNP caused an average log 2-fold reduction of ~6 (64-fold) of TRPM1 mRNA expression.
These finding suggest that the equine TRPM1 SNP can act independently to reduce survival of TRPM1 mRNA escaping the intron 1 transcriptional stop signals in CSNB horses. Coexistence and co-inheritance of two independent TRPM1 mutations across 1000 equine generations suggests a selective advantage for the apparently deleterious CSNB trait.
Community health center (CHC) patients have high rates of smoking. Insurance coverage for smoking cessation assistance, such as that mandated by the Affordable Care Act, may aid in smoking cessation in this vulnerable population.
We aimed to determine if uninsured CHC patients who gain Medicaid coverage experience greater primary care utilization, receive more cessation medication orders, and achieve higher quit rates, compared to continuously uninsured smokers.
Longitudinal observational cohort study using electronic health record data from a network of Oregon CHCs linked to Oregon Medicaid enrollment data.
Cohort of patients who smoke and who gained Medicaid coverage in 2008-2011 after ≥ 6 months of being uninsured and with ≥ 1 smoking assessment in the 24-month follow-up period from the baseline smoking status date. This group was propensity score matched to a cohort of continuously uninsured CHC patients who smoke (n = 4140 matched pairs; 8280 patients).
Gaining Medicaid after being uninsured for ≥ 6 months.
'Quit' smoking status (baseline smoking status was 'current every day' or 'some day' and status change to 'former smoker' at a subsequent visit), smoking cessation medication order, and ≥ 6 documented visits (yes/no variables) at ≥ 1 smoking status assessment within the 24-month follow-up period.
The newly insured had 40 % increased odds of quitting smoking (aOR = 1.40, 95 % CI:1.24, 1.58), nearly triple the odds of having a medication ordered (aOR = 2.94, 95 % CI:2.61, 3.32), and over twice the odds of having ≥ 6 follow-up visits (aOR = 2.12, 95 % CI:1.94, 2.32) compared to their uninsured counterparts.
Newly insured patients had increased odds of quit smoking status over 24 months of follow-up than those who remained uninsured. Providing insurance coverage to vulnerable populations may have a significant impact on smoking cessation.
When PEG tube feeding is complicated by anatomic obstruction, dysmotility, or aspiration, a need arises for feeding beyond the pylorus. The currently available percutaneous gastrojejunostomy (PEG-J) kits have issues with the jejunal extension portion migrating back into the stomach. The aim of this study was to evaluate the feasibility and safety of a novel technique that creates PEG-J tubes by combining an adult percutaneous gastrostomy (PEG) tube with a pediatric PEG tube, the PEG-Pedi-PEG procedure.
This was a retrospective study at a single tertiary care center. The main outcome measures were success of placement, rate of retrograde tube migration, early (<24 h after procedure was performed) and late (>24 h after procedure was performed) adverse events.
Seventeen patients underwent PEG-Pedi-PEG procedures during the study period. Technical success was achieved in all patients (100%). The retrograde migration rate of the jejunal extension tube was 0%. Early adverse events included peristomal pain in 1 patient. Late adverse events included inadvertent tube removal (3 patients), diarrhea (1 patient), prolonged ileus/gastroparesis (1 patient), and tube occlusion (1 patient). Mean follow-up was 290 days.
The PEG-Pedi-PEG procedure is a novel endoscopic technique to facilitate post-pyloric feeding because the pediatric PEG bumper may act like a sail in the small bowel, with peristalsis pushing the bumper distally and thus decreasing the possibility of migration back into the stomach. This study demonstrated excellent technical success, no retrograde migration, and a low rate of adverse events.
Long non-coding RNAs (lncRNAs) have been proved to act as key molecules in cancer development and progression. Dysregulation of lncRNAs is discovered in various tumor tissues and cancer cells where they can serve as oncogenes or tumor suppressors. Long non-coding RNA HOXD-AS (HOXD cluster antisense RNA 1) has recently been identified to be involved in the development of several cancers including neuroblastoma, adenocarcinomas and breast cancer. However, the role of HOXD-AS1 in bladder cancer remains unknown.
The synthetic tetracycline-controllable shRNA was used to modulate the level of HOXD-AS1 by adding different concentrations of doxycycline (dox). RT-qPCR was used to detect the expression level of HOXD-AS1. Cell proliferation was determined by CCK-8 assay and EdU incorporation experiment when HOXD-AS1 was knocked down. We used wound-healing assay for detecting the effect of HOXD-AS1 on cell migration. Eventually, cell apoptosis was determined by caspase 3 ELISA assay and flow cytometry assay.
In this study, we found that the expression level of HOXD-AS1 was significantly increased in bladder cancer tissues and cells. Furthermore, high expression of HOXD-AS1 was significantly related to tumor size, histological grade and TNM stage. In vitro assays confirmed that knockdown of HOXD-AS1 suppressed cell proliferation/migration and increased the rate of apoptotic cell in bladder cancer cells. At last, we used the important element of synthetic biology, tetracycline(tet)-controllable switch, to construct tet-controllable shRNA vectors which can modulate the expression of HOXD-AS1 in a dosage-dependent manner.
Our research suggested that high expression of HOXD-AS1 may be involved in the bladder cancer carcinogenesis through inhibiting the phenotypes and activating endogenous cancer-related molecular pathways. Therefore, HOXD-AS1 may act as an oncogene and provide a potential attractive therapeutic target for bladder cancer. In addition, the synthetic tetracycline-controllable shRNA may provide a novel method for cancer research in vitro assays.
Discussions about real knowledge contained in grand theories and models seem to remain an active quest in the academic sphere. The most fervent of these defendants is Rosemarie Parse
 with her Humanbecoming School of Thought (1981, 1998). This article first highlights the similarities between Parse's theory and Blumer's symbolic interactionism (1969). This comparison will act as a counterargument to Parse's assertions that her theory is original 'nursing' material. Standing on the contemporary philosophy of science, the very possibility for discovering specific nursing knowledge will be questioned. Second, Parse's scientific assumptions will be thoroughly addressed and contrasted with Blumer's more moderate view of knowledge. It will lead to recognize that the valorization of the social nature of existence and reality does not necessarily induce requirements and methods such as those proposed by Parse. According to Blumer's point of view, her perspective may not even be desirable. Recommendations will be raised about the necessity for a distanced relationship to knowledge, being the key to the pursuit of its improvement, not its circular contemplation.
The genetic determinism of the calving and suckling performance of beef cows is little known whereas these maternal traits are of major economic importance in beef cattle production systems. This paper aims to identify QTL regions and candidate genes that affect maternal performance traits in the Blonde d'Aquitaine breed. Three calving performance traits were studied: the maternal effect on calving score from field data, the calving score and pelvic opening recorded in station for primiparous cows. Three other traits related to suckling performance were also analysed: the maternal effect on weaning weight from field data, milk yield and the udder swelling score recorded in station for primiparous cows. A total of 2,505 animals were genotyped from various chip densities and imputed in high density chips for 706,791 SNP. The number of genotyped animals with phenotypes ranged from 1,151 to 2,284, depending on the trait considered.
QTL detections were performed using a Bayes C approach. Evidence for a QTL was based on Bayes Factor values. Putative candidate genes were proposed for the QTL with major evidence for one of the six traits and for the QTL shared by at least two of the three traits underlying either calving or suckling performance. Nine candidate genes were proposed for calving performance among the nine highlighted QTL regions. The neuroregulin gene on chromosome 27 was notably identified as a very likely candidate gene for maternal calving performance. As for suckling abilities, seven candidate genes were identified among the 15 highlighted QTL. In particular, the Group-Specific Component gene on chromosome 6, which encodes vitamin D binding protein, is likely to have a major effect on maternal weaning weight in the Blonde d'Aquitaine breed. This gene had already been linked to milk production and clinical mastitis in dairy cattle.
In the near future, these QTL findings and the preliminary proposals of candidate genes which act on the maternal performance of beef cows should help to identify putative causal mutations based on sequence data from different cattle breeds.
The readiness potential is an ongoing negativity in the EEG preceding a self-initiated movement by approximately 1.5s. So far it has predominantly been interpreted as a preparatory signal with a causal link to the upcoming movement. Here a different hypothesis is suggested which we call the selective slow cortical potential sampling hypothesis. In this review of recent research results we argue that the initiation of a voluntary action is more likely during negative fluctuations of the slow cortical potential and that the sampling and averaging of many trials leads to the observed negativity. That is, empirical evidence indicates that the early readiness potential is not a neural correlate of preconscious motor preparation and thus a determinant of action. Our hypothesis thereafter challenges the classic interpretation of the Libet experiment which is often taken as proof that there is no free will. We furthermore suggest that slow cortical potentials are related to an urge to act but are not a neural indicator of the decision process of action initiation.
Here, we study and compare the mechanisms of action of the GroEL/GroES and the TRiC chaperonin systems on MreB client protein variants extracted from E. coli. MreB is a homologue to actin in prokaryotes. Single-molecule fluorescence correlation spectroscopy (FCS) and time-resolved fluorescence polarization anisotropy report the binding interaction of folding MreB with GroEL, GroES and TRiC. Fluorescence resonance energy transfer (FRET) measurements on MreB variants quantified molecular distance changes occurring during conformational rearrangements within folding MreB bound to chaperonins. We observed that the MreB structure is rearranged by a binding-induced expansion mechanism in TRiC, GroEL and GroES. These results are quantitatively comparable to the structural rearrangements found during the interaction of β-actin with GroEL and TRiC, indicating that the mechanism of chaperonins is conserved during evolution. The chaperonin-bound MreB is also significantly compacted after addition of AMP-PNP for both the GroEL/ES and TRiC systems. Most importantly, our results showed that GroES may act as an unfoldase by inducing a dramatic initial expansion of MreB (even more than for GroEL) implicating a role for MreB folding, allowing us to suggest a delivery mechanism for GroES to GroEL in prokaryotes.
Hetero-nanoparticles represent an important family of composite nanomaterials that in the past years are attracting ever-growing interest. Here, we report a new strategy for the synthesis of water dispersible cobalt ferrite nanoparticles (CoxFe3-xO4 NPs) decorated with ultrasmall (2-3 nm) gold nanoparticles (Au NPs). The synthetic procedure is based on the use of 2,3-meso-dimercaptosuccinic acid (DMSA), which plays a double role. First, it transfers cobalt ferrite NPs from the organic phase to aqueous media. Second, the DMSA reductive power promotes the in situ nucleation of gold NPs in proximity of the magnetic NP surface. Following this procedure, we achieved a water dispersible nanosystem (CoxFe3-xO4-DMSA-Au NPs) which combines the cobalt ferrite magnetic properties with the catalytic features of ultrasmall Au NPs. We showed that CoxFe3-xO4-DMSA-Au NPs act as an efficient nanocatalyst to reduce 4-nitrophenol to 4-aminophenol and that they can be magnetically recovered and recycled. It is noteworthy that such nanosystem is more catalytically active than Au NPs with equal size. Finally, a complete structural and chemical characterization of the hetero-NPs is provided.
The repair of PSII under strong light is particularly sensitive to reactive oxygen species (ROS), such as the superoxide radical and hydrogen peroxide, and these ROS are efficiently scavenged by superoxide dismutase (SOD) and catalase. In the present study, we generated transformants of the cyanobacterium Synechococcus elongatus PCC 7942 that overexpressed an iron superoxide dismutase (Fe-SOD) from Synechocystis sp. PCC 6803; a highly active catalase (VktA) from Vibrio rumoiensis; and both enzymes together. Then we examined the sensitivity of PSII to photoinhibition in the three strains. In cells that overexpressed either Fe-SOD or VktA, PSII was more tolerant to strong light than it was in wild-type cells. Moreover, in cells that overexpressed both Fe-SOD and VktA, PSII was even more tolerant to strong light. However, the rate of photodamage to PSII, as monitored in the presence of chloramphenicol, was similar in all three transformant strains and in wild-type cells, suggesting that the overexpression of these ROS-scavenging enzymes might not protect PSII from photodamage but might protect the repair of PSII. Under strong light, intracellular levels of ROS fell significantly, and the synthesis de novo of proteins that are required for the repair of PSII, such as the D1 protein, was enhanced. Our observations suggest that overexpressed Fe-SOD and VktA might act synergistically to alleviate the photoinhibition of PSII by reducing intracellular levels of ROS, with resultant protection of the repair of PSII from oxidative inhibition.
GPs answer all patient calls to the out-of-hours primary care (OOH-PC) services in Denmark. Knowledge is scarce on how the triage-GPs act on the specific reasons for encounter (RFE).
This study aims to describe the RFEs, the applied diagnoses and the severity of health problems presented in calls to the OOH-PC.
This was a 1-year cross-sectional study based on IT-integrated pop-up questionnaires addressing patients' health problems. We included only telephone contacts that were categorized according to their triage outcome as telephone consultations, direct admissions to hospital or referrals for face-to-face contact. The GP-assessed severity was calculated for age groups and types of outcome. We identified the 20 most frequent primary RFEs and diagnoses for each type of contact termination.
We included 7810 telephone calls. Calls considered non-severe made up two-thirds of the calls terminated as telephone consultations, whereas calls considered potentially severe made up the main part of referrals (52.3%). Overall, the 20 most frequent RFEs accounted for 45.2% of all RFEs, fever being the most frequent (10.0%). Some RFEs were terminated mostly as telephone consultations [e.g. insect bite/sting (75.9%)], whereas others were most often referred for a face-to-face contact [i.e. dyspnoea (79.1%)] or directly to hospital [i.e. chest pain (29.4%)].
The distribution of the RFEs on triage outcomes, dominated by more severe diagnoses in referrals indicates a suitable referral level. However, future research on factors related to the demanding task of telephone triage is highly relevant for postdoctoral training of GPs.
Designing effective nanoscale
 blockers for membrane inserted pores formed by pore forming toxins, which are expressed by several virulent bacterial strains, on a target cell membrane is a challenging and active area of research. Here we demonstrate that PAMAM dendrimers can act as effective pH controlled gating devices once the pore has been formed. We have used fully atomistic molecular dynamics (MD) simulations to characterize the cytolysin A (ClyA) protein pores modified with fifth generation (G5) PAMAM dendrimers. Our results show that the PAMAM dendrimer, in either its protonated (P) or non-protonated (NP) states can spontaneously enter the protein lumen. Protonated dendrimers interact strongly with the negatively charged protein pore lumen. As a consequence, P dendrimers assume a more expanded configuration efficiently blocking the pore when compared with the more compact configuration adopted by the neutral NP dendrimers creating a greater void space for the passage of water and ions. To quantify the effective blockage of the protein pore, we have calculated the pore conductance as well as the residence times by applying a weak force on the ions/water. Ionic currents are reduced by 91% for the P dendrimers and 31% for the NP dendrimers. The preferential binding of Cl(-) counter ions to the P dendrimer creates a zone of high Cl(-) concentration in the vicinity of the internalized dendrimer and a high concentration of K(+) ions in the transmembrane region of the pore lumen. In addition to steric effects, this induced charge segregation for the P dendrimer effectively blocks ionic transport through the pore. Our investigation shows that the bio-compatible PAMAM dendrimers can potentially be used to develop therapeutic protocols based on the pH sensitive gating of pores formed by pore forming toxins to mitigate bacterial infections.
Intracardiac impedance (ICI) is a major determinant of success during internal cardioversion of atrial fibrillation (AF). However, there have been few studies that have examined the dynamic behaviour of atrial impedance during internal cardioversion in relation to clinical outcome. In this study, voltage and current waveforms captured during internal cardioversion of acute AF in ovine models using novel radiofrequency (RF) generated low-tilt rectilinear and conventional capacitor-discharge based shock waveforms were retrospectively analysed using a digital signal processing algorithm to investigate the dynamic behaviour of atrial impedance during cardioversion. The algorithm was specifically designed to facilitate the simultaneous analysis of multiple impedance parameters, including: mean intracardiac impedance (Z M), intracardiac impedance variance (ICIV) and impedance amplitude spectrum area (IAMSA) for each cardioversion event. A significant reduction in ICI was observed when comparing two successive shocks of increasing energy where cardioversion outcome was successful. In addition, ICIV and IAMSA variables were found to inversely correlate to the magnitude of energy delivered; with a stronger correlation found to the former parameter. In conclusion, ICIV and IAMSA have been evidenced as two key dynamic intracardiac impedance variables that may prove useful in better understanding of the cardioversion process and that could potentially act as prognostic markers with respect to clinical outcome.
The optical spectra in the UV-VIS region of the hydrated doubly charged tetramer Ag4(2+) and hydrated multiply charged hexamer Ag6(p+) silver clusters encapsulated inside the sodalite cavity of an LTA-type zeolite have been systematically predicted using DFT, TD-DFT and CASSCF/CASPT2 methods. The optical behaviour of the model hydrated clusters [Ag6(H2O)8(Si24H24O36)](p+) is very sensitive to their charge. Among the cations [Ag6(H2O)8(Si24H24O36)](p+), only the embedded hydrated quadruply charged silver hexamer [Ag6(H2O)8(Si24H24O36)](4+) shows a strong absorption band at ∼420 nm (blue light) and emits light in red color. The absorption spectrum of the hydrated doubly charged silver tetramer cluster [Ag4(H2O)m(Si24H24O36)](2+), which shifts slightly and steadily with the increasing amount of interacting water molecules to longer wavelengths, has a strong peak in the blue region. The water environment forces the silver tetramer to relocate into one side of the cavity instead of at its center as in the case of the non-hydrated [Ag4(Si24H24O36)](2+) cluster. Water molecules act as ligands significantly splitting the energy levels of excited states of the Ag4(2+) and Ag6(4+) clusters. This causes the absorption spectra of the clusters to broaden and the emission to shift to the green-yellow and red part of the visible region.
Papaya fruits accumulate carotenoids during fruit ripening. Although many papaya carotenoid biosynthesis pathway genes have been identified, the transcriptional regulators of these genes have not been characterized. In this study, a NAC transcription factor, designated as CpNAC1, was characterized from papaya fruit. CpNAC1 was localized exclusively in nucleus and possessed transcriptional activation activity. Expression of carotenoid biosynthesis genes phytoene desaturases (CpPDSs) and CpNAC1 was increased during fruit ripening and by propylene treatment, which correlates well with the elevated carotenoid content in papaya. The gel mobility shift assays and transient expression analyses demonstrated that CpNAC1 directly binds to the NAC binding site (NACBS) motifs in CpPDS2/4 promoters and activates them. Collectively, these data suggest that CpNAC1 may act as a positive regulator of carotenoid biosynthesis during papaya fruit ripening possibly via transcriptional activation of CpPDSs such as CpPDS2/4.
Multiple cross-sectional imaging studies have identified structural abnormalities in prefrontal, temporal and limbic regions related to conduct problems (CPs). However, the relationship between development of such neurobiological deficits and developmental pathways of CPs has remained unclear. The current study investigated distinct trajectories of CP and related trajectories of cortical thickness within a community-based sample of adolescents (n=239), age range 12-19, to address this gap. Three trajectory classes were revealed using latent class growth analyses (LCGAs), comprising a 'desisting' CP group, an 'intermediate' CP group and a 'stable low' CP group. Structural magnetic resonance imaging (MRI) scans were collected with a subgroup of 171 adolescents at three waves throughout adolescence (ages 12, 16 and 19). Generalized estimating equation (GEE) analysis-comparing longitudinal changes in cortical thickness and subcortical volume between CP groups for several regions of interest (ROIs)-showed that these CP groups had differential trajectories of cortical thickness in the dorsolateral prefrontal cortex (dl-PFC), and the anterior cingulate cortex (ACC), and volume of the hippocampus. Adolescents in the desisting CP group showed an attenuation of the typical pattern of cortical thinning as present in the intermediate and stable low CP groups, in addition to an exaggeration of the typical pattern of hippocampal volume increase. These findings suggest that a deviant cortical thickness trajectory was related to a desisting CP pathway across adolescence. Such deviant neurodevelopmental growth trajectories may act as an underlying mechanism for developmental CP pathways, and possibly distinguish desisting antisocial adolescents.
Exposure to environmental stressors alters animal phenotypes as well as nutrient metabolism, assimilation, and excretion. While stress-induced shifts in nutrient processes are known to alter organismal carbon (C) and nitrogen (N) stoichiometry, there has been little exploration of how environmental factors influence phosphorous (P). A better understanding of how P cycling varies with animal physiological state may provide insight into across-scale processes, because P is essential to animal function and ecological processes such as production and decomposition. We tested the effects of predator stress and exogenous glucocorticoids on C∶N∶P stoichiometry of larval amphibians. Glucocorticoids altered nutrient stoichiometry, apparently by modulating ossification and renal function. This reduced whole-body P and significantly increased N∶P. Additionally, elevated glucocorticoids caused a long-term reduction in P excretion. This reduction may reflect an initial unmeasured loss of P that glucocorticoids induce over acute timescales. In contrast, exposure to predator cues had no effect on larval C∶N∶P stoichiometry, which highlights that different stressors have varied effects on the endocrine stress response. Predation, in particular, is ubiquitous in the environment; thus, larvae responding to predators have conserved mechanisms that likely prevent or minimize physiological disruption. These results demonstrate the differing physiological roles of N and P, distinct nutrient demands associated with amphibian metamorphosis, and the contrasting effects that different environmental factors have on the physiological stress response. Our results also suggest that anthropogenic changes to the environment that induce chronic stress in amphibians could affect the biogeochemistry of nutrient-poor environments where they may act as keystone species.
The reaction dynamics of time-dependent systems can be resolved through a recrossing-free dividing surface associated with the transition state trajectory-that is, the unique trajectory which is bound to the barrier region for all time in response to a given time-dependent potential. A general procedure based on the minimization of Lagrangian descriptors has recently been developed by Craven and Hernandez [Phys. Rev. Lett., 2015, 115, 148301] to construct this particular trajectory without requiring perturbative expansions relative to the naive
 transition state point at the top of the barrier. The extension of the method to account for dissipation in the equations of motion requires additional considerations established in this paper because the calculation of the Lagrangian descriptor involves the integration of trajectories in forward and backward time. The two contributions are in general very different because the friction term can act as a source (in backward time) or sink (in forward time) of energy, leading to the possibility that information about the phase space structure may be lost due to the dominance of only one of the terms. To compensate for this effect, we introduce a weighting scheme within the Lagrangian descriptor and demonstrate that for thermal Langevin dynamics it preserves the essential phase space structures, while they are lost in the nonweighted case.
Phototheranostics, which is the application of light in the diagnostic imaging and therapy of cancer, has shown great promise for multimodal cancer imaging and effective therapy. Herein, we developed multifunctional gold nanorod@silica-carbon dots (GNR@SiO2-CDs) as a phototheranostic agent by incorporating carbon dots (CDs) with gold nanorods (GNRs), using SiO2 as a scaffold. In GNR@SiO2-CDs, the GNRs act as both photoacoustic (PA) imaging and photothermal therapy (PTT) agents, and the CDs serve as fluorescence (FL) imaging and photodynamic therapy (PDT) agents. The introduction of SiO2 not only improves the chemical stability of the GNRs and CDs in the physiological environment but also prevents the absolute quenching of the fluorescence of the CDs by GNRs. These collective properties make GNR@SiO2-CDs a novel phototheranostic agent, in which high sensitivity and good spatial resolution of FL/PA imaging can be achieved to guide PDT/PTT treatments through i.v. administration. The combination of PDT and PTT proved to be more efficient in killing cancer cells compared to PDT or PTT alone under a low dose of laser irradiation (≤0.5 W cm(-2)). Furthermore, GNR@SiO2-CDs could be cleared out from the body of mice, indicating the low toxicity of this phototheranostic agent. Our work highlights the potential of using GNRs and CDs as novel phototheranostic agents for multifunctional cancer therapies.
MicroRNAs (miRNAs), small noncoding RNAs 19-22 nucleotides in length, play a major role in negative regulation of gene expression at the posttranscriptional level. Several miRNAs act as tumor suppressors or oncogenes that control cell differentiation, proliferation, apoptosis, or angiogenesis during tumorigenesis. To date, 19 research groups have published large-scale expression profiles that identified 261 miRNAs differentially expressed in bladder cancer, of which 76 were confirmed to have consistent expression patterns by two or more groups. These consistently expressed miRNAs participated in regulation of multiple biological processes and factors, including axon guidance, cancer-associated proteoglycans, and the ErbB and transforming growth factorbeta signaling pathways. Because miRNAs can be released from cancer cells into urine via secreted particles, we propose that miRNAs differentially expressed between tissue and urine could serve as predictors of bladder cancer, and could thus be exploited for noninvasive diagnosis.
Vampiristic behaviors are rarely seen clinically and less than 100 cases have been reported in the world literature to date. A distinction is usually made as to whether the patient drinks their own blood or the blood of others. We describe a 38-year-old patient who had vampiristic thoughts and fantasies that began in adolescence, but did not act on these thoughts until after she suffered a traumatic brain injury with a three-week loss of consciousness while serving in the military. Brain imaging showed focal damage to her bilateral frontal lobes. Psychological testing demonstrated impairment of executive function. We review the proposed diagnostic criteria for vampirism and discuss how behavioral disinhibition may have affected the emergence into behavior of her previously inhibited vampiristic thoughts.
High-precision radiation therapy is a clinical approach that uses the targeted delivery of ionizing radiation, and the subsequent formation of reactive oxygen species (ROS) in high proliferative, radiation sensitive cancers. In particular, in thoracic cancer ratdiation treatments, can not avoid a certain amount of cardiac toxicity. Given the low proliferative rate of cardiac myocytes, research has looked at the effect of radiation on endothelial cells and consequent coronary heart disease as the mechanism of ratdiation induced cardiotoxicity. In fact, little is known concerning the direct effect of radiation on mitochondria dynamis in cardiomyocyte. The main effect of ionizing radiation is the production of ROS and recent works have uncovered that they directly participates to pivotal cell function like mitochondrial quality control. In particular ROS seems to act as check point within the cell to promote either mitochondrial biogenesis and survival or mitochondrial damage and apoptosis. Thus, it appears evident that the functional state of the cell, as well as the expression patterns of molecules involved in mitochondrial metabolism may differently modulate mitochondrial fate in response to radiation induced ROS responses. Different molecules have been described to localize to mitochondria and regulate ROS production in response to stress, in particular GRK2. In this review we will discuss the evidences on the cardiac toxicity induced by X ray radiation on cardiomyocytes with emphasis on the role played by mitochondria dynamism.
To elucidate causes for false negative magnetic resonance imaging (MRI) exams by identifying imaging characteristics that predict viable hepatocellular carcinoma (HCC) in lesions previously treated with locoregional therapy when obvious findings of recurrence are absent.
This retrospective institutional review board-approved and Health Insurance Portability and Accountability Act-compliant study included patients who underwent liver transplantation at our center between 1/1/2000 and 12/31/2012 after being treated for HCC with locoregional therapy. All selected patients had a contrast-enhanced MRI after locoregional therapy within 90 d of transplant that was prospectively interpreted as without evidence of residual or recurrent tumor. Retrospectively, 2 radiologists, blinded to clinical and pathological data, independently reviewed the pre-transplant MRIs for 7 imaging features. Liver explant histopathology provided the reference standard, with clinically significant tumor defined as viable tumor ≥ 1.0 cm in maximum dimension. Fisher's exact test was first performed to identify significant imaging features.
Inclusion criteria selected for 42 patients with 65 treated lesions. Fourteen of 42 patients (33%) and 16 of 65 treated lesions (25%) had clinically significant viable tumor on explant histology. None of the 7 imaging findings examined could reliably and reproducibly determine which treated lesion had viable tumor when the exam had been prospectively read as without evidence of viable HCC.
After locoregional therapy some treated lesions that do not demonstrate any MRI evidence of HCC will contain viable tumor. As such even patients with a negative MRI following treatment should receive regular short-term imaging surveillance because some have occult viable tumor. The possibility of occult tumor should be a consideration when contemplating any action which might delay liver transplant.
The phosphate transporter PHT4;6 locates to the trans-Golgi compartment, and its impaired activity causes altered intracellular phosphate compartmentation, leading to low cytosolic Pi levels, a blockage of Golgi-related processes such as protein glycosylation and hemicellulose biosynthesis, and a dwarf phenotype. However, it was unclear whether altered Pi homeostasis in pht4;6 mutants causes further cellular problems, typically associated with limited phosphate availability. Here we report that pht4;6 mutants exhibit a markedly increased disposition to induce dark-induced senescence. In control experiments, in which pht4;6 mutants and wild-type plants developed similarly, we confirmed that accelerated dark-induced senescence in mutants is not a 'pleiotropic' process associated with the dwarf phenotype. In fact, accelerated dark-induced senescence in pht4;6 mutants correlates strongly with increased levels of toxic NH4 (+) and higher sensitivity to ammonium, which probably contribute to the inability of pht4;6 mutants to recover from dark treatment. Experiments with modified levels of either salicylic acid (SA) or trans-zeatin (tZ) demonstrate that altered concentrations of these compounds in pht4;6 plants act as major cellular mediators for dark-induced senescence. This conclusion gained further support from the notion that the expression of the pht4;6 gene is, in contrast to genes coding for major phosphate importers, substantially induced by tZ. Taken together, our findings point to a critical function of PHT4;6 to control cellular phosphate levels, in particular the cytosolic Pi availability, required to energize plant primary metabolism for proper plant development. Phosphate and its allocation mediated by PHT4;6 is critical to prevent onset of dark-induced senescence.
Decitabine (5-aza-2'-deoxycytidine, aza-dCyd) is an anti-cancer drug used clinically for the treatment of myelodysplastic syndromes and acute myeloid leukaemia that can act as a DNA-demethylating or genotoxic agent in a dose-dependent manner. On the other hand, DCTPP1 (dCTP pyrophosphatase 1) and dUTPase are two 'house-cleaning' nucleotidohydrolases involved in the elimination of non-canonical nucleotides. In the present study, we show that exposure of HeLa cells to decitabine up-regulates the
 expression of several pyrimidine metabolic enzymes including DCTPP1, dUTPase, dCMP deaminase and thymidylate synthase, thus suggesting their contribution to the cellular response to this anti-cancer nucleoside. We present several lines of evidence supporting that, in addition to the formation of aza-dCTP (5-aza-2'-deoxycytidine-5'-triphosphate), an alternative cytotoxic mechanism for decitabine may involve the formation of aza-dUMP, a potential thymidylate synthase inhibitor. Indeed, dUTPase or DCTPP1 down-regulation enhanced the cytotoxic effect of decitabine producing an accumulation of nucleoside triphosphates containing uracil as well as uracil misincorporation and double-strand breaks in genomic DNA. Moreover, DCTPP1 hydrolyses the triphosphate form of decitabine with similar kinetic efficiency to its natural substrate dCTP and prevents decitabine-induced global DNA demethylation. The data suggest that the nucleotidohydrolases DCTPP1 and dUTPase are factors involved in the mode of action of decitabine with potential value as enzymatic targets to improve decitabine-based chemotherapy.
Honesty is a fundamental pillar for cooperation in human societies and thus for their economic welfare. However, humans do not always act in an honest way. Here, we examine how insurance coverage affects the degree of honesty in credence goods markets. Such markets are plagued by strong incentives for fraudulent behavior of sellers, resulting in estimated annual costs of billions of dollars to customers and the society as a whole. Prime examples of credence goods are all kinds of repair services, the provision of medical treatments, the sale of software programs, and the provision of taxi rides in unfamiliar cities. We examine in a natural field experiment how computer repair shops take advantage of customers' insurance for repair costs. In a control treatment, the average repair price is about EUR 70, whereas the repair bill increases by more than 80% when the service provider is informed that an insurance would reimburse the bill. Our design allows decomposing the sources of this economically impressive difference, showing that it is mainly due to the overprovision of parts and overcharging of working time. A survey among repair shops shows that the higher bills are mainly ascribed to insured customers being less likely to be concerned about minimizing costs because a third party (the insurer) pays the bill. Overall, our results strongly suggest that insurance coverage greatly increases the extent of dishonesty in important sectors of the economy with potentially huge costs to customers and whole economies.
Invasive species present significant threats to global agriculture, although how the magnitude and distribution of the threats vary between countries and regions remains unclear. Here, we present an analysis of almost 1,300 known invasive insect pests and pathogens, calculating the total potential cost of these species invading each of 124 countries of the world, as well as determining which countries present the greatest threat to the rest of the world given their trading partners and incumbent pool of invasive species. We find that countries vary in terms of potential threat from invasive species and also their role as potential sources, with apparently similar countries sometimes varying markedly depending on specifics of agricultural commodities and trade patterns. Overall, the biggest agricultural producers (China and the United States) could experience the greatest absolute cost from further species invasions. However, developing countries, in particular, Sub-Saharan African countries, appear most vulnerable in relative terms. Furthermore, China and the United States represent the greatest potential sources of invasive species for the rest of the world. The analysis reveals considerable scope for ongoing redistribution of known invasive pests and highlights the need for international cooperation to slow their spread.
Facilitation of social attraction and bonding by the evolutionarily conserved neuropeptide oxytocin is well-established in female mammals. However, accumulating behavioral evidence suggests that oxytocin may have evolved sex-specific functional roles in the domain of human social cognition. A critical question is how oxytocin differentially modulates neural processing of social information in men and women, leading to divergent behavioral responses. Here we show that intranasal oxytocin treatment produces sex- and valence-dependent increases in amygdala activation when women view individuals identified as praising others but in men those who criticize them. Women subsequently show increased liking for the faces of these individuals, whereas in men it is reduced. Thus, oxytocin may act differentially via the amygdala to enhance the salience of positive social attributes in women but negative ones in men. We hypothesize that oxytocin may have evolved different but complementary roles to help ensure successful reproduction by encouraging mothers to promote a prosocial rearing environment for offspring and fathers to protect against antisocial influences.
The amyloid precursor protein (APP), whose mutations cause Alzheimer disease, plays an important in vivo role and facilitates transmitter release. Because the APP cytosolic region (ACR) is essential for these functions, we have characterized its brain interactome. We found that the ACR interacts with proteins that regulate the ubiquitin-proteasome system, predominantly with the E3 ubiquitin-protein ligases Stub1, which binds the NH2 terminus of the ACR, and CRL4(CRBN), which is formed by Cul4a/b, Ddb1, and Crbn, and interacts with the COOH terminus of the ACR via Crbn. APP shares essential functions with APP-like protein-2 (APLP2) but not APP-like protein-1 (APLP1). Noteworthy, APLP2, but not APLP1, interacts with Stub1 and CRL4(CRBN), pointing to a functional pathway shared only by APP and APLP2. In vitro ubiquitination/ubiquitome analysis indicates that these E3 ligases are enzymatically active and ubiquitinate the ACR residues Lys(649/650/651/676/688) Deletion of Crbn reduces ubiquitination of Lys(676) suggesting that Lys(676) is physiologically ubiquitinated by CRL4(CRBN) The ACR facilitated in vitro ubiquitination of presynaptic proteins that regulate exocytosis, suggesting a mechanism by which APP tunes transmitter release. Other dementia-related proteins, namely Tau and apoE, interact with and are ubiquitinated via the ACR in vitro This, and the evidence that CRBN and CUL4B are linked to intellectual disability, prompts us to hypothesize a pathogenic mechanism, in which APP acts as a modulator of E3 ubiquitin-protein ligase(s), shared by distinct neuronal disorders. The well described accumulation of ubiquitinated protein inclusions in neurodegenerative diseases and the link between the ubiquitin-proteasome system and neurodegeneration make this concept plausible.
Xenobiotics exposure increases endoplasmic reticulum (ER) proliferation and cytochrome P-450 (CYP) induction to sustain metabolic requirements. Whether autophagy is essential for the removal of excess ER and CYP and whether an autophagy receptor is involved in this process in mammals remains elusive. In this study, we show that autophagy is induced in mouse livers after withdrawal of the hepatic mitogen 1,4-bis[2-(3,5-dichloropyridyloxy)] benzene (TCPOBOP). Although isolated autophagosomes, autolysosomes, and lysosomes from mouse livers after withdrawal of TCPOBOP contained ER proteins, those in control mouse livers did not. Liver-specific Atg5 knockout mice had higher basal hepatic ER content that was further increased and sustained after withdrawal of TCPOBOP compared with wild-type mice. In addition to regulating ER degradation, our results also suggest that autophagy plays a role in regulating the homeostasis of hepatic CYP because blocking autophagy led to increased CYP2B10 accumulation either at the basal level or following TCPOBOP withdrawal. Furthermore, we found that the autophagy receptor protein sequestosome 1 (SQSTM1)/p62 is associated with the ER. After withdrawal of TCPOBOP, p62 knockout mice had increased ER content in the liver compared with wild-type mice. These results suggest that p62 may act as an autophagy receptor for the autophagic removal of excess ER in the mouse liver. Taken together, our results indicate that autophagy is important for the removal of excess ER and hepatic CYP enzymes in mouse livers, a process associated with the autophagy receptor protein p62.
We wished to examine the effects of the nucleotide-binding oligomerization domain-like receptor protein 3 (NLRP3) inflammasome on periapical periodontitis induced by Enterococcus faecalis and to investigate the molecular mechanisms of lipoteichoic acid (LTA) derived from E. faecalis on the expression of the NLRP3 inflammasome.
A model of periapical periodontitis by sealing E. faecalis into the pulp chambers of rats was established. We then examined the relationship between the expression, location, distribution, and concentration of NLRP3, caspase-1, and interleukin 1β with the inflammatory progression by immunohistochemistry and undertook correlation analyses. RAW264.7 cells were cultured in the absence or presence of LTA together with or without nuclear factor kappa B (NF-κB) inhibitor BAY 11-7082; NLRP3 inflammasome expression was measured by Western blotting, the enzyme-linked immunosorbent assay, and real-time quantitative polymerase chain reaction. An immunofluorescence study was conducted to further detect whether NF-κB can be completely inhibited by BAY 11-7082 or activated by LTA.
An animal model of periapical periodontitis was established successfully. Expression of NLRP3, caspase-1, and interleukin 1β protein was observed in the inflamed area. The expression of these 3 proteins had a significant
 positive correlation (P < .05). Overall, our results showed that, compared with the negative control group, LTA could directly activate expression of messenger RNA and protein of the NLRP3 inflammasome (P < .05), whereas BAY 11-7082 inhibited it (P < .05).
Our results suggested that LTA can act as a directly stimulating factor associated with expression of the NLRP3 inflammasome during periapical periodontitis, which is mainly linked with the NF-κB signaling activation pathway.
Sumoylation is an essential post-translational regulator of plant development and the response to environmental stimuli. SUMO conjugation occurs via an E1-E2-E3 cascade, and can be removed by SUMO proteases (ULPs). ULPs are numerous and likely to function as sources of specificity within the pathway, yet most ULPs remain functionally unresolved. In this report we used loss-of-function reverse genetics and transcriptomics to functionally characterize Arabidopsis thaliana ULP1c and ULP1d SUMO proteases. GUS reporter assays implicated ULP1c/d in various developmental stages, and subsequent defects in growth and germination were uncovered using loss-of-function mutants. Microarray analysis evidenced not only a deregulation of genes involved in development, but also in genes controlled by various drought-associated transcriptional regulators. We demonstrated that ulp1c ulp1d displayed diminished in vitro root growth under low water potential and higher stomatal aperture, yet leaf transpirational water loss and whole drought tolerance were not significantly altered. Generation of a triple siz1 ulp1c ulp1d mutant suggests that ULP1c/d and the SUMO E3 ligase SIZ1 may display separate functions in development yet operate epistatically in response to water deficit. We provide experimental evidence that Arabidopsis ULP1c and ULP1d proteases act redundantly as positive regulators of growth, and operate mainly as isopeptidases downstream of SIZ1 in the control of water deficit responses.
Green fluorescent proteins (GFPs) are invaluable tools for modern cell biology. Even though many properties of GFP have been successfully engineered, a GFP retaining brightness at low pH has not emerged. This limits the use of GFP in quantitative studies performed in fluctuating or acidic conditions. We report the engineering and characterisation of tandem dimer GFP (pH-tdGFP), a bright and stable GFP that can be efficiently excited and maintains its fluorescence properties in acidic conditions. Therefore, pH-tdGFP could act as a quantitative marker for cellular processes that occur at low pH, such as endocytosis, autophagy or starvation.
The regulation of pancreatic β cell mass is a critical factor to help maintain normoglycemia during insulin resistance. Nutrient-sensing G protein-coupled receptors (GPCR) contribute to aspects of β cell function, including regulation of β cell mass. Nutrients such as free fatty acids (FFAs) contribute to precise regulation of β cell mass by signaling through cognate GPCRs, and considerable evidence suggests that circulating FFAs promote β cell expansion by direct and indirect mechanisms. Free Fatty Acid Receptor 2 (FFA2) is a β cell-expressed GPCR that is activated by short chain fatty acids, particularly acetate. Recent studies of FFA2 suggest that it may act as a regulator of β cell function. Here, we set out to explore what role FFA2 may play in regulation of β cell mass. Interestingly, Ffar2(-/-) mice exhibit diminished β cell mass at birth and throughout adulthood, and increased β cell death at adolescent time points, suggesting a role for FFA2 in establishment and maintenance of β cell mass. Additionally, activation of FFA2 with Gαq/11-biased agonists substantially increased β cell proliferation in in vitro and ex vivo proliferation assays. Collectively, these data suggest that FFA2 may be a novel therapeutic target to stimulate β cell growth and proliferation.
Eukaryotic typical 2-cysteine (Cys) peroxiredoxins (Prxs) are multifunctional proteins subjected to complex regulation and play important roles in oxidative stress resistance, hydrogen peroxide (H2O2) signaling modulation, aging, and cancer, but the information on the biochemical functions and regulation mechanisms of prokaryotic atypical 2-Cys Prxs is largely lacking.
In this study, we show that at low peroxide concentrations, the atypical 2-Cys Prx in Corynebacterium glutamicum (CgPrx) mainly exists as monomers and displays thioredoxin (Trx)-dependent peroxidase activity. Moderate oxidative stress causes reversible S-mycothiolation of the H2O2-sensing Cys63 residue, which keeps CgPrx exclusively in dimer form with neither peroxidase nor chaperone activity. Then, the increased levels of H2O2 could act as a messenger to oxidize the redox-sensitive regulator hydrogen peroxide-inducible gene activator, leading to activation of expression of the more efficient mycothiol peroxidase and catalase to eliminate excessive peroxide. If oxidative stress is too severe, the H2O2-sensing Cys63 becomes hyperoxidized to sulfonic acid, which irreversibly inactivates the peroxidase activity, and most of CgPrx will be converted to multimeric chaperones for salvage of damaged proteins.
We demonstrate for the first time that atypical 2-Cys CgPrx acts as both a Trx-dependent peroxidase and a molecular chaperone and plays a regulatory role in modulating the peroxide-mediated signaling cascades.
These results reveal that CgPrx functions as a multifunctional protein crucial for adapting appropriate responses to different levels of oxidative challenge in C. glutamicum. Antioxid. Redox Signal. 00, 000-000.
Eating is a multisensory behavior. The act of placing food in the mouth provides us with a variety of sensory information, including gustatory, olfactory, somatosensory, visual, and auditory. Evidence suggests altered eating behavior in obesity. Nonetheless, multisensory integration in obesity has been scantily investigated so far. Starting from this gap in the literature, we seek to provide the first comprehensive investigation of multisensory integration in obesity. Twenty male obese participants and twenty male healthy-weight participants took part in the study aimed at describing the multisensory temporal binding window (TBW). The TBW is defined as the range of stimulus onset asynchrony in which multiple sensory inputs have a high probability of being integrated. To investigate possible multisensory temporal processing deficits in obesity, we investigated performance in two multisensory audiovisual temporal tasks, namely simultaneity judgment and temporal order judgment. Results showed a wider TBW in obese participants as compared to healthy-weight controls. This holds true for both the simultaneity judgment and the temporal order judgment tasks. An explanatory hypothesis would regard the effect of metabolic alterations and low-grade inflammatory state, clinically observed in obesity, on the temporal organization of brain ongoing activity, which one of the neural mechanisms enabling multisensory integration.
Health care reimbursement is undergoing a fundamental change from volume-driven to value-driven care. The Patient Protection and Affordable Care Act is marshaling this change and empowering hospitals through Accountable Care Organizations to accept risk. ESRD care/nephrology was awarded the only disease-specific Accountable Care Organization, ESRD Seamless Care Organizations. Dialysis providers in partnership with nephrologists will be exploring how ESRD Seamless Care Organizations will drive improvement in care. CKD care and economics will no longer be isolated from ESRD but possibly more closely linked to global patient outcomes. Preparation for these changes will require unique co-operation and collaboration between nephrologists, dialysis providers, payers, and hospitals/health care systems. Early pilot trials, demonstration projects, and special need programs have suggested value care can be delivered. Whether these results are scalable needs to be determined.
Polysialic acid (PSA) is a large negatively charged glycan mainly attached to the neural cell adhesion molecule (NCAM). Several studies have shown that it is important for correct formation of brain circuitries during development and for synaptic plasticity, learning and memory in the adult. PSA also plays a major role in nervous system regeneration following injury. As a next step for clinical translation of PSA based therapeutics, we have previously identified the small organic compounds 5-nonyloxytryptamine and vinorelbine as PSA mimetics. Activity of 5-nonyloxytryptamine and vinorelbine had been confirmed in assays with neural cells from the central and peripheral nervous system in vitro and shown to be independent of their function as serotonin receptor 5-HT1B/1D agonist or cytostatic drug, respectively. As we show here in an in vivo paradigm for spinal cord injury in mice, 5-nonyloxytryptamine and vinorelbine enhance regain of motor functions, axonal regrowth, motor neuron survival and remyelination. These data indicate that 5-nonyloxytryptamine and vinorelbine may be re-tasked from their current usage as a 5-HT1B/1D agonist or cytostatic drug to act as mimetics for PSA to stimulate regeneration after injury in the mammalian nervous system.
Harmonia axyridis (Pallas, 1773) is an Asian coccinellid released in several places to act as a biological control agent of aphids. Dinocampus coccinellae (Schrank, 1802) is an endoparasite that uses more than 40 coccinellid species as hosts. Thus, the aim of this study was to investigate the interactions between D. coccinellae and H. axyridis and to determine the impact of the parasitoid on the establishment capacity of H. axyridis It was also investigate the influence of host on the development of D. coccinellae using other Coccinellidae species as hosts: Cycloneda sanguinea, (L.,
 1763) Cycloneda pulchella (Klug, 1829), Eriopis connexa (Germar, 1824), and Olla v-nigrum (Mulsant, 1866) In no-choice tests, pupa was the least attacked stage, and the fourth instar and adults the most attacked. In choice tests, the pupa was less attacked when combined with all the other stages, and the fourth instar and adults the most attacked. There was statistical difference only for fecundity, fertility, and number of eggs/day, with higher values found in the non-parasitized control group. Due to the low rate of parasitism it is believed that D. coccinellae has little impact on the populations of this coccinellid in Brazil. However, it is noteworthy that an increase in H. axyridis coverage areas can affect the populations of D. coccinellae, as in some places of occurrence, H. axyridis has become the predominant species of Coccinellidae. The result can be a decrease in populations of this species of parasitoid or its better adaptation to the new host.
Multiple anthropogenic stressors act simultaneously on the environment, with consequences different from those caused by single-stressor exposure. We investigated how the combination of the invasive mussel Limnoperna fortunei and a widely applied herbicide, Roundup Max®, affected freshwater microscopic communities and water quality. Further, we compared these results with those induced by the combination of the mussel and technical-grade glyphosate. We carried out a 34-day experiment in outdoor mesocosms, applying the following six treatments: 6 mg L(-1) of technical-grade glyphosate (G), the equivalent concentration of glyphosate in Roundup Max® (R), 100 mussels (M), the combination of mussels and herbicide either in the technical-grade or formulated form (MG and MR, respectively), and control (C). Herbicides significantly increased total phosphorus in water; R and MR showed greater initial total nitrogen and ammonium. R increased picoplankton abundance and caused an eightfold increase in phytoplankton, with high turbidity values; G had a lower effect on these variables. Herbicide-mussel combination induced an accelerated dissipation of glyphosate in water (MG 6.36 ± 0.83 mg G g DW(-1) day(-1) and MR 5.16 ± 1.26 mg G g DW(-1) day(-1)). A synergistic effect on ammonium was observed in MR but not in MG. MR and MG had an antagonistic effect on phytoplankton, which showed a drastic reduction due to grazing, as revealed by M. We provide evidence of differential effects of Roundup Max® and technical-grade glyphosate over water quality and microscopic communities, and in combination with mussels. However, in the combination of mussels and herbicides, mussels seem to play a leading role. In the presence of L. fortunei, the effects of higher nutrient availability provided by herbicides addition were counteracted by the filtration activity of mussels, which released nutrients, grazed on picoplankton and phytoplankton, and boosted the development of other primary producers, periphyton and metaphyton.
IgA nephropathy (IgAN) has variable clinical presentation and outcome. There is a need to identify children who have the potential to progress to end stage renal disease (ESRD). Biomarkers related to the pathogenetic process of IgAN can detect risk factors and identify targets for new therapies. Galactose-deficient IgA1 (Gd-IgA1) is a specific biomarker of IgAN and could be the first treatment target. In experimental mice, reduction of IgA1 deposits and hematuria was observed after treatment with a bacterial protease that selectively cleaves human IgA1. Glycan-targeted drugs that may act to neutralize Gd-IgA1 inhibit abnormal enzymatic glycosylation of IgA1 or deplete cells producing Gd-IgA1. The autoimmune response to Gd-IgA1 produces autoantibodies that are sensitive and specific biomarkers of IgAN development and progression and suggests the possible benefits of anti-B cell therapies directed against CD20, B-cell activating factor (BAFF), or B cell receptor, and also proteasome inhibitors. The activation of complement in IgAN offers new biomarkers and the rationale for using complement inhibitors, including eculizumab. Renal pathological features represent sensitive biomarkers of added value over clinical data and may drive steroid therapy in selected cases. Finally, the hypothesis of the involvement of intestinal mucosal immunity in the pathogenesis of IgAN suggests the possibility of avoiding the systemic effect of steroid. Enteric budesonide targeting Peyer's patches at the ileocecal junction is an interesting option that has provided some preliminary favorable results in IgAN. In conclusion, the identification of new biomarkers is a promising area for therapies targeting IgAN in patients at risk of progression.
Tritrophic interactions between Mythimna separata, its tachinid parasite Exorista civilis and the Cry1Ab were examined. Although 6th instar M. separata mortality increased with increasing Cry1Ab concentration, some tolerance was evident. Likewise, parasitization by E. civilis resulted in only 18% host mortality. However, combination of Cry1Ab and E. civilis parasitization resulted in a significant Cry1Ab dose-dependent increase in mortality over that of either alone, including a 50-56% synergistic increase in efficacy at the two concentrations tested. Pupal weight, adult emergence and lifetime fecundity of M. separata derived from larvae surviving both agents were negatively affected. The ability of E. civilis to parasitize and subsequently develop on the host was not adversely influenced by Cry1Ab. Instead, pupation rate increased significantly among host larvae fed 3.125 μg/g Cry1Ab diet. Overall, our results demonstrate that use of Cry1Ab to control M. separata not only is compatible with the use of the tachinid parasitoid, but that the two methods can act synergistically to manage this destructive pest, provide support for the safety of transgenic Cry1Ab Bt plants in China. This example of two independent pest management strategies acting synergistically against a difficult pest offers a new perspective of broad significance in striving for agricultural sustainability.
To illuminate nurses' experiences and opportunities to discuss sexual health with patients in primary healthcare.
Sexual health is a concept associated with many taboos and research shows that nurses feel uncomfortable talking to patients about sexual health and therefore avoid it. This avoidance forms a barrier between patient and nurse which prevents nurses from giving satisfactory healthcare to patients.
A qualitative descriptive design.
Semi-structured interviews were conducted with nine nurses in primary healthcare in Sweden. Data were analysed by using qualitative content analysis.
During the analysis phase, five subcategories and two main categories were identified. The two main categories were: "Factors that influence nurses' opportunities to talk to patients about sexual health" and "Nurses' experiences of talking to patients about sexual health". Social norms in society were an obstacle for health professionals' opportunities to feel comfortable and act professionally. The nurses' personal attitude and knowledge were of great significance in determining if they brought up the topic of sexual health or not. The nurses found it easier to bring up the topic of sexual health with middle-aged men with for example diabetes. One reason for this is that they found it easier to talk to male patients. A further reason is the fact that they had received training in discussing matters of sexual health in relation to diabetes and other conditions affecting sexual health.
Nurses in primary care express the necessity of additional education and knowledge on the subject of sexual health. The healthcare organization must be reformed to put focus on sexual health.
Guidelines for addressing the topic of sexual health must be implemented to establish conditions that will increase nurse's knowledge and provide them with the necessary tools for discussing sexual health with patients. This article is protected by copyright. All rights reserved.
Osteoimmunology arose from the recognition that cytokines produced by lymphocytes can affect bone homeostasis. We have previously shown that osteoclasts, cells that resorb bone, act as APCs. Cross-presentation of Ags by osteoclasts leads to expression of CD25 and Foxp3, markers of regulatory T cells in the CD8 T cells. Octeoclast-induced Foxp3(+) CD25(+) regulatory CD8 T cells (OC-iTcREG) suppress priming of CD4 and CD8 T cells by dendritic cells. OC-iTcREG also limit bone resorption by osteoclasts, forming a negative feedback loop. In this study, we show that OC-iTcREG express concurrently T-bet and Eomesodermin (Eomes) and IFN-γ. Pharmacological inhibition of IκK blocked IFN-γ, T-bet, and Eomes production by TcREG Furthermore, we show, using chromatin immunoprecipitation, NF-κB enrichment in the T-bet and Eomes promoters. We demonstrate that IFN-γ produced by TcREG is required for suppression of osteoclastogenesis and for degradation of TNFR-associated factor 6 in osteoclast precursors. The latter prevents signaling by receptor activator of NF-κB ligand needed for osteoclastogenesis. Knockout of IFN-γ rendered TcREG inefficient in preventing actin ring formation in osteoclasts, a process required for bone resorption. TcREG generated in vivo using IFN-γ(-/-) T cells had impaired ability to protect mice from bone resorption and bone loss in response to high-dose receptor activator of NF-κB ligand. The results of this study demonstrate a novel link between NF-κB signaling and induction of IFN-γ in TcREG and establish an important role for IFN-γ in TcREG-mediated protection from bone loss.
As a resource allocation strategy, plant growth and defense responses are generally mutually antagonistic. Brassinosteroid (BR) regulates many aspects of plant development and stress
 responses, however, genetic evidence of its integrated effects on plant growth and stress tolerance is lacking. We overexpressed the Arabidopsis BR biosynthetic gene AtDWF4 in the oilseed plant Brassica napus and scored growth and stress response phenotypes. The transgenic B. napus plants, in comparison to wild type, displayed increased seed yield leading to increased overall oil content per plant, higher root biomass and root length, significantly better tolerance to dehydration and heat stress, and enhanced resistance to necrotrophic fungal pathogens Leptosphaeria maculans and Sclerotinia sclerotiorum. Transcriptome analysis supported the integrated effects of BR on growth and stress responses; in addition to BR responses associated with growth, a predominant plant defense signature, likely mediated by BES1/BZR1, was evident in the transgenic plants. These results establish that BR can interactively and simultaneously enhance abiotic and biotic stress tolerance and plant productivity. The ability to confer pleiotropic beneficial effects that are associated with different agronomic traits suggests that BR-related genes may be important targets for simultaneously increasing plant productivity and performance under stress conditions.
Metagenomics has the potential to facilitate the discovery of novel enzymes; however, to date, only a few alkaline proteases have been characterized from environmentally-sourced DNA. We report the identification and characterization of an alkaline serine protease designated as Prt1A from the metagenomic library of tannery activated sludge. Sequence analysis revealed that Prt1A is closely related to S8A family subtilisins with a catalytic triad of Asp143, His173, and Ser326. The putative protease gene (prt-1A) was subcloned in pET 28a (+) vector and overexpressed in Escherichia coli BL21(DE3)pLysS cells. This 38.8 KDa recombinant protease was purified to homogeneity by nickel affinity chromatography and exhibited optimal enzyme activity at elevated pH (11.0) and temperature (55°C). The enzyme activity was enhanced by the addition of 5 mM Ca(2+) ions, and was stable in the presence of anionic detergent, oxidizing agent and various organic solvents. The enzyme displayed high affinity and catalytic efficiency for casein under standard assay conditions (Vmax = 279 U/mg/min, Km = 1.70 mg/mL) and was also compatible with commercial detergents. These results suggest that Prt1A protease could act as an efficient enzyme in various industrial applications.
Olfaction poses one of the most complex ligand-receptor matching problems in biology due to the unparalleled multitude of odor molecules facing a large number of cognate olfactory receptors. We have recently deorphanized an olfactory receptor, TAAR13c, as a specific receptor for the death-associated odor cadaverine. Here we have modeled the cadaverine/TAAR13c interaction, exchanged predicted binding residues by site-directed mutagenesis, and measured the activity of the mutant receptors. Unexpectedly we observed a binding site for cadaverine at the external surface of the receptor, in addition to an internal binding site, whose mutation resulted in complete loss of activity. In stark contrast, elimination of the external binding site generated supersensitive receptors. Modeling suggests this site to act as a gate, limiting access of the ligand to the internal binding site and thereby downregulating the affinity of the native receptor. This constitutes a novel mechanism to fine-tune physiological sensitivity to socially relevant odors.
Anticancer agents based on haloacetic acids are developed for inhibition of pyruvate dehydrogenase kinase (PDK), an enzyme responsible for reversing the suppression of mitochondria-dependent apoptosis. Through molecular docking studies mono- and dihaloacetates are identified as potent PDK2 binders and matched their efficiency with dichloroacetic acid. In silico screening directed their conversion to phospholipid prodrugs, which were subsequently self-assembled to pro-haloacetate nanoparticles. Following a thorough physico-chemical characterization, the functional activity of these novel agents was established in wide ranges of human cancer cell lines in vitro and in vivo in rodents. Results indicated that the newly explored PDK modulators can act as efficient agent for cancer regression. A Pyruvate dehydrogenase (PDH) assay mechanistically confirmed that these agents trigger their activity through the mitochondria-dependent apoptosis.
Circulating cell-free DNA (cfDNA), which can be obtained from plasma or serum by non-invasive procedures, has showed great potential to predict treatment response and survival for cancer patients. Several studies have assessed the prognostic and predictive value of cfDNA in non-small cell lung cancer (NSCLC). However, these studies were often small and reported varying results. To address this issue, a meta-analysis was carried out. A total of 22 studies involving 2518 patients were subjected to the final analysis. Our results indicated that NSCLC patients with higher cfDNA concentration had shorter median progression-free survival (PFS) and overall survival (OS) time. In addition, high levels of cfDNA were significantly associated with poor PFS (hazard ratio or HR, 1.32; 95% CI, 1.02-1.71) and OS (HR, 1.64; 95% CI, 1.26-2.15). With respect to tumor specific mutations, we failed to reveal significant differences for PFS (HR, 1.30; 95% CI, 0.66-2.56) and OS (HR, 1.05; 95% CI, 0.49-2.25) when NSCLC patients were grouped according to KRAS genotype detected in cfDNA. However, NSCLC patients which harbored EGFR activating mutation in cfDNA had a greater chance of response to EGFR-TKIs (odds ratio or OR, 1.96; 95% CI, 1.59-2.42). No significant publication bias was detected in this study. In conclusion, cfDNA could act as a prognostic and predictive biomarker for patients with NSCLC.
Several studies have assessed the clinicopathological and prognostic value of cyclooxygenase-2 (COX-2) expression in patients with head and neck cancer (HNC), but their results remain controversial. To address this issue, a meta-analysis was carried out. A total of 29 studies involving 2430 patients were subjected to final analysis. Our results indicated that COX-2 expression was not statistically associated with advanced tumor stage (OR, 1.23; 95% CI, 0.98-1.55) but correlated with high risk of lymph node metastasis (OR, 1.28; 95% CI, 1.03-1.60) and advanced TNM stage (OR, 1.33; 95% CI, 1.06-1.66). Moreover, COX-2 expression had significant effect on poor OS (HR, 1.93; 95% CI, 1.29-2.90), RFS (HR, 2.02; 95% CI, 1.00-4.08) and DFS (HR, 5.14; 95% CI, 2.84-9.31). The results of subgroup analyses revealed that COX-2 expression was related with high possibility of lymph node metastasis in oral cancer (OR, 1.49; 95% CI, 1.01-2.20) and advanced TNM stage in oral cancer (OR, 1.58; 95% CI, 1.05-2.37) and no site-specific HNC (OR, 1.64; 95% CI, 1.02-2.62). However, subgroup analyses only showed a tendency without statistically significant association between COX-2 expression and survival. Significant heterogeneity was not found when analyzing clinicopathological data, but it appeared when considering survival data. No publication bias was detected in this study. This meta-analysis suggested that COX-2 expression could act as a prognostic factor for patients with HNC.
Obscurins are a family of giant cytoskeletal proteins, originally identified in striated muscles where they have structural and regulatory roles. We recently showed that obscurins are abundantly expressed in normal breast epithelial cells where they play tumor and metastasis suppressing roles, but are nearly lost from advanced stage breast cancer biopsies. Consistent with this, loss of giant obscurins from breast epithelial cells results in enhanced survival and growth, epithelial to mesenchymal transition (EMT), and increased cell migration and invasion in vitro and in vivo. In the current study, we demonstrate that loss of giant obscurins from breast epithelial cells is associated with significantly increased phosphorylation and subsequent activation of the PI3K signaling cascade, including activation of AKT, a key regulator of tumorigenesis and metastasis. Pharmacological and molecular inhibition of the PI3K pathway in obscurin-depleted breast epithelial cells results in reversal of EMT, (re)formation of cell-cell junctions, diminished mammosphere formation, and decreased cell migration and invasion. Co-immunoprecipitation, pull-down, and surface plasmon resonance assays revealed that obscurins are in a complex with the PI3K/p85 regulatory subunit, and that their association is direct and mediated by the obscurin-PH domain and the PI3K/p85-SH3 domain with a KD of ~50 nM. We therefore postulate that giant obscurins act upstream of the PI3K cascade in normal breast epithelial cells, regulating its activation through binding to the PI3K/p85 regulatory subunit.
When must a death that occurs in a health care setting be reported to the coroner? This article explores this question by analysing the Coroners Act 2006 (NZ) and the amendments to the health care-related deaths provisions in the Coroners Amendment Bill 2014 (NZ). At the time of writing, the Bill was at the Select Committee stage. This article examines whether the amendments may improve the inconsistent clinical and coronial practices with respect to reportable health care-related deaths. It concludes that, while the proposed amendments are an improvement on the current legislative drafting, doubt remains about whether they will solve the challenges presented by health care-related reportable deaths. The second and third readings of the Bill should give serious consideration to the submissions received by the New Zealand Law Commission that express the view that the Queensland and Victorian legislation
 should be used as models.
In recent times, Australia's national security concerns have had controversial impacts on regulation of Australian medical practitioners in areas related to immigration detention. This column explores three recent case studies relevant to this issue. The first involves the enactment of the Australian Border Force Act 2015 (Cth), which has a significant impact on the regulation of medical professionals who work with people in immigration detention. The second involves the decision of the High Court of Australia in Plaintiff M68/2015 v Minister for Immigration and Border Protection [2016] HCA 1 that an amendment to Australian federal legislation justified sending children back to immigration detention centres in Papua New Guinea and Nauru. This legislation was previously heavily criticised by the Australian Human Rights Commissioner. The third concerns the deregistration of Tareq Kamleh, an Australian doctor of German-Palestinian heritage who came to public attention on ANZAC Day 2015 with his appearance online in a propaganda video for the Islamic State terrorist organisation al-Dawla al-Islamyia fil Iraq wa'al Sham, also known as Islamic State of Iraq and Syria (ISIS) or Daesh. Australia's professional regulatory system should presumptively respect professional virtues, such as loyalty to the relief of individual patient suffering, when dealing with doctors (whether in Australia or ISIS-occupied Syria) working under regimes whose principles appear inconsistent with those of ethics and human rights.
Attempts at medicinal cannabis law reform in Australia are not new. However, in historical perspective 2015 and 2016 will be seen as the time when community debate about legalisation of medicinal cannabis reached a tipping point in a number of Australian jurisdictions and when community impetus for change resulted in major reform initiatives. In order to contextualise the changes, the August 2015 Report of the Victorian Law Reform Commission (VLRC) and then the Access to Medicinal Cannabis Bill 2015 (Vic) introduced in December 2015 into the Victorian Parliament by the Labor Government are scrutinised. In addition, this editorial reviews the next phase of developments in the course of 2015 and 2016, including the Commonwealth Narcotic Drugs Amendment Act 2016 and the Queensland Public Health (Medicinal Canna- bis) Bill 2016. It identifies the principal features of the legislative initiatives against the backdrop of the VLRC proposals. It observes that the principles underlying the Report and the legislative developments in the three Australian jurisdictions are closely aligned and that their public health approach, their combination of evidence-based pragmatism, and their carefully orchestrated checks and balances against abuse and excess constitute a constructive template for medicinal cannabis law reform.
Breastfeeding is a physiological phenomenon; nonetheless, this act is a learned behaviour that requires continuous active support to make it successful. This study determines the frequency of mothers practicing successful breastfeeding according to the WHO ten steps at tertiary care hospital.
A descriptive cross sectional study was conducted in the Obstetrics department of Military Hospital, Rawalpindi over six month duration from July to December 2014. Booked mothers aged 15-49 years, having given birth to healthy, singleton baby were included in the study. Questions were asked after taking written informed consent from the mothers after delivery. Data was entered and analysed on SPSS version 20.
Out of 148 mothers, 35 (23.7%) mothers were following successful breastfeeding, i.e., knew 7 or more steps. A total of 100 (67.6%) mothers received support for breastfeeding by healthcare staff during their stay in hospital while 19 (12.8%) mothers started breastfeeding within one hour. About 71% had started formula milk along with breastfeeding. About 127 (85.8%) reported that they fed their children on demand and 144 (97.3%) did not use dummies. Statistically significant difference was observed as housewife mothers gave no top feed (p = 0.005) and multiparous mothers started breastfeeding within one hour of delivery (p = 0.04).
The steps to achieve successful breastfeeding are followed to a small extent among mothers. Delayed initiation of breastfeeding and increasing trend towards use of formula feed was observed. Employed, primiparous mothers are the most sensitive group to be focused during antenatal period.
Rare diseases are chronic, progressive genetic disorders, which affect around 6-8% of the general population, mainly children. Therefore, in Israel approximately 500,000 people are probably affected by a rare disease. In this article, we review some of the issues pertaining to rare diseases, such as the need for accurate diagnosis which is necessary not only for specific care and treatment but also for informed family planning. In addition, we review the impact of the activities of patients' organizations on the awareness of rare diseases and their involvement in the creation of the Orphan Drug Act, which was the leading point on the way to drug development worldwide. During the last few years networks for reaching leading specialists' opinions on the way to proper diagnosis were created. Thereafter, the next generation genetic technologies, such as exome sequencing, have been a revolution in terms of options and hope for patients with rare undiagnosed diseases. Patients with rare diseases and their families are a challenge to the health care system, not only in terms of diagnosis and therapy, but also in terms of special needs. In addition, deciphering molecular pathways of rare diseases might be the key for understanding molecular events involved in common disorders. We emphasize the duty to ensure appropriate capacity and equal access to follow-up and clinical management of patients with rare diseases in Israel.
For many oral medicine conditions, the use of compounded topical therapies that are locally absorbed and act directly at the affected site can provide greater efficacy compared with systemically delivered medications while minimizing systemic side effects. The objective of this study was to characterize the utilization and costs associated with the use of compounded medications in an academic, hospital-based oral medicine practice. This was a retrospective analysis of outpatients treated at the Center for Oral Disease at Brigham and Women's Hospital (Boston, Massachusetts) during the five-year period from November 2006 through November 2011. Patient prescription and payment information were obtained from the pharmacy's patient database. Variables included prescription compound, number of prescriptions refilled, prescription cost, and payment contributions from insurance and patients. An electronic medical record review was conducted to obtain patient demographics and diagnoses. There were 510 unique perscriptions corresponding to 423 patients filled during the study period. Four distinct medications comprised the majority (479/510; 94%) of prescriptions filled. The vast majority (94%) of prescriptions filled were at least partially paid for by insurance, with median patient co-pays ranging from $21 (clonazepam solution) to $34 (ketoprofen cream). Compound medications provide an affordable, flexible therapeutic option for patients being treated for a variety of oral medicine conditions.
MicroRNAs are involved in tumor initiation and progression by regulating oncogenes and tumor suppressor genes. Here we found that miR-495 are lower in clinical ESCC tissues than in adjacent non-tumor tissues. Moreover, the lower miR-495 expression correlated with increased lymph node metastasis (LNM), invasion and TNM stage. miR-495 overexpression predicted a favorable outcome in ESCC patients. miR-495 targeted a site in the 3'-UTR of Akt1, and miR-495 levels correlated inversely with Akt1 protein levels in ESCC tissue samples. Overexpression of miR-495 suppressed cell proliferation, blocked G1/S phase transition, and decreased migration and invasion by two ESCC cell lines in vitro and in vivo. Restoration of Akt1 protein levels in miR-495-overexpressing ESCC cells attenuated the inhibitory effects of miR-495. In addition, miR-495 suppressed cell cycle transition and the EMT signaling pathway through targeting Akt1, thereby inhibiting ESCC cell proliferation, migration, and invasion. Our results suggest that miR-495 may act as a tumor suppressor by targeting Akt1 in ESCC.
To examine the value of posttraumatic headaches in predicting return to work (RTW) in patients with mild traumatic brain injury (MTBI).
A total of 109 participants recruited from an outpatient head injury rehabilitation center, British Columbia, Canada.
Logistic regression analyses of secondary data.
The Numerical Pain Rating Scale (NPRS), measure of headache intensity. Nine resulting NPRS scores were used to predict successful versus unsuccessful RTW.
The largest effect size [odds ratio Exp(B)] value of 0.474] indicated that the odds of returning to work successfully are more than cut in half for each unit increase in NPRS rating.
To the author's knowledge, this is the first study of the impact of headache intensity on RTW for patients with MTBI. Posttraumatic headache severity after MTBI should be taken into account when developing models to predict RTW for this population. Headache intensity may act as a confounding variable for at least some injury characteristics (eg, cognitive functioning) and may add to the inconsistencies in the TBI and MTBI literature. Results may be utilized to guide rehabilitation efforts in planning RTW for patients with MTBI.
Previous evidence has shown the association of aberrant miR-198 expression with tumorigenesis and progression of many human malignancies. However, its involvement in human glioma
 is still unclear. Therefore, the aim of the current study was to investigate the expression and function of miR-198 in human gliomas. Using real-time quantitative RT-PCR, we examined miR-198 expression in 122 pairs of human gliomas and matched non-neoplastic brain tissues. The association of miR-198 expression with clinicopathological factors was also analyzed. Then, the effects of miR-198 on the biological behavior of glioma cells in vitro were evaluated. Our results showed that miR-198 expression was significantly downregulated in gliomas compared with corresponding non-neoplastic brain tissues (P < 0.001). Furthermore, low levels of miR-198 were associated with a higher WHO grade and lower Karnofsky performance status (KPS) score. A multivariate Cox regression analysis identified decreased miR-198 expression as an independent factor predicting poor prognosis for glioma patients. Lastly, in vitro functional analysis revealed that overexpression of miR- 198 in U87 cells reduced cell proliferation, promoted cell apoptosis, and inhibited cell invasion and migration. Taken together, these findings indicate that miR-198 may act as a tumor suppressor in human glioma, and may serve as a novel target for molecular therapies of this disease.
This commentary explores the utility of hope as a therapeutic tool for intervention in the case of a patient with a mental illness that is refractory to treatment over time, who expresses her intention to commit suicide. It begins with a short discussion differentiating a deliberative consideration of suicide from an impulsive act. Then the commentary defines hope, how it might be used as a therapeutic tool, and which limitations a clinician might confront in such a case. This commentary also considers the role of a physician in orientation not only to the patient but also to her own thoughts, feelings, and emotions regarding a patient's expressed desire to end her life.
Surface grab and core sediment samples were collected from Lakes Michigan, Superior, and Huron from 2010 to 2012, and concentrations of herbicides atrazine, simazine, and alachlor, as well as desethylatrazine (DEA), were determined. Concentrations of atrazine in surface grabs ranged from 0.01 to 1.7 ng/g dry weight and are significantly higher in the southern basin of Lake Michigan (latitude <44°) than other parts of the three lakes. The highest concentration of alachlor was found in sediments of Saginaw Bay in Lake Huron. The inventory and net fluxes of these herbicides were found to decline exponentially from the south to the north. The concentration ratio of DEA to atrazine (DEA/ATZ) increased with latitude, suggesting degradation of atrazine to DEA during atmospheric transport. DEA/ATZ also increased with sediment depth in the sediment cores. Diffusion of deposited herbicides from the upper sediment into deeper sediments has occurred, on the basis of the observed patterns of concentrations in dated sediment cores. Concentrations of atrazine in pore water were estimated and were higher than those reported for the bulk waters, suggesting the occurrence of solid-phase deposition of atrazine through the water column and that contaminated sediments act as a source releasing atrazine to the overlying water.
Abundant evidence supports that the NaCl cotransporter (NCC) activity is tightly regulated by the with-no-lysine (WNK) kinases. Here, we summarize the data regarding NCC regulation by WNKs, with a particular emphasis on WNK4.
Several studies involving in-vivo and in-vitro models have provided paradoxical data regarding WNK4 regulation of the NCC. Although some studies show that WNK4 can activate the NCC, other equally compelling studies show that WNK4 inhibits the NCC. Recent studies have shown that WNK4 is regulated by the intracellular chloride concentration ([Cl]i), which could account for these paradoxical results. In conditions of high [Cl]i, WNK4 could act as an inhibitor via heterodimer formation with other WNKs. In contrast, when [Cl]i is low, WNK4 can activate Ste20-related, proline-alanine-rich kinase (SPAK)/oxidative stress responsive kinase 1 (OSR1) and thus the NCC. Modulation of WNK4 by [Cl]i has been shown to account for the potassium-sensing properties of the distal convoluted tubule. Other regulators of WNK4 include hormones and ubiquitination.
Modulation of WNK4 activity by [Cl]i can account for its dual role on the NCC, and this has important physiological implications regarding the regulation of extracellular potassium concentration. Defective regulation of WNKs by ubiquitination explains most cases of familial hyperkalemic hypertension.
Simulator sickness is a major obstacle to the use of driving simulators for research, training and driver assessment purposes. The purpose of the present study was to investigate the possible influence of simulator sickness on driving performance measures such as standard deviation of lateral position (SDLP), and the effect of alcohol or repeated simulator exposure on the degree of simulator sickness. Twenty healthy male volunteers underwent three simulated driving trials of 1h's duration with a curvy rural road scenario, and rated their degree of simulator sickness after each trial. Subjects drove sober and with blood alcohol concentrations (BAC) of approx. 0.5g/L and 0.9g/L in a randomized order. Simulator sickness score (SSS) did not influence the primary outcome measure SDLP. Higher SSS significantly predicted lower average speed and frequency of steering wheel reversals. These effects seemed to be mitigated by alcohol. Higher BAC significantly predicted lower SSS, suggesting that alcohol inebriation alleviates simulator sickness. The negative relation between the number of previous exposures to the simulator and SSS was not statistically significant, but is consistent with habituation to the sickness-inducing effects, as shown in other studies. Overall, the results suggest no influence of simulator sickness on SDLP or several other driving performance measures. However, simulator sickness seems to cause test subjects to drive more carefully, with lower average speed and fewer steering wheel reversals, hampering the interpretation of these outcomes as measures of driving impairment and safety. BAC and repeated simulator exposures may act as confounding variables by influencing the degree of simulator sickness in experimental studies.
Many sensory neurons encode temporal information by detecting coincident arrivals of synaptic inputs. In the mammalian auditory brainstem, binaural neurons of the medial superior olive (MSO) are known to act as coincidence detectors, whereas in the lateral superior olive (LSO) roles of coincidence detection have remained unclear. LSO neurons receive excitatory and inhibitory inputs driven by ipsilateral and contralateral acoustic stimuli, respectively, and vary their output spike rates according to interaural level differences. In addition, LSO neurons are also sensitive to binaural phase differences of low-frequency tones and envelopes of amplitude-modulated (AM) sounds. Previous physiological recordings in vivo found considerable variations in monaural AM-tuning across neurons. To investigate the underlying mechanisms of the observed temporal tuning properties of LSO and their sources of variability, we used a simple coincidence counting model and examined how specific parameters of coincidence detection affect monaural and binaural AM coding. Spike rates and phase-locking of evoked excitatory and spontaneous inhibitory inputs had only minor effects on LSO output to monaural AM inputs. In contrast, the coincidence threshold of the model neuron affected both the overall spike rates and the half-peak positions of the AM-tuning curve, whereas the width of the coincidence window merely influenced the output spike rates. The duration of the refractory period affected only the low-frequency portion of the monaural AM-tuning curve. Unlike monaural AM coding, temporal factors, such as the coincidence window and the effective duration of inhibition, played a major role in determining the trough positions of simulated binaural phase-response curves. In addition, empirically-observed level-dependence of binaural phase-coding was reproduced in the framework of our minimalistic coincidence counting model. These modeling results suggest that coincidence detection of excitatory and inhibitory synaptic inputs is essential for LSO neurons to encode both monaural and binaural AM sounds.
Acceptance and commitment therapy (ACT) is a widely utilized psychotherapeutic approach, but randomized, controlled studies are lacking in veterans. This study evaluated the efficacy of ACT for emotional distress among veterans of the conflicts in Iraq and Afghanistan.
One hundred sixty veterans (80% male, Mage = 34 years) with anxiety or depressive disorder according to the Diagnostic and Statistical Manual of Mental Disorders (4th ed.) were randomized to ACT or present-centered therapy (PCT) and assessed before, during, and after treatment and during 3- to 12-month follow-up. The primary outcome was general distress as measured by the Brief Symptom Inventory-18 Global Severity Index. Additional outcomes included symptomatology, disability, quality of life, acceptability, and satisfaction.
There was improvement following treatment in the whole sample across a variety of measures, including general distress (d = 0.74, 95% confidence interval [CI: 0.52, 0.96]) and functioning (d = 0.71, 95% CI [0.50, 0.93]) and moderate to high levels of satisfaction with treatment. Response to the 2 interventions did not differ on the primary outcome or most secondary outcomes, although ACT led to greater improvement in insomnia than did PCT (ds = 0.63 and 0.08, respectively). Treatment dropout did not differ by condition but was high (41.9%).
ACT's efficacy in this group was
 modest and generally did not differ from that for PCT. Additional work is needed to understand the reasons that ACT did not perform as well as predicted in this veteran sample. (PsycINFO Database Record
The illegal trade in wildlife is a serious threat to the existence of wild animals throughout the world. The short supply and high demand for wildlife articles have caused an influx of many different forms of fake wildlife articles into this trade. The task of identifying the materials used in making such articles poses challenges in wildlife forensics as different approaches are required for species identification. Claws constitute 3.8% of the illegal animal parts (n=2899) received at the Wildlife Institute of India (WII) for species identification. We describe the identification of seized suspected tiger claws (n=18) using a combined approach of morphometric and DNA-based analysis. The differential keratin density, determined using X-ray radiographs, indicated that none of the 18 claws were of any large cat but were fake. We determined three claw measurements, viz. ac (from the external coronary dermo-epidermal interface to the epidermis of the skin fold connecting the palmar flanges of the coronary horn), bc (from the claw tip to the epidermis of the skin fold connecting the palmar flanges of the coronary horn) and the ratio bc/ac, for all the seized (n=18), tiger (n=23) and leopard (n=49) claws. Univariate and multivariate statistical analyses were performed using SPSS. A scatter plot generated using canonical discriminant function analysis revealed that of the 18 seized claws, 14 claws formed a cluster separate from the clusters of the tiger and leopard claws, whereas the remaining four claws were within the leopard cluster. Because a discrepancy was observed between the X-ray images and the measurements of these four claws, one of the claw that clustered with the leopard claws was chosen randomly and DNA analysis carried out using the cyt b (137bp) and 16S rRNA (410bp) genes. A BLAST search and comparison with the reference database at WII indicated that the keratin material of the claw was derived from Bos taurus (cattle). This is a pioneering discovery, and we suggest that a hierarchical combination of techniques be used for identifying claws involved in wildlife offences, i.e. that an X-ray, morphometric and DNA-based analysis be carried out, to ascertain whether the claws are of tigers or leopards. To identify species in the illegal wildlife trade morphometric and genetic reference database should be developed. Morphological features as well as DNA profiles need to be used for better implementation of the Wildlife (Protection) Act, 1972 of India and other laws/treaties in South-east Asia.
Self-assembly of amyloid β-protein (Aβ) into neurotoxic oligomers and fibrillar aggregates is a key process thought to be the proximal event leading to development of Alzheimer's disease (AD). Therefore, numerous attempts have been made to develop reagents that disrupt this process and prevent the formation of the toxic oligomers and aggregates. An attractive strategy for developing such reagents is to use peptides derived from Aβ based on the assumption that such peptides would bind to full-length Aβ, interfere with binding of additional full-length molecules, and thereby prevent formation of the toxic species. Guided by this rationale, most of the studies in the last two decades have focused on preventing formation of the core cross-β structure of Aβ amyloid fibrils using β-sheet-breaker peptides derived from the central hydrophobic cluster of Aβ. Though this approach is effective in inhibiting fibril formation, it is generally inefficient in preventing Aβ oligomerization. An alternative approach is to use peptides derived from the C-terminus of Aβ, which mediates both oligomerization and fibrillogenesis. This approach has been explored by several groups, including our own, and led to the discovery of several lead peptides with moderate to high inhibitory activity. Interestingly, the mechanisms of these inhibitory effects have been found to be diverse, and only in a small percentage of cases involved interference with β-sheet formation. Here, we review the strategy of using C-terminal fragments of Aβ as modulators of Aβ assembly and discuss the relevant challenges, therapeutic potential, and mechanisms of action of such fragments.
Mediators in pain transmission are the targets of a multitude of different analgesic pharmaceuticals. This review explores the most significant mediators of pain transmission as well as the pharmaceuticals that act on them.
The review explores many of the key mediators of pain transmission. In doing so, this review uncovers important areas for further research. It also highlights agents with potential for producing novel analgesics, probes important interactions between pain transmission pathways that could contribute to synergistic analgesia, and emphasizes transmission factors that participate in transforming acute injury into chronic pain. Expert commentary: This review examines current pain research, particularly in the context of identifying novel analgesics, highlighting interactions between analgesic transmission pathways, and discussing factors that may contribute to the development of chronic pain after an acute injury.
Most people in the world now live in cities. Urbanisation simultaneously isolates people from nature and contributes to biodiversity decline. As cities expand, suburban development and the road infrastructure to support them widens their impact on wildlife. Even so, urban communities, especially those on the peri-urban fringe, endeavour to support biodiversity through wildlife friendly gardens, green spaces and corridors, and conservation estates. On one hand, many who live on city fringes do so because they enjoy proximity to nature, however, the ever increasing intrusion of roads leads to conflict with wildlife. Trauma (usually fatal) to wildlife and (usually emotional and financial) to people ensues. Exposure to this trauma, therefore, should inform attitudes towards wildlife vehicle collisions (WVC) and be linked to willingness to reduce risk of further WVC. While there is good anecdotal evidence for this response, competing priorities and better understanding of the likelihood of human injury or fatalities, as opposed to wildlife fatalities, may confound this trend. In this paper we sought to explore this relationship with a quantitative study of driver behaviour and attitudes to WVC from a cohort of residents and visitors who drive through a peri-urban reserve (Royal National Park) on the outskirts of Sydney, Australia. We distributed a self-reporting questionnaire and received responses from 105 local residents and 51 visitors to small townships accessed by roads through the national park. We sought the respondents' exposure to WVC, their evasive actions in an impending WVC, their attitudes to wildlife fatalities, their strategies to reduce the risk of WVC, and their willingness to adopt new ameliorative measures. The results were partitioned by driver demographics and residency. Residents were generally well informed about mitigation strategies but exposure led to a decrease in viewing WVC as very serious. In addition, despite most respondents stating they routinely drive slower when collision risk is high (at dusk and dawn), our assessment of driving trends via traffic speeds suggested this sentiment was not generally adhered to. Thus we unveil some of the complexities in tackling driver's willingness to act on reducing risk of WVC, particularly when risk of human trauma is low.
Most assassin bugs are predators that act as important natural enemies of insect pests. Mitochondrial (mt) genomes of these insects are double-strand circular DNAs that encode 37 genes. In the present study, we explore the duplication and rearrangement of tRNA genes in the mt genome of Reduvius tenebrosus, the first mt genome from the subfamily Reduviinae. The gene order rearranges from CR (control region)-trnI-trnQ-trnM-ND2 to CR-trnQ-trnI2-trnI1-trnM-ND2. We identified 23 tRNA genes, including 22 tRNAs commonly found in insects and an additional trnI (trnI2), which has high sequence similarity to trnM. We found several pseudo genes, such as pseudo-trnI, pseudo-CR, and pseudo-ND2, in the hotspot region of gene rearrangement (between the control region and ND2). These features provided evidence that this novel gene order could be explained by the tandem duplication/random loss (TDRL) model. The tRNA duplication/anticodon mutation mechanism further explains the presence of trnI2, which is remolded from a duplicated trnM in the TDRL process (through an anticodon mutation of CAT to GAT). Our study also raises new questions as to whether the two events proceed simultaneously and if the remolded tRNA gene is fully functional. Significantly, the duplicated tRNA gene in the mitochondrial genome has evolved independently at least two times within assassin bugs.
Capsaicin, the pungent ingredient of the hot chili pepper, is known to act on the transient receptor potential cation channel vanilloid subfamily member 1 (TRPV1). TRPV1 is involved in somatic and visceral peripheral inflammation, in the modulation of nociceptive inputs to spinal cord and brain stem centers, as well as the integration of diverse painful stimuli. In this review, we first describe the chemical and pharmacological properties of capsaicin and its derivatives in relation to their analgesic properties. We then consider the biochemical and functional characteristics of TRPV1, focusing on its distribution and biological effects within the somatosensory and viscerosensory nociceptive systems. Finally, we discuss the use of capsaicin as an agonist of TRPV1 to model acute inflammation in slices and other ex vivo preparations.
The
 aims of this study were: (1) to understand the implicit and explicit perceptions of accountability from the perspective of bedside nurses and their managers; (2) to identify the factors that facilitate accountability behaviours.
Despite the importance attributed to accountability in nursing education and practice, empirical research lacks clarity regarding how nurses perceive accountability and decide whether or not to act accountably.
Qualitative study.
Data of a purposeful sample of 23 nurses were collected through in-depth semi-structured interviews during 2015. They were tape-recorded, transcribed verbatim and content analysed.
Nurses agreed that accountability, more particularly responsibility, was crucial to nursing professionalism. However, they perceived the demands for transparency and answerability as unjustified. Bedside nurses held this view more than nursing managers. Still, accountability was not considered an integral organizational norm but the choice of each nurse and his or her assessment of risks or benefits of acting accountably.
Nurses' individual accountability was insufficient to generate accountability behaviours. They tended to weigh up the unit's accountability level in gauging risks and benefits before acting accountably. Risks of accountability behaviour included isolation, resistance and bullying, while benefits included professionalism, empowerment and pride.
Filiform mechanosensory hairs of crickets are of great interest to engineers because of the hairs' highly sensitive response to low-velocity air-currents. In this study, we analyze the biomechanical properties of filiform hairs of the cercal sensory system of a common house cricket. The cercal sensory system consists of two antennalike appendages called cerci that are situated at the rear of the cricket's abdomen. Each cercus is covered with 500-750 flow sensitive filiform mechanosensory hairs. Each hair is embedded in a complex viscoelastic socket that acts as a spring and dashpot system and guides the movement of the hair. When a hair deflects due to the drag force induced on its length by a moving air-current, the spiking activity of the neuron that innervates the hair changes and the combined spiking activity of all hairs is extracted by the cercal sensory system. Filiform hairs have been experimentally studied by researchers, though the basis for the hairs' biomechanical characteristics is not fully understood. The socket structure has not been analyzed experimentally or theoretically from a mechanical standpoint, and the characterization that exists is mathematical in nature and only provides a very rudimentary approximation of the socket's spring nature. This study aims to understand and physically characterize the socket's behavior and interaction with the filiform hair by examining hypotheses about the hair and socket biomechanics. A three-dimensional computer-aided design (CAD) model was first created using confocal microscopy images of the hair and socket structure of the cricket, and then finite-element analyses (FEAs) based on the physical conditions that the insect experiences were simulated. The results show that the socket can act like a spring; however, it has two-tier rotational spring constants during pre- and postcontacts of iris and hair bulge due to its constitutive nonstandard geometric shapes.
Many signalling proteins permanently or transiently localize to specific organelles. It is well established that certain lipids act as biochemical landmarks to specify compartment identity. However, they also influence membrane biophysical properties, which emerge as important features in specifying cellular territories. Such parameters include the membrane inner surface potential, which varies according to the lipid composition of each organelle. Here, we found that the plant plasma membrane (PM) and the cell plate of dividing cells have a unique electrostatic signature controlled by phosphatidylinositol-4-phosphate (PtdIns(4)P). Our results further reveal that, contrarily to other eukaryotes, PtdIns(4)P massively accumulates at the PM, establishing it as a critical hallmark of this membrane in plants. Membrane surface charges control the PM localization and function of the polar auxin transport regulator PINOID as well as proteins from the BRI1 KINASE INHIBITOR1 (BKI1)/MEMBRANE ASSOCIATED KINASE REGULATOR (MAKR) family, which are involved in brassinosteroid and receptor-like kinase signalling. We anticipate that this PtdIns(4)P-driven physical membrane property will control the localization and function of many proteins involved in development, reproduction, immunity and nutrition.
The nuclear receptor E75 is an early-responsive gene in 20-hydroxyecdysone (20E) signaling pathway, and is found to play essential roles in many aspects of arthropods development. In this study, a cDNA encoding the E75 nuclear receptor of the swimming crab, Portunus trituberculatus was cloned using RT-PCR and RACE. The PtE75 cDNA was 3211bp in length, and encodes a protein of 795 amino acids. The DBD region of the predicted amino acid sequence for PtE75 was highly conserved with other arthropoda E75s, while its LBD region was more similar to decapod E75s. Tissue distribution analysis showed that PtE75 transcript was widespread among tissues and relatively abundant in Y-organ, epidermis, eyestalk, and muscles. PtE75 exhibited tissue-specific expression patterns in these four tissues, which may depend on the distinct action of 20E on different tissues. The expression of PtE75 in Y-organ and epidermis were induced by eyestalk ablation (ESA), indicating its responsiveness to the increasing hemolymph 20E titer. To identify potential targets for ecdysteroid control the in Y-organ, epidermis, and eyestalk, the expression change of an ecdysteroid synthesis gene PtSad in Y-organ, a chitin degradation gene PtChi1 in epidermis, and the molt-inhibiting hormone gene PtMIH in eyestalk were investigated after silencing of PtE75 mRNA. The double stranded RNA (dsRNA) of PtE75 caused a loss in PtChi and PtMIH expression, while an increase in PtSad expression. The results suggested that the ecdysteroids may act through E75, and play a stimulatory role on chitin degradation in epidermis and MIH synthesis in eyestalk, and an negative feedback effect on ecdysteroid synthesis in Y-organ.
Proliferation and migration of vascular smooth muscle cells (VSMCs) play crucial roles in the development of vascular restenosis. Our previous study showed that CCN4, namely Wnt1 inducible signaling pathway protein 1 (WISP1), significantly promotes proliferation and migration of rat VSMCs, but its mechanism remains unclear. This study aims to investigate whether and how WISP1 stimulates proliferation and migration of human VSMCs. Western blot analysis showed that FBS treatment increased WISP1 protein levels in human VSMCs in a dose-dependent manner. Overexpression of WISP1 using adenovirus encoding WISP1 (AD-WISP1) significantly increased proliferation rate of human VSMCs by 2.98-fold compared with empty virus (EV)-transfected cells, shown by EdU incorporation assay. Additionally, Scratch-induced wound healing assay revealed that adenovirus-mediated overexpression of WISP1 significantly increased cell migration compared with EV-transfected cells from 6h (4.56±1.14% vs. 11.23±2.25%, P<0.05) to 48h (25.25±5.51% vs. 97.54±13.12%, P<0.01) after injury. Transwell Migration Assay confirmed that WISP1 overexpression significantly promoted human VSMC migration by 2.25-fold compared with EV. Furthermore, WISP1 overexpression stimulated Akt signaling activation in human VSMCs. Blockage of Akt signaling by Akt inhibitor AZD5363 or PI3K inhibitor LY294002, led to an inhibitory effect of WISP1-induced proliferation and migration in human VSMCs. Moreover, we found that WISP1 overexpression stimulated GSK3α/β phosphorylation, and increased expression of cyclin D1 and MMP9 in human VSMCs, and this effect was abolished by AZD5363. Collectively, we demonstrated that Akt signaling pathway mediates WISP1-induced migration and proliferation of human VSMCs, suggesting that WISP1 may act as a novel potential therapeutic target for vascular restenosis.
The search for smart delivery systems for enhanced pre-clinical and clinical pharmaceutical delivery and cell targeting continues to be a major biomedical research endeavor owing to differences in the physicochemical characteristics and physiological effects of drug molecules, and this affects the delivery mechanisms to elicit maximum therapeutic effects. Targeted drug delivery is a smart evolution essential to address major challenges associated with conventional drug delivery systems. These challenges mostly result in poor pharmacokinetics due to the inability of the active pharmaceutical ingredients to specifically act on malignant cells thus, causing poor therapeutic index and toxicity to surrounding normal cells. Aptamers are oligonucleotides with engineered affinities to bind specifically to their cognate targets. Aptamers have gained significant interests as effective targeting elements for enhanced therapeutic delivery as they can be generated to specifically bind to wide range of targets including proteins, peptides, ions, cells and tissues. Notwithstanding, effective delivery of aptamers as therapeutic vehicles is challenged by cell membrane electrostatic repulsion, endonuclease degradation, low pH cleavage, and binding conformation stability. The application of molecularly engineered biodegradable and biocompatible polymeric particles with tunable features such as surface area and chemistry, particulate size distribution and toxicity creates opportunities to develop smart aptamer-mediated delivery systems for controlled drug release. This article discusses opportunities for particulate aptamer-drug formulations to advance current drug delivery
 modalities by navigating active ingredients through cellular and biomolecular traffic to target sites for sustained and controlled release at effective therapeutic dosages while minimizing systemic cytotoxic effects. A proposal for a novel drug-polymer-aptamer-polymer (DPAP) design of aptamer-drug formulation with stage-wise delivery mechanism is presented to illustrate the potential efficacy of aptamer-polymer cargos for enhanced cell targeting and drug delivery.
Real-time PCR (RT-qPCR) expression analysis is a powerful analytical technique, but reliable results depend on the use of stable reference genes for proper normalization. This study proposed to test the expression stability of 13 candidate reference genes in Setaria viridis, a monocot species recently proposed as a new C4 model plant. Gene expression stability of these genes was assayed across different tissues and developmental stages of Setaria and under drought or aluminum stress. In general, our results showed Protein Kinase, RNA Binding Protein and SDH as the most stable genes. Moreover, pairwise analysis showed that two reference genes were sufficient to normalize the gene expression data under each condition. By contrast, GAPDH and ACT were the least stably expressed genes tested. Validation of suitable reference genes was carried out to profile the expression of P5CS and GolS during abiotic stress. In addition, normalization of gene expression of SuSy, involved in sugar metabolism, was assayed in the developmental dataset. This study provides a list of reliable reference genes for transcript normalization in S. viridis in different tissues and stages of development and under abiotic stresses, which will facilitate genetic studies in this monocot model plant.
The complement system is a powerful effector arm of innate immunity that typically confers protection from microbial intruders and accumulating debris. In many clinical situations, however, the defensive functions of complement can turn against host cells and induce or exacerbate immune, inflammatory, and degenerative conditions. Although the value of inhibiting complement in a therapeutic context has long been recognized, bringing complement-targeted drugs into clinical use has proved challenging. This important milestone was finally reached a decade ago, yet the clinical availability of complement inhibitors has remained limited. Still, the positive long-term experience with complement drugs and their proven effectiveness in various diseases has reinvigorated interest and confidence in this approach. Indeed, a broad variety of clinical candidates that act at almost any level of the complement activation cascade are currently in clinical development, with several of them being evaluated in phase 2 and phase 3 trials. With antibody-related drugs dominating the panel of clinical candidates, the emergence of novel small-molecule, peptide, protein, and oligonucleotide-based inhibitors offers new options for drug targeting and administration. Whereas all the currently approved and many of the proposed indications for complement-targeted inhibitors belong to the rare disease spectrum, these drugs are increasingly being evaluated for more prevalent conditions. Fortunately, the growing experience from preclinical and clinical use of therapeutic complement inhibitors has enabled a more evidence-based assessment of suitable targets and rewarding indications as well as related technical and safety considerations. This review highlights recent concepts and developments in complement-targeted drug discovery, provides an overview of current and emerging treatment options, and discusses the new milestones ahead on the way to the next generation of clinically available complement therapeutics.
Coral bleaching is an important environmental phenomenon, whose mechanism has not yet been clarified. The involvement of reactive oxygen species (ROS) has been implicated, but direct evidence of what species are involved, their location and their mechanisms of production remains unknown. Histidine-mediated chemical trapping and singlet oxygen sensor green (SOSG) were used to detect intra- and extracellular singlet oxygen ((1) O2 ) in Symbiodinium cultures. Inhibition of the Calvin-Benson cycle by thermal stress or high light promotes intracellular (1) O2 formation. Histidine addition, which decreases the amount of intracellular (1) O2 , provides partial protection against photosystem II photoinactivation and chlorophyll (Chl) bleaching. (1) O2 production also occurs in cell-free medium of Symbiodinium cultures, an effect that is enhanced under heat and light stress and can be attributed to the excretion of (1) O2 -sensitizing metabolites from the cells. Confocal microscopy imaging using SOSG showed most extracellular (1) O2 around the cell surface, but it is also produced across the medium distant from the cells. We demonstrate, for the first time, both intra- and extracellular (1) O2 production in Symbiodinium cultures. Intracellular (1) O2 is associated with photosystem II photodamage and pigment bleaching, whereas extracellular (1) O2 has the potential to mediate the breakdown of symbiotic interaction between zooxanthellae and their animal host during coral bleaching.
It has been established in the literature that workers within public organisations are intrinsically motivated. This paper is an empirical study of the healthcare sector using methods of qualitative analysis research, which aims to answer the following hypotheses: 1) doctors are intrinsically motivated; 2) economic incentives and control policies may undermine doctors' intrinsic motivation; and 3) well-designed incentives may encourage doctors' intrinsic motivation.
We conducted semi-structured interviews à-la-Bewley with 16 doctors from Navarre's Healthcare Service (Servicio Navarro de Salud-Osasunbidea), Spain. The questions were based on current theories of intrinsic motivation and incentives to test the hypotheses. Interviewees were allowed to respond openly without time constraints. Relevant information was selected, quantified and analysed by using the qualitative concepts of saturation and codification.
The results seem to confirm the hypotheses. Evidence supporting hypotheses 1 and 2 was gathered from all interviewees, as well as indications of the validity of hypothesis 3 based on interviewees' proposals of incentives.
The conclusions could act as a guide to support the optimal design of incentive policies and schemes within health organisations when healthcare professionals are intrinsically motivated.
The mitochondrial alternative oxidase pathway (AOP) has been suggested to act as a sink for excess reducing power generated in the chloroplast under high-light (HL) stress and thus may reduce photoinhibition. The aim of this study was to compare different species to investigate the in vivo regulation and role of AOP under HL stress. The in vivo activities of AOP (νalt ) and the cytochrome oxidase pathway, chlorophyll fluorescence, metabolite profiles, alternative oxidase (AOX) capacity and protein amount were determined in leaves of five C3 species under growth light and after HL treatment. Differences in respiration and metabolite levels were observed among species under growth light conditions. The HL response of νalt was highly species dependent, correlated with the AOP capacity and independent of AOX protein content. Nevertheless, significant correlations were observed between νalt , levels of key metabolites and photosynthetic parameters. The results show that the species-specific response of νalt is caused by the differential post-translational regulation of AOX. Significant correlations between respiration, metabolites and photosynthetic performance across species suggest that AOP may permit stress-related amino acid synthesis, whilst maintaining photosynthetic activity under HL stress.
The cancer cells can acquire migration and invasion capacities during the metastasis process through the developmental regulatory program epithelial-mesenchymal-transition (EMT), and through its reverse process mesenchymal-epithelial transition cancer cells can recolonize at distant metastatic sites. Among the multifaceted effects exerted by this program, reorganization of actin cytoskeleton is the key mechanical drive for the invasive properties gained by cancer cells. Collapsin response mediator protein-1 (CRMP1) is a cytosolic phosphoprotein and originally characterized as the mediator of semaphorin 3A signaling involved in axon differentiation during neural development. Here we report that CRMP1 can act as a suppressor of tumorigenicity and metastasis in prostate cancer cells. We demonstrated that CRMP1 exhibited a decreased expression pattern in high-grade prostate cancer tissues and many prostate cancer cell lines, and its downregulation in cancer cells was attributed to histone deacetylation and direct repression of its gene by the EMT regulator Snail. Functional analyses revealed that CRMP1 suppressed EMT in prostate cancer cells, as its knockdown could trigger EMT and enhance in vitro invasion capacity, whereas its overexpression could inhibit EMT and suppress both in vitro invasion and in vivo metastasis capacities of prostate cancer cells. Moreover, CRMP1 overexpression could significantly confer resistance to EMT induced by Snail or transforming growth factor-β1 in prostatic epithelial cells and prostate cancer cells. Finally, we demonstrated that CRMP1 could associate with actin and WAVE1, an activator of actin nucleation complex Arp2/3, and also its knockdown could stabilize F-actin and trigger the formation of stress fibers in prostate cancer cells. Together, our study shows that CRMP1 acts an EMT and metastasis suppressor in prostate cancer cells via its regulation of actin polymerization and also suggests that targeting the CRMP1-actin
 signaling in actin organization could be a potential strategy for management of prostate cancer metastasis.Oncogene advance online publication, 20 June 2016; doi:10.1038/onc.2016.227.
Recombinant human erythropoietin (rhEPO) is used in breast and ovarian cancer patients to alleviate cancer- and chemotherapy-related anemia. Some clinical trials have reported that rhEPO may adversely impact survival and increase the risk of thrombovascular events in patients with breast cancer but not with ovarian cancer. The latter may potentially benefit the most from rhEPO treatment due to the nephrotoxic and myelosuppresive effects of standard platinum-based chemotherapy used in ovarian cancer disease. However, over the last decade the preclinical data have revealed that EPO is not only the principal growth factor and the hormone which regulates erythropoiesis, but also a cytokine with a pleiotropic activity which also can affect cancer cells. EPO can stimulate survival, ability to form metastases and drug resistance not only in continuous breast- and ovarian cancer cell lines but also in breast cancer stem-like cells. EPO receptor (EPOR) can also be constitutively active in both these cancers and, in breast cancer cells, may act in an interaction with estrogen receptor (ER) and epidermal growth factor receptor-2 (HER-2). EPOR, by an EPO-independent mechanism, promotes proliferation of breast cancer cells in cooperation with estrogen receptor, resulting in decreased effectiveness of tamoxifen treatment. In another interaction, as a result of the molecular antagonism between EPOR and HER2, rhEPO protects breast cancer cells against trastuzumab. Both clinical and preclinical evidence strongly suggest the urgent need to reevaluate the traditional use of rhEPO in the oncology setting.
The Wnt/β-catenin signaling pathway plays a major role in tissue homeostasis, and its dysregulation can lead to various human diseases. Aberrant activation of β-catenin is oncogenic and is a critical driver in the development and progression of human cancers. Despite the significant potential of targeting the oncogenic β-catenin pathway for cancer therapy, the development of specific inhibitors remains insufficient. Using a T cell factor (TCF)-dependent luciferase-reporter system, we screened for small-molecule compounds that act against Wnt/β-catenin signaling and identified MSAB (methyl 3-{[(4-methylphenyl)sulfonyl]amino}benzoate) as a selective inhibitor of Wnt/β-catenin signaling. MSAB shows potent anti-tumor effects selectively on Wnt-dependent cancer cells in vitro and in mouse cancer models. MSAB binds to β-catenin, promoting its degradation, and specifically downregulates Wnt/β-catenin target genes. Our findings might represent an effective therapeutic strategy for cancers addicted to the Wnt/β-catenin signaling pathway.
In a long-term, large-scale serologic study in the western North Pacific Ocean, anti-Brucella antibodies were detected in common minke whales (Balaenoptera acutorostrata) in the 1994-2010 offshore surveys (21%, 285/1353) and in the 2006-2010 Japanese coastal surveys (20%, 86/436), in Bryde's whales (B. edeni brydei) in the 2000-2010 offshore surveys (9%, 49/542), in sei whales (B. borealis) in the 2002-2010 offshore surveys (5%, 40/788) and in sperm whales (Physeter macrocephalus) in the 2000-2010 offshore surveys (8%, 4/50). Anti-Brucella antibodies were not detected in 739 Antarctic minke whales (B. bonaerensis) in the 2000-2010 Antarctic surveys. This suggests that Brucella was present in the four large whale populations inhabiting the western North Pacific, but not in the Antarctic minke whale population. By PCR targeting for genes of outer membrane protein 2, the Brucella infection was confirmed in tissue DNA samples from Bryde's whales (14%, 2/14), sei whales (11%, 1/9) and sperm whales (50%, 2/4). A placental tissue and an apparently healthy fetus from a sperm whale were found to be PCR-positive, indicating that placental transmission might have occurred and the newborn could act as a bacterial reservoir. Marked granulomatous testes were observed only in mature animals of the three species of baleen whales in the western North Pacific offshore surveys, especially in common minke whales, and 29% (307/1064) of total mature males had abnormal testes. This study provides an insight into the status of marine Brucella infection at a global level.
Anticoagulants are the cornerstone of treatment of venous thromboembolism associated with various medical conditions and surgical procedures. They act on different steps of the coagulation pathway and are broadly categorized into heparins, vitamin K antagonists, and inhibitors of thrombin and factor Xa. The classification is evolving as newer and better oral and parenteral anticoagulants are being added. Anticoagulants in dermatology are important not only for their therapeutic application in cutaneous thrombotic dermatoses such as livedoid vasculitis, purpura fulminans, superficial and deep venous thrombosis and others but also for their use in non-thrombotic dermatoses such as lichen planus, recurrent oral aphthosis, chronic urticaria and several others. Further, the use of anticoagulants for any indication is associated with various adverse effects with dermatologic manifestations including specific reactions such as warfarin-induced skin necrosis, heparin-induced thrombocytopenia and anticoagulant-associated cholesterol embolization syndrome.
Stroke, a devastating complication of sickle cell anemia (SCA), can cause irreversible brain injury with physical and cognitive deficits. Transcranial Doppler ultrasonography (TCD) is a non-invasive tool for identifying children with SCA at highest risk of stroke. National guidelines recommend that TCD screening begin at age 2 years, yet there is research to suggest less than half of young children undergo screening. The purpose of this project was to use quality improvement methods to improve the proportion of patients aged 24-27 months who successfully completed their initial TCD from 25% to 75% by December 31, 2013. Quality improvement methods (e.g., process mapping, simplified failure mode effect analysis, and plan-do-study-act cycles) were used to develop and test processes for identifying eligible patients, scheduling TCDs, preparing children and families for the first TCD, and monitoring outcomes (i.e., TCD protocol). Progress was tracked using a report of eligible patients and a chart showing the age in months for the first successful TCD (population metric). As of December 2013, 100% of eligible patients successfully completed their initial TCD screen; this improvement was maintained for the next 20 months. In November 2014, a Welch's one-way ANOVA was conducted. Results showed a statistically significant difference between the average age of first TCD for eligible patients born in 2009 and eligible patients born during the intervention period (2010-2013; F[1,11.712]=16.03, p=0.002). Use of quality improvement methods to implement a TCD protocol was associated with improved TCD screening rates in young children with SCA.
Retinoid X receptors (RXRs) occupy a central position within the nuclear receptor superfamily. They not only function as important transcriptional factors but also exhibit diverse nongenomic biological activities. The pleiotropic actions of RXRs under both physiological and pathophysiological conditions confer RXRs important drug targets for the treatment of cancer, and metabolic and neurodegenerative diseases. RXR modulators have been studied for the purpose of developing both drug molecules and chemical tools for biological investigation of RXR. Development of RXR modulators has focused on small molecules targeting the canonical ligand-binding pocket. However, accumulating results have demonstrated that there are other binding mechanisms by which small molecules interact with RXR to act as RXR modulators. This review discusses the recent development in the design and discovery of RXR modulators with a focus on those targeting novel binding sites on RXR.
The reported flexible and transparent triboelectric generator (FTTG) can only output ultralow power density (∼2 μW cm(-2)), which has seriously hindered its further development and application. The low power density of FTTG is mainly limited by the transparent material and the electrode structure. Herein, for the first time, a FTTG with a superior power density of 60.7 μW cm(-2) has been fabricated by designing asymmetric electrodes where graphene and indium tin oxide (ITO) act as top and bottom electrodes respectively. Moreover, the performance of FTTG with graphene/ITO (G/I) asymmetric electrodes (GI-FTTG) almost remains unchanged even after 700 cycles, indicating excellent mechanical stability. The excellent performance of GI-FTTG can be attributed to the suitable materials and unique asymmetric electrode structure: the extraordinary flexibility of the graphene top electrode ensures the GI-FTTG excellent mechanical robustness and stability even after longer cycles, and the bottom electrode with very low sheet resistance guarantees lower internal resistance and higher production rate of induction charges to obtain higher output power density. It shows that light-emitting diodes (LED) can be easily powered by GI-FTTG, which demonstrates that the GI-FTTG is very promising for harvesting electrical energy from human activities by using flexible and transparent devices.
Electromagnetic resonators are integrated with advanced elastic material to develop a new type of tunable metamaterial. An electromagnetic-elastic metamaterial able to switch on and off its electromagnetic chiral response is experimentally demonstrated. Such tunability is attained by harnessing the unique buckling properties of auxetic elastic materials (buckliballs) with embedded electromagnetic resonators.
 In these structures, simple uniaxial compression results in a complex but controlled pattern of deformation, resulting in a shift of its electromagnetic resonance, and in the structure transforming to a chiral state. The concept can be extended to the tuning of three-dimensional materials constructed from the meta-molecules, since all the components twist and deform into the same chiral configuration when compressed.
There is abundant evidence that H2O2 can act as an endothelium-derived hyperpolarizing factor in the resistance vasculature. However, whilst scavenging H2O2 can abolish endothelial dependent hyperpolarization (EDH) and the associated vascular relaxation in some arteries, EDH-dependent vasorelaxation can often be mimicked only by using relatively high concentrations of H2O2. We have examined the role of H2O2 in EDH-dependent vasodilatation by simultaneously measuring vascular diameter and changes in endothelial cell (EC) [Ca(2+)]i during the application of H2O2 or carbachol, which triggers EDH. Carbachol (10µM) induced dilatation of phenylephrine-preconstricted rat cremaster arterioles was largely (73%) preserved in the presence of indomethacin (3µM) and l-NAME (300µM). This residual NO- and prostacyclin-independent dilatation was reduced by 89% upon addition of apamin (0.5µM) and TRAM-34 (10µM), and by 74% when an extracellular ROS scavenging mixture of SOD and catalase (S&C; 100Uml(-1) each) was present. S&C also reduced the carbachol-induced EC [Ca(2+)]i increase by 74%. When applied in Ca(2+)-free external medium, carbachol caused a transient increase in EC [Ca(2+)]i. This was reduced by catalase, and was enhanced when 1µM H2O2 was present in the bath. H2O2 -induced dilatation, which occurred only at concentrations ≥100µM, was reduced by a blocking antibody to TRPM2, which had no effect on carbachol-induced responses. Similarly, iberotoxin and Rp-8bromo cGMP reduced the vasodilatation induced by H2O2, but not by carbachol. Inhibiting PLC, PLA2 or CYP450 2C9 each greatly reduced the carbachol-induced increase in EC [Ca(2+)]i and vasodilatation, but adding 10µM H2O2 during PLA2 or CYP450 2C9 inhibition completely restored both responses. The nature of the effective ROS species was investigated by using Fe(2+) chelators to block the formation of ∙OH. A cell permeant chelator was able to inhibit EC Ca(2+) store release, but cell impermeant chelators reduced both the vasodilatation and EC Ca(2+) influx, implying that ∙OH is required for these responses. The results indicate that rather than mediating EDH by acting directly on smooth muscle, H2O2 promotes EDH by acting within EC to enhance Ca(2+) release.
Following the adoption of the Cancer Screening and Registry Act (KFRG) to advance the development of the early detection of cancer and to promote quality assurance through Clinical Cancer Registries according to Sect. 65c SGB V, the question is raised as to what extent population-based clinical cancer registries may contribute not only to direct patient treatment benefits, but also to the requirements of health research and to other issues such as, for example, the evaluation of the benefit of new pharmaceutical products. Efforts to improve a nationwide quality management for oncology have so far not been successful in the development of comprehensive documentation at all levels of care. New organizational structures such as population-based clinical cancer registries were supposed to solve this problem more sufficiently, but they must be accompanied by valid trans-sectorial documentation and evaluation of clinical data. The need for specific real-life outcomes (effectiveness) of specific therapies has led to calls for data from outside randomised clinical trials (efficacy). First results are demonstrated in the present article.
Listeria monocytogenes, the causative organism of the serious food-borne disease listeriosis, has a membrane abundant in branched-chain fatty acids (BCFAs). BCFAs are normally biosynthesized from branched-chain amino acids via the activity of branched chain α-keto acid dehydrogenase (Bkd), and disruption of this pathway results in reduced BCFA content in the membrane. Short branched-chain carboxylic acids (BCCAs) added as media supplements result in incorporation of BCFAs arising from the supplemented BCCAs in the membrane of L. monocytogenes bkd mutant MOR401. High concentrations of the supplements also effect similar changes in the membrane of the wild type organism with intact bkd. Such carboxylic acids clearly act as fatty acid precursors, and there must be an alternative pathway resulting in the formation of their CoA thioester derivatives. Candidates for this are the enzymes phosphotransbutyrylase (Ptb) and butyrate kinase (Buk), the products of the first two genes of the bkd operon. Ptb from L. monocytogenes exhibited broad substrate specificity, a strong preference for branched-chain substrates, a lack of activity with acetyl CoA and hexanoyl CoA, and strict chain length preference (C3-C5). Ptb catalysis involved ternary complex formation. Additionally, Ptb could utilize unnatural branched-chain substrates such as 2-ethylbutyryl CoA, albeit with lower efficiency, consistent with a potential involvement of this enzyme in the conversion of the carboxylic acid additives into CoA primers for BCFA biosynthesis.
Sensitization of wide bandgap semiconductors with heterodimers for better solar light sensitivity has attracted widespread attention in the recent times. However, application of heterodimerization for removing soluble water pollutants from waste water is sparse in the literature. In the present study, we have utilized heterodimerization of a model pollutant methylene blue (MB) with a ruthenium based dye N719 for the removal of the pollutant. We have synthesized N719 functionalized carbonate doped TiO2 microspheres (doped MS) which act as a novel material for the detoxification of MB containing water by adsorbing at the surface and eventually killing by photoinduced reduction under visible light irradiation. The mechanism of surface adsorption and photoreduction of MB are explored using steady state and time resolved spectroscopy studies. We have fabricated two types of prototype devices (flow device and active filter) using the functionalized doped MS. Both the devices show excellent dye removal activity and recyclability. The present study would find relevance in the removal of soluble pollutants from waste water.
Adoptive cell therapy (ACT) destroys tumors with infused cytotoxic T lymphocytes (CTLs). Although successful in some settings, ACT is compromised due to impaired survival or functional inactivation of the CTL. To better understand the mechanisms involved, we have exploited a mouse model of leukemia expressing ovalbumin as a tumor neoantigen to address these questions: (i) Is CTL impairment during ACT antigen specific? (ii) If yes, which are the antigen-presenting cells responsible? (iii) Can this information assist the development of complementary therapies to improve ACT? Our results indicate that the target (tumor) cells, not cross-presenting cells, are the main culprits of antigen-specific CTL inactivation. We find that the affinity/avidity of the CTL-tumor cell interaction has little influence on ACT outcomes, while tumor density is a major determinant. Reduction of tumor burden with mild non-lymphoablative and non-inflammatory chemotherapy can dramatically improve the efficacy of ACT and may minimize side-effects. We propose a general mechanism for the inactivation of anti-self CTL in the same tissues where the activity of anti-foreign CTL is preserved, based on the density of target cells. This mechanism, which we tentatively call stunning, may have evolved to protect infected sites from self-destruction and is exploited by tumors to inactivate CTL.
Major histocompatibility complex (MHC) class II molecules are expressed by antigen-presenting cells and stimulate CD4(+) T cells, which initiate humoral immune responses. Over the past decade, interest has developed to therapeutically impact the peptides to be exposed to CD4(+) T cells. Structurally diverse small molecules have been discovered that act on the endogenous peptide exchanger HLA-DM by different mechanisms. Exogenously delivered peptides are highly susceptible to proteolytic cleavage in vivo; however, it is only when successfully incorporated into stable MHC II-peptide complexes that these peptides can induce an immune response. Many of the small molecules so far discovered have highlighted the molecular interactions mediating the formation of MHC II-peptide complexes. As potential drugs, these small molecules open new therapeutic approaches to modulate MHC II antigen presentation pathways and influence the quality and specificity of immune responses. This review briefly introduces how CD4(+) T cells recognize antigen when displayed by MHC class II molecules, as well as MHC class II-peptide-loading pathways, structural basis of peptide binding and stabilization of the peptide-MHC complexes. We discuss the concept of MHC-loading enhancers, how they could modulate immune responses and how these molecules have been identified. Finally, we suggest mechanisms whereby MHC-loading enhancers could act upon MHC class II molecules.
γ-aminobutyric type A (GABAA ) receptors are the main inhibitory neurotransmitter receptors in the brain and are targets for numerous clinically important drugs such as benzodiazepines, anxiolytics, and anesthetics. Previously, pyrazoloquinoline 2-p-methoxyphenylpyrazolo [4,3-c] quinolin-3(5H)-one (CGS 9895) was described as a positive allosteric modulator acting through the α+/β- interface in the extracellular domain of GABAA receptors. The localization of the binding site was based on a steric hindrance approach, rather than on direct effects of point mutations. In this study
 we further characterized modulation by this compound which seems to have multiple sites of action. We investigated GABAA receptors expressed in Xenopus laevis oocytes using voltage-clamp electrophysiology. We have identified the α1 Y209 residue at the α+/β- interface as a key residue for CGS 9895 modulation. In addition, the interaction between this residue and various structural analogs was characterized, allowing tentative positioning of CGS 9895 versus α1 Y209 (rat sequence). Not all compounds were found to be sensitive to mutations at the α1 Y209 residue. In addition, the interaction of CGS 9895 with flurazepam was characterized. Flurazepam is hypothesized to act at the same subunit interface in the extracellular domain. We also provide evidence that the GABAA receptor harbors additional modulatory sites for CGS 9895 at each of the subunit interfaces in the transmembrane domain. GABAA receptors are the main inhibitory neurotransmitter receptors in the brain and are targets for numerous clinically important drugs such as benzodiazepines, anxiolytics and anesthetics. We have identified the α1 Y209 residue present at the extracellular α+/β- subunit interface as a key residue for the positive allosteric modulation of the GABAA receptor by CGS 9895. This receptor harbors additional modulatory sites for this compound at subunit interfaces in the transmembrane domain.
Autophagic mechanisms play critical roles in cell maintenance. Damaged organelles that are not removed by autophagosomes, which act by engulfing and degrading these cellular components, have been linked to various pathologies. Recently, the progression of aging has also been correlated to a compromised autophagic response. Here, we report for the first time a significant reduction in autophagic levels in synchronized aged normal human skin fibroblasts as compared to young fibroblasts. We measured a 77.9% reduction in autophagy as determined by reverse transcription-polymerase chain reaction for LC3B expression, a microtubule-associated protein correlated to late stage autophagosome formation. In addition, we visualized these same changes by immunocytofluorescence with antibodies directed against LC3B. By harvesting synchronized, as well as unsynchronized cells over time, we were also able to measure for the first time a nighttime peak in autophagy that was present in young but absent in aged fibroblasts. Finally, since human skin is constantly subjected to environmentally induced oxidative stress from sunlight, we exposed fibroblasts to 10 J/cm2 ultraviolet A and found, in good agreement with current literature, not only that irradiation could partially reactivate autophagy in the aged cells, but also that this increase was phase shifted earlier from its endogenous temporal pattern because of its loss of synchronization with circadian rhythm.
Down-regulation of DUSP5 has been shown to increase cell proliferation. DUSP5 expression is regulated through epigenetic events involving LncRNA H19 human choriocarcinoma cell line. However, the molecular mechanisms of H19 modulating the DUSP5 expression in cardiac fibrosis remain largely unknown. Here, we identify H19 negatively regulation of DUSP5 gene expression in cardiac fibroblast and fibrosis tissues. In vivo, the expression levels of H19, DUSP5, α-SMA, p-ERK1/2, and ERK1/2 in cardiac fibrosis tissue were estimated by Western blotting, quantitative reverse transcription-polymerase chain reaction and immunohistochemistry. In vitro stimulation of freshly isolated rat cardiac fibroblasts with recombinant marine TGF-β1 was performed, followed by quantitative reverse transcription-polymerase chain reaction and Western blotting to detect changes in H19, DUSP5, p-ERK1/2, and ERK1/2 levels. Cardiac fibroblasts were transfected with pEX-3-H19 overexpressing, H19-RNAi down-regulating, or pEGFP-C1-DUSP5 overexpressing. Finally, cell proliferation was assessed by the MTT assay and cell cycle. H19 endogenous expression is overexpressed in cardiac fibroblast and fibrosis tissues, and an opposite pattern is observed for DUSP5. H19 ectopic overexpression reduces DUSP5 abundance and increases the proliferation of cardiac fibroblast, whereas H19 silencing causes the opposite effects. In a broader perspective, these results demonstrated that LncRNA H19 contributes to cardiac fibroblast proliferation and fibrosis, which act in part through repression of DUSP5/ERK1/2.
To define the degree of deviation from the norm among boys with minor forms of anorectal malformations (ARM).
Between March 2015 and January 2016, we studied the preoperative MRI of nine boys with low-type ARM. For comparison, we included another nine boys (control group) who underwent MRI pelvis for causes other than ARM (e.g. impalpable testes).
In boys with low-type ARM, the rectum descends forwards to touch the back of the prostate (as in the norm), but then goes downwards (with little or no backward deflection) keeping intimately attached to the bulb of the corpus spongiosum and displacing it downwards and forwards. The striated sphincter muscles do not follow the anterior displacement of the bowel termination, but remain orthotopically compacted at the normal predestined site of the anal canal.
Among boys with low ARM, the minor abnormalities at the external anal orifice are associated with deeper anatomical aberrations in the form of anterior misplacement of the anorectum. These findings may help in understanding the disturbed act of defecation among these patients, and provide guidance to the best way of surgical correction.
The non-dioxin-like environmental toxicant 2,2',4,4',5,5'-hexachlorobiphenyl (PCB153), member of a group of persistent organic pollutants wide-spread throughout the environment, reduces gap junction intercellular communication (GJIC), an event possibly associated with tumor promotion. Since very few studies have investigated the signaling effectors and mode(s) of action of PCB153, and it is known that the gap junction (GJ) protein Cx43 can be regulated by the bioactive sphingolipid (SL) sphingosine 1-phosphate (S1P), this in vitro study mainly addresses whether SL metabolism is affected by PCB153 in rat liver epithelial WB-F344 cells. PCB153 treatment obtained significant changes in the S1P/ceramide (Cer) ratio, known to be crucial in determining cell fate. In particular, an increase in S1P at 30 min and a decrease of the bioactive lipid at 3 h were observed, whereas Cer level increased at 1 h and 24 h. Notably, a time-dependent modulation of sphingosine kinase (SphK), the enzyme responsible for S1P synthesis, and of its regulators, ERK1/2 and protein phosphatase PP2A, supports the involvement of these signaling effectors in PCB153 toxicity. Electrophysiological analyses, furthermore, indicated that the lipophilic environmental toxicant significantly reduced GJ biophysical properties, affecting both voltage-dependent (such as those formed by Cx43 and/or Cx32) and voltage-independent channels, thereby demonstrating that PCB153 may act differently on GJs formed by distinct Cx isoforms. SphK down-regulation alone induced GJIC impairment, and, when combined with PCB153, the acute effect on GJ suppression was additive. Moreover, after enzyme-specific gene silencing, the SphK1 isoform appears to be responsible for down-regulating Cx43 expression, while being the target of PCB153 at short-term exposure. In conclusion, we provide the first evidence of novel effectors in PCB153 toxic action in rat liver stem-like cells, leading us to consider SLs as potential markers for preventing GJIC deregulation and, thus, the tumorigenic action elicited by this environmental toxicant.
The emergence of complex animal life forms remains poorly understood despite substantial interest and research in this area. To be informative, the ideal models to study transitions from single-cell organisms to the first animals and then to mammalian-level complexity should be phylogenetically strategically placed and retain ancestral characters. Sponges (Porifera) are likely to be the earliest branching animal phylum. When analysed from morphological, genomic and developmental perspectives, sponges appear to combine features of single-cell eukaryotic organisms and the complex multicellular animals (Eumetazoa). Intriguingly, homologues of components of the eumetazoan regulatory networks specifying the endoderm, the germ-cells and stem cells and (neuro) sensory cells are expressed in sponge choanocytes, archaeocytes and larval sensory cells. Studies using sponges as model systems are already bringing insights into animal evolution, and have opened avenues to further research benefitting from the recent spectacular expansion of genomic technologies.
Attention Deficit Hyperactivity Disorder (ADHD) commonly affects children, although the symptoms persist into adulthood in approximately 50% of cases. Structural imaging studies in children have documented both cortical and subcortical changes in the brain. However, there have been only a few studies in adults and the results are inconclusive.
Voxel-based morphometry (VBM) was applied to 44 adults with ADHD, Combined subtype, aged 18-54 years and 44 healthy controls matched for age, sex and IQ.
ADHD patients showed reduced gray matter (GM) volume in the right supplementary motor area (SMA). Using more lenient thresholds we also observed reductions in the subgenual anterior cingulate (ACC) and right dorsolateral prefrontal (DLPFC) cortices and increases in the basal ganglia, specifically in the left caudate nucleus and putamen. There was a positive correlation between the cumulative stimulant dose and volume in the right SMA and DLPFC clusters.
The findings suggest that adults with ADHD show brain structural changes in regions belonging to the so-called cool executive function network. Long-term stimulant medication may act to normalize
 these GM alterations.
One of the greatest contributors to the overall caesarean section rate is elective repeat caesarean section.
Decisions around mode of birth are often complex for women and influenced by the views of the doctors and midwives who care for and counsel women. Women may be more likely to choose a repeat elective caesarean section (CS) if their health care providers lack skills and confidence in supporting vaginal birth after caesarean section (VBAC).
To explore the views and experiences of providers in caring for women considering VBAC, in particular the decision-making processes and the communication of risk and safety to women.
A descriptive interpretive method was utilised. Four focus groups with doctors and midwives were conducted.
The central themes were: 'developing trust', 'navigating the system' and 'optimising support'. The impact of past professional experiences; the critical importance of continuity of carer and positive relationships; the ability to weigh up risks versus benefits; and the language used were all important elements. The role of policy and guidelines on providing standardised care for women who had a previous CS was also highlighted.
Midwives and doctors in this study were positively oriented towards assisting and supporting women to attempt a VBAC. Care providers considered that women who have experienced a prior CS need access to midwifery continuity of care with a focus on support, information-sharing and effective communication.
Biased information processing styles are a core feature of cognitive models of unipolar depression (UD). The manic-defence hypothesis (MDH) posits that UD and Bipolar Disorder (BD) are subject partially to the same underlying cognitive processes, which may act as putative vulnerability factors. Previous studies have used experimental paradigms as a way of measuring automatic (non-intentional) processing of emotional information in order to test the MDH with some studies providing some evidence for a negatively biased automatic processing of emotionally-relevant information in BD. However, most prior studies used supraliminal stimuli (i.e. presented above perceptual threshold). Based on the MDH we predicted that subliminally presented negative stimuli will affect performance of patients with BD differently than non-clinical participants, but similarly to what has been observed in prior studies with currently depressed patients.
The current study used an affective priming paradigm with both supraliminally and subliminally presented emotional images as primes to measure automatic processing. Seventeen euthymic individuals with a BD diagnosis were recruited along with seventeen non-clinical control participants (NCC) matched for age and gender.
We found interference (increased response times) due to masked, subliminally presented negative primes in patients with BD when negative prime images were followed by negative targets, but decreased response times (facilitation) in NCCs.
We did not include a psychiatric control group and the sample size was small.
Our findings suggest that euthymic patients with BD do exhibit an affective bias suggesting an increased sensitivity to negative emotional information even when euthymic.
My article takes Robert Burt's piece as a starting point to highlight how a lacanian analysis of law differs from the one Robert Burt (rightly) rejected and from the alternative psychotherapeutic scenario Burt develops. I focus on what I consider to be the novel characteristics of a lacanian analysis, particularly its insistence on the castration of the human subject by language, a castration that problematizes our understanding of "freedom" and "free speech", and, in turn, on Law's own castration. The gradual peeling away of the claims made on behalf of the subject by ego psychologists, enables us to arrive at what a lacanian analysis would ideally uncover, that is the subject's extimate core. I illustrate this with the film The Act of Killing, a documentary which displays not only the extimate core at the heart of the subject but the extimate as the Law itself. The encounter between law and psychoanalysis, I conclude, far from leading to mutual understanding, leads to the dissolution of the analysand's pretenses, and, in turn, to the withdrawal of psychoanalysis from the scene altogether.
This analysis uses new questions in the Current Population Survey Annual Social and Economic Supplement to examine rates of offer and take-up of employer-sponsored health insurance over early 2014 and early 2015, as well as reasons reported for why individuals did not enroll. We find increases in offer and eligible rates of 0.5 and 0.9 percentage points, respectively, and a decrease in the take-up rate of 1.5 percentage points, while the coverage rate remained stable. We further find an increase in the proportion of workers covered by another plan and decreases in the proportions eligible for coverage but having a preexisting condition, employed as contract or temporary employees not allowed in the plan, and who have not yet worked for an employer long enough.
Entamoeba histolytica trophozoites dwell in the human intestine as comensals although under still unclear circumstances become invasive and destroy the host tissues. For these activities, trophozoites relay on remarkable motility provided by the cytoskeleton organization. Amebic actin and some of its actin-associated proteins are well known, while components of the myosin II molecule, although predicted from the E. histolytica genome, need biochemical and functional characterization. Recently, an amebic essential light myosin II chain, named EhMLCI, was identified and reported to be phosphorylated in tyrosines. The phosphorylated form of the protein was associated with the soluble assembly incompetent conformation of the heavy myosin chains, while the non-phosphorylated protein was identified with filamentous heavy chains, organized in an assembly competent conformation. It was postulated that EhMLCI tyrosine phosphorylation could act as a negative regulator of myosin II activity by its phosphorylation/dephosphorylation cycles. To test this hypothesis, we constructed an expression vector containing an EhMLCI DNA sequence where two tyrosine residues, with strong probability of phosphorylation and fall within the single EF-hand domain that interacts with the N-terminus of myosin II heavy chains, were replaced by phenylalanines. Transfected trophozoites, expressing the mutant MutEhMLCI protein cannot process it, thereby not incorporated into the phosphorylation/dephosphorylation cycles required for myosin II activity, results in motility defective trophozoites.
Heparin is a sulfated polysaccharide of animal origin showing excellent anticoagulant properties. Although it strongly inhibits the coagulation cascade, its interaction with multiple sites results in several side effects. An ideal alternative compound should not only possess anticoagulant and antithrombotic activities, but also provide specific binding to components of the coagulation cascade to decrease side effects and facilitate the control of pharmacologic actions in patient's body. In this work, we performed a scan of potential targets for chemically sulfated pectin from Citrus sinensis (SCP) that shows an efficient anticoagulant activity by combining proteomics and molecular docking techniques. Defining the interaction partners of SCP is fundamental to evaluate if its pharmacological side effects can be as harmful as those from heparin. SCP interacts directly with heparin cofactor II, probably favoring its interaction with thrombin. SCP interaction with antithrombin depends likely on its association with thrombin or factor Xa. In addition to the interaction with factors related to homeostasis, SCP may also act on the renin-angiotensin and on the complement systems.
The knowledge of potential molecular targets of SCP provides clues to understand its mechanism of action in order to guide molecular changes in this compound to increase its specificity.
Cytochrome c oxidase (CcO) is a vital enzyme that catalyzes the reduction of molecular oxygen to water and pumps protons across mitochondrial and bacterial membranes. While proton uptake channels as well as water exit channels have been identified for A-type CcOs, the means by which water and protons exit B-type CcOs remain unclear. In this work, we investigate potential mechanisms for proton transport above the dinuclear center (DNC) in ba3-type CcO of Thermus thermophilus. Using long-time scale, all-atom molecular dynamics (MD) simulations for several relevant protonation states, we identify a potential mechanism for proton transport that involves propionate A of the active site heme a3 and residues Asp372, His376 and Glu126(II), with residue His376 acting as the proton-loading site. The proposed proton transport process involves a rotation of residue His376 and is in line with experimental findings. We also demonstrate how the strength of the salt bridge between residues Arg225 and Asp287 depends on the protonation state and that this salt bridge is unlikely to act as a simple electrostatic gate that prevents proton backflow. We identify two water exit pathways that connect the water pool above the DNC to the outer P-side of the membrane, which can potentially also act as proton exit transport pathways. Importantly, these water exit pathways can be blocked by narrowing the entrance channel between residues Gln151(II) and Arg449/Arg450 or by obstructing the entrance through a conformational change of residue Tyr136, respectively, both of which seem to be affected by protonation of residue His376.
The control of breast cell survival is of critical importance for preventing breast cancer initiation and progression. The activity of many proteins which regulate cell survival is controlled
 by reversible phosphorylation, so that the relevant kinases and phosphatases play crucial roles in determining cell fate. Several protein kinases act as oncoproteins in breast cancer and changes in their activities contribute to the process of transformation. Through counteracting the activity of oncogenic kinases, the protein phosphatases are also likely to be important players in breast cancer development, but this class of molecules is relatively poorly understood. Here we have investigated the role of the serine/threonine protein phosphatase 4 in the control of cell survival of breast cancer cells.
The breast cancer cell lines, MCF7 and MDA-MB-231, were transfected with expression vectors encoding the catalytic subunit of protein phosphatase 4 (PP4c) or with PP4c siRNAs. Culture viability, apoptosis, cell migration and cell cycle were assessed. The involvement of phosphoprotein enriched in astrocytes 15kDa (PEA15) in PP4c action was investigated by immunoblotting approaches and by siRNA-mediated silencing of PEA15.
In this study we showed that PP4c over-expression inhibited cell proliferation, enhanced spontaneous apoptosis and decreased the migratory and colony forming abilities of breast cancer cells. Moreover, PP4c down-regulation produced complementary effects. PP4c is demonstrated to regulate the phosphorylation of PEA15, and PEA15 itself regulates the apoptosis of breast cancer cells. The inhibitory effects of PP4c on breast cancer cell survival and growth were lost in PEA15 knockdown cells, confirming that PP4c action is mediated, at least in part, through the de-phosphorylation of apoptosis regulator PEA15.
Our work shows that PP4 regulates breast cancer cell survival and identifies a novel PP4c-PEA15 signalling axis in the control of breast cancer cell survival. The dysfunction of this axis may be important in the development and progression of breast cancer.
Most drugs are intended to act on molecular targets residing within a specific tissue or cell type. Therefore, the drug concentration within the target tissue or cells is most relevant to its pharmacological effect. Increasing evidences suggest that drug transporters not only play a significant role in governing systemic drug levels, but are also an important gate keeper for intra-tissue and intracellular drug concentrations. This review focuses on polyspecific organic cation transporters, which include the organic cation transporters 1-3 (OCT1-3), the multidrug and toxin extrusion proteins 1-2 (MATE1-2) and the plasma membrane monoamine transporter (PMAT). Following an overview of the tissue distribution, transport mechanisms, and functional characteristics of these transporters, we highlight the studies demonstrating the ability of locally expressed OCTs to impact intracellular drug concentrations and directly influence their pharmacological and toxicological activities. Specifically, OCT1-mediated metformin access to its site of action in the liver is impacted by genetic polymorphisms and chemical inhibition of OCT1. The impact of renal OCT2 and MATE1/2-K in cisplatin intrarenal accumulation and nephrotoxicity is reviewed. New data demonstrating the role of OCT3 in salivary drug accumulation and secretion is discussed. Whenever possible, the pharmacodynamic response and toxicological effects is presented and discussed in light of intra-tissue and intracellular drug exposure. Current challenges, knowledge gaps, and future research directions are discussed. Understanding the impact of transporters on intra-tissue and intracellular drug concentrations has important implications for rational-based optimization of drug efficacy and safety.
Psychiatric disorders like mood disorders, schizophrenia, or drug addiction affect a sizeable proportion of the human population and severely compromise quality of life. Therefore, measures to prevent the manifestation, and treatments to ameliorate the symptoms, of these disorders are in high demand. Brain lipids determine the localization and function of proteins in the cell membrane of neurons. Lipids may also act as neurotransmitters or other signalling molecules. The lipid composition of the brain can be influenced by nutrition, environmental factors, and by behavioural activity. Thus, lipids represent a target for preventive medicine of psychiatric disorders. Here we review how brain lipids contribute to normal behaviour and to major psychiatric disorders with the focus on phospholipids/fatty acids, sphingolipids, and endocannabinoids. Accumulating evidence suggests a crucial role for membrane forming and signalling lipids in the brain in the etiopathologies of depression, bipolar disorders, schizophrenia, and drug addiction. Lipids also represent potential preventive interventions for these psychiatric disorders by either targeted dietary supplementation or pharmacological manipulation of lipid regulating enzymes.
In bacteria, the FtsK/Xer/dif (chromosome dimer resolution site) system is essential for faithful vertical genetic transmission, ensuring the resolution of chromosome dimers during their segregation to daughter cells. This system is also targeted by mobile genetic elements that integrate into chromosomal dif sites. A central question is thus how Xer/dif recombination is tuned to both act in chromosome segregation and stably maintain mobile elements. To explore this question, we focused on pathogenic Neisseria species harboring a genomic island in their dif sites. We show that the FtsK DNA translocase acts differentially at the recombination sites flanking the genomic island. It stops at one Xer/dif complex, activating recombination, but it does not stop on the other site, thus dismantling it. FtsK translocation thus permits cis discrimination between an endogenous and an imported Xer/dif recombination complex.
Staphylococcus hyicus has caused great losses in the swine industry by inducing piglet exudative epidermitis (EE), sow mastitis, metritis, and other diseases and is a threat to human health. The pathogenesis of EE, sow mastitis, and metritis involves the interaction between the host and virulent protein factors of S. hyicus, however, the proteins that interact with the host, especially the host immune system, are unclear. In the present study, immunoproteomics was used to screen the immunogenic proteins of S. hyicus strain ZC-4. The cellular and secreted proteins of S. hyicus strain ZC-4 were obtained, separated by 2D gel electrophoresis, and further analyzed by western blot with S. hyicus strain ZC-4-infected swine serum. Finally, 28 specific immunogenic proteins including 15 cellular proteins and 13 secreted proteins, 26 of which were novel immunogenic proteins from S. hyicus, were identified by matrix-assisted laser desorption ionization time-of-flight mass spectrometry. To further verify their immunogenicity, two representative proteins (acetate kinase [cellular] and enolase [secreted]) were chosen for expression, and the resultant recombinant proteins could react with S. hyicus ZC-4-infected swine serum. In mice, both acetate kinase and enolase activated the immune response by increasing G-CSF and MCP-5 expression, and acetate kinase further activated the immune response by increasing IL-12 expression. Enolase can confer better protection against S.hycius than acetate kinase in mice. For the first time to our knowledge, our results provide detailed descriptions of the cellular and secreted proteins of S. hyicus strain ZC-4. These immunogenic proteins may contribute to investigation and elucidation of the pathogenesis of S. hyicus and provide new candidates for subunit vaccines in the future.
Effective hair dyeing through in situ incubation of keratin hair with the products of fungal laccase-catalyzed polymerization of plant phenols has been previously demonstrated. However, the dyeing process takes a long time to complete compared to commercial hair-dyeing products. To overcome this bottleneck, pre-synthesized polymeric products of the oxidative reaction of Trametes versicolor laccase on catechin and catechol, either with or without mordant agents (e.g., FeSO4), were here employed to achieve permanent keratin hair dyeing in various colors and shades. The laccase action in acidic sodium acetate buffer led to a deep black coloration after coupling reactions between the plant phenols. The colored dye products were then desalted and concentrated with ultrafiltration. The dyes, with or without mordant agents, caused a significant increase in ΔE values (i.e., color difference value) in gray human hair within 2.5 hours. In addition, different keratin colors and shades were induced depending upon the mordanting and pH changes. The dyed hair also exhibited a strong resistance to detergent treatments, indicating that our methods can give rise to permanent hair dyeing. Overall, our work has provided novel insight into developing eco-friendly hair-dyeing methods as alternatives to commercial toxic diamine-based dyes.
An inkjet-printed, fully passive sensor capable of either humidity or gas sensing is presented herein. The sensor is composed of an interdigitated electrode, a customized printable gas sensitive ink and a specialized dipole antenna for wireless sensing. The interdigitated electrode printed on a paper substrate provides the base conductivity that varies during the sensing process. Aided by the porous nature of the substrate, a change in relative humidity from 18% to 88% decreases the electrode resistance from a few Mega-ohms to the kilo-ohm range. For gas sensing, an additional copper acetate-based customized ink is printed on top of the electrode, which, upon reaction with hydrogen sulphide gas (H₂S) changes, both the optical and the electrical properties of the electrode. A fast response time of 3 min is achieved at room temperature for a H₂S concentration of 10 ppm at a relative humidity
 (RH) of 45%. The passive wireless sensing is enabled through an antenna in which the inner loop takes care of conductivity changes in the 4-5 GHz band, whereas the outer-dipole arm is used for chipless identification in the 2-3 GHz band.
Phytoecdysteroids like 20-hydroxyecdysone ("ecdysterone") can exert a mild, non-hormonal anabolic/adaptogenic activity in mammals, and as such, are frequently used in food supplements. Spinach is well-known for its relatively low ecdysteroid content. Cyanotis arachnoidea, a plant native in China, is among the richest sources of phytoecdysteroids, and extracts of this plant are marketed in tons per year amounts via the internet at highly competitive prices. Here we report the investigation of a series of food supplements produced in Germany and claimed to contain spinach extracts. Twelve ecdysteroids including two new compounds were isolated and utilized as marker compounds. A comparative analysis of the products with Cyanotis and spinach extracts provides evidence that they were manufactured from Cyanotis extracts instead of spinach as stated. Based on the chromatographic fingerprints, 20-hydroxyecdysone 2- and 3-acetate are suggested as diagnostic markers for related quality control. This case appears to represent an unusual type of dietary supplement counterfeiting: undeclared extracts from alternative plants would supposedly 'guarantee' product efficacy.
In acute liver failure (ALF) cerebral oedema and high intracranial pressure (ICP) are potentially deadly complications. Astrocytes cultured in ammonia have shown mitochondrial dysfunction and in rat models of liver failure, de novo lactate production in the brain has been observed and has led to a hypothesis of compromised brain metabolism during ALF. In contrast, normal lactate levels are found in cerebral microdialysate of ALF patients and the oxygen: glucose ratio of cerebral metabolic rates remains normal. To investigate this inconsistency we studied the mitochondrial function in brain tissue with respirometry in animal models of hyperammonaemia. Wistar rats with systemic inflammation induced by lipopolysaccharide or liver insufficiency induced by 90% hepatectomy were given ammonium or sodium acetate for 120 min. A cerebral cortex homogenate was studied with respirometry and substrates of the citric acid cycle, uncouplers and inhibitors of the mitochondrial complexes were successively added to investigate the mitochondrial function in detail. In a separate dose-response experiment cortex from healthy rats was incubated for 120 min in ammonium acetate in concentrations up to 80 mM prior to respirometry. Hyperammonaemia was associated with elevated ICP and increased tissue lactate concentration. No difference between groups was found in total respiratory capacity or the function of individual mitochondrial complexes. Ammonium in concentrations of 40 and 80 mM reduced the respiratory capacity in vitro. In conclusion, acute hyperammonaemia leads to elevated ICP and cerebral lactate accumulation. We found no indications of impaired oxidative metabolism in vivo but only in vitro at extreme concentrations of ammonium.
The limitations of fluorine-18 fluorodeoxy-D-glucose (FDG) in detecting some cancers has prompted a longstanding search for other positron emission tomography (PET) tracers to complement the imaging of glycolysis in oncology, with much attention paid to lipogenesis based on observations that the production of various lipid and lipid-containing compounds is increased in most cancers. Radiolabeled analogs of choline and acetate have now been used as oncologic PET probes for over a decade, showing convincingly improved detection sensitivity over FDG for certain cancers. However, neither choline nor acetate have been thoroughly validated as lipogenic biomarkers, and while acetyl-CoA produced from acetate is used in de-novo lipogenesis to synthesize fatty acids, acetate is also consumed by various other synthetic and metabolic pathways, with recent experimental observations challenging the assumption that lipogenesis is its predominant role in all cancers. Since tumors detected by acetate PET are also frequently detected by choline PET, imaging of choline metabolism might serve as an alternative albeit indirect marker of lipogenesis, particularly if the fatty acids produced in cancer cells are mainly destined for membrane synthesis through incorporation into phosphatidylcholines. Aerobic glycolysis may or may not coincide with changes in lipid metabolism, resulting in combinatorial metabolic phenotypes that may have different prognostic or therapeutic implications. Consequently, PET imaging using dual metabolic tracers, in addition to being diagnostically superior to imaging with individual tracers, could eventually play a greater role in supporting precision medicine, as efforts to develop small-molecule metabolic pathway inhibitors are coming to fruition. To prepare for this advent, clinical and translational studies of metabolic PET tracers must go beyond simply estimating tracer diagnostic utility, and aim to uncover potential therapeutic avenues associated with these metabolic alterations.
-Dietary intake of fruit and vegetables is associated with lower incidence of hypertension, but the mechanisms involved have not been elucidated. Here we evaluated the effect of a high fibre diet and supplementation with the short-chain fatty acid (SFCA) acetate on the gut microbiota and the prevention of cardiovascular disease.
-Gut microbiome, cardiorenal structure/function and blood pressure were examined in sham and mineralocorticoid-excess treated mice with a control diet, high fibre diet or acetate supplementation. We also determined the renal and cardiac transcriptome of mice treated with the different diets.
-We found that high consumption of fibre modified the gut microbiota populations and increased the abundance of acetate-producing bacteria, independently of mineralocorticoid-excess. Both fibre and acetate decreased gut dysbiosis, measured by the ratio of Firmicutes to Bacteroidetes, and increased the prevalence of Bacteroides acidifaciens Compared to mineralocorticoid-excess mice fed a control diet, both high fibre diet and acetate supplementation significantly reduced systolic and diastolic blood pressure, cardiac fibrosis and left ventricular hypertrophy. Acetate had similar effects and also markedly reduced renal fibrosis. Transcriptome analyses showed that the protective effects of high fibre and acetate were accompanied by the down-regulation of cardiac and renal Egr1, a master cardiovascular regulator involved in cardiac hypertrophy, cardiorenal fibrosis and inflammation. We also observed the up-regulation of a network of genes involved in circadian rhythm in both tissues, while down-regulated the renin-angiotensin system in the kidney and mitogen-activated protein kinases (MAPK) signalling in the heart.
-A diet high in fibre led to changes in the gut microbiota which played a protective role in the development of cardiovascular disease. The favourable effects of fibre may be explained by the generation and distribution of one of the main metabolites of the gut microbiota, the SCFA acetate. Acetate effected several molecular changes associated with improved cardiovascular health and function.
Chronic kidney disease (CKD) is associated with increased risk and worse prognosis of cardiovascular disease, including peripheral artery disease. An impaired angiogenic response to ischemia may contribute to poor outcomes of peripheral artery disease in patients with CKD. Hypoxia inducible factors (HIF) are master regulators of angiogenesis and therefore represent a promising target for therapeutic intervention. To test this we induced hind-limb ischemia in rats with CKD caused by 5/6 nephrectomy and administered two different treatments known to stabilize HIF protein in vivo: carbon monoxide and a pharmacological inhibitor of prolyl hydroxylation 2-(1-chloro-4- hydroxyisoquinoline-3-carboxamido) acetate (ICA). Expression levels of pro-angiogenic HIF target genes (Vegf, Vegf-r1, Vegf-r2, Ho-1) were measured by qRT-PCR. Capillary density was measured by CD31 immunofluorescence staining and HIF expression was evaluated by immunohistochemistry. Capillary density in ischemic skeletal muscle was significantly lower in CKD animals compared to sham controls. Rats with CKD showed significantly lower expression of HIF and all measured pro-angiogenic HIF target genes, including VEGF. Both HIF stabilizing treatments rescued HIF target gene expression in animals with CKD and led to significantly higher ischemia-induced capillary sprouting compared to untreated controls. ICA was effective regardless of whether it was administered before or after induction of ischemia and led to a HIF expression in skeletal muscle. Thus, impaired ischemia-induced angiogenesis in rats with CKD can be improved by HIF stabilization, even if started after onset of ischemia.
Stachys guyoniana Noë ex. Batt. and Mentha aquatica L. are two Algerian Lamiaceae used in folk medicine.
To investigate their antioxidant, anticholinesterase and antibacterial activities.
n-Butanol (BESG), ethyl acetate (EESG) and chloroform (CESG) extracts of S. guyoniana and methanol (MEMA) and chloroform (CEMA) aerial part extracts of M. aquatica and methanol (MERMA) and acetone (AERMA) roots extracts of M. aquatica were evaluated for their antioxidant activity by the β-carotene-linoleic acid, DPPH(•) and ABTS(•)(+) scavenging, CUPRAC and metal chelating assays. The anticholinesterase activity was tested against AChE and BChE. The antibacterial activity was assessed by MICs determination against Escherichia coli, Staphylococcus aureus, Pseudomonas aeruginosa, Salmonella heidelberg, Klebsiella pneumoniae, Enterobacter aerogenes and Morganella morganii strains.
In the β-carotene test,
 the CESG (IC50: 2.3 ± 1.27 μg/mL) exhibited the highest activity. The BESG was the best scavenger of DPPH(•) (IC50: 2.91 ± 0.14 μg/mL). In the ABTS test, AERMA was the most active (IC50: 4.21 ± 0.28 μg/mL). However, with the CUPRAC, the BESG exhibited the best activity (A0.50: 0.15 ± 0.05 μg/mL) and was active in metal chelating assay with 48% inhibition at 100 μg/mL. The BESG was the best AChE inhibitor (IC50: 5.78 ± 0.01 μg/mL) however, the AERMA showed the highest BChE inhibitory activity (IC50: 19.23 ± 1.42 μg/mL). The tested extracts exhibited a good antibacterial activity.
This study demonstrated good antioxidant, anticholinesterase and antibacterial potential of S. guyoniana and M. aquatica, which fits in well with their use in folk medicine.
Ostericum koreanum (Maxim.) Kitagawa (Apiaceae) roots are traditionally used as an analgesic and antiulcer agent. However, the antiulcer potential of isoimperatorin isolated from O. koreanum has not yet been explored.
To evaluate the antiulcer activity of isoimperatorin isolated from the roots of O. koreanum.
Isoimperatorin was isolated as cubic crystals by repeated column chromatography of the ethyl acetate fraction and structure was verified with (1)H NMR, (13)C NMR and high-resolution mass spectrometry (HRMS-FAB). The crystals obtained were analyzed with the single crystal X-ray method. The MTT assay was used to determine its cytotoxicity against chondrocytes at different concentrations (0.0-737.74 μM, 24 h). The in vivo antiulcer activity of isoimperatorin (40 mg/kg) was determined against ethanol-, indomethacin- and pyloric ligation-induced ulcers in Sprague-Dawley rats. Furthermore, the effect of isoimperatorin (0.0-737.74 μM, 24 h) on the expression of type II collagen in chondrocytes was determined using western blot method. The in vitro urease inhibitory activity of isoimperatorin (0-80 μM) and molecular docking was also performed against urease.
Isoimperatorin demonstrated significant inhibitory activity (IC50 36.43 μM) against urease as compared to the standard drug thiourea (IC50 33.57 μM) without cytotoxic effects. It provided 70.9%, 67.65% and 54.25% protection in ulcer models induced by ethanol, indomethacin and pyloric ligation, respectively. Isoimperatorin showed the highest expression level of type II collagen at 368.87 μM. The docking results confirmed strong binding affinity with the target protein.
Isoimperatorin may be used to develop antiulcer drugs with decreased side effects.
Pancreatic α-amylase and α-glucosidase inhibitors serve as important strategies in the management of blood glucose. Even though Syzygium cumini (L.) Skeels (Myrtaceae) (SC) is used extensively to treat diabetes; scientific evidence on antidiabetic effects of SC leaves is scarce.
SC leaf extract was investigated for α-amylase inhibitory effect and continued with isolation and identification of α-amylase inhibitors.
Bioassay-guided fractionation was conducted using in vitro α-amylase inhibitory assay (with 20-1000 μg/mL test material) to isolate the inhibitory compounds from ethyl acetate extract of SC leaves. Structures of the isolated inhibitory compounds were elucidated using (1)H NMR and (13)C NMR spectroscopic analysis and direct TLC and HPLC comparison with authentic samples. Study period was from October 2013 to October 2015.
An active fraction obtained with chromatographic separation of the extract inhibited porcine pancreatic α-amylase with an IC50 of 39.9 μg/mL. Furthermore, it showed a strong inhibition on α-glucosidase with an IC50 of 28.2 μg/mL. The active fraction was determined to be a 3:1 mixture of ursolic acid and oleanolic acid. Pure ursolic acid and oleanolic acid showed IC50 values of 6.7 and 57.4 μg/mL, respectively, against α-amylase and 3.1 and 44.1 μg/mL respectively, against α-glucosidase.
The present study revealed strong α-amylase and α-glucosidase inhibitory effects of ursolic acid and oleanolic acid isolated from SC leaves for the first time validating the use of SC leaves in antidiabetic therapy.
Ovarian stimulation of poor ovarian responders still remains a challenging issue. The incidence of poor responders among infertile women is reported in 9-24% IVF cycles and is associated with very low clinical pregnancy rates. Different treatments have been reported in the literature in an attempt to identify the best stimulation protocol for those patients. Administration of dehydroepiandrosterone acetate (DHEA) was suggested as a promising treatment. It is well known that androgens can influence ovarian follicular growth, augment steroidogenesis, promote follicular recruitment and increase the number of primary and pre-antral follicles. The purpose of this review is to evaluate the effect of DHEA supplementation on women with diminished ovarian reserve. Because of the uncertainty of published data, we suggest that well-designed multicentre RCTs are required to provide more insight on the effectiveness of DHEA. The absence of significant side effects should not be considered as an argument to support DHEA treatment.
[(13) C]acetate is known to label metabolites preferentially in astrocytes rather than neurons and it has consequently been used as a marker for astrocytic activity. Recent discoveries suggest that control of acetate metabolism and its contributions to the synthesis of metabolites in brain is not as simple as first thought. Here, using a Guinea pig brain cortical tissue slice model metabolizing [1-(13) C]D-glucose and [1,2-(13) C]acetate, we investigated control of acetate metabolism and the degree to which it reflects astrocytic activity. Using a range of [1,2-(13) C]acetate concentrations we found that acetate is a poor substrate for metabolism and will inhibit metabolism of itself and of glucose at concentrations in excess of 2 mmol/L. By activating astrocytes using potassium depolarization we found that use of [1,2-(13) C]acetate to synthesize glutamine decreases significantly under these conditions showing that acetate metabolism does not necessarily reflect astrocytic activity. By blocking synthesis of glutamine using methionine sulfoximine (MSO) we found that significant amount of [1,2-(13) C]acetate are still incorporated into GABA and its metabolic precursors in neurons, with around 30% of the GABA synthesized from [1,2-(13) C]acetate likely to be made directly in neurons rather than from glutamine supplied by astrocytes. Finally, to test whether activity of the acetate metabolizing enzyme acetyl-CoA synthetase is under acetylation control in brain we incubated slices with the AceCS1 deacetylase SIRT1 activator SRT 1720 and showed consequential increased incorporation of [1,2-(13) C]acetate into metabolites. Taken together, these data show that acetate metabolism is not directly nor exclusively related to astrocytic metabolic activity, that use of acetate is related to enzyme acetylation and that acetate is directly metabolized to a significant degree in GABAergic neurons. Changes in acetate metabolism should be interpreted as modulation of metabolism through changes in cellular energetic status via altered enzyme acetylation levels rather than simply as an adjustment of glial-neuronal metabolic activity. This article is protected by copyright. All rights reserved.
Alisol A 24-acetate, a triterpenoid extracted from Alisma orientale, has shown antiatherosclerotic actions. The purpose of this study was to evaluate the inhibition of alisol A 24-acetate on oxidized low-density lipoprotein (Ox-LDL)-induced phenotypic transformation and migration of rat vascular smooth muscle cells (VSMCs), and to explore the underlying mechanisms. VSMCs were pretreated with alisol A 24-acetate and a specific extracellular signal-regulated kinase (ERK) inhibitor, U0126, and then stimulated with 50 mg/l Ox-LDL in vitro. The expression of VSMC phenotypic marker SM22α was determined using immunocytochemistry, and the migration of VSMCs was detected using a scratch-wound healing assay. The expression of matrix metalloproteinase (MMP)-9, MMP-2, phosphorylated ERK1/2 (pERK1/2) and total ERK was determined. Ox-LDL treatment caused a reduction in SM22α expression, VSMC transformation to the synthetic phenotype, increased MMP-2 and MMP-9 synthesis, the extension of VSMC migration distance and the upregulation of pERK1/2 expression, while the addition of alisol A 24-acetate or U0126 resulted in the elevation of SM22α expression, VSMC transformation to the contractile phenotype, a reduction in MMP-2 and MMP-9 expression, the shortening of cell migration distance and decreased pERK1/2 expression. The results of this study demonstrate that alisol A 24-acetate effectively reverses the phenotypic transformation and inhibits the migration of VSMCs, which may be associated with the suppression of the ERK1/2 signaling pathway.
Insect tachykinin-related peptide (TRP), an ortholog of tachykinin in vertebrates, has been linked with regulation of diverse physiological processes, such as olfactory perception, locomotion, aggression, lipid metabolism and myotropic activity. In this study, we investigated the function of TRP (BdTRP) and its receptor (BdTRPR) in an important agricultural pest, the oriental fruit fly Bactrocera dorsalis. BdTRPR is a typical G-protein coupled-receptor (GPCR), and it could be activated by the putative BdTRP mature peptides with the effective concentrations (EC50) at the nanomolar range when expressed in Chinese hamster ovary cells. Consistent with its role as a neuromodulator, expression of BdTRP was detected in the central nervous system (CNS) of B. dorsalis, specifically in the local interneurons with cell bodies lateral to the antennal lobe. BdTRPR was found in the CNS, midgut and hindgut, but interestingly also in the antennae. To investigate the role of BdTRP and BdTRPR in olfaction behavior, adult flies were subjected to RNA interference,
 which led to a reduction in the antennal electrophysiological response and sensitivity to ethyl acetate in the Y-tube assay. Taken together, we demonstrate the impact of TRP/TRPR signaling on the modulation of the olfactory sensitivity in B. dorsalis. The result improve our understanding of olfactory processing in this agriculturally important pest insect.
Membrane type-1 matrix metalloproteinase (MT1-MMP) is elevated during thoracic aortic aneurysm (TAA) development in mouse models, and plays an important role in the activation of matrix metalloproteinase (MMP)-2 and the release of matrix- bound transforming growth factor-β. In this study, we tested the hypothesis that MT1-MMP is subject to protein kinase C (PKC)-mediated regulation, which alters intracellular trafficking and activity with TAAs.
Levels of MMP-2, native and phosphorylated MT1-MMP, and PKC-δ were measured in aortic tissue from patients with small TAAs (<5 cm; n = 8) and large TAAs (>6.5 cm; n = 8), and compared with values measured in normal controls (n = 8). Cellular localization of green fluorescent protein (GFP)-tagged MT1-MMP was assessed in aortic fibroblasts isolated from control and 4-week TAA mice. The effects of PKC-mediated phosphorylation on MT1-MMP cellular localization and function (active MMP-2 vs phospo-Smad2 abundance) were assessed after treatment with a PKC activator (phorbol-12-myristate-13-acetate [PMA], 100 nM) with and without a PKC-δ-specific inhibitor (röttlerin, 3 μM).
Compared with controls, MT1-MMP abundance was increased in aortas from both TAA groups. Active MMP-2 was increased only in the large TAA group. The abundances of phosphorylated MT1-MMP and activated PKC-δ were enhanced in the small TAA group compared with the large TAA group. MT1-MMP was localized on the plasma membrane in aortic fibroblasts from control mice and in endosomes from TAA mice. Treatment with PMA induced MT1-MMP-GFP internalization, enhanced phospho-Smad2, and reduced MMP-2 activation, whereas röttlerin pretreatment inhibited these effects.
Phosphorylation of MT1-MMP mediates its activity through directing cellular localization, shifting its role from MMP-2 activation to intracellular signaling. Thus, targeted inhibition of MT1-MMP may have therapeutic relevance as an approach to attenuating TAA development.
Acacia ataxacantha (Fabaceae), used in traditional medicine grows in the South-West of Bénin. Ethyl acetate extract of the barks of this species was previously reported to display various bioactivities, including antibacterial, antifungal and antioxidant activities. In the present study, we investigate the antimicrobial and antioxidant activities of compound isolated from ethyl acetate extract of Acacia ataxacantha.
Purification, isolation and structural identification of isolated compound were done using various chromatographic and spectroscopic methods. Antimicrobial activity was investigated using a two-fold serial microdilution method. The inhibitory potency of isolated compound was evaluated by kinetic experiments. The antioxidant activity was also determined using 2, 2-diphenyl-1-picrylhydrazyl.
The isolated compound was identified as 7-hydroxy-2-methyl-6-[β-galactopyranosyl-propyl]-4H-chromen-4-one. As far as we know, this compound, named "acthaside", reported for the first time, was active against all tested microorganisms with minimal inhibitory concentration ranging from 25 to 50 μg/ml. At 50 μl/ml, no growth was observed in almost all tested microbial after 24 h of exposure. The isolated compound had significant antioxidant activity with an IC50 value of 3.61 ± 0.12 μg/ml compared to quercetin (IC50 1.04 ± 0.01 μg/ml).
The present work demonstrates that the new chromen derivative isolated from A. ataxacantha may help treat bacterial and yeast infections. However, further studies are required to clarify the mechanism of action of this compound.
To systematically review the impact of Yasmin (drospirenone pill) compares with other standard treatments for symptoms of Polycystic Ovary Syndrome (PCOS).
The relevant studies of the randomized controlled trials in women with PCOS treated with drospirenone were retrieved and the systematic evaluation was conducted.
Eighteen articles were included. Compared with drospirenone (DRSP) monotherapy, DRSP plus metformin was better in reducing body mass index (BMI), luteinizing hormone (LH) and low-density lipoprotein cholesterol (LDL-C). Compared with metformin, DRSP was better in modulating serum total testosterone (T), sex hormone-binding globulin (SHBG), follicle stimulating hormone (FSH) and free androgen index (FAI), while metformin was more effective in reducing BMI, total cholesterol (TC), LDL-C and Triglyceride (TG). DRSP was superior to cyproterone acetate (CPA) in reducing TC and homeostasis model assessment of insulin resistance (HOMA-IR). DRSP shows better effect in modulating LDL-C and high-density lipoprotein cholesterol (HDL-C) compared with desogestrel (DSG).
The available data suggested that DRSP was effective in modulating hormones, insulin and lipid metabolism in women with PCOS. Compared with commonly used drugs for symptoms of PCOS as CPA and DSG, DRSP shows identical or better effect in improving symptoms and protect cardiovascular system. For the PCOS patients with IR, obesity or high LH/FSH ratio, DRSP combines with metformin maybe more effective than use DRSP alone.
Patients with implanted continuous, non-pulsatile, left ventricular assist devices (LVADs) have increased occurrence of gastrointestinal bleeding (GIB). While the pathophysiology is multifactorial, there are few treatments beyond supportive care. Octreotide acetate is a somatostatin analog that reduces GIB in various patient populations. However, there are sparse case-series that suggest octreotide acetate may reduce GIB in LVAD patients. This 10 patient, 28-week Phase I study evaluated the safety and tolerability of octreotide acetate long-acting release (LAR) 20 mg depot injection every four weeks until week 16 following LVAD placement. Secondary aims were occurrence of GIB, and measurement of vascular endothelial growth factor (VEGF), fibrinogen, von Willebrand factor, and platelet aggregation across the study period. Ten patients were enrolled, and eight completed the study. The two study dropouts were not related to octreotide. None of the patients experienced side effects or safety concerns related to octreotide, nor did GIB occur in the study population. VEGF levels were maintained in the reference range throughout the duration of the study. There did appear to be laboratory evidence of acquired von Willebrand syndrome, with mildly low platelet aggregation studies. In conclusion, octreotide acetate LAR 20 mg depot injection was safe and effective in this population.
The serum protein histidine-rich glycoprotein (HRG) has been implicated in tissue injury and tumour growth. Several HRG functions are regulated by the divalent metal Zn(2+) , including ligand binding and proteolytic processing that releases active HRG fragments. Although HRG can bind divalent metals other than Zn(2+) , the impact of these divalent metals on the biophysical properties of HRG remains poorly understood. We now show that HRG binds Zn(2+) , Ni(2+) , Cu(2+) and Co(2+) with micromolar affinities, but differing stoichiometries, and regulate the release of specific HRG fragments during proteolysis. Furthermore, HRG binding to Zn(2+) promotes HRG dimer formation in a Zn(2+) -concentration- and pH- dependent manner. Our data highlight the complex divalent metal-dependent regulatory mechanisms that govern HRG function. This article is protected by copyright. All rights reserved.
Although stinging nettle (Urtica dioica) has been shown to reduce HM (heavy metal) content in soil, its wider phytoremediation potential has been neglected. Urtica dioica was cultivated in soils contaminated with HMs or polychlorinated biphenyls (PCBs). After four months, up to 33% of the less chlorinated biphenyls and 8% of HMs (Zn, Pb, Cd) had been removed. Bacteria were isolated from the plant tissue, with the endophytic bacteria Bacillus shackletonii and Streptomyces badius shown to have the most significant effect. These bacteria demonstrated not only benefits for plant growth, but also extreme tolerance to As, Zn and Pb. Despite these results, the native phytoremediation potential of nettles could be improved by biotechnologies. Transient expression was used to investigate the functionality of the most common constitutive promoter, CaMV 35S in Urtica dioica. This showed the expression of the CUP and bphC transgenes. Collectively, our findings suggest that remediation by stinging nettle could have a much wider range of applications than previously thought.
Intron lariats are circular, branched RNAs (bRNAs) produced during pre-mRNA splicing. Their unusual chemical and topological properties arise from branch-point nucleotides harboring vicinal 2',5'- and 3',5'-phosphodiester linkages. The 2',5'-bonds must be hydrolyzed by the RNA debranching enzyme Dbr1 before spliced introns can be degraded or processed into small nucleolar RNA and microRNA derived from intronic RNA. Here, we measure the activity of Dbr1 from Entamoeba histolytica by using a synthetic, dark-quenched bRNA substrate that fluoresces upon hydrolysis. Purified enzyme contains nearly stoichiometric equivalents of Fe and Zn per polypeptide and demonstrates turnover rates of ∼3 s(-1) Similar rates are observed when apo-Dbr1 is reconstituted with Fe(II)+Zn(II) under aerobic conditions. Under anaerobic conditions, a rate of ∼4.0 s(-1) is observed when apoenzyme is reconstituted with Fe(II). In contrast, apo-Dbr1 reconstituted with Mn(II) or Fe(II) under aerobic conditions is inactive. Diffraction data from crystals of purified enzyme using X-rays tuned to the Fe absorption edge show Fe partitions primarily
 to the β-pocket and Zn to the α-pocket. Structures of the catalytic mutant H91A in complex with 7-mer and 16-mer synthetic bRNAs reveal bona fide RNA branchpoints in the Dbr1 active site. A bridging hydroxide is in optimal position for nucleophilic attack of the scissile phosphate. The results clarify uncertainties regarding structure/function relationships in Dbr1 enzymes, and the fluorogenic probe permits high-throughput screening for inhibitors that may hold promise as treatments for retroviral infections and neurodegenerative disease.
Poplar clones were studied for their phytoextraction capacity in the second growth cycle (6 growth years) on a site in the Belgian Campine region which is contaminated with Cd and Zn via historic atmospheric deposition of nearby zinc smelter activities. The field trial revealed regrowth problems for some clone that could not be predicted in the first growth cycle. Four allometric relations were assessed for their capacity to predict biomass yield in the second growth cycle. A power function based on the shootdiameter best estimate the biomass production of poplar with R² values between 0.94 and 0.98. The woody biomass yield ranged from 2.1 to 4.8 ton woody DM ha(-1) y(-1). The primary goal was to reduce soil concentrations of metals caused by phytoextraction. Nevertheless increased metal concentrations were determined in the topsoil. This increase can partially be explained by the input of metals from deeper soil layers in the top soil through litter fall. The phytoextraction option with poplar short rotation coppice in this setup did not lead to the intended soil remediation in a reasonable time span. Therefore, harvest of the leaf biomass is put forward as a crucial part of the strategy for soil remediation through Cd/Zn phytoextraction.
Four coordination polymers, formulated as [Zn(L(1))2]n (1), [Cd(L(1))2]n (2), [Zn(L(2))2]n (3) and [Cd(L(2))2]n (4) (HL1 is (E)-2-(((4H-1,2,4-triazol-4-yl)imino)methyl)-4,6-dibromophenol; HL2 is (E)-2-(((4H-1,2,4-triazol-4-yl)imino)methyl)-4,6-dichlorophenol) have been synthesized through vial reactions. The four compounds were structurally characterized by single crystal X-ray diffraction, elemental analysis, PXRD, and fluorescence spectroscopy. For 1-4, a detailed analysis of Hirshfeld surfaces and fingerprint plots facilitates a comparison of intermolecular interactions, which are crucial in building different supramolecular architectures. C-HX (X = Br, Cl) interactions play a crucial role in stabilizing the self-assembly process among adjacent 2-D networks for both complexes. Above all, complexes 1-4 showed highly intense electrochemical luminescence (ECL) in DMF solution and high thermal stability.
Drinking water treatment residue (DWTR), a byproduct generated during potable water production, exhibits a high potential for recycling to control eutrophication. However, this beneficial recycling is hampered by unclear metal/metalloid pollution risks related to DWTR. In this study, the pollution risks of Al, As, Ba, Be, Cd, Co, Cr, Cu, Fe, Mn, Mo, Ni, Pb, and Zn due to DWTR application were first evaluated for lake water based on human health risk assessment models and comparison of regulatory standards. The risks of DWTR were also evaluated for sediments on the basis of toxicity characteristics leaching procedure and fractionation in relation to risk assessment code. Variations in the biological behaviors of metal/metalloid in sediments caused by DWTR were assessed using Chironomus plumosus larvae and Hydrilla verticillata. Kinetic luminescent bacteria test (using Aliivibrio fischeri) was conducted to analyze the possibility of acute and chronic detrimental effects of sediment with DWTR application. According to the obtained results, we identify a potential undesirable effect of DWTR related to Fe and Mn (typically under anaerobic conditions); roughly present a dosage threshold calculation model; and recommend a procedure for DWTR prescreening to ensure safe application. Overall, managed DWTR application is necessary for successful eutrophication control.
In this work, we characterized different phtalocyanine-capped core/shell/shell quantum dots (QDs) in terms of stability, ζ-potential, and size at various pH and ionic strengths, by means of capillary electrophoresis (CE), and compared these results to the ones obtained by laser Doppler electrophoresis (LDE) and dynamic light scattering (DLS). The effect of the phthalocyanine metallic center (Zn, Al, or In), the number (one or four), and nature of substituents (carboxyphenoxy- or sulfonated-) of functionalization on the phthalocyanine physicochemical properties were evaluated. Whereas QDs capped with zinc mono-carboxyphenoxy-phtalocyanine (ZnMCPPc-QDs) remained aggregated in the whole analyzed pH range, even at low ionic strength, QDs capped with zinc tetracarboxyphenoxy phtalocyanine (ZnTPPc-QDs) were easily dispersed in buffers at pH equal to or higher than 7.4. QDs capped with aluminum tetrasulfonated phthalocyanine (AlTSPPc-QDs) and indium tetracarboxyphenoxy phthalocyanines (InTCPPc-QDs) were stable in aqueous suspension only at pH higher than 9.0 due to the presence of functional groups bound to the metallic center of the phthalocyanine. The ζ-potential values determined by CE for all the samples decreased when ionic strength increased, being well correlated with the aggregation of the nanoconjugates at elevated salt concentrations. The use of electrokinetic methodologies has provided insights into the colloidal stability of the photosensitizer-functionalized QDs in physiological relevant solutions and thereby, its usefulness for improving their design and applications for photodynamic therapy. Graphical Abstract Schematic illustration of the phthalocyanine capped QDs nanoconjugates and the capillary electrophoresis methods applied for size and ζ-potential characterization.
Porphyrin-based photosynthetic reaction centre (PRC) mimics, ZnPQ-Q2HP-C60 and MP2Q-Q2HP-C60 (M = Zn or 2H), designed to have a similar special-pair electron donor and similar charge-separation distances, redox processes and photochemical reaction rates to those in the natural PRC from purple bacteria, have been synthesised and extensive photochemical studies performed. Mechanisms of electron-transfer reactions are fully investigated using femtosecond and nanosecond transient absorption spectroscopy. In benzonitrile, all models show picosecond-timescale charge-separations and the final singlet charge-separations with the microsecond-timescale. The established lifetimes are long compared to other processes in organic solar cells or other organic light harvesting systems. These rigid, synthetically flexible molecules provide the closest mimics to the natural PRC so far synthesised and present a future direction for the design of light harvesters with controllable absorption, redox, and kinetics properties.
In this study, we conducted a comprehensive survey to assess the possible sources and distribution of metals in the agricultural soils of Guanzhong Plain, northwest China. A total of 227 samples of agricultural soil were collected to determine the content of Pb, Cr, Co, V, Ni, Zn, Cu, As and Mn by X-ray fluorescence spectrometry. The mean concentrations of metals were 26.2 ± 10.8 mg · kg(-1) , 71.5 ± 16.8 mg · kg(-1) , 12.7 ± 1.81 mg · kg(-1) , 85.1 ± 7.86 mg · kg(-1) , 30.5 ± 6.17 mg · kg(-1) , 71.1 ± 14.1 mg · kg(-1) , 25.2 ± 5.58 mg · kg(-1) , 12.5 ± 1.94 mg · kg(-1) and 635.4 ± 84.7 mg · kg(-1) for Pb, Cr, Co, V, Ni, Zn, Cu, As and Mn, respectively, slightly higher than the regional background values. We used multivariate analysis to identify the metal sources and found that Ni and Cr in the agricultural soils were mainly derived from lithological materials and Pb, Zn and Cu were mainly from traffic emissions; however, Zn and Cu also originated from mineral fertilizers or pesticides. The other metals originated from industrial emissions. We applied the Nemerow index coupled with geographic information system technology to assess the degree and spatial distribution of metal contamination and found that the studied soils were classified as slightly polluted and the most contaminated regions were concentrated in the area surrounding Xi'an city, as well as areas in the southeast and north of the Guanzhong Plain. This article is protected by copyright. All rights reserved.
Fifty-seven samples of soils commonly ingested in South Africa, Swaziland, Democratic Republic of Congo (DRC), and Togo were analyzed for the concentrations of arsenic (As), cadmium (Cd), cobalt (Co), chromium (Cr), copper (Cu), lead (Pb), manganese (Mn), nickel (Ni), and zinc (Zn) and their bioaccessibility in the human gastrointestinal tract. Bioaccessibility values were used to calculate daily intake, and hazard quotient of each trace element, and chronic hazard index (CHI) of each sample. Carcinogenic risk associated with As and Ni exposure were also calculated. Mean pseudo-total concentrations of trace elements in all samples were 7.2, 83.3, 77.1, 15.4, 28.6, 24.9, 56.1, 2.8, and 26.5 mg/kg for As, Cr, Mn, Co, Ni, Cu, Zn, Cd, and Pb, respectively. Percent bioaccessibility of Pb (13-49%) and Zn (38-56%) were highest among trace elements studied. Average daily intake values were lower than their respective reference doses for ell elements except for Pb in selected samples. Samples from DRC presented the highest health risks associated with trace element exposure with most of the samples having CHI values between 0.5 and 1.0. Some samples had higher than unacceptable values of carcinogenic risk associated with As and Ni exposure. Results indicate low trace element exposure risk from ingesting most of the soil samples.Journal of Exposure Science and Environmental Epidemiology advance online publication, 7 December 2016; doi:10.1038/jes.2016.67.
Given
 the many roles proposed for Mg(2+) in nucleic acids, it is essential to accurately determine their binding modes. Here, we surveyed the PDB to classify Mg(2+) inner-sphere binding patterns to nucleobase imine N1/N3/N7 atoms. Among those, purine N7 atoms are considered to be the best nucleobase binding sites for divalent metals. Further, Mg(2+) coordination to N7 has been implied in several ribozyme catalytic mechanisms. We report that Mg(2+) assigned near imine nitrogens derive mostly from poor interpretations of electron density patterns and are most often misidentified Na(+), K(+), NH4(+) ions, water molecules or spurious density peaks. Consequently, apart from few documented exceptions, Mg(2+) ions do not bind to N7 atoms. Without much of a surprise, Mn(2+), Zn(2+) and Cd(2+), which have a higher affinity for nitrogens, may contact N7 atoms when present in crystallization buffers. In this respect, we describe for the first time a potential Zn(2+) ribosomal binding site involving two purine N7 atoms. Further, we provide a set of guidelines to help in the assignment of Mg(2+) in crystallographic, cryo-EM, NMR and model building practices and discuss implications of our findings related to ion substitution experiments.
The energetics and the impact on the conformation of heme containing protein myoglobin (Mb) due to the binding of three transition metal ions (Zn(2+), Ni(2+), and Mn(2+)) have been investigated using isothermal titration calorimetry (ITC), dynamic light scattering (DLS), UV-vis, and circular dichroism (CD) spectroscopy under physiological conditions. The binding affinity of the order of 10(4)M(-1) has been observed for all metal ions from calorimetry as well as from absorption spectroscopy. The binding of these metal ions with Mb is a spontaneous process that exposes the hydrophobic groups away from the protein core as exhibited by the negative Gibbs free energy change (ΔG) and positive heat capacity change (ΔCp) values. Both light scattering and CD results demonstrates that the binding of Zn(2+) and Mn(2+) ions with Mb results in the folding whereas Ni(2+) ion results in the unfolding of the protein. No direct interactions among the transition metal ions and heme moiety of Mb has been observed from absorption study. The results of these studies reveals that Mn(2+) ion influences the biological functions of Mb to a larger extent in spite of its lowest affinity followed by Zn(2+) and Ni(2+) ions.
The nanocomposites based on copper, zinc and nickel were loaded on activated carbon (Cu-Zn-Ni-NPs-AC) and cobalt and nickel nanoparticles was loaded on γ-alumina (Ni-Co-NPs-γAl2O3) and applied for removal of hydrogen sulfide (H2S) from natural gas and their efficiency were compared. Cu-Zn-Ni/AC and Ni-Co/γ-Al2O3 was characterized using different techniques such as energy-dispersive X-ray spectroscopy (EDX), X-ray diffraction (XRD) and field emission scanning electron microscopy (FE-SEM). The effects of variables such as amount of adsorbent, flow rate, temperature, pressure and volume of gas on H2S removal were examined and optimum values were found to be 0.3g adsorbent, and flow rate of 0.15L/min and 15°C and 7Psi for both adsorbent and also 5.5 and 6.5L of sample by Cu-Zn-Ni/C and Co-Ni/γ-Al2O3, respectively. Setting conditions at the above optimum conditions lead to achievement of maximum removal of H2S (94% and 91.6%) by Cu-Zn-Ni/AC and Co-Ni/γ-Al2O3. The negative value of ΔG° and its numerical value confirm physisorption nature of adsorption. The experimental equilibrium data with high efficiency were explained and represented by Langmuir model for both adsorbents with the highest correlation coefficients.
Collismycin A (CMA), a microbial product, has anti-proliferative activity against cancer cells, but the mechanism of its action remains unknown. Here, we report the identification of the molecular target of CMA by ChemProteoBase, a proteome-based approach for drug target identification. ChemProteoBase profiling showed that CMA is closely clustered with di-2-pyridylketone 4,4-dimethyl-3-thiosemicarbazone, an iron chelator. CMA bound to both Fe(II) and Fe(III) ions and formed a 2:1 chelator-iron complex with a redox-inactive center. CMA-induced cell growth inhibition was completely canceled by Fe(II) and Fe(III) ions, but not by other metal ions such as Zn(II) or Cu(II). Proteomic and transcriptomic analyses showed that CMA affects the glycolytic pathway due to the accumulation of HIF-1α. These results suggest that CMA acts as a specific iron chelator, leading to the inhibition of cancer cell growth.
to assess concentration levels of dioxins, PCBs, and chemical elements in sheep milk produced in areas close to the Italian contaminated site (CS) located in the North-West of Sardinia (Southern Italy), named «Aree industriali di Porto Torres e discarica di Calancoi» (i.e., industrial areas of Porto Torres and landfill of Calancoi).
monitoring plan of environmental contaminants on zootechnical productions based on analysis of dioxins, PCBs, heavy metals (Cd, Hg, Pb), and other elements (As, Be, Cr, Ni, Tl , Zn) in sheep bulk milk.
60 samples of sheep bulk milk were collected in rural farms where animals were fed mainly with forage and feed produced in the CS: 30 samples from farms located near the industrial area of Porto Torres and 30 taken from farms spread out the landfill area of Calancoi, a former waste dump in the East of Sassari city.
the concentration levels of target substances were determined and compared to legal thresholds fixed on EU regulations.
concentrations of target substances in all samples were below the maximum limits set by EU regulations. Dioxins and DL-PCBs (expressed as the sum) were in the range 0.20-1.30 pg WHO-TEQ/g fat, NDL-PCB (sum of the six marker congeners) were in the range 0.50-7.50 ng/g, while concentrations of all heavy metals were not detectable or were near the limit of quantitation of the method. Undetectable concentrations were also observed for the toxic elements beryllium and thallium.
concentration levels of micro-pollutants in milk samples were significantly lower than the legal thresholds. Concentrations and congener profiles showed no relevant differences compared to milk samples from areas with low environmental impact, therefore consumption of milk from the studied area do not produce a higher intake of contaminants respect to the regional milk. The results of this study do not make the resident population safe from health risks caused by critical issue of the CS, but provide information limited to the safety of the milk from these areas, without showing peculiar contamination and hazard for food from local sheep farms.
In this work, chitosan (CS) functionalized polyaniline-polypyrrole (Pani-Ppy) copolymer (CS/Pani-Ppy) was synthesized applying a facile one pot method for the enhanced adsorption of Zn(II) and antimicrobial activity for E. coli and E. agglomerans. The synthesized materials were characterized using scanning electron microscopy, energy dispersive X-ray spectroscopy, Fourier transform inferred spectroscopy and X-ray photoelectron spectroscopy. The adsorption of the Zn(II) on the synthesized materials was highly dependent on the pH of the solution, the initial metal ion concentration, and temperature. The adsorption of Zn(II) on the studied materials was as follows: CS/Pani-Ppy>Pani-Ppy>Ppy>Pani>CS. The results reveal that adsorption of Zn(II) follows the Langmuir adsorption isotherm, and that chemisorption occurs through pendant and bridging interactions, with active adsorbent sites. Thermodynamic results show the adsorption is spontaneous and exothermic in nature. The synthesized materials show excellent antimicrobial activity against E. coli and E. agglomerans bacterial organisms, and an approximately 100% decline in the viability of both strains was observed with CS/Pani-Ppy and Pani-Ppy. The order of antimicrobial activity for the synthesized materials was as follows: CS/Ppy-Pani>Ppy-Pani>Ppy>Pani>CS. The results show that the greater activity of CS/Ppy-Pani resulted from the electrostatic interaction between positively charged amine groups and negatively charged bacteria.
The presence of emergent antibiotics, in livestock wastewater may affect constructed wetlands (CWs) performance in the removal of other pollutants. The main objective of this study was to evaluate the influence of two antibiotics commonly used in livestock industry, enrofloxacin and ceftiofur, on metal removal by CWs. Microcosms (0.4m×0.3m×0.3m), simulating CWs, were constructed with Phragmites australis to treat livestock wastewater spiked or not with 100µg/L of enrofloxacin or ceftiofur (individually or in mixture). Wastewater was treated during 20 one-week cycles. After one-week cycle wastewater was removed and replaced by new wastewater (with or without spiking). At weeks 1, 2, 4, 8, 14, 18 and 20, treated wastewater was analysed to determine the removal rates of metals (Zn, Cu, Fe and Mn) and of each antibiotic. At weeks 1, 8 and 20 portions of the plant root substrate were collected and metals determined. At the end of the experiment metal levels were also determined in plant tissues. Removal rate of Fe from wastewater was 99%. Removal rates of Cu and Zn were higher than 85% and 89%, respectively, whereas for Mn removal rates up to 75% were obtained. In general, no significant differences were observed through time in the removals of the different metals, indicating that the systems maintained their functionality during the experimental period. Antibiotics did not interfere with the system depuration capacity, in terms of metals removals from wastewater, and ceftiofur even promoted metal uptake by P. australis. Therefore, CWs seem to be a valuable alternative to remove pollutants, including antibiotics and metals, from livestock wastewaters, reducing the risk the release
 of these wastewaters might pose into the environment, although more research should be conducted with other antibiotics in CWs.
The metallothionein 1 (MT1) coding sequence of red deer was identified and compared to orthologous sequences from other mammals. Over 90% identity was observed between red deer MT1 amino acid sequence and MT1 sequences of other ruminants. Liver and kidney samples of red deer were collected from the industrial zinc smelting site of Miasteczko Slaskie and from the Masuria Lake District serving as a pollution-free control site. The concentrations of cadmium (Cd), lead (Pb), copper (Cu) and zinc (Zn) were analyzed by the atomic absorption spectrometry technique (AAS). The levels of Cd in the liver of red deer from the metal smelting region was about 8 times higher than for the reference control site. Next, the expression of MT1 mRNA in the liver of red deer was quantified by the reverse transcription-quantitative polymerase chain reaction (RT-qPCR) and the expression of MT1/2 protein in the liver and kidneys was analyzed by immunohistochemistry. Positive correlations were found between expression levels for MT1 mRNA and the concentrations of Cu and Zn in liver of red deer, and with the age of animals. Immunohistochemical staining demonstrated the nuclear and cytoplasmatic expression in both liver and kidney tissues, but with no obvious relationship shown for the expression of MT1/2 protein and tissue metal levels. Our results showed that the analysis of MT expression levels in the red deer could not be used independently as a biomarker for identifying exposure to Cd, but could be co-analyzed with tissue metal levels to give better prognosis for environmental exposure to metals.
Recently, enormous research passion has been devoted to enhance the power conversion efficiency (PCE) of porphyrin sensitizers for DSSCs, but the major stumbling block is its absorption defects in visible spectrum region. To address the challenge, herein we reported a duplexing high performance photovoltaic result for DSSCs based on a novel D-π-A sensitizer FW-1 7H-Dibenzo[c,g] carbazole-substituted and fused Zn-porphyrin, co-sensitized with benzotriazole featured dye (WS-5) in iodine and cobalt redox system and got high PCE of 10.21% and 10.42%, respectively. An unprecedented breakthrough was got for supplying the gap of one sensitizer suitable for more electrolyte systems due to the appropriate molecular orbitals and co-sensitizer.
Five copper zinc thiolate complexes [(iPr3PCu)2(ZnEt2)(edt)]2 (1-Et), [(iPr3PCu)2(Zn(iPr)2)(edt)]2 (1-iPr), [(iPr3PCu)4(edt)2(ZnMe2)]2 (2), [(iPr3PCu)3(ZnPh2)(ZnPh)(edt)2]2 (3) and [(iPr3PCu)2Zn2(edt)3]6 (4) were prepared by the reaction of [(iPr3PCu)2(edt)]2 with ZnR2 (R = Me, Et, Ph, iPr) with or without addition of ethanedithiol (edt2- = ethane-1,2-dithiolate). The molecular structures of these complexes were determined by single crystal X-ray diffraction. The ethanedithiolate ligands coordinate in µ3-eta1:eta2:eta1 (2, 4), µ4-eta1:eta1:eta2:eta1 (1-R, 3) and µ5-eta1:eta1:eta2:eta1:eta1 (2) bridging mode, each sulfur atom binds to two or three metal atoms. Evidence for the presence of the weak Zn-S bonds in solution is provided by NMR spectroscopy. Mixtures of 1-Et, 1-iPr or 3, respectively, with Sn(edt)2 were examined by thermogravimetry up to 600 °C, volatile thermolysis products were identified by mass spectrometry. In all thermolysis experiments the formation of Cu2ZnSnS4 as main product besides small amounts of binary metal sulfides is confirmed by X-ray powder diffraction (PXRD) and EDX (energy dispersive X-ray spectroscopy) analysis.
The synthesis of coordination polymers or metal-organic frameworks (MOFs) has attracted considerable interest owing to the interesting structures and potential applications of these compounds. It is still a challenge to predict the exact structures and compositions of the final products. A new one-dimensional coordination polymer, catena-poly[[[bis{1-[(1H-benzimidazol-2-yl)methyl]-1H-tetrazole-κN(3)}zinc(II)]-μ-hexane-1,6-dicarboxylato-κ(4)O(1),O(1'):O(6),O(6')] monohydrate], {[Zn(C6H8O4)(C9H8N6)2]·H2O}n, has been synthesized by the reaction of Zn(Ac)2 (Ac is acetate) with 1-[(1H-benzimidazol-2-yl)methyl]-1H-tetrazole (bimt) and adipic acid (H2adi) at room temperature. In the polymer, each Zn(II) ion exhibits an irregular octahedral ZnN2O4 coordination geometry and is coordinated by two N atoms from two symmetry-related bimt ligands and four O atoms from two symmetry-related dianionic adipate ligands. Zn(II) ions are connected by adipate ligands into a one-dimensional chain which runs parallel to the c axis. The bimt ligands coordinate to the Zn(II) ions in a monodentate mode on both sides of the main chain. In the crystal, the one-dimensional chains are further connected through N-H...O hydrogen bonds, leading to a three-dimensional supramolecular architecture. In addition, the title polymer exhibits fluorescence, with emissions at 334 and 350 nm in the solid state at room temperature.
One of most interesting systems of coordination polymers constructed from the first-row transition metals is the porous Zn(II) coordination polymer system, but the numbers of such polymers containing N-donor linkers are still limited. The title double-chain-like Zn(II) coordination polymer, [Ag2Zn(CN)4(C10H10N2)2]n, presents a one-dimensional linear coordination polymer structure in which Zn(II) ions are linked by bridging anionic dicyanidoargentate(I) units along the crystallographic b axis and each Zn(II) ion is additionally coordinated by a terminal dicyanidoargentate(I) unit and two terminal 1-benzyl-1H-imidazole (BZI) ligands, giving a five-coordinated Zn(II) ion. Interestingly, there are strong intermolecular Ag(I)...Ag(I) interactions between terminal and bridging dicyanidoargentate(I) units and C-H...π interactions between the phenyl rings of BZI ligands of adjacent one-dimensional linear chains, providing a one-dimensional linear double-chain-like structure. The supramolecular three-dimensional framework is stabilized by C-H...π interactions between the phenyl rings of BZI ligands and by Ag(I)...Ag(I) interactions between adjacent double chains. The photoluminescence properties have been studied.
The relationship between essential trace metals (ETMs) and the risk of neural tube defects (NTDs) is still unclear. One of the challenges is to evaluate the intake of ETMs of women during their early period of pregnancy. We proposed the hypothesis that an ETM deficiency in women during their early period of pregnancy is associated with an elevated risk of NTDs in offspring.
We recruited 191 women with NTD-affected pregnancies (case group) and 261 women who delivered healthy infants (control group). Nine ETMs in hair sections grown during maternal early pregnancy were analyzed: iron (Fe), zinc (Zn), copper (Cu), cobalt (Co), manganese (Mn), chromium (Cr), nickel (Ni), molybdenum (Mo), and stannum (Sn). Information on maternal dietary habits were collected by questionnaire.
We observed a significant decreasing trend in the dose-response relationships between the Ni and Mo concentrations in hair and NTD risks. A Zn deficiency was only associated with an elevated risk of spina bifida, and a Sn deficiency was only associated with anencephaly. The Ni and Zn concentrations in hair were positively correlated with the frequency of consumption of fresh green vegetables and fresh fruits, while the Zn concentration was also associated with fish or meat consumption.
We concluded that maternal intakes of the four ETMs (Ni, Mo, Zn, and Sn) played an important role in the formation of NTDs in our study population, and that this intake is related to maternal dietary habits.Birth Defects Research (Part A), 2016.© 2016 Wiley Periodicals, Inc.
Nitric oxide (NO) is both an important regulatory molecule in biological systems and a toxic xenobiotic. Its oxidation products react with sulfhydryl groups and either nitrosylate or oxidize them. The aerobic reaction of NO supplied by diethylamine NONOate (DEA-NO) with pig kidney LLC-PK1 cells and Zn-proteins within the isolated proteome was examined with three fluorescent zinc sensors, zinquin (ZQ), TSQ, and FluoZin-3 (FZ-3). Observations of Zn(2+) labilization from Zn-proteins depended on the specific sensor used. Upon cellular exposure to DEA-NO, ZQ sequestered about 13% of the proteomic Zn(2+) as Zn(ZQ)2 and additional Zn(2+) as proteome·Zn-ZQ ternary complexes. TSQ, a sensor structurally related to ZQ with lower affinity for Zn(2+), did not form Zn(TSQ)2. Instead, Zn(2+) mobilized by DEA-NO was exclusively bound as proteome·Zn-TSQ adducts. Analogous reactions of proteome with ZQ or TSQ in vitro displayed qualitatively similar products. Titration of native proteome with Zn(2+) in the presence of ZQ resulted in the sole formation of proteome·Zn-ZQ species. This result suggested that sulfhydryl groups are involved in non-specific proteomic binding of mobile Zn(2+) and that the appearance of Zn(ZQ)2 after exposure of cells and proteome to DEA-NO resulted from a reduction in proteomic sulfhydryl ligands, favoring the formation of Zn(ZQ)2 instead of proteome·Zn-ZQ. With the third sensor, FluoZin-3, neither Zn-FZ-3 nor proteome·Zn-FZ-3 was detected during the reaction of proteome with DEA-NO. Instead, it reacted independently with DEA-NO with a modest enhancement of fluorescence.
To formulate age- and context-specific complementary feeding recommendations (CFR) for infants and young children (IYC) and to compare the potential of filling population-level nutrient gaps using common sets of CFR across age groups.
Linear programming was used to develop CFR using locally available and acceptable foods based on livelihood- and age-group-specific dietary patterns observed through 24 h dietary recalls. Within each livelihood group, the nutrient potential
 of age-group-specific v. consolidated CFR across the three age groups was tested.
Three food-insecure counties in northern Kenya; namely, settled communities from Isiolo (n 300), pastoralist communities from Marsabit (n 283) and agro-pastoralist communities from Turkana (n 299).
Breast-fed IYC aged 6-23 months (n 882).
Age-specific CFR could achieve adequacy for seven to nine of eleven modelled micronutrients, except among 12-23-month-old children in agro-pastoralist communities. Contribution of Fe, Zn and niacin remained low for most groups, and thiamin, vitamin B6 and folate for some groups. Age-group-consolidated CFR could not reach the same level of nutrient adequacy as age-specific sets among the settled and pastoralist communities.
Context- and age-specific CFR could ensure adequate levels of more modelled nutrients among settled and pastoralist IYC than among agro-pastoralist communities where use of nutrient-dense foods was limited. Adequacy of all eleven modelled micronutrients was not achievable and additional approaches to ensure adequate diets are required. Consolidated messages should be easier to implement as part of a behaviour change strategy; however, they would likely not achieve the same improvements in population-level dietary adequacy as age-specific CFR.
In this paper, a simple and highly sensitive spectrofluorimetric method was developed and validated for the determination of entacapone (ETC). The proposed method is based on forming a highly fluorescent product through the reduction of ETC with Zn/HCl. The produced fluorophore exhibits strong fluorescence at λem 345 nm after excitation at λex 240 nm. The use of fluorescence enhancers such as Tween-80 and carboxy methyl cellulose (CMC) greatly enhanced the fluorescence of the produced fluorophore by 150% and 200%, respectively. Calibration curves showed good linear regression (r2 > 0.9998) within test ranges of 0.05-2.0 and 0.02-1.80 μg mL(-1) with lower detection limits of 1.27 × 10(-2) and 4.8 × 10(-3)  μg mL(-1) and lower quantification limits of 4.21 × 10(-2) and 1.61 × 10(-2)  μg mL(-1) upon using Tween-80 and or CMC, respectively. The method was successfully applied to the analysis of ETC in its pharmaceutical formulations (either alone or in presence of other co-formulated drugs). The results were in good agreement with those obtained using the official method. The methods were further extended to determine the drug in human plasma samples, and to study the pharmacokinetics of ETC. The paper is the first report on the spectrofluorimetric determination of entacapone.
The integral synaptic vesicle protein SV31 has been shown to bind divalent cations. Here, we demonstrate that SV31 protein synthesized within a cell-free system binds Zn(2+) and to a lower extent Ni(2+) and Cu(2+) ions. Expression with Zn(2+) stabilized the protein and increased solubility. SV31 was preferentially monomeric in detergent and revealed specific binding of Zn(2+) . When co-translationally inserted into defined nanodisc bilayers, SV31 assembled into dimeric complexes, resulting in increased binding of Zn(2+) . Putative Zn(2+) -binding motifs within SV31 comprise aspartic acid and histidine residues. Site-directed mutagenesis of two conserved aspartic acid residues leads to a potent decrease in Zn(2+) binding but did not affect dimerization. Chemical modification of histidine residues abolished some of the Zn(2+) -binding capacity. We demonstrate proton-dependent transport of Zn(2+) as by accumulation of fluorescent FluoZin-1 inside of SV31-containing proteoliposomes. Transport activity has a Km value of 44.3 μM and required external Zn(2+) and internal acidic pH. Our results demonstrate that the synaptic vesicle-integral protein SV31 functions as a proton-dependent Zn(2+) transporter. SV31 may attribute specific and yet undiscovered functions to subsets of synapses.
In the expanding field of anticancer drugs, HDAC inhibitors are playing an increasingly important role. To date, four/five HDAC inhibitors have been approved by FDA. All these compounds fit the widely accepted HDAC inhibitors pharmacophore model characterized by a cap group, a linker chain and a zinc binding group (ZBG), able to bind the Zn(2+) ion in a pocket of the HDAC active site. Romidepsin, a natural compound, is the only thiol derivative. We have selected a new class of synthetic HDAC inhibitors, the thio-ω(lactam-carboxamide) derivatives, with ST7612AA1 as drug candidate, pan-inhibitor active in the range of single- to two-digit nanomolar concentrations. Preliminary results of a synthetic optimization attempt towards a fast scale-up process are here proposed.
In the four steps of synthesis, from unsaturated amino acid intermediate to the final product, we explored different synthetic conditions in order to have a transferable process for a scale-up synthetic laboratory.
In the first step, isobutyl chloroformate was used and, after a simple work up with 1M HCl, 2 (96% yield) was obtained as a white solid, which was used directly in the next step. For thioacetic acid addition to the double bond of intermediate 2, two different routes were possible, with addition reaction in the first (D') or last step (D). Reactions of 2 to give 5 or of 4 to give ST7612AA1 were both performed in dioxane. Reactions were fast and did not need the usually advised radical quenching with cyclohexene. The corresponding products were obtained in good yields (step D', 89%; step D, 81%) after a flash chromatography.
, a thiol derivative prodrug of ST7464AA1, is the first of a new generation of HDAC inhibitors, very potent, orally administered, and well tolerated. Here, we have identified a synthetic route, competitive, versatile and easily transferable to industrial processes.
We identified a novel member of the metallothionein (MT) family, Cucumis sativus metallothionein-like 2 (CsMTL2), by screening a young cucumber fruit complementary DNA (cDNA) library. The CsMTL2 encodes a putative 77-amino acid Class II MT protein that contains two cysteine (Cys)-rich domains separated by a Cys-free spacer region. We found that CsMTL2 expression was regulated by metal stress and was specifically induced by Cd(2+) treatment. We investigated the metal-binding characteristics of CsMTL2 and its possible role in the homeostasis and/or detoxification of metals by heterologous overexpression in Escherichia coli cells. Furthermore, we produced a deletion mutant form of the protein, CsMTL2m, that contained the two Cys-rich clusters but lacked the spacer region, in E. coli. We compared the metal-binding properties of CsMTL2 with those of CsMTL2m, the β domain of human metallothionein-like protein 1 (HsMTXb), and phytochelatin-like (PCL) heterologously expressed in E. coli using metal-binding assays. We found that E. coli cells expressing CsMTL2 accumulated the highest levels of Zn(2+) and Cd(2+) of the four transformed cell types, with levels being significantly higher than those of control cells containing empty vector. E. coli cells expressing CsMTL2 had a higher tolerance for cadmium than for zinc ions. These findings show that CsMTL2 improves metal tolerance when heterologously expressed in E. coli. Future studies should examine whether CsMTL2 improves metal tolerance in planta.
An in vitro plasmid scission assay (PSA), the cell apoptosis assay, and ICP-MS were employed to study the oxidative potentials and trace element compositions of the airborne particulate matter (PM) in Beijing during a one year-long field campaign from June 2010 to June 2011. The cell damages induced by PM reveled by the cell apoptosis assay showed a similar variation pattern to the DNA damages obtained by PSA, verifying the feasibility of the PSA in analyzing the oxidative capacity of PM samples. The PSA experiments showed that the particle-induced DNA damage was highest in summer, followed by spring, winter and autumn in descending order. The percentages of the oxidative damages to plasmid DNA induced by the water-soluble fractions of PM under the particle doses from 10 to 250μg/ml were generally lower than 45%, with some values peaking at above 50%. The peak values were frequently present in late spring (i.e. April and May) and early summer (i.e. June) but they were scarcely observed in other seasons. These peak values were mostly associated with haze days or the days with low wind speed (less than 4m/s), indicating that the PM samples during haze had higher oxidative potential than those during non-haze periods. The oxidative potential induced by the water-soluble fraction of the PM displayed a significant positive correlation with the concentrations of the water-soluble elements Cd, Cs, Pb, Rb, Zn, Be and Bi, demonstrating that the particle-induced oxidative potentials were mainly sourced from these elements. The exposure risk represented by the mass concentration of these elements in unit volume of atmosphere was higher in summer and winter, and lower in autumn and spring. The haze day PM samples not only had higher level of oxidative potentials but also had higher concentrations of water-soluble elements.
Surface sediments were collected from Vellar and Coleroon estuaries for determine sediment texture, calcium carbonate, organic matter and heavy metals. Pollution indices such as pollution load index (PLI), contamination factor (CF), enrichment factor (EF) and geo-accumulation index (Igeo) were done for this study to know the level of heavy metals pollution in the estuarine ecosystem. Pearson correlation matrix and factor were used to assess the relationship and source of heavy metals in the estuarine sediments. The results of PLI values reveal that the study area was polluted by all the heavy metals. The calculated values of CF and Igeo followed the decreasing order Cu>Ni>Pb>Co>Cr>Zn>Mn>Fe and illustrate that Cu, Ni and Pb are contaminated due to anthropogenic
 sources in both estuaries. Correlation and factor analysis suggest that FeMn oxyhydroxides, organic matter and fine particles are responsible for high concentration of heavy metals.
Structure-specific ligands are convenient tools for the recognition, targeting or probing of non-canonical DNA structures. Porphyrin derivatives exhibit a preference for interaction with G-quadruplex (G4) structures over canonical duplex DNA and are able to cause photoinducible damage to nucleic acids. Here, we show that Zn(II) 5,10,15,20-tetrakis(N-carboxymethyl-4-pyridinium)porphyrin ( ZNP1: ) interacts with different conformations of the telomeric sequence d(TAGGG(TTAGGG)3) at submicromolar concentrations without any detectible disturbance of the particular fold. Among different folds, potassium (3+1) hybrid G4-structure. reveal the highest affinity to ZNP1: The pattern of guanine oxidation is specific for each telomeric DNA conformation and may serve as an additional tool for probing the G4 topology. The potassium (3+1) and parallel G4 conformations are more susceptible to light-induced oxidation than the sodium G4 conformation or double helix of the telomeric DNA. The major products of the guanine modifications are spiroiminodihydantoin (Sp) and 8-oxoguanine (8-oxoG). ZNP1: -induced oxidation of guanines results in the structural rearrangement of parallel and (3+1) G4 conformations yielding an antiparallel-like G4 conformation. The mechanism of the observed light-induced conformational changes is discussed.
In this study, a novel coumarin-derived compound bearing the furan moiety called 7-diethylamino-3-formylcoumarin (2'-furan formyl) hydrazone (1) has been designed, synthesized and evaluated as a Zn(2+) ratiometric fluorescent probe in ethanol-water system. This probe 1 showed good selectivity and high sensitivity towards Zn(2+) over other metal ions investigated, and a decrease in fluorescence emission intensity at 511nm accompanied by an enhancement in fluorescence emission intensity at 520nm of this probe 1 was observed in the presence of Zn(2+) in ethanol-water (V : V=9 : 1) solution, which provided ratiometric fluorescence detection of Zn(2+). Additionally, the ratiometric fluorescence response of 1 to Zn(2+) was nearly completed within 0.5min, which suggested that this probe 1 could be utilized for sensing and monitoring Zn(2+) in environmental and biological systems for real-time detection.
Two zinc-aminoclays [ZnACs] with functionalized primary amines [(-CH2)3NH2] were prepared by a simple sol-gel reaction using cationic metal precursors of ZnCl2 and Zn(NO3)2 with 3-aminopropyl triethoxysilane [APTES] under ambient conditions. Due to the facile interaction of heavy metals with primary amine sites and Zn-related intrinsic antimicrobial activity, toxicity assays of ZnACs nanoparticles (NPs) prior to their environmental and human-health applications are essential. However, such reports remain rare. Thus, in the present study, a cell viability assay of in-vitro HeLa cells comparing ZnCl2, Zn(NO3)2 salts, and ZnO (~50nm average diameter) NPs was performed. Interestingly, compared with the ZnCl2, and Zn(NO3)2 salts, and ZnO NPs (18.73/18.12/51.49µg/mL and 18.12/15.19/46.10µg/mL of IC50 values for 24 and 48h), the two ZnACs NPs exhibited the highest toxicity (IC50 values of 21.18/18.36µg/mL and 18.37/17.09µg/mL for 24 and 48h, respectively), whose concentrations were calculated on Zn elemental composition. This might be due to the enhanced bioavailability and uptake into cells of ZnAC NPs themselves and their positively charged hydrophilicity by reactive oxygen species (ROS) generation, particularly as ZnACs exist in cationic NP's form, not in released Zn(2+) ionic form (i.e., dissolved nanometal). However, in an in-vivo embryotoxicity assay in zebrafish, ZnACs and ZnO NPs showed toxic effects at 50-100µg/mL (corresponding to 37.88-75.76 of Zn wt% µg/mL). The hatching rate (%) of zebrafish was lowest for the ZnO NPs, particularly where ZnAC-[(NO3)2] is slightly more toxic than ZnAC-[Cl2]. These results are all very pertinent to the issue of ZnACs' potential applications in the environmental and biomedical fields.
Pyrite ash, a waste by-product formed during roasting of pyrite ores, is a good source of valuable metals. The waste is associated with several environmental issues due to its dumping in sea and/or land filling. Although several other management practices are available for its utilization, the waste still awaits and calls for an eco-friendly biotechnological application for metal recovery. In the present study, chemolithotrophic meso-acidophilic iron and sulphur oxidisers were evaluated for the first time towards simultaneous mutli-metal recovery from pyrite ash. XRD and XRF analysis indicated higher amount of Hematite (Fe2O3) in the sample. ICP-OES analysis indicated concentrations of Cu>Zn>Co>As that were considered for bioleaching. Optimization studies indicated Cu - 95%, Co - 97%, Zn - 78% and As - 60% recovery within 8days at 10% pulp density, pH - 1.75, 10% (v/v) inoculum and 9g/L Fe(2+). The productivity of the bioleaching system was found to be Cu - 1696ppm/d (12% dissolution/d), Co - 338ppm/d (12.2% dissolution/d), Zn k 576ppm/d (9.8% dissolution/d) and As - 75ppm/d (7.5% dissolution/d). Synergistic actions for Fe(2+) - S° oxidation by iron and sulphur oxidisers were identified as the key drivers for enhanced metal dissolution from pyrite ash sample.
In order to improve the osseointegration and long-term survival of dental implants, it is urgent to develop a multifunctional titanium surface which would simultaneously have osteogeneic, angiogeneic and antibacterial properties. In this study, a potential dental implant material-dual Zn/Mg ion co-implanted titanium (Zn/Mg-PIII) was developed via plasma immersion ion implantation (PIII). The Zn/Mg-PIII surfaces were found to promote initial adhesion and spreading of rat bone marrow mesenchymal stem cells (rBMSCs) via the upregulation of the gene expression of integrin α1 and integrin β1. More importantly, it was revealed that Zn/Mg-PIII could increase Zn(2+) and Mg(2+) concentrations in rBMSCs by promoting the influx of Zn(2+) and Mg(2+) and inhibiting the outflow of Zn(2+), and then could enhance the transcription of Runx2 and the expression of ALP and OCN. Meanwhile, Mg(2+) ions from Zn/Mg-PIII increased Mg(2+) influx by promoting the expression of MagT1 transporter in human umbilical vein endothelial cells (HUVECs), and then stimulated the transcription of VEGF and KDR via activation of hypoxia inducing factor (HIF)-1α, thus inducing angiogenesis. In addition to this, it was discovered that zinc in Zn/Mg-PIII had certain inhibitory effects on oral anaerobic bacteria (Pg, Fn and Sm). Finally, the Zn/Mg-PIII implants were implanted in rabbit femurs for 4 and 12weeks with Zn-PIII, Mg-PIII and pure titanium as controls. Micro-CT evaluation, sequential fluorescent labeling, histological analysis and push-out test consistently demonstrated that Zn/Mg-PIII implants exhibit superior capacities for enhancing bone formation, angiogenesis and osseointegration, while consequently increasing the bonding strength at bone-implant interfaces. All these results suggest that due to the multiple functions co-produced by zinc and magnesium, rapid osseointegration and sustained biomechanical stability are enhanced by the novel Zn/Mg-PIII implants, which have the potential application in dental implantation in the future. [STATEMENT OF SIGNIFICANCE]: In order to enhance the rapid osseointegration and long-term survival of dental implants, various works on titanium surface modification have been carried out. However, only improving osteogenic activity of implants is not enough, because angiogenesis and bacteria inhibition are also very important for dental implants. In the present study, a novel dental implant material-dual Zn/Mg ion co-implanted titanium (Zn/Mg-PIII) was developed, which was found to have superior osteoinductivity, pro-angiogenic effects and inhibitory effects against oral anaerobes. Furthermore, synergistic effects of Zn/Mg ions on osteogenic differentiation of rBMSCs and the possible mechanism were discovered. In addition, rapid osseointegration and sustained biomechanical stability are greatly enhanced by Zn/Mg-PIII implants, which may have the potential application in dental implantation in the future. We believe this paper may be of particular interest to the readers.
We evaluated concentrations of eight heavy metals Cr, Zn, Pb, Ni, Cu, Cd, Co and V, in tissues of representative macrofauna species from 68 sandy beaches from the coast of Rio de Janeiro state. The links between contamination levels and community descriptors such as diversity, evenness, density and biomass, were also investigated. Metal concentrations from macrofaunal tissues were compared to maximum permissible limits for human ingestion stipulated by the Brazilian regulatory agency (ANVISA). Generalized linear models (GLM's) were used to investigate the variability in macrofauna density, richness, eveness and biomass in the seven different regions. A non-metric multidimensional scaling analysis (n-MDS) was used to investigate the spatial pattern of heavy metal concentrations along the seven regions of Rio de Janeiro coast. Variation partitioning was applied to evaluate the variance in the community assemblage explained by the environmental variables and the heavy metal concentrations. Our data suggested high spatial variation in the concentration of heavy metals in macrofauna species from the beaches of Rio de Janeiro. This result highlighted a diffuse source of contamination along the coast. Most of the metals concentrations were under the limits established by ANVISA. The variability in community descriptors was related to morphodynamic variables, but not with metal contamination values, indicating
 the lack of direct relationships at the community level. Concentration levels of eight heavy metals in macrofauna species from 68 sandy beaches on Rio de Janeiro coast (Brazil) were spatially correlated with anthropogenic activities such as industrialization and urbanization.
Infiltration of heavy metal (HM) polluted wastewater can seriously compromise soil and groundwater quality. Interactions between mineral soil components (e.g. clay minerals) and dissolved organic matter (DOM) play a crucial role in determining HM mobility in soils. In this study, the influence of the timing of addition of DOM, i.e. concurrent with or prior to HMs, on HM mobility was explored in a set of continuous flow column experiments using well defined natural soil samples amended with goethite, birnessite and/or smectite. The soils were subjected to concurrent and sequential additions of solutions of DOM, and Cu, Ni and Zn. The resulting breakthrough curves were fitted with a modified dose-response model to obtain the adsorption capacity (q0). Addition of DOM prior to HMs moderately enhanced q0 of Cu (8-25%) compared to a control without DOM, except for the goethite amended soil that exhibited a 10% reduction due to the blocking of binding sites. Meanwhile, for both Zn and Ni sequential addition of DOM reduced q0 by 1-36% for all tested soils due to preferential binding of Zn and Ni to mineral phases. In contrast, concurrent addition of DOM and HMs resulted in a strong increase of q0 for all tested metals and all tested soil compositions compared to the control: 141-299% for Cu, 29-102% for Zn and 32-144% for Ni. Our study shows that when assessing the impact of soil pollution through HM containing wastewater it is crucial to take into account the presence of DOM.
The castor bean plant, Ricinus communis, grows wild throughout many regions of Australia. The seeds of the plant contain the schedule 1 chemical agent ricin, a type II ribosomal inhibiting protein. Currently there are limited analytical techniques that can be applied in analysis of the seeds to establish attribution. In this study, laser ablation inductively coupled plasma mass spectrometry (LA-ICP-MS) was used for the analysis of seeds collected from 68 plants across 38 locations around Australia. Of the 92 elemental isotopes measured, fifteen ((24)Mg, (27)Al, (44)Ca, (53)Cr, (55)Mn, (57)Fe, (60)Ni, (65)Cu, (66)Zn, (75)As, (85)Rb, (88)Sr, (98)Mo, (138)Ba and (202)Hg) yielded data that were relevant to all collection sites. Data were further analysed using multivariate statistical analysis which facilitated the potential for the identification of unique provenance isotopes. Furthermore, this analysis indicated that (59)Co was present at significant levels in Victorian and Sydney specimens only.
This study was conducted to illustrate the contents and potential ecological risk of heavy metals in ballast tank sediment. Ballast sediment samples were collected from six ships during their stay in shipyard, and the heavy metals were determined by inductive coupled plasma emission spectrometer. Results showed that high concentrations of heavy metals were detected in all six sediment samples following the order: Zn > Cu > Pb > Cr > As > Cd > Hg. The geoaccumulation index explained the average pollution degree of heavy metals decreased as the following: Zn > Pb > Cu > As > Cr > Hg, and the environmental risk indices suggested that concentration found of Zn, Pb, and Cu might be highly toxic to aquatic organisms. Principal component and correlation analysis indicated the metal pollution in ballast tank sediment was affected by complex and different contamination mechanisms, and the corrosion of ballast tank played an important role in this process. In conclusion, this study is very useful for comprehensive consideration and efficient management of ballast tank sediment in order to protect the marine environment.
A quantum chemistry study of mononuclear metal coordination with four 4-methylimidazole ligands (4-MeIm) was investigated. The four complexes [Cu(4-MeIm)4](2+), [Cu(4-MeIm)4, H2O](2+), [Zn(4-MeIm)4](2+) and [Zn(4-MeIm)4, H2O](2+) were studied with particular attention to the Nπ or Nτ possible coordinations of the 4-MeIm ring with the metals, using different DFT methods. The results suggest that the Nτ coordination of 4-MeIm ring to Zn(II) or Cu(II) is more favorable whatever the level of calculation. In contrast, the addition of one water molecule in the first coordination sphere of the metal ions provides five-coordinated complexes showing no Nπ or Nτ preferences. There is good agreement between the DFT-calculated structure and those available experimentally. When metal ions are four-fold coordinated, they adopt a tetrahedral geometry. When Cu(II) and Zn(II) are five-fold coordinated, highly symmetric structures or intermediate structures are calculated. Similar energies are calculated for different structures, suggesting flat potential energy surfaces. The addition of implicit solvent modifies the calculated first coordination sphere, especially for [Cu(4-MeIm)4, H2O](2+) structures. The QTAIM and ELF topological analyses of the interaction between Cu(II) and the neutral ligands, clearly indicate a dative bonding with a strong ionic character.
The aim of this study was to assess the performance of the GeneXpert MTB/RIF assay on extrapulmonary (EP) and respiratory (non-sputum) clinical samples of patients suspected of having tuberculosis (TB) from Queensland, Australia. A total of 269 EP and respiratory (non-sputum) clinical samples collected from Qld patients who were suspected of having TB were subjected to the GeneXpert MTB/RIF analysis, Ziehl-Neelsen (ZN) staining, Mycobacterium tuberculosis (MTB) culture and drug susceptibility testing. Phenotypic and genotypic data were compared. The overall performance analysis of the GeneXpert MTB/RIF assay for detection of MTB complex demonstrated sensitivity of 89%, specificity of 95%, PPV of 89% and NPV of 95% using culture as a reference standard. The GeneXpert MTB/RIF analysis of acid-fast bacilli (AFB) smear positive samples and AFB smear negative samples showed sensitivities of 100% and 77%, respectively. Looking at individual EP and respiratory (non-sputum) sample types, the sensitivity ranged from 60% to 100% although the specificity ranged from 33% to 100% with the specificity of lymph node tissue biopsy being the lowest. The GeneXpert MTB/RIF assay detected 11% more TB cases than culture and 27% more cases than ZN microscopy. Due to insufficient numbers of presenting rifampicin resistance cases, performance analysis of the GeneXpert MTB/RIF assay on rifampicin resistance could not be carried out. The GeneXpert MTB/RIF assay is potentially valuable for TB diagnosis in the majority of the EP and respiratory (other than sputum) samples in our setting. Although the GeneXpert MTB/RIF assay provides rapid diagnostic results, the overall sensitivity to rule out the disease is suboptimal for some specimen types. Performance varied according to specimen type and AFB smear status. The sensitivity and specificity of lymph node tissue was 63% and 33%. Care must be taken when using the GeneXpert MTB/RIF assay for detection of MTB in lymph node tissue samples. All samples should be cultured regardless of the GeneXpert MTB/RIF assay result.
Concentrations of heavy metals in coastal soils, stream sediments and intertidal sediments of Yueqing Bay basin were analyzed to study their distribution and trace the possible sources. According to various single- and multi-index methods, heavy metal enrichment, especially for Cu, Zn, Cr and Ni in stream sediments, should draw environmental concern. Controlling factors such as inorganic scavengers, organic matter, sample grain size and hydrodynamic conditions were identified to influence the transportation and distribution of metals within coastal soils and sediments. Principal component analysis indicated that most metals in soils and stream sediments originate primarily from natural and anthropogenic sources, respectively. Most metals in intertidal sediments, originating both from natural processes and human activities, tend to be concentrated in fine particles. The exchange of water and sediment between the bay and open waters is strong enough to keep the metals in the tidal flats from rising to very high levels.
In this study, swine manure containing sulfachloropyridazine sodium (SCPS) and zinc was subjected to mesophilic (37°C) anaerobic digestion (AD). The absolute abundances (AAs) of antibiotic resistance genes (ARGs) were evaluated, as well as intI1 and intI2, and the degradation of SCPS according to variation in the amount of bio-available zinc (bio-Zn). In digester that only contained SCPS, the concentrations of SCPS were lower than that digesters both contain SCPS and Zn. Compared with the control digester, the addition of SCPS increased the AAs of sul1, sul3, drfA1, and drfA7 by 1.3-13.1 times. However, compared with the digester with SCPS but no added Zn, the AAs of sul3, drfA1, and drfA7 were decreased by 21.4-70.3% in the presence of SCPS and Zn, whereas sul1 and sul2 increased 1.3-10.7 times. There were significant positive correlations (P<0.05) between the concentrations of SCPS with several ARGs and bio-Zn.
Distributions of a total of 21 elements were monitored in significantly lead-zinc polluted area using moss species (Hypnum cupressiforme and Camptothecium lutescens) used interchangeably, covering a denser sampling network. Interspecies comparison was conducted using Box-Cox transformed values, due to their skewed distribution. The median concentrations of trace elements in the both mosses examined decreased in the following order: Fe>Mn>Zn>Pb>Cu>Ni∼Cr∼As>Co>Cd>Hg. For almost all analyzed elements, H. cupressiforme revealed higher bio-accumulative abilities. For arsenic contents was
 obtained ER-value in favor of C. lutescens. The ER for the element contents according to the distance from the pollution source in selected areas was significantly enriched for the anthropogenic introduced elements As, Cd, Cu, Pb and Zn. After Box-Cox transformation of the content values, TB was significantly different for As (4.82), Cd (3.84), Cu (2.95), Pb (4.38), and Zn (4.23). Multivariate factor analysis singled out four elemental associations: F1 (Al-Co-Cr-Fe-Li-Ni-V), F2 (Cd-Pb-Zn), F3 (Ca-Mg-Na-P) and F4 (Cu) with a total variance of 89%. Spatial distribution visualized the hazardously higher contents of "hot spots" of Cd > 1.30 mg/kg, Cu > 22 mg/kg, Pb > 130 mg/kg and Zn > 160 mg/kg. Therefore, main approach in moss biomonitoring should be based on data management of the element distribution by reducing the effect of extreme values (considering Box-Cox data transformation); the interspecies variation in sampling media does not deviate in relation to H. cupressiforme vs. C. lutescens.
The Arabidopsis Tóxicos en Levadura (ATL) protein family is a class of E3 ubiquitin ligases with a characteristic RING-H2 Zn-finger structure that mediates diverse physiological processes and stress responses in plants. We carried out a genome-wide survey of grapevine (Vitis vinifera L.) ATL genes and retrieved 96 sequences containing the canonical ATL RING-H2 domain. We analysed their genomic organisation, gene structure and evolution, protein domains and phylogenetic relationships. Clustering revealed several clades, as already reported in Arabidopsis thaliana and rice (Oryza sativa), with an expanded subgroup of grapevine-specific genes. Most of the grapevine ATL genes lacked introns and were scattered among the 19 chromosomes, with a high level of duplication retention. Expression profiling revealed that some ATL genes are expressed specifically during early or late development and may participate in the juvenile to mature plant transition, whereas others may play a role in pathogen and/or abiotic stress responses, making them key candidates for further functional analysis. Our data offer the first genome-wide overview and annotation of the grapevine ATL family, and provide a basis for investigating the roles of specific family members in grapevine physiology and stress responses, as well as potential biotechnological applications.
Understanding Zn uptake dynamics is critical to rice grain Zn biofortification. Here we examined soil Zn availability and Zn uptake pathways as affected by genotype (high-grain Zn varieties IR69428 and IR68144), Zn fertilization and water management in two pot experiments. Results showed significant interactions (P < 0.05) between genotypes and Zn fertilization on DTPA (diethylenetriaminepentaacetic acid)-extractable soil Zn from early tillering to flowering. DTPA-extractable Zn in soils grown with IR69428 was positively correlated with stem (r = 0.78, P < 0.01), flagleaf (r = 0.60, P < 0.01) and grain (r = 0.67, P < 0.01) Zn concentrations, suggesting improved soil Zn availability and continued soil Zn uptake by IR69428 even at maturity. Conversely for IR68144, DTPA-extractable Zn was positively correlated only with leaf Zn uptake (r = 0.60, P < 0.01) at active tillering, indicating dependence on remobilization for grain Zn loading. Furthermore, the highest grain Zn concentration (P < 0.05) was produced by a combination of IR69428 and Zn fertilization applied at panicle initiation (38.5 μg g(-1)) compared with other treatments (P < 0.05). The results highlight that Zn uptake behavior of a rice genotype determines the fate of Zn from the soil to the grain. This has implications on overcoming Zn translocation barriers between vegetative parts and grains, and achieving grain Zn biofortification targets (30.0 μg g(-1)).
Copper(II) and zinc(II) bis(4,4,4-trifluoro-1-phenylbutane-1,3-dionato) compounds with pyrimidin-2-amine (pyr2a), pyrazine (pyz) and 1,2-bis(4-pyridyl)ethane (dpet) were prepared and solid-state structures of coordination polymers [M(tfpb)2(pyr2a)]∞ [M = Cu (1), Zn (2); tfpb = 4,4,4-trifluoro-1-phenylbutane-1,3-dionate], [M(tfpb)2(pyz)]∞ [M = Cu (3), Zn (4a, 4b)] and [Cu(tfpb)2(dpet)]∞ (5), respectively, were determined by single-crystal X-ray analysis. The coordination of metal centers in all compounds is octahedral with nitrogen ligands occupying the axial positions. Compound (1) crystallizes in the triclinic space group P\bar 1, whereas (2) crystallizes in the monoclinic space group P2/n. Differences are due to the different orientation of adjacent M(tfpb)2 units, whereas the orientation of pyrimidin-2-amine is the same in both compounds. Polymeric chains in (1) and (2) contain intramolecular N-H...O hydrogen bonding between amino and carbonyl groups. Room-temperature structures (3) and (4a) are isomorphous adopting the monoclinic space group C2/m; however, on cooling crystals (4a) to 150 K a single-crystal-to-single-crystal transformation to (4b) possessing the triclinic space group P\bar 1 was observed. Compound (5) crystallizes in the triclinic space group P\bar 1 and contains a parallel aggregation of chains in contrast to the known structure of the non-fluorinated benzoylacetonato ligand, where chains aggregate in a perpendicular fashion. In the compounds studied intramolecular C-H...O and/or C-H...F interactions are present. The neighboring chains are linked by π...π interactions and in some compounds also by C-H...π interactions [(1), (4b), (5)].
Two new non-centrosymmetric polar quaternary selenides, namely, RbZn4In5Se12 and CsZn4In5Se12, have been synthesized and structurally characterized. They exhibit 3D diamond-like framework (DLF) consisting of corner shared MSe4 (M = Zn/In) tetrahedra, in which the A+ ions are located. Both compounds are thermally stable up to 1300 K and exhibit large transmittance in the infrared region (0.65-25 μm) with measured optical band gaps of 2.06 eV for RbZn4In5Se12 and 2.11 eV for CsZn4In5Se12. Inspiringly, they exhibit good balance between strong second harmonic generation (SHG) efficiency (3.9 and 3.5 × AgGaS2) and high laser-induced damage thresholds (13.0 × AgGaS2). Theoretical calculations based on density functional theory (DFT) methods confirm that such strong SHG responses originate from the 3D DLF structure.
Rational design of non-noble materials as highly efficient, economical, and durable bifunctional catalysts for oxygen evolution and reduction reactions (OER/ORR) is currently a critical obstacle for rechargeable metal-air batteries. A new route involving S was developed to achieve atomic dispersion of Fe-Nx species on N and S co-decorated hierarchical carbon layers, resulting in single-atom bifunctional OER/ORR catalysts for the first time. The abundant atomically dispersed Fe-Nx species are highly catalytically active, the hierarchical structure offers more opportunities for active sites, and the electrical conductivity is greatly improved. The obtained electrocatalyst exhibits higher limiting current density and a more positive half-wave potential for ORR, as well as a lower overpotential for OER under alkaline conditions. Moreover, a rechargeable Zn-air battery device comprising this hybrid catalyst shows superior performance compared to Pt/C catalyst. This work will open a new avenue to design advanced bifunctional catalysts for reversible energy storage and conversion devices.
The study was carried out to evaluate the effects of low-dose zinc (Zn) pre-exposure on survival rate, new Zn accumulation, and mitochondrial bioenergetics in the liver and spleen of large yellow croaker exposed to high-dose Zn. To the end, fish were pre-exposed to 0 and 2 mg L(-1) Zn for 48 h and post-exposed to 0 and 12 mg L(-1) Zn for 48 h. Twelve milligrams Zn per liter exposure alone reduced survival rate, but the effect did not appear in the 2 mg L(-1) Zn pre-exposure groups. Two milligrams per liter Zn pre-exposure also ameliorated 12 mg Zn L(-1) induced new Zn accumulation, reactive oxygen species (ROS) levels, and mitochondrial swelling in the liver. However, these effects did not appear in the spleen. In the liver, 2 mg L(-1) Zn pre-exposure apparently relieved 12 mg L(-1) Zn induced down-regulation of activities of ATP synthase (F-ATPase), succinate dehydrogenase (SDH), and malate dehydrogenase (MDH). The mRNA levels of these genes remained relatively stable in fish exposed to 12 mg L(-1) Zn alone, but increased in fish exposed to 12 mg L(-1) Zn with 2 mg L(-1) Zn pre-treatment. In the spleen, 2 mg Zn L(-1) pre-exposure did not mitigate the down-regulation of mRNA levels of genes and activities of relative enzymes induced by 12 mg L(-1) Zn. In conclusion, our study demonstrated low-dose zinc pre-exposure ameliorated high-dose zinc induced mitochondrial dysfunction in the liver but not in the spleen of large yellow croaker, indicating an organ-specific effect.
The purpose of this research was to evaluate the protective effects of apocynin on renal ischemia/reperfusion (I/R) injury (RI/RI) in rats. Rats preconditioned with apocynin were subjected to renal I/R. Zinc levels in serum and renal tissues, blood urea nitrogen (BUN), and serum creatinine (Scr) were detected. We further measured the activity of superoxide dismutase (SOD); the content of malondialdehyde (MDA), IL-4, IL-6, IL-10, and TNF-α; and the expression of metallothionein (MT) in the renal tissues. Results indicated that the levels of MDA, IL-4, IL-6, IL-10, TNF-α, and MT in the kidney tissue and serum BUN and Scr levels in RI/RI group were significantly higher than those in sham-operated group, while the levels of serum Zn and kidney Zn and SOD were reduced in RI/RI group. Apocynin treatment further decreased the levels of MDA, IL-6, TNF-α, and serum BUN and Scr, whereas it significantly increased the levels of Zn, SOD, IL-4, IL-10, and MT in the kidney tissue and serum Zn.
 These findings suggest that apocynin might play a protective role against RI/RI in rats through regulating zinc level and MT expression involving in oxidative stress.
Acetylcholine is an excitatory neurotransmitter important for oxygen sensing in mammals. A cholinergic mechanism in the fish gill has been implicated in the hyperventilatory response to acute hypoxia; however, the identity and distribution of acetylcholine-containing cells in the gills is poorly defined. We test the hypothesis that cholinergic cells are present in the gill filament epithelium in zebrafish (Danio rerio), a model vertebrate for which oxygen chemoreceptors are well characterized, and that these cells would receive nervous innervation. Using immunohistochemistry and confocal microscopy, we observed 10.2 ± 0.6 cells immunoreactive for the vesicular acetylcholine transporter (VAChT) on the efferent aspect of each gill filament, where a high density of serotonergic oxygen-sensitive neuroepithelial cells (NECs) were located. VAChT-positive cells of the efferent epithelium were positioned within 10 μm of NECs. On the afferent aspect of the gill filaments, VAChT-positive cells were greater in number (30.8 ± 3.1 per filament). On the efferent and afferent filament aspects, VAChT-positive cells did not contain serotonin, but did express choline acetyltransferase (ChAT), the enzyme that synthesizes ACh, and were often closely apposed to nerve fibers labeled with the neuronal marker, zn-12. We conclude that cholinergic cells in the zebrafish gills were present in the primary epithelium of gill filaments, and formed contacts with nerve fibers. These studies provide morphological evidence for the presence of a cholinergic system in the zebrafish gill. Such a pathway may contribute to the reflex hyperventilatory response during hypoxia.
Cellular heterogeneity is an inherent condition of cell populations, which results from stochastic expression of genes, proteins, and metabolites. The heterogeneity of individual cells can dramatically influence cellular decision-making and cell fate. So far, our knowledge about how the variation of endogenous metals and non-metals in individual eukaryotic cells is limited. In this study, ICP-MS equipped with a high efficiency cell introduction system (HECIS) was developed as a method of single-cell ICP-MS (SC-ICP-MS). The method was applied to the single-cell analysis of Mn, Fe, Co, Cu, Zn, P, and S in human cancer cell lines (HeLa and A549) and normal human bronchial epithelial cell line (16HBE). The analysis showed obvious variation of the masses of Cu, Fe, Zn, and P in individual HeLa cells, and variation of Fe, Zn, and P in individual A549 cells. On the basis of the single-cell data, a multimodal distribution of the elements in the cell population was fitted, which showed marked differences among the various cell lines. Importantly, subpopulations of the elements were found in the cell populations, especially in the HeLa cancer cells. This study demonstrates that SC-ICP-MS is able to unravel the extent of variation of endogenous elements in individual cells, which will help to improve our fundamental understanding of cellular biology and reveal novel insights into human biology and medicine. Graphical abstract The variations of masses and distribution patterns of elements Mn, Fe, Co, Cu, Zn, P, and S in single cells were successfully detected by ICP-MS coupled with a high efficiency cell introduction system (HECIS).
The primary objective of the study was to assess the level of metals and trace elements in liver, serum, and hair of rats with diet-induced non-alcoholic fatty liver disease (NAFLD) using inductively coupled plasma dynamic reaction cell mass spectrometer (ICP-DRC-MS). 56 female 3-months-old Wistar rats divided into two equal groups were fed either standard (10% calories from fat) or high-fat high-carbohydrate diet (60% calories from fat in chow and 10% sucrose solution) for 6 weeks. Serum was examined for insulin resistance markers, lipid profile, and alanine aminotransferase (ALT) activity. Liver histology was assessed after hematoxylin and eosin staining. Metal and trace element concentrations were assessed by means of ICP-DRC-MS. Overfed animals were characterized by higher values of morphometric parameters. Liver examination revealed large and small droplet steatosis, hepatocyte ballooning and necrosis, being characteristic for NAFLD. Animals with NAFLD were characterized by insulin resistance, atherogenic changes of lipid profile and increased ALT activity. Significantly decreased hepatic Co, Cu, I, Li, Mn, Se, Zn levels were observed in rats with NAFLD. At the same time, only hepatic Mn and Se levels remained decreased after adjustment for total protein. Overfed animals were characterized by significantly lower I, Li, and Mn levels in blood serum, whereas concentration of Co, Se, V, and Sr exceeded the control values. In general, the results of the study demonstrate that NAFLD significantly affects metal and trace element status in experimental animals.
An alarming increase in chronic kidney disease with unknown etiology (CKDu) has recently been reported in several provinces in Sri Lanka and chronic exposures to toxic trace elements were blamed for the etiology of this disease. Keratinized matrices such as hair and nails were investigated to determine the possible link between CKDu and toxic element exposures. Elements Li, B, Al, Cr, Mn, Fe, Co, Ni, Cu, Zn, As, Se, Sr, Mo, Cd, Ba, Hg and Pb of hair and nails of patients and age that matched healthy controls were determined with Inductively Coupled Plasma Mass Spectrometry (ICP-MS). The results showed that trace element contents in the hair of patients varies in the order of Zn>Fe>Al>Mn>Cu>Ba>Sr>Ni>Pb>Cr>B>Hg>Se>Mo>Co>As>Li>Cd while Fe>Al>Zn>Ni>Cu>Mn>Cr>Ba>Sr>B>Pb>Se>Mo>Co>Hg>Li>As>Cd in nail samples. The hair As levels of 0.007-0.165μgg(-1) were found in CKDu subjects. However, no significant difference was observed between cases and controls. The total Se content in hair of CKDu subjects ranged from 0.043 to 0.513μgg(-1) while it was varied from 0.031 to 1.15μgg(-1) in controls. Selenium in nail samples varied from 0.037μgg(-1) to 4.10μgg(-1) in CKDu subjects and from 0.042μgg(-1) to 2.19μgg(-1) in controls. This study implies that substantial proportions of Sri Lankan population are Se deficient irrespective of gender, age and occupational exposure. Although some cutaneous manifestations were observed in patient subjects, chemical analyses of hair and nails indicated that patients were not exposed to toxic levels of arsenic or the other studied toxic elements. Therefore the early suggested causative factors such as exposure to environmental As and Cd, can be ruled out.
A large number of medicinal plants is traditionally known in Kenya and used for treatment of various diseases, for example diabetes, where metals are supposed to be involved in pathogenesis and therapy. Therefore, detailed investigation of the concentration of a large number of metals in medicinal plants is required for improved understanding and optimisation of the therapeutic role of metals and also to exclude potentially toxic effects. Our study focused on the determination of 30 selected elements in 19 medicinal plant species each collected from 3 sampling locations in Nyamira County, Kenya. The obtained comprehensive data set showed large variability and multivariate data analysis revealed that the differences in the elemental composition were stronger dependent on the plant species than on the sampling location. In addition, hot water extractions were performed to mimic the traditional preparation of medicine from the plants. It was found that the mean extraction efficiencies were below 20% except for B, Mg, P, K, Mn, Co, Ni, Cu, Zn, Rb, Mo, Cd and Tl, which are mostly essential elements apart from Cd and Tl. Sequential (ultra)filtration of the extracts was applied as novel approach for molecular size-fractionation of the extracted elemental species. The results indicate more than 50% low molecular weight species (<3kDa) for Mg, Mn, Co, Ni and Zn while predominantly larger size-fractions (>3kDa up to<5μm) were detected for V, Cu, Al and Fe.
The aim of the present study was to assess whether dietary magnesium deficiency can alter distribution of macroelements and trace elements in different organs and tissues. Experiments were carried out on 12 adult female Wistar rats, which were fed either a diet with low Mg content (≤20mgkg(-1) of diet) (LMgD) or a diet with daily recommended Mg content (≈500mgkg(-1)) as control group (CG) for 70 days. On the 70th day of the experiment heart, aorta, femoral skeletal muscle, forebrain, cerebellum, pituitary gland, thyroid gland, ovaries, uterus, liver, kidneys, and spleen were taken for analysis of mineral content. Concentrations of Fe and Ca were measured by inductively coupled plasma-atomic emission spectrometry, and levels of Na, K, Mg, Co, Cu, Zn, Ni, Se, I were determined by inductively coupled plasma mass spectrometry. On the 70th day, LMgD led to significant reduction of Mg level in red blood cells, plasma, aorta, uterus and thyroid gland compared to CG as well as resulted in significant decrease of Mg/Ca ratio in kidneys, spleen and ovaries. Contrary to this, an increase of Mg/Ca ratio was found in cerebellum of LMgD group. Significant decrease of K concentration was shown in aorta of LMgD animals compared to CG whereas myocardial K concentration was increased in LMgD group. Na level was two-fold higher in skeletal muscles of rats that received LMgD in comparison to CG (p=0.006). Increased concentrations of Fe in ovaries and uterus were found in LMgD. Mg restriction did not affect Zn concentration in any of tasted tissues. Se level was higher in spleen and lower in uterus of LMgD animals compared to CG. MgD was accompanied by increased
 level of Co in skeletal muscles and decreased its level in kidneys and uterus. LMgD feeding was associated with decreased concentrations of Ni in heart, thyroid gland, spleen, uterus and Co in heart, aorta, liver, kidneys, spleen and ovaries. The changes of Mg, K, Co content were accompanied by dramatic (10-fold) decrease of I concentration in aorta of LMgD animals. LMgD causes decrease of I content in ovaries and increase of I level in uterus vs CG. Thus, distribution of macroelements (Ca, Na, K) was weakly affected by Mg restriction that led to the most evident alterations of Co and Ni tissue levels. Moreover, mineral balance of uterus seems to be the most susceptible to low Mg intake. Hypomagnesaemia resulted in significant changes of 5 studied trace elements (Fe, Se, Cu, Ni and Co).
Fibrodysplasia Ossificans Progressiva (FOP) is a rare inherited disease characterized by progressive heterotopic ossification. Disease onset, severity and symptoms vary between FOP patients, as does the frequency and activity of so-called flare-ups, during which tendons, ligaments, muscle and soft tissue are replaced by bone. Traumata, infections or other stressors are known inducers of flare-ups, and the hormone Activin A may be involved in disease activity; however, reliable biomarkers for FOP activity are missing, and the basal trace element and inflammatory state of patients are unknown. We hypothesized that FOP patients develop characteristic deficiencies in inflammation-related trace elements and display a chronically increased inflammatory cytokine level, collectively aggravating disease course and flare-up risk. Serum samples from 15 FOP patients and 25 relatives were collected under highest quality standards. Concentrations of Cu, Se and Zn were determined by total reflection X-ray fluorescence, and 27 cytokines along with Activin A by specific antibody-based techniques. Data were tested for normal distribution and analyzed by parametric or non-parametric tests. Concentrations of Se and Cu were not different between the groups, while Zn levels were slightly higher in FOP as compared to controls (1110±251 vs. 970±176ng/ml, P=0.04). The average concentrations of cytokines and Activin A were not different. When focusing on the two patients with self-reported flare-ups, again no obvious differences were noted. The cytokines Eotaxin, G-CSF, hbFGF and TNF-α were within the upper half of measured concentrations, and may warrant further longitudinal analyses. Our data do not support the hypothesis that FOP patients display a characteristic pattern of trace elements or have a generally increased tone of pro-inflammatory cytokines.
Glutamate-mediated excitotoxicity involving N-methyl-d-aspartate (NMDA) receptors has been recognized as a final common outcome in pathological conditions involving death of retinal ganglion cells (RGCs). Overstimulation of NMDA receptors results in influx of calcium (Ca) and sodium (Na) ions and efflux of potassium (K). NMDA receptors are blocked by magnesium (Mg). Such changes due to NMDA overstimulation are also associated with not only the altered levels of minerals but also that of trace elements and redox status. Both the decreased and elevated levels of trace elements such as iron (Fe), zinc (Zn), copper (Cu) affect NMDA receptor excitability and redox status. Manganese (Mn), and selenium (Se) are also part of antioxidant defense mechanisms in retina. Additionally endogenous substances such as taurine also affect NMDA receptor activity and retinal redox status. Therefore, the aim of this study was to evaluate the effect of Mg acetyltaurate (MgAT) on the retinal mineral and trace element concentration, oxidative stress, retinal morphology and retinal cell apoptosis in rats after-NMDA exposure. One group of Sprague Dawley rats received intravitreal injection of vehicle while 4 other groups similarly received NMDA (160nmolL(-1)). Among the NMDA injected groups, 3 groups also received MgAT (320nmolL(-1)) as pre-treatment, co-treatment or post-treatment. Seven days after intravitreal injection, rats were sacrificed, eyes were enucleated and retinae were isolated for estimation of mineral (Ca, Na, K, Mg) and trace element (Mn, Cu, Fe, Se, Zn) concentration using Inductively Coupled Plasma (DRC ICP-MS) techniques (NexION 300D), retinal oxidative stress using Elisa, retinal morphology using H&E staining and retinal cell apoptosis using terminal deoxynucleotidyl transferase dUTP nick-end labeling (TUNEL). Intravitreal NMDA injection resulted in increased concentration of Ca (4.6 times, p<0.0001), Mg (1.5 times, p<0.01), Na (3 times, p<0.0001) and K (2.3 times, p<0.0001) compared to vehicle injected group. This was accompanied with significant increase of Ca/Mg and Na/K ratios, 3 and 1.27 times respectively, compared to control group. The trace elements such as Cu, Fe and Zn also showed a significant increase amounting to 3.3 (p<0.001), 2.3 (p<0.0001) and 3 (p<0.0001) times respectively compared to control group. Se was increased by 60% (p<0.005). Pre-treatment with MgAT abolished effect of NMDA on minerals and trace elements more effectively than co- and post-treatment. Similar observations were made for retinal oxidative stress, retinal morphology and retinal cell apoptosis. In conclusion, current study demonstrated the protective effect of MgAT against NMDA-induced oxidative stress and retinal cell apoptosis. This effect of MgAT was associated with restoration of retinal concentrations of minerals and trace elements. Further studies are warranted to explore the precise molecular targets of MgAT. Nevertheless, MgAT seems a potential candidate in the management of diseases involving NMDA-induced excitotoxicity.
In the current study, a biomonitoring of 18 hair trace elements (Al, As, Cd, Co, Cr, Cu, Fe, Hg, Mg, Mn, Ni, Pb, Se, V, Zn, Ca, Na and P) in school children from Leningradskaya Oblast' is reported. A case group, residing in a proximity to the toxic waste disposal grounds (Krasniy Bor), has been assessed vs. controls from a non-urban settlement Seltso. In total, 166 hair samples were analysed using double focusing sector field inductively coupled plasma mass spectrometry after microwave-assisted sample digestion with nitric acid. For the determination of Ca, Na and P inductively coupled plasma optical emission spectrometry was employed. For the validation, a reference material and spiked hair samples were analysed. The data obtained was processed using parametric statistics and factor analysis. Determined concentrations of trace elements were in agreement with the previously published results on chemically polluted areas. In the case group, linear correlations between Al, Cr, Cu, Fe, Ni and V were observed. Also, these metals correlated to selenium hair content in the case group. Additionally, a correlation between hair Se and P was observed in the case subjects. Several gender differences in trace content were observed within each group. However, no age- or body index-related difference was found. The obtained results show that closely located waste disposal grounds intensifies trace element exposure in school children of Krasniy Bor. However, judging from rather high values for the controls, total environmental status of the region seems to be unstable, so additional monitoring and chemical safety measures are required.
Metals, especially transition metals, seem to be important in the pathogenesis of Alzheimer disease. This study aims to determine the relationship of trace metal elements to the pathogenesis and/or course of Alzheimer Disease in terms of clinical severity.
The hair and nail trace metal levels of 62 Alzheimer Disease patients at different clinical stages (21 mild, 20 moderate, 21 severe) and 60 healthy control subjects were measured by using inductively coupled plasma-mass spectrometry. The statistical comparisons were performed with regards to the study groups, clinical stages, disease duration and age.
The patient and control groups were significantly different from each other in regards to Mn, Fe, Cu, Cd, Hg (p<0.001), Zn (p<0.01) in nail concentrations and, Na, Al, Pb, Co (p<0.001), Fe, Mn (p=0.001), Hg, Cu, Cd, K in hair concentrations (p<0.01). No difference was detected in the levels of Mg and Ca. Nail Na level showed differences among different clinical stages of the disease (p<0.01). In comparing the mild degree Alzheimer patients to the control group; significant differences were detected in nail Mn, Fe, Cu, Co (p<0.001), Hg, Zn (p<0.01) and, hair Pb, Al (p<0.001), Na, K levels (p<0.01).
Our results have shown that transition and posttransition metals are especially important metals for the disease process. The relation of nail Na level with clinical stages of AD is an interesting new finding, making someone to think that alkali metals may be important in the progression of the disease.
The present study was designed for microwave assisted synthesis of zinc nanoparticles (Zn NPs) using Lavandula vera leaf extract in the presence of ZnSO4 (1mM). The biogenic Zn NPs were then characterized using scanning electron microscopy (SEM), energy dispersive X-ray (EDX), X-ray diffraction spectroscopy (XRD), UV-visible spectroscopy, and Fourier transform infrared spectroscopy (FTIR) techniques. Thereafter, the cytotoxic effect of ZnSO4 and Zn NPs on different cell lines was investigated by MTT-based cytotoxicity assay and their antioxidant properties were assessed using DPPH scavenging activity and reducing power assay. The SEM micrograph showed that the Zn NPs had spherical shape with the size range of 30-80nm. For A549, MCF-7, HT-29, and Caco-2 cell lines treated with Zn NPs, the concentration necessary causing 50% cell death (IC50) was found to be 22.3±1.1μgmL(-1), 86±3.7μgmL(-1), 10.9±0.5μgmL(-1), and 56.2±2.8μgmL(-1), respectively. In the case of ZnSO4, the same results (IC50) were
 observed at concentration of 81.6±1.3μgmL(-1) (A549), 121.0±2.4μgmL(-1) (MCF-7), 43.0±1.4μgmL(-1) (HT-29), and 85.7±2.3μgmL(-1) (Caco-2). The obtained results of antioxidant activity showed that the IC50 values of butylated hydroxyanisole (BHA) and Zn NPs were 44μgmL(-1)and 65.3μgmL(-1), respectively, while ZnSO4 at concentration of 200μgmL(-1) exhibited only 10.9% DPPH radical scavenging effect. Moreover, the reducing power of Zn NPs and BHA were significantly higher than ZnSO4 (p<0.05). To sum up, application of L. vera leaf extract combined with microwave heating energy led to simple and fast formation of Zn nanostructures exhibited higher antioxidant and cytotoxic activity compared to soluble Zn(+2) ions. However, identification of the related mechanisms merit further studies.
This study determined the levels of Ca, Mg, Fe, Zn, Cu, and Na in various tissues samples (liver, brain, kidney, intestines, muscle and hair) of diabetic and non-diabetic rats by flame atomic absorption spectroscopy, in order to assess the role of element levels during T2DM. The ratios of Ca/Mg, Zn/Cu, Ca/Zn, and Mg/Zn in diabetic and non-diabetic rat tissues were also calculated. The determined element levels were further subjected to a student-t test statistical analysis and multiple-linear-regression in order to evaluate similarities, differences, and an inter-element association in tissues of diabetic and non-diabetic rats. The results of the study showed high variability in element levels and Ca/Mg Zn/Cu Mg/Zn Ca/Zn ratios in the tissues of diabetic and non-diabetic rats, but are tissue- and element-dependent, suggesting differences in the accumulation of the elements in tissues of diabetics and non-diabetics. The obtained significant differences in the levels of elements and Ca/Mg Zn/Cu Mg/Zn Ca/Zn ratios in several tissues of diabetic and non-diabetic rats in this study suggest that the investigated elements play considerable roles in the T2DM disease process. Strong inter-element associations (R(2)≥0.9) were observed for some elements in tissues of diabetic and non-diabetics rats. However, poor inter-elemental associations were obtained for some elements in the tissues of diabetic and non-diabetic rats.
Many studies on quorum quenching focus on the discovery and characterization of novel acyl-homoserine lactonases (AHL-lactonases) because these enzymes could be used in the control of diseases caused by Gram-negative bacteria. The effects of quorum quenching are also remarkable in the performance of bacterial consortia in applications such as bioremediation. In the current work, we demonstrated the presence of a potential novel AHL-lactonase-encoding locus (Bsph_3377) from Lysinibacillus sphaericus and Geobacillus sp. The deduced amino acid sequences for this enzyme possess the characteristic domains and motifs involved in Zn-binding from AHL lactonases and were grouped into 1 clade within the phylogeny of the lactonases from firmicutes, showing 70% of identity with the lactonase AhlS from Solibacillus silvestris. We demonstrated the locus transcription by RT-qPCR and its relationship with the suppression of the pathogenicity of Pectobacterium carotovorum. Additionally, we analyzed the interaction of these bacilli with a commercial consortium in the bioremediation of a hydrocarbon-contaminated soil, showing inhibitory effects on its establishment. These results represent a new contribution in the understanding of the potential biotechnological applications of L. sphaericus and Geobacillus sp. as well as in the research on antibacterial techniques based on quorum-sensing disruption.
Metal coordination of bioorganic compounds from both natural and synthetic products is not only gaining recognition in drug design and medicinal inorganic chemistry research, also they are being considered in the improvement of the bioactivity of drugs. What is done in this paper is a review of recent advances in the study of coordination-driven drug delivery, i.e., metal-based drugs (MBDs). The role of some late first row transition metal ions namely Fe, Cu and Zn in the biological activities of metallodrugs such as antimalarials and antimicrobials are highlighted. It was revealed that the interaction between these bio-essential transition metal ions and the organic drugs could enhance the diagnostic and therapeutic potentials of such formed drugs. This is because such interactions were proved to have improved the stability, bioavailability and cell delivery functions of the metallodrugs. Emphasizing on the challenge of metal ions toxicity, the researchers concluded on the need for the development of MBDs to combat drug resistant parasites without causing injury to normal cells. This would be of significance in addressing the concern World Health Organisation of ameliorating the increasing mortality rate in developing countries.
Rhizobia may possess other plant growth-promoting mechanisms besides nitrogen fixation. These mechanisms and the tolerance to different environmental factors, such as metals, may contribute to the use of rhizobia inocula to establish a successful legume-rhizobia symbiosis. Our goal was to characterize a collection of native Portuguese chickpea Mesorhizobium isolates in terms of plant growth-promoting (PGP) traits and tolerance to different metals as well as to investigate whether these characteristics are related to the biogeography of the isolates. The occurrence of six PGP mechanisms and tolerance to five metals were evaluated in 61 chickpea Mesorhizobium isolates previously obtained from distinct provinces in Portugal and assigned to different species clusters. Chickpea microsymbionts show high diversity in terms of PGP traits as well as in their ability to tolerate different metals. All isolates synthesized indoleacetic acid, 50 isolates produced siderophores, 19 isolates solubilized phosphate, 12 isolates displayed acid phosphatase activity, and 22 exhibited cytokinin activity. Most isolates tolerated Zn or Pb but not Ni, Co, or Cu. Several associations between specific PGP mechanisms and the province of origin and species clusters of the isolates were found. Our data suggests that the isolate's tolerance to metals and ability to solubilize inorganic phosphate and to produce IAA may be responsible for the persistence and distribution of the native Portuguese chickpea Mesorhizobium species. Furthermore, this study revealed several chickpea microsymbionts with potential as PGP rhizobacteria as well as for utilization in phytoremediation strategies.
High-throughput screening for asymmetric catalysts has stimulated an interest in optically-based enantiomeric-excess (ee) sensors, primarily for their improved time and cost efficiency when compared to the standard HPLC analysis. We present herein substituent-effect studies on a recently reported Zn(II) multicomponent assembly that is used for chiral, secondary alcohol ee detemination. The systematic altering of assemblies formed from select substituted pyridyl ligands pointed to the conclusion that steric effects dominate the mode of interaction at the pyridyl 3- and 6- positions. From these results we identified a new Zn(II)-centered multicomponent assembly with a higher dynamic range than previously reported. Calibration curves of the CD signals resulting from the new assembly led to an ee assay with a 1.7% error. To further the utility of the new assembly, a correlation was developed between alcohol substituent size to the respective enantiopure CD value.
A thermostable and detergent-stable α-amylase from a newly isolated Anoxybacillus sp. AH1 was purified and characterized. Maximum enzyme production (1874.8 U/mL) was obtained at 24 h of incubation. The amylase was purified by using Sephadex G-75 gel filtration, after which an 18-fold increase in specific activity and a yield of 9% were achieved. The molecular mass of the purified enzyme was estimated at 85 kDa by sodium dodecyl sulphate-polyacrylamide gel electrophoresis (SDS-PAGE). The optimum pH and temperature values of the enzyme were 7.0 and 60 °C, respectively. The enzyme was highly stable in the presence of 30% glycerol, retaining 85% of its original activity at 60 °C within 120 min. Km and vmax values were 0.102 µmol and 0.929 µmol/min, respectively, using Lineweaver-Burk plot. The enzyme activity was increased by various detergents, but it was significantly inhibited in the presence of urea. Mg(2+) and Ca(2+) also significantly activated α-amylase, while Zn(2+), Cu(2+) and metal ion chelators ethylenediaminetetraacetic acid (EDTA) and 1,10-phenanthroline (phen) greatly inhibited the enzyme activity. α-Amylase activity was enhanced by β-mercaptoethanol (β-ME) and dithiothreitol (DTT) to a great extent, but inhibited by p-chloromercuribenzoic acid (PCMB). Iodoacetamide (IAA) and N-ethylmaleimide (NEM) had a slight, whereas phenylmethylsulfonyl fluoride (PMSF) had a strong inhibitory effect on the amylase activity.
Metallic salts as well as protic additives are widely employed in transition metal catalyzed C-H bond functionalization reactions to improve the efficiency of catalytic protocols. In one such example, ZnCl2 and pivalic acid are used as additives in a palladium catalyzed synthesis of isoxazolone from a readily available benzohydroxamic acid under one pot conditions. In this article, we present some important mechanistic insights into the role of ZnCl2 and pivalic acid, gained by using density functional theory (M06) computations. Two interesting modes of action of ZnCl2 are identified in various catalytic steps involved in the formation of isoxazolone. The conventional Lewis acid coordination wherein zinc chloride (ZnCl2·(DMA)) binds to the carbonyl group is found to be more favored in the C-H activation step. However, the participation of a hetero-bimetallic Pd-Zn species is preferred in reductive elimination
 leading to Caryl-N bond formation. Pivalic acid helps in relay proton transfer in C-H bond activation through a cyclometallation deprotonation (CMD) process. The explicit inclusion of ZnCl2 and solvent N,N-dimethyl acetamide (DMA) stabilizes the transition state and also helps reduce the activation barrier for the C-H bond activation step. The electronic communication between the two metal species is playing a crucial role in stabilizing the Caryl-N bond formation transition state through a Pd-Zn hetero-bimetallic interaction.
Cyclic arrays consisting of six zinc-porphyrin units are constructed by the supramolecular self-assembly of a dehydrobenzo[12]-annulene derivative having three zinc porphyrin units at the liquid/graphite interface. Binding with C60 furnishes cyclic hexameric arrays of the complexes on the surface.
The aims of the present investigation were to reveal various trace metal accumulation abilities of two common helophytes Typha latifolia and Phragmites australis and to investigate their potential use in the phytoremediation of environmental metal pollution. The concentrations of Fe, Mn, Zn, Cu, Cd, Pb and Ni were determined in roots, rhizomes, stems and leaves of both species studied as well as in corresponding water and bottom sediments from 19 sites selected within seven lakes in western Poland (Leszczyńskie Lakeland). The principal component and classification analysis showed that P. australis leaves were correlated with the highest Mn, Fe and Cd concentrations, but T. latifolia leaves with the highest Pb, Zn and Cu concentrations. However, roots of the P. australis were correlated with the highest Mn, Fe and Cu concentrations, while T. latifolia roots had the highest Pb, Zn and Cd concentrations. Despite the differences in trace metal accumulation ability between the species studied, Fe, Cu, Zn, Pb and Ni concentrations in the P. australis and T. latifolia exhibited the following accumulation scheme: roots > rhizomes > leaves > stems, while Mn decreased in the following order: root > leaf > rhizome > stem. The high values of bioaccumulation factors and low values of translocation factors for Zn, Mn, Pb and Cu indicated the potential application of T. latifolia and P. australis in the phytostabilisation of contaminated aquatic ecosystems. Due to high biomass of aboveground organs of both species, the amount of trace metals stored in these organs during the vegetation period was considerably high, despite of the small trace metals transport.
Miyun Reservoir is one of the most important drinking water sources for Beijing. Thirteen atmospheric PM sampling sites were established around this reservoir to analyze the mineral composition, morphological characteristics, element concentration, and sources of atmospheric PM pollution, using transmission electron microscope, X-ray diffraction, and inductively coupled plasma mass spectrometry analyses. The average monthly dry deposition flux of aerosols was 15.18 g/m(2), with a range of 5.78-47.56 g/m(2). The maximum flux season was winter, followed by summer, autumn, and spring. Zn and Pb pollution in this area was serious, and some of the sample sites had Cr, Co, Ni, and Cu pollution. Deposition fluxes of Zn/Pb in winter and summer reached 99.77/143.63 and 17.04/33.23 g/(hm(2) month), respectively. Principal component analysis showed two main components in the dry deposition; the first was Cr, Co, Ni, Cu, and Zn, and the other was Pb and Cd. Principal sources of the trace elements were iron mining and other anthropogenic activities in the surrounding areas and mountainous area north of the reservoir. Mineralogy analysis and microscopic conformation results showed many iron minerals and some unweathered minerals in dry deposition and atmospheric particulate matter, which came from an iron ore yard in the northern mountainous area of Miyun County. There was possible iron-rich dry deposition into Miyun Reservoir, affecting its water quality and harming the health of people living in areas around the reservoir and Beijing.
A coumarin-appended rhodamine derivative was prepared by reacting rhodamine hydrazide and coumarin-3-carboxylic acid, which fluorescence sensing behavior toward Zn(2+) against other metal ions was investigated in CH3CN. Significantly, the rodamine-coumarin derivative exhibited highly selective and sensitive recognition toward Zn(2+) with a limit of detection (LOD) down to 10(-9) M. Upon addition of Zn(2+), remarkable fluorescent intensities enhanced and also clear color changed from colorless to pink. The Job's plot indicated the formation of 1:1 complex between the rhodamine-coumarin derivative and Zn(2+). The presence of common coexisting alkali, alkaline earth, and transition metal ions showed small or no interference with the detection of Zn(2+). The conjugate dye could be used for "naked-eye" detection of Zn(2+).
Attic dusts were examined as historical archives of anthropogenic emissions, with the goal of elucidating the enrichment pathways associated with hydrothermal exploitation of Cu, Pb, and Zn minerals in the Bregalnica River basin in the eastern part of the Republic of Macedonia. Dust samples were collected from 84 settlements. Atomic emission spectrometry and mass spectrometry with inductively coupled plasma were applied as analytical techniques for the determination of 69 element contents. Multivariate analysis was applied for the extraction of dominant geochemical markers. The lithogenic distribution was simplified to six dominant geochemical markers: F1: Ga-Nb-Ta-Y-(La-Gd)-(Eu-Lu); F2: Be-Cr-Li-Mg-Ni; F3: Ag-Bi-Cd-Cu-In-Mn-Pb-Sb-Te-W-Zn; F4: Ba-Cs-Hf-Pd-Rb-Sr-Tl-Zr; F5: As-Co-Ge-V; and F6: К-Na-Sc-Ti. The anthropogenic effects on the air pollution were marked by a dominance of F3 and secondary dominance of F5. The fifth factor also was determined as a lithogenic marker for the occurrence of the very old Rifeous shales. The first factor also presents a very unique association that despite the heterogeneity relays on natural phenomena of tracking the deposition in areas of Proterosoic gneisses; related to the distribution of fine particles was associated with carbonate-silicate volcanic rocks. Intensive poly-metallic dust depositions were recorded only in the surroundings of localities where the hydrothermal extractions are implemented. Long-term deposition can be considered as pollution indexes for these hot spots. This mainly affects the Cd, Pb, and Zn deposition that is as high as 25, 3900, and 3200 mg/kg, respectively.
The toxicity and mobility of metals in the environment are driven by their specific chemical forms and binding states. However, heavy metal fractionation in sediments from plateau deep lakes in China is rare. This study analyzed surface sediments collected from Fuxian Lake, the largest deep freshwater lake in China; parameters examined included total metal concentrations, chemical partitioning, and biological risk assessment. The average total concentrations (mg/kg) were 7.9 for Cd, 97.6 for Pb, 102.8 for Cr, 60.8 for Ni, 73.6 for Cu, and 112.9 for Zn; these levels were significantly higher than their corresponding background values. Cd was preferentially associated with the acid-soluble fraction; significant portions of the Pb, Cr, Ni, Cu, and Zn were mainly associated with the residual fractions. Overall, surface sediments of Fuxian Lake were associated with a 21% incidence of toxicity based on the mean effects range-median quotient. Cd was mainly at high or very high risk levels, and Cu and Zn were mainly at medium or high risk levels based on the risk assessment code (RAC).
Zinc is involved in both type-1 (T1DM) and type-2 (T2DM) diabetes. The wildtype (WT) form of the beta-cell specific Zn(2+) transporter, ZNT8, is linked to T2DM susceptibility. ZnT8 null mice have a mild phenotype with a slight decrease in glucose tolerance, whereas patients with the ZnT8 R325W polymorphism (rs13266634) have decreased proinsulin staining and susceptibility to T2DM. We measured zinc, insulin, and proinsulin stainings, and IPGTT in transgenic mice overexpressing hZnT8 WT or hZnT8 R325W fed a normal or high fat diet (HFD). The hZnT8 R325W transgenic line had lower pancreatic [Zn(2+)]i and proinsulin, and higher insulin and glucose tolerance compared to control littermates after 10 weeks of a HFD in male mice. The converse was true for the hZnT8 WT transgenic line, and dietary Zn(2+) supplementation also induced glucose intolerance. Finally, pancreatic zinc binding proteins were identified by Zn(2+)-affinity chromatography and proteomics. Increasing pancreatic Zn(2+) (hZnT8WT) induced nucleoside diphosphate kinase B (NDPKB), and Zn(2+) reduction (hZnT8RW) induced carboxypeptidaseA1 (CpA1). These data suggest that pancreatic Zn(2+) and proinsulin levels covary, but are inversely variant with insulin or glucose tolerance in the HFD model of T2DM suggesting novel therapeutic targets.
Bacillus stearothermophilus alkaline protease was conjugated to several oxidized polysaccharides of different chemical structure. The conjugates were evaluated for the kinetic and thermodynamic stability. The conjugated enzyme with oxidized pectin had the highest retained activity (79.5%) and the highest half-life (T1/2) at 50°C and pH 9.0. Compared to the native protease, the conjugated preparation exhibited lower activation energy (Ea), lower deactivation constant rate (kd), higher T1/2, and higher D values (decimal reduction time) within the temperature range of 50-60 °C. The thermodynamic parameters for irreversible inactivation of native and conjugated protease indicated that conjugation significantly decreased entropy (ΔS*) and enthalpy (ΔH*) of deactivation. The calculated value of activation energy for thermal denaturation (Ead) for the conjugated enzyme was 20.4 KJmole(-1) higher over the native one. The results of thermodynamic analysis
 for substrate hydrolysis indicated that the enthalpy of activation (ΔH*) and free energy of activation (free energy of substrate binding) ΔG*E-S and (ΔG*), (free energy of transition state) ΔG*E-T values were lower for the modified protease. Similarly, there was significant improvement of kcat, kcat/Km values. The enzyme proved to be metalloprotease and significantly stimulated by Ca(2+) and Mg(2+) whereas Hg(2+), Fe(3+) Cu(2+) and Zn(2+) inhibited the enzyme activity. There was no pronounced effect on substrate specificity after conjugation.
Parathyroid hormone (PTH) has attracted considerable interest as a bone anabolic agent. PTH plays a central role in regulating calcium phosphate metabolism and its increases in production in response to low serum calcium levels. A continuous hypersecretion of PTH, as occurs in primary hyperparathyroidism, leads to bone resorption. In this study, the effect of different doses of parathyroid hormone (PTH) on bone mineral content (BMC) in rats was investigated by particle-induced X-ray emission (PIXE). This study will help in investigating further the toxicity of extremely high doses of PTH on BMC. For this study, PTH at doses of 15, 45, or 135μg/kg/day were applied to 9-month-old male and female Sprague Dawley (SD) rats. The concentrations of calcium (Ca), phosphorus (P), strontium (Sr), and zinc (Zn) were measured for bone treatment of PTH. From the results of the research, it was revealed that the biomechanical characteristics of the bone as well as the bone mass were enhanced after the treatment. It was further found that the concentrations of other elements also increased, excluding Zn. This research proved that PTH assists in the treatment of osteoporosis as revealed by the characteristics of different elements. PIXE can be used to determine the concentrations of bone mineral content.
Hyperprolificacy in modern pig breeds has led to increased use of artificial rearing and formula feeding of neonatal piglets, which may change their intestinal bacterial ecophysiology. Here, newborn piglets ( = 8 per group) were fed a bovine milk-based formula (FO) or allowed to suckle their mothers (sow milk [SM]) for 2 wk, and digesta samples from the stomach, jejunum, and colon were subsequently analyzed for enzyme activities, bacterial metabolites, and 16S rRNA transcripts of bacterial groups by quantitative real-time PCR. Jejunal lactase activity was lower and lactose concentration was greater in the jejunum and colon in the FO group compared with the SM group ( < 0.05). In the stomach, FO-fed pigs had a lower copy number of 16S rRNA transcripts for all analyzed bacterial groups ( < 0.05) except for the // group. In the jejunum, 16S rRNA transcripts of lactic acid bacteria and clostridial cluster I were lower ( < 0.05) in FO-fed pigs. In turn, transcript abundance of the group and clostridial cluster I was greater in FO-fed pigs in the colon ( < 0.05). In FO-fed piglets, concentrations of and lactate and total and individual short-chain fatty acids were higher in the colon ( < 0.05). Multivariate redundancy analysis revealed that the concentration of minerals (ash, Ca, Mg, K, Na, Mn, and Zn) were associated with reduced bacterial abundance and activity in the upper gastrointestinal tract, whereas lactose had the most pronounced effect on the colon microbiota. The present study revealed that, apart from lactose, the mineral concentration modifies the microbial communities in the gastrointestinal tract of FO-fed piglets.
Angus-cross steers ( = 128) were used to examine the effects of supplementing ferric ammonium citrate (FAC; 300 mg ferric Fe/kg DM) to diets of 20, 40, or 60% dried distillers' grains plus solubles (DDGS) on growth performance, liver mineral and ruminal hydrogen sulfide (HS) concentrations, and carcass traits of finishing steers. Steers were blocked by initial BW (436 ± 10.6 kg) into pens of 4 and randomly assigned to 1 of 6 treatments ( = 5 or 6 pens per treatment) including a 20, 40, or 60% DDGS inclusion diet with (+) or without (-) 300 mg Fe/kg DM from FAC. Liver biopsies (d -9/-10 and 96) and HS measures (d 0, 7, 14, 21, and 95) were determined from 1 steer/pen. Steers were harvested on d 102 and carcass data were collected. A treatment × month effect ( ≤ 0.006) was noted for ADG and G:F, in which the 20-FAC ADG and feed efficiency were greater ( ≤ 0.02) between d 0 to 28 but lesser ( ≤ 0.04) from d 29 to 56 than that of the 20+FAC steers. Final BW linearly decreased ( < 0.01) as DDGS inclusion increased. Final BW tended to be greater ( = 0.10) in the 60+FAC steers than in the 60-FAC steers, whereas final BW was not different ( ≥ 0.32) due to FAC supplementation in the 20 or 40% DDGS diets. A quadratic effect was noted for DMI ( = 0.02), where 60% DDGS decreased DMI. Within the 20% DDGS diet FAC+ improved DMI ( = 0.03) but had no effect within 40 or 60% DDGS inclusion. Ruminal HS concentrations were not affected ( ≥ 0.25) by FAC, but increasing DDGS linearly increased ( < 0.01) ruminal HS values. Liver Cu was decreased ( < 0.01) by FAC across all DDGS inclusions and tended to linearly decrease ( = 0.06) with increasing DDGS inclusion, whereas liver Fe, Mn, and Zn were not altered ( ≥ 0.11) by DDGS inclusion. Liver Zn concentrations tended to be ( = 0.08) or were ( = 0.03) decreased by FAC supplementation within 20 and 40% DDGS, respectively. Increasing the inclusion of DDGS linearly decreased ( = 0.04) HCW and quadratically affected marbling score where the 40% DDGS had the greatest ( = 0.02) marbling scores. Supplementation of FAC within 60% DDGS improved ( ≤ 0.03) HCW and LM area. Marbling scores were greater ( ≤ 0.04) in 20+FAC and 40+FAC compared with 20-FAC and 40-FAC, respectively. In conclusion, although ruminal HS concentrations were not affected by FAC under the conditions of this study, supplementing FAC to diets containing 60% DDGS improved HCW and LM area, suggesting that FAC may be beneficial when dietary S concentrations exceed 0.5%.
Maternal and progeny diets supplemented with 2 sources of trace mineral (TM) were evaluated for effects on the size and severity of osteochondrosis (OC) lesions in progeny produced by 64 Landrace × Large White sows. At breeding, sows were randomly assigned to maternal diets (gestation and lactation) consisting 1 of 2 TM treatments. One treatment consisted of inorganic TM (ITM) with ZnO, MnSO, and CuSO at concentrations to provide 150, 50, and 16.5 mg/kg diet of Zn, Mn, and Cu, respectively. The other treatment consisted of the same ITM concentrations plus an additional 50, 20, and 10 mg/kg diet of Zn, Mn, and Cu, respectively, supplied by a blend of AA-complexed TM (CTM) using Availa Sow. Within maternal dietary treatment groups, selected progeny ( = 280) were fed either ITM- or CTM-supplemented diets. The humerus and femur (1 each) from progeny euthanized at 12 ( = 80) or 24 wk ( = 200) were collected for microscopic (12 wk) or gross (24 wk) assessment of OC lesions. Microscopic OC lesions were present in all pigs at 12 wk. Dietary treatments had limited effects on OC prevalence or severity. A maternal × progeny diet interaction ( = 0.044) revealed femoral OC latens lesions that were approximately twice the size in progeny fed CTM that were produced by sows fed CTM compared with those found in pigs in the other 3 dietary treatment groups. At 24 wk, the sum of gross OC scores at predilection sites of the thoracic (elbow joint) and pelvic (stifle and hock joints) limbs remained similar among treatments, despite greater ( = 0.004) gross OC scores of the medial femoral condyle in progeny from sows fed CTM diets than in progeny from sows fed ITM diets, regardless of progeny diet. Progeny produced by sows fed CTM vs. ITM had increased ADG (0.71 vs. 0.68 ± 0.01 kg/d), regardless of the diet fed to progeny during the growth phases. Covariant analysis using ADG did not alter inferences about maternal or progeny diet effects on OC responses. Although 100% of progeny at 12 wk had histologically apparent OC lesions, only 3 of the 200 pigs examined at 24 wk had gross lesions of sufficient severity to potentially result in clinically apparent disease. Therefore, although some results imply that maternal and progeny CTM diets increased the size (12 wk) and severity (24 wk) of OC in 1 site (the femur), on the whole animal level, no evidence of lameness was noted.
An experiment was conducted to determine the effect of supplementing diets fed to growing pigs with fat sources differing in their composition of fatty acids on the apparent total tract digestibility (ATTD) of minerals. A diet based on corn, potato protein isolate, and 7% sucrose was formulated. Five additional diets that were similar to the previous diet with the exception that sucrose was replaced by 7% tallow, choice white grease, palm oil, corn oil, or soybean oil were also formulated. Diets were formulated to contain 0.70% Ca and 0.33% standardized total tract digestible P. Growing barrows ( = 60; 15.99 ± 1.48 kg initial BW) were allotted to a randomized complete block design with 2 blocks of 30 pigs, 6 dietary treatments, and 10 replicate pigs per treatment. Experimental diets were provided for 12 d with the initial 5 d being the adaptation period. Total feces were collected for a 5-d collection period using the marker-to-marker approach, and the ATTD of minerals, ether extract, and acid hydrolyzed ether extract was calculated for all diets. Digestibility of DM was greater ( < 0.05) in the diet containing soybean oil compared with the diet containing choice white grease or the basal diet, with all other diets being intermediate. The ATTD of Ca, S, and P was greater ( < 0.05) for pigs fed diets containing soybean oil, corn oil, palm oil, or tallow than for pigs fed the basal diet or the diet containing choice white grease. The ATTD of Mg, Zn, Mn, Na, and K were not different
 among dietary treatments. The ATTD of ether extract was greater ( < 0.05) in diets containing palm oil, corn oil, or soybean oil compared with the diet containing choice white grease, and the ATTD of acid hydrolyzed ether extract in the diet containing soybean oil was also greater ( < 0.05) than in the diet containing choice white grease. In conclusion, supplementation of a basal diet with tallow, palm oil, corn oil, or soybean oil may increase the ATTD of some macrominerals, but that appears not to be the case if choice white grease is used. There was no evidence of negative effects of the fat sources used in this experiment on the ATTD of any minerals.
Previous research indicates that finishing steer ADG and G:F increases linearly with increasing dietary Zn-amino acid complex (ZnAA) supplementation in cattle fed ractopamine hydrochloride (RAC). The objective of this study was to determine the influence of supplemental Zn-amino acid complex on growth performance and carcass characteristics of finishing steers fed RAC for 0, 28, or 42 d prior to harvest. This study was organized as 2 groups (GRP) of steers fed concurrently, for 91 (GRP 1) or 84 d (GRP 2). A total of 324 steers (463 ± 23.4 kg) were fed a corn-based finishing diet supplemented with 60 mg Zn/kg diet DM (as ZnSO). Steers were blocked by weight to pens of 6 steers, and assigned to receive either 0 (CON) or 60 mg supplemental Zn/kg DM from ZnAA ( = 27 pens per treatment). Receiving ZnAA for 49 (GRP 1) or 42 d (GRP 2) prior to start of RAC feeding had no impact on growth of steers ≥ 0.19). Forty-two d prior to harvest, pens were equally assigned within CON or ZnAA treatments to receive RAC at 300 mg∙steer∙d for 0 (NoRAC), 28 (28RAC), or 42 d (42RAC) prior to harvest, creating 6 final treatments ( = 9 pens per treatment). All steers within a GRP were harvested on the same day. Pen was the experimental unit, and the statistical model included the fixed effects of ZnAA, RAC, and block nested within GRP, and the random effect of pen. Ractopamine hydrochloride supplementation increased carcass-adjusted ADG, final BW, HCW, and ribeye area ( ≤ 0.007). There was an effect of ZnAA within 28RAC and 42RAC where carcass-adjusted ADG ( ≤ 0.10), and final BW and HCW ( ≤ 0.05) were greater in ZnAA supplemented vs. CON steers, and 28RAC steers supplemented with ZnAA had improved overall carcass-adjusted G:F relative to CON steers ( = 0.04). However, when steers did not receive RAC there was no effect of ZnAA on final BW, ADG, or HCW ( ≥ 0.78). Additionally, ZnAA supplementation had no effect on the difference in performance between steers supplemented with RAC for 28 vs. 42 d ( 0.21). In conclusion, under the conditions of this study supplemental ZnAA did not prevent the diminished response to RAC as days on RAC increased from 28 to 42. However, there appears to be a synergistic effect of ZnAA on RAC-induced cattle growth, as supplementing 60 mg Zn/kg DM from ZnAA to cattle fed RAC improved overall growth and HCW.
Anthropogenic activities at the HudBay Minerals, Inc., Flin Flon (Manitoba, Canada) mining and processing facility have severely affected the surrounding boreal forest ecosystem. Soil contamination occurred via a combination of metal and sulfuric acid deposition and has resulted in forest dieback and ineffective natural recovery. A community-led effort to revegetate areas of the landscape through the application of a dolomitic limestone has been met with varied success. Zinc (Zn) speciation has shown to be closely linked to the presence or absence of an invasive metal-tolerant grass species, with soils being broadly classed into two revegetation response groups. Group I, characterized by the absence of metal-tolerant grasses, and group II, characterized by the presence of metal-tolerant grasses. The systematic approach used to lime areas of the landscape produced a liming chronosequence for each group. This study used a combination of X-ray absorption spectroscopy, X-ray fluorescence mapping, and X-ray diffraction techniques to determine the effect of liming on Zn speciation in these chronosequences. Liming group I soils resulted in the formation of a neo-phase Zn-Al-hydroxy interlayer coprecipitate and subsequent rapid boreal forest revegetation. The effect of liming on Zn speciation on the group II soils resulted in a gradual transition of increasingly stable adsorption species, culminating with a stable Zn-Al-layered double hydroxide precipitate. Boreal forest vegetation has failed to recolonize group II soils during the study. However, the formation of the layered double hydroxide species resulted in a significant reduction in CaCl-extractable Zn. Further research is required to determine how to promote the revegetation of these soils.
Land application of biosolids to low-fertility soil can improve soil quality by increasing concentrations of macronutrients and trace elements. Mixing biosolids with sawdust could reduce the risks of contaminant accumulation posed by rebuilding soils using biosolids alone. We aimed to determine the effects of biosolids and biosolids-sawdust on the plant quality and chemical composition of sorghum, rapeseed, and ryegrass. Plants were grown in a greenhouse over a 5-mo period in a low-fertility soil amended with biosolids (1250 kg N ha), biosolids-sawdust (0.5:1), or urea (200 kg N ha). Biosolids application increased the biomass of sorghum, rapeseed, and ryegrass up to 14.0, 11.9, and 4.1 t ha eq, respectively. Mixing sawdust with biosolids resulted in a growth response similar to biosolids treatments in rapeseed but nullified the effect of biosolids in sorghum. Urea fertilization provided insufficient nutrients to promote rapeseed growth and seed production, whereas seed yields after biosolids application were 2.5 t ha. Biosolids and biosolids-sawdust application enhanced plant quality by increasing element concentrations, especially Zn, and potentially toxic elements (Cd, Cr, Ni) did not exceed food safety standards. An application of 50 t ha of biosolids, equivalent to 1250 kg N ha, did not exceed current soil limits of Cu, Zn, and Cd and hence was effective in rebuilding soil without accumulating contaminants. The effect of mixing sawdust with biosolids varies with plant species but can further enhance plant nutrient quality in biomass and seeds, especially P, Cu, Zn, Mn, Fe, S, and Na.
Several studies have examined the effect of submergence on the mobility of metals present in mine waste materials. This study examines the effect of organic carbon (OC) and sulfur (S) additions and submergence time on redox-induced biogeochemical transformations of lead (Pb), zinc (Zn), and cadmium (Cd) present in mine waste materials collected from the Tri-State mining district located in southeastern Kansas, southwestern Missouri, and northeastern Oklahoma. A completely randomized design, with a two-way treatment structure, was used for conducting a series of column experiments. Two replicates were used for each treatment combination. Effluent samples were collected at several time points, and soil samples were collected at the end of each column experiment. Because these samples are highly heterogeneous, we used a variety of synchrotron-based techniques to identify Pb, Zn, and Cd speciation at both micro- and bulk-scale. Spectroscopic analysis results from the study revealed that the addition of OC, with and without S, promoted metal-sulfide formation, whereas metal carbonates dominated in the nonamended flooded materials and in mine waste materials only amended with S. Therefore, the synergistic effect of OC and S may be more promising for managing mine waste materials disposed of in flooded subsidence mine pits instead of individual S or OC treatments. The mechanistic understanding gained in this study is also relevant for remediation of waste materials using natural or constructed wetland systems.
The greatest obstacle for the treatment of cystic fibrosis patients infected with the Burkholderia species is their intrinsic antibiotic resistance. For this reason, there is a need to develop new effective compounds. Glutamate racemase, an essential enzyme for the biosynthesis of the bacterial cell wall, is an excellent candidate target for the design of new antibacterial drugs. To this aim, we recombinantly produced and characterized glutamate racemase from Burkholderia cenocepacia J2315. From the screening of an in-house library of compounds, two Zn (II) and Mn (III) 1,3,5-triazapentadienate complexes were found to efficiently inhibit the glutamate racemase activity with IC50 values of 35.3 and 10.0 μM, respectively. Using multiple biochemical approaches, the metal complexes have been shown to affect the enzyme activity by binding to the enzyme-substrate complex and promoting the formation of an inhibited dimeric form of the enzyme. Our results corroborate the value of glutamate racemase as a good target for the development of novel inhibitors against Burkholderia.
A ferromagnetic (FM)-metal/oxide stack is the key structure determining the performance of spintronic devices. However, the effect of the electronic polarity of the oxide on the magnetic properties of the adjacent FM-metal has not been investigated previously. Here, we report the magnetic and structural properties of Co ultra-thin films sputter deposited directly on the Zn- and O-polar surfaces of ZnO substrates. The magnetic anisotropy and Curie temperature exhibit dramatic polarity-dependent differences for films on these surfaces. Structural analyses reveal that the heterointerface of the Co/O-polar surface is rather diffusive, whereas that of the Co/Zn-polar surface is atomically flat. These results suggest that the surface polarity plays a key role in determining the properties of the film. This novel FM-metal/polar-oxide system is expected to add new functionality to spintronic
 devices and provide an ideal basis for investigating the effect of a built-in electric field on the magnetism in a metallic monolayer.
Screening of metagenomic library from Taptapani Hot Spring (Odisha) yielded a positive lipase clone (pUC-lip479). Sequence analysis showed an ORF (RK-lip479) of 416 amino acid residues which was overexpressed in Escherichia coli BL21 (DE3). Optimum pH and temperature of purified lipase RK-lip479 were 8.0 and 65 °C, respectively, and found to be stable over a pH range of 7.0-9.0 and temperatures 55-75 °C. RK-lip479 could hydrolyse a wide range of 4-nitrophenyl esters (4-nitrophenyoctanoate, 4-nitrophenyldodecanoate, 4-nitrophenylpalmitate, 4-nitrophenylmyristate and 4-nitrophenylstearate), and maximum activity was observed with 4-nitrophenyldodecanoate. RK-lip479 was resistant to many organic solvents, especially isopropanol, DMSO, methanol, DMF, ethanol, dichloromethane, acetone, glycerol and ethyl acetate. RK-lip479 also showed activity in the presence of monovalent (Na(+) and K(+)), divalent (Mg(2+), Mn(2+), Ca(2+), Hg(2+), Cu(2+), Co(2+), Zn(2+) and Ag(2+) ) and trivalent cations (Fe(3+) and Al(3+)). Yield of biodiesel production was in the range of 40-76% using various waste oils with RK-Lip479 under optimized conditions.
Gold nanoparticles (GNPs) are widely used for medical purposes, both in diagnostics as well as drug delivery, and hence are prone to release and distribution in the environment. Thus, we have explored the effects of GNPs with two distinct surface capping (citrate and PVP), and three different sizes (16, 27, and 37 nm) at 0.01-, 0.1-, and 1-mg L(-1) concentrations on a predominant freshwater alga Scenedesmus obliquus in the sterile freshwater matrix. We have also investigated how an abundant metal ion from freshwater, i.e., Zn(2+) ions may modulate the effects of the selected GNPs (40 nm, citrate, and PVP capped). Preliminary toxicity results revealed that gold nanoparticles were highly toxic in comparison to zinc ions alone. A significant modulation in the toxicity of Zn ions was not noticed in the presence of GNPs. In contrast, zinc ions minimized the toxicity produced by GNPs (both CIT-37 and PVP-37), despite its individual toxicity. Approximately, about 42, 33, and 25% toxicity reduction was noted at 0.05-, 0.5-, and 5-mg L(-1) Zn ions, respectively, for CIT-37 GNPs, while 31% (0.05 mg L(-1)), 24% (0.5 mg L(-1)), and 9% (5 mg L(-1)) of toxicity reduction were noted for PVP-37 GNPs. Maximum toxicity reduction was seen at 0.05 mg L(-1) of Zn ions. Abbott modeling substantiated antagonistic effects offered by Zn(2+) ions on GNPs. Stability and sedimentation data revealed that the addition of zinc ions gradually induced the aggregation of NPs and in turn significantly reduced the toxicity of GNPs. Thus, the naturally existing ions like Zn(2+) have an ability to modulate the toxicity of GNPs in a real-world environment scenario.
Improper disposal of mining waste is still considered a global problem, and further details on the contamination by potentially toxic metals are required for a proper assessment. In this context, it is important to have a combined view of the chemical and biological changes in the mining dump area. Thus, the objective of this study was to evaluate the Pb, Zn and Cd contamination in a slag disposal area using the integration of geochemical and microbiological data. Analyses of soil organic matter (SOM), pH, Eh, pseudo-total concentration of metals, sequential extraction and microbial community by polymerase chain reaction-denaturing gradient gel electrophoresis (PCR-DGGE) were conducted. Metal availability was evaluated based on the geoaccumulation index (I geo), ecological risk ([Formula: see text]), Risk Assessment Code (RAC) and experimental data, and different reference values were tested to assist in the interpretation of the indices. The soil pH was slightly acidic to neutral, the Eh values indicated oxidized conditions and the average SOM content varied from 12.10 to 53.60 g kg(-1). The average pseudo-total concentrations of metals were in the order of Zn > Pb > Cd. Pb and Zn were mainly bound to the residual fraction and Fe-Mn oxides, and a significant proportion of Cd was bound to the exchangeable and carbonate fractions. The topsoil (0-20 cm) is highly contaminated (I geo) with Cd and has a very high potential ecological risk ([Formula: see text]). Higher bacterial diversity was mainly associated with higher metal concentrations. It is concluded that the integration of geochemical and microbiological data can provide an appropriate evaluation of mining waste-contaminated areas.
Zinc (Zn) and copper (Cu) may play a pivotal role in the pathogenesis of diabetes and diabetic complications by mediating oxidative stress. Both Zn deficiency and excess of Cu are associated with an increased risk of type 2 diabetes and cardiovascular disease. We aimed to investigate the relationships between serum Zn/Cu ratio and glycemic status, renal function, and metabolic parameters in patients with and without type 2 diabetes.
We conducted a cross-sectional study on 355 subjects (149 type 2 diabetic and 206 non-diabetic) in whom serum Zn and Cu levels were measured at the same time. Associations between serum Zn/Cu ratio and clinical data were evaluated using multiple regression analysis. We also evaluated associations between serum Zn/Cu ratio and the prevalence of type 2 diabetes and glycemic control by multivariate logistic regression analysis.
Serum Zn/Cu ratio was positively associated with estimated glomerular filtration rate after adjustment for body mass index (BMI) (β = 0.137, p = 0.014). Plasma B-type natriuretic peptide levels were negatively associated with serum Zn/Cu ratio after adjustment for age, sex, and BMI (β = -0.258, p = 0.032). In patients with type 2 diabetes, serum Zn/Cu ratio was negatively associated with plasma HbA1c levels after adjustment for age, sex, and BMI (β = -0.239, p = 0.003). In addition, multivariate logistic regression analysis revealed that the highest quartile of serum Zn/Cu ratio was associated with a reduced risk of poor (HbA1c ≥ 7%) glycemic control (odds ratio = 0.382; 95% confidence interval, 0.165-0.884; p = 0.025) in patients with type 2 diabetes.
Serum Zn/Cu ratio was favorably associated with renal function in all subjects and glycemic control in patients with type 2 diabetes. The Zn/Cu ratio, in addition to the individual serum levels of trace elements, is important for metabolism in humans.
Plastoglobuli (PG) are thylakoid-associated monolayer lipid particles with a specific proteome of ~30 PG core proteins and isoprenoid- and neutral lipids. During senescence, PG increase in size, reflecting their role in dismantling thylakoid membranes. Here we show that the only PG-localized peptidase, PGM48, positively regulates leaf senescence. We discovered that PGM48 is a member of the M48 peptidase family with PGM48 homologs, forming a clade (M48D) only found in photosynthetic organisms. Unlike the M48A, B, and C clades, members of M48D have no transmembrane domains, consistent with their unique subcellular location in the PG. In vitro assays showed Zn-dependent proteolytic activity and substrate cleavage upstream of hydrophobic residues. Overexpression of PGM48 accelerated natural leaf senescence, whereas suppression delayed senescence. Quantitative proteomics of PG from senescing rosettes of PGM48 overexpression lines showed a dramatically reduced level of CAROTENOID CLEAVAGE ENZYME 4 (CCD4), and significantly increased levels of the senescence-induced ABC1 kinase 7 (ABC1K7) and PHYTYL ESTER SYNTHASE 1 (PES1). Yeast-2-hybrid experiments identified PG core proteins ABC1 KINASE 3, PES1, and CCD4 as PGM48 interactors, whereas several other PG-localized proteins and chlorophyll degradation enzymes did not interact. We discuss mechanisms through which PGM48 could possibly accelerate the senescence process.
Sewage sludge derived biochar (SSDB) was used as a supplementary material for municipal sewage sludge (SS) and wood chips mixtures (WC) treated by combined composting and vermicomposting. SSDB added to the mixture before composting resulted in significantly higher reproduction rate: on week 4 the number of cocoons increased by 213% when compared to the mixture with no biochar. On week 6 the average number of juveniles increased 11-fold in the mixture with biochar added before composting and 5-fold in the mixtures with biochar added after composting when compared to the mixture with no biochar. Biochar added before composting reduced bioavailability of Cd and Zn to E. fetida. The biochar-added vermicomposts showed good fertilizing properties except for elevated concentrations of Cr. The pH of all vermicomposts was in the range of 5.27-5.61. The obtained vermicomposts can be used as a growing medium for horticultural purposes or as an amendment in calcareous soils.
Alcohol dehydrogenase (ADH) activity is widely distributed in the three domains of life. Currently, there are three non-homologous NAD(P)+-dependent ADH families reported: Type I ADH comprises Zn-dependent ADHs; type II ADH comprises short-chain ADHs described first in Drosophila; and, type III ADH comprises iron-containing ADHs (FeADHs). These three families arose independently throughout evolution and possess different structures and mechanisms of reaction. While types I and II ADHs have been extensively studied, analyses about the evolution and diversity of (type III) FeADHs have not been published yet. Therefore in this work, a phylogenetic analysis of FeADHs was performed to get insights into the evolution of this protein family, as well as explore the diversity of FeADHs in eukaryotes.
Results showed that FeADHs from eukaryotes are distributed in thirteen protein subfamilies, eight of them possessing protein sequences distributed in the three
 domains of life. Interestingly, none of these protein subfamilies possess protein sequences found simultaneously in animals, plants and fungi. Many FeADHs are activated by or contain Fe2+, but many others bind to a variety of metals, or even lack of metal cofactor. Animal FeADHs are found in just one protein subfamily, the hydroxyacid-oxoacid transhydrogenase (HOT) subfamily, which includes protein sequences widely distributed in fungi, but not in plants), and in several taxa from lower eukaryotes, bacteria and archaea. Fungi FeADHs are found mainly in two subfamilies: HOT and maleylacetate reductase (MAR), but some can be found also in other three different protein subfamilies. Plant FeADHs are found only in chlorophyta but not in higher plants, and are distributed in three different protein subfamilies.
FeADHs are a diverse and ancient protein family that shares a common 3D scaffold with a patchy distribution in eukaryotes. The majority of sequenced FeADHs from eukaryotes are distributed in just two subfamilies, HOT and MAR (found mainly in animals and fungi). These two subfamilies comprise almost 85% of all sequenced FeADHs in eukaryotes.
Objective: The use of Shamma (smokeless tobacco) by certain groups is giving rise to health problems, including cancer, in parts of Saudi Arabia. Our objective was to determine metals levels in Shamma using inductively coupled plasma mass spectrometry (ICP-MS). Methods: Thirty-three samples of Shamma (smokeless tobacco) were collected, comprising four types: brown Shamma (n = 14.0), red Shamma (n = 9.0), white Shamma (n = 4.0), and yellow Shamma (n = 6.0). All samples were collected randomly from Shamma users in the city of Najran. Levels of 11 elements (Al, As, Cd, Co, Cr, Cu, Li, Mn, Ni, Pb, and Zn) were determined by ICP-MS. Results: A mixed standard (20 ppb) of all elements was used for quality control, and average recoveries ranged from 74.7% to 112.2%. The highest average concentrations were found in the following order: Al (598.8–812.2 μg/g), Mn (51.0–80.6 μg/g), and Ni (23.2–53.3 μg/g) in all four Shamma types. The lowest concentrations were for As (0.7–1.0 μg/g) and Cd (0.0–0.06 μg/g). Conclusions: The colour of each Shamma type reflects additives mixed into the tobacco. Cr and Cu were showed significant differences (P < 0.05) among Shamma types. Moreover, Pb levels are higher in red and yellow Shamma, which could be due to use (PbCrO4) as yellow colouring agent and lead tetroxide, Pb3O4 as a red colouring agent. The findings from this study can be used to raise public awareness about the safety and health effects of Shamma, which is clearly a source of oral exposure to metals.
The study was conducted to investigate the effects of dietary administrations of four nutraceuticals in dogs. Seventy four dogs were enrolled in the trials, 24 healthy dogs were fed with a control diet (CT) and the experimental groups received for 60days the same diet supplemented with nutraceuticals, namely Echinacea angustifolia (EA, 0.10mg/kg live weight as echinacoside; 14 dogs), Vaccinium myrtillus (VM, 0.20mg/kg live weight as anthocyanidin, 13 dogs), Curcuma longa (CL, 6.60mg/kg live weight as curcumin, 18 dogs with arthrosis), and Sylibum marianum (SM, 1.5mg/kg live weight as sylibin, 8 dogs with hepatopathy). Dogs were weighted at the beginning of study and blood samples were collected at the beginning (T0) and at the end (T60) of the study. VM significantly down regulated TNF, CXCL8, NFKB1 and PTGS2 and decreased plasma ceruloplasmin (CuCp). The activity of EA was evidenced by the significant decrease of TNF and NFKB1 expression and CuCp levels and by the increase of plasma Zn. Administration of CL caused a significant decrease of CuCp and increase of Zn and a down regulation of TNF, CXCL8, NFKB1 and PTGS2, corroborating the anti-inflammatory action of curcuminoids. After 60days of treatment with SM, plasma ALT/GPT activity was reduced and paraoxonase was increased, supporting the antioxidant activity of silymarin, also confirmed by the significant up regulation of SOD2. Results indicated that nutraceutical administrations in dogs can be an interesting approach to modulate immune response in order to improve health condition of animals.
In this contribution, a computational study of equatorial bound tetranuclear macrocycle (butylene linked) [LnZn(HOM(Bu))](3+) (Ln = La(3+), Ce(3+)) complexes was carried out. Here, the electronic structure, bonding interaction and excitation energies were studied within the relativistic density functional theory framework. From the electronic structure analysis, the frontier molecular orbitals (FMOs) were strongly localized in the d-orbitals of the Zn centers and the f-orbitals of the lanthanide ions. Besides, the inner MOs were found to exhibit a π-character from the organic part of the macrocyclic chain. EDA-NOCV was used as a tool for evaluating the bonding interaction, taking the trinuclear metallomacrocycle (ZnHOM(Bu)) and the lanthanide center as fragments. This analysis showed that the interaction between these fragments was slightly covalent; with this covalency being the result of a charge transfer from the metallomacrocyclic ring to the lanthanide. This phenomenon was observed in the deformation density channels obtained from the EDA-NOCV study; in which π- and σ-charge transfer was observed. Finally, the TD-DFT study of the excitation energies evidenced three sets of bands: the first set with the highest intensity represented the ligand to metal charge transfer bands; the second set could be attributed to the 3d-4f electronic transitions between the metal centers; and the third set represented the f-f bands found for the open-shell cerium complex. This class of complexes accomplishes the "antenna effect" principle, which states that highly absorptive transition-metal (TM) complexes can be used to enhance the luminescence of poorly emissive systems, and are introduced in this study as self-sensitizer bimetallic d-f systems with potential applications in near infra-red (NIR) technologies.
Materials with surfaces that can be switched from high/superhydrophobicity to superhydrophilicity are useful for myriad applications. Herein, we report a metal-organic framework (MOF) assembled from Zn(II) ions, 1,4-benzenedicarboxylate, and a hydrophobic carborane-based linker. The MOF crystal-surface can be switched between hydrophobic and superhydrophilic through a chemical treatment to remove some of the building blocks.
Nitric oxide (NO) has emerged as a signaling molecule in plants being involved in diverse physiological processes like germination, root growth, stomata closing and response to biotic and abiotic stress. S-nitrosoglutathione (GSNO) as a biological NO donor has a very important function in NO signaling since it can transfer its NO moiety to other proteins (trans-nitrosylation). Such trans-nitrosylation reactions are equilibrium reactions and depend on GSNO level. The breakdown of GSNO and thus the level of S-nitrosylated proteins are regulated by GSNO-reductase (GSNOR). In this way, this enzyme controls S-nitrosothiol levels and regulates NO signaling. Here we report that Arabidopsis thaliana GSNOR activity is reversibly inhibited by H2O2in vitro and by paraquat-induced oxidative stress in vivo. Light scattering analyses of reduced and oxidized recombinant GSNOR demonstrated that GSNOR proteins form dimers under both reducing and oxidizing conditions. Moreover, mass spectrometric analyses revealed that H2O2-treatment increased the amount of oxidative modifications on Zn(2+)-coordinating Cys47 and Cys177. Inhibition of GSNOR results in enhanced levels of S-nitrosothiols followed by accumulation of glutathione. Moreover, transcript levels of redox-regulated genes and activities of glutathione-dependent enzymes are increased in gsnor-ko plants, which may contribute to the enhanced resistance against oxidative stress. In sum, our results demonstrate that reactive oxygen species (ROS)-dependent inhibition of GSNOR is playing an important role in activation of anti-oxidative mechanisms to damping oxidative damage and imply a direct crosstalk between ROS- and NO-signaling.
A new paradigm in metallobiochemistry describes the activation of inactive metalloenzymes by metal ion removal. Protein tyrosine phosphatases (PTPs) do not seem to require a metal ion for enzymatic activity. However, both metal cations and metal anions modulate their enzymatic activity. One binding site is the phosphate binding site at the catalytic cysteine residue. Oxyanions with structural similarity to phosphate, such as vanadate, inhibit the enzyme with nanomolar to micromolar affinities. In addition, zinc ions (Zn(2+)) inhibit with picomolar to nanomolar affinities. We mapped the cation binding site close to the anion binding site and established a specific mechanism of inhibition occurring only in the closed conformation of the enzyme when the catalytic cysteine is phosphorylated and the catalytic aspartate moves into the active site. We discuss this dual inhibition by anions and cations here for PTP1B, the most thoroughly investigated protein tyrosine phosphatase. The significance of the inhibition in phosphorylation signaling is becoming apparent only from the functions of PTP1B in the biological context of metal cations as cellular signaling ions. Zinc ion signals complement redox signals but provide a different type of control and longer lasting inhibition on a biological time scale owing to the specificity and affinity of zinc ions for coordination environments. Inhibitor design for PTP1B and other PTPs is a major area of research activity and interest owing to their prominent roles in metabolic regulation in health and disease, in particular cancer and diabetes. Our results explain the apparent dichotomy of both cations (Zn(2+)) and oxyanions such as vanadate inhibiting
 PTP1B and having insulin-enhancing ("anti-diabetic") effects and suggest different approaches, namely targeting PTPs in the cell by affecting their physiological modulators and considering a metallodrug approach that builds on the knowledge of the insulin-enhancing effects of both zinc and vanadium compounds.
Artemisia fragrans is a plant species with ability of growing on heavy metal-polluted soils. Ecotypes of this species naturally growing in polluted areas can accumulate and tolerate different amounts of heavy metals (HM), depending on soil contamination level at their origin. Heavy metal tolerance of various ecotypes collected from contaminated (AP, SP) and non-contaminated (BG) sites was compared by cultivation on a highly HM-contaminated river sediment and a non-contaminated agricultural control soil. Tissue-specific HM distribution was analyzed by laser ablation-inductively-coupled plasma-mass spectroscopy (LA-ICP-MS) and photosynthetic activity by non-invasive monitoring of chlorophyll fluorescence. Plant-mineral analysis did not reveal ecotype-differences in concentrations of Cd, Zn, Cu in shoots of Artemisia plants, suggesting no differential expression of root uptake or root to shoot translocation of HM. There was also no detectable rhizosphere effect on HM concentrations on the contaminated soil. However, despite high soil contaminations, all ecotypes accumulated Zn only in the concentration range of generally reported for normal growth of plants, while Cu and Cd concentrations were close to or even higher than the toxicity level for most plants. As a visible symptom of differences in HM tolerance, only the AP ecotype was able to enter the generative phase to complete its life cycle. Analysis of tissue-specific metal distribution revealed significantly lower concentrations of Cd in the leaf mesophyll of this ecotype, accumulating Cd mainly in the leaf petioles. A similar mesophyll exclusion was detectable also for Cu, although not associated with preferential accumulation in the leaf petioles. However, high mesophyll concentrations of Cd and Cu in the SP and BG ecotypes were associated with disturbances of the photosynthetic activity. The findings demonstrate differential expression of HM exclusion strategies in Artemisia ecotypes and suggest Cd and Cu exclusion from the photosynthetically active tissues as a major tolerance mechanism of the AP ecotype.
A pathological hallmark of Alzheimer disease and other tauopathies is the formation of neurofibrillary tangles mainly composed of bundles of fibrils formed by microtubule-associated protein Tau. Here we study the effects of Zn(2+) on abnormal aggregation and cytotoxicity of a pathological mutant ΔK280 of full-length human Tau. As revealed by Congo red binding assays, transmission electron microscopy, immunofluorescence, Western blot, and immunogold electron microscopy, pathological concentration of Zn(2+) dramatically accelerates the fibrillization of ΔK280 both in vitro and in SH-SY5Y neuroblastoma cells. As evidenced by annexin V-FITC apoptosis detection assay and MTT reduction assay, pathological concentration of Zn(2+) remarkably enhances ΔK280 fibrillization-induced apoptosis and toxicity in SH-SY5Y cells. Substitution of Cys-291 and Cys-322 with Ala, however, essentially eliminates such enhancing effects of Zn(2+) on the fibrillization and the consequent cytotoxicity of ΔK280. Furthermore, Zn(2+) is co-localized with and highly enriched in amyloid fibrils formed by ΔK280 in SH-SY5Y cells. The results from isothermal titration calorimetry show that Zn(2+) binds to full-length human Tau by interacting with Cys-291 and Cys-322, forming a 1:1 Zn(2+)-Tau complex. Our data demonstrate that zinc dramatically accelerates abnormal aggregation of human Tau and significantly increases Tau toxicity in neuronal cells mainly via bridging Cys-291 and Cys-322. Our findings could explain how pathological zinc regulates Tau aggregation and toxicity associated with Alzheimer disease.
The aim of this study was to establish concentrations of a wide range of elements in human lung samples to allow better identification of potential exposures in subsequent cases. This study reports concentrations of 48 elements (Al, As, Au, B, Ba, Be, Bi, Br, Cd, Ce, Co, Cr, Cs, Cu, Fe, Ga, Gd, Ge, Hf, Hg, In, Li, Mn, Mo, Nb, Ni, Os, Pb, Pd, Pt, Rb, Re, Ru, Sb, Se, Sm, Sn, Sr, Ta, Te, Ti, Tl, Tm, V, W, Y, Zn and Zr) in fresh lung tissue samples from 54 hospital patients, of which 93% exhibited various forms of neoplasia. The lung samples were taken from unaffected, background tissue. The samples were stored as fresh tissue in alcohol, dried and microwave digested before analysis by inductively coupled mass spectrometry (ICP-MS). It was possible to establish 95th percentiles for all elements except for rhenium and for 40 elements mixed effects modelling was undertaken. Overall, the levels reported are commensurate with ranges for those elements that had been reported previously. The data were examined for gender, smoking and occupational exposures to metals. The results show that males have higher lung concentrations of Ni, Cr, Gd, Au and Be than females, but significantly lower lung concentrations of Co, Sn, W and In. Cadmium lung concentrations were significantly higher in smokers. Platinum lung concentrations were higher in those who had undergone chemotherapy and gadolinium concentrations were predictably high in those who had undergone imaging scans. More essential elements such as Cu, Br, Fe and also Ge varied the least within lung samples from individuals whilst Be, Hf and Pt had the greatest variances. Between individuals V and Li lung concentrations varied the most, whilst Cu varied least. Analysis of the data for those who reported as having previously worked with metals showed 24 of the 48 elements determined were higher than those from those who had not reported working with metals.
To investigate the effect of Mn on antioxidant status and on the expressions of heat shock proteins/factors in tissues of laying broiler breeders subjected to heat challenge, we used a completely randomised design (n 6) with a factorial arrangement of 2 environmental temperatures (normal, 21±1°C, and high, 32±1°C)×3 dietary Mn treatments (a Mn-unsupplemented basal diet (CON), or a basal diet supplemented with 120 mg Mn/kg diet, either as inorganic Mn sulphate (iMn) or as organic Mn proteinate (oMn)). There were no interactions (P>0·10) between environmental temperature and dietary Mn in any of the measured indices. High temperature decreased (P<0·003) Mn content, and also tended (P=0·07) to decrease Cu Zn superoxide dismutase (CuZnSOD) activity in the liver and heart. However, an increased Mn superoxide dismutase (MnSOD) activity (P<0·05) and a slight increase in malondialdehyde level (P=0·06) were detected in breast muscle. Up-regulated (P<0·05) expressions of heat shock factor 1 (HSF1) and HSF3 mRNA and heat shock protein 70 (HSP70) mRNA and protein were found in all three tissues. Broiler breeders fed either iMn or oMn had higher tissue Mn content (P<0·0001), heart MnSOD and CuZnSOD activities (P<0·01) and breast muscle MnSOD protein levels (P<0·05), and lower (P<0·05) breast muscle HSP70 mRNA and protein levels compared with those fed CON. Broiler breeders fed oMn had higher (P<0·03) bone Mn content than those fed iMn. These results indicate that high temperature decreases Mn retention and increases HSP70, HSF1 and HSF3 expressions in the tissues of laying broiler breeders. Furthermore, dietary supplementation with Mn in either source may enhance the heart's antioxidant ability and inhibit the expression of HSP70 in breast muscle. Finally, the organic Mn appears to be more available than inorganic Mn for bone in laying broiler breeders regardless of environmental temperatures.
The present study deals with the assessment of sequential extraction of particulate matter (PM)-bound metals and the potential health risks associated with them in a growing metropolitan city (Pune) of India. The average mass concentration of both PM2.5-10 and PM2.5 exceeded the National Ambient Air Quality Standards. Significant seasonal variation in mass concentration was found for both size fractions of PM with higher values in winter season and lower in monsoon. Chemical species of the studied trace metals in PM exhibited significant differences, due to difference in sources of pollution. Metals such as Cd, Pb, and Cr in both size fractions and Zn and Co in fine fraction were more efficiently extracted in mobile fractions showing their mobile nature while Ni and Fe showed reduced mobility. Fe showed the highest concentrations among all the analyzed elements in both coarse (PM2.5-10) and fine (PM2.5) PM, while Cd showed least concentration in both size fractions. PCA identified industrial emissions, vehicular activity, coal combustion, diesel exhaust, waste incineration, electronic waste processing, constructional activities, soil, and road dust as probable contributors responsible for the metallic fraction of PM. All the metals showed varying contamination in PM samples. The contamination was higher for fine particles than coarse ones. The average global contamination factor was found to be 27.0-34.3 in coarse and fine PM, respectively. The hazard quotient (HQ) estimated for Cd, Co, and Ni (both total and easily accessible concentrations) exceeded the safe level (HQ = 1), indicating that these metals would result in non-carcinogenic health effects to the exposed population. The HQ ranged from 9.1 × 10(-5) for Cu (coarse) to 8.3 for Ni (fine) PM. The cancer risk for Cd, Ni, and Cr in both sized PM were much higher than the acceptable limits of USEPA.
Moss biomonitoring using the species Hypnum cupressiforme (Hedw.) and Pleurocarpous sp was applied to study air pollution in the Republic of Moldova. A total of 41 elements
 (Na, Mg, Al, Cl, K, Ca, Sc, Ti, V, Cr, Mn, Fe, Co, Ni, Cu, Zn, As, Se, Br, Rb, Sr, Zr, Cd, Sb, Cs, Ba, La, Ce, Nd, Sm, Eu, Gd, Tb, Tm, Yb, Hf, Ta, W, Pb, Th, and U) were determined by instrumental epithermal neutron activation analysis and atomic absorption spectrometry. Principal component analysis was used to identify and characterize different pollution sources. Geographical distribution maps were prepared to point out the regions most affected by air pollution and relate this to potential sources of contamination. Median values of the elements studied were compared with data from the European moss biomonitoring program. The cities of Chisinau and Balti were determined to experience particular environmental stress.
The leaching behaviors of primary copper (Cu) slags originating from Ausmelt, reverbatory, and converter furnaces operating under a single technological process were compared to a residual slag tailing obtained by slag re-processing via flotation and metal recovery. The EN 12457-2 leaching test, used for assessment of the hazardous properties, was followed by the CEN/TS 14997 pH-static leaching test (pH range 3-12). Both leaching experiments were coupled with a mineralogical investigation of the primary and secondary phases as well as geochemical modeling. Metals (Cd, Cu, Pb, Zn) exhibit the highest leaching at low pH. Under acidic conditions (pH 3-6), Ausmelt slag and slag tailing exhibited higher metal leaching compared to other slag types. Very low leaching of metals (far below EU limits for non-hazardous waste) was observed at natural pH (7.9-9.0) for all the studied slag samples. In contrast, relatively high leaching of As was observed over the entire pH range, especially for Ausmelt slag (exceeding the EU limit for hazardous waste by 1.7×). However, geochemical modeling and scanning electron microscopy indicated that formation of stable Ca-Cu-Pb arsenates and the binding of As to newly formed Fe (oxyhydr)oxides play an important role in efficient As immobilization at the slag-water interface. In contrast, no controls were predicted for Sb, whose leaching was almost pH-independent. Nevertheless Sb leached concentrations at natural pH were below EU limit for hazardous waste. Re-processing of primary Cu slags for metal recovery, and subsequent co-disposal of the resulting slag tailing with dolomite-rich mine tailing and local laterite is suitable for stabilizing the remaining contaminants (except Sb) and limiting their leaching into the environment.
Information about heavy metal burden of children in Nigeria related to playground soils and classroom dusts is lacking. Playground soil, classroom dust, blood and spot urine samples (n=253) were collected from 6 urban and 2 semi-rural public schools in Ibadan North-West, Nigeria. Samples were analysed for Pb, Cu, Zn, Fe and Mn. Mean blood Pb levels in urban area (male, 41.66±8.78μg/dl vs. female, 40.64±5.46μg/dl) were twice as high as those in semi-rural area (male, 19.71±3.73μg/dl vs. female, 20.65±2.26μg/dl). Concentrations of Pb, Cu, Zn, and Fe in soil and dust samples in the urban schools were between 2- to 4-fold greater than that of semi-rural schools. No correlation was observed between blood and dust metals. A positive correlation (r=0.168, p=0.008) was observed between blood Pb and playground soil Pb. Pb burden in the children might be from their schools' playgrounds and other yet unidentified sources.
Ocean acidification, caused by increasing atmospheric carbon dioxide (CO2), is a growing concern in marine environments. Land-based sources of pollution, such as metals, have also been a noted problem; however, little research has addressed the combined exposure of both pollutants to coral reef organisms. In this study we examined tissue metal accumulation and physiological effects (activity of anti-oxidant enzymes, catalase and glutathione reductase) in the sea anemone, Exaiptasia pallida after exposure to increased CO2, as well as zinc (Zn) or nickel (Ni). After exposure to four concentrations (nominal values=control, 10, 50, 100μg/L) of Zn or Ni over 7days, both metals accumulated in the tissues of E. pallida in a concentration-dependent manner. Anemones exposed to elevated CO2 (1000ppm) accumulated significant tissue burdens of Zn or Ni faster (by 48h) than those exposed to the same metal concentrations at ambient CO2. No differences were observed in catalase activity due to Zn exposure; however, 50μg/L Ni caused a significant increase in catalase activity at ambient CO2. No significant effect on catalase activity from CO2 exposure alone was observed. Glutathione reductase activity was affected by increased Zn or Ni exposure and those effects were influenced by increased CO2. Results of this study provide insight into the toxic mechanisms and environmental implications of CO2 and Zn or Ni exposure to the cnidarian E. pallida.
Due to the significantly fast urban expansion and increased industrial activities, the soils in the farms in Addis Ababa are contaminated by some toxic and potentially toxic elements (As, V, Cr, Fe, Co, Ni, Cu, B, Ba, Sr, Zn, Mn, Pb and Cd) in varying degrees. The mean concentrations of Cr, Ni, As and B in most of the soil farms were found to be higher than the maximum recommended limits. The mean concentrations of Cd, Cu, Pb, Co, Ni and Mn were found to be higher than the background soil concentrations given for uncontaminated soils. Multivariate analyses coupled with correlation analysis were used to identify possible sources. The geo-accumulation index values for Cr, Mn and Pb indicated that the farm soils were unpolluted to moderately polluted as a result of anthropogenic activities. A comprehensive environmental management strategy should be formulated by the government to measure further pollution of the farmland soil.
Efficient photodynamic inactivation of microbes requires highly efficient photosensitizers which kill microbial cells, but spare host tissues. One way to achieve such selectivity is to use photosensitizers that are rapidly taken up by microbes and, when applied at low concentrations, efficiently kill them after a short illumination. Design of such photosensitizers requires insight into molecular properties which are critical for antimicrobial photo-efficiency. This study explores the contribution of molecular shape and exposure of charges, to the antimicrobial activity of tetra-cationic Zn porphyrin-based photosensitizers.
Two isomers, ortho (2) and meta (3) hexyl and octyl Zn(II) meso-tetrakis(N-alkylpyridinium-2(3)-yl)porphyrins [ZnTnHex-2(3)-PyP and ZnTnOct-2(3)-PyP] were compared for uptake and photo-efficiency against a Gram-negative bacterium, Escherichia coli.
The highest photo-efficiency was displayed by the meta hexyl derivative. At concentration as low as 1.0μM and during only 5min of preincubation with the cells, ZnTnHex-3-PyP decreased viable cell number by about 6 log10 after only 5min of illumination. Since bacterial suspensions were thoroughly washed after preincubation with photosensitizers, this effect can be attributed only to photosensitizer taken up or bound to E. coli. Irrespective of its highest uptake by the cells, the octyl meta isomer, ZnTnOct-3-PyP, did not show higher antibacterial activity than the shorter-chain hexyl derivative, ZnTnHex-3-PyP.
Efficiency and eventually selectivity of antimicrobial photosensitizers can be improved by optimizing the shape of the molecule and the position of electric charges. Increasing lipophilicity and cellular uptake per se, does not necessarily materialize in high antimicrobial efficiency of the photosensitizer.
This study explored the possible preventive effects of dietary phenylalanine (Phe) on antioxidant responses, apoptosis and tight junction protein transcription in the gills of young grass carp (Ctenopharyngodon idella). Fish were fed six different experimental diets containing graded levels of Phe (3.4-16.8 g kg(-1)) for 8 weeks. The results showed that Phe deficiency induced protein oxidation and lipid peroxidation by decreasing the glutathione content and the activities and mRNA levels of Cu/Zn superoxide dismutase (SOD1), catalase (CAT), glutathione peroxidase (GPx), glutathione reductase (GR) and glutathione-S-transferase (GST) in fish gill (P < 0.05). These results may be ascribed to the downregulation of NF-E2-related factor 2 (Nrf2), target of rapamycin (TOR) and ribosomal protein S6 kinase 1 (S6K1), and the upregulation of Kelch-like-ECH-associated protein 1 a (Keap1a) expression in grass carp gills (P < 0.05). Additionally, Phe deficiency induced DNA fragmentation via the up-regulation of Caspase 3, Caspase 8 and Caspase 9 mRNA expression (P < 0.05). These results may be ascribed to the improvement in reactive oxygen species (ROS) levels in the fish gills (P < 0.05). Furthermore, the results indicated that Phe deficiency decreased Claudin b, Claudin 3, Occludin and ZO-1 transcription and increased Claudin 15 expression in the fish gills (P < 0.05). These effects were partly due to the downregulation of interleukin 10 (IL-10), transforming growth factor β (TGF-β) and inhibitor factor κBα (iκBα) and the upregulation of relative mRNA expression of interleukin 1β (IL-1β), interleukin 8 (IL-8), tumour necrosis factor-α (TNF-α) and nuclear transcription factor-κB p65 (NF-κB p65) (P < 0.05). Taken together, the results showed that Phe deficiency impaired the structural integrity of fish gills by regulating the expression of tight junction proteins, cytokines, antioxidant enzymes, NF-κB p65, iκBα, TOR, Nrf2, Keap1 and apoptosis-related genes in the fish gills.
The present study aims (1) to characterize contaminated soils (n=6) and mine tailings samples (n=3) for As, Cu, Fe, Mn, Ni, Pb, and Zn content; and (2) to assess elemental lung bioaccessibility in fine fraction (d<20μm which might contribute to airborne particulate matter
 (PM) and thus be inhaled) by means of in vitro tests using Gamble's solution (GS) and an artificial lysosomal fluid (ALF). Elemental concentrations were high in the majority of samples, particularly for As (up to 2040mg·kg(-1)), Fe (up to 30.7%), Mn (up to 4360mg·kg(-1)), and Zn (up to 4060mg·kg(-1)); and elemental concentrations (As, Cu, and Ni) in the sieved fraction (d<20μm) obtained from contaminated soils were significantly higher than in the bulk fraction (<160μm). In vitro tests with ALF yielded much higher bioaccessibility than tests with GS, and the use of ALF in addition to GS is recommended to assess lung bioaccessibility. Bioaccessibility in ALF was high for all elements after 2weeks of testing both in terms of concentration (e.g. up to 1730mg·kg(-1) for As) and percentages (e.g. up to 81% for Pb). The elemental solubilization rate generally declined rapidly and continuously with time. Similarly, bioaccessibility increased rapidly and tended to reach a plateau with time for most samples and metals. However, it is not possible to recommend a general testing duration as the solubilization behavior was highly element and sample-specific.
Nanotechnology is a rising field and nanomaterials can now be found in a vast variety of products with different chemical compositions, sizes and shapes. New nanostructures combining different nanomaterials are being developed due to their enhancing characteristics when compared to nanomaterials alone. In the present study, the toxicity of a nanostructure composed by a ZnO nanomaterial with Ag nanomaterials on its surface (designated as ZnO/Ag nanostructure) was assessed using the model-organism Daphnia magna and its toxicity predicted based on the toxicity of the single components (Zn and Ag). For that ZnO and Ag nanomaterials as single components, along with its mixture prepared in the laboratory, were compared in terms of toxicity to ZnO/Ag nanostructures. Toxicity was assessed by immobilization and reproduction tests. A mixture toxicity approach was carried out using as starting point the conceptual model of Concentration Addition. The laboratory mixture of both nanomaterials showed that toxicity was dependent on the doses of ZnO and Ag used (immobilization) or presented a synergistic pattern (reproduction). The ZnO/Ag nanostructure toxicity prediction, based on the percentage of individual components, showed an increase in toxicity when compared to the expected (immobilization) and dependent on the concentration used (reproduction). This study demonstrates that the toxicity of the prepared mixture of ZnO and Ag and of the ZnO/Ag nanostructure cannot be predicted based on the toxicity of their components, highlighting the importance of taking into account the interaction between nanomaterials when assessing hazard and risk.
Emissions of pollutants from highways can exert multiple stresses on adjacent ecosystems. In this study air concentrations of NO2 and throughfall deposition of inorganic N (NO3(-) and NH4(+)), SO4(2-), Cl(-), base cations and several metals were measured in all four seasons along a 1.5km hardwood forest gradient extending away from a major highway (Highway 401) in southern Ontario, Canada. Soil and lichen chemistry and herbaceous plant and epiphytic lichen species composition were measured within the hardwood forest to evaluate impacts of these pollutants. Air concentrations of NO2 and deposition of inorganic N, Cl(-), base cations and Cu and Zn in throughfall were significantly elevated within 100m of the road compared with the more distant sites. Concentrations of several pollutants including N (and δ(15)N), Na(+), Al and Fe in epiphytic lichen tissue decreased with distance from the highway, and epiphytic lichen richness was lower at sites within 100m of the road. Despite high throughfall inputs of >15kgNha(-1)y(-1) and 100kgNa(+)ha(-1)y(-1) within 33m of the highway, for example, there was no significant difference in soil chemistry amongst sites. Plant community composition at sites within 80m of the highway differed from sites located further from the road, but it is unclear whether differences were due to highway emissions or were a result of natural forest edge effects.
The evolution of trace metal pollution on the Barcelona city continental shelf during the last few decades was studied by analyzing the historical records of trace metals in sediment cores and surface sediment samples taken at the same locations in 1987 and in 2008. Polluted surface samples taken in 1987 reached enrichment factors of up to 490 for Hg, about 40 for Pb and Cd, and about 17 for Zn, Cr and Cu. The data show a decline of up to one order of magnitude in the trace metal content of surface sediments during the last few decades, with maximum enrichment factors of between 20 and 30 for Hg and Cd and between 5 and 12 for Zn, Cr, Pb and Cu. Although present-day pollution is still significant, it is evident that environmental regulations that are in place, including the operation since 1979 of wastewater treatment plants built in the Besòs River watershed, have drastically reduced the pollution levels in this highly populated and industrialized Mediterranean area. However, water discharge during heavy rain events exceeds the treatment capacity of the existing facilities, leading to the maintenance of still high levels of metals in sediments of the Barcelona city shelf.
This study aimed to evaluate the spatial and temporal distribution of heavy metals (Cd, Cr, Cu, Co, Fe, Pb, Ni, V, and Zn) in the sediments of Bayan Lepas Free Industrial Zone of Penang, Malaysia. Ten sampling stations were selected and sediment samples were collected during low tide (2012-2013). Metals were analyzed and the spatial distribution of metals were evaluated based on GIS mapping. According to interim sediment quality guidelines (ISQG), metal contents ranged from below low level to above high level at different stations. Based on the geoaccumulation index (Igeo) of sediment, sampling stations were categorized from unpolluted to strongly polluted. The enrichment factor (EF) of metals in the sediment varied between no enrichment to extremely high enrichment. The potential ecological risk index (RI) indicated Bayan Lepas FIZ was at low risk.
Determination of rare earth elements (REEs) plays an important role in the extraction process. In this work, surface-enhanced laser-induced breakdown spectroscopy (SENLIBS) was introduced to detect REEs (lanthanum, cerium，praseodymium，and neodymium elements) in an aqueous solution. The emission lines of La II 394.91nm, Ce II 418.66nm, Pr II 422.29nm, and Nd II 406.10nm were selected for quantitative analysis by drying the analytical samples on a Zn metal substrate surface and optimizing the experimental parameters. The results showed that the limits of detection (LoDs) for determining La, Ce, Pr, and Nd elements can reach to 0.85, 4.07, 2.97, and 10.98μgmL(-1), respectively, which proved that SENLIBS is a feasible method for determining REEs.
Metallothioneins are cysteine-rich proteins, which function as (i) metal carriers in basal cell metabolism and (ii) protective metal chelators in conditions of metal excess. Metallothioneins have been characterized from different eukaryotic model and cultivable species. Presently, they are categorized in 15 families but evolutionary relationships between these metallothionein families remain unresolved. Several cysteine-rich protein encoding genes that conferred Cd-tolerance in Cd-sensitive yeast mutants have previously been isolated from soil eukaryotic metatranscriptomes. They were called CRPs for "cysteine-rich proteins". These proteins, of unknown taxonomic origins, share conserved cysteine motifs and could be considered as metallothioneins. In the present work, we analyzed these CRPs with respect to their amino acid sequence features and their metal-binding abilities towards Cd, Zn and Cu metal ions. Sequence analysis revealed that they share common features with different known metallothionein families, but also exhibit unique specific features. Noticeably, CRPs display two separate cysteine-rich domains which, when expressed separately in yeast, confer Cd-tolerance. The N-terminal domain contains some conserved atypical Cys motifs, such as one CCC and two CXCC ones. Five CRPs were expressed and purified as recombinant proteins and their metal-binding characteristics were studied. All these CRPs chelated Cd(II), Zn(II) and Cu(I), although displaying a better capacity for Zn(II) coordination. All CRPs are able to confer Cd-tolerance, and four of them confer Zn-tolerance in the Zn-sensitive zrc1Δ yeast mutant. We designated these CRPs as environmental metallothioneins belonging to a new formerly undescribed metallothionein family.
Substitution is an effective method to create new nonlinear optical (NLO) materials with an enhanced second harmonic generation (SHG) response. However, the large SHG enhancement caused by the substitution of Mg(2+) for Zn(2+) in an isostructural system is rare and has not been investigated yet. Here we elucidate the contribution of Zn(2+) with d(10) electronic configuration to the SHG response based on two isostructural silicates Sr2MSi2O7 (M = Zn and Mg). The powder SHG measurements show that the SHG response of Sr2ZnSi2O7 is approximately 35 times that of α-SiO2 and 7 times higher than its isostructural compound Sr2MgSi2O7. The calculated band structures reveal that the difference in band gaps is minute and the sp hybridization between 4s-orbitals of Zn and 2p-orbitals of O is stronger than that between 3s-orbitals of Mg and 2p-orbitals of O. The significantly enhanced SHG response of Sr2ZnSi2O7 can be interpreted by the enhanced inter-band dipole resulting from strong sp hybridization between Zn and O. This provides a route to design new materials with enhanced NLO properties in the isostructural
 system.
We report a simple synthetic approach to coaxially grow transition metal oxide (TMO) nanostructures on carbon nanotubes (CNT) with ready control of phase and morphology. A thin (~4 nm) sulfonated-polystyrene (SPS) pre-coating is essential for the deposition of transition metal based materials. This layer has abundant sulfonic groups (-SO3(-)) that can effectively attract Ni(2+), Co(2+), Zn(2+) ions through electrostatic interaction and induce them via hydrolysis, dehydration and recrystallization to form coaxial (NiO, Co3O4, NiCoO2 and ZnCo2O4) shells and a nanosheet-like morphology around CNT. These structures possess a large active surface and enhanced structural robustness when used as electrode materials for lithium-ion batteries (LIBs) and electrochemical capacitors (ECs). As electrodes for LIBs, the ZnCo2O4@CNT material shows extremely stable cycling performance with a discharge capacity of 1068 mAh g(-1) after 100 cycles at a current density of 400 mAg(-1). For EC applications, the NiCoO2@CNT exhibits a high capacitance of 1360 Fg(-1) at current densities of 10 Ag(-1) after 3000 cycles and an overall capacitance loss of only 1.4%. These results demonstrate the potential of such hybrid materials meeting the crucial requirements of cycling stability and high rate capability for energy conversion and storage devices.
A 'two birds, one stone' strategy was developed via a one-pot click reaction to simultaneously prepare a novel cyclodextrin (CD) dimer based aggregation induced emission (AIE) sensor (AIE-DCD) and a monomer based chiral stationary phase (CSP-MCD) for chiral high performance liquid chromatography (CHPLC). AIE-DCD was found to afford satisfactory AIE response for specific detection of Zn(2+) with a detection limit of 50 nM. CSP-MCD exhibits excellent enantioseparation ability toward dansyl amino acids, where the resolution of dansyl amino leucine reaches 5.43.
Efficacious chemotherapy does not exist for treatment or prevention of prostate, liver, and pancreatic carcinomas, and some other cancers that exhibit decreased zinc in malignancy. Zinc treatment offers a potential solution; but its support has been deterred by adverse bias. Areas covered: 1. The clinical and experimental evidence for the common ZIP transporter/Zn down regulation in these cancers. 2. The evidence for a zinc approach to prevent and/or treat these carcinomas. 3. The issues that introduce bias against support for the zinc approach. Expert opinion: ZIP/Zn downregulation is a clinically established common event in prostate, hepatocellular and pancreatic cancers. 2. Compelling evidence supports the plausibility that a zinc treatment regimen will prevent development of malignancy and termination of progressing malignancy in these cancers; and likely other carcinomas that exhibit decreased zinc. 3. Scientifically-unfounded issues that oppose this ZIP/Zn relationship have introduced bias against support for research and funding of a zinc treatment approach. 4. The clinically-established and supporting experimental evidence provide the scientific credibility that should dictate the support for research and funding of a zinc approach for the treatment and possible prevention of these cancers. 5. This is in the best interest of the medical community and the public-at-large.
Toluene is a basic chemical that is currently produced from petroleum resources. In this paper, we report a new route for the effective synthesis of toluene from isoprene and acrolein, two reactants readily available from biomass, through a simple two-step reaction. The process includes Diels-Alder cycloaddition of isoprene and acrolein in a Zn-containing ionic liquid at room temperature to produce methylcyclohex-3-enecarbaldehydes (MCHCAs) as intermediates, followed by M (M=Pt, Pd, Rh)/Al2 O3 -catalyzed consecutive dehydrogenation-decarbonylation of the MCHCAs at 573 K to generate toluene with an overall yield up to 90.7 %. Model reactions indicated that a synergistic inductive effect of the C=C double bond and the aldehyde group in MCHCA plays a key role in initiating the consecutive dehydrogenation-decarbonylation, and that methyl benzaldehydes are the key intermediates in the gas-phase transformation of MCHCAs. Microcalorimetric adsorption of CO on different catalysts showed that decarbonylation of the substrate occurs more likely on the strong adsorption sites. To the best of our knowledge, it is the first report of Pt/Al2 O3 -catalyzed consecutive dehydrogenation-decarbonylation of a given compound in one reactor. This work provides a highly efficient and environmental friendly route to toluene by utilizing two compounds that can be prepared from biomass.
As a new class of crystalline nanoporous materials, metal-organic frameworks (MOFs) have recently been used for biomedical applications due to their large surface area, high porosity, and theoretically infinite structures. To improve the biological performance of titanium, MOF films were applied to surface modification of titanium. Zn-based MOF films composed of zeolitic imidazolate framework-8 (ZIF-8) crystals with nanoscale and microscale sizes (nanoZIF-8 and microZIF-8) were prepared on porous titanium surfaces by hydrothermal and solvothermal methods, respectively. The ZIF-8 films were characterized by powder X-ray diffraction (PXRD), Fourier transform infrared spectroscopy (FTIR), and scanning electron microscopy (SEM). The nanoZIF-8 film exhibited good biocompatibility, whereas the microZIF-8 film showed obvious cytotoxicity to MG63 cells. Compared to pure titanium and alkali- and heat-treated porous titanium, the nanoZIF-8 film not only enhanced alkaline phosphatase (ALP) activity, extracellular matrix mineralization, and expression of osteogenic genes (ALP, Runx2) in MG63 cells but also inhibited the growth of Streptococcus mutans. These results indicate that MOF films or coatings may be promising candidates for bone tissue engineering. © 2016 Wiley Periodicals, Inc. J Biomed Mater Res Part A, 2016.
The ability of seven species of aquatic plants (Elodea canadensis, Najas guadelupensis, Vallisneria spiralis L., Riccia fluitans L., Limnobium laevigatum, Pistia stratiotes L., and Salvinia natans L.) to absorb metal nanoparticles from colloidal solutions was studied. It was established that investigated aquatic plants have a high capacity for removal of metal nanoparticles from aqueous solution (30-100%) which indicates their high phytoremediation potential. Analysis of the water samples content for elements including the mixture of colloidal solutions of metal nanoparticles (Mn, Cu, Zn, Ag + Ag2O) before and after exposure to plants showed no significant differences when using submerged or free-floating hydrophytes so-called pleuston. However, it was found that the presence of submerged hydrophytes in aqueous medium (E. canadensis, N. guadelupensis, V. spiralis L., and R. fluitans L.) and significant changes in the content of photosynthetic pigments, unlike free-floating hydrophytes (L. laevigatum, P. stratiotes L., S. natans L.), had occur. Pleuston possesses higher potential for phytoremediation of contaminated water basins polluted by metal nanoparticles. In terms of removal of nanoparticles among studied free-floating hydrophytes, P. stratiotes L. and S. natans L. deserve on special attention.
Up to 50% of patients have zinc deficiency before bariatric surgery. Roux-en-Y gastric bypass (RYGB) is the commonest bariatric procedure worldwide. It can further exacerbate zinc deficiency by reducing intake as well as absorption. The British Obesity and Metabolic Surgery Society, therefore, recommends that zinc level should be monitored routinely following gastric bypass. However, the American guidance does not recommend such monitoring for all RYGB patients and reserves it for patients with 'specific findings'. This review concludes that clinically relevant Zn deficiency is rare after RYGB. Routine monitoring of zinc levels is hence unnecessary for asymptomatic patients after RYGB and should be reserved for patients with skin lesions, hair loss, pica, dysgeusia, hypogonadism or erectile dysfunction in male patients, and unexplained iron deficiency anaemia.
MicroRNAs have been associated with prognosis in oesophageal cancer (EC), suggesting that miRNAs could play a role in guiding treatment decisions. The aim of this study was to evaluate the prognostic potential of miRNAs found to be associated with zinc deficiency in a geographical area with a high incidence of EC. miRNAs found to be associated with zinc deficiency were isolated from EC cell lines cultured with various Zn levels. The expression levels of the miRNAs were quantified using qRT-PCR. The potential prognostic value of the selected miRNAs was assessed in a cohort study of 88 patients from an area in China with a high incidence of EC. Correlations between miRNAs and patient characteristics were assessed using χ(2) statistical tests or Fisher's exact test. A Cox proportional hazards model was used to assess the correlations between miRNAs and overall survival (OS). Forest plots were performed to evaluate the prognostic impact of the miRNAs examined in the present study in the Asian population. The expression levels of miR-21, miR-31, miR-93 and miR-375 were different when Zn levels were varied in EC cell lines, but only miR-21 and miR-375 were associated with patient characteristics and prognosis in patients with EC from an area of China with a high incidence of EC. The patients expressing high levels of miR-21 had poor OS (HR 2.15, 95% CI 1.16-3.97), whereas those with high levels of miR-375 had improved OS (HR 0.47, 95% CI 0.26-0.87).The patients with both a high level of miR-375 and a low level of miR-21 had significantly better outcomes. Forest plots based on an analysis of this Asian population indicated that a high level of miR-21 significantly
 predicted a shortened OS (HR 1.83, 95% CI 1.42-2.37), whereas a high level of miR-375 was significantly correlated with increased survival (HR 0.56, 95% CI 0.43-0.73). MiR-21 and miR-375 could be used as prognostic biomarkers in areas with a high incidence of EC, and combining these markers may results in a better effect.
Biodegradable zinc oxide nanoparticles (ZnO NPs) are considered promising materials for future biomedical applications. To fulfil this potential, biodistribution and elimination patterns of ZnO NPs in the living organism need to be resolved. In order to investigate gastrointestinal absorption of ZnO NPs and their intra-organism distribution, water suspension of ZnO or fluorescent ZnO:Eu (Europium-doped zinc oxide) NPs (10mg/ml; 0.3ml/mouse) was alimentary-administered (IG: intra-gastric) to adult mice. Internal organs collected at key time-points after IG were evaluated by AAS for Zn concentration and analysed by cytometric techniques. We found that Zn-based NPs were readily absorbed and distributed (3 h post IG) in the nanoparticle form throughout the organism. Results suggest, that liver and kidneys were key organs responsible for NPs elimination, while accumulation was observed in the spleen and adipose tissues. We also showed that ZnO/ZnO:Eu NPs were able to cross majority of biological barriers in the organism (including blood-brain-barrier).
During the process of bioleaching, lead (Pb) recovery is low. This low recovery is caused by a problem with the bioleaching technique. This research investigated the bioleaching combination of bioleaching with brine leaching to remove heavy metals from lead-zinc mine tailings. The impact of different parameters were studied, including the effects of initial pH (1.5-3.0) and solid concentration (5-20%) for bioleaching, and the effects of sodium chloride (NaCl) concentration (10-200 g/L) and temperature (25 and 50 °C) for brine leaching. Complementary characterization experiments (Sequential extraction, X-ray diffractometer (XRD), scanning electronic microscope (SEM)) were also conducted to explore the transformation of tailings during the leaching process. The results showed that bioleaching efficiency was significantly influenced by initial pH and solid concentration. Approximately 85.45% of iron (Fe), 4.12% of Pb, and 97.85% of zinc (Zn) were recovered through bioleaching in optimum conditions. Increasing the brine concentration and temperature promoted lead recovery. Lead was recovered from the bioleaching residues at a rate of 94.70% at 25 °C and at a rate of 99.46% at 50 °C when the NaCl concentration was 150 g/L. The study showed that bioleaching significantly changed the speciation of heavy metals and the formation and surface morphology of tailings. The metals were mainly bound in stable fractions after bioleaching.
Geochemical speciation of As, Cd, Co, Cr, Cu, Ni, Pb, V and Zn were determined in the surface sediments of the southern Caspian Sea. A five-step sequential extraction technique was used to determine the chemical forms of metals. Mean concentrations (ppm) of heavy metals were (mean±S.D.) As: 9.94±1.71, Cd: 0.87±0.23, Co: 14.85±2.80, Cr: 72.29±19.48, Cu: 18.91±4.48, Ni: 32.87±5.25, Pb: 12.48±3.22, V: 86.07±20.71 and Zn: 66.85±10.11. Among the metals, Cu, As, Pb and Zn exhibited relatively higher mobility, while Cd, Co, Cr, Ni and V were found mainly in the residual fractions. Cu and As showed the highest percentages in the exchangeable phase while Co and Cr had the lowest percentages in the phase. The Risk Assessment Code (RAC) values indicated that As, Cu and V had medium risk at some sampling sites. According to pollution load index (PLI), sediments from some sampling sites were polluted.
Electrochemical catalysis of O2-incorporated reactions is a promising strategy for metal-air batteries. The performance of metal-air batteries is determined by the catalytic activities of the oxygen reduction reaction (ORR) and oxygen evolution reaction (OER). Therefore, developing efficient catalysts with superior activities for the ORR and OER is of great significance to expand the application range of metal-air batteries. Herein, CoFe alloy nanoparticles adhered to the inside wall of nitrogen doped carbon nanotubes (CoFe@NCNTs) are synthesized and can function as a Janus particle to efficiently catalyze the ORR and OER with desirable activities in 0.1 M KOH solution. Specifically, the CoFe@NCNTs present an onset potential of 0.95 V and a half-wave potential of 0.84 V as an ORR catalyst. When used as an air-cathode catalyst for a Zn-air battery, the CoFe@NCNTs cathode performs better than a Pt/C cathode, showing a high open-circuit potential of 1.45 V, a maximum power density of 150 mW cm(-2) and an average specific capacity of 808 mA h gzn(-1) at current densities from 2 mA cm(-2) to 10 mA cm(-2).
Tetrahedral [Cu(P)4][BF4]-type complexes (P = tertiary phosphine) are a class of monopositively charged compounds that have shown notable antitumor activity in both in vitro and in vivo tests. This biological property appears to be related to the peculiar physicochemical characteristics of these compounds. Although thermodynamically stable, they are labile at micromolar concentrations. Such a behavior allows the Cu(I) ion in [Cu(P)n](+) assemblies (n < 4) to interact with surrounding molecules, including the rich peptide/protein environment that metal complexes have to face in the physiological milieu on the way to tumor cells. The scope of this investigation was to study the interaction products that originate from the treatment in water/methanol mixtures of representative phosphino Cu(I) compounds with an excess of individual amino acids (AAs) selected on the basis of the donor atom likely involved in metal coordination (i.e. O-glycine, S-methionine and N-histidine). These interactions have been investigated in electrospray ionization mass spectrometry (ESI-MS), mainly in the positive ion mode [ESI(+)MS], and the interaction products have been characterized by sequential collisional experiments, performed by an ion trap instrument. Histidine and methionine, but not glycine, were able to mine Cu(I) from [Cu(P)n](+) assemblies through the formation of mixed [Cu(I)(P)(AA)](+) and eventually [Cu(I)(AA)2](+) adducts. The ability to substitute phosphine(s) by AAs and the strongest affinity for Cu(I) was proved by the study of the energetics of collisional-induced decomposition (CID) reactions [Cu(I)(P)(AA)](+) → Cu(I)(AA) + P](+). Among the investigated AAs, histidine displayed the strongest affinity for Cu(I). Transchelation of Cu(I) was similarly observed when [Cu(P)n](+) species were treated with the model tripeptide GlyGlyHis (GGH), the most investigated member of the amino terminal Cu(II) and Ni(II) (ATCUN) peptide family. GGH was able to form robust metal adducts not only with Cu(II) and the related divalent Zn(II) and Ni(II) ions, but also with monovalent ions, including Cu(I) and Ag(I). CID pathways of [Cu(I)(GGH)](+) and [Ag(I)(GGH)](+) were qualitatively superimposable and proceeded through losses of neutral fragments. Similar losses of neutral fragments were observed from [Zn(II)(GGH)] and [Ni(II)(GGH)]. CID pathways of [Cu(II)(GGH)](-/+) adducts instead took place mainly through intramolecular electron-transfer reactions comprising the reduction of Cu(II) to Cu(I) and the formation of fragment radical cations.
The electrospray ionization mass spectrometry competitive method has been used for the determination of the conditional stability constants of phytic acid complexes with Mg(2+), Ca(2+) and Zn(2+) ions. The competing complexation between ethylenediaminetetraacetic acid (EDTA) and phytic acid was studied. For EDTA complexes with Mg(2+), Ca(2+) and Zn(2+) ions, the values of the conditional stability constants are known and were used for the calculation of this constant for the phytic acid complexes. The values obtained are in agreement with the literature data. The method applied permitted a fast and simple determination of conditional stability constants by measuring the response of the ionized coordination complexes.
This study was conducted to investigate how far dietary zinc (Zn) modifies the histomorphological alterations induced by diabetes in rat kidneys. The animals were divided into negative control group (10 rats). Diabetes was induced in thirty animals by streptozotocin. After confirming diabetes, the animals were divided into three groups (n = 10). Group II served as the positive control group (fed on standard diet), group III was fed on Zn deficient diet, and group IV was fed on Zn supplemented diet. Caspase-3 immune staining was used to estimate the caspase activity. Stereological procedures were used to measure the quantity of the immune stain and the surface area of the Bowman's space. The renal cortices of group II rats revealed apparent widening of Bowman's spaces with few apoptotic figures. The filtration barrier showed thickening of the basement membrane. The proximal convoluted tubules showed patchy loss of the apical microvilli with swollen mitochondria. The distal convoluted tubules revealed area of irregular basal enfolding. The picture was aggravated by Zn deficiency in group III besides areas of cortical interstitial fibrosis. The histopathological alterations were minimal in the cortices of group IV. A significant increase of the Bowman's space surface area in group II and IV while decrease in group III compared with group I. The expression of Caspase-3 density was significantly increased in group II and III compared with group I while in group IV was non significant. In conclusion, dietary Zn modulated renal cortical changes caused by diabetes in rats.
Exercise training (ExT) has been reported to benefit hypertension; however, the exact mechanisms involved are unclear. We hypothesized that ExT attenuates hypertension,
 in part, through the renin-angiotensin system (RAS), reactive oxygen species (ROS), and glutamate in the paraventricular nucleus (PVN). Two-kidney, one-clip (2K1C) renovascular hypertensive rats were assigned to sedentary (Sed) or treadmill running groups for eight weeks. Dizocilpine (MK801), a glutamate receptor blocker, or losartan (Los), an angiotensin II type1 receptor (AT1-R) blocker, were microinjected into the PVN at the end of the experiment. We found that 2K1C rats had higher mean arterial pressure (MAP) and renal sympathetic nerve activity (RSNA). These rats also had excessive oxidative stress and overactivated RAS in PVN. Eight weeks of ExT significantly decreased MAP and RSNA in 2K1C hypertensive rats. ExT inhibited angiotensin-converting enzyme (ACE), AT1-R, and glutamate in the PVN, and angiotensin II (ANG II) in the plasma. Moreover, ExT attenuated ROS by augmenting copper/zinc superoxide dismutase (Cu/Zn-SOD) and decreasing p(47phox) and gp(91phox) in the PVN. MK801or Los significantly decreased blood pressure in rats. Together, these findings suggest that the beneficial effects of ExT on renovascular hypertension may be, in part, through the RAS-ROS-glutamate pathway in the PVN.
The objective of the present study was to evaluate serum level of copper, zinc, iron and metabolic parameters in postmenopausal women with diabetes. A total of 413 postmenopausal women were enrolled in the current study. Women were divided into 4 groups with equal age and body mass index according to glycated hemoglobin (HbA1c) levels (≤5.5; 5.5-6.0; 6.0-6.5; >6.5%). Serum Fe, Cu, and Zn levels were assessed using inductively-coupled plasma mass-spectrometry. Blood HbA1c, serum glucose, insulin, C-reactive protein (CRP), ferritin, and ceruloplasmin (Cp) were assessed using commercial kits. Homeostatic model assessment insulin resistance (HOMA-IR) and transferrin (Tf) saturation were calculated. The obtained data demonstrate that every 0.5% increase in HbA1c levels from 5.5% is associated with a significant elevation of glucose, insulin, CRP, and HOMA-IR values. Diabetic patients were characterized by significantly higher Fe (11%), Cu (8%), and Zn (6%) levels as compared to the controls. At the same time, the overall trend to increased metal levels in association with HbA1c was detected only for Fe (p<0.05) and Cu (p<0.05). Serum ferritin levels in diabetic women was 3-fold higher than in the controls, whereas Tf saturation was decreased by 35%. Serum Cp levels were significantly increased by 19% in prediabetes, whereas in diabetic postmenopausal women no such increase was observed. A significant elevation of total metal concentration in diabetic subjects without a concomitant elevation of transport proteins may be indicative of increased levels of "free" Fe and Cu, known to be toxic.
Through a dramatic advance in the coordination chemistry of the zinc-hydride bond, we describe the trajectory for the approach of this bond to transition metals. The dynamic reaction coordinate was interrogated through analysis of a series of solid state structures and is one in which the TM-H-Zn angle becomes increasingly acute as the TM-Zn distance decreases. Parallels may be drawn with the oxidative addition of boron-hydrogen and silicon-hydrogen bonds to transition metal centers.
The health risks of metal exposure due to the high consumption of fish were assessed for a riverine population living on the Caribbean coast of Colombia. The concentrations of metals (Cd, Cr, Cu, Hg, Ni, Pb and Zn) in the edible tissues of fish were determined and used for risk assessment. The daily fish consumption of residents (n = 95) was as high as 283, 366 and 469 g/day in children (CH), women of childbearing age (WCHA) and the remaining population groups (RP), respectively. The estimation of the potential risk (HQ) indicated that there was no health risk from most of the metals, because they did not exceed their related reference doses, with values of HQ < 1. Although the concentrations of Pb and Hg were not particularly high in fish (<0.2 µg/g), their possible health effects for vulnerable groups are of great concern due to the extremely high fish intake. The Pb intake for all groups was higher than the lower confidence limit of the benchmark dose for nephrotoxicity and neurodevelopmental effects in children. The weekly intake of methylmercury was also elevated, with values approximately 3, 2 and 1.5 times the provisional tolerable weekly intake for CH, WCHA and RP, respectively. Moreover, higher Hg levels were found in top predators, whereas maximum levels for other metals were found in bottom-feeding fish. This study highlights that an accurate data of daily intake, a continuous monitoring of metals in fish and their related fish consumption advisories to protect subsistence fishing communities are recommended in a local and worldwide context.
Native soil amendment has been widely used to stabilize mine tailings and speed up the development of soil biogeochemical functions before revegetation; however, it remains poorly understood about the response of microbial communities to ecological restoration of mine tailings with soil-covered strategy. In this study, microbial communities along a 60-cm profile were investigated in mine tailings during ecological restoration of two revegetation strategies (directly revegetation and native soil covered) with different plant species. The mine tailings were covered by native soils as thick as 40 cm for more than 10 years, and the total nitrogen, total organic carbon, water content, and heavy metal (Fe, Cu, and Zn) contents in the 0-40 cm intervals of profiles were changed. In addition, increased microbial diversity and changed microbial community structure were also found in the 10-40 cm intervals of profiles in soil-covered area. Soil-covered strategy rather than plant species and soil depth was the main factor influencing the bacterial community, which explained the largest portion (29.96%) of the observed variation. Compared directly to revegetation, soil-covered strategy exhibited the higher relative abundance of Acidobacteria and Deltaproteobacteria and the lower relative abundance of Bacteroidetes, Gemmatimonadetes, Betaproteobacteria, and Gammaproteobacteria. PICRUSt analysis further demonstrated that soil-covered caused energy metabolic functional changes in carbon, nitrogen, and sulfur metabolism. Given all these, the soil-covered strategy may be used to fast-track the establishment of native microbial communities and is conducive to the rehabilitation of biogeochemical processes for establishing native plant species.
Soil and groundwater from long-term (>50 years) tannery effluent irrigated areas of Kanpur were analyzed and significant buildup of heavy metals such as Cr, Ni, Cd, Pb, Zn, and As in the range of 252-972, 23-30, 2.3-14.1, 23.7-58.8, 138-338 and 6.8-11 mg kg(-1), respectively in soil was found. Few groundwater samples in the effluent irrigated areas also exhibited high Cr concentration above the permissible limit of United States Environmental Protection Agency. The tannery effluents contained 1.53-57.3 ppm Cr, 0-0.12 ppm Ni, 0-0.02 ppm Cd, 0-0.07 ppm Pb, 0-0.48 ppm Zn and 0-0.03 ppm As. The Geo-accumulation index (Igeo) revealed that soil samples were unpolluted to moderately polluted with Cu, Ni, Zn, Pb and As; moderately polluted in case of Cd; and heavily to extremely polluted by Cr.
Microstructural investigation of extremely strained samples, such as severely plastically deformed (SPD) materials, by using conventional transmission electron microscopy techniques is very challenging due to strong image contrast resulting from the high defect density. In this study, low angle annular dark field (LAADF) imaging mode of scanning transmission electron microscope (STEM) has been applied to study the microstructure of a Mg-3Zn-0.5Y (at%) alloy processed by high pressure torsion (HPT). LAADF imaging advantages for observation of twinning, grain fragmentation, nucleation of recrystallized grains and precipitation on second phase particles in the alloy processed by HPT are highlighted. By using STEM-LAADF imaging with a range of incident angles, various microstructural features have been imaged, such as nanoscale subgrain structure and recrystallization nucleation even from the thicker region of the highly strained matrix. It is shown that nucleation of recrystallized grains starts at a strain level of revolution [Formula: see text] (earlier than detected by conventional bright field imaging). Occurrence of recrystallization of grains by nucleating heterogeneously on quasicrystalline particles is also confirmed. Minimizing all strain effects by LAADF imaging facilitated grain size measurement of [Formula: see text] nm in fully recrystallized HPT specimen after [Formula: see text].
Candidate clones which conferred Al tolerance to yeast transformants (TFs) were obtained from a cDNA library derived from a highly Al-tolerant poaceae, Andropogon virginicus L. One such clone, AL3A-4, encoded an S-adenosyl methionine synthetase (SAMS) gene. A full-length cDNA was obtained by 5'-RACE, designated AvSAMS1, and introduced into Arabidopsis thaliana to investigate its biological functions under Al stress. Two TF plant lines both showed higher tolerance than the Col-0 ecotype (non-TF) not only for Al stress, but also for Cu, Pb, Zn and diamide stresses, suggesting the AvSAMS1 was a multiple tolerance gene. More than 40 of A. thaliana Al response-genes (Al induced genes and Al repressed genes) were selected from microarray results and then used for investigations of DNA or histone methylation status under Al stress in Col-0 and the AvSAMS1 TF line. The results indicated that Al stress caused alterations of methylation status in both DNA and histone H3 (H3K4me3 and H3K9me3) and that these alterations were different
 between the AvSAMS1 TF and Col-0, suggesting the differences were AvSAMS1-gene dependent. These results suggested the existence of AvSAMS1-related epigenetic gene-regulation under Al stress.
Giardiasis and cryptosporidiosis are now recognized as neglected tropical parasitic diseases. The risk of their dissemination  in developing countries, such as Gabon, is increasing, due to urban crowding and poor sanitation. Accurate, simple and rapid diagnosis tools are thus necessary for the estimation of their real burden. The aim of this study was to evaluate the performances of the ImmunocardSTAT(®)Crypto/Giardia Rapid Assay test for the detection of Cryptosporidium (C.) spp. and Giardia (G.) duodenalis in children living in Libreville, Gabon. Stool samples of 173 healthy children were screened by routine microscopic using the merthiolate iodine formol concentration technique for Giardia, the modified Ziehl Neelsen (ZN) staining for Cryptosporidium and the ImmunocardSTAT(®) Crypto/Giardia RDT for the detection of Giardia and Cryptosporidium parasite forms and antigens respectively. G. duodenalis was detected with microscopy and the ImmunocardSTAT(®) Crypto/Giardia in 27 (15.6 %) and 22 (13.3 %) fecal samples respectively. C. spp. oocysts were found in 18 (10.4 %) ones, whereas only one sample was positive with the immunochromatographic assay. When microscopic examination was considered as the reference method, sensitivity and specificity of the ImmunocardSTAT(®) Crypto/Giardia Rapid Assay were found to be 63.0 %, 96.6 and 5.5 %, 99.3 % for G. duodenalis and C. spp. respectively. The prevalence of G. duodenalis and C. spp. carriage is high in children from Libreville. A low sensitivity of the ImmunocardSTAT(®) Crypto/Giardia for the detection of both parasites is observed. It is thus inappropriate as a diagnostic tool for detecting asymptomatic carriers.
The diagnosis of extrapulmonary tuberculosis (EPTB) is challenging due to non-specific symptoms, invasive approach for specimen collection and most importantly, the paucibacillary status. The objective of this assay was to evaluate the efficacy of Myco/F lytic system, BACTEC Mycobacteria Growth Indicator Tube (MGIT) 960 system and Lowenstein-Jensen (L-J) medium for recovery of bacilli from sterile body fluids. 214 specimens (114 pleural fluid and 100 pus) from clinically diagnosed EPTB patients were collected and subjected to Ziehl-Neelsen (ZN) smear microscopy, L-J culture, MGIT 960 culture and Myco/F lytic culture.103 out of the 214 sterile body fluid samples yielded positive culture outcomes by any of the three methods. Among all the culture positive specimens, the recovery rate was 86.41% for Myco/F lytic, 75.73% for MGIT 960, and 42.72% for L-J medium. The mean time to positivity (TTP) was 27.06 ± 8.03 days for Myco/F lytic, 22.20 ± 7.84 days for MGIT960 and 42 ± 8.84 days for L-J medium. The rates of contamination were 6.54%, 3.74% and 2.80% for Myco/F lytic, MGIT960 and L-J medium respectively. Both Myco/F lytic and MGIT960 system were superior to L-J medium for recovery of bacilli from sterile body fluids. Myco/F lytic system was more favorable than MGIT960 regarding recovery rate and cost-effectiveness, thus can be considered as a promising alternative to MGIT960 system for diagnosing EPTB.
Extracellular polymeric substances (EPS) isolated from bacteria, are abound of functional groups which can react with metals and consequently influence the immobilization of metals. In this study, we combined with Zn K-edge Extended X-ray Absorption Fine Structure (EXAFS), Fourier Transform Infrared (FTIR) spectroscopy, and High-Resolution Transmission Electron Microscopy (HRTEM) techniques to study the effects of EPS isolated from Bacillus subtilis and Pseudomonas putida on Zn sorption on γ-alumina. The results revealed that Zn sorption on aluminum oxide was pH-dependent and significantly influenced by bacterial EPS. At pH 7.5, Zn sorbed on γ-alumina was in the form of Zn-Al layered doubled hydroxide (LDH) precipitates, whereas at pH 5.5, Zn sorbed on γ-alumina was as a Zn-Al bidentate mononuclear surface complex. The amount of sorbed Zn at pH 7.5 was 1.3-3.7 times higher than that at pH 5.5. However, in the presence of 2 g L(-1) EPS, regardless of pH conditions and EPS source, Zn + EPS + γ-alumina ternary complex was formed on the surface of γ-alumina, which resulted in decreased Zn sorption (reduced by 8.4-67.8%) at pH 7.5 and enhanced Zn sorption (increased by 10.0-124.7%) at pH 5.5. The FTIR and EXAFS spectra demonstrated that both the carboxyl and phosphoryl moieties of EPS were crucial in this process. These findings highlight EPS effects on Zn interacts with γ-alumina.
We reveal a dose-response relationship for bioaccumulation of Zn, Cu and Cr in shrimp Litopenaeus schmitti from Sepetiba Bay, Rio de Janeiro, Brazil. Our model estimates the current risk (AD50 was 70% of the legal limit) and the daily metal uptake rate for each metal. It can also evaluate the relative reliability of predictions for tissue concentrations reaching the legal limits for human consumption (approximately 1year) and predictions related to asymptotic length, arising from (i) direct regression of the metal concentration (MeC) versus total length (TL) and age (duration of exposure), and (ii) correlation of the incorporation rate (IR=MeC/TL) with age. Metal incorporation rates (IR), i.e. a kinetic proxy for absorption during growth up to attainment of asymptotic length, decrease with age, reflecting a slow-down in metal absorption. This pattern mitigates the high initial concentrations observed for juveniles.
During casting of liquid iron and slag a considerable amount of dust is emitted into the cast house of a blast furnace. Usually, this dust is extracted via exhaust hoods and subsequently separated from the ventilation air. In most blast furnaces the cast house dust is recycled. In this study a sample of cast house dust was split by air classification into five size fractions which were then analysed. Micrographs showed that the dominating particle type in all size fractions is that of single spherical-shaped particles. However, some irregular-shaped particles were also found and in the finest size fraction also some agglomerates were present. Almost spherical particles consisted of Fe and O, while highly irregular-shaped particles consisted of C. Edged particles of a compact shape typically consisted of Fe and O and some additional elements like Ca, Mg, Al or Mn. The most abundant element was Fe, followed by Ca and C. These elements were distributed relatively uniformly in the size fractions. As, Cd, Cu, K, Pb, S, Sb and Zn were enriched significantly in the fine size fractions, while Al, Ba, Mg, Mn, Sr, Ti and V were enriched in the coarse size fractions. For the recycling of cast house dust, treatment by air classification would be an effective method for reducing the amount of Zn recycled. By separating a small fraction of fines (about 10%-20%) a reduction of the mass of Zn in the coarse dust recycled in the range of 40%-55% would be possible.
In the present study, the effects of sex, age, nutritional status, and habitat use on hair and internal tissue concentrations of some trace metals (Zn, Cu, Ni, Pb and Cd) in brown rat (Rattus norvegicus) and great gerbil (Rhombomys opimus) from Aran-O-Bidgol City in Central Iran were investigated. Five sampling stations in different land-uses were selected for the study. Concentrations of Cd and Pb in liver and whole body concentration as well as concentration of Zn in hair of male rats were significantly higher than females. A significantly higher concentration was only observed for Pb in kidney of male gerbils than females. In numerous cases, age had significantly negative correlations with concentration of metals in different tissues of both species, and was only significantly (and positively) correlated with the concentration of Cd in kidney and Zn in liver of gerbils. This finding may indicate that the early neonatal age is a critical period for metals accumulation. The relationships between nutritional status and metal concentrations for both species were negative, which can be ascribed to the weight-specific metabolic rate that cause to a relatively low uptake of metals per unit of body weight. No significant differences were observed for soil metals concentrations in different sites. So, this suggests that the influence of life history, microhabitat use and foraging behavior did significantly influence on inter and intra specific variation of metals concentration in small mammals. Our observations suggest that hair cannot be used alone for monitoring exposure of metals.
The co-combustion of sludge (sewage and dredged sludge) with rice husk is expected to become a trend because of its economic and environmental benefits. However, the massive residues from the co-combustion process and the mobility of heavy metals (HMs) warrant special attention. The basic performance and environmental properties of the trace elements (Cr, Cu, Fe, Mn, Ba and Zn) from the co-combustion ashes were studied to promote the further utilization of these materials. These ashes have a shell particle shape, high specific area, high amorphous content and low crystalline phase content. The investigation mainly focused on the environmental properties of these ashes to evaluate the risk of these by-products to the environment. Results show Cu, Mn, and Zn have cumulative leaching concentrations of 1.033, 23.32, and 3.363 mg/L for W, by contrast, Cr, Cu, Fe, Mn, Ba, and Zn have cumulative leaching concentrations of 0.488, 0.296, 8.069, 10.44, 2.568, and 2.691 mg/L for H, which are much greater than the Chinese ground water standard (GB/T14848-93). Meanwhile Mn, Zn, Ba, Cr, and Fe all pose a very high risk for H, while Cu only poses a medium risk, and all HMs in W exhibit much
 lower contamination levels than those in H by the method of risk assessment code (RAC). It indicates that these ashes have undesirably high levels of HMs that demonstrate high mobility and pose environmental risks according to their leachability and chemical speciation. And the HMs in W show lower mobility and environmental hazards than those in H.
Zeolites, having widespread applications in chemical industries, are often synthesized using organic templates. These can be cost-prohibitive, motivating investigations into their role in promoting crystallization. Herein, the relationship between framework structure, chemical composition, synthesis conditions and the conformation of the occluded, economical template tetraethylammonium (TEA(+) ) has been systematically examined by experimental and computational means. The results show two distinct regimes of occluded conformer tendencies: 1) In frameworks with a large stabilization energy difference, only a single conformer was found (BEA, LTA and MFI). 2) In the frameworks with small stabilization energy differences (AEI, AFI, CHA and MOR), less than the interconversion of TEA(+) in solution, a heteroatom-dependent (Al, B, Co, Mn, Ti, Zn) distribution of conformers was observed. These findings demonstrate that host-guest chemistry principles, including electrostatic interactions and coordination chemistry, are as important as ideal pore-filling.
Despite intensive research into support substrates for the dispersal of nanoparticles and their applications, there has been a lack of general methods to produce metal oxide hollow substrates supporting a wide range of metal and metal oxides. Herein, a synthetic protocol for the preparation of CuO hollow structure-supported MOx (M = Zn, Fe, Ni, Sn, Mn, Co, Ce, Mg, and Ag) and noble metals (Pt and Au) with the desired properties and shell structure, such as CuO/Fe2O3, CuO/ZnO, CuO/SnO2, CuO/MgO, CuO/NiO, CuO/Mn2O3, CuO/CoO, CuO/CeO2, CuO/Ag2O, CuO/Pt, CuO/Au hollow cubes, CuO/ZnO double-shell hollow cubes, CuO/SnO2 double-shell hollow octahedra, CuO/SnO2/Fe2O3 and CuO/Mn2O3/NiO double-shell hollow cubes, was developed based on controlled calcination and etching. These hybrid hollow structures were employed not only as support substrates but also as active constituents for catalytic reactions. As an example, we demonstrated that CuO/ZnO hollow cubes are remarkably efficient in converting solid chitin biomass to liquid chemicals in methanol. In addition, CuO/ZnO double-shell hollow cubes were highly effective in the oxidation of benzyl alcohol in the presence of H2O2, whereas CuO/Pt and CuO/Au hollow cubes promoted the oxidation of benzyl alcohol in pure O2. The strategy developed in this work extends the controllable fabrication of high-quality CuO hollow structure-supported nanoparticles using various compositions and shell structures, paving the way to the exploration and systematic comparison of these materials in a wider range of applications.
We report the discovery of a new fluoride-arsenide bulk diluted magnetic semiconductor (Ba,K)F(Zn,Mn)As with the tetragonal ZrCuSiAs-type structure which is identical to that of the "1111" iron-based superconductors. The joint hole doping via (Ba,K) substitution &spin doping via (Zn,Mn) substitution results in ferromagnetic order with Curie temperature up to 30 K and demonstrates that the ferromagnetic interactions between the localized spins are mediated by the carriers. Muon spin relaxation measurements confirm the intrinsic nature of the long range magnetic order in the entire volume in the ferromagnetic phase. This is the first time that a diluted magnetic semiconductor with decoupled spin and charge doping is achieved in a fluoride compound. Comparing to the isostructure oxide counterpart of LaOZnSb, the fluoride DMS (Ba,K)F(Zn,Mn)As shows much improved semiconductive behavior that would be benefit for further application developments.
Reaction of the donor-stabilized silylene [iPrNC(NiPr2 )NiPr]2 Si (1) with FeBr2 , CoBr2 , NiBr2 ⋅MeOCH2 CH2 OMe, ZnCl2 , and ZnBr2 afforded the respective transition-metal silylene complexes 4-8, the formation of which can be described in terms of a Lewis acid/base reaction (4, 5, 7, 8) or a nucleophilic substitution reaction (6). However, the reactivity profile of silylene 1 is not only based on its strong Lewis base character; the different coordination modes of the two guanidinato ligands (4-6 vs. 7 and 8) add an additional reactivity facet. The paramagnetic compounds 4 and 5 and the diamagnetic compounds 6⋅THF, 7, and 8⋅0.5 Et2 O were structurally characterized by single-crystal X-ray diffraction. In addition, compound 6⋅THF was studied by (15) N and (29) Si solid-state NMR spectroscopy, and 7 and 8 were characterized by NMR spectroscopic studies in the solid state ((15) N, (29) Si) and in solution ((1) H, (13) C, (29) Si). Compounds 4-8 represent very rare examples of Fe(II) , Co(II) , Ni(II) , and Zn(II) silylene complexes. Four-coordinate silicon(II) compounds with an SiN3 M skeleton (M=Fe, Co, Ni) and M in the formal oxidation state +2 (4-6) have not yet been reported, and five-coordinate silicon(II) compounds with an SiN4 Zn skeleton (7, 8) are also unprecedented.
Elevated concentrations of potentially toxic elements (PTEs) are usually found in areas of intense industrial activity. Thriasio Plain is a plain near Athens, Greece, where most of the heavy industry of the country has been situated for decades, but it also is a residential and horticultural area. We aimed at measuring the levels of PTEs in soils and indigenous plant species and assessing the health risk associated with direct soil ingestion. Samples of soils at roadsides and growing plants were collected from 31 sites of that area. Concentrations of Al, As, Cd, Co, Cr, Cu, Fe, Mn, Mo, Ni, Pb, V and Zn were measured in both soils (as pseudo-total) and aerial plant tissues. We found that As, Cd, Cr, Cu, Ni, Pb and Zn were higher than maximum regulatory limits. Element concentrations in plants were rather lower than expected, probably because indigenous plants have developed excluder behaviour over time. Copper and Zn soil-to-plant coefficients were highest among the other elements; for Cu this was unexpected, and probably associated with recent Cu-releasing industrial activity. Risk assessment analysis indicated that As was the element contributing more than 50 % of the health risk related to direct soil ingestion, followed by Cr, Pb, and, surprisingly, Mn. We concluded that in a multi-element contamination situation, elevated risk of PTEs (such as As, Cr and Pb) may reduce the tolerance limits of exposure to less-toxic elements (here, Mn).
Ambient PM10 air samples were collected at two industrial sites and one urban residential site in the mining city of Panzhihua, China, from April, 2014, to January, 2015. Mass concentrations of ten trace metals (As, Cd, Cr, Ni, Co, V, Mn, Cu, Pb, and Zn) in PM10 were determined by inductively coupled plasma-mass spectrometry. The results showed Zn, Pb, Cu, Mn and V were the most abundant elements from the industrial sites. Concentrations for Cd, Cr, Co, Ni, Mn and Cu at industrial sites greatly exceeded the air quality standards of the World Health Organization and the Chinese Ministry of Environmental Protection. Principal component analysis indicated that the main sources of the trace metals were steel smelting, fuel combustion, geological and mineral dust. Four different clusters of particles (i.e., mineral, calcium-containing, soot and aluminosilicate) were identified by scanning electron microscopy coupled with energy dispersive X-ray spectrometry. Chromium (Cr) was found to present the highest excess cancer risk, implying the potential for carcinogenic health effects in local inhabitants. Manganese (Mn) presented a non-carcinogenic health risk to children and adults, while the other metals were within acceptable limits.
Immobilization of metal complexes to electrode surfaces has emerged as an attractive strategy to combine homogeneous and heterogeneous catalysis. We recently reported the immobilization of cobalt dithiolene catalytic units via incorporation into extended one and two dimensional (1D and 2D) frameworks. We extend here this methodology to the formation of 1D nickel, iron, and zinc dithiolene coordination polymers based on benzene-1,2,4,5-tetrathiolate (BTT) frameworks and investigate their catalytic H2-evolving activities under fully aqueous conditions. The nickel dithiolene coordination polymer is an active electrocatalyst for the hydrogen evolution reaction (HER). An overpotential of 470 mV was required to reach a current density of 10 mA cm(-2) at pH 1.3, making this system one of the best performing heterogenized molecular catalysts for HER. This overpotential is 90 mV lower than that of the cobalt analogue, suggesting that the nickel coordination polymer is a more efficient H2-evolving catalyst. Additionally, no decrease in activity is observed for the nickel polymer during the first hour of electrolysis, indicating that it is stable under prolonged electrolysis.
Zinc (Zn) is an essential micronutrient for basic cell activities such as cell growth, differentiation, and survival. Zn deficiency depresses both innate and adaptive immune responses. However, the precise physiological mechanisms of the Zn-mediated regulation of the immune system have been largely unclear. Zn homeostasis is tightly controlled by the coordinated activity of Zn transporters and metallothioneins, which regulate the transport, distribution, and storage of Zn. There is growing evidence that Zn behaves like a signaling molecule, facilitating the transduction of a variety of signaling cascades in response to extracellular stimuli. In this review, we highlight the emerging functional roles of Zn and Zn transporters in immunity, focusing on how crosstalk
 between Zn and immune-related signaling guides the normal development and function of immune cells.
Staphylococcus epidermidis is an opportunistic pathogen that can form robust biofilms that render the bacteria resistant to antibiotic action and immune responses. Intercellular adhesion in S. epidermidis biofilms is mediated by the cell wall-associated Accumulation-Associated Protein (Aap), via zinc-mediated self-assembly of its B-repeat region. This region contains up to 17 nearly-identical sequence repeats, with each repeat assumed to be functionally equivalent. However, Aap B-repeats exist as two subtypes, defined by a cluster of consensus or variant amino acids. These variable residues are positioned near the zinc-binding (and dimerization) site and the stability determinant for the B-repeat fold. We have characterized four B-repeat constructs to assess the functional relevance of the two Aap B-repeat subtypes. Analytical ultracentrifugation experiments demonstrated that constructs with the variant sequence show reduced or absent Zn(2+)-induced dimerization. Likewise, circular dichroism thermal denaturation experiments showed that the variant sequence could significantly stabilize the fold, depending on its location within the construct. Crystal structures of three of the constructs revealed that the side chains from the variant sequence form an extensive bonding network that can stabilize the fold. Furthermore, altered distribution of charged residues between consensus and variant sequences changes the electrostatic potential in the vicinity of the Zn(2+) binding site, providing a mechanistic explanation for the loss of zinc-induced dimerization in the variant constructs. These data suggest an assembly code that defines preferred oligomerization modes of the B-repeat region of Aap and a slip-grip model for initial contact and firm intercellular adhesion during biofilm formation.
The RNA exosome is fundamental for the degradation of RNA in eukaryotic nuclei. Substrate targeting is facilitated by its co-factor Mtr4p/hMTR4, which links to RNA-binding protein adaptors. One example is the trimeric human nuclear exosome targeting (NEXT) complex, which is composed of hMTR4, the Zn-finger protein ZCCHC8, and the RNA-binding factor RBM7. NEXT primarily targets early and unprocessed transcripts, which demands a rationale for how the nuclear exosome recognizes processed RNAs. Here, we describe the poly(A) tail exosome targeting (PAXT) connection, which comprises the ZFC3H1 Zn-knuckle protein as a central link between hMTR4 and the nuclear poly(A)-binding protein PABPN1. Individual depletion of ZFC3H1 and PABPN1 results in the accumulation of common transcripts that are generally both longer and more extensively polyadenylated than NEXT substrates. Importantly, ZFC3H1/PABPN1 and ZCCHC8/RBM7 contact hMTR4 in a mutually exclusive manner, revealing that the exosome targets nuclear transcripts of different maturation status by substituting its hMTR4-associating adaptors.
Chemometric analysis are used for food authenticity evaluation, correlating botanical and geographical origins with food chemical composition. This research was carried out in order to prove that it is possible linked red wines to Nero d'Avola and Syrah cultivars of Vitis vinifera according to their mineral content, while the values of the physical and chemical parameters do not affect relevantly this discrimination. The levels of mineral elements were determined by ICP-OES and ICP-MS. Samples from cv Nero d'Avola had the highest content of Zn, Cr, Ni, As and Cd, whereas the highest mineral concentration in cv Syrah samples was represented by K, Mg, Cu, and Sb. The research highlights that it is possible linked red wines to Nero d'Avola and Syrah cultivars of V. vinifera according to their mineral contents, adding knowledge to the determination studies of the wine botanical origin.
Four proximal soil sensors were tested at four smallholder farms in Embu County, Kenya: a portable X-ray fluorescence sensor (PXRF), a mobile phone application for soil color determination by photography, a dual-depth electromagnetic induction (EMI) sensor, and a LED-based soil optical reflectance sensor. Measurements were made at 32-43 locations at each site. Topsoil samples were analyzed for plant-available nutrients (N, P, K, Mg, Ca, S, B, Mn, Zn, Cu, and Fe), pH, total nitrogen (TN) and total carbon (TC), soil texture, cation exchange capacity (CEC), and exchangeable aluminum (Al). Multivariate prediction models of each of the lab-analyzed soil properties were parameterized for 576 sensor-variable combinations. Prediction models for K, N, Ca and S, B, Zn, Mn, Fe, TC, Al, and CEC met the setup criteria for functional, robust, and accurate models. The PXRF sensor was the sensor most often included in successful models. We concluded that the combination of a PXRF and a portable soil reflectance sensor is a promising combination of handheld soil sensors for the development of in situ soil assessments as a field-based alternative or complement to laboratory measurements.
For studying the melting point depression of metals, isolated metallic nanoparticles embedded in a matrix are usually prepared by mechanical milling. Al is the main available matrix material. In this work, to explore possible alternative matrices for further investigation of melting, mechanically milled metal-nonmetal systems are developed, namely Sn-LiF, Zn-LiF and Zn-Al2O3. The outcome indicates that different matrices do not have a significantly different influence on the melting of Sn and Zn. Theoretical analyses of both the thermodynamics and kinetics of surface-induced melting may support this experimental finding.
In contrast with conventional single-molecule junctions, in which the current flows parallel to the long axis or plane of a molecule, we investigate the transport properties of M(II)-5,15-diphenylporphyrin (M-DPP) single-molecule junctions (M=Co, Ni, Cu, or Zn divalent metal ions), in which the current flows perpendicular to the plane of the porphyrin. Novel STM-based conductance measurements combined with quantum transport calculations demonstrate that current-perpendicular-to-the-plane (CPP) junctions have three-orders-of-magnitude higher electrical conductances than their current-in-plane (CIP) counterparts, ranging from 2.10(-2) G0 for Ni-DPP up to 8.10(-2) G0 for Zn-DPP. The metal ion in the center of the DPP skeletons is strongly coordinated with the nitrogens of the pyridyl coated electrodes, with a binding energy that is sensitive to the choice of metal ion. We find that the binding energies of Zn-DPP and Co-DPP are significantly higher than those of Ni-DPP and Cu-DPP. Therefore when combined with its higher conductance, we identify Zn-DPP as the favoured candidate for high-conductance CPP single-molecule devices.
Calcium and phosphorus are essential minerals, closely linked in digestive processes and metabolism. With widespread use of low P diets containing exogenous phytase, the optimal dietary Ca level was verified. The 40-day study evaluated the effects of Ca level (4, 7 and 10 g/kg diet) and Ca source (Ca from CaCO3 and from Lithothamnium calcareum) on mineral utilisation in 72 piglets (7.9 ± 1.0 kg BW) fed an exogenous phytase containing diet with 2.9 g digestible P/kg. Measured parameters were growth performance, stomach mineral solubility, bone breaking strength and urinary, serum and bone mineral concentration. The apparent total tract digestibility of minerals was also assessed in the two diets with 7 g Ca/kg, using 12 additional pigs. Regardless of Ca source, increasing dietary Ca impaired feed conversion ratio, increased urinary pH, increased serum and urinary Ca, decreased serum and urinary P, decreased serum Mg and increased urinary Mg, increased serum AP activity, decreased bone Mg increased bone Zn. Bone breaking strength was improved with 7 compared to 4 g Ca/kg. Compared to CaCO3 , Ca from Lithothamnium calcareum increased serum Mg and with, 10 g Ca/kg, it limited body weight gain. The dose response of Ca in a diet with 2.9 g digestible P/kg and including exogenous phytase indicated that: (i) a low dietary Ca was beneficial for piglet growth, but was limiting the metabolic use of P; (ii) a high dietary Ca level impaired P utilisation; (iii) the optimal P utilisation and bone breaking strength was obtained with a dietary Ca-to-digestible P ratio of 2.1 to 2.4:1; (iv). Increasing dietary Ca reduced Mg utilisation, but not Zn status, when fed at adequate level. Finally, Ca from Lithothamnium calcareum had similar effects on Ca and P metabolism as CaCO3 , but impaired growth when fed at the highest inclusion level.
β-mannanase has shown compelling biological functions because of its regulatory roles in metabolism, inflammation, and oxidation. This study separated and purified the β-mannanase from Bacillus subtilis BE-91, which is a powerful hemicellulose-degrading bacterium using a "two-step" method comprising ultrafiltration and gel chromatography. The purified β-mannanase (about 28.2 kDa) showed high specific activity (79, 859.2 IU/mg). The optimum temperature and pH were 65°C and 6.0, respectively. Moreover, the enzyme was highly stable at temperatures up to 70°C and pH 4.5-7.0. The β-mannanase activity was significantly enhanced in the presence of Mn(2+), Cu(2+), Zn(2+), Ca(2+), Mg(2+), and Al(3+) and strongly inhibited by Ba(2+) and Pb(2+). Km and Vmax values for locust bean gum were 7.14 mg/mL and 107.5 μmol/min/mL versus 1.749 mg/mL and 33.45 µmol/min/mL for Konjac glucomannan, respectively. Therefore, β-mannanase purified by this work shows stability at high temperatures and in weakly acidic or neutral environments. Based on such data, the β-mannanase will have potential applications as a dietary supplement in treatment of inflammatory processes.
A total of 150 bread
 wheat genotypes representing 121 Indian and 29 Turkish origin were screened for nutrient concentrations and grain protein content. Elemental and grain protein composition were studied by Inductively Coupled Plasma-Atomic Emission Spectrophotometer and LECO analyser, respectively. The study was performed to determine the variability in nutrient concentrations present in the collected wheat genetic material from two countries.
Several fold variations among genotypes existed for almost all the elements. Three major components of principal component analysis (PCA) revealed 60.8% variation among the genotypes. Nutrient variables segregated into two groups, one group containing all the macroelements except sulphur; and another cluster containing proteins and all the microelements except Zn and Mn. Pearson correlation analysis and heat-map were in accordance with each other determining strong positive association between P-K, Mn-Zn, Mg-S and Cu-protein content. Also, PCA and hierarchical grouping divided all the Indian and Turkish genotypes in two main clusters.
Nutritional profile differentiated the genotypes from two countries into separate groups. However, some of the varieties were closely associated and indicated the success of global wheat exchange programs. While most of the correlations were in agreement with the previous studies, non-association of zinc with grain protein content directed towards its control by some other genetic factors. Some of the experimental wheat varieties with promising nutrient content have been suggested for future wheat advancement programs. Results obtained will be supportive for breeders involved in wheat biofortification programs, food industries and people relying on whole grain wheat products.
London, like many major cities, has a noted air pollution problem, and a better understanding of the sources of airborne particles in the different size fractions will facilitate the implementation and effectiveness of control strategies to reduce air pollution. Thus, the trace elemental composition of the fine and coarse fraction were analysed at hourly time resolution at urban background (North Kensington, NK) and roadside (Marylebone Road, MR) sites within central London. Unlike previous work, the current study focuses on measurements during the summer providing a snapshot of contributing sources, utilising the high time resolution to improve source identification. Roadside enrichment was observed for a large number of elements associated with traffic emissions (Al, S, Ca, Ti, V, Cr, Mn, Fe, Ni, Cu, Zn, As, Rb and Zr), while those elements that are typically from more regional sources (e.g. Na, Cl, S and K) were not found to have an appreciable increment. Positive Matrix Factorization (PMF) was applied for the source apportionment of the particle mass at both sites with similar sources being identified, including sea salt, airborne soil, traffic emissions, secondary inorganic aerosols and a Zn-Pb source. In the fine fraction, traffic emissions was the largest contributing source at MR (31.9%), whereas it was incorporated within an "urban background" source at NK, which had contributions from wood smoke, vehicle emissions and secondary particles. Regional sources were the major contributors to the coarse fraction at both sites. Secondary inorganic aerosols (which contained influences from shipping emissions and coal combustion) source factors accounted for around 33% of the PM10 at NK and were found to have the highest contributions from regional sources, including from the European mainland. Exhaust and non-exhaust sources both contribute appreciably to PM10 levels at the MR site, highlighting the continuing importance of vehicle-related air pollutants at roadside.
The majority of epidemiological studies correlate the cardiorespiratory effects of air pollution exposure by considering the concentrations of pollutants measured from conventional monitoring networks. The conventional air quality monitoring methods are expensive, and their data are insufficient for providing good spatial resolution. We hypothesized that bioassays using plants could effectively determine pollutant gradients, thus helping to assess the risks associated with air pollution exposure. The study regions were determined from different prevalent respiratory death distributions in the Sao Paulo municipality. Samples of tree flower buds were collected from twelve sites in four regional districts. The genotoxic effects caused by air pollution were tested through a pollen abortion bioassay. Elements derived from vehicular traffic that accumulated in tree barks were determined using energy-dispersive X-ray fluorescence spectrometry (EDXRF). Mortality data were collected from the mortality information program of Sao Paulo City. Principal component analysis (PCA) was applied to the concentrations of elements accumulated in tree barks. Pearson correlation and exponential regression were performed considering the elements, pollen abortion rates and mortality data. PCA identified five factors, of which four represented elements related to vehicular traffic. The elements Al, S, Fe, Mn, Cu, and Zn showed a strong correlation with mortality rates (R(2)>0.87) and pollen abortion rates (R(2)>0.82). These results demonstrate that tree barks and pollen abortion rates allow for correlations between vehicular traffic emissions and associated outcomes such as genotoxic effects and mortality data.
Oxidative stress plays a key role in the pathogenesis of coronary artery disease. The aim of this study was to compare the effects of percutaneous transluminal coronary angioplasty (PTCA) and elective coronary angiography (EC) on erythrocytic antioxidant defense in elderly male patients.
Twenty-three stable angina pectoris (SAP) patients undergoing PTCA and 18 patients with ischemic symptoms scheduled to undergo diagnostic EC were included in the study. The concentrations of malondialdehyde (MDA) and reduced glutathione (GSH) and the activities of Zn,Cu-superoxide dismutase (SOD-1), catalase (CAT), and cytosolic glutathione peroxidase (GSH-Px) were examined in the erythrocytes before, immediately after and 2 weeks following PTCA or EC.
The MDA concentrations were significantly higher and SOD-1, CAT, and GSH-Px activities were significantly lower in the PTCA group than in the EC group at baseline. Two weeks after treatment, the activities of the enzymes significantly increased in both groups, whereas the MDA concentrations decreased only in the PTCA patients.
The results confirm that an advanced state of atherosclerosis is related to greater levels of oxidative stress. The study indicates that both procedures may induce antioxidant defenses; however, PTCA exclusively induces a long-term reduction in lipid peroxidation.
A pot experiment was conducted to evaluate the feasibility of using tree seedlings for the phytoremediation of lead/zinc (Pb/Zn) mine tailings. Seedlings of three Quercus spp. (Q. shumardii, Q. phellos, and Q. virginiana) and rooted cuttings of two Salix spp. (S. matsudana and S. integra) were transplanted into pots containing 50 and 100 % Pb/Zn mine tailings to evaluate their tolerance of heavy metals. The five species showed different tolerance levels to the Pb/Zn tailings treatments. Q. virginiana was highly tolerant to heavy metals and grew normally in the Pb/Zn tailings. The root systems showed marked differences between the Quercus spp. and Salix spp., indicating that different mechanisms operated to confer tolerance of heavy metals. The maximum efficiency of photosystem II photochemistry value of the five species showed no differences among the treatments, except for Q. shumardii. All species showed low metal translocation factors (TFs). However, S. integra had significantly higher TF values for Zn (1.42-2.18) and cadmium (1.03-1.45) than did the other species. In this respect, Q. virginiana showed the highest tolerance and a low TF, implying that it is a candidate for phytostabilization of mine tailings in southern China. S. integra may be useful for phytoextraction of tailings in temperate regions.
An experiment was conducted to estimate the optimal dietary zinc (Zn) level of brown-egg laying hens fed a corn-soybean meal diet from 20 to 40 weeks of age. A total of 120 20-week-old Beijing Red commercial laying hens were randomly allotted by bodyweight to one of five treatments with six replicates of four birds each in a completely randomized design, and fed a Zn-unsupplemented corn-soybean meal basal diet containing 27.95 mg Zn/kg by analysis and the basal diets supplemented with 30, 60, 90, or 120 mg Zn/kg as Zn sulfate (reagent grade ZnSO4·7H2O) for a duration of 20 weeks. Laying performance, egg quality, tissue Zn concentrations, and activities of serum alkaline phosphatase (AKP), and liver copper-Zn superoxide dismutase (CuZnSOD) were measured. Regression analyses were performed to estimate an optimal dietary Zn level whenever a significant quadratic response (P < 0.05) was observed. Tibia Zn concentration (P = 0.002) and serum AKP activity (P = 0.010) showed significant quadratic responses to dietary supplemental Zn levels. The estimates of dietary Zn requirements for brown-egg laying hens from 20 to 40 weeks of age were 71.95 and 64.63 mg/kg for tibia Zn concentration and serum AKP activity, respectively. The results from this study indicate that the tibia Zn might be a more suitable and reliable parameter for Zn requirement estimation, and the optimal dietary Zn level would be about 72 mg/kg for brown-egg laying hens fed a corn-soybean meal diet from 20 to 40 weeks of age.
The maternal transfer of trace elements is a process by which offspring may accumulate trace elements from their maternal parent. Although maternal transfer has been assessed in many vertebrates, there is little understanding of this process in invertebrate
 species. This study investigated the maternal transfer of 13 trace elements (Ag, As, Cd, Co, Cr, Cu, Fe, Hg, Mn, Ni, Pb, Se, and Zn) in Atlantic horseshoe crab (Limulus polyphemus) eggs and compared concentrations to those in adult leg and gill tissue. For the majority of individuals, all trace elements were transferred, with the exception of Cr, from the female to the eggs. The greatest concentrations on average transferred to egg tissue were Zn (140 µg/g), Cu (47.8 µg/g), and Fe (38.6 µg/g) for essential elements and As (10.9 µg/g) and Ag (1.23 µg/g) for nonessential elements. For elements that were maternally transferred, correlation analyses were run to assess if the concentration in the eggs were similar to that of adult tissue that is completely internalized (leg) or a boundary to the external environment (gill). Positive correlations between egg and leg tissue were found for As, Hg, Se, Mn, Pb, and Ni. Mercury, Mn, Ni, and Se were the only elements correlated between egg and gill tissue. Although, many trace elements were in low concentration in the eggs, we speculate that the higher transfer of essential elements is related to their potential benefit during early development versus nonessential trace elements, which are known to be toxic. We conclude that maternal transfer as a source of trace elements to horseshoe crabs should not be overlooked and warrants further investigation.
SnYSL3 encodes a plasma-localized transporter delivering various metal-nicotianamine complexes. The expression of SnYSL3 is up-regulated by excess Cd, suggesting an important role for SnYSL3 in response to Cd stress. The Yellow Stripe-Like (YSL) transporters have been proposed to participate in metal uptake and long-range transport in model plants. In this study, we isolated and characterized a novel member of the YSL gene family, SnYSL3, from the cadmium hyperaccumulator Solanum nigrum. SnYSL3 was constitutively expressed and encodes a plasma membrane-localized protein. In situ RNA hybridization localized the SnYSL3 transcripts predominantly in vascular tissues and epidermal cells of the roots and stems, while in leaves, the mRNA levels were high in the vasculature. The SnYSL3 expression level was up-regulated by excess Cd, excess Fe and Cu deficiency. Heterologous expression of SnYSL3 in yeast revealed that SnYSL3 transports nicotianamine complexes containing Fe(II), Cu, Zn and Cd. SnYSL3 overexpression in Arabidopsis thaliana decreased Fe and Mn concentrations in the roots and increased the root-to-shoot translocation ratios of Fe and Mn. Under Cd exposure, the transgenic plants showed increased translocation ratios of Fe and Cd, but no difference was observed in Mn translocation from roots to shoots between the transgenic and wild-type lines. Although the accurate function of SnYSL3 remains to be confirmed, these results suggest that SnYSL3 is a transporter delivering a broad range of metal-nicotianamine complexes and is potentially important for the response to heavy metal stress, especially due to Cd and Fe.
The present investigation aimed to assess the possibility of using plasma levels of erythropoietin (EPO) hormone and tissue changes of hematopoietic organs as biomarkers of environmental pollution in abu mullet (Liza abu) and tiger tooth croaker (Otolithes ruber) collected from Musa Creek (northwest of the Persian Gulf). 120 L. abu and O. ruber were collected from five stations at the Musa Creek: Petrochemical, Ghanam, Doragh, Zangi and Patil stations. Blood samples were obtained from the caudal vein. Tissue samples were also taken from the spleen and head kidney, and tissue sections were prepared according to routine histological methods. The concentrations of Hg, Pb, Zn, Cu, and Cd were also measured in the sediment samples. The minimum level of EPO and the most severe tissue changes were determined in fish collected near a Petrochemical station. This station is adjacent to the Imam Khomeini Petrochemical Complex and receives highly contaminated effluents from this complex. The highest degree of contamination (Cd) also belonged to this station. The fish collected from the Patil station represented the highest EPO level and the least tissue changes. This station exhibited a lesser degree of contamination. Based on the results, there was a significant correlation between the plasma level of EPO hormone and the degree of environmental contamination.
G-protein-coupled receptor 39 (GPR39) plays a role in cellular and physiological processes, including insulin secretion, cell death inhibition, wound healing, and obesity. Increasing evidence suggests that GPR39 is potently stimulated by zinc ions (Zn(2+)) and is therefore considered a putative Zn(2+) receptor. Given the importance of Zn(2+) in the reproductive system, we proposed that GPR39 might have a functional role in the reproductive system. However, the localization of GPR39 in the reproductive system remains unknown. Here, we used mice expressing a Gpr39 promoter-driven LacZ reporter system to detect Gpr39 expression in the reproductive system at different phases of the estrous cycle and found an interesting region-specific distribution of Gpr39 in the mouse oviduct epithelium, with strong expression at the ampulla and weak expression at the isthmus, which was consistent with the results using reverse transcription polymerase chain reaction and immunofluorescence. Moreover, using ZnSe(AMG) staining, we found that Zn(2+), the putative ligand of GPR39, also found a distribution similar to GPR39 expression, suggesting that their potential interaction mediates fertilization and embryo transportation.
Diagnosis of tuberculosis (TB) in children is difficult in children especially in extrapulmonary tuberculosis (EPTB). This study was conducted to evaluate the use of polymerase chain reaction (PCR) targeting IS6110 in the diagnosis of TB in children with pulmonary TB and EPTB and also to compare its performance with MGIT 960 culture and conventional microscopy.
A total of 142 cases (50 pulmonary, 92 extrapulmonary) of suspected TB patients <15 years of age were included in the study. The clinical specimens obtained from these cases were subjected to Ziehl-Neelsen staining (ZN), MGIT 960 TB culture and PCR targeting insertion sequence IS6110. Sensitivity and specificity of PCR were calculated in pulmonary and extrapulmonary specimens. The results were compared to MGIT culture.
PCR targeting IS6110 sequence had sensitivity of 69.01% in various clinical specimens which was significantly more than MGIT culture showing a sensitivity of 47.41% (p<0.05). Sensitivity of PCR IS6110 in extrapulmonary specimens was 65.21% which was lower than sensitivity in pulmonary specimens (76%) but was not statistically significant (p>0.05).
Diagnostic efficacy of PCR IS6110 in pulmonary and extrapulmonary TB cases was similar. PCR using IS6110 primer had significantly better efficiency than MGIT culture in diagnosing TB in children.
Microbe-assisted phytoremediation has been considered a promising measure for the remediation of heavy metal-polluted soil. The aim of this study was to assess the effect of diazotrophic plant growth-promoting Herbaspirillum sp. GW103 on growth and lead (Pb) and zinc (Zn) accumulation in Zea mays L. The strain GW103 exhibited plant growth-promoting traits such as indole-3-acetic acid, siderophores, and 1-aminocyclopropane-1-carboxylic deaminase. Treatment of Z. mays L. plants with GW103 significantly increased 19, 31, and 52% of plant biomass and 10, 50, and 126% of chlorophyll a contents in Pb, Zn, and Pb + Zn-amended soils, respectively. Similarly, the strain GW103 significantly increased Pb and Zn accumulation in shoots and roots of Z. mays L., which were 77 and 25% in Pb-amended soil, 42 and 73% in Zn-amended soil, and 27 and 84% in Pb + Zn-amended soil. Furthermore, addition of GW103 increased 8, 12, and 7% of total protein content, catalase, and superoxide dismutase levels, respectively, in Z. mays L. plants. The results pointed out that isolate GW103 could potentially reduce the phytotoxicity of metals and increase Pb and Zn accumulation in Z. mays L. plant.
A multispectroscopic exploration was employed to investigate the interaction between the metallo-enzyme alcohol dehydrogenase (ADH) from yeast with bioflavonoid quercetin (QTN). Here, we have characterized the complex formation between QTN and Zn(2+) in aqueous solution and then examined the effect of such complex formation on the enzymatic activity of a zinc(II)-dependent enzyme alcohol dehydrogenase from yeast. We have observed an inhibition of enzymatic activity of ADH in presence of QTN. Enzyme inhibition kinetic experiments revealed QTN as a non-competitive inhibitor of yeast ADH. Perturbation of Circular dichroic (CD) spectrum of ADH in presence of QTN is observed due to the structural changes of ADH on complexation with the above flavonoid. Our results indicate a conformational change of ADH due to removal of Zn(2+) present in the enzyme by QTN. This was further established by molecular modeling study which shows that the flavonoid binds to the Zn(2+) ion which maintains the tertiary structure of the metallo-enzyme. So, QTN abstracts only half of the Zn(2+) ions present in the enzyme i.e. one Zn(2+) ion per monomer. From the present study, the structural alteration and loss of enzymatic activity of ADH are attributed to the complex formation between QTN and Zn(2+).
Sequential extraction procedure was applied to determine the chemical forms of heavy metals in sediments in order to assess their mobility and availability in the aquatic environment. The mean concentrations of Cr, Ni, Pb, Cd, Cu and Zn in exchangeable and carbonate fractions were 14.9, 30.9, 17, 0.37, 4.4 and 14.4mg/kg, respectively. Based on the sediments quality guidelines (SQGs), the adverse biological effects caused by Ni, can occur
 frequently across the study area. Risk assessment code (RAC) suggested that the Cd has the highest level of environmental risk compared with other studied metals. Modified risk assessment code (mRAC) demonstrated a high potential adverse effect in the many of sampling sites. According to the fractionation results, the concentration of Ni in exchangeable and carbonate fractions was very considerable and more than other metals, hence, the potential risk of nickel release can be much more than other investigated metals.
Pulmonary delivery of fluoroquinolones (FQs) is an interesting approach to treat lung infections as it may lead to high local concentrations while minimizing systemic exposure. However, FQs have a rapid diffusion through the lung epithelium giving the pulmonary route no advantage compared to the oral route. Interactions between FQs and metal cations form complexes which limit the diffusion through the epithelial barrier and would reduce the absorption of FQs and maintain high concentrations in the lung. The effects of this complexation depend on the FQ and the metal cations and optimum partners should be selected through in vitro experiments prior to aerosol drug formulation. In this study, CIP was chosen as a representative FQ and 5 cations (Ca(2+), Mg(2+), Zn(2+), Al(3+), Cu(2+)) were selected to study the complexation and its effects on permeability, antimicrobial efficacy and cell toxicity. The results showed that the apparent association constants between CIP and cations ranked with the descending order: Cu(2+)>Al(3+)>Zn(2+)>Mg(2+)>Ca(2+). When a target of 80% complexation was reached with the adequate concentrations of cations, the CIP permeability through the Calu-3 lung epithelial cells was decreased of 50%. Toxicity of the CIP on the Calu-3 cells, with an EC50 evaluated at 7μM, was not significantly affected by the presence of the cations. The minimum inhibitory concentration of CIP for Pseudomonas aeruginosa was not affected or slightly increased in the range of cation concentrations tested, except for Mg(2+). In conclusion, permeability was the main parameter that was affected by the metal cation complexation while cell toxicity and antimicrobial activity were not or slightly modified. Cu(2+), with the highest apparent constant of association and with no effect on cell toxicity and antimicrobial activity of the CIP, appeared as a promising cation for the development of a controlled-permeability formulation of CIP for lung treatment.
Infection with oncogenic human papillomavirus induces deregulation of cellular redox homeostasis. Virus replication and papillomavirus-induced cell transformation require persistent expression of viral oncoproteins E7 and E6 that must retain their functionality in a persistent oxidative environment. Here, we dissected the molecular mechanisms by which E7 oncoprotein can sense and manage the potentially harmful oxidative environment of the papillomavirus-infected cell. The carboxy terminal domain of E7 protein from most of the 79 papillomavirus viral types of alpha genus, which encloses all the tumorigenic viral types, is a cysteine rich domain that contains two classes of cysteines: strictly conserved low reactive Zn(+2) binding and degenerate reactive cysteine residues that can sense reactive oxygen species (ROS). Based on experimental data obtained from E7 proteins from the prototypical viral types 16, 18 and 11, we identified a couple of low pKa nucleophilic cysteines that can form a disulfide bridge upon the exposure to ROS and regulate the cytoplasm to nucleus transport. From sequence analysis and phylogenetic reconstruction of redox sensing states we propose that reactive cysteine acquisition through evolution leads to three separate E7s protein families that differ in the ROS sensing mechanism: non ROS-sensitive E7s; ROS-sensitive E7s using only a single or multiple reactive cysteine sensing mechanisms and ROS-sensitive E7s using a reactive-resolutive cysteine couple sensing mechanism.
Tuning the electronic structure of metal-organic frameworks is the key to extending their functionality to the photocatalytic conversion of absorbed gases. Herein we discuss how the band edge positions in zeolitic imidazolate frameworks (ZIFs) can be tuned by mixing different imidazole-based linkers within the same structure. We present the band alignment for a number of known and hypothetical Zn-based ZIFs with respect to the vacuum level. Structures with a single type of linker exhibit relatively wide band gaps; however, by mixing linkers of a low-lying conduction edge with linkers of a high-lying valence edge, we can predict materials with ideal band positions for visible-light water splitting and CO2 reduction photocatalysis. By introducing copper in the tetrahedral position of the mixed-linker ZIFs, it would be possible to increase both photo-absorption and the electron-hole recombination times.
We report on the synthesis of new derivatives of silylated clusters of the type [Ge9 (SiR3 )3 ](-) (R = SiMe3 , Me = CH3 ; R = Ph, Ph = C6 H5 ) as well as on their reactivity towards copper and zinc compounds. The silylated cluster compounds were synthesized by heterogeneous reactions starting from the Zintl phase K4 Ge9 . Reaction of K[Ge9 {Si(SiMe3 )3 }3 ] with ZnCl2 leads to the already known dimeric compound [Zn(Ge9 {Si(SiMe3 )3 }3 )2 ] (1), whereas upon the reaction with [ZnCp*2 ] the coordination of [ZnCp*](+) to the cluster takes place (Cp*=1,2,3,4,5-pentamethylcyclopentadienyl) under the formation of [ZnCp*(Ge9 {Si(SiMe3 )3 }3 )] (2). A similar reaction leads to [CuPiPr3 (Ge9 {Si(SiMe3 )3 }3 )] (3) from [CuPiPr3 Cl] (iPr=isopropyl). Further we investigated the novel silylated cluster units [Ge9 (SiPh3 )3 ](-) (4) and [Ge9 (SiPh3 )2 ](-) (5), which could be identified by mass spectroscopy. Bis- and tris-silylated species can be synthesized by the respective stoichiometric reactions, and the products were characterized by ESI-MS and NMR experiments. These clusters show rather different reactivity. The reaction of the tris-silylated anion 4 with [CuPiPr3 Cl] leads to [(CuPiPr3 )3 Ge9 (SiPh3 )2 ](+) as shown from NMR experiments and to [(CuPiPr3 )4 {Ge9 (SiPh3 )2 }2 ] (6), which was characterized by single-crystal X-ray diffraction. Compound 6 shows a new type of coordination of the Cu atoms to the silylated Zintl clusters.
Recent studies showed that ZnO nanoparticles (NPs) might induce the toxicity to human endothelial cells. However, little is known about the interaction between ZnO NPs and circulatory components, which is likely to occur when NPs enter the blood. In this study, we evaluated ZnO NP-induced cytotoxicity, oxidative stress and inflammation in human umbilical vein endothelial cells (HUVECs), with the emphasis on the interaction with palmitate (PA) or lipopolysaccharide (LPS), because PA and LPS are normal components in human blood that increase in metabolic diseases. Overall, ZnO NPs induced cytotoxicity and intracellular reactive oxygen species (ROS) at a concentration of 32 μg ml(-1) , but did not significantly affect the release of inflammatory cytokines or adhesion of THP-1 monocytes to HUVECs. In addition, exposure to ZnO NPs dose-dependently promoted intracellular Zn ions in HUVECs. PA and LPS have different effects. Two hundred μm PA significantly induced cytotoxicity and THP-1 monocyte adhesion, but did not affect ROS or release of inflammatory cytokines. In contrast, 1 μg ml(-1) LPS significantly induced ROS, release of inflammatory cytokines and THP-1 monocyte adhesion, but not cytotoxicity. The presence of ZnO NPs did not significantly affect the toxicity induced by PA or LPS. In addition, the accumulation of Zn ions after ZnO NP exposure was not significantly affected by the presence of PA or LPS. We concluded that there was no interaction between ZnO NPs and PA or LPS on toxicity to HUVECs in vitro. Copyright © 2016 John Wiley & Sons, Ltd.
The simple cooperative catalytic system had been successfully developed for the solvent-free N-formylation of amines with CO2 and hydrosilanes at ambient conditions, which was composed of the Zn(salen) catalyst and quaternary ammonium salt. These commercially available binary components could activate the Si-H bonds effectively originated from the intermolecularly synergistic effect between Lewis base-transition metal center (LB-TM), and subsequently facilitate the insertion of CO2 to form the active silyl formats, thereby leading to obtain the excellent catalytic performance at a low catalyst loading. Furthermore, the bifunctional Zn(salen) complexes owning two imidazolium-based ionic liquid (IL) units at the 3,3'-position of salen ligand could be acted as intramolecularly cooperative catalysts and the feature of solvent-regulated separation resulted in the ease of catalyst recycle and reuse.
Understanding the nature of active sites in metal-supported catalysts is of great importance towards establishing their structure-property relationships. The outstanding catalytic performance of metal-supported catalysts is frequently ascribed to the synergic effect of different active sites, which is however not well spectroscopically characterized. Herein, we report the direct detection of surface Zn species and (1) H-(67) Zn internuclear interaction between Zn(2+) ions and Brønsted acid sites on Zn-modified ZSM-5 zeolites by high-field solid-state NMR spectroscopy. The observed promotion of C-H bond activation of methane is rationalized by the enhanced Brønsted acidity generated by synergic effects arising from the spatial proximity/interaction between Zn(2+) ions and Brønsted acidic protons. The concentration of synergic active sites is determined by (1) H-(67) Zn double-resonance solid-state NMR spectroscopy.
The sulfide photocatalyst of Zn0.9 Fe0.1 S was successfully synthesized by a facile microwave-assisted method,
 and Zn0.9 Fe0.1 S photocatalysts were characterized using SEM, EDX, XRD and BET. The specific surface area of synthesized Zn0.9 Fe0.1 S is 78.1 m(2) g(-1) , and total pore volume is 0.4 cm(3) g(-1) . With bisphenol A (BPA) as a target pollutant, photocatalytic system of UV + Zn0.9 Fe0.1 S + H2 O2 was set up. Some influencing parameters, including H2 O2 dosage, initial pH value, initial concentration of BPA and Zn0.9 Fe0.1 S dosage, were investigated, and the stability of the Zn0.9 Fe0.1 S was also studied during the photocatalysis. The optimum values of operating parameters were found at an initial pH value of 5.0, a H2 O2 dosage of 0.15 mmol L(-1) and a Zn0.9 Fe0.1 S dosage of 0.08 g when the initial concentration of BPA was 10 mg L(-1) . Under the optimal conditions, the highest removal rate of BPA achieved 95%. After seven consecutive reaction cycles, the degradation efficiency of BPA could still reach 85% and there was only a little dissolution of Zn(2+) and Fe(2+) . Compared with the traditional photo-Fenton system, the UV + Zn0.9 Fe0.1 S + H2 O2 system can not only improve the degradation efficiency of BPA, but also reduce the dosage of H2 O2 and thus reduce the processing cost.
Here, we report Cu and Zn isotope ratios of bones and teeth of French people from various historical periods with the aim to understand how Cu and Zn isotope ratios of bone, a tissue that is continuously remodeled throughout life but that is prone to post-mortem diagenesis, compare with that of tooth enamel, a tissue that forms once during childhood but that is more resistant to diagenesis. Specifically, we examine (1) the potential existence of sex-related differences in the Cu isotope ratios (represented as δ(65) Cu) in the tooth enamel of identified men and women, and (2) a decrease of Zn isotope delta ratios (represented as δ(66) Zn) related to the increase of meat and fish consumption during the 20(th) century.
Four series of material were studied: the archeological population of Saint-Laurent de Grenoble (17(th) -18(th) centuries AD), an anatomical collection of skulls (19(th) century AD), a contemporary anatomical collection of bones never buried, and contemporary teeth samples. The metals were purified by liquid chromatography and their isotopic ratios measured by means of multicollector inductively coupled plasma mass spectrometry.
We describe a clear offset between bone and tooth enamel for Zn isotope ratios, as previously observed in animals. There is a similar offset for Cu isotope ratios. We did not observe any difference between the δ(65) Cu values of men and women when looking at dental enamel. For the contemporary samples, the δ(66) Zn values of bioapatite decreased, which might be explained by the increase of animal product consumption among the French people during this period, notably when the access to seafood became widespread.
Our study demonstrates that the Cu and Zn isotope compositions of dental enamel are promising tools for childhood diet reconstruction. Meanwhile, the Cu isotope ratio of tooth enamel is unlikely to be useful for the identification of biological sex, even in the case of populations with early menarche. Further works are needed to understand the relationships between trophic level and Zn isotope ratios of human remains.
In this study, a new zinc chloride (ZnCl2) impregnated activated carbon (Zn-AC) was prepared from oak charcoals as low-cost material and used as adsorbent for tetracycline (TC) adsorption. The Zn-AC was characterized using field emission-scanning electron microscope, powder X-ray diffraction, and CHNS-O analyses. Specific surface area of the adsorbent was also measured using the Brunauer, Emmett and Teller (BET) isotherm model. The TC adsorption onto the Zn-AC was investigated as a function of solution pH, adsorbent dosage, and inorganic cations (Li(+), K(+), Mg(2+), Ca(2+), Ni(2+), and Fe(3+)) and anions (HCO3(-), NO3(-) and SO4(2-)) that could interfere in the adsorption of TC. The adsorbate solution pH had no considerable effect on TC adsorption. The adsorption of TC onto the adsorbent was relatively fast and reached the equilibrium after about 120 min. The results showed that all studied cations and anions decreased TC adsorption onto the Zn-AC, but this decrease in TC adsorption was strongly significant for Fe(3+) and Ni(2+) ions. The general order kinetic model and the Redlich-Peterson isotherm model provided the best fit to the experimental data. The maximum amount of TC adsorbed onto the Zn-AC (Qmax) is 282.06 mg g(-1), indicating this adsorbent is a good adsorbent for the removal of TC from aqueous solutions.
Composts are considered one of major sources that contribute heavy metals to the environment. The objective of this study was to investigate historical changes and spatial variation of metal concentrations in Chinese composts by analysing representative compost samples and published data from 2002 to 2013. Mean concentrations of cadmium (Cd), chromium (Cr), lead (Pb), arsenic (As), mercury (Hg), zinc (Zn), nickel (Ni), and copper (Cu) in the composts were 2.42, 35.52, 32.38, 16.33, 0.32, 258.1, 9.71, and 72.24 mg kg(-1), respectively. The percentages of samples with metal concentration exceeding critical levels of Chinese standards for organic fertilizers (NY525-2012) were 28.7, 18.3, 9.6, 1.7, and 0.9%, respectively, for Cd, As, Pb, Cr, and Hg. Modelling predicts that it would take 18, 24, 29, and 48 years for Cu, Zn, Hg, and Cd to reach Category I Environmental Capacity of China (GB15618-1995) according to current application rate. During the 2002-2013 period, concentration of Cd in composts tended to decrease with time, whereas those of Zn, Cu, and As were opposite, which is likely due to less or no control for these elements. Concentrations of Cu, Zn, As, and Cd were generally higher in composts from the economically developed regions in China, where more commercial farms were built that use metal-spiked feeds. Manures from the commercial farms generally had higher metal concentration, as compared to the subsistence farms. Further research is needed to monitor metal concentrations from source materials to composts and assess long-term impact of compost application on soil quality.
Different gold mining and smelting processes can lead to distinctive heavy metal contamination patterns and results. This work examined heavy metal pollution from a large-scale cyanidation gold mining operation, which is distinguished from artisanal and small-scale amalgamation gold mining, in Jilin Province, China. A total of 20 samples including one background sample were collected from the surface of the mining area and the tailings pond in June 2013. These samples were analyzed for heavy metal concentrations and degree of pollution as well as sources of Cr, Cu, Zn, Pb, Ni, Cd, As, and Hg. The mean concentrations of Pb, Hg, and Cu (819.67, 0.12, and 46.92 mg kg(-1), respectively) in soil samples from the gold mine area exceeded local background values. The mean Hg content was less than the first-class standard of the Environmental Quality for Soils, which suggested that the cyanidation method is helpful for reducing Hg pollution. The geochemical accumulation index and enrichment factor results indicated clear signs that enrichment was present for Pb, Cu, and Hg, with the presence of serious Pb pollution and moderate presence to none of Hg and Cu pollution. Multivariate statistical analysis showed that there were three metal sources: (1) Pb, Cd, Cu, and As came from anthropogenic sources; (2) Cr and Zn were naturally occurring; whereas (3) Hg and Ni had a mix of anthropogenic and natural sources. Moreover, the tailings dam plays an important role in intercepting the tailings. Furthermore, the potential ecological risk assessment results showed that the study area poses a potentially strong risk to the ecological health. Furthermore, Pb and Hg (due to high concentration and high toxicity, respectively) are major pollutants on the risk index, and both Pb and Hg pollution should be of great concern at the Haigou gold mines in Jilin, China.
The antibiotics known as bleomycins constitute a family of natural products clinically employed for the treatment of a wide spectrum of cancers. The drug acts as an antitumor agent by virtue of the ability of a metal complex of the antibiotic to cleave DNA. Bleomycins are differentiated by their C-terminal regions. Previous structural studies involving metal-bleomycin-DNA triads have allowed the identification of the bithiazole-(C-terminus substituent) segment in this molecule as the one that most closely interacts with DNA. Three different modes of binding of metallo-bleomycins to DNA (partial or total intercalation of the bithiazole unit between DNA bases, or binding to the minor groove) have been proposed in the literature. The therapeutic use of bleomycin is frequently associated with the development of pulmonary fibrosis. The severity of this side effect has been attributed to the C-terminus of the antibiotic by some researchers. The degree of pulmonary toxicity of bleomycin-A2 and -A5, were found to be higher than those of bleomycin-B2 and peplomycin. Since the introduction of Blenoxane to clinical medicine in 1972, attempts have been made at modifying the basic bleomycin structure at the C-terminus to improve its therapeutic index. However, the pharmacological and toxicological importance of particular C-termini on bleomycin remains unclear. The present study was designed to determine the effect of Zn(II)bleomycin-A2, -A5, -B2, and Zn(II)peplomycin on the structure of a DNA hairpin containing the 5'-GC-3' binding site. We provide evidence that different Zn(II)bleomycins affect the structure of the tested DNA segment in different fashions.
In this study, superfine Ag nanoparticle decorated ultrathin Zn nanoplate electrodes were prepared for
 the reduction of CO2 to CO for the first time. With an extremely tiny amount of superfine 2 nm Ag nanoparticles uniformly deposited on the surface, the CO Faradaic efficiency for the Zn electrode doubled to 84% at about 0.8 V vs. RHE, while the CO current density increased 7 times to 1.89 mA cm(-2).
Oxidative stress is thought to be involved in the pathogenesis of microalbuminuria in Sickle cell anemia (SCA). Antioxidant enzymes such as glutathione peroxidase (GPx) and Cu-Zn superoxide dismutase (SOD) may play an important protective role. This study aimed to evaluate the association between albuminuria and these two antioxidant enzymes.
We consecutively recruited Steady state children aged between 2 and 18 years old with established diagnosis of homozygous SCA in two hospitals of Kinshasa/DR Congo. The relationship between Urinary Albumin Creatinine Ratio (UACR) and other variables of interest (age, systolic blood pressure, diastolic blood pressure, plasma GPx and Cu-Zn SOD, free plasmatic hemoglobin, LDH, indirect bilirubin, white blood cells (WBC), percentage of fetal hemoglobin, serum iron, ferritin, CRP) was analyzed by Bivariate correlation (Pearson's correlation coefficient). Microalbuminuria was defined by urine albumin/creatinine ratio between 30 and 299 mg/g.
Seventy Steady state Black African children with SCA (56% boys; average age 9.9 ± 4.3 years; 53% receiving hydroxyurea) were selected. Prevalence of microalbuminuria was 11.8%. LDH (r = 0.260; p = 0.033) and WBC count (r = 0.264; p = 0.033) were positively correlated with UACR whereas GPx (- 0.328; p = 0.007) and Cu-Zn SOD (- 0.210; p = 0.091) were negatively correlated with UACR.
Albuminuria is associated with decreased antioxidant capacity and increased levels of markers of hemolysis and inflammation. Therefore, strategies targeting the reduction of sickling and subsequent hemolysis, oxidative stress and inflammation could help preventing or at least delaying the progression of kidney disease in SCA children.
Permeable pavement systems (PPS) are a widely-used treatment measure in sustainable stormwater management and groundwater recharge. However, PPS are not very efficient in removing heavy metals from stormwater. A pilot scale study using zeolite or basalt as bed material in PPS removed 41-72%, 67-74%, 38-43%, 61-72%, 63-73% of Cd, Cu, Ni, Pb, and Zn, respectively, from synthetic stormwater (pH 6.5; Cd, Cu, Ni, Pb, and Zn concentrations of 0.04, 0.6, 0.06, 1.0, and 2.0 mg L(-1), respectively) over a period of 80 h. The total volume of stormwater that passed through the PPS was equivalent to runoff in 10 years of rainfall in Sydney, Australia. The concentrations of metals in the PPS effluent failed fresh and marine water quality trigger values recommended in the Australian and New Zealand guidelines. An addition of a post-treatment of a horizontal filter column containing a titanate nano-fibrous (TNF) material with a weight < 1% of zeolite weight and mixed in with granular activated carbon (GAC) at a GAC:TNF weight ratio of 25:1 removed 77% of Ni and 99-100% of all the other metals. The effluent easily met the required standards of marine waters and just met those concerning fresh waters. Batch adsorption data from solutions of metals mixtures fitted the Langmuir model with adsorption capacities in the following order, TNF ≫ zeolite > basalt; Pb > Cu > Cd, Ni, Zn.
In the present work, three different commercial membrane brands were used in an identical electrodialytic cell setup and operating conditions, in order to reduce the leaching of metals and salt anions of two types of municipal solid waste incineration residues: air pollution control residues of a semi-dry flue-gas cleaning system and fly ashes from a plant with wet flue-gas cleaning system. The results showed a general reduction of the leaching in both residues after ED remediation. For the following elements, the leaching was found to be different after ED treatment depending on the membrane used, with statistical significance: • Air pollution control residues of the semi-dry flue-gas cleaning system: Cr, Cu, Ni, Pb, Zn; • Fly ashes from a plant with wet flue-gas cleaning system: Al, Ba, Cu, Ni, Zn, Cl, SO4. Final leaching values for some elements and membranes, but not the majority, were below than those of certified coal fly ash (e.g. Al or Cr), a material which is commonly used in construction materials; at the same time, some of these values were reduced to below the Danish law thresholds on the use of contaminated soil in constructions. These results show the potential of ED as a technology to upgrade municipal solid waste incineration residues.
Transition metals are known to be enriched in organic-coated marine aerosols, but the impact these cations have on their surface properties is not well understood. Here the effect of Zn(2+) enrichment on the surface properties of a dipalmitoylphosphatidylcholine (DPPC) monolayer was investigated and compared to that of the alkaline earth metal Sr(2+), an ion not enriched in aerosols. Phase behavior of the DPPC film on concentrated aqueous solutions was probed with surface pressure-area isotherms while domain morphology was monitored with Brewster angle microscopy (BAM). Infrared reflection-absorption spectroscopy (IRRAS) and vibrational sum frequency generation (VSFG) spectroscopy were used to assess the impact of cations on the conformation and orientation of alkyl chains as well as the hydration state of the carbonyl and phosphatidylcholine (PC) moieties. Results of compression isotherms and BAM show that Zn(2+) strongly interacts with DPPC molecules, and induces condensation of the monolayer while Sr(2+) only weakly interacts with the monolayer in expanded phases. Conformational order and orientation of alkyl chains in the condensed phase are not significantly altered by either cation. IRRAS indicates that Sr(2+) has weak interactions with the PC headgroup. Zn(2+) ions cause dehydration of carbonyl groups and binds to the phosphate group in a 2 : 1 bridging complex. Findings here suggest that Sr(2+) is not enriched in aerosols because it behaves similar to a monovalent ion and only weakly interacts with the monolayer, while enrichment of Zn(2+) is due to strong binding to the lipid film.
Effects of heavy metals on aerobic denitrification have been poorly understood compared with their impacts on anaerobic denitrification. This paper presented effects of four heavy metals (Cd(II), Cu(II), Ni(II), and Zn(II)) on aerobic denitrification by a novel aerobic denitrifying strain Pseudomonas stutzeri PCN-1. Results indicated that aerobic denitrifying activity decreased with increasing heavy metal concentrations due to their corresponding inhibition on the denitrifying gene expression characterized by a time lapse between the expression of the nosZ gene and that of the cnorB gene by PCN-1, which led to lower nitrate removal rate (1.67∼6.67 mg L(-1) h(-1)), higher nitrite accumulation (47.3∼99.8 mg L(-1)), and higher N2O emission ratios (5∼283 mg L(-1)/mg L(-1)). Specially, promotion of the nosZ gene expression by increasing Cu(II) concentrations (0∼0.05 mg L(-1)) was found, and the absence of Cu resulted in massive N2O emission due to poor synthesis of N2O reductase. The inhibition effect for both aerobic denitrifying activity and denitrifying gene expression was as follows from strongest to least: Cd(II) (0.5∼2.5 mg L(-1)) > Cu(II) (0.5∼5 mg L(-1)) > Ni(II) (2∼10 mg L(-1)) > Zn(II) (25∼50 mg L(-1)). Furthermore, sensitivity of denitrifying gene to heavy metals was similar in order of nosZ > nirS ≈ cnorB > napA. This study is of significance in understanding the potential application of aerobic denitrifying bacteria in practical wastewater treatment.
A panel of iron (Fe) and copper (Cu) chelators was screened for growth inhibitory activity against the fungal pathogen Cryptococcus neoformans. Select bidentate metal-binding ligands containing mixed O,S or O,N donor atoms were identified as agents that induce cell killing in a Cu-dependent manner. Conversely, structurally similar ligands with O,O donor atoms did not inhibit C. neoformans growth regardless of Cu status. Studies of Cu(ii) and Cu(i) binding affinity, lipophilicity, and growth recovery assays of Cu-import deficient cells identified lipophilicity of thermodynamically stable Cu(II)L2 complexes as the best predictor of antifungal activity. These same complexes induce cellular hyperaccumulation of Zn and Fe in addition to Cu. The results described here present the utility of appropriate metal-binding ligands as potential antifungal agents that manipulate cellular metal balance as an antimicrobial strategy.
Inspired by recent experimental fabrication of mono-halogenated versions of Metal-Organic Framework MOF-5 (i.e., X-MOF-5, X = F to I) and some experimentally known fully halogenated MOF compounds, we systematically studied frameworks incorporating full halogenation of the BDC linkers of the prototypical Iso-Reticular Metal-Organic Framework (IRMOF) series, exemplified by MOF-5. Using quantum chemistry calculations, we find that halogenation leads to a 90° rotation of the aryl group, which is mainly ascribed to overcrowding between halogen atoms and the carboxyl and benzene ring and strong repulsion among in-plane atoms/groups. The 90° configuration decreases the repulsion, and maximizes the stabilization energy, and is therefore more stable than 0° configuration. We find that the band gap can be tuned from 4.1 to 1.5 eV as we go from F, Cl, Br, to I. This extends the optical response of these experimentally accessible materials through the visible and infrared region. We have also considered a broader range of new materials that substitute various metals for Zn. Totally, 70 materials were systematically examined computationally including (M4O)(BDC-Z4)3 (M = Zn, Cd, Be, Mg, Ca, Sr, Ba;
 Z = H, F, Cl, Br, I). For the full range of materials, we calculate band gaps of 4.2 to 1.0 eV, corresponding to a threshold of absorption of 290-1240 nm. Four selected materials were tested for stability using short 5 ps molecular dynamics simulations up to 600 K. The new materials with the smallest band gaps could potentially be used in near-infrared (NIR) light-emitting devices. Other properties, e.g., bulk moduli, formation energy, chemical bonding, and optical properties, were also investigated. The present results may provide new materials for use as novel photocatalysts, photoactive materials for photovoltaic cells, or functional devices in nanoelectronics and optoelectronics.
Molecular engineering of seven closely related zinc ketoiminates, namely, [Zn(dapki)2], [Zn(daeki)2], [Zn(epki)2], [Zn(eeki)2], [Zn(mpki)2], [Zn(meki)2], and [Zn((n)pki)2], leads to the optimisation of precursor thermal properties in terms of volatilisation rate, onset of volatilisation, reactivity and thermal stability. The influence of functional groups at the imine side chain of the ligands on the precursor properties is studied with regard to their viability as precursors for atomic layer deposition (ALD) of ZnO. The synthesis of [Zn(eeki)2], [Zn(epki)2] and [Zn(dapki)2] and the crystal structures of [Zn(mpki)2], [Zn(eeki)2], [Zn(dapki)2] and [Zn((n)pki)2] are presented. From the investigation of the physico-chemical characteristics, it was inferred that all compounds are monomeric, volatile and exhibit high thermal stability, all of which make them promising ALD precursors. Compound [Zn(eeki)2] is in terms of thermal properties the most promising Zn-ketoiminate. It is reactive towards water, possesses a melting point of 39 °C, is stable up to 24 days at 220 °C and has an extended volatilisation rate compared to the literature known Zn-ketoiminates. It demonstrated self-saturated, water assisted growth of zinc oxide (ZnO) with growth rates in the order of 1.3 Å per cycle. Moreover, it displayed a broad temperature window from TDep = 175-300 °C and is the first report of a stable high temperature (>200 °C) ALD process for ZnO returning highly promising growth rates.
Alpha-synuclein and Cu, Zn superoxide dismutase (SOD1) are both aggregation-prone proteins that are associated with Parkinson's disease (PD) and amyotrophic lateral sclerosis (ALS), respectively. Recently, we showed that alpha-synuclein interacts with SOD1 in various cell types and tissues. Using a cell culture model, we also found that alpha-synuclein nucleates the polymerization of SOD1. Here, we discuss the current literature regarding their interaction and their co-localization in aggregates of human post-mortem tissue. Furthermore we comment on the reported alpha-synuclein-induced SOD1 polymerization in terms of cross-seeding effects in neurodegeneration.
Schiff bases have been prepared from biopolymer chitosan and salicylaldehyde, 5-methoxysalicylaldehyde, and 5-nitrosalicylaldehyde. Ligands were synthesized in a 1:1.5mol ratio, and their Cu(II), Ni(II) and Zn(II) complexes in a 1:1mol ratio (ligand:metal). Ligands were characterized by (1)H NMR and FTIR, resulting in degrees of substitution from 43.7 to 78.7%. Complexes were characterized using FTIR, electronic spectra, XPRD. The compounds were confirmed by the presence of an imine bond stretching in the 1630-1640cm(-1) and νMetal-N and νMetal-O at <600cm(-1). Electronic spectra revealed that both Cu(II) and Ni(II) complexes present a square plane geometry. The crystallinity values were investigated by X-ray powder diffraction. Thermal behavior of all compounds was evaluated by TGA/DTG and DTA curves with mass losses related to dehydration and decomposition, with characteristic events for ligand and complexes. Schiff base complexes presented lower thermal stability and crystallinity than the starting chitosan. Residues were the metallic oxides as confirmed by XPRD, whose amounts were used in the calculation of the percentage of complexed metal ions. Surface morphologies were analyzed with SEM-EDAX. Preliminary cytotoxicity tests were performed using MTT assay with HeLa cells. Despite the differences in solubility, the free bases presented relatively low toxicity.
The estimated daily intakes (EDIs) of six trace elements (Cu, Zn, Pb, Cd, Hg, and As) in vegetables (leafy vegetable, i.e., bok choy, fruit vegetables, i.e., cucumber and tomato, and other categories, i.e., mushroom, kidney bean, and potato), cereals (rice and wheat flour), and meats (pork, mutton, and beef) most commonly consumed by adult inhabitants of Qiqihar, Northeastern China, were determined to assess the health status of local people. The average EDIs of Cu, Zn, Pb, Cd, Hg, and As were with 20.77 μg (kg bw)(-1) day(-1) of Cu, 288 μg (kg bw)(-1) day(-1) of Zn, 2.01 μg (kg bw)(-1) day(-1) of Pb, 0.41 μg (kg bw)(-1) day(-1) of Cd, 0.01 μg (kg bw)(-1) day(-1) of Hg, and 0.52 μg (kg bw)(-1) day(-1) of As, respectively, which are below the daily allowance recommended by FAO/WHO. However, the maximum EDIs of Pb and Cd were 4.56 μg (kg bw)(-1) day(-1) and 1.68 μg (kg bw)(-1) day(-1), respectively, which are above the recommended levels [i.e., 3.58 μg (kg bw)(-1) day(-1) for Pb and 1.0 μg (kg bw)(-1) day(-1) for Cd] by FAO/WHO. This finding indicates that the potential health risk induced by daily ingestion of Pb and Cd for the local residents should receive a significant concern. Similarly, we detected elevated Pb and Cd concentrations, i.e., with average of 13.58 and 0.60 mg kg(-1) dw, respectively, in the adult scalp hairs. Consumption of rice, potato, bok choy, and wheat flour contributed to 75 and 82% of Pb and Cd daily intake from foodstuffs. Nevertheless, human scalp hair is inappropriate biological material for determination of the nutritional status of trace elements in this region.
The main objective of the study was to determine the deleterious effect of fluoride on plasma trace minerals of fluorotic cattle and to evaluate the effect of Tamarindus indica leaf powder toward correction of the same.
A total of 30 cattle exhibiting chronic sign of fluorosis and 10 healthy cattle from nonfluorotic area were incorporated in this study. Fluorotic cattle were divided into three equal groups consisting of 10 cattle each. Group I from fluoride free area served as healthy control. The Group II received no treatment and served as disease control. Groups III and IV were supplemented with tamarind leaf powder at 15 g and 30 g/day with feed for 60 days. Plasma mineral status was evaluated after 60 days of treatment with double beam atomic absorption spectrophotometer.
Statistical analysis of data revealed a significant (p<0.05) decrease in mean plasma copper (Cu) (0.344±0.007 ppm), zinc (Zn) (0.692±0.06 ppm), and iron (Fe) concentration (1.100±0.01 ppm) in fluorotic cattle in comparison to healthy cattle (0.58±0.010, 2.342±0.04, 1.406±0.04 ppm, respectively). Significant (p<0.05) increase in Cu, Zn, and Fe was recorded after supplementation of tamarind leaf powder to the fluorotic cattle.
It was concluded that fluorotic cattle might be supplemented with T. indica leaf powder with feed for the correction of the decreased level of certain plasma minerals.
To determine the performance of FDA vital staining method in detecting viability of acid fast bacilli in comparison with culture and also its correlation with conventional drug susceptibility testing results for isoniazid and rifampicin.
The study was conducted from Jan 2014 to June 2015. Sputum samples of patients taking either Cat I or Cat II anti-TB treatment were tested by Ziehl Neelsen and FDA staining, culture and susceptibility to rifampicin and isoniazid at the end of intensive phase.
Of the 100 ZN positive specimens, 74 were FDA positive of which 70 were reported positive by both the readers. All specimens having higher grades (2+ and 3+) by ZN were positive by FDA staining. 87.88% of 1+ and 45% of scanty smears were positive by FDA staining. MTB was isolated in 75 specimens of which 72 were positive by FDA. Two culture negative specimens were FDA positive. FDA staining had sensitivity and specificity of 96% and 92% respectively. 70.66% of the total culture isolates were MDRTB strains. 2.66% strains demonstrated monoresistance to each of INH and rifampicin.
FDA microscopy can be used as a simple and rapid TB treatment monitoring tool in resource limited settings to identify those patients requiring immediate culture and DST test.
In contrast to other mouse models that are deficient in antioxidant enzymes, mice null for Cu/Zn-superoxide dismutase (Sod1(-/)(-) mice) show a major decrease in lifespan and several accelerated aging phenotypes. The goal of this study was to determine if cell senescence might be a contributing factor in the accelerated aging phenotype observed in the Sod1(-/)(-) mice. We focused on kidney because it is a tissue that has been shown to a significant increase in senescent cells with age. The Sod1(-/)(-) mice are characterized by high levels of DNA oxidation in the kidney, which is attenuated by DR. The kidney of the Sod1(-/)(-) mice also have higher levels of double strand DNA breaks than wild type (WT) mice. Expression (mRNA and protein) of p16 and p21, two of the markers of cellular senescence, which increased with age, are increased significantly in the kidney of Sod1(-/)(-) mice as is β-gal staining cells. In addition, the senescence associated secretory phenotype was also increased significantly in the kidney of Sod1(-/)(-) mice compared to WT mice as measured by the expression of transcripts for IL-6 and IL-1β. Dietary restriction of the Sod1(-/)(-) mice attenuated the increase in DNA damage, cellular senescence, and expression of IL-6 and IL-1β. Interestingly, the Sod1(-/)(-) mice showed higher levels of circulating cytokines than WT mice, suggesting that the accelerated
 aging phenotype shown by the Sod1(-/)(-) mice could result from increased inflammation arising from an accelerated accumulation of senescent cells. Based on our data with Sod1(-/)(-) mice, we propose that various bouts of increased oxidative stress over the lifespan of an animal leads to the accumulation of senescent cells. The accumulation of senescent cells in turn leads to increased inflammation, which plays a major role in the loss of function and increased pathology that are hallmark features of aging.
Various metal phthalocyanines have been studied for their capacity for photodynamic effects on viruses. Two newly synthesized water-soluble phthalocyanine Zn(II) complexes with different charges, cationic methylpyridyloxy-substituted Zn(II)- phthalocyanine (ZnPcMe) and anionic sulfophenoxy-substituted Zn(II)-phthalocyanine (ZnPcS), were used for photoinactivation of two DNA-containing enveloped viruses (herpes simplex virus type 1 and vaccinia virus), two RNA-containing enveloped viruses (bovine viral diarrhea virus and Newcastle disease virus) and two nude viruses (the enterovirus Coxsackie B1, a RNA-containing virus, and human adenovirus 5, a DNA virus). These two differently charged phthalocyanine complexes showed an identical marked virucidal effect against herpes simplex virus type 1, which was one and the same at an irradiation lasting 5 or 20 min (Δlog=3.0 and 4.0, respectively). Towards vaccinia virus this effect was lower, Δlog=1.8 under the effect of ZnPcMe and 2.0 for ZnPcS. Bovine viral diarrhea virus manifested a moderate sensitivity to ZnPcMe (Δlog=1.8) and a pronounced one to ZnPcS at 5- and 20-min irradiation (Δlog=5.8 and 5.3, respectively). The complexes were unable to inactivate Newcastle disease virus, Coxsackievirus B1 and human adenovirus type 5.
Genome engineering is a branch of modern biotechnology composed of a cohort of protocols designed to construct and modify a genotype with the main objective of giving rise to a desired phenotype. Conceptually, genome engineering is based on the so called genome editing technologies, a group of genetic techniques that allow either to delete or to insert genetic information in a particular genomic locus. Ten years ago, genome editing tools were limited to virus-driven integration and homologous DNA recombination. However, nowadays the uprising of programmable nucleases is rapidly changing this paradigm. There are two main families of modern tools for genome editing depending on the molecule that controls the specificity of the system and drives the editor machinery to its place of action. Enzymes such as Zn-finger and TALEN nucleases are protein-driven genome editors; while CRISPR system is a nucleic acid-guided editing system. Genome editing techniques are still not widely applied for the design of new compounds with pharmacological activity, but they are starting to be considered as promising tools for rational genome manipulation in biotechnology applications. In this review we will discuss the potential applications of programmable nucleases for the metabolic engineering of secondary metabolites with biological activity.
Grain size and concentrations of heavy metals (arsenic (As), cadmium (Cd), chromium (Cr), copper (Cu), mercury (Hg), lead (Pb), and zinc (Zn)) of 148 surface sediments and activities of (210)Pb and heavy metal concetrantions of one sediment core from the Pearl River Estuary were analyzed. The surface sediments were dominated by silt and sandy silt. Sediment type controlled the spatial distribution patterns of the heavy metals. The heavy metal concentrations in the sediments ranged from 3.34 to 37.11 mg/kg for As, 0.06 to 2.06 mg/kg for Cd, 12 to 130 mg/kg for Cr, 5.8 to 170.6 mg/kg for Cu, 0.01 to 0.25 mg/kg for Hg, 23 to 78 mg/kg for Pb, and 32 to 259 mg/kg for Zn. Both contents of clay and organic carbons were significantly positively correlated with heavy metals. The baseline values of elements in the study area were 12.97 mg/kg for As, 0.14 mg/kg for Cd, 68 mg/kg for Cr, 28.9 mg/kg for Cu, 0.08 mg/kg for Hg, 33 mg/kg for Pb, and 92 mg/kg for Zn. The metal enrichment factor (EF) and geoaccumulation index (Igeo) were calculated to assess anthropogenic contamination. Results showed slight to moderate Cd contamination in the region. Principle component analysis indicated that Cd could be attributed to anthropogenic sources; As and Hg were predominantly affected by human activities; and Pb, Cr, Cu, and Zn were associated with both natural and anthropogenic sources.
Phosphate compounds and related materials are effective amendments for immobilization of heavy metals in contaminated soils. A greenhouse pot experiment with ryegrass (Lolium perenne) as the test plant was conducted to explore the impact of nanoparticle hydroxyapatite (HAP) on the immobilization and bioavailability of Cu and Zn in a heavy metal-polluted soil. The addition of nanoparticle HAP significantly decreased the uptake of Cu and Zn by ryegrass. As a result, the biomass of ryegrass increased as the rate of nanoparticle HAP increased. The toxicity characteristic leaching procedure (TCLP) and physiologically based extraction test (PBET) results of the treatments showed that the leachable and bioaccessible concentrations of Cu and Zn were significantly reduced after the soil stabilized with nanoparticle HAP. The XRD pattern of nanoparticle HAP was not changed by the presence of Cu and Zn, which suggests that Cu and Zn were immobilized by the formation of solid amorphous phosphate. Nanoparticle HAP was an effective material to immobilize heavy metals in contaminated soils.
To investigate the influence of Sonneratia apetala on nutrients and heavy metals in intertidal sediments, sediment cores of S. apetala marsh and mudflat in Shenzhen Bay, China were analyzed. The results showed that S. apetala improved sediment nutrient properties due to increased total carbon (TC), total nitrogen (TN), and total sulfur (TS). The levels of heavy metals were higher in S. apetala site than in mudflat, including chromium (Cr), nickel (Ni), copper (Cu), zinc (Zn), arsenic (As), cadmium (Cd), lead (Pb), and mercury (Hg). In S. apetala site, TC, TN, and TS were not positively correlated with Cr, Ni, As, Cd, and Pb, indicating their less important roles in trapping heavy metals. There were positive correlations among Ni, Cu, Zn, and Cd in both sites, suggesting similar anthropogenic source. Levels of As were higher than the probable effect level at both sites, indicating their toxicological importance. The geo-accumulation index and potential ecological risk index revealed higher metal contaminations in S. apetala site, especially for Cd, Hg, and As. Multivariate analysis implied that S. apetala alter the biogeochemical cycle of Cd and Cr to a certain extent. These findings indicate that S. apetala may improve soil nutrient properties and facilitate heavy metal accumulation in intertidal sediments.
Strong acid digestions are commonly used to determine heavy metal (HM) contents in soils. In order to understand more fully the acid digestion processes, a logical step is to determine the extent of dissolution of mineral phases. The aims of this study were to compare the efficiency of extraction of HM by different acid digestions and to monitor the associated dissolution of the clay fraction. The context of the study was to develop a milder chemical extraction method (microwave-assisted 1 mol L(-1) HNO3 closed system (NACS)), which recovers more reactive HM and with little dissolution of minerals. The different acid digestion methods dissolved different amounts of minerals from the clay fraction. Both aqua regia (AR) and EPA 3051 dissolved all of the Fe and Al oxides, and the dissolution of kaolin was limited to thinner particles (c dimension), smaller particles in a and b dimensions and grains with lower crystallinity. The lower recovery of HM for AR compared with EPA 3051 was related to the large amount of short-range order phases formed during the AR extraction as these phases have the capacity to re-adsorb HM. The new method (NACS) has the potential to replace other methods of determining bioavailable forms of HM, such as AR and EPA 3051. The contents of Pb, As, Co, Zn, and Cu determined by EPA 3051 and EPA 3052 were quite close.
L-asparaginase has lots of medical and industrial applications. Ever since L-asparaginase anti-tumor activity was first demonstrated, its production using microbial systems has attracted considerable attention owing to their cost-effective and eco-friendly nature. The aim of this study is to obtain L-asparaginase producing bacteria and determining the enzyme activity. Samples were picked up from Jooshan hot springs located in the Sirch, Kerman. The L-asparaginase producing bacteria were screened on the agar medium supplied with L-asparagine and phenol red indicator dye (pH-7.0). L-asparaginase activity was detected on the basis of pink color around the colony. Enzyme production was also performed based on ammonia detection by Nessler method. Among 24 strains, there were 7 strains which could produce L-asparaginase. Sequencing of 16S rRNA showed that, the best isolates producing L-asparaginase belongs to the Pseudomonas genus. Enzyme activity after 24 and 48 h of incubation showed that Pseudomonas pseudoalcaligenes strain JHS-71 was the best strain that produced L-Asparaginase about 240 (U/ml) after 48h of incubation. Results showed that, L-Asparaginase activity enhanced about 27% in the presence of Co(+2). L-asparaginase JHS-71 retained more than 50% of its initial activity in the presence of Cu(+2), Mn(+2), Zn(+2), Mg(+2) and Fe(+2). Because of various applications of L-asparaginase in biotechnology, P. pseudoalcaligenes strain JHS-71 can be used as a suitable candidate in these fields.
Samples of 226 new improved and 21 indigenous rice (Oryza sativa L.) varieties
 were collected from the rice fields in three climatic zones of Sri Lanka and concentrations of 18 trace elements (Li, B, Al, Cr, Mn, Fe, Co, Ni, Cu, Zn, As, Se, Sr, Mo, Cd, Ba, Pb and Bi) were measured giving particular emphasis on Se, Cd and As using ICP-MS. The two way multivariate analysis of variance (MANOVA) method was employed to identify the differences in composition among rice from different climatic zones.
The mean values obtained for both white and red rice were Se (36; 25 µg/kg), As (42; 45 µg/kg) and Cd (70; 123 µg/kg) on dry weight basis. However mean content of Se, As and Cd of native rice varieties were 69, 74 and 33 µg/kg, respectively. Statistical interpretations showed that in the majority of cases, there was a significant difference in Cd content among climatic zones whereas Se and Pb show differences between white and red rice varieties. Arsenic did not indicate any significant difference either between rice types or among climatic regions. Notably Se and As contents in indigenous rice were higher than that of improved rice types. To assess the safety of dietary of intake, daily intake of Se, Cd and As by rice were calculated. Non-gender specific Estimated Daily Intake (EDI) of Se, Cd and As consuming improved rice are 9.31, 24.1 and 12.2 µg day(-1), respectively.
Since over 50 % of daily meals of people contain rice or rice based products, Se intake is expected to be deficient among the Sri Lankan population.
Many biotechnological and industrial applications can benefit from cold-adapted EglCs through increased efficiency of catalytic processes at low temperature. In our previous study, Citrobacter farmeri A1 which was isolated from a wood-inhabiting termite Reticulitermes labralis could secrete a cold-adapted EglC. However, its EglC was difficult to purify for enzymatic properties detection because of its low activity (0.8 U/ml). The objective of the present study was to clone and express the C. farmeri EglC gene in Escherichia coli to improve production level and determine the enzymatic properties of the recombinant enzyme.
The EglC gene was cloned from C. farmeri A1 by thermal asymmetric interlaced PCR. EglC was transformed into vector pET22b and functionally expressed in E. coli. The recombination protein EglC22b was purified for properties detection.
SDS-PAGE revealed that the molecular mass of the recombinant endoglucanase was approximately 42 kDa. The activity of the E. coli pET22b-EglC crude extract was 9.5 U/ml. Additionally, it was active at pH 6.5-8.0 with an optimum pH of 7.0. The recombinant enzyme had an optimal temperature of 30-40 °C and exhibited >50% relative activity even at 5 °C, whereas it lost approximately 90% of its activity after incubation at 60 °C for 30 min. Its activity was enhanced by Co(2+) and Fe(3+), but inhibited by Cd(2+), Zn(2+), Li(+), Triton X-100, DMSO, acetonitrile, Tween 80, SDS, and EDTA.
These biochemical properties indicate that the recombinant enzyme is a cold-adapted endoglucanase that can be used for various industrial applications.
Autism is a complex behaviorally defined disorder.There is a relationship between zinc (Zn) levels in autistic patients and development of pathogenesis, but the conclusion is not permanent.
The present study conducted to estimate this probability using meta-analysis method. In this study, Fixed Effect Model, twelve articles published from 1978 to 2012 were selected by searching Google scholar, PubMed, ISI Web of Science, and Scopus and information were analyzed. I² statistics were calculated to examine heterogeneity. The information was analyzed using R and STATA Ver. 12.2.
There was no significant statistical difference between hair, nail, and teeth Zn levels between controls and autistic patients: -0.471 [95% confidence interval (95% CI): -1.172 to 0.231]. There was significant statistical difference between plasma Zn concentration and autistic patients besides healthy controls: -0.253 (95% CI: 0.498 to -0.007). Using a Random Effect Model, the overall Integration of data from the two groups was -0.414 (95% CI: -0.878 to -0.051).
Based on sensitivity analysis, zinc supplements can be used for the nutritional therapy for autistic patients.
The appropriate selection of representative pure compounds to be used as reference is a crucial step for successful analysis of X-ray absorption near edge spectroscopy (XANES) data, and it is often not a trivial task. This is particularly true when complex environmental matrices are investigated, being their elemental speciation a priori unknown. In this paper, an investigation on the speciation of Cu, Zn, and Sb based on the use of conventional (stoichiometric compounds) and non-conventional (environmental samples or relevant certified materials) references is explored. This method can be useful in when the effectiveness of XANES analysis is limited because of the difficulty in obtaining a set of references sufficiently representative of the investigated samples. Road dust samples collected along the bridge connecting Venice to the mainland were used to show the potentialities and the limits of this approach.
Nanoparticles of two zinc(II) coordination polymers (CPs), [Zn(μ-4,4'-bipy)Cl2]n (1) and [Zn(μ-4,4'-bipy)Br2]n (2) L=bpy=4,4'-bipyridine ligand, have been synthesized by use of a sonochemical process and characterized by scanning electron microscopy (SEM), X-ray powder diffraction (XRPD), Fourier transform infrared spectroscopy (FTIR) spectroscopy and elemental analyses. The single crystal X-ray data of compounds 1 and 2 imply that the Zn(+2) ions are four coordinated. Topological analysis shows that 1D coordination networks of 1 and 2 can be classified as underlying nets of topological types 2C1. Nanoparticles of zinc(II) oxide have been prepared by calcination of two different zinc (II) CPs at 450°C that were characterized by scanning electron microscopy (SEM), X-ray powder diffraction (XRD) and IR spectroscopy.
Different kinds of panels (Si-based panels and CdTe panels) were treated according to a common process route made up of two main steps: a physical treatment (triple crushing and thermal treatment) and a chemical treatment. After triple crushing three fractions were obtained: an intermediate fraction (0.4-1mm) of directly recoverable glass (17%w/w); a coarse fraction (>1mm) requiring further thermal treatment in order to separate EVA-glued layers in glass fragments; a fine fraction (<0.4mm) requiring chemical treatment to dissolve metals and obtain another recoverable glass fraction. Coarse fractions (62%w/w) were treated thermally giving another recoverable glass fraction (52%w/w). Fine fractions can be further sieved into two sub-fractions: <0.08mm (3%w/w) and 0.08-0.4mm (22%w/w). Chemical characterization showed that 0.08-0.4mm fractions mainly contained Fe, Al and Zn, while precious and dangerous metals (Ag, Ti, Te, Cu and Cd) are mainly present in fractions <0.08mm. Acid leaching of 0.08-0.4mm fractions allowed to obtain a third recoverable glass fraction (22%w/w). The process route allowed to treat by the same scheme of operation both Si based panels and Cd-Te panels with an overall recycling rate of 91%.
We provide the explanation of the large discrepancy of three orders of magnitude between the experimentally measured and theoretically calculated magnetic moments in ZnS nanocrystals. We assume that the condensation of Zn vacancies into a single droplet takes place. The energy calculations reveal that the droplet phase is more favorable than the uniformly distributed vacancy configuration. The other assumption made is that a small magnetic moment could arise at the interface between the ZnS crystal and vacancy cluster. The calculations however dismiss this hypothesis because the magnetization of the layered system also vanishes. Thus we suggest that the experimentally low magnetization values could be explained from one of the two following pictures: (a) there are two phases where the vacancy cluster with the zero magnetic moment coexists along with the other phase, in which there are uniformly distributed Zn vacancies with low concentrations or (b) there is only a single vacancy phase-a vacancy droplet being in the metastable state with a weak nonvanishing magnetic moment.
The patellamides (cyclic pseudo-octapeptides) are produced by Prochloron, a symbiont of the ascidians, marine invertebrate filter feeders. These pseudo-octapeptides are present in the cytoplasm and a possible natural function of putative metal complexes of these compounds is hydrolase activity, however the true biological role is still unknown. The dinuclear Cu(II) complexes of synthetic patellamide derivatives have been shown in in vitro experiments to be efficient hydrolase model catalysts. Many hydrolase enzymes, specifically phosphatases and carboanhydrases, are Zn(II)-based enzymes and therefore, we have studied the Zn(II) and mixed Zn(II)/Cu(II) solution chemistry of a series of synthetic patellamide derivatives, including solution structural and computational work, with the special focus on model phosphatase chemistry with bis-(2,4-dinitrophenyl)phosphate (BDNPP) as the substrate. The Zn(II) complexes of a series of ligands are shown to form complexes of similar structure and stability compared to the well-studied Cu(II) analogues and the phosphatase reactivities are also similar. Since the complex stabilities and phosphatase activities are generally a little lower compared to those of Cu(II) and since the concentration of Zn(II) in Prochloron cells is slightly smaller, we conclude that the Cu(II) complexes of the patellamides are more likely to be of biological importance.
Computational metalloenzyme design is a multi-scale problem. It requires treating the metal coordination quantum mechanically, extensive sampling of the protein backbone, and additionally accounting for the polarization
 of the active site by both the metal cation and the surrounding protein (a phenomenon called electrostatic preorganization). We bring together a combination of theoretical methods that jointly offer these desired qualities: QM/DMD for mixed quantum-classical dynamic sampling, quantum theory of atoms in molecules (QTAIM) for the assessment of electrostatic preorganization, and Density Functional Theory (DFT) for mechanistic studies. Within this suite of principally different methods, there are both complementarity of capabilities and cross-validation. Using these methods, predictions can be made regarding the relative activities of related enzymes, as we show on the native Zn(2+)-dependent carboxypeptidase A (CPA), and its mutant proteins, which are hypothesized to hydrolyze modified substrates. For the native CPA, we replicated the catalytic mechanism and the rate in close agreement with the experiment, giving validity to the QM/DMD predicted structure, the DFT mechanism, and the QTAIM assessment of catalytic activity. For most sequences of the modified substrate and tried CPA mutants, substantially worsened activity is predicted. However, for the substrate mutant that contains Asp instead of Phe at the C-terminus, one CPA mutant exhibits a reasonable activity, as predicted across the theoretical methods. CPA is a well-studied system, and here it serves as a testing ground for the offered methods.
Surface water samples were collected from 20 sampling sites throughout the Ganjiang River during pre-monsoon, monsoon, and post-monsoon seasons, and the concentrations of dissolved trace elements were determined by inductively coupled plasma-mass spectrometry (ICP-MS) for the spatial and seasonal variations, risk assessment, source identification, and categorization for risk area. The result demonstrated that concentrations of the elements exhibited significant seasonality. The high total element concentrations were detected at sites close to the intensive mining and urban activities. The concentrations of the elements were under the permissible limits as prescribed by related standards with a few exceptions. The most of heavy metal pollution index (HPI) values were lower than the critical index limit, indicating the basically clean water used as habitat for aquatic life. As was identified as the priority pollutant of non-carcinogenic and carcinogenic concerns, and the inhabitants ingesting the surface water at particular site might be subjected to the integrated health risks for exposure to the mixed trace elements. Multivariate statistical analyses confirmed that Zn, As, Cd, and Tl were derived from mining and urban activities; V, Cd, and Pb exhibited mixed origin; and Co, Ni, and Cu mainly resulted from natural processes. Three categorized risk areas corresponded to high, moderate, and low risks, respectively. As a whole, the upstream of the Ganjiang River was identified as the high-risk area relatively.
We report the synthesis, crystal structure, and thermal, Raman, infrared and magnetic properties of [NH2NH3][M(HCOO)3] (HyM) compounds (M = Mn, Zn, Fe). Our results show that synthesis from methanol solution leads to perovskite polymorphs while that from 1-methyl-2-pyrrolidinone or its mixture with methanol allows obtaining chiral polymorphs. Perovskite HyFe, chiral HyFe and chiral HyMn undergo phase transitions at 347, 336 and 296 K, respectively, with symmetry changes from Pnma to Pna21, P63 to P212121 and P63 to P21. X-ray diffraction and Raman studies show that the phase transitions are governed by dynamics of the hydrazinium ions. Low-temperature magnetic studies show that these compounds exhibit magnetic ordering below 9-12.5 K. Since the low-temperature structures of chiral HyMn and perovskite HyFe are polar, these compounds are possible multiferroic materials. We also report high-pressure Raman scattering studies of chiral and perovskite HyZn, which show much larger stiffness of the latter phase. These studies also show that the ambient pressure polar phases are stable up to at least 1.4 and 4.1 GPa for the chiral and perovskite phase, respectively. Between 1.4 and 2.0 GPa (for chiral HyZn) and 4.1 and 5.2 GPa (for perovskite HyZn) pressure-induced transitions are observed associated with changes in the zinc-formate framework. Strong broadening of Raman bands and the decrease in their number for the high-pressure phase of chiral HyZn suggest that this phase is disordered and has higher symmetry than the ambient pressure one.
We report a computational study of excited state intramolecular proton transfer in a series of related and progressively more complex organic chromophores ranging from 2-(2'-hydroxyphenyl)-benzoxazole (HBO) through to the 5-(benzo[d]oxazol-2-yl)-2-(4-((bis(pyridin-2-ylmethyl)amino)methyl)benzo[d]oxazol-2-yl)-4 hydroxyphenolate (HDBO') anion. The latter chelates group 12 metal cations (X = Zn(2+), Cd(2+) and Hg(2+)), and can serve as a fluorescence-based sensor for such metals. Initial π* ←π excitation of the ground (S0) state enol-tautomer induces charge separation in the first excited singlet (S1) state and drives the subsequent proton transfer (i.e. enol→keto tautomerism). The keto-tautomer constitutes a local minimum on the S1 PES, and is responsible for highly Stokes shifted fluorescent emission; S1(enol) → S0 fluorescence is proposed to account for the shorter wavelength emission from the X-HDBO' complexes. Derivatives of HDBO' that should retain the favourable visible absorption and heavily Stokes shifted emission properties but, additionally, offer higher fluorescence quantum yields (i.e. enhanced metal sensing capability) are proposed.
Templated cooperative binding induced assembly of chromophores is achieved via interactions between Zn-complexes and the DNA phosphodiester backbone. The chromophores are organized in left-handed (M)-helices via double-zipper assembly with the DNA templates.
Salt metathesis has been exploited to generate a series of non-steroidal anti-inflammatory drug (NSAID) based Zn(ii) metallohydrogels displaying both anti-inflammatory and anti-bacterial properties. Relatively low cytotoxicity, rheoreversibility and injectibility of one of these hydrogels make it suitable for multi-drug-self-delivery application.
Zinc (Zn) and its alloys have recently been introduced as a new class of biodegradable metals with potential application in biodegradable vascular stents. Although an in vivo feasibility study pointed to outstanding biocompatibility of Zn-based implants in vascular environments, a thorough understanding of how Zn and Zn(2+) affect surrounding cells is lacking. In this comparative study, three vascular cell types-human endothelial cells (HAEC), human aortic smooth muscle cells (AoSMC), and human dermal fibroblasts (hDF)-were studied to advance the understanding of Zn/Zn(2+)-cell interactions. Aqueous cytotoxicity using a Zn(2+) insult assay resulted in LD50 values of 50 µM for hDF, 70 µM for AoSMC, and 265 µM for HAEC. Direct cell contact with the metallic Zn surface resulted initially in cell attachment, but was quickly followed by cell death. After modification of the Zn surface using a layer of gelatin-intended to mimic a protein layer seen in vivo-the cells were able to attach and proliferate on the Zn surface. Further experiments demonstrated a Zn dose-dependent effect on cell spreading and migration, suggesting that both adhesion and cell mobility may be hindered by free Zn(2+).
In the title polymeric Zn(II) complex, [Zn2(C10H4O8)Cl2(C20H14N4)2] n , the Zn(II) cations are bridged by both 2,5-di-carb-oxy-benzene-1,4-di-carboxyl-ate dianions and 4'-(pyridin-3-yl)-4,2':6',4''-terpyridine ligands, forming ladder-like polymeric chains propagating along [1-10]. The Cl(-) anion further coordinates the Zn(II) cation to complete a distorted tetra-hedral environment. In the 4'-(pyridin-3-yl)-4,2':6',4''-terpyridine ligand, the three sideward pyridine rings are twisted with respect to the central pyridine ring by 39.27 (12), 14.89 (13) and 3.36 (13)°, respectively. In the crystal, classical O-H⋯N hydrogen bonds and weak C-H⋯O and C-H⋯Cl hydrogen bonds link the chains into a three-dimensional supra-molecular architecture. π-π stacking is observed between the pyridine and benzene rings of neighbouring polymeric chains, with a centroid-to-centroid distance of 3.7280 (14) Å.
The structures of three related complexes of general formula M(pds)(nab)2 [pds is the peroxodi-sulfate anion and nab is an nitro-gen-containing aromatic base], viz. bis(2,9-dimethyl-1,10-phenanthroline-κ(2)N,N')(peroxodi-sulfato-κ(2)O,O')cadmium, [Cd(S2O8)(C14H12N2)2], (V), bis-(3,4,7,8-tetra-methy-1,10-phenanthroline-κ(2)N,N')(peroxodi-sulfato-κ(2)O,O')zinc, [Zn(S2O8)(C16H16N2)2], (VI), and bis-(3,4,7,8-tetra-methy-1,10-phenanthroline-κ(2)N,N')(peroxodi-sulfato-κ(2)O,O')cadmium, [Cd(S2O8)(C16H16N2)2], (VII), present the same topological coordination, with three chelating ligands in an MN4O2 polyhedron. The main difference resides in the fact that the first two complexes are bis-ected by a crystallographic twofold axis, thus providing a symmetrical environment to the cation, while in the third one this symmetry is disrupted into a clearly unsymmetrical disposition, probably by way of an unusually strong intra-molecular C-H⋯O hydrogen bond. The situation is compared with similar inter-actions in the literature. The structure of (V) is based on a redetermination in the correct space group C2/c of the structure originally described in the Cc space group [Harvey et al. (2001). Aust. J. Chem.54, 307-311; Marsh (2004 ▸). Acta Cryst. B60, 252-253].
Synchrotron-based X-ray fluorescence imaging (XFI) of zinc (Zn) has been recently implemented to understand the efficiency of various therapeutic interventions targeting post-stroke neuroprotection and neuroplasticity. However, it is uncertain if micro
 XFI can resolve neuroplasticity-induced changes. Thus, we explored if learning-associated behavioral changes would be accompanied by changes in cortical Zn concentration measured by XFI in healthy adult rats. Proficiency in a skilled reach-to-eat task during early and late stages of motor learning served as a functional measure of neuroplasticity. c-Fos protein and vesicular Zn expression were employed as indirect neuronal measures of brain plasticity. A total Zn map (20×20×30μm(3) resolution) generated by micro XFI failed to reflect increases in either c-Fos or vesicular Zn in the motor cortex contralateral to the trained forelimb or improved proficiency in the skilled reaching task. Remarkably, vesicular Zn increased in the late stage of motor learning along with a concurrent decrease in the number of c-fos-ip neurons relative to the early stage of motor learning. This inverse dynamics of c-fos and vesicular Zn level as the motor skill advances suggest that a qualitatively different neural population, comprised of fewer active but more efficiently connected neurons, supports a skilled action in the late versus early stage of motor learning. The lack of sensitivity of the XFI-generated Zn map to visualize the plasticity-associated changes in vesicular Zn suggests that the Zn level measured by micro XFI should not be used as a surrogate marker of neuroplasticity in response to the acquisition of skilled motor actions. Nanoscopic XFI could be explored in future as a means of imaging these subtle physiological changes.
ZnO nanoparticles (ZnO-NPs) are emerging contaminants that raise the concerns of potential risk in the aquatic environment. It has been estimated that the environmental ZnO-NPs concentration is 76 μg/l in the aquatic environment. Our aim was to determine the aquatic toxicity of ZnO-NPs with chronic exposure at environmentally relevant concentrations using the nematode Caenorhabditis elegans. Two simulated environmentally relevant mediums-moderately hard reconstituted water (EPA water) and simulated soil pore water (SSPW)-were used to represent surface water and pore water in sediment, respectively. The results showed that the ZnO-NPs in EPA water has a much smaller hydrodynamic diameter than that in SSPW. Although the ionic release of Zn ions increased time-dependently in both mediums, the Zn ions concentrations in EPA water increased two-fold more than that in SSPW at 48 h and 72 h. The ZnO-NPs did not induce growth defects or decrease head thrashes in C. elegans in either media. However, chronic exposure to ZnO-NPs caused a significant reduction in C. elegans body bends in EPA water even with a relatively low concentration (0.05 μg/l); similar results were not observed in SSPW. Moreover, at the same concentrations (50 and 500 μg/l), body bends in C. elegans were reduced more severely in ZnO-NPs than in ZnCl2 in EPA water. The ATP levels were consistently and significantly decreased, and ROS was induced after ZnO-NPs exposure (50 and 500 μg/l) in EPA water. Our results provide evidences that chronic exposure to ZnO-NPs under environmentally relevant concentrations causes metabolic and locomotive toxicities implicating the potential ecotoxicity of ZnO-NPs at low concentrations in aquatic environments.
Various studies have shown that soils surrounding mining areas are seriously polluted with heavy metals. Determining the effects of natural factors on spatial distribution of heavy metals is important for determining the distribution characteristics of heavy metals in soils. In this study, an 8km buffer zone surrounding a typical non-ferrous metal mine in Suxian District of Hunan Province, China, was selected as the study area, and statistical, spatial autocorrelation and spatial interpolation analyses were used to obtain descriptive statistics and spatial autocorrelation characteristics of As, Pb, Cu, and Zn in soil. Additionally, the distributions of soil heavy metals under the influences of natural factors, including terrain (elevation and slope), wind direction and distance from a river, were determined. Layout of sampling sites, spatial changes of heavy metal contents at high elevations and concentration differences between upwind and downwind directions were then evaluated. The following results were obtained: (1) At low elevations, heavy metal concentrations decreased slightly, then increased considerably with increasing elevation. At high elevations, heavy metal concentrations first decreased, then increased, then decreased with increasing elevation. As the slope increased, heavy metal contents increased then decreased. (2) Heavy metal contents changed consistently in the upwind and downwind directions. Heavy metal contents were highest in 1km buffer zone and decreased with increasing distance from the mining area. The largest decrease in heavy metal concentrations was in 2km buffer zone. Perennial wind promotes the transport of heavy metals in downwind direction. (3) The spatial extent of the influence of the river on Pb, Zn and Cu in the soil was 800m. (4) The influence of the terrain on the heavy metal concentrations was greater than that of the wind. These results provide a scientific basis for preventing and mitigating heavy metal soil pollution in areas surrounding mines.
A population of the metallophyte Noccaea (Thlaspi) caerulescens originating from a Zn-enriched area at Røros Copper Mine (Norway) was studied. N. caerulescens tolerance to accumulate Cd and Zn was evaluated in hydroponic experiments by chlorophyll fluorescence imaging analysis. In the field-collected N. caerulescens mother plants, Zn shoot concentrations were above Zn hyperaccumulation threshold while, in hydroponic experiments under 40-μM Cd exposure, shoot Cd concentrations were clearly above Cd hyperaccumulation threshold. Cadmium ions and, to a less extent, Zn were mainly retained in the roots. Exposure to Cd enhanced Zn translocation to the shoot, while decreased significant total Ca(2+) uptake, suggesting that Cd uptake occurs through Ca(2+) transporters. Nevertheless, it increased Ca(2+) translocation to the leaf, possibly for photoprotection of photosystem II (PSII). Exposure to 800 μM Zn or 40 μM Cd resulted in increased Fe(3+) uptake suggesting that in N. caerulescens, Cd uptake does not take place through the pathway of Fe(3+) uptake and that conditions that lead to Cd and Zn accumulation in plants may also favor Fe accumulation. Despite the significant high toxicity levels of Zn and Cd in leaves, under Zn and Cd exposure, respectively, the allocation of absorbed light energy at PSII did not differ compared to controls. The results showed that N. caerulescens keep Cd and Zn concentrations in the mesophyll cells in non-toxic forms for PSII and that the increased Ca and Fe accumulation in leaves alleviates the toxicity effects. Chlorophyll fluorescence imaging revealed that PSII of N. caerulescens resisted better the phytotoxic effects of 20 times higher Zn than Cd exposure concentration. Overall, it is concluded that the use of chlorophyll fluorescence imaging constitutes a promising basis for investigating heavy metal tolerance of plants.
This study aimed at evaluating the chemophysical properties of experimental resin infiltrants (ERIs) doped with different bioactive particles.
A control resin infiltrant (CR) was formulated using triethylene glycol dimethacrylate (TEGDMA) and ethoxylated bisphenol A dimethacrylate (BisEMA). Moreover, five experimental ERIs were also created by incorporating the following bioactive fillers (10 wt%) into the CR: hydroxyapatite (Hap), amorphous calcium phosphate (ACP), zinc-polycarboxylated bioactive glass (BAG-Zn), bioactive glass 45S5 (BAG 45S5), and calcium silicate modified with beta tricalcium phosphate (β-TCP). ICON® resin infiltrant was also used as control. All the ERIs used in this study were assessed for degree of conversion (DC), Knoop microhardness (KHN), softening ratio (SR), tensile cohesive strength (TCS), modulus of elasticity (E-modulus), water sorption (WS), and solubility (SL). Data were subjected to ANOVA and Tukey's test (α = 5%).
ICON® presented the lowest DC, KHN, TCS, E-modulus, and SR. Incorporation of bioactive fillers into CR caused significant increase in the KHN. Conversely, no significant effect was observed on DC, TCS, and E-modulus. The resin infiltrant containing Hap showed a significant increase in softening ratio, while, ICON® presented the highest WS and SL. The WS of ACP-doped resin infiltrant was significantly higher than that of the Hap-doped infiltrant. The SL of the ACP-doped infiltrant was higher than CR BAG-Zn or BAG 45S5.
The incorporation of bioactive particles into experimental resin infiltrants can improve the chemomechanical properties and reduce water sorption and solubility.
Resin infiltrants doped with bioactive particles may improve the long-term performance of the treatment of white-spot lesions.
The concentrations of nine metals (Cd, Pb, Ni, Cr, Co, Cu, Fe, Mn and Zn) were measured in selected brands of medicated, moisturizing and skin-lightening soaps and shower gels with the aim of evaluating the human health risk associated with metal exposure from the use of these products. The concentrations of metals in these products were determined by means of atomic absorption spectrophotometry after sample digestion with a mixture of acids. The concentration ranges of the metals in the bathing soaps and shower gels were found to be: <0.06-3.4 μg g(-1) for Cd, <0.09-26.5 μg g(-1) for Pb, <0.12-43.0 μg g(-1) for Cr, <0.06-32.5 μg g(-1) for Ni, <0.06-40.5 μg g(-1) for Cu, <0.12-8.0 μg g(-1) for Co, 61.8-4000 μg g(-1) for Fe, <0.09-29.5 μg g(-1) for Mn, and 25.5-1000 μg g(-1) for Zn. The systemic exposure dosage values for these metals obtained from the application of these brands of bathing soaps and shower gels were below their respective
 provisional tolerable daily intake/or recommended daily intake values. The margin of safety values obtained for the metals were greater than 100 which indicated that there was no significant risk to the users of these brands of bathing soaps and shower gels, except in the case of Co.
We conducted a thorough study of Cu(2+) complex formation equilibria with Irbesartan and Losartan, the two primary drugs for the cure of cardiovascular diseases, with the aim of recognising if these drugs could exert a chelating action towards Cu(2+). We used different complementary techniques to gain a clear picture of the involved protonation and complexation equilibria. The low solubility in water of the ligands and of the formed metal complexes prevented the use of water as solvent, so we had to perform the measurements in mixed methanol-water solvents. Further, we studied the related equilibria with Zn(2+) for evaluating a potential interference of this essential metal ion, largely present in biological fluids. Our study provided a strong evaluation of the formed complexes and of the relative stability constants. The binding of both metal ions takes place through the tetrazole moiety except for the Zn(2+)-Irbesartan system. In this last case, NMR measurements gave evidence of a tautomeric equilibrium involving the imidazole ring and the aliphatic chain. The estimated complexation model, and the related stability constants, allowed a speciation study in human plasma, based on a number of simplifying assumptions, which remarked that both drugs, Losartan and Irbesartan, could exert a chelating action, scavenging non-negligible amounts of Cu(2+) from the organism.
Recently, several bioavailability-based models have been shown to predict acute metal mixture toxicity with reasonable accuracy. However, the application of such models to chronic mixture toxicity is less well established. Therefore, we developed in the present study a chronic metal mixture bioavailability model (MMBM) by combining the existing chronic daphnid bioavailability models for Ni, Zn, and Pb with the independent action (IA) model, assuming strict non-interaction between the metals for binding at the metal-specific biotic ligand sites. To evaluate the predictive capacity of the MMBM, chronic (7d) reproductive toxicity of Ni-Zn-Pb mixtures to Ceriodaphnia dubia was investigated in four different natural waters (pH range: 7-8; Ca range: 1-2 mM; Dissolved Organic Carbon range: 5-12 mg/L). In each water, mixture toxicity was investigated at equitoxic metal concentration ratios as well as at environmental (i.e. realistic) metal concentration ratios. Statistical analysis of mixture effects revealed that observed interactive effects depended on the metal concentration ratio investigated when evaluated relative to the concentration addition (CA) model, but not when evaluated relative to the IA model. This indicates that interactive effects observed in an equitoxic experimental design cannot always be simply extrapolated to environmentally realistic exposure situations. Generally, the IA model predicted Ni-Zn-Pb mixture toxicity more accurately than the CA model. Overall, the MMBM predicted Ni-Zn-Pb mixture toxicity (expressed as % reproductive inhibition relative to a control) in 85% of the treatments with less than 20% error. Moreover, the MMBM predicted chronic toxicity of the ternary Ni-Zn-Pb mixture at least equally accurately as the toxicity of the individual metal treatments (RMSEMix = 16; RMSEZn only = 18; RMSENi only = 17; RMSEPb only = 23). Based on the present study, we believe MMBMs can be a promising tool to account for the effects of water chemistry on metal mixture toxicity during chronic exposure and could be used in metal risk assessment frameworks.
Evidence suggests that CO2 modifies the behavior of nanomaterials. Thus, in a few decades, plants might be exposed to additional stress if atmospheric levels of CO2 and the environmental burden of nanomaterials increase at the current pace. Here, we used a full-size free-air CO2 enrichment (FACE) system in farm fields to investigate the effect of elevated CO2 levels on phytotoxicity and microbial toxicity of nTiO2 (0, 50, and 200mgkg(-1)) in a paddy soil system. Results show that nTiO2 did not induce visible signs of toxicity in rice plants cultivated at the ambient CO2 level (370μmolmol(-1)), but under the high CO2 concentration (570μmolmol(-1)) nTiO2 significantly reduced rice biomass by 17.9% and 22.1% at 50mgkg(-1) and 200mgkg(-1), respectively, and grain yield by 20.8% and 44.1% at 50mgkg(-1) and 200mgkg(-1), respectively. In addition, at the high CO2 concentration, nTiO2 at 200mgkg(-1) increased accumulation of Ca, Mg, Mn, P, Zn, and Ti by 22.5%, 16.8%, 29.1%, 7.4%, 15.7% and 8.6%, respectively, but reduced fat and total sugar by 11.2% and 25.5%, respectively, in grains. Such conditions also changed the functional composition of soil microbial communities, alerting specific phyla of bacteria and the diversity and richness of protista. Overall, this study suggests that increases in CO2 levels would modify the effects of nTiO2 on the nutritional quality of crops and function of soil microbial communities, with unknown implications for future economics and human health.
The analysis of highly polar and amphoteric compounds in seawater is a continuing challenge in analytical chemistry due to the possible formation of complexes with the metal cations present in salt-based matrices. Here we provide information for the development of analytical methods for glyphosate, glufosinate, AMPA, and 2-AEP in salt water, based on studies of the effects of salt matrices on reversed-phase liquid chromatography-heated electrospray ionization-tandem mass spectrometry (RP-LC-HESI-MS/MS) after derivatization of the target compounds with FMOC-Cl. The results showed that glyphosate was the only analyte with a strong tendency to form glyphosate-metal complexes (GMC), which clearly influenced the analysis. The retention times (RTs) of GMC and free glyphosate differed by approximately 7.00min, reflecting their distinct RP-LC behaviors. Divalent cations, but not monovalent (Na(+), K(+)) or trivalent (Al(3+), Fe(3+)) cations, contributed to this effect and their influence was concentration-dependent. In addition, Cu(2+), Co(2+), Zn(2+), and Mn(2+) prevented glyphosate detection whereas Ca(2+), Mg(2+), and Sr(2+) altered the retention time. At certain tested concentrations of Ca(2+) and Sr(2+) glyphosate yielded two peaks, which violated the fundamental rule of LC, that under the same analytical conditions a single substance yields only one LC-peak with a specific RT. Salt-matrix-induced ion suppression was observed for all analytes, especially under high salt concentrations. For glyphosate and AMPA, the use of isotopically labeled internal standards well-corrected the salt-matrix effects, with better results achieved for glufosinate and 2-AEP with the AMPA internal standard than with the glyphosate internal standard. Thus, our study demonstrated that Ca(2+), Mg(2+), and Sr(2+) can be used together with FMOC-Cl to form GMC-FMOC which is suitable for RP-LC-HESI-MS/MS analysis.
In this paper, a novel fluorescence-based method for laccase assay was presented. The method was based on the transformation of Amplex Red into a highly fluorescent and colored resorufin catalyzed by laccase in the presence of O2. The catalysis and transformation mechanism were investigated in detail. The kinetic parameters of the Amplex Red catalysis by laccase were determined using the Lineweaver-Burk equation. Vmax and Km were estimated to be 15.63μmolmin(-1) and 76.88μmolL(-1), respectively. Under optimal conditions, a good linear correlation was found between fluorescence intensity and laccase activities within 5.62-702UL(-1) (r=0.9992), with a detection limit of 1.76UL(-1) (S/N=3). A series of repeatability measurements (351UL(-1) laccase) gave reproducible results with a relative standard deviation (RSD) of 1.9% (n=11). The recoveries ranged from 93.7% to 100.0% after standard additions. Common existing species such as Mg(2+), Zn(2+), Ni(2+), Al(3+), Co(2+), Cd(2+), K(+), Ca(2+), Na(+), Fe(3+), Li(+), Cu(2+), Mn(2+), Fe(2+), l-lysine, glycine, glucose, phenol, humic acid, lignin peroxidase, manganese peroxidase alkaline phosphatase, cellulose, glucose oxidase, urease, catalase, invertase, and horseradish peroxidase did not significantly exhibit interference. The test solution (i.e., Amplex Red stock solution) could stabilize at least three months via storage in dark at 4±0.1°C. These results confirmed that the laccase-Amplex Red system was stable and reproducible with strong anti-interference ability and good selectivity, suggesting that this method can has great potential in practical applications for the assay of laccase activity. The proposed method was further successfully used to detect laccase activities in 38 soil samples. We noticed that the laccase activity significantly correlated with total nitrogen content (r=0.559; p<0.01) of soil, indicating laccase activity assay holds great promise as an index of soil analysis. These findings indicate that this presented method has great perspective in ecological investigation and fundamental research of soil environment.
Gynura pseudochina (L.) DC. is a Zn/Cd hyperaccumulative plant. In an in vivo system under controlled plant age, this research reveals that phenolic compounds and lignification play beneficial roles in protecting G. pseudochina from exposure to an excess of Zn and/or Cd, and Zn reduces Cd toxicity under the dual treatments. The total phenolic content (TPC), total flavonoid content (TFC), and half-maximal inhibitory concentration (IC50) values correspond to the metal dose-response curves. Liquid chromatography-electrospray ionization-quadrupole time of flight-tandem mass spectrometry (LC-ESI-QTOF-MS/MS)
 is used to characterize phenolic compounds and their glycosides, which could play roles in antioxidant activities and in the esterification of the cell wall, especially derivatives of p-coumaric and caffeic acid. Confocal laser scanning microscopy (CLSM) and micro X-ray fluorescence (μ-XRF) imaging revealed that the accumulation of Zn and Cd in the cell wall involves flavonoid compounds. Low extractable pools of Cd and Zn in the leaf extracts indicate that these elements are tightly bound to the plant biomass structures. The bulk X-ray absorption near edge structure (XANES) spectra indicate that Zn(2+) and Cd(2+) dominate with O and S ligands, which could be provided by cell walls, phenolic compounds, and sulphur protein. Consequently, the benefit of these results is to support the growth of G. pseudochina for phytoremediation in a Zn- and/or Cd-contaminated site.
One of the biggest environmental problems existing today is air pollution, which is characterized by the presence of toxic gases and metal pollutants, the latter of which is generally associated with emissions of particulate matter (PM) from industries or automotive vehicles. Biomonitoring is a method that can be used to assess air pollution levels because it makes it possible to determine what effects these air pollutants cause in living organisms and their responses. The species Lolium multiflorum Lam., known as ryegrass, is considered a good bioindicator of metals, since it accumulates these substances during exposure. This study proposes to conduct an integrated assessment of air quality using two different monitoring methodologies: biomonitoring with L. multiflorum and active monitoring in areas with different levels of urbanization and industrialization. Concentrations found in ryegrass plants revealed high levels of Pb, Cr, Zn, and Cu, indicating that vehicular and industrial emissions were the main sources of pollution. Analysis of PM also revealed soot and biogenic particles, which can transport metals. Therefore, with the proposed method, the anthropogenic impact on air pollution in the investigated area could be clearly demonstrated.
This paper presents a study on the translocation factors (TFs) and bioconcentration factors (BCFs) of copper (Cu), manganese (Mn), zinc (Zn), cobalt (Co), chromium (Cr), cadmium (Cd), lead (Pb), iron (Fe), nickel (Ni), and arsenic (As) ions in roots, stems, and leaves of tobacco. The results revealed that during the tobacco growth, the roots are able to increase the sensitiveness of the physiological control, reducing the translocation of the metals Ni (0.38) and Pb (0.48) to the leaves. Cd and Zn presented factors TF and BCF >1 in the three tissues under analysis, which indicates the high potential for transportation and accumulation of these metals in all plant tissues. The TF values for Cr (0.65) and As (0.63) revealed low translocation of these ions to the aerial parts, indicating low mobility of ions from the roots. Therefore, tobacco can be considered an efficient accumulator of Ni, Cr, As and Pb in roots and Cd and Zn in all plant parts.
The aim of this study was to evaluate the effects of different dietary levels of zinc (Zn) and α-tocopheryl acetate (α-TOA) on broilers performance, meat quality, Zn, selenium (Se), and α-tocopherol (α-TO) tissue depositions. A total of 1,080 one-day-old Ross 308 broiler chickens (mixed-sex) were allocated to nine dietary treatments. Three levels of supplemental Zn (0, 60, and 120 mg/kg of diet) and three levels of α-TOA (0, 150, and 300 mg/kg of diet) were combined as a completely randomized design with 3 × 3 factorial arrangement. Chicks were penned in groups of 20 with six pens per treatment. The ADFI, ADG, feed conversion ratio (FCR), mortality rate, and European production efficiency factor (EPEF) were not affected by dietary treatments. In addition, supplementation of Zn and α-TOA and their interaction did not affect carcass parts yield. Drip loss of the breast and thigh muscles were significantly reduced 1.27 and 1.47% by α-tocopheryl acetate (α-TOA) supplementation, respectively (P < 0.01). Deposition of Zn in liver, breast, and thigh muscles were linearly increased by dietary Zn supplementation. Furthermore, supplementation of Zn increased Se content in the breast and thigh muscles and liver. Supplementation of either α-TOA or Zn increased deposition of α-TO in liver and the muscles. The Thiobarbituric acid reactive substances (TBARS) values in the breast and thigh muscles and the liver were diminished by supplementation of α-TOA (P = 0.0001) and there was positive interaction between Zn and α-TOA (P < 0.01), in which within each increase in Zn supplementation level, α-TOA supplementation resulted in a reduction of TBARS values. In conclusion, 300 mg/kg dietary supplementation of α-TOA could improve drip loss, nutritional content, and oxidation stability of muscle without any adverse effect on growth performance of chickens. In addition, 120 mg/kg dietary supplementation of Zn could fortify α-TOA effect to improve oxidation stability of the breast and thigh muscles as well as it resulted to higher muscles Zn enrichment.
The effectiveness of β-lactam antibiotics as chemotherapeutic agents to treat bacterial infections is gradually threatened with the emergence of antibiotic resistance mechanism among pathogenic bacteria through the production metallo-β-lactamase (MBL). In this study, we discovered a novel hypothetical protein (HP) termed Bleg1_2437 from the genome of alkaliphilic Bacillus lehensis G1 which exhibited MBL-like properties of B3 subclass; but evolutionary divergent from other circulating B3 MBLs. Domain and sequence analysis of HP Bleg1_2437 revealed that it contains highly conserved Zn(2+)-binding residues such as H54, H56, D58, H59, H131 and H191, important for catalysis, similar with the subclass B3 of MBL. Built 3-D Bleg1_2437 structure exhibited an αββα sandwich layer similar to the well-conserved global topology of MBL superfamily. Other features include a ceiling and floor in the model which are important for accommodation and orientation of β-lactam antibiotics docked to the protein model showed interactions at varying degrees with residues in the binding pocket of Bleg1_2437. Hydrolysis activity towards several β-lactam antibiotics was proven through an in vitro assay using purified recombinant Bleg1_2437 protein. These findings highlight the presence of a clinically important and evolutionary divergent antibiotics-degrading enzyme within the pools of uncharacterized HPs.
Synechococcus sp. strain PCC 7002 has been gaining significance as both a model system for photosynthesis research and for industrial applications. Until recently, the genetic toolbox for this model cyanobacterium was rather limited and primarily relied on tools that only allowed constitutive gene expression. This work describes a two-plasmid, Zn(++)-inducible expression platform, which is coupled with a zurA mutation providing enhanced Zn(++) uptake. The control elements are based on the metal homeostasis system of a class II metallothionein gene (smtA7942) and its cognate SmtB7942 repressor from Synechococcus elongatus strain PCC 7942. Under optimal induction conditions, YFP levels were about half of those obtained with the strong, constitutive phycocyanin (cpcBA6803) promoter of Synechocystis sp. strain PCC 6803. This metal-inducible expression system in Synechococcus sp. strain PCC 7002 allowed titratable gene expression of YFP that was up to 19-fold greater than the background level. This system was utilized successfully to control expression of the Drosophila melanogaster β-carotene 15,15' -dioxygenase, NinaB, which is toxic when constitutively expressed from a strong promoter in Synechococcus sp. strain PCC 7002. Together, these properties establish this metal-inducible system as an additional useful tool that is capable of controlling gene expression for applications ranging from basic research to synthetic biology in Synechococcus sp. strain PCC 7002.
This is the first metal-responsive expression system in cyanobacteria, to our knowledge, that does not exhibit low sensitivity for induction, one of the major hurdles for utilizing this class of genetic tools. In addition, high levels of expression can be generated that approximate those of established constitutive systems, with the added advantage of titratable control. Together, these properties establish this Zn(++)-inducible system, which is based on the smtA7942 operator/promoter and smtB7942 repressor, as a versatile gene expression platform that expands the genetic toolbox of Synechococcus sp. strain PCC 7002.
A large fraction of the volume of Beluga whale (Delphinapterus leucas) teeth consists of cementum, a mineralized tissue which grows throughout the life of the animal and to which the periodontal ligaments attach. Annular growth bands or growth layer groups (GLGs) form within Beluga cementum, and this study investigates GLG structure using X-ray fluorescence mapping and X-ray diffraction mapping with microbeams of synchrotron radiation. The Ca and Zn fluorescent intensities and carbonated hydroxyapatite (cAp) diffracted intensities rise and fall together and match the light-dark bands visible in transmitted light micrographs. Within the bands of maximum Ca and Zn intensity, the ratio of Zn to Ca is slightly higher than in the minima bands. Further, the GLG cAp, Ca and Zn modulation is preserved throughout the cementum for durations >25year.
Cementum is an important tooth tissue to which the periodontal ligaments attach and consists primarily of carbonated apatite mineral and collagen. In optical microscopy of cementum thin sections, light/dark bands are formed annually, and age at death is determined by counting these bands. We employ synchrotron X-ray diffraction and X-ray fluorescence mapping to show the
 bands in Beluga whale cementum result from differences in mineral content and not from differences in collagen orientation as was concluded by others. Variation in Zn fluorescent intensity was found to be very sensitive indicator of changing biomineralization and suggest that Zn plays an important role this process.
The main objective of this work was to study the dynamics of the degradation of polycyclic aromatic hydrocarbons (PAHs) during sewage sludge vermicomposting. This eco-biotechnology employing earthworms as natural bioreactors for decomposing of organic matter may be used for vermiremediation of particular pollutants present in various organic matter sources. In this experiment, sewage sludge was mixed with bulking agents and precomposted. Afterward, adult Eisenia andrei specimens were introduced into the process. Total heavy metal and PAHs concentration were measured in composts and earthworms before and after the process. While heavy metal concentrations fluctuated mildly in the substratum, several metals clearly accumulated in the earthworms' bodies. Body Accumulation Factors could be ranked as follows (Cd > Cu > Zn > Ni > Cr > Pb). Interestingly, addition of earthworms into the process has led to the high percentage of PAHs removal and some of the 16 priority PAHs analyzed in this study have been accumulated in earthworms' bodies. Applied conditions did not affect worms' viability but they almost completely inhibited their reproduction.
Leachate characteristics, applied technologies and energy demand for leachate treatment were investigated through survey in different states of Germany. Based on statistical analysis of leachate quality data from 2010 to 2015, almost half of the contaminants in raw leachate satisfy direct discharge limits. Decrease in leachate pollution index of current landfills is mainly related to reduction in concentrations of certain heavy metals (Pb, Zn, Cd, Hg) and organics (biological oxygen demand (BOD5), chemical oxygen demand (COD), and adsorbable organic halogen (AOX)). However, contaminants of concern remain COD, ammonium-nitrogen (NH4N) and BOD5 with average concentrations in leachate of about 1850, 640, and 120 mg/L respectively. Concentrations of COD and NH4N vary seasonally, mainly due to temperature changes; concentrations during the first quarter of the year are mostly below the annual average value. Electrical conductivity (EC) of leachate may be used as a time and cost saving alternative to monitor sudden changes in concentration of these two parameters, due to high correlations of around 0.8 with both COD and NH4N values which are possibly due to low heavy metal concentrations in leachate. The decreased concentrations of heavy metals and BOD5 favor the retrofitting of an existing biological reactor (nitrification/denitrification) with the deammonification process and post denitrification, as this lowers average annual operational cost (in terms of energy and external carbon source) and CO2 emission by €25,850 and 15,855 kg CO2,eq respectively.
The aim of the study was to estimate the influence of the 2,4-dichlorophenoxy acetic acid and 2-methyl-4-chlorophenoxyacetic acid on the uptake and translocation of Cd, Co, Ni, Cu, Zn, Pb and Mn by wheat (Triticum aestivum L.). Two farmland soils typical for the central Polish rural environment were used. Studies involved soil analyses, contents of bioavailable, exchangeable and total forms for all investigated metals. Atomic absorption spectrometry was used to determine the concentration of the elements. The best correlation between the herbicide rate and the metal concentration was visibly for the underground part of plants. Analysis of variance proved that herbicide treatment of wheat frequently influences the metal transfer from soil and their concentration in roots and shoots. In particular, higher herbicide rates prompted the significant increase of all metals concentration in roots. Additionally, transfer coefficients depended on the type of soil and the herbicide rate applied. Uptake of metals may be also influenced by the formation of sparingly water-soluble metal-herbicide complexes. Its intensity would then depend on the solubility of particular chemical entity with the low solvable Pb, Cu and Cd complexes being the least mobile.
Spring grassland fires are common in boreal areas as a consequence of slash and burn agriculture used to remove dry grass to increase soil nutrient properties and crop production. However, few works have investigated fire impacts on these grassland ecosystems, especially in the immediate period after the fire. The objective of this work was to study the short-term impacts of a spring grassland fire in Lithuania. Four days after the fire we established a 400m(2) sampling grid within the burned area and in an adjacent unburned area with the same topographical, hydrological and pedological characteristics. We collected topsoil samples immediately after the fire (0months), 2, 5, 7 and 9months after the fire. We analysed soil pH, electrical conductivity (EC), major nutrients including calcium (Ca), magnesium (Mg), sodium (Na), and potassium (K), and the minor elements aluminium (Al), manganese (Mn), iron (Fe) and zinc (Zn). We also calculated the soil Na and K adsorption ratio (SPAR), Ca:Mg and Ca:Al. The results showed that this low-severity grassland fire significantly decreased soil pH, Al, and Mn but increased EC, Ca, Mg, and K,. There was no effect on Na, Fe, and Zn. There was a decrease of EC, Ca, Mg, and Na from 0months after the fire until 7months after the fire, with an increase during the last sampling period. Fire did not significantly affect SPAR. Ca:Mg decreased significantly immediately after the fire, but not to critical levels. Ca:Al increased after the fire, reducing the potential effects of Al on plants. Overall, fire impacts were mainly limited to the immediate period after the fire.
Plants have an accumulative response to heavy metals present in soils or deposited from airborne sources of emissions. Therefore, their tissues are very often used in studies of heavy metal contamination originating from different sources as a bioindicator of environmental pollution. This research was undertaken to examine accumulation capacities of Pb, Zn, Cd, Cu and Cr in washed and unwashed needles of Scots pine (Pinus sylvestris L.) and leaves of silver birch (Betula pendula Roth) growing in a contaminated area. We collected needles of Scots pine and leaves of silver birch in an area around a sedimentation pond and metallurgic plant processing Pb and Zn ores near Olkusz, Poland. Concentrations of heavy metals, which have been linked with exposure to emissions, were determined from foliar samples collected at 33 sites. These sites were established at various distances (0.5-3.6 km) from the pond and metallurgic plant so as to identify the predominant accumulative response of plants. Spatial gradients for Pb and Zn were calculated using an ordinary kriging interpolation algorithm. A spatial pattern was identified by a GIS method to visualize maps over the Pb-Zn ore mining area. The accumulation of Zn (R(2) = 0.74, p < 0.05) and Pb (R(2) = 0.85, p < 0.01) in plant tissues correlated with soil concentrations. This tendency was not found in the case of Cu, Cd and Cr.
This study investigates the geochemical characteristics of recent shallow-water aragonite-rich sediments from the karstic marine lakes located in the pristine environment on the island of Mljet (Adriatic Sea). Different trace elements were used as authigenic mineral formation, palaeoredox and pollution indicators. The distribution and the historical record of trace elements deposition mostly depended on the sedimentological processes associated with the formation of aragonite, early diagenetic processes governed by the prevailing physico-chemical conditions and on the recent anthropogenic activity. This study demonstrated that Sr could be used as a proxy indicating authigenic formation of aragonite in a marine carbonate sedimentological environment. Distribution of the redox sensitive elements Mo, Tl, U and Cd was used to identify changes in redox conditions in the investigated lake system and to determine the geochemical cycle of these elements through environmental changes over the last 100 years. The significant enrichment of these elements and the presence of early formed nanostructured authigenic framboidal pyrite in laminated deeper parts of sediment in Malo Jezero, indicate sporadic events of oxygen-depleted euxinic conditions in the recent past. Concentrations of trace elements were in the range characteristic for non-contaminated marine carbonates. However, the increase in the concentrations of Zn, Cu, Pb, Sn, Bi in the upper-most sediment strata of Veliko Jezero indicates a low level of trace element pollution, resulting from anthropogenic inputs over the last 40 years. The presence of butyltin compounds (BuTs) in the surface sediment of Veliko Jezero additionally indicates the anthropogenic influence in the recent past.
This paper analyzes the concentration, distribution, bioavailability, and potential heavy metal contamination risk of Cu, Pb, Cd, Zn, and Cr in the soil and sediment of the Three Gorges Reservoir (TGR). In this paper, 14 stations that cover the upper reaches to the lower reaches of the TGR were selected. The spatial distribution of heavy metals in the TGR showed that the average concentrations of Cu, Pb, Cd, Zn, and Cr were higher in the upper and lower reaches than those in the middle reaches because of industrial and agricultural activities as well as natural processes (e.g., soil erosion, rock weathering). The results also indicated that multiple pollution sources and complex geomorphological, geochemical and biological processes resulted in remarkably higher heavy metal concentrations in the soils of
 the water-level-fluctuation zone (WLFZ) than in the soils of the banks. The Cu, Pb, Cd, Zn, and Cr concentrations in the soils of the TGR did not exceed their respective maximum allowable concentration (MAC) values for agricultural soils in China, indicating that the soil in the TGR was not seriously contaminated with Cu, Pb, Cd, Zn, or Cr. However, the mean concentrations of all the studied metals in the sediments were higher than the geochemical background values and much higher than those in the soils, thus indicating the effect of the pollution sources and the altered hydrologic conditions that occurred after the impoundment of the TGR. A geoaccumulation index analysis indicated that the TGR sediments were moderately polluted with Cu and Cd, unpolluted to moderately polluted with Pb and Cr, and unpolluted with Zn. Fractionation studies indicated that Cd was mainly present in the non-residual fractions and exhibited great instability and bioavailability; furthermore, the alternating wetting and drying of the WFLZ soils enhance the mobility and bioavailability of Cd. Thus, greater attention should be paid to Cd pollution in the TGR because of its higher risk assessment values and potentially adverse biological effects.
Understanding variations of heavy metals in atmospheric particles between different functional areas is significant for pollution control and urban planning in cities. To reveal pollution and spatial distribution of heavy metals in atmospheric particles from different urban functional areas in Shijiazhuang in North China, 43 settled dust samples were collected over the main urban area and heavy metal concentrations were determined in their <63 μm fractions using an ICP-OES. The results suggest that Cr, Mn, Fe, Co, Ni, and V in the dust are not or slightly enriched and their concentrations vary slightly between different sites, implying their natural origins; whereas Cu, Zn, Cd, and Pb are often notably enriched and their concentrations vary significantly between different functional areas, indicating their anthropogenic sources. Integrated pollution indexes (IPIs) of the ten heavy metals are 2.7-13.6 (5.7 ± 2.2), suggesting high or very high pollution levels of most dust. Relatively lower IPIs occur mainly in the administration-education area, the commercial area, and other unclassified sites; while peaks occur mainly in the North Railway Station, the northeastern industrial area, and some sites near heavily trafficked areas, implying the significant influence of intensive industrial (including coal combustion) and traffic activities on atmospheric heavy metal accumulation. These results suggest a clear need of mitigating atmospheric heavy metal pollution via controlling emissions of toxic metals (especially Cd and Pb) from industrial and traffic sources in the city.
The pollution level of Lake Bafa was investigated by collecting fish samples {Dicentrarchus labrax (sea bass), Liza ramada (mullet) and Anguilla anguilla (eel)}, surface sediment, and core samples. In all these samples, (210)Po and (210)Pb concentrations were estimated, and total annual dose rates were obtained for each species. Some heavy metal (Cr, Ni, Pb, Cd, Mn, Fe, and Zn) concentration levels were obtained for the fish and a core sample. The sediment mass accumulation rate was found to be 3.27 g·m(-2)·day(-1) (0.119 g·cm(-2)·y(-1)) from a core sample. The heavy metal concentrations in the vertical profile of samples from the core were also observed. The measured concentration of Zn, Pb, Cd, and Cr were between the ERL (effects range low) and ERM (effects range median) limits, while Ni concentrations were higher than the ERM limit. The observed concentrations of Cd, Pb, and Zn in fish samples did not exceed the limits in accordance with Turkish Food Regulations. Further, the maximum effective dose equivalent of (210)Po in the area was found to be 1.169 µSv·y(-1).
This study aims to evaluate the in vitro angiotensin-converting enzyme (ACE) inhibition activity of different extracts of Orthosiphon stamineus (OS) leaves and their main flavonoids, namely rosmarinic acid (RA), sinensetin (SIN), eupatorin (EUP) and 3'-hydroxy-5,6,7,4'-tetramethoxyflavone (TMF). Furthermore, to identify possible mechanisms of action based on structure-activity relationships and molecular docking. The in vitro ACE inhibition activity relied on determining hippuric acid (HA) formation from ACE-specific substrate (hippuryl-histidyl-leucine (HHL)) by the action of ACE enzyme. A High Performance Liquid Chromatography method combined with UV detection was developed and validated for measurement the concentration of produced HA. The chelation ability of OS extract and its reference compounds was evaluated by tetramethylmurexide reagent. Furthermore, molecular docking study was performed by LeadIT-FlexX: BioSolveIT's LeadIT program. OS ethanolic extract (OS-E) exhibited highest inhibition and lowest IC50 value (45.77 ± 1.17 µg/mL) against ACE compared to the other extracts. Among the tested reference compounds, EUP with IC50 15.35 ± 4.49 µg/mL had highest inhibition against ACE and binding ability with Zn (II) (56.03% ± 1.26%) compared to RA, TMF and SIN. Molecular docking studies also confirmed that flavonoids inhibit ACE via interaction with the zinc ion and this interaction is stabilized by other interactions with amino acids in the active site. In this study, we have demonstrated that changes in flavonoids active core affect their capacity to inhibit ACE. Moreover, we showed that ACE inhibition activity of flavonoids compounds is directly related to their ability to bind with zinc ion in the active site of ACE enzyme. It was also revealed that OS extract contained high amount of flavonoids other than RA, TMF, SIN and EUP. As such, application of OS extract is useful as inhibitors of ACE.
ZnO/graphene (ZnO-G) hybrid composites are prepared via hydrothermal synthesis with graphite, N-methyl-pyrrolidone (NMP), and Zn(NO₃)₂·6H₂O as the precursors. The characterizations, including X-ray diffraction (XRD), thermogravimetric analyses (TGA), Raman spectroscopy, and transmission electron microscopy (TEM) indicate the formation of ZnO-G. Gas sensors were fabricated with ZnO-G composites and ZnO as sensing material, indicating that the response of the ZnO towards acetone was significantly enhanced by graphene doping. It was found that the ZnO-G sensor exhibits remarkably enhanced response of 13.3 at the optimal operating temperature of 280 °C to 100 ppm acetone, an improvement from 7.7 with pure ZnO.
Sediment samples were collected from 22 typical metal-polluted sections along the Xiangjiang River (XJR). Spatial distribution and speciation characteristics of heavy metals in sediments of XJR were determined. Furthermore, ecological risk and enrichment degree of metals were assessed by different indices. The results showed that combined metal pollution occurred in sediments of XJR, with content range of Cd, Pb, Zn, Cu, As, Mn, Cr, and Hg reaching 2.95-29.15, 30.93-235.83, 61.50-3771.11, 9.56-81.81, 3.93-46.28, 774.83-8700.72, 10.64-65.16, and 0.13-5.09 mg kg(-1), respectively. Pollution levels increased in period of industrialization but decreased after thousands of pollution enterprises were banned. Sections with serious pollution and higher risk were mainly located at Hengyang and Chang-Zhu-Tan regions (Changsha, Zhuzhou, and Xiangtan) for contaminations of Cd, As, Pb, and Hg. Values of both enrichment factor and geo-accumulation index followed the order Cd > Hg > Zn > Mn > Pb > Cu > As > Cr. Bioavailable fractions followed the order Cd (66.93 %), Zn (33.80 %), Pb (30.81 %), Mn (18.38 %), Hg (17.58 %), Cu (10.20 %), As (9.81 %), and Cr (7.65 %). Considering their bioavailability, biotoxicity, or abundance, contamination of Cd was the most dominant, and pollution of other metals should not be ignored.
The Three Gorges Project (TGP) is the largest hydropower station ever built in the world. A better understanding of the concentrations of heavy metals in the aquatic environment of the Three Gorges Reservoir (TGR) is crucial for national drinking water security and sustainable ecosystem development. To thoroughly investigate the impact of heavy metals on water quality after the impoundment to the maximum level of 175 m in the TGR, the concentrations of the dissolved heavy metals (Cr, Cu, Zn, Cd, Pb, As) were measured in April and August 2015, by inductively coupled plasma mass spectrometry (ICP-MS). (1) Except Zn and Pb, most of the heavy metal concentrations in the water of the TGR reached the level of the National Surface Water Environmental Quality Standards (GB3838-2002) I of China, revealing that the water quality of the TGR was good overall. (2) There were significant positive correlations among the concentrations of Cu, As, and Cd, revealing that they may exhibit similar geochemical behaviors. (3) The spatial distribution of the heavy metal concentrations was diverse and complex. The Zn concentration obviously increased in the rainy season from upstream to downstream in the Yangtze River, while the other heavy metals exhibited no significant changes in their concentrations. The distribution characteristics of the heavy metal concentrations on both sides and the middle of the river were different at different sites. (4) The health risk of the six elements was assessed through a human health risk assessment (HHRA), and the assessment results were lower than the maximum acceptable risk level designed by the US EPA and International Commission on Radiological Protection (ICRP). The HHRA model in the aquatic environment revealed that the risk of non-carcinogenic heavy metals (Cu, Zn, and Pb) was at a negligible risk level of 10(-11)∼10(-9) a(-1). At all the study sites, the risk of carcinogenic heavy metals (Cr, Cd, and As) was higher than the risk of non-carcinogenic
 heavy metals. As was the most important risk factor, followed by Cr. The results of this study hold great significance for a timely understanding of the changing water quality for affected departments to ensure the health of the residents in the TGR area.
Maintaining optimal intracellular zinc (Zn) concentration is crucial for critical cellular functions. Depleted Zn has been associated with prostate cancer (PCa) progression. Solute carrier family 30 (SLC30A) proteins maintain cytoplasmic Zn balance by exporting Zn out to the extracellular space or by sequestering cytoplasmic Zn into intracellular compartments. In this study, we determined the involvement of Zn-exporters, SLC30A 1-10 in PCa, in the context of racial health disparity in human PCa samples obtained from European-American (EA) and African-American (AA) populations. We also analyzed the levels of Zn-exporters in a panel of PCa cells derived from EA and AA populations. We further explored the expression profile of Zn-exporters in PCa using Oncomine database. Zn-exporters were found to be differentially expressed at the mRNA level, with a significant upregulation of SLC30A1, SLC30A9 and SLC30A10, and downregulation of SLC30A5 and SLC30A6 in PCa, compared to benign prostate. Moreover, Ingenuity Pathway analysis revealed several interactions of Zn-exporters with certain tumor suppressor and promoter proteins known to be modulated in PCa. Our study provides an insight regarding Zn-exporters in PCa, which may open new avenues for future studies aimed at enhancing the levels of Zn by modulating Zn-transporters via pharmacological means.
A series of experiments were conducted for treating heavy metals contaminated sediments sampled from Xiangjiang River, which combined polyvinyl alcohol (PVA) and immobilized sulfate reducing bacteria (SRB) into beads. The sodium lactate was served as the inner cohesive nutrient. Coupling the activity of the SRB with PVA, along with the porous structure and huge specific surface area, provided a convenient channel for the transmission of matter and protected the cells against the toxicity of metals. This paper systematically investigated the stability of Cu, Zn, Pb and Cd and its mechanisms. The results revealed the performance of leaching toxicity was lower and the removal efficiencies of Cu, Zn, Pb and Cd were 76.3%, 95.6%, 100% and 91.2%, respectively. Recycling experiments showed the beads could be reused 5 times with superbly efficiency. These results were also confirmed by continuous extraction at the optimal conditions. Furthermore, X-ray diffraction (XRD) and energy-dispersive spectra (EDS) analysis indicated the heavy metals could be transformed into stable crystal texture. The stabilization of heavy metals was attributed to the carbonyl and acyl amino groups. Results presented that immobilized bacteria with inner nutrient were potentially and practically applied to multi-heavy-metal-contamination sediment.
Soils are playing a central role in the transfer and accumulation of anthropogenic pollutants in urbanized regions. Hence, this study aimed at examining the contamination levels of selected soils collected within and around the Paris conurbation (France). This also evaluated factors controlling contamination. Twenty-three trace and major elements as well as 82 organic micropollutants including polycyclic aromatic hydrocarbons (PAHs), polychlorinated biphenyls (PCBs), phthalates (PAEs), polybrominated diphenyl ethers (PBDEs), alkylphenols (APs), and perfluoroalkylated substances (PFASs) were analyzed. Results reinforced the concern raised by the occurrence and levels of metals such as Zn, Pb, Cu, and Hg, identified as metallic markers of anthropogenic activities, but also pointed out the ubiquitous contamination of soils by organic micropollutants in the 0.2-55,000-μg/kg dw range. For well-documented compounds like PAHs, PCBs, and to a lesser extent PBDEs, contents were in the range of background levels worldwide. The pollutant stock in tested soil was compared to the annual atmospheric input. For PAHs; Pb; and to a lesser extent Zn, Cu, Cd, Hg, Sb, PAEs, and APs, a significant stock was observed, far more important than the recent annual atmospheric fluxes. This resulted from both (i) the persistence of a fraction of pollutants in surface soils and (ii) the cumulative atmospheric inputs over several decades. Regarding PBDEs and PFASs, stronger atmospheric input contributions were observed, thereby highlighting their recent dispersal into the environment.
Urban dust in cities is a useful indicator of ambient environmental conditions and a sink for pollutants emitted through various natural and human activities. In this study, metal distributions in urban dust samples collected in 2007, using vacuuming, and 2012, using brushing, were compared. Experiments comparing the vacuuming and brushing methods were performed and translation equations were developed to correct the vacuuming results so that they could be compared with the brushing results. Cadmium concentrations were lower in 2012 than 2007; this could be because many industries moved out of the Beijing region after 2007. Concentrations of Cr, Cu, and Zn changed slightly, which could result from a combination of decreased industrial pollution and increased traffic pollution. A health risk assessment found that except for Cr, exposure to metals in urban dust in the Beijing study area would not cause serious health impacts on residents in 2007 or 2012. However, the health risk for children was higher than for adults in both years. Chromium had the highest hazxard index (0.44) and the highest carcinogenic risk (4.16 × 10(-6)).
Due to their small size, zinc oxide (ZnO) nanoparticles (NPs) are readily absorbed and easily cross biological barriers, which make them promising candidates as diet additives. However, some studies have reported that ZnO NPs cause toxicity; therefore, their safety and potency as diet additives for farm animals should be established. This study was the first to fully evaluate the effects of ZnO NPs on the homeostasis of eight elements in seven organs/tissues. The regulation of element homeostasis was found to be organ specific with no influence on oxidation status, anti-oxidation capability, or organ damage. ZnO NPs may specifically regulate the homeostasis of mineral elements and affect the following correlations: (1) between the element content in each organ and the concentration of Zn used in ZnSO4 or ZnO NP treatments; (2) between ZnO NP and ZnSO4 treatments for the same element in each organ; and (3) between elements (in each organ in ZnSO4 or ZnO NP treatments) in layers' organs/tissues. The use of ZnO NPs as diet additives for animals should be implemented cautiously because, among other uncertainties, they may affect mineral element content.
The effects of water transfer projects on water channels and the receiving water involved need to be understood. In this research, the compositions and particle size distributions of surface sediment and the Cd, Cr, Cu, Ni, Pb, and Zn contents and distributions in the sediment along a water transfer route from the Wangyu River to Taihu Lake, China, were studied. The correlative relationship between the grain size trend and heavy metal content distribution suggested that heavy metals in Wangyu River sediment have affected the heavy metal contents of Taihu Lake sediment through silt and clay migrating in the transferred water. Enrichment factors and potential ecological risk values were calculated. Low levels of potential ecological risks are posed at 20 sampling sites in Taihu Lake, but higher-to-serious risks (potential ecological risk values >275) are posed at all Wangyu River sites. Toxicity of heavy metals (Cd, Cu, Zn, and Ni) in the Wangyu River sediments is more serious than those in the Taihu Lake, but is similar to the entrance of Gonghu Bay. Multivariate statistical analyses (Pearson correlation, cluster, and factor analyses) suggested heavy metals in the study area have many sources, and the relationships between particle migration and heavy metal contents indicated transferring water are likely to lead to adverse ecological risks being posed in Taihu Lake.
The metal contamination in reclaimed mine soil (RMS) of Jharia coal field, Dhanbad (India) using various contamination indices and their accumulation in tissues of Eucalyptus hybrid were assessed. In RMS, metal concentrations were found higher (202%-533%) than control soil (CS) with major contribution of Co and Mn followed by Zn, Cu and Pb. Principal component analysis (PCA) of metals present in RMS was carried out to assess their origin in RMS. The contamination factor (CF) values in RMS indicated moderate to very high level of pollution (ranged between 2.02 and 5.33). Higher accumulation of Pb in barks (three times), Zn in leaves (4.5 times), Mn in leaves (19 times), and Cu in roots (1.4 times) was found in trees growing on RMS than CS. The study concluded that different tree tissues accumulate varied concentration of heavy metals in RMS and thus for biomonitoring of metals, specific tissues has to be selected.
Homoleptic zinc(II) complexes of di(phenylacetylene)azadipyrromethene (e.g., Zn(WS3)2) are potential non-fullerene electron acceptors for organic photovoltaics. To tune their properties, fluorination of Zn(WS3)2 at various positions was investigated. Three fluorinated azadipyrromethene-based ligands were synthesized with fluorine at the para-position of the proximal and distal phenyl groups, and at the pyrrolic phenylacetylene moieties. Additionally, a CF3 moiety was added to the pyrrolic phenyl positions to study the effects of a stronger electron withdrawing unit at that position. The four ligands were chelated with zinc(II) and BF2(+) and the optical and electrochemical properties were studied. Fluorination had little effect
 on the optical properties of both the zinc(II) and BF2(+) complexes, with λmax in solution around 755 nm and 785 nm, and high molar absorptivities of 100 × 10(3) M(-1)cm(-1) and 50 × 10(3) M(-1)cm(-1), respectively. Fluorination of Zn(WS3)2 raised the oxidation potentials by 0.04 V to 0.10 V, and the reduction potentials by 0.01 V to 0.10 V, depending on the position and type of substitution. The largest change was observed for fluorine substitution at the proximal phenyl groups and CF3 substitution at the pyrrolic phenylacetylene moieties. The later complexes are expected to be stronger electron acceptors than Zn(WS3)2, and may enable charge transfer from other conjugated polymer donors that have lower energy levels than poly(3-hexylthiophene) (P3HT).
In this study, a polymer, prepared by crosslinking cyclodextrin (CD) by means of a polycarboxylic acid, was used for the removal of pollutants from spiked solutions and discharge waters from the surface treatment industry. In spiked solutions containing five metals, sixteen polycyclic aromatic hydrocarbons (PAH) and three alkylphenols (AP), the material exhibited high adsorption capacities: >99% of Co(2+), Ni(2+) and Zn(2+) were removed, between 65 and 82% of the PAHs, as well as 69 to 90% of the APs. Due to the structure of the polymer and its specific characteristics, such as the presence of carboxylic groups and CD cavities, the adsorption mechanism involves four main interactions: ion exchange, electrostatic interactions and precipitation for metal removal, and inclusion complexes for organics removal. In industrial discharge waters, competition effects appeared, especially because of the presence of calcium at high concentrations, which competed with other pollutants for the adsorption sites of the adsorbent.
In most cases, in soils exposed to heavy metals accumulation, the highest content of heavy metals was noted in the surface layers of the soil profile. Accumulation of heavy metals may occur both as a result of natural processes as well as anthropogenic activities. The quality of the soil exposed to heavy metal contamination can be evaluated by indices of pollution. On the basis of determined heavy metals (Pb, Zn, Cu, Mn, Ni and Cr) in the soils of Roztocze National Park the following indices of pollution were calculated: Enrichment Factor (EF), Geoaccumulation Index (Igeo), Nemerow Pollution Index (PINemerow) and Potential Ecological Risk (RI). Additionally, we introduced and calculated the Biogeochemical Index (BGI), which supports determination of the ability of the organic horizon to accumulate heavy metals. A tens of times higher content of Pb, Zn, Cu and Mn was found in the surface layers compared to their content in the parent material. This distribution of heavy metals in the studied soils was related to the influence of anthropogenic pollution (both local and distant sources of emission), as well as soil properties such as pH, organic carbon and total nitrogen content.
Despite salinity has been well documented for its significant effects on the bioaccumulation of many trace elements in biomonitors, no calibration method has been proposed to reduce such influences. For the first time, the present study established a novel method to calibrate biomonitoring data against salinity. Relationships between trace element concentration in oyster Crassostrea hongkongensis and the biological proxy for salinity were quantified based on laboratory exposure experiments. The method was then verified by the biomonitoring data of Pearl River Estuary (PRE). Tissue concentrations of trace elements (Cu, Zn, Ag, Cd, Pb, Cr, As, Se, and Ni) and major cations (Na, Mg, K, and Ca) in oysters exposed at 4 salinities (5, 12, 20, and 28psu) and low concentrations for 6weeks were measured to establish such quantitative relationships. Tissue Na, Mg, and K could be the proxy for salinity, while Na was the best one. Negative correlations between tissue concentrations of trace elements and Na after exposure were observed for metal cations such as Cu, Zn, Ag, Cd, and Pb, while tissue As, Se, and Ni were positively correlated with Na. In PRE, salinity significantly influenced the bioaccumulation of trace elements even under the multifactor-affected field conditions. The calibration method applied to the biomonitoring of PRE was verified to be feasible, and effectively reduced the influences of salinity. Therefore, calibration against salinity could facilitate the interpretation, comparability, and analysis of biomonitoring data.
An aqueous two-phase system composed of Triton X-100-(NH4)2SO4-H2O was proposed for extraction and separation of tungsten(VI) from aqueous solution without using any extractant. The effects of aqueous pH, concentration of ammonium sulfate, Triton X-100 and tungsten, extracting temperature on the extraction of tungsten were investigated. The extraction of tungsten has remarkable relationship with aqueous pH and are to above 90% at pH=1.0-3.0 under studied pH range (pH=1.0-7.0) and increases gradually with increasing Triton X-100 concentration, but decreases slightly with increasing ammonium sulfate concentration. The extraction percentage of tungsten is hardly relevant to temperature but its distribution coefficient linearly increases with increasing temperature within 303.15-343.15K. The distribution coefficient of tungsten increases with the increase of initial tungsten concentration (0.1-3%) and temperature (303.15 K-333.15K). The solubilization capacity of tungsten in Triton X-100 micellar phase is independent of temperature. FT-IR analysis reveals that there is no evident interaction between polytungstate anion and ether oxygen unit in Triton X-100, and DLS analysis indicates that zeta potential of Triton X-100 micellar phase have a little change from positive to negative after extracting tungsten. Based on the above-mentioned results, it can be deduced that polytungstate anions are solubilized in hydrophilic outer shell of Triton X-100 micelles by electrostatic attraction depending on its relatively high hydrophobic nature. The stripping of tungsten is mainly influenced by temperature and can be easily achieved to 95% in single stage stripping. The tungsten (VI) is separated out from solution containing Fe(III), Co(II), Ni(II), Cu(II), Zn(II), Al(III), Cr(III) and Mn(II) under the suitable conditions.
To determine the effects of increasing plant-based foods v. dairy foods on energy and nutrients of concern in adolescent females via diet modelling exercises.
Data from the National Health and Nutrition Examination Survey (NHANES) were used to compare nutrient intakes from usual diet with those from three dietary scenarios that increased current intakes by 100 % of the following: (i) plant-based foods; (ii) protein-rich plant-based foods; and (iii) milk, cheese and yoghurt. The first two scenarios had commensurate reductions in animal products.
What We Eat in America, NHANES 2007-2010.
Female adolescents (n 1594) aged 9-18 years.
When currently consumed plant-based foods were increased by 100 %, there were increases in dietary fibre, added sugar, vitamin E, Fe and folate intakes. These increases were accompanied by decreases in total fat, saturated fat, Zn, vitamin D, Ca and protein intakes. Protein-rich plant foods are consumed in very low quantities in this population such that doubling their intake resulted in no real nutritional impact. When dairy products were increased by 100 % there were increases in intakes of vitamin D, Mg, Zn, Ca, K, energy, saturated fat and protein.
Non-specific recommendations to increase plant foods can lead to unintended nutritional consequences. For adolescent girls, meeting the dietary recommendation of three daily servings of dairy improved the intake of the identified nutrients of concern while simultaneously providing adequate nutrients essential for proper growth and bone health critical during the adolescent phase.
Sodium polyamidoamine-multi dithiocarbamate (PAMAM-DTC) is a kind of heavy metals capturing agent, containing functional groups of dithiocarbamate that could strongly chelate heavy metals. In this paper, it was applied to precipitate heavy metal ions from meal-EDTA and reclaim EDTA during sediment washing process. The extracting performance of fresh EDTA was studied as a function of EDTA concentration, liquid/sediment (L/S), pH, and extraction time. Then the EDTA effluents were treated with PAMAM-DTC, Na2S and sodium diethyldithiocarbamate (DDTC) to compare their effectiveness on capturing metals from metal-EDTA complexes. Four divalent heavy metals were investigated (Pb, Cd, Cu, Zn). PAMAM-DTC shows much better performance. Pb, Cd and Cu could almost be precipitated completely by PAMAM-DTC under the dosage of 350 mg L(-1), while Zn could be only partly precipitated which may due to its failure in competition with the other three metal ions on chelation with PAMAM-DTC. The reclaimed EDTA was reused in three cycles of sediment washing, and the amount of heavy metals extracted just slightly decreased in each cycle.
An efficient 3.168 kW solid-state solar thermal simulator (SSSTS), capable of supplying ~30,000 suns at a focal plane via a fibre optical delivery, has been developed. The source consists of 41 diode lasers, each operated at a wavelength and power of ~915 nm and ~80 watt, respectively. The SSSTS provides a semi-top hat radiation profile and can be focused to a diameter of ~10.5 mm. The electro-optical power efficiency of the SSSTS was evaluated to be 55%, where the maximum value of the uniform radiation flux exceeds 36.6MW/m<sup>2</sup>. As such, the present technology is relevant to solar thermal applications that are not wavelength-sensitive or where narrow line-width is desirable. Additionally, the fibre optical delivery feature enables ease of direction onto a suitable target, without the need
 of large ellipsoidal reflectors usually employed for the conventional arc solar simulators. To demonstrate the new SSSTS, ZnO:Zn particles were introduced into the path of the radiation to investigate the change in their own temperature by using the laser induced phosphorescence technique (LIP). The temperature of the averaged particles was measured at a different radiation flux over a ~87 mm<sup>2</sup> cross sectional area. A change in the average particle temperature of up to 225°C was detected within the measurement volume when the SSSTS was operated at a flux of ~30,000 suns. The unique characteristics of the SSSTS, namely, the uniformity, high power flux, efficiency, ease of delivery, and precise control of the radiation flux responds to the current demands of solar thermal research.
Heavy metal contamination of soil and sediment in estuaries warrants study because a healthy estuarine environment, including healthy soil, is important in order to achieve ecological balance and good aquaculture production. The Ba Lat estuary of the Red River is the largest estuary in northern Vietnam and is employed in various land uses. However, the heavy metal contamination of its soil has not yet been reported. The following research was conducted to clarify contamination levels, supply sources, and the effect of land use on heavy metal concentrations in the estuary. Soil samples were collected from the top soil layer of the estuary, and their arsenic (As), chromium (Cr), cadmium (Cd), copper (Cu), lead (Pb), and zinc (Zn) concentrations were analyzed, as were other soil properties. Most soils in the estuary were loam, silt loam, or sandy loam. The pH was neutral, and the cation exchange capacity ranged from 3.8 to 20 cmol·kg(-1). Manganese and iron concentrations averaged 811 µg·g(-1) and 1.79%, respectively. The magnitude of the soil heavy metal concentrations decreased in the order of Zn > Pb > Cr > Cu > As > Cd. The concentrations were higher in the riverbed and mangrove forest than in other land-use areas. Except for As, the mean heavy metal concentrations were lower than the permissible levels for agricultural soils in Vietnam. The principal component analyses suggested that soil As, Pb, Zn, Cd, and Cu were of anthropogenic origin, whereas Cr was of non-anthropogenic origin. The spatial distribution of concentration with land use indicated that mangrove forests play an important role in preventing the spread of heavy metals to other land uses and in maintaining the estuarine environment.
Two incinerators in Taiwan have recently attempted to reuse the fly and bottom ash that they produce, but the mutagenicity of these types of ash has not yet been assessed. Therefore, we evaluated the mutagenicity of the ash with the Ames mutagenicity assay using the TA98, TA100, and TA1535 bacterial strains. We obtained three leachates from three leachants of varying pH values using the toxicity characteristic leaching procedure test recommended by the Taiwan Environmental Protection Agency (Taiwan EPA). We then performed the Ames assay on the harvested leachates. To evaluate the possible relationship between the presence of heavy metals and mutagenicity, the concentrations of five heavy metals (Cd, Cr, Cu, Pb, and Zn) in the leachates were also determined. The concentrations of Cd and Cr in the most acidic leachate from the precipitator fly ash and the Cd concentration in the most acidic leachate from the boiler fly ash exceeded the recommended limits. Notably, none of the nine leachates extracted from the boiler, precipitator, or bottom ashes displayed mutagenic activity. This data partially affirms the safety of the fly and bottom ash produced by certain incinerators. Therefore, the biotoxicity of leachates from recycled ash should be routinely monitored before reusing the ash.
Systematic first principles calculations were performed for ZnCo2O4 to clarify its structural and electronic properties, and particularly the structural stability as an electrode material for lithium-ion batteries. For samples with low Li concentration, e.g., LinZnCo2O4 with n < 1, Li atoms take the center of oxygen octahedra and may diffuse rapidly. Structure distortions and volume expansions can be observed in LinZnCo2O4 with n > 1 and amorphous structures eventually prevail. The AIMD simulations for Li9ZnCo2O4 suggest the formation of Li2O, Co3O4 and LiZn local compounds or alloys. In particular, the formation of Zn-Co aggregations and the losing of ZnO pairs are identified as the possible reasons that are responsible to the Li capacity fading in ZnCo2O4 anodes.
Natural minerals are widely used in treatment technologies as mineral fertilizer, food additive in animal husbandry, and cosmetics because they combine valuable ion-exchanging and adsorption properties together with unique physicochemical and medical properties. Saponite (saponite clay) of the Ukrainian Podillya refers to the class of bentonites, a subclass of layered magnesium silicate montmorillonite. Clinoptilolits are aluminosilicates with carcase structure. In our work, we have coated biopolymer chitosan on the surfaces of natural minerals of Ukrainian origin - Podilsky saponite and Sokyrnitsky clinoptilolite. Chitosan mineral composites have been obtained by crosslinking of adsorbed biopolymer on saponite and clinoptilolite surface with glutaraldehyde. The obtained composites have been characterized by the physicochemical methods such as thermogravimetric/differential thermal analyses (DTA, DTG, TG), differential scanning calorimetry, mass analysis, nitrogen adsorption/desorption isotherms, scanning electron microscopy (SEM), and Fourier transform infrared (FTIR) spectroscopy to determine possible interactions between the silica and chitosan molecule. The adsorption of microquantities of cations Cu(II), Zn(II), Fe(III), Cd(II), and Pb(II) by the obtained composites and the initial natural minerals has been studied from aqueous solutions. The sorption capacities and kinetic adsorption characteristics of the adsorbents were estimated. It was found that the obtained results have shown that the ability of chitosan to coordinate heavy metal ions Zn(II), Cu(II), Cd(II), and Fe(III) is less or equal to the ability to retain ions of these metals in the pores of minerals without forming chemical bonds.
The safe disposal of post-methanated distillery sludge (PMDS) in the environment is challenging due to high concentrations of heavy metals along with other complex organic pollutants. The study has revealed that PMDS contained high amounts of Fe (2403), Zn (210), Mn (126), Cu (73.62), Cr (21.825), Pb (16.33) and Ni (13.425 mg kg(-1)) along with melanoidins and other co-pollutants. The phytoextraction pattern in 15 potential native plants growing on sludge showed that the Blumea lacera, Parthenium hysterophorous, Setaria viridis, Chenopodium album, Cannabis sativa, Basella alba, Tricosanthes dioica, Amaranthus spinosus L., Achyranthes sp., Dhatura stramonium, Sacchrum munja and Croton bonplandianum were noted as root accumulator for Fe, Zn and Mn, while S. munja, P. hysterophorous, C. sativa, C. album, T. dioica, D. stramonium, B. lacera, B. alba, Kalanchoe pinnata and Achyranthes sp. were found as shoot accumulator for Fe. In addition, A. spinosus L. was found as shoot accumulator for Zn and Mn. Similarly, all plants found as leaf accumulator for Fe, Zn and Mn except A. spinosus L. and Ricinus communis. Further, the BCF of all tested plants were noted <1, while the TF showed >1. This revealed that metal bioavailability to plant is poor due to strong complexation of heavy metals with organic pollutants. This gives a strong evidence of hyperaccumulation for the tested metals from complex distillery waste. Furthermore, the TEM observations of root of P. hysterophorous, C. sativa, Solanum nigrum and R. communis showed formation of multi-nucleolus, multi-vacuoles and deposition of metal granules in cellular component of roots as a plant adaptation mechanism for phytoextraction of heavy metal-rich polluted site. Hence, these native plants may be used as a tool for in situ phytoremediation and eco-restoration of industrial waste-contaminated site.
The rapid urban expansion and presence of volcanoes in the premises of Puebla River basin in central Mexico exert significant influences over its aquatic environments. Twenty surface sediment samples from Puebla River basin consisting of R. Alseseca, R. Atoyac, and Valsequillo dam were collected during September 2009 and analyzed for major (Al, Fe, Mg, Ba, Ca, and K) and trace elements (As, Cd, Co, Cr, Cu, Mn, Ni, Pb, Sr, V, and Zn) in order to identify the metal concentrations and their enrichment. R. Atoyac sediments presented higher concentrations of Ba (1193.8 μg g(-1)) and Pb (27.1 μg g(-1)) in comparison with the local reference sample values. All the metal concentrations except Sr for R. Alseseca sediments were within the range of local reference sample values indicating no significant external influence, whereas Valsequillo dam sediments had elevated concentrations of all the metals suggesting both natural and external influences in the study region. The magnitude of metal contamination was assessed using several indices such as geoaccumulation index (I geo), enrichment factor (EF), degree of contamination (C d ), and pollution load index (PLI). The results suggest that As, Pb, and Zn were predominantly enriched in the Puebla River basin sediments. Comparing with sediment quality guidelines and ecotoxicological values, it is revealed that Cd, Cr, Cu, and Ni have possible harmful effects on the biological community. The present study provides an outlook of metal enrichment in Puebla River basin sediments, highlighting the necessity to conserve this river ecosystem for the near future.
This study was carried out to examine heavy metal accumulation in rice
 grains and brassicas and to identify the different controls, such as soil properties and soil heavy metal fractions obtained by the Community Bureau of Reference (BCR) sequential extraction, in their accumulation. In Guangdong Province, South China, rice grain and brassica samples, along with their rhizospheric soil, were collected from fields on the basis of distance downstream from electroplating factories, whose wastewater was used for irrigation. The results showed that long-term irrigation using the electroplating effluent has not only enriched the rhizospheric soil with Cd, Cr, Cu, and Zn but has also increased their mobility and bioavailability. The average concentrations of Cd and Cr in rice grains and brassicas from closest to the electroplating factories were significantly higher than those from the control areas. Results from hybrid redundancy analysis (hRDA) and redundancy analysis (RDA) showed that the BCR fractions of soil heavy metals could explain 29.0 and 46.5 % of total eigenvalue for heavy metal concentrations in rice grains and brassicas, respectively, while soil properties could only explain 11.1 and 33.4 %, respectively. This indicated that heavy metal fractions exerted more control upon their concentrations in rice grains and brassicas than soil properties. In terms of metal interaction, an increase of residual Zn in paddy soil or a decrease of acid soluble Cd in the brassica soil could enhance the accumulation of Cd, Cu, Cr, and Pb in both rice grains and brassicas, respectively, while the reducible or oxidizable Cd in soil could enhance the plants' accumulation of Cr and Pb. The RDA showed an inhibition effect of sand content and CFO on the accumulation of heavy metals in rice grains and brassicas. Moreover, multiple stepwise linear regression could offer prediction for Cd, Cu, Cr, and Zn concentrations in the two crops by soil heavy metal fractions and soil properties.
Ultrasonic probe sonication (UPS) and microwave-assisted extraction (MAE) were used for rapid single extraction of Cd, Cr, Cu, Ni, Pb, and Zn from soils polluted by former mining activities (Mónica Mine, Bustarviejo, NW Madrid, Spain), using 0.01 mol L(-1) calcium chloride (CaCl2), 0.43 mol L(-1) acetic acid (CH3COOH), and 0.05 mol L(-1) ethylenediaminetetraacetic acid (EDTA) at pH 7 as extracting agents. The optimum extraction conditions by UPS consisted of an extraction time of 2 min for both CaCl2 and EDTA extractions and 15 min for CH3COOH extraction, at 30% ultrasound (US) amplitude, whereas in the case of MAE, they consisted of 5 min at 50 °C for both CaCl2 and EDTA extractions and 15 min at 120 °C for CH3COOH extraction. Extractable concentrations were determined by inductively coupled plasma atomic emission spectrometry (ICP-AES). The proposed methods were compared with a reduced version of the corresponding single extraction procedures proposed by the Standards, Measurements and Testing Programme (SM&T). The results obtained showed a great variability on extraction percentages, depending on the metal, the total concentration level and the soil sample, reaching high values in some areas. However, the correlation analysis showed that total concentration is the most relevant factor for element extractability in these soil samples. From the results obtained, the application of the accelerated extraction procedures, such as MAE and UPS, could be considered a useful approach to evaluate rapidly the extractability of the metals studied.
Todos os Santos (All Saints) Bay area, NE-Brazil, is known for one of the most important cases of urban lead (Pb) contamination in the world. The main objective of this work was to assess and interpret the spatial distribution of As, Cd, Hg, Pb, and Zn in "background" soils of this environmentally impacted bay area, using a combination of geostatistical and multivariate analytical methods to distinguish between natural and anthropogenic sources of those metal(oid)s in soils. We collected 114 topsoil samples (0.0-0.2 m depth) from 38 sites. The median values for trace metal concentrations in soils (mg kg(-1)) followed the order Pb (33.9) > Zn (8.8) > As (1.2) > Cd (0.2) > Hg (0.07), clearly reflecting a Pb-contamination issue. Principal component analysis linked Cd, Pb, and Zn to the same factor (F1), chiefly corroborating their anthropogenic origin; yet, both Pb and Zn are also influenced by natural lithogenic sources. Arsenic and Hg concentrations (F2) are likely related to the natural component alone; their parent material (igneous-metamorphic rocks) seemingly confirm this hypothesis. The heterogeneity of sources and the complexity of the spatial distribution of metals in large areas such as the Todos os Santos Bay warrant, the importance of multivariate and geostatistical analyses in the interpretation of environmental data.
Tinplate cans were used to study if electro-activated brine solution (EAS) is more corrosive than conventional one by ICP analysis. The results showed different effects of EAS on cans, alone or filled with product. Acidic EAS (pH 2-3) and Redox +900 to +1200 mV highly reacted with the cans. The concentrations of Zn, Fe, and Cu in the solution were 0.028, 28.81, and 0.022 ppm, respectively. No Sn migration was observed in this case. When neutral or acidic chlorine-free EAS was used, no significant difference was observed in comparison with the corrosivity of standard NaCl brine. Alkaline EAS with pH>10 and negative E (≤-966 mV) did not affect Zn, Fe, and Cu migration. However, it affected tin migration. Nevertheless, it is important to mention that even if some corrosion was observed, it was in the limit of the permitted level of concentration when the cans were filled with a product.
Exposure to essential and non-essential elements may be elevated for green sea turtles (Chelonia mydas) that forage close to shore. Biomonitoring of trace elements in turtle blood can identify temporal trends over repeated sampling events, but any interpretation of potential health risks due to an elevated exposure first requires a comparison against a baseline. This study aims to use clinical reference interval (RI) methods to produce exposure baseline limits for essential and non-essential elements (Na, Mg, K, Ca, Ti, V, Cr, Mn, Fe, Co, Ni, Cu, Zn, As, Se, Mo, Cd, Sb, Ba, and Pb) using blood from healthy subadult turtles foraging in a remote and offshore part of the Great Barrier Reef. Subsequent blood biomonitoring of three additional coastal populations, which forage in areas dominated by agricultural, urban and military activities, showed clear habitat-specific differences in blood metal profiles relative to the those observed in the offshore population. Coastal turtles were most often found to have elevated concentrations of Co, Mo, Mn, Mg, Na, As, Sb, and Pb relative to the corresponding RIs. In particular, blood from turtles from the agricultural site had Co concentrations ranging from 160 to 840 μg/L (4-25 times above RI), which are within the order expected to elicit acute effects in many vertebrates. Additional clinical blood biochemistry and haematology results indicate signs of a systemic disease and the prevalence of an active inflammatory response in a high proportion (44%) of turtles from the agricultural site. Elevated Co, Sb, and Mn in the blood of these turtles significantly correlated with elevated markers of acute inflammation (total white cell counts) and liver dysfunction (alkaline phosphatase and total bilirubin). The results of this study support the notion that elevated trace element exposures may be adversely affecting the health of nearshore green sea turtles.
The present study aimed to characterize and evaluate the in vitro and in vivo anticoagulant activity of sulfated glycosaminoglycans from the skins of smooth hound (SHSG) and grey triggerfish (GTSG). The analysis of SHSG and GTSG with acetate cellulose electrophoresis in Zn-acetate revealed the presence of hyaluronic acid (HA), chondroitin sulfate (CS) and dermatan sulfate (DS). Both glycosaminoglycans were evaluated for their in vitro anticoagulant activities using activated partial thromboplastin time (aPTT), thrombin time (TT) and prothrombine time (PT) tests. SHSG and GTSG and calciparin were tested as in vivo anticoagulants by subcutaneous (s.c) injection to adult female Wistar rats in a concentration of 75mg/kg of body weight. The administration of SHSG, GTSG and calciparin to rats induced a significant decrease of platelet rates compared to the control. The aPTT assay of SHSG and GTSG was prolonged 1.3 and 1.23-fold respectively compared with the control. Toxicity studies were performed to investigate whether or not SHSG and GTSG can cause pathological changes in the liver, proteins and DNA. The concentration and catalytic activity of liver oxidative stress markers and enzymes, respectively, as well as the observed hepatic morphological changes indicated that calciparin induced hepatic toxicity and oxidative damage in the liver. The higher activity and lower toxicity of SHSG and GTSG recommended these compounds as a better drug candidate than calciparin.
The present investigation reveals the solubilization efficiency of tri-calcium phosphate (TCP), Udaipur rock phosphate (URP), aluminium phosphate (AP) and ferric phosphate (FP) by Aspergillus niger (ITCC 6719) and Trichoderma harzianum (ITCC 6721) as function of carbon concentrations. Increasing glucose concentration from 1 to 7% in the growth medium, though improved the phosphorus (P) solubilization significantly but each fungal strain preferred different optimum carbon concentrations for mediating solubilization of different P sources. The two fungi employed different mechanisms to reduce medium pH for release of P from TCP, AP and FP. However, URP was solubilized solely through fungal production of citric, succinic, propionic, malic and acetic
 acid. A linear increase in citric acid production with increasing carbon concentration was recorded during FP solubilization by T. harzianum. The cell free culture filtrate of A. niger detected high phytase and low acid phosphatase activity titre whereas results were vice versa for T. harzianum. Both the fungal strains possessed plant growth promoting attributes such as auxin and sidreophore production and could solubilize Zn. In hydroponic system (with 60mM of sodium chloride concentration), supplementation with culture filtrate from each fungal strain increased the shoot growth of wheat seedlings significantly compared to non culture filtrate control. Use of A.niger as bio-inoculant could be a sustainable approach to improve soil P availability, promote plant growth and alleviate adverse effect of salt stress.
A high prevalence of undernutrition has previously been reported in indigenous Māori (49 %) and non-Māori (38 %) octogenarians and may be associated with risk of micronutrient deficiencies. We examined vitamin and mineral intakes and the contributing food sources among 216 Māori and 362 non-Māori participating in Life and Living to Advanced age a Cohort Study in New Zealand, using a repeat 24-h multiple-pass recall. More than half of the Māori and non-Māori participants had intakes below the estimated average requirement from food alone for Ca, Mg and Se. Vitamin B6 (Māori women only), folate (women only), vitamin E (Māori women; all men) and Zn (men only) were low in these ethnic and sex subgroups. Women had intakes of higher nutrient density in folate, vitamin C, Ca, Mg, K, vitamin A (non-Māori) and β-carotene (Māori) compared with men (P<0·05). When controlling for age and physical function, β-carotene, folate, vitamin C, Ca and Mg were no longer significantly different, but vitamins B2, B12, E and D, Fe, Na, Se and Zn became significantly different for Māori between men and women. When controlling for age and physical function, vitamins A and C and Ca were no longer significantly different, but vitamin B2, Fe, Na and Zn became significantly different for non-Māori between men and women. For those who took nutritional supplements, Māori were less likely to be deficient in food alone intake of vitamin A, folate and Mg, whereas non-Maori were less likely to be deficient in intakes of Mg, K and Zn, but more likely to be deficient in vitamin B12 intake. A lack of harmonisation in nutrient recommendations hinders the interpretation of nutrient adequacy; nonetheless, Ca, Mg and Se are key micronutrients of concern. Milk and cheese were important contributions to Ca intake, whereas bread was a key source of Mg and Se. Examination of dietary intake related to biochemical status and health outcomes will establish the utility of these observations.
Tuberculosis control program of Rwanda is currently phasing in light emitting diode-fluorescent microscopy (LED-FM) as an alternative to Ziehl-Neelsen (ZN) smear microscopy. This, alongside the newly introduced Xpert (Cepheid, Sunnyvale, CA, USA) is expected to improve diagnosis of tuberculosis and detection of rifampicin resistance in patients at health facilities. We assessed the accuracy of smear microscopy and the incremental sensitivity of Xpert at tuberculosis laboratories in Rwanda.
This was a cross-sectional study involving four laboratories performing ZN and four laboratories performing LED-FM microscopy. The laboratories include four intermediate (ILs) and four peripheral (PLs) laboratories. After smear microscopy, the left-over of samples, of a single early-morning sputum from 648 participants, were tested using Xpert and mycobacterial culture as a reference standard. Sensitivity of each test was compared and the incremental sensitivity of Xpert after a negative smear was assessed.
A total of 96 presumptive pulmonary tuberculosis participants were culture positive for M. tuberculosis. The overall sensitivity in PL of ZN was 55.1 % (40.2-69.3 %), LED-FM was 37 % (19.4-57.6 %) and Xpert was 77.6 % (66.6-86.4 %) whereas in ILs the same value for ZN was 58.3 % (27.7-84.8 %), LED-FM was 62.5 % (24.5-91.5 %) and Xpert was 90 (68.3-98.8 %). The sensitivity for all tests was significantly higher among HIV-negative individuals (all test p <0.05). The overall incremental sensitivity of Xpert over smear microscopy was 32.3 %; p < 0.0001. The incremental sensitivity of Xpert was statistically significant for both smear methods at PL (32.9 %; p = 0.001) but not at the ILs (30 %; p = 0.125) for both smear methods.
Our study findings of the early implementation of the LED-FM did not reveal significant increment in sensitivity compared to the method being phased out (ZN). This study showed a significant incremental sensitivity for Xpert from both smear methods at peripheral centers where majority of TB patients are diagnosed. Overall our findings support the recommendation for Xpert as an initial diagnostic test in adults and children presumed to have TB.
In this study a total of 30 street dusts and 10 surface soils were collected in the central district of Tehran and analyzed for major potentially toxic metals. Street dust was found to be greatly enriched in Sb, Pb, Cu and Zn and moderately enriched in Cr, Mn, Mo and Ni. Contamination of Cu, Sb, Pb and Zn was clearly related to anthropogenic sources such as brake wear, tire dust, road abrasion and fossil fuel combustion. Spatial distribution of pollution load index in street dust suggested that industries located south-west of the city intensify street dust pollution. Microscopic studies revealed six dominant group of morphological structures in calculation of the exposurethe street dusts and surface soils, with respect to different geogenic and anthropogenic sources. The BCR (the European Community Bureau of Reference) sequential extraction results showed that Sb, Ni, Mo, As and Cr bonded to silicates and sulfide minerals were highly resistant to dissolution. In contrast, Zn, Cd, and Mn were mostly associated with the exchangeable phase and thus would be easily mobilized in the environment. Cu was the most abundant metal in the reducible fraction, indicating its adsorption to iron and manganese oxy-hydroxides. Pb was equally extracted from exchangeable and reducible fractions. Anthropogenic sources related to traffic apparently play a small role in Cr, Ni and Mo contamination and dispersed them as bioavailable forms but with reduced mobility and bioavailablity due to high potential of complexation and adsorption to organic matter and iron and manganese oxy-hydroxides. Calculated Hazard Index (HI) suggests ingestion as the most important pathway for the majority of PTMs in children and dermal contact as the main exposure route for Cr, Cd and Sb for adults. The HIs and fractionation pattern of elements revealed Pb as the sole element that bears potential health risk in street dust and surface soil.
Date palm is an important crop plant in the arid and semi-arid regions supporting human population in the Middle East and North Africa. These areas have been largely affected by drought and salinity due to insufficient rainfall and improper irrigation practices. Date palm is a relatively salt- and drought-tolerant plant and more recently efforts have been directed to identifying genes and pathways that confer stress tolerance in this species. Quantitative real-time PCR (qPCR) is a promising technique for the analysis of stress-induced differential gene expression, which involves the use of stable reference genes for normalizing gene expression. In an attempt to find the best reference genes for date palm's drought and salinity research, we evaluated the stability of 12 most commonly used reference genes using the geNorm, NormFinder, BestKeeper statistical algorithms and the comparative ΔCT method. The comprehensive results revealed that HEAT SHOCK PROTEIN (HSP), UBIQUITIN (UBQ) and YTH domain-containing family protein (YT521) were stable in drought-stressed leaves whereas GLYCERALDEHYDE-3-PHOSPHATE DEHYDROGENASE (GAPDH), ACTIN and TUBULIN were stable in drought-stressed roots. On the other hand, SMALL SUBUNIT RIBOSOMAL RNA (25S), YT521 and 18S ribosomal RNA (18S); and UBQ, ACTIN and ELONGATION FACTOR 1-ALPHA (eEF1a) were stable in leaves and roots, respectively, under salt stress. The stability of these reference genes was verified by using the abiotic stress-responsive CYTOSOLIC Cu/Zn SUPEROXIDE DISMUTASE (Cyt-Cu/Zn SOD), an ABA RECEPTOR, and a PROLINE TRANSPORTER 2 (PRO) genes. A combination of top 2 or 3 stable reference genes were found to be suitable for normalization of the target gene expression and will facilitate gene expression analysis studies aimed at identifying functional genes associated with drought and salinity tolerance in date palm.
Carbon molecular sieve membranes (CMSMs) were fabricated by pyrolysis of MOF-doped polyimide mixed matrix membranes. ZIF-108 (Zn(2-nitroimidazolate)2) was used as a dopant to tailor the micropores of the as-prepared CMSMs into narrow ultramicropores, providing a remarkable combination of permeability and selectivity of membranes in CO2/CH4, O2/N2 and N2/CH4 separation.
The contemporary reclamation method in an opencast coal mine closure comprises the use of the preserved surface soil layer (SSL) before mining, and can be directly returned to the areas being rehabilitated. The present study emphasizes a risk in the use of such a SSL in mine rehabilitation due to the possible excessive amount of heavy metals which usually derives from a metal-rich sediment or fluvial character of overburden material. This indication was approved by the bioassessment of cadmium (Cd), chromium (Cr), cobalt (Co), copper (Cu), lead (Pb), nickel (Ni), and zinc (Zn) in root and aerial parts of maize (Zea mays), alfalfa (Medicago sativa), sweet clover (Melilotus officinalis), wheat (Triticum aestivum), barley
 (Hordeum sativum), white clover (Trifolium repens), pasture (Poales sp.), tomato (Solanum lycopersicum), potato (Solanum tuberosum) and carrot (Daucus carota) grown on SSL in the opencast mine area. The fluvial layers of the investigated mine SSL revealed the excessive existence of Ni and Cr, probably of geogenic origin, according to the X-ray diffraction (XRD) which detected Ni- and Cr-bearing minerals in soil fractions. In addition, the highest residual fraction of these two heavy metals, obtained by sequential extraction analyses, together with all other tested soil parameters, supported this assumption. Nevertheless, the accumulations of Cr in tomato fruit (2.93 mg kg(-1)), potato tuber (5.89 mg kg(-1)) and carrot root (7.35 mg kg(-1)) grown on the investigated SSL were found to exceed a critical level of this element for human nutrition. However, despite the evident excess of Ni in the investigated SSL, a similar trend was not found in edible part of plants. The transfer and mobility of the investigated metals was evaluated using the accumulation factor (AF < 1.0) where the root were the preferential organ for the storage of heavy metals. This investigation could bring an important input for its acceptability of use in soil restoration after mining for food/fodder production, or it could indicate the potential risks of the presence of heavy metals regarding its possible use in improving the human surrounding.
The goal of this study is aimed to develop a novel process to recycle the ferrous sulfate, the by-product of titanium dioxide industry. Zinc sulfate was added in the process of milling ferrous sulfate with calcium carbonate (CaCO3). The sulfates were transformed into carbonates to serve as slow-release fertilizers by co-grinding the starting materials of FeSO4·7H2O, ZnSO4·7H2O, and CaCO3 with small amounts of water in a planetary ball mill. The prepared samples were characterized by X-ray diffraction (XRD) analysis and quantitative measurements of the soluble ratios in water and 2% citric acid solution. It was found that Fe and Zn ions as sulfates were successfully combined with CaCO3 to form the corresponding Fe and Zn carbonates respectively. After milling, the release ratios of Fe and Zn nutrients in distilled water could be controlled at 0.1% and 0.7% respectively. Meanwhile, the release ratios of them in 2% citric acid solution were almost 98% and 100%. Milling speed was the critical parameter to facilitate the transformation reaction. The proposed process, as an easy and economical route, exhibits evident advantages, namely allowing the use of widely available and low-cost CaCO3 as well as industrial wastes of heavy metal sulfates as starting samples to prepare applicable products.
Structure of bacterial envelope is one of the major factors contributing to Gram negative bacterial resistance. To develop new agents that target the bacterial membranes, we synthesized, by analogy with our previous peptide conjugates, new amphiphilic 3',4',6-trinaphthylmethylene neamines functionalized at position 5 through a short spacer by a chelating group, tris(2-pyridylmethyl)amine (TPA) and di-(picolyl)amine (DPA) and tetraazacyclotetradecane (Cyclam). ESI(+) mass spectrometry analyses showed that neither Zn(II)(NeaDPA) nor Cu(II)(NeaCyclam) were stable in the Mueller Hinton (MH) medium used for antibacterial assays. In contrast Zn(NeaTPA) was stable in the MH medium. Interestingly, in MH, the free ligand NeaTPA was found bound to zinc, the zinc salt being the most abundant salt in this medium. Thus, the antibacterial activities of all compounds were evaluated as free ligands against E. coli strains, wild type AG100 and E. aerogenes EA289 (a clinical MDR strain that overexpresses AcrAB-TolC efflux pump), as well as AG100A an AcrAB- E. coli strain and EA298 a TolC- derivative. NeaCyclam and Zn(NeaTPA) were by far the most efficient compounds active against resistant isolate EA289 with MICs in the range 16-4 and 4 μM, respectively, while usual antibiotics such as β-lactams and phenicols were inactive (MICs > 128) and ciprofloxacin was at 64 μM. Zn(NeaTPA) and NeaCyclam were shown to target and permeabilize the outer membrane of EA289 by promoting the cleavage of nitrocefin by periplasmic β-lactamase. Moreover, all the neamine conjugates were able to block the efflux of 1,2'-dinaphthylamine in EA289, by acting on the efflux transporter located in the inner membrane. These membranotropic properties contribute to explain the activities of these neamine conjugates toward the MDR EA289 strain.
Laccase is a widely present extracellular phenoloxidase excreted by fungi, bacteria, and high plants. It is able to catalyze one-electron oxidation of phenolic compounds into radical intermediates that can subsequently couple to each other via covalent bonds. These reactions are believed to play an important role in humification process and the transformation of contaminants containing phenolic functionalities in the environment. In this study, we investigated the kinetics of triclosan transformation catalyzed by laccase. It was found that the rate of triclosan oxidation was first order to the concentrations of both substrate and enzyme. Humic acid (HA) could inhibit the reaction by quenching the radical intermediate of triclosan generated by laccase oxidation. Such inhibition was more significant in the presence of divalent metal cations. This is because that binding to metal ions neutralized the negative charge of HA molecules, thus making them more accessible to laccase molecule that is also negatively charged. Therefore, it has greater chance to quench the radical intermediate that is very unstable and can only diffuse a limited distance after being released from the enzyme catalytic center. Based on these understandings, a reaction model was developed by integration of metal-HA binding equilibriums and kinetic equations. This model precisely predicted the transformation rate of triclosan in the presence of HA and divalent metal ions including Ca(2+), Mg(2+), Cd(2+), Co(2+), Mn(2+), Ba(2+), and Zn(2+). Overall, this work reveals important insights into laccase catalyzed oxidative coupling process.
The purpose of the present work was to combine several tools for assessing metal pollution in marine sediments from Cienfuegos Bay. Fourteen surface sediments collected in 2013 were evaluated. Concentrations of As, Cu, Ni, Zn and V decreased respect to those previous reported. The metal contamination was spatially distributed in the north and south parts of the bay. According to the contamination factor (CF) enrichment factor (EF) and index of geoaccumulation (Igeo), Cd and Cu were classified in that order as the most contaminated elements in most sediment. Comparison of the total metal concentrations with the threshold (TELs) and probable (PELs) effect levels in sediment quality guidelines suggested a more worrisome situation for Cu, of which concentrations were occasional associated with adverse biological effects in thirteen sediments, followed by Ni in nine sediments; while adverse effects were rarely associated with Cd. Probably, Cu could be considered as the most dangerous in the whole bay because it was classified in the high contamination levels by all indexes and, simultaneously, associated to occasional adverse effects in most samples. Despite the bioavailability was partially evaluated with the HCl method, the low extraction of Ni (<3% in all samples) and Cu (<55%, except sample 3) and the relative high extraction of Cd (50% or more, except sample 14) could be considered as an attenuating (Ni and Cu) or increasing (Cd) factor in the risk assessment of those element.
Nanostructured polypyrrole (PPy) film doped with Tiron was electrodeposited from aqueous solution on the surface of transparent electrode and used for sensitive, selective and rapid electrically controlled fluorescence detection of Fe(3+) in aqueous media. The fluorescence intensity of PPy-Tiron film decreases linearly in the presence of Fe(3+) by applying negative potential over a concentration range from 5.0 × 10(-8) to 1.0 × 10(-6) mol L(-1), with a relatively fast response time of less than 30 s at pH 7.4. The detection is not affected by the coexistence of other competitive metal ions such as Al(3+), Ce(3+), Tl(3+), La(3+), Bi(3+), Cr(2+), Mn(2+), Fe(2+), Co(2+), Ni(2+), Cu(2+), Zn(2+), Cd(2+), Hg(2+), Pb(2+), Na(+), K(+), Mg(2+), Ca(2+), Sr(2+) and Ba(2+). The proposed electro-fluorescence sensor has a potential application to the determination of Fe(3+) in environmental and biological systems. The fluorescent thin film sensor was also used as a novel probe for Fe(3+)/Fe(2+) speciation in aqueous solution.
Copper and zinc are essential micronutrients in plants but, at high concentrations, they are toxic. Assisted phytoremediation is an emerging "green" technology that aims to improve the efficiency of tolerant species to remove metals from soils through the use of chelants or microorganisms. Rhizobacteria can promote plant growth and tolerance and also affect the mobility, bioavailability, and complexation of metals. A pot experiment was conducted to evaluate the phytoremediation effectiveness of sunflowers cultivated in a Cu- and Zn-spiked soil, in the presence or absence of bacterial consortium and/or chelants. The consortium was constituted of two Stenotrophomonas maltophilia strains and one of Agrobacterium sp. These strains were previously isolated from the rhizosphere of maize plants cultivated on a metal-polluted soil and here molecularly and biochemically characterized. Results showed that the consortium improved sunflower growth and biomass production on the spiked soils. Sunflowers accumulated large amounts of metals in their roots and leaves; however, neither the bacterial consortium nor the chelants, singularly added to pots, influenced significantly
 Cu and Zn plant uptake. Furthermore, the consecutive soil amendment with the EDTA and bacterial consortium determined a consistent accumulation of metals in sunflowers, and it might be an alternative strategy to limit the use of EDTA and its associated environmental risks in phytoremediation.
The present study aimed to assess the effects of anthropogenic activities on the heavy metal levels in the Langat River by transplantation of Corbicula javanica. In addition, potential ecological risk indexes (PERI) of heavy metals in the surface sediments of the river were also investigated. The correlation analysis revealed that eight metals (As, Co, Cr, Fe, Mn, Ni, Pb and Zn) in total soft tissue (TST) while five metals (As, Cd, Cr, Fe and Mn) in shell have positively and significantly correlation with respective metal concentration in sediment, indicating the clams is a good biomonitor of the metal levels. Based on clustering patterns, the discharge of dam impoundment, agricultural activities and urban domestic waste were identified as three major contributors of the metals in Pangsun, Semenyih and Dusun Tua, and Kajang, respectively. Various geochemical indexes for a single metal pollutant (geoaccumulation index (I geo), enrichment factors (EF), contamination factor (C f) and ecological risk (Er)) all agreed that Cd, Co, Cr, Cu, Fe, Mn, Ni and Zn are not likely to cause adverse effect to the river ecosystem, but As and Pb could pose a potential ecological risk to the river ecosystem. All indexes (degree of contamination (C d), combined pollution index (CPI) and PERI) showed that overall metal concentrations in the tropical river are still within safe limit. River metal pollution was investigated. Anthropogenic activities were contributors of the metal pollution. Geochemical indexes showed that metals are within the safe limit.
We investigated the enhancing effect of metal ions on several mutagens and examined their mechanism of action. We performed the Ames tests on six mutagens, i.e., 2-(2-furyl)-3-(5-nitro-2-furyl)acrylamide, 4-nitroquinoline 1-oxide (4NQO), quercetin, 2-aminoanthracene (2-AA), benzo[a]pyrene, and 3-amino-1,4-dimethyl-5H-pyrido-[4,3-b]indole, in the presence of five metal ions: Ca(II), Mg(II), Mn(II), Cu(II), and Zn(II).
Cu(II) enhanced the mutagenicity of only 4NQO and reduced the mutagenicity of the other mutagens. Zn (II) enhanced the mutagenicity of only 2-AA. To clarify the mechanism underlying the enhancing effects of Cu(II), we examined the production of reactive oxygen species (ROS) and 8-oxoguanine (8-oxoG), a DNA damage marker, in human lung carcinoma A549 cells. Cu(II) induced a remarkable increase in intracellular ROS and 8-oxoG production in the presence of 4NQO.
Our results suggest that the enhancing effect of Cu(II) and Zn(II) on the mutagenicity of specific mutagens is caused by an increase in ROS.
Zinc (Zn) plays an essential role in the human and animal body system. Zinc deficiency might cause many disorders, so it is important to provide a sufficient amount of this microelement in both animals and humans. One of the most important sources of Zn is milk. The purpose of this study was to determine whether Zn can pass through the mammary epithelial cell into milk by a co-transport system with amino acid in the lactating ewes. This experimental research included 54 lactating ewes collected from the Agriculture-Jahad Organization of Tehran Province, that were allocated into 9 groups as follows: groups which received inorganic form as Zn chloride (1, 2 and 4 mg/kg), and groups which received organic Zn with different doses of arginine or lysine (1, 2 and 4 mg/kg) in chelate form. Milk samples were taken 30 min before and 6 h after intravenous injection of Zn preparations. Zinc concentration in milk was measured using the flame atomic absorption spectrometric method. There were no significant differences (P>0.05) between groups in Zn concentration of the milk before administration of inorganic or organic Zn. Data analysis showed that administration of inorganic Zn caused a significant increase of Zn concentration in the milk in a dose dependent manner. While administration of arginine or lysine with Zn in chelate form caused a significant decline in Zn concentration of milk compared to inorganic Zn in a dose dependent manner. According to our results, administration of different forms of Zn influenced the Zn concentration in milk.
The effect of replacing dietary Zn supplemented from inorganic (ZnCO3) source with organic Zn (Zn methionine; Zn-met) was investigated in 72 rats (98.42 ± 1.483 g) by randomly allotting to 4 diets (6 replicates/diet, 3 rats/replicate). Basal diet was prepared with purified ingredients without Zn. The control diet (AIN-76A) contained 12 ppm of Zn from ZnCO3 (100-I). In the other diets ZnCO3 was replaced with Zn-met at the rates of 50 (50I:50O), 75 (25I:75O) or 100% (100-O). Weekly body weight and daily feed intake were recorded for 14 weeks. Blood was collected by retro-orbital puncture on the 70th and 80th day to determine haematological and various serum biochemical constituents, and antioxidant enzyme activities in haemolysate, respectively. Rats were antigenically challenged with sheep RBC on day 73 to assess humoral immune response (HIR), and on day 95 for cell mediated immune response (CMIR) and rats were sacrificed at the end of rearing period to collect liver, muscle, pancreas and kidneys for Zn estimation and oxidative stress markers in liver. The data were analysed using completely randomized design. Weight gain and feed intake, hematological and serum biochemical constituents, Zn content in organs (except liver) were not influenced by replacing ZnCO3 with Zn-met. Zinc concentrations in the serum and liver were higher (P<0.05) with 50% replacement of ZnCO3 with Zn-met compared to 0 or 100% replacement. Lower (P<0.05) lipid peroxidation and higher (P<0.05) glutathione peroxidase and glutathione reductase activities were observed with 50 and 75% replacement of ZnCO3 with Zn-met compared to 0 or 100% replacement. Protein carbonyls and reduced glutathione in liver were not affected, while TBARS decreased (P<0.05) with substituting Zn-met (50-100%) for ZnCO3. The HIR and CMIR increased with increasing Zn-met supplementation and the highest response was observed with 75-100% replacement of ZnCO3 with Zn-met. It is concluded that replacement of 50 or 75% of ZnCO3 with Zn-met increased antioxidant and immune response in rats with no effect on growth.
A homozygous mutation in the gene for sigma 1 receptor (Sig1R) is a cause of inherited juvenile amyotrophic lateral sclerosis (ALS16). Sig1R localizes to the mitochondria-associated membrane (MAM), which is an interface of mitochondria and endoplasmic reticulum. However, the role of the MAM in ALS is not fully elucidated. Here, we identified a homozygous p.L95fs mutation of Sig1R as a novel cause of ALS16. ALS-linked Sig1R variants were unstable and incapable of binding to inositol 1,4,5-triphosphate receptor type 3 (IP3R3). The onset of mutant Cu/Zn superoxide dismutase (SOD1)-mediated ALS disease in mice was accelerated when Sig1R was deficient. Moreover, either deficiency of Sig1R or accumulation of mutant SOD1 induced MAM disruption, resulting in mislocalization of IP3R3 from the MAM, calpain activation, and mitochondrial dysfunction. Our findings indicate that a loss of Sig1R function is causative for ALS16, and collapse of the MAM is a common pathomechanism in both Sig1R- and SOD1-linked ALS Furthermore, our discovery of the selective enrichment of IP3R3 in motor neurons suggests that integrity of the MAM is crucial for the selective vulnerability in ALS.
A new terpyridine-diphos hybrid ligand [4'-{p-(Ph2P)2NC6H4}-2,2':6'2''-terpy] (1) and its Ru(II), Pd(II), Au(I) and Zn(II) complexes are described. Preliminary studies on absorption and emission properties are also reported.
Monovalent Zn(+) (3d(10)4s(1)) systems possess a special electronic structure that can be exploited in heterogeneous catalysis and photocatalysis, though it remains challenge to synthesize Zn(+)-containing materials. By careful design, Zn(+)-related species can be synthesized in zeolite and layered double hydroxide systems, which in turn exhibit excellent catalytic potential in methane, CO and CO2 activation. Furthermore, by utilizing advanced characterization tools, including electron spin resonance, X-ray absorption fine structure and density functional theory calculations, the formation mechanism of the Zn(+) species and their structure-performance relationships can be understood. Such advanced characterization tools guide the rational design of high-performance Zn(+)-containing catalysts for efficient energy conversion.
In many nations industrial scale AD of non-agricultural waste materials (such as MSW) has not yet reached its full potential, often constrained by the lack of secure, inexpensive, high quality AD feedstocks, and markets for the resulting digestate material. We tested the output material of a high throughput novel industrial process to define its potential as an AD feedstock (based on quality and consistency). This process, designed to circumvent the constraints of source segregation while still generating segregated waste streams, resulted in the production of a temporally homogenous fibrous material with: an average moisture content of 44.2 (±2.33)%; C:N ratio of ∼32.9:1 (±3.46:1), C:P ratio of ∼228:1 and gross calorific value of 17.4 (±0.29)MJ/kg(DM). This material provided a CH4 yield of between 201 and 297m(3) CH4/tonne(DM) (271-401m(3)CH4/tonne(vs)) comparable to commonly used AD feedstocks. Material contaminant levels were temporally consistent (P>0.05), (average values being Cd 0.63 (±0.19), Cu 56.3 (±7.45), Cr(tot) 51.4 (±4.41), Hg<0.3, Ni 28.9 (±5.17), Pb 79.2 (±23.71), Zn 202 (±44.5), total polyaromatic hydrocarbons
 (PAH) 2.2 (±0.3), and total polychlorinated biphenyls (PCB) (<0.2)mg/kg(DM)). Calculated digestate contaminant levels were below the median contaminant threshold limits for anaerobic digestates of all countries within the European Union i.e. of Cd 3.35, Cu 535, Cr(tot) 535, Hg 8.15, Ni 185, Pb 397.5, Zn 2100mg/kg(DM). We suggest that novel high throughput processes that produce high quality AD feedstocks, may have a place in further diversion of waste from landfill.
In this study, different types of indices were used to assess the ecological risk of trace metal contamination in sediments on the basis of sediment quality guidelines at Veraval Fishery Harbor. Sediment samples were collected from three sectors in pre-, post-, and monsoon seasons in 2006. Trace metal concentrations were higher in the inner sector during post-monsoon, and it showed the highest statistical significance (p<0.01) among the stations. Pollution load index was higher than unity, indicating alternation by effluent discharge from industries. Enrichment factor and geo-accumulation index showed that Cd, Pb, and Zn were enriched in the northern part of the harbor and Pb had accumulated in the harbor sediment. The ecological risk assessment index revealed that Ni, Zn, and Pb were higher than the effect range median values, indicating their potential toxicity to the aquatic environment in the Veraval Harbor. Hence, the harbor is dominated by anthropogenic activities rather than natural process.
An incubation experiment was conducted to investigate the response of ammonia-oxidizing bacteria (AOB), ammonia-oxidizing archaea (AOA), and the nitrification rate to the contamination of Cu, Zn, and Cd in two New Zealand grassland soils. The soils spiked with different concentrations of Cu (20 and 50 mg kg(-1)), Zn (20 and 50 mg kg(-1)), and Cd (2 and 10 mg kg(-1)) were incubated for 14 days and then treated with 500 mg kg(-1) urine-N before continuing incubation for a total of 115 days. Soils were sampled at intervals throughout the incubation. The nitrification rate in soils at each sampling period was determined, and the abundance of AOB and AOA was measured by real-time quantification polymerase chain reaction (qPCR) assay of the amoA gene copy numbers. The results revealed that moderate trace metal stress did not significantly affect the abundance of AOB and AOA in the two soils, probably due to the high organic matter content of the soils which would have reduced the toxic effect of the metals. Nitrification rates were much greater and the observable nitrification period was much shorter in the dairy farm (DF) soil, in which the AOB and AOA abundances were greater than those of the mixed cropping farm (MF) soil. AOB were shown to grow under high nitrogen conditions, whereas AOA were shown to grow under low N environments, with different metal concentrations. Therefore, nitrogen status rather than metal applications was the main determining factor for AOB and AOA growth in the two soils studied.
The aim of this study was to evaluate the use of tree barks as a bioindicator of atmospheric pollution in areas of contrasting population densities and to associate the levels of elements found in this bioindicator with those obtained in fingernail samples collected from students living in the same study areas. Tree bark samples were collected from urban areas near highways in regions with high (Area A), intermediate (Area B), and low (Area C) population densities of Porto Alegre, Brazil, and evaluated for chemical elements concentration. Since these areas also differed in traffic density, NO2 was measured by passive sampling. For a comparative purpose, the elements were also determined in fingernail samples collected from students living in the same areas. Accumulated elements were determined by inductively coupled plasma mass spectrometry (ICP-MS) and principal component analysis (PCA) was used as a tool in exploratory data analysis to identify possible sources. We found that Ba, Cd, Co, Cu, Mg, Mn, Ni, Pb, Sb, Sr, V, and Zn were at higher concentrations in tree barks in Area A, while Cd, Co, Cu, Mg, Mn, Ni, and Sr were at higher levels in students' fingernails of Area A as well. Furthermore, concentrations of elements found in barks were associated with those identified in fingernails collected from students living in the same areas. PCA demonstrated that vehicular traffic explained 66.4 % of the variance in tree bark and 50.8 % of the variance in fingernails. NO2 levels were significantly different among the areas, what is consistent with their respective vehicular flow and population density. In conclusion, we found conformance of elements levels accumulated in barks and fingernails at three monitoring areas with different profiles. The amount of traffic-related elements accumulated appears to be associated with the degree of urbanization and vehicular flow. Overall, data suggests a relationship between fingernails and tree bark as bioindicators of exposure to metals from air pollution.
The complexes of Fe(II), Cd(II) and Zn(II) with Schiff base derived from 2-amino-3-hydroxypyridine and 3-methoxysalicylaldehyde have been prepared. Melting points, decomposition temperatures, Elemental analyses, TGA, conductance measurements, infrared (IR) and UV-Visible spectrophotometric studies were utilized in characterizing the compounds. The UV-Visible spectrophotometric analysis revealed 1:1 (metal-ligand) stoichiometry for the three complexes. In addition to, the prepared complexes have been used as precursors for preparing their corresponding metal oxides nanoparticles via thermal decomposition. The structures of the nano-sized complexes and their metal oxides were characterized by X-ray powder diffraction and transmittance electron microscopy. Moreover, the prepared Schiff base ligand, its complexes and their corresponding nano-sized metal oxides have been screened in vitro for their antibacterial activity against three bacteria, gram-positive (Microccus luteus) and gram-negative (Escherichia coli, Serratia marcescence) and three strains of fungus. The metal chelates were shown to possess more antimicrobial activity than the free Schiff-base chelate and their nano-sized metal oxides have the highest activity. The binding behaviors of the complexes to calf thymus DNA have been investigated by absorption spectra, viscosity mensuration and gel electrophoresis. The DNA binding constants reveal that all these complexes interact with DNA through intercalative binding mode. Furthermore, the cytotoxic activity of the prepared Schiff base complexes on human colon carcinoma cells, (HCT-116 cell line) and hepatic cellular carcinoma cells, (HepG-2) showed potent cytotoxicity effect against growth of carcinoma cells compared to the clinically used Vinblastine standard.
Odonata larvae are frequently used to assess the contamination of aquatic systems, because they tolerate a wide range of chemical and biological conditions in freshwater systems. In early 2000, the sediments of the Hungarian section of the River Tisza and the River Szamos were strongly enriched with heavy metals by an accidental mining spill. Earlier studies demonstrated higher contamination levels in the Szamos than in the Tisza, based on sediment analysis. The aim of our study was to assess the contamination in the Upper Tisza Region, along the upper reach of the Tisza, and the lower reach of the Szamos, based on the trace element concentrations of the Gomphus flavipes larvae. We collected 269 dragonfly specimens for the analyses. The Al, Ba, Cr, Cu, Fe, Mn, Pb, Sr and Zn element contents were analysed in the dragonfly larvae by microwave plasma atomic emission spectrometry (MP-AES). Significantly higher Ba and Cu concentrations were found in the dragonfly larvae of the Tisza than the Szamos. In spite of this, the Cr, Mn, Pb, Sr and Zn concentration was significantly lower in the dragonfly larvae of the Tisza than the Szamos. For all trace elements significant differences were found along the Tisza. Significant differences were also found in all trace element concentrations of dragonfly larvae among studied localities in the Szamos, except in the cases of Al and Ba. Our results demonstrated that the Szamos was more contaminated with Cr, Mn, Pb, Sr and Zn than the Tisza, but that the Tisza was more contaminated with Ba and Cu than the Szamos, based on the trace element concentrations in Gomphus flavipes larvae, which was likely to have been caused by the tributaries of the Tisza. In summary, our results indicated a continuous pollution of the Tisza and the Szamos and their tributaries.
This study provided the first hand data of trace elements into fish muscles (N = 65) collected from river Chenab in Pakistan during 2013, using inductively coupled plasma mass spectrometry (ICP-MS). We monitored the health risk associated with consumption of contaminated fish of river Chenab, by the local population. The mean concentrations (μg/g, wet weight), in descending order were: Zn (35.5-54.4), Cu (1.38-4.57), Mn (2.43-4.5), As (0.23-1.21), Cr (0.21-0.67), Ni (0.14-0.34), Pb (0.14-0.31), Co (0.09-0.12), Cd (0.07-0.12) with higher concentration to be observed in the herbivore fish species (i.e., Cirrhinus reba and Catla catla). The levels of trace elements in different fish species found in this study were compared with similar data worldwide, and with the international standards for consumption. The concentration (μg/g) of arsenic in many cases (>65%) exceeded the FAO/WHO expert committee on food additives permissible limits. From the human health point of view, this study highlights that the local inhabitants, (i.e., fisher folk communities and population frequently consuming fish at about 100 g/day) along the river Chenab are exposed chronically to arsenic pollution with carcinogenic (10(-4) to 10(-6)) and non-carcinogenic
 (THQ>1) risks, especially from the intake of Cirrhinus reba.
A number of studies present the utilization of fly ashes from municipal solid waste incineration (MSWI) in cement production as a recycling alternative to landfilling. While there is a lot of research on the impact of MSWI fly ashes utilization in cement production on the quality of concrete or the leaching of heavy metals, only a few studies have determined the resulting heavy metal content in cements caused by this MSWI fly ashes utilization. Making use of the case of Austria, this study (1) determines the total content of selected heavy metals in cements currently produced in the country, (2) designs a scenario and calculates the resulting heavy metal contents in cements assuming that all MSWI fly ashes from Austrian grate incinerators were used as secondary raw materials for Portland cement clinker production and (3) evaluates the legal recyclability of demolished concretes produced from MSWI fly ash amended cements based on their total heavy metal contents. To do so, data from literature and statistics are combined in a material flow analysis model to calculate the average total contents of heavy metals in cements and in the resulting concretes according to the above scenario. The resulting heavy metal contents are then compared (i) to their respective limit values for cements as defined in a new technical guideline in Austria (BMLFUW, 2016), and (ii) to their respective limit values for recycling materials from demolished concrete. Results show that MSWI fly ashes utilization increases the raw material input in cement production by only +0.9%, but the total contents of Cd by +310%, and Hg, Pb, and Zn by +70% to +170%. However these and other heavy metal contents are still below their respective limit values for Austrian cements. The same legal conformity counts for recycling material derived from concretes produced from the MSWI fly ash cements. However, if the MSWI fly ash ratio in all raw materials used for cement production were increased from 0.9% to 22%, which is suggested by some studies, the limit values for cements as defined by the BMLFUW (2016) will be exceeded. Furthermore, the concrete produced from this cement will not be recyclable anymore due to its high total heavy metal contents. This and the comparatively high contribution of MSWI fly ashes to total heavy metal contents in cements indicate their relatively low resource potential if compared to other secondary raw materials in the cement industry.
As a nutritionally essential metal ion, zinc (Zn) not only constitutes a structural element for more than 3000 proteins but also plays important regulatory functions in cellular signal transduction. Zn homeostasis is tightly controlled by regulating the flux of Zn across cell membranes through specific transporters, i.e. ZnT and ZIP family proteins. Zn deficiency and malfunction of Zn transporters have been associated with many chronic diseases including cancer. However, the mechanisms underlying Zn regulatory functions in cellular signaling and their impact on the pathogenesis and progression of cancers remain largely unknown. In addition to these acknowledged multifunctions, Zn modulates a wide range of ion channels that in turn may also play an important role in cancer biology. The goal of this review is to propose how zinc deficiency, through modified Zn homeostasis, transporter activity and the putative regulatory function of Zn can influence ion channel activity, and thereby contribute to carcinogenesis and tumorigenesis. This review intends to stimulate interest in, and support for research into the understanding of Zn-modulated channels in cancers, and to search for novel biomarkers facilitating effective clinical stratification of high risk cancer patients as well as improved prevention and therapy in this emerging field.
While the spatial distributions of heavy metals in farmland soil of China have been comprehensively delineated, their temporal trends are rarely investigated but are important for environmental risk management. In this study, the current status and temporal trends of heavy metals in the farmland soil of Yangtze River Delta (YRD) were evaluated through field survey and meta-analysis. The field survey conducted in 2014 showed that the concentrations of Cd, Pb, Cu, Zn, and Ni in the farmland topsoil were 0.23 ± 0.14, 37.63 ± 15.60, 25.83 ± 41.62, 88.38 ± 43.30, and 29.21 ± 12.41 mg kg(-1) (mean ± standard deviation), respectively. The heavy metals showed relatively higher concentrations on the borders among Zhejiang, Jiangsu, and Shanghai. In the meta-analysis, we selected 68 published studies related to heavy metal pollution in farmland topsoil of YRD from 2000 to the year (2014) when the field survey was conducted. The results show an increasing trend for Cd (p < 0.05; 0.0081 mg kg(-1) year(-1)), a decreasing trend for Cu (p < 0.05; -0.80 mg kg(-1) year(-1)), and no significant trend for Pb (p = 0.155), Zn (p = 0.746), and Ni (p = 0.305). The increasing rate of Cd from the meta-analysis is consistent with the rate (0.0013 mg kg(-1) year(-1)) derived from the mass balance calculation for Cd, where atmospheric deposition originated from intensive coal combustion is considered as the main source of Cd in the topsoil. The decreasing trend of Cu is likely due to largely reduced application of copper-based agrochemicals. Environmental regulation and soil remediation are needed to protect food safety and ecosystem from heavy metal pollution, especially Cd.
Although a considerable research effort has gone into studying the dietary pathways of metals to the bodies of laying female birds and their eggs in recent years, no detailed investigations have yet been carried out relating the properties of the biogeochemical environment at large spatial scales to eggshell trace element levels in typical soil-invertebrate feeding birds under natural conditions. We used data from a large-scale nationwide monitoring survey of soil quality in Poland (3724 sampling points from the 43 792 available) to predict levels of five trace elements (copper [Cu], cadmium [Cd], nickel [Ni], zinc [Zn] and lead [Pb]) in Rook Corvus frugilegus eggshells from 42 breeding colonies. Our major aim was to test whether differences exist in the explanatory power of soil data (acidity, content of elements and organic matter, and particle size) used as a correlate of concentrations of eggshell trace elements among four different distances (5, 10, 15 and 20 km) around rookeries. Over all four distances around the rookeries only the concentrations of Cu and Cd in eggshells were positively correlated with those in soil, while eggshell Pb was correlated with the soil Pb level at the two longest distances (15 and 20 km) around the rookeries. The physical properties of soil (primarily the increase in pH) adversely affected eggshell Cd and Pb concentrations. The patterns and factors governing metal bioaccumulation in soil invertebrates and eggshells appear to be coincident, which strongly suggests a general similarity in the biochemical pathways of elements at different levels of the food web. The increasing acidification of arable soil as a result of excessive fertilisation and over-nitrification can enhance the bioavailability of toxic elements to laying females and their eggs.
To explore the mechanisms and influence factors on the production of 2,4,6-trichloroanisole (2,4,6-TCA) in surface waters, the 2,4,6-TCA formation potential (FP) test was conducted by incubating the real lake water with the addition of 2,4,6-trichlorophenol (2,4,6-TCP) precursor. Besides bacteria and fungi, two common cyanobacteria and algae species, i.e., Chlorella vulgaris and Anabaena flos-aquae, have been proved to have strong capabilities to produce 2,4,6-TCA, which may contribute the high 2,4,6-TCA FP (152.2 ng/L) of lake water. The microbial O-methylation of 2,4,6-TCP precursor is catalyzed by chlorophenol O-methyltransferases (CPOMTs), and their characteristics were identified by adding inductive methyl donors or excluding microorganisms via ultrafiltration. The results indicated both S-adenosyl methionine (SAM) dependent and non-SAM dependent CPOMTs played important roles; extracellular CPOMTs also participated in the biosynthesis of 2,4,6-TCA. Moreover, investigating the effects of various environmental factors revealed initial 2,4,6-TCP processor concentration, temperature, pH and some divalent metal cations (i.e., Mn(2+), Mg(2+) and Zn(2+)) had obvious effects on the production of 2,4,6-TCA.
The present paper is the first documentation of distribution and contamination status of environmentally important elements of superficial sediments in the Batticaloa lagoon that is connected to the largest bay of the world. Surface sediment samples were collected from 34 sites covering all over the lagoon. Concentrations of elements such as As, Cr, Cu, Fe, Nb, Ni, Pb, Sc, Sr, Th, V, Y, Zn, and Zr were measured by X-ray florescence analysis. Geochemically, the lagoon has three different zones that were influenced mainly by fresh water sources, marine fronts, and intermediate mixing zones. The marine sediment quality standards indicate that Zr and Th values are exceeded throughout the lagoon. According to the freshwater sediment quality standards, Cr levels of all sampling sites exceed the threshold effect level (TEL) and 17 % of them are even above the probable effect level (PEL). Most sampling sites of the channel discharging areas show minor enrichment of Cu, Ni, and Zn with respect to the TEL. Contamination indices show that the lagoon mouth area is enriched with As. Statistical analysis implies that discharges from agricultural channel and marine fluxes of the lagoon effects on the spatial distribution of measured elements. Further research is required to understand the rate of contamination
 in the studied marine system.
Due to environmental pollution, wild animals are exposed to various pollutants. Some game animals, such as wild boars are used by people for food, but their meat is not evaluated regarding pollution transfer, since they are unavailable on the official market. The aim of this paper is to present the concentrations of chosen metals (Cd, Co, Cu, Hg, Pb, and Zn) in the kidneys, liver, and muscles of wild boars (n = 40) hunted in eastern Slovakia, as derivatives of physiological distribution and anthropogenic pollution. We found that sex was not a statistically significant factor for metal concentrations. Tissue differences were observed for all the metals studied except for Co. Cd, Cu, and Hg showed the highest median concentrations in kidney tissue with the lowest in muscle tissue (2.73, 3.78, and 0.061 μg/g w.w., respectively). The highest Zn median concentration was noted in the liver tissue with the lowest in muscle tissue. Co and Cu concentrations varied according to the age groups. Correlations between metal concentrations in muscle and kidney tissue were not especially strong; such relationships were not found in liver tissue. Among all the potential relationships of the given metal concentrations between tissues, the only significant relationship, albeit weak, was noted for Pb in muscle and liver tissue. The concentrations found seem not to be extremely high, but according to EU maximum permitted residue levels for Cd and Pb concentrations in meat, none of the samples studied was fully fit for human consumption. TWI and risk was also excessive for both metals.
Carotenoids and phenolic profile, antioxidant activity as well as concentrations of selected macronutrients (K, N, Mg, Ca and Na) and micronutrients (Zn, Cu and Mn) in flesh and peel of peach fruit were recorded at two harvest dates. Predominant mineral was potassium, followed by calcium, magnesium and sodium. The concentration of most micronutrients was greater in the peel than in the flesh especially in early season. The concentration of most elements in flesh and peel decreased during fruit maturation. Total carotenoids content varied with respect to the cultivar. β-cryptoxanthin and β-carotene were the major carotenoids in both tissues and flesh contain the lowest amounts. Neochlorogenic acid, chlorogenic acid, catechin, epicatechin, gallic acid, rutin, quercetin-3-O-galactoside, cyanidin-3-O-glucoside, cyanidin-3-O-rutinoside, were detected in both peel and flesh, with chlorogenic acid and catechin being the predominant components. Peel extracts showed markedly higher antioxidant activities, when estimated by ABTS or DPPH assays, than the flesh counterparts, consistent with the observed higher phenolic content. Overall, total phenolics levels increased at full ripening stage in both peel and flesh. The results found herein provide important data on carotenoids, phenolic and macro- and micronutrient changes during fruit growth, and emphases peach fruit as a potential functional food.
High pressure frozen (HPF), cryo-substituted microtome sections of 2 μm thickness containing human neutrophils (white blood cells) were analyzed using synchrotron radiation based X-ray fluorescence (SR nano-XRF) at a spatial resolution of 50 nm. Besides neutrophils from a control culture, we also analyzed neutrophils stimulated for 1-2 h with phorbol myristate acetate (PMA), a substance inducing the formation of so-called Neutrophil Extracellular Traps (or NETs), a defense system again pathogens possibly involving proteins with metal chelating properties. In order to gain insight in metal transport during this process, precise local evaluation of elemental content was performed reaching limits of detection (LODs) of 1 ppb. Mean weight fractions within entire neutrophils, their nuclei and cytoplasms were determined for the three main elements P, S and Cl, but also for the 12 following trace elements: K, Ca, Mn, Fe, Co, Ni, Cu, Zn, Se, Br, Sr and Pb. Statistical analysis, including linear regression provided objective analysis and a measure for concentration changes. The nearly linear Ca and Cl concentration changes in neutrophils could be explained by already known phenomena such as the induction of Ca channels and the uptake of Cl under activation of NET forming neutrophils. Linear concentration changes were also found for P, S, K, Mn, Fe, Co and Se. The observed linear concentration increase for Mn could be related to scavenging of this metal from the pathogen by means of the neutrophil protein calprotectin, whereas the concentration increase of Se may be related to its antioxidant function protecting neutrophils from the reactive oxygen species they produce against pathogens. We emphasize synchrotron radiation based nanoscopic X-ray fluorescence as an enabling analytical technique to study changing (trace) element concentrations throughout cellular processes, provided accurate sample preparation and data-analysis.
Due to their strong coordination ability and the diversities of their coordination modes, N-heterocyclic organic compounds are used extensively as ligands for the construction of complexes with fascinating structures and potential applications in many fields. Two new complexes, namely bis{1-[(benzotriazol-1-yl)methyl]-1H-imidazole-κN(3)}dibromidozinc(II), [ZnBr2(C10H9N5)2], (I), and bis{1-[(benzotriazol-1-yl)methyl]-1H-imidazole-κN(3)}diiodidozinc(II), [ZnI2(C10H9N5)2], (II), have been synthesized by reaction of the unsymmetrical N-heterocyclic ligand 1-[(benzotriazol-1-yl)methyl]-1H-imidazole (bmi) with Zn(acetate)2 in the presence of KBr or KI. Single-crystal X-ray diffraction analysis shows that both complexes exhibit a mononuclear structure, in which the bmi ligands coordinate to the central metal ion in a monodentate mode. In the solid state, both complexes possess a three-dimensional network formed by hydrogen bonds and π-π interactions. In addition, the IR spectroscopic properties, PXRD patterns and fluorescence properties of both complexes have been investigated.
Severe zinc deficiency is associated with an increased systemic inflammatory response and mortality after sepsis. However, the impact of mild zinc deficiency, which is more common in populations with chronic illnesses and sepsis, is unknown. In this study, we hypothesized that marginal dietary Zn deprivation (ZM) would amplify tissue inflammation and exacerbate the sepsis-induced decrease in muscle protein synthesis. Adult male C57BL/6 mice were fed a zinc-adequate (ZA) or ZM diet (30 or 10 mg Zn/kg, respectively) over 4 weeks, peritonitis was induced by cecal ligation and puncture (CLP), and mice were examined at either 24 h (acute) or 5 days (chronic) post-CLP Acute sepsis decreased the in vivo rate of skeletal muscle protein synthesis and the phosphorylation of the mTOR substrate 4E-BP1. Acutely, sepsis increased TNF-α and IL-6 mRNA in muscle, and the increase in TNF-α was significantly greater in ZM mice. However, muscle protein synthesis and 4E-BP1 phosphorylation returned to baseline 5 days post-CLP in both ZA and ZM mice. Protein degradation via markers of the ubiquitin proteasome pathway was increased in acute sepsis, yet only MuRF1 mRNA was increased in chronic sepsis and ZM amplified this elevation. Our data suggest that mild zinc deficiency increases TNF-α in muscle acutely after sepsis but does not significantly modulate the rate of muscle protein synthesis.
This study links changes in the tobacco endogenous metal-homeostasis network caused by transgene expression with engineering of novel features. It also provides insight into the concentration-dependent mutual interactions between Zn and Cd, leading to differences in the metal partitioning between wild-type and transgenic plants. In tobacco, expression of the export protein AtHMA4 modified Zn/Cd root/shoot distribution, but the pattern depended on their concentrations in the medium. To address this phenomenon, the expression of genes identified by suppression subtractive hybridization and the Zn/Cd accumulation pattern were examined upon exposure to six variants of low/high Zn and Cd concentrations. Five tobacco metal-homeostasis genes were identified: NtZIP2, NtZIP4, NtIRT1-like, NtNAS, and NtVTL. In the wild type, their expression depended on combinations of low/high Zn and Cd concentrations; co-ordinated responses of NtZIP1, NtZIP2, and NtVTL were shown in medium containing 4 µM Cd, and at 0.5 µM versus 10 µM Zn. In transgenics, qualitative changes detected for NtZIP1, NtZIP4, NtIRT1-like, and NtVTL are considered crucial for modification of Zn/Cd supply-dependent Zn/Cd root/shoot distribution. Notwithstanding, NtVTL was the most responsive gene in wild-type and transgenic plants under all concentrations of Zn and Cd tested; thus it is a candidate gene for the regulation of metal cross-homeostasis processes involved in engineering new metal-related traits.
The present study investigated the levels of As, Cd, Cr, Cu, Hg, Mn, Ni, Pb and Zn in the seagrasses Posidonia oceanica and Cymodocea nodosa, and in the wetland macrophytes Phragmites australis, Arundo donax, Typha domingensis, Apium nodiflorum, and Nasturtium officinale. Results showed that the bioaccumulation capacity from sediments, translocation, total levels in plant tissues, and bioindication of metals in sediments, are generally species-specific. In particular, the patterns of metals in the aquatic plants studied were overall independent of ecology (coasts vs wetlands), biomass, anatomy (rhizomatous vs non rhizomatous plants), and life form (hemicrytophytes vs hydrophytes). However, marine phanerogams and wetland macrophytes shared some characteristics such as high levels of heavy metals in their below-ground organs, similar capacity of element translocation in the rhizosphere, compartmentalization of metals in the different plant organs,
 and potential as bioindicators of Cu, Mn and Zn levels in the substratum. In particular, the present findings indicate that, despite ecological and morphological similarities, different plant species tend to respond differently to exposure to heavy metals. Furthermore, this seems to result from the species individual ability to accumulate and detoxify the various metals rather than being attributed to differences in their ecological and morpho-anatomical characteristics.
In order to better understand the risk to students' health caused by pollution derived from fine particulate matter with an aerodynamic diameter <2.5mm (PM2.5), this study collected 189 samples in one outdoor and four different functional indoor environments of a research center in a university campus. Trace metals (TMs) bound to PM2.5 in outdoor and indoor environments were measured using X-ray fluorescence spectrometry. The TMs measured were: As, Co, Cd, Cr, Ni, Cu, Zn, Mn, Hg, and Pb. The measurements of PM2.5-bound TMs before and during the 2015 Spring Festival held in Northeast China were compared. Results showed that pollution due to PM2.5-bound TMs in outdoor and indoor environments was higher before than during the Spring Festival. Cu (in three indoor environments) and Zn (in an outdoor environment) showed the highest concentrations among the ten TMs that were measured. Hg showed the lowest concentrations in all the environments analyzed. The concentrations of PM2.5-bound TMs declined among four indoor environments in the following order: the atrium, the students' office (sampled just nine days before the Spring Festival), the laboratory, and an empty room. The potential carcinogenic and non-carcinogenic health risks derived from PM2.5-bound TMs were within safe limits for graduate and undergraduate students, according to the standards established by the United States Environmental Protection Agency (USEPA).
This study quantifies the concentration of trace metals in coastal marine macrophytes (seagrasses, Chlorophytae, Phaeophytae and Rhodophytae). We do so by compiling, from 155 peer review research articles, almost 23,000 estimates of trace metals (As, Cd, Co, Cr, Cu, Fe, Hg, Mn, Ni, Pb and Zn) contents in natural populations of marine macroalgae and seagrasses distributed worldwide. The objective was to explore the global distribution of concentrations of these metals in marine macrophytes, provide an estimate of their average and range in its tissues and to identify hotspots of coastal pollution. Our results reveal Phaeophytae as the group with the largest accumulation capacity and tolerance to elevated concentrations of metals regardless the species and the location. The mapping of geographic distribution of metal accumulation in marine macrophytes identifies some coastal areas as hotspots of trace metal contamination, where concentrations could reach levels up to 600 times higher than the mean.
Mg removal from chlorophyll by Mg-dechelatase is the first step of chlorophyll degradation. Recent studies showed that in Arabidopsis, Stay Green (SGR) encodes Mg-dechelatase. Though the Escherichia coli expression system is advantageous for investigating the properties of Mg-dechelatase, Arabidopsis Mg-dechelatase is not successfully expressed in E. coli. Chlamydomonas reinhardtii SGR (CrSGR) has a long, hydrophilic tail, suggesting that active CrSGR can be expressed in E. coli. After the incubation of chlorophyll a with CrSGR expressed in E. coli, pheophytin a accumulated, indicating that active CrSGR was expressed in E. coli. Substrate specificity of CrSGR against chlorophyll b and an intermediate molecule of the chlorophyll b degradation pathway was examined. CrSGR exhibited no activity against chlorophyll b and low activity against 7-hydroxymethyl chlorophyll a, consistent with the fact that chlorophyll b is degraded only after conversion to chlorophyll a. CrSGR exhibited low activity against divinyl chlorophyll a and chlorophyll a', and no activity against chlorophyllide a, protochlorophyll a, chlorophyll c2, and Zn-chlorophyll a. These observations indicate that chlorophyll a is the most favorable substrate for CrSGR. When CrSGR was expressed in Arabidopsis cells, the chlorophyll content decreased, further confirming that SGR has Mg-dechelating activity in chloroplasts.
The main objective of this study was to assess the concentration of various heavy metals (Cd, Pb, Zn, Cu, Hg) in the blood of sheep, followed by biochemical and hematological analysis in order to reveal possible associations. Blood was collected in two different seasons: winter (fed by fodder) and spring (grazing animals). The higher concentrations of Pb (p < 0.01), Cu (p < 0.05) and Hg, but lower of Cd and Zn were found in spring. Evaluation of the biochemical and hematological parameters during different seasons showed a possible environmental effect on the health of animals. A statistically significant increase of Ca (p < 0.001), Mg (p < 0.05), urea (p < 0.001), TP (p < 0.05), glucose (p < 0.01), AST (p < 0.001), ALT (p < 0.001), ALP (p < 0.01), cholesterol (p < 0.001), bilirubin (p < 0.05), triglycerides (p < 0.001) and a decrease of P (p < 0.05), HGB (p < 0.05), MCHC (p < 0.05) and RDWc (p < 0.05) in spring was detected. The results of this study showed statistically significant correlations between Pb and ALP (r = 0.53) level in winter and between Pb and Ca (r = -0.73) in the spring. The hematological analysis revealed a significant correlation between Zn and RBC (r = 0.61), MCV (r = -0.74), MCH (r = -0.71) and between Pb and MCH (r = -0.55), PCT (r = -0.66), PDWC (r = -0.55) in the winter. A high positive significant correlations were found between Cd and RDWC (r = 0.77) and Cu and RDWC (r = 0.75). The significance of this work is the use the data in the preventive diagnosis of metabolic and production diseases. The collected data may serve as a control indicator to detect toxic hazards related to the heavy metal occurrence on animal health status.
Mixed oxides of zinc and cadmium with different proportions were deposited on ordinary glass substrates using the sol-gel spin coating method under optimized deposition conditions using zinc acetate dihydrate and cadmium acetate dihydrate as precursors. X-ray diffraction patterns confirmed the polycrystalline nature of the films. A combination of cubic CdO and hexagonal wurtzite ZnO phases was observed. The oxidation states of Zn, Cd and O in the deposited films were determined by X-ray photoelectron spectroscopic studies. Surface morphology was studied by scanning electron microscopy and atomic force microscopy. The compositional analysis of the thin films was studied by secondary ion mass spectroscopy. The transmittance of the thin films was measured in the range 300-800nm and the optical bandgap was calculated using Tauc's plot method. The bandgap decreased from 3.15eV to 2.15eV with increasing CdO content. The light emission properties of the ZnO:CdO thin films were studied by photoluminescence spectra recorded at room temperature. The current-voltage characteristics were also assessed and showed ohmic behaviour. The resistance decreased with increasing CdO content.
The P2X7 receptor (P2X7R) is an ATP-gated ion channel that is a key player in oxidative stress under pathological conditions. The P2X7R is expressed in the retinal pigmented epithelium (RPE) and neural retina. Chronic oxidative stress contributes to the pathogenesis of age-related macular degeneration (AMD). Mice lacking Cu, Zn superoxide dismutase (Sod1) developed chronic oxidative stress as well as AMD-like features, but whether the P2X7R plays a causative role in oxidative stress-induced AMD is unknown. Thus, the main purpose of this study was to test if concurrent knockout (KO) of P2X7R could block AMD-like defects seen in Sod1 KO mice. Using multiple approaches, we demonstrate that Sod1 KO causes AMD-like defects, including positive staining for oxidative stress markers, 3-nitrotyrosine and carboxymethyl lysine, thinning of the RPE and retina, thickening of Bruch's membrane, presence of basal laminar and linear deposits, RPE barrier disruption and accumulation of microglia/macrophages. Moreover, we find that Sod1 KO mice accumulate more microparticles (MPs) within RPE/choroid tissues. Concurrent KO of the P2X7R protects against AMD-like defects and MP accumulation in Sod1 KO mice. Together, we show for the first time, that deficiency of P2X7R prevents in vivo oxidative stress-induced accumulation of MPs and AMD-like defects. This work could potentially lead to novel therapies for AMD and other oxidative stress-driven diseases.
We investigated the impact of zinc oxide nanoparticles (ZnO NPs; 1000mgkg(-1) soil) on soil microbes and their associated soil functions such as date palm (Phoenix dactylifera) leaf litter (5gkg(-1) soil) carbon and nitrogen mineralization in mesocosms containing sandy soil. Nanoparticles application in litter-amended soil significantly decreased the cultivable heterotrophic bacterial and fungal colony forming units (cfu) compared to only litter-amended soil. The decrease in cfu could be related to lower microbial biomass carbon in nanoparticles-litter amended soil. Likewise, ZnO NPs also reduced CO2 emission by 10% in aforementioned treatment but this was higher than control (soil only). Labile Zn was only detected in the microbial biomass of nanoparticles-litter applied soil indicating that microorganisms consumed this element from freely available nutrients in the soil. In this treatment, dissolved organic carbon and mineral nitrogen were 25 and 34% lower respectively compared to litter-amended soil. Such toxic effects of nanoparticles on litter decomposition resulted in 130 and 122% lower carbon and nitrogen mineralization efficiency respectively. Hence, our results entail that ZnO NPs are toxic to soil microbes and affect
 their function i.e., carbon and nitrogen mineralization of applied litter thus confirming their toxicity to microbial associated soil functions.
The aim of this study was to determine the concentrations of oxidative stress parameters and DNA damage in horses infected by Theileria equi. Initial screening of 110 horses with duplex PCR enabled the selection of 30 infected horses with T. equi and 30 free of infection (control). Specimens from the 60 horses were further analysed by determining the following oxidative stress parameters: extent of haemolysis (EH), plasma free haemoglobin (PHb), catalase (CAT), Cu,Zn superoxide dismutase (SOD1), paraoxonase (PON1), nitrite (NO2(-)), total nitrate and nitrite (NOx), malondialdehyde (MDA) and free thiol groups (-SH). In addition, relative distribution of lactate dehydrogenase (LDH1-LDH5) activity and the DNA-damaging effects of T. equi infection were evaluated. Compared to control horses, horses infected with T. equi had significantly higher SOD1 activities (P <0.05) and PHb (P <0.01), NO2(-) (P <0.001), NOx (P <0.05) and MDA concentrations (P <0.001), and significantly lower EH (P <0.001), CAT (P <0.01) and PON1 (P <0.001) activities, and thiol group concentrations (P <0.05). The comet assay demonstrated significantly increased DNA damage in T. equi infected cells compared to non-infected cells (P <0.001). Infected horses had significantly increased LDH5 isoenzyme activities (P <0.05). There was higher production of ROS/RNS in T. equi-infected horses, which resulted in changes in osmotic fragility, damage to lipids, proteins and DNA, haemolysis and hepatocellular damage. Oxidative stress in horses naturally infected with T. equi could contribute to the pathogenesis of the infection.
During implantation load-bearing devices experience stress that may influence its mechanical and corrosion profile and potentially lead to premature rupture. The susceptibility to stress corrosion cracking (SCC) of the Mg-Al alloy AZ61 and Zn was studied in simulated body fluid (m-SBF) and whole blood by slow strain rate (SSR) testing in combination with electrochemical impedance spectroscopy (EIS) and further ex situ analysis including scanning electron microscopy (SEM) and Fourier transform infrared spectroscopy. AZ61 was found to be highly susceptible to SCC. EIS analysis show that although the majority of cracking occurred during the apparent plastic straining, cracking initiation occurs already in the elastic region at ∼50% of the ultimate tensile strength (UTS). Shifts in EIS phase angle and open circuit potential can be used to detect the onset of SCC. Zinc demonstrated a highly ductile behavior with limited susceptibility to SCC. No significant decrease in UTS was observed in m-SBF but a decrease in time to failure by ∼25% compared to reference samples indicates some effect on the mechanical properties during the ductile straining. The formation of micro cracks, ∼10μm deep, was indicated by the EIS analysis and later confirmed by ex situ SEM. The results of SSR analysis of zinc in whole blood showed a reduced effect compared to m-SBF and no cracks were detected. It appears that formation of an organic surface layer protects the corroding surface from cracking. These results highlight the importance of considering the effect of biological species on the degradation of implants in the clinical situation.
Strain may deteriorate the corrosion properties of metallic implants drastically. We study the influence of load on the corrosion properties of a magnesium alloy and zinc by a combination of electrochemical impedance spectroscopy (EIS) and slow strain rate analysis. This combination of techniques has previously not been used for studying degradation in physiological relevant electrolytes. EIS provide valuable information on the initial formation of cracks, detecting crack nucleation before feasible in slow strain rate analysis. This sensitivity of EIS shows the potential for electrochemical methods to be used for in situ monitoring crack formation of implants in more applied studies.
Mn/Zn ethylene-bis-dithiocarbamate (Mn/Zn-EBDC) fungicides are among some the most widely-used fungicides in the world. Although they have been available for over 50 years, little is known about their mechanism of action in fungi, or their potentially toxic mechanisms in humans. To determine if exposure of Caenorhabditis elegans (C. elegans) to a representative fungicide (Manzate; MZ) from this group inhibits mitochondria or produces reactive oxygen species (ROS), we acutely (30min) exposed worms to various MZ concentrations. Initial oxygen consumption studies showed an overall statistically significant decrease in oxygen consumption associated with addition of Complex I- and/or II-substrate in treatment groups compared to controls (*p<0.05). In order to better characterize the individual complex activity, further studies were completed that specifically assessed Complex II or Complex IV. Data indicated that neither of these two complexes were targets of MZ treatment. Results from tetramethylrhodamine ethyl ester (proton gradient) and ATP assays showed statistically significant reductions in both endpoints (*p<0.05, **p<0.01, respectively). Additional studies were completed to determine if MZ treatment also resulted in increased ROS production. These assays provided evidence that hydrogen peroxide, but not superoxide or hydroxyl radical levels were statistically significantly increased (*p<0.05). Taken together, these data indicate exposure of C. elegans to MZ concentrations to which humans are exposed leads to mitochondrial inhibition and concomitant hydrogen peroxide production. Since mitochondrial inhibition and increased ROS are associated with numerous neurodegenerative diseases, we suggest further studies to determine if MZ catalyzes similar toxic processes in mammals.
Adequate intake of calcium and phosphorus in the appropriate ratio of 1-2:1 (Ca:P), in addition to magnesium and vitamin D, is vital for bone health and development of infants. In this feasibility study, the ratio of Ca:P in conjunction with vitamin D and other essential elements (Cu, Fe, K, Mg, Na, and Zn) in a range of commercial infant food products in the UK was investigated. The elemental analysis was carried out using inductively coupled plasma optical emission spectrometry, and vitamin D levels were determined using an enzyme-linked immunosorbent assay. The quantitative data were further evaluated, based on a standardised menu, to measure the total daily intake of an infant aged 7-12 months against the Reference Nutrient Intake. The results from the study show that the Ca:P ratio of the infant's total dietary intake was within the recommended range at 1.49:1. However, the level of intake for each of the nutrients analyzed, with the exception of sodium, was found to be above the Reference Nutrient Intake, which warrants further investigation in relation to both micronutrient interactions and in situations where the intake of fortified infant formula milk is compromised. Finally, as the study is the first to include consumption of infant snack products, the level of total calorie intake was also calculated in order to assess the total daily estimated energy intake; the results indicate that energy intakes exceed recommendations by 42%, which may have implications for obesity.
Dysfunctional interaction of amyloid-β (Aβ) with excess metal ions is proved to be related to the etiology of Alzheimer's disease (AD). Hence, disruption of these metal-peptide interactions using nanoparticles (NPs) holds considerable promise as a therapeutic strategy to combat this incurable disease. Given that quercetin is a natural product, the biocompatibility and small size essential for permeating the blood-brain barrier make it a potential therapeutic drug candidate for treating AD. Nanocarriers formulated with the US Food and Drug Administration-approved biocompatible and biodegradable polymer PLGA are being widely explored for the controlled delivery of therapeutic drugs, proteins, peptides, oligonucleotides, and genes. With this background, the present study was undertaken to investigate the effects of PLGA-functionalized quercetin (PLGA@QT) NPs on inhibited and disassembled Aβ42 fibrils and the PLGA@QT NPs have low cytotoxicity when tested on SH-SY5Y cells in vitro. As expected, the cytotoxicity studies of the PLGA@QT NPs led to a concentration-related behaviour on the SH-SY5Y human neuroblastoma cells. And, it has demonstrated that PLGA@QT NPs can inhibit the neurotoxicity of Zn(2+)-Aβ42 system and enhance the viability of neuron cells. The results from behavioral tests indicate that injection of PLGA@QT NPs into APP/PS1 mice ameliorate cognition and memory impairments. Most encouragingly, the in vivo systemic toxicity of PLGA@QT NPs examined by histological analysis in major organs did not show any signs of adverse effect to mice. Thus, the prepared quercetin based nanoscale drug delivery carrier efficiently enhanced the therapeutic index and reduced the side effects. Our findings are highly encouraging, providing substantial evidence of the safety of PLGA@QT NPs for biomedical application. We expect these findings will be relevant for other NPs for treatment of AD and have broad implications in NP-based studies and applications.
Silver (Ag(+)), zinc (Zn(2+)) and copper (Cu(2+)) ions, are well known for their broad-spectrum antibacterial activities while generating low resistance. However, whether or multiple metal ions in aqueous solutions acted synergistically or antagonistically antimicrobial properties, remained unknown. Therefore, it was of great significance to investigate the antibacterial properties of multicomponent metal ions-containing aqueous solutions. In this study, the antibacterial activities of multicomponent metal ions-containing
 aqueous solutions were investigated for the first time. We found that the antibacterial activities of multicomponent metal ions-containing aqueous solutions were higher than those of single metal ion-containing aqueous solution. Furthermore, the synergistic antibacterial mechanism of these multicomponent metal ions-containing aqueous solutions was first investigated. The generation of reactive oxygen species (ROS) through electron transfer in the enzymes and Fenton reactions formed the main synergistic antibacterial mechanism of the multicomponent metal ions-containing aqueous solutions. Therefore, the encouraging results demonstrate the great potential applications of multicomponent metal ions for the design of new biomaterials or prosthesis containing Ag-Cu-Zn alloy which can release Ag(+), Zn(2+) and Cu(2+) and minimize the risk of hospital acquired infection.
Mn(II) complexes formed with cis- and trans-DO2A (DO2A=1,4,7,10-tetraazacyclododecane-1,4 (or 1,7) -diacetic acid) chelators were investigated by pH-potentiometry, (1)H relaxometry, UV-vis spectrophotometry and cyclic voltammetry. The physico-chemical characteristics of Mn(II) complexes of these structure isomers do not differ dramatically, however the cis-DO2A platform has better potential for further development. Manganese (Mn(II)) is a promising alternative to gadolinium (Gd(III)) as a magnetic resonance imaging (MRI) agent. Unlike gadolinium, this biogenic metal might be better tolerated by the body, reducing the risk of toxicity associated with dissociation of the complex. Herein we report detailed equilibrium and kinetic studies performed with Mn(II) complexes of 1,4,7,10-tetraazacyclododecane-1,4-diacetic acid (1,4-DO2A or cis-DO2A) and 1,4,7,10-tetraazacyclododecane-1,7-diacetic acid (1,7-DO2A or trans-DO2A). The protonation constants of the ligands as well as stability constants of their Mn(II) complexes have been determined by pH-potentiometry. The stability constants of [Mn(cis-DO2A)] are slightly higher than those of [Mn(trans-DO2A)] (log KMnL=15.68 and 15.22, respectively). Cyclic voltammetric (CV) experiments performed on [Mn(cis-DO2A)] and [Mn(trans-DO2A)] revealed quasireversible systems with a half-wave potential of +636 and +705mV versus Ag/AgCl, respectively. These values indicate that the Mn(II) ion in these complexes is more stabilized against the oxidation than in [Mn(EDTA)](2-). The kinetic inertness of the complexes has been studied in transmetallation reactions with Cu(II) or Zn(II) ions. Kinetic measurements indicate that both Mn(II) complexes primarily undergo acid catalyzed dissociation and positions of the acetate pendant arms do not influence kinetic inertness. The inertness of these complexes is comparable to that of [Mn(NOTA)](-) (NOTA=1,4,7-triazacyclononane-1,4,7-triacetic acid) and about twenty times lower than that of [Mn(DOTA)](2-) (DOTA=1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid). In conclusion, [Mn(cis-DO2A)] displays some very interesting features (thermodynamic and redox stability as well as kinetic inertness) which makes this complex a promising platform for the development of more efficient Mn(II) complexes as alternatives to Gd-based MRI agents.
Inhibition of DNA repair is an established mechanism of arsenic co-carcinogenesis, and may be perpetuated by the binding of As(III) to key zinc finger (zf) DNA repair proteins. Validated molecular targets of As(III) include the first zinc finger domain of Poly (ADP-Ribose) Polymerase 1 (PARP-1), and the zinc finger domain of Xeroderma Pigmentosum Complementation Group A (XPA). In order to gain an understanding of the thermodynamic and kinetic parameters of the interaction of As(III) with these two zinc finger motifs, a fluorescence based approach was used to investigate Zn(II) and As(III) binding to synthetic model peptides corresponding to the zf motif of XPA and first zf motif of PARP-1, referred to in this paper as XPAzf and PARP-1zf-1, respectively. While XPAzf and PARP-1zf-1 display similar relative affinities for As(III), PARP-1zf-1 shows a potential kinetic advantage over XPAzf for As(III) binding, with a rate constant for the fast phase of formation of As(III)-PARP-1zf-1 approximately 4-fold higher than for As(III)-XPAzf. However, the binding of Zn(II) with either peptide proceeds at a faster rate than As(III). Notably, XPAzf demonstrates comparable affinities for binding both metals, while PARP-1zf-1 shows a slightly higher affinity for Zn(II), suggesting that the relative concentrations of Zn(II) and As(III) in a system may significantly influence which species predominates in zinc finger occupancy. These results provide insight into the mechanisms underlying interactions between zinc finger structures and As(III), and highlight the potential utility of zinc supplementation in mitigating adverse effects of As(III) on zinc finger functions in vivo.
Metallo-β-lactamases (MBLs) catalyse the hydrolysis of almost all β-lactam antibacterials including the latest generation carbapenems and are a growing worldwide clinical problem. It is proposed that MBLs employ one or two zinc ion cofactors in vivo. Isolated MBLs are reported to use transition metal ions other than zinc, including copper, cadmium and manganese, with iron ions being a notable exception. We report kinetic and biophysical studies with the di-iron(II)-substituted metallo-β-lactamase II from Bacillus cereus (di-Fe(II) BcII) and the clinically relevant B1 subclass Verona integron-encoded metallo-β-lactamase 2 (di-Fe(II) VIM-2). The results reveal that MBLs can employ ferrous iron in catalysis, but with altered kinetic and inhibition profiles compared to the zinc enzymes. A crystal structure of di-Fe(II) BcII reveals only small overall changes in the active site compared to the di-Zn(II) enzyme including retention of the di-metal bridging water; however, the positions of the metal ions are altered in the di-Fe(II) compared to the di-Zn(II) structure. Stopped-flow analyses reveal that the mechanism of nitrocefin hydrolysis by both di-Fe(II) BcII and di-Fe(II) VIM-2 is altered compared to the di-Zn(II) enzymes. Notably, given that the MBLs are the subject of current medicinal chemistry efforts, the results raise the possibility the Fe(II)-substituted MBLs may be of clinical relevance under conditions of low zinc availability, and reveal potential variation in inhibitor activity against the differently metallated MBLs.
To construct the model of metallohydrolase, two inclusion complexes [MLCl2(β-CD)] (1, M=Zn(II); 2, M=Cu(II); L=N,N'-bis(2-pyridylmethyl)amantadine; β-CD=β-cyclodextrin) were synthesized by mixing β-CDs with the pre-synthesized complexes G1, [ZnLCl2] and G2, [CuLCl2]. Structures of G1, G2, 1 and 2 were characterized by X-ray crystallography, respectively. In solution, two chloride anions of G1 and G2 underwent ligand exchange with solvent molecules according to ESI-MS analysis. The chemical equilibrium constants were determined by potentiometric pH titration. The kinetics of bis(4-nitrophenyl) phosphate (BNPP) hydrolysis catalyzed by G1, G2, 1 and 2 were examined at pHs ranging from 7.50 to 10.50 at 308±0.1K. The pH profile of rate constant of BNPP hydrolysis catalyzed by 1 exhibited an exponential increase with the second-order rate constant of 2.68×10(-3)M(-1)s(-1) assigned to the di-hydroxo species, which was approximately an order of magnitude higher than those of reported mono-Zn(II)-hydroxo species. The high reactivity was presumably hydroxyl-rich microenvironment provided by β-CDs, which might effect in stabilizing either the labile zinc-hydroxo species or the catalytic transition state.
A CE with contactless conductivity detection methodology using a novel background electrolyte for the separation and determination of 17 metal cations (Cs(+) , Rb(+) , K(+) , Ca(2+) , Na(+) , Mg(2+) , Mn(2+) , Sr(2+) , Li(+) , Ba(2+) , Fe(2+) , Pb(2+) , Cd(2+) , Zn(2+) , Co(2+) , Cu(2+) and Ni(2+) ) and ammonium has been investigated. The buffer, based on lactic acid and β-alanine, was experimentally compared with other two commonly used electrolytes, showing important improvements, such as shorter analysis times (<11 min), better electrophoretic resolutions and higher detectabilities for certain analytes, such as Fe(2+) and Pb(2+) . The inclusion of other additives such as 18-Crown-6 and α-hydroxyisobutyric acid was studied in order to obtain the best separation of the analytes of interest. The optimised method was applied to the analysis of 11 water-based pen inks and the determination of their metal composition. The methodology was demonstrated for the comparison and differentiation of pen inks.
Diethylzinc-mediated metalloamination/cyclization of unsaturated N,N-dimethylhydrazines has been extended to the use of 1,2-disubstituted alkenes as N-Zn migratory insertion acceptors. Representative 2-arylethenes and vinylcyclopropanes readily serve as reaction participants in metalloamination/cyclization-allylation cascades.
Two imidazolate-bridged diCu(II) and Cu(II)Zn(II) complexes, [CuZn(dien)2(μ-Im)](ClO4)3·MeOH (1) and [Cu2(dien)2(μ-Im)](ClO4)3 (2) (Im = imidazole, dien=diethylenetriamine), and two complexes formed with Schiff base ligands, [CuZn(salpn)Cl2] (3) and [Cu2(salbutO)ClO4] (4) (H2salpn=1,3-bis(salicylidenamino)propane, H3salbutO=1,4-bis(salicylidenamino)butan-2-ol) have been prepared and characterized. The reaction of [Cu(dien)(ImH)](ClO4)2 with [Zn(dien)(H2O)](ClO4)2 at pH≥11 yields complex 1; at lower pH, the Cu3Zn tetranuclear complex [{(dien)Cu(μ-Im)}3Zn(OH2)(ClO4)2](ClO4)3 (1a) forms as the main reaction product. X-ray diffraction of 1a reveals that the complex contains a metal centered windmill-shaped cation having three blades with a central Zn ion and three peripheral capping Cu(dien) moieties bound to the central Zn ion through three imidazolate bridges. The four complexes
 are able to disproportionate O2(-) in aqueous medium at pH7.8, with relative rates 4>1>2≫3. [Cu2(salbutO)](+) (4) is the most easily reducible of the four complexes and exhibits the highest activity among the SOD models reported so far; a fact related to the ligand flexibility to accommodate the copper ion in both Cu(I) and Cu(II) oxidation states and the lability of the fourth coordination position of copper facilitating stereochemical rearrangements.
Three novel potentially site-activated multitarget tacrine-(hydroxybenzoyl-pyridone) (TAC-HBP) hybrids were designed, synthesized and evaluated as acetylcholinesterase (AChE) inhibitors, antioxidants and biometal chelators. All of them are dual-binding site AChE inhibitors with activity in sub-micromolar range (IC50=0.57-0.78μM), which is comparable to the parent tacrine, and have good 2,2-diphenyl-1-picrylhydrazyl (DPPH) radical scavenging capacity (EC50=204-249μM) conferred by the hydroxybenzoyl-pyridone (HBP) moiety. Their chelating capacity towards redox-active and/or amyloid-β-binding metal ions (Fe(III), Cu(II)), Zn(II)) was evaluated by using 2'-hydroxy-4'-methoxybenzoyl-2-pyridone derivative as a model compound in 30% w/w DMSO/water medium. It was proved that the HBP moiety acts as a moderate/good chelator of these biometals (pFe=13.9, pCu=6.0 and pZn=6.0 at pH6.0, CL/CM=10, CM=10(-6)M), being able to form complexes with β-phenol-keto coordination mode, and that this chelating ability is preserved in the TAC-HBP hybrids.
The reaction of ZnCl2 with the non-steroidal anti-inflammatory drug flufenamic acid (Hfluf) led to the formation of complex [Zn(fluf-O)2(MeOH)4], 1. When the reaction takes places in the presence of a N,N'-donor heterocyclic ligand such as 2.2'-bipyridylamine (bipyam), 2.2'-bipyridine (bipy), 1.10-phenanthroline (phen) and 2.2'-dipyridylketone oxime (Hpko), the complexes [Zn(fluf)2(bipyam)], 2, [Zn(fluf)2(bipy)], 3, [Zn(fluf)(phen)2(H2O)](fluf)·0.2MeOH, 4·0.2MeOH and [Zn(fluf)2(Hpko)2], 5 were isolated, respectively. The complexes were characterized by physicochemical and spectroscopic techniques and the crystal structures of complexes 2 and 4 were determined by X-ray crystallography. The ability of the complexes to scavenge 1.1-diphenyl-picrylhydrazyl, 2.2'-azinobis(3-ethylbenzothiazoline-6-sulfonic acid) and hydroxyl radicals and to inhibit soybean lipoxygenase was evaluated; the complexes were more active than free Hfluf. The interaction of the complexes with serum albumins was investigated by fluorescence emission spectroscopy and the corresponding binding constants were calculated. UV-vis spectroscopy, viscosity measurements and fluorescence emission spectroscopy for the competitive studies of the complexes with ethidium bromide were the techniques employed to monitor the interaction of the complexes with calf-thymus DNA and revealed intercalation as the most possible mode of binding.
Protein degradation leads to the formation of endogenous peptides, the biological activity of which is most often unknown. The peptide AGHLDDLPGALSAL, recently isolated from mouse brain homogenates, has been recognized as a fragment of the α-chain of hemoglobin. AGHLDDLPGALSAL has the ability of inhibiting the peripheral hyperalgesic inflammatory responses through the indirect activation of the μ-opioid receptors. A peculiarity of AGHLDDLPGALSAL is the presence, at its N-terminus of a strong binding site for divalent transition metal ions, similar to that characterizing the human albumin and called "ATCUN motif". The consequential metal binding ability of AGHLDDLPGALSAL can be connected to its biological activity. For this reason, we decided to investigate the coordination properties of AGHLDDLPGALSAL towards Cu(II), Ni(II) and Zn(II) ions, reported here for the first time. The results confirm that AGHLDDLPGALSAL is a strong ligand for those metals: it can even compete with albumin under suitable conditions. In vitro assays on the inhibition of Cu(II) toxicity towards different cell lines confirmed that the binding ability of AGHLDDLPGALSAL can imply relevant biological consequences.
The basic knowledge about biological inorganic chemistry, thermodynamics and metal binding sites of metalloproteins is crucial for the understanding of their metal binding-structure-function relationship. Metal-peptide complexes are useful and commonly used models of metal-enzyme active sites, among which copper and zinc models are one of the most extensively studied. HENRYK is a peptide sequence present in numerous proteins, and serves as a potentially tempting binding site for Cu(2+) and Zn(2+). Maybe more importantly, HENRYK also happens to be the first name of our group leader. The results of this work, which, at the first glance, might seem to be a 'chemical scrabble', went far beyond our expectations and surprised us with a novel, uncommon behavior of a Cu(2+) complex with a peptide with a histidine in position one. At low pH, the binding is a typical histamine-like coordination, but with the increase of pH, the imidazole nitrogen is moved to the axial position and replaced with an amide; at basic pH, the binding mode is a {NH2, 3N(-)} one in the equatorial plane. It is important to note, that no dimeric species are formed in between. Such binding is thermodynamically much more stable than a simple complex with histamine, and quite comparable to complexes with several possible imidazole anchoring sites.
The quality of cultivated consumed vegetables in relation to environmental pollution is a crucial issue for urban and peri-urban areas, which host the majority of people at the global scale. In order to evaluate the fate of metals in urban soil-plant-atmosphere systems and their consequences on human exposure, a field study was conducted at two different sites near a waste incinerator (site A) and a highway (site B). Metal concentrations were measured in the soil, settled atmospheric particulate matter (PM) and vegetables. A risk assessment was performed using both total and bioaccessible metal concentrations in vegetables. Total metal concentrations in PM were (mg kg(-1)): (site A) 417 Cr, 354 Cu, 931 Zn, 6.3 Cd and 168 Pb; (site B) 145 Cr, 444 Cu, 3289 Zn, 2.9 Cd and 396 Pb. Several total soil Cd and Pb concentrations exceeded China's Environmental Quality Standards. At both sites, there was significant metal enrichment from the atmosphere to the leafy vegetables (correlation between Pb concentrations in PM and leaves: r = 0.52, p < 0.05) which depended on the plant species. Total Cr, Cd and Pb concentrations in vegetables were therefore above or just under the maximum limit levels for foodstuffs according to Chinese and European Commission regulations. High metal bioaccessibility in the vegetables (60-79 %, with maximum value for Cd) was also observed. The bioaccessible hazard index was only above 1 for site B, due to moderate Pb and Cd pollution from the highway. In contrast, site A was considered as relatively safe for urban agriculture.
To describe chelation therapy with d-penicillamine for treatment of zinc toxicosis in a dog.
A 1.5-year-old intact female Maltese dog weighing 2.7 kg was presented with acute, progressive anorexia, lethargy, pigmenturia, and melena. The owner reported that the dog had ingested a hook from a dog leash made of a zinc-based alloy 9 days prior. A blood transfusion was administered and an abdominal radiograph revealed a metal-dense foreign body in the stomach. Laboratory findings revealed a serum zinc concentration of 1845.12 μg/dL (reference interval, 70-200 μg/dL) and a decreased hematocrit that remained low despite removal of the zinc foreign body. On day 3, another blood transfusion was performed and d-penicillamine therapy was instituted. After the administration of d-penicillamine, the clinical signs and hemogram progressively improved and the dog was discharged 2 days later. On day 9 after initial presentation, the hematocrit and platelet values were within normal limits and the serum zinc concentration was 280.16 μg/dL.
This case demonstrates the use of d-penicillamine in the treatment of zinc toxicosis. Serum zinc concentration appeared to decline more rapidly after administration of d-penicillamine than before chelation therapy. This is the first report to evaluate serial serum zinc concentrations before and during chelation therapy with d-penicillamine.
The diverse anticancer utility of cisplatin has stimulated significant interest in the development of additional platinum-based therapies, resulting in several analogues receiving clinical approval worldwide. However, due to structural and mechanistic similarities, the effectiveness of platinum-based therapies is countered by severe side-effects, narrow spectrum of activity and the development of resistance. Nonetheless, metal complexes offer unique characteristics and exceptional versatility, with the ability to alter their pharmacology through facile modifications of geometry and coordination number. This has prompted the search for metal-based complexes with distinctly different structural motifs and non-covalent modes of binding with a primary aim of circumventing current clinical limitations. This review discusses recent advances in platinum and other transition metal-based complexes with mechanisms of action involving intercalation. This mode of DNA binding is distinct from cisplatin and its derivatives. The metals focused on in this review include Pt, Ru and Cu along with examples of Au, Ni, Zn and Fe complexes; these complexes are capable of DNA intercalation and are highly biologically active.
Zinc (Zn) and arsenic (As) are typically present as mixed contaminants in mining-impacted areas, however, their joined effects have rarely been evaluated. The present study was set-up to test if Zn(2+) and H2 AsO4(-) (further: As) mixture toxicity to plants is additive or if interactions
 occur. Barley (Hordeum vulgare) root elongation was measured in resin buffered nutrient solutions. The design included ranges of single element concentrations and combinations at three different Ca(2+) concentrations (0.5, 2.2, and 15.0mM) to vary the relative toxicity of Zn(2+) . Increasing Ca concentrations decreased Zn toxicity, while As toxicity was unaffected by Ca. Root elongation was generally more affected in Zn-As mixtures than in corresponding single element treatments. This is merely a joint additive effect, since 96% of the root elongation data were within a factor 1.2 from predictions using the independent action (IA) or concentration addition (CA) model. The CA and IA predictions were similar and data did not allow to identify equal or dissimilar mode of action. Small, but significant Zn-As antagonisms were only found at high effects (>50% inhibition). The present study suggests that mixture effects of Zn and As are environmentally relevant and that current risk assessment underestimates toxicity in multi-element contaminated environments. The CA model can be used as a conservative model for risk assessment, however for soil grown plants, soil exposed studies are needed. This article is protected by copyright. All rights reserved.
Diagnosing foliar nutritional status is essential for fertilizer recommendations and for the identification of nutrient imbalances. This study aimed to verify genetic diversity and establish mean standards (leaf nutrient contents; LNCs) and relationships among leaf nutrients (LNC relationships; LNCRs) in seven conilon coffee genotypes during both pre-flowering and bean-filling stages. Twenty crops from several cities in the northern region of Espírito Santo State, Brazil, with crop yield either equal to or greater than 100 bags per hectare (during two harvests) were assessed. A total of 140 samples were collected during each evaluation period for quantification of leaf nutrient contents (N, P, K, Ca, Mg, S, Fe, Zn, Cu, Mn, and B). The Ward procedure, a hierarchical genetic clustering method, was used to quantify the genetic diversity among genotypes. To examine differences between the LNCs and LNCRs, F-and Scott-Knott tests were used. LNCs and LNCRs showed significant differences among the conilon coffee genotypes during the evaluation periods. Additionally, the 8V, 10V,and 12V genotypes exhibited the highest values for most of the nutrients, especially for N, P, and Cu. Therefore, the clustering method revealed genetic diversity among genotypes for standard leaf nutrient levels, implying that leaf diagnosis could be specific to each genotype and phenological stage.
The binding of metal ions at the interface of protein complexes presents a unique and poorly understood mechanism of molecular assembly. A remarkable example is the Rad50 zinc hook domain, which is highly conserved and facilitates the Zn(2+)-mediated homodimerization of Rad50 proteins. Here, we present a detailed analysis of the structural and thermodynamic effects governing the formation and stability (logK12 = 20.74) of this evolutionarily conserved protein assembly. We have dissected the determinants of the stability contributed by the small β-hairpin of the domain surrounding the zinc binding motif and the coiled-coiled regions using peptides of various lengths from 4 to 45 amino acid residues, alanine substitutions and peptide bond-to-ester perturbations. In the studied series of peptides, an >650 000-fold increase of the formation constant of the dimeric complex arises from favorable enthalpy because of the increased acidity of the cysteine thiols in metal-free form and the structural properties of the dimer. The dependence of the enthalpy on the domain fragment length is partially compensated by the entropic penalty of domain folding, indicating enthalpy-entropy compensation. This study facilitates understanding of the metal-mediated protein-protein interactions in which the metal ion is critical for the tight association of protein subunits.
The d-band center model of Hammer and Nørskov is widely used in understanding and predicting catalytic activity on transition metal (TM) surfaces. Here, we demonstrate that this model is inadequate for capturing the complete catalytic activity of the magnetically polarized TM surfaces and propose its generalization. We validate the generalized model through comparison of adsorption energies of the NH3 molecule on the surfaces of 3d TMs (V, Cr, Mn, Fe, Co, Ni, Cu and Zn) determined with spin-polarized density functional theory (DFT)-based methods with the predictions of our model. Compared to the conventional d-band model, where the nature of the metal-adsorbate interaction is entirely determined through the energy and the occupation of the d-band center, we emphasize that for the surfaces with high spin polarization, the metal-adsorbate system can be stabilized through a competition of the spin-dependent metal-adsorbate interactions.
Zn(2+) deficiency (ZnD) is comorbid with chronic kidney disease (CKD) and worsens kidney complications. Oxidative stress is implicated in the detrimental effects of ZnD. However, the sources of oxidative stress continue to be identified. Since NADPH oxidases (Nox) are the primary enzymes that contribute to renal reactive oxygen species (ROS) generation, this study's objective was to determine the role of these enzymes in ZnD-induced oxidative stress. We hypothesized that ZnD promotes Nox upregulation resulting in oxidative stress and kidney damage. To test this hypothesis, WT mice were pair-fed a ZnD- or Zn(2+) adequate-diet. To further investigate the effects of Zn(2+) bioavailability on Nox regulation, mouse tubular epithelial cells (mTEC) were exposed to the Zn(2+) chelator N,N,N',N'-Tetrakis(2-pyridylmethyl)ethylenediamine (TPEN) or vehicle followed by Zn(2+) supplementation. The findings show that mice fed a ZnD-diet develop microalbuminuria, electrolyte imbalance and whole kidney hypertrophy. These markers of kidney damage are accompanied by elevated Nox2 expression and H2O2 levels. In mTEC, TPEN-induced ZnD stimulates H2O2 generation. In this in vitro model of ZnD, enhanced H2O2 generation is prevented with Nox inhibition by diphenyleneiodonium. Specifically, TPEN promotes Nox2 expression and activation which are reversed when intracellular Zn(2+) levels are restored following Zn(2+) supplementation. Finally, Nox2 knock-down by si-RNA prevents TPEN-induced H2O2 generation and cellular hypertrophy in vitro. Taken together, these findings reveal that Nox2 is a Zn(2+)-regulated enzyme that mediates ZnD-induced oxidative stress and kidney hypertrophy. Understanding the specific mechanisms by which ZnD contributes to kidney damage may have an important impact on the treatment of CKD.
Amorphous indium gallium zinc oxide (IGZO) field effect transistors (FETs) are a promising technology for a wide range of electronic applications. Herein, we fabricated and characterized FETs with a nanostructured IGZO network as a sensing transducer. The IGZO was patterned using colloidal lithography and electrohydrodynamic printing, where an 8 μm wide nanostructured close-packed hexagonal IGZO network was obtained. Electrical characterization of the nanostructured IGZO network FET demonstrated a drain-source current on-off ratio of 6.1 × 10(3) and effective electron mobilities of 3.6 cm(2) V(-1) s(-1). The nanostructured IGZO network was functionalized by aminosilane groups with cross-linked glucose oxidase. The devices demonstrated a decrease in drain-source conductance and a more positive VON with increasing glucose concentration. These changes are ascribed to the acceptor-like surface states associated with positively charged aminosilane groups attached to the nanostructured IGZO surface. Continuous monitoring of the drain-source current indicates a stepwise and fully reversible response to glucose concentrations with a short response time. The specific catalytic reaction between the GOx enzyme and glucose eliminates interference from acetaminophen/ascorbic acid. We demonstrate that nanostructured IGZO FETs have improved sensitivity compared to non-nanostructured IGZO for sensing glucose and can be potentially extended to other biosensor technologies.
Here we report a systematic study of the Pb(2+) substitution in the hybrid iodoplumbate MAPbI3 with a series of elements affecting optoelectronic, structural, and morphological properties of the system. It has been shown that even partial replacement of lead with Cd(2+), Zn(2+), Fe(2+), Ni(2+), Co(2+), In(3+), Bi(3+), Sn(4+), and Ti(4+) results in a significant deterioration of the photovoltaic characteristics. On the contrary, Hg-containing hybrid MAPb1-xHgxI3 salts demonstrated a considerably improved solar cell performance at optimal mercury loading. This result opens up additional dimension in the compositional engineering of the complex lead halides for designing novel photoactive materials with advanced optoelectronic and photovoltaic properties.
We have combined ion mobility mass spectrometry with quantum chemical calculations to investigate the gas-phase structures of multiply negatively charged oligomers of meso-tetra(4-sulfonatophenyl)metalloporphyrins comprising the divalent metal centers Zn(II), Cu(II), and Pd(II). Sets of candidate structures were obtained by geometry optimizations based on calculations at both the semiempirical PM7 and density functional theory (DFT) levels. The corresponding theoretical cross sections were calculated with the projection approximation and also with the trajectory method. By comparing these collision cross sections with the respective experimental values we were able to assign oligomer structures up to the tetramer. In most cases the cross sections of the lowest energy isomers predicted by theory were found to agree with the measurements to within the experimental
 uncertainty (2%). Specifically, we find that for a given oligomer size the structures are independent of the metal center but depend strongly on the charge state. Oligomers in low charge states with a correspondingly larger number of sodium counterions tend to form stacked, cofacial structures reminiscent of H-aggregate motifs observed in solution. By contrast, in higher charge states, the stack opens to form coplanar structures.
The aim of this report is to present the electrospray ionization mass spectrometry results of the non-covalent interaction of two biologically active ligands, N-1-(p-toluenesulfonyl)cytosine, 1-TsC, 1 and N-1-methanesulfonylcytosine, 1-MsC, 2 and their Cu(II) complexes Cu(1-TsC-N3)2 Cl2 , 3 and Cu(1-MsC-N3)2 Cl2 and 4 with biologically important cations: Na(+) , K(+) , Ca(2+) , Mg(2+) and Zn(2+) . The formation of various complex metal ions was observed. The alkali metals Na(+) and K(+) formed clusters because of electrostatic interactions. Ca(2+) and Mg(2+) salts produced the tris ligand and mixed ligand complexes. The interaction of Zn(2+) with 1-4 produced monometal and dimetal Zn(2+) complexes as a result of the affinity of Zn(2+) ions toward both O and N atoms. Copyright © 2016 John Wiley & Sons, Ltd.
CLC anion channels are homodimeric proteins. Each subunit is comprised of 18 α-helices designated "A-R" and an intracellular carboxy-terminus containing two cystathionine-β-synthase (CBS1 and CBS2) domains. Conformational coupling between membrane and intracellular domains via poorly understood mechanisms is required for CLC regulation. The activity of the C. elegans CLC channel CLH-3b is reduced by phosphorylation of a carboxy-terminus "activation domain," which disrupts its interaction with CBS domains. CBS2 interfaces with a short intracellular loop, the H-I loop, connecting membrane helices H and I. Alanine mutation of a conserved H-I loop tyrosine residue, Y232, prevents regulation demonstrating that the loop functions to couple phosphorylation-dependent CBS domain conformational changes to channel membrane domains. To gain further insight into the mechanisms of this coupling, we mutated conserved amino acid residues in membrane helices H and I. Only mutation of the H-helix valine residue V228 to leucine prevented phosphorylation-dependent channel regulation. Structural and functional studies of other CLC proteins suggest that V228 may interact with Y529, a conserved R-helix tyrosine residue that forms part of the CLC ion conduction pathway. Mutation of Y529 to alanine also prevented CLH-3b regulation. Intracellular application of the sulfhydryl reactive reagent MTSET using CLH-3b channels engineered with single-cysteine residues in CBS2 indicate that V228L, Y529A, and Y232A disrupt putative regulatory intracellular conformational changes. Extracellular Zn(2+) inhibits CLH-3b and alters the effects of intracellular MTSET on channel activity. The effects of Zn(2+) are disrupted by V228L, Y529A, and Y232A. Collectively, our findings indicate that there is conformational coupling between CBS domains and the H and R membrane helices mediated by the H-I loop. We propose a simple model by which conformational changes in H and R helices mediate CLH-3b regulation by activation domain phosphorylation.
The structural and functional properties of zinc(ii) complexes of two nitrogen rich polydentate ligands, HTPDP = 1,3-bis(bis-pyridin-2-ylmethylamino)propan-2-ol and HTPPNOL = N,N,N'-tris-(2-pyridylmethyl)-1,3-diaminopropan-2-ol, are compared. HTPDP is a hepta-dentate ligand with four pyridyl groups attached to a 1,3-diaminopropan-2-ol backbone while HTPPNOL contains only three pyridyl groups. In reactions with Zn(ClO4)2, HTPDP forms a dinuclear zinc compound [Zn2(TPDP)(OAc)](ClO4)2, 1. On the other hand, mononuclear [Zn(HTPPNOL)](ClO4)2, 2, and tetranuclear [Zn4(TPPNOL)2(OAc)3](ClO4)3, 3, complexes were isolated with the ligand HTPPNOL. Kinetic measurements with the substrate bis(2,4-dinitrophenyl)phosphate (BDNPP) revealed that compound 1 (kcat = 31.4 × 10(-3) min(-1)) is more reactive than 3 (kcat = 7.7 × 10(-3) min(-1)) at pH = 8.5, whilst the mononuclear compound 2 is inactive. Compound 1 displays a typical steady-state kinetic behaviour, while compound 3 exhibits steady-state behaviour only ∼120 s after starting the reaction, preceded by a burst-phase. (31)P NMR studies confirm that 1 can promote the hydrolysis of both ester bonds in BDNPP, generating the monoester DNPP and inorganic phosphate in the process. In contrast, DNPP is not a substrate for 3. The crystal structure of the complex formed by 3 and DNPP reveals the formation of a tetranuclear zinc complex [Zn4(TPPNOL)2(DNPP)2](ClO4)2, 4, in which the phosphate moiety of DNPP adopts an unusual tridentate μ-η(1):η(1):η(1) coordination mode.
Equimolar reactions between ZntBu2 and diphenyl phosphate (dpphe-H) or dimethyl phosphate (dmphe-H) result in the formation of [tBuZn(O2P(OR')2)]-type compounds which crystallize as tetranuclear aggregates, [tBuZn(dpphe)]4 (14) or [tBuZn(dmphe)]4 (24), with the phosphate ligands spanning 4-coordinate Zn centers. The utility of ZnMe2 instead of ZntBu2 dramatically changes the reaction outcome and leads to [MeZn(O2P(OR')2)]-type moieties incorporating zincoxane units, i.e., pentanuclear [{MeZn(dpphe)}3(Me2Zn2O)(THF)2] (3) and nonanuclear [{MeZn(dmphe)}6(Me2Zn3O2)] (4) aggregates. The resulting compounds were characterized by (1)H and (31)P NMR spectroscopy and single-crystal X-ray diffraction analysis.
Industrial pollutants induce the production of toxic reactive oxygen species (ROS) such as O2(.-), H2O2, and (·)OH in plants, but they have not been well quantified or localized in tissues and cells. This study evaluated the pollutant- (HSO3(-), NH4NO3, Al(3+), Zn(2+), and Fe(2+)) induced toxic effects of ROS on the aerial roots of Chinese banyan (Ficus microcarpa). Root cell viability was greatly reduced by treatment with 20 mM NaHSO3, 20 mM NH4NO3, 0.2 mM AlCl3, 0.2 mM ZnSO4, or 0.2 mM FeSO4. Biochemical assay and histochemical localization showed that O2(.-) accumulated in roots in response to pollutants, except that the staining of O2(.-) under NaHSO3 treatment was not detective. Cytochemical localization further indicated that the generated O2(.-) was present mainly in the root cortex, and pith cells, especially in NH4NO3- and FeSO4-treated roots. The pollutants also caused greatly accumulated H2O2 and (·)OH in aerial roots, which finally resulted in lipid peroxidation as indicated by increased malondialdehyde contents. We conclude that the F. microcarpa aerial roots are sensitive to pollutant-induced ROS and that the histochemical localization of O2(.-) via nitrotetrazolium blue chloride staining is not effective for detecting the effects of HSO3(-) treatment because of the treatment's bleaching effect.
Geogenic and anthropogenic activities introduce certain metals into the environment which tend to deteriorate the quality of both surface and groundwater in the Bosomtwe Crater Lake and its surroundings. In this study spatio-temporal variations in concentrations and risk assessment of selected trace metals (As, Fe, Pb, Zn, Cr, Cd and Ni) were investigated during the wet and dry seasons for surface and groundwater in selected human settlements around the lake. The levels of As, Cd and Ni were generally small and were below the detection limit of the instrument. The results showed no significant seasonal variations in the mean levels of Pb, Fe, Zn and Cr in water from the Bosomtwe Crater Lake. The hazard quotients and health hazard indices through ingestion and dermal contact of lake and groundwater in towns around the lake for both adults and children gave values which were below the acceptable limit of less than unity (< 1), indicating the absence of non-carcinogenic health risk to the communities. The study however reveals that ingestion of both lake and groundwater from the lake and its surroundings poses carcinogenic risk with regard to the level of Pb and Cr. Hence appropriate control measures and interventions should be put in place to protect the health of the human population in the study area.
Solution equilibrium of divalent metal ions (M=Mn(2+), Co(2+), Ni(2+), Cu(2+) and Zn(2+)) with caffeic acid (ligand C) or dihydrocaffeic acid (ligand D) in binary system, and with acetylcysteine (ligand N) in ternary system were investigated at condition similar to human physiological temperature of 310.15 K and ionic strength of 0.15 mol·dm(-3) NaCl. Potentiometry technique was used for the determination of formation constant (log β) assisted by spectrophotometry technique. The results indicated the formation of [ML], [MLH], [ML2], [ML2H] in binary species and [MLN], [MNLH], [MNLH2] in ternary species, where L represents ligands C or D. It was found that ligand D formed more stable complexes than that of ligand C, which were affected by the presence of double bond in the carboxylate moiety of ligand C. The speciation diagrams were simulated by HySS and discussed briefly, additionally the tendency of ternary complexes was evaluated from parameters Δ log KM and log X.
Ultrasound-assisted extraction of curcumin from Curcuma longa was performed in an ultrasonic bath at 30°C using ethanol for 40 min. A successful attempt has been made to prepare curcumin-zinc (Zn) complex using a simple chemical procedure. The complex formation and its stoichiometry were characterized using elemental analysis, Fourier transform (FT)-IR and UV spectroscopy which revealed the interaction of Zn(II) ion (M) with curcumin (ligand, L) to proceed via (ML) complex type formation. Oral administration of curcumin-Zn complex at a concentration of 150 mg/kg body weight/rat/d for 45 d in streptozotocin-induced diabetic rats in comparison to curcumin and/or Zn administration exerted a hypoglycemic effect. A significant reduction in
 blood glucose, glycosylated hemoglobin (Hb)A1c, and lipid profile parameters with an excellent improvement in plasma insulin levels have been attained. Also, the reduced activities of serum aspartate aminotransferase (AST), alanine aminotransferase (ALT), urea, and creatinine in the diabetic rats treated with the complex exhibited the non-toxic nature of the curcumin-Zn complex. Finally, the larger extent of the complex in hyperglycemic improvement in comparison to curcumin and/or Zn supplementation was interpreted by its dual action on glucose and insulin maintenance.
Photon correlation spectroscopy conducted on polymeric metaphosphate melts [NaPO3]1-y[Zn(PO3)2]y shows a systematic decrease in glass fragility as the more strongly bonding Zn cation replaces the more weakly bonding Na cation as a crosslinking agent between PO3 chains. This decrease is similar to that observed previously in Na-Al melts and the decrease in fragility for both systems is shown to be fully consistent with a recently reported universal pattern of fragility in network forming glasses as a function of network connectivity. Unique to the Na-Zn system is the appearance of an ultraslow relaxation in the dynamic structure factor (slower than the viscoelastic decay) that is not present in either Na-Al or Na-Li metaphosphate mixtures. This relaxation appears to originate from the diffusion of the Zn cation within the melt which is partially coupled to the oxide network. Taken together, these results underscore the need to distinguish between network-forming cations of high ionic bond strength that contribute to the connectivity of the oxide network and those of lower bond strength that do not contribute.
Understanding the molecular basis of inorganic chemical toxicity has lagged behind the proliferation of detailed mechanisms that explain the biochemical toxicology of many organic xenobiotics. In this perspective, general barriers to explicating the bioinorganic chemistry of toxic metal are considered, followed by a detailed examination of these issues in relation to the toxicology of Cd(2+). The hypothesis is evaluated that Cd(2+) damages cells by replacing Zn(2+) in key Zn-proteins. Emerging methodology to assess the speciation of metals among cell proteins is described. Then, a more general hypothesis is suggested, namely, that the Zn-proteome is also the toxicological target of other metals such as Pb(2+) as well as NO and reactive oxygen species. The latter may damage cells by altering the structure and function of Zn(2+) binding sites that include thiol ligands. In the process, labilized Zn(2+) may also perturb cell biochemistry. Lastly, reactions of metal chelating ligands with the Zn-proteome, including formation of ligand-Zn-protein adducts, provide other potential avenues of biochemical toxicity.
Hybrid supercapacitors that follow a "rocking-chair"-type mechanism were developed by coupling divalent metal and activated carbon electrodes in nonaqueous electrolytes. Conventional supercapacitors require a large amount of electrolyte to provide a sufficient quantity of ions to the electrodes, due to their Daniell-type mechanism that depletes the ions from the electrolyte while charging. The alternative "rocking-chair"-type mechanism effectively enhances the energy density of supercapacitors by minimizing the necessary amount of electrolyte, because the ion is replenished from the metal anode while it is adsorbed to the cathode. Newly developed nonaqueous electrolytes for Mg and Zn electrochemistry, based on bis(trifluoromethylsulfonyl)imide (TFSI) salts, made the metal hybrid supercapacitors possible by enabling reversible deposition on the metal anodes and reversible adsorption on an activated carbon cathode. Factoring in gains through the cell design, the energy density of the metal hybrid supercapacitors is projected to be a factor of 7 higher than conventional devices thanks to both the "rocking-chair"-type mechanism that minimizes total electrolyte volume and the use of metal anodes, which have substantial merits in capacity and voltage. Self-discharge was also substantially alleviated compared to conventional supercapacitors. This concept offers a route to build supercapacitors that meet dual criteria of power and energy densities with a simple cell design.
Perovskite solar cells, which utilize organometal-halide perovskites as light-harvesting materials, have attracted great attention due to their high power conversion efficiency (PCE) and potentially low cost in fabrication. A compact layer of TiO2 or ZnO is generally applied as electron-transport layer (ETL) in a typical perovskite solar cell. In this study, we explored ternary oxides in the TiO2-ZnO system to find new materials for the ETL. Compact layers of titanium zinc oxides were readily prepared on the conducting substrate via spray pyrolysis method. The optical band gap, valence band maximum and conduction band minimum of the ternary oxides varied significantly with the ratio of Ti to Zn, surprisingly, in a nonmonotonic way. When a zinc-rich ternary oxide was applied as ETL for the device, a PCE of 15.10% was achieved, comparable to that of the device using conventional TiO2 ETL. Interestingly, the perovskite layer deposited on the zinc-rich ternary oxide is stable, in sharp contrast with that fabricated on a ZnO layer, which will turn into PbI2 readily when heated. These results indicate that potentially new materials with better performance can be found for ETL of perovskite solar cells in ternary oxides, which deserve more exploration.
Fluorescent molecular probes based on photo-induced electron transfer (PET) are well-known for which fluorescence is efficiently tuned OFF/ON by a PET process. Now we demonstrate that the triplet excited state of the probes is unable to be quenched by PET, which is in stark contrast to the singlet excited state (fluorescence). This conclusion was proved by the preparation of a fluorescent molecular probe BDP-DPA, which shows enhanced fluorescence upon addition of a Zn(ii) salt. With fluorescence spectroscopy, nanosecond transient absorption spectroscopy and electrochemical studies, we found that the triplet excited state of BDP-DPA was not quenched by any PET process, although the singlet excited state (fluorescence) of BDP-DPA was quenched. The results are useful for the study of the triplet excited states of organic chromophores and for designing external stimuli-activatable triplet photosensitizers for triplet-triplet annihilation upconversion and photodynamic therapy.
Phenanthroline derivatives have been reported as potential bioactive compounds because of their ability to interact with DNA. To evaluate the antiproliferative effect of bis(acetylacetonate-k(2) O,O)(1,10-phenanthroline-k(2) N,N)Zn(II) or Zn(acac)2 (phen) complex, the compound was obtained in a simple manner and further characterized to determine crystal structure, thermal behavior, morphology, and spectroscopic properties. The structure of the complex was confirmed by X-ray single structure as well as by 1H and 13C nuclear magnetic resonance (NMR) in dmso-d6 (dimethyl sulfoxide) solution and in the solid state by 13C CP/MAS. Although preparation of this compound has been described previously, there are no reports on its biological activity; here, we assessed its antiproliferative effect on fibroblasts, A253, FaDu, Cal-27, RH-30, RD, U-373, C6, A-549, MDA-MB-231, and MCF-7 cancer cell lines at different doses (50-100 and 150 μg/ml). The cell viability was determined by MTT assay and high activity was observed for the most of the cell lines, and TUNEL results showed the induction of apoptosis.
The majority of amyotrophic lateral sclerosis (ALS)-related mutations in the enzyme Cu,Zn superoxide dismutase (SOD1), as well as a post-translational modification, glutathionylation, destabilize the protein and lead to a misfolded oligomer that is toxic to motor neurons. The biophysical role of another physiological SOD1 modification, T2-phosphorylation, has remained a mystery. Here, we find that a phosphomimetic mutation, T2D, thermodynamically stabilizes SOD1 even in the context of a strongly SOD1-destabilizing mutation, A4V, one of the most prevalent and aggressive ALS-associated mutations in North America. This stabilization protects against formation of toxic SOD oligomers and positively impacts motor neuron survival in cellular assays. We solve the crystal structure of T2D-SOD1 and explain its stabilization effect using discrete molecular dynamics (DMD) simulations. These findings imply that T2-phosphorylation may be a plausible innate cellular protection response against SOD1-induced cytotoxicity, and stabilizing the SOD1 native conformation might offer us viable pharmaceutical strategies against currently incurable ALS.
Hepcidin mediates the hypoferremia of inflammation by inhibiting iron transfer into circulation; however, a regulator for the hypozincemia observed in individuals with acute and chronic inflammatory and infectious diseases is not known.
The objective of this study was to determine the effects of hepcidin on zinc transport in intestinal epithelial cells.
Differentiated human intestinal Caco-2 cells were untreated or treated with 1 μM hepcidin for 3-24 h. Zinc transport was assessed in cells seeded on Transwell inserts. Media from the apical and basolateral chambers were collected, and zinc concentrations were determined using (67)Zn. Labile zinc pools were imaged and quantified in cells loaded with FluoZin-3-AM and expression of metallothionein and the zinc transporters zrt-/irt-like protein (ZIP)4 (SLC39A4), ZIP5 (SLC39A5), ZIP14 (SLC39A14), and zinc transporter 1 (ZnT1) (SLC30A1) was determined. Cells were transfected with SLC40A1- or SLC30A1-specific small interfering RNA to knock down ferroportin and ZnT1 protein, respectively. Cell surface proteins were
 isolated by cell surface biotinylation and lysosomal and proteasomal degradation was inhibited by treating cells with chloroquine or MG132, respectively.
Hepcidin attenuated zinc transport, as cells treated with hepcidin exported 26% less (67)Zn (P < 0.05) into the basolateral chamber and retained 27% more cellular (67)Zn (P < 0.05) than did control cells. Labile zinc decreased, and the mRNA abundance of metallothionein increased by ∼50% in hepcidin-treated cells compared with control cells (P < 0.05). Hepcidin reduced ZnT1 protein by 75% (P < 0.05) compared with control cells. Hepcidin-mediated reductions in zinc export remained in ferroportin knockdown cells compared with untreated controls (P < 0.05), whereas knockdown of ZnT1 inhibited this effect (P ≥ 0.05). Hepcidin significantly reduced biotinylated cell surface ZnT1 compared with control cells (P < 0.05); chloroquine inhibited hepcidin-mediated degradation of ZnT1 (P ≥ 0.05), whereas MG132 had no effect (P < 0.05).
Hepcidin reduces intestinal zinc export by post-translationally downregulating ZnT1 through a lysosomal-mediated degradation pathway, indicating that hepcidin may contribute to the hypozincemia of inflammation and infection.
Research has been conducted to investigate the effects of daily aeration frequency on leachate quality and waste settlement in simulated hybrid landfill bioreactors. Four laboratory-scale reactors were constructed and operated for about 10 months to simulate different bioreactor operations, including one anaerobic bioreactor and three hybrid bioreactors with different aeration frequencies (one, two, and four times per day). Chemical oxygen demand (COD) and biochemical oxygen demand (BOD5) reduced more than 96% of the initial concentrations in all aerated bioreactors. The differences of COD and BOD5 reductions among tested aeration frequencies were relatively small. For ammonia nitrogen, the higher aeration frequency (two or four times per day) resulted in the quicker reduction. Overall, the concentrations of heavy metals (Cr, Co, Cu, Mn, Ni, and Zn) decreased over time except Cd and Pb. The reduction of redox-sensitive metal concentrations (Mn, Co, Ni, and Cu) was greater in aerated bioreactors than in anaerobic bioreactor. Settlement of municipal solid waste (MSW) was enhanced with higher frequency of aeration events (four times per day).
In recent years, hybird bioreactor landfill technology has gained a lot of attention. Appropriate aeration rate is crucial for hybrid bioreactor operation, but few studies have been done and different results were obtained. Research was conducted to investigate the effects of daily aeration frequency on leachate quality and waste settlement. Results indicated that aeration can effectively accelerate waste stabilization and remove organic carbon concentration and total nitrogen in the leachate.
It is an ongoing challenge to fabricate nonprecious oxygen reduction reaction (ORR) catalysts that can be comparable to or exceed the efficiency of platinum. A highly active non-platinum self-supporting Fe-N/C catalyst has been developed through the pyrolysis of a new type of precursor of iron coordination complex, in which 1,4-bis(1H-1,3,7,8-tetraazacyclopenta(1)phenanthren-2-yl)benzene (btcpb) functions as a ligand complexing Fe(II) ions. The optimal catalyst pyrolyzed at 700 °C (Fe-N/C-700) shows the best ORR activity with a half-wave potential (E1/2 ) of 840 mV versus reversible hydrogen electrode (RHE) in 0.1 m KOH, which is more positive than that of commercial Pt/C (E1/2 : 835 mV vs RHE). Additionally, the Fe-N/C-700 catalyst also exhibits high ORR activity in 0.1 m HClO4 with the onset potential and E1/2 comparable to those of the Pt/C catalyst. Notably, the Fe-N/C-700 catalyst displays superior durability (9.8 mV loss in 0.1 m KOH and 23.6 mV loss in 0.1 m HClO4 for E1/2 after 8000 cycles) and better tolerance to methanol than Pt/C. Furthermore, the Fe-N/C-700 catalyst can be used for fabricating the air electrode in Zn-air battery with a specific capacity of 727 mA hg(-1) at 5 mA cm(-2) and a negligible voltage loss after continuous operation for 110 h.
The micronutrients (vitamins and minerals) are required in small amounts but are essential for health, development, and growth. Micronutrient deficiencies, which affect over two billion people around the globe, are the leading cause of many ailments including mental retardation, preventable blindness, and death during childbirth. Fish is an important dietary source of micronutrients and plays important role in human nutrition. In the present investigation, micronutrient composition of 35 food fishes (includes both finfishes and shellfishes) was investigated from varying aquatic habitats. Macrominerals (Na, K, Ca, Mg) and trace elements (Fe, Cu, Zn, Mn, Se) were determined by either atomic absorption spectroscopy (AAS) or inductively coupled plasma mass spectrometry (ICP-MS)/atomic emission spectrometry (ICP-AES). Phosphorus content was determined either spectrophotometrically or by ICP-AES. Fat-soluble vitamins (A, D, E, K) were analyzed by high-performance liquid chromatography (HPLC). The analysis showed that, in general, the marine fishes were rich in sodium and potassium; small indigenous fishes (SIFs) in calcium, iron, and manganese; coldwater fishes in selenium; and the brackishwater fishes in phosphorous. The marine fishes Sardinella longiceps and Epinephelus spp. and the SIFs were rich in all fat-soluble vitamins. All these recommendations were made according to the potential contribution (daily value %) of the species to the recommended daily allowance (RDA). Information on the micronutrients generated would enhance the utility of fish in both community and clinical nutrition.
The present work has been demonstrated a developed method for the determination of Mn, Fe, Co, Ni, Cu, Zn, Mo, Cd, As, Cr, Pb, and V in different types of black teas collected from Saudi Arabia market using inductively coupled plasma mass spectrometry (ICP-MS). Each sample represents a well-mixed combination of ten packets from the same type collected from the market. Detection limits in ng g(-1) were 76.06, 166.03, 5.94, 2.94, 18.29, 18.29, 9.00, 0.48, 0.48, 7.67, 3.07, and 4.21 for Mn, Fe, Co, Ni, Cu, Zn, Mo, Cd, As, Cr, Pb, and V, respectively. In order to validate the developed method, a certified reference material of green tea was analyzed. Further comparison with the results obtained from high-resolution continuum source atomic absorption spectrometry (HR-CS-AAS) was demonstrated. The obtained good agreement confirms the validity of the investigated method. Fortunately, the concentrations of the heavy metals locate on the range of the international values. The highest metal content was found in Al-Rabee tea, and this type results should be confirmed by using a large number of samples in order to have satisfied and confirmed statistical analysis results.
Levels of zinc (Zn), copper (Cu), potassium (K), calcium (Ca), magnesium (Mg), and phosphorus (P) in plasma of Otaria flavescens females (n = 29) were evaluated. Reference intervals were established for each element, being the first report for this species.
This study was conducted to investigate the effect of zinc chitosan chelate (CS-Zn) on zinc transporter expression and content of tissue zinc in weaned piglets. A total of 90 weaned pigs (Duroc × Landrace × Yorkshire) were randomly allocated to treatment groups with supplementation of 100 mg/kg zinc as ZnSO4, 100 mg/kg zinc as mixture of ZnSO4 and chitosan, or 100 mg/kg zinc as CS-Zn, respectively. After 30 days of trial, 18 piglets (six pigs per treatment) were killed and the samples of duodenal mucosa were taken for analysis of zinc transporter mRNA expressions and protein abundance. The results show that CS-Zn more effectively increases (p < 0.05) the average daily gain (ADG) and serum zinc concentration. Zinc concentration in the liver and kidney did not differ between treatments. The mRNA expressions of ZnT1, ZIP4, and ZIP5 in CS-Zn treatment were all upregulated (p < 0.05) than ZnSO4 or mixture of ZnSO4 and chitosan groups. ZnT1 abundance was greater (p < 0.05) with CS-Zn as compared with ZnSO4 and mixture of ZnSO4 and chitosan treatments, whereas ZIP4 and ZIP5 abundance was higher (p < 0.05) in ZnSO4 group. The results indicate that CS-Zn is more effective in serum zinc accumulation, and it might regulate zinc homeostasis by affecting zinc transporter mRNA expression and absorption mechanism might be different with ZnSO4.
There has been some recent criticism about the reliability of the assays commonly used to measure oxidant status in cattle, because some recent publications suggested that the concentration of different trace elements influences the results of these assays. The aim of this study was to test the correlation in 502 bovine serum samples between the concentration of several trace elements (Br, Co, Cr, Cu, Fe, I, Mn, Mo, Ni, Se, Sr, V and Zn) and markers of oxidant status (reactive oxygen species (ROS) and total serum antioxidant capacity (SAC)). The Oxidative Stress index (OSi) was also calculated as ROS/SAC. Some significant correlations were found, although weak (|ρ| < 0.50). Therefore, the relationships observed might be attributed to the different pro- and antioxidant effect of the different elements rather than to the assays detecting these elements instead of the oxidised molecules or total antioxidant potential, respectively. The OSi was poorly correlated (|ρ| ≤ 0.36) with the concentration of the studied trace elements, and therefore, its use is recommended to assess shifts in the systemic redox balance.
The objective of the study was analysis of hair trace elements content in children with goiter living in Aktubinsk region. Children with goiter and age- and sex-adjusted controls were involved in the current study. Hair
 trace elements content was assessed using inductively coupled plasma mass spectrometry. Thyroid volume was measured using an ultrasound scanner and compared to the previously calculated normal values. The obtained data indicate that children with goiter were characterized by 20 and 15 % lower values of hair Cr and Zn, and 66, 42, 16, and 42 % higher hair levels of I, Mn, Si, and V as compared to the control values, respectively. Moreover, children with goiter were characterized by a twofold higher hair B levels than the control ones. Correlation analysis demonstrated a significant direct association only between thyroid volume and hair B (r = 0.482; p = 0.004), I (r = 0.393; p = 0.021), Mn (r = 0.364; p = 0.034), and Si (r = 0.446; p = 0.008) levels. It is also notable that hair I content was interrelated only with Si (r = 0.346; p = 0.045). No significant correlation was detected between I and B (r = 0.250; p = 0.155) and Mn (r = 0.076; p = 0.669) in hair of children. It is hypothesized that an increase in thyroid volume in children is associated with a complex interplay of iodine with other trace elements rather than with altered iodine status itself.
Our previous results showed that cadmium (Cd)-adapted lung epithelial cells (LECs) developed resistance to apoptosis due to non-responsiveness of the c-Jun N-terminal kinase pathway and augmented expression of cytokeratin 8. Since cellular Cd entry is a prerequisite in order for Cd to elicit its cytotoxicity, therefore, we wonder if there are differential metal ion transport ability and also other phenotypic changes that occurred in these Cd-resistant LECs.
Here, we explored further and found that the zinc (Zn) importer Zip8 was stably abolished in these cells along with a marked decrease of Cd and Zn accumulation. Moreover, by cell migration assays and cytokine antibody array analysis, we found that Cd-adapted cells exhibit enhanced migratory ability possibly due to elevated secretions of vascular endothelial growth factor (VEGF) and macrophage inflammatory protein-3 alpha (MIP-3α).
Taken together, our results show that during chronic Cd exposure, lung cells antagonize excessive cellular Cd-influx by abolishing Zip8 expression to reduce Cd-toxicity; however, this also renders cells with a diminished Zn uptake. The imbalance of Zn homeostasis and elevation of angiogenic and epithelial-mesenchymal transition (EMT)-promoting cytokines in Cd-adapted cells might thus likely promote Zn deficiency, angiogenesis, and cell invasion. This article is protected by copyright. All rights reserved.
Arbuscular mycorrhizal symbioses that involve most plants and Glomeromycota fungi are integral and functional parts of plant roots. In these associations, the fungi not only colonize the root cortex but also maintain an extensive network of hyphae that extend out of the root into the surrounding environment. These external hyphae contribute to plant uptake of low mobility nutrients, such as P, Zn, and Cu. Besides improving plant mineral nutrition, arbuscular mycorrhizal fungi (AMF) can alleviate heavy metal (HM) toxicity to their host plants. HMs, such as Cu, Zn, Fe, and Mn, play essential roles in many biological processes but are toxic when present in excess. This makes their transport and homeostatic control of particular importance to all living organisms. AMF play an important role in modulating plant HM acquisition in a wide range of soil metal concentrations and have been considered to be a key element in the improvement of micronutrient concentrations in crops and in the phytoremediation of polluted soils. In the present review, we provide an overview of the contribution of AMF to plant HM acquisition and performance under deficient and toxic HM conditions, and summarize current knowledge of metal homeostasis mechanisms in arbuscular mycorrhizas.
The controllable isotropic thermal expansion with a broad coefficient of thermal expansion (CTE) window is intriguing but remains challenge. Herein we report a cubic MZrF6 series (M = Ca, Mn, Fe, Co, Ni and Zn), which exhibit controllable thermal expansion over a wide temperature range and with a broader CTE window (-6.69 to +18.23 × 10(-6)/K). In particular, an isotropic zero thermal expansion (ZTE) is achieved in ZnZrF6, which is one of the rarely documented high-temperature isotropic ZTE compounds. By utilizing temperature-dependent high-energy synchrotron X-ray total scattering diffraction, it is found that the flexibility of metal···F atomic linkages in MZrF6 plays a critical role in distinct thermal expansions. The flexible metal···F atomic linkages induce negative thermal expansion (NTE) for CaZrF6, whereas the stiff ones bring positive thermal expansion (PTE) for NiZrF6. Thermal expansion could be transformed from striking negative, to zero, and finally to considerable positive though tuning the flexibility of metal···F atomic linkages by substitution with a series of cations on M sites of MZrF6. The present study not only extends the scope of NTE families and rare high-temperature isotropic ZTE compounds but also proposes a new method to design systematically controllable isotropic thermal expansion frameworks from the perspective of atomic linkage flexibility.
The work in the present investigation reports the syntheses, crystal structures, ESI-MS (positive) and steady state and time resolved photophysical properties of a tetraaminodiphenol macrocyclic ligand H2L (saturated analogue of a tetraiminodiphenol macrocycle obtained on 2 + 2 condensation of 4-ethyl-2,6-diformylphenol and 2,2-dimethyl-1,3-diaminopropane) and its three dinuclear d(10) metal ion (Zn(II), Cd(II) and Hg(II)) complexes having compositions [ZnLCl2]·2CH3OH (1), [CdL(μ-H2O)(H2O)2](NO3)2·4H2O (2) and [HgLCl2] (3). H2L is colorless and weakly fluorescent, Cd compound 2 is colorless and more weakly fluorescent, Zn compound 1 is colorless and highly fluorescent and Hg compound 3 is yellow and nonemissive. The order of the radiative rate constant (Kr), obtained from time-resolved studies, corroborates the order of quantum yields, obtained from steady state studies: 1 (φ = 0.12; Kr = 116.6 × 10(6) s(-1)) ≫ H2L (φ = 0.005; Kr = 7.726 × 10(6) s(-1)) > Cd compound 2 (φ = 0.0014; Kr = 0.675 × 10(6) s(-1)). Spectrophotometric and steady state/time-resolved spectrofluorimetric titrations of H2L with Zn(II), Cd(II) and Hg(II) have been performed. The relative fluorescence efficiencies of H2L, H2L + various single metal ions (Zn(II), Cd(II), Hg(II), Cu(II), Ni(II), Co(II), Fe(II), Mn(II)) and H2L + Zn(II) + another metal ion (metal ion competition study) have been studied. Relative fluorescence efficiency can be well rationalized in terms of photoinduced electron transfer (PET), perturbation of PET by metal coordination (chelation enhanced fluorescence, CHEF), heavy metal ion effect (spin-orbit coupling) and fluorescence quenching mechanism. It has been established from comparative fluorescence spectra of 4-ethylphenol, H2L and 1 that H2L can be reasonably considered as a PET species in which the fluorophore is 4-ethylphenol. The binding constants, as determined from titration experiments, qualitatively corroborate the results of metal ion competition studies. The modulation of the absorption spectra and color of the H2L-Hg(II) solution in the presence of various diamagnetic metal ions has been explored. Significant aspects of structures and spectroscopic properties have been discussed.
To satisfy the requirement of simultaneous extraction and characterization of diverse kinds of multitarget analytes, the preparation, characterization, and application of a novel tetraazacalix[2]arene[2]triazine (TCT) coated magnetic nanoparticle (TCT MNP) adsorbent are presented in this paper. TCT assembles two benzene rings and two triazines with nitrogen cross-bridging links, which exhibits a unique structural framework and versatile recognition features based on the multiple recognition sites. These include π electron stacking, charge transfer, hydrogen bonding, and ion-exchange. TCT MNPs acted as a dispersive SPE adsorbent showing strong interaction with and adsorption of polycyclic aromatic hydrocarbons (PAHs), nitroaromatics, and heavy metal ions. The dispersive magnetic nanoparticle solid phase extraction (d-MNSPE) strategy with the simultaneous extraction and stepwise elution (SESE) procedure was designed and optimized for the five PAHs (phenanthrene, anthracene, pyrene, chrysene, and benzo(a)pyrene), six nitroaromatics (4-nitrotoluene, 2,4-dinitrotoluene, 2,4,6-trinitrotoluene, 4-nitrophenol, 2,4-dinitrophenol, and 2,4,6-trinitrophenol), and four metal ions (Cu, Zn, Mn, Cd) in aqueous samples. Due to the high stability, desirable durability, larger saturation magnetization, reuse and distinct enrichment capacity of TCT MNPs, the d-MNSPE method with the SESE strategy provided high recovery (>90%) and good precision (relative standard deviations, RSD < 10%). Coupled with the commonly used HPLC-fluorescence detection, HPLC-UV detection, and atomic absorption spectrometry, these trace probes in tap water, river water, and lake water were determined with very low detection limits, in the range of 0.09-0.15 pg mL(-1) for PAHs, 6-11 pg mL(-1) for nitroaromatics, and 17-53 pg mL(-1) for metal ions after being enriched by the d-MNSPE. The determination of trace PAHs in urine samples from smokers and nonsmokers was successfully carried out with this method, which implied that the versatile TCT MNPs and the robust method together represent a significant potential application in the analysis of body fluids and disease markers. Such methods for accurate quantification of trace components in water are very valuable as they fulfill an unmet need in environmental and medicinal chemistry.
Interesting reactivity was observed in reactions of SO2 with [Zn(Cp*)2] and [(Cp*)Zn(I)-Zn(I)(Cp*)]. These
 reactions proceeded with insertion of SO2 into the Zn-C bonds. Spectacularly, the lability of the C-S bond in the O2SCp* ligands led to the thermal decomposition of [Zn(O2SCp*)2(tmeda)] to afford [Zn2(μ-SO3)(μ-S2O4)(tmeda)2].
We applied spectroscopy, microscopy, diffraction, and aqueous chemistry methods to investigate the persistence of metals in water and sediments from the Animas River 13 days after the Gold King Mine spill (August 5, 2015). The Upper Animas River watershed, located in San Juan Colorado, is heavily mineralized and impacted by acid mine drainage, with low pH water and elevated metal concentrations in sediments (108.4 ± 1.8 mg kg(-1) Pb, 32.4 ± 0.5 mg kg(-1) Cu, 729.6 ± 5.7 mg kg(-1) Zn, and 51 314.6 ± 295.4 mg kg(-1) Fe). Phosphate and nitrogen species were detected in water and sediment samples from Farmington, New Mexico, an intensive agricultural area downstream from the Animas River, while metal concentrations were low compared to those observed upstream. Solid-phase analyses of sediments suggest that Pb, Cu, and Zn are associated with metal-bearing jarosite and other minerals (e.g., clays, Fe-(oxy)hydroxides). The solubility of jarosite at near-neutral pH and biogeochemical processes occurring downstream could affect the stability of metal-bearing minerals in river sediments. This study contributes relevant information about the association of metal mixtures in a heavy mineralized semiarid region, providing a foundation to better understand long-term metal release in a public and agricultural water supply.
Uricase is a clinical enzyme used for the oxidation of uric acid crystals in gout disease. The present study aimed to increase the suitable surfactant-mediated uricase production on induction by different concentrations of inducers. The efficiency of Bacillus cereus to produce extracellular uricase enzyme was studied in uric acid-containing agar plates. Among the studied inducers, uric acid is the potential inducer for uricase production under submerged fermentations (SMF), which induced 19.41 U/ml uricase in medium containing 2.0 g/L of uric acid, however further increase in the uric acid concentration decreased uricase production, which could be because of substrate inhibition. The physical parameters including agitation speed (rpm) and time duration (h) of uricase production were optimized and found to produce optimum uricase at 150 rpm in 26 h of SMF. Among the studied surfactants, nonionic surfactant, polyvinyl alcohol has shown a remarkable increase in the uricase production of 31.58 U/ml, which is a 61% increase under optimized conditions in SMF. The stability of produced uricase was found at pH 7.5 and temperature 30°C. Also the effects of various metal ions (1 mM) on the uricase activity were studied and observed to be inhibitory in nature in the descending order K(+) > Ca(2+) > Zn(2+) > Fe(3+) > Ni(2+) > Mg(2+) > Mn(2+) > Cu(2+).
To analyze the pollution characteristics, source apportionment, and health risk of heavy metals (HMs) in street dust of Suzhou, China, 23 sampling sites were selected and periodically sampled for 12 months. A total of 276 samples were collected, and the concentrations of selected HMs (e.g., Cr, Cu, Fe, Mn, Pb, V, and Zn) were examined with an X-ray fluorescence spectrum analyzer. Results showed that the mean concentrations of Cr, Cu, Fe, Mn, Pb, V, and Zn in the street dust of Suzhou were 112.9, 27.5, 19941.3, 410.3, 45.2, 75.6, and 225.3 mg kg(-1), respectively. Cr, Cu, Pb, and Zn exceeded their background values in local natural soils by 1.3-3.6-fold, whereas Fe, Mn, and V were all within their background values. However, enrichment factor analysis revealed that Cr, Cu, Mn, Pb, V, and Zn, especially Cr, Cu, Pb, and Zn, were enriched in Suzhou street dust. The HMs showed no significant seasonal changes overall, but spatial distribution analysis implied that the high values of Cr, Cu, Mn, Pb, V, and Zn were mainly distributed in areas with frequent human activities. Results of multivariate techniques (e.g., Pearson correlation, hierarchical cluster, and principal components analyses) suggested that Pb and Zn had complicated sources; Cu and V mainly originated from traffic sources; Fe and Mn mainly came from natural sources; and Cr was dominantly related to industrial district. Health risk assessment revealed that a single heavy metal might not cause both non-cancer and carcinogenic risks to local residents. Nevertheless, the sum of the hazard index of all selected HMs for children slightly exceeded the safety value, thereby implying that the HMs from Suzhou street dust can possibly produce significant risk to children. Cr was the priority pollutant in the study area because of its high concentration, high enrichment, and high contribution to non-cancer risk values.
For the first time, long-term monitoring (from 2002 to 2014) was carried out of surface sediments in Ludaš Lake, a Ramsar site in northern Serbia. Organic (16 EPA PAHs, mineral oils, selected pesticides and polychlorinated biphenyls (PCBs)) and inorganic substances (eight heavy metals: Ni, Zn, Cd, Cr, Cu, Pb, As and Hg) were continually investigated. Dibenzo[a,h]anthracene (DahA) and fluorene (Flo) were found at levels indicative of causing adverse effects to biota. Diagnostic ratios of specific PAHs were dominated by high molecular weight components, particularly DahA, which contributed 81.78 % of the total high carcinogens, benzo[b]fluoranthene (BbF) and Flo. Potential ecological risk factors (ERi) and the high relative standard deviations (RSD) obtained (up to 245 %) for the parameters monitored confirm the high periodical anthropogenic impact from industry, municipal wastewater and agriculture. The highest concentration of inorganic pollution found was for Cd (440-831 mg/kg) at all sites, Cu (439 mg/kg) in the eastern part of the lake and Cu (388 mg/kg) and Hg (771 mg/kg) in the northern part of the lake. Based on factor analysis of principal component analysis (PCA/FA), As and phenanthrene (Phe) had significant loadings (0.808 and 0.907, respectively). This association of As with organic anthropogenic sources was also confirmed with the sum of PAHs, pyrene (Pyr) and mineral oil by 3D factor plot, corroborating the theory of As mobilization from metal-reducing microbes as organic (methylated) forms, accelerated by phenanthrene. According to EU national and regional data results, this research suggests that Cu, As, dibenzo[a,h]anthracene and Flo should be added to the list of priority pollutants within the context of applying the European Water Framework Directive (WFD).
Gastrin, acting via the cholecystokinin-2 receptor (CCK2R), activates its own promoter in a positive-feed-forward loop that may result in hypergastrinemia. Activity of the gastrin promoter is also stimulated by exogenous Zn(2+) ions. Here, the role of intracellular zinc and calcium signaling in the gastrin positive-feed-forward loop was investigated. Gastrin promoter activity was measured in the human gastric carcinoma cell line AGS-CCK2R and in Jurkat cells transfected with various gastrin promoter-luciferase constructs after treatment with gastrin in the presence and absence of zinc- and calcium-chelating agents. The free intracellular zinc ion concentrations were measured in the same cells with the fluorescent indicator FluoZin-3. Cell proliferation and migration/invasion were measured by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide cell proliferation assay and in Boyden chamber assays, respectively. The zinc chelator N,N,N,N-tetrakis-(2-pyridylmethyl)-ethylenediamine (TPEN) abolished gastrin-stimulated gastrin promoter activity, and the inhibition was completely reversed by exogenous Zn(2+) ions. In contrast, the calcium chelator 1,2-Bis(2-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid tetrakis(acetoxymethyl ester) (BAPTA-AM) potentiated gastrin-stimulated gastrin promoter activity. Treatment with gastrin increased the intracellular concentration of free Zn(2+) ions, and the increase was blocked by TPEN, but not by BAPTA-AM. TPEN also inhibited the stimulation of cell proliferation and migration/invasion by gastrin, but BAPTA-AM had no effect. These results, which are the first report of the existence of Zn(2+) signaling downstream of CCK2R activation, suggest that zinc chelation therapies may be effective in counteracting gastrin-dependent tumor growth.
The cellular levels of methylglyoxal (MG), a toxic byproduct of glycolysis, rise under various abiotic stresses in plants. MG is detoxified primarily through the glyoxalase pathway. The first enzyme of the pathway, glyoxalase I (GLYI), is a cytosolic metalloenzyme requiring either Ni(2+) or Zn(2+) for its activity. Plants possess multiple GLYI genes, of which only some have been partially characterized and hence, the precise molecular mechanism, subcellular localization and physiological relevance of these diverse isoforms remain enigmatic. Here, we report the biochemical properties and physiological role of a putative chloroplast-localized GLYI enzyme, OsGLYI-8 from rice, which is strikingly different from all hitherto studied GLYI enzymes in terms of its intracellular localization, metal dependency and kinetics. In contrast to its predicted localization, OsGLYI-8 was found to localize in the nucleus along with its substrate, MG. Further, OsGLYI-8 does not show a strict requirement of metal ions for its activity, is functional as a dimer and exhibits unusual biphasic steady-state kinetics with a low-affinity and a high-affinity substrate binding component. Loss of AtGLYI-2, the closest Arabidopsis ortholog of OsGLYI-8, results in severe germination defects in the presence of MG and growth retardation upon salinity stress. These defects were rescued upon complementation with AtGLYI-2 or OsGLYI-8. Our findings thus, provide evidence for the presence
 of a GLYI enzyme and methylglyoxal detoxification in the nucleus. This article is protected by copyright. All rights reserved.
We present electronic spectra in the π-π* region of a series of tris(bpy)-M(II) complex ions (bpy = 2,2'-bipyridine; M = Mn, Fe, Co, Ni, Cu, Zn) in vacuo for the first time. By applying photodissociation spectroscopy to cryogenically cooled and mass selected [M(II)(bpy)3](2+) ions, we obtain the intrinsic spectra of these ions at low temperature without perturbation by solvent interaction or crystal lattice shifts. This allows spectroscopic analysis of these complex ions in greater detail than possible in the condensed phase. We interpret our experimental data by comparison with time-dependent density functional theory.
Solidification and stabilization are well-known technologies used for treating hazardous waste. These technologies that use cementitious binder have been applied for decades as a final treatment procedure prior to the hazardous waste disposal. In the present work, hazardous waste like fly ash containing high concentrations of heavy metals such Zn (4715.56 mg/kg), Pb (1300.56 mg/kg), and Cu (534.72 mg/kg) and amounts of Ag, Cd, Co, Cr, Mn, and Ni was sampled from a city refuse incinerator facility. This fly ash was utilized in the solidification/stabilization of heavy metal sludge since fly ash has cement-like characteristics. Cement additives such as sodium sulfate, sodium carbonate, and ethylenediaminetetraacetic acid (EDTA) was incorporated to the solidified matrix in order to determine its effect on the solidification/stabilization performance. The solidified matrix was cured for 7, 14, 21, and 28 days prior for its physical and chemical characterizations. The results show that the solidified matrix containing 40% fly ash and 60% cement with heavy metal sludge was the formulation that has the highest fly ash content with a satisfactory strength. The solidified matrix was also able to immobilize the heavy metals both found in the fly ash and sludge based on the toxicity characteristic leaching procedure (TCLP) test. It also shows that the incorporation of sodium carbonate into the solidified matrix not only further improved the compressive strength from 0.36 MPa (without Na2CO3) to 0.54 MPa (with Na2CO3) but also increased its leaching resistance.
The Amarillo River (Famatina range, Argentina, ~29° S and ~67° W) is unusual because acid mine drainage (AMD) is superimposed on the previously existing acid rock drainage (ARD) scenario, as a Holocene paleolake sedimentary sequence shows. In a markedly oxidizing environment, its water is currently ferrous and of the sulfate-magnesium type with high electrical conductivity (>10 mS cm(-1) in uppermost catchments). At the time of sampling, the interaction of the mineralized zone with the remnants of mining labors determined an increase in some elements (e.g., Cu ~3 to ~45 mg L(-1); As ~0.2 to ~0.5 mg L(-1)). Dissolved concentrations were controlled by pH, decreasing significantly by precipitation of neoformed minerals (jarosite and schwertmannite) and subsequent metal sorption (~700 mg kg(-1) As, 320 mg kg(-1) Zn). Dilution also played a significant role (i.e., by the mixing with circumneutral waters which reduces the dissolved concentration and also enhances mineral precipitation). Downstream, most metals exhibited a significant attenuation (As 100 %, Fe 100 %, Zn 99 %). PHREEQC-calculated saturation indices (SI) indicated that Fe-bearing minerals, especially schwertmannite, were supersaturated throughout the basin. All positive SI increased through the input of circumneutral water. PHREEQC inverse geochemical models showed throughout the upper and middle basin, that about 1.5 mmol L(-1) of Fe-bearing minerals were precipitated. The modeling exercise of mixing different waters yielded results with a >99 % of correlation between observed and modeled data.
The fluorescence quantum yield of the 5,10,15,20-tetraphenylporphyrin, 5,10,15,20-tetra(4-OH-phenyl)porphyrin, 5,10,15,20-tetra(4-Cl-phenyl)porphyrin, 5,10,15,20-tetra(4-NH2-phenyl)porphyrin and their complexes with Zn(2+) have been determined and the kinetic rate constants of the porphyrins ligands complexation with Zn(2+) in acetonitrile have been estimated. It was shown that the substituents on the tetrapyrrolic macrocycle periphery have a strong influence on the fluorescent and coordination properties of the investigated porphyrins.
A new bi-functional chemosensor 1 based on 3,5-dichlorosalicylaldehyde and 2-(methylthio)aniline has been synthesized. It can detect Cu(2+) with a color change from pale yellow to dark yellow in aqueous solution. The selective mechanism of 1 for Cu(2+) was proposed to be the enhancement of the intramolecular charge transfer (ICT) band, which was explained by theoretical calculations. The sensor 1 could be used to detect and quantify Cu(2+) in water samples. In addition, the sensor 1 displayed "turn-on" fluorescence response only to Zn(2+), based on an effect of chelation-enhanced fluorescence (CHEF). Therefore, 1 can serve as a 'single sensor for two different targets' with dual modes.
This study was designed to investigate the profile of certain trace elements having therapeutic properties related to diabetes mellitus. The investigated plants were Aloe camperi, Meriandra dianthera, Lepidium sativum, Brassica nigra, and Nigella sativa. These plants are traditionally used in the management of diabetes in Eritrea. The elemental analysis was conducted using inductively coupled plasma optical emission spectrometry (ICP-OES) and flame atomic absorption spectroscopy (FAAS) techniques. The accuracy of the methods was verified using in-house reference materials (CRMs) and no significant differences were observed between the measured and certified values. The analysis displayed variable concentrations of the different trace elements including Zn, Cr, V, Mn, and Se in the plants. Moreover, the levels of major elements, such as Mg, Ca, K, Na, and Ba, and heavy metals, such as Fe, Cu, Ni, Co, As, and Pb, were determined and found to be in the permissible limit defined by WHO. Among the plants, Meriandra dianthera showed the highest levels of Mn, Cr, V, and other elements and the values were significantly different (P < 0.05).
Zhangjiangkou Mangrove National Nature Reserve is a subtropical wetland ecosystem in southeast coast of China, which is of dense population and rapid development. The concentrations, sources, and pollution assessment of trace metals (Cu, Cd, Pb, Cr, Zn, As, and Hg) in surface sediment from 29 sites and the biota specimen were investigated for better ecological risk assessment and environmental management. The ranges of trace metals in mg/kg sediment were as follows: Cu (10.79-26.66), Cd (0.03-0.19), Pb (36.71-59.86), Cr (9.67-134.51), Zn (119.69-157.84), As (15.65-31.60), and Hg (0.00-0.08). The sequences of the bioaccumulation of studied metals are Zn > Cu > As > Cr > Pb > Cd > Hg with few exceptions. Cluster analysis and principal component analysis revealed that the trace metals in the studied area mainly derived from anthropogenic activities, such as industrial effluents, agricultural waste, and domestic sewage. Pollution load index and geoaccumulation index were calculated for trace metals in surface sediments, which indicated unpolluted status in general except Pb, Cr, and As.
FAAS was used for the analysis of trace metals in fresh and dry plant parts of Cymbopogon validus and Hyparrhenia hirta species with the aim of determining the trace metals concentrations in selected traditional plants consumed in Eastern Cape, South Africa. The trace metal concentration (mg/kg) in the samples of dry Cymbopogon validus leaves (DCVL) showed Cu of 12.40 ± 1.000; Zn of 2.42 ± 0.401; Fe of 2.50 ± 0.410; Mn of 1.31 ± 0.210; Pb of 3.36 ± 0.401 mg/kg, while the samples of fresh Hyparrhenia hirta flowers (FHHF) gave Cu of 9.77 ± 0.610; Zn of 0.70 ± 0.200; Fe of 2.11 ± 0.200; Mn of 1.15 ± 0.080; Pb of 3.15 ± 0.100 mg/kg. Abundance of metal concentrations follows the order: Cu > Fe > Pb > Mn > Zn in the flower samples of Cymbopogon validus and Hyparrhenia hirta species. The concentrations of trace metals in both plant parts were below the permissible limits (PL) set by WHO. It is suggested that pharmacovigilance be carried out periodically to improve the quality, safety, and efficiency of various herbal products.
Four new metal complexes [Cu(ISO)2], [Cu(BUT)2] and [Zn(ISO)2], [Zn(BUT)2] of the polyhydroxychalcones (isoliquiritigenin and butein) are synthesized, structurally characterized and their antioxidant activity is investigated. The formation of the complexes [Cu(ISO)2] and [Zn(ISO)2] is followed by Job's plot using NMR titration. The resulting compounds are characterized by mass spectrometry, IR spectroscopy, and elemental analysis. Studies on the radical scavenging activity are performed using DPPH as substrate. The results showed that the antioxidant activities of isoliquiritigenin and butein are enhanced after binding to copper or zinc.

Anthyllis vulneraria is a legume associated with nitrogen-fixing rhizobia that together offer an adapted biological material for mine-soil phytostabilization by limiting metal pollution. Our study evaluated the genetic and phenotypic properties of a 137 rhizobia collection recovered from soils presenting contrasted metal levels to find rhizobia associated with Anthyllis and a given site. Zn-Pb mine soils contained a large majority of metal-tolerant rhizobia belonging mainly to Mesorhizobium metallidurans, or to another sister metal-tolerant species. All of the metal-tolerant isolates harbored the cadA marker gene (a gene encoding a metal-efflux PIB-type ATPase transporter). In constrast, metal-sensitive strains were taxonomically distinct from metal-tolerant populations and consisted of new Mesorhizobium genospecies.
 Based on the symbiosis nodA marker, the populations consist of two symbiovar assemblages (potentially related to Anthyllis or Lotus host preferences) according to soil geographic locations but independently of metal content. Multivariate analysis showed that soil Pb and Cd concentrations were differentially impacting the rhizobial community and that the rhizobial community found in one geographically distant site was highly divergent from the others. In conclusion, heavy metal levels in soils drive the taxonomic composition of Anthyllis-associated rhizobial populations according to their metal-tolerance phenotype but not their symbiotic nodA diversity. In addition to heavy metals, local soil physico-chemical and topo-climatic conditions also impact the rhizobial beta diversity. Mesorhizobium communities were locally adapted and site-specific and their use is recommended for the success of phytostabilization strategies based on Mesorhizobium-legume vegetation.
Phytostabilization of toxic mine spoils aims to limit heavy metal dispersion and environmental pollution by establishing a sustainable plant cover. This eco-friendly method is facilitated by the use of selected and adapted cover crop legumes living in symbiosis with rhizobia that can stimulate plant growth naturally through biological nitrogen fixation. We studied microsymbiont partners of a metal-tolerant legume Anthyllis vulneraria tolerant to very highly metal-polluted soils in mining and non-mining sites. Site-specific rhizobial communities were found linked to taxonomic composition and metal tolerance capacity. The rhizobial species Mesorhizobium metallidurans was dominant in all Zn-Pb mines except one. It was not detected in unpolluted sites where other distinct Mesorhizobium species occur. Given the different soil conditions at the respective mining sites, including their heavy metal contamination, re-vegetation strategies based on rhizobia adapted to local conditions are more likely be successful over the long-term compared to strategies based on introducing less-well-adapted strains.
A gonadotropin-releasing hormone agonist (GnRH-A) implant induces hormonal castration in dogs that is associated with reduced prostate and testes size. We address the molecular events associated with hormonal castration by examining GnRH-A effects on expression and phosphorylation of a number of key signaling proteins. Male beagles were treated for 5 months with a GnRH-A implant, and then surgically castrated at 0, 3, 6, 12, and, 24 weeks after implant removal; untreated animals served as controls. GnRH-A treatment led to activation of c-Raf, Erk1/2, and, p53 in the testes. Phosphorylation of p53 occurred at Ser15, consistent with activation of the c-Raf-Erk1/2-p53 signaling cascade that triggers growth arrest or apoptosis. GnRH-A also suppressed the anti-apoptotic protein Bcl-xL; reduced phosphorylation of the transcription factors CREB and ATF1; and down-regulated expression of StAR and P450scc, proteins involved in steroidogenesis. Although androgen receptor expression was little affected by GnRH-A treatment, levels of ZIP9, a membrane-bound Zn(2+) transporter that mediates non-classical signaling of testosterone, were abrogated. All of these effects were reversed within 24 weeks after implant removal. Thus, molecular signatures of implant-dependent hormonal castration include reversible cell cycle arrest and apoptosis, loss of steroidogenesis, and reduced transcriptional activity. Mol. Reprod. Dev. 9999: 1-10 2016. © 2016 Wiley Periodicals, Inc.
Clostridium difficile is the most commonly reported nosocomial pathogen in the United States and is an urgent public health concern worldwide. Over the past decade, incidence, severity and costs associated with C. difficile infection (CDI) have increased dramatically. CDI is most commonly initiated by antibiotic-mediated disruption of the gut microbiota; however, non-antibiotic-associated CDI cases are well documented and on the rise. This suggests that unexplored environmental, nutrient and host factors probably influence CDI. Here we show that excess dietary zinc (Zn) substantially alters the gut microbiota and, in turn, reduces the minimum amount of antibiotics needed to confer susceptibility to CDI. In mice colonized with C. difficile, excess dietary Zn severely exacerbated C. difficile-associated disease by increasing toxin activity and altering the host immune response. In addition, we show that the Zn-binding S100 protein calprotectin has antimicrobial effects against C. difficile and is an essential component of the innate immune response to CDI. Taken together, these data suggest that nutrient Zn levels have a key role in determining susceptibility to CDI and severity of disease, and that calprotectin-mediated metal limitation is an important factor in the host immune response to C. difficile.
We demonstrate a unique synthetic route for oxygen-deficient mesoporous TiOx by a redox-transmetalation process by using Zn metal as the reducing agent. The as-obtained materials have significantly enhanced electronic conductivity; 20 times higher than that of as-synthesized TiO2 material. Moreover, electrochemical impedance spectroscopy (EIS) and galvanostatic intermittent titration technique (GITT) measurements are performed to validate the low charge carrier resistance of the oxygen-deficient TiOx . The resulting oxygen-deficient TiOx battery anode exhibits a high reversible capacity (∼180 mA h g(-1) at a discharge/charge rate of 1 C/1 C after 400 cycles) and an excellent rate capability (∼90 mA h g(-1) even at a rate of 10 C). Also, the full cell, which is coupled with a LiCoO2 cathode material, exhibits an outstanding rate capability (>75 mA h g(-1) at a rate of 3.0 C) and maintains a reversible capacity of over 100 mA h g(-1) at a discharge/charge of 1 C/1 C for 300 cycles.
Absorption, accumulation and translocation of 12 trace elements in nine dominant mangrove plants in the Indian Sundarban Wetland revealed both organ-specific and site-specific characteristics. An overall enrichment of elements was recorded in rhizosediment, exceeding the prescribed effects range-low (ER-L) of consensus based sediment quality guidelines (SQGs) for Cu and Pb. Avicennia officinalis, A. alba, Ceriops decandra and Excoecaria agallocha exhibited unique potential for accumulating Al, Cd, Co, Cr, Cu, Ni, Mn and Zn and could be considered efficient accumulators. Maximum element accumulation in trunk bark (As 6.16, Cr 49.9, Co 2.67, Cu 91.00 and Zn 85.5 mg kg(-1)) and root/pneumatophore (Al 1000 and Fe 2430 mg kg(-1)) was recorded. Maximum bioconcentration factor (6.23) in A. officinalis and translocation factor (17.5 for Mn) in C. decandra distinguished their phytoremediation capacity. These halophytes could be used for trace element phytoremediation in stressed sites of Sundarban.
The aim of the study was to assess the water pollution in terms of total content of heavy metals by parameter called Heavy metal pollution index (HPI). The water samples were collected from four different locations along the course of the river during spring and the autumn seasons. The concentrations of lead (Pb), cadmium (Cd), iron (Fe), zinc (Zn), manganese (Mn), copper (Cu), arsenic (As) and mercury (Hg) were determined using atomic absorption spectroscopy. The data were used to evaluate HPI of the river water. The mean value of HPI was 67.487 for the spring season, and 80.676 for the autumn season. The average for both seasons and all sampling sites is 74.082. The maximum value of 112.722 found at one sampling site is above the critical index limit of 100. Also, from the values of mean HPI for each sampling site could be concluded that the pollution load at sampling site-4 is the most significant (HPI 89.575).
Heavy metals are among the major contaminants of vegetables. A study was conducted at Wonji Gefersa farms where paper wastewater is used for cultivation of vegetable crops. Four vegetable samples, namely Swiss chard, carrot, tomato, green pepper, as well as paper wastewater were examined for heavy metal [Lead (Pb), Zinc (Zn), Cadmium (Cd), Iron (Fe), Copper (Cu), Chromium (Cr) and Cobalt (Co)] contamination using atomic absorption spectroscopy. The levels of Pb, Cd and Cr in paper wastewater were all above the safe limit for FAO standards for wastewater quality for irrigation. The concentration of Pb in Swiss chard and Green peeper was exceeded the permissible limits. The study reveals that Pb metal contamination in the study area which poses health risk with time unless an urgent step is taken by relevant agencies to address this issue.
Colorimetric fluorescent chemosensors 4 and 5 based on mono- and di- styryl borondipyrromethenes (BODIPY) linked methyl malonyl were designed for detection of hemoglobin (HgB). Their sensing behavior toward various analytes (Br(-), EDTA, Glucose, CO3(2-), Fe(2+), Fe(3+), I(-), NO3(-), PO4(3-), SO4(2-),Cl(-), Urea, K(+), Mg(2+), Na(+), NH4(+), Zn(2+),Ca(2+),Cd(2+), Li(+), Pb(2+), Cs(2+), Ag(+), Mn(2+), Cr(2+), Ni(2+), Hg(2+), Al(3+)) were investigated by fluorescence spectroscopies. Addition of HgB to acetone: water (4:1) solutions of BODIPYs 4 and 5 solutions gave visual color changes, as well as significantly quenched fluorescence emissions, while other analytes induced no or much smaller spectral changes. The sensing method for both BODIPYs 4 and 5 was successfully applied to measure the HgB in human blood with satisfactory results. Spike and recovery tests in human blood samples exhibit good recovery rates for the spiked concentrations close to the limit of detection. It was found that BODIPYs 4 and 5 constituted the HgB selective fluorescent chemosensor (ON-OFF) and the detection limits were calculated to be 1.773 μg. mL(-1) and 1. 295 μg.mL(-1) respectively.
The effect of electronegativity and ion size of the modifier
 cations have been analyzed through a new series of Dy(3+) doped telluroborate glasses prepared by melt quenching technique with the composition of 30TeO2 + 29.5B2O3 + 20MO + 20MF2 + 0.5Dy2O3 (where M = Ba(2+), Sr(2+), Zn(2+), Cd(2+) and Pb(2+)). The various stretching and bending vibrational modes of borate and tellurite network have been identified through FTIR spectral measurements. The conversion of BO3 units into BO4 units increases NBOs in the glass network and the same is confirmed through FTIR spectra. The nephelauxetic ratio ([Formula: see text]) and bonding parameter (δ) value reveals that the Dy-O bond in prepared glasses possesses ionic nature. JO intensity parameters (Ω2, Ω4 and Ω6) of the present glasses follow the trend Ω2 > Ω4 > Ω6 uniformly in all the prepared glasses. Radiative parameters like transition probability (A), stimulated emission cross section[Formula: see text], branching ratio (βR) values have been predicted from the absorption spectra of Dy(3+) ions using JO theory. Among the prepared glasses TBZnD glass posses a better CIE 1931 colour chromaticity coordinates (0.33, 0.39) and CCT value (5019 K). Decay profile of (4)F9/2 state of the Dy(3+) ion exhibits non-exponential nature due to the interaction between Dy(3+)-Dy(3+) ions. The nature of interaction between Dy(3+)-Dy(3+) ions has been analyzed through Inokuti-Hirayama model and the best fit of S = 6 indicates that the dipole-dipole interaction is responsible for the energy transfer between Dy(3+)-Dy(3+) ions. The glass containing Zn(2+) ions posses encouraging results such as higher Y/B intensity ratio, stimulated emission cross section and higher branching ratio ((4)F9/2 → (6)H13/2). Thus the present study identified the Zn(2+) ions as a better modifier ion to develop the Dy(3+) doped glasses for various photonic applications.
A new zinc complex, [Zn (9-AC)2] (1) (9-AC = 9-anthracenecarboxylic acid), was prepared via conventional electrochemical method in a fast and facile process and fully characterized by (1)H NMR, (13)C NMR, IR spectroscopy and elemental analysis. The nano structures of the same compound were successfully produced by a facile and environment-friendly sonoelectrochemical route at different current densities (0.5, 1.2, 1.8, 2.5 and 3.5 mA/cm(2)). The new nano-structure particles were characterized by scanning electron microscopy, X-ray powder diffraction, IR spectroscopy and elemental analysis. Thermal stability of single crystal and nano-size samples of the prepared compound was studied by thermogravimetric and differential thermal analysis. The comparison of the effect of current density without and with ultrasonic irradiation on particle size has been investigated in convectional electrochemical and sonoelectrochemical method respectively. The results showed that using ultrasonic irradiation with increasing the current density lead to decrease the particle sizes unlike conventional electrochemical method. In other words, when the current density increase from 0.5 to 3.5 mA/cm(2), in sonoelectrochemical method, the particle sizes decrease from 100 to 48 nm while, in convectional electrochemical method, the particle sizes increase from 400 to 1200 nm and possible explanation offered. Photoluminescence properties of the nano-structured and crystalline bulk of the prepared complex at room temperature in the solid state have been investigated in detail. The results indicate that the size of the complex particles has an important effect on their optical properties.
An efficient "off-on" type fluorescent chemosensor, (E)-N'-(4-(diethylamino)-2-hydroxybenzylidene)-2-hydroxybenzohydrazide (H 2 L), based on Schiff base for the determination of Al(3+) has been designed, synthesized, and evaluated. Upon treated with Al(3+), the fluorescence of H 2 L was enhanced 45-fold due to the chelation-enhanced fluorescence (CHEF) effect based on the formation of a 1:1 complex between the chemosensor and Al(3+). Other metal ions, such as Na(+), K(+), Mg(2+), Ca(2+), Cu(2+), Ga(3+), Zn(2+), Cr(3+), Cd(2+), Ag(+), Fe(3+), In(3+), Mn(2+), Pb(2+), Co(2+), and Ni(2+) had little effect on the fluorescence. The results demonstrate that the chemosensor H 2 L has stronger affinity with Al(3+) than other metal ions. The detection limit of H 2 L for sensing Al(3+) is 3.60 × 10(-6) M in EtOH-H2O (3:7, v/v) solution. And the recognizing behavior has been investigated both experimentally and computationally.
3,3',5,5'-Tetraphenyl-2,2'-dipyrromethene was described as a highly sensitive and selective Off-on fluorescent colorimetric chemosensor for Zn(2+) based on the chelation-enhanced fluorescence (CHEF) effect. The reaction of dipyrromethene ligand with Zn(2+) induces the formation of the [ZnL2] complex, which exhibits the increasing fluorescence in 120 fold compared with ligand in the propanol-1/cyclohexane (1:30) binary mixture. The Zn(2+) detection limit was 1.4 × 10(-7) М. The UV-Vis and fluorescence spectroscopic studies demonstrated that the dipyrromethene sensor was highly selective toward Zn(2+) cations over other metal ions (Na(+), Mg(2+), Co(2+), Ni(2+), Fe(3+), Cu(2+), Mn(2+), Cd(2+) and Pb(2+)), excluding Hg(2+).
Human exposure to arsenic (As) can lead to oxidative stress that can become evident in organs such as the skin, liver, kidneys and lungs. Several intracellular antioxidant defense mechanisms including glutathione (GSH) and metallothionein (MT) have been shown to minimize As cytotoxicity. The current review summarizes the involvement of MT as an intracellular defense mechanism against As cytotoxicity, mostly in blood. Zinc (Zn) and selenium (Se) supplements are also proposed as a possible remediation of As cytotoxicity. In vivo and in vitro studies on As toxicity were reviewed to summarize cytotoxic mechanisms of As. Intracellular antioxidant defense mechanisms of MT are linked in relation to As cytotoxicity. Arsenic uses a different route, compared to major metal MT inducers such as Zn, to enter/exit blood cells. A number of in vivo and in vitro studies showed that upregulated MT biosynthesis in blood components are related to toxic levels of As. Despite the cysteine residues in MT that aid to bind As, MT is not the preferred binding protein for As. Nonetheless, intracellular oxidative stress due to As toxicity can be minimized, if not eliminated, by MT. Thus MT induction by essential metals such as Zn and Se supplementation could be beneficial to fight against As toxicity.
Prenatal lead exposure is associated with poor intellectual development in children. However, there are few breakthroughs in therapeutic intervention of developmental lead neurotoxicity. The aim of this study is to evaluate the hypothesis that ferulic acid-mediated promotion of neurite outgrowth following lead exposure might mainly result from its antioxidant capability by extracellular signal-regulated kinases 1 and 2 (ERK1/2) activation of nuclear factor erythroid 2-related factor 2 (Nrf2). Exposure of PC12 cells to lead acetate inhibits neurite outgrowth and causes oxidative stress as measured by ROS, LPO, GSH/GSSG, and NAD(+)/NADH. FA treatment significantly, although not completely, protected the cells against lead acetate-induced neurite outgrowth inhibition. The effects of FA could be blocked by PD98059, zinc protoporphyrin (Zn-PP), and Nrf2 shRNA. In addition, FA induced heme oxygenase 1 (HO-1) gene expression, enhanced antioxidant response element (ARE) promoter activity, promoted ERK1/2 phosphorylation, and Nrf2 translocation in PC12 cells exposed to lead acetate. ERK1/2 locate upstream of Nrf2 and regulate Nrf2-dependent HO-1 expression in antioxidative effects of FA. Our results suggest that FA is a promising candidate for treatment of developmental lead neurotoxicity. These promising findings warrant future investigation evaluating the FA-mediated potentiation of neurite outgrowth following lead exposure in vivo.
Mutations in Cu/Zn superoxide dismutase (SOD1) cause autosomal dominant amyotrophic lateral sclerosis (ALS), a devastating neurodegenerative disease with no effective treatment. Despite ample evidence indicating involvement of mutation-induced SOD1 protein misfolding and aggregation in ALS pathogenesis, the molecular mechanisms that control cellular management of misfolded, aggregation-prone SOD1 mutant proteins remain unclear. Here, we report that parkin, an E3 ubiquitin-protein ligase which is linked to Parkinson's disease, is a novel regulator of cellular defense against toxicity induced by ALS-associated SOD1 mutant proteins. We find that parkin mediates K63-linked polyubiquitination of SOD1 mutants in cooperation with the UbcH13/Uev1a E2 enzyme and promotes degradation of these misfolded SOD1 proteins by the autophagy-lysosome system. In response to strong proteotoxic stress associated with proteasome impairment, parkin promotes sequestration of misfolded and aggregated SOD1 proteins to form perinuclear aggresomes, regulates positioning of lysosomes around misfolded SOD1 aggresomes, and facilitates aggresome clearance by autophagy. Our findings reveal parkin-mediated cytoprotective mechanisms against misfolded SOD1 toxicity and suggest that enhancing parkin-mediated cytoprotection may provide a novel therapeutic strategy for treating ALS.
To determine the behavior of oxytetracycline (OTC) and heavy metals in soil, this study assessed the pollutant-induced avoidance behavior of earthworms (E. fetida) exposed to zinc (Zn(2+)), lead (Pb(2+)), and OTC in soil. The results showed a clear avoidance response within 48h of exposure to the highest concentrations of pollutants. Moreover, E. fetida was shown to be more sensitive to Zn(2+) than to Pb(2+) and OTC. Compared with OTC alone, the net response of earthworms increased in the OTC-Zn(2+) and OTC-Pb(2+) combined treatments, indicating a synergistic effect. Moreover, the net response
 (NR) of the earthworms was higher for OTC-Zn(2+) than it was for OTC-Pb(2+), possibly reflecting the differences in essential characteristics of Zn and Pb.
Zinc (Zn) is an essential trace elements, its deficiency is associated with increased incidence of human breast cancer. We aimed to study the effect of Zn on human breast cancer MCF-7 cells cultured in Zn depleted and Zn adequate medium. We found increased cancer cell growth in zinc depleted condition, further Zn supplementation inhibits the viability of breast cancer MCF-7 cell cultured in Zn deficient condition and the IC25, IC50 value for Zn is 6.2μM, 15μM, respectively after 48h. Zn markedly induced apoptosis through the characteristic apoptotic morphological changes and DNA fragmentation after 48h. In addition, Zn deficient cells significantly triggered intracellular ROS level and develop oxidative stress induced DNA damage; it was confirmed by elevated expression of CYP1A, GPX, GSK3β and TNF-α gene. Zinc depleted MCF-7 cells expressed significantly (p≤0.001) decreased levels of CDKN2A, pRb1, p53 and increased the level of mdm2 expression. Zn supplementation (IC50=15μM), increased significantly CDKN2A, pRB1 & p53 and markedly reduced mdm2 expression; also protein expression levels of CDKN2A and pRb1 was significantly increased. In addition, intrinsic apoptotic pathway related genes such as Bax, caspase-3, 8, 9 & p21 expression was enhanced and finally induced cell apoptosis. In conclusion, physiological level of zinc is important to prevent DNA damage and MCF-7 cell proliferation via regulation of tumor suppressor gene.
A family of thiophene-based metal-organic frameworks (MOFs), [Zn(L)(BBI)•(H2O)2] (1) (BBI = 1,1'-(1,4-butanediyl)bis(imidazole)) and [Cd(L)(TPOM)0.75]•xS (2) (TPOM = tetrakis(4-pyridyloxy-methylene) methane, S represents noncoordinated solvent molecules) were constructed by employing a new linear thiophene-functionalized dicarboxylic acid (benzo-(1,2;4,5)-bis(thiophene-2'-carboxylic acid, H2L) to assemble with d10 ions in the presence of flexible ancillary ligand under solvothermal conditions, which exhibit diverse structures. Most strikingly, both compounds 1 and 2 could be efficient luminescent sensory materials for highly selective and sensitive to environmental contaminants, especially for Hg(II), Cu(II), Cr(VI) and salicylaldehyde, and yet remain unaffected by other molecules that may coexit. Furthermore, this is the first report on the MOF-based sensors capable of recyclable detection of Hg (II), Cr(VI) and salicylaldehyde so far. The luminescent sensing mechanism was studied in detail as well. In addition, compound 2 is one of the rare examples of high-performance MOFs trapping 2,4-dichlorophenol from the wasted methanol solution.
A facile, selective, and sensitive detection method for the Cu(2+) ions in environmental and biological solutions has been newly developed by observing the unique CN stretching peaks at ~2108 cm(-1) upon the dissociative adsorption of glycine (GLY) in hydrazine buffer on gold nanoparticles (AuNPs). The relative abundance of Cu species on AuNPs was identified from X-ray photoelectron spectroscopy analysis. UV-Vis spectra also indicated that the Au particles aggregated to result in the color change owing to the destabilization induced by the GLY-Cu(2+) complex. The CN stretching band at ~2108 cm(-1) could be observed to indicate the formation of the CN species from GLY on the hydrazine-covered AuNP surfaces. The other ions of Fe(3+), Fe(2+), Hg(2+), Mg(2+), Mn(2+), Ni(2+), Zn(2+), Cr(3+), Co(2+), Cd(2+), Pb(2+), Ca(2+), NH₄⁺, Na⁺, and K⁺ at high concentrations of 50 µM did not produce such spectral changes. The detection limit based on the CN band for the determination of the Cu(2+) ion could be estimated to be as low as 500 nM in distilled water and 1 µM in river water, respectively. We attempted to apply our method to estimate intracellular ion detection in cancer cells for more practical purposes.
Relationships among selected performance properties have been established using experimental data from a cement-stabilized mixed contaminated soil. The sandy soil was spiked with 3,000 mg/kg each of Cd, Cu, Pb, Ni and Zn, and 10,000 mg/kg of diesel. It was then treated with 5%, 10%, 15%, and 20% dosages of Portland cement. Different water contents were considered for lower dosage mixes. Selected geotechnical and leaching properties were determined on 28-day old samples. These include unconfined compressive strength (UCS), bulk density, porosity, hydraulic conductivity, leachate pH and granular leachability of contaminants. Interrelationships among these properties were deduced using the most reasonable best fits determined by specialized curve fitting software. Strong quadratic and log-linear relationships exist between hydraulic conductivity and UCS, with increasing binder and water contents, respectively. However, the strength of interrelationships between hydraulic conductivity and porosity, UCS and porosity, and UCS and bulk density varies with binder and water contents. Leachate pH and granular leachability of contaminants are best related to UCS and hydraulic conductivity by a power law and an exponential function, respectively. These results suggest how the accuracy of not-easily-measurable performance properties may be constrained from simpler ones. Comparisons with some published performance properties data support this.
A Zn-based metal-organic framework (MOF)/porous coordination polymer (PCP), (EMIM)[Zn(SIP)] (1) (SIP(3-) = 5-sulfoisophthalate, EMIM(+) = 1-ethyl-3-methylimidazolium), was synthesized using the ionothermal reaction. The Zn(2+) ion adopts distorted square pyramid coordination geometry with five oxygen atoms from three carboxylates and one sulfo group. One of two carboxylates in SIP(3-) serves as a μ2-bridge ligand to link two Zn(2+) ions and form the dinuclear SBU, and such SBUs are connected by SIP(3-) ligands to build the three-dimensional framework with rutile (rtl) topology. The cations from the ion-liquid fill the channels. This MOF/PCP shows two-step dielectric anomalies together with two-step dielectric relaxations; the variable-temperature single-crystal structure analyses disclosed the dielectric anomaly occurring at ca. 280 K is caused by an isostructural phase transition. Another dielectric anomaly is related to the dynamic disorder of the cations in the channels. Electric modulus, conductance, and variable-temperature solid-state (13)C CP/MAS NMR spectra analyses revealed that two-step dielectric relaxations result from the dynamic motion of the cations as well as the direct-current conduction and electrode effect, respectively.
To carrying out an integrated analysis on regional environment and human health in China and to detect the association between longevity and daily element intake from food and drinking water.
Cross-sectional study.
All the 18 cities and counties in Hainan Province.
The distribution of elderly population and longevity indexes at a county level in Hainan Province were investigated. Quality of food and drinking water in Hainan was evaluated by comparing the chemical elements with National Standards. In addition, the association between element concentrations in food and water and longevity was examined using spearman's rank correlation.
The proportion of elderly people is higher in the northern part of the province compared with southern counties. Food contributes a greater proportion of daily element intake than drinking water. Compared with the National Standards, reaching rates for elements were over 85% for both food and drinking water. There was a positive correlation between daily intake of Cu, Se, and Zn from food and water and aging and longevity indexes, and a negative correlation between Pb intake and these indexes.
The quality of food and water in Hainan Province are good and that, compared with water, food is a more important source of trace elements. An appropriate supply of Cu, Se, and Zn is important, whereas excessive intake of Pb should be avoided. The findings also provide basic data to support further studies on regional variations in longevity and their relationship to diet and drinking water.
Stiffening of arteries is a natural ageing process. Any diseases/disorders or risk factors that escalate oxidative stress, microvascular inflammation and endothelial damage may promote to premature vascular stiffening. Any imbalance in these trace element levels may independently contribute to the changes in the components in the arterial wall and thus, arterial stiffness via one or more mechanisms.
To evaluate the severity of arterial stiffness in apparently healthy population and also to evaluate role of various risk factors and trace elements in the severity of arterial stiffness.
Male and female subjects living in urban and rural areas of Nellore district, Andhra Pradesh, India, between 20-60 years, apparently normal as judged by the clinician basing on clinical and laboratory findings, were studied. Carotid-Femoral Pulse Wave Velocity (cf-PWV) a marker of arterial stiffness was assessed using non-invasive blood pressure curve monitoring (periscope). Furthermore, we also estimated serum levels of Copper (Cu), Zinc (Zn), Selenium (Se), chromium (Cr), Aluminium (Al), silicon (Si), Manganese (Mn), Molybdenum (Mb), Vanadium (Vn) and lead (Pb) using atomic absorption spectrophotometer. ANOVA and Chi-Square test were used to study the clinical correlations between severity of arterial stiffness, risk factors and trace elements.
A total of 737 apparently healthy subjects participated in this cross-sectional study. Of the total 542 (73.5%) were from rural and the remaining 195 (26.5%) were living in urban areas, 328 (44.5%) were males, and 409 (55.5%) were females. A 63.5% (468/737) had normal arterial stiffness followed by 14.5% (107/737) with mild
 stiffness, 7% (57/737) had moderate stiffness and 14.2% (105/737) had severe arterial stiffness. Smoking, alcohol, blood pressures, fasting blood sugar, and total cholesterol, Cu, Al and Vn correlated (p<0.05) with different grades of arterial stiffness.
A 36.5% had high arterial stiffness despite being apparently healthy. Smoking, alcohol, blood pressures, fasting blood sugars, and total cholesterol, Cu, Al and Vn could have contributed for such an abnormality. Caution has to be executed while understanding the study results since the pathophysiological process is complex.
Residual biogas slurries (BGS) of detoxified mahua cake and cow dung were used as supplements to enhance the yield and nutritional quality of Lentinus sajor-caju on wheat straw (WS). Supplementation with 20% BGS gave a maximum yield of 1155 gkg(-1) fruit bodies, furnishing an increase of 95.1% over WS control. Significant increase (p ≤ 0.05) in protein content (29.6-38.9%), sugars (29.1-32.3%) and minerals (N, P, K, Fe, Zn) was observed in the fruit bodies. Principle component analysis (PCA) was performed to see the pattern of correlation within a set of observed variables and how these different variables varied in different treatments. PC1 and PC2 represented 90% of total variation in the observed variables. Moisture (%), lignin (%), celluloses (%), and C/N ratio were closely correlated in comparison to Fe, N, and saponins. PCA of amino acids revealed that, PC1 and PC2 represented 74% of total variation in the data set. HPLC confirmed the absence of any saponin residues (characteristic toxins of mahua cake) in fruit bodies and mushroom spent. FTIR studies showed significant degradation of celluloses (22.2-32.4%), hemicelluloses (14.1-23.1%) and lignin (27.4-39.23%) in the spent, along with an increase in nutrition content. The study provided a simple, cost effective approach to improve the yield and nutritional quality of L. sajor-caju by resourceful utilization of BGS.
Zinc (Zn) is the most vulnerable cation to complexation with phytate. An experiment was conducted to evaluate the potential of measurements of Zn concentration in the gastrointestinal tract as a marker to assess the anti-nutritional impact of phytate and susceptibility of phytate to phytase in broilers. Ross 308 broilers (n = 180) were fed one of 5 experimental diets with differing phytase activity levels, analyzed at 605, 1150, 1804, 3954, and 5925 U/kg. Broiler performance and Zn concentration, pH, and amount of phytate hydrolyzed in the gizzard, duodenum, and ileum were analyzed at d 21 post hatch. Phytate susceptibility to phytase degradation was determined in vivo and in vitro by measuring total phytate-P hydrolyzed in the tract or in conditions that mimicked the tract, respectively. Phytase activity level had a significant (P < 0.05) impact on Zn concentration and phytate hydrolyzed in the gizzard and ileum, but not in the duodenum. Strong relationships were observed between the amount of phytate hydrolyzed and Zn concentration in the gizzard in birds fed the diets with 1804 U/kg or higher levels of phytase. Phytate and phytase effects could therefore potentially be evaluated by measuring Zn concentration in the gizzard. Susceptible phytate levels measured in vivo and in vitro were almost identical in the diet with phytase activity of 5925 U/kg, but in the diets with lower phytase activity levels the in vitro assay overestimated the amount of P released. There were strong relationships between in vivo susceptible phytate level and pH and amount of phytate hydrolyzed in the gizzard, duodenum, and ileum and Zn concentration in the gizzard and ileum. This illustrates that phytate susceptibility directly effects mineral availability in the gastrointestinal tract. Measurements of Zn concentration in the gastrointestinal tract, particularly in the gizzard, can potentially be used as a marker to assess the anti-nutritional impact of phytate and susceptibility of phytate to phytase in broilers.
Transient self-destroyed micromotors that autonomously disappear in biological media at controlled rates upon completing their task, without leaving a toxic residue, are presented. The propulsion and degradation characteristics of the self-destroyed Mg/ZnO, Mg/Si, and Zn/Fe Janus micromotors and single-component Zn micromotors are described. The degradation of the Janus micromotors relies on the different corrosion rates of their core-shell components. Inductively coupled plasma optical emission spectrometry measurements are used to probe the time-dependent degradation of the different constituents of the micromotors. The toxicity of the transient micromotors is discussed toward their potential use in biomedical applications. This concept of transient micromotors offers considerable potential for diverse practical applications in the near future.
Understanding the structure of ZnO surface reconstructions and their resultant properties is crucial to the rational design of ZnO-containing devices ranging from optoelectronics to catalysts. Here, we are motivated by recent experimental work that showed a new surface reconstruction containing Zn vacancies ordered in a Zn(3 × 3) pattern in the subsurface of (0001)-O-terminated ZnO. Reconstruction with Zn vacancies on (0001)-O is surprising and counterintuitive because Zn vacancies enhance the surface dipole rather than reduce it. In this work, we show using density functional theory (DFT) that subsurface Zn vacancies can form on (0001)-O when coupled with adsorption of surface H and are in fact stable under a wide range of common conditions. We also show that these vacancies have a significant ordering tendency and that Sb-doping-created subsurface inversion domain boundaries (IDBs) enhance the driving force of Zn vacancy alignment into large domains of the Zn(3 × 3) reconstruction.
Although the ubiquitin-proteasome system is believed to play an important role in the pathogenesis of familial amyotrophic lateral sclerosis (FALS), caused by mutations in Cu/Zn-superoxide dismutase 1 (SOD1), the mechanism of how mutant SOD1 protein is regulated in cells is still poorly understood. Here we have demonstrated that cellular inhibitor of apoptosis proteins (cIAPs) are specifically associated with FALS-linked mutant SOD1 (mSOD1) and that this interaction promotes the ubiquitin-dependent proteasomal degradation of mutant SOD1. By utilizing cumate inducible SOD1 cells, we also showed that knock-down or pharmacologic depletion of cIAPs leads to H2O2 induced cytotoxicity in mSOD1 expressing cells. Altogether, our results reveal a novel role of cIAPs in FALS-associated mutant SOD1 regulation.
Versatility in metal substitution is one of the key aspects of metal-organic framework (MOF) chemistry, allowing properties to be tuned in a rational way. As a result, it important to understand why MOF syntheses involving different metals arrive at or fail to produce the same topological outcome. Frequently, conditions are tuned by trial-and-error to make MOFs with different metal species. We ask: is it possible to adjust synthetic conditions in a systematic way in order to design routes to desired phases? We have used in situ X-ray powder diffraction to study the solvothermal formation of isostructural M2 (bdc)2 dabco (M=Zn, Co, Ni) pillared-paddlewheel MOFs in real time. The metal ion strongly influences both kinetics and intermediates observed, leading in some cases to multiphase reaction profiles of unprecedented complexity. The standard models used for MOF crystallization break down in these cases; we show that a simple kinetic model describes the data and provides important chemical insights on phase selection.
In previous work, a snake venom arginine esterase (SVAE), agkihpin from the venom of Gloydius halys Pallas, was isolated and its biochemical data including Mr, PI, amino acid components and sugar content was collected. Here, the agkihpin was cloned and further characterized and we found that agkihpin could promote ADP-induced platelets aggregation, hydrolyze fibrin, cleave Aα and Bβ chains of fibrinogen and reduce the thrombosis induced by thrombin. Moreover, agkihpin hydrolyzed TAME with optimum temperatures at 30 °C-45 °C, and the hydrolysis was inhibited by EDTA, PMSF, DTT and promoted by Ca(2+), Fe(3+), Mg(2+), Zn(2+). The sequence features of agkihpin were detected as follows: the N-terminal residues was determined as I(V)L(Y)GDDECNINE by protein sequencing; the ORF was determined as 705 bp, and the deduced amino acid sequence was identified by peptide mass fingerprinting; the cysteines, cleavage sites, active sites and substrate binding sites of snake venom thrombin-like enzyme (SVTLE), were all conserved in amino acid sequence of agkihpin; 2 Leu(Tyr), 4 Asn and 121 Ile in amino acid sequence of agkihpin were first found in the amino acid sequences of SVTLEs. These findings indicated that agkihpin is a novel SVTLE. What's more, due to its several advantages of fibrino(gen)olytic and thrombosis-reduced activities, and devoid of bleeding risk, agkihpin may be developed into a thrombolytic drug in the future.
Uptake and membrane transport of cadmium (Cd) in roots of the hyperaccumulator Sedum plumbizincicola X.H. Guo et S.B. Zhou ex L.H. Wu was characterized by assessing the impact of various inhibitors and ion channel blockers on Cd accumulation as well as the real-time net Cd(2+) flux at the roots with application of the scanning ion-selective electrode technique. The uncouplers 2,4-dinitrophenol and P-type adenosine triphosphatase inhibitor Na3 VO4 significantly limited Cd(2+) uptake and transport kinetics in the root of S. plumbizincicola. These findings indicate that Cd is actively taken up into the roots. The Cd content in plant was significantly decreased with pretreatments of the Ca(2+) channel blocker La(3+) or Gd(3+) and the K(+) channel blocker
 tetraethylammonium, as well as in the presence of higher concentration of Ca(2+) and K(+) . These findings indicated that uptake of Cd(2+) into the root of S. plumbizincicola proceeds through ion channels that are permeable to both Ca(2+) and K(+) as confirmed by the direct evidence of real-time net Cd(2+) fluxes at the root surface in the treatments with ion channel inhibitors, as well as in the presence of elevated concentrations of Ca(2+) and K(+) . In addition, the results suggested a role for phytochelatin and protein synthesis in mediating Cd(2+) uptake by S. plumbizincicola. These findings increase the understanding of Cd(2+) uptake and membrane transport pathways in roots of the Zn/Cd hyperaccumulator S. plumbizincicola. Environ Toxicol Chem 2016;9999:1-9. © 2016 SETAC.
We describe the synthesis, crystal structures, and optical absorption spectra/colors of 3d-transition-metal-substituted α-LiZnBO3 derivatives: α-LiZn1-x M(II)x BO3 (M(II) =Co(II) (0<x<0.50), Ni(II) (0<x≤0.05), Cu(II) (0<x≤0.10)) and α-Li1+x Zn1-2x M(III)x BO3 (M(III) =Mn(III) (0<x≤0.10), Fe(III) (0<x≤0.25)). The crystal structure of the host α-LiZnBO3 , which is both disordered and distorted with respect to Li and Zn occupancies and coordination geometries, is largely retained in the derivatives, which gives rise to unique colors (blue for Co(II) , magenta for Ni(II) , violet for Cu(II) ) that could be of significance for the development of new, inexpensive, and environmentally friendly pigment materials, particularly in the case of the blue pigments. Accordingly, this work identifies distorted tetrahedral MO4 (M=Co, Ni, Cu) structural units, with a long M-O bond that results in trigonal bipyramidal geometry, as new chromophores for blue, magenta, and violet colors in a α-LiZnBO3 host. From the L*a*b* color coordinates, we found that Co-substituted compounds have an intense blue color that is stronger than that of CoAl2 O4 and YIn0.90 Mn0.10 O3 . The near-infrared (NIR) reflectance spectral studies indicate that these compounds exhibit a moderate IR reflectivity that could be significant for applications as "cool pigments".
Together with several health benefits, fish meat could lead to heavy metal intoxication of consumers. In this study, we discuss Zn, Cu, Pb, Hg and Cd concentrations in fillets of forty specimens of Carcharhinus dussumieri, analyzed with atomic adsorption spectroscopy (AAS). The potential human health risks due to consumption of C. dussumieri was assessed by estimating average daily intake (EDI) and target hazard quotient (THQ) of metals. The average concentrations of metals measured in this study were (ppm dry weight): Cu 7.49 ± 0.25; Zn 3.47 ± 0.26; Pb 0.12 ± 0.03; Hg 0.028 ± 0.02; Cd 0.11 ± 0.03. Our results showed that no metal exceeded the EC and FAO limits. Cu and Cd accumulate in muscles with a body length (age)-dependent manner. The exposure daily intake of all toxic metals analyzed was found lower than the PTDI provided by WHO and the THQ resulted lower than 1, suggesting no risk for human health derived from consumption.
More than half of proteins require binding of metal and acid radical ions for their structure and function. Identification of the ion-binding locations is important for understanding the biological functions of proteins. Due to the small size and high versatility of the metal and acid radical ions, however, computational prediction of their binding sites remains difficult.
We proposed a new ligand-specific approach devoted to the binding site prediction of 13 metal ions (Zn(2+), Cu(2+), Fe(2+), Fe(3+), Ca(2+), Mg(2+), Mn(2+), Na(+), K(+)) and acid radical ion ligands (CO3(2-), NO2(-), SO4(2-), PO4(3-)) that are most frequently seen in protein databases. A sequence-based ab initio model is first trained on sequence profiles, where a modified AdaBoost algorithm is extended to balance binding and non-binding residue samples. A composite method IonCom is then developed to combine the ab initio model with multiple threading alignments for further improving the robustness of the binding site predictions. The pipeline was tested using 5-fold cross validations on a comprehensive set of 2,100 non-redundant proteins bound with 3,075 small ion ligands. Significant advantage was demonstrated compared with the state of the art ligand-binding methods including COACH and TargetS for high-accuracy ion-binding site identification. Detailed data analyses show that the major advantage of IonCom lies at the integration of complementary ab initio and template-based components. Ion-specific feature design and binding library selection also contribute to the improvement of small ion ligand binding predictions.
http://zhanglab.ccmb.med.umich.edu/IonCom CONTACT: hxz@imut.edu.cn or zhng@umich.eduSupplementary information: Supplementary data are available at Bioinformatics online.
The possibilities and limits of pyrolysis as a means of recycling plastic rich fractions derived from discarded phones have been studied. Two plastic rich samples (⩾80wt% plastics) derived from landline and mobile phones provided by a Spanish recycling company, have been pyrolysed under N2 in a 3.5dm(3) reactor at 500°C for 30min. The landline and mobile phones yielded 58 and 54.5wt% liquids, 16.7 and 12.6wt% gases and 28.3 and 32.4wt% solids respectively. The liquids were a complex mixture of organic products containing valuable chemicals (toluene, styrene, ethyl-benzene, etc.) and with high HHVs (34-38MJkg(-1)). The solids were composed of metals (mainly Cu, Zn, and Al) and char (≈50wt%). The gases consisted mainly of hydrocarbons and some CO, CO2 and H2. The halogens (Cl, Br) of the original samples were mainly distributed between the gases and solids. The metals and char can be easily separated and the formers may be recycled, but the uses of the char will be restricted due to its Cl/Br content. The gases may provide the energy requirements of the processing plant, but HBr and HCl must be firstly eliminated. The liquids could have a potential use as energy or chemicals source, but the practical implementation of these applications will be no exempt of great problems that may become insurmountable (difficulty of economically recovering pure chemicals, contamination by volatile metals, etc.).
Chemosensors play important parts in the selective recognition of ions, which is widely applied in various fields of environment, industry and biological sciences. In this work, a chemosensor for multi-metal ions based on rhodamine B derivative was synthesized, which could selectively recognize various metal ions in different solvent system. The addition of Cu(2+) caused the color change from colorless to pink in EtOH/H2O (v/v=1:1) solvent system, which could be quickly identified by the naked eyes with a detection limit of 8.27×10(-8)M. In ethanol solution system, the addition of Fe(3+) and Zn(2+) caused different fluorescence changes with the detection limit of 2.12×10(-7)M and 6.64×10(-7)M respectively. The binding ratios are 1:1 (1-Cu(2+)), 2:1 (1-Fe(3+)) and 1:1 (1-Zn(2+)), respectively. Meanwhile, the probe 1 was used to detect the trace metal ions in real water samples. Besides, the probe 1 showed sensitive fluorescence signals for Fe(3+) in biological cells. The experimental results further verify the application value of the sensor.
Only very limited information is available on measured environmental concentrations of nanoparticles. In this study, several environmental compartments in The Netherlands were probed for the presence of nanoparticles. Different types of water were screened for the presence of inorganic (Ag, Au, TiO2) and organic nanoparticles (C60, C70, [6,6]-phenyl-C61-butyric acid octyl ester, [6,6]-phenyl-C61-butyric acid butyl ester, [6,6]-phenyl-C61-butyric acid methyl ester, [6,6]-bis-phenyl-C61-butyric acid methyl ester, [6,6]-phenyl-C71-butyric acid methyl ester, [6,6]-thienyl-C61-butyric acid methyl ester). Air samples were analysed for the presence of nanoparticulate Mo, Ag, Ce, W, Pd, Pt, Rh, Zn, Ti, Si, B as well as Fe and Cu. ICP-MS, Orbitrap-HRMS, SEM and EDX were used for this survey. Water samples included dune and bank filtrates, surface waters and ground waters as well as influents, effluents and sludge of sewage treatment plants (STPs), and surface waters collected near airports and harbours. Air samples included both urban and rural samples. C60 was detected in air, sewage treatment plants, influents, effluents and sludge, but in no other aqueous samples despite the low detection limit of 0.1ng/L. C70 and functionalised fullerenes were not detected at all. In STP sludge and influent the occurrence of Ag and Au nanoparticles was verified by SEM/EDX and ICP-MS. In air up to about 25m% of certain metals was found in the nanosize fraction. Overall, between 1 and 6% of the total mass from metals in the air samples was found in the size fraction <100nm.
Natural flavonoids such as quercetin, (+)catechin and rutin as well as four methoxylated derivatives of quercetin used as models were investigated to elucidate their impact on the oxidant and antioxidant status of human red blood cells (RBCs). The impact of these compounds against metal toxicity was studied as well as their antiradical activities with DPPH assay. Antihemolytic experiments were conducted on quercetin, (+)catechin and rutin with excess of Fe, Cu and Zn (400 μM), and the oxidant (malondialdehyde, carbonyl proteins) and antioxidant (reduced glutathione, catalase activity) markers were evaluated. The results showed that Fe and Zn have the highest prooxidant effect (37 and 33% of hemolysis, respectively). Quercetin, rutin and (+)catechin exhibited strong antioxidant properties toward Fe, but this effect was decreased with respect to Zn ions. However, the Cu showed a weak antioxidant effect at the highest flavonoid concentration (200 μM), while a prooxidant effect
 was observed at the lowest flavonoid concentration (100 μM). These results are in agreement with the physico-chemical and antiradical data which demonstrated that binding of the metal ions (for FeNTA: (+)Catechin, KLFeNTA = 1.6(1) × 106 M-1 > Rutin, KLFeNTA = 2.0(9) × 105 M-1 > Quercetin, KLFeNTA = 1.0(7) × 105 M-1 > Q35OH, KLFeNTA = 6.3(8.7) × 104 M-1 > Quercetin3'4'OH and Quercetin 3OH, KLFeNTA ~ 2 × 104 M-1) reflects the (anti)oxidant status of the RBCs. This study reveals that flavonoids have both prooxidant and antioxidant activity depending on the nature and concentration of the flavonoids and metal ions.
The present investigation highlights the optimal conditions for production of a non-toxic, bi-functional fibrinolytic enzyme xylarinase produced by endophytic fungus Xylaria curta by solid substrate fermentation using rice chaff medium. The purified enzyme is a monomeric protein with a molecular mass of ∼33 kDa. The enzyme exhibits cleavage of Aα and Bβ chains of fibrin(ogen) and has no effect on γ chain. The optimal fibrinolytic activity of the enzyme was observed at 35 °C and pH 8. The fibrinolytic activity was enhanced in the presence of Ca(2+), whereas it was completely inhibited in the presence of Fe(2+) and Zn(2+) ions and inhibitors like EDTA and EGTA suggesting it to be a metalloprotease. The K m and V max of the enzyme for azocasein were 326 μM and 0.13 μM min(-1). The N-terminal sequence of the enzyme (SNGPLPGGVVWAG) was same when compared to xylarinase isolated from culture broth of X. curta. Thus, xylarinase could be exploited as a potent clot busting enzyme which could be produced on large scale using solid substrate fermentation.
Tributyltin (TBT) concentrations near a marina complex in Benner Bay on St. Thomas, US Virgin Islands, were elevated relative to other areas in a larger study of the southeastern shore of the island. At the request of the USVI Coastal Zone Management Program, sediment cores and surface sediment samples were collected to better define the extent and history of TBT deposition in the vicinity of Benner Bay. The sediment cores were sectioned into 2-cm intervals and dated with (210)Pb and (137)Cs. The core sections and the surface samples were analyzed for butyltins and 16 elements. Deposition rates varied from 0.07-5.0 mm/year, and were highest in the marina complex. Core ages ranged from 54 to 200 years. The bottoms of the cores contained shell hash, but the top layers all consisted of much finer material. Surface concentrations of TBT exceeded 2000 ng Sn/g (dry weight) at two locations. At a depth of 8 cm TBT exceeded 8800 ng Sn/g in the marina complex sediment. Based on the ratio of tributyltin to total butyltins, it appears that the marina sediments are the source of contamination of the surrounding area. There is evidence that vessels from neighboring islands may also be a source of fresh TBT. Copper concentrations increase over time up to the present. Gradients of virtually all metals and metalloids extended away from the marina complex. NOAA sediment quality guidelines were exceeded for As, Pb, Cu, Zn, and Hg.
Herein we report a water-induced single-crystal to single-crystal transformation that involves the formation of hetero-bimetallic paddlewheel clusters in coordination polymers. Through this transformation, which involves the cleavage and formation of different coordination bonds, two different Cu(ii)-Zn(ii) and Cu(ii)-Ni(ii) paddlewheel units exhibiting a 1 : 1 metal ratio were created.
Garlic and onion, which are rich in organo-sulfur compounds, are reported to enhance the bioaccessibility of Ca, Mg, Fe and Zn; however, there is a lack of similar information on the bioaccessibility of copper, manganese and chromium. Therefore, the present study aimed to determine the effect of exogenous garlic and onion on the bioaccessibility of these trace minerals from selected food grains. The effect of two levels of garlic (0.25 and 0.5 g/10 g grain(-1) ) and onion (1.5 and 3 g/10 g grain(-1) ) on the bioaccessibility of these trace minerals from two representative cereals and pulses was determined by employing an in vitro dialysability procedure.
Both garlic and onion significantly improved the bioaccessibility of Cu, especially when added at the higher level, in most of the foods examined. The enhancing effect of garlic on Mn bioaccessibility was found in cooked sorghum and chickpea, whereas onion significantly improved Mn bioaccessibility in cooked rice and chickpea. The addition of both spices did not exert any enhancing effect on Cr bioaccessibility from the cereals and pulses.
The bioaccessibility of Cu, as well as Mn to a lesser extent, from vegetarian diets can be significantly improved by incorporating garlic and onion in the diet. © 2016 Society of Chemical Industry.
Today, fungicides are part of the basic tool kit for indoor surface maintenance. However, fungi develop resistance to fungicides, which consequently accelerates the evolution of virulence. Fungicides also carry the risk of adverse effects in humans. Galvanic microcells are a new tool for fungal control on indoor surfaces. We used two types of electrodes, Zn and Cu, with two potential anti-fungal mechanisms: the oligodynamic action of the metal ions themselves and the electricidal effect of the current between the electrodes. The size of the inhibition zone is related to the distance between the electrodes. We hypothesized that the unique geometric properties of the observed inhibition zone could be modelled using multi foci curve Cassini ovals. Moreover, the size of the inhibition zone possessed two maximum values, while the shape of the observed inhibition zones correlated with the shape of the electric field strength. The control activity of the galvanic microcells correlated with decreasing water content in building materials. Thus, this acute antifungal system works the best in damp building environments where the risk of fungal contamination is highest.
This study aimed to investigate the potential of low-level laser irradiation (LLLI) to promote odontogenic differentiation and biomineralization by dental pulp stem cells (DPSCs) seeded inside bioceramic scaffolds. Mg-based, Zn-doped bioceramic scaffolds, synthesized by the sol-gel technique, were spotted with DPSCs and exposed to LLLI at 660 nm with maximum output power of 140 mw at fluencies (a) 2 and 4 J/cm(2) to evaluate cell viability/proliferation by the MTT assay and (b) 4 J/cm(2) to evaluate cell differentiation, using real-time PCR (expression of odontogenic markers) and a p-nitrophenylphosphate (pNPP)-based assay for alkaline phosphatase (ALP) activity measurement. Scanning electron microscopy (SEM) and X-ray diffraction (XRD) analysis were used for structural/chemical characterization of the regenerated tissues. Exposure of the DPSCs/scaffold complexes to the proposed LLLI scheme was associated with statistically significant increase of odontogenesis-related markers (bone morphogenetic protein 2 (BMP-2): 22.4-fold, dentin sialophosphoprotein (DSPP): 28.4-fold, Osterix: 18.5-fold, and Runt-related transcription factor 2 (Runx2): 3.4-fold). ALP activity was significantly increased at 3 and 7 days inside the irradiated compared to that in the non-irradiated SC/DPSC complexes, but gradually decreased until 14 days. Newly formed Ca-P tissue was formed on the SC/DPSC complexes after 28 days of culture that attained the characteristics of bioapatite. Overall, LLLI treatment proved to be beneficial for odontogenic differentiation and biomineralization of DPSCs inside the bioceramic scaffolds, making this therapeutic modality promising for targeted dentin engineering.
This work aims to assess the operation of the first large scale segregated biowaste composting scheme in Greece to divert Household Food Waste (HFW) from landfill and produce a material which can be recovered and used as compost. The source separation and collection of HFW was deployed in selected areas in Attica Region serving about 3700 households. Sorted HFW is collected & transported to the Mechanical and Biological Treatment (MBT) plant in Attica Region that has been designed to produce Compost Like Output (CLO) from mixed MSW. The MBT facility has been adjusted in order to receive and treat aerobically HFW mixed with shredded green waste in a dedicated composting tunnel. The composting process was monitored against temperature, moisture and oxygen content indicating that the biological conditions are sufficiently developed. The product quality was examined and assessed against the quality specifications of EU End of Waste Criteria for biowaste subjected to composting aiming to specify whether the HFW that has undergone recovery ceases to be waste and can be classified as compost. More specifically, the heavy metals concentrations (Cr, Cu, Ni, Cd, Pb, Zn and Hg) are within the set limits and much lower compared to the CLO material that currently is being produced at the MBT plant. In regard to the hygienic requirements of the product it has been found that the process conditions result in a pathogen free material (i.e. E. Coli and Salmonella) which does not favor the growth of viable weeds and plant propagules, while it acquires sufficient organic matter content for soil fertilization. Noticeable physical impurities (mainly fractions of glass) have been detected exceeding the quality control threshold limit of 0.5% w/w (plastics, metals and glass). The latter is related to the missorted materials and to the limited pre-treatment configurations prior to composting. The above findings indicate that effective source separation of biowaste is prerequisite for good quality production and marketing of compost and special consideration should be made to minimize glass impurities prior composting (i.e. awareness raising and pretreatment stage). Therefore, it is feasible to gradually
 replace the production of questionable quality CLO in MBTs with biowaste compost which is in line with the required quality control standards especially when heavy metals concentrations is concerned.
We report blood and feather concentrations of elements in the Baltic Sea and Arctic population of common eiders (Somateria mollissima). The endangered Baltic Sea population of eiders was demonstrably affected by element pollution in the 1990s. While blood concentrations of Hg were higher in Baltic breeding eiders, blood Se, As and Cd concentrations were higher in Arctic eiders. Blood concentrations of Pb, Cr, Zn and Cu did not differ between the two populations. While blood Pb concentrations had declined in Baltic eiders since the 1990s, Hg concentrations had not declined, and were above concentrations associated with adverse oxidative effects in other bird species. Inconsistent with blood concentrations, feather concentrations suggested that Pb, Zn, and Cd exposure was higher in Baltic eiders, and that Hg exposure was higher in Arctic eiders. Our study thus emphasizes the need for comprehensive evaluation of toxic element status, covering the annual cycle of a species.
With the advance of new instruments and algorithms, and the accumulation of experience over decades, single-particle cryo-EM has become a pivotal part of structural biology. Recently, we determined the structure of a eukaryotic ribosome at 2.5 Å for the large subunit. The ribosome was derived from Trypanosoma cruzi, the protozoan pathogen of Chagas disease. The high-resolution density map allowed us to discern a large number of unprecedented details including rRNA modifications, water molecules, and ions such as Mg(2+) and Zn(2+) . In this paper, we focus on the procedures for data collection, image processing, and modeling, with particular emphasis on factors that contributed to the attainment of high resolution. The methods described here are readily applicable to other macromolecules for high-resolution reconstruction by single-particle cryo-EM.
Small zinc finger (ZnF) motifs are promising molecular scaffolds for protein design owing to their structural robustness and versatility. Moreover, their characterization provides important insights into protein folding in general. ZnF motifs usually possess an exceptional specificity and high affinity towards Zn(II) ion to drive folding. While the Zn(II) ion is canonically coordinated by two cysteine and two histidine residues, many other coordination spheres also exist in small ZnFs, all having four amino acid ligands. Here we used high-resolution mass spectrometry to study metal ion binding specificity and primary coordination sphere robustness of a designed zinc finger, named MM1. Based on the results, MM1 possesses high specificity for zinc with sub-micromolar binding affinity. Surprisingly, MM1 retains metal ion binding affinity even in the presence of selective alanine mutations of the primary zinc coordinating amino acid residues.
Carbon nanotubes (CNT) grown on nanoporous carbon (NPC), which yields coexisting amorphous and graphitic nanoarchitectures, have been prepared on a large scale from zeolitic imidazolate framework (ZIF) by introducing bimetallic ions (Co(2+) and Zn(2+)). Interestingly, the hybrid Co/Zn-ZIF-derived NPC showed rich graphitic CNTs on the surface. This NPC was utilized for a coin-type supercapacitor cell with an aqueous electrolyte, which showed enhanced retention at high current density and good stability over 10 000 cycles.
Coordination of 2,2'-bisdipyrrin based ligands to Zn(ii) cations leads to the formation of binuclear helicates with pre-organized pyrrolic strands as well as peripheral aromatic moieties for Ag-π interactions, thus affording crystalline heterometallic networks upon further interactions with Ag(i) salts without the assistance of additional heteroatom-based coordinating units.
The aim of this research was to assess the ability of amalgam restorations to induce amorphous mineral precipitation at the caries-affected dentin substrate. Sound and caries-affected dentin surfaces were subjected to both Zn-free and Zn-containing dental amalgam restorations. Specimens were submitted to thermocycling (100,000 cycles/5°C-55°C, 3 months). Dentin surfaces were studied by atomic force microscopy (nanoroughness), X-ray diffraction, field emission scanning electron microscopy, and energy-dispersive analysis, for physical and morphological surface characterization. Zn-containing amalgam placement reduced crystallinity, crystallite size, and grain size of calcium phosphate crystallites at the dentin surface. Both microstrain and nanoroughness were augmented in caries-affected dentin restored with Zn-containing amalgams. Caries-affected dentin showed the shortest mineral crystallites (11.04 nm), when Zn-containing amalgams were used for restorations, probably leading to a decrease of mechanical properties which might favor crack propagation and deformation. Sound dentin restored with Zn-free amalgams exhibited a substantial increase in length of grain particles (12.44 nm) embedded into dentin crystallites. Zn-containing amalgam placement creates dentin mineralization and the resultant mineral was amorphous in nature. Amorphous calcium phosphate provides a local ion-rich environment, which is considered favorable for in situ generation of prenucleation clusters, promotong further dentin remineralization.
Coadministration of pomegranate rind extract (PRE) and zinc (II) ions has recently been reported as a potential new topical treatment for Herpes simplex virus (HSV) infections. In the current work we examined the in vitro topical delivery of punicalagin (major phytochemical of PRE) and zinc from hydrogels across epithelial membranes that can become infected with HSV. Porcine epidermal, buccal and vaginal mucous membranes were excised and mounted in Franz diffusion cells and dosed with a simple hydrogel containing PRE and zinc sulphate (ZnSO4). The permeation of punicalagin and zinc were determined by HPLC and ICPMS respectively; punicalagin was also determined in the basal layers by reverse tape stripping. Receptor phases from the epidermal membrane experiment were also used to challenge HSV-1 in Vero host cells, and ex vivo porcine skin was used to probe COX-2 modulation. Punicalagin and zinc permeated each of the three test membranes, with significantly greater amounts of both delivered across the epidermal membrane. The amounts of punicalagin permeating the buccal and vaginal membranes were similar, although the amount of zinc permeating the vaginal membrane was comparatively very large - it is known that zinc interacts with vaginal mucosa. The punicalagin recovered by reverse tape stripping of the epidermal, buccal and vaginal membranes gave 0.47±0.016, 0.45±0.052 and 0.51±0.048nMcm(-2) respectively, and were statistically the same (p<0.05). A 2.5 log reduction was achieved against HSV-1 using diffusion cell receptor phase, and COX-2 expression was reduced by 64% in ex vivo skin after 6h. Overall, a hydrogel containing 1.25mgmL(-1) PRE and 0.25M ZnSO4 was able to topically deliver both the major bioactive compound within PRE and Zn (II) across all membranes and into the site specific region of Herpes simplex vesicular clusters, while maintaining potentiated virucidal and anti-inflammatory properties. This novel therapeutic system therefore has potential for the topical treatment of HSV infections.
Novel multifunctional scaffolds for bone regeneration can be developed by incorporation of bioactive glasses doped with therapeutic and antibacterial metal ions, such as copper (Cu) and zinc (Zn), into a biodegradable polymer. In this context, porous composite materials of biodegradable poly(D, L-lactide) (PDLLA) mixed with sol-gel bioactive glasses (BG) of chemical composition 60SiO2 ; 25CaO; 11Na2 O; and 4P2 O5 (mol.%) doped with either 1 mol% of CuO or ZnO, and with both metals, were prepared. The cytocompatibility of the scaffolds on bone marrow stromal cells (ST-2) depended on both, the amount of glass filler and the concentration of metal ion, as evaluated by lactate dehydrogenase (LDH) activity, cell viability (water-soluble tetrazolium salt (WST-8)), and by cell morphology (scanning electron microscopy (SEM)) tests. In particular, scaffolds having a filler content of 10 wt.% showed the highest cytocompatibility. In addition, compared to the neat polymer, the scaffolds containing Cu promoted the angiogenesis marker (VEGF concentration) to a larger extent while scaffolds containing Zn increased the osteogenesis marker (specific ALP-activity). Noteworthy, the scaffolds with both metal ions showed a combined effect on both properties. Cu and Zn-doped glasses also provided higher antibacterial capacity to PDLLA-based scaffolds against methicillin-resistant S. aureus bacteria than undoped glass. In combination, our results showed that by a proper addition of Cu and Zn-doped bioactive glasses to a PDLLA matrix, multifunctional composite scaffolds with enhanced biological activity can be designed for bone tissue regeneration. This article is protected by copyright. All rights reserved.
Industrialized development of the Yangtze River Delta, China, has resulted in larger amounts of wastes, including sludges from treatment of these wastes. Methods to manage and dispose, including reuse were urgently needed. Sludge and reused products were collected from two largest factories, KEYUAN and HENGJIA where treated sludges were turned into bricks or sludge cake to be placed in landfills, respectively. Metals and organic compounds were quantified in sludges and leachates assessed by use of toxicity characterized leaching procedure (TCLP) while acute toxicity was determined by Daphnia magna. Nine metals were detected in all raw sludges with concentrations of Cr and Ni exceeding Chinese standards.
 For sludge leachate, concentrations of metals were all less than Chinese standards, which changed little after being made into cake by HENGJIA, but were significantly less after being made into brick by KEYUAN. Toxicity units (TU) for all samples are greater than 1.0 indicating that they are potentially toxic to aquatic organisms. TUs changed little after being made into filter cake, but were 10-fold less after being made into bricks. Cr and Ni contributed most to the total toxicity followed by Zn and Cu. Making of sludges into K-brick 1 resulted in better inactivation of contaminants, which resulted in less toxic potencies. So that is the recommended method for handling of industrial sludges. To further assure their safe reuse, additional research on identification of key toxicants and potential hazards, based on additional endpoints, by combining bio-tests and chemical analysis should be done for reused sludges.
Porphobilinogen synthase (PBGS), also known as 5-aminolevulinate dehydratase, is an essential enzyme in the biosynthesis of all tetrapyrroles, which function in respiration, photosynthesis, and methanogenesis. Throughout evolution, PBGS adapted to a diversity of cellular niches and evolved to use an unusual variety of metal ions both for catalytic function and to control protein multimerization. With regard to the active site, some PBGSs require Zn(2+); a subset of those, including human PBGS, contain a constellation of cysteine residues that acts as a sink for the environmental toxin Pb(2+). PBGSs that do not require the soft metal ion Zn(2+) at the active site instead are suspected of using the hard metal Mg(2+). The most unexpected property of the PBGS family of enzymes is a dissociative allosteric mechanism that utilizes an equilibrium of architecturally and functionally distinct protein assemblies. The high-activity assembly is an octamer in which intersubunit interactions modulate active-site lid motion. This octamer can dissociate to dimer, the dimer can undergo a hinge twist, and the twisted dimer can assemble to a low-activity hexamer. The hexamer does not have the intersubunit interactions required to stabilize a closed conformation of the active site lid. PBGS active site chemistry benefits from a closed lid because porphobilinogen biosynthesis includes Schiff base formation, which requires deprotonated lysine amino groups. N-terminal and C-terminal sequence extensions dictate whether a specific species of PBGS can sample the hexameric assembly. The bulk of species (nearly all except animals and yeasts) use Mg(2+) as an allosteric activator. Mg(2+) functions allosterically by binding to an intersubunit interface that is present in the octamer but absent in the hexamer. This conformational selection allosteric mechanism is purported to be essential to avoid the untimely accumulation of phototoxic chlorophyll precursors in plants. For those PBGSs that do not use the allosteric Mg(2+), there is a spatially equivalent arginine-derived guanidium group. Deprotonation of this residue promotes formation of the hexamer and accounts for the basic arm of the bell-shaped pH vs activity profile of human PBGS. A human inborn error of metabolism known as ALAD porphyria is attributed to PBGS variants that favor the hexameric assembly. The existence of one such variant, F12L, which dramatically stabilizes the human PBGS hexamer, allowed crystal structure determination for the hexamer. Without this crystal structure and octameric PBGS structures containing the allosteric Mg(2+), it would have been difficult to decipher the structural basis for PBGS allostery. The requirement for multimer dissociation as an intermediate step in PBGS allostery was established by monitoring subunit disproportionation during the turnover-dependent transition of heteromeric PBGS (comprised of human wild type and F12L) from hexamer to octamer. One outcome of these studies was the definition of the dissociative morpheein model of protein allostery. The phylogenetically variable time scales for PBGS multimer interconversion result in atypical kinetic and biophysical behaviors. These behaviors can serve to identify other proteins that use the morpheein model of protein allostery.
Fernando de Noronha is a small volcanic archipelago in the Southern Atlantic, some 350 km NE of the city of Natal in NE Brazil. These remote volcanic islands represent a largely pristine environment, distant from sources of anthropogenic contamination. This study was carried out to determine the natural concentrations of Ag, Ba, Cd, Co, Cr, Cu, Mo, Ni, Pb, Sb, V and Zn in the A and B horizons of soils of Fernando de Noronha. The aims of the study were twofold: determine whether there is a relationship between the bedrock geology and soils and to establish quality reference values for soils from Fernando de Noronha. Soil samples were subjected to acid digestion by the USEPA method 3051A, and metals were determined by inductively coupled plasma emission spectrophotometry. The results showed that the trace element distribution largely reflects the geochemistry of the underlying volcanic rocks of the Remedios and Quixaba Formations. The results demonstrate that the concentrations of Ba, Cr, Zn, Ni and Cu from the soils of the volcanic Fernando de Noronha archipelago are higher than those found in soils from continental Brazil. However, concentrations of Ni, Cu and Co are lower in soils of the archipelago as compared to other volcanic islands throughout the world. The elevated trace element concentrations of the volcanic parent material of Fernando de Noronha soils seem to be the main factor governing the relatively high natural concentrations of trace elements.
A series of transition and post-transition metal ion (Mn, Cu, Zn, Pb, Bi) binary borate glasses was studied with special consideration of the cations impact on the borate structure, the cations cross-linking capacity, and more generally, structure-property correlations. Infrared (IR) and Raman spectroscopies were used for the structural characterization. These complementary techniques are sensitive to the short-range order as in the differentiation of tetrahedral and trigonal borate units or regarding the number of non-bridging oxygen ions per unit. Moreover, vibrational spectroscopy is also sensitive to the intermediate-range order and to the presence of superstructural units, such as rings and chains, or the combination of rings. In order to clarify band assignments for the various borate entities, examples are given from pure vitreous B2O3 to meta-, pyro-, ortho-, and even overmodified borate glass compositions. For binary metaborate glasses, the impact of the modifier cation on the borate speciation is shown. High field strength cations such as Zn(2+) enhance the disproportionation of metaborate to polyborate and pyroborate units. Pb(2+) and Bi(3+) induce cluster formation, resulting in PbOn- and BiOn-pseudophases. Both lead and bismuth borate glasses show also a tendency to stabilize very large superstructural units in the form of diborate polyanions. Far-IR spectra reflect on the bonding states of modifier cations in glasses. The frequency of the measured cation-site vibration band was used to obtain the average force constant for the metal-oxygen bonding, FM-O. A linear correlation between glass transition temperature (Tg) and FM-O was shown for the metaborate glass series. The mechanical properties of the glasses also correlate with the force constant FM-O, though for cations of similar force constant the fraction of tetrahedral borate units (N4) strongly affects the thermal and mechanical properties. For paramagnetic Cu- and Mn-borate glasses, N4 was determined from the IR spectra after deducing the relative absorption coefficient of boron tetrahedral versus boron trigonal units, α = α4/α3, using NMR literature data of the diamagnetic glasses.
The main aim of this study was the application of excitation-emission fluorescence matrices (EEMs) combined with two decomposition methods: parallel factor analysis (PARAFAC) and nonnegative matrix factorization (NMF) to study the interaction mechanisms between humic acids (HAs) and Zn(II) over a wide concentration range (0-50 mg·dm(-3)). The influence of HA properties on Zn(II) complexation was also investigated. Stability constants, quenching degree and complexation capacity were estimated for binding sites found in raw EEM, EEM-PARAFAC and EEM-NMF data using mathematical models. A combination of EEM fluorescence analysis with one of the proposed decomposition methods enabled separation of overlapping binding sites and yielded more accurate calculations of the binding parameters. PARAFAC and NMF processing allowed finding binding sites invisible in a few raw EEM datasets as well as finding totally new maxima attributed to structures of the lowest humification. Decomposed data showed an increase in Zn complexation with an increase in humification, aromaticity and molecular weight of HAs. EEM-PARAFAC analysis also revealed that the most stable compounds were formed by structures containing the highest amounts of nitrogen. The content of oxygen-functional groups did not influence the binding parameters, mainly due to fact of higher competition of metal cation with protons. EEM spectra coupled with NMF and especially PARAFAC processing gave more adequate assessments of interactions as compared to raw EEM data and should be especially recommended for modeling of complexation processes where the fluorescence intensities (FI) changes are weak or where the processes are interfered with by the presence of other fluorophores.
The discovery of novel materials with very low thermal conductivity is paramount to improving the efficiency of thermoelectric devices. Here we present a series of quaternary semiconducting tellurides AXXTe12 (A = Rb, Cs; X(II) = Mn, Zn, Cd; X(III)
 = Ga, In) with three-dimensional (3D) diamond-like frameworks (DLFs) and they exhibit a very low thermal conductivity (ca. 0.26-0.42 W m(-1) K(-1)) around 800 K.
Rhizomucor miehei NRRL 5282 and Rhizopus oryzae NRRL 1526 can produce lipases with high synthetic activities in wheat bran-based solid state culture. In this study, purification and biochemical characterization of the lipolytic activities of these lipases are presented. SDS-PAGE indicated a molecular mass of about 55 and 35 kDa for the purified R. miehei and Rh. oryzae enzymes, respectively. p-Nitrophenyl palmitate (pNPP) hydrolysis was maximal at 40°C and pH 7.0 for the R. miehei lipase, and at 30°C and pH 5.2 for the Rh. oryzae enzyme. The enzymes showed almost equal affinity to pNPP, but the Vmax of the Rh. oryzae lipase was about 1.13 times higher to that determined for R. miehei using the same substrate. In case of both enzymes, a dramatic loss of activity was observed in the presence of 5 mM Hg²⁺, Zn²⁺ or Mn²⁺, 10 mM NBS or SDS, and 5-10% (v/v) of hexanol or butanol. At the same time, they proved to be extraordinarily stable in the presence of n-hexane, cyclohexane, n-heptane and isooctane. Moreover, isopentanol up to 10% (v/v) and propionic acid in 1 mM concentrations increased the pNPP hydrolyzing activity of R. miehei lipase. Both enzymes had 1,3-regioselectivity, and efficiently hydrolyzed p-nitrophenyl (pNP) esters with C8-C16 acids, exhibiting maximum activity towards pNP-caprylate (R. miehei) and pNP-dodecanoate (Rh. oryzae). The purified lipases are promising candidates for various biotechnological applications.
Highly fluorescent gold nanodots have been synthesized through a novel rapid, facile and one-pot room temperature route using trithiocyanuric acid as mild reducing agent and surface ligand. The proposed synthesis overcomes limitations of other synthetic routes in terms of cost, time, complexity and environmental risks, and gives rise to highly fluorescent gold nanodots within 10 min at room temperature, with a maximum emission wavelength at 623 nm and a large Stokes shift (213 nm). Moreover, the synthesized gold nanodots showed a large emission QY (9.62 × 10(-2)) and excellent photostability and colloidal properties during long periods. Increasing concentrations of CN(-) in aqueous solution progressively quenched the fluorescence emission and produced a slight blue shift of the synthesized gold nanodots. A good linear relationship was observed for CN(-) concentrations between 0.29 and 8.87 μM, obtaining a detection limit estimated according to the 3s IUPAC criteria of 150 nM. Besides, the influence on the fluorescence signal of potential interferents at high concentrations (1000 μM) was studied, including I(-), F(-), citrate, [Formula: see text] [Formula: see text] [Formula: see text] CH3COO(-), EDTA, Br(-), [Formula: see text] Cl(-) and S(2-) K(+), Na(+), Li(+), Mg(2+), Ca(2+), Ba(2+), Cu(2+), Zn(2+), Ni(2+), Al(3+), Fe(2+), Fe(3+), Pb(2+), Cd(2+), Hg(2+) and Co(2+). Results showed a high selectivity towards all the investigated ions, except for Pb(2+), Cd(2+) and Hg(2+), although the use of glutathione and BSA as masking agents drastically minimized the effect of such cations at high concentrations. The synthesized gold nanodots were successfully evaluated as highly sensitive and selective probes for cyanide determination in environmental water samples, including tap, river, lake and sea water, indicating the validity of TCA-AuNDs for analytical CN(-) contamination control.
Plants reorganize their root architecture to avoid growth into unfavorable regions of the rhizosphere. In a screen based on chimeric repressor gene-silencing technology, we identified the Arabidopsis thaliana GeBP-LIKE 4 (GPL4) transcription factor as an inhibitor of root growth that is induced rapidly in root tips in response to cadmium (Cd). We tested the hypothesis that GPL4 functions in the root avoidance of Cd by analyzing root proliferation in split medium, in which only half of the medium contained toxic concentrations of Cd. The wild-type (WT) plants exhibited root avoidance by inhibiting root growth in the Cd side but increasing root biomass in the control side. By contrast, GPL4-suppression lines exhibited nearly comparable root growth in the Cd and control sides and accumulated more Cd in the shoots than did the WT. GPL4 suppression also altered the root avoidance of toxic concentrations of other essential metals, modulated the expression of many genes related to oxidative stress, and consistently decreased reactive oxygen species concentrations. We suggest that GPL4 inhibits the growth of roots exposed to toxic metals by modulating reactive oxygen species concentrations, thereby allowing roots to colonize noncontaminated regions of the rhizosphere.
The electrochemical systems containing zinc dicyanamide salt (Zn(dca)2) in both 1-ethyl-3-methylimidazolium dicyanamide ([C2mim][dca]) and N-butyl-N-methylpyrrolidinium dicyanamide ([C4mpyr][dca]) ionic liquids (ILs) have been studied by atomic force microscopy (AFM) on a highly oriented pyrolytic graphite (HOPG) surface under different conditions and applied potentials. The results reveal the following: (1) interfacial layers exist in both ILs, even after the addition of 3 wt% water and 9 mol% Zn(dca)2 salt. (2) The number of layers is different for the different ILs, with the [C2mim][dca]-based samples exhibiting a much more limited interfacial structure compared to the [C4mpyr][dca] at almost all of the tested conditions. (3) For the [C4mpyr][dca]-based samples, without added zinc salt, the number of detected interfacial layers increases with negative potential. With added zinc, the [C4mpyr][dca] sample shows about the same number of layers independent of the applied potentials, namely between 5-7. Likewise, for the [C2mim][dca] samples, with the zinc added the sample shows the same number of layers at the applied potentials, but for this system only 1-2 layers are detected. And (4) the addition of Zn(dca)2 into the [C2mim][dca] IL does not cause a large change in the interfacial ordering, whereas the addition of the same salt into the [C4mpyr][dca] samples is marked by a stark increase in both the number and the consistency of the perceived interfacial layers. These results are significant because they show a marked difference in the interfacial nanostructure between two zinc-based electrochemical systems that were previously shown to have distinctly different electrochemical behaviour, despite their chemical similarity.
Passivation of surface states is known to reduce the onset photocurrent potential by removing the Fermi level pinning effect at the Helmholtz layer and enhance the photocurrent plateau by suppressing recombination loss in the space charge region. We report for the first time that metal ions can effectively passivate surface states in situ that improves the photoelectrochemical (PEC) performance of hematite electrodes. Among metal ions studied, Cr(iii), Mn(ii), Fe(ii), Co(ii), Cu(ii) and Zn(ii) were found to enhance the photocurrent by 30-300%; whereas photocurrent density significantly dropped by 90% in Ni(ii) solution after 90 min of illumination. We further hypothesized that the surface states might be the high affinity adsorption sites on hematite surfaces. Once the surface states are occupied by metal ions, along with the Schottky barrier effect at the hematite/electrolyte interface formed by adsorbed metal ions, the PEC performance is enhanced. Our results also enable the design of a potential PEC based water treatment method to extract additional energy, for example, in the brines (containing concentrated metal ions and electrolyte) of membrane processed wastewater.
Large-scale and reproducible synthesis of nanomaterials is highly sought out for successful translation into clinics. Flame aerosol technology with its proven capacity to manufacture high purity materials (e.g., light guides) up to kg h(-1) is explored here for the preparation of highly magnetic, nonstoichiometric Zn-ferrite (Zn0.4 Fe2.6 O4 ) nanoparticles coated in situ with a nanothin SiO2 layer. The focus is on their suitability as magnetic multifunctional theranostic agents analyzing their T2 contrast enhancing capability for magnetic resonance imaging (MRI) and their magnetic hyperthermia performance. The primary particle size is closely controlled from 5 to 35 nm evaluating its impact on magnetic properties, MRI relaxivity, and magnetic heating performance. Most importantly, the addition of Zn in the flame precursor solution facilitates the growth of spinel Zn-ferrite crystals that exhibit superior magnetic properties over iron oxides typically made in flames. These properties result in strong MRI T2 contrast agents as shown on a 4.7 T small animal MRI scanner and lead to a more efficient heating with alternating magnetic fields. Also, by injecting Zn0.4 Fe2.6 O4 nanoparticle suspensions into pork tissue, MR-images are acquired at clinically relevant concentrations. Furthermore, the nanothin SiO2 shell facilitates functionalization with polymers, which improves the biocompatibility of the theranostic system.
To evaluate the interactions among endophytes, plants and heavy metal/arsenic contamination, root endophytic bacteria of Prosopis laevigata (Humb and Bonpl. ex Willd) and Sphaeralcea angustifolia grown in a heavy metal(loid)-contaminated zone in San Luis Potosi, Mexico, were isolated and characterized. Greater abundance and species richness were found in Prosopis than in Sphaeralcea and in the nutrient Pb-Zn-rich hill than in the poor nutrient and As-Cu-rich mine tailing. The 25 species identified among the 60 isolates formed three groups in the correspondence analysis, relating to Prosopis/hill (11 species), Prosopis/mine tailing (4 species) and Sphaeralcea/hill (4 species), with six species ungrouped. Most
 of the isolates showed high or extremely high resistance to arsenic, such as ≥100 mM for As(V) and ≥20 mM for As(III), in mineral medium. These results demonstrated that the abundance and community composition of root endophytic bacteria were strongly affected by the concentration and type of the heavy metals and metalloids (arsenic), as well as the plant species.
Novel bio-relevant monometallic Schiff base complexes of the type, [Cu(L(1))2] (1), [Zn(L(1))2]·2H2O (2), [Cu(L(2))2]·2H2O (3) and [Zn(L(2))2]·H2O (4) [L(1)(E)-3-(((3-chloro-4-hydroxyphenyl)imino)methyl)naphthalen-2-ol and L(2)(E)-2-chloro-4-((1-(5-chloro-2-hydroxyphenyl)ethylidene)amino)phenol] were synthesized and characterized. A comparative account of analytical, spectroscopic (FT-IR, (1)H and (13)C NMR, Mass, UV-vis and EPR), thermal (TGA/DTA), XRD and SEM studies revealed a correlation between the structure and function of these biologically active molecular entities. HSA (Human serum albumin) binding profiles of the metal complexes (1-4) were monitored using biophysical techniques viz., absorbance, fluorescence, circular dichromism (CD) and foster resonance energy transfer (FRET). The intrinsic binding constant (Kb) demonstrated substantial binding propensity of L(1) linked complexes (1 and 2) in comparison to L(2) complexes (3 and 4) suggesting L(1) to be more bio-active pharmacophore due to higher planarity and conjugation as compared to L(2) ligand. The outcome of fluorescence study revealed static quenching mechanism on the basis of the quenching of HSA by the complexes (1-4). However, modifications in the secondary structure of HSA by complexes (1-4) inferred via CD measurements which revealed the enhancement of α-helicity (67.47% to 69.20%) with the preference order of 1>2>3>4. Furthermore, in-vitro antibacterial study against different bacteria and antioxidant activities against DPPH and superoxide radical (O2(-)) at variable concentrations outspread discernible bio-potencies of the metal complexes as compared to free ligand scaffolds due to the chelation effect.
Bond lengths between pairs of atoms in covalent molecules are generally predicted well by the sum of their respective covalent radii, such that there are usually only small variations in related compounds. It is, therefore, significant that we have demonstrated that the incorporation of appropriately sized linkers between carbon and a metal center provides a means to modulate the length and nature of a metal-carbon interaction. Specifically, X-ray diffraction studies on a series of tris(1-methylimidazol-2-ylthio)methyl zinc complexes, [Titm(Me)]ZnX, demonstrate how the Zn-C bond lengths are highly variable (2.17-2.68 Å) and are up to 0.67 Å longer than the average value listed in the Cambridge Structural Database (2.01 Å). Furthermore, density functional theory calculations on [Titm(Me)]ZnCl demonstrate that the interaction is very flexible, such that either increasing or decreasing the Zn-C length from that in the equilibrium structure is associated with little energy change in comparison to that for other compounds with Zn-C bonds.
Bee pollen has already proved to be a good supplement rich in iron and zinc. Studies on the application of flower pollen in the food industry and medicine have begun. Bearing in mind the prevalence of maize as a crop culture, its pollen will be easily available. The mineral composition of pollen of seven Serbian maize hybrids was analyzed in order to establish its nutritional value and the benefits of its implementation in the human diet using the inductively coupled plasma method.
The presence of twenty four different macro- (nine) and micronutrients (fifteen) was detected. The most common minerals were phosphorus and potassium, while arsenic, cobalt, lead, nickel and molybdenum were found in some samples.
Comparing the results obtained with recommended or tolerable dietary intake references for adults, it was found that maize pollen can be used as a very good source of zinc, iron, chromium and manganese for humans. With regard to selenium content, pollen samples proved to be moderately good source of this important micronutrient. Contents of some elements (Fe, Zn, Mn, Cr, Se, Al and V) showed significant differences depending on hybrid type. In some samples increased concentrations of aluminum and vanadium were recorded, which may pose a potential problem due to their toxicity. © 2016 Society of Chemical Industry.
Benzotriazole (BTA) and benzimidazole (BZI) are regarded as water pollutants because of their extensive uses in industry and appreciable water solubility. The adsorption of both BTA and BZI from water over a newly synthesized metal-organic framework, MAF-5(Co), was investigated and compared with zeolitic imidazole frameworks (ZIFs), such as ZIF-8(Zn) and ZIF-67(Co), as well as commercial activated carbon. MAF-5(Co) had the highest adsorption capacities for both BTA and BZI. The maximum adsorption capacities of MAF-5(Co) for BTA and BZI were 389 and 175mgg(-1), respectively. Hydrophobic and π-π interactions between the aromatic adsorbate BTA and MAF-5(Co) were suggested as a plausible mechanism. Based on the zeta potential of MAF-5(Co) and effects of pH on the BTA adsorption, electrostatic interactions between the MAF-5(Co) and BTA species might also affect the adsorption of BTA over MAF-5(Co). MAF-5(Co) can be recycled for adsorptive removal of BTA by simple ethanol washing. Therefore, MAF-5(Co) is suggested as a promising adsorbent for the removal of BTA and BZI from water.
Hormesis is an intriguing phenomenon that is characterized by low dose stimulation and high dose inhibition. Several traditional parameters, such as the concentration of the zero equivalent point (ZEP) and the maximal stimulatory effect (Ymax), have been used to characterize the zone of hormesis or the extent of the stimulatory effect. However, the characteristics of hormesis for chemicals cannot be quantified completely by one parameter, which is important to accurately compare the hormetic effects of chemicals and to describe the combined effects of chemical mixtures at low doses. In the present study, a novel parameter, termed the relative standard area of hormetic zone (HorArea(R)), was developed and proposed to quantify the hormetic effects (24h exposure) of nine metal ions (Cr(3+), Cu(2+), Mg(2+), Cd(2+), Fe(3+), Ni(2+), Zn(2+), Co(2+), Cs(+)) towards Vibrio fischeri, both individually and as binary mixtures. The results indicate that HorArea(R) can be used not only to accurately assess the hormetic effects and its relationship with structural characteristics but also to conveniently describe the combined effects of interactive mixtures at low dose. Thus, the HorArea(R) parameter can quantitatively assess the hormetic effects and can offer a useful approach to perform environmental risk assessments of chemicals at low doses.
A unique pH-controlled synthesis of two metallosupramolecular structures from CoAu complex anions and Zn(II) cations is reported. A dense coordination polymer (porosity ∼13%) was formed at a pH of 5.0, whereas a porous ionic framework (porosity ∼61%) that selectively adsorbs CO2 and H2O was created when the pH was adjusted to 5.5.
Hydrothermal reactions of Cu(ii)/Zn(ii)/Cd(ii) with 5,5'-bistetrazole (H2BT) lead to three new energetic coordination polymers: [CuBT(H2O)]n (1), [ZnBT(H2O)2]n (2), and [CdBT(H2O)2]n (3). These crystal structures were determined by single X-ray diffraction. Compound 1 forms regular and compact 3-D frameworks and compounds 2-3 are 1-D chain structures. These compounds show prominent thermostability (Tdec = 349.1 °C for 1, 334.8 °C for 2, and 394.2 °C for 3) investigated by using differential scanning calorimetry (DSC) and thermogravimetric analysis (TGA). Sensitivities towards impact and friction were measured. Compound 1 is sensitive to both impact and friction (100% explosion under the test conditions), while compounds 2-3 are sensitive to neither (0% explosion under the test conditions). The heats of detonation (ΔHdet) of 1-3 were calculated based on density functional theory (DFT). Compound 1 possesses the highest calculated ΔHdet (26.7267 kJ g(-1)) among the reported energetic MOFs. Moreover, compared with the reported energetic MOFs, compound 1 also has a good balance of high nitrogen content (51.46%) and high oxygen balance (-36.76%) as well as a very high crystal density of 2.505 g cm(-3).
The preparation of metal-free, Zn(ii), In(iii), and Cu(ii)-phthalocyanines containing tetrakis-(3-phenylphenoxy) groups was achieved by employing 3-(3-phenylphenoxy)phthalonitrile (1) and 4-(3-phenylphenoxy)phthalonitrile (2) as starting materials. The phthalonitriles and phthalocyanines were characterized by elemental analysis, infrared, proton nuclear magnetic resonance, ultraviolet-visible, and matrix-assisted laser desorption/ionization time-of-flight mass spectroscopic techniques. The effect of the substituent group on the kinetics of benzene vapour adsorption onto these novel compounds was examined using three kinetics models: the pseudo first-order model, the Elovich equation, and a simple adsorption-desorption model. Results show that the benzene adsorption kinetics strongly depend on the position of the substituent groups.
Two new zinc(ii) complexes, [Zn(l-His)(NIP)](+)(1) and [Zn(acac)2(NIP)](2) (where NIP is 2-(naphthalen-1-yl)-1H-imidazo[4,5-f][1,10]phenanthroline, acac = acetyl acetone), have been synthesized and characterized by elemental analysis, UV-vis, fluorescence, IR, (1)H NMR and electron spray ionization mass spectroscopies. Gel retardation assay, atomic force microscopy and dynamic light scattering studies show that 1 and 2 can induce the condensation of circular plasmid pBR322 DNA into nanometer size particles under ambient conditions. Treatment of 2 with 5 mM EDTA restored 30% of the supercoiled form
 of DNA, revealing partial reversibility of DNA condensation. The in vitro transfection experiment demonstrates that the complexes can be used to deliver pCMV-tdTomato-N1 plasmid which expresses red fluorescent protein. The confocal studies show that the fluorescent nature of complexes is advantageous for visualizing the intracellular delivery of metal complexes as well as transfection efficiency using two distinct emission windows.
To assess stress level induced by multiple stressors in aquatic organism, biomarkers have been adopted as early warning indicator due to their high accuracy, rapidity, and sensitivity. We investigated the effects of ectoparasitic isopod infection on heavy metal bioaccumulation (Fe, Cu, Zn, and Cd) in the fish Nemipterus furcosus and profiled the expression of metallothionein (MT) and heat shock proteins 70 (HSP70) genes of the fish host. Sixty individuals (parasitized and nonparasitized with Cymothoa truncata) were collected from three sites differing in the levels of anthropogenic activities off the South China Sea. Our results revealed no significant difference in heavy metal concentrations between infected and nonparasitized fish. We observed a positive correlation between heavy metal bioaccumulation in the fish host and anthropogenic activities. Accordingly, expression analysis of MT genes in fish liver showed significant differences in expression level between sampling sites, with lowest level in the least exploited site (Batu Rakit). A reverse pattern in HSP70 gene expression was demonstrated in fish muscle, showing the highest expression at Batu Rakit. While cymothoid infection in N. furcosus had no significant impact on fish MT gene expression, it resulted in a reduction of HSP70 level in liver of parasitized fish. These findings highlight the putative roles of MT in heavy metal assessment. Future studies should determine the kinetics of cymothoid infection and other potential stressors in characterizing the HSP70 gene expression profile.
Deposition of dust particles on foliage surfaces helps to filter airborne dust particles that occur predominantly in areas near thermal power plants (TPPs). Highly dust-laden foliage surrounding TPPs is a serious issue affecting the vegetation and façade greening adversely. Fly ash (FA) generated by TPPs have an adverse impact on the growth and development of flora. Therefore, identification of their percentage contribution on foliar dust (FD) is of utmost importance. The present study attempted to identify all the contributing sources to FD. Morphological and chemical characterization of FD, FA, and road dust (RD) has been evaluated, followed by their multivariate statistical analysis. Contamination of FD from different sources was estimated by using field emission scanning electron microscope (FE-SEM) coupled with energy dispersive X-ray technique (EDX), Fourier transform infrared spectroscope (FTIR), and atomic absorption spectrophotometer techniques. Particle size distribution of FD revealed that the major portion of FD was <2 µm. FE-SEM and EDX analysis confirmed contamination of FD by FA, resuspension of RD, and local sources. FTIR peaks depicted the presence of different functional groups, including silica from nearby roads, saturated-nonsaturated, and aromatic organic functional groups originating predominantly from different activities of TPPs and traffic. Results of IR were in agreement with results obtained in physicochemical analyses. Heavy metals analysis of FA demonstrated high concentration of carcinogens Cr, Cu, Cd, and Ni and could be considered a marker to them. Certain heavy metals (Fe, Co, Mn, Pb, and Zn) were found to be in the order RD > FA > FD. This explores the necessity for considering other sources other than TPP sources. Principal component analysis (PCA) of heavy metals present in FD revealed that the sampling area was chiefly influenced from three sources: Bokaro thermal power station (55 %), RD (18 %), and local sources (27 %). Cluster analysis complemented the results of Pearson correlation matrix and PCA. Analyses illustrated the substantial influence of TPPs along with other source's significance in contamination of FD.
Cornelia de Lange Syndrome (CdLS) encompasses a broad spectrum of phenotypes characterized by distinctive craniofacial abnormalities, limb malformations, growth retardation, and intellectual disability. CdLS spectrum disorders are referred to as cohesinopathies, with ∼70% of patients having a mutation in a gene encoding a core cohesin protein (SMC1A, SMC3, or RAD21) or a cohesin regulatory protein (NIPBL or HDAC8). Notably, the regulatory function of HDAC8 in cohesin biology has only recently been discovered. This Zn(2+) -dependent hydrolase catalyzes the deacetylation of SMC3, a necessary step for cohesin recycling during the cell cycle. To date, 23 different missense mutants in the gene encoding HDAC8 have been identified in children with developmental features that overlap those of CdLS. Enzymological, biophysical, and structural studies of CdLS HDAC8 protein mutants have yielded critical insight on compromised catalysis in vitro. Most CdLS HDAC8 mutations trigger structural changes that directly or indirectly impact substrate binding and catalysis. Additionally, several mutations significantly compromise protein thermostability. Intriguingly, catalytic activity in many HDAC8 mutants can be partially or fully restored by an N-acylthiourea activator, suggesting a plausible strategy for the chemical rescue of compromised HDAC8 catalysis in vivo.
The contaminated oysters discovered in the Pearl River Estuary (Guangdong province, China) contained high levels of metals in their tissues, especially Cu and Zn, indicating that this large and densely urbanized estuary in Southern China suffers from serious metal pollution. The present study aimed to investigate the impacts of multimetal pollution in the Pearl River Estuary on oyster antioxidant and detoxification systems. The responses of various biochemical biomarkers in the ecologically important oyster Crassostrea hongkongensis collected from 7 sites in the Pearl River Estuary were quantified. Significant correlations were demonstrated between the accumulation of Cu and Zn and oxidative stress (lipid peroxidation) and oxidative stress defenses (catalase, glutathione peroxidase) in the oyster gills. Significant correlations between the accumulation of Cd and Cu and detoxification (glutathione and glutathione transferase) in the gills were also documented. Interestingly, metallothionein concentrations were positively correlated with Cd, but negatively correlated with Cu, Ni, and Zn concentrations in the gills. These measurements indicated that Cu in the Pearl River Estuary induced various biochemical responses in the oysters and influenced the susceptibility of oysters to environmental stress. The present study has provided the first evidence of antioxidant and detoxification responses in native contaminated oysters from a field environment seriously contaminated by metals. Coupling biomarkers with tissue metal concentration measurements was a promising approach to identify the metals causing biological impacts in a multimetal-contaminated estuary. Environ Toxicol Chem 2016;35:2798-2805. © 2016 SETAC.
The authors investigated the effect of binary mixtures of zinc (Zn), copper (Cu), cadmium (Cd), and nickel (Ni) on the growth of a freshwater diatom, Navicula pelliculosa. A 7 × 7 full factorial experimental design (49 combinations in total) was used to test each binary metal mixture. A 3-d fluorescence microplate toxicity assay was used to test each combination. Mixture effects were predicted by concentration addition and independent action models based on a single-metal concentration-response relationship between the relative growth rate and the calculated free metal ion activity. Although the concentration addition model predicted the observed mixture toxicity significantly better than the independent action model for the Zn-Cu mixture, the independent action model predicted the observed mixture toxicity significantly better than the concentration addition model for the Cd-Zn, Cd-Ni, and Cd-Cu mixtures. For the Zn-Ni and Cu-Ni mixtures, it was unclear which of the 2 models was better. Statistical analysis concerning antagonistic/synergistic interactions showed that the concentration addition model is generally conservative (with the Zn-Ni mixture being the sole exception), indicating that the concentration addition model would be useful as a method for a conservative first-tier screening-level risk analysis of metal mixtures. Environ Toxicol Chem 2016;35:2765-2773. © 2016 SETAC.
A major problem with risk assessment of chemicals is the extrapolation of laboratory single-species toxicity tests, which oversimplify the actual field situation by ignoring species interactions, to natural communities. The authors tested if the bioavailability-normalized 5% hazardous concentration (HC5) estimated from chronic planktonic single-species toxicity data (HC5plankton ) for zinc (Zn) is protective for a plankton community and investigated the direct and indirect effects of Zn (at HC5 and HC50) on a freshwater community's structure and function. Microcosms were exposed to 3 different Zn concentrations (background, HC5plankton  = 75 μg Zn/L and HC50plankton  = 300 μg Zn/L) for 5 wk. The planktonic groups revealed a consistent no-observed-effect concentration for the community of 75 μg Zn/L, similar to or higher than the HC5plankton , thus suggesting its protectiveness in the present study. At 300 μg Zn/L a significant reduction in cladocerans resulted in increases of rotifer, ciliate, and phytoplankton abundance. In addition, the phytoplankton community shifted in dominance from grazing-resistant to edible species. Contrary to the species sensitivity distribution
 (SSD) prediction, which identified phytoplankton as the most sensitive group, only the total chlorophyll and the abundance of 2 phytoplankton species were adversely affected at 300 μg Zn/L. Thus, although the HC5 estimated from the bioavailability-normalized SSD was overall protective for the plankton community, the SSD was not able to correctly predict the species sensitivity ranking within their community context at the HC50. Environ Toxicol Chem 2016;35:2698-2712. © 2016 SETAC.
Interaction between old, corroded iron pipe surfaces and bulk water is crucial to the water quality protection in drinking water distribution systems (WDS). Iron released from corrosion products will deteriorate water quality and lead to red water. This study attempted to understand the effects of pipe materials on corrosion scale characteristics and water quality variations in WDS. A more than 20-year-old hybrid pipe section assembled of unlined cast iron pipe (UCIP) and galvanized iron pipe (GIP) was selected to investigate physico-chemical characteristics of corrosion scales and their effects on water quality variations. Scanning Electron Microscope (SEM), Energy Dispersive X-ray Spectroscopy (EDS), Inductively Coupled Plasma (ICP) and X-ray Diffraction (XRD) were used to analyze micromorphology and chemical composition of corrosion scales. In bench testing, water quality parameters, such as pH, dissolved oxygen (DO), oxidation reduction potential (ORP), alkalinity, conductivity, turbidity, color, Fe(2+), Fe(3+) and Zn(2+), were determined. Scale analysis and bench-scale testing results demonstrated a significant effect of pipe materials on scale characteristics and thereby water quality variations in WDS. Characteristics of corrosion scales sampled from different pipe segments show obvious differences, both in physical and chemical aspects. Corrosion scales were found highly amorphous. Thanks to the protection of zinc coatings, GIP system was identified as the best water quality stability, in spite of high zinc release potential. It is deduced that the complicated composition of corrosion scales and structural break by the weld result in the diminished water quality stability in HP system. Measurement results showed that iron is released mainly in ferric particulate form.
Since municipal solid waste (MSW) landfill harbours miscellaneous wastes, pollutants and microorganisms, it gradually becomes a huge potential reservoir for breeding antibiotic resistance genes (ARGs). The objective of this study was to determine the prevalence and diversity of ARGs associated with various mobile genetic elements (MGEs) in MSW landfill leachates. The relationship of ARGs with leachate characteristics was also studied to explore the influence of landfill age. Seven sulfonamides (sulfapyridine, sulfadiazine, sulfathiazole, sulfamethoxazole, sulfamerazine, sulfamethazine and sulfaquinoxaline), three encoded ARGs (sul-I, sul-II and sul-III) and four types of MGEs (plasmids, transposons, integrons and insertion sequences) were quantified in leachates with landfill ages ranging from 3 months-6 years. ARGs increased to an absolute concentration of 10(6) copies/μL and were positively correlated (p < 0.05) to MGEs. Significant correlations (p < 0.05) were also discovered among ARGs and the increasing humic acids, heavy metals (Zn, Cu and Co) and antibiotics (except for sulfathiazole and sulfaquinoxaline), implying landfilling might contribute to the enrichment of ARGs in the long-term. Non-target full scans revealed the role of persistent unknown compounds in stimulating the ARGs dissemination. Overall, this study demonstrates the exacerbation of ARGs pollution in landfill environment and a detailed delineation of the complex inter-relationships between ARGs and the substances harbouring in landfills is badly required.
The new nanophotocatalyst MgZnCr-TiO2 was prepared by co-precipitation under different molar ratio of metals (Zn:Cr) and the loaded amount of TiO2. And it was characterized by X-ray diffraction, Raman spectroscopy, X-ray photoelectron spectroscopy et al. Langmuir model fitted well the adsorption isotherm with the value of R(2) 0.9765, the maximum adsorption capacity was 526.32 mg g(-1), the adsorption followed pseudo second order kinetic by MgZnCr-TiO2 (1:1:2-0.05). The photocatalytic oxidation of Congo red was used to determine the photocatalytic performance of MgZnCr-TiO2 (1:1:2-0.05) under visible light irradiation, and the removal rate reached 98% after reaction for 40 min. The degradation mechanism of Congo red also was proposed, and the MgZnCr-TiO2 (1:1:2-0.05) was stable after five cycles. Compared to the adsorption, Congo red was removed fundamentally by photocatalysis and it is expected to be an effective way to eliminate Congo red.
A pot experiment was conducted to investigate the effect of diverse plant species (four herbaceous and four woody species) on the labile pool of six metals (Ag, Cu, Pb, Zn, Ni and Se) present in their rhizosphere. After three months of cultivation, concentrations of trace elements (TE) in above and below-ground biomass of each species were determined. The labile and presumably bioavailable fraction of these TE in the rhizosphere as well as key soil parameters (e.g. pH, electrical conductivity (EC), percent of organic matter and dissolved organic carbon (DOC)) were also measured and compared as a function of plant species. The concentration of TE in plant tissues differed among species. In general and as expected, concentrations were higher in root tissues of tested plants than in above-ground tissues. While the labile pool of several TE in the rhizosphere, notably Ag, Ni, and Cu, was significantly and differently affected by the presence of the plants, pH, EC and percentage of organic matter remained unchanged. In contrast, DOC was higher in the rhizosphere of all tested plants than in soil of the control pots without plants. In addition, there was a positive relationship between Ni and Cu availability concentrations, and DOC levels. This suggests that root systems of different species can have a distinct influence on soil DOC and consequently modify the labile pools of Ni and Cu in the rhizosphere. These findings have important implications for plant selection in phytoremediation projects.
The aim of the study was to determine content of 17 elements (Co, Cd, Cu, Cr, Ni, Pb, Zn, Mn, Fe, Mg, Na, Ca, K, N, C, S and P) and their bioaccumulation factors (BCF) in bay bolete (Boletus badius (Fr.) Fr.) fruiting bodies (caps and stalks) and underneath soil samples collected from forest sites in lubuskie voivodeship in Poland. Forty-eight samples of Boletus badius (Fr.) Fr. fruiting bodies and the same number of underneath soil substrate samples were collected in forest sites of Sulęcin Forest District in western Poland. Copper and zinc were absorbed most strongly from soil substrate, which is performed by bioaccumulation factors (BCFCap/Soil = 16.57 and 11.60, respectively), wherein Pb, Co, Cr, Fe and Mn were excluded from bioaccumulation (BCF < 1.0). The mean content of Cd in caps and stalks was 1.44 ± 0.88 and 2.01 ± 1.26 mg kg(-1) dry weight, respectively and in contrary to Pb (≈3.00 ± 2.66 and 2.01 ± 1.26 mg kg(-1) d. w.) this metal is strongly accumulated from subsoil (BCFCap/Soil = 11.12 and BCFStipe/Soil = 10.83). The fruiting bodies of Boletus badius were distinguished by elevated content of Cr, Zn, Pb and Cd. Few statistically significant metal-to-metal correlations were observed. The correlation between forest habitat types and metals concentrations was also analysed. An attempt of estimation of Pb and Cd safe dose for human consumption was made.
mushrooms can be a good source of some micro- and macroelements, but they also contain a great amount of toxic heavy metals.
Precision medicine is a personalized disease prevention and treatment program combining modern genetic technology, molecular imaging techniques, and biological information with patients' living environment and clinical data, for accurate classification and diagnosis of diseases.
Our study presents the case of a 7-year-old female patient with clinical manifestations of growth hormone (GH) deficiency. After treatment with recombinant human GH for 2 years, the patient showed a reduced growth rate. Then single nucleotide polymorphisms according to GHD was analyzed, and the 6009 site within cyclin-dependent kinase 4 gene showed a weak response to IGF-1 which was a downstream signal molecules of GH.
Based on these results, both Zn and GH were supplied to the patients, and the growth rate increased significantly. Precision medicine needs more studies on patients to make accurate treatment.
2,4-Bis(1,3,7-trimethyl-pteridine-2,4(1H,3H)-dione-6-yl)-2,3-dihydro-2-methyl-1H-1,5-benzodiazepine (DLMBZD) has been prepared and its molecular and crystal structures have been determined from spectral and XRD data. The benzodiazepine ligand was reacted with zinc(ii), cadmium(ii) and mercury(ii) chloride, bromide and iodide to give complexes with general formula [M(DLMBZD)X2]. The complexes have been synthesized and characterized by IR, NMR and elemental analysis. The structure of seven complexes has been obtained by single crystal X-ray diffraction. In all the cases, the metal is (2 + 2 + 1)-five-coordinated by two halide ligands, two nitrogen atoms from pyrazine and diazepine rings and a carbonyl oxygen from a pteridine ring. The coordinated-metal environment is a square-based pyramid, with increasing trigonality from Hg(ii) to Zn(ii) complexes. To coordinate the metals, the ligand folds itself, establishing four intramolecular σ-π interactions with the pyrimidine and pyrazine rings. A topological analysis of the electron density using the Quantum Theory of Atoms in Molecules and the complexes stability has been performed.
The tetrakisquinoline ligand HT(6-MeO8Q)HPN
 (N,N,N',N'-tetrakis(6-methoxy-8-quinolylmethyl)-2-hydroxy-1,3-propanediamine) exhibited Zn(2+)-induced fluorescence enhancement with high specificity and sensitivity (IZn/I0 = 57 and ICd/IZn = 6% in the presence of 2 equiv of Zn(2+); LOD (limit of detection) = 15 nM). This ligand also exhibited fluorescence enhancement specific to inorganic phosphate (PO4(3-)) in DMF-HEPES buffer (50 mM HEPES, 100 mM KCl, pH = 7.5) (1:1) in the presence of 2 equiv of Zn(2+). The structure of the unprecedented tetranuclear zinc complex with a μ4-PO4 bridge was elucidated by X-ray crystallography as the key species responsible for fluorescence enhancement.
The square-planar monomer NiL2 (Ni1 ), L=2-ethoxy-6-(N-methyl-iminomethyl)phenolate, reacts with M(H2 O)6 (ClO4 )2 , M=Ni or Co, to form heptanuclear disks [Cox Ni7-x (OH)6 (L)6 ](ClO4 )2 ⋅2 CH3 CN (Cox Ni7-x , x=0-7) and the co-crystal [Cox Ni7-x (OH)6 L6 ][NiL2 ](ClO4 )2 ⋅2 CH3 CN (Cox Ni7-x -Ni1 ) under ambient conditions. It has proved possible to explore the bottom-up assembly process of Cox Ni7-x and Cox Ni7-x -Ni1 in real time. The final products have been characterized by thermogravimetric analysis, IR, elemental analysis, ICP-MS, and single-crystal X-ray diffraction. Time-dependent mass spectrometry (MS) revealed the following reaction steps: Ni1 →[M2 L3 ](+) →[M4 (OH)2 L4 ](2+) →[M7 (OH)6 L6 ](2+) . In contrast, the reaction of Ni1 with Zn(2+) only reaches halfway, and crystallographic evidence indicates a butterfly structure for [Zn2 Ni2 (OH)2 Cl2 ] (Zn2 Ni2 ), an intermediate that is difficult to isolate in the above Ni-Co series. A summation method has been used to analyze the MS of bimetallic clusters with very similar atomic masses, as is the case for Co and Ni. The results provide ample information on the distribution of Co and Ni within each cluster and their statistical distribution within selected crystals.
At least 16 nutrient elements are required by plants for growth and survival, but the factors affecting element concentration and their temporal evolution are poorly understood. The objective was to investigate i) element concentration pattern in winter wheat as affected by crop developmental stage and weather, and ii) whether, in the short term, element stoichiometry reflects the type of preceding crop. We assessed the temporal trajectories of element concentration pattern (N, P, K, Ca, Mg, S, Mn, Fe, Cu, Na, Zn) across the life cycle (from seed to seed) of winter wheat field-grown in cool-temperate Sweden during two years with contrasting weather and when cultivated in monoculture or after different non-wheat preceding crops. We found strong influence of developmental stage on concentration pattern, with the greatest deviation from grain concentrations found in plants at the start of stem elongation in spring. Inter-annual differences in weather affected stoichiometry, but no evidence was found for a short-term preceding-crop effect on element stoichiometry. Winter wheat element stoichiometry is similar in actively growing plant tissues and seeds. Nitrogen exerts a strong influence on the concentration pattern for all elements. Three groups of elements with concentrations changing in concert were identified.
Three isolectins denoted hereforth MBaL-30, MBaL-60, and MBaL-80 were isolated from seeds extract of Momordica balsamina by 30%, 60%, and 80% ammonium sulfate saturations, respectively. The native molecular weights of these lectins, as judged by gel filtration, were 108, 56, and 160 kDa, respectively. On SDS-PAGE, under reduced condition, 27 kDa band was obtained for all isolectins. The lectins hemagglutinating activities were variably inhibited by d-galactose (minimum inhibitory concentrations = 12.5mM, 50mM, and 0.391mM, respectively). MBaL-30 and -60 could agglutinate all human blood types with slight preference for the A and O blood groups, whereas MBaL-80 did not agglutinate B and AB blood types. The 3 isolectins were purified from crude seeds extract, collectively, in a single step on the affinity matrix Lactamyl-Seralose 4B; this purified lectin fraction, which contains all isolectins, is termed MBaL. The N-terminal of MBaL till the 25th amino acid was NLSLSELDFSADTYKSFIKNLRKQL, which shares 88% sequence identity with Momordica charantia lectin type-2 ribosomal inactivating protein from Momordica charantia and 50% with momordin II from Momordica balsamina. MBaL retained 100% activity at up to 50°C for 30 minutes. MBaL-30 and MBaL-60 exhibited maximum activities in the pH range between 4 and 8, while MBaL-80 was showing maximum activity in the pH range between 3 and 5. Treatment of MBaL-30 and MBaL-60 with EDTA completely abolished their hemagglutinating activities. Addition of Zn and Fe ions to the ethylenediaminetetraacetic acid-treated MBaL-30 and MBaL-60 lectins did not only regained the loss of activity but also resulted in 200% to 300% increase in activity, respectively. MBaL-30 and -60 agglutinated gram positive Listeria monocytogenes and Staphylococcus aureus, whereas MBaL-30 could merely agglutinate Escherichia coli. None of these lectins could arrest bacterial growth. Addition of MBaL to cancer cell lines (Gastric cancer cell line (AGS) and Gastric cencer cell line (MKN45), Glioblastoma (ECV-304), and Human urinary bladder cancer cell line (U87-MG)) at varying concentrations did not cause statistically significant changes on cell growth and viability.
Enrichment of heavy metals was assessed in the Thi Vai Estuary and in the Can Gio Mangrove Forest (SE, Vietnam). Cd, Co, Cr, Cu, Mn, Ni, Pb and Zn contents in water and in sediments were measured. Total organic carbon, nitrogen, phosphorus and C/N ratios were determined. Cu and Cr values were higher than threshold effect level of toxicity, while Ni exceeded probable effect level, indicating the risk of probable toxicity effects. Enrichment factors (EF), contamination factor (CF) and Geo-accumulation index (I-geo) were determined. CF reveals moderate to considerable pollution with Cr and Ni. EF suggests anthropogenic sources of Cr, Cu and Ni. I-geo indicates low contamination with Co, Cu and Zn and moderate contamination with Cr and Ni. Overall metal contents were lower than expected for this highly industrialized region, probably due to dilution, suggesting that erosion rates and hydrodynamics may also play a role in metal contents distribution.
This paper reports for the first time, a method for simultaneous determination of naphazoline (NPZ) and zinc (Zn) using an analytical separation technique (capillary electrophoresis with capacitively coupled contactless conductivity detection -CE-C(4)D). A single run is possible every 55s (sampling rate=65h(-1)). The separation by CE-C(4)D was achieved on a fused silica capillary (50cm length - 10cm effective, 50μm i.d.) with a background electrolyte (BGE) composed by 20mmolL(-1) of 2-(morpholin-4-yl)ethane-1-sulfonic acid (MES) and 20mmolL(-1) of histidine (HIS) (pH 6.0). Detection limits were estimated at 20 and 30μmolL(-1) and recovery values for spiked samples were 98 and 102% for NPZ and Zn, respectively. The developed procedure was compared to HPLC (NPZ) and FAAS (Zn) and no statistically significant differences were observed (95% confidence level).
Al-50Si alloys were joined by rapid ultrasound-induced transient-liquid-phase bonding method using Zn foil as interlayer at 390°C in air, below the melt point of interlayer. The fracture of oxide films along the edge of Si particles led to contact and inter-diffusion between aluminum substrate and Zn interlayer, and liquefied Zn-Al alloys were developed. The width of Zn-Al alloys gradually decreased with increasing the ultrasonic vibration time due to liquid squeezing out and accelerated diffusion. A stage of isothermal solidification existed, and the completion time was significantly shortened. In the liquid metal, the acoustic streaming and ultrasonic cavitations were induced. As the process developed, much more Si particles, which were particulate-reinforced phases of Al-50Si, gradually migrated to the center of soldering seam. The highest average shear strength of joints reached to 94.2MPa, and the fracture mainly occurred at the base metal.
In this work, ultrasound-assisted oxidative desulfurization (UAOD) of liquid fuels performed with a novel heterogeneous highly dispersed Keggin-type phosphotungstic acid (H3PW12O40, PTA) catalyst that encapsulated into an amino-functionalized MOF (TMU-17-NH2). The prepared composite exhibits high catalytic activity and reusability in oxidative desulfurization of model fuel. Ultrasound-assisted oxidative desulfurization (UAOD) is a new way to performed oxidation reaction of sulfur-contain compounds rapidly, economically, environment-friendly and safely, under mild conditions. Ultrasound waves can be apply as an efficient tool to decrease the reaction time and improves oxidative desulfurization system performance. PTA@TMU-17-NH2 could be completely performed desulfurization of the model oil by 20mg of catalyst, O/S molar ratio of 1:1 in presence of MeCN as extraction solvent. The obtained results indicated that the conversions of DBT to DBTO2 achieve 98% after 15min in ambient temperature. In this work, we prepared TMU-17-NH2 and PTA/TMU-17-NH2 composite by ultrasound irradiation for first time and employed in UAOD process. Prepared catalyst exhibit an excellent reusability without PTA leaching and loss of activity.
Fluxless brazing of bare alumina with Cu was conducted with an ultrasonic-assisted brazing technique by a Zn-14wt.%Al filler. The shear strength of Cu/alumina joints (84MPa) exhibited 27% larger than the alumina/Cu joints (66MPa) due to different intermetallic phases and their morphologies formed in the seam under the same parameters, which are probably attributed to the transmission rate of ultrasonic energy varying with density of the ultrasonic
 horn-contacted materials. Overgrowth of stalactite-like CuZn5 contributes to better thermal dissipation of the ultrasonic-assisted brazed Cu/alumina joints.
A new extraction method for metals from sediment samples was developed. In this procedure, the chelating agent EDTA was combined with a minimal amount of the ionic liquid 1-butyl-3-methylimidazolium tetrafluoroborate (Bmim[BF4]), assisted by ultrasound energy. The available analytes -Cd, Cr, Cu, Ni, Pb and Zn- were extracted under optimal conditions for a 12.5 ratio (extractant volume/sample mass) with 0.005molL(-1) EDTA solution, 0.1molL(-1) NaHCO3, 5.0mmolL(-1) Bmim[BF4] and 7.0min of sonication time, using an ultrasonic bath (output power of 160W). The best extractions were obtained with 100W (power dissipated in the liquid). These conditions were obtained applying the univariate method. It is important to highlight that the conventional method (extraction with 0.05molL(-1) EDTA solution only) consumes 6h to extract available metals from sediment samples selectively, and with the proposed procedure the extraction time is noticeable reduced to 7.0min. Extractable metal concentrations obtained were measured by flame atomic absorption spectrometry. The results showed good agreement with those obtained by the conventional method using a Student's paired t-test.
The present study evaluated inactivation efficiency of a sonophotocatalytic process using ZnO nanofluids including ultrasonic parameters such as power density, frequency and time. The result showed that inactivation efficiency was increased by 20% when ultrasonic irradiation was combined with photocatalytic process in the presence of natural light. Comparison of inactivation efficiency in photocatalytic, ultrasonic and sonocatalytic processes using Escherichia coli as a model bacteria identified that inactivation efficiencies are shown in the following order: ultrasonic irradiation<sonocatalysis<photocatalysis<sonophotocatalysis. Furthermore, inactivation mechanism of sonophotocatalysis was proposed. Studies of reactive oxygen species (ROS) and zinc ions (Zn(2+)) release evaluation revealed that ROS play a key role in bacterial inactivation rather than Zn(2+). Permeability of outer membrane (OM) and inner membrane (IM) of E. coli bacterial cells were studied and exhibited that sonophotocatalysis increased the permeability of OM and IM significantly. The enhanced bacterial inactivation effect in sonophotocatalytic process contributed to acoustic cavitation, sonocatalysis of ZnO and sonoporation phenomenon.
Ultrasound pretreatment is a potent step to disintegrate primary sludge (PS). The supernatant of sonicated PS is recycled as an alternative carbon source for biological phosphorus removal. In this study, we investigated the role of temperature on PS disintegration during sonication. We found that a temperature of 60°C yielded a dissolution rate of about 2% soluble chemical oxygen demand (SCOD) as compared to 7% SCOD using sonication at the specific energy (SE) of 7359kJ/kg TS. Using the SE of 6000kJ/kg TS with heat insulation during sonication, the SCOD dissolution rate of PS was similar to the result at the SE of 7051kJ/kg TS without heat insulation. Upon treatment with sonication, the PS released low concentrations of Cu and Zn into the supernatant. The phosphorus-accumulating organisms (PAOs) used the supernatant of sonicated PS as the carbon source. Supplementation with the diluted sonicated PS supernatant (SCOD≈1000mg/L) in anaerobic phase resulted in the release of phosphorus (36mg/L) and the production of polyhydroxyalkanoates (PHAs) (0.36g PHA/g SS). Compared with sodium acetate, higher polyhydroxyvalerate (PHV) faction in the polyhydroxyalkanoates (PHAs) was observed in the biomass when incubated with sonicated PS as the carbon source. This work provides a simple pathway to conserve energy and to enhance efficiencies of ultrasonic pretreatment and the recovery of carbon source from the sludge for improving the phosphorus removal in the ENR system.
Duloxetine (DXT), a serotonin/norepinephrine reuptake inhibitor, is widely used for the treatment of major depressive disorders. In the present study, we investigated the neuroprotective effect of pre-treated DXT in the hippocampal CA1 region following transient global cerebral ischemia. Pre-treatment with 40mg/kg DXT protected pyramidal neurons in the CA1 region from ischemia-reperfusion injury. In addition, pre-treatment with DXT reduced ischemia-induced activations of microglia and astrocytes in the ischemic CA1 region. On the other hand, we found that pre-treatment with DXT did not increase 4-hydroxy-2-noneal (a marker for lipid peroxidation) and significantly increased the expression of Cu, Zn-superoxide dismutase, an antioxidant, in the CA1 pyramidal neurons compared with non-treated those after ischemia-reperfusion. These results indicate that pre-treated DXT has neuroprotective effect against transient global cerebral ischemia and suggest that the neuroprotective effect of DXT may be due to the attenuation of ischemia-induced glial activation as well as the decrease of oxidative stress.
Zn(2)(+) , the second most prevalent trace element in the body, is essential for supporting a wide range of biological functions. While the majority of Zn(2)(+) in the brain is protein-bound, a significant proportion of free Zn(2)(+) is found co-localized with glutamate in synaptic vesicles and is released in an activity-dependent manner. Clinical studies have shown Zn(2)(+) levels are significantly lower in blood and cerebrospinal fluid of children that suffer febrile seizures. Likewise, investigations in multiple animal models demonstrate that low levels of brain Zn(2)(+) increase seizure susceptibility. Recent work provides human genetic evidence that disruption of brain Zn(2)(+) homeostasis at the level of the synapse is associated with increased seizure susceptibility. In this review, we have explored the clinical, functional and genetic data supporting the view that low synaptic Zn(2)(+) increases cellular excitability and febrile seizure susceptibility. Finally, the review focuses on the potential of therapeutic Zn(2)(+) supplementation for at risk patients.
Recent bauxite mining activities in the vicinity of Kuantan, Pahang, have been associated with apparent environmental quality degradation and have raised environmental concerns among the public. This study was carried out to evaluate the overall ecological impacts on water and sediment quality from the bauxite mining activities. Water and sediment samples were collected at seven sampling locations within the bauxite mining areas between June and December 2015. The water samples were analyzed for water quality index (WQI) and distribution of major and trace element geochemistry. Sediment samples were evaluated based on geochemical indices, i.e., the enrichment factor (EF) and geoaccumulation index (I geo). Potential ecological risk index was estimated to assess the degree to which sediments of the mine-impacted areas have been contaminated with heavy metals. The results showed that WQIs of some locations were classified as slightly polluted and contained metal contents exceeding the recommended guideline values. The EFs indicated minimal to moderate enrichment of metals (Pb, Cu, Zn, Mn, As, Cd, Cr, Ni, Co, and Sr) in the sediments. I geo showed slightly to partially polluted sediments with respect to As at some locations. The potential ecological risk index (RI) showed that As posed the highest potential ecological risk with RI of 52.35-60.92 at two locations, while other locations indicated low risk. The findings from this study have demonstrated the impact of recent bauxite mining activities, which might be of importance to the local communities and relevant authorities to initiate immediate rehabilitation phase of the impacted area.
The chronic toxicity of ZnSO4 and ZnO nanoparticles has been studied in Daphnia magna also considering the life cycle parameters beyond the standard 21-day exposure time. Specimens have been individually followed until the natural end of their life, and some of them sampled for microscopic analyses at 48h, 9 and 21 days. Despite the low level of exposure (0.3mg Zn/L), ultrastructural analyses of the midgut epithelial cells revealed efficient internalization of nanoparticles between 48h and 9d, and translocation to other tissues as well. At 21d, the most affected fields have been recorded for both compounds; in particular samples exposed to ZnO nanoparticles showed swelling of mitochondria, while those exposed to ZnSO4 had a great number of autophagy vacuoles. The life cycle parameters resulted altered as well, with a significant inhibition of reproduction in both groups, when compared to controls. After the 21-day exposure, some interesting results were obtained: animals, previously exposed to nanoZnO at low concentrations, showed a complete recovery of the full reproduction potential, while those previously exposed to ZnSO4 presented a dose-dependent and compound-specific reduction in lifespan. Based on the results from the present research and the effects of the same chemicals at higher doses, it can be concluded that the soluble form plays a key role in ZnO nanoparticle cytotoxicity, and that the nanoparticulate form is able to locally increase the amount of Zn inside the cell, even within the ovary. It's worth noting that ZnO nanoparticles have been internalized despite the very low concentration used: this raises concern about the possible environmental implications which may derive from their use, and which in turn must be carefully considered.
Zinc bioaccessibility from infant formula was estimated by in vitro methods (solubility and dialyzability) and size-exclusion chromatography (SEC) coupled to inductively coupled plasma-mass spectrometry (ICP-MS). Infant
 formula samples were first characterized in terms of Zn bound to lipids and proteins and Zn distribution in the aqueous soluble protein fraction. We found that Zn is not incorporated into the lipid fraction of the samples, being mainly associated with the protein fraction (around 100%). Fractionation of Zn-containing proteins in the soluble protein fraction was achieved by SEC-ICP-MS after performing protein extraction with a solution of 100mM (pH 6.8) Tris-HCl. The percentages of zinc in the soluble protein fraction in the soy-based and lactose-free infant formula were very low, around 7 and 24%, respectively, whereas the content of Zn in the soluble protein fraction of milk-based formula was around 90%. By SEC-ICP-MS, we found that Zn is associated with low-molecular weight compounds (around 10kDa) in all the infant formulas tested. The percentages of Zn estimated in the in vitro gastrointestinal digests of the infant formula ranged from 30 to 70% and from 1 to 10% for solubility and dialyzability assays, respectively. The dialyzability test resulted in lower than expected scores, as SEC-ICP-MS analysis of the gastrointestinal extracts revealed that Zn is bound to biomolecules with a molecular weight ranging from 1 to 7kDa, which suggests that dialysis data should be interpreted with caution. Speciation studies are a valuable tool for establishing availability of nutrients and for validating data from dialyzable in vitro methods.
Metallic alloys have been introduced as biodegradable metals for various biomedical applications over the last decade owing to their gradual corrosion in the body, biocompatibility and superior strength compared to biodegradable polymers. Mg alloys possess advantageous properties that make them the most extensively studied biodegradable metallic material for orthopedic applications such as their low density, modulus of elasticity, close to that of the bone, and resorbability. Early resorption (i.e., <3months) and relatively inadequate strength are the main challenges that hinder the use of Mg alloys for bone fixation applications. The development of resorbable Mg-based bone fixation hardware with superior mechanical and corrosion performance requires a thorough understanding of the physical and mechanical properties of Mg alloys. This paper discusses the characteristics of successful Mg-based skeletal fixation hardware and the possible ways to improve its properties using different methods such as mechanical and heat treatment processes. We also review the most recent work pertaining to Mg alloys and surface coatings. To this end, this paper covers (i) the properties and development of Mg alloys and coatings with an emphasis on the Mg-Zn-Ca-based alloys; (ii) Mg alloys fabrication techniques; and (iii) strategies towards achieving Mg-based, resorbable, skeletal fixation devices.
Two novel imidazole derived Schiff bases, (Z)-1-(1H-benzo[d]imidazol-2-yl)-N-benzylidenemethanamine (L(1)) and 1-(1H-benzo[d]imidazol-2-yl)-N-(4-nitrobenzylidene) methanamine, and a series of their transition metal complexes of the types [M(L(1))2]Cl2 and [M(L(2))2]Cl2 where, M=Cu(II), Ni(II), Co(II) and Zn(II) have been designed and synthesized. These compounds were characterized by various spectral and physicochemical data. UV-Vis, magnetic susceptibility and molar conductivity data indicate that all the complexes adopt square planar geometry. The EPR spectral data of the Cu(II) complexes have provided supportive evidence to the conclusion derived on the basis of electronic absorption and magnetic moment values. Moreover, the interaction of complexes with DNA via intercalation has been explored by absorption, fluorescence spectroscopy, cyclic voltammetry, viscosity and circular dichroism. Agarose gel electrophoresis technique reveals that the complexes are good metallonucleases. All the compounds have relatively high antibacterial and antifungal potencies. Among the metal complexes, Cu(II) complexes exhibit higher efficacy against all the pathogens.
Flowered coatings composed by ZnO crystals were successfully electrodeposited on Zn-Mg alloys. The distinct coatings morphologies were found to be dependent upon the solid interfaces distribution, with the smaller number of bigger flowers (ø 46μm) obtained on Zn-Mg alloy containing 1wt.% Mg (Zn-1Mg) contrasting with the higher number of smaller flowers (ø 38μm) achieved on Zn-Mg alloy with 2wt.% Mg (Zn-2Mg). To assess the in vitro behaviour of these novel resorbable materials, a detailed evaluation of the degradation behaviour, in simulated physiological conditions, was performed by electrochemical impedance spectroscopy (EIS). The opposite behaviours observed in the corrosion resistances resulted in the build-up of distinct corrosion layers. The products forming these layers, preferentially detected at the flowers, were identified and their spatial distribution disclosed by EDS and Raman spectroscopy techniques. The presence of smithsonite, simonkolleite, hydrozincite, skorpionite and hydroxyapatite were assigned to both corrosion layers. However the distinct spatial distributions depicted may impact the biocompatibility of these resorbable materials, with the bone analogue compounds (hydroxyapatite and skorpionite) depicted in-between the ZnO crystals and on the top corrosion layer of Zn-1Mg flowers clearly contrasting with the hindered layer formed at the interface of the substrate with the flowers on Zn-2Mg.
Crystalline Mg-Zinc (Zn)-Strontium (Sr) ternary alloys consist of elements naturally present in the human body and provide attractive mechanical and biodegradable properties for a variety of biomedical applications. The first objective of this study was to investigate the degradation and cytocompatibility of four Mg-4Zn-xSr alloys (x=0.15, 0.5, 1.0, 1.5wt%; designated as ZSr41A, B, C, and D respectively) in the direct culture with human umbilical vein endothelial cells (HUVEC) in vitro. The second objective was to investigate, for the first time, the early-stage inflammatory response in cultured HUVECs as indicated by the induction of vascular cellular adhesion molecule-1 (VCAM-1). The results showed that the 24-h in vitro degradation of the ZSr41 alloys containing a β-phase with a Zn/Sr at% ratio ∼1.5 was significantly faster than the ZSr41 alloys with Zn/Sr at% ∼1. Additionally, the adhesion density of HUVECs in the direct culture but not in direct contact with the ZSr41 alloys for up to 24h was not adversely affected by the degradation of the alloys. Importantly, neither culture media supplemented with up to 27.6mM Mg(2+) ions nor media intentionally adjusted up to alkaline pH 9 induced any detectable adverse effects on HUVEC responses. In contrast, the significantly higher, yet non-cytotoxic, Zn(2+) ion concentration from the degradation of ZSr41D alloy was likely the cause for the initially higher VCAM-1 expression on cultured HUVECs. Lastly, analysis of the HUVEC-ZSr41 interface showed near-complete absence of cell adhesion directly on the sample surface, most likely caused by either a high local alkalinity, change in surface topography, and/or surface composition. The direct culture method used in this study was proposed as a valuable tool for studying the design aspects of Zn-containing Mg-based biomaterials in vitro, in order to engineer solutions to address current shortcomings of Mg alloys for vascular device applications.
Magnesium (Mg) alloys specifically designed for biodegradable implant applications have been the focus of biomedical research since the early 2000s. Physicochemical properties of Mg alloys make these metallic biomaterials excellent candidates for temporary biodegradable implants in orthopedic and cardiovascular applications. As Mg alloys continue to be investigated for biomedical applications, it is necessary to understand whether Mg-based materials or the alloying elements have the intrinsic ability to direct an immune response to improve implant integration while avoiding cell-biomaterial interactions leading to chronic inflammation and/or foreign body reactions. The present study utilized the direct culture method to investigate for the first time the in vitro transient inflammatory activation of endothelial cells induced by the degradation products of Zn-containing Mg alloys.
Calcium-oxalates (Ca-Ox), which are widely produced by microorganisms and plants, are ubiquitous and persistent biominerals in the biosphere. We investigated the potential trapping of two phytotoxic metals, cadmium (Cd) and zinc (Zn) by isomorphous substitution into the crystalline structure of Ca-Ox precipitated over a wide range of Cd(2+)/Ca(2+) or Zn(2+)/Ca(2+) ratio in solution. We employed atomic absorption spectroscopy, X-ray diffraction (XRD), and optical microscopy to evaluate our hypotheses that favorable solid-solution conditions and structural framework of crystal habits promote selective metal trapping within Ca-Ox precipitates. Chemical analysis demonstrated more effective Cd-Ox/Ca-Ox than Zn-Ox/Ca-Ox co-precipitate formation at the same trace metal mole fraction in solution. The XRD results revealed sequestration of Cd, but not Zn, within Ca-Ox monohydrate (whewellite). Comparative chemical analysis with Cd-Ox formation in the absence of Ca-Ox showed that the whewellite solid-solution formation lowered the solubility of Cd(2+) below that of pure Cd-Ox. The XRD patterns indicated that Zn(2+) precipitated as a separate pure Zn-Ox crystal that is largely excluded from the Ca-Ox structure. Furthermore, the presence of Zn(2+) in solution favored the formation of the less stable Ca-Ox dihydrate (weddellite) over whewellite. In agreement with the XRD data, visualization of the co-precipitates by optical microscopy illustrated combined mineral phases of Cd-Ox with Ca-Ox whereas Zn-Ox and Ca-Ox exhibited two distinct mineral morphologies. Our findings
 shed light into the structural factors that are most critical in facilitating the trapping of toxic trace metals within Ca-Ox crystals.
Zoocin A is a Zn-metallopeptidase secreted by Streptococcus zooepidemicus strain 4881. Its catalytic domain is responsible for cleaving the D-alanyl-L-alanine peptide bond in streptococcal peptidoglycan. The solution NMR structure of the Cys74 to Ala74 mutant of the recombinant catalytic domain (rCAT C74A) has been determined. With a previous structure determination for the recombinant target recognition domain (rTRD), this completes the 3D structure of zoocin A. While the structure of rCAT C74A resembles those of the catalytic domains of lysostaphin and LytM, the substrate binding groove is wider and no tyrosine residue was observed in the active site. Proteins 2016. © 2016 Wiley Periodicals, Inc.
First-row transition metals (Co, Ni, Cu and Zn) were successfully used in the preparation of activated carbons from wood biomass via microwave-assisted irradiation. Physical-chemical properties of the produced materials (MWAC) were studied by nitrogen adsorption-desorption curves, SEM, FTIR, UV-vis DRS and synchronous fluorescence spectroscopy, CHN elemental analysis, TGA/DTG, pHzpc, hydrophobic properties, and total acidity and basicity groups. Results showed that the metals were bound successfully in different amounts with surface functional groups of the wood biomass through ion exchange and surface complexation interaction during the impregnation step. Zn(2+) and Cu(2+) formed the most complexes. MWAC impregnated with Zn(2+) showed higher pore volumes and surface areas, followed by Cu(2+), Co(2+) and Ni(2+), independently of the ratio used. As the metal : biomass ratio was increased from 0.5 to 2, the surface area of MWAC increased from 300 to 620m(2)g(-1) for Co-MC, 260 to 381m(2)g(-1) for Ni-MC, 449 to 765m(2)g(-1) for Cu-MC and from 572 to 1780m(2)g(-1) for Zn-MC. The samples showed high values of carbon contents and oxygen-containing groups. An adsorption experiment revealed that samples prepared using ZnCl2 showed the highest sorption capacities (qe) for the tested adsorbates, followed by CuCl2, CoCl2 and NiCl2. These results matched with the surface areas and pore volumes trends, which were found to follow atomic number and melting point trends-Ni(II)<Co(II)<Cu(II)<Zn(II), rather than the Irving-Williams Series. The sorption capacities (qe) of molecules followed this order: 2-nitro phenol>bisphenol A>hydroquinone>4-nitro phenol>2-naphtol>paracetamol>caffeine>resorcinol.
The presence of pathological calcifications, which can be either concretions or ectopic call for physicochemical characterisation techniques in order to define a significant diagnosis. The aim of this review is to present a set of characterisation techniques able to describe at the micrometer scale their structural and chemical characteristics and show their place at the hospital.
Results already published in the last ten years based on characterisation techniques present in laboratories or specific to large-scale instruments are presented. Their usefulness for the clinician is discussed.
The presence and role of heavy metals in urinary stones through data collected through μX-ray fluorescence is debated. If these data suggest a simple substitution process of calcium, recent data suggest that weddellite is associated to a Zn-rich environment, partly favoured by an inflammation process. Investigation on the chemistry and the structure of unusual deposits in kidney biopsies show a great chemical diversity of ectopic calcifications. Such diversity shows that staining procedures to characterize such deposits are obsolete. Finally, several diseases which can be assessed through techniques specific to large-scale instruments and defined by the clinician are presented.
The chemical and structural complexity of pathological calcifications call for a characterization through physicochemical techniques. Only such approach allows the clinician to define a significant diagnosis and to care the patient.
Recent studies showed that deficiencies of essential minerals including Mg, Ca, and K, and trace minerals including Se, Zn, and V, have implications for the development, prevention, and treatment of several chronic diseases including obesity and type 2 diabetes. Our previous studies revealed that balanced deep-sea water (BDSW), which is composed of desalinated water enriched with Mg and Ca, has potential as a treatment for diabetes and obesity. In this study, to determine whether BDSW regulates mitochondrial biogenesis and function, we investigated its effects on mitochondrial DNA (mtDNA) content, mitochondrial enzyme activity, expression of key transcription factors and mitochondria-specific genes, phosphorylation of signaling molecules associated with mitochondrial biogenesis, and mitochondrial function in 3T3-L1 preadipocytes. BDSW increased mitochondrial biogenesis in a dose-dependent manner. Quantitative real-time PCR revealed that BDSW enhances expression of PGC1-α, NRF1, and TFAM genes. Upregulation of these genes was supported by increased mitochondria staining, CytC oxidase activity, and AMPK phosphorylation. The stimulatory effect of BDSW on mitochondrial biogenesis and function suggests a novel mechanism for BDSW-induced anti-diabetic and anti-obesity action.
The aim of this study was to investigate the effect of dietary supplementation of nanosize zinc on zinc digestibility, growth performances, immune response and serum parameters of weanling piglets. Ninety-six LYD weanling piglets were assigned to control, zinc oxide (ZnO), organic-Zn (Zn-methionine) and nanosize ZnO (nano-Zn) groups with four replicates. The zinc was at the 120 mg/kg level in the treatment group's diet, while the control group's was 80 mg/kg Zn. The experiment results indicated that the nano-Zn and organic-Zn groups had significantly higher Zn digestibility compared to the ZnO and control groups. For the immune response traits, the IgG level and goat red blood cells (GRBC) antibody titer were nano-Zn and organic-Zn>ZnO>control; in the phytohemagglutinin (PHA) challenge test result, nano-Zn>organic-Zn>ZnO>control; in regard to the γ-globulin level, nano-Zn and organic-Zn>ZnO and control, with significant difference between groups. In the serum parameters aspect, serum Zn concentration in nano-Zn and organic-Zn groups were higher than in the ZnO and control groups, serum growth hormone concentration was increased in the nano-Zn group than in the other groups. In conclusion, nanosize zinc oxide for dietary supplementation can increase zinc digestibility, serum growth hormone levels and carbonic anhydrase activity and enhance the immune response of weanling piglets.
We have recently proposed that the interaction between food components and nanoparticles (NPs) should be considered when evaluating the toxicity of NPs. In the present study, we used THP-1 differentiated macrophages as a model for immune cells and investigated the combined toxicity of low levels of palmitate (PA; 10 or 50μM) and ZnO NPs. The results showed that PA especially at 50μM changed the size, Zeta potential and UV-vis spectra of ZnO NPs, indicating a possible coating effect. Up to 32μg/mL ZnO NPs did not significantly affect mitochondrial activity, intracellular reactive oxygen species (ROS) or release of interleukin 6 (IL-6), but significantly impaired lysosomal function as assessed by neutral red uptake assay and acridine orange staining. The presence of 50μM PA, but not 10μM PA, further promoted the toxic effects of ZnO NPs to lysosomes but did not significantly affect other endpoints. In addition, ZnO NPs dose-dependently increased intracellular Zn ions in THP-1 macrophages, which was not significantly affected by PA. Taken together, the results of the present study showed a combined toxicity of low levels of PA and ZnO NPs especially to lysosomes in THP-1 macrophages.
An environmental survey was performed in Lake Kyrtjønn, a small lake within an abandoned shooting range in the south of Norway. In Lake Kyrtjønn the total water concentrations of Pb (14µg/L), Cu (6.1µg/L) and Sb (1.3µg/L) were elevated compared to the nearby reference Lake Stitjønn, where the total concentrations of Pb, Cu and Sb were 0.76, 1.8 and 0.12µg/L, respectively. Brown trout (Salmo trutta) from Lake Kyrtjønn had very high levels of Pb in bone (104mg/kg w.w.), kidney (161mg/kg w.w.) and the gills (137mg/kg d.w), and a strong inhibition of the ALA-D enzyme activity were observed in the blood (24% of control). Dry fertilized brown trout eggs were placed in the small outlet streams from Lake Kyrtjønn and the reference lake for 6 months, and the concentrations of Pb and Cu in eggs from the Lake Kyrtjønn stream were significantly higher than in eggs from the reference. More than 90% of Pb accumulated in the egg shell, whereas more than 80% of the Cu and Zn accumulated in the egg interior. Pb in the lake sediments was elevated in the upper 2-5cm layer (410-2700mg/kg d.w), and was predominantly associated with redox sensitive fractions (e.g., organic materials, hydroxides) indicating low potential mobility and bioavailability of the deposited Pb. Only minor amounts of Cu and Sb were deposited in the sediments. The present work showed that the adult brown trout, as well as fertilized eggs and alevins, may be subjected to increased stress due to chronic exposure to Pb, whereas exposure to Cu, Zn and Sb were of less importance.
The environmental acceptability of geotechnical composites made of treated municipal sewage sludge (SwS) and paper ash (PA) after two different curing periods has been investigated. The mineral composition of such composites, including their content of major oxides, is mainly influenced by the PA. The content of potentially toxic elements (PTEs) in the initial materials and in the composites
 varies considerably. In the SwS the Ba, Cd, Cr, Cu, Hg, Ni and Zn contents are above the legally permitted limits. The PTE content of PA are lower, but still somewhat above the permitted values for Ba and Cu. Mixing these two materials together resulted in a decrease in the PTE, but the Ba, Cu and Zn contents are still too high for agricultural application. However, leachates from composites that had been cured for 28 days are highly alkaline, and the As, Ba, Cd, Cr, Hg, Mo, Ni, Pb and Zn contents in them are well below the permitted values. The Cu contents (2.4 to 5.4 mg/kg) are above the permitted limit for inert material, but inside the range for non-hazardous material. In a leachate of composite which was prepared with fresh PA and a lower PA to SwS ratio, the Cu content was 1.4 mg/kg, since fresh PA is more reactive and therefore has a higher ability to immobilise Cu. Therefore, such mixtures can be utilised for covers and liners for sanitary landfills.
Natural toxins produced by freshwater cyanobacteria, such as cylindrospermopsin, have been regarded as an emergent environmental threat. Despite the risks for food safety, the impact of these water contaminants in agriculture is not yet fully understood. Carrots (Daucus carota) are root vegetables, extensively consumed worldwide with great importance for human nourishment and economy. It is, therefore, important to evaluate the possible effects of using water contaminated with cyanotoxins on carrot cultivation. The aim of this work was to investigate cylindrospermopsin effects on D. carota grown in soil and irrigated for 30 days, with a Chrysosporum ovalisporum extract containing environmentally relevant concentrations of cylindrospermopsin (10 and 50 μg/L). The parameters evaluated were plant growth, photosynthetic capacity, and nutritional value (mineral content) in roots of carrots, as these are the edible parts of this plant crop. The results show that, exposure to cylindrospermopsin did not have a clear negative effect on growth or photosynthesis of D. carota, even leading to an increase of both parameters. However, alterations in mineral contents were detected after exposure to crude extracts of C. ovalisporum containing cylindrospermopsin. A general decline was observed for most minerals (Ca, Mg, Na, Fe, Mn, Zn, Mo, and P), although an increase was shown in the case of K and Cu, pointing to a possible interference of the cyanobacterial extract in mineral uptake. This study is the first to evaluate the effects of C. ovalisporum extracts on a root vegetable, however, more research is necessary to understand the effects of this toxin in environmentally relevant scenarios.
Marine pollutants are becoming a growing concern due to their ecological consequences. This study investigates the potential risk posed by microplastics and toxic elements in coastal sediments of Khark Island, the main oil export hub of Iran. Principal component biplots exhibited a significant positive correlation between microplastic quantities (ranging in shape and color) and concentration of heavy metals with industrial activity. Source identification of the heavy metals indicated both natural and anthropogenic origin. Quality and risk assessment of the sediments revealed low to moderate pollution of Zn, Mo, Pb, Cu, Cd and As in some stations. Results of metal fractionation in sediments demonstrated that Cd, Mn, Zn, As and Pb are capable of posing a serious ecological risk due to potential bioavailability. Microplastics, mostly fragments and fibers, were detected in all sediment samples (ranging from 59 to 217 items/200 g dry sediment). A relatively good significant linear relationship exists between microplastic quantities and potentially toxic element/polycyclic aromatic hydrocarbon concentrations in coastal sediments. The results of this study confirmed the key role of microplastics as a "potential contaminant vector" for other types of pollutants.
The common dolphin (Delphinus delphis) is one of the most abundant species in Atlantic Iberia, representing a potentially important tool to assess the bioaccumulation of trace elements in the Iberian marine ecosystem. Nine elements (As, Cd, Cu, Hg, Mn, Ni, Pb, Se and Zn) were evaluated in 36 dolphins stranded in continental Portugal. Dolphins had increasing Hg concentrations (16.72μg·g(-1) ww, liver) compared with previous studies in Atlantic Iberia, whereas Cd concentrations (2.26μg·g(-1) ww, kidney) fell within reported ranges. The concentrations of some trace elements (including Cd and Hg) presented positive relationships with dolphin length, presence of parasites and gross pathologies. Common dolphins may help biomonitoring more offshore Atlantic Iberian areas in future studies, which would otherwise be difficult to assess.
Human dopaminergic system in general, and substantia nigra (SN) neurons, in particular, are implicated in the pathologies underlying the human brain aging. The interplay between aberrations in the structural organization and elemental composition of SN neuron bodies has recently gained in importance as selected metals: Fe, Cu, Zn, Ca were found to trigger oxidative-stress-mediated aberration in their molecular assembly due to concomitant protein (alpha-synuclein, tau-protein) aggregation, gliosis and finally oxidative stress. In the present study, we demonstrate an integrated approach to the analysis of the structural organization, assembly, and metals' accumulation in two distinct areas of SN: in the neuromelanin neurons and neuropil. By using the highly brilliant source of PETRA III and the Kirkpatrick-Baez nano-focus, large area histological brain slices are scanned at the sub-neuronal resolution, taking advantage of continuous motor movement and reduced acquisition time. Elemental analysis with synchrotron radiation based X-ray Fluorescence (SRXRF) is combined with X-ray Phase Contrast Imaging (XPCI) to correct for inherent aberrations in the samples' density and thickness, often referred to as the mass thickness effect. Based on the raw SRXRF spectra, we observed the accumulation of P, S, Cl, K, Ca, Fe, Cu and Zn predominantly in the SN neurons. However, upon the mass thickness correction, the distributions of Cl became significantly more uniform. Simultaneously with the fluorescence signal, the Small Angle X-ray Scattering (SAXS) is recorded by a pixel detector positioned in the far-field, enabling fast online computation of the darkfield and differential phase contrast (DPC). The data has demonstrated the SN neurons and neuropil produces excellent contrast which is due to their different mass density and scattering strength, indicative of differences in local structure and assembly therein. In all, the results show that combined SRXRF-XPCI-SAXS experiments can robustly serve as a unique tool for understanding the interplay between the chemical composition and structural organization that may drive the biochemical age-related processes occurring in the human dopaminergic system.
In this study, a functionalized magnetic hollow porous oval-shape NiFe2O4 (MHPO-NiFe2O4) was designed by a facile synthesis procedure, and employed as magnetic solid phase extraction (MSPE) material to extract several heavy metal ions. As-prepared MHPO-NiFe2O4 exhibited superior adsorption capacities of 20.17, 16.64, 16.82, 9.69 and 16.58mgg(-1), for Cu(II), Cd(II), Cr(III), Co(II) and Zn(II), and was then used to detect these heavy metals elements in real samples by combining with inductively coupled plasma optical emission spectroscopy (ICP-OES). The possible mechanism of the enrichment of heavy metals ions on MHPO-NiFe2O4 was proposed, which involved the dominant adsorption and desorption. The detection limits were as low as 0.015, 0.13, 0.062, 0.035 and 0.46μgL(-1) for Cu(II), Cd(II), Cr(III), Co(II) and Zn(II), respectively. A good repeatability was obtained with the relative standard deviation (RSD) of 3.87%. Moreover, the method was successfully utilized for the analysis of five heavy metals in real samples (cabbage, lettuce, apple, seawater), with satisfactory recoveries in the range of 92-108%.
The study assessed the cytotoxicity and immunomodulatory/anti-inflammatory effect of extract from zinc oxide-eugenol (ZOE)-based dental materials during setting using immortalized human dental pulp stem cells (IHDPSCs) and mouse bone marrow monocytes (IMBMMs), and identified the responsible extract component.
In accord with the ISO 10993-12, we extracted a mixture of ZOE cement and sealer after a specified time. The extract was analyzed by two types of mass spectrometry (ICP-MS and GC-MS). Cell viability was evaluated with extract and serial concentrations of ZnCl2, ZnSO4, and eugenol liquid by WST assay. The immunomodulatory/anti-inflammatory effect of a ZOE component was determined by RT-PCR to detect the downregulatory effect of inflammatory mRNA expression after lipopolysaccharide (LPS)-induced inflammation.
Zn(2+) and eugenol (2-20ppm) were detected in the ZOE cement and sealer extracts. During the early stage of setting, significant cytotoxicity was observed in IHDPSCs and IMBMMs (p<0.05). The half maximal effective concentration of Zn(2+) was 5-8ppm, whereas that of eugenol could not be detected within 80ppm. After extract treatment, the expression of inflammatory mRNA was significantly lower in inflamed IHDPSCs, but not inflamed IMBMMs, than in the LPS control (p<0.05). However, eugenol, not Zn(2+), at 5-20ppm downregulated inflammatory mRNA expression in the inflamed IMBMMs with and without the exchange of LPS-pretreated medium.
ZOE was highly cytotoxic, especially during setting, to both cells due to Zn(2+) while the immunomodulatory/anti-inflammatory effect of ZOE was induced by eugenol.
Phytoremediation is a cost-effective "green technology" that uses plants to improve the soil properties of polluted sites, preventing the
 dispersion of pollutants and reducing the mobility of potentially toxic elements (PTEs) through their adsorption and accumulation by roots or precipitation within the root zone. Being highly tolerant to pollutants and other abiotic stresses, giant reed (Arundo donax L.) is a suitable biomass crop for phytoremediation of contaminated soils. We report the results of a two-year open-air lysimeter study aimed at assessing the adaptability of giant reed to grow on industrial substrates polluted by Pb and Zn and at testing commercial humic acids from leonardite as improvers of plant performance. We evaluated giant reed potential for: 1) biomass production for energy or biomaterial recovery; 2) PTE phytoextraction and 3) soil fertility restoration. Chemical fertility was monitored by measuring soil C while soil biological fertility was estimated by quantifying the abundance of bacterial functional genes regulating nitrogen fixation (nifH) and nitrification (amoA). Giant reed above-ground growth on the polluted soils was slightly lower (-16%) than on a non-polluted soil, with a preferential storage of biomass in the rhizome acting as a survival strategy in limiting growing conditions. Humic acids improved plant stress tolerance and production levels. As aerial biomass (shoots) did not accumulate PTEs, the plant in question can be used for bioenergy or biopolymer production. In contrast, below-ground biomass (rhizomes) accumulated PTEs, and can thus be harvested and removed from soil to improve phytoremediation protocols and also used as industrial biofuel. Giant reed growth increased the abundance of N-cycling bacteria and soil C in the rhizospheric soil, as well as reduced soil Pb and Zn EDTA extractable fraction.
Metals are involved in the formation of reactive oxygen species and can induce oxidative stress. The aim of this study was to assess the effects of several metals on oxidative stress in the skin and muscle of the Pelophylax esculentus "complex" frogs (parental species Pelophylax ridibundus, Pelophylax lessonae, and their hybrid Pelophylax esculentus) that inhabit the wetland Obedska Bara in Serbia, and the potential use of these species as bioindicator organisms in biomonitoring studies. The biomarkers of oxidative stress (SOD, CAT, GSH-Px, GR, GST activities and GSH, SH concentrations) and cholinesterase activity were investigated. The concentrations of nine metals (Fe, Cu, Zn, As, Cd, Cr, Hg, Ni, and Pb) were measured in the water and tissues. Correlations were established between metals and biomarkers in the tissues. The results of metal accumulation distinguished the skin of P. lessonae and muscle of P. ridibundus from other P. esculentus complex species. The oxidative stress biomarkers observed in P. ridibundus and P. esculentus had greater similarity than in P. lessonae. The P. lessonae displayed the highest number of correlations between biomarkers and metals. The results of tissue responses revealed that skin was more susceptible to metal-induced oxidative stress, with only exception of As. In the light of these findings, we can suggest the use of P. esculentus complex species as a biomonitoring species in studies of metal accumulation and metal-induced oxidative stress, but with special emphasis on P. lessonae.
Exposure of cells to ionizing radiation (IR) generates reactive oxygen species (ROS). This results in increased oxidative stress and DNA double strand breaks (DSBs) which are the two underlying mechanisms by which IR causes cell/tissue injury. Cells that are deficient or impaired in the cellular antioxidant response are susceptible to IR-induced apoptosis. The transcription factor CCAAT enhancer binding protein delta (Cebpd, C/EBPδ) has been implicated in the regulation of oxidative stress, DNA damage response, genomic stability and inflammation. We previously reported that Cebpd-deficient mice are sensitive to IR and display intestinal and hematopoietic injury, however the underlying mechanism is not known. In this study, we investigated whether an impaired ability to detoxify IR-induced ROS was the underlying cause of the increased radiosensitivity of Cebpd-deficient cells. We found that Cebpd-knockout (KO) mouse embryonic fibroblasts (MEFs) expressed elevated levels of ROS, both at basal levels and after exposure to gamma radiation which correlated with increased apoptosis, and decreased clonogenic survival. Pre-treatment of wild type (WT) and KO MEFs with polyethylene glycol-conjugated Cu-Zn superoxide dismutase (PEG-SOD) and catalase (PEG-CAT) combination prior to irradiation showed a partial rescue of clonogenic survival, thus demonstrating a role for increased intracellular oxidants in promoting IR-induced cell death. Analysis of mitochondrial bioenergetics revealed that irradiated KO MEFs showed significant reductions in basal, adenosine triphosphate (ATP)-linked, maximal respiration and reserved respiratory capacity and decrease in intracellular ATP levels compared to WT MEFs indicating they display mitochondrial dysfunction. KO MEFs expressed significantly lower levels of the cellular antioxidant glutathione (GSH) and its precursor- cysteine as well as methionine. In addition to its antioxidant function, GSH plays an important role in detoxification of lipid peroxidation products such as 4-hydroxynonenal (4-HNE). The reduced GSH levels observed in KO MEFs correlated with elevated levels of 4-HNE protein adducts in irradiated KO MEFs compared to respective WT MEFs. We further showed that pre-treatment with the GSH precursor, N-acetyl L-cysteine (NAC) prior to irradiation showed a significant reduction of IR-induced cell death and increases in GSH levels, which contributed to the overall increase in clonogenic survival of KO MEFs. In contrast, pre-treatment with the GSH synthesis inhibitor- buthionine sulfoximine (BSO) further reduced the clonogenic survival of irradiated KO MEFs. This study demonstrates a novel role for C/EBPδ in protection from basal as well as IR-induced oxidative stress and mitochondrial dysfunction thus promoting post-radiation survival.
Increasing rates of antibiotic resistance coupled with the lack of novel antibiotics threatens proper clinical treatment and jeopardizes their use in prevention. A photodynamic approach appears to be an innovative treatment option, even for multi-drug resistant strains of bacteria. Three components are utilized in photodynamic inactivation: a photosensitizer, light source, and oxygen. Variations in photosensitizers strongly influence microbial binding and bactericidal activity. In this study, four different cationic metalloporphyrins (Cu(2+), Fe(2+), Pd(2+), Zn(2+)) were compared to the free-base ligand 5,10,15,20-tetrakis(N-methylpyridinium-4-yl)porphyrin regarding their electronic properties and generation of reactive oxygen species upon subsequent 405nm violet-blue irradiation. Staphylococcus aureus and Escherichia coli were used as representatives of Gram-positive and -negative, respectively, to assess bactericidal effects by the photodynamic process. Bacterial cultures were pre-incubated with porphyrins and exposed to varying doses of 405nm irradiation (0-30J/cm(2)). Metalloporphyrins containing Cu(2+) and Fe(2+) demonstrated minimal effects on viability. Pronounced bactericidal activity was evident with free-base ligand, Zn(2+), and Pd(2+); though significantly stronger effects were apparent with Pd(2+). Photodynamic killing was directly proportional to reactive oxygen species production post-illumination. These data provide new insight into the influence of metal chelation on photosensitizer activity on bactericidal singlet oxygen production. The strong anti-microbial photodynamic action through the use of a portable light-emitting diode over short time intervals (seconds) provides support for its potential use in self-treatment.
In the present study, wood ash was modified by alkaline fusion, prior to hydrothermal synthesis, for potential application in the treatment of mine drainage impacted water. With this objective, two types of wood ash (both raw and modified) were evaluated for the treatment of Ni and Zn in contaminated neutral drainage (CND). Batch adsorption experiments were initially conducted on synthetic CND, and then on two real CND, sampled on two active mine sites, contaminated by either Ni (3.7 mg/L) or Zn (9.1 mg/L). Leaching of Zn was observed during the kinetic tests for the raw wood ash, whereas its modification suppressed the leaching. The cation exchange capacity acquired by modification of the two samples of wood ash exceeded 300 meq/100 g (which is two to fourfold higher than those of the raw ash), while sorption capacity for Ni and Zn tripled relative to the raw material. The Langmuir model best described the sorption process for all materials, while potential mechanisms of metal removal include adsorption, precipitation and ion exchange, following pseudo second-order kinetics. Results also showed that within 2 h of contact of mine effluents with one modified wood ash, Ni and Zn concentrations decreased below the maximum authorized monthly mean concentration allowed by the Canadian law (0.5 mg/L), whereas the other modified wood ash allowed reaching the regulatory conformity after 2 h for Ni but 7 days for Zn (although 93% removed after 2 h). Nonetheless, the pH was raised (10.9-11.8) above the legally allowed limits (6-9.5). Based on these findings, modified wood ash could be considered as a promising option for the treatment of Ni and Zn in CND, but the pH correction of final effluent might be necessary.
A facile and metal-free method for the preparation of free base meso-aminodiarylporphyrins from readily available meso-bromodiarylporphyrins is described. Simple treatment of meso-bromoporphyrins with sodium azide and sodium ascorbate in DMF affords the corresponding meso-aminoporphyrins in very good
 yields. This method involves the aromatic nucleophilic substitution (SNAr) of a bromo group with an azido group and the subsequent in situ reduction of the introduced azido group by sodium ascorbate. This amination reaction can be scaled up to gram scale without any decrease of the product yield. The amination reaction of free base meso-dibromoporphyrin affords a monoaminated product selectively, whereas that of the Ni(II) complex furnishes a diaminated product that is oxidized by air under ambient conditions but isolable as a trifluoroacetyl ester. Metal-insertion reactions of the obtained free base aminoporphyrins afford the corresponding metal complexes (Ni(II), Cu(II), Zn(II), and Pd(II)) all in good yields except the Pd(II) complex. Synthetic methods for the preparation of N-mono- or dialkylaminoporphyrins from the free base meso-aminoporphyrins have been also established.
The seasonal variation in physico-chemical properties, anions, and the heavy metal (Cd, Co, Cr, Cu, Mn, Ni, Pb, and Zn) concentration was evaluated in water from nine different rivers in Lake Pontchartrain Basin, Louisiana, USA. The water quality parameters were compared with toxicity reference values (TRV), US Environmental Protection Agency (USEPA) drinking/aquatic life protection, and WHO standards. Among physico-chemical properties, pH, DO, and turbidity were high during spring, while, EC, temperature, and DOC were high during summer and vice versa. The anion study revealed that the concentrations of F(-), Cl(-), and NO3(-) were higher during summer and Br(-) and SO4(-) were higher during spring. Our research findings showed anion concentration decreased in the order of Cl(-) > SO4(-) > NO3(-) > Br(-) > F(-), in accordance with the global mean anion concentration. The dissolved heavy metals (Cd, Co, Cr, Cu, Mn, Ni, Pb) except Zn were higher during spring than summer. None of the rivers showed any Cd pollution for both seasons. Co showed higher concentrations in Amite River, Mississippi River, Industrial Canal, and Lacombe Bayou during summer. The Cr concentration was higher than WHO drinking water standards, implicating water unsuitability for drinking purposes in all the rivers associated with the Lake Pontchartrain Basin. Cu showed no pollution risk for the study area. Mn and Co were similar to concentration in Lacombe Bayou, Liberty Bayou, Blind River, and Industrial Canal. Mn levels were greater than WHO standards for the Tickfaw River, Tangipahoa River, and Blind River in both seasons. Blind River, Tangipahoa River, Tickfaw River, and Amite River will require more monitoring for determining possible Mn pollution. Ni content in river water during both seasons showed low pollution risk. Liberty Bayou and Industrial Canal concentrations were closer to the WHO regulatory standards, indicating possible risk of Pb pollution in these water bodies. The Zn content was near the USEPA aquatic life standards in summer for all water bodies. None of the rivers showed any risk associated with Cd, Co, Cu, and Ni levels but medium to higher risk to aquatic life from Cr and Zn for both seasons for most of the rivers. Metal fractionation revealed the decreasing order of inert > labile > organic. The high inert fraction in the rivers under study reflects the major contribution of natural sources in Lake Pontchartrain Basin. The labile and organic forms of Cd, Cu, Ni, and Zn pose potential higher risk to the aquatic life in the Lake Pontchartrain Basin.
Hepatocellular carcinoma is a lethal cancer with high recurrence ratio and lacks effective therapeutics. In the past few years, it has been reported that increased intake of vegetables and fruits could reduce the cancer incidence, which suggests dietary agents might possess anticancer effects. Eriocitrin is a flavonoid isolated from lemon, which is known as a strong antioxidant agent. We here for the first time demonstrated that eriocitrin could inhibit the proliferation of hepatocellular carcinoma cell lines by arresting cell cycle in S phase through up-regulation of p53, cyclin A, cyclin D3 and CDK6. Furthermore, we found that eriocitrin could trigger apoptosis by activating mitochondria-involved intrinsic signaling pathway. Thus, eriocitrin might be regarded as a potential chemopreventive natural product to inhibit the early malignant transformation of hepatocellular carcinoma.
The present work was designed to detect heavy metal contents of Al, Zn, Fe, Mn, Ni, V, Co, Cr and Cu in sediments and shells of the Trachycardium lacunosum collected in polluted and unpolluted areas along the Persian Gulf.
The samples were taken from surface sediments (0-10 cm) and shells of Trachycardium lacunosum in two separated areas (polluted and unpolluted) in northern part of the Persian Gulf, Asaluyeh Bay, during summer 2013. The prepared samples were analyzed by inductively coupled plasma-optical emission spectrometry (ICP-OES).
Based on the results, all measured metals including Al, Zn, Fe, Mn, Ni, V, Co, Cr and Cu were meaningfully higher in the sediment samples of polluted area compared to unpolluted area and the order of metal concentrations in the sediment samples were Cr > Co > V > Ni > Zn > Cu > Fe > Al > Mn in polluted area. In the case of shell samples of Trachycardium lacunosum, polluted area contained significantly higher contents of Al, Zn, Fe, Mn, Ni, Co, Cr and Cu compared to unpolluted area and the order of metal concentrations in the shell samples were Fe > Zn > Al > Mn > Cu > Cr > Ni > Co in the polluted area.
It was concluded that shells of the Trachycardium lacunosum can be used as a suitable bioindicator for heavy metals in the aquatic environment. Results confirmed that due to the possible contaminations by oil and gas activities near the polluted area perennial monitoring and mitigation measures is extremely necessary.
This study evaluated the effect of popping and fermentation on the chemical composition of three types of Amaranthus caudatus grains cultivated in Ethiopia. Proximate composition, minerals and mineral absorption inhibitors were analyzed. Popping caused a decrease in protein content by 4 % and an increase in fat, ash, acid detergent fiber (ADF) and neutral detergent fiber (NDF) contents by 12, 10, 15 and 67 %, respectively. While fermentation increased protein, fat and ash content by 3, 22 and 14 %, respectively but did not significantly change ADF and NDF content. Fe, Ca and phytic acid (IP6) decreased during popping but Mg, Zn, galloyl and catechol did not change significantly. On the other hand, fermentation increased Fe and Mg content but decreased IP6, galloyl and catechol content. The decrease in mineral absorption inhibitors especially IP6 during popping and fermentation could contribute to enhance mineral bioavailability. However, due to the presence of high phytate content in raw amaranth, all IP6-to-mineral molar ratios were above the recommended values.
The concentrations of heavy metals (Cd, Pb, Cr, Ni, Cu and Zn) were determined in four commercially valuable fish species (Thunnus obesus, Decapterus lajang, Cubiceps squamiceps and Priacanthus macracanthus), collected in the western continental shelf of the South China Sea. Concentrations of Cd, Pb, Cr, Ni, Cu, and Zn in fish muscles were 0.006-0.050, 0.13-0.68, 0.18-0.85, 0.11-0.25, 0.12-0.77, and 2.41-4.73μg/g, wet weight, respectively. Concentrations of heavy metals in all species were below their acceptable daily upper limit, suggesting human consumption of these wild fish species may be safe, with health risk assessment based on the target hazard quotients (THQ) and total THQ, indicating no significant adverse health effects with consumption. The average concentrations of Zn were higher in gills than in stomach contents, backbones or muscle, while conversely, the other heavy metals had higher concentrations in stomach contents than in other tissues.
A simple method based on FAAS was developed for the sequential multi-element determination of Cu, Zn, Mn, Mg and Si in beverages and food supplements with successful results. The main absorption lines for Cu, Zn and Si and secondary lines for Mn and Mg were selected to carry out the measurements. The sample introduction was performed using a flow injection system. Using the choice of the absorption line wings, the upper limit of the linear range increased up to 110mgL(-1) for Mg, 200mgL(-1) for Si and 13mgL(-1) for Zn. The determination of the five elements was carried out, in triplicate, without the need of additional sample dilutions and/or re-measurements, using less than 3.5mL of sample to perform the complete analysis. The LODs were 0.008mgL(-1) for Cu, 0.017mgL(-1) for Zn, 0.011mgL(-1) for Mn, 0.16mgL(-1) for Si and 0.11mgL(-1) for Mg.
The effects of different drying conditions, such as infrared power, drying air temperature and velocity, on quality of strawberry were evaluated. Drying time decreased with increased infrared power, air temperature and velocity. An increase in power from 100W to 300W, temperature from 60 to 80°C and velocity from 1.0m.s(-1) to 2.0m.s(-1) decreased fruit color quality index. For total phenol and anthocyanin content, 300W, 60°C, and 1.0m.s(-1) were superior to the other experimental conditions. The drying processes increased N, P and K and decreased Ca, Mg, Fe, Mn, Zn and Cu contents. The optimal conditions to preserve nutrients in infrared drying of strawberry were 200W, 100°C and 1.5m.s(-1).
Botrydial (BOT) is a non-host specific phytotoxin produced by the polyphagous phytopathogenic fungus Botrytis cinerea. The genomic region of the BOT biosynthetic gene cluster was investigated and revealed two additional genes named Bcbot6 and Bcbot7. Analysis revealed that the G+C/A+T-equilibrated regions that contain the Bcbot genes alternate with A+T-rich regions made of relics of transposable elements that have undergone repeat-induced point
 mutations (RIP). Furthermore, BcBot6, a Zn(II)2Cys6 putative transcription factor was identified as a nuclear protein and the major positive regulator of BOT biosynthesis. In addition, the phenotype of the ΔBcbot6 mutant indicated that BcBot6 and therefore BOT are dispensable for the development, pathogenicity and response to abiotic stresses in the B. cinerea strain B05.10. Finally, our data revealed that B. pseudocinerea, that is also polyphagous and lives in sympatry with B. cinerea, lacks the ability to produce BOT. Identification of BcBot6 as the major regulator of BOT synthesis is the first step towards a comprehensive understanding of the complete regulation network of BOT synthesis and of its ecological role in the B. cinerea life cycle.
The synthesis of stable porous materials with appropriate pore size and shape for desired applications remains challenging. In this work a combined experimental/computational approach has been undertaken to tune the stability under various conditions and the adsorption behavior of a series of MOFs by subtle control of both the nature of the metal center (Co(2+) , Cu(2+) , and Zn(2+) ) and the pore surface by the functionalization of the organic linkers with amido and N-oxide groups. In this context, six isoreticular MOFs based on T-shaped ligands and paddle-wheel units with ScD0.33 topology have been synthesized. Their stabilities have been systematically investigated along with their ability to adsorb a wide range of gases (N2 , CO2 , CH4 , CO, H2, light hydrocarbons (C1 -C4 )) and vapors (alcohols and water). This study has revealed that the MOF frameworks based on Cu(2+) are more stable than their Co(2+) and Zn(2+) analogues, and that the N-oxide ligand endows the MOFs with a higher affinity for CO2 leading to excellent selectivity for this gas over other species.
The separation of 1,3-butadiene from C4 hydrocarbon mixtures is imperative for the production of synthetic rubbers, and there is a need for a more economical separation method, such as a pressure swing adsorption process. With regard to adsorbents that enable C4 gas separation, [Zn(NO2 ip)(dpe)]n (SD-65; NO2 ip=5-nitroisophthalate, dpe=1,2-di(4-pyridyl)ethylene) is a promising porous material because of its structural flexibility and restricted voids, which provide unique guest-responsive accommodation. The 1,3-butadiene-selective sorption profile of SD-65 was elucidated by adsorption isotherms, in situ PXRD, and SSNMR studies and was further investigated by multigas separation and adsorption-desorption-cycle experiments for its application to separation technology.
An asymmetric 'Pacman' metalloligand, [Zn(PXT)], which features a cofacial Zn(II) -porphyrin unit (P) covalently attached to a terpyridine (T) chelating group via a rigid xanthene (X) moiety has been prepared, and its interactions with several different trivalent Ln(III) cations (Nd(III) , Gd(III) , Yb(III) and Lu(III) ) have been examined. The formation of 1:1 metal-ligand complexes was monitored by (1) H NMR spectroscopy and corroborated by HRMS data. Solution-stability constants were determined by UV/Vis titration, and the resulting complexes with Nd(III) or Yb(III) demonstrated sensitised emission in the NIR region due to energy transfer from the Zn(II) -porphyrin donor to Ln(III) acceptor. The energy transfer was investigated by transient absorption techniques, which provided insight into the kinetics and efficiency of the antenna effect.
Bacterial trimethylamine N-oxide (TMAO) demethylase, Tdm, carries out an unusual oxygen-independent demethylation reaction, resulting in the formation of dimethylamine and formaldehyde. In this study, site-directed mutagenesis, homology modelling and metal analyses by inorganic mass spectrometry have been applied to gain insight into metal stoichiometry and underlying catalytic mechanism of Tdm of Methylocella silvestris BL2. Herein, we demonstrate that active Tdm has 1 molar equivalent of Zn(2+) and 1 molar equivalent of non-haem Fe(2+) . We further investigated Zn(2+) - and Fe(2+) -binding sites through homology modelling and site-directed mutagenesis and found that Zn(2+) is coordinated by a 3-sulfur-1-O motif. An aspartate residue (D198) likely bridges Fe(2+) and Zn(2+) centres, either directly or indirectly via H-bonding through a neighbouring H2 O molecule. H276 contributes to Fe(2+) binding, mutation of which results in an inactive enzyme, and the loss of iron, but not zinc. Site-directed mutagenesis of Tdm also led to the identification of three hydrophobic aromatic residues likely involved in substrate coordination (F259, Y305, W321), potentially through a cation-π interaction. Furthermore, a crossover experiment using a substrate analogue gave direct evidence that a trimethylamine-alike intermediate was produced during the Tdm catalytic cycle, suggesting TMAO has a dual role of being both a substrate and an oxygen donor for formaldehyde formation. Together, our results provide novel insight into the role of Zn(2+) and Fe(2+) in the catalysis of TMAO demethylation by this unique oxygen-independent enzyme.
Zinc is one of the most important metal nutrients for species from all kingdoms, being a key structural or catalytic component of hundreds of enzymes, crucial for the survival of both pathogenic microorganisms and their hosts. This work is an overview of the homeostasis of zinc in bacteria and humans. It explains the importance of this metal nutrient for pathogens, describes the roles of zinc sensors, regulators, and transporters, and summarizes various uptake systems and different proteins involved in zinc homeostasis-both those used for storage, buffering, and signaling inside the cell and those excreted in order to obtain Zn(II) from the host. The human zinc-dependent immune system response is explained, with a special focus given to 'zinc nutritional immunity', a process that describes the competition between the bacteria or fungus and the host for this metal, during which both the pathogen and host make huge efforts to control zinc availability. This sophisticated tug of war over Zn(II) might be considered as a possible target for novel antibacterial therapies.
Genetically encoded FRET-based sensor proteins have significantly contributed to our current understanding of the intracellular functions of Zn(2+). However, the external excitation required for these fluorescent sensors can give rise to photobleaching and phototoxicity during long-term imaging, limits applications that suffer from autofluorescence and light scattering, and is not compatible with light-sensitive cells. For these applications, sensor proteins based on Bioluminescence Resonance Energy Transfer (BRET) would provide an attractive alternative. In this work, we used the bright and stable luciferase NanoLuc to create the first genetically encoded BRET sensors for measuring intracellular Zn(2+). Using a new sensor approach, the NanoLuc domain was fused to the Cerulean donor domain of two previously developed FRET sensors, eCALWY and eZinCh-2. In addition to preserving the excellent Zn(2+) affinity and specificity of their predecessors, these newly developed sensors enable both BRET- and FRET-based detection. While the dynamic range of the BRET signal for the eCALWY-based BLCALWY-1 sensor was limited by the presence of two competing BRET pathways, BRET/FRET sensors based on the eZinCh-2 scaffold (BLZinCh-1 and -2) yielded robust 25-30% changes in BRET ratio. In addition, introduction of a chromophore-silencing mutation resulted in a BRET-only sensor (BLZinCh-3) with increased BRET response (50%) and an unexpected 10-fold increase in Zn(2+) affinity. The combination of robust ratiometric response, physiologically relevant Zn(2+) affinities, and stable and bright luminescence signal offered by the BLZinCh sensors allowed monitoring of intracellular Zn(2+) in plate-based assays as well as intracellular BRET-based imaging in single living cells in real time.
Various fluorescent probes have been developed to reveal the biological functions of intracellular labile Zn(2+). Here, we present Green Zinc Probe (GZnP), a novel genetically encoded Zn(2+) sensor design based on a single fluorescent protein (single-FP). The GZnP sensor is generated by attaching two zinc fingers (ZF) of the transcription factor Zap1 (ZF1 and ZF2) to the two ends of a circularly permuted green fluorescent protein (cpGFP). Formation of ZF folds induces interaction between the two ZFs, which induces a change in the cpGFP conformation, leading to an increase in fluorescence. A small sensor library is created to include mutations in the ZFs, cpGFP and linkers between ZF and cpGFP to improve signal stability, sensor brightness and dynamic range based on rational protein engineering, and computational design by Rosetta. Using a cell-based library screen, we identify sensor GZnP1, which demonstrates a stable maximum signal, decent brightness (QY = 0.42 at apo state), as well as specific and sensitive response to Zn(2+) in HeLa cells (Fmax/Fmin = 2.6, Kd = 58 pM, pH 7.4). The subcellular localizing sensors mito-GZnP1 (in mitochondria matrix) and Lck-GZnP1 (on plasma membrane) display sensitivity to Zn(2+) (Fmax/Fmin = 2.2). This sensor design provides freedom to be used in combination with other optical indicators and optogenetic tools for simultaneous imaging and advancing our understanding of cellular Zn(2+) function.
Two highly porous Co-based metal-azolate frameworks (MAFs), MAF-5(Co) and MAF-6(Co), which are isostructural with MAF-5(Zn) and MAF-6(Zn), respectively, were first synthesized in high yield and purity at room temperature. The syntheses compared two mixing methods, slow and fast, using cobalt acetate as the metal ion (Co(2+)) source and 2-ethylimidazole as the ligand. Triethylamine was applied as an additive/promoter in aqueous/ethanol solutions, and benzene
 and cyclohexane were used as hydrophobic templates. Phase-pure MAF-5(Co) and MAF-6(Co) were obtained in high yield by optimizing the mixing speed, reactant composition, and solvent/template ratio. It was found that fast mixing of the reactant mixtures was effective for synthesizing MAF(Co) materials. MAF-5(Co) and MAF-6(Co) were found to be very hydrophobic, similar to the MAFs composed of Zn, suggesting possible applications in water purification. MAF-5(Co) and MAF-6(Co) were then applied to adsorb n-octane as a model oil and nonpolar adsorbate from water, and the obtained results were compared to those of related materials, i.e., MAF-4(Co and Zn), MAF-5(Zn), and MAF-6(Zn), as well as with Cu-BTC (Cu-benzenetricarboxylate) and a conventional adsorbent, activated carbon. Surprisingly, despite having low porosity, MAF-5(Co) showed remarkable competitiveness among the typical porous materials for n-octane removal. The results suggest that the framework structure such as cavity and aperture sizes rather than surface area plays a significant role in n-octane removal. Moreover, MAF-5(Co) can easily be regenerated by simple evacuation and reused, and thus it was found to be a potential adsorbent for the removal of spilled oil from water. Additionally, MAFs were applied in the adsorption of diclofenac sodium from water, showing the competitiveness of MAFs in water purification probably because of hydrophobicity.
In our study, Mg-Al-Zn mingled oxides were prepared by the co-precipitation method. The structure, composition, morphology and thermal stability of the synthesized Mg-Al-Zn mingled oxides were analyzed by powder X-ray diffraction, Fourier transform infrared spectrometry, N2 physisorption, scanning electron microscopy, differential scanning calorimetry and thermogravimetry. Batch experiments were performed to study the adsorption behavior of cobalt(II) and nickel(II) as a function of pH, contact time, initial metal ion concentration, and adsorbent dose. The maximum adsorption capacity of Mg-Al-Zn mingled oxides for cobalt and nickel metal ions was 116.7 mg g(-1), and 70.4 mg g(-1), respectively. The experimental data were analyzed using pseudo-first- and pseudo-second-order kinetic models in linear and nonlinear regression analysis. The kinetic studies showed that the adsorption process could be described by the pseudo-second-order kinetic model. Experimental equilibrium data were well represented by Langmuir and Freundlich isotherm models. Also, the maximum monolayer capacity, qmax, obtained was 113.8 mg g(-1), and 79.4 mg g(-1) for Co(II), and Ni(II), respectively. Our results showed that Mg-Al-Zn mingled oxides can be used as an efficient adsorbent material for removal of heavy metals from industrial wastewater samples.
Homo- and heteronuclear group 12 metal (Zn(2+), Cd(2+), and Hg(2+)) complexes 1-6 containing a newly designed 18-membered N2O2S2 macrocycle incorporating two pyridine subunits (L) were prepared and structurally characterized. The individual complexes isolated exhibit unusual stoichiometries, geometries, oxidation states, and structural topologies and include an infinite mercurous complex and a heteronuclear dumbbell-shaped complex. Both the Zn(II) complex [Zn(L)][ZnBr4] (1) and the Cd(II) complex [Cd(L)Br2] (2) are mononuclear, with the metal ion located inside the macrocyclic cavity. The six-coordinated Zn(II) center in 1 adopts an octahedral geometry and is shielded from the anion and solvent by the strongly bound macrocycle. The Cd(II) center in 2 is seven-coordinate, being bound equatorially to two N donors, two O donors, and a S donor from the macrocycle and axially to two bromide ions on opposite sides of the macrocyclic plane, adopting a pentagonal-bipyramidal geometry. In the Hg(II) complexations, the configuration adopted by the macrocycle L shows a dependence of the nuclearity on the anion used. When mercury(II) bromide was used, the dinuclear complex [Hg(II)2(L)Br4] (3) was obtained, while the reaction with mercury(II) nitrate afforded the unexpected Hg(I) complex {[Hg(I)2(L)](NO3)2}n (4) with a one-dimensional polymeric structure. In heterometallic complexation experiments, one-pot reaction of L with a mixture of ZnBr2 and CdBr2·4H2O resulted in the stepwise isolation of two pure solubility-dependent Cd(II) complexes (2 and 5), including the half-dumbbell-type complex [Cd(L)(μ-Br)(CdBr3)] (5), while a mixture of CdBr2·4H2O and HgBr2 yielded the heterometallic bis(macrocycle) product [(CdL)2(μ-Hg2Br6)](Hg2Br6) (6). This is the first example of a heteronuclear dumbbell-shaped complex in which two terminal macrocyclic Cd(II) complexes are linked by a hexabromodimercury(II) cluster via Cd-Br-Hg bonds. The heterometallic dumbbell 6 can be considered as a good example of competition and collaboration between Cd(II) and Hg(II) ions because its formation is associated with the higher coordination affinity of Cd(II) toward the macrocycle and the formation of the (Hg2Br6)(2-) cluster, which links the two endocyclic Cd(II) complexes directly. Both NMR titration and comparative NMR data indicate a relatively higher coordination affinity of Cd(II) toward the macrocycle than occurs for Hg(II), in parallel to the situation observed in the solid state.
A new type of responsive battery with the fascinating feature of pressure perceptibility has been developed, which can spontaneously, timely and reliably control the power outputs (e.g., current and voltage) in response to pressure changes. The device design is based on the structure of the Zn-air battery, in which graphene-coated sponge serves as pressure-sensitive air cathode that endows the whole system with the capability of self-controlled energy release. The responsive batteries exhibit superior battery performance with high open-circuit voltage (1.3 V), and competitive areal capacity of 1.25 mAh cm(-2) . This work presents an important move towards next-generation intelligent energy storage devices with energy management function.
The bulk analysis of single feathers of 263 feathers belonging to 238 individuals of a migratory passerine (collared flycatcher, Ficedula albicollis, originating from a breeding population in the Pilis-Visegrád Mountains in Hungary) by inductively coupled plasma sector field mass spectrometry (ICP-SF-MS) for determination of elements after proper dissolution allowed the quantitative determination of 38 elements. Calcium, Mg, Mn, Fe, and Zn were found to have a quantitative determination frequency larger than 80 % and a concentration greater than 100 μg/g. Among ecotoxicologically relevant elements, Ni, Cd, Hg, and Pb could be determined in more than 55 % of the tail feather samples. The concentration of Hg with a quantification limit of 0.006 μg/g and Pb with that of 0.015 μg/g was higher than 1 and 10 μg/g, respectively, in more than 80 % of the investigated samples, but generally lower than levels that could cause adverse behavioral effects. The principal component analyses of elemental concentration data followed by the application of general linear models revealed that, for male collared flycatchers, the concentration of Sn, Pb, Ni, Sr, Mg, Zn, Ba, and Sc differed significantly in the wing and tail feathers collected from the same individuals. With females, only the Ca and Sc concentration showed a significant difference between wing and tail feathers. Moreover, the concentration of rare earth elements, V, Fe, Sr, Mg, Mn, Zn, Pb, and Ba in tail feathers allowed differentiation between sexes while the concentration of Se, Bi, and Sc between yearling and adult male individuals. At the same time, Sc differentiated age categories in females. Distribution of major elements along the rachis of feathers could be monitored by laser ablation ICP-SF-MS after normalization of the intensities to either (13)C or (34)S signals.
In the recent years, the use of sewage water for irrigation has attracted the attention of arid and semi-arid countries where the availability of fresh water is poor. Despite the potential use of sewage water in crop irrigation as effective and sustainable strategy, the environmental and human risks behind this use need to be deeply investigated. In this regard, an experiment was carried out under field conditions in Nursery, University College of Agriculture Sargodha, to evaluate the possible health risks of undesirable metals in wheat grains. Wheat variety Sarang was cultivated and irrigated with different combinations of ground (GW) and sewage water (SW). The concentrations of heavy metals (Cr, Cd, Ni, and Pb) and trace elements (Cu, Zn, and Fe) in wheat grains as well as in soil were determined. Moreover, the pollution load index (PLI), accumulation factor (AF), daily intake of metals (DIM), and health risk index (HRI) were calculated. Results showed that the concentration trend of heavy metals was Pb<Cr<Cu<Ni<Cd<Zn<Fe and Cr<Cu<Pb<Cd<Ni<Fe<Zn in soil and wheat, respectively. Among metals, Cd concentration in wheat exceeded the permissible limits regardless water quality, whereas Pb concentration in grain was within the acceptable levels as suggested by World Health Organization, when 100 % of SW was used for irrigation. Similar observation was reported for Cd concentration in the soil when wheat was irrigated with 100 % SW. In comparison to soil, the edible part of wheat presented lower concentration of all studied metals, except for Zn which was much higher compared to the tested soil samples. The higher concentration of Zn was responsible for increasing the DIM of Zn where, in average, the highest value was reported, particularly in 75 % SW treatment. This was reflected also in HRI where the maximum value was reported for Zinc under the same treatment. Higher value of HRI for wheat cultivated on polluted soils suggested that appropriate management of cultivated area is necessary for food safety
 and thus for public health. The results are expected to create awareness among the public on the safety of consuming food products grown in particular areas.
Here, we aim to determine the distribution, ecological risk and sources of heavy metals and metalloids in the surface sediments of the Xiangjiang River, Hunan Province, China. Sixty-four surface sediment samples were collected in 16 sites of the Xiangjiang River, and the concentrations of ten heavy metals and metalloids (Mn, Zn, Cr, V, Pb, Cu, As, Ni, Co, and Cd) in the sediment samples were investigated using an inductively coupled plasma mass spectrometer (ICP-MS) and an atomic fluorescence spectrophotometer (AFS), respectively. The results showed that the mean concentrations of the ten heavy metals and metalloids in the sediment samples followed the order Mn > Zn > Cr > V > Pb > Cu > As ≈ Ni >Co > Cd. The geoaccumulation index (I geo), enrichment factor (EF), modified degree of contamination (mCd), and potential ecological risk index (RI) revealed that Cd, followed by Pb, Zn, and Cu, caused severely contaminated and posed very highly potential ecological risk in the Xiangjiang River, especially in Shuikoushan of Hengyang, Xiawan of Zhuzhou, and Yijiawan of Xiangtan. The Pearson's correlation coefficient (PCC) analysis, principal component analysis (PCA), and hierarchical cluster analysis (HCA) indicated that the ten heavy metals and metalloids in the sampling sediments of the Xiangjiang River were classified into three groups: (1) Cd, Pb, Zn, and Cu which possibly originated from Shuikoushan, Xiawan, and Yijiawan clustering Pb-Zn mining and smelting industries; (2) Co, V, Ni, Cr, and Al from natural resources; and (3) Mn and As. Therefore, our results suggest that anthropogenic activities, especially mining and smelting, have caused severe contamination of Cd, Pb, Zn, and Cu and posed very high potential ecological risk in the Xiangjiang River.
This study aimed to investigate the effects of chromic chloride (CrCl3) on Ca, Mg, Mn, Fe, Cu, and Zn contents in the brain and serum of chicken. Seventy-two chickens were randomly divided into four groups and treated with different doses of CrCl3 via drinking water: 0, 1/8, 1/4, and 1/2 LD50 for 42 days. The contents of the elements were evaluated through inductively coupled plasma mass spectrometry. Results showed that Cr contents in the brain and serum were higher than those in the control groups, although no significant dose-dependent changes (P > 0.05) in brain of the Cr-treated groups were observed at 42 days. As exposure time was prolonged and CrCl3 dosage was increased, Ca contents increased (P < 0.05). Mg and Cu contents in serum decreased; by contrast, Mg and Cu contents initially increased and then decreased in the brain. Fe and Zn contents in the serum increased; conversely, Fe and Zn contents in the brain decreased. CrCl3 exposure did not significantly affect Mn contents at 14 or 28 days, but significantly decreased (P < 0.05) at 42 days. Therefore, excess Cr(3+) intake can disrupt absorption and deposition of other trace elements in the brain and serum; the blood-brain barrier may prevent the accumulation of these elements in the brain exposed to CrCl3.
Chimeric compounds combine the structural features of inhibitors of histone deacetylases (HDACi) and tyrosine kinase inhibitors (TKi), and therefore unite the effects of a dual-targeting strategy in one compound. Here, we describe the generation of such hybrid molecules. Small molecules, known as TKi, are combined with a Zn(2+) chelating motive, preferentially a hydroxamic acid, in addition. The resulting small molecules also can inhibit histone deacetylases, which are dependent on the catalytically active Zn(2+). Moreover, we summarize how the growth-inhibitory effects of these combined compounds can be determined with a simple proliferation assay with a leukemic cell line.
The altered levels of some essential trace elements and antioxidant minerals have been observed in diabetic patients.
The aim of the present study was to compare the concentrations of essential trace elements, copper (Cu), zinc (Zn), and iron (Fe) in the serum of patients who have type 2 diabetes mellitus (T2DM) with those of their non-diabetic first-degree relatives (FDR) and control subjects. The association between glycated hemoglobin (HbA1c) and levels of metals was also evaluated.
We studied 46 subjects with T2DM, 46 FDR, and 50 control subjects matched for age and sex. Serum concentrations of Cu, Zn, and Fe were measured by colorimetric kit. Fasting blood glucose (FBG) and HbA1c were assayed using the standard kit.
An imbalance in the levels of the studied metals was observed in both patients with T2DM and FDR. We found significantly decreased levels of Zn and higher levels of Cu and Fe in the patients with T2DM and FDR when compared with the control subjects (P < 0.05). HbA1c levels were positively correlated with Cu and Fe and inversely correlated with Zn in the patients with T2DM and FDR (P < 0.05).
The patients with T2DM and FDR had altered contents of Cu, Zn, and Fe that might be a predisposing factor to the development of diabetes in future or vice versa the result of diabetes development. Impaired metabolism of these elements may contribute to the augmented risk of developing type 2 diabetes mellitus later in the life of their first-degree relatives.
Misfolding and aggregation of Cu, Zn superoxide dismutase (SOD1) is implicated in the etiology of amyotrophic lateral sclerosis (ALS). The use of small molecules may stabilize the spatial structure of SOD1 dimer, thus, preventing its dissociation and aggregation. In this study, "native" mass spectrometry (MS) was used to study the noncovalent interactions between SOD1 and flavonoid compounds. MS experiments were performed on a quadruple time-of-flight (Q-ToF) mass spectrometer with an electrospray ionization (ESI) source and T-wave ion mobility. ESI-MS was used to detect the SOD1-flavonoid complexes and compare their relative binding strengths. The complement of ion mobility separation allowed comparison in the binding affinities between flavonoid isomers and provided information on the conformational changes. Molecular docking together with molecular dynamics simulations and MM/PBSA methods were applied to gain insights into the binding modes and free energies of SOD1-flavonoid complexes at the molecule level. Among all the flavonoids investigated, flavonoid glycosides preferentially bind to SOD1 than their aglycone counterparts. Naringin, one of the compounds that has the strongest binding affinity to SOD1, was subjected to further characterization. Experiment results show that the binding of naringin can stabilize SOD1 dimer and inhibit the aggregation of SOD1. Molecular simulation results suggest that naringin could reduce the dissociation of SOD1 dimers through direct interaction with the dimer interface. This developed analytical strategy could also be applied to study the interactions between SOD1 and other drug-like molecules, which may have the effect to reduce the aggregation.
An efficient synthetic approach to polysubstituted benzofurans is described, using 2-methoxyquinone as a benzofuran backbone. Nucleophilic addition of terminal alkynes to 2-methoxy-1,4-benzoquinone afforded the corresponding quinols containing an alkyne unit, which were converted to phenols via mild Zn-mediated reduction. After proper protection of the free phenolic OH, 5-endo-dig iodocyclization allowed facile access to a number of 3-iodobenzofurans. In addition, it was demonstrated for the first time that o-methoxyarylalkynes underwent intramolecular hydroalkoxylation under the influence of AgOTf furnishing the corresponding benzofurans.
Fortifying cereal staples with zinc is a strategy for increasing zinc intake in young children in developing countries. However, phytic acid (PA) naturally present in cereals strongly decreases zinc absorption. A stable-isotope zinc absorption study was conducted in young children to investigate the ability of the PA-degrading enzyme phytase to improve zinc absorption, when added to a cereal porridge immediately before consumption.
Fractional absorption of zinc (FAZ) was estimated in 35 young healthy Burkinabe children using the double-isotopic tracer ratio method with (67)Zn as oral tracer and (70)Zn as intravenous tracer, in a crossover design. The test meals were: (a) a millet-based porridge containing 1.4 mg total zinc (native plus 1 mg added as ZnSO4) with a PA:Zn molar ratio of 7.7; (b) the same porridge with the enzyme phytase (20.5 phytase units (FTU)) added immediately before consumption. The exchangeable zinc pool (EZP) was determined as a potential measure of long-term zinc intake in 20 of the 35 children and compared with FAZ.
Mean FAZ increased from 9.5±3.4 to 16.0±5.1% (P<0.0001), when phytase was added to the meal. The mean EZP was 3.6±0.5 mg/kg. There was no correlation between the EZP and FAZ values for either of the two test meals.
Adding phytase immediately prior to consumption of a zinc-fortified cereal-based complementary food can improve zinc absorption in young children.European Journal of Clinical Nutrition advance online publication, 19 October 2016; doi:10.1038/ejcn.2016.199.
Three amendments including limestone, MnO2 and natural zeolite were assessed for their stabilisation effects on Zn, Cu, Pb and Cd in sediment of east Dongting Lake, mid-south China. The metals were first subject to pollution status and potential ecological risk assessment to identify the current and potential hazards to ecology. Speciation of the metals in the sediment treated with amendments was then carried out by BCR sequential extraction procedure in order to evaluate metal contents and their potential mobility. The total concentrations of Zn, Cu, Pb and Cd in the east Dongting Lake were all above the
 means of national stream sediment and soil guidelines. The sediments were currently unpolluted to moderately pollute with Zn, Cu and Pb and strongly polluted with Cd. Zinc, Cu and Pb posed low risks to the lake ecosystem, and Cd had the highest potential risk that caused the overall risk of the sediment to be high or very high. Limestone stabilised Cu and Zn effectively, yet mobilisation of Cd and Pb by such amendment was also observed. MnO2 effectively reduced the extractable Cd and Pb. The effect of natural zeolite on metal stabilisation in the sediment was least notable. Limestone and MnO2 showed higher metal stabilisation efficiencies than zeolite. However, a single amendment is unable to achieve the goal of stabilisation for all metals. A combination use of the advantageous amendments or a search of a stronger stabiliser should be the interest of our future study.
Prolonged exposure to gastric acid is a leading cause of gastroesophageal reflux disease (GERD) and esophagitis. With the ever increasing number of patients showing insensitivity to proton-pump-inhibitor (PPI) therapy with recurrence of symptoms over time, alternative treatment options remain an important issue. Previous studies from our laboratory have shown that a zinc sulfate salt can inhibit HCl generation at the cellular level of the parietal cell. In this paper, we examine the difference between two hydration forms of ZnSO4 (monohydrate H2O and heptahydrate 7H2O) in their entry characteristics into the parietal cell under several physiological conditions associated with acid secretion. Using the Zn sensitive fluorochrome Newport Green, we examined the rate of Zn entry in Δfluorescent units/second (ΔFU/second), at two different concentrations for both hydration states on both fasted and non-fasted animals. In a separate series of studies, we examined the effects of secretagogues on the entry rates and transport mechanisms. Exposure of the secretagogue carbachol transformed the resting parietal cell to an activated state and represents a stimulated condition through the neuronal pathway. The hormonal activation of the parietal cell was achieved by using histamine. Non-fasted conditions were considered to be a state between hormonal and neuronal activation. To demonstrate that ZnSO4 enters the parietal cell through the NKCC1 co-transporter, the inhibitor bumetanide was applied during secretagogue-stimulated acid secretion. Both salts, monohydrate and heptahydrate ZnSO4, show a concentration-dependent cell entry under all conditions studied. During stimulated acid secretion, induced through either the neuronal or the hormonal pathway, heptahydrate ZnSO4 enters the parietal cell significantly faster than monohydrate ZnSO4, whereas monohydrate ZnSO4 exhibits faster entry during resting conditions in fasted animals. At 30 μM following stimulation with histamine, heptahydrate ZnSO4 enters the cell faster than monohydrate ZnSO4 (ΔFU/second 30 μM ZnSO4*7H2O + histamine = 1.782, ΔFU/second 30 μM ZnSO4*H2O+histamine = 1.038, respectively). Three hundred micromolar, heptahydrate ZnSO4 shows a faster entry into the cells (ΔFU/second ZnSO4*7H2O300μM + carbachol = 4.02407) compared to monohydrate ZnSO4 (ΔFU/second ZnSO4*H2O300μM + carbachol = 3.225) following exposure to carbachol. The mechanism of entry of both salts was found to be predominantly via the basolateral NKCC1 transporter with the rate of zinc entry decreasing to minimal values (ΔFU/second = 0.275) after application of bumetanide during stimulated conditions.
Heavy metals are known to cause deleterious effects on human health through food chain. Human health risks were evaluated from consumption of heavy metal contaminated fish from Buriganga River in Bangladesh. Whole body of five fish species (Puntius ticto, Puntius sophore, Puntius chola, Labeo rohita and Glossogobius giuris) were analyzed which contained various concentrations of Cd, As, Pb, Cr, Ni, Zn, Se, Cu, Mo, Mn, Sb, Ba, V and Ag. Concentrations of Mn, Zn, Se and Pb in all fish species were above the Food Safety Guideline (FSG) by WHO/FAO. Assessment of noncarcinogenic health hazard by target hazard quotient (THQ) indicated no concern from consumption of these fish except for Mn. However, all metals together may affect human health as revealed by hazard index (HI). The target cancer risk (TR) values suggested carcinogenic risk from Ni and As. Taken together it can be concluded that there is potential human health risk in consuming fish from river Buriganga.
To evaluate the short-term 24 h urinary excretion of platinum, arsenic, selenium, magnesium and zinc in patients with lung cancer and with cancer other than lungs treated with cisplatin or/and carboplatin from Antofagasta, Chile.
Urine measurements of Pt and Se were made by inductively coupled plasma optical emission spectrometry, As by hydride-generation atomic absorption spectrometry and Mg and Zn by means of flame furnace atomic absorption spectrometry.
All samples were provided by the Oncological Centre of Antofagasta Regional Hospital (Region of Antofagasta, Chile).
Ninety 24-h urine samples from cancer patients after the infusion of Pt-base drugs and 10 24-h urine samples from cancer patients not treated with metal-base drugs.
Concentrations of Pt, Se, As, Zn and Mg coming from 24-h urine samples.
Pt excreted was not significantly different between patients with lung and other cancers treated with cisplatin. The excretion of Mg, Zn and Se was greater than As. Then, Pt favours the excretion of essential elements. For lung and other types of cancers treated with drugs without Pt, excretion of Mg, Zn and Se was also greater than that of As, suggesting antagonism Mg-Zn-Se-anti-cancer drug relationship.
The amounts of Mg, Zn and Se excreted were greater than for As either with or without Pt-containing drugs, suggesting antagonist Mg-Zn-Se-anti-cancer drug relationships. The excretion of As, Mg, Zn and Se is induced by Pt. Knowledge obtained can contribute to understanding the arsenic cancer mechanism and the As-Mg-Zn-Se-Pt inter-element association for lung cancer and other types of cancer.
Multiple Sclerosis (MS) is defined as one of the inflammatory autoimmune disorders and is common. Its exact etiology is unclear. There are some evidences on the role of environmental factors in susceptible genetics. The aim of this study is to evaluate the possible role of Selenium, Zinc, Copper, Lead and Magnesium metals in Multiple Sclerosis patients.
In the present analytical cross-sectional study, 56 individuals including 26 patients and 30 healthy controls were enrolled in the evaluation. The serum level of Se, Zn, Cu, Pb were quantified in graphite furnace conditions and flame conditions by utilizing an atomic absorption Perkin Elmer spectrophotometer 3030. The serum levels of Mg were measured by auto analyzer 1500 BT. The mean level of minerals (Zn, Pb, Cu, Mg, Se) in serum samples were compared in both cases and controls. The mean level of minerals (Zn, Pb, Cu, Mg, Se) in serum samples were compared in both cases and controls by using independent-samples t-test for normal distribution and Mann-Whitney U test as a non-parametric test. All statistical analyses were carried out using SPSS 11.0.
As well as the Zn, Cu, and Se, there was no significant difference between MS patients and healthy individuals in Pb concentrations (p-value = 0.11, 0.14, 0.32, 0.20 respectively) but the level of Mg was significantly different (p= 0.001).
All serum concentrations of Zn, Pb, Se, Cu in both groups were in normal ranges and there was no difference in MS patients compared with the healthy group who were matched in genetics. Blood level of Mg was significantly lower in MS patients. But it should be noted that even with the low level of serum magnesium in MS patients, this value is still in the normal range.
The sirtuin family of proteins catalyze the NAD(+)-dependent deacylation of acyl-lysine residues. Humans encode seven sirtuins (Sirt1-7), and recent studies have suggested that post-translational modification of Sirt1 by cysteine S-nitrosation correlates with increased acetylation of Sirt1 deacetylase substrates. However, the mechanism of Sirt1 inhibition by S-nitrosation was unknown. Here, we show that Sirt1 is transnitrosated and inhibited by the physiologically relevant nitrosothiol S-nitrosoglutathione. Steady-state kinetic analyses and binding assays were consistent with Sirt1 S-nitrosation inhibiting binding of both the NAD(+) and acetyl-lysine substrates. Sirt1 S-nitrosation correlated with Zn(2+) release from the conserved sirtuin Zn(2+)-tetrathiolate and a loss of α-helical structure without overall thermal destabilization of the enzyme. Molecular dynamics simulations suggested that Zn(2+) loss due to Sirt1 S-nitrosation results in repositioning of the tetrathiolate subdomain away from the rest of the catalytic domain, thereby disrupting the NAD(+) and acetyl-lysine-binding sites. Sirt1 S-nitrosation was reversed upon exposure to the thiol-based reducing agents, including physiologically relevant concentrations of the cellular reducing agent glutathione. Reversal of S-nitrosation resulted in full restoration of Sirt1 activity only in the presence of Zn(2+), consistent with S-nitrosation of the Zn(2+)-tetrathiolate as the primary source of Sirt1 inhibition upon S-nitrosoglutathione treatment.
HIV-1 Tat hijacks the human superelongation complex (SEC) to promote proviral transcription. Here we report the 5.9 Å structure of HIV-1 TAR in complex with HIV-1 Tat and human AFF4, CDK9, and CycT1. The TAR central loop contacts the CycT1 Tat-TAR recognition motif (TRM) and the second Tat Zn(2+)-binding loop. Hydrogen-deuterium exchange (HDX) shows that AFF4 helix 2 is stabilized in the TAR complex despite not touching the RNA, explaining how it enhances TAR binding to the SEC 50-fold. RNA SHAPE and SAXS
 data were used to help model the extended (Tat Arginine-Rich Motif) ARM, which enters the TAR major groove between the bulge and the central loop. The structure and functional assays collectively support an integrative structure and a bipartite binding model, wherein the TAR central loop engages the CycT1 TRM and compact core of Tat, while the TAR major groove interacts with the extended Tat ARM.
Heteroatom doped carbon dots (CDs), with high photoluminescence quantum yield (PLQY), are of keen interest in various applications such as chemical sensors, bio-imaging, electronics, and photovoltaics. Zinc, an important element assisting the electron-transfer process and an essential trace element for cells, is a promising metal dopant for CDs, which could potentially lead to multifunctional CDs. In this contribution, we report a single-step, high efficiency, hydrothermal method to synthesize Zn-doped carbon dots (Zn-CDs) with a superior PLQY. The PLQY and luminescence characteristic of Zn-CDs can be tuned by controlling the precursor ratio, and the surface oxidation in the CDs. Though a few studies have reported metal doped CDs with good PLQY, the as prepared Zn-Cds in the present method exhibited a PLQY up to 32.3%. To the best of our knowledge, there is no report regarding the facile preparation of single metal-doped CDs with a QY more than 30%. Another unique attribute of the Zn-CDs is the high monodispersity and the resultant highly robust excitation-independent luminescence that is stable over a broad range of pH values. Spectroscopic investigations indicated that the superior PLQY and luminescence of Zn-CDs are due to the heteroatom directed, oxidized carbon-based surface passivation. Furthermore, we developed a novel and sensitive biosensor for the detection of hydrogen peroxide and glucose leveraging the robust fluorescence properties of Zn-CDs. Under optimal conditions, Zn-CDs demonstrated high sensitivity and response to hydrogen peroxide and glucose over a wide range of concentrations, with a linear range of 10-80 μM and 5-100 μM, respectively, indicating their great potential as a fluorescent probe for chemical sensing.
The electronic structures and magnetism of defect- and transition metal (TM)-embedded stanene monolayers are investigated by using first-principles methods. Single vacancy (SV) and double vacancy (DV) cannot induce magnetism, while embedding a TM can effectively tune the magnetic moments of the stanene monolayer. Moreover, the results show that all 3d TM-embedded stanene monolayers are stable. The TM-embedded SV is easier to form than DV. For TM-embedded SV systems, the Ti-embedded case presents half-metallic properties. However, for TM-embedded DV systems, the Ti-embedded system is a magnetic semiconductor and spin-orbit coupling (SOC) effects remarkably increase its band gap. Interestingly, the SOC interaction induces electronic phase transition from the semiconductor to the half-metal (metal) for Ni (Zn)-embedded DV systems. These results provide a promising route to design stanene-based spintronics devices.
We report simultaneous fluorescence imaging of hydrogen peroxide and zinc ions within mitochondria using two fluorescent probes termed M-H2O2 and M-Zn.
The antiangiogenic and antitumor activities of the 27-amino acid fragment corresponding to the N-terminal domain of endostatin were shown to be dependent on a Zn-binding loop in the N-terminus. To investigate whether the regions outside of the N-terminal loop play a role in the peptide function, the structure and function of a variant containing Ile26Arg mutation (ES-R) were compared with those of the native peptide (ES-Zn). Structural analysis using far-UV CD, intrinsic fluorescence and molecular dynamics simulation provided information regarding the overall changes upon the mutation. In addition, the docking simulations predicted a higher affinity of ES-R to integrins αvβ3 and α5β1 than ES-Zn and a profound reorganization of the binding residues throughout the sequence. In Human Umbilical Vein Endothelial Cells (HUVECs), ES-R inhibited the tube formation and activated caspase-3 more strongly than do ES-Zn. Based on in vivo studies, the growth of breast tumor and expression of CD31, Bcl-2 and nonfunctional p53 were inhibited more effectively by ES-R than by ES-Zn. We conclude that the C-terminal region is involved in the peptide function through some global structural effects.
This work reports zinc-catalyzed [4+2]-annulation reactions of disubstituted N-hydroxy allenylamines with nitrosoarenes to afford substituted 1,2-oxazinan-3-ones with a skeletal rearrangement. This annulation is applicable to a reasonable scope of allenylamines and nitrosoarenes. Our control experiments indicate that nitrosobenzene can also implement this annulation through a radical annulation path, but with poor efficiency. Zn(OTf)2 or AgOTf greatly improves the efficiency of this [4+2]-annulation; the effect of these metal species is discussed in detail.
Understanding ribose reactivity is a crucial step in the "RNA world" scenario because this molecule is a component of all extant nucleotides that make up RNA. In solution, ribose is unstable and susceptible to thermal destruction. We examined how ribose behaves upon thermal activation when adsorbed on silica, either alone or with the coadsorption of inorganic salts (MgCl2 , CaCl2 , SrCl2 , CuCl2 , FeCl2 , FeCl3 , ZnCl2 ). A combination of (13) C NMR, in situ IR, and TGA analyses revealed a variety of phenomena. When adsorbed alone, ribose remains stable up to 150 °C, at which point ring opening is observed, together with minor oxidation to a lactone. All the metal salts studied showed specific interactions with ribose after dehydration, resulting in the formation of polydentate metal ion complexes. Anomeric equilibria were affected, generally favoring ribofuranoses. Zn(2+) stabilized ribose up to higher temperatures than bare silica (180 to 200 °C). Most other cations had an adverse effect on ribose stability, with ring opening already upon drying at 70 °C. In addition, alkaline earth cations catalyzed the dehydration of ribose to furfural and, to variable degrees, its further decarbonylation to furan. Transition-metal ions with open d-shells took part in redox reactions with ribose, either as reagents or as catalysts. These results allow the likelihood of prebiotic chemistry scenarios to be evaluated, and may also be of interest for the valorization of biomass-derived carbohydrates by heterogeneous catalysis.
Pollution and temperature increase are two of the most important stressors that aquatic organisms are facing. Exposure to elevated temperatures and metal contamination both induce heat shock proteins (HSPs), which may thus be involved in the induced cross-tolerance in various organisms. This study aimed to test the hypothesis that exposure to a non-lethal heat shock (NLHS) causes an increased tolerance to subsequent metal exposure. Using gnotobiotic cultures of the brine shrimp Artemia franciscana, the tolerance to Cd and Zn acute exposures was tested after a prior NLHS treatment (30min exposure to 37°C). The effects of NLHS and metal exposure were also assessed by measuring 70kDa-HSPs production, along with the analysis of epigenetic markers such as DNA methylation and histone H3 and histone H4 acetylation. Our results showed that heat-shocked Artemia had increased acute tolerance to Cd and Zn. However, different patterns of HSPs were observed between the two metal compounds and no epigenetic alterations were observed in response to heat shock or metal exposure. These results suggest that HSP production is a phenotypically plastic trait with a potential role in temperature-induced tolerance to metal exposure.
A periplasmic solute binding protein from second of the two gene clusters of Znu system in CLA (CLas-ZnuA2) belong to Cluster A1 family of solute binding proteins (SBPs). The crystal structures in metal-free, intermediate and metal-bound states, in the previous study, revealed the unusual mechanism of metal binding and release for CLas-ZnuA2. Although CLas-ZnuA2 showed maximum sequence identity to the Mn/Fe-specific SBPs, the mechanistic resemblance seems to be closer to Zn-specific SBPs of Cluster A-I family. The present study reports the binding affinity studies using SPR and CD and crystal structure of CLas-ZnuA2 in Zn(2+)-bound state. Despite a similar overall structure, there are noticeable differences at the metal binding site. The SPR and CD analysis confirmed our previous observation that CLas-ZnuA2 exhibits a low metal-binding affinity. The low metal-binding affinity of CLas-ZnuA2 could be attributed to the presence of a proline in linker helix resulting in relatively higher bending and rigidity of the same. This structural feature fixes the C-domain similar to metal-bound states of related SBPs. Further, the binding of both Mn(2+) and Zn(2+) occurs pentavalently with square pyramidal geometry not preferred by either. The site-specific positive Darwinian selection analysis showed that the proline in linker helix is under purifying selection and might have diverged long ago. Our structural and evolutionary analyses suggest that CLasZnua2 might have evolved, particularly for plant pathogens, to facilitate transport of both Mn(2+) and Zn(2+), with reversible binding to Zn(2+), unlike other Mn-binding SBPs (PsaA).
Concentrations of inorganic arsenic (iAs) metabolites in urine present intra- and interindividual variations, which are determined not only by the magnitude of exposure to iAs, but also by differences in genetic, environmental and dietary factors.
To evaluate whether differences in dietary intake of selected micronutrients are associated with the metabolism of iAs.
The intake of 21 micronutrients was estimated for 1027 women living in northern Mexico using a food frequency questionnaire.
 Concentration of urinary metabolites of iAs was determined by high performance liquid chromatography inductively coupled plasma mass spectrometry (HPLC-ICP-MS) and the proportion of iAs metabolites was calculated (%iAs, monomethylarsonic acid [%MMA] and dimethylarsinic acid [%DMA]), as well as ratios corresponding to the first (MMA/iAs), second (DMA/MMA) and total methylation (DMA/iAs).
After adjustment for covariates, it was found that methionine, choline, folate, vitamin B12, Zn, Se and vitamin C favor elimination of iAs mainly by decreasing the %MMA and/or increasing %DMA in urine.
Our results confirm that diet contributes to the efficiency of iAs elimination. Further studies are needed to assess the feasibility of dietary interventions that modulate the metabolism of iAs and the consequent risk of diseases related to its exposure.
This study examined the spatial distribution and the extent of soil contamination by heavy metals resulting from primitive, unconventional informal electronic waste recycling in the Agbogbloshie e-waste processing site (AEPS) in Ghana.
A total of 132 samples were collected at 100 m intervals, with a handheld global position system used in taking the location data of the soil sample points. Observing all procedural and quality assurance measures, the samples were analyzed for barium (Ba), cadmium (Cd), cobalt (Co), chromium (Cr), copper (Cu), mercury (Hg), nickel (Ni), lead (Pb), and zinc (Zn), using X-ray fluorescence. Using environmental risk indices of contamination factor and degree of contamination (Cdeg), we analyzed the individual contribution of each heavy metal contamination and the overall Cdeg. We further used geostatistical techniques of spatial autocorrelation and variability to examine spatial distribution and extent of heavy metal contamination.
Results from soil analysis showed that heavy metal concentrations were significantly higher than the Canadian Environmental Protection Agency and Dutch environmental standards. In an increasing order, Pb>Cd>Hg>Cu>Zn>Cr>Co>Ba>Ni contributed significantly to the overall Cdeg. Contamination was highest in the main working areas of burning and dismantling sites, indicating the influence of recycling activities. Geostatistical analysis also revealed that heavy metal contamination spreads beyond the main working areas to residential, recreational, farming, and commercial areas.
Our results show that the studied heavy metals are ubiquitous within AEPS and the significantly high concentration of these metals reflect the contamination factor and Cdeg, indicating soil contamination in AEPS with the nine heavy metals studied.
To clarify the interaction between different antioxidant enzymes for monitoring oxidative stress and ROS burst in rice senescent leaves, we investigated the genotype-dependent alteration in temporal patterns of the O2(•-) production rate, H2O2 content, and ROS-scavenging enzyme activities during leaf senescence in two rice genotypes, namely, the premature senescence of flag leaf (psf) mutant and its wild type. Results showed that the psf mutant differed obviously from its wild type in leaf O2(•-) generation rate and H2O2 content accumulation, and the decreased activities of SOD, CAT, and APX in the psf leaves were strongly responsible for the increased ROS level and the accelerated leaf senescence. By contrast, the increase in POD activity was positively correlated with the senescence-related enhancement in O2(•-) generation in rice leaves. Among various SOD isoforms, Mn-SOD responded sensitively to the increasing O2(•-) generation rate, whereas Cu/Zn-SOD remained stable with the progression of leaf senescence. These findings suggest that the senescence-related decline in total SOD activity was mostly attributable to the downregulation of both the translation and transcription of Mn-SOD isoform. This occurrence finally resulted in the collapse of SOD defense system and accelerated leaf senescence for the psf mutant. Furthermore, we presented the possible contribution of several Cu/Zn-SOD expression patterns to the senescence-related O2(•-) detoxification in different cell compartments.
Matrix metalloproteinase 7 (MMP7/matrilysin-1) has been implicated in many pathological conditions, such as in cancer and inflammatory diseases; therefore, MMP7 has been targeted for drugs. Success in developing a clinical inhibitor, which exhibits suitable specificity and selectivity, will likely require structural and/or kinetic evaluation of enzyme/inhibitor interactions. To enable these future studies we herein describe the over-expression, purification, and characterization of the catalytic domain of MMP7 (cdMMP7). cdMMP7 was over-expressed in an E. coli over-expression system, and the resulting enzyme was processed into inclusion bodies, which were subsequently solubilized, enabling the enzyme to be re-folded into a catalytically-active form. cdMMP7 was shown to bind 1.8eq of Zn(II), exhibit steady-state kinetic constants of 0.4s(-1) for kcat and 23μM for Km, and yield CD and fluorescence spectra that are consistent with a properly-folded enzyme. Pre-steady state kinetic studies yielded kinetic mechanisms of cdMMP7, and these mechanisms are similar to those of other MMPs. Inhibition studies on cdMMP7 with four zinc binding group (ZBG) inhibitors showed that maltol, thiomaltol, and allothiomaltol are better inhibitors with lower IC50 values and lower Kd values against cdMMP7 and cdMMP16 than the commonly-used ZBG inhibitor acetohydroxamic acid. Docking studies suggest that improved inhibitory character may be due to interactions with the S1' substrate binding pocket. Finally, a ZnCo-heterobimetallic analog of cdMMP7 with Co(II) bound in the catalytic site was prepared and characterized. This study describes a well-characterized analog of MMP7 that is available for future inhibitor design efforts.
Wheat cultivars with wide introgression have strongly impacted global wheat production. Aegilops geniculata (MgUg) is an important wild relative with several useful traits that can be exploited for wheat improvement. Screening of Ae. geniculata addition lines indicated a negative effect of 1Ug and the positive effect of 1Mg chromosome on wheat dough strength. Negative effect of 1Ug is probably associated with variation in number and position of the tripeptide repeat motif in the high molecular weight glutenin (HMW-G) gene. To utilize the positive potential of 1Mg chromosome, three disomic substitution lines (DSLs) 1Mg(1A), 1Mg(1B) and 1Mg(1D) were created. These lines were characterized for morphological, cytogenetic properties and biochemical signatures using FISH, 1D-, 2D-PAGE and RP-HPLC. Contribution of wheat 1A, 1B and 1D chromosomes towards dough mixing and baking parameters, chapatti quality, Fe/Zn content and glume color were identified. Observed order of variation in the dough mixing and baking parameters {1Mg(1D) ≤wheat ≤1Mg(1B) ≤1Mg(1A)} indicated that chromosome specific introgression is desirable for best utilization of wild species' potential.
The adsorption process and mechanism of dibenzothiophene (DBT) over metal-loaded phenolic resin-derived activated carbon (PR-AC) were firstly reported in this work. The metal component (Zn, Ni, or Cu) was respectively introduced to PR-AC support via an impregnation method. The effects of adsorbent component, initial DBT concentration, liquid hourly space velocity (LHSV), adsorption time, and adsorption temperature on the adsorption capacity of the adsorbents were systematically investigated. Furthermore, the adsorption mechanism was discussed by analyzing the properties of adsorption product and saturated adsorbent as well as adsorption kinetics. Experimental results indicate that the PR-AC-loaded metal adsorbents, especially with Zn, present much higher DBT adsorption capability than that of pure PR-AC support. The DBT removal rate over PR-AC-loaded Zn (Zn(2+) = 0.2 mol L(-1)) reaches 89.14 %, which is almost twice higher than that of pure PR-AC (45.6 %). This is due to the π-complexation between DBT and metal ions (dominating factor) and the weakening of the local hard acid sites over PR-AC. The multi-factor orthogonal experiment shows that the DBT removal rate over PR-AC-loaded Zn sample achieved 92.36 % in optimum conditions.
Thirty-two chemical species were determined in PM10 sampled at a suburban site on the north coast of Spain. Enrichment factors were applied to infer their soil/non-soil origin. The geochemical ratios were calculated using two databases: soil composition from locations in the surroundings of the sampling station and the Earth's average upper-crust composition. In the present study, dissimilarities were found between the enrichment factors obtained using these two databases. Al, Ti, La and Ce were taken as the reference elements to normalise the data, reaching analogous conclusions. Bi, Cd, Cu, Sb, Se, Sn and Zn were associated with predominantly non-soil apportionments. As the relevance of soil/non-soil sources for the other analysed elements was found to be variable, they were probably of mixed origin. Furthermore, pairs of elements showed strong relationships, thus pointing to a common origin. Na-Mg and Co-Ni, with Pearson correlation coefficients above 0.9, were respectively related to marine and industrial apportionments. Enrichment factors have proved to be a useful tool to distinguish the soil/non-soil origin of chemical species present in airborne particulate matter. However, the choice of the reference database for soil composition considerably determined the accuracy of the conclusions.
The primary aim of the research was to assess the level of trace elements and electrolytes in serum of postmenopausal diabetic women. Sixty-four postmenopausal women with type 2 diabetes mellitus (DM2) and 64 age- and body mass index-matched controls were examined. Serum
 trace elements were assessed using inductively coupled plasma dynamic reaction cell mass spectrometry (ICP-DRC-MS). Fasting plasma glucose (FPG) and glycated hemoglobin (HbA1c) levels were evaluated using Randox kits. The obtained data demonstrate that DM2 patients were characterized by 42 and 34 % higher FPG and HbA1c levels, respectively (p < 0.001). The level of Cu and Se in diabetic postmenopausal women was increased by 10 and 15 % in comparison to the respective control values (p = 0.002 and <0.001). Serum Mn, Zn, and Ni concentrations were lower than the control ones by 32 % (p = 0.003), 8 % (p = 0.003), and 23 % (p = 0.046), respectively. FPG and HbA1c levels directly correlated with serum Se (p < 0.001) and Cu (p = 0.014 and p = 0.028) concentrations and inversely related to Zn (p < 0.001) and Tl (p = 0.023 and p = 0.029) levels. Multiple regression analysis demonstrated a significant association between serum Zn and Se and FPG and HbA1c levels. It is proposed that Zn and Se play an important role in DM2 pathogenesis. Further studies are required to assess the intimate mechanisms of the observed differences.
Twelve apparently healthy multiparous parturient Sahiwal cows were allocated into two groups having six cows in each one. Six cows were supplemented with antioxidant mixture (mixture containing Cu, Mn, Cr, Zn, and vitamins A and D3) daily from 21 days before parturition till the day relative to calving. Whereas, remaining non-supplemented six cows were kept as the control group. Blood samples were obtained five times: at enrolment (21 days pre-partum), and again at days 0, +7, +14, and +21 relative to calving. In the non-supplemented control group, serum total antioxidant capacity (TAC) was significantly lower at days 0, +7, and +14 as compared to their own day -21 values. Likewise, significantly lower myeloperoxidase (MPO) activities were also exhibited by these cows at days 0 and +7. Conversely, serum malondialdehyde (MDA) and protein carbonyl (PC) levels were significantly higher in these cows at days 0, +7, +14, and +21. However, significant alterations in TAC content among the studied sampling days were not recorded in antioxidants supplemented group. Moreover, TAC content and MPO activities of supplemented group were significantly higher at days 0, +7, and +14 when compared with that of the non-supplemented control group. However, MDA and PC contents of supplemented group were significantly lower at days 0, +7, +14, and +21 as compared to that of the non-supplemented control group. In conclusion, periparturient Sahiwal cows experience substantial oxidative and immunological dents which can be potentially ameliorated by prepartal trace mineral and vitamin supplementation.
Lead (Pb) contaminated soils are a potential exposure hazard to the public. Amending soils with phosphorus (P) may reduce Pb soil hazards. Soil from Cleveland, OH containing 726 ± 14 mg Pb kg(-1) was amended in a laboratory study with bone meal and triple super phosphate (TSP) at 5:1 P:Pb molar ratios. Soil was acidified, neturalized and re-acidified to encourage Pb phosphate formation. PRSTM-probes were used to evaluate changes in soil solution chemistry. Soil acidification did not decrease in vitro bioaccessible (IVBA) Pb using either a pH 1.5, 0.4 M glycine solution or a pH 2.5 solution with organic acids. PRSTM-probe data found soluble Pb increased 10-fold in acidic conditions compared to circumnetural pH conditions. In acidic conditions (p = 3-4), TSP treated soils increased detected P 10-fold over untreated soils. Bone meal application did not increase PRSTM-probe detected P, indicating there may have been insufficient P to react with Pb. X-ray absorption spectroscopy suggested a 10% increase in pyromorphite formation for the TSP treated soil only. Treatments increased soil electrical conductivity above 16 mS cm(-1), potentially causing a new salinity hazard. This study used a novel approach by combining the human ingestion endpoint, PRSTM-probes, and X-ray absorption spectroscopy to evaluate treatment efficacy. PRSTM-probe data indicated potentially excess Ca relative to P across incubation steps that could have competed with Pb for soluble P. More research is needed to characterize soil solutions in Pb contaminated urban soils to identify where P treatments might be effective and when competing cations, such as Ca, Fe, and Zn may limit low rate P applications for treating Pb soils.
A series of bimetallic oxalate-bridged one-dimensional chains with monocationic dabco derivatives, ({R-dabco}[M(solv)2][Cr(ox)3]·n(solv)) (dabco = 1,4-diazabicyclo[2.2.2]octane, H2ox = oxalate; R = H, M = Co (1); R = H, M = Zn (2); R = Bu, M = Co (3); R = Bu, M = Zn (4)) were synthesized. All compounds have one-dimensional zig-zag chain structures with R-dabco cations located between chains. Cryomagnetic studies reveal that 1 and 3 showed intrachain ferromagnetic interactions between Co(ii) and Cr(iii) ions and metamagnetic behaviour due to interchain antiferromagnetic interactions. Permittivity measurements on compound 4 indicate specific paraelectronic relaxation behaviour originating from the rotational motion of the dabco alkyl substituent.
Two novel green β-substituted Zn(II)-porphyrins, G1 and G2, based on a 4D-π-1A type substitution pattern have been synthesized. Their enhanced push-pull character, by reduction of H-L energy gaps, promotes broadening and red-shifting of absorption bands. The effective synthetic pathway and the remarkable spectroscopic properties make G2 ideal for BIPV application.
The rise of multiple-drug resistance in bacterial pathogens imposes a serious public health concern and has led to increased interest in studying various pathways as well as enzymes. Different DNA glycosylases collaborate during bacterial infection and disease by overcoming the effects of ROS- and RNS-mediated host innate immunity response. 3-Methyladenine DNA glycosylase I, an essential DNA repair enzyme, was chosen for the present study from the MDR species of A. baumannii. The enzyme was especially chosen because of its functional significance in A. baumannii and due to its structural variation from its human homologue. MDR strains such as A. baumannii are interesting targets owing to their evolved mechanisms of evading a host defence. In the absence of any structural information, the enzyme was characterized biophysically and biochemically. Binding studies with 3mA and Zn(2+) indicated that the activity of TAG-Ab is an enthalpy-driven process. Fluorescence thermal denaturation studies described that the denaturation of TAG-Ab is a two-step process. Modified RP-HPLC-based glycosylase assay attested that the heterologously expressed and purified TAG-Ab enzyme is active and catalyses the removal of 3mA. Other binding parameters and the effect of adenine on substrate binding are also discussed in detail.
An acylhydrazone zinc porphyrin P1 and its coordination polymers (CPs, denoted as P1M, M = Mn, Co, Ni, Cu, Zn) with different metal ions (Mn(2+), Co(2+), Ni(2+), Cu(2+) and Zn(2+)) were synthesized. Then these coordination polymers were assembled into bilayer structured supramolecular chromophores through axially coordinating with anchoring porphyrin AP, and their performance in dye sensitized solar cells was investigated. Our results reveal that the bilayer structured supramolecular chromophore based solar cells show significantly improved photocurrent conversion efficiency. Particularly, P1Mn and P1Zn based solar cells showed a relatively higher short circuit current density (JSC) due to their broad absorption bands and remarkable light harvesting abilities. Meanwhile, the VOC values of the cells fabricated with the bilayered chromophores slightly decreased. Electrochemical impedance spectroscopy (EIS) in combination with charge extraction (CE) and transient photovoltage decay (TPD) measurements indicates that the decreased VOC resulted from the vigorous electron recombination and the downward shifted conduction band edge (ECB) of titania.
Two hexanuclear metalloprisms possessing three dibenzo[24]crown-8 units were generated in quantitative yields by complexation of the predesigned tetratopic 2,2':6',2''-terpyridine ligand (T) with Cd(II) and Zn(II) ions, respectively. The prismatic hosts were subsequently self-assembled with the trifunctional guest molecule (TriG) containing dibenzylammonium ions to afford the corresponding metallo-supramolecular pseudo-suit[3]anes. It was serendipitously found that the host-guest inclusion rates could be modulated by the subtle dynamic difference in metal-ligand frameworks, finally leading to a selective encapsulation event in the presence of both metallo-suits.
Carbonyl sulfide (COS) is an air pollutant that causes acid rain, ozonosphere damage, and carbon dioxide (CO2) generation. It is a heterocumulene and structural analogue of CO2. Relevant to organic synthesis, it is a source of C═O or C═S groups and thus an ideal one-carbon (C1) building block for synthesizing sulfur-containing polymers through the similar route of CO2 copolymerization. In contrast, traditional synthesis of sulfur-containing polymers often involves the condensation of thiols with phosgene and ring-opening polymerization of cyclic thiocarbonates that are generally derived from thiols and phosgene; thus, COS/epoxide copolymerization is a "greener" route to supplement or supplant current processes for the production of sulfur-containing polymers. This Accounts highlights our efforts on the discovery of the selective formation of poly(monothiocarbonate)s from COS with epoxides via heterogeneous zinc-cobalt double metal cyanide complex (Zn-Co(III) DMCC) and homogeneous (salen)CrX complexes. The catalytic activity and selectivity of Zn-Co(III) DMCC for COS/epoxide copolymerization are similar to those for CO2/epoxide copolymerization. (salen)CrX
 complexes accompanied by onium salts exhibited high activity and selectivity for COS/epoxide copolymerization under mild conditions, affording copolymers with >99% monothiocarbonate units and high tail-to-head content up to 99%. By way of contrast, these catalysts often show moderate or low activity for CO2/epoxide copolymerization. Of note, a specialty of COS/epoxide copolymerization is the occurrence of an oxygen-sulfur exchange reaction (O/S ER), which may produce carbonate and dithiocarbonate units. O/S ER, which are induced by the metal-OH bond regenerated by chain transfer reactions, can be kinetically inhibited by changing the reaction conditions. We provide a thorough mechanistic understanding of the electronic/steric effect of the catalysts on the regioselectivity of COS copolymerization. The regioselectivity of the copolymerization originates from the solely nucleophilic attack of the sulfur anion to methylene of the epoxide, and thus, the chiral configuration of the monosubstituted epoxides is retained. COS-based copolymers are highly transparent sulfur-containing polymers with excellent optical properties, such as high refractive index and Abbe number. Thanks to their good solubility and many available epoxides, COS/epoxide copolymers can potentially be a new applicable optical material. Very recently, crystalline COS-based polymers with or without chiral carbons have been synthesized, which may further expand the scope of application of these new materials.
Cadmium (Cd), a potent toxic heavy metal, is a widespread environmental contaminant. Its cellular traffic via pathways dedicated to transition metals contributes to the toxicity mechanisms. Zinc (Zn) homeostasis is complex, involving both zinc importers (Zip) and zinc exporters (ZnT). Cellular signal transduction pathways are influenced by Zn and redox status of the cell. The aim of the present study is to examine if the accumulation of Cd in the human lymphocyte B cell line BJAB and its capacity to promote oxidative stress and adverse effects could result from changes in the mRNA expression pattern of Zn transporters and metallothioneins. Cells were exposed to 5, 10, 20 and 40μM of CdCl2 equivalent to 0.91, 1.83, 3.66 and 7.33μg/ml respectively, for 24h. Cd significantly reduced the viability of BJAB cells and induced a dose-dependent increase in DNA damage. Cd also induced the formation of 8-hydroxy-2'-deoxyguanosine adducts and augmented MTF1 expression in BJAB cells. We observed interesting responses in relative gene expression to Cd exposure among the seven transporters we analyzed. Cd exposure increased the expression of DMT1 and caused an up-regulation of ZnT1. However, the T calcium channel alpha1G subunit could not be detected. A change in expression of ZnTs and Zips in response to Cd exposure emphasizes the involvement of Zn transporters in Cd cellular metabolism and induced oxidative stress.
Metalloproteins (metal-binding proteins) refer to proteins containing metal ion cofactors. The importance of these proteins has increased owing to their involvement in many biological processes. Here, we introduce an analytical platform based on online coupling of miniaturized asymmetrical flow field-flow fractionation (mAF4) and inductively coupled plasma mass spectrometry (ICPMS) for size separation of proteins followed by the detection of metals associated with plasma metalloproteins. Not only did the mild separation of mAF4 get carried out in a biological buffer solution to minimize disruption of the metal-complex structure but free metal ions and salts from complicated biological samples were also removed during separation by crossflow. The relative quantities of metalloproteins detected by mAF4-ICPMS between plasma samples from patients with lung cancer and healthy controls were compared by determining the peak areas of detected elements and retention times; among these, 7 ((55)Mn, (60)Ni, (63)Cu, (66)Zn, (90)Zr, (127)I, and (137)Ba) out of 16 elements showed substantial changes in patients with lung cancer. For the quantitative comparison of metalloproteins, protein fractions during mAF4 were collected and analyzed by nanoflow liquid chromatography-tandem mass spectrometry using isotope-coded carbamidomethylation. Quantitative analysis showed that some metalloproteins associated with (55)Mn, (60)Ni, (63)Cu, and (66)Zn exhibited changes similar to those in patients. These findings demonstrated the potential of mAF4-ICPMS as a powerful high-speed screening method for targeted metalloproteins related to diseases.
Sample preparation of whole-rock powders is the major limitation for their accurate and precise elemental analysis by laser ablation inductively-coupled plasma mass spectrometry (ICPMS). In this study, a green, efficient, and simplified fusion technique using a high energy infrared laser was developed for major and trace elemental analysis. Fusion takes only tens of milliseconds for each sample. Compared to the pressed pellet sample preparation, the analytical precision of the developed laser fusion technique is higher by an order of magnitude for most elements in granodiorite GSP-2. Analytical results obtained for five USGS reference materials (ranging from mafic to intermediate to felsic) using the laser fusion technique generally agree with recommended values with discrepancies of less than 10% for most elements. However, high losses (20-70%) of highly volatile elements (Zn and Pb) and the transition metal Cu are observed. The achieved precision is within 5% for major elements and within 15% for most trace elements. Direct laser fusion of rock powders is a green and notably simple method to obtain homogeneous samples, which will significantly accelerate the application of laser ablation ICPMS for whole-rock sample analysis.
Single metal Biotic Ligand Models (BLMs) have been developed for a number of metals and model organisms. While these BLMs improve our ability to regulate metals in the aquatic environment, in reality, organisms are often simultaneously exposed to metal mixtures. Recently, several attempts have been made to develop mixture BLMs (mBLMs). Some of these models assume competitive interactions between all metals, while others assume only metals with a similar mode of action (e.g., Na(+) or Ca(2+) antagonists) will competitively interact. To begin testing these assumptions in the mBLM framework, standard 3-h gill metal binding assays with Ag, Cu, and Ni (primary metals), were performed in vivo on freshwater rainbow trout. Fish were exposed across a range of concentrations encompassing the 96-h LC50 for that metal to characterize uptake kinetics for each of these three primary metals (radiolabelled) in the presence and absence of a secondary metal (Ag, Cd, Cu, Ni, Pb, or Zn; not radiolabelled). We observed a complex series of interactions in binary mixtures that frequently contradicted theoretical expectations. Metals with similar modes of action did competitively interact in some instances, but not others, and when they did compete the competition was not necessarily reciprocal (e.g., Cu inhibited Ag uptake but Ag did not inhibit Cu uptake). We also observed examples of interactions between metals with dissimilar modes of action and several examples of metals stimulating the uptake of other metals. The underlying mechanisms for these unexpected interactions are unclear, but suggest that many of the current assumptions in mBLMs regarding the number and types of metal uptake sites and corresponding metal interactions are not correct. Careful characterization of metal mixture interactions is clearly needed before a reliable mBLM can be developed.
The stable isotope signatures of zinc are increasingly used to study plant and soil processes. Complexation with phytosiderophores is a key process and understanding the controls of isotope fractionation is central to such studies. Here, we investigated isotope fractionation during complexation of Zn2+ with the phytosiderophore 2'-deoxymugeneic acid (DMA) - which we synthesised - and with three commercially-available structural analogues of DMA: EDTA, TmDTA and CyDTA. We used ion exchange chromatography to separate free and complexed zinc, and identified appropriate cation exchange resins for the individual systems. These were Chelex-100 for EDTA and CyDTA, Amberlite CG50 for TmDTA and Amberlite IR120 for DMA. With all the ligands we found preferential partitioning of isotopically heavy zinc in the complexed form, and the extent of fractionation was independent of the Zn:ligand ratio used, indicating isotopic equilibrium and that the results were not significantly affected by artefacts during separation. The fractionations (in ‰) were +0.33 ± 0.07 (1, n=3), +0.45 ± 0.02 (1, n=2), +0.62 ± 0.05 (1, n=3) and +0.30 ± 0.07 (1, n=4) for EDTA, TmDTA, CyDTA and DMA, respectively. Despite the similarity in Zn-coordinating donor groups, the fractionation factors are significantly different and extent of fractionation seems proportional to the complexation stability constant. The extent of fractionation with DMA agreed with observed fractionations in zinc uptake by paddy rice in field experiments, supporting the possible involvement of DMA in zinc uptake by rice.
Even though systemic lupus erythematosus (SLE) is associated with high morbidity and mortality rates among young and middle-aged women, the molecular mechanisms of disease pathogenesis are not fully understood. Previous studies from our laboratory suggested an association between oxidative stress and SLE disease activity (SLEDAI). To further assess the role of reactive oxygen species (ROS) in SLE, we examined the contribution of lipid-derived reactive aldehydes (LDRAs)-specific immune complexes in SLE. Sera from 60 SLE patients with varying SLEDAI and 32 age- and gender- matched healthy controls were analyzed for oxidative stress
 and related markers. Patients were divided into two groups based on their SLEDAI scores (<6 and ≥ 6). Both SLEDAI groups showed higher serum 4-hydroxynonenal (HNE)-/malondialdehyde (MDA)-protein adducts and their specific immune complexes (HNE-/MDA-specific ICs) together with IL-17 than the controls, but the levels were significantly greater in the high SLEDAI (≥ 6) group. Moreover, the serum levels of anti-oxidant enzymes Cu/Zn superoxide dismutase (SOD) and catalase (CAT) were significantly reduced in both patient groups compared to controls. Remarkably, for the first time, our data show that increased HNE-/MDA-specific ICs are positively associated with SLEDAI and elevated circulating immune complexes (CICs), suggesting a possible causal relationship among oxidative stress, LDRA-specific ICs and the development of SLE. Our findings, apart from providing firm support to an association between oxidative stress and SLE, also suggest that these oxidative stress markers, especially the HNE-/MDA-specific ICs, may be useful in evaluating the prognosis of SLE as well as in elucidating the mechanisms of disease pathogenesis.
Phytoremediation is an emerging technology that employs higher plants to cleanup contaminated environments, including metal-polluted soils. Because it produces a biomass rich in extracted toxic metals, further treatment of this biomass is necessary. The aim of our study was to assess the five-year potential of the following native wild plants to produce biomass and remove heavy metals from a polluted site: poplar (Populus ssp.), ailanthus (Ailanthus glandulosa L.), false acacia (Robinia pseudoacacia L.), ragweed (Artemisia artemisiifolia L.), and mullein (Verbascum thapsus L). Average soil contamination with Pb, Cd, Zn, Cu, Ni, Cr, and As in the root zone was 22,948.6 mg kg-1, 865.4 mg kg-1, 85,301.7 mg kg-1, 3,193.3 mg kg-1, 50.7 mg kg-1, 41.7 mg kg-1,and 617.9 mg kg-1, respectively. We measured moisture and ash content, concentrations of Pb, Cd, Zn, Cu, Ni, Cr, and As in the above-ground parts of the plants and in ash produced by combustion of the plants, plus gross calorific values. The plants' phytoextraction and phytostabilisation potential was evaluated based on their bioconcentration factor (BCF) and translocation factor (TF). Mullein was identified as a hyperaccumulator for Cd. It also showed a higher gross calorific value (19,735 kJ kg-1) than ragweed (16,469 kJ kg-1).The results of this study suggest that mullein has a great potential for phytoextraction and for biomass generation, and that ragweed could be an effective tool of phytostabilisation.
Cations and anions are replaced with Fe, Mn, and Se in CZTS in order to control the formations of the secondary phase, the band gap, and the micro structure of Cu2ZnSnS4. We demonstrate a simplified synthesis strategy for a range of quaternary chalcogenide nanoparticles such as Cu2ZnSnS4 (CZTS), Cu2FeSnS4 (CFTS), Cu2MnSnS4 (CMTS), Cu2ZnSnSe4 (CZTSe), and Cu2ZnSn(S0.5Se0.5)4 (CZTSSe) by thermolysis of metal chloride precursors using long chain amine molecules. It is observed that the crystal structure, band gap and micro structure of the CZTS thin films are affected by the substitution of anion/cations. Moreover, secondary phases are not observed and grain sizes are enhanced significantly with selenium doping (grain size ~1 μm). The earth-abundant Cu2MSnS4/Se4 (M = Zn, Mn and Fe) nanoparticles have band gaps in the range of 1.04-1.51 eV with high optical-absorption coefficients (~10(4) cm(-1)) in the visible region. The power conversion efficiency of a CZTS solar cell is enhanced significantly, from 0.4% to 7.4% with selenium doping, within an active area of 1.1 ± 0.1 cm(2). The observed changes in the device performance parameters might be ascribed to the variation of optical band gap and microstructure of the thin films. The performance of the device is at par with sputtered fabricated films, at similar scales.
Mass spectrometry has been developed as one of the common tools for the analysis of the organometallic systems in the gas phase over decades. The study of the fragmentation of organics-metal complexes has attracted much attention since the interesting dissociation pathways exhibited by these compounds are usually different from the protonated analogues.
In this work, iohexol complexed with different dications such as Mg(2+) , Cu(2+) , and Zn(2+) have been investigated by ESI tandem mass spectrometry. Additionally, deuterium labeling experiments and analogue of iohexol were utilized to confirm the reaction mechanisms. Computational chemistry method was performed to identify the coordination conformation between iohexol and metal ions in the gas phase. UV detection was also used to identify the interaction between iohexol and metal ions in liquid phase.
A special gas phase open-loop reaction of iohexol induced by Mg(2+) , leading to the formation of [iohexol + Mg-H-HI-C3 H4 O](+) , was observed in the collision induced dissociation of [2(iohexol) + Mg](2+) complexes. Moreover, theoretical calculation shows the proposed coordination configuration of iohexol/Mg(2+) complexes. The Mg(2+) could have tetrahedral coordination with two iohexol molecules.
The percent study is a case for better understanding the formation of a typical organic/metal complex and its gas phase fragmentation reaction. In addition, it provides useful information for researchers working on analysis or structural elucidation of complicated compounds which contain the iohexol analogues. This article is protected by copyright. All rights reserved.
Fish are an important source of nutrients in human nutrition. Although arsenic (As) is considered potentially carcinogenic for human being, very little is known about its toxicity in fish biology. To increase our knowledge of the effect of exposure to waterborne As on fish, gilthead seabream (Sparus aurata) were exposed to 5 μM As2O3 and the bioaccumulation of macronutrients (Ca, K, Mg, Na, P), micronutrients (Fe, Mn, Zn) and Potentially Harmful Elements (As, Cd) was determined using spectrometric techniques. All elements were determined in the muscle and liver of non-exposed fish and those exposed to As for 2, 10 or 30 days. The concentrations of K, Na, Mg, Mn and Zn (in muscle) and Fe and Mn (in liver) of control (non-exposed) fish were higher than those determined in exposed fish. Furthermore, neither As nor Cd accumulated in the edible part (muscle) of seabream and were only evident in liver after 30 days of continuous exposure to As, but both concentrations remained below legally established limits.
Utilizing a new ferrocene-based compartmental ligand, H4L (1), a series of novel heterometallic complexes [{LZn(μ-OAc)Dy}4(μ4-H2O)] (2), [{LZn(μ-OAc)Tb}4(μ4-H2O)] (3), [{LZn(μ-OAc)Ho}4(μ4-H2O)] (4), [L = Fe[(C5H4){-C(Me)[double bond, length as m-dash]N-N[double bond, length as m-dash]C6H3-(o-O)(m-O)}]2] were synthesized and characterized. 2 and 3 crystallize in the monoclinic crystal system in the I2/m space group, whereas 4 crystallizes in the tetragonal crystal system in the I4/m space group. The tetra deprotonated ligand L(4-) has two distinct coordination compartments: one pocket (2N, 2O) suitable for the transition metal (3d) ions and another pocket (4O) suitable for lanthanide (4f) metal ions. Additionally, the terminal phenoxo group can be utilized for cluster expansion. In all the complexes, the Zn(II) ion is in a perfect square pyramidal (2N, 3O) geometry whereas the lanthanide ion has a coordination number of eight (8O) in a distorted biaugmented trigonal-prism geometry. The electrochemical properties of 2 and 3 along with ligand H4L (1) were studied by cyclic voltammetry (CV). All the complexes display a similar type of electrochemical behavior viz., one quasi-reversible oxidation typical of a ferrocene/ferrocenium motif. The magnetic properties of all the complexes have also been investigated.
Immunogenicity induced by recombinant plasmids based on the BAB1_0267 and BAB1_0270 open reading frames (ORFs) of Brucella abortus 2308 was evaluated. Bioinformatics analyses indicate that the BAB1_0267 and BAB1_0270 ORFs encode a protein with a SH3 domain and a Zn-dependent metalloproteinase, respectively. Both ORFs have important effects on intracellular survival and replication of B. abortus 2308, mediated via professional and non-professional phagocytic cells. Our results show that immunization with the recombinant plasmid based on the BAB1_0267 ORF significantly increases the production of IgG1, levels of IFN-γ and the lymphoproliferative response of splenocytes. However, BAB1_0267 did not provide significant levels of protection. The plasmid based on the BAB1_0270 significantly increased IgG2a production, levels of IFN-γ and TNF-α, and the lymphoproliferative response of splenocytes. These results demonstrate that immunization with the BAB1_0270 derived recombinant plasmid induce a Th1-type immune response, correlated with a heightened resistance to B. abortus 2308 infection in mice. It is concluded that the Th1-type immune response against bacterial Zn-dependent metalloproteinase induces a protective response in mice, and that pV270 recombinant plasmid is an effective candidate microbicide against brucellosis.
Single crystals of glycine zinc sulfate penta-hydrate [systematic name: hexa-aqua-zinc tetra-aquadiglycinezinc bis-(sulfate)], [Zn(H2O)6][Zn(C2H5NO2)2(H2O)4](SO4)2, have been grown by isothermal evaporation from aqueous solution at room temperature and characterized by single-crystal neutron diffraction. The unit cell contains two unique ZnO6 octa-hedra on sites of symmetry -1 and two SO4 tetra-hedra with site symmetry 1; the octa-hedra comprise one [tetra-aqua-diglycine zinc](2+) ion (centred on one Zn atom) and one [hexa-aqua-zinc](2+) ion (centred on the other Zn atom); the glycine zwitterion, NH3(+)CH2COO(-), adopts
 a monodentate coordination to the first Zn atom. All other atoms sit on general positions of site symmetry 1. Glycine forms centrosymmetric closed cyclic dimers due to N-H⋯O hydrogen bonds between the amine and carboxyl-ate groups of adjacent zwitterions and exhibits torsion angles varying from ideal planarity by no more than 1.2°, the smallest values for any known glycine zwitterion not otherwise constrained by a mirror plane. This work confirms the H-atom locations estimated in three earlier single-crystal X-ray diffraction studies with the addition of independently refined fractional coordinates and Uij parameters, which provide accurate inter-nuclear X-H (X = N, O) bond lengths and consequently a more accurate and precise depiction of the hydrogen-bond framework.
In the title complex, [Zn(C8H4NO2)2(C10H14N2O)2(H2O)2], the Zn(II) cation, located on an inversion centre, is coordinated by two water mol-ecules, two 4-cyano-benzoate (CB) anions and two di-ethyl-nicotinamide (DENA) ligands in a distorted N2O4 octa-hedral geometry. In the mol-ecule, the dihedral angle between the planar carboxyl-ate group and the adjacent benzene ring is 9.50 (14)°, while the benzene and pyridine rings are oriented at a dihedral angle of 56.99 (5)°. The water mol-ecules exhibit both an intra-molecular hydrogen bond [to the non-coordinating carboxyl-ate O atom, enclosing an S(6) hydrogen-bonding motif, where O⋯O = 2.6419 (19) Å] and an inter-molecular hydrogen bond [to the amide carbonyl O atom, enclosing an R2(2)(16) ring motif, where O⋯O = 2.827 (2) Å]; the latter lead to the formation of supra-molecular chains propagating along the [110] direction.
The quest for new, promising and indigenous plant growth-promoting rhizobacteria and a deeper understanding of their relationship with plants are important considerations in the improvement of phytoremediation. This study focuses on the screening of plant beneficial Cu/Zn-resistant strains and assessment of their bioremediation potential (metal solubilization/tolerance/biosorption and effects on growth of Brassica napus seedlings) to identify suitable rhizobacteria and examine their roles in microbes-assisted phytoremediation. Sixty Cu/Zn-resistant rhizobacteria were initially isolated from Sonchus oleraceus grown at a multi-metal-polluted site in Shanghai, China. From these strains, 19 isolates that were all resistant to 300 mg⋅L(-1) Cu as well as 300 mg⋅L(-1) Zn, and could simultaneously grow on Dworkin-Foster salt minimal medium containing 1-aminocyclopropane-1-carboxylic acid were preliminarily selected. Of those 19 isolates, 10 isolates with superior plant growth-promoting properties (indole-3-acetic acid production, siderophore production, and insoluble phosphate solubilization) were secondly chosen and further evaluated to identify those with the highest bioremediation potential and capacity for bioaugmentation. Strain S44, identified as Acinetobacter sp. FQ-44 based on 16S rDNA sequencing, was specifically chosen as the most favorable strain owing to its strong capabilities to (1) promote the growth of rape seedlings (significantly increased root length, shoot length, and fresh weight by 92.60%, 31.00%, and 41.96%, respectively) under gnotobiotic conditions; (2) tolerate up to 1000 mg⋅L(-1) Cu and 800 mg⋅L(-1) Zn; (3) mobilize the highest concentrations of water-soluble Cu, Zn, Pb, and Fe (16.99, 0.98, 0.08, and 3.03 mg⋅L(-1), respectively); and (4) adsorb the greatest quantities of Cu and Zn (7.53 and 6.61 mg⋅g(-1) dry cell, respectively). Our findings suggest that Acinetobacter sp. FQ-44 could be exploited for bacteria-assisted phytoextraction. Moreover, the present study provides a comprehensive method for the screening of rhizobacteria for phytoremediation of multi-metal-polluted soils, especially those sewage sludge-amended soils contaminated with Cu/Zn.
A procedure based on radiochemical neutron activation analysis was developed for the determination of chromium in biological materials. The procedure consists of irradiation of reference and test samples in a nuclear reactor, microwave sample digestion, selective and quantitative radiochemical separations of chromium and gamma-ray spectrometric measurement of (51)Cr. Separation of chromium from the accompanying elements was done on the column packed with inorganic resin MnO2 Resin. Distribution coefficients of Cr, Zn, Co, Cs and Sc were determined in the system: MnO2 Resin-HCl, HNO3 and H2SO4. Accuracy of the procedure was checked by analysis of certified reference materials.
Passive bioremediation of metal- and sulfate-containing acid mine drainage (AMD) has been investigated in a batch study. Multiple substrates were used in the AMD remediation using spent mushroom compost (SMC), limestone, activated sludge (AS), and woodchips (WC) under anoxic conditions suitable for bacterial sulfate reduction (BSR). Limestones used were of crushed limestone (CLS) and uncrushed limestone, provided at two different ratios in mixed substrates treatment and varied by the proportion of SMC and limestone. The SMC greatly assisted the removals of sulfate and metals and also acted as an essential carbon source for BSR. The mixed substrate composed of 40% CLS, 30% SMC, 20% AS, and 10% WC was found to be effective for metal removal. Mn, Cu, Pb, and Zn were greatly removed (89-100%) in the mixed substrates treatment, while Fe was only removed at 65%. Mn was found to be removed at a greatly higher rate than Fe, suggesting important Mn adsorption onto organic materials, that is, greater sorption affinity to the SMC. Complementary with multiple treatment media was the main mechanism assisting the AMD treatment through microbial metal reduction reactions.
The colon is a promising target for drug delivery owing to its long transit time of up to 78 h, which is likely to increase the time available for drug absorption. Progesterone has a short elimination half-life and undergoes extensive first-pass metabolism, which results in very low oral bioavailability (∼25%). To overcome these shortcomings, we developed an oral multiparticulate system for the colonic delivery of progesterone. Zn-pectinate/chitosan microparticles were prepared by ionotropic gelation and characterized for their size, shape, weight, drug entrapment efficiency, mucoadhesion and swelling behavior. The effect of cross-linking pH, cross-linking time and chitosan concentration on progesterone release were also studied. Spherical microparticles having a diameter of 580-720 µm were obtained. Drug entrapment efficiency of ∼75-100% was obtained depending on the microparticle composition. Microparticle mucoadhesive properties were dependent on the pectin concentration, as well as the cross-linking pH. Progesterone release in simulated gastric fluids was minimal (3-9%), followed by burst release at pH 6.8 and a sustained phase at pH 7.4. The in vivo study revealed that the microparticles significantly increased progesterone residence time in the plasma and increased its relative bioavailability to ∼168%, compared to the drug alone. This study confirms the potential of Zn-pectinate/chitosan microparticles as a colon-specific drug delivery system able to enhance the oral bioavailability of progesterone or similar drugs.
The objective of this study was to investigate the zinc fractional absorption of young Chinese men and women from the Shandong rural region under the routine dietary pattern by stable isotope technique. Ten men and 10 women, aged 20 to 35 years, and with a representative diet during the experiment were recruited from the Shandong rural region. Stable (67)Zn was used as a tracer to label ZnCl2, and Yb was used to monitor the excretion of (67)Zn in urine and feces. All volunteers were given rice containing 4.0 mg (67)Zn and 1.0 mg Yb on the fourth day. Then the food and fecal samples of all subjects were collected for 12 consecutive days. The total zinc and the stable zinc isotope ratio of all samples were determined by atomic absorption spectrophotometer and thermal ionization mass spectrometer, respectively. The determination of the other nutrients was performed based on the Chinese National Standard Methods. Among volunteers, the daily intake of zinc was 15.50 mg, 103.33 % of recommended nutrient intake (RNI, set by the Chinese Nutrition Society) in men and 15.43 mg, 134.17 % in women. The fractional absorption of Zn was 23.42 ± 2.23 % in men, and 22.49 ± 2.19 % in women. The protein candidates got from the typical diets was 93.96 % of RNI in women. Calcium and ascorbic acid intakes were 76.23 % of RNI and 27.91 % of RNI in men, respectively and 51.17 % of RNI and 34.23 % of RNI in women, respectively. Our results showed that a typical meal for someone in the Shandong rural region presented an adequate intake of zinc and a moderate Zn bioavailability. The shortage of protein and the inappropriate protein pattern may play important roles in reducing zinc bioavailability.
Diabetes is a common metabolic disorder characterized by elevated blood glucose level. Trace element homeostasis causes disturbances in diabetes due to hyperglycemia. Superoxide dismutase (SOD), an antioxidant enzyme, contains zinc and copper ions as its cofactors. Defects in SOD level and activity have been observed in diabetes. Resveratrol (RSV) has displayed hypoglycemic effects and is proven to improve oxidative stress. The aim of the present study was to examine the possible effects of RSV on blood glucose level, serum copper and zinc levels, SOD, and a number of other oxidative markers in type 2 diabetic rats. Diabetes was induced in male Wistar rats with administration of streptozotocin and nicotine amide. The studied groups containing six animals per group were as follows: group 1 normal control group; group 2 diabetic control group; groups 3, 4, and 5 diabetic rats that received 1, 5, and 10 mg/kg body
 weight of RSV, respectively for 30 days. Serum glucose, copper, zinc, SOD activity, total oxidant status (TOS) as well as thiol groups were all measured. Blood glucose in RSV treated groups significantly decreased. Similarly, copper significantly decreased in diabetic groups treated with RSV. Treatment with 10 mg/kg RSV resulted in significantly increased serum zinc. Furthermore, Cu/Zn ratio was observed to decrease in treated groups compared with untreated diabetic control group. RSV treated groups revealed an increased level of SOD activity as well as improved oxidative status. In summary, the results showed that RSV has potential hypoglycemic effect, attenuates trace element homeostasis, and consequently increases SOD activity level.
Soil provides a critical environment for microbial community development. However, microorganisms may be sensitive to substances such as heavy metals (HMs), which are common soil contaminants. This study investigated bacterial communities using 16S ribosomal RNA (rRNA) gene fragment sequencing in geographic regions with and without HM pollution to elucidate the effects of soil properties and HMs on bacterial communities. No obvious changes in the richness or diversity of bacterial communities were observed between samples from mining and control areas. Significant differences in bacterial richness and diversity were detected between samples from different geographic regions, indicating that the basic soil characteristics were the most important factors affecting bacterial communities other than HMs. However, the abundances of several phyla and genera differed significantly between mining and control samples, suggesting that Zn and Pb pollution may impact the soil bacterial community composition. Moreover, regression analyses showed that the relative abundances of these phyla and genera were correlated significantly with the soil-available Zn and Pb contents. Redundancy analysis indicated that the soil K, ammoniacal nitrogen (NH4(+)-N), total Cu, and available Zn and Cu contents were the most important factors. Our results not only suggested that the soil bacteria were sensitive to HM stresses but also indicated that other soil properties may affect soil microorganisms to a greater extent.
Honeybees have become important tools for the ecotoxicological assessment of soil, water and air metal contamination due to their extraordinary capacity to bioaccumulate toxic metals from the environment. The level of heavy metal pollution in the Trieste city was monitored using foraging bees of Apis mellifera ligustica from hives owned by beekeepers in two sites strategically located in the suburban industrial area and urban ones chosen as control. The metal concentration in foraging bees was determined by inductively coupled plasma-mass spectrometry. The chemical analysis has identified and quantified 11 trace elements accumulated in two different rank orders: Zn> Cu > Sr > Bi > Ni > Cr > Pb = Co > V > Cd > As in foraging bees from the suburban site and Zn > Cu > Sr > Cr > Ni > Bi > Co = V > Pb > As > Cd in bees from urban site. Data revealed concentrations of Cr and Cu significantly higher and concentration of Cd significantly lower in bees from urban sites. The spatial difference and magnitude order in heavy metal accumulation along the urban-suburban gradient are mainly related to the different anthropogenic activity within sampled sites and represent a risk for the human health of people living in the city. We discussed and compared results with the range of values reported in literature.
Excessive phosphorus (P) input plays an important role on the release of heavy metals in sediments under the eutrophic environment. In this study, a microcosm experiment with 40-day incubation using homogenized sediments was performed to investigate this aspect at a millimeter resolution. Diffusive gradient in thin films (DGT) and dialysis (Peeper) techniques were employed to simultaneously measure labile and dissolved P, Pb, Cd, Zn, Co and Ni in sediments at a millimeter scale, respectively. The results showed that an increase of water P from 0.02mgL(-1) to 0.20 and 2.4mgL(-1) generally led to intensified decrease of DGT-labile metals from the 10th to 20th days after the onset of incubation. The decrease in dissolved metals in pore water also appeared on the 20th day. The degree of decrease in the five metals was in the order of Pb>Cd>Zn>Co>Ni, which has a negative correlation with the solubility constants (Ksp) of each metal-P precipitate. This indicated that the negative effect was caused by the precipitation of metal P. On the 40th day during incubation, the concentrations of DGT-labile metals had different increasing pattern compared to those on the 20th day. The extent of metal recovery was positively correlated with the change of desorption rate constant (k-1) and negatively correlated with the change in the characteristic time (Tc) to reach equilibrium from DGT perturbation derived from DGT-induced fluxes in sediments (DIFS) modeling. This suggested that the recovery of metal lability from elevated water P was a result of the increased releases of metals from sediment solids.
Supplying trace minerals in more bioavailable forms such as amino acid complexes (AAC) could help ameliorate the incidence of hoof disorders in peripartal dairy cows. The aim of this study was to evaluate the effects of supplementing metal AAC during the peripartal period on expression of 28 genes in corium tissue related to claw composition, oxidative stress, inflammation, chemotaxis, and transcriptional regulation. Forty-four multiparous Holstein cows received a common diet from -30 to 30 d relative to parturition and were assigned to receive an oral bolus containing either inorganic trace minerals (INO) or AAC (i.e., organic) Zn, Mn, Cu, and Co to achieve supplemental levels of 75, 65, 11, and 1 ppm, respectively, in the total diet dry matter. Inorganic trace minerals were provided in sulfate form, and AAC were supplied via Availa Zn, Availa Mn, Availa Cu, and COPRO (Zinpro Corp., Eden Prairie, MN). Locomotion score was recorded before enrollment and weekly throughout the experiment. Incidence of hoof health problems at 30 d in milk was evaluated before a hoof biopsy in a subset of cows (INO=10; AAC=9). Locomotion score did not differ between treatments in the prepartum or postpartum period. The incidence of heel horn erosion was lower in AAC cows, but the incidence of sole ulcers did not differ. Downregulation of KRT5, CTH, CALML5, and CYBB, and upregulation of BTD in AAC cows indicated a decrease in the need for activation of cellular pathways to regenerate corium tissue and increase biotin availability in the sole claw. These molecular changes in the sole could have been triggered by the lower incidence of heel erosion in response to AAC. Among the genes associated with oxidative stress, the AAC cows had greater expression of NFE2L2, a transcription factor that regulates the antioxidant response, and the antioxidant enzyme SOD1. Among genes associated with inflammation, AAC cows had greater expression of TLR4, and lower expression of TLR2, IL1B, and TNF compared with INO cows. Supplementation with metal AAC during the peripartal period affected the expression of genes involved in composition, oxidative stress, and inflammation status in the corium. The hoof biopsy procedure used in the present study should be further perfected and implemented in future lameness research to expand our understanding of hoof biology in dairy cows.
Cu/Zn superoxide dismutase (SOD) and catalase (CAT) cDNAs from the polychaete Perinereis aibuhitensis were cloned and characterized in order to investigate the relationship between crude oil exposure and stress response in this worm. The full length of PaSOD was 870 bp and PaCAT was 1967 bp encoding 150 and 506 amino acids, respectively. Gene expression and enzyme activity of Cu/Zn SOD and CAT in response to crude oil contaminated soil (500, 1500, and 3000 mg/kg) were measured. The results showed that expression of the CAT gene and enzyme activity in P. aibuhitensis was positively correlated to the concentration of crude oil and reached a maximum at 15 days of exposure to 3000 mg/kg crude oil. The expression of the SOD gene and enzyme activity of SOD in P. aibuhitensis also increased during exposure to crude oil and reached a maximum at 10 days of exposure to 3000 mg/kg crude oil. These results indicated that SOD and CAT are important for maintaining the balance of cellular metabolism and protecting P. aibuhitensis from crude oil toxicity.
The aim of the study was to evaluate the cadmium and zinc content in the kidneys and liver of moose from north-eastern Poland. Animals were divided with respect to their age. The mean concentration of cadmium in the kidneys of moose studied was 11.31 mg kg(-1), while in the liver it amounted to 2.68 mg kg(-1). Age had a significant effect on the content of cadmium in both organs. In the muscles of most animals studied, the cadmium concentrations were below the detection limit. Elevated concentrations were found in three individuals only. Older animals had over six times higher concentrations of cadmium in both kidneys and liver than younger individuals. The cadmium content in kidneys increased with animals' age while no such relationship was found for zinc. Although older animals had higher mean concentrations of zinc in kidneys, liver, and muscles, the two age groups did not differ significantly. The mean concentration of zinc in the kidneys of moose studied was 38.83 mg kg(-1), while in the liver it amounted to 29.03 mg kg(-1). The cadmium concentration in the kidneys was significantly correlated with the cadmium concentration in the liver (r = 0.53, p ≤ 0.01) and with the zinc concentration in the kidneys (r = 0.52, p ≤ 0.01). The data obtained within study
 correspond with analyses results of the organs of healthy moose in Sweden.
In the present study, we investigated the ability of Cu, Zn-superoxide dismutase (SOD1) to improve the therapeutic potential of adipose tissue-derived mesenchymal stem cells (Ad-MSCs) against ischemic damage in the spinal cord. Animals were divided into four groups: the control group, vehicle (PEP-1 peptide and artificial cerebrospinal fluid)-treated group, Ad-MSC alone group, and Ad-MSC-treated group with PEP-1-SOD1. The abdominal aorta of the rabbit was occluded for 30 min in the subrenal region to induce ischemic damage, and immediately after reperfusion, artificial cerebrospinal fluid or Ad-MSCs (2 × 10(5)) were administered intrathecally. In addition, PEP-1 or 0.5 mg/kg PEP-1-SOD1 was administered intraperitoneally to the Ad-MSC-treated rabbits. Motor behaviors and NeuN-immunoreactive neurons were significantly decreased in the vehicle-treated group after ischemia/reperfusion. Administration of Ad-MSCs significantly ameliorated the changes in motor behavior and NeuN-immunoreactive neuronal survival. In addition, the combination of PEP-1-SOD1 and Ad-MSCs further increased the ameliorative effects of Ad-MSCs in the spinal cord after ischemia. Furthermore, the administration of Ad-MSCs with PEP-1-SOD1 decreased lipid peroxidation and maintained levels of antioxidants such as SOD1 and glutathione peroxidase compared to the Ad-MSC alone group. These results suggest that combination therapy using Ad-MSCs and PEP-1-SOD1 strongly protects neurons from ischemic damage by modulating the balance of lipid peroxidation and antioxidants.
Contamination of aquatic systems with potentially toxic trace elements (PTEs) is a major problem throughout the world. The National Park Tablas de Daimiel (NPTD) is considered to make up one of the two most important wetlands in the Biosphere Reserve called "Wet Spot." Since PTEs are good indicator of the prevailing environmental conditions and possible contamination, soil samples collected from 43 sites were analyzed in order to investigate the levels and its distribution of these elements, in the inundated floodplain area of the NPTD wetland. In addition, some physicochemical parameters such as pH, electrical conductivity and organic matter were measured. The total concentrations of 32 trace elements were determined by X-ray fluorescence. The results show that there was accumulation of lead (Pb), tin (Sn), selenium (Se), antimony (Sb), copper (Cu), vanadium (V), nickel (Ni), zinc (Zn), arsenic (As), strontium (Sr) and zirconium (Zr)-in some cases at high concentrations. The interpolated maps showed that the distributions of some of these elements and in some cases the trend in spatial variability are pronounced and decrease from the inlet to the outlet. The values for some elements are higher than the reference values, which is consistent with contamination (some values are higher by a factor of more than 10 compared to the reference). In the case of iodine (I), the levels at some sample points are significantly more than ten times the reference; Se appears in the range from 1.0 to 9.8 mg/kg, with an average value of 3.1 mg/kg, and these can be considered as seleniferous soils. The concentrations found are consistent with the introduction in the wetland of pollution by human activities, such as agricultural non-point sources, uncontrolled fertilization over many years, treatment with urban wastewater and other possible sources.
This study assessed the concentrations of airborne heavy metals (HMs) in particulate matter with a cutoff size of 10 µm (i.e., PM10) in an industrialized urban area (Naraina Industrial Area) of New Delhi, India. The samples were collected from January to December, 2011. The annual mean concentrations of selected HMs were as follows As (0.002 ± 0.002), Cd (0.030 ± 0.020), Co (0.003 ± 0.002), Cr (0.170 ± 0.081), Cu (0.183 ± 0.120), Fe (4.774 ± 1.889), Mn (0.258 ± 0.145), Ni (0.170 ± 0.146), Pb (0.345 ± 0.207) and Zn (1.806 ± 1.042) µg/m(3). The seasonal trend for HMs followed the order postmonsoon > winter > premonsoon > monsoon. Principal component analysis-multiple linear regression (PCA-MLR) suggested the three major emission sources: industrial emission (70 %), mobile and stationary combustion sources (16 %), and suspended/re-suspended dust (14 %). Mean seasonal concentrations of PM10 exceeded both the 24-hour and annual Indian National Ambient Air Quality Standards (NAAQS) of 60 and 100 µg/m(3), respectively, in all four seasons. Mean seasonal Ni concentrations in Delhi ambient air also exceeded the 24-h annual NAAQS of 0.020 µg/m(3) during all four seasons. Mean Pb concentrations exceeded the annual NAAQS of 0.50 µg/m(3) only during the post monsoon season. The high levels of Ni- and Pb-contaminated PM10 would appear to present the possibility of significant health risks.
Carabids are generally considered to be non-specialized predators, and they have been considered useful ecological indicators. They can play a key role in clarifying the route of contaminants in food webs because they are predators of small invertebrates and, in turn, part of the diet of several vertebrates. The Mediterranean species Parallelomorphus laevigatus, which so far has not been studied from an ecotoxicological point of view, is an excellent ecological indicator in sandy coastal environments. We investigated the accumulation of trace elements in Ionian populations of P. laevigatus and evaluated the transfer of metal through the food chain of the coastal ecosystem. We analyzed 15 metals, including 11 essential metals (Co, Cr, Cu, Fe, Mn, Mo, Ni, Se, Sn, V and Zn) and four toxic metals (As, Cd, Hg and Pb). Significant differences were found in metal concentration in animal tissues among sites. Our results support the existence of defense mechanisms for the studied species. High values of As, Cd, Cr, Pb, Ni, and Hg detected in the beetles from the control site can be explained by both the emission sources from the nearby industrial plants and the intense agricultural activity. The present paper shows increasing Hg concentrations in the simplified trophic web of sandy beaches and confirms the capability of this pollutant to biomagnify. Moreover, the high value of biomagnification factor (BMF) points to the severe pollution level in this protected area.
This study examined the mechanism of toxicity in Arabidopsis thaliana seedlings to zinc oxide nanoparticles (ZnO NPs) and zinc (Zn) ions. We subjected plants to different ZnO NPs and Zn ion concentrations (0, 20, 50, 100 and 200mg/L) and analyzed resulting morphological changes, transcriptional regulation of genes involved in Zn-homeostasis, macro- and microelement homeostasis, as well as auxin regulation. Except for 20mg/L, the fresh weight and primary root length was reduced after exposure to all other concentrations of Zn ion and ZnO NP concentrations. An increase in lateral root formation (19 and 32%) was observed after exposure to 20 and 50mg/L of Zn ions respectively; whereas 20mg/L ZnO NPs treatment triggered a 9% increase in lateral root formation. Both qualitative, using Zynpyr-1 fluorescent probe and quantitative analysis revealed Zn uptake and translocation from roots to shoots after Zn ion exposure. However, ZnO NPs-treated seedlings resulted in no root to shoot translocation and Zn accumulation was mainly located in root tips, primary-lateral root junctions and root- shoot junctions. The macronutrients viz. P (1.34mg/kg DW), K (13.29mg/kg DW), S (1.29mg/kg DW) and micronutrients Cu (0.004mg/kg DW) and Fe (0.345mg/kg DW) contents were highly decreased as a result of exposure to 200mg/L of Zn ions. Similarly, the highest reduction of P (2.30mg/kg DW), K (6.36mg/kg DW), S (2.63mg/kg DW) and Cu (0.004mg/kg DW) was observed after exposure to 200mg/L of ZnO NPs. Gene regulation studies indicated the transcriptional modulation of various genes involved in Zn, macro- and micro nutrient homeostasis as well as hormone regulation. Taken together, it was observed that the mechanism of toxicity of Zn ions and ZnO NPs were different. These findings will help to design safer strategies for the application of ZnO NPs as plant fertilizer without compromising the morphological and nutritional qualities as well as for the future phytoremediation purposes.
Nuclear factor-κB (NF-κB) is the most potent proinflammatory transactivator, and an inhibitor of NF-κB is a good antiinflammatory drug. Glucocorticoids (GCs) are the strongest and the most frequently used antiinflammatory drugs. GC-bound glucocorticoid receptor (GR) inhibits the transcriptional activity of NF-κB and thereby suppresses a broad range of inflammatory processes. Concurrently, in whole body outside the inflammation area, the GR exerts a lot of hormone action, which results in severe side effects. There is a long-awaited need for a new NF-κB inhibitor. Previously we found a small nuclear acidic protein (named MTI-II, also known as Zn(2+)-binding protein or parathymosin), which worked as a coactivator of GR. Here we showed that overexpression of MTI-II inhibited a transcriptional activity of NF-κB independently of GCs and the GR. Vise versa, RNA interference suppression of inherent MTI-II enhanced the transcriptional activity of NF-κB. An immunoprecipitation analysis showed that MTI-II precipitated NF-κB after the stimulation of TNFα. Deletion mutants of MTI-II showed that central acidic region is essential for the inhibition of the transcriptional activity of NF-κB. These results suggest that MTI-II would be an inherent inhibitor that interacts with NF-κB. Next, we constructed MTI-II-based antiinflammatory drugs (three fusion proteins of MTI-II with a protein transduction domain and a fusion peptide of the central acidic region with protein transduction domain). These drugs had significant antiinflammatory
 effects on acute inflammation models and on animal models of human chronic inflammation diseases without an increase of the blood glucose level and repeated-dose toxicity. The MTI-II-based antiinflammatory drug will be a good alternative of GCs.
The soil from an industrial area in Algeria was contaminated with Cr (8370 mg kg(-1)), Ni (1135 mg kg(-1)) and zinc (1200 mg kg(-1)). The electrodialytic remediation of this soil was studied using citric acid and EDTA as facilitating agents. 0.1 M citric acid or EDTA was added directly to the soil before it was introduced in an electrodialytic cell in an attempt to enhance the heavy metal solubility in the interstitial fluid. The more acidic pH in the soil when citric acid was used as the facilitating agent was not enough to mobilize and remove the metals from the soil. Only 7.2% of Ni and 6.7% of Zn were removed from the soil in the test with citric acid. The best results were found with EDTA, which was able to solubilize and complex Zn and Ni forming negatively charged complexes that were transported and accumulated in the anolyte. Complete removal was observed for Ni and Zn in the electrodialytic treatment with EDTA. Minor amounts of Cr were removed with both EDTA and citric acid.
The test strains Bacteroidetes bacterium (Ba), Pseudomonas fluorescens (Pf) and Variovorax sp. (Va) were selected in advance for their in vitro capability for growth promotion of rapeseed in the presence of increased concentrations of Cd, Cu, Pb and Zn in the medium. In the pot experiment the strains were used for single Ba, Pf, Va or combined Ba+Pf, Ba+Va, Pf+Va, Ba+Pf+Va inoculation of B. napus growing in contaminated soil from alluvial deposits. The positive effect of bacterial strains on plant growth was observed in vitro, but was not confirmed in situ in the contaminated soil, where the tested strains inhibited biomass production, rather than stimulating it. However, single inoculation with Ba significantly increased the chlorophyll content and K(+) concentration in the leaves. The inoculation of rapeseed with Ba and Va strains was indicated to be the most promising combination for phytoextraction of Cd and Zn from contaminated soil. Combined inoculation with Pf+Va and Pf+Ba+Va significantly decreased the concentration of heavy metals in the roots of rapeseed. We conclude that suitable combinations of PGPR can control the metal uptake of B. napus, selectively increasing either metal extraction or metal stabilisation in the rhizosphere and offering promising applications in soil remediation.
It had been reported that iron and manganese oxides in steel slag enhanced the production of humic acid (HA) from low-molecular-weight compounds, such as phenolic acids, amino acids, and saccharides. In the present study, this function of steel slag was applied to the composting of raw organic wastes (ROWs). The degree of humification of HAs is an important factor in evaluating compost quality. Thus, HAs were extracted from the prepared composts and the humification parameters were determined, in terms of elemental compositions, acidic functional group contents, molecular weights, spectroscopic parameters from UV-vis absorption and (13)C NMR spectra. The timing for adding steel slag affected the degree of humification of HAs in the composts. The weight average molecular weight of a HA when slag was added initially (29 kDa) was significantly higher than when slag was added after elevating the temperature of the compost pile (17-18 kDa). These results show that ROWs are decomposed to low-molecular-weight compounds after the pile temperature is elevated and the presence of slag enhances the polycondensation of these compounds to produce HAs with a higher degree of humification. Because the slag used in the present study contained several-tens ng g(-1) to several μg g(-1) of toxic elements (B, Cu, Cr, and Zn), leaching tests for these elements from the prepared composts were carried out. Levels for leaching boron from composts prepared by adding slag (0.2-0.4 mg L(-1)) were obviously higher than the corresponding levels without slag (0.05 mg L(-1)).
The objective of the present study was to determine concentrations of zinc (Zn), copper (Cu), iron (Fe), selenium (Se) in blood plasma and manganese (Mn) in the whole blood in patients with long-term home parenteral nutrition (HPN) in comparison to the control group.
We examined 68 patients (16 men and 52 women) aged from 28 to 68 years on a long-term HPN lasting from 4 to 96 months. The short bowel syndrome was an indication for HPN. The daily doses of Zn, Cu, Fe, Se and Mn in the last 3 months were determined.
No significant differences in blood plasma were found for Zn, Cu and Fe in patients with HPN and in the control group (p > 0.05). The concentration of Mn in whole blood was significantly increased in HPN patients (p < 0.0001), while Se concentration in these patients was significantly decreased (p < 0.005). The concentration of Mn in the whole blood of 16 patients with cholestasis was significantly increased compared to the patients without cholestasis (p < 0.001). The Cu concentration was increased with no statistical significance.
In long-term HPN, the status of trace elements in the patients has to be continually monitored and the daily substitution doses of these elements have to be flexibly adjusted. Dosing schedule needs to be adjusted especially in cases of cholestatic hepatopathy. A discussion about the optimal daily dose of Mn in patients on HPN is appropriate. For clinical practice, the availability of a substitution mixture of trace elements lacking Mn would be advantageous.
Zebrafish were exposed to a nonlethal dose (1/350LC50; 50µg/L) of As2O3 and sampled at 7, 15, 30, 60 and 90 days of treatment. The oxidative stress response was assessed in terms of time-dependent histopathological changes, lipid peroxidation, GSH status, activities of detoxification enzymes and expression of antioxidant genes in liver and kidney. As2O3 treatment enhanced lipid peroxidation except at day 90 in liver and day 30 in kidney. Glutathione depleted significantly in the liver except on day 30; whereas in kidney, it increased initially but thereafter depleted significantly. The liver GST activity was high until day 30, low on day 60 and high on day 90. On the other hand, activity of GST in kidney remained high throughout the exposure. GR activity in liver decreased initially but augmented from 30 days onwards whereas in kidney it remained high until 30 days of exposure. Significant increase in GPx and CAT activities in liver and kidney confirmed oxidative stress in zebrafish which correlated with mRNA expression of antioxidant genes. Upregulation in mRNA level of Cu-Zn Sod in liver and kidney was prominent. Gpx1 upregulation was more conspicuous in kidney as compared to liver while the pattern of Cat expression was almost similar in both the organs. Among the mitochondrial genes, expression of Cox1 was significantly high only after 90 days in liver, while in kidney it enhanced at 7, 30 and 60 days of arsenic exposure. Ucp2 was upregulated in liver after 15 days of exposure but significantly downregulated at day 90; in kidney it remained unchanged at other time points except at day 90. An overall increased expression of Bcl2 further confirmed As2O3 induced oxidative stress in zebrafish liver and kidney. The pattern of mRNA expression of Nrf2 was not uniform and was in accordance to its downstream antioxidant genes. Present findings elucidate that low dose of As2O3 exposure induces a time dependent differential modulation of antioxidant status in liver and kidney of zebrafish in a tissue-specific manner.
We have designed and synthesized an isoreticular series of luminescent metal-organic frameworks (LMOFs) by incorporating a strongly emissive molecular fluorophore and functionally diverse colinkers into Zn-based structures. The three-dimensional porous networks of LMOF-261, -262, and -263 represent a unique/new type of nets, classified as a 2-nodal, (4,4)-c net (mot-e type) with 4-fold, class IIIa interpenetration. All compounds crystallize in a body-centered tetragonal crystal system (space group I41/a). A systematic study has been implemented to analyze their interactions with heavy metals. LMOF-263 exhibits impressive water stability, high porosity, and strong luminescence, making it an excellent candidate as a fluorescent chemical sensor and adsorbent for aqueous contaminants. It is extremely responsive to toxic heavy metals at a parts per billion level (3.3 ppb Hg(2+), 19.7 ppb Pb(2+)) and demonstrates high selectivity for heavy metals over light metals, with detection ratios of 167.4 and 209.5 for Hg(2+)/Ca(2+) and Hg(2+)/Mg(2+), respectively. Mixed-metal adsorption experiments also show that LMOF-263 selectively adsorbs Hg(2+) over other heavy metal ions in addition to light metals. The Pb(2+) KSV value for LMOF-263 (55,017 M(-1)) is the highest among LMOFs reported to date, and the Hg(2+) KSV value is the second highest (459,446 M(-1)). LMOF-263 exhibits a maximum adsorption capacity of 380 mg Hg(2+)/g. The Hg(2+) adsorption process follows pseudo-second-order kinetics, removing 99.1% of the metal within 30 min. An in situ XPS study provides insight to help understand the interaction mechanism between Hg(2+) and LMOF-263. No other MOFs have demonstrated such a high performance in both the detection and the capture of Hg(2+) from aqueous solution.
The hypothesis of metal defense as a substitute for a defective biotic stress signaling system in metal hyperaccumulators was tested using the pathosystem Alternaria brassicicola-Noccaea caerulescens under low (2 µM), medium (12 µM) and high (102 µM) Zn supply. Regardless the Zn supply, N. caerulescens responded to fungal attack with the activation of both HMA4 coding for a Zn transporter, and biotic stress signaling
 pathways. Salicylate, jasmonate, abscisic acid and indoleacetic acid concentrations, as well as biotic stress marker genes (PDF1.2, CHIB, LOX2, PR1 and BGL2) were activated 24 h upon inoculation. Based on the activation of defense genes 24 h after the inoculation an incompatible fungal-plant interaction could be predicted. Nonetheless, in the longer term (7 days) no effective protection against A. brassicicola was achieved in plants exposed to low and medium Zn supply. After 1 week the biotic stress markers were even further increased in these plants, and this compatible interaction was apparently not caused by a failure in the signaling of the fungal attack, but due to the lack of specificity in the type of the activated defense mechanisms. Only plants receiving high Zn exhibited an incompatible fungal interaction. High Zn accumulation in these plants, possibly in cooperation with high glucosinolate concentrations, substituted for the ineffective defense system and the interaction turned into incompatible. In a threshold-type response, these joint effects efficiently hampered fungal spread and, consequently decreased the biotic stress signaling.
This study investigates the contamination levels and risk assessments of 14 elements (Ba, Cd, Co, Cr, Cu, Pb, Li, Mn, Mo, Ni, Sb, Sr, V and Zn) in three sub-basins of Himalayan rivers. Water samples were collected and the hazard quotient (HQ), hazard index (HI), and water quality index (WQI) were calculated. Total average concentrations of the metals were 135.03, 80.10 and 98.34 µg/L in Gandaki, Indrawati and Dudh Koshi rivers, respectively. The results of HQ and HI were less than unity, suggesting a low risk of metals in the region. However, HQ for antimony (Sb) was found to be 4.4 × 10(-1), 2.1 × 10(-1) and 5.4 × 10(-1) in three river basins and HI near unity, suggesting its potential risk. Additionally, HI for Cd in Indrawati was 5.4 × 10(-1) also close to unity, suggesting that Cd could have a potential risk to the local residents and aquatic ecosystems. Further, WQI suggested that the rivers Gandaki and Indrawati fell into the excellent water quality and river Dudh Koshi fell into good water quality.
Biofortification of rice (Oryza sativa L.) with micronutrients is widely recognized as a sustainable strategy to alleviate human iron (Fe) and zinc (Zn) deficiencies in developing countries where rice is the staple food. Constitutive overexpression of the rice nicotianamine synthase (OsNAS) genes has been successfully implemented to increase Fe and Zn concentrations in unpolished and polished rice grain. Intensive research is now needed to couple this high-micronutrient trait with high grain yields. We investigated associations of increased grain Fe and Zn concentrations with agro-morphological traits of backcross twice second filial (BC2F2) transgenic progeny carrying OsNAS1 or OsNAS2 overexpression constructs under indica/japonica and japonica/japonica genetic backgrounds. Thirteen agro-morphological traits were evaluated in BC2F2 transgenic progeny grown under hydroponic conditions. Concentrations of eight mineral nutrients (Fe, Zn, copper, manganese, calcium, magnesium, potassium, and phosphorus) in roots, stems/sheaths, non-flag leaves, flag leaves, panicles, and grain were also determined. A distance-based linear model (DistLM) was utilized to extract plant tissue nutrient predictors accounting for the largest variation in agro-morphological traits differing between transgenic and non-transgenic progeny. Overall, the BC2F2 transgenic progeny contained up to 148% higher Fe and 336% higher Zn concentrations in unpolished grain compared to non-transgenic progeny. However, unpolished grain concentrations surpassing 23 μg Fe g(-1) and 40 μg Zn g(-1) in BC2F2indica/japonica progeny, and 36 μg Fe g(-1) and 56 μg Zn g(1) in BC2F2japonica/japonica progeny, were associated with significant reductions in grain yield. DistLM analyses identified grain-Zn and panicle-magnesium as the primary nutrient predictors associated with grain yield reductions in the indica/japonica and japonica/japonica background, respectively. We subsequently produced polished grain from high-yield BC2F2 transgenic progeny carrying either the OsNAS1 or OsNAS2 overexpression constructs. The OsNAS2 overexpressing progeny had higher percentages of Fe and Zn in polished rice grain compared to the OsNAS1 overexpressing progeny. Results from this study demonstrate that genetic background has a major effect on the development of Fe and Zn biofortified rice. Moreover, our study shows that high-yielding rice lines with Fe and Zn biofortified polished grain can be developed by OsNAS2 overexpression and monitoring for Zn overaccumulation in the grain.
A novel lipid nanocapsule with high physical stability and the ability to undergo a water-responsive morphological change was prepared using a facile method from inexpensive and simple materials such as a glycylglycine-containing lipid and zinc acetate. The zinc-coordinated nanocapsule is comprised of solid bilayer membranes, which are stabilized by polyglycine-II type hydrogen-bond network and Zn-lipid coordination resulting in a high thermal stability in the dry state. The nanocapsules can easily encapsulate guest molecules such as methylene blue in the hollow space by dissolving the molecules in ethanol during preparation. When placed in an aqueous environment, the nanocapsules showed distinctive morphological changes and subsequent release of the methylene blue.
Mine-impacted water (MIW) is one of the most serious mining problems and has a high negative impact on water resources and aquatic life. The main characteristics of MIW are a low pH (between 2 and 4) and high concentrations of SO4(2-) and metal ions (Cd, Cu, Ni, Pb, Zn, Fe, Al, Cr, Mn, Mg, etc.), many of which are toxic to ecosystems and human life. Shrimp shell was selected as a MIW treatment agent because it is a low-cost metal-sorbent biopolymer with a high chitin content and contains calcium carbonate, an acid-neutralizing agent. To determine the best metal-removal conditions, a statistical study using statistical planning was carried out. Thus, the objective of this work was to identify the degree of influence and dependence of the shrimp-shell content for the removal of Fe, Al, Mn, Co, and Ni from MIW. In this study, a central composite rotational experimental design (CCRD) with a quadruplicate at the midpoint (2(2)) was used to evaluate the joint influence of two formulation variables-agitation and the shrimp-shell content. The statistical results showed the significant influence (p < 0.05) of the agitation variable for Fe and Ni removal (linear and quadratic form, respectively) and of the shrimp-shell content variable for Mn (linear form), Al and Co (linear and quadratic form) removal. Analysis of variance (ANOVA) for Al, Co, and Ni removal showed that the model is valid at the 95% confidence interval and that no adjustment needed within the ranges evaluated of agitation (0-251.5 rpm) and shrimp-shell content (1.2-12.8 g L(-1)). The model required adjustments to the 90% and 75% confidence interval for Fe and Mn removal, respectively. In terms of efficiency in removing pollutants, it was possible to determine the best experimental values of the variables considered as 188 rpm and 9.36 g L(-1) of shrimp-shells.
Zinc oxide nanoparticles (nano-ZnOs) are widely used and possess great potentials in agriculture and biomedicine. It is inevitable for human exposure to these nanoparticles. However, no study had been conducted to investigate the long term effects of nano-ZnOs. This study aimed at investigating effects of nano-ZnOs on development, zinc metabolism and biodistribution of minerals (Zn, Fe, Cu, and Mn) in mice from week 3 to 35. After the characteristics of nano-ZnOs were determined, they were added into the basal diet at 0, 50, 500 and 5000 mg/kg. Results indicated that added 50 and 500 mg/kg nano-ZnOs showed minimal toxicity. However, 5000 mg/kg nano-ZnOs significantly decreased body weight (from week 4 to 16) and increased the relative weights of the pancreas, brain and lung. Added 5000 mg/kg nano-ZnOs significantly increased the serum glutamic-pyruvic transaminase activity and zinc content, and significantly enhanced mRNA expression of zinc metabolism-related genes, including metallothionein 1(32.66 folds), metallothionein 2 (31.42 folds), ZIP8 (2.21folds), ZIP14 (2.45 folds), ZnT1 (4.76 folds), ZnT2 (6.19 folds) and ZnT4 (1.82 folds). The biodistribution determination showed that there was a significant accumulation of zinc in the liver, pancreas, kidney, and bones (tibia and fibula) after receiving 5000 mg/kg nano-ZnO diet, while no significant effects on Cu, Fe, and Mn levels, except for liver Fe content and pancreas Mn level. Our results demonstrated that long term exposure to 50 and 500 mg/kg nano-ZnO diets showed minimal toxicity. However, high dose of nano-ZnOs (5000 mg/kg) caused toxicity on development, and altered the zinc metabolism and biodistribution in mice.
Interest in the consumption of insects (entomophagy) as an alternative environmentally sustainable source of protein in the diet of humans has recently witnessed a surge. Knowledge of the nutrient composition and, in particular, the bioavailability of minerals from insects is currently sparse. This study evaluated the availability of Fe, Ca, Cu, Mg, Mn, and Zn from four commonly eaten insects and compared these to sirloin beef. Soluble iron from the samples was measured by inductively coupled plasma optical emission spectrometry (ICP-OES). Iron bioavailability was determined using an in vitro simulated peptic-pancreatic digestion, followed by measurement of ferritin (a surrogate marker for iron absorption) in Caco-2 cells. Cricket and sirloin beef had comparably higher levels of Fe, Ca, and Mn than grasshopper, meal, and
 buffalo worms. However, iron solubility was significantly higher from the insect samples than from beef. The complementation of whole-wheat flour with insect or beef protein resulted in overall decreases in mineral content and iron solubility in the composite mixtures. Collectively, the data show that grasshopper, cricket, and mealworms contain significantly higher chemically available Ca, Cu, Mg, Mn, and Zn than sirloin. However, buffalo worms and sirloin exhibited higher iron bioavailability comparable to that of FeSO4. Commonly consumed insect species could be excellent sources of bioavailable iron and could provide the platform for an alternative strategy for increased mineral intake in the diets of humans.
Ethambutoldihydrogenchloride (EMB) with chemical formula C10H24N2O2.2HCl is ethane-1,2-diamine in which one hydrogen attached to each of the nitrogen is substituted by a 1-hydroxybutan-2-yl group (S,S-configuration). It is an FDA approved drug and has been used for treatment of tuberculosis since 1960's. Prolong use of EMB has a side effect of visual impairment and in literature it is related with the depletion of Zn metal from the body. As it is a good chelating agent, many metal II complexes have been synthesized with anti-tubercular activity. The purpose of this work was to synthesize metal II complexes of EMB and to evaluate their antioxidant activity along with enzyme inhibition activity (acetylcholine esterase and protease). The metals used for complex formation were Co, Zn, Fe, Cu and Ni. IR spectral data and physical parameters supported the complex formation. The obtained results showed the synthesized complexes as notable antioxidants and enzyme inhibitors.
A comprehensive and detailed investigation of heavy metal pollution, toxicity, and ecological risk assessment was conducted for the surface river sediments of the Haihe Basin in China based on 220 sampling sites selected in 2013. The average concentrations of Cr, Cu, Ni, Pb, and Zn in the sediments were 129 mg/kg, 63.4 mg/kg, 36.6 mg/kg, 50.0 mg/kg, and 202 mg/kg, respectively. As indicated by the geoaccumulation and pollution load indices, most surface river sediments of the Haihe Basin were contaminated with the investigated metals, especially in the junction region of the Zi Ya He and Hei Long Gang watersheds. The 5 heavy metals in the sediments all had anthropogenic sources, and the enrichment degrees followed the order Cu > Pb > Zn > Cr > Ni, with mean enrichment factors of 3.27, 2.77, 2.58, 1.81, and 1.44, respectively. According to the mean index of comprehensive potential ecological risk (38.9), the studied sediments of the Haihe Basin showed low potential ecological risk, but the sediments were potentially biologically toxic based on the mean probable effect concentration quotient (0.547), which may be the result of speciation of the 5 metals in the sediments. The results indicate that heavy metal pollution should be considered during the development of ecological restoration strategies in the Haihe Basin. Environ Toxicol Chem 2016;9999:1-7. © 2016 SETAC.
Here, we have developed an organic photocathode for water reduction to H2 , delivering more than 1 mA cm(-2) at 0 V versus RHE and above 3 mA cm(-2) at -0.5 V versus RHE with moderate stability under neutral pH conditions. The initial competitive reduction of water to H2 and ZnO to metallic Zn is responsible for the dynamic behaviour of both photocurrent and Faradaic efficiency of the device, which reaches 100 % Faradaic efficiency after 90 min operation. In any case, outstanding stable H2 flow of approximately 2 μmol h(-1) is measured over 1 h at 0 V versus RHE and at neutral pH, after equilibrium between the Zn(2+) /Zn(0) concentration in the AZO film is reached. This achievement opens new avenues for the development of allsolution-processed organic photoelectrochemical cells for the solar generation of H2 from sea water.
We report a combined approach that introduces the use of 4-aminobenzo-15-crown-5 (4AB15C5) for the detection of ferric(III) ions by colorimetric, ultraviolet (UV)-visible light absorption, fluorescence, and live-cell imaging techniques along with density functional theory (DFT) calculations. We have found that 4AB15C5 is sensitive and selective for binding ferric(III) ions in aqueous solutions. DFT calculations using the polarizable continuum model have been used to explain the strong binding of the ferric ion by 4AB15C5 in aqueous solutions. The detection limit in the fluorescence quenching measurements was found to be as low as 50 μM for the ferric ion with a determined Stern-Volmer constant of 1.52 × 10(4)  M(-1) . Fluorescence intensity did not change for other ions tested, Fe(2)(+) , Co(2)(+) , Mn(2)(+) , Mg(2)(+) , Zn(2)(+) , Ca(2)(+) , NH4(+) , Na(+) , and K(+) ions. Live-cell fluorescence imaging was also used to check the intracellular variations in ferric ion levels. Our spectroscopic data indicated that 4AB15C5 can bind ferric ions selectively in aqueous solutions.
Bacteriochlorophyll a (BChl a), a photosynthetic pigment performing the same functions of chlorophylls in plants, features a bacteriochlorin macrocycle ring (18 π electrons) with two reduced pyrrole rings along with a hydrophobic terpenoid side chain (i.e., the phytol residue). Chlorophylls analysis by matrix-assisted laser desorption/ionization mass spectrometry (MALDI MS) is not so straightforward since pheophytinization (i.e., release of the central metal ion) and cleavage of the phytol-ester linkage are invariably observed by employing protonating matrices such as 2,5-dihydroxybenzoic acid, sinapinic acid, and α-cyano-4-hydroxycinnamic acid. Using BChl a from Rhodobacter sphaeroides R26 strain as a model system, different electron-transfer (ET) secondary reaction matrices, leading to the formation of almost stable radical ions in both positive ([M](+•)) and negative ([M](-•)) ionization modes at m/z 910.55, were evaluated. Compared with ET matrices such as trans-2-[3-(4-t-butyl-phenyl)-2-methyl-2-propenylidene]malononitrile (DCTB), 2,2':5',2''-terthiophene (TER), anthracene (ANT), and 9,10-diphenylanthracene (DP-ANT), 1,5-diaminonaphthalene (DAN) was found to provide the highest ionization yield with a negligible fragmentation. DAN also displayed excellent ionization properties for two metal ion-substituted bacteriochlorophylls, (i.e., Zn- and Cu-BChl a at m/z 950.49 and 949.49), respectively. MALDI MS/MS of both radical charged molecular species provide complementary information, thus making analyte identification more straightforward. Graphical Abstract ᅟ.
A microbial treatment of Cr(6+) contaminated wastewater with a chromium reducing bacteria isolated from coal mine area was investigated. In a series of batch study metal removal was executed under different parametric conditions which include pH (2-7), temperature (20-50 °C), initial Cr(6+) concentration (1-100 mg/L), substrate utilization and its overall effect on biomass generation. Impact of oxygen availability was checked at different agitation speed and its role on the remedial process. Liquid phase reduction of Cr(6+) was measured in terms of substrate reduction and total biomass yield. The bacterium species isolated was able to tolerate Cr(6+) over a wide range from 1 to 100 mg/L before it reached minimum inhibition concentration. Apart from Cr(6+), the bacterial isolate showed tolerance towards Fe, As, Cu, Ag, Zn, Mn, Mg and Pb. Removal mechanism adopted by the bacterium recommended that it employed accumulation of Cr(6+) as Cr(3+) both within and outside the cell. Classical Monod equation was used to determine the biokinetics of the bacterial isolate along with the interference of metal ion concentration and substrate utilization. Cr(6+) removal was found prominent even in bimetallic solutions. The bacterial isolate was confirmed to be Rhodococcus erythopolis by 16s rRNA molecular characterization. Thus the bacterial isolate obtained from the coal mine area proved to be a potential agent for microbial remediation of Cr(6+) laden waste water.
We investigate a new case of a self-assembly-stimulated self-assembly in which a triblock polypeptide is combined with a anionic coordination polymer of a dipicolinic acid bis-ligand, and d- or f- block metal ions like Zn(II) or Eu(III) . The polypeptide not only has a silk-like domain that can fold and stack, but also a C-terminal cationic sequence by which it can interact with the supramolecular (coordination) polyanion. In the presence of all three ingredients (polypeptide, bis-ligand, and metal ions), we observe the initiation and slow growth of well-defined metal-containing nanorods of up to 150 nm in length, proving that self-assembly of the polypeptide is triggered by the self-assembly of the coordination polyelectrolyte and vice versa. The particles, which have a striking resemblance to rod-like viruses, are stable up to 1.2 m NaCl, and can be made fluorescent when lanthanides like Eu(III) are used, showing the potential to exploit functional properties and applications of virus-like supramolecular structures.
A common property of Cu/Zn superoxide dismutase 1 (SOD1), harboring mutations associated with amyotrophic lateral sclerosis, is a high propensity to misfold and form abnormal aggregates. The aggregation of mutant SOD1 has been demonstrated in vitro, with purified proteins, in mouse models, in human tissues, and in cultured cell models. In vitro translation studies have determined that SOD1 with amyotrophic lateral sclerosis mutations is slower to mature, and thus perhaps vulnerable to off-pathway folding that could generate aggregates. The aggregation of mutant SOD1 in living cells can be monitored by tagging the protein with fluorescent fluorophores. In this study, we have taken advantage of the Dendra2 fluorophore technology in which excitation can be used to switch the
 output color from green to red, thereby clearly creating a time stamp that distinguishes pre-existing and newly made proteins. In cells that transiently over-express the Ala 4 to Val variant of SOD1-Dendra2, we observed that newly made mutant SOD1 was rapidly captured by pathologic intracellular inclusions. In cell models of mutant SOD1 aggregation over-expressing untagged A4V-SOD1, we observed that immature forms of the protein, lacking a Cu co-factor and a normal intramolecular disulfide, persist for extended periods. Our findings fit with a model in which immature forms of mutant A4V-SOD1, including newly made protein, are prone to misfolding and aggregation.
The present study was conducted to assess the trace element concentration in marine surface sediments after major flood event of Chennai metropolis, India. Thirty surface samples were collected from off Chennai coast. Trace elements, organic matter, CaCO3, sand-silt-clay and C/N ratios were studied to understand the accumulation dynamics on sediments. The elemental concentration, calcium carbonate and OM distribution suggest that they are derived from urban runoff and transported through Adyar and Cooum Rivers. The enrichment factor reveals that the sediments are enriched by Pb, Cu, Zn, Cr, Co, Ni followed by Fe. The observed Igeo value shows that the samples are contaminated by Pb, Cu and Zn. The elemental concentration of the surface sediments is low when compared to other coastal region except Pb. The elevated level of Pb in the surface sediments is probably due to migration of contaminated urban soil from industrial and transportation sectors into marine environment.
Phytomining could represent an innovative low-cost technology for the selective recovery of valuable trace elements from secondary resources. In this context the potential of phytomining from waste incineration bottom ash was tested in a pot experiment. Fresh bottom ash was acidified, leached to reduce salinity and amended with organic material to obtain a suitable substrate for plant growth. Two hyperaccumulator species, Alyssum serpyllifolium subsp. lusitanicum and Sedum plumbizincicola as well as three metal tolerant species, Brassica napus, B. juncea and Nicotiana tabacum were tested for their phytomining potential on the pre-treated and amended bottom ashes from municipal solid waste and hazardous waste incineration. The hyperaccumulators had severe difficulties to establish on the bottom ash and to produce sufficient biomass, likely due to salinity and Cu toxicity. Nevertheless, concentrations of Ni in A. serpyllifolium and Zn in S. plumbizincicola were high, but total metal removal was limited by the low biomass production and was clearly less than on metalliferous soils. The Brassica species proved to be more tolerant to salinity and high Cu concentrations and produced considerably higher biomass, but total metal removal was limited by rather low shoot concentrations. The observed limitations of the phytomining process along with currently low market prices of Ni and Zn suggest that further optimisation of the process is required in order to make phytomining economically feasible on the tested waste incineration bottom ashes.
The Saigon River, Southern Vietnam, crosses one of the most dynamic developing Megacity in Southeast Asia: Ho Chi Minh City (HCMC). The increased economic, industrial, and domestic developments may affect the environmental quality of water and halieutic resources. In this study, we evaluated the seasonal (dry and wet seasons) biogeochemical state of the Saigon River during two snapshot campaigns conducted along the river basin upstream from HCMC; the Saigon River was characterized by slightly acidic (pH 5.7-7.7) and oxygen-depleted water (dissolved oxygen (DO), 0.36-5.18 mg l(-1)). Nutrients (N-NH4 = 0.01-2.41, N-NO3 = 0.14-2.72, and P-PO4 = ~0-0.42 mg l(-1)), DOC (2.2-8.0 mg l(-1)), POC, and trace metal(oid) (As, Cd, Cr, Cu, Zn, and Hg) concentrations were low showing a good quality of the upstream river. In the urban center area, DO dropped to 0.03 mg l(-1) accompanied with a rise of nutrient concentrations (e.g., N-NH4, up to 17.7 mg l(-1)) likely originating from wastewater discharges. Trace metal concentrations also rose sharply (e.g., Cr and Hg rose up to 10-fold higher) in both water and sediments but remained under the World Health Organization (WHO) and Vietnamese concentration guidelines. In the downstream estuarine area, the intrusion of marine waters diluted water flowing from HCMC, leading water quality to return close to the state observed upstream from HCMC. In general, levels of nutrient and metal contaminations along the Saigon River during both seasons appear moderate regarding to Vietnamese and WHO guidelines although the urban area is highlighted as the major contributor for metal(oid) emissions. Finally, we showed that apart from wastewater and industrial discharges that affect the river quality, metal(oid) partitioning between solid and solution is controlled by the change in water geochemistry along the continuum during both seasons, such as DO (e.g., for As and Cr) and pH (e.g., for Pb) which drives their sorption/dissolution dynamics.
Fine aerosol fraction (particulate matter with aerodynamic diameter <= 1.0 μm (PM)1.0) over the Indian Institute of Technology Delhi campus was monitored day and night (10 h each) at 30 m height from November 2009 to March 2010. The samples were analyzed for 5 ions (NH4(+), NO3(-), SO4(2-), F(-), and Cl(-)) and 12 trace elements (Na, K, Mg, Ca, Pb, Zn, Fe, Mn, Cu, Cd, Cr, and Ni). Importantly, secondary aerosol (sulfate and nitrate) formation was observed during dense foggy events, supporting the fog-smog-fog cycle. A total of 76 samples were used for source apportionment of PM mass. Six factors were resolved by PMF analyses and were identified as secondary aerosol, secondary chloride, biomass burning, soil dust, iron-rich source, and vehicular emission. The geographical location of the sources and/or preferred transport pathways was identified by conditional probability function (for local sources) and potential source contribution function (for regional sources) analyses. Medium- and small-scale metal processing (e.g. steel sheet rolling) industries in Haryana and National Capital Region (NCR) Delhi, coke and petroleum refining in Punjab, and thermal power plants in Pakistan, Punjab, and NCR Delhi were likely contributors to secondary sulfate, nitrate, and secondary chloride at the receptor site. The agricultural residue burning after harvesting season (Sept-Dec and Feb-Apr) in Punjab, and Haryana contributed to potassium at receptor site during November-December and March 2010. The soil dust from North and East Pakistan, and Rajasthan, North-East Punjab, and Haryana along with the local dust contributed to soil dust at the receptor site, during February and March 2010. A combination of temporal behavior and air parcel trajectory ensemble analyses indicated that the iron-rich source was most likely a local source attributed to emissions from metal processing facilities. Further, as expected, the vehicular emissions source did not show any seasonality and was local in origin.
Plants are a rich source of elements, and knowledge of their elemental composition determines their use for various purposes, especially for food and medicine. Therefore, it is necessary to create a database of the elemental composition of plants. The present review focuses on the concentration of various heavy metals as reported by various workers from time to time by using different sophisticated techniques. Cluster analysis was applied on the basis of mean values of heavy metals in plants. Co, Cu, and Cr have similar proximities. Cluster analysis was also applied to different families on the basis of their heavy metal contents. Elaeagnaceae, Adoxaceae, Thymelaeaceae, Cupressaceae, and Acoraceae had close proximities with each other. First three components of principal component analysis explained 95.7 % of the total variance. Factor analysis explained four underlying factors for heavy metal analysis. Factor 1 explained for 26.5 % of the total variance and had maximum loadings on Co, Cu, and Cr. Of the total variance, 21.7 % was explained by factor 2 and had maximum loadings on Zn and Cd. Factor 3 accounted for 19.2 % of the total variance and had maximum loadings on Ni and Pb. Mn had maximum loading on factor 4. The mean values of heavy metals as listed in this paper are Cu (18.7 μg/g dw), Mn (99.67 μg/g dw), Cr (22.9 μg/g dw), Co (19.7 μg/g dw), As (1.25 μg/g dw), Hg (0.17 μg/g dw), Zn (94.0 μg/g dw), Pb (6.93 μg/g dw), Cd (26.9 μg/g dw), Ni (19.9 μg/g dw), and Sb (0.25 μg/g dw).
The majority of rivers in the world have been dammed, and over 45,000 large reservoirs have been constructed for multiple purposes. Riparian and reservoir shorelines are the two most important wetland types in a dammed river. To date, few studies have concerned the heavy metal pollution in wetland soils of these river-reservoir systems. In this study, we measured the concentrations of ten heavy metals (Ba, Cd, Co, Cr, Cu, Mn, Ni, Pb, Sr, and Zn) in surface soils collected from riparian and reservoir shorelines along the Han River in different seasons. Our results found that the Co, Cu, and Ni concentrations in riparian wetlands were significantly lower than those in reservoir shorelines. In riparian wetlands, only soil Sr concentration significantly increased after summer and autumn submergence. Multivariate statistical analyses demonstrated that Ba and Cd might originate from industrial and mining sources, whereas Sr and Mn predominantly originated from natural rock weathering. The ecological risk assessment analysis indicated that both riparian and reservoir shorelines along the Han River in China exhibited a moderate ecological risk in soil heavy
 metals. The upper Han River basin is the water resource area of China's Middle Route of the South-to-North Water Transfer Project. Therefore, to control the contamination of heavy metals in wetland soils, more efforts should be focused on reducing the discharge of mining and industrial pollutants into the riparian and reservoir shorelines.
The present study investigates the alkaline modification of raw orange tree sawdust (ROS) for an optimal removal of methylene blue (MB), as a cationic dye model, from synthetic solutions. The effects of operating parameters, namely, sodium hydroxide (NaOH) concentrations, ROS doses in NaOH solutions, stirring times, and initial MB concentrations on dye removal efficiency, were followed in batch mode. The process optimization was performed through the response surface methodology approach (RSM) by using Minitab17 software. The results showed that the order of importance of the followed parameters was NaOH treatment concentrations > stirring times > initial MB concentrations > ROS doses in NaOH solutions. The optimal experimental conditions ensuring the maximal MB removal efficiency was found for a NaOH treatment concentration of 0.14 M, a stirring time of 1 h, a ROS dose in NaOH solutions of 50 g L(-1), and an initial MB concentration of 69.5 mg L(-1). Specific analyses of the raw and alkali-treated biomasses, e.g., SEM/EDS and XRD analyses, demonstrated an important modification of the crystalline structure of the wooden material and a significant increase in its surface basic functional groups. Kinetic and isotherm studies of MB removal from synthetic solutions by ROS and the alkali-treated material (ATOS) showed that for both adsorbents, the pseudo-second-order and Langmuir model fitted the best the experimental data, respectively, which indicates that MB removal might be mainly a chemical and a monolayer process. Furthermore, thanks to the chemical modification of the ROS, the MB maximal uptake capacity has increased from about 39.7 to 78.7 mg g(-1). On the other hand, due to the competition phenomenon, the coexistence of MB and Zn(II) ions could significantly decrease the MB removal efficiency. A maximal decrease of about 32 % was registered for an initial Zn(II) concentration of 140 mg L(-1). Desorption experiments undertaken at natural pH (without adjustment: pH = 6) and with different NaCl concentrations emphasized that the adsorbed MB could be significantly desorbed from both the tested materials, offering their possible reuse as efficient adsorbents. All these results confirmed that NaOH-treated orange tree sawdust could be considered as an efficient, economic, and ecological alternative for the removal of cationic dyes from industrial wastewaters.
Growth inhibition and antioxidative response were investigated in wheat roots cultured in 1/4 Hoagland solution containing zinc (Zn, 500 μM), iron (Fe, 300 μM), and copper (Cu, 300 μM) in combination. Different Zn, Fe, and Cu interactions inhibited seedling growth and increased Zn, Fe, and Cu contents in roots and shoots, with the most significant inhibition due to Zn + Fe + Cu treatment. The elevation of malondialdehyde content and the loss of cell viability resulted from the increases of total and apoplastic hydrogen peroxide (H2O2) and hydroxyl radical (·OH) contents in all treated roots. Except for Zn + Fe stress, root superoxide anion (O2(•-)) level significantly decreased at other combined treatments. The application of 10 μM diphenylene iodonium suggested that NADPH oxidase activity was lower in Fe + Cu-treated and Zn + Fe + Cu-treated roots than in other roots. Additionally, all combined treatments inhibited superoxide dismutase (SOD) and peroxidase (POD) but stimulated total glutathione reductase (GR) activity in roots. However, in root apoplast, decreased SOD and ascorbate peroxidase activities as well as increased POD, catalase, and GR activities were caused by different Zn, Fe, and Cu interactions. In conclusion, combined Zn, Fe, and Cu stresses exhibited significant inhibition on root growth, with the strongest effect due to Zn + Fe + Cu. Here, it is also indicated that each antioxidantive enzyme including apoplastic enzymes showed specific responses and that the stimulation of some of them played an important protective mechanism against oxidative damage, when wheat roots were treated with different Zn, Fe, and Cu treatments in combination.
The emulsification of metal-organic frameworks (MOFs) for the two immiscible phases of water and ionic liquid (IL) was investigated for the first time. It was found that Ni-BDC (BDC = 1,4-dicarboxybenzene) can emulsify water and ILs and favor the formation of high internal phase emulsions (HIPEs) under certain experimental conditions. The microstructures of the HIPEs were characterized by confocal laser scanning microscopy using a fluorescent dye Rhodamine B, which proves that the HIPEs are the IL-in-water type. Further results reveal that the HIPE forms during the IL-in-water to water-in-IL emulsion inversion. The possibilities of the HIPE formation by other MOFs (Cu-BDC and Zn-BDC) were explored and the mechanism for HIPE formation was discussed. The MOF-stabilized HIPE was applied to the in situ synthesis of a MOF/polymer composite by HIPE polymerization. The macroporous MOF/polyacrylamide network and MOF/polystyrene microspheres were obtained from the HIPEs, respectively.
Random mutagenesis in a symbiotic nitrogen-fixing Bradyrhizobium liaoningense CCNWSX0360 (Bln0360) using Tn5 identified five copper (Cu) resistance-related genes. They were functionally sorted into three groups: transmembrane transport (cueA and tolC); oxidation (copA); and protection of the membrane barrier (lptE and ctpA). The gene cueA, together with the upstream csoR (Cu-sensitive operon repressor), constituted a csoR-cueA divergon which plays a crucial role in Cu homeostasis. Deletion of cueA decreased the Cu tolerance of cells, and complementation of this mutant restored comparable Cu resistance to that of the wild-type. Transcriptional and fusion expression analysis demonstrated that csoR-cueA divergon was up-regulated by both the monovalent Cu(+) and divalent Zn(2+)/Cd(2+), and negatively regulated by transcriptional repressor CsoR, via a bidirectional promoter. Deletion of csoR renders the cell hyper-resistant to Cu, Zn and Cd. Although predicted to encode a Cu transporting P-type ATPase (CueA), cueA also conferred resistance to zinc and cadmium; two putative N-MBDs (N-terminal metal binding domains) of CueA were required for the Cu/Zn/Cd tolerance. Moreover, cueA is needed for nodulation competitiveness of B. liaoningense in Cu rich conditions. Together, the results demonstrated a crucial role for the csoR-cueA divergon as a component of the multiple-metal resistance machinery in B. liaoningense.
A self-catenated Zn(II)-organic framework formulated as [Zn2(3,3'-bpeab)(oba)2]·DMF (1) exhibiting a six-connected 4(4)·6(10)·8 topology has been successfully synthesized through the mixed-ligand of kinked 3,3'-bis[2-(4-pyridyl)ethenyl]azobenzene (3,3'-bpeab) and 4,4'-oxybis-benzoic acid (H2oba) under solvothermal condition. UV light triggers isomerization of complex 1 in a single-crystal-to-single-crystal (SCSC) manner, giving rise to a conformational supramolecular isomer 1_UV through the pedal motion of photoresponsive double bonds. Dynamic photo-switching in the obtained light-responsive supramolecular isomers leads to instantly reversible CO2 uptake. Furthermore, the ligand originated fluorescence emission of water-resistant complex 1 is selectively sensitive to 4-nitrotoluene (4-NT) owing to a higher quenching efficiency of the perilous explosive over other structurally similar nitroaromatics, prefiguring the potentials of 1 as a fluorescence sensor towards 4-NT in aquatic media.
We developed a novel Pb(2+)-sensor based on a microcantilever that was modified with a specific Pb(2+)-dependent DNAzyme molecule. This microcantilever sensor could detect Pb(2+) sensitively and selectively in an aqueous solution. Upon complexation with Pb(2+), the DNAzyme duplex unwinded and formed a G-quadruplex conformation, which led to an increase of repulsion between the DNAzyme molecules and a subsequent bending of the microcantilever. This microcantilever sensor could be regenerated, flowing through a strong Pb(2+) chelator, 1,4,7,10-tetraazacyclododecane- 1,4,7,10-tetraacetic acid. The detection limit of the microcantilever sensor for Pb(2+) ions is as low as 10(-8) M. The microcantilever sensor also exhibited a high selectivity to Pb(2+) over other metal ions such as Mg(2+), Fe(3+), Zn(2+), Ca(2+), and Cd(2+).
A simple and effective method for high-sensitivity NMR detection of selected compounds is reported. The method combines 1D NMR diffusion filter experiments and small monolayer-protected nanoparticles as high-affinity receptors. Once bound to the nanoparticles, the diffusion coefficient of the analyte decreases in such way that spectral editing based on diffusion filters can separate its signals from those of other mixture components. Using nanoparticles functionalized with Zn(2+) -triazacyclonane complexes, detection and identification of phosphorylated organic molecules can be achieved. Diphenyl phosphate can be detected at 25 micromolar concentration with good selectivity. The selectivity toward organic carboxylates is enhanced at pD=3.75. In these conditions, commercial tablets containing betamethasone phosphate and a large excess of benzoate could be successfully analyzed.
Infantile CLN1 disease, also known as infantile neuronal ceroid lipofuscinosis, is a fatal childhood neurodegenerative disorder caused by mutations in the CLN1 gene. CLN1 encodes a soluble lysosomal enzyme, palmitoyl protein thioesterase 1 (PPT1), and it is still unclear why neurons are selectively vulnerable to the loss of PPT1
 enzyme activity in infantile CLN1 disease. To examine the effects of PPT1 deficiency on several well-defined neuronal signaling and cell death pathways, different toxic insults were applied in cerebellar granule neuron cultures prepared from wild type (WT) and palmitoyl protein thioesterase 1-deficient (Ppt1 (-/-) ) mice, a model of infantile CLN1 disease. Glutamate uptake inhibition by t-PDC (L-trans-pyrrolidine-2,4-dicarboxylic acid) or Zn(2+)-induced general mitochondrial dysfunction caused similar toxicity in WT and Ppt1 (-/-) cultures. Ppt1 (-/-) neurons, however, were more sensitive to mitochondrial complex I inhibition by MPP(+) (1-methyl-4-phenylpyridinium), and had significantly decreased sensitivity to chemical anoxia induced by the mitochondrial complex IV inhibitor, sodium azide. Our results indicate that PPT1 deficiency causes alterations in the mitochondrial respiratory chain.
Dinuclear clathrochelate complexes with two, three, four, or five cyano groups in the ligand periphery were prepared following two distinct synthetic strategies: (a) zinc(ii)- or cobalt(ii)-templated polycondensation reactions of CN-functionalized arylboronic acids and phenoldioximes, or (b) postsynthetic cross-coupling reactions of polybrominated zinc(ii) clathrochelates with 4-cyanophenylboronic acid. The new clathrochelate complexes were used as metalloligands for the construction of heterometallic Zn(2+)/Ag(+) and Co(2+)/Ag(+) coordination polymers (CPs), which were characterized by single crystal X-ray diffraction and FT-IR. A one-dimensional CP was observed for ditopic clathrochelates, whereas two- and three-dimensional CPs were generated from tetra- and pentatopic metalloligands. The three-dimensional network is unique as it displays an unprecedented network topology with the point symbol (8·10(2))(8(2)·10(4))(8(2)·10)(8(3)·10(3)). Furthermore, it is a self-catenated net with an extremely high topological density.
We report the study of the resistance of archetypal MOFs (MILs, HKUST-1, UiO-66, and ZIF-8) under gamma irradiation. The different porous solids were irradiated with doses up to 1.75 MGy. All the MOFs constructed with transition metals (Cu(2+), Zn(2+), Zr(4+)) exhibit an evident destruction of the framework, whereas the compounds constructed with aluminium remain intact.
The rational design of nanoscale metal oxides with hollow structures and tunable porosity has stimulated tremendous attention due to their vital importance for practical applications. Here, we report the designed synthesis of ZnO/ZnCo2O4 hollow core-shell nanocages (HCSNCs) through a metal-organic framework (MOF) route. The strategy includes the synthesis of a zeolite imidazolate framework-8 (ZIF-8)/Co-Zn hydroxide core-shell nanostructure precursor and subsequent transformation to ZnO/ZnCo2O4 HCSNCs by thermal annealing of the as-prepared precursor in air. Various techniques were employed for characterization of the structure and morphology of the as-prepared ZnO/ZnCo2O4 HCSNCs. When applied as a gas sensing material, the ZnO/ZnCo2O4 HCSNCs show enhanced sensitivity to xylene when compared with ZnCo2O4 shells as well as ZnO nanocages (NCs). In addition, excellent reversibility and superior selectivity of the sensor were observed. The remarkable enhancement in the gas-sensing properties of the ZnO/ZnCo2O4 HCSNCs is attributed to their unique structure and a synergistic effect of ZnO and ZnCo2O4.
The chiral macrocyclic amines R-L and S-L derived from the 3 + 3 condensation of 2,6-diformylpyridine and (1R,2R)-1,2-diaminocyclohexane or (1S,2S)-1,2-diaminocyclohexane form enantiopure trinuclear Ni(ii) and Cu(ii) complexes [Ni3(L)(H2O)2Cl5]Cl and [Cu3(L)Cl4]Cl2 and form the dinuclear complex [Zn2(L)Cl2](ZnCl4) with Zn(ii). The X-ray crystal structures of these complexes indicate remarkably different conformations of the ligand and different binding modes of the chloride anions. The structure of the copper(ii) derivative [Cu3(R-L)Cl4]Cl2·CH3CN·7.5(H2O) indicates unsymmetrical conformation of the macrocycle with three dissimilar pentacoordinate copper(ii) ions bridged by chloride; the structure of [Ni3(R-L)(H2O)2Cl5]Cl·0.4CH3CN·4.2H2O is somewhat more symmetrical, with three Ni(ii) ions of distorted octahedral geometry, also bridged by a common chloride anion. On the other hand, the macrocycle is highly folded in [Zn2(R-L)Cl2](ZnCl4)·CHCl3·0.8CH3OH·3.7H2O, forming a cleft where the third Zn(ii) ion is held via electrostatic interactions as the ZnCl4(2-) anion. The magnetic data for [Cu3(R-L)Cl4]Cl2 indicate the coexistence of antiferromagnetic and ferromagnetic interactions within the quasi isosceles tricopper(ii) core (J = -85.6 cm(-1), j = 77.1 cm(-1)). Compound [Ni3(R-L)(H2O)2Cl5]Cl shows the presence of weak antiferromagnetic coupling (J = -2.56 cm(-1), j = -1.54 cm(-1)) between the three Ni(ii) ions.
The structures of thermoelectric ZnSb and Zn4Sb3 have been studied extensively as a function of temperature but not in detail as a function of pressure. High pressure single crystal X-ray diffraction data allow structure refinements of ZnSb and Zn4Sb3 up to 12.8(2) GPa and 10.6(2) GPa, respectively, and in contrast to previous reports without any signs of phase transitions. At high pressure a redistribution of Zn in Zn4Sb3 is present, which is distinctly different from the thermal response of the structure. Fitting of an equation of state resulted in bulk moduli of 45(2) and 48(1) GPa for ZnSb and Zn4Sb3, respectively.
The nutritional quality of green leafy vegetables can be enhanced by application of plant beneficial micro-organisms. The present study was aimed to increase the food values of lettuce leaves by bacterial treatment. We isolated bacterial strain KE2 from Kimchi food and identified as Bacillus methylotrophicus by phylogenetic analysis. The beneficial effect of B. methylotrophicus KE2 on plants was confirmed by increasing the percentage of seed germination of Lactuca sativa L., Cucumis melo L., Glycine max L. and Brassica juncea L. It might be the secretion of array of gibberellins (GA1, GA3, GA7, GA8, GA9, GA12, GA19, GA20, GA24, GA34 and GA53) and indole-acetic acid from B. methylotrophicus KE2. The mechanism of plant growth promotion via their secreted metabolites was confirmed by a significant increase of GA deficient mutant rice plant growth. Moreover, the bacterial association was favor to enhance shoot length, shoot fresh weight and leaf width of lettuce. The higher concentration of protein, amino acids (Asp, Thr, Ser, Glu, Gly, Ala, Leu, Tyr and His), gama-aminobutric acid and fructose was found in bacterial culture (KE2) applied plants. The macro and micro minerals such as K, Mg, Na, P, Fe, Zn and N were also detected as significantly higher quantities in bacteria treated plants than untreated control plants. In addition, the carotenoids and chlorophyll a were also increased in lettuce at bacterial inoculation. The results of this study suggest that B. methylotrophicus KE2 application to soil helps to increase the plant growth and food values of lettuce.
This study aimed to determine the ecological risk posed by metals, in sediments from the Nyl River system in Limpopo, South Africa. Metals were extracted from sediment samples by aqua regia microwave digestion and were analysed using standard ICP-OES techniques. The ecological risk indices applied to the data included Contamination Factor, Pollution Load Index, Geo-accumulation Index and Enrichment Factor. The results showed that the levels of Ni at STW and NYL in the HF period exceeded the Canadian Sediment Quality Guidelines by a factor of 1.36 and 1.83 respectively whereas NYL and MDD had 2.57 and 1.32 times the allowed limit of Ni in the LF period. During the HF period, the GC site exceeded the allowed limit of Zn by a factor of 1.04 and NYL had 1.21 times the allowed Zn in the LF period. The levels of metals are generally low near the origin of the river and increase moving downstream. The levels of metals in the Nyl River floodplain, a Ramsar accredited wetland, were high with CF scores ranging between 0.905 and 5.82, Igeo values with a range of -0.541 to 2.441 and EF scores ranging from 0.959 to 6.171. and posed a greater risk than the other sites. This indicated that the wetland is performing its ecological function by trapping and removing toxins from the water body. The Pollution Load Index determined that the Golf Course (PLI=4.586) and STW (PLI=2.617) sites were polluted only in the low flow period whereas the Nyl River floodplain (HF PLI=79.845; LF PLI=30378.768) and Moorddrift Dam (HF PLI=1.903; LF PLI=9.256) sites were polluted in high flow and low flow periods.
Soils around coal mining are important reservoir of hazardous elements (HEs), nanominerals, and ultrafine compounds. This research reports and discusses the soil concentrations of HEs (As, Cd, Cr, Cu, Ni, Pb, and Zn) in coal residues of abandoned mines. To assess differences regarding environmental impact and risk assessment between coal abandoned mines from the Santa Catarina state, eighteen coal cleaning rejects with different mineralogical and chemical composition, from eight abandoned mines were collected. Nanominerals and ultra-fine minerals from mining-contaminated areas were analyzed by X-ray diffraction (XRD), field emission scanning electron microscopy (FE-SEM), and high-resolution transmission electron microscope (HR-TEM), providing new information on the mineralogy and nano-mineralogy of these coal residues. The total contents of 57 elements (HEs, alkali metals, and rare earth elements) were analyzed by Inductively Coupled Plasma Mass Spectrometry (ICP-MS). The calculation of NWACs (Normalized Average Weighted Concentration), together with the chemometric analysis by Principal component analysis (PCA) confirmed the variability of the samples regarding their city and their mine of origin. Moreover,
 the results confirmed the existence of hotspots in mines near urban areas.
The effectiveness of single- and multi-metal(loid) immobilization of As, Cd, Cr, Pb and Zn using different doses of nanoscale zero-valent iron (nZVI) was evaluated and compared in two different soils, a calcareous and an acidic one. The effectiveness of nZVI to immobilize metal(loid)s in soil strongly depended on the metal characteristics, soil properties, dose of nZVI and presence of other metal(loid)s. In the case of single contamination, this nanoremediation strategy was effective for all of the metal(loid)s studied except for Cd. When comparing the two soils, anionic metal(loid)s (As and Cr) were more easily retained in acidic soil, whereas cationic metal(loid)s (Cd, Pb and Zn), were immobilized more in calcareous soil. In multi-metal(loid) contaminated soils, the presence of several metal(loid)s affected their immobilization, which was probably due to the competitive phenomenon between metal(loid) ions, which can reduce their sorption or produce synergistic effects. At 10% of nZVI, As, Cr and Pb availability decreased more than 82%, for Zn it ranged between 31 and 75% and for Cd between 13 and 42%. Thus, the application of nZVI can be a useful strategy to immobilize As, Cr, Pb and Zn in calcareous or acidic soils in both single- or multi-metal(loid) contamination conditions.
Acid mine drainages (AMD) are major sources of pollution to the environment. Passive bio-remediation technologies involving sulfate-reducing bacteria (SRB) are promising for treating arsenic contaminated waters. However, mechanisms of biogenic As-sulfide formation need to be better understood to decontaminate AMDs in acidic conditions. Here, we show that a high-As AMD effluent can be decontaminated by an indigenous SRB consortium. AMD water from the Carnoulès mine (Gard, France) was incubated with the consortium under anoxic conditions and As, Zn and Fe concentrations, pH and microbial activity were monitored during 94days. Precipitated solids were analyzed using electron microscopy (SEM/TEM-EDXS), and Extended X-Ray Absorption Fine Structure (EXAFS) spectroscopy at the As K-edge. Total removal of arsenic and zinc from solution (1.06 and 0.23mmol/L, respectively) was observed in two of the triplicates. While Zn precipitated as ZnS nanoparticles, As precipitated as amorphous orpiment (am-As(III)2S3) (33-73%), and realgar (As(II)S) (0-34%), the latter phase exhibiting a particular nanowire morphology. A minor fraction of As is also found as thiol-bound As(III) (14-23%). We propose that the formation of the As(II)S nanowires results from As(III)2S3 reduction by biogenic H2S, enhancing the efficiency of As removal. The present description of As immobilization may help to set the basis for bioremediation strategies using SRB.
Urban gardening is a growing global phenomenon with a positive impact on society. Despite several associated benefits, growing vegetables in urban gardens that are localized in highly polluted areas poses questions about the safety of the produced food. Therefore, the identification of risk factors that result in possible deleterious effects to human health is important for realizing all of the benefits to society. We evaluated the use of two biomonitoring methods in ten urban gardens of Sao Paulo city and one control site: the micronuclei frequencies for early tetrads of Tradescantia pallida (Rose) Hunt. cv. "Purpurea" Boom (hereafter, Trad-MCN) as a short-term indicator of genotoxic response and tree barks to quantify the accumulation of traffic-related chemical elements as a long-term biomarker of air pollution in urban gardens. Mature plants of Tradescantia pallida were exposed in each garden, and their inflorescences were sampled over three months. A random set of 300 early tetrads in 13 to 21 slides per garden were evaluated for micronuclei frequencies. Elemental concentrations in 428 tree barks samples from 107 different trees in the areas surrounding urban gardens were quantified using an energy dispersive X-ray fluorescence spectrometer. The frequency of Trad-MCN has a significant correlation with traffic variables and chemical elements related to road dust and tailpipe emissions deposited in tree barks. Negative associations between Trad-MCN and both the distance through traffic and the presence of vertical obstacles were observed in the community gardens. The Mn/Zn concentrations in tree barks were associated with increased Trad-MCN.
A Schiff base-type fluorescent probe (1) consist of 2-hydroxynaphthaldehyde and glutamide moieties has been designed and synthesized for detection Zn(2+) and Al(3+). The probe shows pH dependent dual-selectivity for Zn(2+) and Al(3+) in Tris-HCl buffer, viz. that can selectively recognized Zn(2+) at pH 7.4 and Al(3+) at pH 6.0, respectively. From Job's plots and MS data, the stoichiometric ratios of the probe with Zn(2+) and Al(3+) appeared to be 1:1 and 2:1, respectively. The probe can detect as low as 5.5 × 10(-8) M(-1) Zn(2+) and 1.27 × 10(-7) M(-1) Al(3+), whereas respective association constants are 4.27 × 10(4) M(-1) and 3.50 × 10(9) M(-1). Furthermore, it is also confirmed that the probe has good cell-permeability and could thus be used to selectively sense intracellular Zn(2+) and Al(3+) by bioimaging in different pH environment. Finally the probe has been used successfully for determination of the analytes in real drug samples.
In this work, an analytical methodology in combination with a low power benchtop total reflection X-ray fluorescence (TXRF) system has been developed for multi-elemental analysis of vegetal materials. An easy and rapid sample preparation consisting in suspending 20mg of sample in de-ionized water showed to be the most suitable for this kind of samples. However, for comparison purposes, two digestion procedures were also applied. A set of fifteen certified reference materials and three real vegetal samples were employed for the quantitative determination of K, Ca, Mn, Fe, Cu, Zn, Br, Rb, Sr, Pb, As and Sn. All the parameters affecting sample preparation and TXRF measurements conditions were carefully evaluated. Accurate and precise results were obtained for mid-high Z elements (Mn-Sr) using internal standardization as quantification approach, while for light Z elements (K and Ca), due to absorption effects, an improvement of analytical results by external calibration was necessary.
In this study, wild honey samples extracted by two different methods (centrifugation and pressed processing) were characterized and compared based on their physicochemical, and nutritional properties, macro- and micro-mineral contents, and pollen counts. Twelve colonies of Africanized Apis mellifera were used; six honey samples were obtained by centrifugation and six by honeycomb press. All physicochemical parameters of honey samples (moisture, pH, total acidity, ash, dry matter, and qualitative absence of hydroxymethylfurfural) were within the limits established by EU legislation, and all parameters in pressed honey were superior (p<0.05). Nutritional contents (total carbohydrates, total lipids, total proteins, flavonoids, and ascorbic acid) and minerals (K, Ca, Mg, Na, Fe, Li, Zn) were also higher in pressed honey. The quantity of pollen in pressed honey samples was 5.6-fold higher than in centrifuged samples. Pressed honey, can be marked as a differentiated product with a higher mineral content and several nutritional properties.
Strong visible light absorption and high charge mobility are desirable properties for an efficient photocatalyst, yet they are hard to be realized simultaneously in a single semiconductor compound. In this work, we demonstrate that these properties coexist in homologous compounds ZnnIn2O3+n (n = 4, 5 and 7) with a peculiar layered structure that combines optical active segment and electrical conductive segment together. Their enhanced visible light absorption originates from tetrahedrally or trigonal-bipyramidally coordinated In atoms in Zn(In)O4(5) layers which enable p-d hybridization between In 4d and O 2p orbitals so that valence band minimum (VBM) is uplifted with a reduced band gap. Theoretical calculations reveal their anisotropic features in charge transport and functionality of different constituent segments, i.e. Zn(In)O4(5) layers and InO6 layers as being for charge generation and charge collection, respectively. Efficient photocatalytic hydrogen evolution was observed in these compounds under full range (λ ≥ 250 nm) and visible light irradiation (λ ≥ 420 nm). High apparent quantum efficiency ~ 2.79% was achieved for Zn4In2O7 under full range irradiation, which is almost fivefold higher than their parent oxides ZnO and In2O3. Such superior photocatalytic activities of these homologous compounds can be understood as layer-by-layer packing of charge generation/collection functional groups that ensures efficient photocatalytic reactions.
Imatinib mesylate (Imt) is a tyrosine kinase inhibitor mainly used in the treatment of Philadelphia chromosome-positive chronic myelogenous leukemia (Ph+CML). Human serum transferrin is the most abundant serum protein responsible for the transport of iron ions and many endogenous and exogenous ligands. In this study the mechanism of interactions between the imatinib mesylate and all states of transferrin (apo-Tf, Htf and holo-Tf) has been investigated by fluorescence, ultraviolet-visible (UV-vis), circular dichroism (CD) and zeta potential spectroscopic methods. Based on the experimental results it was proved that under physiological conditions the imatinib mesylate binds to the each form of transferrin with a binding constant c.a. 10(5)M(-1). The thermodynamic parameters indicate that hydrogen bonds and van der Waals were involved in the interaction of apo-Tf with the drug and hydrophobic and ionic strength participate in the
 reaction of Htf and holo-Tf with imatinib mesylate. Moreover, it was shown that common metal ions, Zn(2+) and Ca(2+) strongly influenced apo-Tf-Imt binding constant. The CD studies showed that there are no conformational changes in the secondary structure of the proteins. No significant changes in secondary structure of the proteins upon binding with the drug and instability of apo-Tf-Imt system are the desirable effects from pharmacological point of view.
The role of Cu(II) in the reduction of N-nitrosodimethylamine (NDMA) with zero-valent metals was investigated by determining the effects of Cu(II) on the removal, kinetics, products, and mechanism. NDMA removal was enhanced, and all reactions followed a pseudo-first-order kinetic model except for the Fe and Fe/0.1 mM Cu(II) systems. The iron mass-normalized pseudo-first-order rate constants (kMFe) increased with the Cu(II) concentration. The zinc mass-normalized pseudo-first-order rate constants (kMZn) were identical to those with the Cu(II) concentrations from 0.1 mM to 1.0 mM and were higher with 2.0 mM Cu(II). The types of products detected were unchanged. Some unknown products were also found. NDMA was reduced to 1,1-dimethylhydrazine (unsymmetrical dimethylhydrazine, UDMH). Then, UDMH was reduced into dimethylamine (DMA) by the Fe/Cu(II) and Zn/Cu(II) systems. Catalytic hydrogenation was proposed as the reduction mechanism. Several copper species, such as Cu(OH)2 in the Fe/Cu(II) system and Cu2O and Cu(OH)2 in the Zn/Cu(II) system enhanced NDMA reduction. Differences between the Fe/Cu(II) and Zn/Cu(II) systems were caused by the reduction potentials and surface conditions of the different metals and the copper species in the various systems.
Women have an increased risk for chemical element deficiencies during reproductive age, particularly due to higher chemical element requirements and poor diets. Twenty-one chemical elements (Al, B, Ba, Ca, Cd, Co, Cr, Cu, Fe, Mg, Mn, Mo, Ni, Pb, Se, Si, Sn, Sr, Ti, V and Zn) in hair samples, which were collected from 71 non-pregnant and 236 pregnant women living in the West Ujimqin Banner, central Inner Mongolia, China, were measured, and the environment, dietary habits and ethnic group influence factors associated with the biomarker were analyzed. The results indicated that the average values of the chemical element contents from hair were greatly different compared to those from other areas, especially the Al, Cd, Pb, Ca and Sr contents. There was no significant difference among the three ethnicities for any element except Mn and Ti in non-pregnant women. Compared to non-pregnant women, in the first trimester group, the levels of nine chemical elements (Ba, Cd, Cu, Pb, Se, Si, Sn and Ti) decreased, while the others increased, and the contents of all of the chemical elements decreased in the second trimester group, while in the third trimester, there was a slight increase. Three chemical elements (Cu, Mn and Zn) displayed a synergistic correlation between each other in the third trimester group, which may protect the placenta from some oxidant damage. The high levels of Cd and Pb in hair likely originate from house renovations and traffic pollution. This study provided basic and useful information on the levels of chemical elements in reproductive-age women, and the results of this study are helpful to control the contents and improve the health of pregnant and non-pregnant women.
We propose a novel biased Widom insertion method that can efficiently compute the Henry coefficient, KH , of gas molecules inside porous materials exhibiting strong adsorption sites by employing purely DFT calculations. This is achieved by partitioning the simulation volume into strongly and weakly adsorbing regions and selectively biasing the Widom insertion moves into the former region. We show that only few thousands of single point energy calculations are necessary to achieve accurate statistics compared to many hundreds of thousands or millions of such calculations in conventional random insertions. The methodology is used to compute the Henry coefficient for CO2 , N2 , CH4 , and C2 H2 in M-MOF-74(M = Zn and Mg), yielding good agreement with published experimental data. Our results demonstrate that the DFT binding energy and the heat of adsorption are not accurate enough indicators to rank the guest adsorption properties at the Henry regime. © 2016 Wiley Periodicals, Inc.
Excessive exercise induces an inflammatory response caused by oxidative stress, which delays recovery of damaged muscle fibers. The reduction of inflammatory response is important for skeletal muscle homeostasis. Peroxisome proliferator-activated receptor gamma (PPARγ) is an anti-inflammatory molecule, but the role of PPARγ in skeletal muscle as anti-inflammatory activity is not clear. Thus, this study examined the anti-inflammatory role of PPARγ against H2O2-induced oxidative stress in skeletal muscle. Sprague Dawley (SD) rats were exercised on a treadmill to induce oxidative stress. In vitro oxidative stress was evaluated in differentiated C2C12 cells stimulated using 200 μM H2O2. Inflammation-related molecules were determined by immunohistochemistry and Western blot analysis. Expressions of the inflammatory molecules tumor necrosis factor-alpha (TNF-α), interleukin-1 beta (IL-1β), cyclooxygenase-2 (COX-2), and matrix metalloproteinase-2 (MMP-2) in muscles of the acute exercise group were highly increased. PPARγ was also highly expressed in these muscles. These inflammatory molecules were also markedly increased in C2C12 cells with H2O2 stimulation. However, PPARγ overexpression in C2C12 transfected by Ad/PPARγ dramatically reduced the inflammatory molecules. PPARγ also enhanced the anti-oxidants molecules like Cu/Zn-SOD, Mn-SOD, and hemeoxygenase-1 by reducing the generation of ROS, even in the presence of H2O2. PPARγ displayed dual anti-inflammatory and anti-oxidant roles by inhibiting the mitogen-activated protein kinase (MAPK) pathway and translocation of nuclear transcriptional factor-κB (NF-κB) from the cytosol to the nucleus. These results demonstrate a potential role of PPARγ in protecting muscle fibers against oxidative stress caused by excessive acute exercise due to its anti-inflammatory and anti-oxidant activity exerted by inhibition of the MAPK/NF-κB pathway.
The objective of this study was to assess the concentration levels of trace metals (Zn, Hg, Cd, Cr, Ni, Pb and Cu) in surface water and bottom sediments of the Hungarian upper section of the Danube River and its main tributaries. A total of 935 samples (water and sediments) were collected from 10 different sampling sites in the period of 2001-2012 and analyzed for the trace metals. Moreover, the dissolved arsenic content was determined in a number of 467 water samples in the period of 2004-2012. The highest dissolved trace element concentrations were observed at the site of Kenyérmezei-patak Creek located near a hazardous waste incinerator. However, the comparison of the dissolved trace metal(loid) concentrations determined with other sections of the Danube River and the European Union environmental quality standards revealed that the dissolved trace metal(loid) concentrations were relatively low in the Hungarian upper section during the 12-year study period (excluding some samples for Hg, Cd and Cr). The concentrations of trace metals in sediments were higher than those found in water samples and varied very much in all sampling sites during the study period. The sediment samples were mainly classified as low or moderate polluted for trace metals. However, some sediment samples collected especially from the Moson Danube branch indicated a considerable (for Zn, Hg, Cd, Ni and Cu) or a very high (for Zn and Hg) contamination.
Proteins purified using affinity-based chromatography often exploit a recombinant affinity tag. Existing methods for the removal of the extraneous tag, needed for many applications, suffer from poor efficiency and/or high cost. Here we describe a simple, efficient, and potentially low-cost approach-split intein-mediated ultrarapid purification (SIRP)-for both the purification of the desired tagged protein from Escherichia coli lysate and removal of the tag in less than 1 h. The N- and C-fragment of a self-cleaving variant of a naturally split DnaE intein from Nostoc punctiforme are genetically fused to the N-terminus of an affinity tag and a protein of interest (POI), respectively. The N-intein/affinity tag is used to functionalize an affinity resin. The high affinity between the N- and C-fragment of DnaE intein enables the POI to be purified from the lysate via affinity to the resin, and the intein-mediated C-terminal cleavage reaction causes tagless POI to be released into the flow-through. The intein cleavage reaction is strongly inhibited by divalent ions (e.g., Zn(2+)) under non-reducing conditions and is significantly enhanced by reducing conditions. The POI is cleaved efficiently regardless of the identity of the N-terminal amino acid except in the cases of threonine and proline, and the N-intein-functionalized affinity resin can be regenerated for multiple cycles of use.
Zn(2+) is concentrated into presynaptic vesicles at many central synapses and is released into the synaptic cleft by nerve terminal stimulation. There is strong evidence that synaptically released Zn(2+) modulates glutamatergic neurotransmission, although there is debate concerning the peak concentration it reaches in the synaptic cleft. Glycine receptors (GlyRs), which mediate inhibitory neurotransmission in the spinal cord and brainstem, are potentiated by low nanomolar Zn(2+) and inhibited by micromolar Zn(2+). Mutations that selectively ablate Zn(2+) potentiation result in hyperekplexia phenotypes suggesting that Zn(2+) is a physiological regulator of glycinergic neurotransmission. There is, however,
 little evidence that Zn(2+) is stored presynaptically at glycinergic terminals and an alternate possibility is that GlyRs are modulated by constitutively bound Zn(2+). We sought to estimate the peak Zn(2+) concentration in the glycinergic synaptic cleft as a means of evaluating whether it is likely to be synaptically released. We employed 'artificial' synapses because they permit the insertion of engineered α1β GlyRs with defined Zn(2+) sensitivities into synapses. By comparing the effect of Zn(2+) chelation on glycinergic IPSCs with the effects of defined Zn(2+) and glycine concentrations applied rapidly to the same recombinant GlyRs in outside-out patches, we inferred that synaptic Zn(2+) rises to at least 1 μM following a single presynaptic stimulation. Moreover, using the fast, high-affinity chelator, ZX1, we found no evidence for tonic Zn(2+) bound constitutively to high affinity GlyR binding sites. We conclude that diffusible Zn(2+) reaches 1 μM or higher and is therefore likely to be phasically released in artificial glycinergic synapses.
Allostery is essential to neuronal receptor function, but its transient nature poses a challenge for characterization. The N-terminal domains (NTDs) distinct from ligand binding domains are a major locus for allosteric regulation of NMDA receptors (NMDARs), where different modulatory binding sites have been observed. The inhibitor ifenprodil, and related phenylethanoamine compounds specifically targeting GluN1/GluN2B NMDARs have neuroprotective activity. However, whether they use differential structural pathways than the endogenous inhibitor Zn(2+) for regulation is unknown. We applied genetically encoded unnatural amino acids (Uaas) and monitored the functional changes in living cells with photo-cross-linkers specifically incorporated at the ifenprodil binding interface between GluN1 and GluN2B subunits. We report constraining the NTD domain movement, by a light induced crosslinking bond that introduces minimal perturbation to the ligand binding, specifically impedes the transduction of ifenprodil but not Zn(2+) inhibition. Subtle distance changes reveal interfacial flexibility and NTD rearrangements in the presence of modulators. Our results present a much richer dynamic picture of allostery than conventional approaches targeting the same interface, and highlight key residues that determine functional and subtype specificity of NMDARs. The light-sensitive mutant neuronal receptors provide complementary tools to the photo-switchable ligands for opto-neuropharmacology.
In this paper we have investigated the dynamics of photo-generated charge carriers in a series of aerotaxy-grown GaAs nanowires (NWs) with different levels of Zn doping. Time-resolved photo-induced luminescence and transient absorption have been employed to investigate radiative (band edge transition) and non-radiative charge recombination processes, respectively. We find that the photo-luminescence (PL) lifetime of intrinsic GaAs NWs is significantly increased after growing an AlGaAs shell over them, indicating that an AlGaAs shell can effectively passivate the surface of aerotaxy-grown GaAs NWs. We observe that PL decay time as well as PL intensity decrease with increasing Zn doping, which can be attributed to thermally activated electron trapping with the trap density increased due to the Zn doping level.
We used fine root and litter mass from a tropical mountain cloud forest to assess their relative contribution to nutrient content and to examine mineralization processes during a laboratory incubation experiment. Our results showed that average fine root mass density ranged from 2.86kgm(-3) to 11.59kgm(-3), while litter mass density ranged from 72.5kgm(-3) to 177.3kgm(-3). On average, fine root mass density represented 4.7% of the mass density of the O horizon. Fine root mass density followed an exponentially declining trend with soil depth. On average, 83% of fine root mass density within the soil profile was concentrated in the O horizon. Mean element pools in litter decreased from 44.08mgcm(-3) to 0.49μgcm(-3) in the following sequence: C>N>Fe>S>Ca>P>K>Mg>Na>Mn>Zn>Cu. For fine roots, a different mean element pool sequence (C>N>Ca>K>Fe>S>Mg>Na>P>Mn>Zn>Cu) in decreasing abundance (from 2.88mgcm(-3) to 0.13μgcm(-3)) was observed with respect to litter. Regarding C, litter mineralized faster than fine roots, with a mean k value of 0.25d(-1) for litter and 0.13d(-1) for fine roots. Principal component analysis (PCA) combined with stepwise regression analysis revealed that the main mass density predictors were N, S, Zn, and Mn for litter (p<0.0001, R(2)=0.92), and S and C/N ratio for fine roots (p<0.0001, R(2)=0.82). These results demonstrate the potential of chemical composition to influence the mineralization of fine root and litter mass and therefore the nutrient availability and C sequestration.
According to the characteristics of the reverse osmosis concentrate (ROC) generated from Iron and Steel Company, we used three sets of parallel horizontal subsurface flow (HSF) constructed wetlands with different plants and substrate layouts to treat the high salinty wastewater. The plant growth and removal efficiencies under saline condition were evaluated. The evaluation was based entirely on routinely-collected water quality data, physical and chemical characteristics of the plants (Phragmites australis, Typha latifolia, Iris wilsonii, and Scirpus planiculmis). The principal parameters of concern in the effluent were chemical oxygen demand (COD), total nitrogen (TN) and total phosphorus (TP). The results showed that the constructed wetlands were able to remove COD, TN and TP from ROC. S. planiculmis was not suitable for treatment of high saline wastewater. The amount of metals accumulated in constructed wetland plants was sequencing as K>Ca>Na>Mg>Zn>Cu. More than 70% of metals were accumulated in the aboveground of Phragmites australis. The constructed wetland filled with gravel and manganese ore and planted with Phragmites australis, Typha latifolia had the best performance of pollutant removal, with average removal of 49.96%, 39.45% and 72.01% for COD, TN and TP, respectively. The effluent water quality met the regulation in China. These results suggested HSF constructed wetland planted with Phragmites australis and Typha latifolia can be applied in ROC pollutants removal.
In the present investigation, four macrophytes, namely, Typha latifolia (L.), Lemna minor (L.), Eichhornia crassipes (Mart.) Solms-Laubach and Miriophyllum aquaticum (Vell.) Verdc, were evaluated for their heavy metal (Cu, Pb, Hg and Zn) hyperaccumulation potential under laboratory conditions. Tolerance analyses were performed for 7 days of exposure at five different treatments of the metals mixture (Cu(+2), Hg(+2), Pb(+2) and Zn(+2)). The production of chlorophyll and carotenoids was determined at the end of each treatment. L. minor revealed to be sensitive, because it did not survive in all the tested concentrations after 72 h of exposure. E. crassipes and M. aquaticum displayed the highest tolerance to the metals mixture. For the most tolerant species of aquatic macrophytes, E. crassipes and M. aquaticum kinetics of removal was carried out, by using the following mixture of metals: Cu 0.5 mg/L and Hg, Pb, Zn 0.25 mg/L. The obtained results revealed that E. crassipes can remove 99.80% Cu, 97.88% Pb, 99.53% Hg and 94.37 Zn. M. aquaticum withdraws 95.2% Cu, 94.28% Pb, 99.19% Hg and 91.91% Zn. The obtained results suggest that these two species of macrophytes could be used for the phytoremediation of this mixture of heavy metals from the polluted water bodies.
Two types of zinc flavonolato complexes ([(6-Ph2TPA)Zn(flavonolato)]ClO4 and Zn(flavonolato)2) of four extended flavonols have been prepared, characterized, and evaluated for visible light-induced CO release reactivity. Zinc coordination of each flavonolato anion results in a red-shift of the lowest energy absorption feature and in some cases enhanced molar absorptivity relative to the free flavonol. The zinc-coordinated flavonolato ligands undergo visible light-induced CO release with enhanced reaction quantum yields relative to the neutral flavonols. Most notable is the discovery that both types of zinc flavonolato derivatives undergo similar visible light-induced CO release reactivity in solution and in the solid state. A solid film of a Zn(flavonolato)2 derivative was evaluated as an in situ CO release agent for aerobic oxidative palladium-catalyzed alkoxycarbonylation to produce esters in ethanol. The CO release product was found to undergo ester alcolysis under the conditions of the carbonylation reaction.
The role of Cu and Zn ions in Alzheimer's disease is linked to the consequences of their coordination to the amyloid-β (Aβ) peptide, i.e. to the modulation of Aβ aggregation and to the production of Reactive Oxygen Species (ROS), two central events of the so-called amyloid cascade. The role of both ions in Aβ aggregation is still controversial. Conversely the higher toxicity of the redox competent Cu ions (compared to the redox inert Zn ions) in ROS production is acknowledged. Thus the Cu ions can be considered as the main therapeutic target. Because Zn ions are present in higher quantity than Cu ions in the synaptic cleft, they can prevent detoxification of Cu by chelators unless they have an unusually high Cu over Zn selectivity. We describe a proof-of-concept study where the role of Zn on the metal swap reaction between two prototypical ligands and the Cu(Aβ) species has been investigated by several complementary spectroscopic techniques (UV-Vis, EPR and XANES). The first ligand has a higher Cu over Zn selectivity relative to the one of Aβ peptide while the second one exhibits a classical Cu over Zn selectivity. How Zn impacts the effect of the ligands on Cu-induced ROS
 production and Aβ aggregation is also reported.
The syntheses of two new ligands based on a calix[4]arene scaffold in the cone conformation functionalized on the phenolic positions 1 and 3 by diethylthiophosphonates (L1) or tetra(tri)thioethyleneglycol (L2) crowns are described. Together with ligand L3, the parent calix[4]arene substituted by a penta(tetra)thioethyleneglycol crown, the spectroscopic properties of the ligands were determined by means of UV-Vis absorption spectroscopy and steady-state and time-resolved fluorescence spectroscopy, showing that the ligands display modest but non-negligible intrinsic fluorescence properties (ϕfluo = 0.023; 0.026 and 0.029 for L1, L2 and L3 in CH2Cl2, respectively). The X-ray crystal structures of ligand L1, and of its synthetic precursor were determined and analyzed for their capacity to accommodate the incoming cationic species. The ligands were further investigated for their complexation properties of divalent cations such as Cu(2+), Zn(2+), Hg(2+) and Cd(2+) (under their nitrate salts) in 1 : 1 CH3CN/CH2Cl2 solutions (I = 0.01 M Et4NNO3, T = 25.0(2) °C), in which the additions of cations were monitored by absorption and steady-state fluorescence spectrophotometries. The stoichiometries of the corresponding complexes were assessed by ESI-MS, while insights into the structures of the complexes in solution were obtained with density functional theory (DFT) calculations. The influence of the sulphur and phenol coordinating moieties was addressed to show that the thiocrown compounds L2 and L3 displayed a marked affinity towards the soft mercuric cation (Δlog K ≥ 2), with no particular size selectivity effect, whereas ligand L1 can accommodate both the thio and phenol units to coordinate with Cu(ii). Altogether, these results point to the use of L3 as a selective fluoroionophore for detection of Hg(2+).
We report temperature-dependent electric, IR and Raman studies of niccolite-type formate frameworks templated by protonated 1,4-diaminobutane. Our results show that the zinc-analogue exhibits a first-order phase transition close to 240 K. Single-crystal dielectric data show a much stronger anomaly at the phase transition for ε' along the a-direction compared to the c-direction. They also reveal that dipole relaxation exists in bnZn. Pronounced temperature-dependence observed for bending and torsion modes of the NH3(+) groups proves that ordering of protonated amine plays a major role in the phase transition mechanism. The ordering is associated with distortion of the zinc formate framework but the number of observed vibrational modes is much smaller than expected assuming 36-fold multiplication of the unit cell below TC. It is also much smaller than reported for the Mn-analogue, which exhibits only a two-fold increase of the unit cell below TC. We discuss the origin of this behavior. Our results also show that the Co-analogue exhibits a similar phase transition to its Zn-counterpart. However, the observed narrowing and splitting of the corresponding bands is significantly smaller, suggesting weaker distortion of the framework and the presence of some disorder for this compound even at 5 K. The Raman and IR spectra of the Fe-analogue show weak narrowing of bands upon cooling, indicative of statistical freezing of the protonated amine at low temperatures. We also report high-pressure Raman scattering studies of the zinc-analogue. This study revealed a pressure-induced reversible phase transition between 3.4 and 4.1 GPa. Large shifts and splitting of modes corresponding to the vibrations of HCOO(-) ions associated with weak changes of the protonated amine prove that the major contribution to the phase transition mechanism comes from distortion of the zinc formate framework.
Two-dimensional (2D) carbonitrides have attracted intense interest because of their intriguing physical and chemical properties. One such 2D system is the so-called phthalo-carbonitride (pc-C3N2) with stoichiometry C3N2 and an extended network of phthalocyanine-like cores. Here we use first-principles calculations to study pc-C3N2 sheets with Al, Zn, or Cu atoms attached at the cores. We describe the structural details of various possible geometries and probe the electronic properties of the most stable configurations. The decorated sheets are metallic, with the exception of the Zn case, which is a semiconductor with a small energy band gap. Moreover, the Cu-laden monolayers bear finite magnetization. These key properties highlight the potential of C3N2-based 2D materials as multi-functional components in various applications.
Zn aqueous batteries typically suffer from poor cycle life because water soluble zincate ions are formed during the oxidation of Zn. When Zn is oxidized, most of the Zn(2+) ions detach from the current collector and become electrochemically inactive, leaving the battery non-rechargeable. Numerous reports demonstrate the use of Bi2O3 as an electrode additive to enhance electrochemical performance and they attribute this phenomenon to the improvement in electrical conductivity. However, conductivity does not have an effect on the intrinsic solubility of the zincate ion. We conduct a series of characterizations to provide a comprehensive mechanistic role of Bi2O3 in the Zn electrode. We find that upon oxidation, zincate ions are formed but they relax into ZnO on the surface of the bismuth species. This work proposes that the reason for the prolonged cycle life is due to the deposition of ZnO through relaxation and this prevents losing electrochemically active materials. This finding paves the way for further improving the cycle life and understanding the mechanism of the Zn based rechargeable aqueous batteries and possibly other conversion types of rechargeable batteries.
The maximum magnetisation (saturation magnetisation) obtainable for iron oxide nanoparticles can be increased by doping the nanocrystals with non-magnetic elements such as zinc. Herein, we closely study how only slightly different synthesis approaches towards such doped nanoparticles strongly influence the resulting sub-nano/atomic structure. We compare two co-precipitation approaches, where we only vary the base (NaOH versus NH3), and a thermal decomposition route. These methods are the most commonly applied ones for synthesising doped iron oxide nanoparticles. The measurable magnetisation change upon zinc doping is about the same for all systems. However, the sub-nano structure, which we studied with Mössbauer and X-ray absorption near edge spectroscopy, differs tremendously. We found evidence that a much more complex picture has to be drawn regarding what happens upon Zn doping compared to what textbooks tell us about the mechanism. Our work demonstrates that it is crucial to study the obtained structures very precisely when "playing" with the atomic order in iron oxide nanocrystals.
The one-step conversion of ethanol to 1,3-butadiene was performed using talc containing Zn (talc/Zn) as a catalyst. The influence of the MgO and Zn in the talc on the formation rate and selectivity for 1,3-butadiene were investigated. MgO as a catalyst afforded 1,3-butadiene with a selectivity that was nearly the same as talc/Zn at ∼40% ethanol conversion at 673 K, although the rate of 1,3-butadiene formation over MgO was about 40 times lower than that over the talc/Zn. The introduced Zn cations were located in octahedral sites in place of Mg cations in the talc lattice. The Zn cations accelerated the rate of CH3CHO formation from ethanol, resulting in an increase in the rate of 1,3-butadiene formation. However, the rate of CH3CHO consumption to form crotonaldehyde was not influenced by Zn, although the distribution of crotonaldehyde was decreased with increasing Zn concentrations. X-ray photoelectron spectra of talc/Zn showed that the O1s binding energy was increased by increasing the concentration of Zn, while those of both Mg2p and Si2p were hardly influenced. DFT calculations were used to estimate the atomic charges on the O, Mg, Si, and Zn atoms when an atom of Zn per unit cell of talc was introduced into an octahedral site. On the basis of the results for the conversion of ethanol into 1,3-butadiene and the corresponding DFT calculations, the roles of the O, Zn, Mg, and Si atoms in the talc catalyst for the formation of 1,3-butadiene from ethanol were discussed.
Binding of Zn(2+) to the coordinating supramolecular vesicle based on an aggregation induced emission amphiphile TPE-BPA immediately triggers the formation of charged vesicles. This induces vesicle fission and fluorescence reduction, suggesting a looser molecular packing in the charged vesicle membrane. Since cancer cells are highly charged, this indicates that the quick fission of cancer cells may have electrical charge origin.
We have systematically investigated the effects of transition-metal (TM) atom (Sc-Zn) doping in 2D d(0) materials SnS2 and ZrS2via the density functional theory method. Our results demonstrate that the conductivity and magnetism of SnS2 and ZrS2 can be engineered to spin-polarize half-metal/metal with appropriate TM dopants. For both materials, nontrivial magnetic interactions can be induced by V/Cr/Mn/Fe/Co doping. Specifically, the various behaviors of the magnetic exchanges in TM-doped SnS2 and ZrS2 are due to the competition between the super-exchange, the double exchange, and the p-d exchange interactions, which are dependent on the dopants' chemistry and spatial positions. Thus, our results give potential guidance for future experiments to create functionalized d(0) nano-electronic devices.
Peptide hydrolysis has been involved in a wide range of biological, biotechnological, and industrial applications. In this perspective, the mechanisms of three distinct peptide bond cleaving enzymes, beta secretase (BACE1), insulin degrading enzyme (IDE),
 and bovine lens leucine aminopeptidase (BILAP), have been discussed. BACE1 is a catalytic Asp dyad [Asp, Asp(-)] containing aspartyl protease, while IDE and BILAP are mononuclear [Zn(His, His, Glu)] and binuclear [Zn1(Asp, Glu, Asp)-Zn2(Lys, Glu, Asp, Asp)] core possessing metallopeptidases, respectively. Specifically, enzyme-substrate interactions and the roles of metal ion(s), the ligand environment, second coordination shell residues, and the protein environment in the functioning of these enzymes have been elucidated. This information will be useful to design small inhibitors, activators, and synthetic analogues of these enzymes for biomedical, biotechnological, and industrial applications.
The ubiquitin-like protein TtuB is a sulfur carrier for the biosynthesis of 2-thioribothymidine (s(2)T) at position 54 in some thermophilic bacterial tRNAs. TtuB captures a S atom at its C-terminus as a thiocarboxylate and transfers it to tRNA by the transferase activity of TtuA. TtuB also functions to suppress s(2)T formation by forming a covalent bond with TtuA. To explore how TtuB interacts with TtuA and switches between these two different functions, high-resolution structure analysis of the TtuA-TtuB complex is required. In this study, the TtuA-TtuB complex from Thermus thermophilus was expressed, purified and crystallized. To mimic the thiocarboxylated TtuB, the C-terminal Gly residue was replaced with Cys (G65C) to obtain crystals of the TtuA-TtuB complex. A Zn-MAD data set was collected to a resolution of 2.5 Å. MAD analysis successfully determined eight Zn sites, and a partial structure model composed of four TtuA-TtuB complexes in the asymmetric unit was constructed.
Many crystal structures in the Protein Data Bank contain zinc ions in a geometrically distorted tetrahedral complex with four Cys and/or His ligands. A method is presented to automatically validate and correct these zinc complexes. Analysis of the corrected zinc complexes shows that the average Zn-Cys distances and Cys-Zn-Cys angles are a function of the number of cysteines and histidines involved. The observed trends can be used to develop more context-sensitive targets for model validation and refinement.
To enhance extraction of strongly bound metals from oxide minerals and organic matter, this study examined the sequential use of reductants, oxidants, alkaline solvents and organic acids followed by a biodegradable chelating agent (EDDS, [S,S]-ethylene-diamine-disuccinic-acid) in a two-stage soil washing. The soil was contaminated by Cu, Zn, and Pb at an e-waste recycling site in Qingyuan city, China. In addition to extraction efficiency, this study also examined the fate of residual metals (e.g., leachability, bioaccessibility, and distribution) and the soil quality parameters (i.e., cytotoxicity, enzyme activities, and available nutrients). The reductants (dithionite-citrate-bicarbonate and hydroxylamine hydrochloride) effectively extracted metals by mineral dissolution, but elevated the leachability and bioaccessibility of metals due to the transformation from Fe/Mn oxides to labile fractions. Subsequent EDDS washing was found necessary to mitigate the residual risks. In comparison, prior washing by oxidants (persulphate, hypochlorite, and hydrogen peroxide) was marginally useful because of limited amount of soil organic matter. Prior washing by alkaline solvents (sodium hydroxide and sodium bicarbonate) was also ineffective due to metal precipitation. In contrast, prior washing by low-molecular-weight organic acids (citrate and oxalate) improved the extraction efficiency. Compared to hydroxylamine hydrochloride, citrate and oxalate induced lower cytotoxicity (Microtox) and allowed higher enzyme activities (dehydrogenase, acid phosphatase, and urease) and soil nutrients (available nitrogen and phosphorus), which would facilitate reuse of the treated soil. Therefore, while sequential washing proved to enhance extraction efficacy, the selection of chemical agents besides EDDS should also include the consideration of effects on metal leachability/bioaccessibility and soil quality.
Recently, greenhouse vegetable production (GVP) has grown rapidly and counts a large proportion of vegetable production in China. In this study, the accumulation, health risk and threshold values of selected heavy metals were evaluated systematically. A total of 120 paired soil and vegetable samples were collected from three typical intensive GVP systems along the Yellow Sea of China. Mean concentrations of Cd, As, Hg, Pb, Cu and Zn in greenhouse soils were 0.21, 7.12, 0.05, 19.81, 24.95 and 94.11 mg kg(-1), respectively. Compared to rootstalk and fruit vegetables, leafy vegetables had relatively high concentrations and transfer factors of heavy metals. The accumulation of heavy metals in soils was affected by soil pH and soil organic matter. The calculated hazard quotients (HQ) of the heavy metals by vegetable consumption decreased in the order of leafy > rootstalk > fruit vegetables with hazard index (HI) values of 0.61, 0.33 and 0.26, respectively. The HI values were all below 1, which indicates that there is a low risk of greenhouse vegetable consumption. Soil threshold values (STVs) of heavy metals in GVP system were established according to the health risk assessment. The relatively lower transfer factors of rootstalk and fruit vegetables and higher STVs suggest that these types of vegetables are more suitable for cultivation in greenhouse soils. This study will provide an useful reference for controlling heavy metals and developing sustainable GVP.
Six polyoxo-titanium clusters (PTCs) with varying nuclearities containing Ti-N bonds and heteronuclearity, namely, [Ti6(μ3-O)2(μ2-O)2(O3P-Phen)2(OiPr)10(1-hbta)2] (PTC-37), Ti8(μ3-O)2(μ2-O)2(O3P-Phen)2(OiPr)16(adn)2(NO3)2] (PTC-38), [Ti4(μ3-O)(μ2-O)(μ2-OiPr)2(OiPr)4(O3P-Phen)3(1,10-phn)](HOiPr) (PTC-39), [Ti4(μ3-O)(μ2-OiPr)3(OiPr)5(O3P-Phen)3(Im)] (PTC-40), [Ti4(μ3-O)(μ2-OiPr)3(OiPr)5(O3P-Phen)3(Im)][Ti3M(μ3-O)(μ2-OiPr)3(OiPr)3(O3P-Phen)3(Im)] (M = Co for PTC-41 and M = Zn for PTC-42; O3P-Phen = phenyl phosphonate, 1-hbta = 1-hydroxy benzotriazolate, adn = adenine, 1,10-phn = 1,10-phenanthroline, Im = imidazolate, and OiPr = isopropoxide) were prepared as crystalline samples and structurally characterized. Simultaneous doping of nitrogen and transition metal heteroatoms into the Ti-O clusters created complex chemical environments in the resulting hybrid materials. Thus, photocatalytic methylene blue degradation studies were performed to understand structure-property relationships in these Ti cluster-based materials. The complex chemical environment created in these novel molecular clusters had proved to exhibit ligand-dependent photocatalytic activities under normal sunlight. Adenine-functionalized PTC-38 presented moderate activities, while other PTCs all show rapid dye degradation.
A weakly fluorescent Pt-bridged dyad composed of zinc(II) porphyrin (Zn; donor) and free base (Fb; acceptor) has been designed and exhibits an ultrafast singlet energy transfer between porphyrins. The use of larger atoms within the central linker significantly increases the MO coupling between the two chromophores and inherently the electronic communication.
This study was performed to assess the growth-promoting potential of dietary magnesium oxide nanoparticles (MgO NPs) in Macrobrachium rosenbergii post-larvae (PL). MgO NPs were supplemented at 0, 100, 200, 300, 400 and 500 mg kg(-1) with the basal diet (containing 0.95 g Mg kg(-1)); the concentrations of Mg in MgO NP-supplemented diets were increased correspondingly (1.07, 1.15, 1.24, 1.37 and 1.46 g Mg kg(-1) respectively). MgO NP-supplemented diets were fed to M. rosenbergii PL (initial weight 0.11 ± 0.04 g) for a period of 90 days. In the carcasses of experimental prawns, the content of Mg was found to be elevated significantly with respect to the individual diet (102.14, 183.29, 205.46, 221.03, 237.10 and 254.36 μg Mg g(-1) respectively) when compared with that of the control. The contents of Cu, Zn, Fe, Ca, Na and K levels were also found to be elevated in the carcasses of experimental prawns. Significant (P < 0.05) improvements were observed in nutritional indices [survival rate (SR), weight gain (WG), specific growth rate (SGR), feed conversion ratio (FCR) and protein efficiency ratio (PER)], activities of digestive enzymes (protease, amylase and lipase), concentrations of basic biochemical constituents (total protein, amino acid, carbohydrate, lipid, profiles of amino acids and fatty acids) and population of haemocytes [total and differential (hyalinocytes, semigranulocytes and granulocytes)] in all the test PL. Maximum performance was recorded in 500 mg kg(-1) MgO NP-supplemented-feed-fed PL. There were no significant elevations recorded in activities of antioxidant enzymes [superoxide dismutase (SOD) and catalase (CAT)], lipid peroxidation (LPO) and metabolic enzymes [glutamic oxaloacetic transaminase (GOT) and glutamic pyruvic transaminase (GPT)] recorded in any of the MgO NP-supplemented-feed-fed PL when compared with the control. Sodium dodecyl sulfate polyacrylamide gel electrophoresis (SDS-PAGE) showed increases in the staining intensity of polypeptide bands resolved in 500 mg kg(-1) MgO NP-supplemented-feed-fed PL when compared with the control. Based on the gradual improvement in attaining survival, growth, FCR, biochemical constituents and haemocyte population, this study recommends MgO NP supplementation of 500 mg kg(-1) for sustainable maintenance of M. rosenbergii PL. As the studied highest concentration of MgO NPs showed the best performance, it is necessary to study with beyond 500 mg kg(-1) of MgO NPs to optimize the actual concentration.
Urban soil contamination is a growing concern for the potential health impact on the increasing number of people living in these
 areas. In this study, the concentration, the distribution, the contamination levels, and the role of land use were investigated in Erbil metropolis, the capital of Iraqi Kurdistan. A total of 74 soil samples were collected, treated, and analyzed for their physicochemical properties, and for 7 heavy metals (As, Cd, Cr, Cu, Fe, Pb, and Zn) and 16 PAH contents. High concentrations, especially of Cd, Cu Pb, and Zn, were found. The Geoaccumulation index (Igeo), along with correlation coefficients and principal component analysis (PCA) showed that Cd, Cu, Pb, and Zn have similar behaviors and spatial distribution patterns. Heavy traffic density mainly contributed to the high concentrations of these metals. The total concentration of ∑PAHs ranged from 24.26 to 6129.14 ng/g with a mean of 2296.1 ng/g. The PAH pattern was dominated by 4- and 5-ring PAHs, while diagnostic ratios and PCA indicated that the main sources of PAHs were pyrogenic. The toxic equivalent (TEQ) values ranged from 3.26 to 362.84 ng/g, with higher values in central parts of the city. A statistically significant difference in As, Cd, Cu, Pb, Zn, and ∑PAH concentrations between different land uses was observed. The highest As concentrations were found in agricultural areas while roadside, commercial, and industrial areas had the highest Cd, Cu, Pb, Zn, and ∑PAH contents.
Some pollutants can qualitatively affect aquatic freshwater such as rivers, and heavy metals are one of the most important pollutants in aquatic fresh waters. Heavy metals can be found in the form of components dissolved in these waters or in compounds with suspended particles and surface sediments. It can be said that heavy metals are in equilibrium between water and sediment. In this study, the amount of heavy metals is determined in water and different sizes of sediment. To obtain the relationship between heavy metals in water and size-fractionated sediments, a canonical correlation analysis (CCA) was utilized in rivers of the southwestern Caspian Sea. In this research, a case study was carried out on 18 sampling stations in nine rivers. In the first step, the concentrations of heavy metals (Cu, Zn, Cr, Fe, Mn, Pb, Ni, and Cd) were determined in water and size-fractionated sediment samples. Water sampling sites were classified by hierarchical cluster analysis (HCA) utilizing squared Euclidean distance with Ward's method. In addition, for interpreting the obtained results and the relationships between the concentration of heavy metals in the tested river water and sample sediments, canonical correlation analysis (CCA) was utilized. The rivers were grouped into two classes (those having no pollution and those having low pollution) based on the HCA results obtained for river water samples. CCA results found numerous relationships between rivers in Iran's Guilan province and their size-fractionated sediments samples. The heavy metals of sediments with 0.038 to 0.125 mm size in diameter are slightly correlated with those of water samples.
Primary biliary cirrhosis (PBC) is a chronic cholestatic liver disease considered as an autoimmune disease. To identify new biomarkers of PBC, serum profiling analysis using Surface-enhanced laser desorption/ionization time-of-flight mass spectrometry (SELDI-TOF-MS) was employed. Twelve patients with either asymptomatic PBC (group 1, n=6) or PBC with a poor response to UDCA (group 2, n=6), were compared to healthy controls (group 3, n=6). Analysing the 18 sera by using four SELDI-TOF arrays under various conditions, we found four biomarkers of PBC at 5.9, 8.6, 8.9 and 9.0 kDa. The combination of the two arrays IMAC-40/Zn(2+) and CM-10/pH 7 improved the positive diagnosis of this disease. We also found a biomarker of severity of PBC at 95.2 kDa on LSAX-30 array which characterized patients with a bad prognosis. In conclusion, our study identified several serum proteomics signatures as potential biomarkers of PBC for its diagnosis or prognosis.
Bauxite extraction by-products (red mud) were used to evaluate their potential ability to stabilize trace elements from dredged and aerated/humidified marine sediment. The investigated by-products were: bauxaline(®)(BX) that is a press-filtered red mud; bauxsol™(BS) that is a press-filtered red mud previously washed with excess of seawater, and gypsum neutralized bauxaline(®) (GBX). These materials were separately mixed to dredged composted sediment sample considering 5% and 20% sediment: stabilizer ratios. For pilot experiments, rainfall events were regularly simulated for 3 months. Concentrations of As, Mo, Cd, Cr, Zn, Cu, and Ni were analyzed in collected leachates as well as toxicity. Results showed that Cd, Mo, Zn, and Cu were efficiently stabilized in the solid matrix when 20% of BX, BS, and GBX was applied. Consequently, toxicity of leachates was lower than for the untreated sediment, meaning that contaminants mobility was reduced. A 5% GBX was also efficient for Mo, Zn and Cu stabilization. In all scenarios, As stabilization was not improved. Compared to all other monitored elements, Mo mobility seemed to depend upon temperature-humidity conditions during pilot experiments suggesting the need of further investigations.
The metal-specific CzcRS two-component system in Pseudomonas aeruginosa is involved in the repression of the OprD porin, causing in turn carbapenem antibiotic resistance in the presence of high zinc concentration. It has also been shown that CzcR is able to directly regulate the expression of multiple genes including virulence factors. CzcR is therefore an important regulator connecting (i) metal response, (ii) pathogenicity and (iii) antibiotic resistance in P. aeruginosa. Recent data have suggested that other regulators could negatively control oprD expression in the presence of zinc. Here we show that the RNA chaperone Hfq is a key factor acting independently of CzcR for the repression of oprD upon Zn treatment. Additionally, we found that an Hfq-dependent mechanism is necessary for the localization of CzcR to the oprD promoter, mediating oprD transcriptional repression. Furthermore, in the presence of Cu, CopR, the transcriptional regulator of the CopRS two-component system also requires Hfq for oprD repression. Altogether, these results suggest important roles for this RNA chaperone in the context of environment-sensing and antibiotic resistance in P. aeruginosa.
Excessive use of antibiotics potentially threatens human health, agricultural production and soil phytoremediation. This arouses concern over the potential adverse effects of a commonly used antibiotic, oxytetracycline (OTC), on plants used for soil remediation and possible stimulation of antibiotic resistance genes in soils. A greenhouse experiment was conducted to investigate different rates (0, 1, 5, and 25 mg kg-1) and frequencies (one single high and daily low application) of OTC addition to soil on phytoremediation of a heavy metal contaminated soil by Sedum plumbizincicola and/or Medicago sativa (alfalfa). After 90 days both Cd and Zn were substantially removed by phytoextraction into S. plumbizincicola shoots especially at the high OTC (25 mg kg-1) treatment which also led to inhibition of anti-oxidative enzyme activities in both plant species. Soil microbial activity decreased significantly with the addition of OTC and this was ameliorated by planting alfalfa and S. plumbizincicola together. OTC at < 5 mg kg-1 increased the biomass of both plant species but the frequency of OTC addition had no effect on the rate of metal removal. Alfalfa exhibited greater detoxification ability and effectiveness in soil microbial activity promotion than S. plumbizincicola with intercropping. Phytoremediation by alfalfa and S. plumbizincicola in association can both promote the removal of heavy metals and also alleviate the toxic effects of pollutants to plants and soil microbes even at relatively high soil OTC concentrations.
Enzymes find their applications in various industries, due to their error free conversion of substrate into product. Tannase is an enzyme used by various industries for degradation of tannin. Biochemical characterization of a specific enzyme from one organism to other is one of the ways to search for enzymes with better traits for industrial applications. Here, tannase encoding gene from Staphylococcus lugdunensis was cloned and suitability of the enzyme in various conditions was analysed to find its application in various industry. The recombinant protein was expressed with 6× His tag and purified using nickel affinity beads. The enzyme was purified up to homogeneity, with approximate molecular weight of 66 kDa. Purified tannase exhibited specific activity of about 716 U/mg. Optimum enzyme activity was found to be 40 °C at pH 7.0. Biochemical characterization revealed; metal ions such as Zn(2+), Fe(2+), Fe(3+) and Mn(2+) inhibited tannase activity, and SDS at lower concentration, increased tannase activity. Non polar organic solvents increased the tannase activity and polar solvents inhibited the tannase activity. Tannase immobilization studies show protection of the enzyme under wide range of pH and temperature. Also in this study we report a method for recovery and repeated use of the tannase.
An optode for Cu(ii), Cd(ii), Zn(ii) and Hg(ii) sensing has been designed by immobilization of dithizone on a triacetylcellulose membrane (mem-DTZ). The sorption of the metal ions on the mem-DTZ has been thoroughly characterized, in particular sorption kinetics, sorption isotherms and profiles as a function of the pH have been studied. Methods to assess the concentrations of the cations, both individually and in a mixture, in unknown samples, have been developed. In particular, UV-vis spectra and digital information of pictures taken by using a common desktop scanner, of the mem-DTZ sensor after equilibration with different
 solutions, were acquired and they were correlated with the concentration of the metal ions in solutions. For the single analyte determination, the RGB parameters of the pictures were subjected to Principal Component Analysis (PCA); otherwise the UV-vis spectra of a mixture of two cations were elaborated by Partial Least Squares (PLS) Regression. The membrane responds to the divalent cations by changing colour reversibly. The response time of the mem-DTZ is about 1 h for Cd(ii), Hg(ii) and Zn(ii), but longer for Cu(ii): more than 10 h are required. The linear interval is in the range of about 10(-7) to 10(-5) M for all metal ions. The limit of detection (LOD) is around 10(-6) M for Cu(ii), Cd(ii) and Hg(ii); for Zn(ii) a lower LOD of 10(-7) M is obtained. The applicability of mem-DTZ to real samples has been proved by analysis of the four metal cations in a certificate material (Sewage Sludge CC136A), white wine, and drinking water samples.
Genetic screening of Pseudomonas aeruginosa (PSDA) and Acinetobacter baumannii (ACB) reveals genes that confer increased susceptibility to β-lactams when disrupted, suggesting novel drug targets. One such target is lytic transglycosylase. Bulgecin A (BlgA) is a natural product of Pseudomonas mesoacidophila and a lytic transglycosolase inhibitor that works synergistically with β-lactams targeting PBP3 for Enterobacteriaceae. BlgA also weakly inhibits di-Zn(2+) metallo-β-lactamases like L1 of Stenotrophomonas maltophilia. We hypothesized that because of its unique mechanism of action, BlgA could restore susceptibility to carbapenems in carbapenem-resistant PSDA (CR-PSDA) and carbapenem-resistant ACB, as well as ACB resistant to sulbactam. A BlgA-containing extract was prepared using a previously published protocol. CR-PSDA clinical isolates demonstrating a variety of carbapenem resistance mechanisms (VIM-2 carbapenemases, efflux mechanisms, and AmpC producer expression) were characterized with agar dilution minimum inhibitory concentration (MIC) testing and polymerase chain reaction. Growth curves using these strains were prepared using meropenem, BlgA extract, and meropenem plus BlgA extract. A concentrated Blg A extract combined with low concentrations of meropenem, was able to inhibit the growth of clinical strains of CR-PSDA for strains that had meropenem MICs ≥8 mg/L by agar dilution, and a clinical strain of an OXA-24 producing ACB that had a meropenem MIC >32 mg/L and intermediate ampicillin/sulbactam susceptibility. Similar experiments were conducted on a TEM-1 producing ACB strain resistant to sulbactam. BlgA with ampicillin/sulbactam inhibited the growth of this organism. As in Enterobacteriaceae, BlgA appears to restore the efficacy of meropenem in suppressing the growth of CR-PSDA and carbapenem-resistant ACB strains with a variety of common carbapenem resistance mechanisms. BlgA extract also inhibits VIM-2 β-lactamase in vitro. BlgA may prove to be an exciting adjunctive compound to extend the life of carbapenems against these vexing pathogens.
Fish is the most important animal-source food (ASF) in Bangladesh, produced from capture fisheries (non-farmed) and aquaculture (farmed) sub-sectors. Large differences in micronutrient content of fish species from these sub-sectors exist. The importance of fish in diets of vulnerable groups compared with other ASF; contribution from non-farmed and farmed species to nutrient intakes; and differences in fish consumption among age, gender, wealth groups and geographic regions were analysed, using quantitative intra-household fish consumption data, focusing on the first 1000 d of life.
Two-stage stratified sample.
Nationally representative of rural Bangladesh.
Households (n 5503) and individuals (n 24 198).
Fish consumption in poor households was almost half that in wealthiest households; and lower in females than males in all groups, except the wealthiest, and for those aged ≥15 years (P<0·01). In infants of complementary feeding age, 56 % did not consume ASF on the survey day, despite 78 % of mothers knowing this was recommended. Non-farmed fish made a larger contribution to Fe, Zn, Ca, vitamin A and vitamin B12 intakes than farmed fish (P<0·0001).
Policies and programmes aimed to increase fish consumption as a means to improve nutrition in rural Bangladesh should focus on women and young children, and on the poorest households. Aquaculture plays an important role in increasing availability and affordability of fish; however, non-farmed fish species are better placed to contribute to greater micronutrient intakes. This presents an opportunity for aquaculture to contribute to improved nutrition, utilising diverse production technologies and fish species, including small fish.
To review articles on the relationship of dietary and circulating micronutrients with sleep patterns, and to identify issues surrounding implications for future research and public health practice.
A systematic review was conducted. PubMed, Embase and Scopus were searched through January 2016.
Both experimental and observational studies were included. However, studies that focused on secondary sleep impairment due to comorbidities were excluded.
Individuals in different age groups, from infants to older adults.
A total of twenty-six articles were selected. In the articles reviewed, researchers generally supported a potential role of micronutrients, particularly Fe and Mg, in the development of sleep stages among infants and in reversing age-related alterations in sleep architecture in older adults. Micronutrient status has also been linked to sleep duration, with sleep duration positively associated with Fe, Zn and Mg levels, and negatively associated with Cu, K and vitamin B12 levels. The mechanisms underlying these relationships include the impact of micronutrients on excitatory/inhibitory neurotransmitters and the expression of circadian genes.
Although the number of studies on the relationship between micronutrient status and sleep remains low, evidence has emerged that suggests a link between dietary/circulating micronutrients and sleep. Future research is needed to investigate the dose-dependent as well as the longitudinal relationships between micronutrient levels and human sleep across populations, test the interactions among micronutrients on sleep outcomes, and ultimately examine the clinical relevance of micronutrients on sleep health.
Double perovskites (DP) of the general formula Ba2MReO6, where M = Mg, Zn, and Y2/3, all based on Re(6+) (5d(1), t2g(1)), were synthesized and studied using magnetization, heat capacity, muon spin relaxation, and neutron-scattering techniques. All are cubic, Fm3̅m, at ambient temperature to within the resolution of the X-ray and neutron diffraction data, although the muon data suggest the possibility of a local distortion for M = Mg. The M = Mg DP is a ferromagnet, Tc = 18 K, with a saturation moment ∼0.3 bohr magnetons at 3 K. There are two anomalies in the heat capacity: a sharp feature at 18 K and a broad maximum centered near 33 K. The total entropy loss below 45 K is 9.68 e.u., which approaches R ln 4 (11.52 e.u.) supporting a j = 3/2 ground state. The unit cell constants of Ba2MgReO6 and the isostructural, isoelectronic analogue, Ba2LiOsO6, differ by only 0.1%, yet the latter is an anti-ferromagnet. The M = Zn DP also appears to be a ferromagnet, Tc = 11 K, μsat(Re) = 0.1 μB. In this case the heat capacity shows a somewhat broad peak near 10 K and a broader maximum at ∼33 K, behavior that can be traced to a smaller particle size, ∼30 nm, for this sample. For both M = Mg and Zn, the low-temperature magnetic heat capacity follows a T(3/2) behavior, consistent with a ferromagnetic spin wave. An attempt to attribute the broad 33 K heat capacity anomalies to a splitting of the j = 3/2 state by a crystal distortion is not supported by inelastic neutron scattering, which shows no transition at the expected energy of ∼7 meV nor any transition up to 100 meV. However, the results for the two ferromagnets are compared to the theory of Chen, Pereira, and Balents, and the computed heat capacity predicts the two maxima observed experimentally. The M = Y2/3 DP, with a significantly larger cell constant (3%) than the ferromagnets, shows predominantly anti-ferromagnetic correlations, and the ground state is complex with a spin frozen component Tg = 16 K from both direct current and alternating current susceptibility and μSR data but with a persistent dynamic component. The low-temperature heat capacity shows a T(1) power law. The unit cell constant of B = Y2/3 is less than 1% larger than that of the ferromagnetic Os(7+) (5d(1)) DP, Ba2NaOsO6.
In this study, ZnSe and ZnSe:Cu quantum dots (QDs) were synthesized using Na2 SeO3 as the Se source by a rapid and room temperature photochemical (UV-assisted) approach. Thioglycolic acid (TGA) was employed as the capping agent and UV illumination activated the chemical reactions. Synthesized QDs were successfully characterized using X-ray diffraction (XRD), transmission electron microscopy (TEM), photoluminescence (PL) and UV-visible (UV-vis) spectroscopy, Fourier transform-infrared (FT-IR), and energy dispersive X-ray spectroscopy (EDX). XRD analysis demonstrated the cubic zinc blend phase QDs. TEM images indicated that round-shaped particles were formed, most of which had a diameter of about 4 nm. The band gap of the ZnSe QDs was higher than that for ZnSe in bulk. PL spectra indicated an emission with three peaks related to the excitonic, surface trap states and deep level (DL) states. The band gap and QD emission were tunable only by UV illumination time during synthesis. ZnSe:Cu showed green emission due to transition of electrons from the Conduction band (CB) or surface trap states to the (2) T2 acceptor levels of Cu(2)(+) . The emission was increased by increasing the Cu(2)(+) ion
 concentration, such that the optimal value of PL intensity was obtained for the nominal mole ratio of Cu:Zn 1.5%.
Zn-metalloproteins are a major class of targets for drug design. They constitute a demanding testing ground for polarizable molecular mechanics/dynamics aimed at extending the realm of quantum chemistry (QC) to very long-duration molecular dynamics (MD). The reliability of such procedures needs to be demonstrated upon comparing the relative stabilities of competing candidate complexes of inhibitors with the recognition site stabilized in the course of MD. This could be necessary when no information is available regarding the experimental structure of the inhibitor-protein complex. Thus, this study bears on the phosphomannose isomerase (PMI) enzyme, considered as a potential therapeutic target for the treatment of several bacterial and parasitic diseases. We consider its complexes with 5-phospho-d-arabinonohydroxamate and three analog ligands differing by the number and location of their hydroxyl groups. We evaluate the energy accuracy expectable from a polarizable molecular mechanics procedure, SIBFA. This is done by comparisons with ab initio quantum-chemistry (QC) calculations in the following cases: (a) the complexes of the four ligands in three distinct structures extracted from the entire PMI-ligand energy-minimized structures, and totaling up to 264 atoms; (b) the solvation energies of several energy-minimized complexes of each ligand with a shell of 64 water molecules; (c) the conformational energy differences of each ligand in different conformations characterized in the course of energy-minimizations; and (d) the continuum solvation energies of the ligands in different conformations. The agreements with the QC results appear convincing. On these bases, we discuss the prospects of applying the procedure to ligand-macromolecule recognition problems. © 2016 Wiley Periodicals, Inc.
In this article, we determined the concentration levels of metals including Zn, Al, Sr, and Co and metalloid of As of ballast water in commercial ships entering Bushehr port, along the Persian Gulf. Ballast water samples were taken from commercial ships entering Bushehr port from 34 ports around the world during 15 February and 25 August 2016. The concentration levels of metals and metalloid were determined by using a graphite furnace absorption spectrometer (AAS).
To test the applicability of lichens in the biomonitoring of atmospheric elemental deposition in a typical steppe zone of Inner Mongolia, China, six foliose lichens (Physcia aipolia, PA; P. tribacia, PT; Xanthoria elegans, XE; X. mandschurica, XM; Xanthoparmelia camtschadalis, XPC; and Xp. tinctina, XPT) were sampled from the Xilin River Basin, Xilinhot, Inner Mongolia, China. Twenty-five elements (Al, Ba, Cd, Ce, Cr, Cs, Cu, Fe, K, La, Mn, Mo, Na, Ni, P, Pb, Sb, Sc, Sm, Tb, Th, Ti, Tl, V and Zn) in the lichens were analysed using inductively coupled plasma mass spectrometry (ICP-MS). The results show that Cd, Pb and Zn were mainly atmospheric in origin, whereas the other elements were predominantly of crustal origin. Compared with other studies, our data were higher in crustal element concentrations and lower in atmospheric element concentrations, matching with the frequent, severe dust storms and road traffic in the area. The elemental concentrations in lichens are both species- and element-specific, highlighting the importance of species selection for biomonitoring air pollution using lichens. We recommend PT, XE, XM and XPT for monitoring atmospheric deposition of crustal elements; XPC and XPT for Cd and Pb; PA for Cd and Zn; and PT for Cd.
The concentration of trace elements (TEs) and their risk to narrow-ridged finless porpoises (Neophocaena asiaeorientalis) are still unclear. The present study determined the concentration of typical TEs in liver, kidney, and muscle tissues from porpoises in the East China Sea, assessed potential health risk of TEs to porpoises, and explored the relationship between TE concentration and metallothionein genes (MTs) polymorphism. It was found that Zn, Cu, Mn, Cd and Hg were highly accumulated in liver, and Cd was highly accumulated in kidney. The concentrations of Cr, As, Pb and Ni were very low in all three tissues. TE concentrations showed significant positive correlation with body length, and sexual variation. The levels of most TEs were higher in tissues of porpoises in Ningbo and Nantong than in Pingtan, which is likely related to the local environment pollution level. The risk assessment showed that porpoises from Nantong and Ningbo could face health risks due to Hg, As, Cd, Pb, and Cr exposure. Moreover, two polymorphic sites on the MT4 gene were found to be significantly associated with increased levels of Hg, Cd, Zn and Mn. Whether these two polymorphic sites are involved in expression of MTs, or other functional processes, needs further research.
As dysregulation of matrix metalloproteinase (MMP) activity is associated with a wide range of pathophysiological processes like cancer, atherosclerosis, and arthritis, MMPs represent a valuable target for the development of new therapeutics and diagnostic tools. We herein present the chiral pool syntheses, in vitro evaluation, and SAR studies of a series of d- and l-proline- as well as of (4R)-4-hydroxy-l-proline-derived MMP inhibitors possessing general formula 1. Some of the synthesized hydroxamic acids were found to be potent MMP inhibitors with IC50 values in the nanomolar range, also demonstrating no off-target effects toward the other tested Zn(2+)-dependent metalloproteases (ADAMs and meprins). Utilizing the structure of the (2S,4S)-configured 4-hydroxyproline derivative 4, a selective picomolar inhibitor of MMP-13, the radiolabeled counterpart [(18)F]4 was successfully synthesized. The radiotracer's biodistribution in mice as well as its serum stability were evaluated for assessing its potential use as a MMP-13 targeting PET imaging agent.
The application of atomic layer deposition (ALD) to metal-organic frameworks (MOFs) offers a promising new approach to synthesize designer functional materials with atomic precision. While ALD on flat substrates is well established, the complexity of the pore architecture and surface chemistry in MOFs present new challenges. Through in situ synchrotron X-ray powder diffraction, we visualize how the deposited atoms are localized and redistribute within the MOF during ALD. We demonstrate that the ALD is regioselective, with preferential deposition of oxy-Zn(II) species within the small pores of NU-1000. Complementary density functional calculations indicate that this startling regioselectivity is driven by dispersion interactions associated with the preferen-tial adsorption sites for the organometallic precursors prior to reaction.
Independently controlling the shape anisotropy and chemical composition of multinary semiconductor particles is important for preparing highly efficient photocatalysts. In this study, we prepared ZnS-AgInS2 solid solution ((AgIn)xZn2(1-x)S2, ZAIS) nanoparticles with well-controlled anisotropic shapes, rod and rice shapes, by reacting corresponding metal acetates with a mixture of sulfur compounds with different reactivities, elemental sulfur, and 1,3-dibutylthiourea, via a two-step heating-up process. The chemical composition predominantly determined the energy gap of ZAIS particles: the fraction of Zn(2+) in rod-shaped particles was tuned by the ratio of metal precursors used in the nanocrystal formation, while postpreparative Zn(2+) doping was necessary to increase the Zn(2+) fraction in the rice-shaped particles. The photocatalytic H2 evolution rate with irradiation to ZAIS particles dispersed in an aqueous solution was significantly dependent on the chemical composition in the case of using photocatalyst particles with a constant morphology. In contrast, photocatalytic activity at the optimum ZAIS composition, x of 0.35-0.45, increased with particle morphology in the order of rice (size: ca. 9 × ca. 16 nm) < sphere (diameter: ca. 5.5 nm) < rod (size: 4.6 × 27 nm). The highest apparent quantum yield for photocatalytic H2 evolution was 5.9% for rod-shaped ZAIS particles, being about two times larger than that obtained with spherical particles.
Concentration values of 24 elements (Al, As, Ba, Be, Ca, Cd, Co, Cr, Cu, Fe, Ge, Hg, Mn, Mo, Pb, Sb, Se, Sn, Sr, Ti, Tl, U, V, and Zn) were determined in 72 honey samples produced in Italy by inductively coupled plasma mass spectrometry (ICP-MS). Considering the recommended established heavy metal daily intakes for humans, in this perspective, an equilibrated and ordinary honey consumption should not be considered matter of concerns for human health, even if particular attention should be addressed if honey is consumed by children, due to different maximum daily heavy metal intakes. Chemometric analysis of the results obtained highlights heavy metal content differences in honey samples obtained from notoriously polluted zones, confirming then that honey can be considered a bio-indicator of environmental pollution. Finally, Pearson coefficients highlighted correlations among element contents in honey samples.
The aquatic environment is affected by heavy metal pollution. This study was conducted to test the hypothesis that environmental factors and anthropogenic activities influence the distributions and the risks posed by heavy metals in surface sediments in shallow lakes in eastern China, which is an area affected by rapid urbanization, industrialization, and population growth. Total Cd, Cr, Cu, Ni, Pb, Se, and Zn concentrations in sediment samples were determined using inductively coupled plasma optical emission spectrometry. The I geo showed that sediments in the lakes were moderately polluted with Cr, Cu, Pb, and Zn, and the EF method showed that Cd and
 Se were significantly enriched in lakes. The heavy metals were found to pose moderate risks in most of the lakes, except for Gaoyou Lake, Honghu Lake, Poyang Lake, and Weishan Lake. The RI method indicated that very high risks were posed in Dongting Lake and Poyang Lake. Cd was found to pose much higher levels of risk than the other metals. Significant correlations were found between the heavy metal concentrations and the total carbon, nitrogen, phosphorus, and sulfur concentrations. The gross domestic product represented anthropogenic activities well. The gross domestic product of an area and the gross domestic products of primary and secondary industries in an area all had significant relationships with the concentrations of Cu and Pb, indicating that anthropogenic activities have different impacts on pollution with different heavy metals. The gross domestic product index was found to be a driving force behind the pollution of lakes with heavy metals.
The aim of the study was to determine the concentrations of selected trace elements in needles and bark of Scots pine (Pinus sylvestris L.), leaves and bark of silver birch (Betula pendula L.), and Norway maple (Acer platanoides L.), as well as in the soil in which the trees grew, depending on their localization and hence the distribution of local pollution sources. The content of trace elements in needles of Scots pine, leaves of silver birch, and Norway maple and in bark of these trees depended on the location, tree species, and analyzed organ. The content of Fe, Mn, and Zn in needles, leaves, and bark of the examined tree species was significantly higher than that of the other elements. The highest average content of Fe and Mn was detected in leaves of Norway maple whereas the highest average content of Zn was found in silver birch leaves. The impact of such locations as the center of Olsztyn or roadside along Road 51 on the content of individual elements tended to be more pronounced than the influence of the other locations. The influence of the sampling sites on the content of trace elements in tree bark was less regular than the analogous effect in needles and leaves. Moreover, the relevant dependences were slightly different for Scots pine than for the other two tree species. The concentrations of heavy metals determined in the soil samples did not exceed the threshold values set in the Regulation of the Minister for the Environment, although the soil along Road 51 and in the center of Olsztyn typically had the highest content of these elements. There were also significant correlations between the content of some trace elements in soil and their accumulation in needles, leaves, and bark of trees.
Novel bioactive complexes of Co(II), Cu(II), Ni(II) and Zn(II) metal ions with Schiff base ligand derived from histidine and 1,3-indandione were synthesized and thoroughly characterized by various analytical and spectral techniques. The biological investigations were carried out to examine the efficiency of the binding interaction of all the complexes with calf thymus DNA (CT-DNA). The binding properties were studied and evaluated quantitatively by Kb and Ksq values using UV-visible, fluorescence spectroscopy and voltammetric techniques. The experimental results revealed that the mode of binding of all the complexes with CT-DNA is via intercalation. It is further verified by viscosity measurements and thermal denaturation experiments. From the results of the cleavage study with pUC19 DNA it is inferred that all the complexes possess excellent cleaving ability. The present investigation proved that the binding interaction of all the complexes are significantly strong and the order of binding strength of the complexes is [Ni(L)2] (Kb = 3.11 × 10(6) M(-1)) > [Co(L)2] (Kb = 2.89 × 10(6) M(-1)) > [Cu(L)2] (Kb = 2.64 × 10(6) M(-1)) > [Zn(L)2] (Kb = 2.41 × 10(5) M(-1)). The complexes were also screened for antibacterial and anticandidal activity. The in vitro cytotoxicity of the ligand and complexes on the NIH/3 T3 mouse fibroblast cell lines were examined using CellTiter-Blue® (CTB) Cell viability assay, which unveiled that all the complexes exhibit more potent activities against NIH/3 T3 cells. Among all the complexes [Zn(L)2] complex showed the maximum efficiency.
A total of 480 pigs (PIC 327 × 1050; initially 48.7 ± 2.3 kg) were used to determine the interactive effects of supplemental Cu, Zn, and ractopamine HCl (RAC) on finishing pig growth performance, carcass characteristics, and antimicrobial susceptibility of enteric bacteria. Treatments were arranged in a 2 × 2 × 2 factorial with the main effects of added Cu (CuSO; 0 vs. 125 mg/kg Cu), Zn (ZnO; 0 vs. 150 mg/kg Zn), and RAC (0 vs. 10 mg/kg during the last 28 d prior to marketing). All diets contained 11 mg/kg Cu and 73 mg/kg Zn from the trace mineral premix. Pens of pigs were balanced and blocked on initial BW and then randomly allotted to 1 of the 4 mineral treatment diets. At 28 d prior to marketing, pens within each block and mineral treatment were randomly assigned to receive either 0 or 10 mg/kg RAC in addition to the mineral treatment. Adding either Cu or Zn alone did not improve ADG or ADFI yet resulted in numerical improvements in overall G:F and caloric efficiencies, but improvements were not additive (Cu × Zn, = 0.057, = 0.068, and = 0.064 for G:F and caloric efficiency on a ME and NE basis, respectively). Ractopamine improved ( < 0.001) overall ADG, G:F, and caloric efficiency, thereby increasing final BW by 3% with no change in ADFI. Ractopamine also increased ( < 0.001) HCW, percentage carcass yield, G:F, loin depth, and percent fat-free lean and decreased ( = 0.014) backfat. Adding Zn or Cu alone to diets containing RAC numerically improved percent yield and HCW G:F, but this effect was absent when the Cu or Zn was added to the control diet or when Cu and Zn were fed in combination in RAC diets (Cu × Zn × RAC, = 0.011 and = 0.018 for yield and HCW G:F, respectively). Fecal samples were collected on d 0 and at the conclusion of the finishing period (d 90) for bacterial isolation and antimicrobial susceptibility determinations according to Clinical and Laboratory Standards Institute minimal inhibitory concentrations breakpoints. spp. and isolates displayed varying levels of resistance to certain antibiotics prior to initiation of treatments on d 0. Resistance to most antibiotics decreased ( < 0.05) over time or was stable for those that had a low baseline percentage of resistance. Neither Zn nor RAC adversely affected antimicrobial resistance. However, extended feeding of 125 mg/kg Cu throughout the finishing period seems to decrease enterococcal susceptability to tetracycline, tylosin, and quinupristin/dalfopristin.
Forty-two Angus crossbred steers (380 ± 5.3 kg) were enrolled in a finishing study to evaluate the influence of a supplemental Zn amino-acid complex (ZnAA; Availa-Zn) on performance and carcass characteristics of finishing steers in combination with ractopamine hydrochloride (RAC). Steers were stratified by BW into 7 pens of 6 steers each, and individual feed intake was measured. Steers were assigned to 1 of 4 treatments for 86 d (pre-RAC period): a dry-rolled corn-based diet supplemented with 60 mg Zn/kg DM from ZnSO and no supplemental ZnAA (CON; analyzed 88 mg Zn/kg DM; = 6) or CON diet supplemented with 30 (Zn30; = 12), 60 (Zn60; = 12), or 90 (Zn90; = 11) mg Zn/kg DM from ZnAA. Day 86 BW and G:F displayed a quadratic tendency ( = 0.09) with Zn60 steers being greater than the other treatments. Plasma cyclic adenosine monophosphate tended to linearly increase with increasing ZnAA ( = 0.10). On d 88, 6 of 12 steers (one of the 2 pens) receiving supplemental ZnAA was randomly selected to be supplemented with RAC at 300 mg∙steer∙d for the final 28 d of the experiment (RAC period). This created 7 final treatments: CON: no supplemental ZnAA, no RAC ( = 5); Zn30: Zn30, no RAC ( = 5); Zn30R: Zn30 + RAC ( = 6); Zn60: Zn60, no RAC ( = 6); Zn60R: Zn60 + RAC ( = 6); Zn90: Zn90, no RAC ( = 5); and Zn90R: Zn90 + RAC ( = 6). During the RAC period, as supplemental ZnAA increased within RAC-supplemented treatments, there was a linear increase in final BW, ADG, and G:F ( < 0.05). However, there was no effect of supplemental ZnAA on BW, ADG, or G:F during this period in non-RAC fed steers ( ≥ 0.44). Day 111 plasma Cu was increased, plasma Fe decreased, and leukocyte counts and serum interleukin-8 concentrations were greater ( < 0.05) in RAC-fed steers suggesting that RAC may elicit a mild inflammatory response. There was a tendency for increasing Zn supplementation to decrease plasma haptoglobin within RAC-fed steers ( = 0.07), suggesting that Zn may alter the inflammatory response. Overall, Zn60 improved growth performance during the pre-RAC period. Zinc supplemented as ZnAA appears to improve growth in combination with RAC supplementation, suggesting that Zn may enhance or support the biological function of RAC. Additionally, these results indicate that feeding RAC impacts trace mineral status, and potentially causes a non-specific inflammatory response, but further research is required to define this response.
The Long-Term Sludge Experiment (LTSE) began in 1994 at nine UK field sites as part of continuing research into the effects of sludge-borne heavy metals on soil fertility. The long-term effects of Zn, Cu, and Cd on the most probable numbers of cells (MPN) of biovar were monitored for 8 yr in sludge-amended soils. To assess the statutory limits set by the UK Sludge (Use in Agriculture) Regulations, the experimental data were reviewed using statistical methods of meta-analysis. Previous LTSE studies have focused predominantly on statistical significance rather than effect size, whereas meta-analysis focuses on the magnitude and direction of an effect, i.e., the practical significance rather than
 its statistical significance. Results showed Zn to be the most toxic element causing an overall significant decrease in MPN of -26.6% during the LTSE. The effect of Cu showed no significant effect on MPN at concentrations below the UK limits, although a -5% decrease in MPN was observed in soils where total Cu ranged from 100 to <135 mg kg. Overall, there was nothing to indicate that Cd had a significant effect on MPN below the current UK statutory limit. In summary, the UK statutory limit for Zn appears to be insufficient for protecting from Zn toxicity effects.
Regions with long-term animal manure applications based on nitrogen (N) requirements have concerns regarding elevated nutrient levels. Most attention has focused on phosphorus (P), but heavy metal accumulation has received attention due to perceived environmental concerns. Composting is a potential management practice that can reduce total manure mass and volume while creating a stabilized product that has less odor and fewer pathogens. However, composting animal manures can lead to high N loss via ammonia volatilization and increased concentrations of nonvolatile nutrients. The objective of this study was to measure copper (Cu) and zinc (Zn) concentrations in runoff water from plots fertilized with composted and fresh poultry litter. Seven treatments were evaluated in the first year: (i) unfertilized control, (ii) fresh poultry litter, (iii) normal compost (no amendment), (iv) composted litter with alum, (v) composted litter with phosphoric acid, (vi) composted litter with a microbial mixture, and (vii) composted litter with alum + microbial mixture. Six of these treatments were evaluated in Year 2 (alum + microbial mixture was not evaluated in Year 2). Rainfall simulators were used to produce a 5 cm h storm event sufficient in length to cause 30 min of continuous runoff. Concentrations of Cu and Zn were elevated in compost compared with fresh poultry litter. However, metal concentrations in compost did not correlate well with metal concentrations in runoff water and may have been affected by compost maturity and amendment. Total Cu and Zn concentrations in runoff water did not differ between alum-amended compost and fresh poultry litter in each year.
Macro- and microelements contained in the feces of cattle egrets () and other colonial birds in heronries can be sources of contamination of nearby waterways. Concentrations of the macroelements potassium (K), calcium (Ca), magnesium (Mg), sodium (Na), sulfur (S) and the microelements zinc (Zn), copper (Cu), iron (Fe), manganese (Mn), and boron (B) were measured in water and fecal samples collected from four locations containing heronries during the breeding seasons of 2011, 2012, and 2013. Nitrogen and phosphorus were measured but not reported in this study. Concentrations of K in feces ranged from 8.19 × 10 ± 4.38 × 10 to 4.88 × 10 ± 7.57 × 10 mg kg, and concentrations in water ranged from 3.92 ± 0.05 to 17.93 ± 0.37 mg L. Similarly, concentrations of Ca in feces ranged from 4.17 × 10 ± 1.84 × 10 to 1.16 × 10 ± 4.14 × 10 mg L, and concentrations in water ranged from 25.28 ± 0.89 to 67.88 ± 2.02 mg L. When birds nested directly over water, concentrations of K, Ca, and Mg in water were significantly higher ( < 0.05) than concentrations in water adjacent to birds nesting on islands. The results from this study show that macroelements from avian feces have the potential to enrich surface water and to negatively affect surface water quality. These results provide information regarding the contribution of nutrients from heronries (comprised primarily by cattle egrets) to watersheds.
The accumulation of phosphorus (P) and metals is a serious concern with the continuous application of manure to agricultural soils. Solid-liquid separation of swine slurry is a promising approach to reduce P and metal loadings through application of separated liquid (SL) as a nutrient source. However, little information is available on nutrient and metal loadings with the application of SL compared with unseparated raw manure (RM). We analyzed element concentrations and calculated nutrient and metal loadings for RM and their respective SL applications, considering an application rate of 100 kg total nitrogen (N) ha. Samples of SL were obtained through three separation techniques: (i) centrifugation without a flocculant, (ii) centrifugation with a flocculant, and (iii) rotary press with a flocculant. Irrespective of separation technique, calculated P loadings with the application of SL were only 50 to 70% of that of RM at equivalent rates of total N yet exceeded crop removal rate. In contrast, calculated K and Na loadings with SL application were significantly greater than with RM, indicating a possible build-up of K and Na in soil. Calculated Ca and Mg loadings were significantly greater with RM than with SL. Loadings of Al, As, Ba, Cd, Cr, Fe, Mn, Ni, Pb, Sn, Se, Ti, and V were low, whereas Cu and Zn loadings were above crop removal rates for RM and SL. For solid-liquid separation to provide a lasting solution to the problem of P and metal accumulation, the SL must be supplemented with commercial N fertilizer to meet crop N demand.
Besides cell death, nanoparticles (Nps) can induce other cellular responses such as inflammation. The potential immune response mediated by the exposure of human lymphoid cells to metal oxide Nps (moNps) was characterized using four different moNps (CeO2, TiO2, Al2O3, and ZnO) to study the three most relevant mitogen-activated protein kinase subfamilies and the nuclear factor kappa-light-chain-enhancer of the activated B-cell inhibitor, IκBα, as well as the expression of several genes by immune cells incubated with these Nps. The moNps activated different signaling pathways and altered the gene expression in human lymphocyte cells. The ZnO Nps were the most active and the release of Zn(2+) ions was the main mechanism of toxicity. CeO2 Nps induced the smallest changes in gene expression and in the IκBα protein. The effects of the particles were strongly dependent on the type and concentration of the Nps and on the cell activation status prior to Np exposure.
Dicer1 is an endoribonuclease involved in the biogenesis of functional molecules such as microRNAs (miRNAs) and endogenous small interfering RNAs (endo-siRNAs). These small non-coding RNAs are important regulators of post-transcriptional gene expression and participate in the control of male fertility. With the knowledge that 1) Dicer1-dependent factors are required for proper sperm maturation in the epididymis, and that 2) miRNAs are potent mediators of intercellular communication in most biological systems, we investigated the role of Dicer1-dependent factors produced by the proximal epididymis (initial segment/caput)- including miRNAs- on the regulation of epididymal gene expression in the distal epididymis regions (i.e. corpus and cauda). To this end, we performed comparative microarray and ANOVA analyses on control vs. Defb41iCre/wt;Dicer1fl/fl mice in which functional Dicer1 is absent from the principal cells of the proximal epididymis. We identified 35 and 33 transcripts that displayed significant expression level changes in the corpus and cauda regions (Fold change > 2 or < -2; p < 0.002), respectively. Among these transcripts, Zn-alpha 2-glycoprotein (Azgp1) encodes for a sperm equatorial protein whose expression in the epididymis of Dicer1 cKO mice is significantly increased compared to controls. In addition, 154 miRNAs, including miR-210, miR-672, miR-191 and miR-204, showed significantly impaired biogenesis in the absence of Dicer1 from the principal cells of the proximal epididymis (Fold change > 2 or < -2; p < 0.01). These miRNAs are secreted via extracellular vesicles (EVs) derived from the DC2 epididymal principal cell line, and their expression correlates with target transcripts involved in distinct biological pathways, as evidenced by in silico analysis. Albeit correlative and based on in silico approach, our study proposes that Dicer1-dependent factors trigger- directly or not-significant genes expression changes in distinct regions of this organ. The paracrine control of functions important to post-testicular sperm maturation by Dicer1-dependent factors may open new avenues for the identification of molecular targets important to male fertility control.
Potassium (K) fertilizer management is beneficial for improving growth, yield and yield components of field crops under moisture stress condition in semiarid climates. Field experiments were conducted to study the response of maize (Zea mays L., cv. Azam) to foliar and soil applied K during summer 2013 and 2014. The experiments were carried out at the Agronomy Research Farm of The University of Agriculture Peshawar, Northwest Pakistan under limited irrigation (moisture stress) condition. It was concluded from the results that application of foliar K at the rate of 1-3% and foliar Zn at the rate of 0.1-0.2% was more beneficial in terms of better growth, higher yield and yield components of maize under moisture stress condition. Early spray (vegetative stage) resulted in better growth and higher yield than late spray (reproductive stage). Soil K treated plots (rest) plots performed better than control (K not applied) in terms of improved growth, higher yield and yield components of maize crop. The results further demonstrated that increasing the rate of soil applied K up to 90 kg P ha(-1) in two equal splits (50% each at sowing and knee height) improve growth and maize productivity under semiarid climates.
Phytochelatin (PC) synthesis is essential for the detoxification of non-essential metals such as cadmium (Cd). In vitro experiments with Arabidopsis thaliana seedlings had indicated a contribution to zinc (Zn) tolerance as well. We addressed the physiological role of PC synthesis
 in Zn homeostasis of plants under more natural conditions. Growth responses, PC accumulation and leaf ionomes of wild-type and AtPCS1 mutant plants cultivated in different soils representing adequate Zn supply, Zn deficiency and Zn excess were analyzed. Growth on Zn-contaminated soil triggers PC synthesis and is strongly impaired in PC-deficient mutants. In fact, the contribution of AtPCS1 to tolerating Zn excess is comparable with that of the major Zn tolerance factor MTP1. For plants supplied with a normal level of Zn, a significant reduction in leaf Zn accumulation of AtPCS1 mutants was detected. In contrast, AtPCS1 mutants grown under Zn-limited conditions showed wild-type levels of Zn accumulation, suggesting the operation of distinct Zn translocation pathways. Contrasting phenotypes of the tested AtPCS1 mutant alleles upon growth in Zn- or Cd-contaminated soil indicated differential activation of PC synthesis by these metals. Experiments with truncated versions identified a part of the AtPCS1 protein required for the activation by Zn but not by Cd.
Mechanically ball-mill prepared clinoptilolite nanoparticles (NC) were used for increasing photocatalytic activity of NiO and ZnO as alone and binary systems. The semiconductors were supported onto the zeolite during calcination of Ni(II)-Zn(II)-exchanged NC at different calcinations temperatures. XRD, FTIR, SEM-EDX, X-ray mapping, DRS, TEM and BET techniques were used for characterization of the samples. The calcined catalysts at 400°C for 4h showed the best photocatalytic activity for metronidazole (MNZ) in aqueous solution. The mole ratio of ZnO/NiO affected the photodegradation efficiency because activity of the coupled catalysts depends to the both e/h production and electron scavenging processes. In the used system, NiO acted as e/h production source and ZnO as an electron sink. Red shifts in band gaps of the supported coupled semiconductors was observed whit respect to monocomponent one, confirming formation of nanoparticles of the semiconductors onto the zeolitic bed. The best activities were obtained for the NiO1.3-ZnO1.5/NC (NZ-NC) and NiO0.7-ZnO4.3/NC (NZ3-NC) catalysts at pH 3, 1.2gL(-1) of the catalysts and 1gL(-1) of MNZ.
Metal buildup was estimated in potato (Solanum tuberosum L.), grown in central Punjab, Pakistan. This crop was irrigated with multiple water sources like ground, sewage and canal water. Concentrations of different metals like zinc (Zn), arsenic (As), lead (Pb), iron (Fe), nickel (Ni), molybdenum (Mo), copper (Cu), and selenium (Se) were assessed in the potato crop irrigated with different types of waters. Sewage water treated crop and soil had higher metal concentrations than those treated with other two treatments. All metals had positive and significant correlation except for Mo which was non-significantly correlated between the vegetable and soil. Highest daily intake was observed for Fe (0.267), whereas the lowest was seen for Se (0.003). The enrichment factor and health index varied between 0.135-15.08 and 0.285-83.77, respectively. This study concludes that vegetables cultivated on soil treated with sewage water is a potent threat for human health as the metals manifest toxicity after entering the food chain.
Photocatalytic fuel cell (PFC) is a potential wastewater treatment technology that can generate electricity from the conversion of chemical energy of organic pollutants. An immobilized ZnO/Zn fabricated by sonication and heat attachment method was applied as the photoanode and Pt/C plate was used as the cathode of the PFC in this study. Factors that affect the decolorization efficiency and electricity generation of the PFC such as different initial dye concentrations and pH were investigated. Results revealed that the degradation of Reactive Green 19 (RG19) was enhanced in a closed circuit PFC compared with that of a opened circuit PFC. Almost 100% decolorization could be achieved in 8 h when 250 mL of 30 mg L(-1) of RG19 was treated in a PFC without any supporting electrolyte. The highest short circuit current of 0.0427 mA cm(-2) and maximum power density of 0.0102 mW cm(-2) was obtained by PFC using 30 mg L(-1) of RG19. The correlation between dye degradation, conductivity and voltage output were also investigated and discussed.
Samples of dried marine macroalgae (Fucus serratus, Palmaria palmata and Ulva lactuca) have been analysed for trace elements by a novel, non-destructive approach involving a Niton field-portable-X-ray fluorescence (FP-XRF) spectrometer configured in a low density plastics mode with thickness correction. Detection limits for a 200-s counting time ranged from <5 μg g(-1) for As and Pb in F. serratus and As in P. palmata to several tens of μg g(-1) for Cd, Sb and Sn in all species tested. Arsenic, Cu, Pb and Zn were detected by the XRF in samples collected from a protected beach (n = 18) and in samples therefrom that had been exposed to additional aqueous elements in combination (n = 72) with concentrations returned (in μg g(-1)) ranging from 3.9 to 39.7 for As, 13.0 to 307 for Cu, 6.1 to 14.7 for Pb and 12.5 to 522 for Zn. Independent measurements of trace elements in the macroalgae by ICP-MS following nitric acid digestion revealed a direct and significant proportionality with concentrations returned by the XRF, with slopes of the XRF-ICP relationships (As = 1.0; Cu = 2.3; Pb = 2.4; Zn = 1.7) that can be used to calibrate the instrument for direct measurements. The approach shows potential for the in situ monitoring of macroalgae in coastal regions that is currently being investigated.
We explored acquired immunity resulting from vaccination in 3 to 7-year-old children, chronically exposed to multiple heavy metals and metalloids, in an e-waste recycling area (Guiyu, China). Child blood levels of ten heavy metals and metalloids, including lead (Pb), arsenic (As), mercury (Hg), chromium (Cr), cadmium (Cd), manganese (Mn), nickel (Ni), copper (Cu), zinc (Zn) and selenium (Se), and seven vaccine antibodies (diphtheria, pertussis, tetanus, hepatitis B, Japanese encephalitis, polio, measles) were measured. The exposed group had higher levels of blood Pb, Mn, Cu, Zn and Cr compared to the reference group (P < 0.05). Levels of all vaccine antibodies in the exposed group were significantly lower than in the reference group (P < 0.01). All vaccine antibodies negatively correlated with blood concentrations of Cu, Zn and Pb, based on spearman rank correlation analysis. Multiple logistic regression and univariate analyses identified the location of residence (Guiyu), high blood Pb (>10 μg/dL) and high blood Cu and Zn (upper median value of each group) to be inversely associated with seven antibody titers. Antibody titers increased with age, BMI, high blood Mn (>15 μg/L), and high blood Cd and Ni (upper median value of each group). Results suggest multiple heavy metal and metalloid exposure, especially to Pb, Zn and Cu, may be a risk factor inhibiting the development of child immunity, resulting in decreased child antibody levels against vaccines.
The evaluation of heavy metals (HMs) in greenhouse soils is crucial for both environmental monitoring and human health; thus, it is imperative to determine their concentrations, identify their sources and assess their potential risks. In this study, eight metals (As, Cd, Cr, Cu, Hg, Ni, Pb, and Zn) in 167 surface soils were investigated in two representative greenhouse vegetable systems of China: perennial solar greenhouse (SG) and seasonal plastic greenhouse (PG). The results indicated accumulations of Cd, Cu, Hg and Zn in the SG soils and Cd, Pb, Hg and Zn in the PG soils, with higher concentrations than the background values. In particular, Cd and Hg exhibited high levels of pollution under both GVP systems due to their positive Igeo values. Principle component analysis (PCA) and correlation analysis suggested that Cd, Cu, Hg and Zn in the SG soils and Cd, Hg and Zn in the PG soils were mainly related to intensive farming practices; Pb in the PG soils was significantly affected by atmospheric deposition. The results showed that soil characteristics, in particular soil organic matter, total nitrogen and total phosphorus, exerted significant influence on Hg, Cu, Cd, and Zn under the SG system. However, the HMs in the PG soils were weakly affected by soil properties. Overall, this study provides comparative research on the accumulation, potential risks and sources of HMs in two typical greenhouse soils in China, and our findings suggest that, Cd and Hg in both greenhouse soils could potentially represent environmental problems.
The addition of Lewis or Brönsted acids (LA = Zn(OTf)2, B(C6F5)3, HBAr(F), TFA) to the high-valent manganese-oxo complex Mn(V)(O)(TBP8Cz) results in the stabilization of a valence tautomer Mn(IV)(O-LA)(TBP8Cz(•+)). The Zn(II) and B(C6F5)3 complexes were characterized by manganese K-edge X-ray absorption spectroscopy (XAS). The position of the edge energies and the intensities of the pre-edge (1s to 3d) peaks confirm that the Mn ion is in the +4 oxidation state. Fitting of the extended X-ray absorption fine structure (EXAFS) region reveals 4 N/O ligands at Mn-Nave = 1.89 Å and a fifth N/O ligand at 1.61 Å, corresponding to the terminal oxo ligand. This Mn-O bond length is elongated compared to the Mn(V)(O) starting material (Mn-O = 1.55 Å). The reactivity of Mn(IV)(O-LA)(TBP8Cz(•+)) toward C-H substrates was examined, and it was found that H(•) abstraction from C-H bonds occurs in a 1:1 stoichiometry, giving a Mn(IV) complex and the dehydrogenated organic product. The rates of C-H cleavage are accelerated for the Mn(IV)(O-LA)(TBP8Cz(•+)) valence tautomer as compared to the Mn(V)(O) valence tautomer when LA = Zn(II), B(C6F5)3, and HBAr(F), whereas for LA = TFA, the C-H cleavage rate is slightly slower than when compared to Mn(V)(O). A large,
 nonclassical kinetic isotope effect of kH/kD = 25-27 was observed for LA = B(C6F5)3 and HBAr(F), indicating that H-atom transfer (HAT) is the rate-limiting step in the C-H cleavage reaction and implicating a potential tunneling mechanism for HAT. The reactivity of Mn(IV)(O-LA)(TBP8Cz(•+)) toward C-H bonds depends on the strength of the Lewis acid. The HAT reactivity is compared with the analogous corrole complex Mn(IV)(O-H)(tpfc(•+)) recently reported (J. Am. Chem. Soc. 2015, 137, 14481-14487).
A novel water-soluble cationic zinc lysine coordination compound, [Zn[(C6H14N2O2)]2Cl]Cl·2H2O (1), has been designed and synthesized and its crystal structure determined. The aqueous solution of this coordination compound is not only transparent and stable at room temperature but it is also nearly neutral (pH ∼ 7). It is worth noting that zinc oxide (ZnO) forms in situ upon dilution of a solution of the compound. The bioactivity of ZnO has been confirmed using an Alarma Blue assay. These unique properties allow the coordination compound to gently grow ZnO coating with excellent antibacterial benefits onto biomaterial surfaces in a facile and safe manner.
The filamentous fungus Penicillium oxalicum is a potential alternative to Trichoderma reesei for industrial production of a complete cellulolytic enzyme system for a bio-refinery. Comparative omics approaches can support rational genetic engineering and/or breeding of filamentous fungi with improved cellulase production capacity. In this study, comparative genomic, transcriptomic and secretomic profiling of P. oxalicum HP7-1 and its cellulase and xylanase hyper-producing mutant EU2106 were employed to screen for novel regulators of cellulase and xylanase gene expression.
The 30.62 Mb P. oxalicum HP7-1 genome was sequenced, and 9834 protein-coding genes were annotated. Re-sequencing of the mutant EU2106 genome identified 274 single nucleotide variations and 12 insertion/deletions. Comparative genomic, transcriptomic and secretomic profiling of HP7-1 and EU2106 revealed four candidate regulators of cellulase and xylanase gene expression. Deletion of these candidate genes and measurement of the enzymatic activity of the resultant mutants confirmed the identity of three regulatory genes. POX02484 and POX08522, encoding a putative Zn(II)2Cys6 DNA-binding domain and forkhead protein, respectively, were found to be novel, while PoxClrB is an ortholog of ClrB, a key transcriptional regulator of cellulolytic enzyme gene expression in filamentous fungi. ΔPOX02484 and ΔPOX08522 mutants exhibited significantly reduced β-glucosidase activity, increased carboxymethylcellulose cellulase and xylanase activities, and altered transcription level of cellulase and xylanase genes compared with the parent strain ΔPoxKu70, with Avicel as the sole carbon source.
Two novel genes, POX02484 and POX08522, were found and characterized to regulate the expression of cellulase and xylanase genes in P. oxalicum. These findings are important for engineering filamentous fungi to improve cellulase and xylanase production.
The essentiality of 14 mineral elements so far have been reported in plant nutrition. Eight of these elements were known as micronutrients due to their lower concentrations in plants (usually ≤100 mg/kg/dw). However, it is still challenging to mention an exact number of plant micronutrients since some elements have not been strictly proposed yet either as essential or beneficial. Micronutrients participate in very diverse metabolic processes, including from the primary and secondary metabolism to the cell defense, and from the signal transduction to the gene regulation, energy metabolism, and hormone perception. Thus, the attempt to understand the molecular mechanism(s) behind their transport has great importance in terms of basic and applied plant sciences. Moreover, their deficiency or toxicity also caused serious disease symptoms in plants, even plant destruction if not treated, and many people around the world suffer from the plant-based dietary deficiencies or metal toxicities. In this sense, shedding some light on this issue, the 13 mineral elements (Fe, B, Cu, Mn, Mo, Si, Zn, Ni, Cl, Se, Na, Al, and Co), required by plants at trace amounts, has been reviewed with the primary focus on the transport proteins (transporters/channels) in plant roots. So, providing the compiled but extensive information about the structural and functional roles of micronutrient transport genes/proteins in plant roots.
Plasmablastic lymphoma is an uncommon aggressive non-Hodgkin B-cell lymphoma type defined as a high-grade large B-cell neoplasm with plasma cell phenotype. Genetic alterations in MYC have been found in a proportion (~60%) of plasmablastic lymphoma cases and lead to MYC-protein overexpression. Here, we performed a genetic and expression profile of 36 plasmablastic lymphoma cases and demonstrate that MYC overexpression is not restricted to MYC-translocated (46%) or MYC-amplified cases (11%). Furthermore, we demonstrate that recurrent somatic mutations in PRDM1 are found in 50% of plasmablastic lymphoma cases (8 of 16 cases evaluated). These mutations target critical functional domains (PR motif, proline rich domain, acidic region, and DNA-binding Zn-finger domain) involved in the regulation of different targets such as MYC. Furthermore, these mutations are found frequently in association with MYC translocations (5 out of 9, 56% of cases with MYC translocations were PRDM1-mutated), but not restricted to those cases, and lead to expression of an impaired PRDM1/Blimp1α protein. Our data suggest that PRDM1 mutations in plasmablastic lymphoma do not impair terminal B-cell differentiation, but contribute to the oncogenicity of MYC, usually disregulated by MYC translocation or MYC amplification. In conclusion, aberrant coexpression of MYC and PRDM1/Blimp1α owing to genetic changes is responsible for the phenotype of plasmablastic lymphoma cases.Modern Pathology advance online publication, 30 September 2016; doi:10.1038/modpathol.2016.162.
In this study, the immobilization and risk assessment of heavy metals (HMs) in sewage sludge (SS) during hydrothermal treatment combined with pyrolysis (HTP) was investigated. The experimental results showed that the immobilization of HMs in SS was significantly affected and that the eco-toxicity/risk of SS to the environment was reduced through HTP, in addition to the enhancement of dehydration and a reduction in the volume of the sewage sludge. After the HTP process, although the majority of HMs were accumulated in the biochar, the HMs could be transformed from bioavailable fractions to more stable fractions, such as the acid soluble/exchangeable fractions (F1) of Zn, Ni and Cd in the biochar, which decreased to less than 6.31%, 2.36% and 3.64%, respectively. Moreover, the leaching potential of HMs decreased after the HTP process.
This study assessed the level of heavy metals (Zn, Cu, Mn, Hg and Fe) accumulation in leaves of five vegetables viz: Telfairia occidentalis, Heinsia crinita, Gnetum africanum, Talinum triangulare and Vernonia amygdalina planted in different gardens in Ibesikpo Asutan and Uyo L.G.As in Akwa Ibom State, Nigeria using standard scientific methods.
Soil samples were obtained at a depth of 0 - 10 cm each at the base of each vegetable using soil auger.
The results obtained from this study showed that the nutrient status and heavy metals concentrations of the soil of the two Local Government Areas were not significantly (P= 0.05) different. However, the levels of the heavy metals contents of the leaves of the vegetables were observed to fall within World Health Organisation (WHO) permissible concentration range. This observation indicated that there are little or no anthropogenic activities in or around the garden leading to the emission of heavy metals into the environment. Also, the result attributes the low heavy metals accumulation in the soil and poor translocation to the use of organic supplements in the gardens.
The finding of this study certifies that there is no risk associated with the consumption of vegetables from these farms. This result is discussed in line with current global trends in pollution management and dietetics.
The aim of this study is to establish changes that may occur after a prolonged application of wastewater sludge treated to biosolids, in the 'soil-fertilizer-plant' system. Thirteen experimental plots with different soil types planted with experimental crops were investigated in order to evaluate the suitability of these biosolids as soil conditioners and fertilizers. The biosolids were incorporated in soil starting in 2006 in different quantities (from 6 tons per ha) for various arrays. The rate of application was calculated on the basis of imported nitrogen and was consistent with the characteristics of the sludge, soil diversity, growing crop requirements, and other factors. In 2013 (after 7 years of land use) average soil samples from the same arrays were taken and analyzed. No chemical fertilizer was applied during the experimental period. The results show that the use of sewage biosolids as a soil improver in accordance with local legislation does not pose any serious environmental risks but can maintain and improve soil fertility and crop yield. A slight increase in Cu and Zn in plants was detected, however the content of heavy metals in all soil samples was below maximum allowable limits and no signs of phytotoxicity were observed.
The family of compounds of general formula [Ln(III)4TM(II)8(OH)8(L)8(O2CR)8(MeOH)y](ClO4)4 {[Gd4Zn8(OH)8(hmp)8(O2C(i)Pr)8](ClO4)4 (1a); [Y4Zn8(OH)8(hmp)8(O2C(i)Pr)8](ClO4)4 (1b); [Gd4Cu8(OH)8(hmp)8(O2C(i)Pr)8](ClO4)4 (2a); [Y4Cu8(OH)8(hmp)8(O2C(i)Pr)8](ClO4)4 (2b); [Gd4Cu8(OH)8(hep)8(O2C(i)Pr)8](ClO4)4 (3a); [Gd4Cu8(OH)8(Hpdm)8(O2C(t)Bu)8](ClO4)4 (4a); [Gd4Cu8(OH)8(ea)8(O2CMe)8](ClO4)4
 (5a); [Gd4Ni8(OH)8(hmp)8(O2CEt)8(MeOH)6](ClO4)4 (6a); [Y4Ni8(OH)8(hmp)8(O2CEt)8(MeOH)6](ClO4)4 (6b); [Gd4Co8(OH)8(hmp)8(O2CEt)8(MeOH)6](ClO4)4 (7a); [Y4Co8(OH)8(hmp)8(O2CEt)8(MeOH)6](ClO4)4 (7b)} can be formed very simply and in high yields from the reaction of Ln(NO3)3·6H2O and TM(ClO4)2·6H2O and the appropriate ligand blend in a mixture of CH2Cl2 and MeOH in the presence of a suitable base. Remarkably, almost all the constituent parts, namely the lanthanide (or rare earth) ions Ln(III) (here Ln = Gd or Y), the transition metal ions TM(II) (here TM = Zn, Cu, Ni, Co), the bridging ligand L (Hhmp = 2-(hydroxymethyl)pyridine; Hhep = 2-(hydroxyethyl)pyridine; H2pdm = pyridine-2,6-dimethanol; Hea = 2-ethanolamine), and the carboxylates can be exchanged while maintaining the structural integrity of the molecule. NMR spectroscopy of diamagnetic complex 1b reveals the complex to be fully intact in solution with all signals from the hydroxide, ligand L, and the carboxylates equivalent on the NMR time scale, suggesting the complex possesses greater symmetry in solution than in the solid state. High resolution nano-ESI mass spectrometry on dichloromethane solutions of 2a and 2b shows both complexes are present in two charge states with little fragmentation; with the most intense peak in each spectrum corresponding to [Ln4Cu8(OH)8(hmp)8(O2C(i)Pr)8](ClO4)2(2+). This family of compounds offers an excellent playground for probing how the magnetocaloric effect evolves by introducing either antiferromagnetic or ferromagnetic interactions, or magnetic anisotropy, by substituting the nonmagnetic Zn(II) (1a) with Cu(II) (2a), Ni(II) (6a) or Co(II) (7a), respectively. The largest magnetocaloric effect is found for the ferromagnetically coupled complex 6a, while the predominant antiferromagnetic interactions in 2a yield an inverse magnetocaloric effect; that is, the temperature increases on lowering the applied field, under the proper experimental conditions. In spite of increasing the magnetic density by adding ions that bring in antiferromagnetic interactions (2a) or magnetic anisotropy (7a), the magnetocaloric effect is overall smaller in 2a and 7a than in 1a, where only four Gd(III) spins per molecule contribute to the magnetocaloric properties.
The interaction between gold nanorods (Au NRs), synthesized by a conventional seeded growth protocol, and the anionic tetrakis-(4-sulfonatophenyl)porphyrin (TPPS4) has been investigated through various spectroscopic techniques. At neutral pH, the formation of H-aggregates and the inclusion of porphyrin monomers in CTAB micelles covering the nanorods have been evidenced. Under mild acidic conditions (pH=3) a nano-hybrid assembly of porphyrin J-aggregates and Au NRs has been revealed. For the sake of comparison, Cu(II) and Zn(II) metal porphyrin derivatives as well as a cationic porphyrin have been studied in the same experimental conditions, showing that: i) CuTPPS4 forms porphyrin H-dimers onto the Au NRs; ii) ZnTPPS4 undergoes to demetallation, followed by acidification of the central core and eventually aggregation onto Au NRs; iii) cationic porphyrin does not interact with Au NRs.
Ultrasonic-assisted sulphuric acid leaching combined with a Fenton-like process, utilizing nanoscale zero-valent iron (nZVI), was investigated to enhance the leaching of zinc from the blast furnace sludge (BFS). The leaching of iron (Fe) and zinc (Zn) from the sludge was investigated using Milli-Q water/BFS ratio of 10 and varying the concentration of hydrogen peroxide, sulphuric acid, the temperature, the input energy for ultrasound irradiation, and the presence or absence of nZVI as a Fenton reagent. The results showed that with 1g/l addition of nZVI and 0.05M of hydrogen peroxide, the kinetic rate of Zn leaching increased with a maximum dissolution degree of 80.2%, after 5min treatment. In the absence of nZVI, the maximum dissolution degree of Zn was 99.2%, after 15min treatment with 0.1M of hydrogen peroxide. The rate of Zn leaching at several concentrations of hydrogen peroxide is accelerated in the presence of nZVI although a reduction in efficiency was observed. The loss of Fe was no more than 3%. On the basis of these results, the possible route for BFS recycling has been proposed (BFS slurry mixed with sulphuric acid and hydrogen peroxide is recirculated under ultrasonic irradiation then separated).
Cereals are a major source of dietary energy and protein but are nutritionally poor in micronutrients. Zinc (Zn) biofortification of staple crops has been proposed as a promising strategy to combat the global challenge of human Zn-deficiency. The aim of this study was to improve the Zn content in the edible part of the barley (Hordeum vulgare L.) grain by enhancing Zn translocation into the developing seeds. We demonstrate that the barley plasma membrane P-type ATPase Zn transporter, HvHMA2 is an efficient candidate for mineral biofortification of crops. Following a cisgenic approach to produce transgenic homozygous barley line over-expressing HvHMA2 in the transfer cells of the grain, resulted in a doubling of a wide range of nutrients including Zn, iron (Fe), and magnesium (Mg) in the inner endosperm. This article is protected by copyright. All rights reserved.
Cd and Zn have been shown to interact antagonistically or synergistically in various plants. In the present study of dwarf polish wheat (DPW)roots, Cd uptake was inhibited by Zn, and Zn uptake was inhibited by Cd, suggesting that Cd and Zn interact antagonistically in this plant. A study of proteomic changes showed that Cd, Zn, and Cd+Zn stresses altered the expression of 206, 303, and 190 proteins respectively. Among these, 53 proteins were altered significantly in response to all these stresses (Cd, Zn, and Cd+Zn), whereas 58, 131, and 47 proteins were altered in response to individual stresses (Cd, Zn, and Cd+Zn, respectively). Sixty-one differentially expressed proteins (DEPs) were induced in response to both Cd and Zn stresses; 33 proteins were induced in response to both Cd and Cd+Zn stresses; and 57 proteins were induced in response to both Zn and Cd+Zn stresses. These results indicate that Cd and Zn induce differential molecular responses, which result in differing interactions of Cd/Zn. A number of proteins that mainly participate in oxidation-reduction and GSH, SAM, and sucrose metabolisms were induced in response to Cd stress, but not Cd+Zn stress. This result indicates that these proteins participate in Zn inhibition of Cd uptake and ultimately cause Zn detoxification of Cd. Meanwhile, a number of proteins that mainly participate in sucrose and organic acid metabolisms and oxidation-reduction were induced in response to Zn stress but not Cd+Zn stress. This result indicates that these proteins participate in Cd inhibition of Zn uptake and ultimately cause the Cd detoxification of Zn. Other proteins induced in response to Cd, Zn, or Cd+Zn stress, participate in ribosome biogenesis, DNA metabolism, and protein folding/modification and may also participate in the differential defense mechanisms.
The new sterically hindered piperidine analog, dispiro[cyclohexane-2,2'-piperidine-6',2″-cyclohexane] (CPC(H), 2), and its N-methylated derivative CPC(Me) (3) were synthesized from commercially available starting materials in short steps. The N-lithiated amide LiCPC (4) was also isolated from 2 as a cyclictrimer in single crystals and showed slightly larger steric hindrance than that of lithium 2,2,6,6-tetramethylpiperidide (LiTMP) in the competitive methylation reaction with methyl trifluoromethanesulfonate. In addition, the heterobimetallic heteroleptic zincate complexes [Li(μ-NR2)(μ-Et)Zn(Et)] (NR2 = CPC, 5, and NR2 = TMP, 6) were obtained as THF- and TMEDA-coordinated monomer 5·(THF)2, 6·(THF)2, 5·TMEDA, and 6·TMEDA (THF = tetrahydrofuran, TMEDA = N,N,N',N'-tetramethylethylenediamine). These molecular structures bearing different amido ligands in single crystals showed little structural differences from crystallographic studies. Diffusion-ordered spectroscopy (DOSY) revealed that the solution structures of the zincate complexes 5·(THF)2 and 6·(THF)2 only differ in the number of coordination THF molecules. In the deprotonation reactions with tert-butyl 3-bromobenzoate, the zincate complexes containing the CPC ligand [Li(μ-CPC)(μ-R)Zn(R)] (R = Et (5), tBu) showed moderately improved regioselectivity for the 6 position in comparison to those containing the TMP ligand [Li(μ-TMP)(μ-R)Zn(R)] (R = Et (6), tBu).
The objective of this study was to assess the impact of metal contamination on microbial functional diversity and enzyme activity in forest soils. This study involved the evaluation of the influence of the texture, carbon content and distance to the source of contamination on the change in soil microbial activity, which did not investigate in previous studies. The study area is located in southern Poland near the city of Olkusz around the flotation sedimentation pond of lead and zinc at the Mining and Metallurgical Company "ZGH Bolesław, Inc.". The central point of the study area was selected as the middle part of the sedimentation pond. The experiment was conducted over a regular 500 × 500-m grid, where 33 sampling points were established. Contents of organic carbon and trace elements (Zn, Pb and Cd), pH and soil texture were investigated. The study included the determination of dehydrogenase and urease activities and microbial functional diversity evaluation based on the community-level physiological profiling approach by Biolog EcoPlate. The greatest reduction in the dehydrogenase and urease activities was observed in light sandy soils with Zn content >220 mg · kg(-1) and a Pb content > 100 mg · kg(-1). Soils with a higher concentration of fine fraction, despite having the greatest concentrations of metals, were characterized by high rates
 of Biolog®-derived parameters and a lower reduction of enzyme activity.
This study was designed to evaluate how varicocele (VCL) can time dependently induce zinc (Zn) and iron (Fe) toxicity in testicular tissue and to analyse the relation between heavy metals toxicity and lipid peroxidation, sperm DNA damage, nitrosative and carbonyl stresses. Twenty-four mature male Wistar rats were divided into control-sham and test groups, which were then submitted to experimentally induced VCL. Non-VCL-induced rats were considered as control-sham. The test groups were subdivided into three groups based on the sample collecting date (2, 6 and 8 months after VCL induction). Zn and Fe distribution in testicles, DNA ladder for sperm DNA fragmentation, testicular total antioxidant capacity (TAC), malondialdehyde (MDA), nitrite oxide (NO) and carbonyl groups (CG) were analysed. A significant (p < .05) enhancement in the percentage of tubules with negative tubular repopulation, differentiation and spermiogenesis indices was revealed. The VCL increased Zn and Fe distribution in testicles. The VCL, time dependently, reduced sperm count, motility and enhanced sperm DNA damage (p < .05). The VCL downregulated the testicular TAC and enhanced the MDA, NO and CG contents. Our data showed that the VCL results in intensive Fe and Zn toxicities. Produced Zn- and Fe-mediated-oxidative stress increases sperm DNA damage associated with NO and CG-induced stresses.
By employing a multidentate ligand, 2,2'-bipyridine-5,5'-dicarboxylic acid (H2bpdc), with both O-donors and N-donors, five uranyl-Cu(II)/Zn(II) heterometallic coordination polymers, (UO2)Cu(μ4-bpdc)(μ3-bpdc) (1-Cu), (UO2)Zn(μ4-bpdc)(μ3-bpdc) (1'-Zn), (UO2)CuCl(μ3-bpdc)(μ2-Hbpdc)(H2O) (2-Cu), (UO2)2Cu2Cl2(μ3-bpdc)2(μ2-Hbpdc)2(H2O)3·2H2O (2-Cu'), and (UO2)2Zn(μ3-SO4)(μ4-bpdc)(μ3-bpdc)(H2O)3 (3-Zn), were prepared under hydrothermal conditions. Thermal stability and luminescent properties of 1-Cu, 1'-Zn, 2-Cu, and 3-Zn were also investigated. Isostructural compounds 1-Cu and 1'-Zn both have a three-dimensional (3D) framework built by polycatenating of two sets of paralleling two-dimensional (2D) grids with octahedral transition metal cations (Cu or Zn) as the cross-linking nodes. As far as we know, compounds 1-Cu and 1'-Zn are the first two cases that possess polycatenated networks in heterometallic uranyl-organic coordination polymers. Compound 2-Cu contains 3-fold interpenetrated 2D networks which are built by the connection of [(UO2)2(bpdc)2(Hbpdc)2](2-) secondary building units and Cu(II). A one-dimensional tilted ladder-like structure in 2-Cu' is constructed by uranyl-bpdc chains connected by Cu(II) and Hbpdc(-). Compound 3-Zn displays a layered-like 2D network contain an unusual [(UO2)2Zn(μ3-SO4)] unit. Interestingly, different anions could lead to the change of coordination sites of transition metal cations, resulting in structural diversity of heterometallic uranyl-organic frameworks.
The purpose of this study was to examine potential long-term post-torsion changes that can occur in the histopathology, biochemistry and spermatogenesis of both torsioned and nontorsioned opposite testes. The study also determines the effect of zinc (Zn) administration on the testicular torsion/detorsion (T/D) damage on both testes. Forty-eight male rats, divided equally into eight groups: (SHAM), (SHAM+,Zn+), (T/D+, Zn- 1 month), (T/D+,Zn- 2 months), (T/D+,Zn- 3 months), (T/D+,Zn+ 1 months), (T/D+,Zn+ 2 months), (T/D+,Zn+ 3 months), have been used. Drug administration was carried out by adding 100 μg (0.016 ml/rat) Zn per rat to drinking water in related groups. Testicular damage decreased superoxide dismutase (SOD) and glutathione (GSH) and increased malondialdehyde (MDA) in the testis tissues of rats, while Zn administration increased SOD and GSH and decreased MDA in the testis tissues in comparison with the SHAM group. The beneficial effect of zinc sulphate was more evident on the nonrotated testis than the rotated testis. In the histopathological study, a significant decrease in torsion and detorsion injuries was observed in the treatment groups compared to the torsion and detorsion groups. We found a protective effect of zinc sulphate on oxidative stress as a result of T/D injuries in rats, especially for the nonrotated testis; results were supported histopathologically.
Metal accumulation in sediments threatens adjacent ecosystems due to the potential of metal mobilization and the subsequent uptake into food webs. Here, contents of heavy metals (Cd, Cr, Cu, Ni, Pb, and Zn) and trace elements (Ga, In, Mo, and Se) were determined for river waters and bed sediments that received sewage discharged from traditional and semiconductor industries. We used principal component analysis (PCA) to determine the metal distribution in relation to environmental factors such as pH, EC, and organic matter (OM) contents in the river basin. While water PCA categorized discharged metals into three groups that implied potential origins of contamination, sediment PCA only indicated a correlation between metal accumulation and OM contents. Such discrepancy in metal distribution between river water and bed sediment highlighted the significance of physical-chemical properties of sediment, especially OM, in metal retention. Moreover, we used Se XANES as an example to test the species transformation during metal transportation from effluent outlets to bed sediments and found a portion of Se inventory shifted from less soluble elemental Se to the high soluble and toxic selenite and selenate. The consideration of environmental factors is required to develop pollution managements and assess environmental risks for bed sediments.
We demonstrate a one-pot, low-cost, and scalable method for fast synthesis of superfine and uniform core-shell Cu nanowires (NWs) coated with optional metals and/or alloy. Cu NWs in high aspect ratio (>3000) were synthesized through an oleylamine-mediated solution method, and tunable shell coating was performed by injecting metal-organic precursors at the last stage of reaction. Superfine Cu@metal NWs (Ti, Zn, V, Ni, Ag, NiZn, etc) were achieved in diameter of ∼30 nm and length of ∼50 μm. Transparent conductive films were obtained by imprinting method, showing high optoelectronic performance (51 Ω/sq at 93% transmittance), high mechanical tenacity over bending, twisting, stretching, and compressing, and robust antioxidant ability (high temperature and high humidity). A transparent film dimmer for light-emitting diode (LED) lighting was fabricated with the stretchable Cu@Ti NWs network. The LED luminance could be accurately tuned by the deformation strain of Cu@Ti NWs film.
Protein N-glycosylation is a ubiquitous and important post-translational modification that has been involved in the development and progression of a series of human-related diseases. Until recently, the highly selective capturing of glycopeptides from complex biosamples was still significant and challenging work due to their changeable structures, ultralow abundance, and strong ion-suppressing effect. Here we first report the preparation and characterization of a novel, hydrophilic, porous biocomposite composed of magnetic graphene functionalized with metal-organic frameworks (MOFs) (MG@Zn-MOFs) able to recognize glycopeptides. Thanks to its strong magnetic responsiveness, large specific surface area, excellent biocompatibility, and unique size-exclusion effect, the MG@Zn-MOFs showed outstanding sensitivity and selectivity and good recyclability in glycopeptides analysis. More excitingly, in practical application, 517 N-glycopeptides within 151 unique glycoproteins were clearly identified from human serum (1 μL) treated with the MG@Zn-MOFs, which is the best result among published reports so far. All the results demonstrate the promising commercialized usage of the biocomposite for the enrichment of glycopeptides in complex samples through a convenient and efficient process. Furthermore, it is anticipated that our strategy may offer promising guidance to develop new biocomposites functionalized with bio-MOFs for glycoproteomic applications.
Pollution in aquatic ecosystems due to negative human activities remains a problem in both freshwater and marine environments and is an ongoing subject of research. Several studies have shown that some fish parasites can be used as a tool for biomonitoring because they demonstrate higher metal accumulation capacity compared to their host tissues. However, compared to acanthocephalans, information regarding the absorption mechanisms and accumulation rates in nematodes is relatively limited. Here, we evaluated the potential of larvae Contracaecum sp. (L3) as indicators of contamination by metals by analyzing thirteen element concentrations: magnesium (Mg), aluminum (Al), titanium (Ti), chromium (Cr), manganese (Mn), iron (Fe), nickel (Ni), copper (Cu), zinc (Zn), arsenic (As), cadmium (Cd), barium (Ba), and lead (Pb) in the parasites and host Acestrorhynchus lacustris, using inductively coupled plasma mass spectrometry. Twelve of the thirteen analyzed elements were detected in at least 2-fold higher concentrations (e.g. Ni) and were up to approximately 50-fold higher (e.g. Pb) in parasites than in host tissues, including elements known for their high toxicity (As, Cd, Pb) and those considered to be essential (Cu and Zn). Our results suggest that Contracaecum sp. larvae can be used as bioindicators of metal contamination because even in early stages of development, numerous essential and non-essential elements were accumulated, making this system a useful tool for monitoring polluted environments.
Agricultural soils of semi-arid Mediterranean areas are often subjected to depletion of their chemical, physical, and biological properties. In this context, organic fertilization, in addition to providing
 nutrients for a longer time in respect to mineral fertilization, improves many other characteristics related to soil fertility. Moreover, the combined use of organic and mineral fertilizers may promote a more sustainable crop production. However, a concern on the long-term use of organic fertilizers arises in relation to the possible accumulation of toxic elements in soil and their transfer to human beings. For this reason, a long-term study on nutrient and toxic element total concentrations and availabilities during fertilization treatments was carried out. In particular, mineral NPK fertilized soils, soils amended with biowaste compost, soils amended with biowaste compost plus mineral nitrogen, and unfertilized soils were analyzed for 11 chemical elements. The results highlighted that temporal variations in total and bioavailable concentrations of both nutrients and toxic elements, occurring also in unfertilized soils, are wider than those related to fertilization treatments. Anyway, soil amendments with biowaste compost, alone or in combination with mineral fertilizers, reduce Cu bioavailability but improve K, Fe, Mn, and Zn availabilities, excluding at the same time a long-term accumulation in soil. Total and bioavailable toxic element concentrations (apart from available Cd) do not vary in relation to fertilization treatments.
Mining and smelting activities engender soil contamination by metals severely. A field survey was conducted to investigate the present situation and health risk of heavy metals (Cd, Pb, Zn, Cu, Cr, As, and Hg) in soils and vegetables in the surrounding area of an 80-year-old zinc smelter in northeastern China. Soil pH, organic matter (SOM), and cation exchange capacity (CEC) were determined, and their relations with heavy metal contents in edible parts of vegetables were analyzed. Results showed that the smelting had led to the significant contamination of the local soils by Cd and Zn, with average concentrations of 3.88 and 403.89 mg kg(-1), respectively. Concentrations of Cd and Zn in greenhouse soils were much lower than those in open farmland soils. Cd concentrations in vegetable edible parts exceeded the permissible limits severely, while other metal concentrations were much lower than the corresponding standards. Leaf and root vegetables had higher concentrations and bioaccumulation factors (BCFs) of Cd than fruit vegetables. Hazard quotient and hazard index showed that cadmium is imposing a health risk to local residents via vegetable consumption. Cd uptake of some vegetables can be predicted by empirical models with the following parameters: soil pH, SOM, CEC, Zn concentrations, and Cd concentrations. Vegetables such as cabbage, Chinese cabbage, tomato, cucumber, and green bean were screened out as being suitable to grow in the studied area.
Copper homeostasis is essential for bacterial pathogen fitness and infection, and has been the focus of a number of recent studies. In Salmonella, envelope protection against copper overload and macrophage survival depends on CueP, a major copper-binding protein in the periplasm. This protein is also required to deliver the metal ion to the Cu/Zn superoxide dismutase SodCII. The Salmonella-specific CueP-coding gene was originally identified as part of the Cue regulon under the transcriptional control of the cytoplasmic copper sensor CueR, but its expression differs from the rest of CueR-regulated genes. Here we show that cueP expression is controlled by the concerted action of CueR, which detects the presence of copper in the cytoplasm, and by CpxR/CpxA, which monitors envelope stress. Copper-activated CueR is necessary for the appropriate spatial arrangement of the -10 and -35 elements of the cueP promoter, and CpxR is essential to recruit the RNA polymerase. The integration of two ancestral sensory systems-CueR, which provides signal specificity, and CpxR/CpxA, which detects stress in the bacterial envelope-restricts the expression of this periplasmic copper resistance protein solely to cells encountering surplus copper that disturbs envelope homeostasis, emulating the role of the CusR/CusS regulatory system present in other enteric bacteria.
Zinc (Zn) is known to interact with lead (Pb) and cadmium (Cd) reversing their toxicity and reducing their concentrations. However, lactating women are at high risk of developing Zn deficiency, which may result in Pb and Cd intoxication or increased exposure of breast-fed infants to Pb and Cd from breast milk. The aim of this study was to determine Zn, Pb, and Cd concentrations and examine their relationship in serum and breast milk of lactating women in Ibadan, Nigeria. Ninety-two lactating women were recruited into this study. Anthropometric measurements were assessed by standard methods while serum and breast milk concentrations of Zn, Pb, and Cd were assessed by atomic absorption spectrophotometry. Data analyzed statistically by Student's t test, Pearson's correlation coefficient, and a multiple regression model were significant at p < 0.05. Zn deficiency was observed in 12 (17.1%) of lactating women. Breast milk levels of Zn, Pb, and Cd were significantly higher than their levels in serum, whereas the ratios Zn:Pb and Zn:Cd in milk were significantly less than serum ratios. Significant negative correlation was observed between milk Pb and serum Zn:Pb while milk Cd correlated positively with milk Zn. Significant positive correlations were observed between serum Zn and serum Zn:Pb, serum Zn and serum Zn:Cd, as well as serum Zn:Cd and serum Zn:Pb. Serum Cd and serum Zn were significantly negatively related. Significant negative correlations between serum Pb and serum Zn:Pb as well as milk Zn:Pb. Serum Cd and serum Zn:Pb as well as serum Zn:Cd correlated negatively. Milk Cd and Zn/Cd positively related with milk Pb while milk Zn was a negatively related with milk Pb in a multiple regression model (R (2) = 0.333; p = 0.023). Breast milk may be contaminated by toxic metals. However, Zn supplementation in deficient mothers may protect maternal and infant health.
Endoplasmic reticulum (ER) stress has been thought to be involved to neurodegenerative diseases such as Alzheimer's disease (AD) or Amyotrophic lateral sclerosis (ALS). The previous studies have shown that SLC30A3 level is decreased in prefrontal cortex of AD patients. In addition, we have shown that level of zinc (Zn) is increased in cerebrospinal fluid and SLC30A3 level is decreased in spinal cord of ALS patients. It was thought that both SLC30A3 and ER stress could be related to the cause of AD and ALS, however the relationship between ER stress and SLC30A3 has not been elucidated. Therefore we investigated that the role of SLC30A3 against ER stress. The level of SLC30A3 mRNA was significantly increased by tunicamycin treatment in human neuroblastoma cell line (SH-SY5Y) and human embryonic kidney cell line (HEK293). Cell viability under tunicamycin treatment was significantly decreased in SLC30A3 knockdown cells by siRNA in comparison with negative control (NC) cells. Cleaved caspase-3 level was significantly increased in SLC30A3 knockdown cells, not in NC cells. These results showed that SLC30A3 has a protective role to ER stress-induced toxicities. The previous study has shown that SLC30A3 protect cells from oxidative stress in ERK1/2 signal dependent manner, thus we determined the activity of ERK1/2 in SLC30A3 knockdown cells under ER stress condition. The level of ERK1/2 phosphorylation was significantly increased by tunicamycin treatment in NC cells, not in SLC30A3 knockdown cells. The ERK1/2 pathway is thought to have an association with defensive effects of SLC30A3 on cellular stress such as ER stress. In conclusion, this study suggested that SLC30A3 is supposed to play a protective role against ER stress, which is related to ERK1/2 activation.
Aquatic environment suffered from serious heavy metal and As pollutions due to rapid industrialization and urbanization in the last decades. In order to evaluate the heavy metal and As contamination in aquatic organism in southern China, the levels of As, Cd, Co, Cr, Cu, Fe, Mn, Pb, and Zn in muscle, gill, and liver of white bream (Parabramis pekinensis) collected from Xiang River were analyzed. The statistically significant differences of the analyzed element concentration (wet weight) between tissues were determined through one-way analysis of variance (ANOVA). The liver presented high affinity for accumulation of Cd, Cu, and Zn due to the binding activity of metallothionein proteins. Mn and Pb mainly accumulated in the gill indicated the major uptake route through the gill. Lack of correlation between analyzed element and fish size might imply no or weak biomagnification of the analyzed elements in fish tissues. The potential health risk associated with exposure to heavy metals and As was evaluated. The uncertainty of target hazard quotient was calculated by Monte Carlo simulation. The results indicated that the analyzed element contents in the white bream muscle posed relatively low-chronic toxic risk to consumers.
During infection, bacterial pathogens must adapt to a nutrient metal-limited environment that is imposed by the host. The innate immune protein calprotectin inhibits bacterial growth in vitro by chelating the divalent metal ions zinc (Zn(2+), Zn) and manganese (Mn(2+), Mn), but pathogenic bacteria are able to cause disease in the presence of this antimicrobial protein in vivo. One such pathogen is Acinetobacter baumannii, a Gram-negative bacterium that causes pneumonia and bloodstream infections that can be complicated by resistance to multiple antibiotics. A. baumannii inhibition by calprotectin is dependent on calprotectin Mn binding, but the mechanisms employed by A. baumannii to overcome Mn limitation have not been identified. This work demonstrates that A. baumannii coordinates
 transcription of an NRAMP family Mn transporter and a urea carboxylase to resist the antimicrobial activities of calprotectin. This NRAMP family transporter facilitates Mn accumulation and growth of A. baumannii in the presence of calprotectin. A. baumannii is found to utilize urea as a sole nitrogen source, and urea utilization requires the urea carboxylase encoded in an operon with the NRAMP family transporter. Moreover, urea carboxylase activity is essential for calprotectin resistance in A. baumannii Finally, evidence is provided that this system combats calprotectin in vivo, as deletion of the transporter impairs A. baumannii fitness in a mouse model of pneumonia, and this fitness defect is modulated by the presence of calprotectin. These findings reveal that A. baumannii has evolved mechanisms to subvert host-mediated metal sequestration and they uncover a connection between metal starvation and metabolic stress.
Acinetobacter baumannii is a bacterium that causes bloodstream, wound, urinary tract, and pneumonia infections, with a high disease burden in intensive care units. Treatment of A. baumannii infection is complicated by resistance to most antibiotics in use today, and resistance to last-resort therapies has become commonplace. New treatments for A. baumannii infection are desperately needed, but our current understanding of the bacterial factors required to cause infection is limited. We previously found that the abundant innate immune protein calprotectin inhibits the growth of A. baumannii by withholding essential metals. Despite this, A. baumannii is still able to infect wild-type mice, which produce calprotectin during infection. Here, we identify factors employed by A. baumannii during infection to overcome calprotectin-mediated metal sequestration. Moreover, we expose a connection between metal starvation and metabolism that may be a "chink in the armor" of A. baumannii and lead to new treatment options.
In this study, we analyzed the relationship between concentration of metals in the host-parasite system (cod - acanthocephalan Echinorhynchus gadi) and Fulton's condition factor (FCF) of the host. The relationship between metal (Ca, Cd, Cr, Cu, Fe, Hg, K, Mg, Mn, Na, Pb, Sr, Zn) concentrations in E. gadi and cod tissues was expressed as a bioconcentration factor (BCF), the ratio of the concentration in the parasite tissue to that in host tissues. Acanthocephalans accumulated mainly toxic metals (Cd, Pb), as well as Sr, Ca, Na. Cadmium showed the highest bioconcentration in parasites (BCF >200) compared to fish muscle. Significant negative correlation was detected between FCF and the concentration of Cd and Hg in cod liver. In contrast, FCF was positively correlated with the concentration of Hg in acanthocephalan tissues.
The status of antioxidant defences of both spermatozoa and their associated fluids during epididymal transit from the caput to cauda have not been studied so far in any species. Herein we report for the first time that sperm antioxidant defences, namely Cu,Zn-superoxide dismutase (Cu,Zn-SOD) and catalase activity, decrease significantly (P<0.05) from the caput to cauda during epididymal transit in parallel with increases in Cu,Zn-SOD, total SOD and total glutathione peroxidase (GPx) activity in the luminal fluid of the respective segments. However, levels of GPX1 and GPX3 in epididymal fluid did not change significantly from the caput to cauda. Catalase was detected for the first time in goat spermatozoa. A significantly higher total antioxidant capacity of caudal fluid than of the caput suggests a requirement for a rich antioxidant environment for the storage of spermatozoa. The retention of cytoplasmic droplets in most of the caudal spermatozoa confirmed that these droplets do not contribute to the increased antioxidant defences of cauda epididymidal fluid. Thus, the antioxidant defences of the spermatozoa and their associated epididymal fluid are modulated from the caput to cauda in a region-specific manner. This may be one of the compensatory mechanisms of epididymal fluid to scavenge any excess reactive oxygen species produced in the microenvironment of spermatozoa.
Contaminants (Cd, Cr, and Pb) as well as minor (B, Cu, Mn, Na, and Zn) and major (Ca and Mg) elements were directly determined in solid fertilizer samples using laser-induced breakdown spectroscopy (LIBS). Factorial designs were used to define the most appropriate LIBS parameters and pellet pressure on solid fertilizers. Emission lines for all of the analytes were collected and employed 12 signal normalization modes. The best results were obtained using a laser energy of 75 mJ, a spot size of 50 μm, a pressure of 10 t/in., and a delay of 2.0 μs. Good correlation was obtained between the calibration model's prediction using the proposed LIBS method and the reference values obtained with ICP-OES. The limits of detection (LOD) for the proposed method varied from 2 mg/kg (for Cd) to 1% (for Zn).
This contribution explores, through detailed (1)H NMR, DOSY NMR, optical absorption, and circular dichroism spectroscopic studies, the aggregation properties in solution of noncoordinating solvents of some new Zn(II) Schiff-base complexes, (R)-1, (S)-1, and (R)-2, derived from the chiral trans-1,2-diaminocyclohexane. It is found that chloroform solutions of 1 are characterized by the presence of three species, the predominance of which consists of large oligomeric aggregates. For chloroform solutions of 1, upon heating or standing, all species are irreversibly converted into a dimer, 1C, which is very stable and hardly disaggregable. Analysis of (1)H NMR, UV/vis, and CD spectroscopic data and chemical evidence allow proposing a double helicate Zn2L2 structure with a tetrahedral coordination around the Zn(II) ions for 1C, as a consequence of the defined stereochemistry of the trans-1,2-diaminocyclohexane chelate bridge. This represents a different, uncommon aggregation mode in Zn(II) complexes of tetradentate Schiff-bases.
Although soybean seeds appear homogeneous, their composition (protein, oil and mineral concentrations) can vary significantly with the canopy position where they were produced. In studies with 10 cultivars grown over a 3-yr period, we found that seeds produced at the top of the canopy have higher concentrations of protein but less oil and lower concentrations of minerals such as Mg, Fe, and Cu compared to seeds produced at the bottom of the canopy. Among cultivars, mean protein concentration (average of different positions) correlated positively with mean concentrations of S, Zn and Fe, but not other minerals. Therefore, on a whole plant basis, the uptake and allocation of S, Zn and Fe to seeds correlated with the production and allocation of reduced N to seed protein; however, the reduced N and correlated minerals (S, Zn and Fe) showed different patterns of allocation among node positions. For example, while mean concentrations of protein and Fe correlated positively, the two parameters correlated negatively in terms of variation with canopy position. Altering the microenvironment within the soybean canopy by removing neighboring plants at flowering increased protein concentration in particular at lower node positions and thus altered the node-position gradient in protein (and oil) without altering the distribution of Mg, Fe and Cu, suggesting different underlying control mechanisms. Metabolomic analysis of developing seeds at different positions in the canopy suggests that availability of free asparagine may be a positive determinant of storage protein accumulation in seeds and may explain the increased protein accumulation in seeds produced at the top of the canopy. Our results establish node-position variation in seed constituents and provide a new experimental system to identify genes controlling key aspects of seed composition. In addition, our results provide an unexpected and simple approach to link agronomic practices to improve human nutrition and health in developing countries because food products produced from seeds at the bottom of the canopy contained higher Fe concentrations than products from the top of the canopy. Therefore, using seeds produced in the lower canopy for production of iron-rich soy foods for human consumption could be important when plants are the major source of protein and human diets can be chronically deficient in Fe and other minerals.
Zinc (Zn) is one of the most essential micronutrients required for the growth and development of human beings. More than one billion people, particularly children and pregnant women suffer from Zn deficiency related health problems in Asia. Rice is the major staple food for Asians, but the presently grown popular high yielding rice varieties are poor supplier of Zn in their polished form. Breeding rice varieties with high grain Zn has been suggested to be a sustainable, targeted, food-based and cost effective approach in alleviating Zn deficiency. The physiological, genetic and molecular mechanisms of Zn homeostasis have been well studied, but these mechanisms need to be characterized from a biofortification perspective and should be well integrated with the breeding processes. There is a significant variation for grain Zn in rice germplasm and efforts are being directed at exploiting this variation through breeding to develop high Zn rice varieties. Several QTLs and gene specific markers have been identified for grain Zn and there is a great potential to use them in Marker-Assisted Breeding. A thorough characterization of genotype and environmental interactions is essential to identify key environmental factors influencing grain Zn. Agronomic biofortification has shown inconsistent results, but a combination of genetic and agronomic biofortification strategies may be more effective. Significant progress has been made in developing high
 Zn rice lines for release in target countries. A holistic breeding approach involving high Zn trait development, high Zn product development, product testing and release, including bioefficacy and bioavailability studies is essential for successful Zn biofortification.
Although aquatic organisms in the environment are exposed to mixtures of metals, risk assessment for metals is most commonly performed on a metal-by-metal basis. To increase the knowledge about chronic mixture effects, the authors investigated whether metal mixture effects are dependent on the biological species, mixture composition, and metal concentration ratio. The authors evaluated the effects of quaternary Ni-Zn-Cu-Cd and ternary Ni-Zn-Cu mixtures on 48-h algal growth rate (Pseudokirchneriella subcapitata) and 7-d daphnid reproduction (Ceriodaphnia dubia) using a ray design. Single metals were 3-fold to 42-fold more toxic for C. dubia than for P. subcapitata, based on the 50% effective concentration expressed as free metal activity, the range representing different metals. Statistical analysis of mixture effects showed that the ternary and quaternary mixture effects were antagonistic on algal growth relative to the concentration addition (CA) model, when the analysis was based on dissolved concentrations and on free metal ion activities. Using the independent action (IA) model, mixture effects in both rays were statistically noninteractive for algal growth when the analysis was based on dissolved concentrations; however, the interactions shifted toward antagonism when based on free ion activities. The ternary Ni-Zn-Cu mixture acted antagonistically on daphnid reproduction relative to both reference models, either expressed as free ion activities or dissolved concentrations. When Cd was added to the mixture, however, the mixture effects shifted toward noninteractivity for daphnids. The metal concentration ratio did not significantly influence the magnitude of observed antagonistic effects. Regardless of statistical interactions observed, based on the present study, CA and in most instances also IA can serve as a protective model for ternary Ni-Zn-Cu and quaternary Ni-Zn-Cu-Cd toxicity to both species. Environ Toxicol Chem 2016;9999:1-11. © 2016 SETAC.
Extracellular polymeric substances (EPS) in sludge samples played a major role in heavy metals removal during wastewater treatment. In this study, the binding quality, adsorption mechanism, as well as the chemical fractional contribution of the sludge EPS from activated sludge, anaerobic granular sludge and anaerobic flocculent sludge to the adsorption of Zn(2+) and Cu(2+) was investigated. For all three sludge samples, Cu(2+) could be more easily adsorbed than Zn(2+), and EPS extracted from the anaerobic granular sludge exhibited a relatively higher adsorption capacity than that of anaerobic flocculent sludge and activated sludge. Specifically, hydrophobic EPS of the activated sludge and anaerobic flocculent sludge was more efficient in adsorbing Cu(2+) and Zn(2+) than that of the hydrophilic EPS. However, hydrophilic EPS in anaerobic granular sludge played a greater role in heavy metals removal. The adsorption of those two heavy metals onto the unfractionated and hydrophobic EPS could be better described by the Langmuir isotherm, while Freundlich models fitted hydrophilic EPS. In addition, the effect of the heavy metals adsorption on the spectrum characteristics of the sludge EPS was also explored by analysis of FT-IR and fluorescent spectra.
Tap water samples were collected from 180 families in four agricultural (KYR: Keyir, KRW: Kariwak, YTR: Yatur, DW: Dawanqi) and two pastoral areas (B: Bulong and Y: Yangchang) in Bay County, Xinjiang, China, and levels of seven trace elements (Cd, Cr, As Ni, Pb, Zn, Se) were analyzed using inductively-coupled plasma mass spectrometry (ICP-MS) to assess potential health risks. Remarkable spatial variations of contamination were observed. Overall, the health risk was more severe for carcinogenic versus non-carcinogenic pollutants due to heavy metal. The risk index was greater for children overall (Cr > As > Cd and Zn > Se for carcinogenic and non-carcinogenic elements, respectively). The total risk index was greater in agricultural areas (DW > KYR > YTR > KRW > B > Y). Total risk indices were greater where well water was the source versus fountain water; for the latter, the total health risk index was greater versus glacier water. Main health risk factors were Cr and As in DW, KYR, YTR, KRW, and B, and Zn, Cr, and As in the Y region. Overall, total trace element-induced health risk (including for DW adults) was higher than acceptable (10(-6)) and lower than priority risk levels (10(-4)) (KYR, YTR, KRW, Y, and B). For DW children, total health risk reached 1.08 × 10(-4), higher than acceptable and priority risk levels (10(-4)).
Deregulated epigenetic activity of Histone deacetylase 1 (HDAC1) in tumor development and carcinogenesis pronounces it as promising therapeutic target for cancer treatment. HDAC1 has recently captured the attention of researchers owing to its decisive role in multiple types of cancer. In the present study a multistep framework combining ligand based 3D-QSAR, molecular docking and Molecular Dynamics (MD) simulation studies were performed to explore potential compound with good HDAC1 binding affinity. Four different pharmacophore hypotheses Hypo1 (AADR), Hypo2 (AAAH), Hypo3 (AAAR) and Hypo4 (ADDR) were obtained. The hypothesis Hypo1 (AADR) with two hydrogen bond acceptors (A), one hydrogen bond donor (D) and one aromatics ring (R) was selected to build 3D-QSAR model on the basis of statistical parameter. The pharmacophore hypothesis produced a statistically significant QSAR model, with co-efficient of correlation r(2)=0.82 and cross validation correlation co-efficient q(2)=0.70. External validation result displays high predictive power with r(2) (o) value of 0.88 and r(2) (m) value of 0.58 to carry out further in silico studies. Virtual screening result shows ZINC70450932 as the most promising lead where HDAC1 interacts with residues Asp99, His178, Tyr204, Phe205 and Leu271 forming seven hydrogen bonds. A high docking score (-11.17kcal/mol) and lower docking energy -37.84kcal/mol) displays the binding efficiency of the ligand. Binding free energy calculation was done using MM/GBSA to access affinity of ligands towards protein. Density Functional Theory was employed to explore electronic features of the ligands describing intramolcular charge transfer reaction. Molecular dynamics simulation studies at 50ns display metal ion (Zn)-ligand interaction which is vital to inhibit the enzymatic activity of the protein.
Biomonitoring permits determinations of trace metal contamination in remote areas like the high mountain ecosystems. In this study, six trace metals (Cd, Cr, Cu, Ni, Pb, and Zn) in seven sympatric alpine species (five tree species: Salix rehderiana, Populus purdomii, Betula albosinensis, Abies fabri, Picea brachytyla, and two dominant mosses: Pleurozium schreberi, Papillaria crocea) at the Hailuogou Glacier foreland, Eastern Tibetan Plateau, were investigated to monitor their contamination. The concentrations of trace metals and Pb isotopic ratios ((206)Pb/(207)Pb and (208)Pb/(206)Pb) in leaves/needles, twigs, bark, roots, and mosses were determined, and the biological factors and enrichment factors were calculated. The concentrations of Cd, Cr, Pb, and Zn in mosses were significantly higher than those in tree tissues and normal plants indicating the exogenous sources. The accumulation of trace metals (except Cd and Zn) was relatively higher in the tree roots, whereas their enrichments were significant in the leaves/needles and bark. According to biological factors, enrichment factors, and factor analysis, Cd, Pb, and Zn in trees and mosses were markedly impacted by anthropogenic emissions, whereas Cr, Cu, and Ni in trees were mainly from root adsorption from soils. The Pb isotopic compositions identified the anthropogenic Pb mainly from mining and smelting, coal combustion, and vehicle exhausts. The results indicated that mosses were still priority indicator of trace metal contamination from atmospheric deposition, and the leaves and bark of S. rehderiana, P. purdomii, and B. albosinensis were the better alternatives to monitor the atmospheric contamination of trace metals in the alpine ecosystem.
Zn, Cu, Ni, V, Al, Pb, Cd, Hg, lipid and water contents were determined in the soft tissues of different shellfish species collected along the Red Sea shoreline. Metal contents showed a descending order of Zn > Cu > Ni > Al > V > Pb > Cd > Hg. The leachable concentrations found in the sediments gathered from the studied locations gave another descending order: Al > Zn > Ni > Pb > V > Cu > Cd. The determined leachable heavy metal contents in the sediment did not exceed the NOAA and CCME (Anonymous 1999) sediment quality guidelines. Accordingly, the sediments along the Egyptian Red Sea area did not pose any adverse impacts on the biological life. According to the hazard quotient (HQ) calculations for heavy metal contents in the soft tissue of shellfish, mercury did not pose any risk on human health; whereas, the other determined heavy metals gave HQ values of 1 < HQ < 10 and showed a possibility of risk on the long term. Cu is above the desirable levels in mussels. The RQ calculations of toddlers and adults reflected that Cu was the only heavy metal that had an adverse effect on toddlers' health. Based on the human organizations (EPA, BOE, MAFF, and NHMRC) that proposed safety concentrations of heavy metals, the studied shellfish were somewhat safe for human consumption.
Due to bacterial drug resistance, a new series of quinazolinone azolyl ethanols were synthesized and evaluated.
In vitro antibacterial assay showed that triazolyl ethanol
 quinazolinone 3a was the most active compound, especially against methicillin-resistant Staphylococcus aureus (MRSA) with minimal inhibitory concentration value of 8 µg/ml, which was superior to chloromycin and comparable to norfloxacin. Molecular docking study displayed that compound 3a could interact with MRSA DNA by the formation of hydrogen bonds. Further interactions of quinazolinone 3a with MRSA DNA suggested that it could intercalate into MRSA DNA to form 3a-DNA complex. DNA cleavage properties of 3a-Cu(2+) and 3a-Zn(2+) complexes were confirmed by agarose gel electrophoresis experiments.
Compound 3a should be a potential lead antibacterial molecule with dual action modes.
Electrocatalysts are required for clean energy technologies (for example, water-splitting and metal-air batteries). The development of a multifunctional electrocatalyst composed of nitrogen, phosphorus, and fluorine tri-doped graphene is reported, which was obtained by thermal activation of a mixture of polyaniline-coated graphene oxide and ammonium hexafluorophosphate (AHF). It was found that thermal decomposition of AHF provides nitrogen, phosphorus, and fluorine sources for tri-doping with N, P, and F, and simultaneously facilitates template-free formation of porous structures as a result of thermal gas evolution. The resultant N, P, and F tri-doped graphene exhibited excellent electrocatalytic activities for the oxygen reduction reaction (ORR), oxygen evolution reaction (OER), and hydrogen evolution reaction (HER). The trifunctional metal-free catalyst was further used as an OER-HER bifunctional catalyst for oxygen and hydrogen gas production in an electrochemical water-splitting unit, which was powered by an integrated Zn-air battery based on an air electrode made from the same electrocatalyst for ORR. The integrated unit, fabricated from the newly developed N, P, and F tri-doped graphene multifunctional metal-free catalyst, can operate in ambient air with a high gas production rate of 0.496 and 0.254 μL s(-1) for hydrogen and oxygen gas, respectively, showing great potential for practical applications.
The dye decolorization rate in a cell-free culture broth of the white rot fungus Trametes versicolor CBR43 was studied, including the effects of inhibitors of NaCl, Zn(II), and Cd(II) on dye decolorization activity. The maximum rates of dye decolorization in cell-free culture broth were 1410, 44.7, 41.2, and 0.19 μmol L(-1) min(-1) for Acid Blue 62, Acid Black 175, Reactive Blue 4, and Acid Red 114, respectively. The inhibition effects of NaCl, Zn(II), and Cd(II) on dye decolorization were quantitatively compared using the half maximal inhibition concentration (IC50), which indicates the concentration of an inhibitor required for 50% inhibition. Based on IC50 values, dye decolorization in the cell-free culture broth of CBR43 was most potently inhibited by Cd(II), whereas the inhibitory effect of NaCl was relatively low. The dye decolorization rates and IC50 data can be used in the design and development of a dye-wastewater treatment process using T. versicolor CBR43 and its operating factors.
As a new eco-friendly thermoelectric material, copper tin sulfide (Cu2SnS3) ceramics were experimentally studied by Zn-doping. Excellent electrical transport properties were obtained by virtue of 3-dimensionally conductive network for holes, which are less affected by the coexistence of cubic and tetragonal phases that formed upon Zn subsitition for Sn; a highest power factors ~0.84 mW m(-1) K(-2) at 723 K was achieved in the 20% doped sample. Moreover, an ultralow lattice thermal conductivity close to theoretical minimum was observed in these samples, which could be related to the disordering of atoms in the coexisting cubic and tetragonal phases and the interfaces. Thanks to the phonon-glass-electron-crystal features, a maximum ZT ~ 0.58 was obtained at 723 K, which stands among the tops for sulfide thermoelectrics at the same temperature.
The Zn(II) ion has been linked to Alzheimer's disease (AD) due to its ability to modulate the aggregating properties of the amyloid-β (Aβ) peptide, where Aβ aggregation is a central event in the etiology of the disease. Delineating Zn(II) binding properties to Aβ is thus a prerequisite to better grasp its potential role in AD. Because of (i) the flexibility of the Aβ peptide, (ii) the multiplicity of anchoring sites, and (iii) the silent nature of the Zn(II) ion in most classical spectroscopies, this is a difficult task. To overcome these difficulties, we have investigated the impact of peptide alterations (mutations, N-terminal acetylation) on the Zn(Aβ) X-ray absorption spectroscopy fingerprint and on the Zn(II)-induced modifications of the Aβ peptides' NMR signatures. We propose a tetrahedrally bound Zn(II) ion, in which the coordination sphere is made by two His residues and two carboxylate side chains. Equilibria between equivalent ligands for one Zn(II) binding position have also been observed, the predominant site being made by the side chains of His6, His13 or His14, Glu11, and Asp1 or Glu3 or Asp7, with a slight preference for Asp1.
The rapid loss of mangroves globally has triggered a call for a better understanding of this habitat, including its dynamics and the threats it is exposed to. The present paper reports the study of trace metals at nine mangrove sites in Singapore in 2012/2013, using the simultaneous application of various tools, namely sediment analyses, the technique of diffusive gradients in thin-films (DGT) and caged/native bivalves (for both chemical and biomarker analyses). DGT devices were successfully deployed over 28days in tropical mangrove waters, and the concentration measured with DGT showed significant correlation with the accumulation for Cu, Zn and Cd in caged mussels, and Cu for native clams, supporting the relevance of DGT to predict metal bioaccumulation. Concentrations in mangrove sediment are reported for As, Cd, Co, Cr, Cu, Ni, Pb and Zn. Sediment levels on a dry weight (dw) basis of Cu (ND-219.5μg/g dw) and Zn (ND-502μg/g dw) exceeded general sediment quality criteria at two sites. Most notably for these two metals, investigations based on the four tools (DGT, sediments, caged mussels and clams) were all able to segregate sites above and below the sediment quality guideline. This was further supported by a range of significant linear correlations between the measurements obtained with the various tools. The present findings support that these monitoring tools are comparable in the field to provide a time-integrated assessment of metals such as Cu and Zn.
Zinc (Zn) is important in a number of processes related to insulin secretion and insulin activity in peripheral tissues, making this element an interesting potential co-adjuvant in the treatment of patients with type 2 diabetes (T2D). This issue has been matter of interest in recent years. The available evidence is analyzed in this review. Information from epidemiologic studies evaluating the relationship between Zn and T2D is inconsistent. Furthermore, few studies examined the association between Zn status and insulin action and/or glucose homeostasis. In terms of usefulness of Zn as a preventive agent for T2D development, information is insufficient to reach firm conclusions. Results from Zn supplementation trials found some positive effects only in those with initial sub normal Zn status in a significant proportion of individuals. In conclusion, the effect of Zn on patients with type 2 diabetes is still an open question, and better study designs are needed to clarify the real impact and characteristics of the Zn-diabetes interaction.
The aim of this study was to develop an effective and non-destructive method for the selection of native Mediterranean plants with phytoremediation potential based on their spontaneous recovery capacities. The study site consisted in a mixed contaminated soils (As, Cu, Pb, Sb, Zn) in the vicinity of a former lead smelting factory abandoned since 1925 in the Calanques National Park (Marseille, southeastern France). We developed an integrated characterization approach that takes into account topsoil metal(loid)s (MM) contamination, plant community composition and structure and mesologic parameters without using destructive methods. From a statistical selection of significant environmental descriptors, plant communities were described and interpreted as the result of spontaneous recovery under multiple stresses and local conditions (both natural and anthropogenic). We collected phytoecological and MM topsoil data using field monitoring and geographic information system (GIS) on a pollution hotspot where natural plant communities occur. The results of the multivariate analysis performed between species and descriptors indicated that a century of MM pollution pressure produced a significant correlation with plant community dynamics in terms of composition, diversity and structure, leading to the co-occurrence of different plant succession stages. Thus, these successions seemed linked to the variability of anthropogenic disturbance regimes within the study site. We recorded high topsoil contamination heterogeneity at the scale both of the plot and of the whole study area that suggested a heterogeneous MM distribution pattern dependent on the source of contaminants and site environmental variability. We identified 4 spontaneous plant communities co-occurring through a MM contamination gradient that could be used later from degraded to reference communities to define ecological restoration target combined to phytoremediation applications with respect to local conditions. Our results suggested that some of the native plant species such as Coronilla juncea and Globularia alypum might be tolerant to high mixed MM soil concentrations and they could thus be used for phytostabilization purposes
 in polluted Mediterranean areas in regard to their life-traits. Our non-destructive methodology led both to the selection of tolerant native plant species and communities and identification of highly polluted priority intervention areas through the study site where phytostabilization should be implemented. Furthermore, by analyzing succession dynamics linked to contamination patterns throughout the area and spontaneous recovery of native tolerant vegetation, our methodology opens up broad perspectives and research fields for ecological restoration for Mediterranean protected and contaminated areas based on ecosystem trajectories and new approaches for the integrative management of polluted soils.
The samples of spatial soils and different organs of Prunus persica L. Batech and Malus domestica were analyzed by methods such as inductively coupled plasma optical emission spectroscopy (ICP-OES), Hierarchical Cluster Analysis (HCA), One-way ANOVA, and calculation of biological accumulation factors (BAFs) with the aim of investigating whether these methods may help in the evaluation of trace metals in plants, as well as in the estimation of plant bioaccumulation potentials. ICP-OES provided accurate data on present concentrations of Cu, Zn, Pb, As, Cd, and Ni which showed that most concentrations were in normal ranges, except in some cases for Cu, Zn, and As. HCA illustrated nicely various specifics in the distribution of metals in both investigated systems plant-soil. One-way ANOVA pointed successfully on the existing statistical differences between metal concentrations. Calculated BAFs showed that both plants had very low accumulation rates for all elements; they acted as metal excluders.
The use of organic foods has been increased in the world. Organic fertilizers, like cattle manure, have emerged as an important component of the organic system production. The production, mass, size, and mineral composition of passion fruit pulp were evaluated when treated with a mineral fertilizer (control) (MIN) or cattle manure at a single dose equivalent to potassium fertilizer (ORG) or double dose (2×ORG). The production and the numbers of fruits of plants treated with MIN and 2×ORG was higher than with ORG. The level of nitrogen (N), phosphorus (P), zinc (Zn), iron (Fe), and copper (Cu) in the fruit pulp was similar with all three fertilizers, but the calcium (Ca) and magnesium (Mg) was higher with ORG and 2×ORG. The number and weight of the fruits of passion fruit treated with 2×ORG were similar to those with MIN fertilizer, but they contained more Ca and Mg.
The effect of dietary crude protein (CP) and additives on odor flux from meat chicken litter was investigated using 180 day-old Ross 308 male chicks randomly allocated to five dietary treatments with three replicates of 12 birds each. A 5 × 3 factorial arrangement of treatments was employed. Factors were: diet (low CP, high CP, high CP+antibiotic, high CP+probiotic, high CP+saponin) and age (15, 29, 35 days). The antibiotic used was Zn bacitracin, the probiotic was a blend of three Bacillus subtilis strains and the saponin came from a blend of Yucca and Quillaja. Odorants were collected from litter headspace with a flux hood and measured using selective ion flow tube mass spectrometry (SIFT-MS). Litter moisture, water activity (Aw), and litter headspace odorant concentrations were correlated. The results showed that low CP group produced lower flux of dimethyl amine, trimethyl amine, H2S, NH3, and phenol in litter compared to high CP group (P < 0.05). Similarly, high CP+probiotic group produced lower flux of H2S (P < 0.05) and high CP+saponin group produced lower flux of trimethylamine and phenol in litter compared to high CP group (P < 0.05). The dietary treatments tended (P = 0.065) to have higher flux of methanethiol in high CP group compared to others. There was a diet × age interaction for litter flux of diacetyl, 3-hydroxy-2-butanone (acetoin), 3-methyl-1-butanol, 3-methylbutanal, ethanethiol, propionic acid, and hexane (P < 0.05). Concentrations of diacetyl, acetoin, propionic acid, and hexane in litter were higher from low CP group compared to all other treatments on d 35 (P < 0.05) but not on d 15 and 29. A high litter moisture increased water activity (P < 0.01) and favored the emissions of methyl mercaptan, hydrogen sulfide, dimethyl sulfide, ammonia, trimethyl amine, phenol, indole, and 3-methylindole over others. Thus, the low CP diet, Bacillus subtilis based probiotic and the blend of Yucca/Quillaja saponin were effective in reducing the emissions of some key odorants from meat chicken litter.
The goal of this study was to determine the effects of feeding a zinc (Zn) deficient diet to broiler chicks for 96 h post-hatch followed by feeding diets with different Zn sources and supplemental levels (5 to 21 d) on the growth performance, tissue, and excreta Zn content. At the start of the study, four hundred 20-day-old male broiler chicks were divided into two groups. One group was fed a corn soybean meal based diet containing 25 mg of Zn/kg (imprinting diet, ID). The second group was fed the basal diet supplemented with 40 mg of Zn/kg from Zn oxide (ZnO) (non-imprinting diet, NID). Both groups were fed these diets for 96 h. At d 5, chicks from each group were randomly assigned to the dietary treatments consisting of the basal diet alone or the basal diet supplemented with 8 or 40 mg/kg Zn as ZnO or Zn proteinate. Main effects of post-hatch Zn ID were observed on feed intake and G:F. ID decreased (P < 0.05) feed intake and improved (P < 0.05) the gain to feed ratio (G:F) of 14 and 21 d old chicks compared to G:F of chicks fed NID. Additionally, G:F for 14 and 21 d was improved (P < 0.05) by interaction of Zn source × level. Furthermore, at d 21 chicks fed the ID had a lower (P < 0.05) Zn content in the tibia ash and excreta, and a higher (P < 0.05) Zn content in the pancreas tissue compared to chicks fed NID. These results suggest that Zn imprinting can affect body Zn stores and early performance.
The present study assessed the effects of a white fluorescent bulb (the control) and two different light-emitting diodes (blue LEDs, LDB; red, LDR) on growth, morphology, and oxidative stress in the liver and ovary of zebrafish for 5 weeks. Growth maintained relatively constant under LDB condition, but was reduced under LDR condition. In the liver, hepatosomatic index (HSI) and protein carbonylation (PC) increased under LDR condition, whereas lipid peroxidation (LPO) declined and HSI remained unchanged under LDB condition. The decrease in oxidative damage by LDB could be attributed to the up-regulated levels of mRNA, protein, and activity of Cu/Zn-SOD and CAT. A failure to activate the activity of both enzymes may result in the enhanced PC levels under LDR condition, though both genes were up-regulated at transcriptional and translational levels. In the ovary, although gonadosomatic index sharply increased under LDR condition, LPO and PC dramatically accumulated. The increase in oxidative damage by LDR might result from the down-regulated levels of protein and activity of Cu/Zn-SOD and CAT, though both genes were up-regulated at a transcriptional level. Furthermore, a sharp increase in expression of transcription factor Nrf2 that targets antioxidant genes was observed in the liver but not in the ovary under LDB and LDR conditions. In conclusion, our data demonstrated a positive effect of LDB and negative effect of LDR on fish antioxidant defenses, emphasizing the potentials of LDB as an effective light source in fish farming.
Recycling of e-waste using informal or crude techniques poses serious health risk not only to the workers but also to the environment as whole. It is against this background that this paper sought to measure health risk faced by informal e-waste workers from exposure to toxicants such as lead, cadmium, chromium, copper, arsenic, tin, zinc and cobalt via oral and dermal contact with bottom ash and soil. Using random sampling techniques, 3 separate sites each (where burning and manual dismantling of e-wastes are usually carried) were identified, and a total of 402 samples were collected. The samples were analysed using standard methods for chemical analysis prescribed by the American Water Works Association (AWWA). Concentrations of Pb, Cd, Cr, Cu, As, Sn, Zn and Co in bottom ash samples from location ASH1 are 5388 ± 0.02 mg/kg (Pb), 2.39 ± 0.01 mg/kg (Cd), 42 ± 0.05 mg/kg (Cr), 7940 ± 0.01 mg/kg (Cu), 20 ± 0.07 mg/kg (As), 225 ± 0.04 mg/kg (Sn), 276 ± 0.04 mg/kg (Zn) and 123 ± 0.04 mg/kg (Co), while concentrations of the aforementioned toxicants in soil samples at location ASG1 are as follows: 1685 ± 0.14 mg/kg (Pb), 26.89 ± 0.30 mg/kg (Cd), 36.86 ± 0.02 mg/kg (Cr), 1427 ± 0.08 mg/kg (Cu), 1622 ± 0.12 mg/kg (As), 234 ± 0.25 mg/kg (Sn), 783 ± 0.31 mg/kg (Zn) and 135 ± 0.01 mg/kg (Co); used as input parameters in assessing health risk faced by workers. The results of cancer health risk faced by e-waste workers due to accidental ingestion of As in bottom ash at ASH1 is 4.3 × 10(-3) (CTE) and 6.5 × 10(-2) (RME), i.e. approximately 4 out of 1000 e-waste workers are likely to suffer from cancer-related diseases via central tendency exposure (CTE parameters), and 7 out of every 100 e-waste worker is also likely to suffer from cancer cases by reasonable maximum exposure (RME) parameters, respectively. The cancer health risk results for the other sampling sites were found to have exceeded the acceptable USEPA cancer risk value of 1 × 10(-4) to 1 × 10(-6) (i.e. 1 case of cancer per every 10,000 people to 1 case of cancer per every 1,000,000 people). The non-cancer health risk results for all the toxicants were higher in all the locations for both adult and children working the e-waste site. From the findings of this study, the government of Ghana has to immediately
 put in place policies that would address the safety of the e-waste workers as well as protect the environment.
The study characterized the enrichment, ecological risk and possible source of heavy metals (As, Cd, Cr, Cu, Hg, Ni, Pb and Zn) in sediments from a typical mariculture bay. The concentrations of the metals were analyzed in sediments collected from Zhelin bay. The distribution variation was examined during the past decade, which had an increase tendency till 2011. The enrichment factor and geoaccumulation indices suggested Pb, As, Cu and Zn were minor enrichment and unpolluted to moderately polluted, and Ni at cage mariculture area was moderately-severe enrichment and strongly polluted. This area had medium to high ecological risk, especially at the northwest coastal area of semi-closed bay, with high-medium to high ecological risk. Correlation and principal component analyses indicated that most of heavy metals, especially for As, Pb and Ni, primarily resulted from the combustion of gasoline and diesel fuel and the ship protective layer.
This study focused on the ability of Lemna minor and Lemna gibba to remove U and Th in the tailing water of Keban, Turkey. These plants were placed in tailing water and individually fed to the reactors designed for these plants. Water and plant samples were collected daily from the mining area. The plants were ashed at 300°C for 1 day and analyzed by ICP-MS for U and Th. U was accumulated as a function of time by these plants, and performances between 110 % and 483 % for L. gibba, and between 218 % and 1194 % for L. minor, were shown. The highest Th accumulations in L. minor and L. gibba were observed at 300 % and 600 % performances, respectively, on the second day of the experiment. This study indicated that both L. gibba and L. minor demonstrated a high ability to remove U and Th from tailing water polluted by trace elements.
Uniform 2-year old seedlings of a commercial olive cultivar (Olea europaea L., cv. Mahzam) were exposed or unexposed to the air pollution from the controlled burning of waste tires. The plants were supplied with zinc sulfate (ZnSO4) or synthesized Zn(Glycine)2 (Zn-Gly) or unsupplied with Zn. Exposure to air pollution resulted in oxidative damage to the olive, as indicated by the higher production of malondialdehyde (MDA). Supplement with Zn partly alleviated oxidative damage induced by the air emissions on the olive. Leaf concentration of MDA was higher at the active period of tire burning than that of the inactive one. Exposure to the emissions from tire burning significantly increased leaf ascorbate peroxidase (APX) activity. Supplement with Zn increased APX activity in plants exposed to the air pollution. According to the results, Zn nutrition was effective in alleviating oxidative stress induced by air pollution on the olive. APX seemed to play a significant role in alleviating oxidative damages induced by air emissions from tire burning on the olive; however, the role of other antioxidant enzymes should be addressed in future studies.
The N-peptide of HIV gp41 forms a trimeric coiled-coil intermediate during host cell-viral fusion. Stable mimics of this coiled coil could potentially serve as HIV vaccine candidates or inhibitors of viral entry. Therefore, a variety of approaches have been investigated to maintain the N-peptide in its trimeric helical conformation. Here, we utilize a genetic method to incorporate the metal chelating noncanonical amino acid (2,2'-bipyridin-5-yl)alanine (BpyAla) into IZN17, an established trimeric coiled-coil gp41 model. We demonstrate that BpyAla-IZN17 acquires Fe(II) during expression in Escherichia coli, resulting in the formation of a highly stable IZN17 helical trimer with a Tm > 95°C. Removal of Fe(II) results in a 27°C decrease in thermal stability. Replacement of Fe(II) with Zn(II) also affords a Tm > 90°C. Thus, the genetic introduction of BpyAla into polypeptide provides a straightforward method for stabilizing coiled-coil structural motifs in recombinantly engineered proteins.
Oxidative potential (OP) of particulate matter (PM) - defined as the capacity of PM to oxidize target molecules generating reactive oxygen species (ROS) - has been proposed as a more health relevant metric than PM mass. In this study two cell-free methods were used to assess the OP of PM filters collected at an urban site and to evaluate correlation with PM mass and PM composition. Among the different assays existing, two inexpensive and user-friendly methods were used both based on spectrophotometric measurements of depletion rate of target reagents oxidized by redox-active species present in PM. One assay measures the consumption of dithiothreitol (OPDTT) and the other the ascorbate (OPAA). Although both assays respond to the same redox-active species, i.e., quinones and transition metals, no correlations were found between OPDTT and OPAA responses to compounds standard solutions as well as to ambient samples. When expressed in relation to air volume, OPDTT m(-3) strongly correlates with PM2.5 mass whereas no correlation was found for OPAA m(-3) with PM2.5. When expressed on mass basis, both OPDTT μg(-1) and OPAA μg(-1) show a strong dependence on the sample composition, with higher OP for summer samples. OPDTT m(-3) were highly correlated with the determined metals (Cu, Zn, Cr, Fe, Ni, Mn) whereas OPAA m(-3) showed only moderate correlation with Cu and Mn. Thus, the two assays could potentially provide complementary information on oxidative potential characteristic of PM. Consequently, the combination of the two approaches can strengthen each other in giving insight into the contribution of chemical composition to oxidative properties of PM, which can subsequently be used to study health effects.
Major depressive disorder (MDD) is a serious psychiatric illness, associated with an increasing rate of suicide. The pathogenesis of depression may be associated with the disruption of zinc (Zn) homeostasis. In the brain, several proteins that regulate Zn homeostasis are present, including Zn transporters (ZnTs) which remove Zn from the cytosol. The present study was designed to investigate whether depression and suicide are associated with alterations in the expression of the ZnTs protein.
Protein levels of ZnT1, ZnT3, ZnT4, ZnT5 and ZnT6 were measured in postmortem brain tissue from two different cohorts. Cohort A contained 10 subjects diagnosed with MDD (7 were suicide victims) and 10 psychiatrically-normal control subjects and cohort B contained 11 non-diagnosed suicide victims and 8 sudden-death control subjects. Moreover, in cohort A we measured protein level of NMDA (GluN2A subunit), AMPA (GluA1 subunit) and 5-HT1A receptors and PSD-95. Proteins were measured in the prefrontal cortex (PFC) using Western blotting. In addition, Zn concentration was measured using a voltammetric method.
There was a significant increase in protein levels of ZnT1, ZnT4, ZnT5 in the PFC in MDD, relative to control subjects, while ZnT3 protein level was decreased in MDD. There was no significant difference in the Zn concentration in the PFC between control and MDD subjects. Similarly, in the PFC of suicide victims (non-diagnosed), an increase in protein levels of ZnT1, ZnT4, ZnT5 and ZnT6 was observed. Conversely, protein levels of ZnT3 were decreased in both suicide victims and subjects with MDD, in comparison with control subjects. There was also a significant decrease in the protein level of GluA1, GluN2A, PSD-95 and 5-HT1A in MDD.
Our studies suggest that alterations in Zn transport proteins are associated with the pathophysiology of MDD and suicide.
Therapeutically improved long-acting insulin preparations require in-depth understanding of the hexamer assembly, structural selectivity, and its stability in solution. This Letter demonstrates, for the first time, an efficient method for the hexamerization of human insulin by a structure-specific triphenylmethane (TPM) dye, Ethyl Violet (EV), particularly, in the absence of Zn(2+). Upon detailed spectroscopic evaluation and comparison with other TPM homologues, we establish that the diethylamino phenyl arms of EV are specific and effective in clipping the three dimer helices in a hexameric assembly. We establish that at physiological pH 7.4 and in the presence of the EV, insulin exists predominantly in its hexameric form, a condition appropriate for storage and preparation of long-acting insulin formulations. On the other hand, the disassembly of the hexamer into the monomeric form is accomplished at pH 5, highlighting its potential as a delivery vehicle for such custom-modified dyes/drugs.
Superoxide dismutase (SOD) as a group of significant and ubiquitous enzymes plays a critical function in plant growth and development. Previously this gene family has been investigated in Arabidopsis and rice; it has not yet been characterized in cotton. In our study, it was the first time for us to perform a genome-wide analysis of SOD gene family in cotton. Our results showed that 10 genes of SOD gene family were identified in Gossypium arboreum and Gossypium raimondii, including 6 Cu-Zn-SODs, 2 Fe-SODs, and 2 Mn-SODs. The chromosomal distribution analysis revealed that SOD genes are distributed across 7 chromosomes in Gossypium arboreum and 8 chromosomes in Gossypium raimondii. Segmental duplication is predominant duplication event and major contributor for expansion of SOD gene family. Gene structure and protein structure analysis showed that SOD genes have conserved exon/intron arrangement and motif composition. Microarray-based expression analysis revealed that SOD genes have important function in abiotic stress. Moreover, the tissue-specific expression profile reveals the functional divergence of SOD genes in different organs development of cotton. Taken together, this study has imparted new insights into
 the putative functions of SOD gene family in cotton. Findings of the present investigation could help in understanding the role of SOD gene family in various aspects of the life cycle of cotton.
We modified the robust analysis of variance (RANOVA) method to calculate sampling uncertainty of selected trace elements determined in soil samples from two heterogeneous remote historic metal ore mining areas. Classical RANOVA is down-weighting the outlying values by replacing them during the calculation process with mean ± c·σ r . Because the arithmetic mean is greatly influenced by outliers, it cannot represent a robust statistic. The main novel contribution of this work is use of median value that is independent on outliers and replace all extreme values during the calculation process with median ± 2·σ r . In our work, 18 duplicate, composite soil samples were collected, digested with aqua regia in a closed microwave system, and analyzed twice for selected trace elements. To extract homogenous groups within sampling areas and make the results more accessible for interpretation, a cluster analysis was done. Subsequently, histograms of each element were prepared and statistical tests were applied to determine the normal distribution of datasets. For abnormally distributed elements, the outlying values were identified by four different methods: boxplot, mean ± c·σ r , mean ± c·σ, and median ± 2·σ r . For five elements, the amount of outliers identified by the median ± 2·σ r procedure was less than 10 %, and for these elements, the sampling uncertainty was computed using a modified RANOVA method. The sampling uncertainty computed with this method was 28.9 % for Cd, 15.2 % for Co, 14.5 % for Mn, 12.7 % for Ni, and 16.3 % for Zn, whereas that computed with a traditional model was 16.7 % for Cd, 9.2 % for Co, 20.5 % for Mn, 17.9 % for Ni, and 16.3 % for Zn.
This study reports an analysis of the IR reflectance and Raman spectra of Cd x Zn(1 - x)P2 solid solutions. We have analyzed the effect of the doping of the CdP2 single crystal by the ZnP2 nanoclusters on the vibrational properties of studied samples: ε 0, ε inf, phonon frequencies, and strengths. These dependencies might be used as an alternative non-destructive way for the control of the Cd x Zn(1 - x)P2 composition. The obtained results show that variation of the concentration of ZnP2 nanoclusters opens a space to design the tailored material properties for the industrial applications.
In order to study element accumulation and trophic transfer in the food web, sixteen benthic invertebrate species and nine fish species were collected from the Daliao River estuary for analysis of toxic elements and nitrogen stable isotope in the muscle tissue. The concentrations ranged between 1.44-17.98, 0.01-9.30, 0.17-36.15, 0.7-145.4, 0.01-0.33, 0.14-14.88, 0.10-2.51, 0.02-0.14, and 19.3-221.1mgkg(-1) for As, Cd, Cu, Hg, Ni, Pb, Sb, and Zn, respectively. As, Cd, Cu, and Zn were significantly higher in the benthic invertebrates than in fish, whereas Hg and Sb were significantly lower. In addition, the benthic invertebrates were characterized by the highest bioaccumulation factor (BAF) for Cd, whereas the fish were characterized by the highest BAF for Hg. A significant decrease in Cd, Cr, Cu, and Ni levels, and a significant increase in Hg and Sb levels were observed with increasing trophic levels.
Pb concentrations and Pb isotopic compositions (total and acid-extractable) in the core sediments collected from Western Xiamen Bay, China, were determined to investigate the Pb pollution history and trace the Pb sources. Pb concentration showed an increasing trend (from 40.3 to 64.2mgkg(-1)) with obvious fluctuation from 1967 to 2013, reflected by the core sediments. The enrichment factors of Pb were between 2 and 5, indicating a moderate enrichment. The relative contributions of Pb-Zn deposit and parent material to total Pb in the core sediments were 51%-62% and 38%-49%, respectively. Acid-extractable Pb isotopic signature was more sensitive than total Pb isotopic signature in identifying anthropogenic Pb sources due to the substantial variability of acid-extractable Pb isotopic ratios exhibited in the core sediments. Based on the acid-extractable Pb isotopic ratios, Pb-Zn deposit and industrial emission were regarded as the main anthropogenic Pb contributors.
The concentration of five heavy metals; Cadmium (Cd), Copper (Cu), Lead (Pb), Mercury (Hg) and Zinc (Zn) in the tissues of periwinkle; Typanotonus fuscatus from Iko River Estuary were determined using UNICAM Solar Atomic Absorption Spectrophotometer 969 model. The results showed that Cd ranged from 68.83 - 130.5mg/kg with a mean value of 104.47±23.85mg/kg, Cu ranged from 34.9 - 73.62mg/kg with a mean value of 57.70±17.19mg/kg, Pb ranged between 54.27 - 102.54mg/kg with a mean value of 85.03±18.52mg/kg, Mercury ranged from 0.01 - 1.84mg/kg with a mean value of 0.41±0.80mg/kg and Zn ranged from 270.2 - 508.16mg/kg with a mean of 384.99±103.99mg/kg. The sequence of heavy metal concentration in the tissue of periwinkle was; Zn ˃ Cd ˃ Pb ˃ Cu ˃ Hg while the sequence of non-essential metals was Cd ˃ Pb ˃ Hg. Metal with the highest concentration was Zinc while the one with the lowest concentration was Mercury. Except for Mercury, the mean concentration of the metals was above the maximum permissible limits recommended by bodies and organizations. The highest concentration of heavy metals was recorded in August and lowest in October. Hence, there is need for regular monitoring of heavy metal concentrations in this water body and the aquatic organism inhabitants because of the long term effects. Relevant patents relating to heavy metal concentration in aquatic molluscs were reviewed.
Melanin is a critical component of biological systems, but the exact chemistry of melanin is still imprecisely known. This is partly due to melanin's complex heterogeneous nature and partly because many studies use synthetic analogues and/or pigments extracted from their natural biological setting, which may display important differences from endogenous pigments. Here we demonstrate how synchrotron X-ray analyses can non-destructively characterise the elements associated with melanin pigment in situ within extant feathers. Elemental imaging shows that the distributions of Ca, Cu and Zn are almost exclusively controlled by melanin pigment distribution. X-ray absorption spectroscopy demonstrates that the atomic coordination of zinc and sulfur is different within eumelanised regions compared to pheomelanised regions. This not only impacts our fundamental understanding of pigmentation in extant organisms but also provides a significant contribution to the evidence-based colour palette available for reconstructing the appearance of fossil organisms.
Increased water demands in dry countries such as Australia, have led to increased adoption of various water reuse practices. Irrigation of greywater (all water discharged from the bathrooms, laundry and kitchen apart from toilet waste) is seen as a potential means of easing water demands; however, there is limited knowledge of how greywater irrigation impacts terrestrial and aquatic environments. This study compared four greywater irrigated residential lots to adjacent non-irrigated lots that acted as controls. Accumulation and potential impacts of metals in soil, groundwater and surface water, as a result of greywater irrigation, were assessed by comparing measured concentrations to national and international guidelines. Greywater increased concentrations of some metals in irrigated soil and resulted in As, B, Cr and Cu exceeding guidelines after only four years of irrigation. Movement of metals from the irrigation areas resulted in metal concentrations in groundwater (Al, As, Cr, Cu, Fe, Mn, Ni and Zn) and surface water (Cu, Fe and Zn) exceeding environmental quality guidelines again within four years. These results are unlikely to be universally applicable but indicate the need to consider metals in greywater in order to minimize potential adverse environmental effects from greywater irrigation.
Ditches are subjected to a large input of nutrients, trace metals, and arsenic and the enhancement of sedimentation due to human activities. However, the influence of different types of land uses on the distribution and associated environmental risk of metals and arsenic in the Red purple Sichuan Basin remains largely unclear, which is needed for water management. This study was carried out to characterize metal/metalloid status in ditch sediments from different land uses. A total of 68 surface sediment samples (0-5 cm) were collected from open ditches distributed in different land use types, i.e., cultivated ditches (CD), barren land ditches (BLD), roadside ditches (RSD), and residential ditches (RD), within the Sichuan Basin. Mean concentrations of Cr, Ni, Cu, Zn, Cd, Pb, and Mn in both RD and RSD were above the soil background values of Sichuan Basin, but Cd in ditch sediments of the basin posed considerable ecological risk to the environment. Overall, metals/metalloid (except Pb) decreased in the following order of RD > RSD > BLD > CD. Of the different land use types in the hilly region, residential and roadside land uses were likely to adverse effects on aquatic life. Multivariate statistical analysis showed that Mn, As, Cu, Ni, Zn, Fe, and Al were mainly influenced by natural weathering (erosion), while Pb might come from heavy vehicular traffic. The degree of contamination (Md), enrichment factor (EF), and the geo-accumulation index (Igeo) showed that Cd causes strong sediment pollution in the basin. Sediment quality guidelines SQG-Q values displayed that metals and arsenic created medium-low potential of adverse biological effects. These results provide baseline information on the metals and arsenic pollution in the Sichuan
 Basin. Awareness of land use type contributions to metals and arsenic requires that these man-made ditches be considered for their mitigation of pollutants in this region.
One hundred and eleven riverbed surface sediment (RSS) samples were collected to determine the heavy metal concentration throughout the Inner Mongolia reach of the Yellow River (IMYR), which has been subjected to rapid economic and industrial development over the past several decades. Comprehensive analysis of heavy metal contamination, including the enrichment factor, geo-accumulation index, contamination factor, pollution load index, risk index, principal component analysis (PCA), hierarchical cluster analysis (HCA), and Pearson correlation analysis, was performed. The results demonstrated that a low ecological risk with a moderate level of heavy metal contamination was present in the IMYR due to the risk index (RI) being less than 150 and the pollution load index (PLI) being above 1, and the averaged concentrations of Co, Cr, Cu, Mn, Ni, Ti, V, and Zn in the RSS, with standard deviations, were 144 ± 69, 77.91 ± 39.28, 22.95 ± 7.67, 596 ± 151, 28.50 ± 8.01, 3793 ± 487, 69.11 ± 18.44, and 50.19 ± 19.26 mg kg(-1), respectively. PCA, HCA, and Pearson correlation analysis revealed that most of the RSS was heavily contaminated with Zn, Ni, and Cu, due to the influence of anthropogenic activities; moderately contaminated with Ti, Mn, V and Cr because of the dual influence of anthropogenic activities and nature; and slightly to not contaminated with Co because it occurs mainly in the bordering desert areas. Graphic abstract ᅟ.
Zinc oxide nanoparticles (nano-ZnO) are one of the most important nanoparticles in the industry. The objectives of this study were (1) to investigate the effects of nano-ZnO on oxidative damage to DNA and on apoptosis in zebrafish (Danio rerio) embryos, and (2) to identify the underlying molecular mechanism affecting theapoptotic process. In addition to nano-ZnO, we also investigated the toxic effects of the Zn(2+) ion. Zebrafish embryos were exposed to 10, 30, 60, 90, or 120mg/L nano-ZnO for 96h postfertilization. Nano-ZnO (at concentrations between 10 and 120mg/L) significantly reduced the rate of embryo hatching. Embryos/larvae exposed to 120mg/L nano-ZnO had significantly higher heart rates. Increased heart rates could be a physiological mechanism compensating for body hypoxia. Embryos/larvae exposed to nano-ZnO exhibited oxidative stress, due to an excessive generation of reactive oxygen species (ROS). Oxidative stress was evidenced by increased levels of superoxide dismutase, by increased lipid peroxidation, and by increased expression of genes related to the antioxidant defense system (sod1, cat, gpx1a, and pparα), which were altered at different degrees. Upon exposure to nano-ZnO, the percentage of apoptotic cells increased in a dose-dependent manner (0.41% to 4.21%). In addition, altered transcriptional regulation of pro-apoptotic genes (bax, puma, and apaf-1) and anti-apoptotic genes (bcl-2) provided further evidence of the activation of apoptosis. In this study, exposure of zebrafish embryos to nano-ZnO triggered an excessive production of ROS, which was followed by several phenomena: the up-regulation of p53, a reduction in the bcl-2/bax ratio,a reduction in the mitochondrial membrane potential (ψm), the release of cytochrome c into the cytosolic fraction, and the activation of caspases 9 and 3. Collectively, our data imply that nano-ZnO induce an excessive production of ROS which then activate the apoptosis pathway mediated by mitochondria and caspases.
A sandwich-configuration electrochemiluminescence (ECL) biosensor was constructed for detecting concanavalin A (ConA) based on peroxydisulfate/oxygen (S2O8(2-)/O2) system. In this work, the gold nanoflower modified Zn-doped SnO2 was used as a substrate to adsorb recognition element horseradish peroxidase (HRP) for binding ConA. Then, Au nanoparticles-thiosemicarbazide functionalized PtNi nanocubes (AuNPs-TSC-PtNi NCs), as a novel ECL signal tracer, were incubated onto the electrode through a specific carbohydrate-ConA interaction, thus achieving a sandwiched structure. The integration of amplifying effect of both TSC and PtNi NCs on the ECL of S2O8(2-)/O2 system endowed the biosensor a high sensitivity. The linear range for ConA detection was from 0.0010ng/mL to 10ng/mL with a detection limit of 0.0002ng/mL (S/N=3).
Hierarchical ZSM-11 and Zn-ZSM-11 catalysts were used in this study. The effects of two methods (direct synthesis and impregnation) of zinc incorporation on methanol conversion were investigated in a continuous-flow isotherm fixed-bed reactor. XRD, SEM, BET, FTIR, and XRF analytical results revealed that the introduction of zinc through direct synthesis generated new Brønsted acid sites that could tune the ratio of light olefins. The damage to the framework structure after zinc incorporation restrained the aromatization, dehydrogenation, and decomposition of methanol. The extent of this impact determined the degree of deactivation behaviors. Thus, the yield of propene and butene was enhanced through the direct synthesis method (2 % ZnZ11-C, 4 % ZnZ11-C), and the sample 4 % ZnZ11-C displayed a fast deactivation.

Surroundings of the Legnica Cu smelter (Poland) offer insight into the behavior of Pb and other metal(oid)s in heavily contaminated soils in a relatively simple site, where lithogenic and anthropogenic Pb contributions have uniform Pb isotope composition over the time of smelter activity. Distribution of metal(oid)s decreases asymptotically with depth and below 30 cm reaches concentrations typical or lower than those of upper continental crust. Usually, such distribution is interpreted as the decrease in anthropogenic Pb contribution with depth. However, calculations based on Pb isotopes indicate that anthropogenic Pb is probably distributed both as Pb-rich particles of slags and fly ashes and Pb-poor soil solutions. Generally, anthropogenic Pb constitutes up to 100 % of Pb in the uppermost 10 cm of the soils and comes often from mechanical mixing with slag and fly ash particles as well as their weathering products. On the other hand, lower soil horizon contains anthropogenic Pb in various forms, and at depths below 30 cm, most of anthropogenic Pb comes from soil solutions and can constitute from 1 to 65 % of the Pb budget. This is consistent with secondary electron microscope (SEM) analyses of heavy mineral particles showing that, in upper horizons, Pb, Cu, and Zn are contained in various particles emitted from the smelter, which show different stages of weathering. Currently, large portion of these metals may reside in the secondary Fe-hydro-oxides. On the other hand, in deeper soil horizons, anthropogenic Pb is probably dominated by Pb coming from leaching of slag or fly ash particles. Overall, metal(oid) mobility is a dynamic process and is controlled by the soil type (cultivated versus forest) and the composition and the structure of the metal-rich particles emitted from the smelter. High proportions of anthropogenic Pb at depths below 30 cm in some soil profiles indicate that Pb (and probably other metal(oid)s) can be transported down the soil profile and the present concentration of anthropogenic Pb depends on the availability of binding sites.
Zinc importer proteins (ZIPs) have been proven as important molecular regulators in different cancers. As a member of the solute carrier family, ZIP9/SLC39A9 is overexpressed in prostate and breast cancer and affects B-cell receptor signaling. Here, we present data indicating that changes in intracellular zinc levels in glioblastoma cells can cause enhanced cell survival and cell migration, both hallmarks of the disease process. In particular, treatment of human glioblastoma cells with sublethal doses of cell-permeable heavy metal (Zn(2+) > Fe(2+) > Mn(2+)) chelator (N,N,N',N'-tetrakis (2-pyridylmethyl)ethylenediamine (TPEN)) induced ZIP9 expression. Either TPEN treatment or expression of ZIP9 cDNA causes enhanced migration behavior of glioblastoma cells. Compared to untreated glioblastoma cells TPEN treatment or expression of ZIP9 results in activation of the tumor suppressor p53 by phosphorylation at serine residue 46 (Ser46) and in inactivation of the migration relevant glycogen synthase kinase 3 beta (GSK-3β) by phosphorylation at serine residue 9 (Ser9). Whilst p53 activation affects cell survival in response to TPEN, GSK-3β inactivation directly affects glioblastoma cell migration. Therefore, ZIP9 expression could regulate the migratory behavior of glioblastoma cells, so that ZIP9 may be of biological, but not of clinical relevance for glioblastomas, since in GBM tumor tissues, ZIP9 expression is not significantly increased compared to normal brain.
A family of mononuclear tetrahedral cobalt(II) thiourea complexes, [Co(L1)4](NO3)2 (1) and [Co(Lx)4](ClO4)2 where x = 2 (2), 3 (3), 4 (4) (where L1 = thiourea, L2 = 1,3-dibutylthiourea, L3 = 1,3-phenylethylthiourea, and L4 = 1,1,3,3-tetramethylthiourea), has been synthesized using a rationally designed synthetic approach, with the aim of stabilizing an Ising-type magnetic anisotropy (-D). On the basis of direct-current, alternating-current, and hysteresis magnetic measurements and theoretical calculations, we have identified the factors that govern the sign and magnitude of D and ultimately the ability to design a single-ion magnet for a tetrahedral cobalt(II) ion. To better understand the magnetization relaxation dynamics, particularly for complexes 1 and 2, dilution experiments were performed using their diamagnetic analogues, which are characterized by single-crystal X-ray diffraction with the general molecular formulas of [Zn(L1)4](NO3)2 (5) and [Zn(L2)4](ClO4)2 (6). Interestingly, intermolecular interactions are shown to play a role in quenching
 the quantum tunneling of magnetization in zero field, as evidenced in the hysteresis loop of 1. Complex 2 exhibits the largest Ueff value of 62 cm(-1) and reveals open hysteresis loops below 4 K. Furthermore, the influence of the hyperfine interaction on the magnetization relaxation dynamics is witnessed in the hysteresis loops, allowing us to determine the electron/nuclear spin S(Co) = (3)/2/I(Co) = (7)/2 hyperfine coupling constant of 550 MHz, a method ideally suited to determine the hyperfine coupling constant of highly anisotropic metal ions stabilized with large D value, which are otherwise hard to determine by conventional methods such as electron paramagnetic resonance.
The detection of ethyne is crucial not only in environmental monitoring but also in process controlling and mechanism studies in industrial fields. Here, a new sensor based on the plasma-assisted cataluminescence (PA-CTL) has been fabricated for the detection of ethyne. Based on the assistance of low-temperature plasma (LTP) generated by air, which can enhance the catalytic ability of catalysts and the reactivity of the analytes, we observed significant cataluminescence (CTL) emissions on the surface of nanomaterials of Zn/SiO2. CTL emission has demonstrated to be affected by the type of discharge gases or the metal ions doping on the catalysts of SiO2. By the optimizations on the working temperature and gas flow rate of the air, a PA-CTL based sensor was constructed for the detection of ethyne. As demonstrated, this sensor exhibited a linearity of 11-1160 ng/mL (10-1000 ppm) with a limit of detection (LOD) of 5 ng/mL (5 ppm), and also showed good selectivity as well as good stability. This sensor is simple, low-cost, and could give stable responses for actual applications, which will expand the applications of CTL and show potentials in industrial substances detections. Graphical Abstract A plasma-assisted cataluminescence gas sensor for ethyne detection.
The aim of the present study was to examine the influence of age and gender on the pro/antioxidant balance in young healthy subject aged 20-40 years. The individuals were divided into women: aged 20-25 years (group A), aged 32-39 years (group B), and men aged 20-25 years (group C). In blood, the metals, markers of oxidative stress and antioxidants were estimated. The Cu level and Cu/Zn ratio in group B was higher than in group A. There were no differences in metals concentrations between groups A and C. The similar levels of malondialdehyde concentrations and gamma-glutamyl transpeptidase activities were observed in all groups. The decrease in glutathione reduced and glutathione peroxidase was in group B than in group A. The higher glutathione reduced, lower glutathione oxidized concentrations and glutathione-dependent enzymes (glutathione reductase and glutathione peroxidase) were observed in group C when compared to group A. The superoxide dismutase and catalase activities were higher in groups B and C than in group A.The age and gender have an influence on the pro/antioxidant status in healthy people aged 20-40 years. The main antioxidants responsible for the removal of free radicals in men aged 20-25 years and women aged 32-39 years are superoxide dismutase and catalase, while the glutathione peroxidase activity declines. The detoxification being mediated through glutathione is weakened in women aged 32-39 years.
Concentrations of 11 elements (As, Ba, Cd, Cu, Fe, Mn, Ni, Pb, Se, Sr, and Zn) from the medicinal and edible mushroom Wolfiporia extensa were determined using atomic fluorescence spectrometry (for As and Se) and inductively coupled plasma atomic emission spectrometry (for Ba, Cd, Cu, Fe, Mn, Ni, Pb, Sr, and Zn). All the samples were collected from 6 regions of Yuxi in Yunnan Province in the southwest of China and were digested with concentrated nitric acid and hydrogen peroxide in a microwave system. The recovery rates of standard addition ranged from 98.24% to 111.8%; the correlation coefficients were all above 0.999. The amounts of As (0.009-0.41 μg · g-1 dry weight [dw]), Cd (0-0.266 μg · g-1 dw), and Pb (0-2.6 μg · g-1 dw) were below the permissible limits in food that are promulgated by the World Health Organization. All the element concentrations determined in this study were proved at the common level. The result of principal component analysis indicated that 5 principal components were extracted from 11 elements, which revealed 74.7% of all variable information. The results of cluster analysis mainly showed the presence of 3 metal groups.
A major goal in metalloprotein design is to build protein scaffolds from scratch that allow precise control over metal coordination. A particular challenge in this regard is the construction of allosteric systems in which metal coordination equilibria are coupled to other chemical events that take place elsewhere in the protein scaffold. We previously developed a metal-templated self-assembly strategy (MeTIR) to build supramolecular protein complexes with tailorable interfaces from monomeric building blocks. Here, using this strategy, we have incorporated multiple disulfide bonds into the interfaces of a Zn-templated cytochrome cb562 assembly in order to create mechanical strain on the quaternary structural level. Structural and biophysical analyses indicate that this strain leads to an allosteric system in which Zn(2+) binding and dissociation are remotely coupled to the formation and breakage of a disulfide bond over a distance of >14 Å. The breakage of this strained bond upon Zn(2+) dissociation occurs in the absence of any reductants, apparently through a hydrolytic mechanism that generates a sulfenic acid/thiol pair.
Voltage-gated proton (Hv1) channels are involved in many physiological processes, such as pH homeostasis and the innate immune response. Zn(2+) is an important physiological inhibitor of Hv1. Sperm cells are quiescent in the male reproductive system due to Zn(2+) inhibition of Hv1 channels, but become active once introduced into the low-Zn(2+)-concentration environment of the female reproductive tract. How Zn(2+) inhibits Hv1 is not completely understood. In this study, we use the voltage clamp fluorometry technique to identify the molecular mechanism of Zn(2+) inhibition of Hv1. We find that Zn(2+) binds to both the activated closed and resting closed states of the Hv1 channel, thereby inhibiting both voltage sensor motion and gate opening. Mutations of some Hv1 residues affect only Zn(2+) inhibition of the voltage sensor motion, whereas mutations of other residues also affect Zn(2+) inhibition of gate opening. These effects are similar in monomeric and dimeric Hv1 channels, suggesting that the Zn(2+)-binding sites are localized within each subunit of the dimeric Hv1. We propose that Zn(2+) binding has two major effects on Hv1: (i) at low concentrations, Zn(2+) binds to one site and prevents the opening conformational change of the pore of Hv1, thereby inhibiting proton conduction; and (ii) at high concentrations, Zn(2+), in addition, binds to a second site and inhibits the outward movement of the voltage sensor of Hv1. Elucidating the molecular mechanism of how Zn(2+) inhibits Hv1 will further our understanding of Hv1 function and might provide valuable information for future drug development for Hv1 channels.
We report rapid photoinitiated intracomplex electron transfer (ET) within a "charge-disproportionated" myoglobin (Mb) dimer with greatly enhanced affinity. Two mutually supportive Brownian Dynamics (BD) interface redesign strategies, one a new "heme-filtering" approach, were employed to "break the symmetry" of a Mb homodimer by pairing Mb constructs with complementary highly positive and highly negative net surface charges, introduced through D/E → K and K → E mutations, respectively. BD simulations using a previously developed positive mutant, Mb(+6) = Mb(D44K/D60K/E85K), led to construction of the complementary negative mutant Mb(-6) = Mb(K45E, K63E, K95E). Simulations predict the pair will form a well-defined complex comprising a tight ensemble of conformations with nearly parallel hemes, at a metal-metal distance ∼18-19 Å. Upon expression and X-ray characterization of the partners, BD predictions were verified through ET photocycle measurements enabled by Zn-deuteroporphyrin substitution, forming the [ZnMb(-6), Fe(3+)Mb(+6)] complex. Triplet ET quenching shows charge disproportionation increases the binding constant by no less than ∼5 orders of magnitude relative to wild-type Mb values. All progress curves for charge separation (CS) and charge recombination (CR) are reproduced by a generalized kinetic model for the interprotein ET photocycle. The intracomplex ET rate constants for both CS and CR are increased by over 5 orders of magnitude, and their viscosity independence is indicative of true interprotein ET, rather than dynamic gating as seen in previous studies. The complex displays an unprecedented timecourse for CR of the CS intermediate I. After a laser flash, I forms through photoinduced CS, accumulates to a maximum concentration, then dies away through CR. However, before completely disappearing, I reappears without another flash and reaches a second maximum before disappearing completely.
Microbial biotechnologies for the decolorization of textile wastewaters have attracted worldwide attention because of their economic suitability and easiness in handling. However, the presence of high amounts of salts and metal ions in textile wastewaters adversely affects the decolorization efficiency of the microbial bioresources. In this regard, the present study was conducted to isolate salt tolerant bacterial strains which might have the potential to decolorize azo dyes even in the presence of multi-metal ion mixtures. Out of the tested 48 bacteria that were isolated from an effluent drain, the strain NA6
 was found relatively more efficient in decolorizing the reactive yellow-2 (RY2) dye in the presence of 50 g L(-1) NaCl. Based on the similarity of its 16S rRNA gene sequence and its position in a phylogenetic tree, this strain was designated as Proteus sp. NA6. The strain NA6 showed efficient decolorization (>90 %) of RY2 at pH 7.5 in the presence of 50 g L(-1) NaCl under static incubation at 30 °C. This strain also had the potential to efficiently decolorize other structurally related azo dyes in the presence of 50 g L(-1) NaCl. Moreover, Proteus sp. NA6 was found to resist the presence of different metal ions (Co(+2), Cr(+6), Zn(+2), Pb(+2), Cu(+2), Cd(+2)) and was capable of decolorizing reactive dyes in the presence of different levels of the mixtures of these metal ions along with 50 g L(-1) NaCl. Based on the findings of this study, it can be suggested that Proteus sp. NA6 might serve as a potential bioresource for the biotechnologies involving bioremediation of textile wastewaters containing the metal ions and salts.
α-MnO2 nanotubes-supported Co3O4 (Co3O4/MnO2) and its carbon nanotubes (CNTs)-hybrids (Co3O4/MnO2-CNTs) have been successfully developed through a facile two-pot precipitation reaction and hydrothermal process, which exhibit the superior bi-functional catalytic activity for both ORR and OER. The high performance is believed to be induced by the hybrid effect among MnO2 nanotubes, hollow Co3O4 and CNTs, which can produce a synergetic enhancement. When integrated into the practical primary and electrochemically rechargeable Zn-air batteries, such a hybrid catalyst can give a discharge peak power density as high as 450 mW cm(-2). At 1.0 V of cell voltage, a current density of 324 mA cm(-2) is achieved. This performance is superior to all reported non-precious metal catalysts in literature for zinc-air batteries and significantly outperforms the state-of-the-art platinum-based catalyst. Particularly, the rechargeable Zn-air battery can be fabricated into all-solid-state one through a simple solid-state approach, which exhibits an excellent peak power density of 62 mW cm(-2), and the charge and discharge potentials remain virtually unchanged during the overall cycles, which is comparable to the one with liquid electrolyte.
Rapid detection and identification of microorganisms is a challenging and important aspect in many areas of our life, beginning with medicine, ending with industry. Unfortunately, classical methods of microorganisms identification are based on time-consuming and labor-intensive approaches. Screening techniques require rapid and cheap grouping of bacterial isolates; however, modern bioanalytics demands comprehensive bacterial studies on molecular level. The new approach to the rapid identification of bacteria is to use the electromigration techniques, especially capillary zone electrophoresis (CZE). CZE is an important technique used in the analysis of microorganisms. However, the analysis of microbial complexes using this technology still encounters several problems-uncontrolled aggregation and/or adhesion to the capillary surface. One way to resolve this issue is the CZE analysis of microbial cell with surface charge modification by bivalent metal ions (e.g., Ca(2+) aq, Zn aq). Under the above conditions, bacterial cells create compact aggregates, and fewer high-intensity signals are observed in electropherograms. The chapter presents the capillary electrophoresis of microbial aggregates approach with UV and one-dimensional intact cell matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (ICM MS) detection.
A Zn(OTf)2-catalyzed simple and efficient method has been developed for the synthesis of imidazole-substituted allenes by the reaction of 1,1,3-triphenylprop-2-yn-1-ol and imidazoheterocycles. A library of tetrasubstituted allenes with broad functionalities have been prepared with excellent yields. The present methodology is also applicable to imidazo[1,2-a]pyrimidine, imidazo[2,1-b]thiazole and benzo[d]imidazo[2,1-b]thiazole.
Generally, Antarctica is considered to be an untouched area of the planet; however, the region's ecosystems have been subject to increased human pressure for at least the past half-century. This study assessed soils of Fildes Peninsula, where trace element pollution is thought to prevail. Four soil samples were collected from different locations and assessed following tier 1 methodologies for chemical and ecotoxicological lines of evidence (LoE) used in typical soil Environmental Risk Assessment (ERA). Trace element quantification was run on soil samples and sequential extracts, and elutriates were used to address their ecotoxicity using a standard ecotoxicological battery. The highest levels of trace elements were found for Cr, Cu, Ni and Zn, which were well above baseline levels in two sites located near previously identified contamination sources. Trace element concentrations in soils were compared with soil quality guidelines to estimate the contribution of the chemical LoE for integrated risk calculations; risk was found high, above 0.5 for all samples. Total concentrations in soil were consistent with corresponding sequentially extracted percentages, with Cu and Zn being the most bioavailable elements. Bacteria did not respond consistently to the elutriate samples and cladocerans did not respond at all. In contrast, the growth of microalgae and macrophytes was significantly impaired by elutriates of all soil samples, consistently to estimated trace element concentrations in the elutriate matrix. These results translated into lower risk values for the ecotoxicological compared to the chemical LoE. Nevertheless, integrated risk calculations generated either an immediate recommendation for further analysis to better understand the hazardous potential of the tested soils or showed that the soils could not adequately sustain natural ecosystem functions. This study suggests that the soil ecosystem in Fildes has been inadequately protected and supports previous claims on the need to reinforce protection measures and remediation activities.
Cement-based stabilization/solidification (S/S) is used to decrease environmental leaching of contaminants from industrial wastes. In this study, two industrial metal treatment filtercakes were characterized by X-ray diffractometry (XRD), thermogravimetric and differential thermogravimetric analysis (TG/DTG) and Fourier transform infrared (FTIR); speciation of nickel was examined by X-ray absorption (XAS) spectroscopy. Although the degree of carbonation and crystallinity of the two untreated filtercakes differed, α-nickel hydroxide was identified as the primary nickel-containing phase by XRD and nickel K edge XAS. XAS showed that the speciation of nickel in the filtercake was unaltered by treatment with any of five different S/S binder systems. Nickel leaching from the untreated filtercakes and all their stabilized/solidified products, as a function of pH in the acid neutralization capacity test, was essentially complete below pH ∼5, but was 3-4 orders of magnitude lower at pH 8-12. S/S does not respeciate nickel from metal treatment filtercakes and any reduction of nickel leaching by S/S is attributable to pH control and physical mechanisms only. pH-dependent leaching of Cr, Cu and Ni is similar for the wastes and s/s products, except that availability of Cr, Cu and Zn at decreased pH is reduced in matrices containing ground granulated blast furnace slag.
Developing highly active electrocatalysts with low cost and high efficiency for oxygen evolution reactions (OER) is important for the practical implementations of hydrogen energy. Here, we report a Zn-doped CoSe2 nanosheets grown on free-standing carbon fabric collector (CFC), which was synthesized by using a metal-organic framework (MOF) as precursor and followed by a selenylation process. Importantly, the Zn-doped CoSe2/CFC electrode exhibited an obviously enhanced catalytic activity for OER in 1 M KOH aqueous solution compared with CoSe2/CFC, showing a small overpotential of 356 mV for a current density of 10 mA cm(-2), a small Tafel slope of 88 mV dec(-1), and an excellent stability. The robust and free-standing electrode shows great potential as an economic catalyst for OER applications.
Cadmium (Cd) is an environmental contaminant that poses serious risks to aquatic organisms and their associated ecosystem. The mechanisms underlying Cd-induced oxidative stress and immunotoxicity in fish remain largely unknown. In this study, adult female zebrafish were exposed to 0 (control), 1mgL(-1) Cd for 24h and 96h, and the oxidative stress and inflammatory responses induced by Cd were evaluated in the brain, liver and ovary. Reactive oxygen species (ROS), nitric oxide (NO), and malondialdehyde (MDA) increased in a time-dependent manner after treatment with Cd in the brain and liver. The increase may result from the disturbance of genes including copper and zinc superoxide dismutase (Cu/Zn-SOD), catalase (CAT), inducible nitric oxide synthase (iNOS), and ciclooxigenase-2 (COX-2) at mRNA, protein and activity levels. Although ROS, NO and MDA were not significantly affected by Cd in the ovary, the up-regulation of Cu/Zn-SOD, CAT, iNOS, and COX-2 was observed. Exposure to Cd induced a sharp increase in the protein levels of tumor necrosis factor alpha (TNF-α) in the brain, liver and ovary, possibly contributing to activate inflammatory responses. Furthermore, we also found a dramatic increase in mRNA levels of NF-E2-related factor 2 (Nrf2) and nuclear transcription factor κB (NF-κB) at 24h in the liver and ovary. The corresponding changes in the mRNA levels of Kelch-like-ECH-associated protein 1 (Keap1a and Keap1b) and the inhibitor of κBα (IκBαa and IκBαb) may contribute to regulate the transcriptional activity of Nrf2 and NF-κB, respectively. Contrarily,
 mRNA levels of Nrf2, NF-κB, Keap1, Keap1b, IκBαa and IκBαb remained stable at 24 and 96h in the brain. Taken together, we demonstrated Cd-induced oxidative stress and immunotoxicity in fish, possibly through transcriptional regulation of Nrf2 and NF-κB and gene modifications at transcriptional, translational, post-translational levels, which would greatly extend our understanding on the Cd toxicity.
Biochar is considered to be a promising material for heavy metal immobilization in soil. However, the immobilization mechanisms of Zn(2+) on biochars derived from many common waste biomasses are not completely understood. Herein, biochars (denoted as PN350, PN550, WS350, and WS550) derived from pine needle (PN) and wheat straw (WS) were prepared at two pyrolysis temperatures (350 °C and 550 °C). The immobilization behaviors and mechanisms of Zn(2+) on these biochars were systematically investigated. The results show that compared with biochars produced at low temperature, biochars produced at high temperature contained higher amounts of ash and exhibited much higher sorption capacities of Zn(2+). By using Zn K-edge EXAFS spectroscopy, we find that the formation of various Zn precipitates/minerals, which was caused by the release of OH(-), CO3(2-), and Si species from biochar, was the immobilization mechanism of Zn(2+) on PN and WS biochars. Hydrozincite and Zn(OH)2 were the main species formed on PN350, PN550, and WS350; while on WS550, besides hydrozincite, a large fraction of hemimorphite was formed. The occurrence of hydrozincite and hemimorphite on biochar during Zn(2+) immobilization is firstly reported in our study, which provides a new insight into the immobilization mechanism of Zn(2+) on biochar.
This study explored associations between free sugars intake (using non-milk extrinsic sugars as proxy) and nutrient intakes among children aged 1·5-18 years in the UK National Diet and Nutrition Survey 2008-2012. Dietary records were completed by 2073 children (95 % completed 4 d). Mean free sugars intakes (% energy) were 11·8, 14·7 and 15·4 % in the 1·5-3, 4-10 and 11-18 years age groups, respectively. Nutrient intakes and nutrient density were compared across quintiles (Q1-Q5) of free sugars intake (% energy) within each age group. Energy intake rose from Q1 to Q5 of free sugars, whereas percentages of energy intake from fat, SFA and protein dropped. Associations with micronutrients (mg/d or mcg/d) were mostly non-significant, but among 11-18-year-olds there were significant negative associations with Zn, Se, Fe, Cu, and vitamin A and D. There were stronger negative associations with micronutrient density (mg/mcg per 4·18 MJ) for most nutrients in all age groups. Associations with vitamin C were positive. Results were similar after excluding misreporters. Children aged 4-18 years who consumed average amounts of free sugars or above (>13 % energy or Q3-Q5) had lower diet quality than those consuming <10 % free sugars (Q1), but there were insufficient data to assess diets with 5 % free sugars. High consumers obtained a higher proportion of free sugars from soft drinks, fruit juice and sugar confectionery and less from breakfast cereals. Ultimately, nutrient intakes depend on the total dietary pattern; however, reducing overconsumption of sugary foods and drinks with low nutrient density may help improve diet quality.
After invading red blood cells (RBCs), Plasmodium falciparum (Pf) can export its own proteins to the host membrane and activate endogenous channels that are present in the membrane of RBCs. This transport pathway involves the Voltage Dependent Anion Channel (VDAC). Moreover, ligands of the VDAC partner TranSlocator PrOtein (TSPO) were demonstrated to inhibit the growth of the parasite. We studied the expression of TSPO and VDAC isoforms in late erythroid precursors, examined the presence of these proteins in membranes of non-infected and infected human RBCs, and evaluated the efficiency of TSPO ligands in inhibiting plasmodium growth, transporting the haem analogue Zn-protoporphyrin-IX (ZnPPIX) and enhancing the accumulation of reactive oxygen species (ROS). TSPO and VDAC isoforms are differentially expressed on erythroid cells in late differentiation states. TSPO2 and VDAC are present in the membranes of mature RBCs in a unique protein complex that changes the affinity of TSPO ligands after Pf infection. TSPO ligands dose-dependently inhibited parasite growth, and this inhibition was correlated to ZnPPIX uptake and ROS accumulation in the infected RBCs. Our results demonstrate that TSPO ligands can induce Pf death by increasing the uptake of porphyrins through a TSPO2-VDAC complex, which leads to an accumulation of ROS.
Occupational exposure to welding fumes causes a higher incidence of cardiovascular disease; however, the association remains unclear. To clarify the possible association, exposure assessment of metal fumes with an aerodynamic diameter of <2.5 μm (PM2.5) in welding and office areas was characterized in a shipyard in Taiwan. Cardiovascular toxicity caused by PM2.5 was determined in workers (in both the welding and office areas). Significant amounts of bimodal metal fume particles with count median diameters (CMDs) of 14.1~15.1 and 126.3~135.8 nm were produced in the shipyard. Metal fume PM2.5 resulted in decreased cell viability and increased levels of 8-hydroxy-2'-deoxyguanosine (8-OHdG), interleukin (IL)-6, and nitric oxide (NO) in human coronary artery epithelial cells (HCAECs). We recruited 118 welding workers and 45 office workers for a personal PM2.5 exposure assessment and determination of urinary levels of 8-OHdG, 8-iso-prostaglandin F2α (8-iso-PGF2α), and various metals. We observed that a 10-μg/m(3) increase in the mean PM2.5 concentration was associated with a 2.15% increase in 8-OHdG and an 8.43% increase in 8-iso-PGF2α in welding workers. Both 8-OHdG and 8-iso-PGF2α were associated with Fe and Zn in the urine. In conclusion, metal fume PM2.5 could increase the risk of cardiovascular toxicity after inhalation.
In this work, a ZnFe2O4 anode material was successfully synthesized by a novel ionic liquid-assisted synthesis method followed by a carbon coating procedure. The as-prepared ZnFe2O4 particles demonstrate a relatively homogeneous particle size distribution with particle diameters ranging from 40 to 80 nm. This material, which is well known to offer an interesting combination of an alloying and conversion mechanism, is capable of accommodating nine equivalents of lithium per unit formula, resulting in a high specific capacity (≥ 1,000 mAh g-1). The resulting composite anode material displayed a stable capacity of ca. 1,091 mAh g-1 for 190 cycles at a medium de-lithiation potential of 1.7 V and at a charge/discharge rate of 1C. Furthermore, the material displays an excellent high rate capability up to 20C, displaying a reversible capacity of still 216 mAh g-1. Studies on Fe and Zn losses of the ZnFe2O4 active material by dissolution in the electrolyte were performed and compared to those of silicon-, germanium- and tin-based high-capacity anode materials. In conclusion, ion dissolution from metal containing anode materials should not be underestimated in view of its impact on the overall cell performance and cycling stability.
To assess the trace metal pollution in the Siran River, sediments were collected from 12 sites, from the left and right banks of the river in 2013. The concentrations, accumulation, distribution pattern, and pollution status of heavy metals in sediments were investigated using geoaccumulation index (I geo) and enrichment factor (EF). The toxic risk of heavy metals was assessed using interim sediment quality guidelines (ISQGs), portable effect level (PEL), threshold effect level (TEL), and toxic effect threshold (TET). I geo and EF values showed that sediments were loaded with Ni, Cd, Pb, and Co and no obvious variations were found among the left and right banks of the river. The EF and I geo values were found in order of Co > Pb > Ni > As > Cd > Cu > Zn > Fe and Cd > Co > Pb > Ni > As > Fe > Zn > Cu > Mn, respectively. Furthermore, multivariate statistical analysis like inter-metal correlation, cluster analysis (CA), and principal component analysis (PCA) results revealed that geogenic and anthropogenic activities were major sources of sediment contamination in the study area. These results indicated that more attention should be paid to the inner loads of sediment in order to achieve improvements in reservoir water quality after the control of external pollution.
The purpose of the paper is to assess the groundwater quality near the landfill sites using landfill water pollution index (LWPI). In order to investigate the scale of groundwater contamination, three landfills (E, H and S) in different stages of their operation were taken into analysis. Samples of groundwater in the vicinity of studied landfills were collected four times each year in the period from 2004 to 2014. A total of over 300 groundwater samples were analysed for pH, EC, PAH, TOC, Cr, Hg, Zn, Pb, Cd, Cu, as required by the UE legal acts for landfill monitoring system. The calculated values of the LWPI allowed the quantification of the overall water quality near the landfill sites. The obtained results indicated that the most negative impact on groundwater quality is observed near the old Landfill H. Improper location of piezometer at the Landfill S favoured infiltration of run-off from road pavement into the soil-water environment. Deep deposition of the groundwater level at Landfill S area reduced the landfill impact on the water quality. Conducted analyses revealed that the LWPI can be used for evaluation of water pollution near a landfill, for assessment of the variability of water pollution with time and for comparison of water quality from different piezometers, landfills or time
 periods. The applied WQI (Water Quality Index) can also be an important information tool for landfill policy makers and the public about the groundwater pollution threat from landfill.
Heavy metals in urban soils may pose risks to both urban environment and human health. However, only a fraction of heavy metals in soil is mobile and/or bioavailable for plant uptake and human ingestion. This study evaluates the chemical fraction and potential mobility and bioaccessibility of heavy metals (Cd, Cr, Cu, Pb, and Zn) in the contaminated urban topsoils from steel-industrial city (Anshan), Northeastern China. Chemical forms of heavy metals in soils are determined using Tessier sequential extraction technique. The toxicity characteristic leaching procedure (TCLP), ethylenediaminetetraacetic acid (EDTA), and US Pharmacopeia methodology (USPM) are used to determine the operationally defined potentially mobile and bioaccessible metal fractions, respectively. Sequential extraction results show that Cd has the highest percentage of exchangeable form, whereas Cr primarily exists in residual form. The non-residual fraction of heavy metals increases in the order of Cr < Cu < Pb < Zn < Cd. The leachability of heavy metals evaluated by TCLP test indicates that Cd, Zn, Cu, and Pb have much higher mobile than Cr. The bioavailability of heavy metals determined by EDTA extraction decreases in the order of Pb > Cu ≅ Zn > Cd > Cr. The order of bioaccessibility determined by USPM extraction is Pb = Cu > Zn > Cd > Cr. The Cr exhibits the lowest leachability and bioaccessibility among the investigated metals. The Pb has the highest bioaccessibility, indicating higher potential hazard for the human health. There are significant relationships between the EDTA- and USPM-extractable metals (Cd, Cu, Pb, and Zn) and the sum of first three steps of sequential extraction. Highly significant correlation is found between amounts of EDTA-extractable Cd, Cu, Pb, and Zn and USPM-extractable metals. The result suggests that EDTA extraction can be helpful to estimate the bioaccessibility of heavy metals for human ingestion. Introduction of mobile and human bioaccessible concentrations into risk assessments can give more realistic implications for urban environmental management.
Louisiana is one of the world's largest producer of crayfish. Arsenic (As) and other metals (Cd, Cu, Pb and Zn) concentrations were determined in crayfish tissues, plant and soil samples collected from Louisiana paddy rice fields, where crayfish/rice rotation farming is a common practice. The samples were collected from November 2013 to April 2014 from three different crayfish farming systems. Concentration of As in rice grain, rice straw, and native vegetation ranged between 0.33 and 0.41, 3.14-4.93, and 3.26-5.89mgkg(-1), respectively. The highest As levels in the crayfish external and internal body parts were found in gill (4.04±1.70mgkg(-1)), followed by hepatopancreas (3.42±1.57mgkg(-1)), exoskeleton (1.52±0.85mgkg(-1)), and muscle (1.50±0.69mgkg(-1)). Positive correlations between As levels in the crayfish muscle and the plant tissue on which they feed were found in all farming systems (r=0.405-0.438). The biomagnification factor (BMF) of As in different tissues varied between 0.29 and 1.08, having gill and hepatopancreas were the highest As accumulation while the lowest biomagnification was observed in crayfish muscle tissues which is a food source for human. The As levels along with other metals in crayfish muscle tissue were in acceptable levels for human consumption under all crayfish/rice rotation practices. Further studies are needed in determining the percentage of organic and inorganic arsenic in crayfish tissue.
Soil aquifer treatment (SAT) systems rely on extensive physical and biogeochemical processes in the vadose zone and aquifer for water quality improvement. In this study, the distribution, quantitative changes, as well as the speciation characteristics of heavy metals in different depth of soils of a two-year operated lab-scale SAT was explored. A majority of the heavy metals in the recharged secondary effluent were efficiently trapped by the steady-state operated SAT (removal efficiency ranged from 74.7% to 98.2%). Thus, significant accumulations of 31.7% for Cd, 15.9% for Cu, 15.3% for Zn and 8.6% for Cr were observed for the top soil after 730 d operation, leading to the concentration (in μg g(-1)) of those four heavy metals of the packed soil increased from 0.51, 46.7, 61.0 and 35.7 to 0.66, 54.2, 70.4 and 38.8, respectively. By contrast, the accumulation of Mn and Pb were quite low. The residual species were the predominant fraction of the six heavy metals (ranged for 59.8-82.4%), followed by oxidisable species. Although the Zn, Cr, Cd, Cu and Mn were efficiently bounded onto the oxide components within the soil, the percentage of the labile metal fractions (water-, acid-exchangeable and reducible metal fractions) exhibited a slight increasing after 2 Y operation. Significantly heavy metals accumulation and slightly decreasing of the proportion of the stable fractions indicated a potentially higher environmental hazard for those six heavy metals after long-term SAT operation (especially for Cu, Zn and Cd). Finally, a linear relationship between the accumulation rate of metal species and the variation of soil organic carbon concentration and water extractable organic carbon was demonstrated.
Evaluation of modified Algerian clay as mineral adsorbent was done for its adsorbing capacity on copper (Cu) and Zinc (Zn) cations. The results obtained show a rapid kinetic adsorption for both metals (less than 2 h) following the pseudo-second order model with high elimination rates of 67.2 and 61.8% for Cu and Zn respectively. The adsorption isotherms analyzed with Langmuir model revealed a correlation with the experimental values. While the use of obtained chitosan at room temperature, as flocculent coagulant, accelerates the decantation of the colloidal particles in suspension generated after adsorption process.
Six sediment cores collected at the Kaohsiung Harbor of Taiwan were analyzed to evaluate their vertical profiles, enrichments, accumulations, and source apportionments of heavy metals. This was performed to investigate any potential ecological risks posed by heavy metals. Results indicated that the mean heavy metal content (mg kg(-1)) in the six sediment cores was as follows: Hg (0.4-6.4), Cd (<0.05-2.4), Cr (18-820), Cu (16-760), Pb (31-140), and Zn (76-1900). The patterns of heavy metal content in the sediment cores differed substantially among the four river mouths. However, the vertical profiles of metals were relatively stable, indicating that wastewater has the constant characteristics and has been discharged into the rivers for a long period of time. Results of pollution assessment of enrichment factor, geo-accumulation index, and pollution load index revealed that river mouths experience severe enrichment, strong accumulation, and high contamination from the primary heavy metals. It was not consistent in the assessment results of mean effect range median quotient, potential ecological risk index, and total toxic unit method. Potential ecological risks caused by Hg in the sediments at Canon River and Love River mouths on aquatic organisms were extremely high. The estimates derived from the receptor modeling of multiple linear regression of the absolute principal component scores indicated that the contributions of the composite heavy metals derived from the Canon River and the Love River on the potential toxicity and risks to the water environment of Kaohsiung Harbor were highest, followed by those derived from Salt River and Jen-Gen River.
A new harmonized EU regulation for the classification of waste came into effect on 1st June 2015, in which the criteria and assessment methods for the classification of hazardous waste are harmonized with other internationally agreed-upon systems for hazard classification of chemicals (CLP). However, criteria and guidance for the assessment of ecotoxicological hazard (Hazard Property 14, HP14) are still lacking for waste classification. This paper have evaluated and compared two HP14 classification frameworks: (i) a calculation method (summation) for mixtures, and (ii) leaching tests. The two frameworks were evaluated by surveying and evaluating ecotoxicological data for Cu, Zn, K and Ca species in bottom ash from incinerated waste, together with geochemical speciation modelling. Classification based on the summation method proved to be highly sensitive to the choice of speciation and ecotoxicological classification. This results in a wide range of critical concentrations triggering hazardous classification (in particular for Cu and Zn). Important parameters governing the availability of toxic elements, such as transformation from one species to another and complexation on organic or inorganic sorbents, are not accounted for. Geochemical modelling revealed that a testing strategy built on CLP based leaching tests (liquid/solid ratio (L/S)⩾10,000, pH range 5.5-8.5) avoids bias and is superior to the summation method with respect to both precision and accuracy. A testing strategy built on leaching tests, designed for risk assessment purposes, (L/S ratio of 10, natural pH of the ash) severely underestimate the hazard associated with the presence of toxic compounds (Cu and Zn), while simultaneously falsely indicate a hazardousness due to the presence of non-toxic compounds (Ca and K). However, the testing methods adopted by CLP are problematic from a practical and functional point of view. To conclude, the L/S ratio and pH were found to be critical for hazard classification based on leaching test methods. Further studies are needed to develop a relevant, practical and functional testing strategy for HP14 hazardous waste
 classification.
Environmental stress can lead to a decrease in the body size of insects. As social insects, ants have a complex caste system; each caste has its own morphological traits and functions in the colony, hence the effects of stress may manifest differentially among different ant castes. Here we investigated the body size of males of the common garden ant, Lasius niger L., 1758, living in a postmining area polluted mainly by Zn, Cd, and Pb. We examined if individual body size decreases with the pollution gradient. The ants were sampled from 39 wild colonies originating from 17 sites located along the metal pollution gradient; head width was used as the estimator of body size. We failed to show a significant correlation between pollution and male body size, indicating no direct effect of pollution on the body size of males of the investigated ant. However, we found a significant dependence with the colony of origin, which is in line with a previous study performed on this species in unpolluted sites. These results further strengthen a general conclusion that morphological traits in ants, such as body size or fluctuating asymmetry, are relatively invariable and stable across gradients of metal pollution.
Fly ash from municipal solid waste incineration (MSWI) was treated with microorganisms (Sporosarcina pasteurii and Myxococcus xanthus) to assess their capacity for cementing this waste material. Leaching tests on the samples treated with bacteria were also performed to assess the possibility of recovering and recycling trace elements from the fly ash. Sequential extractions combined with mineralogical studies demonstrated that Pb is mobile in water when associated with portlandite. Also, Cd, Pb, and Zn are primarily associated with carbonates and are mobile in acidic environments (up to 4.8, 13.9 and 248mg/l of Cd, Pb and Zn, respectively, extracted with acetic acid). Microbial treatment of the fly ash, especially with Sporosarcina pasteurii, led to its cementation and stabilization, preventing its dispersion into the environment. But samples treated with bacteria exhibited a higher capacity for trace element leaching than did untreated fly ash. The ability of these bacteria to mobilize metals can be applied to recover those of economic interest. The use of low cost biotechnologies can be an alternative to chemical treatments currently utilized for the recovery and reuse of these wastes.
A novel magnetic adsorbent, benzyl groups functionalized imidazolium-based polymeric ionic liquid (PIL)-coated magnetic multiwalled carbon nanotubes (MWCNTs) (m-MWCNTs@PIL), has been successfully synthesized and applied for the extraction of Cu, Zn-superoxide dismutase (Cu, Zn-SOD). The m-MWCNTs@PIL were characterized by X-ray diffraction (XRD), Fourier transform infrared spectrometry (FT-IR), thermal gravimetric analysis (TGA), field emission scanning electron microscopy (FESEM), vibrating sample magnetometer (VSM) and zeta-potential nanoparticles. In this method, the m-MWCNTs@PIL could interact with Cu, Zn-SOD through hydrogen bonding, π-π and electrostatic interactions. The extraction performance of the m-MWCNTs@PIL in the magnetic solid-phase extraction (MSPE) procedure was investigated, coupled with the determination by UV-vis spectrophotometer. Compared with m-MWCNTs@IL and m-MWCNTs, the m-MWCNTs@PIL exhibited the highest extraction capacity of 29.1 mg/g for Cu, Zn-SOD. The adsorbed Cu, Zn-SOD remained high specific activity after being eluted from m-MWCNTs@PIL by 1 moL/L NaCl solution. Besides, the m-MWCNTs@PIL could be easily recycled and successfully employed in the extraction of Cu, Zn-SOD from real samples. Under the optimal conditions, the precision, repeatability and stability of the proposed method were investigated and the RSDs were 0.29%, 1.68% and 0.54%, respectively. Recoveries were in the range of 82.7-102.3%, with the RSD between 3.47% and 5.35%. On the basis of these results, the developed method has great potential in the extraction of Cu, Zn-SOD or other analytes from biological samples.
This paper presents multiple biomarkers on metal accumulation and its impacts along the Chennai to Puducherry, southeast coast of India using bivalves as bioindicators. In this regard, water samples and Perna viridis were collected from three stations and the accumulation of metals and its biological impacts were assessed. Among the three sampling stations, the maximum accumulation was noticed in Ennore (S1) than the Puducherry (S3) followed by Kovalam (S2). Mean accumulation pattern of metals in Perna viridis was found to be in the following order Zn > Cu > Ni > Cr > Pb > Cd, which were in close match with the metal concentration in seawater at respective site. The ambient metal concentration and behavior of multiple biomarkers were positively correlated indicating that the uptake of metals might induce biological changes, particularly in the internal organs, thus significantly affecting health of the aquatic organisms. P. viridis provides reliable information concerning the adverse effects and reflects the integrated effects of all contaminants. Thus, study confirmed that Ennore (S1) coast is highly vulnerable for significant pollution, in terms of metal toxicity in the study area. Overall investigation revealed that metal enrichment was observed close to the major urban areas in the S1 and S2 which were associated with industrialized areas. The assessment of multiple biomarkers on metal accumulation was the first step in determining the trophic transfer factors on marine foot web, which can be evaluated in the future based on this study.
The efficiency of five different single leaching reagents (tartaric acid (TA), citric acid (CA), CaCl2, FeCl3, EDTA) and two different composite leaching reagents (CA + FeCl3, CA + EDTA) on removing Cu, Pb, Zn, and Cd from contaminated paddy soil in Hunan Province (in China) was studied. The results indicated that the efficiencies of CA, FeCl3, and EDTA on extracting Cu, Pb, Cd, and Zn from soil were greater than that of TA and CaCl2, and their extraction efficiencies were EDTA ≥ FeCl3 > CA. The efficiencies of CA + FeCl3 on extracting Cu, Pb, Cd, and Zn were higher than that of single CA or FeCl3. The 25 mmol L(-1) CA + 20 mmol L(-1) FeCl3 was a promising composite leaching reagent for paddy soil, and it could remove Cu (57.6 %), Pb (59.3 %), Cd (84.8 %), and Zn (28.0 %), respectively. With the same amount of leaching reagent, the efficiency of continuous leaching by several times was higher than that by once. In addition, the easily reducible and oxidizable fractions of heavy metals showed significant decrease during the process of leaching.
Vegetation indices obtained from radiometric measurements have been used to estimate the stress response of plants grown in contaminated sites. The phytotoxicity of Pb and Zn in Festuca rubra L. and Vulpia myuros L. plants grown under hydroponic conditions was evaluated using vegetation indices obtained from radiometric measurements. The plants were supplied with 3 mM Zn (+Zn), 500 μM Pb (+Pb) and 500 μM Pb with EDTA (+PbEDTA) for 3 months. Significantly higher Zn concentrations in F. rubra shoots compared with V. myuros shoots were detected for Zn and Pb treatments. EDTA increased Pb transport to the shoots for both grasses, while Pb-treated plants retained Pb primarily in the roots. All vegetation indices tested showed the highest differences in F. rubra under +PbEDTA treatment and minor effects under +Zn, whereas the major variations for V. myuros corresponded to +Zn treatment, followed by +PbEDTA. Red edge normalized difference vegetation index, yellowness index and anthocyanin concentration index were the most sensitive indices to report Zn and Pb phytotoxicity in these grasses. According to the results obtained, both metal concentrations and radiometric indices suggested that Pb is more phytotoxic to F. rubra, which tolerates high Zn levels, whereas V. myuros was strongly affected by high Zn levels and markedly tolerant to Pb, even when applied in a mobile form (PbEDTA). Both species could be used in the phytostabilization of Zn- and Pb-contaminated soils. The abilities of F. rubra to accumulate Zn and V. myuros to accumulate Pb in the roots would facilitate a more efficient phytoremediation strategy when used in combination.
The Athabasca's oil sands exploitation is controversial due to its potential risks to water quality but little is known about the temporal changes in the most bioavailable fraction of metal, the free/labile species. In this study, diffusive gradient in thin films (DGT) and the Windermere Humic Aqueous Model (WHAM VII) equilibrium model were used to examine the temporal changes in free/labile metal (Cu, Ni, Zn, Pb) species in three tributaries of the north-flowing Athabasca River in the Athabasca oil sands region (AOSR). The influence of dissolved organic matter (DOM) composition (i.e. fulvic: humic ratio) on modeled Cu and Ni speciation showed a negligible effect on the labile concentration. The best agreements (92 ± 8%) between DGT-labile and WHAM calculated labile concentrations were found assuming the formation of iron oxyhydroxides (FeO(OH)). The agreement was only 70 ± 7% in the presence of inorganic colloidal aluminum oxyhydroxides (AlO(OH)) and in the absence of any inorganic colloids. Together these results suggest that a change in DOM composition had limited impacts on modeled free metal ion concentrations. Although the concentration of the main metal ligand (i.e. DOM), varied from 9 to 40 ppm, no significant temporal differences in the abundance of WHAM-modeled labile species were found, suggesting mobility and bioavailability of Cu, Ni, Pb and Zn were comparable over the 2003-2012 period.
The lytic phage ST79 of Burkholderia pseudomallei can lyse a broad range of its host including antibiotic resistant
 isolates from within using a set of proteins, holin, lysB, lysC and endolysin, a peptidoglycan (PG) hydrolase enzyme. The phage ST79 endolysin gene identified as peptidase M15A was cloned, expressed and purified to evaluate its potential to lyse pathogenic bacteria. The molecular size of the purified enzyme is approximately 18 kDa and the in silico study cited here indicated the presence of a zinc-binding domain predicted to be a member of the subfamily A of a metallopeptidase. Its activity, however, was reduced by the presence of Zn(2+). When Escherichia coli PG was used as a substrate and subjected to digestion for 5 min with 3 μg/ml of enzyme, the peptidase M15A showed 2 times higher in lysis efficiency when compared to the commercial lysozyme. The enzyme works in a broad alkaligenic pH range of 7.5-9.0 and temperatures from 25 to 42 °C. The enzyme was able to lyse 18 Gram-negative bacteria in which the outer membrane was permeabilized by chloroform treatment. Interestingly, it also lysed Enterococcus sp., but not other Gram-positive bacteria. In general, endolysin cannot lyse Gram-negative bacteria from outside, however, the cationic amphipathic C-terminal in some endolysins showed permeability to Gram-negative outer membranes. Genetically engineered ST79 peptidase M15A that showed a broad spectrum against Gram-negative bacterial PG or, in combination with an antibiotic the same way as combined drug methodology, could facilitate an effective treatment of severe or antibiotic resistant cases.
The aim of this study was to evaluate the elemental composition of black tea samples and their infusions in view of their geographical origin. In total, 14 elements were analyzed, 13 (Ca, K, Mg, Na, Mn, Fe, Zn, Cu, Cr, Ni, Co, Cd, and Pb) by flame atomic absorption spectrometry, and P by UV-Vis spectrometry, after mineralization of samples. It was found that K was the most abundant macroelement in the analyzed samples, whereas among microelements, the highest concentration was found for Mn. Based on the obtained data, the percentage of elements leached into the infusions as well as the daily elemental intake from tea were calculated. The daily intake from tea was compared to the recommended daily allowances (RDAs), and the highest percentages of the RDAs were found for Mn (15 %) and Co (10 %). To study the relations between elemental composition and country of origin of samples, factor analysis and cluster analysis were applied. These multivariate techniques proved to be efficient tools able to differentiate samples according to their provenance as well as plantation within the common regions.
The ultrasonic-assisted brazing of α-alumina to copper was achieved in air without flux using Zn-14wt%Al hypereutectic filler at 753K within tens of seconds. The effects of ultrasonic time on the microstructures and mechanical properties of joints were investigated. In the joint interlayer, large amounts of intermetallic phases consisted of binary CuZn5 embedded by many ternary Al4.2Cu3.2Zn0.7 particles were formed. At the ceramic interface, newly formed crystalline Al2O3 aggregated. At the Cu interface, acoustic corrosion on the copper resulted in depriving the surface oxides and forming many pits on its surface, which provided saturated Cu in the melted filler alloys during the brazing. The ultrasonic vibrations had distinct effects on the metallurgical reactions of the joints, resulting in intermetallic-phase-filled composite joints with shear strength of 66MPa. The overgrowth of intermetallic compounds, the newly formed crystalline alumina, and the acoustic pits was probably ascribed to the ultrasonic effects.
This study reports the static and dynamic magnetic characterization of two mononuclear tetrahedral Co(II) complexes, [Co{(i)Pr2P(E)NP(E)(i)Pr2}2], where E = S (CoS4) and Se (CoSe4), which behave as single-ion magnets (SIMs). Low-temperature (15 K) single-crystal X-ray diffraction studies point out that the two complexes exhibit similar structural features in their first coordination sphere, but a disordered peripheral (i)Pr group is observed only in CoS4. Although the latter complex crystallizes in an axial space group, the observed structural disorder leads to larger transverse magnetic anisotropy for the majority of the molecules compared to CoSe4, as confirmed by electron paramagnetic resonance spectroscopy. Static magnetic characterization indicates that both CoS4 and CoSe4 show easy-axis anisotropy, with comparable D values (∼-30 cm(-1)). Moreover, alternating-current susceptibility measurements on these Co(II) complexes, magnetically diluted in their isostructural Zn(II) analogues, highlight the role of dipolar magnetic coupling in the mechanism of magnetization reversal. In addition, our findings suggest that, despite their similar anisotropic features, CoS4 and CoSe4 relax magnetically via different processes. This work provides experimental evidence that solid-state effects may affect the magnetic behavior of SIMs.
Acute and subacute administration of zinc exert neuroprotective effects in hypoxia-ischemia animal models; yet the effect of chronic administration of zinc still remains unknown. We addressed this issue by injecting zinc at a tolerable dose (0.5 mg/kg weight, i.p.) for 14 days before common carotid artery occlusion (CCAO) in a rat. After CCAO, the level of zinc was measured by atomic absorption spectrophotometry, nitrites were determined by Griess method, lipoperoxidation was measured by Gerard-Monnier assay, and mRNA expression of 84 genes coding for cytokines, chemokines, and their receptors was measured by qRT-PCR, whereas nitrotyrosine, chemokines, and their receptors were assessed by ELISA and histopathological changes in the temporoparietal cortex-hippocampus at different time points. Long-term memory was evaluated using Morris water maze. Following CCAO, a significant increase in nitrosative stress, inflammatory chemokines/receptors, and cell death was observed after 8 h, and a 2.5-fold increase in zinc levels was detected after 7 days. Although CXCL12 and FGF2 protein levels were significantly increased, the long-term memory was impaired 12 days after reperfusion in the Zn+CCAO group. Our data suggest that the chronic administration of zinc at tolerable doses causes nitrosative stress, toxic zinc accumulation, and neuroinflammation, which might account for the neuronal death and cerebral dysfunction after CCAO.
Doubly and quadruply quinoline-fused porphyrins were effectively synthesized through a reaction sequence consisting of Suzuki-Miyaura coupling of β-borylated porphyrins with 2-iodoaniline and subsequent Pictet-Spengler cyclization. These quinoline-fused porphyrins display red-shifted absorption bands and higher electron-accepting abilities. This synthetic protocol also allowed the synthesis of phenanthroline-fused porphyrin dimers, which bound either a Ni(II) or Zn(II) cation. The resultant metal complexes displayed further red shifted absorption spectra and molecular twists to effect an almost perpendicular arrangement of the two porphyrins.
A dynamic Zn(II) -MOF has been shown to exhibit extreme breathing behavior under gas pressure. The very narrow pore form of the activated framework opens up in the presence of carbon dioxide, thus making it a suitable material for CO2 capture. Sorption of CO2 at 298 K and relatively high pressure clearly shows a two-step isotherm with giant hysteresis for the second step. In-situ single-crystal diffraction analysis was carried out under CO2 gas pressure at 298 K using an environmental gas cell in order to visualize the interaction between CO2 and the host framework. The results are well supported by pressure-gradient differential scanning calorimetry (P-DSC) and variable-pressure powder X-ray analysis. Theoretical calculations have been carried out in order to further back up the crystallographic data.
Accurate Møller-Plesset (MP2) correlation energies calculated by means of the variational-perturbation and the finite-element methods are presented for several members of the Cu(+) isoelectronic series (N = 28), which represent closed-shell systems containing for the first time the 3d(10)-electron configuration and, consequently, closed M-shell. Total MP2 energies as well as their inner- and inter-shell components are reported for Cu(+), Zn(2+), Ge(4+), Kr(8+), Sr(10+), and Cd(20+). We found that for these ions the Z-dependence of the total MP2 energies is significantly weaker than for the members of the Ar-like series. The origin of this fact is rationalized by a detailed analysis performed at the levels of the shell- and inter-shell contributions to the MP2 energies. To get, for the first time, more general information about the (N, Z) characteristics of the MP2 energies for closed-shell atomic systems, we compare the Z-dependence of the Cu(+)-like systems with the MP2 energies calculated for other isoelectronic series. The weak Z-dependence is found for the He-, Ne-, and Cu(+)-like series, which consist of atoms having perfectly closed-shell K-, KL-, and KLM-electronic structures, respectively. In turn, for the Be-, Mg-, and Ar-series, the Z-dependence is considerably stronger.
Recently O-carboxyanhydrides (OCAs) have emerged as a class of viable monomers which can undergo ring-opening polymerization (ROP) to prepare poly(α-hydroxyalkanoic acid) with functional groups that are typically difficult to achieve by ROP of lactones. Organocatalysts for the ROP of OCAs, such as dimethylaminopyridine (DMAP), may induce undesired epimerization of the α-carbon atom in polyesters resulting in the loss of isotacticity. Herein, we report the use of (BDI-IE)Zn(OCH(CH3 )COOCH3 ) ((BDI)Zn-1, (BDI-IE)=2-((2,6-diethylphenyl)amino)-4-((2,6-diisopropylphenyl)imino)-2-pentene), for the controlled ROP of various OCAs without epimerization. Both homopolymers and block copolymers
 with controlled molecular weights, narrow molecular weight distributions, and isotactic backbones can be readily synthesized. (BDI)Zn-1 also enables controlled copolymerization of OCAs and lactide, facilitating the synthesis of block copolymers potentially useful for various biomedical applications. Preliminary mechanistic studies suggest that the monomer/dimer equilibrium of the zinc catalyst influences the ROP of OCAs, with the monomeric (BDI)Zn-1 possessing superior catalytic activity for the initiation of ROP in comparison to the dimeric (BDI)Zn complex.
Many metal transporters in plants are promiscuous, accommodating multiple divalent cations including some which are toxic to humans. Previous attempts to increase the iron (Fe) and zinc (Zn) content of rice endosperm by overexpressing different metal transporters have therefore led unintentionally to the accumulation of copper (Cu), manganese (Mn) and cadmium (Cd). Unlike other metal transporters, barley Yellow Stripe 1 (HvYS1) is specific for Fe. We investigated the mechanistic basis of this preference by constitutively expressing HvYS1 in rice under the control of the maize ubiquitin1 promoter and comparing the mobilization and loading of different metals. Plants expressing HvYS1 showed modest increases in Fe uptake, root-to-shoot translocation, seed accumulation and endosperm loading, but without any change in the uptake and root-to-shoot translocation of Zn, Mn or Cu, confirming the selective transport of Fe. The concentrations of Zn and Mn in the endosperm did not differ significantly between the wild-type and HvYS1 lines, but the transgenic endosperm contained significantly lower concentrations of Cu. Furthermore, the transgenic lines showed a significantly reduced Cd uptake, root-to-shoot translocation and accumulation in the seeds. The underlying mechanism of metal uptake and translocation reflects the down-regulation of promiscuous endogenous metal transporters revealing an internal feedback mechanism that limits seed loading with Fe. This promotes the preferential mobilization and loading of Fe, therefore displacing Cu and Cd in the seed.
Four new Schiff base ligands carrying naphthalene groups were prepared from the reaction of 2,4-diamino-6-methyl-1,3,5-triazine and 2,4-diamino-6-undecyl-1,3,5-triazine with 2-hydroxy-1-naphthaldehyde. The influence of a series of metal ions including Cu(2+), Co(2+), Hg(2+), Al(3+), Cr(3+), Fe(3+), Pb(2+), Ni(2+), Cd(2+), Zn(2+), Mn(2+), Ag(+), Ba(2+), Ca(2+) and Mg(2+) on the spectroscopic properties of the ligands was investigated by means of absorption and emission spectrometry. The results of spectrophotometric and spectrofluorimetric titrations disclosed the complexation stoichiometry and complex stability constant of the ligands with metal ions. A simple spectrofluorimetric method was developed using the Schiff base derived from 2,4-diamino-6-undecyl-1,3,5-triazine to determine Hg(2+) ion. No cleanup or enrichment of the tap water sample was required. A modified standard addition method was used to eliminate matrix effect. The standard addition graph was linear between 0.2 and 2.6 mg/L in determination of Hg(2+). Detection and quantification limits were 0.08 and 0.23 mg/L, respectively. The simple and cost-effective method can be applied to water samples.
The effect of bentonite and sand, as natural capping agents, on the fluxes of nutrients and trace metals across the sediment-water interface was studied through sediment incubation, and the ecotoxicological impact was assessed by using Daphnia magna. Bentonite and sand were layered on the sediment at 15, 75, and 225 mg cm(-2), and the concentration of cations, nutrients, and trace metals was measured. Sediment incubation showed that bentonite reduced the N flux but increased the P flux as a result of dissolution of non-crystalline P from bentonite, while sand slightly decreased the N fluxes but not the P flux. The concentration of Na increased in the overlying water with increasing application rates of bentonite, while that of Ca decreased. However, regardless of the rate of sand application, concentrations of all cation species remained unchanged. The concentration of As and Cr increased with bentonite application rate but decreased with sand. Both capping materials suppressed fluxes of Cd, Cu, Ni, and Zn compared to control, and the extent of suppression was different depending on the trace metal species and capping agents used. During sediment incubation, the survival rate of D. magna significantly decreased in bentonite suspension but began to decrease at the end in sand suspension. Sediment capping of mildly polluted sediments by using bentonite and sand lowered the level of nutrients and trace metals. However, unexpected or undesirable side effects, such as influxes of P and As from bentonite to the overlying water and a possibility of toxic impacts to aquatic ecosystems, were observed, suggesting that capping agents with an adequate assessment of their side effects and toxicity should be predetermined for site-specific sediment management strategies.
Acid mine drainage (AMD) impacted waters are a worldwide concern for the mining industry and countries dealing with this issue; both active and passive technologies are employed for the treatment of such waters. Mussel shell bioreactors (MSB) represent a passive technology that utilizes waste from the shellfish industry as a novel substrate. The aim of this study is to provide insight into the biogeochemical dynamics of a novel full scale MSB for AMD treatment. A combination of water quality data, targeted geochemical extractions, and metagenomic analyses were used to evaluate MSB performance. The MSB raised the effluent pH from 3.4 to 8.3 while removing up to ∼99% of the dissolved Al, and Fe and >90% Ni, Tl, and Zn. A geochemical gradient was observed progressing from oxidized to reduced conditions with depth. The redox conditions helped define the microbial consortium that consists of a specialized niche of organisms that influence elemental cycling (i.e. complex Fe and S cycling). MSB technology represents an economic and effective means of full scale, passive AMD treatment that is an attractive alternative for developing economies due to its low cost and ease of implementation.
Intentional and unintentional doping in semiconductor nanowires undoubtedly have significant impact on the device performance. However, spatially resolved precise determination of dopant concentration is challenging due to insufficient sensitivity and resolution of conventional techniques. In this paper, quantitative 3D distribution of Si and Zn dopants in planar GaAs nanowires and their interface with AlGaAs film underneath are obtained by using a unique atom probe tomography technique, providing critical insights for the growth and potential applications of these nanowires.
Mineral based preparations are widely used for centuries as antimicrobial agents. However, the efficacy and the mode of action of mineral based preparations are uncertain due to the insufficient antimicrobial studies. Arogyawardhana Vati (AV) and Manikya Rasa (MR) are such two Rasashastra herbo-minerallic drugs commonly in India and other countries in South Asia. Despite of their well known traditional use of skin diseases, reported antimicrobial and mineralogical studies are limited. Therefore, in this study antimicrobial activities of the drugs and their organic, inorganic fractions were evaluated against Pseudomonas aeruginosa, Escherischia coli, Staphylococcus aureus, Methecilline Resistance Staphylococcus aureus - MRSA and Candida albicans.
Antimicrobial activity of the drugs, their inorganic residues and organic extracts were determined using four assay techniques viz agar well diffusion, modified well diffusion, Miles and Misra viable cell counting and broth turbidity measurements. Mineralogical constituents of the drugs were determined using X-ray diffraction, while total cation constituents and water soluble cation constituents were determined using inductively coupled plasma-mass spectrometer and the atomic absorption spectrophotometer respectively. Thermogravimetric analysis was used to determine the weight percentages of organic and inorganic fraction of the drugs. Particle sizes of the drugs were determined using the particle size analyzer.
AV and MR drugs showed antibacterial activity against both gram positive and gram negative bacterial species when analyzed separately. Inorganic residues of the drugs and organic extracts showed activity at least against two or more bacterial species tested. All tested components were inactive against C. albicans. Common mineral constituents of drugs are cinnabar, biotite and Fe-rich phases. Drugs were rich in essential elements such as Na, K, Ca, Mg and Fe and toxic elements such as Zn, Cu and As. However, the water soluble concentrations of the toxic elements were below the detection limits. Both drugs have significantly higher percentages of organic constituents and volatile minerals and particle sizes of drugs are in the nanometer range.
AV and MR Rasashastra preparations could provide alternatives to synthetic antibiotics against human bacterial infections. Improved solubility and reduced particle sizes are influential physicochemical properties used to enhance the antimicrobial efficacy of the drugs. Therefore, traditional knowledge on the use of antimicrobial mineral sources could provide a novel path for the producing of effective antimicrobial drugs. However, further chemical and toxicological studies are urgently needed for a greater understanding of their toxicity to humans.
We report the effect of cross-sex hormonal replacement on antioxidant enzymes from rat retroperitoneal fat adipocytes. Eight rats of each gender were assigned to each of the following groups: control groups were intact female
 or male (F and M, resp.). Experimental groups were ovariectomized F (OvxF), castrated M (CasM), OvxF plus testosterone (OvxF + T), and CasM plus estradiol (CasM + E2) groups. After sacrifice, retroperitoneal fat was dissected and processed for histology. Adipocytes were isolated and the following enzymatic activities were determined: Cu-Zn superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx), glutathione-S-transferase (GST), and glutathione reductase (GR). Also, glutathione (GSH) and lipid peroxidation (LPO) were measured. In OvxF, retroperitoneal fat increased and adipocytes were enlarged, while in CasM rats a decrease in retroperitoneal fat and small adipocytes are observed. The cross-sex hormonal replacement in F rats was associated with larger adipocytes and a further decreased activity of Cu-Zn SOD, CAT, GPx, GST, GR, and GSH, in addition to an increase in LPO. CasM + E2 exhibited the opposite effects showing further activation antioxidant enzymes and decreases in LPO. In conclusion, E2 deficiency favors an increase in retroperitoneal fat and large adipocytes. Cross-sex hormonal replacement in F rats aggravates the condition by inhibiting antioxidant enzymes.
Selenium (Se) is an essential trace element in living systems. Microorganisms play a pivotal role in the selenium cycle both in life and in environment. Different bacterial strains are able to reduce Se(IV) (selenite) and (or) Se(VI) (selenate) to less toxic Se(0) with the formation of Se nanoparticles (SeNPs). The biogenic SeNPs have exhibited promising application prospects in medicine, biosensors and environmental remediation. These microorganisms might be explored as potential biofactories for synthesis of metal(loid) nanoparticles.
A strictly aerobic, branched actinomycete strain, ES2-5, was isolated from a selenium mining soil in southwest China, identified as Streptomyces sp. based on 16S rRNA gene sequence, physiologic and morphologic characteristics. Both SEM and TEM-EDX analysis showed that Se(IV) was reduced to Se(0) with the formation of SeNPs as a linear chain in the cytoplasm. The sizes of the SeNPs were in the range of 50-500 nm. The cellular concentration of glutathione per biomass decreased along with Se(IV) reduction, and no SeNPs were observed in different sub-cellular fractions in presence of NADPH or NADH as an electron donor, indicating glutathione is most possibly involved in vivo Se(IV) reduction. Strain ES2-5 was resistant to some heavy metal(loid)s such as Se(IV), Cr(VI) and Zn(II) with minimal inhibitory concentration of 50, 80 and 1.5 mM, respectively.
The reducing mechanism of Se(IV) to elemental SeNPs under aerobic condition was investigated in a filamentous strain of Streptomyces. Se(IV) reduction is mediated by glutathione and then SeNPs synthesis happens inside of the cells. The SeNPs are released via hypha lysis or fragmentation. It would be very useful in Se bioremediation if Streptomyces sp. ES2-5 is applied to the contaminated site because of its ability of spore reproduction, Se(IV) reduction, and adaptation in soil.
An alginate lyase with high specific enzyme activity was purified from Pseudomonas stutzeri MSEA04, isolated from marine brown algae. The alginate lyase was purified by precipitation with ammonium sulphate, acetone and ethanol individually. 70% ethanol fraction showed maximum specific activity (133.3 U/mg). This fraction was re-purified by anion exchange chromatography DEAE- Cellulose A-52. The loaded protein was separated into 3 peaks. The second protein peak was the major one which contained 48.2% of the total protein recovered and 79.4% of the total recovered activity. The collected fractions of this peak were subjected to further purification by re-chromatography on Sephadex G-100. Alginate lyase activity was fractionated in the Sephadex column into one major peak, and the specific activity of this fraction reached 116 U/mg. The optimal substrate concentration, pH and temperature for alginate lyase activity were 8 mg/ml, pH 7.5 and 37 °C, respectively. While, Km and Vmax values were 1.07 mg alginate/ ml and 128.2 U/mg protein, respectively. The enzyme was partially stable below 50 °C, and the activity of the enzyme was strongly enhanced by K(+), and strongly inhibited by Ba(+2), Cd(+2), Fe(+2) and Zn(+2). The purified enzyme yielded a single band on SDS-PAGE with molecular weight (40.0 kDa).
The effect of zinc oxide nanoparticles (ZnONPs) was studied in wheat (Triticum aestivum L.) seedlings under in vitro exposure conditions. To avoid precipitation of nanoparticles, the seedlings were grown in half strength semisolid Murashige and Skoog medium containing 0, 50, 100, 200, 400 and 500 mg L(-1) of ZnONPs. Analysis of zinc (Zn) content showed significant increase in roots. In vivo detection using fluorescent probe Zynpyr-1 indicated accumulation of Zn in primary and lateral root tips. All concentrations of ZnONPs significantly reduced root growth. However, significant decrease in shoot growth was observed only after exposure to 400 and 500 mg L(-1) of ZnONPs. The reactive oxygen species and lipid peroxidation levels significantly increased in roots. Significant increase in cell-wall bound peroxidase activity was observed after exposure to 500 mg L(-1) of ZnONPs. Histochemical staining with phloroglucinol-HCl showed lignification of root cells upon exposure to 500 mg L(-1) of ZnONPs. Treatment with propidium iodide indicated loss of cell viability in root tips of wheat seedlings. These results suggest that redox imbalances, lignification and cell death has resulted in reduction of root growth in wheat seedlings exposed to ZnONPs nanoparticles.
Bobcats (Lynx rufus) are wide-ranging mammals found throughout the continental USA. As carnivores near the top of their food chain, bobcats would seem to be a useful bioindicator of metal pollution in terrestrial environments. However, there is very limited research on bobcats in toxicology studies. Here, we offer the first analysis of metal (copper, selenium, silver, and zinc) contaminants in the livers of wild bobcats. Liver tissues from 120 adult bobcats (i.e., estimated to be ≥1 year old) were collected from 2003 to 2006 at four sites in Georgia and Florida, USA that experienced relatively similar levels of human disturbance. We found no differences in metal concentrations between males and females. At two of the sites sampled over three consecutive years, there was substantial year-to-year variation in the concentrations of Cu, Se, and Zn. We also documented some variation between sites, but only between sites sampled in different years, which may reflect additional temporal, rather than spatial, variation. Concentrations of Cu and Ag were significantly positively correlated with one another, as were concentrations of Se and Zn. Contrary to expectation, there were no significant relationships between body weight and metal concentrations. Finally, comparison with results from previous metal toxicology studies of nine-banded armadillos (Dasypus novemcinctus) and Virginia opossums (Didelphis virgianus), collected from the same sites during the same years, showed differential patterns of accumulation across species, suggesting that ecological lifestyle is an important influence on metal accumulation. This study provides reference levels of metal contaminants in the liver of bobcats as well as insight into metal accumulation in a top level carnivore.
In the present study, metal-facilitated free radical generation in particulate matter (PM) and its association with deoxyribonucleic acid (DNA) damage were studied. The examined data showed that the concentration of fine PM in Pune exhibited seasonal variations. Inductively coupled plasma-atomic emission spectrometry (ICP-AES) was used to examine the metal composition, which showed the presence of metals such as Cu, Zn, Mn, Fe, Co, Cr, Pb, Cd, and Ni. Fe metal was present in the highest concentrations in both the seasons, followed by Zn. The scanning electron microscopy-energy-dispersive spectrometer (SEM-EDS) results also demonstrated that the fine PM particles deposited in summer samples were less than those of winter samples, suggesting that the PM load in winter was higher as compared to that in summer. Elemental mapping of these particles substantiates deposition of metals as Fe, Zn, etc. on particles. The electron paramagnetic species (EPR) technique was utilized for free radical detection, and plasmid DNA assay was utilized to study the genotoxicity of ambient fine PM. Obtained g values show the presence of radicals in PM samples of Pune. PM contains the C-centered radical with a vicinal oxygen atom (g = 2.003). In addition to this, the g value for Fe was also observed. Therefore, we intend that the radicals related with fine PM comprise metal-mediated radicals and produce DNA damage. The plasmid DNA assay results indicated that the TM50 values (toxic mass of PM causing 50 % of plasmid DNA damage) of PM exhibited seasonal variations with higher TM50 values for summer and lower TM50 values during winter.
We synthesized two one-dimensional compounds K2MSbS3(SH) (M = Zn, Cd) at 473 K, using thiourea as reactive flux. The compounds crystallize in the triclinic space group P1̅. Their structures feature one-dimensional ∞(1)[M2Sb2S6(SH2)](4-) double chains along the crystallographic a axis. The ∞(1)[M2Sb2S6(SH2)](4-) double chains are composed of [M2Sb2S8(SH)2](8-) eight-membered rings. Similar band gaps of the two compounds, Eg = 2.75 eV for K2ZnSbS3(SH) and Eg = 2.71 eV for K2CdSbS3(SH), were obtained from optical absorption measurements, which are consistent with theoretical calculations. The analysis of density of states indicates that the valence band maximum and conduction band minimum consist mainly of S-3p orbitals and Sb-5p orbitals, respectively.
The differences in trace element concentrations
 among 19 different bone elements procured from 10 archaeologically derived human skeletons have been investigated. The 10 individuals are dated archaeologically and some by radiocarbon dating to the medieval and post-medieval period, an interval from ca. AD 1150 to ca. AD 1810. This study is relevant for two reasons. First, most archaeometric studies analyze only one bone sample from each individual; so to what degree are the bones in the human body equal in trace element chemistry? Second, differences in turnover time of the bone elements makes the cortical tissues record the trace element concentrations in equilibrium with the blood stream over a longer time earlier in life than the trabecular. Therefore, any differences in trace element concentrations between the bone elements can yield what can be termed a chemical life history of the individual, revealing changes in diet, provenance, or medication throughout life.
Thorough decontamination and strict exclusion of non-viable data has secured a dataset of high quality. The measurements were carried out using Inductively Coupled Plasma Mass Spectrometry (for Fe, Mn, Al, Ca, Mg, Na, Ba, Sr, Zn, Pb and As) and Cold Vapor Atomic Absorption Spectroscopy (for Hg) on ca. 20 mg samples.
Twelve major and trace elements have been measured on 19 bone elements from 10 different individuals interred at five cemeteries widely distributed in medieval and renaissance Denmark. The ranges of the concentrations of elements were: Na (2240-5660 µg g(-1) ), Mg (440-2490 µg g(-1) ), Al (9-2030 µg g(-1) ), Ca (22-36 wt. %), Mn (5-11450 µg g(-1) ), Fe (32-41850 µg g(-1) ), Zn (69-2610 µg g(-1) ), As (0.4-120 µg g(-1) ), Sr (101-815 µg g(-1) ), Ba (8-880 µg g(-1) ), Hg (7-78730 ng g(-1) ), and Pb (0.8-426 µg g(-1) ).
It is found that excess As is mainly of diagenetic origin. The results support that Ba and Sr concentrations are effective provenance or dietary indicators. Migrating behavior or changes in diet have been observed in four individuals; non-migratory or non-changing diet in six out of the 10 individuals studied. From the two most mobile (most changing diet) individuals in the study, it is deduced that the fastest turnover is seen in the trabecular tissues of the long bones and the hands and the feet, and that these bone elements have higher turnover rates than centrally placed trabecular bone tissue, such as from the ilium or the spine. Comparing Sr and published bone turnover times, it is concluded that the differences seen in Sr concentrations are not caused by diagenesis, but by changes of diet or provenance. Finally, it is concluded that there can be two viable interpretations of the Pb concentrations, which can either be seen as an indicator for social class or a temporal development of increased Pb exposure over the centuries.
We demonstrated that the circular dichroism (CD) exciton chirality method, based on the supramolecular interactions of meso-tetra(4-sulfonatophenyl)porphyrin (MTPPS4, M = Zn or H2), was applicable for the determination of the absolute configuration between the side chains of two basic amino acid residues of stable monomeric β-hairpin peptides (tryptophan zipper: Trpzip). When MTPPS4 was added to an aqueous solution containing Trpzip, a bisignate CD signal was detected in the Soret band region in addition to a decrease in absorbance. These spectral changes indicated the formation of a supramolecule consisting of Trpzip and MTPPS4 via electrostatic interactions between the positively charged lysine residue of Trpzip and the negatively charged sulfonate group of MTPPS4. On the basis of the Job plots, the supramolecular structure of Trpzip-ZnTPPS4 is ZnP-Tz-ZnP or ZnP-Tz-ZnP-Tz-ZnP, whereas that of Trpzip-H2TPPS4 is -(-H2P-Tz-)n- (MP and Tz denote MTPPS4 and Trpzip, respectively). To explain the bisignate CD spectra of the supramolecules, a plausible model, that is, ZnP-Tz-ZnP, was carefully analyzed by the CD exciton chirality method: two orthogonalized electric transition dipole moments of each MTPPS4 and the effects of free rotation of MTPPS4 around the electrostatic bonding axis were considered. The exciton-coupled CD spectral pattern based on ZnTPPS4 reflected the absolute configuration between the side chains of two lysine residues. Our approach can be used to determine the absolute configuration of side chains of other peptides with two basic amino acid residues in the amino acid sequences.
Rechargeable aqueous Zn-ion batteries are attractive cheap, safe and green energy storage technologies but are bottlenecked by limitation in high-capacity cathode and compatible electrolyte to achieve satisfactory cyclability. Here we report the application of nonstoichiometric ZnMn2O4/carbon composite as a new Zn-insertion cathode material in aqueous Zn(CF3SO3)2 electrolyte. In 3 M Zn(CF3SO3)2 solution that enables ∼100% Zn plating/stripping efficiency with long-term stability and suppresses Mn dissolution, the spinel/carbon hybrid exhibits a reversible capacity of 150 mAh g(-1) and a capacity retention of 94% over 500 cycles at a high rate of 500 mA g(-1). The remarkable electrode performance results from the facile charge transfer and Zn insertion in the structurally robust spinel featuring small particle size and abundant cation vacancies, as evidenced by combined electrochemical measurements, XRD, Raman, synchrotron X-ray absorption spectroscopy, FTIR, and NMR analysis. The results would enlighten and promote the use of cation-defective spinel compounds and trifluoromethanesulfonic electrolyte to develop high-performance rechargeable zinc batteries.
A facile route for the fabrication of a novel ZnS shell/Cu-Zn-In-S nanosheets/TiO2 nanorods heterojunction was reported in this work. Especially, the quaternary Cu-Zn-In-S nanosheets were synthesized creatively from the ternary ZnIn2S4 nanosheets by partial exchange reaction, leading to substantial enhancement on the light absorbance. Such heterojunction could increase the surface area and accelerate the charge transfer resulting from its hierarchical 2D/1D structure and favorable energy bands. Moreover, the ZnS coating acted as a passivation layer as well as a potential barrier, significantly suppressing the interface recombination. The above synergistic effects resulted in the largely increased photocurrent density from 0.34 mA cm(-2) for the pristine TiO2 to 0.81 mA cm(-2) for the heterojunction at 0.8 V vs RHE.
The composition of the ionome is closely linked to a plant's nutritional status. Under certain deficiencies, cross-talk induces unavoidable accumulation of some nutrients, which upsets the balance and modifies the ionomic composition of plant tissues. Rapeseed plants (Brassica napus L.) grown under controlled conditions were subject to individual nutrient deficiencies (N, K, P, Ca, S, Mg, Fe, Cu, Zn, Mn, Mo, or B) and analyzed by inductively high-resolution coupled plasma mass spectrometry to determine the impact of deprivation on the plant ionome. Eighteen situations of increased uptake under mineral nutrient deficiency were identified, some of which have already been described (K and Na, S and Mo, Fe, Zn and Cu). Additionally, as Mo uptake was strongly increased under S, Fe, Cu, Zn, Mn, or B deprivation, the mechanisms underlying the accumulation of Mo in these deficient plants were investigated. The results suggest that it could be the consequence of multiple metabolic disturbances, namely: (i) a direct disturbance of Mo metabolism leading to an up-regulation of Mo transporters such as MOT1, as found under Zn or Cu deficiency, which are nutrients required for synthesis of the Mo cofactor; and (ii) a disturbance of S metabolism leading to an up-regulation of root SO4(2-) transporters, causing an indirect increase in the uptake of Mo in S, Fe, Mn, and B deficient plants.
Cadmium, lead, copper, and zinc were analyzed in the dorsal muscle, liver, gonad, and stomach contents of 67 sailfish, Istiophorus platypterus, from the Eastern Pacific. Muscle exhibited the following pattern (μg/g wet weight): Zn (15.05 ± 1.24) > Cu (0.461 ± 0.026) > Cd (0.434 ± 0.099) > Pb (0.025 ± 0.001); liver Zn (119.1 ± 7.6) > Cd (95.1 ± 11.0) > Cu (39.7 ± 2.6) > Pb (0.047 ± 0.004); and gonad Zn (96.8 ± 7.8) > Cd (2.16 ± 0.38) > Cu (2.08 ± 0.14) > Pb (0.033 ± 0.003). Significant (p < 0.05) correlations were observed between elements, length, and weight. I. platypterus feed mainly on fishes and cephalopods with variable concentrations (μg/g wet weight) of Cd (0.081-11.41), Pb (0.002-0.057), Cu (0.204-4.35), and Zn (3.23-86.6). Of the four analyzed elements, only Pb was biomagnified (BMF = 1.85). According to the regulatory limits, muscle exhibited Cd concentrations higher than the Official Mexican Standard, WHO, FDA (28 % of samples), and the European Union (40 %) regulations.
A comprehensive approach has been developed to the assessment of composition and properties of atmospherically deposited dust in the area affected by a copper smelter. The approach is based on the analysis of initial dust samples, dynamic leaching of water soluble fractions in a rotating coiled column (RCC) followed by the determination of recovered elements and characterization of size, morphology and elemental composition of nano-, submicron, and micron particles of dust separated using field-flow fractionation in a RCC. Three separated size fractions of dust (<0.2, 0.2-2, and >2 μm) were characterized by static light scattering and scanning electron microscopy, whereupon the fractions were analyzed by ICP-AES and ICP-MS (after digestion). It has been evaluated that toxic elements, which are characteristics for copper smelter emissions (As, Cu, Zn), are accumulated in fraction >2 μm. At the same time, up to 2.4, 3.1, 8.2, 6.7 g/kg of As, Cu, Zn, Pb, correspondently, were found in nanoparticles (<0.2 μm). It has been also shown that some trace elements
 (Sn, Sb, Ag, Bi, and Tl) are accumulated in fraction <0.2, and their content in this fraction may be one order of magnitude higher than that in the fraction >2 μm, or the bulk sample. It may be assumed that Sn, Sb, Ag, Bi, Tl compounds are adsorbed onto the finest dust particles as compared to As, Cu, Zn compounds, which are directly emitted from the copper smelter as microparticles.
Degradation of dibuytl phthalate (DBP), a plasticizer and also a widely distributed endocrine disruptor, by UV-254 nm/H2O2 advanced oxidation process (AOP) was investigated in this study. A significant DBP removal of 77.1 % at an initial concentration of 1.0 μM was achieved at UV fluence of 160 mJ/cm(2), initial H2O2 dosage of 1.0 mM, and pH of 7.6 ± 0.1. The DBP degradation exhibited a pseudo-first-order reaction kinetic pattern, with the rate constants linearly increasing with increasing H2O2 dosage while decreasing with increasing initial DBP concentration and pH value in a specific range. DBP destruction was significantly inhibited in the presence of alkalinity and natural organic matter (NOM), two known factors that should be taken a serious consideration of in the research and design of UV/H2O2-based AOPs. Presence of common inorganic anions (i.e., Cl(-), SO4(2-), and NO3(-)) and metal cations (i.e., Fe(3+) and Zn(2+)) had a slight impact on the degradation of DBP, although Cu(2+) could improve the degradation efficiency even at a concentration as low as 0.01 mg/L, suggesting a strong potential of applying UV/H2O2 for the removal of DBP with an environmental relevant level of copper.
The etiology of astrocyte dysfunction is not well understood even though neuronal defects have been extensively studied in a variety of neuronal degenerative diseases. Astrocyte defects could be triggered by the oxidative stress that occurs during physiological aging. Here, we provide evidence that intracellular or mitochondrial reactive oxygen species (ROS) at physiological levels can cause hippocampal (neuronal) dysfunctions. Specifically, we demonstrate that astrocyte defects occur in the hippocampal area of middle-aged Tet-mev-1 mice with the SDHC(V69E) mutation. These mice are characterized by chronic oxidative stress. Even though both young adult and middle-aged Tet-mev-1 mice overproduced MitoSOX Red-detectable mitochondrial ROS compared to age-matched wild-type C57BL/6J mice, only young adult Tet-mev-1 mice upregulated manganese and copper/zinc superoxide dismutase (Mn- and Cu/Zn-SODs) activities to eliminate the MitoSOX Red-detectable mitochondrial ROS. In contrast, middle-aged Tet-mev-1 mice accumulated both MitoSOX Red-detectable mitochondrial ROS and CM-H2 DCFDA-detectable intracellular ROS. These ROS levels appeared to be in the physiological range as shown by normal thiol and glutathione disulfide/glutathione concentrations in both young adult and middle-aged Tet-mev-1 mice relative to age-matched wild-type C57BL/6J mice. Furthermore, only middle-aged Tet-mev-1 mice showed JNK/SAPK activation and Ca(2+) overload, particularly in astrocytes. This led to decreasing levels of glial fibrillary acidic protein and S100β in the hippocampal area. Significantly, there were no pathological features such as apoptosis, amyloidosis, and lactic acidosis in neurons and astrocytes. Our findings suggest that the age-dependent physiologically relevant chronic oxidative stress caused astrocyte defects in mice with impaired mitochondrial electron transport chain functionality.
This experiment was conducted to evaluate the effects of feeding different levels of green forages on feed consumption, nutrient and mineral utilization in Golden pheasants (GP). Twenty-seven female GP (BW 617-635 g) were randomly distributed into three groups of nine birds each in an experiment based on completely randomized design (CRD). Birds in group T1 were fed a conventional zoo diet containing 1.4% green forages; however, the diets of the birds in groups T2 and T3 contained 2.7% and 5.0% of green forages, respectively. Intake of total carotenoids increased with increased level of green forages in the diet. Apparent retention of N, Ca, and Zn was higher in GP laying hens fed diet containing 5.0% green forages as compared to those fed conventional diet containing 1.4% green forages. Results of the present study indicate that inclusion of 5% green forage in the diet of GP would improve the utilization of N, Ca, and Zn without any adverse effect on intake and utilization of other nutrients. Data related to nutrient intake, basal endogenous losses (BEL) and coefficient of retention (COR) of N, Ca, P, Mg, Fe, Cu, Mn, and Zn are novel and may be of use for future research. Zoo Biol. 35:522-532, 2016. © 2016 Wiley Periodicals, Inc.
Pathogenic Gram-negative bacteria resistant to almost all β-lactam antibiotics are a major public health threat. Zn(II)-dependent or metallo-β-lactamases (MBLs) produced by these bacteria inactivate most β-lactam antibiotics, including the carbapenems, which are "last line therapies" for life-threatening Gram-negative infections. NDM-1 is a carbapenemase belonging to the MBL family that is rapidly spreading worldwide. Regrettably, inhibitors of MBLs are not yet developed. Here we present the bisthiazolidine (BTZ) scaffold as a structure with some features of β-lactam substrates, which can be modified with metal-binding groups to target the MBL active site. Inspired by known interactions of MBLs with β-lactams, we designed four BTZs that behave as in vitro NDM-1 inhibitors with Ki values in the low micromolar range (from 7 ± 1 to 19 ± 3 μM). NMR spectroscopy demonstrated that they inhibit hydrolysis of imipenem in NDM-1-producing Escherichia coli. In vitro time kill cell-based assays against a variety of bacterial strains harboring blaNDM-1 including Acinetobacter baumannii show that the compounds restore the antibacterial activity of imipenem. A crystal structure of the most potent heterocycle (L-CS319) in complex with NDM-1 at 1.9 Å resolution identified both structural determinants for inhibitor binding and opportunities for further improvements in potency.
It is suspected that some neurodegenerative diseases are a result of the disturbance of copper (Cu) homeostasis, although it remains unclear whether the disturbance of Cu homeostasis has aberrant effects on neurons. Herein, we investigated Cu metabolism specifically in neurons in terms of changes in the intracellular Cu concentration and the expression of Cu-regulating genes, such as Cu transporters and metallothioneins (MTs), before and after the differentiation of rat pheochromocytoma cells (PC12 cells) into neurons. After the differentiation, Cu and Zn imaging with fluorescent probes revealed an increase in intracellular Cu concentration. The concentrations of other essential metals, which were determined by an inductively coupled plasma mass spectrometer, were not altered. The mRNA expression of the Cu influx transporter, Ctr1, was decreased after the differentiation, and the differentiated cells acquired tolerance to Cu and cisplatin, another substrate of Ctr1. In addition, the expression of MT-3, a brain-specific isoform, was increased, contrary to the decreased expression of MT-1 and MT-2. Taken together, the differentiation of PC12 cells into neurons induced MT-3 expression, thereby resulting in intracellular Cu accumulation. The decrease in Ctr1 expression was assumed to be a response aimed at abolishing the physiological accumulation of Cu after the differentiation.
The delivered nanoparticle dose to cells in vitro may depend on nanoparticle sedimentation rate. Here, the conditions under which optical absorption spectroscopy can be used to quantify the deposited nanoparticle dose in vitro are investigated.
Nanoparticle cytotoxicity in both upright and inverted cell culture orientations is studied in the presence and absence of serum.
Dissolvable nanoparticles, such as ZnO, exhibit no difference in upright and inverted cultures due to dissolved Zn(2+) ions that dominate cytotoxicity. Insoluble nanoparticles, however, exhibit different sedimentation rates and deposited doses that are linked to the observed cytotoxicity.
The combined use of upright-inverted cell orientations and optical absorption spectroscopy can provide a simple experimental approach to interpret in vitro nano-biointeractions.
Over the past 20 years, global production of copper (Cu) and zinc (Zn) rank in the top three compared to other metals such as Pb, Cd, Cr, Ni, As and Hg. However, due to the potential for exposure and toxicity to humans, more attention of environmental pollution was paid to other metals such as Cd and Hg. Aquatic organisms are sensitive to Cu and Zn. Even though internal concentrations of these required elements are homeostatically controlled, toxic effects can occur at the fish gill surface. In this work, concentrations in surface waters and toxic effects of Cu, Zn, Ni, Cr, Pb, Cd, As, Hg were determined and risk of various metals in Tai Lake, China were evaluated using both risk quotients and joint probability distributions. Two transition metals, Cu and Zn posed the greatest risks to aquatic organisms while measured concentrations of other metals were less than thresholds for adverse effects. Approximately 99.9% and 50.7% of the aquatic organisms were predicted to be affected by Cu and Zn in surface water of Tai Lake respectively. Our results highlight ecological risks of Cu and Zn in water of a typical, large, urban lake in Eastern China, which was ignored in the past.
We recently reported that an allowed d-d transition of trigonal bipyramidal (TBP) Mn(3+) is responsible for the bright blue color in the YIn1-xMnxO3 solid solution. The crystal field splitting between a'(dz(2)) and e'(dx(2)-y(2), dxy) energy levels is very sensitive to the apical Mn-O distance. We therefore applied chemical pressure
 to compress the apical Mn-O distance in YIn1-xMnxO3, move the allowed d-d transition to higher energy, and thereby tune the color from blue to violet/purple. This was accomplished by substituting smaller cations such as Ti(4+)/Zn(2+) and Al(3+) onto the TBP In/Mn site, which yielded novel violet/purple phases. The general formula is YIn1-x-2y-zMnxTiyZnyAlzO3 (x = 0.005-0.2, y = 0.1-0.4, and z ≤ 0.1), where the color darkens with the increasing amount of Mn. Higher y or small additions of Al provide a more reddish hue to the resulting purple colors. Substituting other rare earth cations for Y has little impact on color. Crystal structure analysis by neutron powder diffraction confirms a shorter apical Mn-O distance compared with that in the blue YIn1-xMnxO3. Magnetic susceptibility measurements verify the 3+ oxidation state for Mn. Diffuse reflection spectra were obtained over the wavelength region 200-2500 nm. All samples show excellent near-infrared reflectance comparable to that of commercial TiO2, making them ideal for cool pigment applications such as energy efficient roofs of buildings and cars where reducing solar heat to save energy is desired. In a comparison with commercial purple pigments, such as Co3(PO4)2, our pigments are much more thermally stable and chemically inert, and are neither toxic nor carcinogenic.
Metal pollution in sediments from the Shima River, a typical transboundary watercourse in the Pearl River Delta area, was investigated. Sediment cores were collected at eight sites from the upper to the lower reaches crossing Shenzhen, Dongguan and Huizhou cities. Sediment physicochemical properties and the total concentrations of trace metals (V, Cr, Co, Ni, Cu, Zn, As, Cd and Pb) were determined. The results showed that riverine sediment was significantly polluted by Cr (content range: 13.8-469mgkg(-1)), Ni (14.1-257mgkg(-1)), Cu (10.8-630mgkg(-1)), Zn (50.2-1700mgkg(-1)) and Cd (0.172-2.26mgkg(-1)). The geoaccumulation indices (Igeo) of trace metals decreased in the order Cd>Zn>Ni>Cu>Co>Cr>Pb>As>V. The pollution load indices and potential ecological risk indices (RI) at the sampling sites were similar, with more severe pollution and greater risk presenting in the upper and middle reaches (S1-S6) compared with the lower reaches (S7 and S8). Cd contributed significantly (77.2-87.6%) to the RI. Source identification based on multivariate statistical techniques, including principal component analysis (PCA), correlation analysis (CA) and hierarchical cluster analysis (HACA), was performed to differentiate the origins of trace metals. PCA and CA yielded similar results, indicating that As and V originated from natural sources (e.g., parent materials) and that the other metals were related to anthropogenic activities. HACA based on the Igeo showed that Cd was associated mainly with fertilizers, and the origins of Cr, Ni, Cu and Zn were probably industrial effluents, whereas Co and Pb were related to traffic activities. HACA of sediment cores suggested that Dongguan and Shenzhen cities contribute large quantities of metals to the riverine sediment, whereas few metals were discharged from Huizhou City.
The use of RNAi to suppress protein synthesis offers a potential way of reducing the level of enzymes or the synthesis of mutant toxic proteins but there are few tools currently available for their delivery. To address this problem, bioconjugated quantum dots (QDs) containing a hydrophobic component (N-palmitate) and a sequence VKIKK designed to traverse across cell membranes and visualize drug delivery were developed and tested on cell lines of brain origin. We used the Zn outer shell of the QD to bind HIS6 in JB577 (W•G•Dap(N-Palmitoyl)•VKIKK•P9 •G2 •H6 ) and by a gel-shift assay showed that siRNAs would bind to the positively charged KIKK sequence. By comparing many peptides and QD coatings, we showed that the QD-JB577-siRNA construct was taken up by cells of nervous system origin, distributed throughout the cytosol, and inhibited protein synthesis, implying that JB577 was also promoting endosome egress. By attaching siRNA for luciferase in a cell line over-expressing luciferase, we showed 70% inhibition of mRNA after 24-48 h. To show more specific effects, we synthesized siRNA for neutral (NSMase2), acid (lysosomal ASMase) sphingomyelinase, and sphingosine kinase 1 (SK1), we demonstrated a dose-dependent inhibition of activity. These data suggest that QDs are a useful siRNA delivery tool and QD-siRNA could be a potential theranostic for a variety of diseases.
One of the most important side effects of contrast pharmaceutical agents, which are used very common in routine radiology practice, is contrast induced nephropathy. Even ischemia, oxidative stress and osmolality related cytotoxic effects are considered, the molecular mechanisms underlying this pathology have not been identified completely yet.
The aim of the current study was to reveal the role of oxidative stress and antioxidant enzymatic defence mechanisms in the aetiopathogenesis of contrast-induced nephropathy. We also studied possible alleviating effects of N-acetylcysteine (NAC), a potent antioxidant, to obtain extra information regarding the molecular mechanisms underlying this pathology.
This is an clinical-experimental study, This study was conducted of Istanbul/Turkey between September 15, 2012 and April 15, 2013. Three groups of male rats were randomly set up as a control group (C), a 100 mg/kg intraperitoneal NAC + 7 mL/kg contrast agent group (N + CIN) and a 7 mL/kg intraperitoneal contrast agent group (CIN). They were placed in individual metabolic cages 48 hours after agent administration to obtain 24-hour urine samples. Renal function tests (albumin, urea, creatinine, total protein) were conducted, oxidative stress parameters (Cu, Zn superoxide dismutase activity - Cu, Zn-SOD; advanced oxidation protein products - AOPP; protein carbonyls - PCO; total thiol groups - T-SH; and lipid hydroperoxides -LHP) were measured and tissues were analysed histopathologically.
Compared with the control group, groups CIN and N + CIN had significantly higher urea and LHP levels (P < 0.05 and P < 0.001, respectively) and significantly lower Cu, Zn-SOD activity and creatinine clearance (P < 0.05). There was no statistically significant difference between the groups in PCO or AOPP levels despite differences in descriptive statistics.
Contrast-agent-induced nephropathic changes are more closely related to the magnitude of lipid peroxidation than protein oxidation.
Low-pH and aluminum (Al) stresses are the major constraints that limit crop yield in acidic soils. Grafting vegetable elite cultivars onto appropriate rootstocks may represent an effective tool to improve crop tolerance to acidity and Al toxicity. Two greenhouse hydroponic experiments were performed to evaluate growth, yield, biomass production, chlorophyll index, electrolyte leakage, mineral composition, and assimilate partitioning in plant tissues of cucumber plants (Cucumis sativus L. "Ekron") either non-grafted or grafted onto "P360" (Cucurbita maxima Duchesne × Cucurbita moschata Duchesne; E/C) or figleaf gourd (Cucurbita ficifolia Bouché; E/F). Cucumber plants were cultured in pots and supplied with nutrient solutions having different pH and Al concentrations: pH 6, pH 3.5, pH 3.5 + 1.5 mM Al, and pH 3.5 + 3 mM Al (Experiment 1, 14 days) and pH 6, pH 3.5, and pH 3.5 + 0.75 mM Al (Experiment 2, 67 days). Significant depression in shoot and root biomass was observed in response to acidity and Al concentrations, with Al-stress being more phytotoxic than low pH treatment. Significant decrease in yield, shoot, and root biomass, leaf area, SPAD index, N, K, Ca, Mg, Mn, and B concentration in aerial parts (leaves and stems) in response to low pH with more detrimental effects at pH 3.5 + Al. Grafted E/C plants grown under low pH and Al had higher yield, shoot, and root biomass compared to E/F and non-grafted plants. This better crop performance of E/C plants in response to Al stress was related to (i) a reduced translocation of Al from roots to the shoot, (ii) a better shoot and root nutritional status in K, Ca, Mg, Mn, and Zn concentration, (iii) a higher chlorophyll synthesis, as well as (iv) the ability to maintain cell membrane stability and integrity (lower electrolyte leakage). Data provide insight into the role of grafting on Al stress tolerance in cucumber.
The Natural Resistance Associated Macrophage Protein (Nramp) represents a transporter family for metal ions in all organisms. Here, we functionally characterized a member of Nramp family in barley (Hordeum vulgare), HvNramp5. This member showed different expression patterns, transport substrate specificity, and cellular localization from its close homolog in rice (Oryza sativa), OsNramp5, although HvNramp5 was also localized to the plasma membrane. HvNramp5 was mainly expressed in the roots and its expression was not affected by Cd and deficiency of Zn, Cu, and Mn, but slightly up-regulated by Fe deficiency. Spatial expression analysis showed that the expression of HvNramp5 was higher in the root tips than that in the basal root regions. Furthermore, analysis with laser microdissection revealed higher expression of HvNramp5 in the outer root cell layers. HvNramp5 showed transport activity for both Mn(2+) and Cd(2+), but not for Fe(2+) when expressed in yeast. Immunostaining with a HvNramp5 antibody showed that this protein was localized in the root epidermal cells without polarity. Knockdown of HvNramp5 in barley resulted in a significant reduction in the seedling growth at low Mn supply, but this reduction was rescued at high Mn supply. The concentration of Mn and Cd, but not other metals including Cu, Zn, and Fe, was decreased in both the roots and shoots of knockdown lines compared with the wild-type barley. These results indicate
 that HvNramp5 is a transporter required for uptake of Mn and Cd, but not for Fe, and that barley has a distinct uptake system from rice.
The eco-friendly combination tanning process has been developed to reduce chromium in existing researches, which is based on zinc tanning agents. This can be considered as a less-chrome substitute for current tanning process. To gain deeper understanding of the binding mechanisms of zinc-collagen interaction, which are affected by tanning pH, experiments have been carried out. Analysis in this paper reveals how chemical bonds from the collagen's main function groups combine with zinc. XPS and NIR data was analyzed for further understanding of where the zinc binding sites lie on collagen fibers at different pH. The results indicate that high pH is helpful to amino-binding sites while low pH promotes carboxyl-binding sites on collagen fibers. Furthermore, from the effect of Zinc-chrome combination tanning, we can see that the new method reduces the chromium dosage in tanning process compared to the conventional chrome tanning method.
As the first three-dimensional structure of the two-subunit type 2-oxoacid:ferredoxin oxidoreductases (OFOR) from archaea, we solved the crystal structures of STK_23000/STK_22980 (StOFOR1) and STK_24350/STK_24330 (StOFOR2) from Sulfolobus tokodaii. They showed similar overall structures, consisting of two a- and b-subunit heterodimers containing thiamin pyrophosphate (TPP) cofactor and [4Fe-4S] cluster, but lack an intramolecular ferredoxin domain. Unlike other OFORs, StOFORs can utilize both pyruvate and 2-oxoglutarate, playing a key role in the central metabolism. In the structure of StOFOR2 in unreacted pyruvate complex form, carboxylate group of pyruvate is recognized by Arg344 and Thr257 from the a-subunit, which are conserved in pyruvate:ferredoxin oxidoreductase from Desulfovbrio africanus (DaPFOR). In the structure of StOFOR1 co-crystallized with 2-oxobutyrate, electron density corresponding to a 1-hydroxypropyl group (post-decarboxylation state) was observed at the thiazole ring of TPP. The binding pockets of the StOFORs surrounding the methyl or propyl group of the ligands are wider than that of DaPFOR. Mutational analyses indicated that several residues were responsible for the broad 2-oxoacid specificity of StOFORs. We also constructed a possible complex structural model by placing a Zn(2+)-containing dicluster ferredoxin of S. tokodaii into the large pocket of StOFOR2, providing insight into the electron transfer between the two redox proteins.
In order to evaluate the heavy metal pollution in the Tiber River and its environmental impact on the Tyrrhenian Sea (Central Mediterranean Sea), eight heavy metals (As, Hg, Cd, Cr, Cu, Ni, Pb and Zn) were determined in the water dissolved phase, suspended particulate matter and sediment samples collected from 21 sites in different seasons. Total heavy metal concentrations ranged from 34.88 to 4201.23 μg L(-1) in water (as the sum of the water dissolved phase and suspended particulate matter) and from 42.81 to 1686.84 mg kg(-1) in sediment samples. The total selected heavy metal load contribution into the sea is calculated in about 21,257.85 kg year(-1), showing that this River should account as one of the main contribution sources of heavy metals in the Mediterranean Sea. In relation to the ecological assessment, the Tiber River and Estuary would be considered as an area in which the ecological integrity is possibly at risk.
Total concentrations of heavy metals in soils may not be enough to understand their mobility and bioavailability. It is important to evaluate the degree of association of heavy metals with different chemical forms of soil. The sequential extraction method was applied to evaluate the mobile behavior of Cd, Cr, Cu, Ni, Pb, and Zn in 42 representative soil samples from the Linhuan subsidence of Huaibei Coalfield, Anhui Province, China. The results showed that mean concentrations of heavy metals were higher than background values of Huaibei City surface soil by a factor of 1.16 to 3.21 (Cd, 3.21; Cr, 1.19; Cu, 1.16; Ni, 1.23; Zn, 1.85) except Pb (0.89). Most of the total Cr, Cu, Ni, Pb, and Zn were present in the residual forms (above 70 %), while Cd was dominated by the exchangeable forms (42 %). The correlations analysis showed that the mobility of Cd, Cu, Pb, and Zn in soil was affected by both physicochemical properties and total metal concentrations. In contrast, the moblity of Cr and Ni of soil was mainly affected by their total metal concentrations. According to assessments by the potential ecological risk index (RI) and the risk assessment code (RAC), Cr, Cu, Ni, Pb, and Zn posed no or low risk. However, Cd presents high to very high risk, due to its higher exchangeable and carbonate-bound fractions.
This study was carried out to determine the concentration of (222)Rn, (226)Ra, and (238)U in 25 different toothpastes available in the local market in Penang, Malaysia, using a CR-39 detector. The results showed the maximum concentration of radon/ radium/uranium to be 4197.644 Bq.m(-3), 54.369 Bq.Kgm(-1), and 0.044 ppm in Colgate4; the annual effective dose was found (0.402 mSvy(-1)) in S07. The average concentration of radon (42 %, 3.224 KBq.m(-3)) was higher than the concentration of (214)Po, (218)Po in POS (32 %, 2.415 KBq.m(-3)) and POW (26 %, 1.979 KBq.m(-3)). Also the values of pH of samples ranged from 4.21 (highly acidic) in S04 to 9.97 (highly basic) in S07, with an average of 6.33 which tended towards an acidic behavior; a low or high pH for a long period of time can cause harmful side-effects and enamel erosion. Concentrations of heavy metals varied from the maximum value 56.156 ppm in the Ca elements in the Colgate 4 sample to a minimum value of -0.858 ppm in the Cd elements in Colgate 6 (Ca 56.156 ppm > Cd 51.572 ppm > Zn 41.039 ppm > Mg 11.682 ppm > Pb 11.009 ppm]. Monitoring the accumulation of these metals in toothpaste samples is very important: the average annual effective dose (0.3118 mSvy(-1)) was below the range (3-10 mSvy(-1)) reported by ICRP (1993), and therefore there is no evidence of health problems. Significant strong positive correlations were found (r = 1, Pearson correlation, p < 0.000) in concentration of radon, radium, uranium, annual effective dose, pH, and electrical conductivity.
Stable metal (e.g. Li, Mg, Ca, Fe, Cu, Zn, and Mo) and metalloid (B, Si, Ge) isotope ratio systems have emerged as geochemical tracers to fingerprint distinct physicochemical reactions. These systems are relevant to many Earth Science questions. The benefit of in situ microscale analysis using laser ablation (LA) over bulk sample analysis is to use the spatial context of different phases in the solid sample to disclose the processes that govern their chemical and isotopic compositions. However, there is a lack of in situ analytical routines to obtain a samples' stable isotope ratio together with its chemical composition. Here, we evaluate two novel analytical routines for the simultaneous determination of the chemical and Si stable isotope composition (δ(30)Si) on the micrometre scale in geological samples. In both routines, multicollector inductively coupled plasma mass spectrometry (MC-ICP-MS) is combined with femtosecond-LA, where stable isotope ratios are corrected for mass bias using standard-sample-bracketing with matrix-independent calibration. The first method is based on laser ablation split stream (LASS), where the laser aerosol is split and introduced simultaneously into both the MC-ICP-MS and a quadrupole ICP-MS. The second method is based on optical emission spectroscopy using direct observation of the MC-ICP-MS plasma (LA-MC-ICP-MS|OES). Both methods are evaluated using international geological reference materials. Accurate and precise Si isotope ratios were obtained with an uncertainty typically better than 0.23‰, 2SD, δ(30)Si. With both methods major element concentrations (e.g., Na, Al, Si, Mg, Ca) can be simultaneously determined. However, LASS-ICP-MS is superior over LA-MC-ICP-MS|OES, which is limited by its lower sensitivity. Moreover, LASS-ICP-MS offers trace element analysis down to the μg g(-1)-range for more than 28 elements due to lower limits of detection, and with typical uncertainties better than 15%. For in situ simultaneous stable isotope measurement and chemical composition analysis LASS-ICP-MS in combination with MC-ICP-MS is the method of choice.
The aim of this study was to evaluate the relationship between antioxidant superoxide dismutase (SOD) enzyme activity, malondialdehyde (MDA) as a lipid peroxidation marker, and some trace elements such as zinc (Zn) and copper (Cu) levels in patients with keratoconus.
A total of 58 patients with keratoconus and 53 control subjects with similar age and sex were evaluated in this study. The modified Krumeich keratoconus classification was used to divide the patients into 4 stages. Serum SOD activity, MDA, and zinc and copper levels were compared between the patient and control groups.
The median serum SOD activity, MDA, and Zn and Cu levels were 27.2 (42.4-13.7) U/mL, 10.2 (11.9-8.5) nmol/mL, 87.9 (104.6-76.5) μmol/L, and 103.2 (117.9-90.3) μmol/L in the keratoconus group and 26.2 (32.5-14.4) U/mL, 8.8 (11.4-7.1) nmol/mL, 100.5 (121.1-81.8) μmol/L, and 98.4 (120.3-83.4) μmol/L in the control group, respectively. There was a statistically significant difference between the MDA and Zn levels of the keratoconus group and control subjects but not between the respective SOD activities or Cu levels (P = 0.016, P = 0.031, P = 0.440, and P = 0.376, respectively). We found no significant difference between the keratoconus group stages for serum SOD activity, serum MDA, and Zn and Cu levels (P > 0.05), and there was also no significant correlation between the keratoconus group stages and serum SOD activity,
 serum MDA, and Zn and Cu levels (P > 0.05).
There is imbalance in the systemic oxidant/antioxidant status where Zn deficiency also plays a role in patients with keratoconus.
Protonolysis by platinum or palladium complexes has been extensively studied because it is the microscopic reverse of the C-H bond activation reaction. The protonolysis of (COD)Pt(II)Me2, which exhibits abnormally large kinetic isotope effects (KIEs), is proposed to occur via a concerted pathway (SE2 mechanism) with large tunneling. However, further investigation of KIEs for the protonolysis of ZnMe2 and others led to a conclusion that there is no noticeable correlation between the mechanism and magnitude of KIE. In this study, we demonstrated that variational transition state theory including multidimensional tunneling (VTST/MT) could accurately predict KIEs and Arrhenius parameters of the protonolysis of alkylmetal complexes based on the potential energy surfaces generated by density functional theory. The predicted KIEs, Ea(D) - Ea(H) values, and AH/AD ratios for the protonolysis of (COD)Pt(II)Me2 and Zn(II)Me2 by TFA agreed very well with experimental values. The protonolysis of ZnMe2 with the concerted pathway has a very flat potential energy surface, which produces a very small tunneling effect and therefore a small KIE. The predicted KIE for the stepwise protonolysis (SE(ox) mechanism) of (COD)Pt(II)Me2 was much smaller than that of the concerted pathway, but greater than the KIE of the concerted protonolysis of ZnMe2. A large KIE, which entails a significant tunneling effect, could be used as an experimental probe of the concerted pathway. However, a normal or small KIE should not be used as an indicator of the stepwise mechanism, and the interplay between experiments and reliable theory including tunneling would be essential to uncover the mechanism correctly.
Antimicrobial resistance (AMR) is becoming a major global-health concern prompting an urgent need for highly-sensitive and rapid diagnostic technology. Traditional assays available for monitoring bacterial cultures are time-consuming and labor-intensive. We present a magnesium zinc oxide (MZO) nanostructure-modified quartz crystal microbalance (MZOnano-QCM) biosensor to dynamically monitor antimicrobial effects on E. coli and S. cerevisiae. MZO nanostructures were grown on the top electrode of a standard QCM using metal-organic chemical-vapor deposition (MOCVD). The MZO nanostructures are chosen for their multifunctionality, biocompatibility, and giant effective sensing surface. The MZO surface-wettability and morphology are controlled, offering high-sensitivity to various biological/biochemical species. MZO-nanostructures showed over 4-times greater cell viability over ZnO due to MZO releasing 4-times lower Zn(2+) density in the cell medium than ZnO. The MZOnano-QCM was applied to detect the effects of ampicillin and tetracycline on sensitive and resistant strains of E.coli, as well as effects of amphotericin-B and miconazole on S. cerevisiae through the device's time-dependent frequency shift and motional resistance. The MZOnano-QCM showed 4-times more sensitivity over ZnOnano-QCM and over 10-times better than regular QCM. For comparison, the optical density at 600nm (OD600) method and the cell viability assay were employed as standard references to verify the detection results from MZOnano-QCM. In the case of S. cerevisiae, the OD600 method failed to distinguish between cytotoxic and cytostatic drug effects whereas the MZOnano-QCM was able to accurately detect the drug effects. The MZOnano-QCM biosensor provides a promising technology enabling dynamic and rapid diagnostics for antimicrobial drug development and AMR detection.
This article contains a statistically analyzed dataset of the heavy metals including Cr, Co, Ni, Cu, Zn and Pb contents of near-surface (~30 cm depth) soils in a Cu-Ni prospecting field at Airstrip North, Central Botswana. The soils developed on paragneisses and amphibolites parent materials in a semi-arid environment with hardveld vegetation, "The geology of the Topisi area" (Key et al., 1994) [1]. Grid sampling was adopted in the field data collection. Heavy metals were determined using the relatively new portable x-ray fluorescence spectrometer (Delta Premium, 510,890, USA) technology in a "soil" mode. The data presented was obtained from the average reading of two soil samples collected from same point but passed through sieves.
The long term (30 days) toxicological effects of environmentally relevant concentrations of Pb(2+) (20μg/L) and Zn(2+) (100μg/L) were characterized in Suaeda salsa using proteomics techniques. The responsive proteins were related to metabolism (Krebs cycle and Calvin cycle), protein biosynthesis, stress and defense, energy, signaling pathway and photosynthesis in Pb(2+), Zn(2+) and Pb(2+)+ Zn(2+) exposed groups in S. salsa after exposures for 30 days. The proteomic profiles also showed differential responses in S. salsa to metal exposures. In Pb(2+)-treated group, the proteins were categorized into cystein metabolism and pentose phosphate pathway. The responsive proteins were basically involved in glutathione metabolism, glycolysis, cystein and methane metabolism, and voltage-dependent anion channel in Zn(2+)-treated group. In Pb(2+)+ Zn(2+)-treated group, the proecular mechanism at protein level remtein responses were devided into tyrosine metabolism and glycolysis. Our results showed that the two typical heavy metals, lead and zinc, could induce toxicological effects in halophyte S. salsa at protein level.
After severe nuclear events, a major fraction of refractory radionuclides such as U and Pu are released to the environment in the form of radioactive particles. After the Fukushima Daiichi Nuclear Power Plant (FDNPP) accident, Pu isotope ratio signals different from that of global fallout have been reported, indicating that spent fuel particles have been released from the reactors or reactor vessels. Radioactive particles containing (37) Cs and other volatile radionuclides, as well as a series of stable refractory metals (Cs, Fe, Zn, U, etc.), have been identified by several authors claiming that these particles originated from the FDNPP fuel. If so, long-lived radioactive isotopes of the refractory metals should have been identified in these particles. It is therefore most probable that volatile radionuclides released as gases during the accidents have deposited on available surfaces such as fly ash, forming condensation particles during release or transport. If spent fuel particles have been deposited in the FDNPP surroundings, information on particle characteristics influencing ecosystem transport, uptake, and effects is essential for assessing environmental impact and risk. More emphasis should therefore be put on the identification of hot spots in the FDNPP environment followed by the characterization of radioactive particles using nanoanalytical-microanalytical techniques to support environmental monitoring, as recommended in the present study. Integr Environ Assess Manag 2016;12:687-689. © 2016 SETAC.
CphA is a Zn(2+)-dependent metallo-β-lactamase that efficiently hydrolyzes only carbapenem antibiotics. To understand the sequence requirements for CphA function, single codon random mutant libraries were constructed for residues in and near the active site and mutants were selected for E. coli growth on increasing concentrations of imipenem, a carbapenem antibiotic. At high concentrations of imipenem that select for phenotypically wild-type mutants, the active-site residues exhibit stringent sequence requirements in that nearly all residues in positions that contact zinc, the substrate, or the catalytic water do not tolerate amino acid substitutions. In addition, at high imipenem concentrations a number of residues that do not directly contact zinc or substrate are also essential and do not tolerate substitutions. Biochemical analysis confirmed that amino acid substitutions at essential positions decreased the stability or catalytic activity of the CphA enzyme. Therefore, the CphA active - site is fragile to substitutions, suggesting active-site residues are optimized for imipenem hydrolysis. These results also suggest that resistance to inhibitors targeted to the CphA active site would be slow to develop because of the strong sequence constraints on function.
Estuarine environment is complex and receives different contaminants from numerous sources that are persistent, bioaccumulative and toxic. The distribution, source, contamination and ecological risk status of heavy metals in sediment of Brisbane River, Australia were investigated. Sediment samples were analysed for major and minor elements using LA-ICP-MS. Principal component analysis and cluster analysis identified three main sources of metals in the samples: marine sand intrusion, mixed lithogenic and sand intrusion as well as transport related. To overcome inherent deficiencies in using a single index, a range of sediment quality indices, including contamination factor, enrichment factor, index of geo-accumulation, modified degree of contamination, pollution index and modified pollution index were utilised to ascertain the sediment quality. Generally, the sediment is deemed to be "slightly" to "heavily" polluted. A further comparison with the Australian Sediment Quality Guidelines indicated that Ag, Cr, Cu, Ni, Pb and Zn had the potential to rarely cause biological effects while Hg could frequently cause biological effects. Application of potential ecological risk index (RI) revealed that the sediment poses moderate to considerable ecological risk. However, RI could not account for the complex sediment behaviour because it uses a simple contamination factor. Consequently, a modified ecological risk index (MRI) employing enrichment factor is proposed. This
 provides a more reliable understanding of whole sediment behaviour and classified the ecological risk of the sediment as moderate to very high. The results demonstrate the need for further investigation into heavy metal speciation and bioavailability in the sediment to ascertain the degree of toxicity.
PM2.5 concentrations were measured in residential indoor environment in slums of central India during 2012-2013. In addition, a suite of chemical components including metals (Al, K, Ca, V, Cr, Mn, Fe, Co, Ni, Cu, Zn, As, Cd, Pb, Mo, Se, Sb, Na, Mg, K and Hg), ions (Na(+), Mg(2+), K(+), Ca(2+), F(-), Cl(-), NH4(+), NO3(-) and SO4(2-)) and carbon (OC and EC) were analyzed for all samples. Indoor PM2.5 concentrations were found to be several folds higher than the 24-h national ambient air quality standard (60 µg/m(3)) for PM2.5 in India, and the concentrations were found to vary from season to season. Mass closure was attempted for PM2.5 data, and close to 100 % mass was accounted for by organic matter, crustal material, secondary organic and inorganic aerosols and elemental carbon. Additionally, carcinogenic and non-carcinogenic health risks associated with exposure to indoor PM2.5 (inhalation, dermal and ingestion) were estimated and while exposures associated with dermal contact and ingestion were found to be within the acceptable limits, risk associated with inhalation exposure was found to be high for children and adults. Elements including Al, Cd, Co, Cr, Mn, Ni, As and Pb were present in high concentrations and contributed to carcinogenic and non-carcinogenic risks for residents' health. Results from this study highlight the need for efforts to reduce air pollution exposure in slum areas.
Steel slag has been widely used as amendment and silicon fertilizer to alleviate the mobility and bioavailability of heavy metals in soil. The objective of this study was to evaluate the influence of particle size, composition, and application rate of slag on metal immobilization in acidic soil, metals uptake by rice and rice growth. The results indicated that application of slag increased soil pH, plant-available silicon concentrations in soil, and decreased the bioavailability of metals compared with control treatment, whereas pulverous slag (S1) was more effective than granular slag (S2 and S3). The acid-extractable fraction of Cd in the spiked soil was significantly decreased with application of S1 at rates of 1 and 3 %, acid-extractable fractions of Cu and Zn were decreased when treated at 3 %. Use of S1 at both rates resulted in significantly lower Cd, Cu, and Zn concentrations in rice tissues than in controls by 82.6-92.9, 88.4-95.6, and 67.4-81.4 %, respectively. However, use of pulverous slag at 1 % significantly promotes rice growth, restricted rice growth when treated at 3 %. Thus, the results explained that reduced particle size and suitable application rate of slag could be beneficial to rice growth and metals stabilization.
A comprehensive analysis of heavy metal speciation, risk, and bioavailability in the sediments of three rivers in northern China (Shaocun River (SR), Wangyang River (WR), and Xiao River (XR)) was conducted. The results showed that higher pollution input resulting from urbanization and industrialization caused higher heavy metal contents and bioavailable proportion in the studied sediments. Total contents of all studied metals (Cr, Cu, Ni, Pb, and Zn) in the sediments of SR, WR, and XR were 270.31, 902.62, and 2367.46 mg/kg, respectively. The average percentages of bioavailable fractions were 31.16, 61.73, and 81.69 %, respectively. Cr, Ni, and Pb were all mainly observed in the B4 (residual) fraction in the studied sediments, with an average percentage of 42.03, 48.19, and 55.08 %, respectively. Cu was mainly observed in the B2 (reducible) fraction (40.53 %). Zn was mainly observed in the B1 (exchangeable/acid soluble/carbonate) fraction (36.01 %), resulting in medium or high risk associated with Zn in the sediments of SR, WR, and XR. Sedimentary heavy metal risk and bioavailability associated with regional urbanization and industrialization should be taken into consideration with respect to the health of aquatic ecosystems.
Crop rotation long-term field experiments were established in 1955 and 1956 at three locations in the Czech Republic (Čáslav, Ivanovice, and Lukavec) differing in their climatic and soil physicochemical properties. The effect of long-term application of farmyard manure and farmyard manure + NPK treatments on plant-available, easily mobilizable, potentially mobilizable, and pseudo-total contents of arsenic (As), cadmium (Cd), copper (Cu), lead (Pb), and zinc (Zn) contents in soils (in 2013) as well as the uptake of these elements by winter wheat (Triticum aestivum L.) grain and straw were analyzed in the two following seasons: 2012 and 2013. The treatments resulted in increasing the soil pH level when compared to the control, but the cation exchange capacity remained unchanged. Although all fertilizers were applied for six decades, the pseudo-total concentration elements in both the soil and wheat plants stayed far below those of the Czech and European threshold limits for agricultural soils and cereals for human nutrition and feedstuff. Although the mobile pools of As, Cu, and Zn were slightly changed at the treated soils, these changes were not related to the element uptake by the wheat plants. Moreover, the effect of the location and growing season was more decisive for the differences in soil and plant element contents than for the individual treatments. Thus, the long-term application of farmyard manure did not result in any substantial change in risk element contents in both soils and winter wheat plants.
Paddy soils and rice (Oryza sativa L.) contaminated by mixed heavy metals have given rise to great concern. Field experiments were conducted over two cultivation seasons to study the effects of steel slag (SS), fly ash (FA), limestone (LS), bioorganic fertilizer (BF), and the combination of SS and BF (SSBF) on rice grain yield, Cd, Pb, and Zn and nutrient accumulation in brown rice, bioavailability of Cd, Pb, and Zn in soil as well as soil properties (pH and catalase), at two acidic paddy fields contaminated with mixed heavy metals (Cd, Pb, and Zn). Compared to the controls, SS, LS, and SSBF at both low and high additions significantly elevated soil pH over both cultivation seasons. The high treatments of SS and SSBF markedly increased grain yields, the accumulation of P and Ca in brown rice and soil catalase activities in the first cultivation season. The most striking result was from SS application (4.0 t ha(-1)) that consistently and significantly reduced the soil bioavailability of Cd, Pb, and Zn by 38.5-91.2 % and the concentrations of Cd and Pb in brown rice by 20.9-50.9 % in the two soils over both cultivation seasons. LS addition (4.0 t ha(-1)) also markedly reduced the bioavailable Cd, Pb, and Zn in soil and the Cd concentrations in brown rice. BF remobilized soil Cd and Pb leading to more accumulation of these metals in brown rice. The results showed that steel slag was most effective in the remediation of acidic paddy soils contaminated with mixed heavy metals.
An approximately 59-year (1955-2014) sedimentary record of metal elements (Cu, Pb, Zn, Ni, Co, Mn, and Fe) in a sediment core, collected from the Huaihe River, Huainan City, Anhui Province, China, was reconstructed by using (210)Pb geochronology. Copper, Zn, Ni, Co, and Mn evaluated by enrichment factor (EF) indicated minor contamination due to water pollution accidents of the Huaihe River that occurred in 1990s and 2004. Lead presented the most severe pollution among the metals studied, especially during 1957-1974. The use of leaded petrol and atmospheric deposition of coal combustion flue gases could have contributed to Pb contamination. In spite of the general good quality (mean sediment pollution index (SPI) 35.69) of the sediment core evaluated by SPI based on the principal component analysis, worse sediment qualities in the upper section (<6 cm, 2004) were still observed, suggesting intensive human activities causing the increasing concentrations of metals in recent decades.
The concentration partitioning between the sediment particle and the interstitial water phase plays an important role in controlling the toxicity of heavy metals in aquatic systems. The aim of this study was to assess the sediment quality in a polluted area of the Ziya River, Northern China. The contamination potential and bioavailability of six metals were determined from the concentrations of total metals and the bioavailable fractions. The results showed that the concentrations of Cr, Cu, Ni, Zn, and Pb exceeded the probable effect concentration at several sites. The high geoaccumulation indices showed that the sediments were seriously contaminated by Cd. The ratio of acid-volatile sulfide (AVS) to simultaneously extracted metal (SEM) was higher than 1, which indicated that the availability of metals in sediments was low. The risk assessment of interstitial waters confirmed that there was little chance of release of metals associated with acid-volatile sulfide into the water column. Values of the interstitial water criteria toxicity unit indicated that none of the concentrations of the studied metals exceeded the corresponding water quality thresholds of the US Environmental Protection Agency. Positive matrix factorization showed that the major sources of metals were related to anthropogenic activities. Further, if assessments are based on total heavy metal concentrations, the toxicity of heavy metals in sediment may be overestimated.
Mosses are useful, ubiquitous accumulation biomonitors and as such can be used for biomonitoring surveys. However, the biomonitoring of atmospheric pollution can be compromised in urban
 contexts if the targeted biomonitors are regularly disturbed, irregularly distributed, or are difficult to access. Here, we test the hypothesis that cemeteries are appropriate moss sampling sites for the evaluation of air pollution in urban areas. We sampled mosses growing on gravestones in 21 urban and peri-urban cemeteries in the Paris metropolitan area. We focused on Grimmia pulvinata (Hedwig) Smith, a species abundantly found in all studied cemeteries and very common in Europe. The concentration of Al, As, Br, Ca, Ce, Cl, Cr, Cu, Fe, K, Mn, Ni, V, P, Pb, Rb, S, Sr, Ti, and Zn was determined by a total reflection X-ray fluorescence technique coupled with a slurry sampling method (slurry-TXRF). This method avoids a digestion step, reduces the risk of sample contamination, and works even at low sample quantities. Elemental markers of road traffic indicated that the highest polluted cemeteries were located near the highly frequented Parisian ring road and under the influence of prevailing winds. The sites with the lowest pollution were found not only in the peri-urban cemeteries, adjoining forest or farming landscapes, but also in the large and relatively wooded cemeteries located in the center of Paris. Our results suggest that (1) slurry-TXRF might be successfully used with moss material, (2) G. pulvinata might be a good biomonitor of trace metals air pollution in urban context, and (3) cemetery moss sampling could be a useful complement for monitoring urban areas. Graphical abstract We tested the hypothesis that cemeteries are appropriate moss sampling sites for the evaluation of air pollution in urban areas. We sampled 110 moss cushions (Grimmia pulvinata) growing on gravestones in 21 urban and peri-urban cemeteries in the Paris metropolitan area. The concentration of 20 elements in mosses was determined by a total reflection X-ray fluorescence technique coupled with a slurry sampling method. Statistical analysis revealed that: - Urbanized Parisian areas crossed by traffic roads have the highest polluted cemeteries with a strong influence of main wind direction on the distribution of air pollutants - As expected, small cemeteries with low tree density were heavily polluted - Less obvious, large green spaces such as large cemeteries (Père Lachaise, Montmartre, Montparnasse) in the center of a dense metropolis like Paris present the same level of atmospheric trace metal pollution as cemeteries in less urbanized areas or nearing a very large forest. This suggests that even in densely urbanized areas, there is more spatial variability in pollution distribution than usually assumed and that large urban areas with low traffic and green filters such as trees are likely to intercept air pollutants.
In this study, a new bio-nanocomposite was prepared and characterized with a focus on the formation of hexagonal ZnO and orthorhombic zinc silicate (Zn2SiO3(OH)2) phases under ultrasonic irradiation. Chitosan/sepiolite/ZnO and chitosan/silica/ZnO bio-nanocomposites were synthesized using a simple solution method in which extreme physical and chemical conditions created by cavitation within the chitosan solution allowed for the transformation of aqueous Zn(OH)2 to crystallized ZnO and Zn2SiO3(OH)2 in room temperature. Both the loading of sepiolite and silica with the zinc precursor significantly influenced the morphology and crystalline structure of the product, however, different zinc compounds were observed. Sepiolite was exfoliated, resulting in a fine, even colloidal solution through ultrasonic dispersion. Exfoliation of sepiolite nanofibers led to the homogeneous dispersion of Zinc in the form of Zn(OH)2 in chitosan matrix. When the same procedure was conducted using the silica component, a formation of ZnO and Zn2SiO3(OH)2 was observed, components that were not observed when the procedure was conducted using sepiolite. The average crystalline size of ZnO was calculated as 36nm for ZnO. In addition, the quantities of crystalline and the ZnO phase volume was determined as 15%. Through zone of inhibition, the silica nanocomposite was discovered to have antibacterial activity. In contrast, the sepiolite compound did not exhibit these properties. We thus hypothesize that HO radicals, formed during ultrasonic irradiation trigger the formation of a silicate ion (SiO3(2-)) and formation of ZnO and Zn2SiO3(OH)2 species in chitosan/silica/ZnO bio-nanocomposite, which causes to exhibit these antibacterial properties against Gram-negative E. coli. Chemical characterization and dispersion of the structure of the ZnO and Zn2SiO3(OH)2 phases were done using X-ray diffraction (XRD) and scanning electron microscopy techniques (SEM) with EDAX and X-ray photoelectron spectroscopy (XPS).
Dissolved trace element concentrations (Ba, Fe, Mn, Si, Sr, and Zn) were investigated in the Haicheng River near to the Liaodong Bay in Northeast China during 2010. Dissolved Ba, Fe, Mn, and Sr showed significant spatial variation, whereas dissolved Fe, Mn, and Zn displayed seasonal variations. Conditions such as water temperature, pH, and dissolved oxygen were found to have an important impact on redox reactions involving dissolved Ba, Fe, and Zn. Dissolved Fe and Mn concentrations were regulated by adsorption or desorption of Fe/Mn oxyhydroxides and the effects of organic carbon complexation on dissolved Ba and Sr were found to be significant. The sources of dissolved trace elements were found to be mainly from domestic sewage, industrial waste, agricultural surface runoff, and natural origin, with estimated seasonal and annual river fluxes established as important inputs of dissolved trace elements from the Haicheng River into the Liaodong Bay or Bohai Sea.
We assessed inter-annual changes in fish assemblages of a tropical bay which experienced a heavily industrialized process in the last decades. A highly significant difference in community structure among the bay zones, and a decrease in fish richness and abundance over time were found. Changes in fish richness and abundance between the two first (1987-1988 and 1993-1995) and the two latter time periods (1998-2001 and 2012-2013) were sharpest in the inner bay zone, the most impacted bay area, and in the middle zone, whereas the outer zone remained comparatively stable over time. These changes coincided with increased metal pollution (mainly, Zn and Cd) in the bay and with the enlargement of the Sepetiba Port. Spatial changes in the fish community structure among the bay zones were related to differences in salinity, transparency and depth with this latter variable acting as a buffer stabilizing temporal community changes.
Using innovative artificial mussels technology for the first time, this study detected eight heavy metals (Cd, Cu, Fe, Mn, Ni, Pb, U, Zn) on a regular basis in waterways across Bangladesh (Chittagong, Dhaka and Khulna). Three heavy metals, viz. Co, Cr and Hg were always below the instrumental detection levels in all the sites during the study period. Through this study, seven metal pollution "hot spots" have been identified, of which, five "hot spots" (Cu, Fe, Mn, Ni, Pb) were located in the Buriganga River, close to the capital Dhaka. Based on this study, the Buriganga River can be classified as the most polluted waterway in Bangladesh compared to waterways monitored in Khulna and Chittagong. Direct effluents discharged from tanneries, textiles are, most likely, reasons for elevated concentrations of heavy metals in the Buriganga River. In other areas (Khulna), agriculture and fish farming effluents may have caused higher Cu, U and Zn in the Bhairab and Rupsa Rivers, whereas untreated industrial discharge and ship breaking activities can be linked to elevated Cd in the coastal sites (Chittagong). Metal pollution may cause significant impacts on water quality (irrigation, drinking), aquatic biodiversity (lethal and sub-lethal effects), food contamination/food security (bioaccumulation of metals in crops and seafood), human health (diseases) and livelihoods of people associated with wetlands.
Landfill soils are sources of emerging carcinogens, teratogens and mutagens in the environment. There is inadequate information on its possible health risk and cytogenotoxicity. This study evaluated chemical characterization of four simulated landfill leachates with their cytotoxicity and DNA damage in human cells. Hepatocarcinoma (HepG2), lymphoma (Jurkat) and osteosarcoma (HOS) cells, incubated with 6.25, 12.5, 25, 50, 75 and 100% of Aba Eku (AEL), Olusosun (OSL), Awotan (AWL) and Nagpur (NPL) simulated leachates for 24 h, were assessed for cell viability using MTT assay and morphological alterations. DNA damage was also assessed after 24 h treatment of cells with sub-lethal concentrations of the leachates using comet assay. Metals and organic compounds in the soil leachates were determined using inductively coupled plasma-mass spectrometry (ICP-MS) and gas chromatography-mass spectroscopy (GC-MS) respectively. The leachates induced significant cytotoxicity in the treated cells with evidence of apoptosis; shrunken morphologies, detachment from the substratum and cytoplasmic vacuolations. Similarly, there was significant DNA damage induced in the treated cells, with increased Olive tail moment, tail length and % tail DNA. Jurkat was the most sensitive (Jurkat > HepG2 > HOS) to the cytotoxic and genotoxic effects of the leachates. All the analyzed metals except Cd, Fe, Zn and Mn were found at levels lower than standard allowable limits. 32, 17, 23 and 23 different PAHs and PCBs were detected in AEL, AWL, OSL and NPL respectively, at varying retention peak times. These toxic constituents induced the observed cytogenotoxicity in the cells and may suggest possible public health risk.
The intensification of grassland management by nitrogen (N) fertilization and irrigation may threaten the future
 integrity of fragile semi-arid steppe ecosystems by affecting the concentrations of base cation and micronutrient in soils. We extracted base cations of exchangeable calcium (Ca), magnesium (Mg), potassium (K), and sodium (Na) and extractable micronutrients of iron (Fe), manganese (Mn), copper (Cu), and zinc (Zn) from three soil aggregate sizes classes (microaggregates, <0.25mm; small macroaggregates, 0.25-2mm; large macroaggregates, >2mm) from a 9-yearN and water field manipulation study. There were significantly more base cations (but not micronutrients) in microaggregates compared to macroaggregates which was related to greater soil organic matter and clay contents. Nitrogen addition significantly decreased exchangeable Ca by up to 33% in large and small macroaggregates and exchangeable Mg by up to 27% in three aggregates but significantly increased extractable Fe, Mn and Cu concentrations (by up to 262%, 150%, and 55%, respectively) in all aggregate size classes. However, water addition only increased exchangeable Na, while available Fe and Mn were decreased by water addition when averaging across all N treatments and aggregate classes. The loss of exchangeable Ca and Mg under N addition and extractable Fe and Mn in soil aggregates under water addition might potentially constrain the productivity of this semi-arid grassland ecosystem.
A field survey was conducted to evaluate soil metal pollution and endogenous trans-zeatin content in the leaves of plants growing at six sites in a metal-polluted area located in Gejiu, Yunnan, China. Five plant species were collected, and the physicochemical properties and concentrations of five metals in the soil were analyzed. The trans-zeatin content in plant leaves was measured by high-performance liquid chromatography. Based on the Nemerow pollution index, the six sites were classified into four levels of pollution (i.e., low, medium, high, and severely high). The degree of soil metal pollution was cadmium (Cd) > arsenic (As) > lead (Pb) > zinc (Zn) > copper (Cu). The leaf trans-zeatin content in Pteris vittata (an arsenic hyperaccumulator) increased significantly by 98.6 % in soil with a severely high level of pollution compared with soil at a low level of pollution. However, in non-hyperaccumulators Bidens pilosa var. radiata and Ageratina adenophora, a significant decrease in leaf trans-zeatin content of 35.6 and 87.6 %, respectively, was observed. The leaf trans-zeatin content in Artemisia argyi also decreased significantly by 73.6 % in high metal-polluted soil compared with that in medium metal-polluted soil. Furthermore, significant correlations were observed between leaf trans-zeatin content in Pteris vittata and As, Pb, and Cd concentrations in the soil; however, either no correlation or a negative one was observed in the other plant species. Therefore, a high content of trans-zeatin in the leaves of Pteris vittata may play an important role in its normal growth and tolerance to metals.
A regional investigation in the Youxian prefecture, southern China, was conducted to analyze the impact of environmental factors including soil properties and irrigation in conjunction with the use of fertilizers on the accumulation of Cd in vegetables. The Cd transfer potential from soil to vegetable was provided by the plant uptake factor (PUF), which varied by three orders of magnitude and was described by a Gaussian distribution model. The soil pH, content of soil organic matter (SOM), concentrations of Zn in the soil, pH of irrigation water and nitrogenous fertilizers contributed significantly to the PUF variations. A path model analysis, however, revealed the principal control of the PUF values resulted from the soil pH, soil Zn concentrations and SOM. Transfer functions were developed using the total soil Cd concentrations, soil pH, and SOM. They explained 56% of the variance for all samples irrespective of the vegetable genotypes. The transfer functions predicted the probability of exceeding China food safety standard concentrations for Cd in four major consumable vegetables under different soil conditions. Poor production practices in the study area involved usage of soil with pH values ≤ 5.5, especially for the cultivation of Raphanus sativus L., even with soil Cd concentrations below the China soil quality standard. We found the soil standard Cd concentrations for cultivating vegetables was not strict enough for strongly acidic (pH ≤ 5.5) and SOM-poor (SOM ≤ 10 g kg(-1)) soils present in southern China. It is thus necessary to address the effect of environmental variables to generate a suitable Cd threshold for cultivated soils.
Copper (Cu) and zinc (Zn) isotope ratios can be used to fingerprint sources and dispersion pathways of pollutants in the environment. Little is known, however, about the potential of δ(65)Cu and δ(66)Zn values in liquid and solid forms of atmospheric deposition to distinguish between geogenic, industrial, local and remote sources of these potentially toxic base metals. Here we present Cu-Zn deposition fluxes at 10 mountain-top sites in the Czech Republic, a region affected by extremely high industrial emission rates 25 years ago. Additionally, we monitored isotope composition of Cu and Zn in vertical and horizontal atmospheric deposition at two sites. We compared δ(65)Cu and δ(66)Zn values in snow and rime, extracted by diluted HNO3 and concentrated HF. Cu and Zn isotope signatures of industrial pollution sources were also determined. Cu and Zn deposition fluxes at all study sites were minute. The mean δ(65)Cu value of atmospheric deposition (-0.07‰) was higher than the mean δ(65)Cu value of pollution sources (-1.17‰). The variability in δ(65)Cu values of atmospheric deposition was lower, compared to the pollution sources. The mean δ(66)Zn value of atmospheric deposition (-0.09‰) was slightly higher than the mean δ(66)Zn value of pollution sources (-0.23‰). The variability in δ(66)Zn values of atmospheric deposition was indistinguishable from that of pollution sources. The largest isotope differences (0.35‰) were observed between the insoluble and soluble fractions of atmospheric deposition. These differences may result from different sources of Cu/Zn for each fraction. The difference in isotope composition of soluble and insoluble particles appears to be a promising tool for pollution provenance studies in Central Europe.
Zinc oxide (ZnO) nanoparticles (NPs) exhibit antibacterial activity against both Gram-positive and Gram-negative bacteria. However, the antimicrobial mechanism of ZnO NPs remains unclear. In this study, we investigated the interactions among ZnO NPs, released chemicals (Zn(2+) and Reactive Oxygen Species, ROS) and Escherichia coli (E. coli) cells. ZnO NPs without contacting with bacterial cells showed strong antibacterial effect. The results of the leakage of intracellular K(+) and integrity of carboxyfluoresce in-filled liposomes showed that ZnO NPs have antimicrobial activity against E. coli by non-specifically disrupting E. coli membranes. Traces of zinc ions (1.25mg/L) and hydrogen peroxide (from 1.25 to 4.5μM/L) were detected in ZnO NPs suspensions, but was insufficient to cause the antibacterial effect. However, the addition of radical scavengers suppressed the bactericidal effect of ZnO coated films against E. coli, potentially implicating ROS generation, especially hydroxyl radicals, in the antibacterial ability of ZnO NPs.
Carbon-based photoluminescent nanodot has currently been one of the promising materials for various applications. The remaining challenges are the carbon sources and the simple synthetic processes that enhance the quantum yield, photostability and biocompatibility of the nanodots. In this work, the synthesis of blue photoluminescent carbon nanodots from limeade via a single-step hydrothermal carbonization process is presented. Lime carbon nanodot (L-CnD), whose the quantum yield exceeding 50% for the 490nm emission in gram-scale amounts, has the structure of graphene core functionalized with the oxygen functional groups. The micron-sized flake of the as-prepared L-CnD powder exhibits multicolor emission depending on an excitation wavelength. The L-CnDs are demonstrated for rapidly ferric-ion (Fe(3+)) detection in water compared to Fe(2+), Cu(2+), Co(2+), Zn(2+), Mn(2+) and Ni(2+) ions. The photoluminescence quenching of L-CnD solution under UV light is used to distinguish the Fe(3+) ions from others by naked eyes as low concentration as 100μM. Additionally, L-CnDs provide exceptional photostability and biocompatibility for imaging yeast cell morphology. Changes in morphology of living yeast cells, i.e. cell shape variation, and budding, can be observed in a minute-period until more than an hour without the photoluminescent intensity loss.
Magnesium (Mg)-based alloys have been extensively considered as biodegradable implant materials for orthopedic surgery. Mg and its alloys are metallic biomaterials that can degrade in the body and promote new bone formation. In this study, the corrosion behavior and cytotoxicity of Mg-Zn-Ca alloys are evaluated with adipose-derived mesenchymal stem cells (ASCs). Mg-2Zn and Mg-2Zn-xCa (x=1, 2 and 3wt.%) alloys were designated. Mg alloys were analyzed with scanning electron microscopy and potentiodynamic polarization. To understand the in-vitro biocompatibility and cytotoxicity of Mg-2Zn and Mg-2Zn-xCa alloys, ASCs were cultured for 24 and 72h in contact with 10%, 50% and 100% extraction of all alloys prepared in DMEM. Cell cytotoxicity and viability of ASCs were examined by MTT assay. Alloying elements including Zn and Ca improved the corrosion resistance of alloys were compared with pure Mg. The cytotoxicity results showed that all alloys had no significant adverse effects on cell viability in 24h. After 72h, cell viability and proliferation increased in the cells
 exposed to pure Mg and Mg-2Zn-1Ca extracts. The release of Mg, Zn and Ca ions in culture media had no toxic impacts on ASCs viability and proliferation. Mg-2Zn-1Ca alloy can be suggested as a good candidate to be used in biomedical applications.
In this study, a highly sensitive and selective fluorescent Zn(2+) probe which exhibited excellent biocompatibility, water solubility, and cell-membrane permeability, was facilely synthesized in a single step by grafting polyethyleneimine (PEI) with quinoline derivatives. The primary amino groups in the branched PEI can increase water solubility and cell permeability of the probe PEIQ, while quinoline derivatives can specifically recognize Zn(2+) and reduce the potential cytotoxicity of PEI. Basing on fluorescence off-on mechanism, PEIQ demonstrated excellent sensing capability towards Zn(2+) in absolute aqueous solution, where a high sensitivity with a detection limit as low as 38.1nM, and a high selectivity over competing metal ions and potential interfering amino acids, were achieved. Inspired by these results, elementary logic operations (YES, NOT and INHIBIT) have been constructed by employing PEIQ as the gate while Zn(2+) and EDTA as chemical inputs. Together with the low cytotoxicity and good cell-permeability, the practical application of PEIQ in living cell imaging was satisfactorily demonstrated, emphasizing its wide application in fundamental biology research.
Zn-based alloys have been viewed as new potential materials for biodegradable implants, such as cardiovascular stents, mainly in consideration of their lower corrosion rate when compared with that of Mg alloys. In this study we developed a new Zinc-4wt.%Copper (Zn-4Cu) alloy as a biodegradable material. Hot extrusion was applied to Zn-4Cu to refine the microstructure and consequently improve its mechanical properties and corrosion resistance. After extrusion, dendritic CuZn5 phases were broken and distributed along the extrusion direction. The grains were refined obviously due to dynamical recrystallization. The yield strength (YS), ultimate tensile strength (UTS) and elongation of the as-extruded alloy are 250±10MPa, 270±10MPa and 51±2%, respectively. The corrosion rate of the as-extruded alloy in Hank's solution is about 9.41(±1.34)μmyear(-1). In vitro evaluation shows that Zn-4Cu presents acceptable toxicity to human endothelial cells, and could effectively inhibit bacteria adhesion and biofilm formation. The present study indicates that the as-extruded Zn-4Cu alloy exhibits excellent strength and ductility, uniform and slow degradation, good biocompatibility and significant antibacterial effect, which make it an excellent candidate material for biodegradable implants, especially for cardiovascular stents application.
This study was carried out to determine the effect of zinc on oxidative DNA damage in rats with experimental acute and chronic kidney deficiency. Six groups of five Wistar-Albino rats each were assigned as controls (C), acute kidney deficiency (AKD), zinc-supplemented (+Zn), acute kidney deficiency, zinc-supplemented (AKD + Zn), chronic kidney deficiency (CKD) and zinc-supplemented chronic kidney deficiency (CKD + Zn). The levels of 8-Oxo-2'-deoxyguanosine (8-OHdG) were determined, being the lowest in the CKD group (p < 0.05), higher in the C group than those of rats with CKD but lower than that of all the other groups (p < 0.05). There were no significant differences between the controls and the CKD + Zn group, or between the AKD and the +Zn groups. Among all groups, the highest 8-OHdG level was found in the AKD + Zn group (p < 0.05). DNA damage was greater in acute renal failure than in rats with chronic renal failure. The DNA damage in the zinc group was significantly higher than in the controls.
Heavy metals pose a potential danger to human health when present in textile materials. In the present study, inductive coupled plasma mass spectrometry (ICPMS) was used to determine the concentrations and the identity of extractable inorganic elements from different brands of women undergarments. A total of 120 samples consisting of 63 cottons, 44 nylons and 13 polyesters manufactured in 14 different countries having different colors were analyzed for their extractable metals contents. Elements analyzed were Ag, Al, As, Ba, Be, Bi, Ca, Cd, Co, Cr, Cu, Fe, Hg, K, Li, Mg, Mn, Na, Ni, Pb, Sb, Se, Sr, Ti, V and Zn. Cotton undergarments were rich in Al, Fe and Zn, nylon undergarments had high levels of Cr, Cu and Al, while polyester fabrics contained higher levels of Ni and Fe compared to cotton or nylon. With respect to manufacturing countries, China, Egypt and India showed the highest concentrations of metals in all fabrics. With respect to the color, black garments were characteristic by high concentration of Fe, blue colors with Cu, brown garments with Fe and Cu, green garments with Cu and Fe, pink garments with Al, purple garments with Al and Cu and red garments with Cr, Zn and Al. The consumer should be made aware of the potential dangers of these metals in their clothing.
Lung cancer is one of the most common human malignancies worldwide, but its oncogenesis process remains unclear. Recent studies demonstrated that zinc (Zn) and Zn transporters were associated with the development and progression of human cancers. The role of Zn transporters including ZIPs and ZnTs in lung cancer, however, has never been evaluated. Thus, we aimed to investigate the expression levels of all human Zn transporters, including 14 ZIPs and 10 ZnTs, in eight different lung cancer cell lines and paired human tumor tissues. We observed great variations in ZIPs and ZnTs mRNA levels across cell lines and human lung cancer specimens. ZIPs showed a tendency to be upregulated, while ZnTs exhibited a downward expression trend. ZIP4 was overexpressed in six lung cancer cell lines and 59% (26/44) of tumor tissues, which was consistent with results from lung cancer datasets including TCGA database. Our results indicated that the dysregulation of Zn transporters may contribute to lung tumorigenesis.
In the present study, the coordination bonds between the Methionine-Lysine-Histidine (Ac-MKH-NHMe) tripeptide model associated with the fifth metal binding site, which triggers the β-sheet formation of human prion protein and the divalent metal cations such as Mn(2+), Cu(2+) and Zn(2+) were studied using B3LYP and M052X levels of theory with LANL2DZ basis set. For each transition divalent metal cation, three different coordination modes (4N, 3NO, and 2NSO) were analyzed. The present result reveals that overall structural parameters of MKH model tripeptide are altered due to the interaction of divalent metal cations. Among these three coordination modes, the 4N-M(2)(+) and 4N2O-Mn(2+) complexes are found to have the larger interaction energy, MIA and deformation energies. The triply deprotonated coordination mode of the Ac-MKH-NHMe tripeptide transfers more amount of charge to the divalent metal cations than the dually and singly deprotonated complexes. Furthermore, the atoms in molecules (AIM) topological analysis confirm that, the interaction between the metal cations Mn(2+), Cu(2+) and Zn(2+) and Ac-MKH-NHMe tripeptide are electrostatic dominant and the coordination modes with triply deprotonation states possess larger electron density at their BCP corresponding to their coordination bonds. The electrostatic potential difference maps of the most stable 4N-M(2+) (M(2+)=Cu(2+) and Zn(2+)) and 4N2O-Mn(2+) reveals that, as the ionic radii of the metal ion increases, the delocalization charges localized on the metal cations are found to be decreased. The Infra-red stretching frequencies of NH, CH, and CH2 groups of each coordination complexes are observed with shift in their stretching frequencies. From these observations we conclude that, the transition divalent metal cations binding in 4N coordination mode will induce more conformational changes of the Prion protein.
Three kinds of sulfonated cross-linked chitosan (SCCR) immobilized with metal ions of Cu(2+), Fe(3+) and Zn(2+) individually were synthesized and firstly used as solid acid catalysts in the hydrolysis of bamboo biomass. FTIR spectra showed that metal ions had been introduced into SCCR and the N-metal ions coordinate bound was formed. The particle sizes of these catalysts were about 500-1000μm with a pore size of 50-160μm. All of the three kinds of catalysts performed well for bamboo hydrolysis with 1-butyl-3-methyl-imidazolium chloride used as solvent. The most effective one was sulfonated cross-linked chitosan immobilized with Fe(3+) (Fe(3+)-SCCR). TRS yields were up to 73.42% for hydrolysis of bamboo powder in [C4mim]Cl with Fe(3+)-SCCR at 120°C and 20RPM after 24h. These novel chitosan-based metal ions immobilized solid acid catalysts with ionic liquids as the solvent might be promising to facilitate cost-efficient conversion of biomass into biofuels and bioproducts.
A detailed study of the structural, surface, and gas-sensing properties of nanostructured CoxZn1-xO films is presented. X-ray diffraction (XRD) analysis revealed a decrease in the crystallization degree with increasing Co content. The X-ray absorption near-edge structure (XANES) and X-ray photoelectron spectroscopies (XPS) revealed that the Co(2+) ions preferentially occupied the Zn(2+) sites and that the oxygen vacancy concentration increased as the amount of cobalt increased. Electrical measurements showed that the Co dopants not only enhanced the sensor response at low ozone levels (ca. 42 ppb) but also led to a decrease in the operating temperature and improved selectivity. The enhancement in the gas-sensing properties was attributed to the presence of oxygen vacancies, which facilitated ozone adsorption.
Three moss (Pleurozium spp., Polytrichum spp., and Rhytidiadelphus spp.) and two lichen (Hypogymnia
 physodes and Pseudevernia furfuracea) taxons covered in the bags were used to monitor air quality. Bags were exposed at the different distances from the tailing pond because of insufficient security and source of heavy metal pollution. Moss/lichen bags were exposed for six weeks at 0-, 50-, 100-, 150- and 200-m distances from Slovinky tailing pond, in the main wind direction (down the valley). Accumulation ability of heavy metals expressed by relative accumulation factor (RAF) increases in the order of Polytrichum spp.<H. physodes <Pleurozium spp.<P. furfuracea <Rhytidiadelphus spp. Moss/lichen species showed different accumulation capacity for individual heavy metals. Rhytidiadelphus spp. was found to possess the significantly highest (P < 0.01) ability to accumulate Cd, Zn, Ni, Mn and Fe. The highest RAF values of Pb, Zn, Ni and Fe were determined in samples exposed at 200-m distance from pollution source.
Metallomacromolecular architectural conversion is expanded by the characterization of three different structures. A quantitative, single-step, self-assembly of a shape-persistent monomer, containing a flexible crown ether moiety, gives an initial Archimedean-based cuboctahedron that has been unequivocally characterized by 1D and 2D NMR spectroscopy, mass spectrometry, and collision cross section analysis. Both dilution and exchange of counterions, transforms this cuboctahedron into two identical octahedrons, which upon further dilution convert into four, superposed, bistrianglar complexes; increasing the concentration reverses the process. Ion binding studies using the cuboctahedral cage were undertaken.
A major cause of groundwater pollution in urban areas is contamination by leachates emanating from municipal solid waste dumpsites. The study evaluated the quality of water of selected boreholes and wells around Olusosun open solid waste dumpsite in Lagos metropolis, using water quality index (WQI) rating and geospatial techniques. Water samples were randomly collected from fifteen boreholes and five wells downslopes of the dumpsite. The samples were analysed for the physico-chemical parameters and heavy metals. Factor Analysis was employed to analyse the information content of the water quality indicators to determine their appropriateness for indexing. The spatial distribution of the WQIs determined using Inverse Distance Weighting (IDW) interpolation procedure. Results showed that the waters were generally acidic with 85% of pH values below the range suggested by WHO for drinking water. All samples contained concentration of dissolved oxygen (DO) in quantities higher than the recommended limit of 2.0 mg/l (average = 4.97 mg/l), while 40% of the samples contained concentration of K above the recommended limit. The concentration of heavy metals was generally low. The major cations (Mg, Na, and K) were highly positively correlated, and were positively correlated with pH, TA, TAL, TH and Cl. Negative correlations were observed between TDS, NO3(-) and PO4(3-); NO3(-) and Ag; and DO with the heavy metals. Eighteen parameters consisting of pH, EC, TDS, TA, TAL, TH, Cl, NO3(-), PO4(3-), Mg, Na, K, Zn, Mn, Fe, Cd, Ag and Pb were found to be the main indicators of groundwater pollution caused by landfill leachate percolation. Evaluation of the WQIs indicated that 35% of the water samples were unsuitable for consumption, while 15%, 15% and 35% were in the good, very good and excellent categorises, respectively. The degree of suitability of the borehole and well waters was closely related to proximity to the dumpsite. It is imperative that appropriate remediation strategies are adopted to forestall further contamination of the groundwater by leachates in the area.
Several mechanisms for the pathogenesis of diabetic complications have been proposed, one of which is abnormal zinc (Zn) homeostasis. Zn is necessary for proper liver function since it has important antioxidant, anti-inflammatory, and antiapoptotic properties. We aimed to investigate whether or not Zn has morphologically protective effect on diabetes-induced liver damage in rats. In addition, we have investigated the role of Zn supplementation on apoptosis, lipid peroxidation levels, and the distribution of metallothionein (MT) in diabetic liver tissue. Wistar albino rats were divided into four groups: control, Zn, diabetic, and Zn-diabetic group. Experimental diabetes was induced by a single-dose streptozotocin intraperitoneally and Zn was administrated via gastric gavage tube for 6 weeks. MT expressions were showed with immunohistochemical staining and terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling assay was used for apoptosis. Also, Zn, MT, and malondialdehyde (MDA) levels were determined in liver of rats. MDA levels of the Zn-supplemented diabetic group was less than the diabetic group though MT levels were increased. The number of apoptotic cells per unit area was found to be significantly decreased in this group. In the Zn-supplemented diabetic group, fibrotic tissue density and the collagen tissue density were observed less than the diabetic group. MT immunoreactivity was observed less in Zn-supplemented diabetic group. In conculusion, the present study indicated that Zn has a potential in preventing or even repairing effect against diabetic damage of the liver cells by increasing expression of MT and by reducing the apoptotic cell death and the oxidative stress.
Characterizing labile metal distribution and biogeochemical behavior in sediments is crucial for understanding their contamination characteristics in lakes, for which in situ, high-resolution data is scare. The diffusive gradient in thin films (DGT) technique was used in-situ at five sites across Lake Taihu in the Yangtze River delta in China to characterize the distribution and mobility of eight labile metals (Fe, Mn, Zn, Ni, Cu, Pb, Co and Cd) in sediments at a 3 mm spatial resolution. The results showed a great spatial heterogeneity in the distributions of redox-sensitive labile Fe, Mn and Co in sediments, while other metals had much less marked structure, except for downward decreases of labile Pb, Ni, Zn and Cu in the surface sediment layers. Similar distributions were found between labile Mn and Co and among labile Ni, Cu and Zn, reflecting a close link between their geochemical behaviors. The relative mobility, defined as the ratio of metals accumulated by DGT to the total contents in a volume of sediments with a thickness of 10 mm close to the surface of DGT probe, was the greatest for Mn and Cd, followed by Zn, Ni, Cu and Co, while Pb and Fe had the lowest mobility; this order generally agreed with that defined by the modified BCR approach. Further analyses showed that the downward increases of pH values in surface sediment layer may decrease the lability of Pb, Ni, Zn and Cu as detected by DGT, while the remobilization of redox-insensitive metals in deep sediment layer may relate to Mn cycling through sulphide coprecipitation, reflected by several corresponding minima between these metals and Mn. These in situ data provided the possibility for a deep insight into the mechanisms involved in the remobilization of metals in freshwater sediments.
The goal of this study was to assess stable isotopes profiles, metals concentration and PCBs in Raja clavata muscle and liver, according to sex and size, and to elucidate its suitability as a Mid-Atlantic biomonitor. The results reflected bioaccumulation and suggested biomagnification processes for As and Hg in muscle tissue. Cd, Cu and Zn were detected in high amounts in liver, Cr, Mn and Rb were relatively stable and low, Pb was not detected and Sr was present in muscle at high levels, decreasing with length. Hg and Se were strongly correlated, suggesting a mitigation role. Both tissues presented low concentrations of PCBs, especially the dioxin-like congeners, although always higher in liver and not correlated with size. None of these contaminants exceed EU legislated limits. However, they need to be monitored given study area's location, volcanic nature and the expected increase of anthropogenic activity related to future prospective mining activities and the establishment of the Transatlantic Trade and Investment Partnership (TTIP) between Europe and the USA.
This multi-site study discusses the content of metals and metalloids (MM) in scalp hair of children, living in different environmental contexts, with the purpose of verifying if hair level of some MM is distinctively gender-specific. A total of 943 hair samples (537 females and 406 males) from adolescents were analyzed for their content of Al, As, Ba, Cd, Co, Cr, Cu, Li, Mn, Mo, Ni, Pb, Rb, Sb, Se, Sr, U, V and Zn. Elemental quantification was performed by ICP-MS. The obtained data identified different metal distributions in adolescent girls which exhibited significantly higher hair concentrations of some trace metals, especially Sr, Zn and Ni, than boys. On the base of the median value, hair of female donors contained 3.8 times more Sr (6.6μg/g) than males (1.7μg/g). Highest concentrations of Zn in females were observed in samples from the mining area of Sardinia (587μg/g). Nickel showed significant differences resulting 2.5-fold higher in female hair. Regardless of the residence site, these elements resulted always significantly different (at p<0.01) between female and male indicating that gender is a confounding factor that has to be more extensively considered for a correct interpretation of metal profiles in human hair.
The homofullerene compound cis-2-C60 (CF2 )2 , which has an unusual kind of open/closed valence tautomerism undergoes consecutive regioselective hydrogenation at bridgehead carbon atoms upon reduction with Zn/Cu couple in H2 O-toluene mixture. The tautomerism barrier in cis-2-C60 (CF2 )2 is negligible in the neutral state, whereas negative
 charging both impedes tautomeric transformation and promotes regioselective addition of electrophilic species at the bridgehead carbon atoms. In light of this observation, two novel homofullerene derivatives, mixed [6,6]-open/closed C60 (CF2 )2 H2 and [6,6]-open cis-2-C60 (CF2 )2 H4 , were synthesized and their structures were unambiguously determined by means of single crystal X-ray crystallography and NMR spectroscopy.
Advancing the use of therapeutic nucleic acids requires understanding the chemical and structural properties that allow these polymers to promote the death of malignant cells. Here we explore Zn(2+) complexation by the fluoropyrimidine polymer F10, which has strong activities in multiple preclinical models of cancer. Delivery of fluoropyrimidine FdUMP in the 10-residue polymer F10 rather than the nucleobase (5-fluorouracil) allows consideration of metal ion binding effects on drug delivery. The differences in metal ion interactions with fluoropyrimidine compared to normal DNA results in conformation changes that affect protein binding, cell uptake, and codelivery of metals such as zinc, and the cytoxicity thereof. Microsecond-time-scale, all-atom simulations of F10 predict that zinc selectively stabilizes the polymer via interactions with backbone phosphate groups and suggest a mechanism of complexation for the zinc-base interactions shown in previous experimental work. The positive zinc ions are attracted to the negatively charged phosphate groups. Once the Zn(2+) ions are near F10, they cause the base's N3 nitrogen to deprotonate. Subsequently, magnesium atoms displace zinc from their interactions with phosphate, freeing the zinc ions to interact with the FdU bases by forming weak interactions with the O4 oxygen and the fluorine attached to C5. These interactions of magnesium with phosphate groups and zinc with nucleobases agree with previous experimental results and are seen in MD simulations only when magnesium is introduced after N3 deprotonation, indicating a specific order of metal binding events. Additionally, we predict interactions between zinc and F10's O2 atoms, which were not previously observed. By comparison to 10mers of polyU and polydT, we also predict that the presence of fluorine increases the binding affinity of zinc to F10 relative to analogous strands of RNA and DNA consisting of only native nucleotides.
Fruit production (NPPf ), the amount of photosynthates allocated to reproduction (%GPPf ) and their controls for spatial and species-specific variability (e.g. nutrient availability, climate) have been poorly studied in forest ecosystems. We characterized fruit production and its temporal behaviour for several tree species and resolved the effects of gross primary production (GPP), climate and foliar nutrient concentrations. We used data for litterfall and foliar nutrient concentration from 126 European forests and related them to climatic data. GPP was estimated for each forest using a regression model. Mean NPPf ranged from c. 10 to 40 g C m(-2)  yr(-1) and accounted for 0.5-3% of GPP. Forests with higher GPPs produced larger fruit crops. Foliar zinc (Zn) and phosphorus (P) concentrations were associated positively with NPPf , whereas foliar Zn and potassium (K) were negatively related to its temporal variability. Maximum NPPf and interannual variability of NPPf were higher in Fagaceae than in Pinaceae species. NPPf and %GPPf were similar amongst the studied species despite the different reproductive temporal behaviour of Fagaceae and Pinaceae species. We report that foliar concentrations of P and Zn are associated with %GPPf , NPPf and its temporal behaviour.
An aqueous one-pot self-templating synthesis method to prepare highly uniform ZIF-67 hollow spheres (ZIF-67-HS) and their transition metal-doped derivatives (M/ZIF-67-HS, M = Cu and/or Zn) was developed. Extension of this approach to another important class of MOFs (metal carboxylates; e.g., HKUST-1) and facile design of derived nanostructures with complex architectures were also achieved.
Vermicomposting (VC) has proven to be a promising method for treating garden, household, and municipal wastes. Although the VC has been used extensively for converting wastes into fertilizers, pathogens such as Escherichia coli (E. coli) survival during this process is not well documented. In this study, both lab and field scale experiments were conducted assessing the impacts of earthworms in reducing E. coli concentration during VC of food waste. In addition, other pertinent parameters such as temperature, carbon and nitrogen content, moisture content, pH, volatile solids, micronutrients (P, K, Ca, Mg, and S), and heavy metals (Zn, Mn, Fe, and Cu) were monitored during the study. The lab and field scale experiments were conducted for 107 and 103 days, respectively. The carbon to nitrogen ratio (C/N) decreased by 54 % in the lab scale study and by 36 % in the field study. Results showed that VC was not significantly effective in reducing E. coli levels in food waste under both lab and field scale settings. The carbon to nitrogen ratio (C/N) decreased by 54 % in the lab scale study and by 36 % in the field study.
The C3-symmetric cyclotriveratrylene (CTV) was covalently bonded via click chemistry to 1, 2, 3, and 6 zinc(II) porphyrin units to various host for C60. The binding constants, Ka, were measured from the quenching of the porphyrin fluorescence by C60. These constants vary between 400 and 4000 M(-1) and are considered weak. Computer modeling demonstrated that the zinc(II) porphyrin units, [Zn], exhibit a strong tendency to occupy the CTV cavity, hence blocking the access for C60 to land on this site. Instead, the pincer of the type [Zn]----[Zn] and in one case [Zn]----CTV, were found to be the most probable geometry to promote host-guest associations in these systems.
We describe the characterization of the centesimal composition, mineral and phenolic content of Eugenia uniflora fruit and the determination of the antioxidant, antimicrobial and quorum quenching activities of the pulp phenolic extract. Centesimal composition was determined according to standard methods; trace elements were measured by total reflection X-ray fluorescence spectroscopy. The phenolic compounds were extracted by solid-phase chromatography and quantified by spectrophotometry. Antioxidant activity was determined by using 3 different methods. Antimicrobial activity was evaluated against a panel of foodborne microorganisms and antiquorum sensing activity in Chromobacterium violaceum was performed by measuring inhibition of quorum sensing dependent violacein production. The centesimal composition (per 100 g of pulp) was as follows: protein 3.68 ± 0.21 g, lipids 0.02 ± 0.03 g, carbohydrates 10.31 g and fiber 2.06 g. Trace elements (mg/g of pulp) were determined as: K 0.90, Ca 3.36, Fe 0.60, Zn 0.17, Cl 0.56, Cr 0.06, Ni 0.04, and Cu 0.07. The pulp is a source of phenolic compounds and presents antioxidant activity similar to other berries. The fruit phenolic extract inhibited all tested bacteria. We also found that the fruit phenolic extract at low subinhibitory concentrations inhibited up to 96% of violacein production in C. violaceum, likely due to the fruit's phenolic content. This study shows the contribution of E. uniflora phenolic compounds to the antioxidant, antimicrobial and the newly discovered quorum quenching activity, all of which could be used by the food and pharmaceutical industries to develop new functional products.
Reproducible synthesis of the elusive merlinoite (mer) topology of zinc imidazolate (mer-Zn(Im)2, or ZIF-10) has been achieved by employing a simple macrocyclic solute-MeMeCH2-as a kinetic template. The corresponding phase-pure material, mer-MeMeCH2@Zn16(Im)32, is confirmed to be porous and exhibits one of the highest experimental surface areas (1893 m(2)/g, BET) yet reported for any ZIF. The X-ray single crystal structure of mer-MeMeCH2@Zn16(Im)32·xsolvent reveals the role of the macrocyle as an 8-fold hydrogen bond acceptor in templating the requisite double-eight rings (d8r) of the mer framework.
The aim of the study was to evaluate the efficacy of the multiflora rose var. 'Jatar' (Rosa multiflora Thunb. ex Mur) and the Virginia fanpetals (Sida hermaphrodita Rusby) to phytoextract heavy metals from municipal sewage sludge. The 6-year field experiment involved four levels of fertilization with sewage sludge at doses of 0, 10, 20, 40, and 60 Mg DM sludge · ha(-1). The increasing doses of sewage sludge were found to increase significantly the yield of multiflora rose and Virginia fanpetals biomass. They also significantly elevated the content of heavy metals in these plants. The highest uptake of heavy metals by the multiflora rose and Virginia fanpetals crops was recorded at the fertilisation dose of 60 Mg DM · ha(-1). Our investigations show that the Virginia fanpetals was more efficient in phytoextraction of Cr, Ni, Cu, Zn, and Cd from the sewage sludge than the multiflora rose, due to the greater yields and higher heavy metal uptake by the former plant. In turn, the multiflora rose phytoextracted greater amounts of Pb from the sewage sludge. The analyses indicate that the Virginia fanpetals can be used for phytoremediation (phytoextraction) of heavy metals contained in sewage sludge.
We have assessed the potential of salophen, a tetradentate Schiff base, in fluorescence sensing of Al(3+) ions. While performing this investigation, we have noticed conflicting literature reports on the fluorescence spectral maximum and quantum yield of salophen. So, the compound has been purified by repeated crystallization. Fluorescence studies have been performed on samples in which the absorption and excitation spectra are completely superimposable. The purified compound exhibits a feeble fluorescence at 545 nm, associated with an ultrafast
 fluorescence decay. This is rationalized by excited state proton transfer and torsional motions within the molecule, which provide efficient nonradiative channels of deactivation of its excited state. The fluorescence quantum yield increases upon complexation of salophen with Zn(2+) as well as Al(3+). The increase is significantly more upon complexation with Al(3+). However, fluorescence maxima are similar for the two complexes. This indicates that fluorescence intensity may not be a good parameter for Al(3+) sensing by salophen, in the presence of a large excess of Zn(2+). This problem can be circumvented if fluorescence lifetime is used as the sensing parameter, as the lifetime of the Al(3+) complex is in the nanosecond time regime while that of the Zn(2+) complex is in tens of picoseconds. The significant difference in the fluorescence quantum yield and lifetime between the two complexes is explained as follows: the Al(3+) complex is monomeric, but the Zn(2+) complex is dimeric. Quantum chemical calculations indicate a higher density of states near the locally excited state for the dimeric complex. This may lead to more efficient nonradiative pathways.
Elemental metals have been widely used to alloy metallic orthopedic implants. However, there is still insufficient research data elucidating the cell responses of osteoblastic cells to alloying elemental metals, which impedes the development of new metallic implant materials. In this study, the cellular responses of osteoblast-like cells (SaOS2) to 17 pure alloying elemental metals, that is, titanium (Ti), zirconium (Zr), hafnium (Hf), vanadium (V), niobium (Nb), tantalum (Ta), chromium (Cr), molybdenum (Mo), manganese (Mn), iron (Fe), ruthenium (Ru), cobalt (Co), nickel (Ni), copper (Cu), zinc (Zn), silicon (Si), and tin (Sn) were comparatively investigated in vitro. Cellular responses including intracellular total protein synthesis and collagen content, cell adhesion, cell proliferation, and alkaline phosphatase (ALP) activity on these elemental metals were systematically assessed and compared. It was found that these elemental metals could be categorized into three groups based on the cellular functions on them. Group 1, including Ti, Zr, Hf, Nb, Ta, Cr, Ru, and Si, showed excellent cell proliferation and varied ALP activity for SaOS2 cells. Cells exposed to Group 2, including Mo and Sn, although initially attached and grew, did not proliferate over time. In contrast, Group 3, including V, Mn, Fe, Co, Ni, Cu, and Zn, showed severe cytotoxicity toward SaOS2 cells. It is vital to consider the cell responses to the elemental metals when designing a new metallic implant material and the findings of this study provide insights into the biological performance of the elemental metals. © 2016 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 105A: 148-158, 2017.
The effects of cadmium (Cd) were evaluated in offspring exposed from birth until weaning (neonatal day 0-21) and 4 weeks after exposure cessation focusing on iron (Fe) and zinc (Zn) levels in organs and hematological parameters. Wistar female rats were administered 50mg Cd/L in drinking water (Cd-exposed) for 4 weeks before mating and during 3 weeks of gestation plus 3 weeks of lactation. Controls were supplied drinking water. At birth, part of Cd-exposed dams' litters was cross-fostered to control dams (CCd group) and their control litters were cross-fostered to Cd-exposed dams (CdC group). This procedure enabled to discern the effects of gestational, lactational and gestational plus lactational Cd exposure until weaning in F1 offspring. Elements were analyzed by atomic absorption spectrometry; hematological parameters manually; and histopathological changes by light microscopy. Gestational plus lactational exposure in Cd-exposed dams and their offspring increased Cd and decreased Fe levels, increased Zn in dams and decreased Zn and body weights in 11- and 21-day pups. In 21-day weanling pups, decreased red blood cell (RBC) count, hemoglobin and hematocrit values and increased reticulocytes in peripheral blood were also found with concomitant histopathological finding of extramedullary hematopoiesis in the liver. In cross-fostered pups with gestational exposure (CCd pups), Fe in the liver decreased on day 11 and Zn increased in the kidney on day 21 whereas in pups with lactational exposure (CdC pups) Zn in the brain decreased on day 11 and Fe decreased in the liver and brain on day 21. Regardless of exposure cessation at weaning, in offspring with gestational plus lactational exposure (Cd-exposed) body weights, kidney and brain Fe levels and RBC and hemoglobin remained decreased in blood until puberty. Furthermore Zn levels increased in the liver, kidney and brain. It was concluded that gestational plus lactational Cd exposure caused decreases in Fe and Zn levels and hematotoxic effects in F1 offspring more pronouncedly than exposure during either gestational or lactational period alone and the adverse effects of maternally mediated Cd exposure continued after exposure cessation into adulthood.
Acne vulgaris is a very common skin disorder affecting human beings. There is a paucity of report on the role of heavy metals-lead (Pb) and cadmium (Cd)-globally, and trace metals-zinc (Zn) and copper (Cd)-particularly in Nigeria in the development/severity of acne vulgaris. This study is aimed to determine the blood levels of some heavy metals-cadmium and lead-and trace metals-zinc and copper-in acne vulgaris sufferers in a Nigerian population. Venous blood samples were collected from a total number of 90 non-obese female subjects consisting of 30 mild, 30 moderate and 30 severe acne vulgaris sufferers for blood Cd, Pb, Cu and Zn determination. They were age-matched with 60 females without acne vulgaris who served as the control subjects. Acne sufferers had significantly higher blood Cd and Pb (P = 0.0143 and P = 0.0001 respectively) and non-significantly different blood levels of Cu and Zn (P = 0.910 and P = 0.2140 respectively) compared to controls. There were significant progressive increases in blood levels of Cd and Pb (P = 0.0330 and P = 0.0001 respectively) and non-significant differences in the mean blood level of Cu and Zn (P = 0.1821 and P = 0.2728 respectively) from mild to moderate and severe acne vulgaris sufferers. Increases in blood Cd and Pb may play critical roles in the pathogenesis/severity of acne vulgaris, while Cu and Zn seem to play less significant roles in the development of this disorder in this environment.
The contents of Cu, Pb, Zn, Cd, Cr, Hg and As in the surface sediments of over 668 sites were monitored in a comprehensive program for assessing the degree of heavy-metal pollution and adverse biological effects of the offshore sediments in China. The contamination factor and geoaccumulation index indicated that As and Pb might be two of the most influential pollution loading in these metals. Cluster analysis separated 19 areas in China's near seas into 7 groups with different pollution characteristic, where the sediments along Zhejiang coast were the most highly-contaminated. Based on biological adverse effects index and sediment quality guideline for As, nearly half of sites in China's near seas induced slight adverse biological effects. With correlation analysis, self-organizing map and factor analysis, different sources as well as various adsorption mechanisms/anthropogenic factors were suggested to be important roles in altering the concentration of heavy metals in the sediments.
We report growth of quaternary Cu2 ZnSnS4 (CZTS) thin films prepared by the electrochemical deposition from salt precursors containing Cu (II), Zn (II) and Sn (IV) metals. The influence of different sulfurization times t (t = 75, 90, 105, and 120 min) on the structural, compositional, morphological, and optical properties, as well as on the electrical properties is studied. The films sulfurized 2 hours showed a prominent kesterite phase with a nearly stoichiometric composition. Samples were characterized by X-ray diffraction (XRD), field-emission scanning electron microscopy (FESEM), and Raman and UV-VIS-NIR spectrometer at different stages of work. X-ray diffraction and Raman spectroscopy analyses confirmed the formation of phase-pure CZTS films. (FESEM) shows that compact and dense morphology and enhanced photo-sensitivity. STEM - EDS elemental map of CZTS cross-section confirms homogeneous distribution. From optical study, energy gap was enlarged with a changed sulfurization times in the range of 1.37-1.47 eV.
Unsweetened natural cocoa has antimalarial properties. Unsweetened natural cocoa powder (UNCP), obtained as a result of the removal of cocoa butter from a cocoa bean protects against malaria episodes. Cocoa powder, which is prepared after removal of the cocoa butter, contains about 1.9 % theobromine and 0.21 % caffeine. Concomitant consumption of cocoa and artemether/lumefantrine (A/L) is a common practice in Ghana, West Africa. This study seeks to determine the elemental composition of UNCP and its protective effect on the heart and kidney against (A/L) administration.
Energy dispersive x-ray fluorescence spectroscopy was used to detect the quality and quantity of the elemental composition in UNCP. Thereafter, 30 nonmalarious male guinea pigs were divided into five groups of six animals each. One group was administered with 75 mg/kg body weight A/L only and another group distilled water (control group). The rest received 300 mg/kg, 900 mg/kg and 1500 mg/kg body weight UNCP for 14 days orally and A/L for the last 3 days (ie day 11 to day 14). Biochemical and histopathological examinations were carried out after euthanisation of the animals.
A total of thirty-eight (38) micro and macro elements were detected with the ED-XRF. Macro elements like sodium (Na), magnesium (Mg), aluminium (Al), phosphorus
 (P), chlorine (Cl), potassium (K), calcium (Ca), manganese (Mn) and iron (Fe) and micro elements like chromium (Cr), copper (Cu), zinc (Zn), arsenic (As), and lead (Pb) were identified and evaluated. Biochemical analysis revealed increases in HDL levels (p>0.05) while there were decreases in LDL levels (p>0.05), creatine kinase and AST levels (P<0.05) in animals that received UNCP compared to A/L only administered group. Urea levels reduced significantly by 53 % (p<0.05) in group that received 1500 mg/kg UNCP. Histopathological examinations of the heart and kidney buttressed the protective effects of cocoa administration.
The percentage of recommended daily allowance of UNCP for chromium is 3750 % for men and 5250 % for women while % RDA for copper corresponds to 103.6 % in both sexes. UNCP proved to possess cardioprotective and renoprotective potential during artemether-lumefantrine administration.
A new asymmetrical fluorescent diarylethene derivative with an acridine unit was synthesized by Schiff base condensation. The derivative was sensitive to lights and special metal ions. Stimulated by UV/vis lights and Zn(2+), distinct changes were observed in UV-vis and fluorescent spectra. Upon addition of Zn(2+), the derivative emission peak was blue-shifted by 34nm and the emission intensity was enhanced by 16 fold, accompanied by the fluorescent color changed from red to light yellow, due to the formation of a 1:1 metal/ligand complex. The complex exhibited excellent fluorescence switching upon irradiation with UV light. Taking advantage of the lights and Zn(2+) stimuli (inputs), and fluorescence intensity at 580nm (output), a molecular logic gate was constructed. Moreover, a new absorption band centered at 420-450nm emerged upon exposure to Zn(2+). The dramatic color change of the solution made the 'naked-eyes' detection of Zn(2+) possible.
To understand traffic-related metal(loid) status and uptake by dominant plants growing naturally in roadside soils in the Tibetan plateau, China, aboveground parts and root samples of three dominant plant species (Kalidium slenderbranch, Stipa purpurea, Kobresia pygmaea) were collected along the Qinghai-Tibet highway, and were analyzed for concentrations of traffic-related metal(loid)s such as chromium (Cr), zinc (Zn), copper (Cu), cadmium (Cd), arsenic (As), and lead (Pb). The results indicated that concentrations of metal(loid)s in plant tissues varied greatly among plant species and sites. Tissue distribution of metal(loid)s was significantly related to distance and demonstrated variability as an exponential function of traffic proximity. It was deduced that Cd in Kalidium slenderbranch and Cu and Zn in S. purpurea were mainly derived from soil; Kalidium slenderbranch and Kobresia pygmaea absorbed Zn, and S. purpurea absorbed Cd, mainly through stomata, from atmospheric deposition; enrichments of Pb and As in S. purpurea presented similar characteristics to those of Cd and Pb in Kobresia pygmaea and were affected by both soil and atmospheric deposition. After excluding the effects of the traffic, the highest value obtained for metal(loid)-translocation capacity (7.51 for translocation factor, TF) was observed for S. purpurea collected from Tuotuohe, while the lowest value for metal(loid)-uptake capacity (0.015 for bioaccumulation factor, BF) was for Kalidium slenderbranch collected from Golmud. The three plant species showed limited soil-to-root transfer of metal(loid)s, possibly due to the high soil pH along the Qinghai-Tibet highway, but demonstrated great potential for metal(loid) transfer from roots to aboveground parts.
Contents of twenty elements (Mg, K, Ca, Na, Fe, Al, Zn, Ba, Mn, Cu, Mo, Cr, Ni, As, Se, Cd, Hg, Tl, Pb and V) in two medical and edible plant species, Alpinia oxyphylla and Morinda officinalis were simultaneously determined by inductively coupled plasma-mass spectrometry (ICP-MS) method after microwave digestion with HNO3-H2O2 (6:1, v/v) as the digestion solvent. Certified standard reference material Poplar leaf was used to assess the accuracy of the method. The greatest contents of Mg, K, Ca, Al, Fe and Na were found in dried Alpinia oxyphylla and Morinda officinalis samples. The contents of five heavy metals including Pb, Cd, As, Hg and Cu in Alpinia oxyphylla did not exceed the limits. The contents of Pb in 76.67% samples and Cd in two batches of Morinda officinalis samples exceeded the limits set by Chinese Pharmacopeia. The contents of the selected elements in different parts (leaves, stems, roots and fruits) of Alpinia oxyphylla varied considerably. The highest concentrations of Mg, Ca, Mn and Se were found in the leaves of Alpinia oxyphylla, at the same time, while, the contents of 9 elements including Cd, Cr, Cu, As, Pb in the roots were the highest. The transfer ratios of selected elements from both species of herbs into their decoctions were reduced. Especially for the heavy metals, the transfer ratios were below 30% except As (79.73%) in Morinda officinalis. The results showed that decoction of the samples may reduce the intake of heavy metals.
To report early confirmation of Mycobacterium tuberculosis (MTB) endophthalmitis by detection of 85B mRNA in vitreous by a reverse transcriptase polymerase chain reaction (RT-PCR) technique.
Retrospective, interventional case series of 5 patients with MTB endogenous endophthalmitis. Vitreous aspirate was subjected to Ziehl-Neelsen (ZN) staining, BACTEC MicroMGIT culture, RT-PCR targeting the 85B gene, real-time PCR targeting the IS6110 region, and nested PCR targeting the MPB64 gene and IS6110 region. Correlation between detection of MTB RNA, culture positivity, and ZN staining was studied.
Five patients with endophthalmitis with no history of tuberculosis revealed acid-fast bacilli on ZN staining of vitreous. RT-PCR detected 85B RNA within 24 h. Culture for MTB was positive in 3/5 patients after 1 month. None of the eyes recovered any useful vision.
RT-PCR can detect viable MTB RNA and provide evidence of active infection much earlier than culture.
Achieving structurally well-defined catalytic species requires a fundamental understanding of surface chemistry. Detailed structural characterization of the catalyst binding sites in situ, such as single site catalysts on silica supports, is technically challenging or even unattainable. Octadecyltrioxysilane (OTOS) monolayers formed from octadecyltrimethoxysilane (OTMS) at the air-liquid interface after hydrolysis and condensation at low pH were chosen as a model system of surface binding sites in silica-supported Zn(2+) catalysts. We characterize the system by grazing incidence X-ray diffraction, X-ray reflectivity (XR), and X-ray fluorescence spectroscopy (XFS). Previous X-ray and infrared surface studies of OTMS/OTOS films at the air-liquid interface proposed the formation of polymer OTOS structures. According to our analysis, polymer formation is inconsistent with the X-ray observations and structural properties of siloxanes; it is energetically unfavorable and thus highly unlikely. We suggest an alternative mechanism of hydrolysis/condensation in OTMS leading to the formation of structurally allowed cyclic trimers with the six-membered siloxane rings, which explain well both the X-ray and infrared results. XR and XFS consistently demonstrate that tetrahedral [Zn(NH3)4](2+) ions bind to hydroxyl groups of the film at a stoichiometric ratio of OTOS:Zn ∼ 2:1. The high binding affinity of zinc ions to OTOS trimers suggests that the six-membered siloxane rings are binding locations for single site Zn/SiO2 catalysts. Our results show that OTOS monolayers may serve as a platform for studying silica surface chemistry or hydroxyl-mediated reactions.
Bayerite was treated under hydrothermal conditions (120, 130, 140, and 150 °C) to prepare a series of layered double hydroxides (LDHs) with an ideal composition of ZnAl4(OH)12(SO4)0.5·nH2O (ZnAl4-LDHs). These products were investigated by both bulk techniques (powder X-ray diffraction (PXRD), transmission electron microscopy, and elemental analysis) and atomic-level techniques ((1)H and (27)Al solid-state NMR, IR, and Raman spectroscopy) to gain a detailed insight into the structure of ZnAl4-LDHs and sample composition. Four structural models (one stoichiometric and three different defect models) were investigated by Rietveld refinement of the PXRD data. These were assessed using the information obtained from other characterization techniques, which favored the ideal (nondefect) structural model for ZnAl4-LDH, as, for example, (27)Al magic-angle spinning NMR showed that excess Al was present as amorphous bayerite (Al(OH)3) and pseudoboehmite (AlOOH). Moreover, no evidence of cation mixing, that is, partial substitution of Zn(II) onto any of four Al sites, was observed. Altogether this study highlights the challenges involved to synthesize pure ZnAl4-LDHs and the necessity to use complementary techniques such as PXRD, elemental analysis, and solid-state NMR for the characterization of the local and extended structure of ZnAl4-LDHs.
We used pulsed-laser ablation in liquids (PLAL) of Cu or Zn foil targets in water or in aqueous Cu or Zn salt solutions. PLAL in neat water generated mixtures of metal and (thermodynamically preferred) metal oxide nanomaterials, whereas the availability of select dissolved anions predictably led to the fabrication of more complex phase-pure nanominerals. PLAL of Cu foil in aqueous CuCl2 solution produced nano-paratacamite, Cu2Cl(OH)3, whereas nano-rouaite, Cu2(NO3)(OH)3, was formed in aqueous Cu(NO3)2 and NH4OH solution. Likewise, we synthesized simonkolleite, Zn5(OH)8Cl2·H2O, or layered zinc hydroxide nitrate, Zn5(OH)8(NO3)2·2H2O, nanoparticles by PLAL of Zn targets in aqueous ablation liquids with added ZnCl2 and NH4OH or Zn(NO3)2, respectively. Bimetallic zincian paratacamite resulted
 from PLAL of Cu foil in aqueous Cu and Zn chloride solution. Our results show that kinetic control exceeded thermodynamic product formation during nanosecond ultraviolet PLAL.
Potassium channel tetramerization domain containing 1 (KCTD1) family members have a BTB/POZ domain, which can facilitate protein-protein interactions involved in the regulation of different signaling pathways. KCTD proteins have potential Zn(2+)/Cu(2+) binding sites with currently unknown structural and functional roles. We investigated potential Cu(2+)-specific effects on KCTD1 using circular dichroism, turbidity measurement, fluorescent dye binding, proteinase K (PK) digestion, cell proliferation and apoptosis assays. These experiments indicate that the KCTD1 secondary structure assumes greater β-sheet content and the proteins aggregate into a PK-resistant form under 20 μM Cu(2+), and this β-sheet-rich aggregation with Cu(2+) promotes fibril formation, which results in increased cell toxicity by apoptosis. Our results reveal a novel role for Cu(2+) in determining the structure and function of KCTD1.
5'-adenylic acid deaminase (AMP deaminase), an important enzyme for the food industry, can catalyze the irreversible hydrolysis of adenosine monophosphate (AMP) to inosine monophosphate (IMP) and ammonia. In this study, a new strain was screened that efficiently produces 3191.6U/g of AMP deaminase at 32°C. After purification, the optimal temperature and pH of the AMP deaminase were found to be 40°C and 6.0, respectively, but it was partially inhibited by Fe(3+), Cu(2+), Al(3+), and Zn(2+). With amplification of the AMP deaminase production system, 6mL of crude enzyme could produce 2.00mg/g of IMP from 2.04mg/g of dried yeast with an 84.8% molar yield after 40min. These results provide a new insight into AMP deaminase production and offer a potential platform for producing 5'-IMP.
Edible mushrooms including Pholiota nameko are excellent sources of extractable bioactive compounds with much to explore. Enzymatic extractions with Cellulase and Viscozyme were responsible for highest extraction yields (67-77%). No strong antioxidant activity was observed although extracts were able to scavenge ABTS(+) and OH(+). Potential prebiotic activity was observed in all extracts, some increasing 1.4-2 Log cycles of Lactobacillus acidophilus La-5 and Bifidobacterium animalis BB12. 30-50% α-glucosidase inhibition was observed in ultrasound, Flavourzyme and Cellulase extracts. Flavourzyme and Cellulase extracts are richer in macro (Mg, K and P) and micro elements (Zn, Mn and Fe) in comparison to mushroom. Monosaccharides content and profile varied slightly among both extracts with predominance of glucose, galactose and mannose with no uronic acids detection; Flavourzyme extract reported higher free amino acids content. Presence of α and β-glycosidic structures such as glucans and glucan-protein complexes are among the polysaccharides found in both extracts.
We report a new polydiacetylene (PDA) sensor strip for simple visual detection of zinc ions in aqueous solution. The specificity of this sensor comes from Zn(2+) DNA aptamer probes conjugated onto PDA. Effects of aptamer length and structure on the sensitivity of PDA's color transition were first investigated. PDA conjugated with the optimal aptamer sequence was then coated onto a strip of polyvinylidene fluoride membrane and photopolymerized by UV exposure. The newly developed sensor successfully exhibited a blue-to-red chromatic change in a semi-quantitative manner in response to zinc ions. No discernable change was observed in solutions containing other common ions. Advantages of this sensor include its ease of fabrication, high specificity, and equipment-free detection, all of which are desirable for in-field applications and use in resource-limited settings.
Extensive contamination of grassland with cadmium (Cd), lead (Pb) and zinc (Zn) is a typical problem close to Pb/Zn smelter sites. The entry of Cd or Pb into the food chain is very likely, as are toxicity effects of Zn in plants. Previous promising results from pot and field experiments showed the high potential of using amendments for immobilisation to reduce metal input into the food chain via crops grown on smelter-contaminated soils at Arnoldstein (Austria) (Friesl et al., 2006). The aim of this study was to find a practical solution for large-scale contaminations in hilly regions that avoids erosion. Field application of amendments without destroying the vegetation cover (grassland) involved two approaches: (a) slurrying (Slu) the amendments into cut gaps in the vegetation cover and (b) injecting (Inj) the amendments through the vegetation cover. Here, we investigate the immobilising and long-term efficiency of treatments [gravel sludge (2.5%) + red mud (0.5%) (GS + RM)]. Risk assessment was based on soil, plant and water samples taken over a period of 10 years. Ammonium-nitrate-extractable Cd was reduced up to 50%, Pb up to 90%, and Zn over 90%. Plant uptake into the grass mixture and narrow leaf plantain was significantly reduced for Cd, Pb, and Zn. Harvesting early in vegetation period can further reduce uptake and meet the threshold for fodder crops. The reduction of these elements in the seepage water in 24 samplings within these 10 years reached 40%, 45% and 50%, respectively. Immobilisation increased microbial biomass and decreased human bioaccessibility for Pb. Our investigation of the long-term efficiency of GS + RM in all treatments shows that the Slu and Inj amendment application techniques have promising potential as a realistic and practical method for extensively contaminated hilly land. Slurrying performed best. We conclude that grassland remediation methods involving tillage are counterproductive from the viewpoint of bioaccessibility and soil protection and therefore should be avoided.
Whether traveling wave ion mobility-mass spectrometry (IM-MS), B3LYP/LanL2DZ density functional theory, and ion size scaled Lennard-Jones (LJ) collision cross sections (CCS) from the B3LYP optimized structures could be used to determine the type of Zn(II) coordination by the oligopeptide acetyl-His1 -Cys2 -Gly3 -Pro4 -Tyr5 -His6 -Cys7 (amb5 ) was investigated. The IM-MS analyses of a pH titration of molar equivalents of Zn(II):amb5 showed that both negatively and positively charged complexes formed and coordination of Zn(II) increased as the His and Cys deprotonated near their pKa values. The B3LYP method was used to generate a series of alternative coordination structures to compare with the experimental results. The method predicted that the single negatively charged complex coordinated Zn(II) in a distorted tetrahedral geometry via the 2His-2Cys substituent groups, whereas, the double negatively charged and positively charged complexes coordinated Zn(II) via His, carbonyl oxygens and the C-terminus. The CCS of the B3LYP complexes were calculated using the LJ method and compared with those measured by IM-MS for the various charge state complexes. The LJ method provided CCS that agreed with five of the alternative distorted tetrahedral and trigonal bipyramidal coordinations for the doubly charged complexes, but provided CCS that were 15 to 31 Å(2) larger than those measured by IM-MS for the singly charged complexes. Collision-induced dissociation of the Zn(II) complexes and a further pH titration study of amb5B , which included amidation of the C-terminus, suggested that the 2His-2Cys coordination was more significant than coordinations that included the C-terminus. Copyright © 2016 John Wiley & Sons, Ltd.
The present study was aimed to analyze the effects of external Zn supply on arsenic (As) toxicity in Hydrilla verticillata (L.f.) Royle. The plants were exposed to arsenite (AsIII; 10 μM) with or without 50 and 100 μM Zn. The level of As accumulation (μg g(-1) dw) after 2 and 4 days was not significantly affected by Zn supply. The plants showed a significant stimulation of the thiol metabolism (non-protein thiols, cysteine, glutathione-S-transferase activity) upon As(III) exposure in the presence of Zn as compared to As(III) alone treatment. Besides, they did not experience significant toxicity, measured in terms of hydrogen peroxide and malondialdehyde accumulation; the indicators of oxidative stress. The minus Zn plants suffered from oxidative stress probably due to insufficient increase in thiols to counteract the stress. Stress amelioration by Zn supply was also evident from antioxidant enzyme activities, which came close to control levels with increasing Zn supply as compared to the increase observed in As(III) alone treatment. Variable Zn supply also modulated the level of photosynthetic pigments and restored them to control levels. In conclusion, an improved supply of Zn to plants was found to augment their ability to withstand As toxicity through enhanced thiol metabolism.
Four plant growth promoting bacteria (PGPB) were used as materials, among them two heavy metal tolerant rhizosphere strains SrN1 (Arthrobacter sp.) and SrN9 (Bacillus altitudinis) were isolated from rhizosphere soil, while two endophytic strains SaN1 (Bacillus megatherium) and SaMR12 (Sphingomonas) were identified from roots of the Cd/Zn hyperaccumulator Sedum alfredii Hance. A pot experiment was carried out to investigate the effects of these PGPB on plant growth and Cd accumulation of oilseed rape (Brassica napus) plants grown on aged Cd-spiked soil. The results showed that the four PGPB significantly boosted oilseed rape shoot biomass production, improved Soil and Plant Analyzer Development (SPAD) value, enhanced Cd uptake of plant and Cd translocation to the leaves. By fluorescent in situ hybridization (FISH) and green fluorescent protein (GFP), we demonstrated the studied S. alfredii endophytic bacterium SaMR12 were able to colonize successfully in the B. napus
 roots. However, all four PGPB could increase seed Cd accumulation. Due to its potential to enhance Cd uptake by the plant and to restrict Cd accumulation in the seeds, SaMR12 was selected as the most promising microbial partner of B. napus when setting up a plant-microbe fortified remediation system.
The antibiotic resistance genes (ARGs) from urban waste may spread to the environment with the discharge of leachate. Fifteen types of ARGs, including tetracycline, sulfonamides, AmpC β-lactamase and the class 1 integron gene were detected in the samples from the largest leachate treatment plant (LTP) in Guangzhou and its effluent receiving bodies (soil and surface water). The results showed that ARGs in leachates were in high levels and varied with seasons. The abundance of ARGs in the influent from high to low was in the turn of summer, winter, spring. About 2 to 4 orders of magnitude of ARGs were eliminated by the whole leachate treatment process. The predominant ARGs in the receiving soil were intI1, tetB, sul2, tetA and tetX, while those in the receiving surface water were sul2, intI1 and sul1, and the concentrations of ARGs in the receiving bodies were higher than those in the other natural bodies by 1 to 2 orders of magnitude. In addition, the results of bivariate correlation analysis showed that the abundances of ARGs (tetC, tetW, sul1, sul2, intI1 and FOX) were in significant correlation with the concentrations of heavy metals (Cu, Zn, Ni and Cr) (p < 0.05). LTPs are more likely to be sources of ARGs than wastewater treatment plant (WWTP) and need to be focused on.
A simulated climate warming experiment was conducted to evaluate the combined effects of elevated temperature and CO2 concentration on the bioaccumulation, translocation and subcellular distributions of Cd and Zn in wheat seedlings (Triticum aestivum L. cv. Xihan 1.) at Dingxi, Gansu Province, China. The objective was to find evidence that global climate change is affecting the bioaccumulation of Cd and Zn in T. aestivum L. cv. Xihan 1. The results showed that compared to control A, elevated temperature and CO2 increased Cd bioaccumulation in the shoots by 1.4-2.5 times, and increased that in the roots by 1.2-1.5 times, but decreased Zn levels in wheat shoots by 1.4-2.0 times, while decreased that in the roots by 1.6-1.9 times. Moreover, temperature and CO2 concentration increase also led to increased Cd concentration, and decreased Zn concentration in subcellular compartments of wheat seedlings. The largest Cd concentration increase (174.4%) was observed in the cell wall and debris fractions of shoots after they were subjected to the highest CO2 and temperature treatment (TC3). The largest Zn concentration decrease (53.1%) was observed in the soluble (F3) fractions of shoots after they were subjected to the medium CO2 and temperature treatment (TC2). The temperature and CO2 increase had no significant effect on the proportional distribution of Cd and Zn in the subcellular fractions. The root-to-shoot translocation of Cd increased with the increasing temperature and CO2 concentration. However, the Zn distributions only fluctuated within a small range.
Few epidemiological studies have explored the effects of soil pollution on multiple sclerosis (MS) risk in Asia.
Based on catchment areas, Isfahan province is divided into five regions (Central, North, East, West, and South), and Soil sampling performed in catchment area with the highest range of MS prevalence and incidence. Samples were analyzed for cobalt (Co), lead (Pb), cadmium (Cd), copper (Cu), zinc (Zn), and absorbable forms of Pb, Cd, and Co. Linear regression is used to examine the association of soil heavy metals with prevalence of MS in central part of Isfahan province.
Multiple sclerosis prevalence ranged from 5.62 to 156.65 in different townships. Based on regression analysis, in case of considering fixed amounts for the rest of elements, a one (SD) increase of absorbable Pb and absorbable Cd are associated with 0.385 (SD) (P < 0.0001) increase and 0.209 (SD) (P < 0.007) decrease in MS prevalence, respectively.
This study documented a significant association between exposure to absorbable Pb and Cd in soil with prevalence of MS in Isfahan. Further work is warranted to confirm this association and if validated, to understand the mechanisms behind the association.
This study has presented specific features that are examined to remove the Trypan blue dye from the waste using Luffa sponge (LS) and modified Luffa sponge with zinc nanoparticles (ZnNPs). Peroxidase enzyme was obtained from Euphorbia amygdaloides plant and it was used with the green synthesis of Zn nanoparticles. Luffa sponge was used to be a support material for immobilized nanoparticles and it also used in remediation work. The obtained membrane forms, fibrous materials, (LS, ZnNPs-LS) were characterized with SEM and XRD. LS and ZnNPs-LS were employed as adsorbent to be used for the removal of Trypan blue dye from aqueous via batch studies. Measurements were made for the equilibrium, pH, temperature, concentration of dye with UV-visible spectrometer (590nm; for Trypan blue dye). The optimum removal of Trypan blue dye was found at pH7, the equilibrium was attained within 30min. The thermodynamic properties ΔG(0), ΔH(0), and ΔS(0) showed that adsorption of Trypan blue dye onto LS and ZnNPs-LS were spontaneous and endothermic. The equilibrium isotherm data were analyzed using Langmuir and Freundlich models and the sorption process was described by the Langmuir isotherm with maximum monolayer adsorption capacity of 45.32 and 47.3mg/g for LS and LS-ZnNPs at 303±1°K, respectively.
Monitoring of environment is a key contemporary issue that has necessitated search for bio-indicators. The very fact that epiphytes do not have a direct contact with soil and absorb nutrients from the environment puts them among the best indicators of environmental conditions. We, therefore, selected Pyrrosia flocculosa (D. Don) Ching-an epiphytic fern that commonly occurs in the Himalaya for this study. The study focused on analyzing heavy metal concentrations in the fronds of P. flocculosa growing along a disturbance gradient. For this, three sites representing different levels of disturbance viz., least disturbed, moderately disturbed, and highly disturbed, were identified in Kangra district of Himachal Pradesh. From each site, fronds of P. flocculosa were collected, categorized into three growth stages (juvenile, young, and mature), and brought to the laboratory for analyses. After drying and powdering, the samples were analyzed for Pb, Cd, Fe, Ni, Cu, Mn, and Zn using atomic absorption spectrophotometer. The results obtained were statistically compared using the software package Statistica. As expected, concentration of the metals varied among the sites and also among the identified growth stages of the species. In general, concentration of the metals was in the order Fe (639.28 ± 81.63) > Ni (56.03 ± 4.97) > Mn (7.54 ± 0.69) > Zn (6.51 ± 0.36) > Cd (4.01 ± 0.86) > Cu (1.93 ± 0.74). Barring Mn, concentration of all the metals increased with disturbance and was positively correlated to it. However, except for Cd and Fe, none of the metals reported higher than threshold values. Effective monitoring of the environment can thus be done using P. flocculosa.
Al(3+), Fe(3+), and Zn(2+) ions can disturb microtubule assembly from tubulin and microtubuleassociated proteins in rat brain. The main structural forms of these microtubules are rings and tangled bundles. These structures are formed only in the presence of Al(3+) and Fe(3+) ions. Therefore, Zn(2+) ions can be excluded from possible causes of structural abnormalities in microtubules during Alzheimer's disease. Al(3+) ions are the most probable etiological cause of Alzheimer's disease. The concentration of Al(3+) ions affecting the structure of microtubules is one order of magnitude lower than that of Fe(3+) ions (10 and 100 μM, respectively), which corresponds to their brain concentration reported in Alzheimer's disease.
Energy-derived waters containing naphthenic acids (NAs) are complex mixtures often comprising a suite of potentially problematic constituents (e.g. organics, metals, and metalloids) that need treatment prior to beneficial use, including release to receiving aquatic systems. It has previously been suggested that NAs can have biostatic or biocidal properties that could inhibit microbially driven processes (e.g. dissimilatory sulfate reduction) used to transfer or transform metals in passive treatment systems (i.e. constructed wetlands). The overall objective of this study was to measure the effects of a commercially available (Fluka) NA on sulfate-reducing bacteria (SRB), production of sulfides (as acid-volatile sulfides [AVS]), and precipitation of divalent metals (i.e. Cu, Ni, Zn). These endpoints were assessed following 21-d aqueous exposures of NAs using bench-scale reactors. After 21-days, AVS molar concentrations were not statistically different (p<0.0001; α=0.05) among NA treatments (10, 20, 40, 60, and 80mg NA/L) and an untreated control (no NAs). Extent of AVS production was sufficient in all NA treatments to achieve ∑SEM:AVS <1, indicating that conditions were conducive for treatment of metals, with sulfide ligands in excess of SEM (Cu, Ni, and Zn). In addition, no adverse effects to SRB (in terms of density, relative abundance, and diversity) were measured following exposures of a commercial NA. In this bench-scale study, dissimilatory sulfate reduction and subsequent metal precipitation were not vulnerable to NAs, indicating passive treatment systems utilizing sulfide production (AVS) could be used to treat metals occurring in NAs affected waters.
An analytical scheme for physical fractionation of Al, Ba, Ca, Co, Fe, K, Mg, Mn, Na, Ni, Sr and Zn in ground roasted and soluble
 coffees brews was proposed. It was based on ultrafiltration through five ultrafiltration membranes having molecular weight cut-offs of 5, 10, 30, 50 and 100kDa. The highest ">100kDa" and the lowest "<5kDa" molecular weight fractions were established to differentiate the studied coffees brews the most. Al, Cu, Fe and Ni were mostly associated with the ">100kDa" fraction, while Co, K, Mg and Na - with the "<5kDa" fraction. For Ba, Ca, Mn, Sr and Zn, ">100kDa" and "<5kDa" fractions contributions were equally accounted. The physical fractionation pattern of selected metals was convenient for discovering important features of brews of both coffee types and differences between them by principal component analysis and then classifying them by linear discriminant analysis.
We report an analytical assessment of an iron oxide (Fe2O3)/graphene (G) nanocomposite electrode used in combination with in situ plated bismuth (Bi) working as an electrochemical sensor for the determination of trace Zn(2+), Cd(2+), and Pb(2+). The as-synthesized nanocomposites were characterized by transmission electron microscopy, scanning electron microscopy, thermo-gravimetric analyzer, and X-ray diffraction. The electrochemical properties of the Fe2O3/G/Bi composite modified electrode were investigated. Differential pulse anodic stripping voltammetry was applied for the detection of metal ions. Due to the synergetic effect between graphene and the Fe2O3 nanoparticles, the modified electrode showed improved electrochemical catalytic activity high sensitivity toward trace heavy metal ions. Several parameters such as the preconcentration potential, bismuth concentration, preconcentration time, and pH were carefully optimized to determine the target metal ions. Under optimized conditions, the linear range of the electrode was 1-100μgL(-1) for Zn(2+), Cd(2+), and Pb(2+), and the detection limits were 0.11μgL(-1), 0.08μgL(-1), and 0.07μgL(-1), respectively (S/N =3). Repeatability (% RSD) was found to be 1.68% for Zn(2+), 0.92% for Cd(2+), and 1.69% for Pb(2+) for single sensor with 10 measurements and 0.89% for Zn(2+), 1.15% for Cd(2+), and 0.91% for Pb(2+) for 5 different electrodes. The Fe2O3/G/Bi composite electrode was successfully applied to the analysis of trace metal ions in real samples. The solventless thermal decomposition method applied to the simple and easy synthesis of nanocomposite electrode materials can be extended to the synthesis of nanocomposites and promising electrode materials for the determination of heavy metal ions.
An analytical scheme for the physical fractionation of Al, Ba, Ca, Cr, Cu, Fe, K, Mg, Mn, Na, Ni, Sr and Zn in black and green teas infusions was proposed. It was based on the ultrafiltration/centrifugation through five membranes having molecular weight cut-offs of 100, 50, 30, 10 and 5kDa. The concentrations of the studied metals in the highest and the lowest molecular weight fractions were found to classify and discriminate the analyzed teas infusions much better than the total metals concentrations. The differences in the physical fractionation patterns of these metals assessed for both tea varieties was profound and let to simply classify the infusions of different black and green teas by principal component analysis and linear discriminant analysis.
The current study for the first time is devoted to the application of whole space genetic algorithm-radial basis function network (wsGA-RBFN) method to determine the content micro minerals of Zn(2+), Fe(2+), Co(2+) and Cu(2+) based on their complexes formation with methylthymol blue (MTB) spectrophotometrically in various pharmaceutical products and vegetable samples. Advantage of wsGA-RBFN compared to GA-RBFN is that centers can be located in any point of the samples spaces. Initially, the parameters controlling behavior of the system were investigated and optimum conditions were selected. Then, an exploratory analysis of complex systems was carried out by chemometrics approaches such as SVD, EFA, MCR-ALS and RAFA. The optimal parameters and conditions for constructing the proposed model of wsGA-RBFN were obtained from processing the data set of synthetic samples. Finally, wsGA-RBFN was successfully applied to the simultaneous determination of Zn(2+), Fe(2+), Co(2+) and Cu(2+) in tomato, white cabbage, red cabbage and lettuce and pharmaceutical products included iron, zinc, multi complete and B12 ampoule.
Zinc (Zn) and cadmium (Cd) are two closely related chemical elements with very different biological roles in photosynthesis. Zinc plays unique biochemical functions in photosynthesis. Previous studies suggested that in some Zn/Cd hyperaccumulators, many steps in photosynthesis may be Cd tolerant or even Cd stimulated. Using RNA-seq data, we found not only that Cd and Zn both up-regulated the CA1 gene, which encodes a β class carbonic anhydrase (CA) in chloroplasts, but that a large number of other Zn up-regulated genes in the photosynthetic pathway were also significantly up-regulated by Cd in leaves of the Zn/Cd hyperaccumulator Sedum alfredii. These genes also include chloroplast genes involved in transcription and translation (rps18 and rps14), electron transport and ATP synthesis (atpF and ccsA), Photosystem II (PSBI, PSBM, PSBK, PSBZ/YCF9, PSBO-1, PSBQ, LHCB1.1, LHCB1.4, LHCB2.1, LHCB4.3 and LHCB6) and Photosystem I (PSAE-1, PSAF, PSAH2, LHCA1 and LHCA4). Cadmium and Zn also up-regulated the VAR1 gene, which encodes the ATP-dependent zinc metalloprotease FTSH 5 (a member of the FtsH family), and the DAG gene, which influences chloroplast differentiation and plastid development, and the CP29 gene, which supports RNA processing in chloroplasts and has a potential role in signal-dependent co-regulation of chloroplast genes. Further morphological parameters (dry biomass, cross-sectional thickness, chloroplast size, chlorophyll content) and chlorophyll fluorescence parameters confirmed that leaf photosynthesis of S. alfredii responded to Cd much as it did to Zn, which will contribute to our understanding of the positive effects of Zn and Cd on growth of this plant.
Muscle fibres, isolated from frog tibialis anterior and mouse flexor digitorum brevis (FDB) were loaded with the fast dye MagFluo-4 to study the effects of potentiators caffeine, nitrate, Zn(2+) and perchlorate on Ca(2+) transients elicited by single action potentials. Overall, the potentiators doubled the transients amplitude and prolonged by about 1.5-fold their decay time. In contrast, as shown here for the first time, nitrate and Zn(2+), but not caffeine, activated a late, secondary component of the transient rising phase of frog but not mouse, fibres. The rise time was increased from 1.9 ms in normal solution (NR) to 3.3 ms (nitrate) and 4.4 ms (Zn(2+)). In NR, a single exponential, fitted the rising phase of calcium transients of frog (τ1 = 0.47 ms) and mouse (τ1 = 0.28 ms). In nitrate and Zn(2+) only frog transients showed a secondary exponential component, τ2 = 0.72 ms (nitrate) and 0.94 ms, (Zn(2+)). We suggest that nitrate and Zn(2+) activate a late slower component of the ΔF/F signals of frog but not of mouse fibres, possibly promoting Ca(2+) induced Ca(2+) release at level of the RyR3, that in frog muscle fibres are localized in the para-junctional region of the triads and are absent in mouse FDB muscle fibres.
The purpose of this research was to evaluate the effect of medical stone (MS) on nitrogen conservation and improving the compost quality during the pig manure (PM) composting. Five treatments were designed with different concentrations of MS0%, 2.5%, 5%, 7.5% and 10% (on dry weight of pig manure basis) mixed with initial feed stock and then composted for 60days. The results showed that MS amendment obviously (p<0.05) promoted the organic waste degradation and prolonged the thermophilic phase as well as enhanced the immobilization of heavy metals Cu and Zn. With increasing the amount of MS, the NH3 loss and N2O emission were significantly reduced by 27.9-48.8% and by 46.6-85.3%, respectively. Meanwhile, the MS amendment could reduce the NO2(-)-N formation and increase the NO3(-)-N content. Finally our results suggested that 10%MS addition could significantly reduce the nitrogen conservation as well as improve the quality of compost.
The HgTe quantum well (QW) is a well-characterized two-dimensional topological insulator (2D TI). Its band gap is relatively small (typically on the order of 10 meV), which restricts the observation of purely topological conductance to low temperatures. Here, we utilize the strain dependence of the band structure of HgTe QWs to address this limitation. We use CdTe-Cd_{0.5}Zn_{0.5}Te strained-layer superlattices on GaAs as virtual substrates with adjustable lattice constant to control the strain of the QW. We present magnetotransport measurements, which demonstrate a transition from a semimetallic to a 2D-TI regime in wide QWs, when the strain is changed from tensile to compressive. Most notably, we demonstrate a much enhanced energy gap of 55 meV in heavily compressively strained QWs. This value exceeds the highest possible gap on common II-VI substrates by a factor of 2-3, and extends the regime where the topological conductance prevails to much higher temperatures.
Acetaminophen can increase the risk of arsenic-mediated hepatic oxidative damage; therefore, the decontamination of water polluted with coexisting acetaminophen and arsenic gives rise to new challenges for the purification of drinking water. In this work, a three-metal layered double hydroxide, namely, Cu-Zn-Fe-LDH, was synthesized and applied as a heterogeneous Fenton-like oxidation catalyst and adsorbent to simultaneously remove acetaminophen (Paracetamol, PR) and arsenic. The results showed that the degradation of acetaminophen was accelerated with decreasing pH or increasing H2O2 concentrations.
 Under the conditions of a catalyst dosage of 0.5 g·L(-1) and a H2O2 concentration of 30 mmol·L(-1), the acetaminophen in a water sample was completely degraded within 24 h by a Fenton-like reaction. The synthesized Cu-Zn-Fe-LDH also exhibited a high efficiency for arsenate removal from aqueous solutions, with a calculated maximum adsorption capacity of 126.13 mg·g(-1). In the presence of hydrogen peroxide, the more toxic arsenite can be gradually oxidized into arsenate and adsorbed at the same time by Cu-Zn-Fe-LDH. For simulated water samples with coexisting arsenic and acetaminophen pollutants, after treatment with Cu-Zn-Fe-LDH and H2O2, the residual arsenic concentration in water was less than 10 μg·L(-1), and acetaminophen was not detected in the solution. These results indicate that the obtained Cu-Zn-Fe-LDH is an efficient material for the decontamination of combined acetaminophen and arsenic pollution.
An experiment was conducted to characterize a gut health challenge model consisting of a diet containing rye, wheat, and feather meal and a mild mixed-species Eimeria challenge, and to evaluate the effect of carbohydrase and protease on growth performance and gut health of young broilers. The study included 4 treatments: negative control, carbohydrase alone, protease alone, and combination of carbohydrase and protease. Each test diet was fed to 18 battery pens of broilers with 8 male birds per pen from 0 to 22 d of age. Carbohydrase improved body weight, feed intake, and feed conversion ratio (FCR) on d 7, 14, and 21(P < 0.01). Protease increased body weight on d 7 and 21 and improved 0 to 7 d FCR (P < 0.05). More lymphocyte infiltration was observed in small intestine mucosa of negative control birds on d 8, carbohydrase supplementation lessened this. Both carbohydrase and protease reduced digesta viscosity on d 22 with the carbohydrase effect being the greater of the two, and the combination effect was not different from the carbohydrase effect alone (P < 0.01). Ileal Clostridium perfringens of 15-day-old broilers was decreased by carbohydrase, a further reduction was achieved by combining carbohydrase with protease (P = 0.01). Liver vitamin E concentration on d 15 (P < 0.01) and 22 (P = 0.02) was increased by carbohydrase, and the carbohydrase effect was greater in the presence of protease on d 22 (P = 0.04). Plasma α-1-acid glycoprotein level and liver Zn and Cu concentrations of broilers were reduced by carbohydrase on d 15 (P < 0.01). Broilers fed carbohydrase had higher levels of plasma zeaxanthin on d 22 and higher levels of plasma lutein on d 15 and 22 (P < 0.01). In summary, a rye wheat based diet containing feather meal when fed to broilers in addition to a mild Eimeria challenge induced subclinical enteritis characterized by digestion inefficiency, dysbacteriosis, inflammation, and gut barrier failure; carbohydrase and protease could be effective tools to improve growth performance and gut health of broilers suffering from this type of subclinical enteritis.
In this study, the accumulation of metals, including Al, Fe, Zn, V, Ni, Cu, Cr, Cd, Co, As, and Pb, in sediments of Anzali wetland in the southwest region of the Caspian Sea was investigated. For this purpose, the sediments were collected from 17 sampling sites in Anzali wetland, Caspian Sea. The samples were then analyzed using inductively coupled plasma-optical emission spectrometry (ICP-OES). Pearson correlation coefficient showed significant and positive correlation between concentration of all metals (except As and Cd). Furthermore, the results implied that Al and Fe are probably responsible for the transportation of heavy metals into the sediments of Anzali wetland. According to mean effects range-median quotient (mean ERM quotient), the sediments from Anzali wetland had a 21% probability of toxicity.
Semax is a heptapeptide (Met-Glu-His-Phe-Pro-Gly-Pro) that encompasses the sequence 4-7 of N-terminal domain of the adrenocorticotropic hormone and a C-terminal Pro-Gly-Pro tripeptide. N-terminal amino group acetylation (Ac-Semax) modulates the chemical and biological properties of parental peptide, modifying the ability of Semax to form complex species with Cu(II) ion. At physiological pH, the main complex species formed by Ac-Semax, [CuLH-2](2-), consists in a distorted CuN3O chromophore with a weak apical interaction of the methionine sulphur. Such a complex differs from the Cu(II)-Semax complex system, which exhibits a CuN4 chromophore. The reduced ligand field affects the [CuLH-2](2-) formal redox potential, which is more positive than that of Cu(II)-Semax corresponding species. In the amino-free form, the resulting complex species is redox-stable and unreactive against ascorbic acid, unlike the acetylated form. Semax acetylation did not protect from Cu(II) induced toxicity on a SH-SY5Y neuroblastoma cell line, thus demonstrating the crucial role played by the free NH2 terminus in the cell protection. Since several brain diseases are associated either to Cu(II) or Zn(II) dyshomeostasis, here we characterized also the complex species formed by Zn(II) with Semax and Ac-Semax. Both peptides were able to form Zn(II) complex species with comparable strength. Confocal microscopy imaging confirmed that peptide group acetylation does not affect the Zn(II) influx in neuroblastoma cells. Moreover, a punctuate distribution of Zn(II) within the cells suggests a preferred subcellular localization that might explain the zinc toxic effect. A future perspective can be the use of Ac-Semax as ionophore in antibody drug conjugates to produce a dysmetallostasis in tumor cells.
Copper-zinc-superoxide dismutase (CuZnSOD) from Hippocampus abdominalis (HaCuZnSOD) is a metalloenzyme which belongs to the ubiquitous family of SODs. Here, we determined the characteristic structural features of HaCuZnSOD, analyzed its evolutionary relationships, and identified its potential immune responses and biological functions in relation to antioxidant defense mechanisms in the seahorse. The gene had a 5' untranslated region (UTR) of 67 bp, a coding sequence of 465 bp and a 3' UTR of 313 bp. The putative peptide consists of 154 amino acids. HaCuZnSOD had a predicted molecular mass of 15.94 kDa and a theoretical pI value of 5.73, which is favorable for copper binding activity. In silico analysis revealed that HaCuZnSOD had a prominent Cu-Zn_superoxide_dismutase domain, two Cu/Zn signature sequences, a putative N-glycosylation site, and several active sites including Cu(2+) and Zn(2+) binding sites. The three dimensional structure indicated a β-sheet barrel with 8 β-sheets and two short α-helical regions. Multiple alignment analyses revealed many conserved regions and active sites among its orthologs. The highest amino acid identity to HaCuZnSOD was found in Siniperca chuatsi (87.4%), while Maylandia zebra shared a close relationship in the phylogenetic analysis. Functional assays were performed to assess the antioxidant, biophysical and biochemical properties of overexpressed recombinant (r) HaCuZnSOD. A xanthine/XOD assay gave optimum results at pH 9 and 25 °C indicating these may be the best conditions for its antioxidant action in the seahorse. An MTT assay and flow cytometry confirmed that rHaCuZnSOD showed peroxidase activity in the presence of HCO3(-). In all the functional assays, the level of antioxidant activity of rHaCuZnSOD was concentration dependent; metal ion supplementation also increased its activity. The highest mRNA expressional level of HaCuZnSOD was found in blood. Temporal assessment under pathological stress showed a delay response by HaCuZnSOD. Our findings demonstrated that HaCuZnSOD is an important antioxidant, which might be involved in the host antioxidant defense mechanism against oxidative stress.
Heavy metals are dangerous pollutants that in spite of occurring naturally are released in major amounts to the environment due to anthropogenic activities. After being released in the environment, the heavy metals end up in the soils where they accumulate as they do not degrade, adversely affecting the biota. Because of the dynamic equilibria between soil constituents, the heavy metals may be present in different phases such as the solid phase (immobilized contaminants) or dissolved in soil solution. The latter form is the most dangerous because the ions are mobile, can leach and be absorbed by living organisms. Different methods for the decontamination of polluted soils have been proposed and they make use of two different approaches: mobilizing the heavy metals, which allows their removal from soil, or immobilization that maintains the metal concentrations in soils but keeps them in an inert form due to mechanisms like precipitation, complexation or adsorption. Mobilization of the heavy metals is known to cause leaching and increase plant uptake, so this treatment can cause greater problems. Aerogels are incredible nanostructured, lightweight materials with high surface area and tailorable surface chemistry. Their application in environmental cleaning has been increasing in recent years and very promising results have been obtained. The functionalization of the aerogels can give them the ability to interact with heavy metals, retaining the latter via strong adsorptive interactions. Thus, this review surveys the existing literature for remediation of soils using an immobilization approach, i.e. with soil amendments that increase the soil sorption/retention capacity for heavy metals. The considered framework was a set of heavy metals with relevance in polluted Iberian soils, namely Cd, Cr, Cu, Ni, Pb and Zn. Moreover, other adsorbents, especially aerogels, have been used for the removal of these contaminants from aqueous media; because groundwater and soil solution have dynamic equilibria with the soil solid phase, these works allowed to draw conclusions
 and perspectives for the use of aerogels not only as adsorbents in aqueous media but also as amendments for the remediation of heavy metal polluted soils.
Zinc (Zn) is known to play crucial roles in numerous brain functions including learning and memory. Zn deficiency is believed to be widespread throughout the world, particularly in patients with Alzheimer's disease (AD). A number of studies have shown that volatile anesthetics, such as isoflurane, might be potential risk factors for the development of AD. However, whether isoflurane exposure accelerates the process of AD and cognitive impairment in AD patients with Zn deficiency is yet to be documented. The aim of the present study was to explore the effects of 1.4% isoflurane exposure for 2 h on learning and memory function, and neuropathogenesis in 10-month-old Zn-adequate, Zn-deficient, and Zn-treated APP/PS1 mice with the following parameters: behavioral tests, neuronal apoptosis, Aβ, and tau pathology. The results demonstrated that isoflurane exposure showed no impact on learning and memory function, but induced transient elevation of neuroapoptosis in Zn-adequate APP/PS1 mice. Exposure of isoflurane exhibited significant neuroapoptosis, Aβ generation, tau phosphorylation, and learning and memory impairment in APP/PS1 mice in the presence of Zn deficiency. Appropriate Zn treatment improved learning and memory function, and prevented isoflurane-induced neuroapoptosis in APP/PS1 mice. Isoflurane exposure may cause potential neurotoxicity, which is tolerated to some extent in Zn-adequate APP/PS1 mice. When this tolerance is limited, like in AD with Zn deficiency, isoflurane exposure markedly exacerbated learning and memory impairment, and neuropathology, indicating that AD patients with certain conditions such as Zn deficiency may be vulnerable to volatile anesthetic isoflurane.
The design and synthesis of functional coordination polymers is motivated not only by their structural beauty but also by their potential applications. Zn(II) and Cd(II) coordination polymers are promising candidates for producing photoactive materials because these d(10) metal ions not only possess a variety of coordination numbers and geometries, but also exhibit luminescence properties when bound to functional ligands. It is difficult to predict the final structure of such polymers because the assembly process is influenced by many subtle factors. Bis(imidazol-1-yl)-substituted alkane/benzene molecules are good bridging ligands because their flexibility allows them to bend and rotate when they coordinate to metal centres. Two new Zn(II) and Cd(II) coordination polymers based on mixed ligands, namely, poly[[μ2-1,4-bis(imidazol-1-ylmethyl)benzene-κ(2)N(3):N(3')]bis(μ3-2,2-dimethylbutanoato-κ(3)O(1):O(4):O(4'))dizinc(II)], [Zn2(C6H8O4)2(C14H14N4)]n, and poly[[μ2-1,4-bis(imidazol-1-ylmethyl)benzene-κ(2)N(3):N(3')]bis(μ3-2,2-dimethylbutanoato-κ(5)O(1),O(1'):O(4),O(4'):O(4))dicadmium(II)], [Cd2(C6H8O4)2(C14H14N4)]n, have been synthesized under hydrothermal conditions and characterized by single-crystal X-ray diffraction, elemental analysis, IR spectroscopy and thermogravimetric analysis. Both complexes crystallize in the monoclinic space group C2/c with similar unit-cell parameters and feature two-dimensional structures formed by the interconnection of S-shaped Zn(Cd)-2,2-dimethylsuccinate chains with 1,4-bis(imidazol-1-ylmethyl)benzene bridges. However, the Cd(II) and Zn(II) centres have different coordination numbers and the 2,2-dimethylsuccinate ligands display different coordination modes. Both complexes exhibit a blue photoluminescence in the solid state at room temperature.
Aided phytostabilization of a barren, alkaline metal(loid)-contaminated technosol developed on steel mill wastes, with high soluble Cr and Mo concentrations, was assessed in a pot experiment using (1) Ni/Cd-tolerant populations of Festuca pratensis Huds., Holcus lanatus L., and Plantago lanceolata L. sowed in mixed stand and (2) six soil treatments: untreated soil (UNT), ramial chipped wood (RCW, 500m(3)ha(-1)), composted sewage sludge (CSS, 120t DW ha(-1)), UNT soil amended with compost (5% w/w) and either vermiculite (5%, VOM) or iron grit (1%, OMZ), and an uncontaminated soil (CTRL). In the CSS soil, pH and soluble Cr decreased whereas soluble Cu, K, Fe, Mn, Mg, Ni and P increased. The RCW treatment enhanced soluble Fe, Mn, and Mg concentrations. After 15 weeks, shoot DW yield and shoot Cd, Cu, Fe, Mn, Mo, Zn, and Mg removals peaked for F. pratensis grown on the CSS soil, with lowest shoot Cr, Ni and Mo concentrations. Holcus lanatus only grew on the CTRL, UNT, and CSS soils and P. lanceolata on the CTRL soil. Best treatment, F. pratensis grown on the CSS soil, led to a dense grass cover but its shoot Mo concentration exceeded the maximum permitted concentration in forage.
Dried raw sludge was pyrolyzed at temperatures ranging from 400 to 600°C at the increase of 50°C intervals to investigate the influence of pyrolysis temperature on properties and environmental safety of heavy metals in biochar derived from municipal sewage sludge. The sludge biochar yield decreased significantly with increasing pyrolysis temperature but the pH, ash content and specific surface area increased. Conversion of sludge to biochar markedly decreased the H/C and N/C ratios. FT-IR analysis confirmed a dramatic depletion of H and N and a higher degree of aromatic condensation in process of biochar formation at higher temperatures. The total concentrations of Cu, Zn, Pb, Cr, Mn, and Ni increased with conversion of sludge to biochar and increasing pyrolysis temperature. However, using BCR sequential extraction and analysis, it was found that most of the heavy metals existed in the oxizable and residual forms after pyrolysis, especially at 600°C, resulting in a significant reduction in their bioavailability, leading to a very low environmental risk of the biochar. The present study indicates pyrolysis is a promising sludge treatment method for heavy metals immobilization in biochar, and highlights the potential to minimize the harmful effects of biochar by controlling pyrolysis temperature.
Trace elements were analyzed in the liver of white-fronted geese (Anser albifrons, n=15), mallards (Anas platyrhynchos, n=4) and spot-billed ducks (Anas poecilorhyncha, n=13) found dead in Gimpo, Korea. All mallards and eight spot-billed ducks had embedded lead shot. Embedded shot could be affected elevated trace element concentrations on geese and ducks. Element concentrations of cadmium (Cd), lead (Pb), chromium (Cr), aluminum (Al), copper (Cr), manganese (Mn) and zinc (Zn) differed among species and white-fronted geese without embedded shot had the lowest concentrations for all elements (geomean 0.36, 0.43, 0.07, 1.46, 7.60, 2.61 and 13.5µg/g dw, respectively). Cadmium in four (3.27-7.77µg/g dw) of 32 individuals and Pb in eight (5.07-9.72µg/g dw) of 32 individuals exceeded a tentative threshold effect level of Cd (>3.0µg/g dw) and Pb (>5.0µg/g dw) for birds; all geese and ducks for Cr (0.07-0.43µg/g dw) were within the background level (<4.0µg/g dw). All trace element concentrations were much greater in waterfowl species with embedded shot than without shot. Essential trace elements such as Cr, Al (geomean 1.46-37.3µg/g dw), Cu (7.60-57.1µg/g dw), Mn (2.61-27.6µg/g dw) and Zn (13.5-176µg/g dw) were within the normal range and were probably maintained by normal homeostatic mechanisms.
Tetragonal and hexagonal phases of monometallic Zn and bimetallic Co/Zn metal-organic frameworks (MOFs), with secondary building units (SBUs) containing a M3O (M = metal) cluster, were synthesized from identical constituents using a benzenetricarboxylate (BTC(3-)) linker that forms decorated 3,6- and 3,5-connected networks, respectively. There exist subtle differences between the SBUs; one of the metal atoms in the M3O cluster in the tetragonal phase has one dissociable DMF solvent molecule while that in the hexagonal phase has three. Connectivities between the SBUs form one-dimensional channels in both MOFs. These MOFs catalyze the chemoselective addition of amines to epoxides, giving exclusively β-hydroxyamine under heterogeneous conditions. A ring-opening reaction of a symmetrical epoxide showed that the hexagonal phase diastereoselectively yields trans-alcohol, exhibiting an exquisite model for structure-dependent activity.
The objective of the study was to investigate hair trace elements content in children suffering from autism spectrum disorder (ASD). A total of 74 ASD children and 74 sex- and age-matched controls divided into two age groups (2-4 and 5-9 years) were investigated. Hair trace elements content was assessed using inductively coupled plasma mass spectrometry. A general cohort of ASD children was characterized by 29 %, 41 %, and 24 % lower hair levels of chromium (Cr), iodine (I), and vanadium (V), respectively, whereas the level of selenium (Se) exceeded the respective control values by 31 %. In ASD children aged 2-4 years hair Cr, I and V content was 68 %, 36 % and 41 % lower than in the controls. Older ASD children were characterized by 45 % increase in hair Se levels. In a general cohort of ASD children hair beryllium (Be) and tin (Sn) levels were 50 % and 34 % lower than the control values. In the first age group (2-4 years) of ASD children 34 %, 42 %, and 73 % lower levels of arsenic (As), boron (B), and Be were detected. In the second age group of ASD children only a nearly significant 25 % decrease in hair lead (Pb) was detected. Surprisingly, no significant group difference in hair mercury (Hg), zinc (Zn), and copper (Cu) content was detected. Generally, the results of the present study demonstrate that children with ASD are characterized by lower values in hair of not only essential but also toxic trace elements.
The achievement of environmentally
 sound and economically feasible disposal strategies for biosolids is a major issue in the wastewater treatment industry around the world, including Swaziland. Currently, an iron ore mine site, which is located within a wildlife sanctuary, is being considered as a suitable place where controlled disposal of biosolids may be practiced. Therefore, this study was conducted to investigate the effects of urban biosolids on iron mine soils with regard to plant metal content and ecotoxicological effects on earthworms. This was done through chemical analysis of plants grown in biosolid-amended mine soil. Earthworm behaviour, reproduction and bioaccumulation tests were also conducted on biosolid-amended mine soil. According to the results obtained, the use of biosolids led to creation of soil conditions that were generally favourable to earthworms. However, plants were found to have accumulated Zn up to 346 mg kg(-1) (in shoots) and 462 mg kg(-1) (in roots). This was more than double the normal Zn content of plants. It was concluded that while biosolids can be beneficial to mine soils and earthworms, they can also lead to elevated metal content in plant tissues, which might be a concern to plant-dependant wildlife species. Nonetheless, it was not possible to satisfactorily estimate risks to forage quality since animal feeding tests with hyperaccumulator plants have not been reported. Quite possibly, there may be no cause for alarm since the uptake of metals from soil is greater in plants grown in pots in the greenhouse than from the same soil in the field since pot studies fail to mimic field conditions where the soil is heterogeneous and where the root system possesses a complex topology. It was thought that further field trials might assist in arriving at more satisfactory conclusions.
Heavy metal uptake and accumulation behavior in dietary vegetables irrigated with sewage waters is an important issue worldwide. The main objective of this study was to examine and compare the physiological and growth responses of leafy vegetables irrigated with sewage water. A pot experiment was conducted in a wire house with three leafy vegetables, coriander (Coriandrum sativum), mint (Mentha arvensis), and fenugreek (Trigonella foenum), grown under ambient conditions. Plants were irrigated with different concentrations, 0, 50 (T 1), and 100 % (T 2), of sewage water. After harvesting, morphological and physiological parameters of plants were measured. Heavy metal (Cd, Cu, Pb, and Zn) concentrations in the sewage water were found much higher than safer limits. The results revealed that the highest plant biomass and lowest metal contents were observed in control treatments in all studied vegetables. The biomass of all the vegetables were negatively affected when irrigated with sewage water. In T 2, coriander accumulated maximum Cd (μg g(-1) DW) in shoots (4.97) as compared to other vegetables. The maximum Pb and Cu concentrations were accumulated in mint roots (44 and 3.9, respectively) as compared to coriander and fenugreek. Zinc was accumulated in the sequence of leaves > roots > shoots under polluted water irrigation. The concentrations of potassium increased in leaves, shoots, and roots in all vegetables, while phosphorous concentrations varied with species and plant parts with increasing sewage water concentration. It was found that the leafy vegetables grown with sewage water irrigation may cause severe human health problems.
The development and improvement of fluorescent Zn(2+) sensors and Zn(2+) imaging techniques have increased our insight into this biologically important ion. Application of these tools has identified an intracellular labile Zn(2+) pool and cultivated further interest in defining the distribution and dynamics of labile Zn(2+). The study of Zn(2+) in live cells in real time using sensors is a powerful way to answer complex biological questions. In this review, we highlight newly engineered Zn(2+) sensors, methods to test whether the sensors are accessing labile Zn(2+), and recent studies that point to the challenges of using such sensors. Elemental mapping techniques can complement and strengthen data collected with sensors. Both mass spectrometry-based and X-ray fluorescence-based techniques yield highly specific, sensitive, and spatially resolved snapshots of metal distribution in cells. The study of Zn(2+) has already led to new insight into all phases of life from fertilization of the egg to life-threatening cancers. In order to continue building new knowledge about Zn(2+) biology it remains important to critically assess the available toolset for this endeavor.
Trace mineral micronutrients are imperative for optimum host response. Populations worldwide are prone to their insufficiency owing to lifestyle changes or poor nutritional intake. Balanced levels of trace minerals like iron (Fe), zinc (Zn), selenium (Se) and copper (Cu) are essential to prevent progression of chronic conditions like periodontitis. Their excess as well as deficiency is detrimental to periodontal health. This is specifically true in relation to Fe. Furthermore, some trace elements, e.g. Se, Zn and Cu are integral components of antioxidant enzymes and prevent reactive oxygen species induced destruction of tissues. Their deficiency can worsen periodontitis associated with systemic conditions like diabetes mellitus. With this background, the present review first focusses on the role of four trace minerals, namely, Fe, Zn, Se and Cu in periodontal health followed by an appraisal of the data from case control studies related to their association with chronic periodontitis.
Metal stabilization using soil amendments is an extensively applied, economically viable and environmentally friendly remediation technique. The stabilization of Pb, Zn and As in contaminated soils was evaluated using natural starfish (NSF) and calcined starfish (CSF) wastes at different application rates (0, 2.5, 5.0 and 10.0 wt%). An incubation study was conducted over 14 months, and the efficiency of stabilization for Pb, Zn and As in soil was evaluated by the toxicity characteristic leaching procedure (TCLP) test. The TCLP-extractable Pb was reduced by 76.3-100 and 91.2-100 % in soil treated with NSF and CSF, respectively. The TCLP-extractable Zn was also reduced by 89.8-100 and 93.2-100 % in soil treated with NSF and CSF, respectively. These reductions could be associated with the increased metal adsorption and the formation of insoluble metal precipitates due to increased soil pH following application of the amendments. However, the TCLP-extractable As was increased in the soil treated with NSF, possibly due to the competitive adsorption of phosphorous. In contrast, the TCLP-extractable As in the 10 % CSF treatment was not detectable because insoluble Ca-As compounds might be formed at high pH values. Thermodynamic modeling by visual MINTEQ predicted the formation of ettringite (Ca6Al2(SO4)3(OH)12·26H2O) and portlandite (Ca(OH)2) in the 10 % CSF-treated soil, while SEM-EDS analysis confirmed the needle-like structure of ettringite in which Pb was incorporated and stabilized in the 10 % CSF treatment.
Immobilized metal affinity chromatography (IMAC) has been widely used for the specific separation of biopolymers. However, leakage of metal ions from IMAC adsorbents is of concern in IMAC. In this study, we designed a novel tridenate bis(5-methyltetrazolium)amine (BMTA) to reduce the leakage of metal ions by improving the affinity to immobilized metal ions. The ligand was bonded onto silica via three-step reaction to prepare a high-performance IMAC stationary phase. The chromatographic behaviors of ribonuclease A, cytochrome c, and lysozyme on the Cu(II)-, Ni(II)-, and Zn(II)-chelated stationary phase were investigated with respect to pH effect and elution with an imidazole gradient. The retention times of these three proteins increased by increasing the pH of the mobile phase but decreased by increasing the concentration of the competitive displacer. The retaining strength of the three proteins on the chelated stationary phase were in the order Cu(II) > Ni(II) > Zn(II). The behavior of these three proteins was consistent with the properties of a typical IMAC. The BMTA ligand exhibited a much stronger affinity for Cu(II) and Ni(II) than iminodiacetic acid (IDA), which is often regarded as a standard tridentate IMAC ligand. Quantum mechanical calculations at the B3LYP/6-31G level were used to image the coordination mode of the protein-metal ions-BMTA complex. In addition, a fused histidine-tagged cecropin b-human epidermal growth factor (CB-EGF) from Escherichia coli crude extract was purified by the Ni(II)-chelated stationary phase, and the purity of the CB-EGF was determined to be at least 90 %. These results suggest that the BMTA ligand may have potential applications in the preparation of therapeutics. Graphical Abstract A novel ligand of tridenate bis(5-methyltetrazolium)amine (BMTA) was designed to reduce the leakage of metal ions from the column in immobolized metal affinity chromatography (IMAC).
Cyclic tetramerization of 3-(dibutylamino)phthalonitrile in refluxing n-pentanol in the presence of magnesium pentanoate afforded the four regioisomer-containing nonperipheral 1,8-/11,15-/18,22-/25-tetrakis(dibutylamino)phthalocyaninato magnesium complexes with the 1,8,15,22-tetrakis(dibutylamino)phthalocyanine isomer Mg{Pc[α-N(C4H9)2]4-C4} (2). This, in combination with its much superior crystallinity over the remaining three isomers, renders the easy isolation of 2 only through two simple recrystallizations from THF and methanol. Treatment of 2 with trifluoroacetic acid induced the isolation of metal-free 1,8,15,22-tetrakis(dibutylamino)phthalocyanine, H2{Pc[α-N(C4H9)2]4-C4} (1), which further reacted with M(OAc)2·nH2O (M = Ni, Zn) in refluxing n-pentanol, giving the 1,8,15,22-tetrakis(dibutylamino)phthalocyaninato
 metal complexes M{Pc[α-N(C4H9)2]4-C4} (M = Ni (3), Zn (4)). The full series of four 1,8,15,22-tetrakis(dibutylamino)phthalocyanine isomeric compounds have been characterized by a series of spectroscopic methods and single-crystal X-ray diffraction analyses. Obviously, the present result provides a simple and effective pathway for the synthesis and isolation of novel 1,8,15,22-tetrakis(dibutylamino)phthalocyanine isomeric derivatives, providing one step forward toward completing bis(alkyl)amino-incorporated phthalocyanine species.
Trace metals play important roles in biological function, and x-ray fluorescence microscopy (XFM) provides a way to quantitatively image their distribution within cells. The faithfulness of these measurements is dependent on proper sample preparation. Using mouse embryonic fibroblast NIH/3T3 cells as an example, we compare various approaches to the preparation of adherent mammalian cells for XFM imaging under ambient temperature. Direct side-by-side comparison shows that plunge-freezing-based cryoimmobilization provides more faithful preservation than conventional chemical fixation for most biologically important elements including P, S, Cl, K, Fe, Cu, Zn and possibly Ca in adherent mammalian cells. Although cells rinsed with fresh media had a great deal of extracellular background signal for Cl and Ca, this approach maintained cells at the best possible physiological status before rapid freezing and it does not interfere with XFM analysis of other elements. If chemical fixation has to be chosen, the combination of 3% paraformaldehyde and 1.5 % glutaraldehyde preserves S, Fe, Cu and Zn better than either fixative alone. When chemically fixed cells were subjected to a variety of dehydration processes, air drying was proved to be more suitable than other drying methods such as graded ethanol dehydration and freeze drying. This first detailed comparison for x-ray fluorescence microscopy shows how detailed quantitative conclusions can be affected by the choice of cell preparation method.
The electronic features of Zn(II) and Ru(II) phthalocyanines (Pcs) have been modulated by direct peripheral attachment of up to eight ferrocenes. The presence of peripheral ferrocenes noticeably impacts the electronic properties of the corresponding ZnPc and RuPc complexes 7, 12 and 9, 15, respectively-a notion that is supported by optical spectroscopy with bathochromic shifts of up to 8-10 nm per ferrocene unit. Cyclic voltammetry and optical spectroscopy reveal long-distance (10-11 bonds) electronic interaction between ferrocene units. The ZnPc and RuPc complexes have been integrated into a series of orthogonal, supramolecular bis(phthalocyanine)-perylenediimide electron donor-acceptor conjugates, 2a,b and 3a,b. In these cart-wheel-shaped arrays, coordination of ditopic perylenediimide 16, containing two pyridyl substituents at its imido positions, enabled selective interactions with the metal centers of phthalocyanines 7, 12, 9, and 15. The presence of ferrocenes in, for example, Zn complexes 2a and 3a triggers a fast energy transfer from the excited-state PDI to ZnPc. In the RuPc-PDI conjugates, substitution with ferrocenes produces a slight acceleration of the charge separation upon photoexcitation of the PDI chromophore. However, charge recombination is accelerated by 2 orders of magnitude in ferrocene-containing conjugates when compared to that in the analogous tert-butyl-substituted array 1b.
Jiangxi red soil was used as the tested soil and water spinach (Ipomoea aquatic) and Chinese chive (Allium tuberosum) were used as the tested vegetables in this study to investigate the effects of different amounts of sewage-sludge application on the growth of vegetables and the migration and enrichment patterns of Cu and Zn in vegetables using the potted method. The results indicated that the application of sewage sludge could improve the properties of red soil and promote vegetable growth. The dry weight of water spinach and Chinese chive reached the maximal levels when treated with the amount of sewage sludge at 4% and 10%, which was 4.38 ± 0.82 g and 1.56 ± 0.31 g, respectively. The dry weights after the application of sewage sludge were all larger than control treatment (CK) without sludge application. With increases in the applied amount of sewage sludge, the concentrations of Cu and Zu in red soil continued to increase, and the peak value was not reached. After the two vegetables were planted, the concentrations of Cu and Zn in red soil decreased by different degrees. The degrees of decrease of Zn were generally higher than those of Cu. The enrichment coefficient of water spinach on Cu showed a trend of increase followed by a decrease and reached the peak value of 1.04 ± 0.38 when the applied amount was 4%. The enrichment coefficient of Chinese chive on Cu overall showed a decreasing trend and did not reach the peak value under the treatment levels used in this experiment. The enrichment pattern of Chinese chive on Zn was not obvious, and the differences among all treatment levels were not significant (p < 0.05). However, the enrichment coefficient after the application of sewage sludge was significantly lower than that without the application of sludge.
Dual action compounds (DACs) based on 4-substituted aza-bicyclo[5.3.0]decane Smac mimetic scaffolds (ABDs) linked to a Zn(2+)-chelating moiety (DPA, o-hydroxy, m-allyl, N-acyl (E)-phenylhydrazone) through their 10 position are reported and characterized. Their synthesis, their target affinity (XIAP BIR3, Zn(2+)) in cell-free assays, their pro-apoptotic effects and cytotoxicity in tumor cells with varying sensitivity to Smac mimetics are described. The results are interpreted to evaluate the influence of Zn(2+) chelators on cell-free potency and on cellular permeability of DACs, and to propose novel avenues towards more potent antitumoral DACs based on Smac mimetics and Zn(2+) chelation.
Streams and rivers strongly affected by acid mine drainage (AMD) have legal vacuum in terms of assessing the water toxicity, since the use of conventional environmental quality biomarkers is not possible due to the absence of macroinvertebrate organisms. The Asian clam Corbicula fluminea has been widely used as a biomonitor of metal contamination by AMD in freshwater systems. However, these clams are considered an invasive species in Spain and the transplantation in the field study is not allowed by the Environmental Protection Agency. To evaluate the use of the freshwater bivalve C. fluminea as a potential biomonitor for sediments contaminated by AMD, the metal bioavailability and toxicity were investigated in laboratory by exposure of clams to polluted sediments for 14 days. The studied sediments were classified as slightly contaminated with As, Cr, and Ni; moderately contaminated with Co; considerably contaminated with Pb; and heavily contaminated with Cd, Zn, and specially Cu, being reported as very toxic to Microtox. On the fourth day of the exposure, the clams exhibited an increase in concentration of Ga, Ba, Sb, and Bi (more than 100 %), followed by Co, Ni, and Pb (more than 60 %). After the fourth day, a decrease in concentration was observed for almost all metals studied except Ni. An allometric function was used to determine the relationship between the increases in metal concentration in soft tissue and the increasing bioavailable metal concentrations in sediments.
While numerous studies of dam reservoirs contamination are reported world-wide, we present a missing link in the study of reservoirs sourced from multiple river catchments. In such reservoirs, different point sources of contaminants and variable composition of their sedimentary matrices add to extremely complex geochemical patterns. We studied a unique, step-wise filled Nové Mlýny dam reservoir, Czech Republic, which consists of three interconnected sub-basins. Their source areas are located in units with contrasting geology and different levels and sources of contamination. The aim of this study is to provide an insight into the provenance of the sediment, including lithogenic elements and anthropogenic pollutants, to investigate the sediment dispersal across the reservoir, and to assess the heavy metal pollution in each basin. The study is based on multi-proxy stratigraphic analysis and geochemistry of sediment cores. There is a considerable gradient in the sediment grain size, brightness, MS and geochemistry, which reflects changing hydrodynamic energy conditions and primary pelagic production of CaCO3. The thickness of sediments generally decreases from proximal to distal parts, but underwater currents can accumulate higher amounts of sediments in distal parts near the thalweg line. Average sedimentation rates vary over a wide range from 0.58cm/yr to 2.33cm/yr. In addition, the petrophysical patterns, concentrations of lithogenic elements and their ratios made it possible to identify two main provenance areas, the Dyje River catchment (upper basin) and the Svratka and Jihlava River catchments (middle and lower basin). Enrichment factors (EF) were used for distinguishing the anthropogenic element contribution from the local background levels. We found moderate Zn and Cu pollution (EF ~2 to 5) in the upper basin and Zn, Cu and Pb (EF ~2 to 4.5) in the middle basin with the peak contamination in the late 1980s, indicating that the two basins have different contamination histories.
Laccases of white-rot fungi provide a promising future as a tool to be used in the field of biodegradation of synthetic dyes with different chemical structures. The aim of this study was production, characterization, and application of laccases from the white-rot fungus Ceriporiopsis subvermispora ATCC 90467 for decolorization of triphenylmethane dyes that could remain persistent in wastewater. Laccase was purified from a
 C. subvermispora culture by a four-step method resulting high specific activity of 2,571 U g(-1) , 88-fold higher than crude laccase. Purified laccase (molecular weight 45 kDa) had the optimum activity at pH 2.0 and the optimum temperature 50 °C using ABTS as chromogenic substrate. Laccases efficiently decolorized triphenylmethane dyes such as Malachite Green (87.8%), Bromocresol Purple (71.6%), and Methyl Violet (68.1%) without redox mediator. However, decolorization percentage of hardly degradable triphenylmethane dyes such as Phenol Red, Bromophenol Blue, and Brilliant Blue R-250 was increased the presence of some low-molecular weight compounds (natural or synthetic redox mediators). Purified laccases were resistant to Mg(2+) , Ca(2+) , Ba(2+) , Mn(2+) , Fe(2+) , Cu(2+) , Zn(2+) , and Sn(2+) (10 mmol L(-1) ). These findings suggest that laccases from C. subvermispora are able to decolorize triphenylmethane dyes without the negative influence of metal ions that can be found in wastewater.
Tissue engineering has attracted a great deal of interest by combining fibrous scaffolds and stem cells regarding bone regeneration applications. In the present study, polymeric fibrous polyethersulphone-polyethylene glycol (PES-PEG) was fabricated by electrospinning. It was then treated with NH3 plasma to enhance surface hydrophilicity, cell attachment, growth and differentiation potential. X-ray photoelectron spectroscopy (XPS) measurements were used to evaluate the modification of the scaffold's surface chemistry. Electrospun scaffolds were coated with willemite (Zn2SiO4) bioceramic nanoparticles. Scaffold characterization was done by scanning electron microscope (SEM), differential scanning calorimetry (DSC), contact angle measurements and tensile analysis. MTT assay was used to assess the biocompatibility of fibrous scaffolds loaded with Zn2SiO4 regarding proliferation support. Osteogenic differentiation of cultured human mesenchymal stem cells (hMSCs) on fibers was evaluated using common osteogenic markers such as alkaline phosphatase (ALP) activity, calcium mineral deposition, quantitative real-time PCR (qPCR) and immunocytochemical analysis (ICC). According to the results, proliferation and osteogenic differentiation of hMSCs were significantly enhanced after coating Zn2SiO4 on fibrous scaffolds. These results were detected by higher ALP activity, biomineralization and expression of osteogenic related genes and proteins in differentiated hMSCs. In conclusion, our results indicated that the combination of Zn2SiO4 nanoparticles and electrospun fibers is able to provide a new, suitable and more efficient matrix to support stem cells differentiation for bone tissue engineering applications.
Attention on semiconductor nanocrystals have been largely focused because of their unique optical and electrical properties, which can be applied as light absorber and luminophore. However, the band gap and structure engineering of nanomaterials is not so easy because of their finite size. Here we demonstrate an approach for preparing ternary AgInS2 (AIS), quaternary AgZnInS (AZIS), AgInS2/ZnS and AgZnInS/ZnS nanocompounds based on cation exchange. First, pristine Ag2S quantum dots (QDs) with different sizes were synthesized in one-pot, followed by the partial cation exchange between In(3+) and Ag(+). Changing the initial ratio of In(3+) to Ag(+), reaction time and temperature can control the components of the obtained AIS QDs. Under the optimized conditions, AIS QDs were obtained for the first time with a cation disordered cubic phase and high photoluminescence (PL) quantum yield (QY) up to 32% in aqueous solution, demonstrating the great potential of cation exchange in the synthesis for nanocrystals with excellent optical properties. Sequentially, Zn(2+) ions were incorporated in situ through a second exchange of Zn(2+) to Ag(+)/In(3+), leading to distinct results under different reaction temperature. Addition of Zn(2+) precursor at room temperature produced AIS/ZnS core/shell NCs with successively enhancement of QY, while subsequent heating could obtain AZIS homogeneous alloy QDs with a successively blue-shift of PL emission. This allow us to tune the PL emission of the products from 483 to 675 nm and fabricate the chemically stable QDs core/ZnS shell structure. Based on the above results, a mechanism about the cation exchange for the ternary nanocrystals of different structures was proposed that the balance between cation exchange and diffusion is the key factor of controlling the band gap and structure of the final products. Furthermore, photostability and in vitro experiment demonstrated quite low cytotoxicity and remarkably promising applications in the field of clinical diagnosis.
The large surface area of metal-organic frameworks (MOFs) sparks great interest for their use in storage applications. While the bulk of MOF applications focuses on incorporation of gases, we demonstrate that these highly porous frameworks are also well-suited for metal ion storage. For well-defined, highly oriented surface-anchored MOF thin films grown on modified gold surfaces using liquid-phase epitaxy (LPE), also referred to as SURMOFs, we determined the loading of two different types of MOF materials with a total of seven types of metal ions (Zn(2+), Ag(+), Pd(2+), Fe(3+), Cd(2+), Ni(2+), and Co(2+)). Measurements using a quartz crystal microbalance (QCM) allowed determination of loading capacities as well as diffusion constants in a quantitative fashion. The adsorption capacities were observed to be highly ion specific; the largest uptake was for Fe(3+) and Pd(2+) ions with six and four metal ions per MOF pore, respectively. By comparing results for SURMOFs fabricated from different types of linkers, we demonstrate that S-containing functionalities in particular drastically improve the storage capacity of MOFs for metal ions.
The studied soil profile under the Main Market Square (MMS) in Krakow was characterised by the influence of medieval metallurgical activity. In the presented soil section lithological discontinuity (LD) was found, which manifests itself in the form of cultural layers (CLs). Moreover, in this paper LD detection methods based on soil texture are presented. For the first time, three different ways to identify the presence of LD in the urban soils are suggested. The presence of LD had an influence on the content and distribution of heavy metals within the soil profile. The content of heavy metals in the CLs under the MMS in Krakow was significantly higher than the content in natural horizons. In addition, there were distinct differences in the content of heavy metals within CLs. Profile variability and differences in the content of heavy metals and phosphorus within the CLs under the MMS were activity indicators of Krakow inhabitants in the past. This paper presents alternative methods for the assessment of the degree of heavy metal contamination in urban soils using selected pollution indices. On the basis of the studied total concentration of heavy metals (Zn, Pb, Cu, Mn, Cr, Cd, Ni, Sn, Ag) and total phosphorus content, the Geoaccumulation Index (Igeo), Enrichment Factor (EF), Sum of Pollution Index (PIsum), Single Pollution Index (PI), Nemerow Pollution Index (PINemerow) and Potential Ecological Risk (RI) were calculated using different local and reference geochemical backgrounds. The use of various geochemical backgrounds is helpful to evaluate the assessment of soil pollution. The individual CLs differed from each other according to the degree of pollution. The different values of pollution indices within the studied soil profile showed that LDS should not be evaluated in terms of contamination as one, homogeneous soil profile but each separate CL should be treated individually.
Folic acid, vitamins and Zinc play essential role in DNA methylation but alcohol consumption is known to affectthe levels of these micronutrients leading to risk of developing various illnesses and certain cancers. This study determinedthe levels of DNA methylation dependent-micronutrients (folate, vitamin B12, vitamin B6, zinc and selenium) andhomocysteine as a suggestion for DNA methylation status in Nigerian alcohol consumers compared with non-consumers ofalcohol. Venous blood (5ml) was obtained from thirty-four males that consume alcoholic beverages for at least 10 years andthirty-two male controls that did not consume alcoholic beverages at least 10 years. Serum concentrations of folate, vitaminB12, vitamin B6, homocysteine (Hcy), selenium (Se) and zinc (Zn) were determined using High Performance LiquidChromatography (HPLC) and Atomic Absorption Spectrophotometry (AAS) as appropriate. Independent Student t-test wasused to compare the mean values between alcohol consumers and control. Mean differences were considered significant atp<0.05. The mean serum levels of Zn and Se were significantly raised in alcohol consumers when compared with nonalcohol consumers while the mean levels of Vitamin B6 and Hcy were significantly reduced in alcohol consumers whencompared with non-alcohol consumers. There were no statistically significant differences in the mean serum levels ofVitamin B12 and folate in alcohol consumers when compared with non-alcohol consumers. Since vitamin B6 and Hcy arerequired for DNA methylation, reduced vitamin B6 and Hcy levels in consumers of alcoholic beverages might suggest DNAhypomethylation in alcohol consumers.
Complementary feeding should fill the gap in energy and nutrients between estimated daily needs and amount obtained from breastfeeding from 6-month onward. However, homemade complementary foods are often reported for inadequacy in key nutrients despite reports of adequacy for energy and proteins. The aim of this study was to assess caregiver's complementary feeding knowledge, feeding practices, and to evaluate adequacy
 daily intakes from homemade complementary foods for children of 6-23 months in food insecure woredas of Wolayita zone, Ethiopia. A cross-sectional study assessing mothers/caregiver's knowledge and complementary feeding practice, adequacy of daily energy, and selected micronutrient intakes using weighed food record method. Multi-stage cluster sampling method was also used to select 68 households. Caregivers had good complementary feeding knowledge. Sixty (88.2%) children started complementary feeding at 6 months and 48 (70.6%) were fed three or more times per day. Daily energy intake, however, was significantly lower (p < 0.05) than estimated daily needs, with only 151.25, 253.77, and 364.76 (kcal/day) for 6-8, 9-11, and 12-23 months, respectively. Similarly, Ca and Zn intakes (milligrams per day) were below the daily requirements (p = 0.000), with value of 37.76, 0.96; 18.83, 1.21; 30.13, 1.96; for the 6-8, 9-11, and 12-23 months, respectively. Significant shortfall in daily intake of Fe (p = 0.000) was observed among the 6-8 and 9-11 months (3.25 and 4.17 mg/day, respectively), even accounting for high bioavailability. The complementary foods were energy dense. Daily energy, Ca, Zn, and Fe (except 12-23 months) intake, however, was lower than estimated daily requirements.
The glyoxalase system including two thiol-dependent enzymes, glyoxalase I (Glo-I) and glyoxalase II, plays an important role in a ubiquitous metabolic pathway involved in cellular detoxification of cytotoxic 2-oxoaldehydes. Tumor cells have high glycolytic activity, leading to increased cellular levels of these toxic metabolites. The increased activity of the detoxification system in cancerous cells makes this pathway a viable target for developing novel anticancer agents. In this study, we examined the potential utility of non-glutathione-based inhibitors of the Glo-I enzyme as novel anticancer drugs.
Computer-aided drug design techniques, such as customized pharmacophoric features, virtual screening, and flexible docking, were used to achieve the project goals. Retrieved hits were extensively filtered and subsequently docked into the active site of the enzyme. The biological activities of retrieved hits were assessed using an in vitro assay against Glo-I.
Since Glo-I is a zinc metalloenzyme, a customized Zn-binding pharmacophoric feature was used to search for selective inhibitors via virtual screening of a small-molecule database. Seven hits were selected, purchased, and biologically evaluated. Three of the seven hits inhibited Glo-I activity, the most effective of which exerted 76.4% inhibition at a concentration of 25 µM.
We successfully identified a potential Glo-I inhibitor that can serve as a lead compound for further optimization. Moreover, our in silico and experimental results were highly correlated. Hence, the docking protocol adopted in this study may be efficiently employed in future optimization steps.
The synthesis of a new ligand (L1) containing two 1,4,7-triazacyclononane ([9]aneN3 ) moieties linked by a 4,5-dimethylenacridine unit is reported. The binding and fluorescence sensing properties toward Cu(2+) , Zn(2+) , Cd(2+) , and Pb(2+) of L1 and receptor L2, composed of two [9]aneN3 macrocycles bridged by a 6,6''-dimethylen-2,2':6',2''-terpyridine unit, have been studied by coupling potentiometric, UV/Vis absorption, and emission measurements in aqueous media. Both receptors can selectively detect Zn(2+) thanks to fluorescence emission enhancement upon metal binding. The analysis of the binding and sensing properties of the Zn(2+) complexes toward inorganic anions revealed that the dinuclear Zn(2+) complex of L1 selectively binds and senses the triphosphate anion (TP), whereas the mononuclear Zn(2+) complex of L2 displays selective recognition of diphosphate (DP). Binding of TP or DP induces emission quenching of the Zn(2+) complexes with L1 and L2, respectively. These results are exploited to discuss the role played by pH, number of coordinated metal cations, and binding ability of the bridging units in metal and/or anion coordination and sensing.
Quantitative indices are classically employed to evaluate the contamination status of metals with reference to the baseline concentrations. The baselines vary considerably across different geographical zones. It is imperative to determine the local geochemical baseline to evaluate the contamination status. No study has been done to establish the background concentrations in tropical rivers of this region. This paper reports the background concentrations of metals in water and sediment of the Baleh River, Sarawak, derived based on the statistical methods where the areas possibly disturbed are distinguished from the undisturbed area. The baseline levels of six elements in water determined were Al (0.34 mg/L), Fe (0.51 mg/L), Mn (0.12 mg/L), Cu (0.01 mg/L), Pb (0.03 mg/L), and Zn (0.05 mg/L). Arsenic and selenium were below the detection limit. For sediment, the background values were established according to statistical methods including (mean + 2σ), iterative 2σ, cumulative distribution frequency, interquartile, and calculation distribution function. The background values derived using the iterative 2σ algorithm and calculated distribution function were relatively lower. The baseline levels calculated were within the range reported in the literatures mainly from tropical and sub-tropical regions. The upper limits proposed for nine elements in sediment were Al (100,879 mg/kg), Cr (75.45 mg/kg), Cu (34.59 mg/kg), Fe (37,823 mg/kg), Mn (793 mg/kg), Ni (22.88 mg/kg), Pb (27.26 mg/kg), Zn (70.64 mg/kg), and Hg (0.33 mg/kg). Quantitative indices calculated suggest low risk of contamination at the Baleh River.
This study explores the environmental impact of metal exposure on humans through detailed phase and structural characterization of gallstones from two environmentally contrasting populations in Huelva Province (SW Spain). A total of 42 gallstone samples, obtained after surgical intervention at the Riotinto Hospital, were studied by powder X-ray diffraction (XRD), Fourier Transformed Infra-Red spectroscopy (FTIR), FTIR-μ-ATR (Attenuated Total Reflection) coupled with an optical microscope, and by Environmental Scanning Electron Microscope with Energy Dispersive X-ray Spectroscopy (ESEM-EDS), and subsequently classified according to their phase composition and structure. Additionally, the patients were enquired for their living habits in order to analyze the source of possible exposure to metal contamination. The gallstones were classified into pure, mixed and composite cholesterol stones, black and brown pigment stones, and carbonate stones. The patients from the study group residing in a region with acknowledged metal contamination of both natural and anthropogenic origin have a higher risk of metal exposure through contaminated soil, particle matter in the air, and consumption of local water and food products. According to our findings, the metal exposure is related to a higher tendency of forming black pigment stones in the study group in comparison to the control group residing in a natural park with nearly pristine environmental conditions. Moreover, the gallstones from the study group showed to contain more abundant metal components, such as Cu, Fe, Ni, and Zn, than those from the control group. To our knowledge this is the first study to examine the regional environmental impact of metal exposure on human gallstones.
Cr(VI) pollution is increasing continuously as a result of ongoing industrialization. In this study, we investigated the thermophilic denitrifying bacterium Chelatococcus daeguensis TAD1, isolated from the biofilm of a biotrickling filter used in nitrogen oxides (NOX) removal, with respect to its ability to remove Cr(VI) from an aqueous solution. TAD1 was capable of reducing Cr(VI) from an initial concentration of 10 mg/L to non-detectable levels over a pH range of 7-9 and at a temperature range of 30-50°C. TAD1 simultaneously removed both Cr(VI) and NO3 (-)-N at 50°C, when the pH was 7 and the initial Cr(VI) concentration was 15 mg/L. The reduction of Cr(VI) to Cr(III) correlated with the growth metabolic activity of TAD1. The presence of other heavy metals (Cu, Zn, and Ni) inhibited the ability of TAD1 to remove Cr(VI). The metals each individually inhibited Cr(VI) removal, and the extent of inhibition increased in a cooperative manner in the presence of a combination of the metals. The addition of biodegradable cellulose acetate microspheres (an adsorption material) weakened the toxicity of the heavy metals; in their presence, the Cr(VI) removal efficiency returned to a high level. The feasibility and applicability of simultaneous nitrate removal and Cr(VI) reduction by strain TAD1 is promising, and may be an effective biological method for the clean-up of wastewater.
Sequencing of the blaIMP-4 -carrying C. freundii B38 using PacBio SMRT technique revealed that the genome contained a chromosome of 5,134,500 bp, and three plasmids, pOZ172 (127,005 bp), pOZ181 (277,592 bp), and pOZ182 (18,467 bp). Plasmid pOZ172 was identified as IncFIIY, like pP10164-NDM and pNDM-EcGN174. It carries a class 1 integron with four cassettes: blaIMP-4-qacG2-aacA4-aphA15, and a complete hybrid tni module (tniR-tniQ-tniB-tniA). The recombination of tniR from Tn402 (identical) with tniQBA (99%) from Tn5053 occurred within the res site of Tn402/5053. The Tn402/5053-like integron, named Tn6017, was inserted into Tn1722 at the res II site. The replication, partitioning and transfer systems of pOZ181 were similar to IncHI2 (e.g. R478) and contained a sul1-type class 1 integron with the cassette array: orf-dfrA1-orf-gcu37-aadA5 linked to an upstream Tn1696 tnpA-tnpR and to a downstream 3' CS and ISCR1 A Tn2 transposon with a blaTEM-1b β-lactamase was identified on pOZ182. Other interesting
 resistance determinants on the B38 chromosome included MDR efflux pumps, AmpC β-lactamase, and resistances to Cu, Ag, As, and Zn. This is the first report of a complete tni module linked to a blaIMP- 4 carrying class 1 integron, and together with other recently reported non-sul1 integrons, represents the emergence of a distinct evolutionary lineage of class 1 integrons lacking a 3' -CS (qacEΔ1-sul1). The unique cassette array, complete tni module of Tn6017, and incompatibility group of pOZ172 suggests a different blaIMP-4 evolutionary pathway in C. freundii B38 compared to other blaIMP-4 foundin Gram-negative bacteria in the Western Pacific Region.
An elaborate survey on the contamination of heavy metals was carried out in surface sediments of different ecosystems such as Vellar-Coleroon estuarine, Pichavaram mangrove and coastal region of Parangipettai, Southeast coast of India. The study was intended since, the coal based thermal power plant and oil refinery plant are proposed to set up along this coast and aquaculture industries and dredging activities are developing. The parameters such as soil texture, pH, total organic carbon (TOC) and heavy metal (Fe, Mn, Cu, Cd, Zn and Ni) concentrations were analyzed for the surface sediments during pre and postmonsoon seasons. Among the metals analyzed, Fe and Mn were found to have dominant as the levels were recorded as 11,804 μg g(-)(1) and 845.2 μg g(-)(1) respectively. A significant correlation was observed between total organic carbon (TOC) and heavy metals. In the mangrove ecosystem, the levels of heavy metals found to be maximum indicating that the rich organic matter acts as an efficient binding agent for metals. The overall finding of the present study indicated that the sediments from the entire Vellar-Coleroon estuarine and Pichavaram mangrove ecosystems were found moderately polluted with cadmium metal. The result of cluster analysis indicated disparity in accumulation of heavy metals in sediments of different ecosystems due to the variations in organic matter. The heavy metals were transported from land to coastal through flood during monsoon season reflecting the variations in their levels in different ecosystems at postmonsoon season.
To describe nutrient intakes, characterize dietary patterns and analyse their associations with sociodemographic characteristics among pregnant women in Shaanxi, China.
Population-based cross-sectional survey.
Twenty counties and ten districts in Shaanxi Province of Northwest China, 2013.
Women (n 7462) were recruited using a stratified multistage random sampling method to report diets during pregnancy, at 0-12 months (median 3 months; 10th-90th percentile, 0-7 months) after delivery.
Pregnant women had higher intakes of fat, niacin and vitamin E than the nutrient reference values, while most micronutrients such as vitamin A, folate, Ca and Zn were reportedly low. Women in the highest education, occupation and household income groups had higher nutrient intakes than those in the lowest groups. Nutrient intake differences also existed by geographic area, residence and maternal age at delivery. Three dietary patterns were identified: balanced pattern, vegetarian pattern and snacks pattern. Participants with high balanced pattern scores tended to be better educated, wealthier, 25-29 years old at delivery, working outside and living in urban areas and central Shaanxi. Women with high scores on the vegetarian pattern and snacks pattern tended to be in low balanced pattern score groups, and had lower nutrient intakes than those in the high balanced pattern score groups.
The study suggested that pregnant women in Shaanxi, China had low intakes of most nutrients such as vitamin A, folate and Ca. Dietary patterns and most nutrient intakes varied by sociodemographic characteristics. Targeted programmes are needed to improve dietary intakes and dietary patterns among sociodemographically disadvantaged groups.
Autonomous transport and release of bacterial cells by self-propelled micromotors were achieved. The motors consisted of zinc and platinum hemispheres formed on polystyrene beads and moved as a result of simultaneous redox reactions occurring on both metal ends. The highly negative redox potential of zinc enabled the selection of a wide variety of organic redox compounds as fuels, such as methanol and p-benzoquinone. The movement of motors was observed in solutions of fuels. To realize autonomous capture, transport, and release of cargo, a self-assembled monolayer (SAM) was formed on the platinum part of the motor. This SAM could be desorbed by coupling the reaction with the dissolution of zinc, which could also be controlled by adjusting the concentration of Zn(2+) ions. Escherichia coli (E. coli) cells were captured by the motor (due to hydrophobic interactions), transported, and released following SAM desorption at the mixed potential.
Ectomycorrhizal (ECM) fungi contribute to the survival of host trees on metal-rich soils by reducing the transfer of toxic metals into roots. However, little is known about the ability of ECM fungi to accumulate elements in ectomycorrhizae (ECMs). Here we report Ag, As, Cd, Cl, Cu, Sb, V, and Zn contents in wild-grown Norway spruce ECMs collected in a smelter-polluted area at Lhota near Příbram, Czech Republic. The ECMs data were compared with the element concentrations determined in the corresponding non-mycorrhizal fine roots, soils, and soil extracts. Bioaccumulation factors were calculated to differentiate the element accumulation ability of ECMs inhabited by different mycobionts, which were identified by ITS rDNA sequencing. Among the target elements, the highest contents were observed for Ag, Cl, Cd, and Zn; Imleria badia ECMs showed the highest capability to accumulate these elements. ECMs of Amanita muscaria, but not of other species, accumulated V. The analysis of the proportions of I. badia and A. muscaria mycelia in ECMs by using species-specific quantitative real-time PCR revealed variable extent of the colonization of roots, with median values close to 5% (w/w). Calculated Ag, Cd, Zn and Cl concentrations in the mycelium of I. badia ECMs were 1 680, 1 510, 2 670, and 37,100 mg kg(-1) dry weight, respectively, indicating substantial element accumulation capacity of hyphae of this species in ECMs. Our data strengthen the idea of an active role of ECM fungi in soil-fungal-plant interactions in polluted environments.
Magnesium alloys have been investigated by many researchers as a new absorbable biomaterial owing to their excellent degradability with non-maleficence or low-maleficence in living tissues. In the present work, the in vitro cytocompatibility of an Magnesium alloy was investigated by culturing cells directly on it. Investigations were carried out in terms of the cell viability along with the use of scanning electron microscopy to observe its morphology. The cell lines used were derived from fibroblast, endothelial, and smooth muscle cells. Pure magnesium and AZ31 alloy composed of magnesium (96 %), aluminum (3 %), and zinc (1 %) were adopted as models. The viability of cells on the metal samples and on the margin area of a multi-well plate was investigated. For direct culturing on metal, a depression in the viability and morphologically stressed cells were observed. In addition, the cell viability was also depressed for the margin area. To clarify the factors causing the negative effects, the amount of eluted metal ions and pH changes in the medium because of the erosion of the Magnesium samples were investigated, together with the cytotoxicity of sole metal ions corresponding to the composition of the metals. It was found that Mg(2+), Zn(2+), and Al(3+) ions were less toxic at the investigated concentrations, and that these factors will not produce negative effects on cells. Consequently, these factors cannot fully explain the results.
Atmospheric deposition was investigated using the terrestrial moss species Hypnum cupressiforme (Hedw.) and Homolothecium lutescens (Hedw.) in the Bregalnica River basin, Republic of Macedonia. Long-term emission occurs in this area due to the hydrothermal exploitation of Pb-Zn deposits (Sasa and Zletovo mines) and copper ore exploitation and floatation (Bučim mine). Determination of the chemical elements was conducted using atomic emission spectrometry with inductively coupled plasma (ICP-AES) and mass spectrometry with inductively coupled plasma (ICP-MS). A combination of multivariate techniques (PCA, FA and CA) was applied for data processing and identification of element association with lithogenic/anthropogenic origin. Seven dominant factors were extracted from the total of 69 analysed elements. Spatial distribution maps were constructed for the determination and localisation of smaller areas with higher contents of certain anthropogenic elements. In this way, the influences of selected human activities on local air pollution can be determined. The summarised data show quantification of the element distributions. This not only allows the determination of the distribution of hazardous elements but also presents complete characterisation of element deposition in the environs of mines.
Accurate quantification depends on normalization of the measured gene expression data. In particular, gene expression studies with exposure to metals are challenging due their toxicity and redox-active properties. Here, we assessed the stability of potential reference genes in three cell lines commonly used to study metal cell metabolism: Caco-2 (colon), HepG2 (liver) and THP-1 (peripheral blood) under copper (Cu) or zinc (Zn) exposure. We used combined statistical tools to identify the best reference genes from a set of eleven candidates, which included traditional "housekeeping" genes such as GAPDH and B-ACTIN, in cell lines exposed to high and low, Zn and
 Cu concentrations. The expression stabilities of ATP5B (ATP synthase) and CYC1 (subunits of the cytochrome) were the highest considering the effect of Zn and Cu treatments whereas SDHA (succinate dehydrogenase) was found to be the most unstable gene. Even though the transcriptional effect of Zn and Cu is very different in term of redox properties, the same best reference genes were identified when Zn or Cu treatments were analyzed together. Our results indicate that ATP5B/CYC1 are the best candidates for reference genes after metal exposure, which can be used as a suitable starting point to evaluate gene expression with other metals or in different cell types in human models.
Aggregation of the amyloid-beta (Aβ) peptide into insoluble plaques is a major factor in Alzheimer's disease (AD) pathology. Another major factor in AD is arguably metal ions, as metal dyshomeostasis is observed in AD patients, metal ions modulate Aβ aggregation, and AD plaques contain numerous metals including redox-active Cu and Fe ions. In vivo, Aβ is found in various cellular locations including membranes. So far, Cu(II)/Aβ interactions and ROS generation have not been investigated in a membrane environment. Here, we study Cu(II) and Zn(II) interactions with Aβ bound to SDS micelles or to engineered aggregation-inhibiting molecules (the cyclic peptide CP-2 and the ZAβ3(12-58)Y18L Affibody molecule). In all studied systems the Aβ N-terminal segment was found to be unbound, unstructured, and free to bind metal ions. In SDS micelles, Aβ was found to bind Cu(II) and Zn(II) with the same ligands and the same KD as in aqueous solution. ROS was generated in all Cu(II)/Aβ complexes. These results indicate that binding of Aβ to membranes, drugs, and other entities that do not interact with the Aβ N-terminal part, appears not to compromise the N-terminal segment's ability to bind metal ions, nor impede the capacity of N-terminally bound Cu(II) to generate ROS.
This study investigated the accumulation Co, Cu, Fe, Mn, Ni, Se, and Zn in Atlantic horseshoe crab (Limulus polyphemus) early life stages (egg, embryo and larvae) and compared the concentrations to the concentration of each element in sediment, pore water and overlying water for 5 sites across Long Island, NY. For the majority of the sites, all essential trace elements accumulated in the embryos and larvae. However, many of the embryos and larvae at specific sites presented different concentration patterns which had no apparent relationship with the local habitat sediment and water values. Generally, Cu, Fe, and Se sequentially increased from egg stage through larval stages for the majority of sites, while Co, Mn, and Ni only did for a few sites. Zinc also showed an increase across sites from embryo to larval stage, however was the only one to show a decrease in concentration from egg to embryo stage at all sites. Interestingly, Mn at Manhasset Bay presented embryo and larval stages to be 50 fold greater than all other sites while the egg stage showed similar values to other sites; this high degree of uptake could be due to a high concentration in the overlying water. All essential trace elements can be accumulated from the environment but greater concentrations may be influenced by abiotic factors and the predominant uptake route (aqueous versus diet) at each life stage. Future laboratory experiments are required to investigate factors that influence essential trace element accumulation and loss in horseshoe crab early life stages.
Surface sediment samples were collected from upstream down to the subaqueous delta of the Red River in Vietnam to assess heavy metal pollution. Sediment Cr and V concentrations are strongly correlated with Al, Fe, Mn and total organic carbon concentrations, as well as particle size, suggesting that these two metals are derived primarily from natural sources and enriched in the fine fraction of sediments. In contrast, Cu, Cd, Pb, Ni and Zn concentrations show weaker correlations with particle size, with very high concentrations observed at several sites in the upper reach of the river, pointing to anthropogenic input as a possible source of these heavy metals. Enrichment factors (EF) of Cu, Cd, Pb, Ni and Zn suggest that heavy metal pollution is present in sediments with significantly high values in the upstream. The data analysis indicates that Cd, Cu and Pb are the dominant pollutants in the Red River, with their concentrations reaching moderate to serious pollution levels.
The Pawtuxet River in Rhode Island, USA, has a long history of industrial activity and pollutant discharges. Metal contamination of the river sediments is well documented and historically exceeded toxicity thresholds for a variety of organisms. The Pawtuxet River dam, a low-head dam at the mouth of the river, was removed in August 2011. The removal of the dam was part of an effort to restore the riverine ecosystem after centuries of anthropogenic impact. Sediment traps were deployed below the dam to assess changes in metal concentrations and fluxes (Ag, Cd, Cr, Cu, Ni, Pb, and Zn) from the river system into Pawtuxet Cove. Sediment traps were deployed for an average duration of 24 days each, and deployments continued for 15 months after the dam was removed. Metal concentrations in the trapped suspended particulate matter dropped after dam removal (e.g., 460 to 276 mg/kg for Zn) and remained below preremoval levels for most of the study. However, particle-bound metal fluxes increased immediately after dam removal (e.g., 1206 to 4248 g/day for Zn). Changes in flux rates during the study period indicated that river volumetric flow rates acted as the primary mechanism controlling the flux of metals into Pawtuxet Cove and ultimately upper Narragansett Bay. Even though suspended particulate matter metal concentrations initially dropped after removal of the dam, no discernable effect on the concentration or flux of the study metals exiting the river could be associated with removal of the Pawtuxet River dam. Integr Environ Assess Manag 2016;00:000-000. Published 2016. This article is a US Government work and is in the public domain in the USA.
Homeostasis of metal ions is critical for life and excessive exposure can promote cellular damage that could be due to oxidative damage. In this context we evaluated the effects of three different elements (copper, zinc and aluminum) on oxidative stress and mitochondrial functionality in nucleated trout erythrocytes (Oncorhynchus mykiss). Flowcytometric measurements using MitoProbe and DCFDA-H2 as fluorescent probes, indicated that redox active copper was able to influence all the biological parameters considered while redox inert, zinc and aluminum, show no significant effects. Toxicity of Al and Zn represent a debated argument and their ability to interact with other endogenous metal ions/metal binding proteins could play a role modulating their cellular toxicity.
The characteristics and mechanisms of competitive adsorption of trace metals on bacteria-associated clay mineral composites have never been studied, despite their being among the most common organic-mineral complexes in geological systems. Herein, competitive adsorption of Pb and Cd on Pseudomonas putida-montmorillonite composite was investigated through adsorption-desorption experiment, isothermal titration calorimetry (ITC), and synchrotron micro X-ray fluorescence (μ-XRF). From the experiment, stronger competition was observed on clay mineral than on bacteria-clay composite because more non-specific sites accounted for heavy metal adsorption on clay mineral surface at the studied pH 5. Both competing heavy metals tended to react with bacterial fractions in the composite, which was verified by the higher correlation of Cd (and Pb) with Zn (R(2) = 0.41) elemental distribution than with Si (R(2) = 0.10). ITC results showed that competitive adsorption exhibited a lower entropy change (ΔS) at the metal-sorbent interfaces compared with single-metal adsorption, revealing that Cd and Pb are bound to the same types of adsorption sites on the sorbent. The competitive effect on bacteria-clay composite was found to be helpful for a better understanding on the fixation, remobilization and subsequent migration of heavy metals in multi-metal contaminated environments.
Precipitates and their associated strain fields significantly influence mechanical properties and, consequently, the industrial performance of aluminum alloys. In this work, we present a direct measurement of strains induced by η' and η precipitates in an Al-Zn-Mg-Cu alloy using aberration-corrected high-resolution transmission electron microscopy and quantitative strain analysis. The results demonstrate that the strain induced by precipitates in the Al-Zn-Mg-Cu alloy shows significant tensile strains perpendicular to the longitudinal direction of the precipitate discs on the side of the discs and along the longitudinal direction at both ends of the η' and η precipitates. This strain field can be described by an equivalent dislocation model, in which the lattice mismatch between the precipitate and the matrix is equivalent to a series of dislocation pairs along the precipitate/matrix interfaces.
Laboratory leaching experiments were performed to study the potential of coarse street sediments (i.e. >250μm) to release dissolved and particulate-bound heavy metals (i.e. Cd, Cr, Cu, Ni, Pb and Zn) during rainfall/runoff. Towards this end, street sediments were sampled by vacuuming at seven sites in five Swedish cities and the collected sediments were characterized with respect to their physical and chemical properties. In the laboratory, the sediments were combined with synthetic rainwater and subject to agitation by a shaker mimicking particle motion during transport by runoff from street surfaces. As a result of such action, coarse street sediments
 were found to release significant amounts of heavy metals, which were predominantly (up to 99%) in the particulate bound phase. Thus, in dry weather, coarse street sediments functioned as collectors of fine particles with attached heavy metals, but in wet weather, metal burdens were released by rainfall/runoff processes. The magnitude of such releases depended on the site characteristics (i.e. street cleaning and traffic intensity), particle properties (i.e. organic matter content), and runoff characteristics (pH, and the duration of, and energy input into, sediment/water agitation). The study findings suggest that street cleaning, which preferentially removes coarser sediments, may produce additional environmental benefits by also removing fine contaminated particles attached to coarser materials.
This study aimed to assess how the current global warming perspective, with increasing air temperature (20°C vs. 25°C) and decreasing soil moisture content (50% vs. 30% of the soil water holding capacity, WHC), affected the toxicity of a metal(loid)-polluted agricultural soil to Enchytraeus crypticus. Enchytraeids were exposed for 21d to a dilution series of the agricultural soil with Lufa 2.2 control soil under four climate situations: 20°C+50% WHC (standard conditions), 20°C+30% WHC, 25°C+50% WHC, and 25°C+30% WHC. Survival, reproduction and bioaccumulation of As, Cd, Co, Cu, Fe, Mn, Ni, Pb and Zn were obtained as endpoints. Reproduction was more sensitive to both climate factors and metal(loid) pollution. High soil salinity (electrical conductivity~3dSm(-1)) and clay texture, even without the presence of high metal(loid) concentrations, affected enchytraeid performance especially at drier conditions (≥80% reduction in reproduction). The toxicity of the agricultural soil increased at drier conditions (10% reduction in EC10 and EC50 values for the effect on enchytraeid reproduction). Changes in enchytraeid performance were accompanied by changes in As, Fe, Mn, Pb and Zn bioaccumulation, with lower body concentrations at drier conditions probably due to greater competition with soluble salts in the case of Fe, Mn, Pb and Zn. This study shows that apart from high metal(loid) concentrations other soil properties (e.g. salinity and texture) may be partially responsible for the toxicity of metal(loid)-polluted soils to soil invertebrates, especially under changing climate conditions.
Zinc transporters (ZnTs) and metallothioneins (MT) are important in maintaining Zn homeostasis in the brain. The present study was designed to find out whether alterations in ZnTs and MTs are associated with the pathophysiology of depression and the mechanism of antidepressant action.
Messenger RNA and proteins of ZnT1, ZnT3, ZnT4, ZnT5, ZnT6 and MT1/2 were measured in the prefrontal cortex (PFC) and hippocampus (Hp) of rats subjected to olfactory bulbectomy (OB) (a model of depression) and chronic amitriptyline (AMI) treatment by Real Time PCR and Western Blot/Immunohistochemistry (IHP).
Results in the OB rats showed: increases in the protein levels of ZnT1 in the PFC and Hp and MT1/2 in the PFC; a decrease in ZnT3 protein level in the PFC; no changes in ZnT4, ZnT5 and ZnT6 in the PFC and Hp. IHP labeling revealed increases in the optical densities of ZnT1-IR in the PFC and Hp and decreases in ZnT3 and ZnT4-IR in the PFC of OB rats. Although OB had no effects on gene expression of ZnTs, mRNAs for MT1/2 were increased. Chronic AMI treatment did not influence protein levels of ZnTs and MT1/2 in Sham and OB rats; however decreased mRNA levels of ZnT4 and ZnT5 in PFC and ZnT1, ZnT3, ZnT4 and ZnT6 in Hp of Sham rats and normalized OB induced increase in MT1/2 gene expression.
Changes in ZnTs and MT1/2 suggest altered cortical distribution of Zn in the OB model which further supports the hypothesis that Zn dyshomeostasis may be involved in the pathophysiology of depression.
Particle toxicity and metal ions from the dissolution of metallic nanoparticles (NPs) can have environmentally toxic effects. Among the diverse metallic NPs, four types of zinc oxide NPs (ZnO-NPs)-two spherical (diameters <50 nm and <100 nm) and two wire (50 nm × 300 nm and 90 nm × 1000 nm) shaped-were examined using dual-color whole-cell bioreporters (WCBs) to elucidate the relationships among size, shape, and toxicity. The amount of Zn(II) ions dissolved from NPs was determined by measuring mCherry expression because the presence of Zn(II) ions induced the expression of mCherry from pZnt-mCherry in dual-color WCBs. The overall toxic effects were assessed by measuring Escherichia coli cell growth. The toxic effect on cell growth was determined by measuring the expression of eGFP from the dual-color WCBs to avoid interferences in the signal acquisition caused by inseparable NPs. The novel approach demonstrated here used dual-color WCBs to simultaneously assess the toxicity of ZnONPs on E. coli and the dissolution rates of ZnO-NPs. Toxicity varied depending upon the size and shape of the ZnONPs. The dissolution rate did not vary significantly according to size and shape; smaller sizes and wire shapes showed higher toxicity. Therefore, the physical properties of ZnONPs play a role in the overall toxic effect as well as dissolved Zn(II) ions.
Estuarine organisms were impacted by the Deepwater Horizon oil spill which released ∼5 million barrels of crude oil into the Gulf of Mexico in the spring and summer of 2010. Crassostrea virginica, the American oyster, is a keystone species in these coastal estuaries and is routinely used for environmental monitoring purposes. However, very little is known about their cellular and molecular responses to hydrocarbon exposure. In response to the spill, a monitoring program was initiated by deploying hatchery-reared oysters at three sites along the Alabama and Mississippi coast (Grand Bay, MS, Fort Morgan, AL, and Orange Beach, AL). Oysters were deployed for 2-month periods at five different time points from May 2010 to May 2011. Gill and digestive gland tissues were harvested for gene expression analysis and determination of aliphatic and polycyclic aromatic hydrocarbon (PAH) concentrations. To facilitate identification of stress response genes that may be involved in the hydrocarbon response, a nearly complete transcriptome was assembled using Roche 454 and Illumina high-throughput sequencing from RNA samples obtained from the gill and digestive gland tissues of deployed oysters. This effort resulted in the assembly and annotation of 27,227 transcripts comprised of a large assortment of stress response genes, including members of the aryl hydrocarbon receptor (AHR) pathway, Phase I and II biotransformation enzymes, antioxidant enzymes and xenobiotic transporters. From this assembly several potential biomarkers of hydrocarbon exposure were chosen for expression profiling, including the AHR, two cytochrome P450 1A genes (CYP1A-like 1 and CYP1A-like 2), Cu/Zn superoxide dismutase (CuZnSOD), glutathione S-transferase theta (GST theta) and multidrug resistance protein 3 (MRP3). Higher expression levels of GST theta and MRP3 were observed in gill tissues from all three sites during the summer to early fall 2010 deployments. Linear regression analysis indicated a statistically significant relationship between total PAH levels in digestive gland tissue samples with CYP1A-like 2, CuZnSOD, GST theta and MRP3 induction. These observations provide evidence of a potentially conserved AHR pathway in invertebrates and yield new insight into the development of novel biomarkers for use in environmental monitoring activities.
We report a class of multiresponsive colorimetric and fluorescent pH probes based on three different reaction mechanisms including cation exchange, protonation, and hydrolysis reaction of K(I), Ca(II), Zn(II), Cu(II), Al(III), and Pd(II) Salen complexes. Compared with traditional pure organic pH probes, these complex-based pH probes exhibited a much better selectivity due to the shielding function of the filled-in metal ion in the complex. Their pH sensing performances were affected by the ligand structure and the central metal ion. This work is the first report of "off-on-on'-off" colorimetric and fluorescent pH probes that possess three different reaction mechanisms and should inspire the design of multiple-responsive probes for important analytes in biological systems.
To evaluate and compare the role of Ziehl-Neelsen (ZN) staining and mycobacterial culture in diagnosis of tuberculous lymphadenitis.
A total of 56 fine needle aspirations (FNAs) from patients who were clinically suspected to have tuberculous lymphadenitis were included. Acid-fast Bacilli detection was attempted by ZN staining on smears as well as culture on Middlebrook 7H9 broth. Percentage positivity of both smears and culture was calculated.
Of the 56 cases, 46 showed cytomorphological features consistent with tuberculosis (TB). The most common pattern was only necrosis in 37 cases followed by necrotizing granulomas in 13 cases. ZN-stained smears were positive in 40 cases while culture was positive in only 27 cases. The highest smear and culture positivity was noted in cases with only necrosis. In six cases, diagnosis of TB was made on culture alone since smear was negative in these cases.
FNA is a reliable technique for early and accurate diagnosis of tuberculous lymphadenitis in many cases. Mycobacterial culture by newer rapid techniques can assist in bacillary detection in smear-negative cases and also allows for drug sensitivity testing. Hence, culture should be resorted to in such cases.
Simultaneous immobilization of heavy metals and decomposition of halogenated organic compounds in different fractions of automobile shredder residue (ASR) were achieved with a nano-sized metallic calcium through a 60-min ball milling treatment. Heavy metal (HM) immobilization and chlorinated/brominated
 compound (CBC) decomposition efficiencies both reached 90-100 %, after ball milling with nanometallic calcium/calcium oxide (Ca/CaO) dispersion, regardless of ASR particle size (1.0, 0.45-1.0, and 0.250 mm). Concentrations of leachable HMs substantially decreased to a level lower than the regulatory standard limits (Co and Cd 0.3 mg L(-1); Cr 1.5 mg L(-1); Fe, Pb, and Zn 3.0 mg L(-1); Mn and Ni 1 mg L(-1)) proposed by the Korean hazardous waste elution standard regulatory threshold. Scanning electron microscopy with energy-dispersive X-ray spectroscopy (SEM-EDS) element maps/spectra showed that while the amounts of HMs and CBCs detectable in ASR significantly decreased, the calcium mass percentage increased. X-ray powder diffraction (XRD) patterns indicate that the main fraction of enclosed/bound materials on ASR includes Ca-associated crystalline complexes that remarkably inhibit HM desorption and simultaneously transform dangerous CBCs into harmless compounds. The use of a nanometallic Ca/CaO mixture in a mechanochemical process to treat hazardous ASR (dry conditions) is an innovative approach to remediate cross-contaminated residues with heavy metals and halogenated compounds.
Many secretory tissues release Zn(II) ions along with other molecules in response to external stimuli. Here we demonstrate that secretion of Zn(II) ions from normal, healthy prostate tissue is stimulated by glucose in fasted mice and that release of Zn(II) can be monitored by MRI. An ∼50% increase in water proton signal enhancement is observed in T1-weighted images of the healthy mouse prostate after infusion of a Gd-based Zn(II) sensor and an i.p. bolus of glucose. Release of Zn(II) from intracellular stores was validated in human epithelial prostate cells in vitro and in surgically exposed prostate tissue in vivo using a Zn(II)-sensitive fluorescent probe known to bind to the extracellular surface of cells. Given the known differences in intracellular Zn(II) stores in healthy versus malignant prostate tissues, the Zn(II) sensor was then evaluated in a transgenic adenocarcinoma of the mouse prostate (TRAMP) model in vivo. The agent proved successful in detecting small malignant lesions as early as 11 wk of age, making this noninvasive MR imaging method potentially useful for identifying prostate cancer in situations where it may be difficult to detect using current multiparametric MRI protocols.
A flexible quasi-solid-state Ni-Zn battery is developed by using tiny ZnO nanoparticles and porous ultrathin NiO nanoflakes conformally deposited on hierar chical carbon-cloth-carbon-fiber (CC-CF) as the anode (CC-CF@ZnO) and cathode (CC-CF@NiO), respectively. The device is able to deliver high performance (absence of Zn dendrite), superior to previous reports on aqueous Ni-Zn batteries and other flexible electrochemical energy-storage devices.
Chloroanisoles are often reported as off-flavor compounds which produce an earthy and musty flavors and odors in drinking water. To improve understanding and ultimately minimize the formation of 2,4-dichloroanisole (2,4-DCA), 2,6-dichloroanisole (2,6-DCA) and 2,4,6-trichloroanisole (2,4,6-TCA), which have low odor threshold concentrations (OTC: 0.03-4 ng L(-1)), a kinetic database for the chlorination of anisole was established by kinetic measurements. The results showed that HOCl reacted with anisole in acidic solution, with the hydrogen ion as an important catalyst. Quantification of product distribution of the produced chloroanisoles demonstrated that a chlorine attack in the para-position was favored over the ortho-position. A kinetic model was formulated, which permitted investigation of the relative importance of the chlorine dose and other water quality parameters including the concentrations of anisole and several metal ions, as well as temperature, on the product distribution of chloroanisoles. In general, high chlorine doses led to low concentrations of intermediates. The presence of ions such as Fe(3+) and Al(3+) facilitated the formation of chloroanisoles, but Zn(2+) and Mn(2+) did not. The kinetic model can be applied to optimize water chlorination and minimize earthy and musty odors.
The colon is a promising site for drug targeting owing to its long transit time and mild proteolytic activity. The aim of this study was to prepare new low methoxy amidated pectin/NaCMC microspheres cross-linked by a mixture of Zn(2+) and Al(3+) ions and test their potential for colonic targeting of progesterone. A 2(4) factorial design was carried out to optimize the preparation conditions. High drug entrapment efficiency (82-99%) was obtained and it increased with increasing drug concentration but decreased with increasing polymer concentration. Drug release rate was directly proportional to the microsphere drug content and inversely related to Al(3+) ion concentration. Drug release was minimal during the first 3h but was significantly improved in the presence of 1% rat caecal contents, confirming the microsphere potential for colonic delivery. The microspheres achieved >2.3-fold enhancement of colonic progesterone permeability. These results confirm the viability of the produced microspheres as colon-targeted drug delivery vehicle.
Chitosan-poly(maleic acid) nanomaterial (PMACS) with the size of 400-900nm was synthesized by grafting poly(maleic acid) onto chitosan and then crosslinking with glutaraldehyde. The synthesis conditions were optimized. The structure and morphology of PMACS were characterized by FT-IR, XRD, SEM and TGA. PMACS was used to adsorb some heavy metal ions such as Hg(II), Pb(II), Cu(II), Cd(II), Co(II), and Zn(II). The results indicated that PMACS had selectivity for Hg(II) sorption. The effects of various variables for sorption of Hg(II) were further explored. The maximum capacity for Hg(II) sorption was found to be 1044mgg(-1) at pH 6.0, which could compare with the maximal value of the recently reported other sorbents. The sorption followed the pseudo-second-order kinetics and Langmuir isotherm models. The rising of temperature benefited the uptake and the sorption was a spontaneous chemical process. The sorbent could be reused with EDTA. Hence, the nanomaterial would be used as a selective and high uptake sorbent in the removal of Hg(II) from effluents.
The ameliorative effects of selenium (Se) against cadmium (Cd)-induced toxicity have been reported extensively. However, few studies have assessed the effects of multiple ions simultaneously on the variations of elements. In this study, the changes in Se, Cd, and 26 other element concentrations were investigated in chicken kidneys. One hundred and twenty-eight 31-week-old laying hens were fed a diet supplemented with either Se, Cd, or both Se and Cd for 90 days. The ion content was analyzed by inductively coupled plasma mass spectrometry (ICP-MS). We found that the Se, Cd, and combined Se and Cd treatments significantly affected the trace elements in the chicken kidneys. The Cd supplement caused ion profile disorders, including reduced concentrations of V, Cr, Mn, Mo, As, Ba, Hg, Ti, and Pb and increased Si, Cu, Li, Cd, and Sb. The Se supplement reduced the contents of Co, Mo, and Pb and increased the contents of Cr, Fe, and Se. Moreover, Se also increased the concentrations of Cr, Mn, Zn, and Se and decreased those of Li and Pb, which in contrast were induced by Cd. Complex interactions between elements were analyzed, and both positive and negative correlations among these elements are presented. The present study indicated that Se can help against the negative effects of Cd and may be related to the homeostasis of the trace elements in chicken kidneys.
Bacteria respond dynamically to the changes in zinc availability. Repression by the Bacillus subtilis transcription factor Zur requires Zn(II), which binds with negative cooperativity to two regulatory sites per dimer to form, sequentially, Zur2:Zn3 and Zur2:Zn4 forms of the repressor. Here we show that, as cells transition from zinc sufficiency to deficiency, operons regulated by Zur are derepressed in three distinct waves. The first includes the alternative RpmEB(L31*) and RpmGC(L33*) ribosomal proteins, which mobilize zinc from the ribosome, whereas the second includes the ZnuACB uptake system and the YciC metallochaperone. Finally, as zinc levels decrease further, the Zur2:Zn3 form loses Zn(II) leading to derepression of RpsNB(S14*) and FolE2, which allow continued ribosome assembly and folate synthesis, respectively. We infer that zinc mobilization from intracellular zinc stores takes priority over energy-dependent import, and our results link the biochemistry of zinc sensing by Zur to the molecular logic of the zinc deprivation response.
Carbonic anhydrases (CA) belong to the family of zinc metalloenzymes that catalyze the reversible hydration of carbon dioxide to bicarbonate. In the present work, we characterized the cDNAs of four Paracoccidioides CAs (CA1, CA2, CA3, and CA4). In the presence of CO2, there was not a significant increase in fungal ca1, ca2 and ca4 gene expression. The ca1 transcript was induced during the mycelium-to-yeast transition, while ca2 and ca4 gene expression was much higher in yeast cells, when compared to mycelium and mycelium-to-yeast transition. The ca1 transcript was induced in yeast cells recovered directly from liver and spleen of infected mice, while transcripts for ca2 and ca4 were down-regulated. Recombinant CA1 (rCA1) and CA4 (rCA4), with 33 kDa and 32 kDa respectively, were obtained from bacteria. The enzymes rCA1 (β-class) and rCA4 (α-class) were characterized regarding pH, temperature, ions and amino acids addition influence. Both enzymes were stable at pHs 7.5-8.5 and temperatures of 30-35 °C. The enzymes were dramatically inhibited by Hg+2 and activated by Zn+2, while only rCA4 was stimulated by Fe2+. Among the amino acids tested (all in
 L configuration), arginine, lysine, tryptophan and histidine enhanced residual activity of rCA1 and rCA4.
The filamentous fungus Sordaria macrospora is a model system to study multicellular development during fruiting body formation. Previously, we demonstrated that this major process in the sexual life cycle is controlled by the Zn(II)2 Cys6 zinc cluster transcription factor PRO1. Here, we further investigated the genome-wide regulatory network controlled by PRO1 by employing chromatin immunoprecipitation combined with next-generation sequencing (ChIP-seq) to identify binding sites for PRO1. We identified several target regions that occur in the promoter regions of genes encoding components of diverse signaling pathways. Furthermore, we identified a conserved DNA-binding motif that is bound specifically by PRO1 in vitro. In addition, PRO1 controls in vivo the expression of a DsRed reporter gene under the control of the esdC target gene promoter. Our ChIP-seq data suggest that PRO1 also controls target genes previously shown to be involved in regulating the pathways controlling cell wall integrity, NADPH oxidase and pheromone signaling. Our data point to PRO1 acting as a master regulator of genes for signaling components that comprise a developmental cascade controlling fruiting body formation.
Citrated Sprague-Dawley rat blood plasma was used as a biologically relevant exposure medium to assess the acellular toxic potential of two metal oxide engineered nanomaterials (ENMs), zinc oxide (nZnO), and cerium oxide (nCeO2). Plasma was incubated at 37 °C for up to 48 h with ENM concentrations ranging between 0 and 200 mg/L. The degree of ENM-induced oxidation was assessed by assaying for reactive oxygen species (ROS) levels using dichlorofluorescein (DCF), pH, ferric reducing ability of plasma (FRAP), lipase activity, malondialdehyde (MDA), and protein carbonyls (PC). Whereas previous in vitro studies showed linear-positive correlations between ENM concentration and oxidative damage, our results suggested that low concentrations were generally pro-oxidant and higher concentrations appeared antioxidant or protective, as indicated by DCF fluorescence trends. nZnO and nCeO2 also affected pH in a manner dependent on concentration and elemental composition; higher nZnO concentrations maintained a more alkaline pH, while nCeO2 tended to decrease pH. No other biomarkers of oxidative damage (FRAP, MDA, PC, lipase activity) showed changes at any ENM concentration or time-point tested. Differential dissolution of the two ENMs was also observed, where as much as ∼31.3% of nZnO was instantaneously dissolved to Zn(2+ )and only negligible nCeO2 was degraded. The results suggest that the direct oxidative potential of nZnO and nCeO2 in citrated rat blood plasma is low, and that a physiological or immune response is needed to generate appreciable damage biomarkers. The data also highlight the need for careful consideration when selecting a model for assessing ENM toxicity.
In this paper, using a simple method, 17 isostructural polyoxotitanates (POTs) were synthesized, including the pristine [Ti12O16(O(i)Pr)16], the monodefected [Ti11O13(O(i)Pr)18], and the heterometal-doped [Ti11O14(O(i)Pr)17(ML)] (M = Mg, Ca, Zn, Cd, Co, or Ni; L = Cl, Br, I, or NO3). The electronic structures of these POTs were determined by UV-vis spectroscopy and DFT calculations. Upon UV irradiation of the POTs, electron spin resonance showed the formation of Ti(III) under anaerobic conditions and superoxide (O2(•-)) in the presence of O2. The photoactivities of the POTs were then probed with Ti(III) production and short-circuit photocurrent experiments. The photophysical processes were studied using steady-state and transient photoluminescence. The results show that within the very similar structures, the deexcitation processes of the photoexcited POTs can be greatly affected by the dopants, which result in enhanced or decreased photoactivities. Co and Ni doping enhances the absorption of the visible light accompanied by serious loss of UV photoactivities. On the other hand, a Ti vacancy (in [Ti11O13(O(i)Pr)18]) does not reduce the band gap of a POT but improves the UV photoactivities by serving as surface reaction site. The POTs were then used as molecular models of titanium oxide nanoparticles to understand some important issues relevant to doped titanate, i.e., coordination environment of the dopant metal, electronic structure, photoactivities, and photophysical processes. Our present findings suggest that for solar energy harvesting applications of titanium oxides like photocatalysis and solar cells substitution of titanium atoms by transition metal ions (like Co and Ni) to extend the absorption edges may not be an efficient way, while loading of Ti vacancies is very effective.
Here we present a novel in situ chemical modification process to form vertical Schottky diodes using palladium (Pd) rectifying bottom contacts, amorphous zinc tin oxide (Zn-Sn-O) semiconductor made via acetate-based solution process, and molybdenum top ohmic contacts. Using X-ray photoelectron spectroscopy depth profiling, we show that oxygen plasma treatment of Pd creates a PdOx interface layer, which is then reduced back to metallic Pd by in situ reactions during Zn-Sn-O film annealing. The plasma treatment ensures an oxygen-rich environment in the semiconductor near the Schottky barrier, reducing the level of oxygen-deficiency-related defects and improving the rectifying contact. Using this process, we achieve diodes with high forward current density exceeding 10(3)A cm(-2) at 1 V, rectification ratios of >10(2), and ideality factors of around 1.9. The measured diode current-voltage characteristics are compared to numerical simulations of thermionic field emission with sub-bandgap states in the semiconductor, which we attribute to spatial variations in metal stoichiometry of amorphous Zn-Sn-O. To the best of our knowledge, this is the first demonstration of vertical Schottky diodes using solution-processed amorphous metal oxide semiconductor. Furthermore, the in situ chemical modification method developed here can be adapted to tune interface properties in many other oxide devices.
G-quadruplex analogues have been widely used as molecular tools for detection of potassium ion (K(+)). However, interference from a higher concentration of sodium ion (Na(+)), enzymatic degradation of the oligonucleotide, and background absorption and fluorescence of blood samples have all limited the use of G-quadruplex for direct detection of K(+) in blood samples. Here, we reported, for the first time, an intermolecular G-quadruplex-based assay capable of direct fluorescent detection of blood K(+). Increased stringency of intermolecular G-quadruplex formation based on our screened G-rich oligonucleotide (5'-TGAGGGA GGGG-3') provided the necessary selectivity for K(+) against Na(+) at physiological ion level. To increase long-term stability of oligonucleotide in blood, the screened oligonucleotide was modified with an inverted thymine nucleotide whose 3'-terminus was connected to the 3'-terminus of the upstream nucleotide, acting as a blocking group to greatly improve antinuclease stability. Lastly, to avoid interference from background absorption and autofluorescence of blood, a G-quadruplex-binding, two-photon-excited ligand, EBMVC-B, was synthesized and chosen as the fluorescence reporter. Thus, based on selective K(+) ion-induced formation of intermolecular G-quadruplex and EBMVC-B binding, this approach could linearly respond to K(+) from 0.5 to 10 mM, which matches quite well with the physiologically relevant concentration of blood K(+). Moreover, the system was highly selective for K(+) against other metal ions, including Na(+), Ca(2+), Mg(2+), Zn(2+) common in blood. The practical application was demonstrated by direct detection of K(+) from real blood samples by two-photon fluorescence technology. To the best of our knowledge, this is the first attempt to exploit molecular G-quadruplex-based fluorescent sensing for direct assay of blood target. As such, we expect that it will promote the design and practical application of similar DNA-based sensors in complex real systems.
Essential trace elements are vital to human health. In this study, our aim was to establish reference intervals of and to evaluate relationships among Ca, Fe, Cu, Mg, and Zn for children.
We collected blood samples of 3210 children aged 0-14 years from Lu'an, China, and concentrations of the above elements were determined by atomizer absorption spectrophotometer. A nonparametric method was used to establish the reference intervals.
Gender-related differences in concentrations were not statistically significant for the elements, except for Fe. There were strong positive and negative correlations between age and Fe (R = 0.305, P < 0.001), Zn (R = 0.573, P < 0.001); and age and Ca (R = -0.372, P < 0.001), Cu (R = -0.127, P < 0.001), respectively. Correlations between Ca-Mg (r = 0.222~0.384, P < 0.001), Fe-Mg (r = 0.495~0.614, P < 0.001), and Fe-Zn (r = 0.239~0.471, P < 0.001) were the strongest compared with others. In multivariable linear regression, after adjusted for confounding factors, the associations between Zn-Fe and Mg-Fe were the strongest with per concentration quintile increase of Fe caused Zn and Mg increasing by 4.19% (β = 0.041; 95% CI: 0.037, 0.045; P < 0.001) and 3.87% (β = 0.038; 95% CI: 0.036, 0.040; P < 0.001), respectively.
Gender- and age-based reference intervals of Ca, Fe, Cu, Mg, and Zn for children were established, and correlations between them were quite complex. More works are needed to illuminate these relationships and their impacts on children's health.
A campaign was conducted to assess and compare the personal exposure in L3 of Tianjin subway, focusing on PM2.5 levels, chemical compositions,
 morphology analysis, as well as the health risk of heavy metal in PM2.5. The results indicated that the average concentration of the PM2.5 was 151.43 μg/m(3) inside the train of the subway during rush hours. PM2.5 concentrations inside car under the ground are higher than those on the ground, and PM2.5 concentrations on the platform are higher than those inside car. Regarding metal concentrations, the highest element in PM2.5 samples was Fe; the level of which is 17.55 μg/m(3). OC is a major component of PM2.5 in Tianjin subway. Secondary organic carbon is the formation of gaseous organic pollutants in subway. SEM-EDX and TEM-EDX exhibit the presence of individual particle with a large metal content in the subway samples. For small Fe metal particles, iron oxide can be formed easily. With regard to their sources, Fe-containing particles are generated mainly from mechanical wear and friction processes at the rail-wheel-brake interfaces. The non-carcinogenic risk to metals Cr, Ni, Cu, Zn and Pb, and carcinogenic hazard of Cr and Ni were all below the acceptable level in L3 of Tianjin subway.
In order to estimate the level of uncertainty arising from sampling, 54 samples (primary and duplicate) of the moss species Pleurozium schreberi (Brid.) Mitt. were collected within three forested areas (Wierna Rzeka, Piaski, Posłowice Range) in the Holy Cross Mountains (south-central Poland). During the fieldwork, each primary sample composed of 8 to 10 increments (subsamples) was taken over an area of 10 m(2) whereas duplicate samples were collected in the same way at a distance of 1-2 m. Subsequently, all samples were triple rinsed with deionized water, dried, milled, and digested (8 mL HNO3 (1:1) + 1 mL 30 % H2O2) in a closed microwave system Multiwave 3000. The prepared solutions were analyzed twice for Cu, Fe, Mn, and Zn using FAAS and GFAAS techniques. All datasets were checked for normality and for normally distributed elements (Cu from Piaski, Zn from Posłowice, Fe, Zn from Wierna Rzeka). The sampling uncertainty was computed with (i) classical ANOVA, (ii) classical RANOVA, (iii) modified RANOVA, and (iv) range statistics. For the remaining elements, the sampling uncertainty was calculated with traditional and/or modified RANOVA (if the amount of outliers did not exceed 10 %) or classical ANOVA after Box-Cox transformation (if the amount of outliers exceeded 10 %). The highest concentrations of all elements were found in moss samples from Piaski, whereas the sampling uncertainty calculated with different statistical methods ranged from 4.1 to 22 %.
Olive oil production is one of the most relevant agroindustrial activities in the Mediterranean region and generates a huge amount of both solid and semi-solid wastes, the uncontrolled disposal of which might lead to serious environmental problems. Due to its organic matter and mineral nutrient content, the waste material can be applied to agricultural soil as a fertilizer. However, due to its high organic matter content, dry olive residue (DOR), commonly called "alperujo," has the potential to immobilize risk elements in contaminated soils. The main objective of this study was to assess the possible effect of DOR on sorption of risk elements such as cadmium (Cd), lead (Pb), and zinc (Zn) in the soil. A set of batch sorption experiments were carried out to assess the ability of DOR to adsorb Cd, Pb, and Zn where the effect of the preceding biotransformation of DOR by four species of fungi: Penicillium chrysogenum, Coriolopsis floccosa, Bjerkhandera adusta, and Chondrostereum purpureum was compared. The Freundlich and Langmuir sorption isotherms were calculated to assess the sorption characteristics of both transformed and non-transformed DOR. The results showed good potential sorption capacity of DOR, especially for Pb and to a lesser extent for Cd and Zn. Better sorption characteristics were reported for the biotransformed DOR samples, which are expected to show higher humification of the organic matter. However, the desorption experiments showed weakness and instability of the DOR-bound elements, especially in the case of Zn. Thus, future research should aim to verify the DOR sorption pattern in contaminated soil as well as the potential stabilization of the DOR element bounds where the increase of the pH levels of the DOR samples needs to be taken into account.
Due to its status as one of the most contaminated regions in Slovakia, 45 soil and plant samples were collected in the Middle Spis region. In soil, the exchangeable soil reaction, humus content and heavy metals content (Zn, Cd, Cu, Pb, Hg) were determined. Total content of heavy metals (TC-HMs) and content of mobile forms (MF-HMs) in soil, as well as metal content in plants, were determined by atomic absorption spectrometry. The concentration ranges for total Zn, Cd, Cu, Pb and Hg in soil were 33.1-953, 0.65-6.73, 11.0-913, 26.5-165 and 0.28--415 mg/kg, respectively. The overall concentration ranges of these metals in plants of two types (Athyrium filix-femina L. and Poaceae herbs) were 12.4-158.6, 0.10-1.63, 3.34-85.7, 0.09-29.7 and 0.01-12.8 mg/kg, respectively. Despite the values of Zn, Cd, Cu, Pb and Hg content in the soil exceeding limit values, only the Hg content in plants presented an ecological risk.
The Fe:Zn(1-x)Mg(x)Se (x = 0.19, 0.27, and 0.38) solid solutions spectroscopic properties were investigated and laser oscillations were achieved for the first time. The increase of the magnesium concentration in the Fe:ZnMgSe crystal was shown to result in an almost similar long wavelength shift of both absorption and fluorescence spectra of about 60 nm per each 10% of magnesium. With the Fe:ZnMgSe crystal temperature decrease, the fluorescence spectrum maximum shifts towards shorter wavelength resulting mainly from strong narrowing of the longest wavelength fluorescence line. Laser radiation wavelength dependence on the magnesium concentration as well as on temperature was observed. The Fe:ZnMgSe x = 0.38 laser oscillation wavelength increased from 4780 nm at 80 K to 4920 nm at 240 K using the optical resonator without any intracavity spectrally-selective element. In comparison with the Fe:ZnSe laser operating in similar conditions, these wavelengths at both temperatures were shifted by about 500 nm towards mid-IR region.
Metal-based ethanolamines, (L(1))-(L(4)) coordinated with Co(II), Cu(II), Ni(II) and Zn(II) metals in 1:2 (metal:ligand) molar ratio to produce new compounds have been reported. These compounds were screened for their bactericidal/fungicidal activity against a number of bacterial (Escherichia coli, Shigella flexneri, Pseudomonas aeruginosa, Salmonella typhi, Staphylococcus aureus and Bacillus subtilis) and fungal strains (Trichophyton longifusus, Candida albicans, Aspergillus flavus, Microsporum canis, Fusarium solani and Candida glabrata) alongside against a shrimp species known as Artemia salina. The screening results indicated that metal complexes have significantly higher activity than uncomplexed ligands against one or more bacterial/fungal species due to chelation. The ligand (L(4)) displayed good bacterial and fungal activity as compared to other ligands. The antibacterial results revealed that the Zn(II) complex (16) of (L(4)) was found to be the most active complex and Co(II) complex (14) of the same ligand (L(4)), demonstrated the highest antifungal activity.
Dominant mutations in Cu/Zn-superoxide dismutase (SOD1) gene have been shown to cause a familial form of amyotrophic lateral sclerosis (SOD1-ALS). A major pathological hallmark of this disease is abnormal accumulation of mutant SOD1 oligomers in the affected spinal motor neurons. While no effective therapeutics for SOD1-ALS is currently available, SOD1 oligomerization will be a good target for developing cures of this disease. Recently, we have reproduced the formation of SOD1 oligomers abnormally cross-linked via disulfide bonds in a test tube. Using our in vitro model of SOD1 oligomerization, therefore, we screened 640 FDA-approved drugs for inhibiting the oligomerization of SOD1 proteins, and three effective classes of chemical compounds were identified. Those hit compounds will provide valuable information on the chemical structures for developing a novel drug candidate suppressing the abnormal oligomerization of mutant SOD1 and possibly curing the disease.
The structures of two zinc complexes containing bidentate benzene-1,2-di-amine ligands are reported. (Benzene-1,2-di-amine-κ(2) N,N')di-chloro-idozinc, [ZnCl2(C6H8N2)], (I), displays a distorted tetra-hedral coordination sphere for the metal cation. The di-amine ligand and the Zn atom reside on a crystallographic mirror plane. In the 1:1 co-crystal salt trans-di-aqua-bis-(4,5-di-methyl-benzene-1,2-di-amine-κ(2) N,N')zinc chloride-4,5-di-methyl-benzene-1,2-di-amine (1/1), [Zn(C8H12N2)2(H2O)2]Cl2·2C8H12N2, (II), the zinc(II) complex cation exhibits a tetra-gonally distorted octa-hedral coordination sphere. The Zn atom sits on a crystallographically imposed inversion center and the di-amine ligands are tilted 30.63 (6)° with respect to the ZnN4 plane. Both complexes exhibit extensive hydrogen bonding. In (I), a stacked-sheet extended structure parallel to (101) is observed. In (II), the co-crystallized di-amine is hydrogen-bonded to the complex cation via O-H⋯N and N-H⋯N linkages. These units are in turn linked into planes along (200) by O-H⋯Cl and N-H⋯Cl hydrogen bonds.
The structure of the title coordination complex, [Zn(C14H14NO4)2(H2O)2]·2C2H6OS, shows that the Zn(II) cation adopts an octa-hedral geometry and lies on an inversion center. Two organic ligands occupy the equatorial positions of the coordination sphere, forming a chelate ring motif via the O atom on the formyl group and another O atom of the carbonyl group (a pseudo-β-diketone motif). Two water mol-ecules
 occupy the remaining coordination sites of the Zn(II) cation in the axial positions. The water mol-ecules are each hydrogen bonded to a single dimethyl sulfoxide mol-ecule that has been entrapped in the crystal lattice.
The title compound, [Zn(C72H44N4O8)(C4H10N2)] or [Zn(TPBP)(pipz] (where TPBP and pipz are 5,10,15,20-tetra-kis-[4-(benzo-yloxy)phen-yl]porphyrinato and piperazine ligands respectively), features a distorted square-pyramidal coordin-ation geometry about the central Zn(II) atom. This central atom is chelated by the four N atoms of the porphyrinate anion and further coordinated by a nitro-gen atom of the piperazine axial ligand, which adopts a chair confirmation. The average Zn-N(pyrrole) bond length is 2.078 (7) Å and the Zn- N(pipz) bond length is 2.1274 (19) Å. The zinc cation is displaced by 0.4365 (4) Å from the N4C20 mean plane of the porphyrinate anion toward the piperazine axial ligand. This porphyrinate macrocycle exhibits major saddle and moderate ruffling deformations. In the crystal, the supra-molecular structure is made by parallel pairs of layers along (100), with an inter-layer distance of 4.100 Å while the distance between two pairs of layers is 4.047 Å. A region of electron density was treated with the SQUEEZE [Spek (2015 ▸). Acta Cryst. C71, 9-18] procedure in PLATON following unsuccessful attempts to model it as being part of disordered n-hexane solvent and water mol-ecules. The given chemical formula and other crystal data do not take into account these solvent mol-ecules.
The asymmetric unit of the title complex, [Zn(SCN)2(C6H6N2O)2], consists of one Zn(2+) cation located on a twofold rotation axis, as well as of one thio-cyanate anion and one neutral isonicotinamide ligand, both occupying general positions. The Zn(2+) cation is tetra-hedrally coordinated into a discrete complex by the N atoms of two symmetry-related thio-cyanate anions and by the pyridine N atoms of two isonicotinamide ligands. The complexes are linked by inter-molecular C-H⋯O and N-H⋯O, and weak inter-molecular N-H⋯S hydrogen-bonding inter-actions into a three-dimensional network.
Tanning sludge enriched with high concentrations of Cr and other metals has adverse effects on the environment. Plants growing in the metalliferous soils may have the ability to cope with high metal concentrations. This study focuses on potentials of using native plants for bioindication and/or phytoremediation of Cr-contaminated sites. In the study, we characterized plants and soils from six tanning sludge storage sites. Soil in these sites exhibited toxic levels of Cr (averaged 16,492 mg kg(-1)) and other metals (e.g., 48.3 mg Cu kg(-1), 2370 mg Zn kg(-1), 44.9 mg Pb kg(-1), and 0.59 mg Cd kg(-1)). Different metal tolerance and accumulation patterns were observed among the sampled plant species. Phragmites australis, Zephyranthes candida, Cynodon dactylon, and Alternanthera philoxeroides accumulated moderate-high concentrations of Cr and other metals, which could make them good bioindicators of heavy metal pollution. High Cr and other metal concentrations (e.g., Cd and Pb) were found in Chenopodium rubrum (372 mg Cr kg(-1)), Aster subulatus (310 mg Cr kg(-1)), and Brassica chinensis (300 mg Cr kg(-1)), being considered as metal accumulators. In addition, Nerium indicum and Z. candida were able to tolerate high concentrations of Cr and other metals, and they may be used as preferable pioneer species to grow or use for restoration in Cr-contaminated sites. This study can be useful for establishing guidelines to select the most suitable plant species to revegetate and remediate metals in tanning sludge-contaminated fields.
The link between trophic ecology and metal accumulation in marine fish species was investigated through a multi-tracers approach combining fatty acid (FA) and stable isotope (SI) analyses on fish from two contrasted sites on the coast of Senegal, one subjected to anthropogenic metal effluents and another one less impacted. The concentrations of thirteen trace metal elements (As, Cd, Co, Cr, Cu, Fe, Li, Mn, Ni, Pb, Sn, U, and Zn) were measured in fish liver. Individuals from each site were classified into three distinct groups according to their liver FA and muscle SI compositions. Trace element concentrations were tested between groups revealing that bioaccumulation of several metals was clearly dependent on the trophic guild of fish. Furthermore, correlations between individual trophic markers and trace metals gave new insights into the determination of their origin. Fatty acids revealed relationships between the dietary regimes and metal accumulation that were not detected with stable isotopes, possibly due to the trace metal elements analysed in this study. In the region exposed to metallic inputs, the consumption of benthic preys was the main pathway for metal transfer to the fish community while in the unaffected one, pelagic preys represented the main source of metals. Within pelagic sources, metallic transfer to fish depended on phytoplankton taxa on which the food web was based, suggesting that microphytoplankton (i.e., diatoms and dinoflagellates) were a more important source of exposition than nano- and picoplankton. This study confirmed the influence of diet in the metal accumulation of marine fish communities, and proved that FAs are very useful and complementary tools to SIs to link metal accumulation in fish with their trophic ecology.
Fish is the main source of animal protein and micronutrients for inhabitants in the lower Mekong River basin. Consumption of fish in the basin ranges from 41 to 51 kg capita(-1) year(-1). Thus, concerns of human health impacts caused by daily intake of metals contained in fish, and the incidence of bacterial contamination from Listeria and Escherichia coli have been raised. This study was conducted to 1) determine concentrations of metals, fecal indicator organisms, and Listeria spp. in cultivated common diet fish, and 2) assess human health risks as results of fish consumption on a daily basis. The results showed significant impacts of metal accumulation in fish especially from the intensive aquaculture. Chemical use to promote the rapid allometric growth of fish was expected to be the explanation for this finding. Concentrations of metals contained in different fish species were not statistically different with the exceptions of Na, Mn, and Zn. This might be due to the mobility of elements in aquaculture farms. Listeria and E. coli log CFU/g were 1.36 ± 0.11 (standard error) and 1.57 ± 0.1 s.e., respectively with higher counts observed in samples collected in market sites. Lastly, for human health risk assessment via fish consumption, it was found that hazard quotients of consuming As, Cu, and Zn contained in all fish species could contribute adverse health effects to the local residents (hazard quotients higher than 1). Therefore, risk management measures must be promoted and implemented in all study areas to reduce potential risks to local Vietnamese residents.
The present paper aims to perform a screening of native plants growing in Kettara mine-Marrakech (Southern Morocco) for its phytoremediation. Plants and soil samples were collected and analyzed for Pb, Zn, Cu and Cd concentrations at several sites in the mine. The results showed that the soil in the vicinity of Kettara mine is deficient in major elements and contain toxic levels of metals. Spontaneously growing native plants were botanically identified then classified into 21 species and 14 families. Significant difference was observed among the average concentrations of four heavy metals (Pb, Zn, Cu and Cd) in plants (P ≤ 0.05). 6 plants of 21 species namely Hammada scoparia (Pomel) Iljin, Hirschfeldi incana, Lamarckia aurea, Calendula algeriensis, Aizoon hispanicum and Melilotus sulcata were considered as the best-performing specimens due to their high ability to accumulate multiple metals in their shoots and roots without sustaining toxicity. This was confirmed by the transfer factors generally higher than 1. Using the most common criteria to classify the hyperaccumulator plants, these species can be classified as new accumulator plants of many heavy metals and be potentially used as remediation tools of metal-contaminated sites.
An electro-thermal annealing (ETA) method, which uses an electrical pulse of less than 100 ns, was developed to improve the electrical performance of array-level amorphous-oxide-semiconductor (AOS) thin-film transistors (TFTs). The practicality of the ETA method was experimentally demonstrated with transparent amorphous In-Ga-Zn-O (a-IGZO) TFTs. The overall electrical performance metrics were boosted by the proposed method: up to 205% for the trans-conductance (gm), 158% for the linear current (Ilinear), and 206% for the subthreshold swing (SS). The performance enhancement were interpreted by X-ray photoelectron microscopy (XPS), showing a reduction of oxygen vacancies in a-IGZO after the ETA. Furthermore, by virtue of the extremely short operation time (80 ns) of ETA, which neither provokes a delay of the mandatory TFTs operation such as addressing operation for the display refresh nor demands extra physical treatment, the semipermanent use of displays can be realized.
The resuspension of polluted sediments by boat traffic could release substantial amounts of metals to the water column, affecting at the same time their bioavailability. In order to characterize the impact of sediment resuspensions on biota, caged amphipods have been deployed on three different channelized watercourses in Northern France. Firstly, the biological responses of transplanted freshwater gammarid amphipods, Gammarus fossarum, described by trace metal accumulation, feeding and reproduction activities were quite similar for the three water courses despite the differences of metal contamination and navigability.
 Secondly, the concentrations of metals accumulated in gammarids never exceeded the contamination thresholds previously defined for Co, Cu, Cr and Zn. Values were in the same order of magnitude whatever the studied site despite: (i) large differences noticed in the sediment quality and (ii) some concentrations in the overlying waters exceeding the Environmental Quality Standards (EQS) defined by the Water Framework Directive. Conversely, Pb was highly bioaccumulated with values systematically exceeding the threshold value whatever the site. Therefore, the impact of navigation cannot be proved and the difference between the 3 monitoring periods is rather attributed to environmental variability, probably linked to the seasonality. Moreover, this study also confirms that organisms sampled from a local population in the vicinity of the three studied watercourses could be used as test organisms, leading to similar results than the ones obtained with reference gammarids initially used for developing all the biological responses. This would simplify and then promote the development of studies based on gammarid amphipod, G. fossarum, as bioindicators.
This report presents a systematic study on the effect of zinc (Zn) carboxylate precursor on the structural and optical properties of red light emitting InP nanocrystals (NCs). NC cores were assessed using X-ray photoelectron spectroscopy (XPS), X-ray absorption spectroscopy (XAS), energy-dispersive X-ray spectroscopy (EDX), and high-resolution transmission electron microscopy (HRTEM). When moderate Zn:In ratios in the reaction pot were used, the incorporation of Zn in InP was insufficient to change the crystal structure or band gap of the NCs, but photoluminescence quantum yield (PLQY) increased dramatically compared with pure InP NCs. Zn was found to incorporate mostly in the phosphate layer on the NCs. PL, PLQY, and time-resolved PL (TRPL) show that Zn carboxylates added to the precursors during NC cores facilitate the synthesis of high-quality InP NCs by suppressing nonradiative and sub-band-gap recombination, and the effect is visible also after a ZnS shell is grown on the cores.
A palladium-catalyzed, norbornene-mediated tandem amination/cyanation reaction via Catellani-type C-H functionalization was developed using N-benzoyloxyamines as the amination reagent and Zn(CN)2 as the terminating agent. This transformation, in which one C-N bond and one C-C bond are formed, provides an efficient approach for the synthesis of ortho-aminated benzonitriles in one pot from easily accessible starting materials.
Cumulating evidence underlines the role of adipose tissue metallothionein (MT) in the development of obesity and type 2 diabetes. Fasting/refeeding was shown to affect MT gene expression in the rodent liver. The influence of nutritional status on MT gene expression in white adipose tissue (WAT) is inconclusive. The aim of this study was to verify if fasting and fasting/refeeding may influence expression of MT genes in WAT of rats.
Fasting resulted in a significant increase in MT1 and MT2 gene expressions in retroperitoneal, epididymal, and inguinal WAT of rats, and this effect was reversed by refeeding. Altered expressions of MT1 and MT2 genes in all main fat depots were reflected by changes in serum MT1 and MT2 levels. MT1 and MT2 messenger RNA (mRNA) levels in WAT correlated inversely with serum insulin concentration. Changes in MT1 and MT2 mRNA levels were apparently not related to total zinc concentrations and MTF1 and Zn transporter mRNA levels in WAT. Fasting or fasting/refeeding exerted no effect on the expression of MT3 gene in WAT. Addition of insulin to isolated adipocytes resulted in a significant decrease in MT1 and MT2 gene expressions. In contrast, forskolin or dibutyryl-cAMP (dB-cAMP) enhanced the expressions of MT1 and MT2 genes in isolated adipocytes. Insulin partially reversed the effect of dB-cAMP on MT1 and MT2 gene expressions.
This study showed that the expressions of MT1 and MT2 genes in WAT are regulated by nutritional status, and the regulation may be independent of total zinc concentration.
The chemical basis for improved removal rates of toxic heavy metals such as Zn and Cu from wastewater secondary sludge has been demonstrated in this study. Instead of using excess corrosive chemicals as the source of free nitrous acid (FNA) for improved solubility of heavy metals in the sludge (in order to enhance electrokinetics), an optimized use of aqua regia has been proposed as an alternative. Fragments of nitrocyl group originated from aqua regia are responsible for the disruption of biogenic mixed liquor volatile suspended solids (MLVSS) and this disruption resulted in enhanced removal of exposed and oxidized metal ions. A diversity of nitric oxide (NO), peroxy nitrous acid, and peroxy nitroso group are expected to be introduced in the mixed liquor by the aqua regia for enhanced electrochemical treatment. The effects of pectin as a post treatment on the Zn removal from sludge were also presented for the first time. Results revealed 63.6% Cu and 93.7% Zn removal efficiencies, as compared to 49% Cu and 74% Zn removal efficiencies reported in a recent study. Also, 93.3% reduction of time-to-filter (TTF), and 95 mL/g of sludge volume index (SVI) were reported. The total operating cost obtained was USD 1.972/wet ton.
We report one-pot synthesis of Fe(III)-polydopamine (PDA) complex nanospheres, their structures, morphology evolution, and underlying mechanism. The complex nanospheres were synthesized by introducing ferric ions into the reaction mixture used for polymerization of dopamine. It is verified that both the oxidative polymerization of dopamine and Fe(III)-PDA complexation contribute to the "polymerization" process, in which the ferric ions form coordination bonds with both oxygen and nitrogen, as indicated by X-ray absorption fine-structure spectroscopy. In the "polymerization" process, the morphology of the complex nanostructures is gradually transformed from sheetlike to spherical at the feed Fe(III)/dopamine molar ratio of 1/3. The final size of the complex spheres is much smaller than its neat PDA counterpart. At higher feed Fe(III)/dopamine molar ratios, the final morphology of the "polymerization" products is sheetlike. The results suggest that the formation of spherical morphology is likely to be driven by covalent polymerization-induced decrease of hydrophilic functional groups, which causes reself-assembly of the PDA oligomers to reduce surface area. We also demonstrate that this one-pot synthesis route for hybrid nanospheres enables the facile construction of carbonized PDA (C-PDA) nanospheres uniformly embedded with Fe3O4 nanoparticles of only 3-5 nm in size. The C-PDA/Fe3O4 nanospheres exhibit catalytic activity toward oxygen reduction reaction and deliver a stable discharge voltage for over 200 h when utilized as the cathode in a primary Zn-air battery and are also good recyclable catalyst supports.
Ternary Pt-Au-M (M = 3d transition metal) nanoparticles show reduced OH adsorption energies and improved activity for the oxygen reduction reaction (ORR) compared to pure Pt nanoparticles, as obtained by density functional theory. The strain and ligand effects in nanoparticles are decoupled and correlated with the extended Pt(111) surface for benchmarking. The ternary metal in the core allows for tuning the catalytic activity through strain effects. Pt-Au-M for M = Cr, Mn, Co, Cu, Zn nanoparticles are of particular interest as they exhibit an optimal contribution of strain, ligand effects and stability. Good agreement is found with experimental studies showing increased activity of Pt-Au-Fe/Ni nanoparticles, and mid to late 3d transition metals are predicted to exhibit enhance activity and stability with respect to pure Pt nanoparticles.
The ubiquinol:cytochrome (cyt) c oxidoreductase (or cyt bc1) is an important membrane protein complex in photosynthetic and respiratory energy transduction. In bacteria such as Rhodobacter capsulatus it is constituted of three subunits: the iron-sulfur protein, cyt b and cyt c1, which form two catalytic domains, the Qo (hydroquinone (QH2) oxidation) and Qi (quinone (Q) reduction) sites. At the Qo site, the pathways of bifurcated electron transfers emanating from QH2 oxidation are known, but the associated proton release routes are not well defined. In energy transducing complexes, Zn(2+) binding amino acid residues often correlate with proton uptake or release pathways. Earlier, using combined EXAFS and structural studies, we identified Zn coordinating residues of mitochondrial and bacterial cyt bc1. In this work, using the genetically tractable bacterial cyt bc1, we substituted each of the proposed Zn binding residues with non-protonatable side chains. Among these mutants, only the His291Leu substitution destroyed almost completely the Qo site catalysis without perturbing significantly the redox properties of the cofactors or the assembly of the complex. In this mutant, which is unable to support photosynthetic growth, the bifurcated electron transfer reactions that result from QH2 oxidation at the Qo site, as well as the associated proton(s) release, were dramatically impaired. Based on these findings, on the putative role of His291 in liganding Zn, and on its solvent exposed and highly conserved position, we propose that His291 of cyt b is critical for proton release associated to QH2 oxidation at the Qo site of cyt bc1.
The luminescence and scintillation properties of ZnO single crystals were studied by photoluminescence and X-ray-induced luminescence (XRIL) techniques. XRIL allowed a direct comparison to be made between the near-band emission (NBE) and trap emissions providing insight into the carrier recombination efficiency in the ZnO crystals. It also provided bulk luminescence measurements that were
 not affected by surface states. The origin of a green emission, the dominant trap emission in ZnO, was then investigated by gamma-induced positron spectroscopy (GIPS) - a unique defect spectroscopy method that enables positron lifetime measurements to be made for a sample without contributions from positron annihilation in the source materials. The measurements showed a single positron decay curve with a 175 ps lifetime component that was attributed to Zn vacancies passivated by hydrogen. Both oxygen vacancies and hydrogen-decorated Zn vacancies were suggested to contribute to the green emission. By combining scintillation measurements with XRIL, the fast scintillation in ZnO crystals was found to be strongly correlated with the ratio between the defect luminescence and NBE. This study reports the first application of GIPS to semiconductors, and it reveals the great benefits of the XRIL technique for the study of emission and scintillation properties of materials.
Polypyridyl ethylenes have been prepared as heterocyclic analogues of tetraphenylethylene. In addition to conventional AIE effects, a derivative possessing a 1,1-bis(2-pyridyl)ethylene fragment displays Zn(2+)-selective enhanced fluorescence in aqueous solution, in contrast to the behavior of isomeric bis(3- and 4-pyridyl)ethylenes. The Zn(2+)-sensing capability of this material is attributed to formation of chelated Zn(2+)-bis(pyridyl) complexes and is supported by the X-ray crystal structure of a bis(2-pyridyl)ethylene-Zn(OAc)2 complex.
Hourly-resolved PM2.5 and PM10-2.5 samples were collected in the industrial city Foshan in the Pearl River Delta region, China. The samples were subsequently analyzed for elemental components and black carbon (BC). A key purpose of the study was to understand the composition of particulate matter (PM) at high-time resolution in a polluted urban atmosphere to identify key components contributing to extreme PM concentration events and examine the diurnal chemical concentration patterns for air quality management purposes. It was found that BC and S concentrations dominated in the fine mode, while elements with mostly crustal and oceanic origins such as Si, Ca, Al and Cl were found in the coarse size fraction. Most of the elements showed strong diurnal variations. S did not show clear diurnal variations, suggesting regional rather than local origin. Based on empirical orthogonal functions (EOF) method, 3 forcing factors were identified contributing to the extreme events of PM2.5 and selected elements, i.e., urban direct emissions, wet deposition and a combination of coarse mode sources. Conditional probability functions (CPF) were performed using wind profiles and elemental concentrations. The CPF results showed that BC and elemental Cl, K, Fe, Cu and Zn in the fine mode were mostly from the northwest, indicating that industrial emissions and combustion were the main sources. For elements in the coarse mode, Si, Al, K, Ca, Fe and Ti showed similar patterns, suggesting same sources such as local soil dust/construction activities. Coarse elemental Cl was mostly from the south and southeast, implying the influence of marine aerosol sources. For other trace elements, we found vanadium (V) in fine PM was mainly from the sources located to the southeast of the measuring site. Combined with CPF results of S and V in fine PM, we concluded shipping emissions were likely an important elemental emission source.
To understand pollution of heavy metals in surface sediments of shallow lakes, surface sediments samples of 11 lakes in Jiangsu province were collected to determine the content of six heavy metals including As, Cr, Cu, Pb, Zn and Ni. GIS was used to analyze the spatial distribution of heavy metals, and geological accumulation index (Igeo), modified contamination index (mCd) pollution load index (PLI) and potential ecological risk index (RI) were used to evaluate heavy metal contamination in the sediments. The results showed that: in the lakes' surface sediments, the average content of As, Cu, Zn, Cr, Pb, Ni in multiples of soil background of Jiangsu province were 1.74-3.85, 0.65-2.66, 0.48-3.56, 0.43-1.52, 0.02-1.49 and 0.12-1.42. According to the evaluation results of Igeo and RI, As, which had high degree of enrichment and great potential ecological risk, was the main pollutant, followed by Cu, and pollution of the rest of heavy metals was relatively light. Combining the results of several evaluation methods, in surface sediments of Sanjiu Lake, Gaoyou Lake and Shaobo Lake, these heavy metals had the most serious pollution, the maximum pollution loading and moderate potential ecological risk; in surface sediments of Gehu Lake, Baima Lake and Hongze Lake, some regions were polluted by certain metals, the overall trend of pollution was aggravating, the pollution loading was large, and the potential ecological risk reached moderate; in the other 5 lakes, the risk of sediments polluted by heavy metals, as well as the pollution loading, was small, and the overall was not polluted.
The environmental magnetism method has been widely applied to identify soil heavy metal pollution, which is characterized by simplicity, efficiency, non-destructivity and sensitivity. The present study used magnetic susceptibility to assess the accumulation of heavy metals in soils of the Caofeidian industrial zone which is a typical reclamation area in northern China. The study area was divided into three sub-zones based on the function, including industrial zone, living zone, natural tidal flat and wetland. A total of 35 topsoil samples (0-10 cm) and 3 soil profiles were collected from the three sub-zones. Magnetic susceptibility (X(lf)), iron oxide (Fe2O3) contents and heavy metals contents (Cr, Ni, Cu, Zn, As, Pb, Mn and V) of the samples were analyzed. The results showed that X(lf) values and heavy metals contents exhibited higher spatial variability in the top soil of the industrial zone, indicating the severe impacts of industrial activities. In the soil profiles of the industrial and living zones, all heavy metals were enriched to different degrees in the upper layer (0-20 cm). However, there was no significant change of heavy metal contents in the soil profiles of tidal flat which was far from the industrial area. The X(lf) value was significantly (P < 0.01) positively correlated with the contents of Fe2O3, Ni, Cu, As and V in the industrial top soil. This indicated that X(lf) could be used as an indicator for heavy metal accumulation in the industrial zone. However, the X(lf) value was not suitable to be an indicator to show the heavy metal accumulation in the soils of living zone and natural tidal flat. This might be associated with the different sources of magnetic materials among the different sub-zones and the special characteristics of the soils in the tidal flat and wetland.
Totally 128 surficial sediments samples were collected from the coastal wetlands, northeastern Hainan Island and analyzed for their concentrations of 14 elements including Al2O3, Fe2O3, MnO, Cu, Ni, Sr, Zn, V, Pb, Cr, Zr, As, Cd and Hg, TOC and grain sizes. The mean concentrations of trace metals V, Cr, Ni, Cu, Zn, As, Pb, Cd and Hg were (40.13 +/- 32.65), (35.92 +/- 26.90), (13.03 +/- 11.46), (11.56 +/- 10.27)-, (48.75 +/- 27.00), (5.48 +/- 1.60), ( 18.70 +/- 8.66), (0.054 +/- 0.045 ), (0.050 +/- 0.050) microg x g(-1), respectively, which were much lower than those in Pearl River Estuary, Yangzi River Estuary, Bohai Bay, upper crust and average shale. The average concentrations of Sr and Zr were much higher, reaching up to (1253.60 +/- 1649.58) microg x g(-1) and (372.40 +/- 516.49) microg x g(-1), respectively. The spatial distribution patterns of Al2O3, Fe2O3, MnO, Cu, Ni, Zn, V, Pb, Cr, Cd and Hg concentrations were the same as each other except for those of As, Sr and Zr. Generally, relatively high concentrations of these elements only appeared in the Haikou Bay, Nandu estuary, Dongzhai Harbor, Qinglan Harbor and Xiaohai in study area. The factor analysis revealed that the trace elements Al2O3 Fe2O3, MnO, Cu, Ni, Zn, V, Pb, Cr and part of Hg were mainly originated from the rock material by natural weathering processes, while the Cd and a part of Hg were from the biological source controlled by TOC. As and part of MnO were influenced by anthropogenic source, especially by aquacultures. Zr and some MnO were derived from heavy minerals dominated by the coarse grain of sediments. In contrast to the ERL, ERM and the results of enrichment factors (EF) , the environment of study area was good in general and the degree of contamination by trace elements was low on the whole. However, there are still some places where anthropogenic input have caused serious enrichments of trace elements and the occasional adverse effect on benthic organism induced by Ni could probably occur in 22% areas of all the sampling stations.
Four types of dust from dormitories, offices, hotels and roads in Beijing were collected and fractionated into 9 fractions, respectively. Totally 36 samples were obtained and analyzed for heavy metals including Cu, Zn, Cr, Pb, Cd and Ni. Particle size distributions of those heavy metals in these four types of dust were investigated and the influencing mechanisms were discussed. Distribution patterns of the same heavy metal in different types of dust showed various characteristics. Also different metals in the same type of dust represented different distribution patterns. Heavy metals in road dust tended to concentrate in finer particles. Two offices from the same building, located in Beijing, China, were selected to study the seasonality of heavy metals in dust. Dust sampling from Office A was conducted at weekly intervals between March 2012 and August 2012, while dust from Office B was sampled fortnightly from March 2012 to December 2012. Generally, levels
 of all heavy metals remained stable among different seasons, however, Cr and Pb represented more significant fluctuations than other four heavy metals. Based on the geo-accumulation index method, the pollution of Zn, Cu and Pb was more serious in the investigated samples, and dust from offices and hotels were moderately polluted by Zn. According to the risk assessment results, the carcinogenic health risks of the six heavy metals in the four types of dust were negligible.
An Ir/Zn dual catalysis has been developed for the enantio- and diastereodivergent α-allylation of unprotected α-hydroxyketones under mild conditions, in the absence of any additional base. The cooperative action of a chiral iridium complex derived from phosphoramidites and a chiral Zn-ProPhenol complex is most likely responsible for its high reactivity, excellent enantioselectivity (up to >99% ee), and good diastereoselectivity (up to >20:1 dr). All four product stereoisomers could be prepared from the same set of starting materials and under identical conditions by simple selection of appropriate catalyst combinations.
Characteristic X rays of energies less than approximately 20 keV are of interest in radiobiology and radiation oncology. There is evidence that these low-energy photons produce higher relative biological effectiveness (RBE) and lower oxygen enhancement ratio (OER) relative to higher energies. Lower energy X rays also offer the advantage of healthy tissue sparing beyond the target treatment depth. Electronic brachytherapy systems that can deliver characteristic and bremsstrahlung X rays of varying energy are in clinical use as well as under development. We performed low-energy extrapolation ionization chamber dosimetry using two methods: 1. the exposure-to-dose method; and 2. the Burlin theory method combined with the extrapolation chamber method of Klevenhagen. We investigated fluorescent X rays emitted from seven metals: titanium (Ti, Z = 22); chromium (Cr, Z = 24); iron (Fe, Z = 26); cobalt (Co, Z = 27); copper (Cu, Z = 29); zinc (Zn, Z = 30); and molybdenum (Mo, Z = 42). X rays were produced by irradiation of the metals with a 55 kVp, 45 mA silver anode spectrum. The data obtained were air kerma rate (cGy/min), and radiation dose rate (cGy/min) in phosphate-buffered saline (PBS) solution and water. Air kerma rates ranged from 3.55 ± 0.10 to 14.36 ± 0.39 cGy/min. Dose rates ranged from 3.85 ± 0.10 to 16.96 ± 0.46 cGy/min in PBS and 3.59 ± 0.10 to 16.06 ± 0.43 cGy/min in water. Dose-rate energy dependence of both models was examined by taking a ratio of measured to Monte Carlo calculated dose rates. Dosimetry method 1 exhibited a linear relationship across all energies with a slope of 0.0127 keV(-1) and R(2) of 0.9276. Method 2 exhibited a linear relationship across all energies with a slope of 0.0467 keV(-1) and R(2) of 0.9933. Method 1 or 2 may be used as a relative dosimetry system to derive dose rates to water by using a second reference ion chamber with a NIST-traceable calibration for the molybdenum spectrum.
Because of different reported effects of parasitism on the accumulation of metals in fish, it is important to consider parasites while interpreting bioaccumulation data from biomonitoring programmes. Accordingly, the first step is to take parasitism into consideration when simulating metal bioaccumulation in the fish host under laboratory conditions. In the present study, the accumulation of metals in fish-parasite systems was simulated by a one-compartment toxicokinetic model and compared to uninfected conspecifics. As such, metal accumulation in fish was assumed to result from a balance of different uptake and loss processes depending on the infection status. The uptake by parasites was considered an efflux from the fish host, similar to elimination. Physiological rate constants for the uninfected fish were parameterised based on the covalent index and the species weight while the parameterisation for the infected fish was carried out based on the reported effects of parasites on the uptake kinetics of the fish host. The model was then validated for the system of the chub Squalius cephalus and the acanthocephalan Pomphorhynchus tereticollis following 36-day exposure to waterborne Pb. The dissolved concentration of Pb in the exposure tank water fluctuated during the exposure, ranging from 40 to 120 μg/L. Generally, the present study shows that the one-compartment model can be an effective method for simulating the accumulation of metals in fish, taking into account effects of parasitism. In particular, the predicted concentrations of Cu, Fe, Zn, and Pb in the uninfected chub as well as in the infected chub and the acanthocephalans were within one order of magnitude of the measurements. The variation in the absorption efficiency and the elimination rate constant of the uninfected chub resulted in variations of about one order of magnitude in the predicted concentrations of Pb. Inclusion of further assumptions for simulating metal accumulation in the infected chub led to variations of around two orders of magnitude in the predictions. Therefore, further research is required to reduce uncertainty while characterising and parameterising the model for infected fish.
Exponential industrialization and rapid urbanization have resulted in contamination of soil by metals from anthropogenic sources in Dongguan, China. The aims of this research were to determine the concentration and distribution of various metals (arsenic (As), cadmium (Cd), chromium (Cr), copper (Cu), mercury (Hg), nickel (Ni), lead (Pb) and zinc (Zn)) in soils and identify their potential health risks for local residents. A total of 106 soil samples were collected from the vicinity of industrial sites in Dongguan. Two types of samples were collected from each site: topsoil (0-20 cm, TS) and shallow soil (20-50 cm, SS). Results showed that the soils were contaminated by metals and pollution was mainly focused on TS. The geoaccumulation index (Igeo) and pollution indexes (PI) implied that there was a slight increase in the concentrations of Cd, Cu, Hg, Ni, and Pb, but the metal pollution caused by industrial activities was less severe, and elements of As and Cr exhibited non-pollution level. The risk assessment results suggested that there was a potential health risk associated with As and Cr exposure for residents because the carcinogenic risks of As and Cr via corresponding exposure pathways exceeded the safety limit of 10(-6) (the acceptable level of carcinogenic risk for humans). Furthermore, oral ingestion and inhalation of soil particles are the main exposure pathways for As and Cr to enter the human body. This study may provide basic information of metal pollution control and human health protection in the vicinity of industrial regions.
Tobacco smoking by pregnant women has a negative effect on fetal development and increases pregnancy risk by changing the oxidative balance and microelements level. Smoking affects the concentration, structure and function of proteins, potentially leading to various negative effects on pregnancy outcomes.
The influence of tobacco smoke on key protein fractions in smoking and non-smoking healthy pregnant women was determined by capillary electrophoresis (CE). Concentrations of the proteins α1-antitrypsin, α1-acid glycoprotein, α2-macroglobulin and transferrin were determined by ELISA tests. Total protein concentration was measured by the Biuret method. Smoking status was established by cotinine levels. Cadmium (Cd) and Zinc (Zn) concentrations were determined by flame atomic absorption spectrometry and the Zn/Cd ratio was calculated based on these numbers. Smoking women had a 3.7 times higher level of Cd than non-smoking women. Zn levels decreased during pregnancy for all women. The Zn/Cd ratio was three times lower in smoking women. The differences between the changes in the protein profile for smoking and non-smoking women were noted. Regarding proteins, α1-antitrypsin and α2-macroglobulin levels were lower in the non-smoking group than in the smoking group and correlated with Cd levels (r = -0.968, p = 0.032 for non-smokers; r = -0.835, p = 0.019 for smokers). Zn/Cd ratios correlated negatively with α1-, α2- and β-globulins.
Exposure to tobacco smoke increases the concentration of Cd in the blood of pregnant women and may lead to an elevated risk of pregnancy disorders. During pregnancy alter concentrations of some proteins. The correlation of Cd with proteins suggests that it is one of the causes of protein aberrations.
We combine solution small-angle X-ray scattering (SAXS) and high-resolution analytical transmission electron microscopy (ATEM) to gain a full mechanistic understanding of substructure formation in nanoparticles templated by block copolymer reverse micelles, specifically poly(styrene)-block-poly(2-vinylpyridine). We report a novel substructure for micelle-templated ZnS nanoparticles, in which small crystallites (∼4 nm) exist within a larger (∼20 nm) amorphous organic-inorganic hybrid matrix. The formation of this complex structure is explained via SAXS measurements that characterize in situ for the first time the intermediate state of the metal-loaded micelle core: Zn(2+) ions are distributed throughout the micelle core, which solidifies as a unit on sulfidation. The nanoparticle size is thus determined by the radius of the metal-loaded core, rather than the quantity of available metal ions. This mechanism leads to particle size counterintuitively decreasing with increasing metal content, based on the modified interactions of the metal-complexed monomers in direct contrast to gold nanoparticles templated by the same polymer.
A conventional solution-based route to a cyclic trimeric organozinc compound [{Zn(Et)(β-diketonate)}3] (β-diketonate=OC(OMe)CHC(Me)O, 1) is described, with 1 structurally characterized
 for the first time. The ligand selection of bidentate β-diketonates is shown to be key to isolating a cyclic trimer. Additional reaction of β-diketonates with diethyl zinc were spectroscopically characterized as compounds of the type [{Zn(Et)(β-diketonate)} n ] (β-diketonate=OC(Me)CHC(Me)O, 2, OC(OtBu)CHC(Me)O, 3). Further studies have shown that selective oxidation of these species produces cubanes of the general formula [{Zn(OC(R)CHC(Me)O)2Zn(Et)OEt}2] (R=OMe, 4; Me, 5; OtBu, 6), allowing a high oxygen content whilst remaining structurally suitable for use as precursors. The successful deposition of thin films of zinc oxide through aerosol-assisted chemical vapor deposition (AACVD), using a novel precursor, is described and fully characterized.
Nutrition in the second year is important as this is a period of rapid growth and development. Milk is a major food for young children and this analysis evaluated the impact of the type of milk consumed on nutrient intakes and nutritional status. Data from the Diet and Nutrition Survey of Infants and Young Children were used to investigate the intakes of key nutrients, and Fe and vitamin D status, of children aged 12-18 months, not breastfed, and consuming >400 g/d fortified milk (n 139) or >400 g/d of whole cows' milk (n 404). Blood samples from eligible children for measurement of Hb (n 113), serum ferritin and plasma 25-hydroxyvitamin D (25(OH)D) concentrations (n 105) were available for approximately 20 % of children. Unpaired Mann-Whitney tests were used to compare nutrient intakes and status between consumers of fortified and cows' milk. Mean daily total dietary intakes of Fe, Zn, vitamin A and vitamin D were significantly higher in the fortified milk group. Mean daily total dietary intakes of energy, protein, Ca, iodine, Na and saturated fat were significantly higher in the cows' milk group. Hb was not different between groups. The fortified milk group had significantly higher serum ferritin (P = 0·049) and plasma 25(OH)D (P = 0·014). This analysis demonstrates significantly different nutrient intakes and status between infants consuming >400 g/d fortified milk v. those consuming >400 g/d whole cows' milk. These results indicate that fortified milks can play a significant role in improving the quality of young children's diets in their second year of life.
Bangladesh is a country with a high burden of micronutrient malnutrition. Stunting affects 41 % of children aged under 5 years. Zn is one of the key micronutrients that is associated with stunting. The present study, as part of the national micronutrient survey 2011-2012, revealed for the first time the nationally representative prevalence of Zn deficiency and determined the associations of the condition. A cross-sectional 'nationwide' survey was conducted in pre-school-age children (6-59 months; PSAC) and non-pregnant non-lactating women (15-49 years; NPNLW). Multistage random sampling was done in 150 clusters; fifty in each of the rural, urban and slum strata. Data were analysed on 662 PSAC and 1073 NPNLW. Serum Zn was assayed by atomic absorption spectrophotometry. Zn deficiency was defined as serum Zn of <9·9 and <10·1 µmol/l in PSAC and NPNLW, respectively. The national prevalence of Zn deficiency was 44·6 and 57·3 % in PSAC and NPNLW, respectively. In PSAC, it was 29·5, 48·6 and 51·7 %, respectively, in urban, rural and slum strata. Household expenses (β = 0·13; P = 0·007), Hb (β = 0·10; P = 0·005), intake of animal-source Zn (β = 0·096; P = 0·02) and asset score (β = 0·11; P = 0·03) were positively associated with serum Zn in NPNLW. Residence in an urban area (β = 0·33; P = 0·03) and intake of plant-origin Zn (β = -0·13; P = 0·038) determined higher and lower status of Zn in PSAC, respectively. Zn deficiency was highly prevalent in Bangladesh, and it was principally related to inadequate quality of diet. To improve Zn nutrition, Bangladesh needs to strengthen research and programmes related to Zn biofortification, fortification and phytate-reducing technologies in the food system in the short and medium term. In addition, promotion of animal-source Zn for all is important in the long run.
Iron (Fe), zinc (Zn), manganese (Mn), and copper (Cu) are essential micronutrient mineral elements for living organisms, as they regulate essential cellular processes, such as chlorophyll synthesis and photosynthesis (Fe, Cu, and Mn), respiration (Fe and Cu), and transcription (Zn). The storage and distribution of these minerals in various cellular organelles is strictly regulated to ensure optimal metabolic rates. Alteration of the balance in uptake, distribution, and/or storage of these minerals severely impairs cellular metabolism and significantly affects plant growth and development. Thus, any change in the metal profile of a cellular compartment significantly affects metabolism. Different subcellular compartments are suggested to be linked through complex retrograde signaling networks to regulate cellular metal homeostasis. Various genes regulating cellular and subcellular metal distribution have been identified and characterized. Understanding the role of these transporters is extremely important to elaborate the signaling between various subcellular compartments. Moreover, modulation of the proteins involved in cellular metal homeostasis may help in the regulation of metabolism, adaptability to a diverse range of environmental conditions, and biofortification. Here, we review progress in the understanding of different subcellular metal transport components in plants and discuss the prospects of regulating cellular metabolism and strategies to develop biofortified crop plants.
Since the introduction of antivenom administration over a century ago to treat venomous snake bite, it has been the most effective therapy for saving life and limb. However, this treatment is not always effective and not without potential life-threatening side effects. We tested a new paradigm to abrogate the plasmatic anticoagulant effects of fibrinogenolytic snake venom metalloproteinases (SVMP) by inhibiting these Zn(+2) -dependent enzymes directly with carbon monoxide (CO) exposure. Assessment of the fibrinogenolytic effects of venoms collected from the Arizona black rattlesnake, Northern Pacific rattlesnake, Western cottonmouth, Eastern cottonmouth, Broad-banded copperhead and Southern copperhead on human plasmatic coagulation kinetics was performed with thrombelastography in vitro. Isolated exposure of all but one venom (Southern copperhead) to CO significantly decreased the ability of the venoms to compromise coagulation. These results demonstrated that direct inhibition of transition metal-containing venom enzymes by yet to be elucidated mechanisms (e.g. CO, binding to Zn(+2) or displacing Zn(+2) from the catalytic site, CO binding to histidine residues) can in many instances significantly decrease fibrinogenolytic activity. This new paradigm of CO-based inhibition of the anticoagulant effects of SVMP could potentially diminish haemostatic compromise in envenomed patients until antivenom can be administered.
Natural spices are commonly used by the people in Nigeria. They may be easily contaminated with heavy metals when they are dried and then pose a health risk for the consumers.
The aim of this study was to determine the levels of heavy metals in some commonly consumed natural spices namely Prosopis Africana, Xylopia aethiopica, Piper gineense, Monodora myristica, Monodora tenuifolia and Capsicum frutescens sold in the local markets of Awka, Anambra state, South East Nigeria to estimate the potential health risk.
The range of heavy metal concentration was in the order: Zn (14.09 - 161.04) > Fe (28.15 - 134.59) > Pb (2.61 - 8.97) > Cr (0.001 - 3.81) > Co (0.28 - 3.07) > Ni (0.34 - 2.89). Pb, Fe and Zn exceeded the maximum allowable concentrations for spices. The Target Hazard Quotient (THQ) of the spices varied from 0.06-0.5. Estimated daily intakes (EDI) were all below the tolerable daily intake (TDI). The lead levels in Prosopis africana, Xylopia aethiopica, Piper gineense, Monodora myristica and Capsicum frutescens which are 8-30 times higher than the WHO/FAO permissible limit of 0.3 mg/kg.
Lead contamination of spices sold in Awka (south east Nigeria) may add to the body burden of lead. A good quality control for herbal food is important in order to protect consumers from contamination.
food products, spices, potential toxic metals, risk assessment, public health.
Different metabolic pathways of supplemental and fortification Fe, or inhibition of Zn absorption by Fe, may explain adverse effects of supplemental Fe in Fe-sufficient infants. We determined whether the mode of oral Fe administration or the amount habitually consumed affects Fe absorption and systemic Fe utilisation in infants, and assessed the effects of these interventions on Zn absorption, Fe and Zn status, and growth. Fe-sufficient 6-month-old infants (n 72) were randomly assigned to receive 6·6 mg Fe/d from a high-Fe formula, 1·3 mg Fe/d from a low-Fe formula or 6·6 mg Fe/d from Fe drops and a formula with no added Fe for 45 d. Fractional Fe absorption, Fe utilisation and fractional Zn absorption were measured with oral (57Fe and 67Zn) and intravenous (58Fe and 70Zn) isotopes. Fe and Zn status, infection and growth were measured. At 45 d, Hb was 6·3 g/l higher in the high-Fe formula group compared with the Fe drops group, whereas serum ferritin was 34 and 35 % higher, respectively, and serum transferrin 0·1 g/l lower in the high-Fe formula and Fe drops groups compared with the low-Fe formula group (all P<0·05). No intervention effects were observed on Fe absorption, Fe utilisation, Zn absorption, other Fe status indices, plasma Zn or growth. We concluded that neither supplemental or fortification Fe nor the amount of Fe habitually consumed altered Fe absorption,
 Fe utilisation, Zn absorption, Zn status or growth in Fe-sufficient infants. Consumption of low-Fe formula as the only source of Fe was insufficient to maintain Fe stores.
A sediment core collected from Zhelin Bay, the biggest mariculture base of the eastern Guangdong Province, was analyzed for trace metal concentrations and chemical fractions. Average total concentrations (mg/kg) were 20.7±15.4 (Pb), 74.6±11.6 (Cr), 40.7±6.0 (Ni), 55.9±13.0 (Cu), and 169.0±11.9 (Zn), with the concentrations of Cr, Ni, Cu and Zn being significantly higher than their corresponding background values. We identified two vertical distribution patterns of the trace metals in the sediment core. In all sub-samples, Pb was mainly associated with the reducible fraction, whereas a major portion (62.2 to 95.2%) of Cr, Ni, Cu, and Zn was strongly associated with the residual fractions. Biological risk assessment based on the mean effects range-median quotient suggests that the Zhelin Bay sediment core has a 21% probability of being toxic.
Metal speciation and transport are seldom assessed in densely populated Tropical River. An evaluation of the phase distribution for Copper (Cu), Lead (Pb) and Zinc (Zn) along with chemical speciation, variance with different water quality parameters and toxicity were conducted in the Brahmaputra River of India from upstream to downstream during wet (monsoon) periods in July 2014. Results indicated that metal free ions and carbonates were dominant in the inorganic fractions whereas metal concentrations were negligible in the anionic inorganic fractions. Due to high sediment load in the river during monsoon, metals were substantially higher in the particulate fractions than in the aqueous phase. Partition coefficient for Cu (3.1-6.1), Pb (3.4-6.5) and Zn (3.5-6.9), demonstrated strong adsorption of the metals on suspended matter. Q-mode hierarchical cluster analysis (HCA) illustrated groupings mainly governed by quality parameters rather than by the river course. R-mode results imply selectivity of the affinities of metals for different ligands. Health risk index (HRI) values were less than 1 for dissolved metal for Cu, Pb and Zn while it was greater than 1 for total metal for Pb and Cu indicating potential human health risk. The study demonstrated that binding of metals with naturally occurring dissolved organic matter or suspended particulate matter affects metal bioavailability in river during wet periods when sediment load is particularly high. A combination of empirical, computational and statistical relationships between ionic species and fractions of metals provided greater certitude in identifying the resemblance among the different locations of the river.
Salt stress is one of the key abiotic stresses threatening future agricultural production and natural ecosystems. This study investigates the salt stress response of two rice seedlings, which were screened from 28 Kenya rice cultivars. A proteomic analysis was carried out and Mapman bin codes employed in protein function categorization. Proteins in the redox, stress, and signaling categories were identified, and whose expression differed between the salt tolerant and the salt sensitive samples employed in the present study. 104 and 102 root proteins were observed as significantly altered during salt stress in the tolerant and sensitive samples, respectively and 13 proteins were commonly expressed. Among the 13 proteins, ketol-acid reductoisomerase protein was upregulated in both 1 and 3days of salt treatment in the tolerant sample, while it was down-regulated in both 1 and 3days of salt treatment in the sensitive sample. Actin-7, tubulin alpha, V-type proton ATPase, SOD (Cu-Zn), SOD (Mn), and pyruvate decarboxylase were among the observed salt-induced proteins. In general, this study improves our understanding about salt stress response mechanisms in rice.
Zinc oxide nanoparticles (ZnO NPs) are widely used in a variety of products used in daily life. However, their impact on human health has not been completely elucidated. This study was designed to investigate the cytotoxicity associated with ZnO NPs, the role of dissolution in the toxicity of ZnO NPs, the molecular mechanisms and mode of cell death induced by ZnO NPs in human aortic endothelial cells (HAECs), and the protective effects of the antioxidant alpha-lipoic acid (LA). ZnO NPs significantly reduced cell viability in a dose- and time-dependent manner, resulted in intracellular oxidative stress and cell membrane leakage when treated with doses of 8-50 μg/mL for 12 and 24 h in HAECs. The toxicity was produced by undissolved ZnO NPs but not dissolved Zn(2+) and metal impurities. Exposure to ZnO NPs was found to induce apoptosis at 12 h and necrosis after 24 h. Apoptosis was confirmed using reactive oxygen species that triggered a decrease in mitochondria membrane potential, increase in Cyt-C release, activation of caspases 3 and caspases9 and increase in the ratio of Bax/Bcl-2. Futhermore, ZnO NPs could activate the Fas death receptor pathway. In addition, the antioxidant LA was able to protect HAECs from apoptosis induced by ZnO NPs.
Heavy metals were measured by flame atomic absorption in male hair from residents in urban and rural areas in Chongqing. The median values of the Cd, Cu, Ni, Pb and Zn were 2.90, 23.9, 9.31, 39.3 and 203 μg/g in urban areas and 0.84, 13.4, 5.56, 14.5 and 169 μg/g in rural area, respectively. The levels of Cd, Ni and Pb both in urban and rural areas lie at the high end of the worldwide figures. The differences in heavy metal distribution pattern indicated that there were more sources of Cd and Pb in urban areas. The levels of Cd were increasing along with the growth of age except for the aged people in urban areas, and no significant relationship was observed between the levels of the heavy metal and the age. It is noticed that the hair of smokers exhibited more heavy metal levels than that of non-smokers both in urban and rural areas. In addition, the hair metal levels of the smokers and non-smokers in urban areas were significantly higher than those in rural area, respectively. Significant pairwise correlations (p < 0.01) were observed among Cd, Cu, Ni and Pb in rural area and only between Cu and Ni and between Pb and Ni in urban areas, indicating the elements in these two areas might originate from different sources. The elevated levels of Cd, Pb and Ni implied that the residents both in urban and rural areas might be at high risk of toxic metal exposure, especially for the children.
The Scots pine is often used in the biomonitoring of forests. Studies on the chemical composition plus variability of its needles morphological structure allow for an assessment of the state of environmental pollution. However, in their natural populations, the response of individual trees to stress differs. This study reports on the influence of long-term soil contamination with trace elements on the morphology of the needles, its possible relation to the differentiation of the genetic pool, and their implications for biomonitoring. In the natural and self-renewable pine stand growing near the point polluter (zinc smelter, Upper Silesia, Poland), two categories of trees are observed with respect to their health status: pollution-tolerant (T) and pollution-sensitive (S). A detailed analysis of the trace element content of the needles reveals that the concentration of Cd, Zn, Pb, and Cu in the needles is significantly higher in S as compared to T individuals. The metal accumulation pattern decidedly follows the sequence Pb > Cd > Cu > Zn. An analysis of the fluctuating asymmetry (FA) of the needles reveals that sensitive trees showed an FA index ten times higher in comparison to tolerant ones. Moreover, the high differences between these S and T tree groups are also observed in the basic genetic diversity parameters investigated by an analysis of DNA simple sequence repeats (SSR). The concentration of trace elements in pine needles, distinct in sensitive and tolerant trees and in connection with their morphological and genetic characteristics, may reflect an adaptation process. The level of Mg and Fe content in the needles could be a physiological-toxicological index for evaluating trace element "lethality" expressed as Mg and Fe mineral-survival strategies. The example of differences described in this Scots pine population should be taken into consideration in ecotoxicological research to better interpret the obtained results.
In the present study, the content of risk elements and content of free amino acids were studied in spinach (Spinacia oleracea L.) and mustard (Sinapis alba L.) subsequently grown on uncontaminated and contaminated soils (5 mg Cd/kg, 1000 mg Pb/kg and 400 mg Zn/kg) with the addition of activated carbon (from coconut shells) or biochar (derived from local wood residues planted for phytoextaction) in different seasons (spring, summer and autumn). The results showed that activated carbon and biochar increased biomass production on contaminated site. Application of amendments decreased Cd and Zn uptake by spinach plants. Mustard significantly increased Pb accumulation in the biomass as well in subsequently grown autumn spinach. Glutamic acid and glutamine were major free amino acids in leaves of all plants (15-34% and 3-45%) from total content. Application of activated carbon and biochar increased content of glutamic acid in all plants on uncontaminated and contaminated soils. Activated carbon and biochar treatments also induced an increase of aspartic acid in spinach plants. Biochar produced from biomass originated from phytoextraction technologies promoted higher spinach biomass yield comparing unamended control and showed a tendency to reduce accumulation of cadmium and zinc and thus it is promising soil amendment.
Mitochondrial respiration was assessed in sixteen
 7-day-old broilers as a subset of a larger study assessing the effects of Cu and Zn supplementation above requirements with a coccidiosis challenge on gain/feed ratio. The birds were selected from four treatments (four birds/treatment): a control diet (Cu 15 mg/kg and Zn 60 mg/kg) + coccidiosis challenge (CC), a Cu diet with 245 mg/kg Cu from tribasic copper chloride (TBCC) + CC, a negative control diet (Cu 15 mg/kg and Zn 60 mg/kg) - CC and a Zn diet with 2000 mg/kg Zn from ZnO. The diets were composed of 49% corn, 40% soybean meal, 6.2% vegetable oil (diet dry matter = 90.62%, crude protein = 21.37%, fat = 7.7%, metabolizable energy = 12.1 MJ/day) and were fed for 14 days. Birds were dissected, and approximately one gram of liver tissue was used for mitochondrial oxygen consumption and proton leak kinetics assays. Respiratory control ratio and mitochondrial proton leak assessed by calculating rates of oxygen consumption at 175mV membrane potential were greater for the negative control group, but there were no differences in average gain/feed among treatments. In summary, broilers that did not undergo coccidiosis challenge had lower proton leak and higher respiratory control ratio. However, the impact of supplementation of Cu and Zn above requirements did not appear to prevent changes in respiratory control ratio and proton leak kinetics with coccidiosis challenge.
Phytohormones, structurally diverse compounds, are involved in multiple processes within plants, such as controlling plant growth and stress response. Zn is an essential micronutrient for plants and its deficiency causes large economic losses in crops. Therefore, the purpose of this study was to analyse the role of phytohormones in the Zn-deficiency response of two economically important species, i.e. Lactuca sativa and Brassica oleracea. For this, these two species were grown hydroponically with different Zn-application rates: 10 μM Zn as control and 0.1 μM Zn as deficiency treatment and phytohormone concentration was determined by U-HPLC-MS. Zn deficiency resulted in a substantial loss of biomass in L. sativa plants that was correlated with a decline in growth-promoting hormones such as indole-3-acetic acid (IAA), cytokinins (CKs), and gibberellins (GAs). However these hormones increased or stabilized their concentrations in B. oleracea and could help to maintain the biomass in this species. A lower concentration of stress-signaling hormones such as ethylene precursor aminocyclopropane-1-carboxylic acid (ACC), abscisic acid (ABA), salicylic acid (SA) and jasmonic acid (JA) and also CKs might be involved in Zn uptake in L. sativa while a rise in GA4, isopentenyl adenine (iP), and ACC and a fall in JA and SA might contribute to a better Zn-utilization efficiency (ZnUtE), as observed in B. oleracea plants.
Currently one of the main sources of atmospheric pollution identified in urban centers is derived from both industrial and motor vehicle emissions. These pollutants can be adsorbed to particulate matter which is present in the air or deposited in the soil and plants, eventually reaching the human food chain. In this context, the present study aimed to determine the concentration of metals such as Cu, Pb, Cd, Ni and Zn in two subspecies of Lactuca sativa L. and in the soil from were lettuce samples were collected. The results for the soil samples analyzed show a possible contamination by Pb with concentration values as high as 140mg.kg(-1), which are above the Brazilian standards defined by Resolution CONAMA 420/2009 (Brazilian Environmental Council). However, the values found in the lettuce itself reveal that it is still suitable for consumption.
The concentration of twenty-seven elements (Li, Be, B, Mg, Al, P, K, Ca, Cr, Mn, Co, Ni, Cu, Zn, As, Se, Sr, Mo, Cd, Sn, Sb, Ba, Hg, Pb, Bi, Th, and U) in green coffee samples and their infusions were determined by using inductively coupled plasma-mass spectrometry (ICP-MS). Prior to analysis, green coffee samples were prepared by microwave digestion, while infusions were analyzed without any pre-treatment. The accuracy and precision of the proposed methods were verified by recovery experiments. Considering samples; K, Cu, and Al had the highest mean concentrations with 6714.5μgg(-1), 12.1μgg(-1), and 25.9μgg(-1) among major, trace and toxic elements, respectively. The impact of brewing type on leachability of elements was also studied and the results outlined that mean leachability of elements to Turkish coffee were greater than to mud coffee. Furthermore, dietary element intakes through green coffee consumption were also estimated. This is the first study presenting wide range of elements in green coffee brews and calculating dietary intakes.
Two novel Schiff base ligands H2L(1) and H2L(2) have been synthesized by condensation reaction of amine derivative of 1,2,4-triazole moiety with 2-hydroxy-4-methoxybenzaldehyde. Co(II), Ni(II), Cu(II) and Zn(II) of the synthesized Schiff bases were prepared by using a molar ratio of ligand:metal as 1:1. The structure of the Schiff bases and synthesized metal complexes were established by (1)H NMR, UV-Vis, IR, Mass spectrometry and molar conductivity. The thermal stability of the complexes was study by TGA. Fluorescence quenching mechanism of metal complexes 1-4 show that Zn(II) and Cu(II) complex binds more strongly to BSA. In DFT studies the geometries of Schiff bases and metal complexes were fully optimized with respect to the energy using the 6-31+g(d,p) basis set. The spectral data shows that the ligands behaves as binegative tridentate. On the basis of the spectral studies, TGA and DFT data an octahedral geometry has been assigned for Co(II), Ni(II), square planar for Cu(II) and tetrahedral for Zn(II) complexes. The anticancer activity were screened against human breast cancer cell line (MCF-7) and human hepatocellular liver carcinoma cell line (Hep-G2). Result indicates that metal complexes shows increase cytotoxicity in proliferation to cell lines as compared to free ligand.
To evaluate the risks of metal mixture effects to natural stream communities under ecologically relevant conditions, the authors conducted 30-d tests with benthic macroinvertebrates exposed to cadmium (Cd) and zinc (Zn) in experimental streams. The simultaneous exposures were with Cd and Zn singly and with Cd+Zn mixtures at environmentally relevant ratios. The tests produced concentration-response patterns that for individual taxa were interpreted in the same manner as classic single-species toxicity tests and for community metrics such as taxa richness and mayfly (Ephemeroptera) abundance were interpreted in the same manner as with stream survey data. Effect concentrations from the experimental stream exposures were usually 2 to 3 orders of magnitude lower than those from classic single-species tests. Relative to a response addition model, which assumes that the joint toxicity of the mixtures can be predicted from the product of their responses to individual toxicants, the Cd+Zn mixtures generally showed slightly less than additive toxicity. The authors applied a modeling approach called Tox to explore the mixture toxicity results and to relate the experimental stream results to field data. The approach predicts the accumulation of toxicants (hydrogen, Cd, and Zn) on organisms using a 2-pKa bidentate model that defines interactions between dissolved cations and biological receptors (biotic ligands) and relates that accumulation through a logistic equation to biological response. The Tox modeling was able to predict Cd+Zn mixture responses from the single-metal exposures as well as responses from field data. The similarity of response patterns between the 30-d experimental stream tests and field data supports the environmental relevance of testing aquatic insects in experimental streams. Environ Toxicol Chem 2016;9999:1-14. Published 2016 Wiley Periodicals Inc. on behalf of SETAC. This article is a US government work and, as such, is in the public domain in the United States of America.
We succeeded in growing a new high quality single crystal of a ternary uranium compound UPd2Cd20. From the electrical resistivity, magnetization, magnetic susceptibility, and specific heat experiments, UPd2Cd20 is found to be an antiferromagnetic heavy-fermion compound with the Néel temperature [Formula: see text]  =  5 K and exhibits the large electronic specific heat coefficient γ exceeding 500 mJ (K(2)· mol)(-1). This compound is the first one that exhibits the magnetic ordering with the magnetic moments of the U atom in a series of UT2X20 (T: transition metal, X  =  Al, Zn, Cd). UPd2Cd20 shows typical characteristic features in heavy-fermion systems such as a broad maximum in the magnetic susceptibility at [Formula: see text] and a large coefficient A of T (2) term in the resistivity.
Human calprotectin (CP, S100A8/S100A9 oligomer, MRP-8/MRP-14 oligomer) is an abundant host-defense protein that is involved in the metal-withholding innate immune response. CP coordinates a variety of divalent first-row transition metal ions, which is implicated in its antimicrobial function, and its ability to sequester nutrient Zn(II) ions from microbial pathogens has been recognized for over two decades. CP has two distinct transition-metal-binding sites formed at the S100A8/S100A9 dimer interface, including a histidine-rich site composed of S100A8 residues His17 and His27 and S100A9 residues His91 and His95. In this study, we report that CP binds Zn(II) at this site using a hexahistidine motif, completed by His103 and His105 of the S100A9 C-terminal tail and previously identified as the high-affinity Mn(II) and Fe(II) coordination site. Zn(II) binding at this unique site shields the S100A9 C-terminal tail from proteolytic degradation by proteinase K. X-ray absorption spectroscopy and Zn(II) competition titrations support
 the formation of a Zn(II)-His6 motif. Microbial growth studies indicate that the hexahistidine motif is important for preventing microbial Zn(II) acquisition from CP by the probiotic Lactobacillus plantarum and the opportunistic human pathogen Candida albicans. The Zn(II)-His6 site of CP expands the known biological coordination chemistry of Zn(II) and provides new insight into how the human innate immune system starves microbes of essential metal nutrients.
Based on the effects of inorganic salts on chloroplast Fe uptake, the presence of a voltage-dependent step is proposed to play a role in Fe uptake through the outer envelope. Although iron (Fe) plays a crucial role in chloroplast physiology, only few pieces of information are available on the mechanisms of chloroplast Fe acquisition. Here, the effect of inorganic salts on the Fe uptake of intact chloroplasts was tested, assessing Fe and transition metal uptake using bathophenantroline-based spectrophotometric detection and plasma emission-coupled mass spectrometry, respectively. The microenvironment of Fe was studied by Mössbauer spectroscopy. Transition metal cations (Cd(2+), Zn(2+), and Mn(2+)) enhanced, whereas oxoanions (NO3(-), SO4(2-), and BO3(3-)) reduced the chloroplast Fe uptake. The effect was insensitive to diuron (DCMU), an inhibitor of chloroplast inner envelope-associated Fe uptake. The inorganic salts affected neither Fe forms in the uptake assay buffer nor those incorporated into the chloroplasts. The significantly lower Zn and Mn uptake compared to that of Fe indicates that different mechanisms/transporters are involved in their acquisition. The enhancing effect of transition metals on chloroplast Fe uptake is likely related to outer envelope-associated processes, since divalent metal cations are known to inhibit Fe(2+) transport across the inner envelope. Thus, a voltage-dependent step is proposed to play a role in Fe uptake through the chloroplast outer envelope on the basis of the contrasting effects of transition metal cations and oxoaninons.
Pore water plays a more significant role than do sediments in pollutant cycling dynamics. Also, concentrations of pollutants in pore water provide important information about their bioavailability or eco-toxicity; however, very few studies have focused on this topic. In this study, four duplicate sediment cores from three typical northern bays as well as the central part of Taihu Lake were collected to investigate the distribution, diffusive fluxes, and toxicity of heavy metals and polycyclic aromatic hydrocarbons (PAHs) in pore water profiles, which will be good in understanding the mobility and toxicity of these toxic pollutants and achieving better environmental management. The diffusive fluxes of heavy metals across the sediment-water interface was estimated through Fick's First Law, and the toxicity of heavy metals and PAHs in pore water was assessed by applying a water quality index (interstitial water toxicity criteria unit, IWCTU) and a hazard index (HI), respectively. The average concentrations of Cr, Cu, Ni, Pb, and Zn in surface pore water were 18.8, 23.4, 12.0, 13.5, and 42.5 μg L(-1), respectively. Also, concentrations of the selected heavy metals in both overlying water and pore water from Taihu Lake were all lower than the standard values of the environmental quality standards for surface water. The concentrations as the pore water depth increased, and the highest detected concentrations of heavy metals were recorded between 3 and 5 cm below the sediment surface. The average diffusive fluxes of these metals were 27.3, 24.8, 7.03, 7.81, and -3.32 μg (m(2) day)(-1), respectively, indicating export from sediment into overlying water, with the exception of Zn. There was a potential risk of toxicity, mainly from Pb and Cu, indicating that heavy metals in pore water had slight to moderate impact on sediment-dwelling organisms by values of the IWCTU and the Nemeraw index. The total PAH concentrations in pore water were higher than those in overlying water, and such gradient implies a potential flux of PAHs from pore water to overlying water. The average HI value of PAHs in surface pore water showed no or low ecological risk. While there may be occasional risk due to the HI values in some sites being greater than 1, the dominant contributors were carcinogenic PAHs. Because of their potential biological impact, heavy metals and PAHs and their comprehensive toxic effects in pore water should be given priority attention to keep the safety of Taihu Lake.
The Klang area of Peninsular Malaysia has experienced rapid industrial growth with intense activities, which can increase the concentration of pollutants in the environment that significantly impact on habitats and the human health. The purpose of this study was to determine the levels of selected heavy metals (Cu, Zn, Ni, Fe, and Pb) in the heart, lung, brain, liver, kidney, muscle tissues, and feathers of house crow, Corvus splendens, in Klang, Peninsular Malaysia. House crow samples were collected from the Klang area through the Department of Public Health at Majlis Perbandaran Klang. Quantitative determination of heavy metals was carried out using atomic absorption spectrophotometer (AAS). The result shows the presence of heavy metals in all biological samples of house crows. For heavy metals in all the house crow tissues analyzed, Fe concentrations were the highest, followed by those of Zn, Cu, Pb, and Ni. The feathers and kidney accumulated high concentrations of Pb, whereas the liver accumulated high concentrations of essential heavy metals (Fe > Zn > Cu > Ni). Significant variations were also detected in the concentrations of Pb among adult and juvenile and male and female bird samples. The results also revealed significant positive correlations between Pb metal concentration in the breast feathers and all internal organs. Accumulation of toxic heavy metals in feathers reflected storing and elimination processes, while the accumulation of toxic heavy metals in the kidney can be consequential to chronic exposure. The present study clearly shows the usefulness of house crow breast feather as a suitable indicator for heavy metal accumulation in the internal organs of house crows in the Klang area.
Toxicokinetics makes up the background for predicting concentrations of chemicals in organisms and, thus, ecological risk assessment. However, physiological and toxicological mechanisms behind toxicokinetics of particular chemicals are purely understood. The commonly used one-compartment model has been challenged recently, showing that in the case of metals it does not describe the pattern observed in terrestrial invertebrates exposed to highly contaminated food. We hypothesised that the main mechanism shaping toxicokinetics of metals in invertebrates at high exposure concentrations in food is the cellular damage to the gut epithelial cells. Gut damage should result in decreased metal assimilation rate, while shedding the dead cells - in increased elimination rate. We performed a typical toxicokinetic experiment, feeding the ground beetles Pterostichus oblongopunctatus food contaminated with Cd, Ni or Zn at 40 mM kg(-1) for 28 days, followed by a depuration period of 14 days on uncontaminated food. The male beetles were sampled throughout the experiment for body metal concentrations and histopathological examinations of the midgut. All metals exhibited a complex pattern of internal concentrations over time, with an initial rapid increase followed by a decrease and fluctuating concentrations during further metal exposure. Histopathological studies showed massive damage to the midgut epithelium, with marked differences between the metals. Cd appeared the most toxic and caused immediate midgut cell degeneration. The effects of Ni were more gradual and pronounced after at least 1 week of exposure. Zn also caused extensive degeneration in the gut epithelium but its effects were the weakest among the studied metals.
Herein, a room temperature chemical process to synthesize functional, hollow nanostructures from zeolitic imidazolate framework-8 (ZIF-8) and poly(vinylphosphonic acid) (PVPA) is reported. Syntheses are initiated by physically blending the components-a process that is accompanied first by encapsulation of ZIF-8 crystallites by PVPA and then by fragmentation of the crystallites. The fragmentation process is driven by partial displacement of the methyl-imidazolate ligands of Zn(II) in ZIF-8 by phosphonate groups on PVPA. Differences in rates of diffusion for the components of the reactive mixture yield a Kirkendall-like effect that is expressed as a hollow-particle morphology. The obtained hollow nanostructures feature hybrid shells containing PVPA, ZIF-8, and their cross-reacted products. The hybrid structures display substantial proton conductivities that increase with increasing temperature, even under the anhydrous conditions prevailing at temperatures above the boiling point of water. For example, at T = 413 K the proton conductivity of ZIF-8@PVPA reaches 3.2 (±0.12) × 10(-3) S cm(-1), a value comparatively higher than that for PVPA (or ZIF-8) in isolation. The high value may reflect the availability in the hybrid structures of free (and partially free), amphoteric imidazole species, and their hydrogen-bonding interactions with phosphonate and/or phosphonic acid units. The persistence of ample conductivity at high temperature reflects the elimination of phosphonic acid group dehydration and dimerization-an effect that strikingly degrades the conductivity of pure PVPA under anhydrous conditions.
A new synthesis of (+)-brefeldin A is reported via Padwa allenylsulfone [3 + 2]-cycloadditive elimination. Cycloadduct 13 was initially elaborated into iodide 27, which, following treatment with Zn, gave aldehyde 28 whose C(9) stereocenter was epimerized.
 Further elaboration into enoate 38 and Julia-Kocienski olefination with 5 subsequently afforded 39, which was deprotected at C(1) and O(15). Yamaguchi macrolactonization of the seco-acid thereafter afforded a macrocycle that underwent O-desilylation and inversion at C(4) to give (+)-brefeldin A following deprotection.
To investigate the effect of the pasteurisation process on trace elements in donor breast milk.
Premature infants often receive donor breast milk when the mother is unable to produce sufficient breast milk. It is widely accepted that donor milk has considerable advantages over formula milk.1 The Royal Brisbane and Women's Hospital (RBWH) has a milk bank that receives milk donated by women which undergoes a pasteurisation process.2 This study investigated the effect of pasteurisation on a range of trace elements in donor milk.A total of 14 participants who donated to the milk bank were recruited in this study. A 2 ml sample was collected pre- and post- pasteurisation, and frozen at -80 °C. Post-natal age of the milk was documented. Inductively-coupled plasma mass-spectrometry was used to analyse the following trace elements - zinc (Zn), copper (Cu), selenium (Se), manganese (Mn), iodine (I), iron (Fe), molybdenum (Mo) and bromine (Br). The study received ethical approval from RBWH and The University of Queensland Ethics Committee.
No significant difference was found between the levels of any of the trace elements tested pre- and post-pasteurisation. The following p-values were calculated - Zn (0.82), Cu (0.80), Se (0.97), Mn (0.63), I (0.99), Fe (0.05), Mo (0.41), Br (0.59). The following ranges in mcg/L of trace elements were calculated - Zn (365.4-5460.0), Cu (157.6-820.5), Se (10.6-23.7), Mn (0.55-3.24), I (66.4-215.3), Fe (101.5-473.1), Mo (0.20-5.45), Br (704.9-3379.0). Spearman's rank correlation analysis showed significant correlations between post-natal age of milk and trace elements - Zn (ρ=-0.578), Se (ρ=-0.627). Fe (ρ=-0.704), and Mo (ρ=-0.534). No significant correlation was found for Cu, Mn, I, and Br.
This study found that the pasteurisation process had minimal effect on trace element levels in donor breast milk. However, it was noted that there was a correlation between post-natal age of donor milk and Zn, Se, Fe and Mo. Further work is needed to establish factors that may influence levels of trace elements in donor milk such as post-natal age.
The preparation and characterization of a series of divalent 3d transition metal complexes supported by a tridentate planar bis(iminopyridine) ligand are reported. The complexes {2,6-[PhC[double bond, length as m-dash]N(tBu2C6H3)]2C5H3N}MBr2 (M = Mn, Fe, Co, Ni, Cu, Zn), 1-6, were characterized by single crystal X-ray structural studies revealing complexes with pentacoordinate distorted square pyramidal coordination environments. This assembly of complexes provided a unique array for examining the relationship between experimental structure and computed electronic structure. While experimental structural features basically correlated with the Irving-Williams series, some clear deviations were rationalized through the computational analysis. A balance of bis(imino)pyridine/metal with bonding/antibonding π interactions was used to explain the divergent directions of Fe(ii)-N and Co(ii)-N bond lengths. Similarly, orbital details were used to justify the opposing change in Cu-Brap and Cu-Brbas bond lengths. Furthermore, computational analysis provided a unique method to document a surprising low bond order for the M-N bonds of bis(imino)pyridine ligand in this series.
A guest-dependent dynamic fivefold interpenetrated 3D porous metal-organic framework (MOF) of Zn(II) ions has been synthesized that exhibits selective carbon dioxide adsorption. Furthermore, the MOF shows excellent luminescence behavior, which is supported by a systematic study on the guest-responsive multicolor emission of a suspension of the MOF. The dual-emission behavior arises from the excited-state intramolecular proton transfer (ESIPT), and the compound also shows remarkable potential to detect traces of water in various organic solvents. The experimental observations were also painstakingly authenticated by using time-dependent density-functional-theory (DFT) calculations.
Harbours, as strategic places in tourism and transportation, are exposed to many sources of contamination. Assessing the quality of harbours sediment by guidelines and regulations does not reflect the actual level of contamination and the risk posed to aquatic ecosystems. Selection of an appropriate management technique for contaminated sediments in those strategic locations is crucial for the aquatic environment. The purpose of this study is to show that insufficient information, provided by sediment quality guidelines (SQGs) to identify the actual contaminants, could lead to a destructive or potentially ineffective decision for risk reduction in contaminated harbours. A comprehensive evaluation on physicochemical characteristics of sediment and water samples of a shallow harbour in St. Lawrence River was performed. Results of trace metal fractionation and risk assessment indicated that Cd and Pb were the contaminants that could pose a threat to aquatic ecosystem, although the SQG outcomes implied that Cu and Zn may cause an adverse effect on the benthic organisms. The results of multivariate statistical analysis demonstrated that the locations in the vicinity of the maintenance area contained the most contaminated sediment samples and require appropriate management. Antifouling paint particles and probably the runoff entering the harbour were the main sources of pollution. Among the diverse range of management strategies, the resuspension technique is suggested as a viable alternative in this specific case for shallow locations with contaminated sediments. A suitable management strategy could reduce the cost of remediation process by identifying the actual contaminated spots and also reduce the risk of remobilization of trace metals.
Seventy samples of foamed plastic collected from a high-energy, sandy beach in SW England have been characterised by FTIR and XRF. Most samples were polyurethane (PU; n=39) or polystyrene (PS; n=27) that were associated with variable concentrations of Br-Cl, Fe and Zn, indicative of the presence of halogenated flame retardants, iron oxides and Zn-based additives, respectively. Many samples of rigid PU contained Pb, historically used as a catalyst, at concentrations of up to 16,000μgg(-1). A physiological extraction test that simulates the conditions in the gizzard of plastic-ingesting seabirds was applied to selected samples and results revealed that while Br and Zn were not measurably bioaccessible, Pb mobilisation progressed logarithmically over a period of time with maximum accessibilities after 220h of ~10% of total metal. Foamed PU is a source of bioaccessible Pb in the marine environment that has not previously been documented.
To determine the pollution sources that influence the level of exposure to particulate matter 2.5 (PM2.5) in the elderly, and calculate the quantitative contributions of difference sources.
Personal exposure PM samples were collected in the summer and winter of 2011 from 101 elderly men in a Tianjin community. Chemical species (elements, water-soluble ions and carbonaceous species) were analyzed in PM samples to determine PM2.5 concentrations and chemical compositions. The Positive Matrix Factorization (PMF) model, which is recommended by the US Environmental Protection Agency, was employed to quantitatively analyze the contribution of each potential sources to personal levels of PM2.5 exposure.
In both summer and winter, the model identified the same six sources of personal exposure to PM2.5 in the elderly: fugitive dust (marker species: Si, Al, Ca, Mg, Fe etc.), coal combustion emissions (marker species: organic carbon (OC) and SO4(2-)), vehicle exhausts (marker species: inorganic carbon and NO3-), secondary sulfates and nitrates (marker species: NO3-, SO42- and NH4(+)), industrial emissions (marker species: Mn, Ni, Cu, Zn, Pb etc.), and indoor sources (marker species: OC, K, Si, Al etc.). Among these six potential sources, vehicle exhausts (summer: 33.6%, winter: 24.2%), secondary sulfates and nitrates (summer: 27.4%, winter: 29.1%), as well as coal combustion emissions (summer: 19.9%, winter: 24.1%) were the greatest contributors.
Coal combustion and vehicle exhaust emissions were the major sources of personal exposure to PM2.5 in the elderly, suggesting that these two sources were the key contributors to the precursor gases of secondary sulfate and nitrate.
Genetically encoded fluorescent Zn(2+) indicators (GEZIs) are highly attractive research tools for studying Zn(2+) homeostasis and signaling in mammalian cells. Most current GEZIs are based on Förster resonance energy transfer (FRET) between a select pair of fluorescent proteins (FPs) fused with Zn(2+)-binding motifs. One drawback of such FRET-based GEZIs is their broad spectral profile bandwidths, creating challenges when monitoring multiple targets or parameters. To address this issue, we have engineered a group of intensiometric GEZIs based on single teal and red FPs that can be utilized to monitor subcellular Zn(2+) diffusion and glucose-induced Zn(2+) secretion in pancreatic INS-1E β-cells. These GEZIs offer the simplicity of intensiometric measurements, compatibility in multicolor imaging, large dynamic ranges, and relatively small molecular sizes, making them valuable additions to the molecular toolbox for imaging Zn(2+).
In the last decade, drug resistant invasive mycoses have become significantly more common and new antifungal drugs and ways to specifically deliver them to the fungal cell are being looked for. One of the biggest obstacles in finding such comes from the fact that
 fungi share essential metabolic pathways with humans. One significant difference in the metabolism of those two cells that can be challenged when looking for possible selective therapeutics is the uptake of zinc, a nutrient crucial for the fungal survival and virulence. This work summarizes the recent advances in the biological inorganic chemistry of zinc metabolism in fungi. The regulation of zinc uptake, various types of its transmembrane transport, storage and the maintenance of intracellular zinc homeostasis is discussed in detail, with a special focus on the concept of a constant 'tug of war' over zinc between the fungus and its host, with the host trying to withhold essential Zn(II), and the fungus counteracting by producing high-affinity zinc binding molecules.
Gradual increase in UV-B component reaching earth surface together with heavy metal contamination appears to be a serious environmental concern. Differential sensitivity in photosynthetic characters of Anabaena doliolum, Microcystis sp., and Nostoc muscorum were observed following exposure to UV-B radiation and heavy metals (Cd and Zn) which displayed reduced photosynthesis with maximum inhibition in Anabaena. PSII was the most sensitive component of the electron transport chain depicting 84, 80, and 70 % inhibition in A. doliolum, Microcystis sp., and N. muscorum, respectively. Cadmium and UV-B-induced inhibition of DCPIP photoreduction could not reversed by artificial electron donors in all the strains. However, they substantially reversed the inhibition caused by Zn as well as Zn + UV-B interactively in N. muscorum, not observed in other two strains. Absorption spectra of all the strains showed differential decrement in chl a peak in treated than the control cells (P < 0.25, r = -0.942). Significantly decreased peaks (P < 0.05) by different states of stresses to all the three cyanobacteria were observed in emission spectra. Excitation spectra of the test strains suggest disorganization or delinking of phycobilisomes from the PSII reaction center, also attested by strong negative correlation between the treatment of stress and phycocyanin (P < 0.025, r = -0.971). The present study qualified N. muscorum as most tolerant followed by Microcystis sp., whereas A. doliolum emerged as the most sensitive one and also endorses high toxicity of Cd as compared to Zn.
Multi-functional nanoparticles possessing magnetic, fluorescence and transition metal ion response properties were prepared and characterized. The particles have a core/shell structure that consists of silica-coated magnetic Fe₃O₄ and 2,6-diaminopyridine anchored on the silica surface via organic linker molecules. The resultant nanoparticles were found by transmission electron microscopy to be well-dispersed spherical particles with an average diameter of 10-12 nm. X-ray diffraction analysis suggested the existence of Fe₃O₄ and silica in/on the particle. Fourier transform infrared spectra revealed that 2,6-diaminopyridine molecules were successfully covalently bonded to the surface of magnetic composite nanoparticles. The prepared particles possessed an emission peak at 364 nm with an excitation wavelength of 307 nm and have a strong reversible response property for some transition metal ions such as Cu(2+) and Zn(2+). This new material holds considerable promise in selective magneto separation and optical determination applications.
Zinc (Zn) nutrition is of key relevance in India, as a large fraction of the population suffers from Zn malnutrition and many soils contain little plant available Zn. In this study we compared organic and conventional wheat cropping systems with respect to DTPA (diethylene triamine pentaacetic acid)-extractable Zn as a proxy for plant available Zn, yield, and grain Zn concentration. We analyzed soil and wheat grain samples from 30 organic and 30 conventional farms in Madhya Pradesh (central India), and conducted farmer interviews to elucidate sociological and management variables. Total and DTPA-extractable soil Zn concentrations and grain yield (3400 kg ha-1) did not differ between the two farming systems, but with 32 and 28 mg kg-1 respectively, grain Zn concentrations were higher on organic than conventional farms (t = -2.2, p = 0.03). Furthermore, multiple linear regression analyses revealed that (a) total soil zinc and sulfur concentrations were the best predictors of DTPA-extractable soil Zn, (b) Olsen phosphate taken as a proxy for available soil phosphorus, exchangeable soil potassium, harvest date, training of farmers in nutrient management, and soil silt content were the best predictors of yield, and (c) yield, Olsen phosphate, grain nitrogen, farmyard manure availability, and the type of cropping system were the best predictors of grain Zn concentration. Results suggested that organic wheat contained more Zn despite same yield level due to higher nutrient efficiency. Higher nutrient efficiency was also seen in organic wheat for P, N and S. The study thus suggests that appropriate farm management can lead to competitive yield and improved Zn concentration in wheat grains on organic farms.
A bioactive pyrazoline derivatives have been synthesized by the base-catalyzed Claisen-Schmidt condensation of imidazole-2-carboxaldehyde with 1-acetyl-2-hydroxynaphthalene followed by cyclization with phenylhydrazine (L(1))/2,3-dimethylphenylhydrazine (L(2)) and 3-nitrophenylhydrazine (L(3)). The metal(II) complexes [Ni(II), Co(II), Cu(II) and Zn(II)] were formed by reacting the corresponding metal acetates with the ligands. All complexes were characterized by elemental analyses, electronic, IR, NMR, mass and ESR spectroscopic techniques. The synthesized metal complexes of pyrazoline compounds showed significant antibacterial activity against the organisms Escherichia coli, Staphylococcus aureus, Klebsiella pneumoniae, Proteus mirabilis and Salmonella typhii when compared with the standard antibiotic (Streptomycin). The ligands and their metal complexes were screened for antioxidant activity using DPPH radical scavenging and superoxide radical scavenging assay methods. All the complexes showed good free radical scavenging activity which is comparable to that of the standards. Among the metal complexes, the copper complex has showed higher activity. The results were indicated that 2-pyrazoline (structural core) and copper ion could be responsible for the potential candidate eliciting antioxidant activity. All compounds were evaluated for their in vitro antimycobacterial activity against Mycobacterium tuberculosis. The ligands and metal complexes were subjected to fluorescence properties and exhibited that the variable fluorescence emission behavior of complexes. It can be attributed to the combined effect of the substituents and naphthyl structural core present in the ligands.
Sodium titanate nanosheets (NaTiO2 NS) have been prepared by a new method and completely characterized by TEM, SEM, XRD, EDX, and XPS techniques. The sensitization of nanosheets is carried out with Zn protoporphyrin IX (ZnPPIX). The emission intensity of ZnPPIX is quenched by NaTiO2 NS, and the dominant process for this quenching has been attributed to the process of photoinduced electron injection from excited ZnPPIX to the nanosheets. Time resolved fluorescence measurement was used to elucidate the process of electron injection from the singlet state of ZnPPIX to the conduction band of NaTiO2 NS. Electron injection from the dye to the semiconductor is very fast (ket ≈ 10(11) s(-1)), much faster than previously reported rates. The large two-dimensional surface offered by the NaTiO2 NS for interaction with the dye and the favorable driving force for electron injection from ZnPPIX to NaTiO2 NS (ΔGinj = -0.66 V) are the two important factors responsible for such efficient electron injection. Thus, NaTiO2 NS can serve as an effective alternative to the use of TiO2 nanoparticles in dye sensitized solar cells (DSSCs).
A new iron phosphate, rubidium zinc iron(III) phosphate, RbZnFe(PO4)2, has been synthesized as single crystals by the flux method. This compound is isostructural to the previously reported KCoAl(PO4)2 [Chen et al. (1997 ▸). Acta Cryst. C53,1754-1756]. Its structure consists of a three-dimensional framework built up from corner-sharing PO4 and (Zn,Fe)O4 tetra-hedra. This mode of linkage forms channels parallel to the [100], [010] and [001] directions in which the Rb(+) ions are located.
Condensation of a 2,3-diaminophenazine or 2,3-diamino-2-quinoxalinol with two equivalents of 3,5-ditertbutylsalicylaldehyde affords new Schiff base ligands. Here, we describe and compare the synthesis, UV-Vis, electrochemical, solution, and solid state behaviour of the free base, salphenazine ligand [L(I)], and M[L(I)] complexes, where M = UO2(vi), Cu(ii), VO(iv), Zn(ii), Co(ii), and Ni(ii). The change in π-overlap and π-stacking between molecules and long-range ordering of the solid-state structure is vastly different depending on the size and electronic character of the metal. A sterically constrained μ-oxo Fe(iii) dimer complex is also reported.
The addition of Sn and Zn ions to [Ge9 ] clusters by reaction of [Ge9 ](4-) with SnPh2 Cl2 , ZnCp*2 (Cp*=pentamethylcyclopentadienyl), or Zn2 [HC(Ph2 P=NPh)2 ]2 is reported. The resulting Sn- and Zn-bridged clusters [(Ge9 )M(Ge9 )](q-) (M=Sn, q=4; M=Zn, q=6) display various coordination modes. The M atoms that coordinate to the open square of a C4v -symmetric [Ge9 ] cluster form strong covalent multicenter M-Ge bonds, in contrast to the M atoms coordinating to triangular cluster faces. Molecular orbital analyses show that the M atoms of the Ge9 M fragments coordinate to a second [Ge9 ] cluster with similar orbitals but in different ways. The [Ge9 Sn](2-) unit donates two electrons to the triangular face of a second [Ge9 ](2-) cluster with D3h symmetry, whereas [Ge9
 Zn](2-) acts as an electron acceptor when interacting with the triangular face of a D3h -symmetric [Ge9 ](4-) unit.
Matrix metalloproteinases (MMPs) constitute a group of over 20 structurally-related proteins which include a Zn(++) ion binding site that is essential for their proteolytic activities. These enzymes play important role in extracellular matrix turnover in order to maintain a proper balance in its synthesis and degradation. MMPs are associated to several physiological and pathophysiological processes, including diabetes mellitus (DM). The mechanisms of DM and its complications is subject of intense research and evidence suggests that MMPs are implicated with the development and progression of diabetic microvascular complications such as nephropathy, cardiomyopathy, retinopathy and peripheral neuropathy. Recent data has associated DM to changes in the tendon structure, including abnormalities in fiber structure and organization, increased tendon thickness, volume and disorganization obtained by image and a tendency of impairing biomechanical properties. Although not fully elucidated, it is believed that DM-induced MMP dysregulation may contribute to structural and biomechanical alterations and impaired process of tendon healing.
In eukaryotes the bimetallic Cu/Zn superoxide dismutase (SOD) enzymes play important roles in the biology of reactive oxygen species by disproportionating superoxide anion. Recently, we reported that the fungal pathogen Candida albicans expresses a novel copper-only SOD, known as SOD5, that lacks the zinc cofactor and electrostatic loop (ESL) domain of Cu/Zn-SODs for substrate guidance. Despite these abnormalities, C. albicans SOD5 can disproportionate superoxide at rates limited only by diffusion. Here we demonstrate that this curious copper-only SOD occurs throughout the fungal kingdom as well as in phylogenetically distant oomycetes or "pseudofungi" species. It is the only form of extracellular SOD in fungi and oomycetes, in stark contrast to the extracellular Cu/Zn-SODs of plants and animals. Through structural biology and biochemical approaches we demonstrate that these copper-only SODs have evolved with a specialized active site consisting of two highly conserved residues equivalent to SOD5 Glu-110 and Asp-113. The equivalent positions are zinc binding ligands in Cu/Zn-SODs and have evolved in copper-only SODs to control catalysis and copper binding in lieu of zinc and the ESL. Similar to the zinc ion in Cu/Zn-SODs, SOD5 Glu-110 helps orient a key copper-coordinating histidine and extends the pH range of enzyme catalysis. SOD5 Asp-113 connects to the active site in a manner similar to that of the ESL in Cu/Zn-SODs and assists in copper cofactor binding. Copper-only SODs are virulence factors for certain fungal pathogens; thus this unique active site may be a target for future anti-fungal strategies.
Bizerte Lagoon is a southern Mediterranean semi-enclosed lagoon with a maximum depth of 12 m. After assessing sediment quality, the authors report on the physicochemical characteristics of the lagoon's surface sediment using SEM (simultaneously extracted metals) and AVS (acid volatile sulfides) as proxies. Biogeochemical tools are used to investigate the environmental disturbance at the water-sediment interface by means of SEM and AVS to seek conclusions concerning the study area's pollution status. Results confirm accumulation of trace elements in sediment. The use of the SEM-AVS model with organic matter in sediment (ƒOC) confirms possible bioavailability of accumulated trace elements, especially Zn, in the southern part of the lagoon, with organic matter playing an important role in SEM excess correction to affirm a nontoxic total metal sediment state. Individual trace element toxicity is dependent on the bioavailable fraction of SEMMetal on sediment, as is the influence of lagoon inflow from southern water sources on element bioavailability. Appropriate management strategies are highly recommended to mitigate any potential harmful effects on health from this heavy-metal-based pollution.
The application of sunscreen is a critical component of a sun-safe strategy, however the possibility of unexpected, adverse outcomes resulting from long-term use of sunscreens containing nanoparticles of titanium dioxide (TiO2) and zinc oxide (ZnO) has not yet been examined. Here, immune-competent hairless mice were exposed over a 36-week period to weekly topical applications of sunscreens containing nanoparticles of ZnO or TiO2, or no metal oxide nanoparticles, with or without subsequent exposure to ultraviolet radiation (UVR). Control groups received no sunscreen applications, with or without UVR.
Mice exposed to UVR in the absence of sunscreen developed statistically significant incidences of histologically-diagnosed malignant and benign skin neoplasms, whereas no statistically significant adverse biological outcomes were found in mice treated with the sunscreens containing ZnO or TiO2 nanoparticles. Elevated levels of Ti were detected in the livers of mice treated with sunscreen containing TiO2 nanoparticles compared to untreated control, but total Zn concentrations did not significantly alter in any major organs except for the skin of mice treated with ZnO sunscreen. Exposure to UVR did not have a significant impact on examined tissue concentrations of Zn or Ti. Few to no transcriptional changes were found in ZnO or TiO2-treated groups, but mice treated with the sunscreen containing only organic filters showed substantial gene disregulation.
Taken together with previous work, this long-term study provided no basis to avoid the use of sunscreens containing metal oxide nanoparticles.
To assess the effects of Fe(III) and anthropogenic ligands on the bioavailability of Ni, Cu, Zn, and Pb, concentrations of bioavailable metals were measured by the DGT (diffusive gradients in thin films) method in some urban rivers, and were compared with concentrations calculated by a chemical equilibrium model (WHAM 7.0). Assuming that dissolved Fe(III) (<0.45 μm membrane filtered) was in equilibrium with colloidal iron oxide, the WHAM 7.0 model estimated that bioavailable concentrations of Ni, Cu, and Zn were slightly higher than the corresponding values estimated assuming that dissolved Fe(III) was absent. In contrast, lower levels of free Pb were predicted by the WHAM 7.0 model when dissolved Fe(III) was included. Estimates showed that most of the dissolved Pb was present as colloidal iron-Pb complex. Ethylene-diamine-tetra-acetic acid (EDTA) concentrations at sampling sites were predicted from the relationship between EDTA and the calculated bioavailable concentration of Zn. When both colloidal iron and predicted EDTA concentrations were included in the WHAM 7.0 calculations, dissolved metals showed a strong tendency to form EDTA complexes, in the order Ni > Cu > Zn > Pb. With the inclusion of EDTA, bioavailable concentrations of Ni, Cu, and Zn predicted by WHAM 7.0 were different from those predicted considering only humic substances and colloidal iron.
We aimed to check the relationships between levels of metals (Ca, Cd, Cu, Fe, Hg and Zn) in cancerous and non-cancerous lung tissues and their link to air pollution, expressed as particulate matter (PM) concentrations. The study also examines the influence on metal concentration in the lung tissue of patients' sex and the distance of their homes from the nearest emitter. We found that the general pattern of ascending concentrations in tumor tissue was as follows: Hg < Cd < Cu < Ca < Zn < Fe. In non-affected lung tissue the order of concentrations of Ca and Fe was reversed. With the exception of Cd and Cu, levels of metals were found in higher accumulations in non-cancerous tissue (e.g., Fe 326.423 and Ca 302.730 μg/g d.w) than in tumorous tissue (Fe 150.735 and Ca 15.025 μg/g d.w). Neither the PM10 (PM of a diameter of 10 μm) concentration nor sex revealed any connection with metal concentrations. The shorter the distance from the emitter, the higher the metal concentrations that tended to be observed for almost all metals, but a statistically significant (but weak) relationship was noted only for Cu in tumor tissue (rs: -0.4869).
Preorganization and predisposition are important molecular recognition concepts exploited by nature to obtain site-specific and selective metal binding to proteins. While native structures containing an MS3 core are often unavailable in both apo- and holo-forms, one can use designed three-stranded coiled coils (3SCCs) containing tris-thiolate sites to evaluate these concepts. We show that the preferred metal geometry dictates the degree to which the cysteine rotamers change upon metal complexation. The Cys ligands in the apo-form are preorganized for binding trigonal pyramidal species (Pb(II)S3 and As(III)S3) in an endo conformation oriented toward the 3SCC C-termini, whereas the cysteines are predisposed for trigonal planar Hg(II)S3 and 4-coordinate Zn(II)S3O structures, requiring significant thiol rotation for metal binding. This study allows assessment of the importance of protein fold and side-chain reorientation for achieving metal selectivity in human retrotransposons and metalloregulatory proteins.
Developing efficient catalysts for converting carbon dioxide (CO2) into varied organic carbonates is an important scientific goal. By using the NH2-functionalized tripodal ligand 2-((bis(2-aminoethyl)amino)methyl)phenol (HL), three dinuclear metal-organic complexes [Zn(L)]2·2ClO4 (1), [Cu(L)]2·2ClO4·2H2O (2) and [Cd(L)]2·2ClO4 (3) have been successfully isolated and structurally characterized using single-crystal X-ray diffraction analyses. Considering the dinuclear metal centers and the NH2-functional groups in the structures, 1-3 were investigated as catalysts for converting CO2 into organic carbonates, and the results show
 that 1-3 exhibit an outstanding ability for converting CO2 into varied organic carbonates at atmospheric pressure (0.1 MPa). The catalytic system also displays a wide substrate scope and high catalytic activity, and the reaction mechanism has been proposed herein.
This study presents a novel method for synthesis and characterization of a metal-organic framework and application in drug delivery. The first step was synthesis of amino functionalized magnetite that was then modified by a metal-organic framework of Zn(2+). This newly developed nano-sorbent was characterized by Fourier transform infrared spectroscopy, scanning electron microscopy, energy dispersive x-ray spectroscopy, thermogravimetric analysis, vibrating sample magnetometer and x-ray diffraction. Doxycycline was loaded to the nano-sorbent and effects of the variable parameters, kinetics of adsorption, release and capacity of adsorption were investigated. Test results specified maximum sorption of 21.5mgg(-1) for doxycycline in conditions of nano-sorbent at pH 7 and optimum time of 10min. Equilibrium adsorption data were analyzed by the Langmuir, Freundlich and Temkin models. Results showed that about 40% of doxycycline was released in simulated gastric fluid for the 30min and more than 70% was released in simulated intestinal fluid during 12h. These results were satisfactory and demonstrate that this new nano-sorbent modified with metal-organic framework had a good level of efficiency for drug delivery of doxycycline.
Removing inorganics from non-metallic fraction (NMF) of waste printed circuit boards (WPCBs) is an effective mean to improve its usability. The effect of size fraction on the triboelectric separation of NMF of WPCBs was investigated in a lab triboelectric separation system and the separation process was optimized in this paper. The elements distribution in raw NMF collected from typical WPCBs recycling plant and each size fraction obtained by sieving were analyzed by X-ray fluorescence (XRF). The results show that the main inorganic elements in NMF are P, Ba, Mn, Sb, Ti, Pb, Zn, Sn, Mg, Fe, Ca, Cu, Al and Si. The inorganic content of each size fraction increased with the size decreasing. The metal elements are mainly distributed in -0.2mm size fraction, and concentrated in middle product of triboelectric separation. The loss on ignition (LOI) of positive product and negative product is higher than that of the middle product for the -0.355mm size fraction, while the LOI presents gradually increasing trend from negative to positive plate for the +0.355mm size fraction. Based on the separation results and mineralogical characterizations of each size fraction of NMF, the pretreatment process including several mineral processing operations was added before triboelectric separation and better separation result was obtained.
In this work, the structure of end-member Bi(Me0.5Ti0.5)O3 (Me = Zn, Ni, Mg, Co) was calculated through a first-principles method and lead-free piezoelectric ternary systems (0.94 -x)(Bi0.5Na0.5)TiO3-0.06BaTiO3-xBi(Me0.5Ti0.5)O3 (Me = Zn, Ni, Mg, Co) (BNT-BT-Bi(Me0.5Ti0.5)O3) were designed to achieve a large strain response for actuator applications. Composition-driven phase transition characteristics and the resulting associated piezoelectric and electromechanical properties were systematically investigated, and schematic phase diagrams were constructed. XRD measurements, Raman spectra analysis and temperature-dependent polarization and strain hysteresis loops indicate that Bi(Me0.5Ti0.5)O3 substitution induces a phase transformation from a ferroelectric rhombohedral to an ergodic relaxor pseudo-cubic phase, accounting for the large strain response (>0.3%) with a high normalized strain Smax/Emax (≥550 pm V(-1)) at around the corresponding critical composition in the vicinity of room temperature. In addition, correlations between the tolerance factor t of the added end-member, the calculated tetragonality and the morphotropic phase boundary (MPB) composition were sought. In comparison to other reported BNT-based systems, there is a noticeable correlation between the MPB composition and the calculated tetragonality of the end-member Bi(Me0.5Ti0.5)O3, and the t value corresponding to the formation of the MPB composition is approximately 0.981 in the present ternary system with low tolerance factor end-members. As a result, we believe that the general correlations and design principles obtained from the present comprehensive research will be effective to predict the approximate MPB region quickly in BNT-based ceramics with an excellent actuating performance.
The assembly sequence of the coordination cluster [Zn5 (H2 L(n) )6 ](NO3 )4 ]⋅8 H2 O⋅2 CH3 OH (Zn5 , H3 L(n) =(1,2-bis(benzo[d]imidazol-2-yl)-ethenol) involves in situ dehydration of 1,2-bis(benzo[d]imidazol-2-yl)-1,2-ethanediol (H4 L) through the formation of the [Zn(H3 L)2 ](+) monomer, dimerization to [Zn2 (H3 L)2 ](+) , dehydration of the ligand to [Zn2 (H2 L(n) )2 ](+) , and the final formation of the pentanuclear cluster. The cluster has the following special characteristics: 1) high stability in both refluxing 37 % HCl and 27 % NH3 , 2) low cytotoxicity, and 3) pH-sensitive fluorescence in the visible-to-near-infrared (Vis/NIR) region in the solid state and in solution. We have applied it as a fluorescent probe both in vivo and in vitro. Its H-bonding ability is the key to its affinity and selectivity for imaging lysosomes in HeLa cells and tumors in male BALB/C mice. It provides a new type of sensitive and biocompatible fluorescent probe for detecting small tumors (13.5 mm(3) ).
Street dust is a hazard for workers in traditional markets. Exposure time is longer than for other people, making them vulnerable to heavy metals in street dust. This study investigated heavy metal concentrations in street dust samples collected from different types of markets. It compared the results with heavy metal concentrations in heavy traffic and rural areas. Street dust was significantly enriched with most heavy metals in a heavy traffic area while street dust from a fish market was contaminated with cupper (Cu), lead (Pb) and zinc (Zn). Street dust from medicinal herb and fruit markets, and rural areas were not contaminated. Principal component and cluster analyses indicated heavy metals in heavy traffic road and fish market dust had different sources. Relatively high heavy metal concentration in street dust from the fish market may negatively affect worker's mental health, as depression levels were higher compared with workers in other markets. Therefore, intensive investigation of the relationship between heavy metal concentrations in street dust and worker's health in traditional marketplaces should be conducted to elucidate the effect of heavy metals on psychological health in humans.
Industrialization and urbanization have led to a deterioration in air quality and provoked some serious environmental concerns. Fifty-four samples of atmospheric deposition were collected from an emerging industrial area and analyzed to determine the concentrations of 11 trace elements (As, Cd, Cu, Fe, Hg, Mn, Mo, Pb, Se, S and Zn). Multivariate geostatistical analyses were conducted to determine the spatial distribution, possible sources and enrichment degrees of trace elements in atmospheric deposition. Results indicate that As, Fe and Mo mainly originated from soil, their natural parent materials, while the remaining trace elements were strongly influenced by anthropogenic or natural activities, such as coal combustion in coal-fired power plants (Pb, Se and S), manganese ore (Mn, Cd and Hg) and metal smelting (Cu and Zn). The results of ecological geochemical assessment indicate that Cd, Pb and Zn are the elements of priority concern, followed by Mn and Cu, and other heavy metals, which represent little threat to local environment. It was determine that the resuspension of soil particles impacted the behavior of heavy metals by 55.3%; the impact of the coal-fired power plants was 18.9%; and the contribution of the local manganese industry was 9.6%. The comparison of consequences from various statistical methods (principal component analysis (PCA), cluster analysis (CA), enrichment factor (EF) and absolute principle component score (APCS)-multiple linear regression (MLR)) confirmed the credibility of this research.
Metal contamination is one of the major issues to the environment worldwide, yet it is poorly known how exposure to metals affects tropical species. We assessed the sensitivity of a tropical micro-crustacean Daphnia lumholtzi to three trace metals: copper (Cu), zinc (Zn) and nickel (Ni). Both, acute and chronic toxicity tests were conducted with metals dissolved in in situ water collected from two sites in the lower part of the Mekong River. In the acute toxicity test, D. lumholtzi neonates were exposed to Cu (3-30μgL(-1)), Zn (50-540μgL(-1)) or Ni (46-2356μgL(-1)) for 48h. The values of median lethal concentrations (48h-LC50) were 11.57-16.67μg Cu L(-1), 179.3-280.9μg Zn L(-1), and 1026-1516μg Ni L(-1). In the chronic toxicity test, animals were exposed to Cu (3 and 4μgL(-1)), Zn (50 and 56μgL(-1)), and Ni (six concentrations from 5 to 302μgL(-1)) for 21days. The concentrations of 4μg Cu L(-1) and 6μg Ni L(-1) enhanced the body length of D. lumholtzi but 46μg Ni L(-1) and 50μg Zn L(-1) resulted in a strong mortality, reduced the body length, postponed the maturation, and lowered the fecundity. The results tentatively suggest that D. lumholtzi showed a higher sensitivity to metals than related species in the temperate region. The results underscore the importance of including the local species in ecological risk assessment in important tropical ecosystems such as the Mekong River to arrive at a better conservational and management plan and regulatory policy to protect freshwater biodiversity
 from metal contamination.
In this study, pure ZnO, CeO2 and ZnO/CeO2 nanocomposites were synthesized using a thermal decomposition method and subsequently characterized using different standard techniques. High-resolution X-ray photoelectron spectroscopy measurements confirmed the oxidation states and presence of Zn(2+), Ce(4+), Ce(3+) and different bonded oxygen species in the nanocomposites. The prepared pure ZnO and CeO2 as well as the ZnO/CeO2 nanocomposites with various proportions of ZnO and CeO2 were tested for photocatalytic degradation of methyl orange, methylene blue and phenol under visible-light irradiation. The optimized and highly efficient ZnO/CeO2 (90:10) nanocomposite exhibited enhanced photocatalytic degradation performance for the degradation of methyl orange, methylene blue, and phenol as well as industrial textile effluent compared to ZnO, CeO2 and the other investigated nanocomposites. Moreover, the recycling results demonstrate that the ZnO/CeO2 (90:10) nanocomposite exhibited good stability and long-term durability. Furthermore, the prepared ZnO/CeO2 nanocomposites were used for the electrochemical detection of uric acid and ascorbic acid. The ZnO/CeO2 (90:10) nanocomposite also demonstrated the best detection, sensitivity and performance among the investigated materials in this application. These findings suggest that the synthesized ZnO/CeO2 (90:10) nanocomposite could be effectively used in various applications.
In the last decades a dramatic loss of Apis mellifera hives has been reported in both Europe and USA. Research in this field is oriented towards identifying a synergy of contributing factors, i.e. pathogens, pesticides, habitat loss and pollution to the weakening of the hive. Cadmium (Cd) is a hazardous anthropogenic pollutant whose effects are proving to be increasingly lethal. Among the multiple damages related to Cd contamination, some studies report that it causes immunosuppression in various animal species. The aim of this paper is to determine whether contamination by Cd, may have a similar effect on the honey bees' immunocompetence. Our results, obtained by immune challenge experiments and confirmed by structural and ultrastructural observations show that such metal causes a reduction in immunocompetence in 3 days Cd exposed bees. As further evidence of honey bee response to Cd treatment, Energy Dispersive X-ray Spectroscopy (X-EDS) has revealed the presence of zinc (Zn) in peculiar electron-dense granules in fat body cells. Zn is a characteristic component of metallothioneins (MTs), which are usually synthesized as anti-oxidant and scavenger tools against Cd contamination. Our findings suggest that honey bee colonies may have a weakened immune system in Cd polluted areas, resulting in a decreased ability in dealing with pathogens.
Although the term nanozymes was coined by us in 2004 to highlight the enzyme-like properties of gold nanoparticles passivated with a monolayer of Zn(II)-complexes in the cleavage of phosphate diesters, systems resembling those metallo-nanoparticles, like micelles and vesicles, have been the subject of investigation since the mid-eighties of the last century. This paper reviews what has been done in the field and compares the different nanosystems highlighting the source of catalysis and frequent misconceptions found in the literature.
The present study investigated dual carbon-bromine isotope fractionation of the common groundwater contaminant ethylene dibromide (EDB) during chemical and biological transformations, including aerobic and anaerobic biodegradation, alkaline hydrolysis, Fenton-like degradation, debromination by Zn(0) and reduced corrinoids. Significantly different correlation of carbon and bromine isotope fractionation (ΛC/Br) was observed not only for the processes following different transformation pathways, but also for abiotic and biotic processes with, the presumed, same formal chemical degradation mechanism. The studied processes resulted in a wide range of ΛC/Br values: ΛC/Br = 30.1 was observed for hydrolysis of EDB in alkaline solution; ΛC/Br between 4.2 and 5.3 were determined for dibromoelimination pathway with reduced corrinoids and Zn(0) particles; EDB biodegradation by Ancylobacter aquaticus and Sulfurospirillum multivorans resulted in ΛC/Br = 10.7 and 2.4, respectively; Fenton-like degradation resulted in carbon isotope fractionation only, leading to ΛC/Br ∞. Calculated carbon apparent kinetic isotope effects ((13)C-AKIE) fell with 1.005 to 1.035 within expected ranges according to the theoretical KIE, however, biotic transformations resulted in weaker carbon isotope effects than respective abiotic transformations. Relatively large bromine isotope effects with (81)Br-AKIE of 1.0012-1.002 and 1.0021-1.004 were observed for nucleophilic substitution and dibromoelimination, respectively, and reveal so far underestimated strong bromine isotope effects.
The crystallization characteristics in supercooled liquid Zn during isothermal relaxation were investigated using molecular dynamics simulations by adopting the cluster-type index method (CTIM) and the tracing method. Results showed that the crystallization process undergo three different stages. The size of the critical nucleus was found to be approximately 90-150 atoms in this system; the growth of nuclei proceeded via the successive formation of hcp and fcc structures with a layered distribution; and finally, the system evolved into a much larger crystal with a distinct layered distribution of hcp and fcc structures with an 8R stacking sequence of ABCBACAB by adjusting all of the atoms in the larger clusters according to a certain rule.
Aerobic composting is usually employed to treat livestock manure. In this study, a bio-surfactant (rhamnolipid, RL) and chemical surfactant (Tween 80, Tw) were added to chicken manure during composting and their effects were determined on the variations in ARGs and intI1. After composting, the reductions in the RAs of ARGs and intI1 with the addition of Tw (1-4.7logs) were generally greater than that with the addition of RL (0.8-3.7logs) and the control (CK) (0.3-2.6logs), and the enrichment of ARGs was higher with CK (0.9-1.8logs). The ARG profiles were affected significantly by temperature and the water-soluble carbon contents. RL and Tw effectively reduced the concentrations of bio-available Cu and Zn, thereby hindering the co-selection of ARGs by heavy metals. The effects of RL and Tw on ARGs and intI1 indicate that the addition of Tw was slightly more effective than RL after composting.
This review will discuss the importance of Zinc in the maintenance of oral health. Zinc (Zn) is a trace element of valuable importance. In the oral cavity, it is naturally present at various sites such as dental plaque, dental hard tissues and saliva. It is proven to be effective against common prevalent oral health problems such as dental caries, gingivitis, periodontitis and malodour. It is being used in various oral health care products to control the formation of dental plaque and inhibiting the formation of dental calculus. It has the potential to sustain and maintain its elevated concentrations for a longer time particularly in the dental plaque and saliva on delivery from the mouth rinses and toothpastes. It has been reported that low concentrations of zinc have the capability to reduce dissolution and promote remineralization under caries simulating conditions. Most importantly low Zn2+ levels in the serum are useful as a tumour marker. Thus taking a note of its potentials, it can be concluded that zinc is a precious element for the maintenance of oral health.
Ultra-fine-ZnO showed low toxicity in complex water matrix containing multiple components such as PBS buffer and the toxic mechanism of ultra-fine-ZnO has not been clearly elucidated. In present study, enhanced antibacterial activity of 200 nm diameter ultra-fine-ZnO in PBS buffer against Bacillus cereus and Escherichia coli were observed in the presence of several organic acids in comparison with ultra-fine-ZnO in PBS buffer alone. These findings indicated that the toxic effects of the ultra-fine-ZnO was dependent on the concentration of released Zn(2+) which was affected by organic acids. The production of reactive oxygen species (ROS) did not responsible to the toxic mechanism of ultra-fine-ZnO which was tested using the antioxidant N-Acetylcysteine (NAC). Indeed, ultra-fine-ZnO induced bacteria cell membrane leakages and cell morphology damages that eventually led to cell death, which were confirmed using propidium monoazide (PMA) in combination with PCR and scanning electron microscopy (SEM). All data gathered herein suggested that released Zn(2+) played a major role in the microbial toxicity of ultra-fine-ZnO.
Magnesium (Mg) and its alloys have been extensively explored as potential biodegradable implant materials for orthopaedic applications (e.g. Fracture fixation). However, the rapid corrosion of Mg based alloys in physiological conditions has delayed their introduction for therapeutic applications to date. The present review focuses on corrosion, biocompatibility and surface modifications of biodegradable Mg alloys for orthopaedic applications. Initially, the corrosion behaviour of Mg alloys and the effect of alloying elements on corrosion and biocompatibility is discussed. Furthermore, the influence of polymeric deposit coatings, namely sol-gel, synthetic aliphatic polyesters and natural polymers on corrosion and biological performance of Mg and its alloy for orthopaedic applications are presented. It was found that inclusion of alloying elements such as Al, Mn, Ca, Zn and rare earth elements provides improved corrosion resistance to Mg alloys. It has been also observed that sol-gel and synthetic aliphatic polyesters based coatings exhibit improved corrosion resistance as compared
 to natural polymers, which has higher biocompatibility due to their biomimetic nature. It is concluded that, surface modification is a promising approach to improve the performance of Mg-based biomaterials for orthopaedic applications.
In light of the superior property profile of favorable biocompatibility, proper corrosion/degradation behavior and good mechanical properties, Mg-based bulk metallic glasses (BMGs) are considered as potential biodegradable biomaterials. In the present study, in vitro responses of bone-forming MC3T3-E1 pre-osteoblasts to Mg-Zn-Ca-Sr BMGs were studied in order to assess their feasibility to serve as orthopedic implants. The Mg-Zn-Ca-Sr BMGs were much more capable of supporting cell adhesion and spreading in comparison with crystalline AZ31B Mg alloy. The Mg-Zn-Ca-Sr BMG extracts showed no cytotoxicity to and slightly stimulated the proliferation of pre-osteoblasts. The cells cultured in 100% BMG extracts exhibited lower alkaline phosphatase activity as compared with that in negative control, which could be mainly ascribed to the inhibition of high concentrations of Zn ions on cell differentiation. With decreasing the extract concentration, the inhibitory effect was diminished and the 5% BMG extract exhibited slight stimulation in cell differentiation and mineralization. The high corrosion resistance of BMGs contributed to smaller environmental variations, compared with AZ31B alloy, thus lowering the unfavorable influences on cellular responses. A comparison among the biodegradable Mg-, Ca- and Sr-based BMGs for their biomedical applications is presented.
Pure Mg and a Mg-6wt.% Zn alloy were investigated as potential candidates for biodegradable implants for the urinary system. The in vitro corrosion behavior was studied by potentiodynamic polarization and immersion tests in simulated body fluid (SBF) at 37°C. The in vivo degradation and histocompatibility were examined through implantation into the bladders of Wistar rats. The alloying element Zn elevated the passivation potential and increased the cathodic current density. Both in vitro and in vivo degradation tests showed a faster corrosion rate for the Mg-6Zn alloy. Tissues stained with hematoxylin and eosin (HE) suggested that both pure Mg and Mg-6Zn alloy exhibited good histocompatibility in the bladder indwelling implantation and no differences between pure Mg and Mg-6Zn groups were found in bladder, liver and kidney tissues during the 2weeks implantation. Overall, this work presented instructive information on the degradation properties and histocompatibility of pure Mg and the Mg-6Zn alloy in the urinary system.
A Mg-Gd-Nd-Zn-Zr alloy was processed by equal channel angular pressing (ECAP) at 375°C. The grain size of Mg-Gd-Nd-Zn-Zr alloy was refined to ~2.5μm with the spherical precipitates (β1 phase) distributing in the matrix. The mechanical properties of ECAPed alloy were significantly improved as a result of the grain refinement and precipitation strengthening. The corrosion rate of the ECAPed magnesium alloy in simulated body fluid dramatically decreased from 0.236mm/a to 0.126mm/a due to the strong basal texture and refined microstructure. This wrought magnesium alloy shows potentials in biomedical application.
Facile and simple processes to get Zn-Fe layered double hydroxide (LDH) with nitrate as the interlayer anion are reported. The method of co-precipitation produced high crystallinity LDH that is marked by XRD, SEM, TEM and FT-IR. Results showed that 99.8% of Cd(+2) removals were at pH11 and 4h. To get the adsorption isotherms, the concentration of metal ions extending from 6 to 18mg/L was utilized. Results supported the Langmuir adsorption model. In contrary, the adsorption process followed the pseudo-second-order reaction kinetics. Interestingly, the prepared LDH shows durable antimicrobial activities against Gram-negative (Proteous vulgaris, Klebsiella pneumoniae, Escherichia coli and Pseudomonas aeruginosa) and Gram-positive (Staphylococcus epidermidis, Staphylococcus aureus, Streptococcus pyogenes and MRSA) and fungi (Candida albicans, Aspergillus fumigatus, Geotricumcandidum, and Trichophyton mentagrophytes). The minimum inhibitory concentration (MIC) of Zn-Fe LDH varied from 0.49 to 15.60μg/mL according to the types of microorganisms. The prepared LDH achieved 90% at pH8.50 which is the pH of wastewater and at the same time exhibited durable antimicrobial activities against MRSA, Gram-negative, Gram-positive and fungi. Results have significant implications in the field of bioremediation of water with little cost, simple operation, high productivity and easiness of the equipment.
Concentrations of 11 trace elements in three tissues of porbeagle shark Lamna nasus (n=33) were determined. The maximum observed concentrations of Cd and Pb in muscle were 0.04 and 0.01mgkg(-1), respectively, and all muscle samples were below European seafood limits for these metals. Hg concentrations in either the red or white muscle that exceeded European regulations for seafood were observed in one-third of specimens. Hg concentration, however, increased with length, and all fish >195cm had concentrations >1.0mgkg(-1), with a maximum observed value of 2.0mgkg(-1). Concentrations of Fe and Cu were, on average, 9.7 and 10 times higher in red muscle than in nearby white muscle, respectively. Mn, Zn, As and Se were also found in significantly higher concentrations in red muscle than in white muscle.
The major cause of toxicity of trivalent arsenicals is due to their interaction with the sulfhydryl groups in proteins. Because of its high content, Metallothionein (MT) provides one of the most favorable conditions for the binding of As(III) ions to it. MT has long been anticipated for providing resistance in case of arsenic (As) toxicity with similar mechanism as in case of cadmium toxicity. The present study investigates whether the sequestration of As ions by MT is one of the mechanisms in providing protection against acute arsenic toxicity. A rat model study on the metal stoichiometric analysis of MT1 isoform isolated from the liver of arsenic treated, untreated and zinc treated animals has been carried out using the combination of particle induced X-ray emission (PIXE) and electrospray ionisation mass spectrometry (ESI-MS). The results revealed the absence of arsenic bound MT1 in the samples isolated from arsenic treated animals. Although, both Cu and Zn ions were present in MT1 samples isolated from all the treatment groups. Moreover, only partially metallated MT1 with varying number of Zn ions were observed in all the groups. These results suggest that the role of MT during acute arsenic toxicity is different from its already established role in case of cadmium toxicity.
Pregnant and lactating women and infants are vulnerable population groups for adverse effects of toxic metals due to their high nutritional needs and the resultant increased gastrointestinal absorption of both, essential and toxic elements. Although breastfeeding is recommended for infants worldwide, as human milk is the best source of nutrients and other required bioactive factors, it is also a pathway of maternal excretion of toxic substances including toxic metals and thus a source of infant exposure. The aim of this research was to assess health risks in breastfeeding women in the coastal area of the Republic of Croatia and their infants (N=107) due to maternal exposure to Cd and Pb via cigarette smoking, and Hg via seafood and dental amalgam fillings, and their interaction with essential elements. Biological markers of exposure were the concentrations of main toxic metals Pb, Cd and Hg in maternal blood and three types of breast milk throughout lactation stages. Biological markers of effects were the levels of essential elements Ca, Fe, Cu, Zn and Se in maternal serum and breast milk. With regard to cigarette smoking as a source of exposure to Cd and Pb, there were effects of smoking on Cd concentration in blood and correlations between the smoking index and Cd concentrations in maternal blood (ρ=0.593; P<0.001) and mature milk (ρ=0.271; P=0.011) and Pb concentration in transitional milk (ρ=0.280; P=0.042). Regarding fish, we found correlations between weekly consumption frequency and total Hg concentrations in maternal blood (ρ=0.292; P=0.003) and mature milk (ρ=0.303; P=0.003). The number of dental amalgam fillings correlated with total Hg concentrations in colostrum (ρ=0.489; P=0.005) and transitional milk (ρ=0.309; P=0.018). As for the essential element status, only Se levels in maternal serum decreased by 10% in persons who continued smoking during pregnancy compared to non-smokers. In conclusion, the levels of main toxic metals Cd, Pb and Hg and essential elements Ca, Fe, Cu, Zn and Se in maternal blood and three types of breast milk samples in the studied area of coastal Croatia showed no risk of disrupted essential element levels with regard of toxic metal exposure in both breastfeeding women and their infants.
The aim of the present study was to assess survival rate, Zn accumulation, reactive oxygen species (ROS) levels, oxidative damage and antioxidant responses after Zn exposure (2 and 8 mg L(-1) Zn) at different exposure times (6, 12, 24, 48 and 96 h) in the liver of large yellow croaker. Survival rate was reduced at 96 h, and hepatic Zn content increased during 24-96 by 8 mg L(-1) Zn. In the 2 mg L(-1) Zn group, no fish died and the increase in Zn content merely occurred at 96 h. Exposure to 8 mg L(-1) Zn induced accumulation of ROS, lipid peroxidation and protein carbonylation during the late stage of exposure. In contrast, exposure to 2 mg L(-1) Zn did not result in oxidative damage, which may result from the up-regulation of antioxidant defenses. Although exposure to 8 mg L(-1) Zn increased activities and mRNA levels of antioxidant enzymes during
 the early stage of exposure, including Cu/Zn-SOD, Mn-SOD, CAT, GPx and GR, the activities of these enzymes except Cu/Zn-SOD were inhibited at 96 h. Furthermore, a sharp increase in Nrf2 expression was observed in fish exposed to 8 mg L(-1) at 6 and 12 h, and 2 mg L(-1) at 12 h and 24 h, suggesting that Nrf2 was required for the protracted induction of these genes. The late increase in Keap1 expression may support its role in switching off the Nrf2 response. In conclusion, the present study demonstrated different effects of low- and high-dose waterborne Zn on antioxidant responses, which could contribute to the understanding of antioxidant and toxic roles of zinc on a molecular level.
Soil heavy metal contamination resulting from mining activities constitutes a major environmental problem worldwide. The spread of heavy metals is often facilitated by scarce vegetation cover, so there is an urgent need to improve plant survival and establishment in these metalliferous areas. This study is aimed at the isolation and analysis of the phylogenetic relationship of culturable bacteria from the rhizosphere of metallophyte plants growing in the Kettara mine, in Marrakech, in order to select plant growth-promoting rhizobacteria (PGPR), which could be used in assisted-phytoremediation. Bacterial isolates were grouped by random amplified polymorphic DNA analysis and identified by 16S rRNA gene sequencing. Strains were further characterized for the production of plant growth-promoting (PGP) substances, such as NH3, siderophores, indol-3-acetic acid (IAA), hydrogen cyanide, and extracellular enzymes, for ACC-deaminase activity, their capacity to solubilize phosphate, and for their tolerance to heavy metals and acidic pH. Rhizosphere soils were highly contaminated with Cu and Zn and presented low fertility. Phylogenetic analysis showed that the rhizobacteria were affiliated to three major groups: γ-Proteobacteria (48 %), β-Proteobacteria (17 %), and Bacilli (17 %). The most represented genera were Pseudomonas (38 %), Bacillus (10 %), Streptomyces (10 %), and Tetrathiobacter (10 %). Overall, rhizobacterial strains showed an ability to produce multiple, important PGP traits, which may be helpful when applied as plant growth promoter agents in contaminated soils. PGPR were also able to withstand high levels of metals (up to 2615.2 mg Zn l(-1), 953.29 mg Cu l(-1), and 1124.6 mg Cd l(-1)) and the order of metal toxicity was Cd > Cu > Zn. The rhizobacterial strains isolated in the present study have the potential to be used as efficient bioinoculants in phytoremediation strategies for the recovery of Kettara mine soils.
This study assessed the impacts of dietary arsenic trioxide (As2O3) on 26 mineral element contents in the liver and kidney of chicken. A total of 100 male Hy-line cocks were randomly divided into 2 groups (50 chickens in each group), including an arsenic-treated group (basic diet supplemented with As2O3 at 30 mg/kg) and a control group (basal diet). The feeding experiment lasted for 90 days and the experimental animals were given free access to feed and water. We determined 26 mineral elements in the liver and kidney by inductively coupled plasma mass spectrometry (ICP-MS). The results showed that nine element levels (Al, Mn, Co, Cu, Zn, Se, Cd, Ba, and Pb) were significantly decreased (P < 0.05) in the liver of chickens exposed to As2O3 compared to the control chickens where three element levels (Ni, As, and Hg) increased significantly (P < 0.05). The results in the kidney showed that nine element levels (Al, K, Ca, Cr, Mn, Ni, Sb, Ba, and Pb) were significantly decreased (P < 0.05) in the chickens exposed to As2O3 compared to the control chickens where four element levels (Mo, As, Cd, and Hg) increased significantly (P < 0.05). These results suggest that supplementation of high levels of arsenic affected trace mineral levels in the liver and kidney of chicken, and the effects vary from organ to organ. The aim of this study is to provide references for further study of heavy metal poisoning by detecting the contents of minerals induced by arsenic in chicken.
The study was conducted with an aim to remediate effluent from a pulp and paper mill, after treating it for 28 days with an aquatic fern, Salvinia cucullata. The effluent had high BOD, COD, TS, TSS, TDS, P, hardness and chloride, and several heavy metals (Cd, Cu, Cr, Ni, Pb, Mg, Mn, Fe and Zn) above national limits. However, the plant survived a wide range of effluent concentrations (25%, 50%, 75% and 100%, v/v), and flourished well, particularly at 25% (v/v), resisted membrane injury and generation of H2O2 and O2, showed better growth and induced all the major antioxidant enzymes. The plants also induced lipid peroxidation. Most of the elemental profiles were higher than the toxic levels stipulated for plants, indicating tolerance to metal. In fact, barring Fe, for Cr, Cu, Pb, Zn, Mg and P, at all the effluent doses, and for Cd, Ni and Mn, up to 75% (v/v) effluent, greater concentrations were observed in leaf than in root. This plant was more suited for nutrient removal, as it effectively reduced BOD, Zn, Fe, Ni, Mg, P and increased dissolve oxygen. Further, pH, hardness, chloride, TS and Mn was reduced optimally by 25-50% (v/v) treatments. SEM revealed prominent structural damages from 50 to 100% treatments. Presence of Pb as well as Fe in the EDX peaks were observed in the cortex rather than in the root vascular zone. This plant could be suggested to be an effective phytoremediator of multi-contaminant effluent with maximum benefit at low doses (25-50%, v/v).
Effect of irrigation with treated municipal wastewater on the accumulation of heavy metals in soils and food crops and potential health risks to human via consumption of these food crops are evaluated. The higher concentrations of iron (Fe), copper (Cu), chromium (Cr) and zinc (Zn) were found in lettuce, radish and carrots, respectively. However, trace metal levels in all vegetables were far lower than the food safety criteria of World Health Organization and European Union. Bioaccumulation factors (BAF) for heavy metals in different vegetables showed a trend in the order: Fe > Zn > Cu > Cr. The trends of estimated dietary intake (EDIs) for adults were in the order of Fe > Zn > Cr > Cu. The highest level of total coliform was recorded in spinach, followed by radish, egg plant, tomatoes and lettuce. The low uptake of heavy metals by vegetables shows that the health risks for human are insignificant. As the variations in transfer factor of metals is related to absorption capability of vegetables, soil properties and nutrient management, the risk of human exposure to metal contamination can be significantly reduced by selecting appropriate crops.
Approximately 40% of the volume of domestic sewage generated in the São Paulo State is untreated and released into water bodies, causing serious pollution problems that affect the water quality and especially the suspended sediments transported by rivers. Thus, this paper investigates the seasonal influence on the origin and fluxes of Cu, Co, Cr, Zn, Cd, Ni, Sc and particulate organic matter (POM) in sediments transported by a disturbed watershed in the São Paulo State, i.e. the Sorocaba River basin. POM was characterized using particulate organic carbon, particulate organic nitrogen, C:N ratio and δ(13)C and δ(15)N stable isotopic composition. Eight sample collections of fine suspended sediments (FSS) were carried out at the mouth of the Sorocaba River from July 2009 to May 2010. During the study period, the discharge rate followed the seasonal variation trend of the past 25 years. Zn was the most abundant trace element in the FSS, followed by Cr, Cu, Ni, Co, Sc and Cd. There was a higher concentration of trace elements during the dry season, except for Sc and Co, which did not vary seasonally. The POM showed the same trend, with higher concentrations during the dry season. The calculated enrichment factors and geoaccumulation index indicated that most of the trace elements are of geogenic origin, except for Zn, which showed significant anthropogenic contributions (55%). The elemental and isotopic analysis of C and N and C:N ratio indicated that the anthropogenic origin of POM found in the FSS is related mainly to domestic sewage (97%), while the significant correlation found between the concentrations of Zn and POM indicates that the main anthropogenic source of Zn is related to this domestic sewage. The FSS load transported during the study period was of 373,194 t y(-1), of which 87% occurred during the rainy season.
The use of a novel hybrid biosorbent, elemental selenium nanoparticles (nSe(0)) immobilized in pellets of Phanerochaete chrysosporium, to remove Zn from aqueous solutions was investigated. Fungal pellets containing nSe(0) (nSe(0)-pellets) showed to be better biosorbents as they removed more Zn (88.1 ± 5.3 %) compared to Se-free fungal pellets (56.2 ± 2.8 %) at pH 4.5 and an initial Zn concentration of 10 mg L(-1). The enhanced sorption capacity of nSe(0)-pellets was attributed to a higher concentration of sorption sites resulting in a more negative surface charge density, as determined by analysis of the potentiometric titration data. Fourier transform infrared spectroscopy (FT-IR) analysis of fungal pellets prior to and after being loaded with Zn showed the functional groups, including hydroxyl and carboxyl groups, involved in the sorption process. The experimental data indicated that the sorption rate of the nSe(0)-pellets fitted well to the pseudo-second order kinetic model (R (2)  = 0.99), and the sorption isotherm was best represented by the Sips model (Langmuir-Freundlich) with heterogeneous factor n = 1 (R (2)  = 0.99), which is equivalent to the Langmuir model. Operational advantages of fungal pelleted reactors and the Zn removal efficiencies
 achieved by nSe(0)-pellets under mild acidic conditions make nSe(0)-pellet based bioreactors an efficient biosorption process.
To increase the Zn level in shoots, AtHMA4 was ectopically expressed in tomato under the constitutive CaMV 35S promoter. However, the Zn concentration in the shoots of transgenic plants failed to increase at all tested Zn levels in the medium. Modification of Zn root/shoot distribution in tomato expressing 35S::AtHMA4 depended on the concentration of Zn in the medium, thus indicating involvement of unknown endogenous metal-homeostasis mechanisms. To determine these mechanisms, those metal-homeostasis genes that were expressed differently in transgenic and wild-type plants were identified by microarray and RT-qPCR analysis using laser-assisted microdissected RNA isolated from two root sectors: (epidermis + cortex and stele), and leaf sectors (upper epidermis + palisade parenchyma and lower epidermis + spongy parenchyma).
Zn-supply-dependent modification of Zn root/shoot distribution in AtHMA4-tomato (increase at 5 μM Zn, no change at 0.5 μM Zn) involved tissue-specific, distinct from that in the wild type, expression of tomato endogenous genes. First, it is suggested that an ethylene-dependent pathway underlies the detected changes in Zn root/shoot partitioning, as it was induced in transgenic plants in a distinct way depending on Zn exposure. Upon exposure to 5 or 0.5 μM Zn, in the epidermis + cortex of the transgenics' roots the expression of the Strategy I Fe-uptake system (ethylene-dependent LeIRT1 and LeFER) was respectively lower or higher than in the wild type and was accompanied by respectively lower or higher expression of the identified ethylene genes (LeNR, LeACO4, LeACO5) and of LeChln. Second, the contribution of LeNRAMP2 expression in the stele is shown to be distinct for wild-type and transgenic plants at both Zn exposures. Ethylene was also suggested as an important factor in a pathway induced in the leaves of transgenic plants by high Zn in the apoplast, which results in the initiation of loading of the excess Zn into the mesophyll of "Zn accumulating cells".
In transgenic tomato plants, the export activity of ectopically expressed AtHMA4 changes the cellular Zn status, which induces coordinated tissue-specific responses of endogenous ethylene-related genes and metal transporters. These changes constitute an important mechanism involved in the generation of the metal-related phenotype of transgenic tomato expressing AtHMA4.
Road dust in industrial areas carries high levels of toxic heavy metals. Exposure to such polluted dust significantly affects the health of people residing in these areas, which is of major concern. The present study was taken up with an aim to highlight the magnitude and potential sources of accumulation of heavy metals in 32 road dust samples collected from six industrial areas of Hyderabad. Acid-digested sample solutions were analyzed by ICP-MS for Cu, Zn, Cr, Co, Pb, Ni, V, Zr, Ce, Y, and Hf. The road dusts exhibit significantly high mean metal levels which are much above their crustal abundances. The relative ordering of mean metal contents is Zr > Zn > Pb > Cr > Ce > Cu > V > Ni > Y > Co > Hf. Elevated pollution indices (I geo, EF, C (i) f, and C deg) reveal that the road dusts are pollution impacted showing varying degree of heavy metal contamination. Strong positive correlations exhibited by metal pairs Cu-Zn, Cr-Ni, Ce-V, Y-Ce, and Hf-Zr imply their origin from common anthropogenic sources. Principal component analysis grouped the metals according to the sources which contributed to their accumulation. The present study confirms to an intensive anthropogenic impact on the accumulation of heavy metals in the studied road dusts attributable mainly to strong influences of vehicular and industrial activity and partly to domestic and natural processes. The results obtained imply the need for further investigations to assess their ecological implications and human health risks.
3-Ketosteroid 9α-hydroxylase (KSH, consisting of KshA and KshB), a key enzyme in steroid metabolism, can catalyze the transformation of 4-androstene-3,17-dione (AD) to 9α-hydroxy-4-androstene-3,17-dione (9OHAD) with NADH as coenzyme. In this work, KSH from Mycobacterium neoaurum JC-12 was successfully cloned and overexpressed in Bacillus subtilis 168. The expression and purification of KSH was analyzed by SDS-PAGE and KSH activity assay. Preliminary characterization of KSH was performed using purified KshA and KshB. The results showed that KSH was very unstable, and its activity was inhibited by most metal ions, especially Zn(2+). The whole-cells of recombinant B. subtilis, co-expression of KSH and glucose 1-dehydrogenase (GDH), were used as biocatalyst to convert AD to 9OHAD. The biocatalyst, in which the intracellular NADH was regenerated, efficiently catalyzed the bioconversion of AD to 9OHAD with a conversion rate of 90.4 % and productivity of 0.45 g (L h)(-1), respectively. This work proposed a strategy for efficiently producing 9OHAD by using B. subtilis as a promising whole-cell biocatalyst host and co-expressing KSH and GDH to construct a NADH regeneration system.
The physiological roles of PAs (putrescine, spermidine, and spermine) were investigated for their ability to confer salt tolerance (200 mM NaCl, 48 h) in mung bean seedlings (Vigna radiata L. cv. BARI Mung-2). Salt stress resulted in Na toxicity, decreased K, Ca, Mg, and Zn contents in roots and shoots, and disrupted antioxidant defense system which caused oxidative damage as indicated by increased lipid peroxidation, H2O2 content, [Formula: see text] generation rate, and lipoxygenase activity. Salinity-induced methylglyoxal (MG) toxicity was also clearly evident. Salinity decreased leaf chlorophyll (chl) and relative water content (RWC). Supplementation of salt affected seedlings with exogenous PAs enhanced the contents of glutathione and ascorbate, increased activities of antioxidant enzymes (dehydroascorbate reductase, glutathione reductase, catalase, and glutathione peroxidase) and glyoxalase enzyme (glyoxalase II), which reduced salt-induced oxidative stress and MG toxicity, respectively. Exogenous PAs reduced cellular Na content and maintained nutrient homeostasis and modulated endogenous PAs levels in salt affected mung bean seedlings. The overall salt tolerance was reflected through improved tissue water and chl content, and better seedling growth.
The cell-wall sulfated polysaccharide of the marine red microalga Porphyridium sp. is a high molecular weight biopolymer that has potential for use as a platform for metal complexation for various applications. This paper describes the structural and rheological characterization and antibacterial activity of the polysaccharide in combination with Zn(2+) (Zn-PS). SAXS and rheology studies indicate that with the addition of ZnCl2 to the sulfated polysaccharide the only change was the increase in viscosity in the entangled regime. The antibacterial activity of Zn-PS solutions was more potent than that of the native polysaccharide against Gram-negative and Gram-positive bacteria. The synergy between the bioactivities of Zn(2+) (which is a key player in wound healing and is active against variety of pathogens) and the unique bioactivities of the polysaccharide (e.g., anti-inflammatory) indicates promising potential for the development of novel products for the pharmaceutical and cosmetics industries.
Among known molecular switches, spiropyrans attract considerable interest because of their reversible responsiveness to external stimuli and the deep conformational and electronic changes that characterize the switching process between the two isomeric forms [spiropyran (SP) and merocyanine (MC)]. Metal coordination is one of the most interesting aspects of spiropyrans for its potential in sensing, catalysis, and medicinal chemistry, but little is known about the details surrounding spiropyran-metal ion binding. We investigated the interplay between an N-modified 8-methoxy-6-nitrospiropyran (SP-E), designed to provide appropriate molecular flexibility and a range of competing/collaborative metal binding sites, with Mg(2+) , Cu(2+) and Zn(2+) , which were chosen for their similar coordination geometry preferences while differing in their hard/soft character. The formed molecular complexes were studied by means of UV/Vis, fluorescence, and NMR spectroscopies and mass spectrometry, and the crystal structure of the SP-E-Cu complex was also obtained. The results indicate that the Mg(2+) , Zn(2+) and Cu(2+) complexes have identical coordination stoichiometry. Furthermore, the Mg(2+) and Zn(2+) complexes display fluorescence properties in solution and visible-light responsiveness. These results provide important spectroscopic and structural information that can serve as a foundation for rational design of spiropyran-based smart materials for metal sensing and scavenging applications.
Graphene aerogels (GAs) anchoring hierarchical, mulberry-like ZnO particles are fabricated in situ using a one-step solvothermal reaction. The resulting composites can function as anodes in lithium ion batteries, where they exhibit a high capacity and cyclic stability. The reversible capacities obtained are 365, 320, and 230 mA h g(-1) at current densities of 1, 2, and 10 A g(-1) . Their high reversible capacity is 445 mA h g(-1) at a current density of 1.6 A g(-1) ; this value is maintained even after the 500th cycle, The excellent electrochemical performance is attributed to strong oxygen bridges between ZnO and graphene, where C-O-Zn linkages provide a good pathway for electron transport during charge/discharge cycles. Additionally, the hierarchical structure of the ZnO microballs suppresses stacking among the graphene layers, allowing the GAs to accelerate the transport of lithium ions.
 Furthermore, the GA framework enhances the electrical conductivity and buffer any volume expansion.
Previous studies on the cytotoxicity of arachidonic acid (ARA) elucidated the involvement of oxidative stress and Ca(2+). In the present study, the Zn(2+)-related cytotoxicity of ARA was studied by a flow cytometric technique with appropriate fluorescent probes in rat thymocytes. Addition of 10 μM ZnCl2 enhanced the increase in cell lethality induced by 10 μM ARA. The removal of Zn(2+) by Zn(2+) chelators attenuated the ARA-induced increase in cell lethality. Thus, Zn(2+) is suggested to be involved in ARA cytotoxicity. ARA at 3-10 μM elevated intracellular Zn(2+) level. The Zn(2+) chelators attenuated the ARA-induced increase in intracellular Zn(2+) level while ARA significantly increased intracellular Zn(2+) level in the presence of 3 μM ZnCl2, suggesting the involvement of external Zn(2+). Zn(2+) reportedly exerts cytotoxic action under oxidative stress induced by hydrogen peroxide, via an excessive increase in intracellular Zn(2+) levels. Since ARA induces oxidative stress, the simultaneous administration of zinc and ARA may be harmful.
As part of a research project, the concentrations of Cd, Cu, Pb, V, and Zn in the tissues of Styela plicata were investigated for the first time to determine if S. plicata is a suitable biological indicator for biomonitoring of heavy metals in eastern Aegean Sea coastal waters. To examine the relationships, heavy metal levels in suspended particulate matters (SPMs) and sediments were also determined. According to the results, the mean metal levels in SPM, sediments, and S. plicata samples could be arranged in the following order of abundance: Zn > Cu > Pb > V > Cd. As for heavy metal levels, significant positive correlations were noted between Cd-Pb, Cd-V, Cd-Zn, Cu-V, and Pb-V in SPM; Cd-Zn, Cu-Zn, Pb-Cd, Pb-Cu, and Pb-Zn in sediment; and Cu-Pb, Cu-Zn, and Pb-Zn in S. plicata samples. Positive relationships between these metals showed that they were originated from same sources and that they were associated with each other. Based on the findings, Zn, Cu, and Pb concentrations in suspended particulate matters, sediments, and S. plicata samples were generally represented with higher levels at stations that were used for boating, shipping, and related activities. As S. plicata is a strongest accumulator of V, the relatively low V levels observed in this study may indicate the lack of anthropogenic sources of this metal in the sampling stations. In conclusion, suspended particulate matter and sediment can be useful tool to detect the pollution status of the marine environment. Furthermore, the findings of this study highlighted that S. plicata is a promising alternative for the monitoring of heavy metal pollution for eastern Aegean Sea coasts.
The objective of this work was to obtain Spirulina (Arthrospira maxima) nanoparticles (SNPs) by using high-impact mechanical milling and to characterize them by electron microscopy and spectroscopy techniques. The milling products were analyzed after various processing times (1-4 h), and particle size distribution and number mean size (NMS) were determined by analysis of high-resolution scanning electron microscopic images. The smallest particles are synthesized after 3 h of milling, had an NMS of 55.6±3.6 nm, with 95% of the particles being smaller than 100 nm. High-resolution transmission electron microscopy showed lattice spacing of ~0.27±0.015 nm for SNPs. The corresponding chemical composition was obtained by energy-dispersive X-ray spectroscopy, and showed the presence of Ca, Fe, K, Mg, Na, and Zn. The powder flow properties showed that the powder density was higher when the average nanoparticle size is smaller. They showed free flowability and an increase in their specific surface area (6.89±0.23 m2/g) up to 12-14 times larger than the original material (0.45±0.02 m2/g). Fourier transform infrared spectroscopy suggested that chemical damage related to the milling is not significant.
Pure sulfide Cu2 ZnSnS4 thin films were fabricated on Mo-coated glass substrates by facile spray deposition of aqueous precursor solutions containing Cu(NO3 )2 , Zn(NO3 )2 , Sn(CH3 SO3 )2 , and thiourea followed by annealing at 600 °C. When a precursor solution containing a stoichiometric composition of Cu, Zn, and Sn was used, the resulting Cu2 ZnSnS4 thin film contained a Cu2-x S impurity phase owing to the evaporation of Sn components during the annealing process. The Cu2-x S impurity in the Cu2 ZnSnS4 thin film was removed by reducing the concentration of Cu in the precursor solution. This resulted in an improvement of the structural features (i.e., grain sizes and compactness) as well as the electric properties such as acceptor densities, the nature of the acceptor defects, and carrier lifetimes. A solar cell based on the Cu2 ZnSnS4 film with an empirically optimal composition showed conversion efficiency of 8.1 %. The value achieved was one of the best efficiencies of Cu2 ZnSnS4 -based cells derived from a non-vacuum process.
Female genital tuberculosis (FGTB) has a profound impact on the reproductive health of patients including infertility. Conventional diagnostic techniques have low sensitivity and specificity as well as long turnaround time. There is a need of developing newer, rapid and practically adaptable technique, especially in low-income countries.
To standardize and evaluate loop-mediated isothermal amplification (LAMP) technique for diagnosis of FGTB.
A total of 300 endometrial biopsy samples from infertile females were subjected to Ziehl-Neelsen (ZN) staining, Lowenstein-Jensen culture, automated culture (BACTEC mycobacterial growth indicator tube), histopathological examination (HPE), nucleic acid amplification by polymerase chain reaction (PCR) and LAMP technique. Composite gold standard (either smear/culture/HPE/PCR positive) was considered for calculation of outcome parameters.
The observed sensitivities of ZN smear, culture, HPE, PCR and LAMP were 2.94%, 10.29%, 8.82%, 95.59% and 66.18%, respectively. Overall concordance between PCR and LAMP was 63%, which shows a good agreement.
This study is the first to evaluate LAMP in the diagnosis of FGTB and found it to be a rapid and convenient technique, especially in low resource endemic settings.
Natural deep eutectic solvents (DESs) dissolve simple metal oxides and are used as a reaction medium to synthesize spinel-type ferrite nanoparticles MFe2 O4 (M=Mg, Zn, Co, Ni). The best results for phase-pure spinel ferrites are obtained with the DES consisting of choline chloride (ChCl) and maleic acid. By employing DESs, the reactions proceed at much lower temperatures than usual for the respective solid-phase reactions of the metal oxides and at the same temperatures as synthesis with comparable calcination processes using metal salts. The method therefore reduces the overall required energy for the nanoparticle synthesis. Thermogravimetric analysis shows that the thermolysis process of the eutectic melts in air occurs in one major step. The phase-pure spinel-type ferrite particles are thoroughly characterized by X-ray diffraction, diffuse-reflectance UV/Vis spectroscopy, and scanning electron microscopy. The properties of the obtained nanoparticles are shown to be comparable to those obtained by other methods, illustrating the potential of natural DESs for processing metal oxides.
We aimed to evaluate the elemental (W, Mo, Zn, Fe, Cu, Co, Bi, Mn, Cd, Cr, As) composition of some plant species spread around the abandoned tungsten mining area of Uludağ Mountain. The plant species tested were Anthemis cretica and Trisetum flavescens which are grown in this area and they are pioneer species on these contaminated sites. W levels in soils were found up to 1378.6 ± 672.3 mg/kg dry weight in contaminated areas. The leaf W contents of the selected plant species were found 41.1 ± 24.4 and 31.1 ± 15.5 mg/kg dry weight for A. cretica and T. flavescens, respectively. Our results indicate that the elemental composition of species changed by the increased tungsten and some element concentrations in soil without detrimental effect. So, these species can be useful tungsten removal and some elements from contaminated sites.
In the past decade the presence of psychopharmaceuticals, including fluoxetine (FLU), in the aquatic environment has been associated with the increasing trend in human consumption of these substances. Aquatic organisms are usually exposed to chronic low doses and, therefore, risk assessments should evaluate the effects of these compounds in non-target organisms. Teleost fish possess an array of active defence mechanisms to cope with the deleterious effects of xenobiotics. These include ABC transporters, phase I and II of cellular detoxification and oxidative stress enzymes. Hence, the present study aimed at characterising the effect of FLU on embryo development of the model teleost zebrafish (Danio rerio) concomitantly with changes in the detoxification mechanisms during early developmental phases. Embryos were exposed to different concentrations of FLU (0.0015, 0.05, 0.1, 0.5 and 0.8μM) for 80hours post fertilization. Development was screened and the impact in the transcription of key genes, i.e., abcb4, abcc1, abcc2, abcg2, cyp1a, cyp3a65, gst, sod, cat, ahr, pxr, pparα, pparβ, pparγ, rxraa, rxrab, rxrbb, rxrga, rxrgb, raraa, rarab, rarga evaluated. In addition, accumulation assays were performed to measure the activity of ABC proteins and antioxidant enzymes (CAT and Cu/ZnSOD) after exposure to FLU. Embryo development was disrupted at the lowest FLU concentration tested (0.0015μM), which is in the range of concentrations found in WWTP effluents. Embryos exposed to higher concentrations of FLU decreased Cu/Zn SOD, and increased CAT (0.0015 and 0.5μM) enzymatic activity. Exposure to higher
 concentrations of FLU decreased the expression of most genes belonging to the detoxification system and upregulated cat at 0.0015μM of FLU. Most of the tested concentrations downregulated pparα, pparβ, pparγ, and raraa, rxraa, rxrab, rxrbb rxrgb and ahr gene expression while pxr was significantly up regulated at all tested concentrations. In conclusion, this study shows that FLU can impact zebrafish embryo development, at concentrations found in effluents of WWTPs, concomitantly with changes in antioxidant enzymes, and the transcription of key genes involved in detoxification and development. These finding raises additional concerns supporting the need to monitor the presence of this compound in aquatic reservoirs.
This review examines recent applications of stable copper, zinc and sulfur isotopes to medical cases and notably cancer. The distribution of the natural stable isotopes of a particular element among coexisting molecular species varies as a function of the bond strength, the ionic charge, and the coordination, and it also changes with kinetics. Ab initio calculations show that compounds in which a metal binds to oxygen- (sulfate, phosphate, lactate) and nitrogen-bearing moieties (histidine) favor heavy isotopes, whereas bonds with sulfur (cysteine, methionine) favor light isotopes. Oxidized cations (e.g., Cu(ii)) and low coordination numbers are expected to favor heavy isotopes relative to their reduced counterparts (Cu(i)) and high coordination numbers. Here we discuss the first observations of Cu, Zn, and S isotopic variations, three elements closely related along multiple biological pathways, with emphasis on serum samples of healthy volunteers and of cancer patients. It was found that heavy isotopes of Zn and to an even greater extent Cu are enriched in erythrocytes relative to serum, while the difference is small for sulfur. Isotopic variations related to age and sex are relatively small. The (65)Cu/(63)Cu ratio in the serum of patients with colon, breast, and liver cancer is conspicuously low relative to healthy subjects. The characteristic time over which Cu isotopes may change with disease progression (a few weeks) is consistent with both the turnover time of the element and albumin half-life. A parallel effect on sulfur isotopes is detected in a few un-medicated patients. Copper in liver tumor tissue is isotopically heavy. In contrast, Zn in breast cancer tumors is isotopically lighter than in healthy breast tissue. (66)Zn/(64)Zn is very similar in the serum of cancer patients and in controls. Possible reasons for Cu isotope variations may be related to the cytosolic storage of Cu lactate (Warburg effect), release of intracellular copper from cysteine clusters (metallothionein), or the hepatocellular and biosynthetic dysfunction of the liver. We suggest that Cu isotope metallomics will help evaluate the homeostasis of this element during patient treatment, notably by chelates and blockers of Cu trafficking, and understand the many biochemical pathways in which this element is essential.
Microparticles of radioactive cesium (Cs)-bearing silicate glass emitted from the Fukushima Daiichi nuclear power plant were investigated mainly using state-of-the-art energy-dispersive X-ray spectroscopy in scanning transmission electron microscopes. Precise elemental maps of the particles were obtained using double silicon drift detectors with a large collection angle of X-rays, and qualitative elemental analysis was performed using high-resolution X-ray spectroscopy with a microcalorimetry detector. Beside the substantial elements (O, Si, Cl, K, Fe, Zn, Rb, Sn and Cs) as previously reported, Mn and Ba were also common, though their amounts were small. The atomic ratios of the substantial elements were not the same but varied among individual particles. Fe and Zn were relatively homogeneously distributed, whereas the concentration of alkali ions varied radially. Generally, Cs was rich and K and Rb were poor outward of the particles but the degree of such radial dependence was considerably different among the particles. A concentration of Sn on the particle surface was observed. High-resolution imaging indicated the formation of SnO2 (cassiterite) nanocrystals on the surface. Synthesis of the bulk glass with a similar composition to the microparticles was attempted by quenching the silicate melt from ∼1600°C. However, homogeneous silicate glass like that of the microparticles could not be obtained due to the segregation of nano-spherules rich in Fe and Zn, suggesting that the microparticles were formed in a very specific condition in the nuclear reactor.
The nanocomposites of MoS2 nanosheets with the metal-organic framework, ZIF-8, have been synthesized starting with the layers of 1T-MoS2 generated by Li intercalation of bulk MoS2, followed by exfoliation. The nanocomposites contain the Zn-S bond and exhibit reasonably high surface areas. They exhibit CO2 uptake higher than ZIF-8. Heating the nanocomposites to 900 °C under a N2 atmosphere yields MoS2-ZnS nanocomposites which show good activity for the visible-light induced hydrogen evolution reaction.
We report a detailed study of the K-edge X-ray absorption spectra of four transition metal phthalocyanines (MPc, M = Fe, Co, Cu and Zn). We identify the important single and multiple scattering contributions to the spectra in the extended energy range and provide a robust treatment of thermal damping; thus, a generally applicable model for the interpretation of X-ray absorption fine structure spectra is proposed. Consistent variations of bond lengths and Debye Waller factors are found as a function of atomic number of the metal ion, indicating a variation of the metal-ligand bond strength which correlates with the spatial arrangement and occupation of molecular orbitals. We also provide an interpretation of the near edge spectral features in the framework of a full potential real space multiple scattering approach and provide a connection to the local electronic structure.
Zinc-based nanoparticles (Zn-NPs), mainly zinc oxide (ZnO) NPs, have promising application in a wide area, but their potential harmful effects on environment and human health have been continuously raised together with their high dissolution rate. In this study, we coated the surface of ZnO NPs with phosphate (ZnP NPs) and sulfide (ZnS NPs) which have very low solubility in water, administered orally (0.5 and 1 mg/kg) to mice for 28 days, and then compared their biodistribution and toxicity. As expected, ZnO NPs were rapidly ionized in an artificial gastric fluid. On the other hand, ZnO NPs were more particlized in an artificial intestinal fluid than ZnP and ZnS NPs. After repeated dosing, all three types of Zn-NPs the most distributed in the spleen and thymus and altered the level of redox reaction-related metal ions in the tissues. We also found that three types of Zn-NPs clearly disturb tissue ion homeostasis and influence immune regulation function. However, there were no remarkable difference in distribution and toxicity following repeated exposure of three types of Zn-NPs, although Na+ and K+ level in the spleen and thymus were notably higher in mice exposed to ZnO NPs compared to ZnP and ZnS NPs. Taken together, we suggest that all three types of Zn-NPs may influence human health by disrupting homeostasis of trace elements and ions in the tissues. In addition, the surface transformation of ZnO NPs with phosphate and sulfide may not attenuate toxicity due to the higher particlization rate of ZnO NPs in the intestine, at least in part. © 2016 Wiley Periodicals, Inc. Environ Toxicol, 2016.
In the present study, the composition of bio-elements (K, Na, Mg, Ca, Fe, Cu, Zn) and toxic elements (Ag, Cd) in seven edible mushrooms from the rural and woodland region of Morąg (north-eastern Poland) and the rural and industrial region of the Tarnobrzeska Upland (south-eastern Poland) were investigated using a validated method. The species examined were Boletus edulis, Cantharellus cibarius, Leccinum aurantiacum, Leccinum versipelle, Lycoperdon perlatum, Suillus luteus, and Xerocomus subtomentosus. Final determination was carried out by flame atomic absorption spectroscopy (FAAS) after microwave-assisted decomposition of sample matrices with solutions of concentrated nitric acid in the pressurized polytetrafluoroethylene vessels. The contents of the alkali elements and alkali earth elements were determined in the species surveyed. The alkali elements, earth alkali elements, and transition metals (Ag, Cu, Zn, Fe, and Mn) were at typical concentrations as was determined for the same or similar species elsewhere in Poland and Europe. The results may suggest a lack of local and regional emissions of those metallic elements from industrialization of some sites in the Tarnobrzeska Plain. Cadmium was at elevated concentrations in L. versipelle from the Tarnobrzeska Plain but the reason-pollution or geogenic source-was unknown, while it was at typical concentrations in other species.
Metals in sediments are present in different chemical forms which affect their ability to transfer. The objective of this body of work was to compare different extraction methods for the bioavailability evaluation of some elements, such as Ba, Cd, Co, Cr, Cu, Fe, K, Mg, Mn, Ni, Pb, V and Zn from Serbian river sediments. A bioavailability risk assessment index (BRAI) was used for the quantification of heavy metal bioavailability in the sediments. Actual and potential element availability was assessed by single extractions with mild (CaCl2 and CH3COONH4) and acidic (CH3COOH) extractants and complexing agents (EDTA). Aqua regia extraction was used for the determination of the pseudo-total element content in river sediments. In different single extraction tests, higher extraction of Cd, Cu, Zn and Pb was observed than for the other elements.
 The results of the single extraction tests revealed that there is a considerable chance of metal leaching from the sediments assessed in this study. When the BRAI was applied, the results showed a high risk of heavy metal bioavailability in Serbian river sediments.
The present study was conducted to explore the effects of waterborne Cu exposure on intestinal Cu transport and lipid metabolism of Synechogobius hasta. S. hasta were exposed to 0, 0.4721 and 0.9442μM Cu, respectively. Sampling occurred on days 0, 21 and 42, respectively. Growth performance, intestinal lipid deposition, Cu content, and activities and mRNA expression of enzymes and genes involved in Cu transport and lipid metabolism were analyzed. Cu exposure decreased WG and SGR on days 21 and 42. Cu exposure increased intestinal Cu and lipid contents. Increased Cu accumulation was attributable to increased enzymatic activities (Cu-ATPase and Cu, Zn-SOD) and genes' (CTR1, CTR2, DMT1, ATP7a, ATP7b, MT1 and MT2) expression involved in Cu transport. Waterborne Cu exposure also increased activities of lipogenic enzymes (6PGD and ICDH on both days 21 and 42, ME on day 42), up-regulated mRNA levels of lipogenic genes (G6PD, 6PGD, ME, ICDH, FAS and ACCa), lipolytic genes (ACCb, CPT I and HSLa) and genes involved in intestinal fatty acid uptake (IFABP and FATP4) on both days 21 and 42. The up-regulation of lipolysis may result from the increased metabolic expenditure for detoxification and maintenance of the normal body functions in a response to Cu exposure. Meantime, Cu exposure increased lipogenesis and fatty acid uptake, leading to net lipid accumulation in the intestine despite increased lipolysis. To our knowledge, this is the first report involved in intestinal lipid metabolism in combination with intestinal Cu absorption following waterborne Cu exposure, which provides new insights and evidence into Cu toxicity in fish.
This study reports spatial and temporal variability of Zn and Cu isotopes in atmospheric particulate matter (PM) collected in two major European cities with contrasting atmospheric pollution, Barcelona and London. We demonstrate that nontraditional stable isotopes identify source contributions of Zn and Cu and can play a major role in future air quality studies. In Barcelona, samples of fine PM were collected at street level at sites with variable traffic density. The isotopic signatures ranged between -0.13 ± 0.09 and -0.51 ± 0.05‰ for δ(66)ZnIRMM and between +0.04 ± 0.20 and +0.33 ± 0.15‰ for δ(65)CuAE633. Copper isotope signatures similar to those of Cu sulfides and Cu/Sb ratios within the range typically found in brake wear suggest that nonexhaust emissions from vehicles are dominant. Negative Zn isotopic signatures characteristic for gaseous emissions from smelting and combustion and large enrichments of Zn and Cd suggest contribution from metallurgical industries. In London, samples of coarse PM collected on the top of a building over 18 months display isotope signatures ranging between +0.03 ± 0.04 and +0.49 ± 0.02‰ for δ(66)ZnIRMM and between +0.37 ± 0.17 and +0.97 ± 0.21‰ for δ(65)CuAE633. Heavy Cu isotope signatures (up to +0.97 ± 0.21‰) and higher enrichments and Cu/Sb ratios during winter time indicate important contribution from fossil fuel combustion. The positive δ(66)ZnIRMM signatures are in good agreement with signatures characteristic for ore concentrates used for the production of tires and galvanized materials, suggesting nonexhaust emissions from vehicles as the main source of Zn pollution.
Some oleaginous fungi can produce large amounts of polyunsaturated fatty acids (PUFAs) which serve many physiological functions. Numerous desaturases are critical for the synthesis of PUFAs. This study aimed to investigate the regulation of lipid production and desaturase gene expression in Mortierella sp. AGED in response to different environmental factors, and the relationships between lipid production and desaturase gene expression.
The fatty acid composition and mRNA levels of desaturase genes were significantly changed under low temperatures. With the exception of Δ5-desaturase, the transcript levels of all desaturase genes increased at a temperature of 20 °C. Changes in content of lipid and PUFAs responding to low temperature were consistent with desaturase gene expression. Time course studies on gene expression showed that mRNA levels of four desaturase genes increased rapidly after transferring the cells to low temperature. Ethanol (1.5% v/v) increased the transcript levels of Δ9-, Δ6- and Δ5-desaturase genes significantly and of Δ12-desaturase gene slightly. Different metal ions such as Ca(2+) , Zn(2+) and Fe(3+) could stimulate PUFA synthesis and up-regulate desaturase gene transcription, while Cu(2+) inhibited desaturase gene expression and lipid accumulation.
This study should enable us to understand the regulatory mechanism of desaturase gene expression and lipid synthesis. It is helpful to improve PUFA productivity in Mortierella sp. AGED. © 2016 Society of Chemical Industry.
Marine pollution has been considered an increasing problem because of the increase in sea transportation day by day. Therefore, a large volume of bilge water which contains petroleum, oil and hydrocarbons in high concentrations is generated from all types of ships. In this study, treatment of bilge water by electrocoagulation/electroflotation and nanofiltration integrated process is investigated as a function of voltage, time, and initial pH with aluminum electrode as both anode and cathode. Moreover, a commercial NF270 flat-sheet membrane was also used for further purification. Box-Behnken design combined with response surface methodology was used to study the response pattern and determine the optimum conditions for maximum chemical oxygen demand (COD) removal and minimum metal ion contents of bilge water. Three independent variables, namely voltage (5-15 V), initial pH (4.5-8.0) and time (30-90 min) were transformed to coded values. The COD removal percent, UV absorbance at 254 nm, pH value (after treatment), and concentration of metal ions (Ti, As, Cu, Cr, Zn, Sr, Mo) were obtained as responses. Analysis of variance results showed that all the models were significant except for Zn (P > 0.05), because the calculated F values for these models were less than the critical F value for the considered probability (P = 0.05). The obtained R(2) and Radj(2) values signified the correlation between the experimental data and predicted responses: except for the model of Zn concentration after treatment, the high R(2) values showed the goodness of fit of the model. While the increase in the applied voltage showed negative effects, the increases in time and pH showed a positive effect on COD removal efficiency; also the most effective linear term was found as time. A positive sign of the interactive coefficients of the voltage-time and pH-time systems indicated synergistic effect on COD removal efficiency, whereas interaction between voltage and pH showed an antagonistic effect.
The aim of this study was to investigate the effects of drought resistant serpentine rhizobacteria on plant growth and metal uptake by Brassica oxyrrhina under drought stress (DS) condition. Two drought resistant serpentine rhizobacterial strains namely Pseudomonas libanensis TR1 and Pseudomonas reactans Ph3R3 were selected based on their ability to stimulate seedling growth in roll towel assay. Further assessment on plant growth promoting (PGP) parameters revealed their ability to produce indole-3-acetic acid, siderophore and 1-aminocyclopropane-1-carboxylate deaminase. Moreover, both strains exhibited high resistance to various heavy metals, antibiotics, salinity and extreme temperature. Inoculation of TR1 and Ph3R3 significantly increased plant growth, leaf relative water and pigment content of B. oxyrrhina, whereas decreased concentrations of proline and malondialdehyde in leaves under metal stress in the absence and presence of DS. Regardless of soil water conditions, TR1 and Ph3R3 greatly improved organ metal concentrations, translocation and bioconcentration factors of Cu and Zn. The successful colonization and metabolic activities of P. libanensis TR1 and P. reactans Ph3R3 represented positive effects on plant development and metal phytoremediation under DS. These results indicate that these strains could be used as bio-inoculants for the improvement of phytoremediation of metal polluted soils under semiarid conditions.
The 14-3-3 gene family identified in all eukaryotic organisms is involved in a wide range of biological processes, particularly in resistance to various abiotic stresses. Here, we performed the first comprehensive study on the molecular characterization, phylogenetics, and responses to various abiotic stresses of the 14-3-3 gene family in Brachypodium distachyon L. A total of seven 14-3-3 genes from B. distachyon and 120 from five main lineages among 12 species were identified, which were divided into five well-conserved subfamilies. The molecular structure analysis showed that the plant 14-3-3 gene family is highly evolutionarily conserved, although certain divergence had occurred in different subfamilies. The duplication event investigation revealed that segmental duplication seemed to be the predominant form by which the 14-3-3 gene family had expanded. Moreover, seven critical amino acids were detected, which may contribute to functional divergence. Expression profiling analysis showed that BdGF14 genes were abundantly expressed in the roots, but showed low expression in the meristems. All seven BdGF14 genes showed significant expression changes under various abiotic stresses, including heavy metal, phytohormone, osmotic, and temperature stresses, which might play important roles in responses to multiple abiotic stresses mainly through participating in
 ABA-dependent signaling and reactive oxygen species-mediated MAPK cascade signaling pathways. In particular, BdGF14 genes generally showed upregulated expression in response to multiple stresses of high temperature, heavy metal, abscisic acid (ABA), and salicylic acid (SA), but downregulated expression under H2O2, NaCl, and polyethylene glycol (PEG) stresses. Meanwhile, dynamic transcriptional expression analysis of BdGF14 genes under longer treatments with heavy metals (Cd(2+), Cr(3+), Cu(2+), and Zn(2+)) and phytohormone (ABA) and recovery revealed two main expression trends in both roots and leaves: up-down and up-down-up expression from stress treatments to recovery. This study provides new insights into the structures and functions of plant 14-3-3 genes.
The quality of edible seeds for human and animal nutrition is crucially dependent on high zinc (Zn) and iron (Fe) seed concentrations. The micronutrient bioavailability is strongly reduced by seed phytate that forms complexes with seed cations. Superior genotypes with increased seed Zn concentrations had been identified, but low micronutrient seed levels often prevail when the plants are grown in Zn-deficient soils, which are globally widespread and correlate with human Zn-deficiency. Here, seed Zn concentrations of Arabidopsis accessions grown in Zn-deficient and Zn-amended conditions were measured together with seed Fe and manganese (Mn), in a panel of 108 accessions. By applying genome-wide association, de novo candidate genes potentially involved in the seed micronutrient accumulation were identified. However, a candidate inositol 1,3,4-trisphosphate 5/6-kinase 3 gene (ITPK3), located close to a significant nucleotide polymorphism associated with relative Zn seed concentrations, was dispensable for seed micronutrients accumulation in Col-0. Loss of this gene in itpk3-1 did neither affect phytate seed levels, nor seed Zn, Fe, and Mn. It is concluded that large natural variance of micronutrient seed levels is identified in the population and several accessions maintain high seed Zn despite growth in Zn-deficient conditions.
Sorghum is a source of several minerals whose content may vary depending on the genotype and the production environment. The objective of this study was to screen sorghum genotypes for mineral content and to investigate the effect of water stress on it. A large variability was observed in the mineral content of 100 sorghum genotypes grown in environments without (WoWS) and with water stress (WthWS). The water stress decreased Mn, P, Mg and S contents in 100, 96, 93 and 56% of genotypes, respectively. The genotypes and other factors seemed to have more impact than water stress on K, Ca, Cu, Fe and Zn levels. In 100 sorghum genotypes, 2 were classified as excellent sources of Fe and 25 of Zn, in both environments. The best two genotypes to Fe content were SC21 and SC655 and to Zn were SC320 and SHAN-QUI-RED which showed great potential for use in biofortification.
ZnO nanomaterials with controlled size, shape and surface chemistry are required for applications in diverse areas, such as optoelectronics, photocatalysis, biomedicine and so on. Here, we report on ZnO nanostructures with rod-like and spherical shapes prepared via laser ablation in liquid using a laser with millisecond-long pulses. By changing laser parameters (such as pulse width and peak power), the size or aspect ratio of such nanostructures could be tuned. The surface chemistry and defects of the products were also strongly affected by applied laser conditions. The preparation of different structures is explained by the intense heating of liquid media caused by millisecond-long pulses and secondary irradiation of already-formed nanostructures.
A selective matrix separation/enrichment method, utilizing a simple batch procedure with nickel/nickel boride (Ni/NixB) nanoparticles was proposed for the determination of inorganic mercury(II), Hg(2+) and methyl mercury(I), CH3Hg(+) in waters prior to cold vapor-atomic fluorescence spectrometry (CV-AFS). The Ni/NixB nanoparticles, were synthesized by the chemical reduction of Ni(II) to Ni/NixB. The novel adsorbent was selective to Hg(2+) and CH3Hg(+) species between pH values of 4 - 10. Both of the mercury species were recovered from the adsorbent using 1.0 mol L(-1) hot HNO3 with high efficiency. It was observed that the adsorbent selectively removed Hg(2+) and CH3Hg(+) from the bulk solution in the presence of several competitor ions (As(3+), Sb(3+), Pb(2+), Zn(2+), Cu(2+), Cd(2+) and Fe(3+)) with ≥96% adsorption. The limit of detection (3σ above blank) was found to be 1.8 ng L(-1) with a preconcentration factor of 20. The validation of the method was tested through spike recovery experiments with several water samples (tap and seawater) at μg L(-1) concentration levels, and all recovery values were found to vary between 95 and 105%.
A novel multi-function Metal-Organic Framework composite Ag@Zn-TSA (zinc thiosalicylate, Zn(C7H4O2S), Zn-TSA) was synthesized as highly efficient immobilization matrixes of myoglobin (Mb)/glucose oxidase (GOx) for electrochemical biosensing. The electrochemical biosensors based on Ag@Zn-TSA composite and ionic liquid (IL) modified carbon paste electrode (CPE) were fabricated successfully. Furthermore, the properties of the sensors were discussed by cyclic voltammetry (CV), electrochemical impedance spectroscopy (EIS) and amperometric current-time curve, respectively. The results showed the proposed biosensors had wide linear response to hydrogen peroxide (H2O2) in the range of 0.3-20,000 μM, to nitrite (NO2(-)) for 1.3 μM-1660 μM and 2262 μM-1,33,000 μM, to glucose for 2.0-1022 μM, with a low detection limit of 0.08 μM for H2O2, 0.5 μM for NO2(-), 0.8 μM for glucose. The values of the apparent heterogeneous electron transfer rate constant (ks) for Mb and GOx were estimated as 2.05 s(-1) and 2.45 s(-1), respectively. Thus, Ag@Zn-TSA was a kind of ideal material as highly efficient immobilization matrixes for sensitive electrochemical biosensing. In addition, this work indicated that MOF nanocomposite had a great potential for constructing wide range of sensing interface.
A series of Fe(2+) spin crossover (SCO) complexes [Fe(5/6)](2+) employing hexadentate ligands (5/6) with cis/trans-1,2-diamino cyclohexanes (4) as central building blocks were synthesised. The ligands were obtained by reductive amination of 4 with 2,2'-bipyridyl-6-carbaldehyde or 1,10-phenanthroline-2-carbaldehyde 3. The chelating effect and the rigid structure of the ligands 5/6 lead to exceptionally robust Fe(2+) and Zn(2+) complexes conserving their structure even in coordinating solvents like dmso at high temperatures. Their solution behavior was investigated using variable temperature (VT) (1)H NMR spectroscopy and VT Vis spectroscopy. SCO behavior was found for all Fe(2+) complexes in this series centred around and far above room temperature. For the first time we have demonstrated that the thermodynamics as well as kinetics for SCO can be deduced by using VT (1)H NMR spectroscopy. An alternative scheme using a linear correction term C(1) to model chemical shifts for Fe(2+) SCO complexes is presented. The rate constant for the SCO of [Fe(rac-trans-5)](2+) obtained by VT (1)H NMR was validated by Laser Flash Photolysis (LFP), with excellent agreement (1/(kHL + kLH) = 33.7/35.8 ns for NMR/LFP). The solvent dependence of the transition temperature T1/2 and the solvatochromism of complex [Fe(rac-trans-5)](2+) were ascribed to hydrogen bond formation of the secondary amine to the solvent. Enantiomerically pure complexes can be prepared starting with R,R- or S,S-1,2-diaminocyclohexane (R,R-trans-4 or S,S-trans-4). The high robustness of the complexes reduces a possible ligand scrambling and allows preparation of quasiracemic crystals of [Zn(R,R-5)][Fe(S,S-5)](ClO4)4·(CH3CN) composed of a 1 : 1 mixture of the Zn and Fe complexes with inverse chirality.
Lipolytic enzymes with cold adaptation are gaining increasing interest due to their biotechnological prospective. Previously, a cold adapted family I.3 lipase (AMS8 lipase) was isolated from an Antarctic Pseudomonas. AMS8 lipase was largely expressed in insoluble form. The refolded His-tagged recombinant AMS8 lipase was purified with 23.0% total recovery and purification factor of 9.7. The purified AMS8 lipase migrated as a single band with a molecular weight approximately 65kDa via electrophoresis. AMS8 lipase was highly active at 30°C at pH 10. The half-life of AMS8 lipase was reported at 4 and 2h under the incubation of 30 and 40°C, respectively. The lipase was stable over a broad range of pH. It showed enhancement effect in its relative activity under the presence of Li(+), Na(+), K(+), Rb(+) and Cs(+) after 30min treatment. Heavy metal ions such as Cu(2+), Fe(3+) and Zn(2+) inhibited AMS8 activity. This cold adapted alkalophilic AMS lipase was also active in various organic solvent of different polarity. These unique properties of this biological macromolecule will provide considerable potential for many biotechnological applications and organic synthesis at low temperature.
The effects of nano-TiO₂ on migration and transformation of heavy metals in soil were investigated by outdoor flooding simulation experiments. Cr, Pb, Zn, Cd and Cu contents of different forms were determined in soil of typical fluctuating zone of Three Gorges Reservoir. The results showed that, after flooding months, both addition of 4 g · kg⁻¹ of rutile and anatase particles resulted in the release of about 30% Cr into the water. Nano-TiO₂ particles mainly promoted the dissolution of oxidizable residual Cr, and elevated its ecological risk. Thus nano-TiO₂promoted the activation of chromium and improved the mobility of chromium in soil. 4 g · kg⁻¹ of rutile particles caused the decrease of acid exchangeable lead
 by 25.92% and oxidizable lead by 33.09%, and enhanced the mobility of Pb. However, anatase particles caused the increase of oxidizable zinc by 30% in soil, which facilitated fixing of zinc. In addition, two types of nano-TiO₂particles had no significant effect on the speciation changes of Cu and Cd. Therefore, the effect of nano-TiO₂ on release and transformation of Cr in soil was the largest, followed by Pb and Zn. This needs special attention when using nano-TiO₂ to remediate heavy metals contaminated soil and assessing its environmental risk.
The opencast mine of East Junggar Basin in Xinjiang is the largest self-contained coalfield in China, and the ecological environment of the opencast is very fragile because of its arid climate and poor soil. In this study, 50 soil samples (from 0 to 30 cm depth soil at intervals of 10 cm) in opencast Mine of East Junggar Basin in Xinjiang were collected in order to explore the heavy metals contamination of the coal mining. The contents of zinc (Zn), copper (Cu), cadmium (Cr), lead (Pb), mercury (Hg) and arsenic (As) were measured and the degree of pollution was assessed by Nemerow index, geo-accumulation (Igeo) index and potential ecological risk index. In addition, the layered comparison, dust fall and the distance between coal mine and samples location were used to analyze the source of heavy metals contamination. The results showed that value of As surpassed the Chinese soil quality standard class I (GB 15618-1995) mostly severely, followed by Cr, a relatively lower surpass was obtained by Hg and Cu, while Zn and Pb did not surpass the standard. According to the standard, the soil heavy metals content of research region was in light pollution status and the pollution index for each heavy metal followed the order of As (2.07) > Cr (0.95) > Cu (0.55) > Zn (0.48) > Hg (0.45) > Pb (0.38), which demonstrated a heavy pollution of As and clean status of others. Additionally, an Igeo value of 1.14 for Hg reflected a moderated pollution. The major contribution factor was Hg with a risk index of 251.40. The source analysis showed that the content of Pb in the surface soil (10-20 cm) was different from that in the deep layer (20-30 cm), which may be caused by coal combustion and other human activities. The sources of Hg and As were similar and may come from coal combustion. The distance to the mining area was not the major factor affecting the diffusion of heavy metals, other candidate factors included terrain, aspect and wind direction, etc.
A long-term experiment was utilized to study the effects of tillage methods on the contents and distribution characteristics of organic matter and heavy metals (Cu, Zn, Pb, Cd, Fe and Mn) in aggregates with different sizes (including 1-2, 0.25-1, 0.05-0.25 mm and < 0.05 mm) in a purple paddy soil under two tillage methods including flooded paddy field (FPF) and paddy-upland rotation (PR). The relationship between heavy metals and organic matter in soil aggregates was also analyzed. The results showed that the aggregates of two tillage methods were dominated by 0.05-0.25 mm and < 0.05 mm particle size, respectively. The contents of organic matter in each aggregate decreased with the decrease of aggregate sizes, however, compared to PR, FPF could significantly increase the contents of organic matter in soils and aggregates. The tillage methods did not significantly affect the contents of heavy metals in soils, but FPF could enhance the accumulation and distribution of aggregate, organic matter and heavy metals in aggregates with diameters of 1-2 mm and 0.25-1 mm. Correlation analysis found that there was a negative correlation between the contents of heavy metals and organic matter in soil aggregates, but a positive correlation between the amounts of heavy metal and organic matter accumulated in soil aggregates. From the slope of the correlation analysis equations, we could found that the sensitivities of heavy metals to the changes of soil organic matters followed the order of Mn > Zn > Pb > Cu > Fe > Cd under the same tillage. When it came to the same heavy metal, it was more sensitive in PR than in FPF.
Environmental quality of soils and sediments around water source area can influence the safety of potable water of rivers. In order to study the pollution characteristics, the sources and ecological risks of heavy metals Zn, Cr, Pb, Cu, Ni and Cd in water source area, surface soils around the waterway and sediments in the estuary of main tributaries were collected in Shunde, and ecological risks of heavy metals were assessed by two methods of potential ecological risk assessment. The mean contents of Zn, Cr, Pb, Cu, Ni and Cd in the surface soils were 186.80, 65.88, 54.56, 32.47, 22.65 and 0.86 mg · kg⁻¹ respectively, and they were higher than their soil background values except those of Cu and Ni. The mean concentrations of Zn, Cr, Pb, Cu, Ni and Cd in the sediments were 312.11, 111.41, 97.87, 92.32, 29.89 and 1.72 mg · kg⁻¹ respectively, and they were higher than their soil background values except that of Ni. The results of principal component analysis illustrated that the main source of Cr and Ni in soils was soil parent materials, and Zn, Pb, Cu and Cd in soils mainly came from wastewater discharge of local manufacturing industry. The six heavy metals in sediments mainly originated from industry emissions around the Shunde waterway. The results of potential ecological risk assessment integrating environmental bioavailability of heavy metals showed that Zn, Cu, Pb and Ni had a slight potential ecological risk. Cd had a slight potential ecological risk in surface soils, but a moderate potential ecological risk in surfaces sediments. Because the potential ecological risk assessment integrating environmental bioavailability of heavy metals took the soil properties and heavy metal forms into account, its results of risks were lower than those of Hakanson methods, and it could avoid overestimating the potential risks of heavy metals.
Contents of heavy metals involving As, Cd, Cr, Cu, Ni, Pb and Zn from atmospheric deposition in 10 parks of Nanjing were analyzed. The pollution level, ecological risk and health risk were evaluated using Geoaccumulation Index, Potential Ecological Risk Index and the US EPA Health Risk Assessment Model, respectively. The results showed that the pollution levels of heavy metals in Swallow Rock Park, Swallow Rock Park and Mochou Lake Park were higher than the others. Compared to other cities such as Changchun, Wuhan and Beijing, the contents of heavy metals in atmospheric deposition of parks in Nanjing were higher. The evaluation results of Geoaccumulation Index showed that Pb was at moderate pollution level, Zn and Cu were between moderate and serious levels, while Cd was between serious and extreme levels. The ecological risk level of Cd was high. The assessment results of Health Risk Assessment Model indicated that there was no non-carcinogenic risk for all the seven heavy metals. For carcinogenic risk, the risks of Cd, Cr and Ni were all negligible (Risk < 1 x 10⁻⁶), whereas As had carcinogenic risk possibility but was considered to be acceptable (10⁻⁶ < Risk < 10⁻⁴).
In order to understand the characteristics and sources of PM₂.₅ pollutant in Lanzhou City, two PM₂.₅ sampling sites were set up in Chengguan district and Xigu district, respectively. Samples were sampled during October (non-heating period) and December (heating period) 2013, and mass concentrations of PM₂.₅ and its 16 kinds of chemical components were analyzed. The results showed that the average mass concentration of PM₂.₅ during the sampling period was 129 µg · m⁻³. The sequence of mass concentrations of inorganic elements was: S > Ca > Fe > Al > Mg > Pb > Zn > Mn > Ti > Cu, while the mass concentrations of S, Ca, Fe, and Al, which were the major element compositions, exceeded 1 µg · m⁻³. The mass concentration of inorganic elements during heating period was higher than that during non-heating period, meanwhile, the mass concentration in Chengguan district was higher than that in Xigu district. The sequence of mass concentrations of water-soluble ions was: SO₄²⁻ > NO₃⁻ > NH₄⁺ > Cl⁻ > K⁺ > Na⁺, while the mass concentrations of SO₄²⁻, NO₃⁻, NH₄⁺, which were the main ion components, exceeded 10 µg · m⁻³. The mass concentration of water- soluble ions during heating period was higher than that during non-heating period, meanwhile, the mass concentration in Xigu district was higher than that in Chengguan district. The result of enrichment factor (EF) analysis showed that the EF values of Al, Ca, Mg and Ti were lower than 1, indicating the contribution of natural source, while the EF values of Cu, Pb, S and Zn were higher than 10, indicating the contribution of anthropogenic pollution. The result of principal component analysis showed that the sources of PM₂.₅ were mainly derived from traffic emission, biomass burning, soil and secondary particles.
The joint effects of NPs with other chemicals is not fully yet understood along with the joint effects of the particulate and dissolved forms/fractions. The predictability of joint effects is of great importance for environmental risk assessment. Therefore this study aimed at inferring on the predictability of NPs binary mixture toxicity based on their ionic counterparts' mixtures, and evaluating if the joint toxicity of two forms of the same element (NP and ion) acts as dilution of each other. Effects of individual and mixtures of ZnO and Ag NPs and their respective salts (AgNO3 and ZnCl2) were studied in immobilization and feeding tests using Daphnia magna. NPs mixture toxicity patterns did not mirror their ionic counterparts' mixture toxicity responses and therefore their prediction should not rely on the available knowledge for regular chemicals. Regarding mixtures from the same element with different
 forms (NP and ions), both Zn and Ag mixtures showed a deviation from additivity, relying on the interaction between NP and ions. A synergistic effect was depicted when the concentrations of Ag ions increased, while antagonism was observed with AgNP increase in suspension. This is an expected pattern in long term studies due to dissolution, relating fate and toxicity.
Zinc oxide nanoparticles (ZnO NPs) are being utilized in an increasing number of fields and commercial applications. While their general toxicity and associated oxidative stress have been extensively studied, the toxicological pathways that they induce in developmental stages are still largely unknown. In this study, the developmental toxicity of ZnO NPs to embryonic/larval zebrafish was investigated. The transcriptional expression profiles induced by ZnO NPs were also investigated to ascertain novel genomic responses related to their specific toxicity pathway. Zebrafish embryos were exposed to 0.01, 0.1, 1, and 10 mg/L ZnO NPs for 96 h post-fertilization. The toxicity of ZnO NPs, based on their Zn concentration, was quite similar to that in embryonic/larval zebrafish exposed to corresponding ZnSO4 concentrations. Pericardial edema and yolk-sac edema were the principal malformations induced by ZnO NPs. Gene-expression profiling using microarrays demonstrated 689 genes that were differentially regulated (fold change >1.5) following exposure to ZnO NPs (498 upregulated, 191 downregulated). Several genes that were differentially regulated following ZnO NP exposure shared similar biological pathways with those observed with ZnSO4 exposure, but six genes (aicda, cyb5d1, edar, intl2, ogfrl2 and tnfsf13b) associated with inflammation and the immune system responded specifically to ZnO NPs (either in the opposite direction or were unchanged in ZnSO4 exposure). Real-time reverse-transcription quantitative polymerase chain reaction confirmed that the responses of these genes to ZnO NPs were significantly different from their response to ZnSO4 exposure. ZnO NPs may affect genes related to inflammation and the immune system, resulting in yolk-sac edema and pericardia edema in embryonic/larval developmental stages. These results will assist in elucidating the mechanisms of toxicity of ZnO NPs during development of zebrafish.
As a drastic environmental change, metal pollution may promote the rapid evolution of genetic adaptations contributing to metal tolerance. In Arabidopsis halleri, genetic bases of zinc (Zn) and cadmium (Cd) tolerance have been uncovered only in a metallicolous accession, although tolerance is species-wide. The genetic determinants of Zn and Cd tolerance in a nonmetallicolous accession were thus investigated for the first time. The genetic architecture of tolerance was investigated in a nonmetallicolous population (SK2) by using first backcross progeny obtained from crosses between SK2 and Arabidopsis lyrata petraea, a nonmetallophyte species. Only one significant and common quantitative trait locus (QTL) region was identified explaining 22.6% and 31.2% of the phenotypic variation for Zn and Cd tolerance, respectively. This QTL co-localized with HEAVY METAL ATPASE 4 (AhHMA4), which was previously validated as a determinant of Zn and Cd tolerance in a metallicolous accession. Triplication and high expression of HMA4 were confirmed in SK2. In contrast, gene duplication and high expression of METAL TOLERANT PROTEIN 1A (MTP1A), which was previously associated with Zn tolerance in a metallicolous accession, were not observed in SK2. Overall, the results support the role of HMA4 in tolerance capacities of A. halleri that may have pre-existed in nonmetallicolous populations before colonization of metal-polluted habitats. Preadaptation to metal-contaminated sites is thus discussed.
A novel thermostable glucoamylase cDNA without starch binding domain (SBD) of Aspergillus flavus NSH9 was successfully identified, isolated, and overexpressed in Pichia pastoris GS115. The complete open reading frame of glucoamylase from Aspergillus flavus NSH9 was identified by employing PCR that encodes 493 amino acids lacking in the SBD. The first 17 amino acids were presumed to be a signal peptide. The cDNA was cloned into Pichia pastoris and the highest expression of recombinant glucoamylase (rGA) was observed after 8 days of incubation period with 1% methanol. The molecular weight of the purified rGA was about 78 kDa and exhibited optimum catalytic activity at pH 5.0 and temperature of 70°C. The enzyme was stable at higher temperature with 50% of residual activity observed after 20 min at 90°C and 100°C. Low concentration of metal (Mg(++), Fe(++), Zn(++), Cu(++), and Pb(++)) had positive effect on rGA activity. This rGA has the potential for use and application in the saccharification steps, due to its thermostability, in the starch processing industries.
Nanomaterial-based enzyme mimetics (nanozymes) is an emerging field of research that promises to produce alternatives to natural enzymes for a variety of applications. The search for the most cost-effective and efficient inorganic nanomaterials, such as metal oxides, cannot be won by pristine CuO. However, unlike CuO, the Zn-doped CuO (Zn-CuO) nanoparticles reported in this paper reveal superior peroxidase-like enzyme activity. This places Zn-CuO in a good position to participate in a range of activities aimed at developing diverse enzyme applications. The peroxidase-like activity was tested and confirmed against various chromogenic substrates in the presence of H2O2 and obeyed the Michaelis-Menten enzymatic pathway. The mechanism of enhanced enzymatic activity was proved by employing terephthalic acid as a fluorescence probe and by electron spin resonance. The nanozyme, when tested for the detection of glucose, showed a substantial enhancement in the detection selectivity. The limit of detection (LOD) was also decreased reaching a limit as low as 0.27 ppm. Such a low LOD has not been reported so far for the metal oxides without any surface modifications. Moreover, the nanozyme (Zn-CuO) was utilized to detect the three antioxidants tannic acid, tartaric acid, and ascorbic acid and the relative strength of their antioxidant capacity was compared.
Herein, the design and syntheses of two new mononuclear oxindolimine-copper(II) (1 and 2) and corresponding heterobinuclear oxindolimine Cu(II)Pt(II) complexes (3 and 4), are described. All the isolated complexes were characterized by spectroscopic techniques (UV/Vis, IR, EPR), in addition to elemental analysis and mass spectrometry. Cyclic voltammetry (CV) measurements showed that in all cases, one-electron quasi-reversible waves were observed, and ascribed to the formation of corresponding copper(I) complexes. Additionally, waves related to oxindolimine ligand reduction was verified, and confirmed using analogous oxindolimine-Zn(II) complexes. The Pt(IV/II) reduction, and corresponding oxidation, for complexes 3 and 4 occurred at very close values to those observed for cisplatin. By complementary fluorescence studies, it was shown that glutathione (GSH) cannot reduce any of these complexes, under the experimental conditions (room temperature, phosphate buffer 50mM, pH7.4), using an excess of 20-fold [GSH]. All these complexes showed characteristic EPR spectral profile, with parameters values gǁ>g⊥ suggesting an axially distorted environment around the copper(II) center. Interactions with calf thymus-DNA, monitored by circular dichroism (CD), indicated different effects modulated by the ligands. Finally, the cytotoxicity of each complex was tested toward different tumor cells, in comparison to cisplatin, and low values of IC50 in the range 0.6 to 4.0μM were obtained, after 24 or 48h incubation at 37°C. The obtained results indicate that such complexes can be promising alternative antitumor agents.
Reports have linked human exposure to Mn/Zn ethylene-bis-dithiocarbamate (Mn/Zn-EBDC) fungicides with multiple pathologies, from dermatitis to central nervous system dysfunction. Although members of this family of agrochemicals have been available for over 50 years, their mechanism of toxicity in humans is still unclear. Since mitochondrial inhibition and oxidative stress are implicated in a wide variety of diseases, we hypothesized that Caenorhabditis elegans (C. elegans) exposed to a commercially-available formulation of an Mn/Zn-EBDC-containing fungicide (Manzate; MZ) would also show these endpoints. Thus, worms were treated chronically (24h) with various MZ concentrations and assayed for reduced mitochondrial function and increased levels of reactive oxygen species (ROS). Oxygen consumption studies suggested Complex I inhibition in all treatment groups compared to controls ((**)p<0.01). In order to verify these findings, assays specific for Complex II or Complex IV activity were also completed. Data analysis from these studies indicated that neither complex was adversely affected by MZ treatment. Additional data from ATP assays indicated a statistically significant decrease ((***)p<0.001) in ATP levels in all treatment groups when compared to control worms. Further studies were completed to determine if exposure of C. elegans to MZ also resulted in increased ROS concentrations. Studies demonstrated that hydrogen peroxide, but not superoxide or hydroxyl radical, levels were statistically significantly increased (*p<0.05). Since hydrogen peroxide is known to up-regulate glutathione-S-transferase (GST), we used a GST:green fluorescent protein transgenic worm strain to test this hypothesis. Results from these studies indicated a statistically significant increase ((***)p<0.001) in green pixel number following MZ exposure. Taken together, these data indicate that C. elegans treated with MZ concentrations to which humans are exposed show mitochondrial Complex I inhibition with concomitant
 hydrogen peroxide production. Since these mechanisms are associated with numerous human diseases, we suggest further studies to determine if MZ exposure induces similar toxic mechanisms in mammals.
The availability of cadmium (Cd) and zinc (Zn) to sunflower (Helianthus annuus) was investigated in rhamnolipid- and ethylenediaminetetraacetic acid (EDTA)-buffered solutions in order to evaluate the influence of aqueous speciation of the metals on their uptake by the plant, in relation to predictions of uptake by the free ion activity model (FIAM). Free metal ion activity was estimated using the chemical equilibrium program MINTEQ or measured by Donnan dialysis. The uptake of Cd followed the FIAM for the EDTA-buffered solution at EDTA concentrations below 0.4 μM; for the rhamnolipid-buffered solution, the uptake of both metals in roots was not markedly affected by increasing rhamnolipid concentrations in solution. This suggests rhamnolipid enhanced metal accumulation in plant roots (per unit free metal in solution) possibly through formation and uptake of lipophilic complexes. The addition of normal Ca concentrations (low millimetre range) to the rhamnolipid uptake solutions reduced Cd accumulation in shoots by inhibiting Cd translocation, whereas it significantly increased Zn accumulation in shoots. This study confirms that although rhamnolipid could enhance accumulation of Cd in plants roots at low Ca supply, it is not suitable for Cd phytoextraction in contaminated soil environments where Ca concentrations in soil solution are orders of magnitude greater than those of Cd.
The development of industry in Beijing, the capital of China, particularly in last decades, has caused severe environmental pollution including particulate matter (PM), dust-haze, and photochemical smog, which has already caused considerable harm to local ecological environment. Thus, in this study, air particle samples were continuously collected in August and December, 2014. And elements (Si, Al, V, Cr, Mn, Fe, Ni, Cu, Zn, Mo, Cd, Ba, Pb and Ti) and ions ([Formula: see text], [Formula: see text], F(-), Cl(-), Na(+), K(+), Mg(2+), Ca(2+) and [Formula: see text]) were analyzed by inductively coupled plasma mass spectrometer and ion chromatography. According to seasonal changes, discuss the various pollution situations in order to find possible particulate matter sources and then propose appropriate control strategies to local government. The results indicated serious PM and metallic pollution in some sampling days, especially in December. Chemical Mass Balance model revealed central heating activities, road dust and vehicles contribute as main sources, account for 5.84-32.05 % differently to the summer and winter air pollution in 2014.
Mechanical resonators based on low-dimensional materials are promising for force and mass sensing experiments. The force sensitivity in these ultra-light resonators is often limited by the imprecision in the measurement of the vibrations, the fluctuations of the mechanical resonant frequency and the heating induced by the measurement. Here, we strongly couple multilayer graphene resonators to superconducting cavities in order to achieve a displacement sensitivity of 1.3 fm Hz(-1/2). This coupling also allows us to damp the resonator to an average phonon occupation of 7.2. Our best force sensitivity, 390 zN Hz(-1/2) with a bandwidth of 200 Hz, is achieved by balancing measurement imprecision, optomechanical damping, and measurement-induced heating. Our results hold promise for studying the quantum capacitance of graphene, its magnetization, and the electron and nuclear spins of molecules adsorbed on its surface.
To determine the normal reference values of 33 elements, Ag, Al, As, Au, B, Ba, Be, Ca, Cd, Co, Cr, Cs, Cu, Fe, Ga, Hg, Li, Mg, Mn, Mo, Ni, Pb, Rb, Sb, Se, Sr, Th, Ti, Tl, U, V, Zn and Zr, in the blood and urine samples from the general population in Sanmen County of Zhejiang province, a typical coastal area of eastern China.
The 33 elements in 272 blood and 300 urine samples were determined by inductively coupled plasma-mass spectrometry (ICP-MS). The normality test of data was conducted using SPSS 17.0 Statistics. The data was compared with other reports.
The normal reference values of the 33 elements in the blood and urine samples from the general population in Sanmen County were obtained, which of some elements were found to be similar with other reports, such as Co, Cu, Mn and Sr, while As, Cd, Hg and Pb were generally found to be higher than those previously reported. There was a wide variation between the reports from different countries in blood Ba.
The normal reference values of the 33 elements in the blood and urine samples from the general population in Sanmen County are established, and successfully applied to two poisoning cases.
A hallmark of Alzheimer's disease is accumulation of amyloid beta (Aβ) deposits, which are associated with neuronal dysfunction, spine loss, and impaired Ca(2+) homeostasis. Amyloid beta (Aβ) binds to and is aggregated by Zn(2+) , a metal released from synaptic glutamatergic vesicles during neuronal activity. Synaptically released Zn(2+) activates a metabotropic Gq-coupled Zn(2+) -sensing receptor, mZnR/GPR39, and induces Ca(2+) -signaling in post-synaptic neurons. We examined if Aβ, as a Zn(2+) binding protein, regulates neuronal Zn(2+) -signaling mediated by mZnR/GPR39 using SHSY-5Y cells and cortical neurons from GPR39 wild-type and knockout mice. Following acute or chronic treatment with Aβ neuronal Zn(2+) -dependent Ca(2+) release via mZnR/GPR39 is significantly reduced. This impairment is overcome when excess Zn(2+) is applied, suggesting that impaired Ca(2+) -signaling results from Aβ binding of Zn(2+) . The Zn(2+) -dependent mZnR/GPR39 activation triggers phosphorylation of extracellular regulated kinase and up-regulates expression of the chaperone protein clusterin (Clu). Importantly, neuronal Zn(2+) -dependent extracellular regulated kinase1/2 phosphorylation and up-regulation of Clu are attenuated by silencing mZnR/GPR39 as well as by Aβ treatment. In contrast, Zn(2+) -dependent AKT phosphorylation is not mediated by mZnR/GPR39 and is not attenuated by Aβ treatment. Thus, Zn(2+) signaling via mZnR/GPR39 is distinctively disrupted by a critical pathological component of Alzheimer's disease. Synaptically released Zn(2+) activates a Zn(2+) -sensing receptor, mZnR/GPR39, and induces Ca(2+) -signaling, followed by ERK1/2 MAPK activation and up-regulation of clusterin. Amyloid beta (Aβ) binds to Zn(2+) thus forming oligomers that are a hallmark of Alzheimer's disease. We show that Aβ attenuates Zn(2+) -dependent Ca(2+) -responses, abolishes ERK1/2 activation and down-regulates clusterin expression. Thus, Zn(2+) signaling via mZnR/GPR39 is disrupted by Aβ, a critical pathological component of Alzheimer's disease.
Data concerning the occurrence of emerging biological contaminants such as antibiotic resistance genes (ARGs) and fecal indicator bacteria (FIB) in aquatic environments in Sub-Saharan African countries is limited. On the other hand, antibiotic resistance remains a worldwide problem which may pose serious potential risks to human and animal health. Consequently, there is a growing number of reports concerning the prevalence and dissemination of these contaminants into various environmental compartments. Sediments provide the opportunity to reconstruct the pollution history and evaluate impacts so this study investigates the abundance and distribution of toxic metals, FIB, and ARGs released from hospital effluent wastewaters and their presence in river sediments receiving systems. ARGs (bla TEM, bla CTX-M, bla SHV, and aadA), total bacterial load, and selected bacterial species FIB [Escherichia coli, Enterococcus (ENT)] and species (Psd) were quantified by targeting species specific genes using quantitative PCR (qPCR) in total DNA extracted from the sediments recovered from 4 hospital outlet pipes (HOP) and their river receiving systems in the City of Kinshasa in the Democratic Republic of the Congo. The results highlight the great concentration of toxic metals in HOP, reaching the values (in mg kg(-1)) of 47.9 (Cr), 213.6 (Cu), 1434.4 (Zn), 2.6 (Cd), 281.5 (Pb), and 13.6 (Hg). The results also highlight the highest (P < 0.05) values of 16S rRNA, FIB, and ARGs copy numbers in all sampling sites including upstream (control site), discharge point, and downstream of receiving rivers, indicating that the hospital effluent water is not an exclusive source of the biological contaminants entering the urban rivers. Significant correlation were observed between (i) all analyzed ARGs and total bacterial load (16S rRNA) 0.51 to 0.72 (p < 0.001, n = 65); (ii) ARGs (except bla TEM) and FIB and Psd 0.57 < r < 0.82 (p < 0.001, n = 65); and (iii) ARGs (except bla TEM) and toxic metals (Cd, Cr, Cu, and Zn) 0.44 to 0.72, (p < 0.001, n = 65). These findings demonstrate that several sources including hospital and urban wastewaters contribute to the spread of toxic metals and biological emerging contaminants in aquatic ecosystems.
To investigate the effect of vitamin A and Zn supplementation on vitamin A status, haemoglobin level and defecation of children with persistent diarrhea, a total of 160 paediatric patients were randomly assigned to one of four intervention groups: daily supplementation of 1,500 IU VA for 14 days; daily Zn supplementation for 14 days; daily supplementation with both VA and Zn for 14 days; no supplementation. One hundred twenty-seven children with persistent diarrhea finished intervention (33 were lost to follow-up). Among the 127 children, 41 (32.28%) had anaemia, 104 (81.89%) had a VA deficiency and 38 (29.92%) had an iron insufficiency. Supplementation with VA or VA + Zn enhanced the serum VA levels and ameliorated anaemia. Supplementation with Zn and
 VA + Zn for 5 days significantly improved defecation, where the VA + Zn treatment resulted in superior outcomes. After 14 days of intervention, the total effectiveness rates were 93.94%, 96.77% and 96.67% in the three groups, significantly greater than that of the non-supplementation group (72.73%). These results indicate that single VA or concurrent VA + Zn supplementation can improve vitamin A status, haemoglobin level and defecation. However, concurrent VA + Zn supplementation is the optimal option and can shorten the duration of persistent diarrhea and markedly improve nutritional status. (www.clinicaltrials.gov registration number: ChiCTR-IOR-14005498).
The impact of sugar beet factory lime (SBFL) on the release dynamics and mobilization of toxic metals (TMs) under dynamic redox conditions in floodplain soils has not been studied up to date. Therefore, the aim of this study was to verify the scientific hypothesis that SBFL is able to immobilize Cd, Co, Cr, Cu, Fe, Mn, Mo, Ni, Pb, and Zn under different redox potentials (EH) in a contaminated floodplain soil. For this purpose, the non-treated contaminated soil (CS) and the same soil treated with SBFL (CS+SBFL) were flooded in the laboratory using a highly sophisticated automated biogeochemical microcosm apparatus. The experiment was conducted stepwise from reducing (-13 mV) to oxidizing (+519 mV) soil conditions. Soil pH decreased under oxic conditions in CS (from 6.9 to 4.0) and in CS+SBFL (from 7.5 to 4.4). The mobilization of Cu, Cr, Pb, and Fe were lower in CS+SBFL than in CS under both reducing/neutral and oxic/acidic conditions. Those results demonstrate that SBFL is able to decrease concentrations of these elements under a wide range of redox and pH conditions. The mobilization of Cd, Co, Mn, Mo, Ni, and Zn were higher in CS+SBFL than in CS under reducing/neutral conditions; however, these concentrations showed an opposite behavior under oxic/acidic conditions and were lower in CS+SBFL than in CS. We conclude that SBFL immobilized Cu, Cr, Pb, and Fe under dynamic redox conditions and immobilized Cd, Co, Mn, Mo, Ni, and Zn under oxic acidic conditions; however, the latter elements were mobilized under reducing neutral conditions in the studied soil. Therefore, the addition of SBFL to acid floodplain soils contaminated with TMs might be an important alternative for ameliorating these soils with view to a sustainable management of these soils.
Herein, we present a combined spectroscopic and computational study on 5,5'-linked and 10,10'-linked corrole dimers, 5CD and 10CD, respectively, to reveal their strikingly different excited-state dynamics. The excited-state dynamics of 10CD indicate relatively small electronic interactions between the two corrole units, which is similar to the case of the meso-meso directly linked Zn(ii) porphyrin dimer. On the other hand, 5CD exhibits characteristic excitation-wavelength-dependent dual fluorescence. Transient absorption spectra of 10CD on the picosecond timescale showed torsional relaxation with a time constant of 25 ps, whereas the torsional relaxation of 5CD was faster, exhibiting a time constant of 10 ps. Quantum calculations have indicated that the eccentric dual fluorescence and the faster torsional relaxation process of 5CD are consequences of a large π-orbital coefficient at the connecting 5-position, which enhances the conjugative stabilization in the excited-state. In contrast, a small π-orbital coefficient at the 10-position and a larger torsional barrier of 10CD cause monomer-like characters in the excited-state.
The first examples of essentially two-coordinate, monomeric zinc hydride complexes, LZnH (L = -N(Ar)(SiR3)) (Ar = C6H2{C(H)Ph2}2R'-2,6,4; R = Me, R' = Pr(i) (L'); R = Pr(i), R' = Me (L*); R = Pr(i), R' = Pr(i) (L(†))) have been prepared and shown by crystallographic studies to have near linear N-Zn-H fragments. The results of computational studies imply that any PhZn interactions in the compounds are weak at best. Preliminary reactivity studies reveal the compounds to be effective for the stoichiometric hydrozincation and catalytic hydrosilylation of carbonyl compounds.
The synthesis of Zn-doped TiO2 nanoparticles by solgel method was investigated in this study, as well as its modification by H2 O2 . The catalyst was characterized by transmission electron microscopy, X-ray diffraction, Brunauer-Emmett-Teller, UV-visible reflectance spectra and X-ray photoelectron spectroscopy (XPS). The results indicated that doping Zn into TiO2 nanoparticles could inhibit the transformation from anatase phase to rutile phase. Zn existed as the second valence oxidation state in the Zn-doped TiO2 . Zn-doped TiO2 that was synthesized by 5% Zn doping at 450°C exhibited the best photocatalytic activity. Then, the H2 O2 modification further enhanced the photocatalytic activity. Zn doping and H2 O2 modifying narrowed the band gap and efficiently increased the optical absorption in visible region. The optimal degradation rate of tetracycline by Zn-doped TiO2 and H2 O2 modified Zn-doped TiO2 was 85.27% and 88.14%. Peroxide groups were detected in XPS analysis of H2 O2 modified Zn-doped TiO2 , favoring the adsorption of visible light. Furthermore, Zn-doped TiO2 modified by H2 O2 had relatively good reusability, exhibiting a potential practical application for tetracycline's photocatalytic degradation.
To describe and evaluate the current practices used to manage and prevent facial eczema (FE) in North Island dairy herds, and determine the within-herd prevalence of cows with elevated activities of gamma glutamyl transferase (GGT), and with concentrations of Zn in serum <18 μmol/L.
Between January and May 2014, 105 herd managers from throughout the North Island of New Zealand were invited to participate in the study when regional spore counts for Pithomyces chartarum started to rise towards 30,000 spores/g pasture. Managers selected 10 representative cattle that were weighed and blood-sampled by the herd veterinarian. Blood samples were analysed for concentrations of Zn in serum and GGT activity. Pasture samples were also collected and submitted for spore count estimation. Finally a survey of farm management practices relating to prevention of FE was completed by the herd manager. A mixed-effects logistic regression model was used to determine associations between herd-level and cow-level explanatory variables and the probability of a cow having a concentration of Zn in serum <18 µmol/L.
Of the 1,071 cows tested, 79 (7.3 (95% CI=5.8-9.0)%) had GGT activity in serum >300 IU/L, and 35/106 (33 (95% CI=24.2-42.8)%) herds had ≥1 of the 10 cows sampled with GGT activity >300 IU/L. Of the 911 cows that were being treated with Zn, concentrations of Zn were between 18-35 μmol/L in 398 (43.6 (95% CI=40.4-46.9)%) cows, were >35 μmol/L in 32 (3.5 (95% CI=2.4-4.1)%) cows, and <18 μmol/L in 479 (52.6 (95% CI=49.3-55.9)%) cows. After adjusting for the confounding effect of region, the odds of a cow having concentrations of Zn in serum <18 μmol/L were 5.5 (95% CI=1.1-29) times greater for cows supplemented with zinc in water compared with those supplemented by drenching. Of the 105 herd managers, 103 (98%) stated that they had access to regional spore count data, but only 35/105 (33%) reported that they measured spore counts on their own farm. Overall, 98/105 (93%) managers reported that they had some form of FE management programme in place. Fungicides were used on their own or in combination with zinc treatments in 10 herds, ZnSO4 in water troughs was used in 68 herds, oral drenching with ZnO in nine herds, and ZnO supplied in-feed in 26 herds. Estimated daily dose rates of zinc were less than that required to treat a 400 kg cow on 42/68 farms that administered ZnSO4 in the water or ZnO as a drench.
This study has shown that FE management on dairy farms in the North Island of New Zealand could be substantially improved. It is likely that improved FE management would occur if herd managers were provided with more feedback on the success (or otherwise) of their FE management programmes.
As a human fungal pathogen, Candida albicans can cause a wide variety of disease conditions ranging from superficial to systemic infections. Many of these infections are caused by an inherent ability of the pathogen to form biofilms on medical devices resulting in high mortality. Biofilms formed by C. albicans are a complex consortium of yeast and hyphal cells embedded in an extracellular matrix and are regulated by a network of transcription factors. Here, we report the role of a novel Zn(II)2-Cys6 binuclear cluster transcription factor, ZCF32, in the regulation of biofilm formation. Global transcriptome analysis reveals that biofilm development is the most altered pathway in the zcf32 null mutant. To delineate the functional correlation between ZCF32 and biofilm development, we determined the set of genes directly regulated by Zcf32. Our data suggests that Zcf32 regulates biofilm formation by repressing the expression of adhesins, chitinases and a significant number of other GPI-anchored proteins. We establish that there is the lesser recruitment of Zcf32 on the promoters of biofilm genes in biofilm condition compared to the planktonic mode of growth. Taking together, we propose that the transcription factor ZCF32 negatively regulates biofilm development in C. albicans.
The concentrations of zinc, copper, cadmium and lead in surface water, sediments and two native snail species, Bellamya bengalensis and Melanoides tuberculata from Latipada reservoir were determined. The concentrations of cadmium and lead in surface water were higher than the WHO recommended limits for drinking water standards; where as those of zinc and copper were within the permissible limits. The concentrations of zinc, copper, cadmium and lead were higher in sediments than in water.
 The observed bioaccumulated level of zinc, copper, cadmium and lead in Bellamya bengalensis were Zn- 197.22, Cu- 172.14, Cd- 11.59 and Pb- 112.57 μg g(-1), while in Melanoides tuberculata were Zn- 136.59, Cu- 132.04, Cd- 13.25 and Pb- 27.69 μg g(-1). The metal concentrations in both species of snails were higher than those of the water and sediment. Bioaccumulated metal concentrations, Bio-Water Accumulation Factor (BWAF) and Bio-Sediment Accumulation Factor (BSAF) values indicated that Bellamya bengalensis had high potential for zinc, copper and lead bioaccumulation than Melanoides tuberculata, while Melanoides tuberculata had high potential for cadmium than Bellamya bengalensis. Therefore, Bellamya bengalensis is proposed as sentinel organism for monitoring zinc, copper and lead, while Melanoides tuberculata for monitoring cadmium in freshwater.
To explore toxic mechanisms of nano-ZnO on marine microalgae, algal growth inhibition test was carried out, and total Zn in the cell and total dissolved Zn in f/2 medium were determined. It was found that nano-ZnO was more toxic than bulk-ZnO on marine microalgae Skeletonema costatum. No matter under nano-ZnO or bulk-ZnO treatment, accumulation of intracellular Zn had a good linear correlation with growth inhibition ratio (IR). The total Zn content in the cell of microalgae was the dominant toxic mechanism of ZnO. Intracellular total Zn could be an indispensable parameter to indicate the toxic effects of nano-ZnO. Higher intracellular total Zn under nano-ZnO treatment than bulk-ZnO resulted in more toxicity of nano-ZnO on microalgae. Compared with Zn(2+) released by nano-ZnO into medium, lipid peroxidation (MDA level) injury, aggregation of nano-ZnO and transmembrane process of nano-ZnO also contributed to toxicity of nano-ZnO on Skeletonema costatum. The accumulation of intracellular Zn provides a new insight into toxic mechanisms of nano-ZnO.
The inoculation of plants with plant-growth-promoting rhizobacteria has become a priority in the phytoremediation of heavy-metal-contaminated soils. A total of 82 bacteria were isolated from Sulla coronaria root nodules cultivated on four soil samples differently contaminated by heavy metals. The phenotypic characterization of these isolates demonstrated an increased tolerance to cadmium reaching 4.1mM, and to other metals, including Zn, Cu and Ni. Polymerase Chain Reaction/Restriction Fragment Length Polymorphism (PCR/RFLP) analysis showed a large diversity represented by genera related to Agrobacterium sp., R. leguminosarum, Sinorhizobium sp., Pseudomonas sp., and Rhizobium sp. Their symbiotic effectiveness was evaluated by nodulation tests. Taking into consideration efficiency and cadmium tolerance, four isolates were chosen; their 16SrRNA gene sequence showed that they belonged to Pseudomonas sp. and the Rhizobium sullae. The selected consortium of soil bacteria had the ability to produce plant-growth-promoting substances such as indole acetic acid and siderophore. The intracellular Cd accumulation was enhanced by increasing the time of incubation of the four soil bacteria cultivated in a medium supplemented with 0.1mM Cd. The existence of a cadmium-resistant gene was confirmed by PCR. These results suggested that Sulla coronaria in symbiosis with the consortium of plant-growth-promoting rhizobacteria (PGPR) could be useful in the phytoremediation of cadmium-contaminated soils.
Cysteine-containing biomolecules are attractive targets in the study of thiol biology. Here we introduce a novel method for the selective enrichment of thiol-containing molecules using a thiol-capture zinc(II) complex of 1,4,7,10-tetraazacyclododecane (Zn(2+)-cyclen). Recognition of N-acetylcysteine amide by Zn(2+)-cyclen has been studied by potentiometric pH titration, revealing formation of a 1:1 thiolate-bound Zn(2+)-cyclen complex with a large thiolate-affinity constant of 10(6.2)M(-1) at 25°C and I=0.10M (NaCl). The Zn(2+)-bound thiolate anion is unexpectedly stable in aqueous solution at pH 7.8 under atmospheric conditions for a few days. These findings have contributed to the development of a convenient method for separation of thiol compounds by using a micropipette tip. A 200μL micropipette tip containing 10μL of hydrophilic cross-linked agarose beads attached to Zn(2+)-cyclen moieties was prepared. All steps for thiol-affinity separation (binding, washing, and eluting) are conducted using aqueous buffers at room temperature. The entire separation protocol requires less than 15min per sample. We demonstrate practical example separations of cysteine-containing molecules. This micropipette tip method would be used preferentially as an alternative to existing tools for reliable enrichment of thiol-containing molecules.
This study was conducted to evaluate the effect of equilibration time on adsorption of zinc [Zn(II)] and nickel [Ni(II)] on pure and modified chitosan beads. The initial adsorption of Zn(II) was high on molybdenum (Mo)-impregnated chitosan beads (MoCB) during the initial 60 min. However, after 240 min, Zn(II) adsorption occurred more on single super phosphate chitosan beads (SSPCB), followed by monocalcium phosphate chitosan beads (MCPCB), untreated pure chitosan beads (UCB), and MoCB. Similarly, Ni(II) adsorption was greatest on MoCB during the initial 60 min. At the conclusion of the experiment (at 240 min), the greatest adsorption was occurred on MCPCB, followed by MoCB, UCB, and SSPCB. Chemical sorption and intra-particle diffusion were probably the dominant processes responsible for Zn(II) and Ni(II) sorption onto chitosan beads. The results demonstrated that modified chitosan beads were effective in adsorbing Zn and Ni and hence, could be used for the removal of these toxic metals from soil.
This work discusses the biological and biochemical characterization of an extracellular protease produced by Pseudomonas fluorescens. The enzyme has a molecular weight of 49.486 kDa and hydrolyzes gelatin, casein, and azocasein, but not BSA. Its maximum activity is found at 37°C and pH 7.5, but it retained almost 70% activity at pH 10.0. It was shown to be a metalloprotease inhibited by Cu(2+), Ni(2+), Zn(2+), Hg(2+), Fe(2+), and Mg(2+), but induced by Mn(2+). After incubation at 100°C for 5min, the enzyme presented over 40% activity, but only 14 to 30% when submitted to milder heat treatments. This behavior may cause significant problems under conditions commonly used for the processing and storage of milk and dairy products, particularly UHT milk. A specific peptide sequenced by mass spectrometer analysis allowed the identification of gene that encodes this extracellular protease in the genome of Pseudomonas fluorescens 07A strain. The enzyme has 477 AA and highly conserved Ca(2+)- and Zn(2+)-binding domains, indicating that Ca(2+), the main ion in milk, is also a cofactor. This work contributes to the understanding of the biochemical aspects of enzyme activity and associates them with its sequence and structure. These findings are essential for the full understanding and control of these enzymes and the technological problems they cause in the dairy industry.
Monitoring the levels of trace elements in hair can allow estimating the effects of the geographical location and also can provide a notion of the metal body burden. However, the use of human hair is controversial due to the different confounding factors that could affect the presence of trace elements in hair. As a result, a comprehensive monitoring study was performed in Alcalá de Henares, one of the major cities in the Madrid region, Spain. Trace elements have been monitored in urban topsoils and in human hair of two well-defined and healthy groups of population: children (6-9 years) and adolescents (13-16 years). The city was divided into four areas or zones with different characteristics to assess the possible effect of area of residence and age in the presence of Al, As, Be, Cd, Cr, Cu, Hg, Mn, Pb, Sn, Ti, Tl and Zn in soils and hair. There is no current hypothesis that explains the possible effect of the area of monitoring in the distribution of Be, Cr, Ni, Sn and Ti found in these urban soils, maybe because urban soils receive high disturbance, and there are many factors involved. The presence of most of the trace elements monitored was significantly higher in the hair of the children population, except for Sn and Zn. This could be attributed mainly to dietary habits. Other factors influencing metal content in hair such as environmental factors would have had a minimal effect in the population groups here studied. Finally, none of the levels of trace elements studied in hair were significantly correlated with levels measured in the topsoils of public parks in Alcalá de Henares, with the exception of Pb in adolescent participants.
The main objectives of this work were to identify and determine the concentrations of polycyclic aromatic hydrocarbons (PAHs) and trace metals in carpet dust samples from various mosques of the city of Riyadh and to assess the health risks associated with the exposure to these pollutants. Therefore, 31 samples of mosque's carpet dust from Riyadh were collected. The results showed that 14 PAHs were present in the dust samples with concentrations ranged from 90 to 22,146 ng g(-1) (mean = 4096 ± 4277 ng g(-1)) where low molecular weight compounds were dominant. The presence of PAHs were in the order of naphthalene > chrysene and benzo(b)fluoranthene > benzo(a)pyrene > acenaphthene and benzo(k)fluoranthene > pyrene and the absence of indeno(1,2,3-cd)pyrene and dibenz(a,h)anthracene. The diagnostic ratio coupled with principle component analysis (PCA) revealed mix sources of petrogenic from traffic, stack emission, and pyrogenic inputs from essence and perfumed wood burning. Trace metals were significant in the dust samples, and their concentrations
 decrease in the order of Zn, Mn, Cu, Cr, Pb, Ni, and V where Zn being the highest (94.4 ± 91.5 μg g(-1)) and indium was the lowest (1.9 ± 9.3 μg g(-1)). The trace metals were major in southern and central parts of Riyadh and followed the order of central Riyadh > southern Riyadh > western Riyadh > eastern Riyadh > northern Riyadh. Estimated risk based on the total PAHs was found to be 4.30 × 10(-11) for adult and 1.56 × 10(-11) for children. Elemental non-cancer risk for adults ranged from 7.9 × 10(-4) for Co to 7.58 × 10(-1) for Li and for children ranged from 3.70 × 10(-3) for Co to 3.54 for Li. Policy implication and mitigations of PAHs in Riyadh and Saudi Arabia were highlighted.
The Qinling panda subspecies (Ailuropoda melanoleuca qinlingensis) is highly endangered with fewer than 350 individuals inhabiting the Qinling Mountains. Previous studies have indicated that giant pandas are exposed to heavy metals, and a possible source is vehicle emission. The concentrations of Cu, Zn, Mn, Pb, Cr, Ni, Cd, Hg, and As in soil samples collected from sites along a major highway bisecting the panda's habitat were analyzed to investigate whether the highway was an important source of metal contamination. There were 11 sites along a 30-km stretch of the 108th National Highway, and at each site, soil samples were taken at four distances from the highway (0, 50, 100, and 300 m) and at three soil depths (0, 5, 10 cm). Concentrations of all metals except As exceeded background levels, and concentrations of Cu, Zn, Mn, Pb, and Cd decreased significantly with increasing distance from the highway. Geo-accumulation index indicated that topsoil next to the highway was moderately contaminated with Pb and Zn, whereas topsoil up to 300 m away from the highway was extremely contaminated with Cd. The potential ecological risk index demonstrated that this area was in a high degree of ecological hazards, which were also due to serious Cd contamination. And, the hazard quotient indicated that Cd, Pb, and Mn especially Cd could pose the health risk to giant pandas. Multivariate analyses demonstrated that the highway was the main source of Cd, Pb, and Zn and also put some influence on Mn. The study has confirmed that traffic does contaminate roadside soils and poses a potential threat to the health of pandas. This should not be ignored when the conservation and management of pandas is considered.
The computational bottleneck of the extremely fast simplified Tamm-Dancoff approximated (sTDA) time-dependent density functional theory procedure [S. Grimme, J. Chem. Phys. 138, 244104 (2013)] for the computation of electronic spectra for large systems is the determination of the ground state Kohn-Sham orbitals and eigenvalues. This limits such treatments to single structures with a few hundred atoms and hence, e.g., sampling along molecular dynamics trajectories for flexible systems or the calculation of chromophore aggregates is often not possible. The aim of this work is to solve this problem by a specifically designed semi-empirical tight binding (TB) procedure similar to the well established self-consistent-charge density functional TB scheme. The new special purpose method provides orbitals and orbital energies of hybrid density functional character for a subsequent and basically unmodified sTDA procedure. Compared to many previous semi-empirical excited state methods, an advantage of the ansatz is that a general eigenvalue problem in a non-orthogonal, extended atomic orbital basis is solved and therefore correct occupied/virtual orbital energy splittings as well as Rydberg levels are obtained. A key idea for the success of the new model is that the determination of atomic charges (describing an effective electron-electron interaction) and the one-particle spectrum is decoupled and treated by two differently parametrized Hamiltonians/basis sets. The three-diagonalization-step composite procedure can routinely compute broad range electronic spectra (0-8 eV) within minutes of computation time for systems composed of 500-1000 atoms with an accuracy typical of standard time-dependent density functional theory (0.3-0.5 eV average error). An easily extendable parametrization based on coupled-cluster and density functional computed reference data for the elements H-Zn including transition metals is described. The accuracy of the method termed sTDA-xTB is first benchmarked for vertical excitation energies of open- and closed-shell systems in comparison to other semi-empirical methods and applied to exemplary problems in electronic spectroscopy. As side products of the development, a robust and efficient valence electron TB method for the accurate determination of atomic charges as well as a more accurate calculation scheme of dipole rotatory strengths within the Tamm-Dancoff approximation is proposed.
Overburden at a coal mine in the Hunter Valley, New South Wales, was stored in a flat-topped artificial mound with 14-degree side slopes. Topsoil was scarce, dispersive and readily eroded. A split-plot factorial experiment applied an enhanced municipal solid waste compost at 0, 60 or 100 t ha(-1) to untreated overburden or to overburden covered with 0.1 m of topsoil. Two seeding treatments, of trees and shrubs or of pasture species, were applied to two 0.5-ha replicates of each surface treatment. Substrate physical and chemical properties and vegetation attributes were assessed 2.5 years later. Compost application to both topsoil and overburden significantly increased total N, P, Cu and Zn, soluble K, Ca and Mg, and significantly reduced soluble Na and pH. Mean tree density, size and total canopy cover were significantly greater with compost applied at 60 t ha(-1) to overburden than with all other treatments, especially those on topsoil where tree growth was inhibited by undesired species. Compost application to overburden and topsoil at 100 t ha(-1) significantly increased biomass of desired pasture species and significantly reduced undesired species cover compared with unamended topsoil and the extent of bare ground compared with unamended overburden. Successful development of woody species on overburden and pastures on both overburden and topsoil treated with compost provides opportunities for new combinations of landscape design, surface preparation and plant species introductions to increase the stability of final landforms, the effectiveness of resource use, and the delivery of commercial and biodiversity benefits from mine site rehabilitation.
In the present study, five fungal strains viz., Aspergillus terreus AML02, Paecilomyces fumosoroseus 4099, Beauveria bassiana 4580, Aspergillus terreus PD-17, Aspergillus fumigatus PD-18, were screened for simultaneous multimetal removal. Highest metal tolerance index for each individual metal viz., Cd, Cr, Cu, Ni, Pb and Zn (500mg/L) was recorded for A. fumigatus for the metals (Cd, 0.72; Cu, 0.72; Pb, 1.02; Zn, 0.94) followed by B. bassiana for the metals (Cd, 0.56; Cu, 0.14; Ni, 0.29; Zn, 0.85). Next, the strains were exposed to multiple metal mixture (Cd, Cr, Cu, Ni, Pb and Zn) of various concentrations (6, 12, 18, 30mg/L). Compared to other strains, B. bassiana and A. fumigatus had higher cube root growth (k) constants indicating their better adaptability to multi metal stress. After 72h, multimetal accumulation potential of B. bassiana (26.94±0.07mg/L) and A. fumigatus (27.59±0.09mg/L) were higher than the other strains at initial multimetal concentration of 30mg/L. However, considering the post treatment concentrations of individual metals in multimetal mixture (at all the tested concentrations), A. fumigatus demonstrated exceptional performance and could bring down the concentrations of Cd, Cu, Ni, Pb and Zn below the threshold level for irrigation prescribed by Food and Agriculture Organization (FAO).
This study investigated the efficacies of gliclazide (GLZ), methylcobalamin (MCA), and GLZ+MCA combination therapy on DPN by evaluating the treatment-related changes in peripheral nerve function, the polyol pathway, and oxidative stress in the sciatic nerve of streptozotocin-induced diabetic rats.
The rat model of streptozotocin-induced diabetes was orally given GLZ (25mg/kg/day), MCA (175μg/kg/day), and GLZ+MCA (25mg/kg/day+175μg/kg/day) combination therapy for 8weeks, in order to observe its effects on the motor nerve conduction velocity (MNCV), on the activities of Na(+), K(+)-ATPase, aldose reductase(AR), AR mRNA expression, on the polyol contents, antioxidative enzyme activities and peroxidation products in the sciatic never tissue.
Most of the indicators of DPN, such as delayed MNCV, altered/damaged nerve structure, inhibited Na(+),K(+)-ATPase activity, enhanced AR activity and AR mRNA expression, increased polyol contents, altered Cu,Zn-superoxide dismutase, catalase, and glutathione-peroxidase activities, and elevated malondialdehyde level in the sciatic nerves of the diabetic rats, were significantly ameliorated by treatment with either GLZ or MCA. Moreover, the combination of GLZ and MCA was found to enhance the curative effect on DPN in parts of above-mentioned parameters as compared to monotherapy.
Monotherapy with GLZ or MCA, and especially the combined application of GLZ and MCA, could be efficient therapeutic strategies for combating experimental DPN in diabetic rats.
Superoxide dismutase [Cu-Zn], or SOD1, is a homo-dimeric protein that functions as an antioxidant by scavenging for superoxides. A wide range of SOD1 variants are linked to inherited, or familial, amyotrophic lateral sclerosis, a progressive and fatal neurodegenerative disease. Aberrant SOD1 oligomerization has been strongly implicated in disease causation, even for sporadic ALS, or SALS, which accounts for ~90 % of ALS cases. Small heat shock proteins (sHSP) have been shown to protect against amyloid fibril formation in
 vitro, and the sHSP αB-crystallin suppresses in vitro aggregation of SOD1. We are seeking to elucidate the structural features of both SOD1 amyloid formation and αB-crystallin amyloid suppression. Specifically, we have used a flexible docking protocol to refine our model of a SOD1 non-obligate tetramer, postulated to function as a transient desolvating complex. Homology modeling and molecular dynamics (MD) are used to supply the missing structural elements of a previously characterized SOD1 amyloid filament, thereby providing a structural analysis for the observed gain of interaction. This completed filament is then further modified using MD to provide a structural model for protofibril capping of SOD1 filaments by αB-crystallin.
In contaminated soils, excessive concentrations of metals and their high mobility pose a serious environmental risk. A suitable soil amendment can minimize the negative effect of metals in soil. This study investigated the effect of different biochars on metal (Cu, Pb, Zn) immobilization in industrial soil. Biochars produced at 300 and 600 °C from conventional (MS, maize silage; WP, wooden pellets) and alternative (SC, sewage sludge compost; DR, digestate residue) feedstocks were used as soil amendments at a dosage of 10 % (w/w). The type of feedstock and pyrolysis temperature affected the properties of the biochars and their ability to immobilize metal in soil. Compared to production at 300 °C, all biochars produced at 600 °C had higher pH (6.2-10.7), content of ash (7.2-69.0 %) and fixed carbon (21.1-56.7 %), but lower content of volatile matter (9.7-37.2 %). All biochars except DR biochar had lower dissolved organic carbon (DOC) content (1.4-2.3 g C/L) when made at 600 °C. Only MS and SC biochars had higher cation exchange capacity (25.2 and 44.7 cmol/kg, respectively) after charring at 600 °C. All biochars contained low concentrations of Cd, Cu, Ni, Pb and Zn; Cd was volatilized to the greatest extent during pyrolysis. Based on FTIR analysis and molar ratios of H/C and O/C, biochars had a greater degree of carbonization and aromaticity after charring at 600 °C. The efficiency of the biochars in metal immobilization depended mainly on their pH, ash content, and concentration of DOC. SC and DR biochars were more effective for Cu and Zn immobilization than MS and WP biochars, which makes them attractive options for large-scale soil amendment.
We fabricated Cu(In,Ga)Se2 (CIGS) solar cells with a chemical bath deposition (CBD)-ZnS buffer layer grown with varying ammonia concentrations in aqueous solution. The solar cell performance was degraded with increasing ammonia concentration, due to actively dissolved Zn atoms during CBD-ZnS precipitation. These formed interfacial defect states, such as hydroxide species in the CBD-ZnS film, and interstitial and antisite Zn defects at the p-n heterojunction. After light/UV soaking, the CIGS solar cell performance drastically improved, with a rise in fill factor. With the Zn-based buffer layer, the light soaking treatment containing blue photons induced a metastable state and enhanced the CIGS solar cell performance. To interpret this effect, we suggest a band structure model of the p-n heterojunction to explain the flow of photocarriers under white light at the initial state, and then after light/UV soaking. The determining factor is a p+ defect layer, containing an amount of deep acceptor traps, located near the CIGS surface. The p+ defect layer easily captures photoexcited electrons, and then when it becomes quasi-neutral, attracts photoexcited holes. This alters the barrier height and controls the photocurrent at the p-n junction, and fill factor values, determining the solar cell performance.
In this work, we examine, by means of computational methods, the mechanism of Zn(2+) sensing by a bipyridine-centered, D-π-A-π-D-type ratiometric molecular probe. According to recently published experimental data [Divya, K. P.; Sreejith, S.; Ashokkumar, P.; Yuzhan, K.; Peng, Q.; Maji, S. K.; Tong, Y.; Yu, H.; Zhao, Y.; Ramamurthy, P.; Ajayaghosh, A. A ratiometric fluorescent molecular probe with enhanced two-photon response upon Zn(2+) binding for in vitro and in vivo bioimaging. Chem. Sci. 2014, 5, 3469-3474], after coordination to zinc ions the probe exhibits a large enhancement of the two-photon absorption cross section. The goal of our investigation was to elucidate the mechanism behind this phenomenon. For this purpose, linear and nonlinear optical properties of the unbound (cation-free) and bound probe were calculated, including the influence of solute-solvent interactions, implicitly using a polarizable continuum model and explicitely employing the QM/MM approach. Because the results of the calculations indicate that many conformers of the probe are energetically accessible at room temperature in solution and hence contribute to the signal, structure-property relationships were also taken into account. Results of our simulations demonstrate that the one-photon absorption bands for both the unbound and bound forms correspond to the bright π → π* transition to the first excited state, which, on the other hand, exhibits negligible two-photon activity. On the basis of the results of the quadratic response calculations, we put forward a notion that it is the second excited state that gives the strong signal in the experimental nonlinear spectrum. To explain the differences in the two-photon absorption activity for the two lowest-lying excited states and nonlinear response enhancement upon binding, we employed the generalized few-state model including the ground, first, and second excited states. The analysis of the optical channel suggests that the large two-photon response is due to the coordination-induced increase of the transition moment from the first to the second excited state.
Different Cu-Zn/TiO2 catalysts were synthesized by using the wet impregnation method. The prepared catalysts were used for the conversion of CO2 into methane by photocatalysis. Various characterization techniques were used to observe the surface morphology, crystalline phase, Brunauer-Emmett-Teller (BET) surface area, presence of impregnated Cu and Zn, and functional group. Scanning electron microscope analysis showed spherical morphology, and slight agglomeration of catalyst particles was observed. BET analysis revealed that the surface area of the catalyst was decreased from 10 to 8.5 m(2)/g after impregnation of Cu and Zn over TiO2 support. Synergetic effect of Cu and Zn over TiO2 support (Cu2.6/TiO2, Zn0.5/TiO2 and Cu2.6-Zn0.5/TiO2) and the effects of Cu loading (0, 1.8, 2.1, 2.6 and 2.9 wt%) were also investigated at different feed molar ratios of H2/CO2 (2:1 and 4:1). The Cu2.6-Zn0.5/TiO2 catalyst showed a maximum conversion of 14.3% at a feed molar ratio of 4. The addition of Zn over the catalyst surface increased the conversion of CO2 from 10% to 14.3% which might be due to synergy of Cu and Zn over TiO2 support.
The aim of the study was to estimate the efficiency of copper (Cu), lead (Pb) and zinc (Zn) phytoextraction by 145 Salix taxa cultivated in an area affected by industrial activity. Survivability and biomass of plants were also analyzed. The highest Cu, Pb and Zn content in shoots was respectively: 33.38±2.91 (S. purpurea × viminalis 8), 24.64±1.97 (S. fragilis 1) and 58.99±4.30 (S. eriocephala 7) mg kg(-1) dry weight, respectively. In the case of unwashed leaves, the highest content of these metals was : 135.06±8.14 (S. purpurea 26), 67.98±5.27 (S. purpurea 45) and 142.56±12.69 (S. alba × triandra 2) mg kg(-1) dw, while in washed leaves: 106.02±11.12 (S. purpurea 45), 55.06±5.75 (S. purpurea 45) and 122.87±12.33 (S. alba × triandra 2) mg kg(-1) dw. The differences between the highest and lowest values for Cu, Pb and Zn were respectively: 545, 20500 and 535% in shoots, 2692, 2560 and 7500% in unwashed leaves and 3286, 2221 and 6950% in washed leaves. S. acutifolia was able to effectively accumulate all three metals jointly, producing shoots that were well developed in both length and diameter when compared with the other tested willows, an ability that would suggest its high suitability for practical application.
P2-type sodium nickel manganese oxide-based cathode materials with higher energy densities are prime candidates for applications in rechargeable sodium ion batteries. A systematic study combining in situ high energy X-ray diffraction (HEXRD), ex situ X-ray absorption fine spectroscopy (XAFS), transmission electron microscopy (TEM), and solid-state nuclear magnetic resonance (SS-NMR) techniques was carried out to gain a deep insight into the structural evolution of P2-Na0.66Ni0.33-xZnxMn0.67O2 (x = 0, 0.07) during cycling. In situ HEXRD and ex situ TEM measurements indicate that an irreversible phase transition occurs upon sodium insertion-extraction of Na0.66Ni0.33Mn0.67O2. Zinc doping of this system results in a high structural reversibility. XAFS measurements indicate that both materials are almost completely dependent on the Ni(4+)/Ni(3+)/Ni(2+) redox couple to provide charge/discharge capacity. SS-NMR measurements indicate that both reversible and irreversible migration of transition metal ions into the sodium layer occurs in the material at the fully charged state. The irreversible migration of transition metal ions triggers a structural distortion, leading to the observed capacity and voltage fading. Our results allow a new understanding of the importance of improving the stability of transition metal layers.
Despite the increasing knowledge on the discharge of silver nanoparticles (AgNPs) into the environment and their potential toxicity to microorganisms, the interaction of AgNPs with heavy metals remains poorly understood. This study focused on the effect of AgNPs on heavy metal concentration and form in sediment contaminated with heavy metals
 from the Xiangjiang River. The results showed that the concentration of Cu, Zn, Pb and Cd decreased and then increased with a change in form. The changes in form and concentrations of heavy metals in pore water suggested that Cu and Zn were more likely to be affected compared to Pb and Cd. The concentrations of Hg in sediment pore water in three AgNPs-dosed containers, increased greatly until they reached their peaks at 4.468 ± 0.133, 4.589 ± 0.235, and 5.083 ± 0.084 μg L(-1) in Bare AgNPs, Citrate AgNPs and Tween 80 AgNPs, respectively. The measurements of Hg concentrations in the sediment pore water, combined with SEM and EDX analysis, demonstrated that added AgNPs stabilized in pore water and formed an amalgam with Hg(0), which can affect Hg transportation over long distance.
Modern flexible consumer electronics require efficient energy storage devices with flexible free-standing electrodes. We report a simple and cost-effective route to a graphene-based composite aerogel encapsulating metal oxide nanoparticles for high energy density, free-standing, binder-free flexible pseudocapacitive electrodes. Hydrothermally synthesized Co3O4 nanoparticles are successfully housed inside the microporous graphene aerogel network during the room temperature interfacial gelation at the Zn surface. The resultant three-dimensional (3D) rGO-Co3O4 composite aerogel shows mesoporous quasiparallel layer stack morphology with a high loading of Co3O4, which offers numerous channels for ion transport and a 3D interconnected network for high electrical conductivity. All solid state asymmetric pseudocapacitors employing the composite aerogel electrodes have demonstrated high areal energy density of 35.92 μWh/cm(2) and power density of 17.79 mW/cm(2) accompanied by excellent cycle life.
Semiconductor nanowires that have been extensively studied are typically in a crystalline phase. Much less studied are amorphous semiconductor nanowires due to the difficulty for their synthesis, despite a set of characteristics desirable for photoelectric devices, such as higher surface area, higher surface activity, and higher light harvesting. In this work of combined experiment and computation, taking Zn2GeO4 (ZGO) as an example, we propose a site-specific heteroatom substitution strategy through a solution-phase ions-alternative-deposition route to prepare amorphous/crystalline Si-incorporated ZGO nanowires with tunable band structures. The substitution of Si atoms for the Zn or Ge atoms distorts the bonding network to a different extent, leading to the formation of amorphous Zn1.7Si0.3GeO4 (ZSGO) or crystalline Zn2(GeO4)0.88(SiO4)0.12 (ZGSO) nanowires, respectively, with different bandgaps. The amorphous ZSGO nanowire arrays exhibit significantly enhanced performance in photoelectrochemical water splitting, such as higher and more stable photocurrent, and faster photoresponse and recovery, relative to crystalline ZGSO and ZGO nanowires in this work, as well as ZGO photocatalysts reported previously. The remarkable performance highlights the advantages of the ZSGO amorphous nanowires for photoelectric devices, such as higher light harvesting capability, faster charge separation, lower charge recombination, and higher surface catalytic activity.
Herein, we report the synthesis of a new mixed-linker Zn(II)-based metal-organic framework (MOF), {[Zn2(atz)2(bpydb)](DMA)8}n (1) (atz = deprotonated 3-amino-1,2,4-triazole, bpydb = deprotonated 4,4'-(4,4'-bipyridine-2,6-diyl) dibenzoic acid, DMA = N,N-dimethylacetamide), through symmetry modulation of a triazole ligand. The desymmetrized triazole linkers not only bond to the Zn(II) ions to result in a new helical Zn-triazolate chain building unit but also lead to the formation of a highly porous framework (N2 uptake: 617 cm(3)/g; BET surface area: 2393 m(2)/g) with 1D helical channels. The adsorption properties of desolved 1 were investigated by H2, C2H2, CO2, and CH4 sorption experiments, which showed that 1 exhibited high uptake capacity for H2 at 77 K and C2H2 around room temperature. More importantly, the high C2H2 uptake capacity but low binding energy makes this MOF a promising candidate for effective C2H2 capture from C2H2/CO2 and C2H2/CH4 mixed gases with low regenerative energy cost. In addition, 1 shows potential application for the luminescence sensing of small aromatic molecules picric acid (PA) and p-xylene (PX).
The 3-dimensional hierarchical ZnO flower-like architectures have been synthesized in a Zn(Ac)2·2H2O-Na2SeO3-KBH4-pyridine solvothermal system at 100°C for 24h. The flower-like architecture is assembled from ZnO nanosheets with a thickness of ∼1.5nm, and the flower-like architecture specific surface area is 132m(2)/g. When the ZnO flower-like architecture is used as the adsorbent for acid fuschin (AF), malachite green (MG), basic fuchsin (BF), congo red (CR) and acid red (AR) in water, the adsorption capacities for AF, MG, BF, CR and AR are 7154.9, 2587.0, 1377.9, 85.0 and 38.0mg/g, respectively. Evidently, the as-obtained ZnO flower-like architectures show excellent adsorption performances for triphenylmethane dyes, and the adsorption capacity of 7154.9mg/g for AF is the highest of all adsorbents for dyes. The adsorption mechanism can be attributed to the electrostatic attraction and the formation of ion-association complex between triphenylmethane dyes and ZnO hierarchical flower-like architectures.
The photophysical properties of molecular arrays are strongly dependent on a variety of structural factors: the constituent chromophores, dihedral angle, linkage length, linkage position, the center-to-center distance between chromophores, and the linker itself. Here, we investigated the exciton coupling dynamics of syn- and anti-type β-β directly linked Zn(ii) porphyrin linear arrays. Focusing on the relationship between the origin of the lowest excited electronic state and the linkage position, we evaluated the exciton coupling strength and carried out time-dependent density functional theory (TDDFT) calculations on model compounds as well as femtosecond transient absorption anisotropy (fs-TAA) measurements. Based on our experiments and calculations, we propose that a different origin of the lowest excited state leads to linkage-position-dependent exciton coupling. In short, compared with syn-type porphyrin arrays, anti-type arrays induce distinct and stronger exciton coupling in the lowest excited state.
Fourteen street-dust samples were collected from Hamedan, western Iran. Street-dust samples received different amounts of heavy-metal pollution. The samples were analyzed for total cadmium (Cd), copper (Cu), lead (Pb), nickel (Ni), and zinc (Zn), and binding forms of heavy metal were determined in five fractions. The results showed Cd was the only metal present appreciably, 25.21% and 25.92%, in the exchangeable and carbonates fractions, respectively, and Cu was the only metal predominantly associated, 31.77%, with organic fraction. Zn, 45.84%, was present mainly in the Fe-Mn oxide fraction, and the residual fraction was the most dominant solid phase pool of Ni and Pb, respectively, with 42.56% and 41.31%. The order of apparent mobility and potential metal bioavailability for these contaminated street-dust samples is Cd > Zn > Cu > Pb > Ni. The risk-assessment code results showed very high risk for Cd; medium risk for Cu, Pb, and Zn; and low risk for Ni.
Since the introduction of antivenom administration 120 years ago to treat venomous snake bit, it has been the gold standard for saving life and limb. However, this therapeutic approach is not always effective and not without potential life-threatening side effects. We tested a new paradigm to abrogate the plasmatic anticoagulant effects of fibrinogenolytic snake venom metalloproteinases by modification of fibrinogen with iron and carbon monoxide and by inhibiting these Zn(2+) dependent metalloproteinases directly with carbon monoxide exposure. Assessment of the fibrinogenolytic effects of venoms collected from Puff adder, Gaboon viper and Indian cobra snakes on plasmatic coagulation kinetics was performed with thrombelastography. Pretreatment of plasma with iron and carbon monoxide exposure markedly attenuated the effects of all three venoms, and direct pretreatment of each venom with carbon monoxide also significantly decreased the ability to compromise coagulation. These results demonstrated that the introduction of a transition metal (e.g., modulation of the α-chain of fibrinogen with iron), modulation of transition metal in heme (e.g., carbon monoxide modulation of fibrinogen-bound heme iron), and direct inhibition of transition metal containing venom enzymes (e.g., CO binding to Zn(2+) or displacing Zn(2+) from the catalytic site) significantly decreased fibrinogenolytic activity. This biometal modulation strategy to attenuate the anticoagulant effects of snake venom metalloproteinases could potentially diminish hemostatic injury in envenomed patients until antivenom can be administered.
Cadmium resistant bacterium, isolated from industrial wastewater, was characterized as Salmonella enterica 43C on the basis of biochemical and 16S rRNA ribotyping. It is first ever reported S. enterica 43C bared extreme resistance against heavy metal consortia in order of Pb(2+)>Cd(2+)>As(3+)>Zn(2+)>Cr(6+)>Cu(2+)>Hg(2+). Cd(2+) stress altered growth pattern of the bacterium in time dependent manner. It could remove nearly 57 % Cd(2+) from the medium over a period of 8 days. Kinetic and thermodynamic studies based on various adsorption isotherm models (Langmuir and Freundlich) depicted the Cd(2+) biosorption as spontaneous, feasible and endothermic in nature. Interestingly, the bacterium followed pseudo first order kinetics, making it a good biosorbent for heavy metal ions. The S. enterica 43C Cd(2+) processivity was significantly influenced by temperature,
 pH, initial Cd(2+) concentration, biomass dosage and co-metal ions. FTIR analysis of the bacterium revealed the active participation of amide and carbonyl moieties in Cd(2+) adsorption confirmed by EDX analysis. Electron micrographs beckoned further surface adsorption and increased bacterial size due to intracellular Cd(2+) accumulation. An overwhelming increase in glutathione and other non-protein thiols levels played a significant role in thriving oxidative stress generated by metal cations. Presence of metallothionein clearly depicted the role of such proteins in bacterial metal resistance mechanism. The present study results clearly declare S. enterica 43C a suitable candidate for green chemistry to bioremediate environmental Cd(2+).
Vetiver (Chrysopogon zizanioides) is a fast-growing, high biomass producing plant employed for environmental rehabilitation. The study evaluated the effects of arbuscular mycorrhizal fungi (AMF) in the growth and trace element phytoextracting capabilities of vetiver in a substrate containing coalmine wastes in Southern Brazil. AMF included Acaulospora colombiana, A. morrowiae, A. scrobiculata, Dentiscutata heterogama, Gigaspora margarita and Rhizophagus clarus. From those, A. colombiana, G. margarita and R. clarus promoted higher growth. AMF stimulated average increments in the accumulated P of 82% (roots), 194% (shoots first harvest - 90 days) and 300% (shoots second harvest - 165 days) and affected the phytoextraction of trace elements by vetiver, with larger concentrations in the roots. Plants inoculated with A. colombiana, A. morrowiae and A. scrobiculata, in addition to the control, presented the highest levels of Cu and Zn in the roots. Overall, G. margarita stimulated the highest production of biomass, and, therefore, showed the most significant levels of trace elements in the plants. This work shows the benefits of certain AMF (especially A. morrowiae, G. margarita and R. clarus) for the production of biomass and P uptake by vetiver, demonstrating the potential of those species for the rehabilitation of coalmine-degraded soils.
The composition of heavy metals (and metalloid) in surface soils of iron ore mine-impacted areas has been evaluated of their potential ecological and human health risks. The mining areas included seven selected locations in the vicinity of active and abandoned iron ore-mining sites in Pahang, Malaysia. Heavy metals such as Fe, Mn, Cu, Zn, Co, Pb, Cr, Ni, and Cd and metalloid As were present in the mining soils of the studied area, while Cu was found exceeding the soil guideline value at all sampling locations. However, the assessment of the potential ecological risk index (RI) indicated low ecological risk (RI between 44 and 128) with respect to Cd, Pb, Cu, As, Zn, Co, and Ni in the surface soils. Contributions of potential ecological risk [Formula: see text]by metal elements to the total potential ecological RI were evident for Cd, As, Pb, and Cu. Contribution of Cu appears to be consistently greater in the abandoned mining area compared to active iron ore-mining site. For non-carcinogenic risk, no significant potential health risk was found to both children and adults as the hazard indices (HIs) were all below than 1. The lifetime cancer risk (LCR) indicated that As has greater potential carcinogenic risk compared to other metals that may induce carcinogenic effects such as Pb, Cr, and Cd, while the LCR of As for children fell within tolerable range for regulatory purposes. Irrespective of carcinogenic or non-carcinogenic risk, greater potential health risk was found among children (by an order of magnitude higher for most metals) compared to adults. The hazard quotient (HQ) and cancer risk indicated that the pathways for the risk to occur were found to be in the order of ingestion > dermal > inhalation. Overall, findings showed that some metals and metalloid were still present at comparable concentrations even long after cessation of the iron ore-mining activities.
Heavy metal (arsenic (As), cadmium (Cd), chromium (Cr), copper (Cu), mercury (Hg), lead (Pb), and zinc (Zn)) concentrations from the Daya Bay and adjacent shelf were determined to evaluate their levels and spatial distributions. The measured concentrations ranged from 1.94-13.67mg/kg for As, 0.03-0.13mg/kg for Cd, 10-85mg/kg for Cr, 1-39.5mg/kg for Cu, 0.01-0.09mg/kg for Hg, 11-56mg/kg for Pb, and 13-125mg/kg for Zn. The spatial distributions exhibited a gradual decrease from west to east, and the concentrations of the seven heavy metals met the China Marine Sediment Quality criteria. Both metal enrichment factor (EF) and geo-accumulation index (Igeo) values showed that Cd, Cr, Cu, Hg, and Zn were not at pollution levels in the region. Multivariate analysis (PCA) revealed that lithogenic factors dominated the distribution of most of the metals, whereas As and Hg were clearly influenced by anthropogenic input.
A coiled structure of meso-pentafluorophenyl-substituted [62]tetradecaphyrin 1 was revealed by X-ray structural analysis. Synthetic protocols were devised to form mono- and bis-Zn(II) complexes, 1 Zn and 1 Zn2 , selectively. The former displayed a trigonal-bipyramidal pentacoordinated Zn(II) ion as a rare case and a cyclic voltammogram exhibiting eleven reversible redox waves. The latter showed a Ci-symmetric structure with modest Hückel aromaticity owing to a 62 π-electronic circuit as the largest aromatic molecule to date.
A new strategy for achieving stable Co single atoms (SAs) on nitrogen-doped porous carbon with high metal loading over 4 wt % is reported. The strategy is based on a pyrolysis process of predesigned bimetallic Zn/Co metal-organic frameworks, during which Co can be reduced by carbonization of the organic linker and Zn is selectively evaporated away at high temperatures above 800 °C. The spherical aberration correction electron microscopy and extended X-ray absorption fine structure measurements both confirm the atomic dispersion of Co atoms stabilized by as-generated N-doped porous carbon. Surprisingly, the obtained Co-Nx single sites exhibit superior ORR performance with a half-wave potential (0.881 V) that is more positive than commercial Pt/C (0.811 V) and most reported non-precious metal catalysts. Durability tests revealed that the Co single atoms exhibit outstanding chemical stability during electrocatalysis and thermal stability that resists sintering at 900 °C. Our findings open up a new routine for general and practical synthesis of a variety of materials bearing single atoms, which could facilitate new discoveries at the atomic scale in condensed materials.
Reaction of [Ru(IPr)2(CO)H]BAr(F)4 with ZnEt2 forms the heterobimetallic species [Ru(IPr)2(CO)ZnEt]BAr(F)4 (2), which features an unsupported Ru-Zn bond. 2 reacts with H2 to give [Ru(IPr)2(CO)(η(2)-H2)(H)2ZnEt]BAr(F)4 (3) and [Ru(IPr)2(CO)(H)2ZnEt]BAr(F)4 (4). DFT calculations indicate that H2 activation at 2 proceeds via oxidative cleavage at Ru with concomitant hydride transfer to Zn. 2 can also activate hydridic E-H bonds (E = B, Si), and computed mechanisms for the facile H/H exchange processes observed in 3 and 4 are presented.
Quantum efficiency measurements of state of the art Cu(In,Ga)Se2 (CIGS) thin film solar cells reveal current losses in the near infrared spectral region. These losses can be ascribed to inadequate optical absorption or poor collection of photogenerated charge carriers. Insight on the limiting mechanism is crucial for the development of more efficient devices. The electron beam induced current measurement technique applied on device cross-sections promises an experimental access to depth resolved information about the charge carrier collection probability. Here, this technique is used to show that charge carrier collection in CIGS deposited by multistage co-evaporation at low temperature is efficient over the optically active region and collection losses are minor as compared to the optical ones. Implications on the favorable absorber design are discussed. Furthermore, it is observed that the measurement is strongly affected by cross-section surface recombination and an accurate determination of the collection efficiency is not possible. Therefore it is proposed and shown that the use of an Al2 O3 layer deposited onto the cleaved cross-section significantly improves the accuracy of the measurement by reducing the surface recombination. A model for the passivation mechanism is presented and the passivation concept is extended to other solar cell technologies such as CdTe and Cu2 (Zn,Sn)(S,Se)4 .
Improved understanding of soil fertility factors limiting crop productivity is important to develop appropriate soil and nutrient management recommendations in sub-Saharan Africa. Diagnostic trials were implemented in Kenya, Malawi, Mali, Nigeria and Tanzania, as part of the African Soils Information Service (AfSIS) project, to identify soil fertility constraints to crop production across various cropping systems and soil fertility conditions. In each country, one to three sites of 10 km × 10 km were included with each site having 12-31 field trials. The treatments tested included a control, an NPK treatment, three treatments in which the N, P and K nutrients were omitted one at a time from the NPK treatment, and three treatments in which secondary and micronutrients (Ca, Mg, S, Zn and B) simply referred here as multi-nutrients, manure and lime were added to the NPK. The field trials were conducted for 1-2 seasons; the test crop was maize except in Mali where sorghum was used. Nitrogen was limiting in all sites and generally the most limiting nutrient except in Sidindi (Kenya) and Kontela (Mali) where P was the most limiting. The general pattern in Kiberashi (Tanzania) shows none of the nutrients were limiting. K is mainly limiting in only one site (Mbinga) although incidences
 of K limitation were seen in almost all sites. Addition of multi-nutrients and manure further improved the yields of NPK in most sites. Cluster analyses revealed that maize crop in 11% of fields were highly responsive to nitrogen application, 25% (i.e., 21% poor and 4% fertile) 'non-responsive' to any nutrient or soil amendment, 28% being 'low responsive' and 36% of 'intermediate response'. This study indicates that constraints to crop production vary considerably even within a site, and that addressing limitations in secondary and micronutrients, and increasing soil carbon can improve response to fertilizers. For sustainable crop production intensification in smallholder farming systems in SSA, there is need to develop management strategies to improve efficiency of fertilizer use and of other inputs, recognizing the site-specific nutrient response patterns at various spatial scales.
The WHO and UNICEF recommend therapeutic zinc supplementation (TZS) for the treatment of diarrhea. In zinc-deficient populations, preventive zinc supplementation might provide greater benefits for reducing diarrhea and malaria incidence and increasing growth and plasma zinc (pZn) concentration. If effective, intermittent preventive zinc supplementation (IPZS) would cost less than daily preventive zinc supplementation (DPZS).
We assessed the effects of IPZS, DPZS, and TZS in children on the primary outcomes of diarrhea incidence, malaria incidence, growth, and pZn concentration compared with nonsupplemented control groups.
Rural Burkinabe children (n = 7641; 6-30 mo old) in 36 clusters were randomly assigned to 1 of 5 treatment groups for 16, 32, or 48 wk: 1) IPZS (10 mg Zn/d for 10 d every 16 wk); 2) DPZS (7 mg Zn/d); 3) TZS (20 mg Zn/d for 10 d for diarrhea); 4) morbidity surveillance control (MSC); or 5) nonintervention control (NIC). Supplemented groups remained masked until completion of primary analyses with mixed models.
At baseline, stunting (28.6%) and low pZn concentration (<65 μg/dL; 43.5%) were common. After 48 wk, mean ± SE pZn increased more (P = 0.008) in the DPZS group (3.9 ± 1.3 μg/dL) than in the TZS (-0.5 ± 1.2 μg/dL) and NIC (-1.2 ± 0.9 μg/dL) groups. All supplemented groups had a moderately lower incidence of reported diarrhea (0.48-0.49 compared with 0.57 episodes/100 d, P = 0.001) and reported fever (1.1-1.2 compared with 1.5 episodes/100d, P < 0.001) and gained slightly less length (3.15-3.20 compared with 3.36 cm/16 wk, P < 0.001) than the MSC group, but did not differ from each other. Prevalence of diarrhea and incidences of confirmed fever and malaria were not different across study groups.
The preventive and TZS groups had reduced diarrhea incidence, but it is uncertain whether this resulted from a functional response to zinc or reporting bias. The comparison should be re-examined in populations known to respond to zinc supplementation. This trial was registered at www.clinicaltrials.gov as NCT00944359.
A series of 9-hydroxy-1,3-diazaphenoxazine-2-one derivatives were synthesized as fluorescent receptor molecules for 8-oxo-dGTP, which attach the cyclen-zinc complex at the 3-N position as the binding site for the triphosphate and the (2-aryloxycarbonylamino)ethyl group at the 9-O position as the hydrogen bonding site for 8-oxoguanine. Among these molecules, the receptor molecule 5a-Zn constructed of the ethyl linker at 3-N and the (2-benzyloxycarbonyl amino)ethyl group at 9-O displayed the best recognition ability for 8-oxoguanosine triphosphate (8-oxo-dGTP) in aqueous media. The receptor 5a-Zn was also shown to selectively detect 8-oxo-dGTP in a cell lysate solution.
This study was conducted on Holothuria polii, Holothuria tubulosa, and Holothuria mammata collected from five stations with different depths in the Northern Mediterranean Sea. The body walls and guts of these holothurians were examined in terms of interactions of 10 metals (iron (Fe), copper (Cu), manganese (Mn), zinc (Zn), chromium (Cr), cobalt (Co), vanadium (V), nickel (Ni), cadmium (Cd), and lead (Pb)) and one metalloid (arsenic (As)) using a multivariate analysis, and interspecies differences were determined. The multivariate analysis of variance (MANOVA) revealed significant differences between the species in terms of metal(loid) accumulations. The principal component analysis (PCA) showed a more association between H. tubulosa and H. polii with regard to the accumulation. The cluster analysis (CA) located Pb concentrations of the guts to the farthest place from all elements regardless of the species. A correlation analysis displayed that the element concentrations of the guts were more closely related to each other compared with those of the walls. The most inconsistent element in terms of correlations was the gut Fe contents. Accordingly, while Fe concentrations of H. mammata and H. tubulosa were correlated with all elements (except Pb) in divalent metal transporter 1 (DMT1) (divalent cation transporter 1 (DCT1) or natural resistance-associated macrophage protein 2 (NRAMP2)) belonging to the NRAM protein family, this was not the case in H. polii. Consequently, significant relationships between accumulated metal(loid)s that changed by tissues and sea cucumber species were observed.
Moso bamboo (Phyllostachys pubescens) has great potential as phytoremediation material in soil contaminated by heavy metals. A hydroponics experiment was conducted to determine organic acid compounds of root exudates of lead- (Pb), zinc- (Zn), copper- (Cu), and cadmium (Cd)-tolerant of Moso bamboo. Plants were grown in nutrients solution which included Pb, Zn, Cu, and Cd applied as Pb(NO3)2 (200 μM), ZnSO4·7H2O (100 μM), CuSO4·5H2O (25 μM), and CdCl2 (10 μM), respectively. Oxalic acid and malic acid were detected in all treatments. Lactic acid was observed in Cu, Cd, and control treatments. The oxalic was the main organic acid exudated by Moso bamboo. In the sand culture experiment, the Moso bamboo significantly activated carbonate heavy metals under activation of roots. The concentration of water-soluble metals (except Pb) in sand were significantly increased as compared with control. Organic acids (1 mM mixed) were used due to its effect on the soil adsorption of heavy metals. After adding mixed organic acids, the Cu and Zn sorption capacity in soils was decreased markedly compared with enhanced Pb and Cd sorption capacity in soils. The sorption was analyzed using Langmuir and Freundlich equations with R (2) values that ranged from 0.956 to 0.999 and 0.919 to 0.997, respectively.
Zinc (Zn(2+)) is an essential cofactor in mammalian cells and neurons. Zn(2+) is released from synaptic vesicles of certain nerve terminals in the hippocampus during neuronal activity. Zn(2+) has been shown to inhibit synaptic GABAA receptors and alter the hippocampal network excitability. However, the ability of Zn(2+) to block extrasynaptic receptors remains unclear. Endogenous neurosteroids, such as allopregnanolone (AP), regulate neuronal excitability by allosteric activation of synaptic and extrasynaptic GABAA receptors. Neurosteroids activate extrasynaptic δGABAA receptor-mediated tonic inhibition in dentate gyrus granule cells (DGGCs), thereby contributing to the regulation of downstream circuit excitability. Here we report a novel inhibitory role of Zn(2+) at neurosteroid-sensitive, extrasynaptic δGABAA receptors by electrophysiological recordings in DGGCs from adult mice. Zn(2+) displayed a concentration-dependent, reversible noncompetitive blockade of AP-sensitive tonic current in DGGCs (IC50, 16 μm). Tonic current was fully blocked by Zn(2+), akin to the GABAA receptor antagonist gabazine. Zn(2+) inhibition of tonic current was lacking in DGGCs from δ-subunit knock-out mice. Moreover, AP-activated synaptic receptor-mediated phasic currents were not affected by Zn(2+) Finally, intrahippocampal infusion of Zn(2+) elicited rapid epileptiform activity and significantly blocked the antiseizure activity of AP in the kindling model of epilepsy. Thus, Zn(2+) inhibition of neurosteroid-sensitive, extrasynaptic GABAA receptors in the hippocampus has direct implications in many brain hyperexcitability conditions, such as seizures, epileptogenesis, and epilepsy. Zn(2+) interactions may aid to further understand the physiology of extrasynaptic GABAA receptors.
Zn(2+) is most abundant in the synaptic vesicles of hippocampal mossy fibers. Zn(2+) release occurs with neuronal excitation, including seizure events, and exerts powerful excitability effects in the hippocampus circuits. Zn(2+) inhibits synaptic GABAA receptors, but its interaction is less well appreciated at the extrasynaptic receptors, which respond sensitively to endogenous neurosteroids. Here, we describe selective functional blockade by Zn(2+) of neurosteroid-sensitive, extrasynaptic GABAA receptors in the mouse hippocampus dentate gyrus, a key region associated with epilepsy and memory disorders. By demonstrating that extracellular Zn(2+) prevents neurosteroid augmentation of tonic current and protection against limbic seizures, our findings provide novel implications of this potential antagonistic interaction in a variety of neurological conditions.
To determine the variability of concentrations of Zn in feed, when used as a supplement to prevent facial eczema, and to determine the variability in concentrations of Zn in serum between cows and herds that are being supplemented with ZnO in feed, using in-shed feeders or on a feed pad.
Sixteen commercial dairy farms in the Waikato region of New Zealand were enrolled, that were supplementing cows with ZnO in the feed using either an automatic in-shed feeder (ASF) or a feed pad (FP) using a feed-out or mixer wagon. On each farm 10 cows were selected by the farmer, that were assumed to be representative of the age and liveweight of the herd. Four hours after supplement feeding,
 each cow was weighed and a blood sample collected for measurement of concentrations of Zn in serum. Three samples of feed were collected from each farm for Zn analysis, from the beginning, middle and end of the feed being distributed. Levene's test for homoscedasticity was used to analyse whether there were differences in variation of individual concentrations of Zn in serum, and in the feed, between the two feeding systems. Multivariable linear regression was used to examine associations between age, feeding method or liveweight and concentrations of Zn in serum, after accounting for the variability between farms.
Of the 163 cows sampled, concentrations of Zn in serum were between 20-35 µmol/L in 75/163 (46 (95% CI=38-54)%) cows; were <20 µmol/L in 71/163 (44 (95% CI=36-52)%) cows, and >35 µmol/L in 17/163 (10 (95% CI=6-16)%) cows. The variation in concentrations of Zn in serum in individual cows differed between farms (p<0.001), and the variability was greater for cows fed using a FP than ASF (p<0.001). There was no difference in the variation of concentrations of Zn in feed between the two feeding methods (p=0.54), but concentrations of Zn in serum were associated with the amount of Zn offered in feed (p=0.008).
There was significant variability between farms in the concentrations of Zn in the serum of cows being supplemented with ZnO in feed. Only 46% of cows sampled had concentrations of Zn between 20-35 µmol/L. Effective management of facial eczema should include monitoring Zn in the feed and in serum to ensure cows are receiving the correct dose they require.
Excessive rates of nitrogen (N) fertilizers may result in elevated concentrations of nitrate (NO3(-) ) in plants. Considering that many programs of biofortification with trace elements are being performed, it has become important to study how the application of these elements affects plant physiology and, particularly, N utilization in leaf crops. The main objective of the present study was to determine whether the NO3(-) accumulation and the nitrogen use efficiency was affected by the application of different doses of Zn in Lactuca sativa plants.
Zn doses in the range 80-100 µmol L(-1) produced an increase in Zn concentration provoking a decrease of NO3(-) concentration and increase of the nitrate reductase, glutamine synthetase and aspartate aminotransferase activities, as well as the photorespiration processes. As result, we observed an increase in reduced N, total N concentration and N utilization efficiency. Consequently, at a dose of 80 µmol L(-1) of Zn, the amino acid concentration increased significantly.
Adequate Zn fertilization is an important critical player in lettuce, especially at a dose of 80 µmol L(-1) of Zn, because it could result in an increase in the Zn concentration, a reduction of NO3(-) levels and an increase the concentration of essential amino acids, with all of them having beneficial properties for the human diet. © 2016 Society of Chemical Industry.
Isovaleryl coenzyme A (IV-CoA) performs a crucial role during development and fruiting-body formation in myxobacteria, which is reflected in the existence of a de novo biosynthetic pathway that is highly upregulated when leucine, the common precursor of IV-CoA, is limited. The final step in de novo IV-CoA biosynthesis is catalyzed by AibC, a medium-chain dehydrogenase/reductase. Here, the crystal structure of AibC from Myxococcus xanthus refined to 2.55 Å resolution is presented. The protein adopts two different conformations in the crystal lattice, which is a consequence of partial interaction with the purification tag. Based on this structure, it is suggested that AibC most probably uses a Zn(2+)-supported catalytic mechanism in which NADPH is preferred over NADH. Taken together, this study reveals structural details of the alternative IV-CoA-producing pathway in myxobacteria, which may serve as a base for further biotechnological research and biofuel production.
Gold nanoparticles (GNPs) are being investigated actively for various applications in cancer diagnosis and therapy. As an effort to improve the imaging of GNPs in vivo, the authors developed bimetallic hybrid Zn@Au NPs with zinc cores and gold shells, aiming to render them in vivo visibility through positron emission tomography (PET) after the proton activation of the zinc core as well as capability to induce radiosensitization through the secondary electrons produced from the gold shell when irradiated by various radiation sources.
Nearly spherical zinc NPs (∼5-nm diameter) were synthesized and then coated with a ∼4.25-nm gold layer to make Zn@Au NPs (∼13.5-nm total diameter). 28.6 mg of these Zn@Au NPs was deposited (∼100 μm thick) on a thin cellulose target and placed in an aluminum target holder and subsequently irradiated with 14.15-MeV protons from a GE PETtrace cyclotron with 5-μA current for 5 min. After irradiation, the cellulose matrix with the NPs was placed in a dose calibrator to assess the induced radioactivity. The same procedure was repeated with 8-MeV protons. Gamma ray spectroscopy using an high-purity germanium detector was conducted on a very small fraction (<1 mg) of the irradiated NPs for each proton energy. In addition to experimental measurements, Monte Carlo simulations were also performed with radioactive Zn@Au NPs and solid GNPs of the same size irradiated with 160-MeV protons and 250-kVp x-rays.
The authors measured 168 μCi of activity 32 min after the end of bombardment for the 14.15-MeV proton energy sample using the (66)Ga setting on a dose calibrator; activity decreased to 2 μCi over a 24-h period. For the 8-MeV proton energy sample, PET imaging was additionally performed for 5 min after a 12-h delay. A 12-h gamma ray spectrum showed strong peaks at 511 keV (2.05 × 10(6) counts) with several other peaks of smaller magnitude for each proton energy sample. PET imaging showed strong PET signals from mostly decaying (66)Ga. The Monte Carlo results showed that radioactive Zn@Au NPs and solid GNPs provided similar characteristics in terms of their secondary electron spectra when irradiated.
The Zn@Au NPs developed in this investigation have the potential to be used as PET-imageable radiosensitizers for radiotherapy applications as well as PET tracers for molecular imaging applications.
The drug olsalazine (H4olz) was employed as a ligand to synthesize a new series of mesoporous metal-organic frameworks that are expanded analogues of the well-known M2(dobdc) materials (dobdc(4-) = 2,5-dioxido-1,4-benzenedicarboxylate; M-MOF-74). The M2(olz) frameworks (M = Mg, Fe, Co, Ni, and Zn) exhibit high surface areas with large hexagonal pore apertures that are approximately 27 Å in diameter. Variable temperature H2 adsorption isotherms revealed strong adsorption at the open metal sites, and in situ infrared spectroscopy experiments on Mg2(olz) and Ni2(olz) were used to determine site-specific H2 binding enthalpies. In addition to its capabilities for gas sorption, the highly biocompatible Mg2(olz) framework was also evaluated as a platform for the delivery of olsalazine and other encapsulated therapeutics. The Mg2(olz) material (86 wt % olsalazine) was shown to release the therapeutic linker through dissolution of the framework under simulated physiological conditions. Furthermore, Mg2(olz) was used to encapsulate phenethylamine (PEA), a model drug for a broad class of bioactive compounds. Under simulated physiological conditions, Mg2(olz)(PEA)2 disassembled to release PEA from the pores and olsalazine from the framework itself, demonstrating that multiple therapeutic components can be delivered together at different rates. The low toxicity, high surface areas, and coordinatively unsaturated metal sites make these M2(olz) materials promising for a range of potential applications, including drug delivery in the treatment of gastrointestinal diseases.
A series of heterobimetallic lantern complexes with the central unit {PtM(SAc)4(NCS)} have been prepared and thoroughly characterized. The {Na(15C5)}[PtM(SAc)4(NCS)] series, 1 (Co), 2 (Ni), 3 (Zn), are discrete compounds in the solid state, whereas the {Na(12C4)2)}[PtM(SAc)4(NCS)] series, 4 (Co), 5 (Ni), 6 (Zn), and 7 (Mn), are ion-separated species. Compound 7 is the first {PtMn} lantern of any bridging ligand (carboxylate, amide, etc.). Monomeric 1-7 have M(2+), necessitating counter cations that have been prepared as {(15C5)Na}(+) and {(12C4)2Na}(+) variants, none of which form extended structures. In contrast, neutral [PtCr(tba)4(NCS)]∞ 8 forms a coordination polymer of {PtCr}(+) units linked by (NCS)(-) in a zigzag chain. All eight compounds have been thoroughly characterized and analyzed in comparison to a previously reported family of compounds. Crystal structures are presented for compounds 1-6 and 8, and solution magnetic susceptibility measurements are presented for compounds 1, 2, 4, 5, and 7. Further structural analysis of dimerized {PtM} units reinforces the empirical observation that greater charge density along the Pt-M vector leads to more Pt···Pt interactions in the solid state. Four structural classes, one new, of {MPt}···{PtM} units are presented. Solid state magnetic characterization of 8 reveals a ferromagnetic interaction in the {PtCr(NCS)} chain between the Cr centers of J/kB = 1.7(4) K.
The primary objective of the current study was the investigation of the influence of zinc asparaginate supplementation for 7 and 14 days on toxic metal and metalloid content in rat organs and tissues. Rats obtained zinc asparaginate in doses of 5 and 15 mg/kg/day for 7 and 14 days. At the end of the experiment rat tissues and organs (liver, kidney, heart, m. gastrocnemius, serum, and hair) were collected for subsequent analysis. Estimation of Zn, Al, As, Li, Ni, Sn, Sr content in the harvested organs was performed using inductively coupled plasma mass
 spectrometry at NexION 300D. The obtained data showed that intragastric administration of zinc significantly increased liver, kidney and serum zinc concentrations. Seven-day zinc treatment significantly affected the toxic trace element content in the animals' organs. Zinc supplementation significantly decreased particularly liver aluminium, nickel, and tin content, whereas lead tended to increase. Zinc-induced changes in kidney metal content were characterized by elevated lithium and decreased nickel concentration. Zinc-induced alteration of myocardical toxic element content was multidirectional. Muscle aluminium and lead concentration were reduced in response to zinc supplementation. At the same time, serum and hair toxic element concentrations remained relatively stable after 7-day zinc treatment. Zinc asparaginate treatment of 14 days significantly depressed liver and elevated kidney lithium content, whereas a significant zinc-associated decrease was detected in kidney strontium content. Zinc supplementation for 14 days resulted also in multidirectional changes in the content of heart toxic elements. At the same time, significant zinc-associated decrease in muscle lithium and nickel levels was observed. Fourteen-day zinc treatment resulted in significantly increased serum arsenic and tin concentrations, whereas hair trace element content remained relatively stable. Generally, the obtained data indicate a significant redistribution of toxic metals in the animal organism under zinc supplementation.
The chemotherapy for tuberculosis (TB) is complicated by its long-term treatment, its frequent drug dosing, and the adverse effects of anti-TB drugs. In this study, we have developed two nanocomposites (A and B) by intercalating the anti-TB drug isoniazid (INH) into Zn/Al-layered double hydroxides. The average size of the nanocomposites was found to bê164 nm. The efficacy of the Zn/Al-layered double hydroxides intercalated INH against Mycobacterium tuberculosis was increased by approximately three times more than free INH. The nanocomposites were also found to be active against Gram-positive and -negative bacteria. Compared to the free INH, the nanodelivery formulation was determined to be three times more biocompatible with human normal lung fibroblast MRC-5 cells and 3T3 fibroblast cells at a very high concentration of 50 µg/mL for up to 72 hours. The in vitro release of INH from the Zn/Al-layered double hydroxides was found to be sustained in human body-simulated buffer solutions of pH 4.8 and 7.4. This research is a step forward in making the TB chemotherapy patient friendly.
Waterborne zinc (Zn) is known to cause toxicity to freshwater animals primarily by disrupting calcium (Ca) homeostasis during acute exposure, but its effects in marine and estuarine animals are not well characterized. The present study investigated the effects of salinity on short-term Zn accumulation and sub-lethal toxicity in the euryhaline green shore crab, Carcinus maenas. The kinetic and pharmacological properties of short-term branchial Zn uptake were also examined. Green crabs (n=10) were exposed to control (no added Zn) and 50μM (3.25mgL(-1)) of waterborne Zn (∼25% of 96h LC50 in 100 seawater) for 96h at 3 different salinity regimes (100%, 60% and 20% seawater). Exposure to waterborne Zn increased tissue-specific Zn accumulation across different salinities. However, the maximum accumulation occurred in 20% seawater and no difference was recorded between 60% and 100% seawater. Gills appeared to be the primary site of Zn accumulation, since the accumulation was significantly higher in the gills relative to the hepatopancreas, haemolymph and muscle. Waterborne Zn exposure induced a slight increase in haemolymph osmolality and chloride levels irrespective of salinity. In contrast, Zn exposure elicited marked increases in both haemolymph and gill Ca levels, and these changes were more pronounced in 20% seawater relative to that in 60% or 100% seawater. An in vitro gill perfusion technique was used to examine the characteristics of short-term (1-4h) branchial Zn uptake over an exposure concentration range of 3-12μM (200-800μgL(-1)). The rate of short-term branchial Zn uptake did not change significantly after 2h, and no difference was recorded in the rate of uptake between the anterior (respiratory) and posterior (ion transporting) gills. The in vitro branchial Zn uptake occurred in a concentration-dependent manner across different salinities. However, the rate of uptake was consistently higher in 20% seawater relative to 60% or 100% seawater - similar to the trend observed with tissue Zn accumulation during in vivo exposure. The short-term branchial Zn uptake was found to be inhibited by lanthanum (a blocker of voltage-independent Ca channels), suggesting that branchial Zn uptake occurs via the Ca transporting pathways, at least in part. Overall, our findings indicate that acute exposure to waterborne Zn leads to the disruption of Zn and Ca homeostasis in green crab, and these effects are exacerbated at the lower salinity.
Unexpected etching of nanocrystals, nanorods, and their heterostructures by one of the most commonly used metal precursors, metal oleates, is reported. Zn oleate is shown to etch CdS nanorods anisotropically, where the length decreases without a significant change in the diameter. Sodium oleate enhances the etch rate, whereas oleic acid alone does not cause etching, indicating the importance of the countercation on the rate of oleate induced etching. Subsequent addition of Se precursors to the partially etched nanorods in Zn oleate solution can lead to epitaxial growth of CdSe particles rather than the expected ZnSe growth, despite an excess amount of Zn precursors being present. The composition of this epitaxial growth can be varied from CdSe to ZnSe, depending on the amount of excess oleic acid or the reaction temperature. Similar tuning of composition can be observed when starting with collinear CdSe/CdS/CdSe rod/rod/rod heterostructures and spherical CdS (or CdSe/CdS core/shell) nanocrystals. Conversion of collinear rod/rod/rod structures to barbells and interesting rod growth from nearly spherical particles among other structures can also result due to the initial etching effect of metal oleates. These observations have important implications on our understanding of nanocrystal heterostructure synthesis and open up new routes to varying the composition and morphology of these materials.
The contents of heavy metals cadmium (Cd), cobalt (Co), chromium (Cr), copper (Cu), manganese (Mn), nickel (Ni), lead (Pb), and zinc (Zn) present in water (wastewater and wetland), soils, and food crops collected from the vicinity of Almeda Textile Factory were quantified using Flame Atomic Absorption Spectrometer (FAAS) in order to assess the environmental impact of the textile factory. The contents of heavy metals determined in the wastewater were found below the recommended limit set by WHO and United States Environmental Protection Agency (US EPA) except for Cr, which was found slightly higher than WHO permissible limit. Besides, the contents of the heavy metals determined in soils were below the permissible level of FAO/WHO and Canada maximum allowable limits. Moreover, only the concentrations of Cd and Pb were found above the permissible level set by FAO/WHO in the crop plants studied. Generally, the mean concentrations of heavy metals in the plants were in the decreasing order of: Mn > Zn > Cu > Pb > Ni > Co > Cr > Cd. Nevertheless, higher bioconcentration factor (BCF) was found for Cd (0.108-1.156) followed by Zn (0.081-0.499). In conclusion, comparison of heavy metal concentrations with the permissible limits in all collected sample types i.e. water, soil, and crop plants did not show significant pollution from the factory.
To examine overall micronutrient intake periconceptionally and throughout pregnancy in a population-based cohort of Australian women.
In a prospective cohort study, micronutrient dosages were extracted from self-reported maternal supplement use, recorded pre-conception, and for each trimester of pregnancy. A food frequency scale (DQESv2) captured usual maternal diet for gestational weeks 14-26. The influence of sociodemographic and lifestyle factors associated with supplement use was examined using logistic regression, and changes in micronutrient intakes prior to and throughout pregnancy were assessed using repeated-measures ANOVA analyses.
Metropolitan hospital sites in Melbourne, Australia.
Women with a viable singleton pregnancy were recruited at less than 19 weeks' gestation (n 2146).
Compared with non-users, women using supplements during pregnancy were more likely to have planned their pregnancy, be >25 years old, primiparous, Caucasian, non-smokers, have a tertiary education and be consuming a folate-rich diet. Intakes of folate, Fe and Zn were significantly lower in the periconceptional period, compared with other periods (P<0·001). Intakes below Recommended Daily Intake levels were common both periconceptionally and throughout pregnancy, with 19-46 % of women not meeting the Recommended Daily Intake for folate, 68-82 % for Fe and 17-36 % for Zn. Conversely, 15-19 % of women consumed beyond the recommended Upper Limit for folate and 11-24 % for Fe.
The study highlights the need for improved public health education on nutritional needs during pregnancy, especially among women with lower educational achievements and income.
Dynamic flow-through extraction is attracting a great deal of attention for real-time monitoring of the bioaccessible fraction of metal species in environmental solid substrates compared to its batchwise manual counterparts. There is however a lack of studies on the harmonization and validation of in vitro dynamic methods for physiologically based extraction tests against in vivo
 bioavailability methods. This work is aimed at evaluating the reliability of dynamic flow-through extraction methods for estimation of oral bioaccessible fractions of Cu, Zn, Pb, Ni, Cr, and As under worst-case extraction conditions in the gastric compartment based on the BGS102 guidance soil using the in vivo validated Unified BARGE (UBM) test, commonly performed under batchwise mode. Good overall agreement between batch and dynamic UBM results was obtained for the tested elements, except for Pb, as a consequence of the slow leaching kinetics identified with the dynamic method and the contribution of readsorption phenomena in the course of the gastric digestion. Metal-soil phase associations and their relationship with gastric bioaccessible fractions were elucidated using the so-called Chemometric Identification of Substrates and Element Distributions method based on sequential extraction with a variety of chemicals of increasing acidity as applied to both static and dynamic bioaccessibility data.
The mineral body exploited in Salafossa (Eastern Dolomites) was one of the largest lead/zinc-containing mineral deposits in Europe. Both metals were mainly present as sulphides (sphalerite, ZnS and galena, PbS). Mining activity started around 1550, but it was only around 1960 that the richest veins of the minerals were discovered. The mine closed in 1985, and concentrations of several trace metals, such as thallium (Tl), iron (Fe), manganese (Mn), lead (Pb) and zinc (Zn), were detected in the soils and plant samples (Biscutella laevigata L.) that were collected from eighteen sites selected outside the mine. B. laevigata is a pseudometallophyta species, and it often grows near mining areas where the soil's metal concentrations are significantly higher than those of soil with a natural geochemical background. The total metal concentrations in the plant tissue (roots and leaves of Biscutella laevigata) and in the soil samples - both bulk-soil and the B. laevigata root system (rhizo-soil) - were determined through Inductively Coupled Plasma Optical Emission Spectrometry (ICP-OES). The metal extractability and leachability of the soil samples were estimated using soil extractions with DTPA (Diethylenetriaminepentaacetic acid). In addition, metal mobility caused by rainwater runoff was estimated by using a leaching test with a dilute solution of H2SO4 and HNO3. The results showed that metals were present in a chemical form available for uptake by the plants' roots. In fact, high concentrations of the metals were also found in the plant tissue (roots and leaves) of B. laevigata, and these concentrations were higher than those whose soils present natural geochemical background levels in the corresponding rhizo-soil. Thus, B. laevigata has shown a marked ability to bioaccumulate trace metals, especially Tl and, to a lesser extent, Zn, Pb, Fe and Mn, and it can influence metal mobility in the rhizo-soil. To assess the uptake and translocation processes of the trace metals, resulting in their bioaccumulation, two different indices were calculated: the enrichment factor in roots (EFr), as the ratio between the metal concentration in belowground biomass and in the respective rhizo-soil, and the translocation factor (TF), as the ratio between the metal concentration in the leaves and the corresponding roots. For both indices, values > 1 denoted enrichment of the metal in the roots or its translocation to the upper tissues. The results showed that EFr and TF were considerably high only for Tl, reaching a maximum value of 60 for EFr and 11.6 for TF. Conversely, the other investigated metals did not show significant bioaccumulation (EFr < 1), and they showed TF > 1 only at a few sites.
Six nanosilver-labelled products and five silver ion (Ag(+))-labelled products were investigated to measure the migration of Ag from food-contact plastics, including nanosilver into various food simulants. The products were obtained in Japanese markets in 2012. Zinc (Zn), another major antimicrobial agent, and three harmful metals, cadmium (Cd), lead (Pb) and arsenic (As), were also examined. Ag and Zn were detected in all six nanosilver products at concentrations of 21-200 and 8.4-140 mg kg(-1), respectively. These metals were also detected in all five Ag(+) products at the same level as nanosilver products. Cd, Pb and As were not detected in any sample. Migrations of Ag and Zn were highest in 4% acetic acid, but also observed in water and 20% ethanol. Big differences were not observed in the migration ratio between nanosilver products and Ag(+) products. The ultrafiltration experiments suggested that the Ag that migrated from nanosilver products into 4% acetic acid was in its ionic form, while that into water and 20% ethanol was in its nanoparticle form.
Zn(O,S) thin films were deposited using a ZnS target under Ar/O2 gases by radio-frequency magnetron sputtering. As the O2 concentration increased, the deposition rates of the Zn(O,S) films decreased due to increase of O-. The crystalline structure of Zn(O,S) was maintained at up to 0.6% O2, while the films became unstable at the condition exceeding 0.8% O2. This was attributed to incomplete nucleation and film growth on the substrate at the room temperature. Additionally, optical emission spectroscopy analysis indicated that an increased O- intensity at high O2 concentration was responsible for the slow deposition rate and increased oxygen concentration of the films. X-ray diffraction and scanning electron microscopy revealed the formation of a Zn(O,S) crystal structure with partial substitution of O for S and uniform and dense grains of the films. X-ray photoelectron spectroscopy showed that the Zn(O,S) films have a uniform composition of each element and consisted of a mixed crystal structure of Zn(O,S) with Zn-O bonding. Overall, the results of this study confirmed that Zn(O,S) films deposited by radio-frequency sputtering using Ar/O2 gas at room temperature can be applied to Cu(In,Ga)Se2 solar cells as a buffer layer.
Al2O3 was prepared by a sol-gel method for use as a support. Pt/Sn/Zn-K/Al2O3 catalyst was then prepared by a sequential impregnation method, and it was applied to the direct dehydrogenation of n-butane to n-butenes and 1,3-butadiene. Physicochemical properties of Pt/Sn/Zn-K/Al2O3 catalyst were examined by X-ray diffraction (XRD), nitrogen adsorption-desorption isotherm, inductively coupled plasma atomic emission spectroscopy (ICP-AES), temperature-programmed reduction (TPR), CO chemisorption, and temperature-programmed oxidation (TPO) measurements. In order to improve the catalyst stability, the effect of hydrogen in the feed on the catalytic performance in the direct dehydrogenation of n-butane was studied. The catalyst stability and reusability in the direct dehydrogenation of n-butane was also investigated. Experimental results revealed that the addition of hydrogen in the feed decreased conversion of n-butane and yield for total dehydrogenation products but improved the stability of the catalyst. The catalytic activity and stability of regenerated Pt/Sn/Zn-K/Al2O3 catalyst in the presence of hydrogen slightly decreased compared to those of fresh Pt/Sn/Zn-K/Al2O3 catalyst due to the slight sintering of platinum particles.
Various morphologies of zinc oxide (ZnO) nanostructures on single layer graphene were synthesized by electrodeposition method. The current density was utilized to control the morphology of the ZnO. The Scanning Electron Microscope (SEM) was used to examine the surface morphology of the samples. SEM analysis shows morphology changes to nanorod, flower, and flakes with increase in the current density from 0.1, 0.2, and 0.3 mA/cm(-1) respectively. The XRD, XPS, and Raman spectroscopy were adopted to characterize the ZnO nanostructure and to understand the formation of various morphologies. The Raman result clearly shows extra modes due to for flakes structure caused by c-axis orientation along the substrate direction. Further, XPS data also supports formation of ZnO without any other intermediate compound such as Zn(OH)2. The formation of various morphologies was correlated to the formation different ratio of Zn2+ and OH- ions and the change in growth direction due to various current densities.
Association of adenocarcinoma and tuberculosis (TB) of the sigmoid colon is a rare clinical condition even in an endemic country as Romania, with challenging diagnosis and treatment. Case report. We present the case of a 57-year-old female patient who was admitted on emergency basis for a diagnosis of obstructive sigmoid adenocarcinoma. The patient was operated on and it an obstructive sigmoid tumor with serosal invasion, adherent (invading) to the body of uterus and left adnexa and urinary bladder serosa, no liver or peritoneal metastases. A sigmoidectomy was performed "en bloc" with subtotal hysterectomy, left adnexectomy and extramucosal cistectomy. The histopathological exam showed a moderately differentiated, ulcerated adenocarcinoma, widely infiltrating the colon wall invading the myometrium. Ziehl Neelsen (ZN) stain identified the presence of metachromatic bacillary structures in the colonic wall, lymph nodes and adnexal areas. Postoperative course was uneventful and the patient was discharged 10 days postoperatively in good clinical condition. After one year when the patient completed the full course of anti-tubercular drugs, a thorough work-up was performed. Colonoscopy, CT of the thorax, abdomen, pelvis showed no signs of recurrence while tumoral marker CEA (1.62 ng/ml - n<3.4) and QFT (Quantiferon-TB Gold) test were within normal range. Discussion and conclusion. Although digestive tuberculosis is included in differential diagnosis for those patients presenting abdominal pain or obstructive digestive symptoms in endemic regions, in this case the absence of TB infection
 criteria and positive endoscopic biopsy for colonic adenocarcinoma did not allow a complete pre- or perioperative diagnosis.
Microstructural evolution of cold-rolled Cu-5%Zn alloy during in situ heating inside field-emission scanning electron microscope was utilized to obtain user-independent parameters in order to trace the progress of static recovery and recrystallization. Electron back-scattered diffraction (EBSD)-based orientation imaging microscopy was used to obtain micrographs at various stages of in situ heating. It is shown that unlike the pre-existing methods, additional EBSD-based parameter can be used to trace the progress of recovery and recrystallization, which is not dependent on user input and hence less prone to error. True strain of 0.3 was imposed during cold rolling of alloy sample. Rolled sample was subjected to in situ heating from room temperature to 500°C (∼0.58 Tm) with soaking time of 10 min, at each of the intermediate temperatures viz. 100, 200, 300, 400 and 450°C. After reaching 500°C, the sample was kept at this temperature for a maximum duration of around 15 h. The sample showed clear signs of recovery for temperature up to 450°C, and at 500°C, recrystallization started to take place. Recrystallization kinetics was moderate, and full recrystallization was achieved in approximately 120 min. We found that EBSD parameter, namely, band contrast intensity can be used as an extra handle to map out the progress of recrystallization occurring in the sample. By contrast, mean angular deviation can be used to understand the evolution of recovery in samples. The parameters mentioned in the current study, unlike other pre-existing methods, can also be used for mapping local microstructural transformations due to recovery and recrystallization. We discuss the benefits and limitations in using these additional handles in understanding the changes taking place in the material during in situ heating.
The environmental stimulants and inhibitors of conjugal plasmid transfer in microbial communities are poorly understood. Specifically, it is not known whether exposure to stressors may cause a community to alter its plasmid uptake ability. We assessed whether metals (Cu, Cd, Ni, Zn) and one metalloid (As), at concentrations causing partial growth inhibition, modulate community permissiveness (that is, uptake ability) against a broad-host-range IncP-type plasmid (pKJK5). Cells were extracted from an agricultural soil as recipient community and a cultivation-minimal filter mating assay was conducted with an exogenous E. coli donor strain. The donor hosted a gfp-tagged pKJK5 derivative from which conjugation events could be microscopically quantified and transconjugants isolated and phylogenetically described at high resolution via FACS and 16S rRNA amplicon sequencing. Metal stress consistently decreased plasmid transfer frequencies to the community, while the transconjugal pool richness remained unaffected with OTUs belonging to 12 bacterial phyla. The taxonomic composition of the transconjugal pools was distinct from their respective recipient communities and clustered dependent on the stress type and dose. However, for certain OTUs, stress increased or decreased permissiveness by more than 1000-fold and this response was typically correlated across different metals and doses. The response to some stresses was, in addition, phylogenetically conserved. This is the first demonstration that community permissiveness is sensitive to metal(loid) stress in a manner that is both partially consistent across stressors and phylogenetically conserved.The ISME Journal advance online publication, 2 August 2016; doi:10.1038/ismej.2016.98.
Cyclic tetrapyrroles are the active core of compounds with crucial roles in living systems, such as hemoglobin and chlorophyll, and in technology as photocatalysts and light absorbers for solar energy conversion. Zinc-tetraphenylporphyrin (Zn-TPP) is a prototypical cyclic tetrapyrrole that has been intensely studied in past decades. Because of its importance for photochemical processes the optical properties are of particular interest, and, accordingly, numerous studies have focused on light absorption and excited-state dynamics of Zn-TPP. Relaxation after photoexcitation in the Soret band involves internal conversion that is preceded by an ultrafast process. This relaxation process has been observed by several groups. Hitherto, it has not been established if it involves a higher lying "dark" state or vibrational relaxation in the excited S2 state. Here we combine high time resolution electronic and vibrational spectroscopy to show that this process constitutes vibrational relaxation in the anharmonic S2 potential.
Though possessing low absorption throughout a wide infrared (IR) spectral regime, owing to a high refractive index, zinc selenide substrates are generally covered by antireflection coatings (ARCs) for practical optical uses. However, achieving a high transmission of ZnSe substrates in the near-IR (NIR) region is still challenging. Herein, for the first time, colloidal ZnSe hollow nanospheres (HNSs) smaller than 100 nm were prepared and adopted to assemble ARCs for ZnSe substrates. The voiding kinetics of the HNSs was found to agree well with the nanoscale Kirkendall effect, and the self-diffusion of the Zn ion in the core was faster than its diffusion through the ZnSe shell. With single-index ARCs, the transmission of ZnSe substrates was remarkably enhanced in the NIR region, with up to an 18% increase at 840 nm. Besides, the ZnSe HNS-based ARCs showed superior mechanical stability even under violent ultrasonication in organic solutions. We expect that ZnSe HNSs will make it possible to construct graded-index ARCs to realize omnidirectional and broadband antireflection in IR, through further tuning of HNSs' void fraction.
We combine nonequivalent substitution and charge-induced emitter-migration approaches and design an efficient method to optionally tune the spectral and duration properties of NaCa2GeO4F:Mn(2+) phosphor. A series of representative codopants have been investigated in detail and classified into two categories: RA (RA = Li(+), Al(3+), N(3-), Ga(3+), B(3+)) and RB (RB = Mg(2+), F(-), Bi(3+), Zn(2+), Cd(2+), Sc(3+), Tm(3+)). Results reveal that the nonequivalent substitution of RA codopants would induce foreign negative defects and stabilize Mn(2+) emitters at octahedral Na/Ca sites for red emission. In constrast, the RB codopants would generate foreign positive defects and make Mn(2+) emitters migrate to tetrahedral Ge(4+) sites for green-yellow emission. At the same time, the RA codopants are in favor of the generation of intrinsic positive traps with shallow trap depth and thus efficiently improve the duration properties of phosphors. On the basis of the experimental results, a possible nonequivalent substitution and charge-induced emitter-migration model has been proposed, and we can optionally tune the spectral (568 ↔ 627 nm) and the duration (minutes to more than 6 h) properties according to this model.
The number of children affected by Autism Spectrum Disorders (ASD) is dramatically increasing as well as the studies aimed at understanding the risk factors associated with the development of ASD. Since the etiology of ASD is partly genetic and partly environmental, factors (i.e., heavy metals, pesticides) as well as lifestyle seem to have a key role in the development of the disease. ASD and Control (CTR) children, aged 5-12 years, were compared. Gas chromatography coupled with trap mass detector was used to measure the level of 3-PBA, the main pyrethroid metabolite in urine in a group of ASD patients, while optical emission spectrometry analysis was employed to estimate the level of metals and microelements in hair in a different group of ASD children. The presence of 3-PBA in urine seems to be independent of age in ASD children, while a positive correlation between 3-PBA and age was observed in the control group of the same age range. Urine concentration of 3-BPA in ASD children had higher values than in the control group, which were marginally significant (p = 0.054). Mg results were significantly decreased in ASD with respect to controls, while V, S, Zn, and Ca/Mg were marginally increased, without reaching statistical significance. Results of Principal Component (PC) analysis of metals and microelements in hair were not associated with either age or health status. In conclusion, 3-PBA in urine and Mg in hair were changed in ASD children relative to control ones.
The Long-Term Sludge Experiments (LTSE) began in 1994 as part of continuing research into the effects of sludge-borne heavy metals on soil fertility. The long-term effects of Zn, Cu, and Cd on soil microbial biomass carbon (Cmic) were monitored for 8 years (1997-2005) in sludge amended soils at nine UK field sites. To assess the statutory limits set by the UK Sludge (Use in Agriculture) Regulations the experimental data has been reviewed using the statistical methods of meta-analysis. Previous LTSE studies have focused predominantly on statistical significance rather than effect size, whereas meta-analysis focuses on the magnitude and direction of an effect, i.e. the practical significance, rather than its statistical significance. The results presented here show that significant decreases in Cmic have occurred in soils where the total concentrations of Zn and Cu fall below the current UK statutory limits. For soils receiving sewage sludge predominantly contaminated with Zn, decreases of approximately 7-11% were observed at concentrations below the UK statutory limit. The effect of Zn appeared to increase over time, with increasingly greater decreases in Cmic observed over a period of 8 years. This may be due to an interactive effect between Zn and confounding Cu contamination which has augmented
 the bioavailability of these metals over time. Similar decreases (7-12%) in Cmic were observed in soils receiving sewage sludge predominantly contaminated with Cu; however, Cmic appeared to show signs of recovery after a period of 6 years. Application of sewage sludge predominantly contaminated with Cd appeared to have no effect on Cmic at concentrations below the current UK statutory limit.
Concentrations and isotopic compositions of Pb and Sr in the surface sediment samples from Jiulong River, Southeast China, were determined to trace the sources of Pb and Sr. The average concentrations of Pb and Sr were 110.9 mg/kg and 69.2 mg/kg, approximately 3.2 and 2.0 times of the local soil background values, respectively. Average 62.9% of total Pb and 36.8% of total Sr in the investigated surface sediment samples were extracted by 0.5 mol/L HNO3. Pb and Sr presented slight contamination, and Pb showed low ecological risk for most of surface sediment samples in Jiulong River according to geo-accumulation index (Igeo) and potential ecological risk index (RI). The results of Pb isotopic compositions in sediment samples and potential sources showed that the Pb accumulated in the surface sediments of Jiulong River was mainly from parent material, coal combustion and Fujian Pb-Zn deposit, with the contribution rates of 34.4%, 34.0%, and 31.6%, respectively. The results of Pb isotopic compositions in 0.5 mol/L HNO3-extraction suggested that dilute HNO3-extraction was more sensitive in identifying anthropogenic Pb sources than total digestion. The results of Sr isotopic compositions showed that Sr accumulated in the surface sediments of Jiulong River estuary mainly derived from external source and natural source (parent material) with the contribution rates of 48.1% and 51.9%, respectively.
Lead (Pb) is a pleiotropic toxicant. The potential role of oxidative stress injury that is associated with Pb poisoning suggests that antioxidants may enhance the efficacy of treatment designed to mitigate Pb-induced toxicity. The aim of this study is to investigate the comparative ameliorative potential of lipoic acid (LA) alone or in combination with calcium (Ca) and zinc (Zn). Pb acetate (50 mg/kg, intraperitoneally) was administered for 3 d. After 24 h of the last toxicant dose, LA (100 mg/kg, orally [po]) alone or in conjuction with Ca (50 mg/kg, po) and Zn (10 mg/kg, po) was administered for 3 d. Significant alterations in the concentration of urea, uric acid, triglycerides, cholesterol, aspartate amino transferase, alanine amino transferase, lipid peroxidation, and reduced glutathione as well as alterations in enzyme activity of δ-aminolevulinic acid (ALA) dehydratase were observed following acute Pb exposure. These findings were also supported by elevated mean DNA damage and Pb body burden in blood and soft tissues compared to controls (p ≤ 0.05). Three d posttreatment with LA along with Zn and Ca could significantly restore the biochemical parameters and Pb body burden to near-normal status through antioxidant activity or by preventing bioaccumulation of Pb within the blood and tissues of experimental rats.
Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease. Mutations in Cu/Zn superoxide dismutase (SOD1) are responsible for approximately 20 % of the familial ALS cases. ALS-causing SOD1 mutants display a gain-of-toxicity phenotype, but the nature of this toxicity is still not fully understood. The Ras GTPase-activating protein-binding protein G3BP1 plays a critical role in stress granule dynamics. Alterations in the dynamics of stress granules have been reported in several other forms of ALS unrelated to SOD1. To our surprise, the mutant G93A SOD1 transgenic mice exhibited pathological cytoplasmic inclusions that co-localized with G3BP1-positive granules in spinal cord motor neurons. The co-localization was also observed in fibroblast cells derived from familial ALS patient carrying SOD1 mutation L144F. Mutant SOD1, unlike wild-type SOD1, interacted with G3BP1 in an RNA-independent manner. Moreover, the interaction is specific for G3BP1 since mutant SOD1 showed little interaction with four other RNA-binding proteins implicated in ALS. The RNA-binding RRM domain of G3BP1 and two particular phenylalanine residues (F380 and F382) are critical for this interaction. Mutant SOD1 delayed the formation of G3BP1- and TIA1-positive stress granules in response to hyperosmolar shock and arsenite treatment in N2A cells. In summary, the aberrant mutant SOD1-G3BP1 interaction affects stress granule dynamics, suggesting a potential link between pathogenic SOD1 mutations and RNA metabolism alterations in ALS.
Despite a long history of use in phytomanagement strategies, the impacts of poplar trees on the structure and function of microbial communities that live in the soil remain largely unknown. The current study combined fungal and bacterial community analyses from different management regimes using Illumina-based sequencing with soil analysis. The poplar phytomanagement regimes led to a significant increase in soil fertility and a decreased bioavailability of Zn and Cd, in concert with changes in the microbial communities. The most notable changes in the relative abundance of taxa and operational taxonomic units unsurprisingly indicated that root and soil constitute distinct ecological microbial habitats, as exemplified by the dominance of Laccaria in root samples. The poplar cultivar was also an important driver, explaining 12% and 6% of the variance in the fungal and bacterial data sets, respectively. The overall dominance of saprophytic fungi, e.g. Penicillium canescens, might be related to the decomposition activities needed at the experimental site. Our data further highlighted that the mycorrhizal colonization of poplar cultivars varies greatly between the species and genotypes, which is exemplified by the dominance of Scleroderma under Vesten samples. Further interactions between fungal and bacterial functional groups stressed the potential of high-throughput sequencing technologies in uncovering the microbial ecology of disturbed environments.
Neisseria gonorrhoeae successfully overcomes host strategies to limit essential nutrients, termed nutritional immunity, by production of TonB-dependent transporters (TdTs)-outer membrane proteins that facilitate nutrient transport in an energy-dependent manner. Four gonococcal TdTs facilitate utilization of iron or iron chelates from host-derived proteins, including transferrin (TbpA), lactoferrin (LbpA), and hemoglobin (HpuB), in addition to xenosiderophores from other bacteria (FetA). The roles of the remaining four uncharacterized TdTs (TdfF, TdfG, TdfH, and TdfJ) remain elusive. Regulatory data demonstrating that production of gonococcal TdfH and TdfJ are unresponsive to or upregulated under iron-replete conditions led us to evaluate the role of these TdTs in the acquisition of nutrients other than iron. In this study, we found that production of gonococcal TdfH is both Zn and Zur repressed. We also found that TdfH confers resistance to calprotectin, an immune effector protein highly produced in neutrophils that has antimicrobial activity due to its ability to sequester Zn and Mn. We found that TdfH directly binds calprotectin, which enables gonococcal Zn accumulation in a TdfH-dependent manner and enhances bacterial survival after exposure to neutrophil extracellular traps (NETs). These studies highlight Zn sequestration by calprotectin as a key functional arm of NET-mediated killing of gonococci. We demonstrate for the first time that N. gonorrhoeae exploits this host strategy in a novel defense mechanism, in which TdfH production hijacks and directly utilizes the host protein calprotectin as a zinc source and thereby evades nutritional immunity.
The study aimed to investigate, for the first time, the association between diet quality (food variety and dietary diversity), intakes of anti-inflammatory nutrients and food groups, and subclinical inflammation as assessed by categories of high-sensitivity C-reactive protein (hs-CRP).
Cross-sectional study.
Resource-poor, rural children in the Eastern Cape, South Africa.
A sample size formula determined a representative sample of 235. Five schools were purposively selected and cluster sampling used to select 240 participants. Measurements included 24 h recall and dietary diversity questionnaires, anthropometric and biochemical measurements.
The sample consisted of 50·4 % (n 118) girls and 49·6 % (n 116) boys. No obesity was found, but overweight was prevalent in 4·2 % of the children. The hs-CRP concentration (median (25th, 75th percentile)) of the low, medium and high risk inflammatory categories was 0·6 (0·4, 0·7), 1·6 (1·2, 2·2) and 4·2 (3·4, 6·4) mg/l, respectively. Body composition parameters did not differ between hs-CRP groups. Most of the anti-inflammatory nutrient intakes (dietary Fe, Zn, Mg, vitamin C, folate, linolenic acid, linoleic acid, MUFA and PUFA) differed significantly between the hs-CRP groups, with intakes increasing from low to high hs-CRP groups, with similar results for linolenic acid (P=0·022) intake. No significant relationships between hs-CRP and any of the food groups could be established, but significant relationships were established between hs-CRP levels and the high density of living arrangements and unhygienic ablution facilities.
Although no link could be established between overnutrition and hs-CRP levels, an association was found between hs-CRP and dietary quality, as well as socio-economic status.
APOBEC3G (A3G) is a potent restriction factor of HIV-1. The N-terminal domain of A3G (A3G-CD1) is responsible for oligomerization and nucleic acid binding, both of which are essential for anti-HIV activity. As a countermeasure, HIV-1 viral infectivity factor (Vif) binds A3G-CD1 to mediate A3G degradation.
 The structural basis for the functions of A3G-CD1 remains elusive. Here, we report the crystal structures of a primate A3G-CD1 (rA3G-CD1) alone and in complex with single-stranded DNA (ssDNA). rA3G-CD1 shares a conserved core structure with the previously determined catalytic APOBECs, but displays unique features for surface charge, dimerization and nucleic acid binding. Its co-crystal structure with ssDNA reveals how the conformations of loops and residues surrounding the Zn-coordinated centre (Zn-centre) change upon DNA binding. The dimerization interface of rA3G-CD1 is important for oligomerization, nucleic acid binding and Vif-mediated degradation. These findings elucidate the molecular basis of antiviral mechanism and HIV-Vif targeting of A3G.
Heavy metals influence the population size, diversity, and metabolic activity of bacteria. In turn, bacteria can develop heavy metal resistance mechanisms, and this can be used in bioremediation of contaminated areas. The purpose of the present study was to understand how heavy metals concentration influence on diversity and distribution of heavy metal-resistant bacteria in Araça Bay, São Sebastião, on the São Paulo coast of Brazil. The hypothesis is that activities that contribute for heavy metal disposal and the increase of metals concentrations in environment can influence in density, diversity, and distribution of heavy metal-resistant bacteria. Only 12 % of the isolated bacteria were sensitive to all of the metals tested. We observed that the highest percentage of resistant strains were in areas closest to the São Sebastião channel, where port activity occurs and have bigger heavy metals concentrations. Bacterial isolated were most resistant to Cr, followed by Zn, Cd, and Cu. Few strains resisted to Cd levels greater than 200 mg L(-1). In respect to Cr, 36 % of the strains were able to grow in the presence of as much as 3200 mg L(-1). Few strains were able to grow at concentrations of Zn and Cu as high as 1600 mg L(-1), and none grew at the highest concentration of 3200 mg L(-1). Bacillus sp. was most frequently isolated and may be the dominant genus in heavy metal-polluted areas. Staphylococcus sp., Planococcus maritimus, and Vibrio aginolyticus were also isolated, suggesting their potential in bioremediation of contaminated sites.
Decreasing the recombination of photogenerated carriers is a major challenge for efficiently converting solar energy into chemical energy by photocatalysis. Here, we have demonstrated that growth of a polar GaN:ZnO solid solution single crystal along its polarization axis is beneficial to efficient separation of photogenerated carriers, owing to the periodic potential barriers and wells generated from the periodically positive and negative atom arrangements in crystal structure. Local charge imbalance caused by replacing Ga(3+) with Zn(2+) leads to a polarization vector in the {0 0 0 1} planes of GaN:ZnO solid solution, thus forming a 1 D electron transport path along [2 1‾  1‾  0] in the {0 0 0 1} planes of GaN:ZnO solid solution to decrease recombination. Shorting the hole-transport distance by synthesizing porous nanoplates can further decrease recombination under the polarization field and improve the performance of polar photocatalyst in photoreduction of CO2 into CH4 .
Total concentrations of Ni, Cr, Cu, Pb and Zn were determined in surface sediments from 30 stations in Guanabara Bay in 1999 and 2008. An approach using various environmental indices was used to assess contamination status of metals. This approach allowed the comparison with different coastal areas. Background Enrichment Index, Contamination index and Ecological Risk index (Pollution Load Index; Sediment Quality Guideline Quotient and Ecological Risk Index) were calculated for the metals. Results revealed a great load of organic matter and significant increases in Cu and Pb levels between 1999 and 2008. The concentrations of Cr and Zn were of great concern, surpassing the values of Probable Effect Level reference values. In spite of the differences of each index, results effectively revealed the striking contamination in Guanabara Bay concerning trace metals, and also suggested potential risk to local biota. The contamination of the northwest area was notably higher than the rest of the bay. In comparison with some other coastal bays around the world, Guanabara Bay stood out as a remarkably contaminated environment.
A series of dinuclear metal(ii)-acetato complexes: [Ni2(μ-L(Cl)O)(μ2-OAc)2](PF6)·3H2O (1), [Ni2(μ-L(Cl)O)(μ2-OAc)2](ClO4)·CH3COCH3 (2), [Cu2(μ-L(Cl)O)(μ2-OAc)(ClO4)](ClO4) (3), [Cu2(μ-L(Cl)O)(OAc)2](PF6)·H2O (4), [Zn2(μ-L(Cl)O)(μ2-OAc)2](PF6) (5) and [Mn2(L(Cl)-O)(μ2-OAc)2](ClO4)·H2O (6), where L(Cl)O(-) = 2,6-bis[bis(2-pyridylmethyl)aminomethyl]-4-chlorophenolate, were synthesized. The complexes were structurally characterized by spectroscopic techniques and single crystal X-ray crystallography. Six-coordinate geometries with doubly bridged acetato ligands were found in Ni(ii), Zn(ii) and Mn(ii) complexes 1, 2, 5 and 6, whereas with Cu(ii) complexes a five-coordinate species was obtained with 4, and mixed five- and six-coordinate geometries with a doubly bridged dimetal core were observed in 3. The magnetic properties of complexes 1-4 and 6 were studied at variable temperatures and revealed weak to very weak antiferromagnetic interactions in 1, 2, 4 and 6 (J = -0.55 to -9.4 cm(-1)) and ferromagnetic coupling in 3 (J = 15.4 cm(-1)). These results are consistent with DFT calculations performed at the B3LYP/def2-TZVP(-f) level of theory. Under physiological conditions, the interaction of the dinculear complexes 1-5 with supercoiled plasmid ds-DNA did not show any pronounced nuclease activity, but Ni(ii) complexes 1 and 2 revealed a strong ability to unwind the supercoiled conformation of ds-DNA. The mechanistic studies performed on the interaction of the Ni(ii) complexes with DNA demonstrated the important impact of the nickel(ii) ion in the unwinding process. In combination with the DNA study, the phosphatase activity of complexes 1, 3, and 5 was examined by the phosphodiester hydrolysis of bis(2,4-dinitrophenol)phosphate (BDNPP) in the pH range of 5.5-10.5 at 25 °C. The Michaelis-Menten kinetics performed at pH 7 and 10.7 showed that catalytic efficiencies kcat/KM (kcat = catalytic rate constant, KM = substrate binding constant) decrease in the order: Ni(ii), 1 > Zn(ii), 5 > Cu(ii), 3. A similar trend was also observed with the turnover numbers at pH = 7. The results are discussed in relation to the coordination geometry and nature of the metal center as well as the steric environment imposed by the compartmental phenoxido ligand.
To determine the elements in Bryonia alba L. roots, collected from the Crimean Peninsula region in Ukraine.
Dry ashing was used as a flexible method and all elements were determined using atomic absorption spectrometry (AAS) equipped with flame and graphite furnace.
The average concentrations of the determined elements, expressed as mg/100 g dry weight of the sample, were as follow: 13.000 for Fe, 78.000 for Si, 88.000 for P, 7.800 for Al, 0.130 for Mn, 105.000 for Mg, 0.030 for Pb, 0.052 for Ni, 0.030 for Mo, 210.000 for Ca, 0.130 for Cu, 5.200 for Zn, 13.000 for Na, 1170.000 for K, 0.780 for Sr, 0.030 for Co, 0.010 for Cd, 0.010 for As, and 0.010 for Hg. Toxic elements such as Cd and Pb were also found but at very low concentration. Among the analyzed elements, K was the most abundant followed by Ca, Mg, P, Si, Fe, Na, and Zn, whereas Hg, As, Cd, Co, Mo, and Pb were found in low concentration.
The results suggest that the roots of Bryonia alba L. plant has potential medicinal property through their high element contents present. Moreover, it showed that the AAS method is a simple, fast, and reliable for the determination of elements in plant materials. The obtained results of the current study provide justification for the usage of such fruit in daily diet for nutrition and for medicinal usage in the treatment of various diseases.
Bio- and hydrometallurgical experimental setups at 2-l reactor scale for the processing of fly ash from municipal waste incinerators were explored. We aimed to compare chemical H2SO4 leaching and bioleaching; the latter involved the use of H2SO4 and a mixed culture of acidophilic bacteria. The leaching yields of several elements, including some of those considered as critical (Mg, Co, Ce, Cr, Ga, Nb, Nd, Sb and Sm), are provided. At the end of the experiments, both leaching methods resulted in comparable yields for Mg and Zn (>90%), Al and Mn (>85%), Cr (∼65%), Ga (∼60%), and Ce (∼50%). Chemical leaching showed the best yields for Cu (95%), Fe (91%), and Ni (93%), whereas bioleaching was effective for Nd (76%), Pb (59%), and Co (55%). The two leaching methods generated solids of different quality with respect to the original material as we removed and significantly reduced the metals amounts, and enriched solutions where metals can be recovered for example as mixed salts for further treatment. Compared to chemical leaching the bioleaching halved the use of H2SO4, i.e., a part of agent costs, as a likely consequence of bio-produced acid and improved metal solubility.
The risk from leaching of heavy metals is a major factor hindering land application of sewage sludge compost (SSC). Understanding the change in heavy metal leaching resulting from soil biological processes provides important information for assessing long-term behavior of heavy metals in the compost amended soil. In this paper, 180days aerobic incubation and 240days anaerobic incubation were conducted to investigate the effects of the aerobic and anaerobic biological processes on heavy metal leaching from soil amended with SSC, combined with chemical speciation modeling. Results showed that leaching concentrations of heavy metals at natural
 pH were similar before and after biological process. However, the major processes controlling heavy metals were influenced by the decrease of DOC with organic matter mineralization during biological processes. Mineralization of organic matter lowered the contribution of DOC-complexation to Ni and Zn leaching. Besides, the reducing condition produced by biological processes, particularly by the anaerobic biological process, resulted in the loss of sorption sites for As on Fe hydroxide, which increased the potential risk of As release at alkaline pH.
Placental-derived mesenchymal stem cells (pMSCs) are promising candidates for regenerative medicine because they possess high proliferative capacity and multi-differentiation potential. Human pMSCs are residing in an environment with low oxygen tension in the body. Heme oxygenase-1 (HO-1) is known to participate in the regulation of MSC differentiation. The present study aimed to investigate the impact of hypoxia on the osteogenic differentiation of human pMSCs, and to elucidate the role of HO-1 in the osteogenic differentiation of hypoxic pMSCs. Human pMSCs were cultured under normoxia (21% O2) or hypoxia (5% O2) for 3 days. We found that hypoxia maintained the morphology and immunophenotype of human pMSCs. The expression of stemness markers Oct4, Nanog, and Sox2 was increased under hypoxia. After a 5-day hypoxic culture, the proliferation ability of pMSCs was increased, which might be correlated with the increased expression of stem cell factor. During osteogenic induction, hypoxia increased the expression of osteogenic genes including osteopontin, osteocalcin, and alkaline phosphatase (ALP). Moreover, hypoxia increased the mineralization and ALP levels of human pMSCs as evidenced by Alizarin Red staining and ALP staining. Upregulation of HO-1 by cobalt-protoporphyrin treatment increased the osteogenic differentiation of pMSCs under hypoxia, while inhibition of HO-1 by Zn-protoporphyrin reduced the osteogenic differentiation of hypoxic pMSCs. Taken together, our data suggest that hypoxia can promote the osteogenic differentiation of human pMSCs. Upregulation of HO-1 can further increase the osteogenesis of human pMSCs under hypoxia. Our findings will highlight the therapeutic potential of MSCs in the tissue engineering of bones.
We have previously reported that testosterone (Tes) is able to interact with magnesium chloride dissolved in methanol. In this study, we have applied (1)H and (13)C NMR spectroscopies to a series of Tes solutions containing Mg(2+) at various concentrations. High-resolution (13)C NMR spectra of Tes/Mg(2+) revealed well-resolved (13)C signals, and the intensities of those arising from C3, C5, C16, and C17 decreased linearly with increasing Mg(2+) concentration. The magnitude of the chelation affinity could be deduced from the slopes of the (13)C intensity variations; typically, the greater the slope the higher the chelation affinity. The results revealed Tes/Mg(2+) chelation to be mediated by the oxygen atom attached to C3 in ring A, and the hydroxyl group attached to C17 in ring D. With regard to the chelation specificity, we showed that Tes chelates Mg(2+), but not Ca(2+) or Zn(2+). We also explored the cation-induced signal shift effects of Tes in the presence of Mg(2+), Ca(2+), or Zn(2+). We demonstrate that high-resolution (13)C NMR spectroscopy provides a better probe than (1)H NMR for the detection of cation chelation and cation-induced signal shift effects for steroid compounds such as Tes.
Metal complexes of the type [Co(phen)2(4-NO2pcyd)2].CH3OH, 1, [Zn(phen)2(4-NO2pcyd)2].CH3OH, 2, [Cd(phen)2(4-NO2pcyd)2], and 3, (phen = 1,10-phenanthroline, 4-NO2pcyd = 4-nitro phenylcyanamide) have been studied. The synthesis, characterization, and the biological activities of complexes 1-3 have been investigated. The geometries of complexes 1-3 were confirmed by single-crystal X-ray crystallography. The interactions of complexes 1-3 with human serum albumin (HSA) were studied using fluorescence and circular dichroism spectroscopy. The thermodynamic studies have showed the reaction for the binding of complexes 1-3 with HSA is hydrophobic (ΔH0 ˂ 0 and ΔS0 > 0). The in vitro cytotoxic potential of complexes 1-3 and their complexes with HSA were examined. The complexes 1-3 with HSA enhance about 3-fold cytotoxicity in cancer cells lines.
A 5-m long sediment core (VC2B), retrieved in the Southwestern Iberian Atlantic shelf, at 96m water depth, was used to assess major changes in climate and human activities during the last 9.7kyrs. Analytical measurements included sedimentological (mean grain size, and the contents of sand, silt and clay), geochemical (major, minor, trace and rare earth elements; REEs) and chronological ((210)Pb and (14)C) parameters. Two episodes of increment of fine-grained particles, occurring at 3050BCE and 1350CE, suggest the retreat of the coast line to the present level and the beginning of a wetter phase associated with the "Little Ice Age". The North American Shale Composite (NASC)-normalized REE-pattern detected in the shelf is similar to that found in the Guadiana estuarine sediments. The possibility of this estuary as a contributor to the sediment load deposited in the adjacent coastal zone was indicated. Trace elements were significantly correlated with Al until 1850CE, pointing that grain-size rules its distribution in sediments. The depth variation of As, Cu and Pb enrichment factors relative to background values shows two periods of intense human activity that can be mainly linked to mining: (i) across the Roman Period, marked by low enrichments; and (ii) starting on the second half of the 19th century until nowadays with significantly increased enrichments, especially of Pb and Cu. In addition to As, Cu and Pb, this period is also marked by high enrichments of Hg and Zn. Despite the decrease/closure of sulphide massive deposits mining exploitation (e.g., São Domingos, Las Herrerias) during the second half of the 20th century, results showed ongoing input of Pb, Cu, As, Hg and Zn to coastal sediments. Thus, the legacy of contamination by these elements, mainly from leaching of slags and tailings, and remobilization/reworking of contaminated estuarine sediments, is still recorded in marine sediments.
A novel atmospheric pressure glow discharge generated in contact with a flowing liquid anode (FLA-APGD) was developed as the efficient excitation source for the optical emission spectrometry (OES) detection. Differences in the appearance and the electrical characteristic of the FLA-APGD and a conventional system operated with a flowing liquid cathode (FLC-APGD) were studied in detail and discussed. Under the optimal operating conditions for the FLA-APGD, the emission from the analytes (Ag, Cd, Hg, Pb, Tl, and Zn) was from 20 to 120 times higher as compared to the FLC-APGD. Limits of detections (LODs) established with a novel FLA-APGD system were on average 20 times better than those obtained for the FLC-APGD. A further improvement of the LODs was achieved by reducing the background shift interferences and, as a result, the LODs for Ag, Cd, Hg, Pb, Tl, and Zn were 0.004, 0.040, 0.70, 1.7, 0.035, and 0.45 μg L(-1), respectively. The precision of the FLA-APGD-OES method was evaluated to be within 2-5% (as the relative standard deviation of the repeated measurements). The method found its application in the determination of the content of Ag, Cd, Hg, Pb, Tl, and Zn in a certified reference material (CRM) of Lobster hepatopancreas (TORT-2), four brass samples as well as mineral water and tea leaves samples spiked with the analytes. In the case of brass samples, a reference method, i.e., inductively coupled plasma optical emission spectrometry (ICP-OES) was used. A good agreement between the results obtained with FLA-APGD-OES and the certified values for the CRM TORT-2 as well as the reference values obtained with ICP-OES for the brass samples was revealed, indicating the good accuracy of the proposed method. The recoveries obtained for the spiked samples of mineral water and tea leaves were within the range of 97.5-102%.
Based on first-principles calculations, the electronic structures and magnetism are investigated in 3d transition metal (TM)-embedded porous two-dimensional (2D) C2N monolayers. Numerical results indicate that except Mn and Co atoms, other TM atoms can be embedded stably in the 2D C2N monolayer. Moreover, the magnetic moments of the TM-embedded C2N monolayer depend highly on the atomic number of the TM atoms. The Sc, Ti, V, Cr, Mn, Fe, Co and Ni atom-embedded C2N monolayers possess a ferromagnetic ground state, while embedding Cu can induce paramagnetic characteristics in the 2D C2N monolayer. Meanwhile, the Zn-embedded C2N monolayer exhibits a nonmagnetic ground state. These results indicate that the magnetism of 2D C2N monolayers can be tuned via embedding TM atoms.
Apolipoprotein B mRNA-editing enzyme, catalytic polypeptide-like 3G (APOBEC3G, A3G), is a human anti-virus restriction protein which works deaminase-dependently and -independently. A3G is known to be ubiquitinated by HIV-1 viral infectivity factor (Vif) protein, leading to proteasomal degradation. A3G contains two zinc ions at the N-terminal domain and the C-terminal domain. Four lysine residues, K(297), K(301), K(303), and K(334), are known to be required for Vif-mediated A3G ubiquitination and degradation. Previously, we reported compound SN-1, a zinc chelator that increases steady-state expression level of A3G in the presence of Vif. In this study, we prepared Biotin-SN-1, a biotinylated derivative of SN-1, to study the SN-1-A3G interaction. A pull-down assay revealed that Biotin-SN-1 bound A3G. A zinc-abstraction experiment indicated that SN-1 binds to the zinc site of A3G. We carried out a SN-1-A3G docking study using molecular operating environment.
 The calculations revealed that SN-1 binds to the C-terminal domain through Zn(2+), H(216), P(247), C(288), and Y(315). Notably, SN-1-binding covers the H(257), E(259), C(288), and C(291) residues that participate in zinc-mediated deamination, and the ubiquitination regions of A3G. The binding of SN-1 presumably perturbs the secondary structure between C(288) and Y(315), leading to less efficient ubiquitination.
The aim of this study was to investigate the overall root/shoot allocation of metal contaminants, the amount of metal removal by absorption and adsorption within or on the external root surfaces, the dose-response of water hyacinth metal uptake, and phytotoxicity. This was examined in a single-metal tub trial, using arsenic (As), gold (Au), copper (Cu), iron (Fe), mercury (Hg), manganese (Mn), uranium (U), and zinc (Zn). Iron and Mn were also used in low-, medium-, and high-concentration treatments to test their dose effect on water hyacinth's metal uptake. Water hyacinth was generally tolerant to metallotoxicity, except for Cu and Hg. Over 80 % of the total amount of metals removed was accumulated in the roots, of which 30-52 % was adsorbed onto the root surfaces. Furthermore, 73-98 % of the total metal assimilation by water hyacinth was located in the roots. The bioconcentration factor (BCF) of Cu, Hg, Au, and Zn exceeded the recommended index of 1000, which is used in selection of phytoremediating plants, but those of U, As, and Mn did not. Nevertheless, the BCF for Mn increased with the increase of Mn concentration in water. This suggests that the use of BCF index alone, without the consideration of plant biomass and metal concentration in water, is inadequate to determine the potential of plants for phytoremediation accurately. Thus, this study confirms that water hyacinth holds potential for a broad spectrum of phytoremediation roles. However, knowing whether these metals are adsorbed on or assimilated within the plant tissues as well as knowing their allocation between roots and shoots will inform decisions how to re-treat biomass for metal recovery, or the mode of biomass reduction for safe disposal after phytoremediation.
This study examines the use of freshwater bream (Abramis brama) as a sentinel organism for genotoxicity assessment of the Danube River using the comet assay. Sampling of bream was performed during February, April, August, and November in 2014 to assess seasonal variation of DNA damage level as a response to genotoxicity in annual cycle. Additionally, concentrations of fecal coliforms and enterococci were analyzed and they indicated a critical to strong level of fecal pollution on investigated locality during annual cycle. Comet assay was performed on blood, liver, and gill cells of bream. DNA damage level was expressed using tail intensity (TI %), Olive tail moment (OTM), and tail length (TL pix). According to TI and OTM, all three tissues had the highest level of DNA damage in August. The lowest level of DNA damage in liver was measured during February, in blood during November, and in gills during April. According to TL, gills had the highest level of DNA damage in February, and liver cells had the lowest level of damage during April. Multiple correspondence analysis (MCA) showed that DNA damage in blood cells is under the strong influence of variations in NO2, NO3(-), NH4(+) levels and also the variation in temperature and oxygen levels. DNA damage in liver cells is highly associated with the variations of Mn, Fe, Cu, Zn, and PO4(3-) levels. DNA damage in gill cells is strongly affected by the variations of As, Cd, Pb, Cr, and COD (Mn) levels. Freshwater bream is shown to be a potentially good indicator organism in genotoxic potential field studies.
An isolate of Cupriavidus (strain MTS-7) was identified from a long-term PAHs and heavy metals mixed contaminated soil with the potential to biodegrade both LMW and HMW PAHs with added unique traits of acid and alkali tolerance, heavy metal tolerance, self-nutrient assimilation by N fixation and P solubilization. This strain completely degraded the model 3 (150 mg L(-1) Phe), 4 (150 mg L(-1) Pyr) and 5 (50 mg L(-1) BaP) ring PAHs in 4, 20 and 30 days, respectively. It could mineralize 90-100% of PAHs (200 mg L(-1) of Phe and Pyr) within 15 days across pH ranging from 5 to 8 and even in the presence of toxic metal contaminations. During biodegradation, the minimum inhibitory concentrations were 5 (Cu(2+)) and 3 (Cd(2+), Pb(2+), Zn(2+)) mg L(-1) of the potentially bioavailable metal ions and over 17 mg L(-1) metal levels was lethal for the microbe. Further, it could fix 217-274 μg mL(-1) of N and solubilize 79-135 μg mL(-1) of P while PAHs degradation. MTS-7 as a superior candidate could be thus used in the enhanced bioaugmentation and/or phytoremediation of long-term mixed contaminated sites.
The aim of the present study is to deepen the current understanding of the microbial communities at two poplar phytomanagement sites to reveal the environmental factors that drive the abundance, diversity and composition of microbial communities. A soil analysis revealed that the two soils displayed contrasting physico-chemical characteristics, with significant lower pH and higher Cd, Zn and Mn CaCl2-extractable fractions at Leforest site, compared with Pierrelaye site. The fungal and bacterial community profiles in the poplar roots and soils were assessed through Illumina MiSeq sequencing. Diversity indices and β-diversity measures illustrated that the root microbial communities were well separated from the soil microbial communities at both sites. A detailed study of the fungal composition showed that Ascomycota dominated the overall fungal communities on poplar soil, the root samples at Pierrelaye, and the unplanted soil at the experimental sites. Conversely, Basidiomycota accounted for a much higher percentage of the fungal community in poplar root samples from the Leforest site. The root bacterial communities were dominated by Alphaproteobacteria and Actinobacteria, and the soil samples were dominated by Alphaproteobacteria and Acidobacteria. The occurrence and dominance of the ectomycorrhizal community at Leforest but not at Pierrelaye is the major feature of our data set. Overall, ectomycorrhizal root symbionts appeared to be highly constrained by soil characteristics at the phytomanagement sites. Our data support the view that mycorrhizal inoculation is needed in highly stressed and nutrient-poor environments.
Discharges from the widely distributed small point sources of pollutants such as septic tanks contribute to microbial and nutrient loading of streams and can pose risks to human health and stream ecology, especially during periods of ecological sensitivity. Here we present the first comprehensive data on the compositional variability of septic tank effluents (STE) as a potential source of water pollution during different seasons and the associated links to their influence on stream waters. To determine STE parameters and nutrient variations, the biological and physicochemical properties of effluents sampled quarterly from 12 septic tank systems were investigated with concurrent analyses of upstream and downstream receiving waters. The study revealed that during the warmer dryer months of spring and summer, effluents were similar in composition, as were the colder wetter months of autumn and winter. However, spring/summer effluents differed significantly (P<0.05) from autumn/winter for concentrations of biological oxygen demand (BOD), arsenic, barium (Ba), cobalt, chromium, manganese, strontium (Sr), titanium, tungsten (W) and zinc (Zn). With the exception of BOD, Ba and Sr which were greater in summer and spring, the concentrations of these parameters were greater in winter. Receiving stream waters also showed significant seasonal variation (P≤0.05) in alkalinity, BOD, dissolved organic carbon, sulphate, sulphur, lithium, W, Zn and Escherichiacoli abundance. There was a clear significant influence of STE on downstream waters relative to upstream from the source (P<0.05) for total suspended solids, total particulate P and N, ammonium-N, coliforms and E. coli. The findings of this study found seasonal variation in STE and place effluent discharges as a factor affecting adjacent stream quality and call for appropriate measures to reduce or redirect STE discharges away from water courses.
In this work, a series of novel Zn-Al-Ce multi-metal oxide (Zn-Al-Ce-MMO) photocatalysts with different Ce doping contents were prepared by calcination of Ce-doped Zn-Al layered double hydroxide (Zn-Al-Ce-LDH) precursors at various temperatures in air atmosphere. The synthesized Zn-Al-Ce-MMO materials were characterized by XRD, FTIR, TGA, BET, SEM, TEM, XPS and UV-vis DRS. The photocatalytic activities of the Zn-Al-Ce-MMO materials were evaluated by the photodegradation of rhodamine B (RhB) dye and paracetamol in aqueous solution under simulated solar light irradiation. The result of photodegradation of RhB showed that the Zn-Al-Ce-MMO samples exhibit much higher photocatalytic activity than that of Zn-Al-MMO, and the optimal Ce doping content is 5% of mole ratio (nCe/n(Zn+Al+Ce)). The enhanced photocatalytic activity of the Zn-Al-Ce-MMO was mainly attributed to the increasing in the separation efficiency of electrons and holes. The effect of calcination temperature was also studied. The photocatalytic activity of Zn-Al-Ce-MMO increased with increasing calcination temperature up to 750°C, which can be ascribed to the formation of well-crystallized metal oxides during calcination. Under experimental conditions, 97.8% degradation efficiency of RhB and 98.9% degradation efficiency of paracetamol were achieved after 240min. Active species trapping and EPR experiments suggested that hole (h(+)), superoxide radical (O2(-)) and hydroxyl radical (OH) played
 important roles during the RhB photocatalytic process. Moreover, the results indicated that the synthesized Zn-Al-Ce-MMO materials had good stability and reusability.
In this study, 45 bisindolylmethanes having sulfonamide moiety had been synthesized through 3 steps. In vitro assay for inhibition of carbonic anhydrase showed that some of the compounds having sulfonamide moiety are capable of inhibiting carbonic anhydrase II. Bisindoles having halogens at fifth position showed better inhibitory activity as compared to unsubstituted bisindoles. The results obtained from in vitro inhibitory activity were subjected through 3D QSAR and docking studies to identify important features contributing to the activity and further improve the structure. Pharmacophore studies suggest that bisindolylmethane moiety is contributing significantly towards the inhibition activity. Docking studies showed that compounds having nitro substituent (5g and 5i) were found to be able interact with Zn(2+) ion, Thr199, His94, His96, and His119, which interferes with the ZnOHThr199Glu106 hydrogen bond network. Bulky nitro substituent at ortho position for compound 5g prevents the compound from interacting with other residues like Thr199 and Thr200. Methyl substituent at ortho position for Compound 5i induces less steric hindrance effect, thus allowing second oxygen atom of sulfonamide to interact with Thr199 (2.51Å). Hydrogen bonding between NH on indole ring with Glu69 might have increased stability of ligand-receptor complex.
The DUF156 family of DNA-binding transcriptional regulators includes metal sensors that respond to cobalt and/or nickel (RcnR, InrS) or copper (CsoR) plus CstR, which responds to persulfide, and formaldehyde-responsive FrmR. Unexpectedly, the allosteric mechanism of FrmR from Salmonella enterica serovar Typhimurium is triggered by metals in vitro, and variant FrmR(E64H) gains responsiveness to Zn(II) and cobalt in vivo Here we establish that the allosteric mechanism of FrmR is triggered directly by formaldehyde in vitro Sensitivity to formaldehyde requires a cysteine (Cys(35) in FrmR) conserved in all DUF156 proteins. A crystal structure of metal- and formaldehyde-sensing FrmR(E64H) reveals that an FrmR-specific amino-terminal Pro(2) is proximal to Cys(35), and these residues form the deduced formaldehyde-sensing site. Evidence is presented that implies that residues spatially close to the conserved cysteine tune the sensitivities of DUF156 proteins above or below critical thresholds for different effectors, generating the semblance of specificity within cells. Relative to FrmR, RcnR is less responsive to formaldehyde in vitro, and RcnR does not sense formaldehyde in vivo, but reciprocal mutations FrmR(P2S) and RcnR(S2P), respectively, impair and enhance formaldehyde reactivity in vitro Formaldehyde detoxification by FrmA requires S-(hydroxymethyl)glutathione, yet glutathione inhibits formaldehyde detection by FrmR in vivo and in vitro Quantifying the number of FrmR molecules per cell and modeling formaldehyde modification as a function of [formaldehyde] demonstrates that FrmR reactivity is optimized such that FrmR is modified and frmRA is derepressed at lower [formaldehyde] than required to generate S-(hydroxymethyl)glutathione. Expression of FrmA is thereby coordinated with the accumulation of its substrate.
Metal ion transport systems have been studied extensively, but the specificity of a given transporter is often unclear from amino acid sequence data alone. In this study, predicted Cu(2+) and Zn(2+) resistance systems in Pseudomonas stutzeri strain RCH2 are compared with those experimentally implicated in Cu(2+) and Zn(2+) resistance, as determined by using a DNA-barcoded transposon mutant library. Mutant fitness data obtained under denitrifying conditions are combined with regulon predictions to yield a much more comprehensive picture of Cu(2+) and Zn(2+) resistance in strain RCH2. The results not only considerably expand what is known about well-established metal ion exporters (CzcCBA, CzcD, and CusCBA) and their accessory proteins (CzcI and CusF), they also reveal that isolates with mutations in some predicted Cu(2+) resistance systems do not show decreased fitness relative to the wild type when exposed to Cu(2+) In addition, new genes are identified that have no known connection to Zn(2+) (corB, corC, Psest_3226, Psest_3322, and Psest_0618) or Cu(2+) resistance (Mrp antiporter subunit gene, Psest_2850, and Psest_0584) but are crucial for resistance to these metal cations. Growth of individual deletion mutants lacking corB, corC, Psest_3226, or Psest_3322 confirmed the observed Zn-dependent phenotypes. Notably, to our knowledge, this is the first time a bacterial homolog of TMEM165, a human gene responsible for a congenital glycosylation disorder, has been deleted and the resulting strain characterized. Finally, the fitness values indicate Cu(2+)- and Zn(2+)-based inhibition of nitrite reductase and interference with molybdenum cofactor biosynthesis for nitrate reductase. These results extend the current understanding of Cu(2+) and Zn(2+) efflux and resistance and their effects on denitrifying metabolism.
In this study, genome-wide mutant fitness data in P. stutzeri RCH2 combined with regulon predictions identify several proteins of unknown function that are involved in resisting zinc and copper toxicity. For zinc, these include a member of the UPF0016 protein family that was previously implicated in Ca(2+)/H(+) antiport and a human congenital glycosylation disorder, CorB and CorC, which were previously linked to Mg(2+) transport, and Psest_3322 and Psest_0618, two proteins with no characterized homologs. Experiments using mutants lacking Psest_3226, Psest_3322, corB, corC, or czcI verified their proposed functions, which will enable future studies of these little-characterized zinc resistance determinants. Likewise, Psest_2850, annotated as an ion antiporter subunit, and the conserved hypothetical protein Psest_0584 are implicated in copper resistance. Physiological connections between previous studies and phenotypes presented here are discussed. Functional and mechanistic understanding of transport proteins improves the understanding of systems in which members of the same protein family, including those in humans, can have different functions.
A facile yet sensitive and selective method was proposed for Hg(2+) detection based on N-acetyl-L-cysteine(NAC)-induced colorimetric response of AuNPs. The proposed method can be easily performed by introducing the premixing of NAC and Hg(2+) into as-prepared citrate-capped AuNPs solution. A combination of experimental and theoretical studies was applied to illustrate the mechanism of this AuNPs colorimetric system. The strong interaction of NAC and AuNPs through Au-S bond could lead to the aggregation of AuNPs, but the formation of NAC-Hg-NAC complex decreased the affinity between NAC and AuNPs and resulted in an anti-aggregation effect. Therefore, the color of the AuNPs solution would progress from purple to red with the increase of Hg(2+) concentration. The proposed method had a high sensitivity with a limit of detection of 9.9nM. Coexistent metal ions, including Cd(2+), Mn(2+), Al(3+), Ag(+), K(+), Mg(2+), Ca(2+), Cr(3+), Cu(2+), Fe(3+), Pb(2+), Ni(2+) and Zn(2+), did not interfere with the detection of Hg(2+). This method can be used to monitor Hg(2+) in tap water.
Vegetables and crops can take up heavy metals when grown on polluted lands. The concentrations and dynamic uptake of heavy metals vary at different growth points for different vegetables. In order to assess the safe consumption of vegetables in weak alkaline farmlands, Chinese cabbage and radish were planted on the farmlands of Baiyin (polluted site) and Liujiaxia (relatively unpolluted site). Firstly, the growth processes of two vegetables were recorded. The growth curves of the two vegetables observed a slow growth at the beginning, an exponential growth period, and a plateau towards the end. Maximum concentrations of copper (Cu), zinc (Zn), lead (Pb), and cadmium (Cd) were presented at the slow growth period and showed a downtrend except the radish shoot. The concentrations of heavy metals (Cu, Zn, and Cd) in vegetables of Baiyin were higher than those of Liujiaxia. In the meanwhile, the uptake contents continued to increase during the growth or halted at maximum at a certain stage. The maximum uptake rates were found on the maturity except for the shoot of radish which took place at the exponential growth stages of root. The sigmoid model could simulate the dynamic processes of growth and heavy metals uptake of Chinese cabbage and radish. Conclusively, heavy metals have higher bioaccumulation tendency for roots in Chinese cabbage and for shoots in radish.
Breast cancer is a complex heterogeneous disease where many distinct subtypes are found. Younger African American (AA) women often present themselves with aggressive form of breast cancer with unique biology which is very difficult to treat. Better understanding the biology of AA breast tumors could lead to development of effective treatment strategies. Our previous studies indicate that AA but not Caucasian (CA) triple negative (TN) breast cancer cells were sensitive to nitrosative stress-induced cell death. In this study, we elucidate possible mechanisms that contribute to nitric oxide (NO)-induced apoptosis in AA TN breast cancer cells.
Breast cancer cells were treated with various concentrations of long-acting NO donor, DETA-NONOate and cell viability was determined by trypan blue exclusion assay. Apoptosis was determined by TUNEL and caspase 3 activity as well as changes in mitochondrial membrane potential. Caspase 3 and Bax cleavage, levels of Cu/Zn superoxide dismutase (SOD) and Mn SOD was assessed by immunoblot analysis. Inhibition of Bax
 cleavage by Calpain inhibitor, and levels of reactive oxygen species (ROS) as well as SOD activity was measured in NO-induced apoptosis. In vitro and in vivo effect of NO treatment on mammary cancer stem cells (MCSCs) was assessed.
NO induced mitocondria-mediated apoptosis in all AA but not in CA TN breast cancer cells. We found significant TUNEL-positive cells, cleavage of Bax and caspase-3 activation as well as depolarization mitochondrial membrane potential only in AA TN breast cancer cells exposed to NO. Inhibition of Bax cleavage and quenching of ROS partially inhibited NO-induced apoptosis in AA TN cells. Increase in ROS coincided with reduction in SOD activity in AA TN breast cancer cells. Furthermore, NO treatment of AA TN breast cancer cells dramatically reduced aldehyde dehydrogenase1 (ALDH1) expressing MCSCs and xenograft formation but not in breast cancer cells from CA origin.
Ethnic differences in breast tumors dictate a need for tailoring treatment options more suited to the unique biology of the disease.
Concentrations of Cu, Zn, Cr, As, Cd, Pb and Hg were determined in 153 samples covering 18 fish species collected from Heilongjiang River, China, and the potential health risks to local residents through fish consumption were estimated. Results revealed that all metals were detected with Cd and Pb having considerably lower detection rate. There were 28.6 % of Lethenteron camtschaticum samples exceeding the limit of inorganic As content established by Chinese legislation. Metal bioaccumulation in fish were poorly correlated with fish sizes, and generally tended to increase with trophic levels. The hazard quotient values of all fish species were far below 1 for general population and fishermen. The carcinogenic risk of As in L. camtschaticum for the local fishermen exceeded the acceptable level of 10(-4) rise in cancer rates, but was considered safe given the migratory habits of the fish.
Bioavailability of nitric oxide (NO) and hydrogen sulfide (H2S) is reduced in heart failure (HF). Recent studies suggest cross-talk between NO and H2S signaling. We previously reported that sodium nitrite (NaNO2) ameliorates myocardial ischemia-reperfusion injury and HF. Nuclear factor-erythroid-2-related factor 2 (Nrf2) regulates the antioxidant proteins expression and is upregulated by H2S. We examined the NaNO2 effects on endogenous H2S bioavailability and Nrf2 activation in mice subjected to ischemia-induced chronic heart failure (CHF).
Mice underwent 60 minutes of left coronary artery occlusion and 4 weeks of reperfusion. NaNO2 (165 μg/kgic) or vehicle was administered at reperfusion and then in drinking water (100 mg/L) for 4 weeks. Left ventricular (LV), ejection fraction (EF), LV end diastolic (LVEDD) and systolic dimensions (LVESD) were determined at baseline and at 4 weeks of reperfusion. Myocardial tissue was analyzed for oxidative stress and respective gene/protein-related assays. We found that NaNO2 therapy preserved LVEF, LVEDD and LVSD at 4 weeks during ischemia-induced HF. Myocardial malondialdehyde and protein carbonyl content were significantly reduced in NaNO2-treated mice as compared to vehicle, suggesting a reduction in oxidative stress. NaNO2 therapy markedly increased expression of Cu,Zn-superoxide dismutase, catalase, and glutathione peroxidase during 4 weeks of reperfusion. Furthermore, NaNO2 upregulated the activity of Nrf2, as well as H2S-producing enzymes, and ultimately increased H2S bioavailability in ischemia-induced CHF in mice as compared with vehicle.
Our results demonstrate that NaNO2 therapy significantly improves LV function via increasing H2S bioavailability, Nrf2 activation, and antioxidant defenses.
Central European floodplain soils are often contaminated with potentially toxic metals. The prediction of their aqueous concentrations is a prerequisite for an assessment of environmental concerns. We tested the aqueous concentrations of cadmium (Cd), copper (Cu), nickel (Ni), lead (Pb) and zinc (Zn) derived from multi-surface adsorption modelling (on hydrous iron, aluminum and manganese oxides, clay and soil organic matter) against those analyzed in situ in the soil solution of four horizons of floodplain soils at the Elbe River, Germany. The input data for the reactive metals were derived from a seven-step sequential extraction scheme or from extraction with 0.43 M nitric acid (HNO3) and evaluated in four modelling scenarios. In all scenarios, measured and modelled concentrations were positively related, except partially for Pb. Close reproduction of the measured data was obtained using measured data of accompanying cations and anions together with amounts of reactive metals from both the sequential extraction or from 0.43 M HNO3 extraction, except for Cu, which was often strongly overestimated, and partially Cd. We recommend extraction with 0.43 M HNO3 to quantify reactive metals in soil because the modelling results were metal-specific with better or equal results using the single extractant, the application of which is also less laborious. Approximations of ion concentrations and water contents yielded similar results. Modelled solid-phase speciation of metals varied with pH and differed from that from sequential extraction. Multi-surface modelling may be an effective tool to predict both aqueous concentrations and solid-phase speciation of metals in soil.
In order to ascertain if Cu, Fe, and Zn are differentially accumulated in fish tissues, metal concentrations were measured in the muscle and liver of bycatch fish from the states of Sinaloa (189 specimens, 7 species) and Guerrero (152 individuals, 8 species) in the Mexican Pacific Coast during March and November 2011. Additionally, metal levels were compared with the maximum allowable limits set by international legislation and contrasted with similar ichthyofauna from other regions. Liver had more elevated concentrations of Cu (Sinaloa 28.3, Guerrero 16.3 μg g(-1)), Fe (Sinaloa 1098, Guerrero 636 μg g(-1)), and Zn (Sinaloa 226, Guerrero 186 μg g(-1)) than the muscle in fish from both studied areas. The relative abundances of analyzed metals in both tissues was Fe > Zn > Cu. As far as limits set by international legislation (Australia, India, New Zealand, Zambia), measured concentrations of Cu in the edible portion of fish were not found to be above the set values. In the case of Zn, the maximum allowable limits set by international legislation were exceeded by the Peruvian mojarra Diapterus peruvianus from Guerrero state (Mexican Pacific). No limits exist for Fe in the edible portion of fishery products in the national and international legislations.
Numerous observations suggest a possible connection between the levels of Mg, Zn, Fe, and Zn and the incidence of depressive symptoms. Depression is two to three times more common in women than in men. The menopausal period is extremely conducive to depressive disorders. The aim of this study was to assess the severity of depressive symptoms in postmenopausal women depending on the levels of Mg, Zn, Ca, Cu, and Fe. The study included 198 healthy postmenopausal women at the average age of 56.26 ± 5.55 years. In the first part of the study, standardized research tools were used, namely the Primary Care Evaluation of Mental Disorders (PRIME-MD) and the Beck Depression Inventory (BDI). The second part involved biochemical analysis of Mg, Zn, Ca, Cu, and Fe levels in blood serum. The lowest Cu levels were observed in women without depressive symptoms (1.07 ± 0.22 mg/l) and the highest in those with severe depressive symptoms (1.19 ± 0.17 mg/l), (p ≤ 0.05). The lowest Mg levels were observed in women with depressive symptoms (14.28 ± 2.13 mg/l), and the highest in women without depressive symptoms (16.30 ± 3.51 mg/l), (p ≤ 0.05). The average serum Mg levels (15.75 ± 3.23 mg/l) decreased compared to the reference values (18.77-24 mg/l). What is striking is a potential relation between the levels of Mg and Cu and depressiveness. Our results indicate to a higher vulnerability to depression in a group of women with lower levels of Mg and higher levels of Cu.
Reductive cross-coupling has emerged as a direct method for the construction of carbon-carbon bonds. Most cobalt-, nickel-, and palladium-catalyzed reductive cross-coupling reactions to date are limited to stoichiometric Mn(0) or Zn(0) as the reductant. One nickel-catalyzed cross-coupling paradigm using Et3N as the terminal reductant is reported. By using this photoredox catalysis and nickel catalysis approach, a direct Csp(2)-Csp(3) reductive cross-coupling of aryl bromides with alkyl bromides is achieved under mild conditions without stoichiometric metal reductants.
An unbranched N3O2 ligand 2,6-bis[((2-pyridinylmethyl)oxy)methyl]pyridine (L1) was used to prepare new mononuclear heteroleptic Group 12 perchlorate complexes characterized by IR, (1)H NMR and X-ray crystallography. Racemic complexes with pentadentate L1 and one to four oxygens from either water or perchlorate bound to a metal ion were structurally characterized. Octahedral [Zn(L1)(OH2)](ClO4)2 (1) and pentagonal bipyramidal [Cd(L1)(OH2)(OClO3)]ClO4 (2) structures were found with lighter congeners. The polymorphic forms of [Hg(L1)(ClO4)2] characterized (3 in P1[combining macron] and 4 in P21/c) had a mix of monodentate, anisobidentate and bidentate perchlorates, providing the first examples of a tricapped trigonal prismatic Hg(ii) coordination geometry, as well as additional examples of a rare square antiprismatic Hg(ii) coordination geometry. Solution state (1)H NMR characterization of the Group 12 complexes in CD3CN indicated intramolecular reorganization remained rapid under conditions where intermolecular M-L1 exchange was slow on the chemical shift time scale for Zn(ii) and on the J(M(1)H) time scale for Cd(ii) and Hg(ii). Solution studies with more than one equivalent
 of ligand also suggested that a complex with a 1 : 2 ratio of M : L1 contributed significantly to solution equilibria with Hg(ii) but not the other metal ions. The behavior of related linear pentadentate ligands with Group 12 perchlorate salts is discussed.
Evidence indicates that the mechanisms controlling photosynthesis efficiency also regulate plant response to biotic and abiotic stress. Light-induced cell death is genetically maintained for the control of innate immunity. In a recent study we showed that the expression of AtWDR26 was induced by light, multiple plant hormones, and abiotic stress; increased AtWDR26 strongly upregulated gene groups related to chloroplast metabolism, disease resistance, and abiotic stress tolerance. Gain- and loss-of-function analyses in transgenic plants demonstrated the involvement of AtWDR26 in signaling pathways; these controls were osmotic as well as salt stress tolerance. More detailed transcriptome evidence suggested that AtWDR26 was a powerful inducer of gene expression associated with chloroplast metabolism. This included the electron transport chain of the photosystem, carbohydrate synthesis, and enzymatic activity involved in photorespiration. Moreover, genes in auxin synthesis (and perception) constituted a significant portion of those that were upregulated. Gene expression involved in disease resistance, control of cell wall flexibility, Zn uptake, and AP2/ERF transcription factors was also be upregulated. We concluded that AtWDR26 is one component in the regulatory network between light-regulated plant growth and the adaptation response to disease resistance and abiotic stress. Auxin signal acts downstream for AtWDR26 regulation and the adaptation response to biotic and abiotic stress: this occurs through modulating cell wall flexibility, Zn homeostasis, and controlling stress-related transcription factors.
In this work, a platform of alginate beads loaded with Prednisolone in hypromellose/gellan gum capsules (F6/Cps) able to delay steroidal anti-inflammatory drug (SAID) release as needed for chronotherapy of rheumatoid arthritis is proposed. Rheumatoid arthritis, showing a worsening in symptoms in the morning upon waking, is a pathology that can benefit from chronotherapy. With the aim to maximize prednisolone therapeutic action allowing the right timing of glucocorticoid therapy, different engineered microparticles (gel-beads) were manufactured using prilling (laminar jet break-up) as micro-encapsulation technique and Zn-alginate as gastroresistant carrier. Starting from various feed solutions and process parameters, the effect of the variables on particles size, morphology, solid state properties and drug release was studied. The optimization of operative and prilling/ionotropic gelation variables led to microspheres with almost spherical shape and a narrow dimensional range. The feed solution with the highest alginate (2.5% w/v) amount and drug/polymer ratio (1:5 w/w) gave rise to the highest encapsulation efficiency (78.5%) as in F6 formulation. As to drug release, F6 exhibited an interesting dissolution profile, releasing about 24% of the drug in simulated gastric fluid followed by a more sustained profile in simulated intestinal fluid. #F6, acting as a gastro-resistant and delayed release formulation, was selected for in vivo studies on male Wistar rats by means of a carrageenan-induced oedema model. Finally, this efficacious formulation was used as core material for the development of a final dosage form: F6/Cps allowed to significantly reduce prednisolone release in simulated gastric fluid (12.6%) and delayed drug release up to about 390 minutes.
Surface sediments were subject to systematic long-term monitoring (2002-2014) in the Republic of Serbia (Province of Vojvodina). Eight heavy metals (Ni, Zn, Cd, Cr, Cu, Pb, As and Hg), mineral oils (total petroleum hydrocarbons), 16 EPA PAHs, selected pesticides and polychlorinated biphenyls (PCB) were monitored. As part of this research, this paper presents a sediment contamination spatial and temporal trend study of diverse pollution sources and the ecological risk status of the alluvial sediments of Carska Bara at three representative sampling sites (S1S3), in order to establish the status of contamination and recommend substances of interest for more widespread future monitoring. Multivariate statistical methods including factor analysis of principal component analysis (PCA/FA), Pearson correlation and several synthetic indicators were used to evaluate the extent and origin of contamination (anthropogenic or natural, geogenic sources) and potential ecological risks. Hg, Cd, As, mineral oils and PAHs (dominated by dibenzo(a,h)anthracene and benzo(a)pyrene, contributing 85.7% of the total) are derived from several anthropogenic sources, whereas Ni, Cu, Cr and Zn are convincingly of geogenic origin, and exhibit dual origins. Cd and Hg significantly raise the levels of potential ecological risk for all sampling locations, demonstrating the effect of long-term bioaccumulation and biomagnification. Pb is isolated from the other parameters, implying unique sources. This research suggests four heavy metals (Zn, Cr, Cu and As) and dibenzo(a,h)anthracene be added to the list of priority pollutants within the context of the application of the European Water Framework Directive (WFD), in accordance with significant national and similar environmental data from countries in the region.
The fluvial systems of the Iberian Pyrite Belt (SW Iberian Peninsula) are affected by acid mine drainage (a lixiviate residue product of mining activities derived from sulfide oxidation). The high acidity and high concentrations of sulfates and metal(loid)s are the main causes of the environmental degradation of the Odiel River basin. The use of weight of evidence approach in areas of the Odiel River basin implies the integration of different lines of evidence (chemistry, toxicity and bioaccumulation) using the freshwater clam Corbicula fluminea as target species. The integration of the results from the application of the different lines of evidence showed that the index of pollution was higher downvalley (Ptriad=12,312), moderate after mining effluent discharges (Ptriad=13.9) and very low where the Odiel River sources (Ptriad=6.31). The multivariate analysis indicated that variables and chemicals were associated with geochemical matrix and background levels (% of fines and toxic metal(loid) concentrations), toxic effects, and metal(loid) bioaccumulation reflecting the geographical distribution of the contamination towards the estuary. Metal(loid) thresholds were calculated for the study area as site-specific values of interim freshwater sediment quality values: As≥171; Cd≥0.48; Co≥8.82; Cr≥38.4; Cu≥451; Ni≥18.4; Pb≥377; Sb≥17.7; Zn≥221mg/kg of freshwater fluvial dry sediment. These results revealed the possibility of using the TEL values proposed by the USEPA and the NOAA for sediments from this site, and proposed lower PEL values for the Iberian Pyrite Belt as result of toxicity effects found in the Asian clam due to the combination of extreme acidity and high metal(loid) concentrations.
A biomonitoring technique was employed to assess metal contamination of several degraded urban streams in the Łódź agglomeration. Presence of heavy metals (Zn, Cu, Fe, Cd, Pb, Cr, was determined in whole bodies of Hydropsyche angustipennis larvae. Larvae of H. angustipennis were the only caddisflies living in most of  investigated streams. These metals as well as other environmental variables were investigated in sediments or free waters of urban streams and in a stretch of a similar size of the Grabia River (reference site), outside the city but still in the vicinity of the Łódź agglomeration. The results of our research demonstrated different levels of contamination of urban streams as well as a correlation between environmental and larval tissue concentrations of heavy metals. Significant differences among sites were observed for metal concentrations in H. angustipennis larval bodies and larval responses to metals were time specific. The highest concentration of heavy metals was observed during the spring months. Differences were evident among various heavy metal levels in the bodies of larvae collected from different streams and at different sampling stations in the same stream.
Four novel unsymmetrical A3B porphyrins 1, 2, 3 and 4 were synthesized following Lindsey procedure. Porphyrins 3 and 4 include one and three l-glutamate groups, respectively, and all porphyrins were metallated with Zn(II) (1a-4a) or Cu(II) (1b-4b). Porphyrins and metalloporphyrins presented values of singlet oxygen quantum yields (ΦD) ranging from 0.21 to 0.67. The tetraaryl derivatives in this study showed phototoxicity in SiHa cells with IC50 values ranging from <0.01 to 6.56±0.11μM, the metalloporphyrin 4a showed the lowest IC50 value. Comparing the phototoxic activity between all porphyrins, functionalization of porphyrins with glutamate increased 100 times phototoxic activity (1 (IC50 4.81±0.34μM) vs. 3 (IC50 0.04±0.02μM) and 2 (IC50 5.19±0.42μM) vs. 4 (IC50 0.05±0.01μM)). This increased activity could be attributed to reduced hydrophobicity and increased ΦΔ, given by functionalization with l-glutamate. Metalloporphyrins 3a (IC50 0.04±0.01μM) and 4a (IC50<0.01μM) presented the best values ​​of phototoxic activity. Therefore, functionalization and zinc metalation increased the phototoxic activity. SiHa cells treated with porphyrins 3, 4, 3a and 4a at a final concentration of 10μM, showed increased activity of caspase-3 enzyme compared to the negative control; indicating the induction of apoptosis. Differential gene expression pattern in SiHa cells was determined; treatments with metalloporphyrins 4a and 4b were performed, respectively, comparing the expression with untreated
 control. Treatments in both cases showed similar gene expression pattern in upregulated genes, since they share about 25 biological pathways and a large number of genes. According to the new photophysical properties related to the structural improvement and phototoxic activity, these molecules may have the potential application as photosensitizers in the photodynamic therapy.
Application of chlorpyrifos (CP) has increased its environmental concentration. Increasing CP concentration has increased chances of adverse health effects. Its removal from environment has attained researcher's attention. CP degrading bacterial strains were isolated from wastewater and agricultural soil. Finally, selected five bacterial strains were identified using 16S rRNA nucleotide sequence analysis as Pseudomonas kilonensis SRK1, Serratia marcescens SRK2, Bacillus pumilus SRK4, Achromobacter xylosoxidans SRK5, and Klebsiella sp. T13. Interaction studies among bacterial strains demonstrated possibility for development of five membered bacterial consortium. Biodegradation potential of bacterial consortium was investigated in the presence of petrochemicals and trace metals. About 98 % CP removal was observed in sequencing batch reactors at inoculum level, 10 %; pH, 7; CP concentration, 400 mgL(-1), and HRT, 48 h. Experimental data has shown an excellent fit to first order growth model. Among all petrochemicals only toluene (in low concentration) has stimulatory effect on biodegradation of CP. Addition of petrochemicals (benzene, toluene, and xylene) in high concentration (100 mg L(-1)) inhibited bacterial activity and decreased CP removal. At low concentration i.e., 1 mg L(-1) of inorganic contaminants (Cu, Hg, and Zn) >96 % degradation was observed. Addition of Cu(II) in low concentration has stimulated CP removal efficiency. Hg(II) in all concentrations has strongly inhibited biodegradation rate except at 1 mgL(-1). In simulated pesticide, wastewater CP removal efficiency decreased to 77.5 %. Outcomes of study showed that both type and concentration of petrochemicals and trace metals influenced biodegradation of CP.
In this paper, the x-ray emissions are measured by the interaction of 1500-3500 keV Xe(q+) (q = 12, 15, 17, 19, 21, 23, 26 and 29) ions with Zn target. When q < 29, we observe Ll, Lα, Lβ1, Lβ2 and Lγ characteristic x-rays from Xe(q+) ions and a broad M-shell molecular orbital (MO) x-ray band from the transient quasi-molecular levels. It is found that their yields quickly increase with different rates as the incident energy increases. Besides, the widths of the broad MO x-ray bands are about 0.9-1.32 keV over the energy range studied and are proportional to v(1/2) (v = projectile velocity). Most remarkably, when the projectile charge state is 29, the broad x-ray band separates into several narrow discrete spectra, which was never observed before in this field.
Seven kinds of indigenous fruits and five imported fruits were compared for their "health quality." Methods including the calorific, antioxidant, and ion ratios were carried out. Results indicated the order of content (in mg/100g) was: Ca(2+) , Murcott orange (218.2) > Kiwifruit (200.0) > pineapple (138.5) > Golden kiwi (117.6); Mg(2+) , Pitaya (192.2), banana (88.0), Kiwifruit (63.4), and Golden kiwi (58.4); Zn(2+) , Pitaya (19.53) > pear (10.8) > Kiwifruit (6.09) > Irwin mango (4.58). Cu(2+) , Kiwifruit (0.70) > Red globe grape (0.67) > Golden kiwi (0.65) > Irwin mango (0.42) ≈ Pitaya (0.40). In terms of ion ratio, Pitaya showed Zn(2+) /Cu(2+) (48.8), Mg(2+) /Ca(2+) (6.7) and uniquely possessed selenium 0.002 mg/100 g; for pear, Zn(2+) /Cu(2+) = 37.2, while Kyoho grape, Red globe grape, and Golden kiwi revealed extremely high Fe(2+) /(Co(2+) +Ni(2+) ) ratios. On the other hands, Irwin mango and Pitaya astonishingly contained huge amount of inositol, reaching 3523.2 mg/100 g and 1998.7 mg/100 g, respectively. To evaluate the "health quality" of fruits, an overall ranking method by combining (a) the Function-directed Caloric Antioxidant Density (CAD) and (b) the ion ratio was developed. The finalized ranking of these selected fruits was: Pitaya > cherry > Irwin mango > Murcott orange = pineapple > banana > Golden kiwi > pear > Kiwifruit > Red globe grape > apple > Kyoho grape. Conclusively, this evaluation method is novel, contemporary and scientific, which could more clearly assess the "health quality" of fruits in view of nutritional, calorific, and antioxidant balance.
Santa Clara, Limeport, and Berkeley are Arabidopsis thaliana accessions previously identified as diversely metal resistant. Yet these same accessions were determined to be genetically indistinguishable from the metal sensitive Col-0. We robustly tested tolerance for Zn, Ni and Cu, and genetic relatedness by growing these accessions under a range of Ni, Zn and Cu concentrations for three durations in multiple replicates. Neither metal resistance nor variance in growth were detected between them and Col-0. We re-sequenced the genomes of these accessions and all stocks available for each accession. In all cases they were nearly indistinguishable from the standard laboratory accession Col-0. As Santa Clara was allegedly collected from the Jasper Ridge serpentine outcrop in California, USA we investigated the possibility of extant A. thaliana populations adapted to serpentine soils. Botanically vouchered Arabidopsis accessions in the Jepson database were overlaid with soil maps of California. This provided no evidence of A. thaliana collections from serpentine sites in California. Thus, our work demonstrates that the Santa Clara, Berkeley and Limeport accessions are not metal tolerant, not genetically distinct from Col-0, and that there are no known serpentine adapted populations or accessions of A. thaliana.
A bioluminescent bacterium, Photobacterium phosphoreum T3 (PPT3), was used as a bio-indicator for the atmospheric fine particulate matter (PM2.5) to determine the eco-toxicity of PM2.5. The PM2.5 contains toxic chemicals, which reduce light output. The PM2.5 samples were collected in the period from March 2014 to January 2015 in Nanjing and analyzed for the chemical composition versus their eco-toxicity. The eco-toxicological responses of each toxicant were detected in PM2.5 samples with PPT3. The dose-response curves obtained were verified using the Weibull fitting function. According to the measured EC50 values (EC50, the concentration of a toxicant that inhibits 50% of the bioluminescence), the toxicity sequence was: B[a]P>hexa-PCB>tetra-PCB>tri-PCB>Pb(2+)>DEHP>Cu(2+)>DBP>BDE209>Zn(2+)>DMP>DEP, where B[a]P is benzo(a)pyrene, PCB is polychlorinated biphenyl, DEHP is diethylhexyl phthalate, DBP is dibutyl phthalate, BDE209 is decabromodiphenyl ether, DMP is dimethyl phthalate, and DEP is diethyl phthalate. All the PM2.5 samples analyzed proved to be weak toxic for PPT3. The toxicity of PM2.5 was assessed by the dose-addition of organic species and heavy metallic elements existing in PM2.5 with PPT3. The bioluminescence test showed that the metals and organics detected in PM2.5 promoted PM2.5 toxicity. The total detectable organics (denoted by ΣOrs) exhibited slightly higher toxicity than the total metals (denoted by ΣMs). In contrast, the sum of water-soluble ions (denoted by ΣIons) was beneficial to PPT3. The PM2.5 toxicity increased as the PM2.5 trapped more organics or metallic elements from the industrial or densely populated urban areas, where the PM2.5 had a high inhibition rate of bioluminescence for PPT3 in contrast to the residential PM2.5 samples, where the minimum inhibition rate was observed. The toxicity of PM2.5 samples varied with the mass concentrations, chemical constituents, and sampling locations. The chemicals in PM2.5, especially organic species and metallic elements, affected its eco-toxicity. These data provided good understanding of the atmospheric PM2.5 pollution in the large portion of the East China.
We report the synthesis, structure, and spectroscopic and dynamic magnetic properties of a series of heterodinuclear complexes, [ZnLn(LH4 )2 ](NO3 )3 ⋅6 H2 O (Ln=Nd, Tb, Dy, Ho, Er, and Yb), with the singly deprotonated form of a new compartmentalized Schiff-base ligand, LH5 . The Ln(III) ions in these systems show a distorted square-antiprism geometry with an LnO8 coordination sphere. EPR spectroscopy and DC magnetic studies have shown that the anisotropic nature of the complexes is far more complicated than predicted on the basis of a simple electrostatic model. Among the investigated systems, only the Dy(III) derivative showed single-ion magnet behavior, in zero and an applied magnetic field, both in pure polycrystalline samples and in a series of polycrystalline samples with different degrees of dilution at the single-crystal level in the isostructural Y(III) derivative. The rich dynamics observed as functions of frequency, field, and temperature reveals that multiple relaxation mechanisms are at play, resulting in a barrier of 189 cm(-1) , which is among the highest reported for a dinuclear Zn-Dy system. Analysis of the dynamic behavior as a function of dilution degree further evidenced the persistence of non-negligible intermolecular interactions, even at the lowest concentration of 1 %.
The gas-phase structures of zinc and cadmium dications bound to serine (Ser) are investigated by infrared multiple photon dissociation (IRMPD) action spectroscopy using the free electron laser FELIX, in combination with ab initio calculations. To identify the structures of the experimentally observed species, [Zn(Ser-H)CH3CN](+) and CdCl(+)(Ser), the measured action spectra are compared to linear absorption spectra calculated at the B3LYP/6-311+G(d,p) level for Zn(2+) containing complexes and B3LYP/def2-TZVP levels for Cd(2+) containing complexes. Good agreement between the observed IRMPD
 spectra and the predicted spectra allows identification of the isomers present. The intact amino acid interacting with cadmium chloride adopts a tridentate chelation involving the amino acid backbone amine and carbonyl groups as well as the hydroxyl group of the side-chain, [N,CO,OH]. The presence of two low-energy conformers is observed for the deprotonated serine-zinc complex, with the same tridentate coordination as for the cadmium complex but proton loss occurs at both the hydroxyl side-chain, [N,CO,O(-)], and the carboxylic acid of the amino acid backbone, [N,CO(-),OH]. These results are profitably compared with the analogous results previously obtained for comparable complexes with cysteine.
Zinc (Zn) is an essential metal for development and maintenance of both the innate and adaptive compartments of the immune system. Zn homeostasis impacts maturation of dendritic cells (DCs) that are important in shaping T cell responses. The mechanisms by which Zn regulates the tolerogenic phenotype of DCs remain largely unknown. In this study, we investigated the effect of Zn on DC phenotype and the generation of Foxp3(+) regulatory T cells (Tregs) using a model of Histoplasma capsulatum fungal infection. Exposure of bone marrow-derived DCs to Zn in vitro induced a tolerogenic phenotype by diminishing surface MHC class II (MHCII) and promoting the tolerogenic markers, programmed death-ligand (PD-L)1, PD-L2, and the tryptophan degrading enzyme, IDO. Zn triggered tryptophan degradation by IDO and kynurenine production by DCs and strongly suppressed the proinflammatory response to stimulation by TLR ligands. In vivo, Zn supplementation and subsequent H. capsulatum infection supressed MHCII on DCs, enhanced PD-L1 and PD-L2 expression on MHCII(lo) DCs, and skewed the Treg-Th17 balance in favor of Foxp3(+) Tregs while decreasing Th17 cells. Thus, Zn shapes the tolerogenic potential of DCs in vitro and in vivo and promotes Tregs during fungal infection.
Modified TiO2 nanomaterials are considered to be promising in energy conversion and ferrites modification may be one of the most efficient modifications. In this research, various ferrites, incorporated with various cations (MFe2O4, M = Ni, Co, Zn, and Sr), are utilized to modify the well aligned TiO2 nanorod arrays (NRAs), which is synthesized by hydrothermal method. It is found that all MFe2O4/TiO2 NRAs show obvious red shift into the visible light region compared with the TiO2 NRAs. In particular, NiFe2O4 modification is demonstrated to be the best way to enhance the photoelectrochemical and photocatalytic activity of TiO2 NRAs. Furthermore, the separation and transfer of charge carriers after MFe2O4 modification are clarified by electrochemical impedance spectroscopy measurements. Finally, the underlying mechanism accounting for the enhanced photocatalytic activity of MFe2O4/TiO2 NRAs is proposed. Through comparison among different transition metals modified TiO2 with the same synthesis process and under the same evaluating condition, this work may provide new insight in designing modified TiO2 nanomaterials as visible light active photocatalysts.
Environmental pollution has increased many folds in recent years and in some places has reached levels that are toxic to living things. Among pollutant types, toxic heavy metals and metalloids are among the chemicals that pose the highest threat to biological systems (Jjemba 2004). Unlike organic pollutants, which are biodegradable, heavy metals are not degraded into less hazardous end products (Gupta et al. 2001). Low concentrations of some heavy metals are essential for life, but some of them like Hg, As, Pb and Cd are biologically non-essential and very toxic to living organisms. Even the essential metals may become toxic if they are present at a concentration above the permissible level (Puttaiah and Kiran 2008). For example, exposure to Zn and Fe oxides produce gastric disorder and vomiting, irritation of the skin and mucous membranes. Intake of Ni, Cr, Pb, Cd and Cu causes heart problems, leukemia and cancer, while Co and Mg can cause anemia and hypertension (Drasch et al. 2006). Similarly, various studies indicated that overexposure to heavy metals in air can cause cardiovascular disorders (Miller et al. 2007; Schwartz 2001), asthma (Wiwatanadate and Liwsrisakun 2011), bronchitis/emphysema (Pope 2000), and other respiratory diseases (Dominici et al. 2006).
Zinc nanoparticles (ZnNPs) are among the least investigated NPs and thus their toxicological effects are not known. In this study, tilapia (Oreochromis niloticus) were exposed to 1 and 10 mg/L suspensions of small size (SS, 40-60 nm) and large size (LS, 80-100 nm) ZnNPs for 14 days under semi-static conditions. Total Zn levels in the intestine, liver, kidney, gill, muscle tissue, and brain were measured. Blood serum glucose (GLU), glutamic oxaloacetic transaminase (GOT), glutamic pyruvic transaminase (GPT), and lactate dehydrogenase (LDH) were examined to elucidate the physiological disturbances induced by ZnNPs. Organ pathologies were examined for the gills, liver, and kidney to identify injuries associated with exposure. Significant accumulation was observed in the order of intestine, liver, kidney, and gills. Zn levels exhibited time- and concentration-dependent increase in the organs. Accumulation in kidney was also dependent on particle size; NPs SS-ZnNPs were trapped more effectively than LS-ZnNPs. No significant accumulation occurred in the brain (p > 0.05) while Zn levels in muscle tissue increased only marginally (p ≥ 0.05). Significant disturbances were noted in serum GOT and LDH (p < 0.05). The GPT levels fluctuated and were not statistically different from those of controls (p > 0.05). Histopathological tubular deformations and mononuclear cell infiltrations were observed in kidney sections. In addition, an increase in melano-macrophage aggregation intensity was identified on the 7th day in treatments exposed to LS-ZnNPs. Mononuclear cell infiltrations were identified in liver sections for all treatments. Both ZnNPs caused basal hyperplasia in gill sections. Fusions appeared in the gills after the 7th day in fish treated with 10 mg/L suspensions of SS-ZnNPs. In addition, separations in the secondary lamella epithelia were observed. The results indicated that exposure to ZnNPs could lead to disturbances in blood biochemistry and cause histopathological injuries in the tissues of O. niloticus. © 2016 Wiley Periodicals, Inc. Environ Toxicol, 2016.
Remediation strategies using soil amendments should consider the time dependence of metal availability to identify amendments that can sustainably reduce available pollutant concentrations over time. Drying-wetting cycles were applied on amendments, soils and soil + amendment mixtures, to mimic ageing at field level and investigate its effect on extractable Cd, Cu, Ni, Pb and Zn concentrations from three contaminated soils. The amendments investigated were municipal waste organic compost and biochars. The amendments, soils and mixtures were characterised by their physicochemical properties at different ageing times. The amendments were also characterised in terms of sorption capacity for Cd and Cu. The sorption capacity and the physicochemical properties of the amendments remained constant over the period examined. When mixed with the soils, amendments, especially the compost, immediately reduced the extractable metals in the soils with low pH and acid neutralisation capacity, due to the increase in pH and buffering capacity of the mixtures. The amendments had a relatively minor impact on the metal availability concentrations for the soil with substantially high acid neutralisation capacity. The most important changes in extractable metal concentrations were observed at the beginning of the experiments, ageing having a minor effect on metal concentrations when compared with the initial effect of amendments.
The present work discloses how high-quality dispersion of fine particles of cobalt ferrite (CF) could be attained on nitrogen-doped reduced graphene oxide (CF/N-rGO) and how this material in association with a microporous carbon phase could deliver significantly enhanced activity toward electrochemical oxygen reduction reaction (ORR). Our study indicates that the microporous carbon phase plays a critical role in spatially separating the layers of CF/N-rGO and in creating a favorable atmosphere to ensure the seamless distribution of the reactants to the active sites located on CF/N-rGO. In terms of the ORR current density, the heat-treated hybrid catalyst at 150 °C (CF/N-rGO-150) is found to be clearly outperforming (7.4 ± 0.5 mA/cm(2)) the state-of-the-art 20 wt % Pt-supported carbon catalyst (PtC) (5.4 ± 0.5 mA/cm(2)). The mass activity and stability of CF-N-rGO-150 are distinctly superior to PtC even after 5000 electrochemical cycles. As a realistic system level exploration of the catalyst, testing of a primary zinc-air battery could be demonstrated using CF/N-rGO-150 as the cathode catalyst. The battery is giving a galvanostatic discharge time of 15 h at a discharge current density of 20 mA/cm(2) and a specific capacity of ∼630 mAh g(-1) in 6 M KOH by using a Zn foil as the anode. Distinctly, the battery performance of this system is found to be superior to that of PtC in less concentrated KOH solution as the electrolyte.
We report on the development of novel saturable absorbers for erbium lasers based on transparent glass-ceramics (GCs) containing a mixture of cobalt-doped β-willemite, Co<sup>2+</sup>:β-Zn<sub>2</sub>SiO<sub>4</sub>, and zinc oxide, Co<sup>2+</sup>:ZnO, nanosized (10-14 nm) crystals. The structure of the parent glass and GCs is studied by x-ray diffraction, differential scanning calorimetry, transmission electron microscopy, and Raman spectroscopy. Variations of absorption spectra with heat-treatment
 reveal that Co<sup>2+</sup> ions from the parent glass enter the crystals of ZnO and β-willemite. GCs are characterized by a broad absorption band due to the A<sub>2</sub>4(F4)→T<sub>1</sub>4(F4) transition of Co<sup>2+</sup> ions in tetrahedral sites spanning up to ∼1.74  μm, relatively low saturation fluence, F<sub>S</sub>=0.75  J/cm<sup>2</sup> at 1.54 μm, short recovery time, τ=830  ns, and high laser damage threshold, ∼14  J/cm<sup>2</sup>. By using the developed GCs in a diode-side-pumped Er, Yb:glass laser, 0.77 mJ/45 ns pulses are generated.
The purpose of this study was to design a targeted anti-cancer drug delivery system for breast cancer. Therefore, doxorubicin (DOX) loaded poly(methyl vinyl ether maleic acid) nanoparticles (NPs) were prepared by ionic cross-linking method using Zn(2+) ions. To optimise the effect of DOX/polymer ratio, Zn/polymer ratio, and stirrer rate a full factorial design was used and their effects on particle size, zeta potential, loading efficiency (LE, %), and release efficiency in 72 h (RE72, %) were studied. Targeted NPs were prepared by chemical coating of tiptorelin/polyallylamin conjugate on the surface of NPs by using 1-ethyl-3-(3-dimethylaminopropyl) carboiimid HCl as cross-linking agent. Conjugation efficiency was measured by Bradford assay. Conjugated triptorelin and targeted NPs were studied by Fourier-transform infrared spectroscopy (FTIR). The cytotoxicity of DOX loaded in targeted NPs and non-targeted ones were studied on MCF-7 cells which overexpress luteinizing hormone-releasing hormone (LHRH) receptors and SKOV3 cells as negative LHRH receptors using Thiazolyl blue tetrazolium bromide assay. The best results obtained from NPs prepared by DOX/polymer ratio of 5%, Zn/polymer ratio of 50%, and stirrer rate of 960 rpm. FTIR spectrum confirmed successful conjugation of triptorelin to NPs. The conjugation efficiency was about 70%. The targeted NPs showed significantly less IC50 for MCF-7 cells compared to free DOX and non-targeted NPs.
The use of zinc oxide (ZnO) nanoparticles (NPs) for cancer is not yet clear for human clinical applications, which is primarily due to the lack of a better understanding of the action mechanisms and cellular consequences of the direct exposure of cells to these NPs. In this work, the authors have selected zinquin ethyl ester, a Zn(2+)-specific fluorescent molecular probe, to efficiently differentiate ZnO NPs and Zn(2+), and combined with confocal laser scanning microscopy (CLSM) to in situ study the Zn(2+) release process of ZnO NPs in cancer cell system through detecting the change of Zn(2+) level over time. During the experiments, the authors have designed the test group ZnO-2 in addition to assess the influence of a long-term storage on the characteristics of ZnO NPs in aqueous solution, and the Zn(2+) release process of ZnO NPs in cancer cell system. After three-month storage at room temperature, the release process became earlier and faster, which was consistent with previous results of transmission electron microscope, UV-Vis and PL spectra. It is a good detection method that combination of Zn(2+)-specific fluorescent molecular probe and CLSM, which will be helpful for ZnO NPs using in clinical research.
In this paper, we reported a ZnO quantum dots-based pH-responsive drug delivery platform for intracellular controlled release of drugs. Acid-decomposable, luminescent aminated ZnO quantum dots (QDs) were synthesized as nanocarriers with ultrasmall size (∼3 nm). The dicarboxyl-terminated poly(ethylene glycol) (PEG) had been introduced to NH2-ZnO QDs, which rendered it stable under physiological fluid. Moreover, a targeting ligand, hyaluronic acid (HA), was conjugated to ZnO QDs for specifically binding to the overexpressed glycoprotein CD44 by cancer cells. Doxorubicin (DOX) molecules were successfully loaded to PEG functionalized ZnO QDs via formation of metal-DOX complex and covalent interactions. The pH-sensitive ZnO QDs dissolved to Zn(2+) in acidic endosome/lysosome after uptake by cancer cells, which triggered dissociation of the metal-drug complex and a controlled DOX release. As result, a synergistic therapy was achieved due to incorporation of the antitumor effect of Zn(2+) and DOX.
The observation of ionic signaling dynamics in intact pancreatic islets has contributed greatly to our understanding of both α- and β-cell function. Insulin secretion from β-cells depends on the firing of action potentials and consequent rises of intracellular calcium activity ([Ca(2+)]i). Zinc (Zn(2+)) is cosecreted with insulin, and has been postulated to play a role in cell-to-cell cross talk within an islet, in particular inhibiting glucagon secretion from α-cells. Thus, measuring [Ca(2+)]i and Zn(2+) dynamics from both α- and β-cells will elucidate mechanisms underlying islet hormone secretion. [Ca(2+)]i and intracellular Zn(2+) can be measured using fluorescent biosensors, but the most efficient sensors have overlapping spectra that complicate their discrimination. Hyperspectral imaging can be used to distinguish signals from multiple fluorophores, but available hyperspectral implementations are either too slow to measure the dynamics of ionic signals or not suitable for thick samples. We have developed a five-dimensional (x,y,z,t,λ) imaging system that leverages a snapshot hyperspectral imaging method, image mapping spectrometry, and light-sheet microscopy. This system provides subsecond temporal resolution from deep within multicellular structures. Using a single excitation wavelength (488 nm) we acquired images from triply labeled samples with two biosensors and a genetically expressing fluorescent protein (spectrally overlapping with one of the biosensors) with high temporal resolution. Measurements of [Ca(2+)]i and Zn(2+) within both α- and β-cells as a function of glucose concentration show heterogeneous uptake of Zn(2+) into α-cells that correlates to the known heterogeneities in [Ca(2+)]i. These differences in intracellular Zn(2+) among α-cells may contribute to the inhibition in glucagon secretion observed at elevated glucose levels.
Flexible power sources with high energy density are crucial for the realization of next-generation flexible electronics. Theoretically, rechargeable flexible zinc-air (Zn-air) batteries could provide high specific energy, while their large-scale applications are still greatly hindered by high cost and resources scarcity of noble-metal-based oxygen evolution reaction (OER)/oxygen reduction reaction (ORR) electrocatalysts as well as inferior mechanical properties of the air cathode. Combining metallic Co4N with superior OER activity and Co-N-C with perfect ORR activity on a free-standing and flexible electrode could be a good step for flexible Zn-air batteries, while lots of difficulties need to be overcome. Herein, as a proof-of-concept experiment, we first propose a strategy for in situ coupling of strung Co4N and intertwined N-C fibers, by pyrolyzation of the novel pearl-like ZIF-67/polypyrrole nanofibers network rooted on carbon cloth. Originating from the synergistic effect of Co4N and Co-N-C and the stable 3D interconnected conductive network structure, the obtained free-standing and highly flexible bifunctional oxygen electrode exhibits excellent electrocatalytic activity and stability for both OER and ORR in terms of low overpotential (310 mV at 10 mA cm(-2)) for OER, a positive half-wave potential (0.8 V) for ORR, and a stable current density retention for at least 20 h, and especially, the obtained Zn-air batteries exhibit a low discharge-charge voltage gap (1.09 V at 50 mA cm(-2)) and long cycle life (up to 408 cycles). Furthermore, the perfect bendable and twistable and rechargeable properties of the flexible Zn-air battery particularly make it a potentially power portable and wearable electronic device.
Among the biologically required first row, late d-block metals from Mn(II) to Zn(II), the catalytic and structural reach of Zn(II) ensures that this essential micronutrient touches nearly every major metabolic process or pathway in the cell. Zn is also toxic in excess, primarily because it is a highly competitive divalent metal and will displace more weakly bound transition metals in the active sites of metalloenzymes if left unregulated. The vertebrate innate immune system uses several strategies to exploit this "Achilles heel" of microbial physiology, but bacterial evolution has responded in kind. This review highlights recent insights into transcriptional, transport, and trafficking mechanisms that pathogens use to "win the fight" over zinc and thrive in an otherwise hostile environment.
Regulation of enzymes through metal ion complexation is widespread in biology and underscores a physiological need for stability and high catalytic activity that likely predated proteins in the RNA world. In addition to divalent metals such as Ca(2+), Mg(2+), and Zn(2+), monovalent cations often function as efficient and selective promoters of catalysis. Advances in structural biology unravel a rich repertoire of molecular mechanisms for enzyme activation by Na(+) and K(+) Strategies range from short-range effects mediated by direct participation in substrate binding, to more distributed effects that propagate long-range to catalytic residues. This review addresses general considerations and examples.
Low concentration of a heavy metal is toxic and can be classified as one of the pollution sources. Industrial and human waste can pollute water with heavy metals and soils breaking down under the effect of acidic rain, which release heavy metals into river, streams, lakes, and ground water. Bioaccumulation of heavy metals in vital organs of the human body damages these organs, including the liver and kidney, which are the main organs for metabolism, detoxification, and excretion. The present study aims to
 investigate into concentrations of such heavy metals (Fe, Cu, Zn, and Pb) in both ground and tap water samples collected from different areas in Hail region, KSA. Then, this study moves forward to examine the effects of such concentrations on the biochemistry of serum in rats. In this regard, the results demonstrate the presence of significant differences (p < 0.05) in the liver function parameters, alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase, total proteins, albumin, and globulin between all the studied groups that were exposed to heavy-metals-polluted water, when compared with the control group. In addition, there were significant differences (p < 0.05) in the kidney function parameters, uric acid, urea, and creatinine, when compared with the control group. Thence, and as this study indicates, heavy-metals-polluted water can cause disturbance in the liver and kidney function parameters, which highlights health risks of the water polluted with heavy metals. In this sense, the concerned authorities should regularly carry out survey and should monitor underground water, and people have to be aware of such risks.
This study characterized diurnal variations in the compositions of total suspended particulates (TSP) and dry deposits of particulates from ambient air, and the metallic elements that are contained in them at harbor, airport and farmland (HAF) sampling sites from August, 2013 to July, 2014. Two-way ANOVA of the amounts of metallic elements in the TSP and dry deposits was carried out in all four seasons at the HAF sampling sites. The metallic elements Cr and Cu originated in local emission sources at the airport. Metallic elements Zn and Pb originated in local emission sources at the harbor. Finally, metallic element Cd originated in local emissions form farmland. The following results were also obtained. (1) The metallic composition of the TSP differed significantly from that of the dry deposits in all four seasons at the harbor and farmland sampling sites, but not at the airport sampling site. (2) High correlations coefficients were found between the amounts of metallic elements Cr and Cu in the TSP and those in the dry deposits at the airport sampling site. (3) Pb was present in the TSP and the dry deposits at the harbor sampling site.
A pot experiment was conducted to investigate the effects of biochars on the availability of heavy metals (Cd, Cu, Mn, Ni, Pb, and Zn) to ryegrass in an alkaline contaminated soil. Biochars only slightly decreased or even increased the availability of heavy metals assesses by chemical extractant (a mixture of 0.05 mol L(-1) ethylenediaminetetraacetic acid disodium, 0.01 mol L(-1) CaCl2, and 0.1 mol L(-1) triethanolamine). The significantly positive correlation between most chemical-extractable heavy metals and the ash content in biochars indicated the positive role of ash in this extraction. Biochars significantly reduced the plant uptake of heavy metals, excluding Mn. The absence of a positive correlation between the chemical-extractable heavy metals and the plant uptake counterparts (except for Mn) indicates that chemical extractability is probably not a reliable indicator to predict the phytoavailability of most heavy metals in alkaline soils treated with biochars. The obviously negative correlation between the plant uptake of heavy metals (except for Mn) and the (O + N)/C and H/C indicates that biochars with more polar groups, which were produced at lower temperatures, had higher efficiency for reducing the phytoavailability of heavy metals. The significantly negative correlations between the plant uptake of Mn and ryegrass biomass indicated the "dilution effect" caused by the improvement of biomass. These observations will be helpful for designing biochars as soil amendments to reduce the availability of heavy metals to plants in soils, especially in alkaline soils.
We measured concentrations of selected metals (Al, Ba, Cu, Mn, Hg, Sr, V, and Zn) in water, sediments, and fish from Lake Chapala and a reference site to evaluate potential negative effects on wildlife, particularly fish-eating birds. Fish metal concentrations ranged from 0.05 µg/g wet weight (ww) for Al and Cu to 64.70 µg/g ww for Sr. There was a positive and significant correlation between fish length and metals particularly for Ba, Cu, Mn, and Zn in Lake Chapala (p < 0.05). However, there were no significant correlations between metal concentrations and δ(15)N values in fish indicating no biomagnification through the food web. Overall, metal concentrations in water, sediments, and fish were similar to and in some cases below those reported for Lake Chapala over the last 20 years. Also, metal concentrations were below those that could be of concern for negative effects on fish and wildlife of Lake Chapala.
This study investigates temporal stability in the scale microchemistry of brown trout Salmo trutta in feeder streams of a large heterogeneous lake catchment and rates of change after migration into the lake. Laser-ablation inductively coupled plasma mass spectrometry was used to quantify the elemental concentrations of Na, Mg, Mn, Cu, Zn, Ba and Sr in archived (1997-2002) scales of juvenile S. trutta collected from six major feeder streams of Lough Mask, County Mayo, Ireland. Water-element Ca ratios within these streams were determined for the fish sampling period and for a later period (2013-2015). Salmo trutta scale Sr and Ba concentrations were significantly (P < 0·05) correlated with stream water sample Sr:Ca and Ba:Ca ratios respectively from both periods, indicating multi-annual stability in scale and water-elemental signatures. Discriminant analysis of scale chemistries correctly classified 91% of sampled juvenile S. trutta to their stream of origin using a cross-validated classification model. This model was used to test whether assumed post-depositional change in scale element concentrations reduced correct natal stream classification of S. trutta in successive years after migration into Lough Mask. Fish residing in the lake for 1-3 years could be reliably classified to their most likely natal stream, but the probability of correct classification diminished strongly with longer lake residence. Use of scale chemistry to identify natal streams of lake S. trutta should focus on recent migrants, but may not require contemporary water chemistry data.
Zinc is a naturally occurring element with roles in wound healing and rescuing tissue integrity, particularly in the gastrointestinal system, where it can be detected in the mucosal and submucosal layers. Zinc chelates are known to have beneficial effects on the gastrointestinal mucosa and in cases of gastric ulcer. We synthesized complexes of zinc featuring a heterocyclic amine binding amino acids then investigated their ability to enhance the gastric self-repair. Zinc-morpholine complex, Zn(L)SCN, namely showed strong free-radical scavenging, promotion of the DNA and RNA polymerases reconstruction and suppression of cell damage. The complex's mode of action is proposed to involve hydrogen bond formation via its bis(thiocyanato-k)zinc moiety. Zn(L)SCN complex had potent effects on gastric enzymatic activity both in vitro and in vivo. The complex disrupted the ulcerative process as demonstrated by changes in the intermediate metabolites of the oxidative pathway - specifically, reduction in the MDA levels and elevation of reduced glutathione together with an attenuation of oxidative DNA damage. Additionally, Zn(L)SCN restored the gastric mucosa, inhibited the production of pro-inflammatory cytokines (IL-6, TNF and the caspases), and preserved the gastric mucous balance. Zn(L)SCN thus exhibited anti-oxidative, anti-inflammatory and anti-apoptotic activities, all of which have cytoprotective effects on the gastric lining.
Zinc (Zn) plays an essential role in many biological processes including immune response. Impaired Zn status promotes immune dysfunction, and it has been associated with enhanced chronic inflammation during aging. It has been suggested that the measurement of circulating Zn by itself could not reflect the real Zn status of an individual. It is therefore necessary to identify other determinants associated with plasma Zn to better understanding how physiopathological conditions during aging may affect the concentration of this metal.
We have investigated the association between Zn levels and some biomarkers in 1090 healthy elderly from five European countries to increase the accuracy in the assessment of the Zn status. Stepwise multivariate linear regression models were used to analyze the influence of factors such as age, dietary intake, inflammatory mediators, laboratory parameters and polymorphisms previously associated with Zn homeostasis.
Plasma Zn decrement was most strongly predicted by age, while positive correlations were found with albumin, RANTES and Zn intake after adjustment for multiple confounders. HSP70 +1267 AA genotype was an independent factor associated with Zn plasma concentrations. Cu/Zn ratio was positively associated with markers of systemic inflammation and age and negatively associated with albumin serum levels.
Our findings show the most important independent determinants of plasma Zn concentration and Cu/Zn ratio variability in elderly population and suggest that the decline with age of Zn circulating levels is more dependent on physiopathological changes occurring with aging rather than to its nutritional intake.
The main subject of this investigation was the assessment of the lithogenic and anthropogenic distribution of 69 elements in the sediments and fluvisol in the Bregalnica river basin. Alluvial soil and fluvisol samples were collected from the total of eighteen locations along the course of the Bregalnica river and additional thirteen samples were collected from its tributaries.
 The matrix elements accumulation patterns followed the order: Fe > Na > Al > Ca > Mg > K > Ti > P. The potentially toxic elements, such as As, Cd, Pb, and Zn, have enriched content in the sediments in the medium course of the river, where the main anthropogenic introduction activities occurred. By multivariate analysis the dominant geochemical associations were extracted, as follows: F1: Y-Eu-Lu-Cr-V-La-Gd-Nb-Co-Hf-Zr-Ga-Mg-Fe-Sr-Ta-Sn-Li-Na-Rb-Ni-Ge-Be-Cs; F2: As-W-Ba-Ag-Cu-Tl-Zn-Sb-Mo-In-Cd-Te-Bi-Pb and F3: I-Sc-Br-K. Lead and zinc contents were strongly correlated with the hydrothermal exploitations, especially in the area of Neogene clastite and vulcanite. These elements occur as dominant geochemical markers of the anthropogenic impacts of polymetallic enrichments due to the hydrothermal ore exploitation (Factor 2). The impact of Oligocene volcanism (Kratovo-Zletovo region) was observed in the lithological enrichments of Pb, Zn, Cu, As, Sb, Mo and Bi. Despite the natural distribution along the course of the Bregalnica river, an exceptional anomaly in the iron distribution of the old polymetallic unused mineralization was detected in Zone 1 (Berovo region).
A partially fluorinated, angular tetracarboxylic acid linker (H4L) incorporating a pendant amine moiety forms a three-dimensional Zn(II) framework, 1. The structure consists of paddle-wheel Zn2(CO2)4 secondary building units (SBUs) and Zn12(CO2)24 supramolecular building blocks (SBBs). Thermal stability of 1 is found to be low. However, it undergoes transmetalation reaction with Cu(II) at room temperature without losing crystallinity affording an isostructural framework, 1Cu. Framework 1Cu is thermally robust and allows generation of the solvent-free porous framework 1Cu' upon activation with coordinatively unsaturated metal centers. Framework 1Cu' exhibits water stability and at 77 K, adsorbs 2.56 wt % of H2 up to 1 bar that significantly increases to 4.01 wt % at 13 bar. Also, this framework gives a high adsorption of 164.70 cc/g of CH4 (11.7 wt %) at 303 K and 60 bar. The channel surfaces decorated with -NH2 group and unsaturated metal centers in 1Cu' allow a promising 36.4 wt % of CO2 adsorption at 1 bar and 273 K. Moreover, it exhibits pronounced selectivity of CO2 adsorption over N2 and H2 at 273 K. Finally, the versatility of 1Cu' is shown by its excellent heterogeneous catalytic activity in the Biginelli coupling reactions involving an aldehyde, urea, and ethylacetoacetate to afford dihydroprimidinones.
In urban and industrial areas, higher plants are used as biomonitors of exposure. The objective of this study was to assess metals accumulation in leaves of dendroflora for the city of Novi Sad, Serbia, in May and September. The investigation was conducted at three sites in the urban area of Novi Sad. Determination of metals concentration for Al, As, Cr, Mn, Fe, Co, Ni, Cu, Zn, Cd, and Pb in the sample was performed by inductively coupled plasma-optical emission spectrometry (ICP/OES). In the leaves of the examined tree species the highest concentrations were obtained for: Al, Fe, Mn, and Zn. The highest mean concentrations of metals were present in leaves of Aesculus hippocastanum in September. Trees from Liman and the Danube Park contained higher mean concentrations of metals in the leaves. In A. hippocastanum and Platanus hybrida an increase of al., As, Cr, Fe, and Pb concentrations occurred from May to September, with higher concentrations of Al and Fe noted in May. However, in Celtis australis, Juglans regia, and Tilia platypyllos there was a reduction in Al, Mn, Fe, and Zn from May to September. The basis for these findings requires further investigation, but diverse washing procedures may account partially for these observations.
The CXCR4 chemokine receptor is implicated in a number of diseases including HIV infection and cancer development and metastasis. Previous studies have demonstrated that configurationally restricted bis-tetraazamacrocyclic metal complexes are high-affinity CXCR4 antagonists. Here, we present the synthesis of Cu(2+) and Zn(2+) acetate complexes of six cross-bridged tetraazamacrocycles to mimic their coordination interaction with the aspartate side chains known to bind them to CXCR4. X-ray crystal structures for three new Cu(2+) acetate complexes and two new Zn(2+) acetate complexes demonstrate metal-ion-dependent differences in the mode of binding the acetate ligand concomitantly with the requisite cis-V-configured cross-bridged tetraazamacrocyle. Concurrent density functional theory molecular modelling studies produced an energetic rationale for the unexpected [Zn(OAc)(H2 O)](+) coordination motif present in all of the Zn(2+) cross-bridged tetraazamacrocycle crystal structures, which differs from the chelating acetate [Zn(OAc)](+) structures of known unbridged and side-bridged tetraazamacrocyclic Zn(2+) -containing CXCR4 antagonists.
A mild Zn-catalyzed intermolecular Diels-Alder/ene tandem reaction with styrene as a 4π-component is reported. A variety of dihydronaphthalene products could be prepared in moderate to good yields. Moreover, a combination of DFT calculations and experiments was performed to further understand the mechanism of this unique tandem reaction.
Metallo-beta-lactamases (MBLs) are broad-spectrum, Zn(II)-dependent lactamases able to confer resistance to virtually every β-lactam antibiotic currently available. The large diversity of active-site structures and metal content among MBLs from different sources has limited the design of a pan-MBL inhibitor. GOB-18 is a divergent MBL from subclass B3 that is expressed by the opportunistic Gram-negative pathogen Elizabethkingia meningoseptica This MBL is atypical, since several residues conserved in B3 enzymes (such as a metal ligand His) are substituted in GOB enzymes. Here, we report the crystal structure of the periplasmic di-Zn(II) form of GOB-18. This enzyme displays a unique active-site structure, with residue Gln116 coordinating the Zn1 ion through its terminal amide moiety, replacing a ubiquitous His residue. This situation contrasts with that of B2 MBLs, where an equivalent His116Asn substitution leads to a di-Zn(II) inactive species. Instead, both the mono- and di-Zn(II) forms of GOB-18 are active against penicillins, cephalosporins, and carbapenems. In silico docking and molecular dynamics simulations indicate that residue Met221 is not involved in substrate binding, in contrast to Ser221, which otherwise is conserved in most B3 enzymes. These distinctive features are conserved in recently reported GOB orthologues in environmental bacteria. These findings provide valuable information for inhibitor design and also posit that GOB enzymes have alternative functions.
In order to better understand air pollution in deve-loping regions, such as China, it is important to investigate the wet deposition behavior of atmospheric trace metals and its sources in the subtropical watershed. This paper studies the seasonal change of trace metal concentrations in precipitation and other potential sources in a typical subtropical watershed (Jiazhuhe watershed) located in the downstream of the Yangtze River of China. The results show that typical crustal elements (Al, Fe) and trace element (Zn) have high seasonal variation patterns and these elements have higher contents in precipitation as compared to other metals in Jiazhuhe watershed. In addition, there is no observed Pb in base flow in this study, and the concentration magnitudes of Al, Ba, Fe, Mn, Sr, and Zn in base flow are significantly higher than that of other metals. During different rainfall events, the dynamic export processes are also different for trace metals. The various trace metals dynamic export processes lead to an inconsistent mass first flush and a significant accumulative variance throughout the rainfall events. It is found that in this region, most of the trace metals in precipitation are from anthropogenic emission and marine aerosols brought by typhoon and monsoon.
Metal contamination from coal ashes (CAs) is widely recognized as a significant environmental concern. To learn more about metal detoxification and accumulation potential of earthworm species, metal-rich tea factory coal ashes (TFCA) were fed to Eisenia fetida and Lampito mauritii by employing a fluorescent tag detection method. Fascinatingly, on feeding fluorescence probed Zn and Cd along with cow dung to Eisenia fetida, the detection of the gut-proteins with a molecular mass higher than 100 kDa was a distinct evidence of metal binding. Significant increases were observed in the content of humified organic C [humic acid (HAC) and fulvic acid C (FAC)] and degree of humification during vermicomposting. Concurrently, considerably large amount of toxic metals (Cr, Cd, Pb, and Zn) was transformed from exchangeable to recalcitrant (organic matter and mineral bound) fractions. Moreover, total metal concentrations were reduced with high removal efficiency upon vermicomposting.
A series of bentonite nanocomposites have been synthesized by modifying bentonite with hexadecyltrimethylammonium bromide (CTMAB) and the common complexing agents, complexone (ethylene diamine tetraacetic acid, EDTA) or mercaptocomplexant (2-Mercaptobenzothiazole, MBT). These adsorbents are used to remove heavy metal ions (Cu(2+), Zn(2+), Mn(2+),Co(2+)). The Bent-CTMAB-MBT adsorbed metal ions are higher than Bent-CTMAB-EDTA under the same ion concentration in AAS. Compared with the single ion system, the adsorption of the mixed ion system of Cu(2+), Zn(2+), Mn(2+), Co(2+) had decreased differently. In the mixed system, the adsorption of Mn(2+) is significantly lower, but the adsorption of Cu(2+) was highest. The adsorption sequence of these four metal ions was Cu(2+) > Zn(2+) > Co(2+) > Mn(2+), and the selective adsorption was closely related to the hydration energy
 of heavy metal ions. We could remove more metal ions in different stages with the adsorption sequence.
Tin generates a wide variety of biological functions due to its chemical character. In this article, the modes of the biological functions of tin(especially organotin compounds) are reviewed, with special emphasis on the connection with the immune system, brain nervous system and endocrine system, on the basis of our data. To sum up this article, the biological functions of organotin compounds appear to be due to the following several processes: (1) their incorporation into the cells in vesicle form through fusion or in a similar manner to their incorporation in cationic form; (2) transport to and accumulation in the regions of the Golgi apparatus and endoplasmic reticulum (ER), but not to or in the plasma membrane or nucleus because of their hydrophobicity; (3) inhibition of intracellular phospholipid transport between organelles due to impairment of the structures and functions of the Golgi apparatus and ER; (4) inhibition of the membrane-mediated signal transduction system leading to DNA synthesis via phospholipid turnover and Ca2+ mobilization, as in cell proliferation systems; (5) disturbance of the trace element balance and the localization of certain elements; (6) disorders of membrane-mediated Ca2+ homeostasis via various channel functions including Zn modulation on the plasma and organelle membranes, and protein phosphorylation, as in the signal transduction systems of memory and olfaction; (7) necrosis or apoptosis in vivo or toxic cell death in vitro.
This review explains the mechanisms of apoptosis related to the impacts of zinc deficiency and organotin exposure on the immune and central nervous systems. In the immune systems, both zinc deficiency and trialkyltin exposure lead to severe thymic atrophy and affect T-lymphocyte development through apoptosis of double positive stage pre-T-cells(CD4+/CD8+) in the cortex region. Their apoptosis are caused mainly through decrease in Bcl-2 expression, activation of ROS production/release, oxidative stress, mitochondrial cytochrome c release and activation of caspase cascade, with increases in glucocorticoids in zinc deficiency, without the involvement of glucocorticoid in organotin exposure In the central nervous system, both zinc deficiency and trialkyltin exposure reduce learning, memory and sensory functions through neuronal apoptosis caused by activation of ROS production/release, release of pro-apoptotic factors such as cytochrome c or apoptosis-inducing factor(AIF), with Fe excessive accumulation leading to ROS production and with depletion of hippocampus Zn (mossy fiber Zn) causing various Ca2+ channel disorder of synapse in the hippocampus, and with excessive accumulation of Ca through cAMP-dependent Ca(2+)-channel disorder by excessive PTH and cAMP excessive production in the olfactory systems such as olfactory epithelium and olfactory bulb.
Trace elements are the essential nutrients. Now, 9 elements, Fe, Zn, Cu, Se, I, Go, Cr, Mn, Mo, are recognized as essential trace elements. Serum concentration of Fe, Zn and Cu are about 100 μg/dL, and have important physiological roles. Zinc needs special care because over 300 enzymes contain Zn, and zin deficiency cause various disorders. In advancing age serum Zn concentration decrease. Although the daily requirement of zinc is 10-15 mg in adults, it is necessary to supply much more zinc than adult, by the reason of low intake and low absorption in the elderly. In the geriatric ward of the hospital, many zinc deficient patients suffered from decubitus ulcers, dermatitis, alopecia, taste disorders etc. A 86 y.o. female with deep sacral decubitus ulcer was shown in this report. Her decubitus ulcer was completely recovered after daily administration of polaprezinc containing 34 mg Zn for 18 months, A 76 y.o. female brought about severe hypocupuremia. Serum Cu concentration decreased from 112 μg/dL to 7 μg/dL after 5 months daily administration of 34 mg Zn. Serum Zn concentration elevated from 47 μg/dL to 117 μg/dL, and Cu/Zn ratio decreased 2.38 to 0.06. After stopped zinc supplementation, serum Cu rapidly increased in a 2 month period. At the same time, serum Zn decreased quickly. It was the interesting fact that anemia improved associated with the increase of serum Cu. In the geriatric ward of the hospital, it is necessary to supply zinc in order to prevent respiratory infections such as pneumonia.
In the dietary reference intakes, EAR(estimated average requirement), RDA(recommended dietary allowance), AL(adequate intake), DG(tentative dietary goal for preventing life style related diseases) and UL(tolerable upper intake level) of eight types of trace elements (iron: Fe, zinc: Zn, copper: Cu, manganese: Mn, iodine: I, selenium: Se, chromium: Cr, molybdenum: Mo) have been set. However, in the meals of hospitals, only iron of which has been taken into account. The content of these trace elements in the enteral nutrient released after 2000 was determined by considering the content of dietary reference intakes of trace elements for Japanese and considered so not fall into deficiency. However, enteral nutrient must be used considering the content of Zn, Cu and the Zn/Cu ratio, the selenium content, and the route of administration, in order to avoid falling into deficiency.
In a healthy condition, trace elements constituting the living body are regulated and maintained their balance of each other and their range of physiological optimum concentration in order to maintain the normal vital functions. When the optimum conditions of their balance and their homeostasis, however, are broken down by deficiency or excess of certain trace element, an excess accumulation or deficiency of specified element is induced and it follows that peculiar disease is caused according to function of each specified element. Generally, the disturbance of major elements such as O, C, H, N, Ca, P will induce a nutrition lesion and electrolytic abnormality, and the disturbance of 10 trace elements such as Fe, F, Si, Zn, Sr, Rb, Br, Pb, Mn, Cu being at ppm order and 14 ultra-trace elements such as Al, Cd, Sn, Ba, Hg, Se, I, Mo, Ni, B, Cr, As, Co, V being at ppb order will give rise to functional disorder of enzyme and physiological active substance in living body.
Novel materials based on Zn(HPB)2 and Ir-complexes were synthesized as blue or red emitters, respectively. White organic light emitting diodes were fabricated using the Zn(HPB)2 as a blue emitting layer, Ir-complexes as a red emitting layer and Alq3 as a green emitting layer. The obtained experimental results, were based on white OLEDs fabricated using double emission layers of Zn(HPB)2 and Alq3:Ir-complexes. The doping rate of the Ir-complexes was varied at 0.4%, 0.6%, 0.8% and 1.0%. When the doping rate of the Alq3:Ir-complexes was 0.6%, a white emission was achieved. The Commission Internationale de l'Eclairage coordinates of the device's white emission were (0.316, 0.331) at an applied voltage of 10.75 V.
A 75-nm-thick ZnO film was deposited by a sol-gel method on indium-tin oxide (ITO)-coated glass. This film served as a liquid crystal (LC) alignment layer. We report the fabrication and characteristics of this film after ion-beam (IB) irradiation. Uniform LC alignment was achieved at an IB incident energy above 2400 eV. The IB-treated ZnO surface was analyzed by X-ray photoelectron spectroscopy (XPS), monitoring the intensity of the Zn 2p and O 1s peaks as a function of IB-irradiation energy density. The electro-optical (EO) characteristics of a twisted nematic-liquid crystal display (TN-LCD) were comparable to rubbed polyimide.
We demonstrate flexible organic/inorganic hybrid thin-film transistors (TFTs) on a polydimethysilox- ane (PDMS) elastomer substrate. The active channel and gate insulator of the hybrid TFT are composed of In-Ga-Zn-O (IGZO) and blends of poly(vinylidene fluoride-trifluoroethylene) [P(VDF- TrFE)] with poly(methyl methacrylate) (PMMA), respectively. It has been confirmed that the fabri- cated TFT display excellent characteristics: the recorded field-effect mobility, sub-threshold voltage swing, and I(on)/I(off) ratio were approximately 0.35 cm2 V(-1) s(-1), 1.5 V/decade, and 10(4), respectively. These characteristics did not experience any degradation at a bending radius of 15 mm. These results correspond to the first demonstration of a hybrid-type TFT using an organic gate insulator/oxide semiconducting active channel structure fabricated on PDMS elastomer, and demonstrate the feasibility of a promising device in a flexible electronic system.
Zn(1-x)Co(x)O (x = 0-0.07) single-crystalline nanorods were prepared by a modified microemulsion route. The crystalline structure, morphology, optical, and hysteresis loop at low and room temperature of as-prepared materials were characterized by XRD, TEM, PL spectra, and magnetic measurement respectively. The nanorods are 80-250 nm in diameter and about 3 μm in length. X-ray diffraction data, TEM images confirm that the materials synthesized in optimal conditions are ZnO:Co single crystalline solid solution without any impurities related to Co. The PL spectra show that the ferromagnetic samples exhibit strong Zn interstitials and oxygen vacancy emission indicating defects may stabilize ferromagnetic order in the obtained diluted magnetic semiconductors. Magnetic measurements show that the Zn(1-x)Co(x)O nanorods exist obvious ferromagnetic characteristics with T(c) above 300 K. M(s) and coercivities first increase and then decrease with dopant concentration increasing, reaching the highest for 3% doping level. The structural and magnetic properties of these samples support the hypothesis that the FM of DMS nanorods is due to a defect mediated mechanism instead of cobalt nanoclusters and carrier mediated.
Perovskite zinc
 titanate (ZnTiO3) nanopowders were synthesized using the sonochemical method combined with calcinations at 500 °C and 900 °C for 2 h to improve their crystallinity. The effect of calcination temperature on their structural, optical, and photocatalytic properties has been studied. The cubic phase and the mixing phase of cubic and hexagonal were observed in sample calcined at 600 °C and 700 °C, respectively, while the spinel ZnTiO3 and rutile TiO2 phase arises in sample calcined over 700 °C. The valence state was investigated by the X-ray absorption near-edge spectroscopy technique, and the corresponding results indicate the existence of Zn(2+) and Ti(4+) in the powders. The chemical states of the samples were scrutinized by X-ray photoelectron spectroscopy. The average particle size is approximately 20-240 nm. The excellent photocatalytic performance of ZnTiO3 nanoparticle calcined at 700 °C gave complete degradation Rhodamine B (RhB) in 75 min under ultraviolet light exposure with the k rate of 0.033 min (-1) and 55% of decolorization RhB in 210 min under visible irradiation. The sample calcined at 700 °C ensures a good dielectric permittivity with a value 20 and the loss tangent of about 10(-2) .
The exposure of heavy metals to lake bed sediment of scenic areas may pose risks on aquatic ecosystems and human health, however very few studies on risk assessment have been reported for scenic areas. Accordingly, this study determined concentration levels, and assessed contamination characteristics and risks, of heavy metals in lake bed sediment of National Scenic Areas Songhuahu (NSAS) in China. The concentrations of Zn, Cr, Pb, Ni, and Cu were determined in 29 bed sediment samples. Results showed that the mean values of Zn, Cr, Pb, Ni, and Cu were 92.69, 90.73, 38.29, 46.77, and 49.44 mg/kg, respectively. Pearson correlation coefficients indicated that organic matter was a major factor influencing distribution of heavy metals. The results for enrichment factors indicated that contamination rates and anthropogenic inputs of single heavy metals decreased in the order Cu > Ni > Pb > Cr > Zn; results of Nemerow integrated pollution index suggested that 72.41% of sampling sites were exposed to low to moderately integrated pollution, and 27.59% of sampling sites were exposed to strongly integrated pollution. According to results for potential ecological risk index, ecological risks of single and all the heavy metals in bed sediment from all the sampling sites were low. Human risks were assessed with hazardous quotients, and the results suggested that exposure of heavy metals to bed sediment posed no or little risk to human health, and the pathway of ingestion significantly contributed to human health risks.
Histone deacetylase 6 (HDAC6) is a critical target for drug design because of its role in oncogenic transformation and cancer metastasis, and is unique among all histone deacetylases in that it contains tandem catalytic domains designated CD1 and CD2. We now report the crystal structures of CD2 from Homo sapiens HDAC6 and of CD1 and CD2 from Danio rerio HDAC6. We correlated these structures with activity measurements using 13 different substrates. The catalytic activity of CD2 from both species exhibited broad substrate specificity, whereas that of CD1 was highly specific for substrates bearing C-terminal acetyllysine residues. Crystal structures of substrate complexes yielded unprecedented snapshots of the catalytic mechanism. Additionally, crystal structures of complexes with eight different inhibitors, including belinostat and panobinostat (currently used in cancer chemotherapy), the macrocyclic tetrapeptide HC toxin, and the HDAC6-specific inhibitor N-hydroxy-4-(2-((2-hydroxyethyl)(phenyl)amino)-2-oxoethyl)benzamide, revealed surprising new insight regarding changes in Zn(2+) coordination and isozyme-specific inhibition.
A series of open-framework metal oxalates (metal = Zn, Co, Mn, Bi, In) were prepared under solvent-free conditions by a supramolecular templating approach. These compounds have cationic, anionic, and neutral frameworks with pore apertures ranging from small 8-membered rings (8 MRs) to extra-large 16 and 20 MRs. The zinc oxalate exhibits a proton conductivity of 2.6 × 10(-3) S cm(-1) at 60 °C under 98% relative humidity.
Second-generation ethanol (2G-bioethanol) uses lignocellulosic feedstocks for ethanol production. Sugarcane is one among the most suitable crops for biofuel production. Its juice is extracted for sugar production, while sugarcane bagasse, straw, and senescing leaves are considered industrial waste. Senescence is the age-dependent deterioration of plant cells, ultimately leading to cell death and completion of the plant life cycle. Because senescing leaves may also be used for biofuel production, understanding the process of natural senescence, including remobilization of nutrients and its effect on cell walls can provide useful information for 2G-bioethanol production from sugarcane leaves.
The natural senescence process in leaves of the commercial sugarcane cultivar RB867515 was investigated. Senescence was characterized by strong reduction in photosynthetic pigments content, remobilization of the nutrients N, P, K, B, Cu, Fe, and Zn, and accumulation of Ca, S, Mg, B, Mn, and Al. No significant changes in the cell-wall composition occurred, and only small changes in the expression of cell wall-related genes were observed, suggesting that cell walls are preserved during senescence. Senescence-marker genes, such as SAG12-like and XET-like genes, were also identified in sugarcane and found to be highly expressed.
Our study on nutrient remobilization under senescence in a vigorous sugarcane cultivar can contribute to the understanding on how nutrient balance in a high-yielding crop is achieved. In general, neutral monosaccharide profile did not change significantly with leaf senescence, suggesting that senescing leaves of sugarcane can be as a feedstock for biofuel production using pretreatments established for non-senescing leaves without additional efforts. Based on our findings, the potential biotechnological applications for the improvement of sugarcane cultivars are discussed.
Three new DOTAM (1,4,7,10-tetrakis(acetamido)-1,4,7,10-tetraazacyclododecane) complexes have been synthesized and characterized by X-ray crystallography: [Co(DOTAM)]Cl2•3H2O, [Ni(DOTAM)]Cl2•4H2O, and [Cu(DOTAM)](ClO4)2•H2O. Solid state and solution IR spectroscopic features for a series of [M(DOTAM)](2+) complexes (M=Mn, Co, Cu, Ni, Ca, Zn) correlate with solid state and solution coordination numbers. [Co(DOTAM)](2+), [Ni(DOTAM)](2+), and [Zn(DOTAM)](2+) are demonstrated to be six-coordinate in both the solid state and in solution, while [Mn(DOTAM)](2+) and [Ca(DOTAM)](2+) are eight-coordinate in the solid state and remain so in solution. [Cu(DOTAM)](2+), which is five-coordinate by X-ray crystallography, is shown to increase its coordination number in solution to six-coordinate.
New first-row transition-metal compounds with the ligand norharmane (9H-Pyrido[3,4-b]indole; Hnor) are reported. The compounds have the general formula [M(LL)(Hnor)(NO3)2](MeOH)0-1 (M=Co, Ni, Cu, Zn; LL=2,2'-bipyridyl (bpy), 1,10-phenanthroline (phen)) and have been characterized by physical and analytical methods. X-ray structural analysis revealed that the compound of formula [Cu(phen)(Hnor)(NO3)2], (1) has a distorted 6-coordinated octahedrally-based geometry, with a planar-based [CuN3O] core, where Cu-L varies between 1.99 and 2.04Å and two weak axial CuO contacts (2.209 and 2.644Å) from two different nitrates. Based on spectroscopic similarities, the other compounds appear to have the same or very similar coordination geometries. The compounds showed clear cell growth inhibitory effects in two different cancer cell lines in vitro, with the copper and zinc complexes being the most toxic and in fact almost comparable to cisplatin. Flow-cytometry analysis confirmed induction of apoptosis in cancer cells treated with the compounds. Interestingly, co-incubation of the cells with metal complexes and CuCl2 induced an increase in the cytotoxic effects, most likely due to the conversion of the metal compounds in the corresponding, and most active, copper analogues.
A high-yield synthesis of [Li{S(H)C(PPh2S)2}]2 [Li2·(3)2] was developed and this reagent was used in metathesis with ZnCl2 and NiCl2 to produce homoleptic complexes 4 and 5b in 85 and 93% yields, respectively. The solid-state structure of the octahedral complex [Zn{S(H)C(PPh2S)2}2] (4) reveals notable inequivalence between the Zn-S(C) and Zn-S(P) contacts (2.274(1) Å vs. 2.842(1) and 2.884(1) Å, respectively). Two structural isomers of the homoleptic complex [Ni{S(H)C(PPh2S)2}2] were isolated after prolonged crystallization processes. The octahedral green Ni(ii) isomer 5a exhibits the two monoprotonated ligands bonded in a tridentate (S,S',S'') mode to the Ni(ii) centre with three distinctly different Ni-S bond lengths (2.3487(8), 2.4500(9) and 2.5953(10) Å). By contrast, in the red-brown square-planar complex 5b the two ligands are S,S'-chelated to Ni(ii) (d(Ni-S) = 2.165(2) and 2.195(2) Å) with one pendant PPh2S group. DFT calculations revealed that the energetic difference between singlet and triplet state octahedral and square-planar isomers of the Ni(ii) complex is essentially indistinguishable. Consistently, VT and (31)P CP/MAS NMR spectroscopic investigations indicated that a mixture of isomers exists in solution at room temperature, while the singlet state square-planar isomer 5b becomes favoured at -40 °C.
Eisenia andrei earthworms were exposed for 7 and 14 days to six samples of soil taken from around an abandoned lead (Pb) mine and characterized by different levels of metal contamination (S6-S1, this latter being the most contaminated soil). The organisms were analyzed
 for metal bioaccumulation and for biological parameters as biomarkers of stress (lysosomal membrane stability; lipofuscin lysosomal content; lysosomal/cytoplasmic volume ratio) and genotoxicity (Micronucleus frequency). Chemical analysis showed the loads of Pb, Cd, Zn, and Cu in the worms following exposure. Among the stress biomarkers, lysosomal membrane stability was significantly affected in the coelomocytes of the earthworms exposed already 7 days to different contaminated soils. Organisms exposed for 14 days to S1 showed in the cells of the chloragogenous tissue, a particularly relevant increase in lipofuscin, a biomarker of oxidative stress, and an increase in the lysosome/cytoplasm volume ratio, indicating stressful condition at the tissue level. Moreover, in the same conditions, a decrease in total body weight was observed. At the longer exposure time, the coelomocytes of worms exposed to S1, S2, and S3 (soils with higher metal concentrations) showed a significant increase in micronuclei (MNi) frequency. Expressions of the P21 and topoisomerase genes, which are involved in DNA repair, showed significant up-regulation in the cells of worms exposed to S1, S2, S3, S4 and to a less extend S6. This may indicate that the worms were only able to successfully reduce the level of DNA damage in S4 and S5 if considering MN frequency data. The biomarker data was integrated by the Earthworm Expert System, allowing an objective interpretation of the complex biological data and clearly defining the areas in which the presence of chemicals is toxic for the edaphic organisms.
The Hofmeister series illustrates how salts produce a wide range of effects in biological systems, which are not exclusively explained by ion charge. In lipid membranes, charged ions have been shown to bind to lipids and either hydrate or dehydrate lipid head groups, and also to swell the water layer in multi-lamellar systems. Typically, Hofmeister phenomena are explained by the interaction of the ions with water, as well as with biological interfaces, such as proteins or membranes. We studied the effect of the divalent cations Mg(2+), Ca(2+), Fe(2+), and Zn(2+) on oriented, stacked, phospholipid bilayers made of dimyristoylphosphatidylcholine (DMPC). Using high-resolution X-ray diffraction, we observed that the cations lead to a swelling of the water layer between the bilayers, without causing significant changes to the bilayer structure. The cations swelled the bilayers in different amounts, in the order Fe(2+) > Mg(2+) > Ca(2+) > Zn(2+). By decomposing the total bilayer electron density into different molecular groups, Zn(2+) and Ca(2+) were found to interact with the glycerol groups of the lipid molecules and cause minor swelling of the bilayers. Mg(2+) and Fe(2+) were found to position near the phosphate groups and cause a strong increase in the number of hydration water molecules. Our results present a molecular mechanism-of-action for the Hofmeister series in phospholipid membranes.
As one of the most impactful industries, coal mining can promote several alterations at surrounding environment. In surface water, elevated concentrations of metals like Mn, Zn, Fe and Al are often observed. Thus, the aim of this study was to investigate the bioaccumulation and the sub-lethal effects of these metals on various organs of the Neotropical bivalve Anodontites trapesialis confined along a stream located near a coal mine, in order to assess a set of biomarkers that could be used for effectively monitoring coal mining areas. Clams were caged, for 96h, at two sites located upstream (Up1 and Up2) and two sites downstream (Dw1 and Dw2) from the mine. Metals bioaccumulation was determined in gills, mantle, digestive gland, muscle and hemolymph and the following biomarkers were measured in A. trapesialis tissues: total antioxidant capacity against peroxyl radicals, metallothionein content, lipid peroxidation (LPO), proteins carbonylation, glutathione S-transferase activity, superoxide dismutase activity and acetylcholinesterase (AChE) activity. The results showed that Al and Fe bioaccumulation in the gills and hemolymph, Al bioaccumulation in the mantle and muscle, increased LPO in the gills (Dw1 and Dw2) and mantle (Dw1), as well as reduced AChE activity in the muscle (Dw1 and Dw2) should be considered effective biomarkers for monitoring coal mining areas. A. trapesialis proved to be an efficient biological model, considering that biomarkers responses were observed in the clams after only 96h of confinement at Dw sites, accordingly this species could be a good candidate for monitoring Neotropical freshwaters.
High salt intake leads to an increase in some proinflammatory cytokines and neurotransmitters involved in the pathogenesis of hypertension. The purpose of this work was to know if oral administration of anti-oxidant and free-radical scavenger CoQ10 may attenuate high salt-induced hypertension via regulating neurotransmitters and cytokines in the hypothalamic paraventricular nucleus (PVN). Adult male Sprague-Dawley (SD) rats were fed with a normal salt diet (NS, 0.3% NaCl) or a high salt diet (HS, 8% NaCl) for 15 weeks to induce hypertension. These rats received CoQ10 (10 mg/kg/day) dissolved in olive oil was given by gavage (10 mg/kg/day) for 15 weeks. HS resulted in higher mean arterial pressure (MAP) and the sympathetic nerve activity (RSNA). These HS rats had higher PVN levels of norepinephrine (NE), tyrosine hydroxylase (TH), interleukin (IL)-1β, NOX2 and NOX4, lower PVN levels of gamma-aminobutyric acid (GABA), IL-10, copper/zinc superoxide dismutase (Cu/Zn-SOD) and the 67-kDa isoform of glutamate decarboxylase (GAD67), as compared with NS group. CoQ10 supplementation reduced NE, TH, IL-1β, NOX2 and NOX4 in the PVN, and induced IL-10, Cu/Zn-SOD and GAD67 in the PVN. These findings suggest that CoQ10 supplementation restores neurotransmitters and cytokines in the PVN, thereby attenuating high salt-induced hypertension.
The pathophysiology of hypertension is complex and multifactorial, and includes exposure to various chemical substances. Several recent studies have documented the reproductive and neurological toxicities of 1-bromopropane (1-BP). Given that 1-BP increased reactive oxygen species in the brain of rats, we hypothesized that 1-BP also has cardiovascular toxicity through increased oxidative stress. To test this hypothesis, male F344 and Wistar Nagoya rats (n = 7-8 per group per test) were exposed to 0 or 1000 ppm of 1-BP via inhalation for 4 weeks (8 h per day, 7 days per week). The exposure to 1-BP increased systolic blood pressure. This effect was associated with a significant decrease in the reduced/oxidized glutathione ratio. A significant increase in nitrotyrosine levels, activation of the NADPH oxidase pathway, which was evidenced by upregulation of gp91phox, a NADPH oxidase subunit, and significant decreases in the expressions of antioxidant molecules such as Cu/Zn- and Mn-superoxide dismutase catalase, and nuclear factor erythroid 2-related factor 2, were observed in the aortas of Wistar Nagoya rats exposed to 1-BP. Our results indicate that subacute (4-week) inhalation exposure to 1-BP increases blood pressure and suggest that this cardiovascular toxic effect is due, at least in part, to increased oxidative stress mediated through activation of the NADPH oxidase pathway. Further study is needed to assess whether NADPH oxidase activation causes the increase in blood pressure in the rats exposed to 1-BP. Copyright © 2016 John Wiley & Sons, Ltd.
In this work, the influence of the metal ions present in vertebrate Sonic Hedgehog was assessed by a series of molecular mechanics molecular dynamics simulations with differing ionic compositions. The obtained data suggest that Ca(ii) binding has a very distinct influence on the composition of the protein surface surrounding the binding site by shaping several ionic interactions with negatively charged sidechains that otherwise would be pointing towards the solvent, repelling potential ligands. Furthermore, the Ca(ii) ions play an important role in the stability of the loop regions where they are coordinated. In contrast, the removal of the Zn(ii) ion results in no noticeable destabilization of its chemical surrounding, however, it is shown that the destabilizing effect of removed Ca(ii) ions is amplified if Zn(ii) is absent as well. Furthermore, a quantum mechanical/molecular mechanical (QM/MM) molecular dynamics simulation of Sonic Hedgehog with special focus on the Zn(ii) binding site has been conducted. The results indicate that QM/MM in contrast to pure MM accurately reproduces structural features also found by experimental studies and therefore is able to provide credible predictions not only of the dynamical properties of the studied system but also of protein-ligand interactions at the metal ion binding site.
In Brazil, children's eating patterns have been characterised by an increased consumption of ultra-processed foods that are fortified. Our aims were to (1) estimate the prevalence of inadequate micronutrient intake among children from low-income families and (2) to assess micronutrient intake from fortified foods. We carried out a cross-sectional study from a randomised field trial conducted at healthcare centres in Porto Alegre, Brazil, with 446 mother-child pairs, with the children aged 2-3 years. Dietary data were assessed using two 24-h recalls. The prevalence of inadequacy for six micronutrients was estimated using the proportion of individuals with intakes below the estimated average requirement (EAR). Micronutrient intakes from fortified foods were evaluated using EAR and upper tolerable level (UL). Healthy foods consumption was below the recommendations, except for beans, and 88·1 % of the children consumed ultra-processed foods. A low prevalence of inadequate micronutrient
 intake was observed for Fe (1·2 %), vitamin C (4·7 %), vitamin A (5·2 %), Ca (11·4 %) and folate (15·2 %). None of the children had intakes less than the EAR for Zn. Fortified foods contributed between 11·3 and 38·3 % to micronutrient intakes, and 43·0 % of the children met the EAR for Fe, 13·9 % for vitamin C and 12·3 % for Zn using fortified foods only. In addition, 4·0 % of the children exceeded the UL for vitamin A, 3·1 % for Zn, 1·1 % for folic acid and 0·2 % for Fe. These results highlight a low prevalence of inadequate micronutrient intakes among children and suggest that such a group could be at risk of excessive micronutrient intakes provided by ultra-processed foods.
Conversion of CO2 and CH4 to value-added products will contribute to alleviating the green-house gas effect but is a challenge both scientifically and practically. Stabilization of the methyl group through CH4 activation and facile CO2 insertion ensure the realization of C-C coupling. In the present study, we demonstrate the ready C-C coupling reaction on a Zn-doped ceria catalyst. The detailed mechanism of this direct C-C coupling reaction was examined based on the results from density functional theory calculations. The results show that the Zn dopant stabilizes the methyl group by forming a Zn-C bond, thus hindering subsequent dehydrogenation of CH4. CO2 can be inserted into the Zn-C bond in an activated bent configuration, with the transition state in the form of a three-centered Zn-C-C moiety and an activation barrier of 0.51 eV. The C-C coupling reaction resulted in the acetate species, which could desorb as acetic acid by combining with a surface proton. The formation of acetic acid from CO2 and CH4 is a reaction with 100% atom economy, and the implementation of the reaction on a heterogeneous catalyst is of great importance to the utilization of the greenhouse gases. We tested other possible dopants including Al, Ga, Cd, In, and Ni and found a positive correlation between the activation barrier of C-C coupling and the electronegativity of the dopant, although C-H bond activation is likely the dominant reaction on the Ni-doped ceria catalyst.
Plastics, foams and ropes collected from beaches in SW England have been analysed for As, Ba, Br, Cd, Cl, Cr, Cu, Hg, Ni, Pb, Sb, Se, Sn and Zn by field-portable-x-ray fluorescence spectrometry. High concentrations of Cl in foams that were not PVC-based were attributed to the presence of chlorinated flame retardants. Likewise, high concentrations of Br among both foams and plastics were attributed to the presence of brominated flame retardants. Regarding heavy metals and metalloids, Cd and Pb were of greatest concern from an environmental perspective. Lead was encountered in plastics, foams and ropes and up to concentrations of 17,500μgg(-1) due to its historical use in stabilisers, colourants and catalysts in the plastics industry. Detectable Cd was restricted to plastics, where its concentration often exceeded 1000μgg(-1); its occurrence is attributed to the use of both Cd-based stabilisers and colourants in a variety of products.
Non-toxic, environment-benign colloidal ZnCulnS Nanocrystals (ZCIS NCs) were synthesized and the temperature dependence of the photoluminescence (PL) energy, line width, and intensity for the ZCIS NCs with different reaction time were studied in the temperature range from 50 to 280 K. Generally, for typical ZCIS NCs ensemble, it has been constantly observed that the PL peaks energy decrease with the experimental temperature raising and the value of Eg(0) decrease with the increase of reaction time. Furthermore, the full width at half maximums (FWHM) of the PL spectra increased with the experimental temperature raising. It was found that the temperature dependence of the integrated PL intensity of ZCIS NCs decrease with the experimental temperature raising and the intensity decrease much with increasing reaction time.
An electrostatically self-assembled multilayer thin film consisting of alternating layers of Keggin polyoxometalate of Zn-substituted tungstoborate (BW11Zn) and Rhodamine B (RhB) has successfully been prepared on a quartz and indium-tin oxide (ITO) glass substrate. The ultraviolet-visible (UV-vis) absorption spectra demonstrated that the electrostatically self-assembled film of (BW11Zn/RhB)n was uniformly deposited layer by layer, and the RhB molecules in the film formed the J-aggregation. The photoelectrochemical investigations showed that the films generated stable cathodic photocurrents that originated from RhB, and the maximal cathodic photocurrent density generated by an eight-layer film was 4.9 µA/cm2 while the film was irradiated with 100 mW/cm2 polychromatic light of 730 nm > λ > 325 nm at an applied potential of 0 V versus a saturated calomel electrode.
Optical Non-Destructive Testing (ONDT) can be applied as penetrating elemental and structure analysis technology in the Pigments identification field. Three-dimensional video microscopy, Raman microscopy and energy dispersive X-ray fluorescence spectroscopy are employed to measure the materials based on a Qing Dynasty meticulous painting. The results revealed that the dark yellow area within the decorative patterns was presented due to the interaction of Emerald green and hematite, and the bright yellow edge area was delineated by Cu-Zn-Pb composition. The interesting thing is that an artificial synthetic ultramarine blue was checked in the painting. According to the first synthesized time of ultramarine blue and Paris green, the time limit of the painting completion can be identified. The principle of Pigment subtractive colorant and nitikaset method were employed to interpreting the results. Optical testing combined with the area of cultural relic identification can be a potential method to build an expert identification system successfully. This work also help lay the optical method groundwork for further cultural relic identification, sterilization, and preservation.
Hybrid solar cells were fabricated using aluminum-doped zinc oxide (AZO) grown by electrochemical deposition from chloride electrolyte solutions with Al/Zn molar ratios of 0.5, 2.5, and 5.0%. The substrates were AZO- and ZnO-seeded ITO. Ordered nanorod structures with high optical transmittance were grown at 0.5% Al/Zn ratio while interconnected micron-sized flakes were grown at 2.5% and 5.0%. The estimated band gap energies increase for higher Al dopant content, showing Burstein-Moss effect. EDX analysis detected high aluminum content in the 5.0% samples suggesting that insulating aluminum oxide phases were formed thus causing reduced solar cell efficiencies. The highest power conversion efficiency of 1.71%, from the 0.5% sample grown on ZnO-seeded ITO, can be attributed to the presence of AZO nanorods which provide a large interfacial area and effective charge transport.
An ethylenediamine functionalized glycidyl methacrylate (GMA) based terpolymeric chelating resin was synthesized for the separation and preconcentration of Cd(II) and Zn(II) by SPE from bread, rice and fruit juice prior to FAAS determination. The resin was characterized by FT-IR, TGA/DTA, SEM, BET analysis and EDS. Synthesized resin shows a good capacity of 53.96mgg(-1) for Cd(II) and 24.19mgg(-1) for Zn(II) at pH 8.0. Five isotherm equilibrium models were studied to explain the sorption phenomenon out of which Langmuir, Dubinin-Radushkevich, Scatchard and Temkin models were found to be the best fitted. The limit of detection (LOD) and limit of quantification (LOQ) were observed to be 1.5 and 5.1μgL(-1) for Cd and 1.2 and 4.1μgL(-1) for Zn. The reliability of the method was investigated by the analysis of SRM and the recovery of analytes from various spiked food samples.
Shooting activities are a very important source of contamination as they are commonly detected high concentrations of Pb in the soils from these facilities. Different remediation methods imply the immobilization of the pollutants by decreasing their mobility and availability and nanotechnology is a promising technique in this field. The effectiveness of calcium phosphate nanoparticles (CPNs) in the remediation of small-arms firing range and trap shooting range soils is evaluated in this work. The operationally defined extractable content of Pb, Cu and Zn is determined together with the interaction of the pollutants with the nanomaterials. Soil samples were treated with the CPNs and after the treatment the extractable contents of Cu, Pb and Zn decrease. To check the retention by the nanoparticles TOF-SIMS (Time of Flight Secondary Ion Mass Spectrometry) and HR-TEM-EDS (High Resolution Transmission Electron Microscopy with Energy Dispersive X-ray Spectroscopy) techniques were applied. The association of Pb and Cu to the CPNs was demonstrated by TOF-SIMS although it also indicated that not all the Pb and Cu contents are linked to the nanoparticles. By means of HR-TEM/EDS it was made out the filamentous shape and the size (50-150nm long and 20-40nm wide) of the CPNs together with their elemental composition (Ca, P and O). The CPNs were identified in treated soil samples together with signals of metals. The decrease on metal extractability detected is, in part, due to the association with CPNs but still more investigation is needed regarding mobility and availability of potentially hazardous elements in soils treated with nanoparticles.
The inclusion of Zn in insect mandibles affects their hardness and is functional to their use during feeding or reproducing. However, little is known on the chemical/structural base of Zn enrichment. Here, we found that cathodoluminescence (CL) technique revealed two different types of CL spectra in the mandibles of Hymenoptera, depending on the Zn enrichment level assessed by Energy Dispersive X-ray Spectroscopy (EDS). Individuals having negligible traces to low %
 of Zn in their mandible teeth (≤3 wt%) presented a wide band of luminescence in the visible range which resembled those observed in the CC structures of graphite. This spectrum is probably characteristic for un-enriched cuticle, since it did not differ from those obtained from the Zn-lacking inner part of mandibles. Individuals with moderate to high % of Zn in their mandible teeth (≥7 wt%), instead, presented additional CL peaks in the ultraviolet range. Comparisons with different minerals of Zn suggest that these peaks could be related with OZnO bonds, with hydroxyl groups and with zinc-chlorine links (in agreement with Cl high levels detected by the EDS). Being a non-destructive technique, CL allows large comparative studies of the chemistry of metal-enriched insect cuticle even using unique specimens, such as those deposited in Natural History Museums.
The thymosin proteins are all short, highly charged, intrinsically unstructured proteins under natural conditions. However, structure can be induced in many of the thymosin proteins by providing charge neutralization at low pH or by the addition of Zn(2+) ions, organic reagents such as trifluoroethanol, hexafluoropropanol, or n-dodecyltrimethylammonium bromide, or interactions with their natural binding partner proteins. The differing structures of thymosin alpha and thymosin beta proteins have been studied by circular dichroism, nuclear magnetic resonance, and crystallographic methods in order to better understand the role of these proteins. In this structural biology review the structures of prothymosin, parathymosin, thymosin alpha-1, and several beta thymosin proteins, in both native states and under secondary structure-inducing conditions are discussed.
The potential application of triethylenetetramine intercalated montmorillonite (TETA-Mt) in mine tailings treatment and AMD (acid mine drainage) remediation was investigated with batch experiments. The structural and morphological characteristics of TETA-Mt were analyzed with XRD, FTIR, DTG-TG and SEM. The inhibition efficiencies of TETA-Mt against heavy metal release from mine tailings when exposed to acid rain leaching was examined and compared with that of triethylenetetramine (TETA) and Mt. Results showed that the overall inhibition by TETA-Mt surpassed that by TETA or Mt for various heavy metal ions over an acid rain pH range of 3-5.6 and a temperature range of 25-40°C. When mine tailings were exposed to acid rain of pH 4.8 (the average rain pH of the mining site where the mine tailings were from), TETA-Mt achieved an inhibition efficiency of over 90% for Cu(2+), Zn(2+), Cd(2+) and Mn(2+) release, and 70% for Pb(2+) at 25°C. It was shown that TETA-Mt has a strong buffering capacity. Moreover, TETA-Mt was able to adsorb heavy metal ions and the adsorption process was fast, suggesting that coordination was mainly responsible. These results showed the potential of TETA-Mt in AMD mitigation, especially in acid rain affected mining area.
It is crucial to develop predictive soil-plant transfer (SPT) models to derive the threshold values of toxic metals in contaminated arable soils. The present study was designed to examine the heavy metal uptake pattern and to improve the prediction of metal uptake by Chinese cabbage grown in agricultural soils with multiple contamination by Cd, Cu, Ni, Pb, and Zn. Pot experiments were performed with 25 historically contaminated soils to determine metal accumulation in different parts of Chinese cabbage. Different soil bioavailable metal fractions were determined using different extractants (0.43M HNO3, 0.01M CaCl2, 0.005M DTPA, and 0.01M LWMOAs), soil moisture samplers, and diffusive gradients in thin films (DGT), and the fractions were compared with shoot metal uptake using both direct and stepwise multiple regression analysis. The stepwise approach significantly improved the prediction of metal uptake by cabbage over the direct approach. Strongly pH dependent or nonlinear relationships were found for the adsorption of root surfaces and in root-shoot uptake processes. Metals were linearly translocated from the root surface to the root. Therefore, the nonlinearity of uptake pattern is an important explanation for the inadequacy of the direct approach in some cases. The stepwise approach offers an alternative and robust method to study the pattern of metal uptake by Chinese cabbage (Brassica pekinensis L.).
Wastewater treatment sludge from a primary lead-zinc smelter is characterized as hazardous waste and requires treatment prior to disposal due to its significant arsenic and heavy metals contents. This study presents a method for the stabilization of arsenic sludge that uses a slag based curing agent composed of smelting slag, cement clinker and limestone. The Unconfined Compressive Strength (UCS) test, the China Standard Leaching Test (CSLT), and the Toxicity Characteristic Leaching Procedures (TCLP) were used to physically and chemically characterize the solidified sludge. The binder ratio was determined according to the UCS and optimal experiments, and the optimal mass ratio of m (smelting slag): m (cement clinker): m (gypsum sludge): m (limestone) was 70:13:12:5. When the binder was mixed with arsenic sludge using a mass ratio of 1:1 and then maintained at 25 °C for 28 d, the UCS reached 9.30 MPa. The results indicated that the leached arsenic content was always less than 5 mg/L, which is a safe level, and does not contribute to recontamination of the environment. The arsenic sludge from the Zn/Pb metallurgy plant can be blended with cement clinker and smelting slag materials for manufacturing bricks and can be recycled as construction materials.
The long-term (i.e., two consecutive annual cycles) ability of Phragmites australis to remediate estuarine sediments contaminated with heavy metals (Co, Ni, Mo, Cd, Pb, Cr, Cu, Fe, Mn, Zn and Hg) and trace elements of concern (As, Se, Ba) was investigated using an experimental approach on a pilot plant scale. The accumulation of these elements on belowground and aboveground tissues was monitored during vegetative and senescence periods for two populations of P. australis, originally from contaminated (MIC) and non-contaminated (GAL) estuaries, respectively. The initial concentration of the elements in the contaminated estuarine sediment decreased in the following order: Fe>Mn>Zn>Pb>Ba>Cr>As>Cu>Ni>Co>Mo>Cd>Se>Hg. A similar trend was recorded in the belowground biomass following remediation, suggesting the potential role of P. australis as an effective biomonitoring tool. Hg was not detected in any plant tissue. An overall annual increase of concentration levels in belowground tissue was observed. Overall, this study suggested that P. australis populations from GAL were substantially more efficient in taking up Ni, Mo and Cr during the second annual cycle in both belowground and aboveground tissue than P. australis populations from MIC. Calculated bio-concentration factors (BCF) suggested a clear metal excluder strategy for Co, Cd, Pb, Cu and Fe, with accumulation and stabilisation belowground, with limited translocation into aerial tissues observed during the length of this study. An excluder behaviour for Zn, Ba and Mn was detected during the second annual cycle, coinciding with a substantial increase of concentration levels belowground. This study demonstrated for the first time the long term efficacy of P. australis for phytoremediation of heavy metal contaminated estuarine sediments.
Glutathione S-transferases (GSTs, EC 2.5.1.18) are categorized as phase II enzymes, which form an important multifunctional family associated with a wide variety of catalytic activities. GSTω, GSTρ, and GSTθ are cytosolic GSTs which have been extensively studied in a variety of organisms; however, few studies have focused on teleosts. Those paralogs from black rockfish (Sebastes schlegelii; RfGSTω, RfGSTρ, and RfGSTθ, respectively) were molecularly, biochemically, and functionally characterized to determine their antioxidant extent and protective aptitudes upon pathogenic stress. RfGSTω, RfGSTρ, and RfGSTθ, contained open reading frames of 717bp, 678bp, and 720bp respectively, which encoded respective proteins of 239, 226, and 240 amino acids in length. In silico analysis revealed that all RfGSTs possessed characteristic N-terminal domains bearing glutathione (GSH)-binding sites, and C-terminal domains containing substrate-binding sites. Recombinant RfGSTω (rRfGSTω) catalyzed the conjugation of GSH to dehydroascorbate (DHA), while rRfGSTθ and rRfGSTρ catalyzed to the model GST substrate 1-Chloro-2,4-dinitrobenzene (CDNB). Kinetic analysis revealed variation in Km and Vmax values for each rRfGST, indicating their different conjugation rates. The optimum conditions (pH and temperature) and inhibition assays of each protein demonstrated different optimal ranges showing their wide range of activity as an assembly. RfGSTω and RfGSTθ paralogs demonstrated their antioxidant potential towards H2O2 and heavy metals (Cd, Zn, and Cu) in vitro, while RfGSTρ had an antioxidant potential only towards heavy metals (Zn and Cu). Though all the paralogs were ubiquitously expressed in different magnitudes, RfGSTω was highly expressed in blood, whereas RfGSTρ and RfGSTθ were highly expressed in liver. The mRNA expression of RfGSTω and RfGSTθ, upon Streptococcus iniae and poly I:C stimulation, revealed a significantly up-regulated expression, whereas RfGSTρ mRNA expression was significantly down-regulated. Collectively, our findings suggest that RfGSTω, RfGSTρ, and RfGSTθ paralogs are potent in detoxifying xenobiotic toxics, capable of protecting cells from oxidative stress generated by both H2O2 and heavy metals, and finally, yet importantly, stimulated under pathogenic stress signals.
The aims of this study were determining the co-induced effects of dietary Cadmium
 (Cd) and high intake of Molybdenum (Mo) on renal toxicity in ducks. 240 healthy 11-day-old ducks were randomly divided into 6 groups, which were treated with Mo or/and Cd at different doses added to the basal diet for 120 days. Ducks of control group were fed with basal diet, LMo and HMo groups were fed with 15mg/kg Mo and 100mg/kg Mo respectively; ducks of Cd group were provided with 4mg/kg Cd which was added into basal diet. Two combination groups were treated with 15mg/kg Mo+4mg/kg Cd and 100mg/kg Mo+4mg/kg Cd respectively. On days 30, 60, 90 and 120, the mRNA expression levels of inflammatory cytokines and contents of trace elements were detected. In addition, transmission electron microscopic examination was used for ultrastructural studies. The results indicated that the mRNA expression levels of tumor necrosis factor-α (TNF-α), nuclear factor-kappa B (NF-κB), and cyclooxygenase-2 (COX-2) showed an upward tendency in treatment groups in comparison with control group, and in the later period of the experiment it showed a significant rise in joint groups compared with the Mo and Cd group (P<0.01); the contents of copper (Cu) and iron (Fe) decreased in joint groups in the later period (P<0.05) while the contents of Mo and Cd significantly increased (P<0.01); zinc (Zn) and selenium (Se) concentration had a slight downtrend in treated groups, but showed no significant difference (P>0.05). The ultrastructural analysis showed that kidney tissues were severely injured in joint groups on day 120. These results suggested that the combination of Mo and Cd could aggravate damages to the kidney. In addition, dietary of Mo or/and Cd caused the decrease of Cu, Fe, Zn, and Se contents, inflammatory response and pathological lesions whose mechanism is somehow linked with Mo and Cd deposition in kidney.
Low-dimensional molecular motifs with diversity developed via the on-surface chemistry are attracting growing interest for their potential in advanced nanofabrication. In this work, scanning tunneling microscopy was employed to investigate the in situ and ex situ metal coordinations between 4,4'-ditetradecyl-2,2'-bipyridine (bpy) and Zn(ii) or Cu(ii) ions at a highly oriented pyrolytic graphite (HOPG)/1-phenyloctane interface under ambient conditions. The results demonstrate that the bpy adopts a flat-lying orientation with its substituted alkyl chains in a tail-to-tail arrangement in a bpy monolayer. For the in situ coordination, the bpy/Zn(ii) and bpy/Cu(ii) complexes are aligned in edge-on fashions, wherein the bpy stands vertically on the HOPG surface and interdigitates at the alkyl chains. In the two-dimensional arrays of ex situ coordinated complexes, metal dependent motifs have been observed with Zn(ii) and Cu(ii), wherein the bipyridine moieties are parallel to the graphite surface. These results suggest that the desired on-surface coordination architectures may be achieved by the intentional selection of the metal centers.
The mining complex of Murçós belongs to the Terras de Cavaleiros Geopark, located in Trás-os-Montes region, northeast Portugal. A stockwork of NW-SE-trending W>Sn quartz veins intruded Silurian metamorphic rocks and a Variscan biotite granite. The mineralized veins contain mainly quartz, cassiterite, wolframite, scheelite, arsenopyrite, pyrite, sphalerite, chalcopyrite, galena, rare pyrrhotite, stannite, native bismuth and also later bismuthinite, matildite, joseite, roosveltite, anglesite, scorodite, zavaritskite and covellite. The exploitation produced 335t of a concentrate with 70% of W and 150t of another concentrate with 70% of Sn between 1948 and 1976. The exploitation took place mainly in four open pit mines as well as underground. Three lakes were left in the area. Remediation processes of confination and control of tailings and rejected materials and phytoremediation with macrophytes from three lakes were carried out between 2005 and 2007. Stream sediments, soils and water samples were collected in 2008 and 2009, after the remediation process. Most stream sediments showed deficiency or minimum enrichment for metals. The sequential enrichment factor in stream sediments W>Bi>As>U>Cd>Sn=Ag>Cu>Sb>Pb>Be>Zn is mainly associated with the W>Sn mineralizations. Stream sediments receiving drainage of a mine dump were found to be significantly to extremely enriched with W, while stream sediments and soils were found to be contaminated with As. Two soil samples collected around mine dumps and an open pit lake were also found to be contaminated with U. The waters from the Murçós W>Sn mine area were acidic to neutral. After the remediation, the surface waters were contaminated with F(-), Al, As, Mn and Ni and must not be used for human consumption, while open pit lake waters must also not be used for agriculture because of contamination with F(-), Al, Mn and Ni. In most waters, the As occurred as As (III), which is toxic and is easily mobilized in the drainage system. The remediation promoted a decrease in metals and As concentrations of soils and waters, however the applied processes were not enough to rehabilitate the area.
In order to acquire the pollution feature and regularities of distribution of metals in the topsoil within the sixth ring road in Beijing, a total of 46 soil samples were collected, and the concentrations of twelve elements (Nickel, Ni, Lithium, Li, Vanadium, V, Cobalt, Co, Barium, Ba, Strontium, Sr, Chrome, Cr, Molybdenum, Mo, Copper, Cu, Cadmium, Cd, Zinc, Zn, Lead, Pb) were analyzed. Geostatistics and multivariate statistics were conducted to identify spatial distribution characteristics and sources. In addition, the health risk of the analyzed heavy metals to humans (adult) was evaluated by an U.S. Environmental Protection Agency health risk assessment model. The results indicate that these metals have notable variation in spatial scale. The concentration of Cr was high in the west and low in the east, while that of Mo was high in the north and low in the south. High concentrations of Cu, Cd, Zn, and Pb were found in the central part of the city. The average enrichment degree of Cd is 5.94, reaching the standard of significant enrichment. The accumulation of Cr, Mo, Cu, Cd, Zn, and Pb is influenced by anthropogenic activity, including vehicle exhaustion, coal burning, and industrial processes. Health risk assessment shows that both non-carcinogenic and carcinogenic risks of selected heavy metals are within the safety standard and the rank of the carcinogenic risk of the four heavy metals is Cr > Co > Ni > Cd.
Langerin, a C-type lectin, is expressed in Langerhans cells. It was reported that langerin binds sulfated glycans, which is an important initial step for its role in blocking human immunodeficiency virus (HIV) transmission by capturing HIV pathogens and mediating their internalization into Birbeck granules for their elimination. It is fundamentally important to understand these interactions at the molecular level for the design of new highly specific therapeutic agents for HIV. Surface plasmon resonance (SPR), which allows for the real-time, direct, quantitative analysis of the label-free molecular interactions, has been used successfully for biophysical characterization of glycosaminoglycan (GAG)-protein interactions. In this study, we report kinetics, structural analysis, and the effects of physiological conditions (e.g., pH, salt concentration, and Ca(2+) and Zn(2+)concentrations) on the interactions between GAGs and langerin using SPR. SPR results revealed that langerin binds to heparin with high affinity (KD ∼ 2.4 nM) and the oligosaccharide length required for the interactions is larger than a tetrasaccharide. This heparin/heparan sulfate-binding protein also interacts with other GAGs, including dermatan sulfate, chondroitin sulfates C-E and KS. In addition, liquid chromatography-mass spectrometry analysis was used to characterize the structure of sulfated glycans that bound to langerin.
The adverse biological effects of ionizing radiation (IR) are commonly attributed to the generation of DNA double-strand breaks (DSBs). IR-induced DSBs are generated by clusters of ionizations, bear damaged terminal nucleotides, and frequently comprise base damages and single-strand breaks in the vicinity generating a unique DNA damage-clustering effect that increases DSB "complexity." The number of ionizations in clusters of different radiation modalities increases with increasing linear energy transfer (LET), and is thought to determine the long-known LET-dependence of the relative biological effectiveness (RBE). Multiple ionizations may also lead to the formation of DSB clusters, comprising two or more DSBs that destabilize chromatin further and compromise overall processing. DSB complexity and DSB-cluster formation are increasingly considered in the development of mathematical models of radiation action, which are then "tested" by fitting available experimental data. Despite a plethora of such mathematical models the ultimate goal, i.e., the "a priori" prediction of the radiation effect, has not yet been achieved. The difficulty partly arises from unsurmountable difficulties in testing the fundamental assumptions of such mathematical models in defined biological model systems capable of providing conclusive answers. Recently, revolutionary advances in methods allowing the generation of enzymatic DSBs at random or in well-defined locations in the genome, generate unique testing opportunities for several key assumptions frequently fed into mathematical modeling - including the role of DSB clusters in the overall effect. Here, we review the problematic of DSB-cluster formation in radiation action and present novel biological technologies that promise to revolutionize the way we address the biological consequences of such lesions. We describe new ways of exploiting the I-SceI endonuclease
 to generate DSB-clusters at random locations in the genome and describe the possible utility of Zn-finger nucleases and of TALENs in generating DSBs at defined genomic locations. Finally, we describe ways to harness the revolution of CRISPR/Cas9 technology to advance our understanding of the biological effects of DSBs. Collectively, these approaches promise to improve the focus of mathematical modeling of radiation action by providing testing opportunities for key assumptions on the underlying biology. They are also likely to further strengthen interactions between experimental radiation biologists and mathematical modelers.
Cadmium is a major toxic heavy-metal pollutant considering their bioaccumulation potential and persistence in the environment. The hyperaccumulating ecotype of Sedum alfredii Hance is a Zn/Cd co-hyperaccumulator inhabiting in a region of China with soils rich in Pb/Zn. Investigations into the underlying molecular regulatory mechanisms of Cd tolerance are of substantial interest. Here, library screening for genes related to cadmium tolerance identified a gene resembling the rubber elongation factor gene designated as SaREFl. The heterologous expression of SaREFl rescued the growth of a transformed Cd-sensitive strain (ycf1). Furthermore, SaREFl-expressing Arabidopsis plants were more tolerant to cadmium stress compared with wild type by measuring parameters of root length, fresh weight and physiological indexes. When under four different heavy metal treatments, we found that SaREFl responded most strongly to Cd and the root was the plant organ most sensitive to this heavy metal. Yeast two-hybrid screening of SaREFl as a bait led to the identification of five possible interacting targets in Sedum alfredii Hance. Among them, a gene annotated as prenylated Rab acceptor 1 (PRA1) domain protein was detected with a high frequency. Moreover, subcellular localization of SaREF1-GFP fusion protein revealed some patchy spots in cytosol suggesting potential association with organelles for its cellular functions. Our findings would further enrich the connotation of REF-like genes and provide theoretical assistance for the application in breeding heavy metal-tolerant plants.
There is a growing interest among consumers and researchers in the globe artichoke [Cynara cardunculus L. subsp. scolymus (L.) Hegi] leaf extract due to its nutraceutical and therapeutic properties. The application of an abiotic stress such as salinity can activate the stress-signaling pathways, thus enhancing the content of valuable phytochemicals. The aim of this study was to assess the metabolic changes in artichokes by probing the leaf metabolome of artichoke plants grown in a floating system and exposed to a relatively mild (30 mM) potassium chloride (KCl) salt stress. Potassium chloride treatment decreased the leaf dry biomass of artichoke, macro- and microelements in leaves (e.g., Ca, Mg, Mn, Zn, and B) but increased the concentrations of K and Cl. Metabolomics highlighted that the hormonal network of artichokes was strongly imbalanced by KCl. The indole-3-acetic acid conjugates, the brassinosteroids hormone 6-deoxocastasterone, and even more the cytokinin precursor N(6)-(Delta-2-isopentenyl)-adenosine-5'-triphosphate, strongly increased in leaves of KCl-treated plants. Moreover, KCl saline treatment induced accumulation of GA4, a bioactive form additional to the already known GA3. Another specific response to salinity was changes in the phenolic compounds profile, with flavones and isoflavones being decreased by KCl treatment, whereas flavonoid glycosides increased. The osmotic/oxidative stress that salinity generates also induced some expected changes at the biochemical level (e.g., ascorbate degradation, membrane lipid peroxidation, and accumulation of mannitol phosphate). These latter results help explain the molecular/physiological mechanisms that the plant uses to cope with potassium chloride stress exposure.
Modeling studies have predicted that coffee crop will be endangered by future global warming, but recent reports highlighted that high [CO2] can mitigate heat impacts on coffee. This work aimed at identifying heat protective mechanisms promoted by CO2 in Coffea arabica (cv. Icatu and IPR108) and Coffea canephora cv. Conilon CL153. Plants were grown at 25/20°C (day/night), under 380 or 700 μL CO2 L(-1), and then gradually submitted to 31/25, 37/30, and 42/34°C. Relevant heat tolerance up to 37/30°C for both [CO2] and all coffee genotypes was observed, likely supported by the maintenance or increase of the pools of several protective molecules (neoxanthin, lutein, carotenes, α-tocopherol, HSP70, raffinose), activities of antioxidant enzymes, such as superoxide dismutase (SOD), ascorbate peroxidase (APX), glutathione reductase (GR), catalase (CAT), and the upregulated expression of some genes (ELIP, Chaperonin 20). However, at 42/34°C a tolerance threshold was reached, mostly in the 380-plants and Icatu. Adjustments in raffinose, lutein, β-carotene, α-tocopherol and HSP70 pools, and the upregulated expression of genes related to protective (ELIPS, HSP70, Chape 20, and 60) and antioxidant (CAT, CuSOD2, APX Cyt, APX Chl) proteins were largely driven by temperature. However, enhanced [CO2] maintained higher activities of GR (Icatu) and CAT (Icatu and IPR108), kept (or even increased) the Cu,Zn-SOD, APX, and CAT activities, and promoted a greater upregulation of those enzyme genes, as well as those related to HSP70, ELIPs, Chaperonins in CL153, and Icatu. These changes likely favored the maintenance of reactive oxygen species (ROS) at controlled levels and contributed to mitigate of photosystem II photoinhibition at the highest temperature. Overall, our results highlighted the important role of enhanced [CO2] on the coffee crop acclimation and sustainability under predicted future global warming scenarios.
Fusarium head blight (FHB) is a serious disease of wheat worldwide. Cultivar resistance to FHB depends on biochemical factors that confine the pathogen spread in spikes. Breeding for cultivar resistance is considered the most practical way to manage this disease. In this study, different spectroscopy and microscopy techniques were applied to discriminate resistance in wheat genotypes against FHB. Synchrotron-based spectroscopy and imaging techniques, including focal plane array infrared and X-ray fluorescence (XRF) spectroscopy were used to understand changes in biochemical and nutrients in rachis following FHB infection. Sumai3 and Muchmore were used to represent resistant and susceptible cultivars to FHB, respectively, in this study. The histological comparison of rachis showed substantial differences in the cell wall thickness between the cultivars after infection. Synchrotron-based infrared imaging emphasized substantial difference in biochemical composition of rachis samples between the two cultivars prior to visible symptoms; in the resistant Sumai3, infrared bands representing lignin and hemicellulose were stronger and more persistent compared to the susceptible cultivar. These bands may be the candidates of biochemical markers for FHB resistance. Focal plane array infrared imaging (FPA) spectra from the rachis epidermis and vascular bundles revealed a new band (1710 cm(-1)) related to the oxidative stress on the susceptible cultivar only. XRF spectroscopy data revealed differences in nutrients composition between cultivars, and between controls and inoculated samples, with substantial increases observed for Ca, K, Mn, Fe, Zn, and Si in the resistant cultivar. These nutrients are related to cell wall stability, metabolic process, and plant defense mechanisms such as lignification pathway and callose deposition. The combination of cell wall composition and lignification plays a role in the mechanism of type II host resistance to FHB. Biochemical profiling using the synchrotron-based spectroscopy holds potential for screening wheat genotypes for FHB resistance.
Exploring highly active, stable and relatively low-cost nanomaterials for the oxygen reduction reaction (ORR) is of vital importance for the commercialization of proton exchange membrane fuel cells (PEMFCs). Herein, a highly active, durable, carbon supported, and monolayer Pt coated Pd-Co-Zn nanoparticle is synthesized via a simple impregnation-reduction method, followed by spontaneous displacement of Pt. By tuning the atomic ratios, we obtain the composition-activity volcano curve for the Pd-Co-Zn nanoparticles and determined that Pd : Co : Zn = 8 : 1 : 1 is the optimal composition. Compared with pure Pd/C, the Pd8CoZn/C nanoparticles show a substantial enhancement in both the catalytic activity and the durability toward the ORR. Moreover, the durability and activity are further enhanced by forming a Pt skin on Pd8CoZn/C nanocatalysts. Interestingly, after 10 000 potential cycles in N2-saturated 0.1 M HClO4 solution, Pd8CoZn@Pt/C shows improved mass activity (2.62 A mg(-1)Pt) and specific activity (4.76 A m(-2)total), which are about 1.4 and 4.4 times higher than the initial values, and 37.4 and 5.5 times higher than those of Pt/C catalysts, respectively. After accelerated stability testing in O2-saturated 0.1 M HClO4 solution for 30 000 potential cycles, the half-wave potential negatively shifts about 6 mV. The results show that the Pt skin plays an important role in enhancing the activity as well as preventing degradation.
Zn- and Na-modulated Fe catalysts were fabricated by a simple coprecipitation/washing method. Zn greatly changed the size of iron species, serving as the structural promoter, while the existence of Na on the surface of the Fe catalyst alters the electronic structure, making the catalyst very active for CO activation. Most importantly, the electronic structure of the catalyst surface suppresses the hydrogenation of double bonds and promotes
 desorption of products, which renders the catalyst unexpectedly reactive toward alkenes-especially C5+ alkenes (with more than 50% selectivity in hydrocarbons)-while lowering the selectivity for undesired products. This study enriches C1 chemistry and the design of highly selective new catalysts for high-value chemicals.
Formation of solid solutions is a good strategy to acquire materials with special properties and bring forth new type of applications or enhance the performance of currently existing devices. In this study, hollow ZnxCd1-xS nanospheres with different molar ratios were synthesized via a facile hydrothermal process. The products were fully characterized by X-ray diffraction, scanning electron microscopy, transmission electron microscopy, energy-dispersive X-ray spectroscopy, and UV-vis absorption spectroscopy. It was found that the photocatalysis performance of the as-prepared samples could be enhanced by formation of ZnxCd1-xS solid solutions. In addition, their photocatalytic activities are dependent on the Zn/Cd molar ratios and nanostructures of ZnxCd1-xS solid solutions. Hollow Zn0.2Cd0.8S spheres exhibit extremely high photocatalytic activity and good re-usability, and the photocatalytic conversion of RhB reaches as high as 96% after 50 min of irradiation.
We investigated the effect of Zn-doping on structural and optical properties as well as cellular response of TiO2 nanoparticles (NPs) in human breast cancer MCF-7 cells. A library of Zn-doped (1-10 at wt%) TiO2 NPs was prepared. Characterization data indicated that dopant Zn was incorporated into the lattice of host TiO2. The average particle size of TiO2 NPs was decreases (38 to 28 nm) while the band gap energy was increases (3.35 eV-3.85 eV) with increasing the amount of Zn-doping. Cellular data demonstrated that Zn-doped TiO2 NPs induced cytotoxicity (cell viability reduction, membrane damage and cell cycle arrest) and oxidative stress (reactive oxygen species generation &glutathione depletion) in MCF-7 cells and toxic intensity was increases with increasing the concentration of Zn-doping. Molecular data revealed that Zn-doped TiO2 NPs induced the down-regulation of super oxide dismutase gene while the up-regulation of heme oxygenase-1 gene in MCF-7 cells. Cytotoxicity induced by Zn-doped TiO2 NPs was efficiently prevented by N-acetyl-cysteine suggesting that oxidative stress might be the primarily cause of toxicity. In conclusion, our data indicated that Zn-doping decreases the particle size and increases the band gap energy as well the oxidative stress-mediated toxicity of TiO2 NPs in MCF-7 cells.
There are conflicting reports on the heavy metal levels in human semen with different fertilities. The purpose of this analysis is to merge and analyze the differences of heavy metal lead (Pb), cadmium (Cd), zinc (Zn), and copper (Cu) levels in male semen with normal and low fertilities. All documents in both Chinese and English were collected from the PubMed, Web of Science, and Chinese National Knowledge Infrastructure (CNKI) database from inception date to February 19, 2016. We have used RevMan software (version 5.2) for the meta-analysis and Stata software (version 12.0) for the meta-regression and sensitivity analyses. A total of 20 literatures were included in the study. The results of the meta-analysis indicate a significant difference between fertility with three metal ions (Pb, Cd, Zn) while no significant difference with copper, detailed as follows: (i) 10 studies on the lead concentrations with a standardized mean difference (SMD) = 2.07, 95 %CI (0.97, 3.17), P < 0.01; (ii) 13 studies on the cadmium concentrations with an SMD = 0.75, 95 %CI (0.44, 1.07), P < 0.01; (iii) 8 studies on the concentrations of zinc with an SMD = -0.61, 95 %CI (-1.08, -0.14), P < 0.01; and (iv) 9 studies on the copper concentrations with an SMD = 0.42, 95 %CI (-0.29, 1.13), P = 0.247. The results indicate that the men with low fertility have higher semen Pb and Cd levels and lower semen Zn levels; more studies are needed to indicate the association of the semen copper level with fertility.
The effect of sewage sludge on the mobility and the bioavailability of trace metals in plant-soil systems have aroused wide interested and been widely explored. Based on a wheat-cultivating experiment, the effect of municipal sludge compost (MSC) on the mobility and bioavailability of Cd in a soil-wheat system was studied. With the application of MSC, soil organic matter (SOM), total nitrogen (TN), and total phosphorus (TP) in the soil increased significantly, while concentrations of trace metals (Cu, Zn, Ni, Pb, Cd) were below the China's minimum thresholds. The application of MSC could improve wheat growth. The application of MSC at the rate of 0.5 % had no significant effect on the chemical fraction distribution of Cd in soil. In two soil treatments, Cd mainly existed in the labile chemical fractions (exchangeable chemical fraction (EXCF) and carbonate chemical fraction (CABF)). However, the application of MSC could reduce accumulation of Cd by wheat. Cd contents in each part of the MSC-applied wheat were significantly less than that of non-MSC-applied wheat. In the tested soils, the extractable concentrations decreased in the order: EDTA > MgCl2 ≈ NH4OAc > DTPA. There were no significant differences between soil treatments in the amounts of extractable Cd when the extraction was done under neutral conditions, although significant differences were observed when the extraction was done under alkaline conditions. In this study, the DTPA extraction procedure provided a good indication of Cd bioavailability. Our results suggest that, in the short term at least, amending soils with MSC may benefit crop dry matter production while not increasing the risk of human exposure to Cd through consumption of wheat grown on MSC-amended soils.
Froth treatment thickened tailings (TT) are a waste product of bitumen extraction from surface-mined oil sands ores. When incubated in a laboratory under simulated moist oxic environmental conditions for ~450d, two different types of TT (TT1 and TT2) exhibited the potential to generate acid rock drainage (ARD) by producing acid leachate after 250 and 50d, respectively. We report here the release of toxic metals from TT via ARD, which could pose an environmental threat if oil sands TT deposits are not properly managed. Trace metal concentrations in leachate samples collected periodically revealed that Mn and Sr were released immediately even before the onset of ARD. Spikes in Co and Ni concentrations were observed both pre-ARD and during active ARD, particularly in TT1. For most elements measured (Fe, Cr, V, As, Cu, Pb, Zn, Cd, and Se), leaching was associated with ARD production. Though equivalent acidification (pH2) was achieved in leachate from both TT types, greater metal release was observed from TT2 where concentrations reached 10,000ppb for Ni, 5000ppb for Co, 3000ppb for As, 2000ppb for V, and 1000ppb for Cr. Generally, metal concentrations decreased in leachate with time during ARD and became negligible by the end of incubation (~450d) despite appreciable metals remaining in the leached TT. These results suggest that using TT for land reclamation purposes or surface deposition for volume reduction may unfavorably impact the environment, and warrants application of appropriate strategies for management of pyrite-enriched oil sands tailings streams.
In this study, a comprehensive analysis of groundwater was performed to assess contamination and phenol content in Batman, Turkey, particularly in residential areas near agriculture, livestock and oil industry facilities. From these areas, where potentially contaminated groundwater used for drinking and irrigation threatens public health, 30 groundwater samples were collected and analyzed for heavy metal concentrations (Al, As, B, Ba, Ca, Cd, Cl, Co, Cr, Cu, Fe, Hg, Li, Mg, Mn, Mo, Na, Ni, NO3, P, Pb, phenol, S, Sb, Se, SO4, Sr, U, and Zn). Compared with the standards of the Environmental Protection Agency, Al, Fe, and Mn concentrations in groundwater exceeded secondary drinking water regulations, NO3 concentrations were high for maximum contaminant levels, and As, Pb, and U concentrations exceeded maximum contaminant level goals in all samples. Ni, Sb, and Se concentrations also exceeded limits set by the Turkish Standards Institution. Nearly all samples revealed concentrations of Se, Sb, Hg, and phenol due to nearby petroleum refineries, oil storage plants, and agricultural and livestock areas. The results obtained from this study indicate that the groundwater in Batman contains elements in concentrations that approach or exceed limits and thus threatens public health with increased blood cholesterol, decreased blood sugar, and circulatory problems.
The extensive applications of ZnO nanoparticles (nano ZnO) and dimethoate (DM) have increased the risk of humans' co-exposure to nano ZnO and DM. Here, we report the synergistic effect of nano ZnO and DM on their biodistribution and subacute toxicity in mice. Nano ZnO and DM had a synergistic toxicity in mice. In contrast, bulk ZnO and DM did not cause an obvious synergistic toxicity in mice. Although nano ZnO was low toxic to mice, coexposure to nano ZnO and DM significantly enhanced DM-induced oxidative damage in the liver. Coadministration of nano ZnO with DM significantly increased Zn accumulation by 30.9 ± 1.9% and DM accumulation by 45.6 ± 2.2% in the liver, respectively. The increased accumulations of DM and Zn in the liver reduced its cholinesterase activity from 5.65 ± 0.32 to 4.37 ± 0.49 U/mg protein and induced hepatic oxidative stress. Nano ZnO had 3-fold or 2.4-fold higher binding capability for serum albumin or DM, respectively, than bulk ZnO. In addition, serum albumin significantly increased the binding capability of nano ZnO for
 DM by approximately four times via the interaction of serum albumin and DM. The uptake of serum albumin- and DM-bound nano ZnO by the macrophages significantly increased DM accumulation in mice. Serum albumins play an important role in the synergistic toxicity of nano ZnO and DM. © 2016 Wiley Periodicals, Inc. Environ Toxicol, 2016.
The proximate composition and element contents of claw muscle tissue of Atlantic blue crabs (Callinectes sapidus) were compared with the native warty crab (Eriphia verrucosa) and the commercially edible crab (Cancer pagurus). The scope of the analysis was to profile the chemical characteristics and nutritive value of the three crab species. Elemental fingerprints showed significant inter-specific differences, whereas non-significant variations in the moisture and ash contents were observed. In the blue crab, protein content was significantly lower than in the other two species, while its carbon content resulted lower than that characterizing only the warty crab. Among micro-elements, Ba, Cr, Cu, Li, Mn, Ni, and Pb showed extremely low concentrations and negligible among-species differences. Significant inter-specific differences were observed for Na, Sr, V, Ba, Cd and Zn; in particular, cadmium and zinc were characterized in the blue crab by concentrations significantly lower than in the other two species. The analysis of the available literature on the three species indicated a general lack of comparable information on their elemental composition. The need to implement extended elemental fingerprinting techniques for shellfish quality assessment is discussed, in view of other complementary profiling methods such as NMR-based metabolomics.
Microorganisms in the rhizosphere mediate the cycling of nutrients, their enhanced mobilisation and facilitate their uptake, leading to increased root growth, biomass and yield of plants. We examined the promise of beneficial cyanobacteria and eubacteria as microbial inoculants, applied singly or in combination as consortia or biofilms, to improve growth and yields of okra. Interrelationships among the microbial activities and the micro/macro nutrient dynamics in soils and okra yield characteristics were assessed along with the changes in the soil microbiome. A significant effect of microbial inoculation on alkaline phosphatase activity was recorded both at the mid-crop and harvest stages. Microbial biomass carbon values were highest due to the Anabaena sp. - Providencia sp. (CR1 + PR3) application. The yield of okra ranged from 444.6-478.4 g(-1) plant and a positive correlation (0.69) recorded between yield and root weight. The application of Azotobacter led to the highest root weight and yield. The concentration of Zn at mid-crop stage was 60-70% higher in the Azotobacter sp. and Calothrix sp. inoculated soils, as compared to uninoculated control. Iron concentration in soil was more than 2-3 folds higher than control at the mid-crop stage, especially due to the application of Anabaena-Azotobacter biofilm and Azotobacter sp. Both at the mid-crop and harvest stages, the PCR-DGGE profiles of eubacterial communities were similar among the uninoculated control, the Anabaena sp. - Providencia sp. (CW1 + PW5) and the Anabaena-Azotobacter biofilm treatments. Although the profiles of the Azotobacter, Calothrix and CR1 + PR3 treatments were identical at these stages of growth, the profile of CR1 + PR3 was clearly distinguishable. The performance of the inoculants, particularly Calothrix (T6) and consortium of Anabaena and Providencia (CR1 + PR3; T5), in terms of microbiological and nutrient data, along with generation of distinct PCR-DGGE profiles suggested their superiority and emphasized the utility of combining microbiological and molecular tools in the selection of effective microbial inoculants.
Numerous epidemiological studies have suggested that metal exposure may promote the atherosclerosis disorder in humans.
This study is carried out to assess the distribution, correlation and multivariate apportionment of cadmium (Cd), cobalt (Co), chromium (Cr), copper (Cu), iron (Fe), manganese (Mn), lead (Pb) and zinc (Zn) in the blood of atherosclerosis patients in comparison with healthy donors.
The quantification of metals is done by atomic absorption spectrometry, after wet-acid digestion of the blood samples.
Significantly higher concentrations of cadmium, chromium, copper, iron and manganese are found in the blood of atherosclerosis patients. The correlation study shows diverse relationships among the metals in blood of the patients and controls. Multivariate cluster analysis based on the metal levels in patients and controls reveals clearly separate grouping for the patients and healthy donors. Moreover, principal component analysis shows divergent grouping of the metals for the patients and healthy donors, which may be associated with the altered metabolism of the metals in atherosclerosis patients.
Overall, the distribution, correlation and multivariate apportionment of selected metals in atherosclerosis patients and healthy donors are significantly divergent. Hence, present findings suggest that the trace and redox metals accumulated in the body may pose a high risk for atherosclerosis development.
Heavy metal(loid) rich ash (≤10,000 mg kg(-1) total As, Cr, Cu and Zn) originating from the combustion of contaminated wood was subjected to several experimental procedures involving its incorporation into an upland pasture soil. Ash was added to soil that had been prior amended with local cattle manure, replicating practices employed at the farm scale. Metal(loid) concentrations were measured in soil pore water and ryegrass grown on soil/manure plus ash mixtures (0.1-3.0% vol. ash) in a pot experiment; toxicity evaluation was performed on the same pore water samples by means of a bacterial luminescence biosensor assay. Thereafter a sequential extraction procedure was carried out on selected soil, manure and ash mixtures to elucidate the geochemical association of ash derived metal(loid)s with soil constituents. Predictive modelling was applied to selected data from the pot experiment to determine the risk of transfer of As to meat and milk products in cattle grazing pasture amended with ash. The inclusion of manure to soils receiving ash reduced phyto-toxicity and increased ryegrass biomass yields, compared to soil with ash, but without manure. Elevated As and Cu concentrations in pore water and ryegrass tissue resulting from ash additions were reduced furthest by the inclusion of manure due to an increase in their geochemical association with organic matter. Zinc was the only measured metal(loid) to remain uniformly soluble and bioavailable regardless of the addition of ash and manure. Risk modelling on pot experimental data highlighted that an ash addition of >1% (vol.) to this pasture soil could result in As concentrations in milk and meat products exceeding acceptable limits. The results of this study therefore suggest that even singular low doses of ash applied to soil increase the risk of leaching of metal(loid)s and intensify the risk of As transfer in the food chain.
This study was planned to investigate some physicochemical and anti-inflammatory, antioxidant, antimicrobial properties of three different degrees of unifloral characters of chestnut honeys. Antihyaluronidase, antiurease and antimicrobial activities were evaluated as anti-inflammatory characteristics. Total phenolic contents, flavonoids, tannins, phenolic profiles, ferric-reducing antioxidant power (FRAP), scavenging activities of 2,2'-azinobis-(3-ethylbenzothiazoline-6-sulfonic acid (ABTS(+)) and 2,2-diphenyl-1-picrylhydrazyl (DPPH) radicals were evaluated as antioxidant properties. Color, optical rotation, conductivity, moisture, pH and ash content were evaluated as physicochemical parameters, and some sugars content, prolin, diastase, HMF and minerals (Na, K, Ca, P, Fe, Cu and Zn) were evaluated as chemical and biochemical parameters. All studied physicochemical and biological active properties were changed in line with the unifloral character of the chestnut honeys. A higher unifloral character was found associated with greater apitherapeutic capacity of the honey, as well as biological active compounds.
Calcium phosphate coatings were prepared on the surface of self-designed Mg-Zn-Ca-Mn alloy using microarc oxidization technology. To characterize the microstructures, cross-section morphologies, and compositions of the coatings, the authors used scanning electron microscopy equipped with an energy-disperse spectrometer, x-ray diffraction, and Fourier transform infrared spectroscopy. Potentiodynamic polarization in the simulated body fluid (SBF) was used to evaluate the corrosion behaviors of the samples. An SBF immersion test was used to evaluate the coating bioactivity and degradability. After the immersion tests, some bonelike apatite formed on the coating surfaces indicate that bioactivity of the coatings is excellent. The coating prepared in electrolyte containing (NaPO3)6 had slower degradation rate after immersion test for 21 days.
As is well documented, platinum nanoparticles, promising for catalysts for fuel cells, exhibit better catalytic activities, when alloyed with Zn. Pre-existing syntheses of Pt-Zn alloy catalysts are composed of a number of complex steps. In this study, we have demonstrated that nanoparticles of Pt-Zn alloys are simply generated by electron-beam irradiation in a transmission electron microscope of a wurtzite ZnO single-crystal specimen. The initial ZnO specimen is considered to have been contaminated by Pt during specimen preparation by focused ion beam milling. The formation of the nanoparticle is explained within the framework of ionization damage (radiolysis) by electron-beam irradiation and accompanying electrostatic charging.
The incidence of
 metabolic syndrome (MetS) has been increasing globally and it is recognized as a major public health problem because MetS is associated with increased risk of diabetes, stroke, cancer, and other chronic diseases. Recently, MetS has been linked to vitamin D deficiency. However, the evidence on the association between vitamin D deficiency and the risk of MetS remains inconclusive. This review therefore aims to depict the existing evidence related to MetS and vitamin D deficiency, and examined some of the possible confounders which may affect the association between vitamin D status and risk of MetS. Earlier studies on the association between vitamin D deficiency and MetS have adjusted for the effect of some confounders including, age, sex, body mass index, race, physical activity, smoking, alcohol consumption, and energy intake. However, these studies failed to consider other potential confounders. There is evidence that vitamin A, zinc (Zn), and magnesium (Mg) play important roles in the activation and function of vitamin D and interact with gene expression. Furthermore, these micronutrients are also related to several components of the MetS including glucose intolerance, dyslipidemia, and obesity. Thus, there could be an interaction between these micronutrients, vitamin D, and MetS. This review highlights the possible interactions of vitamin A, Zn, Mg, and vitamin D with MetS and its components. The findings reinforce the need for further well-designed studies that take into account all potential confounders, including other micronutrients such as vitamin A, Zn, and Mg status, to investigate the independent association of vitamin D status with MetS and its components, and also to scrutinize for possible interactions among other nutrients which may have similar confounding effects.
The content of elements in fish tissues and organs from Swarzędzkie Lake was investigated in order to evaluate the possible risk associated with their consumption by animals as well as humans. Samples of muscle, liver and fish bone of three fish species; roach (Rutilus rutilus), silver bream (Blicca bjoerkna) and crucian carp (Carassius carassius) were collected from seine catches undertaken as part of the biomanipulation of Swarzędzkie Lake. Element concentration (Al, As, Cd, Co, Cr, Cu, Hg, Ni, Pb, Zn) was determined by inductively coupled plasma mass spectrometry (ICP-MS), with the exception of Hg where the flow injection analysis system cold vapour atomic absorption spectrometry (FIAS-CVAAS) was applied. The study indicated a large variation in the occurrence of the investigated elements in different parts of the fish body. The highest content of Al and Zn was stated in all fish organs for each fish species. The majority of the applied statistical and chemometric methods (e.g., PCA, CA) refer to roach since we had a large number of data for this species. The obtained results were assessed in terms of their accuracy and precision using certified reference material of Fish Muscle ERM BB422.
We synthesized and characterized the ligand N,N'-bis[(2,2'-dihydroxybiphen-3-yl)methyl]-N,N'-dimethylethylenediamine (L), which contains two biphenol moieties linked as side arms to an N,N'-dimethylethylenediamine scaffold. The ligand is highly soluble in a 50/50 (v/v) water/ethanol mixture and, in its deprotonated form H-2L(2-), is able to coordinate transition-metal ions such as Ni(II), Zn(II), Cu(II), Cd(II), and Pd(II). The crystal structures of [Ni(H-2L)·2n-BuOH], [Ni(H-2L)·2MeOH], [Cd(H-2L)·2DMF], [Cu(H-2L)(DMF)], and [Pd(H-2L)(DMF)] were also determined and described. Potentiometric titrations were carried out in a mixed solvent with Zn(II), Cu(II), and Ni(II) metal ions to determine the acid-base and stability constants. L was highly fluorescent in the visible range (400 nm). Moreover, its emission intensity increased upon the addition of Zn(II) or Cd(II) ions in an ethanol/water solution and behaved as a chemosensor for the presence of these ions in the solution.
The significance of coal in the world economy remains unquestionable for decades. It is also expected to be the dominant fossil fuel in the foreseeable future. The increased awareness of sustainable development reflected in the relevant regulations implies, however, the need for the development and implementation of clean coal technologies on the one hand, and adequate analytical tools on the other. The paper presents the application of the quantitative Partial Least Squares method in modeling the concentrations of trace elements (As, Ba, Cd, Co, Cr, Cu, Mn, Ni, Pb, Rb, Sr, V and Zn) in hard coal based on the physical and chemical parameters of coal, and coal ash components. The study was focused on trace elements potentially hazardous to the environment when emitted from coal processing systems. The studied data included 24 parameters determined for 132 coal samples provided by 17 coal mines of the Upper Silesian Coal Basin, Poland. Since the data set contained outliers, the construction of robust Partial Least Squares models for contaminated data set and the correct identification of outlying objects based on the robust scales were required. These enabled the development of the correct Partial Least Squares models, characterized by good fit and prediction abilities. The root mean square error was below 10% for all except for one the final Partial Least Squares models constructed, and the prediction error (root mean square error of cross-validation) exceeded 10% only for three models constructed. The study is of both cognitive and applicative importance. It presents the unique application of the chemometric methods of data exploration in modeling the content of trace elements in coal. In this way it contributes to the development of useful tools of coal quality assessment.
Using 4-substituted derivatives of phenol-based compartmental Schiff-base hydroxyl-rich ligand, four multifunctional binuclear Zn(II) complexes have been synthesized and characterized. The photophysical properties of these complexes were explored in the solid state, in solutions, and in poly(methyl methacrylate) (PMMA) matrix, which revealed their good potential as tunable solid state emitters. Some of these complexes acted as efficient catalysts for the transesterification of esters and canola oil showing their potential in biodiesel generation. Mechanistic investigations using ESI-MS revealed that the transesterification catalyzed by these complexes proceeds through two types of acyl intermediates.
Widespread potential dietary deficiencies of calcium (Ca), iron (Fe), iodine (I), selenium (Se) and zinc (Zn) have been identified in Malawi. Several deficiencies are likely to be compounded by high phytic acid (PA) consumption. Rice (Oryza sativa) is commonly consumed in some Malawian populations, and its mineral micronutrient content is important for food security. The considerable irrigation requirements and flooded conditions of paddy soils can also introduce or mobilise potentially toxic elements including arsenic (As), cadmium (Cd) and lead (Pb). The aim of this study was to determine the mineral composition of rice sampled from farmers' fields and markets in Malawi. Rice was sampled from 18 extension planning areas across Malawi with 21 white (i.e. polished) and 33 brown samples collected. Elemental composition was determined by inductively coupled plasma-mass spectrometry (ICP-MS). Arsenic speciation was performed using high-performance liquid chromatography (HPLC)-ICP-MS. Concentration of PA was determined using a PA-total phosphorus assay. Median total concentrations (mg kg(-1), dry weight) of elements important for human nutrition in brown and white rice, respectively, were: Ca = 66.5 and 37.8; Cu = 3.65 and 2.49; Fe = 22.1 and 7.2; I = 0.006 and <0.005; Mg = 1130 and 265; Mn = 18.2 and 9.6; Se = 0.025 and 0.028; and Zn = 17.0 and 14.4. In brown and white rice samples, respectively, median PA concentrations were 5438 and 1906 mg kg(-1), and median PA:Zn molar ratios were 29 and 13. Concentrations of potentially toxic elements (mg kg(-1), dry weight) in brown and white rice samples, respectively, were: As = 0.030 and 0.006; Cd  ≤ 0.002 and 0.006; Pb = 0.008 and 0.008. Approximately 95 % of As was found to be inorganic As, where this could be quantified. Malawian rice, like the more widely consumed staple grain maize, contains inadequate Ca, I, Se or Zn to meet dietary requirements. Biofortification strategies could significantly increase Se and Zn concentrations and require further investigation. Concentrations of Fe in rice grain varied greatly, and this was likely due to contamination of rice samples with soil. Risk of As, Cd or Pb toxicity due to rice consumption in Malawi appears to be minimal.
Tuberculosis remains one of the deadliest communicable diseases. There are number of tests available for the diagnosis of tuberculosis but conventional microscopy has low sensitivity and culture although gold standard, but takes longer time for positivity. On the other side, Nucleic acid amplification techniques due to its rapidity and sensitivity not only help in early diagnosis and management of tuberculosis especially in patients with high clinical suspicion like immunocompromised patients, history of contact with active tuberculosis patient etc., but also curtail the transmission of the disease.
To evaluate the sensitivity, specificity, positive predictive value and negative predictive value of Nucleic acid amplification assay (GeneXpert) using respiratory samples in patients with suspected pulmonary tuberculosis and compare with AFB smear microscopy (Ziehl Neelsen stain) and Acid Fast Bacilli (AFB) culture.
We retrospectively reviewed the respiratory samples of suspected pulmonary tuberculosis (including Bronchoalveolar lavage and sputum) of 170 patients from Jan 2015 to Nov 2015 for ZN stain, culture and
 GeneXpert (Xpert(®) MTB/Rif assay). The sensitivity, specificity, PPV and NPV of GeneXpert and ZN microscopy were calculated using Liquid culture of Mycobacterium tuberculosis as gold standard.
A total of 170 patient samples were evaluated in final analysis. Of these, 14 samples were positive by all three methods used in our study. The overall sensitivity, specificity, PPV and NPV of GeneXpert were 86.8%, 93.1%, 78.5% and 96% respectively and for BAL sample, 81.4%, 93.4%, 73.3% and 95.7% respectively. The overall sensitivity and specificity of AFB smear microscopy were 22.2%, % and 78.5% respectively and for BAL sample 22.2% and 100% respectively. For AFB negative samples sensitivity and specificity were 79.1% and 93.1% respectively.
GeneXpert has a higher sensitivity than AFB smear microscopy in respiratory samples. GeneXpert can be a useful tool for early diagnosis of patients with high clinical suspicion of pulmonary tuberculosis. Positive GeneXpert, but culture negative results should be read cautiously and be well correlated with clinical and treatment history of the patient. The other major advantage of Gene Xpert is that it simultaneously detects Rifampicin resistance and especially beneficial in patient with MDR and HIV associated tuberculosis and should be studied further.
The detailed atomic structure of the binary icosahedral (i) ScZn7.33 quasicrystal has been investigated by means of high-resolution synchrotron single-crystal X-ray diffraction and absolute scale measurements of diffuse scattering. The average atomic structure has been solved using the measured Bragg intensity data based on a six-dimensional model that is isostructural to the i-YbCd5.7 one. The structure is described with a quasiperiodic packing of large Tsai-type rhombic triacontahedron clusters and double Friauf polyhedra (DFP), both resulting from a close-packing of a large (Sc) and a small (Zn) atom. The difference in chemical composition between i-ScZn7.33 and i-YbCd5.7 was found to lie in the icosahedron shell and the DFP where in i-ScZn7.33 chemical disorder occurs on the large atom sites, which induces a significant distortion to the structure units. The intensity in reciprocal space displays a substantial amount of diffuse scattering with anisotropic distribution, located around the strong Bragg peaks, that can be fully interpreted as resulting from phason fluctuations, with a ratio of the phason elastic constants K 2/K 1 = -0.53, i.e. close to a threefold instability limit. This induces a relatively large perpendicular (or phason) Debye-Waller factor, which explains the vanishing of 'high-Q perp' reflections.
Ionizing radiation interacts with biological systems through the generation of free radicals, which induce oxidative stress. Aluminium (Al) can negatively impact human health by direct interaction with antioxidant enzymes. Ellagic acid (EA) and Ferulic acid (FA) are plant polyphenolic compounds, have gained attention due to their multiple biological activities. To date, no studies investigating the antioxidant effect of EA/FA in a model involving both γ radiation and aluminium chloride (AlCl3) have been reported. Herein, we investigated the protective effect of EA and FA against oxidative stress induced by γ radiation and AlCl3 in rats.
Rats were divided into thirteen groups: a negative control group, 3 positive control groups (γ-irradiated, AlCl3-treated and γ-irradiated+AlCl3-treated) and 9 groups (3 γ-irradiated, 3 AlCl3-treated and 3 γ-irradiated+AlCl3-treated) treated with EA and/or FA. Liver function and lipid profile were assessed. Levels of lipid peroxidation, protein oxidation and endogenous antioxidants as well as the concentrations of copper, iron and zinc were estimated in liver tissue homogenate. Furthermore, liver tissue sections were histologically examined.
Oral administration of EA and/or FA resulted in 1) amelioration of AlCl3 and/or γ-radiation-induced hepatic function impairment, dyslipidemia and hepatic histological alterations; 2) reduction in liver MDA and PCC levels; 3) elevation of liver CAT, GPx and SOD activity as well as GSH level; 4) elevation in liver Cu concentrations which was accompanied by a reduction in Fe and Zn concentrations.
Oral administration of EA and/or FA may be useful for ameliorating γ radiation and/or AlCl3-induced oxidative damage.
The high hardness or yield strength of an alloy is known to benefit from the presence of small-scale precipitation, whose hardening effect is extensively applied in various engineering materials. Stability of the precipitates is of critical importance in maintaining the high performance of a material under mechanical loading. The long period stacking ordered (LPSO) structures play an important role in tuning the mechanical properties of an Mg-alloy. Here, we report deformation twinning induces decomposition of lamellar LPSO structures and their re-precipitation in an Mg-Zn-Y alloy. Using atomic resolution scanning transmission electron microscopy (STEM), we directly illustrate that the misfit dislocations at the interface between the lamellar LPSO structure and the deformation twin is corresponding to the decomposition and re-precipitation of LPSO structure, owing to dislocation effects on redistribution of Zn/Y atoms. This finding demonstrates that deformation twinning could destabilize complex precipitates. An occurrence of decomposition and re-precipitation, leading to a variant spatial distribution of the precipitates under plastic loading, may significantly affect the precipitation strengthening.
The therapeutic effect on HCl/ethanol induced gastric injury of Gardenia jasminoides (JXGJ-1 and JXGJ-2) were determined by a animal model. JXGJ-2 group reduced area of its gastric injury as compared to the control group, JXGJ-2 also helped in decreasing the gastric secretion volume results raised in pH value. The NO contents in serum, heart, liver, kidney and stomach of JXGJ-2 group were more than JXGJ-1 and control groups. JXGJ-2 reduce cytokine levels as compared to JXGJ-1 and control group. The serum and gastric tissue SOD, GSH-Px, GSH levels in JXGJ-2 treated mice were higher than JXGJ-1 treated and control mice, but the MDA, PC levels showed the crosscurrents, these levels were close to normal mice. Gardenia jasminoides could increase the occludin, EGF, EGFR, VEGF, IκB-α, nNOS, eNOS, Cu/Zn-SOD, Mn-SOD, CAT, GSH-Px (GSH1) mRNA and protein expressions and decrease the p38MAPK (p38), NF-κB, Bcl-2, COX-2, iNOS expressions in gastric tissues unlike to the control mice, JXGJ-2 had much better effect than JXGJ-1. JXGJ-1contained the higher genipin gentiobioside and gardenoside, they might be the key components of gastric injury inhibition. Gardenia jasminoides had a remarkable effect on gastric injury, and they were derived from two important components of genipin gentiobioside and gardenoside.
Endothelial dysfunction associated with hypercholesterolemia is an early event in atherosclerosis characterized by redox imbalance associated with high superoxide production and reduced nitric oxide (NO) and hydrogen peroxide (H2O2) production. Aerobic exercise training (AET) has been demonstrated to ameliorate atherosclerotic lesions and oxidative stress in advanced atherosclerosis. However, whether AET protects against the early mechanisms of endothelial dysfunction in familial hypercholesterolemia remains unclear. This study investigated the effects of AET on endothelial dysfunction and vascular redox status in the aortas of LDL receptor knockout mice (LDLr(-/-)), a genetic model of familial hypercholesterolemia.
Twelve-week-old C57BL/6J (WT) and LDLr(-/-) mice were divided into sedentary and exercised (AET on a treadmill 1 h/5 × per week) groups for 4 weeks. Changes in lipid profiles, endothelial function, and aortic NO, H2O2 and superoxide production were examined.
Total cholesterol and triglycerides were increased in sedentary and exercised LDLr(-/-) mice. Endothelium-dependent relaxation induced by acetylcholine was impaired in aortas of sedentary LDLr(-/-) mice but not in the exercised group. Inhibition of NO synthase (NOS) activity or H2O2 decomposition by catalase abolished the differences in the acetylcholine response between the animals. No changes were noted in the relaxation response induced by NO donor sodium nitroprusside or H2O2. Neuronal NOS expression and endothelial NOS phosphorylation (Ser1177), as well as NO and H2O2 production, were reduced in aortas of sedentary LDLr(-/-) mice and restored by AET. Incubation with apocynin increased acetylcholine-induced relaxation in sedentary, but not exercised LDLr(-/-) mice, suggesting a minor participation of NADPH oxidase in the endothelium-dependent relaxation after AET. Consistent with these findings, Nox2 expression and superoxide production were reduced in the aortas of exercised compared to sedentary LDLr(-/-) mice. Furthermore, the aortas of sedentary LDLr(-/-) mice showed reduced expression of superoxide dismutase (SOD) isoforms and minor participation of Cu/Zn-dependent SODs in acetylcholine-induced, endothelium-dependent relaxation, abnormalities that were partially attenuated in exercised LDLr(-/-) mice.
The data gathered by this study suggest AET as a potential non-pharmacological therapy in the prevention of very early endothelial dysfunction and redox imbalance in familial hypercholesterolemia via increases in NO bioavailability and H2O2 production.
A pioneering approach towards controlling the efficiency of saponification assisted gelation in ethyl ester based Zn(II) -complexes have been described. Using four new ester containing bis-salen Zn(II) complexes (C1-C4) involving different para-azo phenyl substituted ligands it has been clearly shown that gelation efficiency is greatly influenced by the electronic effects of the substituents (-H (C1), -CH3 (C2), -NO2 (C3), and -OCH3 (C4)).
 Morphological, photophysical, and rheological investigations corroborated the experimental observations well and established that gelation efficiency was enhanced with electron-withdrawing characteristics of substituents (C4<C2<C1<C3). This conclusion was also supported by DFT studies.
The use of plant extract to synthesize nanoparticle has been considered as one of the eco-friendly method. Additionally, it is a strong alternate for conventional methods which includes chemical and physical approach. In this study, microwave assisted extraction of Carissa edulis (C. edulis) at 70°C and 400W was used to extract the secondary metabolites. Further, the metabolites were used as capping agent and Zn (NO3)2 as the metal precursor to synthesize ZnO nanoparticles (ZnO NPs). UV-Vis spectroscopy, FT-IR, XRD, SEM and HR-TEM were used for the characterization of nanoparticles. The Surface Plasmon Resonance around 358nm from the UV-Vis spectroscopy result represents the ZnO NPs formation. The FT-IR confirms the presence of functional groups that acts as the capping agent for the synthesis of ZnO NPs. The crystalline structure of nanoparticles is revealed in the XRD result, morphology showed by SEM results and the size of the ZnO NPs were predicted by HR-TEM. We have carried out the photocatalytic degradation of Congo red at 365nm in photo reactor using ZnO NPs. The result from the photocatalytic degradation Congo red showed rate constant is (-k) 0.4947 with 97% of degradation. This is our first attempt on the C. edulis extract on ZnO NPs preparation and Congo red dye degradation revels that ZnO NPs exhibit good photocatalytic property.
The aim of this work was to evaluate the total content and speciation of heavy metals (As, Cr, Cd, Cu, Fe, Mn, Ni, Pb and Zn) during vermicomposting of sewage sludge by Eisenia fetida earthworm with different additive materials (soil, straw, fly ash and sawdust). Results showed that the pH, total organic carbon were reduced, while the electric conductivity and germination index increased after a combined composting - vermicomposting process. The addition of bulking agents accelerated the stabilization of sludge and eliminated its toxicity. The total heavy metals after vermicomposting in 10 scenarios were lowered as compared with the initial values and the control without amendment. BCR sequential extraction indicated that vermicomposting significantly decreased the mobility of all heavy metals by increasing the residual fractions. The activity of earthworms and appropriate addition of amendment materials played a positive role in sequestering heavy metals during the treatment of sewage sludge.
Phytomanagement by phytostabilisation of metal(loid)-enriched mine tailings in semiarid areas has been proposed as a suitable technique to promote a self-sustainable vegetal cover for decreasing the spread of polluted particles by erosion. The goal of this work was to evaluate the contribution of a pioneer plant species (Zygophyllum fabago) in ameliorating the soil conditions at two mine tailings piles located in a semiarid area in Southeast Spain. The ecophysiological performance of this plant species compared to a control population was assessed by analysing the nutritional and ecophysiological status. The presence of Z. fabago in mine tailings enhanced the soil microbial activity and increased the content of soil organic carbon within the rhizosphere (approx. 50% increasing). Metal(loid) concentrations in the tailings may play a minor role in the establishment of Z. fabago plants due to the low metal(loid) availability in the tailings (low CaCl2-extractable concentrations) and low uptake in the plants (e.g. up to 300 mg kg(-1) Zn in leaves). The lower δ(13)C and δ(13)O in the plants sampled at both tailings compared to the control ones may indicate softer stomatal regulation in relation to the control site plants and therefore lower WUE. The Z. fabago plants may skip some energy-demanding mechanisms such as stomatal control and/or proline synthesis to overcome the environmental stresses posed at the tailings. The Z. fabago plants revealed high plasticity of the species for adapting to the low fertility soil conditions of the tailings and to overcome constraints associated to the dry season.
The Aβ complexes of some redox-active species, such as Cu, cause oxidative stress and induce severe toxicity by generating reactive oxygen species (ROS). Thus, Cu chelation therapy should be considered as a valuable strategy for the treatment of Alzheimer's disease (AD). However, more attention should be paid to the specific chelating ability of these chelating agents. Herein, a tripeptide GGH was used to selectively chelate the Cu(2+) in Aβ-Cu complex in the presence of other metal ions (e.g., K(+), Ca(2+), Ni(2+), Mg(2+), and Zn(2+)) as shown by isothermal titration calorimetry results. GGH decreased the level of HO(•) radicals by preventing the formation of intermediate Cu(I) ion. Thus, the Cu species completely lost its catalytic activity at a superequimolar GGH/Cu(II) ratio (4:1) as observed by UV-visible spectroscopy, coumarin-3-carboxylic acid fluorescence, and BCA assay. Moreover, (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) (MTT) assay indicates that GGH increased PC-12 cell viability from 36% to 63%, and neurotoxicity partly triggered by ROS decreased. These results indicate potential development of peptide chelation therapy for AD treatment.
The faceted nanoparticle synthesized by ion implantation, such as Zn, Cu or Ag nanoparticles, is one of the promising materials for the next generation of optical devices. To understand and better control the manufacturing processes of ion implantation, a theoretical model is applied to investigate the formation and evolution of faceted nanoparticles under various experimental conditions of implantation processing. In this study, the mechanisms of the anisotropic interfacial energy and kinetics with different ion distributions are taken into consideration to demonstrate the role of the crystallographic symmetry, ion energy and temperature on the faceted nanoparticles formation in a crystalline matrix. As presented in the numerical results, the morphological shape of the nanoparticles is mainly affected by the crystallographic symmetry, while the distribution of the precipitates is principally determined by the ion energy. For the condition of high-temperature implantation, a high mobility of ions causes the characteristic length of nanostructures to increase and creates a coarsening morphology of nanoparticles. It is attributed to a longer diffusion distance during the nucleation and growth processes. This model can be widely used for the predictions of the nanostructures formation with various ion implantation processes.
Pure and Fe-doped ZnO nanostructures with different weight ratios (0.5, 1.0, 1.5, and 2.0 at wt% of Fe) were successfully synthesized by a facile microwave combustion method using urea as a fuel. The detailed structural characterization was performed by means of X-ray diffraction (XRD), high resolution scanning electron microscopy (HR-SEM), energy dispersive X-ray analysis (EDX), diffuse reflectance spectroscopy (DRS), photoluminescence (PL) spectroscopy and vibrating sample magnetometry (VSM). XRD patterns refined by the Rietveld method indicated that Fe-doped ZnO have a single pure phase with wurtzite structure, suggesting that Fe ions are successfully incorporated into ZnO crystal lattice by occupying Zn ionic sites. Interestingly, the morphology was found to change substantially from grains to nanoflakes and then into nanorods with the variation of Fe-content. The optical band gap estimated using DRS was found to be red-shifted from 3.220 eV for the pure ZnO nanostructures, then decreases up to 3.200 eV with increasing Fe-content. Magnetic studies showed that Fe-doped ZnO nanostructures exhibit room temperature ferromagnetism (RTFM) and the saturation magnetization attained a maximum value of 8.154 x 10(-3) emu/g for the highest Fe-content. The antibacterial activity of pure and Fe-doped ZnO nanostructures against a Gram-positive bacteria and Gram-negative bacteria was investigated. Pure ZnO and Fe-doped ZnO exhibited antibacterial activity, but it was considerably more effective in the 1.5 wt% Fe-doped ZnO nanostructures.
Bilaterian voltage-gated Na(+) channels (NaV) evolved from voltage-gated Ca(2+) channels (CaV). The Drosophila melanogaster Na(+) channel 1 (DSC1), which features a D-E-E-A selectivity filter sequence that is intermediate between CaV and NaV channels, is evidence of this evolution. Phylogenetic analysis has classified DSC1 as a Ca(2+)-permeable Na(+) channel belonging to the NaV2 family because of its sequence similarity with NaV channels. This is despite insect NaV2 channels (DSC1 and its orthologue in Blatella germanica, BSC1) being more permeable to Ca(2+) than Na(+) In this study, we report the cloning and molecular characterization of the honeybee (Apis mellifera) DSC1 orthologue. We reveal several sequence variations caused by alternative splicing, RNA editing, and genomic variations. Using the Xenopus oocyte heterologous expression system and the two-microelectrode voltage-clamp technique, we find that the channel exhibits slow activation and inactivation kinetics, insensitivity to tetrodotoxin, and block by Cd(2+) and Zn(2+) These characteristics are reminiscent of CaV channels. We also show a strong selectivity for Ca(2+) and Ba(2+) ions, marginal permeability to Li(+), and impermeability to Mg(2+) and Na(+) ions. Based on current ion channel nomenclature, the D-E-E-A selectivity filter, and the properties we have uncovered, we propose that DSC1 homologues should be classified as CaV4 rather than NaV2. Indeed, channels that contain the D-E-E-A selectivity sequence are likely to feature the same properties
 as the honeybee's channel, namely slow activation and inactivation kinetics and strong selectivity for Ca(2+) ions.
Aging population will lead to the increase of incidence of root caries globally. The clinical management of root caries is challenging due to the difficulty in moisture isolation. The root caries is caused by the release of organic acids from cariogenic bacteria which results in the dissolution of cementum and dentin of the root. The purpose of this study is to study the efficacy of modified saturated calcium phosphate solution (CaP) supplement with zinc (Zn(2+)) and/or fluoride (F(-)) in providing root cementum surfaces less susceptible to acid dissolution and bacterial colonization.
Human root cementum sections from extracted premolars were treated with three modified calcium phosphate solutions (M/A-CaPs) respectively: (A) CaP-F/Zn, supplemented with F(-) and Zn(2+); (B) CaP-F, supplemented with F(-) only; (C) CaP-Zn, supplemented with Zn(2+) only. The surface characteristics of treated cementum sections were investigated using scanning electron microscopy (SEM) and fourier transform infrared spectroscopy (FT-IR). Following the acid attack and Streptococcus mutans challenge, M/A-CaPs treated cementum surfaces were analysed using inductive coupled plasma (ICP) and SEM respectively.
Compared with the control group, M/A-CaPs treated cementum presented significant improvements in resistance to acid dissolution and bacterial colonization. Among M/A-CaPs, the CaP-F/Zn treated cementum surfaces released the lowest amount of Ca(2+) ions (2.11 ± 0.51 ppm) upon acid challenge (n = 3, p < 0.01) and also presented the most significant inhibiting effect against the colonization of S. mutans (n = 180, p < 0.05).
Saturated calcium phosphate solution CaP supplemented with both F(-) and Zn(2+) could be applied as an effective coating material providing acid resistance and antibacterial property on cementum surfaces. The modified calcium phosphate-based solution could be a new treatment strategy to prevent the development of root caries and arrest the further progression of root caries.
Pyrolyzing sludge into biochar is a potentially promising recycling/disposal solution for municipal wastewater sludge, and the sludge-derived biochar (SDBC) presents an excellent sorbent for metal immobilization. As SDBC is composed of both mineral oxides and carbonized organic compartment, this study therefore compared the sorption behaviour of Pb and Zn on SDBC to those of individual and mixture of activated carbon (AC) and amorphous aluminium oxide (Al2O3). Batch experiments were conducted at 25 and 45 °C, and the metal-loaded sorbents were artificially aged in the atmosphere for 1-60 days followed by additional sorption experiments. The Pb sorption was generally higher than Zn sorption, and the co-presence of Pb reduced Zn sorption on each studied sorbent. Higher sorption capacities were observed at 45 °C than 25 °C for SDBC and AC, while the opposite was shown for Al2O3, indicating the significance of temperature-dependent diffusion processes in SDBC and AC. Nevertheless, metal sorption was more selective on Al2O3 that showed a greater affinity towards Pb over Zn under competition, correlating with the reducible fraction of sequential extraction. Furthermore, significant amounts of Pb and Zn were additionally sorbed on SDBC following 30-day ageing. The X-ray diffraction revealed the formation of metal-phosphate precipitates, while the X-ray photoelectron spectroscopy showed a larger quantity of metal-oxygen bonding after 30-day ageing of metal-loaded SDBC. The results may imply favourable long-term transformation and additional sorption capacity of SDBC. In conclusion, SDBC resembles the sorption characteristics of both organic and mineral sorbents in different aspects, presenting an appropriate material for metal immobilization during soil amendment.
Copper (Cu) ions are likely the most important immunological metal-related toxin utilized in controlling bacterial infections. Impairment of bacterial Cu resistance reduces viability within the host. Thus, pharmacological enhancement of Cu-mediated antibacterial toxicity may lead to novel strategies in drug discovery and development. Screening for Cu toxicity-enhancing antibacterial molecules identified 8-hydroxyquinoline (8HQ) to be a potent Cu-dependent bactericidal inhibitor of Mycobacterium tuberculosis The MIC of 8HQ in the presence of Cu was 0.16 μM for replicating and nonreplicating M. tuberculosis cells. We found 8HQ's activity to be dependent on the presence of extracellular Cu and to be related to an increase in cell-associated labile Cu ions. Both findings are consistent with 8HQ acting as a Cu ionophore. Accordingly, we identified the 1:1 complex of 8HQ and Cu to be its active form, with Zn, Fe, or Mn neither enhancing nor reducing its Cu-specific action. This is remarkable, considering that the respective metal complexes have nearly identical structures and geometries. Finally, we found 8HQ to kill M. tuberculosis selectively within infected primary macrophages. Given the stark Cu-dependent nature of 8HQ activity, this is the first piece of evidence that Cu ions within macrophages may bestow antibacterial properties to a Cu-dependent inhibitor of M. tuberculosis In conclusion, our findings highlight the metal-binding ability of the 8-hydroxyquinoline scaffold to be a potential focus for future medicinal chemistry and highlight the potential of innate immunity-inspired screening platforms to reveal molecules with novel modes of action against M. tuberculosis.
The o-aminophenol-N,N,O-triacetic acid (APTRA) chelator is employed extensively as a metal-recognition moiety in fluorescent indicators for biological free Mg(2+), as well as in low-affinity indicators for the detection of high levels of cellular Ca(2+). Despite its widespread use in sensor design, the limited metal selectivity of this chelating moiety can lead to binding of competing cations that complicate the fluorescence-based detection of metals of interest in complex samples. Reported herein are the structural characterization of APTRA complexes with various biologically relevant cations, and the thermodynamic analysis of complex formation with Mg(2+), Ca(2+) and Zn(2+). Our results indicate that the low affinity of APTRA for Mg(2+), which makes it a suitable metal-recognition moiety for sensitive analysis of typical millimolar levels of this metal in cells, stems from a much higher enthalpic cost of Mg(2+) binding compared to that of other cations. The results are discussed in the context of indicator design, highlighting the aspects that may aid the future development of fluorescent sensors with enhanced metal selectivity profiles.
The S100 proteins are a unique class of EF-hand Ca(2+) binding proteins distributed in a cell-specific, tissue-specific, and cell cycle-specific manner in humans and other vertebrates. These proteins are distinguished by their distinctive homodimeric structure, both intracellular and extracellular functions, and the ability to bind transition metals at the dimer interface. Here we summarize current knowledge of S100 protein binding of Zn(2+), Cu(2+) and Mn(2+) ions, focusing on binding affinities, conformational changes that arise from metal binding, and the roles of transition metal binding in S100 protein function.
Use of sewage sludge, a biological residue produced from sewage treatment processes in agriculture, is an alternative disposal technique of waste. To study the usefulness of sewage sludge amendment for Helianthus annuus, a pot experiment was conducted by mixing sewage sludge at 2.5, 5, and 7.5 % (w/w) amendment ratios to the agricultural soil. Soil pH decreased whereas electrical conductivity, organic matter, total N, available P, and exchangeable Na, K, and Ca increased in soil amended with sewage sludge in comparison to unamended soil. Sewage sludge amendment led to significant increase in Pb, Ni, Cu, Cr, and Zn concentrations of soil. The increased concentration of heavy metals in soil due to sewage sludge amendment led to increases in shoot and root concentrations of Cr, Cu, Ni, and Zn in plant as compared to those grown on unamended soil. Accumulation was more in roots than shoots for most of the heavy metals. Moreover, high metal removal for the harvestable parts of the crops was recorded. Sewage sludge amendment increased root and shoot length, leaves number, biomass, and antioxidant activities of sunflower. Significant increases in the activities of antioxidant enzymes and in the glutathione, proline, and soluble sugar content in response to amendment with sewage sludge may be defense mechanisms induced in response to heavy metal stress. Graphical abstract Origin, fate and behavior of sewage sludge fertilizer.
A new 4,5-diazafluorene-based fluorescent chemosensor has been synthesized by Schiff base condensation of 9,9-bis(3,5-dimethyl-4-aminophenyl)-4,5-diazafluorene with salicylaldehyde. The interaction of Schiff base with different metal ions has been studied over photofluorescent spectra. The results showed that Schiff base exhibited 194-fold enhancements in fluorescence at 465 nm after Zn(2+) ions. Such fluorescent responses could be detected by naked eye under UV-lamp. The complex solution (L-Zn(2+)) exhibited reversibility with EDTA.
The role of oxidative stress in susceptibility to seizures has been the focus of several recent studies. The aim of the present study was to evaluate the antiepileptic effects of the free radical scavenger edaravone on EL mice, a strain that is highly susceptible to convulsive seizures.
EL mice were treated intraperitoneally with edaravone or saline for 1 week. The levels of reduced glutathione (GSH), oxidized glutathione (GSSG) and 3 isozymes of superoxide dismutase (SOD) (cytoplasmic copper- and zinc-containing SOD, extracellular
 SOD, and mitochondrial manganese-containing SOD) were measured in the hippocampus, and electroencephalograms (EEGs) were used to evaluate seizure sensitivity.
Hippocampal levels of GSSG were lower in the edaravone group than in the untreated control group, and the GSH/GSSG ratio, Cu/Zn-SOD, and EC-SOD activities were higher in the edaravone group. Edaravone shortened the duration of interictal spike discharges and clinically suppressed epileptic seizures.
Edaravone increases antioxidant potency and reduces seizure susceptibility in EL mice, making it a promising novel antiepileptic agent.
Rare studies have been performed to trace the mineral elements in Dendrobium officinale. In this study, we aim to trace the mineral elements in D. officinale collected from ten geographical locations in China. ICP-MS system was used for simultaneous determination of mineral elements. Principal component analysis was performed using the obtained data in the quantification of mineral contents. Cluster analysis was performed using the Ward's method. Several of essential microelments were detected in D. officinale, including ferrum (Fe), manganese (Mn), zinc (Zn), chromium (Cr), nickel (Ni) and vanadium (V). Among these elements, three elements (i.e. Fe, Mn and Zn) were highly and simultaneously detected in the D. officinale collected from the ten locations. The level of Ni was positively associated with that of Zn (r = 0.986, P < 0.01). The level of titanium (Ti) was positively associated with that of V (r = 0.669, P < 0.05), and negatively associated with Cr (r = -0.710, P < 0.05). In addition, the level of Mn was positively associated with that of barium (r = 0.749, P < 0.05). Further, the level of Fe was positively associated with that of Ni (r = 0.664, P < 0.05), Zn (r = 0.742, P < 0.05), and rare earth elements (r = 0.847, P < 0.01), respectively. Three eigenvalues explained about 86.60 % of the total variance, which contributed significantly to the explanation of cumulative variance. Cluster analysis indicated the cultivars were categorized into 3 clusters. Ni, Zn, Fe, Cr, Ti and rare earth elements were designated as the characteristic elements. Cultivars collected from Yulin, Menghai, and Shaoguan ranked the top 3 in the comprehensive scores, indicating the content of the mineral elements was comparatively higher in these locations.
Amazonian fishes employ diverse migratory strategies, but the details of these behaviours remain poorly studied despite numerous environmental threats and heavy commercial exploitation of many species. Otolith microchemistry offers a practical, cost-effective means of studying fish life history in such a system. This study employed a multi-method, multi-elemental approach to elucidate the migrations of five Amazonian fishes: two 'sedentary' species (Arapaima sp. and Plagioscion squamosissimus), one 'floodplain migrant' (Prochilodus nigricans) and two long-distance migratory catfishes (Brachyplatystoma rousseauxii and B. filamentosum). The Sr : Ca and Zn : Ca patterns in Arapaima were consistent with its previously observed sedentary life history, whereas Sr : Ca and Mn : Ca indicated that Plagioscion may migrate among multiple, chemically distinct environments during different life-history stages. Mn : Ca was found to be potentially useful as a marker for identifying Prochilodus's transition from its nursery habitats into black water. Sr : Ca and Ba : Ca suggested that B. rousseauxii resided in the Amazon estuary for the first 1.5-2 years of life, shown by the simultaneous increase/decrease of otolith Sr : Ca/Ba : Ca, respectively. Our results further suggested that B. filamentosum did not enter the estuary during its life history. These results introduce what should be a productive line of research desperately needed to better understand the migrations of these unique and imperilled fishes.
In this study, we modulated the anti-cancer efficacy of 5-Fluorouracil (5-FU) using a carrier system with enhanced targeting efficacy towards folate receptors (FRs) expressing malignant tissues. The 5-FU drug was loaded onto Mn-ZnS quantum dots (QDs) encapsulated with chitosan (CS) biopolymer and conjugated with folic acid (FA) based on a simple wet chemical method. The formation of 5-FU drug loaded composite was confirmed using Fourier transform infrared spectroscopy (FTIR), thermo gravimetric analysis (TGA) and differential scanning calorimetry (DSC). Furthermore, the in vivo biodistribution and tumor targeting specificity of the 5-FU@FACS-Mn:ZnS in the tumor-bearing mice was conducted based on the Zn(2+) tissue bioaccumulation using inductively coupled plasma (ICP) spectroscopy. In addition to the characterization, the in vitro release profile of 5-FU from the conjugates investigated under diffusion controlled method demonstrated a controlled release behaviour as compared against the release behaviour of free 5-FU drug. The as-synthesized 5-FU@FACS-Mn:ZnS nanoparticle (NP) systemically induced higher level of apoptosis in breast cancer cells in vitro as compared to cells treated with free 5-FU drug following both cell cycle and annexin assays, respectively. Also, the in vivo toxicity assessment of the 5-FU@FACS-Mn:ZnS NPs as compared to the control did not cause any significant increase in the activities of the liver and kidney function biomarkers, malondialdehyde (MDA) and nitric oxide (NO) levels. However, based on the FA-FRs chemistry, the 5-FU@FACS-Mn:ZnS NPs specifically accumulated in the tumor of the tumor-bearing mice and thus contributed to the smaller tumor size and less event of metastasis was observed in the lungs when compared to the tumor-bearing mice groups treated with the free 5-FU drug. In summary, the results demonstrated that the 5-FU@FACS-Mn:ZnS QDs exhibits selective anti-tumor effect in MDA-MB231 breast cancer cells in vitro and 4TI breast cancer cells in vivo, providing a blueprint for improving the 5-FU efficacy and tumor targeting specificity with limited systemic toxicity.
Electrode materials derived from transition metal oxides have a serious problem of low electron transfer rate, which restricts their practical application. However, chemically doped graphene transforms the chemical bonding configuration to enhance electron transfer rate and, therefore, facilitates the successful fabrication of Co2Ni3ZnO8 nanowire arrays. In addition, the Co2Ni3ZnO8 electrode materials, considered as Ni and Zn ions doped into Co3O4, have a high electron transfer rate and electrochemical response capability, because the doping increases the degree of crystal defect and reaction of Co/Ni ions with the electrolyte. Hence, the Co2Ni3ZnO8 electrode exhibits a high rate property and excellent electrochemical cycle stability, as determined by electrochemical analysis of the relationship between specific capacitance, IR drop, Coulomb efficiency, and different current densities. From the results of a three-electrode system of electrochemical measurement, the Co2Ni3ZnO8 electrode demonstrates a specific capacitance of 1115 F g(-1) and retains 89.9% capacitance after 2000 cycles at a current density of 4 A g(-1). The energy density of the asymmetric supercapacitor (AC//Co2Ni3ZnO8) is 54.04 W h kg(-1) at the power density of 3200 W kg(-1).
This paper provides physical and chemical performances of mass stabilised organic and inorganic contaminated site soils using a new group of MgO-bearing binders over 3 years and evaluated the time-dependent performance during the 3 years. This study took place at a contaminated site in Castleford, UK in 2011, where MgO, ground granulated blastfurnace slag (GGBS) and Portland cement (PC) were mixed with the contaminated soils in a dry form using the ALLU mass mixing equipment. Soil cores were retrieved 40-day, 1-year and 3-year after the treatment. The core quality, strength, and the leaching properties were determined via physical observation, unconfined compressive strength (UCS) and batch leaching tests. After 3-year treatment, the UCS values of ALLU mixes were in the range of 50-250kPa; the leachate concentrations of Cd, Pb, Cu and Zn (except Ni) in all mixes were lower than their drinking water standards; and the leachability of total organics was in the range of 10-105mg/L. No apparent degradation of the mass stabilised materials after 3 years' exposure to the field conditions was found. MgO-GGBS blends were found able to provide higher strength and less leachability of contaminants compared to PC and MgO-only mixes in mass stabilised soils.
We investigated the concentration levels, fractionation and molecular weight distribution (MWD) of dissolved organic matter (DOM) and metals (V, Cr, Co, Ni, Cu, Zn, As, Cd, Sn, Ba, Hg and Pb) in a polluted groundwater from an industrial area in Northern Sweden. DOM was mainly recovered in the hydrophobic acidic and hydrophobic neutral sub-fractions (45 and 35%, respectively) while most metals were found in the acidic sub-fractions (46-93%) except for V, Fe and As, which were predominant in the basic sub-fractions (74-93%) and Cd in the neutral ones (50%). DOM exhibited a broad MWD in groundwaters, usually from 5 to 200kDa and was dominated by high molecular weight hydrophobic acids, low molecular weight hydrophilic acids and hydrophilic neutral compounds. Most of the studied metals (Fe, Cr, Co, Sn, Ba, Hg) were associated with the high molecular weight DOM fraction (ca. 40-100kDa). Cu, Pb, Zn, Cd and Ni interacted with a broad range of DOM size fractions but were still most abundant in the high molecular weight fraction. Few metal/metalloids (As, V and Cr in some cases) presented a very weak affinity for DOM and presumably existed predominantly as "free" inorganic ions in solution.
In current selective sequential extraction (SSE) methods, heavy metals associated well-crystallized iron oxyhydroxides are not well defined and considered,
 and usually fall into residual forms, which actually make their mobility and environmental risk underestimated. This study compared various fractions of heavy metals in samples of mining tailings and nearby soils under different land uses in Guangdong Province of China. Iron oxides in these soils were mainly Al-substituted goethites and/or hematites. Independent of the land uses, the percentages of various Cd fractions in the soils decrease in the order of well-crystallized iron oxyhydroxides-associated (27.2-91.2%) > residual (2.1-37.0%) > reducible FeMn oxides (3.2-45.7%) > exchangeable (1.0-28.2%) > organic-associated form (0-5.1%). Pb mainly existes in the residual fraction (25.9-74.5%), followed by crystalline iron oxyhydroxides-associated (0.4-69.0%) and reducible fractions (2.4-40.4%). Zn mainly exists in the residual fraction (25.4-85.9%), followed by the well-crystallized iron oxyhydroxides-associated fraction (6.4-55.0%). However, Cu mainly existes in the residual form and the fractionation of Cu varies obviously between samples. The association of these metals with crystalline iron oxyhydroxides in the soils decreases in the sequence of Cd > Pb > Zn > Cu. These results suggest that in heavy-metal-polluted weathered soils in tropical and subtropical areas enriched with iron oxides, it is essential to assess potential bioavailability and toxicity of heavy metals bound to well-crystallized iron oxyhydroxides with appropriate procedures in the fractionation measurement. The modified Tessier method present here can be used to quantify the fractions of heavy metals in such areas.
We synthesized the red emission material, bis(1,4-bis(5-phenyloxazol-2-yl)phenyl) iridium(picolate) [Ir-complexes] and the blue emission material, bis (2-(2-hydroxyphenyl) benzoxazolate)zinc [Zn(HPB)2]. White Organic Light Emitting Diodes were fabricated by using Zn(HPB)2 for a blue emitting layer, Ir-complexes for a red emitting layer and a tris (8-hydroxy quinoline)aluminum [Alq3] for a green emitting layer. The important experimental results obtained, white OLED was fabricated by using double emitting layers of Zn(HPB)2 and Alq3:Ir-complexes, and hole blocking layer of 2,9-dimethyl-4,7-diphenyl-1,10-phenanthroline[BCP]. We also varied the thickness of BCP. When the thickness of BCP layer was 5 nm, white emission was achieved. We obtained a maximum luminance of 5400 cd/m2 at a current density of 650 mA/cm2. The CIE coordinates was (0.339, 0.323) at voltage of 10 V.
X-ray photoelectron spectroscopy spectra showed that the synthesized elements of the CdSe/CdS/ ZnS QDs were Cd, Se, Zn, and S. Organic bistable devices (OBDs) containing CdSe/CdS/ZnS quantum dots (QDs) and a poly(methylmethacrylate) (PMMA) layer were fabricated on indium-tin-oxide (ITO)-deposited glass substrates. Current-voltage (I-V) curves showed that the memory margin of the Al/(CdSe/CdS/ZnS QDs) embedded in PMMA layer/ITO device at 300 K was larger than that of the device without a ZnS shell layer. The retention time of the OBDs was above 1 x 10(4) s, indicative of the stability of the device. The memory mechanisms were described by using charge trapping and tunneling processes on the basis of the energy diagram and the I-V curves.
We report the effect of zinc nitrate (ZN) concentration on the growth of zinc oxide (ZnO) nanorods and their optical and morphological properties. As prepared ZnO nanorods on glass substrate were characterized using field emission scanning electron microscopy (FE-SEM), ultra violet-visible (UV-Vis), Raman and Photo-luminescence (PL) spectroscopy. FE-SEM results show that the nanorods were obtained for the 0.033 and 0.053 M concentration of ZN. As the ZN concentration increased from 0.033 M to 0.053 M, the diameter of the nanorods was increased. It indicated that the diameter of the nanorods was affected by the ZN concentration. The Raman spectra of nanorods show only one peak at 438 cm(-1) corresponding to E2(high) high mode, which means that ZnO nanorods grown perpendicularly on the glass substrate, i.e., the ZnO nanorod arrays are highly c-axis oriented. Room-temperature PL spectrum of the as-grown ZnO nanorods reveals a near-band-edge (NBE) emission peak and defect induced green light emission. The green light emission band at -579 nm might be attributed to surface oxygen vacancies or defects. The UV-visible measurements reflect that the total transmittance for the as grown ZnO nanorods is over 80%. The simple technique presented in this study to grow ZnO nanorods on a glass substrate can be helpful for making the cost effective photovoltaic devices.
Spinel Mn(x)Zn(1-x)Fe2O4 (0.0 ≤ x ≤ 1.0) nanoparticles (NPs) were successfully synthesized by a facile one-pot microwave combustion method using urea as the fuel. The formation of single phase cubic spinel structure was confirmed by powder X-ray diffraction (XRD), Rietveld analysis and Fourier transform infrared (FT-IR) spectroscopy and the calculated average crystallite size is in the range of 37.57 nm to 25.43 nm. The high resolution scanning electron microscopy (HR-SEM) and high resolution transmission electron microscopy (HR-TEM) results indicated that the as-prepared spinel Mn(x)Zn(1-x)Fe2O4 NPs showed high crystallinity and uniform size distribution with particles-like morphologies. The energy dispersive X-ray (EDX) analysis was confirmed the elemental composition and purity of the samples. The estimated band gap energy from UV-Visible diffuse reflectance spectroscopy (UV-Vis. DRS) is about 1.88 eV to 2.35 eV. The broad visible emission band is observed in the entire photoluminescence (PL) spectroscopy for all compositions. The variation of magnetization (M(s)) value of the samples was studied by vibrating sample magnetometer (VSM) and the lower compositions (x = 0.0, 0.2 and 0.4) show a superparamagnetism and the higher composition (x = 0.6, 0.8 and 1.0) show a ferromagnetic behavior with hysteresis and that the M(s) values increased with increasing Mn2+ content to reach a maximum value of 60.99 emu/g for MnFe2O4. All composition of spinel Mn(x)Zn(1-x)Fe2O4 NPs were successfully tested as catalyst for the oxidation of benzyl alcohol into benzaldehyde, which has resulted 83.29 and 96.51% conversion efficiency of ZnFe2O4 and Mn0.6Zn0.4Fe2O4 respectively.
In this work, a facile co-electrodeposition method was used to fabricate CuZnSn alloy films where the content of copper, zinc and tin could be precisely controlled through manipulating the mass transfer process in the electrochemical deposition. By finely tuning the concentration of the cations of Cu2+, Zn2+ and Sn2+ in the electrochemical bath solution, uniform CuZnSn film with desired composition of copper poor and zinc rich was made. Sulphurisation of the CuZnSn alloy film led to the formation of compact and large grains Cu2ZnSnS4 thin film absorber with an optimum composition of Cu/(Zn+Sn) ≈ 0.8, Zn/Sn ≈ 1.2. Both SEM morphology and EDS mapping results confirmed the uniformity of the CuZnSn and Cu2ZnSnS4 films and the homogeneous distribution of Cu, Zn, Sn and S elements in the bulk films. The XRD and Raman measurements indicated that the synthesized Cu2ZnSnS4 film was kesterite phase without impurities detected. Photoelectrochemical tests were carried out to evaluate the CZTS film's photocurrent response under illumination of green light.
The high performance and increased tumor-targeting accumulation of magnetic nanocrystals (MNCs) are the most important considerations in cancer targeted magnetic hyperthermia (TMH). To achieve these goals, our study was firstly done using well-established fluorescence/magnetic Mn-Zn ferrite MNCs (core size: 14 nm) as multi-modal imaging contrast agents and highly-efficient "heat generators", which were coated with a biocompatible PEG-phospholipid (DSPE-PEG2000) and further modified by a cyclic tripeptide of arginine-glycine-aspartic acid (RGD). By using a mouse model bearing breast carcinoma (4T1), we then systematically compared PEGylated MNCs (MNCs@PEG)- and RGD-PEGylated MNCs (MNCs@RGD)-mediated tumor targeting abilities by intravenous administration. The MNCs@PEG-based passive targeting could successfully accumulate at the tumor due to the enhanced permeability and retention (EPR) effects, but the non-targeted localization might make the MNCs@PEG "leaking" from larger pores of tumor fenestrated vascular networks. Our designed MNCs@RGD, simultaneously functionalized with PEG and RGD ligands, might promote a synergistic effect including efficient tumor vasculature active targeting and EPR-mediated passive targeting, improving total MNC concentration and retention time in tumor tissues. By combining fluorescence/magnetic resonance (MR)/thermal multi-modal imaging-guided diagnostics and continuous TMH treatment under an alternating current magnetic field (ACMF, 2.58 kA m(-1), 390 kHz), the tumor surface could be heated to approximately 43-44 °C based on the MNC-mediated repeated injections. Sufficient temperature elevation induced the apoptosis of tumor cells, and inhibited the tumor angiogenesis. Compared with MNCs@PEG, the active MNCs@RGD-based tumor targeting MR image was significantly more efficient due to both the higher and long-lasting tumor accumulation, but its antitumor efficacy was not obviously improved in the TMH treatments. To achieve a singularly promising tumor TMH therapy, a greatly increased MNC content in tumor was needed. This insight indicated that not only the tumor vasculature targeting, but also the active tumor cells targeting of MNCs should receive considerable attention in future clinical TMH therapy application.
Heavy metals at elevated concentrations are a major threat to agricultural and human health. Typically, human activities tend to release these metals to the environment in aqueous solutions, generating high levels of pollution due to the mobility of the heavy
 metals. The aim of the present work was to assess heavy metal tolerance in yeasts isolated from Río Agrio - Lake Caviahue volcanic acidic aquatic environment and to evaluate the capacity of selected strains to capture metals in acidic culture media conditions. The ability of three yeast species, Cryptococcus agrionensis, Cryptococcus sp. 2, and Coniochaeta fodinicola, to tolerate and capture metals in live cultures has been evaluated. These three yeast species showed high tolerance to low pH and elevated concentrations of metals, thus implying their autochthonous status. Minimal inhibitory concentration (MIC) for growth obtained for these isolates showed elevated tolerance to the six heavy metals evaluated and were significantly higher than those registered for other microorganisms. C. agrionensis was able to capture 15.80 mg (g biomass)(-1) of Cu(2+) (MIC: 0.22 g L(-1) ), Cryptococcus sp. 2 was able to capture 36.25 and 65.28 mg (g biomass)(-1) of Ni(2+) and Zn(2+) , respectively (MIC: 0.56 and 1.68, respectively), and C. fodinicola was able to capture 67.11 mg (g biomass)(-1) of Zn(2+) (MIC: 3.75). This work reported the ability of yeasts to capture metals in acidic conditions for the first time. We hope that it represents the step-stone for future researches in the ability and metabolism of yeasts form acidic aquatic environment related to metal tolerance and capture.
Different transition metals have been shown to induce inflammatory responses in lung. We have compared eight different metal ions with regard to cytokine responses, cytotoxicity and signalling mechanisms in a human lung epithelial cell model (BEAS-2B). Among the metal ions tested, there were large differences with respect to pro-inflammatory potential. Exposure to Cd(2+), Zn(2+) and As(3+) induced CXCL8 and IL-6 release at concentrations below 100μM, and Mn(2+) and Ni(2+) at concentrations above 200μM. In contrast, VO4(3-), Cu(2+) and Fe(2+) did not induce any significant increase of these cytokines. An expression array of 20 inflammatory relevant genes also showed a marked up-regulation of CXCL10, IL-10, IL-13 and CSF2 by one or more of the metal ions. The most potent metals, Cd(2+), Zn(2+) and As(3+) induced highest levels of oxidative activity, and ROS appeared to be central in their CXCL8 and IL-6 responses. Activation of the MAPK p38 seemed to be a critical mediator. However, the NF-κB pathway appeared predominately to be involved only in Zn(2+)- and As(3+)-induced CXCL8 and IL-6 responses. Thus, the most potent metals Cd(2+), Zn(2+) and As(3+) seemed to induce a similar pattern for the cytokine responses, and with some exceptions, via similar signalling mechanisms.
Amylin is an endocrine hormone and is a member of the family of amyloid peptides and proteins that emerge as potential scaffolds by self-assembly processes. Zn(2+) ions can bind to amylin peptides to form self-assembled Zn(2+)-amylin oligomers. In the current work the binding sites of Zn(2+) ions in the self-assembled amylin oligomers at various concentrations of zinc have been investigated. Our results yield two conclusions. First, in the absence of Zn(2+) ions polymorphic states (i.e. various classes of amylin oligomers) are obtained, but when Zn(2+) ions bind to amylin peptides to form Zn(2+)-amylin oligomers, the polymorphism is decreased, i.e. Zn(2+) ions bind only to specific classes of amylin. At low concentrations of Zn(2+) ions the polymorphism is smaller than at high concentrations. Second, the structural features of the self-assembled amylin oligomers are not affected by the presence of Zn(2+) ions. This study proposes new molecular mechanisms of the self-assembly of Zn(2+)-amylin oligomers.
The purpose of the present study was the assessment of the serum concentration of antioxidant microelements-zinc, copper, selenium, manganese, and Cu/Zn ratio in children and adolescents with myopia. Eighty-three children were examined (mean age 14.36 ± 2.49 years) with myopia. The control group was 38 persons (mean age 12.89 ± 3.84 years). Each patient had complete eye examination. The serum concentration of zinc, copper, manganese, and selenium was determined by atomic absorption spectrometry. Cu/Zn ratio, which is the indicator of the oxidative stress, was also calculated. The average serum concentration of zinc in myopic patients was significantly lower (0.865 ± 0.221 mg L(-1)) in comparison to the control group (1.054 ± 0.174 mg L(-1)). There was significantly higher Cu/Zn ratio in myopic patients (1.196 ± 0.452) in comparison to that in the control group (0.992 ± 0.203). The average serum concentration of selenium in the study group was significantly lower (40.23 ± 12.07 μg L(-1)) compared with that in the control group (46.00 ± 12.25 μg L(-1)). There were no essential differences between serum concentration of copper and manganese in the study group and the control group. Low serum concentration of zinc and selenium in myopic children may imply an association between insufficiency of these antioxidant microelements and the development of the myopia and could be the indication for zinc and selenium supplementation in the prevention of myopia. Significantly, higher Cu/Zn ratio in the study group can suggest the relationship between myopia and oxidative stress.
Sulfonamide antibiotics (SAs) have been observed to undergo direct and indirect photodegradation in natural water environments. In this study, the density functional theory (DFT) method was employed for the study of direct and indirect photodegradation mechanisms of sulfameter (SME) with excited triplet states of dissolved organic matter ((3)DOM(*)) and metal ions. SME was adopted as a representative of SAs, and SO2 extrusion product was obtained with different energy paths in the triplet-sensitized photodegradation of the neutral (SME(0)) and the anionic (SME(-)) form of SME. The selected divalent metal ions (Ca(2+), Mg(2+), and Zn(2+)) promoted the triplet-sensitized photodegradation of SME(0) but showed an inhibitory effect in triplet-sensitized photodegradation of SME(-). The triplet-sensitized indirect photodegradation mechanism of SME was investigated with the three DOM analogues, i.e., 2-acetonaphthone (2-AN), fluorenone (FN), and thioxanthone (TN). Results indicated that the selected DOM analogues are highly responsible for the photodegradation via attacking on amine moiety of SME. According to the natural bond orbital (NBO) analysis, the triplet-sensitized photodegradation mechanism of SME(0) with 2-AN, FN, and TN was H-transfer, and the SME(-) was proton plus electron transfer with these DOM analogues.
Although the ecotoxicological effects of various metal oxide nanoparticles on aquatic organisms are being actively studied, the contributions of particles and dissolved ions towards toxicity are still not well understood. The current study aims to assess the contribution of ZnO NP(particle) and ZnO NP(ion) to the overall toxicity and accumulation of ZnO NP(total) in Ceriodaphnia dubia. The aggregation and dissolution kinetics were studied for three different sizes (50nm, 100nm and bulk) of ZnO particles at 0.05, 0.12, 0.25 and 0.5mg/L concentrations in the sterile lake water medium at 6, 12, 24, and 48h intervals. The 48h LC50 of ZnO NP(total) was found to be 0.431, 0.605 and 0.701mg/L for 50, 100nm and bulk particles exposure. However, LC50 of Zn(ion) was found to be 1.048, 1.343 and 2.046mg/L for dissolved ions from different sizes (50nm, 100nm, and bulk) of ZnO particles. At LC50 concentration, the accumulation of 90-95% was noted for the NP(particles) across the sizes employed, while only about 4-5% contribution was from the NP(ion) to the overall accumulation NP(total). The relative contribution of ZnO NP(ion) to overall toxicity and accumulation was found to be lesser than that of ZnO NP(particles) across the sizes used in the study.
The combination of conventional anticancer therapy with other treatment modalities such as photodynamic therapy (PDT) is paving the way to novel more effective treatment of solid tumors via light exposure. With this idea in mind, in this paper, nanoparticles (NPs) based on Heptakis (2-oligo(ethyleneoxide)-6-hexadecylthio-)-β-CD (SC16OH) for dual delivery of Zinc-Phthalocyanine (ZnPc) and Docetaxel (DTX) were developed pointing to their potential application as nanomedicine for the combined photodynamic and chemo-therapy of solid tumors. NPs prepared by the emulsion-solvent evaporation technique displayed a hydrodynamic diameter of ≅ 200nm, a negative zeta potential (≅ -27mV) and a satisfactory entrapment efficiency of both drugs at a specific mass ratio. On these bases, NPs containing DTX and ZnPc with theoretical loading of 5% and 0.2% respectively (ZnPc/DTX5-NPs) were selected for further investigations. The allocation of ZnPc and DTX into the colloid was investigated by complementary spectroscopic techniques. In particular, fluorescence emission studies showed the entrapment of ZnPc as a monomer in the carrier, with a low tendency to self-aggregate and consequently a fairly high propensity to photogenerate singlet oxygen. The interaction of SC16OH with DTX, co-entrapped with ZnPc, was elucidated by (1)H NMR and 2D ROESY, which suggested the presence of the chemotherapeutic in the hydrophobic portion of SC16OH. ZnPc/DTX5-NPs were fairly stable in different biological relevant media within 24h. Finally, in vitro potential of the nanoassembly was evaluated in HeLa cancer cells by cell viability exploring both effects of DTX and ZnPc. Overall, results suggest the suitability of NPs based on SC16OH for delivering a combination of DTX with ZnPc to cancer cells, thus inducing photodynamic and antimitotic effects.
Commercially important bivalve Noah's Ark shell (Arca noae Linnaeus, 1758) represents a high-quality seafood product, but the data on levels of metal contaminants that could
 pose a human health risk and also on some essential elements that are important for health protection are lacking. This study examined the concentrations of Cd, Pb, Cr, Ni, Cu, Co, and Zn in the soft tissue of A. noae from harvesting area in the central Adriatic Sea, to survey whether heavy metals are within the acceptable limits for public health and whether tourism could have an impact on them. The concentrations of analysed metals varied for Cd: 0.15-0.74, Pb: 0.06-0.26, Cr: 0.11-0.34, Ni: 0.09-0.22, Cu: 0.65-1.95, Co: 0.04-0.09, and Zn: 18.3-74.7 mg/kg wet weight. These levels were lower than the permissible limits for safe consummation of seafood, and only for Cd, some precautions should be taken into account if older shellfish were consumed. Increase of Cd, Cr, and Cu in shell tissue was observed during the tourist season at the site closest to the marine traffic routes, indicating that metal levels in shellfish tissue should be monitored especially carefully during the peak tourist season to prevent eventual toxic effects due to increased intake of metals, specifically of Cd.
Sirtuins are a family of protein deacylases related by amino acid sequence and cellular function to the yeast Saccharomyces cerevisiae protein Sir2 (Silent Information Regulator-2), the first of this class of enzymes to be identified and studied in detail. Based on its initially discovered activity, Sir2 was classified as a histone deacetylase that removes acetyl groups from histones H3 and H4. The acetylation/deacetylation of these particular substrates leads to changes in transcriptional silencing at specific loci in the yeast genome, hence its name. Sirtuins, however, have been shown to regulate a wide variety of cellular processes beyond transcriptional repression in varied subcellular compartments and in different cell types. Mechanistically distinct from Zn(2+)-dependent deacylases, sirtuins use nicotinamide adenine dinucleotide as a cofactor in the removal of acetyl and other acyl groups linking metabolic status and posttranslational modification. Sirtuins' unique position has made them attractive targets for small-molecule drug development. In this chapter, we describe the biological roles, therapeutic areas in which sirtuins may play a role and development of small-molecule inhibitors of sirtuins employing phenotypic screening technologies ranging from assays in yeast, as well as biochemical screens to yield lead drug development candidates targeting a broad spectrum of human diseases.
The fluorescent 2-[(E)-(2-phenylhydrazinylidene)methyl]phenol nanoparticles (PHPNPs) were prepared by a simple reprecipitation method. The prepared PHPNPs examined by Dynamic Light Scattering show narrower particle size distribution having an average particle size of 93.3nm. The Scanning Electron Microphotograph shows distinct spherical shaped morphology of nanoparticles. The blue shift in UV-absorption and fluorescence spectra of PHPNPs with respect to corresponding spectra of PHP in acetone solution indicates H- aggregates and Aggregation Induced Enhanced Emission (AIEE) for nanoparticles. The nanoparticles show selective tendency towards the recognition of Sn(2+) ions by enhancing the fluorescence intensity preference to Cu(2+), Fe(3+), Fe(2+), Ni(2+), NH4(+), Ca(2+), Pb(2+), Hg(2+) and Zn(2+) ions, which actually seem to quench the fluorescence of nanoparticles. The studies on Langmuir adsorption plot, fluorescence lifetime of PHPNPs, DLS-Zeta sizer, UV-visible and fluorescence titration with and without Sn(2+) helped to propose a suitable mechanism of fluorescence enhancement of nanoparticles by Sn(2+) and their binding ability during complexation. The fluorescence enhancement effect of PHPNPs induced by Sn(2+) is further used to develop an analytical method for detection of Sn(2+) from aqueous medium in environmental samples.
This study aimed to assess the impact of trace element concentrations in fish assemblages of a recovering coastal lagoon. Fish, water and sediment were sampled in winter and summer in the Ria de Aveiro (Portugal). Multivariate analyses were used to examine the relationship between fish assemblages and environmental variables (physical-chemical parameters, contaminants and sediment grain size). In winter, fish density and biomass were mainly affected by the water turbidity, while Li concentration in the water column was found to be significant for fish biomass. During summer, a significant relationship was found between fish density and temperature, Hg, Li and Zn concentration in the sediment. These contaminants were mainly associated with the historically contaminated area, were Liza spp. and Dicentrarchus labrax appeared as dominant species. Environmental variables were not significant for fish biomass. The historical contamination in the Ria de Aveiro still seems to exert some influence on fish community structure.
The Gulf of Urabá (northwestern Colombia) is a geostrategic region, rich in biodiversity and natural resources. Its economy is mainly based on agribusinesses and mining activities. In this research is determined the impact of these activities in bottom surface sediments of the estuary. Thus, grain size, total organic carbon, total nitrogen, carbonates, Ag, Al, Ca, Cr, Cu, Fe, Hg, Mg, Mn, Ni, Pb and Zn concentrations from 17 surface sediment samples were obtained and enrichment factors (EF) as well as geo-accumulation indices (Igeo) were calculated to determine the contamination level in the gulf. EF and Igeo values revealed that the estuary is extremely contaminated with Ag and moderately contaminated with Zn. Therefore, the observed enrichment of Ag may be explained as a residue of the extraction of gold and platinum-group metals and the enrichment with Zn associated mainly to pesticides used in banana plantations.
The objective of this research study was to elucidate the removal and remobilization behaviors of five heavy metals (i.e., Cd, Cu, Ni, Pb, and Zn) that had been fixed onto sorptive filter materials used in decentralized stormwater treatment systems receiving traffic area runoff. Six filter materials (i.e., granular activated carbon, a mixture of granular activated alumina and porous concrete, granular activated lignite, half-burnt dolomite, and two granular ferric hydroxides) were evaluated in column experiments. First, a simultaneous preloading with the heavy metals was performed for each filter material. Subsequently, the remobilization effect was tested by three de-icing salt experiments in duplicate using pure NaCl, a mixture of NaCl and CaCl2, and a mixture of NaCl and MgCl2. Three layers of each column were separated to specify the attenuation of heavy metals as a function of depth. Cu and Pb were retained best by most of the selected filter materials, and Cu was often released the least of all metals by the three de-icing salts. The mixture of NaCl and CaCl2 resulted in a stronger effect upon remobilization than the other two de-icing salts. For the material with the highest retention, the effect of the preloading level upon remobilization was measured. The removal mechanisms of all filter materials were determined by advanced laboratory methods. For example, the different intrusions of heavy metals into the particles were determined. Findings of this study can result in improved filter materials used in decentralized stormwater treatment systems.
By studying the internal compartmentalization of metals in different subcellular fractions we are able to better understand the mechanisms of metal accumulation in organisms and the transfer of metals through trophic chains. We investigated the internal compartmentalization of cadmium (Cd) and zinc (Zn) in mealworm beetle (Tenebrio molitor) larvae by breeding them in flour contaminated with either Cd at 100, 300 and 600mgkg(-1), or Zn at 1000 and 2000mgkg(-1). We separated the cellular components of the larvae into 3 fractions: the S1 or cytosolic fraction containing organelles, heat-sensitive and heat-stable proteins, the S2 or cellular debris fraction and the G or metal-rich granule fraction. The concentration of Cd and Zn in each fraction was measured at 0, 7, 14 and 21 days of being fed the flour. The concentration of Cd in the flour affected the concentration of Cd measured in each larval subcellular fraction (p≤0.0001), while the concentration of Zn in the flour only affected the Zn concentration in the S2 and G fractions (p≤0.02). Both Cd and Zn concentrations in mealworms remained relatively constant during the exposure (days 7, 14 and 21) in all three fractions, but the Cd concentrations were much higher than those found in larvae before the exposure (day 0). The concentration of Cd in the flour, however, did not affect the percentage of Cd in the S1 fraction. The contribution of Cd in the G fraction to the total Cd amount was similar (30-40%) in all Cd treatments. The percentage of Zn in all three fractions was not affected by the concentration of Zn in the flour and the relative contributions of each subcellular fraction to the total burden of Zn remained generally constant for both control and treated larvae. In general, larvae sequestered approximately 30% of Cd and Zn in the S1 fraction, which is important for the transport of metals to higher trophic levels in a food web.
Urban green works as a recorder of atmospheric PM. This paper reports on the utility of combining magnetic- and particle-based techniques to investigate PM leaf deposition as a bio-indicator of metal pollution. Ivy (Hedera helix) leaves were collected from five different land use classes, i.e. forest, rural, roadside, industrial, train. Leaf magnetic measurements were done in terms of saturation isothermal remanent magnetization (leaf SIRM), while ca. 40,000 leaf-deposited particles were analyzed through SEM/EDX to estimate the elemental composition. The influence
 of the different land use classes was registered both magnetically and in terms of metal content. Leaf area-normalized SIRM values ranged from 19.9 to 444.0μA, in the following order forest<rural<roadside<industrial<train. Leaf SIRM showed to be significantly correlated (p<0.01) with the content in Fe, Zn, and Pb, followed by Mn and Cd (p<0.05), while no significant correlation was found with the metals Cr and Cu. Although presenting a similar metal content, roadside and train were magnetically very distinct. By exhibiting a very high content in Pb, and with an Fe content being comparable to the one observed at the forest and rural land uses, the industrial leaf-deposited particles showed to be mainly due to industrial activity. While SEM/EDX is a suitable approach for detailed particle analysis, leaf SIRM of ivy can be used as a rapid discriminatory tool for metal pollution. Their complementary use delivers further knowledge on land use classes reflecting different PM conditions and/or sources.
Synthesis of new metallic complex of cobalt and zinc with amino acid-nucleobase hybrid ligand have been achieved by simple chemical reaction of metal salt with amino acid L-histidine and nucleobase adenine as ligands. Various physicochemical techniques such as elemental analysis, conductometric measurements, FT-IR, UV-visible, (1)H & (13)C NMR, mass spectroscopy and magnetic measurements were employed to characterize the complexes. The results confirmed the formation of the ligand and the complex. The interaction of the complex with calf thymus DNA (CT-DNA) has been carried out using UV-visible titration, fluorescence spectroscopy, cyclic voltammetry and viscosity measurements. The intrinsic binding constant (Kb) and Stern-Volmer constant (Ksv) of the complexes have been calculated. The cleavage activity of the ligand and the complexes with pBR322 DNA was further confirmed by gel electrophoretic technique. The pharmacological activity of the ligand and the complexes was investigated by antioxidant, antimicrobial and cytotoxic activity, and they show promising pharmacological effect. The results of the molecular docking studies of the ligand and the complexes reinforce all the above facts.
Zinc is an essential nutrient for humans; however, a sensitive biomarker to assess zinc status has not been identified. The objective of this systematic review was to compile and assess studies that determined zinc transporter and/or metallothionein expression in various blood cell types and to determine their reliability and sensitivity to changes in dietary zinc. Sixteen studies were identified that determined the expression of zrt-, irt-like protein (ZIP) 1 [solute carrier family (SLC) 39A1], ZIP3 (SLC39A3), ZIP5 (SLC39A5), ZIP6 (SLC39A6), ZIP7 (SLC39A7), ZIP8 (SLC39A8), ZIP10 (SLC39A10), ZIP14 (SLC39A14), zinc transporter (ZnT)1 (SLC30A1), ZnT2 (SLC30A2), ZnT4 (SLC30A4), ZnT5 (SLC30A5), ZnT6 (SLC30A6), ZnT7 (SLC30A7), ZnT9 (SLC30A9), and/or metallothionein in various blood cells isolated from healthy adult men and women in response to zinc supplementation or depletion. Cell types included leukocytes, peripheral blood mononuclear cells, T lymphocytes, monocytes, and erythrocytes. ZIP1, ZnT1, and metallothionein were the most commonly measured proteins. Changes in ZIP1 and ZnT1 in response to zinc supplementation or depletion were not consistent across studies. Leukocyte metallothionein decreased with zinc depletion (-39% change from baseline, <5 mg Zn/d, n = 2 studies) and increased with zinc supplementation in a dose-dependent manner (35%, 15-22 mg Zn/d, n = 7 studies; 267%, 50 mg Zn/d, n = 2 studies) and at the earliest time points measured; however, no change or delayed response was observed in metallothionein in erythrocytes. A greater percentage of studies demonstrated that metallothionein in leukocyte subtypes was a more reliable (100%, n = 12; 69%, n = 16) and responsive (92%, n = 12; 82%, n = 11) indicator of zinc exposure than was plasma zinc, respectively. In conclusion, current evidence indicates that metallothionein in leukocyte subtypes may be a component in determining zinc status.
A multidisciplinary survey was carried out on the quality of water and sediments of a coastal protected marine area, embedded between the inputs from Bagnoli steel plant to the south and a sewage plant, Volturno River and Regi Lagni channel to the north. The study integrated chemical-sedimentological data with biological and ecotoxicological analyses to assess anthropogenic pressures and natural variability. Data reveal marked differences in anthropogenic pollution between southeastern and northwestern zone, with the north affected by both inorganic and organic flows and the south influenced by levels of As, Pb and Zn in the sediments above law limits, deriving from inputs of the Bagnoli brownfield site. Meiobenthic data revealed at south higher relative abundance of sensitive species to pollution and environmental stress to the south, i.e. Lobatula lobatula and Rosalina bradyi, whereas to the north relative abundance of stress tolerant Quinqueloculina lata, Quinqueloculina pygmaea and Cribroelphidium cuvilleri were determined.
In the present study, zinc oxide nanoparticles (ZnO NPs) were rapidly synthesized at room temperature by treating zinc acetate dihydrate with the flower extract of Elaeagnus angustifolia (Russian olive). The formation of ZnO NPs was primarily confirmed by UV-visible absorption spectrum in the range of 250-700nm. XRD analysis and DLS particle size analyzer revealed the size of ZnO NPs. The FTIR spectrum revealed the presence of phytochemicals in the flower extract mediated ZnO NPs. Moreover, the morphology of the ZnO NPs was determined using SEM. Seeds of Solanum lycopersicum (tomato) were separately treated with different concentrations of synthesized ZnO NPs and zinc sulphate (ZnSO4) salt suspensions (common zinc supplement). The effect of these treatments on seed germination, seedling vigor, chlorophyll, protein and sugar contents as well as on the activities of lipid peroxidation and antioxidant enzyme were studied. Leaves of plants treated with 6.1mM concentration of ZnO NPs recorded maximum reflectance while it was minimum in plants treated with 1.2mM concentration of NPs. The effect of synthesized ZnO NPs on seedling vigor, pigment, protein and sugar content was found affirmative at lower concentrations contrary to control and ZnSO4 salt. The inhibitory effect at higher concentration of NPs indicated importance in the precise application of NPs, in Zn deficient system, where plant response varies with concentration. To the best of our knowledge this is the first report on Elaeagnus angustifolia mediated synthesis of ZnO NPs and their effects on germination and physiological activity of tomato.
A study on heavy metal pollution was undertaken in the re-suspended road dusts from different functional areas in Xi'an City of China to investigate the impacts of human activities and land uses on urban environment. The concentrations of Co, Cr, Cu, Mn, Ni, Pb, V, and Zn were determined using X-ray fluorescence spectrometry, and their accumulations were analyzed using enrichment factor. Correlation analysis, principal component analysis, and cluster analysis, combined with the concentration property and enrichment factor, were used to identify the possible sources of heavy metals investigated. The investigated re-suspended road dusts had Co, Cr, Cu, Pb, and Zn concentrations higher than background levels. Samples from different functional areas had diverse heavy metal concentration levels. Co, Cr, Cu, Pb, and Zn presented moderate/significant enrichment in the samples. The source analyses indicated that Mn, Ni, V, Pb, and Zn had the mixed sources of nature and traffic, Cr and Cu mainly originated from traffic source, while Co was primarily derived from construction source. Traffic and construction activities had a significant impact on urban environment. This preliminary research provides a valuable basis for urban environment protection and management.
With use of simple terpyridine zinc nitrate complexes, intriguing visual recognition of adenosine triphosphate (ATP) via selective coordination assembly leading to two-component metallo-hydrogel formation has been realized. With intensive fluorescent study and density functional theory calculations, it may be inferred, besides the selective metal-ligand interaction between Zn center and phosphate groups, the intramolecular π-stacking between the planar nucleobases of ATP and the metal-hybrid aromatic ring of pincer complex strongly affected the geometry of the coordinated adducts and possible molecular self-assembly process, which constitute a completely new sensing strategy in comparison with the conventional approaches. Furthermore, in light of extreme sensitivity of pincer zinc complexes toward ATP at micromolar scale (1.85 μM) and remarkable fluorescent enhancement (ca. 44-fold) upon ATP addition, the feasibility of the low cytotoxicity pincer zinc complexes in monitoring ATP in HeLa cells has been fulfilled with confocal fluorescence microscopy.
Here, we demonstrate that a metal ion binding motif could serve as an efficient and robust tool for site-specific conjugation strategy. Cysteine-containing metal binding motifs were constructed as single repeat or tandem repeat peptides and their metal binding characteristics were investigated. The tandem repeats of the Cysteine-Glycine-Histidine (CGH) metal ion binding motif exhibited concerted binding to Co(II) ions, suggesting that conformational transition of peptide was triggered by the sequential metal ion binding. Evaluation of the free thiol content after reduction by reducing reagent showed that metal-ion binding elicited strong retardation of cysteine oxidation in the order of Zn(II)>Ni(II)>Co(II). The CGH metal ion
 binding motif was then introduced to the C-terminus of antibody heavy chain and the metal ion-dependent characteristics of oxidation kinetics were investigated. As in the case of peptides, CGH-motif-introduced antibody exhibited strong dependence on metal ion binding to protect against oxidation. Zn(II)-saturated antibody with tandem repeat of CGH motif retains the cysteine reactivity as long as 22 hour even with saturating O2 condition. Metal-ion dependent fluorophore labeling clearly indicated that metal binding motifs could be employed as an efficient tool for site-specific conjugation. Whereas Trastuzumab without a metal ion binding site exhibited site-nonspecific dye conjugation, Zn(II) ion binding to antibody with a tandem repeat of CGH motif showed that fluorophores were site-specifically conjugated to the heavy chain of antibody. We believe that this strong metal ion dependence on oxidation protection and the resulting site-selective conjugation could be exploited further to develop a highly site-specific conjugation strategy for proteins that contain multiple intrinsic cysteine residues, including monoclonal antibodies.
An investigation of the redox-active tris[4-(pyridin-4-yl)phenyl]amine (NPy3) ligand in the solution state and upon its incorporation into the solid-state metal-organic framework (MOF) [Zn(NPy3)(NO2)2·xMeOH·xDMF]n (MeOH = methanol and DMF = N,N-dimethylformamide) was conducted using in situ UV/vis/near-IR, electron paramagentic resonance (EPR), and fluorescence spectroelectrochemical experiments. Through this multifaceted approach, the properties of the ligand and framework were elucidated and quantified as a function of the redox state of the triarylamine core, which can undergo a one-electron oxidation to its radical cation. The use of pulsed EPR experiments revealed that the radical generated was highly delocalized throughout the entire ligand backbone. This combination of techniques provides comprehensive insight into electronic delocalization in a framework system and demonstrates the utility of in situ spectroelectrochemical methods in assessing electroactive MOFs.
The tuning of the electronic properties of heavy fermion compounds by chemical substitution provides excellent opportunities for further understanding the physics of hybridized ions in crystal lattices. Here we present an investigation on the effects of Cd doping in flux-grown single crystals of the complex intermetallic cage compound YbFe2Zn20, which has been described as a heavy fermion with a Sommerfeld coefficient of 535 mJ mol(-1) · K(-2). The substitution of Cd for Zn disturbs the system by expanding the unit cell and, in this case, the size of the Zn cages that surround the Yb and Fe. With an increasing amount of Cd, the hybridization between the Yb 4f electrons and the conduction electrons is weakened, as shown by a decrease in the Sommerfeld coefficient, which should be accompanied by a valence shift of the Yb(3+) due to the negative chemical pressure effect. This scenario is also supported by the low temperature DC magnetic susceptibility, which is gradually suppressed and shows an increment of the Kondo temperature, based on a shift to higher temperatures of the characteristic broad susceptibility peak. Furthermore, the DC resistivity decreases with the isoelectronic substitution of Cd for Zn, contrary to expectations in an increasingly disordered system, and implying that the valence shift is not related to charge carrier doping. The combined results demonstrate the excellent complementarity between positive physical pressure and negative chemical pressure, and point to a rich playground for exploring the physics and chemistry of strongly correlated electron systems in the general family of Zn20 compounds, despite their structural complexity.
The present study aimed to evaluate the effect of soil-applied Zn and Cu on absorption and accumulation of Cd applied through irrigation water in legume (chickpea and mungbean) and cereal (wheat and maize) crops. The results revealed that Cd in irrigation water at higher levels (2 and 5 mg L(-1)) significantly (P< 0.05) reduced the plant biomass while the soil application of Zn and Cu, singly or combined, favored the biomass production. Plant tissue Cd concentration increased linearly with the increasing application of Cd via irrigation water. While Cd application caused a redistribution of metals in grains, straw, and roots with the highest concentration of Cd, Zn and Cu occurred in roots followed by straw and grains. Zinc addition to soil alleviated Cd toxicity by decreasing Cd concentration in plant tissues due to a possible antagonistic effect. The addition of Cu to the soil had no consistent effects on Zn and Cd contents across all crops. Inhibitory effects of Cd on the uptake and accumulation of Zn and Cu have also been observed at higher Cd load. Thus, soil-applied Zn and Cu antagonized Cd helping the plant to cope with its toxicity and suppressed the toxic effects of Cd in plant tissues, thus favoring plant growth.
The aim of our work was the isolation and characterization of bacteria from the rhizosphere of Spartina maritima in the metal contaminated Odiel estuary (Huelva, SW Spain). From 25 strains, 84 % were identified as gram-positive, particularly Staphylococcus and Bacillus. Gram-negative bacteria were represented by Pantoea and Salmonella. Salt and heavy metal tolerance, metal bioabsorption, plant growth promoting (PGP) properties, and biofilm formation were investigated in the bacterial collection. Despite the higher abundance of gram-positive bacteria, gram-negative isolates displayed higher tolerance toward metal(loid)s (As, Cu, Zn, and Pb) and greater metal biosorption, as deduced from ICP-OES and SEM-EDX analyses. Besides, they exhibited better PGP properties, which were retained in the presence of metals and the ability to form biofilms. Gram-negative strains Pantoea agglomerans RSO6 and RSO7, together with gram-positive Bacillus aryabhattai RSO25, were selected for a bacterial consortium aimed to inoculate S. maritima plants in metal polluted estuaries for phytoremediation purposes.
Rapid development of steel wire rope industry has led to the generation of large quantities of pickling sludge, which causes significant ecological problems and considerable negative environmental effects. In this study, a novel method was proposed for harmless disposal and resource reutilization of the steel wire rope sludge. Based on the method, two steel wire rope sludges (the Pb sludge and the Zn sludge) were firstly extracted by hydrochloric or sulfuric acid and then mixed with the hydrochloride acid extracting solution of aluminum skimmings to produce composite polyaluminum ferric flocculants. The optimum conditions (acid concentration, w/v ratio, reaction time, and reaction temperature) for acid extraction of the sludges were studied. Results showed that 97.03 % of Pb sludge and 96.20 % of Zn sludge were extracted. Leaching potential of the residues after acid extraction was evaluated, and a proposed treatment for the residues had been instructed. The obtained flocculant products were used to purify the real domestic wastewater and showed an equivalent or better performance than the commercial ones. This method is environmental-friendly and cost-effective when compared with the conventional sludge treatments.
Data are scarce regarding combined high Se and Mn supplementation in livestock diets, however, as Se and Mn are functionally related as cofactors of glutathione peroxidase (GPx) and Mn-superoxide dismutase (SOD), respectively, beneficial synergistic effects on oxidative stability of tissues may result. This experiment evaluated the effect of an oversupply of Se and Mn within European legal limits compared with recommendations on performance, oxidative stability of the organism and meat quality in a randomised complete block design. A total of 60 crossbred gilts were fed maize-barley-soya bean meal diets formulated in a 2×2 factorial approach with inorganic Se (0.2 v. 0.5 mg/kg Se dry matter (DM)) or inorganic Mn (20 v. 150 mg/kg Mn DM) from 31 to 116 kg BW. Se supplementation reduced feed intake, whereas high Mn diets impaired average daily gain (P<0.05). Qualitative carcass characteristics were impaired by Se and Mn predominantly in the semimembranosus muscle. Activity of GPx in liver was increased by high Se diets (P<0.05). Mn supplementation increased catalase (CAT) activity in liver, GPx in plasma and total antioxidative capacity (TAC) in muscle, whereas it decreased CAT activity in plasma (P<0.05). Cu/Zn-SOD in muscle showed higher activity in high-Se-low-Mn diets but lower activity when both high Se and Mn were combined (Se×Mn P<0.05). Mn supplementation increased Mn concentration in longissimus thoracis et lumborum, but simultaneously reduced Se concentration (P<0.05). Upon retail display, Mn increased lipid oxidation more pronouncedly (higher thiobarbituric acid reactive substances; P<0.05) than Se (P<0.10). Despite some positive effects (Mn increased TAC, Se increased GPx, Se and Mn increased tenderness), no synergistic effects of high Se and Mn diets or an overall beneficial impact on meat quality, especially during storage, could be observed. Including the negative effects on performance, feeding Se and Mn up to the maximum legal level cannot be recommended.
The interaction of natural lipopeptide pseudofactin II with a series of doubly charged metal cations was examined by matrix-assisted laser-desorption ionization-time of flight (MALDI-TOF) mass spectrometry and molecular modelling. The molecular modelling for metal-pseudofactin II provides information on the metal-peptide binding sites. Overall, Mg(2+), Ca(2+) and Zn(2+) favor the association with oxygen atoms spanning the peptide backbone, whereas Cu(2+) is coordinated by three nitrogens. Circular
 dichroism (CD) results confirmed that Zn(2+) and Cu(2+) can disrupt the secondary structure of pseudofactin II at high concentrations, while Ca(2+) and Mg(2+) did not essentially affect the structure of the lipopeptide. Interestingly, our results showed that the addition of Zn(2+) and Cu(2+) helped smaller micelles to form larger micellar aggregates. Since pseudofactin II binds metals, we tested whether this phenomena was somehow related to its antimicrobial activity against Staphylococcus epidermidis and Proteus mirabilis. We found that the antimicrobial effect of pseudofactin II was increased by supplementation of culture media with all tested divalent metal ions. Finally, by using Gram-positive and Gram-negative bacteria we showed that the higher antimicrobial activity of metal complexes of pseudofactin II is attributed to the disruption of the cytoplasmic membrane.
Organic amendments play an important role in the eco-friendly remediation of degraded mine site soils. This study investigated the quality (essential nutrients and heavy metal content) of maize grown on organically amended soils from three active mines in Nigeria. Soil samples were collected randomly at 0-15 cm depth, air-dried and sieved. Five kg of soil were amended with poultry manure and sawdust (poultry manure only, sawdust only, poultry manure-sawdust mixtures in 3:1, 2:1 and 1:1 ratios) at 10 g kg(-1). Maize (Zea mays L.) seeds were planted and watered for two consecutive periods of 8 weeks, with the control and treatment experiments set up in the screenhouse in quadruples. Harvested tissues were weighed, dried, ground and digested. Chemical properties were determined using standard methods while atomic absorption spectrophotometry was used to determine total metal concentrations (Ca, Mg, Fe, Zn, Pb, Cd and Cu). ANOVA was used to test for significant differences among treatment groups in the various parameters. Application of poultry manure-sawdust mixtures significantly (p < 0.05) enhanced tissue dry matter yield, as well as N, P, K, and Na contents while Zn, Cd, Cu and Pb were immobilized to approximately 50-100%. Treatment with sawdust alone reduced tissue nutrient content resulting in depressed plant yield while poultry manure only though enhanced crop yield, contained higher heavy metal contents. Soil amendments comprised of poultry manure-sawdust mixtures can be effective remediation strategy for mine site soils, as these organic materials help replenish soil nutrients, immobilize heavy metals, and enhance food productivity.
A Ru(2+)-connected, metallo-organic ligand (L) with three free terpyridines was designed and synthesized. L was assembled with Zn(2+) to generate a helical structure; however, when mixing L with a 1,2,3-tristerpyridine ligand (T), a thermodynamically stable 2D rhombus was assembled. Furthermore, this 2D rhomboidal structure can also be achieved through the dynamic transformation of preassembled helix H with T and Zn(2+) at room temperature.
Haemonchus contortus infection is the major hurdle in growth and productivity in small ruminants especially in tropical countries. Indiscriminate and long term use of currently available chemotherapeutic agents lead to development of resistance in microorganisms and residual problems in population. Therefore, present study was undertaken to evaluate the anthelmintic efficacy of aqueous extract of Zanthoxylum armatum DC. seeds against adult H. contortus worms of small ruminants. Proximate analysis of seed powder shows high crude protein, Cu, Zn and Ca concentration. Phytochemical ingredients of extract revealed high total phenolic, flavonoids and tannin contents. In vitro experimental trial revealed complete mortality of H. contortus worms at the concentration of 100 mg/ml at the time exposure of 8 h. At 50 mg/ml concentration the mortality at 6 and 8 h were 45.45 ± 4.55 and 63.64 ± 4.54 %. Median lethal concentration (LC50) at 6 and 8 h were 59.90 and 28.92 mg/ml, respectively. Levamisole at concentration of 0.5 mg/ml caused 50 % mortality at 2 h post exposure and 100 % mortality at 4 h post exposure. The results confirm the cidal effect of the aqueous extract of Z. armatum DC. seeds on adult H. contortus worms.
We successfully obtained a novel bi-functional electrocatalyst towards the ORR and OER: Co nanoparticle-embedded N-doped carbon nanotube (CNT)/porous carbon (PC) by pyrolyzing metal organic framework (MOF) encapsulated Co3O4. The as-obtained hybrid exhibited highly efficient electrocatalytic activity for the ORR and OER. Furthermore, the assembled Zn-air batteries also revealed promising performance and long-term stability.
The activity of RING ubiquitin ligases (E3s) depends on an interaction between the RING domain and ubiquitin conjugating enzymes (E2), but posttranslational events or additional structural elements, yet largely undefined, are frequently required to enhance or regulate activity. Here, we show for the ubiquitin ligase RNF125 that, in addition to the RING domain, a C2HC Zn finger (ZnF) is crucial for activity, and a short linker sequence (Li2(120-128)) enhances activity. The contribution of these regions was first shown with truncated proteins, and the essential role of the ZnF was confirmed with mutations at the Zn chelating Cys residues. Using NMR, we established that the C2HC ZnF/Li2(120-128) region is crucial for binding of the RING domain to the E2 UbcH5a. The partial X-ray structure of RNF125 revealed the presence of extensive intramolecular interactions between the RING and C2HC ZnF. A mutation at one of the contact residues in the C2HC ZnF, a highly conserved M112, resulted in the loss of ubiquitin ligase activity. Thus, we identified the structural basis for an essential role of the C2HC ZnF and conclude that this domain stabilizes the RING domain, and is therefore required for binding of RNF125 to an E2.
Backbone functionalization of the pre-coordinated, emblematic IMes ligand with the COOH moiety was achieved upon treatment of Cp(CO)2Mn(IMes) with n-BuLi followed by CO2 and HCl to afford Cp(CO)2Mn(IMes(COOH)). The latter reacts with (1,10-phen)M(OAc)2 (M = Cu, Zn) to obtain M3Mn4 polymetallic complexes exhibiting the ambidentate IMes(CO2(-)) moiety as a key structural unit.
Plants on contaminated mining soils often show a reduced growth due to nutrient depletion as well as trace elements (TE) toxicity. Since those conditions threat plant's survival, plant growth promoting rhizobacteria (PGPR) such as rhizobia, might be of crucial importance for plant colonization on TE contaminated soils. Native rhizobia from mining soils are promising candidates for bioaugmented phytoremediation of those soils as they are adapted to the specific conditions. In this work, rhizobia from Zn- and Cd-contaminated mining soils were in vitro screened for their plant growth promoting features (organic acids, indole-3-acetic-acid and siderophore production, 1-aminocyclopropane-1-carboxylate deaminase activity, and Ca3(PO4)2 solubilization) and Zn- and Cd-resistance. In addition, some type and reference rhizobia strains were included in the study as well. The in vitro screening indicated that rhizobia and other native genera have great potential for phytoremediation purposes, by exerting, besides biological N2 fixation, other plant growth promoting traits. Leucaena leucocephala-Mesorhizobium sp. (UFLA 01-765) showed multi-element tolerance and an efficient symbiosis on contaminated soil deacresing the activities of antioxidative enzymes in shoots. This symbiosis is a promising combination to be used for phytostabilization concern.
Soil pollution is an important ecological problem worldwide. Phytoremediation is an environment-friendly option for reducing metal pollution. A greenhouse experiment was conducted to determine growth and physiological response, metal uptake and the phytostabilization potential of a non-toxic Jatropha curcas L. genotype when grown in multi-metal polluted conditions. Plants were established on mine residue (MR) amended or not with corn biochar (B) and inoculated or not with the mycorrhizal fungus Acaulospora sp. (AMF). J. curcas was highly capable of growing in MR and showed no phytotoxic symptoms. After J. curcas growth (105 days), B produced high desorption of Cd and Pb from the MR; however, no increases in metal shoot concentrations were observed. Therefore, Jatropha may be useful for phytostabilization of metals in mine tailings. The use of B is recommended because improved MR chemical properties conduced to plant growth (CEC, OM content, essential nutrients, EC, water holding capacity) and plant growth development (higher biomass, nutritional and physiological performance). Inoculation with an AMF did not improve any plant growth or physiological plant characteristic. Only higher Zn shoot concentration was observed, but it was not phytotoxic. Future studies of B use and its long-term effect on MR remediation should be conducted under field conditions.
In nuclear medicine studies, gallium-68 ((8)Ga) citrate has been recently known as a suitable infection agent in positron emission tomography (PET). In this study, by applying an in-house produced (68)Ge/(68)Ga generator, a simple technique for the synthesis and quality control of (68)Ga-citrate was introduced; followed by preliminary animal studies.
(68)GaCl3 eluted from the generator was studied in terms of quality control factors including radiochemical purity (assessed by HPLC and RTLC), chemical purity (assessed by ICP-EOS), radionuclide purity (evaluated by HPGe), and breakthrough. (68)Ga-citrate was prepared from eluted (68)GaCl3 and sodium citrate under various reaction conditions. Stability of the complex was evaluated in human serum for 2 h at 370C, followed by biodistribution studies in rats for 120 min.
(68)Ga-citrate was prepared with acceptable radiochemical purity (>97 ITLC and
 >98% HPLC), specific activity (4-6 GBq/mM), chemical purity (Sn, Fe<0.3 ppm and Zn<0.2 ppm) within 15 min at 500C. The biodistribution of (68)Ga-citrate was consistent with former reports up to 120 minutes.
This study demonstrated the possible in-house preparation and quality control of (68)Ga-citrate, using a commercially available (68)Ge/(68)Ga generator for PET imaging throughout the country.
Atomic resolution transmission electron microscopy has been used to examine antisite defects in Cu2ZnSnS4 (CZTS) kesterite crystals grown by a hot injection method. High angle annular dark field (HAADF) imaging at sub-0.1 nm resolution, and lower magnification dark field imaging using reflections sensitive to cation ordering, are used to reveal antisite domain boundaries (ADBs). These boundaries, typically 5-20 nm apart, and extending distances of 100 nm or more into the crystals, lie on a variety of planes and have displacements of the type ½[110] or ¼[201], which translate Sn, Cu and Zn cations into antisite positions. It is shown that some ADBs describe a change in the local stoichiometry by removing planes of S and either Cu or Zn atoms, implying that these boundaries can be electrically charged. The observations also showed a marked increase in cation disorder in regions within 1-2 nm of the grain surfaces suggesting that growth of the ordered crystal takes place at the interface with a disordered shell. It is estimated that the ADBs contribute on average ∼0.1 antisite defect pairs per unit cell. Although this is up to an order of magnitude less than the highest antisite defect densities reported, the presence of high densities of ADBs that may be charged suggests these defects may have a significant influence on the efficiency of CZTS solar cells.
We present the synthesis and characterization of alkali metal salts of the new tetraanionic, tetrapodal ligand 2,2'-(pyridine-2,6-diyl)bis(2-methylmalonate) (A4[PY(CO2)4], A = Li(+), Na(+), K(+), and Cs(+)), via deprotection of the neutral tetrapodal ligand tetraethyl 2,2'-(pyridine-2,6-diyl)bis(2-methylmalonate) (PY(CO2Et)4). The [PY(CO2)4](4-) ligand is composed of an axial pyridine and four equatorial carboxylate groups and must be kept at or below 0 °C to prevent decomposition. Exposing it to a number of divalent first-row transition metals cleanly forms complexes to give the series K2[(PY(CO2)4)M(H2O)] (M = Mn(2+), Fe(2+), Co(2+), Ni(2+), Zn(2+)). The metal complexes were comprehensively characterized via single-crystal X-ray diffraction, (1)H NMR and UV-vis absorption spectroscopy, and cyclic voltammetry. Crystal structures reveal that [PY(CO2)4](4-) coordinates in a pentadentate fashion to allow for a nearly ideal octahedral coordination geometry upon binding an exogenous water ligand. Additionally, depending on the nature of the charge-balancing countercation (Li(+), Na(+), or K(+)), the [(PY(CO2)4)M(H2O)](2-) complexes can assemble in the solid state to form one-dimensional channels filled with water molecules. Aqueous electrochemistry performed on [(PY(CO2)4)M(H2O)](2-) suggested accessible trivalent oxidation states for the Fe, Co, and Ni complexes, and the trivalent Co(3+) species [(PY(CO2)4)Co(OH)](2-) could be isolated via chemical oxidation. The successful synthesis of the [PY(CO2)4](4-) ligand and its transition metal complexes illustrates the still-untapped versatility within the tetrapodal ligand family, which may yet hold promise for the isolation of more reactive and higher-valent metal complexes.
The optimization of synthetic pathways is a central challenge in metabolic engineering. OptSSeq (Optimization by Selection and Sequencing) is one approach to this challenge. OptSSeq couples selection of optimal enzyme expression levels linked to cell growth rate with high-throughput sequencing to track enrichment of gene expression elements (promoters and ribosome-binding sites) from a combinatorial library. OptSSeq yields information on both optimal and suboptimal enzyme levels, and helps identify constraints that limit maximal product formation. Here we report a proof-of-concept implementation of OptSSeq using homoethanologenesis, a two-step pathway consisting of pyruvate decarboxylase (Pdc) and alcohol dehydrogenase (Adh) that converts pyruvate to ethanol and is naturally optimized in the bacterium Zymomonas mobilis. We used OptSSeq to determine optimal gene expression elements and enzyme levels for Z. mobilis Pdc, AdhA, and AdhB expressed in Escherichia coli. By varying both expression signals and gene order, we identified an optimal solution using only Pdc and AdhB. We resolved current uncertainty about the functions of the Fe(2+)-dependent AdhB and Zn(2+)-dependent AdhA by showing that AdhB is preferred over AdhA for rapid growth in both E. coli and Z. mobilis. Finally, by comparing predictions of growth-linked metabolic flux to enzyme synthesis costs, we established that optimal E. coli homoethanologenesis was achieved by our best pdc-adhB expression cassette and that the remaining constraints lie in the E. coli metabolic network or inefficient Pdc or AdhB function in E. coli. OptSSeq is a general tool for synthetic biology to tune enzyme levels in any pathway whose optimal function can be linked to cell growth or survival.
The objective of this study was to compare the diagnostic yield of GeneXpert MTB/RIF with Ziehl-Neelson (ZN) sputum smear microscopy among index TB cases and their household contacts.
A cross sectional study was conducted among sputum smear positive index TB cases and their household contacts in Northern Ethiopia.
Of 353 contacts screened, 41 (11%) were found to have presumptive TB. GeneXpert test done among 39 presumptive TB cases diagnosed 14 (35.9%) cases of TB (one being rifampicin resistant), whereas the number of TB cases diagnosed by microscopy was only 5 (12.8%): a 64.3% increased positivity rate by GeneXpert versus ZN microscopy. The number needed to screen and number needed to test to diagnose a single case of TB was significantly lower with the use of GeneXpert than ZN microscopy. Of 119 index TB cases, GeneXpert test revealed that 106 (89.1%) and 5 (4.2%) were positive for rifampicin sensitive and rifampicin resistant TB, respectively.
GeneXpert test led to increased TB case detection among household contacts in addition to its advantage in the diagnosis of Rifampicin resistance among contacts and index TB cases. There should be a consideration in using GeneXpert MTB/RIF as a point of care TB testing tool among high risk groups.
We report the successful synthesis and characterization of a new type I-II-V bulk form diluted magnetic semiconductor (DMS) Li(Zn,Mn,Cu)As, in which charge and spin doping are decoupled via (Cu,Zn) and (Mn,Zn) substitution at the same Zn sites. Ferromagnetic transition temperature up to  ∼33 K has been observed with a coercive field  ∼40 Oe for the 12.5% doping level. μSR measurements confirmed that the magnetic volume fraction reaches nearly 100% at 2 K, and the mechanism responsible for the ferromagnetic interaction in this system is the same as other bulk form DMSs.
Hydrogenation of the ZnO:Ga network has been chosen as a promising avenue to further upgrade the optoelectronic and structural properties of the films. With an optimum incorporation of hydrogen at a low substrate temperature (TS = 100 °C) in RF magnetron sputtering plasma, the ZnO:Ga:H film, with a large crystallite size (∼17 nm) and improved crystallinity along the optimally preferred c-axis orientation with respect to both the ⟨100⟩ (I⟨002⟩/I⟨100⟩ ∼ 74) and ⟨103⟩ (I⟨002⟩/I⟨103⟩ ∼ 10) directions, attains a high electrical conductivity (σ ∼ 1.5 × 10(3)) and ∼90% visible range optical transmission that yields a wide optical band gap of ∼3.78 eV. The dominant c-axis orientation of the ZnO crystals exhibits a distinct UV luminescence band at ∼340 nm that arises as a result of the typical exciton emission or near-band-edge emission, which occurs due to the recombination of photo-generated electrons and holes in the valence band or in traps near the valence band. Vacancies created by the out diffusion of oxygen from the network induces the growth along the ⟨103⟩ crystallographic orientation. With the introduction of an optimum amount of hydrogen into the network, the VO peak (OII) in the O 1s XPS spectrum significantly reduces in intensity while the Zn-OH peak (OIII) increases, indicating enhanced surface absorption of O species, which causes the improvement of c-axis orientation. The increase in the conductivity has been attributed to the centers assigned to isolated hydrogen atoms in the anti-bonding sites (ABO) or bond-centered sites of O-Zn bonds (BC), and Zn vacancies passivated by one or two hydrogen atoms. Hydrogen-induced dopant-like defects in the film and the associated large amount of tensile stress developed within the network has been correlated to the high conductivity and the wide band gap of the ZnO:Ga:H film due to the decreased repulsion between the O 2p and the Zn 4s bands and the Burstein-Moss effect as a consequence of the increased carrier concentration. Highly conducting and transparent c-axis oriented ZnO:Ga:H films grown by a device compatible process at a low TS are extremely useful for various stacked layer thin film devices, including solar cells.
A new Zn(ii) phthalocyanine (Pc) based low bandgap HTM is introduced for perovskite solar cells. Steady state and time-resolved photoluminescence (PL) measurements indicated an evenly matched hole extraction efficiency between sym-HTPcH and spiro-OMeTAD. On account of the low film quality and resulting high recombination, Zn(ii) Pc normally cannot work as an effective HTM. We adopted insulating Al2O3 for the infiltration of sym-HTPcH to form a hybrid interfacial buffer layer, affording perovskite solar cells (PSCs) with an average PCE value of up to 12.3%, which is
 a significant improvement with respect to the control cell without the meso-Al2O3 layer (4.21%) and is the highest value ever reported for Zn(ii) phthalocyanine based devices under AM1.5G standard conditions. A hysteresis test revealed that our device structure with the new HTM exhibited a balanced charge extraction behaviour.
Molecules bearing β-keto-enol functionality are potential candidates for coordination chemistry. Reported herein is the first synthesis and use of a novel designed ligand based on β-keto-enol group embedded with pyridine and thiophene moieties. The product was prepared in a one-step procedure by mixed Claisen condensation and was characterized by EA, m/z, FT-IR, (¹H, (13)C) NMR and single-crystal X-ray diffraction analysis. The new structure was grafted onto silica particles to afford a chelating matrix which was well-characterized by EA, FT-IR, solid-state (13)C-NMR, BET, BJH, SEM and TGA. The newly prepared organic-inorganic material was used as an adsorbent for efficient solid-phase extraction (SPE) of Cu(II), Zn(II), Cd(II) and Pb(II) from aqueous solutions and showed a capture capacity of 104.12 mg·g(-1), 98.90 mg·g(-1), 72.02 mg·g(-1), and 65.54 mg·g(-1), respectively. The adsorption capacity was investigated, in a batch method, using time of contact, pH, initial concentration, kinetics (Langmuir and Freundlich models), and thermodynamic parameters (ΔG°, ΔH° and ΔS°) of the system effects.
Accumulation of reactive oxygen species (ROS) following plant-pathogen interactions can trigger plant defence responses and directly damage pathogens. Thus, it is essential for pathogens to scavenge host-derived ROS to establish a parasitic relationship. However, the mechanisms protecting pathogens from host-derived oxidative stress remain unclear. In this study, a superoxide dismutase (SOD) gene, PsSOD1, was cloned from a wheat-Puccinia striiformis f. sp. tritici (Pst) interaction cDNA library. Transcripts of PsSOD1 were up-regulated in the early infection stage. Heterologous mutant complementation and biochemical characterization revealed that PsSOD1 encoded a Zn-only SOD. The predicted signal peptide was functional in an invertase-mutated yeast strain. Furthermore, immunoblot analysis of apoplastic proteins in Pst-infected wheat leaves and bimolecular fluorescence complementation suggested that PsSOD1 is a secreted protein that potentially forms a dimer during Pst infection. Overexpression of PsSOD1 enhanced Schizosaccharomyces pombe resistance to exogenous superoxide. Transient expression of PsSOD1 in Nicotiana benthamiana suppressed Bax-induced cell death. Knockdown of PsSOD1 using a host-induced gene silencing (HIGS) system reduced the virulence of Pst, which was associated with ROS accumulation in HIGS plants. These results suggest that PsSOD1 is an important pathogenicity factor that is secreted into the host-pathogen interface to contribute to Pst infection by scavenging host-derived ROS.
In this research, Bayer red mud (RM) was pretreated through alkali-thermal activation process, and prepared as an one-part geopolymer precursor, which could be used as geopolymeric solidification/stabilization (S/S) reagent for municipal solid waste incineration fly ash (MSWI FA). Compressive strength test, modified TCLP leaching test and sequential extraction test were conducted to evaluate the effectiveness of the RM-based geopolymeric S/S reagent. The results show that the S/S effects for heavy metals of RM-based geopolymer exhibit the following order: Pb>Cu>Zn>Cr. Most of the Zn, Pb and Cu in the MSWI FA transform from the leachable fractions into the inactive fractions difficult or unavailable to leach out. In the geopolymeric S/S solid, the active aluminosilicates in MSWI FA are dissolved in the alkaline environment formed by pretreated RM and then participate in the geopolymerization, which increases the SiO2/Al2O3 ratio and enhances the structural stability of geopolymeric S/S solid. MSWI FA offsets the strength deterioration of RM based one-part geopolymer and improves the immobilization efficiency for heavy metals in the geopolymer structure.
A one-pot method to remove two organic dye contaminants and alkali simultaneously from alkaline wastewater was developed by forming Zn-Al layered double hydroxide (ZnAl-LDH). Using this process, not only alkali but also methyl orange (MO), an anionic contaminant was totally removed from wastewater. In addition, cationic contaminant, methylene blue (MB) was also removed effectively while maintaining the high removal efficiency of MO. The removal efficiency of MO was almost 100% and the pH of the treated wastewater decreased from 12 to 7.38. The charge-limited removal process, molecular arrangement of the contaminants in LDHs, and the anomalous removal mechanism were analyzed experimentally and through simulation. After MO accumulated in the interlayers of LDH by electrostatic interaction, MB entered and trapped by hydrophobic interaction.
We begin with a brief historical review of the development of our understanding of the normal ordering of nd orbitals of a transition metal interacting with ligands, the most common cases being three below two in an octahedral environment, two below three in tetrahedral coordination, and four below one in a square-planar environment. From the molecular orbital construction of these ligand field splittings evolves a strategy for inverting the normal order: the obvious way to achieve this is to raise the ligand levels above the metal d's; that is, make the ligands better Lewis bases. However, things are not so simple, for such metal/ligand level placement may lead to redox processes. For 18-electron octahedral complexes one can create the inverted situation, but it manifests itself in the makeup of valence orbitals (are they mainly on metal or ligands?) rather than energy. One can also see the effect, in small ways, in tetrahedral Zn(II) complexes. We construct several examples of inverted ligand field systems with a hypothetical but not unrealistic AlCH3 ligand and sketch the consequences of inversion on reactivity. Special attention is paid to the square-planar case, exemplified by [Cu(CF3)4](-), in which Snyder had the foresight to see a case of an inverted field, with the empty valence orbital being primarily ligand centered, the dx2-y2 orbital heavily occupied, in what would normally be called a Cu(III) complex. For [Cu(CF3)4](-) we provide theoretical evidence from electron distributions, geometry of the ligands, thermochemistry of molecule formation, and the energetics of abstraction of a CF3 ligand by a base, all consistent with oxidation of the ligands in this molecule. In [Cu(CF3)4](-), and perhaps more complexes on the right side of the transition series than one has imagined, some ligands are σ-noninnocent. Exploration of inverted ligand fields helps us see the continuous, borderless transition from transition metal to main group bonding. We also give voice to a friendly disagreement on oxidation states in these remarkable molecules.
By using metallic Zn powders as zinc source, we synthesized unusual hierarchical ZnO superstructures, nanoflake-decorated nanonail arrays, on a large scale via a simple low-temperature thermal evaporation method. The hierarchical superstructures were characterized by using X-ray diffraction, scanning electron microscopy, energy dispersive X-ray spectroscopy, high resolution transmission electron microscopy as well as selected area electron diffraction. Studies found that both the ZnO nanonails and the decorated ZnO nanoflakes are single-crystals, with the preferred growth orientations along the (001) direction. The possible formation mechanism for the interesting hierarchical superstructures has been discussed. It was found that the deposition of indium films on a Si substrate and the heterogeneous nucleation of ZnO nanoflakes on the main ZnO nanonails play key roles in the fabrication of ZnO superstructures. Moreover, these special hierarchical superstructures showed much strong and complicated photoluminescent emissions in the visible region.
Pure zinc oxide (ZnO) and Sn-doped ZnO hexagonal sheets were synthesized by template free hydrothermal growth mechanism with controlled morphology by using zinc acetate dihydrate (Zn(CH₃COO)₂· 2H₂O), tin chloride pentahydrate (SnCl₄ · 5H₂O), Polyvinylpyrrolidone (PVP) and H₂O as precursors. The structural, physical, chemical, and magnetic characteristics were investigated by X-ray diffraction, field-emission scanning electron microscopy, energy dispersive X-ray spectroscopy and alternating gradient magnetometer (AGM), respectively. The average crystalline size of hexagonal phase of ZnO sheets was calculated to be about 34 nm from XRD patterns. Energy dispersive spectroscopy provided the compositional analysis of pure and Sn-doped ZnO. Room temperature ferromagnetism (RTFM) was observed by AGM for pure and Sn-doped ZnO hexagonal plates. RTFM increases monotonically for Sn doping and reaches maximum saturation magnetization 0.045 emu/g for 3% Sn-doped ZnO.
Ni₀.₅Cu₀.₃Zn₀.₂Fe₂O₄ thin films with thickness ranging from 25 nm to 500 nm were grown on Si substrate using pulsed laser deposition technique and their structural and magnetic properties were investigated. From the atomic force microscopy (AFM) analysis, it is observed that the film roughness (Ra) depends strongly on the thickness of the fabricated film. The magnetizations of the thin films were found to decrease when the film thickness increases. The thinner films showed a larger magnetization than the thick films. All the films showed a blocking temperature indicating their superparamagnetic behavior.
Nanoneedle Bi/ZnWO₄ photocatalysts were successfully synthesized using a two-step hydrothermal method. In the first hydrothermal experiment ZnO/ZnWO₄ nanoneedle crystals were synthesized from
 NaWO₄· 2H₂O and Zn(NO₃)₂· 6H₂O, using polyacrylamide (PAM) as a template in a hydrothermal environment. Bi cations were then reduced by t-BuONa in a second hydrothermal experiment, adding nanoneedle ZnO/ZnWO₄. The catalysts were then characterized by powder X-ray diffraction (XRD), scanning electron microcopy (SEM), energy dispersive spectrometer (EDS) and UV-vis diffuse reflectance spectrum (DRS). The results show that by adding Bi nanoparticles, the composition of the mixture gradually changed from that of ZnO/ZnWO₄ to Bi/ZnWO₄. The nanoneedle Bi/ZnWO₄samples displayed better UV light photocatalysis than the nanoneedle ZnO/ZnWO₄ samples. The optimum concentration of Bi was investigated using a photocatalytic experiment. A "blue shift" was observed when the molar ratio of Bi was increased.
Ni-doped ZnFe₂O₄(Ni(x)Zn₁₋xFe₂O₄; x = 0.0 to 0.5) nanoparticles were synthesized by a simple microwave combustion method. The X-ray diffraction confirms the presence of cubic spinel ZnFe₂O₄for all compositions. The lattice parameter decreases with an increase in Ni content resulting in the reduction of lattice strain. High resolution scanning electron microscope images revealed that the as-prepared samples are crystalline with particle size distribution in 40-50 nm range. Optical properties were determined by UV-Visible diffuse reflectance and photoluminescence spectroscopy respectively. The saturation magnetization (Ms) shows the super paramagnetic nature of the sample for x = 0.0-0.2, whereas for x = 0.3-0.5, it shows ferromagnetic nature. The Ms value is 1.638 emu/g for pure ZnFe₂O₄ sample and it increases with increase in Ni content.
We have investigated the formation mechanism of ZnO microspheres in polyol medium. The synthesis conditions have been varied with respect to temperature, medium and Zn-precursor concentration. The X-ray diffraction (XRD) and Raman spectroscopy result shows that the prepared ZnO nanoparticles are hexagonal wurtzite crystal structure and quite crystalline in nature. High resolution transmission electron microscopy (HRTEM) image indicates that the microsphere consists of aggregated nanoparticles in the range of 6 nm to 15 nm. The samples prepared in ethylene glycol medium shows a characteristic ether bond vibration mode in FTIR and it is additionally confirmed by NMR analysis. Initially, the nanoparticles are self-assembled into loosely packed microsphere and then the particles are densely packed by ether bonds formed between the glycol molecules adsorbed on adjacent particles which then grow as perfect microspheres. The sample prepared in EG medium at 150 °C did not show much aggregation. This study proposes the possible mechanism for the formation of ZnO microsphere.
Spinel Co(x)Zn₁₋xAl₂O₄ (0 ≤ x ≤ 1) nano-catalysts were synthesized by a simple Aloe vera plant extracted green synthesis route. Powder XRD patterns and Rietveld analysis confirmed the formation of single phase, cubic spinel gahnite structure without other impurities. The lattice parameter increased from 8.089 to 8.125 A with increasing CO²⁺ content. The average crystallite sizes were estimated using Scherrer's method, and it was found to be in the range of 15.72 nm to 26.53 nm. FT-IR spectra showed vibrational stretching frequencies corresponding to the spinel structure. HR-SEM and HR-TEM images showed the features of well particle shaped crystals with nano-sized grains. The elemental compositions of Co, Zn, Al and O were quantitatively obtained from EDX analysis. The band gap energy estimated using Kubelka-Munk method by UV-Visible DRS method, and the values are decreased with increasing the Co²⁺ content (4.12 eV to 3.67 eV), due to the formation of sub bands in between the energy gap. PL spectra showed emission bands in UV as well as in the visible regions for ZnAl₂O₄ and Co-doped ZnAl₂O4, due to the defect centers acting as the trap levels. VSM measurements revealed that pure ZnAl₂O₄ has diamagnetic, while Co doped ZnAl₂O₄ samples (x = 0.2 to 0.8) have superparamagnetism, whereas the sample CoAl₂O₄ has ferromagnetic in nature. Catalytic oxidation of benzyl alcohol to benzaldehyde was found that the sample Co₀.₆Zn₀.₄Al₂O₄ showed 93.25% conversion with 99.56% selectivity, whereas for pure ZnAl₂O₄, the conversion was only 86.31% with 92.85% selectivity.
Magnetic Ni₀.₅Zn₀.₅Fe₂O₄ nanoparticles were prepared via the solution combustion process and their microstructure and magnetic properties were investigated by X-ray diffraction (XRD), scanning electron microscopy (SEM), transmission electron microscopy (TEM) and vibrating sample magnetometer (VSM). The as-prepared magnetic Ni₀.₅Zn₀.₅Fe₂O₄ nanoparticles are characterized with average grain size of about 20 nm and magnetization of 90.3 Am²/kg. The surface of magnetic Ni₀.₅Zn₀.₅Fe₂O₄ nanoparticles was modified by use of sodium silicate and N-(3-Dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride, and the penicillin G acylase (PGA) was successfully immobilized on the surface-modified magnetic Ni₀.₅Zn₀.₅Fe₂O₄ nanoparticles. The results show that the activity for the immobilized PGA is affected less by pH and temperature than that for the free PGA, and the immobilized PGA exhibits a high effective activity, good stability of enzyme catalyst. This immobilized PGA on magnetic Ni₀.₅Zn₀.₅Fe₂O₄ nanoparticles can be separated from the solution by the external magnetic field for cyclic utilization, and they could retain about 70% of initial enzyme activity after 11 consecutive operations. The kinetic parameters (Km and Vmax) were determined, and the value of Km for the immobilized PGA (204.53 mmol/L) is higher than that of the free enzyme (3.50 mmol/L), while Vmax (1.93 mmol/min) is also larger than that of the free enzyme (0.838 mmol/min).
The exact etiology of preeclampsia remains unknown even though several studies have been done. Some studies have shown that supplementation of zinc (Zn) and copper could ameliorate the effects of preeclampsia while other studies did not establish the beneficial role of these elements in preeclampsia. The objective of this study was to compare the Zn and copper levels in the serum of Nigerian women with or without preeclampsia.
In this study, serum Zn and copper levels were determined using atomic absorption spectrometry in 54 patients and 48 healthy normotensive pregnant women. The mean, standard deviation, Student's t-test, and Pearson correlation were employed.
Serum Zn was significantly lower in patients than controls (8.27 ± 0.60 vs. 12.16 ± 1.83 μmol/l. P <0.001) (t-test). Serum copper was also significantly lower in patients than controls (8.14 ± 1.80 vs. 16.62 ± 3.17 μmol/l, P < 0.001).
There was a significant reduction in the levels of Zn and copper in patients with preeclampsia. Dietary supplementation of these trace elements may help to prevent preeclampsia.
In this paper, we report the synthesis, structure and photophysical studies of four new complexes of conformationally flexible 6-chloro-4-phenyl-2-(pyridin-2-yl)quinazoline ligand (L) with Zn(ii). The coordinating ability of the ligand and geometrical preferences of the resultant complexes are tuned by varying the anion of the metal salt as confirmed by structural and DFT studies. The choice of the metal salt (especially anion) directs the stabilisation of different conformations of the ligand arising out of twisting of the pyridyl ring with respect to the quinazoline ring, resulting in complexes with different nuclearity (monomer/dimer) as well as different coordination geometries (tetrahedral/trigonal bipyramidal/octahedral). Photophysical properties are also found to be tuned due to conformational changes on complexation. DFT studies on the ligand establish the conformationally stable forms as observed in the reported structures.
Reactions of the N-heterocyclic carbene derivatives of selenium(ii) dihalides, LSeX2 (X = Cl, Br; L = 1,3-dibutylbenzimidazol-2-ylidene, C15H22N2) (4b, 4b'), L'SeX2 (X = Cl, Br; L' = 1,3-di(n)propylbenzimidazol-2-ylidene, C13H18N2) (4c, 4c') and L''SeX2 (X = Cl, Br; L'' = 1,3-di(i)propylbenzimidazol-2-ylidene, C13H18N2) (4d, 4d') with iron led to the formation of dicationic diselenides, [L2Se2(2+)]2[{FeCl4}(-)]3Cl(-) (7), [L2Se2(2+)][FeBr4](-)Br(-) (8), [L'2Se2(2+)][FeCl4](-)Cl(-) (9), [L'2Se2(2+)][FeBr4](-)Br(-) (10), [L''2Se2(2+)][FeCl4](-)Cl(-) (11) and [L''2Se2(2+)][FeBr4](-)Br(-) (12). The reactions of LSeX2 with copper gave selone (LSe) complexes of cuprous halides, [(LSe)2CuBr] (13) and [(LSe)2(CuI)2] (14) respectively. However, LSeX2 (X = Cl, Br, I) (4b-4b'') on treatment with zinc gave both the dicationic diselenides, [L2Se2(2+)]Y [Y = {ZnCl3(H2O)2}(2-) (15), {ZnBr4}(2-) (17)] and complexes, [(LSe)2ZnX2] (16, 18, 20). The plausible mechanism for the formation of dicationic diselenides, [L2Se2(2+)], has been proposed and is supported by performing various test reactions. To validate these mechanisms, DFT calculations have been carried out. Interestingly, the reactions of the mixture of LSeX2/L'SeX2/L''SeX2 and L'Se(0)/L'Se(0)/L''Se(0) with metal halides (FeCl3, ZnX2; X = Cl, Br, I; CdI2, HgI2, PdCl2, and PtCl2) produced dicationic diselenides, 7-12, 15, 17 and [L2Se2(2+)]Y [Y = {ZnI4}(2-) (19), {CdI4}(2-) (22), {HgI4}(2-) (25), {PdCl4}(2-) (26), {PtCl4}(2-) (27)]. The methodology is more general than the previous method and gives better yields of [L2Se2(2+)]Y. The controlled oxidation of complexes, [(LSe)2MX2] (M = Zn, Cd, Hg; X = Cl, Br, I) (16, 18, 20, 28-32) with halogenating agents (SOCl2/Br2/I2) also gave dicationic diselenides, 15, 17, 19, 22, 25 and [L2Se2(2+)]Y [Y = {CdCl4}(2-) (21), {Hg2Cl6}(2-) (23), {HgBr4}(2-) (24)], proving to be the most general method for the synthesis of [L2Se2(2+)]. Attempted syntheses of unsymmetrical dicationic diselenides, [LSe-SeL'](2+)[FeCl4](-)Cl(-) and dicationic ditelluride, [L2Te2(2+)]2[{FeCl4}(-)]3Cl(-) by the
 reaction of LSeX2/LTeX2 (X = Cl, Br, I) with Fe metal were unsuccessful. This observation has been corroborated with DFT calculations.
In this study, total and available contents of seven typical heavy metals (Cr, Ni, Cu, Zn, As, Cd and Pb) were determined in mangrove wetland sediments in Dongzhai Harbor, and the distribution characteristics and bioavailability of these heavy metals in sediment were analyzed. The results showed that all the metals contents in this area were higher than in mangrove wetlands in Yalong Bay and Sanya Bay, but lower than the average level in mangrove wetlands in South China and other areas in the world, which was at a moderate to low level. The contents of heavy metals in surface layer of sediment significantly differed among barren shoal, the edge and inside of forest. All the metals were obviously accompanyingly deposited in the columnar sediments, which indicated a strong homogeneous source. The available contents of seven heavy metals in the surface sediments were extracted by EDTA, which had the order of Cu>Cr>Zn>Ni>As>Pb>Cd. All the maximum ratios of available to total content of elements appeared in surface or -middle to upper layers, except Ni. There was significant positive correlation between available and total contents of target metals.
Heavy metal contents (As, Cd, Cr, Cu, Hg, Ni, Pb, and Zn) in 99 pairs of soil-rice plant samples were evaluated from the downwind directions of a large thermal power plant in Shaoguan City, Guangdong Province, China. Results indicate that there is a substantial buildup of As, Cd, Cu, Pb, and Zn in the predominant wind direction of the power plant. The significant correlations between S and heavy metals in paddy soil suggest that the power plant represents a source of topsoil heavy metals in Shaoguan City due to sulfur-rich coal burning emissions. Elevated Cd concentrations were also found in rice plant tissues. Average Cd (0.69 mg kg(-1)) and Pb (0.39 mg kg(-1)) contents in rice grain had exceeded their maximum permissible limits (both were 0.2 mg kg(-1)) in foods of China (GB2762-2005). The enrichment of Cd and Pb in rice grain might pose a potential health risk to the local residents.
Brazil is the world's largest sugarcane producer and soils in the northeastern part of the country have been cultivated with the crop for over 450 years. However, so far, there has been no study on the status of heavy metal accumulation in these long-history cultivated soils. To fill the gap, we collect soil samples from 60 sugarcane fields in order to determine the contents of Cd, Cr, Cu, Ni, Pb, and Zn. We used multivariate analysis to distinguish between natural and anthropogenic sources of these metals in soils. Analytical determinations were performed in ICP-OES after microwave acid solution digestion. Mean concentrations of Cd, Cr, Cu, Ni, Pb, and Zn were 1.9, 18.8, 6.4, 4.9, 11.2, and 16.2 mg kg(-1), respectively. The principal component one was associated with lithogenic origin and comprised the metals Cr, Cu, Ni, and Zn. Cluster analysis confirmed that 68 % of the evaluated sites have soil heavy metal concentrations close to the natural background. The Cd concentration (principal component two) was clearly associated with anthropogenic sources with P fertilization being the most likely source of Cd to soils. On the other hand, the third component (Pb concentration) indicates a mixed origin for this metal (natural and anthropogenic); hence, Pb concentrations are probably related not only to the soil parent material but also to industrial emissions and urbanization in the vicinity of the agricultural areas.
Historically abundant and widespread, populations of Atlantic eels have suffered a sharp decline in recent decades, in the ranges 40-80% and 90-99% for American and European eels, respectively. As a result, American eels are now classified as threatened, whereas European eels are considered to be in critical danger of extinction. Several causes have been identified as likely contributors of this decline, including overfishing, obstacles to migration (hydroelectric dams), climate change and habitat contamination. In the context of a larger project investigating the role of organic and inorganic contaminants in this decline, in this study, we measured the liver, kidney and muscle concentrations of essential (Cu, Se and Zn) and non-essential (Ag, As, Cd, Cr, Hg, Ni and Pb) metals in eels sampled at four sites in the South-West of France and four sites in Eastern Canada varying in contamination. Tissue concentrations of Cd, Hg and Se increased with fish size and age. Tissue metal concentrations generally reflected the contamination of their sampling sites. This was the case for Ag, As, Cd, Cu, Hg, Pb and Se. Comparison of tissue concentrations of these metals with the toxicological literature suggests that all of them except As could pose a risk to the health of eels from the most contaminated sites. In particular, European eels may be particularly at risk of Cd and Pb toxicity. Globally, our study suggests that a substantial accumulation of inorganic contaminants in the tissues of both eel species at sites contaminated by historical anthropogenic inputs may play a role in their decline.
Zinc (Zn) is an essential trace element that is vital in a wide range of cellular machineries because of its effect on the expression and activity of various transcription factors and enzymes. Zn deficiency disturbs Zn homeostasis and has pathogenic consequences, including growth retardation and immune impairment in mammals. Zn homeostasis is tightly controlled by the coordinated activity of Zn transporters and metallothioneins, which regulate the distribution, storage, and intracellular and extracellular concentration of Zn. Recent reverse-genetic approaches using Zn transporter-deficient mice have revealed the physiological functions of specific Zn signaling axes (each formed by Zn and a Zn transporter) in various biological programs. In this review, we describe recent discoveries about the role of Zn transporters which facilitate cellular signaling through Zn uptake in physiology and pathogenesis, with particular focus on the influence of Zn signaling in systemic growth and immunity.
Concentrations of trace metals such as iron (Fe), copper (Cu), zinc (Zn), cobalt (Co), nickel (Ni), manganese (Mn), lead (Pb), cadmium (Cd), chromium (Cr), arsenic (As), vanadium (V), and selenium (Se) were determined in seawater and zooplankton from the surface waters off Rushikulya estuary, north-western Bay of Bengal. During the study period, the concentration of trace metals in seawater and zooplankton showed significant spatio-temporal variation. Cu and Co levels in seawater mostly remained non-detectable. Other elements were found at higher concentrations and exhibited marked variations. The rank order distribution of trace metals in terms of their average concentration in seawater was observed as Fe>Ni>Mn>Pb>As>Zn>Cr>V>Se>Cd while in zooplankton it was Fe>Mn>Cd>As>Pb>Ni>Cr>Zn>V>Se. The bioaccumulation factor (BAF) of Fe was highest followed by Zn and the lowest value was observed with Ni. Results of correlation analysis discerned positive affinity and good relationship among the majority of the trace metals, both in seawater and zooplankton suggesting their strong affinity and coexistence.
The thermochemical characteristics and gaseous trace pollutant behaviors during co-combustion medium-to-low ash bituminous coal with typical biomass residues (corn stalk and sawdust) were investigated. Lowering of ignition index, burnout temperature and activation energy in the major combustion stage are observed in the coal/biomass blends. The blending proportion of 20% and 30% are regarded as the optimum blends for corn stalk and sawdust, respectively, in according the limitations of heating value, activation energy, flame stability and base/acid ratio. The reductions of gaseous As, Cd, Cu, Pb, Zn and polycyclic aromatic hydrocarbon (PAHs) were 4.5%, 7.8%, 6.3%, 9.8%, 9.4% and 17.4%, respectively, when co-combustion coal with 20% corn stalk. The elevated capture of trace elements were found in coal/corn stalk blend, while the coal/sawdust blend has the better PAHs control potential. The reduction mechanisms of gaseous trace pollutants were attributed to the fuel property, ash composition and relative residence time during combustion.
Thermophilic Bacillus firmus KIBGE-IB28 produced extracellular α-amylase at temperature 70°C. Enzyme was partially purified by ammonium sulfate precipitation with 42.80 fold purification and specific activity of 1889.6 U/mg. Effects of various metals on enzyme activity were determined and it was found that enzyme activity boosted significantly in presence of Ca(2+), K(2+), Ba(2+), Co(2+) and Ni(2+) whereas Zn(2+), Mg(2+), Na(2+) and Cu(2+) were found inhibitory at concentration 10mM.
Cadmium (Cd) and high molybdenum (Mo) can lead to adverse reactions on animals, but the coinduced toxicity of Mo and Cd to bone in ducks was not well understood. The objective of this study was to investigate the changes in trace elements' contents and morphology in bones of duck exposed to Mo or/and Cd. One hundred twenty healthy 11-day-old male ducks were randomly divided into six groups and treated with commercial diet containing Cd or/and Mo. On the 60th and 120th days, the blood, excretion, and metatarsals were collected to determine alkaline phosphatase (ALP) activity and the contents of Mo, Cd, calcium (Ca), phosphorus (P), copper (Cu), iron (Fe), zine (Zn), and selenium (Se). In addition, metatarsals were subjected to histopathological analysis with the optical microscope and radiography. The results indicated that Mo and Cd contents significantly increased while Ca, P, Cu, and Se contents remarkably decreased in metatarsals in coexposure groups (P < 0.01). Contents of Fe and
 Zn in metatarsals had no significant difference among groups (P > 0.05). Ca content in serum had no significant difference among experimental groups (P > 0.05), but P content was significantly decreased in HMo and HMo + Cd groups (P < 0.05). Contents of Ca and P in excretion and ALP activity were significantly increased in coinduced groups (P < 0.05). Furthermore, osteoporotic lesions, less and thinner trabecular bone were observed in combination groups. The findings suggested that dietary of Cd or/and Mo could lead to bone damages in ducks via disturbing the balance of Ca and P in body and homeostasis of Cu, Fe, Zn, and Se in bones; moreover, the two elements showed a possible synergistic relationship.
The Songhua River represents one of the seven major river systems in China. It flows through Harbin city with 66 km long, locating in the northern China with a longer winter time. This paper aimed to study concentration distributions, stability, risk assessment, and source apportionment of heavy metals including chromium (Cr), cadmium (Cd), lead (Pb), mercury (Hg), arsenic (As), copper (Cu), zinc (Zn), and nickel (Ni) in 11 selected sections of the Songhua River Harbin region. Results showed that Cr, Cd, Pb, Hg, and As exceeded their respective geochemical background values in sediments of most monitoring sections. Compared with other important rivers and lakes in China, Cr, Hg, Cd, and As pollutions in surface sediments were above medium level. Further analysis of chemical speciation indicated that Cr and As in surface sediments were relatively stable while Pb and Cd were easily bioavailable. Correlation analysis revealed sources of these metals except As might be identical. Pollution levels and ecological risks of heavy metals in surface sediments presented higher in the mainstream region (45° 47.0' N ~ 45° 53.3' N, 126° 37.0' E ~ 126° 42.1' E). Source apportionment found Hejiagou and Ashi River were the main contributors to metal pollution of this region. Thus, anthropogenic activities along the Hejiagou and Ashi River should be restricted in order to protect the Songhua River Harbin region from metal contamination.
River quality trajectories are presented for (i) organic pollution, (ii) eutrophication, (iii) nitrate pollution, and (iv) metal contamination over the Longue Durée (130 to 70 years). They are defined by a quantified state indicator (S) specific to each issue, compared to drivers (D) or pressures (P) and to social responses (R) that reflect the complex interactions between society and river quality. The Lower Seine River, naturally sensitive to anthropogenic pressures, greatly impacted by Paris urban growth, industrialization, and intensive agriculture, and well documented by the PIREN-Seine 25-year research program, was chosen to illustrate these trajectories. State indicators, dissolved oxygen, algal pigments, nitrate, and heavy metals (Cd, Cr, Hg, Pb, Zn) in sediments have only been monitored by river basin authorities since 1971. Therefore, their past changes have been reconstructed using three approaches: (i) reassessment of historical sources, (ii) pressure-state models that reconstruct past water quality, and (iii) sedimentary archives of past persistent contamination from dated floodplain cores. The indicators were then transformed into river quality status using contemporary water quality criteria throughout these records. Each environmental issue shows specific trajectories because each has its own relationship between the issue evidence and the social response, but all are characterized by very poor quality in the past, largely ignored: the long-term summer hypoxia (<1880-1995), the summer eutrophication peak (1965-2005), the growing nitrate level since the 1950s, recently stabilized but still high, and the extreme metal contamination (>1935-2000) that peaked in the 1960s. The efficiency of social responses has been highly variable but more efficient in the last 15-25 years.
Glutamatergic neuron activity and/or the modification of the activity with glucocorticoids are closely linked to synaptic Zn(2+) dynamics as well as synaptic Ca(2+) dynamics. The dynamic crosstalk of synaptic Zn(2+) signaling to intracellular Ca(2+) signaling via calcium channels is involved in synaptic plasticity such as long-term potentiation (LTP) and cognitive activity. The influx of extracellular Zn(2+) into postsynaptic neurons, which is closely linked to glutamate signaling in the synaptic cleft, is critical for cognitive activity. However, excess intracellular Zn(2+) signaling induced by excess glutamatergic neuron activity is involved in not only cognitive decline in neurological disorders but also stress-induced cognitive decline. On the other hand, it has been recognized that excess Ca(2+) influx into postsynaptic neurons induces neuronal death, while the involvement of excess intracellular Ca(2+) signaling in cognitive decline is poorly understood. Understanding of synaptic Zn(2+) dynamics, which are modified by glutamate and glucocorticoid signaling, may be meaningful to prevent Zn(2+)-mediated cognitive decline. This paper summarizes the current knowledge on Zn(2+) dynamics under changing synaptic environment and its impact on cognitive decline.
An understanding of the processes controlling sediment, organic matter and metal export is critical to assessing and anticipating risk situations in water systems. Concentrations of suspended particulate matter (SPM), dissolved (DOC) and particulate (POC) organic carbon and metals (Cu, Ni, Pb, Cr, Zn, Mn, Fe) in dissolved and particulate phases were monitored in a forest watershed in the Basque Country (Northern Spain) (31.5km(2)) over three hydrological years (2009-2012), to evaluate the effect of flood events on the transport of these materials. Good regression was found between SPM and particulate metal concentration, making it possible to compute the load during the twenty five flood events that occurred during the study period at an annual scale. Particulate metals were exported in the following order: Fe>Mn>Zn>Cr>Pb>Cu>Ni. Annual mean loads of SPM, DOC and POC were estimated at 2267t, 104t and 57t, respectively, and the load (kg) of particulate metals at 76 (Ni), 83 (Cu), 135 (Pb), 256 (Cr), 532 (Zn), 1783 (Mn) and 95170 (Fe). Flood events constituted 91%-SPM, 65%-DOC, 71%-POC, 80%-Cu, 85%-Ni, 72%-Pb, 84%-Cr, 74%-Zn, 87%-Mn and 88%-Fe of total load exported during the three years studied. Flood events were classified into three categories according to their capacity for transporting organic carbon and particulate metals. High intensity flood events are those with high transport capacity of SPM, organic carbon and particulate metals. Most of the SPM, DOC, POC and particulate metal load was exported by this type of flood event, which contributed 59% of SPM, 45% of organic carbon and 54% of metals.
The low energy spin excitation spectrum of the breathing pyrochlore Ba_{3}Yb_{2}Zn_{5}O_{11} has been investigated with inelastic neutron scattering. Several nearly resolution limited modes with no observable dispersion are observed at 250 mK while, at elevated temperatures, transitions between excited levels become visible. To gain deeper insight, a theoretical model of isolated Yb^{3+} tetrahedra parametrized by four anisotropic exchange constants is constructed. The model reproduces the inelastic neutron scattering data, specific heat, and magnetic susceptibility with high fidelity. The fitted exchange parameters reveal a Heisenberg antiferromagnet with a very large Dzyaloshinskii-Moriya interaction. Using this model, we predict the appearance of an unusual octupolar paramagnet at low temperatures and speculate on the development of intertetrahedron correlations.
Properties of the depleted Heisenberg spin ladder material series (C_{7}H_{10}N)_{2}Cu_{1-z}Zn_{z}Br_{4} have been studied by the combination of magnetic measurements and neutron spectroscopy. Disorder-induced degrees of freedom lead to a specific magnetic response, described in terms of emergent strongly interacting "spin island" objects. The structure and dynamics of the spin islands is studied by high-resolution inelastic neutron scattering. This allows us to determine their spatial shape and to observe their mutual interactions, manifested by strong spectral in-gap contributions.
In addition to being a forage crop, Caliph medic (Medicago truncatula) is also a model legume plant and is used for research focusing on the molecular characterization of the interaction between rhizobia and plants. However, the endophytic microbiome in this plant is poorly defined. Endophytic bacteria play a role in supplying plants with the basic requirements necessary for growth and development. Moreover, these bacteria also play a role in the mechanism of salinity stress adaptation in plants. As a prelude to the isolation and utilization of these bacteria in Caliph medic farming, 41 bacterial OTUs were identified in this project from within the interior of the roots of this plant by pyrosequencing of the small ribosomal subunit gene (16S rDNA) using a cultivation-independent approach. In addition, the differential abundance of these bacteria was studied following exposure of the plants to salinity stress. About 29,064 high-quality reads were obtained from the sequencing of six libraries prepared from control and salinity-treated tissues. Statistical analysis revealed that the abundance of ~70% of the OTUs was significantly (p ≤ 0.05) altered in roots that were exposed to salinity stress. Sequence analysis showed a similarity between some of the identified species and other, known, growth-promoting bacteria, marine and salt-stressed soil-borne bacteria, and nitrogen-fixing bacterial isolates. Determination of the amendments to the bacterial community due to salinity stress in Caliph medic provides a crucial step toward
 developing an understanding of the association of these endophytes, under salt stress conditions, in this model plant. To provide direct evidence regarding their growth promoting activity, a group of endophytic bacteria were isolated from inside of plant roots using a cultivation-dependent approach. Several of these isolates were able to produce ACC-deaminase, ammonia and IAA; and to solubilize Zn+2 and PO4-3. This data is consistent with the predicted occurrence (based on cultivation-independent techniques) of these bacteria and provides some insight into the importance of the endophytic bacteria in Caliph medic when grown under normal and saline conditions.
The visible absorption and photoluminescence (PL) properties of the four neutral ruthenium diimine compounds [Ru(bpy)2(dcb)] (B2B), [Ru(dtb)2(dcb)] (D2B), [Ru(bpy)2(dcbq)] (B2Q), and [Ru(dtb)2(dcbq)] (D2Q), where bpy is 2,2'-bipyridine, dcb is 4,4'-(CO2(-))2-bpy, dtb is 4,4'-(tert-butyl)2-bpy, and dcbq is 4,4'-(CO2(-))2-2,2'-biquinoline, are reported in the presence of Lewis acidic cations present in fluid solutions at room temperature. In methanol solutions, the measured spectra were insensitive to the presence of these cations, while in acetonitrile a significant red shift in the PL spectra (≤1400 cm(-1)) was observed consistent with stabilization of the metal-to-ligand charge transfer (MLCT) excited state through Lewis acid-base adduct formation. No significant spectral changes were observed in control experiments with the tetrabutylammonium cation. Titration data with Li(+), Na(+), Mg(2+), Ca(2+), Zn(2+), Al(3+), Y(3+), and La(3+) showed that the extent of stabilization saturated at high cation concentration with magnitudes that scaled roughly with the cation charge-to-size ratio. The visible absorption spectra of D2Q was particularly informative due to the presence of two well-resolved MLCT absorption bands: (1) Ru → bpy, λmax ≈ 450 nm; and (2) Ru → dcbq, λmax ≈ 540 nm. The higher-energy band blue-shifted and the lower-energy band red-shifted upon cation addition. The PL intensity and lifetime of the excited state of B2B first increased with cation addition without significant shifts in the measured spectra, behavior attributed to a cation-induced change in the localization of the emissive excited state from bpy to dcb. The importance of excited-state localization and stabilization for solar energy conversion is discussed.
Calcium (Ca) has been reported to lessen oxidative damages in plants by upregulating the activities of antioxidant enzymes. However, atrazine mediated reactive oxygen species (ROS) reduction by Ca is limited. This study therefore investigated the effect of exogenously applied Ca on ROS, antioxidants activity and gene transcripts, the D1 protein (psbA gene), and chlorophyll contents in Pennisetum seedlings pre-treated with atrazine. Atrazine toxicity increased ROS production and enzyme activities (ascorbate peroxidase APX, peroxidase POD, Superoxide dismutase SOD, glutathione-S-transferase GST); but decreased antioxidants (APX, POD, and Cu/Zn SOD) and psbA gene transcripts. Atrazine also decreased the chlorophyll contents, but increased chlorophyll (a/b) ratio. Contrarily, Ca application to atrazine pre-treated seedlings lowered the harmful effects of atrazine by reducing ROS levels, but enhancing the accumulation of total chlorophyll contents. Ca-protected seedlings in the presence of atrazine manifested reduced APX and POD activity, whereas SOD and GST activity was further increased with Ca application. Antioxidant gene transcripts that were down-regulated by atrazine toxicity were up-regulated with the application of Ca. Calcium application also resulted in up-regulation of the D1 protein. In conclusion, ability of calcium to reverse atrazine-induced oxidative damage and calcium regulatory role on GST in Pennisetum was presented.
Lead (Pb) and zinc (Zn) concentrations from surface sediments were determined at 17 stations in riverine, estuarine, and marine environments during the wet and dry seasons. The geochemical fractionations were obtained by a sequential extraction procedure in five geochemical forms: exchangeable, bound to carbonate, iron-manganese oxide, organic, and residual fractions. The concentrations of Pb and Zn in the water were higher during the wet season than the dry season and higher in the riverine and marine samples than the estuarine samples. Following geochemical fractionation, the metals were found mainly in the residual fraction. The results indicated that the concentrations were influenced by season, with the sources of Pb and Zn derived mainly from rivers and natural sources. The contamination status in the estuary of the Jeneberang River was classified as weak to moderate pollution and the risk level to aquatic biota attributed was no risk to low risk.
Crops intended for human nutrition and food production containing different essential trace elements, such as copper and zinc, could be contaminated by toxic metals like cadmium and lead. The interrelationship between micronutrients and contaminant trace elements in different cereals was investigated in North-western Italy, where both agricultural and industrial activities are present. Elemental concentrations in sampled cereals were assessed by inductively coupled plasma mass spectrometry (ICP-MS). Rice, oats and barley reached the highest median levels for Al, Cd and Pb content, while corn samples were less contaminated by toxic metals. Regarding essential elements highest median values of Cu and Zn were both found in barley, while Ni median content was higher in oats. Rice had the lowest median levels of essential elements. The correlation study between toxic and essential elements seemed to demonstrate fixed trends in analysed samples, corroborating the importance of a different diet to limit potential adverse effects caused by toxic elements.
Adequate individual supplements of Zn, Co and Mo increased chemical oxygen demand (COD) removal and specific oxygen uptake rates during activated sludge treatment of dyeing wastewater, while overdoses of micronutrients can decrease metabolic rates. The effects of combing Zn, Co, and Mo at different doses were investigated using response surface methodology, with a second order polynomial equation: Y = 78.19+ 0.17X1 + 37.33 X2 +20.20X3 - 5.58X1X2 -63.05 X2X3, where Y means COD removal rate (%), X1 means Co concentration, X2 means Zn concentration, X3 means Mo concentration. The maximum COD removal efficiency of 89.41% was achieved with doses of 0.02 mg/L Co, 0.24 mg/L Zn and 0.45 mg/L Mo. Both the combinations of Zn-Co and Zn-Mo acted antagonistically for COD removal efficiency, and combination of Co-Mo was negligible to COD removal efficiency. Doses of micronutrients, particularly Zn, Co and Mo, were beneficial for microbial shift towards Planctomyces and Bacteroidetes.
The pollution of antibiotic resistance genes (ARGs) in livestock farms is a problem which need to be paid more attention to, due to the severe resistance dissemination and the further human health risk. In this study, all the relevant exposure matrices (manure, soil and water) of sixteen animal farms in Southeastern China were sampled to determine twenty-two ARGs conferring resistance to five major classes of antibiotics including tetracyclines, sulfonamides, quinolones, aminoglycosides, and macrolides. The results showed that the spread property of sul genes was most extensive and strong, followed by tet and erm genes. The abundance of tet genes expressing ribosomal protection proteins (tetM, tetO, tetQ, tetT and tetW) was higher than that expressing efflux pump proteins (tetA, tetC, tetE and tetG) in each type of samples. The high abundance and frequency of ermB gene in the matrices should be paid more attention, because macrolides is a major medicine for human use. For manures, it was found that the similar ARGs distribution rules were existing in poultry manure or porcine manure samples, despite of the different origins of these two types of livestock farms. Meanwhile, it was interesting that the distribution rule of tet genes in animal manure was nearly the same as all the ARGs. For soils, the result of nonmetric multi-dimensional scaling (NMDS) analysis showed that the pollution of ARGs in the soils fertilized by poultry and cattle manures were more substantial in northern Jiangsu, but no significant ARGs diversity was observed among porcine manured soils of five different regions. Furthermore, most ARGs showed significant positive relationships with environmental variables such as concentration of sulfonamides, tetracyclines, Cu, Zn and total organic carbon (TOC). The pollution profile and characteristics of so many ARGs in livestock farms can provide significative foundation for the regulation and legislation of antibiotics in China.
Effect of solid solution treatment (T4) on stress corrosion cracking (SCC) behavior of an as-forged Mg-6.7%Zn-1.3%Y-0.6%Zr (in wt.%) alloy has been investigated using slow strain rate tensile (SSRT) testing in 3.5 wt.% NaCl solution. The results demonstrated that the SCC susceptibility index (ISCC) of as-forged samples was 0.95 and its elongation-to-failure (εf) was only 1.1%. After T4 treatment, the SCC resistance was remarkably improved. The ISCC and εf values of T4 samples were 0.86 and 3.4%, respectively. Fractography and surface observation indicated that the stress corrosion cracking mode for as-forged samples was dominated by transgranular and partially intergranular morphology, whereas the cracking mode for T4 samples was transgranular. In both cases, the main cracking mechanism was associated with hydrogen embrittlement (HE). Through alleviating the corrosion attack of Mg matrix, the influence of HE on the SCC resistance of T4 samples can be greatly suppressed.
Towards the development of a potential remediation
 technology for multiple heavy metals [Zn(II), Cu(II), Cd(II), Cr(VI) and Ni(II)] from contaminated water, present study examined the growth kinetics and heavy metal removal ability of Beauveria bassiana in individual and multi metals. The specific growth rate of B. bassiana varied from 0.025h(-1) to 0.039h(-1) in presence of individual/multi heavy metals. FTIR analysis indicated the involvement of different surface functional groups in biosorption of different metals, while cellular changes in fungus was reflected by various microscopic (SEM, AFM and TEM) analysis. TEM studies proved removal of heavy metals via sorption and accumulation processes, whereas AFM studies revealed increase in cell surface roughness in fungal cells exposed to heavy metals. Present study delivers first report on the mechanism of bioremediation of heavy metals when present individually as well as multi metal mixture by entomopathogenic fungi.
Circulating platinum (Pt) is detectable in the blood of Pt-treated cancer patients for over a decade after the treatment. Prolonged exposure to Pt, in combination with adverse compounds from nutrition and lifestyle, such as cadmium (Cd), could increase the risk from second cancers. The aim of this study was to investigate the effects of simultaneous exposure to Cd- and Pt-compounds on oxidative and DNA damage and the possible protective effects of zinc (Zn) and selenium (Se). The aqueous solutions of PtCl4, CdCl2 × H2O, ZnCl2 and Na2SeO3 were added, alone or in combination, to whole blood and isolated erythrocytes to produce the final concentrations of 2000 μg/L of Pt, 8 μg/L of Cd, 100 μg/L of Se, and 1000 μg/L of Zn. The activity of copper, zinc-superoxide dismutase, glutathione peroxidase and glutathione in whole blood was determined after 1 h exposure in in vitro conditions. The induction of DNA strand-breaks in human peripheral blood leukocytes was determined with the alkaline comet assay after 24 h exposure. Exposure to Pt and/or Cd decreased the activities of antioxidant enzymes and elevated DNA damage compared to control. A statistically significant change in the activity of both enzymes and in the induction of DNA strand-breaks was observed in the cells treated with Pt + Cd combination, while the addition of Se and/or Zn resulted in partial recovery of these effects. The results indicate that combined exposure to Pt and Cd could disrupt antioxidant protection of the organism and increase DNA damage, whereas Se and Zn could partially ameliorate these harmful effects.
Zinc is an essential trace element that plays an important role in differentiation of osteoblasts and bone modeling. This in vitro study aimed to evaluate the osteoblast differentiation of human dental pulp stem cells (DPSCs) on zinc-modified titanium (Zn-Ti) that releases zinc ions from its surface. Based on real-time PCR, alkaline phosphatase (ALP) activity and Western blot analysis data, we investigated osteoblast differentiation of DPSCs cultured on Zn-Ti and controls. DPSCs cultured on Zn-Ti exhibited significantly up-regulated gene expression levels of osteoblast-related genes of type I collagen (Col I), bone morphogenetic protein 2 (BMP2), ALP, runt-related transcription factor 2 (Runx2), osteopontin (OPN), and vascular endothelial growth factor A (VEGF A), as compared with controls. We also investigated extracellular matrix (ECM) mineralization by Alizarin Red S (ARS) staining and found that Zn-Ti significantly promoted ECM mineralization when compared with controls. These findings suggest that the combination of Zn-Ti and DPSCs provides a novel approach for bone regeneration therapy.
In this study, Zn/Al-layered double hydroxides (Zn/Al-LDHs) were synthesized by a co-precipitation method and characterized with X-ray diffraction, Fourier transform infrared spectroscopy, and scanning electron microscopy. Then the hexavalent chromium Cr(VI) adsorption experiments on calcined Zn/Al-LDHs were carried out to analyze the effects of pH, temperature, adsorption time, initial Cr(VI) concentration and adsorbent dosage on the removal of Cr(VI) from aqueous solutions. The maximum adsorption capacity for Cr(VI) on calcined Zn/Al-LDHs under optimal conditions was found to be over 120 mg/g. The kinetic and isotherm of Cr(VI) adsorption on calcined Zn/Al-LDHs can be described with the pseudo-second-order kinetic model and Langmuir isotherm, respectively.
Road deposited sediments (RDS) swept from highways in South Korea were characterized to quantitatively evaluate the reduction in non-point source pollutants by sweeping. The swept RDS consisted primarily of sand (63 μm to 2 mm) particles (80.34 ± 8.33% of total weight) highly contaminated by organics, nutrients and heavy metals. The average concentrations of total organic carbon (TOC), biochemical oxygen demand (BOD), volatile solids (VS), total nitrogen (T-N), and total phosphorus (T-P) were 20.17 ± 9.13, 1.04 ± 0.62, 39.92 ± 16.55, 1.99 ± 0.96, and 0.54 ± 0.19 g kg(-1) (±one standard deviation), respectively, for 63 μm to 2 mm RDS. The concentrations of the pollutants were high for RDS smaller than 63 μm, but most of the mass was associated with the 63 μm to 2 mm RDS. The results suggest that the pollutants associated with RDS swept from highways originated mainly from engine wear, exhaust emissions, and tire wear. These results were different from the RDS on roads in residential and commercial areas, where natural particles and brake wear contribute significantly to RDS. In addition, the reductions in TOC, BOD, VS, T-N, T-P, Cu, Pb, Zn, Fe, and As based on the swept RDS measurements were calculated to be 3,355.3, 175.1, 6,621.4, 323.0, 88.3, 30.3, 13.7, 1.0, 303.4, 11,198.7, and 0.4 g km(-1), respectively.
Bioaccumulation of six heavy metals (Mn, Fe, Co, Ni, Cu, Zn) in the muscle of highly consumed fish species (Mastacembelus armatus) were measured using atomic absorption spectrometer. Fe (213.29 mg/kg dry weight) concentration was the most, followed by Zn (186.19 mg/kg dry weight), Ni (58.98 mg/kg dry weight), Cu (41.36 mg/kg dry weight), Co (9.06 mg/kg dry weight) and Mn (9.03 mg/kg dry weight). Estimated daily intake of heavy metals was calculated by mean fish consumption rate 19.5 × 10(-3) kg/day, on the basis of a calculation of the amount of fish consumed by adult individuals (male and female). The studied fish species pose non carcinogenic risk for Co and Ni [target hazard quotient (THQ) > 1] only. Hazard index (HI) was high. Carcinogenic risk (TR) posed by this fish for male and female was 3.43 × 10(-3) and 3.91 × 10(-3), respectively for Ni (the carcinogenic potency slope factor was available for Ni only). The study is an alert indicating that inhabitants who consume these fishes (particularly females) were at risk of Co and Ni toxicity. In India recommended guidelines have yet not been established for these heavy metals, which is essential for setting of toxicological standards.
The present study was conducted to assess the toxicity of thermal power plant effluent containing heavy metals (Fe > Cu > Zn > Mn > Ni > Co > Cr) on haematological indices, micronuclei, lobed nuclei and activity of pathological marker enzymes [alkaline phosphatase (ALP), aspartate transferase (AST), alanine transferase (ALT) and creatine kinase (CK)] in Channa punctatus. Total erythrocyte count (-54.52 %), hemoglobin (-36.98 %), packed cell volume (-36.25 %), mean corpuscular hemoglobin concentration (-1.41 %) and oxygen (O2) carrying capacity (-37.04 %) declined significantly over reference fish, however total leukocyte count (+25.43 %), mean corpuscular hemoglobin (+33.52 %) and mean corpuscular volume (+35.49 %) showed elevation. High frequency of micronuclei (1133.3 %) and lobed nuclei (150 %) were observed in exposed fish which may indicate mutagenesis. Activities of pathological marker enzymes ALP, AST, ALT and CK increased significantly in serum of exposed fish. The ratio of ALT: AST in exposed fish was beyond 1 which indicates manifestation of pathological processes. These biomarkers show that fish have macrocytic hypochromic anemia. Leukocytosis showed general defence response against heavy metal toxicity and marker enzymes showed tissue degeneration. In conclusion, thermal power plant effluent has strong potential to induce micronuclei, tissue pathology, making the fish anemic, weak, stressed and vulnerable to diseases.
The objective of the present study was to determine the levels of essential nutrients (Na, K, Ca, Mg, Fe, Cu, Zn, Mn) and toxic metals (Pb and Cd) in selected varieties of fruits (banana, grape, guava, mandarin and orange), farmland soils and irrigation waters to assess nutritional impact on health. The freeze dried fruits were digested using HNO3 and HClO4 and the levels of the elements determined using flame atomic absorption spectrometer. The highest amount of K (3480) and Mg (281) and the lowest amount of Na (6.4) and Ca (75) µg/g were obtained in banana compared to other analyzed fruits. Cd was detected in guava (0.2 µg/g), orange (0.3 µg/g) and mandarin (0.1 µg/g), but not detected in banana and grape. Pb was not detected in all the fruits. Appreciable amount of total ascorbic acid was found in guava (1170 µg/g) compared to that of other fruits. Furthermore, farmland soils and irrigation waters were analyzed for the selected metals and physico-chemical properties of soils including pH, electrical conductivity, cation exchange capacity, texture and available phosphorus determined to elucidate factors controlling the availability of metals in fruits. Applying statistical packages, analysis of variances and Pearson correlation, links between metal levels in fruits and those in soil and water samples were evaluated.
Bioaugmentation-assisted phytoremediation implies the administration of selected plant growth promoting bacteria, which significantly improve plant growth and
 sequestration of heavy metals. In this work, 184 bacterial strains associated with roots of Pistacia lentiscus were isolated from plants spontaneously growing in the abandoned Sardinian mining areas (SW Sardinia, Italy) and phylogenetically characterised. Twenty-one bacterial isolates were assayed for properties relevant for plant growth promotion and metal tolerance. Five different strains, belonging to the genera Novosphingobium, Variovorax, Streptomyces, Amycolatopsis, Pseudomonas, were selected based on their properties for the greenhouse phytoremediation tests. Among the tested inocula, the strain Variovorax sp. RA128A, able to produce ACC deaminase and siderophore, was able to significantly enhance germination and increase length and weight of shoots and roots. Irrespective of the applied treatment, mastic shrub was able to accumulate Cd, Pb and Zn especially in roots.
The pathogenesis of Parkinson's disease (PD) is not completely understood, Zinc (Zn(2+) ) and dopamine (DA) have been shown to involve in the degeneration of dopaminergic cells. By microarray analysis, we identified Gadd45b as a candidate molecule that mediates Zn(2+) and DA-induced cell death; the mRNA and protein levels of Gadd45b are increased by Zn(2+) treatment and raised to an even higher level by Zn(2+) plus DA treatment. Zn(2+) plus DA treatment-induced PC12 cell death was enhanced when there was over-expression of Gadd45b and was decreased by knock down of Gadd45b. MAPK p38 and JNK signaling was able to cross-talk with Gadd45b during Zn(2+) and DA treatment. The synergistic effects of Zn(2+) and DA on PC12 cell death can be accounted for by an activation of the Gadd45b-induced cell death pathway and an inhibition of p38/JNK survival pathway. Furthermore, the in vivo results show that the levels of Gadd45b protein expression and phosphorylation of p38 were increased in the substantia nigra by the infusion of Zn(2+) /DA in the mouse brain and the level of Gadd45b mRNA is significantly higher in the substantia nigra of male PD patients than normal controls. The novel role of Gadd45b and its interactions with JNK and p38 will help our understanding of the pathogenesis of PD and help the development of future treatments for PD. Zinc and dopamine are implicated in the degeneration of dopaminergic neurons. We previously demonstrated that zinc and dopamine induced synergistic effects on PC12 cell death. Results from this study show that these synergistic effects can be accounted for by activation of the Gadd45b-induced cell death pathway and inhibition of the p38/JNK survival pathway. We provide in vitro and in vivo evidence to support a novel role for Gadd45b in the pathogenesis of Parkinson's disease.
Cigarette butts are the most common form of litter in the marine environment and represent potential point sources for environmental contamination. The metals leached from cigarette butts have not been studied well in the marine environment. In this study, the levels of metals (Cd, Fe, As, Ni, Cu, Zn and Mn) in cigarette butts were monitored at nine stations along the northern part of the Persian Gulf in Bushehr coastal areas in summer 2015 with a sampling time interval of 10 days. The Cd, Fe, As, Ni, Cu, Zn and Mn contents of cigarette butts were found to vary widely between 0.16 and 0.67 μg/g, 79.01 and 244.97 μg/g, 0.12 and 0.48 μg/g, 1.13 and 3.27 μg/g, 4.29 and 12.29 μg/g, 6.39 and 21.17 μg/g, and 38.29 and 123.1 μg/g, respectively. A Wilcoxon signed rank test showed that there were no significant differences between the Cd, Fe, As, Ni, Cu, Zn and Mn contents of cigarette butts at different sampling times. Considering the estimated number of cigarette butts littered annually, the results of this study indicated that considerable metals including Cd, Fe, As, Ni, Cu, Zn and Mn may enter the marine environment each year from cigarette litter alone.
The goal of this study was to investigate the effects of cupric citrate (CuCit) on growth performance, antioxidant indices, serum lipid metabolites, serum immune indices, and tissue residues of copper (Cu), zinc, and iron in weaned pigs. A total of 180 weaned pigs (Duroc×Landrace×Large White) with an average body weight of 8.98±1.21 kg were randomly assigned to a corn-soybean meal control ration, or 4 similar rations with 30, 60, 120 or 240 mg/kg Cu as CuCit. All diets contained 10 mg/kg Cu as cupric sulfate from the vitamin-mineral premix. The experiment was divided into two phases: 0 to 14 d (phase 1) and 15 to 28 d (phase 2). Results indicated that average daily gain (ADG; linearly, p<0.01) and average daily feed intake (ADFI; linearly and quadratically, p<0.05) were affected by an increase in CuCit during phase 2. Overall period, ADG (p<0.05) and ADFI (p<0.01) were linearly increased with increasing dietary levels of CuCit. Serum malondialdehyde concentrations (p<0.05) and glutathione peroxidase activity (p<0.01) linearly decreased and increased respectively with an increase in CuCit. Serum levels of Cu-Zn superoxide dismutase were linearly affected with an increase in CuCit (p<0.01). Hepatic malondialdehyde levels decreased with an increase in CuCit (linearly and quadratically, p<0.01). Serum total cholesterol concentrations were quadratically affected (p<0.05) and decreased in pigs fed Cu as CuCit at 60 and 120 mg/kg and increased in pigs fed 240 mg/kg Cu as CuCit. Serum high-density lipoprotein concentrations were linearly affected with an increase in CuCit (p<0.01). Serum IL-1β levels were quadratically affected (p<0.05) by dietary treatment. Compared with other treatments, 240 mg/kg Cu from CuCit quadratically increased hepatic (p<0.01) and renal (p<0.05) Cu concentrations, and quadratically decreased hepatic and renal iron concentrations (p<0.05). In conclusion, Cu administered in the form of CuCit at a dosage range of 30 to 60 mg/kg, effectively enhanced the growth performance and antioxidant status of weaned pigs.
This study aimed to evaluate the role of zinc (Zn)-supplemented with high cholesterol diet (HCD) on the serum and whole blood rheological properties of rabbits fed a HCD. Twenty-four New Zealand white rabbits were divided into three groups. The HCD group was fed a diet with 1.0% cholesterol and 1.0% olive oil. The HCD + Zn group was fed a diet with 1.0% cholesterol, 1.0% olive oil, and Zn. Blood viscosity, shear stress, and torque (%) were measured at shear rates ranging from 225 to 1875 s-1 for serum and 75-900 s-1 for whole blood. Serum viscosity and shear stress in HCD rabbits were significantly higher at all shear rates compared to controls; while whole blood viscosity and shear stress in HCD rabbits were significantly lower at all shear rates compared to controls. Viscosity and shear stress in both serum and whole blood from rabbits in the HCD + Zn group returned to normal values at all shear rates. The Zn supplemented to HCD rabbits, delays the progression of atherosclerosis. Changes in blood serum viscosity could reflect changes in non-clotting proteins, glucose, nutrients and trace elements; while changes in whole blood viscosity could result from changes in hematocrit, hemoglobin, and erythrocyte count. One of the factors responsible for increasing the serum viscosity values of HCD rabbits might be attributed to increase in Fe and decrease in Zn levels in the blood serum.
This study was undertaken in order to determine heavy metal contents in twelve (n = 12) henna brands and eleven (n = 11) kohl products. An analytical test was performed for Pb, Cd, Cu, and Zn in henna and kohl products using atomic absorption spectrophotometery. The overall mean concentrations of heavy metals in henna varied between 1.2 and 8.9 μg g(-1) for Pb; 0.8 and 18.6 μg g(-1) for Cd; 0.5 μg g(-1) and 3.3 μg g(-1) for Cu; and 3.7 μg g(-1) and 90.0 μg g(-1) for Zn. As for kohl products, Pb concentrations ranged between 51.1 μg g(-1) and 4839.5 μg g(-1), Cd concentrations ranged between 1.0 μg g(-1) and 158.6 μg g(-1), Cu concentrations ranged between 2.5 μg g(-1) and 162.5 μg g(-1), and Zn concentrations ranged between 0.7 μg g(-1) and 185.0 μg g(-1). The results of our study revealed that Pb, Cd, Cu, and Zn contents in investigated samples were high, making from the prolonged use of such products a potential threat to human health. Therefore, major quality controls are recommended in order to enforce acceptable limits of potential contaminants in cosmetics and good manufacturing practice.
Acute and chronic toxicity tests were conducted with sea cucumber (Apostichopus japonicus) exposed to heavy metals. Acute toxicity values (96 h LC50) were 2.697, 0.133, and 1.574 mg L(-1) for Zn, Cu, and Cd, respectively, and were ranked in order of toxicity: Cu > Cd > Zn. Under chronic metal exposure the specific growth rates of sea cucumbers decreased with the increase of metal concentration for all the three metals. After acute metal exposure, the oxygen consumption rate (OCR) decreased. The OCRs in all groups were significantly different than control (P < 0.05) except in the group treated with 1.00 mg L(-1) Zn (P < 0.05), where the increase of OCR was observed. The OCRs in groups chronically exposed to metals were significantly lower than that in the control group (P < 0.05). The activity of both pyruvate kinase (PK) and hexokinase (HK) in sea cucumbers followed: respiratory tree > muscle > intestine in natural sea water. After chronic Zn, Cu, and Cd exposure, the change pattern of HK and PK in respiratory tree, muscle, and intestine varied slightly. However, the activity of the enzyme showed a general trend of increase and then decrease and the higher the exposure concentration was, the earlier the highest point of enzyme activity was obtained.
The band gap width of the Be-doped ZnO correlates strongly with the distribution of the dopants. By performing first-principles calculations, it is found that
 an interstitial Be (Bei) atom preferably migrates in a basal plane. During the migration, such a Bei atom favorably bonds to a substituted Be (BeZn) atom, forming a new defect complex (2Be)Zn, showing a trend of aggregation of Be atoms in ZnO. Furthermore, the stability of the defect complex (2Be)Zn can be weakened by a substituted Mg (MgZn). So, the Mg impurities in Be-doped ZnO might suppress the aggregation of Be, so as to significantly improve the effect of the doped Be on modulating the band gap of ZnO.
Materials with high volume magnetization are perpetually needed for the generation of sufficiently large magnetic fields by writer pole of magnetic hard disks, especially for achieving increased areal density in storage media. In search of suitable materials combinations for this purpose, we have employed density functional theory to predict the magnetic coupling between iron and gadolinium layers separated by one to several monolayers of 3d transition metals (Sc-Zn). We demonstrate that it is possible to find ferromagnetic coupling for many of them and in particular for the early transition metals giving rise to high moment. Cr and Mn are the only elements able to produce a significant ferromagnetic coupling for thicker spacer layers. We also present experimental results on two trilayer systems Fe/Sc/Gd and Fe/Mn/Gd. From the experiments, we confirm a ferromagnetic coupling between Fe and Gd across a 3 monolayers Sc spacer or a Mn spacer thicker than 1 monolayer. In addition, we observe a peculiar dependence of Fe/Gd magnetic coupling on the Mn spacer thickness.
Spore counts, species composition and richness of arbuscular mycorrhizal fungi, and soil glomalin contents were evaluated in a soil contaminated with Zn, Cu, Cd and Pb after rehabilitation by partial replacement of the contaminated soil with non-contaminated soil, and by Eucalyptus camaldulensis planting with and without Brachiaria decumbens sowing. These rehabilitation procedures were compared with soils from contaminated non-rehabilitated area and non-contaminated adjacent soils. Arbuscular mycorrhizal fungi communities attributes were assessed by direct field sampling, trap culture technique, and by glomalin contents estimate. Arbuscular mycorrhizal fungi was markedly favored by rehabilitation, and a total of 15 arbuscular mycorrhizal fungi morphotypes were detected in the studied area. Species from the Glomus and Acaulospora genera were the most common mycorrhizal fungi. Number of spores was increased by as much as 300-fold, and species richness almost doubled in areas rehabilitated by planting Eucalyptus in rows and sowing B. decumbens in inter-rows. Contents of heavy metals in the soil were negatively correlated with both species richness and glomalin contents. Introduction of B. decumbens together with Eucalyptus causes enrichment of arbuscular mycorrhizal fungi species and a more balanced community of arbuscular mycorrhizal fungi spores in contaminated soil.
Herein, we demonstrate that Zn-MOF-74 enables the ultrafast and one-step generation of the Fe2O3@MOF composite once Zn-MOF-74 contacts with FeSO4 solution. This unique reaction can be further applied in catalysis of U(vi) reduction by Fe(ii) under ambient conditions. The results provide a highly renovated strategy for U(vi) reduction by Fe(ii) just under ambient conditions, which completely subvert all established methods about U(vi) reduction by Fe(ii) in which O2- and CO2-free conditions are absolutely required.
Drought-breaking floods pose a risk to coastal water quality as sediments, nutrients, and pollutants stored within catchments during periods of low flow are mobilized and delivered to coastal waters within a short period of time. Here we use subtidal surface sediment surveys and sediment cores to explore the effects of the 2011 Brisbane River flood on trace metals zinc (Zn), lead (Pb), copper (Cu), nickel (Ni), chromium (Cr), manganese (Mn), and phosphorus (P) deposition in Moreton Bay, a shallow subtropical bay in eastern Australia. Concentrations of Zn, Cu, and Pb in sediments in central Moreton Bay derived from the 2011 flood were the highest yet observed in the Bay. We suggest flushing of metal rich sediments which had accumulated on the Brisbane River floodplain and in its estuary during the preceding 10 to 40years of low flows to be the primary source of this increase. This highlights the importance of intermittent high magnitude floods in tidally influenced rivers in controlling metal transport to coastal waters in subtropical regions.
Cattle grazing in wet riparian pastures may influence nutrient dynamics due to nutrient deposition in feces and urine, soil compaction, and vegetation loss. We conducted a lab incubation study with a saline-sodic riparian soil to study nutrient (N, P, S, Fe, Mn, Cu, and Zn) dynamics in soil pore water using Plant Root Simulator (PRS) probes and release of nutrients into the overlying ponded water during flooding. The treatment factors were organic amendment (manure, roots, and unamended control), compaction (compacted, uncompacted), and burial time (3, 7, and 14 d). Amendment treatment had the greatest impact on nutrient dynamics, followed by burial time, whereas compaction had little impact. The findings generally supported our hypothesis that organic amendments should first increase nitrate loss, then increase Mn mobility, then Fe mobility and associated release of P, and finally increase sulfate loss. Declines in nitrate due to amendment addition were small because nitrate was at low levels in all treatments due to high denitrification potential instead of being released to soil pore water or overlying water. Addition of organic amendment strongly increased Mn and Fe concentrations in overlying water and of adsorbed Fe on PRS probes but only increased Mn on PRS probes on Day 3 due to subsequent displacement from ion exchange membranes. Transport of P to overlying water was increased by organic amendment addition but less so for manure than roots despite higher P on PRS probes. The findings showed that saline-sodic soils in riparian zones are generally a nutrient source for P and are a nutrient sink for N as measured using PRS probes after 3 to 7 d of flooding.
Land application of biosolids is an effective means of recycling plant nutrients and is the primary method of biosolids reuse endorsed by the USEPA. One issue concerning biosolids application is the extent of the contribution of biosolids-borne plant nutrients to the overall crop concentration and uptake or removal of these nutrients. We studied the effects of biosolids application on wheat ( L.) grain P, Zn, Cu, Fe, and Ni concentrations and uptake (removal) at two dryland agroecosystem sites from 1993 to 2014. We hypothesized that biosolids would have the greatest impact on wheat grain and uptake compared with ammonium bicarbonate-diethylenetriaminepentaacetic acid (AB-DTPA)-extractable nutrient levels, soil pH, or soil organic C concentrations. We used path analyses in combination with multiple linear regression to differentiate the direct, indirect, and total effects of cumulative biosolids applications, soil AB-DTPA, soil pH, and organic C. Biosolids rates, applied biennially from 1993 to 2014 at the beginning of a wheat-fallow rotation, were 0, 2.24, 4.48, 6.72, 8.96, and 11.2 Mg ha. None of the parameters had significant direct, indirect, or total effects on grain concentrations. Biosolids applications had the greatest positive direct impact compared with AB-DTPA levels, soil pH, or soil organic C on P, Zn, Fe, and Ni uptake (removal), whereas AB-DTPA had the greatest positive direct impact on Cu uptake. Soil AB-DTPA, pH, and organic C directly affected some grain concentrations and cumulative uptake, but no consistent trends were noted. This pathway approach allowed differentiation between causation and simple correlation for the effects of cumulative biosolids applications on wheat P, Zn, Cu, Fe, and Ni cumulative uptake but did not provide these same results for grain concentrations.
The distribution of trace elements (TEs) in water, sediment, riparian soil and dominant plants was investigated in the Fenghe River, Northwestern China. The Fenghe River ecosystem was polluted with Cd, Cr, Hg and Pb. There was a high pollution risk in the midstream and downstream regions and the risk level for Cd was much higher than that of the other elements. The average values of bioconcentration coefficient for Cd and Zn were 2.21 and 1.75, respectively, indicating a large accumulation of Cd and Zn in the studied species. With broad ecological amplitudes, L. Levl. et Vant. Trin., and L. had the greatest TE concentrations in aboveground and belowground biomass of the studied species and were potential biomonitors or phytoremediators for the study area. Multivariate techniques including cluster analysis, correlation analysis, principal component analysis, and canonical correspondence analysis were used to analyze the relations between TE concentrations in plants and various environmental factors. The soil element concentration is the main factor determining the accumulation of TEs in plants. The co-release behavior of common pollutants and TEs drove the accumulation of Hg, Cd, and As in the studied plants. Significant enrichment of some elements in the Fenghe River has led to a decline in the biodiversity of plants.
The present study was to find out the expression pattern and relative expression level of apoptotic (Bcl2, Bax, Casp3, and PCNA) and antioxidant enzyme [(GPx, Cu/Zn-SOD (SOD1) and Mn-SOD (SOD2)] genes in sheep oocytes and developing embryos produced in vitro by conventional RT-PCR and real time qPCR, respectively. Different developmental stages of embryos were produced in vitro from oocytes collected from local slaughter house ovaries. RT-PCR amplicons showed expression of Bcl2
 and PCNA in all stages except at morula. In contrast Bax and Casp3 were expressed in all stages. GPx and SOD1 were expressed in all stages but SOD2 was not expressed in 8-16 cells, although expressed in the remaining stages. The qPCR analysis reflected that Bcl2 expression was significantly (P < 0.05) downregulated in morula and maximum upregulated expression was observed in in vitro matured oocytes. Higher upregulated expression (P < 0.05) of Bax was in morula and downregulated expression was at 2-4 cells. Casp3 was significantly upregulated at 8-16 cells and downregulated in in vitro matured oocyte. PCNA expression was highest at blastocyst and least expression was at morula. GPx was expressed significantly highest in matured oocytes and least expression was at zygote. SOD1 was expressed significantly highest at 8-16 cells and least expression was at zygote. Expression of SOD2 was least among all the antioxidant enzymes but significantly higher expression of SOD2 was in immature oocyte; however, least expression was at 8-16 cells. It can be concluded from the study that the sheep embryos produced in vitro are highly sensitive to culture condition, which alters the expression level of apoptotic and antioxidant enzyme genes.
Cadmium (Cd) has recently emerged as a major concern not only in environmental toxicology but also in metabolic diseases such as diabetes mellitus and its complications. Conflicting data aside, these studies have not been examined in a clinical population undergoing management as well as possible modulation by the prominent metabolic antagonist of Cd such as zinc (Zn). This study examined the relationship between cadmium levels, glycemic control, and renal pathology in established type II diabetic patients with focus on populations exposed to modern environmental health hazards (MEHHs). Sixty-five participants, consisting of 45 type-2 diabetics and 20 non-diabetics were enrolled for the study, mean age 61.51 ± 5.27 years. Glycated hemoglobin (HbA1c) was used to classify them into three sub-groups: (A) good glycemic control (44.4%), (B) fair glycemic control (24.4%), and (C) poor glycemic control (31.1%). Plasma levels of glucose, Cd, Zn, HbA1c, creatinine, urinary creatinine, microalbuminuria, and estimated glomerular filtration rate (eGFR) were determined in all participants using standard methods. Fasting plasma glucose was higher in diabetics than in non-diabetics (p = 0.000) as well as Zn level, though not significantly. Interestingly, Cd level, Cd/Zn ratio, and urinary creatinine were significantly lower in diabetics than in non-diabetics. The group with poor glycemic control (C) had significantly higher Cd level compared to the one with good glycemic control (group A). The renal function revealed that microalbuminuria and urinary albumin/creatinine ratio (UACR) was significantly higher in diabetics than in non-diabetics, while eGFR was found to be similar in both diabetics and non-diabetics. UACR inversely correlated with Cd level, while plasma creatinine level positively correlated with Cd but not significantly. Correlation between Cd and HbA1c revealed non-significant inverse correlation (r = -0.007; p > 0.05), while Zn showed a significant inverse correlation with Cd (r = -0.317; p < 0.014). The lower Cd level in diabetics compared to non-diabetics probably reflects the modulating effect of Zn in treated diabetics given nutritional education in addition to their regular regime, including good sources of Zn. The renal insufficiency with increasing Cd level may suggest that the progression of renal impairment may not be responsive to the putative modulating effect of Zn.
Tumor necrosis factor (TNF)-α is a well-known pro-inflammatory cytokine. Increased expression of Tnf-α is a feature of inflammatory lung diseases, such as asthma, emphysema, fibrosis, and smoking-induced chronic obstructive pulmonary disease (COPD). Using a mouse line with lung-specific Tnf-α overexpression (SPC-TNF-α) to mimic TNF-α-associated lung diseases, we investigated the role of chronic inflammation in the homeostasis of lung trace elements. We performed a quantitative survey of micronutrients and biometals, including copper (Cu), zinc (Zn), and selenium (Se), in the transgenic mice tissues. We also examined the expression of Cu-dependent proteins in the inflammatory lung tissue to determine whether they were affected by the severe Cu deficiency, including cuproenzymes, Cu transporters, and Cu chaperones. We found consistent lung-specific reduction of the metal Cu, with a mean decrease of 70%; however, Zn and Se were unaffected in all other tissues. RT-PCR showed that two Cu enzymes associated with lung pathology were downregulated: amine oxidase, Cu containing 3 (Aoc3) and lysyl oxidase (Lox). Two factors, vascular endothelial growth factor (Vegf) and focal adhesion kinase (Fak), related with Cu deficiency treatment, showed decreased expression in the transgenic inflammatory lung. We concluded that Cu deficiency occurs following chronic TNF-α-induced lung inflammation and this likely plays an essential role in the inflammation-induced lung damage. These results suggest the restoration of lung Cu status as a potential strategy in both treatment and prevention of chronic lung inflammation and related disorders.
The Sinorhizobium meliloti (S. meliloti) strain CCNWSX0020 displayed tolerance to high levels exposures of multiple metals and growth promotion of legume plants grown in metal-contaminated soil. However, the mechanism of metal-resistant strain remains unknown. We used five P1B-ATPases deletions by designating as ∆copA1b, ∆fixI1, ∆copA3, ∆zntA and ∆nia, respectively to investigate the role of P1B-ATPases in heavy metal resistance of S. meliloti. The ∆copA1b and ∆zntA mutants were sensitive to zinc (Zn), cadmium (Cd) and lead (Pb) in different degree, whereas the other mutants had no significant influence on the metal resistance. Moreover, the expression of zntA was induced by Zn, Cd and Pb whereas copA1b was induced by copper (Cu) and silver (Ag). This two deletions could led to the increased intracellular concentrations of Zn, Pb and Cd, but not of Cu. Complementation of ∆copA1b and ∆zntA mutants showed a restoration of tolerance to Zn, Cd and Pb to a certain extent. Taken together, the results suggest an important role of copA1b and zntA in Zn homeostasis and Cd and Pb detoxification in S. meliloti CCNWSX0020.
Atherosclerosis is a chronic inflammatory disease responsible for the majority of cases of myocardial infarction and ischemic stroke. The electronegative low-density lipoprotein, a modified subfraction of native LDL, is pro-inflammatory and plays an important role in atherogenesis. To investigate the effects of a nanoformulation (scFv anti-LDL(-)-MCMN-Zn) containing a scFv reactive to LDL(-) on the inhibition of atherosclerosis, its toxicity was evaluated in vitro and in vivo and further it was also administered weekly to LDL receptor knockout mice. The scFv anti-LDL(-)-MCMN-Zn nanoformulation did not induce cell death in RAW 264.7 macrophages and HUVECs. The 5mg/kg dose of scFv anti-LDL(-)-MCMN-Zn did not cause any typical signs of toxicity and it was chosen for the evaluation of its atheroprotective effect in Ldlr(-/-) mice. This nanoformulation significantly decreased the atherosclerotic lesion area at the aortic sinus, compared with that in untreated mice. In addition, the Il1b mRNA expression and CD14 protein expression were downregulated in the atherosclerotic lesions at the aortic arch of Ldlr(-/-) mice treated with scFv anti-LDL(-)-MCMN-Zn. Thus, the scFv anti-LDL(-)-MCMN-Zn nanoformulation inhibited the progression of atherosclerotic lesions, indicating its potential use in a future therapeutic strategy for atherosclerosis.
Structural equation models (SEM) are increasingly used in ecology as multivariate analysis that can represent theoretical variables and address complex sets of hypotheses. Here we demonstrate the interest of SEM in ecotoxicology, more precisely to test the three-step concept of metal bioavailability to earthworms. The SEM modeled the three-step causal chain between environmental availability, environmental bioavailability and toxicological bioavailability. In the model, each step is an unmeasured (latent) variable reflected by several observed variables. In an exposure experiment designed specifically to test this SEM for Cd, Pb and Zn, Aporrectodea caliginosa was exposed to 31 agricultural field-contaminated soils. Chemical and biological measurements used included CaC12-extractable metal concentrations in soils, free ion concentration in soil solution as predicted by a geochemical model, dissolved metal concentration as predicted by a semi-mechanistic model, internal metal concentrations in total earthworms and in subcellular fractions, and several biomarkers. The observations verified the causal definition of Cd and Pb bioavailability in the SEM, but not for Zn. Several indicators consistently reflected the hypothetical causal definition and could thus be pertinent measurements of Cd and Pb bioavailability to earthworm in field-contaminated soils. SEM highlights that the metals present in the soil solution and easily extractable are not the main source of available metals for earthworms. This study further highlights SEM as a powerful tool that can handle natural ecosystem complexity, thus participating to the paradigm change in ecotoxicology from a bottom-up to a top-down approach.
The structure-activity and structure-kinetic relationships of a series of novel and selective ortho-aminoanilide inhibitors of histone deacetylases (HDACs) 1 and 2 are described. Different kinetic and thermodynamic selectivity profiles were obtained by varying the moiety occupying an 11Å channel leading to the Zn(2+) catalytic pocket of HDACs 1 and 2, two paralogs with a high degree of
 structural similarity. The design of these novel inhibitors was informed by two ligand-bound crystal structures of truncated hHDAC2. BRD4884 and BRD7232 possess kinetic selectivity for HDAC1 versus HDAC2. We demonstrate that the binding kinetics of HDAC inhibitors can be tuned for individual isoforms in order to modulate target residence time while retaining functional activity and increased histone H4K12 and H3K9 acetylation in primary mouse neuronal cell culture assays. These chromatin modifiers, with tuned binding kinetic profiles, can be used to define the relation between target engagement requirements and the pharmacodynamic response of HDACs in different disease applications.
Controlling the topologies of polymers is a hot topic in polymer chemistry because the physical and/or chemical properties of polymers are determined (at least partially) by their topologies. This study exploits the host-guest interactions between dibenzo-24-crown-8 and secondary ammonium salts and metal coordination interactions between 2,6-bis(benzimidazolyl)-pyridine units with metal ions (Zn(II) and/or Eu(III) ) as orthogonal non-covalent interactions to prepare supramolecular polymers. By changing the ratios of the metal ion additives (Zn(NO3 )2 and Eu(NO3 )3 ) linkers to join the host-guest dimeric complex, the linear supramolecular polymers (100 mol% Zn(NO3 )2 per ligand) and hyperbranched supramolecular polymers (97 mol% Zn(NO3 )2 and 3 mol% Eu(NO3 )3 per ligand) are separately and successfully constructed. This approach not only expands topological control over polymeric systems, but also paves the way for the functionalization of smart and adaptive materials.
The effects of an abandoned mining area, exploited for centuries in the mining district of Cartagena-La Union, result in a continuous supply of heavy metals into the Mar Menor coastal lagoon after rain episodes. As a consequence, concentration of trace elements in water column and sediments of this ecosystem is usually higher than in other areas. For monitoring ecosystem health, this study assessed the ability of Rhizostoma pulmo to bioaccumulate trace elements. A total of 57 individuals were sampled at eight different sampling stations during the summer of 2012. Although the concentrations of different analyzed elements (Al, Ti, Cr, Mn, Fe, Ni, Cu, Zn, As, Cd, Sn, and Pb) were moderate, bioconcentration levels in relation to seawater metal concentration were extremely high. In any case, the use or disposal of these organisms should consider their metal content, because of their potential environmental and health implications.
Urban fugitive dust PM2.5 samples were collected in 11 selected cities in North China, and 9 ions (SO4(2-), NO3(-), Cl(-), F(-), Na(+), NH4(+), K(+), Mg(2+), and Ca(2+)) and 22 elements (Si, Al, S, Cl, K, Ca, Ti, V, Cr, Mn, Fe, Co, Ni, Cu, Zn, Br, Rb, Sr, Sn, Sb, Ba, and Pb) were determined to investigate chemical profiles of PM2.5. The coefficient of divergence (CD) was used to compare the similarities of the chemical profiles for fugitive dust among three regions in North China, and the results showed that their composition are quite similar. Total water soluble ions occupied 9.3% and 10.0% on average of road dust and construction dust, respectively, indicating that most of the materials in urban fugitive dust samples were insoluble. Ca(2+) was the most abundant cation and SO4(2-) dominated in anions. Soil dust loading was calculated to occupy 70.8% and 83.6% in road dust and construction dust, respectively. Ca, Si, Fe, and Al were the most abundant elements in all the samples, and Ca was absolutely the most abundant specie among the 22 detected elements in construction dust samples. Chemical species ratios were used to highlight the characteristics of urban fugitive dust by comparing with other types of aerosols. High Ca/Al ratio was a good marker to distinguish urban fugitive dust from Asian dust and Chinese loess. In addition, low K(+)/K and NO3(-)/SO4(2-), and high Zn/Al and Pb/Al ratios were good indicators to separate urban fugitive dust from desert dust, Chinese loess, or urban PM2.5 samples.
A Au(III)-catalyzed regiospecific hydration of N-(diphenylphosphinoyl)propargyl amines has been developed to produce various β-amino ketones. These reactions are conducted in the presence of NaAuCl4·2H2O (10 mol %) in a mixed solvent of EtOH/H2O/CH2Cl2 (4:1:1) at room temperature to give the products in 45-71% yield. The high enantiomeric purity of a chiral N-(diphenylphosphinoyl)propargyl amine (85% ee) is maintained after hydration, which makes this method useful for the asymmetric synthesis of chiral β-amino ketones. Reduction of a β-amino ketone product with Zn(BH4)2 gives a 1,3-amino alcohol with modest diastereoselectivity.
Xenobiotics such as organochlorine compounds (OCs) and metals have been suggested to play a significant role in the collapse of European eel stocks in the last decades. Several of these pollutants could affect functioning of the nervous system. Still, no information is so far available on levels of potentially neurotoxic pollutants in eel brain. In present study, carried out on female eels caught in Belgian rivers and canals, we analyzed brain levels of potentially-neurotoxic trace elements (Ag, Al, As, Cd, Co, Cr, Cu, Fe, Hg, MeHg, Mn, Ni, Pb, Sn, Sb, Zn) and OCs (Polychlorinated biphenyls, PCBs; Hexachlorocyclohexanes, HCHs; Dichlorodiphenyltrichloroethane and its metabolites, DDTs). Data were compared to levels in liver and muscle tissues. Eel brain contained very high amounts of OCs, superior to those found in the two other tissues. Interestingly, the relative abundance of PCB congeners markedly differed between tissues. In brain, a predominance of low chlorinated PCBs was noted, whereas highly chlorinated congeners prevailed in muscle and liver. HCHs were particularly abundant in brain, which contains the highest amounts of β-HCH and ϒ-HCH. p,p'-DDTs concentration was similar between brain and muscle (i.e., about twice that of liver). A higher proportion of p,p'-DDT was noticed in brain. Except for Cr and inorganic Hg, all potentially neurotoxic metals accumulated in brain to levels equal to or lower than hepatic levels. Altogether, results indicate that eel brain is an important target for organic and, to a lesser extent, for inorganic neurotoxic pollutants.
We have previously demonstrated that in Acidithiobacillus ferrooxidans, resistance to the highly toxic divalent cation Cd(2+) is mediated in part by the sulfur assimilation pathway (SAP) and enhanced intracellular concentrations of cysteine and glutathione(GSH) (Zheng et al., Extremophiles 19:429-436, 2015). In this paper, we investigate the interplay between Zn(2+) and Pb(2+) resistances, SAP gene expression, and thiol-containing metabolite levels. Cells grown in the presence of 300 mM Zn(2+) had enhanced activities of the following enzymes: adenosylphosphosulphate reductase (APR, 40-fold), serine acetyltransferase (SAT, 180-fold), and O-acetylserine (thiol) lyase (OAS-TL, 230-fold). We investigated the concentrations of mRNA transcripts of the genes encoding these enzymes in cells grown in the presence of 600 mM Zn(2+): transcripts for 4 SAP genes-ATPS(ATP sulphurylase), APR, SiR(sulfite reductase), SAT, and OAS-TL-each showed a more than three-fold increase in concentration. At the metabolite level, concentrations of intracellular cysteine and glutathione (GSH) were nearly doubled. When cells were grown in the presence of 10 mM Pb(2+), SAP gene transcript concentrations, cysteine, and GSH concentrations were all decreased, as were SAP enzyme activities. These results suggested that Zn(2+) induced SAP pathway gene transcription, while Pb(2+) inhibited SAP gene expression and enzyme activities compared to the pathway in most organisms. Because of the detoxification function of thiol pool, the results also suggested that the high resistance of A. ferrooxidans to Zn(2+) may also be due to regulation of GSH and the cysteine synthesis pathway.
The study evaluates the health risk caused by heavy metals to the inhabitants of a gold mining area. In this study, 56 soil samples from five mine tailings and 17 from two mine villages were collected and analyzed for Asernic (As), Lead (Pb), Mercury (Hg), Cadmium (Cd), Chromium (Cr), Cobalt (Co), Nickel (Ni), Copper (Cu) and Zinc (Zn) using ICP-MS. Measured concentrations of these heavy metals were then used to calculate the health risk for adults and children. Their concentrations were such that Cr > Ni > As > Zn > Cu > Co > Pb > Hg > Cd, with As, Cr and Ni higher than permissible levels. For the adult population, the Hazard Index value for all pathways was found to be 2.13, making non-carcinogenic effects significant to the adult population. For children, the Hazard Index value was 43.80, a value >1, which poses serious non-carcinogenic effect to children living in the gold mining area. The carcinogenic risk was found to be 1.7 × 10(-4) implying that 1 person in every 5882 adults may be affected. In addition, for children, in every 2725 individuals, 1 child may be affected (3.67 × 10(-4)). These carcinogenic risk values were both higher than acceptable values.
The metropolitan area of the Toluca Valley (MATV) extends over an area of 1208.55 km(2) and has 1,361,500 inhabitants making it the fifth highest populated area in the country and the second highest in the state. The MATV has several environmental problems, with regards to the air quality. Particles PM10 and PM2.5 are considered to be the main pollutant due to these particles frequently exceeding the limit laid down in the standards of the air quality in the country. For this reason, samples of the mosses Fabriona ciliaris and Leskea angustata were collected at different sites in MATV, Mexico in order to establish the atmospheric deposition of heavy metals by means of
 the analysis of the mosses tissues. Results show the average metal concentrations in the mosses in the order of: Zn > Pb > Cr > Cd. The concentration capacities of heavy metals were higher in Fabriona ciliaris than Leskea angustata. Enrichment factors for Cr, Zn, Pb and Cd were obtained using the soils from the same sampling area. Enrichment factors results show that Cr is conservative in both sampling seasons with a terrigenous origin; Zn is moderately enriched in both sampling seasons and mainly associated to pedological-soil or substrate contribution and anthropogenic activities and Cd is highly enriched in the rainy season and Pb is highly enriched in both sampling seasons, with a predominantly anthropogenic origin. This study provides information to be considered in the strategies for similar environmental problems in the world.
The main goal of this paper is to identify the drivers responsible for the high particulate matter concentrations observed in recent years in several urban areas in Poland. The problem was investigated using air quality and meteorological data from routine monitoring network, air mass back trajectories and multivariate statistical modelling. Air pollution in central and southern part of the country was analysed and compared with this in northern-eastern "The Green Lungs of Poland" region. The analysis showed that in all investigated locations, there is a clear annual cycle of observed concentrations, closely following temperature-heating cycles, with the highest concentrations noted in January. However, the main drivers differ along the country, being either connected with regional background pollution (in the central part of the country) or with local emission sources (in the southern part). The occurrence of high PM10 concentrations is most commonly associated with the influence of high-pressure systems that brought extremely cold and stable air masses form East or South of Europe. During analysed episodes, industrial point sources had the biggest (up to 70-80 %) share in PM10 levels on the days with maximum PM pollution, while remote and residential/traffic sources determined the air quality in the early stages of the episodes. Principal component analysis (PCA) shows that secondary inorganic aerosols account for long-range transported pollution, As, Cd, Pb and Zn for industrial point sources, while Cr and Cu for residential and traffic sources of PM10, respectively.
Within the HarvestPlus program there are many collaborators currently using X-Ray Fluorescence (XRF) spectroscopy to measure Fe and Zn in their target crops. In India, five HarvestPlus wheat collaborators have laboratories that conduct this analysis and their throughput has increased significantly. The benefits of using XRF are its ease of use, minimal sample preparation and high throughput analysis. The lack of commercially available calibration standards has led to a need for alternative calibration arrangements for many of the instruments. Consequently, the majority of instruments have either been installed with an electronic transfer of an original grain calibration set developed by a preferred lab, or a locally supplied calibration. Unfortunately, neither of these methods has been entirely successful. The electronic transfer is unable to account for small variations between the instruments, whereas the use of a locally provided calibration set is heavily reliant on the accuracy of the reference analysis method, which is particularly difficult to achieve when analyzing low levels of micronutrient. Consequently, we have developed a calibration method that uses non-matrix matched glass disks. Here we present the validation of this method and show this calibration approach can improve the reproducibility and accuracy of whole grain wheat analysis on 5 different XRF instruments across the HarvestPlus breeding program.
Reverse transcription quantitative PCR (RT-qPCR) as the accurate and sensitive method is use for gene expression analysis, but the veracity and reliability result depends on whether select appropriate reference gene or not. To date, several reliable reference gene validations have been reported in fruits trees, but none have been done on preharvest and postharvest longan fruits. In this study, 12 candidate reference genes, namely, CYP, RPL, GAPDH, TUA, TUB, Fe-SOD, Mn-SOD, Cu/Zn-SOD, 18SrRNA, Actin, Histone H3, and EF-1a, were selected. Expression stability of these genes in 150 longan samples was evaluated and analyzed using geNorm and NormFinder algorithms. Preharvest samples consisted of seven experimental sets, including different developmental stages, organs, hormone stimuli (NAA, 2,4-D, and ethephon) and abiotic stresses (bagging and girdling with defoliation). Postharvest samples consisted of different temperature treatments (4 and 22°C) and varieties. Our findings indicate that appropriate reference gene(s) should be picked for each experimental condition. Our data further showed that the commonly used reference gene Actin does not exhibit stable expression across experimental conditions in longan. Expression levels of the DlACO gene, which is a key gene involved in regulating fruit abscission under girdling with defoliation treatment, was evaluated to validate our findings. In conclusion, our data provide a useful framework for choice of suitable reference genes across different experimental conditions for RT-qPCR analysis of preharvest and postharvest longan fruits.
Though rice is the predominant source of energy and micronutrients for more than half of the world population, it does not provide enough zinc (Zn) to match human nutritional requirements. Moreover, climate change, particularly rising atmospheric carbon dioxide concentration, reduces the grain Zn concentration. Therefore, rice biofortification has been recognized as a key target to increase the grain Zn concentration to address global Zn malnutrition. Major bottlenecks for Zn biofortification in rice are identified as low Zn uptake, transport and loading into the grain; however, environmental and genetic contributions to grain Zn accumulation in rice have not been fully explored. In this review, we critically analyze the key genetic, physiological and environmental factors that determine Zn uptake, transport and utilization in rice. We also explore the genetic diversity of rice germplasm to develop new genetic tools for Zn biofortification. Lastly, we discuss the strategic use of Zn fertilizer for developing biofortified rice.
This study was aimed to establish the elemental profiling and provenance of coffee samples collected from eleven major coffee producing regions of Ethiopia. A total of 129 samples were analyzed for forty-five elements using inductively coupled plasma (ICP)-optical emission spectroscopy (OES), ICP-mass spectrometry (MS) and direct mercury analyzer (DMA). Among the macro elements, K showed the highest levels whereas Fe was found to have the lowest concentration values. In all the samples, Ca, K, Mg, P and S contents were statistically significant (p<0.05). Micro elements showed the concentrations order of: Mn>Cu>Sr>Zn>Rb>Ni>B. Contents of the trace elements were lower than the permissible standard values. Inter-regions differentiation by cluster analysis (CA), linear discriminant analysis (LDA) and principal component analysis (PCA) showed that micro and trace elements are the best chemical descriptors of the analyzed coffee samples.
To evaluate the potential of cooked field peas to be used in Zn biofortification programs, all combinations of soil Zn application of 0, 4 and 8mgZnSO4·7H2Okg(-1) and foliar Zn application of 0 and two sprays of 0.25% or 0.5% (w/v) ZnSO4·7H2O before flowering and at early grain-filling stage were tested. Soil Zn application increased Zn-DTPA concentration 3.7- to 5.6-times depending on the Zn soil treatments. Grain Zn concentrations higher than 60mgZnkg(-1) were obtained with all foliar Zn applications, alone or in combination with soil Zn applications, and grain Zn bioavailability was adequate (phytate:Zn ratios lower than 15). Processing (freezing and cooking) caused a decrease of about 30% in grain Zn concentration and a 17%-increase in phytate:Zn ratios (to ⩽9.5). The combined application of 8mgZnSO4·7H2Okg(-1) soil+0.25% (w/v) ZnSO4·7H2O foliarly could be a good option for biofortifying field peas.
Although pregnant women are required to increase food and nutrient intake to accommodate for the increased nutritional demands, information on dietary behaviour and nutrient intake is limited. This study aimed to identify the adequacy and differences in intake between pregnant and non-pregnant women in a rural community of Butajira district, Southern Ethiopia. Simple random sampling was used to recruit 159 pregnant and 164 non-pregnant women. An interactive multiple pass 24-h recall survey was used to evaluate the food and nutrient intake of the study participants. Except for iron, vitamin A and C, intakes of macro and micronutrient were below the recommendations. Almost all study participants were deficient in energy, protein, calcium, folate and niacin intakes. There was no significant difference in the mean dietary intake of all nutrients between pregnant and non-pregnant women (p > 0.05). The prevalence of inadequacy was comparable between pregnant and non-pregnant women in all of the nutrient intakes except for Zn, where the prevalence of inadequacy was much higher among the pregnant women. Nearly all (99.0%) of the pregnant women were deficient in niacin, folate and calcium. Although all pregnant women considered it important to increase food intake during pregnancy, only a quarter of women reported to do so. In conclusion, pregnant women in the rural community of Butajira district do not make significant dietary intake adjustments to account for increased nutrient needs during
 pregnancy. In food insecure areas, such as ours, nutritional counselling complemented with supplementary feeding programmes could be key to ensure adequate dietary intake. © 2016 Blackwell Publishing Ltd.
The binding of drugs to metalloenzymes is an intricate process that involves several interactions, including binding of the drug to the enzyme active site metal, as well as multiple interactions between the drug and the enzyme residues. In order to determine the free energy contribution of Zn(2+) binding by known metalloenzyme inhibitors without the other interactions, valid active site zinc structural mimetics must be formed and binding studies need to be performed in biologically relevant conditions. The potential of each of five ligands to form a structural mimetic with Zn(2+) was investigated in buffer using Isothermal Titration Calorimetry (ITC). All five ligands formed strong 1 : 1 (ligand : Zn(2+)) binary complexes. The complexes were used in further ITC experiments to study their interaction with 8-hydroxyquinoline (8-HQ) and/or acetohydroxamic acid (AHA), two bidentate anionic zinc-chelating enzyme inhibitors. It was found that tetradentate ligands were not suitable for creating zinc structural mimetics for inhibitor binding in solution due to insufficient coordination sites remaining on Zn(2+). A stable binary complex, [Zn(BPA)](2+), which was formed by a tridentate ligand, bis(2-pyridylmethyl)amine (BPA), was found to bind one AHA in buffer or a methanol : buffer mixture (60 : 40 by volume) at pH 7.25 or one 8-HQ in the methanol : buffer mixture at pH 6.80, making it an effective structural mimetic for the active site of zinc metalloenzymes. These results are consistent with the observation that metalloenzyme active site zinc ions have three residues coordinated to them, leaving one or two sites open for inhibitors to bind. Our findings indicate that Zn(BPA)X2 can be used as an active site structural mimetic for zinc metalloenzymes for estimating the free energy contribution of zinc binding to the overall inhibitor active site interactions. Such use will help aid in the rational design of inhibitors to a variety of zinc metalloenzymes.
PM2.5 has become an important environmental issue in Taiwan during the past few years. Moreover, electricity increased significantly during the summertime and TTPP generated by coal burning base is the main electricity provider in central Taiwan. Therefore, summer season has become the main research target in this study. The ambient air concentrations of particulate matter PM2.5 and PM10 collected by using VAPS at a mixed characteristic sampling site were studied in central Taiwan. The results indicated that the average daytime PM2.5 and PM10 particulate concentrations were occurred in May and they were 44.75 and 57.77 µg/m(3) in this study. The results also indicated that the average nighttime PM2.5 and PM10 particulate concentrations were occurred in June and they were 38.19 and 45.79 µg/m(3) in this study. The average PM2.5/PM10 ratios were 0.7 for daytime, nighttime and 24-h sampling periods in the summer for this study. This value was ranked as the lowest ratios when compared to the other seasons in previous study. Noteworthy, the results further indicated that the metallic element Pb has the mean highest concentrations for 24-h, daytime and nighttime sampling periods when compared to those of the other metallic elements (Ni, Cu, Zn and Cd). The average mean highest metallic Pb concentrations in PM10 were 110.7, 203.0 and 207.2 ng/m(3) for 24-h, daytime and nighttime sampling periods in this study. And there were 59.53, 105.2 and 106.6 ng/m(3) for Pb in PM2.5 for 24-h, daytime and nighttime sampling periods, respectively. Moreover, the results further indicated that mean metallic element Pb concentrations on PM2.5 and PM10 were all higher than those of the other elements for 24 h, day and nighttime.
Studies on leaching behavior of metals associated with coal fly ash (FA) are of great concern because of possible contamination of the aquatic environment. In the present study, leaching behavior of metals (As, Se, Cr, Pb, V, Zn, etc.) in two different FA samples (FA1 and FA2) was investigated at various pH (2-12), temperatures of leachate solution and using TCLP. At pH 2, the highest leaching was observed for Fe (21.6 and 32.8 µg/g), whereas at pH 12, Arsenic was found to have the highest leaching (1.5 and 2.4 µg/g) in FA1 and FA2. Leachate solution temperature showed a positive effect on the metal's leachability. In TCLP, most of the metal's leachability was observed to be higher than that of batch leaching tests. The present study suggests that, leaching of As and Se from FA samples can moderately affect ground/surface water quality at the study locations.
Parkinsonia aculeata L. (Caesalpiniaceae) is a traditional ethnomedicine and has been used for the empiric treatment of hyperglycemia, without scientific background. Mechanistic analyses at molecular level from the antioxidant mechanism observed by P. aculeata are required. Herein the effects of the treatment by hydroethanolic extract partitioned with ethyl acetate of P. aculeata aerial parts (HEPa/EtOAc) in mice fed a high-fat diet that share many obesity phenotypes with humans were evaluated. The animals were treated orally with HEPa/EtOAc (125 and 250 mg/kg/day) and pioglitazone (5 mg/kg/day), for 16 days. After the treatment, HEPa/EtOAc reduced fasting serum glucose and insulin levels, as well as homeostasis model assessment for insulin resistance. In addition, an improvement in glucose intolerance was also observed. Indeed, a reduction in the circulating levels of TNF-α and IL-6 was also observed. Furthermore, at molecular level, it was demonstrated that the HEPa/EtOAc treatment was able to improve these physiological parameters, through the activation of peroxisome proliferator-activated receptor γ (PPARγ) per si, as well as the enhancement of antioxidant mechanism by an increase in PPARγ/Cu(2+), Zn(2+)-superoxide dismutase (CuZn-SOD) axis expression in liver and adipose tissue. In sum, P. aculeata is effective to improve insulin resistance in a mouse model of obesity and this effect seems to involve the antioxidant and anti-inflammatory mechanisms through the increase in PPARγ/CuZn-SOD axis expression.
Surface of glaciers is covered by mineral and organic dust, together with microorganisms forming cryoconite granules. Despite fact that glaciers and ice sheets constitute significance part of land surface, reservoir of freshwater, and sites of high biological production, the knowledge on the cryoconite granules still remain unsatisfactory. This study presents information on radionuclide and heavy metal contents in cryoconites. Cryoconites collected from the Hans Glacier in SW Spitsbergen reveal high activity concentrations of anthropogenic ((238,239,240)Pu, (137)Cs, (90)Sr) and natural ((210)Pb) radionuclides. The (238)Pu/(239+240)Pu activity ratios in these cryoconites significantly exceed the mean global fallout ratio (0.025). The (238)Pu/(239+240)Pu ranged from 0.064 to 0.118. The (239+240)Pu/(137)Cs varied from 0.011 ± 0.003 to 0.030 ± 0.007. Such activity ratios as observed in these cryoconites were significantly higher than the values characterizing global fallout, pointing to possible contributions of these radionuclides from other sources. Heavy metals (Pb, Cd, Cu, Zn, Fe, and Mn) in cryoconites exceed both UCC concentrations and local rocks' concentrations, particularly for cadmium. The concentration ratios of stable lead isotopes ((206)Pb/(207)Pb, (208)Pb/(206)Pb) were determined to discriminate between the natural and anthropogenic sources of Pb in cryoconites and to confirm the strong anthropogenic contribution to heavy metal deposition in the Arctic. In investigated cryoconite holes, two groups of invertebrates, both extremophiles, Tardigrada and Rotifera were detected. Our study indicate that cryoconites are aggregates of mineral and organic substances on surfaces of glaciers are able to accumulate large amounts of airborne pollutants bound to extracellular polymeric substances secreted by microorganisms.
The adsorption characteristics and mechanisms of the biosorbent from waste activated sludge were investigated by adsorbing Pb(2+) and Zn(2+) in aqueous single-metal solutions. A pH value of the metal solutions at 6.0 was beneficial to the high adsorption quantity of the biosorbent. The optimal mass ratio of the biosorbent to metal ions was found to be 2. A higher adsorption quantity of the biosorbent was achieved by keeping the reaction temperature below 55°C. Response surface methodology was applied to optimize the biosorption processes, and the developed mathematical equations showed high determination coefficients (above 0.99 for both metal ions) and insignificant lack of fit (p=0.0838 and 0.0782 for Pb(2+) and Zn(2+), respectively). Atomic force microscopy analyses suggested that the metal elements were adsorbed onto the biosorbent surface via electrostatic interaction. X-ray photoelectron spectroscopy analyses indicated the presence of complexation (between -NH2, -CN and metal ions) and ion-exchange (between -COOH and metal ions). The adsorption mechanisms could be the combined action of electrostatic interaction, complexation and ion-exchange between functional groups and metal ions.
This research applies an integrated sediment quality assessment method using a weight of evidence approach to Cadiz and Algeciras Bays (southern Spain). The method is composed of several analyses (particle size profile, aqua regia extractable metals, acid labile metals, total organic carbon, toxicity bioassay with Photobacterium phosphoreum and macrobenthic community alteration). The proposed method provides a single result, the environmental degradation index (EDI). EDI defined samples as low degraded (outer
 areas of both bays) and moderately degraded (Inner Bay of Cadiz Bay, the surroundings of Algeciras port and the northern part of Algeciras Bay). These samples showed the highest concentration of aqua regia extractable metals, which exceeded effects range-low (ERL) for Zn (51-176mg/l), Cu (11-54mg/l), As (4.3-9.5mg/l), Hg (0.17-0.28mg/l), Ni (23-82mg/l), and. Cr (37-134mg/l). They also exceeded some quality criteria for total organic carbon (4.0-6.5%) and toxicity (120-240TU/g) and showed poor results for macrobenthic community.
Soil washing, an emerging method for treating soils contaminated by heavy metals, requires an evaluation of its efficiency in simultaneously removing different metals, the quality of the soil following remediation, and the reusability of the recycled washing agent. In this study, we employed N,N-bis (carboxymethyl)-l-glutamic acid (GLDA), a novel and readily biodegradable chelator to remove Cd, Pb, and Zn from polluted soils. We investigated the influence of washing conditions, including GLDA concentration, pH, and contact time on their removal efficiencies. The single factor experiments showed that Cd, Pb, and Zn removal efficiencies reached 70.62, 74.45, and 34.43% in mine soil at a GLDA concentration of 75mM, a pH of 4.0, and a contact time of 60min, and in polluted farmland soil, removal efficiencies were 69.12, 78.30, and 39.50%, respectively. We then employed response surface methodology to optimize the washing parameters. The optimization process showed that the removal efficiencies were 69.50, 88.09, and 40.45% in mine soil and 71.34, 81.02, and 50.95% in polluted farmland soil for Cd, Pb, and Zn, respectively. Moreover, the overall highly effective removal of Cd and Pb was connected mainly to their highly effective removal from the water-soluble, exchangeable, and carbonate fractions. GLDA-washing eliminated the same amount of metals as EDTA-washing, while simultaneously retaining most of the soil nutrients. Removal efficiencies of recycled GLDA were no >5% lower than those of the fresh GLDA. Therefore, GLDA could potentially be used for the rehabilitation of soil contaminated by heavy metals.
Wastewater reuse is an important adaptation option for mitigating water stress in rapidly growing urban centers. Reuse potential of nanoparticles (NPs) contaminated wastewater for irrigation of Spinacia oleracea grown in soil media were assessed in this study. Irrigation of plant were done with water containing CuO and ZnO NPs as single compound and in binary mixture (10, 100, 1000 mg/L) till 11 weeks. At 1000 mg/L, reduction in root length: 16 %, 12 % and 18 %, shoot length: 22 %, 16 % and 27 %, total weight 37 %, 27 % and 45 %, chlorophyll: 18 %, 7 % and 29 % and carotenoids: 46 %, 33 % and 54 % were found for CuO NPs, ZnO NPs and binary mixture of NPs respectively. Uptake values were found to be 5.65 ± 0.8 Zn(2+) and 3.48 ± 0.75 Cu(2+) mg/g for the case of ZnO and CuO NPs respectively (at 1000 mg/L). For mixture of NPs, uptake of 3.18 ± 1.05 mg/g of Cu(2+) and 3.18 ± 1.05 mg/g of Zn(2+) ions were found. The results shows that water containing low concentration of NPs (10 mg/L) can be used for irrigating spinach grown in soil media as no significant toxic effect on growth and uptake of metal ion were found as compared to control. The results of this study evaluated the suitability of reusing water contaminated with NPs in agriculture. Further studies are however required to understand the toxic mode of action of mixture of NPs on growth and uptake mechanisms.
A total of 128 surface soil samples were collected, and eight heavy metals, including As, Cd, Cr, Cu, Pb, Ni, Zn, and Hg, were analyzed for their concentrations, potential ecological risks, and human health risks. The mean concentrations of these eight metals were lower than the soil environmental quality standards in China, while they were slightly higher than the background values in Shanxi Province. The enrichment factor, coefficient variation, and potential ecological risk index were used to assess the pollution and eco-risk level of heavy metals, among which, Cd and Hg showed higher pollution levels and potential risks than the others in the studied area. Moreover, multivariate geostatistical analysis suggested that Hg originated mainly from point sources such as industrial emissions, while agricultural activity is the predominant factor for Cd. The human health risk assessment indicated that non-carcinogenic values were below the threshold values. The total carcinogenic risks due to As, Cr, and Ni were within the acceptable range for adults, while for children, they were higher than the threshold value (1.0E-04), indicating that children are facing higher threat to heavy metals in soils. These results provide basic information on heavy metal pollution control and human health risk assessment management in the study regions.
We use ab initio molecular dynamics simulations to study the transport properties and the validity of the Stokes-Einstein relation in Al-rich liquid alloys with Ni, Cu, and Zn as alloying elements. First, we show that the composition and temperature dependence of their transport properties present different behaviors, which can be related to their local structural ordering. Then, we evidence that the competition between the local icosahedral ordering and the local chemical ordering may cause the breakdown of the Stokes-Einstein relation even in the liquid phase. We demonstrate that this breakdown can be captured by entropy-scaling relationships developed by Rosenfeld and using the two-body excess entropy. Our findings provide a unique framework to study the relation between structure, thermodynamics, and dynamics in metallic melts and pave the way towards the explanation of various complex transport properties in metallic melts.
Very little is currently known of subantarctic nearshore invertebrates' sensitivity to environmental metals and the role of temperature in this relationship. This study investigated Cu and Zn toxicity in the common subantarctic intertidal isopod, Exosphaeroma gigas, and the influence of temperature on Cu toxicity and bioaccumulation kinetics. Adult E. gigas are insensitive to Cu and Zn at concentrations of 3200 and 7400μg/L respectively in non-renewal tests at 5.5°C (ambient subtidal temperature) over 14days. Under renewed exposures over the same temperature and time period the LC50 for copper was 2204μg/L. A 10-fold increase in Cu body burden occurred relative to zinc, indicating E. gigas has different strategies for regulating the two metals. Copper toxicity and time to mortality both increased with elevated temperature. However, temperature did not significantly affect Cu uptake rate and efflux rate constants derived from biodynamic modelling at lower Cu concentrations. These results may be attributable to E. gigas being an intertidal species with physiological mechanisms adapted to fluctuating environmental conditions. Cu concentrations required to elicit a toxicity response indicates that E. gigas would not be directly threatened by current levels of Cu or Zn present in Macquarie Island intertidal habitats, with the associated elevated temperature fluctuations. This study provides evidence that the sensitivity of this subantarctic intertidal species to metal contaminants is not as high as expected, and which has significance for the derivation of relevant guidelines specific to this distinct subpolar region of the world.
In this study, the effect of feed-water pH (pH=2-12) on fate and risk of heavy metals (HMs) in hydrochars (HCs) was investigated. Hydrothermal carbonization (HTC) of sewage sludge (SS) was carried out with different feed-water pH at 270°C. The research results showed that changing feed-water pH had a positive effect on accumulating Pb, Ni, Cd and Zn in HCs. Chemical forms of Cu and Cr converted from an unstable state to stable in the alkaline environment while in the acidic condition was opposite. The effect of feed-water pH on the chemical forms of HMs was variable but not significant. Risk assessments of Igeo, Er(i), RAC and RI were applied to evaluate the accumulation levels of individual metal, the potential ecological risks, the bio-availabilities and the comprehensive toxicity and sensitivity of HMs, respectively. The lowest pollution level of HMs was obtained at 270°C with pH=11.
The ligand, N(2),N(3)-bis(3-nitrophenyl)quinoxaline-2.3-diamine was prepared by the condensation of quinoxaline-2.3(1,4H)-dione with 3-nitroaniline. It was treated with Co(II), Ni(II), Cu(II) and Zn(II) acetates to form the metal complexes. These were characterized by elemental analysis, molar conductance, magnetic moment, UV-Vis., IR, (1)H NMR, ESR and mass spectral data. Octahedral geometry has been assigned to Co(II), Ni(II) and Zn(II) complexes, whereas Cu(II) complex has distorted octahedral geometry. From the powder XRD data, crystallite size and unit cell parameters were calculated. The surface morphology of the synthesized compounds were determined using SEM analysis. The antimicrobial activity of the compounds against some bacterial species viz. Escherichiacoli, Klebsiella pneumoniae, Pseudomonas aeuruginosa and Staphylococcus aureus; also the fungal species, Aspergillus niger, and Candida albicans were done by disc diffusion method. DNA binding, cleavage and super oxide anion scavenging activities were also evaluated. The DNA binding activity of the compounds were identified using electronic absorption titrations and DNA cleavage was determined using gel electrophoresis. The anticancer activities of the compounds against HeLa cell line were determined using MTT assay. The highly potent compound among the five against HeLa cell line is subjected to molecular docking study against human papilloma virus receptor molecule and ATP binding site of telomerase.
In this study,
 fine particulate matter (PM2.5) emitted from a municipal solid waste incinerator (MSWI) was collected using dilution sampling method. Chemical compositions of the collected PM2.5 samples, including carbon content, metal elements, and water-soluble ions, were analyzed. Traditional in-stack hot sampling was simultaneously conducted to compare the influences of dilution on PM2.5 emissions and the characteristics of the bonded chemical species. The results, established by a dilution sampling method, show that PM2.5 and total particulate matter (TPM) emission factors were 61.6 ± 4.52 and 66.1 ± 5.27 g ton-waste(-1), respectively. The average ratio of PM2.5/TPM is 0.93, indicating that more than 90% of PM emission from the MSWI was fine particulate. The major chemical species in PM2.5 included organic carbon (OC), Cl(-), NH4(+), elemental carbon (EC) and Si, which account for 69.7% of PM2.5 mass. OC was from the unburned carbon in the exhaust, which adsorbed onto the particulate during the cooling process. High Cl(-) emission is primarily attributable to wastes containing plastic bags made of polyvinyl chloride, salt in kitchen refuse and waste biomass, and so on. Minor species that account for 0.01-1% of PM2.5 mass included SO4(2-), K(+), Na, K, NO3(-), Al, Ca(2+), Zn, Ca, Cu, Fe, Pb, and Mg. The mean ratio of dilution method/in-stack hot method was 0.454. The contents of water-soluble ions (Cl(-), SO4(2-), NO3(-)) were significantly enriched in PM2.5 via gas-to-particle conversion in the dilution process. Results indicate that in-stack hot sampling would underestimate levels of these species in PM2.5.
PM2.5 samples from a municipal solid waste incinerator (MSWI) were collected simultaneously by a dilution sampling technique and a traditional in-stack method. PM2.5 emission factors and chemical speciation profiles were established. Dilution sampling provides more reliable data than in-stack hot sampling. The results can be applied to estimate the PM2.5 emission inventories of MSWI, and the source profile can be used for contribution estimate of chemical mass balance modeling.
A novel tetradendate ligand derived from a tris(pyrrolyl-α-methyl)amine (H3tpa) and rhodamine-based conjugate (PR) has been designed for use as a sensor, synthesized and characterized spectroscopically. PR {(tris(5-rhodamineiminopyrrol-2-ylmethyl)amine)} serves as a selective colorimetric as well as a fluorescent chemosensor for Zn(2+) in acetonitrile/water (1 : 1, v/v). In the presence of Zn(2+), PR exhibited obvious absorption (558 nm) and emission (577 nm) peaks whose intensity increased along with increasing Zn(2+) concentrations. Titration experiments revealed that a large excess of Zn(2+) was required to saturate the absorption (λmax) and emission intensities. Upon the addition of 1000 equivalents of Zn(2+), the fluorescence intensity of the PR underwent an ∼500-fold increase (Φf = 0.34) with the emission maximum at 580 nm. These kinetics studies demonstrated that the absorption and emission changes were proportional to the Zn(2+) concentration. The color of the solution changed from colorless to a dark pink color. The fluorescence of the PR-Zn(2+) complex can be reversibly restored by using ammonium water or by heating. Competitive ion tests revealed that the intensity of PR-Zn(2+) was not suppressed by excess amounts of other metal ions. The counter anions did not exert obvious influences on the absorption and emission profiles. (1)H-NMR and FT-IR spectroscopic investigations of PR and PR-Zn(2+) revealed that the pyrrole motifs, -C[double bond, length as m-dash]N- groups and spirolactam of rhodamine B are capable of coordinating cation guest species. Because each arm of the tripodal ligand tautomerizes independently, only moderate fluorescence enhancement could be seen until all three -C[double bond, length as m-dash]N- groups were coordinated by zinc, which may be due to the spirolactam ring opening mechanism of the rhodamine unit. Once all three -C[double bond, length as m-dash]N- groups were locked by coordinating with excess of Zn(2+), the isomerization was arrested, and PR exhibited highly enhanced fluorescence. In addition, energy optimized structures of PR were found to be cage-like by Gaussian 09, further supporting that it can access a large excess of Zn(2+). Intriguingly, imaging of HeLa cells by using a confocal microscope revealed that this PR probe could be used for biological applications.
We explored two methods for obtaining aqueous extracts: boiling and soaking of Baltic seaweeds (EB and ES, resp.). Algal extracts were characterized in terms of polyphenols, micro- and macroelements, lipids content, and antibacterial properties. The utilitarian properties were examined in the germination tests on Lepidium sativum for three extract dilutions (0.5, 2.5, and 10%). It was found that the extracts were similar in micro- and macroelement concentrations. Water was proved to be a good solvent to extract phenolic compounds. The algal extract produced by soaking biomass did not show inhibitory effect on Escherichia coli and Staphylococcus aureus. Only the boiled extract had an inhibitory activity against E. coli. Germination tests revealed a positive influence of the bioproducts on the cultivated plants. In the group treated with 10% EB, plants were 13% longer than in the control group; the content of elements B, Mo, Zn, and Na in the group treated with 10% ES was higher by 76%, 48%, 31%, and 59% than in the control group, respectively; the content of chlorophyll was 2.5 times higher in 0.5% ES than in the control group. Extracts showed the slight impact on the morphology of plants.
The ability of 2,6-bis(2-benzimidazolyl)pyridine (bbp) as an optical sensor was studied by fluorescence spectroscopy, colorimetric and UV-visible techniques. The fluorescence spectra of bbp demonstrated a red-shifted upon addition of Zn(2+) ion, whereas rest of the cations did not induce any shift. Selectivity of the sensor was examined toward Zn(2+) in the presence of a wide range of cations, as interfering agents, that showed no disruption in its function. In addition, the pH effect was tested on the fluorescence response of bbp; which showed the efficiency of the sensor in a wide pH range. The limit of detection for Zn(2+) was estimated as 2.1 μM. Furthermore, the colorimetric studies were carried out and the observations showed a color change from colorless to purple by the addition of Fe(2+) ion and from colorless to yellow by the addition of Fe(3+). The UV-visible studies were carried out to confirm the colorimetric observations. The color changes occurred when Fe(2+) and Fe(3+) were added to the sensors solution, respectively. The detection limits were calculated as 2.8 × 10(-7) M and 3.5 × 10(-6) M for Fe(2+) and Fe(3+), respectively. Hence, bbp can be used as a dual mode optical sensor for detection of Zn(2+) by fluorescence and discriminately detection of Fe(2+) and Fe(3+) visually.
Fluorescent polydopamine (FPD) is an interesting material with excellent biocompatibility. However, its preparation is currently a lengthy and potentially dangerous process. We herein employ magnetic iron oxide (Fe3O4) nanoparticles as a peroxidase-mimicking nanozyme to produce FPD under mild conditions. Different from previous protocols using multiple steps with up to 6% (∼2 M) H2O2, this preparation takes place in a single step with just 5 mM H2O2 at room temperature. The oxidized product shows excitation-wavelength-dependent emission peaks, similar to previous reports. The reaction kinetics, pH, temperature, and ionic strength are individually optimized. Among a diverse range of other nanomaterials tested, including Fe2O3, CeO2, CoO, Co3O4, NiO, TiO2, gold nanoparticles, and graphene oxide, Fe2O3 and graphene oxide yielded relatively weak emission, while the rest of the materials failed to produce FPD. The Fe3O4 nanoparticles retained ∼90% catalytic activity even after ten cycles of synthesis. Finally, Zn(2+) can enhance the fluorescence of FPD under 360 nm excitation but not under 480 nm excitation, leading to a sensitive light-up sensor with a detection limit of 60 nM Zn(2+). Therefore, this work has demonstrated not only a novel use of nanozymes, but also an interesting application of FPD.
In this study, we developed coordinative amphiphiles for use as novel siRNA transporters. As a modification of a conventional cationic lipid structure, we replaced the cationic head with zinc(II)-dipicolylamine complex (Zn/DPA) as a phosphate-directing group, and used various membrane-directing groups in the place of the hydrophobic tails. These simple amphiphiles are readily synthesized and easy to modify. The Zn/DPA head groups bind to the phosphate backbones of siRNAs, and to our surprise, they prevented the enzymatic degradation of siRNAs by RNase A. Interestingly, the Zn/DPA head itself exhibited moderate transfection efficiency, and its combination with a membrane-directing group-oleoyl (CA1), pyrenebutyryl (CA2), or biotin (CA3)-enhanced the delivery efficiency without imparting significant cytotoxicity. Notably, the uptake pathway was tunable depending on the nature of the membrane-directing group. CA1 delivered siRNAs mainly through caveolae-mediated endocytosis, and CA2 through clathrin- and caveolin-independent endocytosis; CA3 recruited siRNAs specifically into biotin receptor-positive HepG2 cells through receptor-mediated endocytosis. Thus, it appears possible to develop tunable siRNA transporters simply by changing the membrane-directing parts. These are the first examples of amphiphilic siRNA transporters accompanying coordinative interactions between the amphiphiles and siRNAs.
E. coli O157:H7 has three sodC genes encoding for Cu,Zn superoxide dismutase. We evaluated the expression of chromosomal sodC in distinct phases of growth in different strains, and we
 examined the mutual capability of chromosomal and prophagic genes to influence their expression.
We used One Step real-time RT-PCR technology to study the expression of sodC genes in several E. coli strains.
In three of four analysed E. coli O157:H7 strains the chromosomal sodC gene was more expressed in exponential phase than in stationary phase, unlike it occurs in the E. coli K12 strain. The expression of the chromosomal gene was always higher than that of the prophagic copies. Deletion of prophagic or chromosomal sodC genes had no effect on the expression of the residual gene.
Our study highlights an inherent variability in number and level of expression of sodC genes in E. coli O157:H7 strain.
The syntheses, photophysical/electrochemical characterizations of different metallated porphyrins -i.e., Zn(2+), Pt(2+), Pd(2+), and Sn(4+) porphyrins - as well as their first application in light-emitting electrochemical cells are provided. A direct comparison demonstrates that depending on the metallation either efficient (Pt-por) or stable (Zn-por) devices are achieved, demonstrating that the choice of the metal core is a key aspect for future developments.
Pancreatic cancer is very common and difficult to diagnose in early stage. Imaging systems for diagnosing cancer have many disadvantages. However, combining different imaging modalities offer synergistic advantages. Optical imaging is the most multidirectional and widely used imaging modality in both clinical practice and research. In present study, Zinc(II) phthalocyanine [Zn(II)Pc] was synthesized, labeled with iodine-131 and in vitro study was carried out. The intracellular uptake studies of radiolabeled Zn(II)Pc were performed in WI-38 [ATCC CCL-75™, tissue: human fibroblast lung] and MIA PaCa-2 [ATCC CRL-1420™, tissue: human epithelial pancreas carcinoma] cell lines. The intracellular uptake efficiency of radiolabeled Zn(II)Pc in MIA PaCa-2 cellswas determined two times higher than WI-38 cells. Also,fluorescence imaging (FI) efficiency of synthesized Zn(II)Pc was investigated in MIA PaCa-2 cells and significant uptake was observed. In concluding Zn(II)Pc might be used as a new agent for dual fluorescence/nuclear imaging for pancreatic cancer.
Surface soil samples (0-20 cm) from eight different functional areas in Yinchuan city were collected. There were 10 samples respectively in each functional area. The urban soil heavy metals (Zn, Cd, Pb, Mn, Cu and Cr) pollution characteristics and sources in eight different functional areas were evaluated by mathematical statistics and geostatistical analysis method. Meanwhile, the spatial distributions of heavy metals based on the geography information system (GIS) were plotted. The average values of total Zn, Cd, Pb, Mn, Cu and Cr were 74.87, 0.15, 29.02, 553.55, 40.37 and 80.79 mg x kg(-1), respectively. The results showed that the average value of soil heavy metals was higher than the soil background value of Ningxia, which indicated accumulation of the heavy metals in urban soil. The single factor pollution index of soil heavy metals was in the sequence of Cu > Pb > Zn > Cr > Cd > Mn. The average values of total Zn, Cd, Pb and Cr were higher in north east, south west and central city, while the average values of Mn and Cu were higher in north east and central city. There was moderate pollution in road and industrial area of Yinchuan, while the other functional areas showed slight pollution according to Nemoro synthesis index. The pollution degree of different functional areas was as follows: road > industrial area > business district > medical treatment area > residential area > public park > development zone > science and education area. The results indicated that the soil heavy metal pollution condition in Yinchuan City has been affected by human activities with the development of economy.
As the second deepest lake in Africa, Lake Tanganyika plays an important role in supplying fish protein for citizens in the catchment. However, the lake is increasingly threatened by environmental pollution with the development of social economy and expanding of population. In order to reveal the external source of heavy metals in Lake Tanganyika, 16 surface sediment samples from the rivers which flow into the northeast of the lake were collected and analyzed. Besides the contents, the potential ecological risk indices (RI) of each heavy metal were also analyzed. Furthermore, the relationship, between land use and the spatial distribution of heavy metals was also discussed. The average contents of Cu, Zn, Cd, Pb and Hg were 18. 4, 21.2, 0.05, 6.6 mg x kg(-1) and 8.4 ng x g(-1), respectively, with the maximum values of Zn, Pb and Cd located in Bujumbura urban rivers. The data indicated that all the inflow rivers were at low potential ecological risk. RI of heavy metals ranked as the following order: Cd > Hg > Cu > Pb > Zn, as Cd being the key element contributing to the risk. The relationship between land use and heavy metals showed that the contents of heavy metals were highest in urban areas, followed by estuarine wetlands, and woodlands were least polluted by heavy metals. This distribution type implied that human activities could cause the heavy metal accumulation in the surface sediments of nearby rivers. The urban areas and estuarine wetlands need to be concerned in the further study.
To explore the source of heavy metals in lake sediments and their hazard to environment on Tibetan Plateau, China, heavy metal (Cu, Zn, Cd, Pb, Cr, Co, Ni and As) levels in surface sediments of 18 lakes were investigated. Inductively Coupled Plasma Mass Spectrometry (ICP-MS, X-7 series) was used to determine the contents of heavy metals and the concentrations of carbon and nitrogen in sediment samples were analyzed by element analyzer (Vario Max CN, Elementar, Germany). The average concentrations for Cu, Zn, Cd, Pb, Cr, Co, Ni and As were 24.61 mg x kg(-1), 70.14 mg x kg(-1), 0.26 mg x kg(-1), 25.43 mg x kg(-1), 74.12 mg x kg(-1), 7.93 mg x kg(-1), 33.85 mg x kg(-1), 77.69 mg x kg(-1). It was found that heavy-metal concentrations in Tibet sediments were higher than those in Antarctic, but lower than those in the regions affected by anthropogenic activities. The contents of Cu, Zn, Pb, Cr and Co in the samples were lower than the background values of Tibet. Correlation analysis and principal components analysis (PCA) were used to analyze the origins of heavy metals. The result showed that Cu, Zn, Cd, Pb, Co, Ni and As came from soil in drainage basin and atmospheric deposition. Cr was mainly affected by human activities. Assessment on ecological risk of heavy metals was carried out using Hakanson's method and cluster analysis (CA). Assessment on ecological risk indicated that Pumoyum Co, Longmo Co and Bangong Co were at low risks, Bieruoze Co was at high ecological risk level and the other lakes were at different risk levels.
In order to investigate the characteristics of atmospheric trace metals deposition in the hinterland of the Three Gorges Reservoir, the wet and dry deposition samples were collected at an urban area sampling site in Wanzhou during January to June 2014. Besides, the samples were collected at five other sampling sites in April 2014 for comparative analysis, including factory region, town suburb, nature reserve, county suburb, and rural area. pH, conductivity, and trace metals (Al, As, B, Ba, Bi, Cd, Co, Cr, Cu, Fe, Li, Mn, Pb, Ni, Sb, Sr, Sn, Ti, Zn, V) were analyzed. In urban area, the acid rain frequency was 48.44% , and the acid rain occurred mainly in the period of January to April. The order of acid rain frequency in various functional areas was factory region > urban area > county suburb > town suburb > nature reserve > county rural area. All of the trace metals in wet deposition during the sampling period were lower than the National Environmental Quality Standard for Surface Water Standard of Class III. Cd, Cu, Ph and Zn were found exceeding the standard of class I , and the pollution in factory region was more serious compared to other functional areas. The extract pH of dry deposition in urban area was in the range of 4.91-6.74, with an average value of 5.79. The order of dry deposition in various functional areas was factory region > county suburb > urban area > county rural area > town suburb > nature reserve, which was exactly the same as that of the wet deposition, indicating the similar sources of dry and wet deposition. In urban area, the contents of Ba, Co, Cu, Cr, Li, Mn, Ni, Sr, Zn in dry deposition were greater than those in wet deposition, but the contents of Al, As, B, Bi, Cd, Fe, Ph, Sb, Sn, Ti, V showed the opposite trend. Analysis of the enrichment factors showed that Al was in moderate enrichment, while Bi and Cd were significantly enriched.
Trace elements are essential substances for the proper physiological and biochemical functioning of the organism. Hemodialysis patients are potentially at risk of deficiency or excess of these elements. The application of inductively coupled plasma mass spectrometry (ICP-MS) allows the simultaneous quantification of very small amounts of multiple trace elements. The aim was to measure the serum concentration of copper (Cu), zinc (Zn), selenium (Se), and nickel (Ni), and the whole blood concentration of arsenic (As), lead (Pb), and manganese (Mn), in patients undergoing hemodialysis as well as in controls.
The study was carried out in 57 hemodialysis patients compared with 57 controls with normal renal function. Serum and whole blood samples from the dialysis group were collected before and after hemodialysis sessions and Cu, Zn, Se, Ni, As, Pb and Mn levels were determined using ICP-MS.
Hemodialysis patients showed significantly lower blood levels of Cu, Zn and Se than controls (p < 0.001) and higher concentrations of Ni, As and Pb (p < 0.0001). The levels of
 Mn were similar in both groups. After performing hemodialysis, Cu, Zn, Se and Ni concentrations were significantly higher than the pre-hemodialysis levels (p < 0.0001). However, the concentration of As decreased (p < 0.0001) and Pb and Mn levels were not significantly altered after the dialysis session.
Hemodialysis patients are at increased risk of trace elements deficiency (especially for Zn and Se) or excess (Ni) in respect to healthy subjects. Monitoring of blood levels and supplementation of some trace elements may be indicated in patients undergoing hemodialysis.
In this study, 19 biochars from marginal biomass, representing all major biomass groups (woody materials, grass, an aquatic plant, anthropogenic wastes) were investigated regarding their content of available potentially toxic elements (PTEs) and nutrients (determined by NH4NO3-extractions) and their effects on cress (Lepidium sativum) seedling growth. The objective was to assess the potential and actual effects of biochar with increased PTE content on plant growth in the context of use in soil amendments and growing media. It showed that the percentage of available PTEs was highest for biochars produced at the highest treatment temperature (HTT) of 750°C. On average, however, for all 19 biochars, the percentage availability of Cu, Cr, Ni and Zn (<1.5% for all) was similar to the percentage availability reported in the literature for the same elements in soils at similar pH values which is a highly important finding. Most biochars exceeded German soil threshold values for NH4NO3-extractable PTEs, such as Zn (by up to 25-fold), As and Cd. Despite this, cress seedling growth tests with 5% biochar in sand did not show any correlations between inhibitory effects (observed in 5 of the 19 biochars) and the available PTE concentrations. Instead, the available K concentration and biochar pH were highly significantly, negatively correlated with seedling growth (K: p<0.001, pH: p=0.004). K had the highest available concentration of all elements and the highest percentage availability (47.7±19.7% of the total K was available). Consequently, available K contributed most to the osmotic pressure and high pH which negatively affected the seedlings. Although a potential risk if some of these marginal biomass-derived biochar were applied at high concentrations, e.g. 5% (>100tha(-1)), when applied at agriculturally realistic application rates (1-10tha(-1)), the resulting smaller increases in pH and available K concentration may actually be beneficial for plant growth.
The aim of the present study was to evaluate the effects of acute inorganic Hg exposure (0, 32 and 64μgHgL(-1)) on lipid peroxidation, activities and gene expression of antioxidant enzymes (Cu/Zn-SOD, CAT, GPx, GR and GST), and mRNA levels of the Keap1-Nrf2 signaling molecules at different exposure times (6h, 12h, 24h, 48h, and 96h) in the liver of large yellow croaker Pseudosciaena crocea. The results showed that lipid peroxidation was sharply reduced by 32μg Hg L(-1) during 6-12h before returning to control levels. Similarly, lipid peroxidation was significantly reduced during 6-12h followed by a sharp increase towards the end of the exposure in the 64μgHgL(-1) group. There was a negative relationship between lipid peroxidation and antioxidant enzyme activities, and positive relationship between activities and gene expression of antioxidant enzymes, suggesting that the changes at a molecular level may underlie enzymatic level and accordingly affect hepatic lipid peroxidation. Obtained results also showed a coordinated transcriptional regulation of antioxidant genes, suggesting that Nrf2 is required for the protracted induction of these genes. Furthermore, a negative relationship between the mRNA levels of Nrf2 and Keap1 indicated that Keap1 may play an important role in switching off the Nrf2 response. In conclusion, this is the first study to elucidate effects of waterborne Hg on antioxidant system in large yellow croaker through the Keap1-Nrf2 pathway, which will aid our understanding of the molecular mechanisms of waterborne heavy metal on antioxidant responses in fish.
In order to cope with variable mineral nutrient availability, higher plants have developed numerous strategies including the remobilization of nutrients from source to sink tissues. However, such processes remain relatively unknown for magnesium (Mg), which is the third most important cation in plant tissues. Using Mg depletion of Brassica napus, we have demonstrated that Mg is remobilized from old leaves to young shoot tissues. Moreover, this study showed that Mg depletion induces modification of nutrient uptake, especially Zn and Mn. Finally, comparative proteomic analysis of old leaves (source of Mg) revealed amongst other results that some proteins requiring Mg for their functionality (isocitrate dehydrogenase for example) were up-regulated. Moreover, down-regulation of proteases suggested that mobilization of Mg from old leaves was not associated with senescence.
This study investigates the distributions of Br, Ca, Cl, Cr, Cu, K, Fe, Mn, Pb, Ti, V and Zn in Phragmites australis root system and the function of Fe nanoparticles in scavenging metals in the root epidermis using synchrotron X-ray microfluorescence, synchrotron transmission X-ray microscope measurement and synchrotron X-ray absorption near-edge structure techniques. The purpose of this study is to understand the mobility of metals in wetland plant root systems after their uptake from rhizosphere soils. Phragmites australis samples were collected in the Yangtze River intertidal zone in July 2013. The results indicate that Fe nanoparticles are present in the root epidermis and that other metals correlate significantly with Fe, suggesting that Fe nanoparticles play an important role in metal scavenging in the epidermis.
On the basis of our previous field survey, we postulate that the pattern and degree of zinc (Zn) isotope fractionation in the Zn hyperaccumulator Noccaea caerulescens (J. & C. Presl) F. K. Mey may reflect a relationship between Zn bioavailability and plant uptake strategies. Here, we investigated Zn isotope discrimination during Zn uptake and translocation in N. caerulescens and in a nonaccumulator Thlaspi arvense L. with a contrasting Zn accumulation ability in response to low (Zn-L) and high (Zn-H) Zn supplies. The average isotope fractionations of the N. caerulescens plant as a whole, relative to solution (Δ(66)Znplant-solution), were -0.06 and -0.12‰ at Zn-L-C and Zn-H-C, respectively, indicative of the predominance of a high-affinity (e.g., ZIP transporter proteins) transport across the root cell membrane. For T. arvense, plants were more enriched in light isotopes under Zn-H-A (Δ(66)Znplant-solution = -0.26‰) than under Zn-L-A and N. caerulescens plants, implying that a low-affinity (e.g., ion channel) transport might begin to function in the nonaccumulating plants when external Zn supply increases. Within the root tissues of both species, the apoplast fractions retained up to 30% of Zn mass under Zn-H. Moreover, the highest δ(66)Zn (0.75‰-0.86‰) was found in tightly bound apoplastic Zn, pointing to the strong sequestration in roots (e.g., binding to high-affinity ligands/precipitation with phosphate) when plants suffer from high Zn stress. During translocation, the magnitude of isotope fractionation was significantly greater at Zn-H (Δ(66)Znroot-shoot = 0.79‰) than at Zn-L, indicating that fractionation mechanisms associated with root-shoot translocation might be identical to the two plant species. Hence, we clearly demonstrated that Zn isotope fractionation could provide insight into the internal sequestration mechanisms of roots when plants respond to low and high Zn supplies.
AhHMA4 from Arabidopsis thaliana encodes Zn/Cd export protein that controls Zn/Cd translocation to shoots. The focus of this manuscript is the evaluation of AhHMA4 expression in tomato for mineral biofortification (more Zn and less Cd in shoots and fruits). Hydroponic and soil-based experiments were performed. Transgenic and wild-type plants were grown on two dilution levels of Knop's medium (1/10, 1/2) with or without Cd, to determine if mineral composition affects the pattern of root/shoot partitioning of both metals due to AhHMA4 expression. Facilitation of Zn translocation to shoots of 19-day-old transgenic tomato was noted only when plants were grown in the more diluted medium. Moreover, the expression pattern of Zn-Cd-Fe cross-homeostasis genes (LeIRT1, LeChln, LeNRAMP1) was changed in transgenics in a medium composition-dependent fashion. In plants grown in soil (with/without Cd) up to maturity, expression of AhHMA4 resulted in more efficient translocation of Zn to shoots and restriction of Cd. These results indicate the usefulness of AhHMA4 expression to improve the growth of tomato on low-Zn soil, also contaminated with Cd.
Amyotrophic lateral sclerosis (ALS) is the most common form of motor neuron disease, a fatal degenerative disorder in which motor neurons in the central nervous system (CNS) progressively deteriorate. Most cases of ALS are sporadic, but 10% are familial and mutations affecting the copper (Cu)-dependent antioxidant Cu/Zn-superoxide dismutase (SOD1) are the most common familial cause. Cu malfunction is evident in CNS tissue from transgenic mice that over-express mutant SOD1 and modulating Cu bioavailability in the CNS provides positive therapeutic outcomes. In the present study we assessed levels of Cu and Zn, SOD activity, and SOD1 protein levels in CNS and non-CNS tissue from transgenic mutant SOD1 mice (SOD1(G37R)) and non-transgenic controls. Physiological SOD1 binds one structural Zn and one catalytic Cu per subunit. Due to over-expression of the transgene, SOD activity and SOD1 protein levels are elevated in all tissues examined from the
 SOD1(G37R) mice and a commensurate increase in Zn is evident. There is a comparable increase in Cu in non-CNS tissue, but the increase in Cu in the SOD1(G37R) mouse brain is limited and there is no increase in Cu in the spinal cord. The limited change in CNS Cu is associated with a strong disparity between SOD1 protein and SOD activity in the brain and spinal cord. We hypothesise that the limited capacity for CNS tissue to respond to an increased requirement for bioavailable Cu contributes to CNS vulnerability in ALS.
We analyze the geometry and electronic structure of a series of amorphous Zn-Ir-O systems using classical molecular dynamics followed by density functional theory taking into account two different charge states of Ir (+3 and  +4). The structures obtained consist of a matrix of interconnected metal-oxygen polyhedra, with Zn adopting preferentially a coordination of 4 and Ir a mixture of coordinations between 4 and 6 that depend on the charge state of Ir and its concentration. The amorphous phases display reduced band gaps compared to crystalline ZnIr2O4 and exhibit localized states near the band edges, which harm their transparency and hole mobility. Increasing amounts of Ir in the Ir(4+) phases decrease the band gap further while not altering it significantly in the Ir(3+) phases. The results are consistent with recent transmittance and resistivity measurements.
Technetium ((99)Tc) is an abundant, long-lived radioactive fission product whose mobility in the subsurface is largely governed by its oxidation state. Tc immobilization is crucial for radioactive waste management and environmental remediation. Tc(IV) incorporation in spinels has been proposed as a novel method to increase Tc retention in glass waste forms during vitrification. However, experiments under high-temperature and oxic conditions show reoxidation of Tc(IV) to volatile pertechnetate, Tc(VII). Here we examine this problem with ab initio molecular dynamics simulations and propose that, at elevated temperatures, doping with first row transition metal can significantly enhance Tc retention in magnetite in the order Co>Zn>Ni. Experiments with doped spinels at 700 °C provide quantitative confirmation of the theoretical predictions in the same order. This work highlights the power of modern, state-of-the-art simulations to provide essential insights and generate theory-inspired design criteria of complex materials at elevated temperatures.
β-carbonic anhydrases (β-CAs) are ubiquitous metalloenzymes which active site contains a zinc ion (Zn²⁺), and they could catalyze the hydration of carbon dioxide to bicarbonate and protons efficiently and are involved in many biological processes, such as respiration, pH and CO₂ homeostasis, biosynthetic reactions, virulence regulation and so on, and may play a critical role in the life activity of many organisms which contain these enzymes. β-CAs are widely distributed in fungi, bacteria, algae, plants and a small number of protozoan and metazoan except vertebrates. Therefore, as potential drug targets for designing and developing antibacterial and anti-parasitic drugs, β-CAs promise a broad application prospect. This paper focuses on the distribution, physiological function and the progress of researches on β-CAs in parasites and their vectors.
A hexagonal nanosheet LDH@ZIF-8 composite was fabricated by in situ growth of ZIF-8 on Zn-Al LDH without adding any zinc precursor, and exhibited a CO2 adsorption capacity of 1.0 mmol g(-1) at room temperature and 1 bar, which was significantly higher than that of pure Zn-Al LDH or ZIF-8, indicating a synergy between ZIF-8 and Zn-Al LDH.
pH-rate profiles for aqueous-organic protodeboronation of 18 boronic acids, many widely viewed as unstable, have been studied by NMR and DFT. Rates were pH-dependent, and varied substantially between the boronic acids, with rate maxima that varied over 6 orders of magnitude. A mechanistic model containing five general pathways (k1-k5) has been developed, and together with input of [B]tot, KW, Ka, and KaH, the protodeboronation kinetics can be correlated as a function of pH (1-13) for all 18 species. Cyclopropyl and vinyl boronic acids undergo very slow protodeboronation, as do 3- and 4-pyridyl boronic acids (t0.5 > 1 week, pH 12, 70 °C). In contrast, 2-pyridyl and 5-thiazolyl boronic acids undergo rapid protodeboronation (t0.5 ≈ 25-50 s, pH 7, 70 °C), via fragmentation of zwitterionic intermediates. Lewis acid additives (e.g., Cu, Zn salts) can attenuate (2-pyridyl) or accelerate (5-thiazolyl and 5-pyrazolyl) fragmentation. Two additional processes compete when the boronic acid and the boronate are present in sufficient proportions (pH = pKa ± 1.6): (i) self-/autocatalysis and (ii) sequential disproportionations of boronic acid to borinic acid and borane.
We report the identification by in vitro selection of Zn(2+)/Mn(2+)-dependent deoxyribozymes that glycosylate the 3'-OH of a DNA oligonucleotide. Both β and α anomers of aryl glycosides can be used as the glycosyl donors. Individual deoxyribozymes are each specific for a particular donor anomer.
The study aimed at determination of the mineral composition of slimming herbal teas and estimation of the coverage of their total intake with infusions in women's daily diet. The content of Na(+), K(+), Ca(+2), Mg(+2), Zn(+2), Cu(+2), Fe(+2), and Mn(+2) was determined in infusions and mineralisates obtained from the slimming herbal teas. Among macroelements, the highest content was recorded for Ca-on average 3.73 mg·100 ml(-1) in its infusion. Mn was a microelement with the highest concentration amounting to 0.20 mg·100 ml(-1) in the infusion. The investigations revealed that, referring to the dietary reference intakes (DRIs), weight loss herbal infusions cover the recommended daily intake of manganese for women to the highest extent (on average 54 %), which suggests that they can be a major source of this microelement for the organism. Herbal teas only to a slight extent (to approx. 4 %) covered the recommended daily intake of magnesium, sodium, potassium, iron, zinc, copper, and calcium in the daily diet.
Elemental concentrations and bioaccessibility were determined in background soils collected in Canada as part of the North American Geochemical Landscapes Project. The concentrations of As, Cr, Cu, Co, Ni and Zn were higher in the C-horizon (parent material) compared to 0-5 cm (surface soil), and this observation along with the regional distribution suggested that most of the variability in concentrations of these elements were governed by the bedrock characteristics. Unlike the above-stated elements, Pb and Cd concentrations were higher in the surface layer reflecting the potential effects of anthropogenic deposition. Elemental bioaccessibility was variable decreasing in the order Cd > Pb > Cu > Zn > Ni > Co > As > Cr for the surface soils. With the exception of As, bioaccessibility was generally higher in the C-horizon soils compared to the 0-5 cm soils. The differences in metal bioaccessibility between the 0-5 cm and the C-horizon and among the provinces may reflect geological processes and speciation. The mean, median or 95th percentile bioaccessibility for As, Cr, Cu, Co, Ni and Pb were all below 100 %, suggesting that the use of site-specific bioaccessibility results for these elements will yield more accurate estimation of the risk associated with oral bioavailability for sites where soil ingestion is the major contributor of human health risk.
Electrocatalytic CO2 conversion into fuel is a prospective strategy for the sustainable energy production. However, still many parts of the catalyst such as low catalytic activity, selectivity, and stability are challenging. Herein, a hierarchical hexagonal Zn catalyst showed highly efficient and, more importantly, stable performance as an electrocatalyst for selectively producing CO. Moreover, we found that its high selectivity for CO is attributed to morphology. In electrochemical analysis, Zn (101) facet is favorable to CO formation whereas Zn (002) facet favors the H2 evolution during CO2 electrolysis. Indeed, DFT calculations showed that (101) facet lowers a reduction potential for CO2 to CO by more effectively stabilizing a (.) COOH intermediate than (002) facet. This further suggests that tuning the crystal structure to control (101)/(002) facet ratio of Zn can be considered as a key design principle to achieve a desirable product from Zn catalyst.
A new type of Fe, N-doped hierarchically porous carbons (N-Fe-HPCs) has been synthesized via a cost-effective synthetic route, derived from nitrogen-enriched polyquaternium networks by combining a simple silicate templated two-step graphitization of the impregnated carbon. The as-prepared N-Fe-HPCs present a high catalytic activity for the oxygen reduction reaction (ORR) with onset and half-wave potentials of 0.99 and 0.86 V in 0.1 M KOH, respectively, which are superior to commercially available Pt/C catalyst (half-wave potential 0.86 V vs. RHE). Surprisingly, the diffusion-limited current density of N-S-HPCs approaches ∼7.5 mA cm(-2), much higher than that of Pt/C (∼5.5 mA cm(-2)). As a cathode electrode material used in Zn-air batteries, the unique configuration of the N-Fe-HPCs delivers a high discharge peak power density reaching up to 540 mW cm(-2) with a current density of 319 mA cm(-2) at 1.0 V of cell voltage and an energy density >800 Wh kg(-1). Additionally, outstanding ORR durability of the N-Fe-HPCs is demonstrated, as evaluated by the transient cell-voltage behavior of the Zn-air battery retaining an open circuit voltage of 1.48 V over 10 hours with a discharge current density of 100 mA cm(-2).
Contributions of the active site metal to the stability of carbonic anhydrase (CA) were quantified by differential scanning calorimetry and complementary unfolding measurements
 of CA substituted with Co(2+), Cd(2+), Cu(2+), Ni(2+) and Mn(2+). The metal ions stabilize the protein to different extent, with the highest stability provided by the native Zn(2+). This additional stability does not correlate with the enthalpy of the three metal-imidazole (His) bonds at the active site or other properties of the metal ions (charge density, hydration enthalpy). However, DFT calculations reveal an energetic penalty associated with metal coordination at the active site, and the magnitude of this penalty correlates inversely with metal contributions to the stability of the protein. While the affinity of CA for metal ions generally reflects the Irving-Williams series, the additional thermal stability provided by metal ions is modulated by the rigid His3 coordination that is imposed at the protein site.
Three bacterial isolates, GT2, GT3, and GT7, were isolated from the sludge and water of a circulating cooling system of iron and steel plant by screening on Cr(VI)-containing plates. Three isolates were characterized as the members of the genus Pseudomonas on the basis of phenotypic characteristics and 16S rRNA sequence analysis. All isolates were capable of resisting multiple antibiotics and heavy metals. GT7 was most resistant to Cr(VI), with a minimum inhibitory concentration (MIC) of 6.5 mmol L(-1). GT7 displayed varied rates of Cr(VI) reduction in M2 broth, which was dependent on pH, initial Cr(VI) concentration, and inoculating dose. Total chromium analysis revealed that GT7 could remove a part of chromium from the media, and the maximum rate of chromium removal was up to 40.8 %. The Cr(VI) reductase activity of GT7 was mainly associated with the soluble fraction of cell-free extracts and reached optimum at pH 6.0∼8.0. The reductase activity was apparently enhanced by external electron donors and Cu(II), whereas it was seriously inhibited by Hg(II), Cd(II), and Zn(II). The reductase showed a K m of 74 μmol L(-1) of Cr(VI) and a V max of 0.86 μmol of Cr(VI) min(-1) mg(-1) of protein. The results suggested that GT7 could be a promising candidate for in situ bioremediation of Cr(VI).
The effect of mechanical stirring on sol-gel synthesis of thorn-like ZnO nanoparticles (ZnO-NPs) and antimicrobial activities is successfully reported in this study. The in-house synthesized nanoparticles were characterized by XRD, SEM, TEM, FTIR, TGA, DSC and UV-visible spectroscopy. The X-Ray Diffraction analysis revealed the wurtzite crystal lattice for ZnO-NPs with no impurities present. The diametric measurements of the synthesized thorn-like ZnO-NPs (morphology assessed by SEM) were well accounted to be less than 50 nm with the help of TEM. Relative decrease in aspect ratio was observed on increasing the agitation speed. The UV-visible spectroscopy showed the absorption peaks of the ZnO-NPs existed in both UVA and UVB region. A hypsochromic shift in λmax was observed when stirring pace was increased from 500 rpm to 2000 rpm. The FTIR spectroscopy showed the absorption bands of the stretching modes of Zn-O between 500 cm(-1) to 525 cm(-1). The Thermal analysis studies revealed better stability for ZnO-NPs prepared at 2000 rpm (ZnO-2000 rpm). TGA revealed the weight loss between two main temperatures ranges viz. around (90 °C-120 °C) and (240 °C-280 °C). Finally, the effect of ZnO-NPs prepared at different stirring conditions on the growth of Gram-positive (Bacillus subtilis), Gram-negative (Escherichia coli) bacteria and a fungi (Candida albicans) were examined; which showed good antibacterial as well as antifungal properties. These findings introduce a simple, inexpensive process to synthesize ZnO-NPs using conventional methods without the use of sophisticated equipments and its application as a potent nano-antibiotic.
It is confirmed that nano-ZnO (nZnO) has impact on environment and is considered as heavy metal pollutants. It is a new technology that applies coagulation process to simultaneous removal of the nanoparticles and heavy metals. Environmental chemical behavior of ZnO in water, such as the dispersion, aggregation, sedimentation, and dissolution of releasing metal ions, has been systematically studied in this paper. The result shows that three kinds of nZnO state such as compacted sediment, suspended, and released is separately 36.54 %, 40.61 %, and 22.86 %. Enteromorpha polysaccharide (Ep) was used together with polyaluminum chloride (PAC) in surface water purification. In order to study the mechanism of simultaneous removal of residual nZnO particles and Zn(2+), coagulation process was further applied in this study. The evolution of flocs size, strength, and recovery ability and fractal structure due to Ep addition was systematically studied in this paper. Results indicated that PAC-Ep was efficient in removing nZnO and Zn(2+), which leads to more than 95 % particles, 50-60 % natural organic matter (NOM) removed, and 35 % of resolved heavy metal ion adsorbing-chelation. Ep was an efficient coagulant aid in enhancing performance of coagulation and generating flocs with bigger sizes, faster growth rates, and higher recovery abilities. Additionally, the flocs formed by PAC-Ep presented a much looser structure than flocs formed only by PAC. Graphical abstract ᅟ.
Veins are longitudinal cuticular structures that maintain shape of the wing. Drosophila melanogaster has six longitudinal veins (L1-L6) and two cross veins. The Zn-finger transcription factors of Spalt-complex (Sal) are required for positioning of the L2 and L5, and the homeodomain transcription factors of Iroquois complex (Iro-C) are required for formation of the L3 and L5 veins. The homeodomain transcriptional repressor Defective proventriculus (Dve) is uniformly expressed in the wing pouch of the larval imaginal disc. However, dve mutant wings showed loss of the L2 and L5, but not of the L3 and L4 veins. Temporal dve knockdown experiments indicate that the Dve activity is required for vein formation from late third larval instar to the prepupal stage. In the prepupal wing, Dve expression becomes nearly complementary to that of Sal through the Sal-mediated dve repression. Furthermore, coexpression of Dve and Iro-C relieved of Sal-mediated repression is required for the L5 formation in a dose-dependent manner. The relationship between Sal, Dve, and Iro-C in wing vein specification is quite similar to that in ommatidial cell-type specification. Our results provide information about the conserved function of dve regulatory motifs in cell differentiation.
The aim of the present study was to examine trace elements (Zn, Cu, Mn, Se, Fe, Co, Cr, Ni, Cd, Pb), minerals (Ca, Mg, K), amino acids status in children with phenylketonuria and also whether they were correlated with each other in phenylketonuric patients. It has been found out that the HPA group was significantly lower than the control group with regards to Zn, Se, K, Ca, Mg and Zn/Cr levels (p<0.001, p<0.01, p<0.001, p<0.01, p<0.01 and p<0.001 respectively). In the patients with HPA, significantly strong positive correlations were observed between magnesium and calcium (r=0.791; p=0.001), also, indicates negative significant correlation between the concentrations of magnesium and phenylalanine (r=-0.591; p=0.026). The results of this study showed that, in the HPA group, phenylalanine-Mg relationship found, the presence of disease will in the evaluation of phenylalanine and other amino acids, together with the value of magnesium is required to consider.
We have assessed the persistence and lifetime of ZnO nanoparticles (ZnO-NPs) by performing dissolution experiments in three different aqueous media. These experiments were performed at ZnO-NP concentration levels close to the solubility of zincite (∼8 μM or 650 μg l(-1) of ZnO)-a concentration that is orders of magnitude higher than current estimated relevant environmental concentrations. The kinetics were followed by voltammetry, while maintaining the pH at about 7.5 using a CO2/N2 gas mixture to remove di-oxygen interference. Our results show that, under these conditions, ZnO-NPs readily dissolve with a lifetime expectancy that does not exceed 90 min. Water chemistry, especially the presence of dissolved organic matter (DOM), plays an important role in ZnO-NP dissolution. Dissolution rates significantly increase in the presence of strong chelating agents, EDTA and L-cysteine, while the addition of polymeric DOM, such as sodium alginate, has the opposite effect. Our results suggest that ZnO-NPs are unlikely to persist in natural aqueous media and that the toxicity should be primarily related to the released Zn(2+) ions rather than effects commonly associated to the presence of nanoparticles.
The present attempt was made to determine the effects of untreated municipal wastewater (MW) on growth and physiology of maize and to evaluate the role of Ag nanoparticle and plant-growth-promoting rhizobacteria (PGPR) when interacting with MW used for irrigation. It was used for the isolation of PGPR. The isolates were identified and characterized based on the colony morphology, C/N source utilization pattern using miniaturized identification system (QTS 24), catalase (CAT) and oxidase tests, and 16S rRNA sequence analyses. The three PGPR isolates were Planomicrobium chinense (accession no. NR042259), Bacillus cereus (accession no. CP003187) and Pseudomonas fluorescens (accession no. GU198110). The isolates solubilized phosphate and exhibited antibacterial activities against pathogenic bacteria i.e., Staphylococcus aureus, Pseudomonas aeruginosa, Bacillus subtilis, Klebsiella pneumoniae and Escherichia coli and antifungal activities against Helminthosporium sativum and Fusarium solani. The untreated MW irrigation as well as Ag nanoparticle treatment resulted in significant accumulation of Ni in the rhizosphere soil. PGPR induced accumulation of Ni and Pb in
 the rhizosphere soil and maize shoot. Ag nanoparticle also caused Ni and Pb accumulation in maize shoot. Combined treatment with PGPR, Ag nanoparticle and MW resulted in decreased accumulation of Pb and Ni both in the rhizosphere soil and maize shoot. Combined treatment of Ag nanoparticle, MW and PGPR decreased Na accumulation and increased K accumulation. Ag nanoparticle increased Fe and Co accumulation but decreased Zn and Cu accumulation in MW treatment; in combined treatment, it reduced PGPR-induced accumulation of Co and Fe in the rhizosphere and Co accumulation in shoot. PGPR significantly increased root weight, shoot weight, root length, shoot length, leaf area, and proline, chlorophyll and carotenoid content of the maize plant. Ag nanoparticle also enhanced the leaf area, fresh weight, root length and antioxidant activities of maize. Treatment with Ag nanoparticle increased the gibberellic acid (GA) and abscisic acid (ABA) content of maize leaves but decreased the accumulation of GA in the presence of PGPR and MW.
The aim of the study was to estimate the ability of ten tree and bush species to tolerate and accumulate Cd, Cu, Pb, Zn, and As species [As(III), As(V), and total organic arsenic] in industrial sewage sludge extremely contaminated with arsenic (almost 27.5 g kg(-1)) in a pot experiment. The premise being that it will then be possible to select the most promising tree/bush species, able to grow in the vicinity of dams where sewage sludge/flotation tailings are used as landfill. Six of the ten tested tree species were able to grow on the sludge. The highest content of total As was observed in Betula pendula roots (30.0 ± 1.3 mg kg(-1) DW), where the dominant As species was the toxic As(V). The highest biomass of Quercus Q1 robur (77.3 § 2.6 g) and Acer platanoides (76.0 § 4.9 g) was observed. A proper planting of selected tree species that are able to thrive on sewage sludge/flotation tailings could be an interesting and promising way to protect dams. By utilizing differences in their root systems and water needs, we will be able to reduce the risk of fatal environmental disasters.
To examine the most recent literature that provides new data regarding the potential and emerging biomarkers for zinc status in individuals.
Suboptimal dietary zinc intake is estimated to affect 17% of the world's population; however, the assessment of zinc status is notoriously difficult. A systematic review and meta-analysis of studies investigating biochemical biomarkers of zinc status was conducted by the European Micronutrient Recommendations Aligned network. This review summarized the data published from inception to 2007. More recently (2016), an international expert panel, convened by the biomarker of nutrition for development initiative, published an extensive review of the literature addressing biomarkers of zinc status in populations and individuals and categorized the biomarkers as useful [dietary intake, serum Zn concentration and stunting], potentially useful [hair Zn concentration, urine Zn concentration and neurobehavioural function] and emerging [nail Zn concentration, oxidative stress and DNA integrity, zinc kinetics, zinc-dependent proteins and taste acuity].
The most recent data on the potentially useful biomarkers support the further investigation of hair Zn concentration and indices of neurological function, particularly those assessing memory and attention. Of the emerging biomarkers, the measurement of DNA integrity and the expression of zinc transport proteins look promising.
Earthworms are a major part of the total biomass of soil fauna and play a vital role in soil maintenance. They process large amounts of plant and soil material and can accumulate many pollutants that may be present in the soil. Earthworms have been explored as bioaccumulators for many heavy metal species such as Pb, Cu and Zn but limited information is available for mercury uptake and bioaccumulation in earthworms and very few report on the factors that influence the kinetics of Hg uptake by earthworms. It is known however that the uptake of Hg is strongly influenced by the presence of organic matter, hence the influence of ligands are a major factor contributing to the kinetics of mercury uptake in biosystems. In this work we have focused on the uptake of mercury by earthworms (Eisenia andrei) in the presence of humic acid (HA) under varying physical conditions of pH and temperature, done to assess the role of humic acid in the bioaccumulation of mercury by earthworms from soils. The study was conducted over a 5-day uptake period and all earthworm samples were analysed by direct mercury analysis. Mercury distribution profiles as a function of time, bioaccumulation factors (BAFs), first order rate constants and body burden constants for mercury uptake under selected conditions of temperature, pH as well as via the dermal and gut route were evaluated in one comprehensive approach. The results showed that the uptake of Hg was influenced by pH, temperature and the presence of HA. Uptake of Hg(2+) was improved at low pH and temperature when the earthworms in soil were in contact with a saturating aqueous phase. The total amount of Hg(2+) uptake decreased from 75 to 48 % as a function of pH. For earthworms in dry soil, the uptake was strongly influenced by the presence of the ligand. Calculated BAF values ranged from 0.1 to 0.8. Mercury uptake typically followed first order kinetics with rate constants determined as 0.2 to 1 h(-1).
Two novel pyridine pendant-armed macrocycles structurally reinforced by an ethyl bridge, either between adjacent nitrogens (for side-bridged) or non-adjacent nitrogens (for cross-bridged), have been synthesized and complexed with a range of transition metal ions (Co(2+), Ni(2+), Cu(2+) and Zn(2+)). X-ray crystal structures of selected cross-bridged complexes were obtained which showed the characteristic cis-V configuration with potential labile cis binding sites. The complexes have been characterized by their electronic spectra and magnetic moments, which show the expected high spin divalent metal complex in most cases. Exceptions are the nickel side-bridged complex, which shows a mixture of high-spin and low spin, and the cobalt cross-bridged complex which has oxidized to cobalt(III). Cyclic voltammetry in acetonitrile was carried out to assess the potential future use of these complexes in oxidation catalysis. Selected complexes offer significant catalytic potential enhanced by the addition of the pyridyl arm to a reinforced cyclen backbone.
Zolpidem is not a typical GABAA receptor hypnotic. Unlike benzodiazepines, zolpidem modulates tonic GABA currents in the rat dorsal motor nucleus of the vagus, exhibits residual effects in mice lacking the benzodiazepine binding site, and improves speech, cognitive and motor function in human patients with severe brain injury. The receptor by which zolpidem mediates these effects is not known. In this study we evaluated binary α1β3 GABAA receptors in either the 3α1:2β3 or 2α1:3β3 subunit stoichiometry, which differ by the existence of either an α1-α1 interface, or a β3-β3 interface, respectively. Both receptor stoichiometries are readily expressed in Xenopus oocytes, distinguished from each other by using GABA, zolpidem, diazepam and Zn(2+). At the 3α1:2β3 receptor, clinically relevant concentrations of zolpidem enhanced GABA in a flumazenil-sensitive manner. The efficacy of diazepam was significantly lower compared to zolpidem. No modulation by either zolpidem or diazepam was detected at the 2α1:3β3 receptor, indicating that the binding site for zolpidem is at the α1-α1 interface, a site mimicking the classical α1-γ2 benzodiazepine site. Activating α1β3 (3α1:2β3) receptors may, in part, mediate the physiological effects of zolpidem observed under distinct physiological and clinical conditions, constituting a potentially attractive drug target.
Childhood obesity often leads to cardiovascular diseases, such as obesity-related cardiac hypertrophy (ORCH), in adulthood, due to chronic cardiac inflammation. Zinc is structurally and functionally essential for many transcription factors; however, its role in ORCH and underlying mechanism(s) remain unclear and were explored here in mice with obesity induced with high-fat diet (HFD). Four week old mice were fed on either HFD (60%kcal fat) or normal diet (ND, 10% kcal fat) for 3 or 6 months, respectively. Either diet contained one of three different zinc quantities: deficiency (ZD, 10mg zinc per 4057kcal), normal (ZN, 30mg zinc per 4057kcal) or supplement (ZS, 90mg zinc per 4057kcal). HFD induced a time-dependent obesity and ORCH, which was accompanied by increased cardiac inflammation and p38 MAPK activation. These effects were worsened by ZD in HFD/ZD mice and attenuated by ZS in HFD/ZS group, respectively. Also, administration of a p38 MAPK specific inhibitor in HFD mice for 3 months did not affect HFD-induced obesity, but completely abolished HFD-induced, and zinc deficiency-worsened, ORCH and cardiac inflammation. In vitro exposure of adult cardiomyocytes to palmitate induced cell hypertrophy accompanied by increased p38 MAPK activation, which was heightened by zinc depletion with its chelator TPEN. Inhibition of p38 MAPK with its specific siRNA also prevented the effects of palmitate on cardiomyocytes. These findings demonstrate that ZS alleviates but ZD heightens cardiac hypertrophy in HFD-induced obese mice through suppressing p38 MAPK-dependent cardiac inflammatory and hypertrophic pathways.
Using Zn(2+)-BPMP or Cu(2+)-BPMP as a receptor and o-mercaptophenol as an indicator, potentiometric sensing of aqueous phosphate by competition assays was achieved. With attractive features of portability, low cost and resistance to interference from turbidity and color, this sensor was successfully used for phosphate detection
 in biological and water samples.
Cells use the post-translational modification ADP-ribosylation to control a host of biological activities. In some pathogenic bacteria, an operon-encoded mono-ADP-ribosylation cycle mediates response to host-induced oxidative stress. In this system, reversible mono ADP-ribosylation of a lipoylated target protein represses oxidative stress response. An NAD(+) -dependent sirtuin catalyzes the single ADP-ribose (ADPr) addition, while a linked macrodomain-containing protein removes the ADPr. Here we report the crystal structure of the sitruin-linked macrodomain protein from Staphylococcus aureus, SauMacro (also known as SAV0325) to 1.75-Å resolution. The monomeric SauMacro bears a previously unidentified Zn(2+) -binding site that putatively aids in substrate recognition and catalysis. An amino-terminal three-helix bundle motif unique to this class of macrodomain proteins provides a structural scaffold for the Zn(2+) site. Structural features of the enzyme further indicate a cleft proximal to the Zn(2+) binding site appears well suited for ADPr binding, while a deep hydrophobic channel in the protein core is suitable for binding the lipoate of the lipoylated protein target.
The effects of plant-bound zinc (Zn) and cadmium (Cd) on element uptake and their interactions in a parasite-host system were investigated in a model experiment. Male Wistar rats were divided into four groups (C, P, TC and TP). Groups TC and TP were infected with the rat tapeworm Hymenolepis diminuta. Groups C and TC were fed a standard rodent mixture (ST-1) and received 10.5 mg of Zn per week, while groups P and TP were fed a mixture supplemented with the Zn- and Cd-hyperaccumulating plant Arabidopsis halleri at a dosage of 236 mg Zn/week and 3.0 mg Cd/week. Rats were euthanized after 6 weeks, and Cd and Zn levels were determined in rat and tapeworm tissue. The results indicate that tapeworm presence did have an effect on Cd and Zn concentrations in the host tissue; the majority of tissues in infected rats had statistically significant lower Zn and Cd concentrations than did uninfected rats. Tapeworms accumulated more zinc and cadmium than did the majority of host tissues. This important finding confirms the ability of tapeworms to accumulate certain elements (heavy metals) from the host body to their own body tissues. Thus, tapeworms can decrease heavy metal concentrations in host tissues.
The present study was carried out to investigate the heavy metal concentration accumulated by summer squash cultivated in contaminated soil and their health hazards for public consumers at south Cairo Province, Egypt. Soil and plants were sampled from contaminated and reference farms, using 1 m(2) quadrats, for biomass estimation and nutrient analysis. The daily intake of metals (DIM) and health risk index (HRI) were estimated. Significant differences in soil variables (except As) between contaminated and reference sites were recognized. Summer squash showed remarkable reduction in fresh and dry biomass, fruit production, and photosynthetic pigments under pollution stress. The inorganic and organic nutrients in the aboveground and belowground parts showed significant reduction in contaminated site. In addition, higher concentrations of heavy metals were accumulated in the edible parts and roots more than shoots. The bioaccumulation factor of summer squash for investigated metals was greater than 1, while the translocation factor did not exceed unity in both contaminated and reference sites. The DIM for all investigated metals in the reference site and in the contaminated site (except Fe and Mn) did not exceed 1 in both adults and children. However, HRI of Ni and Mn in the reference site and Pb, Cd, Cu, Ni, Fe, Mn, and Zn in the contaminated one exceeded unity indicating great potential to pose health risk to the consumers. The author recommends that people living in the contaminated area should not eat large quantities of summer squash, so as to avoid excess accumulation of heavy metals in their bodies.
In Europe soil contamination has been recognized as a serious problem. The needs to remediate contaminated sites are not questionable, although the remediation actions are often hindered by their very high financial costs. On the other hand, the abandoned contaminated sites may have the potential for redevelopment and creating conditions appropriate for their productive reuse bringing social, economic and environmental benefits. The main concern associated with the contaminated sites is their potential adverse health impact. Therefore, in the process of contaminated site redevelopment the risk assessment and the subsequent risk management decisions will play a crucial role. The main objective of this study was to illustrate the role of the human health risk assessment (HRA) in supporting site remediation and reuse decisions. To exemplify the significance of the HRA process in this field the Nitrastur site, located in Asturias, Spain was used. Risks resulting from soil contamination with arsenic (As), cadmium (Cd), chromium (Cr), copper (Cu), nickel (Ni), mercury (Hg), zinc (Zn) and lead (Pb) were assessed under three potential future land use patterns: industrial, residential and recreational. The results of the study indicated that soil at the Nitrastur site might pose non-cancer and cancer risks to potential future receptors - industrial workers, residents and recreational users. Arsenic and lead are the main substances responsible for the health risk and the primary drivers of remedial decisions at the site. The highest total cancer risks were observed under the residential scenario, followed in descending order by the recreational and industrial ones. The remedial maps illustrate in which areas remediation activities are required, depending on a given land use pattern. The obtained results may be used to develop, analyse, compare and select the remedial options within the intended land use pattern. They may also be used to support the decisions concerning the reuse of the site or to create different redevelopment plans for different parts of the site. The study may help improve understanding and interaction between risk assessors and risk managers which are necessary to make proper, fully informed decisions enhancing public trust and credibility.
Refined exposure assessments were realized for children, 7-9yrs, in the mining/smelting city of Oruro, Bolivia. Aerosols (PM>2.5, PM1-2.5, PM0.4-1 and PM0.5) and dust (separated in different particle size fractions: 2000-200μm, 200-50μm, 50-20μm, 20-2μm and <2μm) were sampled on football fields highly frequented by children in both the mining and smelting areas. Trace element concentrations (Ag, As, Cd, Cu, Pb, Sb, Sn and Zn) in each size fraction of dust and aerosols, lung bioaccessibility of metals in aerosols, and gastric bioaccessibility of metals in dust were measured. Exposure was assessed considering actual external exposure (i.e. exposure pathways: metals inhaled and ingested) and simulated internal exposure (i.e., complex estimation using gastric and lung bioaccessibility, deposition and clearance of particles in lungs). Significant differences between external and simulated internal exposure were attributed to dissemblances in gastric and lung bioaccessibilities, as well as metal distribution within particle size range, revealing the importance of both parameters in exposure assessment.
Astragalus polysaccharide (APS) is an important bioactive component extracted from Chinese herb Astragalus membranaceus. It has been widely used in treatment of cardiovascular diseases. We have previously reported that APS could inhibit isoproterenol-induced cardiac hypertrophy. The present study was designed to evaluate the protective effect of APS on vascular endothelia in cardiac hypertrophy rats induced by isoproterenol (ISO). ISO (10mg×kg(-1)) was intraperitoneally injected once daily for 2weeks to induce cardiac hypertrophy. APS (400 and 800mg×kg(-1)) was intragastrically injected once daily along with ISO. The results showed that combination with APS significantly ameliorates the endothelial dysfunction while attenuates cardiac hypertrophy induced by ISO. We found that administration with APS could attenuate the increase in number of circulating endothelial cell (CEC). APS also decreases the superoxide anion generation and the protein expression of p65 and the levels of TNF-α and IL-6; while increases the cGMP levels, an activity marker for nitric oxide (NO) in aortas. In addition, APS improves the relaxation dysfunction in isolated aortic rings and increases the protein expression of IκBα and Cu/Zn-SOD in aortas. In conclusion, our results suggested that APS had a protective effect against endothelial dysfunction in hypertrophic rats induced by ISO. The underlining mechanisms may be contributed to the anti-inflammatory effects and the improvement of the imbalance between reactive oxygen species (ROS) and NO.
Increased use of graphene materials might lead to their release into the environment. However, only a few studies have investigated the impact of graphene-based materials on green plants. In the present study, effects of graphene on plant roots and shoots after 48h or 30days of hydroponic culture were evaluated to determine its phytotoxicity. Results showed that although exposure to graphene (250, 500, 1000 and 1500mgL(-1)) significantly improved root elongation, root hair production was impaired. These observations might be associated with graphene induced-oxidative stress (indicated by nitroblue tetrazolium (NBT) and Evans blue staining, malondialdehyde (MDA) estimation, and antioxidant enzyme activity assay). After 30days of graphene exposure, shoot biomass, chlorophyll content, PSII activity and levels of several nutrient elements (N, K, Ca, Mg, Fe, Zn and Cu) were reduced,
 indicating that graphene inhibited plant growth and photosynthesis, and caused an imbalance of nutrient homeostasis. Based on these findings, we conclude that graphene has growth-limiting effects on plants, including root hair reduction, oxidative burst, photosynthesis inhibition, and nutritional disorder.
An efficient electrochemical sensor for As(III) was developed based on adsorption of arsenic on a specially modified electrodes at some applied potential and subsequent i) stripping at a fixed potential by anodic stripping voltammetry ii) analysis by generating surface plasmon resonance (SPR). The working glassy carbon electrode was modified by Chitosan-Fe(OH)3 composite and a reducing agent L-cysteine. The composite enhanced adsorption of As(III) and subsequent reduction to As(O) moieties and measurement by anodic stripping. The surface property of modified electrode was characterized by SEM, AFM, FTIR, XPS and electrochemistry was analyzed by impedance spectroscopy (EIS). Surface Plasmon resonance (SPR) was also employed to investigate the As(III) binding capability of polymer matrix. Several optimum voltammetric parameters e.g supporting electrolyte; 0.1M acetate buffer (pH 5.2) deposition potential, -0.9V; deposition time, 100s were established for anodic stripping voltammetry (ASV). A linear correlation was obtained in the range of 2-100ppb for ASV (R(2) 0.974) with limit of detection 0.072ppb. A variety of common coexistent ions such as Mn, Zn, Pb, Cu, Cd in water samples showed no interferences on the As (III) determination. The method was applied successfully to real samples collected from arsenic affected areas of West Bengal, India.
A new, highly selective turn-on fluorescent chemosensor based on 2-(2'-tosylamidophenyl)thiazole (1) for the detection of zinc and phosphate ions in ethanol was synthesized and characterized. Sensor 1 showed a high selectivity for zinc compared to other cations and sequentially detected hydrogen pyrophosphate and hydrogen phosphate. The fluorescence mechanism can be explained by two different mechanisms: (i) the inhibition of excited-state intramolecular proton transfer (ESIPT) and (ii) chelation-induced enhanced fluorescence by binding with Zn(2+). The sequential detection of phosphate anions was achieved by the quenching and subsequent revival of ESIPT.
The Zn-dependent membrane-located protease YvjB has previously been shown to serve as a target receptor for LsbB, a class II leaderless lactococcal bacteriocin. Although yvjB is highly conserved in the genus Lactococcus, the bacteriocin appears to be active only against the subspecies L. lactis subsp. lactis Comparative analysis of the YvjB proteins of a sensitive strain (YvjBMN) and a resistant strain (YvjBMG) showed that they differ from each other in 31 positions. In this study, we applied site-directed mutagenesis and performed directed binding studies to provide biochemical evidence that LsbB interacts with the third transmembrane helix of YvjB in susceptible cells. The site-directed mutagenesis of LsbB and YvjB proteins showed that certain amino acids and the length of LsbB are responsible for the bacteriocin activity, most probably through adequate interaction of these two proteins; the essential amino acids in LsbB responsible for the activity are tryptophan (Trp(25)) and terminal alanine (Ala(30)). It was also shown that the distance between Trp(25) and terminal alanine is crucial for LsbB activity. The crucial region in YvjB for the interaction with LsbB is the beginning of the third transmembrane helix, particularly amino acids tyrosine (Tyr(356)) and alanine (Ala(353)). In vitro experiments showed that LsbB could interact with both YvjBMN and YvjBMG, but the strength of interaction is significantly less with YvjBMG In vivo experiments with immunofluorescently labeled antibody demonstrated that LsbB specifically interacts only with cells carrying YvjBMN IMPORTANCE: The antimicrobial activity of LsbB bacteriocin depends on the correct interaction with the corresponding receptor in the bacterial membrane of sensitive cells. Membrane-located bacteriocin receptors have essential primary functions, such as cell wall synthesis or sugar transport, and it seems that interaction with bacteriocins is suicidal for cells. This study showed that the C-terminal part of LsbB is crucial for the bacteriocin activity, most probably through adequate interaction with the third transmembrane domain of the YvjB receptor. The conserved Tyr(356) and Ala(353) residues of YvjB are essential for the function of this Zn-dependent membrane-located protease as a bacteriocin receptor.
Inadequate nutrient intake as part of a complementary feeding diet is attributable to poor feeding practices and poor access to nutritious foods. Household socio-economic situation (SES) has an influence on food expenditure and access to locally available, nutrient-dense foods and fortified foods. This study aimed to develop and compare complementary feeding recommendations (CFR) for 12-23-month-old children in different SES and evaluate the contribution of fortified foods in meeting nutrient requirements. A cross-sectional survey was conducted in low and medium SES households (n 114/group) in urban Bandung district, West Java province, Indonesia. Food pattern, portion size and affordability were assessed, and CFR were developed for the low SES (LSES) and middle SES (MSES) using a linear programming (LP) approach; two models - with and without fortified foods - were run using LP, and the contribution of fortified foods in the final CFR was identified. Milk products, fortified biscuits and manufactured infant cereals were the most locally available and consumed fortified foods in the market. With the inclusion of fortified foods, problem nutrients were thiamin in LSES and folate and thiamin in MSES groups. Without fortified foods, more problem nutrients were identified in LSES, that is, Ca, Fe, Zn, niacin and thiamin. As MSES consumed more fortified foods, removing fortified foods was not possible, because most of the micronutrient-dense foods were removed from their food basket. There were comparable nutrient adequacy and problem nutrients between LSES and MSES when fortified foods were included. Exclusion of fortified foods in LSES was associated with more problem nutrients in the complementary feeding diet.
The way in which women accommodate for their increased nutritional needs during the lactation period is poorly investigated. In a cross-sectional study involving 220 lactating women (LW), equally distributed in economic quintiles (Q2, Q3, Q4), we investigated whether habitual dietary intake of LW differed from that of 200 pre-pregnant women (PPW) studied using the same methodology. Differences in dietary intake and nutrition sufficiency according to economic status were also investigated. Dietary intake data were collected using 2×24-h dietary recalls and FFQ. Energy, protein, Fe, Ca, Zn and vitamins A and C intakes were calculated utilising local food composition tables and were compared against Indonesian recommendations for adequacy. Energy and protein intakes 25 % of LW. For Q2-LW, this proportion was >50 %, except for protein. LW across all studied economic quintiles approximately doubled their vegetable intake, and 71 % of LW indicated a belief that this enhances lactation performance. Biochemical status parameters were analysed in a subset of forty-five women. Anaemia as well as Fe, Zn and Se deficiencies were prevalent among LW, supporting the nutrient intake deficiency data. Despite increasing intakes in LW compared with PPW, habitual diets in the study area do not provide for daily nutrient requirements in substantial proportions for both LW and PPW across all investigated economic groups.
In this study, the relevance of Fenton's reaction for the treatment of urban anaerobically digested sludge was investigated. In a first part, the impact of the oxidation process on the improvement of the sludge dewaterability was studied. In a second part, the removal of heavy metals from the sludge was examined. Fenton's reaction was carried out with increasing concentrations of Fe(2+) and H2O2 in 1:10 and 1:1 ratios. Dewaterability of the raw sludge was highly improved: the addition of 36 mM Fe(2+) and 360 mM H2O2 led to specific cake resistance (SCR) and capillary suction time (CST) reductions of 99.8% and 98.8%, respectively. Indeed, under these conditions, SCR and CST of respectively 1.04 × 10(11) m kg(-1) and 18.5 ± 0.2 s were measured, and the treated sludge could be considered as having 'good dewaterability'. A significant impact was also observed on the removal of heavy metals from the sludge. After 1-h oxidation, Cd, Cr, Cu, Pb and Zn could be removed by 81.1 ± 0.1%, 25.1 ± 0.1%, 87.2 ± 1.1%, 77.3 ± 4.8% and 99.6 ± 0.3%, respectively. These results were consistent with the heavy metals' fractions in the sludge. It could be concluded that the addition of Fe(2+) and H2O2 in a 1:10 ratio was more effective than in a 1:1 ratio. The results were consistent with the extracellular polymeric substance (EPS) contents in raw and treated sludge, since loosely bound EPS decreased significantly after the treatment.
We propose a combined experimental and numerical study to describe an order-disorder structural phase transition in perovskite-based [(CH3)2NH2][M(HCOO)3] (M = Zn(2+), Mn(2+), Fe(2+), Co(2+) and Ni(2+)) dense metal-organic frameworks (MOFs). The three-fold degenerate orientation of the molecular (CH3)2NH2(+) (DMA(+)) cation implies a selection of the statistical three-state model of the Potts type. It is constructed on a simple cubic lattice where each lattice point can be occupied by a DMA(+) cation in one of the available states. In our model the main interaction is the nearest-neighbor Potts-type interaction, which effectively accounts for the H-bonding
 between DMA(+) cations and M(HCOO)3(-) cages. The model is modified by accounting for the dipolar interactions which are evaluated for the real monoclinic lattice using density functional theory. We employ the Monte Carlo method to numerically study the model. The calculations are supplemented with the experimental measurements of electric polarization. The obtained results indicate that the three-state Potts model correctly describes the phase transition order in these MOFs, while dipolar interactions are necessary to obtain better agreement with the experimental polarization. We show that in our model with substantial dipolar interactions the ground state changes from uniform to the layers with alternating polarization directions.
Fatal neurodegenerative disorders termed transmissible spongiform encephalopathies (TSEs) are associated with the accumulation of fibrils of misfolded prion protein PrP. The noble gas xenon accommodates into four transiently enlarged hydrophobic cavities located in the well-folded core of human PrP(23-230) as detected by [(1)H, (15)N]-HSQC spectroscopy. In thermal equilibrium a fifth xenon binding site is formed transiently by amino acids A120 to L125 of the presumably disordered N-terminal domain and by amino acids K185 to T193 of the well-folded domain. Xenon bound PrP was modelled by restraint molecular dynamics. The individual microscopic and macroscopic dissociation constants could be derived by fitting the data to a model including a dynamic opening and closing of the cavities. As observed earlier by high pressure NMR spectroscopy xenon binding influences also other amino acids all over the N-terminal domain including residues of the AGAAAAGA motif indicating a structural coupling between the N-terminal domain and the core domain. This is in agreement with spin labelling experiments at positions 93 or 107 that show a transient interaction between the N-terminus and the start of helix 2 and the end of helix 3 of the core domain similar to that observed earlier by Zn(2+)-binding to the octarepeat motif.
Model fly ash (MFA) samples were composed of silica, sodium chloride, and activated carbon, and doped with metal (0.1 wt% Cu, Cr, Ni, Zn and Cd) chloride or oxide. Each sample was de novo tested at 350 °C for 1 h, in a flow of gas (N2, N2 + 10% O2, +21% O2 or +10% H2) to investigate the effect of metal catalyst and gas composition on PCDD/F formation. Total PCDD/F yield rises rapidly with oxygen content, while the addition of hydrogen inhibits the formation and chlorination of PCDD/F. The amount of PCDD on average rises linearly with the oxygen concentration, while that of PCDF follows a reaction order of about 1/2; thus the PCDF to PCDD ratio drops when more oxygen becomes available. Some samples do not follow this trend. Chlorides are much more active than oxides, yet there are marked differences between individual metals. Principal component analysis (PCA) was applied to study the signatures from all samples, showing their unique specificity and diversity. Each catalyst shows a different signature within its individual homologue groups, demonstrating that these signatures are not thermodynamically controlled. Average congener patterns do not vary considerably with oxygen content changing from oxidising (air) to reducing (nitrogen, hydrogen).
Cadmium (Cd) pollution is a serious widespread environmental problem that not only destroys the microbial ecology of soil and decreases crop production, but also poses a serious risk to human health. Many methods have been used for the remediation of Cd pollution but none of these is totally satisfactory. Microbial remediation strategies have attracted increasing interest since they are environmentally friendly and cost-effective. In the present study, three Cd-resistant bacteria were isolated and evaluated for potential application in Cd bioremediation. Based on their morphological, physiological and biochemical characteristics, together with 16S rDNA gene sequence analyses, bacteria were identified as Stenotrophomonas acidaminiphila (2#), Pseudomonas aeruginosa (9#) and Delftia tsuruhatensis (12#). Pseudomonas aeruginosa showed very high tolerance to metals, especially Cd (2200mg/L), Zn (1800mg/L) and Pb (1200mg/L), and is thought to be a multi-metal-resistant bacterium. Pseudomonas aeruginosa was also sensitive to 13 different antibiotics. The effects of the bacterial strains on the growth of rice plants and their ability to reduce Cd accumulation from Cd-contaminated soils in pot experiments were also evaluated. For Oryza sativa L. A grown in contaminated soil (3mg/kg Cd), the accumulation of Cd was decreased by 31.2 and 25.5% in brown rice and polished rice, respectively, by strain 9#; Pseudomonas aeruginosa was more effective in reducing Cd accumulation in rice grains than a mixture of strains. For Oryza sativa L. B, a mixture of strains acting synergistically was more effective than a single strain in reducing Cd accumulation; treatment with mixed strains (strains+3mg/kg Cd) resulted in 41.3, 35.9, and 32.6% reductions in Cd accumulation in unhulled rice, brown rice and polished rice, respectively. Although different results were obtained for two rice varieties, it can still be concluded that Cd-resistant bacteria are suitable for reducing Cd accumulation in rice grains and show potential for bioremediation of Cd-contaminated soils.
Zinc (Zn) is an essential trace mineral that contributes to the regulation of several cellular functions; however, it may be also implicated in the progression of breast cancer through different mechanisms. It has been largely reported that the classical estrogen receptor (ER), as well as the G protein estrogen receptor (GPER, previously known as GPR30) can exert a main role in the development of breast tumors. In the present study, we demonstrate that zinc chloride (ZnCl2 ) involves GPER in the activation of insulin-like growth factor receptor I (IGF-IR)/epidermal growth factor receptor (EGFR)-mediated signaling, which in turn triggers downstream pathways like ERK and AKT in breast cancer cells, and main components of the tumor microenvironment namely cancer-associated fibroblasts (CAFs). Further corroborating these findings, ZnCl2 stimulates a functional crosstalk of GPER with IGF-IR and EGFR toward the transcription of diverse GPER target genes. Then, we show that GPER contributes to the stimulatory effects induced by ZnCl2 on cell-cycle progression, proliferation, and migration of breast cancer cells as well as migration of CAFs. Together, our data provide novel insights into the molecular mechanisms through which zinc may exert stimulatory effects in breast cancer cells and CAFs toward tumor progression. © 2016 Wiley Periodicals, Inc.
Substantial epidemiological evidence has consistently reported that fine particulate matter (PM2.5) is associated with an increased risk of cardiovascular outcomes. PM2.5 is a complex mixture of extremely small particles and liquid droplets composed of multiple components, and there has been high interest in identifying the specific health-relevant physical and/or chemical toxic constituents of PM2.5. In the present study, we analyzed 8 heavy metals (Cr, Ni, Cu, Cd, Pb, Zn, Mn and Co) in the PM2.5 collected during four different seasons in Taiyuan, a typical coal-burning city in northern China. Our results indicated that total concentrations of the 8 heavy metals differed among the seasons. Zn and Pb, which are primarily derived from the anthropogenic source, coal burning, were the dominant elements, and high concentrations of these two elements were observed during the spring and winter. To clarify whether these heavy metals in the locally collected PM2.5 were associated with health effects, we conducted health risk assessments using validated methods. Interestingly, Pb was responsible for greater potential health risks to children. Because cardiovascular disease (CVD) is a main contributor to the mortality associated with PM2.5 exposure, we performed experimental assays to evaluate the myocardial toxicity. Our in vitro experiments showed that the heavy metal-containing PM2.5 induced season-dependent apoptosis in rat H9C2 cells through a reactive oxygen species (ROS)-mediated inflammatory response. Our findings suggested that heavy metals bound to PM2.5 produced by coal burning play an important role in myocardial toxicity and contribute to season-dependent health risks.
A moisture-stable three-dimensional (3D) metal-organic framework (MOF), {(Me2NH2)[Zn2(bpydb)2(ATZ)](DMA)(NMF)2}n (1, where bpydb = 4,4'-(4,4'-bipyridine-2,6-diyl)dibenzoate, ATZ = deprotonated 5-aminotetrazole, DMA = N,N-dimethylacetamide, and NMF = N-methylformamide), with uncoordinated N-donor sites and charged framework skeleton was fabricated. This MOF exhibits interesting structural dynamic upon CO2 sorption at 195 K and high CO2/N2 (127) and CO2/CH4 (131) sorption selectivity at 298 K and 1 bar. Particularly, its CO2/CH4 selectivity is among the highest MOFs for selective CO2 separation. The results of Grand Canonical Monte Carlo (GCMC) simulation indicate that the polar framework contributes to the strong framework-CO2 binding at zero loading, and the tetrazole pillar contributes to the high CO2 uptake capacity at high loading. Furthermore, the solvent-responsive luminescent properties of 1 indicate that it could be utilized as a fluorescent sensor to detect trace amounts of nitrobenzene in both solvent and vapor systems.
Amyotrophic lateral sclerosis (ALS) is an adult-onset neurodegenerative disorder that is typically fatal within 3-5 years of diagnosis. While motoneuron death is the defining characteristic of ALS, the events that underlie its pathology are not restricted to the nervous system. In this regard, ALS muscle atrophies and weakens significantly before presentation of neurological symptoms.
 Since the skeletal muscle L-type Ca(2+) channel (CaV1.1) is a key regulator of both mass and force, we investigated whether CaV1.1 function is impaired in the muscle of two distinct mouse models carrying an ALS-linked mutation.
We recorded L-type currents, charge movements, and myoplasmic Ca(2+) transients from dissociated flexor digitorum brevis (FDB) fibers to assess CaV1.1 function in two mouse models expressing a type 1 Cu/Zn superoxide dismutase mutant (SOD1(G93A)).
In FDB fibers obtained from "symptomatic" global SOD1(G93A) mice, we observed a substantial reduction of SR Ca(2+) release in response to depolarization relative to fibers harvested from age-matched control mice. L-type current and charge movement were both reduced by ~40 % in symptomatic SOD1(G93A) fibers when compared to control fibers. Ca(2+) transients were not significantly reduced in similar experiments performed with FDB fibers obtained from "early-symptomatic" SOD1(G93A) mice, but L-type current and charge movement were decreased (~30 and ~20 %, respectively). Reductions in SR Ca(2+) release (~35 %), L-type current (~20 %), and charge movement (~15 %) were also observed in fibers obtained from another model where SOD1(G93A) expression was restricted to skeletal muscle.
We report reductions in EC coupling, L-type current density, and charge movement in FDB fibers obtained from symptomatic global SOD1(G93A) mice. Experiments performed with FDB fibers obtained from early-symptomatic SOD1(G93A) and skeletal muscle autonomous MLC/SOD1(G93A) mice support the idea that events occurring locally in the skeletal muscle contribute to the impairment of CaV1.1 function in ALS muscle independently of innervation status.
Arsenite oxidizing bacteria, isolated from industrial wastewater, showed high resistance against arsenite (40 mM) and other heavy metals (10 mM Pb; 8 mM Cd; 6 mM Cr; 10 mM Cu and 26.6 mM As(5+)). Bacterial isolates were characterized, on the basis of morphological, biochemical and 16S rRNA ribotyping, as Bacillus cereus (1.1S) and Acinetobacter junii (1.3S). The optimum temperature and pH for the growth of both strains were found to be 37 °C and 7. Both the strains showed maximum growth after 24 h of incubation. The predominant form of arsenite oxidase was extracellular in B. cereus while in A. junii both types of activities, intracellular and extracellular, were found. The extracellular aresenite oxidase activity was found to be 730 and 750 µM/m for B. cereus and A. junii, respectively. The arsenite oxidase from both bacterial strains showed maximum activity at 37 °C, pH 7 and enhanced in the presence of Zn(2+). The presence of two protein bands with molecular weight of approximately 70 and 14 kDa in the presence of arsenic points out a possible role in arsenite oxidation. Arsenite oxidation potential of B. cereus and A. junii was determined up to 92 and 88 % in industrial wastewater after 6 days of incubation. The bacterial treated wastewater improved the growth of Vigna radiata as compared to the untreated wastewater. It indicates that these bacterial strains may find some potential applications in wastewater treatment systems to transform toxic arsenite into less toxic form, arsenate.
Species of Trichoderma are widely recognized for their biocontrol abilities, but seldom studied collectively, for their plant growth promotion, abiotic stress tolerance and bioremediation properties. Our study is a concentrated effort to establish the potential of native isolate Trichoderma harzianum KSNM (T103) to tolerate biotic (root pathogens) and abiotic stresses [high salt (100-1000 mM); heavy metal (chromium, nickel and zinc: 1-10 mM); pesticides: malathion (100-600 ppm), carbofuran (100-600 ppb)], along with its ability to support plant growth. In vitro growth promotion assays with T103 treated Vigna radiata, Vigna mungo and Hordeum vulgare confirmed 'non-species specific' growth promotion effects of T103. At lower metal concentration, T103 treatment was found to completely negate the impact of metal stress [60 % increase in radicle length (RL) with no significant decrease in %germination (%G)]. Even at 10 mM metal, T103 inoculation gave 80 % increase in %G and >50 % increase in RL. In vitro experiments confirmed high metal reduction capacity (47 %-Cr, 35 %-Ni and 42 %-Zn) of T103 at concentrations as high as 4 mM. At maximum residual concentrations of malathion (440 ppm) and carbofuran (100 ppb) reported in agricultural soils, T103 maintained 80 and 100 % survivability, respectively. T103 treatment has improved %G and RL in all three hosts challenged with pesticide. Isolate T103 was found to effectively suppress growth of three major root pathogens: Macrophomina phaseolina (65.83 %) followed by Sclerotium rolfsii (19.33 %) and Fusarium oxysporum (19.18 %). In the light of these observations, native T. harzianum (T103) seems to be a competent biocontrol agent for tropical agricultural soils contaminated with residual pesticides and heavy metals.
The current study aims to assess the infusion pattern of three important micronutrients namely copper (Cu), iron (Fe), and zinc (Zn) contents from black tea samples produced in Assam (India) and Thohoyandou (South Africa). Average daily intakes and hazardous quotient were reported for these micronutrients. Total content for Cu, Fe, and Zn varied from 2.25 to 48.82 mg kg(-1), 14.75 to 148.18 mg kg(-1), and 28.48 to 106.68 mg kg(-1), respectively. The average contents of each of the three micronutrients were higher in tea leaves samples collected from South Africa than those from India while the contents in tea infusions in Indian samples were higher than in South African tea samples. Results of this study revealed that the consumption of 600 mL tea infusion produced from 24 g of made tea per day may be beneficial to human in terms of these micronutrients content. Application of nonparametric tests revealed that most of the data sets do not satisfy the normality assumptions. Hence, the use of both parametric and nonparametric statistical analysis that subsequently revealed significant differences in elemental contents among Indian and South African tea.
The aim of this work was to investigate the effects of HgCl2 exposure in the doses of 0, 10 and 50μg Hg(2+)/mL in drinking water during pregnancy on tissue essential metal homeostasis, as well as the effects of HgCl2 exposure in utero and breast milk on behavioral tasks. Pregnant rats exposed to both inorganic mercury doses presented high renal Hg content and an increase in renal Cu and hepatic Zn levels. Mercury exposure increased fecal Hg and essential metal contents. Pups exposed to inorganic Hg presented no alterations in essential metal homeostasis or in behavioral task markers of motor function. In conclusion, this work showed that the physiologic pregnancy and lactation states protected the offspring from adverse effects of low doses of Hg(2+). This protection is likely to be related to the endogenous scavenger molecule, metallothionein, which may form an inert complex with Hg(2+).
Environmentally persistent free radicals (EPFRs) are relatively highly stable and found in the formation of polychlorinated dibenzo-p-dioxins and dibenzofurans (PCDD/Fs). Recent studies have concentrated on model dioxin formation reactions and there are few studies on actual waste incineration fly ash. In order to study EPFRs and the correlation with dioxins and heavy metals in waste incineration fly ash, the spins of EPFRs, concentration of PCDD/Fs and metals in samples from 6 different waste incinerators were detected. The medical waste incineration fly ash from Tianjin, municipal solid waste incineration fly ash from Jiangxi Province, black carbon and slag from municipal solid waste incinerator in Lanxi, Zhejiang Province, all contained EPFRs. Above all the signal in Tianjin sample was the strongest. Hydroxyl radicals, carbon-center radicals and semiquinone radicals were detected. Compared with other samples, Jiangxi fly ash had the highest toxic equivalent quantity (TEQ) of dioxins, up to 7.229 4 ng · g⁻¹. However, the dioxin concentration in the Tianjin sample containing the strongest EPFR signals was only 0.092 8 ng · g⁻¹. There was perhaps little direct numeric link between EPFRs and PCDD/Fs. But the spins of EPFRs in samples presented an increasing trend as the metal contents increased, especially with Al, Fe, Zn. The signal strength of radicals was purposed to be related to the metal contents. The concentration of Zn (0.813 7% ) in the Tianjin sample was the highest and this sample contained much more spins of oxygen-center radicals. We could presume the metal Zn had a greater effect on the formation of EPFRs, and was easier to induce the formation of radicals with a longer half-life period.
The soil with 500 m distance from an aluminum plant in Baotou was studied. A total of 64 soil samples were taken from the 0-5 cm, 5-20 cm, 20-40 cm and 40-60 cm layers, and the contents of Cu, Pb, Zn, Cr, Cd, Ni and Mn were tested, respectively. The correlation analysis and principal component analysis were used to identify the sources of these heavy metals in soils. The results suggested that the contents of Cu, Pb, Zn, Cr, Cd, Ni and Mn in study area were 32.9, 50.35, 69.92, 43.78, 0.54, 554.42 and 36.65 mg · kg⁻¹ respectively. All seven heavy metals tested were overweight compared with the background values of soil in Inner Mongolia. The spatial distribution of heavy metals showed that the horizontal distribution of heavy metals was obviously enriched in the southwest, while in vertical distribution, the heavy metal content (0 to 5 cm) was highest in the surface soil, and the heavy metal content decreased with increasing depth and tended to be stabilized when the depth was over 20 cm. Source analysis showed that the source of Cu, Zn, Cr and Mn might be influenced by the
 aluminum plant and the surrounding industrial activity. The source of Pb and Cd might be mainly related to road transportation. The source of Ni may be affected by agricultural activities and soil parent material together.
Hydrothermal treatment (HTT) of sewage sludge was conducted, focusing on the influence of HTT time on the dewaterability of sludge and transformations of elements N, P, K and heavy metals. The results showed that at a hydrotherma temperature of 160°C, with HTT time increasing from 30 to 120 min, the sludge dewatering performance was significantly improved. The transfer rate of N element in the sludge transferring to aqueous product increased gradually. Almost all of P element remained in the solid phase, and most of K element (57%-62%) was still in the solid phase although it was more easily transferred to the liquid phase than P element. The transferring behavior of heavy metals during the HTT related to their own properties, and their transferring behaviors were different with the increase of HTT time. Compared with the raw sludge, the contents of Cu, Zn, Cr and Pb in the dewatered sludge increased significantly, As increased slowly, while Ni and Cd were first lower than those in raw sludge, and then increased with the prolonging HTT time.
Based on the extracted fulvic acid (FA) from Lake Wuliangsuhai sediments by sequential alkali extraction, this work studied the effects of FA on the adsorption and fraction distribution of heavy metals (HM) on sediments using original sediments and sediments treated with 30% H₂O₂ as adsorbents. The results showed both organic matter and FA had effects on the HM adsorption onto sediments; The treatments of FA-free conditions and the sediments treated by H₂O₂ showed relatively strong influence on Cu²⁺ adsorption, which decreased the Cu²⁺ adsorption by 17.85%. With the increasing FA addition, the adsorption percentage of HM on both types of sediments showed gradually decreasing trends, with the order of Cu²⁺ > Cd²⁺ > Zn²⁺ > Pb²⁺; when the FA content was more than 5% , FA became the governing factor on the decreasing adsorption percentage of HM. With increasing FA addition, forms distribution of HM showed significant changes in both types of sediments; i. e. FA additions showed significant negative and positive correlations with percentages of metals bound to carbonates and organic matter, respectively, since the FA addition increased the H⁺ concentration of the system, in which H⁺ could activate the metals bound to carbonate from the sediments. As an organophilic weak element, the fraction percentage of Cd bound to organic matter was the lowest with the minimal changes.
In order to analyze the spatial variation characteristics of grain diameter, nutrient elements and heavy metal pollution with deposition sediment in tributaries bay of the Three Gorges Reservoir, we selected 9 typical tributaries bay, 54 deposited sediment samples were collected from the riparian zone for analyzing grain diameter distribution, capacity, organic matter, nutrient elements of TN, TP and K, heavy metal elements of Cr, Cu, Ni, Pb, and Zn. The results indicated that particle size distribution from Wujiang River in Fuling to the Modao stream in Yunyang presented a trend of fluctuation, deposited sediment at 160-165 m elevation was coarser than that at 165-175 m elevation,volume percent of sand and clay presented a moderate variation at both altitudes, while silt had small variation. Independent sample t test showed that characteristics difference between the upper and lower sediments in riparian zone was not significant. The geo-accumulation index of heavy metal pollutants in the sediment from riparian zone of the Three Gorges Reservoir tributaries bay indicated that, only Zn element in Zhenxi River, Longdong River and Long River, Pb element in the Modao Stream belonged to non-moderate pollution levels, whereas there were no pollution of all other elements in tributaries.
This study investigated the horizontal distribution characteristics of nutrients and heavy metals (Zn, As, Cr, Cu, Ni, Pb, Cd and Hg) in January, 2014, and assessed the potential ecological risk of Lake Gehu. It was found that the average contents of TN and TP were 2,207.94 and 708.62 mg · kg⁻¹ respectively. TN and TP contents of the sediments at the centre were significantly highei than those in the north, while the TN content in the south was also significantly higher than that in the north of Lake Gehu. The average contents of Zn, As, Cr, Cu, Ni, Pb, Cd, Hg were 766.59, 350.66, 307.98, 59.54, 122.67, 168.97, 2.34, 0.41 mg · kg⁻¹, respectively. The content of Cu at the centre was significantly higher than that in the north, and the Zn content at the centre was significantly greater than that in the south of Lake Gehu, however the difference in the content of other heavy metals at these three areas was not significant. Furthermore, the obvious correlation between elements and granularity was only found in the aspect of TP, Cu and Hg. The comprehensive pollution index (PI) indicated that the Lake Gehu was heavily polluted, especially the centre and south areas. The potential ecological risk index (RI) showed that Cd, As and Hg had caused serious pollution in Lake Gehu while the other heavy metals only induced slight or medium pollution. According to the contribution of Cd, As and Hg to RI, it was concluded that the sediments in Lake Gehu were at a serious potential ecological risk.
Based on the investigation on the distribution of total contents and speciation of 8 heavy metals (As, Cd, Cr, Cu, Hg, Ni, Pb, Zn) in the surface sediments at 14 typical sites of the Yangtze Estuary during three hydrological seasons ( wet, normal, and dry seasons) , this study applied equilibrium partitioning approach to build the sediment quality guidelines (SQGs) of the Yangtze Estuary, and assessed ecological risks of the heavy metals. The relationship between ecological risk and speciation of heavy metals was also revealed. The results showed that, except for Cd, the residual fraction was the main speciation of heavy metals, especially for As, Cr and Hg, their residual fraction proportions were all over 90%. The sediment quality guidelines of the Yangtze Estuary for As, Cd, Cr, Cu, Hg, Ni, Pb, Zn were 43.29, 0.672, 79.65, 19.08, 0.569, 339.09, 30.87, 411.36 µg · g⁻¹, respectively. Cu had the highest ecological risk to aquatic organisms. The upstream of Yangtze Estuary was mainly affected by Yangtze River runoff, where the risks were relatively high in wet season and relatively low in normal and dry seasons. However, the downstream of the estuary was mainly affected by municipal sewage of cities like Shanghai, where the risks were relatively high, especially in normal and dry seasons. There were three different relationships between the ecological risks and speciation of the eight heavy metals.
The unified BARGE method was used to examine the effects of soil particle size on the bioaccessible amounts of potentially toxic elements in multi-contaminated soils from a closed landfill site. The results show that bioaccessible As, Al, Cd, Cr, Cu, Mn, Ni, Pb and Zn increased with decreasing soil particle size and the <0.002 mm soil fraction contained much greater amounts of the bioaccessible elements, as compared to other soil fractions (0.002-0.063 mm, 0.063-0.125 mm, and 0.125-0.250 mm). As, Al and Cr had much lower bioaccessibility, as compared to the six cationic heavy metals. In contrast with other elements, As bioaccessibility tended to be higher in the gastrointestinal phase than in the gastric phase. There was a significant soil particle size effect on bioaccessibility of As and Al in the gastrointestinal phase: As bioaccessibility decreased with decreasing particle size, and the finer soil fractions tended to have a higher Al bioaccessibility, as compared to the coarser soil fractions. The research findings prompt the need for further division of soil particle size fractions in order to more accurately assess the bioaccessible amounts of soil-borne potentially toxic elements in contaminated lands.
While chelant-enhanced soil washing has been widely studied for metal extraction from contaminated soils, there are concerns about destabilization and leaching of residual metals after remediation. This study integrated 2-h soil washing enhanced by biodegradable ethylenediaminedisuccinic acid (EDDS) and 2-month stabilization using agricultural waste product (soybean stover biochar pyrolyzed at 300 and 700 °C), industrial by-product (coal fly ash (CFA)), and their mixture. After integration with 2-month stabilization, the leachability and mobility of residual metals (Cu, Zn, and Pb) in the field-contaminated soil were significantly reduced, especially for Cu, in comparison with 2-h EDDS washing alone. This suggested that the metals destabilized by EDDS-washing could be immobilized by subsequent stabilization with biochar and CFA. Moreover, when the remediation performance was evaluated for phytoavailability and bioaccessibility, prior EDDS washing helped to achieve a greater reduction in the bioavailable fraction of metals than sole stabilization treatment. This was probably because the weakly-bound metals were first removed by EDDS washing before stabilization. Both individual and combined applications of biochar and CFA showed comparable effectiveness regardless of the difference in material properties, possibly due to the high level of amendments (150 ton ha(-1)). Based on the mobility and bioaccessibility results, the estimated human health risk (primarily resulting from Pb) could be mitigated to an acceptable level in water consumption pathway or reduced by half in soil ingestion pathway. These results suggest that an integration of EDDS washing with soil stabilization can alleviate post-remediation impacts of residual metals in the treated
 soil.
There were considerable concerns about the zinc (Zn) pollution caused by electroplating, chemical, and computer-related high-tech industrial discharges in Kaohsiung Rivers situated at south Taiwan. There is, however, a lack of site-specific water chemistry based toxicity assessment and little is known about the sublethal toxicity on freshwater fish. This study proposes an integrated framework to link experimental and mechanistic model-based data analysis of lethal and sublethal Zn toxicities for grass carp (Ctenopharyn odon idellus) populations for providing the site-specific Zn water quality threshold in Kaohsiung Rivers. A biotic ligand model (BLM) that relates toxicity impairment of physiological active sites impacted by Zn species was used to elucidate the site-specific water chemistry affecting the bioavailability and biological response of grass carp exposed to Zn. Results indicated that 96-h LC50 for mortality and 28-d EC50 for growth inhibition were 474.7 ± 1.3 (mean ± SE) and 149 ± 23.5 μg L(-1), respectively. Here the BLM-based predicted steady-state LC50s for mortality were 2110.7, 818.2, 1303.6, 563.3, and 497.1 μg L(-1), whereas measured steady-state EC50s for growth inhibition were 726.8, 326.2, 373.4, 193.9, and 170.5 μg L(-1) for the Agongdian, Houling, Love, Fengshan, and Gaoping Rivers, respectively. A positive correlation between Mg(2+) and EC50 values were found in both acute (r = 0.94, p < 0.01) and chronic (r = 0.97, p < 0.01) Zn exposures. This study suggests that the use of site-specific water chemistry data and ecophysiological traits would enhance the predictive capacities to assess the potential effect of metal toxicity posed to aquatic organisms.
The spatial and seasonal alteration in a battery of biomarkers responses (enzymatic activity of glutathione-S-transferase, catalase and acetylcholinesterase and lipid peroxidation) were investigated to assess the metal derived effects in clam (Ruditapes decussatus) gills, collected from Tunis lagoon (Tunisia). Trace metals (Ag, As, Cd, Cu, Hg, Mn, Ni, Pb, V and Zn) concentrations were assessed seasonally in sediments and tissues of R. decussatus from three different sites (S1, S2 and S3). Bioaccumulation factor (BAF) analysis showed a spatio-temporal variation of metal uptake rates in clams through sediments. Likewise, the multibiomarker approach enabled a time-site trend differentiation between sites with distinctive degrees of anthropogenic contamination. Site S2 was identified as the most impacted region due to the presence of different contamination sources (shipping and industrial activities). The results suggest that biomarker's seasonal variation arises from a complex interaction between environmental conditions (e.g. temperature, salinity) and probably biological factors (mainly the reproduction process) along with anthropogenic pressure. The general biological response measured with the IBR index at all the sampling sites revealed the highest metabolic stress in summer. The combined effects of metal contamination and increased temperature and salinity in summer appear to induce the highest metabolic adaptation response. The selected biomarkers provided an integrated response, which is useful for the assessment of the combined effects of metal contamination and abiotic parameters in clams and the environmental status of coastal lagoon ecosystem.
New fluorescence switch-on meso-substituted free base meta-benziporphodimethenes were synthesized, characterized via acid catalyzed condensation reaction and metallated with Zn(2+). Their photophysical properties were also studied. The fluorescence spectra analysis demonstrates substituent's independent behaviour on emitting λmax. The average Stokes shift of 33nm was observed. Crystal structure of 8 was obtained and gave expected perturbed geometry.
3-(Hetero)arylindazoles are important motifs in several biologically active compounds. Mild and flexible palladium-mediated Negishi reaction conditions are reported for the introduction of (hetero)aryl moieties at the 3-position of N(2)-SEM-protected indazoles in high yields. The requisite Zn-species are readily obtained via regioselective deprotonation and subsequent transmetalation. The methodology tolerates a variety of functional groups on both coupling partners and has been extended to bis-haloarene and heteroarene coupling partners where the most reactive halogen reacts first, leaving the second halogen for subsequent functionalization.
Accumulation of Cu, Zn, Cd, and Pb in the sediment of seagrass ecosystems was examined using mesocosm experiments containing Zostera marina (eelgrass) and reference pools. Lead was approximately 20-fold higher in the surface sediment in the eelgrass pool than in eelgrass leaves and epiphytes on the eelgrass leaves, whereas zinc and cadmium were significantly lower in the surface sediment than in the leaves, with intermediate concentrations in epiphytes. Copper concentrations were similar in both the surface sediment and leaves but significantly lower in epiphytes. Carbon and nitrogen contents increased significantly with increasing δ13C in surface sediments of both the eelgrass and reference pools. Copper, Zn, Cd, and Pb also increased significantly with increasing δ13C in the surface sediment in the eelgrass pool but not in the reference pool. By decomposition of eelgrass leaves with epiphytes, which was examined in the eelgrass pool, copper and lead concentrations increased more than 2-fold and approximately a 10-fold, whereas zinc and cadmium concentrations decreased. The high copper and lead concentrations in the surface sediment result from accumulation in decomposed, shed leaves, whereas zinc and cadmium remobilized from decomposed shed leaves but may remain at higher concentrations in the leaves than in the original sediments. The results of our mesocosm study demonstrate that whether the accumulation or remobilization of trace metals during the decomposition of seagrass leaves is trace metal dependent, and that the decomposed seagrass leaves can cause copper and lead accumulation in sediments in seagrass ecosystems.
Herein, we describe the successful construction of composite DNA nanostructures by the self-assembly of complementary symmetrical 2,6,14-triptycenetripropiolic acid (TPA)-DNA building blocks and zinc protoporphyrin IX (Zn PpIX). DNA-organic molecule scaffolds for the composite DNA nanostructure were constructed through covalent conjugation of TPA with 5'-C12-amine-terminated modified single strand DNA (ssDNA) and its complementary strand. The repeated covalent conjugation of TPA with DNA was confirmed by using denaturing polyacrylamide gel electrophoresis (PAGE), reverse-phase high-performance liquid chromatography (RP-HPLC) and matrix-assisted laser desorption/ionization time-of-flight (MALDI-TOF). The biologically relevant photosensitizer Zn PpIX was used to direct the hybridization-mediated self-assembly of DNA-TPA molecular building blocks as well as a model guest molecule within the DNA-TPA supramolecular self-assembly. The formation of fiber-like composite DNA nanostructures was observed. Native PAGE, circular dichroism (CD) and atomic force microscopy (AFM) have been utilized for analyzing the formation of DNA nanofibers after the coassembly. Computational methods were applied to discern the theoretical dimension of the DNA-TPA molecular building block of the nanofibers. A notable change in photocatalytic efficiency of Zn PpIX was observed when it was inside the TPA-DNA scaffold. The significant increase in ROS generation by Zn PpIX when trapped in this biocompatible DNA-TPA hybrid nanofiber may be an effective tool to explore photodynamic therapy (PDT) applications as well as photocatalytic reactions.
Immune cell and cytokine profiles in relation to metal exposure though much studied in mammals has not been adequately investigated in amphibians, due mainly to lack of suitable reagents for cytokine profiling in non-model species. However, interspecies cross reactivity of cytokines permitted us to assay levels of IFNγ, TNFα, IL6 and IL10in a common anuran, the Indian green frog (Euphlyctis hexadactylus), exposed to heavy metals (Cd, Cr, Cu, Zn and Pb, at ~5ppm each) under field and laboratory settings in Sri Lanka. Enumeration of immune cells in blood and melanomacrophages in the liver, assay of serum and hepatic cytokines, and Th1/Th2 cytokine polarisation were investigated. Immune cell counts indicated overall immunosuppression with decreasing total WBC and splenocyte counts while neutrophil/lymphocyte ratio increased with metal exposure, indicating metal mediated stress. Serum IL6 levels of metal exposed frogs reported the highest (~9360pg/mL) of all cytokines tested. Significantly elevated IFNγ production (P<0.05) was evident in heavy metal exposed frogs. Th1/Th2 cytokine ratio in both serum and liver tissue homogenates was Th1 skewed due to significantly higher production of pro-inflammatory cytokines, IFNγ in serum and TNFα in the liver (P<0.01).Metal mediated aggregations of melanomacrophages in the liver were positively and significantly (P<0.05) correlated with the hepatic expression of TNFα, IL6 and IL10 activity. Overall, Th1 skewed response may well be due to oxidative stress mediated nuclear factor κ-light chain enhancer of activated B cells (NFκB) which enhances the transcription of pro-inflammatory cytokines. Xenobiotic stress has recently imposed an unprecedented level of threat to wildlife, particularly to sensitive species such as amphibians. Therefore, understanding the interactions between physiological stress and related immune responses is fundamental to conserve these environmental sentinels in the face of emerging eco-challenges.
Human leukocyte cell-derived chemotaxin 2 (LECT2), which is predominantly expressed in the liver, is a multifunctional protein.
 LECT2 is becoming a potential therapeutic target for several diseases of worldwide concern such as rheumatoid arthritis, hepatocellular carcinoma, and obesity. Here, we present the crystal structure of LECT2, the first mammalian protein whose structure contains an M23 metalloendopeptidase fold. The LECT2 structure adopts a conserved Zn(II) coordination configuration but lacks a proposed catalytic histidine residue, and its potential substrate-binding groove is blocked in the vicinity of the Zn(II)-binding site by an additional intrachain loop at the N terminus. Consistent with these structural features, LECT2 was found to be catalytically inactive as a metalloendopeptidase against various types of peptide sequences, including pentaglycine. In addition, a surface plasmon resonance analysis demonstrated that LECT2 bound to the c-Met receptor with micromolar affinity. These results indicate that LECT2 likely plays its critical roles by acting as a ligand for the corresponding protein receptors rather than as an enzymatically active peptidase. The intrachain loop together with the pseudo-active site groove in LECT2 structure may be specific for interactions between LECT2 and receptors. Our study reveals a mechanistic basis for the functional evolution of a mammalian protein with an M23 metalloendopeptidase fold and potentially broadens the implications for the biological importance of noncatalytic peptidases in the M23 family.
Antioxidative enzyme efficiency changes in some organs with age. However, no study has been conducted on age-related antioxidant enzyme changes in tongue. In the present study, the authors investigated the activities of four antioxidative enzymes and their protein expressions in the tongues of young and old Fischer 344 rats.
Age-dependent changes in the enzyme activities of total superoxide dismutase (SOD), Mn-SOD, Cu/Zn-SOD, catalase (CAT), and glutathione peroxidase (GPx) were determined using chemical kits, and the protein expressions levels of these enzymes by Western blotting. The study was conducted using rats aged 7 months (the young group, n=8) and 22 months (the old group, n=8).
Total SOD, Cu/Zn-SOD, and GPx activities in the tongues of old rats were lower than in young rats, and similarly, corresponding protein expressions were downregulated in old rats. On the other hand, although the protein expressions of Mn-SOD and CAT were lower in old rats, their enzyme activities were not.
The results of this study provide a possible mechanism for the tongue aging process, as in old Fischer 344 rats the antioxidant defense system was diminished with respect to enzyme activity levels and protein abundances.
Polyhistidine peptides are effective ligands to coat quantum dots (QDs). It is known that both the number of histidine (His) residues repeats and their structural arrangements in a peptide ligand play important roles in the assembly of the peptide onto CdSe/ZnS QDs. However, due to steric hindrance, a peptide sequence with more than six His residue tandem repeats would hardly coordinate well with Zn(2+) in the QD shell to further enhance the binding affinity. To solve this problem, a His-containing peptide ligand, ATTO 590-E2 G (NH)6 (ATTO-NH), was specifically designed and synthesized for assembly with QDs. With sequential injection of QDs and ATTO-NH into the capillary electrophoresis with fluorescence detection, strong Förster resonance energy transfer phenomenon between the QDs and the ATTO 590 dye was observed, indicating efficient self-assembly of the novel peptide onto the QDs to form ATTO-NH capped QDs inside the capillary. The binding stability of the ligand onto the QD was then systematically investigated by titrating with imidazole, His, and a his-tag containing competitive peptide. It is believed that this new in-capillary assay significantly reduced the sample consumption and the analysis time. By functionalizing QDs with certain metal cation-specific group fused peptide ligand, the QD-based probes could be even extended to the online detection of metal cations for monitoring environment in the future.
Selective fluorescence turn on Zn(2+) sensor with long-wavelength emission and a large Stokes shift is highly desirable in Zn(2+) sensing area. We reported herein the synthesis and Zn(2+) recognition properties of a new thiosemicarbazone-based fluorescent sensor L. L displays high selectivity and sensitivity toward Zn(2+) over other metal ions in DMSO-H2O (1:1, v/v, HEPES 10 mM, pH = 7.4) solution with a long-wavelength emission at 572 nm and a large Stokes shift of 222 nm. Confocal fluorescence microscopy experiments demonstrate that L is cell-permeable and capable of monitoring intracellular Zn(2+). Graphical Abstract We report a new thiosemicarbazone-based fluorescent sensor (L) for selective recognition of Zn(2+) with a long wavelength emission and a large Stokes shift.
Zinc oxide thin films were deposited on vertically aligned nitrogen-doped carbon nanotubes (N-CNTs) by atomic layer deposition (ALD) from diethylzinc and water. The study demonstrates that doping CNTs with nitrogen is an effective approach for the "activation" of the CNTs surface for the ALD of metal oxides. Conformal ZnO coatings are already obtained after 50 ALD cycles, whereas at lower ALD cycles an island growth mode is observed. Moreover, the process allows for a uniform growth from the top to the bottom of the vertically aligned N-CNT arrays. X-ray photoelectron spectroscopy demonstrates that ZnO nucleation takes place at the N-containing species on the surface of the CNTs by the formation of the Zn-N bonds at the interface between the CNTs and the ZnO film.
Bioabsorbable magnesium alloys are becoming prominent as temporary functional implants, as they avoid the risks generated by permanent metallic implants such as persistent inflammation and late restenosis. Nevertheless, the overfast corrosion of Mg alloys under physiological conditions hinders their wider application as medical implant materials. Here we investigate a simple one-step process to introduce a cross-linked 3-amino-propyltrimethoxysilane (APTES) silane physical barrier layer on the surface of Mg-Zn-Y-Nd alloys prior to electrostatic spraying with rapamycin-eluting poly(lactic-co-glycolic acid) (PLGA) layer. Surface microstructure was characterized by scanning electron microscope and Fourier transform infrared spectroscopy. Nanoscratch test verified the superior adhesion strength of PLGA coating in the group pretreated with APTES. Electrochemical tests combined with long-term immersion results suggested that the preferable in vitro anticorrosion behavior could be achieved by dense APTES barrier. Cell morphology and proliferation data demonstrated that APTES pretreated group resulted in remarkably preferable compatibility for both human umbilical vein endothelial cells and vascular smooth muscle cells. On the basis of excellent in vitro mechenical property, the animal study on the APTES pretreated Mg-Zn-Y-Nd stent implanted into porcine coronary arteries confirmed benign tissue compatibility as well as re-endothelialization without thrombogenesis or in-stent restenosis at six-month followup.
This experiment was aimed at exploring whether carboxymethyl chitosan zinc and peptide （CMC-Zn(+)-P） can reduce the occurrence and development of periodontal tissue inflammation effectively by observing the change of IL-1,TNF-α and PGE-2 level in gingival crevicular fluid （GCF） before and after brushing, so as to find a new effective material in preventing and treating periodontal diseases.
Miniature pigs were selected as experimental subjects and divided into 4 groups randomly: the control group; CMC-Zn(+)-P group (material group);brushing group; brushing + CMC-Zn(+)-P group (composite group). Gingival crevicular fluid before and one month after the experiment was collected. The levels of IL-1, TNF-α and PGE-2 were examined by enzyme-linked immune-sorbent assay, while the clinical periodontal index was recorded. SPSS 18.0 software package was used for statistical analysis.
There was no significant difference in levels of IL-1, TNF-α and PGE-2 and clinical periodontal index between the 4 groups before experiment. After one month, the levels of IL-1, TNF-α, PGE-2 in GCF had significant difference between 4 groups. The levels of IL-1, TNF-α, PGE-2 in composite group were significant lower than that of the other three groups (P<0.008).The levels of IL-1, TNF-α and PGE-2 in the material group and brushing group were significantly lower than that of the control group (P<0.008). Compared with materials group, the brushing group had significantly lower level of IL-1,significantly higher level of PGE-2 ,but no difference in the level of TNF-α.In addition, the teeth calculus index of composite group was significantly lower than that of other groups (P<0.05).
CMC-Zn(+)-P can effectively reduce periodontal tissue inflammation and cut down the speed of deposition of dental calculus. If used cooperatively with brushing, the effect will be better.
We identify the presence of multiple vascular channels within the spider fang. These channels seem to serve the transport of zinc to the tip of the fang to cross-link the protein matrix by binding to histidine residues. According to amino acid and elemental analysis of fangs extracted shortly after ecdysis, His-rich proteins are deposited before Zn is incorporated into the cuticle. Microscopic and spectroscopic investigations in the electron microscope and synchrotron radiation experiments suggest that Zn ions are transported through these channels in a liable (yet unidentified) form, and then form stable complexes upon His binding. The resulting cross-linking through the Zn-His complexes is conferring hardness to the fang. Our observations of nano-channels serving the Zn-transport within the His-rich protein matrix of the
 fibre reinforced spider fang may also support recent bio-inspired attempts to design artificial polymeric vascular materials for self-healing and in-situ curing.
The P (Pi as KH2PO4 and Po as ATP) removal processes by phototrophic periphyton were investigated by determining the removal kinetics, metal content (Ca, Mg, Al, Fe, Cu, and Zn) of the solution and P fractions (Labile-P, Fe/Al-P, Ca-P, and Res-P) within the periphyton. Results showed that the periphyton was able to remove completely both Pi and Po after 48h when periphyton content was greater than 0.2gL(-1) (dry weight). The difference between Pi and Po removal was the conversion of Po into Pi by the periphyton, after that the removal mechanism was similar. The P removal mechanism was mainly due to the adsorption on the surfaces of the periphyton, including two aspects: i) the adsorption of PO4(3-) onto metal salts such as calcium carbonate (~50%) and ii) complexation between PO4(3-) and metal cations such as Ca(2+) (~40%). However, this bio-adsorptional process was significantly influenced by the extracellular polymeric substance (EPS) of periphyton, water hardness, initial P concentration, temperature and light intensity. This study not only deepens the understanding of P biogeochemical process in aquatic ecosystem, but provides a potential biomaterial for combining phosphorous removal and recovery from non-point source wastewaters, especially around salt-soil zone.
This study investigated the effect of metal ions on the oxidation of sterols and their kinetics in oil-in-water emulsions. Sterol substrates were added with different metal ions (Cu(2+), Fe(2+), Mn(2+), Zn(2+), Na(+), and Mg(2+)) of five concentrations and investigated after 2 h of heating at 90 °C. The substrates added with Fe(2+) and Cu(2+) were heated continuously to evaluate the kinetics of four sterols and their corresponding sterol oxidation products (SOPs). Sterol oxidation increased as the metal ion concentration increased and the heating time was prolonged. The capability of the metal ions oxidizing sterols ranked as followed: Fe(2+) > Cu(2+) > Mn(2+) > Zn(2+) > Mg(2+) ≈ Na(+). 7-Ketosterol, 7β/7α-Hydroxysterol, 5β,6β/5α,6α-Epoxysterol, and Triols were the main oxides on the B ring, whereas 6β-Hydroxysterol was not or only slightly influenced. The acceleration of sterol degradation induced by Fe(2+) and Cu(2+), as well as the formation of oxidation products, followed first-order formation/elimination kinetics. The acceleration effect may be partly ascribed to the increase in elimination rate constant and formation rate constant. Transition metal ions can significantly induce sterol oxidation, which reduces food nutritional quality and triggers the formation of undesirable compounds, such as SOPs.
The reactions of 2-pyridinecarboxaldehyde-phenylhydrazonatolithium C5H4Npy-CH[double bond, length as m-dash]Ni-NaLi(Ph) (abbreviated as Li) with a 1/2 equivalent of anhydrous metal (Zn, Sn, Fe and Co) chlorides or NiCl2(DME) (DME = 1, 2-dimethoxyethane) produced the corresponding mononuclear metal(ii) complexes ( and ), in which each ligand acts as a bidentate ligand and the coordination geometries around the metals are shown to be tetrahedral within the complexes , , and , respectively, and a tetragonal pyramid in the complex . The reaction of Li successively with sodium tert-butoxide and anhydrous ZrCl4 afforded the unanticipated bizirconium complex , in which each monoanionic ligand behaves as a tridentate bridge. Whereas treatment of Li with NiCl2 and then CH2Cl2 led to an interesting methylene-bridged bis(2-pyridyl-phenylhydrazone) compound in moderate yield; a comparative experiment showed that when the Li reacted with CH2Cl2, the coupling compound was also obtained but in very low yield. A plausible mechanism of compound formation was also proposed and supported by the density functional theory (DFT) calculations. All the synthesized compounds were characterized by single-crystal X-ray diffraction.
A luminescent Eu(iii)-based coordination polymer, {[Eu(H2O)5(BTEC)][H(C5H6N2)]·3H2O} () has been synthesized under hydrothermal conditions using 1,2,4,5-benzenetetracarboxylic acid (H4BTEC) as a linker. Compound possesses an anionic zig-zag chain constructed from the BTEC ligands and [EuO4(H2O)5] nodes. The protonated 4-aminopyridine groups as guests are located between chains. exhibits the characteristic sharp emission bands of Eu(3+) at 578, 593, 615, 652 and 693 nm upon excitation at 290 nm. The strong emission of could be quenched effectively by trace amounts of Fe(3+) ions even in the presence of other metal ions including Al(3+), Ca(2+), Cd(2+), Co(2+), Cr(3+), Cu(2+), Fe(2+), K(+), Mg(2+), Mn(2+), Pd(2+) and Zn(2+). Similarly, also exhibits superior selectivity and sensitivity towards 4-nitrophenol (4-NP) compared with other competing interfering analytes, such as 2,4,6-trinitrophenol, 2,6-dinitrotolune, 4-nitrotoluene, nitrobenzene, 1,3-dinitrobenzene, o-xylene, nitromethane, nitropropane, phenol, 4-bromophenol and bromobenzene, through a fluorescence quenching mechanism. The possible fluorescence quenching mechanisms are discussed. Moreover, could be used as a visual fluorescent test paper for selectively detecting trace amounts of Fe(3+) and 4-NP.
The present work was carried to decipher the trace element accumulation in surface sediments of Palk Strait, southeast coast of Tamil Nadu, India. The elemental concentration and correlation results suggest that fine fractions with CaCO3 content followed by organic matter (OM) of the surface sediments control the trace element accumulation in the study area. In addition, Fe and Mn concentration is chiefly contributed from riverine process and controlled by the mangrove ecosystem. The other elements are derived into marine environment through confluence of untreated industrial pollutants into the river system. The EF result shows that the studied marine sediments are enriched by Ni, Mn, Cu, Pb, Cd, Cr, followed by Zn. The order of the pollution intensity with respect to geo-accumulation index suggests the following ascending order: Ni>Mn>Fe>Cu>Pb>Cd>Cr>Zn. Pollution Load Index (PLI) values reveal that all the samples are falling under moderately to unpolluted category.
Sediment collected from the estuarine mangroves of the Zuari estuary and Cumbharjua canal were analyzed to assess the concentration, contamination and bioavailability of metals. Mangrove pneumatophores were also analyzed to understand the metal bioaccumulation in mangrove plants. The results indicated the variation of metal concentrations in sediment along the estuary was attributed to changing hydrodynamic conditions, type of sediment and metal sources. Further, speciation studies revealed that Fe, Cr, Co, Ni, Cu and Zn were mainly of lithogenic origin and less bioavailable while high Mn content in the sediment raised concerns over its potential mobility, bioavailability and subsequent toxicity. The mangrove plants exhibited difference in metal accumulation due to variations in sediment parameters and metal availability, in addition to difference in plant species and tissue physiology that affect metal uptake. Moreover, the mangrove plants reflected the quality of the underlying sediment and can be used as a potential bio-indicator tool.
In our previous studies, we reported that the activity of an anti-oxidant enzyme, Cu,Zn-superoxide dismutase (Cu,Zn-SOD) became decreased as the result of glycation in vitro and in vivo. Glycated Cu,Zn-SOD produces hydroxyl radicals in the presence of transition metals due to the formation of a Schiff base adduct and a subsequent Amadori product. This results in the site-specific cleavage of the molecule, followed by random fragmentation. The glycation of other anti-oxidant enzymes such as glutathione peroxidase and thioredoxin reductase results in a loss or decrease in enzyme activity under pathological conditions, resulting in oxidative stress. The inactivation of anti-oxidant enzymes induces oxidative stress in aging, diabetes and neurodegenerative disorders. It is well known that the levels of Amadori products and N(e)-(carboxylmethyl)lysine (CML) and other carbonyl compounds are increased in diabetes, a situation that will be discussed by the other authors in this special issue. We and others, reported that the glycation products accumulate in the brains of patients with Alzheimer's disease (AD) patients as well as in cerebrospinal fluid (CSF), suggesting that glycation plays a pivotal role in the development of AD. We also showed that enzymatic glycosylation is implicated in the pathogenesis of AD and that oxidative stress is also important in this process. Specific types of glycosylation reactions were found to be up- or downregulated in AD patients, and key AD-related molecules including the amyloid-precursor protein (APP), tau, and APP-cleaving enzymes were shown to be functionally modified as the result of glycosylation. These results suggest that glycation as well as glycosylation are involved in oxidative stress that is associated with aging, diabetes and neurodegenerative diseases such as AD.
The focus of this work is introduction of GelRed (GR) as a stable, sensitive and environmentally safe fluorescent DNA dye instead of the highly toxic ethidium bromide (EB). Competitive DNA-binding studies between metal complexes, [Cu(phen-dion)(phen)Cl]Cl (1), [Cu(phen-dione)(bpy)Cl]Cl (2), [Cu(dppt)2(H2O)]PF6 (3), [Ni(dppt)2Cl2] (4), [Zn(dppt)2Cl2] (5), and K3[Fe(CN)6] (6) (where phen-dione is 1,10-phenanthroline-5,6-dione, phen is 1,10- phenanthroline, bpy is 2,2'-bipyridine, and dppt is 5,6-diphenyl-3-(2-pyridyl)-1,2,4-triazine), and GelRed have been investigated under physiological conditions by fluorescence spectroscopy. This simple method can reveal the binding affinity and mode of metal complexes with DNA. The method is based on
 the decrease of fluorescence derived from the displacement of GelRed from DNA by metal complexes. The % fluorescence decrease is directly related to the extent of DNA binding. Results indicate the DNA binding affinities of complexes follow the order 3 > 4 > 1 > 2 > 5 > 6. The significant quenching of the emission band of the GR-DNA with the addition of complexes 1, 3, and 4 suggests that complexes compete for DNA-binding sites with GR and displace GR from the GR-DNA, which is usually characteristic of the intercalative interaction of compounds with DNA. A small quenching of the emission band of the GR-DNA with the addition of the complex 2 was observed that show the complex weaker competes for DNA-binding sites with GR than complexes 1, 3, and 4. Results show complexes 5 and 6 cannot compete for DNA-binding sites with GR and their interaction with DNA is external binding (groove or electrostatic bindig).
A simple and effective preconcentration procedure based on dispersive micro solid-phase extraction prior to energy dispersive X-ray fluorescence spectrometric (EDXRF) determination of trace amounts of Ni, Cu, and Zn in coffee infusions was proposed. The method is based on the adsorption of 8-hydroxyquinoline metal complexes on micro amounts of graphene nanoparticles. In order to optimize adsorption process, the influence of some parameters such as pH, graphene mass, concentration of 8-hydroxyquinoline (8-HQ) and Triton X-100, sample volume, and sorption time were examined. At optimal preconcentration conditions, calibration curves were linear from 1 to 150 ng mL(-1) for Ni and Cu and from 1 to 200 ng mL(-1) for Zn. The recoveries of the metal ions were in the 95-98% range with the precision lower than 4.6%. The obtained detection limits were 0.08 ng mL(-1) for Ni and 0.09 ng mL(-1) for Cu and Zn. The proposed method was successfully applied to determination of Ni, Cu, and Zn in coffee infusions. Accuracy and repeatability of the proposed procedure were confirmed by the standard addition method and compared to the results obtained by ICP-OES technique.
Concentrations of eight elements were measured in Chelonia mydas and Lepidochelys olivacea eggs collected along the Pacific coast of Panama. Manganese (Mn), iron (Fe), copper (Cu), zinc (Zn), arsenic (As), cadmium (Cd), and mercury (Hg) concentrations were similar to previous reports of these species from around the world, while lead (Pb) was lower than previous reports. Cd posed the highest health risk to people who regularly eat the eggs, with average consumption rates leading to target hazard quotients (THQ) of up to 0.35 ± 0.15. Our conclusions indicate that current turtle egg consumption in isolated, coastal Pacific communities may pose a health concern for young children, and that youth and young adults should limit their consumption of turtle eggs to reduce their total intake of nonessential metals.
Based on the same toxic level of 0.6% LC50 for 96-h and the severe situation of water pollution, we compared effects of chronic Zn (180μgL(-1)) and Cd exposures (30μgL(-1)) on growth, survival, histology, ultrastructure, and oxidative stress in the liver of zebrafish for 5 weeks. Growth performance and survival rate remained relatively constant under Zn stress, but was reduced under Cd exposure. Cd exposure also induced severe pyknotic nuclei, evident ultrastructure damage, and considerable lipid inclusions in the hepatocytes. However, these phenomena were not pronounced under Zn exposure. The negative effects caused by Cd may be explained by an increase in hepatic oxidative damage, as reflected by the enhanced levels of lipid peroxidation (LPO) and protein carbonylation (PC). The reduced activity of Cu/Zn-superoxide dismutase (Cu/Zn-SOD) and catalase (CAT) may result in the enhanced hepatic oxidative damage, though the mRNA and protein levels of both genes increased and remained unchanged respectively. On the contrary, Zn up-regulated the levels of mRNA, protein and activity of Cu/Zn-SOD, which may contribute to the decreased LPO levels. Nonetheless, the sharply up-regulated mRNA levels of CAT did not induce an increase in the protein and activity levels of CAT under Zn stress. Furthermore, transcription factor NF-E2-related factor 2 (Nrf2) expression parelleled with its target genes, suggesting that Nrf2 is required for the protracted induction of antioxidant genes. In conclusion, our data demonstrated that essential and non-essential metals induced some differences in oxidative damage in fish. The differences were not caused by the transcriptional level of related genes but depended on post-transcriptional modifications.
Health risk of residents dwelling around e-waste recycling zones has been a global concern, but has not been adequately examined. The present study was intended to evaluate the potential health risk of residents through inhalation exposure to size-fractionated particle-bound heavy metals in a typical e-waste recycling zone, South China. Anthropogenic metals (Zn, Se, Pb, Sb, As, and Cd) were predominantly enriched in fine particles (Dp<1.8μm), whereas the crustal elements (Ti, Fe, and Co) tended to accumulate in coarse particles (Dp>1.8μm). Although the daily inhalation intakes of the target metals were significantly lower than those through food consumption and ingestion of house dust, the hazard quotients of total metals for adults (95% CI: 1.0-5.5) and children (95% CI: 3.0-17) were greater than 1. Moreover, the incremental lifetime cancer risks of five carcinogenic metals (Cr, Co, Ni, As, and Cd) for adults and children were 1.3×10(-3) (95% CI: 4.1×10(-4)-3.0×10(-3)) and 3.9×10(-3) (95% CI: 1.3×10(-3)-8.6×10(-3)), respectively, substantially higher than the acceptable cancer risk range of 10(-6)-10(-4). All these findings suggested that health risks were high for local residents dwelling around the e-waste recycling zone through inhalation exposure to particle-bound heavy metals, for both adults and children.
The recovery of silver from hazardous jarosite residues was studied employing thiourea as leaching agent at acid pH and 90°C. The stability of the thiourea in synthetic solutions was evaluated in the presence of some cations that can be present in this leaching system: cupric and ferric ions as oxidant species, and zinc, lead and iron as divalent ions. Two silver leaching methods were studied: the simultaneous jarosite decomposition-silver leaching, and the jarosite decomposition followed by the silver leaching. The study with synthetic solutions demonstrated that cupric and ferric ions have a negative effect on thiourea stability due to their oxidant properties. The effect of cupric ions is more significant than the effect of ferric ions; other studied cations (Fe(2+), Zn(2+), Pb(2+)) had no effect on the stability of thiourea. When the decomposition of jarosite and the silver leaching are carried out simultaneously, 70% of the silver can be recovered. When the acid decomposition was performed at pH 0.5 followed by the leaching step at pH 1, total silver recovery increased up to 90%. The zinc is completely dissolved with any of these processes while the lead is practically insoluble with these systems producing a lead-rich residue.
Hybrid materials composed of metal nanoparticles and metal-organic frameworks (MOFs) have attracted much attention in many applications, such as enhanced gas storage and catalytic, magnetic, and optical properties, because of the synergetic effects between the metal nanoparticles and MOFs. In this Forum Article, we describe our recent progress on novel synthetic methods to produce metal nanoparticles covered with a MOF (metal@MOF). We first present Pd@copper(II) 1,3,5-benzenetricarboxylate (HKUST-1) as a novel hydrogen-storage material. The HKUST-1 coating on Pd nanocrystals results in a remarkably enhanced hydrogen-storage capacity and speed in the Pd nanocrystals, originating from charge transfer from Pd nanocrystals to HKUST-1. Another material, Pd-Au@Zn(MeIM)2 (ZIF-8, where HMeIM = 2-methylimidazole), exhibits much different catalytic activity for alcohol oxidation compared with Pd-Au nanoparticles, indicating a design guideline for the development of composite catalysts with high selectivity. A composite material composed of Cu nanoparticles and Cr3F(H2O)2O{C6H3(CO2)3}2 (MIL-100-Cr) demonstrates higher catalytic activity for CO2 reduction into methanol than Cu/γ-Al2O3. We also present novel one-pot synthetic methods to produce composite materials including Pd/ZIF-8 and Ni@Ni2(dhtp) (MOF-74, where H4dhtp = 2,5-dihydroxyterephthalic acid).
A phytoremediation pilot emulating a shallow aquifer planted with Juncus acutus showed to be effective for remediating Bisphenol-A (BPA) contaminated groundwater. Biostimulation with root exudates, low molecular weight organic acids, of J. acutus did not improve BPA-degradation rates. Furthermore, the endophytic bacterial community of J. acutus was isolated and characterized. Many strains were found to possess increased tolerance to metals such as Zn, Ni, Pb and Cd. Moreover, several endophytic bacterial strains tolerated and even used BPA and/or two antibiotics (ciprofloxacin and sulfamethoxazole) as a sole carbon source. Our results demonstrate that the cultivable bacterial endophytic community of J. acutus is able to use organic contaminants as carbon sources, tolerates metals and is equipped with plant-growth promoting traits. Therefore, J. acutus has potential to be exploited in constructed wetlands when co-contamination is one of the restricting factors.
This paper studies the synergism between transition metals (TMs) and activated carbon (AC) as a catalyst support used in the catalytic decomposition of PCBs. A series of AC-supported TM catalysts was prepared according to two distinct methods: impregnation and ion exchange which were defined as LaTM-C and IRTM-C,
 respectively. The catalytic reactions between 2,2',4,4',5,5'-hexachlorobiphenyl (PCB-153) and AC-supported Fe, Ni, Cu and Zn catalysts were conducted under N2 atmosphere. Changes in the nature of the catalysts as well as the decomposition mechanism of PCB-153 are discussed. Important findings include: (i) a higher metal concentration and a better metal distribution on AC is realized using ion-exchange, despite a lower AC specific surface area, (ii) IRTM-C had better effects on the decomposition of PCB-153 than LaTM-C, (iii) the role of Ni, Cu, and Fe as electron donors in PCB dechlorination was evaluated vs. the stability of Zn, and (iv) both temperature and chemical composition of TM catalysts influenced the decomposition efficiency of PCBs.
The misfolding and self-assembly of amyloid-β (Aβ) into oligomers and fibres is fundamental to Alzheimer's disease pathology. Alzheimer's disease is a multifaceted disease. One factor that is thought to have a significant role in disease aetiology is Zn(2+) homeostasis, which is disrupted in the brains of Alzheimer's disease sufferers and has been shown to modulate Alzheimer's symptoms in animal models. Here, we investigate how the kinetics of Aβ fibre growth are affected at a range of Zn(2+) concentrations and we use transmission electron microscopy to characterise the aggregate assemblies formed. We demonstrate that for Aβ(1-40), and Aβ(1-42), as little as 0.01mol equivalent of Zn(2+) (100nM) is sufficient to greatly perturb the formation of amyloid fibres irreversibly. Instead, Aβ(1-40) assembles into short, rod-like structures that pack tightly together into ordered stacks, whereas Aβ(1-42) forms short, crooked assemblies that knit together to form a mesh of disordered tangles. Our data suggest that a small number of Zn(2+) ions are able to influence a great many Aβ molecules through the rapid exchange of Zn(2+) between Aβ peptides. Surprisingly, although Cu(2+) binds to Aβ 10,000 times tighter than Zn(2+), the effect of Zn(2+) on Aβ assembly dominates in Cu(2+)/Zn(2+) mixtures, suggesting that trace levels of Zn(2+) must have a profound effect on extracellular Aβ accumulation. Trace Zn(2+) levels profoundly influence Aβ assembly even at concentrations weaker than its affinity for Aβ. These observations indicate that inhibitors of fibre assembly do not necessarily have to be at high concentration and affinity to have a profound impact.
Archaeal family-D DNA polymerases (Pol-D) comprise a small (DP1) proofreading subunit and a large (DP2) polymerase subunit. Pol-D is one of the least studied polymerase families, and this publication investigates the enzyme from Archaeoglobus fulgidus (Afu Pol-D). The C-terminal region of DP2 contains two conserved cysteine clusters, and their roles are investigated using site-directed mutagenesis. The cluster nearest the C terminus is essential for polymerase activity, and the cysteines are shown to serve as ligands for a single, critical Zn(2+) ion. The cysteines farthest from the C terminal were not required for activity, and a role for these amino acids has yet to be defined. Additionally, it is shown that Afu Pol-D activity is slowed by the template strand hypoxanthine, extending previous results that demonstrated inhibition by uracil. Hypoxanthine was a weaker inhibitor than uracil. Investigations with isolated DP2, which has a measurable polymerase activity, localised the deaminated base binding site to this subunit. Uracil and hypoxanthine slowed Afu Pol-D "in trans", that is, a copied DNA strand could be inhibited by a deaminated base in the alternate strand of a replication fork. The error rate of Afu Pol-D, measured in vitro, was 0.24×10(-5), typical for a polymerase that has been proposed to carry out genome replication in the Archaea. Deleting the 3'-5' proofreading exonuclease activity reduced fidelity twofold. The results presented in this publication considerably increase our knowledge of Pol-D.
Cadmium (Cd) is linked with increased risk of fetal growth restriction (FGR). Nevertheless, the mechanism remains unknown. This study established a mouse model of Cd-induced FGR through two exposure methods. Pregnant mice were either administered with CdCl2 (5, 50 and 250ppm) throughout pregnancy through drinking water or intraperitoneally injected with CdCl2 (4.5mg/kg) on GD9. As expected, fetal weight and crown-rump length were reduced in a gender-independent manner. Interestingly, Mt1 and Mt2, two metallothionein genes, were up-regulated in maternal liver. Correspondingly, Cd accumulated mainly in maternal liver and kidney, and only trace amounts of Cd could pass from dam to placentas and fetuses. Further analysis showed that placental Zn concentration was elevated. Conversely, embryonic Zn concentration was reduced. Moreover, placental Znt1 and Znt2, two zinc transporters, were down-regulated in Cd-exposed mice. These results suggest that maternal Cd exposure during pregnancy reduces placental Zn transport and induces fetal growth restriction.
The mangrove crab Ucides cordatus is widespread in the Brazilian coast, which has an important role in nutrient cycling. This species reproduces in summer and females carry eggs about a month, when they maintain contact with water and sediments. It remains unclear if trace metals can be absorbed or adsorbed by the eggs during development. The present study aims to investigate, for the first time, trace metal concentrations in ovigerous female tissues and eggs of U. cordatus in two areas with different metal pollution levels in the Southeastern Brazil. Samples were collected in two different mangroves, Guanabara Bay (GB) highly polluted environment and Paraíba do Sul River (PSR). In both populations, we observed significant increase of V, Cr, and Mn concentrations along eggs maturation. The higher metals averages were found in PSR population. This trend was reported since the 1990s and lower concentrations in GB marine organisms were attributed to reducing conditions, high organic load, and the presence of sulfide ions. These conditions restrict the bioavailability of metals in the bay, with exception of Mn. No significant differences were observed in gills and muscles. In both populations of the present study, V, Zn, As, and Pb were higher in eggs of initial stage, whereas Mn, Ni, Cu, and Cd were higher in hepatopancreas. Beside this, V, Cr, Mn, As, and Pb showed an increase concerning egg development. Thus, V, As, and Pb in eggs come from two sources previous discussed: females and environment. Zinc came mainly from females due to essential function. Those new information should be considered as one of the mechanisms of trace metal transfer to the trophic chain, between benthonic and pelagic environment.
Spent batteries contain hazardous materials, including numerous metals (cadmium, lead, nickel, zinc, etc.) that are present at high concentrations. Therefore, proper treatment of these wastes is necessary to prevent their harmful effects on human health and the environment. Current recycling processes are mainly applied to treat each type of spent battery separately. In this laboratory study, a hydrometallurgical process has been developed to simultaneously and efficiently solubilize metals from spent batteries. Among the various chemical leaching agents tested, sulfuric acid was found to be the most efficient and cheapest reagent. A Box-Behnken design was used to identify the influence of several parameters (acid concentration, solid/liquid ratio, retention time and number of leaching steps) on the removal of metals from spent batteries. According to the results, the solid/liquid ratio and acid concentration seemed to be the main parameters influencing the solubilization of zinc, manganese, nickel, cadmium and cobalt from spent batteries. According to the results, the highest metal leaching removals were obtained under the optimal leaching conditions (pulp density = 180 g/L (w/v), [H2SO4] = 1 M, number of leaching step = 3 and leaching time = 30 min). Under such optimum conditions, the removal yields obtained were estimated to be 65% for Mn, 99.9% for Cd, 100% for Zn, 74% for Co and 68% for Ni. Further studies will be performed to improve the solubilization of Mn and to selectively recover the metals.
In the developing world, vegetables are commonly grown in suburban areas irrigated with untreated wastewater containing potentially harmful elements (PHEs). In Pakistan, there is no published work on the bioaccessibility aspect of PHEs and dietary minerals (DMs) in sewage-irrigated soil or the vegetables grown on such soils in Pakistan. Several industrial districts of Pakistan were selected for assessment of the risk associated with the ingestion of vegetables grown over sewage-irrigated soils. Both the total and bioaccessible fraction of PHEs (Cd, Co, Cr, Ni, and Pb) and DMs (Fe, Cu, Mn, Zn, Ca, Mg, and I) in soils and vegetable samples were measured. The concentrations of these PHEs and DMs in sewage-irrigated and control soils were below published upper threshold limits. However, compared to control soils, sewage irrigation over the years decreased soil pH (7.7 vs 8.1) and enhanced dissolved organic carbon (1.8 vs 0.8 %), which could enhance the phyto-availability of PHEs and DMs to crops. Of the PHEs and DMs, the highest transfer factor (soil to plant) was noted for Cd and Ca, respectively. Concentrations of PHEs in most of the sewage-irrigated vegetables were below the published upper threshold limits, except for Cd in the fruiting portion of eggplant and bell pepper (0.06-0.08 mg/kg Cd, dry weight) at three locations in Gujarat and Kasur districts. The bioaccessible fraction of PHEs can reduce the context of dietary intake measurements compared to total concentrations, but differences between both measurements were not significant for Cd. Since the soils of the sampled districts are
 not overly contaminated compared to control sites, vegetables grown over sewage-irrigated soils would provide an opportunity to harvest mineral-rich vegetables potentially providing consumers 62, 60, 12, 104, and 63 % higher dietary intake of Cu, Mn, Zn, Ca, and Mg, respectively. Based on Fe and vanadium correlations in vegetables, it is inferred that a significant proportion of total dietary Fe intake could be contributed by soil particles adhered to the consumable portion of vegetables. Faecal sterol ratios were used to identify and distinguish the source of faecal contamination in soils from Gujranwala, Gujarat, and Lahore districts, confirming the presence of human-derived sewage biomarkers at different stages of environmental alteration. A strong correlation of some metals with soil organic matter concentration was observed, but none with sewage biomarkers.
This study aimed to investigate effect of erythrocyte suspension (ES) transfusion on Cu, Zn, and Fe levels. It was conducted on 53 premature infants who were admitted to Hacettepe Hospital and received EST for first time. Blood samples were drawn before and 96h after ES transfusion to determine Cu, Zn, and Fe levels in plasma and/or erythrocytes. The mean plasma Cu levels were 99±3μg/dl and 113±3μg/dl; Zn levels were 105±2μg/dl and 115±23μg/dl; mean plasma Fe level was 58.1±19.4 and 75.2±25.4μg/dl and mean erythrocyte Fe level was 4182±2314μg/ml and 7009±5228μg/ml, before and after ES transfusion. The differences between before and after ES transfusion in Cu, Zn and Fe levels were significant. Correlation between plasma and erythrocyte Fe levels was significant both before and after ES transfusion. Though Fe overload is a major cause of morbidity/mortality after ES transfusion, alterations in trace elements should also be considered when transfusing blood to infants and children.
Cadmium (Cd) contamination is a worldwide environmental problem, and remediation of Cd pollution is of great significance for food production as well as human health. Here, the responses of sweet sorghum cv. 'M-81E' to cadmium stress were studied for its potential as an energy plant in restoring soils contaminated by cadmium. In hydroponic experiments, the biomass of 'M-81E' showed no obvious change under 10 μM cadmium treatment. Cadmium concentration was the highest in roots of seedlings as well as mature plants, but in agricultural practice, the valuable and harvested parts of sweet sorghum are shoots, so promoting the translocation of cadmium to shoots is of great importance in order to improve its phytoremediation capacity. Further histochemical assays with dithizone staining revealed that cadmium was mainly concentrated in the stele of roots and scattered in intercellular space of caulicles. Moreover, the correlation analysis showed that Cd had a negative relationship with iron (Fe), zinc (Zn), and manganese (Mn) in caulicles and leaves and a positive relationship with Fe in roots. These results implied that cadmium might compete with Fe, Zn, and Mn for the transport binding sites and further prevent their translocation to shoots. In addition, transmission electron microscopic observations showed that under 100 μM cadmium treatment, the structure of chloroplast was impaired and the cell wall of vascular bundle cells in leaves and xylem and phloem cells in roots turned thicker compared to control. In summary, morphophysiological characteristic analysis demonstrated sweet sorghum can absorb cadmium and the growth is not negatively affected by mild level cadmium stress; thus, it is a promising material for the phytoremediation of cadmium-contaminated soils considering its economic benefit. This study also points out potential strategies to improve the phytoremediation capacity of sweet sorghum through genetic modification of transporters and cell wall components.
A novel endo-type β-agarase, AgaB, was cloned from an agar-degrading bacterium, Flammeovirga sp. SJP92. The gene agaB consists of 2, 550 bp and encodes a protein of 849 amino acids including a 19 amino acids signal peptide. Based on the amino acid sequence similarity, AgaB belongs to the glycoside hydrolase family GH16. The recombinant AgaB was expressed in Escherichia coli and exhibited maximal activity at around 45 °C and pH 8.0, with a specific activity of 254.2 U/mg, a Km of 3.99 mg/ml and a Vmax of 700 U/mg for agarose. The agarase was stable at neutral to mildly alkaline condition, and remained 85%-90% of activity after treatment for 1 h, a characteristic much more different from other agarases reported. The recombinant enzyme was sensitive to some metal ions (Cu(2+), Co(2+) and Zn(2+)), but resistant to some denaturants (urea and SDS). It can hydrolyze the β-1, 4-glycosidic linkages of agarose, yielding neoagarotetraose and neoagarohexaose as the main products. These properties could make AgaB has a potential application in the food, cosmetic and medical industries.
Zinc Oxide (ZnO) nanoparticles are widely used both in the industry and in biomedical applications for their chemical and physical nanomaterial properties. It is therefore essential to go in depth into the cytotoxicity mechanisms and interactions between nanomaterials and cells. The aim of this work was to evaluate the dissolution of ZnO nanoparticles and their uptake, from a few minutes after treatments up to 24h. ZnO nanoparticles routes of entry into the human colon carcinoma cells (LoVo) were followed at different times by a thorough ultrastructural investigation and semiquantitative analysis. The intracellular release of Zn(2+) ions by Zinquin fluorescent dye, and phosphorylated histone H2AX (γ-H2AX) expression were evaluated. The genotoxic potential of ZnO nanoparticles was also investigated by determining the levels of 8-hydroxyl-2'-deoxyguanosine (8-oxodG). The experimental data show that ZnO nanoparticles entered LoVo cells by either passive diffusion or endocytosis or both, depending on the agglomeration state of the nanomaterial. ZnO nanoparticles coming into contact with acid pH of lysosomes altered organelles structure, resulting in the release of Zn(2+) ions. The simultaneous presence of ZnO nanoparticles and Zn(2+) ions in the LoVo cells determined the formation of reactive oxygen species at the mitochondrial and nuclear level, inducing severe DNA damage.
Zinc is essential for a wide variety of cellular processes in all cells. It is a critical dietary nutrient, particularly in the early stages of life. In the early neonatal period, adequate sources of zinc can be obtained from breast milk. In rare circumstances, the mammary gland produces zinc deficient milk that is potentially lethal for exclusively breast-fed infants. This can be overcome by zinc supplementation to the infant. Alterations to key zinc transporters provide insights into the mechanisms of cellular zinc homeostasis. The bioavailability of zinc in food depends on the presence of constituents that may complex zinc. In many countries, zinc deficiency is a major health issue due to poor nourishment. Young children are particularly affected. Zinc deficiency can impair immune function and contributes to the global burden of infectious diseases including diarrhoea, pneumonia and malaria. Furthermore, zinc deficiency may extend its influence across generations by inducing epigenetic effects that alter the expression of genes. This review discusses the significance of adequate zinc nutrition in infants, factors that influence zinc nutrition, the consequences of zinc deficiency, including its contribution to the global burden of disease, and addresses some of the knowledge gaps in zinc biology.
Metal doped ZnO nanomaterials have attracted considerable attention as a chemical sensor for toxic gases. Here, the electronic sensitivity of pristine and Sc-, Ti-, V-, Cr-, Mn-, and Fe-doped Zn12O12 nanoclusters toward CO gas is investigated using density functional theory calculations. It is found that replacing a Zn atom by a Sc or Ti atom does not change the sensitivity of cluster but doping V and Cr atoms significantly increase the sensitivity. Also, Mn, or Fe doping slightly improves the sensitivity. It is predicted that among all, the Cr-doped ZnO cluster may be the most favorable sensor for CO detection because its electrical conductivity considerably changes after the CO adsorption, thereby, generating an electrical signal. The calculated Gibbs free energy change for the adsorption of CO molecule on the Cr-doped cluster is about -51.2 kcal mol(-1) at 298.15 K and 1 atm, and the HOMO-LUMO gap of the adsorbent is changed by about 117.8 %.
The design of effective phytoremediation programs is severely hindered by poor seed germination on metal polluted soils. The possibility that inoculation with plant growth promoting rhizobacteria (PGPR) could help overcoming this problem is hypothesized. Our aim was investigating the role of PGPR in Spartina densiflora seed germination on sediments with different physicochemical characteristics and metal pollution degrees. Gram negative Pantoea agglomerans RSO6 and RSO7, and gram positive Bacillus aryabhattai RSO25, together with the consortium of the three strains, were used for independent inoculation experiments. The presence of metals (As, Cu, Pb and Zn) in sediments reduced seed germination by 80%. Inoculation with Bacillus aryabhattai RSO25 or Pantoea agglomerans RSO6 and RSO7 enhanced up to 2.5 fold the germination rate of S. densiflora in polluted sediments regarding non-inoculated controls. Moreover, the germination process was accelerated and the germination period was extended. The consortium did not achieve further improvements in seed germination.
The structures of the leucine transporter, drosophila dopamine transporter, and human serotonin transporter show a secondary binding site (designated S2 ) for drugs and substrate in the extracellular
 vestibule toward the membrane exterior in relation to the primary substrate recognition site (S1 ). The present experiments are aimed at disrupting S2 by mutating Asp476 and Ile159 to Ala. Both mutants displayed a profound decrease in [(3) H]DA uptake compared with wild-type associated with a reduced turnover rate kcat . This was not caused by a conformational bias as the mutants responded to Zn(2+) (10 μM) similarly as WT. The dopamine transporters with either the D476A or I159A mutation both displayed a higher Ki for dopamine for the inhibition of [3H](-)-2-β-carbomethoxy-3-β-(4-fluorophenyl)tropane binding than did the WT transporter, in accordance with an allosteric interaction between the S1 and S2 sites. The results provide evidence in favor of a general applicability of the two-site allosteric model of the Javitch/Weinstein group from LeuT to dopamine transporter and possibly other monoamine transporters. X-ray structures of transporters closely related to the dopamine (DA) transporter show a secondary binding site S2 in the extracellular vestibule proximal to the primary binding site S1 which is closely linked to one of the Na(+) binding sites. This work examines the relationship between S2 and S1 sites. We found that S2 site impairment severely reduced DA transport and allosterically reduced S1 site affinity for the cocaine analog [(3) H]CFT. Our results are the first to lend direct support for the application of the two-site allosteric model, advanced for bacterial LeuT, to the human DA transporter. The model states that, after binding of the first DA molecule (DA1 ) to the primary S1 site (along with Na(+) ), binding of a second DA (DA2 ) to the S2 site triggers, through an allosteric interaction, the release of DA1 and Na(+) into the cytoplasm.
China is one of the largest producers and consumers of lead and zinc in the world. Lead and zinc mining and smelting can release hazardous heavy metals such as Cd, Pb, Zn, and As into soils, exerting health risks to human by chronic exposure. The concentrations of Cd, Zn, Pb, and As in soil samples collected from a Pb-Zn mining area with exploitation history of 60 years were investigated. Health risks of the heavy metals in soil were evaluated using US Environmental Protection Agency (US EPA) recommended method. A geo-statistical technique (Kriging) was used for the interpolation of heavy metals pollution and Hazard Index (HI). The results indicated that the long-term Pb/Zn mining activities caused the serious pollution in the local soil. The concentrations of Cd, As, Pb, and Zn in topsoil were 40.3 ± 6.3, 103.7 ± 37.3, 3518.4 ± 896.1, and 10,413 ± 2973.2 mg/kg dry weight, respectively. The spatial distribution of the four metals possessed similar patterns, with higher concentrations around Aayiken (AYK), Maseka (MSK), and Kuangshan (KS) area and more rapidly dropped concentrations at upwind direction than those at downwind direction. The main pollutions of Cd and Zn were found in the upper 60 cm, the Pb was found in the upper 40 cm, and the As was in the upper 20 cm. The mobility of metals in soil profile of study area was classed as Cd > Zn ≫ Pb > As. Results indicated that there was a higher health risk (child higher than adult) in the study area. Pb contributed to the highest Hazard Quotient (57.0 ~ 73.9 %) for the Hazard Index.
Hooghly Estuary along with the Sunderban mangroves forms one of the most diverse ecosystems in the world. We investigated the vertical and horizontal distribution of elements at nine sampling locations in this estuary for assessing the degree of elemental contamination. The elemental concentrations were analyzed by an Energy Dispersive X-ray Flurosence spectrometer (EDXRF). A higher enrichment factor (EF) value of trace elements (V, Cr, Mn, Fe, Ni, Cu and Zn) is evident considering all the sampling locations. Geo-accumulation index (Igeo) values of all the sampling locations and core depth reveals Cr and Cu are under Igeo Class I level of contamination. The value of the pollution load index (PLI) varies between 0.94-1.65 with maximum at Chemaguri and minimum at Haldi Estuary and Petuaghat. The overall variation in elemental concentration may be due to differential discharge pattern of storm water and agricultural run-off, industrial effluent and domestic sewage.
Groundwater ecosystems globally are threatened by anthropogenic contamination, yet there are few ecotoxicological data using obligate groundwater biota on which to base risk assessments. Copepods are found inhabiting aquifers of different geologies around the world and so are a useful taxon for use in ecotoxicological studies of groundwater. The aim of this study was to test the sensitivity of obligate groundwater copepods to metal contaminants (arsenic(III), chromium(VI) and zinc) in groundwater in static 96 h, 14 days and 28 days exposure tests. The copepods were variably sensitive to As, Cr and Zn, with Cr being the most toxic across all taxa. No taxon was consistently most sensitive and there was no apparent relationship between the hardness, pH and organic carbon concentration of the diluent water and the sensitivity of biota. As expected, toxicity increased with exposure period and we encourage the use of longer exposure periods in future toxicity tests with groundwater organisms to reflect the greater exposure periods likely to be associated with groundwater contamination.
The distal hydrogen bond (H-bond) in dioxygen-binding proteins is crucial for the discrimination of O2 with respect to CO or NO. We report the preparation and characterization of a series of Zn(II) porphyrins, with one of three meso-phenyl rings bearing both an alkyl-tethered proximal imidazole ligand and a heterocyclic distal H-bond donor connected by a rigid acetylene spacer. Previously, we had validated the corresponding Co(II) complexes as synthetic model systems for dioxygen-binding heme proteins and demonstrated the structural requirements for proper distal H-bonding to Co(II) -bound dioxygen. Here, we systematically vary the H-bond donor ability of the distal heterocycles, as predicted based on pKa values. The H-bond in the dioxygen adducts of the Co(II) porphyrins was directly measured by Q-band Davies-ENDOR spectroscopy. It was shown that the strength of the hyperfine coupling between the dioxygen radical and the distal H-atom increases with enhanced acidity of the H-bond donor.
Low methoxyl pectin is known to gel with divalent cations (e.g. Ca(2+), Zn(2+)). In this study, a new way of pectin gelation in the presence of an active pharmaceutical ingredient, chlorhexidine (CX), was highlighted. Thus chlorhexidine interactions with pectin were investigated and compared with the well-known pectin/Ca(2+) binding model. Gelation mechanisms were studied by several physico-chemical methods such as zeta potential, viscosity, size measurements and binding isotherm was determined by Proton Nuclear Magnetic Resonance Spectroscopy ((1)H NMR). The binding process exhibited similar first two steps for both divalent ions: a stoichiometric monocomplexation of the polymer followed by a dimerization step. However, stronger interactions were observed between pectin and chlorhexidine. Moreover, the dimerization step occurred under stoichiometric conditions with chlorhexidine whereas non-stoichiometric conditions were involved with calcium ions. In the case of chlorhexidine, an additional intermolecular binding occurred in a third step.
Peptide receptors with Zn(ii)-DPA units and a covalently bound fluorescent coumarin indicator on an oxazole-containing scaffold are shown to function as more selective pyrophosphate sensors than the analogous chemosensing ensembles in indicator displacement assays.
The analysis of metal mixture toxicity to plants is complicated by mutual interactions. In the present study, mixture effects of zinc (Zn), cadmium (Cd), and copper (Cu) on barley (Hordeum vulgare L.) root elongation were analyzed using oxidative stress parameters. The hypothesis was that toxic mixture effects on plant growth are better explained by biochemical parameters than by exposure information, because the former excludes interactions among metals for root uptake. Barley seedlings were exposed for 5 d or 14 d to these metals in nutrient solutions, added in isolation and as mixtures. Root elongation in Cu+Cd mixtures was well predicted from free metal ion concentrations in solution, using concentration addition (CA) or independent action (IA) reference models. In contrast, Zn acted antagonistically when combined with Cu and/or Cd, relative to both CA and IA. This protective effect of Zn correlated with the biomarkers measured in the long-term experiment; oxidative stress (indicated by malondialdehyde level, for example) decreased after addition of Zn. In addition, it was found that some biomarkers were sensitive to both Cu and Cd dosed in isolation, but not to Cu+Cd mixtures. Overall, the exposure explained mixture effects better than most of the 16 measured biomarkers (i.e., the biochemical effects). It is concluded that these biomarkers are not robust indicators for metal mixture toxicity, potentially because different metals have different parallel modes of action on growth that are insufficiently indexed by the biomarkers. Environ Toxicol Chem 2016;9999:1-11. © 2016 SETAC.
The primary objective of the current study was to assess the influence of early high-fat feeding on tissue trace element content in young male Wistar rats. Twenty weanling male Wistar rats were divided into two groups fed standard (STD) or high-fat diet (HFD) containing 10 and 31.6 % of total calories from fat, respectively, for 1 month. Serum lipid spectrum, apolipoproteins, glucose, insulin, adiponectin, and leptin levels were assessed. The level of trace elements was estimated using inductively coupled plasma mass spectrometry. High-fat
 feeding significantly increased epidydimal (EDAT) and retroperitoneal adipose tissue (RPAT), as well as total adipose tissue mass by 34, 103, and 59 %, respectively. Serum leptin levels in HFD animals were twofold higher than those in the control rats. No significant difference in serum lipid spectrum, apolipoproteins, glucose, adiponectin, and insulin was detected between the groups. HFD significantly altered tissue trace element content. In particular, HFD-fed animals were characterized by significantly lower levels of Cu, I, Mn, Se, and Zn in the liver; Cr, V, Co, Cu, Fe, and I content of EDAT; Co, Cu, I, Cr, V, Fe, and Zn concentration in RPAT samples. At the same time, only serum Cu was significantly depressed in HFD-fed animals as compared to the control ones. Hair Co, Mn, Si, and V levels were significantly increased in comparison to the control values, whereas Se and I content was decreased. HFD feeding induced excessive adiposity and altered tissue trace element content in rats without insulin resistance, adiponectin deficiency, and proatherogenic state. Hypothetically, trace element disbalance may precede obesity-associated metabolic disturbances.
Round robin test results of a percolation column leaching procedure (CEN/TS 14405:2004), organised by the Flemish Institute for Technological Research (VITO), over a time span of 13years with a participation of between 8 and 18 different laboratories are presented and discussed. Focus is on the leachability of heavy metals As, Cd, Cr, Cu, Hg, Ni, Pb and Zn from mineral waste materials. By performing statistical analyses on the obtained results, insight into the reproducibility and repeatability of the column leaching test is gathered. A ratio of 1:3 between intra- and inter-laboratory variability is found. The reproducibility of the eluates' element concentrations differ significantly between elements, materials and fractions (i.e. different liquid-to-solid ratios). The reproducibility is discussed in light of the application of the column leaching test for legal and environmental policy purposes. In addition, the performances of laboratories are compared.
Lead contamination is one of the most serious problems in drinking water facing humans. In this study, a novel zirconium phosphate modified polyvinyl alcohol (PVA)-PVDF membrane was developed for lead removal. The zirconium ions and PVA were firstly coated onto a PVDF membrane through crosslinking reactions with glutaraldehyde, which was then modified by phosphate. The adsorption kinetics study showed that most of ultimate uptake occurred in 5 h. The adsorption increased with an increase in pH; the optimal adsorption was achieved at pH 5.5. The experimental data were better described by Langmuir equation than Freundlich equation; the maximum adsorption capacity was 121.2 mg-Pb/g at pH 5.5, much higher than other reported adsorptive membranes. The membrane exhibited a higher selectivity for lead over zinc with a relative selectivity coefficient (Pb(2+)/Zn(2+)) of 9.92. The filtration study showed that the membrane with an area of 12.56 cm(2) could treat 13.9 L (equivalent to 73,000 bed volumes) of lead containing wastewater with an influent concentration of 224.5 μ g/L to meet the maximum contaminant level of 15 μ g/L. It was demonstrated that the membrane did well in the removal of lead in both simulated wastewater and lead-spiked reservoir water and had a good reusability in its applications. The XPS studies revealed that the lead uptake was mainly due to cation exchange between hydrogen ions and lead ions.
Despite evidence for the effects of metals on neurodevelopment, the long-term effects on mental health remain unclear due to methodological limitations. Our objective was to determine the feasibility of studying metal exposure during critical neurodevelopmental periods and to explore the association between early-life metal exposure and adult schizophrenia.
We analyzed childhood-shed teeth from nine individuals with schizophrenia and five healthy controls. We investigated the association between exposure to lead (Pb(2+)), manganese (Mn(2+)), cadmium (Cd(2+)), copper (Cu(2+)), magnesium (Mg(2+)), and zinc (Zn(2+)), and schizophrenia, psychotic experiences, and intelligence quotient (IQ). We reconstructed the dose and timing of early-life metal exposures using laser ablation inductively coupled plasma mass spectrometry.
We found higher early-life Pb(2+) exposure among patients with schizophrenia than controls. The differences in log Mn(2+) and log Cu(2+) changed relatively linearly over time to postnatal negative values. There was a positive correlation between early-life Pb(2+) levels and psychotic experiences in adulthood. Moreover, we found a negative correlation between Pb(2+) levels and adult IQ.
In our proof-of-concept study, using tooth-matrix biomarker that provides direct measurement of exposure in the fetus and newborn, we provide support for the role of metal exposure during critical neurodevelopmental periods in psychosis.
The progressively declining ecological condition of the Chesapeake Bay is attributed to the influx of contaminants associated with sediment loads supplied by its largest tributaries. The continued urban expansion in the suburbs of Virginia cities, modern agricultural activities in the Shenandoah Valley, the anthropogenic and climate driven changes in fluvial system hydrodynamics and their potential associated impacts on trace metals enrichment in the bay's tributaries necessitate constant environmental monitoring of these important water bodies. Eight (210)Pb and (137)Cs dated sediment cores and seventy two sediment grab samples were used to analyze the spatial and temporal distributions of Al, Ca, Mg, Cr, Cd, As, Se, Pb, Cu, Zn, Mn, and Fe in the waterways of the Virginia portion of the Chesapeake Bay basin. The sediment cores for trace metal historical fluctuation analysis were obtained in lower fluvial-estuarine environments and reservoirs in the upper reaches of the basin. The trace metal profiles revealed high basal enrichment factors (EF) of between 0.05 and 40.24, which are interpreted to represent early nineteenth century agricultural activity and primary resource extraction. Surficial enrichment factors on both cores and surface grab samples ranged from 0.01 (Cu) to 1421 (Cd), with Pb, Cu, Zn, and Cd enrichments a plausible consequence of modern urban expansion and industrial development along major transportation corridors. Contemporary surficial enrichments of As, Se, and Cr also ranged between 0 and 137, with the higher values likely influenced by lithological and atmospheric sources. Pearson correlation analyses suggest mining and agricultural legacies, coupled with aerosol deposition, are responsible for high metal concentrations in western lakes and headwater reaches of fluvial systems, while metal accumulation in estuarine reaches of the major rivers can be attributed to urban effluence and the remobilization of legacy sediments.
Chinese pine seed orchards are in a period of transition from first-generation to advanced-generations. How to effectively select populations for second-generation seed orchards and significantly increase genetic gain through rational deployment have become major issues. In this study, we examined open- and control-pollinated progeny of the first-generation Chinese pine seed orchards in Zhengning (Gansu Province, China) and Xixian (Shanxi Province, China) to address issues related to phenotypic selection for high volume growth, genetic diversity analysis and genetic distance-based phylogenetic analysis of the selections by simple sequence repeats (SSRs), and phylogenetic relationship-based field deployment for advanced-generation orchards. In total, 40, 28, 20, and 13 superior individuals were selected from the large-scale no-pedigree open-pollinated progeny of Zhengning (ZN-NP), open-pollinated families of Zhengning (ZN-OP), open-pollinated families of Xixian (XX-OP), and control-pollinated families of Xixian, with mean volume dominance ratios of 0.83, 0.15, 0.25, and 0.20, respectively. Phylogenetic relationship analysis of the ZN-NP and XX-OP populations showed that the 40 superior individuals in the ZN-NP selected population belonged to 23 families and could be further divided into five phylogenetic groups, and that families in the same group were closely related. Similarly, 20 families in the XX-OP population were related to varying degrees. Based on these results, we found that second-generation Chinese pine seed orchards in Zhengning and Xixian should adopt a grouped, unbalanced, complete, fixed block design and an unbalanced, incomplete, fixed block design, respectively. This study will provide practical references for applying molecular markers to establishing advanced-generation seed orchards.
Essential trace elements (Cu(2+), Zn(2+), etc) lead to toxic effects above a certain threshold, which is a major environmental problem in many areas of the world. Here, environmentally relevant sub-micromolar concentrations of Cu(2+) and simulations of natural light and temperature cycles were applied to the aquatic macrophyte Ceratophyllum demersum a s a model for plant shoots. In this low irradiance study resembling non-summer conditions, growth was optimal in the range 7.5-35nM Cu, while PSII activity (Fv/Fm) was maximal around 7.5nM Cu. Damage to the light harvesting complex of photosystem II (LHCII) was the first target of Cu toxicity (>50nM Cu) where Cu replaced Mg in the LHCII-trimers. This was associated with a subsequent decrease of Chl a as well as heat dissipation (NPQ). The growth rate was decreased from the first week of Cu deficiency. Plastocyanin malfunction due to the lack of Cu that is needed for its active centre was the likely cause of diminished electron flow through PSII (ΦPSII). The pigment decrease added to the
 damage in the photosynthetic light reactions. These mechanisms ultimately resulted in decrease of starch and oxygen production.
High-pressure structural and electrical properties of Sr2ZnWO6 double perovskite were investigated using in situ angle-dispersive synchrotron X-ray diffraction (XRD), Raman, and alternating current (AC) impedance spectroscopy. A structural transition from monoclinic (P21/n) to triclinic (P1̅) phase around 9 GPa was observed due to the pressure-induced distortion of (W, Zn)O6 octahedron. In situ high-pressure Raman spectroscopy showed the increasing interaction among O-W-O in WO6 octahedron with pressure and a transition pressure consistent with the XRD results. From the AC impedance spectroscopy measurements, the resistivity increased steeply by ∼1 order of magnitude around 11 GPa, indicating an electronic transition accompanying the symmetry change. The increase in the interaction among O-W-O enhances the attraction of O(2-) electrons toward W(6+), thus increasing the covalence, which in turn lowers the charge transfer energy between O(2-) and W(6+) and induces the resistivity increase under high pressure.
The title compound, [Co2Na2{μ2-N(SiMe3)2}4](μ4-O), (I), represents a new entry in the class of inverse crown ethers. In the mol-ecule, each Co atom is formally in the oxidation state +II. The structure contains one half of a unique mol-ecule per asymmetric unit with the central μ4-oxido ligand residing on an inversion center, leading to a planar coordination to the Na and Co atoms. In the crystal, bulky tri-methyl-silyl substituents prevent additional inter-actions with cobalt. However, weak inter-molecular Na⋯H3C-Si inter-actions form an infinite chain along [010]. The structure is isotypic with its Mg, Mn and Zn analogues.
The title three-dimensional metal-organic framework (MOF) compound, {(NH4)2[Zn2(C9H3O6)2]·2C5H9NO} n , features an anionic framework constructed from Zn(2+) cations and benzene-1,3,5-tri-carboxyl-ate (BTC) organic anions. Charge balance is achieved by outer sphere ammonium cations formed by degradation of di-n-butyl-amine in the solvothermal synthesis of the compound. Binuclear {Zn2(COO)2} entities act as the framework's secondary building units. Each Zn(II) atom has a tetrahedral coordination environment with an O4 set of donor atoms. The three-dimensional framework adopts a rutile-type topology and channels are filled in an alternating fashion with ordered and disordered 1-methyl-pyrrolidin-2-one solvent mol-ecules and ammonium cations. The latter are held in the channels via four N-H⋯O hydrogen bonds, including three with the benzene-1,3,5-tri-carboxyl-ate ligands of the anionic framework and one with a 1-methyl-pyrrolidin-2-one solvent mol-ecule.
Nucleotide excision repair (NER) is a pivotal life process for repairing DNA nucleotide mismatch caused by chemicals, metal ions, radiation, and other factors. As the initiation step of NER, the xeroderma pigmentosum complementation group A protein (XPA) recognizes damaged DNA molecules, and recruits the replication protein A (RPA), another important player in the NER process. The stability of the Zn(2+)-chelated Zn-finger domain of XPA center core portion (i.e., XPA98-210) is the foundation of its biological functionality, while the displacement of the Zn(2+) by toxic metal ions (such as Ni(2+), a known human carcinogen and allergen) may impair the effectiveness of NER and hence elevate the chance of carcinogenesis. In this study, we first calculated the force field parameters for the bonded model in the metal center of the XPA98-210 system, showing that the calculated results, including charges, bonds, angles etc., are congruent with previously reported results measured by spectrometry experiments and quantum chemistry computation. Then, comparative molecular dynamics simulations using these parameters revealed the changes in the conformation and motion mode of XPA98-210 Zn-finger after the substitution of Zn(2+) by Ni(2+). The results showed that Ni(2+) dramatically disrupted the relative positions of the four Cys residues in the Zn-finger structure, forcing them to collapse from a tetrahedron into an almost planar structure. Finally, we acquired the binding mode of XPA98-210 with its ligands RPA70N and DNA based on molecular docking and structural alignment. We found that XPA98-210's Zn-finger domain primarily binds to a V-shaped cleft in RPA70N, while the cationic band in its C-terminal subdomain participates in the recognition of damaged DNA. In addition, this article sheds light on the multi-component interaction pattern among XPA, DNA, and other NER-related proteins (i.e., RPA70N, RPA70A, RPA70B, RPA70C, RPA32, and RPA14) based on previously reported structural biology information. Thus, we derived a putative cytotoxic mechanism associated with the nickel ion, where the Ni(2+) disrupts the conformation of the XPA Zn-finger, directly weakening its interaction with RPA70N, and thus lowering the effectiveness of the NER process. In sum, this work not only provides a theoretical insight into the multi-protein interactions involved in the NER process and potential cytotoxic mechanism associated with Ni(2+) binding in XPA, but may also facilitate rational anti-cancer drug design based on the NER mechanism.
29 inorganic compounds (Al, As, B, Ba, Be, Bi, Ca, Cd, Ce, Co, Cr, Cu, Fe, Gd, K, Mg, Mn, Mo, Na, Nd, Ni, Pb, Sb, Se, Sr, Tl, U, V and Zn) were measured in the tap water of 484 representative homes of children aged 6months to 6years in metropolitan France in 2008-2009. Parents were asked whether their children consumed tap water. Sampling design and sampling weights were taken into account to estimate element concentrations in tap water supplied to the 3,581,991 homes of 4,923,058 children aged 6months to 6years. Median and 95th percentiles of concentrations in tap water were in μg/L: Al: <10, 48.3, As: 0.2, 2.1; B: <100, 100; Ba: 30.7, 149.4; Ca: 85,000, 121,700; Cd: <0.5, <0.5; Ce: <0.5, <0.5; Co: <0.5, 0.8; Cr: <5, <5; Cu: 70, 720; K: 2210, 6740; Fe: <20, 46; Mn: <5, <5; Mo: <0.5, 1.5; Na: 14,500, 66,800; Ni: <2, 10.2; Mg: 6500, 21,200; Pb: <1, 5.4; Sb: <0.5, <0.5; Se: <1, 6.7; Sr: 256.9, 1004; Tl: <0.5, <0.5; U: <0.5, 2.4; V: <1, 1; Zn: 53, 208. Of the 2,977,123 young children drinking tap water in France, some were drinking water having concentrations above the 2011 World Health Organization drinking-water quality guidelines: respectively 498 (CI 95%: 0-1484) over 700μg/L of Ba; 121,581 (CI 95%: 7091-236,070) over 50mg/L of Na; 2044 (CI 95%: 0-6132) over 70μg/L of Ni, and 78,466 (17,171-139,761) over 10μg/L of Pb. Since it is representative, this tap water contamination data can be used for integrated exposure assessment, in conjunction with diet and environmental (dust and soil) exposure data.
Seasonal accumulation of trace elements and contaminants in the muscle tissue of five shrimp species; Speckled Shrimp, Deepwater Rose Shrimp, Red Shrimp, Grooved Shrimp and Green Tiger Shrimp, from Iskenderun Bay of Eastern Mediterranean Sea were investigated. It was observed the period of year for the accumulation of such elements is important. Results indicate that peaks are generally reached in autumn and in spring. The levels of Zn, Fe, Cu and Ni were the highest in autumn whereas the maximum Sn and Cr concentrations were obtained in spring. The levels of Cu and Zn were found to be within the permissible limits for human consumption. Contaminants were accumulated at the highest levels in autumn. Attention has to be drawn that Cd values were above permissible limits for deepwater pink shrimp caught in autumn and winter, and for green tiger shrimp caught in autumn. Besides, the accumulation of high level of Pb in the tissue of all species except grooved shrimp whose value was low in spring should also be considered as a warning signal.
The objective of this study was to investigate trace-metal [cadmium (Cd), copper (Cu), lead (Pb), zinc (Zn)] biotransference and biomagnification in terrestrial biota at different trophic levels (primary producer-top predator) of a wetland ecosystem. We investigated whether metal concentrations in the sediment are reflected in terrestrial arthropods and aquatic plants. We sampled the floating-leaved plant Trapa japonica; its species-specific primary consumer, the leaf beetle Galerucella nipponensis; and two predatory arthropods (the water strider Gerris sp. and the wolf spider Arctosa sp.) from three wetlands with different sedimentary metal concentrations. The δ(13)C and δ(15)N signatures in the trophic link between the plants and the leaf beetles supported the specificity of their feeding relationship. The stable isotope signatures indicate that the leaf beetle could be an important link in the trophic transfer of the metals. Transference factors (TFs) were <1 for Pb in all trophic links, and concentrations in the organisms were negatively correlated with the trophic levels. There was no evidence of Pb biomagnification in the food chain. Cu and Zn had TF >1 for all biota, and the concentrations were positively correlated with the trophic levels. Thus, there may be Cu and Zn biomagnification in the arthropods. We noted TF <1 for Cd between the plants and the leaf beetles, but TF was >1 among the arthropods. Therefore, Cd is probably not biomagnified between T. japonica and G. nipponensis, but it might be biomagnified in the arthropods. The metal burden in terrestrial arthropods may also be influenced by uptake from the sediment by aquatic plants.
Plant growth-promoting yeasts are often over looked as a mechanism to improve phytoremediation of heavy metals. In this study, Cryptococcus sp. NSE1, a Cd-tolerant yeast with plant growth capabilities, was isolated from the rhizosphere of the heavy metal hyperaccumulator Sedum plumbizincicola. The yeast exhibited strong tolerance to a range
 of heavy metals including Cd, Cu, and Zn on plate assays. The adsorption rate Cd, Cu, Zn by NSE1 was 26.1, 13.2, and 25.2 %, respectively. Irregular spines were formed on the surface of NSE1 when grown in MSM medium supplemented with 200 mg L(-1) Cd. NSE1 was capable of utilizing 1-aminocyclopropane-1-carboxylate (ACC) as a sole nitrogen source and was capable of solubilization of inorganic phosphate at rates of 195.2 mg L(-1). Field experiments demonstrated that NSE1 increased phytoremediation by increasing the biomass of Cd hyperaccumulator S. plumbizincicola (46 %, p < 0.05) during phytoremediation. Overall, Cd accumulation by S. plumbizincicola was increased from 19.6 to 31.1 mg m(-2) though no difference in the concentration of Cd in the shoot biomass was observed between NSE1 and control. A Cd accumulation ratio of 38.0 % for NSE1 and 17.2 % for control was observed. The HCl-extractable Cd and CaCl2-extractable Cd concentration in the soil of the NSE1 treatment were reduced by 39.2 and 29.5 %, respectively. Community-level physiology profiling, assessed using Biolog Eco plates, indicated functional changes to the rhizosphere community inoculated with NSE1 by average well color development (AWCD) and measurement of richness (diversity). Values of Shannon-Weiner index, Simpson index, and McIntosh index showed a slight but no significant increases. These results indicate that inoculation of NSE1 could increase the shoot biomass of S. plumbizincicola, enhance the Cd accumulation in S. plumbizincicola, and decrease the available heavy metal content in soils significantly without overall significant changes to the microbial community.
A family of mixed transition-metal oxides (MTMOs) has great potential for applications as anodes for lithium ion batteries (LIBs). However, the reaction mechanism of MTMOs anodes during lithiation/delithiation is remain unclear. Here, the lithiation/delithiation processes of ZnFe2O4 nanoparticles are observed dynamically using in situ transmission electron microscopy (TEM). Our results suggest that during the first lithiation process the ZnFe2O4 nanoparticles undergo a conversion process and generate a composite structure of 1-3 nm Fe and Zn nanograins within Li2O matrix. During the delithiation process, volume contraction and the conversion of Zn and Fe take place with the disappearance of Li2O, followed by the complete conversion to Fe2O3 and ZnO not the original phase ZnFe2O4. The following cycles are dominated by the full reversible phase conversion between Zn, Fe and ZnO, Fe2O3. The Fe valence evolution during cycles evidenced by electron energy-loss spectroscopy (EELS) techniques also exhibit the reversible conversion between Fe and Fe2O3 after the first lithiation, agreeing well with the in situ TEM results. Such in situ TEM observations provide valuable phenomenological insights into electrochemical reaction of MTMOs, which may help to optimize the composition of anode materials for further improved electrochemical performance.
Doubly charged molecular ions of alkaline earth metals and argon could be identified as spectral interferences in an inductively coupled plasma mass spectrometer. These molecular ions were found to occur at abundances reaching about 10(-4) relative to the alkaline earth atomic ion abundances. They can thus substantially affect ultratrace analyses and, when present at similar concentration as the analyte elements, also isotope ratio measurements. For the case of Cu and Zn isotope ratio analyses, the same mass concentration of Sr was found to alter the measured (63)Cu/(65)Cu and (64)Zn/(66)Zn isotope ratios by -0.036‰ to -0.95‰ due to SrAr(2+), appearing at m/Q 63 and 64. BaAr(2+) can affect Sr isotope analyses, MgAr(2+) may impair S isotope ratio measurements, while CaAr(2+) may cause interference to Ca(+) isotopes. The abundances of the doubly charged molecular ions were higher than those of the corresponding singly charged species, which is in accordance with their generally higher bond dissociation energies. The relative abundances were found to depend significantly on the inductively coupled plasma (ICP) operating conditions and generally increase with increasing carrier gas flow rates or lower gas temperature of the ICP. They also increase by about an order of magnitude when a desolvated aerosol is introduced to the ICP.
Newly developed inorganic single-wall carbon nanotube (SWCNT) inks of the Zn/Al complex and colloidal silica give a quite homogeneous SWCNT film on the polyethylene terephthalate (PET) substrate by the bar-coating method, whereas the surfactant-based SWCNT inks of sodium dodecyl sulfonate (SDS) and sodium dodecyl benzene sulfonate (SDBS) cannot give a homogeneous film. The key properties of SWCNT inks were studied for the production of homogeneous SWCNT films. The contact angle and surface tension of the inorganic dispersant-based SWCNT inks were 70° and 72 mN m(-1), respectively, being close to those of water (71.5° and 71 mN m(-1)). The viscosity was significantly higher than that of water (0.90 mPa·s), consequently, providing sufficient wettability, spreadability, and slow drying of the ink on the substrate, leading to homogeneous film formation. On the other hand, the surfactant dispersant-aided SWCNT inks have the contact angle and surface tension twice lower than the inorganic dispersant-based SWCNT inks, guaranteeing better wettability and spreadability than the inorganic dispersant-based inks. However, the small viscosity close to that of water induces a heterogeneous flow of SWCNT ink on rapid drying, leading to inhomogeneous film formation.
- In chronic liver disease, trace element levels in plasma are usually low. However, the specific cause and functional implications of this abnormality are yet not well understood. These element levels may decrease as a result of abnormal liver function in patients with cirrhosis and/or malnutrition.
- To evaluate the nutritional status and the profile of trace elements in plasma of patients with cirrhosis on a liver transplant list and to correlate them with disease severity.
- This cross-sectional study evaluated 31 male patients diagnosed with compensated liver cirrhosis on a waiting list for liver transplant. Nutritional status was objectively evaluated through anthropometry using Mendenhall score and Blackburn classification, subjectively through the Detsky questionnaire and severity of the disease by MELD and CTP score. Trace elements (Zn, Se, Cu, Ca, Fe, Mg and Mn) in plasma were analyzed by inductively coupled plasma mass spectrometry (ICP-MS). Statistical analysis was performed using Mann-Whitney test.
- According to the nutritional assessment 19 (61.3%) were malnourished and 12 (38.7%) were overweight. Regarding disease severity 12 (39%) were classified as Child A, 17 (55%), Child B and 2 (6%) Child C, with 46.9% of patients with MELD score >17. The trace element analysis indicated that 31 (100%) had Mn levels above the reference range, 23 (74.2%) low levels of Cu, 29 (93.5%) with deficiency of Se, and 31 (100%) low levels of Ca and Mg. Disease severity did not show statistical difference between the studied trace elements, in contrast to the nutritional status, in which the malnourished group showed higher levels of Mn (P=0.01) and Fe (P=0.01) and low levels of Zn (P=0.03) when compared to the overweight group.
- The results showed that the trace elements in plasma are altered in chronic liver disease; without significant correlation to disease severity, but correlated to nutritional status. Malnutrition is present in the patients studied, nonetheless a new scenario with an increase in the prevalence of overweight was verified regardless of the degree of hepatic decompensation.
The zinc binding hormone pituitary human prolactin (hPRL) is stored in secretory granules of specialized cells in an aggregated form. Glycosaminoglycans (GAGs) are anionic polysaccharides commonly associated with secretory granules, indicating their involvement in granule formation. Here we, for the first time, study the impact of GAGs in combination with Zn(2+) on the reversible hPRL aggregation across the pH range of 7.4-5.5. Zn(2+) alone causes hPRL aggregation at pH 7.4, while aggregation between pH 7.4 and 5.5 requires both Zn(2+) and GAGs. GAGs alone cause hPRL aggregation below pH 5.5. Comprehensive thermal stability investigations show that hPRL is particularly destabilized toward thermal denaturation at pH 5.5 and that GAGs increasingly destabilize hPRL at decreasing pH values. We propose that Zn(2+) causes hPRL aggregation through low-affinity Zn(2+) binding sites on hPRL with GAGs facilitating Zn(2+) binding by neutralizing repulsive positive charges of hPRL in the acidic environments of the TGN and mature secretory granules. In a manner independent of the aggregation-causing agent(s), the different hPRL aggregates show very similar secondary structure and amorphous morphology. We speculate that this may be a recognizable sorting signal in the formation of hPRL granular vesicles.
In this study, we examined the structural and electronic complementarities of convex 1-Zn(II), comprising functionalized tris(2-pyridylmethyl)amine (TPA) ligand, and concave baskets 2 and 3, having glycine and (S)-alanine amino acids at the rim. With the assistance of (1)H NMR spectroscopy and mass spectrometry, we found that basket 2 would entrap 1-Zn(II) in water to give equimolar 1-Zn⊂2in complex (K = (2.0 ± 0.2) × 10(3) M(-1)) resembling Russian nesting dolls. Moreover, C3 symmetric and enantiopure basket 3, containing (S)-alanine groups at the rim, was found to transfer its static chirality to entrapped 1-Zn(II) and, via intermolecular ionic contacts, twist the ligand's pyridine rings into a left-handed (M) propeller (circular dichroism spectroscopy). With molecular baskets embodying the second coordination
 sphere about metal-containing TPAs, the here described findings should be useful for extending the catalytic function and chiral discrimination capability of TPAs.
According to the WHO report, alcohol is the third most significant health risk factor for the global population. There are contrary reports about heavy metals concentrations in patients with alcoholic liver cirrhosis. The aim of this study was to investigate serum concentrations of selected heavy metals in patients with alcoholic liver cirrhosis living in the eastern part of Poland according to cirrhosis stage. The participants came from various hospitals of the Lublin region were enrolled. The study group included 46 male and 16 female patients. The control group consisted of 18 healthy individuals without liver disease. High Performance Ion Chromatography was used to determine the concentrations of metal ions (Cd, Zn, Cu, Ni, Co, Mn, and Pb) in serum samples. The concentrations of copper, zinc, nickel, and cobalt were found to be significantly lower in patients with alcoholic liver cirrhosis compared to the control group. The serum concentration of cadmium was significantly higher in patients with advanced alcoholic liver cirrhosis compared to the control group. We hypothesize that disorders of metabolism of heavy metals seem to be the outcome of impaired digestion and absorption, which are common in cirrhosis, improper diet, environmental and occupational exposure.
The rate of the complexation reaction between anionic porphyrins and 11 metal ions was found to be accelerated by the presence of β-cyclodextrin (β-CD) in aqueous media at room temperature without the need for additional heating or sonication. The porphyrin complexation reaction with metal ions under aqueous conditions can be difficult due to the strong hydration energy between the metal ions and water. In this study, the specific role of β-CD as an accelerator was determined and found to enhance the typically slow reaction of the porphyrin with metal ions. A significant acceleration effect was exhibited when the model anionic porphyrin, 5,10,15,20-tetraphenyl-21H,23H-porphine-tetrasulfonic acid, and Pb(II) ions were combined in the presence of β-CD. Other than for Hg ion, the addition of β-CD decreased the metalation reaction time from 30 to 2 min. The order in the degree of acceleration was Pb > Zn, Cd > Cu > Fe, Pd > Sn > Ag, Co, Mn. Using Pb(II) as the model ion, it was determined that the complexation rate constant was enhanced by a factor of 2.4, while the dissociation rate constant was diminished by a factor of 135 in the presence of added β-CD relative to that in its absence. Overall, the complex was much more stable (formation equilibrium constant 324-fold greater in the β-CD medium. The formation of a ternary complex (cf. bicapped complex; (β-CD)2-porphyrin-metal ion) was demonstrated through the use of nuclear magnetic-resonance spectroscopy and mass spectrometry. This acceleration effect is expected to be applicable systems in which porphyrin ligands are employed for determining of metal ions in chemical analysis and separation science.
The dietary uptake of Cd and Pb may contribute to the decline of migratory red-crowned cranes (Grus japonensis) on the Asian mainland. To uncover the relevance of this hypothesis, we determined the concentrations of Pb and Cd as well as further macro and trace elements (Ca, Mg, Cu, Zn, Hg and As) in the gastric contents, gastric wall, intestinal wall, liver, kidney, muscle, and feathers of two individuals found dead in Zhalong Wetland in Northeastern China. Indeed, the Pb concentrations in the liver and kidney tissues was with 31.4 and 60.3 mg kg(-1) dry weight (dw), respectively, above concentrations considered as potentially toxic level in common birds (i.e. 30 mg kg(-1)). These Pb concentration may have possibly been associated with lethal toxicosis in this endangered species suggesting Pb as major threat for G. japonensis populations. Thus, the inputs of Pb into Zhalong Wetland should be reduced to maintain and reestablish environmental conditions supporting the population development of these migratory red-crowned cranes in the Zhalong Wetland, a critical crane habitat for the long-term sustainability of this species.
The incidence of Alzheimer's disease (AD) is increasing. Major risk factors for AD are advancing age and diabetes. Lately, obesity has been associated with an increased risk of dementia. Obese and diabetic individuals are prone to decreased circulating levels of zinc, reducing the amount of zinc available for crucial intracellular processes. In the brain, zinc co-localizes with glutamate in synaptic vesicles, and modulates NMDA receptor activity. Intracellular zinc is involved in apoptosis and fluctuations in cytoplasmic Zn(2+) affect modulation of intracellular signaling. The ZNT and ZIP proteins participate in intracellular zinc homeostasis. Altered expression of zinc-regulatory proteins has been described in AD patients. Using microarray data from human frontal cortex (BrainCloud), this study investigates expression of the SCLA30A (ZNT) and SCLA39A (ZIP) families of genes in a Caucasian and African-American sample of 145 neurologically and psychiatrically normal individuals. Expression of ZNT3 and ZNT4 were significantly reduced with increasing age, whereas expression of ZIP1, ZIP9 and ZIP13 were significantly increased. Increasing body mass index (BMI) correlated with a significant reduction in ZNT1 expression similar to what is seen in the early stages of AD. Increasing BMI also correlated with reduced expression of ZNT6. In conclusion, we found that the expression of genes that regulate intracellular zinc homeostasis in the human frontal cortex is altered with increasing age and affected by increasing BMI. With the increasing rates of obesity throughout the world, these findings warrant continuous scrutiny of the long-term consequences of obesity on brain function and the development of neurodegenerative diseases.
Rice ( Oryza sativa L.) is one of the main staple food crops which is inherently low in micronutrients, especially iron (Fe), and can lead to severe Fe deficiency in populations having higher consumption of rice. Soils polluted with nickel (Ni) can cause toxicity to rice and decreased Fe uptake by rice plants. We investigated the potential role of biochar (BC) and gravel sludge (GS), alone and in combination, for in situ immobilization of Ni in an industrially Ni-contaminated soil at original and sulfur-amended altered soil pH. Our further aim was to increase Fe bioavailability to rice plants by the exogenous application of ferrous sulfate to the Ni-immobilized soil. Application of the mixture of both amendments reduced grain Ni concentration, phytate, Phytate/Fe, Phyt/Zn molar ratios, and soil DTPA-extractable Ni. In addition, the amendment mixture increased 70 % Fe and 229 % ferritin concentrations in rice grains grown in the soil at original pH. The Fe and ferritin concentrations in S-treated soil was increased up to 113 and 383 % relative to control respectively. This enhanced Fe concentration and corresponding ferritin in rice grains can be attributed to Ni/Fe antagonism where Ni has been immobilized by GS and BC mixture. This proposed technique can be used to enhance growth, yield, and Fe biofortification in rice by reducing soil pH while in parallel in situ immobilizing Ni in polluted soil.
Doping Zn(2+) in CuS nanoflower into chemically homogeneous superlattice crystal structure is proposed to convert p-type CuS semiconductor to an n-type CuS semiconductor for significantly enhanced photoelectric response performance. In this study, the chemically homogeneous Zn-doped CuS nanoflowers (Zn0.06Cu0.94S, Zn0.26Cu0.73S1.01, Zn0.36Cu0.62S1.02, Zn0.49Cu0.50S1.01, Zn0.58Cu0.40S1.02) are synthesized by reacting appropriate amounts of CuCl and Zn(Ac)2·2H2O with sulfur powders in ethanol solvothermal process. By tuning the Zn/Cu atomic ratios to ∼1:1, the chemically homogeneous Zn-doped CuS nanoflowers could be converted to the perfect Zn0.49Cu0.50S1.01 superlattice structure, corresponding to the periodic Cu-S-Zn atom arrangements in the entire crystal lattice, which can induce an effective built-in electric field with n-type semiconductor characteristics to significantly improve the photoelectric response performance, such as the lifetime of photogenerated charge carriers up to 6 × 10(-8)-6 × 10(-4) s with the transient photovoltage (TPV) response intensity to ∼44 mV. This study reveals that the Zn(2+) doping in CuS nanoflowers is a key factor in determining the superlattice structure, semiconductor type, and the dynamic behaviors of charge carriers.
The chelating properties of diethanoldithiocarbamate (DEDC) and π-electron flow from the nitrogen atom to the sulfur atom via a plane-delocalized π-orbital system (quasi ring) was studied using a density functional theory method. The molecular structure of DEDC and its complexes with Zn(II), Cd(II), and Hg(II) were also considered. First, the geometries of this ligand and DEDC-Zn(II), DEDC-Cd(II), and DEDC-Hg(II) were optimized, and the formation energies of these complexes were then calculated based on the electronic energy, or sum of electronic energies, with the zero point energy of each species. Formation energies indicated the DEDC-Zn(II) complex as the most stable complex, and DEDC-Cd(II) as the least stable. Structural data showed that the N1-C2 π-bond was localized in the complexes rather than the ligand, and a delocalized π-bond over S7-C2-S8 was also present. The stability of DEDC-Zn(II), DEDC-Cd(II), and DEDC-Hg(II) complexes increased in the presence of the non-specific effects of the solvent (PCM model), and their relative stability did not change. There was π-electron flow or resonance along N1-C2-S7 and along S7-C2-S8 in the ligand. The π-electron flow
 or resonance along N1-C2-S7 was abolished when the metal interacted with sulfur atoms. Energy belonging to van der Waals interactions and non-covalent delocalization effects between the metal and sulfur atoms of the ligand was calculated for each complex. The results of nucleus-independent chemical shift (NICS) indicated a decreasing trend as Zn(II) < Cd(II) < Hg(II) for the aromaticity of the quasi-rings. Finally, by ignoring van der Waals interactions and non-covalent delocalization effects between the metal and sulfur atoms of the ligand, the relative stability of the complexes was changed as follows:[Formula: see text] Graphical Abstract Huge electronic cloud localized on Hg(II) in the Hg(II)-DEDC complex.
Tuberculosis of Navicular bone is a rare entity. Osteoarticular tuberculosis of foot is uncommon and that of navicular bone is extremely rare. It is important to recognize skeletal tuberculosis in the initial stages as early treatment can effectively eliminate long-term morbidity.
A 42 yrs old male presented to OPD with swelling and dull aching pain over dorsum of left foot. Radiograph of foot showed lytic puctate lesion in the navicular bone. Further investigations in the form of aspiration biopsy and ZN staining showed presence of multiple tuberculous bacilli. Anti-Kochs treatment was started immediately and patient was treated conservatively. Four drugs (HRZE) were given for a period of 12 months. Radiographs at 2 years follow-up showed a healed lesion.
TB navicular bone is a very rare condition and can be treated conservatively unless associated with metastatic changes or any other complications. Conservative treatment with AKT has excellent results without any complications.
This study aimed to investigate the potential of Mg-based bioceramic scaffolds combined with human treated-dentin matrices (hTDMs) and dentinogenesis-related morphogens to promote odontogenic differentiation and dentin-like tissue formation by Dental Pulp Stem Cells-DPSCs.
DPSC cultures were established and characterized by flow cytometry. Experimental cavities were prepared inside crowns of extracted teeth and demineralized by EDTA (hTDMs). Zn-doped, Mg-based bioceramic scaffolds, synthesized by the sol-gel technique, were hosted inside the hTDMs. DPSCs were spotted inside the hTDMs/scaffold constructs with/without additional exposure to DMP-1 or BMP-2 (100ng/ml, 24h). Scanning Electron Microscopy-SEM, live/dead fluorescence staining and MTT assay were used to evaluate cell attachment and viability; Real time PCR for expression of osteo/odontogenic markers; Inductively Coupled Plasma-Atomic Emission Spectrometry-ICP/AES for scaffold elemental release analysis; ELISA for hTDM growth factor release analysis; SEM and X-ray Diffraction-XRD for structural/chemical characterization of the regenerated tissues.
Scaffolds constantly released low concentrations of Mg(2+), Ca(2+), Zn(2+) and Si(4+), while hTDMs growth factors, like DMP-1, BMP-2 and TGFβ-1. hTDMs/scaffold constructs supported DPSC viability, inducing their rapid odontogenic shift, indicated by upregulation of DSPP, BMP-2, osteocalcin and osterix expression. Newly-formed Ca-P tissue overspread the scaffolds partially transforming into bioapatite. Exposure to DMP-1 or BMP-2 pronouncedly enhanced odontogenic differentiation phenomena.
This is the first study to validate that combining the bioactivity and ion releasing properties of bioceramic materials with growth factor release by treated natural dentin further supported by exogenous addition of key dentinogenesis-related morphogens (DMP-1, BMP-2) can be a promising strategy for targeted dentin regeneration.
According to the elemental defense hypothesis the accumulation of trace elements by plants may substitute for organic defenses, while the joint effects hypothesis proposes that trace elements and organic defenses can have additive or synergistic effects against pathogens or herbivores. To evaluate these hypotheses the response of the pathosystem Alternaria brassicicola-Arabidopsis thaliana to control (2μM) and surplus (12μM) Zn was evaluated using the camalexin deficient mutant pad3-1 and mtp1-1, a mutant with impaired Zn vacuolar storage, along with the corresponding wildtypes. In vitro, a 50% inhibition of fungal growth was achieved by 440μM Zn. A. thaliana leaves could accumulate equivalent concentrations without harm. In fact, surplus Zn enhanced the resistance of A. thaliana to fungal attack in Columbia (Col-0), Wassilewskija (WS), and mtp1-1. However, surplus Zn was unable to protect pad3-1 demonstrating that Zn cannot substitute for camalexin, the main organic defense in A. thaliana. High, non phytotoxic leaf Zn concentrations enhanced the resistance to A. brassicicola of A. thaliana genotypes able to produce camalexin. This was mainly due to Zn-induced enhancement of the JA/ETH signaling pathway leading to enhanced PAD3 expression. These results support the joint effects hypothesis and highlight the importance of adequate Zn supply for reinforced pathogen resistance.
Mangroves are complex and dynamic ecosystems highly dependent on diverse microbial activities. In the last decades, these ecosystems have been exposed to and affected by diverse human activities, such as waste disposal and accidental oil spills. Complex microbial communities inhabiting the soil and sediment of mangroves comprise microorganisms that have developed mechanisms to adapt to organic and inorganic contaminants. The resistance of these microbes to contaminants is an attractive property and also the reason why soil and sediment living microorganisms and their enzymes have been considered promising for environmental detoxification. The aim of the present study was to identify active microbial genes in heavy metals, i.e., Cu, Zn, Cd, Pb and Hg, and antibiotic resistomes of polluted and pristine mangrove sediments through the comparative analysis of metatranscriptome data. The concentration of the heavy metals Zn, Cr, Pb, Cu, Ni, Cd, and Hg and abundance of genes and transcripts involved in resistance to toxic compounds (the cobalt-zinc-cadmium resistance protein complex; the cobalt-zinc-cadmium resistance protein CzcA and the cation efflux system protein CusA) have been closely associated with sites impacted with petroleum, sludge and other urban waste. The taxonomic profiling of metatranscriptome sequences suggests that members of Gammaproteobacteria and Deltaproteobacteria classes contribute to the detoxification of the polluted soil. Desulfobacterium autotrophicum was the most abundant microorganism in the oil-impacted site and displayed specific functions related to heavy metal resistance, potentially playing a key role in the successful persistence of the microbial community of this site.
A new Zn(ii) based coordination polymer (CP) built by the cohesive pilling of 2D Shubnikov type layers is reported. This material exhibits time dependent multicoloured emission, part of which shows a persistent green phosphorescence visible for up to two seconds to the naked eye, which originates from multiple charge transfer mechanisms.
Tetracarboxylic Zn(ii) phthalocyanine-amino functionalized graphene oxide (ZnPcC4-NGO) hybrid materials have been prepared by a covalent functionalization method. The characterizations indicate that the amino-functionalization of GO has an important influence on the structure and photophysical properties of the ZnPcC4-NGO hybrid. The ZnPcC4-NGO hybrid exhibits enhanced photo-induced electron transfer or energy transfer (PET/ET), compared to the ZnPcC4 covalent functionalized GO (ZnPcC4-GO), owing to the presence of the extended sp(2) carbon configurations, along with the partial reduction of the NGO nanosheets and the introduction of electron-donating ethylenediamine. The nonlinear optical (NLO) properties of the hybrids were investigated using the Z-scan technique at 532 nm with 4 ns laser pulses. The results show that the efficient covalent functionalization and partial reduction of NGO cause the ZnPcC4-NGO hybrid to possess evidently larger NLO properties than the individual NGO, ZnPcC4 and the ZnPcC4-GO hybrid. The enhanced NLO performance can be attributed to the increased excited state absorption from the extended sp(2) carbon configurations of the NGO moiety, reverse saturable absorption arising from ZnPcC4 moiety, and the contribution of the efficient PET/ET process between the ZnPcC4 and NGO moieties in the hybrid.
The implications of metal nanoparticles (MeNPs) are still unknown for many food crops. The purpose of this study was to evaluate the effects of cerium oxide (nCeO₂) and titanium oxide (nTiO₂) nanoparticles in soil at 0, 500 and 1000 mg·kg(-1) on the nutritional parameters of barley (Hordeum vulgare L.) kernels. Mineral nutrients, amylose, β-glucans, amino acid and crude protein (CP) concentrations were measured in kernels. Whole flour samples were analyzed by ICP-AES/MS, HPLC and Elemental CHNS Analyzer. Results showed that Ce and Ti accumulation under MeNPs treatments did not differ from the control treatment. However, nCeO₂ and nTiO₂ had an impact on composition and nutritional quality of barley kernels in contrasting ways. Both MeNPs left β-glucans unaffected but reduced amylose content by approximately 21%. Most amino acids and CP increased. Among amino acids, lysine followed by proline saw the largest increase (51% and 37%, respectively). Potassium and S were both negatively impacted by MeNPs, while B was only affected by 500 mg nCeO₂·kg(-1). On the contrary Zn and Mn concentrations were improved by 500 mg nTiO₂·kg(-1), and Ca by both nTiO₂ treatments. Generally, our findings demonstrated that kernels are negatively affected by nCeO₂ while nTiO₂ can potentially have beneficial effects. However, both MeNPs have the potential to negatively impact malt and feed production.
Bidentate enantiopure Schiff
 base ligands, (R or S)-N-1-(Ar)ethyl-2-oxo-1-naphthaldiminate (R- or S-N^O), diastereoselectively provide Λ- or Δ-chiral-at-metal four-coordinated Zn(R- or S-N^O)2 {Ar = C6H5; Zn-1R or Zn-1S and p-C6H4OMe; Zn-2R or Zn-2S}. Two R- or S-N^O-chelate ligands coordinate to the zinc(II) in a tetrahedral mode and induce Λ- or Δ-configuration at the zinc metal center. In the solid state, the R- or S-ligand diastereoselectively gives Λ- or Δ-Zn configuration, respectively, and forms enantiopure crystals. Single crystal structure determinations show two symmetry-independent molecules (A and B) in each asymmetric unit to give Z' = 2 structures. Electronic circular dichroism (ECD) spectra show the expected mirror image relationship resulting from diastereomeric excess toward the Λ-Zn for R-ligands and Δ-Zn for S-ligands in solution. ECD spectra are well reproduced by TDDFT calculations, while the application of the exciton chirality method, in the common point-dipole approximation, predicts the wrong sign for the long-wavelength couplet. A dynamic diastereomeric equilibrium (Λ vs Δ) prevails for both R- and S-ligand-metal complexes in solution, respectively, evidenced by (1)H NMR spectroscopy. Variable temperature (1)H NMR spectra show a temperature-dependent shift of the diastereomeric equilibrium and confirm Δ-Zn configuration (for S-ligand) to be the most stable one and favored at low temperature. DSC analyses provide quantitative diastereomeric excess in the solid state for Zn-2R and Zn-2S, which is comparable to the results of solution studies.
Magnetically softened iron oxide (MSIO) nanofluid, PEGylated (Mn0.5Zn0.5)Fe2O4, was successfully developed for local induction of heat shock proteins (HSPs) 72 in retinal ganglion cells (RGCs) for ocular neuroprotection. The MSIO nanofluid showed significantly enhanced alternating current (AC) magnetic heat induction characteristics including exceptionally high SLP (Specific Loss Power, > 2000 W/g). This phenomenon was resulted from the dramatically improved AC magnetic softness of MSIO caused by the magnetically tailored Mn(2+) and Zn(2+) distributions in Fe3O4. In addition, the MSIO nanofluid with ultra-thin surface coating layer thickness and high monodispersity allowed for a higher cellular uptake up to a 52.5% with RGCs and enhancing "relaxation power" for higher AC heating capability. The RGCs cultured with MSIO nanofluid successfully induced HSPs 72 by magnetic nanofluid hyperthermia (MNFH). Moreover, it was interestingly observed that systematic control of "AC magnetically-induced heating up rate" reaching to a constant heating temperature of HSPs 72 induction allowed to achieve maximized induction efficiency at the slowest AC heating up rate during MNFH. In addition to in-vitro experimental verification, the studies of MSIO infusion behavior using animal models and a newly designed magnetic coil system demonstrated that the MSIO has promising biotechnical feasibility for thermally-induced HSPs agents in future glaucoma clinics.
The exceptional porosity of Metal-Organic Frameworks (MOFs) could be harnessed for countless practical applications. However, one of the challenges currently precluding the industrial exploitation of these materials is a lack of green methods for their synthesis. Since green synthetic methods obviate the use of organic solvents, they are expected to reduce the production costs, safety hazards and environmental impact typically associated with MOF fabrication. Herein we describe the stepwise optimisation of reaction parameters (pH, reagent concentrations and reaction time) for the room temperature, water-based synthesis of several members of the CPO-27/MOF-74-M series of MOFs, including ones made from Mg(II), Ni(II), Co(II) and Zn(II) ions. Using this method, we built MOFs with excellent BET surface areas and unprecedented Space-Time Yields (STYs). Employing this approach, we have synthesised CPO-27-M MOFs with record BET surface areas, including 1279 m(2) g(-1) (CPO-27-Zn), 1351 m(2) g(-1) (CPO-27-Ni), 1572 m(2) g(-1) (CPO-27-Co), and 1603 m(2) g(-1) (CPO-27-Mg). We anticipate that our method could be applied to produce CPO-27-Ni, -Mg, -Co and -Zn with STYs of 44 Kg m(-3) day(-1), 191 Kg m(-3) day(-1), 1462 Kg m(-3) day(-1) and a record 18720 Kg m(-3) day(-1), respectively.
Sediment geochemistry of the Jakarta region, a densely populated tropical coast, is studied - with particular focus on rivers discharging to Jakarta Bay. Weathering volcanics in the river catchment area control the composition of major elements, As, Cr and in part Cu. In contrast, Zn, Ni, Pb and partly Cu are affected by anthropogenic sources, mainly in central Jakarta City. The data reflect a high variability of local emission sources, among which metal processing industries, fertilizers or untreated animal waste may be important. In particular, the role of street dusts is emphasized. Locally, heavy metals reach levels considered to have adverse biological effects. River discharge leads to anthropogenic enrichment of heavy metals in the coastal sediments. Element data also show geogenic effects on the composition of the coastal sediments, such as mixing of detrital silicates with biogenic carbonates as well as suspended particulate matter from the ocean.
Fluxes of dissolved trace metals (Cd, Co, Cr, Cu, Mn, Ni, Pb, and Zn) via groundwater discharge along the southern Baltic Sea have been assessed for the first time. Dissolved metal concentrations in groundwater samples were less variable than in seawater and were generally one or two orders of magnitude higher: Cd (2.1-2.8nmolL(-1)), Co (8.70-8.76nmolL(-1)), Cr (18.1-18.5nmolL(-1)), Mn (2.4-2.8μmolL(-1)), Pb (1.2-1.5nmolL(-1)), Zn (33.1-34.0nmolL(-1)). Concentrations of Cu (0.5-0.8nmolL(-1)) and Ni (4.9-5.8nmolL(-1)) were, respectively, 32 and 4 times lower, than in seawater. Groundwater-derived trace metal fluxes constitute 93% for Cd, 80% for Co, 91% for Cr, 6% for Cu, 66% for Mn, 4% for Ni, 70% for Pb and 93% for Zn of the total freshwater trace metal flux to the Bay of Puck. Groundwater-seawater mixing, redox conditions and Mn-cycling are the main processes responsible for trace metal distribution in groundwater discharge sites.
Nano zero-valent iron (nZVI) is currently investigated as a stabilising amendment for contaminated soils. The effect of pH (4-8) and time (48 and 192 h) on the behaviour of nZVI-treated Pb-Zn and As-contaminated soil samples was assessed. Additionally, soil leachates were subsequently used to study the direct interaction between soil solution components and nZVI particles in terms of mineralogical changes and contaminant retention. A typical U-shaped leaching trend as a function of pH was observed for Cd, Pb and Zn, while As was released predominantly under alkaline conditions. Oxidising conditions prevailed, so pH was the key controlling parameter rather than redox conditions. Generally, longer contact time resulted in increased soluble concentrations of metal(loid)s. However, the stabilisation effect of nZVI was only observed after the direct soil leachate-nZVI interactions, showing enhanced redox and sorption processes for the studied metals. A significant decrease of dissolved As concentrations was observed for both experimental soils, but with different efficiencies depending on neutralisation capacity, organic matter content or solid fractionation of As related to the origin of the soils. Scorodite (FeAsO4·2H2O) was predicted as a potential solubility-controlling mineral phase for As. Sorption of metal(loid)s onto secondary Fe- and Al-(oxyhydr)oxides (predicted to precipitate at pH > 5) represents an important scavenger mechanism. Moreover, transmission electron microscopy confirmed the retention of Zn and Pb under near-neutral and alkaline conditions by newly formed Fe oxides or aluminosilicates. This study shows that the efficiency of nZVI application strongly depends not only on soil pH-Eh conditions and contaminant type, but also on the presence of organic matter and other compounds such as Al/Fe/Mn oxyhydroxides and clay minerals.
European Union regulations state that consumers must be rightfully informed about the provenance of fishery products to prevent fraudulent practices. However, mislabeling of the geographical origin is a common practice. It is therefore paramount to develop forensic methods that allow all players involved in the supply chain to accurately trace the origin of seafood. In this study, trace elemental signatures (TES) of the goose barnacle Pollicipes pollicipes, collected from ten sites along the Portuguese coast, were employed to discriminate individual's origin. Barium (Ba), boron (B), cadmium (Cd), chromium (Cr), lithium (Li), magnesium (Mg), manganese (Mn), phosphorous (P), lead (Pb), strontium (Sr) and zinc (Zn) - were quantified using Inductively Coupled Plasma-Mass Spectrometry (ICP-MS). Significant differences were recorded among locations for all elements. A regularized discriminant analysis (RDA) revealed that 83% of all individuals were correctly assigned. This study shows TES can be a reliable tool to confirm the geographic origin of goose barnacles at fine spatial resolution. Although additional studies are required to ascertain the reliability of TES on cooked specimens and the temporal stability of the signature, the approach holds great promise for the management of goose barnacles fisheries, enforcement of conservation policies and assurance in accurate labeling.
Mucorales are saprobes, ubiquitously distributed and able to infect a heterogeneous population of human hosts. The fungi require robust stress responses to survive in human host. We tested the growth of Mucorales in the presence of different abiotic stress. Eight pathogenic species of Mucorales, including Rhizopus arrhizus, Rhizopus microsporus, Rhizomucor pusillus, Apophysomyces elegans,
 Licthemia corymbifera, Cunninghamella bertholletiae, Syncephalastrum racemosum and Mucor racemosus, were exposed to different stress inducers: osmotic (sodium chloride and d-sorbitol), oxidative (hydrogen peroxide and menadione), pH, cell wall and metal ions (Cu, Zn, Fe and Mg). Wide variation in stress responses was noted: R. arrhizus showed maximum resistance to both osmotic and oxidative stresses, whereas R. pusillus and M. indicus were relatively sensitive. Rhizopus arrhizus and R. microsporus showed maximum resistance to alkaline pH, whereas C. bertholletiae, L. corymbifera, M. racemosus and A. elegans were resistant to acidic pH. Maximum tolerance was noted in R. microsporus to Cu, R. microsporus and R. arrhizus to Fe and C. bertholletiae to Zn. In contrast, L. corymbifera, A. elegans and M. indicus were sensitive to Cu, Zn and Fe respectively. In conclusion, R. arrhizus showed high stress tolerance in comparison to other species of Mucorales, and this could be the possible reason for high pathogenic potential of this fungi.
The concentration distribution and toxicological assessment of eight heavy metals including lead (Pb), cadmium (Cd), copper (Cu), chromium (Cr), nickel (Ni), mercury (Hg), arsenic (As), and zinc (Zn) in agricultural soils from Kenya, Eastern Africa, were investigated in this study. The results showed mean concentrations of eight heavy metals of Zn, Pb, Cr, Cu, As, Ni, Hg, and Cd in agricultural soils as 247.39, 26.87, 59.69, 88.59, 8.93, 12.56, 8.06, and 0.42 mg kg(-1), respectively. These mean values of eight heavy metals were close to the toxicity threshold limit of USEPA standard values of agricultural soils, indicating potential toxicological risk to the food chain. Pollution index values revealed that eight heavy metals severely decreased in the order Hg > Cd > As > Cu > Pb > Zn > Ni > Cr and the mean value of the overall pollution index of Hg and Cd was 20.31, indicating severe agriculture ecological risk. Potential pollution sources of eight heavy metals in agricultural soils were mainly from anthropogenic activities and natural dissolution. The intensification of human agricultural activities, the growing industrialization, and the rapid urbanization largely influenced the concentration levels of heavy metals in Kenya, Eastern Africa. Moreover, the lack of agricultural normalization management and poor enforcement of environmental laws and regulations further intensified the widespread pollution of agricultural soils in Kenya.
Herein, we exploit the induction of chirality by chiral Zn(ii) Schiff-base complexes, followed by their spontaneous dissociation in aqueous solution, providing for the first time a possibility of overcoming the template removal steps, to demonstrate memorization of chirality in porphyrin hetero-aggregates.
Both occupational and environmental exposure to asbestos-mineral fibres can be associated with lung diseases. The pathogenic effects are related to the dimension, biopersistence and chemical composition of the fibres. In addition to the major mineral elements, mineral fibres contain trace elements and their content may play a role in fibre toxicity. To shed light on the role of trace elements in asbestos carcinogenesis, knowledge on their concentration in asbestos-mineral fibres is mandatory. It is possible that trace elements play a synergetic factor in the pathogenesis of diseases caused by the inhalation of mineral fibres. In this paper, the concentration levels of trace elements from three chrysotile samples, four amphibole asbestos samples (UICC amosite, UICC anthophyllite, UICC crocidolite and tremolite) and fibrous erionite from Jersey, Nevada (USA) were determined using inductively coupled plasma mass spectrometry (ICP-MS). For all samples, the following trace elements were measured: Li, Be, Sc, V, Cr, Mn, Co, Ni, Cu, Zn, As, Rb, Sr, Y, Sb, Cs, Ba, La, Pb, Ce, Pr, Nd, Sm, Eu, Gd, Tb, Dy, Ho, Er, Tm, Yb, Lu, Th, U. Their distribution in the various mineral species is thoroughly discussed. The obtained results indicate that the amount of trace metals such as Mn, Cr, Co, Ni, Cu and Zn is higher in anthophyllite and chrysotile samples, whereas the amount of rare earth elements (REE) is higher in erionite and tremolite samples. The results of this work can be useful to the pathologists and biochemists who use asbestos minerals and fibrous erionite in-vitro studies as positive cyto- and geno-toxic standard references.
In this study we have examined the currents and hydrological characteristics of the water column off the mouth of the Gromolo Torrent (north-western Italy) in relation to the grain-size, mineralogical characteristics and metal distribution in the marine sediment sampled. Our purpose was to quantify and map the contamination that was carried out to sea from the abandoned Libiola Fe-Cu sulphide mine that has heavily impacted the torrent. Our results show high concentrations of Cu and Zn, and relatively high concentrations of Cd and Ni inside the bay into which the Gromolo Torrent flows. However, high concentrations of As, Cr, Hg, Mn, Pb, and V found in the northern and/or eastern parts of the study area originated from other sources. The subdivision of study stations in terms of metal and mineral contents in the bottom sediments highlighted the clear influence of the currents on their dispersion and distribution in the area.
Quinoline-derived fluorescent complexes were designed; synthesized by the reaction of 5-nitro-8-hydroxyquinoline and 5-chloro-8-hydroxyquinoline with Al(3+), Mg(2+), Zn(2+), and Cd(2+) salts (1-8); and characterized. The (1)H NMR spectra of complexes 1 and 5, containing Al(3+), were consistent with an octahedral structure having approximate D3 symmetry, and the results supported the favored facial isomer (fac). Data for complexes 2-4 and 6-8 supported the formation of tetrahedral structures. Intense luminescence was detected for complexes 5-8, even with the naked eye, as indicated by quantum yield values of 0.087, 0.094, 0.051, and 0.021, respectively. Furthermore, in contrast to 5-nitro-8-hydroxyquinoline, the 5-chloro-8-hydroxyquinoline ligand exhibited bands at different energies depending on the coordinated metal, which supported its potential application in ionic and biological probes, as well as in cell imaging.
We report in this study the magnetic properties and partitioning patterns of selected trace metals (Pb, Zn, Cu, Cd, Ni) in roadside and off-road (>200m distance from the road edge) agricultural soils collected along two major highways in Greece. Sequential extractions revealed that the examined trace metals for the entire data set were predominantly found in the residual fraction, averaging 37% for Cd up to 80% for Cu. Due to the strong influence of lithogenic factors, trace metal pseudototal contents of the roadside soils did not differ significantly to those of the off-road soils. Magnetic susceptibility and frequency dependent magnetic susceptibility determinations showed a magnetic enhancement of soils; however, it was primarily related to geogenic factors and not to traffic-derived magnetic particles. These results highlight that in areas characterized by strong geogenic backgrounds, neither pseudototal trace metal contents nor magnetic properties determinations effectively capture traffic-related contamination of topsoils. The vehicular emission signal was traced by the increased acid-soluble and reducible trace metal contents of the roadside soils compared to their off-road counterparts. In the case of Cu and Zn, changes in the partitioning patterns were also observed between the roadside and off-road soils. Environmental risks associated with agricultural lands extending at the margins of the studied highways may arise from the elevated Ni contents (both pseudototal and potentially mobile), and future studies should investigate Ni levels in the edible parts of plants grown on these agricultural soils.
To assess the effects of exposure to Cd and Zn on rat testicular development, offspring, from mothers receiving either tap water, Cd, Zn or Cd+Zn during gestation and lactation periods, were observed on gestational day (GD) 20 and on postnatal days (PND) 12, 21 and 35. During gestation, Cd induced maternal hypozincemia and less transfer of Zn to the fetus. During lactation, progressive Cd accumulation and Zn depletion in testis at PND12 and PND21 were noted. An increase of abnormal seminiferous tubules and a decrease in testis weight and plasmatic testosterone concentration were also observed at PND21 and PND35 respectively. Interestingly, Zn supply induced a significant protection against Cd toxicity. These results suggest that the toxic effects of Cd observed during development are mediated by the disruption of Zn metabolism, which is established in mothers during pregnancy causing Zn deficiency in fetuses and continues to become more pronounced during lactation.
It is a big challenge to develop fluorescent probes for selective detection of DNA with specific sequences in aqueous buffers. We report a new tetraphenylethene-based Zn(2+)-cyclen complex (TPECyZn), and a chemo-sensing ensemble of the Zn complex with phenol red. TPECyZn showed significant fluorescence enhancement upon binding to thymine-rich DNA in HEPES buffers. But its selectivity was not high enough to eliminate the interference from some random DNA. By constructing the chemo-sensing ensemble of TPECyZn with phenol red, the background fluorescence was eliminated due to the energy transfer from TPECyZn to phenol red. Moreover, this chemo-sensing ensemble revealed high selectivity in detecting thymine-rich single-stranded DNA over other DNA in aqueous buffer. It can detect poly deoxythymidylic acid sequence as short as 2 nt. This detection in aqueous media makes this probe feasible in real application.
This contribution aimed to characterize
 physicochemical and kinetic parameters of the brain cholinesterases (ChEs) from Parachromis managuensis and investigate the in vitro effects of pesticides and metal ions on its activity intending to propose as biomarker. This species is suitable for this investigation because (1) it was recently introduced in Brazil becoming invasive (no restrictions on capture) and (2) occupies the top of the food chain (being subject to bioaccumulation). The enzyme extract was exposed to 10 metal ions (Al(3+), Ba(2+), Cd(2+), Cu(2+), Hg(2+), Mg(2+), Mn(2+), Pb(2+), Fe(2+) and Zn(2+)) and ChEs selective inhibitors (BW284c51, Iso-OMPA, neostigmine and serine). The extract was also incubated with organophosphate (dichlorvos) and carbamate pesticides (carbaryl and carbofuran). Inhibition parameters (IC20, IC50 and ki) were determined. Selective inhibitors and kinetic parameters confirmed acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) -like as responsible for the ChE activities, most AChE. The IC50 values for pesticides were: 1.68μM (dichlorvos); 4.35μM (carbaryl) and 0.28μM (carbofuran). Most of the analyzed ions did not show significant effect at 1mM (p=0.05), whereas the following ions inhibited the enzyme activity in the order: Hg(2+)>Cu(2+)>Cd(2+)>Zn(2+). Mercury ion strongly inhibited the enzyme activity (IC20=0.7μM). The results about allow to conclude that P. managuensis brain AChE is a potential biomarker for heavy metals and pesticides under study, mainly for the carbamate carbofuran once it was capable to detect 6-fold lower levels than the limit concentration internationally recommended.
Chemical bioimaging offers an important contribution to the investigation of biochemical functions, biosorption and bioaccumulation processes of trace elements via their localization at the cellular and even at the subcellular level. This paper describes the combined use of high contrast transmission electron microscopy (HC-TEM), energy dispersive X-ray spectroscopy (X-EDS), and nano secondary ion mass spectrometry (NanoSIMS) applied to a model organism, the unicellular green algae Chlamydomonas reinhardtii. HC-TEM providing a lateral resolution of 1nm was used for imaging the ultrastructure of algae cells which have diameters of 5-10μm. TEM coupled to X-EDS (TEM/X-EDS) combined textural (morphology and size) analysis with detection of Ca, P, K, Mg, Fe, and Zn in selected subcellular granules using an X-EDS probe size of approx. 1μm. However, instrumental sensitivity was at the limit for trace element detection. NanoSIMS allowed chemical imaging of macro and trace elements with subcellular resolution (element mapping). Ca, Mg, and P as well as the trace elements Fe, Cu, and Zn present at basal levels were detected in pyrenoids, contractile vacuoles, and granules. Some metals were even localized in small vesicles of about 200nm size. Sensitive subcellular localization of trace metals was possible by the application of a recently developed RF plasma oxygen primary ion source on NanoSIMS which has shown good improvements in terms of lateral resolution (below 50nm), sensitivity, and stability. Furthermore correlative single cell imaging was developed combining the advantages of TEM and NanoSIMS. An advanced sample preparation protocol provided adjacent ultramicrotome sections for parallel TEM and NanoSIMS analyses of the same cell. Thus, the C. reinhardtii cellular ultrastructure could be directly related to the spatial distribution of metals in different cell organelles such as vacuoles and chloroplast.
Tidal current survey as well as geochemical and benthic foraminiferal analyses of sediment cores were conducted in an abalone farm and a Zostera bed to understand the degree to which the abalone farm facilities installed along a channel in a shallow sea affect the benthic environment and ecology. In the abalone farm, Ammonia beccarii-Pseudoparrella naraensis-Elphidium somaense-Rosalina globularis-Trochammina hadai and P. naraensis-E. somaense-A. beccarii-T. hadai assemblages appeared owing to an increase in the total nitrogen content from the biodeposits. The Zostera bed consisted of A. beccarii-P. naraensis-Buccella frigida-T. hadai assemblage owing to the gradual expansion of a brackish shallow-water environment by the rapidly decreasing current speed, and it may have flourished. Moreover, the total sulfur, Zn, Cr, and Cu contents in the sediments decreased remarkably more than those of the pre-abalone farming did, caused by the vigorous activity of Zostera marina physiology.
The presence of antibiotics and their metabolites in natural waters has raised some concern among scientists around the world because it can lead to bacterial resistance and other unknown consequences to mankind and wildlife. Persulfate (PS)-driven oxidation is a new technology that has been used successfully to remediate contaminated sites, but its use to treat wastewater, especially sewage treatment plant (STP) effluent, is still scarce. This paper describes the effect of several persulfate activation methods for degrading sulfathiazole (STZ) in Milli-Q water and in STP effluent. Some parameters, such as pH, persulfate concentration, presence of Mn(2+), Zn(2+), Cu(2+), Fe(2+), and Fe(3+), as well as copper and iron organic complexes, were studied in STZ degradation. Raising the pH from 5 to 9, as well as the persulfate concentration, resulted in increased STZ degradation. Among the transition metals evaluated, only Fe(2+) and Cu(2+) were able to activate persulfate molecules. Copper was a better activator than iron since its effect lasts longer. Citrate was the best ligand evaluated increasing Fe(II) activation capacity at pH 7. Hydroxylamine addition to Fe(II) on persulfate system extended the Fe(II) effect. The presence of bicarbonate or humic acid did not affect PS-driven degradation of STZ. Finally, the degradation of STZ in STP effluent promoted by PS-driven oxidation (25 °C) was as fast as in Milli-Q water, proving to be successful.
Crocetin ester (CE) is the active ingredient of Crocus sativus L. stigmas and Gardenia jasminoides Ellis fruit. The main purpose of the present study was to investigate the protective effect of CE on isoproterenol (ISO)-induced acute myocardial ischemia (AMI) through Rho/ROCK/NF-κB pathway and explore its underlying mechanism. Administration of CE (25 and 50mg/kg) could significantly reduce the serum contents of pro-inflammatory cytokines including tumor necrosis factor-alpha (TNF-α), interleukin-1 beta (IL-1β) and interleukin-6 (IL-6). In addition, pretreatment with CE attenuated the contents of creatine kinase (CK), malondialdehyde (MDA) and the activities of lactate dehydrogenase (LDH), superoxide dismutase (SOD) in serum. Treatment with CE also improved the histopathological alteration and decreased the ST elevation. Furthermore, CE could ameliorate the cardiac expressions of Cu, Zn-superoxide dismutase (SOD1), MDA5, Rho, ROCK, p-IκB and p-NF-κBp65 in ISO-induced rats. It was assumed that CE might be a new therapeutic candidate for the treatment of AMI possibly through the inhibition of Rho/ROCK/NF-κB pathway.
This corrects the article DOI: 10.1103/PhysRevLett.116.182502.
An extraction procedure using Tris-HCl buffer solution was employed in order to extract water-soluble proteins from seed samples of oat, wheat and soybean. Initially, the total protein concentration was determined by the Bradford method in each solution, after the extraction procedure. The soybean sample showed a higher concentration of total protein compared to the others. The protein extracts obtained were separated by reverse-phase chromatography (RP-HPLC-UV). The protein fractions were collected and analyzed by graphite furnace atomic absorption spectrometry (GFAAS) and matrix-assisted laser desorption/ionization (MALDI-TOF-MS) for determination of Cu, Fe, Mn and Zn and identification of proteins, respectively. The combination of techniques such as RP-HPLC-UV, GFAAS and MALDI-TOF-MS allowed the identification of several proteins bound to metals present in the seed samples.
The impact of different concentrations of Na(+), K(+), Ca(2+), Mg(2+), Fe(2+), and Zn(2+) on the degradation of adenosine triphosphate (ATP) and the influence of these ions on the activity of adenosine monophosphate deaminase (AMP-deaminase) and acid phosphatase (ACP) in common carp fillets (in vivo) during 4°C storage was examined. The content of ATP, inosine monophosphate (IMP), and hypoxanthine (Hx), and the activity of AMP-deaminase and ACP were determined. Results indicated that the effects of different concentrations of six kinds of metal ions on AMP-deaminase and ACP were not the same. Na(+), K(+), Fe(2+), and Zn(2+) enhanced AMP-deaminase activity, which led to the rapid degradation of ATP and to the generation of a large quantity of IMP within a short time. Ca(2+) and Mg(2+) delayed the change in AMP-deaminase and ACP activity in carp and caused a further delay in the degradation of ATP. Fe(2+) and Zn(2+) inhibited ACP activity, which reduced the decomposition of IMP and the formation of Hx.
Food traceability is increasingly relevant with respect to safety, quality and typicality issues. Lemon fruits grown in a typical lemon-growing area of southern Italy (Siracusa), have been awarded the PGI (Protected Geographical Indication) recognition as 'Limone di Siracusa'. Due to its peculiarity, consumers have an increasing interest about this product. The detection of potential fraud could be improved by using the tools linking the composition of this production to its typical features. This study used a wide range of analytical techniques, including conventional techniques and analytical approaches, such as spectral (NIR spectra), multi-elemental (Fe, Zn, Mn, Cu, Li, Sr) and isotopic ((13)C/(12)C, (18)O/(16)O) marker investigations, joined with multivariate statistical
 analysis, such as PLS-DA (Partial Least Squares Discriminant Analysis) and LDA (Linear Discriminant Analysis), to implement a traceability system to verify the authenticity of 'Limone di Siracusa' production. The results demonstrated a very good geographical discrimination rate.
This work studies the effects of the substitution of NaCl with KCl and CaCl2 on the physicochemical, mineral and sensory profile of fermented green Spanish-style Manzanilla olives, using an enlarged centroid mixture design. An increasing presence of CaCl2 in the initial brines improved the colour index, L(∗), b(∗) values, and firmness. The Na in the olives decreased (linearly) while the levels of K and Ca increased (quadratic) as a function of the KCl and CaCl2 concentrations in the initial brines. CaCl2 also improved the retention of Zn and P in the flesh. PLS showed a strong relationship between Ca and bitterness, hardness, fibrousness, crunchiness and saltiness (negative) and allowed for the prediction of sensory attributes (except acid) from the mineral contents in the flesh. Most of the treatments could lead to new green Spanish-style Manzanilla olive presentations with reduced Na and healthier characteristics.
In this study, a simple and rapid solid phase extraction/preconcentration procedure was developed for determination of Cd(II), Co(II), Cr(III), Cu(II), Fe(III), Mn(II), Pb(II), and Zn(II) trace metals by flame atomic absorption spectrometry (FAAS). A new chelating resin, poly(N-cyclohexylacrylamide-co-divinylbenzene-co-2-acrylamido-2-methyl-1-propanesulfonic acid) (NCA-co-DVB-co-AMPS) (hereafter CDAP) was synthesized and characterized. The influences of the analytical parameters such as pH of the sample solution, type and concentration of eluent, flow rates of the sample and eluent, volume of the sample and eluent, amount of chelating resin, and interference of ions were examined. The limit of detection (LOD) of analytes were found (3s) to be in the range of 0.65-1.90μgL(-1). Preconcentration factor (PF) of 200 and the relative standard deviation (RSD) of ⩽2% were achieved (n=11). The developed method was applied for determination of analytes in some dairy samples and certified reference materials.
This work aims to examine the influence of the metabolic state of the yeast Pichia kudriavzevii on the susceptibility to a metals mixture (5 mg L(-1) Cd, 10 mg L(-1) Pb, and 5 mg L(-1) Zn). Cells exposed to the metals mixture in the presence of 25 mmol L(-1) glucose displayed a higher loss of membrane integrity and proliferation capacity, compared to cells incubated in the absence of glucose. The analysis of the effect of individual metals revealed that glucose increased the toxic effect of Cd marginally, and of Pb significantly. The increased susceptibility to heavy metals due to glucose was attenuated in the simultaneous presence of a mitochondrial respiration inhibitor such as sodium azide (NaN3 ). ATP-depleted yeast cells, resulting from treatment with the non-metabolizable glucose analogue 2-deoxy-d-glucose, showed an increased susceptibility to heavy metals mixture. Pre-incubation of yeast cells with 1 or 1.5 mmol L(-1) Ca(2+) reduced significantly (P < 0.05) the loss of membrane integrity induced by the metals mixture. These findings contribute to the understanding of metals mechanisms of toxicity in the non-conventional yeast P. kudriavzevii.
Prunella vulgaris polysaccharides have been reported to have antioxidant, antitumor and immunomodulatory activities. In this study, P. vulgaris polysaccharide (P1)-zinc complex (P1-Zn) was first prepared by a facile method and its antiproliferative effect on HepG2 human hepatocellular carcinoma cells was also investigated. Results showed that P1-Zn could effectively inhibit the proliferation (98.4% inhibition rate at 500μg/mL) of HepG2 cells through induction of apoptosis, evidenced by morphological changes, chromatin condensation and G0/G1 phase cell cycle arrest. The intracellular mechanism of P1-Zn induced apoptosis was found to be the involvement of the activation of caspase-3 and -9, reactive oxygen species (ROS) overproduction and mitochondrial dysfunction. Our findings suggest that P1-Zn may be a potent candidate for human hepatocellular carcinoma treatment and prevention in functional foods and pharmacological fields.
In the last 35 years, zinc (Zn) has been examined for its potential role in the disease multiple sclerosis (MS). This review gives an overview of the possible role of Zn in the pathogenesis of MS as well as a meta-analysis of studies having measured Zn in serum or plasma in patients with MS. Searching the databases PubMed and EMBASE as well as going through reference lists in included articles 24 studies were found measuring Zn in patients with MS. Of these, 13 met inclusion criteria and were included in the meta-analysis. The result of the meta-analysis shows a reduction in serum or plasma Zn levels in patients with MS with a 95% CI of [-3.66, -0.93] and a p value of .001 for the difference in Zn concentration in μM. One of six studies measuring cerebrospinal fluid, Zn levels found a significant increase in patients with MS with controls. The studies measuring whole blood and erythrocyte Zn levels found up to several times higher levels of Zn in patients with MS compared with healthy controls with decreasing levels during attacks in relapsing-remitting MS patients. Future studies measuring serum or plasma Zn are encouraged to analyze their data through homogenous MS patient subgroups on especially age, sex, and disease subtype since the difference in serum or plasma Zn in these subgroups have been found to be significantly different. It is hypothesized that local alterations of Zn may be actively involved in the pathogenesis of MS.
Mangroves ecosystems support livelihood and economic activities of coastal communities in the tropics and subtropics. Previous reports have documented the inefficiency of waste treatment facilities in Tanzania to contain trace metals. Therefore, the rapidly expanding coastal population and industrial sector is likely to threaten mangrove ecosystems with metal pollution. This study analysed trace metals in 60 sediment samples and 160 giant tiger prawns from the Tanzanian coast in order to document the distribution of trace metals and to establish if measured levels present a threat to mangrove fauna and are of public health importance. High levels of Cr, Co, Cu, Fe, Mn, Ni, and V was observed in mangroves of river Pangani, Wami, and Rufiji. Multivariate analysis showed that they originate mainly from weathering and erosion in the river catchments. Extreme enrichment of Cd was observed in a mangrove affected by municipal sewage. The distribution of Hg, Pb, and Zn was related with urbanisation and industrial activities along the coast. The metal pollution index was high at Pangani, Saadani, and Rufiji, suggesting that these estuarine mangroves are also affected by human activities in the catchment. Moderate to considerable ecological risks were observed in all sampled mangroves, except for Kilwa Masoko. It was revealed that As, Cd, and Hg present moderate risks to fauna. High levels of Cu, Fe and Zn were observed in prawns but the level of the non-essential Cd, Hg, and Pb did not exceed the maximum allowed levels for human consumption. However, based on the trends of fish consumption in the country, weekly intake of Hg is likely to exceed provisional tolerable weekly intake level, especially in fishing communities. This calls for measures to control Hg emissions and to strengthen sewage and waste treatment in coastal cities and urban centres in the basin of major rivers.
Zinc (Zn) is an essential metal that vertebrates sequester from pathogens to protect against infection. Investigating the opportunistic pathogen Acinetobacter baumannii's response to Zn starvation, we identified a putative Zn metallochaperone, ZigA, which binds Zn and is required for bacterial growth under Zn-limiting conditions and for disseminated infection in mice. ZigA is encoded adjacent to the histidine (His) utilization (Hut) system. The His ammonia-lyase HutH binds Zn very tightly only in the presence of high His and makes Zn bioavailable through His catabolism. The released Zn enables A. baumannii to combat host-imposed Zn starvation. These results demonstrate that A. baumannii employs several mechanisms to ensure bioavailability of Zn during infection, with ZigA functioning predominately during Zn starvation, but HutH operating in both Zn-deplete and -replete conditions to mobilize a labile His-Zn pool.
A biogeochemistry field study was conducted in the Siena urban area (Italy) with the main objective of establishing the relationship between available amounts of heavy metals in soil assessed by a chemical method (soil fractionation) and bioavailability assessed by a biological method (bioaccumulation in earthworm tissues). The total content of traffic-related (Cd, Cu, Pb, Sb, Zn) and geogenic (Co, Cr, Ni, U) heavy metals in uncontaminated and contaminated soils and their concentrations in soil fractions and earthworms were used for this purpose. The bioavailability of heavy metals assessed by earthworms did not always match the availability defined by soil fractionation. Earthworms were a good indicator to assess the bioavailability of Pb and Sb in soil, while due to physiological mechanisms of regulation and excretion, Cd, Cu and Zn tissue levels in these invertebrates gave misleading estimates of their bioavailable pool. No relationship was identified between chemical and biological availability for the geogenic heavy metals, characterized by a narrow range of total contents in soil. The study highlighted that chemical and biological methods should be combined to provide more complete information about heavy element bioavailability in soils.
The bromine-rich
 zinc bromides Zn6Br12(18-crown-6)2×(Br2)5 (1), Zn4Br8(18-crown-6)2×(Br2)3 (2), and Zn6Br12(18-crown-6)2×(Br2)2 (3) are prepared by reaction of ZnBr2, 18-crown-6, and elemental bromine in the ionic liquid [MeBu3N][N(Tf)2] (N(Tf)2 = bis(trifluoromethylsulfonyl)amide). Zn6Br12(18-crown-6)2×(Br2)5 (1) is formed instantaneously by the reaction. Even at room temperature, compound 1 releases bromine, which was confirmed by thermogravimetry (TG) and mass spectrometry (MS). The release of Br2 can also be directly followed by the color and density of the title compounds. With controlled conditions (2 weeks, 25 °C, absence of excess Br2) Zn6Br12(18-crown-6)2×(Br2)5 (1) slowly releases bromine with conconcurrent generation of Zn4Br8(18-crown-6)2×(Br2)3 (2) (in ionic liquid) and Zn6Br12(18-crown-6)2×(Br2)2 (3) (in inert oil). All bromine-rich zinc bromides contain voluminous uncharged (e.g., Zn3Br6(18-crown-6), Zn2Br4(18-crown-6)) or ionic (e.g., [Zn2Br3(18-crown-6)](+), [(Zn2Br6)×(Br2)2](2-)) building units with dibromine molecules between the Zn oligomers and partially interconnecting the Zn-containing building units. Due to the structural similarity, the bromine release is possible via crystal-to-crystal transformation with retention of the crystal shape.
In this study, the concentrations of heavy metals Pb, Cu, Zn, Cd, Ni, Fe, Mn and Cr were determined using an inductively coupled plasma and optical emission spectrophotometer (ICP-OES), and water quality parameters pH, temperature, and conductivity were measured using the YSI 556 MPS water probe. The water samples were collected monthly from five different street tap water points sourced from Mt. Agi (Ağı Dağı in Turkish) spring waters between May 2012 and February 2013 in Çan (Canakkale, Turkey). All results were compared with the drinking water standards of the Turkish Standards Institute (TSE 266), World Health Organization, European Union and US Environmental Protection Agency. While concentrations of Cu, Zn, Fe, and Mn were within limit values, Pb, Cd, Ni, and Cr were at undetectable limits. The highest concentrations of Cu, Zn, Fe, and Mn were 0.010 ppm, 0.018 ppm, 0.058 ppm, and 0.014 ppm, respectively. The findings revealed that although there was no public health risk in view of heavy metal concentrations, there was an acidity problem due to lower pH levels correlated with some heavy metals such as Cu (R = 0.419), Fe (R = -0.421) and Mn (R = -0.687).
Human immunodeficiency virus (HIV) infection has become a global pandemic. Persistent generalized lymphadenopathy (PGL) is very common manifestation of HIV infection. Moreover, different opportunistic infections such as tuberculosis (TB) and malignancies may present with lymphadenopathy. Mycobacterium avium complex (MAC) infection is most common with cluster of differentiation (CD)4+ count ≤50 cells/μL. Fine-needle aspiration cytology (FNAC) offers a simple and effective modality for obtaining a representative sample of the material from lymph nodes, permitting cytological evaluation and other investigations.
The aim of this study is to find out the different etiologies of lymphadenopathy in HIV-infected patients and to establish a possible correlation with CD4+ count.
A total of 100 HIV-infected patients having significant (>1 cm) extrainguinal lymphadenopathy were studied in 1 year at the Department of Pathology by FNAC and the stains used were Leishman-Giemsa, Ziehl-Neelsen (ZN), Papanicoloau, and Gram stains. For tubercular culture, Löwenstein-Jensen (LJ) medium was used. CD4+count was done by flow cytometer.
The present study revealed four types of cytomorphological variants in lymphadenopathy cases by FNAC, which include: Reactive hyperplasia and caseation necrosis; caseation necrosis and ill-formed granuloma; well-formed granuloma without any necrosis; and non-Hodgkin lymphoma (NHL). The highest acid-fast bacilli (AFB) positivity was among the patients showing caseation necrosis. Tubercular culture in LJ media turned out as a more sensitive method for diagnosis than routine ZN staining. The 2 cases that showed well-formed epithelioid granuloma without any necrosis turned out to be histoplasmosis and cryptococcosis, respectively. In this study, we found 2 cases of NHL. The study also revealed that caseation necrosis and AFB positivity along with opportunistic infections increases with decreased CD4+ count.
The paper deals with the results of an investigation of the release of selected amino acids (histidine, tryptophan, tyrosine) from model suspensions prepared by co-precipitation with zinc chloride. It has been proven that the influence of the Zn(II)/amino acid molar ratio on dissolution profiles of the tested amino acids and dissolution half-life (t1/2) of histidine or tryptophan is significant. The amount of amino acid in the dispersed phase (supporting dose) is a determinant of the amino acid release profile. There is a minimal supporting dose (30.0 μmol of histidine or 17.4 μmol of tryptophan) that provides release of similar amounts of amino acid (4.1-4.6 μmol of histidine or 8.7-9.9 μmol of tryptophan) after the same time intervals. The tyrosine release profiles follow first order kinetics since the supporting dose (0.9-11.2 μmol) is limited by the tyrosine low solubility in water.
Studies suggest a relationship between semen quality and the concentration of trace elements in serum or seminal plasma. However, trace elements may be linked to DNA and capable of altering the gene expression patterns. Thus, trace element interactions with DNA may contribute to the mechanisms for a trans-generational reproductive effect. We developed an analytical method to determine the amount of trace elements bound to the sperm DNA, and to estimate their affinity for the sperm DNA by the ratio: R = Log [metal concentration in the sperm DNA/metal concentration in seminal plasma]. We then analyzed the concentrations of 15 trace elements (Al, Cd, Cr, Cu, Hg, Mn, Mo, Ni, Pb, Ti, V, Zn, As, Sb, and Se) in the seminal plasma and the sperm DNA in 64 normal and 30 abnormal semen specimens with Inductively Coupled Plasma/Mass Spectrometry (ICP-MS). This study showed all trace elements were detected in the seminal plasma and only metals were detected in the sperm DNA. There was no correlation between the metals' concentrations in the seminal plasma and the sperm DNA. Al had the highest affinity for DNA followed by Pb and Cd. This strong affinity is consistent with the known mutagenic effects of these metals. The lowest affinity was observed for Zn and Ti. We observed a significant increase of Al linked to the sperm DNA of patients with oligozoospermia and teratozoospermia. Al's reproductive toxicity might be due to Al linked to DNA, by altering spermatogenesis and expression patterns of genes involved in the function of reproduction.
Atomic layer deposition (ALD) is a method for applying conformal nanoscale coatings on three-dimensional structures. We hypothesized that surface functionalization of multi-walled carbon nanotubes (MWCNTs) with polycrystalline ZnO by ALD would alter pro-inflammatory cytokine expression by human monocytes in vitro and modulate the lung and systemic immune response following oropharyngeal aspiration in mice.
Pristine (U-MWCNTs) were coated with alternating doses of diethyl zinc and water over increasing ALD cycles (10 to 100 ALD cycles) to yield conformal ZnO-coated MWCNTs (Z-MWCNTs). Human THP-1 monocytic cells were exposed to U-MWCNTs or Z-MWCNTs in vitro and cytokine mRNAs measured by Taqman real-time RT-PCR. Male C57BL6 mice were exposed to U- or Z-MWCNTs by oropharyngeal aspiration (OPA) and lung inflammation evaluated at one day post-exposure by histopathology, cytokine expression and differential counting of cells in bronchoalveolar lavage fluid (BALF) cells. Lung fibrosis was evaluated at 28 days. Cytokine mRNAs (IL-6, IL-1β, CXCL10, TNF-α) in lung, heart, spleen, and liver were quantified at one and 28 days. DNA synthesis in lung tissue was measured by bromodeoxyuridine (BrdU) uptake.
ALD resulted in a conformal coating of MWCNTs with ZnO that increased proportionally to the number of coating cycles. Z-MWCNTs released Zn(+2) ions in media and increased IL-6, IL-1β, CXCL10, and TNF-α mRNAs in THP-1 cells in vitro. Mice exposed to Z-MWCNTs by OPA had exaggerated lung inflammation and a 3-fold increase in monocytes and neutrophils in BALF compared to U-MWCNTs. Z-MWCNTs, but not U-MWCNTs, induced IL-6 and CXCL10 mRNA and protein in the lungs of mice and increased IL-6 mRNA in heart and liver. U-MWCNTs but not Z-MWCNTs stimulated airway epithelial DNA synthesis in vivo. Lung fibrosis at 28 days was not significantly different between mice treated with U-MWCNT or Z-MWCNT.
Pulmonary exposure to ZnO-coated MWCNTs produces a systemic acute phase response that involves the release of Zn(+2), lung epithelial growth arrest, and increased IL-6. ALD functionalization with ZnO generates MWCNTs that possess increased risk for human exposure.
The underwater silk of an aquatic casemaking caddisfly larvae (Hesperophylax occidentalis) is viscoelastic, and displays distinct yield behaviour, large strain cycle hysteresis and near complete recovery of its initial strength and stiffness when unloaded. Yield followed by a stress plateau has been attributed to sequential rupture of serial Ca(2+)-cross-linked phosphoserine (pS) β-domains. Spontaneous recovery has been attributed to refolding of the Ca(2+)/pS domains powered by an elastic network. In this study, native Ca(2+) ions were exchanged with other metal ions, followed by combined mechanical and FTIR analysis to probe the contribution of pS/metal ion complexes to silk mechanical properties. After exchange of Ca(2+) with Na(+), the fibres are soft elastomers and the infrared spectra are consistent with Cv3 symmetry of the -[Formula: see text] groups. Multivalent metal
 ions decreased the -[Formula: see text] symmetry and the symmetric stretching modes (vs) split in a manner characteristic of ordered phosphate compounds, such as phosphate minerals and lamellar bilayers of phosphatidic acid lipids. Integrated intensities of the vs bands, indicative of the metal ion's effect on transition dipole moment of the P-O bonds, and thereby the strength of the phosphate metal complex, increased in the order: Na(+) < Mg(2+) < Sr(2+) < Ba(2+) < Ca(2+) < Eu(3+) < La(3+) < Zn(2+) < Fe(2+) With a subset of the metal ion series, the initial stiffness and yield stress of metal ion-exchanged fibres increased in the same order: [Formula: see text] [Formula: see text] establishing the link between phosphate transition dipole moments and silk fibre strength.
Luminescent properties are affected by lattice environment of luminescence centers. The lattice environment of emission centers can be effectively changed due to the diversity of lattice environment in multiple site structure. But how precisely control the doped ions enter into different sites is still very difficult. Here we proposed an example to demonstrate how to control the doped ions into the target site for the first time. Alkali metal ions doped ZnMoO4:Bi(3+), Eu(3+) phosphors were prepared by the conventional high temperature solid state reaction method. The influence of alkali metal ions as charge compensators and remote control devices were respectively observed. Li(+) and K(+) ions occupy the Zn(2) sites, which impede Eu and Bi enter the adjacent Zn(2) sites. However, Na(+) ions lie in Zn(1) sites, which greatly promoted the Bi and Eu into the adjacent Zn(2) sites. The Bi(3+) and Eu(3+) ions which lie in the immediate vicinity Zn(2) sites set off intense exchange interaction due to their short relative distance. This mechanism provides a mode how to use remote control device to enhance the energy transfer efficiency which expected to be used to design efficient luminescent materials.
This study evaluates the elemental (W, Mo, Zn, Fe, Cu, Cd, Mn, Pb, Cr, Co, B, and Bi) composition of Marrubium astracanicum Jacq. (Lamiaceae), around the abandoned tungsten mine on Uludağ Mountain, Turkey, to determine if it is an appropriate candidate for phytomonitoring and/or phytoremediation purposes. Three sample sites were selected around the mine for soil and plant sampling. Two sites approximately 500 m from the mine were assumed to be unpolluted sites. The other site was selected from a waste removal pool (WRP) and was assumed to be a polluted site. The soil and different organs (roots, leaves, and flowers) of plant samples were analyzed by inductively coupled plasma-mass spectrometry (ICP-MS) to determine the elemental content. The classic open wet digestion procedure was applied to the samples with 5 mL HNO3 and 3 mL H2O2 in a borosilicate glass vessel for the roots, leaves, and the flowers of the plants. Kjeldahl digestion was used for the soil samples. The W, Zn, Fe, Cu, Cd, Mn, Pb, B, and Bi contents were found to be higher in the soil samples from the waste removal pools compared with the samples from the unpolluted sites. We also found that the elemental composition of M. astracanicum has generally been increased by the activity of the tungsten mine, and there were significant correlations between the elemental contents of the soil samples and plant parts, except for Mo and Cr. The high level of many elements in the soil samples indicates the presence of contamination related to tungsten-mining activity on Uludağ Mountain. Assessing the elemental contents of M. astracanicum, we can suggest this species as a candidate for phytoremediation purposes of W-contaminated sites due to its high W-accumulation capacity.
Chemical immobilization by phosphates has been widely and successfully applied to treat Pb in wastewater and contaminated soils. Pb in wastewaters and soils, however, always coexists with other heavy metals and their competitive reactions with phosphates have not been quantitatively and systematically studied. In this approach, immobilization of Pb, Zn, and Cd by mono-, di-, and tripotassium phosphate (KH2PO4, K2HPO4, and K3PO4) was observed in the single- and ternary-metals solutions. The immobilization rates of the three metals were determined by the residual concentration. The mineral composition and structure of the precipitates were characterized by powder X-ray diffraction (XRD) analysis and scanning electron microscopy (SEM). The results indicated that competitive reaction occurred in Pb-Zn-Cd ternary system, with immobilization rates decrease of <3.6%, <78%, and <89% for Pb, Zn and Cd (molar ratios of P: metal <1), respectively, compared to single metal system. The reaction of Pb with three phosphates exhibited intense competitiveness and the phosphates had a stronger affinity for Pb when Cl(-) was added. Pb-phosphate minerals formed by KH2PO4 with the better crystalline characteristics and largest size were very stable with a low dissolution rate (<0.02%) in the solution of pH 2.88, compared to K2HPO4 and K3PO4. This study demonstrated that Pb could be firstly and effectively immobilized by phosphates in multi-metal solutions containing Pb, Zn and Cd. Moreover, the research provided the insight of the importance of phosphate with low pH (e.g. KH2PO4) and the presence of Cl(-) for more efficient immobilization of Pb in the multi-metals pollution system.
After the removal of amalgam restorations, black staining of dentin is often observed, which is attributed to the penetration of corrosion products from amalgam. A study was carried out to determine whether this amalgam stained dentin is a proper substrate for bonding resin composites. A literature study and an in vitro study showed that Sn and Zn in particular are found in amalgam stained dentin, and this was the case only in demineralised dentin. In vitro, demineralised dentin acted as porte d'entrÈe for amalgam corrosion products. Bond strength tests with 5 adhesive strategies showed no differences between bond strengths to amalgam stained and to sound dentin, but did show different failure types. A clinical study showed good survival of extensive cusp replacing resin composite restorations. No failures were attributed to inadequate adhesion. It is concluded that staining of dentin by amalgam corrosion products has no negative effect upon bond strength of resin composite. It is suggested that Sn and Zn may have a beneficial effect upon dentin, thus compensating the effects of previous carious attacks, preparation trauma and physico-chemical challenges during clinical lifetime.
Na verwijdering van amalgaamrestauraties wordt vaak zwarte verkleuring van dentine aangetroffen die wordt toegeschreven aan corrosieproducten uit amalgaam. Onderzocht werd of composiet­restauraties goed aan dit verkleurde dentine kunnen hechten. Uit literatuur- en laboratoriumonderzoek bleek dat verkleuring alleen in gedemineraliseerd dentine plaatsvond en dat vooral tin en zink in verkleurd dentine worden aangetroffen. Gedemineraliseerd dentine bleek in vitro een porte d’entree te vormen voor corrosieproducten. Hechtsterktetests met 5 hechtstrategieën toonden geen verschillen in hechtsterktes aan tussen door amalgaam verkleurd dentine en gezond dentine, maar wel verschillen in breuktype. Klinisch onderzoek toonde een goede overleving van knobbelvervangende uitgebreide composietrestauraties na amalgaamvervanging, zonder mislukkingen door falende hechting. Geconcludeerd werd dat verkleurd dentine geen negatieve invloed heeft op de hechtsterkte van composiet en dat tin en zink uit amalgaam mogelijk een gunstig effect hebben op dentine, waardoor effecten van vroegere demineralisatie, preparatietrauma en fysisch-chemische processen tijdens het klinisch functioneren gecompenseerd worden.
On page 1310 J. S. Merzaban, A. E. Porter, and co-workers present fluorescently labeled RGD-targeted ZnO nanoparticles (NPs; green) for the targeted delivery of cytotoxic ZnO to integrin αvβ3 receptors expressed on triple negative breast cancer cells. Correlative light-electron microscopy shows that NPs dissolve into ionic Zn(2+) (blue) upon uptake and cause apoptosis (red) with intra-tumor heterogeneity, thereby providing a possible strategy for targeted breast cancer therapy. Cover design by Ivan Gromicho.
Osteoclasts and osteoblasts are responsible for regulating bone homeostasis during which the trace element zinc has been shown to exert a cumulative effect on bone mass by stimulating osteoblastic bone formation and inhibiting osteoclastic bone resorption.
The aim of the present study was to investigate the effects of zinc (Zn) on orthodontic tooth movement (OTM) in a rat model.
A total of 44 male Wistar rats were divided into four groups of 11 animals each and received 0, 1.5, 20 and 50 ppm Zn in distilled water for 60 days. In the last 21 days of the study, nickel-titanium closed coil springs were ligated between maxillary right incisors and first molars of all rats, and tooth movement was measured at the end of this period. Histological analysis of hematoxylin/eosin slides was performed to assess root resorption lacunae, osteoclast number and periodontal ligament (PDL) width.
Mean OTM was calculated as 51.8, 49.1, 35.5 and 45 µm in the 0, 1.5, 20 and 50 ppm zinc-receiving groups, respectively. There were no significant differences in neither OTM nor histological parameters among the study groups (p > 0.05).
According to the results obtained in the current investigation, increase in supplementary zinc up to 50 ppm does not affect the rate of OTM neither bone and root resorption in rats.
Mineral limitation of mesozooplankton production is possible in waters with low trace metal availability. As a step toward estimating mesozooplankton Fe and Zn requirements under such conditions, we measured tissue concentrations of
 major and trace nutrient elements within size-fractioned zooplankton samples collected in and around the Costa Rica Upwelling Dome, a region where phytoplankton growth may be co-limited by Zn and Fe. The geometric mean C, N, P contents were 27, 5.6 and 0.21 mmol gdw(-1), respectively. The values for Fe and Zn were 1230 and 498 nmol gdw(-1), respectively, which are low compared with previous measurements. Migrant zooplankton caused C and P contents of the 2-5 mm fraction to increase at night relative to the day while the Fe and Zn contents decreased. Fe content increased with size while Zn content decreased with size. Fe content was strongly correlated to concentrations of two lithogenic tracers, Al and Ti. We estimate minimum Fe:C ratios in large migrant and resident mixed layer zooplankton to be 15 and 60 µmol mol(-1), respectively. The ratio of Zn:C ranged from 11 µmol mol(-1) for the 0.2-0.5 mm size fraction to 33 µmol mol(-1) for the 2-5 mm size fraction.
The Costa Rica Dome (CRD) is a unique open-ocean upwelling system, with picophytoplankton dominance of phytoplankton biomass and suppressed diatoms, yet paradoxically high export of biogenic silica. As a part of Flux and Zinc Experiments cruise in summer (June-July 2010), we conducted shipboard incubation experiments in the CRD to examine the potential roles of Si, Zn, Fe and light as regulating factors of phytoplankton biomass and community structure. Estimates of photosynthetic quantum yields revealed an extremely stressed phytoplankton population that responded positively to additions of silicic acid, iron and zinc and higher light conditions. Size-fractioned Chl a yielded the surprising result that picophytoplankton, as well as larger phytoplankton, responded most to treatments with added silicic acid incubated at high incident light (HL + Si). The combination of Si and HL also led to increases in cell sizes of picoplankton, notably in Synechococcus. Such a response, coupled with the recent discovery of significant intracellular accumulation of Si in some picophytoplankton, suggests that small phytoplankton could play a potentially important role in Si cycling in the CRD, which may help to explain its peculiar export characteristics.
Mesozooplankton production in high-nutrient low-chlorophyll regions of the ocean may be reduced if the trace element concentrations in their food are insufficient to meet growth and metabolic demands. We used elemental microanalysis (SXRF) of single-celled plankton to determine their trace metal contents during a series of semi-Lagrangian drift studies in an HNLC upwelling region, the Costa Rica Dome (CRD). Cells from the surface mixed layer had lower Fe:S but higher Zn:S and Ni:S than those from the subsurface chlorophyll maximum at 22-30 m. Diatom Fe:S values were typically 3-fold higher than those in flagellated cells. The ratios of Zn:C in flagellates and diatoms were generally similar to each other, and to co-occurring mesozooplankton. Estimated Fe:C ratios in flagellates were lower than those in co-occurring mesozooplankton, sometimes by more than 3-fold. In contrast, Fe:C in diatoms was typically similar to that in zooplankton. RNA:DNA ratios in the CRD were low compared with other regions, and were related to total autotrophic biomass and weakly to the discrepancy between Zn:C in flagellated cells and mesozooplankton tissues. Mesozooplankton may have been affected by the trace element content of their food, even though trace metal limitation of phytoplankton was modest at best.
The Costa Rica Dome (CRD) is a wind-driven feature characterized by high primary production and an unusual cyanobacterial bloom in surface waters. It is not clear whether this bloom arises from top-down or bottom-up processes. Several studies have argued that trace metal geochemistry within the CRD contributes to the composition of the phytoplankton assemblages, since cyanobacteria and eukaryotic phytoplankton have different transition metal requirements. Here, we report that total dissolved zinc (Zn) is significantly depleted relative to phosphate (P) and silicate (Si) within the upper water column of the CRD compared with other oceanic systems, and this may create conditions favorable for cyanobacteria, which have lower Zn requirements than their eukaryotic competitors. Shipboard grow-out experiments revealed that while Si was a limiting factor under our experimental conditions, additions of Si and either iron (Fe) or Zn led to higher biomass than Si additions alone. The addition of Fe and Zn alone did not lead to significant enhancements. Our results suggest that the depletion of Zn relative to P in upwelled waters may create conditions in the near-surface waters that favor phytoplankton with low Zn requirements, including cyanobacteria.
The Costa Rica Dome (CRD) is an open-ocean upwelling system in the Eastern Tropical Pacific that overlies the ocean's largest oxygen minimum zone (OMZ). The region has unique characteristics, biomass dominance by picophytoplankton, suppressed diatoms, high biomass of higher consumers and presumptive trace metal limitation, but is poorly understood in terms of pelagic stock and process relationships, including productivity and production controls. Here, we describe the goals, project design, physical context and major findings of the Flux and Zinc Experiments cruise conducted in June-July 2010 to assess trophic flux relationships and elemental controls on phytoplankton in the CRD. Despite sampling during a year of suppressed summertime surface chlorophyll, cruise results show high productivity (∼1 g C m(-2) day(-1)), high new production relative to export, balanced production and grazing, disproportionate biomass-specific productivity of large phytoplankton and high zooplankton stocks. Zinc concentrations are low in surface waters relative to phosphorous and silicate in other regions, providing conditions conducive to picophytoplankton, like Synechococcus, with low Zn requirements. Experiments nonetheless highlight phytoplankton limitation or co-limitation by silicic acid, driven by a strong silica pump that is linked to low dissolution of biogenic silica in the cold shallow thermocline of the lower euphotic zone.
A universally applicable method for promoting the fast formation and growth of high-density Sn whiskers on solders was developed by fabricating Mg/Sn-based solder/Mg joints using ultrasonic-assisted soldering at 250 °C for 6 s and then subjected to thermal aging at 25 °C for 7 d. The results showed that the use of the ultrasonic-assisted soldering could produce the supersaturated dissolution of Mg in the liquid Sn and lead to the existence of two forms of Mg in Sn after solidification. Moreover, the formation and growth of the high-density whiskers were facilitated by the specific contributions of both of the Mg forms in the solid Sn. Specifically, interstitial Mg can provide the persistent driving force for Sn whisker growth, whereas the Mg2Sn phase can increase the formation probability of Sn whiskers. In addition, we presented that the formation and growth of Sn whiskers in the Sn-based solders can be significantly restricted by a small amount of Zn addition (≥3 wt.%), and the prevention mechanisms are attributed to the segregation of Zn atoms at grain or phase boundaries and the formation of the lamellar-type Zn-rich structures in the solder.
Earthworms have the potential to reduce the retention of pollutant and plant essential metals in the forest floor (organic horizons) by decomposing organic matter and increasing exchangeability of metals. We conducted a laboratory experiment to investigate the effects of two exotic earthworms, Amynthas agrestis and Lumbricus rubellus, on forest floor decomposition, metal exchangeability, and metal bioaccumulation. Eighty-one pots containing homogenized forest floor material were incubated for 20, 40, or 80 days under three treatments: no earthworms, A. agrestis added, or L. rubellus added. For earthworm treatments, A. agrestis and L. rubellus were stocked at densities observed in previous field studies. Pots containing either A. agrestis or L. rubellus had lost more forest floor mass than the control plots after 40 and 80 days of incubation. Forest floor pots containing A. agrestis had significantly lower % C (16 ± 1.5 %) than control pots (21 ± 1.2 %) after 80 days. However, L. rubellus consumed more forest floor and C mass than A. agrestis, when evaluated on a per earthworm biomass basis. Exchangeable (0.1 M KCl + 0.01 M AcOH extractable) and stable (15 M HNO3+ 10 M HCl extractable) concentrations of Al, Ca, Cd, Cu, Mg, Mn, Pb, and Zn in forest floor material were measured. Stable concentrations and % exchangeable metals in forest floor material were similar among treatments. Although exchangeable metal concentrations varied significantly for most metals among treatments (except Mg and Zn), we conclude that earthworms did not increase or decrease the exchangeability of metals. However, earthworms bioaccumulated Cu, Cd, Zn, and Mg and had potentially hazardous tissue concentrations of Al and Pb. This was best illustrated by calculating bioaccumulation factors using exchangeable concentrations rather than total concentrations. Future research is needed to understand the effect of earthworms on metals in other soil types.
We analysed possible time-dependent changes in nitrergic perivascular innervation function from diabetic rats and mechanisms implicated.
In endothelium-denuded mesenteric arteries from control and four- (4W) and eight-week (8W) streptozotocin-induced diabetic rats the vasoconstriction to EFS (electrical field stimulation) was analysed before and after preincubation with L-NAME. Neuronal NO release was analysed in the absence and presence of L-arginine, tetrahydrobiopterine (BH4) and L-arginine plus BH4. Superoxide anion (O2-), peroxynitrite
 (ONOO-) and superoxide dismutase (SOD) activity were measured. Expressions of Cu-Zn SOD, nNOS, p-nNOS Ser1417, p-nNOS Ser847, and Arginase (Arg) I and II were analysed.
EFS response was enhanced at 4W, and to a lesser extent at 8W. L-NAME increased EFS response in control rats and at 8W, but not at 4W. NO release was decreased at 4W and restored at 8W. L-arginine or BH4 increased NO release at 4W, but not 8W. SOD activity and O2- generation were increased at both 4W and 8W. ONOO- decreased at 4W while increased at 8W. Cu-Zn SOD, nNOS and p-NOS Ser1417 expressions remained unmodified at 4W and 8W, whereas p-nNOS Ser847 was increased at 4W. ArgI was overexpressed at 4W, remaining unmodified at 8W. ArgII expression was similar in all groups.
Our results show a time-dependent effect of diabetes on neuronal NO release. At 4W, diabetes induced increased O2- generation, nNOS uncoupling and overexpression of ArgI and p-nNOS Ser847, resulting in decreased NO release. At 8W, NO release was restored, involving normalisation of ArgI and p-nNOS Ser847 expressions.
The concentrations of heavy metals (As, Ba, Co, Cr, Cu, Mn, Ni, Pb, V, and Zn) in campus dust from kindergartens, elementary schools, middle schools, and universities in the city of Xi'an, China, were determined by X-ray fluorescence spectrometry. The pollution levels and hotspots of metals were analyzed using a geoaccumulation index and Local Moran's I, an indicator of spatial association, respectively. The dust samples from the campuses had metal concentrations higher than background levels, especially for Pb, Zn, Co, Cu, Cr, and Ba. The pollution assessment indicated that the campus dusts were not contaminated with As, Mn, Ni, or V, were moderately or not contaminated with Ba and Cr and were moderately to strongly contaminated with Co, Cu, Pb, and Zn. Local Moran's I analysis detected the locations of spatial clusters and outliers and indicated that the pollution with these 10 metals occurred in significant high-high spatial clusters, low-high, or even high-low spatial outliers. As, Cu, Mn, Ni, Pb, V, and Zn had important high-high patterns in the center of Xi'an. The western and southwestern regions of the study area, i.e., areas of old and high-tech industries, have strongly contributed to the Co content in the campus dust.
An extensive spatial survey was conducted on trace metal content in stream sediments from Oued El Maadene basin, northern Tunisia. Our objectives were to evaluate the level of trace metal pollution and associated ecological risk and identify the major sources of metal pollution. A total of 116 stream sediment samples were collected and analysed for total As, Cd, Cr, Cu, Ni, Pb, V, Zn, and Zr concentrations. The results showed that concentrations of Cr, Ni, V, and Zr were close to natural levels. In contrast, As, Cd, Cu, Pb, and Zn had elevated concentrations and enrichment factors compared to other contaminated regions in northern Tunisia. Ecological risk to aquatic ecosystems was highlighted in most areas. Principal component analysis showed that Cr, Ni, V, and Zr mainly derived from local soil and bedrock weathering, whilst As, Cd, Pb, and Zn originated from mining wastes. Trace metals could be dispersed downstream of tailings, possibly due to surface runoff during the short rainy season. Surprisingly, Cu, and to a lesser extent As, originated from agricultural activities, related to application of Cu-based fungicides in former vineyards and orchards. This study showed that, despite the complete cessation of mining activities several decades ago, metal pollution still impacts the local environment. This large pollution, however, did not mask other additional sources, such as local agricultural applications of fungicides.
This work reports the chemical monitoring of saline water and sediments at Aratu port, All Saints Bay, Brazil, when subjected to a deep dragging process (DDP) over a 2-year period (2010-2012). The aim of this work was to detect which metals had possible deleterious effects on the biota. It analyzed percentage of silt + clay and TOC and metal concentrations (As, Cd, Cu, Cr, Ni, Pb, and Zn) before, during, and after the DDP. The determination of metal concentration in sediments used the following techniques: atomic absorption spectrometer with flame, also with hydrate generation, and cold vapor spectrophotometry. The DDP disturbed the concentrations of metals in sediments and water, but 15 months after the DDP, only Cu and Zn were detectable on the bottom saline water, and 20 months after the DDP, only Zn was detectable in water. This fact indicates that these metals were longer available for absorption by the marine biota with probable deleterious effect. Indeed, studies by others during the DDP in Aratu port, indicated the decrease from 50 to 40 of the number of microalgae species identified. On the other hand, in the sediments, 20 months after the DDP, the concentrations of As, Cr, Cu, Pb, and Hg, returned to the original values, but Ni and Zn did not return to their original values. Comparison with studies by others indicated that the sediments from dredging were inappropriate for disposal at sea. This work indicated that the metals Cu, Ni, and Zn are the most deleterious elements to the marine environment.
In the current study, we evaluated the protective effect of zinc (Zn) against bromobenzene (BB) -induced lethal toxicity. We used Zn because this element is known to be an inducer of metallothionein (MT), which is in turn known to serve as an endogenous scavenger of free radicals. We administered Zn (as ZnSO4) at 50 mg/kg subcutaneously once-daily for 3 successive days prior to a single intraperitoneal administration of 1.2 g/kg BB in male ddY mice. Our results showed that pretreatment with Zn completely abolished the BB-induced mortality of mice until 48 h. We also found that pretreatment of mice with Zn significantly decreased the functional marker levels and reduced the histological damage both in liver and kidney as assessed at 18 h post-BB. We also showed that pretreatment with Zn enhanced antioxidative activity, resulting in decreased lipid peroxidation in both liver and kidney. Moreover, BB-induced calcium levels were downregulated by pretreatment with Zn. In addition, Zn-induced MT was decreased in Zn + BB-treated animals, implying that MT was consumed by BB-induced radicals. These findings suggest that prophylaxis with Zn protects mice from BB-induced lethal toxicity by decreasing oxidative stress in liver and kidney, presumably by induction of MT, which scavenges radicals induced by BB exposure.
Chemical reactivity descriptors within the conceptual density functional theory can be used to understand the nature of the interactions between two monomers of the Group 2B metal halides. This information might be valuable in the development of adequate force law parameters for simulations in the liquid state. In this study, MX2 monomers and dimers, where M = Zn, Cd, Hg and X = F, Cl, Br, I, were investigated in terms of chemical reactivity descriptors. Relativistic effects were taken into account using the effective core potential (ECP) approach. Correlations were produced between global and local reactivity descriptors and dimerization energies. Results presented in this work represent the first systematic investigation of Group 2B metal halides in the literature from a combined point of view of both relativistic effects and chemical reactivity descriptors. Steric effects were found to be responsible for the deviation from the chemical reactivity principles. They were introduced into the chemical reactivity descriptors such as local softness.
A total of 141 surface sediments were collected and analyzed for their geochemistry, total organic carbon, and grain size to assess the heavy metal pollution in the Bohai and Yellow Seas. The enrichment factor (EF) and geoaccumulation index (Igeo) of Cu, Pb, Zn, Cr, Cd, Ni, As, and Hg were calculated to assess anthropogenic contamination, and the results suggest that moderate Pb, Cd, and As contamination occurs in the study area. Sediment quality guidelines were applied to assess the adverse biological effects of these metals. The spatial distribution of the mean Effects Range-Median quotient for the vast majority of the study area is between 0.1 and 0.5, indicating low impact and potential negative biological effects. Multivariate analysis indicates that Cu, Pb, Zn, Cr, and Ni resulted primarily from lithogenic sources, whereas As, Cd, and Hg were mainly attributed to anthropogenic sources.
Due to their redox capabilities, thiols have an important role in biological oxidative/reductive processes through the formation of disulfides or their oxidation to into sulfenic, sulfinic, or sulfonic derivatives being also relevant for specific enzyme activities. The mechanisms of these biological pathways often involve metal ion(s). In this case, deciphering metal-assisted transformation of the S-S bond is of primary interest. This report details the reactivity of the disulfide-containing 2,6-bis[(bis(pyridylmethyl)amino)methyl]-4-methylmercaptophenyldisulfide (L(Me(BPA)S-S)) ligand with Cu(II) using different experimental conditions (anaerobic, H2O-only, H2O/O2, or O2-only). Crystallographic snapshots show the formation of tetranuclear disulfide, dinuclear sulfinate, and sulfonate complexes. Mechanistic investigations using Zn(II) as control indicate a non-metal-redox-assisted process in all cases. When present, water acts as nucleophile and attacks at the S-S bond. Under anhydrous conditions, a different pathway involving a direct O2 attack at the disulfide is proposed.
Hippocampal Zn(2+) homeostasis is critical for cognitive activity and hippocampus-dependent memory. Extracellular Zn(2+) signaling is linked to extracellular glutamate signaling and leads to intracellular Zn(2+) signaling,
 which is involved in cognitive activity. On the other hand, excess intracellular Zn(2+) signaling that is induced by excess glutamate signaling is involved in cognitive decline. In the hippocampal formation, the dentate gyrus is the most vulnerable to aging and is thought to contribute to age-related cognitive decline. The layer II of the entorhinal cortex is the most vulnerable to neuronal death in Alzheimer's disease. The perforant pathway provides input from the layer II to the dentate gyrus and is one of the earliest affected pathways in Alzheimer's disease. Medial perforant pathway-dentate granule cell synapses are vulnerable to either excess intracellular Zn(2+) or β-amyloid (Aβ)-bound zinc, which induce transient cognitive decline via attenuation of medial perforant pathway LTP. However, it is unknown whether the vulnerability to excess intracellular Zn(2+) is involved in region-specific vulnerability to aging and Alzheimer's disease. To discover a strategy to prevent short-term cognitive decline in normal aging process and the pre-dementia stage of Alzheimer's disease, the present paper deals with vulnerability of medial perforant pathway-dentate granule cell synapses to intracellular Zn(2+) dyshomeostasis and its possible involvement in differential vulnerability to aging and Alzheimer's disease in the hippocampal formation.
Incineration fly ash, a waste from municipal solid waste incineration plant can be used to replace conventional filler as reinforcing filler to enhance the mechanical strength of a composite. Surface modification was performed on the incineration fly ash before mixing into the soft polymer matrix so as to improve interfacial bond of the filler and epoxy resin. In this study, detailed characterisation of mechanical, morphological and leaching behaviours of municipal solid waste incineration (MSWI) fly ash infused composite has been carried out. Flexural and tensile test was conducted to determine the effect on mechanical properties of the composite by varying the concentration of incineration fly ash filler added into polymer matrix and surface modification of incineration fly ash filler using silane coupling agent and colloidal mesoporous silica (CMS). The results indicated that composite infused with incineration fly ash filler surface treated with CMS shown improvement on the tensile and flexural strengths. In addition, SEM images showed that surface modification of incineration fly ash with colloidal mesoporous silica enhanced the interfacial bonding with polymer resin which explained the improvement of mechanical strength. Leaching test showed result of toxic metals such as Pb, Zn, Fe, Cu, Cr, Cd and Rb immobilised in the polymer matrix of the composite. Hence, the use of MSWI fly ash as reinforcing filler in the composite appears green and sustainable because this approach is a promising opportunity to substitute valuable raw material with MSWI fly ash.
Bioavailability of heavy metals can be modified by different root exudates. Among them, low molecular weight organic acids (LMWOAs) play an important role in this process. Three plant species (Poa annua, Medicago polymorpha and Malva sylvestris), potentially used for phytoremediation, have been assessed for both metal uptake and LMWOAs excretion in contaminated environments with different concentrations of Cd, Cu and Zn. The experiments have been carried out in washed sand and in three contaminated soils where two organic amendments were added (biosolid compost and alperujo compost). The most abundant LMWOAs excreted by all studied plants were oxalic and malic acids, although citric and fumaric acids were also detected. The general tendency was that plants responded to an increase of heavy metal stress releasing higher amounts of LMWOAs. This is an efficient exclusion mechanism reducing the metal uptake and allowing the plant growth at high levels of contamination. In the experiment using wash sand as substrate, the organic acids composition and quantity depended mainly on plant species and metal contamination. M. polymorpha was the species that released the highest concentrations of LMWOAs, both in sand and in soils with no amendment addition, whereas a decrease of these acids was observed with the addition of amendments. Our results established a clear effect of organic matter on the composition and total amount of LMWOAs released. The increase of organic matter and nutrients, through amendments, improved the soil quality reducing phytotoxicity. As a result, organic acids exudates decreased and were solely composed of oxalic acid (except for M. polymorpha). The release of LMWOAs has proved to be an important mechanism against heavy metal stress, unique to each species and modifiable by means of organic amendment addition.
Diversity, distribution and composition of bacterial community of soils contaminated long-term with both polycyclic aromatic hydrocarbons (PAHs) and heavy metals were explored for the first time following 454 pyrosequencing. Strikingly, the complete picture of the Gram positive (+ve) and Gram negative (-ve) bacterial profile obtained in our study illustrates novel postulates that include: (1) Metal-tolerant and PAH-degrading Gram -ves belonging to the class Alphaproteobacteria persist relatively more in the real contaminated sites compared to Gram +ves, (2) Gram +ves are not always resistant to heavy metal toxicity, (3) Stenotrophomonas followed by Burkholderia and Pseudomonas are the dominant genera of PAH degraders with high metabolic activity in long-term contaminated soils, (4) Actinobacteria is the predominant group among the Gram +ves in soils contaminated with high molecular weight PAHs that co-exist with toxic heavy metals like Pb, Cu and Zn, (5) Microbial communities are nutrient-driven in natural environments and (6) Catabolically potential Gram +/-ves with diverse applicability to remediate the real contaminated sites evolve eventually in the historically-polluted soils. Thus, the most promising indigenous Gram +/-ve strains from the long-term contaminated sites with increased catabolic potential, enzymatic activity and metal tolerance need to be harnessed for mixed contaminant cleanups.
Heavy metal concentrations in edible organisms from the core area of Daya Bay's Fishery Resource Reserve, South China Sea, were determined. Samples of 14 crustacean, fish, and shellfish species were collected and analyzed. The As, Cd, Cr, Cu, Hg, Ni, Pb, and Zn concentrations were 0.18-1.16, 0.002-0.919, 0.40-2.85, 0.07-4.10, 0.004-0.055, 0.14-1.19, 0.014-0.070, and 4.57-15.94μg/g wet weight, respectively. The As concentrations were higher than the Chinese maximum permissible levels in all of the fish and shellfish species and two crustacean species, indicating that consumption of these wild species by humans may pose health risks. However, calculations of the health risks posed to humans indicated that no significant adverse health effects would be associated with consuming these species.
Manganese (Mn) is a trace element required for normal physiological processes in animals and humans. Organic forms of trace elements are expected to have higher bioavailability in comparison with inorganic sources. The effect of feeding a diet supplemented with different sources of manganese to lambs was studied in a 112-d feeding trial. The aim of this study was to investigate the deposition of Mn in relation to activities of superoxide dismutase (SOD), manganese superoxide dismutase (MnSOD) and arginase in the tissues of lambs fed the diet supplemented with an inorganic or an organic source of manganese up to the maximum total Mn content allowed in the European Union (150mg Mn/kg). A total of eighteen female lambs of the improved Valachian breed were randomly allocated to three dietary treatments and fed an unsupplemented basal diet (Control, 31mg Mn/kg) or the identical diet supplemented with manganese sulphate (MnSO4) or manganese chelate of glycine hydrate (Mn-Gly) with a total Mn content up to 150mg/kg. Regardless of the source, feed supplementation with manganese increased Mn concentrations in plasma (P˂0.05) and the liver (P˂0.001) as well as the activity of liver MnSOD (P˂0.05) and arginase (P˂0.001) compared with the control lambs. In the kidney cortex, the concentration of Mn was greatest in lambs fed the diet supplemented with the chelated Mn source compared with animals receiving the inorganic Mn source (P˂0.05) and the unsupplemented diet (P˂0.001). The 112-d intake of feed enriched with manganese did not result in any change in Mn levels, SOD or MnSOD activity in pancreas and kidney tissues. Plasma Cu concentration was depressed in both supplemented treatments. No analyzed tissue showed a change in zinc and copper levels, except the greater Cu concentration in the liver of lambs fed the diet with Mn-Gly. The presented results did not indicate any differences between dietary Mn sources either in Mn tissue deposition or activity of SOD, MnSOD and arginase in lamb tissues; however, it seems that manganese intake of up to 150mg/kg in feed may decrease plasma Cu concentration in lambs.
The Natural Protected Area San Antonio bay is of particular importance for its congregation of migratory shorebirds and it has been declared one of the Western Hemisphere Shorebird Reserve Network International site (WHSRN). Present study represents the first assessment of variation on oxidative stress biomarkers in male crab Neohelice granulata from San Antonio bay (Río Negro, Argentina) under field conditions, associated mainly to metal contamination coming from passive mining wastes. Three sites were sampled once every three months from November 2012 to August 2013 within this sea inlet (Pile, Fishery and Port) and a control site at the southeast of the bay (Punta Perdices). Accumulation of Ni, Zn, Cr and Al varied only with seasons although
 without a constant trend, meanwhile Cd, Cu and Pb also varied among sites being highest in Pile and Port. Biochemical results indicated that variations in catalase activity was only site specific being maximum in Pile; meanwhile lipid radical, α-tocopherol and metallothioneins were only seasonal specific being higher in autumn and winter. Seasonal variation was also found for total thioles, being the content higher in summer and autumn than in winter. Correlation analysis revealed that malondialdehyde and α-tocopherol have a positive association with Al and negative with Ni, meanwhile GST has a positive association with Fe. Crabs from the closest area to the waste pile did not exhibit a differentiated oxidative pressure despite the higher accumulation of metals. It is possible that crabs from contaminated areas have developed a tolerance to metals, indicating a strong ecotoxicological selective pressure. More studies are needed to assess whether there is a transfer of metals through the food chain.
The study assessed the long-term effects of anthropogenic pressure of the sulfur industry on turf-covered soils located in the vicinity of the sulfur mine Grzybów. The study assumes that 20 years which elapsed since the end of the exploitation of sulfur is a period sufficiently long for the content of sulfur compounds in soils not to exceed the permissible level and that soil of the region can be classified as not contaminated. A part of the study involved identification of changes in the contents Stot. and SSO4(2-) in soils collected in the 1970s and early twenty-first century. It was also traced the relationship between the content of sulfur compounds and selected soil properties and estimated risk of soil environment pollution by heavy metals. Mean contents of trace elements studied amounted to 10.2-10.8 mg kg(-1) for Pb, 14.3-39.4 mg kg(-1) for Zn, 0.2-0.4 mg kg(-1) for Cd, 3.8-32.2 mg kg(-1) for Cr, 2.7-15.1 mg kg(-1) for Cu and 2.9-18.7 mg kg(-1) for Ni. Based on the results of SSO4(2-) content in soils collected at a distance of 1 km from the mine, it was found out that despite the passage of years, the amount of this type of sulfur still is increased and exceeds 0.14 g kg(-1). As the distance from the mine grew lower (from 0.017 to 0.03 g kg(-1)) average content of the sulfur form was observed. In the studied soil material we found generally positive, strong correlation between the Stot. and SSO4(2-) content and analyzed trace elements. The degree of contamination of examined soils with heavy metals was estimated on the basis of the integrated pollution index, which pointed to a moderate and low level of antropogenization of this area. In addition, the relationship between the determined characteristics of soils (Corg. contents, the fraction <0.002 mm and pH) and heavy metals confirms that the trace elements present in soils do not occur in mobile forms in the soil solution.
The five metal azolate/carboxylate (MAC) compounds [Cd(dmpzc)(DMF)(H2O)] (Cd-dmpzc), [Pd(H2dmpzc)2Cl2] (Pd-dmpzc), [Cu(Hdmpzc)2] (Cu-dmpzc), [Zn4O(dmpzc)3]·Solv (Zn-dmpzc·S), and [Co4O(dmpzc)3]·Solv (Co-dmpzc·S) were isolated by coupling 3,5-dimethyl-1H-pyrazol-4-carboxylic acid (H2dmpzc) to cadmium(II), palladium(II), copper(II), zinc(II), and cobalt(II) salts. While Cd-dmpzc and Pd-dmpzc had never been prepared in the past, for Cu-dmpzc, Zn-dmpzc·S, and Co-dmpzc·S we optimized alternative synthetic paths that, in the case of the copper(II) and cobalt(II) derivatives, are faster and grant higher yields than the previously reported ones. The crystal structure details were determined ab initio (Cd-dmpzc and Pd-dmpzc) or refined (Cu-dmpzc, Zn-dmpzc·S, and Co-dmpzc·S) by means of powder X-ray diffraction (PXRD). While Cd-dmpzc is a nonporous 3D MAC framework, Pd-dmpzc shows a 3D hybrid coordination/hydrogen-bonded network, in which Pd(H2dmpzc)2Cl2 monomers are present. The thermal behavior of the five MAC compounds was investigated by coupling thermal analysis to variable-temperature PXRD. Their catalytic activity was assessed in oxidative and C-C coupling reactions, with the copper(II) and cadmium(II) derivatives being the first nonporous MAC frameworks to be tested as catalysts. Cu-dmpzc is the most active catalyst in the partial oxidation of cyclohexane by tert-butyl hydroperoxide in acetonitrile (yields up to 12% after 9 h) and is remarkably active in the solvent-free microwave-assisted oxidation of 1-phenylethanol to acetophenone (yields up to 99% at 120 °C in only 0.5 h). On the other hand, activated Zn-dmpzc·S (Zn-dmpzc) is the most active catalyst in the Henry C-C coupling reaction of aromatic aldehydes with nitroethane, showing appreciable diastereoselectivity toward the syn-nitroalkanol isomer (syn:anti selectivity up to 79:21).
As a special biofilm structure, microbial attachment is believed to play an important role in the granulation of aerobic granular activated sludge (AGAS). This experiment was to investigate the biological effect of Ca(2+), Mg(2+), Cu(2+), Fe(2+), Zn(2+), and K(+) which are the most common ions present in biological wastewater treatment systems, on the microbial attachment of AGAS and flocculent activated sludge (FAS), from which AGAS is always derived, in order to provide a new strategy for the rapid cultivation and stability control of AGAS. The result showed that attachment biomass of AGAS was about 300% higher than that of FAS without the addition of metal ions. Different metal ions had different effects on the process of microbial attachment. FAS and AGAS reacted differently to the metal ions as well, and in fact, AGAS was more sensitive to the metal ions. Specifically, Ca(2+), Mg(2+), and K(+) could increase the microbial attachment ability of both AGAS and FAS under appropriate concentrations, Cu(2+), Fe(2+), and Zn(2+) were also beneficial to the microbial attachment of FAS at low concentrations, but Cu(2+), Fe(2+), and Zn(2+) greatly inhibited the attachment process of AGAS even at extremely low concentrations. In addition, the acylated homoserine lactone (AHL)-based quorum sensing system, the content of extracellular polymeric substances and the relative hydrophobicity of the sludges were greatly influenced by metal ions. As all these parameters had close relationships with the microbial attachment process, the microbial attachment may be affected by changes of these parameters.
There is considered the possibility of the use of risk indices with regard to their use in certification and validation of conformity assessment and food conformance, including those recommended for children. There were investigated samples of oatmeals, potted meats, liver pate, fruit-vegetable puree. The calculation of risk values was based on original data of quantitative analysis that was performed with the use of thermogravimetric, photometric, titrimetric, and potentiometric methods, as well as methods of gas-liquid chromatography and atomic absorption spectrophotometry. On the base of data of the chemical analysis of the ingredients of a set of food products, including assigned for baby nutrition, all the tested samples were shown to meet the requirements for the controlled regulatory standards on control indices of quality. The calculation of average daily doses of the intake of metal compounds (Cu, Zn, Fe, Na, Ca, Mg) consumed by adult and child's organisms through tested food showed that such doses are allowable since they do not exceed maximum daily dose and average daily requirements. However, some samples were referred to the category of high risk food, because the used method of individual's lifetime risk calculation takes into consideration all possible negative effects (carcinogenic, mutagenic, teratogenic, embryogenic, etc) of the impact of pollutants on the human body. It is shown that in addition to the sanitary and hygienic criteria of food quality, the risks of such food consumption should be taken into consideration by the Technical Regulations and other normative documentations.
By methods of atom-emission and mass spectrometry with inductively bonded argon plasma there was determined the content of 25 macro- and trace elements in tap cold drinking water used by the residents of the city of Magadan for food purposes and in hair samples of 30 young male Europeans aged of 17-23 years, who are the residents, of the city of Magadan. According to our data the content of 25 elements in drinking water conforms to standards, but that content of such essential elements as Co, Cr Cu, I, Mn, Na, Se, Zn is shown to be lower than referential indices. After boiling the water the concentration of trace elements is changed. The content of Cd, Cu, K, P Pb, Zn, Ni becomes lower significantly. In healthy young men aged of 17-23 years, from the number of natives Europeoids, residents of the North there was detected deficit of Co and I (86% and 62%, respectively), lower concentrations of Ca, Mg, Se, Zn (76%, 69%, 24%, 24%, respectively). The constant use by residents of the city of Magadan of ultrafresh brackish drinking water in food aims may be the one of the main reasons of the imbalance of macro- and micronutrients in the body, characterized by features of the so-called "northern" type with a marked deficiency of basic essential elements.
Diatoms are the dominant group of phytoplankton in the modern ocean, accounting for approximately 40% of oceanic primary productivity and critical foundation of coastal food web. Rising dissolution of anthropogenic CO2 in seawater may directly/indirectly cause ocean acidification and desalination. However, little is known about dietary diatom-associated changes, especially for diatom heavy metal consumption sensitivity to these processes, which is important for seafood safety and nutrition assessment. Here we show some links between ocean acidification/desalination and heavy metal consumption
 by Thalassiosira weissflogii. Excitingly, under desalination stress, the relationships between Cu, Zn, and Cd were all positively correlated, especially between Cu and Zn (r=0.989, total intracellular concentration) and between Zn and Cd (r=0.962, single-cell intracellular concentration). Heavy metal consumption activity in decreasing order was acidification<acidification+desalination<desalination for Zn, acidification<desalination<acidification+desalination for Cu and Cd, i.e., heavy metal uptake (or release) were controlled by environmental stress. Our findings showed that heavy metal uptake (or release) was already responded to ongoing excessive CO2 emission-driven acidification and desalination, which was important for risk assessment of climate change on diatom heavy metal consumption, food web and then seafood safety in future oceans.
We have applied the micronucleus (MN) assay to the measurement of genotoxicity in microcrustaceans. Daphnids (Daphnia magna) and Copepods (Acanthocyclops robustus) were collected in situ and acclimated in the lab for 24h. The MN assay was successful with the Daphnids but not with the Copepods. Adult Daphnids were exposed to sublethal concentrations of metals (Cu, Zn, Cd) or insecticide (deltamethrin) for 2 and 7d. Dose-dependent induction of MN was observed after 2 d exposure, with 2-fold induction at the highest doses for each chemical tested. The advantages and ecological relevance of using Daphnids in genotoxicity assessment are highlighted. The Daphnid assay may be a reliable test for aquatic genotoxicity hazard/risk assessment and a useful alternative to studies of amphibians.
To determine the contribution of forest foods to dietary intake and estimate their association with household food insecurity.
Cross-sectional survey conducted among 279 households. Using a 7 d recall questionnaire, information on household food consumption was collected from women and used to determine the household dietary diversity score, food variety score and forest food consumption score (FFCS). Household Food Insecurity Access Scale (HFIAS) score was determined and Spearman rank correlation was used to establish the relationship between consumption of forest foods and HFIAS score. Women's dietary intake was estimated from two 24 h recalls. The contribution of forest foods to women's nutrient intakes was calculated and women's nutrient intakes were compared with estimated average nutrient requirements.
Rural forest-dependent households in twelve villages in eastern and southern Cameroon.
Household heads and their non-pregnant, non-lactating spouses.
Forty-seven unique forest foods were identified; of these, seventeen were consumed by 98 % of respondents over the course of one week and by 17 % of women during the two 24 h recall periods. Although forest foods contributed approximately half of women's total daily energy intake, considerably greater contributions were made to vitamin A (93 %), Na (100 %), Fe (85 %), Zn (88 %) and Ca (89 %) intakes. Despite a highly biodiverse pool of foods, most households (83 %) suffered from high food insecurity based on the HFIAS. A significant inverse correlation was observed between the HFIAS score and the FFCS (r 2=-0·169, P=0·0006), demonstrating that forest foods play an important role in ensuring food security in these forest-dependent communities.
Forest foods are widely consumed by forest-dependent communities. Given their rich nutrient content, they have potential to contribute to food and nutrition security.
The crude recycling activities of e-waste have led to the severe and complex contamination of e-waste workshop topsoil (0-10 cm) by heavy metals. After nano-hydroxyapatite (NHAp) application in June 2013, plant and soil samples were obtained in November 2013, December 2013, March 2014 and June 2014. The results showed that NHAp effectively reduced the concentration of CaCl2-extractable Pb, Cu, Cd, and Zn in the topsoil and significantly reduced the metal content in ryegrass and also increased the plant biomass compared with that of the control. Moreover, the concentrations of CaCl2-extractable metals in the soil decreased with increasing NHAp. NHAp application also increased the activities of soil urease, phosphatase and dehydrogenase. Moreover, the soil bacterial diversity and community structure were also altered after NHAp application. Particularly, Stenotrophomonas sp. and Bacteroides percentages were increased. Our work proves that NHAp application can alleviate the detrimental effects of heavy metals on plants grown in e-waste-contaminated soil and soil enzyme activities, as well as soil microbial diversity.
Biochar has emerged as an efficient tool to affect bioavailability of heavy metals in contaminated soils. Although partially understood, a carefully designed incubation experiment was performed to examine the effect of biochar on mobility and redistribution of Cd, Cu, Pb and Zn in a sandy loam soil collected from the surroundings of a copper smelter. Bamboo and rice straw biochars with different mesh sizes (<0.25 mm and <1 mm), were applied at three rates (0, 1, and 5% w/w). Heavy metal concentrations in pore water were determined after extraction with 0.01 M CaCl2. Phytoavailable metals were extracted using DTPA/TEA (pH 7.3). The European Union Bureau of Reference (EUBCR) sequential extraction procedure was adopted to determine metal partitioning and redistribution of heavy metals. Results showed that CaCl2-and DTPA-extractable Cd, Cu, Pb and Zn concentrations were significantly (p < 0.05) lower in the bamboo and rice straw biochar treated soils, especially at 5% application rate, than those in the unamended soil. Soil pH values were significantly correlated with CaCl2-extractable metal concentrations (p < 0.01). The EUBCR sequential extraction procedure revealed that the acid extractable fractions of Cd, Cu, Pb and Zn decreased significantly (p < 0.05) with biochar addition. Rice straw biochar was more effective than bamboo biochar in decreasing the acid extractable metal fractions, and the effect was more pronounced with increasing biochar application rate. The effect of biochar particle size on extractable metal concentrations was not consistent. The 5% rice straw biochar treatment reduced the DTPA-extractable metal concentrations in the order of Cd < Cu < Pb < Zn, and reduced the acid extractable pool of Cd, Cu, Pb and Zn by 11, 17, 34 and 6%, respectively, compared to the control. In the same 5% rice straw biochar treatments, the organic bound fraction increased by 37, 58, 68 and 18% for Cd, Cu, Pb and Zn, respectively, compared to the control, indicating that the immobilized metals were mainly bound in the soil organic matter fraction. The results demonstrated that the rice straw biochar can effectively immobilize heavy metals, thereby reducing their mobility and bioavailability in contaminated soils.
Inefficient response to oxidative stress has been associated with ageing and health risk. Metals are known to inhibit DNA repair and may modify the antioxidant response. How genetic variability and lifestyle factors modulate the response to oxidative stress is poorly explored. Our study aims to disentangle the contribution of genetics and environmental exposures to oxidative stress response using data from twin pairs. The non-enzymatic antioxidant capacity (NEAC), the repair capacity of 8-oxo-7,8-dihydroguanine (OGG activity) and the levels of 12 metals were measured in blood of 64 monozygotic and 31 dizygotic twin pairs. The contributions of genetic and environmental effects were assessed using standard univariate twin modelling. NEAC and OGG activity significantly decreased with age. Gender-, age- and body mass index-associated differences were identified for some metals. Principal Component Analysis identified two groups of metals whose levels in blood were highly correlated: As, Hg, Pb, Se, Zn and Al, Co, Cr, Mn, Ni. The environmental influence was predominant on OGG activity and NEAC variance whereas for most metals the best-fitting model incorporated additive genetic and unique environmental sources of variance. NEAC and OGG activity were both inversely correlated with blood levels of various metals. The inhibition of OGG activity by Cd was largely explained by smoking. Our data show a substantial role of environmental factors in NEAC and OGG activity variance that is not explained by twins' age. Exogenous environmental factors such as metals contribute to oxidative stress by decreasing NEAC and inhibiting repair of oxidatively-induced DNA damage.
Fabrication of reliable large-sized p-ZnO is a major challenge to realise ZnO-based electronic device applications. Here we report a novel technique to grow high-quality free-standing undoped acceptor-rich ZnO (A-ZnO) microtubes with dimensions of ~100 μm (in diameter) × 5 mm (in length) by optical vapour supersaturated precipitation. The A-ZnO exhibits long lifetimes (>1 year) against compensation/lattice-relaxation and the stable shallow acceptors with binding energy of ~127 meV are confirmed from Zn vacancies. The A-ZnO provides a possibility for a mimetic p-n homojunction diode with n(+)-ZnO:Sn. The high concentrations of holes in A-ZnO and electrons in n(+)-ZnO make the dual diffusion possible to form a depletion layer. The diode threshold voltage, turn-on voltage, reverse saturated current and reverse breakdown voltage are 0.72 V, 1.90 V, <10 μA and >15 V, respectively. The A-ZnO also demonstrates quenching-free donor-acceptor-pairs (DAP) emission located in 390-414 nm with temperature of 270-470 K. Combining the temperature-dependent DAP violet emission with native green emission, the visible luminescence of A-ZnO microtube can be modulated in a wide region of colour space across white light. The present work opens up new opportunities to achieve ZnO with rich and stable acceptors
 instead of p-ZnO for a variety of potential applications.
New 5,5-diethylbarbiturate (barb) complexes of Ni(ii), Cu(ii) and Zn(ii) with 1,10-phenanthroline (phen) and 2,2'-dipyridylamine (dpya), namely [Ni(phen-κN,N')3]Cl(barb)·7H2O (), [Cu(barb-κN)(barb-κ(2)N,O)(phen-κN,N')]·H2O (), [Cu(barb-κN)2(phen-κN,N')] (), [Zn(barb-κN)2(phen-κN,N')]·H2O (), [Ni(barb-κ(2)N,O)(dpya-κN,N')2]Cl·2H2O (), [Cu(barb-κ(2)N,O)2(dpya-κN,N')]·2H2O () and [Zn(barb-κN)2(dpya-κN,N')] (), were synthesized and characterized by elemental analysis, UV-vis, FT-IR and ESI-MS. The structures of the complexes were determined by X-ray crystallography. Notably, and were fluorescent in MeOH : H2O at rt. The interaction of the complexes with fish sperm (FS) DNA and bovine serum albumin (BSA) was investigated in detail by various techniques. The complexes exhibited groove binding along with a partial intercalative interaction with DNA, while the hydrogen bonding and hydrophobic interactions played a major role in binding to BSA. It is noteworthy that exhibited the highest affinity towards DNA and BSA. Enzyme inhibition assay showed that show a preference for both A/T and G/C rich sequences in pUC19 DNA, while and display a binding specificity to the G/C and A/T rich regions, respectively. These findings were further supported by molecular docking. The cellular uptake studies suggested that was deposited mostly in the membrane fraction of the cells. Among the present complexes, exhibited a very strong cytotoxic effect on A549, MCF-7, HT-29 and DU-145 cancer cells, being more potent than cisplatin. Moreover, induces cell death through the apoptotic mode obtained by flow cytometry.
This study aimed to examine associations between urinary metal concentrations and sperm DNA damage. Thirteen metals [arsenic (As), cadmium (Cd), cobalt (Co), chromium (Cr), copper (Cu), iron (Fe), lead (Pb), manganese (Mn), molybdenum (Mo), mercury (Hg), nickel (Ni), selenium (Se), and zinc (Zn)] were detected in urine samples of 207 infertile men from an infertility clinic using inductively coupled plasma mass spectrometry, and also, sperm DNA damage (tail length, percent DNA tail, and tail distributed moment) were assessed using neutral comet assay. We found that urinary Hg and Ni were associated with increasing trends for tail length (both p for trend<0.05), and that urinary Mn was associated with increasing trend for tail distributed moment (p for trend=0.02). These associations did persist even when considering multiple metals. Our results suggest that environmental exposure to Hg, Mn, and Ni may be associated with increased sperm DNA damage.
The use of the marine gastropod, Cellana tramoserica, as a biomonitor of metal exposure was investigated. The factors influencing metal concentrations, such as mass, gender, substrate, shoreline position and temporal variation were examined. Tissue metal concentrations were mostly found to be independent of mass and gender. When metal concentrations were significantly correlated with mass, correlations were low and explained little variability. The underlying substrate and position in the littoral zone had only a small influence on metal concentrations. Variation between individuals, inherent variability due to genetic variability, was the most significant contribution to the overall variation in metal concentrations, resulting in positive skewing of population distributions. The mean metal concentrations varied temporally; metal masses were relatively constant with fluctuations in metal concentrations related to fluctuations in metal body burdens. The populations from a metal-contaminated site had significantly higher tissue Cu, Zn, As and Pb concentrations than the populations from relatively uncontaminated locations. C. tramoserica therefore can be considered to be a net accumulator of metals. A sample number of >10 is required to detect changes of 25 % from the mean concentrations at uncontaminated locations. This species meets the requirements of a suitable biomonitor for metal contaminants in the environment i.e. hardy, sessile, widespread, sufficient tissue mass and a metal accumulator. As the measurement of metal concentrations in C. tramesoria were influenced by substrate and shore position and, sometimes, mass, sites with similar substrates and organisms of similar mass and shoreline position should be chosen for comparison. When comparing metal concentrations in gastropods from different locations, they should be collected over the same period to minimise variability due to mass differences, spawning and other seasonal/temporal effects.
In this study, pure, Zn, Cu, Zn,Cu co-doped WO3 nanoparticles samples were prepared by precipitation and co-precipitation methods. These nanoparticles were characterized by field emission scanning electron microscopy (FE-SEM), X-ray diffraction (XRD), energy dispersive X-ray spectrometer (EDX), Dynamic light scattering (DLS), UV-visible and photoluminescence (PL) spectroscopy. The synthesized pure, Zn, Cu, Zn,Cu co-doped WO3 nanoparticles have smart optical properties and average sizes with 3.2, 3.12, 3.08 and 2.97eV of band-gap, 18.1, 23.2, 25.7 and 30.2nm, respectively. Photocatalytic activity of four nanoparticles was studying towards degradation of gentamicin antibiotic under ultraviolet and visible light irradiation. The result showed that Zn,Cu co-doped WO3 possessed high photocatalytic activity. The photocatalytic activity of WO3 nanoparticles could be remarkably increased by doping the Zn and Cu impurity. This can be attributed to the fact that the red shift of absorption edge and the trapping effect of the mono and co-doped WO3 nanoparticles. The research result presents a general and effective way to prepare different photocatalysts with enhanced visible and UV light-driven photocatalytic performance. Antibacterial activity of four different WO3 nanoparticles against Escherichia coli bacterium has been assessed by the agar disc method under light irradiation and dark medium. It is concluded from the present findings that WO3 nanoparticles can be used as an efficient antibacterial agent.
This study was carried out to detect the concentrations of some heavy metals (copper, iron, zinc, cadmium and chromium) in the muscle of Capoeta trutta (Heckel, 1843) and in their surrounding water in order to study the potential human risk of consumption. The relationship between the heavy metal load of fish and some of their biological aspects (weight, length and sex) was also examined. In addition, the accumulation factors of heavy metals in this species were determined. The concentrations of Cu, Fe, Zn, Cd and Cr in water and muscle samples were analysed using ICP. Cu, Zn and Fe were detected in all samples, but Cd and Cr were not found in detectable levels. The results showed that heavy metals accumulation in muscle of fish was higher than that in the water. It was found that the level of heavy metals in the muscle of fish showed differences according to weight, length and sex of fish.
Benzimidazole based compound 3 is designed and synthesized. The compound 3 is evaluated as fluorogenic sensor for metal ions in mixed aqueous solutions. Among all the metal ions tested, the compound 3 selectively senses Zn(2+) ions. The imine bond of 3 gets cleaved by Zn(2+) ions. Thus, 3 behave as 'turn on' fluorescent chemodosimeter for Zn(2+) ions with limit of detction in micromolar range. Furthurmore, we demonstated that 3 can detect Zn(2+) ions in cells of Allium cepa. Graphical Abstract Benzimidazole based ligand 3 is designed and synthesized which behave as chemodosimeter for Zn(2+) ions. We further demonstrated that 3 can detect Zn(2+) ions in cells of Allium cepa.
Zn(2+) ions are essential for the normal processing and storage of insulin and altered pancreatic insulin content is associated with all forms of diabetes mellitus. Work of the past decade has identified variants in the human SLC30A8 gene, encoding the zinc transporter ZnT8 which is expressed highly selectively on the secretory granule of pancreatic islet β and α cells, as affecting the risk of Type 2 Diabetes. Here, we review the regulation and roles of Zn(2+) ions in islet cells, the mechanisms through which SLC30A8 variants might affect glucose homeostasis and diabetes risk, and the novel technologies including recombinant targeted zinc probes and knockout mice which have been developed to explore these questions.
Jiulong River Estuary, located in southern China, was heavily contaminated by metal pollution. In this study, the estuarine oysters Crassostrea hongkongensis were transplanted to two sites with similar hydrological conditions but different levels of metal pollution in Jiulong River Estuary over a six-month period. We characterized the time-series change of metal bioaccumulation and final metabolomics responses of oysters. Following transplantation, all metals (Cd, Cu, Cr, Ni, Pb, and Zn) in the oyster digestive glands had elevated concentrations over time. By the end of six-month exposure, Cu, Zn and Cd were the main metals significantly differentiating the two sites. Using (1)H NMR metabolite approach, we further demonstrated the disturbance in osmotic regulation, energy metabolism, and glycerophospholipid metabolism induced by metal contaminations. Six months later, the oysters transplanted in the two sites showed a similar metabolite variation pattern when compared with the initial oysters regardless of different metal levels in the tissues. Interestingly, by comparing the oysters from two sites, the more severely polluted oysters accumulated significantly higher amounts of osmolytes (betaine and homarine) and lower energy storage compounds (glycogen) than the less polluted oysters; these changes could be the potential biomarkers for different levels of metal pollution. Our study demonstrated the complexity of biological effects
 under field conditions, and NMR metabolomics provides an important approach to detect sensitive variation of oyster inner status.
The performance, microbial activity, and microbial community of a sequencing batch reactor (SBR) were investigated under the long-term exposure of ZnO nanoparticles (ZnO NPs). Low ZnO NPs concentration (less than 5mg/L) had no obvious effect on the SBR performance, whereas the removals of COD, NH4(+)-N, and phosphorus were affected at 10-60mg/L ZnO NPs. The variation trend of nitrogen and phosphorus removal rate was similar to that of microbial enzymatic activity with the increase of ZnO NPs concentrations. The richness and diversity of microbial community showed obvious variations at different ZnO NPs concentrations. ZnO NPs appeared on the surface and cell interior of activated sludge, and the Zn contents in the effluent and activated sludge increased with the increase of ZnO NPS concentration. The present results provide use information to understand the effect of ZnO NPS on the performance of wastewater biological treatment systems.
The aim of this study was to evaluate essential and toxic element concentration of ten commercially available veal cuts, together with diaphragm, cardiac muscle and liver tissue from 10 animals of "Galician Supreme Veal". Essential trace elements (Co, Cr, Cu, Fe, Mn, Mo, Ni, Se and Zn) and toxic elements (As, Cd, Hg and Pb) were determined by ICP-MS. Essential trace element concentrations ranged from 0.002-55.64mg/kg between muscles. Toxic element concentrations were very low, and high numbers of samples showed unquantifiable residues of Cd and Pb. Veal cuts including muscles with a high proportion of oxidative slow-twitch fibers (diaphragm and cardiac muscle) showed significantly higher essential trace element concentrations, the lower concentrations being found in veal cuts including glycolytic fast-twitch fibers (eye round). Our results suggest that essential and toxic trace element concentration could be used as a new meat quality parameter, or to add further value to certain products (i.e. livestock reared on extensive systems with high physical activity).
Cellulose is the most abundant renewable and biodegradable material available in nature. Its insoluble character in water as well as common organic and inorganic liquids, however, curtails the wholesome utility. The continuous rise for biodegradable products based on cellulose coupled with its intrinsic ability to form a viable substitute for the petroleum-based materials necessitates the critical need for solubilizing the cellulose. Herein, we demonstrate the feasibility of ZnCl2 solutions, especially the 64-72% concentrations, to dissolve cellulose. FTIR results suggest that Zn(2+) ions promote Zn⋯O3H interactions, which in-turn weaken the intrinsic O3H⋯O5 hydrogen bonds that are responsible for strengthening the cellulose chains. Interestingly, Ca(2+) ions promote interactions among the Zn-cellulose chains leading to the formation of nano fibrils and yield gelling solutions. The tensile strength of the Ca(2+) added Zn-cellulose films increases by around 250% compared to the Zn-cellulose films. Overall, utilization of inorganic salt solutions to solubilize and crosslink cellulose is cost-effective, recyclable and certainly stands out tall among the other available systems. More importantly, the proposed protocol is simple and is a "green" process, and thus its large-scale adaptability is quite feasible. We strongly believe that the outcome opens up a new window of opportunities for cellulose in the biomedical, pharmaceutical, food and non-food applications.
Protein misfolding is implicated in neurodegenerative diseases such as ALS, where mutations of superoxide dismutase 1 (SOD1) account for about 20% of the inherited mutations. Human SOD1 (hSOD1) contains four cysteines, including Cys(57) and Cys(146), which have been linked to protein stability and folding via forming a disulfide bond, and Cys(6) and Cys(111) as free thiols. But the roles of the cellular oxidation-reduction (redox) environment in SOD1 folding and aggregation are not well understood. Here we explore the effects of cellular redox systems on the aggregation of hSOD1 proteins. We found that the known hSOD1 mutations G93A and A4V increased the capability of the thioredoxin and glutaredoxin systems to reduce hSOD1 compared with wild-type hSOD1. Treatment with inhibitors of these redox systems resulted in an increase of hSOD1 aggregates in the cytoplasm of cells transfected with mutants but not in cells transfected with wild-type hSOD1 or those containing a secondary C111G mutation. This aggregation may be coupled to changes in the redox state of the G93A and A4V mutants upon mild oxidative stress. These results strongly suggest that the thioredoxin and glutaredoxin systems are the key regulators for hSOD1 aggregation and may play critical roles in the pathogenesis of ALS.
Emperor penguins (Aptenodytes forsteri) are sensitive to the Antarctic climate change because they breed on the fast sea ice. Studies of paleohistory for the emperor penguin are rare, due to the lack of archives on land. In this study, we obtained an emperor penguin ornithogenic sediment profile (PI) and performed geochronological, geochemical and stable isotope analyses on the sediments and feather remains. Two radiocarbon dates of penguin feathers in PI indicate that emperor penguins colonized Amanda Bay as early as CE 1540. By using the bio-elements (P, Se, Hg, Zn and Cd) in sediments and stable isotope values (δ(15)N and δ(13)C) in feathers, we inferred relative population size and dietary change of emperor penguins during the period of CE 1540-2008, respectively. An increase in population size with depleted N isotope ratios for emperor penguins on N island at Amanda Bay during the Little Ice Age (CE 1540-1866) was observed, suggesting that cold climate affected the penguin's breeding habitat, prey availability and thus their population and dietary composition.
Organic fertilizers are obtained from waste of plant or animal origin. One of the advantages of organic fertilizers is that, from the composting, it recycles waste-organic of urban and agriculture origin, whose disposal would cause environmental impacts. Fast and accurate analysis of both major and minor/trace elements contained in organic mineral and inorganic fertilizers of new generation have promoted the application of modern analytical techniques. In particular, laser induced breakdown spectroscopy (LIBS) is showing to be a very promising, quick and practical technique to detect and measure contaminants and nutrients in fertilizers. Although, this technique presents some limitations, such as a low sensitivity, if compared to other spectroscopic techniques, the use of double pulse (DP) LIBS is an alternative to the conventional LIBS in single pulse (SP). The macronutrients (Ca, Mg, K, P), micronutrients (Cu, Fe, Na, Mn, Zn) and contaminant (Cr) in fertilizer using LIBS in SP and DP configurations were evaluated. A comparative study for both configurations was performed using optimized key parameters for improving LIBS performance. The limit of detection (LOD) values obtained by DP LIBS increased up to seven times as compared to SP LIBS. In general, the marked improvement obtained when using DP system in the simultaneous LIBS quantitative determination for fertilizers analysis could be ascribed to the larger ablated mass of the sample. The results presented in this study show the promising potential of the DP LIBS technique for a qualitative analysis in fertilizers, without requiring sample preparation with chemical reagents.
Soil contamination is one of the greatest concerns among the threats to soil resources in Europe and globally. Despite of its importance there was only very course scale (1/5000km(2)) data available on soil heavy metal concentrations prior to the LUCAS topsoil survey, which had a sampling density of 200km(2). Based on the results of the LUCAS sampling and auxiliary information detailed and up-to-date maps of heavy metals (As, Cd, Cr, Cu, Hg, Pb, Zn, Sb, Co and Ni) in the topsoil of the European Union were produced. Using the maps of heavy metal concentration in topsoil we made a spatial prediction of areas where local assessment is suggested to monitor and eventually control the potential threat from heavy metals. Most of the examined elements remain under the corresponding threshold values in the majority of the land of the EU. However, one or more of the elements exceed the applied threshold concentration on 1.2Mkm(2), which is 28.3% of the total surface area of the EU. While natural backgrounds might be the reason for high concentrations on large proportion of the affected soils, historical and recent industrial and mining areas show elevated concentrations (predominantly of As, Cd, Pb and Hg) too, indicating the magnitude of anthropogenic effect on soil quality in Europe.
Zinc is an essential trace element for proper cellular function and bone formation. However, its exact role in the osteogenic differentiation of human dental pulp cells (hDPCs) has not been fully clarified before. Here, we speculated that zinc may be effective to regulate their growth and osteogenic differentiation properties. To test this hypothesis, different concentrations (1 × 10(-5), 4 × 10(-5), and 8 × 10(-5) M) of zinc ions (Zn(2+)) were added to the basic growth culture medium and osteogenic inductive medium. Cell viability and migration were measured by cell counting kit-8 (CCK-8) and transwell migration assay in the basic growth culture medium, respectively. The reverse transcription-quantitative polymerase chain reaction (RT-qPCR) was used to detect the gene expression levels of selective osteogenic differentiation markers and zinc transporters. Alkaline phosphatase (ALP) activity analysis and
 alizarin red S staining were used to investigate the mineralization of hDPCs. Exposure of hDPCs to Zn(2+) stimulated their viability and migration capacity in a dose- and time-dependent manner. RT-qPCR assay revealed elevated expression levels of osteogenic differentiation-related genes and zinc transporters genes in various degrees. ALP activity was also increased with elevated Zn(2+) concentrations and extended culture periods, but enhanced matrix nodules formation were observed only in 4 × 10(-5) and 8 × 10(-5) M Zn(2+) groups. These findings suggest that specific concentrations of Zn(2+) could potentiate the vitality, migration, and osteogenic differentiation of hDPCs. We may combine optimum zinc element into pulp capping materials to improve their biological performance.
The levels and distribution of trace metals (Cr, Mn, Co, Ni, Cu, Zn, Cd and Pb) at eleven water and sediment stations on the Little Akaki River (LAR) in Addis Ababa, Ethiopia, were determined. The binding forms of the metals in various geochemical fractions of the sediments were also quantified. The molar ratio of the sum of the simultaneously extractable metals (∑SEM) and acid-volatile sulphide (AVS)-as a measure for predicting metal-induced toxicity-was estimated. LAR trace levels in water for Cu, Zn, and, particularly Mn were, in most instances, higher than the recommended guidelines for healthy aquatic ecosystems. Total trace metal (TTM) contents in the LAR sediments at certain stations exceeded "threshold effect concentrations" and even "probable effect concentrations", especially in the cases of Zn, Cu, Ni, Pb, and at all stations for Mn. This became more apparent after applying "normalizations" to the relatively lower TTM adsorption capacities of coarse-grained, organic-poor sediments. Sequential extraction of the sediments showed that trace metals generally have a higher affinity for Fe-Mn oxide and organic matter/sulphidic fractions, followed by the residual fraction. Mn was relatively strongly bound to the exchangeable, carbonate bound fractions, whereas a large proportion of Cr was found in the residual fraction. The Σ[SEM]/[AVS] ratio pointed to potential metal-induced toxicity of sediments collected from seven out of the eleven stations. The results indicate that trace metal pollution pose risks to the health of ecosystems, and to human communities that use the river for a range of different purposes.
Due to its potential toxic properties, metal mobilization is of major concern in areas surrounding Pb-Zn mines. In the present study, metal contents and toxicity of soils, aqueous extracts from soils and mine drainage waters from an abandoned F-Ba-Pb-Zn mining area in Osor (Girona, NE Spain) were evaluated through chemical extractions and ecotoxicity bioassays. Toxicity assessment in the terrestrial compartment included lethal and sublethal endpoints on earthworms Eisenia fetida, arthropods Folsomia candida and several plant species, whereas aquatic tests involved bacteria Vibrio fischeri, microalgae Raphidocelis subcapitata and crustaceans Daphnia magna. Total concentrations of Ba (250-5110 mg kg(-1)), Pb (940 to >5000 mg kg(-1)) and Zn (2370-11,300 mg kg(-1)) in soils exceeded intervention values to protect human health. Risks for the aquatic compartment were identified in the release of drainage waters and in the potential leaching and runoff of metals from contaminated soils, with Cd (1.98-9.15 µg L(-1)), Pb (2.11-326 µg L(-1)) and Zn (280-2900 µg L(-1)) concentrations in filtered water samples surpassing US EPA Water Quality Criteria (2016a, b). Terrestrial ecotoxicity tests were in accordance with metal quantifications and identified the most polluted soil as the most toxic. Avoidance and reproduction tests with earthworms showed the highest sensitivity to metal contamination. Aquatic bioassays performed in aqueous extracts from soils confirmed the results from terrestrial tests and also detected toxic effects caused by the mine drainage waters. Algal growth inhibition was the most sensitive aquatic endpoint. In view of the results, the application of a containment or remediative procedure in the area is encouraged.
In this work a green digestion method which only used H2O2 as an oxidant and high temperature and pressure in the single reaction chamber system (SRC-UltraWave™) was applied for subsequent elemental determination by inductively coupled plasma-based techniques. Milk powder was chosen to demonstrate the feasibility and advantages of the proposed method. Samples masses up to 500mg were efficiently digested, and the determination of Ca, Fe, K, Mg and Na was performed by inductively coupled plasma optical emission spectrometry (ICP-OES), while trace elements (B, Ba, Cd, Cu, Mn, Mo, Pb, Sr and Zn) were determined by inductively coupled plasma mass spectrometry (ICP-MS). Residual carbon (RC) lower than 918mgL(-1) of C was obtained for digests which contributed to minimizing interferences in determination by ICP-OES and ICP-MS. Accuracy was evaluated using certified reference materials NIST 1549 (non-fat milk powder certified reference material) and NIST 8435 (whole milk powder reference material). The results obtained by the proposed method were in agreement with the certified reference values (t-test, 95% confidence level). In addition, no significant difference was observed between results obtained by the proposed method and conventional wet digestion using concentrated HNO3. As digestion was performed without using any kind of acid, the characteristics of final digests were in agreement with green chemistry principles when compared to digests obtained using conventional wet digestion method with concentrated HNO3. Additionally, H2O2 digests were more suitable for subsequent analysis by ICP-based techniques due to of water being the main product of organic matrix oxidation. The proposed method was suitable for quality control of major components and trace elements present in milk powder in consonance with green sample preparation.
Leadmium Green is a commercially available, small molecule, fluorescent probe advertised as a detector of free intracellular cadmium (Cd(2+)) and lead (Pb(2+)). Leadmium Green has been used in various paradigms, such as tracking Cd(2+) sequestration in plant cells, heavy metal export in protozoa, and Pb(2+) absorption by vascular endothelial cells. However very little information is available regarding its affinity and selectivity for Cd(2+), Pb(2+), and other metals. We evaluated the in vitro selectivity of Leadmium Green using spectrofluorimetry. Consistent with manufacturer's claims, Leadmium Green was sensitive to Cd(2+) (KD ~600 nM) and also Pb(2+) (KD ~9.0 nM) in a concentration-dependent manner, and furthermore proved insensitive to Ca(2+), Co(2+), Mn(2+) and Ni(2+). Leadmium Green also responded to Zn(2+) with a KD of ~82 nM. Using fluorescence microscopy, we evaluated Leadmium Green in live mouse hippocampal HT22 cells. We demonstrated that Leadmium Green detected ionophore-mediated acute elevations of Cd(2+) or Zn(2+) in a concentration-dependent manner. However, the maximum fluorescence produced by ionophore-delivered Zn(2+) was much less than that produced by Cd(2+). When tested in a model of oxidant-induced liberation of endogenous Zn(2+), Leadmium Green responded weakly. We conclude that Leadmium Green is an effective probe for monitoring intracellular Cd(2+), particularly in models where Cd(2+) accumulates rapidly, and when concomitant fluctuations of intracellular Zn(2+) are minimal.
A multi-disciplinary approach was used to evaluate the health of yellow perch (Perca flavescens) in the St. Lawrence River (Quebec, Canada), which is experiencing a severe population decline in the downstream portion of the river. Physiological parameters, liver alterations, trace metal concentrations, parasite prevalence and abundance, stable isotope composition, and the presence/absence of the viral hemorragic septicemia virus (VHSV) were evaluated in perch collected at six sites along the river: Lake St. François, Lake St. Louis (north and south), Beauregard Island, and Lake St. Pierre (north and south). Trace metal concentrations in surface water were higher in Lake St. Louis and downstream of a major urban wastewater treatment plant discharge, indicating that this effluent was a significant source of Cu, As, Ag, Zn, and Cd. Levels of Pb in surface water exceeded thresholds for the protection of aquatic life in Lake St. Louis and were negatively correlated with body condition index in this lake. In Lake St. Pierre, Cu, Ag, and Cd bioaccumulated significantly in perch liver and lower body condition index and greater liver damage were observed compared to upstream sites. Parasite analyses indicated a higher abundance of metacercariae of the trematodes Apophallus brevis and Diplostomum spp. in Lake St. Louis, and VHSV was not detected in the liver of yellow perch for all studied sites. Overall, results suggested that the global health of yellow perch from Lake St. Pierre is lower compared to upstream studied sites, which could contribute to the documented population collapse at this site.
To improve the production and activity of an alkaline zinc metalloprotease from Salinivibrio proteolyticus in response to ZnSO4 (ionic and nanoparticle forms) and low intensity direct electric current (LIDC).
A DC of 50 µA for 10 min increased enzyme production from 35 to 53 U ml(-1) when applied to the stationary phase bacterial cells. Zn(2+) improved enzyme production better than zinc nanoparticles (52 vs. 43.5 U ml(-1)). Zinc nanoparticles (0.5 mM) added to an enzyme reaction mixture containing casein (0.65 %) and 20 mM Tris/HCl buffer (pH 8) improved enzyme activity more than Zn(2+) (42 vs. 36 U ml(-1)).
LIDC exposure (50 µA, 10 min) to the stationary phase bacterial cells increases metalloprotease production
 in Salinivibrio. A low concentration of zinc nanoparticles (0.5 mM) increases maximum enzyme activity.
Manganese (Mn) overexposure induced neurological damages, which could be potentially protected by sodium para-aminosalicylic acid (PAS-Na). In this study, we systematically detected the changes of divalent metal elements in most of the organs and analyzed the distribution of the metals in Mn-exposed rats and the protection by PAS-Na. Sprague Dawley (SD) rats received intraperitoneal injections of 15mg/kg MnCl2·4H2O (5d/week for 3 weeks), followed by subcutaneous (back) injections of PAS-Na (100 and 200mg/kg, everyday for 5 weeks). The concentrations of Mn and other metal elements [Iron (Fe), Copper (Cu), Zinc (Zn), Magnesium (Mg), Calcium (Ca)] in major organs (liver, spleen, kidney, thighbone and iliac bone, cerebral cortex, hippocampus and testes) and blood by Inductively Coupled Plasma-Atomic Emission Spectrometry (ICP-AES). The results showed that Mn overexposure significantly increased Mn in most organs, Fe and Zn in liver, Fe and Mg in blood; however decreased Fe, Cu, Zn, Mg and Ca in cortex, Cu and Zn in kidney, Cu and Mg in iliac bone, and Zn in blood. In contrast, PAS-Na treatment restored most changes particularly in cortex. In conclusion, excessive Mn exposure disturbed the balance of other metal elements but PAS-Na post-treatments could restore these alterations.
Although zinc (Zn) deficiency is often suspected in patients with taste disorders, it may be difficult to diagnose Zn deficiency, especially in patients without any clear risk factors. Accordingly, the aim of the present study was to detect possible markers for taste disorders or zinc deficiency. To achieve this aim, we analyzed data obtained from 122 Japanese men who were not using medicines and had no diseases requiring treatment. We evaluated the following factors: awareness of dysgeusia; salty taste recognition threshold (SRT); the serum concentrations of Zn, copper (Cu), iron, alkaline phosphatase, and albumin; and the Cu/Zn ratio. The serum Cu/Zn ratio was positively correlated with the both the SRT and the awareness of dysgeusia. The serum Zn concentration was not correlated with the SRT or the awareness of dysgeusia in univariate analyses. However, in multivariate logistic regression, the serum Zn concentration was associated with the awareness of dysgeusia. In conclusion, the serum Cu/Zn ratio is a good diagnostic marker for taste disorders and the value of 1.1 may be a threshold level for detecting taste disorders.
The influence of Boron (B) supplementation on immune and antioxidant status of rats with or without abiotic stress induced by dietary calcium (Ca) restriction was studied in a feeding trial of 90 days. Wistar strain rats (3-4 wk age, n=84) were divided into 7 dietary groups (4 replicates of 3 each) viz., normal-calcium (100%) basal diet alone (NC, control) or supplemented with B at 5 (NCB-5), 10 (NCB-10), 20 (NCB-20) and 40ppm (NCB-40) levels; low-calcium (50%) basal diet alone (LC) or supplemented with 40ppm B (LCB-40). After 75 days of experimental feeding, rats were challenged with intraperitoneal injection of sheep RBCs to assess their humoral immunity. At the end of the trial, cell-mediated immunity was assessed as foot pad reaction to sheep RBCs injected into the hind leg paws. Eight rats from each group were sacrificed to collect blood for estimation of minerals and total antioxidant activity, and liver for superoxide dismutase gene expression analysis. Supplementation of graded levels of B (5, 10, 20 and 40ppm) as borax in NC diets significantly increased (P<0.01) the footpad thickness and serum total antioxidant activity, hepatic expression levels of both Cu-Zn SOD (SOD1) and Mn-SOD (SOD2) mRNAs. The erythrocytic SOD activity and humoral response did not differ significantly among the dietary groups. In Ca restricted groups, humoral immune response was significantly decreased (P<0.01) compared to control but increased (P<0.05) with 40ppm B supplementation. Serum levels of copper (Cu) and zinc (Zn) remained similar among the dietary groups, while the manganese (Mn) content was significantly decreased (P<0.01) with increased levels of dietary B. In conclusion, B supplementation increased the hepatic mRNA expression levels of both SOD isoenzymes, thereby improving the immune and antioxidant status.
Deficiency of essential trace elements (such as Cu or Zn) and accumulation of potentially toxic trace elements (as Cd or Pb) are both known to have adverse effects in hemodialysis (HD) patients. Up to our knowledge, no studies about the permeability of low and high flux polysulfone membranes on metal ions during hemodialysis are available. Therefore, the aim of the present study was to address this issue. Forty one hemodialysis patients (19 were using high flux polysulfone membrane while the remaining were using low flux one) participated in the study. Blood levels of Cu, Zn, Cd and Pb were determined by graphite furnace atomic absorption spectrometry among HD patients, before and after dialysis session, as well as among matched 40 healthy persons. Blood concentrations of Cu and Zn in the whole hemodialysis group was significantly lower than those of the healthy control group, on the other hand the toxic metals (Cd and Pb) levels were observed to be significantly higher among HD patients compared to the normal persons. Among the hemodialysis group, there were no significant differences between the low and high flux dialyzer groups in terms of pre-dialysis blood levels of Cu, Zn, Cd and Pb. In addition, significantly decreased levels of all metal ions were observed after dialysis sessions using either low or high flux membranes. An exception was Pb which did not show any difference between pre-dialysis and post-dialysis values in the low flux groupIn conclusion Zn and Cu deficiencies should be considered in the treatment of these patients. High flux membranes are more efficient than low flux ones in removing excess Cd and Pb. Therefore, when high flux membranes are used, chelation therapy might not be required for Cd and Pb overload.
The role of trace elements bound to proteins in the etiology and pathogenesis of rheumatoid arthritis (RA) remains unclear. In this sense, the identification and detection of metalloproteins has a strong and growing interest. Metalloprotein studies are currently carried out by polyacrylamide gel electrophoresis (PAGE) associated to inductively coupled plasma mass spectrometry (ICPMS), and despite that complete information can be obtained for metals such as Fe, Cu and Zn, difficulties due to poor sensitivity for other trace elements such as Sn, As, etc, are currently faced. In the present work, a simple and fast method for the determination of trace metals bound to synovial fluid (SF) proteins was optimized. Proteins from SF (long and short-term RA) were separated in ten fractions by native PAGE, then dissolved in nitric acid and peroxide hydrogen, and analyzed by ICPMS. Fifteen metals were determined in each separated protein fraction (band). Adequate calibration of proteins molecular weight allowed stablishing which protein type were bound to different metals.
The present study aimed to investigate metal bioaccumulation in mullet (M. liza) from a tropical bay located in Southeastern Brazil, comparing a previously considered reference site to a known contaminated area of the bay, as well as to conduct human health risk assessments with regard to the consumption of this species. The metal concentrations were compared to the maximum residue level (MRL) in foods established by the different national and international regulatory agencies, and the Provisional Tolerable Daily Intake (PTDI) was determined and compared to reference values. Chromium (Cr), Zinc (Zn), Copper (Cu), Manganese (Mn), Nickel (Ni), Cadmium (Cd) and Lead (Pb) concentrations were determined in the gills, muscle and liver of 28 mullet by ICP-MS after acid digestion. Certain metals exceeded MRL guidelines established by different regulatory agencies, indicating human health risks associated to these metals. PTDI values, however, did not exceed corresponding metal values proposed by the World Health Organization. The metal concentrations found in the mullet samples indicate that the previously considered reference site is now showing signs of anthropogenic contamination.
This paper presents a database of radionuclide activity and metal concentrations for the Alligator Rivers Region (ARR) uranium province in the Australian wet-dry tropics. The database contains 5060 sample records and 57,473 concentration values. The data are for animal, plant, soil, sediment and water samples collected by the Environmental Research Institute of the Supervising Scientist (ERISS) as part of its statutory role to undertake research and monitoring into the impacts of uranium mining on the environment of the ARR. Concentration values are provided in the database for 11 radionuclides ((227)Ac, (40)K, (210)Pb, (210)Po, (226)Ra, (228)Ra, (228)Th, (230)Th, (232)Th, (234)U, (238)U) and 26 metals (Al, As, Ba, Ca, Cd, Co, Cr, Cu, Fe, Hg, K, Mg, Mn, Na, Ni, P, Pb, Rb, S, Sb, Se, Sr, Th, U, V, Zn). Potential uses of the database are discussed.
Within EU FP7 project NANOVALID, the (eco)toxicity of 7 well-characterized engineered nanomaterials (NMs) was evaluated by 15 bioassays in 4 laboratories. The highest tested nominal concentration of NMs was 100 mg/l. The panel of the bioassays yielded the following toxicity order: Ag > ZnO > CuO > TiO2 > MWCNTs > SiO2 > Au. Ag, ZnO and CuO proved very toxic in the majority of assays, assumingly due to dissolution. The latter was supported by the parallel analysis of the toxicity of respective soluble metal salts. The most sensitive tests/species were Daphnia magna (towards Ag NMs, 24-h EC50 = 0.003 mg Ag/l), algae Raphidocelis
 subcapitata (ZnO and CuO, 72-h EC50 = 0.14 mg Zn/l and 0.7 mg Cu/l, respectively) and murine fibroblasts BALB/3T3 (CuO, 48-h EC50 = 0.7 mg Cu/l). MWCNTs showed toxicity only towards rat alveolar macrophages (EC50 = 15.3 mg/l) assumingly due to high aspect ratio and TiO2 towards R. subcapitata (EC50 = 6.8 mg Ti/l) due to agglomeration of TiO2 and entrapment of algal cells. Finally, we constructed a decision tree to select the bioassays for hazard ranking of NMs. For NM testing, we recommend a multitrophic suite of 4 in vitro (eco)toxicity assays: 48-h D. magna immobilization (OECD202), 72-h R. subcapitata growth inhibition (OECD201), 30-min Vibrio fischeri bioluminescence inhibition (ISO2010) and 48-h murine fibroblast BALB/3T3 neutral red uptake in vitro (OECD129) representing crustaceans, algae, bacteria and mammalian cells, respectively. Notably, our results showed that these assays, standardized for toxicity evaluation of "regular" chemicals, proved efficient also for shortlisting of hazardous NMs. Additional assays are recommended for immunotoxicity evaluation of high aspect ratio NMs (such as MWCNTs).
Graphene oxide (GO) is a good adsorbent for heavy-metal ions because the oxygen functional groups offer active adsorption sites, but a small-size GO with dense oxygen-containing groups has high water solubility causing difficulty in separation. Herein, GO is bound to large brianyoungite (BY) by Zn-O coordination via a hydrothermal reaction that produces BY-GO composites with hollow spherical and flakelike morphologies that are easy to remove. By producing abundant oxygen-containing groups on GO, the Cu(2+) adsorption capacity increases to 1724.1 mg/g, which is the highest value in graphene-related materials. The experimental and theoretical analysis clearly shows that the infrared spectral shifts toward the low-frequency side of C-O-H and O═C-O bending vibrations in the BY-GO composites stem from the Zn(2+) (or Cu(2+)) coordination with O atoms in GO. The BY-GO also exhibits tunable deep-red photoluminescence up to 750 nm with a quantum yield of about 1%, which may be useful in infrared optoelectronic devices and solar energy exploitation. The photoluminescence which is different from that previously reported from chemically derived GO can be attributed to the optical transition in the disorder-induced localized states of the carbon-oxygen functional groups.
A novel synthetic protocol has been developed for free-base 10-azacorroles. Ni(0)-mediated homocoupling of nitrogen-bridged bisdipyrrin Zn(II) complexes afforded a series of free-base 5,15-diaryl-10-azacorroles in good yields. Pd(II) and Cu(II) complexes have been prepared through metalation of free-base 10-azacorroles. Optical and electrochemical properties of 10-azacorrole metal complexes can be tuned by meso-aryl substituents and central metals. Cyclic voltammetry and theoretical calculations elucidated that the central metals of 10-azacorroles significantly affected their electronic properties.
The absolute stereochemistry of cyanohydrins, derived from ketones and aldehydes, is obtained routinely, in a microscale and derivatization-free manner, upon their complexation with Zn-MAPOL, a zincated porphyrin host with a binding pocket comprised of a biphenol core. The host-guest complex leads to observable exciton-coupled circular dichroism (ECCD), the sign of which is easily correlated to the absolute stereochemistry of the bound cyanohydrin. A working model, based on the ECCD signal of cyanohydrins with known configuration, is proposed.
Arundo donax L. has a high biomass production and a tendency toward community dominance in many habitats and thereby a tolerance to a wide range of environmental conditions. Therefore, the present study investigated the potentiality of A. donax to accumulate nutrients and trace metals in its biomass. Six main habitats (Nile Bank, Drain Bank, Canal Bank, Field Edges, Railways and Roadsides) were recognized. At each habitat, six quadrats (each 1 m(2)), distributed equally in two sites, were selected for growth measurements (e.g., density, shoot height, diameter, leaf area and biomass), plant and soil analyses. Plants from Nile, Canal and Drain Banks had the highest values of most growth measurements, while those from Railways and Roadsides had the lowest. Canal Bank plants accumulated the highest concentrations of P, Cu and Pb in their leaves; Zn in the stem; and Mg, Cd and Fe in the rhizome. The bioaccumulation factor (BF) of A. donax, for Cd, Fe, Mn and Zn, was greater than 1, while the translocation factor (TF) of most trace metals was less than unity in most habitats. In conclusion, A. donax showed morphological plasticity in response to habitat heterogeneity, and its growth was most vigorous in the riparian habitats. The high BF, as well as the significant positive correlations between trace metals, especially Cd, in soil and plant, renders A. donax a powerful phytoremediator.
In this study, an in-situ approach was used to synthesise zinc oxide nanoparticles on the surface of cotton fabric. The effect of alkaline pre- and after-treatment and Zn(2+) concentration was studied on the morphological, structural, thermal, photocatalytic, and antibacterial properties of loaded cotton fabrics. Scanning electron microscopy, energy dispersive X-ray spectroscopy, X-ray diffractometer, thermogravimetric analysis, and attenuated total reflection Fourier transform infrared spectrometer were used to characterise the properties of loaded cotton fabrics. Alkaline after-treatment of cotton fabric presented more dispersed zinc oxide nanoparticles, and an increase in Zn(2+) concentration led to form agglomerated nanoparticles on the surface of cotton fibres. The loaded cotton fabrics with zinc oxide nanoparticles presented an inhibition zone against Staphylococcus aureus and Escherichia coli. In addition, the stain of methylene blue on the surface of loaded samples was degraded after irradiated under visible light.
To evaluate the time effect on the distribution of zinc oxide nanoparticles (ZnO NPs) in tissues from rats and mice, a search on the PubMed, Embase, SpringerLink, Scopus, Science Direct, Cochrane, CNKI, Wanfang, and vip databases up to September 2014 was performed, followed by screening, data extraction, and quality assessment. Thirteen studies were included. At 24 h, Zn content was mainly distributed in the liver, kidney, and lung. At ≥7 days, Zn content was mainly distributed in the liver, kidney, lung, and brain. ZnO NPs are readily deposited in tissues. Furthermore, as time increases, Zn content decreases in the liver and kidney, but increases in the brain.
Luminescent metal complexes are used in photooptical devices. Zinc(II) complexes are of interest because of the ability to tune their color, their high thermal stability and their favorable carrier transport character. In particular, some zinc(II) complexes with aryl diimine and/or heterocyclic ligands have been shown to emit brightly in the blue region of the spectrum. Zinc(II) complexes bearing derivatized imidazoles have been explored for possible optoelectronic applications. The structures of two zinc(II) complexes of 5,6-dimethyl-2-(pyridin-2-yl)-1-[(pyridin-2-yl)methyl]-1H-benzimidazole (L), namely dichlorido(dimethylformamide-κO){5,6-dimethyl-2-(pyridin-2-yl-κN)-1-[(pyridin-2-yl)methyl]-1H-benzimidazole-κN(3)}zinc(II) dimethylformamide monosolvate, [ZnCl2(C20H18N4)(C3H7NO)]·C3H7NO, (I), and bis(acetato-κ(2)O,O'){5,6-dimethyl-2-(pyridin-2-yl-κN)-1-[(pyridin-2-yl)methyl]-1H-benzimidazole-κN(3)}zinc(II) ethanol monosolvate, [Zn(C2H3O2)2(C20H18N4)]·C2H5OH, (II), are reported. Complex (I) crystallized as a dimethylformamide solvate and exhibits a distorted trigonal bipyramidal coordination geometry. The coordination sphere consists of a bidentate L ligand spanning axial to equatorial sites, two chloride ligands in equatorial sites, and an O-bound dimethylformamide ligand in the remaining axial site. The other complex, (II), crystallized as an ethanol solvate. The Zn(II) atom has a distorted trigonal prismatic coordination geometry, with two bidentate acetate ligands occupying two edges and a bidentate L ligand occupying the third edge of the prism. Complexes (I) and (II) emit in the blue region of the spectrum. The results of density functional theory (DFT) calculations suggest that the luminescence of L results from π*←π transitions and that the luminescence of the complexes results from interligand charge-transfer transitions. The orientation of the 2-(pyridin-2-yl) substituent with respect to the benzimidazole system was found to have an impact on the calculated HOMO-LUMO gap (HOMO is highest occupied molecular orbital and LUMO is lowest unoccupied molecular orbital).
Sthenoteuthis oualaniensis is a species of cephalopod that is becoming economically important in the South China Sea. As, Cd, Cr, Cu, Hg, Pb, and Zn concentrations were determined in the mantle, arms, and digestive gland of S. oualaniensis from 31 oceanographic survey stations in the central and southern South China Sea. Intraspecific and interspecific comparisons with previous studies were made. Mean concentrations of trace elements analyzed in arms and mantle were in the following orders: Zn > Cu > Cd > Cr > As > Hg. In digestive gland, the concentrations of Cd and Cu exceed that of Zn. All the Pb concentrations were under the detected limit.
The study aimed to monitor heavy metal (chromium, Cr; cadmium, Cd; nickel, Ni; copper, Cu; lead, Pb; iron, Fe; manganese, Mn; and zinc, Zn) footprints in biological matrices (urine, whole blood, saliva, and hair), as well as in indoor industrial dust samples, and their toxic effects on oxidative stress and health risks in exposed workers. Overall, blood, urine, and saliva samples exhibited significantly higher concentrations of toxic metals in exposed workers (Cr;
 blood 16.30 μg/L, urine 58.15 μg/L, saliva 5.28 μg/L) than the control samples (Cr; blood 5.48 μg/L, urine 4.47 μg/L, saliva 2.46 μg/L). Indoor industrial dust samples also reported to have elevated heavy metal concentrations, as an example, Cr quantified with concentration of 299 mg/kg of dust, i.e., more than twice the level of Cr in household dust (136 mg/kg). Superoxide dismutase (SOD) level presented significant positive correlation (p ≤ 0.01) with Cr, Zn, and Cd (Cr > Zn > Cd) which is an indication of heavy metal's associated raised oxidative stress in exposed workers. Elevated average daily intake (ADI) of heavy metals resulted in cumulative hazard quotient (HQ) range of 2.97-18.88 in workers of different surgical units; this is an alarming situation of health risk implications. Principal component analysis-multiple linear regression (PCA-MLR)-based pie charts represent that polishing and cutting sections exhibited highest metal inputs to the biological and environmental matrices than other sources. Heavy metal concentrations in biological matrices and dust samples showed a significant positive correlation between Cr in dust, urine, and saliva samples. Current study will help to generate comprehensive base line data of heavy metal status in biomatrices and dust from scientifically ignored industrial sector. Our findings can play vital role for health departments and industrial environmental management system (EMS) authorities in policy making and implementation.
Vegetation associated with lacustrine systems in Northern Patagonia was studied for heavy metal and trace element contents, regarding their elemental contribution to these aquatic ecosystems. The research focused on native species and exotic vascular plant Salix spp. potential for absorbing heavy metals and trace elements. The native species studied were riparian Amomyrtus luma, Austrocedrus chilensis, Chusquea culeou, Desfontainia fulgens, Escallonia rubra, Gaultheria mucronata, Lomatia hirsuta, Luma apiculata, Maytenus boaria, Myrceugenia exsucca, Nothofagus antarctica, Nothofagus dombeyi, Schinus patagonicus, and Weinmannia trichosperma, and macrophytes Hydrocotyle chamaemorus, Isöetes chubutiana, Galium sp., Myriophyllum quitense, Nitella sp. (algae), Potamogeton linguatus, Ranunculus sp., and Schoenoplectus californicus. Fresh leaves were analyzed as well as leaves decomposing within the aquatic bodies, collected from lakes Futalaufquen and Rivadavia (Los Alerces National Park), and lakes Moreno and Nahuel Huapi (Nahuel Huapi National Park). The elements studied were heavy metals Ag, As, Cd, Hg, and U, major elements Ca, K, and Fe, and trace elements Ba, Br, Co, Cr, Cs, Hf, Na, Rb, Se, Sr, and Zn. Geochemical tracers La and Sm were also determined to evaluate contamination of the biological tissues by geological particulate (sediment, soil, dust) and to implement concentration corrections.
P-type macroporous gallium phosphide (GaP) photoelectrodes have been prepared by anodic etching of an undoped, intrinsically n-type GaP(100) wafer and followed by drive-in doping with Zn from conformal ZnO films prepared by atomic layer deposition (ALD). Specifically, 30 nm ALD ZnO films were coated on GaP macroporous films and then annealed at T = 650 °C for various times to diffuse Zn in GaP. Under 100 mW cm(-2) white light illumination, the resulting Zn-doped macroporous GaP consistently exhibit strong cathodic photocurrent when measured in aqueous electrolyte containing methyl viologen. Wavelength-dependent photoresponse measurements of the Zn-doped macroporous GaP revealed enhanced collection efficiency at wavelengths longer than 460 nm, indicating that the ALD doping step rendered the entire material p-type and imparted the ability to sustain a strong internal electric field that preferentially drove photogenerated electrons to the GaP/electrolyte interface. Collectively, this work presents a doping strategy with a potentially high degree of controllability for high-aspect ratio III-V materials, where the ZnO ALD film is a practical dopant source for Zn.
Electrostatic potential maps of GaAs nanowire, p-n junctions have been measured via off-axis electron holography and compared to results from in situ electrical probing, and secondary electron emission microscopy using scanning electron microscopy. The built-in potential and depletion length of an axial junction was found to be 1.5 ± 0.1 V and 74 ± 9 nm, respectively, to be compared with 1.53 V and 64 nm of an abrupt junction of the same end point carrier concentrations. Associated with the switch from Te to Zn dopant precursor was a reduction in GaAs nanowire diameter 3 ± 1 nm that occurred prior to the junction center (n = p) and was followed by a rapid increase in Zn doping. The delay in Zn incorporation is attributed to the time required for Zn to equilibrate within the Au catalyst.
A highly asymmetric A2BC type zinc phthalocyanine (Zn-di-PcNcTh) has been designed and synthesized. The Zn-di-PcNcTh used a π electron rich thiophene ring in place of the benzenoid rings of phthalocyanine which acted as an electron donor, diphenylphenoxy substituents to retard aggregation and a carboxyl-naphthalene unit as an electron acceptor. The asymmetric phthalocyanine shows a strongly split Q-band and wide spectral absorption in the visible/near-IR light region, which can extend the spectral response region of graphitic carbon nitride (g-C3N4) from ∼450 nm to more than 800 nm. By using it as a sensitizer of 1.0 wt% Pt-loaded graphitic carbon nitride (g-C3N4), the experimental results indicate that Zn-di-PcNcTh-Pt/g-C3N4 shows a H2 production efficiency of 249 μmol h(-1) with an impressive turnover number (TON) of 9960.8 h(-1) under visible light (λ≥ 420 nm) irradiation, much higher than that of pristine Pt/g-C3N4. Owing to the introduction of a highly bathochromic shift of 3,4-dicyanothiophene and the valuable "push-pull" effect from the thiophene (electron donor) to the carboxyl-naphthalene (electron acceptor) unit, Zn-di-PcNcTh/g-C3N4 gives an extremely high apparent quantum yield (AQY) of 2.44%, 3.05%, and 1.53% under 700, 730, and 800 nm monochromatic light irradiation, respectively, under optimized photocatalytic conditions.
To assess the influence of soil properties and aging on the availability and toxicity of zinc (Zn) applied as nanoparticles (Zn oxide [ZnO]-NPs) or as Zn(2+) ions (Zn chloride [ZnCl2 ]), 3 natural soils were individually spiked with either ZnO-NPs or ZnCl2 and incubated for up to 6 mo. Available Zn concentrations in soil were measured by porewater extraction (ZnPW), whereas earthworms (Eisenia andrei) were exposed to study Zn bioavailability. Porewater extraction concentrations were lower when Zn was applied as NPs compared to the ionic form and decreased with increasing soil pH. For both Zn forms and Zn-PW values were affected by aging, but they varied among the tested soils, highlighting the influence of soil properties. Internal Zn concentration in the earthworms (ZnE) was highest for the soil with high organic carbon content (5.4%) and basic pH (7.6) spiked with Zn-NPs, but the same soil spiked with ZnCl2 showed the lowest increase in ZnE compared to the control. Survival, weight change, and reproduction of the earthworms were affected by both Zn forms; but differences in toxicity could not be explained by soil properties or aging. This shows that ZnO-NPs and ZnCl2 behave differently in soils depending on soil properties and aging processes, but differences in earthworm toxicity remain unexplained. Environ Toxicol Chem 2016;9999:1-10. © 2016 SETAC.
Premature infants often receive pasteurized donor human milk when mothers are unable to provide their own milk. This study aims to establish the effect of the pasteurization process on a range of trace elements in donor milk.
Breast milk was collected from 16 mothers donating to the milk bank at the Royal Brisbane and Women's Hospital. Samples were divided into pre- and post-pasteurization aliquots and were Holder pasteurized. Inductively coupled plasma mass spectrometry was used to analyze the trace elements zinc (Zn), copper (Cu), selenium (Se), manganese (Mn), iodine (I), iron (Fe), molybdenum (Mo) and bromine (Br). Differences in trace elements pre- and post-pasteurization were analyzed.
No significant differences were found between the trace elements tested pre- and post-pasteurization, except for Fe (P<0.05). The median (interquartile range, 25 to 75%; μg l(-1)) of trace elements for pre- and post- pasteurization aliquots were-Zn: 1639 (888-4508), 1743 (878-4143), Cu: 360 (258-571), 367 (253-531), Se: 12.34 (11.73-17.60), 12.62 (11.94-16.64), Mn: (1.48 (1.01-1.75), 1.49 (1.11-1.75), I (153 (94-189), 158 (93-183), Fe (211 (171-277), 194 (153-253), Mo (1.46 (0.37-2.99), 1.42 (0.29-3.73) and Br (1066 (834-1443), 989 (902-1396).
Pasteurization had minimal effect on several trace elements in donor breast milk but high levels of inter-donor variability of trace elements were observed. The observed decrease in the iron content of pasteurized donor milk is, however, unlikely to be clinically relevant.
Via the activation treatment of carbonized almond shells with HNO3 and KOH, activated microporous carbon (AMC-3 and AMC-2) was successfully synthesized. These two AMC electrodes demonstrate remarkable electrochemical behaviors such as high rate capability, high specific capacitance, and excellent cycle stability when serving as electrodes for supercapacitors. More importantly, through the use of a Zn-Ni-Co ternary oxide (ZNCO) positive electrode and the AMC negative electrode, asymmetric supercapacitors (ASC) were assembled that deliver superior energy density (53.3 Wh kg(-1) at a power density of 1126.1 W kg(-1) for ASC-2 and 53.6 Wh kg(-1) at a power density of 1124.5 W kg(-1) for ASC-3) and excellent stability (82.7% and 83.4% specific capacitance
 retention for ZNCO//AMC ASC-2 and ZNCO//AMC ASC-3, respectively, after 5000 cycles). Through these two methods, low-cost, renewable, and environmentally friendly electrode materials can be provided for high energy density supercapacitors.
Considering the critical role of mitochondria in the life and death of cells, non-invasive long-term tracking of mitochondria has attracted considerable interest. However, a high-performance mitochondria-specific labeling probe with high photostability is still lacking. Herein a highly photostable hyperbranched polyglycerol (hPG)-based near-infrared (NIR) quantum dots (QDs) nanoplatform is reported for mitochondria-specific cell imaging. Comprising NIR Zn-Cu-In-S/ZnS QDs as extremely photostable fluorescent labels and alkyl chain (C12 )/triphenylphosphonium (TPP)-functionalized hPG derivatives as protective shell, the tailored QDs@hPG-C12 /TPP nanoprobe with a hydrodynamic diameter of about 65 nm exhibits NIR fluorescence, excellent biocompatibility, good stability, and mitochondria-targeted ability. Cell uptake experiments demonstrate that QDs@hPG-C12 /TPP displays a significantly enhanced uptake in HeLa cells compared to nontargeted QDs@hPG-C12 . Further co-localization study indicates that the probe selectively targets mitochondria. Importantly, compared with commercial deep-red mitochondria dyes, QDs@hPG-C12 /TPP possesses superior photostability under continuous laser irradiation, indicating great potential for long-term mitochondria labeling and tracking. Moreover, drug-loaded QDs@hPG-C12 /TPP display an enhanced tumor cell killing efficacy compared to nontargeted drugs. This work could open the door to the construction of organelle-targeted multifunctional nanoplatforms for precise diagnosis and high-efficient tumor therapy.
Whereas the stereochemical rigidity of the coordination sphere of boxmi/Cu(II) catalysts is key to achieving high enantioselectivity in the electrophilic alkylation of β-ketoesters, this pathway is outperformed by a radical process for the corresponding catalytic transformation of oxindoles, giving rise to racemic products. For the corresponding Zn(II) catalysts, the selectivity in the latter process is outstanding despite the greater plasticity of the coordination shell. This reaction was thus developed into a highly useful synthetic method, which enabled the conversion of wide range of substrates with high yields and enantioselectivities.
Current laboratory diagnosis of Buruli ulcer (BU) is based on microscopic detection of acid fast bacilli, quantitative real-time PCR (qPCR), histopathology or cultivation. Insertion sequence (IS) 2404 qPCR, the most sensitive method, is usually only available at reference laboratories. The only currently available point-of-care test, microscopic detection of acid fast bacilli (AFB), has limited sensitivity and specificity.
Here we analyzed AFB positive tissue samples (n = 83) for the presence, distribution and amount of AFB. AFB were nearly exclusively present in the subcutis with large extracellular clusters being most frequently (67%) found in plaque lesions. In ulcerative lesions small clusters and dispersed AFB were more common. Beside this, 151 swab samples from 37 BU patients were analyzed by IS2404 qPCR and ZN staining in parallel. The amount of M. ulcerans DNA in extracts from swabs correlated well with the probability of finding AFB in direct smear microscopy, with 56.1% of the samples being positive in both methods and 43.9% being positive only in qPCR. By analyzing three swabs per patient instead of one, the probability to have at least one positive swab increased from 80.2% to 97.1% for qPCR and from 45% to 66.1% for AFB smear examination.
Our data show that M. ulcerans bacteria are primarily located in the subcutis of BU lesions, making the retrieval of the deep subcutis mandatory for examination of tissue samples for AFB. When laboratory diagnosis is based on the recommended less invasive collection of swab samples, analysis of three swabs from different areas of ulcerative lesions instead of one increases the sensitivity of both qPCR and of smear microscopy substantially.
HIGHLIGHTS ASS234 is a MTDL compound containing a moiety from Donepezil and the propargyl group from the PF 9601N, a potent and selective MAO B inhibitor. This compound is the most advanced anti-Alzheimer agent for preclinical studies identified in our laboratory.Derived from ASS234 both multipotent donepezil-indolyl (MTDL-1) and donepezil-pyridyl hybrids (MTDL-2) were designed and evaluated as inhibitors of AChE/BuChE and both MAO isoforms. MTDL-2 showed more high affinity toward the four enzymes than MTDL-1.MTDL-3 and MTDL-4, were designed containing the N-benzylpiperidinium moiety from Donepezil, a metal- chelating 8-hydroxyquinoline group and linked to a N-propargyl core and they were pharmacologically evaluated.The presence of the cyano group in MTDL-3, enhanced binding to AChE, BuChE and MAO A. It showed antioxidant behavior and it was able to strongly complex Cu(II), Zn(II) and Fe(III).MTDL-4 showed higher affinity toward AChE, BuChE.MTDL-3 exhibited good brain penetration capacity (ADMET) and less toxicity than Donepezil. Memory deficits in scopolamine-lesioned animals were restored by MTDL-3.MTDL-3 particularly emerged as a ligand showing remarkable potential benefits for its use in AD therapy. Alzheimer's disease (AD), the most common form of adult onset dementia, is an age-related neurodegenerative disorder characterized by progressive memory loss, decline in language skills, and other cognitive impairments. Although its etiology is not completely known, several factors including deficits of acetylcholine, β-amyloid deposits, τ-protein phosphorylation, oxidative stress, and neuroinflammation are considered to play significant roles in the pathophysiology of this disease. For a long time, AD patients have been treated with acetylcholinesterase inhibitors such as donepezil (Aricept®) but with limited therapeutic success. This might be due to the complex multifactorial nature of AD, a fact that has prompted the design of new Multi-Target-Directed Ligands (MTDL) based on the "one molecule, multiple targets" paradigm. Thus, in this context, different series of novel multifunctional molecules with antioxidant, anti-amyloid, anti-inflammatory, and metal-chelating properties able to interact with multiple enzymes of therapeutic interest in AD pathology including acetylcholinesterase, butyrylcholinesterase, and monoamine oxidases A and B have been designed and assessed biologically. This review describes the multiple targets, the design rationale and an in-house MTDL library, bearing the N-benzylpiperidine motif present in donepezil, linked to different heterocyclic ring systems (indole, pyridine, or 8-hydroxyquinoline) with special emphasis on compound ASS234, an N-propargylindole derivative. The description of the in vitro biological properties of the compounds and discussion of the corresponding structure-activity-relationships allows us to highlight new issues for the identification of more efficient MTDL for use in AD therapy.
The ultra-low redox potential and zinc binding properties of the intracellular pool of mammalian metallothioneins (MT) suggest a role for MT in the transduction of redox signals into intracellular zinc signals. Increased expression of MT after exposure to heavy metals, oxidative stress, or inflammatory cytokines leads to an increased intracellular redox-mobilizable zinc pool that can affect downstream zinc-sensitive signaling pathways. CD4(+) T helper cells are poised to be influenced by MT transduced zinc signaling because they produce intracellular reactive oxygen species following activation through the T cell receptor and are sensitive to small changes in intracellular [Zn(2+)].
MT expression and intracellular [Zn(2+)] are both increased during primary activation and expansion of naïve CD4(+) T cells into the Tr1 phenotype in vitro. When Tr1 cells from wildtype mice are compared with congenic mice lacking functional Mt1 and Mt2 genes, the expression of intracellular MT is associated with a greater increase in intracellular [Zn(2+)] immediately following exposure to reactive oxygen species or upon restimulation through the T cell receptor. The release of Zn(2+) from MT is associated with a greater increase in p38 MAPK activation following restimulation and decreased p38 MAPK activation in MT knockout Tr1 cells can be rescued by increasing intracellular [Zn(2+)]. Additionally, IL-10 secretion is increased in MT knockout Tr1 cells compared with wildtype controls and this increase is prevented when the intracellular [Zn(2+)] is increased experimentally.
Differences in zinc signaling associated with MT expression appear to be a result of preferential oxidation of MT and concomitant release of Zn(2+). Although zinc is released from many proteins following oxidation, release is greater when the cell contains an intracellular pool of MT. By expressing MT in response to certain environmental conditions, CD4(+) T cells are able to more efficiently release intracellular zinc and regulate signaling pathways following stimulation. The link between MT expression and increased zinc signaling following activation represents an important immunomodulatory mechanism of MT and illuminates the complex role MT plays in shaping immune responses.
Although the use of catalytic rather than stoichiometric amounts of metal mediator in cross-coupling reactions between organic halides and organometallic counterparts improves significantly the atom economy and waste production, the use of solvents and stoichiometric generation of main-group byproducts (B, Sn and Zn) hamper the 'greenness' and industrial efficiency of these processes. Here we present a highly selective and green Pd-catalysed cross-coupling between organic halides
 and organolithium reagents proceeding without additional solvents and with short reaction times (10 min). This method bypasses a number of challenges previously encountered in Pd-catalysed cross-coupling with organolithium compounds such as strict exclusion of moisture, dilution and slow addition. Operational ease of this protocol combines the use of industrially viable catalysts loadings (down to 0.1 mol%), scalability of the process (tested up to 120 mmol) and exceptionally favourable environmental impact (E factors in several cases as low as 1).
Carbon tetrachloride (CCl4) is commonly used as a chemical inducer of experimental liver injury. In addition, many studies showed that CCl4 can induce kidney damage. In the current study, we evaluated the protective effect of zinc (Zn) against CCl4-induced nephrotoxicity. We hypothesized that this protective effect would result from the ability of Zn to serve as an inducer of metallothionein (MT), a known endogenous scavenger of free radicals. We administered Zn (as ZnSO4) 50 mg/kg subcutaneously once daily for 3 successive days prior to a single intraperitoneal administration of CCl4 4 g/kg in male ddY mice. Our results showed that Zn pretreatment significantly decreased creatinine and blood urea nitrogen levels and reduced renal histopathological damage at 6 h post-CCl4 injection, observations consistent with enhanced antioxidative activity in the kidney. Moreover, kidney MT levels in the Zn+CCl4-treated group decreased by greater than 70% compared with levels in the Zn-alone group, implying that MT was consumed by CCl4-induced radicals. These findings suggest that prophylaxis with Zn protects mice from CCl4-induced acute nephrotoxicity, presumably by induction of MT, which in turn scavenges radicals induced by CCl4 exposure.
Magdalena Bay is an important habitat for marine organisms, some of which have been the subject of metal bioaccumulation studies. Cannery waste is discharged into the bay providing a plausible source of contamination but this study finds that some metals occur geogenically. Bay sediments and rocks (n=59) were analyzed for total metals and clustered (HCA) into two distinct groups with PCA indicating concentrations of Cr, Cu, Mn, and Ni influenced samples near ophiolite outcrops, which reported some metal concentrations exceeding averages in the crust by an order of magnitude (up to 4450ppm Cr and 1269ppm Ni). Metals at the cannery are rarely elevated above crustal averages except Zn (max. 160ppm), however, acid-extracted Zn was below recommended sediment quality guidelines in contrast to 80% of ophiolitic samples reporting Ni extractability exceeding such guidelines. This study raises awareness of geogenic metals when considering sources of contamination in marine environments.
Nitrogen-doped zinc oxide (N: ZnO) films have been prepared by oxidizing reactive RF magnetron-sputtering zinc nitride (Zn-N) films. The effect of oxidation temperature and oxidation time on the growth, transmittance, and electrical properties of the film has been explored. The results show that both long oxidation time and high oxidation temperature can obtain the film with a good transmittance (over 80 % for visible and infrared light) and a high carrier concentration. The N: ZnO film exhibits a special growth model with the oxidation time and is first to form a N: ZnO particle on the surface, then to become a N: ZnO layer, and followed by the inside Zn-N segregating to the surface to oxidize N: ZnO. The surface particle oxidized more adequately than the inside. However, the X-ray photoemission spectroscopy results show that the lower N concentration results in the lower N substitution in the O lattice (No). This leads to the formation of n-type N: ZnO and the decrease of carrier concentration. Thus, this method can be used to tune the microstructure, optical transmittance, and electrical properties of the N: ZnO film.
Since many Zn complexes have been developed to enhance the insulin-like activity and increase the exposure and residence of Zn in the animal body, these complexes are recognized as one of the new candidates with action mechanism different from existing anti-diabetic drugs. However, the molecular mechanism by which Zn complexes exert an anti-DM effect is unknown. Therefore, we evaluated the activity of Zn complexes, especially related to the phosphorylation of insulin signaling pathway components. We focused on the insulin-like effects of the bis(hinokitiolato)zinc complex, [Zn(hkt)2], using 3T3-L1 adipocytes. [Zn(hkt)2] was taken up by cells and induced Akt phosphorylation in a time-dependent manner. Additionally, it showed inhibitory activity against PTP1B and PTEN, which are major negative regulators of insulin signaling. It did not promote the phosphorylation of IR (insulin receptor)-β or IRS (insulin receptor substrate)-1 by itself, but in combination with insulin, it enhanced the phosphorylation of IRβ. We conclude that [Zn(hkt)2] has effects on the proteins of insulin signaling pathway without insulin receptor mediation, and [Zn(hkt)2] promotes insulin function and shows the anti-DM effects. Thus, [Zn(hkt)2] may be the basis for improved DM treatments.
S100 proteins are a large family of calcium binding proteins present only in vertebrates. They function intra- and extracellularly both as regulators of homeostatic processes and as potent effectors during inflammation. Among these, S100A8 and S100A9 are two major constituents of neutrophils that can assemble into homodimers, heterodimers and higher oligomeric species, including fibrillary structures found in the ageing prostate. Each of these forms assumes specific functions and their formation is dependent on divalent cations, notably calcium and zinc. In particular, zinc appears as a major regulator of S100 protein function in a disease context. Despite this central role, no structural information on how zinc bind to S100A8/S100A9 and regulates their quaternary structure is yet available.
Here we report two crystallographic structures of calcium and zinc-loaded human S100A8. S100A8 binds two zinc ions per homodimer, through two symmetrical, all-His tetracoordination sites, revealing a classical His-Zn binding mode for the protein. Furthermore, the presence of a (Zn)2-cacodylate complex in our second crystal form induces ligand swapping within the canonical His4 zinc binding motif, thereby creating two new Zn-sites, one of which involves residues from symmetry-related molecules. Finally, we describe the calcium-induced S100A8 tetramer and reveal how zinc stabilizes this tetramer by tightening the dimer-dimer interface.
Our structures of Zn(2+)/Ca(2+)-bound hS100A8 demonstrate that S100A8 is a genuine His-Zn S100 protein. Furthermore, they show how zinc stabilizes S100A8 tetramerization and potentially mediates the formation of novel interdimer interactions. We propose that these zinc-mediated interactions may serve as a basis for the generation of larger oligomers in vivo.
Optimization of process parameters for phytase production by Enterobacter sp. ACSS led to a 4.6-fold improvement in submerged fermentation, which was enhanced further in fed-batch fermentation. The purified 62 kDa monomeric phytase was optimally active at pH 2.5 and 60 °C and retained activity over a wide range of temperature (40-80 °C) and pH (2.0-6.0) with a half-life of 11.3 min at 80 °C. The kinetic parameters K m, V max, K cat, and K cat/K m of the pure phytase were 0.21 mM, 131.58 nmol mg(-1) s(-1), 1.64 × 10(3) s(-1), and 7.81 × 10(6) M(-1) s(-1), respectively. The enzyme was fairly stable in the presence of pepsin under physiological conditions. It was stimulated by Ca(+2), Mg(+2) and Mn(+2), but inhibited by Zn(+2), Cu(+2), Fe(+2), Pb(+2), Ba(+2) and surfactants. The enzyme can be applied in dephytinizing animal feeds, and the baking industry.
Researches conducted worldwide indicate a frequent deficiency in mineral matters. Due to the increased need during the period of accelerated growth and development, children belong to the group that is exposed to the highest risk of mineral matter deficiency. Our objectives were to determine the iron, zinc, copper, manganese, and calcium intake in the collective diet of the preschool population in the in the northwestern region of Bosnia- in the Republic of Srpska and to estimate the adequacy of the application of the international food composition tables for nutrition planning relating to mineral matters. Samples of food intended for children's diet were collected in the preschool institution "Radost" (a kindergarten), in the city of Prijedor. In daily portions, Fe, Zn, Cu, Mn, and Ca contents were determined by flame atomic absorption spectrophotometry. Contents of mineral matters in daily meals were also calculated by the food composition tables. An average daily meal contained 2.86 mg of Fe, 1.71 mg of Zn, 0.19 mg of Cu, 0.21 mg of Mn, and 83.5 mg of Ca. With calculation method, contents of all minerals are significantly higher than the experimental data for all used food composition tables. The obtained results indicate a significant deficiency in mineral matters in the collective diet of the preschool population in the Republic of Srpska, a certain non-compliance with the applicable recommendations, and also suggest a need to create food composition tables for food being consumed in our region.
At childbirth (parturition), zinc (Zn) homeostasis in cord blood (CB) can be affected by a number of factors: Zn in maternal blood, parturition related stress as well as metallothionein (MT). Both Zn and stress are known inducers of MT which is primarily involved in Zn homeostasis. This study analyzed Zn concentration [Zn], in CB components and MT-2A transcription in CB mononuclear cells (MNC) in relation to primiparous and multiparous childbirth. [Zn] in CB (n = 47) plasma, erythrocytes,
 and MNCs were measured by atomic absorption spectrophotometry (λ = 213.9 nm). The MT-2A transcription in CB-MNC was quantified using real-time PCR. Significant correlations (Pearson r) were found between: plasma-[Zn] and erythrocyte-[Zn] (p = 0.002); [Zn] and MT-2A messenger RNA (mRNA) (p = 0.000) in CB-MNC. Student's t tests showed higher levels of MT-2A mRNA and MNC-[Zn] in CB of older (≥25 years) compared to younger mothers (≤24 years) (p = 0.043 and p = 0.016, respectively). Significantly higher [Zn] was found in CB plasma (p = 0.017) and MNC (p = 0.041) of older primiparous compared to the younger primiparous and older multiparous mothers respectively. MT-2A mRNA in CB-MNC was significantly lower in CB of younger primiparous mothers compared to their older counterparts (p = 0.001). Path analysis showed that MNC-[Zn] (β = 0.83; p = 0.000) had a greater influence on MT-2A mRNA expression, compared to parity (β = -0.14; p = 0.033). Higher [Zn] in CB of primiparous mothers could be linked to higher stress during parturition, however, might be beneficial for the growth and development of the child. Together MNC-[Zn] and parity contributed ~70 % of the MT-2A transcription in CB-MNC.
Fourteen aquatic organism samples were collected from Bohai Bay, and concentrations of five heavy metals were measured to evaluate the pollution levels in aquatic organisms and the potential risk to human health. The concentrations of Zn and Cu were much higher than those of Cd, Cr, and Pb in all the organisms. In general, the heavy metal concentration levels were in the order phytoplankton < zooplankton < fish < shrimp < shellfish. Heavy metal concentrations in higher trophic-level aquatic organisms in Bohai Bay were compared to those in the organisms from other worldwide coastal waters. The concentration levels of most heavy metals were higher than the 75th percentile, except that Pb concentration was between the 25th and 50th percentiles. The calculated bioconcentration factors (BCF) of Cr, Cu, and Pb for phytoplankton were less than 100, indicating no accumulation in primary producers. The bioaccumulation factor (BAF) of Pb for zooplankton was the highest, indicating significant Pb accumulation in zooplankton. For higher trophic-level aquatic organisms, the order of BAF values was fish < shrimp < shellfish for most metals except for Pb. The human health risk assessment suggests that strict abatement measures of heavy metals must be taken to decrease the health risk caused by consuming aquatic products.
While a variety of template-based strategies have been developed in the fabrication of nanowires (NWs), a uniform pore filling across the template still poses a major challenge. Here, we present a large area controlled pore filling strategy in the reproducible fabrication of various magnetic and metallic NW arrays, embedded inside anodic aluminum oxide templates. Using a diffusive pulsed electrodeposition (DPED) technique, this versatile strategy relies on the optimized filling of branched nanopores at the bottom of templates with Cu. Serving the Cu filled nanopores as appropriate nucleation sites, the DPED is followed by a uniform and homogeneous deposition of magnetic (Ni and Fe) and metallic (Cu and Zn) NWs at a current density of 50 mA cm(-2) for an optimal thickness of alumina barrier layer (∼18 nm). Our strategy provides large area uniformity (exceeding 400 μm(2)) in the fabrication of 16 μm long free-standing NW arrays. Using hysteresis loop measurements and scanning electron microscopy images, the electrodeposition efficiency (EE) and pore filling percentage (F p) are evaluated, leading to maximum EE and F p values of 91% and 95% for Ni and Zn, respectively. Moreover, the resulting NW arrays are found to be highly crystalline. Accordingly, the DPED technique is capable of cheaply and efficiently controlling NW growth over a large area, providing a tool for various nanoscale applications including biomedical devices, electronics, photonics, magnetic storage medium and nanomagnet computing.
A series of custom-designed, high yield, isoskeletal tetranuclear Zn/4f coordination clusters showing high efficiency as catalysts with low catalytic loadings in Friedel-Crafts alkylation are described for the first time. The possibility of altering the 4f centers in these catalysts without altering the core topology allows us to further confirm their stability via EPR and NMR, as well to gain insights into the plausible reaction mechanism, showcasing the usefulness of these bimetallic systems as catalysts.
Bioabsorbable metal zinc (Zn) is a promising new generation of implantable scaffold for cardiovascular and orthopedic applications. In cardiovascular stent applications, zinc ion (Zn(2+)) will be gradually released into the surrounding vascular tissues from such Zn-containing scaffolds after implantation. However, the interactions between vascular cells and Zn(2+) are still largely unknown. We explored the short-term effects of extracellular Zn(2+) on human smooth muscle cells (SMCs) up to 24 h, and an interesting biphasic effect of Zn(2+) was observed. Lower concentrations (<80 μM) of Zn(2+) had no adverse effects on cell viability but promoted cell adhesion, cell spreading, cell proliferation, cell migration, and enhanced the expression of F-actin and vinculin. Cells treated with such lower concentrations of Zn(2+) displayed an elongated shape compared to controls without any treatment. In contrast, cells treated with higher Zn(2+) concentrations (80-120 μM) had opposite cellular responses and behaviors. Gene expression profiles revealed that the most affected functional genes were related to angiogenesis, inflammation, cell adhesion, vessel tone, and platelet aggregation. Results indicated that Zn has interesting concentration-dependent biphasic effects on SMCs with low concentrations being beneficial to cellular functions.
Prepared Ghanaian traditional foods, mostly consist of starchy staples such as yams (Dioscorea spp.), cassava (Manihot esculenta), millet (Pennisetum glaucum), maize (Zea mays) and rice (Oryza sativa) etc. These traditional foods are a main source of energy and macronutrients. Little or no information however exist on the mineral and phytate contents of prepared traditional Ghanaian foods. The mineral and phytate contents of twenty commonly eaten Ghanaian foods, prepared using popular recipes were analysed for their Fe, Cu, Zn, Mg, Mn, Ca, Na and K as well as phytate contents after foods were dried. Sodium was high in most of the foods, ranging from 557 mg/100 g for Akple with okro soup, to 193.7 for Kooko and bread. Boiled cowpeas with fried plantain was found to contain the highest amount of potassium (409.0 mg/100 g) followed by konkonte with groundnut soup (384.7 mg/100 g). Kooko with bread recorded the lowest potassium content of 131.72 mg/100 g. Konkonte with palm-nut soup and also with groundnut soup were among the foods found to contain high amounts of iron (14.1 mg/100 g and 13.2 mg/100 g respectively). All the foods were very good sources of minerals and will significantly contribute to the mineral intakes of consumers; however, their sodium contents were of concern.
In this review, we provide a broad overview of solution-phase synthesis of transition metal oxide nanocrystals (NCs), including a substantial catalog of published methods, and a unifying classification and discussion. Prevalent subcategories of solution-phase synthesis are delineated and general features are summarized. The diverse morphologies achievable by solution-phase synthesis are defined and exemplified. This is followed by sequential consideration of the solution-phase synthesis of first-row transition metal oxides. The common oxides of Ti, V, Mn, Fe, Co, Ni, Cu, and Zn are introduced; major crystal lattices are presented and illustrated; representative examples are explained; and numerous synthesis formulae are tabulated. Following this presentation of experimental studies, we present an introduction to theories of NC nucleation and growth. Various models of NC nucleation and growth are addressed, and important concepts determining the growth and structure of colloidal NCs are explained. Overall, this review provides an entry into systematic understanding of solution-phase synthesis of nanocrystals, with a reasonably comprehensive survey of results for the important category of transition metal oxide NCs.
A facile strategy has been developed to synthesize double-shelled Zn(OH)2 nanoflowers (DNFs) at room temperature. The nanoflowers were generated via conversion of Cu2 O nanoparticles (NPs) using ZnCl2 and Na2 S2 O3 by a simple process. Outward diffusion of the Cu(2+) , produced by an oxidation process on the surface of NPs, and the inward diffusion of Zn(2+) by coordination and migration, eventually lead to a hollow cavity in the inner NPs with a double-shelled 3D hollow flower shapes. The thickness of the inner and outer shells is estimated to be about 20 nm, and the thickness of nanopetals is about 7 nm. The nanoflowers have large surface areas and excellent adsorption properties. As a proof of potential applications, the DNFs exhibited an excellent ability to remove organic molecules from aqueous solutions.
The growing importance of urban allotments in planning and managing urban areas is due to the combined positive effects on ecosystem services, the economy and human well-being, especially of groups of the urban population that can be vulnerable (e.g. the elderly, immigrants, low-income families). Some studies have highlighted the potential risk of contamination by metals of vegetables grown in urban areas and the lack of appropriate site-specific risk assessments. However, surveys are still lacking on the possibilities of using urban soil as a good substrate to produce vegetables for home consumption. We assessed the soil quality
 in two areas in Pisa (Italy), one intended for urban horticulture and the other already cultivated for that purpose. We analysed the soils for the main chemical and physical characteristics (texture, bulk density, water stability index, pH, cation exchange capacity, organic carbon, total nitrogen, phosphorous) and elements (Pb, Cu, Ni, Cr, Zn, Cd, As, K, Al and Mn). Our results showed that both areas had physical and chemical heterogeneity due to the effects of urbanization and to the different cultivation techniques employed. The metal content was lower than the guidelines limits, and the soil conditions (pH = 8) greatly reduced the metal mobility. Copper concentration in some of the cultivated area samples was higher than the limits, representing a possible stress factor for the microbial biodiversity and fauna. Our findings demonstrate that site-specific surveys are necessary before planning urban cultivation areas, and educating urban gardeners regarding sustainable cultivation techniques is a priority for a safe environment.
Micro- and nano-rods and plates of two 3D, porous Zn(II)-based metal-organic frameworks [Zn(oba)(4-bpdh)0.5]n·(DMF)1.5 (TMU-5) and [Zn(oba)(4-bpmb)0.5]n (DMF)1.5 (TMU-6) were prepared by sonochemical process and characterized by scanning electron microscopy, X-ray powder diffraction and IR spectroscopy. These MOFs were synthesized using a non-linear dicarboxylate (H2oba=4,4-oxybisbenzoic acid) and two linear N-donor (4-bpdh=2,5-bis(4-pyridyl)-3,4-diaza-2,4-hexadiene and 4-bpmb=N(1),N(4)-bis((pyridin-4-yl)methylene)benzene-1,4-diamine) ligands by ultrasonic irradiation. Sonication time and concentration of initial reagents influencing size and morphology of nano-structured MOFs, were also studied. Calcination of TMU-5 and TMU-6 at 550°C under air atmosphere yields ZnO nanoparticles. TMU-5 and TMU-6 exhibited maximum percent adsorption of 96.2% and 92.8% of 100ppm rhodamine B dye, respectively, which obeys first order reaction kinetics.
Filamentous fungi are attractive hosts for heterologous protein expression due to their capacity to secrete large amounts of enzymes into the extracellular medium. Xyloglucanases, which specifically hydrolyze xyloglucan, have been recently applied in lignocellulosic biomass degradation and conversion in many other industrial processes. In this context, this work aimed to clone, express, and determine the functional properties of a recombinant xyloglucanase (AtXEG12) from Aspergillus terreus, and also its solid-state (SSF) and submerged (SmF) fermentation in bioreactors. The purified AtXEG12 showed optimum pH and temperature of 5.5 and 65 °C, respectively, demonstrating to be 90 % stable after 24 h of incubation at 50 °C. AtXEG12 activity increased in the presence of 2-mercaptoethanol (65 %) and Zn(+2) (45 %), while Cu(+2) and Ag(+) ions drastically decreased its activity. A substrate assay showed, for the first time for this enzyme's family, xylanase activity. The enzyme exhibited high specificity for tamarind xyloglucan (K M 1.2 mg mL(-1)) and V max of 17.4 μmol min(-1) mg(-1) of protein. The capillary zone electrophoresis analysis revealed that AtXEG12 is an endo-xyloglucanase. The heterologous xyloglucanase secretion was greater than the production by wild-type A. terreus cultivated in SmF. On the other hand, AtXEG12 activity reached by SSF was sevenfold higher than values achieved by SmF, showing that the expression of recombinant enzymes can be significantly improved by cultivation under SSF.
Antioxidants essential trace elements (TEs), selenium (Se), zinc (Zn) and copper (Cu) are key dietary components and their supplementation in parenteral nutrition (PN) is recommended. However, the frequency of marginal deficiencies and related clinical outcomes remain poorly known in patients receiving long-term PN.
We conducted a retrospective observational study whose aim was to determine in a cohort of patients (n = 73) with chronic intestinal failure (CIF) enrolled in a tertiary home PN center and receiving long-term PN with systematic multi-TE supplementation, the prevalence of low serum TEs levels. The goal was also to assess mid-term incidence of serious infection and its associated factors.
Among the 73 studied patients, 21.9%, 13.9% and 21.1% had low serum Se (<0.9 μmol/l), Cu (<12.7 μmol/l) and Zn (<12.5 μmol/l) levels, respectively. There was no difference between short bowel syndrome (SBS) and non-SBS patients. 30 patients had at least one of the three serum TEs levels under the cut-off values of deficiency. No specific disease and/or underlying intestinal anatomy were associated with low serum TEs concentration. Cumulative incidence rates of serious infection were 11.1% 95CI[5.7-21.0] and 19.5% 95CI[12.0-30.7] at 6 months and 1 year, respectively. Central venous catheter-related bloodstream infection was the most common infection. Low serum Se was independently associated with a higher risk to develop serious infection (HR 2.65 95CI[1.01-6.97]).
Low serum TEs concentration is a frequent condition in patients with CIF even with systematic multi-TE supplementations. Se deficiency exposes to a greater risk of serious infection. This suggests that frequent TEs dosage in this population as well as individually tailored supplementation may be beneficial.
Ejaculation is a synchronized cascade of events that has the ultimate goal of activating sperm and enabling them to reach an egg for fertilization. The seminal plasma contains a complex mixture of fluids that is secreted from the testes, epididymis and male accessory glands. The prostate gland has a pivotal role in this process, as prostatic fluid enriched in Zn(2+), citrate and kallikreins is crucial for the molecular synchronization of the functional cascade triggered by ejaculatory stimuli. The prostate is the target of a number of common diseases that can affect male fertility at different ages. In both young and aged men, prostatic diseases or an unhealthy prostate can affect spermatozoa functioning and, therefore, male fertility. Consideration of prostate physiology emphasizes a number of points: the central role of Zn(2+) and citrate in the regulation of prostate epithelium homeostasis and in ejaculation; the influence of bacteria-related prostatic inflammation on male fertility; and the potential role of prostatic inflammation in promoting the development of prostatic hyperplastic growth and carcinogenesis.
An analysis of wastewater samples collected from different industrial regions of Egypt demonstrated dangerously high levels of nickel (0.27-31.50mgL(-1)), chromium (1.50-7.41mgL(-1)) and zinc (1.91-9.74mgL(-1)) in the effluents. Alarmingly, these heavy metals are among the most toxic knownones to humans and wildlife. Sixty-nine Actinomycete isolates derived from contaminated sites were evaluated under single, binary, and ternary systems for their biosorption capacity for Ni(2+), Cr(6+) and Zn(2+) from aqueous solutions. The results of the study identified isolates MORSY1948 and MORSY2014 as the most active biosorbents. Phenotypic and chemotypic characterization along with molecular phylogenetic evidence confirmed that the two strains are members of the Nocardiopsis and Nocardia genera, respectively. The results also proved that for both the strains, heavy metal reduction was more efficient with dead rather than live biomass. The affinity of the dead biomass of MORSY1948 strain for Ni(2+), Cr(6+) and Zn(2+) under the optimized pH conditions of 7, 8 and 7, respectively at 40°C temperature with 0.3% biosorbent dosage was found to be as follows: Ni(2+) (87.90%)>Zn(2+) (84.15%)>Cr(6+) (63.75%). However, the dead biomass of MORSY2014 strain under conditions of pH 8 and 50°C temperature with 0.3% biosorbent dose exhibited the highest affinity which was as follows: Cr(6+) (95.22%)>Ni(2+) (93.53%)>Zn(2+) (90.37%). All heavy metals under study were found to be removed from aqueous solutions in entirety when the sorbent dosage was increased to 0.4%.
The ionic liquid trihexyl(tetradecyl)phosphonium thiocyanate has been used for the extraction of the transition metal ions Co(ii), Ni(ii), Zn(ii), and the rare-earth ions La(iii), Sm(iii) and Eu(iii) from aqueous solutions containing nitrate or chloride salts. The transition metal ions showed a high affinity for the ionic liquid phase and were efficiently extracted, while the extraction efficiency of the rare-earth ions was low. This difference in extraction behavior enabled separation of the pairs Co(ii)/Sm(iii), Ni(ii)/La(iii) and Zn(ii)/Eu(iii). These separations are relevant for the recycling of rare earths and transition metals from samarium cobalt permanent magnets, nickel metal hydride batteries and lamp phosphors, respectively. The extraction of metal ions from a chloride or nitrate solution with a thiocyanate ionic liquid is an example of "split-anion extraction", where different anions are present in the aqueous and ionic liquid phase. Close to 100% loading was possible for Co(ii) and Zn(ii) up to a concentration of 40 g L(-1) of the transition metal salt in the initial aqueous feed solution, whereas the extraction efficiency for Ni(ii) gradually decreased with increase in the initial feed concentration. Stripping of Co(ii), Zn(ii) and Ni(ii) from the loaded ionic liquid phase was possible by a 15 wt% NH3 solution. The ionic liquid could reused after extraction and stripping.
The peripartum (or transition) period is the most-critical phase in the productive life of lactating dairy cows and optimal supply of trace minerals through more bioavailable forms could minimize the negative effects associated with this phase. Twenty Holstein cows received a common prepartal diet and postpartal diet. Both diets were partially supplemented with an inorganic (INO) mix of Zn, Mn, and Cu to supply 35, 45, and 6 ppm, respectively, of the diet dry matter (DM). Cows were
 assigned to treatments in a randomized completed block design, receiving an daily oral bolus with INO or organic trace minerals (AAC) Zn, Mn, Cu, and Co to achieve 75, 65, 11, and 1 ppm supplemental, respectively, in the diet DM. Liver tissue and blood samples were collected throughout the experiment. The lower glutamic-oxaloacetic transaminase concentration after 15 days in milk in AAC cows indicate lower hepatic cell damage. The concentration of cholesterol and albumin increased, while IL-6 decreased over time in AAC cows compared with INO indicating a lower degree of inflammation and better liver function. Although the acute-phase protein ceruloplasmin tended to be lower in AAC cows and corresponded with the reduction in the inflammatory status, the tendency for greater serum amyloid A concentration in AAC indicated an inconsistent response on acute-phase proteins. Oxygen radical absorbance capacity increased over time in AAC cows. Furthermore, the concentrations of nitric oxide, nitrite, nitrate, and the ferric reducing ability of plasma decreased with AAC indicating a lower oxidative stress status. The expression of IL10 and ALB in liver tissue was greater overall in AAC cows reinforcing the anti-inflammatory response detected in plasma. The greater overall expression of PCK1 in AAC cows indicated a greater gluconeogenic capacity, and partly explained the greater milk production response over time. Overall, feeding organic trace minerals as complexed with amino acids during the transition period improved liver function and decreased inflammation and oxidative stress.
In the last few decades use of metal-based nanoparticles (MNPs) has been increased significantly that eventually contaminating agricultural land and limiting crop production worldwide. Moreover, contamination of food chain with MNPs has appeared as a matter of public concern due to risk of potential health hazard. Brassinosteroid has been shown to play a critical role in alleviating heavy metal stress; however, its function in relieving zinc oxide nanoparticles (ZnO NPs)-induced phytotoxicity remains unknown. In this study, we investigated the potential role of 24-epibrassinolide (BR) in mitigating ZnO NPs-induced toxicity in tomato seedlings. Seedling growth, biomass production, and root activity gradually decreased, but Zn accumulation increased with increasing ZnO NPs concentration (10-100 mg/L) in growth media (½ MS). The augmentation of BR (5 nM) in media significantly ameliorated 50 mg/L ZnO NPs-induced growth inhibition. Visualization of hydrogen peroxide (H2O2), and quantification of H2O2 and malondialdehyde (MDA) in tomato roots confirmed that ZnO NPs induced an oxidative stress. However, combined treatment with BR and ZnO NPs remarkably reduced concentration of H2O2 and MDA as compared with ZnO NPs only treatment, indicating that BR supplementation substantially reduced oxidative stress. Furthermore, the activities of key antioxidant enzymes such as superoxide dismutase (SOD), catalase, ascorbate peroxidase and glutathione reductase were increased by combined treatment of BR and ZnO NPs compared with ZnO NPs only treatment. BR also increased reduced glutathione (GSH), but decreased oxidized glutathione (GSSG)] and thus improved cellular redox homeostasis by increasing GSH:GSSG ratio. The changes in relative transcript abundance of corresponding antioxidant genes such as Cu/Zn SOD, CAT1, GSH1, and GR1 were in accordance with the changes in those antioxidants under different treatments. More importantly, combined application of BR and ZnO NPs significantly decreased Zn content in both shoot and root of tomato seedlings as compared with ZnO NPs alone. Taken together, this study, for the first time, showed that BR could not only improve plant tolerance to ZnO NPs but also reduce the excess zinc content in tomato seedlings. Such a finding may have potential implication in safe vegetable production in the MNPs-polluted areas.
The etiology of amyotrophic lateral sclerosis (ALS), a fatal motor neuron disorder characterized by progressive muscle weakness and spasticity, remains largely unknown. Approximately 5-10% of cases are familial, and of those, 15-20% are associated with mutations in the gene encoding Cu/Zn superoxide dismutase (SOD1). Mutations of the SOD1 gene interrupt cellular homeostasis and contribute to cellular toxicity evoked by the presence of altered SOD1, along with other toxic species, such as advanced glycation end products (AGEs). AGEs trigger activation of their chief cell surface receptor, RAGE (receptor for advanced glycation end products), and induce RAGE-dependent cellular stress and inflammation in neurons, thereby affecting their function and leading to apoptosis. Here, we show for the first time that the expression of RAGE is higher in the SOD1 transgenic mouse model of ALS vs. wild-type mouse spinal cord. We tested whether pharmacological blockade of RAGE may delay the onset and progression of disease in this mouse model. Our findings reveal that treatment of SOD1 transgenic mice with soluble RAGE (sRAGE), a natural competitor of RAGE that sequesters RAGE ligands and blocks their interaction with cell surface RAGE, significantly delays the progression of ALS and prolongs life span compared to vehicle treatment. We demonstrate that in sRAGE-treated SOD1 transgenic animals at the final stage of the disease, a significantly higher number of neurons and lower number of astrocytes is detectable in the spinal cord. We conclude that RAGE antagonism may provide a novel therapeutic strategy for ALS intervention.
Miro homologues are small mitochondrial Rho GTPases belonging to the Ras superfamily across organisms and are generally unexplored in filamentous fungi. Here we identified a Miro orthologue (bMiro) in Beauveria bassiana, a filamentous fungal insect pathogen as a classic biological control agent of insect pests. This orthologue was proven to anchor on mitochondrial outer membrane in a manner depending completely upon a short C-terminal transmembrane domain. As a result of bmiro deletion, mitochondria in hyphal cells were largely aggregated, and their mass and mobility were reduced, accompanied with a remarkable decrease in ATP content but little change in mitochondrial morphology. The deletion mutant became 42%, 37%, 19% and 10% more tolerant to Ca(2+), Mn(2+), Zn(2+) and Mg(2+) than wild-type, respectively, during cultivation in a minimal medium under normal conditions. The deletion mutant also showed mild defects in conidial germination, vegetative growth, thermotolerance, UV-B resistance and virulence despite null response to oxidative and osmotic stresses. All these phenotypic changes were restored by targeted gene complementation. Our results indicate that bMiro can control mitochondrial distribution and movement required for the transport of ATP-form energy and metal ions and contributes significantly to the fungal potential against insect pests through the control.
Mutations in Cu/Zn-superoxide dismutase (SOD1) cause familial amyotrophic lateral sclerosis (ALS). Previous papers showed that mutant SOD1 accumulates and undergoes misfolding in motor neurons and that the specific interaction of mutant SOD1 with derlin-1 leads to endoplasmic reticulum (ER) stress and activation of the unfolded protein response (UPR). Because evidence shows that mutant SOD1 expression also damages sensory neurons, we hypothesized that, similarly to motor neurons, the sensory neurons of ALS mouse model SOD1(G93A) accumulate mutant/misfolded SOD1 and suffer from ER stress and UPR activation. Our results reveal that SOD1(G93A) sensory neurons accumulate mutant/misfolded SOD1 but, surprisingly, do not suffer from ER stress and UPR activation. Moreover, the sensory neurons do not express detectable levels of the SOD1 interactor derlin-1. These results suggest a potential molecular mechanism underlying the differential vulnerability of motor and sensory neurons to mutant SOD1 toxicity.
Four novel mononuclear complexes, [Cd(L)2·2H2O] (1), [Ni(L)2·2H2O] (2) [Cu(L)2·H2O] (3), and [Zn(L)2·2H2O] (4) (CCDC numbers: 1444630-1444633 for complexes 1-4) (HL=4-(2,3-dichlorophenyl)piperazine-1-carboxylic acid) were synthesized, and have been characterized by IR spectroscopy, elemental analysis, and X-ray crystallography. Molecular docking study preliminarily revealed that complex 1 had potential telomerase inhibitory activity. In accordance with the result of calculation, in vitro tests of the inhibitory activities of complex 1 against telomerase showed complex 1 (IC50=8.17±0.91μM) had better inhibitory activities, while complexes 2, 3 and 4 showed no inhibitory activities. Antiproliferative activity in human cancer cell line HepG2 was further determined by MTT assays. The IC50 value (6.5±0.2μM) for the complex 1 having good inhibitory activity against HepG2 was at the same micromolar concentrations with cis-platinum (2.2±1.2μM). While the IC50 value for the metal-free ligand, complex 2, 3 and 4 was more than 100μM. These results indicated that telomerase was potentially an anticancer drug target and showed that complex 1 was a potent inhibitor of human telomerase as well as an antiproliferative compound.
The possibility of developing new advanced optical limiters of laser radiation at 532 nm with low limiting thresholds has been demonstrated on thermally stable phthalocyanine J-type dimeric complexes of Mg, Zn, Cu, Ni, and Co. A new "threshold" model based on radiative transfer phenomena in nonlinear optical media was suggested for the exact definition of nonlinear absorption coefficient β and optical limiting threshold Ic. This model allows the determination of the optical characteristics of the limiter in the same active material with layers of different thicknesses, as well as the use of different parameters of laser radiation, such as cross-sectional
 spatial profiles of the laser beam and shapes of the laser pulse over time. The maximum value of the nonlinear absorption coefficient (β = 360 cm GW(-1)) and the lowest limiting threshold (Ic = 0.03 J cm(-2)) were estimated for a J-type zinc phthalocyanine dimer.
Self-assembled colorimetric sensors have been prepared from Zn(II)-DPA-attached phenylboronic acid (·Zn) and catechol-type dyes. The ·Zn-dye sensors display selectivity towards oligophosphate over monophosphates. The colorimetric sensor assay (·Zn-dye) is utilized to monitor a model of a metabolic reaction where ATP is hydrolyzed to pyrophosphate (PPi) and AMP.
The co-ordination chemistry of a tristhiourea tris(2-pyridylmethyl)amine ligand () with a series of transition metal ions has been investigated. Crystallographic data show that large metal ions, with no geometrical preferences, such as Mn(ii) and Cd(ii), will form seven co-ordinate monocapped octahedral complexes, while smaller metal ions such as Zn(ii) favour five co-ordinate trigonal bipyramidal structures. In a similar manner to the related bisthiourea complexes, the Ni(ii) complex shows a strong preference for octahedral geometries resulting in the ligand binding asymmetrically. Spectroscopic (IR and NMR), spectrometric (MS) as well as electrochemical data for these complexes are reported.
In the present study, an investigation of the mineralogy and morphology, the heavy metal content and the health risk of urban road dusts from the second largest city of Greece was conducted. For this reason road dust samples from selected sites within the city core area were collected. No differences were observed in the mineralogy of road dusts coming from different sampling sites, and they were mainly consisted of quartz and calcite, while an elevated amorphous content was detected. Morphologically road dusts presented Ca-rich, Fe-rich and silicates particles with various shapes and sizes. The mean concentrations of Cd, Cr, Cu, Mn, Ni, Pb and Zn in road dust were 1.76, 104.9, 662.3, 336.4, 89.43, 209 and 452.8 μg g(-1), respectively. A series of spatial distribution patterns revealed that the hotspot areas were tended to associate with major road junctions and regions with high traffic. Combination of pollution indexes and statistical analyses (correlation analysis, cluster analysis and principal component analysis) revealed that road dusts have a severe influence by anthropogenic activities. In attempt to identify the source of metals through geostatistical and multivariate statistical analyses, it was concluded as follows: Cr, Cu, Fe and Zn mainly originated from tire/break wear and vehicle abrasions, while Cd, Mn and Pb were mainly related to fuel/oil leakage from automobiles along with oil lubricants and vehicle abrasion. Hazard quotient values for children based on total metal concentrations for the road dust ingestion route were lower than safe level (=1). However, the fact that the Hazard Index value for Pb (0.459) which is a particularly toxic metal, was close to safe level, renders essential further investigation in order to provide more reliable characterizations of potential health risks.
Secondary phases zinc sulfide/selenide and copper sulfide in Cu2ZnSnS4 (CZTS) and Cu2ZnSnSe4 (CZTSe) thin film samples are investigated by X-ray absorption near edge structure (XANES) analysis at the chalcogen K-edges. Because of the formation of secondary phases the composition of the kesterite phase can deviate significantly from the total sample composition. For a large set of non-stoichiometric samples we find that the cation ratios of the kesterite phase never exceed Zn/Sn = 1 even for Zn-rich CZTS and CZTSe, with all excess Zn being contained in secondary phases. For CZTS the cation ratios are found to be additionally constrained by Cu/Sn ≤ 2, which means that Cu-excess always leads to the formation of CuxS secondary phases. These results give clear bounds on the Cu-rich and Zn-rich sides of the single phase region in polycrystalline CZTS/Se thin films.
Studies about the mobilization of potentially toxic elements (PTEs) in deltaic soils can be challenging, provide critical information on assessing the potential risk and fate of these elements and for sustainable management of these soils. The impact of redox potential (EH), pH, iron (Fe), manganese (Mn), sulfate (SO4(2-)), chloride (Cl(-)), aliphatic dissolved organic carbon (DOC), and aromatic dissolved organic carbon (DAC) on the mobilization of copper (Cu), selenium (Se), and zinc (Zn) was studied in two soils collected from the Nile and Mississippi Rivers deltaic plains focused on increasing our understanding of the fate of these toxic elements. Soils were exposed to a range of redox conditions stepwise from reducing to oxidizing soil conditions using an automated biogeochemical microcosm apparatus. Concentrations of DOC and Fe were high under reducing conditions as compared to oxidizing conditions in both soils. The proportion of DAC in relation to DOC in solution (aromaticity) was high in the Nile Delta soil (NDS) and low in the Mississippi Delta soil (MDS) under oxidizing conditions. Mobilization of Cu was low under reducing conditions in both soils which was likely caused by sulfide precipitation and as a result of reduction of Cu(2+) to Cu(1+). Mobilization of Se was high under low EH in both soils. Release of Se was positively correlated with DOC, Fe, Mn, and SO4(2-) in the NDS, and with Fe in the MDS. Mobilization of Zn showed negative correlations with EH and pH in the NDS while these correlations were non-significant in the MDS. The release dynamics of dissolved Zn could be governed mainly by the chemistry of Fe and Mn in the NDS and by the chemistry of Mn in the MDS. Our findings suggest that a release of Se and Zn occurs under anaerobic conditions, while aerobic conditions favor the release of Cu in both soils. In conclusion, the release of Cu, Se, and Zn under different reducing and oxidizing conditions in deltaic wetland soils should be taken into account due to increased mobilization and the potential environmental risks associated with food security in utilizing these soils for flooded agricultural and fisheries systems.
Iron (Fe) is an essential micronutrient for humans. Fe deficiency disease is widespread and has led to extensive studies on the mechanisms of Fe uptake and storage, especially in staple food crops such as rice. However, studies of functionally related genes in rice and other crops are often time and space demanding. Here, we demonstrate that transgenic Arabidopsis suspension culture cells and Arabidopsis plants can be used as an efficient expression system for gain-of-function study of selected transporters, using Fe transporters as a proof-of-principle. The vacuolar membrane transporters OsVIT1 and OsVIT2 have been described to be important for iron sequestration, and disruption of these two genes leads to Fe accumulation in rice seeds. In this study, we have taken advantage of the fluorescent-tagged protein GFP-OsVIT1, which functionally complements the Fe hypersensitivity of ccc1 yeast mutant, to generate transgenic Arabidopsis suspension cell lines and plants. GFP-OsVIT1 was shown to localize on the vacuolar membrane using confocal microscopy and immunogold EM. More importantly, the Fe concentration, as well as the concentration of Zn, in the transgenic cell lines and plants were significantly increased compared to that in the WT. Taken together, our study shows that the heterologous expression of rice vacuolar membrane transporter OsVIT1 in Arabidopsis system is functional and effectively enhances iron accumulation, indicating an useful approach for studying other putative transporters of crop plants in this system.
Deep ocean water (DOW) obtained from a depth of more than 200 m includes abundant nutrients and minerals. DOW was proven to positively increase monascin (MS) and ankaflavin (AK) production and the anti-adipogenesis effect of Monascus-fermented red mold dioscorea (RMD). However, the influences that the major metals in DOW have on Monascus secondary metabolite biosynthesis and anti-adipogenesis remain unknown. Therefore, the major metals in DOW were used as the culture water to produce RMD. The secondary metabolites production and anti-adipogenesis effect of RMD cultured with various individual metal waters were investigated. In the results, the addition of water with Mg, Ca, Zn, and Fe increased MS and AK production and inhibited mycotoxin citrinin (CT). However, the positive influence may be contributed to the regulation of pigment biosynthesis. Furthermore, in the results of cell testing, higher lipogenesis inhibition was seen in the treatments of various ethanol extracts of RMD cultured with water containing Mg, K, Zn, and Fe than in those of RMD cultured with ultra-pure water. In conclusion, various individual metals resulted in different effects on MS and AK productions as well as the anti-adipogenesis effect of RMD, but the specific metals contained in DOW may cause synergistic or comprehensive effects that increase the significantly positive influence.
Two CHI genes from Chitinolyticbacter meiyuanensis SYBC-H1 encoding chitinases were identified and their protein 3D structures were predicted. According to the amino acid sequence alignment, CHI1 gene encoding 166 aa had a structural domain similar to the GH18 type II chitinase, and CHI2 gene encoding 383 aa had the same catalytic domain as the glycoside hydrolase family 19 chitinase. In this study, CHI2 chitinase were expressed in Escherichia coli BL21 cells, and this protein was purified by ammonium sulfate precipitation, DEAE-cellulose, and Sephadex G-100 chromatography. Optimal activity of CHI2 chitinase occurred at a temperature of 40 °C and a pH of 6.5. The presence of metal ions Fe(3+), Fe(2+), and Zn(2+) inhibited CHI2 chitinase activity,
 while Na⁺ and K⁺ promoted its activity. Furthermore, the presence of EGTA, EDTA, and β-mercaptoethanol significantly increased the stability of CHI2 chitinase. The CHI2 chitinase was active with p-NP-GlcNAc, with the Km and Vm values of 23.0 µmol/L and 9.1 mM/min at a temperature of 37 °C, respectively. Additionally, the CHI2 chitinase was characterized as an N-acetyl glucosaminidase based on the hydrolysate from chitin. Overall, our results demonstrated CHI2 chitinase with remarkable biochemical properties is suitable for bioconversion of chitin waste.
The leaching behavior of Pb and Zn from lead blast furnace (LBF) and imperial smelting furnace (ISF) slags sampled in the North of France was studied as a function of pHs and under two atmospheres (open air and nitrogen). The leaching of major elements from the slags was monitored as a function of pH (4, 5.5, 7, 8.5 and 10) under both atmospheres for different slag-water interaction times (1 day and 9 days). The leaching results were coupled with a geochemical model; Visual MINTEQ version 3.0, and a detailed morphological and mineralogical analysis was performed on the leached slags by scanning and transmission electron microscopy (SEM and TEM). Significant amounts of Ca, Fe and Zn were released under acidic conditions (pH 4) with a decrease towards the neutral to alkaline conditions (pH 7 and 10) for both LBF and ISF slags. On the other hand, Fe leachability was limited at neutral to alkaline pH for both slags. The concentrations of all elements increased gradually after 216 h compared to initial 24 h of leaching period. The presence of oxygen under open-air atmosphere not only enhanced oxidative weathering but also encouraged formation of secondary oxide and carbonate phases. Formation of carbonates and clay minerals was suggested by Visual MINTEQ which was further confirmed by SEM & TEM. The hydration and partial dissolution of hardystonite, as well as the destabilization of amorphous glassy matrix mainly contributed to the release of major elements, whereas the spinel related oxides were resistant against pH changes and atmospheres within the time frame concerned for both LBF and ISF slags. The total amount of Pb leached out at pH 7 under both atmospheres suggested that both LBF and ISF slags are prone to weathering even at neutral environmental conditions.
Salicylidine-cefalexin-Zn(II)·2H2O, a new derivative of cefalexin, has been reported to possess enhanced anti-microbial activity and lower toxicity than cefalexin. It is, therefore, desirable to carry out a pre-formulation study to determine its pharmaceutical properties which will be useful in conversion of the new molecule into various dosage forms.
The compound was synthesized by the previously reported method and characterized by elemental, Fourier-transform infrared and electronic spectral analyses. Crystallinity was determined by powder x-ray diffraction. Particle size distribution was determined by a laser-based sizer. Other properties including flow, density and compaction strength were determined by use of appropriate standard methods. The compound was also evaluated as a prodrug through dissolution study by the USP method.
It was found that the new derivative is an amorphous powder with different bulk density, porosity, compressibility, plasticity and flow properties as compared to cefalexin. The amorphous character of the new compound suggests that it will have better bioavailability. The dissolution study indicated that this compound is hydrolyzed to produce cefalexin in water in a sustained manner, thus it will act as a prodrug in vivo. The release data fitted well into Highuchi model.
Various pharmaceutical properties essentially required for formulation of salicylidine-cefalexin-Zn(II)·2H2O into dosage forms were determined. This study has shown that the new drug would behave as a prodrug for cefalexin with better bioavailability.
Rheumatoid arthritis (RA) is a chronic autoimmune inflammatory disease, which mainly involves the joints. RA is prevalent worldwide with increasing prevalence in elderly people. The mechanism of RA pathogenesis is still undefined, and it is interplaying between genetic susceptibility and environmental factors. Although risk factors for RA are not fully established, various studies have focused on the role of trace elements in association with RA. Trace elements act as co-factors for most of the enzymes, and their deficiency is associated with many untoward effects on human health. The homeostatic alterations in the metabolism of trace elements may partly be due to inflammatory response in RA. The objective of the present study was to determine the serum concentrations and correlation of zinc, copper, and iron in RA patients and healthy controls. The study comprised of 61 RA patients and 61 age- and sex-related healthy individuals of Pakistani population. Serum levels of Zn, Cu, and Fe were measured in all the participants by atomic absorption spectrophotometer. Serum Zn and Fe were significantly reduced in the RA patients than those in the healthy controls. Serum Cu concentrations were found elevated in the RA patients. Correlation studies of trace elements determine that there was negative correlation between Zn and Cu in the RA patients and no correlation in the control group. It is very important to explore the deficiency of essential trace metals in biological samples of the RA patients in different populations which may be helpful for diagnosis and supplementary management of rheumatoid arthritis patients.
Phytoextraction has been proposed as an alternative remediation technology for heavy metal contamination, and it is well known that chelators may alter the toxicity of heavy metals and the bioavailability in plants. Our previous work demonstrated that an adsorbent-column chromatography can effectively separate melanoidin-like product (MLP) from sugarcane molasses. The aim of this study was to examine the chelating property of MLP and to evaluate the facilitatory influence on the phytoextraction efficiency of Japanese radish. The result showed that MLP binds to all the metal ions examined and the binding capacity of MLP toward Cu(2+) seems to be the highest among them. The metal detoxification by MLP followed the order of Pb(2+) > Zn(2+) > Ni(2+) > Cu(2+) > Fe(2+) > Cd(2+) > Co(2+). Furthermore, in the phytoextraction experiment using copper sulfate, the application of MLP accelerated the detoxification of copper and the bioavailability in radish sprouts. Thus, these results suggest that MLP possesses the potential for an accelerator of phytoextraction in the copper-contaminated media.
Objetivos: oligoelementos como zinc (Zn), hierro (Fe) y cobre (Cu) tienen una influencia significativa en el mantenimiento de la función inmune y del metabolismo normales; modulan la función immune e influyen en la susceptibilidad del organismo ante infecciones. Pero la relación entre trazas de estos elementos y la bronconeumonía resultó incierta. Métodos: en este estudio fueron incluidos 28 niños con bronconeumonía y 46 niños sanos agrupados por edad. Se determinaron los niveles de Zn, Cu, Fe, calcio (Ca) y/o magnesio (Mg) en el suero de los niños con bronconeumonía y sin ella mediante espectrofotometría de absorción atómica. Resultados: los resultados muestran que varios niveles de microelementos como Zn, Ca, Mg y Fe en el grupo con bronconeumonía son menores que en el grupo control. En el grupo de niños con bronconeumonía el nivel de Ca en el suero está asociado positivamente con el zinc (Zn) (p < 0,05) y el hierro (Fe) (p < 0,05), mientras que hay una correlación positiva entre el cobre (Cu) y el calcio (Ca) (p < 0,05), magnesio (mg) (p < 0,05). Conclusión: el nivel de oligoelemento en el suero puede estar asociado con el riesgo de bronconeumonía entre los niños.
The possibility of choices of protein ligands and coordination geometries leads to diverse Zn(II) binding sites in zinc-proteins, allowing a range of important biological roles. The prokaryotic Cys2His2 zinc finger domain (originally found in the Ros protein from Agrobacterium tumefaciens) tetrahedrally coordinates zinc through two cysteine and two histidine residues and it does not adopt a correct fold in the absence of the metal ion. Ros is the first structurally characterized member of a family of bacterial proteins that presents several amino acid changes in the positions occupied in Ros by the zinc coordinating residues. In particular, the second position is very often occupied by an aspartic acid although the coordination of structural zinc by an aspartate in eukaryotic zinc fingers is very unusual. Here, by appropriately mutating the protein Ros, we characterize the aspartate role within the coordination sphere of this family of proteins demonstrating how the presence of this residue only slightly perturbs the functional structure of the prokaryotic zinc finger domain while it greatly influences its thermodynamic properties.
Complexes of germanone containing formal Ge=O→M bonds (M=Zn, B, Ge, Sn) were isolated and characterized. The compounds were prepared through a novel synthetic route using a germanium μ-oxo dimer 3 as the starting material. This method circumvents the need to employ germanones to prepare complexes of germanones.
The Gulf of Aqaba is of significant strategic and economic value to all gulf-bordering states, particularly to Jordan, where it provides Jordan with its only marine outlet. The Gulf is subject to a variety of impacts posing imminent ecological risk to its unique marine ecosystem. We attempted to investigate the status of metal pollution in the coastal sediments of the Jordanian Gulf of Aqaba. The distribution of Cd, Cr, Zn, Cu, Pb, Al, Fe, and Mn concentrations were determined in trapped and bottom-surface sediments at three selected sites at different depths. In addition, monthly
 sedimentation rates at varying water depths were also estimated at each sampling site using sediment traps. The high concentrations of Cd, Cr, Zn were recorded at the Phosphate Loading Birth (PLB) site followed by the Industrial Complex (IC) site indicating their dominant anthropogenic source (i.e., the contribution of industrial activities). However, Fe, Al, and Mn contents were related to inputs from the terrigenous (crustal) origin. Except for Al, Fe and Mn at the PLB site, the concentrations of metals exhibited a decreasing trend with increasing water depth (distance from the shoreline). The PLB site also showed the highest sedimentation rate which decreased with increasing water depth. The Enrichment factors (EFs) showed that Cd was the most enriched element in the sediment (indicating that Cd pollution is widespread), whereas the least enriched metal in sediments was Cu. EF values suggested that the coastal area is impacted by a combination of human and natural sources of metals, where the anthropogenic sources are intense in the PLB site (north of Gulf of Aqaba). The MSS area is potentially the least polluted, consistent with being a marine reserve. The IC sediments have been found to be impacted by human activities but less intensely compared to the PLB area. These results suggested that there are two sources of metals in sediments; the primary source is likely closer to PLB, while the secondary is nearby the IC.
Leaching experiments were conducted in a greenhouse to simulate seawater leaching combined with alternating seawater inundation and air drying. We investigated the heavy metal release of soils caused by changes associated with seawater inundation/air drying cycles in the reclaimed soils. After the treatment, the contents of all heavy metals (Cd, Pb, Cr, and Cu), except Zn, in surface soil significantly decreased (P < 0.05), with removal rates ranging from 10% to 51%. The amounts of the exchangeable, carbonate, reducible, and oxidizable fractions also significantly decreased (P < 0.05). Moreover, prolonged seawater inundation enhanced the release of heavy metals. Measurement of diffusive gradients in thin films indicated that seawater inundation significantly increased the re-mobility of heavy metals. During seawater inundation, iron oxide reduction induced the release of heavy metals in the reducible fraction. Decomposition of organic matter, and complexation with dissolved organic carbon decreased the amount of heavy metals in the oxidizable fraction. Furthermore, complexation of chloride ions and competition of cations during seawater inundation and/or leaching decreased the levels of heavy metals in the exchangeable fraction. By contrast, air drying significantly enhanced the concentration of heavy metals in the exchangeable fraction. Therefore, the removal of heavy metals in the exchangeable fraction can be enhanced during subsequent leaching with seawater.
Artificial infiltration facilities (AIFs) are useful to control urban runoff and regulate combined sewer overflows. Over the years, AIFs accumulate significant amounts of soakaway sediments and organic matter. The prolonged retention of soakaway sediments in AIFs is likely to cause metal remobilization due to ageing processes. The measurement of the individual consequence of ageing demands homogeneity in physical and chemical profiles of samples. This leads to assessment of metal remobilization in a single soil core through solid-phase extractions and isotopic exchangeability (E value). Depth-wise variation in the physicochemical properties and metal content of the underlying soil (below 1 m of AIFs) was created through 2 weeks of continuous leaching with artificial road runoff (ARR). Ten samples obtained from a 50-cm core by sectioning it at 5-cm intervals were subsequently incubated for 18 months. The results suggest that degradation of organic matter and changes in functional groups due to ageing govern metal remobilization. In general, the top segment showed significant alteration due to ageing. Post incubation, Zn increased dramatically in contrast to subdued Cu and Pb levels in exchangeable fractions with concomitant rise in organic-bound fractions. Isotopic exchangeability of Cd and Zn showed pronounced effect of ageing, although the effect of ageing was distinct in chemical partitioning and isotopic exchangeability of metals; a comparative study of short-term versus long-term incubation will benefit assessment of initial dynamics and final equilibrium. Consequently, the outcome from this work is a viable tool in risk prediction related to soakaway sediment accumulation in AIF.
Four heavy metals (Cd, Cu, Pb and Zn), two metalloids (As and Sb) and two rare metals (In and Tl) were selected as target elements to ascertain their concentrations and accumulation in the soil-plant system and their effects on the structure of the soil microbial community in a typical area of rare metal smelting in south China. Twenty-seven soil samples 100, 500, 1000, 1500 and 3000 m from the smelter and 42 vegetable samples were collected to determine the concentrations of the target elements. Changes in soil micro-organisms were investigated using the Biolog test and 454 pyrosequencing. The concentrations of the eight target elements (especially As and Cd) were especially high in the topsoil 100 m from the smelter and decreased markedly with increasing distance from the smelter and with increasing soil depth. Cadmium bio-concentration factors in the vegetables were the highest followed by Tl, Cu, Zn, In, Sb, Pb, and then As. The concentrations of As, Cd and Pb in vegetables were 86.7, 100 and 80.0 %, respectively, over the permissible limits and possible contamination by Tl may also be of concern. Changes in soil microbial counts and average well colour development were also significantly different at different sampling distances from the smelter. The degree of tolerance to heavy metals appears to be fungi > bacteria > actinomycetes. The 454 pyrosequencing indicates that long-term metal contamination from the smelting activities has resulted in shifts in the composition of the soil bacterial community.
 Background. Nutritional deficiencies may aggravate the course of chronic hepatitis C (CHC). Our aim has been to perform a comprehensive analysis of body composition and nutritional deficiencies in CHC patients in non-cirrhotic and compensated cirrhotic stages to correlate the detected deficiencies with the fibrosis stage.
Body multifrequency bioimpedance analysis (BIA) and a wide and simultaneous analytical profile were prospectively performed in 74 CHC patients (36 male) with known METAVIR fibrosis stage established with liver biopsy or transient elastography. Results were analyzed to identify deviations from the normal range and variations according to the fibrosis stage.
Body fat compartment was greater in women. Body composition did not change among the 4 stages of liver fibrosis. Low levels (< 30 μg/L) of vitamin D were detected in 74.3% of patients irrespective of the fibrosis stage. Most analytical results remained into the normal range with the exceptions of thrombocytopenia and vitamin A deficiency, that were limited to the stage 4 of fibrosis, and low Zn and LDL-cholesterol values, that were frequently found in patients with advanced (F3 and F4) fibrosis stage.
Body composition and most biochemical parameters, including cyanocobalamin, folic acid and vitamin E, are well preserved in compensated patients with CHC, with the exception of generalized vitamin D insufficiency and of deficiencies of vitamin A and zinc that are restricted to the more advanced, although still compensated, stages of the disease.
Mononuclear Co(II), Ni(II), Cu(II) and Zn(II) complexes of an unsymmetric Schiff base ligand, 3-(-(3-(-3,5-dichloro-2-hydroxybenzylideneamino)propylimino)methyl)quinoxalin-2(1H) -one (L) were synthesized and characterized by various analytical and spectral techniques. The molar conductance values of metal complexes indicate non-electrolytic behavior of the metal complexes. The Schiff base act as tetra dentate ONNO donor ligand in Co(II), Ni(II), Zn(II) complexes and tridentate NNO donor in Cu(II) complex. Thermal stabilities of the newly synthesized compounds were determined by thermal analysis. Crystallinity, average grain size and unit cell parameters were determined from powder X-ray diffraction study. Electrochemical behaviors of the compounds were examined by cyclic voltammetry technique. The Schiff base and its complexes have been screened for their in vitro antimicrobial activities against some bacterial and fungal strains by disc diffusion method. The interaction of the compounds with calf thymus DNA (CT DNA) has been investigated by electronic absorption spectral titration and viscosity measurement (hydrodynamic) methods. Furthermore, the pUC18 DNA cleavage activities of the complexes have been explored. The compounds were also subjected to in vitro antioxidant, anticancer activity screening, druglikeness and bioactivity predictions using Molinspiration software. Molecular docking studies of the present compounds were carried out against B-DNA dodecamer d(CGCGAATTCGCG)2 and vascular endothelial growth factor receptor (VEGFR-2) kinase. Quantum chemical calculations were done with DFT method to determine the optimum geometry of the ligand and its metal complexes. From the quantum chemical parameters, the reactivity parameters of the compounds were established.
Instrumental neutron activation analyses (INAA) have been used to achieve accurate knowledge about the elemental analysis of phosphate ore deposits collected from Hazm El-Jalamid Northeast of Saudi Arabia. The samples were prepared for irradiation by thermal neutrons using a thermal neutron flux of 7×10(12)ncm(-2)s(-1) at ACT Lab Canada. The concentrations of 19 elements were determined.
 These included 12 major, minor and trace elements (Au, As, Ba, Br, Cr, Mo, Sb, Sc, Sr, Th, U and Zn) and 7 rare earth elements (REEs) (La, Ce, Nd, Sm, Eu, Yb and Lu). Major elements (Si, Al, Fe, Ca, Mg, Na, K, Cr, Ti, Mn, P, Sr and Ba) were determined using an inductively coupled plasma-mass spectrometer (ICP-MS). The comparison of the concentration of U and the REEs in the Hazm El-Jalamid phosphate samples with those of the Umm Wu'al phosphate from Saudi Arabia and El-Sibayia and El Hamrawein phosphate from Egypt shows that the contents of U and REEs are clearly higher in the Umm Wu'al, El-Sibayia and El Hamrawein phosphates than in the Hazm El-Jalamid phosphate samples. The results of major, trace elements, uranium and rare earth elements (REE) from El Jalamid phosphate have been compared with the global values of these elements. The concentrations for most of the elements studied are lower than the concentrations reported in the literature. The acquired data will serve as a reference for the follow-up studies to assess the agronomic effectiveness of the Hazm El-Jalamid phosphate rocks.
Photocatalytic activity of the coupled ZnO-CuO and ZnS-CuS semiconductors supported onto clinoptilolite nanoparticles (CNP) and micronized one (CMP) was studied in photodegradation of benzophenone (BP) aqueous solution. The ZnO-CuO/CNP (or MCP) and ZnS-CuS/CNP (or MCP) catalysts were prepared via calcination and sulfiding of their Zn(II)-Cu(II) ion-exchanged samples, respectively. XRD patterns confirmed loading of the mentioned semiconductors onto the zeolite, and nano dimension of the catalysts was confirmed by XRD and TEM results. Typical Tauc plots obtained from UV-vis DRS spectra showed red shifts for the band gap energies of the supported coupled semiconductors with respect to the supported monocomponent ones especially for ZnO/NCP and ZnS/NCP catalysts. Also, in both indirect and direct transitions, these red shifts were more considerable in the oxidic systems with respect to the sulfidic systems. Accordingly, the supported oxidic systems showed better photocatalytic activity than the sulfidic one. In the oxidic systems changing the dose of CuO played important role while in the sulfidic systems ZnS played considerable role in the degradation of BP. In the used systems, CuO and ZnS played the main e/h generators in the oxidic and sulfidic systems, respectively, while ZnO and CuS played the preventer e/h recombination. Based on the results, production of e/h is the rate limiting step in the used systems. The maximum degradation activity of the catalysts was obtained at: 0.12gL(-1) of ZnO0.80-CuO3.18/NCP and 0.10gL(-1) of ZnS1.39-CuS2.88/NCP catalysts, initial BP concentration of 30mgL(-1) at pH 7.5.
DNA polymerases (pols) are sophisticated protein machines operating in the replication, repair and recombination of genetic material in the complex environment of the cell. DNA pol reactions require at least two divalent metal ions for the phosphodiester bond formation. We explore two understudied roles of metals in pol transactions with emphasis on polα, a crucial enzyme in the initiation of DNA synthesis. We present evidence that the combination of many factors, including the structure of the template/primer, the identity of the metal, the metal turnover in the pol active site, and the influence of the concentration of nucleoside triphosphates, affect DNA pol synthesis. On the poly-dT70 template, the increase of Mg(2+) concentration within the range typically used for pol reactions led to the severe loss of the ability of pol to extend DNA primers and led to a decline in DNA product sizes when extending RNA primers, simulating the effect of "counting" of the number of nucleotides in nascent primers by polα. We suggest that a high Mg(2+) concentration promotes the dynamic formation of unconventional DNA structure(s), thus limiting the apparent processivity of the enzyme. Next, we found that Zn(2+) supported robust polα reactions when the concentration of nucleotides was above the concentration of ions; however, there was only one nucleotide incorporation by the Klenow fragment of DNA pol I. Zn(2+) drastically inhibited polα, but had no effect on Klenow, when Mg(2+) was also present. It is possible that Zn(2+) perturbs metal-mediated transactions in pol active site, for example affecting the step of pyrophosphate removal at the end of each pol cycle necessary for continuation of polymerization.
Solvolytic dissociation rate constants (kd) of bovine carbonic anhydrase II (CA) and its metallovariants (M-CAs, M=Co(II), Ni(II), Cu(II), Zn(II), and Cd(II)) were estimated by a ligand substitution reaction, which was monitored by affinity capillary electrophoresis to selectively detect the undissociated CAs in the reaction mixture. Using EDTA as the competing ligand for Zn-CA, the dissociation followed the unimolecular nucleophilic substitution (SN1) mechanism with kd=1.0×10(-7)s(-1) (pH7.4, 25°C). The corresponding solvolysis half-life (t1/2) was 80days, showing the exceptionally high kinetic stability of t Zn-CA, in contrast to the highly labile [Zn(II)(H2O)6](2+), where the water exchange rate (kex) is high. This behavior is attributed to the tetrahedral coordination geometry supported by the tris(histidine) unit (His3) of CA. In the case of Co-CA, it showed a somewhat larger kd value (5.7×10(-7)s(-1), pH7.4, 25°C) even though it shares the same tetrahedral coordination environment with Zn-CA, suggesting that the d(7) electronic configuration of Co(II) in the transition state of the dissociation is stabilized by the ligand field. Among M-CAs, only Ni-CA showed a bimolecular nucleophilic substitution (SN2) reaction path in its reaction with EDTA, implying that the large coordination number (6) of Ni(II) in Ni-CA allows EDTA to form an EDTA-Ni-CA intermediate. Overall, kd values roughly correlated with kex values among M-CAs, with the kd value of Zn-CA deviating strongly from the trend and highlighting the exceptionally high kinetic stabilization of Zn-CA by the His3 unit.
Vitamin K acts as a coenzyme in the γ-carboxylation of vitamin K-dependent proteins, including coagulation factors, osteocalcin, matrix Gla protein (MGP), and the growth arrest-specific 6 (GAS6) protein. Osteocalcin is a key factor for bone matrix formation. MGP is a local inhibitor of soft tissue calcification. GAS6 activity prevents the apoptosis of vascular smooth muscle cells. Few data on vitamin K intake in chronic kidney disease patients and no data in patients on a Mediterranean diet are available. In the present study, we evaluate the dietary intake of vitamin K1 in a cohort of patients undergoing haemodialysis.
In this multi-centre controlled observational study, data were collected from 91 patients aged >18 years on dialysis treatment for at least 12 months and from 85 age-matched control subjects with normal renal function. Participants completed a food journal of seven consecutive days for the estimation of dietary intakes of macro- and micro-nutrients (minerals and vitamins).
Compared to controls, dialysis patients had a significant lower total energy intake, along with a lower dietary intake of proteins, fats, carbohydrates, fibres, and of all the examined minerals (Ca, P, Fe, Na, K, Zn, Cu, and Mg). With the exception of vitamin B12, vitamins intake followed a similar pattern, with a lower intake in vitamin A, B1, B2, C, D, E, folates, K1 and PP. These finding were confirmed also when normalized for total energy intake or for body weight. In respect to the adequate intakes recommended in the literature, the prevalence of a deficient vitamin K intake was very high (70-90%) and roughly double than in controls. Multivariate logistic model identified vitamin A and iron intake as predictors of vitamin K deficiency.
Haemodialysis patients had a significantly low intake in vitamin K1, which could contribute to increase the risk of bone fractures and vascular calcifications. Since the deficiency of vitamin K intake seems to be remarkable, dietary counselling to HD patients should also address the adequacy of vitamin K dietary intake and bioavailability. Whether diets with higher amounts of vitamin K1 or vitamin K supplementation can improve clinical outcomes in dialysis patients remains to be demonstrated.
Airborne fine particulate matter (PM2.5) from five megacities including Beijing, Tianjin, Shijiazhuang, Baoding, and Jinan were collected during November 2014 and compared with similar periods in 2012 and 2013. The November 2014 period coincided with the Asia Pacific Economic Cooperation (APEC) Leaders Meeting during which measures to control pollution of the air were introduced. Concentrations of 11 elements in PM2.5 were quantified by inductively coupled plasma-mass spectrometry (ICP-MS) after microwave-assisted digestion. Potential effects of five toxic trace metals including Mn, Ni, Cu, Zn, Pb, and the metalloid As on health were assessed. In 2014, concentrations of PM2.5 were significantly less than during the same period in 2012 and 2013. Mean concentrations of six elements ranked in decreasing order, Zn > Pb > Cu ≈ Mn > As > Ni, and spatial concentrations ranked in decreasing order, Shijiazhuang > Baoding > Tianjin > Jinan > Beijing. Risks of the five metals and the metalloid As to health of humans were small, except for Mn in Shijiazhuang. Risks to health posed by other elements were less during the period of study. Risks posed by the five metals and As in Beijing were greater to varying degrees after the APEC meeting. Risks to health of humans during the APEC were overall lesser than the same period in 2012 and 2013, mostly due to lesser emissions due to the short-term control measures.
The lakes' fisheries play an important role in Egyptian economy. In 1980s, they provided more than 50 % of harvested fish in Egypt but now their contribution to the
 Egypt fish production decreased to only 12.5 % in 2012. Lake Timsah, one of the Suez Canal lakes, faced many challenges that lead to serious changes in its water and fish quality, fish production, as well as the catch composition. The present work investigated the impact of pollution, food availability, and excessive fishing mortality on the haffara production in lake Timsah. The distribution of four heavy metals (Pb, Zn, Ni, and Fe) was detected seasonally in water and in muscles, gills, and livers of Rhabdosargus haffara, during 2012 through 2013. Fe and Zn were presented by high values in liver, while Pb and Ni in gills. Generally, the lowest concentrations of all metals were found in muscles. The recorded crustacean organisms (the main food of haffara) decreased from 12 species and 32,079 organisms⁄m(2) in 2012 to only 7 species and 7290 organisms⁄m(2) in 2013 while the amphipods completely disappeared. This serious change was due to the severe pollution in the lake. A logistic surplus production model was fitted to the catch per unit effort indices, to estimate the maximum sustainable yield and the optimum level of fishing effort. The results revealed that haffara stock at lake Timsah is overfished, and the estimated precautionary target reference points advised the reduction of fishing effort by about 30-50 %.
The study was carried out to evaluate the effect of Zn-Gly supplementation on the selected antioxidative enzymes and on the mineral composition in the liver and faeces as well as the biochemical and haematological parameters of chicken blood. Two hundred and fifty-one-day-old Ross 308 male broiler chicks were randomly allotted to five dietary treatments, each of which was replicated five times (10 birds in each cage). Five experimental groups were formed: control negative (CN)-without Zn, control positive supplemented with 100 mg ZnO, and three groups supplemented with 100, 50, and 25 mg Zn-Gly. An increase (P < 0.05) was recorded in the concentration of Cu and Zn in chicken livers after Zn-Gly supplementation, irrespective of the level of supply with the diet. The addition of 100 mg·Zn-Gly improved the activity of SODCuZn (P < 0.05) and reduced the MDA value (P < 0.05) in chicken livers. The addition of 100, 50, and 25 mg Zn-Gly reduced the concentration of zinc in the birds' droppings, compared to the CN and 100 mg ZnO group. Zn-Gly at the level of 50 mg increased the concentration of Cu and Ca in chicken blood. The results indicate that the addition of Zn-Gly increased the antioxidative capacity of the body and storage of Zn and Cu in the liver; it also reduced the amount of Zn excreted with faeces. Zn-Gly can be an alternative to ZnO in providing a good source of Zn to enrich feed mixtures for broilers.
A comprehensive study was carried out to assess metal contamination in five cities spanning from temperate to tropical environment along the coastal line of China with different hydrographical conditions. At each of the five cities, Artificial Mussels (AM) were deployed together with a native species of mussel at a control site and a polluted site. High levels of Cr, Cu and Hg were found in Qingdao, high level of Cd, Hg and Pb was found in Shanghai, and high level of Zn was found in Dalian. Furthermore, level of Cu contamination in all the five cities was consistently much higher than those reported in similar studies in other countries (e.g., Australia, Portugal, Scotland, Iceland, Korea, South Africa and Bangladesh). Levels of individual metal species in the AM showed a highly significant correlation with that in the native mussels (except for Zn in Mytilus edulis and Cd in Perna viridis), while no significant difference can be found between the regression relationships of metal in the AM and each of the two native mussel species. The results demonstrated that AM can provide a reliable time-integrated estimate of metal concentration in contrasting environments over large biogeographic areas and different hydrographic conditions, and overcome the shortcomings of monitoring metals in water, sediment and the use of biomonitors.
A sulfonamide 1-tosyl-1-H-benzo(d)imidazol-2-amine (TBZA) and three new complexes of Co(II), Cu(II), and Zn(II) have been synthesized. The compounds have been characterized by elemental analyses, FTIR, (1)H, and (13)C-NMR spectroscopy. The structure of the TBZA, and its Co(II) and Cu(II) complexes, was determined by X-ray diffraction methods. TBZA and its Co(II) complex crystallize in the triclinic P-1 space group, while the Cu(II) complex crystallizes in the monoclinic P21/c space group. Antifungal activity was screened against eight pathogenic yeasts: Candida albicans (DMic 972576), Candida krusei (DMic 951705), Candida glabrata (DMic 982882), Candida tropicalis (DMic 982884), Candida dubliniensis (DMic 93695), Candida guilliermondii (DMic 021150), Cryptococcus neoformans (ATCC 24067), and Cryptococcus gattii (ATCC MYA-4561). Results on the inhibition of various human (h) CAs, hCA I, II, IV, VII, IX, and XII, and pathogenic beta and gamma CAs are also reported.
Nase (Chodrostoma nasus L. 1758) specimens of four age classes (1(+) to 4(+)) were caught in July 2013 in the Medjuvršje Reservoir. Concentrations of 14 metals and elements (Al, B, Ba, Cd, Co, Cr, Cu, Fe, Mn, Mo, Ni, Si, Sr, Zn) in the muscle, gills and liver were analyzed by inductively-coupled plasma optical spectrometry (ICP-OES). The highest concentrations of Al, Ba, Co, Cr, Mn, Si, Sr and Zn were detected in gills, while Cd, Cu, Fe and Mo reached the highest values in the liver. The majority of the analyzed elements were found in minimal concentrations in the muscle. Younger age classes (1(+), 2(+)) were differentiated by higher concentrations of Mn, Sr and Zn in muscle tissue, while the older ones were mainly differentiated by higher concentrations for Ni and Cu. The youngest age class (1(+)) was distinguished by higher concentrations of Zn, while the oldest age class (4(+)) was distinguished by higher concentrations of Ba, Cu, Mo and Sr in gills. Results obtained were likely caused by differences in the physiology and feeding habits between younger (1-2(+)) and older (3-4(+)) age groups of nase.
Biocompatible Zinc-hydroxyapatite-titania and Zinc-hydroxyapatite nanocomposite coatings have been prepared by electrodeposition on NiTi shape memory alloy. Structures of coatings were characterized using X-ray diffraction (XRD). It was found that addition of TiO2 particles cause to reduction of crystallite size of coating. Scanning Electronic Microscope (SEM) observation showed that the Zn-HA/TiO2 coating consists of plate-like regions which can express that this plate-like structure can facilitate bone growth. X-ray photoelectron microscope (XPS) was performed to investigation of chemical state of composite coating and showed that Zinc matrix was bonded to oxygen. high-resolution transmission electron microscope (HRTEM) result illustrated the crystalline structure of nanocomposite coating. Mechanical behavior of coating was evaluated using microhardness and ball on disk wear test. The TiO2 incorporated composite coatings exhibited the better hardness and anti-wear performance than the Zn-HA coatings. Polarization measurements have been used to evaluate the electrochemical coatings performance. The Zn-HA/TiO2 composite coatings showed the highest corrosion resistance compared with Zn-HA and bare NiTi.
The purpose of this study was to evaluate the remineralization ability of an etch-and-rinse Zn-doped resin applied on caries-affected dentin (CAD). CAD surfaces were subjected to: (i) 37% phosphoric acid (PA) or (ii) 0.5M ethylenediaminetetraacetic acid (EDTA). 10wt% ZnO nanoparticles or 2wt% ZnCl2 were added into the adhesive Single Bond (SB), to create the following groups: PA+SB, PA+SB-ZnO, PA+SB-ZnCl2, EDTA+SB, EDTA+SB-ZnO, EDTA+SB-ZnCl2. Bonded interfaces were submitted to mechanical loading or stored during 24h. Remineralization of the bonded interfaces was studied by AFM nano-indentation (hardness and Young׳s modulus), Raman spectroscopy [mapping with principal component analysis (PCA), and hierarchical cluster analysis (HCA)] and Masson׳s trichrome staining technique. Dentin samples treated with PA+SB-ZnO attained the highest values of nano-mechanical properties. Load cycling increased both mineralization and crystallographic maturity at the interface; this effect was specially noticed when using ZnCl2-doped resin in EDTA-treated carious dentin. Crosslinking attained higher frequencies indicating better conformation and organization of collagen in specimens treated with PA+SB-ZnO, after load cycling. Trichrome staining technique depicted a deeper demineralized dentin fringe that became reduced after loading, and it was not observable in EDTA+SB groups. Multivariate analysis confirmed de homogenizing effect of load cycling in the percentage of variances, traces of centroids and distribution of clusters, especially in specimens treated with EDTA+SB-ZnCl2.
The Tubarão River (Santa Catarina, Brazil) is affected by hazardous elements (HEs) pollution from abandoned coal mines, agricultural activities, urban discharges, industrial and leisure zones, etc. In order to study the distribution and sources of HEs contamination in a polluted estuary after a tropical storm, waters and surface sediments were collected from 15 sampling sites along the Tubarão River. The concentration of 24 elements (Ag, Al, As, Ba, Cd, Co, Cr, Cu, Fe, Hg, Mg, Mn, Mo, Ni, Pb, Sb, Se, Sn, Sr, Ti, Tl, V, W, and Zn) were measured by Inductively Coupled Plasma Mass Spectrometry (ICP-MS) and the mineralogical composition of the sediments by Raman spectroscopy and X-ray diffraction (XRD). The metal concentrations in water and sediment showed wide spatial variation due to the variability in water discharges and anthropogenic inputs after a storm. In general,
 higher metal concentration in water and lower in sediments were found upstream (closer to coal mining). Downstream sampling sites and the Oratorio River sampling site (one of the eight tributaries of the estuary) showed the highest values in sediment samples. Normalized and Weighed Average Concentrations (NWAC) were calculated, which allow us to identify, in a very simple way, the sampling sites of higher concern (hotspots of contamination) in the studied area. NWAC suggested that the strong rainfall events could affect to the metal distribution in sediments. The results of this study were compared with a previous study in the same area during dry season by Principal Component Analysis (PCA), showing changes in environmental pollution of the sediment after a strong storm event.
Human blood contains substantial amounts of metal ions such as Mg(2+), Ca(2+), Fe(2+), Cu(2+), Zn(2+), Cd(2+), Pb(2+), and Al(3+). Most biomedical applications of nanoparticles require understanding the influence of these metal ions because adsorbed metal ions can affect the function of nanoparticles to limit their sensitivity, performance, stability, and/or resolution in applications. In the present work, the adsorption of various metal ions at the surface of GdVO4:Eu nanoparticles was studied to assess their spectral filter effect on the fluorescence of GdVO4:Eu. Due to the negative surface potential, the electrostatic attraction caused an intensive adsorption reaction of GdVO4:Eu nanoparticles with metal cations. Compared to the adsorption of other common metal ions in human blood, the distinct fluorescence quenching of GdVO4:Eu was induced in the presence of Cu(2+) ions. On the basis of the UV-vis absorption spectrum of an aqueous CuCl2 solution and reflectance spectrum of Cu(OH)2, in which the surroundings of Cu(2+) ions are supposedly similar to the hydroxylated surface of GdVO4:Eu nanoparticles, it is proposed that the complementary overlap of the emission band of GdVO4:Eu with the absorption band of Cu(2+) results in the effective filter effect to quench the red emission. Because GdVO4:Eu nanoparticles are attractive candidates for applications as magnetic/fluorescent multimodal nanoprobes, it is important to recognize that the average amount of Cu(2+) ion in human blood is sufficient to interfere with or limit the fluorescence probe function of GdVO4:Eu nanoparticles.
Human carbonic anhydrase II (hCAII) represents an ultimate example of the perfectly efficient metalloenzymes, which is capable of catalyzing the hydration of carbon dioxide with a rate approaching the diffusion controlled limit. Extensive experimental studies of this physiologically important metalloprotein have been done to elucidate the fundamentals of its enzymatic actions: what residues anchor the Zn(2+) (or another divalent cation) at the bottom of the binding pocket; how the relevant residues work concertedly with the divalent cation in the reversible conversions between CO2 and HCO3(-); what are the protonation states of the relevant residues and acetazolamide, an inhibitor complexed with hCAII, etc. In this article, we present a detailed computational study on the basis of the all-atom CHARMM force field where Zn(2+) is represented with a simple model of divalent cation using the transferrable parameters available from the current literature. We compute the hydration free energy of Zn(2+), the characteristics of hCAII-Zn(2+) complexation, and the absolute free energy of binding acetazolamide to the hCAII-Zn(2+) complex. In each of these three problems, our computed results agree with the experimental data within the known margin of error without making any case-by-case adjustments to the parameters. The quantitatively accurate insights we gain in this all-atom molecular dynamics study should be helpful in the search and design of more specific inhibitors of this and other carbonic anhydrases.
The contributions of major driving forces on temporal changes of heavy metals in the soil in a representative river-alluviation area at the lower of Yangtze River were successfully quantified by combining geostatistics analysis with the modified principal component scores & multiple linear regressions approach (PCS-MLR). The results showed that the temporal (2003-2014) changes of Cu, Zn, Ni and Cr presented a similar spatial distribution pattern, whereas the Cd and Hg showed the distinctive patterns. The temporal changes of soil Cu, Zn, Ni and Cr may be predominated by the emission of the shipbuilding industry, whereas the significant changes of Cd and Hg were possibly predominated by the geochemical and geographical processes, such as the erosion of the Yangtze River water and leaching because of soil acidification. The emission of metal-bearing shipbuilding industry contributed an estimated 74%-83% of the changes in concentrations of Cu, Zn, Ni and Cr, whereas the geochemical and geographical processes may contribute 58% of change of Cd in the soil and 59% of decrease of Hg.
Physicochemical characteristics and Mn(2+) adsorption of annealed red mud were investigated in this study. The annealing temperature (105-900 °C) changed the mineralogical components and the point of zero charge of red mud. By comparison, annealed red mud at 700 °C (ARM700) had a better adsorption effect than other annealed samples, associated with the activated components of available Fe2O3, Al2O3, SiO2 and Na5Al3(SiO4)3CO3 (natrodavyne). The removal efficiency of Mn(2+) by ARM700 was dependent on initial pH, contact time, and initial Mn(2+) concentration of aqueous solution and was ∼56.5% with initial Mn(2+) concentration 385 mg/L at initial pH > 5. The kinetics process was predicted better by the pseudo-second-order model. The Langmuir isotherm displayed a better fitting model than the Freundlich isotherm and the Mn(2+) maximum adsorption capacity of ARM700 was 88.3 mg/g. The competing effects of Cu(2+) and Zn(2+) on Mn(2+) removal were most obvious. There was efficient Mn(2+) removal at the application of ARM700 to the leachate of electrolytic manganese residue.
Bark from Pinus pinaster is one of the most abundant forestry wastes in Europe, and among the proposed technologies for its reutilization, the removal of heavy metals from wastewater has been gaining increasing attention. In this work, we have studied the performance of pine bark for heavy metal biosorption on competitive systems. Pb, Cu, Ni, Zn and Cd sorption and desorption at equilibrium were studied in batch experiments, whereas transport was studied in column experiments. Batch experiments were performed adding simultaneously different concentrations (0.08-3.15mM) of two or more metals in solution to pine bark samples. Column experiments were performed with 10mM solutions of two metals or a 5mM solution of the five metals. In general, the results under competitive conditions were different to those obtained in monoelemental experiments. The multi-metal batch experiments showed the adsorption sequence Pb≈Cu>Cd>Zn>Ni for lower metal doses, Pb>Cu>Cd>Zn>Ni for intermediate doses, and Pb>Cu>Cd≈Zn≈Ni for high metal doses. Desorption followed the sequence Pb<Cd<Cu<Zn<Ni for the lowest metal doses, and Pb<Cu<Zn<Cd<Ni for the highest ones. The bi-metal batch experiments indicated that Cu and Pb suffered the highest retention, with high capacity to displace Cd, Ni and Zn from adsorption sites on pine bark. The transport experiments produced comparable results to those obtained in the batch experiments, with pine bark retention capacity following the sequence Pb>Cu>Zn>Cd>Ni. The presence of a second metal affected the transport of all the elements studied except Pb, and confirmed the strong influence of Pb and Cu on the retention of the other metals. These results can help to appropriately design decontamination systems using this forestry waste.
Eleven dimetallic Zn(II)-Ln(III) complexes of the general formula [Zn(µ-L)(µ-OAc)Ln(NO3)2]·CH3CN (Ln(III) = Pr (1), Nd (2), Sm (3), Eu (4), Gd (5), Tb (6), Dy (7), Ho (8), Er (9), Tm (10), Yb (11)) have been prepared in a one-pot reaction from the compartmental ligand N,N'-dimethyl-N,N'-bis(2-hydroxy-3-formyl-5-bromo-benzyl)ethylenediamine (H2L). In all these complexes, the Zn(II) ions occupy the internal N2O2 site whereas the Ln(III) ions show preference for the O4 external site. Both metallic ions are bridged by an acetate bridge, giving rise to triple mixed diphenoxido/acetate bridged Zn(II)Ln(III) compounds. The Nd, Dy, Er and Yb complexes exhibit field induced single-ion magnet (SIM) behaviour, with Ueff values ranging from 14.12 to 41.55 K. The Er complex shows two relaxation processes, but only the second relaxation process with an energy barrier of 21.0 K has been characterized. The chromophoric L(2-) ligand is able to act as an "antenna" group, sensitizing the near-infrared (NIR) Nd(III) and Yb(III)-based luminescence in complexes 2 and 11 and therefore, both compounds can be considered as magneto-luminescent materials. In addition, the Sm(III), Eu(III) and Tb(III) derivatives exhibit characteristic emissions in the visible region.
Hydrogen sulfide (H2S) has gained recent attention as an important biological analyte that interacts with bioinorganic targets. Despite this importance, stable H2S or HS(-) adducts of bioinorganic metal complexes remain rare due to the redox activity of sulfide and its propensity to form insoluble metal sulfides. We report here reversible coordination of HS(-) to Zn(didpa)Cl2, which is enabled by an intramolecular hydrogen bond between the zinc hydrosulfido product and the pendant tertiary amine of the didpa ligand.
This study investigated the effects of short-term subclinical Zn deficiency on exocrine pancreatic activity and changes in digestive capacity. A total of forty-eight weaned piglets were fed ad libitum a basal diet (maize and soyabean meal) with adequate
 Zn supply (88 mg Zn/kg diet) during a 2-week acclimatisation phase. Animals were then assigned to eight dietary treatment groups (n 6) according to a complete randomised block design considering litter, live weight and sex. All pigs were fed restrictively (450 g diet/d) the basal diet but with varying ZnSO4.7H2O additions, resulting in 28·1, 33·6, 38·8, 42·7, 47·5, 58·2, 67·8 and 88·0 mg Zn/kg diet for a total experimental period of 8 d. Pancreatic Zn concentrations and pancreatic activities of trypsin, chymotrypsin, carboxypeptidase A and B, elastase and α-amylase exhibited a broken-line response to stepwise reduction in dietary Zn by declining beneath thresholds of 39·0, 58·0, 58·0, 41·2, 47·5, 57·7 and 58·0 mg Zn/kg diet, respectively. Furthermore, carboxypeptidase B and α-amylase activities were significantly lower in samples with reduced pancreatic Zn contents. Coefficients of faecal digestibility of DM, crude protein, total lipids and crude ash responded similarly to pancreatic enzyme activities by declining below dietary thresholds of 54·7, 45·0, 46·9 and 58·2 mg Zn/kg diet, respectively. In conclusion, (1) subclinical Zn deficiency impaired pancreatic exocrine enzymes, (2) this response was connected to pancreatic Zn metabolism and (3) the decline in catalytic activity impaired faecal digestibility already after 1 week of insufficient alimentary Zn supply and very early before clinical deficiency symptoms arise.
We utilized a multi-biomarker approach (Integrated Biomarker Response version 2, IBRv2) to investigate the scope and dispersion of groundwater contamination surrounding a rare earth mine tailings impoundment. Parameters of SD rat included in our IBRv2 analyses were glutathione levels, superoxide dismutase, catalase, and glutathione peroxidase activities, total anti-oxidative capacity, chromosome aberration, and micronucleus formation. The concentration of 20 pollutants including Cl(-), SO4 (2-), Na(+), K(+), Mg(2+), Ca(2+), TH, CODMn, As, Se, TDS, Be, Mn, Co, Ni, Cu, Zn, Mo, Cd, and Pb in the groundwater were also analyzed. The results of this study indicated that groundwater polluted by tailings impoundment leakage exhibited significant ecotoxicological effects. The selected biomarkers responded sensitively to groundwater pollution. Analyses showed a significant relationship between IBRv2 values and the Nemerow composite index. IBRv2 could serve as a sensitive ecotoxicological diagnosis method for assessing groundwater contamination in the vicinity of rare earth mine tailings. According to the trend of IBRv2 value and Nemerow composite index, the maximum diffusion distance of groundwater pollutants from rare earth mine tailings was approximately 5.7 km.
A series of Ni(II), Co(II), Zn(II) and Cd(II) complexes with polytopic Schiff base ligands have been synthesized. The single-crystal X-ray crystallography results show that tetranuclear complexes have common face-shared defective dicubane cores, whereas trinuclear Cd(II) complexes are almost linear entities. Synthesis methods (solvent evaporation and hydrothermal synthesis), reaction conditions (pH, solvents and dosage) and coligands (azide, methanol, chloride and acetate) play vital roles in determining the final structure of the complexes and therefore their magnetic properties. In complexes , the terminal and central M(2+) ions are connected through mixed bridges, μ-phenoxido/μ1,1,1-X and μ-Oalphatic/μ1,1,1-X, while central two M(2+) ions are linked by double bridges, μ1,1,1-X (X = azido and methoxido groups for and respectively). For complex , two central Ni(II) ions are connected through two μ1,1,1-N3(-) which is relatively less reported. For complexes , there are two kinds of Cd(II), the centre Cd(II) ions are eight-coordinated with triangle dodecahedral geometries, while the two side Cd(II) ions are six-coordinated with trigonal prism geometries using chlorides or acetates as terminal ligands. Magnetic susceptibility measurements (χM) for compounds have been performed, and they reveal predominant ferromagnetic exchange interactions in Co(II) and Ni(II) tetramers. The photoluminescence studies show that the Zn(II) complex and three Cd(II) complexes have strong fluorescence, and the lifetimes are measured to be in the 10(2) nanosecond timescale.
In order to determine the effect of a dam on metal concentrations in riverine fish species, we studied fish inhabiting the influent (Cachapoal River) and effluent (Rapel River) of the Rapel Reservoir in central Chile. Heavy metals were quantified in gills, liver and muscle of the catfish Trichomycterus areolatus and the silverside Basilichthys microlepidotus. Also, the bioaccumulation index (BAI) was estimated by considering heavy metal concentrations obtained from water and sediment. Results showed the presence of Al, Cu, Fe, Mn, Pb and Zn in the fish organs. The analysis showed high metal concentrations in catfish inhabiting the influent compared to those collected in the effluent. These results indicate a possible filter effect of the dam for most of the metals identified in the fish organs, because metal concentrations decreased in the effluent. Finally, catfish exhibited a larger BAI for most metals analyzed.
It remains a huge challenge to create advanced elastomers combining high strength and great toughness. Despite enhanced strength and stiffness, elastomeric nanocomposites suffer notably reduced extensibility and toughness. Here, inspired by the concept of sacrificial bonding associated with many natural materials, a novel interface strategy is proposed to fabricate elastomer/graphene nanocomposites by constructing a strong yet sacrificial interface. This interface is composed of pyridine-Zn(2+) -catechol coordination motifs, which is strong enough to ensure uniform graphene dispersion and efficient stress transfer from matrix to fillers. Moreover, they are sacrificial under external stress, which dissipates much energy and facilitates chain orientation. As a result, the strength, modulus, and toughness of the elastomeric composites are simultaneously strikingly enhanced relative to elastomeric bulk. This work suggests a promising methodology of designing advanced elastomers with exceptional mechanical properties by engineering sacrificial bonds into the interface.
Membrane-bound matrix metalloproteinase 16 (MMP16/MT3-MMP) is considered a drug target due to its role(s) in disease processes such as cancer and inflammation. Biochemical characterization of MMP16 is critical for developing new generation MMP inhibitors (MMPi), which exhibit high efficacies and selectivities. Herein, a modified over-expression and purification protocol was used to prepare the catalytic domain of MMP16 (cdMMP16). The resulting recombinant enzyme exhibited steady-state kinetic constants of K m = 10.6 ± 0.7 μM and k cat = 1.14 ± 0.02 s(-1), when using FS-6 as substrate, and the enzyme bound 1.8 ± 0.1 eq of Zn(II). The enzymatic activity of cdMMP16 is salt concentration-dependent, and cdMMP16 exhibits autoproteolytic activity under certain conditions, which may be related to an in vivo regulatory mechanism of MMP16 and of other membrane-type MMPs (MT-MMPs). Co(II)-substituted analogs (Co2- and ZnCo) of cdMMP16 were prepared and characterized using several spectroscopic techniques, such as UV-Vis, (1)H NMR, and EXAFS spectroscopies. A well-characterized cdMMP16 is now available for future inhibitor screening efforts.
By adopting inductively coupled plasma mass spectrometry (ICP-MS) combined with chemometric analysis technology, 23 kinds of minerals in four kinds of characteristic honey derived from Yunnan province were analyzed. The result showed that 21 kinds of mineral elements, namely Na, Mg, K, Ca, V, Cr, Mn, Fe, Co, Ni, Cu, Zn, As, Se, Sr, Mo, Cd, Sb, Ba, Tl and Pb, have significant differences among different varieties of honey. The results of principal component analysis (PCA) showed that the cumulative variance contribution rate of the first four main components reached 77.74%, seven kinds of elements (Mg, Ca, Mn, Co, Sr, Cd, Ba) from the first main component contained most of the honey information. Through the stepwise discriminant analysis, seven kinds of elements (Mg, K, Ca, Cr, Mn, Sr, Pb) were filtered. out and used to establish the discriminant function model, and the correct classification rates of the proposed model reached 90% and 86.7%, respectively, which showed elements contents could be effectively indicators to discriminate the four kinds characteristic honey in southern Yunnan Province. In view of all the honey samples were harvested from apiaries located at south Yunnan Province where have similar climate, soil and other environment conditions, the differences of the mineral elements contents for the honey samples mainly due to their corresponding nectariferous plant. Therefore, it is feasible to identify honey botanical source through the differences of mineral elements.
We report synthesis of cetyltrimethyl ammonium bromide (CTAB) stabilized Zn1+xSnO3+x (0 ≤ x ≤1) nano-crystallites by facile cost-effective wet chemistry route. The X-ray diffraction patterns of as-synthesized powders at the Zn/Sn ratio of 1 exhibited formation of ZnSn(OH)6. Increasing the Zn/Sn ratio further resulted in the precipitation of an additional phase corresponding to Zn(OH)2. The decomposition of these powders at 650°C for 3h led to the formation of the orthorhombic phase of ZnSnO3 and tetragonal SnO2-type phase of Zn2SnO4 at the Zn/Sn ratio of 1 and 2, respectively, with the formation of their mixed phases at intermediate compositions, i.e., at Zn/Sn ratio of 1.25, 1.50 and 1.75, respectively. The lattice parameters of orthorhombic and tetragonal phases were a ~ 3.6203 Å, b ~ 4.2646 Å and c ~ 12.8291Å (for ZnSnO3) and a = b ~ 5.0136 Å and c ~ 3.3055Å (for Zn2SnO4). The transmission electron micrographs revealed the
 formation of nano-crystallites with aspect ratio ~ 2; the length and thickness being 24, 13 nm (for ZnSnO3) and 47, 22 nm (for Zn2SnO4), respectively. The estimated direct bandgap values for the ZnSnO3 and Zn2SnO4 were found to be 4.21 eV and 4.12 eV, respectively. The ac conductivity values at room temperature (at 10 kHz) for the ZnSnO3 and Zn2SnO4 samples were 8.02 × 10-8 Ω-1 cm-1 and 6.77 × 10-8 Ω-1 cm-1, respectively. The relative permittivity was found to increase with increase in temperature, the room temperature values being 14.24 and 25.22 for the samples ZnSnO3 and Zn2SnO4, respectively. Both the samples, i.e., ZnSnO3 and Zn2SnO4, exhibited low values of loss tangent up to 300 K, the room temperature values being 0.89 and 0.72, respectively. A dye-sensitized solar cell has been fabricated using the optimized sample of zinc stannate photo-anode, i.e., Zn2SnO4. The cyclic voltammetry revealed oxidation and reduction around 0.40 V (current density ~ 11.1 mA/cm2) and 0.57 V (current density- 11.7 mA/cm2) for Zn2SnO4 photo-anode in presence of light.
Two new quaternary molybdenum(VI) antimony(III) oxides, ZnMoSb2O7 and CdMoSb4O10, have been synthesized in phase-pure form. The title compounds consist of highly polarizable cations, i.e., d(0) (Mo(6+)) and d(10) (Zn(2+) or Cd(2+)), and lone-pair cations (Sb(3+)). ZnMoSb2O7 exhibits a three-dimensional framework with ZnO4, MoO4, and SbO4 polyhedra in the polar space group P21, whereas CdMoSb4O10 exhibits one-dimensional tubule structures with CdO6, MoO4, and SbO3 polyhedra in the space group P21/m. Several synthetic efforts suggest that the the dissimilar radii of Zn(2+) and Cd(2+) that can accommodate polyhedra of Sb(3+) cations influence the stoichiometry as well as the centricity for the reported materials. Spectroscopic, thermal, and elemental analyses are reported along with dipole moment calculations. Nonlinear optical properties and their structural origin are examined for polar ZnMoSb2O7 as well.
The excitation functions were measured for the (nat)Cu(α,x)(66,67)Ga,(65)Zn,(57,58,60)Co reactions in the energy range of 16.5 -50MeV. A conventional stacked-foil activation technique combined with HPGe γ-ray spectrometry was employed to determine cross-sections. The measured cross-sections were critically compared with relevant previous experimental data and also with the evaluated data in the TENDL-2014 library. Present results confirmed some of the previous experimental data, whereas only a partial agreement was found with the evaluated data. The measured data are useful for reducing the existing discrepancies in the literature, to improve the nuclear reaction model codes, and to enrich the experimental database towards various applications.
Two chiral porous 2,3-dihydroimidazo[1,2-a]pyridine (DHIP)-based metal-organic frameworks (MOFs) are assembled from an enantiopure dipyridyl-functionalized DHIP bridging ligand. The Zn-DHIP MOF shows a good enantioseparation performance toward aromatic sulfoxides, and the heterogeneous adsorbent can be readily recovered and reused without significant degradation of the separation performance.
A high yield preparation, spectroscopic and crystallographic investigation of the crystalline Zn-complex of a di(β,β'-sulfoleno)pyrrin are reported here. In the brightly green fluorescent Zn-complex of the hardly luminescent di(β,β'-sulfoleno)pyrrin, the metal ion is bound by two di(β,β'-sulfoleno)pyrrin ligands, as revealed first by its mass spectra. The crystal structure of this Zn-complex of the di(β,β'-sulfoleno)pyrrin confirmed a regular 2:1 composition of the bidentate di(β,β'-sulfoleno)pyrrin ligand and the metal ion. The latter was coordinated in a distorted tetrahedral fashion, as found in other dipyrrin Zn-complexes. The here studied Zn-complex of a designed di(β,β'-sulfoleno)pyrrin ligand provides insights into the coordination properties of the proposed (2:1)- and (2:2)-complexes of phylloxanthobilin and bilirubin, respectively, which are two abundant natural bilin-type tetrapyrroles.

The main sources of non-exhaust vehicular emissions that contribute to road dust are tire, brake and clutch wear, road surface wear, and other vehicle and road component degradation. This study is an attempt to identify and investigate heavy metals in urban and motorway road dusts as well as in dust from brake linings and tires. Road dust was collected from sections of the A-4 motorway in Poland, which is part of European route E40, and from urban roads in Katowice, Poland. Dust from a relatively unpolluted mountain road was collected and examined as a control sample. Selected metals Cd, Cr, Cu, Ni, Pb, Zn, Fe, Se, Sr, Ba, Ti, and Pd were analyzed using inductively coupled plasma-mass spectrometry, inductively coupled plasma (ICP)-optical emission spectroscopy, and atomic absorption spectroscopy on a range of size-fractionated road dust and brake lining dust (<20, 20-56, 56-90, 90-250, and >250 μm). The compositions of brake lining and tire dust were also investigated using scanning electron microscopy-energy-dispersive spectroscopy. To estimate the degree of potential environmental risk of non-exhaust emissions, comparison with the geochemical background and the calculations of geo-accumulation indices were performed. The finest fractions of urban and motorway dusts were significantly contaminated with all of the investigated metals, especially with Ti, Cu, and Cr, which are well-recognized key tracers of non-exhaust brake wear. Urban dust was, however, more contaminated than motorway dust. It was therefore concluded that brake lining and tire wear strongly contributed to the contamination of road dust.
In previous studies, variability was high among replicate acute cadmium (Cd) Daphnia magna lethality tests (e.g., >10-fold range of median effect concentrations [EC50s]), less among zinc (Zn) tests, and relatively low for copper (Cu) and nickel (Ni) tests. Although the US Environmental Protection Agency's (USEPA's) protocol includes starting toxicity tests with neonates less than 24 h old, the authors hypothesized that age-related differences in sensitivity to metals might occur even within that relatively narrow age range. Daphnia magna neonates were collected during 3 age windows (0-4 h, 10-14 h, and 20-24 h old) and immediately exposed to each of the 4 metals for 48 h using the standard USEPA protocol. In repeated sets of tests during different weeks, the Cd EC50 of the youngest neonates was approximately 10-fold greater than the EC50 of the oldest neonates (i.e., Cd was less toxic to the youngest neonates) and the EC50 of neonates aged 10 h to 14 h was intermediate. Age-related differences were negligible in Cu, Ni, and Zn tests. Therefore, variability in toxicity of Cd may partly be caused by temporal variability in neonate age at the start of toxicity tests. Decreasing the age range of D. magna used in toxicity tests could help to improve the accuracy and precision of toxicity models, particularly for metal mixtures. Environ Toxicol Chem 2016;9999:1-7. © 2016 SETAC.
Metabolic syndrome is a frequent precursor of type 2 diabetes mellitus (T2D), a disease that currently affects ∼8% of the adult population worldwide. Pancreatic beta-cell dysfunction and loss are central to the disease process, although understanding of the underlying molecular mechanisms is still fragmentary.
Oversupply of nutrients, including glucose and fatty acids, and the subsequent overstimulation of beta cells, are believed to be an important contributor to insulin secretory failure in T2D. Hypoxia has also recently been implicated in beta-cell damage. Accumulating evidence points to a role for oxidative stress in both processes. Although the production of reactive oxygen species (ROS) results from enhanced mitochondrial respiration during stimulation with glucose and other fuels, the expression of antioxidant defense genes is unusually low (or disallowed) in beta cells.
Not all subjects with metabolic syndrome and hyperglycemia go on to develop full-blown diabetes, implying an important role in disease risk for gene-environment interactions. Possession of common risk alleles at the SLC30A8 locus, encoding the beta-cell granule zinc transporter ZnT8, may affect cytosolic Zn(2+) concentrations and thus susceptibility to hypoxia and oxidative stress.
Loss of normal beta-cell function, rather than total mass, is increasingly considered to be the major driver for impaired insulin secretion in diabetes. Better understanding of the role of oxidative changes, its modulation by genes involved in disease risk, and effects on beta-cell identity may facilitate the development of new therapeutic strategies to this disease. Antioxid. Redox Signal. 00, 000-000.
Trace metals contamination in commercial fish and crustaceans have become a great problem in Bangladesh. This study was conducted to determine seven trace metals concentration (Cr, Ni, Cu, Zn, As, Cd, and Pb) in some commercial fishes and crustaceans collected from coastal areas of Bangladesh. Trace metals in fish samples were in the range of Cr (0.15 - 2.2), Ni (0.1 - 0.56), Cu (1.3 - 1.4), Zn (31 - 138), As (0.76 - 13), Cd (0.033 - 0.075), and Pb (0.07 - 0.63 mg/kg wet weight (ww)), respectively. Arsenic (13 mg/kg ww) and Zn (138 mg/kg ww) concentrations were remarkably high in fish of Cox's Bazar due to the interference of uncontrolled huge hatcheries and industrial activities. The elevated concentrations of Cu (400), Zn (1480), and As (53 mg/kg ww) were also observed in crabs of Cox's Bazar which was considered as an absolutely discrepant aquatic species with totally different bioaccumulation pattern. Some metals in fish and crustaceans exceeded the international quality guidelines. Estimated daily intake (EDI) and target cancer risk (TR) revealed high dietary intake of As and Pb, which was obviously a matter of severe
 public health issue of Bangladeshi coastal people which should not be ignored and concentrate our views to solve this problem with an integrated approaches. Thus, continuous monitoring of these toxic trace elements in seafood and immediate control measure is recommended.
To provide growing population with sufficient food, greenhouse vegetable production has expanded rapidly in recent years in China and sustainability of its farming practices is a major concern. Therefore, this study assessed the sustainability of greenhouse vegetable farming practices from environmental, economic, and socio-institutional perspectives in China based on selected indicators. The empirical data were collected through a survey of 91 farm households from six typical greenhouse vegetable production bases and analysis of environmental material samples. The results showed that heavy fertilization in greenhouse vegetable bases of China resulted in an accumulation of N, P, Cd, Cu, Pb, and Zn in soil, nutrient eutrophication in irrigation water, and high Cd in some leaf vegetables cultivated in acidic soil. Economic factors including decreased crop yield in conventional farming bases, limited and site-dependent farmers' income, and lack of complete implementation of subsidy policies contributed a lot to adoption of heavy fertilization by farmers. Also, socio-institutional factors such as lack of unified management of agricultural supplies in the bases operated in cooperative and small family business models and low agricultural extension service efficiency intensified the unreasonable fertilization. The selection of cultivated vegetables was mainly based on farmers' own experience rather than site-dependent soil conditions. Thus, for sustainable development of greenhouse vegetable production systems in China, there are two key aspects. First, it is imperative to reduce environmental pollution and subsequent health risks through integrated nutrient management and the planting strategy of selected low metal accumulation vegetable species especially in acidic soil. Second, a conversion of cooperative and small family business models of greenhouse vegetable bases to enterprises should be extensively advocated in future for the unified agricultural supplies management and improved agricultural extension service efficiency, which in turn can stabilize vegetable yields and increase farmers' benefits.
The Ardley Cove area (located on the Maxwell Bay shoreline, Fildes Peninsula, King George Island, Antarctica) is characterized not only by its high biodiversity, but also by a high density of scientific stations, making it potentially one of the most impacted areas of Antarctica. In order to assess the source, contamination levels, distribution and availability of several trace elements (Cr, Ni, Cu, Zn, As, Pb, Cd and Hg) in and around Maxwell Bay, soil and seawater samples were collected. Soil samples were also collected in the study reference site near the Bellingshausen Dome area, as it lies far from centers of human activity and associated infrastructure. Enrichment factors (EFs) and sequential extractions were also used to assess the degree of contamination and availability of the trace elements under investigation. The results obtained in this study pointed to the existence of several contamination hotspots, mainly related to high levels of Zn, Pb, Cd, Cr and Ni. Comparison of the contaminant distribution patterns with data from earlier studies allowed the identification of anthropogenic sources. Use of the EF approach and sequential extractions confirmed these findings. In particular, higher extraction proportions were obtained for Zn and Pb (68 and 71%, respectively), which were also the same elements where the highest EFs were determined. The results obtained in this study clearly point to human impact on the natural environment in this region of Antarctica and we recommend the implementation of appropriate contamination control and remediation methods.
The ability to precisely control interfaces of atomic layer deposited (ALD) zinc oxysulfide (Zn(O,S)) buffer layers to other layers allows precise tuning of solar cell performance. The O K- and S K-edge X-ray absorption near edge structure (XANES) of ∼2-4 nm thin Zn(O,S) films reveals the chemical and structural influences of their interface with ZnO, a common electrode material and diffusion barrier in solar cells. We observe that sulfate formation at oxide/sulfide interfaces is independent of film composition, a result of sulfur diffusion toward interfaces. Leveraging sulfur's diffusivity, we propose an alternative ALD process in which the zinc precursor pulse is bypassed during H2S exposure. Such a process yields similar results to the nanolaminate deposition method and highlights mechanistic differences between ALD sulfides and oxides. By identifying chemical species and structural evolution at sulfide/oxide interfaces, this work provides insights into increasing thin film solar cell efficiencies.
In this study, an extracellular alkali-thermostable phytase producing bacteria, Bacillus subtilis B.S.46, were isolated and molecularly identified using 16S rRNA sequencing. Response surface methodology was applied to study the interaction effects of assay conditions to obtain optimum value for maximizing phytase activity. The optimization resulted in 137% (4.627 U/mL) increase in phytase activity under optimum condition (56.5 °C, pH 7.30 and 2.05 mM sodium phytate). The enzyme also showed 60-73% of maximum activity at wide ranges of temperature (47-68 °C), pH (6.3-8.0) and phytate concentration (1.40-2.50 mM). The partially purified phytase demonstrated high stability over a wide range of pH (6.0-10.0) after 24 h, retaining 85% of its initial activity at pH 6 and even interestingly, the phytase activity enhanced at pH 8.0-10.0. It also exhibited thermostability, retaining about 60% of its original activity after 2 h at 60 °C. Cations such as Ca(2+) and Li(+) enhanced the phytase activity by 10-46% at 1 mM concentration. The phytase activity was completely inhibited by Cu(2+), Mg(2+), Fe(2+), Zn(2+), Hg(2+) and Mn(2+) and the inhibition was in a dose dependent manner. B. subtilis B.S.46 phytase had interesting characteristics to be considered as animal feed additive, dephytinization of food ingredients, and bioremediation of phosphorous pollution in the environment.
Lactic acid is an important platform molecule in the synthesis of a wide range of chemicals. However, in aqueous solutions without alkali, its efficient preparation via the direct catalysis of sugars is hindered by a side dehydration reaction to 5-hydroxymethylfurfural due to Brønsted acid, which originates from organic acids. Herein, we report that a previously unappreciated combination of common two metal mixed catalyst (Zn-Sn-Beta) prepared via solid-state ion exchange synergistically promoted this reaction. In water without a base, a conversion exceeding 99% for sucrose with a lactic acid yield of 54% was achieved within 2 hours at 190 °C under ambient air pressure. Studies of the acid and base properties of the Zn-Sn-Beta zeolite suggest that the introduction of Zn into the Sn-Beta zeolite sequentially enhanced both the Lewis acid and base sites, and the base sites inhibited a series of side reactions related to fructose dehydration to 5-hydroxymethylfurfural and its subsequent decomposition.
The successful use of anaerobic reactors for bioremediation of acid mine drainage has been shown in systems with neutral pH. However, the choice of an efficient and suitable process for such wastewater must consider the capability of operating at acidic pH and in the presence of metals. This work studies the performance of an anaerobic batch reactor, under conditions of varying initial pH for its efficiencies in sulfate removal and metal precipitation from synthetic acid mine drainage. The chemical oxygen demand/sulfate (COD/SO4(2-)) ratio used was 1.00, with ethanol chosen as the only energy and carbon source. The initial pH of the synthetic drainage was progressively set from 7.0 to 4.0 to make it as close as possible to that of real acid mine drainage. Metals were also added starting with iron, zinc, and finally copper. The effectiveness of sulfate and COD removal from the synthetic acid mine drainage increased as the initial pH was reduced. The sulfate removal increased from 38.5 ± 3.7% to 52.2 ± 3%, while the removal of organic matter started at 91.7 ± 2.4% and ended at 99 ± 1%. These results indicate that the sulfate reducing bacteria (SRB) community adapted to lower pH values. The metal removal observed was 88 ± 7% for iron, 98.0 ± 0.5% for zinc and 99 ± 1% for copper. At this stage, an increase in the sulfate removal was observed, which reaches up to 82.2 ± 5.8%. The kinetic parameters for sulfate removal were 0.22 ± 0.04 h(-1) with Fe, 0.26 ± 0.04 h(-1) with Fe and Zn and 0.44 ± 0.04 h(-1) with Fe, Zn, and Cu.
Panasqueira mine is a tin-tungsten mineralization hosted by metasediments with quartz veins rich in ferberite. The mineralization also comprises wolframite, cassiterite, chalcopyrite, several sulfides, carbonates and silver sulfosalts. The mining and beneficiation processes produce arsenic-rich mine wastes laid up in huge tailings (Barroca Grande and Rio tailings). The contents of As, Cd, Cr, Cu, Pb and Zn were estimated in rhizosphere soils, irrigation waters, road dusts and in potatoes, cabbages, lettuces and beans, collected on local gardens of four neighborhood Panasqueira mine villages: S. Francisco de Assis (SFA) and Barroca suffering the influence of tailings; Unhais-o-Velho and Casegas considered as non-polluted areas. The mean concentrations of metals in rhizosphere soils and vegetables exceed the reference guidelines values and seem to be linked to the sulfides. The rhizosphere ecological risks were ranked in the order
 of Cd > As > Cu > Pb > Zn > Cr and SFA > Barroca > Casegas > Unhais-o-Velho. Metal concentrations, in vegetables, were found in the order of lettuce > cabbage > potatoes and SFA > Barroca > Casegas > Unhais-o-Velho. For cabbages and lettuces, the tendency of contamination is roots > leaves and for potatoes is roots > leaves > tubers. The risk for residents, due to ingesting of metals/metalloid, by consuming vegetables grown around the sampling area, was calculated and the result indicates that the inhabitants of these villages are probably exposed to some potential health risks through the intake of heavy metals and metalloids via consuming their vegetables.
In this work we investigate the presence of divalent cations bound to the Glossoscolex paulistus (HbGp) hemoglobin and their effect over the protein stability and the peroxidase (POD) activity. Atomic absorption studies show that the HbGp iron content is consistent with the presence of 144 ions per protein. Moreover, using iron as a reference, the content of calcium was estimated as 30±4 ions per protein, independently of the EDTA pre-treatment or not prior to the acidic treatment performed in the protein digestion. The zinc content was 14±2 ions in the absence of EDTA pre-treatment, and 3±1 ions per protein in the presence of EDTA pre-treatment, implying the presence of one zinc ion per protomer (1/12 of the whole molecule). Finally, the copper concentration is negligible. Different from the vertebrate hemoglobins, where the effectors are usually organic anions, the hexagonal bilayer hemoglobins have as effectors inorganic cations that increase the oxygen affinity and stabilize the structure. Previous studies have suggested that the presence of divalent cations, such as copper and zinc, is related to the different types of antioxidant enzymatic activities as the superoxide dismutase (SOD) activity shown by giant hemoglobin from Lumbricus terrestris (HbLt). Recently, studies on HbGp crystal structure have confirmed the presence of Zn(2+) and Ca(2+) binding sites. The Ca(2+) sites are similar as observed in the HbLt crystal structure. Otherwise, the Zn(2+) sites have no relation with those observed in Cu/Zn SODs. Our peroxidase assays with guaiacol confirm the POD activity and the effect of the zinc ions for HbGp. Our present results on HbGp metal content and their stability effects is the first step to understand the role of these cations in HbGp function in the future.
The dynamic loading in human body, along with the corrosive body fluid, presents a great challenge for the practical use of biodegradable magnesium implants. In this study, a high purity magnesium (99.99wt.%) and two typical promising biodegradable magnesium alloys (binary Mg-1Ca and ternary Mg-2Zn-0.2Ca) were chosen as the experimental materials. Their dynamic mechanical performances were comparatively evaluated by carrying out fatigue tests in air and in simulated body fluid (SBF). The fatigue strengths of HP-Mg, Mg-1Ca and Mg-2Zn-0.2Ca were all around 90MPa in air, however, they decreased to 52MPa, 70MPa and 68MPa in SBF at 4×10(6)cycles, respectively. The fatigue cracks initiated from the microstructural defects when tested in air, but nucleated from surface corrosion pits when tested in SBF. Cyclic loading significantly increased the corrosion rates of all the experimental materials compared to that in static SBF. Moreover, based on our findings, the fatigue failure processes and interactions between material, corrosion and cyclic loading were systematically discussed.
Fatigue strength and life are vital parameters to the design of metallic implant devices. For the corrosion fatigue of biomedical magnesium alloys, we reported the corrosion fatigue behavior of AZ91D and WE43 in SBF (Acta Biomaterialia, 6 (2010) 4605-4613), and till now there is no other reports to our knowledge. We spent 3years to finish the fatigue testing and get S-N curves for three more magnesium biomaterials, and our significant finding is that the fatigue strengths of HP-Mg, Mg-1Ca and Mg-2Zn-0.2Ca are all around 90MPa in air but 52MPa, 70MPa and 68MPa in SBF at 4×10(6)cycles, which will provide the first-hand data for the future magnesium implants design.
The persistent problem of antibiotic resistance has created a strong demand for new methods for therapy and disinfection. Photodynamic inactivation (PDI) of microbes has demonstrated promising results for eradication of antibiotic-resistant strains. PDI is based on the use of a photosensitive compound (photosensitizer, PS), which upon illumination with visible light generates reactive species capable of damaging and killing microorganisms. Since photogenerated reactive species are short lived, damage is limited to close proximity of the PS. It is reasonable to expect that the larger the number of damaged targets is and the greater their variety is, the higher the efficiency of PDI is and the lower the chances for development of resistance are. Exact molecular mechanisms and specific targets whose damage is essential for microbial inactivation have not been unequivocally established. Two main cellular components, DNA and plasma membrane, are regarded as the most important PDI targets. Using Zn porphyrin-based PSs and Escherichia coli as a model Gram-negative microorganism, we demonstrate that efficient photoinactivation of bacteria can be achieved without detectable DNA modification. Among the cellular components which are modified early during illumination and constitute key PDI targets are cytosolic enzymes, membrane-bound protein complexes, and the plasma membrane. As a result, membrane barrier function is lost, and energy and reducing equivalent production is disrupted, which in turn compromises cell defense mechanisms, thus augmenting the photoinduced oxidative injury. In conclusion, high PDI antimicrobial effectiveness does not necessarily require impairment of a specific critical cellular component and can be achieved by inducing damage to multiple cellular targets.
Ag(+) mediated aggregation behaviour of two different amphiphilic zinc phthalocyanines (Zn-Pcs) (symmetric and asymmetric) has been investigated in solution, at the air-water interface and in Langmuir-Blodgett (LB) films transferred onto glass substrates. A 4 : 1 ([Ag(+)]/[Pc]) complexation was observed for both symmetric and asymmetric Zn-Pcs at high [Ag(+)] concentrations which led to the formation of H-aggregates in solution. At the air-water interface, both symmetric and asymmetric Zn-Pcs showed a tilted, edge-on orientation in columnar stacks. Addition of Ag(+) to the subphase enhanced the order in the monolayers. LB films on glass substrates showed a split Q-band indicating the presence of "herring-bone" type aggregation consisting of both H- and J-aggregates. For LB films deposited from a Ag(+) containing subphase, a shoulder appeared in the absorption spectra at longer wavelengths which indicates that the fraction of J-aggregates was enhanced by Ag(+) in LB films. The molecular orientation in LB films was investigated by polarized absorption spectroscopy and a tilt angle was calculated to be 49° with the substrate normal for symmetric and 74.6° for the asymmetric Zn-Pc. The presence of Ag(+) cations in the subphase decreased the tilt angles slightly by 4-5°. These results indicate that Ag(+) induced the aggregation of Zn-Pcs and acted as a linker between Pc molecules in the ultrathin films of both symmetric and asymmetric Zn-Pcs. These results are important in inducing J-aggregates for the fabrication of molecular devices based on phthalocyanine thin films.
Aqueous waste streams of the metallurgical industry often contain considerable concentrations of metal salts. Previous research showed that the metal chloride salts of zinc(ii), manganese(ii) and iron(iii) can be recovered by solvent extraction using a sustainable and renewable fatty acid based ionic liquid as the extractant. In this paper, the extraction mechanism of Zn(ii), Co(ii) and Ni(ii) from chloride media has been studied systematically. The metal extraction performances of the precursors, sodium oleate and tetraoctylammonium chloride, were compared to the extraction performance of the ionic liquid tetraoctylammonium oleate. Slope analysis experiments were performed to determine the number of ionic liquid molecules involved in the extraction. The experimental data showed that Co(ii) and Ni(ii) were extracted in the pH range from 6 to 8 by the formation of negatively charged metal carboxylate complexes with tetraalkylammonium counter ions. In contrast, Zn(ii) gets extracted as a mixed metal chloride carboxylate anionic complex with tetraalkylammonium counter ions. This extraction mechanism was supported by EXAFS measurements.
The purpose of this study is to evaluate the contamination in As, Ba, Co, Cu, Mn, Ni, Sr, V, Zn and REE, in a high uranium activity (up to 21,000Bq∙kg(-1)) area, downstream of a former uranium mine. Different geochemical proxies like enrichment factor and fractions from a sequential extraction procedure are used to evaluate the level of contamination, the mobility and the availability of the potential contaminants. Pb isotope ratios are determined in the total samples and in the sequential leachates to identify the sources of the contaminants and to determine the mobility of radiogenic Pb in the context of uranium mining. In spite of the large uranium contamination measured in the soils and the sediments (EF≫40), trace element contamination is low to moderate (2<EF<5), except for Ba (5<EF<15), due to the precipitation of barium sulfate resulting from mining activities. Most of the trace elements are associated with the most mobile fractions of the sediments/soils, implying an enhanced potential availability. Even if no Pb enrichment is highlighted, the Pb isotopic signature of the contaminated soils is strongly
 radiogenic. Measurements performed on the sequential leachates reveal inputs of radiogenic Pb in the most mobile fractions of the contaminated soil. Inputs of low-mobile radiogenic Pb from mining activities may also contribute to the Pb signature recorded in the residual phase of the contaminated samples. We demonstrate that Pb isotopes are efficient tools to trace the origin and the mobility of the contaminants in environments affected by uranium mining.
A 3D porous Cu current collector is fabricated through chemical dealloying from a commerial Cu-Zn alloy tape. The interlinked porous framework naturally integrated can accommodate Li deposition, suppressing dendrite growth and alleviating the huge volume change during cycling. The Li metal anode combined with such a porous Cu collector demonstrates excellent performance and commerial potentials in Li-based secondary batteries.
Excessive use of nitrogen (N) fertilizer has increased ammonium (NH4(+) ) accumulation in many paddy soils to levels that reduce rice vegetative biomass and yield. Based on studies of NH4(+) toxicity in rice (Oryza sativa, Nanjing 44) seedlings cultured in agar medium, we found that NH4(+) concentrations above 0.75 mM inhibited the growth of rice and caused NH4(+) accumulation in both shoots and roots. Use of excessive NH4(+) also induced rhizosphere acidification and inhibited the absorption of K, Ca, Mg, Fe and Zn in rice seedlings. Under excessive NH4(+) conditions, exogenous γ-aminobutyric acid (GABA) treatment limited NH4(+) accumulation in rice seedlings, reduced NH4(+) toxicity symptoms and promoted plant growth. GABA addition also reduced rhizosphere acidification and alleviated the inhibition of Ca, Mg, Fe and Zn absorption caused by excessive NH4(+) . Furthermore, we found that the activity of glutamine synthetase/NADH-glutamate synthase (GS; EC 6.3.1.2/NADH-GOGAT; EC1.4.1.14) in root increased gradually as the NH4(+) concentration increased. However, when the concentration of NH4(+) is more than 3 mM, GABA treatment inhibited NH4(+) -induced increases in GS/NADH-GOGAT activity. The inhibition of ammonium assimilation may restore the elongation of seminal rice roots repressed by high NH4(+) . These results suggest that mitigation of ammonium accumulation and assimilation is essential for GABA-dependent alleviation of ammonium toxicity in rice seedlings.
Agaricus bisporus (white button mushroom) is an important culinary and medicinal species of worldwide importance. The present study investigated for the first time whether it may be grown on substrates supplemented with Se alone or in combination with Cu and/or Zn (0.1-0.8 mM) to produce fruiting bodies of increased nutritional value.
As found, substrate supplementation did not affect yielded biomass up to 0.6 mM element concentrations regardless cultivation model. At 0.8 mM Se + Cu and Se + Zn supplementation still developed biomass comparable with controls. The accumulation of trace elements in the fruiting bodies generally increased over concentration gradient reaching its maximum at 0.6 mM (for Se + Zn and Se + Cu + Zn) and 0.8 mM (for Se and Se + Cu). The organic Se constituted the greatest share in total Se quota. As calculated, each 10 g of dried fruiting bodies of A. bisporus obtained from 0.6 or 0.8 mM supplementation would represent 342-469% of Recommended Daily Allowance (RDA) for Se, 43.4-48.5% for Cu and 5.2-5.8% for Zn.
Considering an inexpensive methods of A. bisporus cultivation, global popularity and use of this mushroom, its biofortification with Se, Cu and Zn could have a practical application in deficiency prevention and assisted treatment.
A Zr-based metal-organic framework with zinc tetrakis(carboxyphenyl)-porphyrin (ZnTCPP) groups (MOF-525-Zn) was utilized to develop a novel electrochemiluminescence (ECL) biosensor for highly sensitive protein kinase activity assay. In this work, in terms of ECL measurements and cyclic voltammetry, the cathodic ECL behaviors of MOF-525-Zn in aqueous media were thoroughly investigated for the first time. The photoelectric active groups ZnTCPP on the MOF-525-Zn frameworks could promote the generation of singlet oxygen ((1)O2) via a series of electrochemical and chemical reactions, resulting in a strong and stable red irradiation at 634 nm. Additionally, the surfactant tetraoctylammonium bromide (TOAB) further facilitated dissolved oxygen to interact with the active sites ZnTCPP of MOF-525-Zn. Furthermore, the inorganic Zr-O clusters of MOF-525-Zn were simultaneously served as the recognition sites of phosphate groups. And then, an ultrasensitive ECL sensor was proposed for protein kinase A (PKA) activity detection with a linear range from 0.01 to 20 U mL(-1) and a sensitive detection limit of 0.005 U mL(-1). This biosensor can also be applied for quantitative kinase inhibitor screening. Finally, it exhibits good performance with high stability and acceptable fabrication reproducibility, which provide a valuable strategy for clinic diagnostics and therapeutics.
Pollution of surface water with heavy metals from industrial activities especially those from scrap yard has caused a major threat to human life exposing man to series of hazard, diseases, disability and consequently death. This study focuses on water quality indices of Owode-Onirin and Lafenwa scrap yard with respect to its physicochemical parameters and heavy metal concentrations by evaluating Heavy Metal Pollution Index (HPI), Metal Index (MI) and Potential Ecological Risk Index (PERI). Fifteen water samples were selected randomly from two locations by purposive sampling methods. Five heavy metals which includes Nickel (Ni), Zinc (Zn), Copper (Cu), Cadmium (Cd), Lead (Pb) were analyzed using Atomic Absorption Spectroscopy and standard analytical procedure were follow to ensure accuracy. One way analysis of variance was carried out to analyse the data. The concentrations of the heavy metals were significantly different between sampling locations. However, the mean concentrations of Cd (0.0121 mg/L) were found to be above the highest permissible value of Standard Organization of Nigeria standards for drinking water (SON 2007) and WHO (Guidelines for drinking water quality: incorporating 1st and 2nd Addlenda. World Health Organization, Geneva, 2004) for drinking water. Although Pb was present in two out of the fifteen water samples with a mean value of (0.0324 mg/L) which was also above the highest permissible value. The mean concentrations of Zn (0.2149 mg/L) and Cu (0.0341 mg/L) are found to be below the highest permissible value of the mentioned guideline while no trace of Ni was found in the water samples across the two sampling locations. The mean HPI 518.55 is far above the critical value of 100, indicates that selected water samples are critically polluted with heavy metals. MI revealed low quality water with mean value 4.83, suggests that the selected water is seriously affected with the present of heavy metal. The Hakanson PERI indicated that of the five heavy metals, the risk coefficient of Zn, Pb, Cu, and Ni had light levels of contamination while the level of Cd contamination posed the most serious potential ecological risk, with an index value between 14.1 and 234. The study concluded that order of magnitude to this five heavy metals contamination is Cd > Pb > Zn > Cu > Ni.
Eu(2)(+) -doped Sr2 SiO4 phosphor with Ca(2)(+) /Zn(2)(+) substitution, (Sr1-x Mx )2 SiO4 :Eu(2)(+) (M = Ca, Zn), was prepared using a high-temperature solid-state reaction method. The structure and luminescence properties of Ca(2)(+) /Zn(2)(+) partially substituted Sr2 SiO4 :Eu(2)(+) phosphors were investigated in detail. With Ca(2)(+) or Zn(2)(+) added to the silicate host, the crystal phase could be transformed between the α-form and the β-form of the Sr2 SiO4 structure. Under UV excitation at 367 nm, all samples exhibit a broad band emission from 420 to 680 nm due to the 4f(6) 5d(1)  → 4f(7) transition of Eu(2)(+) ions. The broad emission band consists of two peaks at 482 and 547 nm, which correspond to Eu(2)(+) ions occupying the ten-fold oxygen-coordinated Sr.(I) site and the nine-fold oxygen-coordinated Sr.(II) site, respectively. The luminescence properties, including the intensity and lifetime of Sr2 SiO4 :Eu(2)(+) phosphors, improved remarkably on Ca(2)(+) /Zn(2)(+) addition, and promote its application in white light-emitting diodes. Copyright © 2016 John Wiley & Sons, Ltd.
The leaching of Sb from waste-to-energy (WtE) bottom ash (BA) often exceeds the Dutch limit value of 0.32mgkg(-1) for recycling of BA in open construction applications. From the immobilization mechanisms described in the literature, it could be concluded that both Ca and Fe play an important role in the immobilization of Sb in WtE BA. Therefore, Ca and Fe containing compounds were added to the samples of the sand fraction of WtE BA, which in contrast to the granulate fraction is not recyclable to date, and the effect on the Sb leaching was studied by means of batch leaching tests. Results showed that addition of 0.5 and 2.5% CaO, 5% CaCl2, 2.5% Fe2(SO4)3 and 1% FeCl3 decreased the Sb leaching from 0.62±0.02mgkgDM(-1) to 0.20±0.02, 0.083±0.044, 0.25±0.01, 0.27±0.002 and 0.29±0.02mgkgDM(-1), respectively. Due to the increase in pH from 11.41 to 12.53 when 2.5% CaO was added, Pb and Zn leaching increased and exceeded the respective leaching limits. Addition of 5% CaCO3 had almost no effect on the Sb leaching, as evidenced by the resulting 0.53mgkgDM(-1) leaching concentration. This paper shows a complementary enhancement of the effect of Ca and Fe, by comparing the aforementioned Sb leaching results with those of WtE BA with combined addition of 2.5% CaO or 5% CaCl2 with 2.5% Fe2(SO4)3 or 1% FeCl3. These lab scale results suggest that formation of romeites with a high Ca content and formation of iron antimonate
 (tripuhyite) with a very low solubility are the main immobilization mechanisms of Sb in WtE BA. Besides the pure compounds and their mixtures, also addition of 10% of two Ca and Fe containing residues of the steel industry, hereafter referred to as R1 and R2, was effective in decreasing the Sb leaching from WtE BA below the Dutch limit value for reuse in open construction applications. To evaluate the long term effect of the additives, pilot plots of WtE BA with 10% of R1 and 5% and 10% of R2 were built and samples were submitted to leaching tests at regular intervals over time. The Sb leaching from untreated WtE BA was just below or above the Dutch limit value. The Sb leaching from the pilot plots of BA with additives first remained stable around 0.13mgkg(-1) but had a tendency to slightly increase after 6months, indicating the need for further research on the effect of weathering, and more specifically of carbonation, on Sb leaching from WtE BA.
Willows (Salix spp.) can be used to phytoremediate soils contaminated by Zn and Cd under certain conditions. In this study, the ability of 14 Salix cultivars to concentrate Cd, Zn and S in leaves was measured in hydroponic culture with 10 and 200 µM Cd and Zn, respectively, in the nutrient medium. The cultivars showed a wide range of biomass yields, tolerance to metals, and foliar concentrations of Zn and Cd, with some cultivars accumulating up to 1000 mg kg(-1) Zn, 70 mg kg(-1) Cd and 10,000 mg kg(-1) S with only mild phytotoxicity symptoms attributable to excess Zn. Cultivars with higher foliar Zn concentrations tended to have higher foliar Cd concentrations as well, and competition between Zn and Cd for uptake was observed. Exposure of Salix cultivars to Cd and Zn did not affect foliar concentrations of secondary metabolites such as polyphenols, but trace metal concentrations in leaves were significantly reduced (Fe and Cu) or increased (Mn) by exposure to excess Zn and Cd. Sulfur-XANES spectroscopy showed foliar S to be predominantly in highly oxidized (sulfate plus sulfonate) and reduced (thiol) forms, with oxidized S more prevalent in willows with the highest total S content.
Metallothionein (MT) is a cysteine-rich, low-molecular-weight protein, which adopts a unique dumbbell-shaped structure with a stable C-terminal α-domain and a reactive N-terminal β-domain. The specific configuration serves as a unique scaffold for the synthesis of ultra-small fluorescent metal nanoclusters (NCs). For the first time, MT-templated Ag NCs (MT-Ag NCs) with excellent antioxidant capacity and superior biocompatibility were facilely synthesized. The NCs were thoroughly characterized by various techniques. Zn(2+) in the β-domain was preferentially replaced by Ag(+), which was then reduced by NaBH4 to yield Ag NCs, while Zn(2+) in the α-domain was intactly tetrahedrally-coordinated through thiolate ligands in MT. Fluorescent imaging of HeLa cells was achieved by attaching folic acid (FA) to MT-Ag NCs. Due to the strong binding capacity toward the thiolate ligands in the α-domain, Hg(2+) was assayed via quenching the fluorescence of Ag NCs by an energy transfer process. The methodology described herein may be extended to the synthesis of other metal NCs with potential applications in biosensing and cell imaging.
In this work, a non-commercial triaxial geometry energy dispersive X-ray Fluorescence (EDXRF) setup and a benchtop µ-XRF system were used to identify postmortem contamination in buried bones. For two of the individuals, unusually high concentrations of Cu and Pb, but also Zn (in one individual) were observed. The pigments of the burial shroud coverings have been identified as the source of contamination. Accurate and precise quantitative results were obtained by nondestructive process using fundamental parameters method taking into account the matrix absorption effects. A total of 30 bones from 13 individuals, buried between the mid-XVIIIth to early XIXth centuries, were analyzed to study the elemental composition and elemental distribution. The bones were collected from a church in Almada (Portugal), called Ermida do Espírito Santo, located near the Tagus River and at the sea neighbourhood. The triaxial geometry setup was used to quantify Ca, Fe, Cu, Zn, Br, Sr and Pb of powder pressed bone pellets (n=9 for each bone). Cluster analysis was performed considering the elemental concentrations for the different bones. There was a clear association between some bones regarding Fe, Cu, Zn, Br and Pb content but not a categorization between cortical and trabecular bones. The elemental distribution of Cu, Zn and Pb were assessed by the benchtop μ-analysis, the M4 Tornado, based on a polycapillary system which provides multi-elemental 2D maps. The results showed that contamination was mostly on the surface of the bone confirming that it was related to the burial shroud covering the individuals.
A large number of studies demonstrated that acanthocephalans exhibit a high metal accumulation potential and thus can be used as sensitive accumulation indicators. However, similar to free-living bioindicators, a seasonal variation in metal concentrations in parasites might occur. Accordingly, the influence of seasonality has to be elucidated if parasites should be applied as sentinels.
In order to assess a possible seasonal profile of element concentrations, the concentrations of As, Cd, Co, Cu, Fe, Mn, Mo, Ni, Pb, V and Zn in the acanthocephalan Pomphorhynchus laevis and in its host barbel (Barbus barbus) were analysed in a seasonal manner (spring, summer and autumn) using inductively coupled plasma mass spectrometry (ICP-MS).
Five elements (As, Cd, Cu, Pb and Zn) were detected in significantly higher concentrations in the parasites compared to host muscle, intestine and liver. Their levels in P. laevis showed a clear seasonal pattern, while the concentrations in the fish tissues remained similar during the year. The highest concentrations in the parasites were found in autumn, followed by spring and summer. Evidence from the literature suggests that this profile coincides with the seasonality of acanthocephalan transmission, as their annual concentration profile reflected the mean individual weight pattern during the year. Parasite infrapopulations in autumn consisted mainly of young worms which are characterised by an accelerated metabolism and a higher surface to volume ratio resulting in higher element concentrations when compared to older worms which are assumed to slow down their metabolism and additionally excrete metals with their eggs.
Based on the available data from the present study and literature, a model is suggested, which visualises the accumulation kinetic of several elements under natural conditions. According to the element accumulation data the lifespan of P. laevis in barbel was roughly estimated to range between six and eight months.
Selecting plant species that can overcome unfavorable conditions and increase the recovery of degraded mined lands remains a challenge. A pot experiment was conducted to evaluate the feasibility of using transplanted tree seedlings for the phytoremediation of lead/zinc and copper mine tailings. One-year-old bare-root of woody species (Rhus chinensis Mill, Quercus acutissima Carruth, Liquidambar formosana Hance, Vitex trifolia Linn. var. simplicifolia Cham, Lespedeza cuneata and Amorpha fruticosa Linn) were transplanted into pots with mine tailings and tested as potential metal-tolerant plants. Seedling survival, plant growth, root trait, nutrient uptake, and metal accumulation and translocation were assessed. The six species grew in both tailings and showed different tolerance level. A. fruticosa was highly tolerant of Zn, Pb and Cu, and grew normally in both tailings. Metal concentrations were higher in the roots than in the shoots of the six species. All of the species had low bioconcentration and translocation factor values. However, R. chinensis and L. formosana had significantly higher translocation factor values for Pb (0.88) and Zn (1.78) than the other species. The nitrogen-fixing species, A. fruticosa, had the highest tolerance and biomass production, implying that it has great potential in the phytoremediation of tailing areas in southern China.
2-[2-[2-[2-[bis(carboxylatomethyl)amino]-5-methoxyphenoxy]ethoxy]-4-(2,7-difluoro-3-oxido-6-oxo-4a,9a-dihydroxanthen-9-yl)anilino]acetate (FluoZin-3) is used very broadly in life sciences as intra- and extracellular Zn(II) sensor selective for Zn(II) over Co(II), Ca(II) and Mg(II) ions at their physiological concentrations. It has been used for determination of relative and absolute levels of exchangeable Zn(II) in cells and extracellular fluids. Despite its popularity, the knowledge of its acid/base and Zn(II) coordination abilities and of its spectroscopic properties remained very limited. Also the published conditional dissociation constant ((C)Kd) values at pH7.4 are slightly discrepant, (15nM or 8.9nM). In this work we determined the (C)Kd for Zn(II) complexation by FluoZin-3 at pH7.4 with nitrilotriacetic acid (NTA) as competitor using two independent methods: fluorimetry and UV-Vis spectroscopy. For the first time, we investigated FluoZin-3 alone and complexed with Zn(II) in the wide range of pH, determining the total of eight pKa values from fluorescence spectra and from various regions of UV-Vis spectra. The validated values of (C)Kd (9.1±0.4nM; -log (C)Kd=8.04) and of the absolute (pH-independent) stability constant log βZnL (8.16±0.05) were provided by fluorescence spectroscopy experiments performed at 1μM concentrations. Our experiments demonstrated that both of aminocarboxylate moieties of FluoZin-3 bind the Zn(II) ion synergistically.
This communication presents synthesis and spectral characterization of metalloporphyrin [Zn(X)TMPyP4] (TMPyP4 is 5,10,15,20-tetrakis (N-methylpyridinium-4-yl)porphyrin),
 and studies its binding onto anionic surface sites of synthetic double stranded polynucleotide Poly(A)-Poly(U). [Zn(X)TMPyP4] binding with Poly(A)-Poly(U) was monitored by UV-Vis absorbance spectroscopy, two fluorescence spectroscopies and 1H NMR in a working aqueous medium of 0.15M ionic strength, pH7.0 and at 25°C. The evidence provided by spectroscopic measurements and multivariate data analysis suggests the use of this metalloporphyrin as a probe for investigation of the polynucleotide surface. In contrast to TMPyP4 intercalation, an outside adsorption of [Zn(X)TMPyP4] induces an attenuation of luminescence intensity and has little influence on the shape of luminescence band. Special attention was paid to the quantitative description of the interaction between neighboring ligands on the Poly(A)-Poly(U) surface. The intrinsic binding constant to an isolated binding site lgKin 5.8±0.1, the cooperativity parameter ω 1.8±0.2, and number of monomers occupied by a ligand n=2 (25°C; pH7.0) were calculated based upon the recently proposed non-linear least-squares fitting procedure. The discovered cooperativity of binding of [Zn(X)TMPyP4] metalloporphyrin to Poly(A)-Poly(U) is significantly lower as compared to free porphyrin TMPyP4, reflecting minimal mutual influence between the nearest neighboring ligands bound with functional PO4(-) groups of the polynucleotide surface.
In this article, a sensitive and selective turn-off fluorescence chemosensor, Tyloxapol (one kind of water soluble oligomer), was developed for the label-free detection of Fe(3+) ions in aqueous solution. Fluorescence (FL) experiments demonstrated that Tyloxapol was a sensitive and selective fluorescence sensor for the detection of Fe(3+) directly in water over a wide range of metal cations including Na(+), K(+), Ag(+), Hg(2+), Cd(2+), Co(2+), Cu(2+), Cr(3+), Mn(2+), Ba(2+), Zn(2+), Ni(2+), Mg(2+), Ca(2+), and Pb(2+). Moreover, the fluorescence intensity of Tyloxapol has shown a linear response to Fe(3+) in the concentration range of 0-100 μmol L(-1) with a detection limit of 2.2 μmol L(-1) in aqueous solution. Next, based on a competition mechanism, another turn-on sensing application of the Tyloxapol/Fe(3+) platform to probe dopamine (DA) against various other biological molecules such as other neurotransmitters or amino acids (norepinephrine bitartrate, acetylcholine chloride, alanine, valine, phenylalanine, tyrosine, leucine, glycine, histidine) were also investigated. It is expected that our strategy may offer a new approach for developing simple, cost-effective, rapid and sensitive sensors in biological and environmental applications.
The Burullus Lagoon north Nile Delta of Egypt is a UNESCO-protected area. Recently it has become a sediment sink which led to shrinking in its area and depth accompanying with increasing contaminant levels. In this study we attempt to explore the spatial distribution and their mobility of heavy metals (Zn, Cu, Ni, Cr and Pb) based on 21surface sediment samples recovered from Burullus lagoon basin and nine drains. The risk assessment code of the studied heavy metals can be arranged as Zn>Cu>Pb>Cr>Ni for all the samples collected from the lagoon basin and nine different drains. The heavy metals tend to accumulate in fine sediments and human activities promote the accumulation of contaminated sediments in water courses.
Three sub-basins of the Seine River (France) under contrasted land uses (i.e., forested, agricultural, and urban) have been investigated in order to assess the origin and seasonal variation of trace metals, and evaluate their geochemical background and dynamics. Our results highlight a high anthropogenic impact on all elements for both the dissolved and particulate fractions. The main source for each element in the dissolved phase was determined and shows that transition and post-transition metals mainly originate from forested areas, while alkali and alkaline earth elements, metalloids, and halogens rather originate from agricultural land use. Conversely, for the particulate phase, most of the elements cannot be associated with a specific land use. Seasonal variation of elements was assessed according to the forested and agricultural land uses, and geochemical backgrounds were determined using average export rates, highlighting that the geochemical background for the forested land use is higher than the agricultural one for most of the elements. Finally, to confirm those results, Zn dynamics in the three characteristic sub-basins and between the different land uses was investigated using a combination of Zn speciation, Zn isotopic ratio, and Zn export rates.
Dredging of sediments, a requirement for harbor maintenance, removes millions of tons of mineral wastes, contaminated at varying degrees with trace metals, from the water. In previous investigations, Cu and Zn have been identified as highly concentrated trace metals associated to sulfides, mineral phases sensitive to oxidation. In order to ensure their sustainable management, the solidification/stabilization (S/S) and/or the valorization of contaminated sediments as secondary raw materials is a way to be promoted. Indeed, their reuse as a substitute of sand in cemented mortar formulation would allow combining both treatment and valorization of such wastes.
In the present study, the environmental assessment of mortars formulated with raw and weathered marine sediments (in particular contaminated with Cu, Pb and Zn), compared to sand reference mortars, was conducted through two kinetic leaching tests: weathering cell tests (WCTs), in which mortars were crushed and leached twice a week, and a tank monolith leaching test (MLT), in which leaching was performed on monolithic mortars with increasing leachate renewal time.
In both leaching tests, calcium and sulfur were released continuously from sediment mortars, showing the oxidation-neutralization processes of sulfides and carbonates. In the MLT, Cu was released by sediment mortars through diffusion, particularly by weathered mortars, at low concentrations during 60 days of the test duration. With the more aggressive WCT, Cu concentrations were higher at the beginning but became negligible after 7 days of testing. Pb was released through diffusion mechanisms until depletion in both tests, whereas Zn was particularly well immobilized in the cemented matrices.
The S/S process applied using hydraulic binders proved to be efficient in the stabilization of Cu, Pb, and Zn highly presents in studied sediments, and further valorization in civilian engineering applications could be considered.
Charged polar interfaces such as charged ferroelectric walls or heterostructured interfaces of ZnO/(Zn,Mg)O and LaAlO3/SrTiO3, across which the normal component of electric polarization changes suddenly, can host large two-dimensional conduction. Charged ferroelectric walls, which are energetically unfavourable in general, were found to be mysteriously abundant in hybrid improper ferroelectric (Ca,Sr)3Ti2O7 crystals. From the exploration of antiphase boundaries in bilayer-perovskites, here we discover that each of four polarization-direction states is degenerate with two antiphase domains, and these eight structural variants form a Z4 × Z2 domain structure with Z3 vortices and five distinct types of domain walls, whose topology is directly relevant to the presence of abundant charged walls. We also discover a zipper-like nature of antiphase boundaries, which are the reversible creation/annihilation centres of pairs of two types of ferroelectric walls (and also Z3-vortex pairs) in 90° and 180° polarization switching. Our results demonstrate the unexpectedly rich nature of hybrid improper ferroelectricity.
We preformed this meta-analysis to investigate the influence of ABCA1 (ATP-binding cassette sub-family A member 1) rs2422493 (C-477T), rs1800977 (C-14T), rs2066718 (V771M), and PTGS2 (Prostaglandin-endoperoxide synthase 2) rs20417 (G-765C) polymorphisms on the risk of Alzheimer's disease (AD). Seventeen eligible case-control studies were acquired from PubMed, Embase, Alzgene, Chinese National Knowledge Infrastructure and Wanfang databases. The pooled odds ratios (ORs) with 95 % confidence intervals (95 % CI) were calculated to evaluate the association under five genetic models. Combined data indicated that ABCA1 rs2422493 polymorphism was statistically significant associated with increasing AD risk in three genetic models (allelic T vs C: OR = 1.12, 95 % CI: 1.01-1.24; homozygous TT vs CC: OR = 1.26, 95 % CI: 1.03-1.55; and recessive TT vs TC + CC: OR = 1.33, 95 % CI: 1.12-1.58) while no association was found between two other ABCA1 polymorphisms and AD susceptibility. Nevertheless, a further risk-stratification analysis showed that ApoE-ε4 carriers with any ABCA1 polymorphism suffered a much higher probability to be AD patients. Meanwhile, PTGS2 rs20417 polymorphism was linked to decreasing AD risk with a P < 0.0001 in five genetic models (e.g., allelic C vs G: OR = 0.59, 95 % CI: 0.50-0.70; homozygous CC vs GG: OR = 0.31, 95 % CI: 0.18-0.52; and heterozygous CG vs GG: OR = 0.64, 95 % CI: 0.52-0.78). In summary, our meta-analysis results showed that ABCA1 rs2422493 polymorphism was a risk factor for AD while PTGS2 rs20417 variant showed a protective effect on AD risk. In addition, ABCA1 rs2066718 and rs1800977 polymorphisms might not contribute to AD susceptibility in general population, but they should play a role on AD development when interacted with ApoE-ε4.
In Reticulitermes chinensis, a close relative of R. speratus with asexual queen succession, unfertilized eggs can be produced but do not hatch as larvae. To explain this phenomenon, we analyzed the physiological differences between unfertilized eggs/unmated queens and fertilized eggs/mated queens. Fertilized eggs had significantly lower quantities of five amino
 acids (Cys, Met, Ile, Leu and Tyr), Ca, protein and cholesterol during development. The higher levels of four trace elements (Na, K, Zn and Fe) in fertilized eggs and their lower levels in mated queens indicated that mated queens might transfer these trace elements to fertilized eggs to aid development. The higher levels of Mn, triglycerides and serotonin in mated queens and higher levels of Mn and glucose in fertilized eggs suggested that these substances are very important for normal ovarian and embryonic growth. The different expression of three reproductive genes (vtg 1, rab 11 and JHE 1) suggested that they might be involved in the regulation of ovarian and embryonic growth. Overall, changes in these physiological indices may substantially affect ovarian and embryonic growth and inhibit development of unfertilized eggs in R. chinensis.
Two novel compounds [Zn2(Endc)2(bipy)2(H2O)3]·4(H2O)·2(O)(1), [Zn2(Endc)2(phen)2(H2O)]·(O)(2) (bipy = 2,2-bipyridine, phen = 1,10-phenanthroline, and Endc = endo-norbornene-cis-5,6-dicarboxylicacid) have been synthesized and characterized. In this paper abbreviations are FS-DNA (fish sperm DNA), HeLa (human cervix epithelia carcinoma cells), KB (human oral epithelial carcinoma cells), LO2 (human liver cell L-O2), EtBr (ethidium bromide), DMF (Dimethyl Formamide), MTT ([3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium]). The binding of complexes with Fish Sperm DNA were measured by electronic absorption spectra and fluorescence spectroscopy. The ability of these complexes to cleave the pBR322 plasmid DNA or the KB and HeLa DNA extracted in our laboratory was demonstrated by gel electrophoresis assay. The cytotoxic effects of these complexes were examined on two tumor cell lines, HeLa, KBr and one normal cell line LO-2. UV absorption and fluorescence spectra indicate the ability of the complexes bond to DNA with different binding affinity. Gel electrophoresis assay demonstrates which one complex more effective DNA-cleavage activity. The cytotoxic activity of the complexes was tested against two different cancer and one normal cell lines. The two complexes exhibited cytotoxic specificity and significant cancer cell inhibitory rate and lower cytotoxicity toward the normal cell lines. The unique interaction mode with DNA and cancer cells inhibition effect clearly revealed the relationship between the structure and the activity of the novel antitumor agent Zn(II) complexes.
The metal ions Zn(2+) , Cu(2+) , and Fe(2+) play a significant role in the aggregation mechanism of Aβ peptides. However, the nature of binding between metal and peptide has remained elusive; the detailed information on this from the experimental study is very difficult. Density functional theory (dft) (M06-2X/6-311++G (2df,2pd) +LANL2DZ) has employed to determine the force field resulting due to metal and histidine interaction. We performed 200 ns molecular dynamics (MD) simulation on Aβ1-42 -Zn(2+) , Aβ1-42 -Cu(2+) , and Aβ1-42 -Fe(2+) systems in explicit water with different combination of coordinating residues including the three Histidine residues in the N-terminal. The present investigation, the Aβ1-42 -Zn(2+) system possess three turn conformations separated by coil structure. Zn(2+) binding caused the loss of the helical structure of N-terminal residues which transformed into the S-shaped conformation. Zn(2+) has reduced the coil and increases the turn content of the peptide compared with experimental study. On the other hand, the Cu(2+) binds with peptide, β sheet formation is observed at the N-terminal residues of the peptide. Fe(2+) binding is to promote the formation of Glu22-Lys28 salt-bridge which stabilized the turn conformation in the Phe19-Gly25 residues, subsequently β sheets were observed at His13-Lys18 and Gly29-Gly37 residues. The turn conformation facilitates the β sheets are arranged in parallel by enhancing the hydrophobic contact between Gly25 and Met35, Lys16 and Met35, Leu17 and Leu34, Val18 and Leu34 residues. The Fe(2+) binding reduced the helix structure and increases the β sheet content in the peptide, which suggested, Fe(2+) promotes the oligomerization by enhancing the peptide-peptide interaction. Proteins 2016; 84:1257-1274. © 2016 Wiley Periodicals, Inc.
During episodic rainfall events, land application of treated municipal sludge ('biosolids') may give rise to surface runoff of metals, which may be potentially harmful to human health if not fully treated in a water treatment plant (WTP). This study used surface runoff water quality data generated from a field-scale study in which three types of biosolids (anaerobically digested (AD), lime stabilised (LS), and thermally dried (TD)) were spread on micro-plots of land and subjected to three rainfall events at time intervals of 24, 48 and 360h following application. Making the assumption that this water directly entered abstraction waters for a WTP without any grassed buffer zone being present, accounting for stream dilution, and modelling various performance scenarios within the WTP, the aim of this research was to conduct a human health risk assessment of metals (Cu, Ni, Pb, Zn, Cd and Cr), which may still be present in drinking water after the WTP. Different dose-response relationships were characterised for the different metals with reference to the lifetime average daily dose (LADD) and the Hazard Quotient (HQ). The results for the LADD show that child exposure concentrations were highest for Cu when the measured surface runoff concentrations from the LS biosolids treatment were used as input into the model. The results for the HQ showed that of all the scenarios considered, Cu had the highest HQ for children. However, values were below the threshold value of risk (HQ<0.01 - no existing risk). Under the conditions monitored, metal concentrations in the biosolids applied to grassland were not considered to result in a risk to human health in surface water systems.
In a rapidly urbanizing world, trace element pollution may represent a threat to human health and wildlife, and it is therefore crucial to assess both exposition levels and associated effects of trace element contamination on urban vertebrates. In this study, we investigated the impact of urbanization on trace element contamination and stress physiology in a wild bird species, the common blackbird (Turdus merula), along an urbanization gradient (from rural to moderately urbanized areas). Specifically, we described the contamination levels of blackbirds by 4 non-essential (Ag, Cd, Hg, Pb) and 9 essential trace elements (As, Co, Cr, Cu, Fe, Mn, Ni, Se, Zn), and explored the putative disrupting effects of the non-essential element contamination on corticosterone levels (a hormonal proxy for environmental challenges). We found that non-essential trace element burden (Cd and Pb specifically) increased with increasing urbanization, indicating a significant trace element contamination even in medium sized cities and suburban areas. Interestingly, the increased feather non-essential trace element concentrations were also associated with elevated feather corticosterone levels, suggesting that urbanization probably constrains birds and that this effect may be mediated by trace element contamination. Future experimental studies are now required to disentangle the influence of multiple urban-related constraints on corticosterone levels and to specifically test the influence of each of these trace elements on corticosterone secretion.
The effect of contact time, solution pH, and the presence of humic acid (HA) on the combined removal of As, Cd, Cr, Cu, Ni and Zn is investigated in batch tests using alumina, granulated activated carbon (GAC), and bauxsol coated sand (BCS) as sorbents. It is found that the equilibrium time for Cd, Cu, Ni and Zn is about 4h, while no clear equilibrium is observed for As and Cr. It is also found that increasing the pH until pH~8 enhanced Cd, Cu, Ni and Zn removal, but increasing the pH above this point had no major effect. In the cases of As and Cr, higher pH values (i.e. >7) decreased their removal. The presence of both 20 and 100mg/L HA suppressed the heavy metal removal except for Cr, and the suppression was higher at the higher HA concentration. Geochemical simulations suggest that this is due to the formation of dissolved HA-metal complexes preventing effective metal sorption. In the case of Cr, the presence of HA increased the removal when using alumina or BCS, while hindering the removal when using GAC. The findings show that the pH-value of the stormwater to be treated must be in the range of 6-7 in order to achieve removal of the full spectrum of metals. The results also show that natural organic matter may severely influence the removal efficiency, such that, for most metals the removal was reduced to the half, while for Cr it was increased to the double for alumina and BCS. Consequently, a properly working filter set up may not work properly anymore when receiving high loads of natural organic acids during the pollen season in spring or during defoliation in autumn and early winter, and during mixing of runoff with snowmelt having a low pH.
Zinc(II), a dimolybdenum(II) paddlewheel tetramine A, and 2-formylpyridine self-assembled to generate a cubic Zn(II)8(L(A))6 assembly. The paddlewheel faces of this assembly exhibited two distinct conformations, whereas the analogous Fe(II)8(L(A))6 framework displayed no such perturbation to its structure. This variation in behavior is attributed to the subtle difference in ligand rotational freedom between the Zn(II)- and Fe(II)-cornered cubes. The incorporation of a fluorinated Mo(II)2 paddlewheel, B, into analogous Zn(II)8(L(B))6 and Fe(II)8(L(B))6 structures resulted in changes to the rotational dynamics of the ligands. These differing dynamics perturbed the energies of the frontier orbitals of
 these structures, as determined through spectroscopic and electrochemical methods. The result of these perturbations was an inversion of the halide binding preference of the Zn(II)8(L(B))6 host as compared to its Zn(II)8(L(A))6 congener, whereas the Fe(II)8(L(B))6 host maintained a similar binding hierarchy to Fe(II)8(L(A))6.
Cisplatin and its derivatives are the main metallodrugs used in cancer therapy. However, low selectivity, toxicity and drug resistance are associated with their use. The zinc(II) (Zn(II)) thiosemicarbazone complexes [Zn(atc-Et)₂] (1) and [Zn(atc-Ph)₂] (2) (atc-R: monovalent anion of 2-acetylpyridine N4-R-thiosemicarbazone) were synthesized and fully characterized in the solid state and in solution via elemental analysis, Fourier transform infrared (FTIR), ultraviolet-visible (UV-Vis) and proton nuclear magnetic resonance (¹H NMR) spectroscopy, conductometry and single-crystal X-ray diffraction. The cytotoxicity of these complexes was evaluated in the HepG2, HeLa, MDA-MB-231, K-562, DU 145 and MRC-5 cancer cell lines. The strongest antiproliferative results were observed in MDA-MB-231 and HepG2 cells, in which these complexes displayed significant selective toxicity (3.1 and 3.6, respectively) compared with their effects on normal MRC-5 cells. In vivo studies were performed using an alternative model (Artemia salina L.) to assure the safety of these complexes, and the results were confirmed using a conventional model (BALB/c mice). Finally, tests of oral bioavailability showed maximum plasma concentrations of 3029.50 µg/L and 1191.95 µg/L for complexes 1 and 2, respectively. According to all obtained results, both compounds could be considered as prospective antiproliferative agents that warrant further research.
The contamination of agricultural areas by heavy metals has a negative influence on food quality and human health. Various remediation techniques have been developed for the removal and/or immobilization of heavy metals (HM) in contaminated soils. Phytoremediation is innovative technology, which has advantages (low cost, easy monitoring, high selectivity) and limitations, including long time for procedure and negative impact of contaminants on used plants. Greenhouse investigations have shown that monosilicic acid can be used for regulation of the HM (Cd, Cr, Pb and Zn) mobility in the soil-plant system. If the concentration of monosilicic acid in soil was increased from 0 to 20 mg L(-1) of Si in soil solution, the HM bioavailability was increased by 30-150%. However, the negative influence on the barley by HM was reduced under monosilicic acid application. If the concentration of monosilicic acid was increased more than 20 mg L(-1), the HM mobility in the soil was decreased by 40-300% and heavy metal uptake by plants was reduced 2-3 times. The using of the monosilicic acid may increase the phytoremediation efficiency. However the technique adaptation will be necessary for phytoremediation on certain areas.
Recombinant ferrochelatase (BsFECH) from Bacillus subtilis expressed in Escherichia coli BL21(DE3) was found by UV-visible spectroscopy to bind the model substrate tetraphenylporphyrin-sulfonate, TPPS, with Ka=3.8 10(5)mol/L in aqueous phosphate buffer pH 5.7 at 30°C, and to interact with metmyoglobin with Ka=1.07±0.13 10(5)mol/L at 30°C. The iron/zinc exchange in myoglobin occurring during maturation of Parma hams seems to depend on such substrate binding to BsFECH and was facilitated by limited pepsin proteolysis of myoglobin to open a reaction channel for metal exchange still with BsFECH associated to globin. BsFECH increased rate of zinc insertion in TPPS significantly and showed saturation kinetics with an apparent binding constant of Zn(II) to the [enzyme-TPPS] complex of 1.3 10(4)mol/L and a first-order rate constant of 6.6 10(-1)s(-1) for dissociation of the tertiary complex, a similar pattern was found for zinc/iron transmetallation in myoglobin.
Samples of soil, the broad bean plant, Vicia faba and irrigation water were collected from the same agricultural site in Dokan, in the Kurdistan region of Iraq. Total arsenic and arsenic speciation were determined in all materials by ICP-MS and HPLC-ICP-MS, respectively. Available arsenic (11%) was also determined within the soil, together with Cd, Cr, Cu, Ni, Zn, Fe and Mn. The concentrations of total arsenic were: soil (5.32μgg(-1)), irrigation water (1.06μgL(-1)), roots (2.065μgg(-1)) and bean (0.133μgg(-1)). Stems, leaves and pods were also measured. Inorganic As(V) dominated soil (90%) and root (78%) samples. However, organo-arsenic (MMA, 48% and DMA, 19%) was the more dominant species in the edible bean. The study provides an insight into the uptake, preferred disposal route, speciation changes and loss mechanism involved for arsenic with this food source.
This paper describes the determination and evaluation of the major and trace element composition (Al, As, Ba, Ca, Cd, Co, Cu, Fe, K, Mg, Mn, Na, Pb, Sr and Zn) of Sechium edule (Jacq) Swartz fruits collected from four different places of production in Corrientes province, Argentina. Element concentrations were determined by using inductively coupled plasma optical emission spectrometry (ICP OES) after microwave digestion. The accuracy was confirmed with standard reference material of spinach leaves (NIST, 1570a) and spiking tests. Principal component analysis (PCA), linear discriminant analysis (LDA), k-nearest neighbors (kNN), partial least square-discriminant analysis (PLS-DA) and support vector machine (SVM) were applied to the results for discriminating the geographical origin of S. edule fruits. Finally, the LDA method was found to perform best with up to 90% accuracy rate based on the following elements: Ca, Ba, Cu, Mn, Na, Sr, and Zn.
A new biodegradable polyhydroxybutyrate diethanol amine (PHB-DEA) polymer was used as adsorbent for the sensitive and selective separation, preconcentration and determination of Pb(II), Cd(II) and Zn(II) by using atomic absorption spectrometry. Diethyl dithiocarbamate was used as chelating reagent. Analytical parameters such as pH, eluent type and its volume, flow rates of sample solution, ligand amount, sample volume were optimized. Effects of some cations, anions and transition metal ions were also investigated. Enrichment factor and relative standard deviation were found to be 100 and 3%, respectively. The limits of detection based on three times standard deviation of blanks (N=21) were found 1.05μgL(-1) for Pb(II), 0.42μgL(-1) for Cd(II) and 0.13μgL(-1) for Zn(II). Limits of quantification (10s, N=21) were found 3.47μgL(-1) for Pb(II), 1.39μgL(-1) for Cd(II) and 0.43μgL(-1) for Zn(II). Accuracy evaluation of the method was confirmed with analyses of certified reference materials (NIST SRM 1515 Apple leaves, IAEA 336 Lichen, GBW 07605 Tea). Optimized method was applied to tap water and food samples after microwave digestion method. Cadmium and lead values in some samples were found higher than legal limits.
The aim of this study was to investigate the presence of metal contamination in water, sediments and three different fish species. All samples were taken from the Danube River in Belgrade Region, a location upstream from Grocka. Concentrations of Cd, Hg and Pb in water samples were not detected, while concentrations of Zn, Fe, Cu and As were in the range of 0.004-0.41 mg L(-1). Iron was the most deposited metal in sediment samples (17,530.00 mg kg(-1)). For the purpose of heavy metal determination in fish tissue, silver carp, common carp and wels catfish were collected. Concentrations of Pb, Cd and As were determined in muscle, digestive tract and liver by inductively coupled plasma-optical emission spectrophotometry (IPC-OES). The highest concentration of Pb was in the digestive tract of all three fish species, while Cd was mostly deposited in the liver. The highest concentration of Hg was in the muscle tissue of wels catfish, and these values are above the maximum residual levels prescribed by the European Union and the maximum allowed concentrations (MACs) for Serbia. Concentration of As was mostly deposited in the liver, but under the MAC.
Nanoparticles released into the environment could pose a risk to resident organisms that feed on suspended particles in aquatic ecosystems. The purpose of this study was to examine the effects of silver nanoparticles (nanoAg) of different sizes in freshwater mussels using a multi-elemental (metallomic) approach in order to determine signature effects of nanoparticulate and ionic Ag. Mussels were exposed to three concentrations (0.8, 4 and 20μg/L) of 20-nm and 80-nm nanoAg and AgNO3 for 48h at 15°C. After the exposure period, mussels were placed in clean, aerated water for a depuration step and analyzed for the following total elements in gill, digestive gland and gonad tissues: Al, Ag, As, Ba, Be, Ca, Cd, Co, Cr, Cu, Fe, K, Mg, Mn, Mo, Pb, Na, Ni, Se, Sr, Th, U, V and Zn. Metallothioneins (MT; digestive gland only) and lipid peroxidation (LPO) were also determined in gills, digestive glands and gonads. The 20-nm-diameter nanoAg was detected in all three tissues at 20μg/L, while the 80-nm nanoAg was detected more strongly in the digestive gland. Ionic Ag was found at higher levels in gills than in other tissues. Correlation analysis revealed that gonad Ag levels were significantly correlated with Al (r=0.28), V (r=0.28), Cr (r=0.31), Co (r=0.32), Se (r=0.34) and MT levels (r=0.28). Indeed, the MT levels in the digestive gland were significantly increased by 20-nm nanoAg (20μg/L) and 80-nm nanoAg (4μg/L) and AgNO3 (<0.8μg/L). LPO was observed in gills, digestive glands and even gonads for all Ag forms. Discriminant function analysis revealed that all forms of Ag differed from each other and from unexposed mussels, where ionic Ag was more closely related to the 80-nm-diameter nanoAg. Factorial
 analysis revealed that Ba, Ca, Co, Mn, Sr, U and Zn had consistently high factorial weights in all tissues; that explained 80% of the total variance. Moreover, the following elements showed strong correlations (r>0.7) with each other: Sr, Ba, Zn, Ca, Mg Cr, Mn and U. Comparisons of these elements with other elements showing low or no correlations (e.g., transition elements) revealed that these elements had significantly lower standard reduction potential and electronegativity, suggesting that stronger reducing elements were most influenced by the oxidizing effects of nanoAg and ionic Ag in tissues. Indeed, tissues with oxidative stress (LPO) had decreased levels for most of these reducing elements. We conclude that exposure to Ag nanoparticles produces a characteristic change in the elemental composition of gills, digestive gland and gonad tissues in freshwater mussels. Elements most responsive to oxidative stress were more influenced by both nanoAg and ionic Ag. Sr and Ba were readily decreased by Ag and appeared to respond more sensitively to nanoAg than to ionic Ag. The metallomic approach could contribute in the understanding of fundamental mode of action of nanoparticles in mussels.
Two new zinc complexes, namely Zn(L(1))ClCH2NO(1) and {Zn(L(2))CH2NO}n▪N(CH3)3▪ClO4(2) (L(1) = 3,5-di(1H-imidazol-1-yl)pyridine L(2) = 1,3,5-tris(1-imidazolyl) benzene), have been synthesized, and characterized by IR spectra, elemental analysis, and a single crystal X-ray diffraction. Fluorescence spectroscopy indicated that two complexes presented strong DNA binding affinity constants to fish sperm DNA (FS-DNA). Gel electrophoresis assay demonstrated the ability of the complex to cleave the HL-60 DNA. Apoptotic study showed the complex exhibited significant cancer cell(KB) inhibitory rate.
Concentrations of Hg, Se, Cd, Cu, Zn, Fe, Mn and As, in kidney, liver, muscle and blubber from 7 specimens of Stenella coeruleoalba, stranded along the Israeli Mediterranean coast (IMC) from 2006 to 2011 (2011-series) were determined and compared to previous data on S. coeruleoalba from the IMC (2001-series). No differences were observed in essential and toxic elements concentrations, between the two series, except for hepatic Mn which was higher in the latter. Hg/Se molar ratios in blubber, kidney and liver increased linearly with log Hg concentrations, while muscle was more heterogenic in this respect. Means (±SD) of hepatic Hg concentrations (134±89 and 181±200mgkg(-1), from the 2011 and 2001 series, respectively) were similar to that found in 2007-2009 specimens from Spain, possibly reflecting the relatively high natural background levels of mercury in the Mediterranean Sea.
The present study aimed to geochemical speciation of metals in the surface sediments of the northern Persian Gulf. Metal contents in the sediment were observed in the order: Al>Fe>Cr>Ni>V>Zn>Cu>Co>As>Pb>Cd. The results of sequential extraction procedure revealed that all metals were predominantly associated with the residual fraction. Among the metals, Cu and As exhibited higher bioavailability. The risk assessment code (RAC) indicated that Cu, As and Cd had medium environmental risk at some sampling sites. Based on enrichment factor (EF), Cd and As had moderate to significant enrichment.
Surface sediments were collected from Guanabara Bay, at 14 stations distributed in five sectors, over three sampling campaigns. Analyses of metals, grain size fractions and total organic carbon analyses were performed. The geo-accumulation index and the enrichment factor were estimated to assess contamination status based on background values. Additionally, the sediment quality guidelines were applied to evaluate the adverse biological effects. Results show that there was no seasonal variation in sediment quality based on any methodology, and all methods utilized showed that NW sector and HRJ sector were the worst affected and that the NE sector had the best conditions. The sediments of GB are polluted mainly by Cr, Pb and Zn. According to ΣSEM/AVS, these metals are not available to the biota, although toxicity tests dispute this. Among the various methods employed, those using background values for the area seem to best reflect the local historical contamination.
Lignite (PK), bituminous (FI) and biomass (SE) fly ashes (FAs) were mineralogically and geochemically characterised, and their element leachability was studied with batch leaching tests. The potential for acid neutralisation (ANP) was quantified by their buffering capacity, reflecting their potential for neutralisation of acid mine drainage. Quartz was the common mineral in FAs detected by XRD with iron oxide, anhydrite, and magnesioferrite in PK, mullite and lime in FI, and calcite and anorthite in SE. All the FAs had high contents of major elements such as Fe, Si, Al and Ca. The Ca content in SE was six and eight times higher compared to PK and FI, respectively. Sulphur content in PK and SE was one magnitude higher than FI. Iron concentrations were higher in PK. The trace element concentrations varied between the FAs. SE had the highest ANP (corresponding to 275 kg CaCO3 tonne(-1)) which was 15 and 10 times higher than PK and FI, respectively. The concentrations of Ca(2+), SO4 (2-), Na(+) and Cl(-) in the leachates were much higher compared to other elements from all FA samples. Iron, Cu and Hg were not detected in any of the FA leachates because of their mild to strong alkaline nature with pH ranging from 9 to 13. Potassium leached in much higher quantity from SE than from the other ashes. Arsenic, Mn and Ni leached from PK only, while Co and Pb from SE only. The concentrations of Zn were higher in the leachates from SE. The FAs used in this study have strong potential for the neutralisation of AMD due to their alkaline nature. However, on the other hand, FAs must be further investigated, with scaled-up experiments before full-scale application, because they might leach pronounced concentrations of elements of concern with decreasing pH while neutralising AMD.
Zinc plays important roles in regulating physiological and pathological processes. Regrettably, mild to moderate zinc deficiency is common worldwide. Hair Zn(2+) concentration, which reflects a zinc storage status, is useful for tracking trends in zinc status within populations. In this work, we report BODIPY-based self-assembled nanoparticles (NPs) as fluorescence turn-on sensor for the selective sensing of Zn(2+) in human hair. The BODIPY monomers (BAN) self-assemble in aqueous medium to form nonfluorescent NPs. In the presence of Zn(2+) ions, the NPs selectively show an obvious turn-on fluorescence change. This selective response of the NPs allows the determination and quantification of Zn(2+) in human hair with a detection limit of 61.3nM. This study demonstrates that the small molecule self-assembled nanoparticle is a versatile and useful tool, and shows great potential for applications in sensing of important analytes in biological systems.
A polypyrrole/2,5-diaminobenzenesulfonic acid (PPy/DABSA) composite, synthesised by the in situ oxidative polymerization of pyrrole in the presence of DABSA, was studied as an adsorbent for the removal of Cr(VI) from aqueous solution. The structure and morphology of the composite were investigated by ATR-FTIR, FE-SEM, EDX, TGA, XRD and XPS studies. The adsorption of Cr(VI) by PPy/DABSA composite was highly pH dependent and optimum removal was achieved at pH 2. Adsorption of Cr(VI) was confirmed by EDX and XPS studies. The isotherm data fitted the linear Langmuir model well, with a maximum adsorption capacity of 303mg/g at 25°C. Thermodynamic parameters (ΔG°, ΔH° and ΔS°) were calculated using isotherm data and confirmed that the adsorption process was spontaneous and endothermic. Adsorption kinetics was best described by the pseudo-second-order model. The activation energy of the adsorption process suggested that Cr(VI) was chemisorbed by PPy/DABSA composite. PPy/DABSA composite could be used for three consecutive adsorption-desorption cycles without loss of its original adsorption capacity. Highly selective removal of Cr(VI) was observed even when co-existing ions such as Cu(2+), Zn(2+), Ni(2+), Cl(-), SO4(2)(-) and NO3(-) were present in the solution. In summary, the potential of PPy/DABSA composite for remediating industrial wastewater contaminated by Cr(VI) has been demonstrated.
Sediment samples were collected to a depth of 60 cm along a 350-m sampling belt in a short-term-flooding riparian wetland in the Yellow River Delta of China in three sampling seasons. Contents of heavy metals were determined to investigate their spatial and temporal distributions, sources and ecotoxities. Our results showed that As contents in the top 20 cm sediments increased before decreasing along the sampling belt in summer, whereas they kept stable before increasing in fall and spring. Cd contents increased along the sampling belt in three sampling seasons, whereas Ni and Cr generally exhibited a decreasing tendency. Comparatively, Cu, Pb and Zn consistently increased at the first 50 m distance and then decreased before increasing from the distance of 150 m in summer and fall and increased to the maximum at the distance of 250 m and then showed a decrease in spring. Two "hotspots" of heavy metal accumulation in sediment cores along the belt were observed at the distance from 50 to 100 m in summer and at the distance from 200 to 300 m in spring. Most of sediment samples contained higher heavy metals in excess of threshold effect levels except for Zn and Pb in three sampling seasons and the values of toxic units in more than 30% of sediment samples exceeded 4 in summer. As, Ni and Cr had relatively higher contribution to the values of toxic units compared with other heavy metals in three sampling seasons. Multivariance analysis showed that
 As and Cd might originate from the same source and Cu, Zn, Cr, Pb and Ni might derive from another similar source. Cd was significantly correlated with salinity (p < 0.01) and pH (p < 0.05). Meanwhile, these heavy metals were also significantly correlated with other properties such as S, Al, TP, SOM and Silt + Clay.
Lacosamide is a new antiepileptic drug which is widely used to treat partial-onset seizures. In this study, we examined the neuroprotective effect of lacosamide against transient ischemic damage and expressions of antioxidant enzymes such as Zn-superoxide dismutase (SOD1), Mn-superoxide dismutase (SOD2), catalase (CAT) and glutathione peroxidase (GPX) in the hippocampal cornu ammonis 1 (CA1) region following 5 min of transient global cerebral ischemia in gerbils. We found that pre-treatment with 25 mg/kg lacosamide protected CA1 pyramidal neurons from transient global cerebral ischemic insult using hematoxylin-eosin staining and neuronal nuclear antigen immunohistochemistry. Transient ischemia dramatically changed expressions of SOD1, SOD2 and GPX, not CAT, in the CA1 pyramidal neurons. Lacosamide pre-treatment increased expressions of CAT and GPX, not SOD1 and 2, in the CA1 pyramidal neurons compared with controls, and their expressions induced by lacosamide pre-treatment were maintained after transient cerebral ischemia. In brief, pre-treatment with lacosamide protected hippocampal CA1 pyramidal neurons from ischemic damage induced by transient global cerebral ischemia, and the lacosamide-mediated neuroprotection may be closely related to increases of CAT and GPX expressions by lacosamide pre-treatment.
Vineyard sandy acid soils from South Brazil have experienced heavy metal contamination due to replacement of copper (Cu)-based by zinc (Zn)-based products to control foliar diseases. Thus, we evaluate physiological and nutritional status of black oat (Avena strigosa Schreb.), a common interrow crop in vineyards from this region. Soil was collected in a natural field from Santana do Livramento, in Rio Grande do Sul, the southernmost state of Brazil. Black oat was cultivated for 30 days in a greenhouse with application of 0, 30, and 60 mg Cu kg(-1) combined with 0, 15, 30, 60, 120, and 180 mg Zn kg(-1). After the trial period, dry matter accumulation of roots and shoots, Cu and Zn contents in roots and shoots, chlorophyll a fluorescence, photosynthetic pigments and catalase (CAT, EC 1.11.1.6) and peroxidase (POD, EC 1.11.1.7) activity were determined. Cu and Zn toxicity was evidenced by the decrease in plant growth of black oat as well as by the decrease of photochemical efficiency associated with the decrease in photosynthetic pigment content, especially with the highest doses of Cu and Zn. Furthermore, the activity of antioxidant enzymes (CAT and POD) was increased in intermediate doses of Zn, indicating the activation of the antioxidant system, but the stress condition in treatments with high levels of Cu and Zn was not reversed.
The roles of reactive oxygen species (ROS) as both toxic by-products and as signaling molecules have been reported in fruit development and ripening. Superoxide dismutase (SOD), catalase (CAT) and glutathione peroxidase (GPX) play important roles in balancing the induction and removal of ROS in plants, and are respectively encoded by families of closely homologous genes. In the present study, we investigated the roles of ROS and the above-mentioned antioxidant genes during the development and ripening of peach fruit. The experimental results indicated that O2(-) and H2O2 acted as potential signaling molecules in the middle stage of fruit development, and only H2O2 might function as a main toxic molecule to stimulate lipid peroxidation and oxidative stress in the late stage of fruit ripening. PpaCu/Zn-SODs were the most abundant members in the PpaSOD gene family and they expressed steadily in peach fruit development and ripening. Low temperature (4 °C) postponed and suppressed the climacteric peaks of respiration and ethylene, significantly enhanced the activities of CAT and GPX, and up-regulated the expression of PpaCAT1 and PpaGPX6 in the late stage of fruit ripening. PpaCAT1 and PpaGPX6 were two key genes in alleviating oxidative stress in the late stage of fruit ripening.
Two bis(pyrrol-2-yl-methyleneamine) chemo-sensors, 1, 3- and 1, 4-bis[3,4-dimethyl-5-ethyloxy -carbonyl-pyrrol-2-yl-methyleneamine]benzene (H2L(1) and H2L(2), respectively) have been synthesized and characterized, which exhibit high selectivity as off-on fluorescence sensors toward Zn(2+) in CH3CN/H2O (9:1, v/v) solution. The detection limits of both sensors are at the parts per million level. Moreover, the probes H2L(1) and H2L(2) could sense Zn(2+) by "naked eye" with a color change from colorless to yellow, and from yellow to dark yellow, respectively. To test the practical use of the probes, the determination of Zn(2+) in real water samples was also evaluated.
Developing fluorescent probes for monitoring intracellular Cu(+) is important for human health and disease, whereas a few types of their receptors showing a limited range of binding affinities for Cu(+) have been reported. In the present study, we first report a novel peptide receptor of a fluorescent probe for the detection of Cu(+). Dansyl-labeled tripeptide probe (Dns-LLC) formed a 1:1 complex with Cu(+) and showed a turn-on fluorescent response to Cu(+) in aqueous buffered solutions. The dissociation constant of Dns-LLC for Cu(+) was determined to be 12 fM, showing that Dns-LLC had more potent binding affinity for Cu(+) than those of previously reported chemical probes for Cu(+). The binding mode study showed that the thiol group of the peptide receptor plays a critical role in potent binding with Cu(+) and the sulfonamide and amide groups of the probe might cooperate to form a complex with Cu(+). Dns-LLC detected Cu(+) selectively by a turn-on response among various biologically relevant metal ions, including Cu(2+) and Zn(2+). The selectivity of the peptide-based probe for Cu(+) was strongly dependent on the position of the cysteine residue in the peptide receptor part. The fluorescent peptide-based probe penetrated the living RKO cells and successfully detected Cu(+) in the Golgi apparatus in live cells by a turn-on response. Given the growing interest in imaging Cu(+) in live cells, a novel peptide receptor of Cu(+) will offer the potential for developing a variety of fluorescent probes for Cu(+) in the field of copper biochemistry.
We have presented an extensible, facile and sensitive multidimensional sensor based on DNA-gold nanoparticle (DNA-AuNP) conjugates for heavy metal ions (Ag(+), Hg(2+), Cr(3+), Sn(4+), Cd(2+), Cu(2+), Pb(2+), Zn(2+), and Mn(2+)) discrimination. In the presence of metal ions, the excluded effect of DNA and AuNPs with the same negative charges is disrupted, and the amount of FAM-labeled DNA adsorbed on AuNP surfaces increases, resulting in a more obvious fluorescence quenching effect. With the addition of NH2OH and HAuCl4, AuNPs grow into morphologically varied nanostructures (spherical to branched) depending on the resulting aptamer coverage, which gives rise to different colored solutions (reddish blush, purple and blue) observed by naked eyes. By simply changing the DNA sequences, three sensing elements can be easily obtained and added into this dual-channel multidimensional sensor. 9 heavy metal ions are distinguished by linear discriminant analysis (LDA) and primary component analysis (PCA). A highly sensitive discrimination of metal ion targets with the detection limit as low as 50nM with 100% identification accuracy is obtained. Remarkably, Cu(2+) and Hg(2+) ions with similar catalytic performance at various concentrations (300nM, 400nM, 500nM, respectively) and the mixture of the two metal ions with different volume ratios (total metal ion concentration: 500nM) can be successfully discriminated. In addition, nine heavy metal ions are also well-distinguished in river samples, and the accuracy of discrimination of these metal ions samples reaches 100%. Therefore, it will broaden the application field of DNA-AuNP conjugates-based multidimensional sensors.
6-Chloro-2-benzoxazolinone (CDHB) is a precursor of herbicide, insecticide, and fungicide synthesis and has a broad spectrum of biological activity. Pigmentiphaga sp. strain DL-8 can transform CDHB into 2-amino-5-chlorophenol (2A5CP), which it then utilizes as a carbon source for growth. The CDHB hydrolase (CbaA) was purified from strain DL-8, which can also hydrolyze 2-benzoxazolinone (BOA), 5-chloro-2-BOA, and benzamide. The specific activity of purified CbaA was 5,900 U · mg protein(-1) for CDHB, with Km and kcat values of 0.29 mM and 8,500 s(-1), respectively. The optimal pH for purified CbaA was 9.0, the highest activity was observed at 55°C, and the inactive metal-free enzyme could be reactivated by Mg(2+), Ni(2+), Ca(2+), or Zn(2+) Based on the results obtained for the CbaA peptide mass fingerprinting and draft genome sequence of strain DL-8, cbaA (encoding 339 amino acids) was cloned and expressed in Escherichia coli BL21(DE3). CbaA shared 18 to 21% identity with some metal-dependent hydrolases of the PF01499 family and contained the signature metal-binding motif Q127XXXQ131XD133XXXH137 The conserved amino acid residues His288 and Glu301 served as the proton donor and acceptor. E. coli BL21(DE3-pET-cbaA) resting cells could transform 0.2 mM CDHB into 2A5CP. The mutant strain DL-8ΔcbaA lost the ability to degrade CDHB but retained the ability to degrade 2A5CP, consistent with strain DL-8. These results indicated that cbaA was the key gene responsible for CDHB degradation by strain DL-8.
2-Benzoxazolinone (BOA) derivatives are widely used as synthetic intermediates and are also an important group of allelochemicals acting in response to tissue damage
 or pathogen attack in gramineous plants. However, the degradation mechanism of BOA derivatives by microorganisms is not clear. In the present study, we reported the identification of CbaA and metabolic pathway responsible for the degradation of CDHB in Pigmentiphaga sp. DL-8. This will provide microorganism and gene resources for the bioremediation of the environmental pollution caused by BOA derivatives.
The extremely thermoacidophilic archaeon Metallosphaera sedula mobilizes metals by novel membrane-associated oxidase clusters and, consequently, requires metal resistance strategies. This issue was examined by "shocking" M. sedula with representative metals (Co(2+), Cu(2+), Ni(2+), UO2 (2+), Zn(2+)) at inhibitory and subinhibitory levels. Collectively, one-quarter of the genome (554 open reading frames [ORFs]) responded to inhibitory levels, and two-thirds (354) of the ORFs were responsive to a single metal. Cu(2+) (259 ORFs, 106 Cu(2+)-specific ORFs) and Zn(2+) (262 ORFs, 131 Zn(2+)-specific ORFs) triggered the largest responses, followed by UO2 (2+) (187 ORFs, 91 UO2 (2+)-specific ORFs), Ni(2+) (93 ORFs, 25 Ni(2+)-specific ORFs), and Co(2+) (61 ORFs, 1 Co(2+)-specific ORF). While one-third of the metal-responsive ORFs are annotated as encoding hypothetical proteins, metal challenge also impacted ORFs responsible for identifiable processes related to the cell cycle, DNA repair, and oxidative stress. Surprisingly, there were only 30 ORFs that responded to at least four metals, and 10 of these responded to all five metals. This core transcriptome indicated induction of Fe-S cluster assembly (Msed_1656-Msed_1657), tungsten/molybdenum transport (Msed_1780-Msed_1781), and decreased central metabolism. Not surprisingly, a metal-translocating P-type ATPase (Msed_0490) associated with a copper resistance system (Cop) was upregulated in response to Cu(2+) (6-fold) but also in response to UO2 (2+) (4-fold) and Zn(2+) (9-fold). Cu(2+) challenge uniquely induced assimilatory sulfur metabolism for cysteine biosynthesis, suggesting a role for this amino acid in Cu(2+) resistance or issues in sulfur metabolism. The results indicate that M. sedula employs a range of physiological and biochemical responses to metal challenge, many of which are specific to a single metal and involve proteins with yet unassigned or definitive functions.
The mechanisms by which extremely thermoacidophilic archaea resist and are negatively impacted by metals encountered in their natural environments are important to understand so that technologies such as bioleaching, which leverage microbially based conversion of insoluble metal sulfides to soluble species, can be improved. Transcriptomic analysis of the cellular response to metal challenge provided both global and specific insights into how these novel microorganisms negotiate metal toxicity in natural and technological settings. As genetics tools are further developed and implemented for extreme thermoacidophiles, information about metal toxicity and resistance can be leveraged to create metabolically engineered strains with improved bioleaching characteristics.
We studied atmospheric deposition of heavy metals in Wuxi, China, using moss (Haplocladium microphyllum and H. angustifolium) as a biomonitoring agent. Moss samples were collected from 49 sites determined by a systematic sampling method. The top layer of soil on each site was also sampled. No significant correlation (P < 0.05) was observed between the moss and soil concentrations for any of the six heavy metal elements (Cd, Cr, Cu, Ni, Pb, and Zn), indicating that the soil substrate had little effect on the heavy metal concentrations in the moss materials. The metal enrichment capacity of the moss material, characterized by the concentration ratio between the moss and soil samples for each heavy metal, was topped by Cd and then followed by Zn, Pb, Cu, Cr, and Ni, respectively. Significant (P < 0.05) correlations were found among the six elements in mosses, suggesting potential anthropogenic inputs of these heavy metal pollutants. Based on concentrations of the heavy metals in mosses and the calculated contamination factors, we evaluated the contamination level of each heavy metal on the 49 sampling sites. Spatial distribution maps of heavy metal deposition for each element were interpolated using ArcGIS 9.0. A total pollution coefficient was calculated for each sampling site to identify the seriously polluted areas in the region.
Current research has focused on the preparation of Zinc-clinoptilolite/Graphene Oxide (Zn-Clin/GO) hybrid nanostructure and investigating its biocompatibility for the first time. As prepared samples were characterized by X-ray diffraction (XRD), Scanning electron microscopy (SEM), Thermo gravimetric analysis (TGA) and Fourier transform infrared (FT-IR). In order to use it as a drug carrier two important factors were investigated: cytocompatibility of nanocomposites and their drug loading capacity. The results showed that the prepared nanocomposite is cytocompatible and its high loading capacity and slow release performance for Doxorubicin (DOX), as a cancer drug, proved that it can be used as a drug carrier. At last in-vitro toxicity of DOX loaded nanocomposite was compared with pure DOX.
Concentrations of PAHs, OCs, PCBs and trace metals were determined in the white muscle of sand flathead Platycephalus bassensis collected at 6 locations in Port Phillip Bay during 2015. No PAHs, OCs or PCBs were detected in the white muscle of sand flathead at any of the locations, however measurable levels of As, Cu, Hg, Se and Zn were detected at all sites. Only As and Hg exhibited regional difference in white muscle concentrations, with As present only in a non-toxic organic form and Hg measured at levels that are comparable to levels reported in reference sites in other studies. All contaminants detected in the white muscle of sand flathead collected in Port Phillip Bay in 2015 were below Australian Food Standards guideline values, and by world standards, the Port Phillip Bay sand flathead population is considered minimally contaminated. Furthermore, tissue contaminant concentrations appear to be decreasing over time.
The urban soils suffered seriously from heavy metal pollutions with rapid industrialization and urbanization in China. In this study, 54 urban soil samples were collected from Changsha, a mine-impacted city located in Southern China. The concentrations of heavy metals (As, Cd, Co, Cu, Mn, Ni, Pb, and Zn) were determined by ICP-MS. The pollution sources of heavy metals were discriminated and identified by the combination of multivariate statistical and geostatistical methods. Four main sources were identified according to the results of hierarchical cluster analysis (HCA), principal component analysis (PCA), and spatial distribution patterns. Co and Mn were primarily derived from soil parent material. Cu, Pb, and Zn with significant positive relationships were associated with mining activities and traffic emissions. Cd and Ni might be affected by commercial activities and industrial discharges. As isolated into a single group was considered to have correlation with coal combustion and waste incineration. Risk assessment of heavy metals in urban soils indicated an overall moderate potential ecological risk in the urban region of Changsha.
Sue Yai Utit is an old community located in Bangkok, Thailand which dismantles waste electrical and electronic equipment (WEEE). The surface soil samples at the dismantling site were contaminated with copper (Cu), lead (Pb), zinc (Zn), and nickel (Ni) higher than Dutch Standards, especially around the WEEE dumps. Residual fractions of Cu, Pb, Zn, and Ni in coarse soil particles were greater than in finer soil. However, those metals bonded to Fe-Mn oxides were considerably greater in fine soil particles. The distribution of Zn in the mobile fraction and a higher concentration in finer soil particles indicated its readily leachable character. The concentration of Cu, Pb, and Ni in both fine and coarse soil particles was mostly not significantly different. The fractionation of heavy metals at this dismantling site was comparable to the background. The contamination characteristics differed from pollution by other sources, which generally demonstrated the magnification of the non-residual fraction. A distribution pathway was proposed whereby contamination began by the deposition of WEEE scrap directly onto the soil surface as a source of heavy metal. This then accumulated, corroded, and was released via natural processes, becoming redistributed among the soil material. Therefore, the concentrations of both the residual and non-residual fractions of heavy metals in WEEE-contaminated soil increased.
The Gulf Coast tick (Amblyomma maculatum) is an arthropod vector of Rickettsia parkeri, the causative agent of American boutonneuse fever and an infectious agent of public health significance. In this study, we evaluated the biological significance of the superoxide dismutases (SODs) of A. maculatum in hematophagy and R. parkeri colonization within the tick host.
An RNA interference approach was used to measure the functional roles of tick SODs (Cu/Zn-SOD and Mn-SOD) in R. parkeri colonization of the tick vector. Total microbial load, R. parkeri infection rate, and compensatory mechanisms by tick genes were examined using quantitative polymerase chain reaction (PCR) and quantitative reverse-transcriptase PCR assays. SOD enzymatic activity assays and malondialdehyde (MDA) lipid peroxidation were employed to determine the redox states in the tick tissues.
Knockdown of the Cu/Zn-SOD gene caused the upregulation of Mn-SOD in transcript levels. Single and dual knockdowns of the SOD genes caused an increase in MDA lipid peroxidation while SOD enzymatic activities did not show a significant change.
 Mn-SOD knockdown resulted in a substantial increase in the microbial load; however, Cu/Zn-SOD transcript depletion prompted an upsurge in the midgut bacterial load, and significantly decreased the bacterial load in salivary gland tissues. Additionally, Cu/Zn-SOD transcript silencing led to significantly fewer R. parkeri DNA copy numbers in both tick tissues (midguts and salivary glands).
SOD enzymes play an important function in the regulation of bacterial communities associated with tick vectors and also in the defense mechanisms against the damage caused by reactive oxygen species within the tick. Knockdown experiments increased the levels of total oxidative stress in ticks, revealing the interplay between SOD isozymes that results in the transcriptional regulation of tick antioxidants. Moreover, the tick's Cu/Zn-SOD aids in the colonization of R. parkeri in tick tissues providing evidence of A. maculatum's vectorial success for a spotted fever group rickettsial pathogen.
Conventional proton beam range verification using positron emission tomography (PET) relies on tissue activation alone and therefore requires particle therapy PET whose installation can represent a large financial burden for many centers. Previously, we showed the feasibility of developing patient implantable markers using high proton cross-section materials ((18)O, Cu, and (68)Zn) for in vivo proton range verification using conventional PET scanners. In this technical note, we characterize those materials to test their usability in more clinically relevant conditions. Two phantoms made of low-density balsa wood (~0.1 g cm(-3)) and beef (~1.0 g cm(-3)) were embedded with Cu or (68)Zn foils of several volumes (10-50 mm(3)). The metal foils were positioned at several depths in the dose fall-off region, which had been determined from our previous study. The phantoms were then irradiated with different proton doses (1-5 Gy). After irradiation, the phantoms with the embedded foils were moved to a diagnostic PET scanner and imaged. The acquired data were reconstructed with 20-40 min of scan time using various delay times (30-150 min) to determine the maximum contrast-to-noise ratio. The resultant PET/computed tomography (CT) fusion images of the activated foils were then examined and the foils' PET signal strength/visibility was scored on a 5 point scale by 13 radiologists experienced in nuclear medicine. For both phantoms, the visibility of activated foils increased in proportion to the foil volume, dose, and PET scan time. A linear model was constructed with visibility scores as the response variable and all other factors (marker material, phantom material, dose, and PET scan time) as covariates. Using the linear model, volumes of foils that provided adequate visibility (score 3) were determined for each dose and PET scan time. The foil volumes that were determined will be used as a guideline in developing practical implantable markers.
Collinear laser spectroscopy is performed on the _{30}^{79}Zn_{49} isotope at ISOLDE-CERN. The existence of a long-lived isomer with a few hundred milliseconds half-life is confirmed, and the nuclear spins and moments of the ground and isomeric states in ^{79}Zn as well as the isomer shift are measured. From the observed hyperfine structures, spins I=9/2 and I=1/2 are firmly assigned to the ground and isomeric states. The magnetic moment μ (^{79}Zn)=-1.1866(10)μ_{N}, confirms the spin-parity 9/2^{+} with a νg_{9/2}^{-1} shell-model configuration, in excellent agreement with the prediction from large scale shell-model theories. The magnetic moment μ (^{79m}Zn)=-1.0180(12)μ_{N} supports a positive parity for the isomer, with a wave function dominated by a 2h-1p neutron excitation across the N=50 shell gap. The large isomer shift reveals an increase of the intruder isomer mean square charge radius with respect to that of the ground state, δ⟨r_{c}^{2}⟩^{79,79m}=+0.204(6)  fm^{2}, providing first evidence of shape coexistence.
Cullin-RING ubiquitin ligases are the largest E3 ligase family in eukaryotes and are multiprotein complexes. In these complexes, the Cullin protein serves as a scaffold to connect two functional modules of the ligases, the catalytic subunit and substrate-binding subunit. To date, eight members of the Cullin family proteins have been identified. In the Cul3 ubiquitin ligases, Bric-a-brac/Tramtrack/Broad complex (BTB) domain-containing proteins function as a bridge to connect Cul3 and substrates. While the BTB domain is responsible for Cul3 binding, these proteins usually contain an additional domain for substrate interaction, such as MATH, kelch, Zn finger, and PAM, Highwire, and RPM-1 (PHR domain). With the existence of a large number of BTB proteins in human, the Cul3 ubiquitin ligases ubiquitinate a wide range of substrates involving in diverse cellular functions. In this review, we will discuss recent advances on the functions of Cul3 ubiquitin ligases in cancer development, progression, and therapeutic response and the dysregulation of Cul3-mediated ubiquitination events in human malignancies. In particular, we will focus on three Cul3 substrate adaptors, kelch-like ECH-associated protein (Keap1), kelch-like family member 20 (KLHL20), and speckle type BTB/POZ protein (SPOP), with the intent to highlight novel targets in cancer therapy.
Heavy metals are frequently reported for their mutagenic and teratogenic effects on benthic organisms. Thus, this study aimed to determine the toxicity of cadmium (Cd) and zinc (Zn) in the gametes of T. gratilla and to compare its fertilization and embryonic development under the highest nongametotoxic concentrations of these heavy metals. Gamete viability of T. gratilla under CdCl2 and ZnSO4 treatments was assayed through resazurin reduction test (RRT) and was confirmed through gamete morphology assay. ZnSO4 was more toxic to T. gratilla gametes than CdCl2 and egg cells were more sensitive to both than the sperm cells. Higher concentrations of CdCl2 and ZnSO4 induced gamete apoptosis and necrosis while highest nongametotoxic concentrations were determined at 1 × 10(-3) M and 1 × 10(-4) M, respectively, and were used in an in vitro fertilization and embryonic development experiment. ZnSO4 treatment inhibited fertilization more than CdCl2 and yielded more deformed embryos, while both induced abnormalities and hindered further embryonic development. This study gives the first report on the specific concentrations of Cd and Zn that are toxic to T. gratilla gametes and has confirmed the teratogenic effects of these heavy metals.
The increase of heavy metals in the environment involves a high exposure of aquatic organisms to these pollutants. The present study is planned to investigate the effects of zinc chloride (ZnCl2) on the bone embryonic development of Danio rerio and confirm the use of zebrafish as a model organism to study the teratogenic potential of this pollutant. Zebrafish embryos were exposed to different ZnCl2 concentrations and analyzed by ICP-MS. The skeletal anomalies were evaluated to confocal microscope after staining with calcein solution and RhodZin(TM)-3,AM. The data show a delay in hatching compared with the controls, malformations in the process of calcification and significant defects in growth. In conclusion, the current work demonstrates for the first time the Zn toxic effects on calcification process and confirm zebrafish (Danio rerio) as suitable alternative vertebrate model to study the causes and the mechanisms of the skeletal malformations.
Promoter elements enhance the activity and selectivity of heterogeneous catalysts. Here, we show how methanol synthesis from synthesis gas over copper (Cu) nanoparticles is boosted by zinc oxide (ZnO) nanoparticles. By combining surface area titration, electron microscopy, activity measurement, density functional theory calculations, and modeling, we show that the promotion is related to Zn atoms migrating in the Cu surface. The Zn coverage is quantitatively described as a function of the methanol synthesis conditions and of the size-dependent thermodynamic activities of the Cu and ZnO nanoparticles. Moreover, experimental data reveal a strong interdependency of the methanol synthesis activity and the Zn coverage. These results demonstrate the size-dependent activities of nanoparticles as a general means to design synergetic functionality in binary nanoparticle systems.
The synthesis of hierarchically mesoporous polymers with multiple functionalities is challenging. Herein we reported a template-free strategy for synthesis of phenolic azo-polymers with hierarchical porous structures based on diazo-coupling reaction in aqueous solution under mild conditions. The resultant polymers have surface areas up to 593 m(2)  g(-1) with the mesopore ratio of >80 %, and a good ability to complex with metal ions, such as Cu(2+) , Zn(2+) ,Ni(2+) , achieving a metal loading up to 26.24 wt %. Moreover, the polymers complexed with Zn showed excellent performance for catalyzing the reaction of CO2 with epoxide, affording a TOF of 2570 h(-1) in the presence of tetrabutyl ammonium bromide (7.2 mol %). The polymer complexed with Cu could catalyze the oxidation of alcohol with high efficiency.
Low-cost alkaline water electrolysis has been considered a sustainable approach to producing hydrogen using renewable energy inputs, but preventing hydrogen/oxygen mixing and efficiently using the instable renewable energy are challenging. Here, using nickel hydroxide as a redox mediator, we decouple the hydrogen and oxygen production in alkaline water electrolysis, which overcomes the gas-mixing issue and may increase the use of renewable energy. In this architecture, the hydrogen production occurs at the cathode by water reduction, and the anodic Ni(OH)2 is simultaneously oxidized into NiOOH. The subsequent oxygen production involves
 a cathodic NiOOH reduction (NiOOH→Ni(OH)2) and an anodic OH(-) oxidization. Alternatively, the NiOOH formed during hydrogen production can be coupled with a zinc anode to form a NiOOH-Zn battery, and its discharge product (that is, Ni(OH)2) can be used to produce hydrogen again. This architecture brings a potential solution to facilitate renewables-to-hydrogen conversion.
Great efforts have been made to develop fluorescent probes for pyrophosphate (PPi) detection. Nucleus staining with fluorescence microscopy has been also widely investigated. But fluorescent probes for PPi detection with high sensitivity in water medium and nucleus staining with low-cost non-precious metal complexes in living cells are still challenging. Herein, we report simple terpyridine-Zn(II) complexes for selective nanomolar PPi detection over ATP and ADP in water based on aggregation induced emission (AIE) and intramolecular charge transfer (ICT). In addition, these terpyridine-Zn(II) complexes were successfully employed for nucleus staining in living cells. These results demonstrated simply obtained terpyridine-Zn(II) complexes are powerful tool for PPi detection and the development of PPi-related studies.
To provide a comprehensive synthesis of the effects of Zn supplementation on childhood body composition and adiposity-related hormone levels.
Five electronic databases were searched for randomized controlled trials of Zn supplementation studies published before 28 February 2015. No statistical pooling of results was carried out due to diversity in study designs.
Community- or hospital-based, from fourteen developing and developed countries.
Children and adolescents aged 0 to 10 years.
Seven of the fourteen studies reported an overall or subgroup effect of Zn supplementation on at least one parameter of body composition, when determined by anthropometric measurements (increased mid upper-arm circumference, triceps skinfold, subscapular skinfold and mid upper-arm muscle area, and decreased BMI). Three out of the fourteen studies reported increased mean value of total body water estimated by bio-impedance analysis and increased fat-free mass estimated by dual energy X-ray absorptiometry and by total body water. Zn supplementation was associated with increased fat-free mass among stunted children. One study found supplementation decreased leptin and insulin concentrations.
Due to the use of anthropometry when determining body composition, a majority of the studies could not accurately address whether alterations in the fat and/or fat-free mass components of the body were responsible for the observed changes in body composition. The effect of Zn supplementation on body composition is not consistent but may modify fat-free mass among children with pre-existing growth failure.
Heavy metals (As, Cd, Cr, Cu, Hg, Pb, Zn), organic carbon and grain size of 237 surface sediment samples and one sediment core, taken from the west Guangdong coastal region in January 2008, were analyzed to evaluate the spatial distribution and pollution status. Results show that the ranges of the measured heavy metal concentrations in sediments are as follows: 8.33-39.49mg/kg for As, 0.1-1.49mg/kg for Cd, 33-108mg/kg for Cr, 11.5-78.8mg/kg for Cu, 0.04-0.26mg/kg for Hg, 21-73mg/kg for Pb, 56-248mg/kg for Zn. The heavy metal enrichment is closely associated with Corg and grain size. Both the metal enrichment factor and geoaccumulation index indicate that there was no detected pollution on metals As, Cr, Cu, Pb in our study area and a slight to moderate contamination of Cd, Hg and Zn. However, As, Cr and Cu have showed a certain risk.
33 surface sediment samples from the Luanhe River Estuary have been analyzed for heavy metals to evaluate the spatial distribution pattern and their potential ecological risk. Higher metal concentrations were found in the river mouth and southern areas where being covered by fine particulate matters. In comparison with the threshold effect level and the probable effect level, Cu, Pb, Cr, Ni, and As had occasionally adverse biological effects on the aquatic ecosystems. Both the enrichment factor and geoaccumulation index values show that all the regions have been weakly polluted by Pb, Hg, As, and Cd with an exception of being moderately to strongly polluted by Hg in the river mouth and southern areas. The sources of Zn, Ni, Cd, Hg, and Cr were mainly from the river input and coastal discharge, whereas Cu, Pb, and As were mainly derived from vehicle emissions, coal and oil combustion.
This study focuses on the extent of zinc (Zn), copper (Cu), cadmium (Cd), cobalt (Co), manganese (Mn), lead (Pb), mercury (Hg), and arsenic (As) bioaccumulation in edible muscles of Caspian kutum (Rutilus frisii kutum), in both male and female sexes at Noor and Babolsar coastal regions from the southern basin of Caspian Sea. These values were compared with the WHO and the UNFAO safety standards regarding the amount of the abovementioned heavy metals in fish tissues (mg/kg ww). Results showed that the accumulation of these elements (except for Zn) was not significantly different between sexes of male and female in Babolsar coastal regions (P > 0.05). In the other hand, accumulation of Hg and As at edible muscles of Caspian kutum has significant difference between two sexes of male and female in Noor coastal regions (P < 0.05), the female had higher concentration than the male. Furthermore, it was not significantly correlated with sex and rivers in length and weight of fish (R (2) < 0.50; P > 0.05). Based on the results, the concentration of heavy metals in the studied fish tissues proved to be significantly lower than international standards (P < 0.05), so its consumption is not a threat to the health of consumers.
Food insecurity is a growing concern for indigenous communities worldwide. While the risk of heavy metal contamination associated to wild food consumption has been extensively studied in the Arctic, data are scarce for the Boreal zone. This study addressed the concerns over possible heavy metal exposure through consumption of traditional food in four Anishnaabeg communities living in the Eastern North American boreal forest. Liver and meat samples were obtained from 196 snowshoe hares (Lepus americanus) trapped during winter 2012 across the traditional lands of the participating communities and within 56-156km of a copper smelter. Interviews were conducted with 78 household heads to assess traditional food habits, focusing on snowshoe hare consumption. Concentrations in most meat and liver samples were below the detection limit for As, Co, Cr, Ni and Pb. Very few meat samples had detectable Cd and Hg concentrations, but liver samples had mean dry weight concentrations of 3.79mg/kg and 0.15mg/kg respectively. Distance and orientation from the smelter did not explain the variability between samples, but percent deciduous and mixed forest cover had a marginal negative effect on liver Cd, Cu and Zn concentrations. The estimated exposition risk from snowshoe hare consumption was low, although heavy consumers could slightly exceed recommended Hg doses. In accordance with the holistic perspective commonly adopted by indigenous people, the nutritional and sociocultural importance of traditional food must be considered in risk assessment. Traditional food plays a significant role in reducing and preventing serious health issues disproportionately affecting First Nations, such as obesity, diabetes, and cardiovascular diseases.
Foshan is a major international ceramic center and the most polluted city in the Pearl River Delta (PRD). Here we present the results of the first long-term PM2.5 (particles <2.5μm) sampling and chemical characterization study of the city. A total of 2774 samples were collected at six sites from 2008 to 2014, and analyzed for water soluble species, elements and carbonaceous species. The major constituents of PM2.5 were sulfate, OC (Organic Carbon), nitrate, ammonium and EC (Elemental Carbon), which accounted for 50%-88% of PM2.5. PM2.5 and the most abundant chemical species decreased from 2008 to 2011, but rebounded in 2012-2013. After 2008, the chemical composition of PM2.5 changed dramatically due to the implementation of pollution control measures. From 2008 to 2011, SO4(2-) and NO3(-) were the two largest components; subsequently, however, OC was the largest component. The respective contributions of SO4(2-), NO3(-) and OC to the sum of water soluble species and carbonaceous species were 30.5%, 22.9% and 19.9% in 2008; and 20.2%, 16.5% and 30.2% in 2014. Distinct differences in nitrate and sulfate, and in mass ratio [NO3(-)]/[SO4(2-)] imply that mobile sources tended to more important in Foshan during 2012-2014. The results indicate that pollution control measures implemented during 2008-2014 had a large effect on anthropogenic elements (Pb, As, Cd, Zn and Cu) and water soluble species, but little influence on crustal elements (V, Mn, Ti, Ba and Fe) and carbonaceous species. The PMF method was used for source apportionment of PM2.5. Industry (including the ceramic industry and coal combustion), vehicles and dust were the three most important sources and comprised 39.2%, 20.0% and 18.4% of PM2.5 in 2008, respectively. However, secondary aerosols, vehicles and industry were the three most important sources and comprised 29.5%, 22.4% and 20.4% of PM2.5 in 2014, respectively. During the seven year study interval, the contributions of primary sources (industry and dust) decreased significantly, but secondary sources increased dramatically. Industry, dust and vehicles contributed 36.6μgm(-3), 13.9μgm(-3), and 9.2μgm(-3) to the reduction of PM2.5, respectively.
Agricultural soil is typically an important component of urban ecosystems, contributing directly or indirectly to the general quality of human life. To understand which factors influence
 metal accumulation in agricultural soils in urban ecosystems is becoming increasingly important. Land use, soil type and urbanization indicators all account for considerable differences in metal accumulation in agricultural soils, and the interactions between these factors on metal concentrations were also examined. Results showed that Zn, Cu, and Cd concentrations varied significantly among different land use types. Concentrations of all metals, except for Cd, were higher in calcareous cinnamon soil than in fluvo-aquic soil. Expansion distance and road density were adopted as urbanization indicators, and distance from the urban center was significantly negatively correlated with concentrations of Hg, and negatively correlated with concentrations of Zn, and road density was positively correlated with Cd concentrations. Multivariate analysis of variance indicated that Hg concentration was significantly influenced by the four-way interaction among all factors. The results in this study provide basic data to support the management of agricultural soils and to help policy makers to plan ahead in Beijing.
Zinc oxide (ZnO) nanoparticles (NPs) have been applied in numerous industrial products and personal care products like sunscreens and cosmetics. The released ZnO NPs from consumer and household products into the environment might pose potential health issues for animals and humans. In this study the expression of microRNAs and the correlations of microRNAs and their targeted genes in ZnO NPs treated chicken ovarian granulosa cells were investigated. ZnSO4 was used as the sole Zn2+ provider to differentiate the effects of NPs from Zn2+. It was found that ZnO-NP-5 μg/ml specifically regulated the expression of microRNAs involved in embryonic development although ZnO-NP-5 μg/ml and ZnSO4-10 μg/ml treatments produced the same intracellular Zn concentrations and resulted in similar cell growth inhibition. And ZnO-NP-5 μg/ml also specifically regulated the correlations of microRNAs and their targeted genes. This is the first investigation that intact NPs in ZnO-NP-5 μg/ml treatment specifically regulated the expression of microRNAs, and the correlations of microRNAs and their targeted genes compared to that by Zn2+. This expands our knowledge for biological effects of ZnO NPs and at the same time it raises the health concerns that ZnO NPs might adversely affect our biological systems, even the reproductive systems through regulation of specific signaling pathways.
The development of frequency-conversion technology in the infrared region is in urgent need of new excellent infrared nonlinear optical (IR NLO) materials. How to achieve a good balance between laser damage threshold (LDT) and NLO coefficient (dij) for new IR NLO candidates is still a challenge. The combination of the highly electropositive alkali metal (Na) and Zn with d(10) electronic configuration into crystal structure affords one new IR NLO material, Na2ZnGe2S6. It exhibits excellent properties including a wide transparent region (0.38-22 μm), large band gap (3.25 eV), and especially a balance between a strong NLO coefficient (30-fold that of KDP) and a high LDT (6-fold that of AgGaS2), indicating a promising application in the IR region. Moreover, novel common-vertex-linked wavelike ∞[GeS3]n chains are interestingly discovered in Na2ZnGe2S6, which rarely exist in the reported thiogermanides containing alkali metals. In addition, calculated SHG density and dipole moment demonstrate that the large NLO response is mainly attributed to the cooperative effects of the [GeS4] and [ZnS4] units.
Determining mechanism-based biomarkers that distinguish adaptive and adverse cellular processes is critical to understanding the health effects of environmental exposures. Shifting from in vivo, low-throughput toxicity studies to high-throughput screening (HTS) paradigms and risk assessment based on in vitro and in silico testing requires utilizing toxicity pathway information to distinguish adverse outcomes from recoverable adaptive events. Little work has focused on oxidative stresses in human airway for the purposes of predicting adverse responses. We hypothesize that early gene expression-mediated molecular changes could be used to delineate adaptive and adverse responses to environmentally-based perturbations. Here, we examined cellular responses of the tracheobronchial airway to zinc (Zn) exposure, a model oxidant. Airway derived BEAS-2B cells exposed to 2-10 μM Zn2+ elicited concentration- and time-dependent cytotoxicity. Normal, adaptive, and cytotoxic Zn2+ exposure conditions were determined with traditional apical endpoints, and differences in global gene expression around the tipping point of the responses were used to delineate underlying molecular mechanisms. Bioinformatic analyses of differentially expressed genes indicate early enrichment of stress signaling pathways, including those mediated by the transcription factors p53 and NRF2. After 4 h, 154 genes were differentially expressed (p < 0.01) between the adaptive and cytotoxic Zn2+ concentrations. Nearly 40% of the biomarker genes were related to the p53 signaling pathway with 30 genes identified as likely direct targets using a database of p53 ChIP-seq studies. Despite similar p53 activation profiles, these data revealed widespread dampening of p53 and NRF2-related genes as early as 4 h after exposure at higher, unrecoverable Zn2+ exposures. Thus, in our model early increased activation of stress response pathways indicated a recoverable adaptive event. Overall, this study highlights the importance of characterizing molecular mechanisms around the tipping point of adverse responses to better inform HTS paradigms.
Three topologically non-trivial cadmium(ii)-based complexes-Cd-[2]C, Cd-TK and Cd-SL-were simultaneously self-assembled in a dynamic library, individually isolated and fully characterized using solid-state, gas-phase and solution-phase techniques. Post-synthetic modifications, including reduction and transmetalation, were subsequently achieved. Imine bond reduction followed by demetallation led to the isolation of the corresponding organic molecules [2]C, TK and SL. Transmetalation of Cd-TK and Cd-SL with the zinc(ii) cation resulted in isolation of the corresponding zinc(ii)-containing complexes Zn-TK and Zn-SL.
Bioaccumulation kinetics of five dissolved metals were determined in the mangrove oyster Crassostrea gasar, using corresponding radiotracers ((54)Mn, (57)Co, (65)Zn, (109)Cd and (110m)Ag). Additionally, their bioaccessibility to human consumers was estimated. Results indicated that over a 14-day exposure (54)Mn and (57)Co were linearly concentrated in oysters whereas (109)Cd, (65)Zn and (110m)Ag were starting to saturate (steady-state not reached). Whole-body concentration factors at 14 days (CF14d in toto) ranged from 187 ± 65 to 629 ± 179 with the lowest bioconcentration capacity for Co and the highest for Ag. Depuration kinetics were best described by a double-exponential model with associated biological half-lives ranging from 26 days (Ag) to almost 8 months (Zn and Cd). Bioaccessible fraction of the studied elements was estimated using in vitro digestions, which suggested that oysters consumed seasoned with lemon enhanced the accessibility of Cd, Mn and Zn to human consumers, but not Ag and Co.
This study investigated heavy metal pollution in sediments of the Rosetta branch of the River Nile of Egypt to quantify the toxic distribution potential of metals into the surrounding environment. Sediment samples were collected at 9 sites during in four seasons. Organic matter and total metal concentrations were determined using loss on ignition and inductively coupled plasma spectrometry, respectively. Principal component analysis has been applied to evaluate the metal sources and the relationships between metals in sediments. Metal concentrations showed the following order: winter > autumn > spring > summer. Mean concentrations of Cu, Zn, Cd, and Pb in sediments were above the average background value of metals in shale. Pb and Cd showed higher enrichment during all seasons at stations N3/N4, Zn at stations N1 to N4, and Cu at stations N6/N8. The variations in heavy metal total concentration and organic matter are due to different input sources, physico-chemical conditions, and adsorption/precipitation/redox conditions in sediments. Mean values of Geo-accumulation index (Igeo) for Fe, Mn, and Cu were below 0 which were classified as unpolluted during spring, summer, and autumn, except Cu increased from unpolluted to moderately polluted during winter. Igeo values for Cd, Pb, and Zn increased from unpolluted-moderately polluted to highly-very highly polluted during autumn and winter. Pollution Load Index was recorded in highest values during winter, especially at Fuwwah/Basioun and in lowest values during summer at after the Edfina Barrage/before Kafer El-Zayat due to industrial/human activities. Both natural and anthropogenic sources contributed to the metal accumulations in sediments, and industrial, agricultural, and municipal sewage effluents discharged from non-point sources may be the main anthropogenic sources for metals in the Rosetta branch.
Two new luminescent compounds containing fluorescein-amino acid units have been designed and synthesized via an ester linkage between a fluorescein ethyl ester and Boc-Ser(TBDMS)-OH or Boc-Cys(4-MeBzl)-OH, and their photophysical properties have been explored. The optical response of both compounds (2 and 3) towards the metal ions Na(+), K(+), Hg(+), Ag(+), Ca(2+), Co(2+), Ni(2+), Cu(2+), Zn(2+), Cd(2+), Pb(2+), Hg(2+), Al(3+), Fe(3+), Ga(3+)and Cr(3+) was investigated in pure acetonitrile and in acetonitrile/water mixtures. A strong CHEF (Chelation-Enhanced Fluorescence) effect was observed with all the trivalent metals and Hg(2+) ions in both
 solvents. UV-vis absorption, steady state and time resolved emission spectroscopy methods were employed. The results show the formation of mononuclear complexes with Al(3+), Fe(3+), Ga(3+), Cr(3+), and Hg(2+). Theoretical calculation using Density Functional Theory was performed in order to obtain atomistic insights into the coordination geometry of Al(3+) and Hg(2+) to the fluorescein 3, which is in accordance with the experimental stoichiometry results obtained in the Job's plot method. Among the active cations, the minimum detectable amount is under 1 μM for most of the cases in both absorption and fluorescence spectroscopy methods.
A novel smart supramolecular organic gelator G-16 containing anion and metal-coordination ability has been designed and synthesized. It shows excellent and robust gelation capability as a strong blue fluorescent supramolecular organic gel OG in DMF. Addition of Zn(2+) produced Zn(2+)-coordinated supramolecular metallogel OG-Zn. Organic gel OG and organometallic gel OG-Zn exhibited efficient and different sensing behaviors towards fluoride ion due to the variation in self-assembling nature. Supramolecular metallogel OG-Zn displayed specific selectivity for fluoride ion and formed OG-Zn-F with dramatic color change from blue to blue green in solution and gel to gel states. Furthermore after directly addition of fluoride into OG produced fluoride containing organic gel OG-F with drastically modulation in color from blue to greenish yellow fluorescence via strong aggregation-induced emission (AIE) property. A number of experiments were conducted such as FTIR, (1)H NMR, and UV/Vis spectroscopies, XRD, SEM and rheology. These results revealed that the driving forces involved in self-assembly of OG, OG-Zn, OG-Zn-F and OG-F were hydrogen bonding, metal coordination, π-π interactions, and van der Waal forces. In contrast to the most anion responsive gels, particularly fluoride ion responsive gels showed gel-sol state transition on stimulation by anions, the gel state of OG and OG-Zn did not show any gel-to-sol transition during the whole F(-) response process.
This study was carried out to evaluate the concentration of trace metals (Cd, Cu, Ni, Pb and Zn) in the muscle of four fish species from the Persian Gulf. Trace metals were analyzed using atomic absorption spectroscopy and consumption rates advisory for minimizing chronic systemic effects in children and adults were estimated. The metals concentrations in analyzed fish samples were lower than legal limits. Cadmium target hazard quotient values suggested that the threshold to avoid the potential risk for children health is an exposure level lower than 3 meals per week. Hazard index values based on four metals (not including Pb) for the child age class were higher than those of the adult age class, suggesting that children may suffer from a higher health risk. This study provides information about the consumption limits of certain metals, in particular Cd, necessary for minimizing potential health risks resulting from human consumption.
The recently proposed fast switching double annihilation (FS-DAM) [Cardelli et al., J. Chem. Theory Comput., 2015, 11, 423] is aimed at computing the absolute standard dissociation free energies for the chemical equilibrium RL ⇌ R + L occurring in solution through molecular dynamics (MD) simulations at the atomistic level. The technique is based on the production of fast nonequilibrium annihilation trajectories of one of the species (the ligand) in the solvated RL complex and in the bulk solvent. As detailed in the companion theoretical paper, the free energies of these two nonequilibrium annihilation processes are recovered by using an unbiased unidirectional estimate derived from the Crooks theorem exploiting the inherent Gaussian nature of the annihilation work. The FS-DAM technique was successfully applied to the evaluation of the dissociation free energy of the complexes of Zn(ii) cations with an inhibitor of the Tumor Necrosis Factor α converting enzyme. Here we apply the technique to a real drug-receptor system, by satisfactorily reproducing the experimental dissociation free energies of FK506-related bulky ligands towards the native FKBP12 enzyme and by predicting the dissociation constants for the same ligands towards the mutant I56D. The effect of such mutations on the binding affinity of FK506-related ligands is relevant for assessing the thermodynamic forces regulating molecular recognition in FKBP12 inhibition.
Mangrove communities were selected in the state of Santa Catarina, Brazil, near their southernmost limit of distribution, to study mineral nutrient relation in soils and plants. Communities included three true mangrove species, Rhizophora mangle, Laguncularia racemosa and Avicennia germinans, and two associated species, the fern Acrostichum danaeifolium, and the grass Spartina densiflora. The sites included communities in the lower Río Tavares near Florianopolis city, Sonho beach near Palhoça city, and the Santo Antonio lagoon. These sites included a full range of mangroves under humid climate where winter temperatures, instead of salinity, may be the main factor regulating their productive capacity and species composition. Soil salinity was determined by the concentration of soluble Na, and soil C and N were linearly correlated indicating their association in organic matter. Tavares site showed higher specific conductivity, and concentrations of Na and Mg in the soil layer below 40 cm depth, indicating larger influence of marine water. Isotopic signature of C increased with soil depth suggesting that microorganisms decomposing organic matter are releasing 13C depleted CO2. Nitrogen isotopic signature decreased with soil depth, indicating enrichment in 15N possibly as a result of denitrification in the upper soil layers. Mineral elements in leaf tissues showed A. schaueriana with higher concentrations of N, P, Na, K, Cu, Zn, and Na/Ca ratio. Spartina densiflora was characterized by the lowest N and K concentrations, and the highest concentrations of Al and Fe. Rhizophora mangle and L. racemosa had the highest Ca concentrations. Carbon isotopic signatures identified S. densiflora as a C4 plant, and A. schaueriana as the mangrove species occupying comparatively more water stressed microsites than the rest. Leaf nitrogen isotopic signatures were positive, in correspondence with the soil values. The results support the hypothesis that sites sampled were comparatively fertile, because sediment transport through fresh water run-off is predominant in humid coasts, and therefore plants were not limited by nutrient supply, nor particularly stressed by soil salinity.
Superoxide dismutase is an antioxidant enzyme that is involved in defence mechanisms against oxidative stress. Cu/Zn SOD is a variant that is located in exon3/intron3 boundary. The aim of the present study was to investigate whether the Cu/Zn SOD (+35A/C) gene polymorphism is associated with the susceptibility to type 2 diabetes mellitus among south Indian population. The study included patients with type 2 diabetes mellitus (n = 100) and healthy controls (n = 75). DNA was isolated from the blood and genotyping of Cu/Zn SOD gene polymorphism was done by polymerase chain reaction based restriction fragment length polymorphism method. Occurrence of different genotypes and normal (A) and mutant (C) allele frequencies were determined. The frequency of the three genotypes of the total subjects was as follows: homozygous wild-type A/A (95%), heterozygous genotype A/C (3%), and homozygous mutant C/C (2%). The mutant (C) allele and the mutant genotypes (AC/CC) were found to be completely absent among the patients with type 2 diabetes mellitus. Absence of mutant genotype (CC) shows that the Cu/Zn SOD gene polymorphism may not be associated with the susceptibility to type 2 diabetes mellitus among south Indian population.
Cardiomyopathy is a frequent cause of death in patients with Friedreich ataxia (FA), and a characteristic pathological feature is the focal accumulation of iron (Fe) in cardiomyocytes. This restricted localization of the metal contrasts with the diffuse cardiac Fe overload in hemochromatosis and transfusion siderosis. Nevertheless, heart Fe in FA contributes to cardiomyocyte necrosis, inflammation, and scarring as the disease progresses. A putative mechanism of cardiomyopathy in FA is Fe-mediated oxidative damage. Two other transition metals zinc (Zn) and copper (Cu), are diffusely distributed throughout normal hearts and the hearts of patients with FA. The myocardium in FA is also prone to deposits of calcium in the form of scattered concretions. In this study, heart tissues (left and right ventricular walls and ventricular septum) of 23 patients with genetically confirmed FA and 8 normal controls were obtained at autopsy and analyzed for Fe, Zn, Cu, and calcium. The principal assay methods were inductively coupled plasma optical emission spectrometry and plasma mass spectrometry. Total levels of Fe in bulk extracts were not significantly higher than normal, and the concentrations of Zn also remained in the normal range. Cu levels, however, were significantly lower in FA. In conclusion, the decrease of Cu may be important in consideration of the potential benefit of Cu supplements in FA cardiomyopathy.
The use of transplanted moss (Pleurozium schreberi) in active biomonitoring of traffic-related emissions of Pd, Pt, and Rh was studied. Moss mats were transplanted to three locations along highway E75 (in Oulu, Finland) at three different distances from the highway. Five samples were collected from a background site after the same exposure period. Mass fractions of Pd, Pt, and Rh as well as mass fractions of 18 other elements were determined in these samples. The results indicated that P. schreberi is well suited for active
 biomonitoring of Pd, Pt, and Rh. Mass fractions above the background values were observed in the samples exposed to traffic-related emissions. When the results were compared with those of the other elements, high correlations of Pd, Pt, and Rh with commonly traffic-related elements (e.g., Cu, Ni, Sb, Zn, etc.) were found. It was also found that the amounts of Pd, Pt, and Rh in moss samples decreased when the distance to the highway increased. This trend gives evidence for the suitability of P. schreberi for active biomonitoring of Pd, Pt, and Rh. Furthermore, it can be concluded that the mass fractions determined in this study provide valuable evidence about the current state of Pd, Pt, and Rh emissions in Oulu, Finland.
An alginate lyase-producing bacterial strain, Cobetia sp. WG-007 was isolated and identified from rotting seaweed. The alginate lyase, Aly-W02, was purified by procedures of ultrafiltration, Q-FF, Phenyl Sepharose 6 Fast Flow and Superdex-G100 with specific activity of 21285.5 U/mg. Aly-W02 had an apparent molecular mass of 35 kDa. It exhibited maximum activity at 45°C in 50 mM sodium phosphate buffer (pH 8.5). This alginate lyase was stable in the pH range of 6.0-8.5. Among the tested metal ions, addition of K(+) , Na(+) and Mg(2+) ions can enhance the enzyme activities, while Ba(2+) , Ni(+) , Cu(2+) , Mn(2+) , Zn(2+) , Ag(+) , and EDTA decreased the activities. It displayed high salt-tolerant ability, 0.8 M NaCl or 1.5 M KCl significantly enhanced the enzyme activity. Furthermore, Aly-W02 mainly released disaccharide, trisaccharide, and tetrasaccharid from alginate. It showed potential in producing low-molecular weight alginate oligosaccharides. This article is protected by copyright. All rights reserved.
Increasing exposure to arsenic (As) contaminated ground water is a great threat to humanity. Suitable technology for As immobilization and removal from water, especially for As(III) than As(V), is not available yet. However, it is known that As(III) is more toxic than As(V) and most groundwater aquifers, particularly the Gangetic basin in India, is alarmingly contaminated with it. In search of a viable solution here, we took a cue from the natural mineralization of Tooeleite, a mineral containing Fe(III) and As(III)ions, grown under acidic condition, in presence of SO4(2-) ions. Complying to this natural process, we could grow and separate Tooeleite-like templates from Fe(III) and As(III) containing water at overall circumneutral pH and in absence of SO4(2-) ions by using highly polar Zn-only ends of wurtzite ZnS nanorods as insoluble nano-acidic-surfaces. The central idea here is to exploit these insoluble nano-acidic-surfaces (called as INAS in the manuscript) as nucleation centres for Tooeleite growth while keeping the overall pH of the aqueous media neutral. Therefore, we propose a novel method of artificial mineralization of As(III) by mimicking a natural process at nanoscale.
In order to explore the possibilities of using zinc (Zn) stable isotope ratios as dietary indicators, we report here on the measurements of the ratio of stable isotopes of zinc ((66)Zn/(64)Zn, expressed here as δ(66)Zn) in bioapatite (bone and dental enamel) of animals from a modern food web in the Koobi Fora region of the Turkana Basin in Kenya. We demonstrate that δ(66)Zn values in both bone and enamel allow a clear distinction between carnivores and herbivores from this food web. Differences were also observed between browsers and grazers as well as between carnivores that consumed bone (i.e. hyenas) compared to those that largely consume flesh (i.e. lions). We conclude that Zn isotope ratio measurements of bone and teeth are a new and promising dietary indicator.
Impaired childhood development has lifelong consequences for educational attainment and wage-earning potential. Micronutrient supplements have the potential to improve development. The objective of this study was to determine the effect of daily zinc and/or multivitamin (vitamins C, E and B-complex) supplements on development among Tanzanian infants. In this randomized, 2 × 2 factorial, double-blind trial, 2400 infants were randomized to zinc (Zn), multivitamins (MV), zinc and multivitamins (Zn + MV) or placebo at 6 weeks of age. At approximately 15 months, a sub-sample of 247 children underwent developmental assessment using the cognitive, language (receptive and expressive) and motor (fine and gross) scales of the Bayley Scales of Infant and Toddler Development Third Edition (BSID-III). Mean BSID-III scores were compared using univariate and multivariate linear regression models adjusted for child's sex, post-conceptual age and test administrator. Logistic regressions were used to assess odds of low developmental scores. We did not detect a significant difference in mean BSID-III scores in any of the five domains in univariate or multivariate models comparing each of the four treatment groups. We also did not detect a significant difference in mean BSID-III scores when comparing children who received zinc supplements versus those who did not, or in comparisons of children who received multivitamin supplements versus those who did not. There was no significant difference in odds of a low BSID-III score in any of the five domains in treatment arms either. Because neither daily zinc nor multivitamin (vitamins B-complex, C and E) supplementation led to improvements in any of the developmental domains assessed using the BSID-III, we recommend pursuing alternative interventions to promote early childhood development in vulnerable populations. © 2016 John Wiley & Sons Ltd.
Low-temperature-tolerant microorganisms and their cold-active enzymes could be an innovative and invaluable tool in various industrial applications. In the present study, bacterial isolates from the sediment samples of Kongsfjord, Norwegian Arctic, were screened for β-galactosidase production. Among the isolates, KS25, KS85, KS60, and KS92 have shown good potential in β-galactosidase production at 20 °C. 16SrRNA gene sequence analysis revealed the relatedness of the isolates to Enterobacter ludwigii. The optimum growth temperature of the isolate was 25 °C. The isolate exhibited good growth and enzyme production at a temperature range of 15-35 °C, pH 5-10. The isolate preferred yeast extract and lactose for the maximum growth and enzyme production at conditions of pH 7.0, temperature of 25 °C, and agitation speed of 100 rpm. The growth and enzyme production was stimulated by Mn(2+) and Mg(2+) and strongly inhibited by Zn(2+), Ni(2+), and Cu(+). β-Galactosidases with high specific activity at low temperatures are very beneficial in food industry to compensate the nutritional problem associated with lactose intolerance. The isolate exhibited a remarkable capability to utilize clarified whey, an industrial pollutant, for good biomass and enzyme yield and hence could be well employed in whey bioremediation.
A kind of core-shell catalyst with Fe-Zn-Zr as the core and a zeolite (HZSM-5, Hbeta, and HY) as the shell was synthesized by a simple cladding method. The catalyst has an obvious confinement effect on the synthesis of isoalkanes by CO2 hydrogenation. Especially, the Fe-Zn-Zr@HZSM-5-Hbeta catalyst with a double-zeolite shell exhibits an extraordinary high i-HC/t-HC ratio.
In the present work, the concentration of eight metals (Cd, Cr, Cu, Fe, Mn, Ni, Pb, Zn) was determined in the sediments and transplanted and native mussels (Mytilus galloprovincialis). The study was conducted in Turkish marinas, shipyards, and shipbreaking yards. The effect of metal pollution was evaluated by determining the levels of metallothionein (MT) in the mussels. The extent of contamination for each single metal was assessed by using the geoaccumulation index (I geo) and enrichment factor (EF). Whereas, to evaluate the overall metal pollution and effect, the pollution load index (PLI), modified contamination degree (mC d), potential toxicity response index (RI), mean effects range median (ERM) quotient (m-ERM-Q), and mean PEL quotient (m-PEL-Q) were calculated. The influence of different background values on the calculations was discussed. The results indicated a significant metal pollution caused by Cu, Pb, and Zn especially in shipyard and shipbreaking sites. Higher concentrations of MT were observed in the ship/breaking yard samples after the transplantation.
To examine levels, health risks, sources, and spatial distributions of potentially toxic elements in settled dust over Beijing urban area, 62 samples were collected mostly from residential building outdoor surfaces, and their <63 μm fractions were measured for 12 potentially toxic elements. The results show that V, Cr, Mn, Co, Ni, and Ba in dust are from predominantly natural sources, whereas Cu, Zn, As, Cd, Sb, and Pb mostly originate from anthropogenic sources. Exposure to these elements in dust has significant non-cancer risks to children but insignificant to adults. Cancer risks of Cr, Co, Ni, As, and Cd via inhalation and dermal contact are below the threshold of 10(-6)-10(-4) but As via dust ingestion shows a tolerable risk. The non-cancer risks to children are contributed mainly (75%) by As, Pb, and Sb, and dominantly (92%) via dust ingestion, with relatively higher risks mainly occurring in the eastern and northeastern Beijing urban areas. Although Cd, Zn, and Cu in dust are heavily affected by anthropogenic sources, their health risks are insignificant. Source appointments suggest that coal burning emissions, the dominant source of As, are likely the largest contributors to the health risk, and traffic-related and industrial emissions are also important because they contribute most of the Pb and Sb in dust.
The expression and activity of DNA-dependent protein kinase (DNA-PK) is related to DNA repair status in the response of cells to exogenous and
 endogenous factors. Recent studies indicate that Epidermal Growth Factor Receptor (EGFR) is involved in modulating DNA-PK. It has been shown that a compound 4-nitro-7-[(1-oxidopyridin-2-yl)sulfanyl]-2,1,3-benzoxadiazole (NSC), bearing a nitro-benzoxadiazole (NBD) scaffold, enhances tyrosine phosphorylation of EGFR and triggers downstream signaling pathways. Here, we studied the behavior of DNA-PK and other DNA repair proteins in prostate cancer cells exposed to compound NSC. We showed that both the expression and activity of DNA-PKcs (catalytic subunit of DNA-PK) rapidly decreased upon exposure of cells to the compound. The decline in DNA-PKcs was associated with enhanced protein ubiquitination, indicating the activation of cellular proteasome. However, pretreatment of cells with thioglycerol abolished the action of compound NSC and restored the level of DNA-PKcs. Moreover, the decreased level of DNA-PKcs was associated with the production of intracellular hydrogen peroxide by stable dimeric forms of Cu/Zn SOD1 induced by NSC. Our findings indicate that reactive oxygen species and electrophilic intermediates, generated and accumulated during the redox transformation of NBD compounds, are primarily responsible for the rapid modulation of DNA-PKcs functions in cancer cells.
In this work, the synthesis and the nonlinear absorption and population dynamics investigation of a series of zinc phthalocyanines (ZnPcs) dissolved in chloroform are reported. In order to determine the relevant spectroscopic parameters, such as absorption cross-sections of singlet and triplet excited states, fluorescence relaxation times, intersystem crossing, radiative decay and internal conversion, different optical and spectroscopic techniques were used. By single pulse and pulse train Z-scan techniques, respectively, singlet and triplet excited states' absorption cross-section were determined at 532 nm. Furthermore, the intersystem crossing time was obtained by using both techniques combined with the fluorescence lifetime determined by time-resolved fluorescence. The radiative and internal conversion rates were determined from the fluorescence quantum yield of the samples. Such spectroscopy parameters are fundamental for selecting photosensitizers used in photodynamic therapy, as well as for many other applications.
For the effective application of a modified packed bed biofilm reactor (PBBR) in wastewater industrial practice, it is essential to distinguish the tolerance of the system for heavy metals removal. The industrial contamination of wastewater from various sources (e.g. Zn, Cu, Cd and Ni) was studied to assess the impacts on a PBBR. This biological system was examined by evaluating the tolerance of different strengths of composite heavy metals at the optimum hydraulic retention time (HRT) of 2 hours. The heavy metal content of the wastewater outlet stream was then compared to the source material. Different biomass concentrations in the reactor were assessed. The results show that the system can efficiently treat 20 (mg/l) concentrations of combined heavy metals at an optimum HRT condition (2 hours), while above this strength there should be a substantially negative impact on treatment efficiency. Average organic reduction, in terms of the chemical oxygen demand (COD) of the system, is reduced above the tolerance limits for heavy metals as mentioned above. The PBBR biological system, in the presence of high surface area carrier media and a high microbial population to the tune of 10 000 (mg/l), is capable of removing the industrial contamination in wastewater.
A versatile new fluorogenic Schiff base probe (L) has been synthesized by the reaction of quinoline-2-carbohydrazide (which acts as the chelating site) and 4-dimethylamino cinnamaldehyde (which acts as the signaling unit). L can sense three of the most biologically and environmentally important metal ions, Zn(2+), Cd(2+) and Pb(2+), among various tested metal ions through selective TURN-ON fluorescence responses in physiological pH. Interestingly, L can not only sense Zn(2+), Cd(2+) and Pb(2+) fluorometrically in physiological conditions but can also distinguish one from another by exhibiting individual intrinsic left-right-center TURN-ON emission signal swings. These selective fluorescence responses were explained by a chelation-enhanced fluorescence (CHEF) mechanism. Theoretical calculations were carried out to ascertain the preferred L-metal ion binding mode.
The use of bacterial l-asparaginase (LA) is one of the alternative approaches for acrylamide reduction in food stuffs as it catalyzes the conversion of l-asparagine to l-aspartic acid and ammonia. In present investigation, purification of extracellular LA from isolate of Bacillus subtilis sp. strain KDPS-1 was carried out by solid state fermentation process. The effects of solid substrates, initial moisture content, moistening agents, temperature, and incubation time on LA production was studied, and the highest asparaginase activity (47 IU/ml) was achieved in the medium having orange peel as substrate. The enzyme was purified to homogeneity by diethylaminoethyl (DEAE) cellulose ion exchange chromatography; with 84.89 % yield and 12.11 fold purity. LA showed stimulant activity against β-mercaptoethanol and was greatly inhibited by Zn(2+) and Hg(2+) metal ions. Reduction of acrylamide in fried potatoes was detected by high performance liquid chromatography, which showed clear degradation of acrylamide by height and area (%) in the chromatograms of standard sample to that of the test sample. Hydrolysates analysis by high performance thin layer chromatography confirmed the test sample to be LA.
Using two-dimensional gel electrophoresis, the foot muscle proteome of three geographical populations of Haliotis diversicolor were examined, with a total of 922 ± 21 protein spots detected in the Japanese population (JJ), 904 ± 25.6 in the Taiwanese population (TT), and 936 ± 16.2 in the Vietnamese population (VV). Of these, 254 spots showed differential expression and 85 protein spots percentage volumes varied more than twofold. Both "genotype" and "spot" analysis of variance approaches significantly showed differences among the three populations. Hierarchical clustering analysis showed that TT and VV clustered together followed by clustering with JJ, which is consistent with their geographical location. Following matrix-assisted laser desorption/ionization time-of-flight mass spectrometry, 30 differentially expressed proteins involved in major biological processes including energy production and storage and stress response were identified. Of these proteins, proteins pertaining to muscle contraction and muscle protein regulation showed highest expression levels in VV samples. Proteins involved in energy production and storage, including ATP synthase beta subunit, fructose-1,6-bisphosphate aldolase, arginine kinase, enolase, triosephosphate isomerase, and tauropine dehydrogenase, showed diverse expression patterns among the three populations. For stress-responsive proteins, the expression of heat shock protein 70 was JJ > VV > TT. The expression pattern of Cu/Zn-superoxide dismutase was JJ > VV > TT. Overall, these results may aid in the detection of new differentially expressed proteins within three different abalone populations.
Zinc (Zn(2+)) is required for numerous cellular functions. As such, the homeostasis and distribution of intracellular zinc can influence cellular metabolism and signaling. However, the exact distribution of free zinc within live cells remains elusive. Previously we showed the release of zinc from thapsigargin/IP3-sensitive endoplasmic reticulum (ER) storage in cortical neurons. In the present study, we investigated if other cellular organelles also contain free chelatable zinc and function as organelle storage for zinc. To identify free zinc within the organelles, live cells were co-stained with Zinpyr-1, a zinc fluorescent dye, and organelle-specific fluorescent dyes (MitoFluor Red 589: mitochondria; ER Tracker Red: endoplasmic reticulum; BODIPY TR ceramide: Golgi apparatus; Syto Red 64: nucleus). We examined organelles that represent potential storing sites for intracellular zinc. We showed that zinc fluorescence staining was co-localized with MitoFluor Red 589, ER Tracker Red, and BODIPY TR ceramide respectively, suggesting the presence of free zinc in mitochondria, endoplasmic reticulum, and the Golgi apparatus. On the other hand, cytosol and nucleus had nearly no detectable zinc fluorescence. It is known that nucleus contains high amount of zinc binding proteins that have high zinc binding affinity. The absence of zinc fluorescence suggests that there is little free zinc in these two regions. It also indicates that the zinc fluorescence detected in mitochondria, ER and Golgi apparatus represents free chelatable zinc. Taken together, our results support that these organelles are potential zinc storing organelles during cellular zinc homeostasis.
Inadequate dietary Zn consumption increases susceptibility to esophageal and other cancers in humans and model organisms. Since Zn supplementation can prevent cancers in rodent squamous cell carcinoma (SCC) models, we were interested in determining if it could have a preventive effect in a rodent skin cancer model, as a preclinical basis for considering a role for Zn in prevention of human nonmelanoma skin cancers, the most frequent cancers in humans. We used the 7,12-dimethyl benzanthracene carcinogen/phorbol myristate acetate tumor promoter treatment method to induce skin tumors in Zn-sufficient wild-type and Fhit (human or mouse protein) knockout mice. Fhit protein expression is lost in >50% of human cancers, including skin SCCs, and Fhit-deficient mice show increased sensitivity to carcinogen induction of tumors. We hypothesized that: (1) the skin cancer
 burdens would be reduced by Zn supplementation; (2) Fhit(-/-) (Fhit, murine fragile histidine triad gene) mice would show increased susceptibility to skin tumor induction versus wild-type mice. 30 weeks after initiating treatment, the tumor burden was increased ~2-fold in Fhit(-/-) versus wild-type mice (16.2 versus 7.6 tumors, P < 0.001); Zn supplementation significantly reduced tumor burdens in Fhit(-/-) mice (males and females combined, 16.2 unsupplemented versus 10.3 supplemented, P = 0.001). Most importantly, the SCC burden was reduced after Zn supplementation in both strains and genders of mice, most significantly in the wild-type males (P = 0.035). Although the mechanism(s) of action of Zn supplementation in skin tumor prevention is not known in detail, the Zn-supplemented tumors showed evidence of reduced DNA damage and some cohorts showed reduced inflammation scores. The results suggest that mild Zn supplementation should be tested for prevention of skin cancer in high-risk human cohorts.
In the present study, nine native plant species were collected to determine their potential to clean up nine heavy metals from soil of a sewage sludge dump site. Almost all nine plant species grown at sewage sludge dump site showed multifold higher concentrations of heavy metals as compared to plants grown at the reference site. All the investigated species were characterized by a bioaccumulation factor (BF) > 1.0 for some heavy metals. BF was generally higher for Cd, followed by Pb, Co, Cr, Cu, Ni, Mn, Zn, and Fe. The translocation factor (TF) varied among plant species, and among heavy metals. For most studied heavy metals, TFs were <1.0. The present study proved that the concentrations of all heavy metals (except Cd, Co, and Pb) in most studied species were positively correlated with those in soil. Such correlations indicate that these species reflect the cumulative effects of environmental pollution from soil, and thereby suggesting their potential use in the biomonitoring of most heavy metals examined. In conclusion, all tissues of nine plant species could act as bioindicators, biomonitors, and remediates of most examined heavy metals. Moreover, Bassia indica, Solanum nigrum, and Pluchea dioscoridis are considered hyperaccumulators of Fe; Amaranthus viridis and Bassia indica are considered hyperaccumulators of Pb; and Portulaca oleracea is considered hyperaccumulator of Mn.
Despite the rarity, large negative linear compressibility (NLC) was observed in metal-organic framework material Zn(HO3PC4H8PO3H)∙2H2O (ZAG-4) in experiment. We find a unique NLC mechanism in ZAG-4 based on first-principle calculations. The key component to realize its large NLC is the deformation of H3O(+) tetrahedron. With pressure increase, the oxygen apex approaches and then is inserted into the tetrahedron base (hydrogen triangle). The tetrahedron base subsequently expands, which results in the b axis expansion. After that, the oxygen apex penetrates the tetrahedron base and the b axis contracts. The negative and positive linear compressibility is well reproduced by the hexagonal model and ZAG-4 is the first MOFs evolving from non re-entrant to re-entrant hexagon framework with pressure increase. This gives a new approach to explore and design NLC materials.
A new series of symmetric, bis-cholesteryl-appended, isosorbide derivatives (BCIE, BCIC2 and BCIC4) were designed as gelators to respond to changes in their environment and were synthesized successfully. Among these derivatives, BCIE can gel a wide variety of organic solvents (23 solvents), suggesting that BCIE acts as a more versatile gelator than BCIC2 and BCIC4. The CGC of the gels varies from 1.53 mM in 1-hexanol to 23 mM in pyridine. The results of the gelation ability in different solvents revealed that changing the linking group (ester/carbamate) attached to the cholesteryl units can produce a dramatic change in the gelation behavior of the compounds. The morphology of the as-formed organogels can be regulated by changing the types of organic solvents. The results from electron microscopy studies revealed that the gelator molecule self-assembled into different aggregates, from wrinkled fibers to dense fibers, with the change of solvents. The gels of BCIE in 1-hexanol and 1-octanol exhibited strong CD (circular dichroism) signals, indicating that the gelation induced supramolecular chirality in these gel systems. Secondary forces of van der Waals and π-π stacking (from both 1,2,3-triazole and aromatic units) played important roles in the aggregation of compounds in the solvents according to FTIR and variable temperature (1)H-NMR analysis, and a mechanism for the gel formation was proposed. The gel-to-sol phase transition can be triggered by the addition of trifluoroacetic acid (TFA), and the gel state was obtained slowly (after 1 day) when neutralizing with triethyl amine (TEA), which indicated that the sol ⇄ gel phase transitions are tunable by pH, which is further supported by (1)H-NMR and SEM analysis. In addition, the gel stability of BCIE was investigated using Cu(2+), Cd(2+), Ag(2+), Fe(3+), Hg(2+), Mg(2+), Pd(2+), Al(3+) and Zn(2+), and the results showed that the gel-to-sol phase transition process could be selectively controlled by interaction with Pd(2+) and Zn(2+) because complexation with 1,2,3-triazoles destroyed the interactions between the triazoles, collapsing the gel, which was further evidenced by (1)H-NMR and SEM analysis. However, the gel stability of BCIE was enhanced by the addition of Pd(2+) and Zn(2+) in the presence of pyridine, whereas the gel collapsed in other solvents, which may be due to the chelating effect of the pyridine moiety. Another interesting feature of this gel is that when using the gelator as a stabilizer, stable water in oil (W/O) gel-emulsions were created, in which styrene can be used as the continuous phase and water as the dispersed phase with the stabilizer in the continuous phase of only 2% (w/v). Gel-emulsions were observed with any ratio of water to styrene.
The efficacy of Moringa oleifera seed lectin (WSMoL) as a metal remover in water and the effects of metals on its hemagglutinating and antibacterial activities were determined. Aqueous metal solutions were incubated with WSMoL for 8 h at 4°C and the concentrations of metals were determined using atomic absorption spectroscopy. Hemagglutination and antibacterial assays were conducted with WSMoL and lectin exposed or not to the metals. The removal efficiency of WSMoL was 49.00%, 53.21%, 71.45%, 55.42%, 69.88%, 62.14%, and 49.36% for Cd+2, Pb+2, Cu+2, Zn+2, Mg+2, Mn+2, and Al+3, respectively. WSMoL showed bacteriostatic and bactericidal activities against Escherichia coli and Salmonella enterica serovar Enteritidis. However, hemagglutinating and antibacterial activities were impaired after exposure to metals. In conclusion, WSMoL efficiently removed metals present in water but the interaction with metals impaired lectin carbohydrate-binding ability and antibacterial activity. This should be considered when properties of WSMoL other than metal removal are desired.
Birnessite minerals (layer-type MnO2), which bear both internal (cation vacancies) and external (particle edges) metal sorption sites, are important sinks of contaminants in soils and sediments. Although the particle edges of birnessite minerals often dominate the total reactive surface area, especially in the case of nanoscale crystallites, the metal sorption reactivity of birnessite particle edges remains elusive. In this study, we investigated the sorption selectivity of birnessite particle edges by combining Cd(ii) and Pb(ii) adsorption isotherms at pH 5.5 with surface structural characterization by differential pair distribution function (d-PDF) analysis. We compared the sorption reactivity of δ-MnO2 to that of the nanomineral, 2-line ferrihydrite, which exhibits only external surface sites. Our results show that, whereas Cd(ii) and Pb(ii) both bind to birnessite layer vacancies, only Pb(ii) binds extensively to birnessite particle edges. For ferrihydrite, significant Pb(ii) adsorption to external sites was observed (roughly 20 mol%), whereas Cd(ii) sorption was negligible. These results are supported by bond valence calculations that show comparable degrees of saturation of oxygen atoms on birnessite and ferrihydrite particle edges. Therefore, we propose that the sorption selectivity of birnessite edges follows the same order of that reported previously for ferrihydrite: Ca(ii) < Cd(ii) < Ni(ii) < Zn(ii) < Cu(ii) < Pb(ii).
Rhizosphere and endophytic bacteria are well known producers of siderophores, organic compounds that chelate ferric iron (Fe(3+)), and therefore play an important role in plant growth promotion in metalliferous areas, thereby improving bioremediation processes. However, in addition to their primary function in iron mobilization, siderophores also have the capacity to chelate other heavy metals, such as Al(3+), Zn(2+), Cu(2+), Pb(2+) and Cd(2+), that can affect homeostasis and the heavy metal tolerance of microorganisms. The main goal of our study was to select the most efficient siderophore-producing bacterial strains isolated from the roots (endophytes) and rhizosphere of Betula pendula L. and Alnus glutinosa L. growing at two heavy metal contaminated sites in southern Poland. Siderophore biosynthesis of these strains in the presence of increasing concentrations of Cd(2+) (0, 0.5, 1, 2 and 3 mM) under iron-deficiency conditions was analysed using spectrophotometric chemical tests for hydroxamates, catecholates and phenolates, as well as the separation of bacterial siderophores by HPLC and characterization of their structure by UHPLC-QTOF/MS. We proved that (i) siderophore-producing bacterial strains seems to be more abundant in the rhizosphere (47%) than in root endophytes (18%); (ii) the strains
 most effective at siderophore synthesis belonged to the genus Streptomyces and were able to secrete three types of siderophores under Cd(2+) stress: hydroxamates, catecholates and phenolates; (iii) in general, the addition of Cd(2+) enhanced siderophore synthesis, particularly ferrioxamine B synthesis, which may indicate that siderophores play a significant role in tolerance to Cd(2+) in Streptomyces sp.
Metal-organic frameworks (MOFs) are promising porous materials for gas separation and storage as well as sensing. In particular, a series of isostructural MOFs with coordinately unsaturated metal centers, namely, CPO-27-M or M-MOF-74 (M = Mg, Zn, Mn, Fe, Ni, Co, Cu), have shown exceptional adsorption capacity and selectivity compared to those of classical MOFs that contain only fully coordinated metal sites. Although it is widely accepted that the interaction between guest molecules and exposed metal centers is responsible for good selectivity and large maximum uptake, the investigation of such guest-metal interaction is very challenging because adsorbed molecules are usually disordered in the pores and undergo rapid thermal motions. (2)H solid-state NMR (SSNMR) spectroscopy is one of the most extensively used techniques for capturing guest dynamics in porous materials. In this work, variable-temperature (2)H wide-line SSNMR experiments were performed on CPO-27-M (M = Mg, Zn) loaded with four prototypical guest molecules: D2O, CD3CN, acetone-d6, and C6D6. The results indicate that different guest molecules possess distinct dynamic behaviors inside the channel of CPO-27-M. For a given guest molecule, its dynamic behavior also depends on the nature of the metal centers. The binding strength of guest molecules is discussed on the basis of the (2)H SSNMR data.
This study aimed at assessing the effects of global warming (increasing air temperature and decreasing soil moisture content) on the bioaccumulation kinetics of As, Cd and Zn in the earthworm Eisenia andrei in two polluted soils (mine tailing and watercourse soil). Earthworms were exposed for up to 21 d under four climate conditions: 20 °C + 50% soil water holding capacity (WHC) (standard conditions), 20 °C + 30% WHC, 25 °C + 50% WHC and 25 °C + 30% WHC. Porewater metal/metalloid availability did not change in the mine tailing soil after the incubation period under the different climate conditions tested. However, in the watercourse soil, porewater Cd concentrations decreased from ∼63 to ∼32-41 μg L(-1) after 21 d and Zn concentrations from ∼3761 to ∼1613-2170 μg L(-1), especially at 20 °C and 50% WHC. In both soils, As and Zn showed similar bioaccumulation patterns in the earthworms, without major differences among climate conditions. Earthworm concentrations peaked after 1-3 d of exposure (in μg g(-1) dry weight: As∼32.5-108, Zn∼704-1172) and then remained constant (typical pattern of essential elements even for As). For Cd the bioaccumulation pattern changed when changing the climate conditions. Under standard conditions, earthworm Cd concentrations increased to ∼12.6-18.5 μg g(-1) dry weight without reaching equilibrium (typical pattern of non-essential elements). However when increasing temperature and/or decreasing soil moisture content the bioaccumulation pattern changed towards that more typical of essential elements due to increased Cd elimination rates (from ∼0.11 to ∼0.24-1.27 d(-1) in the mine tailing soil, from ∼0.07 to ∼0.11-0.35 d(-1) in the watercourse soil) and faster achievement of a steady state. This study shows that metal/metalloid bioaccumulation pattern in earthworms may change dependent on climate conditions.
A nonbonded dummy model for metal ions is highly imperative for the computation of complex biological systems with for instance multiple metal centers. Here we present nonbonded dummy parameters of 11 divalent metallic cations, namely, Mg(2+), V(2+), Cr(2+), Mn(2+), Fe(2+), Co(2+), Ni(2+), Zn(2+), Cd(2+), Sn(2+), and Hg(2+), that are optimized to be compatible with three widely used water models (TIP3P, SPC/E, and TIP4P-EW). The three sets of metal parameters reproduce simultaneously the solvation free energies (ΔGsol), the ion-oxygen distance in the first solvation shell (IOD), and coordination numbers (CN) in explicit water with a relative error less than 1%. The main sources of errors to ΔGsol that arise from the boundary conditions and treatment of electrostatic interactions are corrected rationally, which ensures the independence of the proposed parameters on the methodology used in the calculation. This work will be of great value for the computational study of metal-containing biological systems.
This work describes the synthesis of Chevrel phase Mo6S8 nanocubes and its application as the anode material for rechargeable Zn-ion batteries. Mo6S8 can host Zn(2+) ions reversibly in both aqueous and nonaqueous electrolytes with specific capacities around 90 mAh/g, and exhibited remarkable intercalation kinetics and cyclic stability. In addition, we assembled full cells by integrating Mo6S8 anodes with zinc-polyiodide (I(-)/I3(-))-based catholytes, and demonstrated that such full cells were also able to deliver outstanding rate performance and cyclic stability. This first demonstration of a zinc-intercalating anode could inspire the design of advanced Zn-ion batteries.
Zinc (Zn) deficiency is a major problem in agricultural crops of many world regions. N metabolism plays an essential role in plants and changes in their availability and their metabolism could seriously affect crop productivity. The main objective of the present work was to perform a comparative analysis of different strategies against Zn deficiency between two plant species of great agronomic interest such as Lactuca sativa cv. Phillipus and Brassica oleracea cv. Bronco. For this, both species were grown in hydroponic culture with different Zn doses: 10μM Zn as control and 0.01μM Zn as deficiency treatment. Zn deficiency treatment decreased foliar Zn concentration, although in greater extent in B. oleracea plants, and caused similar biomass reduction in both species. Zn deficiency negatively affected NO3(-) reduction and NH4(+) assimilation and enhanced photorespiration in both species. Pro and GB concentrations were reduced in L. sativa but they were increased in B. oleracea. Finally, the AAs profile changed in both species, highlighting a great increase in glycine (Gly) concentration in L. sativa plants. We conclude that L. sativa would be more suitable than B. oleracea for growing in soils with low availability of Zn since it is able to accumulate a higher Zn concentration in leaves with similar biomass reduction. However, B. oleracea is able to accumulate N derived protective compounds to cope with Zn deficiency stress.
Record greenhouse gas emissions have spurred the search for clean energy sources such as hydrogen (H2) fuel cells. Metal-organic frameworks (MOFs) are promising H2 adsorption and storage media, but knowledge of H2 dynamics and adsorption strengths in these materials is lacking. Variable-temperature (VT) (2)H solid-state NMR (SSNMR) experiments targeting (2)H2 gas (i.e., D2) shed light on D2 adsorption and dynamics within six representative MOFs: UiO-66, M-MOF-74 (M = Zn, Mg, Ni), and α-M3(COOH)6 (M = Mg, Zn). D2 binding is relatively strong in Mg-MOF-74, Ni-MOF-74, α-Mg3(COOH)6, and α-Zn3(COOH)6, giving rise to broad (2)H SSNMR powder patterns. In contrast, D2 adsorption is weaker in UiO-66 and Zn-MOF-74, as evidenced by the narrow (2)H resonances that correspond to rapid reorientation of the D2 molecules. Employing (2)H SSNMR experiments in this fashion holds great promise for the correlation of MOF structural features and functional groups/metal centers to H2 dynamics and host-guest interactions.
There is growing evidence that GABA (γ-aminobutyric acid) can activate GABAA receptors (GABAARs) in the absence of an α subunit. In this study, we compared the pharmacology of homomeric and binary α4, β3 or δ subunits with ternary α4β3δ to identify subunit interfaces that contribute to the pharmacology of GABA, THIP, and DS2, and the antagonists, Zn(2+), gabazine and bicuculline. β3δ receptors form functional GABA-gated channels when expressed in Xenopus oocytes with a pharmacology that differs to homomeric β3, binary α4β3 and ternary α4β3δ receptors. GABA had similar potency at α4β3 and β3δ receptors (25µM and 26µM, respectively) but differed at α4β3δ receptors where GABA exhibited a biphasic concentration-response (EC50 (1)=12.6nM; EC50 (2)=6.3μM). THIP activated β3δ receptors (EC50=456μM) but was a more potent activator of α4β3 (EC50=27μM) and α4β3δ receptors (EC50 (1)=27.5nM; EC50 (2)=29.5μΜ), indicating that the α4 subunit significantly contribute to its potency. The δ-preferring modulator, DS2 had marginal or no effect at β3δ and α4β3 receptors, indicating a role for both the α4 and δ subunits for its potency. Gabazine inhibited GABA-elicited currents at β3δ receptors whereas bicuculline activated these receptors. Mutational analysis verified that GABA binds to the β3(+)δ(-) interface formed by the β3 and δ subunits. In conclusion, evaluating agents against binary GABAARs such as β3δ and α4β3 receptors enables identification of interfaces that may contribute to the pharmacology of the more complex ternary α4β3δ receptors.
Although many synthetic gonadoliberin analogs have been developed, only a few of them, including buserelin, were introduced into clinical practice. Dalarelin, which differs from buserelin by just one aminoacid in the position 6 (D-Ala), is not widely used so far. Gonadotropin-releasing hormone (GnRH) analogs are used to treat many different illnesses and are available in different forms like solution for injection, nasal spray, microspheres, etc. Unfortunately, none of the above drug formulations can release the hormones for 24 h.
 We assumed that classical suspension could solve this problem.
Two sets of experiments were performed. In the first one, buserelin and dalarelin were injected into mature female rats in two forms: suspension, in which the analogs are bounded by Zn(2+) ions and solution. The pharmacokinetic parameters and bioavailability of the analogs were calculated, based on their concentration in the plasma measured by high-performance liquid chromatography method (HPLC). In the second experiment, the hormones in two different forms were injected into superovulated immature female rats and then the concentration of Luteinizing hormone (LH), Follicle-stimulating hormone (FSH) and 17β-estradiol in the serum was measured by radioimmunological method.
The Extent of Biological Availability (EBA), calculated on the base of AUC0-∞, showed that in the form of solution buserelin and dalarelin display, respectively, only 13 and 8 % of biological availability of their suspension counterparts. Comparing both analogs, the EBA of dalarelin was half (53 %) that of buserelin delivered in the form of solution and 83 % when they were delivered in the form of suspension. The injection of buserelin or dalarelin, in the form of solution or suspension, into superovulated female rats increased LH, FSH and estradiol concentration in the serum. However, after injection of the analogs in the form of suspension, the high concentration of LH and FSH in the serum persisted longer.
Performed studies indicate that GnRH analogs in the form of suspension have higher bioavailability than their solution counterparts. It influences the effects of their action, especially in relation to LH and FSH.
Polar surfaces of semiconducting metal oxides can exhibit structures and chemical reactivities that are distinct from their non-polar surfaces. Using first-principles calculations, we examine O adatom and O2 molecule adsorption on 8 different known ZnO reconstructions including Zn-terminated (Zn-ZnO) and O-terminated (O-ZnO) polar surfaces, and non-polar surfaces. We find that adsorption tendencies are largely governed by the thermodynamic environment, but exhibit variations due to the different surface chemistries of various reconstructions. The Zn-ZnO surface reconstructions which appear under O-rich and H-poor environments are found to be most amenable to O and O2 adsorption. We attribute this to the fact that on Zn-ZnO, the O-rich environments that promote O adsorption also simultaneously favor reconstructions that involve adsorbed O species. On these Zn-ZnO surfaces, O2 dissociatively adsorbs to form O adatoms. By contrast, on O-ZnO surfaces, the O-rich conditions required for O or O2 adsorption tend to promote reconstructions involving adsorbed H species, making further O species adsorption more difficult. These insights about O2 adsorption on ZnO surfaces suggest possible design rules to understand the adsorption properties of semiconductor polar surfaces.
Information regarding chemical pollutant levels in farmed fish and shellfish, along with the risks associated with their consumption is still scarce. This study was designed to assess levels of exposure to 21 trace elements in fish (Dicentrarchus labrax), mussels (Mytilus galloprovincialis) and oysters (Crassostrea gigas) collected from aquaculture marine ecosystems of the northwestern Mediterranean Sea. Metal concentrations showed great variability in the three species; the highest values of the nonessential elements As and Cd were found in oysters while the highest levels of Al, Pb and V were found in mussels. The essential elements Cu, Mn and Zn were highest in oysters, but Fe, Cr, Ni, Se, Co and Mo levels were highest in mussels. Fish had the lowest concentrations for all trace elements, which were at least one order of magnitude lower than in bivalves. The rare earth elements cerium and lanthanum were found at higher levels in mussels than in oysters, but undetectable in fish. The maximum values set by European regulations for Hg, Cd and Pb were never exceeded in the examined samples. However, comparing the estimated human daily intakes (EHDIs) with the suggested tolerable copper and zinc intakes suggested a potential risk for frequent consumers of oysters. Similarly, people who consume high quantities of mussels could be exposed to concentrations of Al that exceed the proposed TWI (tolerable weekly intake).
Lead and zinc (PbZn) mines are a common occurrence worldwide; and while approximately 240 mines are active, the vast majority have been abandoned for decades. Abandoned mining wastes represent a serious environmental hazard, as Pb, Zn and associated metals are continuously released into the environment, threatening the health of humans and affecting ecosystems. Iron sulfide minerals, when present, can form acid mine drainage and increase the toxicity by mobilizing the metals into more bioavailable forms. Remediation of the metal waste is costly and, in the case of abandoned wastes, the responsible party(ies) for the cleanup can be difficult to determine, which makes remediation a complex and lengthy process. In this review, we provide a common ground from a wide variety of investigations about concentrations, chemical associations, and potential mobility of Pb, Zn and cadmium (Cd) near abandoned PbZn mines. Comparing mobility results is a challenging task, as instead of one standard methodology, there are 4-5 different methods reported. Results show that, as a general consensus, the metal content of soils and sediments vary roughly around 1000mg/kg for Zn, 100 for Pb and 10 for Cd, and mobilities of Cd>Zn>Pb. Also, mobility is a function of pH, particle size, and formation of secondary minerals. New and novel remediation techniques continue to be developed in laboratories but have seldom been applied to the field. Remediation at most of the sites has consisted of neutralization (e.g. lime,) for acid mine discharge, and leveling followed by phytostabilization. In the latter, amendments (e.g. biochar, fertilizers) are added to boost the efficiency of the treatment. Any remediation method has to be tested before being implemented as the best treatment is site-specific. Potential treatments are described and compared.
Magnesium alloys are considered as good candidates for biomedical applications, the influence of Ce/La microalloying on the microstructure, mechanical property and corrosion performance of extruded Mg-5.3Zn-0.6Ca (wt%) alloy has been investigated in the current study. After Ce/La addition, the conventional Ca2Mg6Zn3 phases are gradually replaced by new Mg-Zn-Ce/La-(Ca) phases (T1'), which can effectively divide the Ca2Mg6Zn3 phase. The Ca2Mg6Zn3/T1' structure in Mg-Zn-Ca-0.5Ce/La alloy is favorably broken into small particles during the extrusion, resulting in an obvious refinement of secondary phase. The dynamic recrystallized grain size is dramatically decreased after 0.5Ce/La addition, and the tensile yield strength is improved, while further addition reverses the effect, due to the grain coarsening. However, the corrosion resistance of extruded Mg-Zn-Ca alloy deteriorates after Ce/La addition, because the diameter of secondary phase particle is remarkably decreased, which increases the amount of cathodic sites and accelerates the galvanic corrosion process.
The present study describes the ecofriendly method for the preparation of chitosan film loaded with silver nanoparticles (CS-AgNPs) and application of this film as efficient sorbent for separation and enrichment of Al(III), Cd(II), Cu(II), Co(II), Fe(III), Ni(II), Pb(II) and Zn(II). The stable CS-AgNPs colloid was prepared by dispersing the AgNPs sol in chitosan solution at appropriate ratio and further used to obtain a cast film with very good stability under storage and good mechanical strength for easy handling in aqueous medium. The incorporation of AgNPs in the structure of CS film and interaction between the polymer matrix and nanoparticles were confirmed by UV-vis and FTIR spectroscopy. The homogeneously embedded AgNPs (average diameter 29nm, TEM analysis) were clearly observed throughout the film by SEM. The CS-AgNPs nanocomposite film shows high sorption activity toward trace metals under optimized chemical conditions. The results suggest that the CS-AgNPs nanocomposite film can be feasibly used as a novel sorbent material for solid-phase extraction of metal pollutants from surface waters.
In this study, the synergism between activated carbon (AC) as a catalyst support and transition metals (TMs) is used to destroy low concentrations of PCBs. AC-supported TM catalysts were prepared according to two different methods: impregnation and ion exchange. Thermal reactions between 2,2',4,4',5,5'-hexachlorobiphenyl (PCB-153) and catalysts generated using AC-supported Ni or Cu ion exchange were conducted under a N2 atmosphere and resulted in a decomposition efficiency > 99.0%. Decomposition efficiency of PCB-153, the residual PCB-153 distribution, and the fingerprint characteristics of the decomposition products are investigated. Important findings include: (i) establishing a ranking of TM reactivities with respect to PCB decomposition of: Ni > Cu > Zn > Fe, (ii) PCB degradation reactions proceed via adsorption, reaction, and desorption, (iii) for ion-exchange-type catalysts, the activation energy order was IRNi-C < IRCu-C < IRZn-C < IRFe-C, which matches the order of the catalytic effects of the catalyst.
A total of sixteen composite soil and sediment samples were collected during the rainy and dry season in Asientos, Aguascalientes, Mexico, an area recently affected by increased mining operations. Physicochemical characterization showed that substrates were moderately to strongly calcareous with predominantly neutral to slightly alkaline pH, moderate to high cation-exchange capacity and high organic matter content. Due to these conditions,
 Cd, Pb, Cu and Zn were not water leachable despite high concentrations; up to 105.3, 7052.8, 414.7 and 12,263.2 mg kg(-1) respectively. However, Cd and Pb were considered to be easily mobilizable as they were found predominantly associated with exchangeable and carbonate fractions, whereas Cu and Zn were found associated with Fe/Mn oxide and organic matter fractions. The results highlighted the influence of physicochemical substrate properties on the mobility of metals and its importance during the evaluation of the potential current and future risk metal contamination presents in affected areas.
Cytoplasmic accumulation of the nuclear protein transactive response DNA-binding protein 43 (TDP-43) is an early determinant of motor neuron degeneration in most amyotrophic lateral sclerosis (ALS) cases. We previously disclosed this accumulation in circulating lymphomonocytes (CLM) of ALS patients with mutant TARDBP, the TDP-43-coding gene, as well as of a healthy individual carrying the parental TARDBP mutation. Here, we investigate TDP-43 subcellular localization in CLM and in the constituent cells, lymphocytes and monocytes, of patients with various ALS-linked mutant genes.
TDP-43 subcellular localization was analysed with western immunoblotting and immunocytofluorescence in CLM of healthy controls (n = 10), patients with mutant TARDBP (n = 4, 1 homozygous), valosin-containing protein (VCP; n = 2), fused in sarcoma/translocated in liposarcoma (FUS; n = 2), Cu/Zn superoxide dismutase 1 (SOD1; n = 6), chromosome 9 open reading frame 72 (C9ORF72; n = 4), without mutations (n = 5) and neurologically unaffected subjects with mutant TARDBP (n = 2).
TDP-43 cytoplasmic accumulation was found (P < 0.05 vs. controls) in CLM of patients with mutant TARDBP or VCP, but not FUS, in line with TDP-43 subcellular localization described for motor neurons of corresponding groups. Accumulation also characterized CLM of the healthy individuals with mutant TARDBP and of some patients with mutant SOD1 or C9ORF72. In 5 patients, belonging to categories described to carry TDP-43 mislocalization in motor neurons (3 C9ORF72, 1 TARDBP and 1 without mutations), TDP-43 cytoplasmic accumulation was not detected in CLM or in lymphocytes but was in monocytes.
In ALS forms characterized by TDP-43 mislocalization in motor neurons, monocytes display this alteration, even when not manifest in CLM. Monocytes may be used to support diagnosis, as well as to identify subjects at risk, of ALS and to develop/monitor targeted treatments.
Biogas slurry is a product of anaerobic digestion of manure that has been widely used as a soil fertilizer. Although the use for soil fertilizer is a cost-effective solution, it has been found that repeated use of biogas slurry that contains high heavy metal contents can cause pollution to the soil-plant system and risk to human health. The objective of this study was to investigate effects of biogas slurry on the soil-plant system and the human health. We analyzed the heavy metal concentrations (including As, Pb, Cu, Zn, Cr and Cd) in 106 soil samples and 58 plant samples in a farmland amended with biogas slurry in Taihu basin, China. Based on the test results, we assessed the potential human health risk when biogas slurry containing heavy metals was used as a soil fertilizer. The test results indicated that the Cd and Pb concentrations in soils exceeded the contamination limits and Cd exhibited the highest soil-to-root migration potential. Among the 11 plants analyzed, Kalimeris indica had the highest heavy metal absorption capacity. The leafy vegetables showed higher uptake of heavy metals than non-leafy vegetables. The non-carcinogenic risks mainly resulted from As, Pb, Cd, Cu and Zn through plant ingestion exposure. The integrated carcinogenic risks were associated with Cr, As and Cd in which Cr showed the highest risk while Cd showed the lowest risk. Among all the heavy metals analyzed, As and Cd appeared to have a lifetime health threat, which thus should be attenuated during production of biogas slurry to mitigate the heavy metal contamination.
Human beings working or living near an industrial site where toxic chemicals such as As, Hg, Cd, Cu, Mn, Pb, Zn and or their compounds are used or indiscriminately discharged into the environment, are constantly exposed to such chemicals via ingestion (drinking or eating), dermal contact or inhalation (breathing). However, in developing countries such as Ghana, limited data on levels of the aforementioned chemicals in whole blood and serum of human beings as a result of exposure to the aforementioned chemicals from mining communities and non-mining communities is preventing effective policy formulation to protect human health. Hence, this study was undertaken to measure the levels of the aforementioned toxic chemicals in whole blood and serum of 300 resident adults from mining (Tarkwa Nsuaem Municipality Assembly (TNMA) and Prestea Huni Valley District (PHVD)) and non-mining (Cape Coast Metropolis) communities in Ghana, using neutron activation analysis (NAA). Blood samples were taken from 200 resident adults (105 males and 95 females) from mining and 100 resident adults (60 males and 40 males) from non-mining communities in the study area following the completion of an informed consent and the issuance of ethical clearance by the Ghana Health Service Ethical Committee. The mean concentrations for As, Hg, Cd, Cu, Mn, Pb and Zn in whole blood of residents from mining communities were as follows: 38 ± 320 μg/L, 63 ± 0.23 μg/L, 303 ± 117 μg/L, 3300 ± 953, 195 ± 90 μg/L, 28 ± 14 μg/L and 1405 ± 458 μg/L, respectively; while the levels of measured toxic chemicals in the serum of resident adults from mining communities were as follows: 65 ± 14 μg/L, 358 ± 22 μg/l, 134 ± 12 μg/L, 3590 ± 254 μg/L, 401 ± 113 μg/L, 58 ± 5.8 μg/L and 49 ± 31 μg/L, respectively, for As, Hg, Cd, Cu, Mn, Pb and Zn and were found to have exceeded the permissible WHO guideline values.
Notwithstanding evidence is present that physicochemical characteristics of ambient particles attribute to adverse health effects, there is still some lack of understanding in this complex relationship. At this moment it is not clear which properties (such as particle size, chemical composition) or sources of the particles are most relevant for health effects. This study investigates the in vitro toxicity of PM10 in relation to PM chemical composition, black carbon (BC), endotoxin content and oxidative potential (OP). In 2013-2014 PM10 was sampled (24h sampling, 108 sampling days) in ambient air at three sites in Flanders (Belgium) with different pollution characteristics: an urban traffic site (Borgerhout), an industrial area (Zelzate) and a rural background location (Houtem). To characterize the toxic potential of PM10, airway epithelial cells (Beas-2B cells) have been exposed to particles in vitro. Different endpoints were studied including cell damage and death (cell viability) using the Neutral red Uptake assay, the production of pro-inflammatory molecules by interleukin 8 (IL-8) induction and DNA-damaging activity using the FPG-modified Comet assay. The endotoxin levels in the collected samples were analysed and the capacity of PM10 particles to produce reactive oxygen species (OP) was evaluated by electron paramagnetic resonance (EPR) spectroscopy. Chemical characteristics of PM10 (BC, As, Cd, Cr, Cu, Mn, Ni, Pb, Zn) and meteorological conditions were recorded on the sampling days. PM10 particles exhibited dose-dependent cytotoxicity in Beas-2B cells and were found to significantly induce the release of IL-8 in samples from the three locations. Oxidatively damaged DNA was observed in exposed Beas-2B cells. Endotoxin levels above the detection limit were detected in half of the samples. OP was measurable in all samples. Associations between PM10 characteristics and biological effects of PM10 were assessed by single and multiple regression analyses. The reduction in cell viability was significantly correlated with BC, Cd and Pb. The induction of IL-8 in Beas-2B cells was significantly associated with Cu, Ni and Zn and endotoxin. Endotoxin levels explained 33% of the variance in IL-8 induction. A significant interaction between ambient temperature and endotoxin on the pro-inflammatory activity was seen. No association was found between OP and the cellular responses. This study supports the hypothesis that, on an equal mass basis, PM10 induced biological effects differ due to differences in PM10 characteristics. Metals (Cd, Cu, Ni and Zn), BC, and endotoxin were among the main determinants for the observed biological responses.
Sphagnum fuscum was collected from twenty-five ombrotrophic (rain-fed) peat bogs surrounding open pit mines and upgrading facilities of Athabasca Bituminous Sands (ABS) in northern Alberta (AB) in order to assess the extent of atmospheric contamination by trace elements. As a control, this moss species was also collected at a bog near Utikuma (UTK) in an undeveloped part of AB and 264km SW of the ABS region. For comparison, this moss was also collected in central AB, in the vicinity of the City of Edmonton which is approximately 500km to the south of the ABS region, from the Wagner Wetland which is 22km W of the City, from Seba Beach (ca. 90km W) and from Elk Island National Park (ca. 45km E). All of the moss samples were digested and trace elements concentrations determined using ICP-SMS at a commercial laboratory, with selected samples also analyzed using instrumental neutron activation analysis at the University of Alberta. The mosses from the ABS region yielded lower concentrations of Ag, As, Bi, Cd, Cu, Pb, Sb, Tl, and Zn compared to the moss from the Edmonton area. Concentrations of Ni and Mo in the mosses were comparable in these two regions, but V was more abundant in the ABS samples. Compared
 with the surface vegetation of eight peat cores collected in recent years from British Columbia, Ontario, Quebec and New Brunswick, the mean concentrations of Ag, As, Bi, Cd, Cu, Mo, Ni, Pb, Sb, Tl and Zn in the mosses from the ABS region are generally much lower. In fact, the concentrations of these trace elements in the samples from the ABS region are comparable to the corresponding values in forest moss from remote regions of central and northern Norway. Lithophile element concentrations (Ba, Be, Ga, Ge, Li, Sc, Th, Ti, Zr) explain most of the variation in trace metal concentrations in the moss samples. The mean concentrations of Th and Zr are greatest in the moss samples from the ABS region, reflecting dust inputs to the bogs from open pit mines, aggregate quarries, and gravel roads. Linear regressions of V, Ni, and Mo (elements enriched in bitumen) versus Sc (a conservative, lithophile element) show excellent correlations in the mosses from the ABS region, but this is true also of Ag, Pb, Sb and Tl: thus, most of the variation in the trace metal concentrations can be explained simply by the abundance of dust particles on the plants of this region. Unlike the moss samples from the ABS region and from UTK where Pb/Sc ratios resemble those of crustal rocks, the moss samples from the other regions studied yielded much greater Pb/Sc ratios implying significant anthropogenic Pb contributions at these other sites.
One-pot ketone synthesis has been developed with in situ activation of alkyl halides to alkylzinc halides in the presence of thioesters and Pd-catalyst. The new method provides us with a reliable option for a coupling at a late stage in a convergent synthesis of complex molecules, with use of a near 1:1 molar ratio of coupling partners. First, two facile, orthogonal methods have been developed for preparation of alkylzinc halides: (1) direct insertion of zinc dust to 1°- and 2°-alkyl halides in the presence of LiI in DMI and (2) early transition-metal assisted activation of alkyl halides via a single electron transfer (SET) process. CrCl2 has been found as an unprecedented, inevitable mediator for preparation of alkylzinc halides from alkyl halides, where CrCl2 likely functions to trap R·, generated via a SET process, and transfer it to Zn(II) to form RZnX. In addition to a commonly used CoPc, a new radical initiator NbCpCl4 has been discovered through the study. Second, with use of the two orthogonal methods, three sets of coupling conditions have been developed to complete one-pot ketone synthesis, with Condition A (Pd2dba3, PR3, Zn, LiI, TESCl, DMI), Condition B (A + CrCl2), and Condition C (B + NbCpCl4 or CoPc) being useful for simple linear and α-substituted substrates, simple linear and β-substituted substrates, and complex substrates, respectively. Condition C is applicable to the broadest range of substrates. Overall, one-pot ketone synthesis gives excellent yields, with good functional group tolerance. Controlled formation of alkylzinc halides by a combination of CrCl2 and NbCpCl4 or CoPc is crucial for its application to complex substrates. Interestingly, one-pot ketone synthesis does not suffer from the chemical instability due to the inevitable radical pathway(s), for example a 1,5-H shift. Notably, even with the increase in molecular size, no significant decrease in coupling efficiency has been noticed. To illustrate the synthetic value at a late stage in a complex molecule synthesis, ketone 4sc, containing all the carbons of Eribulin, has been synthesized from 1s and 3c.
The chemical status of five dredged spoil disposal sites in the Belgian Part of the North Sea is evaluated. A linear mixed-effect model was applied to PCB, PAH and heavy metal data from 2005 to 2014. No decrease in PCB concentrations was found, with even an increase at two disposal sites. Hg/AL ratios increased with 62% at one disposal site (BR&WS2) from 2005 to 2006 to 2013-2014. Cu and Zn concentrations increased at two disposal sites. Additional harbour sampling suggests that the latter is possibly linked to antifouling paints. Based on OSPAR environmental assessment criteria, the current chemical status of the sites suggests no chronic effect of dredged spoil disposal. However, increasing time trend data for PCB, Hg, Cu and Zn demonstrate the importance of monitoring to identify adverse trends.
The ferric uptake regulator (Fur) family proteins include sensors of Fe (Fur), Zn (Zur), and peroxide (PerR). Among Fur family proteins, Fur and Zur are ubiquitous in most prokaryotic organisms, whereas PerR exists mainly in Gram positive bacteria as a functional homologue of OxyR. Gram positive bacteria such as Bacillus subtilis, Listeria monocytogenes and Staphylococcus aureus encode three Fur family proteins: Fur, Zur, and PerR. In this study, we identified five Fur family proteins from B. licheniformis: two novel PerR-like proteins (BL00690 and BL00950) in addition to Fur (BL05249), Zur (BL03703), and PerR (BL00075) homologues. Our data indicate that all of the five B. licheniformis Fur homologues contain a structural Zn2+ site composed of four cysteine residues like many other Fur family proteins. Furthermore, we provide evidence that the PerR-like proteins (BL00690 and BL00950) as well as PerRBL (BL00075), but not FurBL (BL05249) and ZurBL (BL03703), can sense H2O2 by histidine oxidation with different sensitivity. We also show that PerR2 (BL00690) has a PerR-like repressor activity for PerR-regulated genes in vivo. Taken together, our results suggest that B. licheniformis contains three PerR subfamily proteins which can sense H2O2 by histidine oxidation not by cysteine oxidation, in addition to Fur and Zur.
Brass shavings have been proposed as a cost-effective filter material to remove Hg from contaminated groundwater. This method, which is based on the reduction of reactive Hg(II) and subsequent formation of amalgams, has been shown to be fast and effective in the short term. However, the effectiveness of brass filters and their stability over the long term, especially if used in passive filter systems such as permeable reactive barriers (PRB) under high flow conditions, is unknown. To evaluate the performance and limitations of brass shavings for Hg removal from contaminated groundwater, we performed long-term pilot scale filtration tests (6 and 28 months) at two former wood impregnation sites with severe groundwater contamination (up to 870 μg L(-1) Hg). The results showed that even under high flow conditions (>60 m d(-1)), 60-80% of the Hg was removed in the first 8 mm of the brass shavings filter bed. The kinetics of filtration, Hg total removal performance (>99.95%), and loading capacity (164 g L(-1)) surpassed those of a Hg-specific synthetic resin (LEWATIT(®)MonoPlus TP-214). However, under natural pH conditions (pH 6.4 and 6.7), Zn was leached from the brass and exceeded the threshold value (0.5 mg L(-1)) in the filter outflow by up to a factor of 40. Increasing pH (>8.5) decreased the Zn concentration (<0.05 mg L(-1)) but affected Hg removal due to the formation of Zn-hydroxide/carbonate coatings on the brass (up to 15% performance reduction). Thus, the use of brass shavings as an exclusive filter material in PRBs is restricted to aquifers with high pH. However, brass is ideal as a low-cost, thin-bed prefilter in onsite systems to remove the main Hg load from groundwater when Zn release is managed.
Four new complexes, [Co(dmbpy)2(dca)2]·CH3OH (1), [Ni(dmbpy)2(dca)2]·CH3OH (2), [Zn(dmbpy)2(dca)2]·(3) and [Cu(dmbpy)2(OH)2]·5H2O (4) (dca=dicyanamide), derived from 4,4'-dimethyl-2,2'-bipyridine (dmbpy) have been synthesized and characterized by elemental analysis, TGA and single-crystal X-ray diffraction. Crystal structures and Hirshfeld surfaces analysis revealed that the complexes 1-3 were mainly supported by OH⋯N, CH⋯N and π⋯π intermolecular interactions, and for complex 4, the uncoordinated water molecules play a key role in the construction of the 3D stacking motif. UV spectrum measurements demonstrate that all of the complexes show typical metal to ligand charge transfer (MLCT) absorption bands between 301 and 306nm. Moreover, after complexation, the absorption maximum bands about intraligand π→π* transitions similarly show slightly red shift compared to dmbpy ligand, consisting with the DFT calculations.
The present study aims at exploiting Bacillus amyloliquefaciens for the biosynthesis of titanium dioxide nanoparticles and also investigates role of bacterial enzymes in the biosynthesis of titanium dioxide nanoparticles. Bacterial synthesized as well as metal doped titanium dioxide nanoparticles were characterized by X-ray diffractometer (XRD), Fourier transform infrared spectroscopy (FTIR), Transmission electron microscopy (TEM), Energy dispersive X-ray spectroscopy (EDAX). Amylase activity (43.37IU) in culture supernatant evinced a potential involvement of extracellular enzyme in TiO2 nanoparticle biosynthesis. Crystallite size of bio-synthesized nanoparticles was found to be in the range of 15.23-87.6nm. FTIR spectroscopy and native-PAGE (Polyacrylamide Gel Electrophoresis) clearly indicated involvement of alpha amylase in biosynthesis of TiO2 nanoparticles and in their stabilization. TEM micrographs of the synthesized titanium dioxide nanoparticles revealed the formation of spherical nanoparticles with a size range of 22.11-97.28nm. Photocatalytic degradation of Reactive Red 31 (RR31) dye was carried out using bio-synthesized TiO2 nanoparticles under UV radiation. Photocatalytic activity of synthesized nanoparticles was enhanced by Ag, La, Zn and Pt doping. Platinum doped TiO2 showed highest potential (90.98%) in RR31 degradation as compared to undoped (75.83%).
The cystic fibrosis transmembrane conductance regulator (CFTR) chloride channel is activated by ATP binding-induced dimerization of nucleotide-binding
 domains, the interaction between the phosphorylated regulatory (R) domain and the curcumin-sensitive interface between intracellular loop (ICL) 1 and ICL4, and the resultant inward-to-'outward' reorientation of transmembrane domains. Although transmembrane helices (TM) 2 and TM11 link the ICL1-ICL4 interface with the interface between extracellular loop (ECL) 1 and ECL6, it is unknown whether both interfaces are gating-coupled during the reorientation. Herein, R334C and T1122C mutations were used to engineer two Zn(2+) bridges near and at the ECL1-ECL6 interface, respectively, and the gating effects of a Zn(2+) disturbance at the ECL1-ECL6 interface on the stimulatory ICL1/ICL4-R interaction were determined. The results showed that both Zn(2+) bridges inhibited channel activity in a dose- and Cl(-) -dependent manner, and the inhibition was reversed by a washout or suppressed by thiol-specific modification. Interestingly, their Cl(-) -dependent Zn(2+) inhibition was weakened at higher Zn(2+) concentrations, their Zn(2+) affinity was stronger in the resting state than in the activated state, and their activation current noises were decreased by external Zn(2+) binding. More importantly, the external Zn(2+) inhibition was reversed by internal curcumin in the R334C construct but not in the T1122C mutant. Therefore, although both Zn(2+) bridges may promote channel closure, external Zn(2+) may disturb the ECL1-ECL6 interface and thus prevent the stimulatory ICL1/ICL4-R interaction and curcumin potentiation via a gating coupling between these two interfaces.
Zinc (Zn) is an essential trace element in all living organisms, and the first eukaryotic Zn uptake transporter was discovered in the yeast, Saccharomyces cerevisiae. Zinc-enriched yeast is a currently available Zn supplement. The purpose of the investigation was to compare and evaluate the effect of Zn enriched yeast in rainbow trout. The fish (mean body weight 10 ± 0.5 g) were fed a commercial diet supplemented with 0 (control), 1 × 10(6), 1 × 10(7) and 1 × 10(8) CFU/g of Zn-enriched yeast for 60-days. Results showed that significant increase in serum lysozyme activity, complement activity and total immunoglobulin were seen in all treatment groups during feeding trial when compared to the control group. On the basis of our findings, Zn-enriched improved rainbow trout growth, some immune parameters and disease resistance.
Carbonic anhydrase (CA) is a biocatalyst that catalyzes the hydration of CO2 to bicarbonate and protons, thus useful in mitigating green house effect by sequestering CO2 from various point sources. An alkalistable and moderately thermostable α- carbonic anhydrase encoding gene (BhCA) from Bacillus halodurans TSLV1 has been cloned and expressed in Escherichia coli. A 31.4-fold enhancement in CA production was achieved due to cloning and expression in E. coli. About 50% of the CA produced was secreted when recombinant E. coli with BhCA-pET22b was cultivated in a medium with EDTA and lysozyme because of the efficient pelB leader sequence. rBhCA is a ∼75kDa homodimeric protein with a Tm of 72°C and T1/2 values of 66 and 24min at 50 and 60°C, respectively. SDM analysis revealed that H137, H139, H156 and H110 present in the active site play an important role in catalysis. Mineralization of CO2 using rBhCA led to the accelerated precipitation of CaCO3 in calcite form. rBhCA also functions as an efficient virtual peroxidase when Zn(2+) is substituted with Mn(2+).
Rapeseed (Brassica napus L.) is a Cd/Zn-accumulator whereas soil conditioners such as biochars may immobilize trace elements. These potentially complementary soil remediation options were trialed, singly and in combination, in a pot experiment with a metal(loid)-contaminated technosol.
The technosol [total content in mg kg(-1) Zn 6089, Cd 9.4, Cu 110, and Pb 956] was either amended (2% w/w) or not with a poultry manure-derived biochar. Rapeseed was cultivated for both soil treatments during 24 weeks up to harvest under controlled conditions.
Biochar incorporation into the technosol promoted the As, Cd, Cu, Mo, Ni, Pb and Zn solubility. It decreased foliar B, Cu and Mo concentrations, and Mo concentration in stems, pericarps and seeds. But, it did not impact neither the biomass of aerial rapeseed parts (except a decrease for seeds), nor their C (except a decrease for stems), seed fatty acid, seed starch and soluble sugar contents, and antioxidant capacity in both leaves and seeds. Biochar amendment increased the phytoextraction by aerial plant parts for K, P, and S, reduced it for N, Ca, B, Mo, Ni and Se, whereas it remained steady for Mg, Zn, Fe, Mn, Cu, Cd and Co.
The biochar incorporation into this technosol did not promote Cd, Cu and Zn phytoextraction by rapeseed and its potential oilseed production, but increased the solubility of several metal(loid)s. Here Zn and Cd concentrations in the soil pore water were decreased by rapeseed, showing the feasibility to strip available soil Zn and Cd in combination with seed production.
In this work, open-tubular capillary column coated with zeolite imidazolate framework-8 (ZIF-8) nanocrystals was prepared by a layer-by-layer method. The coating was formed by growing ZIF-8 nanocrystals on either bare fused silica capillary wall or the capillary column premodified with amino groups. The shape and the thickness of the coating formed by using these two methods were almost the same. However, the coverage of the ZIF-8 crystals on the bare fused silica capillary wall was higher than that on the capillary column premodified with amino groups. The ZIF-8 coated capillary column was evaluated for open-tubular capillary electrochromatography. The effect of pH value, buffer concentration, and applied voltage on the separation of phenols was investigated. Good separation of nine phenolic isomers was achieved because of the strong interaction between unsaturated Zn sites and phenols. The column performance for o-nitrophenol was as high as 208 860 plates m(-1) . The run-to-run, day-to-day, and column-to-column reproducibility of retention time and resolution for p-nitrophenol and o-nitrophenol were very good with RSDs of less than 6.5%.
A rechargeable hybrid aqueous battery (ReHAB) containing NASICON-type M3V2(PO4)3 (M = Li, Na) as the cathodes and Zinc metal as the anode, working in Li2SO4-ZnSO4 aqueous electrolyte, has been studied. Both of Li3V2(PO4)3 and Na3V2(PO4)3 cathodes can be reversibly charge/discharge with the initial discharge capacity of 128 mAh g(-1) and 96 mAh g(-1) at 0.2C, respectively, with high up to 84% of capacity retention ratio after 200 cycles. The electrochemical assisted ex-XRD confirm that Li3V2(PO4)3 and Na3V2(PO4)3 are relative stable in aqueous electrolyte, and Na3V2(PO4)3 showed more complicated electrochemical mechanism due to the co-insertion of Li(+) and Na(+). The effect of pH of aqueous electrolyte and the dendrite of Zn on the cycling performance of as designed MVP/Zn ReHABs were investigated, and weak acidic aqueous electrolyte with pH around 4.0-4.5 was optimized. The float current test confirmed that the designed batteries are stable in aqueous electrolytes. The MVP//Zn ReHABs could be a potential candidate for future rechargeable aqueous battery due to their high safety, fast dynamic speed and adaptable electrochemical window. Moreover, this hybrid battery broadens the scope of battery material research from single-ion-involving to double-ions -involving rechargeable batteries.
This study assessed a 6 month resin/dentin bond's durability and cytotoxic effect of Zn-doped model dentin adhesives. The mechanical and physicochemical properties were also tested.
A model etch-and-rinse single-bottle adhesive was formulated (55wt.% Bis-GMA, 45wt.% HEMA, 0.5wt.% CQ, 0.5wt.% DMAEMA) and Zinc methacrylate (Zn-Mt) or ZnO nanoparticles (ZnOn) were added to the model's adhesive, resulting in three groups: Group Control (control model adhesive); Group Zn-Mt (1wt.% Zn-Mt incorporated to adhesive) and Group ZnOn (1wt.% ZnOn incorporated to adhesive). The microtensile bond strength (mTBS) was assessed after 24h or 6 months in water storage. Mechanical properties (diametral tensile strength/DTS, flexural strength/FS, flexural modulus/FM, resilience modulus/RM, and compressive strength/CS) and physicochemical properties (polymerization shrinkage/PS, contact angle/CA, water sorption/WS, and water solubility/WS) were also tested. Cytotoxicity was evaluated with SRB biochemical assay.
No significant difference in the DTS, FS, FM, CS, CA, WS, and WS were found when 1% of ZnOn or Zn-Mt was added to the model dentin adhesive. Group Zn-Mt decreased the RM of adhesive. Groups Zn-Mt and ZnOn decreased the PS of adhesives. Group ZnOn reduced the cytotoxicity of adhesive. Group ZnOn preserved mTBS after 6 months storage without degradation areas as seen by SEM analysis.
The 1wt.% ZnOn may preserve the integrity of the hybrid layer and may reduce cytotoxicity and polymerization shrinkage of model dentin adhesive. The addition of Zn-Mt to the adhesive had no beneficial effects.
The uptake and accumulation of metals in plants is a potential pathway for the transfer of environmental contaminants in the food chain, and poses potential health and environmental risks. In light of increased population growth and urbanisation, the safe disposal of sewage sludge, which can contain significant levels of toxic contaminants, remains an environmental challenge globally. The aims of this experiment were to apply municipal sludge, having undergone treatment by thermal drying, anaerobic digestion, and lime stabilisation, to permanent grassland in order to assess the bioaccumulation of metals (B, Al, Ti, V, Cr, Mn, Co, Ni, Cu, Zn, As, Nb, Mo, Sb, Ba, W, Pb, Fe, Cd) by perennial ryegrass over a period of up to 18 weeks after application. The legislation currently prohibits
 use of grassland for fodder or grazing for at least three weeks after application of treated sewage sludge (biosolids). Five treatments were used: thermally dried (TD), anaerobically digested (AD) and lime stabilised (LS) sludge all from one wastewater treatment plant (WWTP), AD sludge from another WWTP, and a study control (grassland only, without application of biosolids). In general, there was no significant difference in metal content of the ryegrass between micro-plots that received treated municipal sludge and the control over the study duration. The metal content of the ryegrass was below the levels at which phytotoxicity occurs and below the maximum levels specified for animal feeds.
Parallel, tetramolecular G-quadruplex (G4) DNA possessing TINA monomer, (R)-1-O-[4-(1-pyrenylethynyl)phenylmethyl]glycerol, were synthesised and evaluated in complexes with tris(2,2'-bipyridine)ruthenium(II), [Ru(bpy)3 ](2+) , and the Zn(2+) derivative of 5,10,15,20-tetrakis-(1-methyl-4-pyridyl)-21 H,23H-porphine, ZnTMpyP4. UV/Vis, fluorescence, and circular dichroism (CD) spectroscopy showed that the use of G4-DNA as a template resulted in the effective communication between the ligands and the TINA molecule that was covalently attached to the 5'-end and between T and dG at the 5'-end of the dTG4 T sequence. Only one G4-DNA possessing the TINA molecule at the 5'-end of the dTG4 T sequence was able to yield a green-to-blue photochemical upconversion (PUC, λem =420 nm) in the presence of [Ru(bpy)3 ](2+) upon excitation at 500 nm. Different DNA secondary structures can thus be used in DNA-based assemblies for PUC and the way of attachment of chromophores to DNA plays a pivotal role for the creation of a photosynthetic centre.
Various porous Zn1-xCdxS/CdS heteorostructures were achieved via in situ synthesis method with organic amines as the templates. Because of the larger radius of Cd(2+) than that of Zn(2+), CdS quantum dots are formed and distributed uniformly in the network of Zn1-xCdxS. The Zn1-xCdxS/CdS heterostructure with small Cd content (10 at%) derived from ethylenediamine shows very high H2-evolution rate of 667.5 μmol/h per 5 mg photocatalyst under visible light (λ ≥ 420 nm) with an apparent quantum efficiency of 50.1% per 5 mg at 420 nm. Moreover, this Zn1-xCdxS/CdS heterostructure photocatalyst also shows an excellent photocatalytic stability over 100 h.
Investigation of genetic determinants of Cd tolerance in the Zn/Cd hyperaccumulator Arabidopsis halleri allowed the identification of the vacuolar Ca(2+)/H(+) exchanger encoding CAX1 gene. CAX1 was proposed to interfere with the positive feedback loop between Reactive Oxygen Species (ROS) production and Cd-induced cytosolic Ca(2+) spikes, especially at low external Ca(2+) supply. In this study expression of genes involved in ROS homeostasis, cell wall composition, apoplastic pH regulation and Ca(2+) homeostasis were monitored in Arabidopsis thaliana wild-type and cax1-1 knock-out mutant and in Arabidopsis halleri wild-type exposed to cadmium or in control conditions. Clustering the outputs of the expression analysis in a gene co-expression network revealed that CAX1 and genes involved in Ca(2+) cellular homeostasis, apoplastic pH and oxidative stress response were highly correlated in A. thaliana, but not in A. halleri. Many of the studied genes were already highly expressed in A. halleri and/or their expression was not modified by exposure to Cd. The results further supported the role of CAX1 in the regulation of cytosolic ROS accumulation as well as the existence of different cell wall modifications strategies in response to Cd in Arabidopsis thaliana and halleri.
A field study was carried out near Jeddah Industrial Zone to estimate the leaf impairment, physiological disorders, and air pollutant accumulation potential of Ziziphus tree. The experiment was triplicated in RCBD design with factorial arrangement having seasonality as the main plot and washing as subplot treatments along with the control. Accumulation of heavy metals and micronutrients in plant foliage varied significantly under the influence of seasons and washing treatments. The maximum accumulation of cadmium, chromium, nickel, and lead were perceived in summer season while the minimum was observed in winter. Contrarily, a greater acquisition of iron, copper, zinc, and manganese was observed in autumn. Washing significantly reduced the accumulation of Cd, Cr, Ni, and Pb by 58, 90, 80, and 96 %, while Fe, Cu, Zn, and Mn by 89, 37, 60, and 93 %, respectively. Leaf protein and nitrogen content illustrated a greater adjustment for pollutants by presenting a minimum variation (14-18 % and 2-3 %) to seasonality. In contrast, leaf area and stomatal aperture were significantly disturbed and resulted in minimum recovery under washing. Correlation analysis revealed a stronger negative interaction of heavy metal accumulation to leaf features while non-significant interaction was perceived for microelements. In conclusion, planting of Ziziphus trees along industrial areas may impede potential threats of toxic pollutants to human and ecosystem.
Predictability estimated through cross-validation approach showed moderate to high level; hence, genomic selection approach holds great potential for biofortification breeding to enhance grain zinc and iron concentrations in wheat. Wheat (Triticum aestivum L.) is a major staple crop, providing 20 % of dietary energy and protein consumption worldwide. It is an important source of mineral micronutrients such as zinc (Zn) and iron (Fe) for resource poor consumers. Genomic selection (GS) approaches have great potential to accelerate development of Fe- and Zn-enriched wheat. Here, we present the results of large-scale genomic and phenotypic data from the HarvestPlus Association Mapping (HPAM) panel consisting of 330 diverse wheat lines to perform genomic predictions for grain Zn (GZnC) and Fe (GFeC) concentrations, thousand-kernel weight (TKW) and days to maturity (DTM) in wheat. The HPAM lines were phenotyped in three different locations in India and Mexico in two successive crop seasons (2011-12 and 2012-13) for GZnC, GFeC, TKW and DTM. The genomic prediction models revealed that the estimated prediction abilities ranged from 0.331 to 0.694 for Zn and from 0.324 to 0.734 for Fe according to different environments, whereas prediction abilities for TKW and DTM were as high as 0.76 and 0.64, respectively, suggesting that GS holds great potential in biofortification breeding to enhance grain Zn and Fe concentrations in bread wheat germplasm.
The study assessed the levels of some heavy metals in soils in the vicinity of a municipal solid waste dumpsite with a view to providing information on the extent of contamination, ecological risk of metals in the soils and human health risk to the residents in Uyo. Soil samples were collected in rainy and dry seasons and analyzed for metals (Pb, Cd, Zn, Mn, Cr, Ni and Fe) using atomic absorption spectrometry. The concentrations of heavy metals (mg/kg) at the dumpsite in rainy season were Pb (9.90), Zn (137), Ni (12.56), Cr (3.60), Cd (9.05) and Mn (94.00), while in dry season, the concentrations were Pb (11.80), Zn (146), Ni (11.82), Cr (4.05), Cd (12.20) and Mn (91.20). The concentrations of metals in the studied sites were higher than that of the control site (P < 0.05). Pollution indices studies revealed that soil samples from dumpsite and distances from 10 and 20 m east of the dumpsite were highly polluted with cadmium. Ecological risk assessment carried out showed that cadmium contributed 98-99 % of the total potentially ecological risk. No probable health risk was observed as the total hazard index of all the metals was less than one. However, children were found to be more susceptible to heavy metal contamination than adult.
Streams in urban ecosystems receive metal inputs primarily from stormwater runoff and wastewater effluent. The relative contribution of these metal sources to stream impairment is difficult to discern based on simple water characteristics and biological surveys. Stream impairment in these systems is often indicated by reduced abundance and diversity of aquatic insects, which tend to be more sensitive to chronic metal exposures. Metal species and controls on metal species in both the waterborne and dietborne exposure pathways to aquatic organisms are reviewed here. In addition, ecological changes that can control dietborne species are discussed. A main focus is on how organic matter from different anthropogenic sources may control both aqueous metal speciation as well as interaction with various inorganic or microbiological surfaces in streams. Most of the reviewed research focuses on Cu, Zn or Pb as those are the primary metals of concern in developed systems and Cu and Pb have unique and strong interactions with organic matter. Recommendations for further research are described in the context of exposure species, dynamics of exposure, stoichiometry, or advanced analytical tools, and regulatory implications are discussed.
The present article reports the application of hexamethylsilazane (HMDS) modified filter paper for ultrasensitive detection of Hg(2+), Co(2+) and Zn(2+). By chemical vapor deposition of HMDS, a highly hydrophilic filter paper was fabricated to a low wetting (hydrophobic) substrate. The water contact angle (θ) of modified paper was ∼128°, whereas scanning electron and atomic force microscopy confirmed the surface modification. Using chromogenic reagents, a one-step assay for aforementioned ions was demonstrated onto pristine as well as hydrophobic paper. The assay was completed in less than 10 min and the end-result was in form of a color change that could be easily read by the naked eye. The limit of detection on modified paper was 0.5 ppb, which was 5-order of magnitude superior to that observed
 on pristine paper. The proposed method was successfully applied for semi-quantitative determination of Hg(2+) ions in real wastewater samples.
Novel approaches including nonpharmacological methodologies for prevention and control of microbial pathogens and emerging antibiotic resistance are urgently needed. Procellera is a wound care device consisting of a matrix of alternating silver (Ag) and zinc (Zn) dots held in position on a polyester substrate with a biocompatible binder. This electroceutical medical device is capable of generating a direct current voltage (0.5-0.9 Volts). Wound dressings containing metals such as Ag and/or Zn as active ingredients are being used for control of colonized and infected wounds. Reports on the presence of electric potential field across epithelium and wound current on wounding have shown that wound healing is enhanced in the presence of an external electrical field. However, majority of the electrical devices require an external power source for delivering pulsed or continuous electric power at the wound site. A microelectric potential-generating system without an external power source is an ideal treatment modality for application in both clinical and field settings. The research presented herein describes efficacy evaluation of a wireless bioelectric dressing against both planktonic and biofilm forms of wound pathogens including multidrug resistant organisms.
In many parts of the world, soil acidification and heavy metal contamination has become a serious concern due to the adverse effects on chemical properties of soil and crop yield. The aim of this study was to investigate the effect of pH (in the range of 1 to 3 units above and below the native pH of soils) on calcium (Ca), magnesium (Mg), potassium (K), and phosphorus (P) solubility in non-spiked and heavy metal-spiked soil samples. Spiked samples were prepared by cadmium (Cd), copper (Cu), nickel (Ni), and zinc (Zn) as chloride salts and incubating soils for 40 days. The pH buffering capacity (pHBC) of each sample was determined by plotting the amount of H(+) or OH(-) added (mmol kg(-1)) versus the related pH value. The pHBC of soils ranged from 47.1 to 1302.5 mmol kg(-1) for non-spiked samples and from 45.0 to 1187.4 mmol kg(-1) for spiked soil samples. The pHBC values were higher in soil 2 (non-spiked and spiked) which had higher calcium carbonate content. The results indicated the presence of heavy metals in soils generally decreased the solution pH and pHBC values in spiked samples. In general, solubility of Ca, Mg, and K decreased with increasing equilibrium pH of non-spiked and spiked soil samples. In the case of P, increasing the pH to about 7, decreased the solubility in all soils but further increase of pH from 7, enhanced P solubility. The solubility trends and values for Ca, Mg, and K did not differed significantly in non-spiked and spiked samples. But in the case of P, a reduction in solubility was observed in heavy metal-spiked soils. The information obtained in this study can be useful to make better estimation of the effects of soil pollutants on anion and cation solubility from agricultural and environmental viewpoints.
When present at elevated levels in the environment, heavy metals are toxic for most organisms. However, so-called hyperaccumulator plants tolerate heavy metals and use chelators for their internal long-distance transport. Thus, phloem-sucking insects may come in contact with the chelated metals. In the present study, the effects of individual and combined heavy metals, zinc (Zn) and cadmium (Cd), as well as of common chelators, nicotianamine and phytochelatin, were investigated on the performance, preferences, and metal accumulation of the generalist aphid Myzus persicae, using artificial diets. Added Zn increased aphid growth, whereas Cd reduced the survival of aphids. Chelators had neither protective nor negative effects on aphids. The combination of the 2 heavy metals in chelated or nonchelated form caused a potentiation effect that led to an extinction of the aphids within less than 2 wk, before they could reproduce. Both Cd and Zn accumulated in the aphids, indicating a possible biomagnification. In choice assays, aphids preferred diets amended with Zn with or without nicotianamine compared to a control diet. In contrast, a Cd-containing diet led to neither attraction nor aversion. The present study provides insight into how mixtures of heavy metals and their chelators influence the life history of a generalist aphid. The results have implications for the use of phytoremediation to remove heavy metals from contaminated soils. Environ Toxicol Chem 2016;35:3023-3030. © 2016 SETAC.
The alkylative carboxylation of allenamide catalyzed by an N-heterocyclic carbene (NHC)-copper(I) complex [(IPr)CuCl] with CO2 and dialkylzinc reagents was investigated. The reaction of allenamides with dialkylzinc reagents (1.5 equiv) and CO2 (1 atm.) proceeded smoothly in the presence of a catalytic quantity of [(IPr)CuCl] to afford (Z)-α,β-dehydro-β-amino acid esters in good yields. The reaction is regioselective, with the alkyl group introduced onto the less hindered γ-carbon, and the carboxyl group introduced onto the β-carbon atom of the allenamides. The first step of the reaction was alkylative zincation of the allenamides to give an alkenylzinc intermediate followed by nucleophilic addition to CO2 . A variety of cyclic and acyclic allenamides were found to be applicable to this transformation. Dialkylzinc reagents bearing β-hydrogen atoms, such as Et2 Zn or Bu2 Zn, also gave the corresponding alkylative carboxylation products without β-hydride elimination. The present methodology provides an easy route to alkyl-substituted α,β-dehydro-β-amino acid ester derivatives under mild reaction conditions with high regio- and stereoselectivtiy.
Aquatic macrophytes, viz. Sagittaria sagittifolia L., Lemna gibba L., Elodea canadensis Michx., Batrachium trichophyllum (Chaix.) Bosch., Ceratophyllum demersum L. and Potamogeton sp. (P. perfoliatus L., P. alpinus Balb., P. crispus L., P. berchtoldii Fieber, P. friesii Rupr., P. pectinatus L.) were collected from 11 sites for determining their metal accumulation and thiols content. Cu(2+), Ni(2+), Mn(2+), Zn(2+), and Fe(3+) exceeded maximum permissible concentrations in chosen sites. Significant transfer of metals from water to leaves is observed in the order of Ni(2+) < Cu(2+) < Zn(2+) < Fe(3+) < Mn(2+). The maximum variation of bioconcentration factor was noticed for manganese. The accumulation of heavy metals in leaves was correlated with non-protein and protein thiols, confirming their important role in metal tolerance. The largest contribution was provided by Cu(2+) (on the average r = 0.88, p < 0.05), which obviously can be explained as an important role of these ions in thiols synthesis. Increased synthesis of thiols in the leaves allows the usage of SH-containing compounds as biomarkers of metal tolerance. Considering accumulation of metals and tolerance, B. trichophyllum, C. demersum and L. gibba are the most suitable species for phytoremediation of highly multimetal contamination, while E. canadensis and some species of Potamageton are suitable for moderately metal-polluted sites.
Chalkiness has a deleterious influence on rice appearance and milling quality. We identified a notched-belly mutant with a high percentage of white-belly, and thereby developed a novel comparison system that can minimize the influence of genetic background and growing conditions. Using this mutant, we examined the differences in chemical composition between chalky and translucent endosperm, with the aim of exploring relations between occurrence of chalkiness and accumulation of starch, protein and minerals.
Comparisons showed a significant effect of chalkiness on chemical components in the endosperm. In general, occurrence of chalkiness resulted in higher total starch concentration and lower concentrations of the majority of the amino acids measured. Chalkiness also had a positive effect on the concentrations of As, Ba, Cd, Cr, Mn, Na, Sr and V, but was negatively correlated with those of B, Ca, Cu, Fe and Ni. By contrast, no significant chalkiness effect on P, phytic acid-P, K, Mg or Zn was observed. In addition, substantial influence of the embryo on endosperm composition was detected, with the embryo showing a negative effect on total protein, amino acids such as Arg, His, Leu, Lys, Phe and Tyr, and all the 17 minerals measured, excluding Ca, Cu, P and Sr.
An inverse relation between starch and protein as well as amino acids was found with respect to chalkiness occurrence. Phytic acid and its colocalized elements K and Mg were not affected by chalkiness. The embryo exerted a marked influence on chemical components of the endosperm, in particular minerals, suggesting the necessity of examining the role of the embryo in chalkiness formation. © 2016 The Authors. Journal of the Science of Food and Agriculture published by John Wiley & Sons Ltd on behalf of Society of Chemical Industry.
Zinc oxide (ZnO) is a highly important material, and Zn(2+) is a key metal ion in biology. ZnO and Zn(2+) interconvert via dissolution and hydrolysis/condensation. In this work, we explore their interactions with DNA, which is important for biointerface, analytical, and bioinorganic chemistry. Fluorescently labeled DNA oligonucleotides were adsorbed by a low concentration (around 5 μg/mL) of ZnO nanoparticles, near the solubility limit. Right after mixing, fluorescence quenching occurred, indicating DNA adsorption. Then, fluorescence recovered, attributable to ZnO dissolution. The dissolution rate followed A5 > T5 > C5. Dissolution was slower with longer DNA. The adsorption affinity was also measured by a displacement assay to be G5 > C5 > T5 > A5, suggesting that tightly adsorbed DNA can retard ZnO dissolution.
 Electrostatic interactions are important for DNA adsorption because ZnO is positively charged at neutral pH, and a high salt concentration inhibits DNA adsorption. Next, in situ formation of ZnO from Zn(2+) was studied. First, titrating Zn(2+) into a fluorescently labeled oligonucleotide at pH 7.5 resulted in an abrupt fluorescence quenching beyond 0.2 mM Zn(2+). At pH 6, quenching occurred linearly with the Zn(2+) concentration, suggesting the effect of Zn(2+) precipitation at pH 7.5. Second, a Zn(2+)-dependent DNA-cleaving DNAzyme was studied. This DNAzyme was inhibited at higher than 2 mM Zn(2+), attributable to Zn(2+) precipitation and adsorption of the DNAzyme. This paper has established the interplay between DNA, Zn(2+), and ZnO. This understanding can avoid misinterpretation of DNA assay results and adds knowledge to DNA immobilization.
Demetalation of zinc 5,10,15,20-tetraphenylporphyrin (ZnTPP) under acidic conditions and ion exchange with Cu(2+) ions at neutral pH are both rapid reactions in the liquid medium. However, for ZnTPP monolayers adsorbed on a Au(111) surface exposed to aqueous solution, we find that, although ion exchange takes place rapidly as expected, demetalation does not occur, even at pH values as low as 0. Based on this, we conclude that metal center exchange on the surface does not proceed through a free-base porphyrin as an intermediate. Furthermore, once formed, CuTPP is stable on the surface and the reverse exchange from CuTPP to ZnTPP in the presence of Zn(2+) ions could not be achieved. The preference for copper is so strong that even an attempt to exchange adsorbed ZnTPP with Ni(2+) ions in the presence of traces of Cu(2+) yielded CuTPP rather than NiTPP.
In this study we determined the concentration of metals (Cd, Cr, Cu, Fe, Mn, Ni, Pb and Zn) in the water lower São Francisco River basin, to evaluate the influence of urbanization and industrialization on environmental changes in the water resource. All samples were analyzed using the IUPAC adapted method and processed in an atomic absorption spectrophotometer. The sampling stations located near the industrial areas were influenced by industrialization because they presented higher concentrations of Cd, Cr, Ni and Cu. The other sampled locations showed changes with regard the trace elements probably originating in the soil, like Fe, Zn and Pb. There was a gradual increase in the concentrations of metals, in general, in the period of highest rainfall of the hydrographic network. Overall, except for Zn and Mn, the trace elements exceeded the maximum allowed value established by national legislation (CONAMA). Lower São Francisco River basin has suffered interference from urbanization and industrialization, so awareness programs should be developed so as to control and lessen future problems.
The authors present the changes of the As, Cd, Fe, Mn, Pb and Zn contents in two plant-considered metallophytes: common bent Agrostis capillaris (blades) and birch Betula pendula (leaves and seeds), recorded in a Zn-Pb industrial region of Olkusz (Poland) in 1994 and 2014. The highest amounts of Cd (12 ppm) and Zn (2524 ppm) in the common bent occur in the vicinity of the mining and metallurgical works 'Bolesław' in Bukowno. However, these values are significantly lower than those in 1994: Cd by 87 % and Zn by 52 %. The highest contents of Fe (2674 ppm), Mn (130 ppm) and Pb (334 ppm) in this grass species are in the vicinity of the closed Olkusz mine. These contents have increased in comparison with the 1994 figures: Fe by 56 %, Mn by 120 % and Pb by 6 %. In the birch leaves, the metal contents averaged for four sites are the following: As 2.1, Cd 6.5, Fe 261, Mn 110, Pb 70 and Zn 1657 ppm, being lower from the figures in 1994. The highest As, Fe and Pb contents of birch leaves occur in the habitat closest to the former Olkusz mine, while those of Cd, Mn and Zn in the habitat distant at 100 m from the active plant in Bukowno. The common bent grass generates better resistance mechanisms against the metals than does the birch. In the birch leaves, the contents of the metals are significantly lower than those of the grass blades, but higher from those of the birch seeds collected from the same tree individuals. It is a proof of good functioning of the mechanisms preventing excessive metal amounts from the cell metabolism and of the presence of physiological barriers protecting birch seeds as the generative organs.
In this work, environmental heavy metal contamination in the Val d'Agri area of Southern Italy was monitored, measuring the accumulation of 18 heavy metals (U, Hg, Pb, Cd, As, Sr, Sn, V, Ni, Cr, Mo, Co, Cu, Zn, Ca, Mn, Fe, and Al) in the organs of animals raised in the surrounding area (kidney, lung, and liver of bovine and ovine species). Val d'Agri features various oil processing centers which are potentially a significant source of environmental pollution, making it essential to perform studies that will outline the state of the art on which any recovery plans and interventions may be developed. The analysis was carried out using official and accredited analytical methods based on inductively coupled plasma mass spectrometry, and the measurements were statistically processed in order to give a contribution to risk assessment. Even though five samples showed Pb and Cd concentrations above the limits defined in the European Commission Regulation (EC) No 1881/2006, the mean concentrations of most elements suggest that contamination in this area is low. Consequently, these results also suggest that there is no particular risk for human exposure to toxic trace elements. Nevertheless, the findings of this work confirm that element accumulation in ovine species is correlated with geographical livestock area. Therefore, ovine-specific organs might be used as bioindicators for monitoring contamination by specific toxic elements in exposed areas.
Due to chemical and biochemical similarities between cadmium (Cd) and zinc (Zn), application of Zn may minimize Cd uptake by plants and ameliorate its toxicity. However, there is poor understanding of the comparative effectiveness of the foliar Zn application at different growth stages on Cd toxicity and accumulation in wheat. The present study was carried out to compare the effectiveness of foliarly applied Zn at different stages of plant growth to minimize Cd accumulation in wheat grains. Wheat (cv AARI-2011) was grown at three levels of soil Cd (0, 2.5, and 5.0 mg kg(-1)). Foliar application of Zn was carried out at either tillering, jointing, booting, heading, or grain filling stage using 0.05 % w/v aqueous solution of ZnSO4 · 7H2O. Increasing soil Cd had a negative effect on growth and yield attributes, including tiller production, root length and dry weight, plant height, 100-grain weight and grain and straw yield. Zinc foliar spray increased grain yield by increasing tiller production; importantly, an application at booting was more effective than at other stages. Foliarly applied Zn decreased Cd concentration in the roots, straw, and grain. Similar to grain yield, the largest decrease (74 %) in Cd concentration was associated with Zn foliar spray at booting. Grain yield was negatively related to grain Cd concentration which in turn showed a negative relationship with Zn concentration in leaves and grains. It is concluded that the booting stage is the suitable time for foliar application of Zn to (i) effectively minimize a Cd-induced loss in grain yield and (ii) decrease grain Cd concentration.
The objective of this study is to evaluate the current status of heavy metal concentrations in constructed wetland, Shaoguan (Guangdong, China). Sediments, three wetland plants (Typha latifolia, Phragmites australis, and Cyperus malaccensis), and six freshwater fish species [Carassius auratus (Goldfish), Cirrhinus molitorella (Mud carp), Ctenopharyngodon idellus (Grass carp), Cyprinus carpio (Wild common carp), Nicholsicypris normalis (Mandarin fish), Sarcocheilichthys kiangsiensis (Minnows)] in a constructed wetland in Shaoguan were collected and analyzed for their heavy metal compositions. Levels of Pb, Zn, Cu, and Cd in sediments exceeded approximately 532, 285, 11, and 66 times of the Dutch Intervention value. From the current study, the concentrations of Pb and Zn in three plants were generally high, especially in root tissues. For fish, concentrations of all studied metals in whole body of N. mormalis were the highest among all the fishes investigated (Pb 113.4 mg/kg, dw; Zn 183.1 mg/kg, dw; Cu 19.41 mg/kg, dw; 0.846 mg/kg, dw). Heavy metal accumulation in different ecological compartments was analyzed by principle component analysis (PCA), and there is one majority of grouped heavy metals concentration as similar in composition of ecological compartment, with the Cd concentration quite dissimilar. In relation to future prospect, phytoremediation technology for enhanced heavy metal accumulation by constructed wetland is still in early stage and needs more attention in gene manipulation area.
Shewanella sp. G5, a psychrotolerant marine bacterium, has a cold-shock protein (CspA) and three β-glucosidases, two of which were classified in the glycosyl hydrolase families 1 and 3 and are encoded by bgl-A and bgl genes, respectively. Shewanella sp. G5 was cultured on Luria-Bertani (LB) and Mineral Medium Brunner (MMB) media with glucose and cellobiose at various temperatures and pH 6 and 8. Relative quantification of the expression levels of all three genes was studied by real-time PCR with the comparative Ct method (2(-ΔΔCt)) using the gyrB housekeeping gene as a normalizer. Results showed that the genes had remarkably different genetic expression levels under the conditions evaluated, with increased expression of all genes obtained on MMB with cellobiose at 30 °C. Specific growth rate and specific β-glucosidase
 activity were also determined for all the culture conditions. Shewanella sp. G5 was able to grow on both media at 4 °C, showing the maximum specific growth rate on LB with cellobiose at 37 °C. The specific β-glucosidase activity obtained on MMB with cellobiose at 30 °C was 25 to 50 % higher than for all other conditions. At pH 8, relative activity was 34, 60, and 63 % higher at 30 °C than at 10 °C, with three peaks at 10, 25, and 37 °C on both media. Enzyme activity increased by 61 and 47 % in the presence of Ca(2+) and by 24 and 31 % in the presence of Mg(2+) on LB and MMB at 30 °C, respectively, but it was totally inhibited by Hg(2+), Cu(2+), and EDTA. Moreover, this activity was slightly decreased by SDS, Zn(2+), and DTT, all at 5 mM. Ethanol (14 % v/v) and glucose (100 mM) also reduced the activity by 63 and 60 %, respectively.
In this study, we assessed the effects of inorganic and organic pollutants [As, Cu, Fe, Mn, Pb, Zn, PAHs (11 compounds) and total phenols] from a panel of biomarkers [O2, H2O2, thiobarbituric acid reactive substances (TBARS), carbonyl proteins (RCO), superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx) and total cytochrome P450 activities] evaluated in the Snout Scraping (SS), Serum (S) and Peripheral Blood Cells (PBC) of the Morelet's crocodile (Crocodylus moreletii) inhabiting the reference locality (Lake Mocu) and polluted locality (Champoton River) using Principal Component Analysis (PCA). In male crocodiles from the reference site, only H2O2 in PBC was related to levels of fluoranthene on the Keel of Caudal Scales (KCS), but, in females, no association was detected. In contrast, a sex-linked response was detected in specimens from the polluted locality. Levels of benzo[a]pyrene, benzo[a]anthracene, chrysene, pyrene, phenanthrene, acenaphthene, Zn, Cu, and Pb in KCS of the female crocodil were related to the oxidative stress biomarkers on PBC, incluing the total CYP450 activity and levels of O2, H2O2 in serum. However, in male crocodiles, the oxidative stress in SS and in the serum (TBARS, RCO, CAT, GPx), and SOD in PBC was related to As, Pb, Cu, Fe, and benzo[a]pyrene water concentrations and to the burdens of As, Fe, Mn, indeno[1,2,3cd]pyrene in KCS. These results confirm the usefulness of minimal or non-invasive methods of evaluating the oxidative stress response for the environmental monitoring program on the wild Morelet's crocodile that is subject to special protection in Mexican guidelines.
In the classical signaling pathway, testosterone regulates gene expression by activating the cytosolic/nuclear androgen receptor. In the non-classical pathway, testosterone activates cytosolic signaling cascades that are normally triggered by growth factors. The nature of the receptor involved in this signaling pathway is a source of controversy. In the Sertoli cell line 93RS2, which lacks the classical AR, we determined that testosterone stimulates the non-classical signaling pathway, characterized by the phosphorylation of Erk1/2 and transcription factors CREB and ATF-1. We also demonstrated that testosterone increases the expression of the tight junction (TJ) proteins claudin-1 and claudin-5. Both of these proteins are known to be essential constituents of TJs between Sertoli cells, and as a consequence of their increased expression transepithelial resistance across Sertoli cell monolayers is increased. ZIP9 is a Zn(2+)transporter that was recently shown to be a membrane-bound testosterone receptor. Silencing its expression in 93RS2 Sertoli cells by siRNA completely prevents Erk1/2, CREB, and ATF-1 phosphorylation as well the stimulation of claudin-1 and -5 expression and TJ formation between neighboring cells. The study presented here demonstrates for the first time that in Sertoli cells testosterone acts through the receptor ZIP9 to trigger the non-classical signaling cascade, resulting in increased claudin expression and TJ formation. Since TJ formation is a prerequisite for the maintenance of the blood-testis barrier, the testosterone/ZIP9 effects might be significant for male physiology. Further assessment of these interactions will help to supplement our knowledge concerning the mechanism by which testosterone plays a role in male fertility.
The reactivity of metal sites in proteins is tuned by protein-based ligands. For example, in blue copper proteins such as plastocyanin (Pc), the structure imparts a highly elongated bond between the Cu and a methionine (Met) axial ligand to modulate its redox properties. Despite extensive study, a complete understanding of the contribution of the protein to redox activity is challenged by experimentally accessing both redox states of metalloproteins. Using infrared (IR) spectroscopy in combination with site-selective labeling with carbon-deuterium (C-D) vibrational probes, we characterized the localized changes at the Cu ligand Met97 in the oxidized and reduced states, as well as the Zn(II) or Co(II)-substituted, the pH-induced low-coordinate, the apoprotein, and the unfolded states. The IR absorptions of (d3-methyl)Met97 are highly sensitive to interaction of the sulfur-based orbitals with the metal center and are demonstrated to be useful reporters of its modulation in the different states. Unrestricted Kohn-Sham density functional theory calculations performed on a model of the Cu site of Pc confirm the observed dependence. IR spectroscopy was then applied to characterize the impact of binding to the physiological redox partner cytochrome (cyt) f. The spectral changes suggest a slightly stronger Cu-S(Met97) interaction in the complex with cyt f that has potential to modulate the electron transfer properties. Besides providing direct, molecular-level comparison of the oxidized and reduced states of Pc from the perspective of the axial Met ligand and evidence for perturbation of the Cu site properties by redox partner binding, this study demonstrates the localized spatial information afforded by IR spectroscopy of selectively incorporated C-D probes.
Rechargeable Zn-air battery is an ideal type of energy storage device due to its high energy and power density, high safety, and economic viability. Its large-scale application rests upon the availability of active, durable, low-cost electrocatalysts for the oxygen reduction reaction (ORR) in the discharge process and oxygen evolution reaction (OER) in the charge process. Herein we developed a novel ORR/OER bifunctional electrocatalyst for rechargeable Zn-air batteries based on the codoping and hybridization strategies. The B/N-codoped mesoporous nanocarbon supported Co(II)1-xCo(0)x/3Mn(III)2x/3S nanoparticles exhibit a superior OER performance compared to that of IrO2 catalyst and comparable Zn-air battery performance to that of the Pt-based battery. The rechargeable Zn-air battery shows high discharge peak power density (over 250 mW cm(-2)) and current density (180 mA cm(-2) at 1 V), specific capacity (∼550 mAh g(-1)), small charge-discharge voltage gap of ∼0.72 V at 20 mA cm(-2) and even higher stability than the Pt-based battery. The advanced performance of the bifunctional catalysts highlights the beneficial role of the simultaneous formation of Mn(III) and Co(0) as well as the dispersed hybridization with the codoped nanocarbon support.
The environmental conditions of semi-enclosed coastal water-bodies are directly related to the catchment, human activities, and oceanographic setting in which they are located. As a result of low tidal forcing, and generally weak currents, waters in Mediterranean harbours are poorly renewed, leading to quality deterioration. Here, we characterise the seasonal variation of trace metals (i.e. Co, Cd, Cu, Fe, Mo, Ni, Pb, and Zn) in surface waters, and trace metal content in sediments from Maó Harbour, a semi-enclosed coastal ecosystem in the NW Mediterranean Sea. Our results show that most of the dissolved trace metals in the waters of Maó Harbour exhibit a marked inner-outer concentration gradient, suggesting a permanent input into the inner part of the harbour. In general, metal concentrations in the waters of Maó Harbour are higher than those in offshore waters. Concentration of Cu (21±8nM), Fe (9.2±3.2nM) and Pb (1.3±0.4nM) are particularly high when compared with other coastal areas of the Mediterranean Sea. The concentration of some metals such as Cu and Zn increases during summertime, when the human population and boat traffic increase during the tourism season, and when resuspension from the metal enriched sediments is higher. The evaluation of the metal sources in the harbour reveals that, compared with other putative sources such as runoff, aerosol deposition and fresh groundwater discharges, contaminated sediments are the main source of the metals found in the water column, most likely through vessel-driven resuspension events. This study contributes to the understanding of the processes that control the occurrence and distribution of trace metals in Maó Harbour, thus aiding in the effective management of the harbour, and enhancing the overall quality of the seawater ecosystem.
Multinuclear solid-state nuclear magnetic resonance, mass spectrometry, first-principles molecular dynamics simulations, and other complementary evidence reveal that the coordination environment around the Zn(2+) ions in MOF-5, one of the most iconic materials among metal-organic frameworks (MOFs), is not rigid. The Zn(2+) ions bind solvent molecules, thereby increasing their coordination number, and dynamically dissociate from the framework itself. On average, one ion in each cluster has at least one coordinated N,N-dimethylformamide (DMF) molecule, such that the formula of as-synthesized MOF-5 is defined as Zn4O(BDC)3(DMF) x (x = 1-2). Understanding the dynamic behavior of MOF-5 leads to a rational low-temperature cation exchange approach for the synthesis
 of metastable Zn4-x Co x O(terephthalate)3 (x > 1) materials, which have not been accessible through typical high-temperature solvothermal routes thus far.
Nonylphenol polyethoxylates (NPEOs) are a group of surfactants that are widely used in industrial and household products and often detected in the environment. The metabolite of NPEOs, named nonylphenol (NP), has proven to be an endocrine disruptor, and its environmental behavior and eco-toxicity have been widely investigated in previous studies. However, to the best of our knowledge, insight into the toxicity differences of NP and NPEOs on important crops remains limited. Therefore, this study investigated the comparative toxicity of NP, nonylphenol-4-ethoxylate (NP4EO), and nonylphenol-10-ethoxylate (NP10EO) on wheat seedlings using hydroponic experiments. The results indicated that NP is most toxic to wheat followed by NP4EO, and NP10EO is the least toxic to wheat. The adverse effects of NP on wheat were observed for all the tested parameters including germination, shoot length, root length, chlorophyll, lipid peroxidation, and enzymatic activities. To gain insight into the molecular response, we analyzed the transcript abundance of SOD-Cu/Zn and CAT with NP, NP4EO, and NP10EO exposure using quantitative real-time PCR. The data revealed that both genes exhibited up- or down-regulated expression patterns that were consistent with the activities of the two enzymes. This result further conformed that NP is most toxic to wheat plants.
Metallo-β-lactamases (MBLs) confer resistance to carbapenems, and their increasing global prevalence is a growing clinical concern. To elucidate the mechanisms by which these enzymes recognize and hydrolyze carbapenems, we solved 1.4 to 1.6 Å crystal structures of SMB-1 (Serratia metallo-β-lactamase 1), a subclass B3 MBL, bound to hydrolyzed carbapenems (doripenem, meropenem, and imipenem). In these structures, SMB-1 interacts mainly with the carbapenem core structure via elements in the active site, including a zinc ion (Zn-2), Q157[113] (where the position in the SMB-1 sequence is in brackets after the BBL number), S221[175], and T223[177]. There is less contact with the carbapenem R2 side chains, strongly indicating that SMB-1 primarily recognizes the carbapenem core structure. This is the first report describing how a subclass B3 MBL recognizes carbapenems. We also solved the crystal structure of SMB-1 in complex with the approved drugs captopril, an inhibitor of the angiotensin-converting enzyme, and 2-mercaptoethanesulfonate, a chemoprotectant. These drugs are inhibitors of SMB-1 with Ki values of 8.9 and 184 μM, respectively. Like carbapenems, these inhibitors interact with Q157[113] and T223[177] and their thiol groups coordinate the zinc ions in the active site. Taken together, the data indicate that Q157[113], S221[175], T223[177], and the two zinc ions in the active site are key targets in the design of SMB-1 inhibitors with enhanced affinity. The structural data provide a solid foundation for the development of effective inhibitors that would overcome the carbapenem resistance of MBL-producing multidrug-resistant microbes.
In this study, a total of 35 tree nut samples of walnut, pecan, pine seed, hickory nut and torreya were obtained from 5 farm product markets in Hangzhou, China, and investigated for essential (Cr, Mn, Fe, Mo, Cu, Zn, Se and Sr) and toxic (Al, As, Cd and Pb) elements by inductively coupled plasma-mass spectroscopy. Mean elemental concentrations of different tree nuts were in the following ranges: Cr 0.26-0.78 mg kg(-1), Mn 42.1-174 mg kg(-1), Fe 33.7-43.9 mg kg(-1), Mo 0.11-0.48 mg kg(-1), Cu 10.3-17.6 mg kg(-1), Zn 21.6-56.1 mg kg(-1), Se 0.015-0.051 mg kg(-1), Al 1.44-37.6 mg kg(-1), As 0.0062-0.047 mg kg(-1), Cd 0.016-0.18 mg kg(-1) and Pb 0.0069-0.029 mg kg(-1). The estimated provisional tolerable daily intake of Al, As, Cd and Pb was much lower than the provisional tolerable daily intake.
Z-type interactions between bis(perfluorophenyl)zinc and platinum(ii) diaryl complexes supported by 1,10-phenanthroline (phen), 2,2'-bipyridine (bpy), and bis(dimethylphosphino)ethane (dmpe) ligands are reported. In the solid state, the nature of the Pt-Zn interaction depends on the bidentate ligand; the phen-supported complex exhibits an unsupported Pt-Zn bond, while the dmpe derivative features additional bridging aryl interactions. A strongly accelerated rate of reductive elimination is observed for phen- and bpy-supported complexes, while aryl exchange between Pt and Zn is observed for the dmpe complex.
In a sewage irrigation area of northwest China, 52 topsoil samples were collected to measure the contents of arsenic (As), chromium (Cr), copper (Cu), mercury (Hg), manganese (Mn), nickel (Ni), lead (Pb) and zinc (Zn). To identify their sources, multivariate statistics and geostatistics were applied to separate pedogenic elements (As and Mn) from anthropogenic elements (Cr, Cu, Hg, Ni, Pb and Zn). The accumulation of soil Hg was mainly attributed to long-term sewage irrigation, whereas Cr, Ni and Zn were mainly from industrial activities and dust deposition. In addition to the impacts of industry and dust, traffic-related factors were the main sources of Pb and Cu contamination. Based on the relationships of heavy metals with various soil properties and reflectance spectra, co-kriging (CK) was used to improve the interpolation of heavy metals. Comparatively, soil spectra were more suitable as covariates due to their ease and low-cost of collecting as features.
The toxicity, reactivity, and behavior of zinc oxide (ZnO) nanoparticles (NPs) released in the environment are highly dependent on environmental conditions. Myo-inositol hexakisphosphate (IHP), a common organic phosphate, may interact with NPs and generate new transformation products. In this study, the role of IHP in mediating the dissolution and transformation of ZnO NPs was investigated in the laboratory kinetic experiments using powder X-ray diffraction, attenuated total reflectance Fourier transform infrared spectroscopy, (31)P nuclear magnetic resonance spectroscopy, high-resolution transmission electronic microscopy, and synchrotron-based extended X-ray absorption fine structure spectroscopy. The results indicate that IHP shows a dissolution-precipitation effect, which is different from citrate and EDTA that only enhances Zn dissolution. The enhanced dissolution and transformation of ZnO NPs by IHP (<0.5 h) is found to be strikingly faster than that induced by inorganic phosphate (Pi, > 3.0 h) at pH 7.0, and the reaction rate increases with decreasing pH and increasing IHP concentration. Multitechnique analyses reveal that interaction of ZnO NPs with IHP induces rapid transformation of ZnO NPs into zinc phytate complexes initially and poorly crystalline zinc phytate-like (Zn-IHP) phase finally. Additionally, ZnO NPs preferentially react with IHP and transform to Zn-IHP when Pi and IHP concurrently coexist in a system. Overall, results from this study contribute to an improved understanding of the role of organic phosphates (e.g., IHP) in the speciation and structural transformation of ZnO NPs, which can be leveraged for remediation of ZnO-polluted water and soils.
CF3 -derivatized fullerenes prove once again to be promising scaffolds for regioselective fullerene functionalization: now with the smallest possible addends-hydrogen atoms. Hydrogenation of Cs -C70 (CF3 )8 and C1 -C70 (CF3 )10 by means of reduction with Zn/Cu couple in the presence of water proceeds regioselectively, yielding only one major isomer of C70 (CF3 )8 H2 and only two for C70 (CF3 )10 H2 , whose addition patterns are combined in the only abundant isomer of C70 (CF3 )10 H4 . The observed selectivity is governed by the electronic structure of trifluoromethylated substrates. Interestingly, we discovered that Clar's theory can be utilized to predict the regiochemistry of functionalization, and we look forward to testing it on forthcoming cases of derivatization of pre-functionalized fullerene building blocks.
4,4'-Bipyridine-N-oxide (BIPYMO, 1), a less commonly employed coordination polymer linker, has been used as a ditopic spacer to bridge double-four-ring (D4R) zinc phosphate clusters to form novel framework coordination polymers. Zinc phosphate framework compounds [Zn4(X-dipp)4(BIPYMO)2]n·2MeOH [X = H (2), Cl (3), Br (4), I (5); dipp = 2,6-diisopropylphenyl phosphate] have been obtained by treating a methanol solution of zinc acetate with X-dippH2 and BIPYMO (in a 1:1:1 molar ratio) at ambient conditions. Framework phosphates 2-5 can also be obtained by treating the preformed D4R cubanes [Zn(X-dipp)(DMSO)]4 with required quantities of BIPYMO in methanol. Single-crystal X-ray diffraction studies reveal that these framework solids are two-dimensional (2D) networks as opposed to the diamondoid networks obtained when the parent unoxidized 4,4'-bipyridine is used as the linker (Inorg. Chem. 2014, 53, 8959). The two types of voids (viz., smaller intra-D4R and larger inter-D4R) present in these framework solids can be utilized for different types of encapsulation processes. For example, the in situ generated 2D framework 2 encapsulates fluoride ions accompanied by a change in the dimensionality of the framework to yield {[(nC4H9)4N][F@(Zn4(dipp)4(BIPYMO)2)]}n (6). The three-dimensional framework 6 represents the first structurally characterized example of a fluoride-ion-encapsulated polymeric coordination compound or a metal-organic framework. The possibility of utilizing inter-D4R voids as hosts for small organic molecules has been explored by treating in situ generated 2 with a series of organic molecules of appropriate size. Framework 2 has been found to be a selective host for benzil and not for other structurally similar molecules such as benzoquinone, benzidine, anthracene,
 naphthalene, α-pyridoin, etc. The benzil-occluded isolated framework [benzil@{Zn4(dipp)4(BIPYMO)2}]n (7) has been isolated as single crystals, and its crystal structure determination revealed the binding of benzil molecules to the framework through strong π-π interactions.
The interaction between plant growth-promoting bacteria (PGPB) and plants can enhance biomass production and metal tolerance of the host plants. This work aimed at isolating and characterizing the cultivable bacterial community associated with Brassica napus growing on a Zn-contaminated site, for selecting cultivable PGPB that might enhance biomass production and metal tolerance of energy crops. The effects of some of these bacterial strains on root growth of B. napus exposed to increasing Zn and Cd concentrations were assessed. A total of 426 morphologically different bacterial strains were isolated from the soil, the rhizosphere, and the roots and stems of B. napus. The diversity of the isolated bacterial populations was similar in rhizosphere and roots, but lower in soil and stem compartments. Burkoholderia, Alcaligenes, Agrococcus, Polaromonas, Stenotrophomonas, Serratia, Microbacterium, and Caulobacter were found as root endophytes exclusively. The inoculation of seeds with Pseudomonas sp. strains 228 and 256, and Serratia sp. strain 246 facilitated the root development of B. napus at 1,000 µM Zn. Arthrobacter sp. strain 222, Serratia sp. strain 246, and Pseudomonas sp. 228 and 262 increased the root length at 300 µM Cd.
Low concentration of zinc (Zn) in the endosperm of cereals is a major factor contributing to Zn deficiency in human populations. We have investigated how combined Zn and nitrogen (N) fertilization affects the speciation and localization of Zn in durum wheat (Triticum durum). Zn-binding proteins were analysed with liquid chromatography ICP-MS and Orbitrap MS(2) , respectively. Laser ablation ICP-MS with simultaneous Zn, sulphur (S) and phosphorus (P) detection was used for bioimaging of Zn and its potential ligands. Increasing the Zn and N supply had a major impact on the Zn concentration in the endosperm, reaching concentrations higher than current breeding targets. The S concentration also increased, but S was only partly co-localized with Zn. The mutual Zn and S enrichment was reflected in substantially more Zn bound to small cysteine-rich proteins (apparent size 10-30 kDa), whereas the response of larger proteins (apparent size > 50 kDa) was only modest. Most of the Zn-responsive proteins were associated with redox- and stress-related processes. This study offers a methodological platform to deepen the understanding of processes behind endosperm Zn enrichment. Novel information is provided on how the localization and speciation of Zn is modified during Zn biofortification of grains.
The study focused on the phytoattenuation effects of monocropping and intercropping of maize (Zea mays) and/or legumes on Cu, Zn, Pb, and Cd in weakly alkaline soils. Nine growth stages of monocropping maize were chosen to study the dynamic process of extraction of heavy metals. The total content of heavy metals extracted by the aerial part of monocropped maize increased in a sigmoidal pattern over the effective accumulative temperature. The biggest biomass, highest extraction content, and lowest heavy metals bioaccumulation level occurred at physiological maturity. Among the different planting patterns, including monocropping and intercropping of maize and/or soybean (Glycine max), pea (Pisum sativum), and alfalfa (Medicago sativa), the extraction efficiency of Cu, Zn, Pb, and Cd varied greatly. Only intercropping of maize and soybean yielded relatively higher extraction efficiency for the four metals with no significant difference in the total biomass. Moreover, the heavy metals concentrations in dry biomass from all the planting patterns in the present study were within China's national legal thresholds for fodder use. Therefore, slightly polluted alkaline soils can be safely used through monocropping and intercropping of maize and/or legumes for a range of purposes. In particular, this study indicated that intercropping improves soil ecosystems polluted by heavy metals compared with monocropping.
The topsoil around Beijing metropolis, China, is experiencing impacts of rapid urbanization, intensive farming, and extensive industrial emissions. We analyzed the concentrations of Cu, Ni, Pb, Zn, Cd, and Cr from 87 topsoil samples in the pre-rainy season and 115 samples in the post-rainy season. These samples were attributed to nine land use types: forest, grass, shrub, orchard, wheat, cotton, spring maize, summer maize, and mixed farmland. The pollution index (PI) of heavy metals was calculated from the measured and background concentrations. The ecological risk index (RI) was assessed based on the PI values and toxic-response parameters. The results showed that the mean PI values of Pb, Cr, and Cd were > 1 while those of Cu, Ni, and Zn were < 1. All the samples had low ecological risk for Cu, Ni, Pb, Zn, and Cr while only 15.35% of samples had low ecological risk for Cd. Atmospheric transport rather than land use factors best explained the seasonal variations in heavy metal concentrations and the impact of atmospheric transport on heavy metal concentrations varied according to the heavy metal types. The concentrations of Cu, Cd, and Cr decreased from the pre- to post-rainy season, while those of Ni, Pb, and Zn increased during this period. Future research should be focused on the underlying atmospheric processes that lead to these spatial and seasonal variations in heavy metals. The policymaking on environmental management should pay close attention to potential ecological risks of Cd as well as identifying the transport pathways of different heavy metals.
Cryptosporidiosis is an important major cause of enteric parasitic infection among infants and children in developing countries with morbidity and mortality especially among immune- deficient individuals. Poor performance of traditional diagnostic procedures in many laboratories can resulted in misdiagnosis and mistreatment, thereby probably promotes drug resistance. This study was carried out to determine the prevalence of enteric Cryptosporidiosis in children attending primary health centers in Egbedore local government area of Osun State, Nigeria between July-December 2014. Informed consent questionnaires were administered to collect demographic data and a total of 180 stool samples were collected to detect Cryptosporidium oocyst and antigen using Modified Ziehl Neelsen (MZN) and enzyme-linked immunosorbent assay (ELISA) methods, respectively. Prevalence of 38.3% (72/188) and 46.8% (88/188) was obtained by MZN and ELISA, respectively. The prevalence was higher in children between 1-2.5 years and lower in children above 2.5 years. There was significant association between diarrhea and prevalence rate (P = 0.006; P < 0.05) for ELISA and ZN, respectively. The present results show that cryptosporidiosis poses a public health challenge in children found in Egbedore. This study also warrants intensified effort towards awareness of the disease and proper diagnosis is needed most especially among immunocompromised individuals.
Zinc oxide nanosheets (ZnONSs) were successfully synthesized using Zn(NO3)2·4H2O as the starting reagent in ammonia atmosphere at room temperature by a novel gas-solution precipitation method. XRD and EDS patterns indicated that pure ZnONSs were produced only in 15min reaction time. Besides, investigating the optical properties of the as-prepared ZnO nanosheets using UV-Vis diffused reflectance spectroscopy (DRS) exhibited their semiconducting property by revealing one optical band gap in 3.3eV. Moreover, rhodamine B and methylene blue degradation were used as a probe reaction to test the as-synthesized ZnONSs photoactivity. Furthermore, a possible reaction mechanism for ZnONSs formation was discussed. On the other hand, operation of ZnONSs in Dye-sensitized solar cell (DSSC) was investigated by current density-voltage (Jsc-Voc) curve. Finally, a pencil graphite electrode was decorated using ZnONSs and pure MWCNT to provide an electrochemical device for Pb(+2) ions sensing. This modified electrode showed agreeable responses to trace amounts of Pb(+2) in NaOAC/HOAC buffer solutions. The limit of detection was found to be 0.112nmolL(-1) for Pb(+2).
In vitro degradation behavior of squeeze cast (CAST) and equal channel angular pressed (ECAP) ZM21 magnesium alloy (2.0wt% Zn-0.98wt% Mn) was studied using immersion tests up to 4w in three different biological environments. Hanks' Balanced Salt Solution (Hanks), Earle's Balanced Salt Solution (Earle) and Eagle minimum essential medium supplemented with 10% (v/v) fetal bovine serum (E-MEM+10% FBS) were used to investigate the effect of carbonate buffer system, organic compounds and material processing on the degradation behavior of the ZM21 alloy samples. Corrosion rate of the samples was evaluated by their Mg(2+) ion release, weight loss and volume loss. In the first 24h, the corrosion rate sequence of the CAST samples was as following: Hanks>E-MEM+10% FBS>Earle. However, in longer immersion periods, the corrosion rate sequence was Earle>E-MEM+10% FBS≥Hanks. Strong buffering effect provided by carbonate buffer system helped to maintain the pH avoiding drastic increase of the corrosion rate of ZM21 in the initial stage of immersion. Organic compounds also contributed to maintain the pH of the fluid. Moreover, they adsorbed on the sample surface and formed an additional barrier on the insoluble salt layer, which was effective to retard the corrosion of CAST samples. In case of ECAP, however, this effect was overcome by the occurrence of strong localized corrosion due to the lower pH of the medium. Corrosion of ECAP samples was much
 greater than that of CAST, especially in Hanks, due to higher sensitivity of ECAP to localized corrosion and the presence of Cl(-). The present work demonstrates the importance of using an appropriate solution for a reliable estimation of the degradation rate of Mg-base degradable implants in biological environments, and concludes that the most appropriate solution for this purpose is E-MEM+10% FBS, which has the closest chemical composition to human blood plasma.
When performing screening-level and baseline risk assessments, assessors usually compare estimated exposures of wildlife receptor species with toxicity reference values (TRVs). We modeled the exposure of American robins (Turdus migratorius) to 10 elements (As, Cd, Cr, Cu, Hg, Mn, Pb, Se, Zn, and V) in spring and early summer, a time when earthworms are the preferred prey. We calculated soil benchmarks associated with possible toxic effects to these robins from 6 sets of published TRVs. Several of the resulting soil screening-level benchmarks were inconsistent with each other and less than soil background concentrations. Accordingly, we examined the derivations of the TRVs as a possible source of error. In the case of V, a particularly toxic chemical compound (ammonium vanadate) containing V, not normally present in soil, had been used to estimate a TRV. In the cases of Zn and Cu, use of uncertainty values of 10 in estimating TRVs led to implausibly low soil screening values. In the case of Pb, a TRV was calculated from studies demonstrating reductions in egg production in Japanese quail (Coturnix coturnix japonica) exposed to Pb concentrations well below than those causing toxic effects in other species of birds. The results on quail, which were replicated in additional trials, are probably not applicable to other, unrelated species, although we acknowledge that only a small fraction of all species of birds has been tested. These examples underscore the importance of understanding the derivation and relevance of TRVs before selecting them for use in screening or in ecological risk assessment. Integr Environ Assess Manag 2016;12:000-000. ©2016 SETAC.
Many populations of bat species across the globe are declining, with chemical contamination one of many potential stressors implicated in these demographic changes. Metals still contaminate a wide range of habitats, but the risks to bats remain poorly understood. This study is the first to present a national scale assessment of toxic metal (Cd, Pb) and essential trace metal (Cu, Zn) concentrations in bats. Metal concentrations in tissues (kidneys, liver, stomach -stomach content, bones and fur) were measured in 193 Pipistrellus sp. in England and Wales using ICP-MS, and compared to critical toxic concentrations for small mammals. The concentrations of metals determined in bat tissues were generally lower than those reported elsewhere. Strong positive associations were found between concentrations in tissues for a given metal (liver and kidneys for Cd, Cu and Pb; stomach and fur and fur and bones for Pb), suggesting recent as well as long term exposure to these contaminants. In addition, positive correlations between concentrations of different metals in the same tissues (Cd and Zn, Cu and Zn, Cd and Pb, Pb and Zn) suggest a co-exposure of metals to bats. Approximately 21% of the bats sampled contained residues of at least one metal at concentrations high enough to elicit toxic effects (associated with kidney damage), or to be above the upper level measured in other mammal species. Pb was found to pose the greatest risk (with 7-11% of the bats containing concentrations of toxicological concern), followed by Cu (4-9%), Zn (0.5-5.2%) and Cd (0%). Our data suggest that leaching of metals into our storage matrix, formaldehyde, may have occurred, especially for Cu. The overall findings suggest that metal contamination is an environmental stressor affecting bat populations, and that further research is needed into the direct links between metal contamination and bat population declines worldwide.
The agricultural waste, date palm leaflets, was carbonized chemically using sulfuric acid treatment. Produced dehydrated carbon (DC) was subjected to surface functionalization using ethylene diamine producing chelating dehydrated carbon (CDC). In the process, ∼80 % of the carboxylic content on DC was converted to amide successfully. DC acts as a cation exchanger because of the high content of carboxylic groups on its surface showing acidic nature. However, CDC possesses amine and amide groups showing basic nature. Both amine and amide groups are capable of chelating Zn(2+) at high pH; however, at low pH, the amine group becomes protonated acting as anion exchanger. Sorption of Zn(2+) and SO4(2-) was investigated in terms of contact time, initial pH, concentration, and carbon reuse. Zn(2+) shows maximum sorption at initial pH 5; however, maximum sorption of SO4(2-) takes place at initial pH 2. Kinetic and equilibrium studies were carried out at initial 5 and 2 for Zn(2+)and SO4(2-), respectively. Sorption kinetics data follow well the pseudo second-order model. The equilibrium sorption data follow the Langmuir isotherm more than the Freundlich isotherm. CDC shows better sorption performance for Zn(2+) and SO4(2-) than DC. DC and CDC show combined equimolar removal of both Zn(2+) and SO4(2-) at initial pH 2.3 and 2.6, respectively, with efficient recycle properties. Combined removal of Zn(2+) and SO4(2-) from spiked municipal wastewater shows less uptake on both carbons than from deionized water.
The aim of this work was to compare 10 mostly edible aboveground and 10 wood-growing mushroom species collected near a heavily trafficked road (approximately 28,000 vehicles per 24 h) in Poland with regard to their capacity to accumulate 26 trace elements (Ag, Al, As, Au, B, Ba, Bi, Cd, Co, Cr, Cu, Fe, Ga, Ge, In, Li, Mn, Ni, Pb, Re, Sb, Se, Sr, Te, Tl, and Zn) in their fruit bodies in order to illustrate mushroom diversity in element accumulation. All analyses were performed using an inductively coupled plasma optical emission spectrometry (ICP-OES) spectrometer in synchronous dual view mode. The aboveground species had significantly higher levels of 12 elements, including Ag, As, Pb, and Se, compared to the wood-growing species. An opposite relationship was observed only for Au, Ba, and Sr. The results of principal component analysis (PCA) and hierarchical cluster analysis (HCA) implied some new relationships among the analyzed species and elements. Of the analyzed mushroom species, lead content in Macrolepiota procera would seem to pose a health risk; however, at present knowledge regarding lead bioaccessibility from mushrooms is quite limited.
By virtue of their compactness, long-term stability, minimal reagent consumption and robustness, miniaturized sequential injection instruments are well suited for automation of assays onboard research ships. However, in order to reach the sensitivity and limit of detection required for open-ocean determinations of trace elements, it is necessary to preconcentrate the analyte prior its derivatization and subsequent detection by fluorescence. In this work, a novel method for the determination of dissolved zinc (Zn) at subnanomolar levels in seawater is described. The proposed method combines, for the first time, automated matrix removal, extraction of the target element, and fluorescence detection within a miniaturized flow manifold, based on the Lab-On-Valve (LOV) concept. The key feature of the microfluidic manipulation of the sample is flow programming, designed to pass sample through a mini-column where the target analyte and other complexable cations are retained, while the seawater matrix is washed out. Next, zinc is eluted and merged with a Zn selective fluorescent probe (FluoZin-3) at the confluence point of the LOV central channel using two high-precision stepper motor driven pumps that are operated in concert. Finally, the thus formed Zn complex is transported to the LOV flow cell for selective fluorescence measurement. This work describes the characterization and optimization of the method including Solid Phase Extraction using the Toyopearl AF-Chelate-650M resin, and detailed assay protocol controlled by a commercially available software and instrument. The proposed method features a LOD of 0.02 nM, high precision (<3% at 0.1 and 2 nM Zn levels), an assay cycle of 13 min and a reagent consumption of 150 μL FluoZin-3 per sample, which makes the method highly suitable for oceanographic shipboard analysis. The accuracy of the method has been validated through the analysis of seawater reference standards and comparison with ICP-MS determinations on seawater samples collected in the upper 1300 m of the subtropical south Indian Ocean. This work confirms that integration of sample pretreatment with optical detection in the LOV format offers a widely applicable approach to trace analysis of seawater.
Food consumption is the most likely route of human exposure to metals. Tea (Camellia sinensis L.) is among the most widely consumed non-alcoholic beverages. Concentrations of heavy metals and minerals in tea from 15 different brands in Kumasi, Ghana were measured to assess the health risk associated with their consumption. The mineral and metal contents (Fe, Cu, Zn, Pb, As, Cd) were analyzed using atomic absorption spectrophotometer (Z-8100 polarized Zeeman). The results revealed that the mean concentrations were in the order: Ca > Fe > As > Cd > Zn > Pb. The average contents of Ca, Fe, Zn, Pb, Cd, and As in the samples were 94.08, 6.15, 0.20, 0.16, 0.36, and 1.66 mg/kg, respectively. All the minerals and heavy metals were below the maximum permissible limits stipulated by the World Health Organization (WHO) and US Pharmacopeia (USP). Metal-to-metal correlation indicated strong correlations
 between As/Zn, Cd/Zn, Cd/As, and Pb/As pairs. Factor analysis demonstrated a clear separation between minerals, grouped on one side, and heavy metals, clustered on another side. Both the target hazard quotient (THQ) and hazard index (HI) levels in green tea were far below 1, suggesting that consumption of green tea should pose no potential risk to human health. However, carcinogenic risk levels for arsenic were high; R > 10(-6). The results showed that residents in Kumasi consume tea could be at risk from exposure to these heavy metals and minerals.
To determine whether the discharge control of heavy metals in the Yangtze River basin can significantly change the pollution level in the estuary, this study analyzed the sources (upper river, the estuarine region, and the adjacent sea) of ten heavy metals (As, Cd, Co, Cr, Cu, Hg, Ni, Pb, Sb, and Zn) in dissolved and particulate phases in the surface water of the estuary during wet, normal, and dry seasons. Metal sources inferred from section fluxes agree with those in statistical analysis methods. Heavy metal pollution in the surface water of Yangtze Estuary primarily depends on the sediment suspension and the wastewater discharge from estuary cities. Upper river only constitutes the main source of dissolved heavy metals during the wet season, while the estuarine region and the adjacent sea (especially the former) dominate the dissolved metal pollution in the normal and dry seasons. Particulate metals are mainly derived from sediment suspension in the estuary and the adjacent sea, and the contribution of the upper river can be neglected. Compared with the hydrologic seasons, flood-ebb tides exert a more obvious effect on the water flow directions in the estuary. Sediment suspension, not the upper river, significantly affects the suspended particulate matter concentration in the estuary.
Soft sediments are often hotspots of chemical contamination, and a thorough ecotoxicological assessment of this habitat can help to identify the causes of stress and to improve the health of the respective ecosystems. As an important component of the ecologically relevant meiobenthic fauna, nematodes can be used for sediment assessments, with various assay tools ranging from single-species toxicity tests to field studies. In the present study, microcosms containing sediment were used to investigate direct and indirect effects of zinc on natural nematode assemblages, and acute community toxicity tests considering only direct toxicity were conducted. The responses of the various freshwater nematode species in both approaches were compared with those of Caenorhabditis elegans, determined in standardized tests (ISO 10872). At a median lethal concentration (LC50) of 20 mg Zn/L, C. elegans represented the median susceptibility of 15 examined nematode species examined in the acute community toxicity tests. In the microcosms, Zn affected the nematodes dose-dependently, with changes in species composition first detected at 13 mg Zn/kg to 19 mg Zn/kg sediment dry weight. The observed species sensitivities in the microcosms corresponded better to field observations than to the results of the acute community toxicity tests. Environ Toxicol Chem 2016;35:2987-2997. © 2016 SETAC.
Whey protein nanofibrils are gaining interest to fabricate cold-set hydrogels due to their ability to gel at lower concentrations than parent proteins. In the present research, fibrillated protein solution was gelled with three different divalent cation salts including CaCl2, MnCl2 and ZnCl2 and the textural and functional characteristics of the resulting hydrogel samples were studied. Atomic force microscopy indicated that the flexible micron-scaled fibrils with nanometric thickness (up to 8.0nm) that formed at pH 2.0 underwent breaking in length upon post-formation pH rise to 7.5. Whilst heat-denatured protein solution failed to form self-supporting gel at pH 7.5, fibrillated protein solution gelled by all three types of cations. Fibrillation increased the protein solution consistency coefficient (K) much more than heat denaturation. It was suggested based on Fourier-transform infra-red (FT-IR) spectra that some hydrogen bonds were disrupted by fibrillation. Zn(2+)-induced gel was firmer, had a higher water holding capacity and a more compact microstructure, as well, required a higher compressive stress to fracture than its counterparts. Nonetheless, the Mn(2+)- and Ca(2+)-induced gels disintegrated to a much lesser extent in both pepsin-free and pepsin-present simulated gastric juice than Zn(2+)-induced sample. Chitosan coating approximately halved the simulated degradability of all gel samples.
Lipases catalyze the hydrolysis of triglycerides (TAG). Open reading frames (ORF) predicted to encode enzymes involved in fatty acids breakdown are abundant in Mycobacterium tuberculosis genome. To define the function of M. tuberculosis rv1400c (LipI), a putative Hormone Sensitive Lipase (HSL) subfamily ORF, the rv1400c was cloned, expressed and purified in Escherichia coli as fusion protein. The purified LipI preferred short carbon chain substrates with an optimal activity at 37 °C/pH 8.0 and stable between pH 6.0 to 9.0. Its specific activity was calculated to 35.71 U/mg with pNP-butyrate as a preferred substrate. SDS, CTAB and Zn(2+) can inhibit this enzyme. The conserved residues Ser165 and His291 were shown to be important for the catalysis activity of Rv1400c by site-directed mutagenesis. The biochemical and genetical data showed M. tuberculosis LipI might be a good candidate catalyst for polyunsaturated fatty acids.
Cd, Zn, Cu, As, Fe, Cr, Ni, Al, and Pb were analyzed in the edible and inedible parts of the muricid gastropod Hexaplex trunculus sampled along the Tunisian coast in 2004, 2007, and 2011. The concentration ranges (μg/g dry weight) in the whole soft tissue were 0.1-19.2 for Cd, 198.7-564.6 for Zn, 31.9-363.1 for Cu, 12.8-177.8 for As, 35.4-179.0 for Fe, 0.0-5.8 for Cr, 0.1-4.6 for Ni, 1.0-41.4 for Al, and 0.0-0.6 for Pb. The highest concentrations were recorded in Gabès for Cd, Menzel Jemil for Zn and Cu, Bizerte channel for As, Zarat for Cr and Pb, and Tunis North Lake for Fe, Al, and Ni. The European standards compiled by FAO for mollusks were exceeded in several localities. The temporal trends revealed a decreasing metal contamination in most sampling stations from 2004 to 2011. The calculated intake of metals (μg/week/kg body weight) through human consumption of the snail edible portion varied from 0.0 to 4.4 of Cd, 55.9 to 172.1 of Zn, 8.7 to 92.7 of Cu, 3.0 to 42.6 of As, 9.5 to 49.1 of Fe, 0.0 to 1.52 of Cr, 0.0 to 1.4 of Ni, and 0.3 to 11.4 of Al. Comparison of these metal intakes with those of the standard provisional tolerable weekly intake (PTWI) values stipulated by the WHO recommends precaution in terms of human consumption of this marine snail.
Coordination reaction of a known three-dimensional (3D) polymer precursor {Na3[Na9(Cbdcp)6(H2O)18]}n (A, Cbdcp = N-(4-carboxybenzyl)-(3,5-dicarboxyl)pyridinium) with Zn(NO3)2·6H2O in H2O or H2O/DMF at 100 °C and in the presence of aspirin, 5-fluorouracil (5-FU) as modulators, trans-1,2-bis(4-pyridyl)ethylene (bpe) or 1,2-bis(4-pyridyl)ethane (bpea) as ancillary ligands afforded six novel Zn(II)-based metal-organic frameworks (MOFs), that is, {[Zn(Cbdcp)(H2O)3]·H2O}n (1, 1D zigzag chain), {[Zn(HCbdcp)2]·H2O}n (2, 2D sheet), {[Zn(Cbdcp)(bpe)1/2]·2H2O}n (3, 3D polymer), {[Zn(Cbdcp)(bpe)1/2]·2H2O}n (4, 2D network), {[Zn(Cbdcp)(bpea)1/2]·2H2O}n (5, 3D polymer) and {[Zn(Cbdcp)(bpea)1/2]·2H2O}n (6, 2D network). Among them, compound 2 contains aromatic rings, positively charged pyridinium, Zn(2+) cation centers and carboxylic acid groups lined up on the 2D sheet structure with a certain extended surface exposure. The unique structure of 2 facilitates effective association with carboxyfluorescein (FAM) labeled probe single stranded DNA (probe ss-DNA, delineates as P-DNA) to yield a P-DNA@2 system, and leads to fluorescence quenching of FAM via a photoinduced electron transfer process. The P-DNA@2 system is effective and reliable for the detection of human immunodeficiency virus 1 ds-DNA (HIV ds-DNA) sequences and capable of distinguishing complementary HIV ds-DNA from mismatched target sequences with the detection limit as low as 10 pM (S/N = 3).
Interference of organic compounds in the matrix of heavy metal solution could suppress their pre-concentration and detection processes. Therefore, this work aimed to develop simple and facile methods for separation of heavy metals before ICP-MS analysis. Fe3O4@SiO2@TiO2 core-double shell magnetic adsorbent was prepared and characterized by TEM, SEM, FTIR, XRD and surface area, and tested for Magnetic Solid Phase Extraction (MSPE) of Cu(II), Zn(II), Cd(II) and Pb(II). TEM micrograph of Fe3O4@SiO2@TiO2 reveals the uniform coating of TiO2 layer of about 20nm onto the Fe3O4@SiO2 nanoparticles and indicates that all nanoparticles are monodispersed and uniform. The saturation magnetization from the room-temperature hysteresis loops of Fe3O4 and Fe3O4@SiO2@TiO2 was found to be 72 and 40emug(-1), respectively, suggesting good separability of the nanoparticles. The Fe3O4@SiO2@TiO2 showed maximum adsorption capacity of 125, 137, 148 and 160mgg(-1) for Cu(II), Zn(II), Cd(II) and Pb(II) respectively, and the process was found to fit with the second order kinetic model and Langmuir isotherm. Fe3O4@SiO2@TiO2 showed efficient photocatalytic decomposition for tartrazine and sunset yellow (consider as Interfering organic compounds) in aqueous solution under the irradiation of UV light. The maximum recovery% was achieved at pH 5, by elution with 10mL of 2M nitric acid solution. The LODs were found to be 0.066, 0.049, 0.041 and 0.082µgL(-1) for Cu(II), Zn(II), Cd(II) and Pb(II), respectively while the LOQs were found to be 0.20, 0.15, 0.12 and
 0.25µgL(-1) for Cu(II), Zn(II), Cd(II) and Pb(II), respectively.
An Inductively Coupled Plasma Optical Emission Spectrometry method for simultaneous determination of Al, Ca, Cu, Fe, In, Mn, Ni, Si, Sr, Y, Zn, Zr and rare earth elements (La, Ce, Pr, Nd, Sm, Eu, Gd, Tb, Dy, Ho, Er, Tm, Yb, and Lu) in magnesium alloys, including the new rare earth elements-alloyed magnesium, has been developed. Robust conditions have been established as nebulizer argon flow rate of 0.5mLmin(-1) and RF incident power of 1500W, in which matrix effects were significantly reduced around 10%. Three acid digestion procedures were performed at 110°C in closed PFA vessels heated in an oven, in closed TFM vessels heated in a microwave furnace, and in open polypropylene tubes with reflux caps heated in a graphite block. The three digestion procedures are suitable to put into solution the magnesium alloys samples. From the most sensitive lines, one analytical line with lack or low spectral interferences has been selected for each element. Mg, Rh and Sc have been studied as internal standards. Among them, Rh was selected as the best one by using Rh I 343.488nm and Rh II 249.078nm lines as a function of the analytical lines. The trueness and precision have been established by using the Certified Reference Material BCS 316, as well as by means of recovery studies. Quantification limits were between 0.1 and 9mgkg(-1) for Lu and Pr, respectively, in a 2gL(-1) magnesium matrix solution. The method developed has been applied to the commercial alloys AM60, AZ80, ZK30, AJ62, WE54 and AE44.
The aim of this study was to develop an in situ hybridized poly(vinyl alcohol)/calcium silicate (PVA/Ca2OSi) nanofibrous antibacterial wound dressing with calcium phosphate [Ca3(PO4)2] surface precipitation for enhanced bioactivity. This was achieved by hybridizing the antibacterial ions Zn(2+) and/or Ag(+) in a Ca2O4Si composite. The hybridization effect on the thermal behavior, physicochemical, morphological, and physicomechanical properties of the nanofibers was studied using Differential Scanning calorimetric (DSC), X-ray Diffraction (XRD), Fourier Transform Infrared Spectroscopy (FTIR), Scanning Electron Microscopy (SEM) and Textural Analysis, respectively. In vitro bioactivity, biodegradation and pH variations of the nanofiber composite were evaluated in Simulated Body Fluid (SBF). The antibacterial activity was assessed against Staphylococcus aureus and Pseudomonas aeruginosa. Hybridization of Zn(2+) and/or Ag(+) into the PVA/Ca2O4Si nanofiber composite was confirmed by DSC, XRD and FTIR. The thickness of the nanofibers was dependent on the presence of Zn(2+) and Ag(+) as confirmed by SEM. The nanofibers displayed enhanced tensile strength (19-115.73MPa) compared to native PVA. Zn(2+) and/or Ag(+) hybridized nanofibers showed relatively enhanced in vitro bioactivity, biodegradation (90%) and antibacterial activity compared with the native PVA/Ca2O4Si nanofiber composite. Results of this study has shown that the PVA/Ca2O4Si composite hybridized with both Zn(2+) and Ag(+) may be promising as an antibacterial wound dressing with a nanofibrous archetype with enhanced bioactivity.
Ion mobility/mass spectrometry techniques are employed to investigate the binding of Zn(2+) to the nine-residue peptide hormone oxytocin (OT, Cys(1)-Tyr(2)-Ile(3)-Gln(4)-Asn(5)-Cys(6)-Pro(7)-Leu(8)-Gly(9)-NH2, having a disulfide bond between Cys(1) and Cys(6) residues). Zn(2+) binding to OT is known to increase the affinity of OT for its receptor [Pearlmutter, A. F., Soloff, M. S.: Characterization of the metal ion requirement for oxytocin-receptor interaction in rat mammary gland membranes. J. Biol. Chem. 254, 3899-3906 (1979)]. In the absence of Zn(2+), we find evidence for two primary OT conformations, which arise because the Cys(6)-Pro(7) peptide bond exists in both the trans- and cis-configurations. Upon addition of Zn(2+), we determine binding constants in water of KA = 1.43 ± 0.24 and 0.42 ± 0.12 μM(-1), for the trans- and cis-configured populations, respectively. The Zn(2+) bound form of OT, having a cross section of Ω = 235 Å(2), has Pro(7) in the trans-configuration, which agrees with a prior report [Wyttenbach, T., Liu, D., Bowers, M. T.: Interactions of the hormone oxytocin with divalent metal ions. J. Am. Chem. Soc. 130, 5993-6000 (2008)], in which it was proposed that Zn(2+) binds to the peptide ring and is further coordinated by interaction of the C-terminal, Pro(7)-Leu(8)-Gly(9)-NH2, tail. The present work shows that the cis-configuration of OT isomerizes to the trans-configuration upon binding Zn(2+). In this way, the proline residue regulates Zn(2+) binding to OT and, hence, is important in receptor binding. Graphical Abstract ᅟ.
Type-2 diabetics have an increased risk of cardiomyopathy, and heart failure is a major cause of death among these patients. Growing evidence indicates that proinflammatory cytokines may induce the development of insulin resistance, and that anti-inflammatory medications may reverse this process. We investigated the effects of the oral administration of zinc and acetylsalicylic acid, in the form of bis(aspirinato)zinc(II)-complex Zn(ASA)2, on different aspects of cardiac damage in Zucker diabetic fatty (ZDF) rats, an experimental model of type-2 diabetic cardiomyopathy.
Nondiabetic control (ZL) and ZDF rats were treated orally with vehicle or Zn(ASA)2 for 24 days. At the age of 29-30 weeks, the electrical activities, left-ventricular functional parameters and left-ventricular wall thicknesses were assessed. Nitrotyrosine immunohistochemistry, TUNEL-assay, and hematoxylin-eosin staining were performed. The protein expression of the insulin-receptor and PI3K/AKT pathway were quantified by Western blot.
Zn(ASA)2-treatment significantly decreased plasma glucose concentration in ZDF rats (39.0 ± 3.6 vs 49.4 ± 2.8 mM, P < 0.05) while serum insulin-levels were similar among the groups. Data from cardiac catheterization showed that Zn(ASA)2 normalized the increased left-ventricular diastolic stiffness (end-diastolic pressure-volume relationship: 0.064 ± 0.008 vs 0.084 ± 0.014 mmHg/µl; end-diastolic pressure: 6.5 ± 0.6 vs 7.9 ± 0.7 mmHg, P < 0.05). Furthermore, ECG-recordings revealed a restoration of prolonged QT-intervals (63 ± 3 vs 83 ± 4 ms, P < 0.05) with Zn(ASA)2. Left-ventricular wall thickness, assessed by echocardiography, did not differ among the groups. However histological examination revealed an increase in the cardiomyocytes' transverse cross-section area in ZDF compared to the ZL rats, which was significantly decreased after Zn(ASA)2-treatment. Additionally, a significant fibrotic remodeling was observed in the diabetic rats compared to ZL rats, and Zn(ASA)2-administered ZDF rats showed a similar collagen content as ZL animals. In diabetic hearts Zn(ASA)2 significantly decreased DNA-fragmentation, and nitro-oxidative stress, and up-regulated myocardial phosphorylated-AKT/AKT protein expression. Zn(ASA)2 reduced cardiomyocyte death in a cellular model of oxidative stress. Zn(ASA)2 had no effects on altered myocardial CD36, GLUT-4, and PI3K protein expression.
We demonstrated that treatment of type-2 diabetic rats with Zn(ASA)2 reduced plasma glucose-levels and prevented diabetic cardiomyopathy. The increased myocardial AKT activation could, in part, help to explain the cardioprotective effects of Zn(ASA)2. The oral administration of Zn(ASA)2 may have therapeutic potential, aiming to prevent/treat cardiac complications in type-2 diabetic patients.
Chemical extractants used to measure labile soil metal must ideally select for and solubilise the labile fraction, with minimal solubilisation of non-labile metal. We assessed four extractants (0.43 M HNO3, 0.43 M CH3COOH, 0.05 M Na2H2EDTA and 1 M CaCl2) against these requirements. For soils contaminated by contrasting sources, we compared isotopically exchangeable Ni, Cu, Zn, Cd and Pb (EValue, mg kg(-1)), with the concentrations of metal solubilised by the chemical extractants (MExt, mg kg(-1)). Crucially, we also determined isotopically exchangeable metal in the soil-extractant systems (EExt, mg kg(-1)). Thus 'EExt - EValue' quantifies the concentration of mobilised non-labile metal, while 'EExt - MExt' represents adsorbed labile metal in the presence of the extractant. Extraction with CaCl2 consistently underestimated EValue for Ni, Cu, Zn and Pb, while providing a reasonable estimate of EValue for Cd. In contrast, extraction with HNO3 both consistently mobilised non-labile metal and overestimated the EValue. Extraction with CH3COOH appeared to provide a good estimate of EValue for Cd; however, this was the net outcome of incomplete solubilisation of labile metal, and concurrent mobilisation of non-labile metal by the extractant (MExt<EExt>EValue). The Na2H2EDTA extractant mobilised some non-labile metal in three of the four soils, but consistently solubilised the entire labile fraction for all soil-metal combinations (MExt ≈ EExt). Comparison of EValue, MExt and EExt provides a rigorous means of assessing the underlying action of soil chemical extraction methods and could be used to refine long-standing soil extraction methodologies.
The chemical composition of three edible seaweeds (Codium capitatum, Hypnea spicifera and Sargassum elegans) and two inedible seaweeds (Halimeda cuneata and Spyridia hypnoides) from the Indian Ocean along the KwaZulu-Natal East Coast, South Africa were investigated as a function of seasonal variation. The proximate compositions of the edible seaweeds were determined. In edible seaweeds, the moisture level ranged from 85.4 to 89.5%, protein from 6.1 to 11.8%, lipids from 7.5 to 13.1% and carbohydrates from 37.8 to 71.9%. Elemental concentrations in the five studied seaweeds varied significantly with season (P < 0.05) with mean elemental concentrations (in µg g(-1),
 dry weight) being: Ca (29 260), Mg (6 279), Fe (1 086), Cu (145.9), Mn (48.32), As (24.29), Zn (15.65), Ni (9.83), Cr (5.78), Pb (4.84), Co (0.87) and Se (0.86). The concentrations of As were particularly high in S. elegans, ranging from 94.70 ± 6.6 µg g(-1) in winter to 65.10 ± 2.3 µg g(-1) in summer. Hierarchical cluster analysis showed similar distribution of elements in edible seaweeds which was dissimilar to that in inedible seaweeds. This study suggests that edible macro alga, C. capitatum and H. spicifera, could be potential sources of most essential nutrients and may contribute positively to the diet without posing the risk of adverse health effects due to low concentrations of toxic elements. However, due to high levels of As in S. elegans, its consumption should be moderated to reduce dietary exposure to this toxic element.
Sensing platforms that allow rapid and efficient detection of metal ions would have applications in disease diagnosis and study, as well as environmental sensing. Here, we report the first microstructured optical fiber-based biosensor for the reversible and nanoliter-scale measurement of metal ions. Specifically, a photoswitchable spiropyran Zn(2+) sensor is incorporated within the microenvironment of a liposome attached to microstructured optical fibers (exposed-core and suspended-core microstructured optical fibers). Both fiber-based platforms retains high selectivity of ion binding associated with a small molecule sensor, while also allowing nanoliter volume sampling and on/off switching. We have demonstrated that multiple measurements can be made on a single sample without the need to change the sensor. The ability of the new sensing platform to sense Zn(2+) in pleural lavage and nasopharynx of mice was compared to that of established ion sensing methodologies such as inductively coupled plasma mass spectrometry (ICP-MS) and a commercially available fluorophore (Fluozin-3), where the optical-fiber-based sensor provides a significant advantage in that it allows the use of nanoliter (nL) sampling when compared to ICP-MS (mL) and FluoZin-3 (μL). This work paves the way to a generic approach for developing surface-based ion sensors using a range of sensor molecules, which can be attached to a surface without the need for its chemical modification and presents an opportunity for the development of new and highly specific ion sensors for real time sensing applications.
To study the compositional trends associated with the spatial and layer wise distribution of heavy metals as well as the sediment response towards the untreated chemical wastes, we have analyzed river (Buriganga, Bangladesh) sediments by instrumental neutron activation analysis (INAA) and energy dispersive X-ray fluorescence (EDXRF). In nine sediment samples 27 elements were determined where Na, Al, K, Ca, Sc, Ti, V, Cr, Mn, Fe, Co, Zn, As, Rb, Cs, La, Ce, Sm, Dy, Hf, Th and U were determined by INAA and Cu, Sr, Ba, Hg and Pb were determined by EDXRF. Pollution level and the origin of pollutants were evaluated by the aid of geo-accumulation index (Igeo), enrichment factor (EF), pollution load index (PLI) and the inter-element correlation analysis. Major elements are somehow buffered even though the pollution level is severe while the trace metals seem to be highly responsive. Among the heavy metals, Cr is the dominant pollutant, though the pollution level varies systematically with the sampling depth and the distance from the contamination source. Positive linear correlation between Cr and Zn (0.94) ensures the similar anthropogenic source(s) for these two metals, but the sediments of this study respond differently depending upon their geochemical behavior. Rare earth elements (here La, Ce, Sm and Dy), Th and U seem to have crustal origin and the Th/U ratio varies from 2.58 to 4.96.
We prepared in this work an anchoring porphyrin and a series of hat-porphyrins. The zinc atom of the hat-porphyrins can be coordinated axially with the pyridine moiety of the anchoring porphyrin which is anchored on the titania surface by a carboxyl group. The structures of the assemblies were confirmed using computational calculations, transmission electron microscopy (TEM) and energy dispersive spectrometry (EDS). Solar cell devices of the monomer anchoring porphyrin and its assemblies were fabricated and the photovoltaic performances were measured under standard AM 1.5 sunlight irradiance. We found that the assembly devices showed higher JSC and lower VOC than that of the monomer anchoring porphyrin device. However, the comprehensive influence of JSC and VOC led to an enhancement in the solar-to-electric power-conversion efficiency (PCE) of the assemblies. We also studied the variation of JSC and VOC using electronic absorption and emission spectroscopy, charge extraction measurements, transient photovoltage decay measurements and electrochemical impedance spectroscopy.
Nanostructures of three Zinc(II) coordination polymers, [Zn(NNO)2(H2O)4]n (1), [Zn(PNNO)2(H2O)2]n (2) and [Zn(H2O)6]·(INNO)2 (3) {NNO: Nicotinic acid N-oxide, PNNO: Picolinic acid N-oxide and INNO: Isonicotinic acid N-oxide}, have been synthesized by a sonochemical process and reaction of ligands with Zn(CH3COO)2. The Zinc(II) oxide nano-particles have been synthesized from thermolysis of [Zn(NNO)2(H2O)4]n (1), [Zn(PNNO)2(H2O)2]n (2) and [Zn(H2O)6]·(INNO)2 (3) at two different methods (with surfactant and without surfactant) and two temperatures (200 and 600°C). The ZnO nanoparticles were characterized by X-ray diffraction (XRD) and scanning electron microscopy (SEM). Comparison of the SEM images of ZnO nano-particles at two different methods and temperatures shows that higher temperature results in an increasing of agglomeration and thus small and spherical ZnO particles with good separation were produced by thermolysis of compounds at 200°C and by use of surfactant.
We previously reported on supramolecular complexes 4 and 5, formed by the 4 : 4 : 4 or 2 : 2 : 2 assembly of a dimeric zinc(II) complex (Zn2L(1)) having 2,2'-bipyridyl linker, dianion of cyanuric acid (CA) or 5,5-diethylbarbituric acid (Bar), and copper(II) ion (Cu(2+)) in an aqueous solution. The supermolecule 4 possesses Cu2(μ-OH)2 centers and catalyzes hydrolysis of phosphate monoester dianion, mono(4-nitrophenyl)phosphate (MNP), at neutral pH. In this manuscript, we report on design and synthesis of hydrophobic supermolecules 9 and 10 by 4 : 4 : 4 and 2 : 2 : 2 self-assembly of hydrophobic Zn2L(2) and Zn2L(3) containing long alkyl chains, CA or Bar, and Cu(2+) and their phosphatase activity for the hydrolysis of MNP and bis(4-nitrophenyl)phosphate (BNP) in two-phase solvent systems. We assumed that the Cu2(μ-OH)2 active sites of 9 and 10 would be more stable in organic solvent than in aqueous solution and that product inhibition of the supermolecules might be avoided by the release of HPO4(2-) into the aqueous layer. The findings indicate that 9 and 10 exhibit phosphatase activity in the two-phase solvent system, although catalytic turnover was not observed. Furthermore, the hydrolysis of BNP catalyzed by the hydrophobic 2 : 2 : 2 supermolecules in the two-phase solvent system is described.
The ability of mucilage from Dicerocaryum eriocarpum (DE) plant to act as biosorption medium in the removal of metals ions from aqueous solution was investigated. Functional groups present in the mucilage were identified using Fourier transform infrared spectroscopy (FTIR). Mucilage was modified with sodium and potassium chlorides. This was aimed at assessing the biosorption efficiency of modified mucilage: potassium mucilage (PCE) and sodium mucilage (SCE) and comparing it with non-modified deionised water mucilage (DCE) in the uptake of metal ions. FTIR results showed that the functional groups providing the active sites in PCE and SCE and DCE include: carboxyl, hydroxyl and carbonyl groups. The chloride used in the modification of the mucilage did not introduce new functional groups but increased the intensity of the already existing functional groups in the mucilage. Results from biosorption experiment showed that DE mucilage displays good binding affinity with metals ions [Zn(II), Cd(II) Ni(II), Cr(III) and Fe(II)] in the aqueous solution. Increase in the aqueous solution pH, metal ions initial concentration and mucilage concentration increased the biosorption efficiency of DE mucilage. The maximum contact time varied with each species of metal ions. Optimum pH for [Zn(II), Cd(II) Ni(II) and Fe(II)] occurred at pH 4 and pH 6 for Cr(III). Kinetic models result fitted well to pseudo-second-order with a coefficient values of R(2) = 1 for Cd(II), Ni(II), Cr(III), Fe(II) and R(2) = 0.9974 for Zn(II). Biosorption isotherms conforms best with Freundlich model for all the metal ions with correlation factors of 0.9994, 0.9987, 0.9554, 0.9621 and 0.937 for Zn(II), Ni(II), Fe(II), Cr(III) and Cd(II), respectively. Biosorption capacity of DE mucilage was 0.010, 2.387, 4.902, 0688 and 0.125 for Zn(II), Cr(III), Fe(II), Cd(II) and Ni(II) respectively. The modified mucilage was found to be highly efficient in the removal of metal ions than the unmodified mucilage.
Gallium-68 citrate has been successfully applied in the PET imaging of infections and inflammation in some centers; however further evaluation of the tracer in inflammation models is of great importance.
68Ga-citrate prepared from [68Ga]GaCl3 (eluted form an SnO2 based 68Ge/68Ga generator) and sodium citrate at optimized conditions followed by quality control tests was injected to normal and turpentine-oil induced rats PET/CT imaging studies up to 290 min.
68Ga-citrate was prepared with acceptable radiochemical purity (>99 ITLC, >99% HPLC), specific activity (28-30 GBq/mM), chemical purity (Sn, Fe <0.3 ppm; Zn<0.2 ppm) in 15 min at 50C. PET/CT imaging of the tracer demonstrated
 early detection of inflamed site in animal models in 60-80 min.
This study demonstrated possible early detection of inflammation foci in vivo using 68Ga-citrate prepared using commercially available 68Ge/68Ga generators for PET imaging.
In order to determine the potential of phoomdi to accumulate nutrients and metals, 11 dominant species belonging to 10 different families, sediment, and water were analyzed for a period of 2 years from the largest freshwater wetland of north-east India, Loktak (Ramsar site). Results revealed nutrient (TN and TP) and metal (Fe, Mn, Zn, and Cu) compartmentalization in the order phoomdi > sediment > water. Iron concentrations in water (0.37 ± 0.697 to 0.57 ± 1.010 mg L(-1)) and sediments (81.8 ± 0.45 to 253.1 ± 0.51 mg kg(-1)) show high metal discharge into the wetland. Metal accumulation in phoomdi ranged up to 212.3 ± 0.46-9461.4 ± 1.09 mg kg(-1) for Fe; 85.9 ± 0.31-3565.1 ± 0.87 mg kg(-1) for Mn; 9.6 ± 0.41-85.39 ± 0.58 mg kg(-1) for Zn; and 0.31 ± 0.04-9.2 ± 0.04 mg kg(-1) for Cu, respectively. High bioaccumulation factors (BAF) for metals (S. cucullata, 5.8 × 10(4) Fe, 3.9 × 10(4) Mn, and 1.7 × 10(4) Cu, and O. javanica, 4.9 × 10(3) Zn) and nutrients (S. polyrhiza, 9.7 × 10(2) TN, and Z. latifolia, 7.9 × 10(4) TP) revealed good accumulation in phoomdi compared to the wetland water column and indicate their potential to maintain a safe environment of Loktak. Further, the paper analyzed the health hazard of metals via phoomdi wild edible consumption, with the results confirming potential risk. Thus, the paper showed the need of in-depth monitoring and ample management strategies to ensure nutritional safety conditions of locals from the metals.
The applications of coordination chemistry to molecular imaging has become a matter of intense research over the past 10 years. In particular, the applications of bis(thiosemicarbazonato) metal complexes in molecular imaging have mainly been focused on compounds with aliphatic backbones due to the in vivo imaging success of hypoxic tumors with PET (positron emission tomography) using (64) CuATSM [copper (diacetyl-bis(N4-methylthiosemicarbazone))]. This compound entered clinical trials in the US and the UK during the first decade of the 21(st) century for imaging hypoxia in head and neck tumors. The replacement of the ligand backbone to aromatic groups, coupled with the exocyclic N's functionalization during the synthesis of bis(thiosemicarbazones) opens the possibility to use the corresponding metal complexes as multimodal imaging agents of use, both in vitro for optical detection, and in vivo when radiolabeled with several different metallic species. The greater kinetic stability of acenaphthenequinone bis(thiosemicarbazonato) metal complexes, with respect to that of the corresponding aliphatic ATSM complexes, allows the stabilization of a number of imaging probes, with special interest in "cold" and "hot" Cu(II) and Ga(III) derivatives for PET applications and (111) In(III) derivatives for SPECT (single-photon emission computed tomography) applications, whilst Zn(II) derivatives display optical imaging properties in cells, with enhanced fluorescence emission and lifetime with respect to the free ligands. Preliminary studies have shown that gallium-based acenaphthenequinone bis(thiosemicarbazonato) complexes are also hypoxia selective in vitro, thus increasing the interest in them as new generation imaging agents for in vitro and in vivo applications.
Ultraviolet (UV) absorption characteristics of poly-Al-Zn-Fe (PAZF), a polymerized coagulant containing three kinds of metallic elements prepared from a galvanized-aluminum slag, was analyzed by UV-visible spectrophotometry during its polymerization process. Pollutant removal by PAZF in treating various wastewaters was investigated, in comparison with that of polyaluminum chloride (PAC). The results showed that PAZF can be applied to different wastewaters and had excellent coagulation behavior due to its special internal composition. Various complicated substances having different absorption wavelengths and polymeric properties were produced during the PAZF polymerization process, and the structures of these complicated substances were adjusted continuously with the increasing of the polymerization time. PAZF posed better turbidity and organic matter (chemical oxygen demand, COD(Cr)) removal than PAC for different wastewaters, and the required dosage of PAZF was far lower than that of PAC when achieving the same coagulation performance. For pharmaceutical, sugar, dyeing, simulated pesticide and landscape wastewaters, PAZF gave higher removal of turbidity or COD(Cr) than PAC, by up to 79.5% (coagulant dose: 74 mg/L) or 16% (148 mg/L), 13.4% (111 mg/L) or 10% (185 mg/L), 26.5% (148 mg/L) or 8.1% (18.5 mg/L), 40% (18.5 mg/L) or 13.4% (111 mg/L), and 5% (70 mg/L) or 5% (70 mg/L), respectively.
Fragile X premutation alleles have 55-200 CGG repeats in the 5' UTR of the FMR1 gene. Altered zinc (Zn) homeostasis has been reported in fibroblasts from >60 years old premutation carriers, in which Zn supplementation significantly restored Zn-dependent mitochondrial protein import/processing and function. Given that mitochondria play a critical role in synaptic transmission, brain function, and cognition, we tested FMRP protein expression, brain bioenergetics, and expression of the Zn-dependent synaptic scaffolding protein SH3 and multiple ankyrin repeat domains 3 (Shank3) in a knock-in (KI) premutation mouse model with 180 CGG repeats. Mitochondrial outcomes correlated with FMRP protein expression (but not FMR1 gene expression) in KI mice and human fibroblasts from carriers of the pre- and full-mutation. Significant deficits in brain bioenergetics, Zn levels, and Shank3 protein expression were observed in the Zn-rich regions KI hippocampus and cerebellum at PND21, with some of these effects lasting into adulthood (PND210). A strong genotype × age interaction was observed for most of the outcomes tested in hippocampus and cerebellum, whereas in cortex, age played a major role. Given that the most significant effects were observed at the end of the lactation period, we hypothesized that KI milk might have a role at compounding the deleterious effects on the FMR1 genetic background. A higher gene expression of ZnT4 and ZnT6, Zn transporters abundant in brain and lactating mammary glands, was observed in the latter tissue of KI dams. A cross-fostering experiment allowed improving cortex bioenergetics in KI pups nursing on WT milk. Conversely, WT pups nursing on KI milk showed deficits in hippocampus and cerebellum bioenergetics. A highly significant milk type × genotype interaction was observed for all three-brain regions, being cortex the most influenced. Finally, lower milk-Zn levels were recorded in milk from lactating women carrying the premutation as well as other Zn-related outcomes (Zn-dependent alkaline phosphatase activity and lactose biosynthesis-whose limiting step is the Zn-dependent β-1,4-galactosyltransferase). In premutation carriers, altered Zn homeostasis, brain bioenergetics and Shank3 levels could be compounded by Zn-deficient milk, increasing the risk of developing emotional and neurological/cognitive problems and/or FXTAS later in life.
Molybdenum (Mo) is an essential trace element for animals and human beings. However, the negative effects on rumen function and distribution of trace elements in tissues induced by excessive Mo have not been well understood. Therefore, the purpose of present study was to investigate the impact of Mo on rumen microbiota, distribution of trace elements in various organs, and hematological parameters of goats. A total of 36 goats were randomly distributed into three groups with equal number and low-Mo and high-Mo groups were orally administered ammonium molybdate at 15 and 45 mg · Mo · kg(-1) · BW respectively, while the control group received corresponding quantitative deionized water. The results showed that the total number of ciliate and protozoa protein concentration decreased significantly (P < 0.01) on days 25 and 50. Concentrations of ammonia nitrogen and bacterial protein were significantly higher (P < 0.05) in low-Mo group, while they were lower (P < 0.05) in high-Mo group than the control group on days 25 and 50. In addition, Mo accumulated in serum and all detected tissues. Copper (Cu) and zinc (Zn) contents significantly decreased (P < 0.05) in hair and serum on days 25 and 50, while Cu contents increased (P < 0.05) and the change of Zn contents were not obvious (P > 0.05) in other tissues on days 25 and 50. Besides, there was no obvious variation in iron (Fe) contents during whole experiment period (P > 0.05). Furthermore, excessive Mo content had no significant effect on red blood cell (RBC) counts and hemoglobin (HGB) concentration (P > 0.05) on days 25 and 50, while white blood cell (WBC) counts increased significantly (P < 0.05) on day 50. These results indicated that excessive Mo content could impact the balance of ruminal microorganisms and interfere with the absorption and distribution of Mo and Cu mainly.
Eggs from hens raised on rural or domestic farms are a good indicator of environmental contamination, as the hens are in close contact with the ground and the air and can therefore accumulate heavy metals and other toxic contaminants from the environment as well as from the diet. In this paper, we report the results of the determination of 19 trace elements (As, Be, Cd, Co, Cr, Cu, Hg, Mo, Mn, Ni, Pb, Sb, Se, Sn, Sr, Tl, U, V, Zn) in 39 hen egg samples collected from domestic poultry farms in the territory dubbed the "Land of fires" in the Campania region (Italy). This area is characterized by environmental problems caused by the illegal dumping of industrial or domestic waste in fields or by roadsides. In some cases, these wastes have
 been burned, thereby spreading persistent contaminants into the atmosphere. The content of trace elements in whole egg samples was determined by mass spectrometer after a microwave-assisted digestion procedure. Because European legislation does not indicate maximum values of these elements in this foodstuff, the results were compared with the content of trace elements reported in literature for eggs, in particular home-produced eggs, in various countries. In some cases (Cd, Cu, Ni, Mn), the content determined in this study was in line with those reported elsewhere, in other cases (Pb, Cr), lower values were found.
This study was performed to determine the levels of eight heavy metals in irrigation well water and soil and to assess the suitability of some leafy green plants that are commonly cultivated in the Al-Kharj region, Saudi Arabia, for human consumption using an atomic absorption spectrometer. The mean concentrations of metals ranged from 0.0001 to 0.436 mg/L in well water and from 0.248 to 164.52 mg/kg in soil. The heavy metal concentrations showed significant differences among the different leafy green plants studied. Parsley (4.98 mg/kg) exhibited higher levels of Pb than other leafy green plants, whereas mallow (0.097 mg/kg) revealed greater amounts of Cd than other plants. All of the leafy green plants retained essential metals (Cu, Zn, Fe and Mn) more than the toxic metals (Pb and Cd). The levels of some of the metals in the leafy green plants were found to meet the FAO/WHO-recommended limits. The monitoring of heavy metals in leafy green plants must be continued because these plants are the main source of food for humans in many parts of the world and are considered to be bio-indicators for environmental pollution.
We determined the Cd, Cr, Cu, Ni, Pb, and Zn concentrations in soil samples collected along the eight main outlet roads of Poznań. Samples were collected at distances of 1, 5, and 10 m from the roadway edges at depth intervals of 0-20 and 40-60 cm. The metal content was determined in seven grain size fractions. The highest metal concentrations were observed in the smallest fraction (<0.063 mm), which were up to four times higher than those in sand fractions. Soil Pb, Cu, and Zn (and to a lesser extent Ni, Cr, and Cd) all increased in relation to the geochemical background. At most sampling sites, metal concentrations decreased with increasing distance from roadway edges and increasing depth. In some locations, the accumulation of metals in soils appears to be strongly influenced by wind direction. Our survey findings should contribute in predicting the behavior of metals along outlet road, which is important by assessing sources for further migration of heavy metals into the groundwater, plants, and humans.
Mine wastes and tailings are considered hazardous to human health because of their potential to generate large quantities of highly toxic emissions of particulate matter (PM). Human exposure to As and other trace metals in PM may occur via inhalation of airborne particulates or through ingestion of contaminated dust. This study describes a laboratory-based method for extracting PM2.5-10 (coarse) and PM2.5 (fine) particles from As-rich mine waste samples collected from an historical gold mining region in regional, Victoria, Australia. We also report on the trace metal and metalloid content of the coarse and fine fraction, with an emphasis on As as an element of potential concern. Laser diffraction analysis showed that the proportions of coarse and fine particles in the bulk samples ranged between 3.4-26.6 and 0.6-7.6 %, respectively. Arsenic concentrations were greater in the fine fraction (1680-26,100 mg kg(-1)) compared with the coarse fraction (1210-22,000 mg kg(-1)), and Co, Fe, Mn, Ni, Sb and Zn were found to be present in the fine fraction at levels around twice those occurring in the coarse. These results are of particular concern given that fine particles can accumulate in the human respiratory system. Our study demonstrates that mine wastes may be an important source of metal-enriched PM for mining communities.
The present study investigates the quality of surface sediments from the Bizerte lagoon (North Tunisia) using an integrated approach including chemical contaminant analysis, bioassays and sediment quality guidelines (SQGs). Sediment samples were collected at 9 sites and analyzed for eight heavy metals (Hg, Cd, Cr, Cu, Pb, Zn, Ni, Fe and Mn). PAHs, PCBs, OCPs were measured previously in the same sediment samples. Our results indicated that the highest concentrations of metals were found near urban areas due to the municipial and industrial wastewater discharges. Sediment pollution assessment was carried out using geoaccumulation index and enrichment factor, which indicate a widespread pollution by Cd, Pb, Ni and Zn in the studied sediments. For bioassays, aqueous and organic extracts were used to assess toxicity and genotoxicity in sediments by using Microtox(®) and SOS Chromotest, respectively. Toxicity levels were compared to metallic and organic pollutants contents. Our results highlight differences in the pattern of responses between the different assays and show no correlation with all the studied contaminants, emphasizing the influence of other contaminants not analyzed in the present study. Based on SQGs, the results of toxicity assessment indicated that adverse effects caused by Ni and Zn would be expected frequently. Nickel was found to have the highest predicted acute toxicity, followed by Zn, Pb, Cd, Cu and Cr. There was no significant relationship between sediment toxicity calculated from heavy metal concentrations (SQG approach) and those measured with bioassays. These findings support the use of integrated approachs for evaluating the environmental risks of sediments.
The chemistry of organically templated metal sulfates has attracted interest from the materials science community and the development of synthetic strategies for the preparation of organic-inorganic hybrid materials with novel structures and special properties is of current interest. Sulfur-oxygen-metal linkages provide the possibility of using sulfate tetrahedra as building units to form new solid-state materials. A series of novel organically templated metal sulfates of 2-aminopyridinium (2ap) with aluminium(III), cobalt(II), magnesium(II), nickel(II) and zinc(II) were obtained from the respective aqueous solutions and studied by single-crystal X-ray diffraction. The compounds crystallize in centrosymmetric triclinic unit cells in three structure types: type 1 for 2-aminopyridinium hexaaquaaluminium(III) bis(sulfate) tetrahydrate, (C5H7N2)[Al(H2O)6](SO4)2·4H2O, (I); type 2 for bis(2-aminopyridinium) tris[hexaaquacobalt(II)] tetrakis(sulfate) dihydrate, (C5H7N2)2[Co(H2O)6]3(SO4)4·2H2O, (II), and bis(2-aminopyridinium) tris[hexaaquamagnesium(II)] tetrakis(sulfate) dihydrate, (C5H7N2)2[Mg(H2O)6]3(SO4)4·2H2O, (III); and type 3 for bis(2-aminopyridinium) hexaaquanickel(II) bis(sulfate), (C5H7N2)2[Ni(H2O)6](SO4)2, (IV), and bis(2-aminopyridinium) hexaaquazinc(II) bis(sulfate), (C5H7N2)2[Zn(H2O)6](SO4)2, (V). The templating role of the 2ap cation in all of the reported crystalline substances is governed by the formation of characteristic charge-assisted hydrogen-bonded pairs with sulfate anions and the presence of π-π interactions between the cations. Additionally, both coordinated and uncoordinated water molecules are involved in hydrogen-bond formation. As a consequence, extensive three-dimensional hydrogen-bonding patterns are formed in the reported crystal structures.
Metal-organic frameworks (MOFs) are a new class of porous materials that have received widespread attention due to their potential applications in gas storage and/or separation, catalysis, luminescence, and so on. The title compound, poly[[(μ2-3,3'-dimethyl-4,4'-bipyridine-κ(2)N:N')bis(μ4-4,4'-oxydibenzoato-κ(4)O:O':O'':O''')dizinc] tetrahydrate], {[Zn2(C14H8O5)2(C12H12N2)]·4H2O}n, has been prepared by the solvothermal assembly of Zn(NO3)2·6H2O, 4,4'-oxydi(benzoic acid) and 3,3'-dimethyl-4,4'-bipyridine. The two Zn(II) atoms adopt the same five-coordinated distorted square-pyramidal geometry (i.e. ZnO4N), bonding to four O atoms from four different 4,4'-oxydibenzoate (oba) ligands and one N atom from a 3,3'-dimethyl-4,4'-bipyridine (dmbpy) ligand. The supramolecular secondary building unit (SBU) is a paddle-wheel [Zn2(COO)4] unit and these units are linked by oba ligands within the layer to form a two-dimensional net parallel to the b axis, with the dmbpy ligands pointing alternately up and down, which is further extended by dmbpy ligands to form a three-dimensional framework with rob topology. The single net leaves voids that are filled by mutual interpenetration of an independent equivalent framework in a twofold interpenetrating architecture. The title compound shows thermal stability up to 673 K and is stable in aqueous solutions in the pH range 5-9. Excitation and luminescence data observed at room temperature show that it emits a bright-blue fluorescence.
Viral-encoded ATPase can act as a part of molecular motor in genome packaging of DNA viruses, such as vaccinia virus and adenovirus, by ATP hydrolysis and interaction with DNA. Poxviral ATPase (also called A32) is involved in genomic double-stranded DNA (dsDNA) encapsidation, and inhibition of the expression of A32 causes formation of immature virions lacking viral DNA. However, the role of A32 in goatpoxvirus genome packaging and its dsDNA binding property are not known. In this study, purified recombinant goatpoxvirus A32 protein (rA32) was examined for its dsDNA binding property as well as the effect of dsDNA on ATP hydrolysis. We found that rA32 could bind dsDNA, and its ATPase activity was significant increased with dsDNA binding. Effects of magnesium and calcium ions
 on ATP hydrolysis were investigated also. The ATPase activity was dramatically enhanced by dsDNA in the presence of Mg(2+); in contrast, ATPase function was not altered by Ca(2+). Furthermore, the enzyme activity of rA32 was completely blocked by Zn(2+). Regarding DNA-protein interaction, the rA32-ATP-Mg(2+) showed lower dsDNA binding affinity than that of rA32-ATP-Ca(2+). The DNA-protein binding was stronger in the presence of zinc ion. Our results implied that A32 may play a role in viral genome encapsidation and DNA condensation.
TiO2 has excellent electrochemical properties but limited solar photocatalytic performance in light of its large bandgap. One important class of visible-wavelength sensitizers of TiO2 is based on ZnFe2 O4 , which has shown fully a doubling in performance relative to pure TiO2 . Prior efforts on this important front have relied on presynthesized nanoparticles of ZnFe2 O4 adsorbed on a TiO2 support; however, these have not yet achieved the full potential of this system since they do not provide a consistently maximized area of the charge-separating heterointerface per volume of sensitizing absorber. A novel atomic layer deposition (ALD)-enhanced synthesis of sensitizing ZnFe2 O4 leaves grown on the trunks of TiO2 trees is reported. These new materials exhibit fully a threefold enhancement in photoelectrochemical performance in water splitting compared to pristine TiO2 under visible illumination. The new materials synthesis strategy relies first on the selective growth of FeOOH nanosheets, 2D structures that shoot off from the sides of the TiO2 trees; these templates are then converted to ZnFe2 O4 with the aid of a novel ALD step, a strategy that preserves morphology while adding the Zn cation to achieve enhanced optical absorption and optimize the heterointerface band alignment.
Most research on the effects of wildfires on stream water quality has focused on suspended sediment and nutrients in streams and water bodies, and relatively little research has examined the effects of wildfires on trace elements. The purpose of this study was two-fold: 1) to determine the effect of the 2009 Station Fire in the Angeles National Forest northeast of Los Angeles, CA on trace element concentrations in streams, and 2) compare trace elements in post-fire stormflow water quality to criteria for aquatic life to determine if trace elements reached concentrations that can harm aquatic life. Pre-storm and stormflow water-quality samples were collected in streams located inside and outside of the burn area of the Station Fire. Ash and burned soil samples were collected from several locations within the perimeter of the Station Fire. Filtered concentrations of Fe, Mn, and Hg and total concentrations of most trace elements in storm samples were elevated as a result of the Station Fire. In contrast, filtered concentrations of Cu, Pb, Ni, and Se and total concentrations of Cu were elevated primarily due to storms and not the Station Fire. Total concentrations of Se and Zn were elevated as a result of both storms and the Station Fire. Suspended sediment in stormflows following the Station Fire was an important transport mechanism for trace elements. Cu, Pb, and Zn primarily originate from ash in the suspended sediment. Fe primarily originates from burned soil in the suspended sediment. As, Mn, and Ni originate from both ash and burned soil. Filtered concentrations of trace elements in stormwater samples affected by the Station Fire did not reach levels that were greater than criteria established for aquatic life. Total concentrations for Fe, Pb, Ni, and Zn were detected at concentrations above criteria established for aquatic life.
This study was conducted to investigate the effects of oridonin (ORI) on growth performance and antioxidant capacity in broiler chickens that were repeatedly challenged with lipopolysaccharide (LPS). A total of 384 one-day-old male Arbor Acre broiler chickens were randomly assigned to 8 treatments with 6 replicate cages per treatment and 8 birds per replicate. There were 4 dietary treatments: the control group (birds fed the basal diet), the ORI 50 group, the ORI 80 group, and the ORI 100 group (the basal diet supplemented with 50, 80, and 100 mg/kg oridonin, respectively). Broilers were intraperitoneally injected with either 250 μg/kg BW LPS or an equivalent amount of sterile saline at 16, 18, and 20 d of age. LPS decreased the average daily weight gain (ADG), the average daily feed intake (ADFI), and the feed conversion ratio (FCR) of broiler chickens (P < 0.05); oridonin supplementation had no effects on performance whether before or after LPS injection (P > 0.05). LPS stimulation increased the relative weight of the spleen and bursa (P < 0.05); oridonin inclusion markedly attenuated the increased spleen index (P < 0.05). Additionally, the LPS-induced increases in the concentrations of malondialdehyde (MDA) and decreases in activities of total superoxide dismutase (T-SOD), total antioxidant capacity (T-AOC) and catalase (CAT) were dramatically attenuated by oridonin in both the serum and liver (P < 0.05). Furthermore, LPS down-regulated the mRNA expressions of nuclear factor erythroid 2-related factor 2 (Nrf2), copper and zinc superoxide dismutase (Cu/Zn-SOD), manganese superoxide dismutase (Mn-SOD), glutathione peroxidase (GPx1), and CAT in the liver (P < 0.05), However, oridonin inclusion increased the liver mRNA expression levels of Nrf2, Cu/Zn-SOD, Mn-SOD, CAT, and GPx1 (P < 0.05). It was concluded that the dietary oridonin supplementation at an optimum dose of 100 mg/kg improves the antioxidant capacity in broilers, as evidenced by the decrease in MDA and the increase in total SOD activities and mRNA expression levels of the liver antioxidant genes, although the effects on growth performance was negligible.
Using multiple interactions, a simple self-assembly based on a Zn(ii) coordination compound and squaraine () demonstrated a selective turn-on fluorescence response to ATP in the near infrared (NIR) region. More importantly, the self-assembly has been successfully applied to ATP imaging in the mitochondria of the gastric cancer cell line SGC-7901 and monitoring of level fluctuation of ATP during the mitotic period.
Concentrations of ten elements (Cd, Cr, Cu, Fe, Ni, Pb, Se, Sr, V and Zn) were determinate in muscle tissues of 13 fish species from Aratu Bay, Bahia, Brazil by inductively coupled plasma optical emission spectrometry. The accuracy and precision of our results were checked by using two certified reference materials: BCR-422 cod muscle and SRM 1566b oyster tissue. The average trace element concentrations in the fish species varied in the following ranges, in μg g-1: 0.03-0.8 for Cr; 2.0-33.7 for Cu, 2.4-135.1 for Fe, 1.6-25.6 for Se; 1.6-35.1 for Sr; and 2.8-40.5 for Zn. The Diaptereus rhombeus (carapeba) specie presented the highest concentrations of Se, Cu and Fe. Chromium and Se were present at levels above the limit of tolerance allowed by the National Agency of Sanitary Vigilance (ANVISA). The results were also evaluated using the multivariate analysis techniques: principal component analysis (PCA) and hierarchical cluster analysis (HCA).
This study aimed to determine Cu/Zn ratio, nutritional and inflammatory status in patients during the perioperative period for colorectal cancer.
The study included patients with histological diagnosis of colorectal adenocarcinoma (Cancer Group, n=46) and healthy volunteers (Control Group, n=28). We determined habitual food intake, body composition, laboratory data of nutritional status, serum calprotectin and plasma Cu and Zn concentrations. Mann-Whitney U-test was performed between-group comparisons and Spearman correlation test for correlations between the variables.
Individuals in the Cancer Group presented significantly lower BMI, fat mass, plasma hemoglobin, total protein and albumin as compared with the Control Group. Serum calprotectin[70.1 ng/mL (CI95% 55.8-84.5) vs.53.3 ng/mL (40.3-66.4), p=0.05], plasma Cu concentrations [120 µg/dL(CI95% 114-126) vs. 106 µg/dL(CI95% 98-114), p<0.01] and the Cu/Zn ratio [1.59 (CI95% 1.48-1.71)vs. 1.35 (CI95% 1.23-1.46), p=0.01]were higher in patients with colorectal cancer than in controls. Additionally, the Cancer Group showed negative correlations between the Cu/Zn ratio and Zn intake, hemoglobin, serum albumin, and positive correlation between the Cu/Zn ratio and serum calprotectin.
These results indicate that an increased plasma Cu/Zn ratio and serum calprotectin, and decreased protein values may be a result of the systemic inflammatory response to the tumor process.
The geographical distribution of concentration values for harmful elements was determined in the Campania region, Italy. The study area consists of the drainage basin of the River Calore, a tributary of the river Volturno, the largest Southern Italian river. The results provide reliable analytical data allowing a quantitative assessment of the trace element pollution threat to the ecosystem and human health. Altogether 562 stream sediment samples were collected at a sampling density of 1 site per 5 km(2). All samples were air-dried, sieved to <100 mesh fraction and analyzed for 37 elements after an aqua regia extraction by a combination of ICP-AES and ICP-MS. In addition to elemental analysis, gamma-ray spectrometry data were collected (a total of 562 measurements) using a hand-held Scintrex GRS-500 spectrometer. Statistical analyses were performed to show the single-element distribution and the distribution of elemental association factor scores resulting from R-mode factor analyses. Maps showing element distributions were made using GeoDAS and ArcGIS software. Our study showed that, despite evidence from concentrations of many elements for enrichment over natural background values, the spatial distribution of major
 and trace elements in Calore River basin is determined mostly by geogenic factors. The southwestern area of the basin highlighted an enrichment of many elements potentially harmful for human health and other living organisms (Al, Fe, K, Na, As, Cd, La, Pb, Th, Tl, U); however, these anomalies are due to the presence of pyroclastic and alkaline volcanic lithologies. Even where sedimentary lithologies occur, many harmful elements (Co, Cr, Mn, Ni) showed high concentration levels due to natural origins. Conversely, a strong heavy metal contamination (Pb, Zn, Cu, Sb, Ag, Au, Hg), due to an anthropogenic contribution, is highlighted in many areas characterized by the presence of road junctions, urban settlements and industrial areas. The enrichment factor of these elements is 3-4 times higher than the background values. The southwestern area of the basin is characterized by a moderate/high degree of contamination, just where the two busiest roads of the area run and the highest concentration of industries occurs.
An analysis method has been established to test 27 elements (Li, Be, B, Mg, Al, Sc, Ti, V, Cr, Mn, Fe, Co, Ni, Cu, Zn, Ga, As, Sr, Mo, Cd, Sn, Sb, Ba, La, Hg, Pb, Bi) in Maca nationality's medicine with microwave digestion-ICP-MS. Sample solutions were analyzed by ICP-MS after microwave digestion, and the contents of elements were calculated according to their calibration curves, and internal standard method was adopted to reduce matrix effect and other interference effects. The experimental results showed that the linear relations of all the elements were very good; the correlation coefficient (r) was 0.9994-1.0000 (Hg was 0.9982) ; the limits of detection were 0.003-2.662 microg x L(-1); the relative standard deviations for all elements of reproducibility were lower than 5% (except the individual elements); the recovery rate were 78.5%-123.7% with RSD lower than 5% ( except the individual elements). The analytical results of standard material showed acceptable agreement with the certified values. This method was applicable to determinate the contents of multi-elements in Maca which had a high sensitivity, good specificity and good repeatability, and provide basis for the quality control of Maca.
Histamine is an important neurotransmitter that exerts its physiological actions through H1-4 metabotropic receptors in mammals. It also directly activates ionotropic GABAA receptor (GABAAR) β3 homooligomers and potentiates GABA responses in αβ heterooligomers in vitro, but the respective histamine binding sites in GABAARs are unknown. We hypothesized that histamine binds at the extracellular β+β- interface at a position homologous to the GABA binding site of heterooligomeric GABAARs. To test this, we individually mutated several residues at the putative ligand binding minus side of a rat GABAAR β3 wild type subunit and of a β3 subunit that was made insensitive to trace Zn(2+) inhibition [β3(H267A); called (Z)β3]. (Z)β3, (Z)β3(Y62L), (Z)β3(Q64A), (Z)β3(Q64E), α1(Z)β3, or α1(Z)β3(Y62L) receptors were studied in HEK293T cells using whole cell voltage clamp recording. β3, β3(Y62C), β3(Q64C), β3(N41C), β3(D43C), β3(A45C) or β3(M115C) receptors were examined in Xenopus oocytes using two-electrode voltage clamp. Histamine directly activated (Z)β3 and β3 homooligomers and potentiated GABA actions in α1(Z)β3 heterooligomers. Receptors containing (Z)β3(Y62L), β3(Y62C) and β3(D43C) showed markedly reduced histamine potency, but homo- and heterooligomers with (Z)β3(Q64E) exhibited increased potency. The GABAAR αβ(γ) competitive antagonist bicuculline elicited sub-maximal agonist currents through (Z)β3 homooligomers, the potency of which was strongly decreased by (Z)β3(Y62L). Mutations β3(N41C), β3(A45C) and β3(M115C) disturbed receptor expression or assembly. Computational docking into the crystal structure of homooligomeric β3 receptors resulted in a histamine pose highly consistent with the experimental findings, suggesting that histamine activates β3 receptors via a site homologous to the GABA site in αβγ receptors.
A nitrogenase-inspired biomimetic chalcogel system comprising double-cubane [Mo2Fe6S8(SPh)3] and single-cubane (Fe4S4) biomimetic clusters demonstrates photocatalytic N2 fixation and conversion to NH3 in ambient temperature and pressure conditions. Replacing the Fe4S4 clusters in this system with other inert ions such as Sb(3+), Sn(4+), Zn(2+) also gave chalcogels that were photocatalytically active. Finally, molybdenum-free chalcogels containing only Fe4S4 clusters are also capable of accomplishing the N2 fixation reaction with even higher efficiency than their Mo2Fe6S8(SPh)3-containing counterparts. Our results suggest that redox-active iron-sulfide-containing materials can activate the N2 molecule upon visible light excitation, which can be reduced all of the way to NH3 using protons and sacrificial electrons in aqueous solution. Evidently, whereas the Mo2Fe6S8(SPh)3 is capable of N2 fixation, Mo itself is not necessary to carry out this process. The initial binding of N2 with chalcogels under illumination was observed with in situ diffuse-reflectance Fourier transform infrared spectroscopy (DRIFTS). (15)N2 isotope experiments confirm that the generated NH3 derives from N2 Density functional theory (DFT) electronic structure calculations suggest that the N2 binding is thermodynamically favorable only with the highly reduced active clusters. The results reported herein contribute to ongoing efforts of mimicking nitrogenase in fixing nitrogen and point to a promising path in developing catalysts for the reduction of N2 under ambient conditions.
The pollution of agricultural soils, waters and products in the regions of lignite mines and fired power plants is of great importance. The concentration of As, Βa, Co, Cr, Sr, Sc, Th, U, Zn in soils and waters in the vicinity of a lignite-fired power plant in Northern Greece was determined using Instrumental Neutron Activation Analysis. The determination frequency was every three months during a period of one year in order to evaluate the seasonal impact of the pollution to the environment. Measurements were performed in three locations around the lignite mine as well as in one reference location at a certain distance from the mine. The results, which exhibited a slight seasonal variation, were compared, where possible, with literature values from other countries. The obtained data in most of the cases did not exceed the normal levels and indicated that the investigated area was only slightly contaminated. The concentration of heavy and trace metals was also measured in three common garden crops (tomato, cucumber and parsley) grown in this area. The calculated transfer factors (TF) from soil to vegetables and health risk quotients (HQ) do not denote a health risk.
We report here the effect of micro-environmental changes from biodegradable magnesium alloys on the activities of cells - osteoblasts, osteoclasts and macrophages - which play critical roles in each phase of the bone-regeneration process. Despite positive bone formation effects from several in vivo studies, minimal progress has been made in identifying underlying mechanisms through in vitro studies, which are currently concentrated on osteoblastic activities. The observed in vitro and in vivo results indicated that alkaline pH and released magnesium and zinc ions derived from Mg-5 wt% Ca-1 wt% Zn alloy biodegradation promote the progress of bone formation. In contrast, alkaline pH and magnesium ions remarkably suppressed osteoclastic activities and pro-inflammatory cytokine production, closely related to osteolysis and prosthesis failure. Findings from the present study conclude that the degradation of Mg-5 wt% Ca-1 wt% Zn alloys can promote new bone formation by simultaneously affecting the complex combination of variable cellular activities and phases. Copyright © 2016 John Wiley & Sons, Ltd.
To provide a basis for controlling the quality of rhubarb under artificial cultivation, the present work was designed to evaluate the contents of 14 active pharmaceutical ingredients (API) of rhubarb in major rhubarb production areas in China and analyze the correlations between the contents of API and such factors as species, geographic distribution and soil. The levels of fourteen API in rhubarb were measured using HPLC. The geographic distributions were collected using GPS and the nutrients in the soil were measured using the methods in the literature. The results showed that the levels of major API vary significantly among plants of different locations according to variance analysis. The species factor has few obvious effect on the overall properties of the rhubarb by the cluster analysis because of the two source species occurring in all divided three groups. However, Rheum tanguticum Maxim.ex Balf. is less effective at synthesizing and accumulating 9 API out of 14 than Rheum palmatum L. The correlation analysis and regression analysis also indicated that a lower latitude should be considered in the accumulation of API and a lower longitude should be considered to produce more compound anthraquinones. Lower levels of total P, rapidly available P and available molybdenum (Mo) and higher available K and available Zn in the soil were significantly correlated to accumulation of API in rhubarb. These results provide a basis for the clinical application and controlling the levels of the major API of rhubarb during artificial cultivation.
The luminescent and mesomorphic properties of a series of metal complexes based on hexacatenar 2,2':6',2''-terpyridines are investigated using experimental methods and density functional theory (DFT). Two types of ligand are examined, namely 5,5''-di(3,4,5-trialkoxyphenyl)terpyridine with or without a fused cyclopentene ring on each pyridine and their complexes were prepared with the following
 transition metals: Zn(II) , Co(III) , Rh(III) , Ir(III) , Eu(III) and Dy(III) . The exact geometry of some of these complexes was determined by single X-ray diffraction. All complexes with long alkyl chains were found to be liquid crystalline, which property was induced on complexation. The liquid-crystalline behaviour of the complexes was studied by polarising optical microscopy and small-angle X-ray diffraction. Some of the transition metal complexes (for example, those with Zn(II) and Ir(III) ) are luminescent in solution, the solid state and the mesophase; their photophysical properties were studied both experimentally and using DFT methods (M06-2X and B3LYP).
The Virginia opossum (Didelphis virginiana) is widespread in the USA, ranging south through Latin America. The ecology of opossums is such that they are in frequent contact with soils, suggesting that they may function as a valuable bioindicator for chemical contamination in terrestrial environments. Surprisingly, there have been virtually no toxicology studies on opossums. Here, we provide the first analysis of metal contaminants in opossum liver tissues. Liver samples were obtained from 471 opossums, collected from 2003 to 2006, at four sites in North Florida and South Georgia, USA, and concentrations of copper, lead, nickel, selenium, and zinc were measured. We found little evidence of age differences in the concentration of any of the metals. However, there were at least some significant differences between years, males and females, and between sites for each metal, although the pattern of these differences was not always consistent across metals. Concentrations of metals in liver tissue were positively correlated with one another, primarily of each metal (except Pb) with zinc. Reference levels of metal contaminants are not available for opossums, but concentrations of Cu, Ni, Pb, and Zn in our samples were for the most part significantly higher than those reported from liver tissues of nine-banded armadillos (Dasypus novemcinctus) collected at the same sites and in the same years. Data from other small mammals studied elsewhere further indicate that metal concentrations in opossums were high, but at this time, it is not possible to determine if these elevated levels generated toxicity. The substantial temporal and spatial variation we found in metal concentrations suggests that determination of baseline levels for opossums may not be straightforward. Nonetheless, this is the first study quantifying metal accumulation in the livers of Didelphis virginiana and, as such, provides an important starting point for future research.
Endometriosis is a very common disease, affecting 10% of women in the reproductive age. To date, a significant delay between onset of the symptoms and definitive diagnosis is caused by the lack of a reliable non-invasive diagnostic test. Recently, the potential value as diagnostic markers for endometriosis of three proteins (Zn-alpha2-glycoprotein, serum albumin, and complement C3 precursor), has been showed. In this article, we have defined the experimental conditions for the development of a multiplex bead array assay for rapid and simultaneous quantification of these three biomarkers in the serum of patients with endometriosis. Finally, pivotal experiments on a small cohort of patients have confirmed the diagnostic value of this assay. J. Cell. Physiol. 231: 2622-2627, 2016. © 2016 Wiley Periodicals, Inc.
In our effort to develop coordination polymers (CPs)-based single-site catalysts for the selective synthesis of mono-oxazolines, two Zn-based CPs, [{Zn6 (idbt)4 (phen)4 } ⋅3 H2 O]n  (1) and [{Zn3 (idbt)2 (H2 O)4 }⋅2 H2 O]n  (2) (H3 idbt= 5,5'-(1H-imidazole-4,5-diyl)-bis-(2H-tetrazole), phen=1,10-phenanthroline) have been synthesized. They exhibit two-dimensional structure and contain isolated and accessible catalytically active sites, mimicking the site isolation of many catalytic enzymes. Micro CPs 1 and 2 are obtained by using surfactant-mediated hydrothermal methods, and an investigation is conducted to explore how different surfactants affect their morphologies and particle sizes. Furthermore, micro 1 and 2 have shown to be effective heterogeneous catalysts for the reaction of amino alcohols and aromatic dinitriles, and exerted a significant influence on the selectivity of the catalytic reactions, yielding mono-oxazolines as the major reaction product.
Sediment can be applied on land as a soil conditioner. However, toxic substances such as heavy metals within the sediment often lead to soil contamination if no proper management is conducted prior to land application. In order to reduce the bioavailable portion of heavy metals such as Pb, Cu, Zn and Cd, zeolite as a kind of stabilizer was investigated on the effect of metal stabilization in sediment. Zeolite was firstly modified and screened to get the best condition for removal of heavy metals. Results showed that the granulated zeolite with NaCl conditioning had the highest CEC and metal sorption. Using BCR sequential extraction, the selected modified zeolite effectively stabilized Pb, Cu, Zn and Cd in sediment to different extents. It was most suitable for Cd stabilization by reducing its acid exchangeable fraction while increasing the contents of the reducible and residual fractions. Modified zeolite also immobilized Cu, Zn and Pb in sediment by enhancing one stable fraction while decreasing the acid exchangeable fraction.
Amyotrophic lateral sclerosis (ALS) is a lethal neurodegenerative disease affecting both upper and lower motor neurons, and currently, there is no cure or effective treatment. Mutations in a gene encoding a ubiquitous antioxidant enzyme, Cu,Zn-superoxide dismutase (SOD1), have been first identified as a cause of familial forms of ALS. It is widely accepted that mutant SOD1 proteins cause the disease through a gain in toxicity but not through a loss of its physiological function. SOD1 is a major copper-binding protein and regulates copper homeostasis in the cell; therefore, a toxicity of mutant SOD1 could arise from the disruption of copper homeostasis. In this review, we will briefly review recent studies implying roles of copper homeostasis in the pathogenesis of SOD1-ALS and highlight the therapeutic interventions focusing on pharmacological as well as genetic regulations of copper homeostasis to modify the pathological process in SOD1-ALS.
Biosolids (sewage sludge) can be beneficially applied to degraded lands to improve soil quality. Plants grown on biosolids-amended soils have distinct concentrations of macronutrients and trace elements, which can be beneficial or present a risk to humans and ecosystems. Potentially, biosolids could be blended with other biowastes, such as sawdust, to reduce the risks posed by rebuilding soils using biosolids alone. We sought to determine the effect of mixing biosolids and sawdust on the macronutrient and trace element concentration of ryegrass over a 5-mo period. was grown in a low fertility soil, typical for marginal farm areas, that was amended with biosolids (1250 kg N ha), biosolids + sawdust (0.5:1) and urea (200 kg N ha), as well as a control. Biosolids increased the growth of from 2.93 to 4.14 t ha. This increase was offset by blending the biosolids with sawdust (3.00 t ha). Urea application increased growth to 4.93 t ha. The biowaste treatments increased N, P, Cu, Mn, and Zn relative to the control, which may be beneficial for grazing animals. Although biowaste application caused elevated Cd concentrations (0.15-0.24 mg kg) five- to eightfold higher than control and urea treatments, these were below levels that are likely to result in unacceptable concentrations in animal tissues. Mixing biosolids with sawdust reduced Cd uptake while still resulting in increased micronutrient concentrations (P, S, Mn, Zn, Cu) in plants. There were significant changes in the elemental uptake during the experiment, which was attributed to the decomposition of the sawdust.
Heavy metals in exposed mine tailings threaten ecosystems that surround thousands of abandoned mines in the United States. Biochars derived from the pyrolysis or gasification of biomass may serve as a valuable soil amendment to revegetate mine sites. We evaluated the ability of two biochars, produced by gasification of either Kentucky bluegrass seed screenings (KB) or mixed conifer wood (CW), to support the growth of plants in mine spoils from the abandoned Formosa and Almeda Mines in Oregon. To evaluate the potential for plant establishment in mine tailings, wheat was grown in tailings amended with biochar at rates ranging from 0 to 9% (w/w). Both KB and CW biochars promoted plant establishment by increasing soil pH, increasing concentrations of macro- and micronutrients, and decreasing the solubility and plant uptake of heavy metals. Formosa tailings required at least 4% biochar and Almeda soil required at least 2% biochar to promote healthy wheat growth. A complimentary experiment in which mine spoils were leached with simulated precipitation indicated that biochar amendment rates ≥4% were sufficient to neutralize the elution pH and reduce concentrations of potentially toxic elements (Zn, Cu, Ni, Al) to levels near or below concern. These findings support the use of gasified biochar amendments to revegetate acid mine soils.
The contamination of urban soil with sodium (Na) and trace metals can be one of the major concerns for groundwater contamination and street tree health. The bioavailability of Na, copper (Cu), zinc (Zn), cadmium (Cd), and lead (Pb) in urban soil amended with 0, 5, and 10% w/w compost was evaluated at none, medium, and high contamination levels of soil mixtures. The relationship between soil properties, compost addition, contamination level and metal uptake by barley ( L.) was determined using multivariate linear regression and
 path analysis. The results indicated the direct negative effect of compost on metal absorption possibly through specific complexation for Cu, Zn, Cd, and Pb. Compost can also affect the absorption of Na and Cd indirectly by means of cation exchange capacity (CEC) and pH. The degree of soil contamination with metals can affect the competition of cations for the complexing sites of the soil mixtures and, therefore, can induce changes in metal availability for plants. Compost addition to the soil also increased nutrient availability, except for ammonium (NH) and nitrate (NO). We concluded that in the short term, the addition of compost significantly reduced metal bioavailability and improved nutrient availability. However, more studies are required to monitor the long-term ability of the compost to reduce Na and trace metal bioavailability in urban soil.
The mobility and bioavailability of nitro explosives (2,4-dinitrotoluene [DNT], 2,4,6-trinitrotoluene [TNT], and hexahydro-1,3,5-trinitro-1,3,5-triazine [RDX]) in biochar-amended soils and toxic metals (As, Cd, Cu, Pb, and Zn) in biochar-amended mine tailings were investigated via various types of leaching procedures in laboratory-scale batch experiments. The results from the toxicity characteristic leaching procedure (TCLP) and hydroxypropyl-β-cyclodextrin (HPCD) extraction showed that approximately 55 to 95% of the explosives were released from the contaminated soils and would thus be considered as mobile. With the addition of biochar, the extracted concentrations of explosives were reduced to less than 10% of the initial concentrations after 10 d. According to the results from a Korean waste leaching method, the TCLP method, and diethylenetriaminepentaacetic acid (DTPA) extraction, adding biochar to mine tailings reduced the extractability and bioavailability of metals. The chemical forms of the metals, types of extractants, pH, and curing period strongly affected the extractability of metals from mine tailings. The results suggest that biochar is a promising immobilizer of explosives and metals in contaminated soils and mine tailings under limited conditions.
Phytoextraction has the potential to remove heavy metals from contaminated soil, and chelants can be used to improve the capabilities of phytoextraction. However, environmentally persistent chelants can cause metal leaching and groundwater pollution. A column experiment was conducted to evaluate the viability of biodegradable nitrilotriacetic acid (NTA) to increase the uptake of heavy metals (Cd, Cr, Ni, Pb, Cu, and Zn) by L. in municipal solid waste (MSW) compost and to evaluate the effect of two permeable barrier materials, bone meal and crab shell, on metal leaching. The application of NTA significantly increased the concentrations and uptake of heavy metals in . The enhancement was more pronounced at higher dosages of NTA. In the 15 mmol kg NTA treatment using a crab shell barrier, the Cr and Ni concentrations in the plant shoots increased by approximately 8- and 10-fold, respectively, relative to the control. However, the addition of NTA also caused significant heavy metal leaching from the MSW compost. Bone meal and crab shell barriers positioned between the compost and the subsoil were effective in preventing metal leaching down through the soil profile by the retention of metals in the barrier. The application of a biodegradable chelant and the use of permeable barriers is a viable form of enhanced phytoextraction to increase the removal of metals and to reduce possible leaching.
Prolonged feeding of sericea lespedeza (SL) previously led to reduced serum concentrations of Mo, a cofactor in an enzyme complex that may be involved in weight gain. The current objective was to determine the effect of Mo supplementation on changes in serum, fecal, urine, and liver concentrations of trace minerals in lambs fed SL leaf meal pellets. Thirty ram lambs weaned in May (84 ± 1.5 d of age and 27 ± 1.1 kg; D 0) were blocked by BW, breed type (full or three-fourths Katahdin), and EBV of parasite resistance and randomly assigned to be fed 900 g/d of an alfalfa-based supplement (CON; = 10) or a SL-based supplement ( = 20) for 103 d. Supplements were formulated to be isonitrogenous and isocaloric and to meet trace mineral requirements. Within the SL group, individual lambs were administered either 5 mL water or 5 mL of water with 163.3 mg of sodium molybdate (SLMO). Serum was collected on d 28, 56, and 104; a liver sample was collected by biopsy on d 104 to determine concentrations of trace minerals. Data were analyzed using a mixed model and orthogonal contrasts. Serum concentrations of Mo increased in response to the drench and were greatest in SLMO lambs and then CON lambs and lowest in SL lambs ( < 0.001). Concentrations of Mo in the liver ( < 0.001) were similar between CON and SLMO lambs and were lower in SL lambs than other groups. Serum ( < 0.001) and liver ( = 0.013) concentrations of zinc (Zn) were reduced in both SL and SLMO lambs compared with CON lambs. Serum concentrations of cobalt (Co) increased in CON lambs compared with SL and SLMO lambs between d 0 and 56 but were similar on d 104 (diet × day, < 0.005) as with concentrations in the liver. Serum and liver concentrations of copper (Cu) were greatest ( < 0.001 and < 0.001, respectively) in CON lambs followed by SL lambs and then SLMO lambs. Serum concentrations of selenium (Se) tended ( = 0.10) to be reduced in SL lambs compared with CON and SLMO lambs, but concentrations in the liver were reduced in SL lambs compared with CON lambs and even more so in SLMO lambs ( < 0.003). Although the dietary Mo did increase stores of Mo in the animal and reduced copper, trace minerals associated with metalloproteins-Mo, copper, selenium, and zinc-were reduced in the liver of SL- and/or SLMO-fed lambs. These reductions could be associated with the lower weight gains previously observed after prolonged feeding of SL.
The catalytic activity of an artificial phosphodiesterase that combines a ligated metal ion (Cu(II), Zn(II)) with a guanidinium unit connected by a 1,2-vicinal calix[4]arene spacer was investigated in the transesterification of RNA models HPNP and four diribonucleoside 3',5'-monophosphates. Comparison with previous data related to the 1,3-distal regioisomeric metal complexes confirms the superiority of the Cu(II) complexes over the Zn(II) analogs and shows that in the reactions of HPNP, GpU, and UpU, the catalytic efficiency depends very little on whether the substitution pattern is 1,2-vicinal or 1,3-distal. On the other hand, CpA turned out to be a good substrate for the Cu(II) complex of the 1,2-vicinal catalyst and a bad substrate for the corresponding 1,3-distal regioisomer, whereas the opposite holds for GpA. Extension of the investigation to the cleavage of the DNA model BNPP showed that both Zn(II) and Cu(II) complexes exhibit good catalytic efficiency, with a superiority of the 1,2-vicinal catalyst in both cases. The data reported in this work show that rate accelerations over background for the best catalyst-substrate combinations at 0.5 mM catalyst concentration are 3.6 × 10(5)-fold for HPNP, 1.1 × 10(6)-fold for BNPP, and range from 1.3 × 10(6)- to 1.3 × 10(7)-fold for diribonucleoside monophosphates.
The xero-halophyte Atriplex halimus L., recently described as Cd-hyperaccumulator, was examined to determine Cd toxicity threshold and the physiological mechanisms involved in Cd tolerance. An experiment was conducted to investigate the effect of cadmium from 0 to 1350 μM on chlorophyll fluorescence parameters, gas exchange, photosynthetic pigment concentrations and antioxidative enzyme activities of A. halimus. Cadmium, calcium, iron, manganese, magnesium, potassium, phosphorous, sodium and zinc concentrations were also analyzed. Plants of A. halimus were not able to survive at 1350 μM Cd and the upper tolerance limit was recorded at 650 μM Cd; although chlorosis was observed from 200 μM Cd. Cadmium accumulation increased with increase in Cd supply, reaching maxima of 0.77 and 4.65 mg g(-1) dry weight in shoots and roots, respectively, at 650 μM Cd. Dry mass, shoot length, specific leaf area, relative growth rate, net photosynthetic rate, stomatal conductance, pigments contents and chlorophyll fluorescence were significantly reduced by increasing Cd concentration. However, the activities of superoxide dismutase (SOD; EC1.15.1.1), catalase (CAT; EC1.11.1.6) and guaiacol peroxidase (GPx; EC1.11.1.7) were significantly induced by Cd. Exposures to Cd caused also a significant decrease in P contents in roots, Mg and Mn contents in shoots and Fe and K contents in roots and shoots and had no effect on Ca, Na and Zn contents. The tolerance of A. halimus to Cd stress might be related with its capacity to avoid the translocation of great amounts of Cd in its aboveground tissues and higher activities of enzymatic antioxidants in the leaf.
Iron (Fe) and zinc (Zn) are important micronutrients for plant growth and development. Zinc-regulated transporters and the iron-regulated transporter-like protein (ZIP) are necessary for the homeostatic regulation of these metal micronutrients. In this study, the physiological function of ZmZIP7 which encodes a ZIP family transporter was characterized. We detected the expression profiles of ZmZIP7 in maize, and found that the accumulation of ZmZIP7 in root, stem, leaf, and seed was relatively higher than tassel and young ear. ZmZIP7 overexpression transgenic Arabidopsis lines were generated and the metal contents in transgenic and wild-type (WT) plants were examined using inductively coupled plasma atomic emission spectroscopy (ICP-OES) and Zinpyr-1 staining. Fe and Zn concentrations were elevated in the roots and shoots of ZmZIP7-overexpressing plants, while only Fe content was elevated in the seeds. We also analyzed the
 expression profiles of endogenous genes associated with metal homeostasis. Both endogenic Fe-deficiency inducible genes and the genes responsible for Zn and Fe transport and storage were stimulated in ZmZIP7 transgenic plants. In conclusion, ZmZIP7 encodes a functional Zn and Fe transporter, and ectopic overexpression of ZmZIP7 in Arabidopsis stimulate endogenous Fe and Zn uptake mechanisms, thereby facilitating both metal uptake and homeostasis. Our results contribute to improved understanding of ZIP family transporter functions and suggest that ZmZIP7 could be used to enhance Fe levels in grains.
3,4-dihydro-2H-1,2,4,3-triazaborol-3-yl-lithium 3 was synthesized and fully characterized. The (11)B NMR spectrum, X-ray diffraction analysis, and computational studies revealed the ionic nature of the B-Li bond, and indeed 3 displays nucleophilic property which allowed preparation of a series of 1,2,4,3-triazaborol-3-yl-metal complexes (Al; 5, Au; 6, Zn; 7, Mg; 8, Sb; 9, and Bi; 10). 3 reacted with CO (1 atm) and various isonitriles under ambient condition, and mechanistic study suggests that the reactions with CO and aryl isonitriles proceed via an insertion of CO and isonitrile carbon into the B-Li bond followed by isomerization to yield transient carbene species, one of which was confirmed by trapping with S8. With PhNC, compounds 5 and 7·(thf) underwent exchange of THF molecule coordinating to the metal center with isonitrile, whereas insertion of isonitrile carbon occurred at the B-Bi bond in 10 which afforded stable bismuth (boryl)iminomethane 20.
Zinc oxide (ZnO)-coated zeolite adsorbents were developed by both nitric acid modification and Zn(NO3)2·6H2O functionalization of zeolite 4A. The developed adsorbents were used for the removal of humic acid (HA) from aqueous solutions. The synthesized materials were characterized by porosimetry analysis, scanning electron microscopy, X-Ray diffraction analysis, and high resolution transmission electron microscopy. The maximum adsorption capacity of the adsorbents at 21±1°C was about 60mgCg(-1). The results showed that the positive charge density of ZnO-coated zeolite adsorbents was proportional to the amount of ZnO coated on zeolite and thus, ZnO-coated zeolite adsorbents exhibited a greater affinity for negatively charged ions. Furthermore, the adsorption capacity of ZnO-coated zeolite adsorbents increased markedly after acid modification. Adsorption experiments demonstrated ZnO-coated zeolite adsorbents possessed high adsorption capacity to remove HA from aqueous solutions mainly due to strong electrostatic interactions between negative functional groups of HA and the positive charges of ZnO-coated zeolite adsorbents.
Cu-deficient graded-zinc Cu-In-Zn-S (CIZS) quantum dots (QDs) were synthesized by a two-step solvothermal method. These CIZS QDs exhibited size and composition tunable photoluminescence characteristics with emission color tunable from greenish-yellow to orange to red with a relatively high quantum yield between 45 and 60%. Novel white-light-emitting (WLE) hybrid composite is fabricated by integrating the blue-emissive 1,4-bis-2-(5-phenyl oxazolyl)-benzene (POPOP) organic fluorophore and quaternary CIZS inorganic QDs. Integrating CIZS QDs with POPOP fluorophore resulted in series of tunable emission colors with CIE coordinates lying in a straight line between the coordinates of the end member. WLE was shown for hybrid mixture comprising 0.5 nM of POPOP and 3 mg/mL of CIZS QDs with color coordinates (0.3312, 0.3324). Thin films of this hybrid mixture in PMMA matrix coated on UV-LED or on glass substrates with UV backlit light also showed broadband WLE with ideal CIE color coordinates of (0.34, 0.33), high color-rendering index value of 92, and correlated color temperature value of 5143 K. The hybrid composite exhibit Forster resonance energy transfer cascading from POPOP to CIZS which results in emission covering the entire visible spectral range. POPOP and CIZS QDs hybrid composite is a versatile material for WLED applications.
Sulfated glycosaminoglycans (SGNL) were extracted for the first time from Norway lobster (Nephrops norvegicus) shell. The monosaccharide composition analysed by GC/MS revealed the presence of galacturonic acid, glucuronic acid, N-acetylgalactosamine and N-acetylglucosamine. The analysis of SGNL with acetate cellulose electrophoresis in Zn-acetate revealed the presence of heparan sulfate (HS) and dermatan sulfate (DS). SGNL were evaluated for their anticoagulant activities using activated partial thromboplastin time (aPTT), thrombin time (TT) and prothrombine time (PT) tests. After 21h incubation, HCT116 cell proliferation was inhibited (p<0.05) between 39.7 and 54.8% at 1.5-7.5mg/mL of SGNL. SGNL don't show hemolytic activity towards bovine erythrocytes and no cytotoxicity against the normal lymphocytes. The antiproliferative efficacy of these lobster glycosaminoglycans were probably related with the higher sulfate content. SGNL demonstrated promising antiproliferative and anticoagulant potential, which may be used as a novel, effective and promising antithrombotic agent.
We report a highly selective method for identification and detection of iron (III) (ferric iron, Fe(3+)) using Nile red (NR) as a complexing agent. Fe(3+) preferentially binds with NR in dimethylformamide (DMF)/water (1:1) solution over other cations such as Fe(2+), Cu(2+), Pb(2+), Hg(2+), Mn(2+), Ni(2+), Zn(2+), Co(2+) and Cd(2+) at room temperature. In the presence of Fe(3+), the color of NR solution changes from purple to dark brown, which is detectable with bare eyes. Using UV-vis spectroscopy, we could measure the amount of Fe(3+) in the sample solution by monitoring changes in absorption from 540 to 580nm; the linear range and the limit of detection are 30-1000µM and 24.9µM, respectively. Taking advantage of the NR selectivity, we treated partially oxidized graphene sheets (po-Gr) with NR to obtain po-Gr-NR dispersion by ultrasonication. The NR-treated po-Gr flakes (po-Gr-NR) were characterized by UV-vis, FT-IR, and Raman spectroscopies and FE-SEM, which indicated attachment of NR on po-Gr sheets. The po-Gr-NR hybrid film deposited glassy carbon electrode (po-Gr-NR/GCE) served as the Fe(3+) sensor. Differential pulse voltammetry was used to investigate the detection of Fe(3+) in 0.05M HCl+0.05M KCl solution. The linear range and the limit of detection of Fe(3+) were from 37.5nM to 21.53µM and 18.7nM, respectively. Furthermore, this sensor was successfully used to measure Fe(3+) content in red wine samples.
This study was focused on the assessment of single and sequential extraction methods to predict the bioavailability of metals in the vineyard soil-grapevine system. The modified BCR sequential extraction method and two single-step extraction methods based on the use of EDTA and acetic acid were applied to differently amended vineyard soils. The variety effect was studied on the uptake of metals by leaves and grapes. Most of the elements studied (Ca, Mg, Cu, Fe, Mn, Zn and Pb) were weakly mobilized from vineyard soils, with the exception of Cu and Mn. The determination of total metal content in leaves and grapes showed a different accumulation pattern in the two parts of the vine. A significant relationship was observed, for all the elements studied except for Fe, between the content bioavailable in the soil and the accumulated in both leaves and grapes (R=0.602-0.775, p<0.01).
In this work, a sensitive electrochemical aptasensor was designed for lipopolysaccharide (LPS) detection based on Ce-based metal-organic frameworks (Ce-MOFs) and Zn(2+) dependent DNAzyme-assisted recycling as dual signal amplifiers. Herein, Ce-MOFs were decorated with gold nanoparticles (AuNPs) to obtain AuNPs/Ce-MOFs, and the resultant AuNPs/Ce-MOFs not only acted as nanocarriers to capture -SH terminated hairpin probes 2 (HP2) for acquiring HP2/AuNPs/Ce-MOFs signal probes, but also as catalysts to catalyze the oxidation of ascorbic acid (AA). In the presence of target LPS, report DNA was released from the prepared duplex DNA and then hybridized with hairpin probes 1 (HP1, which were immobilized on the electrode). With the help of Zn(2+), report DNA could act as Zn(2+) dependent DNAzyme to cleave HP1 circularly. Then a large amount of capture probes were produced on the electrode to combine with HP2/AuNPs/Ce-MOFs signal probes. When the detection solution contained electrochemical substrate of AA, AuNPs/Ce-MOFs could oxide AA to obtain enhanced signal. Under the optimized conditions, this proposed aptasensor for LPS exhibited a low detection limit of 3.3 fg/mL with a wide linear range from 10fg/mL to 100ng/mL.
Yellow perch (Perca flavescens) collected from 11 lakes in the Canadian mining regions of Sudbury (Ontario) and Rouyn-Noranda (Quebec) display wide ranges in the concentrations of cadmium (Cd), nickel (Ni), selenium (Se), and thallium (Tl) in their livers. To determine if these trace elements, as well as copper (Cu) and zinc (Zn), are causing oxidative stress in these fish, we measured three biochemical indicators (glutathione (GSH), glutathione disulfide (GSSG) and thiobarbituric acid-reactive substances (TBARS)) in their livers. We observed that 44% of the yellow perch that we collected were at risk of cellular oxidative stress and lipid peroxidation. Considering all fish from all lakes, higher liver Se concentrations were coincident with both lower proportions of GSSG compared to GSH and lower concentrations of TBARS, suggesting that the essential trace-element Se acts as an antioxidant. Furthermore, fish suffering oxidative stress had higher proportions of Cd, Cu and Zn in potentially sensitive subcellular fractions (organelles and heat-denatured proteins) than did fish not suffering from stress. This result suggests that reactive oxygen species may oxidize metal-binding
 proteins and thereby reduce the capacity of fish to safely bind trace metals. High Cd concentrations in metal-sensitive subcellular fractions likely further exacerbate the negative effects of lower Se exposure.
Pb tolerant mechanisms, plant physiological response and Pb sub-cellular localization in the root cells of Iris halophila were studied in sand culture and the Pb mine tailings. Results showed that the activities of superoxide dismutase (SOD) and peroxidase (POD) in the underground parts and the activity of catalase (CAT) in the aboveground and underground parts increased as Pb level was enhanced. Glutathione (GSH) and ascorbic acid (AsA) contents increased by Pb treatments. Pb deposits were found in the middle cell walls or along the inner side of epibiotic protoplasm of some cells which accumulated a large quantity of Pb and died. The dry weights (DWs) of aboveground parts under all Pb tailings treatments decreased insignificantly, while the DW of the underground parts growing in the pure Pb tailings decreased significantly. Pb, Cu, Cd, and Zn contents increased significantly as the levels of Pb tailings were enhanced and Pb contents in the aboveground and underground parts reached 64.75 and 751.75 μg/g DW, respectively, at pure Pb tailings treatment. The results indicated that I. halophila is a promising plant in the phytoremediation of Pb contaminated environment. Some antioxidant enzymes, antioxidants and compartmentalization of Pb were played major roles in Pb tolerance of I. halophila.
Heavy metal (HM) contamination in sediments of Three Gorges Reservoir (TGR) is a particularly important issue for the safety of water quality due to the potential threats of metal toxicity to local and downstream human health. Surface sediments from riparian and submerged areas in the entire TGR mainstream were collected in 2014 to investigate the spatial distribution of HMs (Cd, Cu, Pb, and Zn), identify their possible sources, and assess their potential risk by multiple indices and metal fraction. Results showed that the concentrations of HMs in the sediments increased after the TGR operation, but were lower than those in other Chinese rivers of developed areas. The acid-soluble Cd accounted for more than 50% of total Cd in the sediments, whereas that of other HMs was very low. The Cd concentrations in the riparian sediments increased towards the dam; however, other metals in the riparian sediments and all HMs in the submerged sediments did not show any regular variation trend spatially. The stocks of HMs were significantly higher in the submerged sediments than in the riparian sediments. The high accumulation of HMs in the riparian sediments emerged between Fuling and Fengjie, and those in the submerged sediments existed in the near dam areas. Grain size and Fe/Mn oxides controlled the mobility and transfer of HMs in the sediments. Human activity in the catchment including industrial and agricultural production, shipping industry, mining, etc., increased inputs of HMs in the sediments, and altered their spatial distribution patterns. The sediments were moderately to highly contaminated by Cd, and slightly contaminated by other HMs. The results indicate the current priority of Cd contamination in the TGR, and will conduce to ecological protection in the TGR region.
His-Asn-His (HNH) proteins are a very common family of small nucleic acid-binding proteins that are generally associated with endonuclease activity and are found in all kingdoms of life. Although HNH endonucleases from mesophiles have been widely investigated, the biochemical functions of HNH endonucleases from thermophilic bacteriophages remain unknown. Here, we characterized the biochemical properties of a thermostable HNH endonuclease from deep-sea thermophilic bacteriophage GVE2. The recombinant GVE2 HNH endonuclease exhibited non-specific cleavage activity at high temperature. The optimal temperature of the GVE2 HNH endonuclease for cleaving DNA was 60-65 °C, and the enzyme retained its DNA cleavage activity even after heating at 100 °C for 30 min, suggesting the enzyme is a thermostable endonuclease. The GVE2 HNH endonuclease cleaved DNA over a wide pH spectrum, ranging from 5.5 to 9.0, and the optimal pH for the enzyme activity was 8.0-9.0. Furthermore, the GVE2 HNH endonuclease activity was dependent on a divalent metal ion. While the enzyme is inactive in the presence of Cu(2+), the GVE2 HNH endonuclease displayed cleavage activity of varied efficiency with Mn(2+), Mg(2+), Ca(2+), Fe(2+), Co(2+), Zn(2+), and Ni(2+). The GVE2 HNH endonuclease activity was inhibited by NaCl. This study provides the basis for determining the role of this endonuclease in life cycle of the bacteriophage GVE2 and suggests the potential application of the enzyme in molecular biology and biotechnology.
This study aims to develop novel ammonium and phosphonium ionic liquids (ILs) with thiosalicylate (TS) derivatives as anions and evaluate their extracting efficiencies towards heavy metals in aqueous solutions. Six ILs were synthesized, characterized, and investigated for their extracting efficacies for cadmium, copper, and zinc. Liquid-liquid extractions of Cu, Zn, or Cd with ILs after 1-24h using model solutions (pH 7; 0.1M CaCl2) were assessed using flame atomic absorption spectroscopy (F-AAS). Phosphonium-based ILs trihexyltetradecylphosphonium 2-(propylthio)benzoate [P66614][PTB] and 2-(benzylthio)benzoate [P66614][BTB] showed best extraction efficiency for copper and cadmium, respectively and zinc was extracted to a high degree by [P66614][BTB] exclusively.
The role of soluble zinc has been determined in Daphnia magna by a morphological approach, integrating a previous paper in which the ultrastructural damages to gut epithelial cells have been studied after ZnO nanoparticles exposure. In the present paper, the toxicity and morphological effects of soluble zinc from ZnSO4 have been determined in a 48-h acute exposure test. Daphnids have been exposed to six nominal zinc concentrations (0.075, 0.15, 0.3, 0.6, 1.2, and 2.4mg Zn/L) and then fixed for microscopic analyses. Data from the acute toxicity tests gave an EC50 value of 0.99mg/L and showed that no immobilization appeared up to 0.3mg Zn/L. Ultrastructural analyses of samples from the two highest concentrations showed large vacuolar structures, swelling of mitochondria, multilamellar bodies, and a great number of autophagy vacuoles. These findings have been compared to those from our previous study, and similarities and/or differences discussed. Based on the overall results it can be concluded that dissolved zinc ions played a key role in ZnO nanoparticle toxicity and that the morphological approach is an extremely useful tool for comparing toxicological effects as well. A possible common toxic mechanism of soluble zinc and ZnO nanoparticles was also proposed.
This research aims at identifying the main deleterious effects of Cr(VI) on the photosynthetic apparatus and at selecting the most sensitive endpoints related to photosynthesis. To achieve this goal, we used lettuce (Lactuca sativa), a sensible ecotoxicological crop model. Three-week-old plants were exposed to 0, 50, 150 and 200 mg L(-1) of Cr(VI). These concentrations ranged from levels admitted in irrigation waters to values found in several Cr industry effluents and heavily contaminated environments. After 30 days of exposure, plants accumulated Cr preferably in roots and showed nutritional impairment, with decreases of K, Mg, Fe and Zn in both roots and leaves. Cr(VI)-exposed plants showed decreased levels of chlorophyll (Chl) a and anthocyanins, as well as decreased effective quantum yield of photostystem II (ΦPSII) and photochemical Chl fluorescence quenching (qp), but increases in the non-photochemical Chl fluorescence quenching (NPQ) and in the de-epoxidation state (DEP) of the xanthophyll cycle. Net CO2 assimilation rate (P N ) and RuBisCO activity were mostly impaired in the highest Cr(VI) concentration tested. Concerning the final products of photosynthesis, starch content was not affected, while soluble sugar contents increased. These alterations were accompanied by a reduction in protein content and in plant growth. Our results support that endpoints related to the photosynthesis photochemical processes (ΦPSII and the qp) and the content of anthocyanins are sensitive predictors of Cr(VI) toxicity. The advantages of using these parameters as biomarkers for Cr toxicity in plants are discussed. Finally, we report that, despite showing physiological disorders, L. sativa plants survived and accumulated high doses of Cr, and their use in environmental/decontamination studies is open to debate.
Pyridoxal-2-hydrazinopyridine Schiff-base (1) was prepared by one-step synthesis from commercially available materials of pyridoxal and 2-hydrazinopyridine. Compound 1 could be applied as a fluorescent chemosensor for Zn(II) in aqueous solution at pH 7.4. After binding to Zn(II) with a molar ratio of 1:1, 1 exhibited 17-fold fluorescence enhancement. In addition, 1 showed a good selectivity toward Zn(II) over other metal ions, which can especially distinguish Zn(II) from Cd(II). A linear range of 5.0-20.0μmolL(-1) and a detection limit of 70nmolL(-1) were also achieved. Moreover, the utility of chemosensor 1 in bioimaging of Zn(II) in living cells was demonstrated, which suggested that 1 could be used as a Zn(II)-selective chemosensor in biological samples.
The mechanism of matrix metalloproteinase-8 (MMP-8) inhibition was investigated using ellipsometric measurements of the interaction of MMP-8 with a surface bound peptide inhibitor, tether-metal abstraction peptide (MAP), bound to self-assembled monolayer films. MMP-8 is a collagenase whose activity and dysregulation have been implicated in a number of disease states, including cancer metastasis, diabetic neuropathy,
 and degradation of biomedical reconstructions, including dental restorations. Regulation of activity of MMP-8 and other matrix metalloproteinases is thus a significant, but challenging, therapeutic target. Strong inhibition of MMP-8 activity has recently been achieved via the small metal binding peptide tether-MAP. Here, the authors elucidate the mechanism of this inhibition and demonstrate that it occurs through the direct interaction of the MAP Tag and the Zn(2+) binding site in the MMP-8 active site. This enhanced understanding of the mechanism of inhibition will allow the design of more potent inhibitors as well as assays important for monitoring critical MMP levels in disease states.
Metal-organic frameworks (MOFs) are attractive stationary phases in the field of separation sciences for their unique properties such as large specific surface areas, high porosity, and diverse structures. However, there are few MOFs, which have ultrahigh porosities and gas uptake capacities. In this work, MOF-180 with exceptional porosity, a cage size of 15 × 23 Å, was grown on inner wall of capillary as a novel stationary phase for open-tubular CEC. It has been demonstrated that the MOF-180-modified capillary column exhibited good performance for separation of acidic, basic, and neutral analytes. As compared with MOF-199-modified column, MOF-180-modified column exhibited specific recognition and size selectivity to the tested compounds. The characteristics observed by SEM and FTIR indicated that MOF-180 was successfully grafted on the inner wall of the capillary. The precisions (RSDs) of retention time, peak area, and W1/2 for methylbenzene, ethylbenzene, n-propylbenzene, chlorobenzene, o-dichlorobenzene, and 1,2,4-trichlorobenzene were 0.50-0.54%, 3.31-4.13%, 0.35-1.61%, 1.73-4.22%, 2.67-4.37%, and 1.60-3.38%, respectively. Besides, the run-to-run, day-to-day, and column-to-column RSDs of EOF were 0.6%, 4.19%, and 4.31%, respectively.
Bacitracin is a mixture of nonribosomal peptides (NRPs) that is extensively used as an antibiotic in both human and veterinary medicine. Despite its widespread use over the past six decades, very few studies have addressed the environmental fate of bacitracin and zinc-bacitracin complexes. In this study, the photochemical transformation of bacitracin components (i.e., cyclic dodecapeptides) in the aquatic environment was investigated. A high resolution mass spectrometry (HRMS)-based approach enabled monitoring of the photochemical degradation kinetics of individual bacitracin components, investigation of the relative contribution of reactive oxygen species (e.g., singlet oxygen, (1)O2) in dissolved organic matter-sensitized photoreactions, and identification of oxidative modifications in bacitracin photoproducts. The results of this study support the hypothesis that indirect photochemical oxidation of the histidine (His) residue by (1)O2 is a major degradation pathway for bacitracin A, the most potent congener of the mixture. Furthermore, the photooxidation rate of bacitracin A with (1)O2 decreased upon bacitracin A coordination with Zn(2+), demonstrating that the photochemistry of metal-bound His is different from that of metal-free His. Overall, these results provide insight into the fate of bacitracin components in the aquatic environment and highlight the potential of utilizing this HRMS-based methodology to study transformations of other environmentally relevant NRPs.
The high organic matter content in agricultural soils tends to complex and retain contaminants such as heavy metals. Electrokinetic remediation was tested in an agricultural soil contaminated with Co(+2), Zn(+2), Cd(+2), Cu(+2), Cr(VI), Pb(+2) and Hg(+2). The unenhanced electrokinetic treatment was not able to remove heavy metals from the soil due to the formation of precipitates in the alkaline environment in the soil section close to the cathode. Moreover, the interaction between metals and organic matter probably limited metal transportation under the effect of the electric field. Citric acid and ethylenediaminetetraacetic acid (EDTA) were used in the catholyte as complexing agents in order to enhance the extractability and removal of heavy metals from soil. These complexing agents formed negatively charged complexes that migrated towards the anode. The acid front electrogenerated at the anode favored the dissolution of heavy metals that were transported towards the cathode. The combined effect of the soil pH and the complexing agents resulted in the accumulation of heavy metals in the center of the soil specimen.
The plate-like Zn-Al layered double hydroxide modified with 1-aminopropyl-3-methylimidzaolium tetrafluoroborate (named as ILs-LDH) was synthesized by coprecipitation method. Several techniques confirmed the layered structure of ILs-LDH with a disk-like morphology. A novel electrochemical sensor based on ILs-LDH modified glass carbon electrode (GCE) was developed for bisphenol A (BPA) determination. Experimental factors including modified content, pH, scan rate, accumulation time and potential had been carefully optimized. ILs-LDH/GCE performed the excellent electro-oxidation ability toward BPA with the more negative oxidation overpotential and larger peak current than bare GCE or LDH/GCE. Differential pulse voltammetry determination of BPA afforded a wider linear range from 0.02 to 3μM with the detection limit of 4.6nM (S/N=3). The fabricated sensor demonstrated an acceptable reproducibility, good stability and high sensitivity. The proposed method was successfully used to detect BPA in real water samples with satisfactory recovery ranging from 94.9% to 102.0%.
In this work, brushite and brushite/hydroxyapatite (BS, CaHPO4·H2O; HA, Ca10(PO4)6(OH)2) coatings were deposited on 316L stainless steel (316LSS) from a solution containing Ca(NO3)2·4H2O and NH4H2PO4 by a displacement reaction based on a galvanic contact, where zinc acts as sacrificial anode. Driving force for the cementation reaction arises from the difference in the electrochemical standard potentials of two different metallic materials (316LSS and Zn) immersed in an electrolyte, so forming a galvanic contact leading to the deposition of BS/HA on nobler metal. We found that temperature and deposition time affect coating features (morphology, structure, and composition). Deposits were characterized by means of several techniques. The morphology was investigated by scanning electron microscopy, the elemental composition was obtained by X-ray energy dispersive spectroscopy, whilst the structure was identified by Raman spectroscopy and X-ray diffraction. BS was deposited at all investigated temperatures covering the 316LSS surface. At low and moderate temperature, BS coatings were compact, uniform and with good crystalline degree. On BS layers, HA crystals were obtained at 50°C for all deposition times, while at 25°C, its presence was revealed only after long deposition time. Electrochemical studies show remarkable improvement in corrosion resistance.
Heavy metal concentrations and distribution were studied in sediments, seawater, and molluscs, and the possible heavy metal sources in the coastal waters of Guangdong Province, South China were discussed. The results showed that the concentrations of Cu, Pb, Zn, and Cr in sediments in eastern coastal waters were generally higher than those in the western coastal waters. However, concentrations of most metals in seawater and molluscs in western waters were higher than in the eastern waters, which was tightly related to the local economics and urbanization development, especially, the different industrial structure in two regions. The main heavy metal sources were attributed to the industrial and agricultural effluent, domestic sewage, and even waste gas. Furthermore, heavy metal contamination assessment indicated that high contamination levels of Cd, Zn, and Pb occurred in sediments in local areas, especially in the bays and harbors. The metal accumulation levels by molluscs ranked following the order of Cd > Cu > As > Zn > Pb > Cr, and the ecological risks introduced by heavy metals in different areas were in the order of Zhanjiang > Yangmao > Shantou > Shanhui.
The compounds of 3-aminopyridine-2-carboxylic acid with K(+) (1) and Zn(2+) (2) were found to be AIE-active. The AIE behaviours could be attributed to the restriction of intramolecular rotation (RIR) and vibration (RIV) via hydrogen bonds, resulting in rigidity enhancement of the molecules. An AIE-based fluorescence turn on chemosensor for the Zn(ii) ion has been developed in aqueous media with high selectivity and sensitivity.
Genetic biofortification requires knowledge on natural variation and the underlying mechanisms of micronutrient accumulation. We therefore studied diversity in grain micronutrient concentrations and spatial distribution in barley (Hordeum vulgare), a genetically tractable model cereal and an important crop with widespread cultivation. We assembled a diverse collection of barley cultivars and landraces and analysed grain micronutrient profiles in genebank material and after three independent cultivations. Lines with contrasting grain zinc (Zn) accumulation were selected for in-depth analysis of micronutrient distribution within the grain by micro-proton-induced X-ray emission (μ-PIXE). Also, we addressed association with grain cadmium (Cd) accumulation. The analysis of > 120 lines revealed substantial variation, especially in grain Zn concentrations. A large fraction of this variation is due to genetic differences. Grain dissection and μ-PIXE analysis of contrasting lines showed that differences in grain Zn accumulation apply to all parts of the grain including the endosperm. Cd concentrations exceeded the Codex Alimentarius threshold in most of the representative barley lines after cultivation in a Cd-contaminated agricultural soil.
 Two important conclusions for biofortification are: first, high-Zn grains contain more Zn also in the consumed parts of the grain; and second, higher micronutrient concentrations are strongly associated with higher Cd accumulation.
A reaction sequence of 2-(diphenylsilyl)phenylation by Negishi coupling and intramolecular sila-Friedel-Crafts reaction has been explored for the synthesis of mono-triphenylsilane-fused porphyrins 5 M and 6 M (M= Ni, Zn) and bis-triphenylsilane-fused porphyrins 7 M and 8 Ni. A triply linked triphenylsilane-fused Ni(II) porphyrin, 13 Ni, was synthesized in a stepwise manner involving the above reaction sequence and a final Pd-catalyzed C-H activating arylative cyclization. The silicon atom in 13 Ni takes a distorted planarized structure with an almost perpendicular Si-phenyl group, causing an electronic effect due to effective σ*-π* interaction.
For the first time, the influence of different types of atoms (Zn and O) on the antibacterial activities of nanosized ZnO was quantitatively evaluated with the aid of a 3D-printing-manufactured evaluation system. Two different outermost atomic layers were manufactured separately by using an ALD (atomic layer deposition) method. Interestingly, we found that each outermost atomic layer exhibited certain differences against gram-positive or gram-negative bacterial species. Zinc atoms as outermost layer (ZnO-Zn) showed a more pronounced antibacterial effect towards gram-negative E. coli (Escherichia coli), whereas oxygen atoms (ZnO-O) showed a stronger antibacterial activity against gram-positive S. aureus (Staphylococcus aureus). A possible antibacterial mechanism has been comprehensively discussed from different perspectives, including Zn(2+) concentrations, oxygen vacancies, photocatalytic activities and the DNA structural characteristics of different bacterial species.
Tuberculosis is a prevalent public health problem especially in the poor developing countries and results in significant mortality. Albeit tuberculosis almost always affects any organ or system of the body, abdominal tuberculosis is less frequent; moreover, tuberculous appendicitis is very rare with an incidence estimated at about 0.1-0.6% of all gastrointestinal tuberculosis. The purpose of this report was to present an unusual case of primary tuberculous appendicitis and the approach used for accurate diagnosis as well as a current update on the disease. We are reporting a 30-year-old male who presented with acute abdominal pain, fever, and vomiting and was admitted with the clinical diagnosis of acute appendicitis. Patient was investigated thoroughly and histopathologic examination was strongly suggestive of tuberculous appendicitis; however, Ziehl-Neelsen (ZN) was negative in tissue section. To confirm the diagnosis, molecular biology [polymerase chain reaction (PCR)] study was performed from the formalin fixed paraffin embedded (FFPE) appendicular tissue and revealed presence of Mycobacterium tuberculosis. As there are numerous differential diagnoses in granulomatous lesions of appendix and due to the fact that appendicular tuberculosis is a rare phenomenon; verification etiologic agent is crucial for appropriate management of the disease.
In this randomized, double-blind, placebo controlled clinical trial, the effects of Dendropanax morbifera (D. morbifera) Léveille on heavy metal (cadmium and mercury) excretion as well as on lipid peroxidation and Cu, Zn-superoxide dismutase (SOD1) activity were investigated. For this study, tablets containing placebo or 300 mg of the leaf extract from D. morbifera Léveille were used. A total of 60 eligible healthy subjects were enrolled in this randomized, double-blind, placebo-controlled study. The differences in cadmium, mercury, and malondialdehyde (MDA) levels and SOD1 activity were measured in the serum 60 days after treatment with placebo or D. morbifera Léveille extracts. No significant differences between baseline characteristics and biochemical values were identified in subjects in the placebo and D. morbifera Léveille groups. Serum levels of cadmium, mercury and MDA decreased following consumption of D. morbifera Léveille extracts; however, no significant differences were identified. In addition, female, but not male, subjects who consumed D. morbifera Léveille extracts showed a significant increase in SOD1 activity. This result suggests that chronic consumption of D. morbifera Léveille extract can help to facilitate excretion of cadmium and mercury from serum and increase the antioxidant capacity in humans.
Coronary artery diseases are multifactorial, and over the last several decades particular consideration and research have been devoted to investigating the imbalance of patient elemental levels. Our current study aimed to investigate the comparative distribution of Ca, Mg, Fe, Zn, Cu, Co, Mn, Cr, Cd and Pb in the blood of coronary artery disease patients and healthy subjects.
Blood samples collected from both groups were digested into a HNO3-HCLO4 (10:1 v/v) mixture in a microwave oven, followed by quantification of the elements by atomic absorption spectrometry.
The average levels of Pb and Cr were markedly higher (p < 0.001) while those of Ca, Fe, Cu and Mn were moderately higher (p < 0.05) in blood of the patients compared to the controls. However, correlation study showed divergent relationships between various elements in the blood of both groups. Multivariate cluster analysis revealed two major clusters of the elements for patients: Ca-Mg-Mn-Co-Cd and Pb-Cu-Fe-Zn-Cr; whereas three common groups were observed for controls: Ca-Mg-Zn-Cu, Cr-Mn-Fe and Co-Cd-Pb. Variations in the elemental levels were also observed to be associated with gender, habitat, food and smoking habits of the subjects.
Overall, the distribution, correlation and apportionment of elemental data indicated an imbalance of the toxic/essential elements in blood of the patients compared to the controls.
AAS; Blood; Cluster analysis; Coronary artery disease; Essential/toxic element.
To study the effect of anti-copper treatment for survival of hepatic cells expressing different ATP7B mutations in cell culture.
The most common Wilson disease (WD) mutations p.H1069Q, p.R778L and p.C271*, found in the ATP7B gene encoding a liver copper transporter, were studied. The mutations represent major genotypes of the United States and Europe, China, and India, respectively. A human hepatoma cell line previously established to carry a knockout of ATP7B was used to stably express WD mutants. mRNA and protein expression of mutant ATP7B, survival of cells, apoptosis, and protein trafficking were determined.
Low temperature increased ATP7B protein expression in several mutants. Intracellular ATP7B localization was significantly impaired in the mutants. Mutants were classified as high, moderate, and no survival based on their viability on exposure to toxic copper. Survival of mutant p.H1069Q and to a lesser extent p.C271* improved by D-penicillamine (DPA) treatment, while mutant p.R778L showed a pronounced response to zinc (Zn) treatment. Overall, DPA treatment resulted in higher cell survival as compared to Zn treatment; however, only combined Zn + DPA treatment fully restored cell viability.
The data indicate that the basic impact of a genotype might be characterized by analysis of mutant hepatic cell lines.
Hypoxia-inducible factor-1α (HIF-1α) is involved in the pathogenesis of hepatocellular carcinoma (HCC). However, the roles of trace elements in the activation of HIF-1α during hepatocarcinogenesis have been unclear. We investigated whether copper (Cu) and zinc (Zn) participated in the activation of HIF-1α in the process of hepatocarcinogenesis or not. Nine patients with chronic hepatitis (CH), five with liver cirrhosis (LC), 12 with HCC, and nine normal healthy controls were enrolled in this study. Their serum HIF-1α, Cu, and Zn levels were determined in the enrolled patients. Hepatic HIF-1α expression was evaluated, using an immunohistochemical procedure. The HCC patients had significantly higher serum HIF-1α levels than the CH patients (6.47 ± 1.57 vs. 5.09 ± 1.22 ng/ml, p = 0.0344). The serum Cu level in the HCC patients was also significantly higher than those in the CH and LC patients (137 ± 24 vs. 107 ± 15 μg/dl, 114 ± 24 μg/dl). Interestingly, a positive correlation was observed between serum HIF-1α and Cu levels in the enrolled patients (r = 0.425, p = 0.0137). In contrast, no significant differences in serum Zn levels were present between the HCC patients and the CH or LC patients. The serum HIF-1α was not positively correlated with the serum Zn level in the enrolled patients, either. Immunohistochemical analysis revealed that two of the five HCC patients had HIF-1α expression in the tumor tissues, whereas none of CH and LC had hepatic HIF-1α expression in the liver tissues. These data suggest that the activation of HIF-1α derived from a Cu accumulation in the liver may cause hepatocarcinogenesis.
Previous studies have demonstrated that zinc (Zn) is an essential trace element which is involved in male reproduction. The zinc transporter (ZnT) family, SLC30a, is involved in the maintenance of Zn homeostasis and in mediating intracellular signaling events; however, relatively little is known regarding the effect of ZnTs on testosterone synthesis. Thus, in the present study, we aimed to determine the effect of Zn transporter 7 (ZnT7) on testosterone synthesis in male CD-1 mice and mouse Leydig cells. The findings of the present study revealed that the concentrations of Zn in the testes and Leydig cells were significantly lower in mice fed a Zn-deficient diet compared with the control mice fed a Zn-adequate diet. In addition, ZnT7 was principally expressed and colocalized with steroidogenic acute regulatory protein (StAR) in the Leydig cells of male CD-1 mice. ZnT7
 expression was downregulated in the mice fed a Zn-deficient diet, which led to decreases in the expression of the enzymes involved in testosterone synthesis namely cholesterol side chain cleavage enzyme (P450scc) and 3β-hydroxysteroid dehydrogenase/D5-D4 isomerase (3β-HSD) as well as decreased serum testosterone levels. These results suggested that Znt7 may be involved in testosterone synthesis in the mouse testes. To examine this hypothesis, we used the mouse Leydig tumor cell line (MLTC-1 cell line) in which the ZnT7 gene had been silenced, in order to gauge the impact of changes in ZnT7 expression on testosterone secretion and the enzymes involved in testosterone synthesis. The results demonstrated that ZnT7 gene silencing downregulated the expression of StAR, P450scc and 3β-HSD as well as progesterone concentrations in the human chorionic gonadotrophin (hCG)-stimulated MLTC-1 cells. Taken together, these findings reveal that ZnT7 may play an important role in the regulation of testosterone synthesis by modulating steroidogenic enzymes, and may represent a therapeutic target in testosterone deficiency.
Lead-zinc deposits are often difficult to classify because clear criteria are lacking. In recent years, new tools, such as Cd and Zn isotopes, have been used to better understand the ore-formation processes and to classify Pb-Zn deposits. Herein, we investigate Cd concentrations, Cd isotope systematics and Zn/Cd ratios in sphalerite from nine Pb-Zn deposits divided into high-temperature systems (e.g., porphyry), low-temperature systems (e.g., Mississippi Valley type [MVT]) and exhalative systems (e.g., sedimentary exhalative [SEDEX]). Our results showed little evidence of fractionation in the high-temperature systems. In the low-temperature systems, Cd concentrations were the highest, but were also highly variable, a result consistent with the higher fractionation of Cd at low temperatures. The δ(114/110)Cd values in low-temperature systems were enriched in heavier isotopes (mean of 0.32 ± 0.31‰). Exhalative systems had the lowest Cd concentrations, with a mean δ(114/110)Cd value of 0.12 ± 0.50‰. We thus conclude that different ore-formation systems result in different characteristic Cd concentrations and fraction levels and that low-temperature processes lead to the most significant fractionation of Cd. Therefore, Cd distribution and isotopic studies can support better understanding of the geochemistry of ore-formation processes and the classification of Pb-Zn deposits.
Iron supplementation is usually given to pregnant and lactating women who may also have marginal deficiency of zinc. The negative impact of supplemental iron and calcium on zinc status is a cause of concern. The present investigation was undertaken to examine the effect of inclusion of iron and calcium in the diet at supplementary levels on zinc status of experimental rats.
Groups of experimental rats were maintained on diets supplemented with iron (Molar ratio - Zn:Fe 1:30) and calcium (Molar ratio - Zn:Ca 1:667) both individually and in combination for six weeks. Zinc status of these rats was assessed by determining zinc concentration in circulation and in organs, and the activities of zinc containing enzymes in serum and liver.
The zinc status of experimental rats receiving supplemental levels of iron and calcium was significantly compromised. Zinc concentration in serum, kidney, spleen and liver was reduced significantly by both these minerals. Six weeks of supplementation of iron and calcium individually, significantly reduced the activity of liver and serum superoxide dismutase and alkaline phosphatase. Activity of liver alcohol dehydrogenase was lowered in calcium supplemented group and in calcium + iron supplemented group, while that of carbonic anhydrase was significantly reduced by iron, calcium and their combination.
Supplemental levels of iron and calcium, both individually and in combination, significantly compromised the zinc status of experimental rats. This negative effect of these two minerals was more prominent when these were supplemented for a period of six weeks.
The possibility to finely control nanostructured cubic ferrites (M(II)Fe2O4) paves the way to design materials with the desired magnetic properties for specific applications. However, the strict and complex interrelation among the chemical composition, size, polydispersity, shape and surface coating renders their correlation with the magnetic properties not trivial to predict. In this context, this work aims to discuss the magnetic properties and the heating abilities of Zn-substituted cobalt ferrite nanoparticles with different zinc contents (ZnxCo1-xFe2O4 with 0 < x < 0.6), specifically prepared with similar particle sizes (∼7 nm) and size distributions having the crystallite size (∼6 nm) and capping agent amount of 15%. All samples have high saturation magnetisation (Ms) values at 5 K (>100 emu g(-1)). The increase in the zinc content up to x = 0.46 in the structure has resulted in an increase of the saturation magnetisation (Ms) at 5 K. High Ms values have also been revealed at room temperature (∼90 emu g(-1)) for both CoFe2O4 and Zn0.30Co0.70Fe2O4 samples and their heating ability has been tested. Despite a similar saturation magnetisation, the specific absorption rate value for the cobalt ferrite is three times higher than the Zn-substituted one. DC magnetometry results were not sufficient to justify these data, the experimental conditions of SAR and static measurements being quite different. The synergic combination of DC with AC magnetometry and (57)Fe Mössbauer spectroscopy represents a powerful tool to get new insights into the design of suitable heat mediators for magnetic fluid hyperthermia.
Abnormal accumulation of brain metals is a key feature of Alzheimer's disease (AD). Formation of amyloid-β plaque cores (APC) is related to interactions with biometals, especially Fe, Cu and Zn, but their particular structural associations and roles remain unclear. Using an integrative set of advanced transmission electron microscopy (TEM) techniques, including spherical aberration-corrected scanning transmission electron microscopy (Cs-STEM), nano-beam electron diffraction, electron holography and analytical spectroscopy techniques (EDX and EELS), we demonstrate that Fe in APC is present as iron oxide (Fe3O4) magnetite nanoparticles. Here we show that Fe was accumulated primarily as nanostructured particles within APC, whereas Cu and Zn were distributed through the amyloid fibers. Remarkably, these highly organized crystalline magnetite nanostructures directly bound into fibrillar Aβ showed characteristic superparamagnetic responses with saturated magnetization with circular contours, as observed for the first time by off-axis electron holography of nanometer scale particles.
Development of new strategies for the sensitive and selective detection of ultra-low concentrations of specific cancer markers is of great importance for assessing cancer therapeutics due to its crucial role in early clinical diagnoses and biomedical applications. In this work, we have developed two types of fluorescence polarization (FP) amplification assay strategies for the detection of biomolecules by using TiS2 as a FP enhancer and Zn(2+)-dependent self-hydrolyzing deoxyribozymes as catalysts to realize enzyme-catalyzed target-recycling signal amplification. One approach is based on the terminal protection of small-molecule-linked DNA, in which biomolecular binding to small molecules in DNA-small-molecule chimeras can protect the conjugated DNA from degradation by exonuclease I (Exo I); the other approach is based on the terminal protection of biomolecular bound aptamer DNA, in which biomolecules directly bound to the single strand aptamer DNA can protect the ssDNA from degradation by Exo I. We select folate receptor (FR) and thrombin (Tb) as model analytes to verify the current concept. It is shown that under optimized conditions, our strategies exhibit high sensitivity and selectivity for the quantification of FR and Tb with low detection limits (0.003 ng mL(-1) and 0.01 pM, respectively). Additionally, this strategy is a simple "mix and detect" approach, and does not require any separation steps. This biosensor is also utilized in the analysis of real biological samples, the results agree well with those obtained by the enzyme-linked immunosorbent assay (ELISA).
Inorganic electrolyte solutions are very important in our society as they dominate many biochemical and geochemical processes. Herein, an in-depth study was performed to illustrate the ion-induced effect on water structure by coupling NMR, viscometer, Raman and Molecular Dynamic (MD) simulations. The NMR coefficient (BNMR) and diffusion coefficient (D) from NMR, and viscosity coefficient (Bvis) from a viscometer all proved that dissolved metal ions are capable of enhancing the association degree of adjacent water molecules, and the impact on water structure decreased in the order of Cr(3+) > Fe(3+) > Cu(2+) > Zn(2+). This regularity was further evidenced by Raman analysis; however, the deconvoluted Raman spectrum indicated the decrease in high association water with salt concentration and the increase in low association water before 200 mmol·L(-1). By virtue of MD simulations, the opposite changing manner proved to be the result of the opposite effect on short-/long-range water structure induced by metal ions. Our results may help to explain specific protein denaturation induced by metal ions.
An aqueous rechargeable Zn//Co3 O4 battery is demonstrated with Zn@carbon fibers and Co3 O4 @Ni foam as the negative and positive electrodes, respectively, using an electrolyte of 1 m KOH and 10 × 10(-3) m Zn(Ac)2 . It can operate at a cell voltage as high as 1.78 V with an energy density of 241 W h kg(-1) and presents excellent cycling.
 The battery is also assembled into a flexible shape, which can be applied in flexible or wearable devices requiring high energy.
We report a transgenic zebrafish (Danio rerio) designed to respond to heavy metals using a metal-responsive promoter linked to a fluorescent reporter gene (DsRed2). The metallothionein MT-Ia1 promoter containing metal-responsive elements was derived from the Asian green mussel, Perna viridis. The promoter is known to be induced by a broad spectrum of heavy metals. The promoter-reporter cassette cloned into the Tol2 transposon vector was microinjected into zebrafish embryos that were then reared to maturity. A transgene integration rate of 28 % was observed. The confirmed transgenics were mated with wild-type counterparts, and pools of F1 embryos were exposed to sub-lethal doses of Cd(2+), Cu(2+), Hg(2+), Pb(2+) and Zn(2+). The red fluorescence response of zebrafish embryos was observed 8 h post- exposure to these sub-lethal doses of heavy metals using a fluorescence microscope. Reporter expression estimated by real-time PCR revealed eightfold, sixfold and twofold increase on exposure to highest concentrations of Hg(2+), Cd(2+) and Cu(2+), while Pb(2+) and Zn(2+) had no effect. This biosensor could be a first-level screening method for confirming aquatic heavy metal bio-toxicity to eukaryotes.
Removal of selected metals from municipal wastewater using a constructed wetland with a horizontal subsurface flow was studied. The objective of the work was to determine the efficiency of Cu, Zn, Ni, Co, Sr, Li, and Rb removal, and to describe the main removal mechanisms. The highest removal efficiencies were attained for zinc and copper (89.8 and 81.5%, respectively). It is apparently due to the precipitation of insoluble sulfides (ZnS, CuS) in the vegetation bed where the sulfate reduction takes place. Significantly lower removal efficiencies (43.9, 27.7, and 21.5%) were observed for Li, Sr, and Rb, respectively. Rather, low removal efficiencies were also attained for Ni and Co (39.8 and 20.9%). However, the concentrations of these metals in treated water were significantly lower compared to Cu and Zn (e.g., 2.8 ± 0.5 and 1.7 ± 0.3 μg/l for Ni at the inflow and outflow from the wetland compared to 27.6 ± 12.0 and 5.1 ± 4.7 μg/l obtained for Cu, respectively). The main perspective of the constructed wetland is the removal of toxic heavy metals forming insoluble compounds depositing in the wetland bed. Metal uptake occurs preferentially in wetland sediments and is closely associated with the chemism of sulfur and iron.
The development of rechargeable zinc ion batteries with high capacity and high cycling stability is a great challenge in aqueous solution due to hydrogen evolution and dendritic growth of zinc. In this study, we present a zinc ion secondary battery, comprising a metallic zinc anode, a bio-ionic liquid-water electrolyte, and a nanostructured prussian blue analogue (PBA) cathode. Both the Zn anode and the PBA cathode exhibit good compatibility with the bio-ionic liquid-water electrolyte, which enables the electrochemical deposition/dissolution of zinc at the zinc anode, and reversible insertion/extraction of Zn(2+) ions at the PBA cathode. The cell exhibits a well-defined discharge voltage plateau of ∼1.1 V with a specific capacity of about 120 mAh g(-1) at a current of 10 mA g(-1) (∼0.1 C). The Zn anode shows great reversibility, and dendrite-free Zn deposits were obtained after 100 deposition/dissolution cycles. The integration of an environmentally friendly PBA cathode, a nontoxic and low-cost Zn anode, and a biodegradable ionic liquid-water electrolyte provides new perspective to develop rechargeable zinc ion batteries for various applications in electric energy storage.
Cationic dye sorption by Zn-Al-layered double hydroxides (LDHs) modified with anionic surfactants was examined using methylene blue (MB) dye as a compound model in aqueous solutions. The modification of Zn-Al LDHs was performed by reconstruction method using dodecyl sulfate anion (DS) solutions. DS contained Zn-Al LDHs were characterized by XRD, FTIR, thermogravimetric, and SEM analysis. The reconstructed organo/Zn-Al LDHs comprise the crystalline phases (DS-intercalated LDHs, hydrotalcite), and the amorphous phase. The intercalation of DS ions into the interlayer galleries and DS adsorption on the surface of the LDHs occurred causing the MB adsorption on the external and its sorption in the internal surfaces of modified LDHs. The presence of DS greatly increased the affinity of organo/Zn-Al LDHs for MB due to hydrophobic interactions between the surfactants and the dye molecules. The optical properties of sorbed MB were studied.
The growth response, metal tolerance and phytoaccumulation properties of water spinach (Ipomoea aquatica) and okra (Abelmoschus esculentus) were assessed under different contaminated spiked metals: control, 50 mg Pb/kg soil, 50 mg Zn/kg soil and 50 mg Cu/kg soil. The availability of Pb, Zn and Cu metals in both soil and plants were detected using flame atomic absorption spectrometry. The concentration and accumulation of heavy metals from soil to roots and shoots (edible parts) were evaluated in terms of translocation factor, accumulation factor and tolerance index. Okra recorded the highest accumulation of Pb (80.20 mg/kg) in its root followed by Zn in roots (35.70 mg/kg) and shoots (34.80 mg/kg) of water spinach, respectively. Different accumulation trends were observed with, Pb > Zn > Cu in okra and Zn > Pb > Cu in water spinach. Significant differences (p < 0.01) of Pb, Zn and Cu accumulation were found in both water spinach and okra cultivated among tested treatments. However, only the accumulation of Pb metal in the shoots of water spinach and okra exceeded the maximum permissible levels of the national Malaysian Food Act 1983 and Food Regulations 1985 (2006) as well as the international Codex Alimentarius Commission limits. This study has shown that both water spinach and okra have good potential as Pb and Zn phytoremediators.
The role of plasma membrane transporters in cancer is receiving increasing attention in recent years. Several transporters for essential nutrients are up-regulated in cancer and serve as tumour promoters. Transporters could also function as tumour suppressors. To date, four transporters belonging to the SLC gene family have been identified as tumour suppressors. SLC5A8 is a Na(+)-coupled transporter for monocarboxylates. Among its substrates are the bacterial fermentation products butyrate and propionate and the ubiquitous metabolite pyruvate. The tumour-suppressive function of this transporter relates to the ability of butyrate, propionate and pyruvate to inhibit histone deacetylases (HDAC). SLC5A8 functions as a tumour suppressor in most tissues studied thus far, and provides a molecular link to Warburg effect, a characteristic feature in most cancers. It also links colonic bacteria and dietary fibre to the host. SLC26A3 as a tumour suppressor is restricted to colon; it is a Cl(-)/HCO(-) 3 exchanger, facilitating the efflux of HCO(-) 3 The likely mechanism for the tumour-suppressive function of SLC26A3 is related to intracellular pH regulation. SLC39A1 is a Zn(2+) transporter and its role in tumour suppression has been shown in prostate. Zn(2+) is present at high concentrations in normal prostate where it elicits its tumour-suppressive function. SLC22A18 is possibly an organic cation transporter, but the identity of its physiological substrates is unknown. As such, there is no information on molecular pathways responsible for the tumour-suppressive function of this transporter. It is likely that additional SLC transporters will be discovered as tumour suppressors in the future.
Respiratory complex I has an L-shaped structure formed by the hydrophilic arm responsible for electron transfer and the membrane arm that contains protons pumping machinery. Here, to gain mechanistic insights into the role of subunit NuoL, we investigated the effects of Mg(2+), Zn(2+) and the Na(+)/H(+) antiporter inhibitor 5-(N-ethyl-N-isopropyl)-amiloride (EIPA) on proton pumping activities of various isolated NuoL mutant complex I after reconstitution into Escherichia coli double knockout (DKO) membrane vesicles lacking complex I and the NADH dehydrogenase type 2. We found that Mg(2+) was critical for proton pumping activity of complex I. At 2 µM Zn(2+), proton pumping of the wild-type was selectively inhibited without affecting electron transfer; no inhibition in proton pumping of D178N and D400A was observed, suggesting the involvement of these residues in Zn(2+) binding. Fifteen micromolar of EIPA caused up to ∼40% decrease in the proton pumping activity of the wild-type, D303A and D400A/E, whereas no significant change was detected in D178N, indicating its possible involvement in the EIPA binding. Furthermore, when menaquinone-rich DKO membranes were used, the proton pumping efficiency in the wild-type was decreased significantly (∼50%) compared with NuoL mutants strongly suggesting that NuoL is involved in the high efficiency pumping mechanism in complex I.
Granulosa cells (GCs) are those somatic cells closest to the female germ cell. GCs play a vital role in oocyte growth and development, and the oocyte is necessary for multiplication of a species. Zinc oxide (ZnO) nanoparticles (NPs) readily cross biologic barriers to be absorbed into biologic systems that make them promising candidates as food additives. The objective of the present investigation was to explore the impact of intact NPs on gene expression and the functional classification of altered genes in hen GCs in vivo, to compare the data from in vivo and in vitro studies, and finally to point out the adverse effects of ZnO NPs on the reproductive system. After a 24-week treatment, hen GCs were isolated and gene expression
 was quantified. Intact NPs were found in the ovary and other organs. Zn levels were similar in ZnO-NP-100 mg/kg- and ZnSO4-100 mg/kg-treated hen ovaries. ZnO-NP-100 mg/kg and ZnSO4-100 mg/kg regulated the expression of the same sets of genes, and they also altered the expression of different sets of genes individually. The number of genes altered by the ZnO-NP-100 mg/kg and ZnSO4-100 mg/kg treatments was different. Gene Ontology (GO) functional analysis reported that different results for the two treatments and, in Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment, 12 pathways (out of the top 20 pathways) in each treatment were different. These results suggested that intact NPs and Zn(2+) had different effects on gene expression in GCs in vivo. In our recent publication, we noted that intact NPs and Zn(2+) differentially altered gene expression in GCs in vitro. However, GO functional classification and KEGG pathway enrichment analyses revealed close similarities for the changed genes in vivo and in vitro after ZnO NP treatment. Furthermore, close similarities were observed for the changed genes after ZnSO4 treatments in vivo and in vitro by GO functional classification and KEGG pathway enrichment analyses. Therefore, the effects of ZnO NPs on gene expression in vitro might represent their effects on gene expression in vivo. The results from this study and our earlier studies support previous findings indicating ZnO NPs promote adverse effects on organisms. Therefore, precautions should be taken when ZnO NPs are used as diet additives for hens because they might cause reproductive issues.
Heavy metal contaminated sites are frequently characterized by the simultaneous presence of several heavy metals. However, many studies report metal-induced plant responses after long-term exposure to just one metal. By contrast, whole genome expression microarrays were employed here to investigate the early (3 h) transcriptional responses of Arabidopsis thaliana plants exposed to polymetallic treatment (Pb, Hg, Cu, Cd, Co, Ni, Zn, and Mn) at low (L) and high (H) concentrations. After 3 h of exposure to polymetallic treatment, a total of 1315 noticeably (≥2-fold) and significantly (P < 0.05) differentially expressed genes were identified: 656 and 351 upregulated and 314 and 200 downregulated genes in L and H treatments, respectively. Functional analysis revealed that many genes involved in oxidative stress and perception/signalling/regulation systems were activated. Genes encoding proteins involved in hormone regulation (jasmonic acid, abscisic acid, ethylene, and auxins), glucosinolate metabolism and sulphur and nitrogen transport were also modulated. RT-qPCR analysis of four downregulated (AOP2, SAUR16, BBX31, and MTPC3) and upregulated genes (ASN1, DIN2, BT2, and EXL5), markedly responsive to both L and H treatments, validated our microarray data and suggested the potential of some of these genes (AOP2, SAUR16, ASN1, and DIN2) as early biomarkers of metal exposure. Relevant changes in gene expression occur as early as 3 h after exposure to polymetallic treatment. Four genes deserve further studies as novel putative biomarkers of early metal exposure and also owing to their potential implications in stress-related mechanisms: sulphur balance (AOP2), phytohormone regulation of plant growth and development (SAUR16), ammonium detoxification (ASN1) and senescence (DIN2).
Framework-isomeric three-dimensional (3D) Zn-Ln heterometallic metal-organic frameworks, {[Ln2Zn(abtc)2(H2O)4]·2H2O}∞ {Ln = Sm(1), Tb(2)}, were synthesized using a convenient solvothermal reaction. They can serve as excellent sensors for the specific identification of benzaldehyde and NO2(-) through a fluorescence quenching process.
Heavy metals (As, Cd, Co, Cr, Cu, Mn, Ni, Pb and Zn) in various vegetables (cabbage, green onion, lettuce, parsley, rocket, spinach, carrot, onion, potato and cauliflower) from the market in Jordan were measured using inductively coupled plasma-mass spectrometry. As, Cd, Co, Cr, Cu, Mn, Ni, Pb and Zn ranged from 0.009-0.275 mg kg(-1) wet weight, 0.004-0.060 mg kg(-1), 0.003-0.401 mg kg(-1), 0.105-3.51 mg kg(-1), 0.15-1.15 mg kg(-1), 0.93-14.39 mg kg(-1), 0.044-0.702 mg kg(-1), 0.072-0.289 mg kg(-1) and 2.23-6.65 mg kg(-1), respectively. Parsley, followed by spinach, contained the highest concentration of heavy metals. Onion contained high levels of toxic heavy metals. The content of Cu in parsley and spinach and Pb in onion exceeded the Codex limits. However, the daily intake of heavy metals from the tested vegetables was lower than the maximum limits for allowable intake.
Although soil contamination by potentially toxic elements (PTEs) in Europe has a history of many centuries, related problems are often considered as having been dealt with due to the enforcement of tight legislations. However, there are many unsolved issues. We aimed to assess PTE levels in highly contaminated soils and in garden edible vegetables using human health risk indices in order to evaluate the availability and mobilization of arsenic (As), copper (Cu), manganese (Mn), mercury (Hg), lead (Pb), and zinc (Zn). In four gardens in Germany, situated on, or in the vicinity of, a mine dump area, we planted beans (Phaseolus vulgaris ssp. nanus), carrots (Daucus sativus) and lettuce (Lactuca sativa ssp. capitata). We examined soil-to-plant mobilization of elements using transfer coefficient (TC), as well as soil contamination using contamination factor (CF), enrichment factor (EF), and bioaccumulation index (Igeo). In addition, we tested two human health risk assessment indices: Soil-induced hazard quotient (HQS) (representing the "direct soil ingestion" pathway), and vegetable-induced hazard quotient (HQV) (representing the "vegetable intake" pathway). The studied elements were highly elevated in the soils. The values in garden 2 were especially high (e.g., Pb: 13789.0 and Hg: 36.8 mg kg(-1)) and largely exceeded the reported regulation limits of 50 (for As), 40 (Cu), 400 (Pb), 150 (Zn), and 5 (Hg) mg kg(-1). Similarly, element concentrations were very high in the grown vegetables. The indices of CF, EF and Igeo were enhanced even to levels that are rarely reported in the literature. Specifically, garden 2 indicated severe contamination due to multi-element deposition. The contribution of each PTE to the total of measured HQS revealed that Pb was the single most important element causing health risk (contributing up to 77% to total HQS). Lead also posed the highest risk concerning vegetable consumption, contributing up to 77% to total HQV. The presence of lead in both cases was followed by that of As, Mn and Hg. We conclude that in multi-element contamination cases, along with high-toxicity elements (here, Pb, As and Hg) other elements may also be responsible for increasing human health risks (i.e., Mn), due to the possibility of adverse synergism of the PTEs.
Sediments may be a repository of contaminants in freshwater ecosystems. One way to assess the quality of this compartment, in terms of potentially bioavailable metals, is by the analysis of acid-volatile sulfide (AVS) and simultaneously extracted metals (SEM). In order to investigate the bioavailability, toxicity, and compartmentalization of different metals (Cd, Cr, Cu, Ni, Pb, Zn), sampling of surface sediments was performed at nine stations along the Paiva Castro reservoir (São Paulo, Brazil). The metals were analyzed using atomic absorption spectroscopy. Sediment organic matter (OM), organic carbon (OC), and grain size were also measured. The parameters pH, EH, temperature, and dissolved oxygen were determined at the sediment-water interface. Chronic and acute toxicological tests were performed with sediments from the area where water was extracted for the public water supply. Low levels of OM, associated with loss of stratification in the water column, explained the relatively low AVS values. The molar ratio ∑[SEM]-[AVS]/fOC was less than 130 mmol/kg(-1) for all the sampling stations, indicating that the metals were not bioavailable. With the exception of Cd, metal levels were in accordance with background concentrations and the threshold effect level (TEL) established by the Canadian Council of Ministers of the Environment. The ecotoxicological tests confirmed the absence of toxic effects to biota. Application of principal component analysis indicated the presence of four compartments along the reservoir: (1) a riverine zone, potentially threatened by contamination with Cd; (2) an intermediate zone; (3) a limnic area; and (4) the area where water was taken for the public water supply.
The eastern and southern parts of the Faisalabad city produce considerable quantities of industrial and municipal pollutants, much of which is drained into the River Chenab, reducing the productivity of fauna and flora in the river. This study was aimed to determine whether cysteine is useful as a biomarker of exposure to polluted fresh water. The amino acid profile of fish muscle was analyzed by paper chromatography in Cirrhinus mrigala and Labeo rohita from the River Chenab to determine habitat related variations due to the pollution from industrial and domestic sources. C. mrigala showed higher level of metal contamination in muscle tissues for Sn, Cr, Pb, Zn, Mn, Cu, and Cd when compared to L. rohita. Both fish species collected from polluted areas of the river Chenab showed significantly (P < 0.01) higher levels of metals in comparison to upstream and farmed fish. Farmed C. mrigala showed cysteine concentrations in the muscle tissue as 22 ± 1 mg/g dry weight, but concentrations increased to 45 ± 2 mg/g dry weight for fish from a mildly polluted section of the river, and further increased to 83 ± 2 mg/g dry weight in more heavily polluted sections. Cysteine concentration in farmed L. rohita was detected as 28 ± 2
 and 25 ± 4 mg/g dry weight, respectively for farmed fish and fish from a mildly polluted section of the river, and then increased to 94 ± 3 mg/g dry weight for fish from highly polluted water. C. mrigala from a mildly polluted area of the river also had higher levels of cysteine in the muscle, along with increases in aspartic acid, glutamic acid, and alanine. Elevated concentrations of cysteine seem to be associated with a threat to these fish species in polluted sections of the river, and thus may be used as a biomarker.
The solution and complexation chemistry of zinc ions is the basis for zinc biology. In living organisms, zinc is redox-inert and has only one valence state: Zn(II). Its coordination environment in proteins is limited by oxygen, nitrogen, and sulfur donors from the side chains of a few amino acids. In an estimated 10% of all human proteins, zinc has a catalytic or structural function and remains bound during the lifetime of the protein. However, in other proteins zinc ions bind reversibly with dissociation and association rates commensurate with the requirements in regulation, transport, transfer, sensing, signalling, and storage. In contrast to the extensive knowledge about zinc proteins, the coordination chemistry of the "mobile" zinc ions in these processes, i.e. when not bound to proteins, is virtually unexplored and the mechanisms of ligand exchange are poorly understood. Knowledge of the biological inorganic chemistry of zinc ions is essential for understanding its cellular biology and for designing complexes that deliver zinc to proteins and chelating agents that remove zinc from proteins, for detecting zinc ion species by qualitative and quantitative analysis, and for proper planning and execution of experiments involving zinc ions and nanoparticles such as zinc oxide (ZnO). In most investigations, reference is made to zinc or Zn(2+) without full appreciation of how biological zinc ions are buffered and how the d-block cation Zn(2+) differs from s-block cations such as Ca(2+) with regard to significantly higher affinity for ligands, preference for the donor atoms of ligands, and coordination dynamics. Zinc needs to be tightly controlled. The interaction with low molecular weight ligands such as water and inorganic and organic anions is highly relevant to its biology but in contrast to its coordination in proteins has not been discussed in the biochemical literature. From the discussion in this article, it is becoming evident that zinc ion speciation is important in zinc biochemistry and for biological recognition as a variety of low molecular weight zinc complexes have already been implicated in biological processes, e.g. with ATP, glutathione, citrate, ethylenediaminedisuccinic acid, nicotianamine, or bacillithiol.
Anaerobic sediments of urban watercourses are subjected to industrial pollution and frequently tend to accumulate heavy metals. The biocatalyzed oxidation and reduction of sulphur compounds that occur within the sediment are key reactions that determine mobility of metals such as that occurred in mine acidic drainage reactions. The aim of this work was to study the application of these processes using heap leaching technology for the remediation of anaerobic contaminated sediments from Reconquista River basin. The bioleaching potentiality for remediation was demonstrated through batch tests in shake flasks with different pulp densities of anaerobic sediment containing 338 mg kg(-1) of Zn and 117 mg kg(-1) of Cu. Subsequently, bioleaching heap systems were compiled into columns of 12-cm height and 6-cm diameter, fitted with perlite to improve drainage. In order to assess the effect of elementary sulphur over the mobility of metals from the bioheap to the aqueous solution, increasing concentrations of elementary sulphur (1, 2, 5 % w/w) were added. After 3 months of acidification generated by periodic watering, the extraction of 70 % of the initial Zn and 43 % of the initial Cu was achieved. Polluted sediments from waterways as Reconquista River should not be indiscriminately manipulated if acid drainage is possible. Remediation by a simple and economically viable strategy like heap leaching is feasible.
India has a giant jute-producing basket which produces considerable quantity of toxic jute mill waste (JMW). Conversely, report on usability potential of JMW is rather scanty. The present study illustrates the efficiency of vermicomposting in bioconversion of JMW for agricultural use. Various combinations of JMW, cow dung, and vegetable waste were fed to Metaphire posthuma in vermireactors. Rapid increment of earthworm count, body weight, and cocoon production was evidenced. Total organic carbon and pH reduction was noteworthy, but N, P, and K availability, formation of stable humic acid C, fulvic acid C, and microbial biomass C substantially increased due to vermicomposting. FTIR spectroscopy confirmed a higher stability of vermicomposted JMW over the composted product. A significant decline in heavy metal concentration (Cr, Pb, Fe, and Zn) in the vermicomposted JMW further establishes the potential of vermicomposting with M. posthuma in successful conversion of the toxic JMW into valuable product.
The influence of a regular (for 7 and 14 days) 10-minute dosed exercise in isolation and on the background of intragastric administration of 5 and 15 mg/kg of zinc (II) asparaginate on the distribution of this metal in the organs and tissues of experimental animals and the indicators of muscle activity such as the level of lactate, creatinine and creatine kinase (EC 2.7.3.2.) serum were studied. It has been shown that exercise stress for 14 days causes a more pronounced change in homeostasis Zn, compared with 7 day, it is reflected in increased levels in the kidney, serum, liver, skeletal muscle and fur animals. It has been shown that graduated exercise for 14 days causes a more pronounced change in Zn homeostasis, compared with 7 day that expressed in increased its levels in the kidney, serum, liver, skeletal muscle and fur animals. Introduction zinc (II) asparaginate accompanied by an increase of its content in the liver, kidneys, hair and serum, but not skeletal and cardiac muscle. The combination of physical activity and the introduction of zinc positive effect on homeostasis of Zn, and the terms of muscle activity. The protective effect of zinc asparaginate with graduated exercise in the experiment was concluded.
A discrete nanospheric icosametallic cluster comprised of 20 Cu ions (1) was self-assembled from facile synthesis. Adjustment of the synthesis by the choice of ligands gave rise to another cluster (2) with an intact icosacupric core and improved stability. Referring to the synthesis of 1 and 2, a heterometallic cluster (3), which contains 12 Cu(II) and 8 Zn(II), was designed and characterized by single-crystal X-ray diffraction, combined with elemental analysis, energy-dispersive X-ray, X-ray photoelectron spectroscopy, thermogravimetric analysis, and element mapping. The magnetic measurements of 2 and 3 and the scanning electron microscopy images and UV-visible diffuse-reflectance measurements of metal oxides from 2 and 3 indicate that isolation of {Cu12M8} is a new synthetic route to materials with engineered properties.
Heavy metals enriched agricultural soils have been the subject of great concern because these metals have potential to be transferred to the soil solution and afterward accumulated in food chain. To study the trace metal persistence in crop soil, 90 representative soil samples were collected and analyzed for heavy metal (As, Cd, Cu, Fe, Mn, Ni, Pb, and Zn) and anions (chloride, nitrates, phosphates and sulfates). Cluster and factor analysis techniques were used for the source identification of these excessive heavy metal levels and ecological risk was determined with potential ecological risk assessment. The degree of enrichment of eight studied heavy metals in comparison with the corresponding background levels decreased in order: Cd > Pb > Fe > Ni > Mn > As > Cu ~ Zn. Arsenic and cadmium exhibited 1.30- and 1.64-fold exceeded levels than threshold limits set by National environment quality standards, respectively. Cd in cotton field's soil may lead to higher potential risk than other heavy metals. On overall basis, the cumulative mean potential ecological risk for the district (207.75) corresponded to moderate risk level with higher contributions from As and Pb especially from Cd. Cadmium formed strong positive correlation with phosphate content of soil at p < 0.01. Cluster analysis indicated that Cluster 1 (extremely polluted) probably originated from anthropogenic inputs of phosphate fertilizer and past usage of arsenical pesticides.
Cluster chemistry of intermetallics with valence electron counts (VECs) in the range of 2.0-3.0 is intriguing. Lithiation of polar intermetallics in this VEC region is found to be an effective chemical route to produce new complex structures with different stability mechanisms. In this work, two new complex intermetallic structures have been discovered in the Ca-Li-Zn system: Ca12LixZn59-x and Ca15LixZn75-x. Ca12LixZn59-x, x ≈ 5.65(3)-14.95(3), forms in the trigonal space group R3̅m, with a = 9.074(1)-9.1699(2) Å, c = 53.353(1)-53.602(1) Å, and Z = 3. In comparison, Ca15LixZn75-x, x ≈ 19.07(2), crystallizes in the space group P63/mmc, with a ≈ 9.183(1) Å, c ≈ 45.191(5) Å), and Z = 2. Both structures are members of a large intergrowth family featuring slabs of dimers (D) and trimers (T) stacking along [001], with the sequences DTDDTDDTD for Ca12LixZn59-x and TDDDTDDD for Ca15LixZn75-x. Each dimer consists of two face-sharing Zn-centered hypho-icosahedra, and each trimer comprises a Li-centered icosahedron sandwiched by two hypho-icosahedra. This intergrowth family includes several known intermetallic structure types involving
 very electropositive metals, e.g., SrMg5.2, Ba2Li4.21Al4.79, and Sr9Li17.5Al25.5. Because of cluster defects and condensation, both Ca12LixZn59-x and Ca15LixZn75-x are electronically akin to close-packed metals, and their structural stabilities can be interpreted by a Hume-Rothery mechanism rather than the Zintl-Klemm concept.
Sha Shen Mai Men Dong Tang (SMD-2; shā shēn mài dōng tāng) is a Chinese medicinal herb (CMH; zhōng cǎo yào) used to treat symptoms associated with cancer therapy. The objective of this study was to assess the effect of SMD-2 on the levels of urinary copper (Cu), zinc (Zn), and selenium (Se) in lung cancer patients and head and neck cancer patients receiving chemoradiotherapy. Forty-two head and neck cancer patients and 10 lung cancer patients participated in our clinical trial. Each patient received chemoradiotherapy for 4 weeks. In addition, each patient was treated with SMD-2 for 8 weeks, including 2 weeks prior to and after the chemoradiotherapy treatment. Comparison of urinary Cu, Zn, and Se levels and the ratios of Zn to Cu and Se to Cu at three time points in the two types of cancer were assessed using the generalized estimating equations (GEEs). After the patients received chemoradiotherapy for 4 weeks, SMD-2 treatment was found to be associated with a significant decrease in urinary Cu levels, whereas urinary Zn and Se levels increased significantly. In addition, the ratios of Zn to Cu and Se to Cu in the urine samples of these patients also increased significantly. Both the urinary Zn levels and the ratio of Zn to Cu in head and neck cancer patients were significantly higher than in lung cancer patients. Urinary Zn and Se levels and the ratios of Zn to Cu and Se to Cu, but not urinary Cu levels, increased significantly during and after treatment when assessed using the GEE model. The SMD-2 treatments significantly increased Zn and Se levels in the urine of head and neck cancer patients. Increased Zn and Se levels in urine strengthened immune system.
CMP-sialic acid synthetase (CSAS) is a key enzyme of the sialylation pathway. CSAS produces the activated sugar donor, CMP-sialic acid, which serves as a substrate for sialyltransferases to modify glycan termini with sialic acid. Unlike other animal CSASs that normally localize in the nucleus, Drosophila melanogaster CSAS (DmCSAS) localizes in the cell secretory compartment, predominantly in the Golgi, which suggests that this enzyme has properties distinct from those of its vertebrate counterparts. To test this hypothesis, we purified recombinant DmCSAS and characterized its activity in vitro Our experiments revealed several unique features of this enzyme. DmCSAS displays specificity for N-acetylneuraminic acid as a substrate, shows preference for lower pH and can function with a broad range of metal cofactors. When tested at a pH corresponding to the Golgi compartment, the enzyme showed significant activity with several metal cations, including Zn(2+), Fe(2+), Co(2+) and Mn(2+), whereas the activity with Mg(2+) was found to be low. Protein sequence analysis and site-specific mutagenesis identified an aspartic acid residue that is necessary for enzymatic activity and predicted to be involved in co-ordinating a metal cofactor. DmCSAS enzymatic activity was found to be essential in vivo for rescuing the phenotype of DmCSAS mutants. Finally, our experiments revealed a steep dependence of the enzymatic activity on temperature. Taken together, our results indicate that DmCSAS underwent evolutionary adaptation to pH and ionic environment different from that of counterpart synthetases in vertebrates. Our data also suggest that environmental temperatures can regulate Drosophila sialylation, thus modulating neural transmission.
Recent studies have indicated that mammalian cells contain a cytosolic protein disaggregation machinery comprised of Hsc70, DnaJ homologs, and Hsp110 proteins, the last of which acts to accelerate a rate-limiting step of nucleotide exchange of Hsc70. We tested the ability of transgenic overexpression of a Thy1 promoter-driven human Hsp110 protein, HspA4L (Apg1), in neuronal cells of a transgenic G85R SOD1YFP ALS mouse strain to improve survival. Notably, G85R is a mutant version of Cu/Zn superoxide dismutase 1 (SOD1) that is unable to reach native form and that is prone to aggregation, with prominent YFP-fluorescent aggregates observed in the motor neurons of the transgenic mice as early as 1 mo of age. The several-fold overexpression of Hsp110 in motor neurons of these mice was associated with an increased median survival from ∼5.5 to 7.5 mo and increased maximum survival from 6.5 to 12 mo. Improvement of survival was also observed for a G93A mutant SOD1 ALS strain. We conclude that neurodegeneration associated with cytosolic misfolding and aggregation can be ameliorated by overexpression of Hsp110, likely enhancing the function of a cytosolic disaggregation machinery.
Near-forward Raman scattering combined with ab initio phonon and bond length calculations is used to study the 'phonon-polariton' transverse optical modes (with mixed electrical-mechanical character) of the II-VI ZnSe1-x S x mixed crystal under pressure. The goal of the study is to determine the pressure dependence of the poorly-resolved percolation-type Zn-S Raman doublet of the three oscillator [1  ×  (Zn-Se), 2  ×  (Zn-S)] ZnSe0.68S0.32 mixed crystal, which exhibits a phase transition at approximately the same pressure as its two end compounds (~14 GPa, zincblende  →  rocksalt), as determined by high-pressure x-ray diffraction. We find that the intensity of the lower Zn-S sub-mode of ZnSe0.68S0.32, due to Zn-S bonds vibrating in their own (S-like) environment, decreases under pressure (Raman scattering), whereas its frequency progressively converges onto that of the upper Zn-S sub-mode, due to Zn-S vibrations in the foreign (Se-like) environment (ab initio calculations). Ultimately, only the latter sub-mode survives. A similar 'phonon freezing' was earlier evidenced with the well-resolved percolation-type Be-Se doublet of Zn1-x Be x Se (Pradhan et al 2010 Phys. Rev. B 81 115207), that exhibits a large contrast in the pressure-induced structural transitions of its end compounds. We deduce that the above collapse/convergence process is intrinsic to the percolation doublet of a short bond under pressure, at least in a ZnSe-based mixed crystal, and not due to any pressure-induced structural transition.
Novel binuclear Zn(ii) complexes (1-2) derived from bis-chelating salen type ligands (H2L(1) and H2L(2)) possessing N,N-diethylamine moieties on the periphery of the molecules have been synthesized and thoroughly characterized by satisfactory elemental analyses and spectral (FT-IR, (1)H, (13)C NMR, UV-vis, fluorescence and ESI-MS) studies. The structures of H2L(1) and 1 have been authenticated by single crystal X-ray diffraction analyses. Complexes 1 and 2 strongly fluoresce and act as highly selective and sensitive chemosensors for picric acid in different organic as well as aqueous media. Both 1 and 2 showed strong potential to detect traces of PA in vapour/solid phase through contact mode analysis. Spectral and theoretical (DFT) studies suggested that the observed fluorescence quenching may be associated with ground state (GS) charge transfer as well as electrostatic interactions between 1/2 and PA. The fluorescence lifetime for the representative complex 1 displayed a double exponential curve and unaltered lifetime (τav, 0.63 nm) in the absence and presence of PA and strongly suggested that quenching follows a static mechanism. Further, DFT calculations on 1 and 2 strongly supported the static mechanism through GS charge transfer between complexes and PA. In addition, (1)H NMR spectral studies on 1-2 in the presence of PA firmly advocated strong hydrogen bonding and π-π stacking between the phenolic rings of 1-2 and the aromatic ring of PA. These complexes are capable of detecting PA either individually or in a competitive environment of other nitro- explosives. Florescence spectral studies on the model complex M lacking N,N-diethylamine groups revealed moderate selectivity and sensitivity towards PA and supported the key role of N,N-diethylamine moieties in the selectivity and sensitivity of complexes.
A new metal-organic framework Zn2(H2O)(dobdc)·0.5(H2O) (UTSA-74, H4dobdc = 2,5-dioxido-1,4-benzenedicarboxylic acid), Zn-MOF-74/CPO-27-Zn isomer, has been synthesized and structurally characterized. It has a novel four coordinated fgl topology with one-dimensional channels of about 8.0 Å. Unlike metal sites in the well-established MOF-74 with a rod-packing structure in which each of them is in a five coordinate square pyramidal coordination geometry, there are two different Zn(2+) sites within the binuclear secondary building units in UTSA-74 in which one of them (Zn1) is in a tetrahedral while another (Zn2) in an octahedral coordination geometry. After activation, the two axial water molecules on Zn2 sites can be removed, generating UTSA-74a with two accessible gas binding sites per Zn2 ion. Accordingly, UTSA-74a takes up a moderately high and comparable amount of acetylene (145 cm(3)/cm(3)) to Zn-MOF-74. Interestingly, the accessible Zn(2+) sites in UTSA-74a are bridged by carbon dioxide molecules instead of being terminally bound in Zn-MOF-74, so UTSA-74a adsorbs a much smaller amount of carbon dioxide (90 cm(3)/cm(3)) than Zn-MOF-74 (146 cm(3)/cm(3)) at room temperature and 1 bar, leading to a superior MOF material for highly selective C2H2/CO2 separation. X-ray crystal structures, gas sorption isotherms, molecular modeling, and simulated and experimental breakthroughs comprehensively support this result.
This study aimed to isolate, identify, and characterise metal-tolerant fungi colonising poplar roots at a metal-contaminated phytoremediation site.
 Poplar roots were colonised by arbuscular mycorrhizal, ectomycorrhizal, and endophytic fungi, and the species were determined by ITS molecular analyses. Eight different isolates were successfully isolated into pure culture. Three isolates belonging to the Helotiales (P02, P06) and the Serendipita vermifera species (P04) were highly tolerant to metals (Cd, Zn, Pb, and Cu) compared to the mycorrhizal Hebeloma isolates. The three isolates degraded complex carbohydrates, such as xylan and cellulose, indicating that they could partially degrade root cell walls and penetrate into cells. This hypothesis was confirmed by further in vitro re-synthesis experiments, which showed that the three isolates colonised root tissues of poplar plantlets whereas two of them formed microsclerotia-like structures. Taken together, these results suggest an endophytic lifestyle of these isolates. This is the first evidence of S. vermifera as a root endophyte of poplar. A new endophytic putative species belonging to the Helotiales and closely related to Leohumicola is also reported. Interestingly, and when compared to mock-inoculated plants, both P06 and P04 isolates increased the number of root tips of inoculated poplar plantlets in vitro. Moreover, the S. vermifera P04 isolate also increased the shoot biomass. The results are discussed in relation to the potential use of endophytic strains for tree-based phytoremediation of metal-contaminated sites.
Poly(l-lactide)-b-poly(ethylene oxide) block copolymer (mPEG-b-PLLA) micelles were fabricated and applied as a new biodegradable and biocompatible nanocarrier for solubilization of hydrophobic zinc (II) phthalocyanine (ZnPc). The nanocarrier demonstrated a good colloidal stability and its in vitro sustained cargo release profile was assessed. Photobleaching of ZnPc, both in its native form and encapsulated in the obtained polymeric micelles, was studied by means of spectroscopic measurements. The photodynamic reaction (PDR) protocol for cyto- and photocytotoxicity was performed on metastatic melanoma cells (Me45), normal human keratinocytes (HaCaT) being used for comparison. The intracellular accumulation of free and encapsulated ZnPc was visualized at various time periods (1, 3 and 24h). The proapoptotic potential of the encapsulated phthalocyanine was evaluated by monitoring DNA double strand break damage fragmentation (TUNEL assay) and caspase 3/7 activity. In addition, in vitro biocompatibility studies were conducted by determining hemolytic activity of Zn-Pc-loaded mPEG-b-PLLA micelles and their lack of cytotoxicity against macrophages (P388/D1) and endothelial cells (HUV-EC-C). Our results suggest that the PDR using Zn-Pc-loaded mPEG-b-PLLA micelles can be effective in inhibiting tumor cell growth and apoptosis induction with higher responses, observed for Me45 cells. Additionally, the ZnPc-loaded micelles appear to be hemato-biocompatible and safe for normal keratinocytes, macrophages and endothelial cells.
Metal ion-assisted drug loading model, in which metal ion was used to modify the microstructure of lipid layer, has been developed to improve drug loading efficiency of solid lipid nanoparticles (SLNs). The microstructure and properties of metal ion-assisted cisplatin-loading SLNs were investigated by infra-red spectroscopy, fluorescence spectroscopy and zetasizer. The reactions of hydrogenated soybean lecithin with Zn(2+), Cu(2+), Mn(2+ )and Mg(2+ )have been detected; the mechanism for higher drug encapsulation efficiency (EE) has been investigated. In metal ion introduction SLNs, the compact degree of the lipid molecules was increased due to the electrostatic interaction between metal ions and phospholipid acyl and choline polarity groups, which result in increasing of drug EE. Meanwhile, these electrostatic interactions slowed the releasing rate of encapsulated drug. The study of cytotoxic activity in vitro indicated that the cell cytotoxicity of metal ions introduction SLNs depended on both cell uptake of SLNs and drug releasing from SLNs.
In order to improve the chemotherapy of tuberculosis, there is an urgent need to enhance the efficacy of existing agents and also to develop more efficient drug delivery systems. Here, we synthesized a novel anti-TB drug complex consisting of zinc and rifampicin (Zn-RIF), and encapsulated it into transferrin-conjugated silver quantum-dots (Zn-RIF-Tf-QD) to improve delivery in macrophages. Successful synthesis of Zn-RIF and Zn-RIF-Tf-QD was confirmed by UV/Vis-spectroscopy, TEM, FTIR, photoluminescence, XRD, XPS, and NMR. The sizes of silver QDs and transferrin-conjugated QDs were found to be in the range of 5-20 nm. Activity assays showed that Zn-RIF-Tf-QD exhibited 10-fold higher antibacterial activity against Mycobacterium smegmatis and Mycobacterium bovis-BCG as compared to Zn-RIF, RIF and Zn. Immunofluorescence studies showed that Zn-RIF-Tf-QD-conjugates were actively endocytosed by macrophages and dendritic cells, but not by lung epithelial cells. Treatment with Zn-RIF-Tf-QD efficiently killed mycobacteria residing inside macrophages without exhibiting cytotoxicity and genotoxicity. Moreover, the conjugates remained stable for upto 48 h, were taken up into the late endosomal compartment of macrophages, and released the drug in a sustainable manner. Our data demonstrate that Zn-RIF-Tf-QDs have a great potential as anti-TB drugs. In addition, transferrin-conjugated QDs may constitute an effective drug delivery system for tuberculosis therapy.
In our efforts of developing novel compounds as potential anticancer agents, a series of tamibarotene analogs containing Zn(2+) -binding moieties were designed and developed. Biological characterization identified compound 7b as the most potent one with improved antiproliferative activities against multiple cancer cell lines, compared to parent compound tamibarotene. Further characterization also demonstrated that compound 7b exhibited moderate activities as a histone deacetylase inhibitor with IC50 of 1.8 ± 0.1 μm, thus suggesting that this could contribute to the improved antiproliferative activities of 7b. Pharmacokinetic studies revealed that compound 7b could release tamibarotene after administration and prolong the circulation time of tamibarotene, and this may also potentially contribute to the improved antiproliferative activities. Collectively, the results demonstrated that compound 7b could serve as a new lead for further development of more potent analogs as potential anticancer agents.
Magnetic and geochemical parameters of soils are determined with respect to geology, pedogenesis and anthropopression. Depending on local conditions these factors affect magnetic and geochemical signals simultaneously or in various configurations. We examined four type of soils (Entic Podzol, Eutric Cambisol, Humic Cambisol and Dystric Cambisol) developed on various bedrock (the Tumlin Sandstone, basaltoid, amphibolite and serpentinite, respectively). Our primary aim was to characterize the origin and diversification of the magnetic and geochemical signal in soils in order to distinguish the most reliable methods for correct interpretation of measured parameters. Presented data include selected parameters, both magnetic (mass magnetic susceptibility - χ, frequency-dependent magnetic susceptibility - χfd and thermomagnetic susceptibility measurement - TSM), and geochemical (selected heavy metal contents: Co, Cr, Cu, Fe, Mn, Ni, Pb, Zn). Additionally, the enrichment factor (EF) and index of geoaccumulation (Igeo) were calculated. Our results suggest the following: (1) the χ/Fe ratio may be a reliable indicator for determining changes of magnetic signal origin in soil profiles; (2) magnetic and geochemical signals are simultaneously higher (the increment of χ and lead and zinc was noted) in topsoil horizons because of the deposition of technogenic magnetic particles (TMPs); (3) EF and Igeo evaluated for lead and zinc unambiguously showed anthropogenic influence in terms of increasing heavy metal contents in topsoil regardless of bedrock or soil type; (4) magnetic susceptibility measurements supported by TSM curves for soil samples of different genetic horizons are a helpful tool for interpreting the origin and nature of the mineral phases responsible for the changes of magnetic susceptibility values.
ZnO nanoparticles (NPs) are reported to show a high degree of cancer cell selectivity with potential use in cancer imaging and therapy. Questions remain about the mode by which the ZnO NPs cause cell death, whether they exert an intra- or extracellular effect, and the resistance among different cancer cell types to ZnO NP exposure. The present study quantifies the variability between the cellular toxicity, dynamics of cellular uptake, and dissolution of bare and RGD (Arg-Gly-Asp)-targeted ZnO NPs by MDA-MB-231 cells. Compared to bare ZnO NPs, RGD-targeting of the ZnO NPs to integrin αvβ3 receptors expressed on MDA-MB-231 cells appears to increase the toxicity of the ZnO NPs to breast cancer cells at lower doses. Confocal microscopy of live MDA-MB-231 cells confirms uptake of both classes of ZnO NPs with a commensurate rise in intracellular Zn(2+) concentration prior to cell death. The response of the cells within the population to intracellular Zn(2+) is highly heterogeneous. In addition, the results emphasize the utility of dynamic and quantitative imaging in understanding cell uptake and processing of targeted therapeutic ZnO NPs at the cellular level by heterogeneous cancer cell populations, which can be crucial for the development of optimized treatment strategies.
The effects of pig manure, from diets incorporating veterinary pharmaceuticals, on survival and reproduction of Folsomia candida were evaluated. Manures derived from the following diets: corn and soymeal (CS); 85% CS diet+15% wheat meal (TR); CS diet+100ppm
 doxycycline+50ppm colistin+2500ppm Zn oxide (CSa); TR diet+100ppm doxycycline+50ppm colistin+2500ppm Zn oxide (TRa). Manures were tested in two subtropical soils representative of southern (Oxisol and Entisol). Despite the antibiotics no significant differences were found between the four manures within each soil. However, strong differences were found on the toxicity between soils. In Oxisol, LC50 values were around 100m(3)ha(-1), and EC50 values around 80m(3)ha(-1). In Entisol these were much lower, with LC50 values oscillating around 20m(3)ha(-1) and EC50 values between 10-15m(3)ha(-1). The observed toxicity on both soils was attributed to excess of nitrogen, Cu and Zn in the highest doses. The strong difference between soils could be explained by soil properties, namely CEC, organic matter, and clay contents that were lower in Entisol, indicating a poor ability to retain contaminants increasing their availability in soil. Results suggest that the application of these residues should be regulated not only using a volume-based criterion, but should incorporate data on soil properties, complemented by an ecotoxicological assessment.
Biochar (BC) is a carbonaceous material obtained by pyrolysis of organic waste materials and has been proposed as a soil management strategy to mitigate global warming and to improve crop productivity. Once BC has been applied to the soil, its imperfect and incomplete mixing with soil during the first few years and the standard agronomic practices (i.e. tillage, sowing) may generate spatial heterogeneity of the BC content in the soil, which may have implications for soil properties and their effects on plant growth. We investigated how, after two agronomic seasons, the spatial heterogeneity of olive-tree prunings BC applied to a vertisol affected soil characteristics and wheat growth and yield. During the second agronomic season and just before wheat germination, we determined the BC content in the soil by an in-situ visual categorization based on the soil darkening, which was strongly correlated to the BC content of the soil and the soil brightness. We found a high spatial heterogeneity in the BC plots, which affected soil characteristics and wheat growth and yield. Patches with high BC content showed reduced soil compaction and increased soil moisture, pH, electrical conductivity, and nutrient availability (P, Ca, K, Mn, Fe, and Zn); consequently, wheat had greater tillering and higher relative growth rate and grain yield. However, if the spatial heterogeneity of the soil BC content had not been taken into account in the data analysis, most of the effects of BC on wheat growth would not have been detected. Our study reveals the importance of taking into account the spatial heterogeneity of the BC content.
Acid-fast bacilli microscopy is the first step in the diagnosis and screening of pulmonary tuberculosis (PTB) in developing countries. It remains a rapid and inexpensive diagnostic tool for diagnosing a large number of PTB cases with limited resources.
To evaluate three different staining techniques used in the detection of acid-fast bacilli. The conventional Ziehl-Neelsen (ZN) stain and two cold stains, Gabbett's cold stain and modified cold stain (MCS), were compared with sputum culture.
A total of 300 sputum samples from 100 clinically suspected PTB patients referred to Maamorah Chest Hospital in Alexandria, Egypt, were tested. For staining and culture, three sputum samples from each patient were collected (one 'on spot' and two early morning samples) and pooled together. Smears were prepared using three different staining methods (ZN, Gabbett's cold stain, and MCS) and were inoculated in the Lowenstein-Jensen media.
Comparison of sputum staining results using three different staining techniques versus culture proved that the highest sensitivity and specificity were seen for Gabbett's stain (76.6 and 98.5%, respectively). ZN stain had a sensitivity and specificity of 70 and 97.1%, whereas MCS had a sensitivity and specificity of 60 and 95.7%, respectively.
Gabbett's stain was more accurate in the diagnosis of PTB compared with both ZN and MCS, even though the results were not statistically significant. It can replace ZN for initial diagnosis and follow up of cases. It is also easier, faster, and does not require a heating step.
Two 3d-4d heteropolynuclear clusters with Ag-Zn ratios of 9:2 and 9:4 were stepwise constructed from a robust nonanuclear silver cluster. Their crystal structures consist of a common bucket-shaped [Ag9(mba)9](9-) (H2mba = 2-mercaptobenzoic acid) core with different numbers of Zn(II) connected by different exo-oriented carboxylates. Most fascinating is the observation of emission (∼703 nm) in the near-infrared (NIR) region at 300 K that may be compared to the related Ag9Zn3 cluster with aliphatic polyamine as auxiliary ligand that emits from the visible (∼580 nm). The shift is associated with the change of ligand field of the 2,2'-bipyridine. The emission intensity and lifetime were dramatically enhanced along with the slight bathochromic shift upon cooling from 300 K to 80 K. The results raise two significant issues: (a) the structural and electronic effects of the secondary metal binding to the metalloligand and the factors influencing the heteropolynuclear cluster assembly and (b) the use of NIR fluorescence, introduced by integrating two luminophores into one heteropolynuclear entity, in detecting free-moving zinc in biological systems both in vivo and in vitro.
Lipopolysaccharide (LPS)-induced oxidative stress is a main feature observed in the sepsis by increasing endothelial oxidative damage. Many studies have demonstrated that Ulinastatin (UTI) can inhibit pro-inflammatory proteases, decrease inflammatory cytokine levels and suppress oxidative stress. However, the potential molecular mechanism underlying UTI which exerts its antioxidant effect is not well understood. In this study, we aimed to investigate the effects of UTI on the LPS-induced oxidative stress and the underlying mechanisms using human umbilical vein endothelial cells (HUVECs). After oxidative stress induced By LPS in HUVECs, the cell viability and reactive oxygen species (ROS) in cytoplasm were measured. In addition, superoxide dismutase (SOD) and malondialdehyde (MDA) were examined. We found that LPS resulted in a profound elevation of ROS production and MDA levels. The decrease in Cu/Zn-SOD protein and increased in Mn-SOD protein were observed in a time- and dose-dependent manner. These responses were suppressed by an addition of UTI. The increase in c-Jun N-terminal kinases (JNK) phosphorylation by LPS in HUVECs was markedly blocked by UTI or JNK inhibitor SP600125. Our results suggest that UTI exerts its anti-oxidant effects by decreasing overproduction of ROS induced by LPS via suppressing JNK/c-Jun phosphorylation. Therefore UTI may play a protective role in vascular endothelial injury induced by oxidative stress such as sepsis. This study may provide insight into a possible molecular mechanism by which Ulinastatin inhibits LPS-induced oxidative stress.
The dipyrrin-1,9-dione scaffold of heme metabolite propendyopent coordinates late transition metals (Co, Ni, Cu, and Zn) forming homoleptic, pseudo-tetrahedral complexes. Electrochemical and spectroscopic studies reveal that the monoanionic, bidentate ligands behave as electron reservoirs as the complexes reversibly host one or two ligand-based radicals.
The Antarctic fungal strain Aspergillus glaucus 363 produces cold-active (CA) Cu/Zn-superoxide dismutase (SOD). The strain contains at least one gene encoding Cu/Zn-SOD that exhibited high homology with the corresponding gene of other Aspergillus species. To our knowledge, this is the first nucleotide sequence of a CA Cu/Zn-SOD gene in fungi. An effective laboratory technology for A. glaucus SOD production in 3 L bioreactors was developed on the basis of transient cold-shock treatment. The temperature downshift to 10 °C caused 1.4-fold increase of specific SOD activity compared to unstressed culture. Maximum enzyme productivity was 64 × 10(3) U kg(-1) h(-1). Two SOD isoenzymes (Cu/Zn-SODI and Cu/Zn-SODII) were purified to electrophoretic homogeneity. The specific activity of the major isoenzyme, Cu/Zn-SODII, after Q-Sepharose chromatography was 4000 U mg(-1). The molecular mass of SODI (38 159 Da) and of SODII (15 835 Da) was determined by electrospray quadropole time-of-flight (ESI-Q-TOF) mass spectrometry and dynamic light scattering (DLS). The presence of Cu and Zn were confirmed by inductively coupled plasma mass spectrometry (ICP-MS). The N-terminal amino acid sequence of Cu/Zn-SODII revealed a high degree of structural homology with Cu/Zn-SOD from other fungi, including Aspergillus species.
Using high-resolution NMR spectroscopy, we studied peculiarities of the unfolding process of the bacteriophage T5 endolysin (EndoT5) by strong denaturants. It was shown that in the absence of zinc ions this protein is mostly unfolded in the solution of 8 M urea or 6 M guanidine hydrochloride. However, in the presence of zinc ions EndoT5 unfolding can be achieved only in acidic solutions (at pH < 4.0), whereas at pH > 4.0 NMR spectra of the metal-bound protein (Zn(2+)-Ca(2+)-EndoT5 or Zn(2+)-EndoT5 complexes) exhibit a few chemical shifts characteristic of the native or native-like proteins. Our data, including the pH-titration curve with the pK of ~5, suggested involvement of the zinc-binding histidines in the stabilization of this protein. Up-field signals that appear in the NMR spectra of apo-EndoT5 in the presence of high concentrations of strong denaturants are probably derived from the amino acid residues included in the formation of structured hydrophobic cluster, which likely corresponds to the 81-93 region of EndoT5 and contains some residual tertiary structure. It is possible
 also that this hydrophobic fragment serves as a foundation for the formation of structured cluster in the unfolded state.
Dinuclear clathrochelate complexes are easily accessible by reaction of zinc(ii) triflate or cobalt(ii) nitrate with arylboronic acids and phenoldioximes. The utilization of brominated arylboronic acids and/or brominated phenoldioximes allows preparing clathrochelates with two, three, five or seven bromine atoms on the outside. These clathrochelates can undergo Pd-catalyzed cross-coupling reactions with 3- and 4-pyridylboronic acid to give new metalloligands featuring up to seven pyridyl groups. The pyridyl-capped clathrochelates display characteristics which make them interesting building blocks for structural supramolecular chemistry: they are rigid, large (up to 2.7 nm), luminescent (for M = Zn), and anionic. The pentatopic pyridyl ligands display an unusual trigonal bipyramidal geometry.
Currently, there is an urgent need for biocompatible metal-ion chelators capable of antioxidant activity and disassembly of amyloid beta (Aβ)-aggregates as potential therapeutics for Alzheimer's disease (AD). We recently demonstrated the promising antioxidant activity of adenine/guanine 2',3' or 3',5'-bis(thio)phosphate analogues, 2'-dA/G3'5'PO/S and A2'3'PO/S, and their affinity to Zn(ii)-ions. These findings encouraged us to evaluate them as agents for the dissolution of Aβ42-Zn(ii)/Cu(ii) aggregates. Specifically, we explored their ability to bind Cu(ii)/Zn(ii)-ions, the geometry and stoichiometry of these complexes, Cu(ii)/Zn(ii)-binding-sites and binding mode, and the ability of these analogues to dissolve Aβ42-Zn(ii)/Cu(ii) aggregates, as well as their effect on the secondary structure of those aggregates. Finally, we identified the most promising agents for dissolution of Aβ42-Zn(ii)/Cu(ii) aggregates. Specifically, we observed the formation of a 1 : 1 complex between 2'-dG3'5'PO and Cu(ii), involving O4 ligands. Zn(ii) was coordinated by both thiophosphate groups of 2'-dA3'5'PS and A2'3'PS involving O2S2 ligands in a 1 : 1 stoichiometry. A2'3'PS dissolves Aβ42-Zn(ii) and Aβ42-Cu(ii) aggregates as effectively as, and 2.5-fold more effectively than EDTA, respectively. Furthermore, 2'-dG3'5'PS and A2'3'PS reverted the Aβ42-M(ii) structure, back to that of the free Aβ42. Finally, cryo-TEM and TEM images confirmed the disassembly of Aβ42 and Aβ42-M(ii) aggregates by A2'3'PS. Hence, 2'-dG3'5'PS and A2'3'PS may serve as promising scaffolds for new AD therapeutics, acting as both effective antioxidants and agents for solubilization of Aβ42-Cu(ii)/Zn(ii) aggregates.
To harness the unique properties of graphene and ZnO nanoparticles (NPs) for novel applications, the development of graphene-ZnO nanoparticle hybrid materials has attracted great attention and is the subject of ongoing research. For this contribution, graphene-oxide-ZnO (GO-ZnO) and thiol-functionalized reduced graphene oxide-ZnO (TrGO-ZnO) nanohybrid materials were prepared by novel self-assembly processes. Based on electron paramagnetic resonance (EPR) and photoluminescence (PL) investigations on bare ZnO NPs, GO-ZnO and TrGO-ZnO hybrid materials, we found that several physical phenomena were occurring when ZnO NPs were hybridized with GO and TrGO. The electrons trapped in Zn vacancy defects (VZn(-)) within the core of ZnO NPs vanished by transfer to GO and TrGO in the hybrid materials, thus leading to the disappearance of the core signals in the EPR spectra of ZnO NPs. The thiol groups of TrGO and sulfur can effectively "heal" the oxygen vacancy (VO(+)) related surface defects of ZnO NPs while oxygen-containing functionalities have low healing ability at a synthesis temperature of 100 °C. Photoexcited electron transfer from the conduction band of ZnO NPs to graphene leads to photoluminescence (PL) quenching of near band gap emission (NBE) of both GO-ZnO and TrGO-ZnO. Simultaneously, electron transfer from graphene to defect states of ZnO NPs is the origin of enhanced green defect emission from GO-ZnO. This observation is consistent with the energy level diagram model of hybrid materials.
Metal ions play crucial roles in numerous biological processes, facilitating biochemical reactions by binding to various proteins. An increasing body of evidence suggests that neurotoxicity associated with exposure to nonessential metals (e.g., Pb(2+)) involves disruption of synaptic activity, and these observed effects are associated with the ability of Pb(2+) to interfere with Zn(2+) and Ca(2+)-dependent functions. However, the molecular mechanism behind Pb(2+) toxicity remains a topic of debate. In this review, we first discuss potential neuronal Ca(2+) binding protein (CaBP) targets for Pb(2+) such as calmodulin (CaM), synaptotagmin, neuronal calcium sensor-1 (NCS-1), N-methyl-d-aspartate receptor (NMDAR) and family C of G-protein coupled receptors (cGPCRs), and their involvement in Ca(2+)-signalling pathways. We then compare metal binding properties between Ca(2+) and Pb(2+) to understand the structural implications of Pb(2+) binding to CaBPs. Statistical and biophysical studies (e.g., NMR and fluorescence spectroscopy) of Pb(2+) binding are discussed to investigate the molecular mechanism behind Pb(2+) toxicity. These studies identify an opportunistic, allosteric binding of Pb(2+) to CaM, which is distinct from ionic displacement. Together, these data suggest three potential modes of Pb(2+) activity related to molecular and/or neural toxicity: (i) Pb(2+) can occupy Ca(2+)-binding sites, inhibiting the activity of the protein by structural modulation, (ii) Pb(2+) can mimic Ca(2+) in the binding sites, falsely activating the protein and perturbing downstream activities, or (iii) Pb(2+) can bind outside of the Ca(2+)-binding sites, resulting in the allosteric modulation of the protein activity. Moreover, the data further suggest that even low concentrations of Pb(2+) can interfere at multiple points within the neuronal Ca(2+) signalling pathways to cause neurotoxicity.
Landfill leachate has become an important source of environmental pollution in past decades, due to the increase of waste volume. Acute toxic and genotoxic hazards to organisms can be caused by landfill leachate. Thus, how to efficiently recover water from landfill leachate and effectively eliminate combined toxicity of landfill leachate are the most pressing issues in waste management. In this study, EDTA-Na2Zn as draw solution (DS) was used to remove the toxicity of membrane bioreactor-treated landfill leachate (MBR-treated landfill leachate) in forward osmosis (FO) process, and nanofiltration (NF) was designed for recovering the diluted DS. Zebrafish and human cells were used for toxicity assay after the novel wastewater treatment process using EDTA-Na2Zn as DS. Results showed that the water recovery rate of MBR-treated landfill leachate (M-LL) in FO membrane system could achieve 66.5% and 71.2% in the PRO and FO mode respectively, and the diluted DS could be efficiently recovered by NF. Toxicity tests performed by using zebrafish and human cells showed that M-LL treated by EDTA-Na2Zn had no toxicity effect on zebrafish larvae and human cells, but it had very slight effect on zebrafish embryos. In conclusion, all results indicated that EDTA-Na2Zn as DS can effectively eliminate toxicity of landfill leachate and this method is economical and eco-friendly for treatment of different types of landfill leachate.
Albumin has gained considerable interest as a material for fabricating nanoparticulate systems due to its biomedical advantages, such as biocompatibility and chemical functionality. Here, we report a new pH-sensitive albumin nanocomplex prototype with a zinc-imidazole coordination bond. Albumin was conjugated with 1-(3-aminopropyl)imidazole and mPEG10kDa-NHS, and the resulting albumin conjugate (PBI) was then modified with either Cy5.5 or BHQ-3. The newly formed albumin nanocomplex (C/BQ-PBI Zn NCs: ∼116nm) system was facilely self-assembled around pH 7.4 in the presence of Zn(2+), but it quickly disassembled in an acidic environment (∼pH 5.0). Based on this pH-sensitivity, C/BQ-PBI Zn NCs emitted strong near-infrared fluorescence and released Zn(2+), turning "off" at pH ∼7.4 (e.g., plasma) and "on" at pH ∼5.0 (e.g., endo/lysosomes in tumor cells) on account of fluorescence resonance energy transfer. C/BQ-PBI Zn NCs displayed significant cytotoxicity due to an increase in cellular Zn(2+) in response to endosomal pH (∼5.0) in breast cancer MCF-7 cells and lung adenocarcinoma A549 cells. Particularly, confocal laser scanning microscopic images showed a strong fluorescence signal caused by the disassembly of C/BQ-PBI Zn NCs in the endosomal region of MCF-7 cells. Based on these results, we believe that this albumin nanocomplex is an attractive biocompatible tumor targeting probe carrier for the theranostic purpose.
The objective of the study was to evaluate utilization of dietary minerals and trace elements in pregnant heifers with distinct residual feed intakes (RFI). Feed intake, body weight (BW), and body composition traits were recorded in 36 crossbred heifers over a period of 37 wk, starting shortly after weaning at 8.3 (0.10; standard deviation) mo of age with an average BW of 276 (7.8) kg. Both BW and body composition were monitored regularly throughout the study, whereas individual feed intake was assessed during the last 84 d of the trial. Data recorded were used to calculate RFI for each heifer. Heifers were ranked based on RFI and assigned to high (n=14) or low (n=10) RFI groups. After the RFI study, 24 selected heifers [age 18.2 (0.14) mo; 87.5 (4.74) d in gestation; 497 (8.5) kg of BW] were used in an indirect digestibility trial (lignin as internal marker). Heifers were fed a ration containing corn silage, haylage, and a mineral premix in which Ca, P, K, Na, Mg, S, Cu, Fe,
 Mn, Mo, Se, Zn, and Co were provided in the diet according to National Research Council requirements of pregnant replacement heifers. The digestibility trial lasted 1 wk, during which samples of feces were gathered twice daily, and blood and liver biopsy samples were collected on the last day. We noted no significant differences between low- and high-RFI heifers in dry matter digestibility. Apparent absorption of Cu, Zn, and Mn was increased in heifers with low RFI, and apparent absorption of Co tended to be greater for these animals. Concentrations of macrominerals and trace elements in serum of pregnant heifers were similar for both groups except for Se, which was increased in the serum of low-RFI heifers. Liver concentrations of Cu, Fe, Mn, Mo, Se, and Zn did not differ between low- and high-RFI heifers. In conclusion, whereas improved absorption of some trace elements (Cu, Zn, Mn, and Co) and increased Se serum concentration appear to be associated with superior feed efficiency in pregnant heifers, further studies are needed to investigate the causality of such relationships.
Rice and chickpea GDPD s are transcriptionally influenced by mineral deficiencies; especially, by phosphate starvation and CaGDP1 encodes an active glycerophosphodiester phosphodiesterase enzyme. Glycerophosphodiester phosphodiesterases (GDPDs) are enzymes involved in the degradation of glycerophosphodiesters into sn-glycerol-3-phosphate and corresponding alcohols. These phospholipid remodeling genes have been suggested to play important roles in phosphate homeostasis. However, comprehensive information about the role of GDPDs under low phosphate (P) and other nutrient deficiencies (N, K, Fe, Zn) in rice and chickpea is missing. Here, we identified 13 OsGDPDs and 6 CaGDPDs in rice and chickpea, respectively, and partly characterized their roles in multiple nutrient stresses. Expression profiling after 7 and 15 days of deficiency treatments revealed unique and overlapping differential expression patterns of OsGDPDs and CaGDPDs under different nutrient stresses. Principal component analysis on the expression patterns of OsGDPDs and CaGDPDs revealed their preferential role in P starvation. Some of the GDPDs were also induced by N, K, Fe and Zn deficiency in temporal manner in both crops suggesting their roles in multiple nutrient stresses. Biochemical characterization of highly responsive chickpea GDPD, CaGDPD1, confirmed its in vitro GDPD activity and revealed its optimal temperature, pH and cofactor requirements. Further, CaGDPD1 showed its accumulation in ER and endomembranes. We hereby propose CaGDPD1 and various OsGDPDs as low P responsive marker genes in chickpea and rice, respectively. Our data uphold role of GDPDs in multinutrient responses and suggest them as candidates for rice and chickpea improvement for tolerance to various nutrient deficiencies.
Low iron (Fe) stores may result in increased absorption of divalent metals, in particular cadmium (Cd). We have previously shown that in non-smoking women participating in the Norwegian HUNT2 cohort study this also included other divalent metals, e.g. manganese (Mn) and cobalt (Co). The diet is the main source of metals in non-smoking individuals, whereas in smoking individuals tobacco smoke contributes significant amounts of Cd and lead (Pb). The aim of the present study was to investigate the impact of smoking on the relationship between low iron status and divalent metals. Blood concentrations of the divalent metals Cd, Mn, Co, Pb, copper (Cu) and zinc (Zn), determined using an Element 2 sector field mass spectrometer (ICP-MS), were investigated in smoking women of fertile age (range 21-55 years) (n=267) from the HUNT2 cohort. Among these, 82 were iron-deplete (serum ferritin<12μg/L) and 28 had iron deficiency anaemia (serum ferritin<12μg/L & Hb<120g/L). 150 (56%) women smoked 10 or more cigarettes daily, 101 (38%) had smoked for more than 20 years, and 107 (40%) had smoked for 11-20 years. Results from the smoking population were compared with results from our previous study in non-smoking women (n=448) of which 132 were previous smokers, all from the same cohort. Increasing concentrations of Cd in blood were observed for previous smokers, low-to-moderate smokers and high intensity smokers in all subgroups compared to never smokers, and according to age groups, education level, BMI and serum ferritin. Smokers had higher Pb concentrations than non-smokers in all subgroups, but less pronounced than for Cd. Smoking was not associated with Mn and Co concentrations in blood. In multiple regression models, low ferritin was associated with increased blood concentrations of Cd, Pb, Mn and Co. Ferritin was strongly associated with Cd at low smoking intensity, but was not a significant factor in heavy smokers, where intensity and duration of smoking emerged as main determinants. Ferritin associations with Co and Pb varied with tertiles of blood Cd. Ferritin emerged as the main determinant of blood Co and Mn, while for blood Pb, age and smoking intensity had higher impact. Cu and Zn remained within reference values and no significant associations with ferritin were found. Strong positive associations between blood concentrations of Pb, Mn, Cd and Co were observed, also when controlled for their common association with ferritin. Apart from these associations, the models showed no significant interactions between the divalent metals studied. Mild anaemia (110<Hb<120g/L) did not seem to have any effect independent of low ferritin. The results indicate that low serum ferritin facilitates absorption of certain divalent metal ions in female smokers as well as the previously shown effect in non-smokers. Even if smoking provides Pb and Cd, the mutual associations between Cd and other divalent metals in blood persisted in medium and heavy smokers. This indicates that the interrelationship between Cd and divalent metals not only reflect effects on the absorption, but possibly also on kinetic processes such as transportation in blood and other compartments, including excretion.
Quantification of the contributions from anthropogenic sources to soil heavy metal loadings on regional scales is challenging because of the heterogeneity of soil parent materials and high variability of anthropogenic inputs, especially for the species that are primarily of lithogenic origin. To this end, we developed a novel method for apportioning the contributions of natural and anthropogenic sources by combining sequential extraction and stochastic modeling, and applied it to investigate the heavy metal pollution in the surface soils of the Pearl River Delta (PRD) in southern China. On the average, 45-86% of Zn, Cu, Pb, and Cd were present in the acid soluble, reducible, and oxidizable fractions of the surface soils, while only 12-24% of Ni, Cr, and As were partitioned in these fractions. The anthropogenic contributions to the heavy metals in the non-residual fractions, even the ones dominated by natural sources, could be identified and quantified by conditional inference trees. Combination of sequential extraction, Kriging interpolation, and stochastic modeling reveals that approximately 10, 39, 6.2, 28, 7.1, 15, and 46% of the As, Cd, Cr, Cu, Ni, Pb, and Zn, respectively, in the surface soils of the PRD were contributed by anthropogenic sources. These results were in general agreements with those obtained through subtraction of regional soil metal background from total loadings, and the soil metal inputs through atmospheric deposition as well. In the non-residual fractions of the surface soils, the anthropogenic contributions to As, Cd, Cr, Cu, Ni, Pb, and Zn, were 48, 42, 50, 51, 49, 24, and 70%, respectively.
Zinc, an essential mineral element, regulates various physiological functions such as immune responses and hormone secretion. Cholecystokinin (CCK), a gut hormone, has a role in protective immunity through the regulation of gastrointestinal motility, appetite, and inflammatory response. Here, we examined the effect of zinc on CCK secretion in STC-1 cells, an enteroendocrine cell line derived from murine duodenum, and in rats. Extracellular zinc triggered CCK secretion accompanied with increased intracellular Ca(2+) and Zn(2+) mobilization in STC-1 cells. Zinc-induced CCK secretion was abolished in the absence of intracellular Zn(2+) or extracellular calcium. Upon inhibition of transient receptor potential ankyrin 1 (TRPA1), extracellular zinc failed to increase intracellular Ca(2+) and subsequent CCK secretion. In rats, oral zinc administration decreased gastric emptying through the activation of CCK signaling. These results suggest that zinc is a novel stimulant for CCK secretion through the activation of TRPA1 related to intracellular Zn(2+) and Ca(2+) mobilization.
The Zn(2+) in cardiomyocytes is buffered by structures near T-tubulus and/or sarcoplasmic/endoplasmic reticulum (S(E)R) while playing roles as either an antioxidant or a toxic agent, depending on the concentration. Therefore, we aimed first to examine a direct effect of ZnPO4 (extracellular exposure) or Zn(2+) pyrithione (ZnPT) (intracellular exposure) application on the structure of the mitochondrion in ventricular cardiomyocytes by using histological investigations. The light microscopy data demonstrated that Zn(2+) exposure induced marked increases on cellular surface area, an indication of hypertrophy, in a concentration-dependent manner. Furthermore, a whole-cell patch-clamp measurement of cell capacitance also supported the hypertrophy in the cells. We observed marked increases in mitochondrial matrix/cristae area and matrix volume together with increased lysosome numbers in ZnPO4- or ZnPT-incubated cells by using transmission electron microscopy, again in a concentration-dependent manner. Furthermore, we observed notable clustering and vacuolated
 mitochondrion, markedly disrupted and damaged myofibrils, and electron-dense small granules in Zn(2+)-exposed cells together with some implications of fission-fusion defects in the mitochondria. Moreover, we observed marked depolarization in mitochondrial membrane potential during 1-μM ZnPT minute applications by using confocal microscopy. We also showed that 1-μM ZnPT incubation induced significant increases in the phosphorylation levels of GSK3β (Ser21 and Ser9), Akt (Ser473), and NFκB (Ser276 and Thr254) together with increased expression levels in ER stress proteins such as GRP78 and calregulin. Furthermore, a new key player at ER-mitochondria sites, promyelocytic leukemia protein (PML) level, was markedly increased in ZnPT-incubated cells. As a summary, our present data suggest that increased cytosolic free Zn(2+) can induce marked alterations in mitochondrion morphology as well as depolarization in mitochondrion membrane potential and changes in some cytosolic signaling proteins as well as a defect in ER-mitochondria cross talk.
Natural and artificial radionuclides and heavy metals in the surface soil of the uranium mining area of Tongliao, China, were measured using gamma spectrometry, flame atomic absorption spectrophotometry, graphite furnace atomic absorption spectrophotometry and microwave dissolution atomic fluorescence spectrometry respectively. The estimated average activity concentrations of (238)U, (232)Th, (226)Ra, (40)K and (137)Cs are 27.53±16.01, 15.89±5.20, 12.64±4.27, 746.84±38.24 and 4.23±4.76Bq/kg respectively. The estimated average absorbed dose rate in the air and annual effective dose rate are 46.58±5.26nGy/h and 57.13±6.45μSv, respectively. The radium equivalent activity, external and internal hazard indices were also calculated and their mean values are within the acceptable limits. The heavy metal concentrations of Pb, Cd, Cu, Zn, Hg and As from the surface soil were measured and their health risks were then determined. Although the content of Cd is much higher than the average background in China, its non-cancer and cancer risk indices are all within the acceptable ranges. These calculated hazard indices to estimate the potential radiological health risk in soil and the dose rate are well below their permissible limit. In addition the correlations between the radioactivity concentrations of the radionuclides and the heavy metals in soil were determined by the Pearson linear coefficient.
Endophytic plant growth-promoting bacteria (endophytes) were isolated from a variety of (pseudo)metallophytes growing in an abandoned Zn/Pb mine and then characterized according to their plant growth-promoting traits (i.e. ACC deaminase activity, IAA production, siderophore production, phosphate solubilising capacity, metal and salt tolerance and phenotypic characterization). Initially, under growth chamber conditions, an endophyte-assisted aided phytostabilization study was carried out with Festuca rubra plants (native vs. commercial variety) inoculated with a Pseudomonas sp. isolate and cow slurry as organic amendment. The effect of treatments on soil physicochemical and microbial indicators of soil quality, as well as plant physiological parameters and metal concentrations, was assessed. We performed a complementary interpretation of our data through their grouping within a set of ecosystem services. Although the application of cow slurry had the most pronounced effects on soil quality indicators and ecosystem services, the growth of native F. rubra plants reduced soil bioavailability of Cd and Zn by 19 and 22%, respectively, and enhanced several soil microbial parameters. On the other hand, endophyte (Pseudomonas sp.) inoculation improved the physiological status of F. rubra plants by increasing the content of carotenoids, chlorophylls and Fv/Fm by 69, 65 and 37%, respectively, while also increasing the values of several soil microbial parameters. Finally, a consortium of five endophyte isolates was used for an endophyte-assisted aided phytostabilization field experiment, where lower metal concentrations in native excluder plants were found. Nonetheless, the field inoculation of the endophyte consortium had no effect on the biomass of native plants.
Rutin exists in medicinal herbs, fruits, vegetables, and a number of plant-derived sources. Dietary sources containing rutin are considered beneficial because of their potential protective roles in multiple diseases related to oxidative stresses. In the present study, the change and antioxidation activity of rutin in Maillard reaction with lysine through a heating process were investigated. There is release of glucose and rhamnose that interact with lysine to give Maillard reaction products (MRPs), while rutin is converted to less-polar quercetin and a small quantity of isoquercitrin. Because of their high cell-membrane permeability, the rutin-lysine MRPs increase the free radical-scavenging activity in HepG2 cells, showing cellular antioxidant activity against Cu(2+)-induced oxidative stress higher than that of rutin. Furthermore, the MRPs significantly increased the Cu/Zn SOD (superoxide dismutase) activity and Cu/Zn SOD gene expression of HepG2 cells, consequently enhancing antioxidation activity.
The purpose of this study was to determine whether Zn(2+) is involved in endoplasmic reticulum (ER) stress inhibition-induced cardioprotection against ischemia/reperfusion (I/R) injury by modulation of the mitochondrial permeability transition pore (mPTP) opening. Isolated rat hearts were subjected to 30-min regional ischemia followed by 2 h of reperfusion. Expression of glucose regulated protein 78 (GRP 78 or BIP), an ER homeostasis marker, was not increased during ischemia but was increased upon reperfusion, indicating that ER stress was initiated upon reperfusion but not during ischemia. The ER stress inhibitor tauroursodeoxycholic acid (TUDCA) given at reperfusion resulted in a significant reduction of GRP78 expression 30 and 60 min after the onset of reperfusion, an effect that was reversed by the zinc chelator N,N,N',N'-tetrakis-(2-pyridylmethyl) ethylenediamine (TPEN). The immunofluorescence study also showed that the effect of TUDCA on GRP78 expression was reversed by TPEN. TUDCA reduced infarct size and this was reversed by the mPTP opener atractyloside, indicating that ER stress inhibition may induce cardioprotection by modulating the mPTP opening. Experiments with transmission electron microscopy and hematoxylin-eosin staining also revealed that TUDCA prevented endoplasmic reticulum and mitochondrial damages at reperfusion, which was blocked by TPEN. Exposure of cardiac H9c2 cells to H2O2 increased GRP 78 and GRP 94 expressions, suggesting that oxidative stress can induce ER stress. Cells treated with H2O2 showed a significant decrease in tetramethylrhodamine ethyl ester (TMRE) fluorescence, indicating that H2O2 triggers the mPTP opening. In contrast, TUDCA prevented the loss of TMRE fluorescence, the effect that was blocked by TPEN, indicating a role of Zn in the preventive effect of ER stress inhibition on the mPTP opening. In support, TUDCA significantly increased intracellular free zinc. These data suggest that reperfusion but not ischemia initiates ER stress and inhibition of ER stress protects the heart from reperfusion injury through prevention of the mPTP opening. Increased intracellular free Zn accounts for the cardioprotective effect of ER stress inhibition.
The interactions between heterotrophic bacteria and primary producers have a profound impact on the functioning of marine ecosystem. We characterized the enzymatic and metal resistance properties of fourteen heterotrophic bacteria isolated from a unicellular cyanobacterium Synechocystis sp. that came from a heavy metal contaminated region of Cochin estuary, southwest coast of India. Based on 16S rRNA gene sequence similarities, the heterotrophic bacteria were grouped into three phyla: namely Actinobacteria, Firmicute, and Proteobacteria. Overall Proteobacteria showed a higher level of enzyme expression while Actinobacteria and Firmicutes showed higher tolerance to heavy metals. Among Proteobacteria, an isolate of Marinobacter hydrocarbonoclasticus (MMRF-584) showed highest activities of β-glucosidase (1.58 ± 0.2 μMml(-1)  min(-1) ) and laminarinase (1170.17 ± 95.4 μgml(-1)  min(-1) ), while other two isolates of M. hydrocarbonoclasticus, MMRF-578 and 581, showed highest phosphatase (44.71 ± 0.2 μMml(-1)  min(-1) ) and aminopeptidase (33.22 ± 0 μMml(-1)  min(-1) ) activities respectively. Among Firmicutes, the Virgibacillus sp. MMRF-571 showed exceptional resistance against the toxic heavy metals Cd (180 mM), Pb (150 mM), and Hg (0.5 mM). Bacillus cereus, MMRF-575, showed resistance to the highest concentrations of Co (250 mM), Cd (150 mM), Pb (180 mM), Hg (0.5 mM), Ni (280 mM), and Zn (250 mM) tested. Our results show that heterotrophic bacteria with varied enzymatic and metal resistance properties are associated with Synechocystis sp. Further studies to delineate the role of these heterotrophic bacteria in protecting primary producers from toxic effects of heavy metals and their potential application in bioremediation will be appreciated.
A series of metal-organic frameworks (MOFs) M2 (dobpdc) (M=Mn, Co, Ni, Zn; H4 dobpdc=4,4'-dihydroxy-1,1'-biphenyl-3,3'-dicarboxylic acid), with a highly dense arrangement of open metal sites along hexagonal channels were prepared by microwave-assisted or simple solvothermal reactions. The activated materials were structurally expanded when guest molecules including CO2 were introduced into the pores. The Lewis acidity of the open metal sites varied in the order Mn<Co<Ni>Zn, as confirmed by C=O stretching bands in the IR spectra, which are related to the CO2 adsorption enthalpy. DFT calculations revealed that the high CO2 binding affinity of transition-metal-based
 M2 (dobpdc) is primarily attributable to the favorable charge transfer from CO2 (oxygen lone pair acting as a Lewis base) to the open metal sites (Lewis acid), while electrostatic effects, the underlying factor responsible for the particular order of binding strength observed across different transition metals, also play a role. The framework stability against water coincides with the order of Lewis acidity. In this series of MOFs, the structural stability of Ni2 (dobpdc) is exceptional; it endured in water vapor, liquid water, and in refluxing water for one month, and the solid remained intact on exposure to solutions of pH 2-13. The DFT calculations also support the experimental finding that Ni2 (dobpdc) has higher chemical stability than the other frameworks.
The endogenous dipeptide l-carnosine, and its derivative homocarnosine, prevent and reduce several pathologies like amytrophic lateral sclerosis (ALS), Alzheimer's disease, and Parkinson's disease. Their beneficial action is severely hampered because of the hydrolysis by carnosinase enzymes, in particular the human carnosinase, hCN1. This belongs to the metallopeptidase M20 family, where a cocatalytic active site is formed by two Zn(2+) ions, bridged by a hydroxide anion. The protein may exist as a monomer and as a dimer in vivo. Here we used hybrid quantum mechanics/molecular mechanics simulations based on the dimeric apoenzyme's structural information to predict the Michaelis complexes with l-carnosine and its derivative homocarnosine. On the basis of our calculations, we suggest that (i) l-carnosine degradation occurs through a nucleophilic attack of a Zn(2+)-coordinated bridging moiety for both monomer and dimer. This mechanistic hypothesis for hCN1 catalysis differs from previous proposals, while it is in agreement with available experimental data. (ii) The experimentally measured higher affinity of homocarnosine for the enzyme relative to l-carnosine might be explained, at least in part, by more extensive interactions inside the monomeric and dimeric hCN1's active site. (iii) Hydrogen bonds at the binding site, present in the dimer but absent in the monomer, might play a role in the experimentally observed higher activity of the dimeric form. Investigations of the enzymatic reaction are required to establish or disprove this hypothesis. Our results may serve as a basis for the design of potent hCN1 inhibitors.
In this study, investigation were done on the Mahanadi River water and health of dwelling Indian Knife fish Notopterus notopterus from three sites along the course of the river in an around Cuttack city (Odisha). Oxidative stress biomarker assays such as thiobarbituric acid reactive substances, protein carbonyls, protein and non-protein thionyls, reduced glutathione, metallothionein, superoxide dismutase, catalase, glutathione peroxidase/reductase couple, glutathione-S-transferase, and tissue metal (Fe, Cu, Ni, Cd, Pb and Zn) levels along with water quality assessments were assayed to measure the impacts on fish health. Results indicate that except Fe all other metals studied were within approved limits for fish liver and gill as approved by FAO/WHO. However, the muscle tissue do not have any metal beyond the permissible limit. A site and tissue specific response of the above mentioned oxidative biomarkers as well as metal accumulation in the fish tissues were noticed. Lipid peroxidation and protein carbonylation were increased gradually in the fish tissues collected from experimental sites along the course of the River in comparison to upstream reference site. Glutathione-S-transferase, glutathione peroxidase/reductase couple, reduced glutathione and non-protein thiol content were significantly decreased in fish tissues from experimental sites. An increase in metallothionein content was observed while superoxide dismutase and catalase showed tissue specific responses. Multivariate (Discriminant Function) analysis revealed that lipid peroxidation, protein carbonylation and superoxide dismutase have highest association as predictors of impact in the muscle and liver while that for gill is protein carbonylation, superoxide dismutase and glutathione reductase.
Three metal complexes (1-3) of the type [Mn(acac)2(py)·H2O] (1), [Co(acac)2(py)·H2O] (2) and [Zn(acac)2(py)·H2O] (3), [Where acac=acetylacetone, py=pyridine] were synthesized and characterized by spectral (UV-vis, FT-IR, ESI-mass) analysis. The structure of complex 2 has been determined by single crystal X-ray diffraction studies and the configuration of ligand-coordinated to metal(II) ion was well described as distorted octahedral coordination geometry. The interaction of the complexes with CT-DNA has been explored by absorption, fluorescence, circular dichromism spectroscopy, viscosity measurements and molecular docking studies. The intrinsic binding constant Kb of complexes 1-3 with CT-DNA obtained from UV-vis absorption spectral studies were 2.1×10(4), 2.1×10(5) and 1.98×10(4)M(-1), respectively, which revealed that the complexes could interact with CT-DNA through groove binding. The results indicated that the complexes (1-3) were able to bind to DNA with different binding affinity, in the order: 2>1>3. The interaction of the compounds with bovine serum albumins were also investigated using fluorescence methods and the gel electrophoresis assay demonstrates weak cleavage ability of the pBR322 plasmid DNA in the presence of the metal complexes (1-3) with various activators. Further, the in vitro cytotoxic effect of the complexes were examined on cancerous cell line, with human breast cancer cells MCF-7.
In this study, the effect of environmental metal exposure on the accumulation and subcellular distribution of metals in the digestive gland of clams with special emphasis on metallothioneins (MTs) was investigated. Specimens of indigenous Moerella iridescens were collected from different natural habitats in Maluan Bay (China), characterized by varying levels of metal contamination. The digestive glands were excised, homogenized and six subcellular fractions were separated by differential centrifugation procedures and analyzed for their Cu, Zn, Cd and Pb contents. MTs were quantified independently by spectrophotometric measurements of thiols. Site-specific differences were observed in total metal concentrations in the tissues, correlating well with variable environmental metal concentrations and reflecting the gradient trends in metal contamination. Concentrations of the non-essential Cd and Pb were more responsive to environmental exposure gradients than were tissue concentrations of the essential metals, Cu and Zn. Subcellular partitioning profiles for Cu, Zn and Cd were relatively similar, with the heat-stable protein (HSP) fraction as the dominant metal-binding compartment, whereas for Pb this fraction was much less important. The variations in proportions and concentrations of metals in this fraction along with the metal bioaccumulation gradients suggested that the induced MTs play an important role in metal homeostasis and detoxification for M. iridescens in the metal-contaminated bay. Nevertheless, progressive accumulation of non-essential metals (Cd, and especially Pb) resulting from "spillover" was observed in putative metal- sensitive (e.g., mitochondria and heat-denaturable protein (HDP)) or lysosome/microsome fractions, demonstrating that metal detoxification was incomplete and increased the toxicological risk to M. iridescens inhabiting the metal-impacted environments. Through multiple stepwise regression analysis, the induction of MTs was statistically correlated with the HSP concentrations of Cu, and to a lesser extent with Zn, and ultimately to the Cd concentrations, exhibiting significant dose-dependent relationships. Overall, these findings not only revealed the fates of accumulated metals, but scientifically favored an improved understanding of the detoxification at the subcellular level in response to metal accumulation, supporting the focus of metabolic availability assessment on the intracellular processes or events occurring within organisms.
Sampling of the offshore seabed sediments of southwestern part of the Caspian Sea was carried out by gravity corer in order to study heavy metal concentration and the physicochemical factors controlling their distribution in the fine-grained fraction. The grain size distribution, amount, and type of clay minerals, total organic carbon (TOC) content, and Eh-pH of the sediments were determined. The average concentrations of the heavy metals in ppm are Mn (563), Cu (207.5), Sr (187), Zn (94), Pb (26.3), Ni (14.5), Co (11.5), Cd (2.56), and Ag (1.04) in their order of abundances. Co and Zn mostly indicate increase in silt-size fraction of the sediments suggesting their probable detrital provenance but the Mn, Ni, Cu, Sr, Pb, Cd, and Ag concentrations show a similar trend to distribution of the clay-size fraction. The concentrations of Mn, Co, and Cd increase with increase in the TOC content but the Cu, Pb, Ni, Ag, and Sr concentrations decrease with increase of the TOC content. The amounts of Zn, Cu, Sr, Pb, Cd, and Ag increase with increase in the CaCO3 content. The calculated enrichment factor indicates that the sediments are very strong to extremely enriched in Ag, significantly enriched in Cu and Cd, and depleted to mineral for Pb, Sr, Co, Ni, and Zn. Variations of the Cu, Sr, Cd, Ag, and Pb concentrations are similar to the clay and CaCO3 distributions.
Potential nanoparticle (NP) toxicity poses a growing concern in marine coastal environments. Among NPs, zinc oxide nanoparticles (nZnO) are widely used in many common products that ultimately become deposited in coastal habitats from multiple non-point sources. In this study, we evaluated the in vivo effects of nZnO in the clam Ruditapes philippinarum. Animals were exposed to
 nZnO (1 and 10 μg/L) and ZnCl2 (10 μg/L) for 7 days. ZnCl2 was used to compare the effects of the NPs to those of Zn(2+) and to ascertain whether nZnO toxicity is attributable to the release of ions into the aquatic medium. At differing time intervals during the exposure, several biochemical and cellular responses were evaluated in the clam gills, digestive gland, and haemolymph. The results showed that nZnO, at concentrations close to the predicted environmental levels, significantly affected various parameters in clam tissues. Significant increases in catalase and superoxide dismutase activities and a decreasing trend of glutathione S-transferase activity indicated the involvement of oxidative stress in nZnO toxicity. In clams exposed to ZnCl2, slight variations in antioxidant enzyme activities were detected with respect to nZnO-treated clams. However, no damage to lipids, proteins or DNA was revealed in all exposure conditions, suggesting a protection of antioxidant enzymes in the tissues. Of the various haemolymph parameters measured, haemocyte proliferation increased significantly, in ZnCl2-treated clams in particular. Under nZnO (10 μg/L) and ZnCl2 exposure, DNA damage in haemocytes was also revealed, but it was lower in clams exposed to ZnCl2. A decreasing trend in gill AChE activity of treated clams proposed a possible role of zinc ions in nZnO toxicity. However, the dissimilar modulation of the responses in the nZnO- and ZnCl2-exposed clams suggested different mechanisms of action, with nZnO toxicity possibly depending not only on the release of zinc ions but also on NP-specific features. Changes in the biological parameters measured in the clams were consistent with Zn accumulation in their gills and digestive glands.
The potential release of metal oxide engineered nanoparticles (ENP) into agricultural systems has created the need to evaluate the impact of these materials on crop yield and food safety. The study here grew sweet potato (Ipomoea batatas) to maturity in field microcosms using substrate amended with three concentrations (100, 500 or 1000 mg kg DW(-1)) of either nZnO, nCuO, or nCeO2 or equivalent amounts of Zn(2+), Cu(2+), or Ce(4+). Adverse effects on tuber biomass were observed only for the highest concentration of Zn or Cu applied. Exposure to both forms of Ce had no adverse effect on yield and a slight positive benefit at higher concentrations on tuber diameter. The three metals accumulated in both the peel and flesh of the sweet potato tubers, with concentrations higher in the peel than the flesh for each element. For Zn, >70% of the metal was in the flesh and for Cu >50%. The peels retained 75-95% of Ce in the tubers. The projected dietary intake of each metal by seven age-mass classes from child to adult only exceeded the oral reference dose for chronic toxicity in a scenario where children consumed tubers grown at the highest metal concentration. The results throughout were generally not different between the ENP- and ionic-treatments, suggesting that the added ENPs underwent dissolution to release their component ions prior to accumulation. The results offer insight into the fate and impact of these ENPs in soils.
The aim of this study was to investigate the beneficial effects of zinc (Zn) in preventing lead (Pb)-induced reproductive toxicity in Wistar rats. The rats were divided into four groups, namely, control group, Pb group, Zn group, and Pb + Zn group. Animals were exposed to Pb (819 mg of Pb/L) or Zn (71 mg of Zn/L) or both through drinking water for 65 days. Rats exposed to Pb showed decreased weights of testes and accessory sex organs. Significant decrease in the testicular daily sperm production, epididymal sperm count, motility, viability, and number of hypoosmotic tail coiled sperm was observed in Pb-exposed rats. Testicular 3β- and 17β-hydroxysteroid dehydrogenase activity levels and circulatory testosterone levels were also decreased significantly in Pb-exposed rats. A significant increase in the lipid peroxidation products with a significant decrease in the activities of catalase and superoxide dismutase were observed in the testes and epididymis of Pb-exposed rats. Moreover, the testicular architecture showed lumens devoid of sperm in Pb-exposed rats. Supplementation of Zn mitigated Pb-induced oxidative stress and restored the spermatogenesis and steroidogenesis in Pb-exposed rats. In conclusion, cotreatment of Zn is effective for recovering suppressed spermatogenesis, steroidogenesis, elevated oxidative status, and histological damage in the testis of rats treated with Pb.
We examined the roles of lithology, topography, vegetation and fire in generating local-scale (<1 km2) soil spatial variability in a seasonally dry tropical forest (SDTF) in southern India. For this, we mapped soil (available nutrients, Al, total C, pH, moisture and texture in the top 10 cm), rock outcrops, topography, all native woody plants ≥1 cm diameter at breast height (DBH), and spatial variation in fire frequency (times burnt during the 17 years preceding soil sampling) in a permanent 50-ha plot. Unlike classic catenas, lower elevation soils had lesser moisture, plant-available Ca, Cu, Mn, Mg, Zn, B, clay and total C. The distribution of plant-available Ca, Cu, Mn and Mg appeared to largely be determined by the whole-rock chemical composition differences between amphibolites and hornblende-biotite gneisses. Amphibolites were associated with summit positions, while gneisses dominated lower elevations, an observation that concurs with other studies in the region which suggest that hillslope-scale topography has been shaped by differential weathering of lithologies. Neither NO3(-)-N nor NH4(+)-N was explained by the basal area of trees belonging to Fabaceae, a family associated with N-fixing species, and no long-term effects of fire on soil parameters were detected. Local-scale lithological variation is an important first-order control over soil variability at the hillslope scale in this SDTF, by both direct influence on nutrient stocks and indirect influence via control of local relief.
Soil developed on mineralised bedrock areas of the Sierra de Aracena Natural Park (SW Spain) is geochemically characterised by naturally high levels of heavy metals and metalloids (notably Zn, Pb, Ag and Cd, but also As, Sb, Cu and Tl). To assess environmental availability, geochemical speciation and potential health risk of such geogenic trace elements, 24 randomly selected soil samples were subjected to one-step extraction procedures (0.01M CaCl2 and 0.05M EDTA), aqueous speciation modelling, and site-specific risk analysis. Metal fraction available for plant uptake or leaching to groundwater was found to be negligible (<1%) due to the low activity of dissolved and exchangeable ions in soil solution, as predicted from the CaCl2 extracts. Based on modelling calculations, free metal ions, primarily Cd(2+) and Zn(2+), were the dominant species in solution over the soil pH range of 5.8 to 7.8. For most metals, the EDTA-extractable fraction generally accounted for <5% suggesting that a limited reservoir of trace elements, mainly bound to Fe oxy-hydroxides, could be potentially available. The results of the health risk assessment for ingestion exposure to groundwater affected by soil leaching revealed that the hazard quotients of heavy metals are within the acceptable risk level. The cumulative hazard index (HI=0.55) fell below the regulatory threshold value of 1.0, even in the worst-case scenario being evaluated, leading to the conclusion that no toxic effects are expected to humans under the conditions and assumptions of the assessment.
Wastewater irrigation can elevate metal concentrations in soils and crops and increase the metal-associated health risks via vegetable ingestion in arid and semiarid northwestern China. Here, we investigated the As, Cd, Cr, Cu, Ni, Pb, and Zn concentrations in four vegetable species from Dongdagou and Xidagou farmlands in Baiyin, Gansu, China. We evaluated the effects of irrigation type (Dongdagou: industrial wastewater; Xidagou: domestic wastewater) and cultivation mode (open field and greenhouse) on the vegetable metal concentration, metal partitioning, soil-to-plant bioconcentration factor (BCF), and the health risk index. All stream waters, soils, and vegetables were found most severely polluted by As and Cd, with higher severity in the industrial-wastewater-irrigated Dongdagou than the domestic-wastewater-irrigated Xidagou. All vegetables had higher or, at least, comparable metal mass allocated in the shoot than in the root. Greenhouse cultivation could reduce metal-ingestion-associated health risks from edible vegetable biomass by decreasing the soil to plant bioaccumulation (BCF) and the metal concentration. This effect was always significant for all vegetables within Xidagou, and for carrot within Dongdagou. This mitigation effect of greenhouse cultivation could be attributed to the metal sorption by a higher level of soil organic matter and faster growth rate over metal uptake rate in greenhouses compared to open fields. Such mitigation effect was, however, insignificant for leafy vegetables within Dongdagou, when much more severely polluted water for irrigation was applied in greenhouses compared to open fields within Dongdagou. The present study highlights greenhouse cultivation as a potential mitigating approach to providing less-polluted vegetables for residents in the severely polluted area in addition to the source pollution control.
The evaluation of the contribution of coal-fired thermo-electrical power plants to particulate matter (PM) is important for environmental management, for evaluation of health risks, and for its potential influence on climate. The application of receptor models, based on chemical composition of PM, is not straightforward because the chemical
 profile of this source is loaded with Si and Al and it is collinear with the profile of crustal particles. In this work, a new methodology, based on Positive Matrix Factorization (PMF) receptor model and Si/Al diagnostic ratio, specifically developed to discriminate the coal-fired power plant contribution from the crustal contribution is discussed. The methodology was applied to daily PM10 samples collected in central Italy in proximity of a large coal-fired power plant. Samples were simultaneously collected at three sites between 2.8 and 5.8km from the power plant: an urban site, an urban background site, and a rural site. Chemical characterization included OC/EC concentrations, by thermo-optical method, ions concentrations (NH4(+), Ca(2+), Mg(2+), Na(+), K(+), Mg(2+), SO4(2-), NO3(-), Cl(-)), by high performances ion chromatography, and metals concentrations (Si, Al, Ti, V, Mn, Fe, Ni, Cu, Zn, Br), by Energy dispersive X-ray Fluorescence (ED-XRF). Results showed an average primary contribution of the power plant of 2% (±1%) in the area studied, with limited differences between the sites. Robustness of the methodology was tested inter-comparing the results with two independent evaluations: the first obtained using the Chemical Mass Balance (CMB) receptor model and the second correlating the Si-Al factor/source contribution of PMF with wind directions and Calpuff/Calmet dispersion model results. The contribution of the power plant to secondary ammonium sulphate was investigated using an approach that integrates dispersion model results and the receptor models (PMF and CMB), a sulphate contribution of 1.5% of PM10 (±0.3%) as average of the three sites was observed.
Sensitivity of four tropical cyanobacteria viz. Coelosphaerium sp., Synechococcus sp., Oscillatoria sp. and Chroococcus sp. to environmentally relevant concentrations of Cr(6+), Cd(2+) and Zn(2+)was assessed based on fluorescence change as a proxy for growth reduction. At 24 h exposure, the growth reduction inthe cyanobacteria followed the order: Zn(2+) < Cr(6+) ≤ Cd(2+). Of the four cyanobacteria, Synechococcus was the most sensitive for Cr(6+), where as Chroococcus was the most sensitive for Cd(2+)and Zn(2+). Sensitivity was gradually decreased by 96 h implying the acquisition of tolerance by cyanobacteria to heavy metal ions with prolonged exposure.
The aim of this study was to investigate the possibility of using cottonseed hulls (CSH) and olive press cake (OPC) as new supplement materials for substrate preparation in Hericium americanum cultivation. Some chemical properties of the substrates prepared by mixtures of oak sawdust (OS) with wheat bran (WB), CSH and OPC in different ratios were determined. In addition, the effect of mixtures of OS:CSH and OS:OPC on spawn run time, yield and biological efficiency (BE), average mushroom weight and nutrition content of the fruit body were compared with the control substrate (8OS:2WB).
The yield, BE and average mushroom weight of substrates containing CSH and OPC were higher than the control substrate and increased with an increase in the rate of CSH and OPC in the mixtures. H. americanum showed (on a dry weight basis) 8.5-23.7% protein, 9.9-21.2 g kg(-1) P, 26.6-35.8 g kg(-1) K, 0.63-1.33 g kg(-1) Mg, 0.19-0.23 g kg(-1) Ca, 1.34-1.78 g kg(-1) Na, 49.5-72.2 mg kg(-1) Fe, 6.22-10.11 mg kg(-1) Mn, 32.8-82.8 mg kg(-1) Zn and 8.6-11.2 mg kg(-1) Cu on different growing substrates. The nutritional value of mushrooms was greatly affected by the growing media.
The results revealed that CSH and OPC could be used as new supplement materials for substrate preparation in H. americanum cultivation.
This research evaluates the analytical capabilities of a field portable X-ray fluorescence spectrometer (pXRF) for the measurement of contaminated soil samples using a matrix-matched calibration. The calibrated pXRF generated exceptional data quality from the measurement of ten soil reference materials. Elemental recoveries improved for all 11 elements post-calibration with reduced measurement variation and detection limits in most cases. Measurement repeatability of reference values ranged between 0.2 and 10% relative standard deviation, while the majority (82%) of reference recoveries were between 90 and 110%. Definitive data quality, the highest of the US EPA's three level quality ranking, was achieved for 15 of 19 elemental datasets. Measurement comparability against inductively coupled plasma atomic emission spectrometry (ICP-AES) values was excellent for most elements (e.g, r(2) 0.999 for Mn and Pb, r(2) > 0.995 for Cu, Zn and Cd). Parallel measurement of reference materials revealed ICP-AES and ICP-MS measured Ti and Cr poorly when compared to pXRF. Individual recoveries of soil reference materials by both ICP-AES and pXRF showed that pXRF was equivalent to or better than ICP-AES values for all but two elements (Ni, As). This study demonstrates pXRF as a suitable alternative to ICP-AES analysis in the measurement of Ti, Cr, Mn, Fe, Cu, Zn, Sr, Cd, and Pb in metal-contaminated soils. Where funds are limited, pXRF provides a low-cost, high quality solution to increasing sample density for a more complete geochemical investigation.
Acidification is a major constraint for revegetation of sulphidic metal-contaminated soils, as exemplified by the limited literature reporting the successful phytostabilization of mine soils associated with pH<3 and high acidification potential. In this study, a combination of ameliorants (lime and chicken manure) and five acid-tolerant plant species has been employed in order to establish a self-sustaining vegetation cover on an extremely acid (pH<3) polymetallic pyritic mine waste heap in southern China exhibiting high acidification potential. The results from the first two-year data showed that the addition of the amendments and the establishment of a plant cover were effective in preventing soil acidification. Net acid-generating potential of the mine soil decreased steadily, whilst pH and acid neutralization capacity increased over time. All the five acid-tolerant plants colonized successfully in the acidic metal-contaminated soil and developed a good vegetation cover within six months, and subsequent vegetation development enhanced organic matter accumulation and nutrient element status in the mine soil. The two-year remediation program performed on this extremely acid metalliferous soil indicated that aided phytostabilization can be a practical and effective restoration strategy for such extremely acid mine soils.
Because of their physico-chemical inherent properties, mangrove sediments may act as a sink for pollutants coming from catchments. The main objective of this study was to assess the distribution of some trace metals in the tissues of various mangrove plants developing downstream highly weathered ferralsols, taking into account metals partitioning in the sediment. In New Caledonia, mangroves act as a buffer between open-cast mines and the world's largest lagoon. As a result of the erosion of lateritic soils, Ni and Fe concentrations in the sediment were substantially higher than the world average. Whatever the mangrove stand and despite low bioaccumulation and translocations factors, Fe and Ni were also the most abundant metals in the different plant tissues. This low bioaccumulation may be explained by: i) the low availability of metals, which were mainly present in the form of oxides or sulfur minerals, and ii) the root systems acting as barriers towards the transfer of metals to the plant. Conversely, Cu and Zn metals had a greater mobility in the plant, and were characterized by high bioconcentration and translocation factors compared to the other metals. Cu and Zn were also more mobile in the sediment as a result of their association with organic matter. Whatever the metal, a strong decrease of trace metal stock was observed from the landside to the seaside of the mangrove, probably as a result of the increased reactivity of the sediment due to OM enrichment. This reactivity lead to higher dissolution of bearing phases, and thus to the export of dissolved trace metals trough the tidal action. Cu and Zn were the less concerned by the phenomenon probably as a result of higher plant uptake and their restitution to the sediment with litter fall in stands where tidal flushing is limited.
In dam contexts, sluicing operations can be performed to reestablish sediments continuity, as proposed by the EU Water Framework Directive, as well as to preserve the reservoirs' water storage capacity. Such management permits the rapid release of high quantities of reservoir sediments through the opening of dam bottom valves. This work aims to study the impact of such operation on the evolution of environmental physicochemical conditions notably changes in dissolved metallic elements concentrations (Al, As, Cd, Cr, Cu, Fe, Mn, Ni, Pb, Zn) through field and laboratory investigations. Results were interpreted in terms of concentrations and fluxes, and compared with data collected on an annual basis regarding both suspended matter and metallic elements. The release of high quantities of sediments (4,500tons dry weight in 24h), with concentrations representing up to 300 times the inter-annual mean suspended sediments discharge, significantly modified water parameters, notably solid/liquid (S/L) ratio, pH and redox conditions. Despite the fact that they are mainly trapped in stable phases, a clear increase of the solubilized metals content was measured, representing up to 60 times the maximum values of current exploitation. This solubilization is related to desorption phenomena from sediments through changes in chemical equilibriums as highlighted by laboratory characterizations and experiments. These chemical modifications are mainly attributed to S/L ratio variations. Indeed, the low S/L ratios
 (≤1.3g·L(-1)) measured in situ are typically the ones for which metals solubilization is the highest, as shown by laboratory experiments. Additional thermodynamic modeling highlighted that the decrease in pH measured during the operation favors the release of the free forms of metallic elements (Al and Cu), and decreases the OM complexation influence. These changes, either in term of physical conditions or speciation, increasing metals long term bioavailability notably during redeposition phase, may have adverse effects on aquatic biota.
This study aimed to investigate the effects that stand age and forest structure have on microbiological soil properties, enzymatic activities and nutrient content. Thirty forest compartments were randomly selected at the Palancares y Agregados managed forest area (Spain), supporting forest stands of five ages; from 100 to 80years old to compartments with trees that were 19-1years old. Forest area ranging from 80 to 120years old and without forest intervention was selected as the control. We measured different soil enzymatic activities, soil respiration and nutrient content (P, K, Na, Mg, Cr, Mn, Fe, Co, Ni, Cu, Zn, Pb and Ca) in the top cm of 10 mineral soils in each compartment. Results showed that the lowest forest stand age and the forest structure created by management presented lower values of organic matter, soil moisture, water holding capacity and litterfall and higher values of C/N ratio in comparison with the highest forest stand age and the related forest structure, which generated differences in soil respiration and soil enzyme activities. The forest structure created by no forest management (control plot) presented the highest enzymatic activities, soil respiration, NH4(+) and NO3(-). Results did not show a clear trend in nutrient content comparing all the experimental areas. Finally, the multivariate PCA analysis clearly clustered three differentiated groups: Control plot; from 100 to 40years old and from 39 to 1year old. Our results suggest that the control plot has better soil quality and that extreme forest stand ages (100-80 and 19-1years old) and the associated forest structure generates differences in soil parameters but not in soil nutrient content.
Trace elements have long been suspected to be involved in Parkinson's disease (PD) pathogenesis, but their exact roles have been remained controversial. In this study, we assessed the levels of copper (Cu), iron (Fe) and zinc (Zn) in different stage of PD patients.
Serum concentrations of iron, copper and zinc were measured in 109 patients with PD by colorimetric methods. Staging of the disease was evaluated according to Hoehn and Yahr (H and Y) and Unified PD Rating Scale III (UPDRS).
Severity values of PD measured by UPRDSIII and HY stages with mean ± SD were 22.9 ± 1.81 and 1.8 ± 1.1, respectively. Mean ± SD values of iron, zinc and copper are 100.7 ± 289.2, 68.3 ± 5.32, and 196.8 ± 162.1 μg/dl, respectively. Serum iron level in most of the patients was normal (76.6%). Whereas zinc concentration in most participants was below the normal range (64.5%) and serum Cu in the majority of patients had a high normal concentration (42.7%) and did not significantly differ among various PD stages.
The result of this study does not confirm strong correlation between PD stages and serum levels of tested trace elements. The actual correlations between these elements and PD and whether modulating of these agents levels could be an effective approach in the treatment of this disease remain to be elucidated.
Witches' broom disease of lime (WBDL), caused by 'Candidatus Phytoplasma aurantifolia', is a very serious disease of acid limes. The disease destroyed more than one million lime trees in the Middle East. WBDL results in the production of small, clustered leaves in some branches of lime trees. Branches develop symptoms with time and become unproductive, until the whole tree collapses within 4-8 years of first symptom appearance. This study was conducted to investigate differences in minerals between symptomatic and asymptomatic leaves of infected lime trees. The study included one set of leaves from uninfected trees and two sets of infected leaves: symptomatic leaves and asymptomatic leaves obtained from randomly selected acid lime trees. Nested polymerase chain reaction detected phytoplasma in the symptomatic and asymptomatic leaves from the six infected trees, but not from the uninfected trees. Phylogenetic analysis showed that all phytoplasmas belong to the 16S rRNA group II-B. Mineral analysis revealed that the level of Na significantly increased by four times in the symptomatic leaves compared to the non-symptomatic leaves and to the uninfected leaves. In addition, symptom development resulted in a significant increase in the levels of P and K by 1.6 and 1.5 times, respectively, and a significant decrease in the levels of Ca and B by 1.2 and 1.8 times, respectively. There was no significant effect of WBDL on the levels of N, Cu, Zn, and Fe. The development of witches' broom disease symptoms was found to be associated with changes in some minerals. The study discusses factors and consequences of changes in the mineral content of acid limes infected by phytoplasma.
The present study successfully developed orally deliverable multimodular zinc (Zn) iron oxide (Fe3O4)-saturated bovine lactoferrin (bLf)-loaded polymeric nanocapsules (NCs), and evaluated their theranostic potential (antitumor efficacy, magnetophotothermal efficacy and imaging capability) in an in vivo human xenograft CpG-island methylator phenotype (CIMP)-1(+)/CIMP2(-)/chromosome instability-positive colonic adenocarcinoma (Caco2) and claudin-low, triple-negative (ER(-)/PR(-)/HER2(-); MDA-MB-231) breast cancer model. Mice fed orally on the Zn-Fe-bLf NC diet showed downregulation in tumor volume and complete regression in tumor volume after 45 days of feeding. In human xenograft colon cancer, vehicle-control NC diet-group (n=5) mice showed a tumor volume of 52.28±11.55 mm(3), and Zn-Fe-bLf NC diet (n=5)-treated mice had a tumor-volume of 0.10±0.073 mm(3). In the human xenograft breast cancer model, Zn-Fe-bLf NC diet (n=5)-treated mice showed a tumor volume of 0.051±0.062 mm(3) within 40 days of feeding. Live mouse imaging conducted by near-infrared fluorescence imaging of Zn-Fe-bLf NCs showed tumor site-specific localization and regression of colon and breast tumor volume. Ex vivo fluorescence-imaging analysis of the vital organs of mice exhibited sparse localization patterns of Zn-Fe-bLf NCs and also confirmed tumor-specific selective localization patterns of Zn-Fe-bLf NCs. Dual imaging using magnetic resonance imaging and computerized tomography scans revealed an unprecedented theranostic ability of the Zn-Fe-bLf NCs. These observations warrant consideration of multimodular Zn-Fe-bLf NCs for real-time cancer imaging and simultaneous cancer-targeted therapy.
A self-healing dielectric elastomer is achieved by the incorporation of metal-ligand coordination as cross-linking sites in nonpolar polydimethylsiloxane (PDMS) polymers. The ligand is 2,2'-bipyridine-5,5'-dicarboxylic amide, while the metal salts investigated here are Fe(2+) and Zn(2+) with various counteranions. The kinetically labile coordination between Zn(2+) and bipyridine endows the polymer fast self-healing ability at ambient condition. When integrated into organic field-effect transistors (OFETs) as gate dielectrics, transistors with FeCl2 and ZnCl2 salts cross-linked PDMS exhibited increased dielectric constants compared to PDMS and demonstrated hysteresis-free transfer characteristics, owing to the low ion conductivity in PDMS and the strong columbic interaction between metal cations and the small Cl(-) anions which can prevent mobile anions drifting under gate bias. Fully stretchable transistors with FeCl2-PDMS dielectrics were fabricated and exhibited ideal transfer characteristics. The gate leakage current remained low even after 1000 cycles at 100% strain. The mechanical robustness and stable electrical performance proved its suitability for applications in stretchable electronics. On the other hand, transistors with gate dielectrics containing large-sized anions (BF4(-), ClO4(-), CF3SO3(-)) displayed prominent hysteresis due to mobile anions drifting under gate bias voltage. This work provides insights on future design of self-healing stretchable dielectric materials based on metal-ligand cross-linked polymers.
High-mobility zinc oxynitride (ZnON) semiconductors were grown by RF sputtering using a Zn metal target in a plasma mixture of Ar, N2, and O2 gas. The RF power and the O2 to N2 gas flow rates were systematically adjusted to prepare a set of ZnON films with different relative anion contents. The carrier density was found to be greatly affected by the anion composition, while the electron mobility is determined by a fairly complex mechanism. First-principles calculations indicate that excess vacant nitrogen sites (VN) in N-rich ZnON disrupt the local electron conduction paths, which may be restored by having oxygen anions inserted therein. The latter are anticipated to enhance the electron mobility, and the exact process parameters that induce such a phenomenon can only be found experimentally. Contour plots of the Hall mobility and carrier density with respect to the RF power and O2 to N2 gas flow rate ratio indicate the existence of an optimum region where maximum electron mobility is obtained. Using ZnON films grown under the optimum conditions, the fabrication of high-performance devices with field-effect mobility values exceeding 120 cm(2)/Vs is demonstrated based on simple reactive RF sputtering methods.
Electron capture dissociation (ECD) and electron transfer dissociation (ETD) in metal-peptide complexes are dependent on the metal cation in the complex. The divalent transition
 metals Ni(2+), Cu(2+), and Zn(2+) were used as charge carriers to produce metal-polyhistidine complexes in the absence of remote protons, since these metal cations strongly bind to neutral histidine residues in peptides. In the case of the ECD and ETD of Cu(2+)-polyhistidine complexes, the metal cation in the complex was reduced and the recombination energy was redistributed throughout the peptide to lead a zwitterionic peptide form having a protonated histidine residue and a deprotonated amide nitrogen. The zwitterion then underwent peptide bond cleavage, producing a and b fragment ions. In contrast, ECD and ETD induced different fragmentation processes in Zn(2+)-polyhistidine complexes. Although the N-Cα bond in the Zn(2+)-polyhistidine complex was cleaved by ETD, ECD of Zn(2+)-polyhistidine induced peptide bond cleavage accompanied with hydrogen atom release. The different fragmentation modes by ECD and ETD originated from the different electronic states of the charge-reduced complexes resulting from these processes. The details of the fragmentation processes were investigated by density functional theory. Graphical Abstract ᅟ.
The present study deals with production of phytase from Rhizopus oligosporus MTCC 556 by solid state fermentation (SSF) using different (ADT27, IR20, PAIYUR1, KG, and RASI) rice bran varieties, in which ADT27 rice bran yield maximum of 6.2 U gds⁻¹ phytase. Statistical optimization was employed by Central Composite Design (CCD); the results showed that 3.0 g dextrose, 2.5 g ammonium nitrate, substrate size of 80 mesh, 10 mg calcium chloride was 116 hr at optimal for phytase production by SSF, with maximum of 23.14 U gds'. Phytase production improved by 4 fold (31.3 U/gds) due to chemical mutagenesis (mutant Rhizopus oligosporus MTCC 1116) in optimized media composition. Partially purified phytase showed approximately 90 kDa of molecular mass and was optimally active at 5.5 pH and 50°C temperature. Substrate specificity exhibited in sodium phytic acid and phytase activity was stimulated by Zn²⁺ and Ca²⁺.
The adsorption of glufosinate (GLU), a widely used herbicide similar to glyphosate (GLY), onto goethite was investigated as a function of the pH, ionic strength, background cations and anions, heavy metal ions and fulvic acids (FAs) by using batch adsorption experiments. In situ ATR-FTIR spectroscopy and density functional theory (DFT) calculations were carried out to characterize the molecular interactions between GLU and goethite surfaces. The macroscopic results indicated that an increasing pH exerted an adverse effect on GLU adsorption because of the electrostatic repulsion, and the adsorption was not sensitive to ionic strengths or background cation types, indicating that an inner-sphere surface complex was involved. GLU adsorption can be considerably depressed by PO4(3-), SO4(2-), and a high level of FA because of the competitive effect, while being enhanced by Cu(2+) with a maximum adsorption at approximately pH5 because of the metal ion bridging effect. Other examined divalent metal cations (Cd(2+), Zn(2+), and Pb(2+)) showed almost no effect on GLU adsorption, indicating weak interaction between them. ATR-FTIR spectra and the DFT calculations further proved that GLU was bonded to goethite surfaces through the formation of a monodentate mononuclear inner-sphere complex between the phosphinic moiety and surface Fe(III) centers under an acidic condition. The results showed that GLU had a similar adsorption mechanism to that of GLY onto goethite, but with a lower adsorption affinity, possibly exerting higher mobility and risk in soils.
Interactions of multivalent metal counterions with anionic sulfonate gemini surfactant 1,3-bis(N-dodecyl-N-propanesulfonate sodium)-propane (C12C3C12(SO3)2) and the induced aggregate transitions in aqueous solution have been studied. Divalent metal ions Ca(2+), Mg(2+), Cu(2+), Zn(2+), Mn(2+), Co(2+), and Ni(2+) and trivalent metal ions Al(3+), Fe(3+), and Cr(3+) were chosen. The results indicate that the critical micelle concentration (CMC) of C12C3C12(SO3)2 is greatly reduced by the ions, and the aggregate morphologies of C12C3C12(SO3)2 are adjusted by changing the nature and molar ratio of the metal ions. These metal ions can be classified into four groups because the ions in each group have very similar interaction mechanisms with C12C3C12(SO3)2: (I) Cu(2+) and Zn(2+); (II) Ca(2+), Mn(2+) and Mg(2+); (III) Ni(2+) and Co(2+); and (IV) Cr(3+), Al(3+) and Fe(3+). Cu(2+), Mg(2+), Ni(2+), and Al(3+) then were selected as representatives for each group to further study their interaction with C12C3C12(SO3)2. C12C3C12(SO3)2 interacts with the multivalent metal ions by electrostatic interaction and coordination interaction. C12C3C12(SO3)2 forms prolate micelles and plate-like micelles with Cu(2+), vesicles and wormlike micelles with Al(3+) or Ni(2+), and viscous three-dimensional network structure with Mg(2+). Moreover, precipitation does not take place in aqueous solution even at a high ion/surfactant ratio. The related mechanisms have been discussed. The present work provides guidance on how to apply the anionic surfactant into the solutions containing the multivalent metal ions, and those aggregates may have potential usage in separating heavy metal ions from aqueous solutions.
During the period of menopause as an effect of changes in hormone status, one of the most common ailments for women is hair loss. Taking into consideration fact that the ingredients of diet contained in various groups of consumed food products are both precursors in steroid hormones synthesis as well as have direct impact on structure, growth and keeping hair in skin integument, this is the reason why nourishing support for women during this period of life as well as during the hair loss therapy is reasonable. Standard value proteins containing Sulphur amino-acids: cysteine and methionine as precursor to keratin hair protein synthesis are basic element of diet conditioning of hair building. Irreplaceable having impact on keeping hair in skin integument is exogenous L-lysine, mainly present in the inner part of hair root is responsible for hair shape and volume. Fats present in the diet take part in steroid hormones synthesis (from cholesterol) thus have influence on keeping hair in skin integument. Women diet should contain products rich in complex carbohydrates, with low glycemic index and load containing fiber regulating carbohydrate-lipid metabolism of the body. Vitamins also have impact on the state of hair: C vitamin, group B and A vitamins. Minerals which influence hair growth are: Zn, Fe, Cu, Se, Si, Mg and Ca. It is worthwhile to pay closer attention to diet in women who besides hormone changes and undertaken pharmacotherapy are additionally exposed to chronic stress and improperly conducted cosmetic's and hairdresser's treatments.
Salinity is a major abiotic stress factor affecting crops production and productivity. Triticum monococcum is closely related to Triticum urartu (A(U)A(U)), which is used as a model plant of wheat A genome study. Here, salt stress induced dynamic proteome and phosphoproteome profiling was focused. The T. monococcum seedlings were initially treated with different concentrations of NaCl ranging from 80 to 320mM for 48h followed by a recovery process for 48h prior to proteomic and phosphoproteomic analysis. As a result, a total of 81 spots corresponding to salt stress and recovery were identified by MALDI-TOF/TOF-MS from 2-DE gels. These proteins were mainly involved in regulatory, stress defense, protein folding/assembly/degradation, photosynthesis, carbohydrate metabolism, energy production and transportation, protein metabolism, and cell structure. Pro-Q Diamond staining was used to detect the phosphoproteins. Finally, 20 spots with different phosphorylation levels during salt treatment or recovery compared with controls were identified. A set of potential salt stress response and defense biomarkers was identified, such as cp31BHv, betaine-aldehyde dehydrogenase, leucine aminopeptidase 2, Cu/Zn superoxide dismutase, and 2-Cys peroxiredoxin BAS1, which could lead to a better understanding of the molecular basis of salt response and defense in food crops.
Soil salinity reduces the yield of the major crops, which is one of the severest problems in irrigated agriculture worldwide. However, how crops response and defense during different levels of salt treatment and recovery processes is still unclear, especially at the post-translational modification level. T. monococcum is a useful model for common wheat. Thus, proteomic and phosphoproteomic analyses of T. monococcum leaves were performed in our study, which provided novel insights into the underlying salt response and defense mechanisms in wheat and other crops.
Algae wall polysaccharide, laminarin (Lam), has an established role on induction of plant disease resistance. In this study, application of Lam increased Arabidopsis fresh weight and enhanced tolerance to salt and heat stress by stabilizing chloroplast under adverse environment. Transcriptome analysis indicated that, in addition to induced a large number of genes associated with the host defense, genes involved in the regulation of abiotic stress tolerance mostly the heat stress response constituted the largest group of the up-regulated genes. Lam induced expression of IRT1, ZIP8, and copper transporters involved in transport of Fe, Zn, Cu ions associated with the activity of chloroplast antioxidant system. Lam also up-regulated genes involved in the synthesis of terpenoid, a plastidial-derived secondary metabolite with antioxidant activity. Overexpression of a Lam-induced defensin like 202 (DEFL202) resulted in increased chloroplast stability under salt stress and increased plant growth activity after heat stress. Expression of antioxidant
 enzymes including SOD and ascorbate peroxidase (APX), photosystem PsbA-D1 and ABA-dependent responsive to desiccation 22 (RD22) was induced to higher levels in the transgenic seedlings. In sum, our results suggest that Lam is an potent inducer for induction of chloroplastic antioxidant activity. Lam affect plant abiotic stress tolerance partially through regulation of the DEFL-mediated pathway.
Metallic stents are used to promote revascularization and maintain patency of plaqued or damaged arteries following balloon angioplasty. To mitigate the long-term side effects associated with corrosion-resistant stents (i.e., chronic inflammation and late stage thrombosis), a new generation of so-called "bioabsorbable" stents is currently being developed. The bioabsorbable coronary stents will corrode and be absorbed by the artery after completing their task as vascular scaffolding. Research spanning the last two decades has focused on biodegradable polymeric, iron-based, and magnesium-based stent materials. The inherent mechanical and surface properties of metals make them more attractive stent material candidates than their polymeric counterparts. A third class of metallic bioabsorbable materials that are based on zinc has been introduced in the last few years. This new zinc-based class of materials demonstrates the potential for an absorbable metallic stent with the mechanical and biodegradation characteristics required for optimal stent performance. This review compares bioabsorbable materials and summarizes progress towards bioabsorbable stents. It emphasizes the current understanding of physiological and biological benefits of zinc and its biocompatibility. Finally, the review provides an outlook on challenges in designing zinc-based stents of optimal mechanical properties and biodegradation rate.
Functional compatibility in cucumber mycorrhizas in terms of plant and fungal growth, and foliar nutrient composition from all possible combinations of six cucumber varieties and three species of arbuscular mycorrhizal (AM) fungi was evaluated. Measurements of foliar nutrient composition included N, P, K, Mg, Ca, Na, Fe, Zn, Mn and Cu. Growth of AM fungi was measured in terms of root colonisation, as examined with microscopy and the AM fungus biomarker fatty acid 16:1ω5 from both phospholipids and neutral lipids. Different responses of plant growth and foliar nutrient profiles were observed for the different AM symbioses examined. The AM fungus Claroideoglomus claroideum caused growth depression in association with four out of six cucumber varieties; Rhizophagus irregularis caused growth promotion in one of six cucumber varieties; whereas Funneliformis mosseae had no effect on the growth performance of any of the cucumber varieties examined. All three AM fungi markedly altered host plant shoot nutrient composition, with the strongest contrast observed between cucumber-R. irregularis symbioses and non-mycorrhizal cucumber plants, independent of cucumber variety. On the other hand, AM fungal growth in roots differed between the three AM fungi, but was unaffected by host genotype. Strong build-up of storage lipids was observed for R. irregularis, which was more moderate in the two other AM fungi. In conclusion, strong differential responses of cucumber varieties to inoculation with different AM fungi in terms of growth and shoot nutrient composition revealed high functional diversity in AM symbioses in cucumber plants.
Mercury (Hg) is likely bound to large biomolecules (e.g. proteins) in living organisms, and in order to assess Hg metabolic pathways and possible toxicological effects, it is essential to study these Hg containing biomolecules. However, the exact nature of most metal binding biomolecules is unknown. Such studies are still in their infancy and information on this topic is scarce because the analysis is challenging, mainly due to their lability upon digestion or extraction from the tissue. New analytical methods that allow complex Hg-biomolecules to be analysed intact are needed and only few very recent studies deal with this approach. Therefore, as an initial step towards the characterization of Hg containing biomolecules, an analytical procedure has been optimised using size-exclusion chromatography (SEC) with inductively coupled plasma mass spectrometry (ICP-MS) detection. We applied this technique to elucidate the distribution and elution profile of Hg and Se, and some physiological important elements such as Fe, Ni, Zn and Cu, to assess metal binding profiles in liver and kidney samples of red deer (Cervus elaphus) and wild boar (Sus scrofa) who roam freely within the largest Hg mining district on Earth, Almadén in Spain. Elemental fractionation profiles of the extracts from different tissues were obtained using two different SEC columns (BioSep-SEC-S2000 GL 300-1kDa and Superdex 75 10/300 GL 70-3kDa). Similar profiles of Hg were observed in red deer and wild boar; however, significant differences were evident for liver and kidney. Moreover, the profiles of Se showed a single peak at high-medium molecular weight in all investigated tissues, while co-elution of Hg with Fe, Ni, Zn and Cu was observed.
A mixture of 2D and 1D metal-organic complexes, [ZnL(H2O)2·G1·DEF·2H2O]n (1a: G1 = naphthalene-2,7-disulfonate; DEF = N,N-diethylformamide) and [ZnL(H2O)3·G1·DEF·2H2O]n (2), has been prepared from a hydrogenated Schiff base L and Zn(II) in a DEF-contained solvent system under mild conditions. The yields of 1a and 2 are equivalent; however, they can be tuned by varying the amount of DEF solvent. Increasing the use of DEF tends to form pure 1a, while decreasing it generates 2. Without DEF, another novel 3D four-connected CdSO4 (cds) framework [ZnL(H2O)2·G1·2H2O]n (3) composed of alternated right-handed and left-handed helical chains has been constructed. The amount of DEF solvent has a significant impact on the diverse coordination architectures of 1-3, which is rare in the preparation of metal-organic complexes. The photoluminescence of complexes 1-3 along with naphthalene-2,7-disulfonate has been investigated in the solid state. The luminescent emission of G1 was enhanced greatly after being confined into metal-organic networks. In addition, complexes 1-3 display second-harmonic generation efficiencies, which are approximately 0.58, 0.42, 0.32, and 0.52 times as much as that of potassium dihydrogen phosphate.
In order to study the influence of different substituent groups on the fluorescence properties, a series of bis-Schiff bases (L) with electron-donating groups (salicylaldehyde, o-vanillin, 2,4-dihydroxybenzaldehyde) and electron-drawing group (4-formylbenzoic acid) have been synthesized, and characterized by IR spectrum, NMR, mass spectrum, and fluorescence spectroscopy. The investigation of the fluorescent properties reveals that the fluorescence can be enhanced when the bis-Schiff base ligands with electron-donating groups complex with Zn ion, while other kinds of metal complexes with these ligands do not show any enhancement, whereas no fluorescence enhancement can be observed when the ligand with electron-drawing group complexes with all different types of metal ions. In addition, as for the ligands with electron-donating groups detecting zinc ion, the fluorescence intensity is linear correlated with the concentration of zinc ion. Therefore, the study indicates that the ligands with electron-donating groups can be used as Zn ion fluorescent sensor.
The employment of a multidentate salicylamide salen-like ligand, 2-hydroxy-N-(2-(2-hydroxybenzylidene)amino)ethyl)benzamide (H3L), in aid of NO3(-) anions under weak basic conditions in Zn(II)-Ln(III) chemistry (Ln = Eu, and Dy, ) led to the isolation of two novel butterfly heterometallic dodecanuclear clusters with six Ln(III) ions occupying the body position and six Zn(II) ions the outer wing-tip sites. All of them are fully characterized by elemental analysis, FT-IR spectroscopy, TG analysis, single-crystal X-ray diffraction, and X-ray powder diffraction (XRPD) techniques. Luminescence studies indicate that exhibits dual emission, while exhibits a bright blue emission under visible light excitation. Furthermore, magnetic susceptibility studies carried out for indicate that the magnetic exchange between Dy(III) ions revealed ferromagnetic interactions with interesting slow relaxation of magnetization of the SMM behavior.
In this article the interaction between H2 and Ag(+), Cu(+), Mg(2+), Cd(2+), and Zn(2+) cations in cluster models of several sizes has been studied computationally. Depending on the changes imposed by the adsorption process on the H2 molecule the activation can vary in a wide range - from only slight weakening of the H-H bond to complete dissociation of the H2 molecule. The NOCV (Natural Orbitals for Chemical Valence) analysis allowed for decomposition of the electron density distortion into contributions easier for interpretation. Three essential factors have been identified (i-iii). In the case of bare cations the main contribution is a donation from σH2 to the cation (i). When a zeolite framework surrounding the cation is introduced, it hinders σ-donation and enhances π-backdonation from the cation to the antibonding orbital of the molecule (ii). For Cu(i) and Ag(i) sites π-backdonation becomes dominant, while for Mg(ii), Cd(ii), and Zn(ii) cations, the σ-donation, albeit diminished, still remains a dominant contribution. Calculations showed that the localization and coordination of Zn(ii) have crucial influence on its interaction with H2. We identified a Zn(2+) position at which the H2 molecule dissociates - here the interaction between H2 and oxygen framework (iii) plays a crucial role. Based on the calculations the mechanism of H2 transformation has been proposed. Upon heterolytic dissociation of H2 the Zn(0) moiety and two OH groups
 can be formed. Eventually, in two elementary steps, the H2 molecule can be restored. In this case, the ability of the site to activate/dissociate hydrogen is caused by the low coordination number of the zinc cation and the geometry of the site which allows positively charged H2 to interact with framework oxygen what enhances the formation of OH and Z-O-(ZnH)(+) groups.
Zinc (Zn) deficiency in major food crops has been considered as an important factor affecting the crop production and subsequently the human health. Rice (Oryza sativa) is sensitive to Zn deficiency and thereby causes malnutrition to most of the rice-eating Asian populations. Application of zinc solubilizing bacteria (ZSB) could be a sustainable agronomic approach to increase the soil available Zn which can mitigate the yield loss and consequently the nutritional quality of rice. Understanding the molecular interactions between rice and unexplored ZSB is useful for overcoming Zn deficiency problems. In the present study, the role of zinc solubilizing bacterial strain Enterobacter cloacae strain ZSB14 on regulation of Zn-regulated transporters and iron (Fe)-regulated transporter-like protein (ZIP) genes in rice under iron sufficient and deficient conditions was assessed by quantitative real-time reverse transcription PCR. The expression patterns of OsZIP1, OsZIP4, and OsZIP5 in root and shoot of rice were altered due to the Zn availability as dictated by Zn sources and ZSB inoculation. Fe sufficiency significantly reduced the root and shoot OsZIP1 expression, but not the OsZIP4 and OsZIP5 levels. Zinc oxide in the growth medium up-regulated all the assessed ZIP genes in root and shoot of rice seedlings. When ZSB was inoculated to rice seedlings grown with insoluble zinc oxide in the growth medium, the expression of root and shoot OsZIP1, OsZIP4, and OsZIP5 was reduced. In the absence of zinc oxide, ZSB inoculation up-regulated OsZIP1 and OsZIP5 expressions. Zinc nutrition provided to the rice seedling through ZSB-bound zinc oxide solubilization was comparable to the soluble zinc sulfate application which was evident through the ZIP genes' expression and the Zn accumulation in root and shoot of rice seedlings. These results demonstrate that ZSB could play a crucial role in zinc fertilization and fortification of rice.
Plants survival depends on their ability to cope with multiple nutrient stresses that often occur simultaneously, such as the limited availability of essential elements inorganic phosphate (Pi), zinc (Zn), and iron (Fe). Previous research has provided information on the genes involved in efforts by plants to maintain homeostasis when a single nutrient (Pi, Zn, or Fe) is depleted. Recent findings on nutritional stress suggest that plant growth capacity is influenced by a complex tripartite interaction between Pi, Zn, and Fe homeostasis. However, despite its importance, how plants integrate multiple nutritional stimuli into complex developmental programs, and which genes are involved in this tripartite (Pi ZnFe) interaction is still not clear. The aim of this study was to examine the physiological and molecular responses of rice (Oriza sativa L.) to a combination of Pi, Zn, and/or Fe deficiency stress conditions. Results showed that Fe deficiency had the most drastic single-nutrient effect on biomass, while the Zn deficiency-effect depended on the presence of Pi in the medium. Interestingly, the observed negative effect of Fe starvation was alleviated by concomitant Pi or PiZn depletion. Members of the OsPHO1 family showed a differential transcriptional regulation in response PiZnFe combinatory stress conditions. Particularly, the transcripts of the OsPHO1;1 sense and its natural antisense cis-NatPHO1;1 showed the highest accumulation under PiZn deficiency. In this condition, the Ospho1;1 mutants showed over-accumulation of Fe in roots compared to wild type plants. These data reveal coordination between pathways involved in Fe transport and PiZn signaling in rice which involves the OsPHO1; 1, and support the hypothesis of a genetic basis for Pi, Zn, and Fe signaling interactions in plants.
The physicochemical, compositional and functional properties of flour from green plantains (Musa acuminata) of the large green plantain variety, oyster mushrooms (Pleorotus ostreatus), pineapple peel (Ananas comosus) of the 'apple pineapple' variety, yellow peas (Pisum sativum), chickpeas (Cicer arietinum), whole grain rice (Oryza sativa), whole grain corn (Zea mays) and whole grain white quinoa (Chenopodium quinoa) were evaluated by using one-way analysis of variance, Pearson correlations and principal component analysis chemical composition of the eight flours, statistically differed (p < 0.05). Oyster mushroom and yellow pea flours had the greatest protein content (28.92 and 21.02%, respectively), whereas the pineapple peel, peas and corn stood out for their high contents of Fe and Zn. All flours exhibited emulsifying and foaming activities, while hydration and interfacial properties showed statistically significant negative correlations. There was a clear relationship between levels of protein and carbohydrates and gelation and syneresis phenomena in thermally treated flour suspensions. According to principal component analysis of functional, physicochemical and compositional properties, flours were classified into five groups of raw materials: (1) yellow peas, (2) chickpeas, rice, corn and quinoa, (3) green plantain, (4) pineapple peel and (5) oyster mushrooms. Results are promising to formulate mixes and composite flours for fortification and/or enrichment of food products by using different technological processes.
Zinc reagents (Me2PhSi)2Zn and [(Me3Si)3Si]2Zn undergo highly regio- and stereoselective addition across the carbon-carbon triple bond of nitrogen-, sulfur-, oxygen-, and phosphorus-substituted terminal alkynes in the absence of copper or any other catalyst. Both reagents yield exclusively β-isomers, and the stereoselectivity is determined by the silyl group: Me2PhSi for cis or (Me3Si)3Si for trans. These stereodivergent silylzincation protocols offer an efficient access to heteroatom-substituted vinylsilanes with either double bond geometry, including trisubstituted vinylsilanes by one-pot electrophilic substitution of the intermediate C(sp(2))-Zn bond by copper(I)-mediated carbon-carbon bond formation.
Aljustrel mines were classified as having high environmental hazard due to their large tailings volume and high metal concentrations in waters and sediments. To assess acid mine drainage impacted systems whose environmental conditions change quickly, the use of biological indicators with short generation time such as diatoms is advantageous. This study combined geochemical and diatom data, whose results were highlighted in 3 groups: Group 1, with low pH (1.9-5.1) and high metal/metalloid (Al, As, Cd, Co, Cu, Fe, Mn, Ni, Pb, Zn; 0.65-1032 mg/L) and SO4 (405-39124 mg/L) concentrations. An acidophilic species, Pinnularia aljustrelica, was perfectly adapted to the adverse conditions; in contrast, teratological forms of Eunotia exigua were found, showing that metal toxicity affected this species. The low availability of metals/metalloids in sediments of this group indicates that metals/metalloids of the exchangeable fractions had been solubilized, which in fact enables metal/metalloid diatom uptake and consequently the occurrence of teratologies; Group 2, with sites of near neutral pH (5.0-6.8) and intermediate metal/metalloid (0.002-6 mg/L) and SO4 (302-2179 mg/L) concentrations; this enabled the existence of typical species of uncontaminated streams (Brachysira neglectissima, Achnanthidium minutissimum); Group 3, with samples from unimpacted sites, showing low metal/metalloid (0-0.8 mg/L) and SO4 (10-315 mg/L) concentrations, high pH (7.0-8.4) and Cl contents (10-2119 mg/L) and the presence of brackish to marine species (Entomoneis paludosa). For similar conditions of acidity, differences in diversity, abundance and teratologies of diatoms can be explained by the levels of metals/metalloids.
Protons (H(+)) as well as different major and trace elements may inhibit cadmium (Cd) uptake in aquatic organisms and thus alleviate Cd toxicity. However, little is known about such interactions in soil organisms. In this study, the independent effects of the cations calcium (Ca(2+)), magnesium (Mg(2+)), potassium (K(+)), H(+) and zinc (Zn(2+)) on Cd toxicity were investigated with 5-day long barley root elongation tests in nutrient solutions. The tested concentrations of selected cations and trace metal ions were based on the ranges that occur naturally in soil pore water. The toxicity of Cd decreased with increasing activity of Ca(2+), Mg(2+), H(+) and Zn(2+), but not K(+). Accordingly, conditional binding constants were obtained for the binding of Cd(2+), Ca(2+), Mg(2+), H(+), and Zn(2+) with the binding ligand: logK(CdBL) 5.19, logK(CaBL) 2.87, logK(MgBL) 2.98, logK(HBL) 5.13 and logK(ZnBL) 5.42, respectively. Furthermore, it was calculated that on average 29% of the biotic ligand sites needed to be occupied by Cd to induce a 50% decrease in root elongation. Using the estimated constants, a biotic ligand model was successfully developed to predict the Cd toxicity to barley root elongation as a function of solution characteristics. The feasibility and accuracy of its application for predicting Cd toxicity in soils were discussed.
Changes in metal concentrations in the litter of Potamogeton crispus were monitored during a consecutive 40-day in situ decomposition experiment using the litterbag method. The accumulation index was calculated and used to indicate the changes in the metals in litter. The results showed that the concentrations of Al, Cd, Cr, Fe, Mn, and Pb in litter increased significantly during the decomposition, while Cu and Zn concentrations
 decreased dramatically. Significant positive correlations were found between the concentrations of Al, Cr, Fe, and Mn and between Cu and Zn. Moreover, Cu and Zn both negatively correlated with Al and Fe. The remaining dry mass was negatively correlated with Al and Fe concentrations but positively correlated with Cu and Zn concentrations. Generally the accumulation index values of metals other than Al were less than one, indicating that the litter of P. crispus acted as a source of metals to the surrounding water body. Al was the only metal that showed continuous net accumulation in litter. The net accumulation of Fe and Mn in litter during the last 10 days of the experiment may indicate the precipitation of Fe- and Mn-oxides. It was estimated that 160 g/m(2) (dry weight) P. crispus was decomposed in 40 days. This was equivalent to releasing the following amounts of metals: 0.01 mg Cd, 0.03 mg Cr, 0.71 mg Cu, 0.55 mg Mn, 0.02 mg Pb and 13.8 mg Zn into surrounding water, and accumulating 149 mg Al and 11 mg Fe, in a 1m(2) area.
The concentrations and spatial distributions of eight heavy metals in surface sediments and sediment core samples from a shallow lake in China were investigated to evaluate the extent of the contamination and potential ecological risks. The results showed that the heavy metal concentrations were higher in the northern and southwestern lake zones than those in the other lake zones, with lower levels of As, Hg, Zn, Cu, Pb, Cr, and Ni primarily observed in the central and eastern lake regions and Cd primarily confined to areas surrounding the lake. The concentrations of the eight heavy metals in the sediment profiles tended to decrease with increasing sediment depth. The contents of Ni, Cu, Zn, Pb, and Cd in the surface sediment were approximately 1.23-18.41-fold higher than their background values (BVs), whereas the contents of Cr, As, and Hg were nearly identical to their BVs. The calculated pollution load index (PLI) suggested that the surface sediments of this lake were heavily polluted by these heavy metals and indicated that Cd was a predominant contamination factor. The comprehensive potential ecological risk index (PERI) in the surface sediments ranged from 99.2 to 2882.1, with an average of 606.1. Cd contributed 78.7 % to the PERI, and Hg contributed 8.4 %. Multivariate statistical analyses revealed that the surface sediment pollution with heavy metals mainly originated from industrial wastewater discharged by rivers located in the western and northwestern portion of the lake.
Cobalt-catalyzed carboxyzincation reactions employing carbon dioxide and zinc metal powder are developed. By using alkynes as substrates, regio- and stereodefined (Z)-β-zincated acrylates are provided. The corresponding alkenylzinc moiety can be converted to various substituents, affording multisubstituted acrylic acids. Furthermore, by adding electron-deficient alkene to the reaction system, the four-component coupling reactions of alkyne, alkene, CO2, and the Zn atom proceed via carboxyzincation.
Because of their extremely small size, silver nanoparticles (AgNPs) show unique physical and chemical properties, with specific biological effects, which make them particularly attractive for being used in a number of consumer applications. However, these properties also influence the potential toxicity of AgNPs. In this study, we assessed the potential toxic effects of an in vivo oral sub-chronic exposure to polyvinyl pyrrolidone coated AgNPs (PVP-AgNPs) in adult male rats. We also assessed if oral PVP-AgNPs exposure could alter the levels of various metals (Fe, Mg, Zn and Cu) in tissues. Rats were orally given 0, 50, 100 and 200 mg/kg/day of PVP-AgNPs. Silver (Ag) accumulation in tissues, Ag excretion, biochemical and hematological parameters, metal levels, as well as histopathological changes and subcellular distribution following PVP-AgNPs exposure, were also investigated. After 90 days of treatment, AgNPs were found within hepatic and ileum cells. The major tissue concentration of Ag was found in ileum of treated animals. However, all tissues of PVP-AgNPs-exposed animals showed increased levels of Ag in comparison with those of rats in the control group. No harmful effects in liver and kidney, as well as in biochemical markers were noted at any treatment dose. In addition, no hematological or histopathological changes were found in treated animals. However, significant differences in Cu and Zn levels were found in thymus and brain of PVP-AgNPs-treated rats.
Air pollution is a major concern in China. Lichens are a useful biomonitor for atmospheric elemental deposition but have rarely been used in North China. The aim of this study was to investigate the atmospheric depositions of 30 trace elements (Al, Ba, Ca, Cd, Ce, Co, Cr, Cs, Cu, Fe, K, La, Mg, Mn, Mo, Na, Ni, P, Pb, Rb, Sb, Sc, Sm, Sr, Tb, Th, Ti, Tl, V and Zn) in a region of the Taihang Mountains, Hebei Province, China using lichens as biomonitors. Epilithic foliose lichen Xanthoria mandschurica was sampled from 21 sites and analyzed using inductively coupled plasma mass spectrometry (ICP-MS). The results show that 1) eight elements (Cd, Cr, Cu, Mo, P, Pb, Sb and Zn) are of atmospheric origin and are highly influenced by the atmospheric transportation from the North China Plain, as well as local mining activities, while 2) the remaining 22 elements are primarily of crustal origin, the concentration of which has been enhanced by local mining and quarrying activities. These results clearly validate the applicability of lichens in biomonitoring of atmospheric elemental deposition and demonstrate the spatial pattern for air pollution in the region.
Lethal Toxin from Clostridium sordellii (TcsL) and Toxin B from Clostridium difficile (TcdB) belong to the family of the "Large clostridial glycosylating toxins." These toxins mono-O-glucosylate low molecular weight GTPases of the Rho and Ras families by exploiting UDP-glucose as a hexose donor. TcsL is casually involved in the toxic shock syndrome and the gas gangrene. TcdB-together with Toxin A (TcdA)-is causative for the pseudomembranous colitis (PMC). Here, we present evidence for the in vitro metal ion activation of the glucosyltransferase and the UDP-glucose hydrolysis activity of TcsL and TcdB. The following rating is found for activation by divalent metal ions: Mn(2+) > Co(2+) > Mg(2+) > Ca(2+), Cu(2+), Zn(2+). TcsL and TcdB thus require divalent metal ions providing an octahedral coordination sphere. The EC50 values for TcsL were estimated at about 28 µM for Mn(2+) and 180 µM for Mg(2+). TcsL and TcdB further require co-stimulation by monovalent K⁺ (not by Na⁺). Finally, prebound divalent metal ions were dispensible for the cytopathic effects of TcsL and TcdB, leading to the conclusion that TcsL and TcdB recruit intracellular metal ions for activation of the glucosyltransferase activity. With regard to the intracellular metal ion concentrations, TcsL and TcdB are most likely activated by K⁺ and Mg(2+) (rather than Mn(2+)) in mammalian target cells.
This study focuses on the effects of three different thermal preparation methods (roasting, boiling, and microwave cooking) on the mineral concentrations of beef and pork, as well as on the comparison of mineral levels between these two types of meat. In this study, raw and cooked beef and pork samples were selected and analyzed by ICP-OES in order to determine mineral concentrations. In general, thermal preparation clearly increased mineral concentrations in cooked samples compared to raw meat. The highest mineral concentration was identified in the roasted samples. Trace element concentrations in beef were significantly higher compared to pork. In pork, Na concentration decreased in all samples, suggesting that Na is lost with water. Zn mean content in cooked beef samples registered significant differences compared to pork cooked samples. The percentage of water loss during the microwave thermal preparation for beef samples was higher than the other two treatments.
Metal ions in metallo-β-lactamases (MBLs) play a major role in catalysis. In this study we investigated the role of the metal ions in the Zn1 and Zn2 sites of MBL L1 during catalysis. A ZnCo (with Zn(II) in the invariant Zn1 site and Co(II) in the Zn2 site) analog of MBL L1 was prepared by using a biological incorporation method. Extended X-ray Absorption Fine Structure (EXAFS) spectroscopic studies were used to confirm that the ZnCo analog was prepared. To study the roles of the Zn(II) and Co(II) ions during catalysis, rapid freeze quench (RFQ)-EXAFS studies were used to probe the reaction of the ZnCo-L1 analog with chromacef when quenched at 10 ms, 50 ms, and 100 ms. The L1-product complex was also analyzed with EXAFS spectroscopy. The data show that the Zn-Co distance is 3.49 Å in the resting enzyme and that this distance increases by 0.3 Å in the sample that was quenched at 10 ms. The average Zn-Co distance decreases at the other time points until reaching a distance of 3.58 Å in the L1-product complex. The data also show that a Co-S interaction is present in the 100 ms quenched sample and in the L1-product complex, which suggests that there is a significant rearrangement of product in the active site.
The present study was designed to investigate the mineral content and antimicrobial activity of Curcuma Longa extracts and its essential oil. We also determined the lipid peroxidation inhibition activity of the ethanolic extract against sodium nitroprusside (SNP) induced thiobarbituric acid reactive species (TBARS) formation in rat's brain, kidney and liver homogenates. Major constituents of essential oil identified by gas chromatography and mass spectrometry (GCMS) were beta-sesquiphellandrene (38.69%), alpha-curcumene (18.44%) and p-mentha-1,4 (8)-diene (16.29%). Atomic absorption spectroscopy (AAS)
 was used for the quantitative estimation of Calcium (Ca), Magnesium (Mg), Iron (Fe), Copper (Cu), Zinc (Zn), Chromium (Cr), Nickel (Ni) and Manganese (Mn). The extract showed highest Mg (49.4 mg/l) concentration followed by Ca (35.42 mg/l) and Fe (1.27 mg/l). Our data revealed that the ethanolic extract of Curcuma Longa at 1-10 mg/kg significantly inhibited TBARS production in all tested homogenates. Crude extracts and essential oil were tested against three gram positive bacteria i.e. Bacillus subtilis, Bacillus atrophoeus, Staphylococcus aureus, six gram negative bacteria i.e. Escherichia coli, Klebsiella pneumonias, Salmonella typhi, Pseudomonas aeruginosa, Erwinia carotovora, Agrobacterium tumefaciens and one fungal strain namely Candida albicans by disc diffusion assay. Essential oil showed highest anti-microbial activity as compared to the crude extracts. The present study confirms the significant antimicrobial and antioxidant potential of the studied plant, which can be considered as a diet supplement for a variety of oxidative stress induced or infectious diseases.
Amylin, a small peptide co-secreted from pancreatic β-cells together with insulin, is one of the hallmarks of type II diabetes. In the course of this disease, it misfolds into small oligomers or into an aggregated β-sheet amyloid fiber. The misfolding mechanism is not yet well understood, but it is clear that metal ions such as zinc and copper play an important role in the process. In this work, the coordination chemistry of Zn(2+) and Cu(2+) with the membrane-disrupting part of amylin (amylin1-19) is discussed. Cu(2+) alters the structure of amylin1-19 only locally, by binding to His18 imidazole and to three preceding amides at the N-terminal side of this residue. Zn(2+) binds to the imidazole of His18 and the amine group of Lys1, imposing a kink in the peptide between these residues. This zinc-induced kink might be a partial explanation of the formation of prefibrillar oligomeric aggregates of amylin, which are much more toxic to β-cells than large fibrillar deposits.
Type 1 diabetes mellitus (T1DM) may lead to deficiencies in trace elements that have substantial functions in the human organism. Changes in serum magnesium (Mg), copper (Cu), and zinc (Zn) levels are correlated with metabolic control and diabetes complications. The aim of this study was to evaluate the intra-erythrocyte levels of trace elements and urinary Mg excretion following intravenous (iv) Mg tolerance testing in children with T1DM.
A total of 43 children aged 2-18 years with T1DM and age/gender-matched 25 healthy children were included in the study. The iv Mg tolerance test was performed following the measurement of intra-erythrocyte Mg (eMg1), Cu (eCu1), and Zn (eZn1) levels using the atomic absorption spectrophotometer method. The Mg retention ratio was estimated from measurements in 24 h urine samples.
No statistically significant difference was found for eMg1, eCu1, and eZn1 levels between the patient and control groups (p>0.05). In the patient group, the eMg1, eCu1, and eZn1 levels measured after the iv Mg tolerance test significantly increased compared with the baseline levels (p<0.05), and the Mg excretion ratio measured from the urine collected after the iv MgSO4 infusion was >50%.
The increased retention value following the iv Mg tolerance testing indicates intracellular Mg deficiency in children with T1DM.
Cave ecosystems remain largely unstudied and risk being severely degraded as a result of anthropogenic activities. The Wonderfontein Cave, situated in the extensive gold mining region of the Witwatersrand Basin, is one such system that hosts a population of Clarias gariepinus, which is exposed to the influx of polluted mine water from the Wonderfontein Spruit River. The aim of this study was to investigate the bioaccumulation of metals, as well as relevant biomarkers, in C. gariepinus specimens sampled from the Wonderfontein Cave during high (April 2013) and low (September 2013) flow surveys. Results were also compared to a surface population associated with the Wonderfontein Spruit River. There were temporal differences in metal bioaccumulation patterns and this was attributed to the lack of dilution during the low flow period. Metals associated with acid mine drainage, i.e. Co, Mn and Zn were significantly higher in the Wonderfontein Cave population and were reflected in an increase in oxidative stress biomarkers (catalase, protein carbonyls and superoxide dismutase) and the induction of metallothionein, a biomarker of metal exposure. The surface population was exposed to metals associated with geological weathering processes, i.e. Fe and Al.
Contaminants often occur as mixtures in the environment, but investigations into toxicity usually employ a single chemical. Metal contaminant mixtures from anthropogenic activities such as mining and coal combustion energy are widespread, yet relatively little research has been performed on effects of these mixtures on amphibians. Considering that amphibians tend to be highly sensitive to copper (Cu) and that metal contaminants often occur as mixtures in the environment, it is important to understand the interactive effects that may result from multiple metals. Interactive effects of Cu and zinc (Zn) on amphibians have been reported as antagonistic and, conversely, synergistic. The goal of our study was to investigate the role of Zn in Cu toxicity to amphibians throughout the embryonic developmental period. We also considered maternal effects and population differences by collecting multiple egg masses from contaminated and reference areas for use in four experiments across three species. We performed acute toxicity experiments with Cu concentrations that cause toxicity (10-200 μg/L) in the absence of other contaminants combined with sublethal concentrations of Zn (100 and 1000 μg/L). Our results suggest very few effects of Zn on Cu toxicity at these concentrations of Zn. As has been previously reported, we found that maternal effects and population history had significant influence on Cu toxicity. The explanation for a lack of interaction between Cu and Zn in this experiment is unknown but may be due to the use of sublethal Zn concentrations when previous experiments have used Zn concentrations associated with acute toxicity. Understanding the inconsistency of amphibian Cu/Zn mixture toxicity studies is an important research direction in order to create generalities that can be used to understand risk of contaminant mixtures in the environment.
In this paper we explored the heavy metal bioaccumulation (Cd, Cu, Pb and Zn) in Procambarus clarkii, a crayfish recently suggested as a potential bioindicator for metals pollution in freshwater systems. The present study is focused on crayfishes populations caught in a heavily polluted industrial and in a reference sites (Central Italy), though the results are generalized with a thorough analysis of literature metadata. In agreement with the literature, the hepatopancreas (Hep, detoxification tissues) of the red swamp crayfish showed a higher concentration of heavy metals in comparison to the abdominal muscle (AbM, not detoxification tissues) in the sites under scrutiny. Hep/AbM concentration ratio was dependent on the specific metal investigated and on its sediment contamination level. Specifically we found that Hep/AbM ratio decreases as follows: Cd (11.7)>Cu (5.5)>Pb (3.6)>Zn (1.0) and Pb (4.34)>Cd (3.66)>Zn (1.69)>Cu (0.87) for the industrial and reference sites, respectively. The analysis of our bioaccumulation data as well as of literature metadata allowed to elaborate a specific contamination index (Toxic Contamination Index, TCI), dependent only on the bioaccumulation data of hepatopancreas and abdominal muscle. In the industrial site, TCI expressed values much higher than the unit for Cd and Cu, confirming that these metals were the main contaminants; in contrast for lower levels of heavy metals, as those observed in the reference site for Cu, Zn and Pb, the index provided values below unit. TCI is proposed as a useful and easy tool to assess the toxicity level of contaminated sites by heavy metals in the environmental management.
Foreign substances get into the internal environment of living bodies and accumulate in various organs. Cristobalite and hematite particles in the glial cells of pons cerebri of human brain with diagnosis of Behhet disease with scanning electron microscopy (SEM), energy-dispersive microanalysis (EDX), and transmission electron microscopy (TEM) with diffraction were identified. SEM with EDX revealed the matter of irregular micrometer-sized particles sometimes forming polyhedrons with fibrilar or stratified structure. It was found in some particles Ti, Fe, and Zn. Some particles contained Cu. TEM and electron diffraction showed particles of cristobalite and hematite. The presence of the particles can be a result of environmental effect, disruption of normal metabolism, and transformation of physiologically iron-ferrihydrite into more stable form-hematite. From the size of particles can be drawn the long-term accumulation of elements in glial cells.
Exposure to trace metals typically causes oxidative stress; these consequences are better-characterized in estuarine and marine species than in freshwater species. How cellular-level responses to metal pollution influence whole-organism and population-level traits is poorly understood. We tested whether exposure to single metals (zinc and cadmium) and to metal mixtures (water in equilibrium with sediment from a highly polluted lake) alters two ecologically-relevant traits in freshwater clams, locomotion and reproduction. Fingernail clams (Musculium spp.) from unimpacted habitats were exposed to single metals and the metal mixture for up to 49days. The single metal doses (≤5mg/L Zn and ≤20μg/L Cd)
 were not toxicologically meaningful as clam survival, burial, and climbing activity did not differ across treatments. Water in equilibrium with the lake sediment contained cadmium, copper, lead, and zinc. Clams exposed to this metal mixture had decreased climbing activity but no change in burial activity. Metal-exposed clams had lower fecundity (number of shelled juveniles extruded by adult clams) and patterns in metal accumulation corresponded with lake sediment dose and clam activity. In contrast to the functional traits, stress protein expression and whole-clam glycogen content did not vary across treatment groups. These results indicate that fingernail clams of the genus Musculium are appropriate for development as sentinel species for metal pollution and can serve as a model for determining how metal pollution alters metabolic allocation patterns in freshwater organisms.
Growing evidence links neurodegenerative diseases to metal exposure. Aberrant metal ion concentrations have been noted in Alzheimer's disease (AD) brains, yet the role of metals in AD pathogenesis remains unresolved. A major factor in AD pathogenesis is considered to be aggregation of and amyloid formation by amyloid-β (Aβ) peptides. Previous studies have shown that Aβ displays specific binding to Cu(II) and Zn(II) ions, and such binding has been shown to modulate Aβ aggregation. Here, we use nuclear magnetic resonance (NMR) spectroscopy to show that Mn(II) ions also bind to the N-terminal part of the Aβ(1-40) peptide, with a weak binding affinity in the milli- to micromolar range. Circular dichroism (CD) spectroscopy, solid state atomic force microscopy (AFM), fluorescence spectroscopy, and molecular modeling suggest that the weak binding of Mn(II) to Aβ may not have a large effect on the peptide's aggregation into amyloid fibrils. However, identification of an additional metal ion displaying Aβ binding reveals more complex AD metal chemistry than has been previously considered in the literature.
Some trace metals may increase risk of amyotrophic lateral sclerosis (ALS), whereas others may be beneficial. Our goal was to examine associations of ALS with blood levels of selenium (Se), zinc (Zn), copper (Cu), and manganese (Mn). We conducted a case-control study of 163 neurologist confirmed patients from the National Registry of Veterans with ALS and 229 frequency-matched veteran controls. We measured metal levels in blood using inductively coupled plasma mass spectrometry and estimated odds ratios (ORs) and 95% confidence intervals (CIs) for associations between ALS and a doubling of metal levels using unconditional logistic regression, adjusting for age, gender, and race/ethnicity. ALS was inversely associated with both Se (OR=0.4, 95% CI: 0.2-0.8) and Zn (OR=0.4, 95% CI: 0.2-0.8). Inverse associations with Se were stronger in patients with bulbar compared to spinal onset, worse function, longer diagnostic delay, and longer collection delay; inverse associations with Zn were stronger for those with worse function and longer collection delay. In contrast, ALS was positively associated with Cu (OR=3.4, 95% CI: 1.5-7.9). For Mn, no linear trend was evident (OR=0.9, 95% CI: 0.6-1.3, Ptrend=0.51). Associations of Se, Zn, Cu, and Mn with ALS were independent of one another. Adjustment for lead levels attenuated the positive association of ALS with Cu but did not change associations with Se, Zn, or Mn. In conclusion, Se and Zn were inversely associated with ALS, particularly among those with worse function, suggesting that supplementation with these metals may benefit such patients, while Cu was positively associated with ALS. Deficiencies of Se and Zn and excess Cu may have a role in ALS etiology.
Vibrio parahaemolyticus is a causative agent of human serious seafood-borne gastroenteritis disease and even death. Shrimps, often eaten raw or undercooked, are an important reservoir of the bacterium. In this study, we isolated and characterized a total of 400 V. parahaemolyticus strains from commonly consumed fresh shrimps (Litopenaeus vannamei, Macrobrachium rosenbergii, Penaeus monodon, and Exopalaemon carinicauda) in Shanghai fish markets, China in 2013-2014. The results revealed an extremely low occurrence of pathogenic V. parahaemolyticus carrying two major toxic genes (tdh and trh, 0.0 and 0.5 %). However, high incidences of antibiotic resistance were observed among the strains against ampicillin (99 %), streptomycin (45.25 %), rifampicin (38.25 %), and spectinomycin (25.50 %). Approximately 24 % of the strains derived from the P. monodon sample displayed multidrug resistant (MDR) phenotypes, followed by 19, 12, and 6 % from the E. carinicauda, L. vannamei, and M. rosenbergii samples, respectively. Moreover, tolerance to heavy metals of Cr(3+) and Zn(2+) was observed in 90 antibiotic resistant strains, the majority of which also displayed resistance to Cu(2+) (93.3 %), Pb(2+) (87.8 %), and Cd(2+)(73.3 %). The pulsed-field gel electrophoresis (PFGE)-based genotyping of these strains revealed a total of 71 distinct pulsotypes, demonstrating a large degree of genomic variation among the isolates. The wide distribution of MDR and heavy-metal resistance isolates in the PFGE clusters suggested the co-existence of a number of resistant determinants in V. parahaemolyticus population in the detected samples. This study provided data in support of aquatic animal health management and food safety risk assessment in aquaculture industry.
The vibrational spectra of group 12 difluorides, MF2 (M = Zn, Cd, Hg), were investigated via coupled cluster singles, doubles, and perturbative triples, CCSD(T), including core correlation, with a series of correlation consistent basis sets ranging in size from triple-zeta through quintuple-zeta quality, which were then extrapolated to the complete basis set (CBS) limit using a variety of extrapolation procedures. The explicitly correlated coupled cluster method, CCSD(T)-F12b, was employed as well. Although exhibiting quite different convergence behavior, the F12b method yielded the CBS limit estimates closely matching more computationally expensive conventional CBS extrapolations. The convergence with respect to basis set size was examined for the contributions entering into composite vibrational spectroscopy, including those from higher-order correlation accounted for through the CCSDT(Q) level of theory, second-order spin-orbit coupling effects assessed within four-component and two-component relativistic formalisms, and vibrational anharmonicity evaluated via a perturbative treatment. Overall, the composite results are in excellent agreement with available experimental values, except for the CdF2 bond-stretching frequencies compared to spectral assignments proposed in a matrix isolation infrared and Raman study of cadmium difluoride vapor species [Loewenschuss et al., J. Chem. Phys. 50, 2502 (1969); Givan and Loewenschuss, J. Chem. Phys. 72, 3809 (1980)]. These assignments are called into question in the light of the composite results.
Dietary composition and rearing regime largely determine the trace elemental composition of pigs, and consequently their concentration in animal products. The present study evaluates thirteen macro- and trace element concentrations in pork from organic and conventional farms. Conventional pigs were given a commercial feed with added minerals; organic pigs were given a feed based on organic feedstuffs. The content of macro-elements (Na, K, Mg and Ca) and some trace elements (Ni, Fe, Zn and Sr) in organic and conventional meat samples showed no significant differences (P>0.05). Several trace element concentrations in organic pork were significantly higher (P<0.05) compared to conventional pork: Cr (808 and 500μg/kg in organic and conventional pork, respectively), Mn (695 and 473μg/kg) and Cu (1.80 and 1.49mg/kg). The results showed considerable differences in mineral content between samples from pigs reared in organic and conventional systems. Our results also indicate that authentication of organic pork can be realized by applying multivariate chemometric methods such as discriminant analysis to this multi-element data.
Transfer factors of natural radionuclides and (137)Cs from soil to plants used in traditional medicine were determined. The transfer factors (TF) were calculated as Bq kg(-1) of dry plant per Bq kg(-1) of dry soil. Mass activity concentrations of (226)Ra, (232)Th, (40)K and (137)Cs in soil and plant samples were measured with high purity germanium detector (HPGe). The concentrations of As, Co, Cr, Cu, Mn, Ni, Pb and Zn were determined, as well as the cation exchange capacity (CEC) and the content of exchangeable cations (Ca, Mg, K, Na). Wide ranges of values were obtained for all the metals, especially for Cr and Ni. The Absalom model was used for determination of the amount of (137)Cs transferred from soil to plant based on soil characteristics such as pH, exchangeable potassium, humus and clay contents. The estimated transfer factors were in the range from 0.011 to 0.307 with an arithmetic mean of 0.071, median of 0.050, geometric mean of 0.053 and geometric standard deviation (GSD) of 2.08. This value agreed well with that calculated from the measurements of 0.069, geometric mean 0.040 and GSD 3.19. Correlations between radionuclides, metals, physicochemical properties and transfer factors were determined by Spearman correlation coefficient. There was a strong positive correlation between (137)Cs transfer factor and the ratio of transfer factor for K and (137)Cs. Principal Component Analysis (PCA) was performed in order to identify some pattern of data.
A series of hetero-bimetallic transition metal-substituted polyoxometalates (TMSPs) were synthesized based on the Co(II)-centered ligand [Co(II)W11O39](10-). The eight complex series, [Co(II)(M(x)OHy)W11O39]((12-x-y)-) (M(x)OHy
 = V(IV)O, Cr(III)(OH2), Mn(II)(OH2), Fe(III)(OH2), Co(II)(OH2), Ni(II)(OH2), Cu(II)(OH2), Zn(II)(OH2)), of which six are reported for the first time, was synthesized starting from [Co(III)W11O39](9-) and studied using spectroscopic, electrochemical, and computational techniques to evaluate the influence of substituted transition metals on the photodynamics of the metal-to-polyoxometalate charge transfer (MPCT) transition. The bimetallic complexes all show higher visible light absorption than the plenary [Co(II)W12O40](6-) and demonstrate the same MPCT transition as the plenary complex, but they have shorter excited-state lifetimes (sub-300 ps in aqueous media). The decreased lifetimes are rationalized on the basis of nonradiative relaxation due to coordinating aqua ligands, increased interaction with cations due to increased negative charge, and the energy gap law, with the strongest single factor appearing to be the charge on the anion. The most promising results are from the Cr- and Fe-substituted systems, which retain excited-state lifetimes at least 50% of that of [Co(II)W12O40](6-) while more than tripling the absorbance at 400 nm.
The present study reports contents and the bioavailability of Fe and Zn from 25 selected raw and cooked food samples. The results showed highest variation of Fe content in raw food samples ranging from 2.19 ± 0.04 to 0.93 ± 0.03 mg/100g in legumes. The raw black eye bean, cheese and fish showed high Zn content up to 8.85 ± 0.01, 12.93 ± 0.26 and 172.03 ± 5.09 mg/100g, respectively. Pulses and cereals showed high level of ionizable Fe. Zn bioavailability was quite low in cereals as compared to pulses; 4.02% in yellow split to 17.40% in Bengal gram. Zn bioavailability of 17.40% is in cheese. Fe bioavailability is high in cooked rice 160.60%, white bread 428.30% and milk powder 241.67% showing that Fe bioavailability increased after cooking whereas the lowest in fish 0.84%. The multivariate and cluster analysis categorized studied foods into two main groups.
Though the fruits of Averrhoa bilimbi and A. carambola are economically and medicinally important, they remain underutilized. The present study reports heavy metal quantitation in the fruit samples of A. bilimbi and A. carambola (Oxalidaceae), collected at two stages of maturity. Heavy metals are known to interfere with the functioning of vital cellular components. Although toxic, some elements are considered essential for human health, in trace quantities. Heavy metals such as Cr, Mn, Co, Cu, Zn, As, Se, Pb, and Cd were analyzed by atomic absorption spectroscopy (AAS). The samples under investigation included, A. bilimbi unripe (BU) and ripe (BR), A. carambola sour unripe (CSU) and ripe (CSR), and A. carambola sweet unripe (CTU) and ripe (CTR). Heavy metal analysis showed that relatively higher level of heavy metals was present in BR samples compared to the rest of the samples. The highest amount of As and Se were recorded in BU samples while Mn content was highest in CSU samples and Co in CSR. Least amounts of Cr, Zn, Se, Cd, and Pb were noted in CTU while, Mn, Cu, and As were least in CTR. Thus, the sweet types of A. carambola (CTU, CTR) had comparatively lower heavy metal content. There appears to be no reason for concern since different fruit samples of Averrhoa studied presently showed the presence of various heavy metals in trace quantities.
This study aimed to identify dietary patterns using reduced rank regression (RRR) and to explore their associations with depressive symptoms over 9 years in the Invecchiare in Chianti study. At baseline, 1362 participants (55·4 % women) aged 18-102 years (mean age 68 (sd 15·5) years) were included in the study. Baseline data collection started in 1998 and was repeated after 3, 6 and 9 years. Dietary intake information was obtained using a country-specific, validated FFQ with 188 food items. For baseline diet, dietary pattern scores in quartiles (Q) were derived using RRR with the nutrients EPA+DHA, folate, Mg and Zn as response variables. Continuous depression scores from the Centre for Epidemiologic Studies Depression (CES-D) scale were used for assessing depressive symptoms. The derived dietary pattern was rich in vegetables, olive oil, grains, fruit, fish and moderate in wine and red and processed meat, and was labelled as 'typical Tuscan dietary pattern'. After full adjustment, an inverse association was observed between this dietary pattern and depressive symptoms at baseline (Q1 v. Q4, B -2·77; 95 % CI -4·55, -0·98). When examining the relationship between the above-mentioned dietary pattern at baseline and depressive symptoms over 9 years, a similar association was found after full adjustment for confounding factors (Q1 v. Q4, B -1·78; 95 % CI -3·17, -0·38). A diet rich in vegetables, olive oil, grains, fruits, fish and moderate in wine and red and processed meat was consistently associated with lower CES-D scores over a 9-year period in the Tuscan population.
Airborne nanoparticles PM0.1 (<100 nm in diameter) were collected and their chemical composition was determined. Al was by far the most abundant metal in the PM0.1 followed by Zn, Cr, Mn, Cu, Pb and Ni. Exposure to PM0.1 resulted in a cell viability decrease in human neuronal cells SH-SY5Y in a concentration-dependent manner. Upon treatment with N-acetylcysteine, however, cell viability was significantly recovered, suggesting the involvement of reactive oxygen species (ROS). Cellular DNA damage by PM0.1 was also detected by the Comet assay. PM0.1 -induced autophagic cell death was explained by an increase in the expression of microtubule-associated protein light chain 3A-ІІ (LC3A-ІІ) and autophagy-related protein Atg 3 and Atg 7. Analysis of 2-DE gels revealed that six proteins were upregulated, whereas eight proteins were downregulated by PM0.1 exposure. Neuroinflammation-related lithostathine and cyclophilin A complexed with dipeptide Gly-Pro, autophagy-related heat shock protein gp96 and neurodegeneration-related triosephosphate isomerase were significantly changed upon exposure to PM0.1 . These results, taken together, suggest that PM0.1 -induced oxidative stress via ROS generation plays a key role in autophagic cell death and differential protein expressions in SH-SY5Y cells. This might provide a plausible explanation for the underlying mechanisms of PM0.1 toxicity in neuronal cells and even the pathogenesis of diseases associated with its exposure. Copyright © 2016 John Wiley & Sons, Ltd.
According to the previous studies, the anticancer activity of flavonoids could be enhanced when they are coordinated with transition metal ions. In this work, kaempferol-zinc(II) complex (kaempferol-Zn) was synthesized and its chemical properties were characterized by UV-VIS, FT-IR, (1)H NMR, elemental analysis, electrospray mass spectrometry (ES-MS) and fluorescence spectroscopy, which showed that the synthesized complex was coordinated with a Zn(II) ion via the 3-OH and 4-oxo groups. The anticancer effects of kaempferol-Zn and free kaempferol on human oesophageal cancer cell line (EC9706) were compared. MTT results demonstrated that the killing effect of kaempferol-Zn was two times higher than that of free kaempferol. Atomic force microscopy (AFM) showed the morphological and ultrastructural changes of cellular membrane induced by kaempferol-Zn at subcellular or nanometer level. Moreover, flow cytometric analysis indicated that kaempferol-Zn could induce apoptosis in EC9706 cells by regulating intracellular calcium ions. Collectively, all the data showed that kaempferol-Zn might be served as a kind of potential anticancer agent.
Curcumin conjugated ZnO, referred as Zn(cur)O, nanostructures have been successfully synthesized, these sub-micro grain-like structures are actually self-assemblies of individual needle-shaped nanoparticles. The nanostructures as synthesized possess the wurtzite hexagonal crystal structure of ZnO and exhibit very good crystalline quality. FT-Raman and TGA analysis establish that Zn(cur)O is different from curcumin anchored ZnO (ZnO@cur), which is prepared by physically adsorbing curcumin on ZnO surfaces. Chemically Zn(cur)O is more stable than ZnO@cur. Diffuse reflectance spectroscopy indicates Zn(cur)O have more impurities compared to ZnO@cur. The solid-state photoluminescence of Zn(cur)O has been investigated, which demonstrates that increase of curcumin concentration in Zn(cur)O suppresses visible emission of ZnO prepared through the same method, this implies filling ZnO defects by curcumin. However, at excitation wavelength 425 nm the emission is dominated by fluorescence from curcumin. The study reveals that Zn(cur)O can remove to a far extent high concentrations of perylene, fluoranthene, and chrysene faster than ZnO. The removal depends on the extent of curcumin conjugation and is found to be faster for PAHs having smaller number of aromatic rings, particularly, it is exceptional for fluoranthene with 93% removal after 10 minutes in the present conditions. The high rate of removal is related to photo-degradation and a mechanism has been proposed.
The diet of Indonesian women of childbearing age is relatively poor, posing increased risk for suboptimal pregnancy outcome. In a cross-sectional study including 403 women in three economic quintiles (Q), we investigated differences in dietary intake and nutrition sufficiency according to economic status and whether regular dietary intakes of pregnant women (PW, n 203) differ from that of pre-pregnant women (PPW, n 200). Dietary intake data were collected using 2×24 h dietary recall and FFQ. Energy, protein, Fe, Ca, Zn, vitamin A and vitamin C intakes were calculated utilising Food Composition Tables and compared with Indonesian recommendations for adequacy. Energy and protein intakes <70 % and Fe, Ca, Zn, vitamin A and vitamin C intakes <77 % of the local
 recommendation were considered insufficient. A higher intake of milk/dairy products (Q3, Q4), fruits and vegetables (Q2) and snacks (Q3) in PW was observed compared with PPW, but insufficient to meet nutrient requirements. Nutrient intake calculations showed insufficiency in 26 % of PPW for protein and up to 70 % for Fe. Deficient nutrient intakes in PW were found in 49 % of the subjects for energy and up to 85 % for Fe. Energy and protein intakes decreased with decreasing economic quintiles in PPW and PW. Ca and vitamin A intakes were lower in Q2 compared with Q4. The proportion of animal protein in Q2-PW was low (31 %). Biochemical status parameters in a subset showed that anaemia and Fe and Zn deficiencies were prevalent among PPW and PW. Habitual diets in the study area did not meet the nutrient requirements for both PPW and PW across the investigated economic groups.
Metallothioneins (MTs) are a family of Cys-rich, low molecular weight, cytoplasmic metal binding proteins. MTs are present in all eukaryotes as well as some prokaryotes. Plant MTs are divided into four types based on Cys distribution pattern in their amino acid sequences. In the present work, the gene encoding OsMTI-2b, a type 2 MT found in rice, was cloned into pET41a vector. The resulting construct was transformed into Escherichia coli strain Rosetta (DE3). Following the induction with Isopropyl β-d-1-thiogalactopyranoside the OsMTI-2b was expressed as carboxyl-terminal extensions of glutathione-S-transferase (GST-tag), a 6His-tag, and an S-tag. The expressed recombinant fusion protein was named GST-OsMTI-2b. As compared with control, transgenic E. coli cells expressing GST-OsMTI-2b accumulated more Pb(2+), Ni(2+), Cd(2+), Zn(2+) and Cu(2+) from culture medium and showed increased tolerance against these metals. Furthermore the E. coli cells expressing OsMTI-2b accumulated significantly higher Pb(2+) than previously made strains which expressing other rice OsMT isoforms. The recombinant GST-OsMTI-2b was purified using affinity chromatography. According to in vitro assays the protein GST-OsMTI-2b was able to form complexes with Pb(2+), Ni(2+), Cd(2+) and Zn(2+). However, the binding ability for the different metals differed in the order: Pb(2+)>Cd(2+)>Zn(2+)>Ni(2+).
A field trial was conducted in an abandoned Pb/Zn mine tailings to evaluate the effectiveness of three industrial wastes [sweet sorghum vinasse (SSV), medicinal herb residues (MHR) and spent mushroom compost (SMC)] as organic amendments on plant growth, soil nutrients and enzyme activities, and heavy metal concentrations in plant tissues and the mine tailings. (1) The main findings were as follows: (1) The mean concentrations of diethylene-triamine-pentaacetic acid (DTPA)-extractable Cd, Cu, Pb and Zn in SSV, MHR and SMC treatments decreased by 24.2%-27.3%, 45.7%-48.3%, 18.0%-20.9% and 10.1%-14.2% as compared to the control tailings. When compared to the control tailings, the mean values of organic matter, ammonium-N and available P in SSV, MHR and SMC treatments increased by 2.27-2.32, 12.4-12.8 and 4.04-4.74 times, respectively. Similarly, the addition of SSV, MHR and SMC significantly enhanced soil enzyme activities (dehydrogenase, beta-glucosidase, urease and phosphatase), being 5.51-6.37, 1.72-1.96, 6.32-6.62 and 2.35-2.62 times higher than those in the control tailings. (2) The application of these wastes promoted seed germination and seedling growth. The vegetation cover reached 84%, 79% and 86% at SSV, MHR and SMC subplots. For Lolium perenne and Cynodon dactylon, the addition of SSV, MHR and SMC led to significant increases in the shoot biomass yields with 4.2-5.6 and 15.7-17.3 times greater than those in the tailings. Moreover, the addition of SSV, MHR and SMC significantly reduced the concentrations of Cd, Cu, Pb and Zn in the shoots of L. perenne and C. dactylon in comparison with the control tailings. (3) Pearson's correlation coefficients showed that the vegetation cover and biomass were positively correlated with soil nutrient elements and enzyme activities. Significant negative correlations were observed between DTPA-extractable metal concentrations and vegetation cover and biomass. The metal concentrations in plants were positively correlated with soil DTPA-extractable metal concentrations and negatively correlated with soil nutrient elements and enzyme activities. The results obtained in this field study confirmed that the three organic-rich industrial wastes could be used as amendments for aided phytostabilization of some types of mine tailings.
With acceleration of urbanization, water shortages will become a serious problem. Usage of reclaimed water for flushing and watering of the green areas will be common in the future. To study the heavy metal contamination of soils after green area irrigation using recycled wastewater from special industries, we selected sewage and laboratory wastewater as water source for integrated oxidation ditch treatment, and the effluent was used as irrigation water of the green area. The irrigation units included broad-leaved forest, bush and lawn. Six samples sites were selected, and 0-20 cm soil of them were collected. Analysis of the heavy metals including Cr, Mn, Ni, Cu, Zn, As, Cd and Pb in the soil showed no significant differences with heavy metals concentration in soil irrigated with tap water. The heavy metals in the soil irrigated with recycled water were mainly enriched in the surface layer, among which the contents of Cr, Ni, Cu, Zn and Pb were below the soil background values of Beijing. A slight pollution of As and Cd was found in the soil irrigated by recycled water, which needs to be noticed.
The particle size, total organic carbon (TOC), total nitrogen (TN), C/N ratio and metal concentrations as well as activities of 210Pb were determined in Liaohe River estuary area (LN-2) and Shenyang area (LN-5), and the organic matter resources were discussed in two core sediments. Also the index of geoaccumulation (Igeo) and enrichment factors (EFs) methods were applied to evaluate the state of heavy metal contamination in the studied sties. The study showed that both sediment cores LN-2 and LN-5 were dominated by silts, and the vertical variations of grain-size composition and organic matter were well distributed in LN- 2 while fluctuated in LN-5. According to the organic matter source analysis through C/N ratio, C/N ratio varied in the scale of 5. 24-7.93 in LN-2 which was dominated by river source, and 9.94-14.21 in LN-5 which was dominated by terrestrial input. Al, Ca, Fe, Mn, Ni, Cu, Zn, Cd, Pb and Cr in two sediment cores had different vertical changing rules, Ni and Zn in LN-2 as well as Pb and Zn in LN-5 were affected by both natural and human factors, other elements had similar distributions to those of organic matters, which showed that these elements were mainly affected by the natural activities. Based on Igeo and EFs, both sediment cores were more severely polluted with Ni, Zn and Pb than other metals. The effects of human activities on the environment were also discussed in this study, combined with the economical development of Liaoning Province and the studied sites in the past 20 years.
In order to make effective plan to provide the scientific basis for prevention and control of re-suspended dust (RD), samples of particulate sources including RD and other pollution sources of Jincheng were collected. Elements, ions and carbon in particulate sources were analyzed. Enrichment factor, potential ecological risk assessment, and chemical mass balance model were used to analyze the chemical composition and the source of RD. The result indicated that the main components in RD of Jingeheng were Si, TC, Ca, OC, Al, Mg, Na, Fe, K and SO4(2-), contributing 61.14% of total mass of RD. The most abundant content of RD was crustal elements, and the ions were enriched in the fine particles. The mass fraction of OC in PM2. was higher, whereas the mass fraction of EC in PM10 was higher, indicating that secondary organic pollutants were mainly dominated in the fine particles. The dust PM2.5 and PM10 potential ecological risk indexes were extremely strong, and PM2.5 had higher ecological harm than PM10. Pb had the highest enrichment factor of 196.97 in PM2.5, which was followed by As, Cr, Ni, V, Zn and Cu, the enrichment factors of which were all greater than 10, indicating that they were apparently enriched and affected by human activities. Soil dust, construction dust, vehicle exhaust, and coal dust were the main sources of RD.
PM₂.₅ samples were collected in six different functional zones in Nanchang City during autumn in 2013. PM₂.₅ mass concentration and enrichment characteristics of eighteen metal elements (Mg, Al, K, Ca, Ti, V, Ba, Co, Cr, Mn, Fe, Ni, Cu, Zn, Cd, Pb, As and Hg) were analyzed. The pollution sources of the above elements in PM₂.₅ were discussed based on the results of multivariate statistical analysis. The results showed that the average daily mass concentration of PM₂.₅ during autumn in Nanchang City met the secondary standard limit (≤ 75 µg · m⁻³) of National Ambient Air Quality Standards (GB 3095-2012). The enrichment factors of Mn, Ti, Al and V were lower than 1.0, indicating that these elements were barely enriched. The enrichment factors of Fe, Cr, Co, K, Mg, Ba, Ca, Cu and As ranged from 1.7 to 7.8, suggesting the influence of both natural sources and anthropogenic sources. Hg, Zn, Pb, Ni and Cd were obviously affected by anthropogenic emissions since their enrichment factors ranged from 21. 9 to 481.2. The combined results of correlation analysis, principal components analysis and cluster analysis revealed the pollution sources of these metals in PM₂.₅: Mg, K, Al, Ca and Ti mainly came from natural soil and building material dust; As and Hg were mainly from coal combustion; Ba, Ni and Mn were mainly from
 industrial emission of metal smelting; V, Cu, Fe, Cd, Pb, Cr and Co mainly came from traffic sources; Zn was influenced by metal smelting and coal burning.
The new dinuclear Zn(II)-Dy(III) and trinuclear Zn(II)-Dy(III)-Zn(II) complexes of formula [(LZnBrDy(ovan) (NO3)(H2O)](H2O)·0.5(MeOH) (1) and [(L(1)ZnBr)2Dy(MeOH)2](ClO4) (3) (L and L(1) are the dideprotonated forms of the N,N'-2,2-dimethylpropylenedi(3-methoxysalicylideneiminato and 2-{(E)-[(3-{[(2E,3E)-3-(hydroxyimino)butan-2-ylidene ]amino}-2,2-dimethylpropyl)imino]methyl}-6-methoxyphenol Schiff base compartmental ligands, respectively) have been prepared and magnetostructurally characterized. The X-ray structure of 1 indicates that the Dy(III) ion exhibits a DyO9 coordination sphere, which is made from four O atoms coming from the compartmental ligand (two methoxy terminal groups and two phenoxido bridging groups connecting Zn(II) and Dy(III) ions), other four atoms belonging to the chelating nitrato and ovanillin ligands, and the last one coming to the coordinated water molecule. The structure of 3 shows the central Dy(III) ion surrounded by two L(1)Zn units, so that the Dy(III) and Zn(II) ions are linked by phenoxido/oximato bridging groups. The Dy ion is eight-coordinated by the six O atoms afforded by two L(1) ligands and two O atoms coming from two methanol molecules. Alternating current (AC) dynamic magnetic measurements of 1, 3, and the previously reported dinuclear [LZnClDy(thd)2] (2) complex (where thd = 2,2,6,6-tetramethyl-3,5-heptanedionato ligand) indicate single molecule magnet (SMM) behavior for all these complexes with large thermal energy barriers for the reversal of the magnetization and butterfly-shaped hysteresis loops at 2 K. Ab initio calculations on 1-3 show a pure Ising ground state for all of them, which induces almost completely suppressed quantum tunnelling magnetization (QTM), and thermally assisted quantum tunnelling magnetization (TA-QTM) relaxations via the first excited Kramers doublet, leading to large energy barriers, thus supporting the observation of SMM behavior. The comparison between the experimental and theoretical magnetostructural data for 1-3 has allowed us to draw some conclusions about the influence of ligand substitution around the Dy(III) on the SMM properties. Finally, these SMMs exhibit metal- and ligand-centered dual emissions in the visible region, and, therefore, they can be considered as magnetoluminescent bifunctional molecular materials.
The concentrations of both essential nutrients and chemically similar toxic analogues accumulated in cereal grains have a major impact on the nutritional quality and safety of crops. Naturally occurring genetic diversity can be exploited for the breeding of improved varieties through introgression lines (ILs). In this study, multi-element analysis was conducted on vegetative leaves, senesced flag leaves and mature grains of a set of 54 ILs of the wild ancestral Hordeum vulgare ssp. spontaneum in the cultivated variety Hordeum vulgare ssp. vulgare cv. Scarlett. Plants were cultivated on an anthropogenically heavy metal-contaminated soil collected in an agricultural field, thus allowing simultaneous localization of quantitative trait loci (QTL) for the accumulation of both essential nutrients and toxic trace elements in barley as a model cereal crop. For accumulation of the micronutrients Fe and Zn and the interfering toxin Cd, we identified 25, 16 and 5 QTL, respectively. By examining the gene content of the introgressions, we associated QTL with candidate genes based on homology to known metal homeostasis genes of Arabidopsis and rice. Global comparative analyses suggested the preferential remobilization of Cu and Fe, over Cd, from the flag leaf to developing grains. Our data identifies grain micronutrient filling as a regulated and nutrient-specific process, which operates differently from vegetative micronutrient homoeostasis. In summary, this study provides novel QTL for micronutrient accumulation in the presence of toxic analogues and supports a higher degree of metal specificity of trace element partitioning during grain filling in barley than previously reported for other cereals.
Tunnel rehabilitation work involves exposure to various air contaminants, including airborne particulate matter (APM). Little is known on the contents of different chemical components of APM generated during tunnel work. The objective of the present study was to characterize exposure to APM and various elements for different job categories in different size fractions of APM during a subsea tunnel rehabilitation project carried out in Western Norway. Personal as well as stationary samples of inhalable, thoracic and respirable dust were collected from workers divided into 11 different job categories based on work operations performed, and air concentrations of a range of elements were determined using high-resolution inductively coupled plasma-mass spectrometry (HR-ICP-MS). Overall, APM concentrations were low, but with some measurements exceeding the American Conference of Governmental Industrial Hygienists (ACGIH) Threshold Limit Value (TLV) for inhalable particles, and considerable proportions of respirable and especially inhalable APM exceeding 10% of the TLVs. For most elements, air concentrations measured were quite low, in the ng/m(3) range, except for the major crustal elements Si, Fe, Al, and Mg, which were found to be in the µg/m(3) range. Asphalt millers overall had the highest exposure levels for APM and most measured elements; for instance, mean concentrations of V, Rb, and Mn were 380, 210, and 2000 ng/m(3) in inhalable and 33, 44, and 310 ng/m(3) in respirable APM. Mounting PVC membrane seemed to generate elevated levels of Cr, Zn, Sn, Pb, Sb, As, Mn, Fe, and Ni, whereas typical bedrock elements were elevated during drilling activities compared to the low exposed categories lead car drivers, foremen/surveyors, drivers of heavy-duty vehicles, and electricians. Overall, stationary samples contained lower amounts of dust and elemental constituents compared to personal samples. Elemental air concentrations were highly variable with occasional elevated values for APM and certain elements, particularly Cr and Zn.
The main aim of this study was the analysis of the interaction between humic acids (HAs) from different soils and Zn(II) ions at wide concentration ranges and at two different pHs, 5 and 7, by using fluorescence and FTIR spectroscopy, as well as potentiometric measurements. The presence of a few areas of HAs structures responsible for Zn(II) complexing was revealed. Complexation at α-sites (low humified structures of low-molecular weight and aromatic polycondensation) and β-sites (weakly humified structures) was stronger at pH 7 than 5. This trend was not observed for γ-sites (structures with linearly-condensed aromatic rings, unsaturated bonds and large molecular weight). The amount of metal complexed at pH5 and 7 by α and γ-structures increased with a decrease in humification and aromaticity of HAs, contrary to β-areas where complexation increased with increasing content of carboxylic groups. The stability of complexes was higher at pH 7 and was the highest for γ-structures. At pH 5, stability decreased with C/N increase for α-areas and -COOH content increase for β-sites; stability increased with humification decrease for γ-structures. The stability of complexes at α and β-areas at pH 7 decreased with a drop in HAs humification. FTIR spectra at pH 5 revealed that the most-humified HAs tended to cause bidentate bridging coordination, while in the case of the least-humified HAs, Zn caused bidentate bridging coordination at low Zn additions and bidentate chelation at the highest Zn concentrations. Low Zn doses at pH 7 caused formation of unidentate complexes while higher Zn doses caused bidentate bridging. Such processes were noticed for HAs characterized by high oxidation degree and high oxygen functional group content; where these were low, HAs displayed bidentate bridging or even bidentate chelation. To summarize, the above studies have showed significant impact of Zn concentration, pH and some properties of HAs on complexation reactions of humic acids with zinc.
"Daodi herb" enjoys a good reputation for its quality and clinical effects. As one of the most popular daodi herbs, Astragalus membranaceus (Fisch.) Bge var. mongholicus (Bge.) Hsiao (A. membranaceus) is popularly used for its anti-oxidant, anti-inflammatory and immune-enhancing properties. In this study, we used inductively coupled plasma atomic emission spectrometry (ICP-AES) technique to investigate the inorganic elements contents in A. mongholicu and its soil samples from daodi area (Shanxi) and non-daodi areas (Inner Mongolia and Gansu). A total of 21 inorganic elements (Pb, Cd, As, Hg, Cu, P, K, Zn, Mn, Ca, Mg, Fe, Se, B, Al, Na, Cr, Ni, Ba, Ti and Sr) were simultaneously determined. Principal component analysis (PCA) was performed to differentiate A. mongholicu and soil samples from the three main producing areas. It was found that the inorganic element characteristics as well as the uptake and accumulation behavior of the three kinds of samples were significantly different. The high contents of Fe, B, Al, Na, Cr and Ni could be used as a standard in the elements fingerprint to identify daodi and non-daodi A. Mongholicus. As the main effective compounds were closely related to the pharmacodynamics activities, the inter-relationships between selected elements and components could reflect that the quality of A. Mongholicus from Shanxi were superior to others to a certain degree. This finding highlighted the usefulness of ICP-AES elemental analysis and evidenced that the inorganic element profile can be employed to evaluate the genuineness of A. mongholicus.
To evaluate the potential use of zinc chelation
 for prostate cancer therapy using a new liposomal formulation of the zinc chelator, N,N,N',N'-tetrakis(2-pyridylmethyl)-ethylenediamine (TPEN).
TPEN was encapsulated in nontargeted liposomes or liposomes displaying an aptamer to target prostate cancer cells overexpression prostate-specific membrane antigen. The prostate cancer selectivity and therapeutic efficacy of liposomal (targeted and nontargeted) and free TPEN were evaluated in vitro and in tumor-bearing mice.
TPEN chelates zinc and results in reactive oxygen species imbalance leading to cell death. Delivery of TPEN using aptamer-targeted liposomes results in specific delivery to targeted cells. In vivo experiments show that TPEN-loaded, aptamer-targeted liposomes reduce tumor growth in a human prostate cancer xenograft model.
This study addresses the reactivity and risks of metals (Ba, Cd, Co, Cr, Cu, Ni, Pb, Zn, As and Sb) at a Swedish site with large glass waste deposits. Old glassworks sites typically have high total metal concentrations, but as the metals are mainly bound within the glass waste and considered relatively inert, environmental investigations at these kinds of sites are limited. In this study, soil and landfill samples were subjected to a sequential chemical extraction procedure. Data from batch leaching tests and groundwater upstream and downstream of the waste deposits were also interpreted. The sequential extraction revealed that metals in <2 mm soil/waste samples were largely associated with geochemically active fractions, indicating that metals are released from pristine glass and subsequently largely retained in the surrounding soil and/or on secondary mineral coatings on fine glass particles. From the approximately 12,000 m(3) of coarse glass waste at the site, almost 4000 kg of Pb is estimated to have been lost through corrosion, which, however, corresponds to only a small portion of the total amount of Pb in the waste. Metal sorption within the waste deposits or in underlying soil layers is supported by fairly low metal concentrations in groundwater. However, elevated concentrations in downstream groundwater and in leachates of batch leaching tests were observed for several metals, indicating on-going leaching. Taken together, the high metal concentrations in geochemically active forms and the high amounts of as yet uncorroded metal-rich glass, indicate considerable risks to human health and the environment.
The exploitation of arbuscular mycorrhizal (AM) fungi has become of great interest in agriculture due to their potential roles in reducing the need for agrochemicals, while improving plant growth and nutrition. Nevertheless, the application of AM fungi by dispersing inocula in granular form to open agricultural fields is not feasible because nontargeted spreading of inocula over large surface areas results in high cost per plant. Seed coating has the potential to significantly reduce the amount of inoculum needed, resulting in cost reduction and increased efficiency. The aim of this study was to assess whether seed coating with AM fungal inoculum is a feasible delivery system for production of common wheat (Triticum aestivum L.). Wheat seeds were coated with inoculum of Rhizophagus irregularis BEG140 and grown under different fertilization conditions: (1) none, (2) partial, or (3) complete. Data indicated that mycorrhizal inoculation via seed coating significantly increased the dry weight of shoot and seed spikes of wheat associated with reduced fertilization. Assessment of nutritional status of wheat showed that plants inoculated with R. irregularis via seed coating displayed enhanced stem concentrations of potassium (K), sulfur (S), and zinc (Zn). There were no significant differences in root colonization between plants conventionally inoculated with R. irregularis in soil and those inoculated via seed coating. Seed coating with AM fungi may be as effective as conventional soil inoculation and may contribute to reduce the utilization of chemical fertilizers. The application of AM via seed coating is proposed as an ecotechnological approach for sustainable agricultural wheat production.
This investigation reports a rapid and simple screening technique for the quantification of titanium and zinc in commercial sunscreens using portable X-ray fluorescence spectroscopy (pXRF). A highly evolved technique, inductively coupled plasma-mass spectroscopy (ICP-MS) was chosen as a comparative technique to pXRF, and a good correlation (r(2) > 0.995) with acceptable variations (≤25%) in results between both techniques was observed. Analytical figures of merit such as detection limit, quantitation limit, and linear range of the method are reported for the pXRF technique. This method has a good linearity (r(2) > 0.995) for the analysis of titanium (Ti) in the range of 0.4-14.23 wt%, and zinc (Zn) in the range of 1.0-23.90 wt%. However, most commercial sunscreens contain organic ingredients, and these ingredients are known to cause matrix effects. The development of appropriate matrix matched working standards to obtain the calibration curve was found to be a major challenge for the pXRF measurements. In this study, we have overcome the matrix effect by using metal-free commercial sunscreens as a dispersing media for the preparation of working standards. An easy extension of this unique methodology for preparing working standards in different matrices was also reported. This method is simple, rapid, and cost-effective and, in comparison to conventional techniques (e.g., ICP-MS), did not generate toxic wastes during sample analysis.
A new strategy for the ultrasensitive sensing of cations and anions based on the control of C[double bond, length as m-dash]N isomerization has been developed. Imine-derived ligand is non-fluorescent due to the C[double bond, length as m-dash]N isomerization process, whereas its ternary complex with ZnCl2 is moderately fluorescent because of the partial inhibition of C[double bond, length as m-dash]N isomerization. Such a ternary complex can give a remarkable fluorescence increase when it interacts with nitrite because of the much more efficient suppression of C[double bond, length as m-dash]N isomerization. This modulation process of C[double bond, length as m-dash]N isomerization can thus be used for the highly selective detection of Zn(2+) and NO2(-) in an aqueous solution.
Alterations in the trace element content can induce metabolic disorders as these elements are involved in the regulation of metabolism. Obesity increases the likelihood of various diseases, particularly cardiovascular disease and type 2 diabetes, and is more prevalent in Saudi Arabia, especially in women. This study explored the potential of alterations in hair trace elements as long-term markers in diabetic and/or obese Saudi females. In total, 65 diabetic obese women, 47 non-diabetic obese women, and 70 normal-weight women were recruited. Clinical and familial history and anthropometric variables were recorded. Hair Se, Zn, Cu, Mn, and Fe levels were analyzed. Fasting blood sugar (FBS), glycated hemoglobin (HbA1c), and lipid profile were analyzed. Our findings revealed a marked decrease of hair Zn, Mn, and Fe and elevated Se and Cu levels in obese women. In addition, Zn and Fe levels were decreased in diabetic women. Thus, the metabolic distress occurring in obesity and hyperglycemia may affect trace element status by increasing the excretion and decreasing the bioavailability of trace elements or redistributing them among various pools. Hair trace elements can serve as important long-term markers for metabolic disorders; however, larger prospective studies are warranted to validate their diagnostic and follow-up utilities.
To evaluate the reliability and validity of the FFQ administered to participants in the follow-up of the Melbourne Collaborative Cohort Study (MCCS), and to provide calibration coefficients.
A random sample stratified by country of birth, age, sex and BMI was selected from MCCS participants. Participants completed two FFQ and three 24 h recalls over 1 year. Reliability was evaluated by intraclass correlation coefficients (ICC). Validity coefficients (VC) were estimated from structural equation models and calibration coefficients obtained from regression calibration models.
Adults born in Australia, Greece or Italy.
Nine hundred and sixty-five participants consented to the study; of these, 459 participants were included in the reliability analyses and 615 in the validity and calibration analyses.
The FFQ showed good repeatability for twenty-three nutrients with ICC ranging from 0·66 to 0·80 for absolute nutrient intakes for Australian-born and from 0·51 to 0·74 for Greek/Italian-born. For Australian-born, VC ranged from 0·46 (monounsaturated fat) to 0·83 (Ca) for nutrient densities, comparing well with other studies. For Greek/Italian-born, VC were between 0·21 (Na) and 0·64 (riboflavin). Calibration coefficients for nutrient densities ranged from 0·39 (retinol) to 0·74 (Mg) for Australian-born and from 0·18 (Zn) to 0·54 (riboflavin) for Greek/Italian-born.
The FFQ used in the MCCS follow-up study is suitable for estimating energy-adjusted nutrients for Australian-born participants. However, its performance for estimating intakes is poorer for southern European migrants and alternative dietary assessment methods ought to be considered if dietary data are to be measured in similar demographic groups.
This work reports changes on cell number, growth rate, trace element content, chlorophyll a (Chl a) and carotenoid concentrations, and laser-induced fluorescence (LIF) spectra of Phaeodactylum tricornutum exposed to Co, Ni, Cu, Zn, Cd, Hg, Pb, and a mixture of all elements combined (Mix). The total levels of trace elements associated with the cells were significantly higher in the exposed than in control ones. Concomitantly,
 specific cell growth was significantly lower in exposed P. tricornutum, suggesting that trace elements affected the microalgae physiology. The LIF emission spectra showed two typical emission bands in red (683-698 nm) and far-red (725-730 nm) regions. Deviations in LIF spectra and changes in F685/F735 ratio were investigated as indicators of trace element-induced changes. Fluorescence intensity emitted by exposed microalgae decreased in far-red region when compared to control cells, suggesting Chl a damage and impairment of pigment biosynthesis pathways by trace elements, confirmed by Chl a and carotenoid concentration decrease. Significant increase in F685/F735 ratio was detected for all elements except Zn and more accentuated for Co, Hg, and Mix. Significant deviations in wavelength emission maxima in red region were also more significant (between 8 and 13 nm) for Co, Hg, and Mix. Growth changes agreed with deviations in LIF spectra and F685/F735 ratio, supporting their applicability as indicators. This study clearly shows F685/F735 ratio and the deviations in wavelength emission maxima as adequate trace element stress indicators and P. tricornutum as a promising biomonitor model species. LIF-based techniques can be used as time-saving, highly sensitive, and effective alternative tool for the detection of trace element stress, with potential for remote sensing and trace element contamination screening in marine coastal areas.
The objectives of this study are to analyse the pollution status and spatial correlation of soil heavy metals and identify natural and anthropogenic sources of these heavy metals at different spatial scales. Two hundred and twenty-four soil samples (0-20 cm) were collected and analysed for eight heavy metals (Cd, Hg, As, Cu, Pb, Cr, Zn and Ni) in soils of different land-use types in the Yangtze River Delta of Eastern China. The multivariate methods and factorial Kriging analysis were used to achieve the research objectives. The results indicated that the human and natural effects of different land-use types on the contents of soil heavy metals were different. The Cd, Hg, Cu, Pb and Zn in soils of industrial area were affected by human activities, and the pollution level of these heavy metals in this area was moderate. The Pb in soils of traffic area was affected by human activities, and eight heavy metals in soils of residential area and farmland area were affected by natural factor. The ecological risk status of eight heavy metals in soils of the whole study area was light. The heavy metals in soils showed three spatial scales (nugget effect, short range and long range). At the nugget effect and short range scales, the Cd, Hg, Cu, Pb and Zn in soils were affected by human and natural factors. At three spatial scales, the As, Cr and Ni in soils were affected by soil parent materials.
A new host-guest system is formed between a benzene tricarboxamide linked zinc trisporphyrinate and a chiral monoalcohol (1-phenylethylalcohol). CD spectra show the chirality induction and inversion processes, which are controlled by the corresponding 1 : 1 and 1 : 2 coordination complexes. The binding constants calculated by UV-vis and CD spectral data are much larger than that for [Zn(TPP)] (TPP = tetraphenylporphyrin). The crystallographic structure of the host-guest complex reveals that multiple intramolecular hydrogen bonds and π-π interactions could contribute to its high binding affinity to 1-phenylethylalcohol. The DFT calculations suggest that the spatial orientations of porphyrin moieties change from the 1 : 1 complex to the 1 : 2 complex. The chirality induction and inversion processes are rationalized by the summation of pairwise interactions among multichromophores according to pairwise additivity.
High quality cadmium-free Zn-In-S:Ag doped-nanocrystals (d-NCs) were synthesized via a simple one-step noninjection route using silver nitrate, indium acetate, zinc acetate, oleylamine, S powder and 1-dodecanethiol as starting materials in an organic phase. The size and optical properties can be effectively tailored by controlling the reaction time, reaction temperature, Ag(+) dopant concentration, and the molar ratio of In to Zn. The photoluminescence wavelength of as-prepared Zn-In-S:Ag NCs covered a broad visible range from 458 nm to 603 nm. After being passivated by protective ZnS shell, the photoluminescence quantum yield (PLQY) of Zn-In-S:Ag(+) /ZnS was greatly improved to 43.5%. More importantly, the initial high PLQY of the obtained core/shell d-NCs in organic media can be preserved when being transferred into the aqueous media via ligand exchange. Finally, high quality Zn-In-S:Ag(+) /ZnS d-NCs in aqueous phase were applied as bio-imaging agents for identifying living KB cells.
Zinc plant purification residue (ZPR), a typical Zn-hydrometallurgical waste, was collected from the Três Marias Zn plant (MG, Brazil). ZPR was characterized for its metal content and fractionation, mineralogy, toxicity and leachability. Toxicity characteristics leaching procedure (TCLP) and European Community Bureau of Reference (BCR) sequential extraction results revealed that this ZPR displays high percentages of metals (Cd, Cu, Zn and Pb) in the highly mobilizable fractions, increasing its hazardous potential. Bulk chemical analysis, pH dependent leaching and acid (H2SO4) leaching studies confirm that the ZPR is polymetallic, rich in Cd, Cu and Zn. The sulfuric acid concentration (1 M), agitation speed (450 rpm), temperature (40 °C) and pulp density (20 g L(-1)) were optimized to leach the maximum amount of heavy metals (Cd, Cu and Zn). Under optimum conditions, more than 50%, 70% and 60% of the total Cd, Cu and Zn present in the ZPR can be leached, respectively. The metals in the acid leachates were investigated for metal sulfide precipitation with an emphasis on selective Cu recovery. Metal sulfide precipitation process parameters such as initial pH and Cu to sulfide ratio were optimized as pH 1.5 and 1:0.5 (Cu:sulfide) mass ratio, respectively. Under optimum conditions, more than 95% of Cu can be selectively recovered from the polymetallic ZPR leachates. The Cu precipitates characterization studies reveal that they are approximately 0.1 μm in diameter and mainly consist of Cu and S. XRD analysis showed covellite (CuS), chalcanthite (CuSO4·5H2O) and natrochalcite (NaCu2(SO4)2(OH)·H2O) as the mineral phases. ZPRs can thus be considered as an alternative resource for copper production.
The late endo-/lysosomal P-type ATPase ATP13A2 (PARK9) is implicated in Parkinson's disease (PD) and Kufor-Rakeb syndrome, early-onset atypical Parkinsonism. ATP13A2 interacts at the N-terminus with the signaling lipids phosphatidic acid (PA) and phosphatidylinositol (3,5) bisphosphate (PI(3,5)P2), which modulate ATP13A2 activity under cellular stress conditions. Here, we analyzed stable human SHSY5Y cell lines overexpressing wild-type (WT) or ATP13A2 mutants in which three N-terminal lipid binding sites (LBS1-3) were mutated. We explored the regulatory role of LBS1-3 in the cellular protection by ATP13A2 against mitochondrial stress induced by rotenone and found that the LBS2-3 mutants displayed an abrogated protective effect. Moreover, in contrast to WT, the LBS2 and LBS3 mutants responded poorly to pharmacological inhibition of, respectively, PI(3,5)P2 and PA formation. We further demonstrate that PA and PI(3,5)P2 are also required for the ATP13A2-mediated protection against the toxic metals Mn(2+), Zn(2+), and Fe(3+), suggesting a general lipid-dependent activation mechanism of ATP13A2 in various PD-related stress conditions. Our results indicate that the ATP13A2-mediated protection requires binding of PI(3,5)P2 to LBS2 and PA to LBS3. Thus, targeting the N-terminal lipid binding sites of ATP13A2 might offer a therapeutic approach to reduce cellular toxicity of various PD insults including mitochondrial stress.
The Commerson's dolphin is the most common endemic odontocete of subantarctic waters of Tierra del Fuego, Argentina incidentally caught in fishing nets. The species is classified as "Data Deficient" by the IUCN. Metallothioneins (MTs) are considered as suitable biomarkers for health and environmental monitoring. The aims of the study were to assess MT concentrations in the liver and kidney of bycaught specimens. Moreover, correlations with Zn, Se, Cd, Ag and Hg, and the molar ratios of MT:metals were estimated to evaluate if there is an indication of their respective protective role against metal toxicity in tissues. Hepatic and renal MT concentrations were similar, ranging from 11.6 to 29.1nmol·g(-1) WW, and Kidney/Liver ratios ranging from 0.73 to 1.93 corresponded to normal ranges. Results suggest that MTs are related to physiological ranges for the species. This information constitutes the first MT report on Commerson's dolphins and possibly considered as baseline for species' conservation.
A series of zinc(II) silylenes was prepared by using the silylene {PhC(NtBu)2 }(C5 Me5 )Si. Whereas reaction of the silylene with ZnX2 (X=Cl, I) gave the halide-bridged dimers [{PhC(NtBu)2 }(C5 Me5 )SiZnX(μ-X)]2 , with ZnR2 (R=Ph, Et, C6 F5 ) as reagent the monomers [{PhC(NtBu)2 }(C5 Me5 )SiZnR2 ] were obtained. The stability of the complexes and the Zn-Si bond lengths clearly depend on the substitution pattern of the zinc atom. Electron-withdrawing groups stabilize these adducts, whereas electron-donating groups destabilize them. This could be rationalized by quantum chemical calculations. Two different bonding modes in these molecules were identified, which are responsible for the differences in reactivity: 1) strong polar Zn-Si single bonds with short Zn-Si distances, Zn-Si force constants close to that of a classical single bond, and strong binding energy (ca. 2.39 Å, 1.33 mdyn Å(-1) , and 200 kJ mol(-1) ), which suggest an ion pair
 consisting of a silyl cation with a Zn-Si single bond; 2) relatively weak donor-acceptor Zn-Si bonds with long Zn-Si distances, low Zn-Si force constants, and weak binding energy (ca. 2.49 Å, 0.89 mdyn Å(-1) , and 115 kJ mol(-1) ), which can be interpreted as a silylene-zinc adduct.
An asymmetrical diarylethene (1O) with a bi-8-carboxamidoquinoline unit was synthesized. Its photochromic and fluorescence performances on stimulation with both light and metal ions showed that the diarylethene could serve as a highly selective ratiometric fluorescent chemosensor to detect Zn(2+) ions based on internal charge transfer and chelation-enhanced fluorescence processes. The diarylethene could selectively discriminate Zn(2+) from Cd(2+) in acetonitrile. Furthermore, Job's plots based on fluorescence titration and electrospray ionization mass spectrometry analysis showed 1 : 1 binding stoichiometry between 1O and Zn(2+) . The binding constant of 1O with Zn(2+) , estimated using the Benesi-Hildebrand method, and the limit of detection were 3.37 × 10(5)  M(-1) and 4.6 × 10(-8) mol/L, respectively. Additionally, the light and metal-responsive fluorescence behavior of 1O was used successfully to construct a molecular logic circuit with four inputs and one output. Copyright © 2016 John Wiley & Sons, Ltd.
Tunçbilek, one of the major thermal power plants (TTPP) in Turkey running on coal, has capacity to generate 365 MW (per year) electricity. Fifty top soil samples were collected from a depth about 0-20 cm in the close vicinity of the TTPP from random points and at different distances. The samples were analyzed using ICP-MS for heavy metals. Heavy metal contents in soils around TTPP varied from 4.4 to 317.5 mg/kg for As, 0.03 to 0.26 mg/kg for Cd, 20.3 to 1028 mg/kg for Cr, 4.8 to 76.8 mg/kg for Cu, 0.09 to 9.3 mg/kg for Hg, 16.6 to 2385 mg/kg for Ni, 4.8 to 58.6 mg/kg for Pb, and 14.5 to 249.5 mg/kg for Zn. Geoaccumulation index (I geo) and enrichment factor (EF) have been calculated in order to evaluate heavy metal pollution in the soils. According to the I geo calculations, the surface soils around TTPP are contaminated by As, Hg, and Ni from uncontaminated to extremely contaminated. I geo values for Cr show practically uncontaminated to be heavily contaminated. The contamination of soil samples changes from practically uncontaminated to moderately contaminated degree for Pb and Zn. The soil samples were uncontaminated for Cd and Cu metals. The enrichment factors of As, Cr, Hg, and Ni in most of the sampling locations indicate significant to extremely high enrichment. The EF for Pb is also high and indicates moderate to very high enrichment of chromium in the soils. The average EF values for Cd, Cu, and Zn are showing moderate enrichment.
Mulberry leaves (Morus alba) have been used in folk medicine to mitigate symptoms of diabetes. The mulberry plant contains phenolic compounds that are able to decrease blood glucose concentration. Since various phenolics have antioxidant and metal binding properties, they can be used to alleviate oxidative stress and chelate trace elements involved in redox reactions. The aim of this study was to evaluate the effects of dietary supplementation with mulberry leaf extracts (acetone-water (AE) and ethanol-water (EE)) on the trace element status (Fe, Zn and Cu) in relation to diabetes management and antioxidant indices in high-fat diet-fed/STZ diabetic rats. The experiment was performed on 38 male Wistar rats with diabetes (induced by high-fat diet (HF) and streptozotocin injection) or the control fed with AIN-93M or high-fat diet. As a result, five experimental groups were used: (1) a healthy control group fed with AIN-93M; (2) an HF control group; (3) a diabetic HF group; (4) a diabetic HF + AE group (6 g/kg diet); (5) a diabetic HF + EE group (6 g/kg diet). The rats were fed with appropriate diets for 4 weeks. The content of trace elements (Fe, Zn and Cu) in the serum and tissues was measured by means of atomic absorption spectrometry (AAS). Biochemical analyses (glucose, TBARS, FRAP) were performed on the blood serum. It was shown that the AE decreased hepatic and renal Fe stores, while the EE increased hepatic Cu levels in diabetic rats and confirmed their ability to regulate the Fe and Cu status in diabetes. The results confirmed a significant hypoglycaemic and antioxidant potential of both mulberry leaf extracts in diabetic rats.
Pure ZnO and Neodymium (Nd) doped ZnO nanoparticles (NPs) were synthesized by the co-precipitation method. The synthesized nanoparticles retained the wurtzite hexagonal structure. From FESEM studies, ZnO and Nd doped ZnO NPs showed nanorod and nanoflower like morphology respectively. The FT-IR spectra confirmed the Zn-O stretching bands at 422 and 451 cm(-1) for ZnO and Nd doped ZnO NPs respectively. From the UV-VIS spectroscopic measurement, the excitonic peaks were found around 373 nm and 380 nm for the respective samples. The photoluminescence measurements revealed that the broad emission was composed of ten different bands due to zinc vacancies, oxygen vacancies and surface defects. The antibacterial studies performed against extended spectrum β-lactamases (ESBLs) producing strains of Escherichia coli and Klebsiella pneumoniae showed that the Nd doped ZnO NPs possessed a greater antibacterial effect than the pure ZnO NPs. From confocal laser scanning microscopic (CLSM) analysis, the apoptotic nature of the cells was confirmed by the cell shrinkage, disorganization of cell wall and cell membrane and dead cell of the bacteria. SEM analysis revealed the existence of bacterial loss of viability due to an impairment of cell membrane integrity, which was highly consistent with the damage of cell walls.
A comparable study were carried out by determination of trace elements on five marine-derived shell traditional Chinese medicine (TCM) (Ostreae Concha, Haliotidis Concha, Margaritifera Concha, Meretricis Concha, and Arcae Concha), which were recorded in the Chinese Pharmacopoeia (2010 version). Seven trace elements in 51 batches of this type of shell TCM were analyzed by Inductively Coupled Plasma Mass Spectrometry (ICP-MS), combined with principal component analysis (PCA) methods. The content of element Se, which exhibited significant differences among different drugs, could be used as a key element to distinguish this type of drugs. Meanwhile, the contents of elements Co, Cu, Mo, and Ba in Haliotidis Concha, Co and As in Margaritifera Concha, Mo and As in Meretricis Concha, Mo, As, and Ba in Arcae Concha, and Zn in Meretricis Concha were relatively stable. In the PCA plot, Arcae Concha and Meretricis Concha could be efficiently distinguished from Ostreae Concha together with Haliotidis Concha, and Margaritifera Concha. The results also showed a correlation with their medicinal function. In conclusion, trace elements in marine-derived shell TCM could not be neglected for their quality control.
Microgravity exposure can cause cardiovascular and immune disorders, muscle atrophy, osteoporosis, and loss of blood and plasma volume. A clinostat device is an effective ground-based tool for simulating microgravity. This study investigated how melatonin suppresses autophagy caused by simulated microgravity in preosteoblast MC3T3-E1 cells. In preosteoblast MC3T3-E1 cells, clinostat rotation induced a significant time-dependent increase in the levels of the autophagosomal marker microtubule-associated protein light chain (LC3), suggesting that autophagy is induced by clinostat rotation in these cells. Melatonin treatment (100, 200 nM) significantly attenuated the clinostat-induced increases in LC3 II protein, and immunofluorescence staining revealed decreased levels of both LC3 and lysosomal-associated membrane protein 2 (Lamp2), indicating a decrease in autophagosomes. The levels of phosphorylation of mammalian target of rapamycin (p-mTOR) (Ser2448), phosphorylation of extracellular signal-regulated kinase (p-ERK), and phosphorylation of serine-threonine protein kinase (p-Akt) (Ser473) were significantly reduced by clinostat rotation. However, their expression levels were significantly recovered by melatonin treatment. Also, expression of the Bcl-2, truncated Bid, Cu/Zn- superoxide dismutase (SOD), and Mn-SOD proteins were significantly increased by melatonin treatment, whereas levels of Bax and catalase were decreased. The endoplasmic reticulum (ER) stress marker GRP78/BiP, IRE1α, and p-PERK proteins were significantly reduced by melatonin treatment. Treatment with the competitive melatonin receptor antagonist luzindole blocked melatonin-induced decreases in LC3 II levels. These results demonstrate that melatonin suppresses clinostat-induced autophagy through increasing the phosphorylation of the ERK/Akt/mTOR proteins. Consequently, melatonin appears to be a potential therapeutic agent for regulating microgravity-related bone loss or osteoporosis.
Little is understood regarding the effects of mixtures of different metal-based nanoparticles (NPs). Using concentration-addition (CA) and independent-action (IA) models, we evaluated the combined toxicity of Cu and ZnO NPs based on five nested combinations, i.e., Cu(NO3)2-CuNPs, Zn(NO3)2-ZnONPs, Cu(NO3)2-ZnONPs, Zn(NO3)2-CuNPs, and CuNPs-ZnONPs on root elongation of Lactuca sativa L. The CA and IA models performed equally well in estimating the toxicity of mixtures of Cu(NO3)2-CuNPs, Zn(NO3)2-ZnONPs, and Zn(NO3)2-CuNPs, whereas the IA model was significantly better for fitting the data of Cu(NO3)2-ZnONPs and CuNPs-ZnONPs mixtures. Dissolved Cu proved to be the most toxic metal species to lettuce roots in the tests, followed by Cu NPs, dissolved Zn, and ZnO NPs, respectively. An antagonistic effect was observed for ZnO NPs on the toxicity of Cu NPs. This antagonistic effect is expected to be the result of interactions between dissolved
 Cu and dissolved Zn, particulate Zn and dissolved Zn, particulate Cu and dissolved Zn, and between particulate Zn and dissolved Cu. In general terms, assuming additivity gives a first indication of the combined toxicity with soluble and insoluble metal particles, both being important in driving the toxicity of metal-based NPs to higher plants.
Chalcogenides are the most promising mid- and far-infrared materials for nonlinear optical (NLO) applications. Yet, most of them are sulfides and selenides, and tellurides are still rare. Herein, we report three new KCd4Ga5S12-structure type NLO-active tellurides, CsX(II)4In5Te12 (X(II) = Mn, Zn, Cd), synthesized by solid-state reactions. The structure features a 3D diamond-like framework constructed by vertex-sharing asymmetric MTe4 tetrahedra that are stacked along the c-axis. CsCd4In5Te12 exhibits the strongest powder second-harmonic generation (SHG) intensity at 2050 nm (0.61 eV) among tellurides to date, 9 × benchmark AgGaS2 in the range of 46-74 μm particle size. The primary studies reveal the 1.42 eV direct band gap and high absorption coefficient in the visible spectral region for CsCd4In5Te12, suggesting it is a new potential solar cell absorber material. In addition, CsMn4In5Te12 also displays a spin-canted antiferromagnetic property below 50 K.
The spatial variation and distribution features of the metals tested in the surface runoff in Xikuangshan Bao Daxing miming area were analyzed by combining statistical methods with a geographic information system (GIS). The results showed that the maximum concentrations of those five kinds of the metals (Sb, Zn, Cu, Pb, and Cd) in the surface runoff of the antimony mining area were lower than the standard value except the concentration of metal Ni. Their concentrations were 497.1, 2.0, 1.8, 22.2, and 22.1 times larger than the standard value, respectively. This metal pollution was mainly concentrated in local areas, which were seriously polluted. The variation coefficient of Sb, Zn, Cu, Ni, Pb, and Cd was between 0.4 to 0.6, wherein the Sb's spatial variability coefficient is 50.56%, indicating a strong variability. Variation coefficients of the rest of metals were less than 50%, suggesting a moderate variability. The spatial structure analysis showed that the squared correlation coefficient (R (2)) of the models fitting for Sb, Zn, Cu, Ni, Pb, and Cd was between 0.721 and 0.976; the ratio of the nugget value (C 0) to the abutment value (C + C 0) was between 0.0767 and 0.559; the semivariogram of Sb, Zn, Ni, and Pb was in agreement with a spherical model, while semivariogram of Cu and Cd was in agreement with Gaussian model, and both had a strong spatial correlation. The trend and spatial distribution indicated that those pollution distributions resulting from Ni, Pb, and Cd are similar, mainly concentrated in both ends of north and south in eastern part. The main reasons for the pollution were attributed to the residents living, transportation, and industrial activities; the Sb distribution was concentrated mainly in the central part, of which the pollution was assigned to the mining and the industrial activity; the pollution distributions of Zn and Cu were similar, mainly concentrated in both ends of north and south as well as in west; the sources of the metals were widely distributed.
The ongoing concern about bee decline has largely focused on honey bees and neonicotinoid insecticides, while native pollinators such as Neotropical stingless bees and agrochemicals such as other insecticide groups, pesticides in general, and fertilizers-especially leaf fertilizers-remain neglected as potential contributors to pollination decline. In an effort to explore this knowledge gap, we assessed the lethal and sublethal behavioral impact of heavy metal-containing leaf fertilizers in a native pollinator of ecological importance in the Neotropics: the stingless beeFriesella schrottkyi(Friese). Two leaf fertilizers-copper sulfate (24% Cu) and a micronutrient mix (Arrank L: 5% S, 5% Zn, 3% Mn, 0.6% Cu, 0.5% B, and 0.06% Mo)-were used in oral and contact exposure bioassays. The biopesticide spinosad and water were used as positive and negative controls, respectively. Copper sulfate compromised the survival of stingless bee workers, particularly with oral exposure, although less than spinosad under contact exposure. Sublethal exposure to both leaf fertilizers at their field rates also caused significant effects in exposed workers. Copper sulfate enhanced flight take-off on stingless bee workers, unlike workers exposed to the micronutrient mix. There was no significant effect of leaf fertilizers on the overall activity and walking behavior of worker bees. No significant effect was observed for the respiration rate of worker bees under contact exposure, but workers orally exposed to the micronutrient mix exhibited a reduced respiration rate. Therefore, leaf fertilizers do affectF. schrottkyi, what may also occur with other stingless bees, potentially compromising their pollination activity deserving attention.
Among cereals, rice has a genetic propensity to accumulate high levels of cadmium (Cd) in grains. Xylem-mediated root-to-shoot translocation rather than root uptake has been suggested as the main physiological factor accounting for the genotypic variation observed in Cd accumulation in shoots and grains. Several evidence indicate OsHMA2 - a putative zinc (Zn) transporter - as the main candidate protein that could be involved in mediating Cd- and Zn-xylem loading in rice. However, the specific interactions between Zn and Cd in rice often appear anomalous if compared to those observed in other staple crops, suggesting that root-to-shoot Cd translocation process could be more complex than previously thought. In this study we performed a complete set of competition experiments with Zn and Cd in order to analyze their possible interactions and reciprocal effects at the root-to-shoot translocation level.
The competition analysis revealed the lack of a full reciprocity when considering the effect of Cd on Zn accumulation, and vice versa, since the accumulation of Zn in the shoots was progressively inhibited by Cd increases, whereas that of Cd was only partially impaired by Zn. Such behaviors were probably dependent on Cd-xylem loading mechanisms, as suggested by: i) the analysis of Zn and Cd content in the xylem sap performed in relation to the concentration of the two metals in the mobile fractions of the roots; ii) the analysis of the systemic movement of (107)Cd in short term experiments performed using a positron-emitting tracer imaging system (PETIS).
Our results suggest that at least two pathways may mediate root-to-shoot Cd translocation in rice. The former could involve OsHMA2 as Zn(2+)/Cd(2+) xylem loader, whereas the latter appears to involve a Zn-insensitive system that still needs to be identified.
This study examines the distribution, mobility, and potential environmental risks of heavy metals in various particle size fractions of urban soils. Representative urban topsoils (ten) collected from Anshan, Liaoning (northeastern China), were separated into six particle size fractions and their heavy metal contents (Cr, Cu, Cd, Pb, and Zn) were determined. The bioaccessibility and leachability of heavy metals in particle size fractions were evaluated using the toxicity characteristic leaching procedure (TCLP) and ethylenediaminetetraacetic acid (EDTA) extraction, respectively. The results indicated that the contents of five heavy metals (Cd, Cr, Cu, Pb and Zn) in the size fractions increased with the decrease of particle size. The clay fraction of <2 μm had the highest content of heavy metals, indicating that the clay fraction was polluted by heavy metals more seriously than the other size fractions in urban topsoils. Cr also concentrated in the coarse fraction of 2000-1000 μm, indicating a lithogenic contribution. However, the dominant size fraction responsible for heavy metal accumulation appeared to belong to particle fraction of 50-2 μm. The lowest distribution factors (DFs) of heavy metals were recorded in the 2000- to 1000-μm size fraction, while the highest in the clay fraction. The DFs of heavy metals in the clay fraction followed Zn (3.22) > Cu (2.84) > Pb (2.61) > Cr (2.19) > Cd (2.05). The enrichment factor suggested that the enrichment degree of heavy metal increased with the decrease of the particle size, especially for Cd and Zn. The TCLP- and EDTA-extractable concentrations of heavy metals in the clay fraction were relatively higher than those in coarse particles. Cd bioavailability was higher in the clay fraction than in other fractions or whole soils. In contrast, Cr exhibits similar bioaccessibilities in the six size fractions of soils. The results suggested that fine particles were the main sources of potentially toxic metals in urban soils. The variation of heavy metals in various size fractions should be taken into account in environment assessments.
A large number of methods have been applied to evaluate genotoxic damage in different aquatic species. Comet assay, as a method for detecting DNA alterations, and micronucleus test, as an index of chromosomal damage are the most widely used and authentic methods in laboratory and field studies. The primary objective of the study was to evaluate the genotoxic effects of heavy metals generated by toxic industrial effluents and various kinds of pollutants from urban and agricultural areas and domestic waste on Catla catla and Cirrhinus mrigala due to water pollution in the Chenab River, Pakistan. The heavy metals Cd, Cu, Mn. Zn, Pb, Cr, Sn, and Hg were detected by atomic absorption spectrophotometry from water samples collected from predetermined sampling sites. All the physicochemical parameters and heavy metals were found to exceed the upper limits recommended by various
 agencies. Comet assays showed significant (p < 0.05) DNA damage in C. mrigala compared to C. catla for tail length and olive tail moment from three different sites. Significant (p < 0.05) differences were reported between fish collected from polluted sites and farmed fish, but only non-significant (p > 0.05) findings were observed between fish collected from farmed and non-polluted upstream waters. Micronucleus assays showed similar findings for single and double micronucleus induction in C. catla and C. mrigala. A significantly (p < 0.05) higher micronuclei induction and percent tail DNA was observed in C. mrigala specimen collected from the polluted site. These findings infer that DNA damage could be used as a biomarker of pollution load and its early monitoring by using simple and reliable techniques such as the comet and micronucleus assays, expedient methods for toxicity screening of aquatic environments. Regular monitoring is necessary to assess eco-health of the Chenab River by choosing perhaps C. mrigala, being a bottom feeder, as a bioindicator that could provide more reliable information to determine the status of the environmental quality of the river.
This study evaluated the combined effect of pH and metals on the egg fertilization process of two estuarine species, the blue mussel (Mytilus edulis), the oyster (Crassostrea gigas) and a marine species, the sea urchin (Paracentrotus lividus). The success of egg fertilization was examined after exposure of gametes to sediment extracts of various degrees of contamination at pH 6.0, 6.5, 7.0, 7.5 and 8.0. At the pH levels from 6.5 to 8.0, the egg fertilization of the different species demonstrated different sensitivity to metal and/or acidic exposure. In all species, the results revealed that egg fertilization was almost completely inhibited at pH 6.0. The egg fertilization of the blue mussel M. edulis was the least sensitive to the exposure while that of the sea urchin P. lividus demonstrated a concentration-dependent response to the pH levels from 6.5 to 8.0. The results of this study revealed that acidity increased the concentration of several metal ions (Cr, Ni, Cu, Zn, Cd, and Pb) but reduced its availability to the organisms, probably related to the reactivity of the ions with most non-metals or to the competition among metals and other waterborne constituents.
The generation of acid rock drainage (ARD) was observed after the oxidation dissolution of pyrite-rich black shales, which were excavated during the construction of a highway in León (Spain). ARDs are characterized by the presence of high concentrations of sulfate and metals (Al, Fe, Mn, Zn, Cu, Co, Ni, Th, and U) that affect the La Silva stream. Dissolved element concentrations showed values between one and four orders of magnitude higher than those of natural waters of this area. A passive treatment system was constructed; the aim of which was to improve the quality of the water of the stream. This work provides a hydrochemical characterization of the La Silva stream after its transit through the different elements that constitute the passive treatment system (open limestone channel (OLC), small ponds, and a wetland), during its first year of operation. The passive treatment system has two sections separated by a tunnel 230 m long. The first section, which stretches between the highway and the tunnel entrance, is an OLC 350 m long with a slope of 16 %. The second section, which stretches from the tunnel exit to the end wetland, has a length of 700 m and a slope of 6 %; it is in this section where six small ponds are located. In the first section of this passive treatment system, the OLC was effectively increasing the pH from 3 to 4-4.5 and eliminating all of the dissolved Fe and the partially dissolved Al. These elements, after hydrolysis at a pH 3-3.5 and 4-4.5, respectively, had precipitated as schwertmannite and hydrobasaluminite, while other dissolved metals were removed totally or partially for adsorption by the precipitates and/or by coprecipitation. The second section receives different inputs of water such as ARDs and natural waters. After exiting the treatment system, the stream is buffered by Al at a pH of 4-4.3, showing high Al concentrations (19-101 mg/L) but with a complete removal of dissolved Fe. Unfortunately, the outflow shows similar or higher acidity than the inflow into the system due to the discharge of ARDs (mainly from the tunnel) that is received and to the existence of a natural stream, which is affected by a waste-rock pile. The predictions and calculations necessary for the design of any remediation/attenuation techniques are quite difficult. Despite the fact that the selected design is the most adequate one for this valley and type of passive treatment system (including adequate slopes), we must admit that the physicochemical characteristics of the ARD were not the most appropriate according to the literature. Moreover, during the design, engineers were unaware of the existence of the inflow from two highly polluting sources, which have rendered the passive treatment system ineffective and which therefore suggest that certain improvement measures could be considered.
Electroplating sludge (ES) containing large quantities of heavy metals is regarded as a hazardous waste in China. This paper introduced a simple method of treating ES using environmentally friendly fixatives biochar (BC) and iron sulfide (FeS), respectively. After 3 days of treatment with FeS at a FeS-to-ES mass ratio of 1:5, the toxicity characteristic leaching procedure (TCLP)-based leachability of total Cr (TCr), Cu(II), Ni(II), Pb(II), and Zn(II) was decreased by 59.6, 100, 63.8, 73.5, and 90.5 %, respectively. After 5 days of treatment with BC at a BC-to-ES mass ratio of 1:2, the TCLP-based leachability was declined by 35.1, 30.6, 22.3, 23.1, and 22.4 %, respectively. Pseudo first-order kinetic model adequately simulated the sorption kinetic data. Structure and morphology analysis showed that adsorption, electrostatic attraction, surface complexation, and chemical precipitation were dominant mechanisms for heavy metals immobilization by BC, and that chemical precipitation (formation of metal sulfide and hydroxide precipitates), iron exchange (formation of CuFeS2), and surface complexation were mainly responsible for heavy metals removal by FeS. Economic costs of BC and FeS were 500 and 768 CNY/t, lower than that of Na2S (940 CNY/t). The results suggest that BC and FeS are effective, economic, and environmentally friendly fixatives for immobilization of heavy metals in ES before landfill disposal.
Soil was examined for vanadium (V) and related metal contamination near a stone coal mine in Hubei Province, China. In total, 92 surface and vertical (0-200 cm) soil samples were collected from the site. A handheld X-ray fluorescence spectrometer was used for in situ analysis of the soil concentrations of heavy metals, including V, chromium (Cr), copper (Cu), manganese (Mn), zinc (Zn), and lead (Pb). The mean concentrations of these metals were 931, 721, 279, 223, 163, and 11 mg/kg, respectively. Based on the Chinese Environmental Quality Standard for Soils guidelines, up to 88.0, 76.1, and 56.5 % of the soil samples had single factor pollution indices >3 for V, Cr, and Cu, respectively. Furthermore, 2.2 % of samples were slightly polluted with Zn, while there was no Mn or Pb contamination. GaussAmp curve fitting was performed based on the sample frequency distribution of the Nemerow pollution index. The fitted mean was 5.99, indicating severe pollution. The heavy metals were clustered into two groups, V/Cr/Cu/Zn and Mn/Pb, based on the spatial distributions, the Pearson correlation and principal component analyses. The positive correlations within the V/Cr/Cu/Zn group suggested that they originated from roasted stone coal slag. Finally, the negative correlation between the two groups was attributed to mechanical mixing of the slag and original soil.
Extracellular Cu/Zn superoxide dismutases (SODs) are critical for balancing the level of reactive oxygen species in the extracellular matrix of eukaryotes. In the present study we have detected constitutive SOD activity in the haemolymph and defensive secretions of different leaf beetle species. Exemplarily, we have chosen the mustard leaf beetle, Phaedon cochleariae, as representative model organism to investigate the role of extracellular SODs in antimicrobial defence. Qualitative and quantitative proteome analyses resulted in the identification of two extracellular Cu/Zn SODs in the haemolymph and one in the defensive secretions of juvenile P. cochleariae. Furthermore, quantitative expression studies indicated fat body tissue and defensive glands as the main synthesis sites of these SODs. Silencing of the two SODs revealed one of them, PcSOD3.1, as the only relevant enzyme facilitating SOD activity in haemolymph and defensive secretions in vivo. Upon challenge with the entomopathogenic fungus, Metarhizium anisopliae, PcSOD3.1-deficient larvae exhibited a significantly higher mortality compared to other SOD-silenced groups. Hence, our results serve as a basis for further research on SOD regulated host-pathogen interactions. In defensive secretions PcSOD3.1-silencing affected neither deterrent production nor activity against fungal growth. Instead, we propose another antifungal mechanism based on MRJP/yellow proteins in the defensive exudates.
Cell migration is a fundamental feature of tumour metastasis and angiogenesis. It is regulated by a variety of signalling molecules including H2O2 and Ca(2+) Here, we asked whether the H2O2-sensitive transient receptor potential melastatin 2 (TRPM2) Ca(2+) channel serves as a molecular link between H2O2 and Ca(2+) H2O2-mediated activation of TRPM2 channels induced filopodia formation, loss of actin stress fibres and
 disassembly of focal adhesions, leading to increased migration of HeLa and prostate cancer (PC)-3 cells. Activation of TRPM2 channels, however, caused intracellular release of not only Ca(2+) but also of Zn(2+) Intriguingly, elevation of intracellular Zn(2+) faithfully reproduced all of the effects of H2O2, whereas Ca(2+) showed opposite effects. Interestingly, H2O2 caused increased trafficking of Zn(2+)-enriched lysosomes to the leading edge of migrating cells, presumably to impart polarisation of Zn(2+) location. Thus, our results indicate that a reciprocal interplay between Ca(2+) and Zn(2+) regulates actin remodelling and cell migration; they call for a revision of the current notion that implicates an exclusive role for Ca(2+) in cell migration.
An artificial neural network (ANN)-based modelling approach is used to determine the synergistic effect of five major components of growth medium (Mg, Cu, Zn, nitrate and sucrose) on improved in vitro biomass yield in multiple shoot cultures of Centella asiatica. The back propagation neural network (BPNN) was employed to predict optimal biomass accumulation in terms of growth index over a defined culture duration of 35 days. The four variable concentrations of five media components, i.e. MgSO4 (0, 0.75, 1.5, 3.0 mM), ZnSO4 (0, 15, 30, 60 μM), CuSO4 (0, 0.05, 0.1, 0.2 μM), NO3 (20, 30, 40, 60 mM) and sucrose (1, 3, 5, 7 %, w/v) were taken as inputs for the ANN model. The designed model was evaluated by performing three different sets of validation experiments that indicated a greater similarity between the target and predicted dataset. The results of the modelling experiment suggested that 1.5 mM Mg, 30 μM Zn, 0.1 μM Cu, 40 mM NO3 and 6 % (w/v) sucrose were the respective optimal concentrations of the tested medium components for achieving maximum growth index of 1654.46 with high centelloside yield (62.37 mg DW/culture) in the cultured multiple shoots. This study can facilitate the generation of higher biomass of uniform, clean, good quality C. asiatica herb that can efficiently be utilized by pharmaceutical industries.
Metallic glass-reinforced metal matrix composites are an emerging class of composite materials. The metallic nature and the high mechanical strength of the reinforcing phase offers unique possibilities for improving the engineering performance of composites. Understanding the structure at the amorphous/crystalline interfaces and the deformation behavior of these composites is of vital importance for their further development and potential application. In the present work, Zr-based metallic glass fibers have been introduced in Al7075 alloy (Al-Zn-Mg-Cu) matrices using spark plasma sintering (SPS) producing composites with low porosity. The addition of metallic glass reinforcements in the Al-based matrix significantly improves the mechanical behavior of the composites in compression. High-resolution TEM observations at the interface reveal the formation of a thin interdiffusion layer able to provide good bonding between the reinforcing phase and the Al-based matrix. The deformation behavior of the composites was studied, indicating that local plastic deformation occurred in the matrix near the glassy reinforcements followed by the initiation and propagation of cracks mainly through the matrix. The reinforcing phase is seen to inhibit the plastic deformation and retard the crack propagation. The findings offer new insights into the mechanical behavior of metal matrix composites reinforced with metallic glasses.
The quaternary compound semiconductor Cu2ZnSnS4 (CZTS) is a promising photovoltaic absorber material for thin-film solar cell applications. Density-functional theory calculations have been performed to investigate the structural and electronic properties of the CdS/CZTS heterointerfaces in CZTS-based cells. We find that CdS favors epitaxial growth on the Cu-Zn plane of CZTS along the direction of [100], which can eliminate the effects of the wrong bonds at the interfaces and enhance the energetic barrier for charge carrier recombination across the interfaces with an increased band gap. The band alignment is calculated for the epitaxial CZTS/CdS heterointerface by employing the HSE06 functional and the results show a type-II band alignment with VBO and CBO values of 0.95 eV and -0.05 eV, respectively. Also, the experimental phenomenon of Zn segregation at CdS/CZTS interfaces is corroborated. Zn segregation can enhance the stability of the heterointerfaces, but damage the solar cell performance by decreasing the band gap when the Zn concentration is sufficiently high. We show that besides the defects and undesired phases in CZTS, the heterointerfaces between the absorption layers (CZTS) and the buffer layer (CdS) can also be an important factor that affects the performance of CZTS cells. The present work provides a theoretical base for engineering the heterointerfaces and achieving better performance of CZTS-based solar cells.
Zinc (Zn) deficiency is one of the leading nutrient disorders in rice (Oryza sativa). Many studies have identified Zn-efficient rice genotypes, but causal mechanisms for Zn deficiency tolerance remain poorly understood. Here, we report a detailed study of the impact of Zn deficiency on crown root development of rice genotypes, differing in their tolerance to this stress. Zn deficiency delayed crown root development and plant biomass accumulation in both Zn-efficient and inefficient genotypes, with the effects being much stronger in the latter. Zn-efficient genotypes had developed new crown roots as early as 3 days after transplanting (DAT) to a Zn deficient field and that was followed by a significant increase in total biomass by 7 DAT. Zn-inefficient genotypes developed few new crown roots and did not increase biomass during the first 7 days following transplanting. This correlated with Zn-efficient genotypes retranslocating a higher proportion of shoot-Zn to their roots, compared to Zn-inefficient genotypes. These latter genotypes were furthermore not efficient in utilizing the limited Zn for root development. Histological analyses indicated no anomalies in crown tissue of Zn-efficient or inefficient genotypes that would have suggested crown root emergence was impeded. We therefore conclude that the rate of crown root initiation was differentially affected by Zn deficiency between genotypes. Rapid crown root development, following transplanting, was identified as a main causative trait for tolerance to Zn deficiency and better Zn retranslocation from shoot to root was a key attribute of Zn-efficient genotypes.
This study was conducted to evaluate the impact of hot dry, hot humid and comfortable season on physiological, hematological, biochemical, and oxidative stress parameters in Surti buffaloes.
Ten lactating Surti buffaloes of similar physiological status were selected. Based on the temperature-humidity index (THI), their natural exposure to the environment was categorized as hot dry (THI1), hot humid (THI2) and moderate winter/comfort season (THI3). Blood/serum samples were collected and analyzed for physiological, hematological, biochemical, and oxidative stress parameters. The results were analyzed using standard statistical methods.
With increase in THI, significant rise in physiological parameters such as respiration rate (RR), hematological parameters such as red blood cell (RBC), hematocrit, hemoglobin (Hb) and mean cell Hb concentration (MCHC), biochemical parameters such as alanine aminotransferase (ALT), Na, K, creatinine, blood urea nitrogen, Mn, Cu and Zn, hormones such as cortisol and oxidative stress parameters such as glutathione peroxidase (GPx), superoxide dismutase (SOD), lipid peroxide (LPO) and total antioxidant status (TAS) and significant decline in glucose, cholesterol and triiodothyronine (T3) was observed.
It was concluded that THI is a sensitive indicator of heat stress and is impacted by ambient temperature more than the relative humidity in buffaloes. Higher THI is associated with significantly increased RR, total RBC count, Hb, hematocrit, MCHC, ALT, urea, sodium, creatinine, triiodothyronine, SOD, GPx, LPO and TAS and with significant decrease in glucose, cholesterol and triiodothyronine (T3).
The main purpose of the present study is to assess human dietary exposure to essential and non-essential trace elements via consumption of selected homegrown foodstuffs. Twelve essential and non-essential trace elements (Cd, Co, Cu, Cr, Hg, Mo, Ni, Pb, Sb, Se, Zn and As) were detected in various homegrown foodstuffs. Detailed questionnaires were also applied among a sample of the local population to collect information on sociodemographic characteristics. The results of the present study clearly indicate that the majority of the trace elements are at highly elevated levels in the studied foodstuffs, in comparison to international recommendations. The maximum measured levels of ETE and NETE are as follows [μgkg(-1)]: Cd 873, Co 1370, Cu 21700, Cr 59633, Hg 26, Mo 6460, Ni14.5, Pb 11100, Sb 181, Se 0.30, Zn 102 and As 693. Additionally, age, body mass index and gender were significantly associated with levels of dietary exposure. Further research is warranted on the potential health implication of this exposure.
The study merges the accumulation of ETE and NETE in home-grown foodstuffs and reflects considerably high health risks for inhabitants.
HudBay Minerals, Inc., has mined and/or processed Zn and Cu ore in Flin Flon, MB, Canada, since the 1930s. The boreal forest ecosystem and soil surrounding these facilities have been severely impacted by mixed metal contamination and HSO deposition. Zinc is one of the most prevalent smelter-derived contaminants and has been identified as a key factor that may be limiting revegetation. Metal toxicity is related to both total concentrations and speciation; therefore,
 X-ray absorption spectroscopy and X-ray fluorescence mapping were used to characterize Zn speciation in soils throughout the most heavily contaminated areas of the landscape. Zinc speciation was linked to two distinct soil types. Group I soils consist of exposed soils in weathered positions of bedrock outcrops with Zn present primarily as franklinite, a (ZnFeO) spinel mineral. Group II soils are stabilized by an invasive metal-tolerant grass species, with Zn found as a mixture of octahedral (Fe oxides) and tetrahedral Mn oxides) adsorption complexes with a franklinite component. Soil erosion influences Zn speciation through the redistribution of Zn and soil particulates from Group I landscape positions to Group II soils. Despite Group II soils having the highest concentrations of CaCl-extractable Zn, they support metal-tolerant plant growth. The metal-tolerant plants are probably preferentially colonizing these areas due to better soil and nutrient conditions as a result of soil deposition from upslope Group I areas. Zinc concentration and speciation appears to not influence the colonization by metal-tolerant grasses, but the overall soil properties and erosion effects prevent the revegetation by native boreal forest species.
Eighty-four multiparous, nonlactating, pregnant Angus × Hereford cows were ranked by pregnancy type (56 AI and 28 natural service), BW, and BCS and allocated to 21 drylot pens at the end of their second trimester of gestation (d 0). Pens were assigned to receive forage-based diets containing 1) sulfate sources of Cu, Co, Mn, and Zn (INR); 2) an organic complexed source of Cu, Mn, Co, and Zn (AAC; Availa 4; Zinpro Corporation, Eden Prairie, MN); or 3) no supplemental Cu, Co, Mn, and Zn (CON). Diets were offered from d 0 until calving and formulated to meet requirements for energy, protein, macrominerals, Se, I, and vitamins. The INR and AAC diets provided the same daily amount of Cu, Co, Mn, and Zn. Cow BW and BCS were recorded and liver samples were collected on d -10 and 2 wk (d 75) before the calving season. Within 3 h after calving, calf BW was recorded, liver samples were collected, and the expelled placenta was retrieved ( = 47 placentas). Calves were weaned on d 283 of the experiment, preconditioned for 45 d (d 283 to 328), transferred to a growing lot on d 328, and moved to a finishing lot on d 440 where they remained until slaughter. Liver Co, Cu, and Zn concentrations on d 75 were greater ( ≤ 0.05) for INR and AAC cows compared with CON cows, whereas INR cows had reduced ( = 0.04) liver Co but greater ( = 0.03) liver Cu compared with AAC cows. In placental cotyledons, Co concentrations were greater ( ≤ 0.05) in AAC and INR cows compared with CON cows, whereas Cu concentrations were increased ( = 0.05) only in AAC cows compared with CON cows. Calves from INR and AAC cows had greater ( < 0.01) liver Co concentrations at birth compared with calves from CON cows. Liver Cu and Zn concentrations at birth were greater ( ≤ 0.05) in calves from AAC cows compared with cohorts from CON cows. Weaning BW was greater ( ≤ 0.05) in calves from AAC cows compared with cohorts from CON cows, and this difference was maintained until slaughter. In the growing lot, calves from AAC cows had reduced ( < 0.01) incidence of bovine respiratory disease compared with CON and INR cohorts. Collectively, these results suggest that feeding the AAC diet to late-gestating beef cows stimulated programming effects on postnatal offspring growth and health compared with the CON diet. Therefore, supplementing late-gestating beef cows with an organic complexed source of Co, Cu, Zn, and Mn instead of no supplementation appears to optimize offspring productivity in beef production systems.
Research has indicated that trace mineral (TM) supplementation may alter immune function and reduce morbidity associated with bovine respiratory disease. The objective of this experiment was to determine the influence of dietary Cu, Mn, and Zn supplementation on the performance, clinical signs, and TM balance of calves following a bovine viral diarrhea virus (BVDV) and (MH) combination respiratory pathogen challenge. Steers ( = 16; 225 ± 20 kg BW) from a single ranch were processed, weaned, and randomly pairwise assigned to either the TM-supplemented (MIN) or the control (CON) experimental treatments. The MIN calves received an additional 150 mg of Cu, 130 mg of Mn, and 320 mg of Zn daily and the CON calves received the basal diet with no additional Cu, Mn, or Zn supplementation. The basal diet contained sufficient Mn and Zn but inadequate Cu based on published nutrient requirements. After 46 d on the experimental treatments, all calves were naturally exposed to a heifer persistently infected with BVDV type 1b for 4 d and then subsequently intratracheally challenged with MH. Data were analyzed using the GLIMMIX procedure of SAS with sampling time serving as a repeated measure and calf serving as the experimental unit. The respiratory challenge was validated via increased BVDV type 1b antibody concentrations, MH whole cell and leukotoxin antibody concentrations, rectal temperatures (TEMP), and subjective clinical severity scores (CS). Calf performance ( ≥ 0.48) was not affected by TM supplementation. Mineral supplementation also did not impact the CS or TEMP of calves ( ≥ 0.53). There was a treatment × time ( < 0.001) interaction observed for liver Cu concentrations. The concentrations of Cu, Mn, Zn, and Fe within the liver; Cu, Mn, and Zn within the muscle; and Cu, Zn, and Fe within the serum were all impacted by time ( ≤ 0.03). Calves receiving the MIN treatment had greater ( < 0.01) liver Cu and Mn concentrations compared with CON calves. In contrast, serum Cu and Fe concentrations were increased ( ≤ 0.05) in CON calves compared with MIN calves. Mineral supplementation did not impact TM concentrations within the muscle ( ≥ 0.38). The supplementation of Cu, Mn, and Zn can improve the Cu and Mn status within the liver and serum of calves in response to a BVDV and MH challenge. When Cu is supplemented to calves receiving a marginally Cu-deficient diet, Cu status within the body is significantly improved.
Colloidal quantum dots (QDs) show great promise as LED phosphors due to their tunable narrow-band emission and ability to produce high-quality white light. Currently, the most suitable QDs for lighting applications are based on cadmium, which presents a toxicity problem for consumer applications. The most promising cadmium-free candidate QDs are based on InP, but their quality lags much behind that of cadmium based QDs. This is not only because the synthesis of InP QDs is more challenging than that of Cd-based QDs, but also because the large lattice parameter of InP makes it difficult to grow an epitaxial, defect-free shell on top of such material. Here, we propose a viable approach to overcome this problem by alloying InP nanocrystals with Zn(2+) ions, which enables the synthesis of InxZnyP alloy QDs having lattice constant that can be tuned from 5.93 Å (pure InP QDs) down to 5.39 Å by simply varying the concentration of the Zn precursor. This lattice engineering allows for subsequent strain-free, epitaxial growth of a ZnSezS1-z shell with lattice parameters matching that of the core. We demonstrate, for a wide range of core and shell compositions (i.e., varying x, y, and z), that the photoluminescence quantum yield is maximal (up to 60%) when lattice mismatch is minimal.
Objectives were to determine the effects of feeding ractopamine hydrochloride (RAC) with zinc (Zn) and chromium (Cr) on feedlot growth performance, carcass characteristics, and meat quality. Steers ( = 179; initial BW = 533 ± 94 kg) were blocked by BW and allotted to 30 pens, and pens were randomly assigned 1 of 5 treatments: (1) control (CONT), (2) RAC only (RO), (3) RAC + Zn (RZ), (4) RAC + Cr (RC), or (5) RAC + Zn + Cr (RZC). Trace minerals were fed from d 0 to 63 to target 1 g of Zn/steer·d (KemTRACE Zn; Kemin Industries, Inc., Des Moines, IA) and 3 mg Cr/steer·d (KemTRACE Chromium; Kemin Industries, Inc.) for Zn and Cr treatments, respectively. Dry-rolled corn, 0.605 kg/steer, was removed from the diet and 400 mg RAC, per 0.605 kg of ground corn carrier, was top dressed per steer immediately following feed delivery to pens fed RAC. There were no effects ( ≥ 0.45) of trace mineral supplementation on DMI, ADG, or G:F before RAC feeding. There were also no treatment effects ( ≥ 0.46) over all 63 d of the trial on DMI, ADG, or G:F. Despite the lack of differences in live performance, steers fed RO and RC averaged 0.10 kg/d greater ( = 0.10) carcass ADG than steers fed RZC and CONT, while steers fed RZ were intermediate and not different. Steers fed RO had the greatest ( = 0.09) carcass G:F, while steers fed CONT had the least carcass G:F, 0.0875 and 0.0774, respectively. Steers fed RO and RC averaged 5.5 kg heavier ( = 0.09) HCW than steers fed RZC and CONT, while steers fed RZ were intermediate and not different. There were no treatment effects ( ≥ 0.32) on LM area, 12th rib fat, marbling score, KPH, carcass yield, or USDA yield grade and distribution. However, carcasses from steers fed RC had the greatest ( = 0.10) percentage grading USDA Select. There were no treatment effects ( ≥ 0.20) on shear force, intramuscular fat, pH, a*, and b*. Steaks from steers fed RO and RC had 11.4% greater ( = 0.08) cook loss than steaks from steers fed CONT and RZC, whereas steaks from steers fed RZ were intermediate and not different. Also, steaks from steers fed RC had 2.11 units greater ( = 0.03) L* values (i.e., were lighter) than steaks from steers fed RZ; steaks from steers fed CONT, RO, and RZC were intermediate. In feedlot steers, the addition of both Cr and Zn supplementation did not improve growth performance or meat quality when fed in combination with 28 d of RAC supplementation;
 however, RAC, fed alone or in combination with Cr, did increase HCW.
The deoiled residue from the production of heterotrophic microalgae can be combined with soyhulls to form a novel feedstuff called algae meal (ALG). To determine the effects of replacing corn in a finishing diet with ALG on growth, mineral status, carcass characteristics, and longissimus thoracis fatty acid profile, crossbred steers (168) were blocked by BW (432 ± 30.8 kg) into pens of 6 steers (7 pens per treatment). Pens received 1 of 4 diets: a corn-based control (CON), 14% ALG, 28% ALG (ALG28), and 42% ALG (ALG42). Corn was replaced by ALG on a DM basis. Steer BW were taken on d 0, 1, 28, 56, 74, 101, and 102, and steers were harvested on d 103. Pen was the experimental unit and DMI, ADG, and G:F data were analyzed as repeated measures. Two steers per pen were selected for sampling of blood and liver (d -1 and 96) and collection of rib steaks at harvest. There was a treatment by × time effect ( = 0.10) for overall DMI, where DMI linearly increased ( ≤ 0.008) across all time periods except Day 28 through, 56 when DMI was not different between ALG28 and ALG42. There was a treatment by time effect for ADG ( < 0.01), with ADG linearly decreasing ( ≤ 0.03) in the first and third month, not differing ( = 0.95) in the second month, and linearly increasing ( < 0.01) in the fourth month as ALG increased in the diet. Final BW and HCW did not differ ( ≥ 0.50) between CON- and ALG-fed cattle. There was a treatment × time effect for G:F ( < 0.01), with G:F linearly decreasing ( ≤ 0.01) in the first 3 mo as ALG increased in the diet, whereas G:F linearly increased ( < 0.01) in the fourth month. Based on steer performance, calculated dietary NEg linearly decreased ( < 0.01) as ALG increased in the diet. Yield grade linearly decreased ( = 0.02) and there was a tendency for dressing percent and 12th-rib back fat to linearly decrease ( ≤ 0.10) as ALG increased in the diet. Plasma Cu, Fe, and Mg concentrations were not different ( ≥ 0.31) in CON vs. ALG cattle; however, plasma Zn concentrations linearly increased ( = 0.03) as ALG increased in the diet. Total lipid, SFA, MUFA, and PUFA concentrations in the longissimus thoracis did not differ ( ≥ 0.13) between CON- and ALG-fed cattle. Interestingly, the atherogenic index linearly decreased ( < 0.01) as ALG increased in the diet. Algae meal may have a lesser energy value than corn; however, a minimal effect on carcass performance suggests ALG may serve as a potential replacement for corn in feedlot diets.
Ten ileal T-cannulated pigs (19.26 ± 1.06 kg) were used to evaluate the effects of a novel phytase on apparent ileal digestibility (AID) of AA and apparent total tract digestibility (ATTD) and hindgut disappearance of DM, GE, CP, crude fiber, NDF, and ADF as well as minerals balance. Pigs were fed in a duplicated 5 × 4 incomplete Latin square design (5 diets with 4 periods). Each period consisted of a 5-d adjustment period followed by a 3-d total collection of feces and urine and then a 2-d collection of ileal digesta. The 5 diets included a P-deficient basal diet (0.43% Ca and 0.38% total P) that was supplemented with 0 (negative control [NC]), 500, 1,000, or 20,000 phytase units (FTU)/kg phytase and a positive control (PC) diet that was P adequate (0.64% Ca and 0.52% total P). The addition of phytase to the NC diet improved ( < 0.05) AID of phytate from 11.1 to 62.8, 70.6, and 90.5% at the inclusion rates of 500, 1,000, and 20,000 FTU/kg, respectively. In general, phytase supplementation at a dose of 20,000 FTU/kg further increased ( < 0.05) AID of Ca, total P, and phytate and reduced ( < 0.05) the ileal phytate concentration compared with diets with 500 or 1,000 FTU/kg phytase. Pigs fed the diet with 20,000 FTU/kg phytase but not diets with 500 and 1,000 FTU/kg phytase showed improved ( < 0.05) ATTD of CP and AID of DM, GE, CP, Leu, Lys, Thr, Val, Asp, and Ser compared with pigs fed the PC or NC diet. However, hindgut disappearance of crude fiber and NDF ( < 0.05) were reduced in pigs fed the diet with 20,000 FTU/kg phytase compared with pigs fed the PC or NC diet. Pigs fed diets with 500 or 1,000 FTU/kg phytase had greater ATTD and retention of Ca and P than pigs fed the NC diet but less compared with pigs fed the diet with 20,000 FTU/kg phytase. Supplementation of 20,000 FTU/kg phytase to the NC diet improved ( < 0.05) digestibility of Na, Mn, and Zn as well as retention (%) of Zn. Increasing phytase supplementation doses from 0 to 1,000 FTU/kg linearly improved ( < 0.05) retention of Mg; meanwhile, digestibility of Mg and Mn and AID of Thr showed a linear increase trend ( = 0.084). In conclusion, supplementation of the novel phytase at doses up to 20,000 FTU/kg hydrolyzed most of the phytate (90%) and consequently further improved mineral and protein utilization.
Photodynamic therapy (PDT) is a treatment of cancer whereby tumours are destroyed by reactive oxygen species generated upon photoactivation of a photosensitizer drug. Hydrophobic photosensitizers are known to be ideal for PDT; however, their hydrophobicity necessitates that they are typically administered using emulsions. Here, a delivery vehicle for photodynamic therapy based on the co-self-assembly of both a Zn(ii)-phthalocyanine derivative photosensitizer and a polyethylene glycol (PEG) derivative onto gold nanoparticles is reported. The PEG on the particle surface ensured that the conjugates were water soluble and enhanced their retention in the serum, improving the efficiency of PDT in vivo. The pharmacokinetic behaviour of the nanoparticle conjugates following intravenous injection into C57/BL6 mice bearing a subcutaneous transplanted B78H1 amelanotic melanoma showed a significant increase of retention of the nanoparticles in the tumour. PDT tumour destruction was achieved 3 h following injection of the nanoparticle conjugates leading to a remarkable 40% of the treated mice showing no tumour regrowth and complete survival. These results highlight that dual functionalised nanoparticles exhibit significant potential in PDT of cancer especially for difficult to treat cancers such as amelanotic melanoma.
M8L12 cubic cages (M = Mn(II), Zn(II) or Cd(II)), with all eight metal ions having all facial Δ or facial Λ configurations and having an encapsulated anion, were prepared by the self-assembly of m-xylene-bridged imidazolyl-imine ligands and MX2 (X = PF6(-), SbF6(-), TfO(-)) salts; the encapsulated anion exchange with different anions (SbF6(-), Tf2N(-), NO3(-), TsO(-)) was studied and the results with NO3(-) and TsO(-) indicate that anions on the cage surfaces affect the encapsulated anion exchange and the occupancy of the cage.
Although several new biomarkers have been recently proposed for psoriasis (Ps) and psoriasis arthritis (PsA), nothing is known about their diagnostic sensitivity and specificity, and their routine use. We therefore searched in-depth for new biomarker candidates using a biobank with EDTA-plasma from 158 individuals, patients and healthy controls. Samples from 6 selected pairs (patients against healthy controls) were searched proteomically using a workflow of extensive and precise design that is highly comprehensive. Subsequent verification was performed using ELISA and the entire biobank. By proteomic methods, 208 altered proteins were identified. Of these, 15 biomarker candidates were selected for verification. Of these 15, 4 individual parameters and 11 combinations significantly discriminated between patient and control groups. These individual parameters were Zn-α2-glycoprotein, complement C3, polymeric immunoglobulin receptor, and plasma kallikrein. Significant discrimination was obtained by combinations of 2 or 3 parameters. One combination seemed suitable for diagnosing PsA. Moreover, several candidates desmoplakin, complement C3, polymeric immunoglobulin receptor, and cytokeratin 17, correlated with PASI in all patients. This first comprehensive proteomic study on non-depleted plasma identified several biomarker candidates that have not been described before as well as some known from previous studies.
Our non-gel proteomic analysis is based on the highly comprehensive and significantly optimized chromatographic protein pre-fractionation. The method allows a biomarker search in non-depleted plasma. The subsequent verification by ELISA identifies several biomarker-candidates for the unbiased diagnosis of psoriasis and psoriasis arthritis. Four of the identified candidate markers might be used individually. Combinations of several parameters improve the diagnostic sensitivity and specificity. The still not validated candidates form a reserve for further evaluation. Moreover, mass spectrometric data uncover several biomarker-candidates which show diverse protein species of the same protein with opposing changes in the same sample.
The SNP-based high-resolution QTL mapping mapped eight major genomic regions harbouring robust QTLs governing seed-Fe and Zn concentrations (39.4% combined phenotypic variation explained/PVE) on six chromosomes of an intra-specific high-density genetic linkage map (1.56 cM map-density). 24620 SNPs discovered from genome-wide GBS (genotyping-by-sequencing) and 13 known cloned Fe and Zn contents-related chickpea gene-orthologs were genotyped in a structured population of 92 sequenced desi and kabuli accessions. The large-scale 16591 SNP genotyping- and phenotyping-based GWAS (genome-wide association study) identified 16 genomic loci/genes associated (29% combined PVE) with seed-Fe and Zn concentrations. Of these, 11 trait-associated SNPs in the genes linked tightly with eight QTLs were validated by QTL mapping. The seed-specific expression, including pronounced differential-regulation of 16 trait-associated genes particularly in accessions/mapping individuals with contrasting level of seed-Fe
 and Zn contents was apparent. Collectively, the aforementioned rapid integrated genomic strategy led to delineate novel functional non-synonymous and regulatory SNP allelic-variants from 16 known/candidate genes, including three strong trait-associated genes (encoding late embryogenesis abundant and yellow stripe-like 1 protein, and vacuolar protein sorting-associated protein) and eight major QTLs regulating seed-Fe and Zn concentrations in chickpea. These essential inputs thus have potential to be deployed in marker-assisted genetic enhancement for developing nutritionally-rich iron/zinc-biofortified chickpea cultivars.
Copper chloride (0.01mM, 2h) did not have significant influence on the survival of cerebellar granule neurons (CGNs) incubated in balanced salt solution. However, CuCl2 caused severe neuronal damage by glucose deprivation (GD). The glutamate NMDA-receptors blocker MK-801 partially and antioxidant N-acetyl-l-cysteine (NAC) or Zn(2+) chelator, N,N,N',N'-tetrakis(2-pyridylmethyl)ethylenediamine (TPEN) almost entirely protected CGNs from this toxic effect. Measurements of intracellular calcium ions using Fluo-4 AM, or zinc ions with FluoZin-3 AM demonstrated that 1 h-exposure to GD induced intensive increase of Fluo-4 but not FluoZin-3 fluorescence in neurons. The supplementation of solution with CuCl2 caused an increase of FluoZin-3, Fluo-4 and CellROX Green (reactive oxygen species probe) fluorescence by GD. The stimulation of Fluo-4 but not FluoZin-3 fluorescence by copper could be prevented partially by MK-801 and as well as CellROX Green fluorescence by NAC at GD. This data imply that during GD copper ions induce intense displacement zinc ions from intracellular stores, in addition free radical production, glutamate release and Ca(2+) overload of CGNs, that causes death of neurons as a result.
APOBEC3F (A3F) is a member of the apolipoprotein B mRNA-editing enzyme catalytic polypeptide-like (APOBEC) family of proteins that can deaminate cytosine (C) to uracil (U) on nucleic acids. A3F is one of the four APOBEC members with two Zn-coordinated homologous cytosine deaminase (CD) domains, with the others being A3G, A3D, and A3B. Here we report the in vitro characterization of DNA binding and deaminase activities using purified wild-type and various mutant proteins of A3F from an Escherichia coli expression system. We show that even though CD1 is catalytically inactive and CD2 is the active deaminase domain, presence of CD1 on the N-terminus of CD2 enhances the deaminase activity by over an order of magnitude. This enhancement of CD2 catalytic activity is mainly through the increase of substrate single-stranded (ss) DNA binding by the N-terminal CD1 domain. We further show that the loop 7 of both CD1 and CD2 of A3F plays an important role for ssDNA binding for each individual domain, as well as for the deaminase activity of CD2 domain in the full-length A3F.
Herein, we exploit two typical crystal growth modes, namely, "stacking" and "carving" routes, to synthesize Pt-based bimetallic nanomaterials with defect-rich surface structures, which exhibit enhanced electrocatalytic properties toward both methanol oxidation reaction (MOR) and oxygen reduction reaction (ORR) compared with commercial Pt/C.
The rigid and planar tetracarboxylic acid 5,5'-(1H-2,3,5-triazole-1,4-diyl)diisophthalic acid (H4L), incorporating a triazole group, has been used with no or different pyridine-based linkers to construct a family of d(10) coordination polymers, namely, {[H2N(CH3)2]3[Cd3(L)2(HCOO)]}n (), {[Cd2(L)(py)6]·H2O}n (), {[H2N(CH3)2] [Cd2(L)(HCOO)(H2O)4]}n (), {[Zn(H2L)]·H2O}n (), and {[Zn(H2L)(4,4'-bipy)0.5]·C2H5OH·H2O}n () (py = pyridine, 4,4'-bipy = 4,4'-bipyridine). constructs a 3D porous network containing two kinds of channels: one is filled with coordinated HCOO(-) anions, and the other with [H2N(CH3)2](+) cations. The framework of can be described as a rare (5,6,7)-connected net with the Schläfli symbol of (4(12)·5·6(2))(4(5)·5(3)·6(2))2(4(8)·5(3)·6(8)·8(2))2. The Cd(ii) ions in are connected through the carboxylate ligands to form a 2D layer, with aperture dimensions of ∼15.1 Å × 16.2 Å. The network of features a 3D (3,4)-connected (6·8·10)2(6·8(3)·10(2)) topology. A 3D network with the (4(2)·6·8(3)) topology of possesses an open 1D channel with the free volume of 29.2%. is a 2D layer structure with the (4(2)·6(3)·8)(4(2)·6) topology. The fluorescence lifetime τ values of are on the nanosecond timescale at room temperature. In particular, central-metal exchange in leads to a series of isostructural M(ii)-Cd frameworks [M = Cu (), Co (), Ni ()] showing improved catalytic activity for the synthesis of 1,4,5,6-tetrahydropyrimidine derivatives. Based on this, a plausible mechanism for the catalytic reaction has been proposed and the reactivity-structure relationship has been further clarified.
Here, we used stopped-flow fluorescence techniques to conduct a comparative kinetic analysis of the conformational transitions in human apurinic/apyrimidinic endonuclease 1 (APE1) and in DNA containing an abasic site in the course of their interaction. Effects of monovalent (K(+)) and divalent (Mg(2+), Mn(2+), Ca(2+), Zn(2+), Cu(2+), and Ni(2+)) metal ions on DNA binding and catalytic stages were studied. It was shown that the first step of substrate binding (corresponding to formation of a primary enzyme-substrate complex) does not depend on the concentration (0.05-5.0 mM) or the nature of divalent metal ions. In contrast, the initial DNA binding efficiency significantly decreased at a high concentration (5-250 mM) of monovalent K(+) ions, indicating the involvement of electrostatic interactions in this stage. It was also shown that Cu(2+) ions abrogated the DNA binding ability of APE1, possibly, due to a strong interaction with DNA bases and the sugar-phosphate backbone. In the case of Ca(2+) ions, the catalytic activity of APE1 was lost completely with retention of binding potential. Thus, the enzymatic activity of APE1 is increased in the order Zn(2+) < Ni(2+) < Mn(2+) < Mg(2+). Circular dichroism spectra and calculation of the contact area between APE1 and DNA reveal that Mg(2+) ions stabilize the protein structure and the enzyme-substrate complex.
High quality single-crystal fcc-Co(x)(Mg(y)Zn(1-y))(1-x)O(1-v) epitaxial thin films with high Co concentration up to x = 0.5 have been fabricated by molecular beam epitaxy. Systematic magnetic property characterization and soft X-ray absorption spectroscopy analysis indicate that the coexistence of ferromagnetic regions, superparamagnetic clusters, and non-magnetic boundaries in the as-prepared Co(x)(Mg(y)Zn(1-y))(1-x)O(1-v) films is a consequence of the intrinsic inhomogeneous distribution of oxygen vacancies. Furthermore, the relative strength of multiple phases could be modulated by controlling the oxygen partial pressure during sample preparation. Armed with both controllable magnetic properties and tunable band-gap, Co(x)(Mg(y)Zn(1-y))(1-x)O(1-v) films may have promising applications in future spintronics.
Recently, a silicate with the composition SrxBa1-xZn2Si2O7 was reported, which exhibits a negative coefficient of thermal expansion. The compound BaZn2Si2O7 shows a highly positive coefficient of thermal expansion up to a temperature of 280 °C and then transfers to a high temperature phase, which exhibits a coefficient of thermal expansion near zero or negative over a limited temperature range up to around 500 °C. This high temperature modification can be stabilized to room temperature if Ba(2+) is replaced by Sr(2+). In the solid solution SrxBa1-xZn2Si2O7, also Zn(2+) can be replaced in a wide concentration range by other cations with the respective valency. In the present study, Zn was partially or completely replaced by Mg, Co, Mn, Ni, or Cu. If the high temperature phase is stable at room temperature, the thermal expansion is negative, and if the partial substitution exceeds a certain concentration threshold, the low temperature phase with the crystal structure of BaZn2Si2O7 and highly positive thermal expansion is formed. The lowest mean coefficients of thermal expansion were measured for the composition Ba0.5Sr0.5Zn1.4Co0.6Si2O7 with a value of -2.9 × 10(-6) K(-1). In general, a lower Zn-concentration leads to a higher anisotropy and a lower mean coefficient of thermal expansion.
The search for a degradable metal simultaneously showing mechanical properties equal or higher to that of stainless steel and uniform degradation is still an open challenge. Several magnesium-based alloys have been studied, but their degradation rate has proved to be too fast and rarely homogeneous. Fe-based alloys show appropriate mechanical properties but very low degradation rate. In the present work, four novel Zn-Mg and two Zn-Al binary alloys were investigated as potential biodegradable materials for stent applications. The alloys were developed by casting process and homogenized at 350°C for 48h followed by hot extrusion at 250°C. Tube extrusion was performed at 300°C to produce tubes with outer/inner diameter of 4/1.5mm as precursors for biodegradable stents. Corrosion tests were performed using Hanks׳ modified solution. Extruded alloys exhibited slightly superior corrosion resistance and slower degradation rate than those of their cast counterparts, but all had corrosion rates roughly half that of a standard purity Mg control. Hot extrusion of Zn-Mg alloys shifted the corrosion regime from localized pitting to more uniform erosion, mainly due to the refinement of second phase particles. Zn-0.5Mg is the most promising material for stent applications with a good combination of strength, ductility, strain hardening exponent and an appropriate rate of loss of mechanical integrity during degradation. An EBSD analysis in the vicinity of the laser cut Zn-0.5Mg tube found no grain coarsening
 or texture modification confirming that, after laser cutting, the grain size and texture orientation of the final stent remains unchanged. This work shows the potential for Zn alloys to be considered for stent applications.
Reaction of Zn(OAc)2 ⋅2 H2 O with 2,6-diisopropylphenyl phosphate (dippH2 ) in the presence of pyridine-4-carboxaldehyde (Py-4-CHO) in methanol resulted in the isolation of a tetrameric zinc phosphate cluster [Zn(dipp)(Py-4-CH(OH)(OMe))]4 ⋅4 MeOH (1) with four hemiacetal moieties stabilized on the double-4-ring inorganic cubane cluster. The change of solvent from methanol to acetonitrile leads to the formation of [Zn(dipp)(Py-4-CHO)]4 (2), in which the coordinated Py-4-CHO retains its aldehydic form. Dissolution of 1 in CD3 CN readily converts it to the aldehydic form and yields 2. Similarly 2, which exists in the aldehyde form in CD3 CN, readily converts to the hemiacetal form in CD3 OD/CH3 OH. Compound 1 is an unprecedented example in which four hemiacetals have been stabilized on a single molecule in the solid state retaining its stability in solution as revealed by its (1) H NMR spectrum in CD3 OD. The solution stability of 1 and 2 has further been confirmed by ESI-MS studies. To generalize the stabilization of multiple hemiacetals on a single double-four-ring platform, pyridine-2-carboxaldehyde (Py-2-CHO) was used as the auxiliary ligand in the reaction between zinc acetate and dippH2 , leading to isolation of [Zn(dipp)(Py-2-CH(OH)(OMe))]4 (3). Understandably, recrystallization of 3 from acetonitrile yields the parent aldehydic form, [Zn(dipp)(Py-2-CHO)]4 (4). Single-crystal X-ray diffraction studies reveal that supramolecular bonding, aided by hydrogen-bonding interactions involving the hemiacetal functionalities (C-OH, C-OMe, and C-H), are responsible for the observed stabilization. The hemiacetal/aldehyde groups in 1 and 2 readily react with p-toluidine, 2,6-dimethylaniline, and 4-bromoaniline to yield the corresponding tetra-Schiff base ligands, [Zn(dipp)(L)]4 (L=4-methyl-N-(pyridin-4-ylmethylidene)aniline (5), 2,6-dimethyl-N-(pyridin-4-ylmethylene)-aniline (6), and 4-bromo-N-(pyridin-4-ylmethylene)aniline (7)). Isolation of 5-7 opens up further possibilities of using 1 and 2 as new supramolecular synthons and ligands.
The intramolecular benzylic C-H amination catalyzed by bimetallic paddlewheel complexes was investigated by using density functional theory calculations. The metal-metal bonding characters were investigated and the structures featuring either a small HOMO-LUMO gap or a compact SOMO energy scope were estimated to facilitate an easier one-electron oxidation of the bimetallic center. The hydrogen-abstraction step was found to occur through three manners, that is, hydride transfer, hydrogen migration, and proton transfer. The imido N species are more preferred in the Ru-Ru and Pd-Mn cases whereas coexisting N species, namely, singlet/triplet nitrene and imido, were observed in the Rh-Rh and Pd-Co cases. On the other hand, the triplet nitrene N species were found to be predominant in the Pd-Ni and Pd-Zn systems. A concerted asynchronous mechanism was found to be modestly favorable in the Rh-Rh-catalyzed reactions whereas the Pd-Co-catalyzed reactions demonstrated a slight preference for a stepwise pathway. Favored stepwise pathways were seen in each Ru-Ru- and Pd-Mn-catalyzed reactions and in the triplet nitrene involved Pd-Ni and Pd-Zn reactions. The calculations suggest the feasibility of the Pd-Mn, Pd-Co, and Pd-Ni paddlewheel complexes as being economical alternatives for the expensive dirhodium/diruthenium complexes in C-H amination catalysis.
Metallothioneins (MTs) are low molecular weight proteins, characterized by a high cysteine content and the ability to coordinate large amounts of d(10) metal ions, for example, Zn(II), Cd(II), and Cu(I), in form of metal-thiolate clusters. Depending on intracellular conditions such as redox potential or metal ion concentrations, MTs can occur in various states ranging from the fully metal-loaded holo- to the metal-free apo-form. The Cys thiolate groups in the apo-form can be either reduced or be involved in disulfide bridges. Although oxidation-mediated Zn(II) release might be a possible mechanism for the regulation of Zn(II) availability by MTs, no concise information regarding the associated pathways and the structure of oxidized apo-MT forms is available. Using the well-studied Zn2 γ-Ec -1 domain of the wheat Zn6 Ec -1 MT we attempt here to answer several question regarding the structure and biophysical properties of oxidized MT forms, such as: (1) does disulfide bond formation increase the stability against proteolysis, (2) is the overall peptide backbone fold similar for the holo- and the oxidized apo-MT form, and (3) are disulfide bridges specifically or randomly formed? Our investigations show that oxidation leads to three distinct disulfide bridges independently of the applied oxidation conditions and of the initial species used for oxidation, that is, the apo- or the holo-form. In addition, the oxidized apo-form is as stable against proteolysis as Zn2 γ-Ec -1, rendering the currently assumed degradation of oxidized MTs unlikely and suggesting a role of the oxidation process for the extension of protein lifetime in absence of sufficient amounts of metal ions. © 2016 Wiley Periodicals, Inc. Biopolymers (Pept Sci) 106: 295-308, 2016.
Severe trace metal pollution due to industrial effluents releases was found in Jiulong River Estuary, Southern China. In this study, water samples were collected during effluent release events to study the dynamic changes of environmental conditions and metal partitioning among dissolved, particulate and colloidal phases controlled by estuarine mixing. Intermittent effluent discharges during low tide caused decreasing pH and dissolved oxygen, and induced numerous suspended particulate materials and dissolved organic carbon to the estuary. Different behaviors of Cu, Zn, Ni, Cr and Pb in the dissolved fraction against the conservative index salinity indicated different sources, e.g., dissolved Ni from the intermittent effluent. Although total metal concentrations increased markedly following effluent discharges, Cu, Zn, Cr, Pb were predominated by the particulate fraction. Enhanced adsorption onto particulates in the mixing process resulted in elevated partitioning coefficient (Kd) values for Cu and Zn, and the particle concentration effect was not obvious under such anthropogenic impacts. Colloidal proportion of these metals (especially Cu and Zn) showed positive correlations with dissolved or colloidal organic carbon, suggesting the metal-organic complexation. However, the calculated colloidal partitioning coefficients were relatively constant, indicating the excess binding capacity. Overall, the intermittent effluent discharge altered the particulate/dissolved and colloidal/soluble phase partitioning process and may further influence the bioavailability and potential toxicity to aquatic organisms.
Trace elements (TEs) transported by atmospheric fluxes can negatively impact isolated ecosystems. Modelling based on moss-borne TE accumulation makes tracking TE deposition in remote areas without monitoring stations possible. Using a single moss species from ombrotrophic hummock peatlands reinforces estimate quality. This study used a validated geomatic model of particulate matter dispersion to identify the origin of Cd, Zn, Pb and Cu accumulated in Sphagnum capillifolium and the distance transported from their emission sources. The residential and industrial sectors of particulate matter emissions showed the highest correlations with the TEs accumulated in S. capillifolium (0.28(Zn)-0.56(Cu)) and (0.27(Zn)-0.47(Cu), respectively). Distances of dispersion varied depending on the sector of emissions and the considered TE. The greatest transportation distances for mean emissions values were found in the industrial (10.6 km when correlating with all TEs) and roads sectors (13 km when correlating with Pb). The residential sector showed the shortest distances (3.6 km when correlating with Cu, Cd, and Zn). The model presented here is a new tool for evaluating the efficacy of air pollution abatement policies in non-monitored areas and provides high-resolution (200 × 200 m) maps of TE accumulation that make it possible to survey the potential impacts of TEs on isolated ecosystems.
Coordinatively unsaturated Fe(III) metal sites were successfully incorporated into the iconic MOF-5 framework. This new structure, Fe(III) -iMOF-5, is the first example of an interpenetrated MOF linked through intercalated metal ions. Structural characterization was performed with single-crystal and powder XRD, followed by extensive analysis by spectroscopic methods and solid-state NMR, which reveals the paramagnetic ion through its interaction with the framework. EPR and Mössbauer spectroscopy confirmed that the intercalated ions were indeed Fe(III) , whereas DFT calculations were employed to ascertain the unique pentacoordinate architecture around the Fe(III) ion. Interestingly, this is also the first crystallographic evidence of pentacoordinate Zn(II) within the MOF-5 SBU. This new MOF structure displays the potential for metal-site addition as a framework connector, thus creating further opportunity for the innovative development of new MOF materials.
Constructed rapid infiltration systems (CRIS) are a reasonable option for treating wastewater, owing to their simplicity, low cost and low energy consumption. Layered double hydroxides (LDHs), novel materials with high surface area and anion exchange capacity, faced the problem of the application in CRIS due to the powdered form. To overcome this shortcoming, Zn-LDHs (FeZn-LDHs, CoZn-LDHs, AlZn-LDHs) were prepared by co-precipitation method and in-situ coated on the surface of the
 natural bio-ceramic to synthesize the core-shell bio-ceramic/Zn-LDHs composites. Characterization by Scanning Electron Microscope (SEM) and X-ray Fluorescence Spectrometer (XRFS) indicated that the Zn-LDHs were successful loaded on the natural bio-ceramic. Column tests experiments indicated that the bio-ceramic/Zn-LDHs efficiently enhanced the removal performance of phosphorus. The efficiently removal rates of bio-ceramic/FeZn-LDHs were 71.58% for total phosphorous (TP), 74.91% for total dissolved phosphorous (TDP), 82.31% for soluble reactive phosphorous (SRP) and 67.58% for particulate phosphorus (PP). Compared with the natural bio-ceramic, the average removal rates were enhanced by 32.20% (TP), 41.33% (TDP), 49.06% (SRP) and 10.50% (PP), respectively. Adsorption data of phosphate were better described by the Freundlich model for the bio-ceramic/Zn-LDHs and natural bio-ceramic, except for the bio-ceramic/CoZn-LDHs. The maximum adsorption capacity of bio-ceramic/AlZn-LDHs (769.23 mg/kg) was 1.77 times of the natural bio-ceramic (434.78 mg/kg). The effective desorption of phosphate could achieve by using a mixed solution of 5 M NaCl + 0.1 M NaOH, it outperformed the natural bio-ceramic of 18.95% for FeZn-LDHs, 7.59% for CoZn-LDHs and 12.66% for AlZn-LDHs. The kinetic data of the bio-ceramic/Zn-LDHs were better described by the pseudo-second-order equation. Compared the removal amount of phosphate by the natural bio-ceramic, the physical effects were improved little, but the chemical effects were enhanced for 112.49% for FeZn-LDHs, 111.89% for CoZn-LDHs and 122.67% for AlZn-LDHs. Therefore, the way of coating Zn-LDHs on the bio-ceramic efficiently improved the chemical effects in phosphate removal, supporting that it can use as potential substrates for the removal of phosphorus in CRIS.
Water makes up more than 80% of the total weight of milk. However, the influence of water chemistry on the milk proteome has not been extensively studied. The objective was to evaluate interaction of water-sourced iron (low, medium, and high levels) on milk proteome and implications on milk oxidative state and mineral content. Protein composition, oxidative stability, and mineral composition of milk were investigated under conditions of iron ingestion through bovine drinking water (infused) as well as direct iron addition to commercial milk in 2 studies. Four ruminally cannulated cows each received aqueous infusions (based on water consumption of 100L) of 0, 2, 5, and 12.5mg/L Fe(2+) as ferrous lactate, resulting in doses of 0, 200, 500 or 1,250mg of Fe/d, in a 4×4Latin square design for a 14-d period. For comparison, ferrous sulfate solution was directly added into commercial retail milk at the same concentrations: control (0mg of Fe/L), low (2mg of Fe/L), medium (5mg of Fe/L), and high (12.5mg of Fe/L). Two-dimensional electrophoresis coupled with matrix-assisted laser desorption/ionization-tandem time-of-flight (MALDI-TOF/TOF) high-resolution tandem mass spectrometry analysis was applied to characterize milk protein composition. Oxidative stability of milk was evaluated by the thiobarbituric acid reactive substances (TBARS) assay for malondialdehyde, and mineral content was measured by inductively coupled plasma mass spectrometry. For milk from both abomasal infusion of ferrous lactate and direct addition of ferrous sulfate, an iron concentration as low as 2mg of Fe/L was able to cause oxidative stress in dairy cattle and infused milk, respectively. Abomasal infusion affected both caseins and whey proteins in the milk, whereas direct addition mainly influenced caseins. Although abomasal iron infusion did not significantly affect oxidation state and mineral balance (except iron), it induced oxidized off-flavor and partial degradation of whey proteins. Direct iron addition to milk led to lipid oxidation during storage at 4°C. Oxidation level was positively associated with the concentration of added iron. Minerals (Mg, P, Na, K, Ca, Zn) in milk were not affected by the added iron in milk. This study indicated that a small amount of iron contamination in bovine drinking water at the farm or incidental iron addition from potable water sources causes oxidation, affects milk protein composition and stability, and affects final milk quality.
Aluminum-based water treatment residual (WTR)-coated wood mulches were synthesized and tested for removal of heavy metals and phosphorus (P) in synthetic urban stormwater. WTRs are an industrial waste produced from coagulation in water treatment facilities, primarily composed of amorphous aluminum or iron hydroxides. Batch tests showed that the composite filter media could effectively adsorb 97% lead (Pb), 76% zinc (Zn), 81% copper (Cu) and 97% P from the synthetic stormwater (Pb = 100 μg/L, Zn = 800 μg/L, Cu = 100 μg/L, P = 2.30 mg/L, and pH = 7.0) within 120 min, due to the presence of aluminum hydroxides as an active adsorbent. The adsorption was a 2(nd)-order reaction with respect toward each pollutant. Column tests demonstrated that the WTR-coated mulches considerably alleviated the select pollutants under a continuous-flow condition over the entire filtration period. The effluent Pb, Zn, Cu, and P varied at 0.5-8.9%, 33.4-46.7%, 45.8-55.8%, and 6.4-51.9% of their respective initial concentrations with the increasing bed volume from 0 to 50. Synthetic precipitation leaching procedure (SPLP) and toxicity characteristic leaching procedure (TCLP) tests indicated that leached contaminants were all below the U.S. criteria, suggesting that the release of undesired chemicals under rainfall or landfilling conditions is not a concern during application. This study demonstrates that the WTR-coated mulches are a new, low-cost, and effective filter media for urban stormwater treatment. Equally important, this study provides a sustainable approach to beneficially reuse an industrial waste for environmental pollution control.
In this study, the natural and anthropogenic radioactivity levels in the sediment samples collected from the Marmara Sea in Turkey were determined. The average activity concentrations (range) of (226)Ra, (238)U, (232)Th, (40)K and (137)Cs were found to be 23.8 (13.8-34.2) Bq kg(-1), 18.8 (6.4-25.9) Bq kg(-1), 23.02 (6.3-31.1) Bq kg(-1), 558.6 (378.8-693.6) Bq kg(-1) and 9.14 (4.8-16.3) Bq kg(-1), respectively. Our results showed that the average activity concentrations of (226)Ra, (238)U and (232)Th in the sediment samples were within the acceptable limits; whereas the average activity concentration of (40)K in the sediment samples was higher than the worldwide average concentration. The average radium equivalent activity, the average absorbed dose rate and the average external hazard index were calculated as 100.01 Bq kg(-1), 48.32 nGy h(-1) and 0.27, respectively. The average gross alpha and beta activity in the seawater samples were found to be 0.042 Bq L(-1) and 13.402 Bq L(-1), respectively. The gross alpha and beta activity concentrations increased with water depth in the same stations. The average heavy metal concentrations (range) in the sediment samples were 114.6 (21.6-201.7) μg g(-1) for Cr, 568.2 (190.8-1625.1) μg g(-1) for Mn, 39.3 (4.9-83.4) μg g(-1) for Cu, 85.5 (11.0-171.8) μg g(-1) for Zn, 32.9 (9.1-73.1) μg g(-1) for Pb and 49.1 (6.8-103.0) μg g(-1) for Ni. S5 station was heavily polluted by Cr, Cu, Ni and Pb. The results showed that heavy metal enrichment in sediments of the Marmara Sea was widespread.
The concentration of Al, Cr, Fe, Mn, Ni, Cu, Zn, Hg, Sr, Mo, Ag, Cd, Pb and As was analyzed in water, sediment, and muscle of Odontesthes bonariensis from the eutrophic San Roque Lake (Córdoba-Argentina). The monitoring campaign was performed during the wet, dry and intermediate season. The concentration of Cr, Fe, Pb, Zn, Al and Cd in water exceeded the limits considered as hazardous for aquatic life. The highest metal concentrations were observed in sediment, intermediate concentrations, in fish muscle, and the lowest in water, with the exception of Cr, Zn, As and Hg, which were the highest in fish muscle. Potential ecological risk analysis of heavy metal concentrations in sediment indicated that the San Roque Lake posed a low ecological risk in all sampling periods. The target hazard quotients (THQs) and carcinogenic risk (CR) for individual metals showed that As in muscle was particularly hazardous, posing a potential risk for fishermen and the general population during all sampling periods. Hg poses a potential risk for fishermen only in the intermediate season. It is important to highlight that none of these two elements exceeded the limits considered as hazardous for aquatic life in water and sediment. This result proves the importance of performing measurements of contaminants, in both abiotic and biotic compartments, to assess the quality of food resources. These results suggest that the consumption of this fish species from this reservoir is not completely safe for human health.
The structural, electronic, and optical properties of core-shell nanoclusters, (CdSe)(x)@(CdSe)(y) and their Zn-substituted complexes of x = 2-4 and y = 16-28, were studied with density functional theory calculations. The substitution was applied in the cores, the shells, and/or the whole clusters. All these clusters are characterized by their core-shell structures in which the core-shell interaction was found different from those in core or in shell, as reflected by their bondlengths, volumes, and binding energies. Moreover, the core and shell combine together to compose a new cluster with electronic and optical properties different from those of separated individuals, as reflected by their HOMO-LUMO gaps and optical absorptions. With the substitution of Cd by Zn, the structural, electronic, and optical properties of clusters change regularly. The binding energy increases with Zn content,
 attributed to the strong Zn-Se bonding. For the same core/shell, the structure with a CdSe shell/core has a narrower gap than that with a ZnSe shell/core. The optical absorption spectra also change accordingly with Zn substitution. The peaks blueshift with increasing Zn concentration, accompanying with shape variations in case large number of Cd atoms are substituted. Our calculations reveal the core-shell interaction and its influence on the electronic and optical properties of the core-shell clusters, suggesting a composition-structure-property relationship for the design of core-shell CdSe and ZnSe nanoclusters.
Photodynamic therapy (PDT) is based on exposing a light-sensitive material that has been localized in target tissues with visible light. In the current study, symmetric Zn(II) octaoctadodecylphthalocyanine (1) and the asymmetrically substituted hydroxyhexyloxy derivative (2) were examined as a multifunctional agent for tumour nuclear imaging and for PDT potential. Zn(II)Pc 1 and Zn(II)Pc 2 were radiolabelled with (131) I using an iodogen method with high efficiency (93.5 ± 3.5% and 93.0 ± 2.8%, respectively) under the optimum conditions. Biodistribution study results showed that radiolabelled Zn(II)Pc 1 had a high uptake in the large intestine and unchanging uptake in the ovary. However, radiolabelled Zn(II)Pc 2 uptake was statically significant in the large intestine, pancreas, ovary and lung. For the PDT studies, EMT6/P (mouse mammary cell line) and HeLa (cervical adenocarcinoma cell line) with Zn(II)Pc 1 and Zn(II)Pc 2 were exposed to red light (650 nm) at 10-30 J/cm(2) . Zn(II)Pc 1 and Zn(II)Pc 2 had a good PDT efficacy in the EMT6/P cell line. In conclusion, radiolabelled Zn(II)Pc 1 might be a promising imaging agent for pancreas, ovary and colon tumours. However, the radiolabelled Zn(II)Pc 2 might be a promising nuclear imaging and PDT agent for colon, lung, pancreas and ovary tumours.
A highly efficient enantioselective [2+2] cycloaddition between alkynones and cyclic enol silyl ethers was developed by using a chiral N,N'-dioxide-zinc(II) complex as a catalyst. This method functions well for a variety of terminal alkynes as well as cyclic enol silyl ethers, with good to excellent enantioselectivity (up to 97 % ee). This is also the first successful example for the catalytic enantioselective [2+2] cycloaddition of internal alkynes with cyclic enol silyl ethers to give fully substituted cyclobutenes. Meanwhile, the desired cyclobutene product can easily be transformed into fused cyclobutane derivatives.
Zinc (Zn) and copper (Cu) are important trace elements for cognitive development and normal neurological functioning. Autism spectrum disorder (ASD) is a common neurological disorder, which has previously been associated with the levels of some trace elements in the blood. However, clinical data regarding the potential implication of Zn and Cu in patients with ASD are still insufficient. Therefore, the aim of the present study was to investigate the whole blood levels of Zn and Cu in a cohort of 28 children with ASD and 28 age- and gender-matched healthy controls. Whole blood Zn and Cu levels were assessed using inductively-coupled plasma-sector field mass spectrometry. Both in the control and in the ASD group, the values of whole blood Cu and Zn were characterized by a Gaussian distribution. The results indicate that the ASD children were characterized by ~10 % (p = 0.005) and ~12 % (p = 0.015) lower levels of whole blood Zn and Zn/Cu ratio, respectively, in comparison to controls. No significant difference in whole blood Cu was observed. However, Cu/Zn ratio was ~15 % (p = 0.008) higher in ASD children than that in the control ones. The results of the present study may be indicative of Zn deficiency in ASD children. Taking into account Zn-mediated up-regulation of metallothionein (MT) gene expression, these findings suggest a possible alteration in the functioning of the neuroprotective MT system. However, further investigations are required to test this hypothesis.
A glycosyl-rhodamine fluorescent probe with good water-solubility has been designed and synthesized through click reaction. Compared with control compound 1, the obtained target compound (RBGlc-3) could be independently applied for the detection of Hg(2+) in water medium, and not disturbed by Ce(3+), Eu(3+), Ca(2+), Cd(2+), Fe(2+), Ba(2+), Co(2+), Cu(2+), Zn(2+), Pb(2+), Mg(2+), Ni(2+), K(+), Ag(+), Na(+), NH4(+), CH3COO(-), S2O4(2-), SO4(2-), SO3(2-) and Cl(-). 1:1 Stoichiometry is the most likely recognition mode of RBGlc-3 toward Hg(2+) ion, and the OFF-ON fluorescent mechanism of RBGlc-3 is proposed.
This study investigated the effects of 48h heavy metal exposure upon the metabolic profiles of Ruditapes decussatus and Ruditapes philippinarum using (1)H NMR metabolomics. Both species were exposed to increasing concentrations of lead nitrate (10, 40, 60 and 100μg/L) and zinc chloride (20, 50, 100 and 150μg/L), under laboratory conditions. ICP-OES analysis was further performed on the clams' samples in order to verify the occurrence of heavy metal bioaccumulation. With respect to the controls, the metabolic profiles of treated R. decussatus exhibited higher levels of organic osmolytes and lower contents of free amino acids. An opposite behavior was shown by R. philippinarum. In terms of heavy metal, the exposure effects were more evident in the case of Pb rather than Zn. These findings show that NMR-based metabolomics has the required sensitivity and specificity for the identification of metabolites that can act as sensitive indicators of contaminant-induced stress.
Novel immobilized sulfate-reducing bacteria (SRB) beads were prepared for the treatment of synthetic acid mine drainage (AMD) containing high concentrations of Fe, Cu, Cd and Zn using up-flow anaerobic packed-bed bioreactor. The tolerance of immobilized SRB beads to heavy metals was significantly enhanced compared with that of suspended SRB. High removal efficiencies of sulfate (61-88%) and heavy metals (>99.9%) as well as slightly alkaline effluent pH (7.3-7.8) were achieved when the bioreactor was fed with acidic influent (pH 2.7) containing high concentrations of multiple metals (Fe 469 mg/L, Cu 88 mg/L, Cd 92 mg/L and Zn 128 mg/L), which showed that the bioreactor filled with immobilized SRB beads had tolerance to AMD containing high concentrations of heavy metals. Partially decomposed maize straw was a carbon source and stabilizing agent in the initial phase of bioreactor operation but later had to be supplemented by a soluble carbon source such as sodium lactate. The microbial community in the bioreactor was characterized by denaturing gradient gel electrophoresis (DGGE) and sequencing of partial 16S rDNA genes. Synergistic interaction between SRB (Desulfovibrio desulfuricans) and co-existing fermentative bacteria could be the key factor for the utilization of complex organic substrate (maize straw) as carbon and nutrients source for sulfate reduction.
Electronic cigarette use has rapidly increased in recent years. In assessing their safety, and in view of coming regulations, trace elements (TE) are among the potentially toxic compounds required to be evaluated in electronic cigarette refill fluids ("e-liquids"). An analytical method using inductively coupled plasma with mass spectrometric detection (ICP-MS) was developed and rigorously validated in order to determine concentrations of 15 TE in 54 e-liquids from a French brand. Despite a significant matrix effect from the main e-liquid constituents, and difficulties related to the current lack of reference materials, our method demonstrated satisfactory linearity, precision and robustness, and permitted the quantification of low concentrations of these 15 elements: lower limits of quantification (LLQ) obtained were ≤4 ppb for all elements except for Ni, Cu and Zn (16 ppb, 20 ppb and 200 ppb, respectively). All TE concentrations in all tested samples were <510 ppb, mostly near or below the LLQs. This method is transposable and is timely for laboratories seeking to meet a prospective demand in light of current or future regulations.
It is a challenge to fabricate high quality Cu2ZnSnSe4 (CZTSe) film with low Cu content (Cu/(Zn + Sn) < 0.8). In this work, the growth mechanisms of CZTSe films under different Se vapor composition are investigated by DC-sputtering and a postselenization approach. The composition of Se vapor has important influence on the compactability of the films and the diffusion of elements in the CZTSe films. By adjusting the composition of Se vapor during the selenization process, an optimized two step selenization process is proposed and highly crystallized CZTSe film with low Cu content (Cu/(Zn + Sn) = 0.75) is obtained. Further study of the effect of Cu content on the morphology and photovoltaic performance of the corresponding CZTSe solar cells has shown that the roughness of the CZTSe absorber film increases when Cu content decreases. As a consequence, the reflection loss of CZTSe solar cells reduces dramatically and the short circuit current density of the cells improve from 34.7 mA/cm(2) for Cu/(Zn + Sn) = 0.88 to 38.5 mA/cm(2) for Cu/(Zn + Sn) = 0.75. In addition, the CZTSe solar cells with low Cu content show longer minority carrier lifetime and higher open circuit voltage than the high Cu content devices. A champion performance CZTSe solar cell with 10.4% efficiency is fabricated with Cu/(Zn + Sn) = 0.75 in the CZTSe film without antireflection coating.
The effects of applied digested pig slurry on a vegetable crops field were studied. The study included a 3-year investigation on nutrient characteristics, heavy metals contamination and hygienic risks of a vegetable crops field in Wuhan, China. The results showed that, after anaerobic digestion, abundant N, P and K remained in the digested
 pig slurry while fecal coliforms, ascaris eggs, schistosoma eggs and hookworm eggs were highly reduced. High Cr, Zn and Cu contents in the digested pig slurry were found in spring. Digested pig slurry application to the vegetable crops field led to improved soil fertility. Plant-available P in the fertilized soils increased due to considerable increase in total P content and decrease in low-availability P fraction. The As content in the fertilized soils increased slightly but significantly (p = 0.003) compared with control. The Hg, Zn, Cr, Cd, Pb, and Cu contents in the fertilized soils did not exceed the maximum permissible contents for vegetable crops soils in China. However, high Zn accumulation should be of concern due to repeated applications of digested pig slurry. No fecal coliforms, ascaris eggs, schistosoma eggs or hookworm eggs were detected in the fertilized soils.
Thailand is predominantly an agriculture-based country. Organic farming is enlisted as an important national agenda to promote food safety and international export. The present study aimed to determine the concentrations of trace elements in commercial organic fertilizers (fermented and nonfermented) composed of pig and cattle manures available in Thailand. Pig and cattle manures as well as animal feeds were also collected from either animal farms or markets. The results were compared to the literature data from other countries. Fermented fertilizer composed of pig manure contained higher concentrations of nitrogen (N) and phosphorus (P) than fertilizer composed of cattle manure. High concentrations of copper (Cu) and zinc (Zn) were also found in fertilizers and manures. Some organic fertilizers had high concentrations of arsenic (As), cadmium (Cd), and lead (Pb). The range of As concentration in these fertilizers was 0.50-24.4 mg/kg, whereas the ranges of Cd and Pb were 0.10-11.4 and 1.13-126 mg/kg, respectively. Moreover, pig manure contained As and Cd (15.7 and 4.59 mg/kg, respectively), higher than their levels in cattle manure (1.95 and 0.16 mg/kg, respectively). The use of pig manure as soil supplement also resulted in high Cd contamination in herbal tea (Gynostemma pentaphyllum Makino; GP). The Cd concentration in GP plants positively correlated with the Cd concentration in the soil. Therefore, the application of some organic fertilizers or animal manures to agricultural soil could increase some potentially toxic elements in soil, which may be absorbed by plants and, thus, increase the risk of contamination in agricultural products.
Seabird subfossils were collected on three islands of the Xisha Archipelago, South China Sea. Via elemental analysis, we identified that bird guano was a significant source for heavy metals Cu, Zn, and Hg. Cu and Zn levels in these guano samples are comparable to their levels in wildbird feces, but guano Hg was lower than previously reported. Trophic positions significantly impacted transfer efficiency of heavy metals by seabirds. Despite of a common source, trace elements, as well as stable isotopes (i.e., guano δ(13)C and collagen δ(15)N), showed island-specific characteristics. Bird subfossils on larger island had relatively greater metal concentrations and revealed higher trophic positions. Partition of element and isotope levels among the islands suggested that transfer efficacy of seabirds on different islands was different, and bird species were probably unevenly distributed among the islets. Island area is possibly a driving factor for distributions of seabird species.
A comprehensive geochemical investigation of potentially harmful elements (PHEs) in household dust from the town of Idrija (Slovenia), once a world-famous Hg mining town that is now seriously polluted, was performed for the first time. After aqua regia digestion, the content of mercury (Hg), arsenic (As), cadmium (Cd), cobalt (Co), chromium (Cr), copper (Cu), molybdenum (Mo), nickel (Ni), lead (Pb) and zinc (Zn) was measured. PHE-bearing particles were recognised and observed by scanning electron microscopy and energy-dispersive spectrometry before and after exposure to simulated stomach acid (SSA). Mercury binding forms were identified by Hg thermal desorption technique and gastric bioaccessible Hg was estimated after SSA extraction by ICP-MS. With regard to rural and urban background values for Slovenia, high Hg content (6-120 mg/kg) and slightly elevated As content (1-13 mg/kg) were found. Mercury pollution is a result of past mining and ore processing activities. Arsenic content is potentially associated with As enrichment in local soils. Four Hg binding forms were identified: all samples contained Hg bound to the dust matrix, 14 samples contained cinnabar, two samples contained metallic Hg (Hg(0)), and one sample assumingly contained mercury oxide. After exposure to SSA, Hg-bearing phases showed no signs of dissolution, while other PHE-bearing phases were significantly morphologically and/or chemically altered. Estimated gastric Hg bioaccessibility was low (<0.006-0.09 %), which is in accordance with identified Hg binding forms and high organic carbon content (15.9-31.5 %) in the dust samples.
We investigated the occurrence of cadmium (Cd), copper (Cu), chromium (Cr), nickel (Ni), lead (Pb), Znic (Zn), iron (Fe), manganese (Mn), and magnesium (Mg) in sediments, as well as in related soils and aquatic plants in the Liangtan River, a typical secondary anabranch of the Yangtze River in the Three Gorges Reservoir Region (TGRR) of China. We found that sediments accumulated more metals than soils and aquatic plants. Concentrations of the nine metals in sediments and soils followed the same sequence, while their concentrations in aquatic plants followed a different sequence. Potential adverse effects of contaminated sediments on benthic fauna were evaluated, and the results showed that the toxic effect on benthic organisms followed the sequence Zn > Ni > Cr > Cu > Cd > Pb. The potential ecological risk index analysis indicated that Cd in sediments had considerable ecological risk, whereas Cr, Cu, Zn, Ni, and Pb had low ecological risk. The potential ecological risk index (RI) of the heavy metals in sediments of the Liangtan River was 174.9, indicating moderate ecological risk. The transfer factor trend of metals for aquatic plants showed that Cd and Ni had the most and least accumulation, respectively. For Cu, Cd, Mg, Pb, and Cr, a significant positive correlation of the metal concentrations was observed between sediments and soils, but no correlations (excluding Cr) were detected between sediments and aquatic plants. Our study indicated that anthropogenic input may be the primary source of metal contamination in the Liangtan River, and that Zn and Cd pollution in the Liangtan River should be further explored.
A number of dumpsites occur on the island of Saipan and in the surrounding coastal waters. Many of these sites date back to the immediate post WWII clean-up period and contain a variety of wartime wastes. Metallic debris is generally the most visible waste material and commonly includes bomb fragments, artillery shells, bullets, and other military hardware. In this investigation, we examined the heavy metal status of soils from around several of these dumpsites and in any obvious drainage pathways leading from them to the coast. Sediments were also taken for analysis from a number of coastal discharge points and three submerged sites. Metal enrichment was evident for one or more elements in deposits from two of the three submerged sites and 24 of the 32 land-based sites visited. Copper, Pb, and Zn were the most commonly encountered contaminant metals with levels well in excess of 1000 μg/g(-1) in several instances. Elevated Hg and Cd concentrations were also relatively widespread throughout the study area although levels of each element seldom exceeded 1.0 and 10.0 μg/g(-1), respectively. Silver, another element of toxicological concern, was only occasionally detected despite registering a high of 42 μg/g(-1) at one particular site. The metal data were weighed against established benchmarks formulated for the protection of human and ecological health. Implications of the findings and issues of primary concern are briefly addressed.
Acanthamoeba is an opportunistic protozoan pathogen that plays a pivotal role in the ecosystem. It may cause blinding keratitis and fatal encephalitis involving the central nervous system. Here we synthesized pure and Zn doped TiO2 nanoparticles (~10-30nm) via sol-gel and sol-hydrothermal methods and demonstrated its impact on the biological characteristics of pathogenic Acanthamoeba castellanii. Our results revealed that pure and Zn doped TiO2 nanoparticles synthesized by sol-hydrothermal methods (ranging 5, 10, 25 and 50μg/ml) exhibited amoebicidal effects i.e., >60% of trophozoites executed under normal light at maximum dose (50μg/ml) within 1h incubation. In contrast pure/doped TiO2 obtained via sol gel method showed ~40% amoeba damage. Furthermore, amoebae growth assay demonstrated that Zn doped TiO2 also inhibited Acanthamoeba numbers up to 7days in dose dependent manner. It was interesting to note that all the tested TiO2 nanoparticles have shown maximum amoebicidal effects at pH7 which is quite relevant to amoebic growth favorable conditions. Our results confirmed that TiO2 has inhibitory effects on Acanthamoeba growth and viability. Overall, we reported the amoebicidal and amoebic growth inhibition potential of pure and Zn doped TiO2 nanoparticles against Acanthamoeba due to attached OH(-) groups, reduced size and decreased band gap of sol hydrothermally synthesized TiO2 nanoparticles.
Cistus monspeliensis L. is a species that grows spontaneously in contaminated mining areas from the Iberian Pyrite Belt. This species can have high concentrations of Zn in the shoots without visible signs of phytotoxicity.
 In order to understand the physiological mechanisms underlying this tolerance, C. monspeliensis was grown at several concentrations of Zn(2+) (0, 500, 1000, 1500, 2000µM) and the effects of this metal on plant development and on the defence mechanisms against oxidative stress were evaluated. Independently of the treatment, Zn was mainly retained in the roots. The plants with the highest concentrations of Zn showed toxicity symptoms such as chlorosis, low leaf size and decrease in biomass production. At 2000µM of Zn, the dry biomass of the shoots decreased significantly. High concentrations of Zn in shoots did not induce deficiencies of other nutrients, except Cu. Plants with high concentrations of Zn had low amounts of chlorophyll, anthocyanins and glutathione and high contents of H2O2. The highest concentrations of Zn in shoots of C. monspeliensis triggered defence mechanisms against oxidative stress, namely by triggering antioxidative enzyme activity and by direct reactive oxygen species (ROS) scavenging through carotenoids, that are unaffected by stress due to stabilisation by ascorbic acid.
The exchange of subunits between homodimeric mutant Cu, Zn superoxide dismutase (SOD1) and wild-type (WT) SOD1 is suspected to be a crucial step in the onset and progression of amyotrophic lateral sclerosis (ALS). The rate, mechanism, and ΔG of heterodimerization (ΔGHet) all remain undetermined, due to analytical challenges in measuring heterodimerization. This study used capillary zone electrophoresis to measure rates of heterodimerization and ΔGHet for seven ALS-variant apo-SOD1 proteins that are clinically diverse, producing mean survival times between 2 and 12 years (postdiagnosis). The ΔGHet of each ALS variant SOD1 correlated with patient survival time after diagnosis (R(2) = 0.98), with more favorable ΔGHet correlating with shorter survival by 4.8 years per kJ. Rates of heterodimerization did not correlate with survival time or age of disease onset. Metalation diminished the rate of subunit exchange by up to ∼38-fold but only altered ΔGHet by <1 kJ mol(-1). Medicinal targeting of heterodimer thermodynamics represents a plausible strategy for prolonging life in SOD1-linked ALS.
A series of novel azo-functionalized copolymerized networks (simply known as NOP-34 series) with tunable permanent microporosity and highly selective carbon dioxide capture are disclosed. The synthesis was accomplished by Zn-induced reductive cross-coupling copolymerization of two nitrobenzene-like building blocks with different 'internal molecular free volumes' (IMFVs), i.e., 2,7,14-trinitrotriptycene and 2,2',7,7'-tetranitro-9,9'-spirobifluorene, with different molar ratios. Increasing the content of spirobifluorene (SBF) segments with a smaller IMFV relative to that of triptycene leads to an unconventional rise-fall pattern in porosity. Unlike most reported porous copolymers whose surface area lies between the corresponding homopolymers, the copolymer NOP-34@7030 with 30% SBF segments unprecedentedly shows the largest Brunauer-Emmett-Teller specific surface area (up to 823 m(2) g(-1)) as well as promoted CO2 uptake abilities (from 2.31 to 3.22 mmol g(-1), at 273 K/1.0 bar). The 100% triptycene(TPC)-derived homopolymer (NOP-34@1000) with a moderate surface area shows the highest CO2/N2 IAST selectivity of 109 (273 K) among the five samples, surpassing most known nanoporous organic polymers. This may contribute significantly to our understanding of the relationship of IMFVs with the properties of copolymerized materials.
The molecular conformation of a bis-helicenic terpyridine system is strongly modified upon binding to Zn(ii) ion, a process that is accompanied by large changes in the optical and chiroptical properties. This system affords a new type of helicene-based chiroptical switching.
Phosphorus (P) is a limiting factor to plant growth and productivity in almost half of the world's arable soil, and its uptake in plants is often constrained because of its low solubility in the soil. To avoid repeated and large quantity application of rock phosphate as a P fertilizer and enhance the availability of native P acquisition by the plant root surface, in this study a biosynthesized ZnO nanoparticle was used. Zn acts as a cofactor for P-solubilizing enzymes such as phosphatase and phytase, and nano ZnO increased their activity between 84 and 108%. The level of resultant P uptake in mung bean increased by 10.8%. In addition, biosynthesized ZnO also improves plant phenology such as stem height, root volume, and biochemical indicators such as leaf protein and chlorophyll contents. In the rhizosphere, increased chlorophyll content and root volume attract microbial populations that maintain soil biological health. ICP-MS results showed ZnO nanoparticles were distributed in all plant parts, including seeds. However, the concentration of Zn was within the limit of the dietary recommendation. To the best of our knowledge, this is the first holistic study focusing on native P mobilization using ZnO nanoparticles in the life cycle of mung bean plants.
The tobacco plants transformed with popW gene showed enhanced drought tolerance, and the mechanism was found with primed antioxidant defenses and reduced drought stress damages in the transgenic lines. Harpin proteins are elicitors produced by several gram-negative plant pathogenic bacteria, triggering multiple beneficial responses in plants, such as induction of defense response against diverse pathogens and insects, growth promotion, and drought tolerance. In this study, the harpin-encoding gene popW derived from Ralstonia solanacearum ZJ3721 was transferred to tobacco. We examined the tolerance of transgenic tobacco plants toward drought stress under greenhouse conditions and analyzed the molecular mechanisms underlying the enhanced drought tolerance. The results revealed that the transgenic lines primed antioxidant defenses and reduced drought stress damages. In addition, they displayed lower malondialdehyde and relative electrical conductivity, while higher relative water content and recovery intension than the tobacco plants transformed with empty vector pBI121 and the wild-type (WT) plants under drought stress. Furthermore, the transgenic lines displayed a significant increase in peroxidase, superoxide dismutase, catalase activities, and ascorbic acid content compared with control plants under drought stress, and these levels were up to 1.95, 1.68, 1.34, and 1.43 times higher than those of WT plants, respectively. Overexpression of popW in tobacco also significantly enhanced the relative transcript levels of oxidative stress-responsive genes NtAPX, NtCAT1, NtGST, and NtCu/Zn-SOD under drought stress. The relative transcript levels of these genes in the transgenic line PW12 were up to 1.94, 2.36, 5.24, and 3.62 times higher than those of WT plants, respectively. These results confirmed that the popW gene, which was transformed into tobacco primed antioxidant responses, increased tolerance to drought stress in tobacco plants.
Chemical imaging of single cells at the molecular level is important in capturing biological dynamics. Single cell correlative imaging is realized between super-resolution microscopy, namely, structured illumination microscopy (SIM), and time-of-flight secondary ion mass spectrometry (ToF-SIMS) using a multimodal microreactor (i.e., System for Analysis at the Liquid Vacuum Interface, SALVI). SIM characterized cells and guided subsequent ToF-SIMS analysis. Lipid fragments were identified in the cell membrane via dynamic ToF-SIMS depth profiling. Positive SIMS spectra show intracellular potassium and sodium ion transport due to exposure to nanoparticles. Spectral principal component analysis elucidates differences in chemical composition among healthy alveolar epithelial mouse lung C10 cells, cells that uptake zinc oxide nanoparticles, and various wet and dry control samples. The observation of Zn(+) gives the first direct evidence of ZnO NP uptake and dissolution by the cell membrane. Our results provide submicron chemical mapping for investigating cell dynamics at the molecular level.
We carried out a systematic study of the hole transport properties for a series of symmetrically stacked porphyrin dimers. In the first part of this study, we evaluated the sensitivity of electronic couplings to orbital relaxation due to molecular ionization and intermolecular interactions for a series of halogenated porphyrins. The effect of polarization was estimated by comparing electronic couplings from fragment orbital density functional theory (FODFT) and frozen density embedding electron transfer (FDE-CT). For the dimers considered, the effect of polarization was estimated to be less than 20%, in line with previous studies on different molecular dimers. Thus, we decided to employ a computationally cheaper FODFT method to continue our study of the effect of metals and substituents on the electronic couplings for hole transfer. We find that, compared to the non-metallated porphyrins, Ni, Fe and Pt significantly reduce the coupling, while Zn, Ti, Cd and Pd increase it. The effect of substituents was studied on a series of meso-substituted porphyrins (meso-tetrapyridineporphyrin, meso-tetraphenylporphyrin and derivatives) for which we could relate a reduction of the coupling to steric effects that reduce the overlap between the frontier orbitals of the monomers.
A case study was undertaken to assess the risk of sewage-irrigated soils in relation to the transfer of trace elements to rice and wheat grain. For this purpose, peri-urban agricultural lands under the Keshopur Effluent Irrigation Scheme (KEIS) of Delhi were selected. These agricultural lands have been receiving irrigation through sewage effluents since 1979. Sewage effluent, groundwater, soil, and plant (rice and wheat grain) samples were
 collected with GPS coordinates from this peri-urban area. Under wheat crop, sewage irrigation for four decades resulted into a significant buildup of zinc (141 %), copper (219 %), iron (514 %), nickel (75.0 %), and lead (28.1 %) in sewage-irrigated soils over adjacent tube well water-irrigated ones. Under rice crop, there was also a significant buildup of phosphorus (339 %), sulfur (130 %), zinc (287 %), copper (352 %), iron (457 %), nickel (258 %), lead (136 %), and cadmium (147 %) in sewage-irrigated soils as compared to that of tube well water-irrigated soils. The values of hazard quotient (HQ) for intake of trace toxic elements by humans through consumption of rice and wheat grain grown on these sewage-irrigated soils were well within the safe permissible limit. The variation in Zn, Ni, and Cd content in wheat grain could be explained by solubility-free ion activity model (FIAM) to the extent of 50.1, 56.8, and 37.2 %, respectively. Corresponding values for rice grain were 49.9, 41.2, and 42.7 %, respectively. As high as 36.4 % variation in As content in rice grain could be explained by solubility-FIAM model. Toxic limit of extractable Cd and As in soil for rice in relation to soil properties and human health hazard associated with consumption of rice grain by humans was established. A similar exercise was also done in respect of Cd for wheat. The conceptual framework of fixing the toxic limit of extractable metals and metalloid in soils with respect to soil properties and human health hazard under the modeling framework was established.
The aim of this descriptive-analytical study was to measure the concentration of heavy metals (HMs) in the leaf and bark of Ulmus carpinifolia as new biological indicators, and the ecological risk assessment of these metals in the ambient air. To achieve these goals, 48 sampling locations were selected in the city and concentration of four HMs-zinc (Zn), copper (Cu), lead (Pb), and cadmium (Cd)-was measured in the mentioned indicator using atomic absorption spectroscopy method. After this, ecological risk assessment, source appointment, and spatial distribution were conducted. In this regard, the enrichment factor (EF), potential ecological risk factor (E r), potential ecological risk index (RI), correlation coefficient (r), and other indices were calculated. The results showed that the concentration of HMs in the leaf and bark in ascending order is as Cd<Cu<Pb<Zn and Cd<Pb<Cu<Zn, respectively. The EF results indicated that the main origin of all measured HMs except Zn is anthropogenic sources. Also, the principal component analysis (PCA) and spatial distribution proved that the concentration of HMs is mainly originated from the traffic and other human activities. On the other hand, the results RI presented that the majority of locations sampled in the study area was exposed to serious ecological risk in terms of surveyed HMs. The leaf and bark of U. carpinifolia can be applied as bio-indicators of the presence of heavy metals in the ambient air and ecological risk imposed by them.
Trace metals adsorbed onto fine particles can be transported long distances and ultimately deposited in Polar Regions via the cold condensation effect. This study indicated the possible sources of silver (Ag), cadmium (Cd), copper (Cu), lead (Pb), antimony (Sb) and zinc (Zn) in soils on the eastern slope of Mt. Gongga, eastern Tibetan Plateau, and deciphered the effects of vegetation and mountain cold condensation on their distributions with elevation. The metal concentrations in the soils were comparable to other mountains worldwide except the remarkably high concentrations of Cd. Trace metals with high enrichment in the soils were influenced from anthropogenic contributions. Spatially, the concentrations of Cu and Zn in the surface horizons decreased from 2000 to 3700 m a.s.l., and then increased with elevation, whereas other metals were notably enriched in the mid-elevation area (approximately 3000 m a.s.l.). After normalization for soil organic carbon, high concentrations of Cd, Pb, Sb and Zn were observed above the timberline. Our results indicated the importance of vegetation in trace metal accumulation in an alpine ecosystem and highlighted the mountain cold trapping effect on trace metal deposition sourced from long-range atmospheric transport.
This study uses a mathematical approach to assessing the inhibitory effect of Zn(2)(+)(0-10 mM, obtained from ZnCl2 and ZnSO4) in presence of NaCl (0-8%) and hydroxytyrosol (0-2588 mg/L), on a yeast cocktail formed by species Pichia galeiformis, Pichia kudriavzevii, Pichia manshurica and Candida thaimueangensis obtained from spoilt green olive packages. The logistic/probabilistic models were built in laboratory medium using a total of 1980 responses (1188 for NaCl and 792 for hydroxytyrosol). ZnCl2 showed significantly higher inhibitory effect than ZnSO4 in the presence of both NaCl (p < 0.033) and hydroxytyrosol (p < 0.009). NaCl did not interfere the effect of Zn(2)(+)while hydroxytyrosol, at high levels, had a slight antagonistic effect. According to models, Zn(2)(+)inhibits (p = 0.01) the yeast cocktail in the range 4.5-5.0 mM for ZnCl2, or 8.5-9.5 mM for ZnSO4. Therefore, this work confirms the fungicidal activity of zinc compounds (mainly ZnCl2) in synthetic medium, and also shows that the loss of zinc effectiveness in real green Spanish-style olive packaging is not due to the presence of NaCl or hydroxytyrosol, two of the most abundant chemical compounds in the product.
This study aimed to identify the aluminum (Al)-induced proteomes in tomato (Solanum lycopersicum, "Micro-Tom") after long-term exposure to the stress factor. Plants were treated in Magnavaca's solution (pH 4.5) supplemented with 7.5 μM Al(3+) ion activity over a 4 month period beginning at the emergence of flower buds and ending when the lower mature leaves started to turn yellow. Proteomes were identified using a 8-plex isobaric tags for relative and absolute quantification (iTRAQ) labeling strategy followed by a two-dimensional (high- and low-pH) chromatographic separation and final generation of tandem mass spectrometry (MS/MS) spectra of tryptic peptides on an LTQ-Orbitrap Elite mass spectrometer. Principal component analysis revealed that the Al-treatment had induced systemic alterations in the proteomes from roots and leaves but not seed tissues. The significantly changed root proteins were shown to have putative functions in Al(3+) ion uptake and transportation, root development, and a multitude of other cellular processes. Changes in the leaf proteome indicate that the light reaction centers of photosynthetic machinery are the primary targets of Al-induced stress. Embryo and seed-coat tissues derived from Al-treated plants were enriched with stress proteins. The biological processes involving these Al-induced proteins concur with the physiological and morphological changes, such as the disturbance of mineral homeostasis (higher contents of Al, P, and Fe and reduced contents of S, Zn, and Mn in Al-treated compared to nontreated plants) in roots and smaller sizes of roots and the whole plants. More importantly, the identified significant proteins might represent a molecular mechanism for plants to develop toward establishing the Al tolerance and adaptation mechanism over a long period of stress treatment.
Τhe present research investigates the partitioning of six selected toxic metals (Ni, Cr, Pb, Zn, Cu, and As) in eight sediment samples; half of them were collected from Elefsis Gulf, and the other half were taken from Koumoundourou Lake, Athens, Greece. Each one of them was treated by applying Tessier's five-step sequential extraction procedure. Regarding gulf sediments, the results indicated that Cu exhibits a strong affinity to the organic matter with percentages ranging from 65 to 78 %. Considerable amount of Zn (32-40 %) is bound to the Fe-Mn fraction and the non-residual fraction, while Cr and Ni are bound to the organic fraction, an observation that suits all toxic metals examined. Regarding lake sediments, Pb is the predominant metal bound to Fe-Mn (48-51 %). It is also noteworthy that the percentage of Zn bound to carbonated fraction (5-15 %), indicating biological availability. In conclusion, the application of several ecological risk indicators demonstrated that Elefsis Gulf sediments correspond to a moderate pollution level, with Pb and Ni being less bioavailable than in the lake's samples, in contrast to Zn which is more bioavailable. Finally, Koumoundourou Lakes' basin is characterized of "low risk."
In this study, some heavy metal (Cd, Pb, Ni, Fe, Co, Cr, Mn, Cu, and Zn) concentrations were measured in the blood serum samples of 25 patients who suffered from the multiple sclerosis (MS) disease living in two industrial regions of Isfahan, Iran, using inductively coupled plasma (ICP) instrument. Also, blood serum levels of heavy metals in 25 healthy people of Isfahan and 25 healthy people of Shiraz were analyzed as controls. In industrial regions, some of the heavy metals were also measured in the soils and food crop samples (wheat, rice, and onion). The results showed that the blood serum levels of Cd, Co, Ni, and Pb of MS patients (0.032, 0.56, 1.60, and 2.90 μg L(-1), respectively) were significantly higher than those of healthy people. These values exceeded the permissible ranges that are 0.08-0.50, 0.14-1.0, and 0.80-2.50 μg L(-1) for the Co, Ni, and Pb, respectively. The mean concentrations of Fe and Zn in the blood serum of MS patients (529 and 547 μg L(-1)) were significantly lower than those in the healthy people and also less than the acceptable ranges (700-1700 and 660-1100 μg L(-1), respectively). The target hazard quotients of Pb (2.23) and Cd (1.25) via wheat and Pb (1.34) via rice consumption were higher than one. Therefore, it is proposed that
 consumption of local contaminated food crops may have drastically increased the concentrations of heavy metals in the human blood serum of inhabitants of industrial regions.
NRD convertase, also termed Nardilysin, is a Zn(++) metalloendopeptidase that specifically cleaves the N-terminus of arginine and lysine residues into dibasic moieties. Although this enzyme was found located within the testis, its function in male reproduction is largely unknown. In addition, the precise distribution of this enzyme within germ cells remains to be determined.
To answer these questions, we developed an immuno-gold electron microscopy analysis to detect Nardilysin at ultrastructural level in mice. In addition, we performed a quantitative analysis of these gold particles to statistically estimate the distribution of Nardilysin in the different subcellular compartments of differentiating late spermatids/spermatozoa.
Expression of Nardilysin in wild-type mice was restricted to germ cells and markedly increased during the last steps of spermiogenesis. In elongated spermatids, we found the enzyme mainly localized in the cytoplasm, more precisely associated with two microtubular structures, the manchette and the axoneme. No labelling was detected over the membranous organelles of the spermatids. To test whether this localization is dependent of the functional microtubules organization of the flagella, we analysed the localization into a specific mouse mutant ebo/ebo (ébouriffé) known to be sterile due to an impairment of the final organization of the flagellum. In the ebo/ebo, the enzyme was still localized over the microtubules of the axoneme and over the isolated cytoplasmic microtubules doublets. Quantification of gold particles in wild-type and mutant flagella revealed the specific association of the enzyme within the microtubular area of the axoneme.
The strong and specific accumulation of Nardilysin in the manchette and axoneme suggests that the enzyme probably contributes either to the establishment of these specific microtubular structures and/or to their functional properties.
La NRD convertase aussi appelée Nardilysine, une Zn(++) metalloendopeptidase qui clive spécifiquement dans la région N terminale des résidus arginine et lysine des sites dibasiques, est impliquée dans la transformation/maturation des proprotéines. Le but de cette étude est de localiser cette enzyme durant la spermiogénèse afin de comprendre son rôle au cours de la maturation des spermatides.
La Nardilysine est révélée par immunohistochimie au niveau ultrastructural chez des souris contrôles fertiles et chez un mutant stérile (ébouriffé : ebo/ebo). Des analyses quantitatives sont effectuées par comptage des grains d’or colloïdal qui permettent de détecter la localisation spécifique de l’enzyme au cours de la croissance des spermatides dans des régions particulières.
L’expression de la Nardilysine chez les souris sauvages et stériles ebo/ebo est limitée aux cellules germinales avec une augmentation significative dans les étapes ultimes de la spermiogénèse. L’enzyme est fortement exprimée dans le cytoplasme des spermatides allongées et dans les structures microtubulaires, la manchette et le flagelle. Aucun marquage n’est observé au niveau des organites cellulaires des spermatides. Chez le mutant ebo/ebo, dont le flagelle est anormal, l’enzyme est toujours présente sur les doublets de microtubules du flagelle. La quantification des particules d’or chez la souris sauvage et chez le mutant révèle une association spécifique de l’enzyme avec les microtubules du flagelle.
L’accumulation spécifique de la Nardilysine au niveau de la manchette et du flagelle suggère que cette enzyme pourrait contribuer à l’établissement de ces structures microtubulaires particulières et/ou à leurs propriétés fonctionnelles.
Aim of the present study was to compare different methods, viz., Sheather's sugar flotation (SSF), Ziehl-Neelsen (ZN), Kinyoun's acid-fast method (KAF), safranin-methylene blue staining (SMB), and negative staining techniques such as nigrosin staining, light green staining, and malachite green staining for the detection of Cryptosporidium spp. oocysts in bovines.
A total of 455 fecal samples from bovines were collected from private, government farms and from the clinical cases presented to Department of Medicine, Veterinary College, Bengaluru. They were subjected for SSF, ZN, KAF, SMB and negative staining methods.
Out of 455 animal fecal samples screened 5.71% were found positive for Cryptosporidium spp. oocysts. The species were identified as Cryptosporidium parvum in calves and Cryptosporidium andersoni in adults based on the morphological characterization and micrometry of the oocysts.
Of all the techniques, fecal flotation with sheather's was found to be more specific and sensitive method for the detection of Cryptosporidium spp. oocysts. Among the conventional staining methods, the SMB gives better differentiation between oocysts and yeast. Among the three negative staining methods, malachite green was found sensitive over the other methods.
A phenylamine-oligothiophene-based fluorescent sensor 2TBEA was reported. This sensor exhibited highly selective, sensitive and rapid detection of Hg(2+) ion in THF/H2O (7/3, v/v) solution through fluorescence quenching. The detection was unaffected by the coexistence of other competitive metal cations including Na(+), K(+), Ag(+), Ca(2+), Fe(3+), Al(3+), Co(2+), Cu(2+), Ni(2+), Zn(2+), Pb(2+), Cd(2+), Fe(2+) and Cr(3+). A1:1 binding ratio for 2TBEA - Hg(2+) was demonstrated by Job's plot and mole-ratio curves. The coordination process was chemically reversible with EDTA. The detection limit was evaluated to be as low as 6.164×10(-8)M.
The study of interactions between metal ions and nucleobases, nucleosides, nucleotides, or nucleic acids has become an active research area in chemical, biological, and therapeutic fields. In this respect, the coordination behavior of nucleobase derivatives to transition metals was studied in order to get a better understanding about DNA-metal interactions in in vitro and in vivo systems. Two nucleobase derivatives, 3-benzoyl-1-[3-(thymine-1-yl)propamido]thiourea and 3-benzoyl-1-[3-(uracil-1-yl)propamido]thiourea, were synthesized and their dissociation constants were determined at different temperatures and 0.3 ionic strength. Potentiometric studies were carried out on the interaction of the derivatives towards some divalent metals in 50% v/v ethanol-water containing 0.3 mol.dm(-3) KCl, at five different temperatures. The formation constants of the metal complexes for both ligands follow the order: Cu(2+) > Ni(2+) > Co(2+) > Zn(2+) > Pb(2+) > Cd(2+) > Mn(2+). The thermodynamic parameters were estimated; the complexation process has been found to be spontaneous, exothermic, and entropically favorable.
Trace element bioavailability can play a role in several metabolic and physiological pathways known to be altered during the aging process. We aimed to explore the association of trace elements with increased lifespan by analyzing the circulating levels of seven trace elements (Cr, Cu, Fe, Mn, Mo, Se and Zn) in a cohort of healthy centenarians or 'dodgers' (≥100 years, free of major age-related diseases) in comparison with sex-matched younger elderly controls. Centenarians showed significant lower Cu (783.7 (76.7, 1608.9) vs 962.5 (676.3, 2064.4)μg/mL, P<0.001), but higher Fe (1.3 (0.4, 4.7) vs 1.1 (0.5, 8.4)μg/mL, P=0.003) and Se (85.7 (43.0, 256.7) vs 77.8 (24.3, 143.8)ng/mL, P=0.002) values compared with elderly controls. The logistic regression analysis identified the combination of Cu and Se as significant predictor variables associated with successful aging (P=0.001), while receiver operating characteristic (ROC) analysis confirmed that Cu and Se (either alone or in combination) were independent variables associated with healthy aging. An 'improved' trace element profile (reduced Cu and elevated Se, which are involved in key physiological processes) could play a role in the resistance to disease showed by centenarian 'dodgers', and, therefore, at least partly, be involved in the healthy aging phenotype shown by these subjects. These results should be confirmed in larger cohorts of other geographic/ethnic origin and the potential cause-effect association tested in mechanistic experimental settings.
The aim of this study was to investigate the changes in iron apparent absorption (IAA%) during and after iron and zinc supplementation in rats. The study was conducted on 6-week old male Wistar rats in 3 stages: 4-week period of adaptation to the control (C) and iron deficient (D) diets (stage I); 4-week period of supplementation with 10-time more iron (CSFe, DSFe), zinc (CSZn, DSZn) or both iron and zinc (CSFeZn, DSFeZn) compared to C diet (stage II); 2-week of post-supplementation period (rats were fed the same diets as in the adaptation period, stage III). IAA% was measured in five consecutive days directly after introducing and discontinuation of iron and zinc supplementation as well as in the end of stage II (days: 22-24th) and stage III (days: 8-10th). Overall in the second day after introducing and in the fifth day after discontinuation of iron or iron and zinc supplementation, the IAA% had undergone to the level compatible with the values in the end of each stage. At the end of stage II, IAA% in CSFeZn (54.1 ± 2.7%) rats was not different from the IAA% in CSFe rats (53.9 ± 1.9%), but in DSFeZn group IAA% (49.4 ± 2.1%) was significantly lower than in DSFe (57.4 ± 2.3%) group. Moreover, IAA% after stage II and stage III in DSZn group was significantly lower (39.2 ± 2.8% and 38.6 ± 2.6%, respectively) than in group D (60.7 ± 1.9% and 54.3 ± 3.0%, respectively). In conclusion, zinc administered simultaneously with iron (Zn:Fe weight ratio=1:1) decreased IAA% in adult rats fed on iron deficient
 diet, but not in rats fed on control diet. IAA% reduction by zinc supplementation has been extended to 10 days after discontinuation of the treatment. Adaptation of the rats to high doses of iron or iron and zinc and also to the cessation of these treatments was relatively fast. However, IAA% was stabilized faster after introducing the supplementation than it's discontinuation.
Dietary intake of macro-, trace and toxic elements was determined among the young adult population of Eastern Poland. The study was performed in 2011-2013 and involved 583 participants living in Lublin and its province. Dietary intakes of metals were determined using a 24h dietary recall technique and a market basket method. The analytical quantification of As, Ca, Cd, Cu, Fe, K, Mg, Mn, Mo, Na, Ni, Pb, Se and Zn was performed using ICP-MS technique, whereas the content of mercury was determined using the Mercury Analyzer. Performed investigations revealed that daily dietary intakes of the majority of the study elements (macro- and trace) and toxic elements such as As, Pb or Hg are within the range of reference values. However, high consumption of Na and improper Na/K ratio combined with low intake of Mg may be harmful to the health of the population. Moreover, obtained data suggest that the risk of developing diseases among population in Eastern Poland related to high exposure to Ni and Cd absorbed from foodstuffs was high.
A study was conducted to determine the effect of high dietary zinc (Zn) oxide on trace element accumulation in various organs with special emphasis on the kidney. A total of 40 weaned piglets were allocated into two groups with 16 and 24 piglets each receiving a diet containing normal (NZn; 100mg Zn/kg) or high (HZn; 2,100mg Zn/kg) Zn concentration, respectively. After two weeks, eight piglets from each treatment were killed and organ samples were taken. Eight piglets from the remaining 16 pigs fed HZn diets were changed to NZn diets (CZn). All remaining piglets were killed after another two weeks for organ sampling. Trace element concentration was determined in the jejunum, liver, kidney, pancreas, bone (metacarpal IV), spleen, lung, thymus, tonsils and lymph nodes of jejunum, ileum and colon. Kidney mRNA expression of Zn transporter ZnT1 and ZIP4, genes involved in Cu metabolism (Ctr1, Atox1, SOD1, ATP7A, CCS, CP) and divalent metal ion transport (DMT1) and binding (MT-1a, MT-2b, MT-3) were determined. The Zn concentration in jejunum, liver, pancreas tissue and metacarpal IV was higher (P<0.05) in HZn group compared with NZn and CZn groups. Trace element concentration in organs of CZn pigs was similar to those fed NZn diets. Zn concentration in muscle, lung and lymphatic organs as thymus, tonsils, spleen and lymph nodes of jejunum, ileum and colon did not differ between the groups. Zn and Cu were positively correlated (R=0.67; P<0.05) in the kidney. No significant differences for Cu chaperones, Cu transporters and Cu-dependent factors were determined despite decreased expression of Atox1 after two weeks and increased Ctr1 expression over time in the HZn group. Expression of MT-1a, MT-2b and MT-3 were significantly higher in HZn fed pigs with most pronounced effects for MT-1a > MT-2b > MT-3. Gene expression of MTs in pigs fed CZn diets did not differ from pigs fed NZn diets. The data suggest that high dietary Zn feeding in pigs leads to Cu co-accumulation in the kidney of pigs with minor effect on genes relevant for Cu metabolism. In addition, the organ Zn and Cu accumulation is reversible after two weeks of withdrawal of high dietary Zn.
The density functional theory (DFT) method has been performed to study the effects of CO and CO2 on the desulfurization of H2S over a ZnO sorbent. It shows that COS is inevitably formed on the ZnO(101¯0) surface, which tends to be adsorbed onto the surface via a S-C bond binding with either a long or a short Zn-O bond. Potential energy profiles for the COS formation via reactions between H2S and CO, and H2S and CO2 on the ZnO(101¯0) surface have been constructed. In the presence of CO, the dissociated active S of H2S reacting with CO leads to the formation of COS, and the activation energy of the rate-determining step is 87.7 kJ mol(-1). When CO2 is present, the linear CO2 is first transferred to active CO2 in a triplet state, and then combines with active S to form COS with the highest energy barrier of 142.4 kJ mol(-1). Rate constants at different temperatures show that the formation of COS via the reaction of CO and H2S is easier than that of CO2 and H2S over the ZnO surface.
Peptide radical cations that contain an aromatic amino acid residue cleave to give [zn - H]˙⁺ ions with [b2 - H - 17]˙⁺ and [c1 - 17](+) ions, the dominant products in the dissociation of [zn - H]˙⁺, also present in lower abundance in the CID spectra. Isotopic labeling in the aromatic ring of [Yπ˙GG](+) establishes that in the formation of [b2 - H - 17]˙⁺ ions a hydrogen from the δ-position of the Y residue is lost, indicating that nucleophilic substitution on the aromatic ring has occurred. A preliminary DFT investigation of nine plausible structures for the [c1 - 17](+) ion derived from [Y(π)˙GG](+) shows that two structures resulting from attack on the aromatic ring by oxygen and nitrogen atoms from the peptide backbone have significantly better energies than other isomers. A detailed study of [Y(π)˙GG](+) using two density functionals, B3LYP and M06-2X, with a 6-31++G(d,p) basis set gives a higher barrier for attack on the aromatic ring of the [zn - H]˙⁺ ion by nitrogen than by the carbonyl oxygen. However, subsequent rearrangements involving proton transfers are much higher in energy for the oxygen-substituted isomer leading to the conclusion that the [c1 - 17](+) ions are the products of nucleophilic attack by nitrogen, protonated 2,7-dihydroxyquinoline ions. The [b2 - H - 17]˙⁺ ions are formed by loss of glycine from the same intermediates involved in the formation of the [c1 - 17](+) ions.
Unraveling the drivers controlling the response and adaptation of biological communities to environmental change, especially anthropogenic activities, is a central but poorly understood issue in ecology and evolution. Comparative genomics studies suggest that lateral gene transfer (LGT) is a major force driving microbial genome evolution, but its role in the evolution of microbial communities remains elusive. To delineate the importance of LGT in mediating the response of a groundwater microbial community to heavy metal contamination, representative Rhodanobacter reference genomes were sequenced and compared to shotgun metagenome sequences. 16S rRNA gene-based amplicon sequence analysis indicated that Rhodanobacter populations were highly abundant in contaminated wells with low pHs and high levels of nitrate and heavy metals but remained rare in the uncontaminated wells. Sequence comparisons revealed that multiple geochemically important genes, including genes encoding Fe(2+)/Pb(2+) permeases, most denitrification enzymes, and cytochrome c553, were native to Rhodanobacter and not subjected to LGT. In contrast, the Rhodanobacter pangenome contained a recombinational hot spot in which numerous metal resistance genes were subjected to LGT and/or duplication. In particular, Co(2+)/Zn(2+)/Cd(2+) efflux and mercuric resistance operon genes appeared to be highly mobile within Rhodanobacter populations. Evidence of multiple duplications of a mercuric resistance operon common to most Rhodanobacter strains was also observed. Collectively, our analyses indicated the importance of LGT during the evolution of groundwater microbial communities in response to heavy metal contamination, and a conceptual model was developed to display such adaptive evolutionary processes for explaining the extreme dominance of Rhodanobacter populations in the contaminated groundwater microbiome.
Lateral gene transfer (LGT), along with positive selection and gene duplication, are the three main mechanisms that drive adaptive evolution of microbial genomes and communities, but their relative importance is unclear. Some recent studies suggested that LGT is a major adaptive mechanism for microbial populations in response to changing environments, and hence, it could also be critical in shaping microbial community structure. However, direct evidence of LGT and its rates in extant natural microbial communities in response to changing environments is still lacking. Our results presented in this study provide explicit evidence that LGT played a crucial role in driving the evolution of a groundwater microbial community in response to extreme heavy metal contamination. It appears that acquisition of genes critical for survival, growth, and reproduction via LGT is the most rapid and effective way to enable microorganisms and associated microbial communities to quickly adapt to abrupt harsh environmental stresses.
Coarse (particulate matter (PM)2.5-10) and fine (PM2.5) fraction of PM samples were collected between December 2014 and February 2015 at an urban sampling site located at the Bolu plain, of the western Black Sea region of Turkey. The collected samples were analyzed in terms of metals (Al, As, Ba, Ca, Cu, Fe, K, Mg, Mn, Na, Pb, S, Si, Ti, V, and Zn); elemental carbon (EC); and organic carbon (OC). Elevated concentrations measured in this wintertime study were ∼7.8 μg/m(3) in sum of PM2.5-10 and PM2.5 for SO4 (2-) and ∼59.9 μg/m(3) in PM2.5 for OC. The contributions of primary and secondary OC (POC and SOC, respectively) to total OC mass were 60 and 40 %, respectively, while contribution of SOC to OC increased by up to 74 % in stable atmospheric conditions. The significantly high OC/EC ratio (∼10.1) found in this study relative to other wintertime studies was attributed to increased emissions from residential heating and lower mixing height observed during
 the study. Two and three factors were resolved by factor analysis for PM2.5-10 and PM2.5, respectively. Two Saharan dust episodes were observed on 31 January and 1 February, during which crustal PM components such as Mg, Si, and Al increased as much as three times their background concentrations.
The synthesis and properties of a new compound, viz., (N,N'-[1,10-phenanthroline-4,7-diyldi((E)methylylidene)]bis(1,10-phenanthrolin-5-amine) (1), is described. Compound 1 can be used as a selective fluorescent Zn(2+) sensor in buffered solution. Furthermore, 1 induces turn on fluorogenic response to H(+) ions. Finally, it is shown that an OR logic gate can be constructed with 1 by using Zn(2+) and H(+) as two-inputs. Graphical Abstract In this paper, the design, synthesis and physicochemical properties of a new compound 1 based on 1,10-phenanthroline scaffold, is reported. It is noted that 1 can be used as a selective fluorescent Zn(2+) sensor in 0.01 M HEPES buffer containing DMF (2 % v/v, pH = 7.4) at room temperature. Furthermore, the spectrophotometric results suggest that compound 1 can be used as a pH reporter in highly acidic conditions (pH < 5). Finally, it was also shown that an OR logic gate can be constructed with 1 by using Zn(2+) and H(+) as two-inputs.
To assess the efficiency of seven treatments including biochars produced from dried faecal matter and manures as stabilizing agents of cadmium (Cd)-spiked soils, lettuce was grown in glasshouse on two contrasting soils. The soils used were moderately fertile silty loam and less fertile sandy loam and the applied treatments were 7 % w/w. The reduction of bioavailable Cd (ammonium nitrate extractable) and its phytoavailability for lettuce were used as assessment criteria in the evaluation of stabilization performance of each treatment. Moreover, the agronomic values of the treatments were also investigated. Ammonium nitrate extraction results indicated that faecal matter biochar, cow manure biochar and lime significantly reduced bioavailable Cd by 84-87, 65-68 and 82-91 %, respectively, as compared to the spiked controls. Unpredictably, coffee husk biochar induced significant increment of Cd in NH4NO3 extracts. The immobilization potential of faecal matter biochar and lime were superior than the other treatments. However, lime and egg shell promoted statistically lower yield and P, K and Zn concentrations response of lettuce plants compared to the biochar treatments. The lowest Cd and highest P tissue concentrations of lettuce plants were induced by faecal matter and cow manure biochar treatments in both soils. Additionally, the greatest Cd phytoavailability reduction for lettuce was induced by poultry litter and cow manure biochars in the silty loam soil. Our results indicate that faecal matter and animal manure biochars have shown great potential to promote Cd immobilization and lettuce growth response in heavily contaminated agricultural fields.
In recent years, biodegradable magnesium alloys emerge as a new class of biomaterials for tissue engineering and medical devices. Deploying biodegradable magnesium-based materials not only avoids a second surgical intervention for implant removal but also circumvents the long-term foreign body effect of permanent implants. However, these materials are often subjected to an uncontrolled and fast degradation, acute toxic responses and rapid structural failure presumably due to a localized, too rapid corrosion process. The patented Mg-Nd-Zn-based alloys (JiaoDa BioMg [JDBM]) have been developed in Shanghai Jiao Tong University in recent years. The alloy series exhibit lower biodegradation rate and homogeneous nanophasic degradation patterns as compared with other biodegradable Mg alloys. The in vitro cytotoxicity tests using various types of cells indicate excellent biocompatibility of JDBM. Finally, bone implants using JDBM-1 alloy and cardiovascular stents using JDBM-2 alloy have been successfully fabricated and in vivo long-term assessment via implantation in animal model have been performed. The results confirmed the reduced degradation rate in vivo, excellent tissue compatibility and long-term structural and mechanical durability. Thus, this novel Mg-alloy series with highly uniform nanophasic biodegradation represent a major breakthrough in the field and a promising candidate for manufacturing the next generation biodegradable implants.
A study was undertaken to investigate the effect of organic zinc (zinc nicotinate, Zn-nic) supplementation (6, 9, and 12 ppm) compared to inorganic zinc (12 ppm) on growth performance, hematology, serum biochemical constituents oxidative stress, and immunity in weaned female Sprague-Dawley rats.
A 48 weaned rats (285.20±1.95 g) were randomly distributed to 4 dietary treatments with 6 replicates in each and reared in polypropylene cages for 10 weeks. Basal diet (BD) was formulated with purified ingredients without zinc (Zn). Four dietary treatments were prepared by adding 12 ppm Zn from ZnCO3 (control) and 6, 9, and 12 ppm Zn from Zn-nic to the BD. On 42(nd) day, blood was collected by retro-orbital puncture for analyzing hematological constituents, glucose, cholesterol, alkaline phosphatase, total protein, albumin, and globulin and antioxidant enzyme activities. At 43(rd) day, rats were antigenically challenged with sheep red blood cell (RBC) to assess humoral immune response and on 70(th) day cell-mediated immune response.
Weekly body weight gains, daily feed intake, blood hematological constituents (white blood cell, RBC, hemoglobin concentration, packed cell volume, mean corpuscular volume, lymphocyte, monocyte, and granulocyte concentration) and serum glucose, total protein levels were comparable among the rats feed Zn from ZnCO3 and Zn-nic (6, 9, and 12 ppm). Serum cholesterol reduced with organic Zn supplementation at either concentration (6-12 ppm). Serum globulin concentration reduced (p<0.05) with 6 ppm Zn-nic supplementation compared to other dietary treatments. Lipid peroxidation lowered (p<0.05) reduced with 12 ppm organic Zn; thiobarbituric acid reacting substances and protein carbonyls concentrations in liver reduced (p<0.05) with 9 and 12 ppm levels of organic Zn supplementation compared to 12 ppm Zn supplementation from inorganic source. RBC catalase and glutathione peroxidase enzymes activities were highest (p<0.05) in rats supplemented with 12 ppm Zn-nic, followed by 9 ppm. Comparable immune response (humoral and cell-mediated) was observed between 12 ppm inorganic Zn and 9 ppm organic Zn and higher (p<0.05) immune response was noticed at 12 ppm Zn-nic supplementation.
Based on the results, it is concluded that dietary Zn concentration can be reduced by 50% (6 ppm) as Zn nicotinate without affecting growth performance, hemato-biochemical constituents, antioxidant status, and immunity. In addition, replacement of 12 ppm inorganic Zn with 12 ppm organic Zn significantly improved antioxidant status and immune response.
Nano minerals are widely used in diversified sectors including agriculture, animal, and food systems. Hence, their multiple uses provoke the production of nanomaterials at the laboratory level, which can be achieved through physical, chemical or biological methods. Every method is having its own merits and demerits. But keeping all in mind, chemical methods are more beneficial, as uniform nano-sized particles can be produced, but the use of corrosive chemicals is the main demerits. When it comes to environmental issues, biological methods are better as these are free from corrosive chemicals, but maintaining the culture media is the disadvantage. For animal feeding, chemical methods are mostly followed to produce nano minerals as it is cheap and less time consuming. These nano minerals also showed their significant effects even at lower doses of recommendations than the conventional mineral sources. These nano minerals have significant growth promoting, immuno-modulatory, antibacterial effects than the conventional counterparts. They also alter the rumen fermentation pattern on supplementation in the animal feeds. Apart from these, nano minerals are reported to enhance the reproduction in the livestock and poultry.
This study was aimed to determine the prevalence of bovine tuberculosis (bTB) in slaughtered cattle in Bauchi State, Nigeria. The cause (s) of grossly suspected bTB lesions encountered at the abattoirs during post-mortem (PM), as whether due to Mycobacterium bovis alone or together with other acid fast bacilli (AFB).
A cross-sectional abattoir based study was conducted on 800 cattle slaughtered in the Northern, Central and Southern zonal abattoirs of Bauchi State, Nigeria, from June to August 2013; using PM meat inspection, Ziehl-Neelsen staining (ZN) and confirmatory polymerase chain reaction (PCR) techniques.
The occurrence of bTB lesions from the organs of slaughtered cattle in Bauchi State, showed that the lungs had the highest number of suspected tissues 65 (54.20%), followed by the lymph nodes 28 (23.30%) while the heart, liver, spleen, intestines and mammary glands had the other 8.3%, 6.7%, 5.0%, 1.7%, and 0.8%, suspected tissues respectively. By ZN microscopic staining all 100% (2/2) of the intestines were positive for bTB, followed by the heart with 50% (5/10), then the lungs 29.23% (19/65); while the liver, lymph nodes, and spleen had 25%, 21.43% and 16.67% respectively were tested positive for bTB. It was only the mammary gland that tested negative for bTB in all the suspected tissues sampled. By PCR, the intestines had the highest positive bTB with 100% (2/2), followed by the liver with 12.5% (1/8), and then the lungs with 7.8% (5/65). The lymph nodes had 7.14% (2/28) tissues that tested positive for bTB. However, the spleen, heart and mammary gland were all tested negative with 0%; indicating that the false positive for bTB detected
 by ZN were confirmed by PCR. While based on the location of the abattoirs in the three senatorial zones of Bauchi State, Bauchi zonal abattoir had the highest number of suspected bTB cases 75 (62.50%), followed by Katagum zonal slaughter house with 32 (26.7%) and then Misau with 13 (10.8%). By the ZN staining technique, there were 25 (33.33%) positivity in Bauchi Zonal abattoir, while Katagum and Misau abattoirs had 9 (28.13%) and 1 (7.72%) positive respectively. By the PCR technique, 9 (12.00%), 1 (3.13%) and 0 (0.00%) positive cases were recorded for Bauchi, Katagum and Misau abattoirs respectively.
The present study estimated the prevalence rate of bTB in Bauchi State, using PM, ZN and PCR techniques at 15.0%, 29.16% and 8.33%, respectively. Bovine TB lesions found at PM were not all due to M. bovis alone, as other MTBC and AFB organisms may cause bTB-like lesions that were excluded by PCR specific primers. The prevalence of bTB was higher in Bauchi abattoir that supplies larger population of the state with beef. These findings also demonstrate the urgent need for public health authorities in the state to intervene in the control of the zoonotic bTB.
A simple, low cost, and highly sensitive electrochemical sensor, based on a Nafion/ionic liquid/graphene composite modified screen-printed carbon electrode (N/IL/G/SPCE) was developed to determine zinc (Zn(II)), cadmium (Cd(II)), and lead (Pb(II)) simultaneously. This disposable electrode shows excellent conductivity and fast electron transfer kinetics. By in situ plating with a bismuth film (BiF), the developed electrode exhibited well-defined and separate peaks for Zn(II), Cd(II), and Pb(II) by square wave anodic stripping voltammetry (SWASV). Analytical characteristics of the BiF/N/IL/G/SPCE were explored with calibration curves which were found to be linear for Zn(II), Cd(II), and Pb(II) concentrations over the range from 0.1 to 100.0 ng L(-1). With an accumulation period of 120 s detection limits of 0.09 ng mL(-1), 0.06 ng L(-1) and 0.08 ng L(-1) were obtained for Zn(II), Cd(II) and Pb(II), respectively using the BiF/N/IL/G/SPCE sensor, calculated as 3σ value of the blank. In addition, the developed electrode displayed a good repeatability and reproducibility. The interference from other common ions associated with Zn(II), Cd(II) and Pb(II) detection could be effectively avoided. Finally, the proposed analytical procedure was applied to detect the trace metal ions in drinking water samples with satisfactory results which demonstrates the suitability of the BiF/N/IL/G/SPCE to detect heavy metals in water samples and the results agreed well with those obtained by inductively coupled plasma mass spectrometry.
Based on an organic ligand involving both carboxylate and tetrazole groups, a chemically stable Zn(II) metal-organic framework has been rationally synthesized and behaves as a fluorescence chemosensor for the highly selective and sensitive detection of picric acid, an extremely hazardous and strong explosive.
It has been proven that carbon nanoparticles or diesel exhaust particles stimulate platelet activation. However, the effect of fine particle matter (PM2.5 ) on platelet activation remains unknown, which motivates this study.
PM2.5 samples were collected in an urban area of Zhengzhou, China. To study the morphological characteristics and the mass concentrations of trace elements of PM2.5 samples, a filed-emission scanning electron microscope, the Image-J software, and an inductively coupled plasma mass spectrometry were used. Washed human platelets or platelet-rich-plasma were used to study the effect of PM2.5 on platelet aggregation, P-selectin expression, or platelet signaling pathways. The cytotoxicity in platelets exposed to PM2.5 was evaluated by a lactate dehydrogenase assay kit. In addition, platelet adhesion and spreading were studied on collagen-coated surfaces in stable conditions.
The filed-emission scanning electron microscope scanning showed that PM2.5 samples varied in shape and size distributions. The mean equivalent spherical diameter of these particles was 1.97 ± 0.04 μm, of which 82.40% were particles with equivalent spherical diameters of less than 2.5 μm. The mass concentration of Ca was higher than that of other elements. The other elements followed the trend of Al>Fe>Zn>Mg>Pb>K>Mn>Cu>Ti>Ba>As>Sr>Sn>Sb>Cd>B>Se>Mo>Ag>Ni>TI>V>Co. Furthermore, pretreatment of PM2.5 significantly inhibited rather than potentiated collagen-induced platelet aggregation and P-selectin expression, whereas it had no significant effect on ADP-induced platelet aggregation and P-selectin expression. The lactate dehydrogenase analysis showed trivial cytotoxic effect of PM2.5 exposure on platelets. Pretreatment of PM2.5 inhibited platelet adhesion on immobilized collagen-coated surfaces; however, it almost did not impact the platelet spreading. Immunoblotting analysis indicated that PM2.5 reduced collagen-induced phosphorylation of phospholipase C gamma-2 (PLCγ2) at Tyr759, Akt at Ser473, and glycogen synthase kinase 3β (GSK3β) at Ser9.
PM2.5 attenuated collagen-induced platelet aggregation, α-granule secretion and adhesion, with the potential mechanism of impairing PLCγ2, Akt, and GSK3β signaling. © 2016 Wiley Periodicals, Inc. Environ Toxicol, 2016.
With a continuously increasing aging population and the improvement of living standards, large demands of biomaterials are expected for a long time to come. Further development of novel biomaterials, that are much safer and of much higher quality, in terms of both biomedical and mechanical properties, are therefore of great interest for both the research scientists and clinical surgeons. Compared with the conventional crystalline metallic counterparts, bulk metallic glasses have unique amorphous structures, and thus exhibit higher strength, lower Young's modulus, improved wear resistance, good fatigue endurance, and excellent corrosion resistance. For this purpose, bulk metallic glasses (BMGs) have recently attracted much attention for biomedical applications. This review discusses and summarizes the recent developments and advances of bulk metallic glasses, including Ti-based, Zr-based, Fe-based, Mg-based, Zn-based, Ca-based and Sr-based alloying systems for biomedical applications. Future research directions will move towards overcoming the brittleness, increasing the glass forming ability (GFA) thus obtaining corresponding bulk metallic glasses with larger sizes, removing/reducing toxic elements, and surface modifications.
Bulk metallic glasses (BMGs), also known as amorphous alloys or liquid metals, are relative newcomers in the field of biomaterials. They have gained increasing attention during the past decades, as they exhibit an excellent combination of properties and processing capabilities desired for versatile biomedical implant applications. The present work reviewed the recent developments and advances of biomedical BMGs, including Ti-based, Zr-based, Fe-based, Mg-based, Zn-based, Ca-based and Sr-based BMG alloying systems. Besides, the critical analysis and in-depth discussion on the current status, challenge and future development of biomedical BMGs are included. The possible solution to the BMG size limitation, the brittleness of BMGs has been proposed.
Access to laboratory diagnosis can be a challenge for individuals suspected of Buruli Ulcer (BU). Our objective was to develop a clinical score to assist clinicians working in resource-limited settings for BU diagnosis.
Between 2011 and 2013, individuals presenting at Akonolinga District Hospital, Cameroon, were enrolled consecutively. Clinical data were collected prospectively. Based on a latent class model using laboratory test results (ZN, PCR, culture), patients were categorized into high, or low BU likelihood. Variables associated with a high BU likelihood in a multivariate logistic model were included in the Buruli score. Score cut-offs were chosen based on calculated predictive values. Of 325 patients with an ulcerative lesion, 51 (15.7%) had a high BU likelihood. The variables identified for the Buruli score were: characteristic smell (+3 points), yellow color (+2), female gender (+2), undermining (+1), green color (+1), lesion hyposensitivity (+1), pain at rest (-1), size >5cm (-1), locoregional adenopathy (-2), age above 20 up to 40 years (-3), or above 40 (-5). This score had AUC of 0.86 (95%CI 0.82-0.89), indicating good discrimination between infected and non-infected individuals. The cut-off to reasonably exclude BU was set at scores <0 (NPV 96.5%; 95%CI 93.0-98.6). The treatment threshold was set at a cut-off ≥4 (PPV 69.0%; 95%CI 49.2-84.7). Patients with intermediate BU probability needed to be tested by PCR.
We developed a decisional algorithm based on a clinical score assessing BU probability. The Buruli score still requires further validation before it can be recommended for wide use.
Zinc thiocyanate complexes have been found to be biologically active compounds. Zinc is also an essential element for the normal function of most organisms and is the main constituent in a number of metalloenzyme proteins. Pyrimidine and aminopyrimidine derivatives are biologically very important as they are components of nucleic acids. Thiocyanate ions can bridge metal ions by employing both their N and S atoms for coordination. They can play an important role in assembling different coordination structures and yield an interesting variety of one-, two- and three-dimensional polymeric metal-thiocyanate supramolecular frameworks. The structure of a new zinc thiocyanate-aminopyrimidine organic-inorganic compound, (C6H9ClN3)2[Zn(NCS)4]·2C6H8ClN3·2H2O, is reported. The asymmetric unit consist of half a tetrathiocyanatozinc(II) dianion, an uncoordinated 4-amino-5-chloro-2,6-dimethylpyrimidinium cation, a 4-amino-5-chloro-2,6-dimethylpyrimidine molecule and
 a water molecule. The Zn(II) atom adopts a distorted tetrahedral coordination geometry and is coordinated by four N atoms from the thiocyanate anions. The Zn(II) atom is located on a special position (twofold axis of symmetry). The pyrimidinium cation and the pyrimidine molecule are not coordinated to the Zn(II) atom, but are hydrogen bonded to the uncoordinated water molecules and the metal-coordinated thiocyanate ligands. The pyrimidine molecules and pyrimidinium cations also form base-pair-like structures with an R2(2)(8) ring motif via N-H...N hydrogen bonds. The crystal structure is further stabilized by intermolecular N-H...O, O-H...S, N-H...S and O-H...N hydrogen bonds, by intramolecular N-H...Cl and C-H...Cl hydrogen bonds, and also by π-π stacking interactions.
From the viewpoint of crystal engineering, the construction of crystalline polymeric materials requires a rational choice of organic bridging ligands for the self-assembly process. Multicarboxylate ligands are of particular interest due to their strong coordination activity towards metal ions, as well as their various coordination modes and versatile conformations. The structural chemistry of dicarboxylate-based coordination polymers of transition metals has been developed through the grafting of N-containing organic linkers into carboxylate-bridged transition metal networks. A new luminescent two-dimensional zinc(II) coordination polymer containing bridging 2,2-dimethylsuccinate and 4,4'-bipyridine ligands, namely poly[[aqua(μ2-4,4'-bipyridine-κ(2)N:N')bis(μ3-2,2-dimethylbutanedioato)-κ(4)O(1),O(1'):O(4):O(4');κ(5)O(1):O(1),O(4):O(4),O(4')-dizinc(II)] dihydrate], {[Zn2(C6H8O4)2(C10H8N2)(H2O)]·2H2O}n, has been synthesized under hydrothermal conditions and characterized by single-crystal X-ray diffraction and elemental, IR and thermogravimetric analyses. In the structure, the 2,2-dimethylsuccinate ligands link linear tetranuclear Zn(II) subunits into one-dimensional chains along the c axis. 4,4'-Bipyridine acts as a tethering ligand expanding these one-dimensional chains into a two-dimensional layered structure. Hydrogen-bonding interactions between the water molecules (both coordinated and free) and carboxylate O atoms strengthen the packing of the layers. Furthermore, the luminescence properties of the complex were investigated. The compound exhibits a blue photoluminescence in the solid state at room temperature and may be a good candidate for potential hybrid inorganic-organic photoactive materials.
Bimetallic macrocyclic complexes have attracted the attention of chemists and various organic ligands have been used as molecular building blocks, but supramolecular complexes based on semi-rigid organic ligands containing 1,2,4-triazole have remained rare until recently. It is easier to obtain novel topologies by making use of asymmetric semi-rigid ligands in the self-assembly process than by making use of rigid ligands. A new semi-rigid ligand, 3-[(pyridin-4-ylmethyl)sulfanyl]-5-(quinolin-2-yl)-4H-1,2,4-triazol-4-amine (L), has been synthesized and used to generate two novel bimetallic macrocycle complexes, namely bis{μ-3-[(pyridin-4-ylmethyl)sulfanyl]-5-(quinolin-2-yl)-4H-1,2,4-triazol-4-amine}bis[(methanol-κO)(nitrato-κ(2)O,O')nickel(II)] dinitrate, [Ni2(NO3)2(C17H14N6S)2(CH3OH)2](NO3)2, (I), and bis{μ-3-[(pyridin-4-ylmethyl)sulfanyl]-5-(quinolin-2-yl)-4H-1,2,4-triazol-4-amine}bis[(methanol-κO)(nitrato-κ(2)O,O')zinc(II)] dinitrate, [Zn2(NO3)2(C17H14N6S)2(CH3OH)2](NO3)2, (II), by solution reactions with the inorganic salts M(NO3)2 (M = Ni and Zn, respectively) in mixed solvents. In (I), two Ni(II) cations with the same coordination environment are linked by L ligands through Ni-N bonds to form a bimetallic ring. Compound (I) is extended into a two-dimensional network in the crystallographic ac plane via N-H...O, O-H...N and O-H...O hydrogen bonds, and neighbouring two-dimensional planes are parallel and form a three-dimensional structure via π-π stacking. Compound (II) contains two bimetallic rings with the same coordination environment of the Zn(II) cations. The Zn(II) cations are bridged by L ligands through Zn-N bonds to form the bimetallic rings. One type of bimetallic ring constructs a one-dimensional nanotube via O-H...O and N-H...O hydrogen bonds along the crystallographic a direction, and the other constructs zero-dimensional molecular cages via O-H...O and N-H...O hydrogen bonds. They are interlinked into a two-dimensional network in the ac plane through extensive N-H...O hydrogen bonds, and a three-dimensional supramolecular architecture is formed via π-π interactions between the centroids of the benzene rings of the quinoline ring systems.
Zinc the essential trace element, plays a significant role in the brain development and in the proper brain functions at every stage of life. Misbalance of zinc (Zn(2+)) ions in the central nervous system is involved in the pathogenesis of numerous neurodegenerative disorders such as Alzheimer's disease, Depression, and Epilepsy. In brain, Zn(2+) has been identified as a ligand, capable of activating and inhibiting the receptors including the NMDA-type glutamate receptors (NMDARs), GABAA receptors, nicotinic acetylcholine receptors (nAChRs), glycine receptors (glyR) and serotonin receptors (5-HT3). Recently GPR39 has been identified as a zinc-specific receptor, widely expressed in brain tissues including the frontal cortex, amygdala, and hippocampus. GPR39, when binding with Zn(2+) has shown promising therapeutic potentials. This review presents current knowledge regarding the role of GPR39 zinc sensing receptor in brain, with a focus on Alzheimer's disease and Epilepsy. Although the results are encouraging, further research is needed to clarify zinc and GPR39 role in the treatment of Alzheimer's disease and Epilepsy.
Contaminated soil has become a growing issue in recent years. The most common technique used to remove contaminants (such as metals) from the soil is the soil washing process. However, this process produces a final effluent containing chelating agents (i.e., ethylenediaminedisuccinic acid, also known as EDDS) and extracted metals (i.e., Cu, Fe, and Zn) at concentrations higher than discharge limits allowed by the Italian and Brazilian environmental law. Therefore, it is necessary to develop further treatments before its proper disposal or reuse. In the present study, soil washing tests were carried out through two sequential paths. Moreover, different artificial sunlight-driven photocatalytic treatments were used to remove Cu, Zn, Fe, and EDDS from soil washing effluents. Metal concentrations after the additional treatment were within the Brazilian and Italian regulatory limits for discharging in public sewers. The combined TiO2-photocatalytic processes applied were enough to decontaminate the effluents, allowing their reuse in soil washing treatment. Ecotoxicological assessment using different living organisms was carried out to assess the impact of the proposed two-step photocatalytic process on the effluent ecotoxicity. Graphical Abstract ᅟ.
The contents of Cd, Cu, Fe, Mn, Ni, Pb, and Zn in leaves of Typha latifolia (broadleaf cattail), water and bottom sediment from 72 study sites designated in different regions of Poland were determined using atomic absorption spectrometry. The aim of the study was to evaluate potential use of T. latifolia in biomonitoring of trace metal pollution. The self-organizing feature map (SOFM) identifying groups of sampling sites with similar concentrations of metals in cattail leaves was able to classify study sites according to similar use and potential sources of pollution. Maps prepared for water and bottom sediment showed corresponding groups of sampling sites which suggested similarity of samples features. High concentrations of Fe, Cd, Cu, and Ni were characteristic for industrial areas. Elevated Pb concentrations were noted in regions with intensive vehicle traffic, while high Mn and Zn contents were reported in leaves from the agricultural area. Manganese content in leaves of T. latifolia was high irrespectively of the concentrations in bottom sediments and water so cattail can be considered the leaf accumulator of Mn. Once trained, SOFMs can be applied in ecological investigations and could form a future basis for recognizing the type of pollution in aquatic environments by analyzing the concentrations of elements in T. latifolia.
We aimed to synthesize a new series of triazacyclononanyl-porphyrins (4 and 5) with the potential ability to bind DNA. For this, the free-base porphyrin 4 and the corresponding Zn(ii)-complex 5 were synthesized by the Schiff base formation reaction. The binding ability of the porphyrin derivatives 4 and 5 with DNA from calf-thymus was studied by UV-vis and emission spectroscopy. Detailed analysis of the results suggests that the interaction of these systems most probably occurs through π-stacking and secondary hydrogen interaction surface binding with ct-DNA. Moreover, we also demonstrate the substantial ability of porphyrins 4 and 5 to generate (1)O2 and to photocleave plasmid DNA after irradiation.
In this paper we have synthesized different morphological ZnO nanostructures via microwave hydrothermal methods at low temperature within a short time. We described different morphologies of ZnO at different Zn(NO3)2/KOH mole ratio. The ZnO nanostructures were characterized via X-ray diffraction (XRD), field emission scanning electron microscopy (FE-SEM) and UV-vis spectrophotometry. All ZnO structures have hexagonal wurtzite type structures. The FESEM images showed various morphologies of ZnO such as plate, rod and nanoparticles. Dye sensitized solar cells have been assembled by these different morphological structures photo electrode and tannic acid or Fe-tannic acid complex dye as sensitizer. We have achieved at maximum
 efficiencies of photovoltaic cells prepared with ZnO plate in all dye systems. The conversion efficiencies of dye sensitized solar cells are 0.37% and 1.00% with tannic acid and Fe-tannic acid complex dye, respectively.
The photoluminescence (PL) properties of the Cu:Zn-In-S core quantum dots (QDs) and core-shell QDs were systematically investigated by using steady-state and time-resolved PL spectra at temperatures ranging from 80 to 400 K. The effects of the shell structure and the host bandgap on the thermal stability of Cu dopant emissions were studied by measuring the change in the PL intensity and the lifetime. It was found that the PL intensities and lifetimes of the core and core/shell QDs with green, yellow, and red emissions almost decrease with increasing temperatures while their PL was quenched at 300 K and 400 K, respectively, indicating the shell-enhanced thermal stability of the PL. The emission wavelength of the QDs as a function of temperature was also provided. The mechanisms of Cu dopant emission and thermal quenching were discussed. Finally, the green, yellow, red, and white light emitting light emitting diodes (LEDs) were fabricated based on Cu:Zn-In-S QDs.
Assessment of heavy metal concentrations in the soil samples of urban parks and playgrounds is very important for the evaluation of potential risks for residents, especially children. Until recently, there has been very little data about urban parks pollution in Montenegro. To evaluate the sources of potential contamination and concentration of heavy metals, soil samples from coastal urban parks and kindergartens of Montenegro were collected. Based on the heavy metal concentrations, multivariate analysis combined with geochemical approaches showed that soil samples in coastal areas of Montenegro had mean Pb and Cd concentrations that were over two times higher than the background values, respectively. Based on principal component analysis (PCA), soil pollution with Pb, Cd, Cu, and Zn is contributed by anthropogenic sources. Results for Cr in the surface soils were primarily derived from natural sources. Calculation of different ecological contamination factors showed that Cd is the primary contribution to ecological risk index (RI) origins from anthropogenic, industry, and urbanization sources. This data provides evidence about soil pollution in coastal municipalities of Montenegro. Special attention should be paid to this problem in order to continue further research and to consider possible ways of remediation of the sites where contamination has been observed.
Alkaline phosphatase is a homodimeric metallo-hydrolase where both Zn(2+) and Mg(2+) are important for catalysis and stability. Cold-adapted alkaline phosphatase variants have high activity at low temperatures and lower thermal stability compared with variants from mesophilic hosts. The instability, and thus inactivation, could be due to loose association of the dimers and/or loosely bound Mg(2)(+) in the active site, but this has not been studied in detail for the cold-adapted variants. Here, we focus on using the intrinsic fluorescence of Trp in alkaline phosphatase from the marine bacterium Vibrio splendidus (VAP) to probe for dimerization. Trp→Phe substitutions showed that two out of the five native Trp residues contributed mostly to the fluorescence emission. One residue, 15Å away from the active site (W460) and highly solvent excluded, was phosphorescent and had a distant role in substrate binding. An additional Trp residue was introduced to the dimer interface to act as a possible probe for dimerization. Urea denaturation curves indicated that an inactive dimer intermediate, structurally equivalent to the native state, was formed before dimer dissociation took place. This is the first example of the transition of a native dimer to an inactive dimer intermediate for alkaline phosphatase without using mutagenesis, ligands, or competitive inhibition.
Zinc oxides have gained exciting achievements in antimicrobial fields because of their advantageous properties, whereas their biological effects on bacteria are currently underexplored. In this study, biological effects of flower-shaped nano zinc oxides on bacteria were systematically investigated. Zinc oxide nanoflowers with controllable morphologies (viz., rod flowers, fusiform flowers, and petal flowers) were synthesized by modulating merely base type and concentration using the hydrothermal process. Their antibacterial power is in an order of petal flowers > fusiform flowers > rod flowers because of their differences in microscopic parameters such as specific surface area, pore size, and Zn-polar plane, etc. More importantly, the role of morphology in influencing biological effect on bacteria was examined, focusing on the morphology-induced effect on integrality of cell wall, permeability of cell membrane, DNA cleavage, etc. As for cytotoxicity, all petal flowers, fusiform flowers, and rod flowers show trivial cytotoxicity to the Hela cells. This work provides a guide for enhancing biological effect of the biocides on pathogenic bacteria by the morphological modulation.
A tacn based ligand bearing two methylthiazolyl arms (no2th) was synthesized with the aim to find ligands forming very stable and inert complexes with Cu(ii) and Cu(i) in aqueous medium for radiopharmaceutical applications. The no2th ligand was efficiently prepared following the orthoamide intermediate synthesis. The complexes with Cu(2+) and Zn(2+) were obtained and analyzed by X-ray diffraction. The [Cu(no2th)](2+) complex presents a pentacoordinated distorted square pyramidal coordination geometry, while the metal ion in [Zn(no2th)](2+) adopts a hexacoordinated distorted trigonal prismatic geometry involving the coordination of a perchlorate counter ion. The acid-base properties of no2th have been studied using potentiometric titrations, and the stability constants of Cu(2+) and Zn(2+) complexes were determined by potentiometric and UV-vis titrations using H4edta as a competitor ligand. The stability constant determined for the Cu(2+) complex is rather high (log KCuL = 20.77 and pCu = 17.15), and moreover no2th exhibits a high selectivity for copper(ii) in relation to zinc(ii). The kinetics of the copper(ii) complexation process is very fast even in acidic medium. In addition, the [Cu(no2th)](2+) complex was found to be inert under rather harsh conditions (up to 2 M HCl and 60 °C), displaying a very high half-life time of about 15 days in 2 M HCl at 90 °C. The electrochemical reduction of the copper(ii) complex in water leads to the reversible formation of a stable copper(i) species. Spectroscopic studies performed by NMR, UV-vis and EPR, assisted by theoretical calculations, show that the [Cu(no2th)](2+) complex presents a structure in solution similar to that observed in the solid state. When compared to its cyclam di-N-methylthiazolyl counterpart, the results reported in this paper unambiguously show that replacing the cyclam unit by a tacn moiety improves the stability and inertness of its Cu(ii) and Cu(i) complexes.
Four class-modeling techniques (soft independent modeling of class analogy (SIMCA), unequal dispersed classes (UNEQ), potential functions (PF), and multivariate range modeling (MRM)) were applied to multielement distribution to build chemometric models able to authenticate chili pepper samples grown in Calabria respect to those grown outside of Calabria. The multivariate techniques were applied by considering both all the variables (32 elements, Al, As, Ba, Ca, Cd, Ce, Co, Cr, Cs, Cu, Dy, Fe, Ga, La, Li, Mg, Mn, Na, Nd, Ni, Pb, Pr, Rb, Sc, Se, Sr, Tl, Tm, V, Y, Yb, Zn) and variables selected by means of stepwise linear discriminant analysis (S-LDA). In the first case, satisfactory and comparable results in terms of CV efficiency are obtained with the use of SIMCA and MRM (82.3 and 83.2% respectively), whereas MRM performs better than SIMCA in terms of forced model efficiency (96.5%). The selection of variables by S-LDA permitted to build models characterized, in general, by a higher efficiency. MRM provided again the best results for CV efficiency (87.7% with an effective balance of sensitivity and specificity) as well as forced model efficiency (96.5%).
The environmental behaviors of five heavy metals (Cd, Cr, Cu, Pb, and Zn) in a Chinese oilfield were investigated using a steady-state multimedia aquivalence (SMA) model. The modeling results showed good agreement with the actual measured values, with average residual errors of 0.69, 0.83, 0.35, 0.16, and 0.54 logarithmic units for air, water, soil, sediment, and vegetation compartments, respectively. Model results indicated that most heavy metals were buried in sediment, and that transfers between adjacent compartments were mainly deposition from the water to the sediment compartment (48.59 %) and from the air to the soil compartment (47.74 %) via atmospheric dry/wet deposition. Sediment and soil were the dominant sinks, accounting for 68.80 and 25.26 % of all the heavy metals in the multimedia system, respectively. The potential ecological risks from the five heavy metals in the sediment and soil compartments were assessed by the potential ecological risk index (PERI). The assessment results demonstrate that the heavy metals presented low levels of ecological risk in the sediment compartment, and that Cd was the most significant contributor to the integrated potential ecological risk in the oilfield. The SMA model provided useful simulations of the transport and fate of heavy metals and is a useful tool for ecological risk assessment and contaminated site management.
Contamination of heavy metals in sediment is regarded as a global crisis with a large share in industrializing cities like Sfax (Tunisia). Seven heavy metals such as Cadmium (Cd), Copper (Cu), Iron (Fe), Mercury (Hg), Nickel
 (Ni), Lead (Pb), and Zinc (Zn), and one metalloid such as Arsenic (As) in sediments and fish (D. annularis, L. aurata, and S. vulgaris) were investigated from the Southern coast of Sfax in Tunisia. The range of metals in sediments were 13.11-36; 4.42-7.92; 8.23-28.56; 50,564-11,956; 2.9-6.8; 9.13-30.51; 65.06-151.50, and 47-546 kg(-1) DW for As, Cd, Cu, Fe, Hg, Ni, Pb, and Zn. The level of studied metals in sediment samples exceeded the limits of the quality assessment guidelines (SQGs). The potential ecological risk index (PERI) proved that the investigated region could pose moderate risk for the aquatic biota. Metal bioaccumulation in the fish muscles varied significantly among species. Indeed, S. vulgaris and D. annularis accumulated higher amount of metal than L. aurata. The target hazard quotients (THQ) of individual heavy metals in fish, except for As and Hg, revealed safe levels for human consumption. Nevertheless, the total THQ indexes exceeded 1 suggesting the combined effects on muscles fish, which may constitute a risk to population's health.
In the present study, the trace elements partitioning behavior during cement manufacture process were systemically investigated as well as their distribution behaviors in the soil surrounding a cement plant using hazardous waste as raw materials. In addition to the experimental analysis, the thermodynamic equilibrium calculations were simultaneously conducted. The results demonstrate that in the industrial-scale cement manufacture process, the trace elements can be classified into three groups according to their releasing behaviors. Hg is recognized as a highly volatile element, which almost totally partitions into the vapor phase. Co, Cu, Mn, V, and Cr are considered to be non-volatile elements, which are largely incorporated into the clinker. Meanwhile, Cd, Ba, As, Ni, Pb, and Zn can be classified into semi-volatile elements, as they are trapped into clinker to various degrees. Furthermore, the trace elements emitted into the flue gas can be adsorbed onto the fine particles, transport and deposit in the soil, and it is clarified here that the soil around the cement plant is moderately polluted by Cd, slightly polluted by As, Cr, Ba, Zn, yet rarely influenced by Co, Mn, Ni, Cu, Hg, and V elements. It was also estimated that the addition of wastes can efficiently reduce the consumption of raw materials and energy. The deciphered results can thus provide important insights for estimating the environmental impacts of the cement plant on its surroundings by utilizing wastes as raw materials.
Choosing native vascular plants as nutrient and toxic element accumulators for passive biomonitoring of urban river quality is not an easy task in Mediterranean rivers, due to the particular climate determining high variations in river hydrology. To identify potential biomonitors for this area, the roots of seven species (Angelica sylvestris, Apium nodiflorum, Tradescantia fluminensis, Nasturtium officinale, Persicaria lapathifolia, Arctium lappa, Typha latifolia), growing in seven sites along the River Irno (Southern Italy), were collected in July 2010 and analyzed regarding their capability to accumulate Cd, Cr, Cu, Fe, K, Mg, Mn, Na, Ni, Pb, V, and Zn through atomic absorption spectrometry. Notwithstanding the expected different accumulation degree among the species, they highlighted similar spatial contamination gradients, and all of them appeared suitable, alone or in combination, for river passive biomonitoring. A. nodiflorum, in particular, appeared the best biomonitor for the River Irno, where severe anthropogenic impacts were detected: high Cu and Cd contamination from vine cultivation in the upper stretch, and Pb, Zn, and Mn contamination in the medium stretch from airborne dusts coming from a cast iron foundry.
The concentrations of heavy metals (Cd, Cu, Fe, Pb, Ni, and Zn) were measured in the liver, gills, and muscle of Solea vulgaris, Liza aurata, and Diplodus annularis, collected from the south coast of Sfax (Gabes Gulf, southwestern Mediterranean). The concentrations of heavy metals in water exhibited the following decreasing order (expressed in μg l(-1)): Fe > Ni > Zn > Cu > Pb > Cd whereas the trend is somewhat different in sediments (mg kg(-1) D.W.) Fe > Zn > Pb > Ni > Cu > Cd. The levels of heavy metals varied significantly among fish species and tissues. Heavy metal levels were found generally higher in the liver and gills than the muscle in all species. The liver was the target organ for Cd, Cu, Fe, Ni, and Zn accumulation. Nickel and lead, however, exhibited their highest concentrations in the gills. The three studied fishes showed a difference in metals accumulation decreasing in following order S. vulgaris > D. annularis > L. aurata. Solea vulgaris with the highest TFwater, TFsediment, and metal concentrations in tissues would be considered as a potential bio-indicator in the south coast of Sfax for the assessment of environmental pollution status. Comparative studies with Luza zone indicate considerable bioaccumulation of heavy metals (Pb and Zn) in the various tissues of fish samples of the south coast of Sfax.
Kufor-Rakeb syndrome (KRS) is an autosomal recessive, juvenile-onset Parkinson's disease (PD) caused by loss-of-function mutations in ATP13A2 (PARK9). Impaired energy metabolism is considered a pathogenic mechanism in PD and mitochondrial dysfunction resulting from Zn(2+) dyshomeostasis has been found in KRS patient-derived cells. In addition to mitochondrial energy production, glycolysis plays an important role in cellular energy metabolism and glucose hypometabolism has been reported in PD. However, glycolytic status in KRS remains undetermined despite its potential importance.
We assessed glycolytic function in ATP13A2-deficient KRS patient-derived human olfactory neurosphere cells and fibroblasts and determined the effect of pyruvate supplementation on improving cellular energy production.
We found impaired extracellular acidification, reduction in pyruvate production and a decrease in the NAD(+)/NADH ratio, indicative of glycolytic dysfunction. In addition, gene expression analysis revealed an altered expression profile for several glycolytic enzymes. Glycolytic dysfunction was aggravated when the intracellular Zn(2+) concentration was increased, while ATP13A2 overexpression and pyruvate supplementation blocked the observed Zn(2+)-mediated toxicity. Moreover, supplementation with pyruvate significantly increased basal mitochondrial ATP production and abolished Zn(2+)-induced cell death.
These findings indicate that glycolytic dysfunction contributes to pathogenesis and pyruvate supplementation improves overall cellular bioenergetics in our KRS patient-derived cell model, highlighting a therapeutic potential.
In this study, concentrations of Aluminum (Al), Iron (Fe), Chromium (Cr), Copper (Cu), Nickel (Ni), Vanadium (V), Zinc (Zn), Arsenic (As), Cobalt (Co) and lead (Pb) in the surface sediments from Chabahar Bay were studied to assess the degree of heavy metal pollution as a consequence of natural and anthropogenic sources. Metal contents in the sediments were observed in the order of: Al>Fe>Cr>V>Ni>Zn>Cu>As>Pb>Co. According to enrichment factor (EF), Arsenic was higher than 1.5 at some sites, indicating anthropogenic inputs. Contents of Ni, As and Cr in the some sampling sites were higher than sediment quality guideline implying adverse impacts of these metals. Based on potential ecological risk (PER), the Chabahar Bay had low ecological risk.
The condensation product of phenylalanine and salicylaldehyde (L) was synthesised and characterised which was found to be selective fluorescent "off-on" sensor for Zn(2+) ion with the detection limit 10(-5) M. The sensor is free of interferences from metal ions - Na(+), K(+), Al(3+), Mn(2+), Co(2+), Ni(2+), Cu(2+), Pb(2+), Cd(2+) and Hg(2+). The Fluorescence and the UV/visible spectral data reveals a 1:1 interaction between the sensor and Zn(2+) ion with binding constant 10(8). The DFT and TDDFT calculations confirm the structures of the sensor and the sensor-Zn(2+) complex.
Cd is a toxic metal that has a destructive impact on most organ systems. This work aims to determine Zn or Mg protective effects against Cd renal toxicity. In this study, rats were divided into six groups. The Cd group was treated with 1 mg Cd/kg, and the control group received 0.5 cm(3) normal saline, intraperitoneally. The other four groups received one of the following dosages of 1 mg/kg Cd + 0.5 mg/kg Zn, 1 mg/kg Cd + 1.5 mg/kg Zn, 1 mg/kg Cd + 0.5 mg/kg Mg, or 1 mg/kg Cd + 1.5 mg/kg Mg through IP injection for 3 weeks. Kidney malondialdehyde (MDA) and serum sodium, potassium, urea, creatinine, and protein were measured. Light microscopic examination was used for histological studies. Cd reduced serum creatinine and protein, and increased urea, sodium, and potassium. Moreover, Cd exposure caused a significant enhancement in MDA levels as well as histological damage in kidneys. Zn or Mg treatment prevented and reversed toxic alterations induced by Cd. These results suggest that Zn and Mg may have protective effects against Cd renal toxicity.
This study concerns application of flame atomic absorption spectrometry (FAAS) in assessment of macro- and microelement and toxic metal levels (Mg, Ca, K, Na, Mn, Cu, Fe, Zn, Cr, Ni, Co, Cd and Pb) in dark (Pu-erh) and fruit tea leaves and their infusions. Phosphorus was also determined in the form of phosphomolybdate by spectrophotometric method. The reliability of the method was checked using three certified reference materials. The results of analysis were in agreement with the certified values, with analytical recovery ranging from 86 to 113 %. Significant correlations (p < 0.001) were found between concentrations of P, Zn, K, Ni, Fe, Co, Cr, and Pb in Pu-erh tea, whereas in fruit tea,
 such interdependences were found between Mg, Fe, P, Ni, and Co. Kruskal-Wallis test results have related differences in Pu-erh tea quality as well as technological processing of fruit tea to their mineral composition. In order to characterize tea elemental content, chemometric techniques such as factor analysis (FA) and cluster analysis (CA) were used. Their application allowed on differentiation of samples in view of the fermentation type, technological processing, and overall quality.
Thallium (Tl) is a non-essential element in humans and it is considered to be highly toxic. In this study, the contents, sources, and dispersal of Tl were investigated in surface sediments from a riverine system (the western Pearl River Basin, China), whose catchment has been contaminated by mining and roasting of Tl-bearing pyrite ores. The isotopic composition of Pb and total contents of Tl and other relevant metals (Pb, Zn, Cd, Co, and Ni) were measured in the pyrite ores, mining and roasting wastes, and the river sediments. Widespread contamination of Tl was observed in the sediments across the river, with the highest concentration of Tl (17.3 mg/kg) measured 4 km downstream from the pyrite industrial site. Application of a modified Institute for Reference Materials and Measurement (IRMM) sequential extraction scheme in representative sediments unveiled that 60-90% of Tl and Pb were present in the residual fraction of the sediments. The sediments contained generally lower (206)Pb/(207)Pb and higher (208)Pb/(206)Pb ratios compared with the natural Pb isotope signature (1.2008 and 2.0766 for (206)Pb/(207)Pb and (208)Pb/(206)Pb, respectively). These results suggested that a significant fraction of non-indigenous Pb could be attributed to the mining and roasting activities of pyrite ores, with low (206)Pb/(207)Pb (1.1539) and high (208)Pb/(206)Pb (2.1263). Results also showed that approximately 6-88% of Tl contamination in the sediments originated from the pyrite mining and roasting activities. This study highlights that Pb isotopic compositions could be used for quantitatively fingerprinting the sources of Tl contamination in sediments.
The present study was carried out to investigate the degradation of phenol by ultrasonically dispersed nano-metallic particles (NMPs) in an aqueous solution of phenol. Leaching liquor from automobile shredder residue (ASR) was used to obtain the NMPs. The prepared NMPs were analyzed by scanning electron microscopy (SEM), X-ray photoelectron spectroscopy (XPS), Fourier transform infrared spectroscopy (FTIR), and by X-ray diffraction (XRD). The SEM images show that the diameters of the NMPs were less than 50 nm. An SEM-EDX elemental analysis reveals that Fe was the most commonly found element (weight %) in the NMPs. The FTIR and XRD peaks indicate the presence of metals oxides on the surfaces of the NMPs. The results of the XPS analysis indicate that various elements (e.g., C, O, Zn, Cu, Mn, Fe) are present on the surfaces of the NMPs. The effects of the NMP dose, the initial solution pH, and of different concentrations of phenol and H2O2 on the phenol degradation characteristics were evaluated. The results of this study demonstrate that phenol degradation can be improved by increasing the amount of NMPs, whereas it is reduced with an increase in the phenol concentration. The degradation of phenol by ultrasonically dispersed NMPs followed the pseudo-first-order kinetics. The probable mechanism of phenol degradation by ultrasonically dispersed NMPs was the oxidation of phenol caused by the hydroxyl radicals produced during the reaction between H2O2 and the NMPs during the ultrasonication process.
Several studies have suggested that the majority of iron (Fe) and zinc (Zn) in wheat grains are associated with phytate, but a nuanced approach to unravel important tissue-level variation in element speciation within the grain is lacking. Here, we present spatially resolved Fe-speciation data obtained directly from different grain tissues using the newly developed synchrotron-based technique of X-ray absorption near-edge spectroscopy imaging, coupling this with high-definition μ-X-ray fluorescence microscopy to map the co-localization of essential elements. In the aleurone, phosphorus (P) is co-localized with Fe and Zn, and X-ray absorption near-edge structure imaging confirmed that Fe is chelated by phytate in this tissue layer. In the crease tissues, Zn is also positively related to P distribution, albeit less so than in the aleurone. Speciation analysis suggests that Fe is bound to nicotianamine rather than phytate in the nucellar projection, and that more complex Fe structures may also be present. In the embryo, high Zn concentrations are present in the root and shoot primordium, co-occurring with sulfur and presumably bound to thiol groups. Overall, Fe is mainly concentrated in the scutellum and co-localized with P. This high resolution imaging and speciation analysis reveals the complexity of the physiological processes responsible for element accumulation and bioaccessibility.
To study the effects of long-term mining activities on the agricultural soil quality of Mengnuo town in Yunnan province, China, the heavy metal and soil enzyme activities of soil samples from 47 sites were examined. The results showed that long-term mining processes led to point source heavy metal pollution and Pb, Cd, Zn and As were the primary metal pollutants. Polyphenoloxidase was found the most sensitive soil enzyme activity and significantly correlated with almost all the metals (P < 0.05). Amylase (for C cycling), acid phosphatase (for P cycling) and catalase (for redox reaction) activities showed significantly positive correlations (P < 0.05) with Pb, Cd, Zn and As contents. The correlations between soil enzymes activities and Cd, Pb and Zn contents were verified in microcosm experiments, it was found that catalase activity had significant correlations (P < 0.05) with these three metals in short-term experiments using different soils under different conditions. Based on both field investigation and microcosm simulation analysis, oxidoreductases activities (rather than a specific enzyme activity) were suggested to be used as "core enzyme", which could simply and universally indicate the heavy metal pollution degrees of different environments. And hydrolases (for C, N, P and S recycling) could be used as a supplement to improve correlation accuracy for heavy metal indication in various polluted environments.
The development of mining and metallurgic industries of Pb and Zn ores in the Biała Przemsza catchment area has had a strong influence on the condition of the surface water and bottom sediments. In the following study, total contents of metals and metalloids were researched in the water and bottom sediment samples from the Biała Przemsza River. The samples were collected monthly in 2014 at five sampling points along the river. The research helped to determine correlations between the parameters and components of the water environment (metals/metalloids, cations/anions, pH, Eh, conductivity, carbon (TOC, IC, TC), and suspension). The contents of metals and metalloids were determined with inductively coupled plasma-mass spectrometry (ICP-MS), whereas anions and cations were investigated with ion chromatography (IC). The simplified Community Bureau of Reference (BCR) three-step sequential chemical extraction was performed on Biała Przemsza River bottom sediments collected in April, July, and October. At its lower course, the Biała Przemsza River water did not meet the Polish surface water quality standards. The Biała Przemsza River water is mainly loaded with metals. Toxic concentrations of Cd, Pb, and Zn were observed at sampling points in Okradzionów and Sławków. The toxic Tl concentration was exceeded (2-6 μg/L) at three sampling points. The Biała Przemsza River bottom sediments were composed mostly of medium and fine sand. The BCR extraction of the bottom sediments demonstrated that Cd and Zn were bound to cations/anions and carbonates loosely adsorbed on the bottom sediments in spring and summer. Such a situation was observed at all the sampling points, except for BP3 in Okradzionów. The organic carbon concentration increased along the river course.
Gold mining has increased the prevalence and occurrence of heavy metals contamination at the Earth's surface and is causing major concern due to the potential risk involved. This study investigated the impact of gold mine on heavy metals (As, Cd, Cr, Cu, Pb, Hg, Ni, Fe, Mn, and Zn) pollution and evaluated the potential health risks to local residents via consumption of polluted groundwater, agricultural soils, and vegetable crops grown at three community farms surrounding the mine at Obuasi municipality of Ghana. The results showed levels of As, Cd, Cr, Hg, Fe, and Mn higher than the allowable drinking water standards. The vegetable samples analyzed showed high accumulation of As and Ni above the normal value. Bioaccumulation factors of heavy metals were significantly higher for vegetables grown in the Sanso soils. Estimated average daily intake and hazard quotient for As in drinking water as well as As, Pb, and Hg in vegetable samples exceeded permissible limit. Unacceptable non-cancer health risk levels were found in vegetable samples analyzed for As, Pb, and Hg. An unacceptable cancer risk was found via drinking of groundwater, in consumption of vegetables, and in soil. The hazard index for vegetables was higher than 1, indicating very high health risk to heavy metals contamination through consumption of vegetables grown around the sampling sites. The results recommend the need for regular monitoring of groundwater and food crops to protect consumers' health.
Superoxide dismutases (SODs) are scavengers of superoxide radicals, one of the main reactive oxygen species (ROS)
 in the cell. SOD-based ROS scavenging system constitutes the frontline defense against intra- and extracellular ROS, but the roles of SODs in the important cereal pathogen Fusarium graminearum are not very clear. There are five SOD genes in F. graminearum genome, encoding cytoplasmic Cu-Zn SOD1 and MnSOD3, mitochondrial MnSOD2 and FeSOD4, and extracellular CuSOD5. Previous studies reported that the expression of SOD1 increased during infection of wheat coleoptiles and florets. In this work we showed that the recombinant SOD1 protein had the superoxide dismutase activity in vitro, and that the SOD1-mRFP fusion protein localized in the cytoplasm of F. graminearum. The Δsod1 mutants had slightly reduced hyphal growth and markedly increased sensitivity to the intracellular ROS generator menadione. The conidial germination under extracellular oxidative stress was significantly delayed in the mutants. Wheat floret infection assay showed that the Δsod1 mutants had a reduced pathogenicity. Furthermore, the Δsod1 mutants had a significant reduction in production of deoxynivalenol mycotoxin. Our results indicate that the cytoplasmic Cu-Zn SOD1 affects fungal growth probably depending on detoxification of intracellular superoxide radicals, and that SOD1-mediated deoxynivalenol production contributes to the virulence of F. graminearum in wheat head infection.
The prevalence of helminth infection, which is known to affect nutritional status of the host, varies with age. The complex interplay between ages, nutrient requirements, and infection necessitated the need to recommend micronutrient supplementation during helminth infection among different age groups.
The aim of this study was to determine the pattern of alteration in selected micronutrients in pregnant women and preschool- and school-aged children with helminth infection.
We screened 245 pregnant women and 349 children for helminth infection. Of these, 17 (6.9%) pregnant women and 102 (29.2%) children (42 preschool- and 60 school-aged) had helminth infection. Only Ascaris lumbricoides was found in pregnant women, whereas the children had A lumbricoides, hookworm, Fasciola hepatica, and Trichuris trichiura infections. The helminth-infected (HI) pregnant women, preschool-aged children, and school-aged children were matched with helminth-negative (HN) pregnant women (n = 21), preschool-aged children (n = 42), and school-aged children (n = 50) who served as controls. Venous blood samples were obtained and analyzed for iron (Fe), zinc (Zn), selenium (Se), and vitamins A and C. Statistical analysis was done using Student's t test, and P < 0.05 was considered statistically significant.
Serum levels of Fe, Zn, and Se were significantly lower in HI pregnant women than HN pregnant women. In preschool-aged children, serum levels of Fe, Zn, and vitamin A were significantly lower in the HI than in the HN group. Similarly, serum levels of Zn and vitamin A were significantly lower in HI school-aged children than in the HN group. However, serum levels of Se were significantly higher in HI children (both age groups) than in the corresponding HN group.
Helminth infection alters different types of micronutrients in children and pregnant women. Results from the present study therefore suggest monitoring Fe, Zn, or vitamin A supplementation with an anti-helminthic regimen.
Presented here are two open-framework zinc phosphites, namely, Zn(dabco)0.5(HPO3) (SCU-18) and Zn4(Hdabco)2(CH3COO)2(HPO3)4 (SCU-20), where dabco = 1,4-diazabicyclo[2.2.2]octane. SCU-18 features a rare 3-connected inorganic skeleton with a chiral qtz-h topology. It contains 18-membered-ring (18 MR) channels displaying porosity and second-harmonic-generation response. SCU-20 has a bnn topology containing large 20 MR channels that shows a strong blue emission as a result of excitation at 375 nm.
Polycarboxylate ligands are among the most important building blocks for the synthesis of metal-organic frameworks (MOFs). The ability to access these ligands in an efficient way is of key importance for future applications of MOFs. Here, we demonstrate that mono- and dinuclear clathrochelate complexes are versatile scaffolds for the preparation of polytopic carboxylate ligands. The largely inert clathrochelate complexes have a trigonal-bipyramidal shape. The synthesis of functionalized clathrochelates with two, three, four, or five carboxylic acid groups in the ligand periphery can be achieved in a few steps from simple starting materials. Apart from being easily accessible, the metalloligands display interesting characteristics for applications in metallasupramolecular chemistry and materials science: they are rigid, large (up to 2.2 nm), and robust and they can show additional functions (e.g., fluorescence or extra charge) depending on the metal ion that is present in the clathrochelate core. The utility of these new metalloligands in MOF chemistry is demonstrated by the synthesis of zinc- and zirconium-based coordination polymers. The combination of Zn(NO3)2 with clathrochelates having two or three carboxylic acid groups gives MOFs in which the clathrochelate ligands are connected by Zn4O clusters or zinc paddlewheel links. The structures of the resulting two- and three-dimensional networks could be established by single-crystal X-ray crystallography. The reaction of carboxylic acid functionalized clathrochelates with ZrCl4 gives amorphous powders that display permanent porosity after solvent removal.
Waste incineration is the main waste management strategy used in treating hospital waste in many developing countries. However, the release of dioxins, POPs, and heavy metals in fly and bottom ash poses environmental and public health concerns. To determine heavy metal (Hg, Pb, Cd, Cr, and Ag) in levels in incinerator bottom ash and soils 100 m around the incinerator bottom ash dump site, ash samples and surrounding soil samples were collected at 20 m, 40 m, 60 m, 80 m, 100 m, and 1,200 m from incinerator. These were analyzed using the absorption spectrophotometer method. The geoaccumulation (I geo) and pollution load indices (PLI) were used to assess the level of heavy metal contamination of surrounding soils. The study revealed high concentrations in mg/kg for, Zn (16417.69), Pb (143.80), Cr (99.30), and Cd (7.54) in bottom ash and these were above allowable limits for disposal in landfill. The study also found soils within 60 m radius of the incinerator to be polluted with the metals. It is recommended that health care waste managers be educated on the implication of improper management of incinerator bottom ash and regulators monitor hospital waste incinerator sites.
A simple, rapid and sensitive method for determination of trace levels of domoic acid (DA) in seawater was developed, based on a magnetic solid-phase extraction (MSPE) followed by high-performance liquid chromatography with tandem mass spectrometry (HPLC-MS/MS). Five kinds of ferrite magnetic nanospheres (MFe2O4; M=Fe, Co, Ni, Cu and Zn) were prepared and first used as sorbents for MSPE of DA and removal of salt interference. Under the same extraction and elution conditions, CuFe2O4 magnetic nanospheres provided the best pretreatment performance, which were then characterized in detail. After further optimization of conditions, the developed method showed good linearity (r(2)=0.9991) with the range of 5-1000 pg mL(-1), low limit of detection (2.5 pg mL(-1); S/N=3:1), low limit of quantification (5.0 pg mL(-1); S/N=10:1), and good recoveries (86.0-98.1%) with acceptable repeatability (RSD ≤ 6.5%; n=3) in seawater samples. The results demonstrated that the ferrite magnetic nanospheres are promising sorbents for efficient extraction of highly polar analytes from high ionic strength solutions.
The purpose of this study was to determine the concentrations of heavy metals (cadmium, iron, manganese, lead and zinc) in current-year, 1-year old and 2-year old needles of Pinus sylvestris L. Trees were from three heavily polluted (immediate vicinity of zinc smelter, iron smelter and power plant) and three relatively clean sites (nature reserve, ecologically clean site and unprotected natural forest community) in southern Poland. Analysis also concerned the antioxidant response and contents of protein, proline, total glutathione, non-protein thiols and activity of guaiacol peroxidase (GPX) in the needles. Generally, in pine needles from the polluted sites, the concentrations of the metals were higher and increased with the age of needles, and in most cases, antioxidant responses also were elevated. The highest levels of Cd, Pb and Zn were found in 2-year old pine needles collected near the polluted zinc smelter (respectively: 6.15, 256.49, 393.5 mg kg(-1)), Fe in 2-year old pine needles in the vicinity of the iron smelter (206.82 mg kg(-1)) and Mn in 2-year old needles at the ecologically clean site (180.32 mg kg(-1)). Positive correlations were found between Fe, Mn and Pb and the content of proteins and NPTs, between Cd and non-protein -SH groups, and between Zn and proline levels. The activity of GPX increased under the influence of Mn, while glutathione levels tended to decrease as Mn levels rose. The data obtained show that the levels of protein and non-protein -SH groups may be useful in biological monitoring, and that these ecophysiological parameters seem to be good evidence of elevated oxidative stress caused by heavy metals.
PGRP-SC2, the member of PGRP family, plays an important role in regulation of innate immune response. In this paper, a PGRP-SC2 gene of Nile tilapia, Oreochromis niloticus (designated as On-PGRP-SC2) was cloned and its expression pattern under the infection of Streptococcus agalactiae was investigated. Sequence analysis showed main structural features required for amidase activity were detected in the deduced amino acid sequence of On-PGRP-SC2.
 In healthy tilapia, the On-PGRP-SC2 transcripts could be detected in all the examined tissues, with the most abundant expression in the muscle. When infected with S. agalactiae, there was a clear time-dependent expression pattern of On-PGRP-SC2 in the spleen, head kidney and brain. The assays for the amidase activity suggested that recombinant On-PGRP-SC2 protein had a Zn(2+)-dependent PGN-degrading activity. Moreover, our works showed that recombinant On-PGRP-SC2 protein could significantly reduce bacterial load in target organs attacked by S. agalactiae. These findings indicated that On-PGRP-SC2 may play important roles in the immune response to S. agalactiae in Nile tilapia.
Xylarinase is a bi-functional fibrinolytic metalloprotease isolated from the culture filtrate of endophytic fungus Xylaria curta which is monomeric with a molecular mass of ∼33.76 kDa. The enzyme displayed both plasmin and tissue plasminogen activator like activity under in vitro conditions. It hydrolyses Aα and Bβ chains of the fibrinogen. Optimal fibrinolytic activity of xylarinase is observed at 35 °C, pH 8. Ca(2+) stimulated the fibrinolytic activity of xylarinase while Fe(2+) and Zn(2+) inhibited suggesting it to be a metalloprotease. The Km and Vmax values of xylarinase were 240.9 μM and 1.10 U/ml for fibrinogen and 246 μM and 1.22 U/ml for fibrin, respectively. Xylarinase was found to prolong the activated partial thromboplastin time and prothrombin time. The N-terminal sequence of xylarinase (SNGPLPGGVVWAG) did not show any homology with previously known fibrinolytic enzymes. Thus xylarinase is a novel fibrinolytic metalloprotease which could be possibly used as a new clot busting enzyme.
Tuberculosis is a global health problem, and its early diagnosis is the ultimate strategy for prevention and control. The current study was undertaken to evaluate conventional and molecular diagnostic assays for the detection of mycobacteria in pulmonary tuberculosis (TB) patients from Khyber Pakhtunkhwa region of Pakistan. A total of 259 clinically suspected patients of TB were processed for Zeihl Neelsen (ZN) microscopy, BACTEC MGIT liquid culture and GeneXpert assay. Among 259 samples, 28 (10.81%) were positive for acid fast bacilli (AFB) on ZN microscopy. In liquid culture, the growth of mycobacterium species was obtained in 36 (13.89%) samples while the GeneXpert assay detected Mycobacterium tuberculosis (MTB) in 49 (18.91%) samples. Detection rate of MTB was significantly high (n = 49, p < 0.0095) on GeneXpert as compared to microscopy (n = 28); however no significant difference (p = 0.1230) was observed on GeneXpert (n = 49) and culture (n = 36) based detection of MTB. The strength of agreement between GeneXpert and microscopy was also poor (Kappa value < 0.114, 95% CI: -0.72 - 0.301) which support our results. MTB detection rate among female was high as compared to male TB patients while in age wise, the age group 55-64 years has almost high detection rate on microscopy, culture and GeneXpert assay. Findings of the present study highlighted that GeneXpert is more efficient tool for timely diagnosis and proper TB control in high TB endemic area.
Through investigating and comparing the fatigue behavior of an as-forged Mg-6.7Zn-1.3Y-0.6Zr (wt.%) alloy before and after solid solution treatment (T4) in laboratory air, the effect of T4 treatment on fatigue crack initiation was disclosed. S-N curves illustrated that the fatigue strength of as-forged samples was 110 MPa, whereas the fatigue strength of T4 samples was only 80 MPa. Observations to fracture surfaces demonstrated that for as-forged samples, fatigue crack initiation sites were covered with a layer of oxide film. However, due to the coarse grain structure and the dissolution of MgZn2 precipitates, the activation and accumulation of {10-12} twins in T4 samples were much easier, resulting in the preferential fatigue crack initiation at cracked twin boundaries (TBs). Surface characterization demonstrated that TB cracking was mainly ascribed to the incompatible plastic deformation in the twinned area and nearby α-Mg matrix.
Halostachys caspica is a short shrub distributed in the semi-arid and saline-alkali area, which evolved various mechanisms for modulating salt and metal level. In the present study, a Type 2 metallothionein (HcMT) gene was cloned from the salt induced suppression subtractive hybridization (SSH) cDNA library of H.caspica. Quantitative real time PCR (qRT-PCR) analysis indicated that HcMT gene was up-regulated under the stress of Cu(2+), Zn(2+) and Cd(2+), and the tolerance of E. coli strain harboring with the recombinant HcMT (pET-32a-HcMT) to Cu(2+), Zn(2+) and Cd(2+) was enhanced compared to strain with control vector (pET-32a). Moreover, the purified TrxA-HcMT fusion protein from E. coli cells grown in the presence of 0.3mM CuSO4, 0.3mM ZnSO4, or 0.1mM CdCl2 could bind more metal ions than TrxA alone. The predicted 3D structure showed that HcMT could form a single metal-thiolate cluster, which confers the ability to bind five divalent metal ions through fourteen cysteine residues. These data indicate that HcMT may be involved in processes of metal tolerance in H. caspica and could be employed as a potential candidate for heavy metal phytoremediation.
The total recoverable and dissolved concentrations of 29 metals and metalloids were analyzed in snowpack collected at 91 sites in the Athabasca oil sands region, Canada in winter 2011. Based on deposition pattern from geographical centre, three groups were found: Type-1 metals (i.e. dissolved and total recoverable V; Mo) showed a significant exponential decrease with distance, suggesting oil sands development sources; Type-2 elements (e.g. Al, Sb, As, Ba, Fe, Ni, Tl, and Ti and Zn) showed exponentially decline patterns but with some local point sources; Type-3 elements (e.g. Cd, Cl, Cr, Mn, Sr and Th) deposition pattern represented local sources. A self-organizing map showed that sites with the highest elemental concentrations (Cluster I) were mainly located in the vicinity of upgrading facilities and along the north-south transects. The lowest elemental concentration sites (Cluster III) were the most distal sites or located in the western region of the study area.
Nitric oxide (NO), identified over the last several decades in many physiological processes and pathways as both a beneficial and detrimental signaling molecule, has been the subject of extensive research. Physiologically, NO is transported by a class of donors known as S-nitrosothiols. Both endogenous and synthetic S-nitrosothiols have been reported to release NO during interactions with certain transition metals, primarily Cu(2+) and Fe(2+). Ag(+) and Hg(2+) have also been identified, although these metals are not abundantly present in physiological systems. Here, we evaluate Pt(2+), Fe(2+), Fe(3+), Mg(2+), Zn(2+), Mn(2+), Co(2+), Ni(2+), and Cu(2+) for their ability to generate NO from S-nitroso-N-acetyl-d-penicillamine (SNAP) under physiological pH conditions. Specifically, we report NO generation from RSNOs initiated by three transition metal ions; Co(2+), Ni(2+), and Zn(2+), which have not been previously reported to generate NO. Additionally, preliminary in vivo evidence of zinc wires implanted in the rat arterial wall and circulating blood is presented which demonstrated inhibited thrombus formation after 6 months. One potentially useful application of these metal ions capable of generating NO from RSNOs is their use in the fabrication of biodegradable metallic stents capable of generating NO at the stent-blood interface, thereby reducing stent-related thrombosis and restenosis.
Radiolabeled metalloprobes offer sensitive tools for evaluating quantitative accumulation of chemical entities within pooled cell populations. Although beneficial in translational nuclear imaging, this method precludes interrogation of effects resulting from variations at a single cell level, within the same segment of cell population. Compared with radiotracer bioassays, fluorescence imaging offers a cost-efficient technique to assess accumulation of metalloprobes at a single cell level, and determine their intracellular localization under live cell conditions. To evaluate, whether or not radiotracer assay and fluorescence imaging provide complementary information on utility of metalloprobes to assess functional expression of P-glycoprotein (Pgp) on plasma membrane of tumor cells, imaging studies of fluorescent cationic Ga(III)-ENBDMPI (bis(3-ethoxy-2-hydroxy-benzylidene)-N,N'-bis(2,2-dimethyl-3-amino-propyl)ethylenediamine) and its neutral counterpart Zn(II)-ENBDMPI are performed. While the uptake profiles of the cationic metalloprobe are inversely proportional to expression of Pgp in tumor cells, the accumulation profiles of the neutral Zn(II)-ENBDMPI in non-MDR and MDR cells are not significantly impacted. The cationic Ga(III)-ENBDMPI maps with Mito-Tracker Red, thereby confirming localization within mitochondria of non-MDR (Pgp-) cells. Depolarization of both plasmalemmal and mitochondrial potentials decreased retention of the cationic Ga(III)-ENBDMPI within the mitochondria. Additionally, LY335979, an antagonist-induced accumulation of the cationic Ga(III) metalloprobe in MDR (Pgp+) cells indicated specificity of the agent. Compared with traits of Ga(III)-ENBDMPI as a Pgp recognized substrate, Zn(II)-ENBDMPI demonstrated uptake in both MDR and non-MDR cells thus indicating the significance of overall molecular charge in mediating Pgp recognition profiles. Combined data indicate that live cell imaging can offer a cost-effective methodology for monitoring functional Pgp expression.
We have observed that sperm quality parameters indicative of spermatozoa hyperactivation such are lower "linearity" and "straightness", and as showed by this research "elongation", were more pronounced
 in patients with normal spermiogram compared to the group of men with reduced sperm motility who were undergoing routine in vitro fertilisation. The research encompassed 97 men diagnosed with normozoospermia (n = 20), asthenozoospermia (n = 54) and oligoasthenozoospermia (n = 23). The findings indicate that sperm quality of patients with normal spermiogram diagnosed according to WHO criteria, may be compromised by showing premature spontaneous hyperactivation which can decrease the chances of natural conception. We assessed synergistic effects of multiple chemical elements in ejaculated semen to find if premature spontaneous hyperactivation of spermatozoa can be a sign of imbalanced semen composition especially of elements K, Ca, Cu and Zn. Human semen samples showing low or high baseline status of chemical elements concentrations were found in samples from all three diagnostic groups. However, correlation of K/Ca and Cu/Zn ratios, taking into account samples from all three groups of men, were negative at statistical significance level p = 0.01. We tested if the negative correlation between K/Ca and Cu/Zn ratio works for greater number of semen samples. We found the negative correlation to be valid for 175 semen samples at statistical significance of p = 0.00002. The ratio of K/Ca and Cu/Zn, i.e. increased concentrations of K and Zn in comparison to concentrations of Ca and Cu, were associated with a decrease of "straightness" in the group of men with normal spermiogram and pronounced spontaneous hyperactivation of spermatozoa, implying that these elements act in synergy and that the balance of elements and not their absolute concentrations plays the major role in premature spermatozoa hyperactivation in ejaculated semen.
Protein-based sensors and switches provide attractive tools for the real-time monitoring and control of molecular processes in complex biological environments. Fluorescent sensor proteins have been developed for a wide variety of small molecules, but the construction of genetically encoded light-responsive ligand binding proteins remains mostly unexplored. Here we present a generic approach to reengineer a previously developed FRET-based Zn(2+) sensor into a light-activatable Zn(2+) binding protein using a design strategy based on mutually exclusive domain interactions. These so-called VividZn proteins consist of two light-responsive Vivid domains that homodimerize upon illumination with blue light, thus preventing the binding of Zn(2+) between two Zn(2+) binding domains, Atox1 and WD4. Following optimization of the linker between WD4 and the N-terminus of one of the Vivid domains, VividZn variants were obtained that show a 9- to 55-fold decrease in Zn(2+) affinity upon illumination, which is fully reversible following dark adaptation. The Zn(2+) affinities of the switch could be rationally tuned between 1 pM and 2 nM by systematic variation of linker length and mutation of one of the Zn(2+) binding residues. Similarly, introduction of mutations in the Vivid domains allowed tuning of the switching kinetics between 10 min and 7 h. Low expression levels in mammalian cells precluded the demonstration of light-induced perturbation of cytosolic Zn(2+) levels. Nonetheless, our results firmly establish the use of intramolecular Vivid dimerization as an attractive light-sensitive input module to rationally engineer light-responsive protein switches based on mutually exclusive domain interactions.
Arginine kinase is an essential enzyme which is closely related to energy metabolism in marine invertebrates. Arginine kinase provides a significant role in quick response to environmental change and stress. In this study, we simulated a tertiary structure of Sepia pharaonis arginine kinase (SPAK) based on the gene sequence and conducted the molecular dynamics simulations between SPAK and Zn(2+). Using these results, the Zn(2+) binding sites were predicted and the initial effect of Zn(2+) on the SPAK structure was elucidated. Subsequently, the experimental kinetic results were compared with the simulation results. Zn(2+) markedly inhibited the activity of SPAK in a manner of non-competitive inhibitions for both arginine and ATP. We also found that Zn(2+) binding to SPAK resulted in tertiary conformational change accompanying with the hydrophobic residues exposure. These changes caused SPAK aggregation directly. We screened two protectants, glycine and proline, which effectively prevented SPAK aggregation and recovered the structure and activity. Overall, our study suggested the inhibitory effect of Zn(2+) on SPAK and Zn(2+) can trigger SPAK aggregation after exposing large extent of hydrophobic surface. The protective effects of glycine and proline against Zn(2+) on SPAK folding were also demonstrated.
Phytoremediation of contaminated mine soils requires the use of fast-growing, deep-rooted, high-biomass, and metal-tolerant plants with the application of soil amendments that promote metal uptake by plants. A pot experiment was performed to evaluate the combined use of vetiver grass (Chrysopogon zizanioides) and humic acid for phytoremediation of Cu and Zn in mine soils. Vetiver plants were grown in soil samples collected from two mine sites of Spain mixed with a commercial humic acid derived from leonardite at doses of 0, 2, 10, and 20 g kg(-1). Plant metal concentrations and biomass were measured and metal bioavailability in soils was determined by a low molecular weight organic acid extraction. Results showed that humic acid addition decreased organic acid-extractable metals in soil. Although this extraction method is used to estimate bioavailability of metals, it was not a good estimator under these conditions due to competition with the strong chelators in the added humic acid. High doses of humic acid also promoted root growth and increased Cu concentrations in plants due to formation of soluble metal-organic complexes, which enhanced removal of this metal from soil and its accumulation in roots. Although humic acid was not able to improve Zn uptake, it managed to reduce translocation of Zn and Cu to aerial parts of plants. Vetiver resulted unsuitable for phytoextraction, but our study showed that the combined use of this species with humic acid at 10-20 g kg(-1) could be an effective strategy for phytostabilization of mine soils.
A new method for the decarboxylative coupling of alkyl N-hydroxyphthalimide esters (NHP esters) with aryl iodides is presented. In contrast to previous studies that form alkyl radicals from carboxylic acid derivatives, no photocatalyst, light, or arylmetal reagent is needed, only nickel and a reducing agent (Zn). Methyl, primary, and secondary alkyl groups can all be coupled in good yield (77% ave yield). One coupling with an acid chloride is also presented. Stoichiometric reactions of (dtbbpy)Ni(2-tolyl)I with an NHP ester show for the first time that arylnickel(II) complexes can directly react with NHP esters to form alkylated arenes.
The relationship between trace elements (TE) and essential hypertension (EH) is subtle and complex. This relationship is mediated by endothelial dysfunction, insulin resistance, oxidative stress (OS) and athero-inflammatory state. The aim of this study was to examine the TE impact; particularly selenium (Se), zinc (Zn), copper (Cu) and manganese (Mn) as predictive type 2 diabetes biomarkers in a hypertensive subject. The study was undertaken on 400 adult patients (40-60 years), who were divided in 4 groups: hypertensive (H), type 2 diabetes (T2D), hypertensive-diabetic (HD) and healthy group. Patients were phenotyped regarding their metabolic syndrome profile using the NCEP/ATPIII criteria. Hypertension was defined as systolic (SBP) and diastolic (DBP) blood pressure ≥ 140/90 mmHg, respectively. The SBP and DBP measurements by electronic blood pressure using Omron 705 CP(®) type. Insulin resistance was assessed by Homa-IR model. Metabolic and inflammatory parameters were determined by Cobas Integra(®); the TE investigated by mass spectrometric atomic absorption; the OS markers evaluated by Randox kits. Serum Se concentrations are reduced in all groups, concomitantly with a marked depletion GPx activity in the HD group. However, Zn levels were decreased than in H and HD groups, but unchanged in T2D group. In contrast, Mn levels are increased in all groups; whereas the Cu levels increased only in H and HD groups, concomitantly with cytosolic SOD-Cu/Zn and mitochondrial SOD-Mn depletion. The Zn/Cu ratio decreases significantly in hypertensive group but not in diabetics groups. It appears that Zn/Cu ratio reflects the transition from hypertension phase to hypertension associated with T2D. Ultimately, TE plays an important role in the hypertension pathophysiology and can be considered as predictive T2D biomarkers in hypertensive patients.
To investigate the effect of long-term exposure to environmental cadmium on eight mineral element's metabolic balance of human body.
To choose a high cadmium area polluted by smelting and mining north of Guangdong province and a cadmium-free area with a similar economic level, and living and eating habit of residents as a contrast from April 2011 to August 2012. Stratified random sampling and clustered sampling method were adopted to choose the non-occupationally cadmium-exposed respondents who have lived in local area for more than 15 years, older than 40 years, having local rice and vegetable as the main dietary source, with simple and relatively stable diet, and without diabetes, kidney disease, thyroid disease, liver disease or other history of chronic disease. This study included 298 respondents, of whom 155 were in cadmium exposure group and 143 in control group. Questionnaires was used to acquire their health status and their morning urine samples were collected. Electrolytically coupled plasma mass spectrometry
 (ICP-MS) was used to test the concentrations of sodium(Na), magnesium (Mg), phosphorus (P), potassium (K), calcium (Ca), copper (Cu), zinc (Zn) and iodine (I). The Mann-Whitney U test method was used to compare the differences of concentrations of urinary cadmium, Na, Mg, P, K, Ca, Cu, Zn, I, and the ratio of Na to K (Na/K), Ca to P (Ca/P) between exposed group and control group.χ(2) test was used to compare the abnormal rate of urinary cadmium between exposed group and control group. Pearson correlation and multiple regression method were used to investigate the relationship between urinary cadmium levels, gender, age, smoking, passive smoking, and minerals.
The urinary cadmium level P50 (P25-P75) in exposed group was 5.45 (2.62-10.68) μg/g·cr, which was higher than that of the control group, which was 1.69 (1.22-2.36) μg/g·cr (Z=-10.49,P<0.001). The abnormal rate of urinary cadmium was 51.6% (80/155), which was higher than that of the control group (2.8 %(4/143)) (χ(2)= 87.56, P<0.001). The urinary Ca, Cu, Zn, and I level P50 (P25-P75) of exposed group were 173.80 (114.40-251.70), 20.55 (14.95-28.44), 520.23 (390.25-647.15), and 246.94 (203.65-342.97) μg/g·cr, which were higher than those in control group (142.42 (96.87-179.11), 15.44 (12.26-20.98), 430.09 (309.85-568.78) and 213.85 (156.70-281.63) μg/g·cr, respectively) (Z values were-4.33,-5.04,-3.47 and-4.24, all P values <0.001). The urinary P, K level P50 (P25-P75) of exposed group were 582.50 (463.20-742.8), 890.10(666.00-1 305.40) μg/g·cr, which were lower than control group (694.50 (546.20-851.17), 1 098.58(904.53-1 479.18) μg/g·cr) (Z values were-3.36,-4.02, all P values <0.001). on Based the results of Pearson correlation analysis, urinary cadmium was positively correlated with urinary Ca, Cu, Zn, and I, and the correlation coefficients were 0.31, 0.61, 0.38, and 0.25, respectively (all P values <0.05). Based on the results of multiple regression analysis, urinary cadmium levels contributed most to the metabolic balance of urinary Ca, Cu, Zn and I. The standardized regression coefficients were 0.31, 0.59, 0.39, and 0.24, respectively (all P values<0.001).
Long-term environmental exposure to cadmium affected the metabolic balance of Ca, Cu, Zn and I in human body.
The antidepressant effect of simple Zn(II) salts has been proved in several animal models of depression. In this study, a coordination metal complex of Zn(II) having a sulfur containing ligand is tested as antidepressant for the first time. Forced swimming test method on male Wistar rats shows a decrease in the immobility and an increase in the swimming behavior after treatment with [Zn(S-Met)2] (S-Met=S-methyl-l-cysteine) being more effective and remarkable than ZnCl2. The thiobarbituric acid and the pyranine consumption (hydroxyl and peroxyl radicals, respectively) methods were applied to evaluate the antioxidant activity of S-Met and [Zn(S-Met)2] showing evidence of attenuation of hydroxyl but not peroxyl radicals activities. UV-vis studies on the inhibition of acid phosphatase enzyme (AcP) demonstrated that S-methyl-l-cysteine did not produce any effect but, in contrast, [Zn(S-Met)2] complex behaved as a moderate inhibitor. Finally, bioavailability studies were performed by fluorescence spectroscopy denoting the ability of the albumin to transport the complex.
Obesity, particularly child obesity, is one of the most common public health problems in the world and raises the risk of end-stage renal disease. Zinc (Zn) is essential for multiple organs in terms of normal structure and function; however, effects of Zn deficiency or supplementation among young individuals with obesity have not been well studied.
Weaned mice were fed high-fat diets (HFD) with varied contents of Zn (Zn deficient, adequate, and supplemented) for 3 or 6 months. This study examined associations between renal pathogenesis and dietary Zn levels, specifically assessing inflammatory pathways by utilizing P38 MAPK inhibitor SB203580.
HFD feeding induced typical syndromes of obesity-related renal disorders, which worsened by Zn marginal deficiency. The progression of obesity-related renal disorders was delayed by Zn supplementation. HFD induced renal inflammation, reflected by increased P38 MAPK phosphorylation along with increases of inflammatory cytokines MCP-1, IL-1β, IL-6, and TNF-α. P38 MAPK inhibition prevented renal pathological changes in mice fed with HFD and HFD/Zn deficiency.
P38 MAPK mediated the renal inflammatory responses, which played a central role in the pathogenesis of HFD-induced renal disorders. Zn could delay the progression of obesity-related kidney disease by down-regulating P38 MAPK-mediated inflammation.
Copper and zinc have been found to contribute to the burden of amyloid-β (Aβ) aggregations in neurodegenerative Alzheimer's disease (AD). Dysregulation of these metals leads to the generation of reactive oxygen species (ROS) and eventually results in oxidative damage and accumulation of the Aβ peptide, which are the key elements of the disease. Aiming to pursue the discovery of new modulators for the disease, we here rationally focused on conjugating the core hydroxyquinoline of the metal-protein attenuating compound PBT2 and the N-methylanilide analogous moiety of the Aβ imaging agent to build a new type of multi-target modulators of Aβ aggregations. We found that the N,N-dimethylanilinyl imines 7a, 8a, and the corresponding amines 7b, 8b exerted efficient inhibition of Cu(2+) - or Zn(2+) -induced Aβ aggregations and significant disassembly of metal-mediated Aβ aggregated fibrils. Further, 7a and 7b also exhibited significant ROC scavenging effects compared to PBT2. The results suggested that 7a and 7b are promising lead compounds for the development of a new therapy for AD.
An investigation into the substitution effects in Li15 Si4 , which is discussed as metastable phase that forms during electrochemical charging and discharging cycles in silicon anode materials, is presented. The novel partial substitution of lithium by magnesium and zinc is reported and the results are compared to those obtained for aluminum substitution. The new lithium silicides Li14 MgSi4 (1) and Li14.05 Zn0.95 Si4 (2) were synthesized by high-temperature reactions and their crystal structures were determined from single-crystal data. The magnetic properties and thermodynamic stabilities were investigated and compared with those of Li14.25 Al0.75 Si4 (3). The substitution of a small amount of Li in metastable Li15 Si4 for more electron-rich metals, such as Mg, Zn, or Al, leads to a vast increase in the thermodynamic stability of the resulting ternary compounds. The (6,7) Li NMR chemical shift and spin relaxation time T1 -NMR spectroscopy behavior at low temperatures indicate an increasing contribution of the conduction electrons to these NMR spectroscopy parameters in the series for 1-3. However, the increasing thermal stability of the new ternary phases is accompanied by a decrease in Li diffusivity, with 2 exhibiting the lowest activation energy for Li mobility with values of 56, 60, and 62 kJ mol(-1) for 2, Li14.25 Al0.75 Si14 , and 1, respectively. The influence of the metastable property of Li15 Si4 on NMR spectroscopy experiments is highlighted.
Continuous cropping of rice (Oryza sativa L.) and wheat (Triticum aestivum L.) deplete soil fertility and crop productivity. One strategy to increase crop productivity under rice-wheat system is balanced application of crop nutrients. Field experiment was conducted to assess the impact of phosphorus (0, 40, 80, 120 kg P ha(-1)) and zinc (0, 5, 10, 15 kg Zn ha(-1)) on the productivity of rice genotypes (fine and coarse) and their residual effects on the grain yield (GY) and its components (YC) of the succeeding wheat crop under rice-wheat cropping system (RWCS) in North Western Pakistan during 2011-12 and 2012-13. After rice harvest in both years, wheat variety "Siren-2010" was grown on the same layout but no additional P, K and Zn was applied to wheat crop in each year. The GY and YC of wheat significantly increased in the treatments receiving the higher P levels (120 > 80 > 40 > 0 kg P ha(-1)) and Zn (15 > 10 > 5 > 0 kg Zn ha(-1)) in the previous rice crop. The residual soil P and Zn contents after rice harvest, GY and YC of wheat increased significantly under low yielding fine genotype (B-385) as compared to the high yielding coarse genotypes (F-Malakand and Pukhraj). The residual soil P and Zn, GY and of wheat increased significantly in the second year as compared with the first year of experiment. These results confirmed strong carry over effects of both P and Zn applied to the previous rice crop on the subsequent wheat crop under RWCS.
Tobacco (Nicotiana tabacum L.) is a commercial plant. Tobacco leaves naturally accumulate and concentrate relatively high levels of heavy metals and particular cadmium in leaves. Tobacco is one of the basic agricultural products, in Ethiopia, with social and economic importance. However, there is no report in the literature on the determination of levels of heavy metals in Ethiopian tobacco leaves. Hence this research is intended to determine the levels of heavy metals in the raw and processed Ethiopian Virginia tobacco leaves. Samples of raw Virginia tobacco leaves were collected from two different regions of Ethiopia (Billate and Shewa Robit). The three processed tobacco samples were collected from National Tobacco Enterprise, Addis Ababa, Ethiopia. The samples were wet-digested using 3 mL HNO3 (69-72 %) and 3 mL HClO4 (70 %) at 350 °C for 3.5 h and concentrations of heavy metals (Cd, Cr, Cu, Ni, Pb and Zn) in the samples were determined by flame atomic absorption spectrometer. The mean metals concentrations (in µg/g dry weight) in the raw Virginia tobacco leaves from Billate and Shewa Robit, respectively, were: Cu (4.38, 7.30), Zn (53.7,
 33.2), Cd (1.20, 1.30), Cr (ND, 1.45), Ni (ND, 1.90). The mean metals concentrations (in µg/g dry weight) in the processed tobacco from Billate and Shewa Robit, respectively, were: Cu (9.80, 12.8), Ni (2.35, 2.20) Cd (1.45, 1.90), Cr (1.65, 1.75), Zn (101, 83.8). The mean metals concentrations (in µg/g dry weight) in the processed tobacco Nyala (Ethiopian cigarette leaves) were: Cu (8.95), Cd (1.55), Cr (1.62), Ni (4.70), Zn (79.3). The concentrations of Cr and Ni in tobacco leaves from Billate and Pb in all the tobacco samples were below the detection limits. This study showed that the metal contents of tobacco leaves varied with the geographical origin in which the tobacco plant grows. The metal contents of processed tobacco were higher than the corresponding raw leaves. Pb was not detected in both the raw and processed Ethiopian tobacco leaves.
Snails are used as biological indicators of the environment pollution for heavy metals. Living snail samples were collected from different sites at the city of Irbid-Jordan and classified according to their morphological features including Helix pelasga, Eobania vermiculata, Xeropicta derbentina, Oychilus, Xerocrassa seetzenii, Xerocrassa simulata, and Pila. Zn, Cd, As, Cu, Pb, and Fe levels were measured by inductively coupled plasma-optical emission spectroscopy. Results indicated that metal concentrations in all snail shell samples were with an average and range for Zn 22.4 (6.5-105.5) μg g(-1), Cd 7.8 (0.4-48.1) μg g(-1), As 25.9 (0.7-248.5) μg g(-1), Cu 15.1 (1.6-69.0) μg g(-1), Pb 0.4 (0.2-1.7) μg g(-1), and Fe 119.6 (14.0-1102.0) μg g(-1), whereas, in soil samples, the average and range for Zn 204.0 (12.0-709.0) μg g(-1), Cd 5.7 (0.2-39.5) μg g(-1), As 3.2 (1.8-5.2) μg g(-1), Cu 22.1 (2.3-77.4) μg g(-1), Pb 0.2 (0.1-0.3) μg g(-1), and Fe 242.4 (25.0-680.0) μg g(-1).
This study was performed to investigate pollution of traffic-related heavy metals (HMs-Zn, Pb, Cu, Cr, and Cd) in roadside soils and their uptake by wild plants growing along highways in Hunan Province, China. For this, we analyzed the concentration and chemical fractionation of HMs in soils and plants. Soil samples were collected with different depths in the profile and different distances from highway edge. And leaves and barks of six high-frequency plants were collected. Results of the modified European Community Bureau of Reference (BCR) showed that the mobile fraction of these HMs was in the order of Cd > Pb > Zn > Cu > Cr. A high percentage of the mobile fraction indicates Cd, Pb, and Zn were labile and available for uptake by wild plants. The total concentration and values of risk assessment code (RAC) showed that Cd was the main risk factor, which were in the range high to very high risk. The accumulation ability of HMs in plants was evaluated by the biological accumulation factor (BAF) and the metal accumulation index (MAI), and the results showed that all those plant species have good phyto-extraction ability, while accumulation capacity for most HMs plants tissues was bark > leaf. The highest MAI value (5.99) in Cinnamomum camphora (L) Presl indicates the potential for bio-monitoring and a good choice for planting along highways where there is contamination with HMs.
This study presents the effects of environmental pollution on the quality of domestic roof-harvested rainwater (DRHRW) using fuzzy comprehensive assessment (FCA). Seven metals (Cu, Cd, Pb, Zn, Fe, Ca, and Mg) and six water-quality parameters (Acidity, PO4 (3-), SO4 (2-), NO3 (-) , Cl(-), and pH) were investigated in DRHRW sampled from 12 sampling points each from Ibadan (residential) and Lagos (industrial) environments, Nigeria. The results of these parameters were formulated into membership function fuzzy matrices based on four contamination classifications of high, marginal, low, and poor qualities using regulatory limits as criteria. The products membership function matrices and weight matrices generated indices that classified the degree of anthropogenic activity impact on the sites. Results of FCA classified the DRHRW from residential environment as between high and marginal quality, whereas DRHRW from industrial environment is classified between marginal and low quality. Lead and Cd were major contaminants of concern found in these harvested water.
Zinc (Zn) is one of the most important trace elements required for several biological processes. Diabetes negatively affects many organs, and diabetic patients are often hypozincemic. The present study aims to investigate the role of Zn supplementation in the testes, epididymis, and sperms of streptozotocin (STZ)-induced diabetic rat. Serum, testicular, and sperm Zn contents were found to be altered in diabetic rat. Biochemical, histopathological, and protein expression profiles were determined to decipher the role of Zn in protecting the cellular perturbations. Further, histopathological analyses of testes and epididymis showed deranged architecture along with other noted abnormalities. Diabetic testes showed decreased Nrf2, HO-1, SOD1, PCNA, and Bcl-2 expressions whereas increased COX-2, NF-κB, MT, IL-6, and p-ERK levels. SOD1 and GPX5 were decreased in the epididymis of diabetic rat, whereas Zn supplementation attenuated these changes. The present results demonstrate the beneficial role of Zn supplementation in diabetes-associated testicular alterations of rat.
Soil contamination by heavy metals in coal mine wastelands is a significant environmental issue in most developing countries. The purpose of this study is to evaluate contamination characteristics in the coal mine wastelands of Sanlidong coal mine, Tongchuan, China. To achieve this goal, we conducted field sampling work, followed by further analysis of the properties of soil contamination and accumulation characteristics in woody plants. At this site, the pH value ranged from 4.41 to 7.88, and the nutrient content of the soil rose gradually with the time after deposition due to the weathering effect improving the soil quality. Meanwhile, the levels of Cd, Cr, Cu, Ni, and Zn gradually decreased with the passage time. Generally, heavy metal contamination was found to be more serious in the discharge refuse area, with Cd contamination at moderate or heavy levels; Ni, Zn, and Cu contamination at light levels; and with no Cr contamination. The geoaccumulation index (I geo) was highest for Cd (2.38-3.14), followed by Ni, Zn, Cu, and Cr. Heavy metals accumulated on the lower slopes and spread to the surrounding areas via hydrodynamic effects and wind. According to transfer and enrichment coefficient analyses, Robinia pseudoacacia, Ulmus pumila, and Hippophae rhamnoides with considerable biomass could be used as pollution-resistant tree species for vegetation restoration. This study provided a theoretical basis for the restoration of the ecological environment in the mining area. This report described a link between heavy metal contamination of soils and growth dynamics of woody plants in China.
In this investigation, anodic aluminum oxide (AAO) with arrayed and regularly arranged nanopores is used as a template in the high-vacuum die casting of molten zinc metal (Zn) into the nanopores. The proposed technique yields arrayed Zn nanowires with an aspect ratio of over 600. After annealing, arrayed zinc oxide (ZnO) nanowires are obtained. Varying the anodizing time yields AAO templates with thicknesses of approximately 50 μm, 60 μm, and 70 μm that can be used in the fabrication of nanowires of three lengths with high aspect ratios. Experimental results reveal that a longer nanowire generates a greater measured piezoelectric current. The ZnO nanowires that are fabricated using an alumina template are anodized for 7 h and produce higher piezoelectric current of up to 69 pA.
Diagnosis followed by effective treatment of tuberculosis (TB) reduces transmission and saves lives in persons living with HIV (PLHIV). Sputum smear microscopy is widely used for diagnosis, despite limited sensitivity in PLHIV. Evidence is needed to determine the optimal diagnostic approach for these patients.
From May 2011 through June 2012, we recruited PLHIV from 15 HIV treatment centers in western Kenya. We collected up to three sputum specimens for Ziehl-Neelsen (ZN) and fluorescence microscopy (FM), GeneXpert MTB/RIF (Xpert), and culture, regardless of symptoms. We calculated the incremental yield of each test, stratifying results by CD4 cell count and specimen type; data were analyzed to account for complex sampling.
From 778 enrolled patients, we identified 88 (11.3%) laboratory-confirmed TB cases. Of the 74 cases who submitted 2 specimens for microscopy and Xpert testing, ZN microscopy identified 25 (33.6%); Xpert identified those plus an additional 18 (incremental yield = 24.4%). Xpert testing of spot specimens identified 48 (57.0%) of 84 cases; whereas Xpert testing of morning specimens identified 50 (66.0%) of 76 cases. Two Xpert tests detected 22/24 (92.0%) TB cases with CD4 counts <100 cells/μL and 30/45 (67.0%) of cases with CD4 counts ≥100 cells/μl.
In PLHIV, Xpert substantially increased diagnostic yield compared to smear microscopy and had the highest yield when used to test morning specimens and specimens from PLHIV with CD4 count <100 cells/μL. TB programs unable to replace smear microscopy with Xpert for all symptomatic PLHIV should consider targeted replacement and using morning specimens.
The benzene pollutant in gaseous phase was successfully degraded by using ZnO + Zn2TiO4 multicomponent oxide thin films as photocatalysts. The films were obtained with different Ti/Zn ratios (0, 0.20, 0.40, 0.45, 0.50, 0.67, 0.84, and 1) by the sol-gel route. The initial level of benzene concentration was 110 ± 10 ppm. The process was carried out under different conditions of relative humidity (RH): 25, 50, and 80 % in a batch-type reactor, at room temperature.
 The results show benzene degradation near to 95 % at t = 240 min, where the multicomponent oxide semiconductor has a Ti/Zn ratio of 0.67. Meanwhile, with the TiO2 thin films, only a degradation of 70 % was reached at the same measurement conditions. This synergistic effect on the photocatalytic activity is a result of the coupling of both semiconductor oxides. An adverse effect on the photocatalytic activity was observed as the relative humidity increases.
During many years of industrial development, soil system was contaminated with large amounts of toxic metals. In order to investigate the mobility and availability of metals from soil to mushrooms, the content of 13 elements (Al, Ba, Cd, Co, Cr, Cu, Fe, Mn, Ni, Pb, Sr, Ti, and Zn), in caps and stipes of wild-grown edible mushroom Macrolepiota procera and soil substrates, collected from five sites in Rasina region in central Serbia, was determined. Soil samples were subjected to the sequential extraction procedure proposed by the Community Bureau of Reference in order to fractionate acid-soluble/exchangeable, reducible, oxidizable, and residual fractions. Metal concentrations were determined by inductively coupled plasma optical emission spectrometer and inductively coupled plasma mass spectrometer and the results subjected to multivariate data analysis. A principal component analysis distinguished mushrooms samples from different geographical areas and revealed the influence of soil composition on metal content in mushrooms. Hierarchical cluster analyses confirmed that the first three phases of extraction were the most important for metal uptake by mushrooms from soil. The bioconcentration factors and translocation factors for each metal were also calculated. These results showed that M. procera could serve as a good dietary source of essential elements, especially Cu, Zn, Mn, and Fe but the consumption of mushrooms may pose a health risk for consumers during the "season of mushrooms," due to the presence of cadmium.
The Kuril Islands region is considered promising for development of salmon aquaculture. There are 41 salmon fish hatcheries in the Sakhalin Island and the Kuril Islands, 34 of them are hatcheries of the chum. Therefore, concentrations of six elements (Zn, Cu, Cd, Pb, As, and Hg) were determined in chum salmon were caught in this region. The contents of toxic elements (Cd, Pb, As, and Hg) don't exceed their maximum permissible concentrations (MPC) according to the Russian sanitary standards, but concentration of Pb are closely to MPC. Increased concentrations of Pb in wild chum have the natural origin. The unusual conditions of the Western Pacific are formed under the influence such factors as volcanism and upwelling.
Acute aortic dissection (AAD) is characterized by excessive smooth muscle cell (SMC) loss, extracellular matrix (ECM) degradation and inflammation. In response to certain stimulations, oxidative stress is activated and regulates apoptosis and inflammation. Excessive apoptosis promotes aortic inflammation and degeneration, leading to AAD formation. This study aimed to clarify role of oxidative stress in the pathogenesis of AAD and whether the antioxidant ursodeoxycholic acid (UDCA) attenuates AAD formation.
Angiotensin II (Ang II) was infused in 8-months male ApoE-/- mice for one week to establish a model of AAD. UDCA (10 mg/kg/day) was administered via intragastric gavage for 3 consecutive days before AngII infusion and also during the AngII infusion for another consecutive 7 days.
Ang II-infusion resulted in the incidence of AAD at a rate of 35% (13/37) and UDCA markedly reduced the incidence of AAD to 16% (6/37), accompanied with reduced maximal aortic diameter measured at the suprarenal region of the abdominal aorta. Additionally, UDCA pretreatment prevented Ang II induced generations of reactive oxygen species (ROS) and apoptosis of vascular smooth muscle cells (VSMCs) both in vivo and in. vitro Mechanistically, we found UDCA markedly increased Nrf2 expression in VSMCs and prevented Ang II induced expression of NADPH subunits (p47, p67 and gp91) in Nrf2-dependent manner and rescued the activity of redox enzymes (Cu/Zn-SOD, Mn-SOD and CAT), thereby inhibiting apoptosis of VSMCs.
These results demonstrate that UDCA prevented AAD formation by reducing apoptosis of VSMCs caused by oxidative stress in Nrf2 dependent manner and suggest that UDCA might have clinical potential to suppress AAD formation.
Historic mine sites are a major source of contamination to terrestrial and river environments. To demonstrate the importance of determining the significance of point and diffuse metal contamination and the related bioavailability of the metals present from abandoned mines a case study has been carried out. The study provides a quantitative assessment of a historic mine site, Wheal Betsy, southwest England, and its contribution to non-compliance with Water Framework Directive (WFD) Environmental Quality Standards (EQS) for Cd, Cu, Pb and Zn. Surface water and sediment samples showed significant negative environmental impacts even taking account of the bioavailability of the metal present, with lead concentration in the stream sediment up to 76 times higher than the Canadian sediment guidelines 'Probable Effect Level'. Benthic invertebrates showed a decline in species richness adjacent to the mine site with lead and cadmium the main cause. The main mine drainage adit was the single most significant source of metal (typically 50% of metal load from the area, but 88% for Ni) but the mine spoil tips north and south of the adit input added together discharged roughly an equivalent loading of metal with the exception of Ni. The bioavailability of metal in the spoil tips exhibited differing spatial patterns owing to varying ambient soil physico-chemistry. The data collected is essential to provide a clear understanding of the contamination present as well as its mobility and bioavailability, in order to direct the decision making process regarding remediation options and their likely effectiveness.
As the di-2-pyridylketone thiosemicarbazone (DpT) and 2-acetylpyridine thiosemicarbazone (ApT) series show potent antitumor activity in vitro and in vivo, we synthesized their fluorescent zinc(II) complexes to assess their intracellular distribution. The Zn(II) complexes generally showed significantly greater cytotoxicity than the thiosemicarbazones alone in several tumor cell-types. Notably, specific structure-activity relationships demonstrated the importance of the di-2-pyridyl pharmacophore in their activity. Confocal fluorescence imaging and live cell microscopy showed that the Zn(II) complex of our lead compound, di-2-pyridylketone 4-cyclohexyl-4-methyl-3-thiosemicarbazone (DpC), which is scheduled to enter clinical trials, was localized to lysosomes. Under lysosomal conditions, the Zn(II) complexes were shown to transmetallate with copper ions, leading to redox-active copper complexes that induced lysosomal membrane permeabilization (LMP) and cytotoxicity. This is the first study to demonstrate direct lysosomal targeting of our novel Zn(II)-thiosemicarbazone complexes that mediate their activity via transmetalation with copper ions and LMP.
Arsenic (As) is identified by the EPA as the third highest toxic inorganic contaminant. Almost every 9th or 10th human in more than 70 countries including mainland China is affected by As. Arsenic along with other toxins not only affects human life but also creates alarming situations such as the deterioration of farm lands and desertion of industrial/mining lands. Researchers and administrators have agreed to opt for phytoremediation of As over costly cleanups. Boehmeria nivea L. can soak up various heavy metals, such as Sb, Cd, Pb, and Zn. But the effect of As pollution on the biology and metabolism of B. nivea has been somewhat overlooked. This study attempts to evaluate the extent of As resistance, chlorophyll content, and metabolic changes in As-polluted (5, 10, 15, and 20 mg L(-1) As) B. nivea in hydroponics. Toxic effects of As in the form of inhibited growth were apparent at the highest level of added As. The significant changes in the chlorophyll, electrolyte leakage, and H2O2, significant increases in As in plant parts, catalase (CAT), and malondialdehyde (MDA), with applied As revealed the potential of B. nivea for As decontamination. By employing the metabolic machinery of B. nivea, As was sustainably removed from the contaminated areas.
The recycling of spent lithium-ion batteries brings benefits to both economic and environmental terms, but it can also lead to contaminants in a workshop environment. This study focused on metals, non-metals and volatile organic compounds generated by the discharging and dismantling pretreatment processes which are prerequisite for recycling spent lithium-ion batteries. After discharging in NaCl solution, metal contents in supernate and concentrated liquor were detected. Among results of condition #2, #3, #4 and #5, supernate and concentrated liquor contain high levels of Na, Al, Fe; middle levels of Co, Li, Cu, Ca, Zn; and low levels of Mn, Sn, Cr, Zn, Ba, K, Mg, V. The Hg, Ag, Cr and V are not detected in any of the analyzed supernate. 10wt% NaCl solution was a better discharging condition for high discharge efficiency, less possible harm to environment. To collect the gas released from dismantled LIB belts, a set of gas collecting system devices was designed independently. Two predominant organic vapour compounds were dimethyl carbonate (4.298mgh(-1)) and tert-amylbenzene (0.749mgh(-1)) from one dismantled battery cell. To make sure the concentrations of dimethyl carbonate under recommended industrial exposure limit (REL) of 100mgL(-1), for a workshop on dismantling capacity of 1000kg spent LIBs, the minimum flow rate of ventilating pump should be 235.16m(3)h(-1).
Herein,
 we report rGO/Fe3O4 nanocomposites (NCs) free from noble metals, synthesized by facile one step chemical reduction method, for electrochemical detection of arsenite in water by square wave anodic stripping Voltammetry (SWASV). The synthesized NCs were characterized for its optical, morphological and structural properties. The NCs modified glassy carbon (GCE), NCs/GCE, electrodes showed a higher sensitivity (0.281μA/ppb) and lower LOD (0.12ppb) under optimized experimental conditions. The proposed NCs/GCE electrodes show no interference towards arsenite species in the presence of common cationic interferants, namely, Cu(II), Pb(II), Ni(II), Co(II), Cd(II), Cr(II), Zn(II), etc. In addition, the proposed electrode demonstrates a good stability, reproducibility and potential practical application in electrochemical detection of arsenite.
By employing an aromatic methyl substituted V-shaped diphosphonic acid as a ligand, a series of metal diphosphonates, namely [Cu3(HL)2(H2O)2][(H2O)2] (1), [Cu(H2L)(pyz)(H2O)2][(H2O)2] (2), [Cu(H2L)(2,2'-bipy)] (3), [Cu(H2L)(4,4'-bipy)(H2O)2] (4), [Zn(H2L)(2,2'-bipy)] (5) and [Cd(H2L)(2,2'-bipy)(H2O)][(H2O)6] (6), have been synthesized. The structural studies reveal that these compounds exhibit diverse crystal structures. The introduction of the methyl group and pyridine derived auxiliary ligands results in the formation of plenty of C-HO, C-Hπ and ππ interactions, which contribute to the crystallization of metal diphosphonates. It was found that the Zn and Cd containing compounds showed intense intraligand emissions.
Nitric oxide (NO) storage and release measurements have been recorded for Ni-doped CPO-27 (Mg) and CPO-27 (Zn), and the biological effect of the released NO was assessed in porcine coronary artery relaxation tests. The results indicate that the doping strategy leads to increased levels of NO storage and delivery compared to the parent materials and that the NO dosage and biological response can be tuned via this approach to suit the requirements of particular applications.